Asymmetric synthesis of new chiral cyclic ketols

Full text of DOI:10.1021/jo980344w

J . Org. Chem. 1999, 64, 2513-2515
2513
Notes
Sch em e 1
Asym m etr ic Syn th esis of New Ch ir a l Cyclic
Ketols
Philippe Renouf, J ean-Marie Poirier,† and
Pierre Duhamel*
Universite´ de Rouen-Laboratoire des fonctions azote´es
oxyge´ne´es complexes de l’IRCOF, UPRES A 6014,
76821 Mont Saint Aignan Cedex, France
Received February 24, 1998
Sch em e 2
In tr od u ction
In our previous work1,2 we reported an asymmetric
enantioselective synthesis of keto enol acetates 2 (>98%
ee) bearing a quaternary stereogenic center by enzymatic
hydrolysis of prochiral dienol diacetates 1. In this paper,
we now demonstrate that starting from these chiral
materials 2, the synthesis of new enantiopure compounds
can be achieved with a total control of the absolute
configuration. To test the potential of these new synthons,
we chose to prepare stereoisomeric cyclic ketols 3a -c
from keto enol acetate 2a (Schemes 1 and 3). This kind
of ketol has been used for the synthesis of bioactive
compounds such as Zoapatanol.3
In the literature chiral six-membered ring ketols are
prepared by microorganism asymmetric reduction of the
corresponding prochiral diketones. This reaction leads to
a mixture of two diastereoisomeric alcohols, and ratios
depend on diketone substitution. Ketols 3b and 3d , with
an (S) configuration on the stereogenic center bearing the
hydroxy group, have been prepared using this methodol-
ogy (Scheme 2).4
acetate 2a , and subsequent cleavage of the enol ester
group by reaction with potassium tert-butoxide5 provided
ketone 5. Alcohol 6b was then obtained using LiBHEt3
as reducing agent.6 The major diastereoisomer (1S,2S/
1R,2S: 96/4) was isolated by chromatography in 91%
yield. Compound 6b was finally converted to ketol 3b by
treatment with 3 N HCl.
For the preparation of ketol 3c (2S,3R), diastereo-
selectivity of carbonyl reduction of the ketone 5 (Scheme
3) has to be inverted. We chose to apply the Luche
procedure7 using a lanthanide chloride derivative as
chelating agent. Treatment of ketone 5 with europium
trichloride8 and sodium borohydride in methanol pro-
vided a diastereoisomeric mixture out of which alcohol
6c, presenting (1R,2S) configuration, was isolated. Hy-
drolysis with 3 N HCl afforded the ketol 3c. The
configurations of 3a -c prepared as shown in Scheme 3
were attributed according to literature values4 for 3b and
3d .
In conclusion, enantiopure ketols 3a ,c have been easily
synthesized from keto enol acetate 2a obtained by
enzymatic hydrolysis of prochiral dienol diacetate 1a .
Ketol 3c has never before been prepared to our knowl-
edge. Our methodology which allows the preparation of
ketols such as 3a and 3c, with an (R) configuration for
the stereogenic center bearing the hydroxy group, is
complementary of the asymmetric reduction of diketones4
which affords the alcoholic group with an (S) configura-
tion. This work is currently being developed on the
synthesis of linear enantiomerically pure ketols by
transformation of cyclic chiral molecules.
Resu lts a n d Discu ssion
In our preliminary studies, we synthesized ketol 3a
(2R,3R) to assign the (S) absolute configuration to the
quaternary stereogenic center of keto acetate 2a , which
had been obtained by enzymatic hydrolysis.2 Our ap-
proach relyied on the NaBH4 reduction of 2a followed by
the cleavage of the enol ester function with methyllithium
and purification to afford ketol 3a (R,R) in 40% overall
yield (Scheme 3).
We have now been able to prepare the (S,S) enantiomer
(ketol 3b) from the same keto acetate 2a (Scheme 3).
Dioxolane 4 was indeed obtained in good yield from keto
* Corresponding author. E-mail: L.Duhamel@univ-rouen.fr. Phone
33 (0)2 35 52 29 10. Fax 33 (0)2 35 52 24 11.
† Deceased on May, 7, 1997.
(1) Duhamel, P.; Renouf, P.; Cahard, D.; Yebga, A.; Poirier, J . M.
Tetrahedron Asymmetry 1993, 4, 2447-2450.
(2) Renouf, P.; Poirier, J . M.; Duhamel, P. J . Chem. Soc., Perkin
Trans. 1 1997, 1739-1745.
(3) (a) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J . Org. Chem.
1985, 50, 3411-3414. (b) Kanojia, R. M.; Wachter, M. P.; Levine, S.
D.; Adams, R. E.; Chen, R.; Chin, E.; Cotter, M. L.; Hirsch, A. F.;
Huettemann, R.; Kane, V.; Ostrowski, P.; Shaw, C. J . J . Org. Chem.
1982, 47, 1310-1319.
(4) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J . Org. Chem.
1987, 52, 3223-3232.
(5) Duhamel, P.; Cahard, D.; Poirier, J . M. J . Chem. Soc., Perkin
Trans. 1 1993, 2509-2511.
(6) Krief, A.; Surleraux, D.; Ropson, N. Tetrahedron: Asymmetry
1993, 4, 289-292.
(7) (a) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226-2227. (b)
Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-5459.
(8) Krief, A.; Surleraux, D. Synlett 1991, 273-275.
10.1021/jo980344w CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/17/1999

2514 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
Sch em e 3
169.2; IR (neat) νmax /cm-1 1760, 1640; MS m/z (EI) 55, 69, 73,
Furthermore, it is noteworthy that this method can be
used as a good tool to produce six-membered cyclic
compounds with three stereogenic centers by suitable
modifications of the carbonyl moiety of 3a -c.
86, 99, 109, 124, 169, 210, 252; [R]25 (c ) 1, CH2Cl2).
D
(S)-3,3-(E t h ylen ed ioxy)-2-m et h yl-2-(p r op -2-en yl)cyclo-
h exa n -1-on e (5). A solution of keto acetate 4 (330 mg, 1.3 mmol)
in THF (2.5 mL) was added at -20 °C to a suspension of
potassium tert-butoxide (162 mg, 1.43 mmol) in THF (2.5 mL).
The mixture was stirred for 45 min after which 1 N hydrochloric
acid and diethyl ether (10 mL) were added to it. The aqueous
layer was extracted with Et2O, and the combined organic layers
were washed with brine, dried over MgSO4, concentrated,
chromatographed (Et2O/petroleum ether: 10/100/silica gel: 60
Å, >440 mesh) to afford ketone 5 (230 mg, 83%); 1H NMR δH
(200 MHz) 1.22 (s, 3H), 1.37-1.78 (m, 4H), 2.00-2.25 (m, 2H),
2.36-2.63 (m, 2H), 3.32-3.37 (m, 4H), 4.92-5.04 (m, 1H); 13C
NMR* δC (50 MHz) 14.3, 19.3, 29.6, 37.2, 39.3, 58.8, 63.1, 65.3,
113.4, 117.5, 133.5, 211.4; IR (neat) νmax /cm-1 1715, 1640; MS
Exp er im en ta l Section
1H and 13C NMR spectra were recorded on a spectrometer
operating at 200 MHz for 1H and 50 MHz for 13C from CDCl3
solutions unless otherwise noted. J values are given in hertz.
IR spectra were obtained with a FT-IR spectrophotometer. Mass
spectra were recorded on a mass spectrometer (EI: electronic
impact; CI: chemical ionization with tBuH). GLC analysis were
performed on a gas chromatograph, using an HP-1 (5 m × 0.53
mm × 2.65 µm film) column for GC routine, HP-1 (25 m × 0.25
mm) column for diastereomers separation. Flash chromatogra-
phy was performed on (230-400 mesh ASTM) silica gel, unless
otherwise noted, with petroleum ether (distillation temp < 60
°C)-diethyl ether mixtures as eluent. The progress of reactions
was monitored by GC or by TLC (Et2O-petroleum ether).
Microanalyses were performed by the INSA Laboratories, Rouen.
(S)-1-Acet oxy-3,3-(et h ylen ed ioxy)-2-m et h yl-2-(p r op -2-
en yl)cycloh ex-1-en e (4). Keto acetate 2a (105 mg, 0.5 mmol)
was added to a solution of ethylene glycol (0.5 mL, 9 mmol) and
p-TsOH (5 mg, 0.03 mmol) in benzene (10 mL) and the mixture
refluxed for 2 h in a Dean-Stark apparatus. Saturated aqueous
NaHCO3 was added. Aqueous layer was extracted with pentane.
Combined organic layers were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. Flash chro-
matography (Et2O/petroleum ether: 15/100) on silica gel (60 Å,
> 440 mesh) afforded the dioxolane 4 (106 mg, 83%). 1H NMR
δH (200 MHz) 1.05 (s,3H), 1.69-1.80 (m,2H), 2.08 (s,3H), 2.30
(dt, J 7.2, J 1.2, 2H), 3.92-3.97 (m,4H), 4.90-5.01 (m,2H) and
5.37 (t, J 4.0, 1H);_1H NMR δH (200 MHz, C6D6) 1.28 (s,3H),
1.46-1.72 (m,2H), 1.70 (s,3H), 2.01-2.14 (m,2H), 2.55 (dt, J 7.3,
J 1.3, 2H), 3.35-3.50 (m,4H), 5.00-5.17 (m,2H), 5.50 (t, J 4.0,
1H), 6.09-6.30 (m,1H);_13C NMR δC (50 MHz) 18.4, 20.7, 21.1,
26.9, 40.6, 44.6, 64.6, 64.7, 111.4, 113.9, 115.5, 136.2, 149.5,
m/z (CI, tBuH) 99, 211; [R]25 (c ) 1, CH2Cl2). Anal. Calcd for
D
C12H18O3: C, 68.55; H, 8.63. Found: C, 68.71; H, 8.63; mp 48 °C.
(1S,2S)-3-(1,3-Dioxola n -2-yl)-2-m eth yl-2-(p r op -2-en yl)cy-
cloh exa n -1-ol (6b). To a solution of ketone 5 (210 mg, 1.0 mmol)
in THF (5 mL) was added dropwise at - 78 °C a solution of
lithium triethylborohydride in THF (1 M in THF, 1.1 mL, 1.1
mmol). The mixture was stirred overnight. Methanol (6 mL) and
water (6 mL) were added at - 78 °C, and the mixture was stirred
for 30 min. The suspension was concentrated in vacuo, and the
residue was dissolved in Et2O and washed with 1 N hydrochloric
acid (acidic pH). The layers were separated, and the aqueous
layer was extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4, and evaporated to afford
(210 mg) alcohol 6 in a 96/4 1S,2S/1R,2S diastereomeric ratio.
The major diastereomer (1S,2S)-6b was obtained by flash
chromatography (Et2O/petroleum ether: 5/100) on silica gel (60
1
Å, >440 mesh) (195 mg, 91%); H NMR δH (200 MHz) 0.99 (s,
3H), 1.48-1.76 (m, 6H), 2.00 (dd, J 13.3, J 8.2, 1H), 3.14 (t, J
10.2, OH), 3.60 (dt, J 10.2, J 3.1, 1H), 3.84-4.00 (m,4H), 5.01-
5.13 (m,2H) and 5.78-5.96 (m,1H); 13C NMR δC (50 MHz) 17.7,
19.0, 28.0, 30.1, 35.1, 44.9, 64.0, 65.3, 75.5, 112.9, 117.5 and

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2515
135.0; IR (neat) νmax /cm-1 3450, 1640; MS m/z (CI) 195, 213;
m/z (EI) 55, 69, 86, 99, 108, 122, 139, 150, 194, 212.
(2S,3S)-3-Hyd r oxy-2-m eth yl-2-(p r op -2-en yl)cycloh exa n -
1-on e (3b). H NMR δH (200 MHz) 1.13 (s,3H), 1.60-2.11 (m,-
1
(1R,2S)-3-(1,3-Dioxola n -2-yl)-2-m eth yl-2-(p r op -2-en yl)cy-
cloh exa n -1-ol (6c). To a solution of ketone 5 (200 mg, 0.95
mmol) in methanol (5 mL) was added at -78 °C europium
trichloride (520 mg, 1.4 mmol), and the mixture was stirred for
1 h. Sodium borohydride (36 mg, 0.95 mmol) was added, and
the mixture was stirred overnight. Saturated aqueous NaHCO3
(5 mL) was added at -78 °C and then Et2O (5 mL) at room
temperature. The layers were separated, and the aqueous layer
was extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4, and evaporated to afford
(200 mg) alcohol 6 in a 44/56 1S,2S/1R,2S diastereomeric ratio.
The major diastereomer (1R,2S)-6c was obtained by flash
chromatography (Et2O/petroleum ether: 5/100) on silica gel (60
4H), 2.32-2.44 (m, 4H), 2.70 (s,OH), 3.57 (dd, J 7.0, J 3.3, H),
5.02-5.13 (m,2H), 5.62-5.83 (m,1H);_13C NMR δC (50 MHz)
19.5, 20.5, 28.4, 36.4, 37.6, 54.1, 76.3, 117.7, 133.6, 214.5; IR
(neat) νmax /cm-1 3480, 1700, 1640; m/z (CI) 151, 169; MS m/z
(EI) 55, 67, 81, 93, 109, 122, 135, 150, 168. Anal. Calcd for
C10H16O2: C, 71.39; H, 9.59, Found: C, 71.53; H, 9.38; [R]23 (c
D
) 0.48, CHCl3), for comparison Literature4: (2S,3S) 3b:
XXXXX
(c ) 0.42, CHCl3), (2R,3S) 3d : [R]23 (c ) 0.6, CHCl3).
D
(2S,3R)-3-Hyd r oxy-2-m eth yl-2-(p r op -2-en yl)cycloh exa n -
1-on e (3c). Yield: 80 mg, 80%; 1H NMR δH (200 MHz) 1.11 (s,-
3H), 1.58-2.07 (m,4H), 2.25-2.45 (m, 4H), 2.82 (s,OH), 3.85 (dd,
J 7.3, J 3.0, H), 5.03-5.12 (m,2H), 5.63-5.84 (m,1H); 13C NMR
δC (50 MHz) 17.6, 20.3, 28.3, 37.6, 40.0, 54.3, 74.9, 117.8, 133.8,
214.2; IR (neat) νmax /cm-1 3520, 1705, 1645; m/z (CI) 151 and
169; MS m/z (EI) 55, 67, 81, 93, 109, 122, 135, 150, 168. Anal.
Calcd for C10H16O2: C, 71.39; H, 9.59, Found: C, 71.53; H, 9.38;
1
Å, >440 mesh) (112 mg, 56%); H NMR δH (200 MHz) 1.00 (s,
3H), 1.49-1.72 (m, 6H), 2.25-2.32 (m, 2H), 2.84 (OH), 3.65-
6.72 (m, 1H), 3.85-3.97 (m, 4H), 4.97-5.10 (m, 2H), 5.81-6.02
(m, 1H); 13C NMR δC (50 MHz) 15.1, 18.1, 28.1, 29.7, 39.4, 46.0,
64.4, 64.8, 74.0, 113.0, 116.8, 135.8; IR (neat) νmax /cm-1 3540
and 1640; MS m/z (CI) 195 and 213; m/z (EI) 55, 69, 86, 99, 108,
122, 139, 150, 194, 212.
[R]25 (c ) 0.5, CHCl3). For literature comparison, (2S,3S) 3b:
D
[R]23 (c ) 0.42, CHCl3); (2R,3S) 3d : [R]23 (c ) 0.6, CHCl3).
D
D
Ketols 3b a n d 3c. Solutions of the alcohols 6b or 6c (120
mg, 0.6 mmol) in 3 N hydrochloric acid (4 mL) were stirred
overnight at room temperature. The solution was extracted with
CH2Cl2 (4 × 2 mL), washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by flash chroma-
tography (Et2O/petroleum ether: 20/100) to afford respectively
ketols 3b or 3c (80 mg, 80%).
Ack n ow led gm en t. We gratefully acknowledge the
French Ministe`re de la Recherche for a grant to P. R.
J O980344W