6460 J . Org. Chem., Vol. 61, No. 18, 1996
Notes
°C and 300 rpm. After 24 h the enzyme was removed by
filtration and the reaction mixture, containing (+)-2 (77%) and
3 (23%), processed as above to afford (+)-2 (290 mg, 74%, 90%
ee) ([R]D +197° (c 0.48, C6H6)).
anion to the carbonyl carbon taking place exclusively syn
with respect to the ester at C-6, thus giving, after
treatment with K2CO3 in MeOH, the single tetrol deriva-
tive (+)-9 [(+)-conduritol F] with ee >95%. An analogous
procedure applied to (-)-8b gave the enantiomer (-)-9.
Osm yla tion of (-)-2 w ith NMMO. A solution (10 mL) of
NMMO (320 mg, 2.73 mmol) and OsO4 (7 mg, 0.027 mmol) in
CH2Cl2 was added to a solution of (-)-2 (400 mg, 2.6 mmol) in
t-BME (40 mL). After 15 h of stirring at rt, the reaction was
stopped by evaporation of solvent. Conventional acetylation
(Ac2O/Py) at room temperature of the residue followed by
chromatographic purification (SiO2, acetone-CH2Cl2 1:9) af-
forded (+)-4 (510 mg, 63%) and 5 (220 mg, 27%). The enantio-
meric excess of (+)-4 was determined as 15% after hydrolysis
to (+)-conduritol E ([R]D +50° (c 1, H2O), lit.7c [R]D +330° (c 4.5,
H2O)).
Osm yla tion of (-)-(2) w ith t-Bu OH/H2O2. To a solution
of (-)-2 (0.95 g, 6.17 mmol, >98% ee) in t-BME (95 mL) were
successively added 5 mL of a 6.3% solution of H2O2 in t-BuOH
prepared according to the Milas procedure15 and 6 mL of a 0.5%
solution of OsO4 in t-BuOH. The mixture was stirred at 0 °C
until TLC analysis showed the nearly complete disappearance
of (-)-2 (ca. 12 h), then the reaction was quenched by filtration
on a Sep-pack cartridge and the solvent evaporated under
reduced pressure. 1H-NMR analysis of the residue showed the
presence of two monoesters (6a and 6b) in a 3:2 ratio, as
calculated from the integrated areas of the resonances for the
carboxymethine (δ 5.01 and 5.63, respectively).
Half of the osmylation mixture was submitted to conventional
acetylation followed by chromatography (SiO2, hexane-Et2O 1:1)
to afford (+)-(4S,5S,6R)-4,5,6-t r ia cet oxycycloh ex-2-en on e
(+)-7: (720 mg, 86%, 20% ee), [R]D +13° (c 1, CHCl3); 1H-NMR δ
2.06 (3H, s), 2.14 (3H, s), 2.18 (3H, s), 5.43 (1H, dd, J ) 11.2
and 3.9 Hz), 5.75 (1H, d, J ) 11.2 Hz), 5.80 (1H, dd, J ) 5.9 and
3.9 Hz), 6.27 (1H, d, J ) 9.9 Hz), 6.92 (1H, dd, J ) 9.9 and 5.9
Hz); 13C-NMR δ 20.04, 20.56, 20.62, 65.27, 68.62, 72.01, 131.98,
140.93, 169.60, 169.88, 169.92, 190.93.
The second half of the crude osmylation product was treated
with propanoic anhydride/pyridine in CH2Cl2. After 10 h of
stirring at rt, the solution was extracted with 1 N HCl and taken
to dryness under reduced pressure, and the residue was sub-
jected to column chromatography (Si gel, hexane-Et2O 60:40)
to give (+)-8a (445 mg, 48%) and (-)-8b (295 mg, 32%).
(+)-(4S ,5S ,6R )-5-Ace t oxy-4,6-d ip r op yloxycycloh e x-2-
en on e [(+)-8a ]: [R]D +118°, (c 0.3, CHCl3); 1H-NMR δ 1.18 (3H,
t, J ) 7.6 Hz), 1.19 (3H, t, J ) 7.6 Hz), 2.05 (3H, s), 2.44 (4H,
m), 5.44 (1H, dd, J ) 11.2 and 3.9 Hz), 5.77 (1H, d, J ) 11.2
Hz), 5.84 (1H, dd, J ) 5.9 and 3.9 Hz), 6.28 (1H, d, J ) 10 Hz),
6.93 (1H, dd, J ) 5.9 and 10 Hz); 13C-NMR δ 9.07, 9.13, 20.55,
27.26, 27.38, 65.09, 68.73, 71.84, 132.00, 140.97, 169.59, 173.42,
173.52, 191.11.
(-)-(4R ,5R ,6S )-4-Ace t oxy-5,6-d ip r op yloxycycloh e x-2-
en on e [(-)-8b]: [R]D -82°, (c 0.2, CHCl3); 1H-NMR δ 1.13 (3H,
t, J ) 7.6 Hz), 1.18 (3H, t, J ) 7.5 Hz), 2.14 (3H,s), 2.51 (4H,
m), 5.46 (1H, dd, J ) 3.8 and 11.1 Hz), 5.78 (1H, d, J ) 11.1
Hz), 5.82 (1H, dd, J ) 5.9 and 3.8 Hz), 6.28 (1H, d, J ) 10 Hz),
6.93 (1H, dd, J ) 10 and 5.9); 13C-NMR δ 8.88, 9.06, 20.66, 27.24,
27.28, 65.34, 68.50, 71.84,132.04, 140.88, 169.94, 173.01, 173.39,
191.12.
(+)-Con d u r itol F [(+)-9]. NaBH4 (46 mg) was added por-
tionwise to a stirred solution of (+)-8a (150 mg, 0.5 mmol) in
0.1 M CeCl3 (8 mL, 0.8 mmol) in methanol.17 After 15 min at 0
°C the resulting mixture was poured in water and extracted with
AcOEt. The organic phase was taken to dryness and K2CO3 was
then added to the residue dissolved in MeOH. Hydrolysis
proceeded smoothly to give (+)-9 (66 mg, 90%), the 1H-NMR data
of which were in agreement with the literature values6 ([R]D
+68.5° (c 0.13, CH3OH); lit.6 [R]D +70.8° (c 0.13, CH3OH)).
(-)-Con d u r itol F [(-)-9]. A solution of (-)-8b (150 mg, 0.5
mmol) was treated as above to give (-)-9 (64 mg, 88%) ([R]D
-68.7° (c 0.2, CH3OH); lit.6 [R]D -71.7° (c 0.75, CH3OH)).
Con clu sion s
In brief, enantiotoposelective esterification and alco-
holysis assisted by lipase are convenient ways to obtain
both enantiomers of 1-acetoxy-2-hydroxycyclohexa-3,5-
diene with high chemical and optical yields. This com-
pound is a valuable starting material for the synthesis
of chiral conduritol derivatives. In particular, dihydroxyl-
ation of (-)-2 with H2O2 in the presence of catalytic
amounts of OsO4 is highly stereoselective and moderately
regioselective, yielding the two monoacetates 6a and 6b.
Treatment of the crude reaction mixture with propanoic
anhydride afforded the mixed esters (+)-8a and (-)-8b
that were separated by conventional column chromatog-
raphy and each subjected to NaBH4 reduction followed
by alkaline hydrolysis to give (+)-9 and (-)-9, respec-
tively. Compounds (+)-8a and (-)-8b have structural
features that prelude their use as starting material for
the preparation of other conduritol derivatives.
Exp er im en ta l Section
All chemicals were purchased from Aldrich and used as
received. Vinyl acetate was distilled prior to use. Solvents were
dried according to literature procedures. Column chromatog-
raphy was performed on silica gel or Si Diol; analytical TLC was
carried out on Merck silica gel 60-F254 precoated glass plates
and compounds were visualized by spraying with molybdo-
phosphoric acid. Lipases from C. cylindracea, P. cepacia (PSL),
R. javanicus, and A. niger were from Amano International
Enzyme Co. Lipase from porcine pancreas was obtained from
Sigma. Novozym 435 (immobilized lipase from Candida ant-
arctica) and Lipozyme IM (immobilized lipase from Mucor
miehei) are registred marks from Novo Nordisk. 1H- and 13C-
NMR spectra were recorded in CDCl3 at 250.13 and 62.9 MHz,
respectively. Chemical shifts are in ppm (δ) downfield from
Me4Si . (R)-(-)-1-(9-Anthryl)-2,2,2-trifluoroethanol (Pirkle’s
alcohol) or europium(III) tris-[3-(heptafluoropropyl)hydroxy-
methylene]-(+)-camphorate were used as chiral shift reagents
to determine enantiomeric ratios. Optical rotations were meas-
ured on a DIP 135 J ASCO instrument. GC analyses were
performed on Chiraldex G-DA (dialkyl γ-cyclodextrin) capillary
column.
Gen er a l P r oced u r e for En zym a tic Ester ifica tion of cis-
1,2-Dih yd r oxycycloh exa -3,5-d ien e (1). For a typical enzy-
matic esterification, the lipase of choice (10 mg) and vinyl acetate
(0.02 mL) were added to a solution of 1 (10 mg) in t-BME (1
mL), and the suspension was stirred at 40 °C and 300 rpm.
Substrate conversion was determined by 1H-NMR at regular
time intervals. The enantiomeric excess of (-)-2 was determined
by 1H-NMR in the presence of Pirkle’s alcohol or by chirospecific
GC of the corresponding tetrahydro derivative.11
En zym a tic P r ep a r a tion of (-)-(1R,2S)-1-Acetoxy-2-h y-
d r oxycycloh exa -3,5-d ien e [(-)-(2)]. PSL (0.5 g) was added
to a solution of 1 (0.5 g, 4.46 mmol) and vinyl acetate (1 mL) in
t-BME (50 mL), and the mixture was shaken at 40 °C and 300
rpm. After 3 h the reaction was stopped by filtering off the
enzyme and the solvent evaporated under a stream of N2.
Conversion of substrate and ratio of the products were deter-
mined by 1H-NMR analysis. After purification on Si Diol with
hexane/CH2Cl2 5:95, (-)-2 (580 mg, 85%, >98% ee) ([R]D -215°
(c 1, C6H6)) was recovered.
Ack n ow led gm en t. This work has financially been
supported by Italian National Council of Research under
the scheme “Progetto Strategico: Tecnologie Chimiche
En zym a tic P r ep a r a tion of (+)-(1S,2R)-1-a cetoxy-2-h y-
d r oxycycloh exa -3,5-d ien e [(+)-(2)]. PSL (0.5 g) was added
to a solution of 3 (0.5 g, 2.55 mmol) and n-butanol (0.5 mL) in
t-BME (50 mL), and the resulting suspension was shaken at 40
(17) Le Drian, C.; Vieira, E; Vogel, P. Helv. Chim. Acta 1989, 72,
338.