Idene analogs of mevalonolactone and derivatives thereof

Compounds of the formula ##STR1## the use thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, pharmaceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such compounds.

This invention relates to compounds of the formula 
##STR2## 
wherein R.sub.o is C.sub.1-6 alkyl not containing an asymmetric carbon 
atom, C.sub.3-7 cycloalkyl or 
##STR3## 
wherein R.sub.4 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, 
C.sub.1 -C.sub.3 alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, 
chloro, phenoxy or benzyloxy, 
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, 
fluoro, chloro, phenoxy or benzyloxy, and 
R.sub.6 is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, 
with the provisos that not more than one of R.sub.4 and R.sub.5 is 
trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy, and 
not more than one of R.sub.4 and R.sub.5 is benzyloxy, 
R is hydrogen or primary or secondary C.sub.1-6 alkyl not containing an 
asymmetric carbon atom, and 
R.sub.1 is primary or secondary C.sub.1-6 alkyl not containing an 
asymmetric carbon atom or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 --, wherein 
m is 2, 3, 4, 5 or 6, 
R.sub.2 is hydrogen, C.sub.1-3 alkyl, n-butyl, i-butyl, t-butyl, C.sub.1-3 
alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or 
benzyloxy, 
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, 
fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than 
one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of 
R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and 
R.sub.3 benzyloxy, 
X is --(CH.sub.2).sub.n --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH-- or 
--CH.dbd.CH--CH.sub.2 --, wherein n is 1, 2 or 3, and 
##STR4## 
wherein Q is 
##STR5## 
wherein each R.sub.7 is primary or secondary C.sub.1-6 alkyl not 
containing an asymmetric carbon atom, the two R.sub.7 s, is being the 
same, or 
the two R.sub.7 s taken together are --(CH.sub.2).sub.q --, wherein q is 2 
or 3, 
R.sub.10 is hydrogen or C.sub.1-3 alkyl, and 
R.sub.11 is hydrogen, R.sub.12 or M, wherein R.sub.12 is a physiologically 
acceptable ester group, and 
M is a pharmaceutically acceptable cation, 
with the provisos that (1) Z may be a group of Formula c only when (i) X is 
--CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH--, (ii) R.sub.10 is C.sub.1-3 
alkyl or (iii) both (i) and (ii) and (2) when Z is a group of Formula c 
wherein Q is 
##STR6## 
R.sub.11 must be R.sub.12 or M, processes for and intermediates in the 
synthesis thereof, pharmaceutical compositions comprising a compound of 
Formula I and the use of the compounds of Formula I for inhibiting 
cholesterol biosynthesis and lowering the blood cholesterol level and, 
therefore, in the treatment of hyperlipoproteinemia and atherosclerosis. 
By the term "physiologically acceptable ester group" is meant a group 
which, together with the --COO-- radical to which it is attached, forms an 
ester group which is physiologically acceptable The preferred such groups 
are physiologically acceptable and hydrolyzable ester groups. By the term 
"physiologically acceptable and hydrolyzable ester group" is meant a group 
which, together with the --COO-- radical to which it is attached, forms an 
ester group which is physiologically acceptable and hydrolyzable under 
physiological conditions to yield a compound of Formula I wherein R.sub.11 
is hydrogen and an alcohol which itself is physiologically acceptable, 
i.e., non-toxic at the desired dosage level, and which, preferably, is 
free of centers of asymmetry. Examples of such groups are C.sub.1-3 alkyl, 
n-butyl, i-butyl, t-butyl and benzyl, collectively referred to as 
R.sub.12. 
For the avoidance of doubt, throughout this specification it is the 
right-hand side of the X radical that is attached to the Z group. 
The compounds of Formula I may be divided into six groups, viz., the 
compounds of Formula I wherein R is hydrogen or primary or secondary 
C.sub.1-6 alkyl not containing an asymmetric carbon atom, R.sub.1 is 
primary or secondary C.sub.1-6 alkyl not containing an asymmetric carbon 
atom, and Z is a group of Formula a (Group IAa), the corresponding 
compounds wherein Z is a group of Formula b (Group IAb), the corresponding 
compounds wherein Z is a group of Formula c (Group IAc), the compounds of 
Formula I wherein R and R.sub.1 taken together are --(CH.sub.2).sub.m -- 
or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 --, and Z is a group of Formula a 
(Group IBa), the corresponding compounds wherein Z is a group of Formula b 
(Group IBb) and the corresponding compounds wherein Z is a group of 
Formula c (Group IBc). 
As is self-evident to those in the art, each compound of Groups IAa, IAb, 
IBa and IBb (and every subscope and species thereof) has two centers of 
asymmetry (the two carbon atoms bearing the hydroxy groups in the group of 
Formula a and the carbon atom bearing the hydroxy group and the carbon 
atom having the free valence in the group of Formula b) and, therefore, 
there are four stereoisomeric forms (enantiomers) of each compound (two 
racemates or pairs of diastereoisomers), provided that R and R.sub.1 are 
identical or taken together are --(CH.sub.2).sub.m -- or (Z)--CH.sub.2 
--CH.dbd.CH--CH.sub.2 -- and that R.sub.11 does not contain any center of 
asymmetry. The four stereoisomers may be designated as the R,R, R,S, S,R 
and S,S enantiomers, all four stereoisomers being within the scope of this 
invention. When R and R.sub.1 are different and/or R.sub.11 contains one 
or more centers of asymmetry, there are eight or more stereoisomers. Since 
it is preferred that R and R.sub.1 be identical or taken together 
--(CH.sub.2).sub.m -- or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 -- and that 
R.sub.11 not contain a center of asymmetry and for reasons of simplicity 
any additional stereoisomers resulting from the presence of a center of 
asymmetry in the 1-position of the indene ring and/or one or more centers 
of asymmetry in R.sub.11 will usually be ignored, it being assumed that R 
and R.sub.1 are identical or taken together are --(CH.sub.2).sub.m -- or 
(Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 -- and that R.sub.11 is free of 
centers of asymmetry. As is also self-evident, each compound of Groups IAc 
and IBc (and every subscope and species thereof) has one center of 
asymmetry (the carbon atom bearing the hydroxy group in the group of 
Formula c) and, therefore, there are two enantiomers of each compound, 
provided that R and R.sub.1 are identical or taken together are 
--(CH.sub.2).sub.m -- or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 -- and that 
R.sub.11 does not contain any center of asymmetry. The two stereoisomers 
may be designated as the 3 R and 3S isomers, both being within the scope 
of this invention. When R and R.sub.1 are different and/or R.sub.11 
contains one or more centers of asymmetry, there are four or more 
stereoisomers. For the reasons set forth above, any additional 
stereoisomers resulting from the presence of a center of asymmetry in the 
1-position of the indene ring and/or one or more centers of asymmetry in 
R.sub.11 will usually be ignored. 
Q is preferably --CO--. 
R.sub.o is preferably R.sub.o ', where R.sub.o ' is C.sub.1-4 alkyl not 
containing an asymmetric carbon atom or Ring A, particularly Ring A, more 
preferably R.sub.o ", where R.sub.o " is Ring A wherein R.sub.4 is R.sub.4 
', R.sub.5 is R.sub.5 ', and R.sub.6 is R.sub.6 ', even more preferably 
R.sub.o '", where R.sub.o '" is Ring A wherein R.sub.4 is R.sub.4 ", 
R.sub.5 is R.sub.5 ", and R.sub.6 is R.sub.6 ", and most preferably 
R.sub.o "", where R.sub.o "" is Ring A wherein R.sub.4 is R.sub.4 '", 
R.sub.5 is R.sub.5 '", and R.sub.6 is R.sub.6 '". In R.sub.o "", R.sub.4 
'" is preferably R.sub.4 "". 
When R is hydrogen or primary or secondary C.sub.1-6 alkyl not containing 
an asymmetric carbon atom: 
R is preferably R', where R' is hydrogen or primary or secondary C.sub.1-4 
alkyl not containing an asymmetric carbon atom, ore preferably R", where 
R" is hydrogen or C.sub.1-2 alkyl, and most preferably C.sub.1-2 alkyl, 
and 
R.sub.1 is preferably R.sub.1 ', where R.sub.1 ' is primary or secondary 
C.sub.1-4 alkyl not containing an asymmetric carbon atom, more preferably 
R.sub.1 ", where R.sub.1 " is C.sub.1-3 alkyl, and most preferably 
C.sub.1-2 alkyl. 
Preferably, when R, R', etc. is other than hydrogen, R, R', etc., as the 
case may be, is identical to R.sub.1, R.sub.1 ', etc., as the case may be. 
When R and R.sub.1 taken together are --(CH.sub.2).sub.m -- or 
(Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 --, they are preferably 
--(CH.sub.2).sub.m --, more preferably --(CH.sub.2).sub.m' --, even more 
preferably --(CH.sub.2).sub.m" -- and most preferably --(CH.sub.2).sub.m'" 
--, especially --(CH.sub.2).sub.4 --, wherein m is as defined above, and 
m', m" and m'" are as defined below 
R.sub.2 is preferably R.sub.2 ', where R.sub.2 ' is hydrogen, C.sub.1-3 
alkyl, methoxy, fluoro, chloro or benzyloxy, more preferably R.sub.2 ", 
where R.sub.2 " is hydrogen or C.sub.1-3 alkyl, and most preferably 
hydrogen. 
R.sub.3 is preferably R.sub.3 ', where R.sub.3 ' is hydrogen or C.sub.1-3 
alkyl, and more preferably hydrogen. 
Preferably, not more than one of R.sub.2 and R.sub.3 is a member of the 
group consisting of t-butyl, trifluoromethyl, phenoxy and benzyloxy More 
preferably, R.sub.2 and R.sub.3 are not ortho to each other unless at 
least one of them is a member of the group consisting of hydrogen, 
C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro and chloro. 
R.sub.4 is preferably R.sub.4 ', where R.sub.4 ' is hydrogen, C.sub.1-3 
alkyl, trifluoromethyl, fluoro or chloro, more preferably R.sub.4 ", where 
R.sub.4 " is hydrogen or C.sub.1-2 alkyl, and most preferably R.sub.4 '", 
where R.sub.4 '" is hydrogen or methyl, especially R.sub.4 "", where 
R.sub.4 "" is hydrogen or 3-methyl. 
R.sub.5 is preferably R.sub.5 ', where R.sub.5 ' is hydrogen, C.sub.1-2 
alkyl, fluoro or chloro, more preferably R.sub.5 ", where R.sub.5 " is 
hydrogen or fluoro, and most preferably R.sub.5 '", where R.sub.5 '" is 
hydrogen or 4-fluoro. 
R.sub.6 is preferably R.sub.6 ', where R.sub.6 ' is hydrogen or C.sub.1-2 
alkyl, more preferably R.sub.6 ", where R.sub.6 " is hydrogen or methyl, 
and most preferably R.sub.6 ", where R.sub.6 '" is hydrogen or 5-methyl. 
Preferably, not more than one of R.sub.4 and R.sub.5 is a member of the 
group consisting of t-butyl, trifluoromethyl, phenoxy and benzyloxy. More 
preferably, no two of R.sub.4 (R.sub.4 ', R.sub.4 ", etc.), R.sub.5 
(R.sub.5 ', R.sub.5 ", etc.) and R.sub.6 (R.sub.6 ', R.sub.6 ", etc.) are 
ortho to each other unless at least one member of each pair of 
substituents that are ortho to each other is a member of the group 
consisting of hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro and 
chloro. 
The preferred R.sub.4 -bearing phenyl groups are phenyl, 4-fluorophenyl, 
3,4- and 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl and 
3,5-dimethyl-4-fluorophenyl, with 4-fluorophenyl and 3,5-dimethylphenyl 
being more preferred. 
Preferably, each R.sub.7 is C.sub.1-3 alkyl or both R.sub.7 's taken 
together are --(CH.sub.2).sub.q --; more preferably, each R.sub.7 is 
C.sub.1-2 alkyl or both R.sub.7 's taken together are --(CH.sub.2).sub.q 
--; and most preferably each R.sub.7 is C.sub.1-2 alkyl. 
R.sub.10 is preferably R.sub.10 ', where R.sub.10 ' is hydrogen or methyl, 
and more preferably hydrogen. 
R.sub.11 is preferably R.sub.11 ', where R.sub.11 ' is hydrogen, R.sub.12 ' 
or M, more preferably R.sub.11 '", where R.sub.11 " is hydrogen, C.sub.1-3 
alkyl or M, even more preferably R.sub.11 '", where R.sub.11 '" is 
hydrogen, C.sub.1-2 alkyl or M, and most preferably M, especially sodium. 
R.sub.12 is preferably R.sub.12 ', where R.sub.12 ' is C.sub.1-3 alkyl, 
n-butyl, i-butyl, t-butyl or benzyl, more preferably C.sub.1-3 alkyl, and 
most preferably C.sub.1-2 alkyl, especially ethyl. 
X is preferably X', where X' is --CH.sub.2 CH.sub.2 -- or (E)--CH.dbd.CH--, 
and more preferably (E)--CH.dbd.CH--. 
Z is preferably a group of Formula a or c wherein R.sub.11 is R.sub.11 ' or 
a group of Formula b, more preferably a group of Formula a or c wherein 
R.sub.11 is R.sub.11 " or a group of Formula b, even more preferably a 
group of Formula a wherein R.sub.11 is R.sub.1 '" or a group of Formula b, 
and most preferably a group of Formula a wherein R.sub.11 is M, especially 
sodium. 
m is preferably m', where m' is 2, 3, 4 or 5, more preferably m", where m" 
is 2, 3 or 4, and most preferably m'", where m'" is 2 or 4, especially 4. 
n is preferably 2. 
M is preferably free from centers of asymmetry and is more preferably M', 
where M' is sodium, potassium or ammonium, and most preferably sodium. For 
simplicity, each formula in which M appears has been written as if M were 
monovalent and, preferably, it is. However, it may also be divalent or 
trivalent and, when it is, it balances the charge of two or three carboxy 
groups, respectively. Thus, Formula I and every other formula containing 
an M embraces compounds wherein M is divalent or trivalent, i.e., which 
contains two or three carboxylate-containing anions per cation M. 
As between otherwise identical compounds of Formula I, those wherein Z is a 
group of Formula a or b are generally preferred over those wherein Z is a 
group of Formula c, with those wherein Z is a group of Formula a being 
generally preferred over those wherein Z is a group of Formula b. 
Insofar as the compounds of Groups IAa and IBa and each of the subgroups 
thereof are concerned, the erythro isomers are preferred over the threo 
isomers, erythro and threo referring to the relative positions of the 
hydroxy groups in the 3- and 5-positions of the group of Formula a. 
Insofar as the compounds of Groups IAb and IBb and each of the subgroups 
thereof are concerned, the trans lactones are generally preferred over the 
cis lactones, cis and trans referring to the relative positions of 
R.sub.10 and the hydrogen atom in the 6-position of the group of Formula 
b. 
The preferred stereoisomers of the compounds of Formula I having only two 
centers of asymmetry wherein X is --CH.dbd.CH-- or --CH.sub.2 
--CH.dbd.CH--, and Z is a group of Formula a are the 3R,5S and 3R,5R 
isomers and the racemate of which each is a constituent, i.e., the 
3R,5S-3S,5R (erythro) and 3R,5R-3S,5S (threo) racemates, with the 3R,5S 
isomer and the racemate of which it is a constituent being more preferred 
and the 3R,5S isomer being most preferred. 
The preferred stereoisomers of the compounds of Formula I having only two 
centers of asymmetry wherein X is --(CH.sub.2).sub.n - or 
--CH.dbd.CH--CH.sub.2 --, and Z is a group of Formula a are the 3R,5R and 
3R,5S isomers and the racemate of which each is a constituent, i.e., the 
3R,5R-3S,5S (erythro) and 3R,5S-3S,5R (threo) racemates, with the 3R,5R 
isomer and the racemate of which it is a constituent being more preferred 
and the 3R,5R isomer being most preferred. 
The preferred stereoisomers of the compounds of Formula I having only two 
centers of asymmetry wherein X is --CH.dbd.CH-- or --CH.sub.2 
--CH.dbd.CH--, and Z is a group of Formula b are the 4R,6S and 4R,6R 
isomers and the racemate of which each is a constituent, i.e., the 
4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cis lactone) racemates, with 
the 4R,6S isomer and the racemate of which it is a constituent being more 
preferred and the 4R,6S isomer being most preferred. 
The preferred stereoisomers of the compounds of Formula I having only two 
centers of asymmetry wherein X is --(CH.sub.2).sub.n -- or 
--CH.dbd.CH--CH.sub.2 --, and Z is a group of Formula b are the 4R,6R and 
4R,6S isomers and the racemate of which each is a constituent, i.e., the 
4R,6R-4S,6S (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with 
the 4R,6R isomer and the racemate of which it is a constituent being more 
preferred and the 4R,6R isomer being most preferred. 
The preferences set forth in the preceding four paragraphs also apply to 
the compounds of Groups IAa, IAb, IBa and IBb having more than two centers 
of asymmetry and represent the preferred configurations of the indicated 
positions. 
The preferred stereoisomers of the compounds of Formula I having just one 
center of asymmetry wherein Z is a group of Formula c are the 3R isomer 
and the racemate of which it is a constituent, i.e., the 3R-3S racemate, 
with the 3R isomer being more preferred. These preferences also apply to 
the compounds of Groups IAc and IBc having more than one center of 
asymmetry and represent the preferred configuration of the indicated 
position. 
Each of the preferences set forth above applies, not only to the compounds 
of Formula I, but also to the compounds of Groups IAa, IAb, IAc, IBa, IBb 
and IBc as well as to every subgroup thereof set forth in the 
specification, e.g., Groups (i) et seq., unless otherwise indicated. When 
any preference contains a variable, the preferred significances of that 
variable apply to the preference in question, unless otherwise indicated. 
Preferred groups of compounds of Formula I include the compounds 
(i) of Group IAa wherein R.sub.o is R.sub.o ', especially R.sub.o ", R is 
R', R.sub.1 is R.sub.1 ', R.sub.2 is R.sub.2 ', R.sub.3 is R.sub.3 ', 
R.sub.10 is R.sub.10 ', R.sub.11 is R.sub.11 ', and X is X', 
(ii) of (i) wherein R.sub.o is R.sub.o ", R.sub.10 is hydrogen, R.sub.11 is 
R.sub.11 ", and X is (E)--CH.dbd.CH--, 
(iii) of (ii) wherein R.sub.o is R.sub.o '", R is R", R.sub.1 is R.sub.1 ", 
R.sub.2 is R.sub.2 ", R.sub.3 is hydrogen, and R.sub.11 is R.sub.11 '", 
particularly M, 
(iv) of (iii) wherein R.sub.o is R.sub.o "" wherein R.sub.4 '" is R.sub.4 
"", R is C.sub.1-2 alkyl, R.sub.1 is C.sub.1-2 alkyl, and R.sub.2 is 
hydrogen, 
(v) of (iv) wherein R.sub.11 is M, particularly M', and especially sodium, 
(vi) of Group IAb wherein R.sub.o is R.sub.o ', especially R.sub.o ", R is 
R', R.sub.1 is R.sub.1 ', R.sub.2 is R.sub.2 ', R.sub.3 is R.sub.3 ', 
R.sub.10 is R.sub.10 ', and X is X', 
(vii) of (vi) wherein R.sub.o is R.sub.o ", R.sub.10 is hydrogen, and X is 
(E)--CH.dbd.CH--, 
(viii) of (vii) wherein R.sub.o is R.sub.o '", R is R", R.sub.1 is R.sub.1 
", R.sub.2 is R.sub.2 ", and R.sub.3 is hydrogen, 
(ix) of (viii) wherein R.sub.o is R.sub.o "" wherein R.sub.4 '" is R.sub.4 
"", R is C.sub.1-2 alkyl, R.sub.1 is C.sub.1-2 alkyl and R.sub.2 is 
hydrogen, 
(x) of Group IBa wherein R.sub.o is R.sub.o ', especially R.sub.o ", R and 
R.sub.1 taken together are --(CH.sub.2).sub.m --, R.sub.2 is R.sub.2 ', 
R.sub.3 is R.sub.3 ', R.sub.10 is R.sub.10 ', R.sub.11 is R.sub.11 ', and 
X is X', 
(xi) of (x) wherein R.sub.o is R.sub.o ", R.sub.10 is hydrogen, R.sub.11 is 
R.sub.1 ", and X is (E)--CH.dbd.CH--, 
(xii) of (xi) wherein R.sub.o is R.sub.o '", R.sub.2 is R.sub.2 ", R.sub.3 
is hydrogen, R.sub.11 is R.sub.1 '", particularly M, and m is m', 
(xiii) of (xii) wherein R.sub.o is R.sub.o "" wherein R.sub.4 '" is R.sub.4 
"", R.sub.2 is hydrogen, and m is m", 
(xiv) of (xiii) wherein R.sub.11 is M, particularly M', and especially 
sodium, 
(xv) of Group IBb wherein R.sub.o is R.sub.o ', especially R.sub.o ", R and 
R.sub.1 taken together are --(CH.sub.2).sub.m --, R.sub.2 is R.sub.2 ', 
R.sub.3 is R.sub.3 ', R.sub.10 is R.sub.10 ', and X is X', 
(xvi) of (xv) wherein R.sub.o is R.sub.o ", R.sub.10 is hydrogen, and X is 
(E)--CH.dbd.CH--, 
(xvii) of (xvi) wherein R.sub.o is R.sub.o '", R.sub.2 is R.sub.2 ', 
R.sub.3 is hydrogen, and m is m', 
(xviii) of (xvii) wherein R.sub.o is R.sub.o "" wherein R.sub.4 '" is 
R.sub.4 "", R.sub.2 is hydrogen, and m is m", 
(xix)-(xxviii) of (i)-(v) and (x)-(xiv) wherein the hydroxy groups in the 
3- and 5-positions of the group of Formula a have the erythro 
configuration, 
(xxix)-(xxxvi) of (vi)-(ix) and (xv)-(xviii) wherein R.sub.10 and the 
hydrogen atom in the 6-position of the group of Formula b are trans to 
each other, i.e., the trans lactones, 
(xxxvii) of Group IAc wherein R.sub.o is R.sub.o ', especially R.sub.o ", R 
is R', R.sub.1 is R.sub.1 ', R.sub.2 is R.sub.2 ', R.sub.3 is R.sub.3 ', 
each R.sub.7 is C.sub.1-3 alkyl or the two R.sub.7 's taken together are 
--(CH.sub.2).sub.q --, R.sub.10 is R.sub.10 ', R.sub.11 is R.sub.11 ', and 
X is X', with the provisos that R.sub.11 may be hydrogen only when Q is 
--CO--, and X may be --CH.sub.2 CH.sub.2 -- only when R.sub.10 is methyl, 
(xxxviii) of (xxxvii) wherein R.sub.o is R.sub.o ", each R.sub.7 is 
C.sub.1-2 alkyl or the two R.sub.7 's taken together are 
--(CH.sub.2).sub.q --, R.sub.10 is hydrogen, R.sub.11 is R.sub.11 ", and X 
is (E)--CH.dbd.CH--, 
(xxxix) of (xxxviii) wherein R.sub.o is R.sub.o '", R is R", R.sub.1 is 
R.sub.1 ", R.sub.2 is R.sub.2 ", R.sub.3 is hydrogen, each R.sub.7 is 
C.sub.1-2 alkyl, and R.sub.11 is R.sub.11 '", particularly M, 
(xl) of (xxxix) wherein R.sub.o is R.sub.o "" wherein R.sub.4 '" is R.sub.4 
"", R is C.sub.1-2 alkyl, R.sub.1 is C.sub.1-2 alkyl, and R.sub.2 is 
hydrogen, 
(xli) of (xl) wherein R.sub.11 is M, particularly M', and especially 
sodium, 
(xlii) of Group IBc wherein R.sub.o is R.sub.o ', especially R.sub.o ", R 
and R.sub.1 taken together are --(CH.sub.2).sub.m --, R.sub.2 is R.sub.2 
', R.sub.3 is R.sub.3 ', each R.sub.7 is C.sub.1-3 alkyl or the two 
R.sub.7 's taken together are --(CH.sub.2).sub.q --, R.sub.10 is R.sub.10 
', R.sub.11 is R.sub.11 ', and X is X', with the provisos that R.sub.11 
may be hydrogen only when Q is --CO--, and X may be --CH.sub.2 CH.sub.2 -- 
only when R.sub.10 is methyl, 
(xliii) of (xlii) wherein R.sub.o is R.sub.o '", each R.sub.7 is C.sub.1-2 
alkyl or the two R.sub.7 's taken together are --(CH.sub.2).sub.q --, 
R.sub.10 is hydrogen, R.sub.11 is R.sub.11 ", and X is (E)--CH.dbd.CH--, 
(xliv) of (xliii) wherein R.sub.o is R.sub.o '", R.sub.2 is R.sub.2 ", 
R.sub.3 is hydrogen, each R.sub.7 is C.sub.1-2 alkyl, R.sub.11 is R.sub.11 
", particularly M, and m is m', 
(xlv) of (xliv) wherein R.sub.o is R.sub.o ""0 wherein R.sub.4 '" is 
R.sub.4 "", R.sub.2 is hydrogen, and m is m", 
(xlvi) of (xlv) wherein R.sub.11 is M, particularly M', and especially 
sodium, and 
(xlvii)-(lvi) of (xxxvii)-(xlvi) wherein Q is --CO--. 
Groups (i)-(xviii) and (xxxvii)-(lvi) embrace each of the possible 
stereoisomers, racemates and mixtures of diastereoisomers. Groups 
(xix)-(xxviii) embrace the 3R,5S and 3S,5R isomers and the 3R,5S-3S,5R 
racemate of the compounds wherein X is (E)--CH.dbd.CH-- having just two 
centers of asymmetry and the corresponding compounds having more than two 
centers of asymmetry, and Groups (xix) and (xxiv) also embrace the 3R,5R 
and 3S,5S isomers and the 3R,5R-3S,5S racemate of the compounds wherein X 
is --CH.sub.2 CH.sub.2 -- having just two centers of asymmetry and the 
corresponding compounds having more than two centers of asymmetry. Groups 
(xxix)-(xxxvi) embrace the 4R,6S and 4S,6R isomers and the 4R,6S-4S,6R 
racemate of the compounds wherein X is (E)--CH.dbd.CH-- having just two 
centers of asymmetry and the corresponding compounds having more than two 
centers of asymmetry, and Groups (xxix) and (xxxiii) also embrace the 
4R,6R and 4S,6S isomers and the 4R,6R-4S,6S racemate of the compounds 
wherein X is --CH.sub.2 CH.sub.2 -- having just two centers of asymmetry 
and the corresponding compounds having more than two centers of asymmetry. 
The compounds of Formula I may be synthesized as follows: 
REACTION SCHEME I 
The compounds of Formula I wherein X is --(CH.sub.2).sub.n -- or 
(E)--CH.dbd.CH--, and Z is a group of Formula a wherein R.sub.10 is 
hydrogen and R.sub.11 is R.sub.12 ' may be synthesized by the following 
series of reactions: 
##STR7## 
REACTION SCHEME II 
The compounds of Formula I wherein X is --(CH.sub.2).sub.n -- or 
(E)--CH.dbd.CH--, and Z is a group of Formula a wherein R.sub.10 is 
C.sub.1-3 alkyl and R.sub.11 is M.sub.2.sup..sym. may be synthesized by 
the following series of reactions: 
##STR8## 
REACTION SCHEME III 
The compounds of Formula I wherein X is --CH.sub.2 CH.sub.2 --, --CH.sub.2 
CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or, 
--CH.sub.2 --CH.dbd.CH--, and Z is a group of Formula a wherein R.sub.11 
is R.sub.12 ' may be synthesized by the following series of reactions: 
##STR9## 
REACTION SCHEME IV 
The compounds of Formula I wherein X is --CH.dbd.CH-- or --CH.sub.2 
--CH.dbd.CH--, and Z is a group of Formula b having the 4R,6S 
configuration or X is --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 
CH.sub.2 --, and Z is a group of Formula b having the 4R,6R configuration 
may be synthesized by the following series of reactions: 
##STR10## 
REACTION SCHEME V 
The compounds of Formulae V, XIV, etc. may be converted into the 
corresponding compounds of Formula I wherein Z has a different 
significance of Formula a or b by the following series of reactions: 
##STR11## 
REACTION SCHEME VI 
The compounds of Formula I wherein Z is a group of Formula c may be 
synthesized by the following series of reactions: 
##STR12## 
REACTION SCHEME VII 
The compounds of Formula II may be synthesized by the following series of 
reactions: 
##STR13## 
REACTION SCHEME VIII 
The compounds of Formula XXX may be synthesized by the following series of 
reactions: 
##STR14## 
REACTION SCHEME IX 
The compounds of Formula XXXI may be synthesized by the following series of 
reactions: 
##STR15## 
In the foregoing reaction schemes, Ind is 
##STR16## 
wherein R.sub.o -R.sub.3 are as defined above, 
R.sub.10a is C.sub.1-3 alkyl, 
R.sub.13 is C.sub.1-2 alkyl, preferably methyl, 
R.sub.14 is C.sub.1-3 alkyl, n-butyl or t-butyl, preferably ethyl or 
t-butyl, 
R.sub.15 is R.sub.1 ', --(CH.sub.2).sub.m -Y' or (Z)--CH.sub.2 
--CH.dbd.CH--CH.sub.2 --Y', wherein R.sub.1 and m are as defined above, 
and Y' is as defined below, 
each R.sub.16 is independently C.sub.1-2 alkyl, the two C.sub.1-2 alkyl 
groups preferably being the same, 
X.sub.1 is --(CH.sub.2).sub.n -- or (E)--CH.dbd.CH--, especially 
(E)--CH.dbd.CH--, wherein n is 1, 2 or 3, 
X.sub.2 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --, 
X.sub.3 is a direct bond or --CH.sub.2 --, 
X.sub.4 is --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 -- or --CH.sub.2 
--CH.dbd.CH--, preferably (E)--CH.dbd.CH--, (E)--CH.dbd.CH--CH.sub.2 -- or 
(E)--CH.sub.2 --CH.dbd.CH-- and especially (E)--CH.dbd.CH--, 
X.sub.5 is --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --, 
especially --CH.sub.2 CH.sub.2 --, 
X.sub.6 is --CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH--, preferably 
--CH.dbd.CH-- and especially (E)--CH.dbd.CH--, 
X.sub.7 is --(CH.sub.2).sub.n --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH-- 
or --CH.dbd.CH--CH.sub.2 when R.sub.10 is C.sub.1-3 alkyl and is 
--CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH-- when R.sub.10 is hydrogen, 
wherein n is 1, 2 or 3, 
Y is chloro, bromo or iodo, 
Y' is chloro or bromo, 
M.sub.2.sup..sym. is sodium or potassium, and each of the other variables 
is as defined above. 
__________________________________________________________________________ 
Reac- Inert 
tion/ Atmos- 
Type Reagents, Molar Ratios and Comments 
Temperature 
Time Solvent phere 
__________________________________________________________________________ 
A (1) Generation of dianion of III: 1 mole 
-50.degree.-10.degree. C., 
0.3-1.5 
AIO, e.g., 
Yes 
III and 2-2.2 equivalents strong base, 
pref. -30.degree.-5.degree. C. 
hrs. pref. THF 
pref. 1-1.1 moles sodium hydride then 
1-1.1 moles -n-butyllithium or 2-2.2 moles 
lithium diisopropylamide. 
(2) 1-2.5 moles, pref. 1.2-2.2 moles, more 
-80.degree.-0.degree. C., 
0.3-4 hrs., 
Same as Step 
Yes 
pref. 1.3-2.0 moles, of dianion of III 
-60.degree.-0.degree. C., 
pref. 0.3-2 
(assuming 100% conversion of III to its 
pref. -30.degree.- 
hrs. 
dianion) per mole II. Product (IV) is 
-10.degree. C. 
racemic. 
(3) Quench with, for example, ammonium chlo- 
-80.degree.-25.degree. C. 
1-5 min. 
Same as Step 1 
ride solution or 1 N. hydrochloric acid. 
B (a) Non-stereoselective: 1-4, pref. 2-4, 
-10.degree.-30.degree. C. 
1-8 hrs. 
IO, e.g., 
Yes 
(Reduc- 
equivalents of transferable hydride per lower alkanol, 
tion) 
mole IV, pref. sodium borohydride or esp. ethanol 
complex of .sub.- t-butylamine and borane. 
When a racemic IV is utilized, product 
(V) is a mixture of all four possible 
stereoisomers (the erythro and threo 
racemates) wherein the ratio of the 
erythro stereoisomers to the threo 
stereoisomers ranges from 3:2 to 2:3. 
(b) Stereoselective: 
(1) 1-1.3 moles, pref. 1.02-1.3 moles, 
0.degree.-50.degree. C., 
0.5-6 hrs., 
AIO, pref. 
Yes 
tri-(primary or secondary 0.degree.-25.degree. C. 
pref. 1-3.5 
esp. THF, or 
C.sub.2-4 alkyl)borane, pref. triethylborane, 
hrs. pref., mixture 
and, pref., 0.3-8 liters, e.g., of THF and 
0.75-6.5 liters, air (at 25.degree. C. and methanol, more 
760 mm. Hg.) per mole IV. pref. a 3-4:1 
mixture 
(2) 0.4-3.5 moles, pref. 1.5- 2.5 moles, 
-100.degree.--40.degree. C., 
2-48 hrs., 
Same as Step 
Yes 
sodium borohydride per mole IV. After 
pref. -100.degree.- 
pref. 16-48 
the reaction, quench the reaction 
-70.degree. C. 
hrs. 
mixture with, for example, 1 N. hydro- 
chloric acid at -78.degree.--20.degree. C. and 
isolate the crude product by extracting 
with a suitable inert organic solvent 
(e.g., diethyl ether) and evaporating 
the solvent at reduced pressure. It 
is pref. to crystallize the cyclic 
boron ester, if possible. If the reac- 
tion mixture is quenched with water 
instead of acid, product of this step 
may be a mixture containing the boron 
ester and a compound of Formula XVI. 
(3) large excess of anhydrous methanol, 
20.degree.-40.degree. C., 
0.7-60 Neat -- 
e.g., 50-500 moles per mole IV, or a 
pref. 20.degree.-25.degree. C., 
hrs., pref. 
mixture of methanol (e.g., 10-20 l. 
with methanol 
4-60 hrs., 
per mole IV), hydrogen peroxide 
alone and -30.degree.- 
with 
(e.g., 4- 8 l. of 30% aqueous hydrogen 
25.degree. C., pref. 
methanol 
peroxide per mole IV), and a 
-10.degree.-10.degree. C., 
alone and 
pH 7-7.2 aqueous phosphate buffer 
a mixture of 
0.5-2 hrs. 
(pref. 6-10 l. of a pH 7 aqueous 
methanol, hydro- 
with a mix- 
phosphate buffer (e.g., 0.054 M. sodium, 
gen peroxide and 
ture of 
0.024 M. potassium and 0.047 M. 
buffer methanol, 
phosphate) per mole IV). The amount hydrogen 
of buffer must be sufficient to main- 
peroxide 
tain a pH of 7-7.2. Dissolve product and buffer 
of Step 2 in methanol and add buffer 
and aqueous hydrogen peroxide. See 
Narasaka et al., Tetrahedron 40, 
2233-2238 (1984). 
(c) Alternative Stereoselective: 
(1) 1-5 moles zinc borohydride (pref. as 
-80.degree.--50.degree. C., 
0.5-5 hrs., 
AIO, pref. 
Yes 
0.1-0.2 M. solution in anhydrous 
pref. -80.degree.- 
pref. 1-4 
esp. diethyl 
diethyl ether produced as described 
-70.degree. C. 
hrs. ether or mix- 
in Gensler et al., J. Am. Chem. Soc. ture of diethyl 
82, 6074-6081 (1960) per mole IV. ether with 
another ES 
(2) Add excess methanol (e.g., 10-100 
-80.degree.--50.degree. C., 
1-2 hrs. 
Same as Step 1 
moles per mole IV) and allow to 
pref. -80.degree.- 
slowly warm to 20.degree.-25.degree. C. 
-70.degree. C.,.fwdarw.20.degree.- 
25.degree. C. 
(3) Add excess dilute aqueous acetic 
20.degree.-25.degree. C. 
-- Same as Step 
-- 
acid to quench the reaction mixture. 
Can also add the dilute acetic acid 
at -80.degree.--50.degree. C. and then allow to 
warm to 20.degree.-25.degree. C. 
When a racemic IV is utilized in Alterna- 
tive b or c, product (V) is a mixture of 
the four possible stereoisomers wherein 
the ratio of the erythro isomers 
(racemate) to the threo isomers (racemate) 
is about 4-20:1, usually 5-15:1, except as 
noted below. Repeated recrystallization of 
the cycloc boron ester produced in Step 2 of 
Alternative b, if a solid, may raise the 
ratio or even yield pure erythro racemate 
and mother liquors enriched with threo 
racemate. When, however, the solvent in Step 
1 of Alternative b is a mixture of THF and 
methanol, said ratio may be as high as 
50-100:1. 
C (1) Generation of monoanion of VI: 1-1.1 
-80.degree.--40.degree. C., 
0.25-1.5 
AIO, e.g., 
Yes 
equivalents strong base, pref. lithium 
pref. -80.degree.- 
hrs. pref. THF 
diisopropylamide, per mole VI. 
(2) 1-4 moles, pref. 3 moles, of monoanion 
-80.degree.--40.degree. C., 
0.25-1.5 
Same as Step 
Yes 
of VI (assuming 100% conversion of VI 
pref. -80.degree.- 
hrs. 
to its monoanion) per mole II. 
-75.degree. C. 
(3) Quench with, for example, ammonium 
-80.degree.-25.degree. C. 
1-5 min. 
Same as Step 
-- 
chloride solution. 
D 1-3 moles, pref. 2 moles, VIII or IX per 
-10.degree.-50.degree. C., 
2-18 hrs., 
Pyridine 
Yes 
(Acyla- 
mole VII. When an ES is used as the solvent, 
pref. 20.degree.-30.degree. C. 
pref. 4-12 
anhydrous ES, 
tion) 
also use 1-4 moles, pref. 2.5-3 moles, of a 
hrs. pref. THF 
tertiary amine, e.g., pyridine or, pref., 
4-dimethylaminopyridine, per mole VII. 
E (1) Generation of monoanion of XI: 1-1.1 
-80.degree.-0.degree. C. 
0.25-1 hr. 
AIO, e.g., 
Yes 
equivalents strong base, pref. lithium pref. THF 
diisopropylamide, per mole XI. 
(2) 1-4 moles, pref. 3 moles, or monoanion 
-80.degree.--40.degree. C., 
0.25-1.5 
Same as Step 
Yes 
of XI (assuming 100% conversion of XI 
pref. -80.degree.- 
hrs. 
to its monoanion) per mole X. 
-70.degree. C. 
(3) Quench with, for example, ammonium 
-80.degree.-25.degree. C. 
1-5 min. 
Same as Step 
-- 
chloride solution. 
F 2-2.3 moles, pref. 2-2.2 moles, XIII per 
0.degree. C.-reflux, 
1-4 hrs. 
Inert aqueous 
-- 
(Hydrol- 
mole XII. pref. 0.degree.-75.degree. C., 
organic, e.g., 
ysis) esp. 20.degree.-50.degree. C. 
mixture of 
water and lower 
alkanol, pre. 
mixture of 
water and 
methanol or, 
esp., ethanol 
G (1) 1-1.2 moles strong base, pref. -n-butyl- 
-20.degree.-0.degree. C. 
0.5-1.5 
AIO, pref. 
Yes 
(Wit- 
lithium or lithium diisopropylamide (or 
hrs. esp. THF 
tig) complex thereof, e.g., lithium diiso- 
propylamide .multidot. monotetrahydrofuran) and, 
optionally, 1.75-2 moles lithium chloride 
per mole XXX. Add strong base to other 
reactant(s). 
(2) 1-1.2 moles XXXI per mole XXX used in 
-20.degree.-0.degree. C. 
0.3-12 Same as Step 
Yes 
Step 1. hrs. 
(3) Quench with, e.g., saturated ammonium 
-20.degree.-25.degree. C. 
1-5 min. 
-- -- 
chloride solution. 
Product (XXXII) is a mixture of the (Z) and 
(E) (cis and trans, respectively) isomers 
which may be separated by chromatography. 
Only a very small amount of the (Z) isomer is 
produced as a general rule. 
H 2-12 moles, pref. 4-8 moles, fluoride re- 
20.degree. -60.degree. C. 
2-120 hrs. 
AIO, e.g., 
--, 
(Depro- 
agent, esp. tetra- -n-butylammonium fluoride, 
pref. THF, or 
tection) 
per mole XXXII and 0.5-2 moles, pref. 1.2-1.5 
mixture of ES, 
moles, glacial acetic acid per mole fluoride 
pref. THF, and 
reagent. Pref., first add glacial acetic acetonitrile 
acid to solution of XXXII, then add fluoride 
reagent. 
I Excess hydrogen (more than 1 mole per mole 
20.degree.-25.degree. C. 
Until 1 
Lower alkanol, 
-- 
(Hydro- 
XXXII) and catalytic amount of platinum 
mole e.g., ethanol 
gena- 
dioxide (e.g., 1-5 g. per mole XXXII). Ini- 
hydrogen 
tion) 
tial hydrogen pressure is conveniently 30-60 
per mole 
p.s.i. XXXII is 
taken up 
J Same as Reaction H (Molar quantities are 
Same as H Same as H 
Same as 
-- 
(Depro- 
per mole XXXIV). 
tection) 
K Same as Reaction G. (Reactant in Step 2 
Same as G Same as G 
Same as 
Yes 
(Wittig) 
is XXXVI). Product (XXXVII) is a mixture of 
the (Z) and (E) (cis and trans, respectively) 
isomers which may be separated by chromatog- 
raphy. Only a very small amount of the (Z) 
isomer is produced as a general rule. 
L Same as Reaction H except utilize 1-4 moles, 
Same as H Same as H 
Same as 
-- 
(Depro- 
pref. 2-4 moles, fluoride reagent per mole 
tection) 
XXXVII. 
M Same as Reaction I (Molar quantities are 
Same as I Same as I 
Same as 
-- 
(Hydro- 
per mole XXXVII). 
gena- 
tion) 
N Same as Reaction H except utilize 1-4 moles, 
Same as H Same as H 
Same as 
-- 
(Depro- 
pref. 2-4 moles, fluoride reagent per mole 
tection) 
XXXIX. 
O 1-1.3 equivalents XIII per mole XV or, if it 
0.degree. C.-reflux, 
0.5-4 hrs. 
Inert equeous 
-- 
(Hydrol- 
is desired to isolate XVI, pref. 0.95-0.995 
pref. 0.degree.-75.degree. C., 
organic, e.g., 
ysis) 
equivalent XIII per mole XV. 
esp. 0.degree.-25.degree. C. 
mixture of 
water and lower 
alkanol, pref. 
mixture of 
water and 
methanol or, 
esp., ethanol 
P At least 1 equivalent, e.g., 1-1.25 
0.degree.-25.degree. C. 
1-5 min. 
Water or 
--x- 
(Acidi- 
equivalents, acid, e.g., 2 N. hydrochloric ture of water 
fica- 
acid, per mole XVI. and water- 
tion) miscible inert 
organic solvent 
e.g., methanol, 
ethanol, 
diethyl ether 
or THF 
Q 0.95-0.99 equivalent, pref. 0.96-0.98 
0.degree.-25.degree. C., 
2-10 min. 
Same as 
-- 
(Neutral- 
equivalent, XVIII per mole XVII. 
20.degree.-25.degree. C. 
ization) 
R (a) Use of catalytic amount of a strong acid 
75.degree. C.-reflux, 
3-18 hrs., 
AIO, pref. 
--, 
(Lacton- 
such as -p-toluenesulfonic acid monohydrate 
pref. 75.degree.- 
pref. 4-7 
e.g., benzene, 
ization) 
is optional but usually omit. Use of 
150.degree. C., esp. 
hrs. toluene or 
Dean-Stark trap is pref. if solvent 
80.degree.-120.degree. C. 
xylene or mix- 
forms azeotrope with water. ture thereof 
(b) 1- 1.5 moles of a lactonization agent, 
10.degree.-35.degree. C., 
2-8 hrs., 
AIO, pref. 
--A, 
e.g., a carbodiimide, pref. a water- 
pref. 20.degree.-25.degree. C. 
pref. 3-4 
esp. methylene 
soluble carbodiimide such as N-cyclohexyl- 
hrs. chloride 
N'-[2'-(N"-methylmorpholinium)ethyl]- 
carbodiimide -p-toluenesulfonate, per mole 
XVII. 
Alternative b often results in higher 
yields of XX than Alternative a. 
Racemic erythro XVII yields racemic trans 
(lactone) XX, racemic threo XVII yields 
racemic cis (lactone) XX, mixture of 
racemic erythro and threo XVII yields mix- 
ture of racemic trans and cis (lactones) 
XX, and single enantiomer of XVII yields 
single enantiomer of XX, e.g., 3R, 5S 
erythro XVII yields 4R, 6S trans XX. 
S At least 2 moles, e.g., 2-10 moles, pref. 
0.degree.-70.degree. C., 
1-12 hrs., 
AIO, e.g., 
-- 
(Esteri- 
2.05-2.5 moles, XXI per mole XX. 
0.degree.-25.degree. C. 
pref. 1-3 
such as THF or 
fica- 
Racemic trans (lactone) XX yields racemic 
R.sub.12 is primary 
hrs. when 
alcohol of the 
tion) 
erythro XXII, racemic cis (lactone) XX 
alkyl R.sub.12 is 
formula R.sub.12 --OH 
yields racemic threo XXII, mixture of racemic 
primary 
(R.sub.12 must be 
trans and cis (lactones) XX yields mixture 
alkyl same as in 
of racemic erythro and threo XXII, and single 
XXI), if a 
enantiomer of XX yields single enantiomer liquid 
of XXII, e.g., 4R, 6S trans XX yields 3R, 5S 
erythro XXII. 
T 1-1.3 equivalents XIII per mole XX or, if 
0.degree. C.-reflux, 
0.5-6 hrs., 
Same as 
-- 
(Hydrol- 
it is desired to isolate XVI, 0.94-1 
pref. 0.degree.-75.degree. C., 
pref. 1-4 
ysis) 
equivalent, preferably 0.97-0.99 equivalent, 
more pref. 20.degree.- 
hrs. 
XIII per mole XX. 75.degree. C. 
Racemic trans (lactone) XX yields racemic 
erythro XVI, racemic cis (lactone) XX 
yields racemic threo XVI, mixture of racemic 
trans and cis (lactones) XX yields mixture 
of racemic erythro and threo XVI, and 
single enantiomer of XX yields single 
enantiomer of XVI, e.g., 4R, 6S trans XX 
yields 3R, 5S erythro XVI. 
U (a) When X is --CH.dbd.CH-- or --CH.sub.2 --CH.dbd.CH--: 
20.degree.-80.degree. C., 
1-4 days 
AIO, pref. 
Yes 
(Oxida- 
moles manganese dioxide (pref. activated) 
40.degree.-80.degree. C. 
or HC, esp. 
tion) 
per mole LXVII. toluene 
(b) When X is --(CH.sub.2).sub.n -- or --CH.dbd.CH--CH.sub.2 --: 
(1) Preparation of Swern's Reagent: 0.9596 
-20.degree.-0.degree. C. 
5-15 min. 
Neat Yes 
l. oxalyl chloride and 1.561 l. 
dimethyl sulfoxide per mole LXVII to be 
used in Step 2. 
(2) Swern's Reagent from Step 1 and 6.969 
-60.degree.--40.degree. C., 
1-6 hrs. 
Methylene 
Yes 
l. triethylamine per mole LXVII. 
pref. -50.degree. C. 
chloride 
V Same as Reaction O (Molar quantities are 
Same as O Same as O 
Same as 
-- 
(Hydrol- 
per mole LXVIII). 
ysis) 
W Same as Reaction P (Molar quantities are 
Same as P Same as P 
Same as 
-- 
(Acidi- 
per mole LXIX). 
fication) 
X Same as Reaction Q (Molar quantities are 
Same as Q Same as Q 
Same as 
-- 
(Neutral- 
per mole LXX). 
ization) 
Y 1-5 moles LXXII and catalytic amount of acid, 
20.degree.-40.degree. C. 
1-6 hrs. 
AIO, e.g., 
-- 
(Esteri- 
e.g., -p-toluenesulfonic acid .multidot. monohydrate, 
such as THF or 
fica- 
per mole LXX. When reaction is run neat, neat (if LXII 
tion) 
use large excess of LXXII, e.g., 50-100 is a liquid) 
moles, per mole LXX. 
Z (a) When each R.sub.7 is C.sub.1-6 alkyl not containing 
20.degree.-25.degree. C. 
24-72 hrs. 
AIO, e.g., 
Yes 
(Ketal- 
an asymmetric carbon atom: 3-5 moles or HC, esp. 
ization) 
LXXVIII and catalytic amount of methylene 
pyridinium -p-toluenesulfonate per mole chloride or 
LXXIII. benzene 
(b) When the two R.sub.7 's taken together 
20.degree.-25.degree. C. 
24-72 hrs. 
Same as Yes 
are --(CH.sub.2).sub.q --: 2-3 moles LXXIX and 
Alternative 
catalytic amount (e.g., 1-3 g.) of a 
pyridinium -p-toluenesulfonate per mole 
LXXIII. 
ZA Same as Reaction Z (Molar quantities are 
Same as Z Same as Z 
Same as 
Yes 
(Ketal- 
per mole (LXVIII). 
ization) 
ZB Same as Reaction O (Molar quantities are 
Same as O Same as O 
Same as 
-- 
(Hydrol- 
per mole LXXV). 
ysis) 
ZC (Ion 
Utilize an ion exchange resin such as Amber- 
20.degree.-25.degree. C. 
-- -- -- 
Ex- lite IR-P64 having the desires M.sup..sym. ions by 
change) 
the conventional procedure, e.g., dissolve 
LXXVI in water, load onto ion exchange resin 
column and elute with appropriate buffer. 
AA (1) Formation of Grignard Reagent: 0.95-1.2 
10.degree. C.-reflux, 
Until mag- 
Anhydrous 
Yesrt 
(Grig- 
moles magnesium turnings, trace of 
pref. 30.degree.-38.degree. C. 
nesium com- 
ES, esp. THF or 
nard + 
iodine and, optionally, small amount of 
in diethyl ether 
pletely or 
diethyl ether 
Dehydra- 
1,2-dibromoethane or methyl iodide per 
and 35.degree.-65.degree. C. 
nearly 
tion) 
mole R.sub.o -Y (XLIIA). Add magnesium turnings 
THF completely 
to solution of other reactants or, pref., 
dissolves, 
solution of XLIIA to other reactants, 
e.g., 0.5- 
in either case at a rate such that the 
4 hrs. 
reaction mixture refluxes gently. 
(2) Reaction of Grignard Reagent: 1-1.7 
20.degree.-25.degree. C. 
1-18 hrs., 
Same as Step 
Yes 
moles, pref. 1-1.25 moles, XLII per mole 
usually 
XLI. 1-3 hrs. 
(3) Dehydration: Dissolve hydroxy group- 
90.degree. C.-reflux, 
0.25-2 Neat -- 
containing product of Step 2 in glacial 
pref. 100.degree. C.- 
hrs., 
acetic acid, e.g., 0.3-1.5 l. per mole 
reflux, esp. 
pref. 0.5- 
XLI, and heat. Alternatively, can add a 
110.degree. C.-reflux, 
1.5 hrs. 
cooled mixture of saturated ammonium 
with glacial 
chloride solution and concentrated hydro- 
acetic acid and 
chloric acid, e.g., 0.5-1 l. of the former 
0.degree.-25.degree. C. with 
and 0.1-0.25 l. of the latter per mole 
aqueous acid 
LXI, to the product of Step 2 and stir the 
resulting two phase mixture. 
AB (1) Formation of iminium salt: 1 mole XLIV 
0.degree.-35.degree. C., 
5-45 min., 
Acetonitrile 
Yes 
(Vils- 
per mole XLV. Reaction can be run neat 
20.degree.-25.degree. C. 
pref. 20-40 
or neat 
meier- 
or can use excess XLIV or acetonitrile 
min. 
Haack) 
as solvent. 
(2) Reaction of iminium salt with XLIII: 
10.degree.-30.degree. C., 
3-24 hrs., 
Acetonitrile 
Yes 
1-1.25 moles iminium salt per mole 
10.degree. C..fwdarw.20.degree.-25.degree. 
C. usually 
or neat 
XLIII. Usually add solution of XLIII in 
6.16 hrs. 
acetonitrile to product (iminium salt) 
of Step 1. Pref., mix reactants at 10.degree. C. 
and then allow to warm to 20.degree.-25.degree. C. 
(3) Hydrolysis: Excess water of dilute sodium 
0.degree.-25.degree. C. 
1-10 min. 
Water -- 
hydroxide solution. 
Generally, Steps 1 and, especially, 2 
are faster when run neat, and the more 
dilute the reaction mixture, the 
longer the reaction time. However, 
when the reaction is run neat, the 
reaction mixture tends to solidify when 
stirred. Therefore, the reaction mixture 
should not be stirred if the reaction is 
run neat, and it is often necessary or 
desirable to utilize a solvent, 
particularly in Step 2. 
AC 1-1.3 moles XLVII per mole XLVI. 
50.degree.C.-reflux, 
3-8 hrs., 
AIO, pref. 
Yes 
(Wittig) pref. pref. e.g., THF, or 
60.degree.-115.degree. C., 
4-8 hrs. 
HC, e.g., 
90.degree.-115.degree. C. 
toluene, esp. 
toluene 
AD (1) Generation of mono- or di-carbanion: 
-5.degree.-5.degree. C., 
8-45 min. 
AIO, pref. 
Yes 
(Alkyl- 
For L wherein R is hydrogen and R.sub.1 is 
0.degree. C. dimethylform- 
ation) 
aklyl: 0.99-1.02 moles sodium hydride amide or THF 
(e.g., as 50%-80% dispersion in mineral optionally con- 
oil) per mole XLVIII. For L wherein R taining a small 
and R.sub.1 are identical and are alkyl or amount of oil 
where R and R.sub.1 taken together are (from the so- 
--(CH.sub.2).sub.m -- or (Z)-CH.sub.2 --CH.dbd.CH--CH.sub. 2 --: 
dium hydride) 
moles sodium hydride (e.g., as 50%-80% 
dispersion in mineral oil) per mole 
XLVIII. 
(2) Reaction of mono- or di-carbanion: 
-5.degree..fwdarw.25.degree. C. 
4-18 hrs., 
Same as Step 
Yes 
For L wherein R is hydrogen and R.sub.1 is 
pref. 5-12 
aklyl or R and R.sub.1 taken together are 
hrs. 
--(CH.sub.2).sub.m -- or (Z)-CH.sub.2 --CH.dbd.CH--CH.sub.2 --: 
1-1.05 
moles XLIX per mole XLVIII used in Step 
1. For L wherein R and R.sub.1 are identical 
and are alkyl: 2-2.1 moles XLIX per 
mole XLVIII used in Step 1. Generally, 
add XLIX neat or dissolved in the 
solvent to the product of Step 1 stirred 
at -5.degree.-5.degree. C. and then allow the reaction 
mixture to gradually warm to 20.degree.-25.degree. C. 
To synthesize L wherein R and R.sub.1 are 
different alkyl groups, utilize this reaction 
to synthesize L wherein R is hydrogen and R.sub.1 
is alkyl and then repeat this reaction 
utilizing said compound in lieu of XLVIII 
and an XLIX having a different R.sub.15. 
AE Strong metal hydride reducing agent, 
-80.degree.-25.degree. C., 
0.3-4 hrs. 
AIO, pref. 
Yes 
(Reduc- 
e.g., lithium aluminum hydride or 
pref. -80.degree.-0.degree. C., 
e.g., THF, HLA, 
tion) 
diisobutylaluminum hydride. At least 2 
esp. -80.degree.- 
esp. methylene 
equivalents, pref. 2.5-5 equivalents, of 
-50.degree. C. chloride, or 
transferable hydride per mole L, e.g., at mixture of HLA 
least 0.5 mole, pref. 1-1.25 moles, lithium and toluene 
aluminum hydride or at least 2 moles, 
preferably 2.5-5 moles, diisobutylaluminum 
hydride per mole L. 
AF 5-50 moles, pref. 7-25 moles, manganese 
20.degree.-80.degree. C., 
2-72 hrs., 
IO, pref. 
--A, 
(Oxida- 
dioxide (pref. activated) per mole LI. 
20.degree.-25.degree. C. 
pref. 12-48 
esp. methylene 
tion) hrs. chloride, or 
HC, esp. 
toluene 
AG Same as Reaction AA (Molar quantities in 
Same as AA 
Same as AA 
Same as 
Yes 
(Grig- 
Step 2 are per mole LIII). 
nard) 
AH Same as Reaction AB except use in Step 2 1-5 
Same as AB ex- 
Same as AB 
Same as 
Yes 
(Vils- 
moles iminimum salt per mole LIV. 
cept 25.degree.-82.degree. C., 
except 32- 
meier- pref. 75.degree.-82.degree. C., 
96 hrs. in 
Haack) in Step 2 Step 2 
AI (1) Synthesis of ylide: 1-1.05 moles strong 
-40.degree.-0.degree. C., 
1-4 hrs. 
AIO, pref. 
Yes 
(Wittig) 
base, e.g., sodium hydride, phenyllithium 
pref. -35.degree.- 
e.g., THF 
or, pref., -n-butyllithium per mole 
-20.degree. C. 
LVI. Pref., slowly add solution of 
strong base to solution of LVI. 
(2) Synthesis of enol ether: Ylide from 1- 
-30.degree.-0.degree. C., 
1-4 hrs. 
Same as Step 
Yes 
1.05 moles LVI per mole LV. 
pref. -20.degree.-0.degree. C. 
(3) Hydrolysis of enol ether: Large molar 
0.degree.-30.degree. C. 
8-24 hrs. 
Mixture 
-- 
excess, e.g., 2-20 moles, strong acid, aqueous acid 
e.g., 70% perchloric acid, per mole LV and ES, e.g., 
used in Step 2. mixture of 70% 
perchloric acid 
and THF 
AJ Same as Reaction AI (Molar quantities in 
Same as AI 
Same as AI 
Same as 
Same as 
(Wittig) 
Steps 2 and 3 are per mole LVII). AI 
AK Same as Reaction AI (Molar quantities in 
Same as AI 
Same as AI 
Same as 
Same as 
(Wittig) 
Steps 2 and 3 are per mole LVIII). AI 
AL Same as Reaction AC (Molar quantities are 
Same as AC 
8-24 hrs., 
Same as 
Yes 
(Wittig) 
per mole LV). pref. 12- 
24 hrs. 
AM Same as Reaction AD (Molar quantities are 
Same as AD 
Same as AD 
Same as 
Yes 
(Alkyl- 
per mole XLIII). 
ation) 
BA 1-5 equivalents, pref. 2-4.5 equivalents, of 
-10.degree.-30.degree. C. 
1-24 hrs. 
IO, e.g., 
(Reduc- 
transferable hydride per mole LX, pref. lower alkanol, 
tion) 
sodium borohydride or complex of .sub.- t-butylamine 
esp. ethanol, 
and borane. or mixture of 
ES and lower 
alkanol 
BB 1-2 moles, pref. 1.3-1.8 moles, LXII or 
-10.degree.-80.degree. C. 
2-18 hrs. 
AIO, pref. 
--, 
(Halo- 
LXIII per mole LXI. e.g., diethyl 
gena- ether or THF, 
tion) HLA, e.g., 
methylene 
chloride, or 
HC, e.g., 
benzene 
BC 1-1.1 moles LXV per mole LXIV. Can use 
20.degree.-140.degree. C., 
6-24 hrs., 
HC, e.g., 
Yes 
excess LXV as the solvent. usually 100.degree.- 
usually 
benzene or 
140.degree. C. 
10-16 hrs. 
xylene or neat 
(excess LXV 
is solvent) 
FA (1) Generation of dianion of III: 1 mole 
-50.degree.-10.degree. C., 
0.3-1.5 
AIO, e.g., 
Yes 
III and 2-2.2 equivalents strong 
pref. -10.degree.- 
hrs., pref. 
pref. THF 
base, e.g., 2- 2.2 moles lithium 
10.degree. C. 
0.5-1 hr. 
diisopropylamide or, pref., 1-1.1 moles 
sodium hydride followed by 1-1.1 moles 
-n-butyllithium. 
(2) 1-1.2 moles dianion of III (assuming 
-30.degree.-0.degree. C., 
2.4 hrs. 
Same as Step 
Yes 
100% conversion of III to its dianion) 
pref. -40.degree.- 
per mole LXXX. Slowly add solution of 
-20.degree. C., esp. 
LXXX in, pref., dry THF to solution of 
-35.degree.--30.degree. C., 
dianion stirred at -80.degree.-0.degree. C., pref. 
.fwdarw.20.degree.-25.degree. C. 
-20.degree. C., esp. -35.degree.--30.degree. C., stir at same 
temperature for 30 min. and allow to 
warm to 20.degree.-25.degree. C. over a 2 hr. period. 
(3) Quench with, for example, saturated 
-80.degree.-25.degree. C. 
1-5 min. 
-- -- 
ammonium chloride solution. 
Product (LXXXI) is a racemate. 
FB (a) Non-stereoselective: Same as Reaction B, 
Same as B, a 
Same as B, a 
Same as B, 
Yes 
(Reduc- 
Alternative a (Molar quantities are per 
tion) 
mole LXXXI). Product (LXXXII) is a 
mixture of all four possible stereo- 
isomers (the erythro and threo racemates), 
the erythro to threo ratio being approx- 
imately 3:2 to 2:3. 
(b) Stereoselective: 
(1) 1-1.25 moles, pref. 1.05-1.25 moles, 
0.degree.-50.degree. C., 
1-6 hrs., 
AIO, pref. 
--, 
esp. 1.2-1.25 moles, tri-(primary 
20.degree.-25.degree. C. 
pref. 1.5- 
esp. THF, or 
or secondary C.sub.2-4 alkyl)borane, pref. 
3 hrs. mixture of THF 
triethylborane or tri- -n-butylborane, and methanol, 
esp. the latter, per mole LXXXI. Use pref. a 3-4:1 
of air as in Step 1 of Alternative b mixture 
of Reaction B is optional. 
(2) 0.4-1.5 moles, pref. 1-1.25 moles, 
-100.degree.--40.degree. C., 
2-60 hrs., 
Same as Step 
-- 
sodium borohydride per mole LXXXI. 
pref. -90.degree.- 
pref. 24- 
After the reaction, reaction mixture 
-70.degree. C., esp. 
48 hrs. 
is quenched with, for example, 10% 
-90.degree.--78.degree. C. 
hydrochloric acid and crude product 
is isolated by extraction with, for 
example, diethyl ether and evaporation 
of the solvent. 
(3) Large excess of methanol (e.g., 
0.degree.-25.degree. C., 
0.7-5 hrs., 
As indicated 
-- 
50-100 moles per mole LXXXI) or 
0.degree.-10.degree. C., 
pref. 2-4 
mixture of methanol (e.g., 10-20 l. 
using a mixture 
hrs. 
per mole LXXXI), hydrogen peroxide 
of methanol, 
(e.g., 4-8 l. 30% aqueous hydrogen 
hydrogen per- 
peroxide per mole LXXXI) and a pH 
oxide and buffer 
7-7.2 aqueous phosphate buffer (pref. 
and 20.degree.-60.degree. C. 
6-10 l. of a pH 7 aqueous phosphate 
when using 
buffer (e.g., 0.054 M. sodium, 0.024 M. 
methanol alone 
potassium and 0.047 M. phosphate) per 
mole LXXXI). The amount of buffer 
must be sufficient to maintain a pH 
of 7-7.2. Dissolve product of Step 2 
in methanol and add buffer and aqueous 
hydrogen peroxide. Use of methanol 
alone is preferred. 
FC 2-8 moles, pref. 4 moles, LXXXIII per mole 
20.degree.-30.degree. C., 
16-19 hrs. 
Dry dimethyl- 
Yes 
(Sily- 
LXXXII and 2 moles imidazole per mole 
20.degree.-25.degree. C. 
formamide 
lation) 
LXXXIII. Slowly add LXXXIII to solution of 
LXXXII and imidazole (at rate such that 
temperature does not exceed 30.degree. C.) and stir 
at, pref., 20.degree.-25.degree. C. for balance of reaction 
time. 
FD (1) 1.8-2.1 moles, pref. 2 moles, LXXXIV per 
-70.degree.-25.degree. C., 
1-15 hrs., 
AIO, pref. 
Yes 
(Grig- 
mole LXXXI. pref. -50.degree.-0.degree. C. 
pref. 2-8 
ES, esp. THF 
nard) hrs. 
(2) Quench with, for example, saturated 
-20.degree.-25.degree. C. 
5-15 min. 
-- -- 
ammonium chloride solution. 
FE Same as Reaction FC (Molar quantities of 
Same as FC 
Same as FC 
Same as 
Yes 
(Sily- 
LXXXIII are per mole LXXXV). 
lation) 
FF Excess ozone. Bubble ozone through solution 
-80.degree.--70.degree. C., 
2-30 min. 
C.sub.1-3 alkanol, 
-- 
(Ozon- 
of LXXXVI until a bluish coloration persists 
pref. -78.degree. C. 
esp. methanol, 
olysis) 
and then quench reaction mixture with or HLA, esp. 
dimethyl sulfide or triphenylphosphine. methylene 
chloride, or 
ethyl acetate 
FG Same as Reaction AI (Molar quantities are 
Same as AI 
Same as AI 
Same as 
Yes 
(Wittig) 
per mole LXXXVII). 
__________________________________________________________________________ 
In the preceding table, 
AIO=anhydrous inert organic solvent 
ES=ether solvent, for example, diethyl ether, 1,2-diethoxyethane, 
1,2-dimethoxyethane, tetrahydrofuran and mixtures thereof 
esp.=especially 
HC=hydrocarbon solvent, for example, benzene, toluene, xylene and mixtures 
thereof 
HLA=halogenated lower alkane solvent, for example, carbon tetrachloride, 
chloroform, 1,1-di-chloroethane, 1,2-dichloroethane, methylene chloride 
and 1,1,2-trichloroethane, usually preferably methylene chloride 
hr. (hrs.)=hour(s) 
IO=inert organic solvent 
min.=minutes 
pref.=preferably, preferred 
THF=tetrahydrofuran 
Most of the molar amounts (ratios) given in the preceding table are merely 
exemplary and may be varied, as is evident to one of ordinary skill in the 
art. For example, in a reaction of two compounds one of which is readily 
available and one of which isn't, an excess of the readily available 
compound may be used to drive the reaction further towards completion 
(unless the use of an excess would increase the synthesis of an undesired 
compound). 
Likewise, most of the temperature ranges given in the preceding table are 
merely exemplary, and it is within the ability of one of ordinary skill in 
the art to vary those that are not critical. 
The reaction times set forth in the preceding table are also merely 
exemplary and may be varied. As is wellknown, the reaction time is often 
inversely related to the reaction temperature. Generally, each reaction is 
monitored by, for example, thin layer chromatography and is terminated 
when at least one starting material is no longer present, when it appears 
that no more of the desired product is being formed, etc. 
Conventional work-up procedures have generally been omitted from the 
preceding table. 
As utilized in the preceding table, the term "solvent" embraces mixtures of 
solvents and implies that the reaction medium is a liquid at the desired 
reaction temperature. It should, therefore, be understood that not all of 
the solvents listed for a particular reaction may be utilized for the 
entire recited temperature range. It should also be understood that the 
solvent must be at least substantially inert to the reactants employed, 
intermediates generated and end products under the reaction conditions 
utilized. 
The term "inert atmosphere", as utilized in the preceding table, means an 
atmosphere that does not react with any of the reactants, intermediates or 
end products or otherwise interfere with the reaction. While a carbon 
dioxide atmosphere is suitable for certain reactions, the inert atmosphere 
is usually dry nitrogen, helium, neon, argon or krypton, or a mixture 
thereof, and most often dry nitrogen, to maintain anhydrous conditions. 
Most reactions, including those where the use of an inert atmosphere is 
not specified, are carried out under an inert atmosphere, usually dry 
nitrogen, for convenience. 
In the preceding table, n-butyllithium is preferably employed as a 
1.3-1.7M. solution in hexane, and lithium diisopropylamide is preferably 
prepared in situ from n-butyllithium and diisopropylamine. 
Reactions analogous to Reactions A-F, H, J, L, N-T, V-Y, ZB, AE, AF, AI-AK, 
BA and BB are described in detail in copending application Ser. No. 
06/722,288, filed by Faizulla G. Kathawala on April 11, 1985 and titled 
Indole Analogs of Mevalonolactone and Derivatives Thereof. These reactions 
may be carried out analogously to, for example, Reactions A-N, R-T, Z and 
BB-HH of said application. Said application, particularly pages 14-21, 
28-30, 33-42, 44-47, 65-76, 82-100, 106, 107 and 116-122 thereof, is 
hereby incorporated by reference. Generally, where the reaction conditions 
set forth in said application differ from those set forth in this 
specification, the reaction conditions set forth in said application may 
also be utilized for the compounds of this specification. See also U.S. 
Pat. No. 4,739,073. 
Reactions FA-FC and FF are described in further detail in U.S. Pat. No. 
4,650,890. Columns 9-11 of said patent are hereby incorporated by 
reference. 
The product of each reaction may, if desired, be purified by conventional 
techniques such as recrystallization (if a solid), column chromatography, 
preparative thin layer chromatography, gas chromatography (if sufficiently 
volatile), fractional distillation under high vacuum (if sufficiently 
volatile) or high pressure (performance) liquid chromatography (HPLC). 
Often, however, the crude product of one reaction may be employed in the 
following reaction without purification. 
As is evident to those in the art, each of the compounds of Formulae I 
wherein Z is a group of Formula c (including those of Formulae 
LXVIII-LXXI, LXXIII-LXXVII, etc.), IV, VII, X and LXXXI has a single 
center of asymmetry provided that R and R.sub.1, if present, are identical 
or taken together are --(CH.sub.2).sub.m -- or (Z)--CH.sub.2 
--CH.dbd.CH--CH.sub.2 -- and, therefore. may be resolved into two 
optically active isomers. When a compound of Formula IV, X or LXXXI is 
converted into a compound of Formula V, XII or LXXXII or LXXXV, 
respectively, an additional center of asymmetry is generated. 
Consequently, when a racemic compound Of Formula IV, X or LXXXI is 
utilized, four stereoisomers (two pairs of diastereoisomers) of the 
resulting compound of Formula V, XII or LXXXII or LXXXV are formed, 
whereas when an optically pure compound of Formula IV, X or LXXXI is 
utilized, two diastereoisomers of the compound of Formula V, XII or LXXXII 
or LXXXV are formed, provided, of course, that R and R.sub.1, if present, 
are identical or taken together are --(CH.sub.2).sub. m -- or 
(Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 -- and that the synthesis is not 
stereospecific. 
The compounds of Formulae I wherein Z is a group of Formula a or b 
(including those of Formulae V, XIV-XVII, XIX, XX, XXII, LXVII, etc.), 
XII, XXXI, XXXII, XXXIV, LXXXII, LXXXV-LXXXVIII, etc. have at least two 
centers of asymmetry and, therefore, may exist in four or more 
stereoisomeric forms. Except where the compound is formed from an 
optically pure precursor already having each chiral carbon atom or where 
the reaction involves the use of a stereospecific reagent that gives an 
optically pure product, the compound is obtained as a mixture of two (if 
formed from an optically pure compound having one center of asymmetry), 
four (if formed from a racemic compound having one center of asymmetry), 
etc. stereoisomers. 
The obtained mixtures of stereoisomers may be separated by conventional 
means. For example, diastereoisomers may be separated by fractional 
crystallization, column chromatography, preparative thin layer 
chromatography and HPLC. Each mixture of four stereoisomers of a compound 
of Formula XX wherein R and R.sub.1 are identical or taken together are 
--(CH.sub.2).sub.m -- or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 -- may, for 
example, be separated by HPLC into its cis and trans (lactone) components, 
each of which is a racemate that may be resolved into two optically active 
enantiomers 
Techniques for resolving a racemate into its two optically active 
enantiomers are known. For example, a racemic compound having a carboxylic 
acid group may be reacted with an optically pure organic base having at 
least one center of asymmetry to form a mixture of diastereoisomeric salts 
that may be separated by fractional crystallization, column 
chromatography, etc. or it may be reacted with an optically pure alcohol 
having at least one center of asymmetry to form a mixture of 
diastereoisomeric esters which may be separated by conventional techniques 
such as those set forth above or below. Likewise, a racemic compound 
having a carboxylic acid, acyl halide, ester or lactone group may be 
reacted with an optically pure organic base, i.e., an amine, to form a 
mixture of diastereoisomeric amides that may be separated by conventional 
means, e.g., fractional crystallization, column chromatography and/or 
HPLC. For example, a racemic lactone of Formula XX may be reacted with an 
excess of R-(+)-.alpha.-methylbenzylamine (or the corresponding S-(-) 
compound) to form a mixture of two diastereoisomeric .sub..alpha. 
-methylbenzylamides which may be separated by, for example, column 
chromatography on a silica gel column and/or by HPLC using a Partisil 
column. Often it is desirable to utilize both techniques, i.e., to 
partially separate the diastereoisomers by column chromatography and to 
purify each fraction by HPLC. Typically, the .alpha.-methylbenzylamides 
are synthesized by reacting the racemic lactone with a large molar excess 
of the amine at 20.degree.-25.degree. C. for 16-24 hours. The reaction is 
run neat, with the excess amine serving as the solvent After the reaction, 
the excess amine is removed by vacuum distillation at 
25.degree.-35.degree. C. After separation, each chiral amide may be 
hydrolyzed to the corresponding, for example, sodium, salt by, for 
example, refluxing with 1.5-3, preferably 2-2.2, equivalents of a base 
such as sodium hydroxide for 5-25 hours in a mixture of water and ethanol. 
The resulting salts may be converted to the corresponding free acids, 
esters, lactones and other salts by conventional means such as the 
reactions set forth in Reaction Schemes V and VI. On the other hand, a 
racemic compound having at least one hydroxy group may be esterified with 
an optically pure carboxylic acid having at least one center of asymmetry 
to form a mixture of diastereoisomeric esters or it may be reacted with an 
equimolar amount of an optically pure trisubstituted silyl halide having 
an asymmetric silicon atom, e.g., 
(-)-.alpha.-naphthylphenylmethylchlorosilane (Sommer et al., J. Am. Chem. 
Soc. 80, 3271 (1958).), in, for example, the presence of 2 moles of 
imidazole per mole of the silyl halide in dry dimethylformamide at 
20.degree.-32.degree. C. for 12-24 hours to form a mixture of two 
diastereoisomeric silyloxy compounds, which mixture may be separated by 
conventional techniques. For example, diastereoisomeric 
(-)-.alpha.-naphthylphenylmethylsilyl derivatives of a lactone of Formula 
XX may be separated on a silica column having covalently bound 
L-phenylglycine. After separation, the optically pure salts, amides, 
esters or silyloxy compounds are reconverted to the corresponding carboxy 
group- or hydroxy group-containing compounds with retention of optical 
purity. For example, (-)-.alpha.-naphthylphenylmethylsilyl and other silyl 
groups may be cleaved by treatment with, for example, 1-4 moles of 
tetra-n-butylammonium fluoride per mole of the silyloxy compound and 1-2 
moles, preferably 1.2-1.5 moles, of glacial acetic acid per mole of 
tetra-n-butylammonium fluoride at 20.degree.-60.degree. C., preferably 
20.degree.-25.degree. C., for 2-30 hours, preferably 3-8 hours, in an 
anhydrous ether solvent, preferably tetrahydrofuran, the silyloxy compound 
being added to a solution of the other reactants. 
The compounds of Formulae III, VI, VIII, IX, XI, XIII, XVIII, XXI, XLI-XLV, 
XLVII, XLIX, LIII, LIV, LVI, LXII, LXIII, LXV, LXXII, LXXVIII, LXXIX, 
LXXX, LXXXIII and LXXXIV and the reagents not designated by a Roman 
numeral are known or, if unknown, may be synthesized by processes 
analogous to those described in the literature for similar known 
compounds. 
A preferred process for the synthesis of the erythro racemate of the 
compound of Formula LXXXVII wherein R.sub.10 is hydrogen, and R'.sub.12 is 
methyl is disclosed in Kapa, Tetrahedron Letters 25, 2435-2438 (1984). The 
other compounds of Formula LXXXVII wherein R.sub.10 is hydrogen in racemic 
erythro form may be synthesized similarly See also U.S. Pat. No. 
4,571,428. Said patent, particularly columns 3-10 thereof, is hereby 
incorporated by reference. 
The preferred process for the synthesis of the 3R,5S enantiomer of the 
compound of Formula LXXXVII wherein R.sub.10 is hydrogen and R'.sub.12 is 
t-butyl is disclosed in U.S. Pat. No. 4,808,607, columns 63-69 of which 
are hereby incorporated by reference, U.S. Pat. No. 4,822,799, columns 
31-38 of which are hereby incorporated by reference, and U.S. Pat. No. 
4,870,199, column 1, lines 13-55, column 7, lines 10-66, column 9, line 
1--column 19, line 16 and column 26, line 36--column 33, line 52 of which 
are hereby incorporated by reference. U.S. Pat. No. 4,870,199 also 
discloses the synthesis of other compounds of Formula LXXXVII wherein 
R.sub.10 is hydrogen in 3R,5S enantiomeric form. 
The compound of Formula XXXVI and its synthesis is disclosed in U.S. Pat. 
No. 4,613,610. Columns 19, 20 and 38-42 of said patent are hereby 
incorporated by reference. 
Since any compound of Formula I wherein Z is a group of Formula a or c 
wherein R.sub.11 is a cation other than M may be converted into the 
corresponding compound wherein R.sub.11 is hydrogen, M or R.sub.12 by the 
processes of Reaction Schemes V and VI, the compounds of Formula I wherein 
Z is a group of Formula a or c and R.sub.11 is a pharmaceutically 
unacceptable cation are also within the scope of this invention since they 
are useful as intermediates. However, such compounds are not compounds of 
Formula I as utilized in this specification, except where indicated to the 
contrary. 
Also within the scope of this invention are the intermediates of Formulae 
II, IV, VII, X, XII, XXXII, XXXIV, XXXVII, XXXIX, XLVIII, L-LII, LV, 
LVII-LXI and LXIV. The preferences for each variable are the same as those 
set forth for the compounds of Formula I, with the preferred groups of 
such compounds including those that correspond to Groups (i)-(xxxvi) to 
the extent consistent therewith. 
The entire specification of grandparent application Ser. No. 06/677,917, 
particularly pages 1-8, 34-40 and 60-67, is hereby incorporated by 
reference, as if set forth herein in its entirety. 
Besides having the utility set forth below, every compound of Formula I is 
useful as an intermediate in the synthesis of one or more other compounds 
of Formula I utilizing the reactions set forth in Reaction Schemes V and 
VI. 
The compounds of Formula I are competitive inhibitors of 
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate 
limiting enzyme in cholesterol biosynthesis, and, therefore, they are 
inhibitors of cholesterol biosynthesis. Consequently, they are useful for 
lowering the blood cholesterol level in animals, e.g., mammals, especially 
larger primates such as humans, and, therefore, as hypolipoproteinemic and 
anti-atherosclerotic agents. The biological activity of the compounds of 
Formula I may be demonstrated in the following two tests: 
Test A. In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition: 
200 .mu.l. aliquots (1.08-1.50 mg./ml.) of rat liver microsomal 
suspensions, freshly prepared from male Sprague-Dawley rats (150-225 g. 
body weight), in Buffer A with 10 mmol. dithiothreitol are incubated with 
10 .mu.l. of a solution of the test substance in dimethylacetamide and 
assayed for HMG-CoA reductase activity as described in Ackerman et al., J. 
Lipid Res. 18, 408-413 (1977), the concentration of the test substance in 
the assay system being 0.0001-2,000 .mu.molar. In the assay the microsomes 
are the source of the HMG-CoA reductase enzyme which catalyzes the 
reduction of HMG-CoA to mevalonate. The assay employs a chloroform 
extraction to separate the product, [.sup.14 C]mevalonolactone, formed by 
the HMG-CoA reductase reduction of the substrate, [.sup.14 C]HMG-CoA. 
[.sup.3 H]mevalonolactone is added as an internal reference. Inhibition of 
HMG-CoA reductase is calculated from the decrease in specific activity 
([.sup.14 C/.sup.3 H]mevalonate) of test groups compared to controls. 
Test B. In Vivo Cholesterol Biosynthesis Inhibition Test: 
In vivo studies utilize male Wistar Royal Hart rats weighing 150.+-.20 g. 
which have been kept for 7-10 days on an 
altered light cycle (6:30 A.M.-6:30 P.M. dark) housed two per cage and fed 
powdered Purina Rat Chow and water ad libitum. Three hours before the 
diurnal maximum of cholesterol synthesis at mid-dark, the rats are orally 
administered the test substance (e.g., 0.01-200 mg./kg. body weight) 
dissolved or as a suspension in 0.5% carboxymethylcellulose in a volume of 
1 ml./100 g. body weight. Controls receive vehicle alone. One hour after 
receiving the test substance (or the vehicle alone), the rats are injected 
intraperitoneally with about 25 .mu.Ci/100 g. body weight of sodium 
[1-.sup.14 C]acetate 1-3 mCi/mmol. Two hours after mid-dark, blood samples 
are obtained under sodium hexobarbitol anesthesia, and the serum is 
separated by centrifugation. 
Serum samples are saponified and neutralized, and the 
3.beta.-hydroxysterols are precipitated with digitonin basically as 
described in Sperry et al., J. Biol. Chem. 187, 97 (1950). The [.sup.14 
C]digitonides are then counted by liquid scintillation spectrometry. After 
correcting for efficiencies, the results are calculated in nCi 
(nanocuries) of 3.beta.-hydroxysterol formed per 100 ml. of serum. 
Inhibition of 3.beta.-hydroxysterol synthesis is calculated from the 
reduction in the nCi of 3.beta.-hydroxysterols formed from test qroups 
compared to controls. 
The following results were obtained: 
______________________________________ 
Test A: 
Example 2 IC.sub.50 = 
0.005 .mu.molar 
Example 2A IC.sub.50 = 
0.003 .mu.molar 
Example 7 IC.sub.50 = 
0.15 .mu.molar 
Example 8 IC.sub.50 = 
0.007 .mu.molar 
Example 17 IC.sub.50 = 
4.7 .mu.molar 
Example 20 IC.sub.50 = 
0.53 .mu.molar 
Example 24 IC.sub.50 = 
0.019 .mu.molar 
Compactin IC.sub.50 = 
1.01 .mu.molar 
Mevinolin IC.sub.50 = 
0.14 .mu.molar 
______________________________________ 
IC.sub.50 is the concentration of the test substance in the assay system 
calculated or observed to produce a 50% inhibition of HMG-CoA reductase 
activity. 
______________________________________ 
Test B: 
Example 2 ED.sub.50 = 
0.07 mg./kg. 
Example 2A ED.sub.50 = 
0.02 mg./kg. 
Example 8 ED.sub.50 = 
0.31 mg./kg. 
Example 24 ED.sub.50 = 
0.71 mg./kg. 
Compactin ED.sub.50 = 
3.5 mg./kg. 
Mevinolin ED.sub.50 = 
0.38 mg./kg. 
______________________________________ 
ED.sub.50 is the dose of the test substance calculated or observed to 
produce a 50% inhibition of 3.beta.-hydroxysterol synthesis. 
As set forth above, the compounds of Formula I (including each and every 
subgroup thereof set forth in the specification and/or the claims) inhibit 
cholesterol biosynthesis and are useful for lowering the blood cholesterol 
level in animals, particularly mammals and more particularly larger 
primates, and, therefore, as hypolipoproteinemic and antiatherosclerotic 
agents. 
The compounds of Formula I may be formulated into conventional 
pharmaceutical compositions and administered by conventional modes of 
administration. The compounds of each and every subgroup thereof in the 
specification and/or claims may likewise be formulated into conventional 
pharmaceutical compositions. 
The compounds of Formula I may be combined with one or more 
pharmaceutically acceptable carriers and, optionally, one or more other 
conventional pharmaceutical adjuvants and administered orally in the form 
of tablets, dispersible powders, granules, capsules, elixirs, suspensions 
and the like or parenterally in the form of sterile injectable solutions 
or suspensions. The compositions may be prepared by conventional means. 
The preferred pharmaceutical compositions from the stand-point of ease of 
preparation and administration are solid compositions, particularly 
tablets and capsules. 
The precise dosage of the compound of Formula I to be employed for 
inhibiting cholesterol biosynthesis depends upon several factors including 
the host, the nature and the severity of the condition being treated, the 
mode of administration and the particular compound employed However, in 
general, satisfactory inhibition or reduction of cholesterol biosynthesis 
(i.e., satisfactory reduction of the blood cholesterol level and 
satisfactory treatment of hyperlipoproteinemia and atherosclerosis) is 
achieved when a compound of Formula I is administered orally at a daily 
dosage of 0.01-100 mg./kg. body weight, e.g., 0.01-10 mg./kg. body weight 
for the more active compounds and 0.01-2.5 mg./kg. for the compounds of 
Examples 2, 2A and 8. For most larger primates, a suitable oral daily 
dosage is indicated to be 1-2,000 mg., preferably 1-150 mg., e.g., 1-30 
mg., for the more active compounds. For the compounds of Examples 2, 2A 
and 8 it is indicated to be 1-30 mg., e.g., 1-10 mg. (1-4 mg. for the 
compound of Example 2A). 
The daily dosage is usually divided into two to four equal portions or 
administered in sustained release form. Usually, a small dosage is 
administered initially, and the dosage is gradually increased until the 
optimal dosage for the host under treatment is determined. For 
administration by injection, a dosage somewhat lower than would be used 
for oral administration of the same compound to the same host having the 
same condition is usually employed. However, the above dosages are also 
typically used for i.v. administration. 
A typical dosage unit for oral administration may contain 0.25-500 mg. of a 
compound of Formula I. Preferred dosage units contain 0.25-5 mg. of a 
compound of Formula I such as the compounds of Examples 2, 2A and 8. 
The compounds of Formula I (including those of each and every subgroup 
thereof) may be formulated into such pharmaceutical compositions 
containing an amount of the active substance that is effective for 
inhibiting cholesterol biosynthesis, such compositions in unit dosage form 
and such compositions comprising a solid pharmaceutically acceptable 
carrier. 
Representative formulations suitable for encapsulation in a hard gelatin 
capsule by conventional techniques are: 
______________________________________ 
Compound of Formula I, e.g., the compound of 
1 mg. 
Example 2 or 2A 
Corn starch 248 mg. 
Magnesium stearate 1 mg. 
______________________________________ 
A representative formulation suitable for preparing tablets by conventional 
means is: 
______________________________________ 
Compound of Formula I, e.g., the compound of 
2.5 mg. 
Example 8 
Polyvinylpyrrolidone USP 5 mg. 
Powdered lactose 181.5 mg. 
Corn starch 10 mg. 
Magnesium stearate 1 mg. 
______________________________________

The following examples show representative compounds encompassed by this 
invention and their synthesis. However, it should be understood that they 
are for purposes of illustration only. 
EXAMPLE 1 
Ethyl 
erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1 
H)-inden]-2'-yl]hept-6-enoate 
##STR17## 
Step 1 (Reaction AA) 
3-(4'-Fluororophenyl)-1H-indene (Compound CII) 
A solution of 5.1 g. (39 mmoles) of 1-indanone in 15 ml. of anhydrous 
diethyl ether is added over a 30 minute period to a solution of 
4-fluorophenylmagnesium bromide (prepared from 7.97 g. (45.5 mmoles) of 
1-bromo-4-fluorobenzene, 1.33 g. (54.7 mmoles) of magnesium turnings and a 
trace of iodine in 25 ml. of anhydrous diethyl ether) stirred at 
20.degree.-25.degree. C. under nitrogen. The reaction mixture is stirred 
at 20.degree.-25.degree. C. under nitrogen for 16 hours and quenched with 
saturated ammonium chloride solution. The organic phase is separated, 
dried over anhydrous sodium sulfate and evaporated at reduced pressure, 
and the residual oil (8.4 g.) is dissolved in 16 ml. of glacial acetic 
acid. The obtained solution is refluxed for 15 minutes, and the acetic 
acid is evaporated at reduced pressure. The residue is flash 
chromatographed on a silica gel column utilizing 10% ethyl 
acetate/petroleum ether as the eluant, and the eluant is evaporated at 
reduced pressure to obtain a solid (6.4 g.) which is recrystallized from 
95% ethanol to obtain the product (3.6 g.), m.p. 35.degree.-36.degree. C. 
First revised procedure 
About 10 ml. (.about.15.9 g.; 0.091 mole) of 1-bromo-4-fluorobenzene is 
added to a mixture of 60 g. (2.47 moles) of magnesium turnings, about 50 
mg. of iodine and 250 ml. of dry tetrahydrofuran stirred at 
20.degree.-25.degree. C. under nitrogen during the course of which the 
temperature rises to about 40.degree. C. A solution of 243 ml. (387.1 g., 
2.21 moles) of 1-bromo-4-fluorobenzene in 750 ml. of dry tetrahydrofuran 
is added dropwise over a 2 hour period at a rate such that the reaction 
mixture refluxes gently, the reaction mixture is refluxed for 1 hour, 
cooled to 15.degree. C. and added dropwise to a solution of 250 g. (1.89 
moles) of 1-indanone in 500 ml. of dry tetrahydrofuran over a period of 1 
hour, the temperature of the reaction mixture being 15.degree.-30.degree. 
C. during the addition, and the reaction mixture is stirred at 
20.degree.-25.degree. C. for 16 hours, the reaction mixture being stirred 
under nitrogen throughout. The reaction mixture is poured into a cooled 
mixture of 1 1. of saturated ammonium chloride solution and 250 ml. of 
concentrated hydrochloric acid, the two phase mixture is stirred for 30 
minutes, and the lower (aqueous) phase is separated and discarded. The 
organic phase is washed twice with 1 1. portions of saturated sodium 
chloride solution (until the washing is neutral) and concentrated at 
45.degree.-50.degree. C. and reduced pressure to a volume of about 250 
ml., 200 ml. of n-heptane is added, and the mixture is evaporated at 
50.degree. C. and reduced pressure to an oil. 800 ml. of methanol is 
added, the mixture is stored at 0.degree. C. for 16 hours, and the 
resulting tan precipitate is collected by filtration, washed twice with 
200 ml. portions of cold methanol and vacuum dried at 
20.degree.-25.degree. C. to constant weight to obtain the product (255.5 
g.), m.p. 38.degree.-40.degree. C. The mother liquor is concentrated to a 
volume of about 250 ml. and cooled, and the resulting precipitate is 
collected, washed twice with 50 ml. portions of cold methanol and vacuum 
dried to constant weight (72 g.), m.p. 35.degree.-37.degree. C. Total 
yield: 327.5 g. (82.4%). 
Second revised procedure 
10 ml. (15.93 g., 0.091 mole) of 1-bromo-4-fluorobenzene is added to a 
mixture of 60 g. (2.47 moles) of magnesium turnings, .about.50 mg. of 
iodine and 250 ml. of tetrahydrofuran (dried over molecular sieves) 
stirred at 20.degree.-25.degree. C. under nitrogen and, when the reaction 
commences (the internal temperature rising to about 40.degree. C. ), a 
solution of 243 ml. (387.1 g., 2.21 moles) of 1-bromo-4-fluorobenzene in 
750 ml. of tetrahydrofuran (dried over molecular sieves) is added dropwise 
over a period of 2 hours while maintaining a gentle reflux 
(.about.70.degree. C. internal temperature), the reaction mixture is 
refluxed for 1 hour and cooled to 15.degree. C., a solution of 250 g. 
(1.89 moles) of 1-indanone in 500 ml. of tetrahydrofuran (dried over 
molecular sieves) is added dropwise over a period of 1 hour (the internal 
temperature being 15.degree.- 30.degree. C. ), and the reaction mixture is 
stirred at 20.degree.-25.degree. C. for 16 hours, the reaction mixture 
being stirred under nitrogen throughout. The reaction mixture is 
cautiously poured into a cold mixture of 1 1. of saturated ammonium 
chloride solution and 250 ml. of concentrated hydrochloric acid (the 
addition being exothermic), the mixture is stirred for 30 minutes, the 
aqueous (lower) phase is discarded, and the organic phase is washed three 
times with 1 1. portions of saturated sodium chloride solution (until the 
washing is neutral) and concentrated at 45.degree.-50.degree. C. (external 
temperature) and reduced pressure to a volume of about 250 ml. 800 ml. of 
methanol is added, the resulting mixture is maintained at 
0.degree.-10.degree. C. for 16 hours, stirred at -10.degree.-0.degree. C. 
and seeded, and the resulting solid is collected by filtration, washed 
with 200 ml. of cold methanol and vacuum dried at 20.degree.-25.degree. C. 
to obtain the product (275 g.), m.p. 39.degree.-41.degree. C. The mother 
liquor is concentrated, 200 ml. of methanol is added, the mixture is 
maintained at 0.degree.-10.degree. C. , and the resulting solid is 
collected by filtration and vacuum dried at 20.degree.-25.degree. C. to 
obtain a less pure second crop (57.5 g.), m.p. 33.degree.-39.degree. C. 
Step 2 (Reaction AB) 
3-(4'-Fluorophenyl)-1H-indene-2-carboxaldehyde (Compound CIII) 
5 ml. of acetonitrile is added to a mixture of 0.973 ml. (10 mmoles) of 
phosphorus oxychloride and 1.3 ml. (10 mmoles) of N-methylformanilide 
stirred at 20.degree.-25.degree. C., the reaction mixture is stirred at 
20.degree.-25.degree. C. for 30 minutes and cooled to 5.degree. C., a 
solution of 2 g. (9.5 mmoles) of Compound CII in 5 ml. of acetonitrile is 
added dropwise with stirring, and the reaction mixture is stirred at 
20.degree.-25.degree. C. for 6.5 hours, the reaction mixture being 
maintained under nitrogen throughout. The reaction mixture is poured onto 
ice and extracted several times with 4:1 diethyl ether/petroleum ether. 
The extracts are combined, washed with water, washed with saturated sodium 
chloride solution, dried over anhydrous sodium sulfate, passed through a 
short silica gel column and evaporated at reduced pressure to obtain the 
crude product as an oil (2.04 g.). The oil is dissolved in chloroform and 
flash chromatographed on a silica gel column, the eluant is evaporated at 
reduced pressure, and the residue is crystallized from petroleum ether to 
obtain the product (2.9 g.), m.p. 70.degree.-71.degree. C. 
Revised procedure 
A mixture of 26.6 ml. (43.8 g.; 285.4 mmoles) of phosphorus oxychloride and 
35.2 ml. (38.5 g.; 285.1 mmoles) of N-methylformanilide is allowed to 
stand at 20.degree.-25.degree. C. for 30 minutes under nitrogen. The 
resulting yellow solution is cooled to 10.degree. C., a solution of 50 g. 
(238 mmoles) of Compound CII in 120 ml. of acetonitrile is added dropwise, 
and the reaction mixture is stirred at 20.degree.-25.degree. C. for 16 
hours, the reaction mixture being stirred under nitrogen throughout. The 
reaction mixture is poured into cold water, and the mixture is extracted 
twice with diethyl ether. The diethyl ether extracts are combined, washed 
with water, washed with saturated sodium chloride solution, dried over 
anhydrous sodium sulfate and evaporated at reduced pressure to obtain the 
crude product as a brown oil (57.5 g.). 
Step 3 (Reaction AC) 
Methyl (E)-3-[3'-(4"-fluorophenyl)-1H-inden-2'-yl]propenoate (Compound CV) 
A solution of 573 mg. (2.42 mmoles) of Compound CIII and 1.01 g. (2.91 
mmoles) of (carbomethoxymethylene)triphenylphosphorane (Compound CIV) in 6 
ml. of dry toluene is refluxed under nitrogen for 7 hours. The reaction 
mixture is cooled to 20.degree.-25.degree. C., diethyl ether is added, and 
the mixture is filtered through a short silica gel column. The eluate is 
evaporated at reduced pressure to obtain a yellow oil which is 
crystallized from 95% ethanol to obtain the product (302 mg.), m.p. 
121.degree.-122.degree. C. 
Revised procedure 
80.9 g. (241.9 mmoles) of Compound CIV is added to a solution of 48 g. 
(.ltoreq.201 mmoles) of crude Compound CIII (from Step 2, revised 
procedure) in 300 ml. of toluene, the reaction mixture is refluxed for 6 
hours and cooled to 20.degree.-25.degree. C., the reaction mixture being 
stirred under nitrogen throughout. 1 1. of diethyl ether is added, and the 
mixture is filtered through a short pad (150 g.) of 230-400 mesh A.S.T.M. 
silica gel and evaporated at reduced pressure. The obtained solid is 
recrystallized from methanol to obtain the product as a yellow solid (39 
g.). The mother liquor is concentrated at reduced pressure and flash 
chromatographed through a silica gel column utilizing 1:1 diethyl 
ether/petroleum ether as the eluant The filtrate is evaporated at reduced 
pressure to obtain additional product (9.89 g.). Total yield: 48.89 g. 
(82%). M.p. 121.degree.-122.degree. C. 
Step 4 (Reaction AD) 
Methyl 
(E)-3-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]propen 
oate (Compound CVI) 
112 mg. (2.3 mmoles) of sodium hydride (as a 50% by weight dispersion in 
mineral oil) is added to a solution of 340 mg. (1.16 mmoles) of Compound 
CV in 5 ml. of dry dimethylformamide stirred at 0.degree. C. , the 
reaction mixture is stirred at 0.degree. C. for 10 minutes, 0.143 ml. 
(1.16 mmoles) of 1,4-dibromobutane is added dropwise with stirring over a 
5 minute period, and the reaction mixture is allowed to gradually warm to 
20.degree.-25.degree. C. with stirring and stirred at 
20.degree.-25.degree. C. for 16 hours, the reaction mixture being 
maintained under nitrogen throughout. The reaction mixture is diluted with 
diethyl ether, dilute hydrochloric acid is added, and the mixture is 
extracted three times with diethyl ether. The diethyl ether extracts are 
combined, washed with water, washed with saturated sodium chloride 
solution, dried over anhydrous sodium sulfate, filtered and evaporated to 
dryness at reduced pressure. The residue is chromatographed on a silica 
gel column utilizing 4:1 petroleum ether/acetone as the eluant to obtain 
the product (250.4 mg.), m.p. 143.degree.-145.degree. C. 
Revised procedure 
12 g. of 50% sodium hydride/mineral oil (246 mmoles) is added portionwise 
to a solution of 36 g. (123 mmoles) of Compound CV in 320 ml. of dry 
dimethylformamide stirred at 0.degree. C., the reaction mixture is stirred 
at 0.degree. C. for 10 minutes, 14.7 ml. (123 mmoles) of 1,4-dibromobutane 
is added dropwise with stirring at 0.degree. C., and the reaction mixture 
is allowed to warm to 20.degree.-25.degree. C. and stirred at 
20.degree.-25.degree. C. for 16 hours, the reaction mixture being stirred 
under nitrogen throughout. The reaction mixture is poured into cold dilute 
hydrochloric acid, and the mixture is extracted three times with diethyl 
ether. The diethyl ether extracts are combined, washed with water, washed 
with saturated sodium chloride solution, dried over anhydrous sodium 
sulfate, filtered and evaporated at reduced pressure. In order to esterify 
any small amount of free acid that may be present, 150 ml. of methanol and 
0.5 ml. of acetyl chloride are added to the residual solid, and the 
mixture is refluxed for 5 hours, cooled and evaporated at reduced 
pressure. The residue is recrystallized from methanol to obtain the 
product as a yellow solid (30 g. (71%)), m.p. 143.degree.-145.degree. C. 
Step 5 (Reaction AE) 
(E)-3-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]prop-2- 
en-1-ol (Compound CVII) 
2 ml. of 1.5M. diisobutylaluminum hydride/toluene (3 mmoles) is added 
dropwise to a solution of 220 mg. (0.632 mmole) of Compound CVI in 4 ml. 
of dry methylene chloride stirred at -78.degree. C. under nitrogen, and 
the reaction mixture is stirred under the same conditions for 20 minutes, 
quenched with dilute hydrochloric acid and extracted several times with 
methylene chloride. The methylene chloride extracts are combined, washed 
with water, washed with saturated sodium chloride solution, dried over 
anhydrous sodium sulfate, filtered and evaporated at reduced pressure to 
obtain the product which solidifies upon standing (184 mg.), m.p. 
102.degree.-104.degree. C. 
Revised procedure 
110 ml. of 1.5M. diisobutylaluminum hydride/toluene (165 mmoles) is added 
dropwise to a solution of 29 g. (83 mmoles) of Compound CVI in 250 ml. of 
methylene chloride stirred at -50.degree. C., and the reaction mixture is 
stirred at -50.degree. C. for 15 minutes, the reaction mixture being 
stirred under nitrogen throughout. The reaction mixture is poured into 
cold 1N. hydrochloric acid and extracted three times with methylene 
chloride. The methylene chloride extracts are combined, washed with water, 
washed with saturated sodium chloride solution, dried over anhydrous 
sodium sulfate, filtered and evaporated at reduced pressure to obtain the 
crude product as a pale yellow solid (26.5 g.). 
Step 6 (Reaction AF) 
(E)-3-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]prop-2- 
enal (Compound CVIII) 
300 mg. (3.45 mmoles) of activated manganese dioxide is added to a solution 
of 170 mg. (0.531 mmole) of Compound CVII in 4 ml. of dry toluene stirred 
at 20.degree.-25.degree. C., and the reaction mixture is stirred at 
20.degree.-25.degree. C. under nitrogen for 24 hours, filtered to remove 
the manganese dioxide and evaporated at reduced pressure to obtain the 
yellow product which solidifies upon standing (150 mg.), m.p. 
123.degree.-125.degree. C. 
Revised procedure 
A mixture of 26 g. (.ltoreq.81 mmoles) of crude Compound CVII (from Step 5, 
revised procedure), 60 g. (690 mmoles) of activated manganese dioxide and 
300 ml. of toluene is stirred at 20.degree.-25.degree. C. for 48 hours 
under nitrogen, 300-600 ml. of diethyl ether is added to dilute the 
reaction mixture, and the mixture is filtered through a short pad (50 g.) 
of 230-400 mesh A.S.T.M. silica gel. The filtrate is evaporated at reduced 
pressure, and the residue is recrystallized from diethyl ether/petroleum 
ether to obtain the product as a yellow solid (15.5 g. (60% (Steps 5 and 6 
combined))), m.p. 129.degree.-130.degree. C. 
Step 7 (Reaction A) 
Ethyl 
(E)-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]-5-hyd 
roxy-3-oxohept-6-enoate (Compound CIX) 
(a) A stock solution of the dianion of ethyl acetoacetate is prepared as 
follows: 7.5 ml. of 1.6M. n-butyllithium/hexane (12.0 mmoles) is added 
over a period of 5 minutes to a solution of 1.23 g. (12.2 mmoles) of 
diisopropylamine in 25 ml. of dry tetrahydrofuran stirred at 
-5.degree.-0.degree. C. under nitrogen, the rate of addition being such 
that the temperature does not exceed 5.degree. C. The reaction mixture is 
stirred at -30.degree. C. for 15 minutes under nitrogen, 780.8 mg. (6 
mmoles) of ethyl acetoacetate (dried over molecular sieves) is slowly 
added, and the reaction mixture is stirred at -30.degree.--20.degree. C. 
under nitrogen for 45 minutes. 
(b) 3.3 ml. of the stock solution of the dianion of ethyl acetoacetate of 
Part (a) (0.6 mmole) is added to a solution of 126 mg. (0.396 mmole) of 
Compound CVIII in 3 ml. of dry tetrahydrofuran stirred at -60.degree. C. 
under nitrogen, and the reaction mixture is stirred under the same 
conditions for 1 hour, quenched with water, acidified with dilute 
hydrochloric acid and extracted three times with ethyl acetate. The ethyl 
acetate extracts are combined, washed with water, washed with saturated 
sodium chloride solution, dried over anhydrous sodium sulfate, filtered 
and evaporated to dryness at reduced pressure. The residue is purified by 
preparative thin layer chromatography on silica gel plates utilizing 4:1 
petroleum ether/acetone as the solvent to obtain the product as a pale 
yellow oil (140 mg.). 
Revised procedure 
12 ml. (94 mmoles) of ethyl acetoacetate is added to a solution of lithium 
diisopropylamide in dry tetrahydrofuran (prepared from 26.4 ml. (188.3 
mmoles) of diisopropylamine, 118 ml. of 1.6M. n-butyllithium/hexane (188.8 
mmoles) and 150 ml. of dry tetrahydrofuran at 0.degree. C. for 5 minutes 
under nitrogen) stirred at -30.degree. C., the reaction mixture is stirred 
at -30.degree.--20.degree. C. for 30 minutes, a solution of 15 g. (47 
mmoles) of Compound CVIII in 50 ml. of dry tetrahydrofuran is added 
dropwise with stirring at -30.degree. C., and the reaction mixture is 
stirred at -30.degree.-20.degree. C. for 30 minutes, the reaction mixture 
being stirred under nitrogen throughout. The reaction mixture is poured 
into an about 1:5 mixture of cold 1N. hydrochloric acid and ethyl acetate, 
the organic phase is separated, the aqueous phase is extracted with ethyl 
acetate, and the ethyl acetate extract and the organic phase are combined, 
washed with water, washed with saturated sodium chloride solution, dried 
over anhydrous sodium sulfate, filtered and evaporated at reduced pressure 
to obtain the crude product as an oil (16 g.). 
The product is a racemate that may be resolved by conventional means to 
obtain the 5R and 5S enantiomers. 
Step 8 (Reaction B) 
Ethyl 
erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1 
H)-inden]-2'-yl]hept-6-enoate (Compound CX) 
(a) 0.8 ml. of 1M. triethylborane/tetrahydrofuran (0.8 mmole) is added to a 
solution of 300 mg. (0.67 mmole) of Compound CIX in 10 ml. of dry 
tetrahydrofuran stirred at 20.degree.-25.degree. C. , 0.2 ml. of air is 
added via syringe, the reaction mixture is stirred at 
20.degree.-25.degree. C. for 2 hours and cooled to -78.degree. C., 0.06 g. 
(1.59 mmoles) of sodium borohydride is added in one portion, and the 
reaction mixture is stirred at -78.degree. C. for 48 hours, the reaction 
mixture being maintained under nitrogen throughout. The cooling bath is 
removed, and 1N. hydrochloric acid is slowly added dropwise until the 
evolution of hydrogen ceases and the mixture is acidic (pH .about.5), the 
internal temperature of the mixture being maintained below -20.degree. C. 
throughout. 10 ml. of water is added, the mixture is extracted three times 
with diethyl ether, and the diethyl ether extracts are combined, washed 
twice with water, washed with saturated sodium chloride solution, dried 
over anhydrous sodium sulfate, filtered and evaporated at reduced pressure 
to obtain a crude oil. 
(b) A solution of the product of Part (a) in 5 ml. of methanol is stirred 
at 20.degree.-25.degree. C. for 66 hours under nitrogen and evaporated to 
dryness at reduced pressure. The residue is chromatographed on a silica 
gel column utilizing 1:1 diethyl ether/petroleum ether as the eluant to 
obtain the crude product which solidifies on standing (182 mg.). Repeated 
recrystallization from diethyl ether/hexane gave the product as a white 
solid, m.p. 90.degree.-92.degree. C. 
Revised procedure 
(a) 40 ml. of 1M. triethylborane/tetrahydrofuran (40 mmoles) is added to a 
solution of 16 g. (.ltoreq.33 mmoles) of crude Compound CIX (from Step 7, 
revised procedure) in 200 ml. of tetrahydrofuran, 10 ml. of air (at 
25.degree. C. and 760 mm. Hg) is bubbled in via syringe, the reaction 
mixture is stirred at 20.degree.-25.degree. C. for 2 hours and cooled to 
-78.degree. C., 2 g. (53 mmoles) of solid sodium borohydride is added, and 
the reaction mixture is stirred at -78.degree. C. for 48 hours, the 
reaction mixture being stirred under nitrogen throughout. The cooling bath 
is removed, the reaction mixture is slowly quenched at 
-78.degree.-60.degree. C. with 110 ml. of 1N. hydrochloric acid, 500 ml. 
of water is added, and the mixture is extracted three times with diethyl 
ether. The diethyl ether extracts are combined, washed with water, washed 
with saturated sodium chloride solution, dried over anhydrous sodium 
sulfate, filtered and evaporated at reduced pressure to obtain a pale 
yellow oil (17.2 g.). 
(b) A solution of the pale yellow oil of Part (a) in 100 ml. of methanol is 
stirred at 20.degree.-25.degree. C. for 48 hours and evaporated at reduced 
pressure, and the residual oil is flash chromatographed through a silica 
gel column utilizing 1:1 diethyl ether/petroleum ether as the eluant. The 
eluant is evaporated at reduced pressure to obtain a white solid (9 g.) 
which is recrystallized two or three times from diethyl 1 ether/petroleum 
ether to obtain the pure product (.about.4-5 g.), m.p. 
90.degree.-93.degree. C. 
N.M.R. (CDCl.sub.3): 1.3 (t, 3H), 1.6-1.9 (m, 4H), 2.2 (m, 6H), 2.5 (m, 
2H), 3.2 (bs, 1H), 3.7 (bs, 1H), 4.15 (q, 2H), 4.25 (m, 1H), 4.45 (m, 1H), 
5.8 (dd (J.sub.1 =8 Hz., J.sub.2 =20 Hz.), 1H), 6.5 (d (J=20 Hz.), 1H), 
7.0-7.5 (m, 8H) 
The product is an about 19:1 (revised procedure) or 24:1 (initial 
procedure) mixture of the erythro and threo racemates which may be 
separated by conventional means. The principal product, the erythro 
racemate, may be resolved into two optically pure enantiomers, the 3R,5S 
and 3S,5R isomers, of which the former is preferred. The minor product, 
the threo racemate, may be resolved into the 3R,5R and 3S,5S isomers, of 
which the former is preferred. The use of a nonstereoselective reduction 
would afford a mixture of all four stereoisomers wherein the ratio of the 
erythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3. 
EXAMPLE 1A 
1,1-Dimethylethyl 
(3R,5S)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'-( 
1H)-inden]2'-yl]hept-6-enoate 
##STR18## 
Step 1 (Reaction AM) 
3-(4'-Fluorophenyl)spiro[cyclopentane-1,1'(1H)-indene](Compound CXXXI) 
135 g. of 60% sodium hydride/mineral oil (3.375 moles) is added portionwise 
over a period of 40 minutes to a solution of 275 g. (1.31 moles) of 
Compound CII in 2.7 1. of HPLC grade tetrahydrofuran stirred at 
0.degree.-5.degree. C., the mixture is stirred at 0.degree. C. for 30 
minutes, 156 ml. (282 g., 1.31 moles) of 1,4-dibromobutane is added over a 
period of 15 minutes with stirring at 0.degree.-5.degree. C. , and the 
reaction mixture is allowed to slowly warm to 20.degree.-25.degree. C. and 
is stirred at 20.degree.-25.degree. C. for 16 hours, the reaction mixture 
being stirred under nitrogen throughout. The reaction mixture is poured 
into 3 l. of cold 2N. hydrochloric acid, and the mixture is extracted 
twice with 1 l portions of ethyl acetate. The ethyl acetate extracts are 
combined, washed with 1.5 l of water, washed with 1.5 l of saturated 
sodium chloride solution, dried over anhydrous sodium sulfate, filtered 
and evaporated at 50.degree. C. and reduced pressure to obtain a red oil 
(474 g.). The red oil is divided in half, and each 237 g sample is 
dissolved in the minimum amount of 10% acetone/hexane and chromatographed 
on a mixture of 500 g. of 70-230 mesh A.S.T.M. silica gel and 500 g. of 
230-400 mesh A.S.T.M. silica gel utilizing 6 l of hexane as the eluant The 
fractions containing the product as indicated by thin layer chromatography 
(TLC) are combined and evaporated at reduced pressure to obtain the 
product as a yellow oil (242 g.). 
Step 2 (Reaction AH) 
3-(4'-Fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2-carboxaldehyde 
(Compound CXXXII) 
778 g. (5.07 moles) of phosphorus oxychloride is added to 685 g. (5.07 
moles) of N-methylformanilide stirred at 20.degree.-25.degree. C. (the 
temperature rising to 35.degree. C.), the reaction mixture is cooled to 
20.degree.-25.degree. C. and stirred at this temperature for 25 minutes, a 
solution of 269 g. (1.02 moles) of Compound CXXXI in 650 ml. of 
acetonitrile is added with stirring at 25.degree.-38.degree. C. over a 
period of 20 minutes, and the reaction mixture is heated to reflux (it 
exotherms at .about.75.degree.-85.degree. C. ), refluxed for 32 hours and 
stirred at 20.degree.-25.degree. C. for 3 days, the reaction mixture being 
stirred under nitrogen throughout. The reaction mixture is poured 
portionwise into a mixture of 6 l of 10% sodium hydroxide solution and 4 
kg. of ice, and the mixture is extracted three times with 2 l portions of 
ethyl acetate. The ethyl acetate extracts are combined, washed twice with 
6 l portions of water and once with 4 l of saturated sodium chloride 
solution, dried over anhydrous sodium sulfate, filtered and evaporated at 
50.degree.-55.degree. C. and reduced pressure to obtain a brown oil (600 
g.). The brown oil is divided in half, and each 300 g. sample is dissolved 
in the minimum amount of methylene chloride and chromatographed on a pad 
consisting of a mixture of 500 g. of 70-230 mesh A.S.T.M. silica gel and 
500 g of 230-400 mesh A.S.T.M. silica gel utilizing 5 l of 20% ethyl 
acetate/hexane as the eluant. The fractions of each chromatography 
containing the product (as indicated by TLC) are combined and evaporated 
at 50.degree.-55.degree. C. and reduced to stand at 20.degree.-25.degree. 
C. for 11 days, and the resulting yellow solid is collected, 
recrystallized from isopropanol/heptane (and vacuum dried at 
20.degree.-25.degree. C. to obtain the pure product as a yellow solid (46 
g.), m.p. 118.degree.-120.degree. C. The mother liquors from the initial 
crystallization and the recrystallization are combined and evaporated at 
50.degree.-55.degree. C. and reduced pressure, and the resulting oil is 
chromatographed on a mixture of 2 kg. of 70-230 mesh A.S.T.M. silica gel 
and 2 kg. of 230-400 mesh A.S.T.M. silica gel utilizing 5% ethyl 
acetate/hexane and then 10% ethyl acetate/hexane as the eluants. The 
fractions containing relatively pure product (as indicated by TLC) are 
combined and evaporated at reduced pressure to obtain the crude product as 
a yellow solid (55 g.). The crude product is recrystallized from 
isopropanol/hexane and vacuum dried to obtain additional pure product as a 
yellow solid (27 g.), m.p. 117.degree.-119.degree. C. The fractions from 
the second chromatography containing some product (as indicated by TLC) 
are combined and evaporated at reduced pressure to obtain a yellow oil 
(120 g.) which is crystallized from isopropanol/hexane to obtain 
additional pure product (12 g.). The mother liquors from the two previous 
crystallizations are combined and evaporated at reduced pressure to obtain 
a yellow oil (132 g.) which is chromatographed on a mixture of 400 g. of 
70-230 mesh A.S.T.M. silica gel and 400 g. of 230-400 mesh A.S.T.M. silica 
gel utilizing hexane and then 5% ethyl acetate/hexane as the eluants. 
Unreacted starting material is recovered from the fractions containing it, 
the fractions containing relatively pure product are combined and 
evaporated at reduced pressure, and the obtained yellow oil is 
crystallized from isopropanol with cooling at 0.degree. C. The yellow 
solid is collected by filtration, washed with cold hexane and vacuum dried 
at 20.degree.-25.degree. C. to obtain additional pure product as a yellow 
solid (10 g.). Total yield: 96 g., m.p. 115.degree.-118.degree. C. 
Step 3 (Reaction BA) 
3-(4'-Fluorophenyl)spiro[cyclopentane-1,1'(1H)-inden]-2methanol (Compound 
CXXXIII) 
A solution of 96 g. (328.4 mmoles) of Compound CXXXII in 445 ml. of HPLC 
grade tetrahydrofuran is added to a mixture of 14.2 g. (375 mmoles) of 
sodium borohydride, 445 ml. of HPLC grade tetrahydrofuran and 177 ml. of 
HPLC grade isopropanol (stirred at 15.degree.-20.degree. C. (the addition 
being exothermic), and the reaction mixture is stirred at 
20.degree.-25.degree. C. for 24 hours, the reaction mixture being stirred 
under nitrogen throughout. The reaction mixture is cautiously poured into 
800 ml. of saturated ammonium chloride solution stirred at 
20.degree.-25.degree. C. (the addition being exothermic), and the organic 
phase is separated. The aqueous phase is extracted with 500 ml. of ethyl 
acetate, and the ethyl acetate extract is combined with the previous 
organic phase. The combined solution is dried over anhydrous magnesium 
sulfate and filtered, and the filter cake is washed with 200 ml. of ethyl 
acetate. The washing is combined with the filtrate, and the combined 
solution is concentrated at 50.degree. C. (external temperature) and 
reduced pressure to a volume of about 150 ml. 500 ml. of heptane is added, 
and the mixture is concentrated at 50.degree. C. (external temperature) 
and reduced pressure until it becomes opaque and cooled to 0.degree. C. 
After 1 hour, the solids are collected by filtration, washed with 100 ml. 
of cold heptane and vacuum dried for 4 hours at 45.degree. C. to constant 
weight to obtain the product (68.6 g.), m.p. 84.degree.-86.degree. C. A 
less pure second crop is obtained from the mother liquor (11.9 g.). The 
two crops are combined and dissolved in 1 1. of methanol, the methanol is 
evaporated at 50.degree. C. and reduced pressure, 1 1. of methanol is 
added, the methanol is evaporated at 50.degree. C. and reduced pressure to 
obtain a yellow oil containing some methanol, and 400 ml. of heptane is 
added. The mixture is slowly cooled to 10.degree. C. and maintained at 
0.degree. C. for 30 minutes. The resulting solid is collected by 
filtration, washed with heptane and vacuum dried at 40.degree. C. for 16 
hours to obtain the product as a beige solid (70 g.), m.p. 
90.degree.-92.degree. C. The mother liquor is evaporated at reduced 
pressure, and the residue is crystallized from 50 ml. of heptane, 
collected by filtration, washed with heptane and vacuum dried at 
20.degree.-25.degree. C. for 16 hours to obtain a second crop (6.5 g.). 
Step 4 (Reaction BB) 
2-Chloromethyl-3-(4'-fluorophenyl)spiro[cyclopentane-1,1'(1H)-indene](Compo 
und CXXXIV) 
27 ml. (41 g., 350 mmoles) of thionyl chloride is added over a period of 15 
minutes to a solution of 76.5 g. (260 mmoles) of Compound CXXXIII in 1.4 l 
of methylene chloride stirred at 19.degree.-23.degree. C. (the addition 
being slightly exothermic), and the reaction mixture is stirred at 
20.degree.-25.degree. C. for 16 hours, the reaction mixture being stirred 
under nitrogen throughout. The methylene chloride is evaporated at reduced 
pressure. 300 ml. toluene is added, the toluene is evaporated at reduced 
pressure, and this is repeated twice more to obtain the crude product as a 
greenish oil (90 g.). 
Step 5 (Reaction BC) 
Dimethyl 
3-(4'-fluorophenyl)spirocyclopentane-1,1'(1H)-inden]-2'-yl]methylphosohona 
te (Compound CXXXV) 
A mixture of 90 g. (.ltoreq.0.26 mole) of crude Compound CXXXIV and 220 ml. 
(231 g., 1.86 moles) of trimethyl phosphite is stirred at 
100.degree.-105.degree. C. under nitrogen for 16 hours and evaporated at 
65.degree. C. and reduced pressure. 300 ml. of toluene is added, the 
toluene is evaporated at reduced pressure, and this is repeated twice. 400 
ml. of heptane is added, and the heptane is evaporated at reduced 
pressure. 300 ml. of heptane and 50 ml. of diethyl ether are added, and 
the resulting solid is collected by filtration, washed with heptane and 
vacuum dried to obtain a pale green solid. The pale green solid is 
dissolved in 100 ml. of methylene chloride with heating, 500 ml of heptane 
is added, .about.200 ml of heptane is evaporated at reduced pressure, and 
the mixture is cooled. The resulting solid is collected by filtration, 
washed with heptane and vacuum dried at 45.degree. C. for 16 hours to 
obtain the product as an off-white solid (78 g.), m.p. 
91.degree.-92.5.degree. C. A less pure second crop is obtained from the 
mother liquor (13 g.). 
Step 6 (Reaction G) 
1,1-Dimethylethyl 
(3R,5S)-(E)-3,5-di-(1',1'-dimethylethyl-diphenylsilyloxy)-7-[3'-(4"-fluoro 
phenyl)spiro[cyclopentane1,1'(1H)-inden]-2'-yl]hept-6-enoate (Compound 
CXXXVII) 
20.75 ml of 1.5M. lithium diisopropylamide monotetrahydrofuran/cyclohexane 
(31.1 mmoles) is added to a solution of 10.0 g. (25.9 mmoles) of Compound 
CXXXV in 90 ml. of dry tetrahydrofuran stirred at -20.degree.-0.degree. C. 
, the reaction mixture is stirred at-20.degree.-15.degree. C. for 30 
minutes, a solution of 21.6 g. (31.1 mmoles) of Compound CXXXVI (disclosed 
in U.S. Pat. Nos. 4,808,607, 4,822,799 and 4,870,199 in 50 ml. of dry 
tetrahydrofuran is added dropwise with stirring at-20.degree. C., and the 
reaction mixture is stirred at-20.degree.-10.degree. C. for 20 minutes, 
the reaction mixture being stirred under nitrogen throughout. 150 ml. of 
saturated ammonium chloride solution is added, and the mixture is 
extracted three times with ethyl acetate. The ethyl acetate extracts are 
combined, washed with water, washed with saturated sodium chloride 
solution, dried over anhydrous magnesium sulfate, filtered and evaporated 
at reduced pressure to obtain the crude product as a yellow solid (28.9 
g.). The crude product is chromatographed on a Waters Prep-500 HPLC 
apparatus having a silica gel column and using 30% methylene 
chloride/hexane as the eluant to obtain the product as a white solid foam 
(19.28 g.), [.alpha.].sub.D.sup.25 32 -127.7.degree. (c=1.360 g./dl., 
CH.sub.3 OH). 
Step 7 (Reaction H) 
1,1-Dimethylethyl 
(3R,5S)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1 
H)-inden]-2'-yl]hept-6-enoate (Compound CXXXVIII) 
111.0 ml of 1M. tetra-n-butylammonium fluoride/tetrahydrofuran (111.0 
mmoles) is added to a solution of 8.88 g. (9.30 mmoles) of Compound 
CXXXVII in 250 ml. of tetrahydrofuran, 3.05 ml. (3.20 g., 53.3 mmoles) of 
glacial acetic acid is added, 25.5 ml. of acetonitrile is added, and the 
reaction mixture is stirred at 60.degree. C. for 29.5 hours and at 
20.degree.-25.degree. C. for 88 hours, the reaction mixture being stirred 
under nitrogen throughout. 150 ml. of saturated sodium bicarbonate 
solution is added, and the mixture is extracted twice with 750 ml. 
portions of ethyl acetate. The ethyl acetate extracts are combined, washed 
with water, washed with saturated sodium chloride solution, dried over 
anhydrous magnesium sulfate and filtered. The filter cake is washed with 
ethyl acetate, the washing is combined with the filtrate, and the combined 
solution is evaporated at reduced pressure to obtain the crude product as 
a brown oil (12.69 g.). The crude product is chromatographed on a Waters 
Prep-500 HPLC apparatus having a silica gel column using 10% ethyl 
acetate/hexane as the eluant to obtain the 98.85% pure product (3.32 9.), 
m.p. 110.degree.-112.degree. C. 
EXAMPLE 2 
Sodium 
erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1 
H)-inden]-2'-yl]hept-6-enoate (Compound CXI) 
##STR19## 
0.11 ml. of 1N. sodium hydroxide solution (0.11 mmole) is added to a 
solution of 50 mg. (0.111 mmole) of Compound CX in 3 ml. of absolute 
ethanol stirred at 0.degree. C., and the reaction mixture is stirred at 
0.degree. C. under nitrogen for 1.5 hours and evaporated to dryness at 
reduced pressure. The residue is washed three times with diethyl ether to 
obtain the product (42 mg.), m.p. &gt;170.degree. C. (dec.). 
Revised procedure 
10 ml. of 1N. sodium hydroxide solution (10 mmoles) is added dropwise to a 
solution of 4.77 g. (10.6 mmoles) of Compound CX in 100 ml. of absolute 
ethanol stirred at 0.degree. C. The reaction mixture is stirred at 
0.degree. C. for 30 minutes under nitrogen, diethyl ether is added, and 
the precipitate is collected by filtration, washed with diethyl ether and 
vacuum dried to obtain the product as a pale yellow solid (4.0 g.). 
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.5-2.5 (m, 12H), 4.1 (m, 1H), 4.3 (m, 
1H), 5.8 (dd (J.sub.1 =8 Hz., J.sub.2 =20 Hz.), 1H), 6.4 (d (J=20 Hz.), 
1H), 7.0-7.5 (m, 8H) 
The product is an about 19:1 (revised procedure) or 24:1 (initial 
procedure) mixture of the erythro and threo racemates which may be 
separated by conventional means. The principal product, the erythro 
racemate, may be resolved into two optically pure enantiomers, the 3R,5S 
and 3S,5R isomers, of which the former is preferred. The minor product, 
the threo racemate, may be resolved into the 3R,5R and 3S,5S isomers, of 
which the former is preferred. The use of a starting material synthesized 
by utilizing a non-stereoselective reduction in Step 8 of Example 1 would 
afford a mixture of all four stereoisomers wherein the ratio of the 
erythro isomers to the threo isomers ranges from 3:2 to 2:3. 
EXAMPLE 2A 
Sodium 
(3R,5S)-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'(1 
H)-inden]-2'-yl]hept-6-enoate (Compound CXXXIX) 
##STR20## 
7.07 ml. of 1N. sodium hydroxide solution (7.07 mmoles) is added dropwise 
to a solution of 3.45 g. (7.22 mmoles) of Compound CXXXVIII in 50 ml. of 
absolute ethanol stirred at 0.degree. C., the reaction mixture is stirred 
at 0.degree. C. for 2 hours, an additional 0.5 ml. of 1N. sodium hydroxide 
solution (0.5 mmole) is added, and the reaction mixture is stirred at 
0.degree. C. for 1.25 hours, the reaction mixture being stirred under 
nitrogen throughout. Diethyl ether is added, and the precipitate is 
collected by filtration, washed with diethyl ether and vacuum dried to 
constant weight to obtain the product as a pinkish-white solid (3.08 g.), 
[.alpha.].sub.D.sup.25 =+32.09.degree. (c=1.427 g./dl., CH.sub.3 OH). 
EXAMPLES 3-5 
(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-i 
nden]-2'-yl]hept-6-enoic acid, its sodium salt and its ethyl ester 
##STR21## 
Step 1 (Reaction AA) 
3-(3',5'-Dimethylphenyl)-1H-indene (Compound CXII) 
20 mg. of iodine and 0.2-0.3 ml. of 1,2-dibromoethane are added to a 
suspension of 5 g. (0.21 mole) of magnesium in 15 ml. of dry 
tetrahydrofuran stirred at 20.degree.-25.degree. C. under nitrogen. When 
the reaction commences and the color of iodine disappears, a solution of 
38 g. (0.205 mole) of 1-bromo-3,5-dimethylbenzene in 150 ml. of dry 
tetrahydrofuran is added dropwise over a period of about 1 hour at a rate 
such that the reaction mixture gently refluxes, the reaction mixture is 
refluxed for 1 hour and cooled to 20.degree.-25.degree. C., a solution of 
26 g. (0.197 mole) of 1-indanone in 150 ml. of dry tetrahydrofuran is 
added dropwise over a period of 30 minutes, and the reaction mixture is 
maintained at 20.degree.-25.degree. C. for 30 minutes, the reaction 
mixture being stirred under nitrogen throughout. The reaction mixture is 
poured into cold (0.degree.- 5.degree. C.) saturated ammonium chloride 
solution, and the mixture is extracted three times with ethyl acetate. The 
ethyl acetate extracts are combined, washed with water, washed with 
saturated sodium chloride solution, dried over anhydrous sodium sulfate, 
filtered and evaporated at reduced pressure to obtain a yellow oil (54 
g.). The obtained oil is dissolved in 70 ml. of glacial acetic acid, and 
the reaction mixture is refluxed for 30 minutes and evaporated at reduced 
pressure to obtain a brown oil. The oil is subjected to a Kugelrohr 
distillation to obtain the product as a yellow oil (34 g. (79%)) 
(collected at a bath temperature of 115.degree.-125.degree. C. at 1 mm. 
Hg.). 
Step 2 (Reaction AB) 
3-(3',5'-Dimethylphenyl)-1H-indene-2-carboxaldehyde (Compound CXIII) 
A mixture of 4.8 ml. (51.8 mmoles) of phosphorus oxychloride and 6.4 ml. 
(51.8 mmoles) of N-methylformanilide is allowed to stand at 20.degree. C. 
under nitrogen for 30 minutes. The resulting yellow solution is cooled to 
10.degree. C., a solution of 9.5 g. (43.18 mmoles) of Compound CXII in 10 
ml. of acetonitrile is added dropwise, and the reaction mixture is stirred 
at 20.degree.-25.degree. C. for 6 hours, the reaction mixture being 
maintained under nitrogen throughout. The reaction mixture is quenched 
with ice-water, and the mixture is extracted three times with diethyl 
ether. The diethyl ether extracts are combined, washed with water, washed 
with saturated sodium chloride solution, dried over anhydrous sodium 
sulfate, filtered and evaporated at reduced pressure to obtain the crude 
product as a dark yellow oil (10.6 g.). 
Step 3 (Reaction AC) 
Methyl (E)-3-[3'-(3",5"-dimethylphenyl)-1H-inden-2'-yl]propenoate (Compound 
CXIV) 
18 g. (58.8 mmoles) of (carbomethoxymethylene)triphenylphosphorane is added 
to a solution of 10.6 g. (.ltoreq.42.7 mmoles) of crude Compound CXIII in 
90 ml. of toluene, and the reaction mixture is refluxed for 4 hours (until 
no Compound CXIII is detectable by thin layer chromatography) and cooled 
to 20.degree.-25.degree. C., the reaction mixture being maintained under 
nitrogen throughout. 600 ml. of diethyl ether is added, and the mixture is 
filtered through a short pad (90 g.) of 230-400 mesh silica gel, decolored 
with 3-4 g. of Norit, filtered and evaporated at reduced pressure to an 
oil. The oil is triturated with petroleum ether and the resulting solid is 
vacuum dried to obtain the yellow product (12 g. (92% Steps 2 and 3 
combined)), m.p. 98.degree.-100.degree. C. 
Step 4 (Reaction AD) 
Methyl 
(E)-3-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]p 
ropenoate (Compound CXV) 
442 mg. (9.21 mmoles) of sodium hydride (as a 50% by weight dispersion in 
mineral oil) is added portionwise to a solution of 1.4 g. (4.6 mmoles) of 
Compound CXIV in 15 ml. of dry dimethylformamide stirred at 0.degree. C., 
the reaction mixture is stirred at 0.degree. C. for 10 minutes, 0.6 ml. 
(4.8 mmoles) of 1,4-dibromobutane is added dropwise, and the reaction 
mixture is allowed to slowly warm to 20.degree.-25.degree. C. and stirred 
at this temperature for 4-5 hours (until no Compound CXIV is detectable by 
thin layer chromatography), the reaction mixture being maintained under 
nitrogen throughout. The reaction mixture is poured into cold 
(0.degree.-5.degree. C.) water, and the mixture is extracted three times 
with diethyl ether. The diethyl ether extracts are combined, washed with 
water, washed with saturated sodium chloride solution, dried over 
anhydrous sodium sulfate, filtered and evaporated at reduced pressure. The 
residual oil is crystallized from methanol to obtain the pale yellow 
product (930 mg. (58%)), m.p. 118.degree.-120.degree. C. Additional 
product and the corresponding free acid may be obtained from the mother 
liquor. The free acid may be esterified to obtain still more product. 
Preferably, however, the entire residual oil is refluxed for 6 hours in a 
mixture of methanol and concentrated hydrochloric acid to esterify any 
free acid present prior to the crystallization from methanol 
Step 5 (Reaction AE) 
(E)-3-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]pr 
op-2-en-1-ol (Compound CXVI) 
35 ml. of 1.5M. diisobutylaluminum hydride/toluene (52.5 mmoles) is added 
to a solution of 7.0 g. (19.53 mmoles) of Compound CXV in 120 ml. of 
methylene chloride stirred at -75.degree. C. under nitrogen, and the 
reaction mixture is stirred under the same conditions for 2.5 hours and 
poured into about 200 ml. of ice-water. The mixture is acidified with 3N. 
hydrochloric acid to pH 3-4, 5 ml. of acetic acid is added, and the 
mixture is extracted three times with ethyl acetate. The ethyl acetate 
extracts are combined, washed with water, saturated sodium bicarbonate 
solution, water and saturated sodium chloride solution, dried over 
anhydrous sodium sulfate, filtered and evaporated at reduced pressure to 
obtain the crude product as a yellow oil (7 g.). 
Step 6 (Reaction AF) 
(E)-3-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-inden]-2'-yl]pr 
op-2-enal (Compound CXVII) 
A mixture of 7 g. (.ltoreq.21.2 mmoles) of crude Compound CXVI (from Step 
5), 14 g. (161 mmoles) of activated manganese dioxide and 140 ml. of 
toluene is stirred at 20.degree.-25.degree. C. under nitrogen for about 12 
hours (until no Compound CXVI is detectable by thin layer chromatography), 
500 ml. of diethyl ether is added, the mixture is filtered through a pad 
(20 g.) of 230-400 mesh silica gel and evaporated at reduced pressure, and 
the residual oil is triturated with petroleum ether to obtain the product 
as a yellow solid (6.05 g. (93% Steps 5 and 6 combined)), m.p. 
149.degree.-150.degree. C. 
Step 7 (Reaction A) 
Ethyl 
(E)-7-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-inden-2'-yl-5- 
hydroxy-3-oxohept-6-enoate (Compound CXVIII) 
51.3 ml. of 1.6M. n-butyllithium/hexane (84.3 mmoles) is slowly added to a 
solution of 11.8 ml. (84.3 mmoles) of diisopropylamine in dry 
tetrahydrofuran stirred at 0.degree. C., the reaction mixture is stirred 
at 0.degree. C. for 10 minutes and cooled to -30.degree. C., 5.35 ml. 
(41.9 mmoles) of ethyl acetoacetate is slowly added, and the resulting 
yellow solution is stirred at -30.degree.--20.degree. C. for 30 minutes, 
the reaction mixture being maintained under nitrogen throughout. The 
reaction mixture is added via syringe to a solution of 7.2 g. (21.9 
mmoles) of Compound CXVII in 60 ml. of dry tetrahydrofuran stirred at 
-30.degree. C., and the reaction mixture is stirred at 
-30.degree.--20.degree. C. for about 30 minutes (until no Compound CXVII 
is detectable by thin layer chromatography), the reaction mixture being 
maintained under nitrogen throughout. The reaction mixture is poured into 
a mixture of cold (0.degree. -5.degree. C.) 1N. hydrochloric acid and 
ethyl acetate, the organic phase is separated, the aqueous phase is 
extracted twice with ethyl acetate, and the ethyl acetate phase and 
extracts are combined, washed with water, washed with saturated sodium 
chloride solution, dried over anhydrous sodium sulfate, filtered and 
evaporated at reduced pressure to obtain the crude oily product (12.0 g.). 
The product is a racemate that may be resolved by conventional means to 
obtain the 5R and 5S enantiomers. 
Step 8 (Reactions B, O and P) 
(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-i 
nden]-2'-yl]hept-6-enoic acid (Compound CXX), its sodium salt (Compound 
CXXA) and its ethyl ester (Compound CXIX) 
(a) 31 ml. of 1M. triethylborane/tetrahydrofuran (31 mmoles) is added to a 
solution of 12.0 g. (.ltoreq.26.2 mmoles) of Compound CXVIII in 500 ml. of 
dry tetrahydrofuran stirred at 20.degree.-25.degree. C., 50 ml. of air (at 
25.degree. C. and 760 mm. Hg.) is added via a syringe, the reaction 
mixture is stirred at 20.degree.-25.degree. C. for 2 hours and cooled to 
-78.degree. C., 1.14 g. (30.2 mmoles) of sodium borohydride is added in 
one portion, and the reaction mixture is stirred for 16 hours at 
-78.degree. C. and allowed to warm to 20.degree.-25.degree. C., the 
reaction mixture being maintained under nitrogen throughout. The reaction 
mixture is evaporated to dryness at reduced pressure, the residue is 
vacuum dried, diethyl ether is added, the insoluble material is removed by 
filtration, and the filtrate is evaporated at reduced pressure. 50 ml. of 
water is added to the oily residue, and the mixture is extracted twice 
with diethyl ether. The diethyl ether extracts are combined and cooled to 
0.degree. C., 10 ml. of methanol, 5 ml. of 30% aqueous hydrogen peroxide 
and 10 ml. of an aqueous phosphate buffer having a pH of 7 (0.054M. 
sodium, 0.024M. potassium and 0.047M. phosphate) are added, and the 
reaction mixture is stirred at 0.degree. C. under nitrogen for 45 minutes. 
Most of the diethyl ether and methanol is evaporated at reduced pressure, 
the residual aqueous solution is extracted with diethyl ether three times, 
and the diethyl ether extracts are combined and evaporated at reduced 
pressure to obtain crude Compound CXIX as a yellow oil (3 g.) (Example 3). 
N.M.R. (CDCl.sub.3): 1.25 (t, 3H), 1.6-2.3 (m, 10H), 2.4 (s, 6H), 2.5 (m, 
2H), 3.5 (s, 1H), 3.7 (d, 1H), 4.15 (q, 2H), 4.25 (m, 1H), 4.4 (m, 1H), 
5.7 (dd, 1H), 6.5 (d (J=20 Hz.), 1H), 6.95-7.4 (m, 7H) 
(b) The aqueous layer from the initial diethyl ether extraction (prior to 
the addition of methanol, hydrogen peroxide and buffer) is acidified with 
dilute hydrochloric acid, and the mixture is extracted twice with ethyl 
acetate. The ethyl acetate extracts are combined, dried over anhydrous 
sodium sulfate, filtered and evaporated at reduced pressure to obtain 
crude Compound CXX as a foam (7 g.) (Example 4). 
(c) 6.5 ml. of 1N. sodium hydroxide solution (6.5 mmoles) is added to a 
solution of 3 g. (.ltoreq.6.5 mmoles) of crude Compound CXIX (from Part 
(a)) in 25 ml. of ethanol stirred at 0.degree. C., and the reaction 
mixture is stirred at 0.degree. C. under nitrogen for 30 minutes, washed 
with diethyl ether, acidified with dilute hydrochloric acid and extracted 
with diethyl ether twice. The diethyl ether extracts are combined, dried 
over anhydrous sodium sulfate, filtered and evaporated at reduced pressure 
to obtain Compound CXX as an oil (1.7 g.). 
The reaction mixture, prior to the acidification, contains the sodium salt 
of Compound CXX (Compound CXXA (Example 5)). It may be isolated and 
purified conventionally. M.p. .gtoreq.160.degree. C. (dec.). 
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.5.2.35 (m, 12H), 2.3 (s, 6H), 4.1 (m, 
1H), 4.3 (m, 1H), 5.75 (dd, 1H), 6.45 (d (J=20 Hz.), 1H), 6.95-7.4 (m, 7H) 
Compounds CXIX, CXX and CXXA are approximately 3-9:1 mixtures of the 
erythro and threo racemates which may be separated by conventional means, 
e.g., lactonization of the free acid, separation of the cis and trans 
lactones, hydrolysis of the lactones, etc. The principal product, the 
erythro racemate in each case, may be resolved into two optically pure 
enantiomers, the 3R,5S and 3S,5R enantiomers, of which the former is 
preferred The minor product, the threo racemate in each case, may be 
resolved to obtain the 3R,5R and 3S,5S enantiomers, of which the former is 
preferred. The use of a non-stereoselective reduction would afford a 
mixture of all four stereoisomers wherein the ratio of the erythro 
stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3. 
Note: To maximize the yield of Compound CXIX, it is preferable to carry out 
this step in accordance with the procedure of Step 8 of Example 1. 
EXAMPLES 6 AND 7 
(E)-Trans-6-(2'-[3"-(3'",5'"-dimethylphenyl)spiro[cyclopentane-1,1'(1H)-ind 
en]-2"-yl]ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound 
CXXI) and the corresponding cis lactone (Compound CXXII) 
##STR22## 
(a) 8.7 g. (20.5 mmoles) of 
N-cyclohexyl-N'-[2'-(N"-methylmorpholinium)ethyl]carbodiimide 
p-toluenesulfonate is added to a solution of 8.7 g. (.ltoreq.20.1 mmoles) 
of Compound CXX (from Parts (a) and (c) of Step 8 of Examples 3-5) in 250 
ml. of methylene chloride (freshly filtered through basic alumina), and 
the reaction mixture is stirred at 20.degree.-25.degree. C. under nitrogen 
for about 3 hours (until no Compound CXX is detectable by thin layer 
chromatography) and evaporated to dryness at reduced pressure. Water is 
added, and the mixture is extracted three times with diethyl ether. The 
diethyl ether extracts are combined, washed with saturated sodium chloride 
solution, dried over anhydrous sodium sulfate, filtered and evaporated to 
dryness at reduced pressure to obtain an about 3-4:1 mixture of Compounds 
CXXI and CXXII as a yellow foam. 
(b) The product of Part (a) is separated on a Waters Prep-500 high pressure 
liquid chromatography apparatus utilizing a silica gel column and 
15:4.5:10.5 n-hexane/acetonitrile/methyl t-butyl ether to elute the trans 
lactone (Compound CXXI) (3.0 g.), a solid foam (Example 6). 
N.M.R. (CDCl.sub.3): 1.7-2.3 (m, 10H), 2.35 (s, 6H), 2.7 (m, 2H), 4.4 (m, 
1H), 5.25 (m, 1H), 5.75 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.55 
(d (J=20 Hz.), 1H), 6.9-7.5 (m, 7H) 
Also eluted from the column is the cis lactone (Compound CXXII), also a 
solid foam (Example 7). 
N.M.R. (CDCl.sub.3): 1.7-2.5 (m, 10H), 2.35 (s, 6H), 2.8 (m, 2H), 4.3 (m, 
1H), 4.7 (m, 1H), 5.75 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.5 (d 
(J=20 Hz.), 1H), 6.95-7.4 (m, 7H) 
Compounds CXXI and CXXII are both racemates that may be resolved by 
conventional means to obtain, in the case of the former, the 4R,6S and 
4S,6R enantiomers, of which the former is preferred, and, in the case of 
the latter, the 4R,6R and 4S,6S enantiomers, of which the former is 
preferred. 
EXAMPLE 8 
Sodium 
erythro-(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1 
,1'(1H)-inden]-2'-yl]hept-6-enoate 
##STR23## 
0.16 ml. of 1N. sodium hydroxide solution (0.16 mmole) is added to a 
solution of 70 mg. (0.169 mmole) of Compound CXXI in 3 ml. of absolute 
ethanol stirred at 0.degree. C., and the reaction mixture is stirred at 
0.degree. C. under nitrogen for 30 minutes and evaporated to dryness at 
reduced pressure. The residue is washed with anhydrous diethyl ether and 
vacuum dried to obtain the product as a pale yellow solid (65 mg.), m.p. 
&gt;170.degree. C. (dec.) 
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): 1.5-2.35 (m, 12H), 2.3 (s, 6H), 4.1 (bs, 
1H), 4.3 (bs, 1H), 5.75 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.45 
(d (J=20 Hz.), 1H), 6.95-7.4 (m, 7H) 
Compound CXXIII is a racemate that may be resolved by conventional means to 
obtain the 3R,5S and 3S,5R enantiomers, of which the former is preferred. 
EXAMPLE 9 
Sodium 
threo-(E)-3,5-dihydroxy-7-[3'-(3",5"-dimethylphenyl)spiro[cyclopentane-1,1 
'(1H)-inden]-2'-yl]hept-6-enoate 
##STR24## 
The product is obtained from Compound CXXII essentially according to the 
process of Example 8. M.p. &gt;160.degree. C. (dec.) 
N.M.R. (CDCl.sub.3 +CD.sub.3 OD): Essentially the same as that of Compound 
CXXIII 
Compound CXXIV is a racemate that may be resolved by conventional means 
(e.g., Reactions P and R, conversion of the racemic lactone to 
diastereoisomeric silyloxy compounds, separation of the diastereoisomeric 
silyloxy compounds, cleavage of the silyl group and Reaction T) to obtain 
the 3R,5R and 3S,5S enantiomers, of which the former is preferred. 
EXAMPLE 10 
Ethyl 
(.+-.)-(E)-7-[3'-(4"-fluorophenyl)spiro[cyclopentane-1,1'-(1H)-inden]-2'-y 
l]-3-hydroxy-5-oxohept-6-enoate 
##STR25## 
A mixture of 310 mg. (0.69 mmole) of Compound CX, 600 mg. (4.2 mmoles) of 
activated manganese dioxide and 5 ml. Of toluene is stirred under nitrogen 
at 20.degree.-25.degree. C. for 24 hours, at 60.degree. C. for 8 hours, at 
20.degree.-25.degree. C. for 16 hours and at 80.degree. C. for 8 hours and 
allowed to cool to 20.degree.-25.degree. C. Diethyl ether is added, the 
mixture is filtered, and the filtrate is evaporated at reduced pressure to 
obtain an oil. The oil is purified by preparative thin layer 
chromatography on a silica gel plate utilizing 80% diethyl ether/petroleum 
ether as the solvent. The band containing the product is scraped and 
eluted with ethyl acetate and the solution is filtered and evaporated at 
reduced pressure to obtain the product as a yellow solid (110 mg.), m.p. 
107.degree.-109.degree. C. 
The product is a racemate that may be resolved by conventional means to 
obtain the 3R and 3S enantiomers. 
EXAMPLE 11 
Ethyl 
(.+-.)-(E)-5,5-dimethoxy-7-[3'-(4"-fluorophenyl)spiro-[cyclopentane-1,1'(1 
H)-inden]-2'-yl]-3-hydroxyhept-6-enoate 
##STR26## 
A mixture of 90 mg. (0.20 mmole) of Compound CXXV, 0.1 ml. (0.91 mmole) of 
trimethyl orthoformate, 2 mg. of pyridinium p-toluenesulfonate and 3 ml of 
methylene chloride is stirred under nitrogen for 45 hours at 
20.degree.-25.degree. C. and evaporated at reduced pressure, and the 
residual oil is purified by preparative thin layer chromatography on a 
silica gel plate utilizing 60% diethyl ether/petroleum ether as the 
solvent. The band containing the product is scraped and eluted with ethyl 
acetate, and the solution is filtered and evaporated at reduced pressure 
to obtain the product as a yellow oil (31 mg.). 
N.M.R. (C.sub.6 D.sub.6): 0.9 (t (J=10 Hz.), 3H), 1.2-3.1 (m, 12H), 3.2 
(2s, 6H), 3.9 (q (J=10 Hz.), 2H), 4.8 (m, 1H), 6.5 (d (J=20 Hz.), 1H), 
6.8-7.4 (m, 8H), 7.7 (d (J=20 Hz.), 1H) 
The product is a racemate that may be resolved by conventional means to 
obtain the 3R and 3S enantiomers. 
TABLE I 
__________________________________________________________________________ 
Examples 12-19 
The following compounds of Group IAa wherein R.sub.o is Ring A may be 
synthesized by the processes set forth above: 
R R.sub.1 
R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 
R.sub.6 
X R.sub.10 
R.sub.11 
Isomers 
M.P. 
__________________________________________________________________________ 
Ex. 12 
H .sub.- i-C.sub.3 H.sub.7 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
D1; E:T = 
Oil 
.about.85:15 
Ex. 13 
H .sub.- i-C.sub.3 H.sub.7 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H Na D1; E &lt;190.degree. C. (dec.) 
Ex. 14 
CH.sub.3 
CH.sub.3 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
E:T = .about.9:1 
Oil 
Ex. 15 
CH.sub.3 
CH.sub.3 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H Ha E &lt;160.degree. C. (dec.) 
Ex. 16 
C.sub. 2 H.sub.5 
C.sub.2 H.sub.5 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
E:T = .about.4:1 
Oil 
Ex. 17 
C.sub.2 H.sub.5 
C.sub.2 H.sub.5 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H Na E:T = .about.4:1 
&lt;170.degree. C. (dec.) 
Ex. 18 
CH.sub.3 
CH.sub.3 
H H 3-CH.sub.3 
H 5-CH.sub.3 
(E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
E:T = .about.9:1 
Oil 
Ex. 19 
CH.sub.3 
CH.sub.3 
H H 3-CH.sub.3 
H 5-CH.sub.3 
(E)-CH.dbd.CH-- 
H Ha E:T = .about.9:1 
&lt;190.degree. C. 
__________________________________________________________________________ 
(dec.) 
TABLE II 
__________________________________________________________________________ 
Examples 20-23 
The following compounds of Group IAa 
wherein R.sub.o is Ring A may be synthesized by the processes set forth 
above: 
R R.sub.1 
R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 
R.sub.6 
X R.sub.10 
Isomers 
M.P. 
__________________________________________________________________________ 
Ex. 20 
H .sub.- i-C.sub.3 H.sub.7 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H D1; trans 
Oil 
Ex. 21 
H .sub.- i-C.sub.3 H.sub.7 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H D1; cis: 
Oil 
trans = .about.4:1 
Ex. 22 
CH.sub.3 
CH.sub.3 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H trans 64.degree.-66.degree. C. 
Ex. 23 
CH.sub.3 
CH.sub.3 
H H 3-CH.sub.3 
H 5-CH.sub.3 
(E)-CH.dbd.CH-- 
H trans:cis = 
Foam 
.about.4:1 
__________________________________________________________________________ 
3 TABLE III 
Examples 24- 43 The following compounds of Group IBa wherein R.sub.o is 
Ring A may be synthesized by the processes set forth above: R + R.sub.1 
R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 X R.sub.10 R.sub.11 Isomers 
M.P. Ex. 24 CH.sub.2 CH.sub.2 H H H 4-F H (E)CHCH H C.sub.2 H.sub.5 
E:T = .about.89:11 Oil Ex. 25 CH.sub.2 CH.sub.2 H H H 4-F H (E)CHCH H Na 
E:T = .about.9:1 &gt;160.degree. C. (dec.) Ex. 26 (CH.sub.2).sub.5 H H H 
4-F H (E)CHCH H C.sub.2 H.sub.5 E:T = 
.about.3:1 Oil Ex. 27 (CH.sub.2).sub.4 H H H H H (E)CHCH H C.sub.2 
H.sub.5 E:T = .about.3:1 Oil Ex. 28 (CH.sub.2).sub.4 H H H 4-F H 
CH.sub.2 CH.sub.2 H C.sub.2 H.sub.5 E:T = 
.about.9:1 Oil Ex. 29 (CH.sub.2).sub.4 4-CH.sub.3 H H 4-F H (E)CHCH H 
C.sub.2 H.sub.5 E Oil Ex. 30 (CH.sub.2).sub.4 4-CH.sub.3 H H 4-F H 
(E)CHCH H Na E 213.degree.-216.degree. C. (dec.) Ex. 31 (CH.sub.2).sub.4 
6-CH.sub.3 H H 4-F H (E)CHCH H C.sub.2 
H.sub.5 E Oil Ex. 32 (CH.sub.2).sub.4 6-CH.sub.3 H H 4-F H (E)CHCH H Na 
E 185.degree.-189.degree. C. (dec.) Ex. 33 (CH.sub.2).sub.4 6-OCH.sub.3 
H H 4-F H (E)CHCH H C.sub.2 H.sub.5 E Oil Ex. 34 (CH.sub.2).sub.4 
6-OCH.sub.3 H H 4-F H (E)CHCH H Na E 199.degree.-202.degree. C. (dec.) 
Ex. 35 (CH.sub.2).sub.4 7-CH.sub.3 H H 4-F H (E)CHCH H C.sub.2 H.sub.5 E 
Oil Ex. 36 (CH.sub.2).sub.4 7-CH.sub.3 H H 4-F H (E)CHCH H Na E 190.degre 
e. C. (dec.) Ex. 37 (CH.sub.2).sub.4 4-OCH.sub.3 6-OCH.sub.3 H 4-F H 
(E)CHCH H C.sub.2 H.sub.5 E 117.degree.-118.degree. 
C. Ex. 38 (CH.sub.2).sub.4 4-OCH.sub.3 6-OCH.sub.3 H 4-F H (E)CHCH H Na 
E 196.degree.-200.degree. C. (dec.) Ex. 39 (Z)CH.sub.2CHCHCH.sub.2 H H H 
4-F H (E)CHCH H C.sub.2 H.sub.5 E Oil Ex. 40 (Z)CH.sub.2CHCHCH.sub.2 H H 
H 4-F H (E)CHCH HNa E 202.degree.-206.degree. 
C. (dec.) Ex. 41 (CH.sub.2).sub.4 H H H 4-F H (E)CHCH H CH.sub.2C.sub.6 
H.sub.4 -4-Br E Solid Ex. 42 (CH.sub.2).sub.4 H H H 4-F H (E)CHCH H 
##STR27## 
E Oil Ex. 43 (CH.sub.2).sub.4 H H H 4-F H (E)CHCH H Pyrid-3-yl-methyl 
E Solid Foam 
TABLE IV 
__________________________________________________________________________ 
Examples 44-47 
The following compounds of Group IBa may be synthesized by the processes 
set forth above: 
R.sub.o R + R.sub.1 
R.sub.2 
R.sub.3 
X R.sub.10 
R.sub.11 
Isomers 
M.P. 
__________________________________________________________________________ 
Ex. 44 
.sub.- i-C.sub.3 H.sub.7 
--(CH.sub.2).sub.4 -- 
H H (E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
E:T = .about.9:1 
Oil 
Ex. 45 
.sub.- i-C.sub.3 H.sub.7 
--(CH.sub.2).sub.4 -- 
H H (E)-CH.dbd.CH-- 
H Na E:T = .about.9:1 
198.degree.-200.degree. C. 
(dec.) 
Ex. 46 
Cyclohexyl 
--(CH.sub.2).sub.4 -- 
H H (E)-CH.dbd.CH-- 
H C.sub.2 H.sub.5 
E Solid Foam 
Ex. 47 
Cyclohexyl 
--(CH.sub.2).sub.4 -- 
H H (E)-CH.dbd.CH-- 
H Na E 190.degree.-194.degree. C. 
__________________________________________________________________________ 
(dec.) 
TABLE V 
__________________________________________________________________________ 
Example 48 
The following compound of Group IBb 
wherein R.sub.o is Ring A may be synthesized by the processes set forth 
above: 
R + R.sub.1 
R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 
R.sub.6 
X R.sub.10 
Isomers 
M.P. 
__________________________________________________________________________ 
Ex. 48 
--(CH.sub.2).sub.4 -- 
H H H 4-F 
H (E)-CH.dbd.CH-- 
H trans:cis = 
Oil 
.about.3:1 
__________________________________________________________________________ 
In Tables I-V 
D1=approximately 1:1 mixture of diastereoisomers with respect to the 
1-position of the indene ring 
E=erythro racemate (E:T.gtoreq.19:1 unless otherwise indicated) 
T=threo racemate 
cis=cis lactone 
trans=trans lactone (trans:cis.gtoreq.19:1 unless otherwise indicated 
Thus, for example, "D1; E:T=.about.85:15" means that the compound is a 
mixture of eight stereoisomers wherein the ratio of the four erythro 
stereoisomers to the four threo stereoisomers is about 85:15 and the ratio 
of the four stereoisomers wherein R.sub.1 has one configuration to the 
four stereoisomers wherein R.sub.1 has the opposite configuration is about 
1:1. 
TABLE VI 
__________________________________________________________________________ 
N.M.R. Data 
__________________________________________________________________________ 
Ex. 12 (CDCl.sub.3): 
0.3 (d (J=10 Hz.), 3H), 1.2 (t, 3H), 1.35 
(d (J=10 Hz.), 3H), 1.7 (m, 2H), 2.5 (m, 2H), 
3.3 (s, 1H), 3.7 (m, 1H), 4.2 (q, 2H), 
4.3 (m, 1H), 4.5 (m, 1H), 5.8 (dd (J.sub.1 =10 Hz., 
J.sub.2 =20 Hz.), 1H), 6.5 (d (J=20 Hz.), 1H), 
7.0-7.5 (m, 8H) 
Ex. 13 (CDCl.sub.3 +CD.sub.3 OD): 
0.35 (d (J=10 Hz.), 3H), 1.4 
(d (J=10 Hz.), 3H), 1.65 (m, 2H), 
2.2-2.6 (m, 3H), 3.75 (bs, 1H), 
4.15 (m, 1H), 4.4 (m, 1H), 5.9 
(dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.55 
(d (J=20 Hz.), 1H), 7.0-7.5 (m, 8H) 
Ex. 14 (CDCl.sub.3): 
1.3 (t, 3H), 1.5 (d, 6H), 1.6-1.9 (m, 2H), 
2.5 (d, 2H), 4.2 (q, 2H), 4.3 (m, 1H), 4.5 
(m, 1H), 6.0 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 
6.55 (d (J=20 Hz.), 1H), 7.1-7.4 (m, 8H) 
Ex. 15 (CDCl.sub.3 + CD.sub.3 OD): 
1.4 (d, 6H), 1.5 (m, 2H), 2.2 (m, 2H), 
4.15 (m, 1H), 4.3 (m, 1H), 5.9 
(dd J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.4 
(d (J=20 Hz.), 1H), 7.0-7.4 (m, 8H) 
Ex. 16 (CDCl.sub.3): 
0.35 (m, 6H), 1.3 (t (J=10 Hz.), 3H), 1.7 
(m, 4H), 2.0 (m, 4H), 2.5 (d (J=10 Hz.), 2H), 
4.2 (q (J=10 Hz.), 2H), 4.3 (m, 1H), 4.45 
(m, 1H), 5.9 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 
6.5 (d (J=20 Hz.), 1H), 7.1-7.4 (m, 8H) 
Ex. 17 (CDCl.sub.3 +CD.sub.3 OD): 
0.35 (m, 6H), 1.7 (m, 2H), 2.0 (m, 4H), 
2.3 (m, 2H), 4.1 (m, 1H), 4.35 (m, 1H), 
5.9 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 
6.5 (d (J=20 Hz.), 1H), 7.0-7.5 
(m, 8H) 
Ex. 18 (CDCl.sub.3): 
1.25 (t, 3H), 1.5 (d (J=8 Hz.), 6H), 1.55-1.9 
(m, 2H), 2.35 (s, 6H), 2.5 (d, 2H), 4.15 
(q, 2H), 4.3 (m, 1H), 4.45 (m, 1H), 5.9 
(dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.55 
(d (J=20 Hz.), 1H), 7.0-7.4 (m, 7H) 
Ex. 19 (CDCl.sub.3 +CD.sub.3 OD): 
1.4 (d, 6H), 1.5-1.9 (m, 2H), 2.2-2.5 
(m, 8H), 4.1 (m, 1H), 4.45 (m, 1H), 5.9 
(dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.5 
(d (J=20 Hz.), 1H), 7.0-7.4 (m, 7H) 
Ex. 20 (CDCl.sub.3): 
0.35 (d (J=10 Hz.), 3H), 1.4 (d (J=10 Hz.), 
3H), 1.8-2.2 (m, 3H), 2.4-2.9 (m, 3H), 3.8 
(bs, 1H), 4.45 (bs, 1H), 5.3 (m, 1H), 5.9 
(dq, 1H), 6.6 (d (J=20 Hz.), 1H), 7.0-7.6 
(m, 8H) 
Ex. 21 (CDCl.sub.3): 
0.35 (d (J=10 Hz.), 3H), 1.4 (d (J=10 Hz.), 
3H), 1.8-2.2 (m, 2H), 2.25-3.05 (m, 4H), 
3.8 (bs, 1H), 4.3 (m, 1H), 4.8 (m, 1H), 
5.9 (m, 1H), 6.6 (d (J=20 Hz.), 1H), 
7.0-7.6 (m, 8H) 
Ex. 22 (CDCl.sub.3): 
1.5 (d (J=8 Hz.), 6H), 1.8-2.1 (m, 2H), 
2.5-2.8 (m, 2H), 4.4 (m, 1H), 5.2 (m, 1H), 
5.9 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.55 
(d (J=20 Hz.), 1H), 7.1-7.5 (m, 8H) 
Ex. 23 (CDCl.sub.3): 
1.5 (d, 6H), 1.8-2.1 (m, 2H), 2.4 (s, 6H), 
2.5-3.0 (m, 2H), 4.4 (m, 1H), 5.2 (m, 1H), 
5.9 (dd, 1H), 6.6 (d, 1H), 6.95-7.45 (m, 7H) 
Ex. 24 (CDCl.sub.3): 
1.3 (t, 3H), 1.5-2.0 (m, 6H), 2.5 (d, 2H), 
3.2 (s, 1H), 3.8 (s, 1H), 4.2 (q, 2H), 
4.2-4.45 (m, 2H), 5.5 (dd (J.sub.1 =10 Hz., J.sub.2 =20 
Hz.), 1H), 6.5 (d (J=20 Hz.), 1H), 7.0-7.45 
(m, 8H) 
Ex. 25 (CDCl.sub.3 +CD.sub.3 OD): 
1.5-2.4 (m, 8H), 4.1 (m, 1H), 4.3 
(m, 1H), 5.5 (dd (J.sub.1 =10 Hz., 
J.sub.2 =20 Hz.), 1H), 6.4 (d (J=20 Hz.), 
1H), 7.0-7.5 (m, 8H) 
Ex. 26 (C.sub.6 D.sub.6): 
0.9 (t (J=10 Hz.), 3H), 1.1-2.4 (m, 14H), 3.8 
(q (J=10 Hz.), 2H), 3.9-4.4 (m, 2H), 6.0 (dd 
(J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.7 (m, 1H), 
6.8-7.8 (m, 8H) 
Ex. 27 (C.sub.6 D.sub.6): 
0.9 (m, 3H), 1.2-2.5 (m, 12H), 3.8 (m, 2H), 
4.0 (m, 1H), 4.1-4.3 (m, 1H), 5.9 (dd (J.sub.1 =10 
Hz., J.sub.2 =20 Hz.), 1H), 6.8 (dd (J.sub.1 =10 Hz., 
J.sub.2 =20 Hz.), 1H), 6.9-7.5 (m, 9H) 
Ex. 28 (CDCl.sub.3): 
1.3 (t, 3H), 1.4-2.5 (m, 16H), 3.7 (m, 2H), 
4.2 (q (J=10 Hz.), 2H), 6.8-7.3 (m, 8H) 
Ex. 29 (CDCl.sub.3): 
1.27 (t, 3H), 1.5-2.3 (m, 10H), 1.82 (s, 3H), 
2.48 (d, 2H), 3.11 (bs, 1H), 3.7 (bs, 1H), 
4.16 (q, 2H), 4.23-4.4 (m, 2H), 5.68 (dd 
(J.sub.1 =8 Hz., J.sub.2 =18 Hz.), 1H), 6.13 (d (J=18 
Hz.), 1H), 6.91-7.37 (m, 7H) 
Ex. 31 (CDCl.sub.3): 
1.25 (t, 3H), 1.5-2.3 (m, 10H), 2.4 (s, 3H), 
2.5 (d, 2H), 3.1 (s, 1H), 3.7 (s, 1H), 4.2 
(q, 2H), 4.2-4.5 (m, 2H), 5.75 (q, 1H), 6.4 
(d, 1H), 7.0-7.4 (m, 7H) 
Ex. 33 (CDCl.sub. 3): 
1.3 (t, 3H), 1.65-2.4 (m, 10H), 2.5 (m, 2H), 
3.1 (s, 1H), 3.7 (s, 1H), 3.9 (s, 3H), 4.2 
(q, 2H), 4.3 (m, 1H), 4.5 (m, 1H), 5.8 (q, 
1H), 6.5 (d, 1H), 6.8 (d, 1H), 7.15 (m, 2H), 
7.2 (t, 2H), 7.4 (m, 2H) 
Ex. 35 (CDCl.sub.3): 
1.3 (t, 3H), 1.4-1.7 (m, 2H), 1.8-2.5 (m, 
10H), 2.51 (s, 3H), 3.1 (bs, 1H), 3.65 (bs, 
1H), 4.15 (m, 3H), 4.35 (bs, 1H), 5.6 (q, 
1H), 6.3 (d, 1H), 6.8-7.4 (m, 7H) 
Ex. 38 (CDCl.sub.3 +CD.sub.3 OD): 
1.4-2.4 (m, 12H), 3.4 (s, 3H), 3.8 (s, 
3H), 4.1 (bs, 1H), 4.3 (bs, 1H), 5.6 
(q, 1H), 6.2 (d, 1H), 6.3 (d, 1H), 6.6 
(d, 1H), 6 9-7.3 (m, 4H) 
Ex. 39 (CDCl.sub.3): 
1.3 (t, 3H), 1.6 (m, 2H), 2.45 (m, 2H), 2.65 
(m, 2H), 2.9 (m, 2H), 4.2 (q, 2H), 4.3 (m, 
1H), 4.5 (m, 1H), 5.6 (q, 1H), 6.0 (s, 2H), 
6.5 (d, 1H), 7.1-7.4 (m, 8H) 
Ex. 40 (CDCl.sub.3 +CD.sub.3 OD): 
1.6 (m, 2H), 2.2-3.0 (m, 6H), 4.1 (m, 
1H), 4.3 (m, 1H), 5.6 (q, 1H), 6.0 (s, 
2H), 6.5 (d, 1H), 7.1-7.4 (m, 8H) 
Ex. 41 (CDCl.sub.3): 
1.64-2.37 (m, 10H), 2.5-2.6 (m, 2H), 3.02 (s, 
1H), 3.63 (s, 1H), 4.2-4.5 (m, 2H), 5.09 (s, 
2H), 5.79 (dd (J.sub.1 =8 Hz., J.sub.2 =18 Hz.), 1H), 
6.45 (d (J=18 Hz.), 1H), 7.08-7.52 (m, 12H) 
Ex. 42 (CDCl.sub.3): 
1.4 (d, 6H), 1.72-2.4 (m, 10H), 2.54 (d, 2H), 
3.2 (m, 1H), 3.65-3.81 (m, 2H), 4.0-4.5 (m, 
5H), 5.78 (dd (J.sub.1 =8 Hz., J.sub.2 =18 Hz.), 1H), 
6.45 (d (J=18 Hz.), 1H), 7.07-7.5 (m, 8H) 
Ex. 44 (C.sub.6 D.sub.6): 
0.9 (t (J=10 Hz.), 3H), 1.4 (dd (J.sub.1 =10 Hz., 
J.sub.2 =20 Hz.), 6H), 1.5-2.4 (m, 12H), 3.4 (m, 
1H), 3.8 (q (J=10 Hz.), 2H), 4.15 (m, 1H), 
4.4 (m, 1H), 5.8 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 
1H), 6.9 (dd (J.sub.1 =1 Hz., J.sub.2 =20 Hz.), 1H), 
7.0-7.6 (m, 4H). Also the following minor 
peaks due to the threo isomer: 4.55 (m), 5.9 
(dd), 6.8 (d) 
Ex. 46 (CDCl.sub.3): 
1.25 (t, 3H), 1.3-2.2 (m, 20H), 2.5 (d, 2H), 
2.9 (t, 1H), 3.25 (s, 1H), 3.8 (s, 1H), 4.2 
(q, 2H), 4.35 (s, 1H), 4.55 (s, 1H), 5.8 (q, 
1H), 6.65 (d, 1H), 7.2-7.6 (m, 4H) 
Ex. 48 (CDCl.sub.3): 
1.8-3.0 (m, 12H), 4.4 (m, 1H), 5.2 (m, 1H), 
5.7 (dd (J.sub.1 =10 Hz., J.sub.2 =20 Hz.), 1H), 6.5 (d 
(J=20 Hz.), 1H), 7.1-7.5 (m, 8H). Also the 
following minor peaks due to the cis lactone: 
4.3 (m), 4.7 (m), 5.8 (dd), 6.45 (d) 
__________________________________________________________________________ 
Each of Examples 12 and 42 may be separated by conventional means into four 
racemates each of which may be resolved by conventional means to obtain a 
total of eight stereoisomers; insofar as the hydroxy groups of the group 
of Formula a are concerned, the erythro isomers are preferred over the 
threo isomers, with the 3R,5S isomer being the most preferred and the 
3R,5R isomer being the preferred threo isomer. Example 13 may be separated 
by conventional means into two racemates each of which may be resolved by 
conventional means to obtain a total of four stereoisomers; insofar as the 
group of Formula a is concerned, the 3R,5S isomer is preferred. Each of 
Examples 14, 16-19, 24-27, 29-41 and 43-47 may be separated by 
conventional means to obtain the pure erythro racemate and the pure threo 
racemate (if any is present) each of which may be resolved by conventional 
means to obtain the 3R,5S and 3S,5R isomers from the erythro racemate and 
the 3R,5R and 3S,5R isomers from the threo racemate; the erythro isomers 
are preferred over the threo isomers, with the 3R,5S isomer being the most 
preferred and the 3R,5R isomer being the preferred threo isomer. Example 
15 may be resolved to obtain the 3R,5S and 3S,5R isomers, with the former 
being preferred. Example 28 may be separated by conventional means to 
obtain the pure erythro racemate and the pure threo racemate each of which 
may be resolved by conventional means to obtain the 3R,5R and 3S,5S 
isomers from the erythro racemate and the 3R,5S and 3S,5R isomers from the 
threo racemate; the erythro isomers are preferred over the threo isomers, 
with the 3R,5R isomer being the most preferred and the 3R,5S isomer being 
the preferred threo isomer. 
Example 20 may be separated by conventional means into two racemates each 
of which may be resolved by conventional means to obtain a total of four 
stereoisomers; insofar as the group of Formula b is concerned, the 4R,6S 
isomer is preferred. Example 21 may be separated by conventional means 
into four racemates each of which may be resolved by conventional means to 
obtain a total of eight stereoisomers; insofar as the group of Formula b 
is concerned, the trans lactones are preferred over the cis lactones, with 
the 4R,6S isomer being most preferred and the 4R,6R isomer being the 
preferred cis lactone isomer. Each of Examples 22 and 48 may be resolved 
by conventional means to obtain the 4R,6S and 4S,6R isomers, with the 
4R,6S isomer being preferred. Example 23 may be separated by conventional 
means to obtain the pure trans racemate and the pure cis racemate each of 
which may be resolved by conventional means to obtain the 4R,6S and 4S,6R 
isomers from the trans racemate and the 4R,6R and 4S, 6S isomers from the 
cis racemate; the trans isomers are preferred over the cis isomers, with 
the 4R,6S isomer being most preferred and the 4R,6R isomer being the 
preferred cis isomer. 
Throughout the examples, the term "reduced pressure" denotes aspirator 
pressure. Where no solvent is specified in connection with a solution, the 
solvent is water, and all solvent mixtures are by volume. When a reaction 
is carried out under nitrogen, dry nitrogen is used to maintain anhydrous 
conditions. 
All nuclear magnetic resonance spectra were taken at ambient temperature on 
a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (.delta.) 
relative to tetramethylsilane, and where a single .delta. value is given 
for anything other than a sharp singlet, it is its center point. In the 
N.M.R. data: 
bs=broad singlet 
d=doublet 
dd=doublet of a doublet 
dq=doublet of a quartet 
m=multiplet 
q=quartet 
s=singlet 
t=triplet 
The compounds of Examples 2, 5, 8, 9, 13, 15, 17, 19, 25, 30, 32, 34, 36, 
38, 40, 45 and 47 (wherein Z is a group of Formula a wherein R.sub.11 is 
sodium) may be converted into the corresponding compounds wherein R.sub.11 
is hydrogen or a different cation M, particularly M', by the processes set 
forth in the specification. 
Each of the compounds of Examples 1-48 (including each of the components 
and each of the possible stereoisomers thereof) may be administered to an 
animal, e.g., a larger primate, to inhibit cholesterol biosynthesis and 
thereby lower the blood cholesterol level for, for example, the treatment 
of atherosclerosis and hyperlipoproteinemia. The dosages are those set 
forth supra.