Simple and practical routes to enantiomerically pure 5-(Trialkylsilyl)-2-cyclohexenones

Article abstract of DOI:10.1021/ol990805f

Formula presented Enantiomerically pure chiral 5-silylated 2-cyclohexenones are easily prepared in high yield using as a key step kinetic resolution with a commercially available lipase. Fully active enzyme can be recovered very efficiently for reuse. The

Full text of DOI:10.1021/ol990805f

ORGANIC
LETTERS
1999
Vol. 1, No. 5
811-814
Simple and Practical Routes to
Enantiomerically Pure
5-(Trialkylsilyl)-2-cyclohexenones
Georgios Sarakinos and E. J. Corey*
Department of Chemistry and Chemical Biology, 12 Oxford Street,
HarVard UniVersity, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received July 13, 1999
ABSTRACT
Enantiomerically pure chiral 5-silylated 2-cyclohexenones are easily prepared in high yield using as a key step kinetic resolution with a
commercially available lipase. Fully active enzyme can be recovered very efficiently for reuse. The synthetic steps are outlined in Schemes
1 and 3. Enantiomerically pure 2-cyclohexenones such as 1 and 2 are versatile intermediates for the synthesis of a multitude of chiral targets
by means of a variety of diastereoselective reactions such as those illustrated in Scheme 2.
Chiral 2-cyclohexenones such as pulegone and carvone have
been utilized as starting materials for the total synthesis of
a large and structurally diverse collection of natural products.1
This note describes a very convenient method for the
synthesis of both enantiomers of 5-(dimethylphenylsilanyl)-
cyclohex-2-enone (1) and 5-(trimethylsilanyl)cyclohex-2-
enone (2) which makes these chiral enones readily available.
more stable equivalent of the hydroxyl core functional
group.2 Asaoka and co-workers have already described a
preparation of chiral 2 and its application to the synthesis of
several terpenoids (for example, chiral curcumone and methyl
citronellate).3,4 However, possibly because of the cumber-
some and inefficient mode of synthesis of chiral 2,3 this
starting material has not seen further use.
The starting material for the synthesis of (S)-1 and the
enantiomer uses (()-3-(dimethylphenylsilanyl)cyclohex-
anone (3), which is available in 96% yield from 2-cyclo-
hexenone by reaction with (Me2PhSi)Et2ZnLi.5
(3) Asaoka, M.; Shima, K.; Takei, H. Tetrahedron Lett. 1987, 28, 5669.
(4) (a) Asaoka, M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988,
44, 4757. (b) Asaoka, M.; Sonoda, S.; Fujii, N.; Takei, H. Tetrahedron
1990, 46, 1541. (c) Asaoka, M.; Sakurai, M.; Takei, H. Tetrahedron Lett.
1990, 31, 4159. (d) Asoako, M.; Hayashibe, S.; Sonoda, S.; Takei, H.
Tetrahedron Lett. 1990, 31, 4761. (e) Takano, S.; Higashi, Y.; Kamikubo,
T.; Moriya, M.; Ogasawora, K. Synth. 1993, 948.
The stereocenter in 1 and 2 is strategically placed for the
elaboration of these substrates to a wide variety of chiral
multisubstituted cyclohexanone derivatives with control of
stereochemistry, and the â-silyl substituent is a useful and
(5) Crump, R. A. N. C.; Fleming, I.; Urch, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 701.
1
(6) Determined by H NMR analysis of 4 in CDCl3 solution.
(7) For other resolutions of cyclohexanol derivatives by enantioselective
acetylation under lipase catalysis see: (a) Tanikaga, R.; Morita, A.
Tetrahedron Lett. 1998, 39, 635. (b) Fujisawa, T.; Yamanaka, K.; Mobele,
B. I.; Shimizu, M. Tetrahedron Lett. 1991, 32, 399. (c) Fukazawa, T.;
Hashimoto, T. Tetrahedron: Asymmetry 1993, 4, 2323. (d) Hiratake, J.;
Inagaki, M.; Nishioka, T.; Oda, J. J. Org. Chem. 1988, 53, 6130. (e)
Weissfloch, A. N. E.; Kazlauskas, R. J. J. Org. Chem. 1995, 60, 6959.
(1) Ho, T.-L. EnantioselectiVe Synthesis: Natural Products from Chiral
Terpenes; Wiley: New York, 1992.
(2) By Tamao-Fleming oxidation; for a review of silyl groups as masked
hydroxyl equivalents see: Fleming, I.; Henning, R.; Parker, D. C.; Plaut,
H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
10.1021/ol990805f CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999

Scheme 1
Reduction of 3 with LiAl(t-BuO)3H in tetrahydrofuran
the corresponding ketone (93%), (2) addition of this ketone
to a solution of lithium hexamethyldisilazane (LHMDS) and
trimethylchlorosilane (TMSCl) in THF at -78 °C to form
2-((trimethylsilyl)oxy)-4-(dimethylphenylsilanyl)cyclohex-
ene (with ca. 40:1 position selectivity in the deprotonation
step),10 and (3) oxidation of this silyl enol ether in dimethyl
(THF) at -60 °C for 16 h afforded the cis alcohol (()-4 in
99% yield with >14:1 cis/trans selectivity. After two
recrystallizations from pentane at -60 °C, the cis alcohol
(()-4 in 99% stereochemical purity was obtained,6 mp 42.5-
44 °C.
Racemic 4 underwent highly enantioselective acetylation
when treated in diisopropyl ether solution with isopropenyl
acetate in the presence of Amano Lipase PS powder
(essentially insoluble in i-Pr2O) for 60 h at 23 °C. At the
end of this period, the fully active enzyme was recovered
for reuse by filtration. Concentration of the filtrate and
chromatographic separation on silica gel afforded 96% of
the theoretical yield of the (R)-alcohol 5 (>99% ee) and 99%
yield of the acetate of the enantiomer 6 (>99% ee), as
outlined in Scheme 1.7,8 Proof of absolute configurations is
provided below. Methoxide-catalyzed methanolysis of 6
provided the (S)-alcohol 7 in 99% yield.9 The (R)-alcohol 5
was readily transformed to enantiomerically pure (R)-1 by
the following three-step sequence: (1) oxidation of the
alcohol 5 by pyridinium dichromate (PDC) in CH2Cl2 at 23
°C for 26 h in the presence of 4 Å molecular sieves to form
(12) A stirred solution of dry hexamethyldisilazane (6.165 mL, 29.22
mmol) in hexanes (24 mL) at -5 to -10 °C was treated with a solution of
n-butyllithium in hexanes (3.90 M, 6.94 mL, 27.1 mmol, Alfa). Within 10
min a precipitate appeared. The mixture was stirred for an additional period
of 15 min, THF (90 mL) was introduced, and the solution was cooled to
-78 °C. To this cold solution was added neat, dry TMSCl (6.865 mL,
54.11 mmol) down the walls of the flask, followed by 5 (2.514 g, 10.82
mmol) as a precooled (-78 °C) solution in THF (10 mL). The reaction
mixture was stirred for 30 min and treated with dry Et3N (12 mL) and then
saturated aqueous NaHCO3 (200 mL). The mixture was warmed to room
temperature, and the solvents were removed in vacuo. The residue was
extracted with ether (2 × 150 mL), and the combined organic layers were
washed with water (2 × 150 mL) and brine (150 mL) and dried over
anhydrous K2CO3. After filtration and evaporation of the solvent in vacuo,
the crude residue (a 97.5:2.5 mixture of regioisomeric enol ethers,
determined by GC using a J&W DB1701 capillary column) was dried
azeotropically with benzene (2 × 20 mL) at 80 mmHg and 40-50 °C. A
solution of this crude product and Pd(OAc)2 (243.0 mg, 1.082 mmol, 0.10
equiv based on 5, Aldrich) in dry DMSO (90 mL) in a 500 mL flask was
placed under 1 atm of oxygen (balloon). The orange solution turned dark
within min. After the mixture was stirred for 11 h at 23 °C, additional
Pd(OAc)2 (24.3 mg, 0.108 mmol, 0.01 equiv) was added. After a total time
of 14 h, the reaction mixture was poured into water (600 mL) and the
products were extracted into 1:1 ether-pentane (250 mL + 150 mL). The
combined organic layers were washed, dried (K2CO3), and concentrated in
vacuo. The oily residue was dissolved in pentane (25 mL), filtered through
Celite, and crystallized by cooling to -20 °C (seeding was sometimes
necessary). The product (-)-1 (2.131 g, 85% yield based on 5) was obtained
(8) A stirred solution of (()-4 (4.88 g, 20.8 mmol, 99% cis) in i-Pr2O
(83 mL, Aldrich) at 23 °C was treated with Lipase PS powder (1.12 g,
Amano Pharmaceutical Co., Inc.) and isopropenyl acetate (2.27 mL, 20.6
mmol, Aldrich). The progress of the reaction was monitored by chiral phase
analytical HPLC, using a Chiralcel OJ column (Daicel Chemical Industries,
Ltd.), until one enantiomer of the starting material was completely
consumed. After a total time of 60 h, the insoluble enzyme was removed
by filtration, washed with several portions of ether, dried in air for 5-10
min, and stored at -20 °C under N2 for reuse. Concentration of the filtrate
in vacuo and silica gel flash chromatography (ethyl acetate-hexanes
gradient) afforded the unreacted alcohol 5 (2.38 g, 98% of theoretical yield,
ca. 98% cis, oil) and the acetate ester 6 (2.82 g, 98% of theoretical yield,
oil). For 5, >99% ee, determined by chiral phase HPLC using a Daicel OJ
column, 5% i-PrOH in hexanes as eluent at a flow rate of 0.6 mL/min,
detection at 215 nm with elution times tminor ) 11 min, tmajor ) 14 min. For
6, [R]24D ) +36.4° (c 4.38, CHCl3); >99% ee, determined by chiral phase
HPLC using an S,S Whelk O1 column (Regis Chemical Co.), 0.25% i-PrOH
in hexanes as eluent at a flow rate of 1 mL/min, detection at 215 nm with
elution times tmajor ) 14.5 min, tminor ) 18.0 min.
as pale yellow crystals: [R]23 ) -7.8 ( 0.1° (c 1.08, CHCl3); mp 35-
D
35.5 °C; Rf ) 0.31 (ether-pentane 1:3); FTIR (film) ν 2955, 1682, 1675,
1
1427, 1384, 1249, 1166, 1152, 1115, 900, 873, 833, 815 cm-1; H NMR
(CDCl3, 500 MHz) δ 7.49-7.47 (m, 2H), 7.39-7.35 (m, 3H), 6.98 (ddd,
J ) 2.4, 5.6, 10.1 Hz, 1H), 5.98-5.96 (m, 1H), 2.44 (dd, J ) 3.5, 16.3 Hz,
1H), 2.31-2.14 (m, 3H), 1.65 (tdd, J ) 11.7, 4.4, 3.7 Hz, 1H), 0.33 (s,
6H); 13C NMR (CDCl3, 101 MHz) δ 199.9, 151.4, 136.2, 133.9, 129.5,
129.4, 128.0, 38.6, 26.9, 22.9, -5.3, -5.5; HRMS (EI+) m/z calcd for
[C14H18OSi]+ 230.1127, found 230.1131; >99% ee as determined by HPLC
using a Chiralpak AS column (Daicel Chemical Industries, Ltd.), 4% i-PrOH
in hexanes as eluent at a flow rate of 1 mL/min, detection of 220 nm with
elution times tmajor ) 15 min, tminor ) 20 min. The enantiomer, (+)-1, was
prepared similarly in >99% ee; [R]22 ) +7.8 ( 0.1° (c 1.21, CHCl3).
D
(13) (a) X-ray data for (1R,4R,6R)-(+)-8: C14H18O2Si; monoclinic; P21;
a ) 6.5347(11) Å, b ) 17.880(3) Å, c ) 11.411(2) Å; R ) 90°, â )
93.175(17)°, γ ) 90°; Z ) 4; R1(I > 2σ(I)) ) 0.0380. (b) Detailed X-ray
crystallographic data are available from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(9) Found for 7, >99% ee, determined as above for 5.
(10) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(11) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng,
D. Tetrahedron Lett. 1995, 36, 2423.
812
Org. Lett., Vol. 1, No. 5, 1999

Scheme 2
sulfoxide solution with 1 atm of O2 and 11 mol % of Pd-
DMF at 55 °C for 1 h16 gave the known (R)-R,â-enone 1117
(OAc)2 at 23 °C for 14 h to form the enone (R)-1 (85% yield
over two steps).11,12 The enantiomer (S)-1 was prepared by
a parallel sequence of three steps in a similar yield (ca. 80%
overall from 7).
in 75% yield, in accord with expectations.
For the preparation of (S)-2, racemic â,γ-unsaturated
ketone 13 was synthesized from anisole, lithium (dispersion
in mineral oil), and TMSCl in 63% overall yield, according
to the known literature procedures (Scheme 3).3,18 Reduction
of 13 with LiAl(t-BuO)3H in 3:1 ether-THF at -60 °C for
13 h afforded a 97:3 mixture of cis/trans alcohols 14 in 94%
yield. The cis alcohol was easily purified after one recrys-
tallization from pentane at -15 °C in 77% yield based on
13. Enantioselective lipase catalyzed acetylation of 14 with
isopropenyl acetate in i-Pr2O at 23 °C for 64 h produced the
optically pure alcohol (-)-14 and acetate ester (+)-16, each
in 98% of the theoretical yield after silica gel chromatog-
raphy. Both products were obtained in >99% ee, as
determined by chiral HPLC.19
The absolute configuration of the chiral cyclohexanol 5
and compounds derived therefrom was proven by X-ray
crystallographic analysis of the crystalline product 8 (Scheme
2), obtained by epoxidation of the levorotatory enone (R)-1
with H2O2 and LiOH in aqueous THF at 0 °C for 45 min
(99:1 trans/cis ratio).13 Highly trans-selective (96:4) R,â-
methylene addition to (R)-1 to form 9 was also observed in
the reaction with dimethyloxosulfonium methylide Me2S-
(O)CH2, as shown in Scheme 2.14 The cis relationship
between the endo proton of the cyclopropyl methylene group
and the cyclohexyl C-H R to the SiMe2Ph group of 9 was
established by the observation of a 13% NOE effect in the
1H NMR spectrum.
The ester (+)-16 underwent methanolysis by NaOMe in
MeOH at 0 °C for 3 h, and the resulting alcohol was oxidized
under Swern conditions to the dextro ketone (+)-13 ([R]21
) +219.3° (c 1.31, CHCl3)) in quantitative yield. Isomer-
ization of (+)-13 to the desired enone (+)-2 was effected
using 2.3 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene in the
Reaction of (-)-(R)-1 with lithium di-n-butylcyanocop-
per15 in THF at -78 °C for 30 min afforded, as expected,
the trans conjugate adduct 10, as outlined in Scheme 2 (50:1
trans/cis selectivity). Reaction of 10 with cupric chloride in
D
Scheme 3
Org. Lett., Vol. 1, No. 5, 1999
813

presence of a minimum amount of THF at 4 °C for 12 h
(79% yield after workup and silica gel chromatography).20
The ee of (+)-2 was 98.4%, as determined by enantioselec-
tive HPLC analysis.21 The known S absolute configuration
of (+)-2 agrees with the expected sense of asymmetric
induction of the lipase-catalyzed acetylation.
(14) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(15) See: Lipshutz, B. H. In Organocopper Reagents: a Practical
Approach; Taylor, R. J. K., Ed.; Oxford University Press: New York, 1994;
pp 105-128.
Acknowledgment. This research was supported finan-
cially by the National Institutes of Health and the National
Science Foundation. We are grateful to Drs. Michael J.
Grogan and Richard J. Staples for the X-ray crystallographic
analysis of 8 and to Eduardo J. Martinez for assistance with
the NOE experiment.
(16) Asaoka, M.; Shima, K.; Takei, H. J. Chem. Soc., Chem. Commun.
1988, 430.
(17) Asaoka, M.; Takenouchi, K.; Takei, H. Chem. Lett. 1988, 921.
(18) Bennetau, B.; Rajarison, F.; Dunogue´s, J.; Babin, P. Tetrahedron
1994, 50, 1179.
(19) For determination of ee, (-)-14 was converted to (-)-16 and the
ee’s of both (+)- and (-)-16 were measured by enantioselective HPLC
analysis using an S,S Whelk O1 column, 0.25% i-PrOH in hexanes as eluent
at a flow rate of 0.7 mL/min and detection at 215 nm with elution times
t(+) ) 14.5 min, t(-) ) 17.0 min.
OL990805F
(21) Chiralcel OJ column, 0.2% i-PrOH in hexanes as eluent at a flow
rate of 1 mL/min, detection at 215 nm with elution times tminor ) 10 min,
tmajor ) 11 min.
(20) [R]20 ) +5.6° (c 0.61, CHCl3); lit.3 [R]20 ) +9.40° (c 2.19,
D
D
CHCl3).
814
Org. Lett., Vol. 1, No. 5, 1999