Syntheses of highly substituted enantiopure C6 and C7 enones

Article abstract of DOI:10.1021/ja026760m

Enantiopure epoxyvinyl sulfones SS-9a, SS-9b, produced from Jacobsen epoxidation of 2-phenylsulfonyl 1,3-cyclohexa- and cycloheptadiene, are used as a template for the construction of substituted cycloalkenones and as chiral synthetic equivalents of enone

Full text of DOI:10.1021/ja026760m

Published on Web 08/24/2002
Syntheses of Highly Substituted Enantiopure C6 and C7
Enones1
Jerry Evarts, Eduardo Torres, and Philip L. Fuchs*
Contribution from the Department of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
Received May 2, 2002
Abstract: Enantiopure epoxyvinyl sulfones SS-9a, SS-9b, produced from Jacobsen epoxidation of
2-phenylsulfonyl 1,3-cyclohexa- and cycloheptadiene, are used as a template for the construction of
substituted cycloalkenones and as chiral synthetic equivalents of enones a and b. The addition of carbon
nucleophiles to SS-9a, SS-9b is high yielding and stereospecific. Enantiopure R,â- and γ-substituted
cycloalkenones are easily constructed using a variety of methods.
Scheme 1
Introduction
Development of chiral 2,5-cyclohexadienone synthons has
received only modest attention in the literature. A differentiated
pair of enones that can enantiospecifically add nucleophiles,
trap electrophiles, or participate in Diels-Alder reactions are
valuable in the synthesis of multifunctionalized cyclohexane
molecules, providing access to the substrate is efficient. Two
current methods are shown in Scheme 1. The first involves
enantiopure 5-silyloxy-cyclohexenone 2 which directs Michael
addition through avoidance of 1,3 diaxial interactions, followed
by â-elimination of OTBS to generate enone 3.2 Synthesis of 2
from commercially available 1 requires seven operations, 50%
yield.3 The second strategy employs tricyclic enone 5, which
masks one of the olefins as a Diels-Alder adduct. Directed
Michael addition followed by retro Diels-Alder then reveals
the functionalized enone 3.4 Substrate 5 is synthesized either
through enzymatic or catalytic desymmetrization (Scheme 1).5,6
Regardless of the brevity of the latter synthesis using catalytic
desymmetrization, the catalyst is prohibitively expensive ($60/
50 mg, $1.2 M/mol, used at 5%). The lipase-mediated desym-
metrization of compound 4 occurs in 79% yield, but requires
16 days reaction time.
Scheme 2 a
a G ) Me 86% ee, i-Pr 95% ee, t-Bu 92% ee, Ph 93% ee.
substituents are desired, the synthesis of the prochiral 4-sub-
stituted cyclohexanone 6 must be performed (Scheme 2). The
method is further limited by symmetry to cycloalkanones with
an even number of carbons.
In 1993, Koga et al. demonstrated a general method for the
construction of 4-alkyl and 4-aryl cyclohexenones 8 using chiral
lithium amides.7 The method is very sound; however, it requires
a stoichiometric equivalent of chiral base. Also, if more elaborate
Results and Discussion
We are pleased to report epoxy vinyl sulfone chemistry
provides improved methodology for the general synthesis of
chiral 4-alkylcycloalkenones and for enantiopure 2,5-cyclo-
hexadienone synthons. By analogy to our previous report in the
racemic series,8 epoxyvinyl sulfone SS-9a can be considered
as a synthon for both unpoled enone 10a as well as chiral 2,5-
cyclohexadienone equivalent 11a in which one masked enone
is charge-inverted, and the latent enone is normally polarized
(Scheme 3).
* To whom correspondence should be addressed. E-mail: pfuchs@
purdue.edu.
(1) Syntheses via vinyl sulfones 85 and Chiral Carbon Catalog #8. For previous
paper, see: Myers, D.; Fuchs, P. L. J. Org. Chem. 2002, 67, 200.
(2) Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997, 38, 8299.
(3) Kitamura, M.; Ohkuma, T.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1988,
29, 1555.
(4) Hiroya, K.; Zhang, H.; Ogasawara, K. Synlett 1999, 529. Kamikubo, T.;
Ogasawara, K. Chem. Commun. 1995, 1951. Shimizu, M.; Kamikubo, T.;
Ogasawara, K. Synlett 1998, 655.
(5) Takano, S.; Higashi, Y.; Kamikubo, T.; Moriya, M.; Ogasawara, K.
Synthesis 1993, 948.
(6) Ogasawara, K.; Kurihara, Y.; Hiroya, K. Angew. Chem., Int. Ed. Engl. 1995,
34, 2287.
(8) Jin, Z.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 5995. (The six- and
seven-membered 2-phenylsulfonyl-1,3-dienes are commercially available
from Aldrich Chemical Co.)
(7) Aoki, K.; Nakajima, M.; Tomioka, K.; Koga, K. Chem. Pharm. Bull. 1993,
41, 994.
9
10.1021/ja026760m CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 11093-11101
11093

A R T I C L E S
Evarts et al.
Scheme 3
Scheme 5
Table 1. Alkyl Cuprate Additions to SS-9a
% yield
HPLC ratio
R )
Mea
Et
i-Pr
t-Bu
PhMe2Si
Ph
M )
Li
MgBr
MgCl
Li
12t,c
12t/12c
% yield
98
92
94
93
87
90
>50/1
>50/1
>50/1
>50/1
>50/1
3/1
13t-Me 99
13t-Et 97
13t-Pr 99
13t-tBu 98
13t-PhMe2Si 93
not run
Table 2. Cyclohexenones 14 from γ-MeO-Vinyl Sulfones
Li
MgBr
R
% yield
% eea
%de
a 20% MeLi/20% CuI, 1.2 equiv of Me3Al.
Scheme 4
Me
Et
i-Pr
t-Bu
PhMe2Si
14Me 93
14Et 93
14Pr 94
14tBu 89
NR
93b
93.7
94.8c
91.2
>99
>99
>99c
98
a HPLC analysis. b By rotation, HPLC inseparable. c Enriched by crystal-
lization.16
mixture to reflux in CH2Cl2, then in dichloroethane, and finally
adding DBU, did not positively affect the ratio, and side products
began to dominate the crude NMR. Because acidic conditions
seemed to facilitate elimination, the process was repeated, and
the oxalic acid hydrolysis step was allowed to stir overnight.
The ratio, as analyzed by NMR, was worse, 75% 16 and 25%
14Me.
Adding the crude 16/14Me mixture to THF/water containing
3% Et3N and allowing the reaction to stir at 25 °C for 9 h was
highly effective. The ratio of THF to water is critical. The
substrate is dissolved in THF (approximately 0.09 M), water is
added until the reaction becomes slightly cloudy, and then the
minimum amount of THF is added to establish homogeneity.
This process is ineffective without an aqueous wash of the initial
reaction, because the lithium salt content does not allow the
THF and water to be completely miscible.
Presumably, the basic aqueous conditions are more effective
than those in CH2Cl2 because of the greater polarity of the
media. Furthermore, the literature reveals that elimination of
sulfinate from γ-ketosulfones is a reversible process and that
the equilibrium lies far toward the side of the â-ketosulfone
under acidic conditions.11
With a convenient method for conversion of the isomerized
allyl sulfone to the desired enone finally in hand, 4-methyl-
cyclohex-2-en-1-one 14Me was produced in 93% yield. It is
significant that the sp3 cuprate additions to SS-9a are ∼100%
anti throughout the series of methyl, ethyl, isopropyl, and tert-
butyl substituents as assayed by chiral HPLC of the resulting
enones (14) shown in Table 2.
The enone synthesis begins with an update of our overly
conservative NMR estimate that methylation of epoxyvinyl
sulfone SS-99 proceeds with ∼96/4 trans/cis specificity10 for
trans adduct 14. Duplication of this reaction with enantiopure
SS-9 using chiral HPLC analysis reveals that the reaction is
essentially stereospecific (Table 1, entry 1). Repetition of the
process for the additional alkyl groups shown in Table 1 can
be conveniently conducted with cuprates derived from both
lithium and Grignard reagents without the need for addition of
any alkyl aluminum reagent (Scheme 4). The reactions are all
high yielding, and the product can be directly O-methylated as
crude material. Methylation using MeI in basic DMSO is high
yielding, fast, and does not require chromatography either before
or after the process (Table 1). Substantial empirical efforts failed
to increase the selectivity of phenyl addition beyond 3:1.
Addition of t-BuLi at -78 °C to 13t generates a bright orange
solution which, after 15 min, is quenched with saturated
NaHCO3 providing a mixture of sulfone diastereomers 15 in
high yield accompanied by less than 3% of the desired enone
14Me by NMR (Scheme 5). An attempt to hydrolyze diaster-
eomeric vinyl ethers 15 to ketone 14Me using 5% oxalic acid
in 1:1 methanol/water was interrupted after 1 h at 25 °C. TLC
analysis incorrectly suggested that the reaction contained only
the mixture of starting vinyl ethers 15. It was later revealed
that 15, 14Me, and 16 have the same Rf value on TLC in the
assay system employed. During workup, 10% NaOH was added
to the diluted reaction mixture, which was then extracted with
CH2Cl2. NMR analysis showed that 15 had been completely
hydrolyzed to 16 with approximately 40% conversion to enone
14Me. Et3N was added to a mixture of γ-ketosulfones 16 and
enone 14Me in CH2Cl2. The ratio did not change. Heating the
Epoxy vinyl sulfone SS-9a can be obtained in >99% ee, but
in this experiment the ee of epoxide SS-9a was fixed at 93%
by doping with racemic material, providing an unambiguous
HPLC control. Except for 14Me (chiral HPLC inseparable; 93%
by rotation), all of the ee values in Table 2 were determined by
HPLC analysis. With the possible exception of the tert-butyl
(9) Both enantiomers are equally available by catalytic epoxidation of the
2-phenylsulfonyl-1,3-dienes via Jacobsen epoxidation: Hentemann, M. F.;
Fuchs, P. L. Tetrahedron Lett. 1997, 38, 5615.
(11) Girlanda-Junges, C.; Keyling-Bilger, F.; Schmitt, G.; Luu, B. Tetrahedron
1998, 54, 7735.
(10) Saddler, J. C.; Fuchs, P. L. J. Am. Chem. Soc. 1981, 103, 2112.
9
11094 J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002

Syntheses of Highly Substituted Enantiopure Enones
A R T I C L E S
Scheme 6
Scheme 7
Scheme 8
Table 3. Enantiopure 3,4-Disubstituted Enones
4
3
R
R
% yield
% ee or rotation
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Mea
allyla
Mea
allyla
i-Pra
Bua
14a 92
14b 96
14d 90
14e trace
14f no rxn
14g no rxn
14e 92
14f trace
14g 84
106°
-153°
93
allylb
i-Prb
Bub
-69°
-12°
a No HMPA added. b HMPA added.
Table 5. Synthesis of Enones 24
R )
yield 21
yield 22
yield 23
yield 24
Table 4. 3,4-Disubstituted Enones from 17 + Cuprates
Me
i-Pr
90
94
96
98
87
99
93
92
4
3
R
R
% yield
% ee or rotation
17a Me
17a Me
17a Me
17b i-Pr
Me
14a 92
14b 96
14c 45
14d 60
+106°
-153°
+119°
92
allyl
i-Pr
Me
and elimination to the desired enone.7,13 Application of this
technology to 12tb gives enone 19 in 90% yield (Scheme 8).
Extension of the strategy for synthesis of 2,3,4-trisubstituted
enones was also examined beginning with alcohol 12tb. In this
instance, addition of the methyllithium and subsequent capture
of the anion with the methyl iodide produce 20 as a mixture of
isomers. Oxidation of 20 followed by elimination furnishes
trisubstituted enone 21 in excellent yield (92%).
Enantiopure epoxyvinyl sulfone SS-9a also can serve as a
synthon for differentiated cyclohexa-2,5-dienones. Treatment
of SS-9a with 1 equiv of LiHMDS followed by addition of
methyl- or isopropyl-lithium proceeds via sequential γ-meta-
lation/epoxide fragmentation followed by OM-directed conjugate-
addition with quenching R to the sulfone moiety to generate 22
as shown in Table 5 and Scheme 9. Mo(CO)3-catalyzed directed
epoxidation with tBu-OOH gives 23; DBU treatment of 23 for
the absolute minimal time (<1 h) cleanly effects â-elimination
of the epoxide moiety. Methylation of the resulting γ-sulfonyl
allyl alcohol may be done in the same operation to provide 24
in the yields indicated in Table 5. Treatment of 24 with tert-
butyllithium affords an allylic anion which reacts with methyl
iodide (HMPA essential) to give enantiopure enones 25 in
>92% yield. Hydrolysis of the highly substituted substrates to
their corresponding enones was found to work better under
slightly acidic media (SiO2).
experiment, the reactions in Table 2 are held to be 100%
enantiospecific within the limits of experimental detection.
As previously reported, γ-methoxyallyl sulfone anions can
be quenched with electrophiles.8 Extension of this method to
the more highly functionalized materials prepared in this study
reveals that alkylations of proximally substituted γ-methoxyallyl
sulfone anions are strongly influenced by the steric demands
of the electrophile (Scheme 6). As can be seen in Table 3,
synthesis of 3-substituted-4-alkyl cyclohex-2-en-1-ones bearing
a secondary substituent in the 4-position are reluctant to alkylate
under “standard” conditions, but can be successfully alkylated
proVided that HMPA is added to the γ-methoxyallyl sulfone
anion during the alkylation phase. Still, these conditions cannot
overcome the steric demands of the electrophile, with the 3,4-
bisisopropyl adduct only being formed in 5-10% yield even
using the HMPA protocol.
A complementary method for synthesis of 3-substituted-4-
alkyl cyclohex-2-en-1-ones 14 involves reversing the role of
nucleophile and electrophile. Oxidation of allylic alcohols 12ta
and 12tb to â-sulfonyl enones 17a and 17b, respectively, using
activated MnO2 is high yielding. Michael addition of hetero-
cuprates with subsequent â-elimination of sulfinate gives the
desired 3,4-disubstituted enones 14 in fair yield (Table 4,
Scheme 7). While cuprate reactions are well known for
vinylogous thiolesters,12 this is apparently the first report with
vinylogous acyl sulfones 17 (â-sulfonyl enones).
2-Phenylsulfonyl-1,3-cycloheptadiene gives epoxide SS-9b
in high yield and ee with Jacobsen’s AE.9 Nucleophilic
methylation of SS-9b is regio- and stereospecific providing vinyl
sulfone 26. In contrast to the cyclohexyl examples, use of
aluminum reagents is required to get clean conversion and high
yield. Conversion to 4-methylcyclohept-2-en-1-one 28 is high
yielding, but 3 days is required to convert 27 to enone 28. As
2-Substituted 4-alkylcyclohexenones are also available by the
addition of 2 equiv of alkyl or aryllithium followed by oxidation
(12) Dieter, R. K. Tetrahedron 1986, 42, 3029. Dieter, R. K.; Silks, L. A., III.
J. Org. Chem. 1986, 51, 4687. Coates, R. M.; Sandefur, L. O. J. Org.
Chem. 1974, 39, 275.
(13) Conrad, P. C.; Fuchs, P. L. J. Am. Chem. Soc. 1978, 100, 346.
9
J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002 11095

A R T I C L E S
Evarts et al.
Scheme 9 a
Scheme 10 a
a a1. 1.1 equiv of LiHMDS, THF, -78 °C; a2. MeLi or i-PrMgCl (4
equiv), -78 °C, 2 h; b1. 2% Mo(CO)6, 1.1 equiv of TBHP, C6H6, 80 °C,
2 h; b2. 1.2 equiv of TBSOTf, 1.5 equiv of Et3N, CH2Cl2, 0.5 h, 25 °C; c1.
1.1 equiv of DBU, THF, reflux, 50 min; c2. 10 equiv of MeI, KOH, DMSO,
25 °C, 20 min; d1. 2.0 equiv of t-BuLi, -78 °C, 5.0 equiv of HMPA, 0.1
M THF, 20 min, then 5 equiv of MeI; d2. SiO2, CHCl3, 3 h, 25 °C.
previously demonstrated,8 metalation/fragmentation/silylation of
SS-9b provides 29,14 in near-quantitative yield. This substrate
undergoes ready conjugate-addition to provide allyl sulfone 30.
Oxidation of allyl sulfone 30 yielded epoxide 31, which was
treated with DBU to afford vinyl sulfone 32 whose structure
was verified by single-crystal X-ray analysis of the methyl
derivative 33.15 Alcohol methylation followed by metalation/
alkylation/elimination of 32 provides enantiopure enone 34,
while nucleophilic methylation/oxidation/elimination generates
isomeric enone 36 with equal facility (Scheme 10).
a a. MeCu (cat), AlMe3, THF, Et2O, -78 °C, 2 h; b. MeI (10 equiv),
KOH, DMSO, 15 min; c1. t-BuLi, THF, -78 °C, 10 min; c2. Et3N, THF,
H2O, 3 d; d. MeLi, THF, -78 °C, 0.5 h; e. 2.5 equiv of m-CPBA, CH2Cl2,
24 h, 25 °C; f. DBU, THF reflux, 18 h; g. MeI (10 equiv), KOH, DMSO,
5 min; h1. t-BuLi, THF, -78 °C, 10 min; h2. MeI, warm to 25 °C, 15 min;
i. SiO2, CHCl3, 6 h, 25 °C; j. 3.0 equiv of MeLi, THF, -50 to 0 °C, 1 h;
k. PCC, CH2Cl2, 5 h, 25 °C, then 10% NaOH, THF, 8 h, 25 °C.
Å molecular sieves (Aldrich) were oven and/or flame activated under
vacuum prior to use. Glassware was oven dried and/or flame dried.
All reactions were carried out under a positive pressure of argon in
anhydrous solvents (unless otherwise indicated), and the reaction flasks
were fitted with rubber septa for the introduction of substrates and
reagents via syringe. Unless otherwise noted, all reactions were worked
up using standard conditions. Standard workup conditions are the
addition of an equal volume of the stated organic solvent followed by
two equal volumes of water or aqueous solution. All subsequent washes
are perfomed with volumes equal to the organic solution being washed.
The progress of reactions was monitored by thin-layer chromatography
(TLC) in comparison with the starting material(s). TLC was performed
on glass-backed silica gel 60 F 254 plates (EM reagents, 0.25 mm)
and eluted with (v/v) ethyl acetate (EA) in hexanes (Hex) or the
specified solvent solutions. The TLC plates were visualized with a UV
lamp (254 nm) and/or with TLC visualizing solutions activated with
heat. The two commonly employed TLC visualizing solutions were (i)
p-anisaldehyde solution (1350 mL of absolute ethanol, 50 mL of
concentrated H2SO4, 15 mL of glacial acetic acid, 37 mL of p-
anisaldehyde), and (ii) permanganate solution (weight percents of 1%
KmnO4 and 2% Na2CO3 in H2O). All organic extracts were dried with
MgSO4 unless otherwise noted. Analytical samples were obtained from
flash silica gel chromatography (SGC), using silica gel of 230-400
mesh, or from recrystallization of the crude products. Silica gel was
washed with Et3N and acetone to render it deactivated. Melting points
were obtained on a MEL-TEMP capillary melting point apparatus and
uncorrected. Optical rotations were taken on a Rudolph Research
Conclusion
SN2′ addition of alkyl organometallic reagents to cross-
conjugated six- and seven-membered epoxyvinyl sulfones results
in enantiospecific anti 1,4-addition. These initial vinyl sulfone
adducts may be further functionalized to ultimately give high
yields of enones which have been alkylated in the R,â- and
γ-positions. The cyclohexyl substrate may be elaborated to an
enone bearing both a reactive and a latent enone, thus providing
improved access to the enantiopure cyclohexadienone synthon.
Similar processing has also been accomplished on the cyclo-
heptyl substrate generating enones alkylated in the R,â-, γ-, and
δ-positions, which also bear a protected alcohol moiety in the
δ-position.
Experimental Procedures
All purchased reagents were used as received. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were distilled from sodium benzophenone ketyl.
Benzene, toluene, dichloromethane (CH2Cl2), anhydrous methanol
dimethyl sulfoxide (DMSO), and dimethyl formamide (DMF) were
distilled from calcium hydride. Acetonitrile (CH3CN), chloroform
(CHCl3), and methanol were spectra-grade. n-BuLi and t-BuLi were
titrated prior to use by dropwise addition to a solution of N-
benzylbenzamide in THF at -78 to 0 °C. Sodium sulfate (Na2SO4)
and magnesium sulfate (MgSO4) were used as received. Powdered 4
1
Autopol III instrument at 25 °C. H NMR spectra were recorded on
Varian INOVA-300 (300 MHz) and Varian VXR (500 MHz) spec-
trometers. 13C NMR spectra were recorded on Varian INOVA-300 (75
MHz) and Varian VXR (125 MHz) spectrometers. NMR spectra were
determined in chloroform-d1 (CDCl3) solution and are reported in parts
per million (ppm) from the residual chloroform (7.26 and 77.00 ppm).
Peak multiplicities in 1H NMR spectra, when reported, are abbreviated
as s (singlet), d (doublet), t (triplet), m (multiplet), and b (broad). Mass
(14) Jiang, W.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2000, 2, 2181.
(15) X-ray data for compounds 23Me a, 23Pr a, and 33 have been submitted
to the Cambridge Crystallographic database. A depiction of the X-ray
structure of 33 has been included in the Supporting Information.
(16) The ee of the starting epoxide SS-9a was 93%, and the ee of 18 was
calculated to be 93% by rotation value. SS-9a can be obtained in >99%
ee, but, to aid in HPLC analysis, the normally enantiopure material was
doped with racemic epoxide to give 93% ee.
9
11096 J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002

Syntheses of Highly Substituted Enantiopure Enones
A R T I C L E S
spectra were run by the Purdue University campus wide mass
spectrometry facility. The low resolution EI and CI (isobutane) spectra
were obtained on a Finnigan 4000 mass spectrometer with a Nova 4
data system with the molecular ion designated as “M+” (all mass-to-
charge ratios are reported as m/z). The high-resolution mass spectra
were obtained on a Kratos MS-50 instrument.
1H), 3.42 (s, 3H), 2.29 (m, 1H), 2.00-1.40 (m, 5H), 1.32 (m, 1H),
0.85 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3): δ 146.52, 139.75, 137.28,
133.20, 129.07, 127.92, 72.91, 56.64, 35.05, 24.21, 23.76, 21.92, 11.39.
LRMS: (EI) 280 (highest mass), 139 (base peak). (CI) 281 (M + H).
HRMS: calculated for C15H20O3S 280.1133, found 280.1132. [R]D (c
2.30, CHCl3) ) -150°.
General Procedure for the Addition of Mixed Alkyl Cuprates
to Epoxyvinyl Sulfone SS-9a. To 530 mg (5.9 mmol) of anhydrous
CuCN in 25 mL of THF cooled to -78 °C was added 1.15 equiv (4.86
mmol) of the desired alkyllithium or Grignard reagent. The stirred
mixture was allowed to warm to -20 °C for 15 min. The reaction
temperature was returned to -78 °C, and 1.0 g (4.23 mmol) of SS-9a
in 10 mL of THF was added via cannula. The reaction was then allowed
to stir for 4-6 h without further cooling. When complete by TLC, the
reaction was quenched with saturated NH4Cl and extracted with ether.
The organic layer was then washed again with 5% HCl. After being
dried and the solvent was removed in vacuo, the resulting material can
typically be used without purification and was 95% pure by NMR.
General Procedure for the Etherification of γ-Hydroxy Vinyl
Sulfones. Crude γ-hydroxy vinyl sulfone (4.0 mmol) was dissolved
and rapidly stirred in 30 mL of anhydrous DMSO and cooled in a 25
°C water bath. Next 20-30 equiv of MeI was added. Powdered KOH
was added slowly, approximately one pellet every 3 min for a total of
five pellets. When complete by TLC, the dark mixture was poured into
ice water. The mixture was extracted with ether three times, and the
solvent was removed in vacuo. SGC, 6:4 Hex/EA, provided the desired
methyl ethers in nearly quantitative yield.
(S)-4-Ethylcyclohex-2-enone (14Et). 93% yield. Clear colorless oil.
1H NMR (CDCl3): δ 6.90 (ddd, J ) 10.2, 2.6, 1.4 Hz, 1H), 6.01 (ddd,
J ) 10.2, 2.4, 0.8 Hz, 1H), 2.54 (dt, J ) 16.8, 5.3 Hz, 1H), 2.40 (m,
2H), 2.16 (m, 1H), 1.60 (m, 3H), 1.04 (t, J ) 7.3 Hz, 3H). 93.7% ee
HPLC Chiralcel AD 0.75 mL/min 99.5:0.5 Hex:2-propanol. 15.57 min
minor enantiomer, 16.59 min major enantiomer.
(1S,4R)-3-Benzenesulfonyl-4-isopropylcyclohex-2-enol (12t-Pr).
94% yield. White solid. mp 105 °C. 1H NMR (CDCl3): δ 7.85 (d, J )
9.5 Hz, 2H), 7.60 (m, 3H), 7.10 (m, 1H), 4.32 (m, 1H), 2.94 (d, J )
5.8 Hz, 1H), 2.50 (m, 2H), 2.1 (m, 1H), 1.80 (m, 1H), 1.4 (m, 2H),
0.87 (d, J ) 6.8 Hz, 3H), 0.50 (d, J ) 6.8 Hz, 3H). 13C NMR
(CDCl3): δ 144.77, 143.97, 140.00, 133.19, 129.04, 127.91, 66.57,
39.73, 30.33, 27.98, 20.19, 19.07, 15.80. LRMS: (EI) 262 (highest
mass), 77 (base peak). (CI) 281 (M + H). HRMS: calculated for
C15H20O3S 280.1133, found 280.1129. mp 105 °C. [R]D (c 5.22, CHCl3)
) -24°.
(3S,6R)-(6-Isopropyl-3-methoxycyclohex-1-enesulfonyl)-
benzene (13t-Pr). Quantitative yield. White solid. mp 113 °C. 1H NMR
(CDCl3): δ 7.95 (m, 2H), 7.60 (m, 3H), 7.13 (m, 1H), 3.87 (m, 1H),
3.44 (s, 3H), 2.50 (m, 2H), 2.1 (m, 1H), 1.80 (m, 1H), 1.4 (m, 2H),
0.92 (d, J ) 6.8 Hz, 3H), 0.64 (d, J ) 6.8 Hz, 3H). 13C NMR
(CDCl3): δ 144.58, 141.72, 133.16, 129.03, 128.04, 75.29, 56.35, 39.93,
28.13, 27.10, 20.21, 15.95. LRMS: (EI) 294 (highest mass), 110 (base
peak). (CI) 295 (M + H). HRMS: calculated for C16H22O3S 294.1290,
found 294.1282. mp 113 °C. [R]D (c 1.44, CHCl3) ) -87°.
(R)-4-Isopropylcyclohex-2-enone (14iPr). 94% yield. Clear color-
General Procedure for the Conversion of γ-Methoxy Vinyl
Sulfones to Enones. First, 1.2 equiv of t-BuLi (0.61 mmol) was added
to the γ-methoxy vinyl sulfone (0.51 mmol) in 20 mL of THF at -78
°C over 2 min. The resulting bright orange reaction was stirred at this
temperature for 25 min. Ten milliliters of a saturated solution of
NaHCO3 was added, and the reaction was allowed to warm to room
temperature. The mixture was extracted into 40 mL of ether and
concentrated. Fifteen milliliters of THF was added followed by water
until the two solvents begin to separate. More THF was added just
until the solution becomes homogeneous. Next 0.5 mL of Et3N was
added, and the reaction was stirred for 15 h. Monitoring the reaction
was best accomplished by NMR. When complete, ether and water were
added, the organic layer was separated, and the solvent was removed
in vacuo. SGC, 8:2 Hex/EA, provided the desired enones in good yield.
(3S,6S)-(3-Methoxy-6-methylcyclohex-1-enesulfonyl)-benzene
1
less oil. H NMR (CDCl3): δ 6.94 (dt, J ) 10.4, 2.1 Hz, 1H), 6.04
(dd, J ) 10.4, 2.6 Hz, 1H), 2.56 (dt, J ) 16.6, 4.3 Hz, 1H), 2.40 (m,
2H), 2.10 (m, 1H), 1.80 (m, 2H), 1.01 (d, J ) 6.8 Hz, 3H), 1.00 (d, J
) 6.8 Hz, 3H). 94.7% ee HPLC Chiralcel AD 0.75 mL/min 99.5:0.5
Hex:2-propanol. 21.20 min minor enantiomer, 24.70 min major
enantiomer.
(1S,4R)-3-Benzenesulfonyl-4-tert-butylcyclohex-2-enol (12t-tBu).
1
93% yield. Sticky clear, colorless film. H NMR (CDCl3): δ 7.85 (d,
J ) 9.5 Hz, 2H), 7.60 (m, 3H), 6.86 (d, J ) 2.1 Hz, 1H), 4.32 (m,
1H), 2.56 (m, 2H), 2.17 (m, 1H), 1.84 (m, 1H), 1.53 (m, 1H), 1.37 (m,
1H), 1.03 (s, 9H). 13C NMR (CDCl3): δ 145.92, 144.25, 140.19, 133.16,
129.06, 128.03, 64.20, 42.10, 34.92, 29.88, 29.12, 22.40. LRMS: (EI)
261 (highest mass), 220 (base peak). (CI) 295 (M + H). HRMS:
calculated for C16H22O3S 294.1290, found 294.1277. [R]D (c 7.35,
CHCl3) ) -107°.
(3S,6R)-(6-tert-Butyl-3-methoxycyclohex-1-enesulfonyl)-
benzene (13t-tBu). 98% yield. White oily solid. 1H NMR (CDCl3): δ
7.85 (d, J ) 9.5 Hz, 2H), 7.60 (m, 3H), 6.91 (d, J ) 2.6 Hz, 1H), 3.85
(m, 1H), 3.32 (s, 3H), 2.59 (dd, J ) 6.1, 3.1 Hz, 1H), 2.14 (m, 1H),
1.84 (m, 1H), 1.54 (m, 1H), 1.31 (m, 1H), 1.05 (s, 9H). 13C NMR
(CDCl3): δ 146.54, 142.28, 140.53, 133.14, 129.09, 128.11, 73.09,
56.42, 42.56, 35.22, 29.88, 26.12, 22.71, 10.22. LRMS: (EI) 293
(highest mass), 220 (base peak). (CI) 309 (M + H). HRMS: calculated
for C17H24O3S 308.1446, found 308.1436. [R]D (c 4.47, CHCl3) )
-142°.
1
(13t-Me). Quantitative yield. clear oil. H NMR (CDCl3): δ 7.85 (d,
J ) 9.5 Hz, 2H), 7.60 (m, 3H), 7.03 (d, J ) 2.6 Hz, 1H), 3.86 (m,
1H), 3.40 (s, 3H), 2.45 (m, 1H), 1.93-1.60 (m, 3H), 1.38 (m, 1H),
1.17 (d, J ) 7 Hz, 3H). 13C NMR (CDCl3): δ 147.17, 139.71, 136.63,
133.27, 129.13, 128.02, 73.04, 56.74, 28.68, 27.26, 23.90, 19.02. LRMS:
(EI) 266 (highest mass), 125 (base peak). (CI) 129 (M + H). HRMS:
calculated for C14H18O3S 267.1055, found 267.1053. [R]D (c 2.28,
CHCl3) ) -132°.
(S)-4-Methylcyclohex-2-enone (14Me). 93% yield. Clear colorless
1
oil. H NMR (CDCl3): δ 6.80 (ddd, J ) 10.2, 4.8, 2.2 Hz, 1H), 5.94
(dd, J ) 10.2, 4.8 Hz, 1H), 2.60-2.30 (m, 3H), 2.10 (m, 1H), 1.67
(m, 1H), 1.16 (d, J ) 7 Hz, 3H). [R]D (c 0.56, CHCl3) ) -116°.
(1S,4S)-3-Benzenesulfonyl-4-ethylcyclohex-2-enol (12t-Et). 92%
1
yield. Clear colorless oil. H NMR (CDCl3): δ 7.85 (d, J ) 9.5 Hz,
2H), 7.60 (m, 3H), 6.98 (d, J ) 3.4 Hz, 1H), 4.32 (m, 1H), 3.16 (d, J
) 6 Hz, 1H), 2.29 (m, 1H), 2.00-1.40 (m, 5H), 1.22 (m, 1H), 0.78 (t,
J ) 7.3 Hz, 3H). 13C NMR (CDCl3): δ 145.61, 139.89, 139.61, 133.24,
129.06, 127.74, 64.03, 34.80, 26.93, 24.07, 21.55, 11.28. LRMS: (EI)
266 (highest mass), 125 (base peak). (CI) 267 (M + H). HRMS:
calculated for C14H18O3S 266.0977, found 266.0975. [R]D (c 9.07,
CHCl3) ) -87°.
(S)-4-tert-Butylcyclohex-2-enone (14tBu). 89% yield. 1H NMR
(CDCl3): δ 7.05 (dt, J ) 10.5, 2.0 Hz, 1H), 6.07 (ddd, J ) 10.5, 2.9,
1.2 Hz, 1H), 2.56 (dt, J ) 16.5, 3.4 Hz, 1H), 2.40 (m, 1H), 2.23 (m,
1H), 2.18 (m, 1H), 1.8 (m, 1H), 1.01 (s, 9H). 91% ee HPLC Chiralcel
AD 1.0 mL/min 99:1 Hex:2-propanol. 10.60 min minor enantiomer,
13.86 min major enantiomer.
(3S,6S)-(6-Ethyl-3-methoxycyclohex-1-enesulfonyl)-benzene
(13t-Et). 97% yield. Clear colorless oil. 1H NMR (CDCl3): δ 7.85 (d,
J ) 9.5 Hz, 2H), 7.60 (m, 3H), 7.05 (d, J ) 3.2 Hz, 1H), 3.86 (m,
(1S,4S)-3-Benzenesulfonyl-4-(dimethylphenylsilanyl)cyclohex-2-
enol (12t-PhMe2Si). 87% yield. Clear colorless oil. 1H NMR
(CDCl3): δ 7.76-7.33 (m, 10H), 6.80 (d, J ) 3.7 Hz, 1H), 4.20 (m,
9
J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002 11097

A R T I C L E S
Evarts et al.
1H), 2.06 (m, 2H), 1.60 (m, 4H), 0.55 (s, 3H), 0.48 (s, 3H). 13C NMR
(CDCl3): δ 146.48, 138.72, 137.96, 134.81, 134.08, 133.25, 129.04,
128.11, 127.64, 62.97, 29.41, 24.90, 21.39, 13.65, 10.35, -1.83, -1.94.
LRMS: (EI) 372 (highest mass), 135 (base peak). (CI) 372 (M+).
HRMS: calculated for C20H24O3SSi 372.1215, found 372.1197. [R]D
(c 3.49, CHCl3) ) -174°.
(1S,4S)-(2-Benzenesulfonyl-4-methoxycyclohex-2-enyl)-1-dimeth-
ylphenylsilane (13t-PhMe2Si). 93% yield. Clear colorless oil. 1H NMR
(CDCl3): δ 7.76-7.35 (m, 10H), 6.92 (m, 1H), 3.66 (m, 1H), 3.36 (s,
3H), 2.01 (m, 1H), 1.60 (m, 4H), 1.40 (m, 1H), 0.56 (s, 3H), 0.49 (s,
3H). 13C NMR (CDCl3): δ 146.63, 138.94, 138.06, 134.10, 133.24,
133.15, 129.03, 129.00, 128.09, 127.63, 71.83, 56.61, 26.07, 25.00,
21.86, -1.86, -1.95. LRMS: (EI) 386 (highest mass), 135 (base peak).
HRMS: calculated for C21H26O3SSi 386.1372, found 386.1355. [R]D
(c 3.00, CHCl3) ) -186°.
(1S,4S)-3-Benzenesulfonyl-4-methylcyclohept-2-enol (25). 93%
yield. Clear colorless oil. 1H NMR (CDCl3): δ 7.85 (m, 2H), 7.55 (m,
3H), 7.20 (m, 1H), 4.63 (m, 1H), 3.40 (d, J ) 4.9 Hz, 1H), 2.78 (m,
1H), 2.00-1.40 (m, 5H), 1.20 (m, 1H), 0.95 (d, J ) 6.2 Hz, 3H). 13C
NMR (CDCl3): δ 148.27, 143.80, 138.76, 133.17, 129.03, 127.95,
70.71, 35.83, 31.94, 31.71, 20.52, 16.10. LRMS: (EI) 237 (highest
mass), 125 (base peak). (CI) 267 (M + H). HRMS: calculated for
C14H18O3S 266.0977, found 266.0964. [R]D (c 2.26, CHCl3) ) -21°.
reaction was filtered through a 1:1 mixture of Celite and SiO2. The
resulting enones did not require purification and were routinely used
crude.
General Procedure for Generation of â-Substituted Enones via
Addition/Elimination. Alkyl cuprates, prepared as above, were added
to â-sulfonyl-enones at -78 °C in THF. The reactions were allowed
to warm slowly to room temperature overnight. Ether and water were
added to the reactions. The organic layer was dried and concentrated
in vacuo. SGC, 8:2, Hex:EA, provided the desired enones in the yields
indicated with the remaining mass recovered as unreacted starting
material.
(S)-3-Benzenesulfonyl-4-methylcyclohex-2-enone (17a). 92% yield.
1
Clear colorless oil. H NMR (CDCl3): δ 7.95 (m, 2H), 7.69 (m, 3H),
6.57 (s, 1H), 2.93 (m, 1H), 2.63 (ddd, J ) 18.7, 13.6, 5.2 Hz, 1H),
2.44 (dt, J ) 17.9, 3.8 Hz, 1H), 2.09 (m, 1H), 1.94 (m, 1H), 1.33 (d,
J ) 6.4 Hz, 3H). 13C NMR (CDCl3): δ 197.78, 163.83, 137.82, 134.35,
130.00, 129.54, 128.66, 32.86, 30.13, 28.50, 18.19. LRMS: (EI) 250
(highest mass), 81 (base peak). (CI) 251 (M + H). HRMS: calculated
for C13H14O3S 250.0664, found 250.0660. [R]D (c 5.19, CHCl3) ) -11°.
(R)-3-Benzenesulfonyl-4-isopropylcyclohex-2-enone (17b). 91%
yield. Clear colorless oil. 1H NMR (CDCl3): δ 7.95 (m, 2H), 7.68 (m,
3H), 6.61 (m, 1H), 2.82 (m, 1H), 2.65-2.30 (m, 3H), 2.20 (m, 1H),
1.92 (m, 1H), 1.12 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 6.9 Hz, 3H). 13
C
NMR (CDCl3): δ 198.14, 162.75, 138.33, 134.25, 131.89, 129.50,
128.60, 39.38, 34.81, 30.29, 22.92, 21.55, 18.79. LRMS: (EI) 278
(highest mass), 236 (base peak). (CI) 279 (M + H). HRMS: calculated
for C15H18O3S 278.0977, found 278.0968. [R]D (c 1.71, CHCl3) ) -75°.
(S)-3,4-Dimethylcyclohex-2-enone (14a). 92% yield. Clear colorless
(3S,7S)-1-Benzenesulfonyl-3-methoxy-7-methylcycloheptene (26).
1
88% yield. Clear colorless oil. H NMR (CDCl3): δ 7.85 (m, 2H),
7.55 (m, 3H), 7.20 (m, 1H), 4.63 (dt, J ) 11.4, 2.1 Hz, 1H), 2.80 (m,
1H), 2.00-1.20 (m, 6H), 1.00 (d, J ) 7.2 Hz, 3H). 13C NMR (CDCl3):
δ 145.45, 145.08, 138.95, 133.11, 129.00, 128.02, 79.80, 56.60, 32.23,
31.93, 31.79, 20.72, 16.24. LRMS: (EI) 280 (highest mass), 239 (base
peak). (CI) 281 (M + H). HRMS: calculated for C15H20O3S 280.1133,
found 280.1126. [R]D (c 8.06, CHCl3) ) -74°.
1
oil. H NMR (CDCl3): δ 5.80 (t, J ) 1.2 Hz, 1H), 2.50-2.20 (m,
3H), 2.10 (m, 1H), 1.75 (m, 1H), 1.18 (d, J ) 7.1 Hz, 3H). 13C NMR
(CDCl3): δ 199.60, 166.59, 126.26, 34.48, 34.29, 30.24, 22.66, 17.66.
[R]D (c 0.51, CHCl3) ) +106°.
(S)-4-Methylcyclohept-2-enone (27). 90% yield. Conversion to
(S)-3-Allyl-4-methylcyclohex-2-enone (14b). 96% allyl bromide
1
enone required 3 days. Clear colorless oil. H NMR (CDCl3): δ 6.36
1
capture. Clear, light yellow oil. H NMR (CDCl3): δ 5.86 (s, 1H),
(ddd, J ) 12.2, 3.6, 0.8 Hz, 1H), 5.96 (dd, J ) 12.2, 2.4 Hz, 1H), 2.63
(m, 3H), 1.96 (m, 1H), 1.83 (m, 2H), 1.55 (m, 1H), 1.20 (d, J ) 7.2
Hz, 3H). 13C NMR (CDCl3): δ 204.42, 151.68, 130.61, 43.60, 35.65,
34.27, 21.88, 20.63. [R]D (c 2.03, CHCl3) ) -94°.
5.83 (m, 1H), 5.19 (m, 2H), 3.00 (d, J ) 7.0 Hz, 2H), 2.53 (m, 2H),
2.36 (m, 1H), 2.16 (m, 1H), 1.83 (m, 1H), 1.24 (d, J ) 7.2 Hz, 3H).
13C NMR (CDCl3): δ 199.41, 167.93, 133.52, 125.68, 118.11, 39.80,
34.12, 32.84, 30.10, 17.53. LRMS: (EI) 150 (highest mass), 79 (base
peak). (CI) 151 (M + H). HRMS: calculated for C10H14O 150.1045,
found 150.1043. [R]D (c 1.40, CHCl3) ) -153°.
General Procedure for Generation of â-Substituted Enones via
Electrophile Capture. Following the general procedure for the
conversion of γ-methoxy vinyl sulfones to enones, the orange anionic
solution was quenched with 1.1 equiv of the desired electrophile. The
reaction decolorizes at -78 °C after 15 min. A saturated solution of
NaHCO3 was added followed by ether. The organic layer was dried
over MgSO4 and concentrated in vacuo. The residue was dissolved in
CHCl3 1 mL/mmol, and SiO2 250 mg/mmol was added. After 2 h, the
solution was filtered, and the solvent was removed in vacuo. The enones
are typically 90-95% pure. Silica gel chromatography can be used if
necessary.
(S)-3-Isopropyl-4-methylcyclohex-2-enone (14c). 45% yield, i-
1
PrCu(CN)Li addition. Clear colorless oil. H NMR (CDCl3): δ 5.87
(m, 1H), 2.53 (m, 2H), 2.34 (dt, J ) 17.4, 5.1 Hz, 1H), 2.12 (m, 1H),
1.84 (m, 1H), 1.24 (d, J ) 6.9 Hz, 3H), 1.15 (d, J ) 6.6 Hz, 3H), 1.13
(d, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ 200.09, 176.52, 122.43,
33.64, 32.93, 32.38, 30.26, 22.30, 20.68, 17.89. LRMS: (EI) 152
(highest mass), 109 (base peak). (CI) 153 (M + H). HRMS: calculated
for C10H16O 152.1201, found 152.1199. [R]D (c 0.43, CHCl3) ) +119°.
(R)-4-Isopropyl-3-methylcyclohex-2-enone (14d). 90% yield MeI
capture, 60% yield MeCu(CN)Li addition. Clear colorless oil. 1H NMR
(CDCl3): δ 5.95 (m, 1H), 2.48 (ddd, J ) 17.1, 7.2, 5.1 Hz, 1H), 2.27
(m, 2H), 2.00 (m, 1H), 1.99 (m, 3H), 1.93 (m, 2H), 1.06 (d, J ) 6.9
Hz, 3H), 0.86 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3): δ 200.32,
165.75, 128.86, 45.94, 36.51, 29.18, 23.82, 22.61, 21.92, 18.38. 93%
ee HPLC Chiralcel AD 1.0 mL/min 97.5:2.5 Hex:2-propanol. 7.68 min
minor enantiomer, 8.36 min major enantiomer.
(4S)-3-Allyl-4-isopropylcyclohex-2-enone (14e). Using HMPA,
92% yield allyl bromide capture. Clear colorless oil. 1H NMR
(CDCl3): δ 5.92 (m, 1H), 5.77 (m, 1H), 2.98 (d, J ) 6.9 Hz, 2H),
2.47 (m, 1H), 2.22 (m, 3H), 1.94 (m, 2H), 1.03 (d, J ) 6.7 Hz, 3H),
0.87 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3): δ 199.75, 166.74, 133.85,
127.47, 43.83, 40.49, 35.46, 28.83, 22.43, 21.47, 18.39. LRMS: (EI)
178 (highest mass), 135 (base peak). HRMS: calculated for C12H18O
178.1358, found 178.1354. [R]D (c 6.80, CHCl3) ) -69°.
HMPA-Modified Procedure for Generation of â-Substituted
Enones via Electrophile Capture. First, 1.2 equiv of t-BuLi (0.61
mmol) was added to the mixture of γ-methoxy vinyl sulfone (0.51
mmol) and HMPA (2.5 mmol) in 20 mL of THF at -78 °C over 2
min. The resulting dark orange reaction was stirred at this temperature
for 10 min. The solution was quenched with 3.1 equiv of the desired
electrophile. The reaction decolorizes at -78 °C after 15 min. A
saturated solution of NaHCO3 was added followed by ether. The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue
was dissolved in CHCl3 1 mL/mmol, and SiO2 250 mg/mmol was
added. After 3 h, the solution was filtered, and the solvent was removed
in vacuo. The enones are typically 90-95% pure. Silica gel chroma-
tography can be used if necessary.
General Procedure for the Oxidation of γ-Hydroxy Vinyl
Sulfones. First, 2 mmol of γ-hydroxy vinyl sulfone was dissolved in
100 mL of ether. Activated MnO2 was added portionwise with rapid
stirring until the reaction was complete as determined by TLC. The
(4R)-3-Butyl-4-isopropylcyclohex-2-enone (14g). Using HMPA,
84% yield butyl iodide capture. Clear colorless oil. 1H NMR (CDCl3):
9
11098 J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002

Syntheses of Highly Substituted Enantiopure Enones
A R T I C L E S
1
δ 5.91 (m, 1H), 2.46 (m, 1H), 2.20 (m, 5H), 1.93 (m, 2H), 1.42 (m,
4H), 1.03 (d, J ) 6.7 Hz, 3H), 0.92 (t, J ) 7.2 Hz, 3H), 0.86 (d, J )
6.7 Hz, 3H). 13C NMR (CDCl3): δ 199.93, 169.32, 126.64, 43.90,
36.70, 35.47, 29.85, 28.98, 22.48, 21.51, 18.46, 13.85. LRMS: (EI)
194 (highest mass), 110 (base peak). HRMS: calculated for C13H22O
194.1671, found 1941675. [R]D (c 5.8, CHCl3) ) -12°.
and a 9:1 ratio of diastereomers. H NMR (CDCl3): δ 7.88 (m, 2H),
7.61 (m, 3H), 5.97 (m, 1H), 5.54 (m, 1H), 4.17 (m, 1H), 3.62 (m, 1H),
2.47 (m, 1H), 2.28 (m, 1H), 2.05 (m, 1H), 1.77 (m, 1H), 1.07 (d, J )
6.9 Hz, 3H). 13C NMR (CDCl3): δ 137.9, 133.7, 132.3, 129.1, 128.9,
117.5, 68.6, 66.2, 32.7, 30.3, 15.5. LRMS: (CI) highest mass 253 (M
+ H), base peak 143. HRMS: (CI) calculated for C13H16O3S 253.0898,
found 253.0905.
(R)-4-Isopropyl-2-methylcyclohex-2-enone (19). Three equivalents
of MeLi (1.5 mmol) was added to 140 mg (0.5 mmol) of 12t-iPr in 20
mL of THF at -78 °C. After 1 h, ether and water were added to the
reaction. The organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was dissolved in 20 mL of acetone and cooled to
0 °C. Jones reagent was added until an orange color persisted. Several
drops of 2-propanol were added to bring the reaction back to green.
The entire contents of the flask were filtered through a plug of fluorosil,
and the solvent was removed in vacuo. The residue was dissolved in
20 mL of CHCl3, 0.76 g (0.5 mmol) of DBU was added, and the
reaction was heated to reflux for 2 h. The solvent was removed in vacuo.
The crude material was loaded directly onto silica. SGC, 8:2, Hex:EA,
(1S,5S,6S)-5-Benzenesulfonyl-6-isopropylcyclohex-3-enol (22Pr).
To a solution of epoxy-dienyl sulfone SS-9a (0.350 g, 1.5 mmol) in
THF (10 mL) at -78 °C was slowly added LiHMDS (1.6 mL, 1.6
mmol). The solution was stirred for 30 min, followed by addition of a
saturated solution of NH4Cl (5 mL). Et2O (5 mL) was added to the
mixture and separated. The aqueous layer was extracted with Et2O (2
× 5 mL), and the organic layers are combined, dried over MgSO4, and
concentrated. To the resulting solid in THF (10 mL) at -78 °C was
slowly added iPrMgCl (3.7 mL, 7.4 mmol) over a period of 15 min;
addition must be done slowly to minimize aromatization. The orange
solution was stirred for 20 min, and the temperature was allowed to
slowly rise to -10 °C over a period of 1 h. The solution was quenched
by slowly adding a solution of saturated NH4Cl (10 mL). The
temperature was allowed to rise to 25 °C, and diethyl ether was added
(10 mL). The organic layer was separated, and the aqueous layer was
extracted with diethyl ether (2 × 10 mL). The organic layers were
combined, dried over MgSO4, and concentrated. The resultant mixture
was filtered through a 1 in. silica gel plug eluting with a 3:1 mixture
of ethyl acetate:hexanes to give 0.375 g of the desired sulfone as an
oil in 89% yield and a 30:1 ratio of diastereomers. 1H NMR (CDCl3):
δ 7.88 (m, 2H), 7.59 (m, 3H), 5.99 (m, 1H), 5.66 (m, 1H), 4.31 (m,
1H), 3.77 (m, 1H), 2.17 (m, 4H), 0.81 (d, J ) 6.9 Hz, 3H), 0.76 (d, J
) 6.9 Hz, 3H). 13C NMR (CDCl3): δ 137.6, 133.7, 133.2, 129.1, 129.0,
118.5, 65.6, 63.9, 42.6, 31.5, 24.8, 22.1, 19.7. LRMS: (CI) highest
mass 281 (M + H), base peak 143. HRMS: (CI) calculated for
C15H20O3S 281.1211, found 281.1199.
1
provided 19 as a clear colorless liquid. 57 mg, 75% yield. H NMR
(CDCl3): δ 6.68 (m, 1H), 2.56 (dt, J ) 16.6, 4.3 Hz, 1H), 2.33 (m,
2H), 2.00 (m, 1H), 1.81 (dd, J ) 2.4, 1.4 Hz, 3H), 1.76 (m, 2H), 0.99
(d, J ) 6.7 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 3H). 13C NMR (CDCl3): δ
200.35, 149.45, 135.45, 42.82, 37.61, 31.70, 25.62, 19.64, 19.40, 16.10.
91.2% ee HPLC Chiralcel AD 1.0 mL/min 99:1 Hex:2-propanol. 5.79
min minor enantiomer, 6.49 min major enantiomer.
(4R)-4-Isopropyl-2,3-dimethylcyclohex-2-enone (21). Three equiva-
lents of MeLi (1.65 mmol) was added to a mixture of 157 mg (0.55
mmol) of 12t-iPr and HMPA (0.48 mL, 2.75 mmol) in 6 mL of THF
at -78 °C. After 30 min, methyl iodide (0.17 mL, 2.75 mmol) was
added, and the temperature was allowed to rise to -30 °C. Ether (10
mL) and water (5 mL) were added to the reaction, and the mixture
was then extracted. The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was dissolved in 10 mL of acetone
and cooled to 0 °C. Jones reagent was added until an orange color
persisted. Several drops of 2-propanol were added to bring the reaction
back to green. The entire contents of the flask were filtered through a
plug of fluorosil, and the solvent was removed in vacuo. The residue
was dissolved in 20 mL of CHCl3, 0.123 mL (0.83 mmol) of DBU
was added, and the reaction was heated to reflux for 2 h. The solvent
was removed in vacuo. The crude material was loaded directly onto
silica. SGC, 8:2, hexane:ethyl acetate, provided 21 as a clear colorless
(2R,3S,4S)-(3-Benzenesulfonyl-2-methylcyclohept-4-enyloxy)-tert-
butyldimethylsilane (30). To a solution of dienyl sulfone 29 (0.322
g, 0.89 mmol) in THF (9 mL) at -78 °C was slowly added MeLi (1.8
mL, 1.95 mmol) in Et2O over a period of 10 min. The orange solution
was stirred for 20 min and was then quenched by slowly adding a
solution of saturated NH4Cl (10 mL). The temperature was allowed to
rise to 25 °C, and diethyl ether was added (10 mL). The organic layer
was separated, and the aqueous layer was extracted with diethyl ether
(2 × 10 mL). The organic layers were combined, dried over MgSO4,
and concentrated. The resultant mixture was filtered through a 1 in.
silica gel plug eluting with a 3:1 mixture of ethyl acetate:hexanes to
give 0.317 g of the desired sulfone as an oil in 94% yield and a 20:1
1
liquid. 83.7 mg, 92% yield. H NMR (CDCl3): δ 2.50 (m, 1H), 2.29
(m, 1H), 2.14 (m, 2H), 1.90 (m, 9H), 1.02 (d, J ) 6.6 Hz, 3H), 0.85
(d, J + 6.6 Hz, 3H). 13C NMR (CDCl3): δ 199.01, 158.04, 132.11,
46.86, 35.24, 29.44, 22.15, 21.51, 20.67, 18.68, 11.32. LRMS: (EI)
166 (highest mass), 124 (base peak). HRMS: calculated for C11H18O
166.1358, found 166.1355. [R]D (c 1.40, CHCl3) ) +10°.
1
ratio of diastereomers. H NMR (CDCl3): δ 7.87 (m, 2H), 7.58 (m,
3H), 6.03 (m, 1H), 5.87 (m, 1H), 4.60 (m, 1H), 3.83 (m, 1H), 2.42 (m,
4H), 1.77 (m, 1H), 1.63 (m, 1H), 1.41 (m, 1H), 1.09 (d, J ) 7.0 Hz,
3H), 0.85 (s, 9H), -0.02 (s, 3H), -0.08 (s, 3H). 13C NMR (CDCl3):
δ 139.0, 134.9, 133.4, 129.1, 128.5, 123.2, 73.6, 62.3, 35.9, 27.1, 25.7,
20.0, 17.9, 12.3, -5.1. LRMS: (CI) highest mass 381 (M + H), base
peak 249. HRMS: (CI) calculated for C20H32O3SSi 381.1920, found
381.1917.
Procedure for Nucleophilic Addition to γ-Hydroxy Dienyl Sul-
fones. (1S,5S,6S)-5-Benzenesulfonyl-6-methylcyclohex-3-enol (22Me).
To a solution of epoxy-dienyl sulfone SS-9a (0.377 g, 1.6 mmol) in
THF (10 mL) at -78 °C was slowly added LiHMDS (1.8 mL, 1.8
mmol). The solution was stirred for 30 min, followed by addition of
saturated solution of NH4Cl (5 mL). Et2O (5 mL) was added to the
mixture and separated. The aqueous layer was extracted with Et2O (2
× 5 mL), and the organic layers are combined, dried over MgSO4, and
concentrated. The resulting solid was dissolved in THF (10 mL) at
-78 °C, and MeLi (3.4 mL, 4.8 mmol) in Et2O was added over a period
of 15 min; addition must be done slowly to minimize aromatization.
The orange solution was stirred for 20 min and then quenched by slowly
adding a solution of saturated NH4Cl (5 mL). The temperature was
allowed to rise to 25 °C, and diethyl ether was added (10 mL). The
organic layer was separated, and the aqueous layer was extracted with
diethyl ether (2 × 10 mL). The organic layers were combined, dried
over MgSO4, and concentrated. The resultant mixture was filtered
through a 1 in. silica gel plug eluting with a 3:1 mixture of ethyl acetate/
hexanes to give 0.370 g of the desired sulfone as an oil in 92% yield
General Procedure for Molybdenum-Catalyzed Epoxidations. To
a solution of hydroxy allyl sulfone (0.98 mmol) in benzene (10 mL)
was added solid molybdenum hexacarbonyl (0.005 g, 0.021 mmol, 5
mol %). The solution was heated to reflux, and tert-butyl hydrogen-
peroxide (0.312 mL, 1.56 mmol) in decanes was slowly added over a
period of 5 min. The solution was heated at reflux for 1.5 h. The reaction
was allowed to cool to 25 °C, and diethyl ether (10 mL) was added to
the reaction mixture. The mixture was washed with a saturated solution
of sodium bisulfite (5 mL), and the organic layer was concentrated.
The resultant mixture was filtered through a 1 in. silica gel plug eluting
with a 1:1 mixture of ethyl acetate/hexanes, which upon concentration
affords epoxy sulfone as a crystalline solid in a high yields and the
same ratio as that of the corresponding starting material. The crystalline
9
J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002 11099

A R T I C L E S
Evarts et al.
product can be further recrystallized from chloroform and hexanes to
separate the diastereomers.
22.0, 17.9, -4.7, -5.0. LRMS: (CI) highest mass 411 (M + H), base
peak 137. HRMS: (CI) calculated for C21H34O4SSi 411.2025, found
411.2005. [R]D (c 38.0, CHCl3) ) -1°.
(1R,3S,4S,5R,6R)-5-Benzenesulfonyl-4-methyl-7-oxabicyclo[4.1.0]-
heptan-3-ol (23Me a). 99% yield 6:1 ratio, after recrystallization 83%
General Procedure for Base-Induced Epoxide Opening Followed
by Etherification of γ-Hydroxy Vinyl Sulfones. To a solution of the
silylated epoxy sulfone (0.25 mmol) in THF (2.5 mL) was added DBU
(0.30 mmol). The stirring solution was heated to reflux for 1 h. The
temperature was lowered to room temperature, and diethyl ether (5
mL) was added to the mixture followed by water (5 mL). The organic
phase was separated and concentrated. The resulting mixture was filtered
through a 1 in. silica gel plug eluting with a 1:1 solution of ethyl acetate/
hexanes, which upon concentration gives the vinyl sulfone in high yield.
Etherification is performed as explained previously.
1
yield 30:1 ratio. H NMR (CDCl3): δ 7.96 (m, 2H), 7.67 (m, 3H),
3.64 (m, 1H), 3.58 (d, J ) 3.8 Hz, 1H), 3.51 (d, J ) 9.3 Hz, 1H), 3.40
(m, 1H), 2.68 (d, J ) 10.8 Hz, 1H, (OH)), 2.40 (ddd, J ) 15.7 Hz, 5.6
Hz, 2.7 Hz, 1H), 2.03 (m, 1H), 1.90 (dddd, 15.7 Hz, 5.0 Hz, 3.8 Hz,
1.2 Hz, 1H), 1.25 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3): δ 137.9,
134.3, 129.6, 128.7, 69.2, 64.0, 53.4, 51.2, 32.4, 29.8, 18.8. LRMS:
(CI) highest mass 269 (M + H), base peak 233. HRMS: (CI) calculated
for C13H16O4S 269.0848, found 269.0852. mp 133.5-134.0 °C. [R]D
(c 2.90, CHCl3) ) +27°.
(1R,4S,5S)-3-Benzenesulfonyl-5-(tert-butyldimethylsilanyloxy)-4-
methylcyclohex-2-enol (24Me a). 96% yield. H NMR (CDCl3): δ
(1R,3S,4S,5R,6R)-5-Benzenesulfonyl-4-isopropyl-7-oxabicyclo-
[4.1.0]heptan-3-ol (23Pr a). 95% >50:1 ratio. H NMR (CDCl3): δ
1
1
7.88 (m, 2H), 7.58 (m, 3H), 6.92 (d, J ) 3.2 Hz, 1H), 4.43 (m, 1H),
3.75 (m, 1H), 2.60 (m, 1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.02 (d, J )
6.9 Hz, 3H), 0.82 (s, 9H), 0.01 (s, 3H), -0.04 (s, 3H). 13C NMR
(CDCl3): δ 145.1, 139.9, 138.7, 133.4, 129.2, 128.0, 69.0, 66.0, 35.3,
35.2, 25.7, 18.0, 13.7, -4.8, -5.0. LRMS: (CI) highest mass 383 (M
+ H), base peak 365. HRMS: (CI) calculated for C19H30O4SSi (M +
H - H2O) 365.1607, found 365.1595. [R]D (c 88.0, CHCl3) ) -2°.
(2S,3S,5R)-(3-Benzenesulfonyl-5-methoxy-2-methylcyclohex-3-
enyloxy)-tert-butyldimethylsilane (24Me b). Reaction time: 10 min;
98% yield. 1H NMR (CDCl3): δ 7.87 (m, 2H), 7.57 (m, 3H), 6.92 (d,
J ) 2.4 Hz, 1H), 4.03 (m, 1H), 3.65 (m, 1H), 3.40 (s, 3H), 2.59 (m,
1H), 1.97 (m, 1H), 1.70 (m, 1H), 0.95 (d, J ) 6.9 Hz, 3H), 0.83 (s,
9H), -0.03 (s, 3H), -0.04 (s, 3H). 13C NMR (CDCl3): δ 146.4, 139.8,
136.0, 133.4, 129.2, 128.1, 68.4, 56.3, 35.0, 31.6, 25.6, 18.0, 13.1, -4.9.
LRΜS: (CI) highest mass 397 (M + H), base peak 263. HRMS: (CI)
calculated for C20H32O4SSi 396.1791, found 396.1787. [R]D (c 27.0,
CHCl3) ) -0.5°.
(1R,4S,5S)-3-Benzenesulfonyl-5-(tert-butyldimethylsilanyloxy)-4-
isopropylcyclohex-2-enol (24Pr a). 99% yield. 1H NMR (CDCl3): δ
7.85 (m, 2H), 7.58 (m, 3H), 6.88 (d, J ) 3.4 Hz, 1H), 4.45 (m, 1H),
3.40 (dt, J ) 12.7 Hz, 4.0 Hz, 1H), 2.27 (m, 1H), 2.01 (m, 2H), 1.74
(m, 1H), 1.14 (d, J ) 7.0 Hz, 3H), 0.97 (d, J ) 7.3 Hz, 3H), 0.80 (s,
9H), -0.13 (s, 3H), -0.16 (s, 3H). 13C NMR (CDCl3): δ 144.1, 139.1,
133.4, 129.2, 128.4, 70.4, 66.2, 46.0, 35.8, 25.7, 25.2, 24.4, 21.8, 18.0,
-5.1, -5.2. LRMS: (CI) highest mass 411 (M + H), base peak 137.
HRMS: (CI) calculated for C21H34O4SSi 411.2025, found 411.2012.
mp 133.5-134.5 °C. [R]D (c 5.0, CHCl3) ) -60°.
7.94 (m, 2H), 7.67 (m, 3H), 4.05 (m, 1H), 3.89 (d, J ) 8.4 Hz, 1H),
3.61 (d, J ) 3.7 Hz, 1H), 3.38 (m, 1H), 2.28 (m, 2H), 1.88 (m, 1H),
1.74 (m, 1H), 1.06 (d, J ) 7.5 Hz, 3H), 1.03 (d, J ) 7.5 Hz, 3H). 13
C
NMR (CDCl3): δ 138.0 134.2, 129.5, 128.7, 64.8, 60.7, 53.4, 51.7,
30.2, 29.5, 20.6, 18.3. LRMS: (CI) highest mass 269 (M + H), base
peak 233. HRMS: (CI) calculated for C15H20O4S 297.1161, found
297.1173. mp 147.5-148.0 °C. >99% ee HPLC Chiralcel OD 1.0 mL/
min 90:10 Hex:2-propanol. 16.04 min minor enantiomer, 14.60 min
major enantiomer. [R]D (c 3.1, CHCl3) ) +63°.
(1R,2R,3R,4S,7R)-(2-Benzenesulfonyl-3-methyl-8-oxabicyclo[5.1.0]-
oct-4-yloxy)-tert-butyldimethylsilane (31). To a stirring solution of
allyl sulfone 30 (0.884 g, 2.33 mmol) in CH2Cl2 (23 mL) at room
temperature was added m-CPBA (1.56 g, 6.33 mmol). The mixture
was stirred for 18 h, at which point diethyl ether (20 mL) was added
followed by a saturated solution of sodium bisulfite (20 mL). The
organic phase was separated and washed with 10% NaOH (2 × 20
mL), and then dried over MgSO4 and concentrated to give 0.848 g of
1
the desired epoxy sulfone as a single diastereomer in 92% yield. H
NMR (CDCl3): δ 7.92 (m, 2H), 7.61 (m, 3H), 3.86 (m, 1H), 3.42 (m,
2H), 3.06 (m, 1H), 2.68 (m, 1H), 1.91 (m, 1H), 1.75 (m, 1H), 1.53 (m,
2H), 1.25 (d, J ) 7.5 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 3H), -0.01 (s,
3H). 13C NMR (CDCl3): δ 139.4, 133.7, 129.2, 128.5, 72.2, 63.6, 53.2,
51.6, 37.6, 26.3, 25.6, 22.1, 17.8, 13.0, -5.1, -5.2. LRMS: (EI) highest
mass 359 (M - C4H9), base peak 73. HRMS: (EI) calculated for
C20H32O4SSi 396.1791, found 396.1782.
General Procedure for Silyl Protection of the Epoxy Alcohols.
To a stirring solution of the epoxy sulfone (0.42 mmol) and triethyl-
amine (0.63 mmol) in CH2Cl2 (4.0 mL) at room temperature was added
tert-butyldimethylsilyl triflouromethylsulfonate (0.50 mmol). The solu-
tion was stirred for 30 min. Diethyl ether (10 mL) was added, and the
crude mixture was concentrated. The mixture was then filtered through
a 1 in. silica plug eluting with a 1:3 solution of ethyl acetate/hexanes
to give, after concentration, the desired protected alcohol in quantitative
yield.
(1R,3S,4S,5R,6R)-(5-Benzenesulfonyl-4-methyl-7-oxa-bicyclo[4.1.0]-
hept-3-yloxy)-tert-butyldimethylsilane (23Me b). Quantitative yield.
1H NMR (CDCl3): δ 7.91 (m, 2H), 7.62 (m, 3H), 4.15 (ddd, J ) 10.4
Hz, 6.3 Hz, 4.4 Hz, 1H), 3.59 (d, J ) 2.4 Hz, 1H), 3.35 (d, J ) 3.5
Hz, 1H), 3.25 (dd, J ) 5.0 Hz, 4.3 Hz, 1H), 2.32 (m, 1H), 1.98 (m,
2H), 1.01 (d, J ) 7.2 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H). 13C NMR
(CDCl3): δ 138.3 134.0, 129.4, 128.4, 65.7, 65.3, 52.1, 49.4, 31.8,
28.5, 14.1, -4.8, -4.9. LRMS: (CI) highest mass 383 (M + H), base
peak 383. HRMS: (CI) calculated for C19H30O4SSi 383.1712, found
383.1700. [R]D (c 5.0, CHCl3) ) +16°.
(1S,2S,5R)-(3-Benzenesulfonyl-2-isopropyl-5-methoxycyclohex-3-
enyloxy)-tert-butyldimethylsilane (24Pr b). Reaction time: 10 min;
1
98% yield. mp 133.5-134.5 °C. H NMR (CDCl3): δ 7.85 (m, 2H),
7.57 (m, 3H), 6.97 (d, J ) 3.5 Hz, 1H), 4.01 (m, 1H), 3.41 (s, 3H),
3.38 (m, 1H), 2.24 (m, 2H), 1.97 (m, 1H), 1.74 (m, 1H), 1.13 (d, J )
6.9 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 3H), 0.80 (s, 9H), -0.13 (s, 3H),
-0.16 (s, 3H). 13C NMR (CDCl3): δ 144.7, 139.2, 136.6, 133.3, 129.1,
128.4, 74.6, 70.5, 56.6, 49.1, 32.8, 25.7, 25.3, 24.5, 21.6, 18.0, -5.1,
-5.2. LRMS: (CI) highest mass 424 (M + H), base peak 133.
HRMS: (CI) calculated for C21H34O4SSi 425.2182, found 425.2176.
[R]D (c 3.0, CHCl3) ) -39°.
(1R,4R,5S)-3-Benzenesulfonyl-5-(tert-butyldimethylsilanyloxy)-4-
methylcyclohept-2-enol (32). Reaction time: 5 h; 97% yield. 1H NMR
(CDCl3): δ 7.87 (m, 2H), 7.55 (m, 3H), 7.19 (d, J ) 3.5 Hz, 1H),
4.51 (m, 1H), 3.80 (ddd, J ) 7.2 Hz, 4.6 Hz, 2.3 Hz, 1H), 2.86 (dq, J
) 7.3 Hz, 2.1 Hz, 1H), 2.65 (d, J ) 6.6 Hz, 1H, (OH)), 2.14 (m, 1H),
1.92 (m, 1H), 1.80 (m, 1H), 1.69 (m, 1H), 0.97 (d, J ) 7.3 Hz, 3H),
0.75 (s, 9H), -0.07 (s, 3H), -0.19 (s, 3H). 13C NMR (CDCl3): δ 145.5,
142.5, 139.5, 133.1, 129.1, 128.5, 71.0, 70.0, 40.0, 28.6, 28.0, 25.8,
18.0, 16.3, -5.0, -5.5. LRMS: (EI) highest mass 339 (M - C4H9),
base peak 75. (CI) highest mass 397 (M + H), base peak 379. HRMS:
(EI) calculated for C20H32O4SSi 396.1791, found 396.1772.
(1R,3S,4S,5R,6R)-(5-Benzenesulfonyl-4-isopropyl-7-oxa-bicyclo-
[4.1.0]hept-3-yloxy)-tert-butyldimethylsilane (23Pr b). Quantitative
1
yield. H NMR (CDCl3): δ 7.93 (m, 2H), 7.64 (m, 3H), 4.41 (ddd, J
) 11.1 Hz, 6.9 Hz, 4.3 Hz, 1H), 3.84 (m, 1H), 3.42 (m, 1H), 3.31 (m,
1H), 1.98 (m, 4H), 0.91 (d, J ) 6.6 Hz, 3H), 0.88 (s, 9H), 0.66 (d, J
) 6.4 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H). 13C NMR (CDCl3): δ 138.3,
134.0, 129.4, 128.5, 67.0, 62.6, 52.5, 48.8, 42.6, 29.0, 26.9, 25.8, 23.5,
(1S,2R,5R)-(3-Benzenesulfonyl-5-methoxy-2-methylcyclohept-3-
enyloxy)-tert-butyldimethylsilane (33). Reaction time: 10 min; 98%
9
11100 J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002

Syntheses of Highly Substituted Enantiopure Enones
A R T I C L E S
1
yield. White solid. mp 116.0-117.5 °C. H NMR (CDCl3): δ 7.84
was allowed to warm to room temperature. The mixture was extracted
into diethyl ether (5 mL) and concentrated in vacuo. CHCl3 (1 mL)
was added followed by SiO2 (0.500 g), and the reaction was stirred for
4 h. Monitoring the reaction was best accomplished by NMR. When
complete, the silica was filtered, and the solution was concentrated.
Silica gel chromatography eluting with 1:4 ethyl acetate/hexanes
(m, 2H), 7.52 (m, 3H), 7.19 (m, 1H), 3.95 (dt, J ) 11.4 Hz, 2.9 Hz,
1H), 3.74 (m, 1H), 3.38 (s, 3H), 2.82 (dq, J ) 12.1 Hz, 7.3 Hz, 1H),
1.78 (m, 4H), 0.93 (d, J ) 7.5 Hz, 3H), 0.72 (s, 9H), -0.10 (s, 3H),
-0.21 (s, 3H). 13C NMR (CDCl3): δ 145.5, 142.5, 139.5, 133.1, 129.1,
128.5, 71.0, 70.0, 40.0, 28.6, 28.0, 25.8, 18.0, 16.3, -5.0, -5.5.
LRMS: (CI) highest mass 411 (M + H), base peak 411. HRMS: (CI)
calculated for C21H34O4SSi 411.2025, found 411.2030.
Enone Formation. (4R,5S)-5-(tert-Butyldimethylsilanyloxy)-3,4-
dimethylcyclohex-2-enone (25Me). t-BuLi (0.32 mL, 0.38 mmol) was
slowly added to a mixture of HMPA (0.17 mL, 0.95 mmol) and
γ-methoxy vinyl sulfone 24Me (0.08 g, 0.19 mmol) in 2 mL of THF
at -78 °C. The resulting bright orange mixture was stirred at -78 °C
for 5 min. Iodomethane (0.06 mL, 0.95 mmol) was added and was
stirred for 15 min. One milliliter of a saturated solution of NaHCO3
was added, and the reaction was allowed to warm to room temperature.
The mixture was extracted into diethyl ether (4 mL) and concentrated
in vacuo. CHCl3 (1 mL) was added followed by SiO2 (0.500 g), and
the reaction was stirred for 2 h. Monitoring the reaction was best
accomplished by 1H NMR. When complete, the silica was filtered, and
the solution was concentrated. Silica gel column purification eluting
with 1:4 ethyl acetate/hexanes provided the desired enone in 0.044 g,
1
provided the desired enone in 0.011 g, 84% yield. H NMR (CDCl3):
δ 5.85 (s, 1H), 3.87 (ddd, J ) 8.1 Hz, 5.6 Hz, 2.4 Hz, 1H), 2.84 (dq,
J ) 16.3 Hz, 10.8 Hz, 1H), 2.49 (m, 2H), 2.04 (m, 1H), 1.92 (d, J )
1.2 Hz, 3H), 1.82 (m, 1H), 1.14 (d, J ) 7.3 Hz, 3H), 0.88 (s, 9H), 0.06
(s, 6H). 13C NMR (CDCl3): δ 204.2, 155.4, 128.5, 72.7, 47.6, 37.8,
27.5, 26.4, 18.1, 18.0, -4.7, -4.9. LRMS: (EI) highest mass 211 (M
+ H - C4H9), base peak 75. HRMS: (EI) calculated for C15H28O2Si
268.1859, found 268.1848. 99.2% ee HPLC Chiralcel AD 1.0 mL/min
99.0:1.0 Hex:2-propanol. 11.18 min minor enantiomer, 9.27 min major
enantiomer. [R]D (c 0.4, CHCl3) ) +50°.
(4S,5S)-5-(tert-Butyldimethylsilanyloxy)-2,4-dimethylcyclohept-
2-enone (36). To a solution of hydroxy dienyl sulfone 32 (0.132 g,
0.33 mmol) in THF (3.3 mL) at -78 °C was slowly added MeLi (0.83
mL, 0.99 mmol) in Et2O over a period of 10 min. The temperature
was allowed to slowly rise to -10 °C and was then quenched by slow
addition of a solution of saturated NH4Cl (5 mL). The temperature was
allowed to rise to 25 °C, and diethyl ether was added (10 mL). The
organic layer was separated, and the aqueous layer was extracted with
diethyl ether (2 × 10 mL). The organic layers were combined, dried
over MgSO4, and concentrated. CH2Cl2 (6 mL) was added to the mixture
followed by PCC (0.310 g, 1.44 mmol). The mixture was allowed to
stir for 2 h. THF (5 mL) was added followed by 10% NaOH (2 mL),
and the mixture was allowed to stir for 10 h. At this point, H2O (5
mL) was added followed by diethyl ether (10 mL), the mixture
separated, and the aqueous layer was extracted with diethyl ether (2 ×
10 mL). The combined organic layer was dried over MgSO4 and
concentrated. Purification was done by silica gel chromatography eluting
with a 1:9 solution of ethyl acetate/hexanes to give 0.84 g of the desired
enone as an oil in 88% yield. 1H NMR (CDCl3): δ 6.06 (m, 1H), 3.65
(dt, J ) 8.2 Hz, 3.8 Hz, 1H), 2.75 (m, 1H), 2.59 (m, 1H), 2.48 (m,
1H), 1.95 (m, 1H), 1.80 (s, 3H), 1.79 (m, 1H), 1.17 (d, J ) 6.9 Hz,
3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (CDCl3): δ 205.4, 144.1,
137.3, 73.8, 40.2, 37.9, 30.8, 25.8, 19.3, 18.0, -4.3, -4.8. LRMS: (EI)
highest mass 268 (M + H), base peak 73. (CI) highest mass 269 (M +
H), base peak 269. HRMS: (CI) calculated for C15H28O2Si 269.1937,
found 269.1930. 99.7% ee HPLC Chiralcel AD 1.0 mL/min 99.0:1.0
Hex:2-propanol. 3.70 min minor enantiomer, 4.08 min major enanti-
omer. [R]D (c 11.0, CHCl3) ) +139°.
1
93% yield. H NMR (CDCl3): δ 5.83 (s, 1H), 4.17 (dt, J ) 10.7 Hz,
5.2 Hz, 1H), 2.32 (m, 3H), 1.99 (s, 3H), 1.16 (d, J ) 7.2 Hz, 3H), 0.89
(s, 9H), 0.06 (s, 6H). 13C NMR (CDCl3): δ 198.4, 165.5, 126.1, 69.2,
42.2, 41.8, 25.7, 23.1, 18.0, 11.7, -4.7, -4.9. LRMS: (CI) highest
mass 255 (M + H), base peak 255. HRMS: (CI) calculated for
C14H26O2Si 255.1780, found 255.1779. 98.7% ee HPLC Chiralcel OD
1.0 mL/min 90.0:10.0 Hex:2-propanol. 5.25 min minor enantiomer, 4.46
min major enantiomer. [R]D (c 9.9, CHCl3) ) -41°.
(4R,5S)-5-(tert-Butyldimethylsilanyloxy)-4-isopropyl-3-methyl-
cyclohex-2-enone (25Pr). t-BuLi (0.15 mL, 0.18 mmol) was slowly
added to a mixture of HMPA (0.08 mL, 0.45 mmol) and γ-methoxy
vinyl sulfone 24Pr (0.0382 g, 0.09 mmol) in 2 mL of THF at -78 °C.
The resulting bright orange mixture was stirred at -78 °C for 5 min.
Iodomethane (0.03 mL, 0.45 mmol) was added and was stirred for 15
min. Saturated NaHCO3 (2 mL) was added, and the reaction was
allowed to warm to room temperature. The mixture was extracted into
diethyl ether (5 mL) and concentrated in vacuo. CHCl3 (1 mL) was
added followed by SiO2 (0.500 g), and the reaction was stirred for 3 h.
1
Monitoring the reaction was best accomplished by H NMR. When
complete, the silica was filtered, and the solution was concentrated.
Silica gel column purification eluting with 1:4 ethyl acetate/hexanes
1
provided the desired enone in 0.023 g, 91% yield. H NMR (CDCl3):
δ 5.92 (s, 1H), 4.21 (dt, J ) 11.4 Hz, 5.8 Hz, 1H), 2.46 (m, 3H), 2.25
(m, 1H), 2.01 (d, J ) 1.4 Hz, 1H), 1.14 (d, J ) 7.0 Hz, 3H), 0.90 (s,
9H), 0.88 (d, J ) 7.2 Hz, 3H), 0.070 (s, 3H), 0.065 (s, 3H). 13C NMR
(CDCl3): δ 199.0, 163.9, 127.8, 69.9, 53.1, 42.9, 26.0, 25.7, 25.4, 24.5,
21.0, -4.7, -4.8. LRMS: (CI) highest mass 283 (M + H), base peak
283. HRMS: (CI) calculated for C16H30O2Si 283.2093, found 283.2094.
97.7% ee HPLC Chiralcel OD 1.0 mL/min 90.0:10.0 Hex:2-propanol.
4.67 min minor enantiomer, 4.13 min major enantiomer. [R]D (c 4.0,
CHCl3) ) -68°.
Acknowledgment. We thank Karl Wood and Arlene Rothwell
for mass spectral data and Daniel Lee for elemental analysis.
J.E. gratefully acknowledges financial support from Kodak in
the form of a graduate fellowship. E.T. wishes to thank Pfizer,
Inc., for a Fellowship. We thank Dr. Kenji Koga for his
information and advice in the chiral HPLC analysis. We also
wish to thank Dr. Douglas Lantrip for his technical assistance.
(4S,5S)-5-(tert-Butyldimethylsilanyloxy)-3,4-dimethylcyclohept-
2-enone (34). t-BuLi (0.06 mL, 0.07 mmol) was added to the γ-methoxy
vinyl sulfone 33 (0.02 g, 0.05 mmol) in 1 mL of THF at -78 °C over
2 min. The resulting bright orange solution was stirred at -78 °C for
5 min. Iodomethane (0.02 mL, 0.25 mmol) was added and was stirred
for 15 min. Saturated NaHCO3 (1 mL) was added, and the reaction
Supporting Information Available: Copies of spectra (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA026760M
9
J. AM. CHEM. SOC. VOL. 124, NO. 37, 2002 11101