Vitamin D.sub.3 derivatives and production process thereof

A vitamin D.sub.3 derivative represented by the following formula: ##STR1## wherein, R is, independently, a hydrogen atom, tri(C.sub.1 to C.sub.7 hydrocarbon)silyl group, C.sub.2 to C.sub.8 acyl group, or group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is ##STR2## where, R.sup.1 is a methyl group or methylene group, and when R.sup.1 is a methylene group, the bond between the R.sup.1 and the 3-position of the lactone ring is a double bond, R.sup.2 is a hydrogen atom or C.sub.1 to C.sub.3 alkyl group, R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 together indicate a substitutable single methylene group.

TECHNICAL FIELD 
This application is a 371 of PCT/JP95/01145 filed Jun 7, 1995. 
The present invention relates to a vitamin D.sub.3 derivative useful as a 
pharmaceutical. More specifically, it relates to a 1.alpha.-hydroxy 
vitamin D.sub.3 derivative useful as a pharmaceutical such as an agent for 
promoting bone formation, an agent for suppressing proliferation of tumor 
cells, an agent for high calcium blood diseases, and an immunosuppression 
agent, a production process thereof, and a production intermediate. 
BACKGROUND ART 
It is fully recognized through disclosures in patent publications and a 
large number of general references that vitamin D.sub.3 metabolites play 
an extremely important role as substances controlling the metabolism of 
calcium and phosphates in the body. Recently, further, an increase has 
been seen in clinical application as drugs for the treatment of various 
diseases such as with the numerous vitamin D.sub.3 metabolites found to 
have the function of inducing differentiation of tumorous bone marrow 
cells. On the other hand, recently, a novel vitamin D.sub.3 active 
metabolite having an .alpha.-hydroxylactone ring at the steroid side chain 
has been found. Arch. Bio-chem. Biophys., 204, 387-391 (1980); FEBS 
LETTERS, 134, 207-211 (1981)!. This compound is 
1.alpha.,25-dihydroxy-vitamin D.sub.3 -26,23-lactone and is represented by 
the following structural formula: 
##STR3## 
This compound has been reported to have an action for reducing the 
concentration of calcium in blood serum (Japanese Unexamined Patent 
Publication (Kokai) No. 58-118516), an action for suppressing the 
proliferation of tumor cells (Japanese Unexamined Patent Publication 
(Kokai) No. 58-210011), an action for promoting bone formation (Japanese 
Unexamined Patent Publication (Kokai) No. 60-185715), etc. 
DISCLOSURE OF THE INVENTION 
The object of the present invention is to provide a novel vitamin D.sub.3 
derivative having activity to promote bone formation, a production process 
therefor, and production intermediates. 
In accordance with the present invention, there is provided a vitamin 
D.sub.3 derivative having the following formula (I): 
##STR4## 
wherein, R is, independently, a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.2 to C.sub.8 acyl group, or a group forming 
an acetal bond together with an oxygen atom of a hydroxyl group, A is 
##STR5## 
where, R.sup.1 is a methyl group or methylene group, and when R.sup.1 is a 
methylene group, the bond between R.sup.1 and the 3-position of the 
lactone ring is a double bond, R.sup.2 is a hydrogen atom or C.sub.1 to 
C.sub.3 alkyl group, R.sup.3 is a hydrogen atom, or R.sup.2 and R.sup.3 
together are a substitutable single methylene group.

BEST MODE FOR WORKING THE INVENTION 
That is, according to the first aspect of the present invention, there is 
provided a vitamin D.sub.3 derivative represented by the following formula 
(1-1): 
##STR6## 
In the above formula (1-1), the configurations of the asymmetric centers 
of the C-1 position and C-4 position of the cyclopentene ring may be 
either of the (R) configuration or (S) configuration, respectively. 
Further, the present invention includes mixtures of any proportions of 
these four types of stereo isomers. Among them, ones where the asymmetric 
center of the C-1 position is the (R) configuration, ones where the 
asymmetric center of the C-4 position is the (S) configuration, and ones 
where the asymmetric center of the C-1 position is the (S) configuration 
and the asymmetric center of the C-4 position is the (S) configuration are 
preferred. 
Specific examples of the preferred vitamin D.sub.3 derivative of the first 
aspect of the present invention are as follows: 
1) 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1-hydroxy-1-methyl)-2-cyclop 
enten-4-yl!-vitamin D.sub.3 
2) 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R,4S)-(1-hydroxy-1-methyl)- 
2-cyclopenten-4-yl!-vitamin D.sub.3 
3) 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R,4R)-(1-hydroxy-1-methyl)- 
2-cyclopenten-4-yl!-vitamin D.sub.3 
4) 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1S,4R)-(1-hydroxy-1-methyl)- 
2-cyclopenten-4-yl!-vitamin D.sub.3 
5) 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1S,4S)-(1-hydroxy-1-methyl)- 
2-cyclopenten-4-yl!-vitamin D.sub.3 
Further, the present invention includes a production process of the vitamin 
D.sub.3 derivative represented by the above formula (1-1). 
That is, it includes a production process of a vitamin D.sub.3 derivative 
represented by the above formula (1-1) characterized by reacting a 
cyclopentene derivative represented by the following formula (1-2): 
##STR7## 
wherein R.sup.1.sub.1 is a hydrogen atom, a tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, a C.sub.2 to C.sub.7 acyl group, or a group 
forming an acetal bond with an oxygen atom of a hydroxyl group, and 
X.sub.1 is a bromine atom or iodine atom and an enyne derivative 
represented by the following formula (1-3) 
##STR8## 
wherein R.sup.2.sub.1 and R.sup.3.sub.1 are a hydrogen atom, tri(C.sub.1 
to C.sub.7 hydrocarbon)silyl group, C.sub.2 to C.sub.7 acyl group, or a 
group forming an acetal bond with an oxygen atom of a hydroxyl group in 
the presence of a palladium catalyst to obtain a vitamin D.sub.3 
derivative represented by the following formula (1-4): 
##STR9## 
wherein, R.sup.1.sub.1, R.sup.2.sub.1, and R.sup.3.sub.1 are the same as 
defined above and optionally performing a deblocking reaction. 
In the production process of a vitamin D.sub.3 derivative according to the 
first aspect of the present invention, the configurations of the 
asymmetric centers of the C-1 position and C-4 position of the 
cyclopentene ring of the starting material, that is, the cyclopentene 
derivative represented by the above formula (1-2), may respectively be 
either of the (R) configuration or (S) configuration. Further, the 
derivative may be a mixture of any ratio of these stereo isomers. For 
example, when a cyclopentene derivative represented by the above formula 
(1-2) wherein the asymmetric center of the C-1 position of the 
cyclopentene ring is the (R) configuration and the asymmetric center of 
the C-4 position is the (S) configuration is used, the configurations of 
these portions are preserved during the reaction and a vitamin D.sub.3 
derivative represented by the above formula (1-1) wherein the asymmetric 
center of the C-1 position of the cyclopentene ring is the (R) 
configuration and the asymmetric center of the C-4 position is the (S) 
configuration is obtained. 
In the same way, when a cyclopentene derivative represented by the above 
formula (1-1) where the asymmetric center of the C-1 position of the 
cyclopentene ring is the (S) configuration and the asymmetric center of 
the C-4 position is the (S) configuration is used, a vitamin D3 derivative 
represented by the above formula (1-1) wherein the asymmetric center of 
the C-1 position of the cyclopentene ring is the (S) configuration and the 
asymmetric center of the C-4 position is (S) configuration is obtained. 
Here, when R.sup.1.sub.1, R.sup.2.sub.1, or R.sup.3.sub.1 is a tri(C.sub.1 
to C.sub.7 hydrocarbon)silyl group, specific examples are preferably a 
tri(C.sub.1 to C.sub.4 alkyl)silyl group such as a trimethylsilyl, 
triethylsilyl, or t-butyldimethylsilyl group, a phenyl(C.sub.1 to C.sub.4 
alkyl)silyl group such as a t-butyldiphenylsilyl group, etc. Further, when 
R.sup.1.sub.1, R.sup.2.sub.1, or R.sup.3.sub.1 is a C.sub.1 to C.sub.7 
acyl group, the specific examples are preferably an acetyl, propionyl, 
n-butyryl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 
benzyloxycarbonyl group, etc. Further, when R.sup.1.sub.1, R.sup.2.sub.1, 
or R.sup.3.sub.1 is a group forming an acetal bond with an oxygen atom of 
a hydroxyl group, specific examples are preferably, a methoxymethyl, 
(2-methoxyethoxy)methyl, 2-methoxy-2-propyl, 2-tetrahydrofuranyl, 
2-tetrahydropyranyl group, etc. 
The vitamin D.sub.3 derivative represented by the above formula (1-4) is 
produced by reacting the cyclopentene derivative represented by the above 
formula (1-2) with an enyne derivative represented by the above formula 
(1-3) in the presence of a palladium catalyst. Here, the palladium 
catalyst used is a zero-valent or bivalent organopalladium compound. 
Examples of such a palladium compound, are tetrakis(triphenylphosphine) 
palladium or any mixture of a tris(dibenzylideneacetone) palladium, 
tris(dibenzylideneacetone)palladium chloroform, palladium acetate, etc. 
with a phosphorus compound such as triphenylphosphine or tributylphosphine 
(molar ratio of 1:1 to 1:10). As the palladium catalyst among these, a 
combination of tris(dibenzylideneacetone) palladium and triphenylphosphine 
(1:1 to 1:10) or tris(dibenzylideneacetone)palladium chloroform and 
triphenylphosphine (1:1 to 1:10) is preferred. 
Here, the cyclopentene derivative represented by the above formula (1-2) 
and the enyne derivative represented by the above formula (1-3) 
stoichiometrically react equimolarly, but it is preferable to use a slight 
excess of the more readily available compound. Further, the palladium 
catalyst is used in a range of 0.1 to 100 molar %, preferably 1 to 20 
molar %, with respect to the cyclopentene derivative of the above formula 
(1-2). 
Examples of the reaction solvent used in this reaction are a hydrocarbon 
type solvent such as hexane and toluene, an ether type solvent such as 
diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, a 
water-soluble solvent such as N,N-dimethylformamide and acetonitrile, and 
mixed solvents of the same. All of these are preferably used after 
sufficient deaeration. 
As the reaction temperature, a range of from room temperature to the 
boiling point of the solvent is used. The reaction time differs depending 
on the reaction temperature. Usually, the reaction is preferably continued 
until one of the cyclopentene derivative represented by the above formula 
(1-2) or the enyne derivative represented by the above formula (1-3) is 
found to be consumed by an analytical means such as thin layer 
chromatography. 
Further, to trap the acids such as the hydrogen halides in the reaction 
system, it is preferable to perform the reaction added with a base such as 
triethylamine or diisopropylethylamine. As the amount of the base, it is 
preferable to use at least one equivalent of the cyclopentene derivative 
represented by the above formula (1-2). It may also be used together as a 
solvent. Therefore, the vitamin D.sub.3 derivative represented by the 
above formula (1-4) is produced in the reaction system, but it is possible 
to effect a deprotection reaction when necessary to obtain the vitamin 
D.sub.3 derivative represented by the above formula (1-1). 
As the method of the deblocking reaction, when deblocking for example the 
silyl groups, it is possible to use a known method (for example, Calveley, 
M. J., Tetrahedron, 20, 4609-4619, 1987). Examples of the deprotection 
agent in this case are tetrabutylammonium fluoride, pyridinium-p-toluene 
sulfonate, etc. 
Further, in the process of the present invention, the compound represented 
by the above formula (1-2) which is used as a starting material may be 
synthesized in accordance with the following scheme: 
##STR10## 
wherein, in the above scheme, R.sup.1.sub.1, R.sup.4.sub.1, and 
R.sup.12.sub.1 are a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.2 to C.sub.7 acyl group, or group forming 
an acetal bond with an oxygen atom of a hydroxyl group. 
Here, preferable specific examples of R.sup.4.sub.1 and R.sup.12.sub.1 are 
those as mentioned for the above R.sup.1.sub.1, R.sup.2.sub.1, and 
R.sup.3.sub.1. 
##STR11## 
wherein, R.sup.1.sub.1 and R.sup.3.sub.1 may be the same or different and 
represent a hydrogen atom, tri(C.sub.1 to C.sub.7 hydrocarbon)silyl group, 
C.sub.1 to C.sub.7 acyl group, or group forming an acetal bond with an 
oxygen atom of a hydroxyl group. 
Preferable specific examples of the cyclopentene derivative of the present 
invention of the above formula (1-5) are as follows: 
1) 
(1R,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
2) 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
3) 
(1S,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
4) 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
5) 
(1R,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-(t-butyldimethylsilyloxy)-7a-methy 
l-1H-inden-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopenten 
e 
6) 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-(t-butyldimethylsilyloxy)-7a-methy 
l-1H-inden-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopenten 
e 
7) 
(1S,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-(t-butyldimethylsilyloxy)-7a-methy 
l-1H-inden-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopenten 
e 
8) 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-(t-butyldimethylsilyloxy)-7a-methy 
l-1H-inden-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopenten 
e 
9) 
(1R,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol 
10) 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol 
11) 
(1S,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol 
12) 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol 
##STR12## 
wherein, R.sup.1.sub.1 is a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.1 to C.sub.7 acyl group, or group forming 
an acetal bond with an oxygen atom of a hydroxyl group. 
Further, preferable specific examples of the cyclopentene derivative of the 
present invention of the above formula (1-6) are as follows: 
1) 
(1R,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
2) 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
3) 
(1S,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
4) 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
5) 
(1R,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
6) 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
7) 
(1S,4R)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
8) 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
Further, in the above scheme, preferable specific examples of the 
cyclopentene derivative of the present invention of the above formula 
(1-2) are as follows: 
1) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
2) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
3) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
4) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
5) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
6) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
7) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
8) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
9) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
10) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
11) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
12) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-trimethylsilyloxy-1-methyl-2-cyclopentene 
13) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
14) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
15) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
16) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyloxy}-1-(t-butyldimethylsilyloxy)-1-methyl-2-cyclopentene 
17) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
18) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
19) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
20) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
21) 
(1R,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
22) 
(1R,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
23) 
(1S,4R)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
24) 
(1S,4S)-4-{(2R)-2-(1R,7aR)(4E)-octahydro-4-iodomethylene-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
According to the second aspect of the present invention, there is provided 
a vitamin D.sub.3 derivative represented by the following formula (2-1): 
##STR13## 
In the above formula (2-1), R.sup.1.sub.2 may be either of a methyl group 
or methylene group. Note that when R.sup.1.sub.2 is a methylene group, the 
bond between R.sup.1.sub.2 and the 3-position of the lactone ring is a 
double bond (same below). Further, when R.sup.1.sub.2 is a methyl group, 
the configuration of the asymmetric center of the 3-position of the 
lactone ring is the (S) configuration and the configuration of the 
asymmetric center of the 5-position may be either of the (S) or (R) 
configuration. Further, the derivative may be a mixture of any ratio of 
(S) and (R). Further, when R.sup.1.sub.2 is a methylene group, the 
configuration of the asymmetric center of the 5-position of the lactone 
ring may be either of the (S) or (R) configuration. Further, the 
derivative may be a mixture of any of (S) or (R). Among these, those where 
the asymmetric center of the 5-position is an (S) configuration are 
preferred. 
In the above formula 1!, R.sup.2.sub.2 and R.sup.3.sub.2 may be the same 
or different and represent a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, or C.sub.2 to C.sub.8 acyl group. 
Here, when R.sup.2.sub.2 or R.sup.3.sub.2 is a tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, examples of specific examples are preferably a 
tri(C.sub.1 to C.sub.4 alkyl)silyl group such as a trimethylsilyl, 
triethylsilyl, and t-butyldimethylsilyl group, a phenyl(C.sub.1 to C.sub.4 
alkyl)silyl group such as a t-butyldiphenylsilyl group, and a 
tribenzylsilyl group. Further, a dimethyl(2,4,6-tri-t-butylphenoxy)silyl 
group may be used. 
Further, when R.sup.2.sub.2 or R.sup.3.sub.2 is a C.sub.2 to C.sub.8 acyl 
group, the specific examples are preferably an acetyl, propionyl, 
n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, caproyl, enanthyl, 
benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl group, etc. 
Among these, a C.sub.2 to C.sub.6 acyl group, for example, an n-butyryl, 
iso-butyryl, methoxycarbonyl, ethoxycarbonyl group, and benzoyl group are 
preferred. 
Preferable specific examples of the vitamin D.sub.3 derivative represented 
by the above formula (2-1) of the second aspect of the present invention 
are as follows: 
1) 1.alpha.-hydroxyvitamin D.sub.3 -26,23-lactone 
2) 23(S),25(S)-1.alpha.-hydroxyvitamin D.sub.3 -26,23-lactone 
S) 23(R),25(S)-1.alpha.-hydroxyvitamin D.sub.3 -26,23-lactone 
4) 1.alpha.-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone 
5) 23(S)-1.alpha.-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone 
6) 23(R)-1.alpha.-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone 
The present invention further includes a process of production of the 
vitamin D.sub.3 derivative of the above formula (2-1). That is, it 
provides a production process of the vitamin D.sub.3 derivative 
represented by the above formula (2-1), characterized by reacting of a 
lactone compound represented by the following formula (2-2) 
##STR14## 
wherein X.sub.2 is a bromine atom or iodine atom, R.sup.1.sub.2 is a 
methyl group or methylene group with an enyne compound represented by the 
following formula (2-10) 
##STR15## 
wherein, R.sup.2.sub.2 and R.sup.3.sub.2 are the same as defined above in 
the presence of a palladium catalyst. 
This vitamin D.sub.3 derivative can be made the vitamin D.sub.3 derivative 
represented by the following formula (2-11) 
##STR16## 
wherein, R.sup.1.sub.2 is the same as defined above optionally by 
effecting a deprotection reaction. 
In the production process of the vitamin D.sub.3 derivative according to 
the present invention, for the configurations of the 3-position and 
5-position of the lactone ring of the lactone compound represented by the 
above formulas (2-2), (2-1), and (2-11), when R.sup.1.sub.2 is a methyl 
group, the 3-position is the (S) configuration, but the 5-position may be 
either of the (S) or (R) configuration. The derivative may also be any 
mixture thereof. 
Further, when R.sup.1.sub.2 is a methylene group, the configuration of the 
5-position of the lactone ring may be either of the (S) or (R) 
configuration. The derivative may also be any mixture thereof. For 
example, when a compound represented by the above formula (2-2) wherein 
the asymmetric center of the 3-position of the lactone ring is the (S) 
configuration and the asymmetric center of the 5-position is the (S) 
configuration is used, the configurations of these positions are preserved 
during the reaction and a lactone compound represented by the above 
formula (2-1) where the asymmetric center of the 3-position of the lactone 
ring is the (S) configuration and the asymmetric center of the 5-position 
is the (S) configuration is obtained. 
In the same way, when a compound represented by the above formula (2-2) 
wherein the asymmetric center of the 3-position of the lactone ring is the 
(S) configuration and the asymmetric center of the 5-position is the (R) 
configuration is used, a lactone compound represented by the above formula 
(2-1) where the asymmetric center of the 3-position of the lactone ring is 
the (S) configuration and the asymmetric center of the 5-position is the 
(R) configuration is obtained. 
The vitamin D.sub.3 derivative represented by the above formula (2-11) is 
produced by reacting the lactone compound represented by the above formula 
(2-2) with an enyne compound represented by the above formula (2-10) in 
the presence of a palladium catalyst. Here, the palladium catalyst means, 
for example, a zero-valent or bivalent organopalladium. Examples of such a 
palladium compound are tetrakis(triphenylphosphine)palladium or a mixture 
of tris(dibenzylideneacetone)palladium, 
tris(dibenzylideneacetone)palladium chloroform, and palladium acetate with 
a phosphorus compound such as triphenylphosphine or tributylphosphine 
(molar ratio of 1:1 to 1:10). Among these, as the palladium catalyst, a 
combination of tris(dibenzylideneacetone)palladium and triphenylphosphine 
(1:1 to 1:10) or tris(dibenzylideneacetone)palladium chloroform and 
triphenylphosphine (1:1 to 1:10) is preferred. 
Here, the lactone compound represented by the above formula (2-2) and the 
enyne compound represented by the above formula (2-10) stoichiometrically 
react equimolarly, but to ensure the reaction is reliably completed, it is 
usually preferable to use a slightly excess amount of either one of the 
two reactants, whichever is more readily available. 
Further, the palladium catalyst is used in a range of 1 to 100 molar %, 
preferably 5 to 30 molar %, with respect to the lactone compound 
represented by the above formula (2-2). 
Examples of the organic solvent used in the process of production, are a 
hydrocarbon type solvent such as hexane or toluene, an ether type solvent 
such as tetrahydrofuran or dioxane, a water-soluble solvent such as 
N,N-dimethylformamide or acetonitrile, and mixed solvents thereof. For all 
of these, it is important to sufficiently deaerate them before use. 
As the reaction temperature, in general a range of from room temperature to 
the boiling point of the solvent is used. The reaction time differs 
according to the reaction solvent used and the reaction temperature, but 
usually the reaction is preferably performed until either of the lactone 
compound represented by the above formula (2-2) or the enyne compound 
represented by the above formula (2-10) is consumed as determined using an 
analytical means such as thin layer chromatography. 
Further, in addition to the palladium catalyst, to trap the hydrogen 
halide, the reaction is preferably performed in the presence of a base 
such as, for example, triethylamine or diisopropylethylamine. 
As the amount of the base, at least one equivalent of the lactone compound 
of the above formula (2-2) is preferable. The combined use as a solvent is 
also possible, if necessary. 
Further, the vitamin D.sub.3 derivative represented by the above formula 
(2-1) of the present invention may if necessary be made the vitamin 
D.sub.3 derivative represented by the above formula (2-11) by deblocking. 
As the deblocking reaction, for example, when deblocking the silyl groups, 
a known method (for example, Calvely, M. J., Tetrahedoron, 20, 4609 to 
4619, 1987) may be used. Examples of the deblocking agent in this case are 
tetrabutylammonium fluoride, pyridinium-p-toluene sulfonate, etc. 
The compound represented by the above formula (2-2) used as a starting 
material in the process of the present invention may, for example, be 
synthesized in accordance with the following scheme. When X is an iodine 
atom, the configuration differs in the same way. 
##STR17## 
That is, the lactone compound represented by the above formula (2-2) is 
obtained by halomethylation of the lactone compound represented by the 
above formula (2-3). Further, the compound represented by the above 
formula (2-3) is obtained by deblocking, if necessary, and then oxidizing 
the lactone compound represented by the above formula (2-5). Further, the 
lactone compound represented by the above formula (2-5) may be synthesized 
from the heptanoic acid derivative represented by the above formula (2-6). 
On the other hand, the lactone compound represented by the above formula 
(2-2) may be derived from the heptanoic acid derivative represented by the 
above formula (2-4). Further, the heptanoic acid derivative represented by 
the above formula (2-4) may be synthesized from the compound represented 
by the above formula (2-7). These reactions will be shown more 
specifically in the Examples: 
##STR18## 
wherein R.sup.1.sub.2 is a methyl group or methylene group, when 
R.sup.1.sub.2 is a methylene group, the bond between R.sup.1.sub.2 and the 
3-position of the lactone ring being a double bond. 
##STR19## 
wherein X is a bromine atom or iodine atom. 
##STR20## 
wherein R.sup.4.sub.2 is a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.1 to C.sub.7 acyl group, or group forming 
an acetal group together with an oxygen atom of a hydroxyl group. 
##STR21## 
wherein R.sup.4.sub.2 is the same as defined above 
##STR22## 
wherein X is a bromine atom or iodine atom, Y is a cyano group, formyl 
group, tosyl group, mesyl group, phenylsulfonyloxy group, tri(C.sub.1 to 
C.sub. hydrocarbon)silyl group, C.sub.1 to C.sub.7 acyl group, or hydroxyl 
group which may be blocked by an acetal group together with the oxygen 
atom of a hydroxyl group. 
The present invention includes compounds represented by the above formulas 
(2-2), (2-3), (2-4), (2-5), (2-6), and (2-7) serving as intermediates for 
the synthesis of the vitamin D.sub.3 derivative represented by the above 
formula (2-1). 
Here, when the R.sup.1 of the lactone compound represented by the above 
formula (2-3) and (2-5) is a methyl group, the asymmetric center of the 
3-position of the lactone ring is the (S) configuration and the asymmetric 
center of the 5-position may be either of the (R) configuration or (S) 
configuration. The derivative may also be any mixture thereof at any 
ratio. 
Further, in the heptanoic acid derivative represented by the above formula 
(2-4) or (2-6), the asymmetric center of the 4-position may be either of 
the (R) configuration or (S) configuration. The derivative may also be a 
mixture of any ratio of the two. 
Preferable specific examples of the compound represented by the above 
formula (2-2) according to the present invention are as follows: 
1) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon 
2) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon 
3) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
4) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
5) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl 
!propyl}-3-methylene-dehydro-2(3H)-furanon 
6) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl 
!propyl}-3-methylene-dehydro-2(3H)-furanon 
7) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
8) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
Preferable specific examples of the compound represented by the above 
formula (2-3) according to the present invention are as follows: 
1) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3 
-methylene-dehydro-2(3H)-furanon 
2) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3 
-methylene-dehydro-2(3H)-furanon 
3) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl 
}-3-methyl-dehydro-2(3H)-furanon 
4) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl 
}-3-methyl-dehydro-2(3H)-furanon 
Preferable specific examples of the compound represented by the above 
formula (2-4) according to the present invention are as follows: 
1) 
(4S,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene 
2) 
(4R,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene 
3) 
(4S,6R)-6-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl!-2-m 
ethoxycarbonyl-4-hydroxy-1-heptene 
4) 
(4R,6R)-6-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl!-2-m 
ethoxycarbonyl-4-hydroxy-1-heptene 
Preferable specific examples of the compound represented by the above 
formula (2-5) according to the present invention are as follows: 
1) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylene-dehydro-2(3H)-furanon 
2) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylene-dehydro-2(3H)-furanon 
3) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pr 
opyl}-3-methyl-dehydro-2(3H)-furanon 
4) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pr 
opyl}-3-methyl-dehydro-2(3H)-furanon 
5) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden- 
1-yl!propyl}-3-methylene-dehydro-2(3H)-furanon 
6) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden- 
1-yl!propyl}-3-methylene-dehydro-2(3H)-furanon 
7) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-rimethylsilyloxy-7a-methyl-1H-inde 
n-1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
8) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
9) 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H- 
inden-1-yl!propyl}-3-methylene-dehydro-2(3H)-furanon 
10) 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H- 
inden-1-yl!propyl}-3-methylene-dehydro-2(3H)-furanon 
11) 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl- 
1H-inden-1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
12) 
(3S,5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl- 
1H-inden-1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
Preferable specific examples of the compound represented by the above 
formula (2-6) according to the present invention are as follows: 
1) 
(4S,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene 
2) 
(4R,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene 
3) 
(4S,6R)-6-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl! 
-2-methoxycarbonyl-4-hydroxy-1-heptene 
4) 
(4R,6R)-6-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl! 
-2-methoxycarbonyl-4-hydroxy-1-heptene 
5) 
(4S,6R)-6-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden 
-1-yl!-2-methoxycarbonyl-4-hydroxy-1-heptene 
6) 
(4R,6R)-6-(1R,7aR)-octahydro-4-t-butyldimethylsilyloxy-7a-methyl-1H-inden 
-1-yl!-2-methoxycarbonyl-4-hydroxy-1-heptene 
Preferable specific examples of the compound represented by the above 
formula (2-7) according to the present invention are as follows: 
1) 
(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!propyl 
paratoluenes ulfonate 
2) 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butyro 
nitrile 
3) 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butana 
l 
4) 
(2R)-2-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl!propylp 
aratoluene-sulfonate 
5) 
(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl!butyron 
itrile 
6) 
(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1-yl!butanal 
The vitamin D.sub.3 derivative represented by the above formula (2-1) may 
be used as an agent for promoting bone growth. Further, the compounds 
represented by the above formulas (2-2), (2-3), (2-4), (2-5), (2-6), and 
(2-7) may be used as intermediates for the synthesis thereof. 
That is, according to the third aspect of the present invention, there is 
provided a vitamin D.sub.3 derivative represented by the following formula 
(3-1): 
##STR23## 
wherein R.sup.1.sub.3 is a hydrogen atom or C.sub.1 to C.sub.3 alkyl group 
R.sup.2.sub.3 is a hydrogen atom, or R.sup.1.sub.3 and R.sup.2.sub.3 
together indicate a substitutable single methylene group R.sup.2.sub.3 is 
a hydrogen atom, tri(C.sub.1 to C.sub.7 hydrocarbon)silyl group, C.sub.2 
to C.sub.8 acyl group, or a group forming an acetal bond together with an 
oxygen atom of a hydroxyl group. 
Here, when R.sup.1.sub.3 is a C.sub.1 to C.sub.3 alkyl group, specific 
examples are preferably methyl, ethyl, and propyl. Further, examples of 
the substituent, when R.sup.1.sub.3 and R.sup.2.sub.3 together represent a 
substitutable single methylene group, are preferably a t-butyl group, 
phenyl group, or methyl group. When R.sup.3.sub.3 is a tri(C.sub.1 to 
C.sub.7 hydrocarbon)silyl group, a tri(C.sub.1 to C4 alkyl)silyl group 
such as a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group or 
a phenyl(C.sub.1 -C.sub.4 alkyl)silyl group such as a t-butyldiphenylsilyl 
group are preferable. 
Further, when R.sup.3.sub.3 is a C.sub.2 to C.sub.8 acyl group, an acetyl, 
propionyl, N-butyryl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 
or benzyloxycarbonyl group are preferable. Further, when R.sup.3.sub.3 is 
a group forming an acetal bond with an oxygen atom of a hydroxyl group, a 
methoxymethyl, 2-methoxy-ethoxymethyl, 2-methoxy-2-propyl, 
2-tetrahydrofuranyl, or 2-tetrahydropyranyl group are preferable. 
Here, the configuration of the 25-position of the vitamin D.sub.3 
derivative of the present invention may be either of the (R) configuration 
or (S) configuration. The derivative may also be any mixture thereof at 
any ratio of the two components. Specific examples of the vitamin D.sub.3 
derivative according to the third aspect of the present invention are 
given below: 
1) 1.alpha.,25(R)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
2) 1.alpha.,25(S)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
3) 1.alpha.,25(R)-dihydroxyvitamin D.sub.3 -26-carboxylic acid methylester 
4) 1.alpha.,25(S)-dihydroxyvitamin D.sub.3 -26-carboxylic acid methylester 
5) 1.alpha.,25(R)-dihydroxyvitamin D.sub.3 -26-carboxylic acid ethylester 
6) 1.alpha.,25(S)-dihydroxyvitamin D.sub.3 -26-carboxylic acid ethylester 
7) 1.alpha.,25(R)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
methylester-1,3-bistrimethylsilylether 
8) 1.alpha.,25(S)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
methylester-1,3-bistrimethylsilylether 
9) 1.alpha.,25(R)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
ethylester-1,3-bistrimethylsilylether 
10) 1.alpha.,25(S)-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
ethylester-1,3-bistrimethylsilylether 
11) 
25,26,27-trinol-1.alpha.-hydroxy-24-(2S,5R)-2-t-butyl-5-methyl-1,3-dioxol 
an-4-one-5-yl!-vitamin D.sub.3 
12) 
25,26,27-trinol-1.alpha.-hydroxy-24-(2S,5R)-2-t-butyl-5-methyl-1,3-dioxol 
an-4-one-5-yl!-vitamin D.sub.3 -1,3-bistrimethylsilylether 
13) 
25,26,27-trinol-1.alpha.-hydroxy-24-(2S,5R)-2-t-butyl-5-methyl-1,3-dioxol 
an-4-one-5-yl!-vitamin D.sub.3 -1,3-bis(t-butyldimethylsilylether) 
Further, the present invention includes a production process of a vitamin 
D.sub.3 derivative represented by the above formula (3-1). 
That is, it provides a production process of a vitamin D.sub.3 derivative 
represented by the above formula (3-1) characterized by reacting a 
heptanoic acid derivative represented by the following formula (3-2): 
##STR24## 
wherein R.sup.2.sub.3 and R.sup.3.sub.3 are the same as defined above with 
an enyne compound represented by the following formula (3-5): 
##STR25## 
wherein R.sup.3.sub.3 is the same as defined above in the presence of a 
palladium catalyst. 
In the production process of the vitamin D.sub.3 derivative according to 
the present invention, the configuration of the asymmetric center of the 
2-position of the starting material, that is, the heptanoic acid 
derivative represented by the above formula (3-2), may be either of the 
(R) configuration or (S) configuration. Further, the derivative may be any 
mixture of these stereo isomers at any ratio. 
For example, when a heptanoic acid derivative represented by the above 
formula (3-2) where the asymmetric center of the 2-position is the (R) 
configuration is used, the configuration is preserved during the reaction 
and a vitamin D.sub.3 derivative represented by the above formula (3-1) 
where the asymmetric center of the 25-position is the (R) configuration is 
obtained. 
In the same way, when a heptanoic acid derivative represented by the above 
formula (3-2) where the asymmetric center of the 2-position is an (S) 
configuration is used, a vitamin D.sub.3 derivative represented by the 
above formula (3-1) where the asymmetric center of the 25-position is the 
(R) configuration is obtained. 
The vitamin D.sub.3 derivative represented by the above formula (3-1) is 
produced by reacting the heptanoic acid derivative represented by the 
above formula (3-2) with the enyne compound represented by above formula 
(3-5) in the presence of a palladium catalyst. Here, as the palladium 
catalyst used, mention may be made for example of a zero-valent or 
bivalent organopalladium compound. Examples of such a palladium compound 
are tetrakis(triphenyl phosphine)palladium or a mixture of a 
tris(dibenzylidene-acetone palladium, tris(dibenzylideneacetone)palladium 
chloroform, palladium acetate, etc. with a phosphorus compound such as 
triphenylphosphine or tributylphosphine (molar ratio of 1:1 to 1:10). 
Among these, as the palladium catalyst, the combination of 
tris(dibenzyli-deneacetone)palladium and triphenylphosphine (1:1 to 1:10) 
or tris(dibenzylideneacetone)palladium chloroform and triphenylphosphine 
(1:1 to 1:10) is preferred. 
Here, the heptanoic acid derivative represented by the above formula (3-2) 
and the enyne compound represented by the above formula (3-5) 
stoichiometrically react equimolarly, but it is desirable to use a slight 
excess of the more readily available compound. Further, the palladium 
catalyst is used in the range of 0.1 to 100 molar %, preferably 1 to 20 
molar %, with respect to the heptanoic acid derivative represented by the 
above formula (3-2). 
Examples of the reaction solvent used in this reaction are a hydrocarbon 
type solvent such as hexane or toluene, an ether type solvent such as 
ether, tetrahydrofuran, dioxane, or dimethoxyethane, a water soluble 
solvent such as N,N-dimethylformamide or acetonitrile, or any mixed 
solvents thereof. All of these are preferably used after sufficient 
deaeration. 
As the reaction temperature, a range of from room temperature to the 
boiling point is used. The reaction time differs according to the reaction 
temperature, but usually it is preferable that the reaction be performed 
until one of the heptanoic acid derivative represented by the above 
formula (3-2) or enyne compound represented by the above formula (3-5) is 
consumed as determined using an analytical means such as thin layer 
chromatography. 
Further, to trap the acids such as the hydrogen halides produced during the 
reaction, it is preferable to add a base such as, for example, 
triethylamine or diisopropylethylamine and cause a reaction. As the amount 
of the base, at least one equivalent of the heptanoic acid derivative 
represented by the above formula (3-2) is preferably used. It is also 
possible to use together as a solvent. Therefore, the vitamin D.sub.3 
derivative represented by the above formula (3-1) is produced in the 
reaction system, but it is further possible to effect a deblocking 
reaction, if necessary. 
As the method of the deblocking reaction, it is possible to use a known 
method in the case of deblocking, for example, the silyl groups (for 
example, Calveley, M. J., Tetrahedron, 20, 4609 to 4619, 1987). Examples 
of the deblocking agent in this case are tetrabutylammonium fluoride and 
pyridinium-p-toluene sulfonate. 
An example of the synthesis method of a heptanoic acid derivative 
represented by the above formula (3-2) used as a starting material in the 
process of the present invention is shown in the following scheme. The 
same applies when R.sup.2.sub.3 and R.sup.3.sub.3 are other groups. 
##STR26## 
wherein, in the above scheme, R.sup.41 is a hydrogen atom, tri(C.sub.1 to 
C.sub.7 hydrocarbon)silyl group, or a group forming an acetal bond with an 
oxygen atom of a hydroxyl group. 
##STR27## 
wherein, R.sup.1.sub.3 is a hydrogen atom or C.sub.1 to C.sub.3 alkyl 
group, R.sup.2.sub.3 is a hydrogen atom, or R.sup.1.sub.3 and 
R.sup.2.sub.3 together represent a substitutable single methylene group 
(examples of the substituent at this time are a C.sub.1 to C.sub.6 alkyl 
group such as methyl, t-butyl, or phenyl). 
##STR28## 
wherein, R.sup.1.sub.3 and R.sup.2.sub.3 are the same as defined above, 
and R.sup.4.sub.3 is a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.1 to C.sub.7 acyl group, or represent an 
acetal group together with the oxygen atom of the hydroxyl group. 
That is, the heptanoic acid derivative represented by the above formula 
(3-2) is obtained by bromomethylation of the heptanoic acid derivative 
represented by the above formula (3-3). Further, the heptanoic acid 
derivative represented by the above formula (3-3) is obtained by 
deprotecting the heptanoic acid derivative represented by the above (3-4) 
when necessary. Specific examples of these reactions are shown in the 
Examples. Here, the configuration of the 2-position of the heptanoic acid 
derivatives represented by the above formula (3-2), (3-3), or (3-4) may be 
either of the (R) configuration or (S) configuration. The derivative may 
also be any mixture thereof at any ratio. 
The present invention includes intermediates for synthesis of the vitamin 
D.sub.3 derivative according to the present invention represented by the 
above formulas (3-2), (3-3), or (3-4). 
Preferable examples of the heptanoic acid derivative represented by the 
above formula (3-2) of the present invention are as follows: 
1) 
(2S,5R)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
2) 
(2R,5S)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!pentyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
3) 
(2S,5R)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
4) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-hydroxy-2-methylheptanoic acid 
5) 
(2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-hydroxy-2-methylheptanoic acid 
6) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-hydroxy-2-methylheptanoic acid methylester 
7) 
(2S,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-hydroxy-2-methylheptanoic acid ethylester 
8) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-trimethylsilyloxy-2-methylheptanoic acid methylester 
9) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-t-butyldimethylsilyloxy-2-methylheptanoic acid methylester 
10) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-acetoxy-2-methylheptanoic acid methylester 
11) 
(2R,6R)-6-{(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
}-2-methoxymethyloxy-2-methylheptanoic acid methylester 
Further, preferable examples represented by the heptanoic acid derivative 
of the above (3-3) according to the present invention are as follows: 
1) 
(2R,5S)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
2) 
(2R,5S)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
3) 
(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
4) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-m 
ethylheptanoic acid 
5(2S,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-m 
ethylheptanoic acid 
6) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-m 
ethylheptanoic acid methylester 
7(2S,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-hydroxy-2-m 
ethylheptanoic acid ethylester 
8) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-trimethylsi 
lyloxy-2-methylheptanoic acid methylester 
9) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-t-butyldime 
thylsilyloxy-2methylheptanoic acid methylester 
10) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-acetoxy-2-m 
ethylheptanoic acid methylester 
11) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl}-2-methoxymeth 
yloxy-2-methylheptanoic acid methylester 
Further, preferable examples of the heptanoic acid derivative represented 
by the above (3-4) according to the present invention are as follows: 
1) 
(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
2) 
(2R,5S)-5-{(4R)-4-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-2-t-butyl-5-methyl-1,3-dioxolan-4-one 
3) 
(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
4) 
(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
5(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-benzyloxy-7a-methyl-1H-inden-1-yl! 
pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
6) 
(2S,5R)-5-{(4R)-4-(1R,7aR)-octahydro-4-methoxymethyloxy-7a-methyl-1H-inde 
n-1-yl!pentyl}-2-phenyl-5-methyl-1,3-dioxolan-4-one 
7) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-hydroxy 
-2-methylheptanoic acid 
8) 
(2S,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-hydroxy 
-2-methylheptanoic acid 
9) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl} 
-2-hydroxy-2-methylheptanoic acid 
10) 
(2S,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl} 
-2-hydroxy-2-methylheptanoic acid 
11) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-hydroxy 
-2-methylheptanoic acid 
12) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl} 
-2-hydroxy-2-methylheptanoic acid methylester 
13) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-hydroxy 
-2-methylheptanoic acid methylester 
14) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl} 
-2-hydroxy-2-methylheptanoic acid ethylester 
15) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl}-2-trimeth 
ylsilyloxy-2-methylheptanoic acid methylester 
16) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-acetoxy-7a-methyl-1H-inden-1-yl}-2-trimeth 
ylsilyloxy-2-methylheptanoic acid methylester 
17) 
(2R,6R)-6-{(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl} 
-2-acetoxy-2-methylheptanoic acid methylester 
18) (2R, 6R)-6-{(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl}-2-methoxymethy 
loxy-2-methylheptanoic acid methylester 
The vitamin D.sub.3 derivative represented by the above formula (3-1) may 
be used as an agent for promoting bone formation. Further, the heptanoic 
acid derivatives represented by the above formulas (3-2), (3-3), and (3-4) 
may be used as intermediates for the synthesis thereof. 
According to the present invention, as a manufacturing intermediate for the 
vitamin D.sub.3 derivative according to the present invention, there is 
the exomethylene derivative represented by the following formula (4-1): 
##STR29## 
wherein R.sup.1.sub.4 is a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.2 to C.sub.7 acyl group, or group forming 
an acetal bond with an oxygen atom of a hydroxyl group, and X.sub.4 is a 
bromine atom or iodine atom. 
In the present invention, in the compound represented by the above formula 
(4-1), the configurations of the asymmetric centers of the C-3 position 
and C-5 position of the 2(3H)-furanon ring may respectively be either of 
the (R) configuration or (S) configuration. Further, the present invention 
includes mixtures of these four types of stereo isomers at any ratio. 
Among these, those where the asymmetric center of the C-3 position is the 
(R) configuration and the asymmetric center of the C-5 position is the (R) 
configuration and ones where the asymmetric center of the C-3 position is 
the (R) configuration and the asymmetric center of the C-5 position is the 
(S) configuration are preferred. Further, the configuration of the 
carbon-carbon double bond of the halomethylene portion is the (E) 
configuration. 
Specific examples of the exomethylene derivative of the above formula (4-1) 
of the present invention are given below: 
1) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
2) (3R,5S)-5-{(3R)-3-(1R, 
7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-butyl}-3-methyl-3 
-hydroxy-2(3H)-furanon 
3) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
4) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
5) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
6) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
7) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
8) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
9) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-(t-butyldimethylsilyloxy)-2(3H)-furanon 
10) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-(t-butyldimethylsilyloxy)-2(3H)-furanon 
11) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-(t-butyldimethylsilyloxy)-2(3H)-furanon 
12) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-(t-butyldimethylsilyloxy)-2(3H)-furanon 
13) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-acetoxy-2(3H)-furanon 
14) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-acetoxy-2(3H)-furanon 
15) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-acetoxy-2(3H)-furanon 
16) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-acetoxy-2(3H)-furanon 
17) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
18) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
19) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methYl-3-ethoxycarbonyloxy-2(3H)-furanon 
20) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
21) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
22) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
23) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
24) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
25) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
26) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
27) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
28) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
29) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
30) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
31) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
32) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-hydroxy-2(3H)-furanon 
33) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
34) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
35) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
36) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-iodomethylene-7a-methyl-1H-inden-1 
-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
Further, the present invention provides a process for producing the 
exomethylene derivative represented by the above formula (4-1). 
That is, it provides a process causing a reaction of a 2(3H)-furanon 
derivative represented by the following formula (4-2) 
##STR30## 
wherein R.sup.1.sub.4 is a hydrogen atom, tri(C.sub.1 to C.sub.7 
hydrocarbon)silyl group, C.sub.2 to C.sub.7 acyl group, or group forming 
an acetal bond together with an oxygen atom of a hydroxyl group with a 
halogenated methylenetriphenylphosphonium halide in the presence of a base 
so as to produce an exomethylene derivative represented by the following 
formula (4-1): 
##STR31## 
wherein, R.sup.1.sub.4 and X are the same as defined above. 
In the production process of an exomethylene derivative according to the 
present invention, the configurations of the asymmetric center of the C-3 
position and C-5 position of the 2(3)H-furanon ring of the starting 
material, that is, the 2(3)H-furanon derivative represented by the above 
formula (4-2), may respectively be either of the (R) configuration or (S) 
configuration. Further, the derivative may be any mixture of these stereo 
isomers at any ratio. 
For example, when a 2(3H)-furanon derivative of the above formula (4-2) 
wherein the asymmetric center of the C-3 position of the 2(3H)-furanon 
ring is the (R) configuration and the asymmetric center of the C-5 
position is the (R) configuration, the configuration of these portions are 
preserved during the reaction and an exomethylene derivative represented 
by the above formula (4-1) wherein the asymmetric center of the C-3 
position of the 2(3H)-furanon ring is the (R) configuration and the 
asymmetric center of the C-5 position is the (R) configuration is 
obtained. 
In the same way, when a 2(3H)-furanon derivative represented by the above 
formula (4-2) where the asymmetric center of the C-3 position of the 
(3H)-furanon ring is the (R) configuration and the asymmetric center of 
the C-5 position is the (S) configuration is used, an exomethylene 
derivative represented by the above formula (4-1) where the asymmetric 
center of the C-3 position of the 2(3H)-furanon ring is the (R) 
configuration and the asymmetric center of the C-5 position is the (S) 
configuration is obtained. 
Here, when R.sup.1.sub.4 is a tri(C.sub.1 to C.sub.7 hydrocarbon)silyl 
group, specific examples are preferably a tri(C.sub.1 to C.sub.4 
alkyl)silyl group such as a trimethylsilyl, triethylsilyl, or 
t-butyldimethylsilyl group or a phenyl(C.sub.1 to C.sub.4 alkyl)silyl 
group such as a t-butyldiphenylsilyl group. 
Further, when R.sup.1.sub.4 is a C.sub.2 to C.sub.7 acyl group, specific 
examples are preferably an acetyl, propionyl, N-butyryl, pivaloyl, 
benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl group. 
Further, when R.sup.1.sub.4 is a group forming an acetal bond together 
with an oxygen atom of a hydroxyl group, specific examples are preferably 
a methoxymethyl, (2-methoxyethoxy)-methyl, 2-methoxy-2-propyl, 
2-tetrahydrofuranyl, or 2-tetrahydropyranyl group. 
The exomethylene derivative represented by the above formula (4-1) is 
produced by reacting the 2(3H)-furanon derivative represented by the above 
formula (4-2) with a halogenated methylenetriphenylphosphonium halide in 
the presence of a base. Here, as the halogenated 
methylenetriphenylphosphonium halide which is used, 
bromomethylenetriphenylphosphonium bromide etc. are preferred. Further, as 
the base used, lithium diisopropylamide, lithium bistrimethylsilyl-amide, 
sodium bistrimethylsilylamide, etc. may be exemplified as preferable 
examples. Further, as the amount of the base used, 1 to 10 times the 
amount of the 2(3H)-furanon derivative is preferable. 
Here, as the amount of the halogenated methylenetriphenylphosphonium halide 
for reacting with the 2(3H)-furanon derivative of the above formula (4-2), 
1 to 10 times the amount of the 2(3H)-furanon derivative is preferably 
used. 
Examples of the reaction solvent used in this reaction are an ether type 
solvent such as diethyl ether, tetrahydrofuran, and dimethoxyethane. As 
the reaction temperature, a range of from -60.degree. C. to room 
temperature is used. The reaction time differs according to the reaction 
temperature, but usually that the reaction be continued until the 
2(3H)-furanon derivative of the above formula (4-2) is consumed as 
determined using an analytical means such as thin layer chromatography. 
The compound represented by the above formula (4-2) used as a starting 
material in the present invention may be synthesized, for example, in 
accordance with the following scheme: 
##STR32## 
wherein, in the above scheme, R.sup.4 and R.sup.12 are a hydrogen atom, 
tri(C.sub.1 to C.sub.7 hydrocarbon)silyl group, C.sub.2 to C.sub.7 acyl 
group, or group forming an acetal bond with an oxygen atom of a hydroxyl 
group. 
Specific examples of the 2(3H)-furanon derivative represented by the 
chemical formula (4-2) preferred in the present invention are as follows: 
1) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon 
2) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon 
3) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon 
4) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon 
5) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
6) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
7) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
8) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
9) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-(t-butyl-dimethylsilyloxy)-2(3H)-furanon 
10) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-(t-butyl-dimethylsilyloxy)-2(3H)-furanon 
11) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-(t-butyl-dimethylsilyloxy)-2(3H)-furanon 
12) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-(t-butyl-dimethylsilyloxy)-2(3H)-furanon 
13) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-acetoxy-2(3H)-furanon 
14) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-acetoxy-2(3H)-furanon 
15) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-acetoxy-2(3H)-furanon 
16) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-acetoxy-2(3H)-furanon 
17) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
18) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
19) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
20) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-ethoxycarbonyloxy-2(3H)-furanon 
21) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
22) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
23) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
24) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-methoxymethyloxy-2(3H)-furanon 
25) 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
26) 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
27) 
(3S,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
28) 
(3S,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-tetrahydropyranyloxy-2(3H)-furanon 
EXAMPLES 
The present invention will now be explained in further detail by way of 
Examples, which, however, do not restrict the present invention in any 
way. 
EXAMPLE 1-1 
Production of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opyl-p-toluenesulfonate 
##STR33## 
A 2.0 g amount of the compound (1-7), (2R)-2-(1R, 
7aR)(4E)-octahydro-4-hydroxy-7a-methyl-1-H-inden-1-yl!-propanol, and 2.3 g 
of p-toluenesulfonyl chloride were placed into a 100 ml eggplant-shaped 
flask. These were dissolved in 10 ml of dried dichloromethane, then the 
solution was stirred under ice-cooling. A 4 ml amount of pyridine was 
added thereto, then the solution was stirred under ice cooling for 6 
hours. 
The reaction solution was poured into 100 ml of ethyl acetate and 20 ml of 
water and extracted. The organic layer was washed 2 times with a saturated 
aqueous solution of potassium hydrogensulfate, a saturated aqueous 
solution of sodium bicarbonate, and saturated saline, then was dried over 
anhydrous magnesium sulfate. The desiccant was filtered out, then the 
solvent was distilled off under reduced pressure to obtain a crude product 
in an amount of 4.2 g. This was placed in a 100 ml eggplant-shaped flask, 
then 2.04 g of imidazole was added. Thereto 20 ml of dried dichloromethane 
was added. The solution was then stirred under ice-cooling. Next, 1.91 ml 
of trimethylsilyl chloride was added thereto and the solution was stirred 
at room temperature over night. The reaction solution was poured into 100 
ml of ethyl acetate and 20 ml of water and extracted. The organic layer 
was then washed 2 times with saturated saline, then was dried over 
anhydrous magnesium sulfate. The desiccant was filtered out and the 
solvent was distilled off under reduced pressure to obtain a crude product 
in an amount of 4.07 g. This was purified by a silica gel column (IR-60, 
200 g, hexane/ethyl acetate=9/1) to obtain the desired product (1-8), 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opyl-p-toluenesulfonate in an amount of 3.27 g (yield 87%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
7.78 (d, 2H, J=18 Hz), 7.34 (d, 2H, J=18 Hz), 3.9 to 4.0 (m, 1H), 3.95 (dd, 
1H, J=3 & 9.2 Hz), 3.79 (dd, 1H, J=4.3 & 9.2 Hz), 2.45(s, 3H), 1.00 to 
2.00 (m, 13H), 0.89 (d, 3H J=18 Hz), 0.83 (s, 3H), 0.03 (s, 9H) 
EXAMPLE 1-2 
Process of production of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-io 
dopropane 
##STR34## 
A 3.27 g amount of the compound (1-8), (2R)-2-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-propyl-p-tolue 
nesulfonate, was dissolved in 200 ml of acetone in a 500 ml eggplant-shaped 
flask. To this was added 5 g of sodium iodide. The solution was then 
heated and refluxed over night. 
The reaction solution was allowed to cool, then the precipitate was 
filtered out and the solvent was distilled off under reduced pressure. A 
300 ml amount of ether and 200 ml of water were added to the residue and 
separation performed. Extraction was performed from the aqueous layer by 
200 ml of ether, then the organic layer was washed 2 times with a 
saturated aqueous solution of sodium hydrogencarbonate and saturated 
saline. The result was dried over anhydrous magnesium sulfate, the 
desiccant was filtered out, then the solvent was distilled off under 
reduced pressure to obtain a crude product in an amount of 4.5 g. This was 
purified by a silica gel column (IR-60, 80 g, hexane) to obtain the 
desired product (1-9), 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-io 
dopropane, in an amount of 2.72 g (yield 94%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
3.99 (m, 1H), 3.33 (dd, 1H J=2 & 5 Hz), 3.17 (dd, 1H J=5 & 9 Hz), 1.00 to 
2.00 (m, 13H), 0.99 (d, 3H, J=5.6 Hz), 0.92 (s, 3H), 0.05 (s, 9H) 
EXAMPLE 1-3 
Production of 
(4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden- 
1-yl!-propyl}-2-cyclopenten-1-one 
##STR35## 
A 10 ml amount of ether was placed into a 100 ml eggplant-shaped flask and 
cooled to -78.degree. C., followed by adding 14.3 ml of a hexane solution 
of t-butyllithium (1.54 mol/liter). A 3.94 g amount of the compound (1-9), 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-io 
dopropane was dissolved in 10 ml of ether and then added to the above 
solution which was then stirred at -78.degree. C. for 1 hour. A 2.1 g 
amount of copper iodide and 5.5 ml of tri(N-butyl)phosphine were dissolved 
in 10 ml of tetrahydrofuran, the solution was then added to the above 
reaction solution, then this was stirred at -78.degree. C. for 1 hour. 
Thereto 2.54 g of (4S)-4-(t-butyldimethylsilyloxy)-2-cyclopenten-1-one 
dissolved in 10 ml of tetrahydrofuran was added. The solution was then 
stirred at -40.degree. C. for 2 hours. This was poured into 30 ml of a 
saturated aqueous solution of ammonium chloride, then extraction was 
performed by 50 ml, 30 ml of ether. The organic layer was washed 2 times 
with saturated saline, then was dried over anhydrous sodium sulfate, the 
desiccant was filtered out, and the solvent was distilled off under 
reduced pressure to obtain a crude product in an amount of 11.7 g. This 
was dissolved in 150 ml of dichloromethane, 2 ml of 
1,8-diazabicyclo5.4.0!undecene was added, then the solution was stirred 
at room temperature over night. Thereto 400 ml of ether was added. This 
was then washed by a saturated aqueous solution of potassium 
hydrogensulfate, a saturated aqueous solution of sodium hydrogencarbonate, 
and saturated saline and was dried over anhydrous magnesium sulfate. The 
desiccant was filtered out, then the solvent was distilled off under 
reduced pressure to obtain a crude product in an amount of 10.9 g. This 
was purified by a silica gel column (IR-60, 400 g, hexane/ethyl 
acetate=40/1, 19/1, 9/1) to obtain the desired product (1-10), 
(4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden- 
1-yl!-propyl}-2-cyclopenten-1-one in an amount of 1.76 g (yield 50%). 
.sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
7.57 (dd, 1H, J=2.3 & 5.6 Hz), 6.10 (dd, 1H J=2 & 5.6 Hz), 3.99 (m, 1H), 
2.80 to 3.10 (m, 1H), 2.50 (dd, 1H, J=6.3 & 18.8 Hz), 1.00 to 2.00 (m, 
16H), 0.97 (d, 3H J=6.3 Hz), 0.90 (s, 3H), 0.05 (s, 9H) 
EXAMPLE 1-4 
Production of (1R, 
4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1 
-yl!-propyl}-1-methyl-2-cyclopenten-1-ol and 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
##STR36## 
A 1.76 g amount of the compound (1-10), (4S)-4-{(2R)-2-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-propyl}-2-cycl 
openten-1-one was placed into a 300 ml eggplant-shaped flask. A 150 ml 
amount of tetrahydrofuran was added and the solution stirred and cooled to 
-78.degree. C., and then, 6.5 ml of an ether solution of methyllithium 
(1.16 mol/liter) was added, followed by stirring for 15 minutes. A 50 ml 
amount of saturated saline was added, the excess methyllithium was broken 
down, then 100 ml of ether was added for separation. The organic layer was 
washed with saturated saline, then was dried over anhydrous magnesium 
sulfate. The desiccant was filtered out, the solvent was distilled off 
under reduced pressure, and the crude product was purified by a silica gel 
column (Merck gel: 300 g, hexane/ethyl acetate=15/1 to 9/1) to obtain the 
desired product (1-11), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 1.55 g (yield 
84%) and the desired product (1-12), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol, in an amount of 0.27 g (yield 
14%). 
Compound (1-11) .sup.1 H-NMR (D.sub.6 -acetone, .delta. ppm) 
5.40 to 5.60 (m, 2H), 4.00 (brs, 1H), 2.50 to 2.70 (m, 1H), 0.90 to 2.20 
(m, 18H), 1.18 (s, 3H), 0.88 (d, 3H J=5 Hz), 0.87 (s, 3H), 0.03 (s, 9H) 
Compound (1-12) .sup.1 H-NMR (D.sub.6 -acetone, .delta. ppm) 
5.54 (s, 2H), 3.90 to 4.00 (m, 1H), 2.80 to 3.00 (m, 1H), 0.90 to 2.10 (m, 
18H), 1.26 (s, 3H), 0.87 (d, 3H, J=6.3 Hz), 0.87 (s, 3H), 0.03 (s, 9H) 
EXAMPLE 1-5 
Production of 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol 
##STR37## 
A 1.55 g amount of the compound (1-11), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol was taken in a 100 ml 
eggplant-shaped flask, then 20 ml of THF was added and the solution 
stirred under ice-cooling. Then, 5.1 ml of a tetrahydrofuran solution (1 
mol/liter) of tetra-n-butylammonium fluoride was added thereto and, then 
the solution was stirred for 1 hour. The reaction solution was poured in 
100 ml of ether and 30 ml of water and extracted. The organic layer was 
washed 4 times with saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 1.29 g. This was purified by a silica gel column (IR-60, 150 g, 
hexane/ethyl acetate=15/1 to 1/1) to obtain the desired product (1-13), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 1.21 g (yield 
97%). 
##STR38## 
Similarly, 260 mg of the compound (1-12), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol was treated in the same way to 
obtain the desired product (1-14), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol in an amount of 174 mg (yield 84%). 
Compound (1-13) .sup.1 H-NMR (D.sub.6 -acetone, .delta. ppm) 
5.50 to 5.70 (m, 2H), 4.08 (brs, 1H), 2.60 to 2.80 (m, 1H), 1.00 to 2.20 
(m, 19H), 1.32 (s, 3H), 1.06 (s, 3H), 1.03 (d, 3H, J=9.3 Hz) 
Compound (1-14) .sup.1 H-NMR (D.sub.6 -acetone, .delta. ppm) 
5.59 (s, 2H), 4.08 (brs, 1H), 2.80 to 3.00 (m, 1H), 1.00 to 2.30 (m, 19H), 
1.32 (s, 3H), 0.98 (s, 3H), 0.93 (d, 3H J=9.6 Hz) 
EXAMPLE 1-6 
Production of 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-methyl-2-cyclopenten-1-ol 
##STR39## 
A 277 mg amount of the compound (1-13), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol was dissolved in 25 ml of toluene in a 
100 ml eggplant-shaped flask, then the solution was stirred under a 
nitrogen atmosphere. Thereafter, 115 mg of tetrakis-triphenylphosphine 
ruthenium dihydride and 5 ml of methylallyl carbonate was added thereto, 
and then the solution was stirred at 80.degree. to 100.degree. C. for 1 
day. The reaction solution was filtered by Celite, the solvent was 
distilled off under reduced pressure, and the residue was purified by a 
silica gel column (IR-60, 80 g, hexane/ethyl acetate=3/1, 1/1) to obtain 
the desired product (1-15), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
loxy}-1-methyl-2-cyclopenten-1-ol, in an amount of 221 mg (yield 79%). 
##STR40## 
A 62 mg amount of the compound (1-14), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-p 
ropyl}-1-methyl-2-cyclopenten-1-ol, was treated in the same way to obtain 
the desired product (1-16), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-methyl-2-cyclopenten-1-ol in an amount of 52 mg (yield 84%). 
Compound (1-15) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.60 to 5.70 (m, 2H), 2.60 to 2.80 (m, 1H), 1.20 to 2.50 (m, 18H), 1.35 (s, 
3H), 0.99 (d, 3H J=9.3 Hz), 0.65 (s, 3H) 
Compound (1-16) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.60 to 5.70 (m, 2H), 2.80 to 3.00 (m, 1H), 1.00 to 2.50 (m, 18H), 1.43 (s, 
3H), 0.99 (d, 3H, J=9.3 Hz), 0.66 (s, 3H) 
EXAMPLE 1-7 
Production of 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-methyl-1-trimethylsilyloxy-2-cyclopentene 
##STR41## 
A 177 mg amount of the compound (1-15), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
loxy}-1-methyl-2-cyclopenten-1-ol, and 128 mg of imidazole were placed in a 
100 ml eggplant-shaped flask. Next, 20 ml of dried dichloromethane was 
added and the solution was stirred. A 120 .mu.l amount of trimethylsilyl 
chloride was added under ice cooling, then the solution was stirred at the 
same temperature for 30 minutes. The reaction solution was poured in 50 ml 
of ether and 30 ml of water and extracted. The organic layer was washed 2 
times with saturated saline, then was dried over anhydrous magnesium 
sulfate. The desiccant was filtered out and the solvent was distilled off 
under reduced pressure. The obtained residue was purified by a silica gel 
column (IR-60, 80 g, hexane/ethyl acetate=19/1, 4/1) to obtain the desired 
product (1-17), (1R, 
4S)-4-{(2R)-2-(1R,7aR)-octadehydro-4-oxo-7a-methyl-1H-inden-1-yl!-propylo 
xy}-1-methyl-1-trimethylsilyloxy-2-cyclopentene in an amount of 188 mg 
(yield 85%). 
##STR42## 
A 52 mg amount of the compound (1-16), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-methyl-2-cyclopenten-1-ol, was treated in the same way to obtain the 
desired product (1-18), 
(1S,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
l}-1-methyl-2-cyclopenten-1-ol in an amount of 49 mg (yield 75%). 
Compound (1-17) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.71 (dd, 1H, J=2 & 5.6 Hz), 5.56 (dd, 1H, J=1.65 & 5.6 Hz), 2.60 to 2.80 
(m, 1H), 1.10 to 2.50 (m, 17H), 1.31 (s, 3H), 0.98 (d, 3H, J=9.3 Hz), 0.65 
(s, 3H), 0.12 (s, 9H) 
Compound (1-18) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.50 to 5.65 (m, 2H), 2.80 to 2.90 (m, 1H), 1.10 to 2.50 (m, 17H), 1.31 (s, 
3H), 0.98 (d, 3H J=9.3 Hz), 0.56 (s, 3H), 0.07 (s, 9H) 
EXAMPLE 1-8 
Production of 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol 
##STR43## 
A 5.30 g amount of bromomethylene-triphenylphosphonium bromide was taken in 
a 200 ml eggplant-shaped flask, 30 ml of dried tetrahydrofuran was added, 
and the solution was stirred and cooled by a -65.degree. C. bath. Next, 
12.2 ml of a 1M solution of sodium bistrimethylsilylamide in 
tetrahydrofuran was added dropwise and the solution stirred at the same 
temperature for 1 hour. Thereafter, 10 ml of a tetrahydrofuran solution of 
882 mg of the compound (1-17), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-propy 
loxy}-1-methyl-1-trimethylsilyloxy-2-cyclopentene was added dropwise, the 
cooling bath was removed, then the solution was stirred at room 
temperature for 30 minutes. Further, hexane was added to the reaction 
solution which was then further stirred. The precipitate was filtered out 
and the solvent was distilled off under reduced pressure. The obtained 
residue was dissolved in 10 ml of tetrahydrofuran and the solution stirred 
while cooling by ice. To this was added 5 ml of a tetrahydrofuran solution 
(1 mol/liter) of tetra(n-butyl)ammonium fluoride, then the solution was 
stirred under ice cooling for 1 hour. The reaction solution was poured in 
100 ml of ethyl acetate and 30 ml of water and separated. The organic 
layer was washed with saline, then was dried over anhydrous magnesium 
sulfate. The desiccant was filtered out, then the solvent was distilled 
off under reduced pressure and the obtained residue was purified by a 
silica gel column (IR-60, 200 g, hexane/ethyl acetate=19/1 to 2/1) to 
obtain the desired product (1-19), (1R, 
4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl 
!-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 422 mg (yield 47%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.50 to 5.70 (br, 3H), 2.80 to 2.90 (m, 1H), 2.60 to 2.80 (m, 1H), 2.10 to 
2.25 (m, 1H), 1.20 to 2.00 (m, 16H), 1.35 (s, 3H), 0.96 (d, 3H J=6.3 Hz), 
0.57 (s, 3H) 
EXAMPLE 1-9 
Production of 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-propyl}-1-methyl-1-trimethylsilyloxy-2-cyclopentene 
##STR44## 
A 422 mg amount of the compound (1-19), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol and 158 mg of imidazole were 
added to a 100 ml eggplant-shaped flask. Next, 5 ml of dried 
dichloromethane was added and stirred in, then 175 .mu.l f trimethylsilyl 
chloride was added under ice cooling and the solution stirred at the same 
temperature for 30 minutes. The reaction solution was poured into 50 ml of 
ether and 20 ml of water and extracted. The organic layer was washed 2 
times with saturated saline, then was dried over anhydrous magnesium 
sulfate, the desiccant was filtered out, the solvent was distilled off 
under reduced pressure, and the obtained residue was purified by a silica 
gel column (IR-60, 150 g, hexane/ethyl acetate=50/1 to 19/1) to obtain the 
desired product (1-20), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 422 mg (yield 
84%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.50 to 5.70 (m, 2H), 5.53 (s, 1H), 1.10 to 3.00 (m, 18), 1.35 (s, 3H), 
0.94 (d, 3H, J=6.3 Hz), 0.56 (s, 3H), 0.11 (s, 9H) 
EXAMPLE 1-10 
Production of 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R,4S)-1-trimethylsilyloxy-1 
-methyl-2-cyclopenten-4-yl!-vitamin D.sub.3 
-1.alpha.,3-bistrimethylsilylether 
##STR45## 
A 63.7 mg amount of triphenylphosphine was taken in a dried eggplant-shaped 
flask and deaerated. To this was added 20 mg of 
tris(dibenzylideneacetone)dipalladium chloroform, followed by further 
deaeration. A 7.2 ml amount of a mixed solvent of distilled 
toluene/diisopropylethylamine=1/1 was added under a nitrogen atmosphere, 
then the solution was stirred at room temperature for 20 minutes. Next, 88 
mg of the compound (1-20), 
(1R,4S)-4-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-propyl}-1-methyl-1-trimethylsilyloxy-2-cyclopentene and 57 mg of the 
compound (1-21), (3S,5R)-bistrimethylsilyloxy-1-octen-7-yne were dissolved 
in 2 ml of a mixed solvent of distilled toluene/diisopropylethylamine=1/1 
and then added dropwise to the above reaction solution. The solution was 
heated and refluxed for 1.5 hours, then returned to room temperature. The 
reaction solution was poured into 50 ml of ethyl acetate and 10 ml of a 
saturated aqueous solution of potassium hydrogensulfate and extracted. The 
organic layer was washed by a saturated aqueous solution of sodium 
hydrogencarbonate and saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 300 mg. This was purified by a silica gel column (Merck gel, 200 
g, hexane/ethyl acetate=100/1 to 20/1) to obtain the desired product 
(1-22), 23,24,25,26,27-pentanol-1.alpha., 
3-hydroxy-22-(1R,4S)-1-trimethylsilyloxy-1-methyl-2-cyclopenten-4-yl!-vit 
amin D.sub.3 -1.alpha.,3-bistrimethylsilyl-ether in an amount of 58.8 mg 
(yield 46%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.27 (d-like, 1H), 6.04 (d-like, 1H), 5.50 to 5.60 (m, 2H), 5.20 (s, 1H), 
4.90 (brs, 1H), 4.30 to 4.40 (m, 1H), 4.10 to 4.20 (m, 1H), 1.10 to 3.00 
(m, 22H), 1.32 (s, 3H), 0.94 (d, 3H J=6.3 Hz), 0.55 (s, 3H), 0.00 to 0.20 
(m, 18H) 
EXAMPLE 1-11 
Production of 23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R, 
4S)-1-hydroxy-1-methyl-2-cyclopenten-4-yl!-vitamin D.sub.3 
##STR46## 
A 58.8 mg amount of the compound (1-22), 
23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R,4S)-1-trimethylsilyloxy-1 
-methyl-2-cyclopenten-4-yl!-vitamin D.sub.3 
-1.alpha.,3-bistrimethylsilylether, was taken in a 25 ml eggplant-shaped 
flask, then 5 ml of dried tetrahydrofuran was added and the solution 
stirred. A 0.5 ml amount of a 1M solution of tetrabutylammoniumfluoride in 
tetrahydrofuran was added and the solution stirred under ice cooling for 3 
hours. The reaction solution was poured in 50 ml of ethyl acetate and 10 
ml of a saturated aqueous solution of potassium hydrogensulfate and 
extracted. The organic layer was washed with a saturated aqueous solution 
of sodium bicarbonate and saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out, the solvent was 
distilled off under reduced pressure, and the obtained crude product was 
purified by a silica gel column (IR-60 Merck gel, 250 g, hexane/ethyl 
acetate=1/1 to 1/3) to obtain the desired product 
(1-23),23,24,25,26,27-pentanol-1.alpha.-hydroxy-22-(1R, 
4S)-1-hydroxy-1-methyl-2-cyclopenten-4-yl!-vitamin D.sub.3 in an amount of 
22.1 mg (yield 57%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.38 (d, 1H, J=11.2 Hz), 6.01 (d, 1H, J=11.2 Hz), 5.64 (s, 2H), 5.33 (s, 
1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 1H), 4.15 to 4.30 (m, 1H), 1.20 to 
2.90 (m, 25H), 1.32 (s, 3H), 0.96 (d, 3H J=6.3 Hz), 0.55 (s, 3H) 
EXAMPLE 2-1 
Production of 
(4S,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene and 
(4R,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene 
##STR47## 
A 3.0 g amount of 
(3R)-3-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!butanal was 
placed in a 500 ml eggplant-shaped flask, 100 ml of tetrahydrofuran was 
added, and the solution was stirred and cooled by an ice-cooled bath. A 
3.2 ml amount of methyl-2-bromomethylacrylate was added dropwise to this. 
Next, 1.37 g of zinc powder and 390 ml of a saturated aqueous solution of 
ammonium chloride were added and the solution was stirred at the same 
temperature for 45 minutes. 
A 150 ml amount of ethyl acetate was added to the reaction solution for 
extraction. The organic layer was washed 2 times with saturated saline, 
then was dried over anhydrous magnesium sulfate. The desiccant was 
filtered out and the solvent was distilled off under reduced pressure to 
obtain a crude product in an amount of 5.0 g. This was purified by a 
silica gel column (Merck gel, 250 g, hexane/ethyl acetate=9/1 to 3/1) to 
obtain 
(4S,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene (more polar) in an amount of 2.03 g and 
(4R,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene (less polar) in an amount of 1.522 g (yield 
81%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.25 (d, 1H, J=2 Hz), 5.66 (d, 1H, J=2 Hz), 4.07 (br, 1H), 3.82 to 3.88 
(br, 1H), 3.77 (s, 3H), 2.51 (dd, 1H, J1=1 Hz, J2=9 Hz), 2.36 (dd, 1H, 
J1=8 Hz, J2=14 Hz), 0.96 (s, 1H), 0.94 (d, 3H, J=6 Hz), 6.27 (d, 1H, J=1 
Hz), 5.69 (d, 1H, J=1 Hz), 4.07 (br, 1H), 3.80 to 3.86 (br, 1H), 3.77 (s, 
3H), 2.69 (dd, 1H, J1=1 Hz, J2=10 Hz), 2.18 (dd, 1H, J1=9 Hz, J2=14 Hz), 
0.98 (d, 3H, J=7 Hz), 0.95 (s, 3H). 
EXAMPLE 2-2 
Production of 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylene-dehydro-2(3H)-furanon 
##STR48## 
A 1.00 g amount of 
(4S,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene was taken in a 100 ml eggplant-shaped flask, 
then 15 ml of tetrahydrofuran was added to dissolve it. Further, 15 ml of 
water was added and the solution was stirred and cooled by an ice-cooled 
bath. To this was added 6 ml of a 4N aqueous solution of lithium 
hydroxide, then the solution was stirred at the same temperature for 1 
hour. Next, at the same temperature, concentrated hydrochloric acid was 
dropwise added to adjust the pH to 2, then the solution was stirred at 
room temperature for 3 hours. To the reaction solution were added 50 ml of 
water and 200 ml of ethyl acetate for extraction. The organic layer was 
further washed 3 times with water and was washed 2 times with saturated 
saline, then was dried over anhydrous magnesium sulfate. The desiccant was 
filtered out and the solvent was distilled off under reduced pressure to 
obtain 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylene-dehydro-2(3H)-furanon in an amount of 880 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.22 (t, 1H, J=3 Hz), 5.62 (t, 1H, J=2 Hz), 4.58 (dd, 1H, J1=7 Hz, J2=14 
Hz), 4.08 (d, 1H, J=3 Hz), 3.01 to 3.10 (m, 1H), 2.56 to 2.6 (m, 1H), 1.00 
(d, 3H, J=7 Hz), 0.95 (s, 3H). 
EXAMPLE 2-3 
Production of 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylenedehydro-2(3H)-furanon 
##STR49## 
A 570 mg amount of 
(4R,6R)-6-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!-2-methoxy 
carbonyl-4-hydroxy-1-heptene was taken in a 100 ml eggplant-shaped flask, 
then 5 ml of tetrahydrofuran was added to dissolve it. Further, 5 ml of 
water was added and the solution stirred and cooled by an ice-cooled bath. 
To this was added 3 ml of a 4 N aqueous solution of lithium hydroxide. The 
solution was stirred at the same temperature for 1 hour. Next, under the 
same temperature, concentrated hydrochloric acid was added dropwise to 
adjust the pH to 2, then the solution was stirred at room temperature for 
hours. To the reaction solution were added 50 ml of water and 200 ml of 
ethyl acetate for extraction. The organic layer was further washed 3 times 
with water and 2 times with saturated saline, then was dried over 
anhydrous magnesium sulfate. The desiccant was filtered out and the 
solvent was distilled off under reduced pressure to obtain 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylenedehydro-2(3H)-furanon in an amount of 451 mg. 
EXAMPLE 2-4 
Production of 
(5S)-5-{(2R)-2-(1R,7R)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3- 
methylenedehydro-2(3H)-furanon 
##STR50## 
A 2.38 g amount of pyridinium bichromate was taken in a 200 ml 
eggplant-shaped flask, 50 ml of dimethyl formamide was added, then the 
solution was cooled by an ice-cooled bath. Thereafter, a solution of 880 
mg of 
(5S)-5-{(2R)-2-(1R,7R)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propyl 
}-3-methylene-dehydro-2(3H)-furanon dissolved in 20 ml of dimethyl 
formamide was dropwise added and the solution was stirred at room 
temperature for 3 hours. A 200 ml amount of ether was added to the 
reaction solution, the insolubles were filtered out, then the result was 
washed with water and then saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 1.02 g. This was purified by a silica gel column (Daiso gel 
IR-60, 150 g, hexane/ethyl acetate=3/1 to 2/1) to obtain 
(5S)-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3-m 
ethylene-dehydro-2 (3H)-furanon in an amount of 700 mg (yield 69%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.23 (t, 1H, J=3 Hz), 5.63 (t, 1H, J=2 Hz), 4.6 to 4.7 (m, 1H), 3.0 to 3.13 
(m, 1H), 2.4 to 2.6 (m,1H), 1.05 (d, H, J=7 Hz), 0.67 (s, 3H). 
EXAMPLE 2-5 
Production of 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3 
-methylene-dehydro-2 (3H)-furanon 
##STR51## 
A 648 mg amount of pyridinium bichromate was taken in a 200 ml 
eggplant-shaped flask, 10 ml of dimethyl formamide was added, and the 
solution was cooled by an ice-cooled bath. Thereafter a solution of 240 mg 
of 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propy 
l}-3-methylene-dehydro-2(3H)-furanon dissolved in 10 ml of dimethyl 
formamide was dropwise added and the solution was stirred at room 
temperature for 3 hours. A 100 ml amount of ether was added to the 
reaction solution, the insolubles were filtered out, then the result was 
washed with water and saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 600 mg. This was purified by a silica gel column (Daiso gel 
IR-60, 100 g, hexane/ethyl acetate=3/1 to 2/1) to obtain 
(5R)-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3-m 
ethylene-dehydro-2(3H)-furanon in an amount of 327 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.23 (t, 1H, J=3 Hz), 5.63 (t, 1H, J=2 Hz), 4.59 (t, 1H, J=7 Hz), 3.0 to 
3.10 (m, 1H), 2.4 to 2.6 (m, 1H), 1.07 (d, 3H, J=6 Hz), 0.66 (s, 3H). 
EXAMPLE 2-6 
Production of 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl 
}-3-methyl-dehydro-2(3H)-furanon 
##STR52## 
A 200 mg amount of 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl}-3 
-methylene-dehydro-2(3H)-furanon was taken in a 100 ml eggplant-shaped 
flask, 50 ml of ethanol was added, and the solution was stirred for 
dissolution. A 50 mg amount of 10% Pd/carbon was added under a nitrogen 
atmosphere, the atmosphere was replaced with hydrogen (balloon), then the 
solution was stirred at room temperature for 3 hours. The atmosphere was 
replaced with nitrogen, then the catalyst was filtered out and the solvent 
was distilled off under reduced pressure to obtain 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl 
}-3-methyl-dehydro-2(3H)-furanon in an amount of 185 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
4.40 to 4.51 (m, 1H), 2.62 to 2.72 (m, 1H), 2.41 to 2.51 (m, 2H), 2.27 (d, 
3H, J=7 Hz), 1.03 (d, 3H, J=7 Hz), 0.66 (s, 3H). 
EXAMPLE 2-7 
Production of 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon 
##STR53## 
A 1.79 g amount of bromomethylenetriphenylphosphonium bromide was taken in 
a 100 ml eggplant-shaped flask, 20 ml of dried tetrahydrofuran was added, 
and the solution was stirred and cooled by a -70.degree. C. cooling bath. 
Thereafter 3.9 ml of a 1 M (CH.sub.3).sub.3 Si!.sub.2 NNA/tetrahydrofuran 
solution was dropwise added, then the solution was stirred at the same 
temperature for 1 hour. Next, a solution of 120 mg of 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propyl 
}-3-methyl-dehydro-2(3H)-furanon dissolved in 5 ml of dried tetrahydrofuran 
was dropwise added to this. The cooling bath was removed, then the 
solution was stirred for 2 hours. Next, hexane was added and the 
insolubles filtered out, then the solvent was distilled off under reduced 
pressure to obtain a crude product in an amount of 1.2 g. This was 
purified by a silica gel column (Daiso gel IR-60, 80 g, hexane/ethyl 
acetate=15/1) to obtain 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!propyl}-3-methyl-dehydro-2(3H)-furanon in an amount of 69 mg (yield 
46%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.65 (d,1H, J=2 Hz), 4.40 to 4.50 (m, 1H), 2.85 to 2.90 (m, 1H), 2.62 to 
2.72 (m, 1H), 2.41 to 2.50 (m, 1H), 2.67 (d, 3H, J=7 Hz), 1.00 (d, 3H, J=7 
Hz), 0.58 (s, 3H). 
EXAMPLE 2-8 
Production of 
(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!propyl 
paratoluene sulfonate 
##STR54## 
A 2.39 g amount of bromomethylenetriphenylphosphonium bromide was taken in 
a 100 ml eggplant-shaped flask, 40 ml of dried tetrahydrofuran was added, 
and the solution was stirred and cooled by a -70.degree. C. cooling bath. 
Thereafter 5.28 ml of a 1 M (CH.sub.3).sub.3 Si!.sub.2 
NNa/tetrahydrofuran solution was dropwise added, then the solution was 
stirred at the same temperature for 1 hour. Next, a solution of 300 mg of 
(2R)-2-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!propylparatoluene 
sulfonate dissolved in 10 ml of dried tetrahydrofuran was added dropwise. 
The cooling bath was removed and then the solution was stirred for 1 hour. 
Next, hexane was added and the insolubles were filtered out, then the 
solvent was distilled off under reduced pressure to obtain a crude product 
in an amount of 2.5 g. This was purified by a silica gel column (Merck 
gel, 100 g, hexane/ethyl acetate=14/1, 9/1) to obtain 
{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!propy 
lparatoluene sulfonate in an amount of 178 mg (yield 48%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
7.78 (d, 2H, J=8 Hz), 7.35 (d, 2H, J=8 Hz), 5.64 (s,1H), 3.96 (dd, 1H, J1=3 
Hz, J2=9 Hz), 3.82 (dd, 1H, J1=6 Hz, J2=9 Hz), 2.45 (s, 3 Hz), 0.99 (d, 
3H, J=7 Hz), 0.53 (s, 3H). 
EXAMPLE 2-9 
Production of 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butyro 
nitrile 
##STR55## 
A 178 mg amount of 
(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!propyl 
paratoluenes sulfonate was taken in a 50 ml eggplant-shaped flask, then 6 
ml of dimethyl formamide was added for dissolution. To this was then 
charged 215 mg of KCN, then the solution was stirred in a 50.degree. C. 
bath for 24 hours. To the reaction solution was added 50 ml of water, then 
extraction was performed with ether. The organic layer was washed with 
water and saturated saline, then was dried over anhydrous magnesium 
sulfate and the desiccant was filtered out. The solvent was distilled off 
under reduced pressure to obtain a crude product in an amount of 110 mg. 
This was purified by a silica gel column (Daiso gel, hexane/ethyl 
acetate=14/1) to obtain 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butyro 
nitrile in an amount of 84 mg (yield 69%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.67 (s, 1H), 2.86 to 2.91 (m, 1H), 2.21 to 2.35 (m, 2H), 1.18 (d, 3H, J=6 
Hz), 0.59 (s, 3H). 
EXAMPLE 2-10 
Production of 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butano 
l 
##STR56## 
A 84 mg amount of 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butyro 
nitrile was taken in a 25 ml eggplant-shaped flask, then 5 ml of dried 
dichloromethane was then added to dissolve the same. The solution was 
cooled by a -70.degree. C. bath, then 660 .mu.l of a 1.5 M 
(CH.sub.3).sub.2 CHCH.sub.2 !.sub.2 AlH/toluene solution was added 
dropwise. The solution was stirred at the same temperature for 1 hour, 
then 0.5 ml of a saturated aqueous solution of sodium sulfate, 0.3 ml of 
methanol, 0.5 ml of 2 N hydrochloric acid, and 15 ml of ethyl acetate were 
added and the solution stirred for 30 minutes. The reaction solution was 
filtered by Celite, then was washed by a saturated solution of ammonium 
chloride and saturated saline, then was dried over anhydrous magnesium 
sulfate and the desiccant filtered out. The solvent was distilled off 
under reduced pressure to obtain 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butano 
l in an amount of 85 mg. 
EXAMPLE 2-11 
Production of 
(4S,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene and 
(4R,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene 
##STR57## 
A 105 mg amount of 
(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!butano 
l was taken in a 50 ml eggplant-shaped flask, then 8 ml of dried 
tetrahydrofuran was then added to dissolve the same. The solution was 
cooled by an ice cooled bath, then 84 ml of methyl-2-bromomethylacrylate 
was added dropwise. Further, 35 mg of zinc powder and 10 ml of a saturated 
aqueous solution of ammonium chloride were added, then the solution was 
stirred at the same temperature for 1 hour. The reaction solution was 
extracted by ethyl acetate, the organic layer was washed with saturated 
saline, then was dried over anhydrous magnesium sulfate. The desiccant was 
filtered out, then the solvent was distilled off under reduced pressure to 
obtain a crude product in an amount of 166 mg. This was purified by a 
silica gel column (Merck gel, hexane/ethyl acetate=9/1) to obtain 
(4S,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene in an amount of 43 mg and 
(4R,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene in an amount of 55 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.269 (d, 1H, J=1 Hz), 5.66 (d, 2H, J=10 Hz), 3.77 (s, 3H), 2.84 to 2.93 
(m, 1H), 2.65 to 2.72 (m, 1H), 2.13 to 2.27 (m, 1H), 1.02 (d, 3H, J=7 Hz), 
0.58 (s, 3H), 6.249 (d, 1H, J=1 Hz), 5.65 (d, 2H, J=5 Hz), 3.77 (s, 3H), 
2.84 to 2.90 (m, 1H), 2.53 to 2.55 (m, 1H), 2.31 to 2.39 (m, 1H), 0.97 (d, 
3H, J=7 Hz), 0.59 (s, 3H) 
EXAMPLE 2-12 
Production of 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon 
##STR58## 
A 55 mg amount of 
(4S,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene was taken in a 50 ml eggplant-shaped 
flask, then 6 ml of tetrahydrofuran was added to dissolve the same. 
Further, 6 ml of water was added, the solution was cooled by an ice-cooled 
bath, 0.25 ml of 4 N lithium hydroxide was added dropwise, and the 
solution was stirred at the same temperature for 1 hour. Next, 
concentrated hydrochloric acid was added dropwise under the same 
temperature to adjust the pH to 2 and the solution was stirred at room 
temperature for 3 hours. To the reaction solution were added 10 ml of 
water and 100 ml of ethyl acetate for extraction. The organic layer was 
washed 3 times with water and 2 times with saturated saline, then was 
dried over anhydrous magnesium sulfate. The desiccant was filtered out and 
the solvent was distilled off under reduced pressure to obtain 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 51 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.23 (t, 1H, J=3 Hz), 5.62 (t, 1H, J=2 Hz), 5.65 (d, H, J=2 Hz), 4.12 (dd, 
1H, J1=7 Hz, J2=14 Hz), 3.00 to 3.11 (m, 1H), 2.85 to 2.9 (m, 1H), 2.47 to 
2.57 (m, 1H), 1.03 (d, 3H, J=7 Hz), 0.58 (s, 3H). 
EXAMPLE 2-13 
Production of 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon 
##STR59## 
A 70 mg amount of 
(4R,6R)-6-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-yl!-2- 
methoxycarbonyl-4-hydroxy-1-heptene was taken in a 50 ml eggplant-shaped 
flask, then 6 ml of tetrahydrofuran was added for dissolution. Further, 6 
ml of water was added, the solution was cooled by an ice-cooled bath, 0.35 
ml of 4 N lithium hydroxide was added dropwise, and the solution was 
stirred at the same temperature for 1 hour. Next, concentrated 
hydrochloric acid was added dropwise under the same temperature to adjust 
the pH to 2 and the solution was stirred at room temperature for 3 hours. 
To the reaction solution were added 10 ml of water and 100 ml of ethyl 
acetate for extraction. The organic layer was washed 3 times with water 
and 2 times with saturated saline, then was dried over anhydrous magnesium 
sulfate. The desiccant was filtered out and the solvent was distilled off 
under reduced pressure to obtain 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon in an amount of 60 mg. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.23 (t, 1H, J=3 Hz), 5.62 (t, 1H, J=2 Hz), 5.65 (d, 1H, J=2 Hz), 4.59 to 
4.69 (m, 1H), 3.01 to 3.12 (m, 1H), 2.85 to 2.9 (m, 1H), 2.47 to 2.57 (m, 
1H), 1.02 (d, 3H, J=7 Hz), 0.59 (s, 3H). 
EXAMPLE 2-14 
Production of 23(S),25(S)-1a-hydroxyvitamin D.sub.3 -26, 23-lactone 
##STR60## 
A 28 mg amount of triphenylphosphine was taken in a dried eggplant-shaped 
flask and deaerated. Thereafter, 19 mg of 
tris(dibenzylideneacetone)dipalladium chloroform was added, followed by 
further deaeration, then 6 ml of a mixed solvent of distilled 
toluene/diisopropylethylamine =1/1 was added under nitrogen and the 
solution was stirred at 50.degree. C. for 20 minutes. Next, a solution of 
65 mg of 
(3S,5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!propyl}-3-methyldehydro-2(3H)-furanon and 60 mg of (3S),(5R)-3,5-bis 
(trimethylsilyloxy)-1-octen-7-yne dissolved in 3 ml of a mixed solvent of 
distilled toluene/diisopropylethylamine=1/1 was added dropwise. This 
reaction solution was stirred at 100.degree. C. for 1.5 hours. This was 
returned to room temperature, then the reaction solution was poured into 
50 ml of ethyl acetate and 10 ml of a saturated aqueous solution of 
potassium hydrogensulfate for extraction. The organic layer was washed 
with a saturated aqueous solution of sodium hydrogencarbonate and 
saturated saline, then was dried over anhydrous sodium sulfate. The 
desiccant was filtered out and the solvent was distilled off under reduced 
pressure to obtain a crude product in an amount of 120 mg. This was 
purified by a silica gel column (Merck gel, hexane/ethyl acetate=14/1 to 
9/1) to obtain 23(S),25(S)-1a-hydroxy-vitamin D.sub.3 
-26,23-lactone-1,3-bistrimethylsilylether in an amount of 52 mg (yield 
50%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of 
methanol was added to dissolve it. The solution was cooled by an 
ice-cooled bath, then 100 mg of polymer-bonded pyridinium 
toluene-4-sulfonate was added and the solution stirred for 15 hours. The 
reaction solution was filtered by Celite, then the solvent was distilled 
off under reduced pressure to obtain a crude product in an amount of 110 
mg. This was purified by a silica gel column (Merck gel, hexane/ethyl 
acetate=2/1 to 1/1) to obtain 23(S),25(S)-1a-hydroxyvitamin D.sub.3 
-26,23-lactone in an amount of 28 mg (yield 72%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.37 (d, 1H, J=11 Hz), 6.00 (d, 1H, J=11 Hz), 5.33 (s, 1H), 5.01 (s, 1H), 
4.44 (br, 2H), 4.24 (br, 1H), 1.265 (d, 3H, J=8 Hz), 0.99 (d, 3H, J=6 Hz), 
0.56 (s, 3H) 
EXAMPLE 2-15 
Production of 23(S)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone 
##STR61## 
A 22 mg amount of triphenylphosphine was taken in a dried eggplant-shaped 
flask and then deaearated. Thereafter, 14 mg of tris(dibenzylideneacetone) 
dipalladium chloroform was added, followed by further deaeration, then 3 
ml of a mixed solvent of distilled toluene/diisopropylethylamine=1/1 was 
added under nitrogen and the solution was stirred at 50.degree. C. for 20 
minutes. Next, a solution of 51 mg of 
(5S)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon and 61 mg of 
(3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octene-7-in dissolved in 4 ml of a 
mixed solvent of distilled toluene/diisopropylethylamine=1/1 was added 
dropwise. This reaction solution was stirred at 100.degree. C. for 1.5 
hours, then was returned to room temperature. The reaction solution was 
poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous 
solution of potassium hydrogensulfate for extraction. The organic layer 
was washed with a saturated aqueous solution of sodium hydrogencarbonate 
and saturated saline, then was dried over anhydrous sodium sulfate. The 
desiccant was filtered out and the solvent was distilled off under reduced 
pressure to obtain a crude product in an amount of 120 mg. This was 
purified by a silica seppack (Waters, hexane/ethyl acetate=19/1 to 9/1) to 
obtain 23(S)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 
-23,26-lactone-1a,3-bistrimethylsilylether in an amount of 46 mg (yield 
50%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of 
methanol was added for dissolution. The solution was cooled by an 
ice-cooled bath, 50 mg of polymer-bonded pyridinium toluene-4-sulfonate 
was added, then the solution was stirred for 15 hours. The reaction 
solution was filtered by Celite, then the solvent was distilled off under 
reduced pressure to obtain a crude product in an amount of 110 mg. This 
was purified by a silica seppack (Waters, hexane/ethyl acetate=3/1 to 1/1) 
to obtain 23(S)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone in 
an amount of 12 mg (yield 40%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.37 (d, 1H, J=12 Hz), 6.22 (t, 1H, J=3 Hz), 6.00 (d, 1H, J=11 Hz), 5.62 
(t, 1H, J=3 Hz), 5.323 (d, 1H, J=1 Hz), 5.00 (s, 1H), 4.59 (t, 1H, J=7 
Hz), 4.43 to 4.54 (br, 1H), 4.22 to 4.24 (br, 1H), 2.99 to 3.11 (m, 1H), 
2.79 to 2.85 (m, 1H), 2.48 to 2.61 (m, 2H), 2.28 to 2.35 (m, 1H), 1.03 (d, 
3H, J=6 Hz), 0.56 (s, 3H) 
EXAMPLE 2-16 
Production of 23(R)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 -26,23-lactone 
##STR62## 
A 26 mg amount of triphenylphosphine was taken in a dried eggplant-shaped 
flask and deaerated. To this was further added 20 mg of 
tris(dibenzylideneacetone) dipalladium chloroform followed by further 
deaeration, then 3 ml of a mixed solvent of distilled 
toluene/diisopropylethylamine=1/1 was added under nitrogen and the 
solution was stirred at 50.degree. C. for 20 minutes. Next, a solution of 
70 mg of 
(5R)-5-{(2R)-2-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden-1-y 
l!propyl}-3-methylene-dehydro-2(3H)-furanon and 84 mg of 
(3S),(5R)-3,5-bis(trimethylsilyloxy)-1-octen-7-yne dissolved in 4 ml of a 
mixed solvent of distilled toluene/diisopropylethylamine=1/1 was added 
dropwise. This reaction solution was stirred at 100.degree. C. for 1.5 
hours, then was returned to room temperature. The reaction solution was 
poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous 
solution of potassium hydrogensulfate for extraction. The organic layer 
was washed with a saturated aqueous solution of sodium hydrogencarbonate 
and saturated saline, then was dried over anhydrous sodium sulfate. The 
desiccant was filtered out and the solvent was distilled off under reduced 
pressure to obtain a crude product in an amount of 190 mg. This was 
purified by a silica gel seppack (Waters, hexane/ethyl acetate=19/1 to 
9/1) to obtain 23(R)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 
-26,23-lactone-1a,3-bistrimethylsilylether in an amount of 50 mg (yield 
40%). This was placed in a 25 ml eggplant-shaped flask, then 5 ml of 
methanol was added to dissolve it. The solution was cooled by an 
ice-cooled bath, then 100 mg of pyridinium toluene-4-sulfonate bonded to a 
polymer was added, then the solution was stirred for 15 hours. The 
reaction solution was filtered by Celite, then the solvent was distilled 
off under reduced pressure to obtain a crude product in an amount of 110 
mg. This was purified by silica seppack (Waters, hexane/ethyl acetate =3/1 
to 1/1) to obtain 23(R)-1a-hydroxy-25,27-dehydro-vitamin D.sub.3 
-26,23-lactone in an amount of 14 mg (yield 43%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.37 (d, 1H, J=11 Hz), 6.225 (t, 1H, J=3 Hz), 6.00 (d, H, J=11 Hz), 5.62 
(t, 1H, J=2 Hz), 5-33 (t, 1H, J=2 Hz), 5.00 (s, 1H), 4.59 to 4.69 (m, 1H), 
4.41 to 4.45 (m, 1H), 4.21 to 4.25 (m, 1H), 3.01 to 3.10 (m, 1H), 2-79 to 
2.85 (m, 1H), 2.47 to 2.58 (m, 2H), 2.28 to 2.35 (m, 1H), 1.02 (d, 3H, J=6 
Hz), 0.58 (s, 3H) 
REFERENCE EXAMPLE 3-1 
Production of (2R)-2-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!propanol 
##STR63## 
A 10.78 g amount of (2R)-2-(1R, 
7aR)(4E)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!propanol dissolved in 
80 ml of pyridine was added to a 100 ml eggplant-shaped flask and the 
solution was stirred under ice-cooling. Thereafter, 6.57 ml of pivaloyl 
chloride was added, then the solution was stirred over night. 
To this reaction solution was added 150 ml of water. The solution was then 
extracted 3 times by 200 ml of ether. The organic layer was washed 2 times 
each by a saturated aqueous solution of potassium hydrogensulfate, a 
saturated aqueous solution of sodium bicarbonate, and saturated saline, 
then was dried over anhydrous magnesium sulfate. The desiccant was 
filtered out and the solvent was distilled off under reduced pressure to 
obtain a crude product in an amount of 14.7 g. This was placed in a 200 ml 
eggplant-shaped flask, 10.9 g of imidazole was added, 60 ml of dried 
dichloromethane was added, and the solution was stirred under ice-cooling. 
To this was added 10.2 ml of trimethylsilyl chloride, then the solution 
was stirred over night at room temperature. The reaction solution was 
poured in 300 ml of ethyl acetate and 100 ml of water for extraction. The 
organic layer was washed 2 times each by a saturated aqueous solution of 
potassium hydrogensulfate, a saturated aqueous solution of sodium 
bicarbonate, and saturated saline, then was dried over anhydrous magnesium 
sulfate. The desiccant was filtered out and the solvent was distilled off 
under reduced pressure to obtain a crude product in an amount of 18.11 g. 
A 17.2 g amount of t-butoxy potassium was placed in a 1-liter 
eggplant-shaped flask, then 440 ml of ether was added and the solution was 
stirred under ice-cooling. A 2.1 ml amount of water was added, then a 
solution of 8.11 g of the above residue dissolved in 120 ml of ether was 
added and the solution was stirred over night at room temperature. A 200 
ml amount of water was poured into the reaction solution for separation, 
then extraction was performed with 500 ml of ether. The organic layer was 
washed 2 times with saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 15.2 g. This was purified by a silica gel column (IR-60, 1 kg, 
hexane/ethyl acetate=19/1 to 6/1) to obtain (2R)-2-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!propanol in an 
amount of 12.6 g (yield 87%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
3.95 (d, 1H, J=3 Hz), 3.58 (m, 1H), 3.31 (m, 1H), 1.00 to 2.00 (m, 14H), 
0.96 (d, 3H, J=8 Hz), 0.85 (s, 3H), 0.03 (s, 9H) 
REFERENCE EXAMPLE 3-2 
Production of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!pro 
panal 
##STR64## 
A 427 mg amount of cellite, 37 mg of sodium acetate, and 444 mg of 
pyridinum chlorochromate were placed in a 50 ml eggplant-shaped flask, 
then 10 ml of dichloromethane was added and the solution stirred. 
Thereafter, a dichloromethane solution (3 ml) of 426 mg of (2R)-2-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!propanol was 
added, then the solution was stirred at room temperature for 3.5 hours. 
The reaction solution was filtered by Celite, then was concentrated and the 
obtained residue was purified by a silica gel column to obtain 
(2R)-2-(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!pr 
opanal in an amount of 254 mg (yield 60%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
9.56 (d, 1H J=3 Hz), 3.90 to 4.00 (m, 1H), 2.20 to 2.50 (m, 1H), 1.00 to 
2.00 (m, 12H), 0.92 (d, 3H, J=6.3 Hz), 0.91 (s, 3H), 0.05 (s, 9H) 
REFERENCE EXAMPLE 3-3 
Production of 
methyl(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1- 
yl!-2-pentenoate 
##STR65## 
A 3.27 g amount of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!pro 
panal and 11.9 g of methyl(triphenylphosphoranilidene)acetate were placed 
in a 200 ml eggplant-shaped flask, 70 ml of toluene was added, and the 
solution was stirred at 80.degree. C. over night. This was cooled to room 
temperature, then 100 ml of hexane was added, the precipitated deposit was 
filtered out, and the filtrate was concentrated under reduced pressure to 
obtain a crude product in an amount of 4.1 g. This was purified by a 
silica gel column (IR-60, 200 g, hexane/ethyl acetate=40/1) to obtain 
methyl(4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2-pentenoate 
in an amount of 3.82 g (yield 96%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.83 (dd, 1H, J=9.9 & 16 Hz), 5.73 (d, 1H, 16 Hz), 3.99 (brs, 1H), 3.72 (s, 
3H), 2.10 to 2.30 (m, 2H), 1.00 to 2.00 (m, 15H), 1.00 (d, 3H, J=6.6 Hz), 
0.92 (s, 3H), 0.05 (s, 9H) 
REFERENCE EXAMPLE 3-4 
Production of 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2- 
penten-1-ol 
##STR66## 
A 3.66 g amount of 
methyl(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1- 
yl!-2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml 
of hexane and 40 ml of toluene were then added to dissolve it. The 
solution was cooled to -95.degree. C., then 12.2 ml of diisobutylaluminum 
hydride was slowly added and the solution stirred at the same temperature 
for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, 
followed by stirring for 2 hours. The consumption of the material was 
confirmed by thin layer chromatography, then the excess reducing agent was 
broken down by methanol and a saturated aqueous solution of sodium sulfate 
and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution 
of ammonia chloride were added for separation. Extraction was performed 
from the aqueous layer by 100 ml of ethyl acetate, then the organic layer 
was washed with saturated saline and was dried by anhydrous magnesium 
sulfate. The desiccant was filtered out, then the filtrate was 
concentrated under reduced pressure to obtain a crude product in an amount 
of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 
to 4/1) to obtain (4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l!-2-penten-1-ol 
in an amount of 3.31 g (98%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.5 to 5.6 (m, 2H), 4.07 (brd, 2H), 3.99 (brs, 1H), 1.0 to 2.2 (m, 14H), 
1.00 (d, J=6.6 Hz, 3H), 0.90 (s, 3H), 0.05 (s, 9H) 
REFERENCE EXAMPLE 3-5 
Production of 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2- 
penten-1-al 
##STR67## 
A 1.34 g amount of 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2- 
penten-1-ol and 760 mg of N-methylmorpholine-N-oxide were placed in a 100 
ml eggplant-shaped flask, then were dissolved in 30 ml of acetone. 
Thereafter, RuCl.sub.2 (PPh.sub.3).sub.3 was added, then the solution was 
stirred at room temperature for 1.5 hours. 
To the reaction solution were added 50 ml of hexane and 1.5 g of Celite, 
the solution was stirred for 15 minutes, then was filtered and the solvent 
distilled off under reduced pressure. The residue was purified by a silica 
gel column (hexane/ethyl acetate=50/1 to 30/1) to obtain (4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2-penten-1-al 
in an amount of 0.854 g (yield 86%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
9.51 (d, J=7.9 Hz, 1H), 6.71 (dd, J=8.6 & 16 Hz, 1H), 6.04 (dd, J=7.9 & 16 
Hz, 1H), 4.01 (brs, 1H), 2.3 to 2.4 (m, 1H), 1.1 to 2.2 (m, 12H), 1.11 (d, 
J=6.6 Hz, 3H), 0.94 (s, 3H), 0.05 (s, 9H) 
REFERENCE EXAMPLE 3-6 
Production of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1, 3-dioxolan-4-one 
##STR68## 
A 15 ml amount of tetrahydrofuran and 910 .mu.l of diisopropylamine were 
placed in a 100 ml eggplant-shaped flask, then the solution was cooled to 
-78.degree. C. Thereafter, 2.52 ml of n-BuLi was added, then the solution 
was stirred at the same temperature for 15 minutes, was stirred at 
0.degree. C. for 30 minutes, then was again cooled to -78.degree. C. and 
was stirred for 15 minutes. To this was added a tetrahydrofuran solution 
(6 ml) of 627 mg of (5S,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-one. The 
solution was stirred at the same temperature for 15 minutes, then a 
tetrahydrofuran solution (8 ml) of 854 mg of (4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-2-penten-1-al 
was added and the solution was reacted at -78.degree. C. for 30 minutes. 
To the reaction solution were added a saturated aqueous solution of 
ammonium chloride and ether for separation, then extraction was performed 
from the aqueous layer by ethyl acetate. The organic layer was washed with 
saturated saline, then was dried over anhydrous magnesium sulfate and 
filtered, then the solvent was distilled off under reduced pressure. The 
residue was purified by a silica gel column (hexane/ethyl acetate=15/1 to 
4/1) to obtain 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-1-hydroxy-2-penten-1-yl}-5-methyl-2t-butyl-1,3-dioxolan-4-one in 
an amount of 1.24 g (yield 96%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.0 to 5.7 (m, 3H), 4.1 to 4.2 (m, 1H), 3.99 (brs, H), 1.0 to 2.2 (m, 17H), 
0.88 to 1.0 (m, 15H), 0.04 (s, 
REFERENCE EXAMPLE 3-7 
Production of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxola 
n-4-one 
##STR69## 
A 1.24 g amount of (5R,2S)-5-{(4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y 
l!-1-hydroxy-2-penten-1-yl}-5-methyl-2-t-butyl-1, 3-dioxolan-4-one and 1.0 
g of 4-dimethylaminopyridine were dissolved in 15 ml of dichloromethane in 
a 50 ml eggplant-shaped flask. The solution was stirred under ice-cooling 
while slowly adding 315 .mu.l of methyl chloroformate, then was stirred at 
the same temperature for 15 minutes and at room temperature for 1.5 hours. 
A 100 ml amount of ethyl acetate and 30 ml of water were added for 
separation, and extraction was performed from the aqueous layer by 50 ml 
of ethyl acetate. The organic layer was washed by a saturated aqueous 
solution of potassium hydrogensulfate, a saturated aqueous solution of 
sodium hydrogencarbonate, and saturated saline and was dried over 
anhydrous magnesium sulfate. The desiccant was filtered out, then the 
filtrate was concentrated under reduced pressure to obtain a crude product 
in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl 
acetate=19/1 to 9/1) to obtain 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxola 
n-4-one in an amount of 1.388 g (98%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.3 to 5.9 (m, 2H), 5.25 (s, 1H), 5.11 (d, J=7 Hz, 1H), 3.99 (brs, 1H), 
3.78 & 3.75 (s, 3H), 1.0 to 2.2 (m, 16H), 0.8 to 1.0 (m, 15H), 0.05 (s, 
9H) 
EXAMPLE 3-1 
Production of (5R,2S)-5-{(4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-t-yl!pentyl}-5-methy 
l-2-t-butyl-l,3-dioxolan-4-one 
##STR70## 
Pd(OAc).sub.2 was placed in a 100 ml eggplant-shaped flask and dissolved in 
50 ml of tetrahydrofuran. Further, 0.54 ml of n-Bu.sub.3 P was added, the 
solution stirred at room temperature for 15 minutes, 681 mg of ammonium 
formate was added, a tetrahydrofuran solution (10 ml) of 1.38 g of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!-1-methoxycarbonyloxy-2-penten-1-yl}-5-methyl-2-t-butyl-1,3-dioxola 
n-4-one was added, and the solution was reacted at 40.degree. C. over 
night. 
To the reaction solution were added 50 ml of hexane and 50 ml of ether 50 
ml, the solution was filtered, then the solvent was distilled off under 
reduced pressure to obtain 920.8 mg of any oily substance. This was 
subjected to the following reaction divided into two times without 
purification. A 398 mg amount of the oily substance was dissolved in ethyl 
acetate, 10% Pd/C was placed in Microspatel Cup, then this was stirred 
over night under a flow of hydrogen. The solution was filtered, then 
concentrated to obtain a crude product in an amount of 0.43 g. A 520 mg 
amount of the remaining oily substance was treated in the same way to 
obtain 0.494 g. These were combined and purified to obtain 0.867 mg of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one (yield 73%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.19 (s, 1H), 3.99 (brs, 1H), 1.41 (s, 3H), 1.0 to 2.0 (m, 19H), 0.96 (s, 
9H), 0.88 (d-like, 3H), 0.87 (s, 3H), 0.05 (s, 9H) 
EXAMPLE 3-2 
Production of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one 
##STR71## 
A 913 mg amount of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-ind 
en-1-yl!pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one was placed in a 100 
ml eggplant-shaped flask and dissolved in 10 ml of tetrahydrofuran. A 
tetrahydrofuran solution (1 M, 2.5 ml) of tetrabutylammonium fluoride was 
added under ice cooling, then the solution was stirred at the same 
temperature for 15 minutes, was returned to room temperature, then was 
stirred for 1 hour. Thereafter, 100 ml of ether and 20 ml of water for 
separation were added, extraction was performed from the aqueous layer by 
ether, then the organic layer was washed with saline and then was dried 
over anhydrous magnesium sulfate. Further, this was concentrated, then 
purified by a silica column (hexane/ethyl acetate=9/1 to 6/1) to obtain 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 764 mg (99%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.19 (s, 1H), 4.08 (brs, 1H), 1.44 (s, 3H), 1.0 to 2.1 (m, 20H), 0.96 (s, 
9H), 0.93 (s, 3H), 0.90 (d, 3H, J=6.6 Hz) 
EXAMPLE 3-3 
Production of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-5-methyl-2-t-butyl-1,3-dioxolan-4-one 
##STR72## 
A 384 mg amount of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl!pe 
ntyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one and 74 mg of RuH.sub.2 
(PPh.sub.3).sub.4 were placed in a 100 ml two-necked flask and dissolved 
in 20 ml of toluene. Thereafter, 8 ml of methylallyl carbonate was added, 
then the solution was stirred at 100.degree. C. over night. 
The reaction solution was allowed to cool, then the precipitate was 
filtered out, the solvent was distilled off under reduced pressure, and 
the residue was purified by a silica gel column (hexane/ethyl acetate=19/1 
to 10/1) to obtain 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 370 mg (yield 96%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.19 (s, 1H), 1.44 (s, 3H), 1.0 to 2.0 (m, 19H), 0.96 (brs, 12H), 0.64 (s, 
3H) 
EXAMPLE 3-4 
Production of 
(5R,2S)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one 
##STR73## 
A 5.19 g amount of PPh.sub.3 CH2Br.cndot.Br was placed in a 100 ml 
eggplant-shaped flask, was suspended in 30 ml of tetrahydrofuran, and 
stirred at -78.degree. C. Thereafter, 11.3 ml of TMS.sub.2 NNa (1 M-THF) 
was added, then the solution was stirred at room temperature for 1 hour 
and, then, was further added a tetrahydrofuran solution (10 ml) of 449 mg 
of 
(5R,2S)-5-{(4R)-4-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!pentyl 
}-5-methyl-2-t-butyl-1,3-dioxolan-4-one, then the solution was returned to 
room temperature and stirred for 30 minutes. To the reaction solution was 
added ether, the solution was stirred at room temperature, then the 
precipitate was filtered out and the solvent was distilled off under 
reduced pressure. The result was purified by a silica gel column 
(hexane/ethyl acetate=100/0 to 100/1 to 4/1) to obtain (5R, 
2S)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 242 mg 
(yield 45%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.65 (s, 1H), 5.19 (s, 1H), 2.80 to 3.00 (m, 1H), 1.44 (s, 3H), 1.0 to 2.1 
(m, 18H), 0.96 (s, 9H), 0.93 (d, 3H J=6 Hz), 0.56 (s, 3H) 
EXAMPLE 3-5 
Production of 
25,26,27-trinol-1a-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-o 
n-5-yl}-vitamin D.sub.3 -1a, 3-bistrimethylsilylether 
##STR74## 
A 17 mg amount of Pd.sub.2 (dibenzylideneacetone).sub.3 .cndot.CHCl.sub.3 
and 51.7 mg of PPh.sub.3 were placed in a 100 ml two-neck eggplant-shaped 
flask and dissolved in 9 ml of toluene and 9 ml of diisopropylethylamine. 
Thereafter, 141.5 mg of 
(5R,2S)-5-{(4R)-4-(1R,7aR)(4E)-octahydro-4-bromomethylene-7a-methyl-1H-in 
den-1-yl!pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one dissolved in 2 ml of 
toluene and 2 ml of diisopropylethylamine was added, then the solution was 
heated and refluxed for 1.5 hours. The solution was allowed to cool, then 
20 ml of hexane was added, the precipitate filtered out, and the filtrate 
was washed with a saturated solution of potassium hydrogensulfate and 
saturated saline, then was dried over anhydrous magnesium sulfate, 
filtered and concentrated. The obtained residue was purified by a silica 
gel column (hexane/ethyl acetate=100/1 to 30/1) to obtain 
25,26,27-trinol-1a-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-o 
n-5-yl}-vitamin D.sub.3 -1a,3-bistrimethylsilylether in an amount of 118.5 
mg (yield 58%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.27 (d, 1H, J=12 Hz), 6.04 (d, 1H, J=12 Hz), 5.19 (brs, 2H), 4.90 (brs, 
1H), 4.30 to 4.40 (m, 1H), 4.15 to 4.25 (m, 1H), 1.0 to 2.9 (m, 23H), 1.43 
(s, 3H), 0.96 (s, 9H), 0.93 (d, 3H, J=6 Hz), 0.54 (s, 3H), 0.12 (s, 18H) 
EXAMPLE 3-6 
Production of 
25,26,27-trinol-1a-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-o 
n-5-yl}vitamin D.sub.3 
##STR75## 
A 112 mg amount of 25,26,27-trinol-1a-hydroxy-24-{(5R, 
2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-on-5-yl}-vitamin D.sub.3 
-1a,3-bistrimethylsilylether was placed in a 50 ml eggplant-shaped flask 
and dissolved in 30 ml of methanol, then 50 mg of pyridinium-para-toluene 
sulfonate was added and the solution stirred at room temperature for 2 
hours. The reaction solution was filtered, the filtrate was concentrated, 
and the obtained residue was purified by a silica gel column (hexane/ethyl 
acetate=1/1) to obtain 
25,26,27-trinol-1a-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-o 
n-5-yl}-vitamin D3 in an amount of 40.2 mg (yield 46%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.38 (d, 1H, J=11 Hz), 6.01 (d, 1H, J=11 Hz), 5.32 (s, 1H), 5.19 (s, 1H), 
5.00 (s, 1H), 4.40 to 4.50 (m, 1H), 4.20 to 4.30 (m, 1H), 1.0 to 2.9 (m, 
25H), 1.44 (s, 3H), 0.96 (s, 9H), 0.93 (d, 3H, J=6 Hz), 0.54 (s, 3H) 
EXAMPLE 3-7 
Production of 1a,25-dihydroxyvitamin D.sub.3 -26-carboxylic acid 
methylester 
##STR76## 
A 40 mg amount of 
25,26,27-trinol-1a-hydroxy-24-{(5R,2S)-5-methyl-2-t-butyl-1,3-dioxolan-4-o 
n-5-yl}-vitamin D.sub.3 was placed in a 50 ml eggplant-shaped flask and 
dissolved in 5 ml of methanol, then 4 N lithium hydroxide was added and 
the solution was stirred at room temperature for 1 hour. The reaction 
solution was neutralized, tetrahydrofuran was added, the solution was 
washed five times by saturated saline, then was dried over anhydrous 
magnesium sulfate. The solution was filtered and concentrated, the 
obtained residue was dissolved in benzene/methanol (4/1), 0.8 ml of a 
hexane solution (about 10%) of trimethylsilyldiazomethane was added, and 
the solution was stirred at room temperature for 1 hour. The excess 
reagent was broken down by formic acid, then the solution was 
concentrated. The obtained residue was purified by a silica gel column 
(hexane/ethyl acetate=2/3 to 1/3) to obtain 1a,25-dihydroxyvitamin D.sub.3 
-26-carboxylic acid methylester in an amount of 24.4 mg (yield 68%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.38 (d, 1H, J=11 Hz), 6.01 (d, 1H, J=11 Hz), 5.33 (s, 1H), 5.00 (s, 1H), 
4.35 to 4.45 (m, 1H), 4.20 to 4.30 (m, 1H), 3.79 (s, 3H), 1.0 to 3.1 (m, 
26H), 1.40 (s, 3H), 0.90 (d, 3H, J=6 Hz), 0.53 (s, 3H) 
EXAMPLE 4-1 
Production of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opanol 
##STR77## 
A 10.78 g amount of the compound (4-3), (2R)-2-(1R, 
7aR)(4E)-octahydro-4-hydroxy-7a-methyl-1-H-inden-1-yl!-propanol was 
dissolved in 80 ml of pyridine in a 100 ml eggplant-shaped flask, then was 
stirred under ice cooling. To this was added 6.57 ml of pivaloyl chloride, 
then the solution was stirred over night. 
Into the reaction solution was placed 150 ml of water, then extraction was 
performed 3 times by 200 ml of ether. The organic layer was washed 2 times 
each with a saturated aqueous solution of potassium hydrogensulfate, 
saturated aqueous solution of sodium bicarbonate, and saturated saline, 
was dried over anhydrous magnesium sulfate, the desiccant was filtered 
out, and the solvent was distilled off under reduced pressure to obtain a 
crude product in an amount of 14.7 g. This was placed in a 200 ml 
eggplant-shaped flask, 10.9 g of imidazole was added, then 60 ml of dried 
dichloromethane was further added and the solution stirred under 
ice-cooling. To this was added 10.2 ml of trimethylsilyl chloride and the 
solution was stirred at room temperature over night. The reaction solution 
was poured into 300 ml of methyl acetate and 100 ml of water for 
extraction. The organic layer was washed two times by each of a saturated 
aqueous solution of potassium hydrogensulfate, saturated aqueous solution 
of sodium bicarbonate, and saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 18.11 g. A 17.2 g amount of t-butoxy potassium was placed in a 
1-liter eggplant-shaped flask, 440 ml of ether was added, and the solution 
was stirred under ice-cooling. A 2.1 ml amount of water was added, then a 
solution comprised of 18.11 g of the above residue dissolved in 120 ml of 
ether was added and the solution was stirred at room temperature over 
night. A 200 ml amount of water was poured into the reaction solution for 
separation, then extraction was performed by 500 ml of ether. The organic 
layer was washed 2 times with saturated saline, then was dried over 
anhydrous magnesium sulfate. The desiccant was filtered out and the 
solvent was distilled off under reduced pressure to obtain a crude product 
in an amount of 15.2 g. This was purified by a silica gel column (IR-60, 1 
kg, hexane/ethyl acetate =19/1 to 6/1) to obtain the desired product 
(4-4), (2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1 
-yl!-propanol in an amount of 12.6 g (yield 87%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
3.95 (d, 1H, J=3 Hz), 3.58 (m, 1H), 3.31 (m, 1H), 1.00 to 2.00 (m, 14H), 
0.965 (d, 3H, J=8 Hz), 0.85 (s, 3H), 0.03 (s, 9H) 
EXAMPLE 4-2 
Production of 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opanal 
##STR78## 
A 427 amount of Celite, 37 mg of sodium acetate, and 444 mg of pyridinium 
chlorochromate were placed in a 50 ml eggplant-shaped flask, then 10 ml of 
dichloromethane was added and the solution stirred. Thereafter, a 
dichloromethane solution (3 ml) of 426 mg of the compound (4-4), that is, 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opanol was added and the solution stirred at room temperature for 3.5 
hours. 
The reaction solution was filtered by Celite, then concentrated and the 
obtained residue was purified by a silica gel column to obtain the desired 
product (4-5), 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opanol in an amount of 254 mg (yield 60%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
9.56 (d, 1H, J=3 Hz), 3.90 to 4.00 (m, 1H), 2.20 to 2.50 (m, 1H), 1.00 to 
2.00 (m, 12H), 0.92 (d, 3H, J=6.3 Hz), 0.91 (s, 3H), 0.05 (s, 9H) 
EXAMPLE 4-3 
Production of 
methyl(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1- 
yl!-heptanoate 
##STR79## 
A 3.27 g amount of the compound (4-5), 
(2R)-2-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pr 
opanal and 11.9 g of methyl(triphenylphosphoranilidene)acetate were placed 
in a 200 ml eggplant-shaped flask, 70 ml of toluene was added, and the 
solution was stirred at 80.degree. C. over night. The solution was cooled 
to room temperature, then 100 ml of hexane was added, the precipitated 
deposit was filtered out, and the filtrate was concentrated under reduced 
pressure to obtain a crude product in an amount of 4.1 g. This was 
purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate=40/1 
up) to obtain an oily substance in an amount of 3.82 g. This was dissolved 
in 200 ml of ethanol, then 0.5 g of 10% Pd/C was added, and the solution 
was stirred under a flow of hydrogen at room temperature over night. The 
Pd/C was removed by Celite filtration, then the result was concentrated to 
obtain 3.66 g of a crude product. This was purified by a silica gel column 
(hexane/ethyl acetate =20/1) to obtain the desired product methyl(4-6), 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-he 
ptanoate in an amount of 2.66 g yield 67%, from compound (4-5)!. 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
4.10 (brs, 1H), 3.66 (s, 3H), 2.10 to 2.30 (m, 2H), 1.00 to 2.00 (m, 15H), 
0.93 (s, 3H), 0.90 (d, 3H, J=6.6 Hz), 0.05 (s, 9H) 
EXAMPLE 4-4 
Production of (4R)-4-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-p 
##STR80## 
A 3.79 g amount of the compound (4-6), 
methyl(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1- 
yl!-heptanoate was taken in a 300 ml eggplant-shaped flask, 100 ml of 
hexane was added, and the solution was stirred and cooled to -95.degree. 
C. Thereafter 12.3 ml of a hexane solution (0.93 mol/liter) of 
diisobutylaluminum hydride was added and the solution stirred for 1 hour. 
A 100 ml amount of methanol was used to break down the excess reducing 
agent, then 30 ml of a saturated aqueous solution of ammonia chloride and 
50 ml of ether were added and the solution was stirred at room temperature 
for 1 hour. The insolubles were removed by filtration by Celite, then the 
solution was separated and the aqueous layer was extracted by ether. The 
organic layer was washed two times by saturated saline in an amount of 50 
ml, then was dried over anhydrous magnesium sulfate. The desiccant was 
filtered out, then the solvent was distilled off under reduced pressure to 
obtain a crude product in an amount of 4.07 g. This was purified by a 
silica gel column (Merck gel: 300 g, hexane/ethyl acetate=50/1) to obtain 
the desired product (4-7), 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pe 
ntanal in an amount of 3.17 g (yield 92%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
9.77 (t, 1H, J=2 Hz), 3.99 (d-like, 1H), 2.20 to 2.50 (m, 2H), 0.90 to 2.00 
(m, 15H), 0.89 (d, 3H, J=7.3 Hz), 0.88 (s, 3H), 0.05 (s, 9H) 
EXAMPLE 4-5 
Production of 
(7R)-2-acetoxymethyl-7-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1 
H- 
##STR81## 
A 1.72 g amount of the compound (4-7), 
(4R)-4-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-pe 
ntanal and 1.10 g of 2-(trimethylsilylmethyl)-2-propenyl acetate were taken 
in a 200 ml eggplant-shaped flask, then 30 ml of dichloromethane was added 
and the solution stirred at -78.degree. C. To this was added 0.86 ml of 
BF.cndot.Et.sub.2 O, then the solution stirred at -78.degree. C. for 1 
hour. Further, 3 ml of triethylamine was added to stop the reaction, then 
the solvent was distilled off under reduced pressure. The obtained residue 
was purified by a silica gel column (IR-60, 150 g, hexane/ethyl 
acetate=50/1 to 9/1) to obtain the desired product (4-8), 
(7R)-2-acetoxymethyl-7-(1R,7aR)-octahydro-4-trimethylsilyloxy-7in an 
amount of 1.32 g (yield 57%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.16 (s, 1H), 5.06 (s, 2H), 4.56 (s, 2H), 3.99 (d-like, 1H), 3.60 to 3.70 
(m, 1H), 2.10 (s, 3H), 1.00 to 2.30 (m, 20H), 0.91 (d, 3H, J=2.3 Hz), 0.88 
(s, 3H), 0.05 (s, 9H) 
EXAMPLE 4-6 
Production of 
(7R)-2-acetoxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)-octahydro-4-t 
rimethyl 
##STR82## 
A 2.18 g amount of the compound (4-8), 
(7R)-2-acetoxymethyl-7-(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1 
H-inden-1-yl and 1.06 g of imidazole were placed in a 100 ml 
eggplant-shaped flask and dissolved in 30 ml of dichloromethane, then the 
solution stirred under ice-cooling. Thereafter, 1.16 g of 
t-butyldimethylsilyl chloride was added, then the solution was returned to 
room temperature and stirred 30 over night. To the reaction solution were 
added 50 ml of ether and 20 ml of water for separation, then extraction 
was performed from the aqueous layer by ether. The organic layer was 
washed by saturated saline and was dried over anhydrous magnesium sulfate. 
After filtration by Celite, the solvent was distilled off under reduced 
pressure. The obtained residue was purified by a silica gel column (IR-60, 
80 g, hexane/ethyl acetate=3/1, 1/1) to obtain the desired product (4-9), 
(7R)-2-acetoxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7in an amount of 
2.59 g (yield 93%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.09 (s, 1H), 4.96 (s, 2H), 4.54 (s, 2H), 3.98 (brs, 1H), 3.60 to 3.80 (m, 
1H), 2.09 (s, 3H), 1.00 to 2.30 (m, 19H), 0.80 to 0.90 (m, 15H), 0.00 to 
0.10 (m, 15H) 
EXAMPLE 4-7 
Production of 
(7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)-octahydro-4-t 
rimethyl 
##STR83## 
A 2.59 g amount of the compound (4-9), 
(7R)-2-acetoxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)-octahyde-4-tr 
imethylsilyloxy-7a-methyl-1H-inden-1yl!-octene was placed in a 100 ml 
eggplant-shaped flask and dissolved in 20 ml of tetrahydrofuran and 5 ml 
of methanol, then the solution was stirred under ice-cooling. Thereafter, 
2 ml of a 4 N aqueous solution of lithium hydroxide was added, then the 
solution was stirred under ice cooling for 1 hour. The reaction solution 
was placed in 100 ml of ether and 20 ml of water and was extracted from 
the aqueous layer by ether. The organic layer was washed by a saturated 
aqueous solution of potassium hydrogensulfate, a saturated aqueous 
solution of sodium bicarbonate, and saturated saline and was dried over 
anhydrous magnesium sulfate. After filtration by Celite, the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 2.39. This was purified by a silica gel column (IR-60, 80 g, 
hexane/ethyl acetate=19/1, 9/1) to obtain the desired product (4-10), 
(7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octene in an 
amount of 2.15 g (yield 90%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
5.10 (s, 1H), 4.89 (s, 2H), 4.12 (d-like, 2H), 3.99 (brs, 1H), 3.70 to 3.80 
(m, 1H), 0.90 to 2.50 (m, 20H), 0.80 to 0.95 (m, 15H), 0.00 to 0.10 (m, 
15H) 
EXAMPLE 4-8 
Production of (7R,2R)-1, 
2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octane 
##STR84## 
A 20 ml amount of dichloromethane was placed in a 200 ml eggplant-shaped 
flask, 1.36 ml of titanium tetraisopropoxide was added, then the solution 
was cooled to -20.degree. C. and stirred. Thereafter, 1.05 g of 
D(-)-diethyl tartrate dissolved in 5 ml of dichloromethane and the 
solution stirred at -25.degree. C. for 20 minutes was placed and then, 
2.14 g of the compound (4-10), 
(7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octene, 
dissolved in 10 ml of dichloromethane, was added, then the solution was 
stirred for 30 minutes. Further, 4.3 ml of t-butyldiperoxide was added and 
the solution was stirred at the same temperature for 30 minutes. The 
reaction solution was poured into 20 ml of a 10% aqueous solution of 
tartaric acid, the solution was stirred at that temperature for 30 minutes 
and at room temperature for 1 hour, then separation was performed and 
extraction performed from the aqueous layer by dichloromethane. The 
organic layer was washed by a 10% aqueous solution of tartaric acid and 
saturated saline and was dried over anhydrous magnesium sulfate. After 
filtration by Celite, the solvent was distilled off under reduced 
pressure, the obtained residue was dissolved in 50 ml of ether, 18 ml of 1 
N sodium hydroxide was added, then the solution was stirred under ice 
cooling for 1 hour. After separation, extraction was performed from the 
aqueous layer by ether. The organic layer was washed with saturated 
saline, then was dried over anhydrous magnesium sulfate, then filtered by 
Celite. The filtrate was concentrated under reduced pressure to obtain 
2.40 g of a crude product. This was purified by a silica gel column 
(IR-60, 200 g, hexane/ethyl acetate=15/1 to 4/1) to obtain the desired 
product (4-11), (7R, 
2R)-1,2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)-octa 
hydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octane in an amount of 
2.08 g (yield 94%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
3.99 (d-like, 1H), 3.50 to 3.80 (m, 3H), 2.50 to 2.90 (m, 2H), 1.00 to 2.00 
(m, 20H), 0.80 to 1.00 (m, 15H), 0.00 to 0.10 (m, 15H) 
EXAMPLE 4-9 
Production of 
(7R,2R)-2-hydroxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)- 
octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octane 
##STR85## 
A 2.08 g amount of the compound (4-11), (7R,2R)-1, 
2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1,7aR)-octahydro-4 
-trimethylsilyloxy-7a-methyl was placed in a 200 ml eggplant-shaped flask, 
50 ml of ether was added, and the solution was stirred under ice-cooling. 
Thereafter, 380 mg of lithium aluminum hydride was added, then the 
solution was stirred under ice cooling for 15 minutes, at room temperature 
for 15 minutes, then was heated and refluxed for 2 hours. The solution was 
allowed to cool, then the excess reducing agent was broken down by a 
saturated aqueous solution of mirabilite, 100 ml of ethyl acetate was 
added, and the solution was stirred for 30 minutes. This solution was 
dried over anhydrous magnesium sulfate and filtered by cellite, then the 
solvent was distilled off under reduced pressure to obtain a crude product 
in an amount of 1.98 g. This was purified by a silica gel column (IR-60, 
200 g, hexane/ethyl acetate=9/1 to 1/1) to obtain the desired product 
(4-12), 
(7R,2R)-2-hydroxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(R, 
7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octane in an 
amount of 0.84 g (yield 54%). 
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
3.99 (d-like, 1H), 3.75 to 3.85 (m, 1H), 3.62 (d, 1H J=11.2 Hz), 3.44 (d, 
1H, J=12.4 Hz), 0.90 to 2.10 (m, 20H), 1.16 (s, 3H), 0.80 to 0.90 (s, 6H), 
0.05 (s, 9H) 
EXAMPLE 4-10 
Production of (3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inde 
(3H)-furanon and 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1(3H)-furanon 
##STR86## 
A 1.06 g amount of platinum oxide was placed in a 500 ml three-necked flask 
and suspended in 100 ml of water, and the solution was stirred over night 
in a hydrogen atmosphere. The atmosphere was returned to nitrogen, then 
1.03 g of the compound (4-12), 
(7R,2R)-2-hydroxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-(1R,7aR)- 
octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl!-octane and 30 mg of 
sodium laurate dissolved in 100 ml of acetone was added, and the solution 
was heated and stirred under an oxygen atmosphere for 3 days at 50.degree. 
C. After being allowed to cool, the reaction solution was filtered by 
Celite, the filtrate was concentrated under reduced pressure, extraction 
was performed from the residue by ethyl acetate, and the organic layer was 
washed with saturated saline, then was dried over anhydrous magnesium 
sulfate. The solution was filtered by Celite, then the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 1.05 g. This was purified by a silica gel column (IR-60, 200 g, 
hexane/ethyl acetate=3/1 to 1/3) to obtain the desired product (4-13), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-b 
(3H)-furanon in an amount of 369 mg (yield 44%) and (4-13'), 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon in an amount of 350 mg (yield 41%). 
Compound (4-13) .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
4.50 to 4.60 (m, 1H), 1.20 to 2.60 (m, 20H), 1.52 (s, 3H), 0.97 (d, 3H, 
J=5.6 Hz), 0.65 (s, 3H) 
Compound (4-13') .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
4.20 to 4.40 (m, 1H), 1.20 to 2.60 (m, 20H), 1.49 (s, 3H), 0.98 (d, 3H, 
J=5.9 Hz), 0.65 (s, 3H) 
EXAMPLE 4-11 
Production of 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon 
##STR87## 
A 383 mg amount of the compound (4-13), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl 
}-3-methyl-3-hydroxy-2(3H)-furanon and 250 mg of imidazole were placed in a 
50 ml eggplant-shaped flask. Next, 10 ml of dried dichloromethane was 
added and the solution stirred. Under ice cooling, 0.23 ml of 
trimethylsilyl chloride was added, the solution was stirred at the same 
temperature for 60 minutes, then the reaction solution was poured into 50 
ml of ether and 30 ml of water for extraction. The organic layer was 
washed 2 times with saturated saline, then was dried over anhydrous 
magnesium sulfate. The desiccant was filtered out and the solvent was 
distilled off under reduced pressure to obtain a crude product in an 
amount of 0.64 g. This was purified by a silica gel column (IR-60, 80 g 
hexane/ethyl acetate=9/1, 4/1) to obtain the desired product (4-14), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-(3H)-furanon in an 
amount of 423 mg (yield 90%). 
##STR88## 
A 301 mg amount of the compound (4-13'), (3R, 
5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-butyl}- 
(3H)-furanon was treated in the same way to obtain the desired product 
(4-14'), 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1(3H)-furanon in an 
amount of 358 mg (yield 75%). 
Compound (4-14) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 4.50 to 4.60 (m, 
1H), 1.20 to 2.50 (m, 21H), 1.48 (s, 3H), 0.97 (d, 3H, J=5.9 Hz), 0.64 (s, 
3H), 0.16 (s, 9H) 
Compound (4-14') .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
4.20 to 4.35 (m, 1H), 1.10 to 2.50 (m, 21H), 1.48 (s, 3H), 0.98 (d, 3H, 
J=5.9 Hz), 0.64 (s, 3H), 0.19 (s, 9H) 
EXAMPLE 4-12 
Production of 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-(3H)-fura 
non 
##STR89## 
A 1.03 g amount of bromomethylenetriphenylphosphonium bromide was taken in 
a 50 ml eggplant-shaped flask, 7 ml of dried tetrahydrofuran was added, 
and the solution was stirred and cooled by a -65.degree. C. bath. Next, 
2.35 ml of a 1 M solution of sodium bistrimethylsilylamide in 
tetrahydrofuran was added dropwise and the solution stirred at the same 
temperature for 10 minutes and at room temperature for 30 minutes. After 
cooling again to -65.degree. C., 2 ml of a tetrahydrofuran solution of 186 
mg of the compound (4-14), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-meth (3H)-furanon was 
dropwise added thereto. The cooling bath was removed, the solution was 
stirred at room temperature for 30 minutes, then hexane was added to the 
reaction solution and the solution stirred. The precipitate was filtered 
out, the solvent was distilled off under reduced pressure, and the 
resultant residue was purified by a silica gel column (IR-60, 200 g, 
hexane/ethyl acetate=40/1 to 19/1) to obtain the desired product (4-15), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1 (3H)-furanon in an amount of 78 mg (yield 35%). 
##STR90## 
A 169 mg amount of the compound (4-14'), 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-oxo-7a-methyl-1H-inden-1-yl!-b 
(3H)-furanon was treated in the same way to obtain the desired product 
(4-15'), 
(3R,5S)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-(3H)-furanon in an 
amount of 103 mg (yield 51%). 
Compound (4-15) .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.65 (s, 1H), 4.40 to 4.50 (m, 1H), 2.80 to 2.90 (m, 1H), 1.20 to 2.40 (m, 
21H), 1.48 (s, 3H), 0.94 (d, 3H J=6.4 Hz), 0.57 (s, 3H), 0.16 (s, 9H) 
Compound (4-15') .sup.1 H-NMR (CD.sub.3 Cl, .delta. ppm) 
5.65 (s, 1H), 4.20 to 4.40 (m, 1H), 2.80 to 2.90 (m, 1H), 1.00 to 2.40 (m, 
21H), 1.48 (s, 3H), 0.95 (d, 3H J=6.3 Hz), 0.57 (s, 3H), 0.19 (s, 9H) 
REFERENCE EXAMPLE 4-1 
Production of 
(23R,25R)-22-homo-1.alpha.-hydroxy-25-trimethylsilyloxy-vitamin D.sub.3 
-26,23-1actone-1.alpha.,3-bis-t-butyldimethylsilylether 
##STR91## 
A 51.3 mg amount of triphenylphosphine was taken in a dried eggplant-shaped 
flask, then deaerated. Thereafter, 16.9 mg of tris(dibenzylideneacetone) 
dipalladium chloroform was added, followed by further deaeration, then 6.0 
ml of a mixed solvent of distilled toluene/diisopropylethylamine=1/1 was 
added under a nitrogen atmosphere and the solution stirred at room 
temperature for 20 minutes. Next, 77 mg of the compound (4-15), 
(3R,5R)-5-{(3R)-3-(1R,7aR)-octahydro-4-bromomethylene-7a-methyl-1H-inden- 
1-yl!-butyl}-3-methyl-3-trimethylsilyloxy-2(3H)-furanon and 72 mg of the 
compound (4-16), (3S,5R)-bis(t-butyldimethylsilyloxy)-1-octen-7-yne were 
dissolved in 2 ml of a mixed solvent of distilled 
toluene/diisopropylethylamine=1/1 and added dropwise into the above 
reaction solution. The solution was heated and refluxed for 1.5 hours, 
then was returned to room temperature, then the reaction solution was 
poured into 50 ml of ethyl acetate and 10 ml of a saturated aqueous 
solution of potassium hydrogensulfate for extraction. The organic layer 
was washed with a saturated aqueous solution of sodium hydrogencarbonate 
and saturated saline, then was dried over anhydrous magnesium sulfate. The 
desiccant was filtered out and the solvent was distilled off under reduced 
pressure to obtain a crude product in an amount of 200 mg. This was 
purified by a silica gel column (Merck gel, 200 g, hexane/ethyl 
acetate=100/1 to 20/1) to obtain the desired product (4-17), 
(23R,25R)-22-homo-1.alpha.-hydroxy-25-trimethylsilyloxy-vitamin D.sub.3 
-26,23-1actone-1.alpha.,3-bis-t-butyldimethylsilylether in an amount of 
86.6 mg (yield 70%). 
##STR92## 
A 65 mg amount of the compound (4-15'), (3R,5S)-5{(3R)-3-(1R,7aR)-octah 
(3H)-furanon was treated in the same way to obtain the desired product 
(4-17'), (23R,25R)-22-homo-1.alpha.-hydroxy-25-trimethylsilyloxy-vitamin 
D.sub.3 -26,23-1actone-1.alpha.,3-bis-t-butyldimethylsilylether in an 
amount of 78 mg (yield 
Compound (4-17) .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.22 (d, J=11.8 Hz), 6.00 (d, J=11.2 Hz), 5.18 (brs, 1H), 4.86 (brs, 1H), 
4.40 to 4.50 (m, 1H), 4.30 to 4.40 (m, 1H), 4.10 to 4.20 (m, 1H), 1-10 to 
3.00 (m, 23H), 1.48 (s, 3H), 0.80 to 1.00 (m, 21H), 0.53 (s, 3H), 0.16 (s, 
12H), 0.06 (s, 9H) 
Compound (4-17') .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.23 (d-like, 1H), 6.00 (d-like, 1H), 5.18 (brs, 1H), 4.87 (brs, 1H), 4.40 
to 4.50 (m, 1H), 4.15 to 4.40 (m, 2H), 1.00 to 2.90 (m, 23H), 1.48 (s, 
3H), 0.60 to 0.80 (m, 21H), 0.53 (s, 3H), 0.19 (s, 12H), 0.11 (s, 9H) 
REFERENCE EXAMPLE 4-2 
Production of (23R,25R)-22-homo-1.alpha.,25-dihydroxy-vitamin D.sub.3 
-26,23-1actone 
##STR93## 
A 86 mg amount of the compound (4-17), 
(23R,25R)-22-homo-1.alpha.-hydroxy-25-trimethylsilyloxy-D.sub.3 -26, 
23-1actone-1.alpha.,3-bis-t-butyldimethylsilylether, was taken in a 25 ml 
eggplant-shaped flask, then 10 ml of tetrahydrofuran was added and the 
solution stirred. Under ice cooling, 2.0 ml of a 1 M solution of 
tetrabutylammonium fluoride in tetrahydrofuran was added and the solution 
stirred at room temperature over night. Into the reaction solution was 
placed 5 ml of a saturated aqueous solution of potassium hydrogensulfate, 
then the solution was stirred for 30 minutes at room temperature. The 
reaction solution was extracted by ethyl acetate, the organic layer was 
washed with a saturated aqueous solution of sodium bicarbonate and 
saturated saline, then was dried over anhydrous magnesium sulfate. The 
desiccant was filtered out, the solvent was distilled off under reduced 
pressure, and the obtained crude product was purified by a silica gel 
column (IR-60, 80 g, hexane/ethyl acetate=2/3 to 1/3) to obtain the 
desired product (4-18), (23R, 25R)-22-homo-1.alpha.,25-dihydroxy-vitamin 
D.sub.3 -26,23-1actone in an amount of 23 mg (yield 48%). 
##STR94## 
A 77 mg amount of the compound (4-17'), 
(23S,25R)-22-homo-1.alpha.-hydroxy-25-trimethylsilyl D.sub.3 
-26,23-lactone-1.alpha.,3-bis-t-butyldimethylsilylether was treated in the 
same way to obtain the desired product (4-18'), 
(23S,25R)-22-homo-1.alpha.,25-dihydroxy-vitamin D.sub.3 -26, 23-lactone in 
an amount of 11 mg (yield 24%). 
Compound (4-18) .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 
6.38 (d, 1H, J=11.2 Hz), 6.02 (d, 1H, J=11.2 Hz), 5.33 (s, 1H), 5.00 (s, 
1H), 4.50 to 4.65 (m, 1H), 4.40 to 4.20 (m, 2H), 1.00 to 3.00 (m, 23H), 
1.49 (s, 3H), 0.95 (d, 3H J=6.3 Hz), 0.55 (s, 3H) 
Compound (4-18') .sup.1 H-NMR (CDCl.sub.3, .delta. ppm) 6.38 (d, 1H, J=11.2 
Hz), 6.01 (d, 1H, J=11.2 Hz), 5.33 (s, 1H), 5.00 (s, 1H), 4.40 to 4.50 (m, 
1H), 4.30 to 4.40 (m, 1H), 4.10 to 4.20 (m, 1H), 1.00 to 3.00 (m, 23H), 
1.51 (s, 3H), 0.94 (d, 3H, J=6.3 Hz), 0.55 (s, 3H) 
EXAMPLE 5-1 
Measurement of Action of Suppression of Formation of Osteoclasts Induced by 
1.alpha.,25(OH).sub.2 D.sub.3 
Marrow cells were separated from the femur and tibia of mice (C57/Black 6, 
5 weeks old, male) and incubated for 7 days in .alpha.-MEM containing 10% 
fetal calf serum in the presence of 1.alpha.,25(OH).sub.2 D.sub.3 
(10.sup.-8 M) with the addition of certain concentrations of compounds. 
The cells were dyed by tartaric acid resistant acid phosphase (TRAP), and 
the nuclei were dyed by Methyl Green. Next, the cells with at least 3 
nuclei dyed by TRAP (osteoclasts) were counted under a microscope. The 
results are shown in the following Table 5-1. 
TABLE 5-1 
______________________________________ 
TRAP-positive 
Compound MNC cell/well 
______________________________________ 
1.alpha.,25(OH).sub.2 D.sub.3 (VD.sub.3) 
10.sup.-8 M 
61.3 .+-. 16.0 
VD.sub.3 (10.sup.-8 M + Example 2-15 
10.sup.-9 M 
47.7 .+-. 9.2 
compound 10.sup.-8 M 
34.5 .+-. 9.9 
VD.sub.3 (10.sup.-8 M) + Example 2-16 
10.sup.-9 M 
23.2 .+-. 10.4 
compound 10.sup.-8 M 
24.0 .+-. 6.9 
10.sup.-7 M 
17.5 .+-. 6.6 
______________________________________ 
EXAMPLE 5-2 
Affinity of compound to 1.alpha.,25-dihydroxyvitamin D.sub.3 receptor (VDR) 
in chicken intestinal membrane cells 
The 1.alpha.,25-dihydroxyvitamin D.sub.3 receptor in chicken intestinal 
membrane cells was isolated and evaluated in receptor affinity by a known 
method (Steroids, 37, 33-43 (1981). That is, 20 pg of 26,27-methyl- 
.sup.3 H!1.alpha.,25-dihydroxyvitamin D.sub.3 (158 Ci/mmol, 16,800 dpm) 
and the test compound dissolved in 50 .mu.l of ethanol were added to 
12.times.75 mm polypropylene tubes. To these were added 0.2 mg amounts of 
1.alpha.,25-dihydroxyvitamin D.sub.3 receptor protein in chicken 
intestinal membrane cells and 1 mg of gelatin dissolved in 1 ml of a 
phosphate buffer (pH 7.4), then the solutions were reacted at 25.degree. 
C. for one hour. After the reaction, 1 ml portions of a 40% solution of 
polyethylene glycol 6,000 were added to the tubes which were then shaken 
vigorously, then were centrifugally separated at 4.degree. C. and 
2,260.times.g for 60 minutes. The tubes of the sediment portions were cut 
off by a cutter knife and placed in liquid sintillation vials, a dioxane 
sintillator was added in amounts of 10 ml, and the radioactivity was 
measured by a liquid sintillation counter. The results are shown in the 
later given Table 5-2. 
EXAMPLE 5-3 
Affinity of compounds to vitamin D bonded proteins in fetal calf serum 
The affinity of 25-hydroxyvitamin D.sub.3 and a test compound to the 
vitamin D bonded proteins in fetal calf serum was determined by the method 
of J. Steroid Biochem. Molec. Biol. 41, 109-112 (1992). That is, 200 pg 
amounts of 26,27-methyl-.sup.3 H!25-hydroxyvitamin D.sub.3 (28 Ci/mmol, 
31,000 dpm) dissolved in a 0.01% Triton X-100 solution and the test 
compound dissolved in 10 .mu.l of ethanol were added to 12.times.105 mm 
gas tubes. To these were added 0.2 ml amounts of a solution of fetal calf 
serum diluted 2500-fold by a 0.9% sodium chloride-containing phosphate 
buffer (pH 7.0), the solutions were reacted at 4.degree. C. for 24 hours, 
then 0.5 ml of 0.5% charcoal, 0.075% dextrin and 0.5% bovine serum albumin 
solution were added, the solutions reacted at 4.degree. C. for 15 minutes, 
then centrifugally separated at 2,260.times.g for 10 minutes. 0.5 ml 
amounts of the supernatent were taken in liquid sintillation vials and the 
radioactivity of the 26,27-methyl-.sup.3 H!25-hydroxyvitamin D.sub.3 
bonded to the vitamin D bonded protein was measured by a liquid 
sintillation counter. 
The results are shown in the following Table 5-2. 
TABLE 5-2 
______________________________________ 
1.alpha.,25-(OH).sub.2 
Vitamin 
D.sub.3 receptor 
D-bonded 
(molar protein (molar 
Compound ratio) ratio) 
______________________________________ 
1.alpha.,25-(OH).sub.2 D.sub.3 
1 1 
Example 1-11 compound (23) 
104 1.2 
Example 2-14 compound 
207 41.8 
Example 2-15 compound 
9.8 10.7 
Example 2-16 compound 
13.8 39.4 
Example 3-17 compound 
3.6 &gt;500 
______________________________________ 
EXAMPLE 5-4 
Synthesis of Collagen and Noncollagen Protein by osteoblasts 
A murine osteoblast cell strain (MCJT cells) was dispersed in an 
.alpha.-MEM medium containing 10% fetal calf serum (FCS) (1.times.10.sup.4 
cells/ml medium). This was sown in 2 ml amounts in 35 mm incubation 
dishes, then incubated at 37.degree. C. under 5% CO.sup.2. After 4 days, 
after confluent was reached, the incubation solution was replaced by the 
same solution, then an ethanol solution of the test compound 
(1.times.10.sup.-4 M and 1.times.10.sup.-5 M) was added in 2 .mu.l 
amounts. The control group had only ethanol added in an amount of 2 .mu.l. 
The specimens were incubated at 37.degree. C. under 5% CO.sub.2. After 45 
hours incubation, the medium was replaced by an .alpha.-MEM medium 
containing 0.1% bovine serum albumin (BSA), 0.1 mM ascorbic acid, and 0.5 
mM fumaric acid-.beta.-aminopropionitrile, the same amount of the ethanol 
solution of the test compound or ethanol as the previous time was added 
again, then incubation performed for 30 minutes, then 4 .mu.Ci of .sup.3 
H! proline were added to petri dishes and were allowed to be taken up by 
the osteoblasts for 3 hours. The amounts of the synthesized collagen and 
noncollagen protein were measured by the method of Perterkofsky et al. 
(Biochemistry, 10, 988-994 (1971)). 
The results are shown in FIG. 1 and FIG. 2. 
INDUSTRIAL APPLICABILITY 
As explained above, the vitamin D.sub.3 derivative according to the present 
invention is useful as an agent for the promotion of bone formation.