Optical resolution of 3-(silyloxy)glutaric acid half esters and their utilization for enantioconvergent synthesis of a HMG-CoA reductase inhibitor

Article abstract of DOI:10.1021/jo9722156

Useful chiral synthons, (3R)- and (3S)-[(tert- butyldimethylsilyl)oxy]pentanedioic acid monomethyl ester, (R)-1 and (S)-1, were obtained by optical resolution of a racemic mixture of 1. Sulfoxide 8 has been developed from (S)-1 as a new building block for preparing HMG-CoA reductase inhibitors. Two alternate chiral synthons 2 and 8, synthesized from (R)-1 and (S)-1, respectively, were employed for enantioconvergent synthesis of potent inhibitor 15 containing a pyrrole moiety.

Full text of DOI:10.1021/jo9722156

J . Org. Chem. 1998, 63, 3037-3040
3037
Op tica l Resolu tion of 3-(Silyloxy)glu ta r ic Acid Ha lf Ester s a n d
Th eir Utiliza tion for En a n tiocon ver gen t Syn th esis of a HMG-CoA
Red u cta se In h ibitor
Toshiro Konoike,* Tetsuo Okada, and Yoshitaka Araki
Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553, J apan
Received December 8, 1997
Useful chiral synthons, (3R)- and (3S)-[(tert-butyldimethylsilyl)oxy]pentanedioic acid monomethyl
ester, (R)-1 and (S)-1, were obtained by optical resolution of a racemic mixture of 1. Sulfoxide 8
has been developed from (S)-1 as a new building block for preparing HMG-CoA reductase inhibitors.
Two alternate chiral synthons 2 and 8, synthesized from (R)-1 and (S)-1, respectively, were employed
for enantioconvergent synthesis of potent inhibitor 15 containing a pyrrole moiety.
Sch em e 1
In tr od u ction
Success with three HMG-CoA reductase (HMGR)
inhibitors for treating hypercholesterolemia,1 lovastatin,
pravastatin, and simvastatin, led to a surge in novel
HMGR inhibitors2 that are more potent and synthesized
by simple chemical processes. A number of synthetic
approaches3,4 have been reported for the preparation of
HMGR inhibitors, and two useful chiral synthons5-7 have
been developed for their synthesis.
We previously reported7 a practical synthesis of enan-
tiomerically pure 3-[(tert-butyldimethylsilyl)oxy]pen-
tanedioic acid monomethyl ester in either of these
enantiomeric forms by desymmetrization of 3-[(tert-
butyldimethylsilyl)oxy]pentanedioic anhydride by means
of chiral benzyl mandelate. Two chiral synthons for
HMG-CoA reductase inhibitors, Wittig reagent 2 and
Horner-Wadsworth-Emmons (HWE)-type synthon 3,
were derived from these chiral half esters, and Wittig
reagent 2 was converted to pyrrole-containing potent
HMGR inhibitor 158 by way of 5b (Scheme 1). The
desymmetrization approach was also employed for syn-
thesis of (+)-6-epi-mevinolin.4
Resu lts a n d Discu ssion
To supply a large amount of drug candidate 15
(Scheme 3) for biological evaluation, the sequence of the
synthesis was optimized from an economical point of
Sch em e 2
(1) For reviews, see: Endo, A. J . Med. Chem. 1985, 28, 401. Endo,
A.; Hasumi, K. Nat. Prod. Rep. 1993, 10, 541.
(2) Connolly, P. J .; Westin, C. D.; Loughney, D. A.; Minor, L. K. J .
Med. Chem. 1993, 36, 3674 and references therein.
(3) For a review on synthetic work, see: Chapleur, Y. The Chemistry
and Total Synthesis of Mevinic Acids. In Recent Progress in the
Chemistry of Antibiotics; Lukacs, G., Ueno, S., Eds.; Springer: New
York, 1993; Vol. 2; pp 829-937.
(4) Araki, Y.; Konoike, T. J . Org. Chem. 1997, 62, 5299.
(5) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1993, 58, 142
and references therein.
(6) Karanewsky, D. S.; Malley, M. F.; Gougoutas, J . Z. J . Org. Chem.
1991, 56, 3744.
(7) Konoike, T.; Araki, Y. J . Org. Chem. 1994, 59, 7849.
(8) (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai,
K. Bioorg. Med. Chem. 1997, 5, 437. (b) Hirai, K.; Ishiba, T.; Koike,
H.; Watanabe, M. European Application EP-A-0464845, 1992; Chem.
Abstr. 1992, 116, 173999z. (c) Hirai, K.; Ishiba, T.; Koike, H.; Wa-
tanabe, M. J pn. Kokai Tokkyo Koho J P 04-352767 [92-352767], 1992.
(9) Hirai, K.; Okada, T. J pn. Kokai Tokkyo Koho J P 05-32680 [93-
32680], 1993; Chem. Abstr. 1993, 119, 138753e.
view. This led us to develop an optical resolution method
for racemic monomethyl ester 19 by salt formation of 1
with enantiopure amines, which is more practical and
less expensive than the desymmetrization methods.5-7
Racemic 1 was prepared from dimethyl acetonedicar-
boxylate in three steps. Sodium borohydride reduction,
TBDMS protection, and subsequent partial hydrolysis of
methyl ester gave 1 in 72% yield. Optical resolution was
S0022-3263(97)02215-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/14/1998

3038 J . Org. Chem., Vol. 63, No. 9, 1998
Konoike et al.
Sch em e 3
from (S)-1 and its application for the synthesis of HMGR
inhibitor 15.
Novel chiral synthon 8 was developed from (S)-1 in a
similar way to that of HWE reagent 3 (Scheme 2).
Enantioenriched (S)-1 (98% ee) was treated with an
excess of lithium anion of DMSO to give a diastereomeric
mixture (1:1) of hexanoic acid 6, whose additional chiral
center was derived from the sulfoxide. Diazomethane
treatment of 6 led to methyl ester 8, although this was a
drawback to large-scale preparation. Therefore, we
developed an alternative way to obtain enantiopure 8 via
cyclic enol lactone 7, which is safe and applicable for
large-scale preparation. Hexanoic acid 6 was converted
to enol lactone 7 by treatment with methanesulfonyl
chloride and triethylamine. Three isomers of 7 were
1
detected by H NMR. Subsequent lactone cleavage by
sodium methoxide in methanol gave a mixture of dia-
stereomeric methyl ester 8.
Our synthesis of HMGR inhibitor 15 from sulfoxide 8
was accomplished by a judicious choice of a pyrrole
counterpart (Scheme 3). After several unsuccessful at-
tempts to condense 8 with pyrroles that have reactive
functional groups at the 3-position such as the chlorom-
ethyl group, we finally obtained Mannich base 10.13
[(Dimethylamino)methyl]pyrrole 10 was prepared from
914 using Eschenmoser’s salt;15 however, this gramine-
type intermediate did not undergo condensation with 8.
Methylation of 10 by methyl triflate gave quaternary
ammonium salt 11, which in turn showed effective
condensation with 8. Treatment of activated species 11
and 8 with t-BuOK afforded a diastereomeric mixture of
condensed product 13 in a good yield, presumably via the
intermediate enimine 12. The diastereomeric mixture
of 13 underwent thermal sulfenate elimination to exclu-
sively give (E)-heptenoic acid methyl ester 5a (98% ee).16
This was mesylated to 5b and further converted to syn
dihydroxy methyl ester 14 by the conventional pathway
of deprotection and stereoselective hydride reduction.
Sodium salt 15 was prepared from 14 by ester hydrolysis
for biological evaluation.
In conclusion, we were able to achieve optical resolu-
tion of racemic 1, and both enantiomers (R)-1 and (S)-1
were obtained with high optical purity from the racemate
in high yield. Enantioenriched 1 is a versatile chiral
building block, and one example of its synthetic applica-
tion is the enantioconvergent synthesis of HMGR inhibi-
tor 15. Each enantiomeric 1 was converted to a chiral
synthon for HMGR inhibitor, Wittig reagent 2, and
sulfoxide 8, from which a single enantiomeric HMGR
inhibitor 15 can be prepared.
achieved as follows. Racemic 1 was treated with an
equimolar amount of (+)-dehydroabietylamine, and the
(+)-dehydroabietylamine salt of (R)-1 was obtained as a
crystalline powder in 43% yield (>96% ee). The mother
liquor was acidified to remove (+)-dehydroabietylamine,
and the resulting (S)-rich 1 was treated with an equimo-
lar amount of (S)-(-)-1-phenethylamine to give a salt of
(S)-1 and (S)-(-)-1-phenethylamine in 46% yield (98% ee).
Acidic treatment of the salts of (R)- and (S)-1 followed
by chromatographic purification afforded (R)-1 and (S)-1
of high optical purity. This separation process was
optimized in cooperation with Ube Industries, Ltd., and
both (R)-1 and (S)-1 are now commercially available.10
Each enantiomer was successfully converted to chiral
synthon 2 or 35,6,11 (Scheme 1) as shown in our previous
paper.7 Each chiral synthon was considered to undergo
olefination with a suitable aldehyde to give an optically
pure hydroxy heptenoate moiety such as 5a or 5b, which
would be a precursor of HMGR inhibitor 15. Wittig
reagent 2 underwent condensation with N-(methane-
sulfonyl) pyrrole aldehyde 4b (methanesulfonyl ) mesyl)
to give unsaturated ketone 5b.7 However, HWE reagent
3 did not condense with either pyrrole aldehyde 4a or
4b under various conditions. Pyrrole 4a was recovered
unchanged, while 4b was hydrolyzed to the parent
pyrrole 4a in most cases employing a variety of bases.
These results led to the conclusion that only one enan-
tiomer (R)-1 could contribute to the synthesis of pyrrole-
containing HMGR inhibitor 15, and the other (S)-1 is
useless unless it can be converted to (R)-1 or another
chiral synthon for 15. To fully utilize both enatiomeric
forms of 1 obtained by optical resolution, we developed a
novel chiral synthon, sulfoxide 8,12 from (S)-1. We
describe herein the preparation of sulfoxide 8 derived
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were carried out under a
nitrogen atmosphere in anhydrous solvents (dried over mo-
lecular sieves type 4A). Organic extracts were dried over
anhydrous MgSO4. Solvent removal was accomplished at
aspirator pressure using a rotary evaporator. TLC was
(12) A part of this work has been published in the patent. Konoike,
T.; Araki, Y. PCT Int. Appl., WO 92/22560, 1992; Chem. Abstr. 1993,
119, 95827n.
(10) Both enantiomers (99% ee) are now available through the
cooperation of Shionogi & Co., Ltd. and Ube Industries, Ltd. For
samples of (R)-1 and (S)-1, send inquiries to T. Hashimoto at Ube
Industries, Ltd., 2-3-11, Higashi-Shinagawa, Shinagawa-ku, Tokyo 140,
J apan.
(11) Okada, T.; Konoike, T. J pn. Kokai Tokkyo Koho J P 07-118233
[95-118233], 1995; Chem. Abstr. 1995, 123, 286068h.
(13) Kozikowski, A. P.; Ishida, H. Heterocycles 1980, 14, 55.
(14) Pyrrole 9 was prepared by a slight modification of Watanabe’s
method8a using 3-methyl-2-butanone instead of ethyl 4-methyl-3-
oxoheptanoate as a starting material.
(15) Schreiber, J .; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(16) Enatiomeric excess was determined by HPLC; see ref 8.

Synthesis of a HMG-CoA Reductase Inhibitor
J . Org. Chem., Vol. 63, No. 9, 1998 3039
1
performed with Merck precoated TLC plates silica gel 60 F254
,
1731 cm-1; H NMR δ 0.07 (s, 3), 0.08 (s, 3), 0.85 (s, 9), 2.5-
and compound visualization was effected with 10% H2SO4
containing 5% of ammonium molybdate and 0.2% of ceric
sulfate. Gravity chromatography was done with Merck silica
gel 60 (70-230 mesh). Melting points are uncorrected. 1H
NMR and 13C NMR spectra were determined as CDCl3
solutions at 200 and 50.3 MHz, unless specified otherwise. J
values are given in hertz. High-resolution mass spectra (HR-
LSIMS) were recorded on a Hitachi M-90 instrument.
Op tica l Resolu tion of 1. Racemic 1 was treated with an
equimolar amount of (+)-dehydroabietylamine in methanol,
and the solvent was evaporated. The residue was dissolved
in pentane and stored at 0 °C overnight. Crystals were
collected, and the complex of (R)-1 and (+)-dehydroabietyl-
amine was obtained in 43% yield (>96% ee). The mother
liquor was concentrated, dissolved in Et2O, and treated with
4 N HCl/EtOAc. The insoluble materials were filtered, and
the filtrate was concentrated and purified by silica gel chro-
matography to give (S)-rich 1 (93% ee). This compound was
dissolved in Et2O and treated with an equimolar amount of
(S)-(-)-1-phenethylamine. Pentane was added, and the mix-
ture was stored at room temperature for 1 h. Crystals were
collected, and the complex of (S)-1 and (S)-(-)-1-phenethyl-
amine was obtained in 46% yield (98% ee). Acidic treatment
of both amine complexes gave crude half esters, and further
chromatographic purification afforded (R)-1 and (S)-1, respec-
tively.
2.6 (m, 2), 2.69 (s, 3), 2.89 (t, 2, J ) 5.4), 3.67 (s, 3), 3.75 (dd,
1, J ) 5.1, 14.1), 3.85 (dd, 1, J ) 6.6, 14.1), 4.5-4.6 (m, 1); 13
C
NMR δ -4.9, -4.8, 17.9, 25.7, 39.1, 42.0, 42.0, 51.6, 52.1, 52.2,
65.1, 65.1, 65.2, 65.3, 171.2, 200.6, 200.8; TLC (CHCl3/MeOH
) 10/1) Rf 0.46. Anal. Calcd for C14H28O5SSi‚0.3H2O: C,
49.28; H, 8.43; S, 9.38. Found: C, 49.21; H, 8.20; S, 9.33.
[[4-(4-F lu or op h en yl)-2-isop r op yl-5-m eth yl-1H-p yr r ol-
3-yl]m eth yl]d im eth yla m in e (10). To a solution of 9 (22.2
g, 102 mmol) in CH2Cl2 (200 mL) was added Eschenmoser’s
salt (18.9 g, 102 mmol) in one portion at room temperature.
The mixture was refluxed for 1 h and quenched with H2O. The
aqueous NaOH was added, and the mixture was extracted with
CH2Cl2. The organic phase was separated, washed with brine,
dried, and concentrated. Obtained crude 10 was sufficiently
pure and used without purification for the next step. Analyti-
cally pure sample was obtained by chromatography on neutral
alumina (EtOAc/hexane ) 1/4) and crystallization from cold
hexane gave 10: mp 87-89 °C; IR (CHCl3) 3465, 2965, 1505
cm-1 1H NMR δ 1.25 (d, 6, J ) 7.0), 2.13 (s, 6), 2.23 (s, 3),
;
3.14 (s, 2), 3.19 (quintet, 1, J ) 7.0), 7.03 (dd, 2, J ) 9.0, 9.0),
7.43 (dd, 2, J ) 6.0, 9.0), 7.58 (br s, 1); 13C NMR δ 12.0, 23.2,
25.1, 44.8, 53.1, 113.2, 114.6 (J ) 21.4), 121.4 (J ) 55.1), 131.7
(J ) 7.6), 132.8 (J ) 2.9), 158.9, 161.1 (J ) 244); TLC (CHCl3/
MeOH ) 3/1) Rf 0.10. Anal. Calcd for C17H23N2F‚0.3H2O: C,
72.98; H, 8.50; N, 10.01; F, 6.79. Found: C, 72.95; H, 8.36; N,
9.90; F, 6.84.
(3R)-[(ter t-Bu tyldim eth ylsilyl)oxy]-6-(m eth an esu lfin yl)-
5-oxoh exa n oic Acid (6). To a solution of DMSO (7.66 mL,
108 mmol) in THF (120 mL) was added BuLi (65.4 mL of 1.56
M hexane solution, 102 mmol) dropwise at -30 °C. The
mixture was stirred at 2 °C for 40 min, and after being cooled
to -66 °C, (S)-1 (8.29 g, 30 mmol) in THF (60 mL) was added
dropwise over 10 min. The mixture was stirred at -30 °C for
45 min and then poured into ice and 1 N HCl (110 mL). The
mixture was extracted with EtOAc (2 × 300 mL), and the
organic phase was washed with brine (4 × 200 mL), dried,
and concentrated to give a 1:1 diastereomeric mixture of acid
6 (9.87 g, quant): IR (CHCl3) 3507, 1714 cm-1; 1H NMR δ 0.08
(s, 3), 0.10 (s, 3), 0.85 (s, 9), 2.56 (d, 2, J ) 6.0), 2.73 (s, 1.5),
2.74 (s, 1.5), 2.88 (dd, 1, J ) 6.0, 16.8), 2.93 (dd, 1, J ) 6.0,
16.8), 3.8-4.0 (m, 2), 4.57 (quintet, 1, J ) 6.6); 13C NMR δ
-4.8, -4.8, 17.9, 25.7, 38.6, 41.7, 51.8, 51.8, 64.5, 64.6, 65.1,
65.2, 174.4, 174.4, 200.6, 200.8; TLC (EtOAc/AcOH/H2O ) 30/
1/1) Rf 0.35.
[[4-(4-F lu or op h en yl)-2-isop r op yl-5-m eth yl-1H-p yr r ol-
3-yl]m eth yl]tr im eth yla m m on iu m Tr iflu or om eth a n esu l-
fon a te (11). To a solution of amine 10 (2.32 g, 8.46 mmol) in
CH2Cl2 (20 mL) was added methyl trifluoromethanesulfonate
(1.10 mL, 9.30 mmol) dropwise at room temperature. Stirring
was continued for 30 min, and the mixture was concentrated
to give crude ammonium salt 11. Obtained crude 11 was
sufficiently pure and used without purification for the next
step. Analytically pure sample was obtained from pure 10:
1
mp 99-102 °C; IR (CHCl3) 3322, 2969, 1507 cm-1; H NMR
(CD3OD) δ 1.31 (d, 6, J ) 6.9), 2.15 (s, 3), 2.72 (s, 9), 3.1-3.2
(m, 1), 4.40 (s, 2), 7.16 (dd, 2, J ) 9.0, 9.0), 7.25 (dd, 2, J )
5.4, 9.0); 13C NMR (CD3OD) δ 11.3, 23.2, 26.4, 52.2, 62.0, 103.3,
116.7 (J ) 21.7), 121.1, 121.8 (J ) 319), 126.7 (J ) 11.7), 133.0
(J ) 7.6), 133.9, 141.6 (J ) 11.7), 162.9 (J ) 244); TLC (CHCl3/
MeOH
) 3/1) Rf 0.27. Anal. Calcd for C19H26N2O3-
SF4‚1.2H2O: C, 49.60; H, 6.22; N, 6.09. Found: C, 49.35; H,
5.82; N, 6.39.
(4R)-[(ter t-Bu t yld im et h ylsilyl)oxy]-6-[(m et h a n esu lfi-
n yl)m eth ylen e]tetr a h yd r op yr a n -2-on e (7). To a solution
of crude acid 6 (9.87 g, 30 mmol) in CH2Cl2 (100 mL) was added
triethylamine (10.0 mL, 72 mmol) dropwise over 10 min
followed by MsCl (2.79 mmol, 36 mmol) also added dropwise
over 10 min at 0 °C. The cooling bath was then removed, and
the reaction mixture was warmed to 15 °C over 15 min.
Stirring was continued at that temperature for 30 min. The
mixture was poured into ice and 1 N HCl and extracted twice
with EtOAc. Each organic phase was washed with saturated
NaHCO3 and brine, dried, and concentrated. The resulting
orange solid was crystallized from CHCl3 (10 mL)-hexane (300
mL) to give 7 (6.50 g, 74% yield) as orange crystals: mp 99-
(3R)-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-[4-(4-flu or op h e-
n yl)-2-isop r op yl-5-m et h yl-1H -p yr r ol-3-yl]-6-(m et h a n e-
su lfin yl)-5-oxoh ep t a n oic Acid Met h yl E st er (13). To a
solution of sulfoxide 8 (2.22 g, 6.6 mmol) in tert-butyl alcohol
(16 mL) and THF (4 mL) was added t-BuOK (741 mg, 6.6
mmol) in one portion at 0 °C. After being stirred at 0 °C for
15 min, 11 (2.63 mg, 6.0 mmol) was added, and the reaction
mixture was stirred at 0 °C for 2 h. EtOAc and saturated NH4-
Cl were added, and the organic phase was separated. The
aqueous phase was extracted with EtOAc, and each organic
layer was washed with brine, dried, and concentrated. Puri-
fication by silica gel chromatography (EtOAc/hexane ) 1/1)
gave a diastereomeric mixture of ester 13 (1.98 g, 58% yield
1
100 °C; IR (CHCl3) 1783, 1650 cm-1
;
1H NMR δ 0.09 (s, 3),
from 9): IR (KBr) 1738, 1505 cm-1; H NMR δ -0.05 (s, 3),
0.10 (s, 3), 0.86 (s, 4.5), 0.88 (s, 4.5), 2.68 (s, 1.5), 2.70 (s, 1.5),
2.6-2.7 (m, 3), 2.7-2.8 (m, 2), 4.2-4.4 (m, 1), 5.5-5.6 (m, 1);
13C NMR δ -4.9, -4.8, 18.0, 25.5, 25.6, 35.7, 35.8, 39.6, 39.7,
40.9, 40.9, 62.4, 62.5, 117.2, 117.4, 152.2, 152.8, 163.9; TLC
(CHCl3/MeOH ) 10/1) Rf 0.39 and 0.43. Anal. Calcd for
-0.02 (s, 3), 0.7-0.8 (m, 9), 1.1-1.2 (m, 6), 2.11 (s, 3), 2.1-3.4
(m, 7), 3.60 (s, 3), 4.3-4.5 (m, 1), 7.0-7.3 (m, 4), 7.76 (br s, 1);
TLC (EtOAc/hexane ) 1/1) Rf 0.26-0.35. Anal. Calcd for
C
29H44NO5SSiF‚0.3H2O: C, 60.98; H, 7.87; N, 2.45. Found:
C, 61.06; H, 7.69; N, 2.48.
C
13H24O4SSi: C, 51.28; H, 7.95. Found: C, 51.22; H, 8.02.
(3R)-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-[4-(4-flu or op h e-
n yl)-2-isop r op yl-5-m et h yl-1H -p yr r ol-3-yl]-5-oxo-6-h ep -
ten oic Acid Meth yl Ester (4a ). A solution of 13 (484 mg,
0.855 mmol) in toluene (5 mL) was refluxed for 1 h and then
concentrated. Purification by silica gel chromatography (EtOAc/
hexane ) 1/2) gave 4a (389 mg, 91% yield): IR (CHCl3) 3459,
(3R)-[(ter t-Bu tyldim eth ylsilyl)oxy]-6-(m eth an esu lfin yl)-
5-oxoh exa n oic Acid Meth yl Ester (8). To a solution of 7
(6.27 g, 20.6 mmol) in MeOH (60 mL) was added NaOMe (4.12
mL of 1 N MeOH solution, 4.12 mmol) dropwise over 2 min at
0 °C. After 30 min, the reaction mixture was poured into ice
and 1 N HCl (10 mL), saturated with NaCl, and extracted with
EtOAc (2 × 300 mL). Each organic layer was washed with
brine (3 × 50 mL), dried, and concentrated. The residual oil
was purified by silica gel chromatography (CHCl3/MeOH )
50/1 to 10/1) to give 8 (6.77 g, 98% yield): IR (CHCl3) 2954,
1
2956, 1733 cm-1; H NMR δ -0.01 (s, 3), 0.02 (s, 3), 0.81 (s,
9), 1.30 (d, 6, J ) 6.9), 2.11 (s, 3), 2.4-2.7 (m, 4), 3.33 (quintet,
1, J ) 6.9), 3.64 (s, 3), 4.5-4.6 (m, 1), 5.92 (d, 1, J ) 16.2),
7.07 (dd, 2, J ) 9.0, 9.0), 7.21 (dd, 2, J ) 5.4, 9.0), 7.60 (d, 1,
J ) 16.2), 8.38 (br s, 1); 13C NMR δ -5.1, -4.7, 11.2, 17.9,

3040 J . Org. Chem., Vol. 63, No. 9, 1998
Konoike et al.
22.7, 25.5, 25.7, 42.7, 48.6, 51.4, 66.7, 113.2, 115.3 (J ) 21.1),
120.3, 121.6, 125.1, 131.7, 131.9 (J ) 7.6), 137.0, 141.6, 161.7
(J ) 245), 171.7, 198.1; [R]25D +2.1 ( 0.4 (c 1.005, CHCl3); TLC
(EtOAc/hexane ) 1/1) Rf 0.52. Anal. Calcd for C28H40NO4-
SiF‚0.6H2O: C, 65.62; H, 8.10; N, 2.73. Found: C, 65.62; H,
7.93; N, 2.90.
3), 3.4-3.5 (m, 1), 3.70 (s, 3), 3.96 (quintet, 1, J ) 7.2), 4.3-
4.5 (m, 1), 5.51 (d, 1, J ) 16.0), 7.0-7.2 (m, 4), 7.78 (d, 1, J )
16.0); [R]24D +14.5 (c 1.106, CHCl3); TLC (EtOAc/hexane ) 1/1)
Rf 0.25.
To a solution of the ketone (67 mg, 0.14 mmol) in THF (1.2
mL) and MeOH (0.3 mL) was added Et2BOMe (0.160 mL of
1.0 M THF solution, 0.160 mmol) at -78 °C. The mixture was
stirred at -78 °C for 20 min, and NaBH4 (6.0 mg, 0.16 mmol)
was added. The reaction mixture was stirred at -78 °C for
1.5 h, diluted with EtOAc, and poured into ice and saturated
NaHCO3. The organic phase was separated, and the aqueous
phase was extracted with EtOAc. Each organic layer was
washed with brine, dried, and concentrated. The residual oil
was dissolved in MeOH and concentrated. This operation was
repeated three times. Purification by silica gel chromatogra-
phy (EtOAc/hexane ) 1/1) gave syn-diol 14 (61 mg, 91%
yield): IR (CHCl3) 3486, 2952, 1720 cm-1; 1H NMR δ 1.2-1.5
(m, 2), 1.32 (d, 6, J ) 7.2), 2.16 (s, 3), 2.3-2.4 (m, 2), 2.91 (br
s, 1), 3.10 (s, 3), 3.56 (br s, 1), 3.64 (s, 3), 3.75 (quintet, 1, J )
7.2), 3.9-4.1 (m, 1), 4.1-4.3 (m, 1), 4.93 (dd, 1, J ) 6.3, 16.0),
6.48 (dd, 1, J ) 1.1, 16.0), 6.9-7.1 (m, 4); 13C NMR δ 13.7,
22.5, 22.6, 26.4, 41.4, 42.5, 43.2, 51.8, 68.0, 72.5, 115.0, 115.2,
121.2, 125.5, 128.2, 131.0 (J ) 2.6), 132.5 (J ) 45.6), 135.0,
137.8, 161.9 (J ) 247), 172.9; [R]24D +10.9 (c 1.14, CHCl3); TLC
(EtOAc/hexane ) 1/1) Rf 0.21.
(3R)-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-[4-(4-flu or op h e-
n yl)-2-isopr opyl-1-(m eth an esu lfon yl)-5-m eth yl-1H-pyr r ol-
3-yl]-5-oxo-6-h ep ten oic Acid Meth yl Ester (4b). To a
solution of 4a (100 mg, 0.20 mmol) in THF (1.0 mL) was added
LHMDS (0.22 mL of 1.0 M THF solution, 0.22 mmol) dropwise
at -78 °C. After being stirred for 30 min, methanesulfonic
anhydride (39 mg, 0.22 mmol) was added, and the mixture
was stirred at -78 °C for 2 h and at 0 °C for 4 h. The reaction
mixture was poured into a mixture of 1 N HCl and EtOAc,
and the organic layer was separated. The aqueous phase was
extracted with EtOAc, and each organic layer was washed with
saturated NaHCO3 and brine, dried, and concentrated. Pu-
rification by silica gel chromatography (EtOAc/toluene ) 1/19-
1/9) gave 4b (72 mg, 62% yield): IR (CHCl3) 2955, 2931, 1734,
1681 cm-1; 1H NMR δ -0.01 (s, 3), 0.02 (s, 3), 0.80 (s, 9), 1.46
(d, 6, J ) 7.5), 2.22 (s, 3), 2.41 (dd, 1, J ) 6.9, 15.0), 2.47 (dd,
J ) 6.9, 15.0), 2.47 (dd, 1, J ) 6.3, 15.6), 2.58 (dd, 1, J ) 6.3,
15.6), 3.25 (s, 3), 3.65 (s, 3), 3.95 (quintet, 1, J ) 7.2), 4.48
(quintet, 1, J ) 6.3), 5.53 (d, 1, J ) 15.9), 7.0-7.2 (m, 4), 7.73
(d, 1, J ) 15.9); 13C NMR δ -5.0, -4.8, 13.6, 17.9, 23.3, 25.7,
26.5, 42.6, 43.8, 49.1, 51.5, 66.2, 115.7 (J ) 22.4), 119.4, 124.6,
126.8, 129.6, 130.4 (J ) 4.2), 134.5, 143.6, 162.4 (J ) 247),
171.6, 197.4; [R]23D +5.9 (c 0.828, CHCl3); TLC (EtOAc/toluene
) 1/9) Rf 0.41; HR-LSIMS m/ z 580.2562 [M + H]+ (calcd for
(3R,5S)-7-[4-(4-F lu or op h en yl)-2-isop r op yl-1-(m eth a n e-
su lfon yl)-5-m eth yl-1H-p yr r ol-3-yl]-3,5-d ih yd r oxy-6-h ep -
ten oic Acid Sod iu m Sa lt (15). To a solution of 14 (48 mg,
0.10 mmol) in MeOH (0.5 mL) was added 2 N NaOH (77 µL,
0.15 mmol) dropwise at 0 °C. After being stirred at 0 °C for 2
h, solvent was removed, and the residue was purified by
column chromatography on Diaion CHP-20P resin (40% aq
MeOH) and freeze-dried to give 15 (29 mg, 59% yield): mp
C
29H42NO6SSiF 580.2563). Anal. Calcd for C29H42NO6SSiF:
C, 60.08; H, 7.30; N, 2.42; S, 5.53; F, 3.28. Found: C, 60.44;
H, 7.44; N, 2.58; S, 6.06; F, 3.34.
(3R,5S)-7-[4-(4-F lu or op h en yl)-2-isop r op yl-1-(m eth a n e-
su lfon yl)-5-m eth yl-1H-p yr r ol-3-yl]-3,5-d ih yd r oxy-6-h ep -
ten oic Acid Meth yl Ester (14). A 1:19 mixture of a 46%
aqueous HF solution and CH3CN (1.5 mL) was added to 4b
(106 mg, 0.183 mmol) at room temperature. The reaction
mixture was stirred for 1 h, diluted with EtOAc, and poured
into ice and saturated NaHCO3. The organic phase was
separated, and the aqueous phase was extracted with EtOAc.
Each organic layer was washed with brine, dried, and con-
centrated. The residue was purified by silica gel chromatog-
raphy (EtOAc/hexane ) 1/1) to give the alcohol (69 mg, 81%
yield): IR (CHCl3) 3547, 1731 cm-1; 1H NMR δ 1.47 (d, 2, J )
7.2), 2.22 (s, 3), 2.48 (d, 2, J ) 6.4), 2.53 (d, 2, J ) 6.0), 3.26 (s,
1
187-189 °C; IR (CHCl3) 3367, 1580 cm-1; H NMR (CD3OD)
δ 1.2-1.4 (m, 1), 1.40 (d, 6, J ) 7.2), 1.4-1.6 (m, 1), 2.1-2.3
(m, 2), 2.21 (s, 3), 3.35 (s, 3), 3.8-4.0 (m, 2), 4.18 (q, 1, J )
6.6), 5.03 (dd, 1, J ) 6.6, 16.2), 6.57 (dd, 1, J ) 0.9, 16.2), 7.0-
7.2 (m, 4); 13C NMR (CD3OD) δ 13.8, 22.7, 23.0, 27.5, 45.0,
45.0, 68.3, 72.1, 116.0 (J ) 21.0), 122.4, 122.6, 126.7, 129.3,
132.7 (J ) 3.9), 133.8 (J ) 7.9), 136.6, 138.9, 163.3 (J ) 245),
180.5; [R]25 +29 (c 0.86, CH3OH); TLC (EtOAc/AcOH/H2O )
D
30/1/1) Rf 0.59. Anal. Calcd for C22H27NO6SFNa‚1.7H2O: C,
52.21; H, 6.05; N, 2.77. Found: C, 52.11; H, 5.68; N, 3.07.
J O9722156