Intermediates and processes for 6-carboxy HMG-CoA reductase inhibitors

This invention discloses intermediates and a process for the preparation of 6-desmethyl-6-carboxy derivatives of lovastatin and analogs thereof at the 9-acyl side chain.

BACKGROUND OF THE INVENTION 
Hypercholesterolemia is known to be one of the prime risk factors for 
ischemic cardiovascular disease, such as arteriosclerosis. Bile acid 
sequestrants have been used to treat this condition; they seem to be 
moderately effective but they must be consumed in large quantities, i.e. 
several grams at a time and they are not very palatable. 
Mevacor (lovastatin), now commercially available, is one of a group of very 
active antihypercholesterolemic agents that function by limiting 
cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In 
addition to the natural fermentation products, mevastatin and lovastatin, 
there are a variety of semi-synthetic and totally synthetic analogs 
thereof. 
The naturally occurring compounds and their semi-synthetic analogs have the 
following general structural formulae: 
##STR1## 
wherein: 
R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a 
member of the group consisting of phenyl, dimethylamino, or acetylamino; 
and 
R.sup.4 is 
##STR2## 
wherein Q is 
##STR3## 
R.sup.5 is H or OH; M is 
##STR4## 
R.sup.6 is hydrogen or hydroxy; 
R.sup.7 is hydrogen or methyl; and a, b, c, and d represent single bonds, 
one of a, b, c or d represents a double bond, or both a and c or both b 
and d represent double bonds provided that when a is a double bond, Q is 
##STR5## 
and when d is a double bond, M is 
##STR6## 
U.S. Pat. No. 4,517,373 discloses semi-synthetic hydroxy containing 
compounds represented by the above general formula wherein R.sup.4 is 
##STR7## 
U.S. Pat. No. 4,537,859 and U.S. Pat. No. 4,448,979 also disclose 
semi-synthetic hydroxy-containing compounds represented by the above 
general formula wherein R.sup.4 is 
##STR8## 
These compounds are prepared by the action of certain microorganisms on the 
corresponding non-hydroxylated substrates. One such organism described in 
U.S. Pat. No. 4,537,859 is of the genus Nocardia. 
U.S. Pat. No. 4,376,863 discloses a fermentation product, isolated after 
cultivation of a microorganism belonging to the genus Aspergillus, which 
has a hydroxy containing butyryloxy side chain and is represented by the 
above general formula wherein R.sup.4 is 
##STR9## 
Japanese unexamined patent application J59-122,483-A discloses a 
semi-synthetic hydroxy-containing compound represented by the above 
general formula wherein R.sup.4 is 
##STR10## 
Copending U.S. patent application Ser. No. 048,136 filed May 15, 1987 
discloses 6-substituted compounds of the above general formula wherein 
R.sub.4 is 
##STR11## 
wherein R is CH.sub.2 OH, 
##STR12## 
CO.sub.2 R.sup.4 or 
##STR13## 
and R.sup.1, R.sup.3, R.sup.4, R.sup.6 and R.sup.7 are broadly defined 
organic moieties. 
The compounds of the above-mentioned U.S. patent application, Ser. No. 
048,136 wherein a and c are double bonds were prepared by a 
microbiological conversion of lovastatin or an analog thereof with a 
6-methyl substituent. Compounds where one of a, b or c represent a double 
bond or a, b, c all represent single bonds were prepared by a synthetic 
sequence from the 8-hydroxy-6-methyl derivative. 
The literature discloses a reaction known as the Barton Reaction by which a 
hydrogen in the .delta. position to an OH group can be abstracted to 
afford a carbon radical which can be oxidized. (See Hesse Adv. 
Free-Radical Chem. 3, 83-137 (1969); Barton, Pure Appl. Chem. 16, 1-15 
(1968); Arthar, Adv. Photochem. 2, 263-304 (1964).

DETAILED DESCRIPTION OF THE INVENTION 
This invention relates to novel intermediates, and a novel process for 
their preparation, where said intermediates are useful in a novel 
preparation of 6-desmethyl-6-carboxy (I) derivatives of lovastatin and 
analogs thereof at the 8-acyl side chain. Said 6-carboxy derivatives of 
lovastatin and analogs thereof are useful in treating hypercholesterolemia 
and are disclosed in copending patent application, Ser. No. 048,136 filed 
May 15, 1987. 
The overall process of this invention for preparing the 
6-desmethyl-6-carboxy (I) derivatives of lovastatin is shown in scheme 1. 
##STR14## 
The intermediates (3) of the instant invention are prepared in a novel 
process (i) which comprises: 
(A) contacting the compound (2) 
##STR15## 
wherein: n is 0 to 3; 
R.sub.1 and R.sub.2 independently are hydrogen, C.sub.1-5 alkyl, or R.sub.1 
and R.sub.2 together with the carbon atom to which they are attached form 
a carbocyclic ring of 3 to 8 carbon atoms; 
R.sub.3 and R.sub.4 are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 
cycloalkyl, C.sub.1-3 alkylthio, phenyl, phenylthio or substituted phenyl 
in which the substituents are V and W and when n is 2 to 3, each of the 
R.sub.3 s and R.sub.4 s are independently hydrogen, C.sub.1-3 alkyl, 
C.sub.3-7 cycloalkyl or only one of the R.sub.3 s and R.sub.4 s is phenyl 
or substituted phenyl; 
R.sub.5 is hydrogen, halogen, hydroxy, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, 
phenyl or substituted phenyl in which the substituents are V and W, or 
R.sub.5 is a group selected from: 
(a) C.sub.1-5 alkylthio or phenylthio or substituted phenylthio in which 
the substituents are V and W, 
(b) C.sub.1-5 -alkanoyloxy-C.sub.1-4 -alkyl, 
(c) 
##STR16## 
in which m is 0 to 3 and R.sub.6 is C.sub.1-5 alkyl; (d) 
##STR17## 
in which R.sub.7 and R.sub.8 are independently C.sub.1-5 alkyl or R.sub.7 
and R.sub.8 together with the nitrogen atom to which they are attached 
form a heterocycle selected from piperidinyl, morpholinyl, pyrrolidinyl, 
piperazinyl or thiomorpholinyl; 
(e) 
##STR18## 
in which q is 0 to 2 and R.sub.9 is C.sub.1-5 alkyl or phenyl or 
substituted phenyl in which the substituents are V and W; 
V and W independently are hydrogen, halogen, hydroxy, trifluoromethyl, 
C.sub.1-3 alkyl, C.sub.1-3 alkyloxy and hydroxy-C.sub.1-3 alkyl; 
T is a hydroxy protecting group such as tert-butyldimethylsilyl, 
tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl 
or tetrahydropyranyl; 
with a halogenating agent such as a phenylselenyl halide or phenylsulfinyl 
chloride in an inert solvent at about -80.degree. C. then treating the 
product with an oxidizing agent such as hydrogen peroxide or a peroxyacid 
in an ethereal solvent at ambient temperature to yield a compound (3) 
wherein X=Cl or Br; 
##STR19## 
Intermediates (3) are used to form intermediates (7) in a process (ii) 
which comprises: 
(B) reacting the compound (3) with nitrosyl chloride and a base to yield a 
compound (4); 
##STR20## 
(C) irradiating the compound (4) with light to obtain compound (5); 
##STR21## 
(D) heating the compound (5) in a protic solvent to afford compound (6); 
##STR22## 
(E) treating compound (6) with an aqueous paraformaldehyde solution in the 
presence of an acid catalyst to yield a compound (7); 
##STR23## 
Intermediates (7) are used to form intermediates (8) in a novel process 
(iii) which comprises: 
(F) contacting compound (7) with an oxidizing agent such as pyridinium 
chlorochromate (PCC) or chromium trioxide or chromium trioxide-pyridine or 
silver carbonate in an inert solvent to yield a compound (8); 
##STR24## 
Intermediates (8) are used to form the 6-desmethyl-6-carboxy derivatives 
(I) of lovastatin and analogs thereof in a novel process (iv) which 
comprises: 
(G) treating the compound (8) with samarium (II) iodide in an ethereal 
solvent to afford compound (9). 
##STR25## 
(H) Removal of the hydroxy-protecting group of compound (9) under standard 
acidic conditions such as an aqueous HF/CH.sub.3 CN mixture to afford 
product (I). 
##STR26## 
It should be understood that the alkyl, alkylthio, alkenyl and alkanoyl 
groups of this invention may either be in a straight chain or branched 
configuration. 
One embodiment of this invention is the compounds of formula (3): 
##STR27## 
In one class of this embodiment are the compounds of formula (3) wherein: 
R.sub.1 is methyl; 
R.sub.2 is hydrogen or methyl; 
R.sub.3 and R.sub.4 are independently hydrogen or C.sub.1-3 alkyl. 
In a subclass: 
R.sub.5 is hydrogen, halogen, hydroxy, C.sub.1-5 alkyl, phenyl or 
substituted phenyl in which the substituents are V and W; 
T is tert-butyldimethylsilyl; and X is Cl. 
Exemplifying this subclass are compounds (3) wherein: 
(1) n is 0, R.sub.2 is methyl, R.sub.5 is ethyl; 
(2) n is 0, R.sub.2 is hydrogen, R.sub.5 is ethyl. 
A second embodiment of this invention is the process for the preparation of 
intermediates (3) from the starting materials (2). This process consists 
of contacting a compound of formula (2) with a halogenating agent in an 
inert solvent followed by treatment with an oxidizing agent in an ethereal 
solvent. 
A third embodiment of the instant invention is the compounds of formula 
(7): 
##STR28## 
In one class of this embodiment are the compounds of formula (7) wherein: 
R.sub.1 is methyls 
R.sub.2 is hydrogen or methyl; 
R.sub.3 and R.sub.4 are independently hydrogen or C.sub.1-3 alkyl. 
In a subclass: 
R.sub.5 is hydrogen, halogen, hydroxy, C.sub.1-5 alkyl, phenyl or 
substituted phenyl in which the substituents are V and W; 
T is tert-butyldimethylsilyl; and X is Cl. 
Exemplifying this subclass are compounds (7) wherein: 
(1) n is 0, R.sub.2 is methyl, R.sub.5 is ethyl; 
(2) n is 0, R.sub.2 is hydrogen, R.sub.5 is ethyl. 
A fourth embodient of the instant invention is the compounds of formula 
(8): 
##STR29## 
In one class of this embodiment are the compounds of formula (8) wherein: 
R.sub.1 is methyl; 
R.sub.2 is hydroen or methyl; 
R.sub.3 and R.sub.4 are indpendently hydrogen or C.sub.1-3 alkyl. 
In a subclass: 
R.sub.5 is hydrogen, halogen, hydroxy, C.sub.1-5 alkyl, phenyl or 
substituted phenyl in which the substituents are V and W; 
T is tert-butyldimethylsilyl; and X is Cl. 
Exemplifying this subclass are compounds (8) wherein: 
(1) n is 0, R.sub.2 is methyl, R.sub.5 is ethyl; 
(2) n is 0, R.sub.2 is hydrogen, R.sub.5 is ethyl. 
A fifth embodiment of the instant invention is the process for the 
preparation of intermediates (8) from intermediates (7). This process 
consists in oxidizing a compound of formula (7) with an agent such as 
pyridinium chlorochromate or chromium trioxide or chromium 
trioxide-pyridine or silver carbonate. 
A sixth embodiment of the present invention is the process for the 
preparation of intermediates (9) from intermediates (8). This process 
consists in contacting a compound of formula (8) with a samarium (II) 
halide, such as samarium (II) iodide in an ethereal solvent. 
The diene (2) of step (A) is treated with a halogenating agent such as 
phenylselenyl chloride or bromide or phenylsulfinyl chloride, preferably 
phenylselenyl chloride, in an approximately equimolar ratio in an inert 
solvent at about -80.degree. C., for approximately 20 minutes; 
illustrative of such inert solvents are methylene chloride, ether and the 
like. After a standard workup the product residue is dissolved in an 
ethereal solvent, chilled to about 0.degree. C. and oxidized with an agent 
such as 30% hydrogen peroxide or a peroxy acid such as peroxybenzoic acid 
to yield a halohydrin analog (3). Compound (3) is treated with nitrosyl 
chloride at a temperature between -10.degree. and 10.degree. C., 
preferably 0.degree. C. for several minutes in a basic solvent until TLC 
analysis of an aliquot showed the reaction to be complete. Illustrative of 
such basic solvents are pyridine and quinoline and the like. 
The irradiation of a compound of formula (4) is conducted using light of 
wavelength greater than 320 .ANG.. One source of the irradiation is a 
medium pressure mercury lamp, at a temperature between 0.degree. and 
30.degree. C., preferably at about 20.degree. C., for a period of from 0.5 
to 5 hours, most preferably about 0.7 hours at 20.degree. C., in an inert 
solvent such as benzene, pyridine, hexane or the like, or a mixture of 
inert solvents. 
The rearrangement of a compound of formula (5) to a compound of formula (6) 
is conducted at a temperature between 60.degree. and 100.degree. C., 
preferably at 80.degree. C. for a period of 0.5 to 10 hours, most 
preferably for 1 hour at about 80.degree. C., in a protic solvent and an 
amine base. Illustrative of such protic solvents are alcohols such as 
isopropanol or 2-butanol and the like. Examples of amine bases are 
pyridine, triethylamine, quinoline, and the like. 
The conversion of an oxime (6) to a lactol (7) is conducted using an 
approximately 40% aqueous paraformaldehyde solution and a carboxylic acid 
such as acetic acid. 
The lactol (7) is oxidized with pyridinium chlorochromate ("PCC") or 
chromium trioxide or a chromium trioxide-pyridine complex or silver 
carbonate, preferably PCC in an inert solvent at about 25.degree. C. for 
about 5 to 7 hours, preferably 7 hours. Illustrative of the inert solvents 
are methylene chloride, benzene and the like. The mole ratio of oxidizing 
agent to lactol (7) is approximately 2:1. 
The samarium iodide is formed in situ by treating 1,2-diiodoethane with 
samarium powder in an ethereal solvent at about 25.degree. C. for about 1 
hour. The mole ratio of 1,2-diiodoethane to samarium powder is 1:2. The 
lactone (8) is treated with preformed samarium iodide at 25.degree. to 
80.degree. C., preferably 75.degree. C. for about 0.5 to 4 hours, 
preferably 1.5 hours, in an ethereal solvent. The mole ratio of lactone to 
samarium powder is approximately 1:2. Examples of such ethereal solvents 
are ethyl ether, tetrahydrofuran or dimethoxyethane. 
The silyl ether or tetrahydropyranyl protecting group is removed by 
treating a compound (9) in acrtonitrile with an aqueous HF/CH.sub.3 CN 
mixture at about 0.degree. C. for about 2.0 hours. 
Starting material (2) wherein the acyl side chain is 2-methylbutyryloxy is 
obtained from lovastatin by reaction with a silyl chloride protecting 
group such as tert-butyldimethylsilyl chloride following the procedure in 
U.S. Pat. No. 4,444,784 or by treatment with dihydropyran to yield the 
tetrahydropyranyl protecting moiety. Lovastatin is prepared according to 
the fermentation procedure disclosed in U.S. Pat. No. 4,231,938. 
Starting compounds (2) wherein the acyl side chain is other than 
2-methylbutyryloxy are prepared from lovastatin by hydrolysis of the 
8-acyl side chain, following the procedure in U.S. Pat. No. 4,444,784, 
followed by acylation with an appropriate alkanoyl chloride in the 
presence of lithium bromide and dimethylaminopyridine in pyridine using 
the procedure in copending U.S. Application Ser. No. 038,580 filed Apr. 
15,1987. Alternatively, the acylation is conducted with an alkanoyl 
chloride or an alkanoic acid under standard reaction conditions. 
The following examples illustrate the present invention and as such are not 
to be considered as limiting the invention set forth in the claims 
appended hereto. 
EXAMPLE 1 
Preparation of 
6(R)-[2-[6(R)-carboxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-1,2,6,7,8, 
8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyra 
n-2-one (I') 
(a) 
6(R)-[2-[5(S)-Chloro-4a(S)-hydroxy-8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R) 
-dimethyl-1,2,5,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl]-4(R)-(t-butyldimet 
hylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (3') 
A solution of phenylselenyl chloride (10 g, 52 mmol) in methylene chloride 
(50 ml) was added dropwise to a stirred solution of 
6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,-8,8a(R) 
-hexahydronaphthyl-1(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy)-3,4,5,6-tetra 
hydro-2H-pyran-2-one (25.2 g, 48 mmol) in methylene chloride (350 ml) 
cooled in a dry ice/i-propanol bath (-78.degree. C.). The resulting 
mixture was stirred at -78.degree. C. for 20 mintues, poured into cold 
water (300 ml) and extracted with ether twice (400 ml, then 150 ml). The 
combined extracts were dried (MgSO.sub.4), filtered and concentrated to 
afford an oily residue which was dissolved in tetrahydrofuran (300 ml). 
This solution was chilled in an ice bath (0.degree. C.), and 30% hydrogen 
peroxide (15 ml) was added. The resulting mixture was stirred at 0.degree. 
C. for 5 mintues, then warmed to room temperature and stirring continued 
for 1 hour. The reaction mixture was poured into cold water and extracted 
with chloroform three times (400 ml, then 2.times.100 ml). The combined 
extracts were dried (MgSO.sub.4), filtered and concentrated to yield a 
residue which was purified by flash chromatography on a silica gel column. 
Elution with hexane:ethyl acetate (5:1/v:v) removed ay impurities. Further 
elution with hexane-ethyl acetate (4:1/v:v) provided the title compound as 
a pale yellow gum which later solidified on standing: mp 
117.degree.-8.degree. C., nmr (CDCl.sub.3) .delta.0.075 (3H, s), 0.08 (3H, 
s), 0.85 (3H, t, J=7 Hz), 0.88 (9H, s), 0.89 (3H, d, J=7 Hz), 1.15 (3H, 
s), 1.16 (3H, s), 1.32 (3H, d, J=7 Hz), 1.58 (2H, q, J=7 Hz), 3.39 (H, s), 
4.05, (H, bs), 4.30 (H, m), 4.60 (H, m), 5.32 (H, m), 5.59 (H, d, J=11 
Hz), 5.79 (H, d of d, J=11, 6 Hz). 
Anal. Calc'd for C.sub.31 H.sub.53 ClO.sub.6 Si: C, 63.61; H, 9.13 
Found: C, 63.80; H, 9.04 
(b) 
6(R)-[2-[5(S)-Chloro-4a(S)-nitrosyloxy-8(S)-(2,2-dimethylbutyryloxy)-2(S), 
6(R)-dimethyl-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl]-4(R)-(t-buty 
ldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (4') 
Nitrosyl chloride gas was passed through a solution of compound 3' (4 g, 
6.83 mmol) in pyridine (40 ml) at 0.degree. C. for several mintues and the 
reaction became a dark brown colored mixture. An aliquot was taken and 
partitioned between ether and water. When TLC analysis.sup.1 of the ether 
layer indicated the reaction to be complete, the reaction mixture was 
poured into an ice/water mixture (ca. 100 ml) and extracted with benzene 
(150 ml). The organic phase was separated and the aqueous phase was 
extracted with another portion of benzene (50 ml). The combined extracts 
were then dried (MgSO.sub.4) and filtered. The filtrate.sup.2 was diluted 
with benzene to a volume of ca. 530 ml and used immediately in the 
subsequent photolysis. 
FNT .sup.1 When eluted with hexane:ethyl acetate (v:v/4:1), the R.sub.f values 
of the starting compound 3' and product 4' are 0.25 and 0.39, 
respectively. 
FNT .sup.2 The amount of pyridine present in this solution was not determined. 
The presence of pyridine is critical for the stabilization of compound 4'. 
(c) 
6(R)-[2-[5(S)-Chloro-4a(S)-hydroxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-meth 
yl-6(S)-nitrosylmethyl-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl]-4(R 
)-(t-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (5') 
A solution of compound 4' in benzene and pyridine, freshly prepared from 
compound 3' (4 g, 6.83 mmol) as described in step (b) was deoxygenated by 
bubbling nitrogen gas through the solution for 10 minutes. Then, it was 
irradiated (450 W Hanovia medium pressure mercury lamp, pyrex sleeve) at 
room temperature for 40 minutes while nitrogen continued to bubble through 
the solution. The photolyzed solution was transferred to a 500 ml R-B 
flask and concentrated in vacuo to a volume of ca. 25 ml. This residue was 
diluted with ether and shaken with dilute hydrochloric acid (1N, 150 ml) 
to remove pyridine. After washing with water (100 ml) and 5% sodium 
bicarbonate solution, the solution was dried (MgSO.sub.4) and filtered. 
Evaporation of the filtrate left a residue which was purified by flash 
chromatography. Elution with hexane:ethyl acetate (v:v/4:1) removed side 
products. Then, elution with hexane-ethyl acetate (v:v/2:1) gave 
6(R)-[2-[5(S)-chloro-4a(S)-hydroxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-meth 
yl-6(S)-hydroxyiminomethyl-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl] 
-4(R)(t-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (6'), and 
compound 5' as an off-white solid: m.p. 155.degree.-7.degree. C. 
(decomp.); nmr (CDCl.sub.3) .delta.0.07 (3H, s), 0.08 (3H, s), 0.86 (3H, 
t, J=7 Hz), 0.9 (9H, s), 0.95 (3H, d, J=7 Hz), 1.18 (3H, s), 1.20 (3H, s), 
2.84 (H, s), 2.91 (H, m), 4.18 (H, s), 4.30 (H, m), 4.36 (H, d of d, J=10, 
7 Hz), 4.60 (H, m), 4.94 (H, d of d, J=10, 7 Hz), 5.27 (H, m), 5.56 (H, d, 
J=10 Hz), 6.81 (H, d of d, J=10, 6 Hz). 
Anal. Calc'd for C.sub.31 H.sub.52 ClNO.sub.7 Si: C, 60.61; H, 8.53; N, 
2.28 
Found: C, 60.77; H, 8.75; N, 2.59 
(d) 
6(R)-[2-[5(S)-Chloro-4a(S)-hydroxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-meth 
yl-6(S)-hydroxyiminomethyl-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl] 
-b 4(R)-(t-butyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one (6') 
Pyridine (1.5 ml) was added to a stirred solution of compound 5' (5.66 g, 
9.21 mmol) in i-propanol (150 ml). The resulting mixture was heated at 
reflux for 1 hour. After cooling, the reaction mixture was concentrated in 
vacuo to afford the title compound as a foamy gum: nmr (CDCl.sub.3) 
.delta.0.08 (3H, s), 0.90 (9H, s), 3.12 and 3.64 (H, both m), 4.30 (H, m), 
4.30 and 4.38 (H, both s), 4.60 (H, m), 5.28 and 5.23 (H, both m), 5.57 
(H, d, J=10 Hz), 5.84 (H, d, J=10, 6 Hz), 7.21 and 7.75 (H, both d, J=6 
Hz), 7.32 (H, bs). 
(e) 
6(R)-[2-[5(S)-Chloro-6(S)-formyl-4a(S)-hydroxy-2(S)-methyl-8(S)-(2,2-dimet 
hylbutyryloxy)-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl]-4(R)-(t-but 
yldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, lactol (7') 
A 40% aqueous paraformaldehyde solution.sup.3 (250 ml) and acetic acid 
(0.53 ml, 9.28 mmol) were added to a solution of the oxime 6' (5.7 g, 9.28 
mmol) in acetone (350 ml) and the cloudy reaction mixture was stirred at 
ambient temperature overnight. The acetone was removed in vacuo at 
30.degree. C. and the aqueous residue was extracted with ether 
(3.times.100 ml). The ether extracts were combined, washed with saturated 
NaHCO.sub.3 solution (25 ml), H.sub.2 O (25 ml), brine (2.times.25 ml) and 
dried over MgSO.sub.4. Filtration and evaporation in vacuo gave the crude 
lactol 7' as a tan foam which was used in Step f without further 
purification: nmr (CDCl.sub.3) .delta.0.87 (9H, s), 1.15 (3H, s), 1.17 
(3H, s), 2.58 (2H, m), 4.28 (H, m), 4.49 (H, d, J=4 Hz), 4.56 (H, m), 5.14 
(H, m), 5.39 (H, d, J=10 Hz), 5.42 (H, s), 6.14 (H, d of d, J=10, 6 Hz). 
FNT .sup.3 40% aqueous paraformaldehyde solution was prepared by refluxing a 
mixture of paraformaldehyde (100 g) in H.sub.2 O (250 ml) for 1.5 hours 
(oil bath=130.degree. C.). The reaction was cooled and filtered to remove 
some gelatinous polymer. 
(f) 
6(R)-[2-[6(S)-Carboxy-5(S)-chloro-4a(S)-hydroxy-2(S)-methyl-8(S)-(2,2-dime 
thylbutyryloxy)-1,2,5,6,7,8,8a(S)-heptahydronaphthyl-1(S)]ethyl]-4(R)-(t-bu 
tyldimethylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, lactone (8') 
A solution of the lactol 7' (2.05 g, 3.42 mmol) in CH.sub.2 Cl.sub.2 (20 
ml) was added to a stirred suspension of pyridinium chlorochromate (1.47 
g, 6.84 mmol) in CH.sub.2 Cl.sub.2 (100 ml) and the mixture was stirred at 
ambient temperature. After 7 hours.sup.4, the reaction was diluted with 
ether and the resulting mixture was filtered. The solid residue was 
stirred in ether (2.times.100 ml) and filtered. The filtrates were 
combined and concentrated in vacuo to a semisolid (2.1 g) which was 
purified by flash chromatography on a 4.times.15 cm column of silica gel 
(230-400 mesh). The column was eluted with acetone/CH.sub.2 Cl.sub.2 
(1:99/v:v) to give the lactone 8' as a colorless solid, m.p. 
166.degree.-8.degree. C: nmr (CDCl.sub.3) .delta.0.063 (3H, s), 0.074 (3H, 
s), 0.82 (3H, t, J=7 Hz), 0.87 (9H, s), 0.92 (3H, d, J=7 Hz), 1.12 (3H, 
s), 1.14 (3H, s), 2.79 (H, m), 4.29 (H, m), 4.35 (H, d, J=5 Hz), 4.55 (H, 
m), 5.26 (H, m), 5.42 (H, d, J=10 Hz), 6.27 (H, d of d, J=10, 6 Hz). 
Anal. Calc'd for C.sub.31 H.sub.49 ClO.sub.7 Si: C, 62.33; H, 8.27 
Found: C, 62.49; H, 8.40 
FNT .sup.4 The reaction was followd by TLC [Whatman Silica gel 60 A, 
EtOAc-hexane (3:7)] R.sub.f of 7'=0.2, R.sub.f of 8'=0.4. 
(g) 
6(R)-[2-[6(R)-Carboxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-1,2,6,7,8, 
8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-(t-butyldimethylsilyloxy)-3,4,5,6- 
tetrahydro-2H-pyran-2-one, (9') 
A THF.sup.5 solution (25 ml) of 1,2-diiodoethane.sup.6 (2.55 g, 9.04 mmol) 
was added dropwise to magnetically-stirred samarium powder (2.72 g, 18.08 
mmol), contained in an oven-dried flask, at a rate sufficient to maintain 
a gentle reflux under a nitrogen atmosphere. After stirring an additional 
45 minutes at ambient temperature, a THF solution (25 ml) of the lactone 
8' (2.7 g, 4.52 mmol) was added and the reaction was heated in a 
75.degree. C. oil bath for 1.5 hours.sup.7. The reaction was cooled to 
0.degree. C. (ice/acetone bath) and slowly treated with 5% HCl (max. 
temp.=10.degree. C.) until acidic (pH=4). The resulting mixture was 
stirred 10 minutes at 0.degree. C. and poured into ether (100 ml). The 
aqueous layer was extracted with 2.times.100 ml ether and the ether 
extracts were combined, washed with brine (25 ml) and dried over 
MgSO.sub.4. Filtration and evaporation gave the acid 9' as a pale yellow 
foam. A portion of the acid was purified by flash chromatography on silica 
gel (230-400 mesh) column. Elution with isopropanol/hexane (1:9/v:v) 
provided the acid as a colorless solid, m.p. 111.degree.-113.degree. C: 
nmr (CDCl.sub.3) .delta.0.070 (3H, s), 0.078 (3H, s), 0.79 (3H, t, J=7 
Hz), 0.88 (9H, s), 1.03 (3H, s), 1.05 (3H, s), 3.21 (H, m), 4.28 (H, m), 
4.58 (H, m), 5.33 (H, m), 5.74 (H, m), 5.87 (H, d of d, J=10, 6 Hz), 6.05 
(H, d, J=10 Hz). 
Anal. Calc'd for C.sub.30 H.sub.50 O.sub.7 Si: C, 66.15; H, 8.96 
Found: C, 66.02; H, 8.97 
FNT .sup.5 THF was distilled under nitrogen from sodium benzophenone ketyl. 
FNT .sup.6 An ether solution of 1,2-diiodoethane was washed with aqueous sodium 
thiosulfate solution and water and then dried over MgSO.sub.4. Filtration 
and evaporation gave a colorless solid which was stored in the freezer. 
FNT .sup.7 The reaction was followed by TLC [Whatman Silica gel 60 A, 
EtOAc-hexane (3:7)]. R.sub.f of 8'=0.4, R.sub.f of 9'=0.0 to 0.17. 
(h) 
6(R)-[2-[6(R)-carboxy-8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-1,2,6,7,8, 
8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra-hydro-2H-pyr 
an-2-one (I') 
A solution of 48% HF/CH.sub.3 CN (1:19/V:V, 1 ml) was added to a 
magnetically stirred CH.sub.3 CN solution (2 ml) of the silyl ether 9' (8 
mg, 0.015 mmol). The solution was stirred under ambient conditions for 2.0 
hours and then poured into ether (50 ml). The ether solution was washed 
with saturated NaHCO.sub.3 solution (5 ml), brine (2.times.10 ml) and 
dried over MgSO.sub.4. Filtration and evaporation gave the desilylated 
lactone I' as a viscous oil which was purified by flash chromatography on 
a 1.times.7 cm column of silica gel (230-400 mesh). Elution of the column 
with isopropanol-hexane (1:4/V:V) removed the less polar impurities. 
Further elution with isopropanol-HOAc (19:1/V:V) provided the title 
compound: nmr (CDCl.sub.3) .delta. 0.80 (3H, t, J=7 Hz), 1.04 (3H, s), 
1.07 (3H, s), 3.24 (H, m), 4.38 (H, m), 4.60 (H, m), 5.38 (H, m), 5.78 
(H, m), 5.87 (H, dd, J=10, 6 Hz), 6.05 (H, d, J=10 Hz), 8.55 (H, bm).