β-hydroxysulfoxides as chiral cyclic ketone equivalents: Enantioselective synthesis of polysubstituted cyclohexanones, cyclohexenones and cyclohexenediones

Article abstract of DOI:10.1039/b209121f

The β-hydroxysulfoxide moiety, after oxidation to sulfone, acts as a masked carbonyl group in a cyclic system, opening an easy access to differently substituted enantiomerically pure cyclic ketones by means of aluminium-mediated conjugate additions, stereoselective reductions and elimination by retrocondensation in basic medium.

Full text of DOI:10.1039/b209121f

b-Hydroxysulfoxides as chiral cyclic ketone equivalents: enantioselective
synthesis of polysubstituted cyclohexanones, cyclohexenones and
cyclohexenediones†
M. Carmen Carreño,* Manuel Pérez-González, María Ribagorda, Álvaro Somoza and Antonio
Urbano
Departamento de Química Orgánica (C-I), Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid,
Spain. E-mail: carmen.carrenno@uam.es
Received (in Cambridge, UK) 17th September 2002, Accepted 28th October 2002
First published as an Advance Article on the web 18th November 2002
The b-hydroxysulfoxide moiety, after oxidation to sulfone,
acts as a masked carbonyl group in a cyclic system, opening
an easy access to differently substituted enantiomerically
pure cyclic ketones by means of aluminium-mediated
conjugate additions, stereoselective reductions and elimina-
tion by retrocondensation in basic medium.
BALH afforded carbinol (4R)-4 resulting from the exclusive
axial hydride attack on the most stable conformation A of 3a
fixed by the equatorial (p-tolylsulfonyl)methyl substituent.
Attempts to recover the masked carbonyl group from 4 in the
presence of different bases were again unsuccessful due to
difficulties in the isolation of the final 4-hydroxyenone.
Fortunately, the TBDMS protected derivative 5 could be
transformed into cyclohexenone 6 in the presence of several
bases under different conditions. The best results were obtained
with 2 equivalents of the weak base Cs2CO3 in CH3CN at rt
(Table 1, entry 1) which gave a clean mixture of cyclohexenone
The utilization of chiral cyclohexanones and 2-cyclohexenones
in asymmetric synthesis continues to attract considerable
interest as an important class of starting materials and synthetic
intermediates en route to a wide range of natural products like
cyclitols,1 carbasugars1b,2 or terpenes.3 The stereocontrolled
transformation of cyclic ketones is a general way of access to
these important compounds. Currently, this is achieved through
the conversion of ketones into their chiral acetals4 or hydra-
zones.5 Recently, enantiopure a-acetoxysulfones generated
catalytically have been introduced into the synthetic arsenal as
chiral aldehyde equivalents.6 Although some of these method-
ologies allow an efficient control of the asymmetric transforma-
tions, new chiral carbonyl equivalents are welcome.
20
6 and methyl p-tolyl sulfone, from which 6 {[a]D = +67.0 (c
0.4, acetone)} was isolated with 89% yield in enantiomerically
pure form, as determined after desilylation into the correspond-
ing carbinol.§
In connection with a program devoted to asymmetric
synthesis mediated by sulfoxides,7 we have recently reported a
general synthetic approach to (S,R)-4-hydroxy-4-[(p-tolylsulfi-
nyl)methyl]-2,5-cyclohexadienones 1 and studied the ster-
eoselectivity of their conjugate additions.8 This study revealed
that the b-hydroxy sulfoxide exercises a differentiation between
the diastereotopic faces of the double bonds directing conjugate
additions of organoaluminium reagents from the face contain-
ing the OH group in a highly diastereoselective way and with
efficient desymmetrization of the cyclohexadienone moiety.
Synthetic applications of these results required the elimination
of the chiral auxiliary once the p-quinol system had been
adequately functionalized. We now report the liberation of
ketone functionalities through the oxidation of the correspond-
ing b-hydroxy sulfoxides and elimination of the resulting
sulfone. This sequence shows that the readily accessible b-
hydroxy sulfoxide moiety can be regarded as a chiral ketone
equivalent. In spite of the extended use of b-hydroxy sulfoxides
in asymmetric synthesis,7a this is the first example where such
a fragment is used as a chiral ketone equivalent.‡
Derivatives 2a–d, bearing the enantiopure b-hydroxy sulf-
oxide moiety, were prepared through the highly stereoselective
organoaluminium conjugate addition8 on the corresponding
enantiopure p-quinols 1a–b, as unique diastereomers in good
yields (Scheme 1). Attempts to eliminate methyl p-tolyl
sulfoxide from 2 through a retrocondensation in basic medium
were unsuccessful, probably due to the poor quality of the
methyl sulfinyl anion as nucleofuge. We then transformed
sulfoxides 2 into sulfones 3. Treatment of sulfone 3a with
different bases led to the expected elimination of methyl p-
tolylsulfone but with simultaneous aromatization to the corre-
sponding 2-methylhydroquinone. Reduction of 3a with DI-
Scheme 1 Reagents and conditions: i, m-CPBA, CH2Cl2, rt, 1–2 h, 85–95%;
ii, DIBALH, THF, 278 °C, 30 min, 95% from 3a; iii, TBDMSOTf,
† Electronic supplementary information (ESI) available: full experimental
details and NMR spectra. See http://www.rsc.org/suppdata/cc/b2/
b209121f/
2,6-lutidine, CH2Cl2, rt, 2 h, 93%; iv, Cs2CO3, CH3CN, rt; v, L-Selectride,
THF, 278 °C, 3 h, 64%; vi, NaBH4, CeCl3, MeOH, 278 °C, 3–4 h,
64%.
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This journal is © The Royal Society of Chemistry 2002

20
stituted cyclohexanones 11 {[a]D = 21.7 (c 1.1, CHCl3)}
The stereoselective reductions of ketone 3b on the now most
stable conformation B, which avoids severe interactions
between R1 = Me and the equatorial (p-tolylsulfonyl)methyl
substituent present in conformation A (Scheme 1), afforded
20
and 12 {[a]D = 24.5 (c 1.1, CHCl3)} in enantiomerically
pure form, as determined after desilylation into the correspond-
ing carbinols.§
carbinols 7 (
L
-Selectride, 95% equatorial attack) and 8 (NaBH4,
In summary, the enantiopure b-hydroxysulfoxide moiety can
be considered as a chiral cyclic ketone equivalent which can be
recovered after oxidation to a sulfone and mild basic treatment.
An additional advantage of the b-hydroxysulfone as carbonyl
protecting group in cyclic systems is that further transforma-
tions on such rigid systems occur in a stereocontrolled manner.
Moreover, both the a-hydroxysulfoxides and the corresponding
sulfones are very stable and can be easily handled and purified
either by chromatography or crystallization. We are now
applying this new efficient methodology to the total enantiose-
lective synthesis of several natural products.
CeCl3, 80% axial attack), whose treatment with Cs2CO3 (entries
2 and 3, respectively) allowed us to obtain in enantiomerically
20
pure form§ both enantiomers of 9, {[a]D = +48 (c 2, EtOH)
and 244 (c 0.2, EtOH)}, known as Phorenol, a synthetic
intermediate used for the enantioselective syntheses of several
natural products.11 Till now, these chiral synthons were mainly
accessible through enzymatic resolutions.12
We then focused our attention on the base-induced elimina-
tion of methyl p-tolylsulfone on cyclohexenones 3b–d en route
to chiral cyclohexenediones (Scheme 1). Stirring sulfone 3b in
CH3CN solution with an excess of Cs2CO3 gave, after flash
chromatography, achiral 4-oxoisophorone 10b (entry 4). The
synthesis of enantiomerically pure¶ oxoisophorone analogues
We thank DGICYT (Grant PB98-0062) and MCYT (Grant
BQU2002-03371) for financial support, MEC for a fellowship
to M. R. and CAM for a fellowship to A. S.
10c13 {[a]D = +0.6 (c 0.6, CHCl3)} and 10d {[a]D = 23.0
(c 0.8, CHCl3)} could be achieved in a similar easy way from
sulfones 3c (entry 5) and 3d (entry 6), respectively.
20
20
In order to know if the driving force for the easy elimination
of methyl p-tolylsulfone was the formation of the conjugated
cyclohexenone or cyclohexenedione fragment, we decided to
explore the synthetic sequence en route to trisubstituted
cyclohexanones 11 and 12 (Scheme 2). The precursors were
obtained as follows. The stereoselective addition of Et3Al on 2a
afforded cyclohexanone 13 as the unique diastereoisomer with
the R absolute configuration at the new chiral center.8 m-CPBA
oxidation of sulfoxide 13 gave sulfone 14 which was ster-
Notes and references
‡ b-Hydroxy sulfoximines have been used to resolve chiral racemic cyclic
ketones.9
§ The optical purity was determined from the Mosher’s esters.10
¶ The optical purity for 10c,d was determined after reduction at C-4 using
NaBH4–CeCl3 and formation of the Mosher’s esters.10
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eoselectively reduced to carbinol 15 ( -Selectride, 90% equato-
L
rial attack) or to the epimer 16 (NaBH4, CeCl3, 95% axial
attack). The elimination of methyl p-tolyl sulfone was once
again unsuccessful on free carbinols 15 and 16 and had to be
carried out on the TBDMS protected derivatives 17 and 18.
Simply stirring a CH3CN solution of 17 or 18 with Cs2CO3
(entries 7 and 8) afforded, respectively, the desired trisub-
Table 1 Treatment of cyclic b-hydroxysulfones with Cs2CO3 in CH3CN at
rt
b-Hydroxy Cs2CO3
Yield
(%)
Ee
(%)
Entry sulfone
equiv.
t/h
Cyclic ketone
1
2
3
4
5
6
7
8
5
7
8
3b
3c
3d
17
18
2
3
3
2
2
2
2
2
17
1
0.25
0.3
0.5
0.25
20
6
(4R,6S)-6
(4R)-9
(4S)-9
89
90
93
54
70
68
89
82
> 95
> 95
> 95
—
> 95
> 95
> 95
> 95
5 Review: A. Job, C. F. Janeck, W. Bettray, R. Peters and D. Enders,
Tetrahedron, 2002, 58, , 2253.
6 B. M. Trost, M. L. Crawley and C. Bom Lee, J. Am. Chem. Soc., 2000,
122, 6120.
10b
(6S)-10c
(6R)-10d
(2R,4S,6S)-11
(2R,4R,6S)-12
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C. Carreño, A. Urbano and C. Di Vitta, Chem. Eur. J., 2000, 6, 906; M.
C. Carreño, S. García-Cerrada, M. J. Sanz-Cuesta and A. Urbano, Chem.
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1451; R. Zell, E. Widmer, T. Lukac, H. G. W. Leuenberger, P.
Schoenholzer and E. A. Broger, Helv. Chim. Acta, 1981, 64, 2447; J. A.
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Semadeni, Aust. J. Chem., 1995, 48, 145.
12 H. Kiyota, M. Nakabayashi and T. Oritani, Tetrahedron: Asymmetry,
1999, 10, 3811 and references therein.
Scheme 2 Reagents and conditions: i, m-CPBA, CH2Cl2, rt, 1–2 h, 98%; ii,
13 This derivative has been recently described for the first time, albeit in
racemic form: A. Aponick, R. S. Buzdygon, R. J. Tomko, A. N. Fazal,
E. L. Shughart, D. M. McMaster, M. C. Myers, W. H. Pitcock and C. T.
Wigal, J. Org. Chem., 2002, 67, 242.
L
-Selectride, THF, 278 °C, 2 h, 73%; iii, NaBH4, CeCl3, MeOH, 278 °C,
3–4 h, 75%; iv, TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 2 h, 81–87%; v,
Cs2CO3, CH3CN, rt.
CHEM. COMMUN., 2002, 3052–3053
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