Efficient synthesis of optically pure (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydropyran-2-one and its enantiomer

Full text of DOI:10.1021/jo015774s

J . Org. Chem. 2001, 66, 6803-6806
6803
Sch em e 1. Ch em oen zym a tic Syn th esis of 1 a n d
Efficien t Syn th esis of Op tica lly P u r e
(4R,6S)-4-(ter t-Bu tyld im eth ylsilyloxy)-
6-(h yd r oxym eth yl)tetr a h yd r op yr a n -2-on e
a n d Its En a n tiom er
en t-1 fr om P h lor oglu citol 2a
Sandeep R. Ghorpade,† Uttam R. Kalkote,*,†
Subhash P. Chavan,† Sunil R. Bhide,†
T. Ravindranathan,*,† and Veda G. Puranik‡
Division of Organic Chemistry: Technology and Physical
Chemistry Division, National Chemical Laboratory,
Pune, India-411 008
kalkote@dalton.ncl.res.in
Received May 21, 2001
After the discovery of compactin,1 a potent competitive
inhibitor of HMG CoA reductase, the statin group of
drugs, e.g. atorvastatin, lovastatin, and fluvastatin, have
emerged as leading antihyperlipoproteinemic agents. All
these drugs have (4R,6S)-â-hydroxy-δ-lactone (1) or its
open chain acid as a common essential structural feature.
Even though various chemical and chemoenzymatic
approaches have been reported for the synthesis of 1 and
its analogues,2 development of efficient, cost-effective
synthesis of this lactone moiety would be the major task
toward an industrial process for these drugs. As a part
of our chemoenzymatic process development program for
various commercially valuable drugs and intermediates,3
we planned to develop a cost-effective process for lactone
1.
Sakai and co-workers have reported a chemoenzymatic
route for lactone 1 analogue starting from phloroglucitol
(2) wherein they have attempted Baeyer-Villiger oxida-
tion of diprotected 3,5-dihydroxycyclohexanone to obtain
the desired lactone, but almost equal quantities of two
regioisomers were obtained; hence, a lengthier and low-
yielding route based on ozonolysis was followed (overall
yield 1.73%).4 We decided to study this phloroglucitol
approach for synthesis of lactone 1, wherein a regiose-
lective Baeyer-Villiger oxidation was desired to achieve
shorter and more efficient process. Here we describe our
preliminary successful results toward the synthesis of
a
Key: (a) chemoenzymatic route; (b) DHP, dry CH2Cl2, 0 °C,
99%; (c) K2CO3, MeOH, 96%; (d) PCC, CH2Cl2, 80%; (e) MgBr2
etherate, dry ether, 3 h, 90%; (f) 2 equiv of 3-chloroperbenzoic acid,
RT, 45%; (g) PCC, CH2Cl2, 95%; (h) PLE, buffer pH 6.5, 75%.
(4R,6S) 4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-
tetrahydropyran-2-one involving Baeyer-Villiger oxida-
tion as the key step.
It was desired to obtain an optically pure 3-hydroxy-
cyclohexanone derivative from phloroglucitol to study the
Baeyer-Villiger oxidation. We have developed efficient
chemoenzymatic synthesis of 3-hydroxy-5-(tert-butyldim-
ethylsilyloxy)-(1S,3R,5R)-cyclohexyl acetate (3, ee > 96%)
from phloroglucitol through the enzymatic desymmetri-
zation method.5 We planned to utilize this chiral inter-
mediate (3) for the synthesis of desired hydroxycyclohex-
anone. Compound 3 of >96% ee was subjected to further
chemical transformations as shown in Scheme 1. Free
-OH in 3 was protected as THP ether 4 at 0 °C, which
on solvolysis in methanol, followed by PCC oxidation,
afforded 3,5-disubstituted cyclohexanone 6. Magnesium
bromide assisted selective deprotection of the OTHP
group6 afforded the desired 3-hydroxycyclohexanone
derivative 7 in 76% yield from compound 3. The next
important step was efficient Baeyer-Villiger oxidation
of 7.
† Division of Organic Chemistry: Technology.
‡ Physical Chemistry Division.
(1) (a) Endo, A.; Kuroda, M.; Tsujita, Y. J . Antibiot. 1976, 29, 1346.
(b) Endo, A.; Kuroda, M.; Tanzawa, K. FEBS Lett. 1976, 72, 323. (c)
Brown, A. G.; Smale, T. C.; King, T. J .; Hasenkamp, R.; Thompson, R.
H. J . Chem. Soc., Perkin Trans 1 1976, 1165. (d) Kathawala. U.S.
Patent 4,739,073, 1988. (e) Bocan, T. M. A.; Ferguson, E.; Shaw, M.
K.; BakMueller, S.; Uhlendorf, P. D.; Roth, B. D.; Sliskovic, D. R.;
Newton, R. S. Abstracts of the Xth International Symposium on Drugs
Affecting Lipid Metabolism; Houston, TX, Nov 8-11, 1989; p 55. (f)
Shaw, M. K.; Newton, R. S.; Sliskovic, D. R.; Roth, B. D.; Ferguson,
E.; Krause, B. R. Biochem. Biophys. Res. Commun. 1990, 170, 726.
(2) (a) Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909. (b)
Hsu, C.-T.; Wang, N.-Y.; Latimer, L. H.; Sih, C. J . J . Am. Chem. Soc.
1983, 105, 593.
(3) (a) Ghorpade, S. R.; Kharul, R. K.; J oshi, R. R.; Kalkote U. R.;
Ravindranathan, T. Tetrahedron: Asymmetry 1999, 10, 891. (b)
Ghorpade, S. R.; Bastawde, K. B.; Gokhale, D. V.; Shinde, P. D.;
Mahajan, V. A.; Kalkote, U. R.; Ravindranathan, T. Tetrahedron:
Asymmetry 1999, 10, 4115. (c) Kalkote, U. R.; Ghorpade, S. R.; J oshi,
R. R.; Ravindranathan, T.; Bastawde, K B.; Gokhale, D. V. Tetrahedron:
Asymmetry 2000, 11, 2965.
Cyclohexanone 7 was subjected to Baeyer-Villiger
oxidation under standard conditions using 3-chloroper-
benzoic acid in dichloromethane for several hours, but
(4) Suemune, H.; Takahashi, M.; Maeda, S.; Xie, Z.-F.; Sakai, K.
Tetrahedron: Asymmetry 1990, 1, 425.
(5) Submitted for publication elsewhere.
(6) Kim, S.; Park, J . H. Tetrahedron Lett. 1987, 28, 439.
10.1021/jo015774s CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/05/2001

6804 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
the substrate 7 was found to be unreactive under these
conditions. Various reaction conditions were attempted,
but hydroxycyclohexanone 7 was either unreactive or
unstable under conditions attempted. But fortunately
when it was mixed with 3-chloroperbenzoic acid under
neat conditions and kept for few hours, it reacted to afford
of -20 (c ) 1, CHCl3). To further minimize â-elimination,
enzymatic hydrolysis was carried under slightly acidic
conditions (pH 6.5), and en t-7 of the same enantiopurity
could be isolated in 75% yield. en t-7 reacted with
3-chloroperbenzoic acid under neat conditions to afford
lactone en t-1 in 45% isolated yield. The optical rotation
of en t-1 was -1.96 (c ) 1, CHCl3), and its ee was found
to be 99% by chiral HPLC analysis. The structure of
en t-1 was also confirmed by single-crystal X-ray analysis.
Thus, this route affords en t-1 in less steps more ef-
ficiently in 18% overall yield and more importantly avoids
epimerization, obviating the need for extra purification.
Therefore, the process to achieve en t-3 by this route
would afford lactone 1 much more efficiently.8
Thus, a much shorter and efficient chemoenzymatic
synthesis of optically pure (4R,6S)-4-(tert-butyldimeth-
ylsilyloxy)-6-(hydroxymethyl)-tetrahydropyran-2-one (1)
and its enantiomer was advantageously carried out from
cis-phloroglucitol through effective Baeyer-Villiger oxi-
dation as compared to the earlier phloroglucitol route
based on ozonolysis. We hope a good chemoenzymatic
route for lactone 1 is established, and addressing further
some of the key cost factors, viz. cost of enzyme and
oxidizing agent, would lead to a commercially viable route
for lactone 1.
1
lactone 1 as a single isomer in 45% yield. H NMR, 13C
1
NMR, and H NOE data for 1 matched exactly with that
of literature reported values.7 No traces of the regioiso-
meric lactone arising out of oxygen insertion from other
side of the ring could be detected by NMR of the crude
reaction mixture. Thus, our speculation of affecting a
Baeyer-Villiger oxidation was found to be correct where
the corresponding 7-membered lactone underwent rear-
rangement to the thermodynamically more stable 6-mem-
bered lactone 1 under our reaction conditions. The optical
rotation of the lactone obtained was found to be +3 (c )
1, CHCl3), whereas the reported value is -7 (c ) 1,
CHCl3).7 To clear the ambiguity, which perhaps arose out
of impurity in the sample(s) or inadequate purification
methods employed, we prepared its tosyl derivative. The
rotation of the pure tosyl derivative {[R]D ) +7 (c )2,
CHCl3)} matched well with the reported value of +5 (c
) 1, CHCl3)7 (our material was even purer optically).
Thus, our configuration assignment was found to be
correct. Enatiomeric excess of the lactone 1 was deter-
mined to be 86% by the chiral HPLC of its benzoate
[Lichrocart (R, R) Whelk-O1 (5µm) column]. There could
have been epimerization during the -OTHP deprotection
stage, resulting in deterioration of ee. Enantiomeric
excess could be improved up to 98% by a single recrys-
tallization from petroleum ether + chloroform mixture
(yield 75%). The specific rotation of this recrystallized
lactone 1 was found to be +1.9 (c ) 1, CHCl3)! There could
have been some diastereomeric impurity responsible for
the higher rotation value (epimerization possible at THP
deprotection stage; vide infra), which was removed during
recrystallization. Thus, synthesis of enantiopure lactone
1 was achieved in overall 13% yield.
Exp er im en ta l Section
Gen er a l Met h od s. All the reagents were purchased from
Aldrich and were used without further purification. NMR spectra
were recorded on a Brucker NMR (200 MHz) spectrometer. IR
spectra were recorded on a Research Series FTIR spectrometer.
Optical rotations were recorded on a J asco Dip-181 and J asco
P-1020 polarimeter using a sodium vapor lamp. Enantiomeric
excess (ee) was determined by comparing the specific rotation
value [R]D with the literature value. PPL and PLE were
purchased from Sigma.
P r ep a r a tion of 3-Tetr a h yd r o-2H-2-(p yr a n yloxy)-5-(ter t-
bu tyld im eth ylsilyloxy)-(1S,3R,5R)-cycloh exyl Aceta te (4).
3-Hydroxy-5-(tert-butyldimethylsilyloxy)-(1S,3R,5R)-cyclohex-
yl acetate (3, 2.9 g, 9.73 mmol) was dissolved in dry dichlo-
romethane (30 mL). The solution was cooled below 0 °C in an
ice-salt bath. To the stirred solution, dihydropyran (1 g, 12
mmol) was added and p-toluenesulfonic acid monohydrate (0.1
g) was added as catalyst. The reaction mixture was stirred at
-10 °C for 2 h. The reaction was quenched by adding aqueous
sodium bicarbonate solution. Both the layers were separated.
The aqueous layer was extracted with dichloromethane (2 × 10
mL). The organic layers were combined and washed with water
followed by brine. The solution was then dried on anhydrous
sodium sulfate, and the solvent was removed under vacuum. The
residue was purified by flash column chromatography to yield
3-tetrahydro-2H-2-(pyranyloxy)-5-(tert-butyldimethylsilyloxy)-
(1S,3R,5R)-cyclohexyl acetate (4) (yield 3.7 g, 99.5%) as an oily
liquid.
1H NMR (CDCl3): δ 0.05 (s, 6H), 0.87 (s, 9H), 1.25-1.90 (m,
9H), 2.04 (s, 3H), 2.05-2.40 (m, 3H), 3.40-3.75 (m, 3H), 3.86
(m, 1H), 4.55-4.80 (m, 2H). 13C NMR (CDCl3): δ -4.90, 18.00,
19.40, 19.50, 25.20, 25.80, 30.90, 36.80, 40.70, 41.00, 42.80, 62.00,
62.50, 66.00, 68.00, 69.70, 95.00, 96.80, 169.90.
IR (CHCl3): 752.08, 768.22, 838.35, 1029.76, 1114.56, 1215.63,
1251.94, 1727.19, 2858.86, 2950.80, 3016.74 cm-1. Mass: base
m/e ) 85; other m/e 231, 211, 171, 159, 129, 117, 105, 101, 85,
79, 75, 67, 55. Anal. Calcd for C19H36O5Si: C, 61.29; H, 9.68.
Found: C, 61.37; H, 10.03. Specific rotation: [R]D ) +1.39 (c )
1, CHCl3).
Since the epimerization encountered in the above-
discussed scheme demands extra purification measures
to improve ee with concomitant loss of yield, a route
wherein a protection-deprotection sequence and subse-
quent epimerization can be avoided was sought. As
shown in Scheme 1, compound 3 was oxidized efficiently
with PCC to afford â-ketoacetate 8. Now a mild hydrolytic
condition for hydrolysis of 8 was required to avoid
â-elimination. It could not be achieved by chemical
methods, e.g. methanol-K2CO3, methanol-NH3, etc.
Therefore, enzymatic hydrolysis under neutral pH condi-
tion was attempted using PLE as catalyst. When hy-
drolysis was carried out in buffer media containing 10%
DMSO, the desired hydroxyketone en t-7 was isolated in
50% yield. Its optical rotation was found to be -22.5 (c
) 1, CHCl3), whereas that of 7 obtained in the earlier
route was only +16.8 (c ) 1, CHCl3). This indicates that
enzymatic hydrolysis is not only mild enough to minimize
â-elimination and avoid epimerization but possibly helped
achieve higher optical purity by kinetic resolution of 8.
This assumption was confirmed by carrying out hydroly-
sis of racemic 8 under the same reaction conditions
wherein we could isolate en t-7 showing optical rotation
P r ep a r a tion of 3-Tetr a h yd r o-2H-2-(p yr a n yloxy)-5-(ter t-
bu tyldim eth ylsilyloxy)-(1S,3R,5S)-cycloh exan -1-ol (5). 3-Tet-
(7) (a) Beecher, J .; Brackenridge, I.; Roberts, S. M.; Tang, J .; Willetts,
A. J . J . Chem. Soc., Perkin Trans. 1 1995, 1641. (b) Tang, J .;
Brackenridge, I.; Roberts, S. M.; Beecher, J .; Willetts, A. J . Tetrahedron
1995, 51, 13217.
(8) An efficient large-scale chemoenzymatic synthesis of en t-3 has
been reported recently by the following: Wirz, B.; Iding, H.; Hilpert,
H. Tetrahedron: Asymmetry 2000, 11, 4171.

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6805
r a h ydr o-2H -2-(pyr a n yloxy)-5-(ter t-bu t yldim et h ylsilyloxy)-
(1S,3R,5R)-cyclohexyl acetate (4, 3.5 g, 9.16 mmol) was dissolved
in dry methanol (25 mL). To the solution anhydrous potassium
carbonate (0.828 g, 6 mmol) was added, and the mixture was
stirred at room temperature for 2 h. Methanol was removed
under vacuum, and the residue was extracted with dichlo-
romethane (3 × 10 mL). The dichloromethane layers were
combined and washed with water followed by brine wash. The
solution was dried on anhydrous sodium sulfate. Solvent was
removed under vacuum, and the residue was purified by flash
column chromatography to yield 3-tetrahydro-2H-2-(pyranyloxy)-
5-(tert-butyldimethylsilyloxy)-(1S,3R,5S)-cyclohexan-1-ol (5, yield
3 g, 96%) as a viscous liquid.
1H NMR (CDCl3): δ 0.06 (s, 6H), 0.87 (s, 9H), 1.35-1.90 (m,
10H), 2.05-2.35 (m, 3H), 3.40-3.75 (m, 4H), 3.80-3.98 (m, 1H),
4.73 (s, 1H). 13C NMR (CDCl3): δ -4.90, 18.00, 19.50, 25.20,
25.80, 30.90, 40.00, 40.70, 42.00, 42.30, 44.70, 62.00, 62.50, 65.80,
66.90, 69.50, 70.00, 96.40, 96.80. IR (CHCl3): 753.06, 766.83,
838.54, 867.39, 1020.84, 1048.02, 1114.23, 1215.02, 1253.72,
2858.73, 2884.47, 2947.49, 3013.80, 3418.48 cm-1. Mass: base
m/e ) 75; other m/e 309, 189, 171, 129, 119, 101, 85, 79, 75, 67,
55. Anal. Calcd for C17H34O4Si: C, 61.82; H, 10.30. Found: C,
61.83; H, 11.00. Specific rotation: [R]D ) +0.93 (c ) 1, CHCl3).
69, 59. Anal. Calcd for C12H24O3Si: C, 59.01; H, 9.83. Found:
C, 58.85; H, 10.18. Specific rotation: [R]D ) +16.20 (c ) 1,
CHCl3).
P r ep a r a t ion of (4R,6S)-4-(ter t-b u t yld im et h ylsilyloxy)-
6-(h yd r oxym eth yl)tetr a h yd r op yr a n -2-on e (1). 3-Hydroxy-
5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one (7, 0.1 g,
0.394 mmol) and 50% 3-chloroperbenzoic acid (0.275 g, 0.79
mmol) were mixed and kept in the dark for 15 h. The reaction
mixture was dissolved in ethyl acetate (5 mL) and washed
successively with cold sodium metabisulfite solution and sodium
bicarbonate solution followed by a brine wash. It was then dried
on anhydrous sodium sulfate, and solvent was removed under
vacuum. The residue was purified by flash column chromatog-
raphy to yield white, crystalline (4R,6S)-4-(tert-butyldimethyl-
silyloxy)-6-(hydroxymethyl)tetrahydropyran-2-one (1, yield 0.048
g, 45%, mp 91 °C). It was recrystallized from petroleum ether
(2 mL) containing 5% chloroform (yield ) 0.036 g, 75%, mp 95
°C).
1H NMR (CDCl3): δ 0.09, 0.07 (2s, 6H), 0.89 (s, 9H), 1.64 (bs,
1H), 1.74-1.92 (m, 2H), 2.60 (d, 2H, J ) 3), 3.65 (dd, 1H, J )
12), 3.88 (dd, 1H, J ) 12), 4.39 (m, 1H), 4.81 (m, 1H). 13C NMR
(CDCl3): δ -4.93, 17.93, 25.68, 32.15, 39.26, 63.61, 64.59, 76.86,
170.10. IR (CHCl3): 666.31, 898.12, 1021.88, 1061.06, 1086.17,
1118.98, 1390.84, 1463.17, 1729.43, 2857.28, 3418.25 cm-1
.
P r ep a r a t ion
of 3-Tet r a h yd r o-2H -2-(p yr a n yloxy)-5-
Mass: base m/e ) 75; other m/e 260, 229, 203, 185, 161, 143,
129, 111, 101, 69, 59. Anal. Calcd for C12H24O4Si: C, 55.38; H,
9.20. Found: C, 55.42; H, 9.03. Specific rotation: [R]D ) +3.0 (c
) 1, CHCl3) before recrystallization, ee 86%; [R]D ) +1.9 (c ) 1,
CHCl3) after recrystallization, ee 98% (ee determined by chiral
HPLC of corresponding benzoate derivative, column-Whelk-O1
[4.0 mm i.d. × 25 cm] AT-256; λ )254 nm, flow rate 1 mL/min;
mobile phase hexane:2-propanol, 92:08; retention time for ben-
zoate of 1 ) 13.78 and for benzoate of en t-1 ) 15.72).
P r ep a r a t ion of 3-Oxo-5-(ter t-b u t yld im et h ylsilyloxy)-
(1R,5S)-cycloh exyl Aceta te (8). cis,cis-3-Hydroxy-5-(tert-bu-
tyldimethylsilyloxy)-(1S,3R,5R)-cyclohexyl acetate (3, 1.40 g,
2.78 mmol) was dissolved in dichloromethane (5 mL). To the
solution were added sodium acetate (0.1 g) and pyridinium
chlorochromate (1.57 g, 7.3 mmol). The mixture was stirred for
5 h at RT (room temperature). The residue was extracted with
ether (3 × 10 mL). The organic extracts were combined and
filtered through Celite. The filtrate was washed with brine +
water (1:1) and finally with brine. The organic layer was dried
on anhydrous sodium sulfate and concentrated under vacuum.
The residue was filtered through silica gel column to afford
3-oxo-5-(tert-butyldimethylsilyloxy)-(1R,5S)-cyclohexyl acetate
(8, 1.30 g, 94%) as an oily liquid.
(ter t-bu tyld im eth ylsilyloxy)-(3S,5R)-cycloh exa n -1- on e (6).
3-Tetrahydro-2H-2-(pyranyloxy)-5-(tert-butyldimethylsilyloxy)-
(1S,3R,5S)-cyclohexan-1-ol (5, 2.85 g, 8.38 mmol) was dissolved
in dry dichloromethane (25 mL) under argon atmosphere. To
the solutiom were added anhydrous sodium acetate (0.2 g) and
pyridinium chlorochromate (13 g, 12.6 mmol) in one portion, and
the mixture was stirred under argon atmosphere for 8 h. Then
reaction mixture was diluted with diethyl ether (30 mL) and
stirred well. The solution was decanted, and the remaining black
tar was extracted with diethyl ether (3 × 15 mL). The organic
layers were combined and were filtered through a small Celite
bed. Then, the organic layer was washed with water (3 × 20
mL) followed by brine. It was dried on anhydrous sodium sulfate,
and solvent was removed under vacuum. The residue was
purified by flash column chromatography to afford 3-tetrahydro-
2H-2-(pyranyloxy)-5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclo-
hexan-1-one (6, 2.24 g, 80%) as an oily liquid.
1H NMR (CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.35-1.95 (m,
8H), 2.2-2.8 (m, 4H), 3.50 (m, 1H), 3.85 (m, 3H), 4.60 & 4.75
(2s, 1H). 13C NMR (CDCl3): δ -4.9, 18.0, 19.5, 19.9, 25.8, 26.0,
30.9, 41.0, 42.5, 47.0, 48.5, 51.5, 62.5, 63.0, 69.0, 69.8, 97.5, 206.5,
207.0. IR (CHCl3): 858.87, 980.49, 1028.79, 1053.00, 1254.14,
1360.70, 1377.86, 1462.85, 1717.24, 2857.60, 2892.24 cm-1
.
1H NMR (CDCl3): δ 0.07 (d, 6H), 0.88 (d, 9H), 2.06 (s, 3H),
2.41 (m, 4H), 2.65 (m, 2H), 4.01 (m, 1H), 5.00 (m, 1H). 13C NMR
(CDCl3): δ -4.96, 17.80, 20.95, 25.56, 39.32, 45.91, 50.28, 65.96,
67.21, 169.85, 205.25. IR (CHCl3): 442.57, 756.83, 1218.50,
Mass: base m/e ) 187, 85; other m/e 271, 227, 169, 159, 143,
127, 95, 75, 67. Anal. Calcd for C17H32O4Si: C, 62.19; H, 9.75.
Found: C, 61.90; H, 10.10. Specific rotation: [R]D ) +3.71 (c )
1, CHCl3).
1244.99, 1723.00, 2857.44, 2932.80, 2953.64, 3019.98 cm-1
.
P r epar ation of 3-Hydr oxy-5-(ter t-bu tyldim eth ylsilyloxy)-
(3S,5R)-cycloh exa n -1-on e (7).3-Tetrahydro-2H-2-(pyranyloxy)-
5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one (6, 1 g,
2.96 mmol) was placed in a 50 mL two-necked round-bottom
flask equipped with a two-way stopcock and rubber septum. The
flask was evacuated and flushed with argon. To it was added
dry ether (10 mL), and the resulting solution was stirred
vigorously. To the stirred solution magnesium bromide etherate
(2.3 g, 8.9 mmol) was added, and the mixture was stirred for 3
h. The reaction mixture was cooled in an ice bath, and the
reaction was quenched by adding saturated ammonium chloride
solution. Both the layers were separated. The aqueous layer was
extracted with ether (3 × 10 mL). The organic layers were
combined and washed with brine. Then the solution was dried
on anhydrous sodium sulfate and solvent was removed under
vacuum. The residue was purified to yield 3-hydroxy-5-(tert-
butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one (7, yield 0.69 g,
90%) as a viscous liquid.
Mass: base m/e ) 163; other m/e 185, 169, 145, 127, 117, 111,
101, 95, 75, 59. Anal. Calcd for C14H26O4Si: C, 58.74; 9.09.
Found: C, 58.60; H, 9.28. Specific rotation: [R]D ) -11.54 (c )
1, CHCl3).
P r epar ation of 3-Hydr oxy-5-(ter t-bu tyldim eth ylsilyloxy)-
(3R,5S)-cycloh exa n -1-on e (en t-7). 3-Oxo-5-(tert-butyldimeth-
ylsilyloxy)-(1R,5S)-cyclohexyl acetate (8, 1.2 g, 4.2 mmol) was
dissolved in DMSO (10 mL) and 0.1 M phosphate buffer (pH
6.5, 90 mL). To the mixture was added PLE (0.1 g), and the
reaction mixture was shaken for 48 h. It was filtered through
Celite, and the filtrate was extracted with ethyl acetate (3 ×
100 mL). The organic extracts were combined and washed with
brine. The organic layer was dried on anhydrous sodium sulfate
and concentrated under vacuum. The residue was chromato-
graphed on silica gel to afford 3-hydroxy-5-(tert-butyldimethyl-
silyloxy)-(3R,5S)-cyclohexan-1-one (en t-7, 0.77 g, 75%) as a
viscous liquid.
1H NMR (CDCl3): δ 0.10 (s, 6H), 0.87 (s, 9H), 1.95-2.4 (m,
2H), 2.45-2.78 (m, 4H), 3.98 (bs, 1H), 4.39 (m, 1H), 4.58 (m,
1H). 13C NMR (CDCl3): δ -5.50, -5.28, 17.55, 25.34, 38.24,
49.56, 49.89, 68.86, 70.48, 206.78. IR (CHCl3): 668.15, 759.18,
837.70, 1216.14, 1255.02, 1676.48, 1712.47, 2930.89, 2955.00,
3018.43, 3387.52, 3406.91. Mass: base m/e ) 75; other m/e 187,
169, 145, 129, 101, 95, 75, 69, 59. Anal. Calcd for C12H24O3Si:
1H NMR (CDCl3): δ 0.10 (s, 6H), 0.88 (s, 9H), 1.95-2.30 (m,
2H), 2.45-2.78 (m, 4H), 3.95 (d, 1H), 4.36 (m, 1H), 4.56 (m, 1H).
13C NMR (CDCl3): δ -5.50, -5.28, 17.55, 25.34, 38.24, 49.56,
49.89, 68.86, 70.48, 206.78. IR (CHCl3): 777.13, 835.81,
1010.66, 1045.71, 1095.81, 1254.55, 1381.17, 1413.71, 1464.09,
1715.72, 2857.70, 2892.64, 2932.26, 2951.84, 3439.28 cm-1
Mass: base m/e ) 75; other m/e 187, 169, 145, 129, 101, 95, 75,
.

6806 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
C, 59.01; H, 9.83. Found: C, 59.1; H, 9.98. Specific rotation: [R]D
) -22.06 (c ) 1, CHCl3).
1H NMR data for both the tosyl derivatives were identical and
were as follows:
P r ep a r a tion of (4S,6R)-4-(ter t-Bu tyld im eth ylsilyloxy)-
6-(h yd r oxym et h yl)t et r a h yd r op yr a n -2-on e (en t -1). 3-Hy-
droxy-5-(tert-butyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one (en t-
7, 0.1 g, 0.394 mmol) and 50% 3-chloroperbenzoic acid (0.275 g,
0.79 mmol) were mixed and kept in the dark for 15 h. The
reaction mixture was dissolved in ethyl acetate (5 mL) and
washed successively with cold sodium metabisulfite solution and
sodium bicarbonate solution followed by brine wash. It was then
dried on anhydrous sodium sulfate, and solvent was removed
under vacuum. The residue was purified by flash column
chromatography to yield white, crystalline (4S,6R)-4-(tert-bu-
tyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydropyran-2-one
(en t-1, yield 0.047 g, 45%; mp 95 °C).
1H NMR (CDCl3) δ 0.06, 0.07 (2s, 6H), 0.86 (s, 9H), 1.76-2
(m, 2H), 2.46 (s, 3H), 2.54 (d, 2H, J ) 3), 4.18 (m, 2H), 4.36 (m,
1H), 7.36 (d, 2H, J ) 12), 7.80 (d, 2H, J ) 12). Specific rotation
for the tosyl of 1: [R]D ) +6.85 (c ) 1.94, CHCl3) {lit.7 [R]D
)
+5 (c ) 0.82, CHCl3)}. Specific rotation for the tosyl of en t-1:
[R]D ) -6.61 (c ) 1.87, CHCl3).
P r ep a r a tion of Ra cem ic 4-(ter t-Bu tyld im eth ylsilyloxy)-
6-(h yd r oxym eth yl)tetr a h yd r op yr a n -2-on e [(()-1]. Racemic
3-hydroxy-5-(tert-butyldimethylsilyloxy)cyclohexyl acetate [(()-
3] was processed as mentioned earlier for the preparation of
(+)-1 to afford a racemic sample of 4-(tert-butyldimethylsilyloxy)-
6-(hydroxymethyl)tetrahydropyran-2-one [(()-1].
P r ep a r a tion of Ben zoa tes of La cton es 1, en t-1, a n d
Ra cem ic 1. Lactone 1 (0.01 g, 0.038 mmol) was dissolved in
dichloromethane (1 mL). To the solution was added triethy-
lamine (0.014 g, 0.02 mL, 0.138 mmol), and the resulting solution
was cooled to 0 °C in an ice-salt bath. To the cold reaction
mixture was added a solution of benzoyl chloride (0.008 g, 0.057
mmol) in dry dichloromethane (0.5 mL). The reaction mixture
was stirred at RT for 10 h. The reaction was quenched by adding
cold, dilute hydrochloric acid. The organic layer was separated
and washed with dilute hydrochloric acid followed by washing
with brine + water, aqueous NaHCO3, and finally brine. The
organic layer was dried on anhydrous sodium sulfate, and
solvent was removed under vacuum to afford the benzoate of
lactone 1 (yield 0.01 g). The same procedure was followed for
the other two lactones.
1H NMR (CDCl3): δ 0.08, 0.09 (2s, 6H), 0.89 (s, 9H), 1.55-
2.00 (m + bs, 3H), 2.60 (d, 2H, J ) 3), 3.66 (dd, 1H, J ) 12),
3.90 (dd, 1H, J ) 12), 4.38 (m, 1H), 4.80 (m, 1H). 13C NMR
(CDCl3): δ -5.17, 17.66, 25.41, 31.59, 38.90, 63.24, 64.19, 76.73,
170.31. IR (CHCl3): 666.31, 898.12, 1021.88, 1061.06, 1086.17,
1118.98, 1390.84, 1463.17, 1729.43, 2857.28, 3418.25 cm-1
.
Mass: base m/e ) 101; other m/e 260, 229, 203, 185, 161, 143,
129, 111, 75, 68, 59. Anal. Calcd for C12H24O4Si: C, 55.38; H,
9.20. Found: C, 55.40; H, 9.30. Specific rotation: [R]D ) -1.96
(c 1, CHCl3); ee 99% (determined by chiral HPLC of correspond-
ing benzoate derivative, column-Whelk-O1 [4.0 mm i.d. × 25 cm]
AT-256; λ )254 nm, flow rate 1 mL/min; mobile phase hexane:
2-propanol, 92:08; retention time for benzoate of 1 ) 17.96 and
for benzoate of en t-1 ) 19.97).
P r ep a r a tion of (4R,6S)-4-(ter t-Bu tyld im eth ylsilyloxy)-
6-(p -t olylsu lfon ylm et h yl)t et r a h yd r op yr a n -2-on e a n d It s
En an tiom er . (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxym-
ethyl)tetrahydropyran-2-one (1, 0.02 g, 0.077 mmol) was dis-
solved in dry pyridine (0.2 mL). The solution was cooled to 0 °C
in an ice-salt mixture. To the cold solution was added p-
toluenesulfonyl chloride (0.025 g, 0.13 mmol), and the reaction
mixture was stirred at RT for 12 h. The reaction mixture was
diluted with ether (5 mL). The ether layer was washed with
dilute hydrochloric acid followed by washings with brine +
water, aqueous NaHCO3, and finally brine. The organic layer
was dried on anhydrous sodium sulfate, and the solvent was
removed under vacuum. The residue was purified on silica gel
column (20% ethyl acetate in petroleum ether) to afford the tosyl
of lactone 1 (yield 0.27 g). The same procedure was followed for
preparation of the tosyl of en t-1.
1H NMR data for the benzoate were as follows:
1H NMR (CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.93 (m, 2H),
2.64 (d, 2H), 4.40 (m, 1H), 4.53 (d, 2H), 5.00 (m, 1H), 7.45 (t,
2H), 7.59 (t, 1H), 8.06 (d, 2H).
Ack n ow led gm en t. S.R.G. is thankful to the CSIR,
New Delhi, for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and detailed spectral data of all the compounds, a few
representative spectra, chiral HPLC charts, and an ORTEP
diagram for the single-crystal structure of en t-1 and its
crystallographic data. This material is available free of charge
via the Internet http//pubs.acs.org.
J O015774S