Asymmetric organocatalytic Michael addition of ketones to vinyl sulfone

Article abstract of DOI:10.1039/b816307c

Highly enantioselective organocatalytic Michael addition of ketones to vinyl sulfone catalyzed by a cinchona alkaloid-derived primary amine is reported for the first time; the described synthetic methodology was applied to the synthesis of sodium cyclamate. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b816307c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Asymmetric organocatalytic Michael addition of ketones
to vinyl sulfonew
Qiang Zhu,ab Lili Chenga and Yixin Lu*ab
Received (in Cambridge, UK) 17th September 2008, Accepted 10th October 2008
First published as an Advance Article on the web 5th November 2008
DOI: 10.1039/b816307c
Highly enantioselective organocatalytic Michael addition of
ketones to vinyl sulfone catalyzed by a cinchona alkaloid-derived
primary amine is reported for the first time; the described
synthetic methodology was applied to the synthesis of sodium
cyclamate.
Sulfones are useful intermediates in synthetic and medicinal
Scheme 1 The enamine intermediates in the enamine catalysis.
chemistry.1 Vinyl sulfones2 are valuable precursors in organic
synthesis, and their asymmetric Michael reactions with carbon
nucleophiles provide an easy access to optically pure sulfones.3
Recently, d’Angelo and co-workers employed 1-phenylethylamine-
derived chiral imines in Michael additions to vinyl sulfones.4
With the spectacular advance of organocatalysis in the
past few years,5 a couple of reports employing organocatalytic
approaches appeared in the literature. Deng et al. described a
cinchona alkaloid-mediated enantioselective conjugate addi-
tion of a-cyanoacetates to vinyl sulfones for the construction
of all carbon quaternary stereocentres.6 Recently, Alexakis
and his co-workers reported asymmetric organocatalytic
Michael additions of aldehydes to vinyl sulfones which
were promoted by their well-designed N-iPr-2,20-bipyrrolidine
catalysts.7 Very recently, we disclosed an enantioselective
organocatalytic Michael addition of aldehydes to vinyl
sulfones mediated by silylated biarylprolinol.8 Despite all these
advances, a practical asymmetric organocatalytic Michael
addition of ketones to vinyl sulfones is still elusive. Herein
we wish to report the first highly enantioselective organocata-
lytic Michael reaction of cyclic ketones with vinyl sulfone
catalyzed by a cinchona alkaloid-derived organocatalyst
containing a primary amino function.
could promote highly enantioselective aldol and Mannich
reactions of hydroxyacetone, affording useful chiral 1,2-diol
and 1,2-amino alcohol building blocks.12 To develop an
organocatalytic Michael addition of ketones to vinyl sulfone,
we reasoned primary amines might be suitable catalysts. The
crucial enamine intermediate may be readily formed in the
presence of primary amine, whereas steric hindrance may
hinder efficient enamine formation when a secondary amine
is used as the catalyst (Scheme 1).
For the initial studies, we tested a few common secondary
and primary amino catalysts in the Michael addition of
cyclohexanone 1 to vinyl sulfone 2 (Table 1). Not surprisingly,
proline and silylated biarylprolinols 4 only afforded the de-
sired adducts in very low yield (entries 1–3). Threonine-derived
catalysts (5a–c), previously developed by our group for aldol
and Mannich reactions,12 catalyzed the formation of the
desired product in high yield, but the enantioselectivity was
disappointing (entries 4–6). Serine-based catalysts (6a–c) were
much more effective, and the desired Michael adducts were
formed in excellent yield and with moderate enantioselectivity
(entries 7–9). The cinchonidine-derived primary amine 7
turned out to be an excellent catalyst, giving the desired
product in excellent yield and with good enantioselectivity
(entry 10). Screening of solvents and acidic additives revealed
that chloroform was the best solvent and benzoic acid was the
additive of choice (entry 16). When the temperature was
lowered to 0 1C, the Michael product 3 was obtained in
excellent yield and with excellent enantioselectivity. The abso-
lute configuration of the Michael product 3 was determined
to be R.13
Aminocatalysis via the enamine intermediate is one of the
most important activation methods in asymmetric organo-
catalysis, and proline and its various structural analogues have
found enormous applications in a wide range of reactions.9
Very recently, chiral primary amines were shown to be effec-
tive catalysts in asymmetric organocatalysis.10 Our group
demonstrated for the first time that natural tryptophan is an
effective catalyst in intermolecular aldol reactions.11 Sub-
sequently, we showed that threonine-derived organocatalysts
The scope of the reaction was investigated by employing
various ketones (Table 2). In the presence of primary amine 7,
the Michael reactions between vinyl sulfone and different
cyclic ketones proceeded smoothly, affording the desired
adducts in good yield, with moderate diastereoselectivity and
excellent enantioselectivity. However, the reactions are not
applicable to acyclic ketones.14
a Department of Chemistry, National University of Singapore,
3 Science Drive 3, Singapore, 117543, Republic of Singapore.
E-mail: chmlyx@nus.edu.sg; Fax: +65-6779-1691;
Tel: +65-6516-1569
b Medicinal Chemistry Program, Life Sciences Institute, National
University of Singapore, Republic of Singapore
w Electronic supplementary information (ESI) available: Experimental
details, analytical data, HPLC chromatogram and NMR spectra of
Michael adducts. See DOI: 10.1039/b816307c
The Michael adducts of ketones with vinyl sulfone are useful
synthetic intermediates. The facile conversion of the ketone
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 6315–6317 | 6315

View Article Online
Table 1 Screening of organocatalysts for the asymmetric Michael
addition of cyclohexanone 1 to vinyl sulfone 2a
Table 2 Organocatalytic Michael addition of various cyclic ketones
to vinyl sulfonea
Entry
1
Product
Yieldb (%)
89
drc
—
eed (%)
91
2
3
76
84
—
95
96
Temp./
1C
Yieldb
(%)
eec
(%)
Entry Catalyst Solvent
Additive
1
Proline
Toluene RT
—
—
—
—
—
—
—
—
—
o 20
31
—
48
—
21
ꢁ2
7
60
44
46
71
79
27
78
38
49
89
85
85
90
92
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4a
4b
5a
5b
5c
6a
6b
6c
7
7
7
7
7
7
7
7
7
7
7
Toluene RT
Toluene RT
Toluene RT
Toluene RT
Toluene RT
Toluene RT
Toluene RT
Toluene RT
Toluene RT
5 : 1
o 20
85
70
83
96
95
95
4
5
6
92
93
90
6 : 1
3 : 1
4 : 1
97
95
94
PhCOOH 86
PhCOOH 71
PhCOOH 95
PhCOOH 94
PhCOOH 89
PhCOOH 95
PhCOOH 86
THF
MeOH
RT
RT
CH2Cl2 RT
DMSO RT
CH3CN RT
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
RT
RT
RT
ꢁ20
0
TFA
CSA
87
91
PhCOOH 45
PhCOOH 94
a
The reactions were performed with cyclohexanone (0.5 mmol), vinyl
sulfone (0.05 mmol) and catalyst (0.01 mmol) in anhydrous solvent
(0.1 mL) at room temperature for 2 h, unless otherwise specified.
b
c
Isolated yield. The ee value was determined by chiral HPLC analysis.
7
8
78
2.5 : 1
90
functionality into an alcohol or amine, in combination with
well-established desulfonylation methods,15 offers a unique
asymmetric entry to a-alkylated ketones and their derivatives.
To illustrate the value of our asymmetric organocatalytic
Michael addition, we applied our methodology as the key step
to construct sodium cyclamate, an important compound in
the artificial sweeteners industry.16 As shown in Scheme 2,
cinchonidine-derived primary amine 7 mediated efficient
Michael addition of cyclohexanone to vinyl sulfone, affording
the adduct 3 with 92% ee. Subsequent reduction with LiAlH4
gave cis-10 in good diastereoselectivity. Conversion of the
hydroxy group into azide, followed by reduction and protec-
tion, then yielded trans-12 as a single diastereomer. Desulfo-
nation with magnesium in methanol and removal of the amino
protective group afforded chiral amine salt 13, the transforma-
tion of which into sodium cyclamate is well documented in the
literature.16 It should be noted that the reduction of ketone 3
with L-selectride yielded trans-10,17 thus providing an easy
access to both cis- and trans-isomers of sodium cyclamate.
In conclusion, we have disclosed the first highly enantio-
selective organocatalytic Michael addition of cyclic ketones to
85
87
5 : 1
88
90
9
—
a
The reactions were performed with cyclic ketone (0.5 mmol), vinyl
sulfone (0.05 mmol) and 7 (0.01 mmol) in anhydrous CHCl3 (0.1 mL)
at 0 1C for 2 h. Isolated yield. Determined by 1H NMR analysis of
the crude product. The ee value of the major diastereomer, deter-
mined by chiral HPLC analysis.
b
c
d
vinyl sulfone mediated by a cinchona alkaloid-derived primary
amine catalyst. The methodology described in this report
provides an easy access to a-alkylated carbonyl compounds
and their derivatives, and we anticipate these synthetic
methods will find wide applications in organic synthesis.
ꢀc
This journal is The Royal Society of Chemistry 2008
6316 | Chem. Commun., 2008, 6315–6317

View Article Online
and Experimental Procedures, ed. P. I. Dalko, Wiley-VCH,
Weinheim, 2007.
6 H. Li, J. Song, X. Liu and L. Deng, J. Am. Chem. Soc., 2005, 127,
8948.
7 S. Mosse and A. Alexakis, Org. Lett., 2005, 7, 4361.
8 Q. Zhu and Y. Lu, Org. Lett., 2008, 10, 4803.
9 (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas
III, J. Am. Chem. Soc., 2001, 123, 5260. For selected reviews on
proline catalysis, see: (c) B. List, Synlett, 2001, 1675; (d) B. List,
Acc. Chem. Res., 2004, 37, 548; (e) S. Mukherjee, J. W. Yang,
S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471.
10 For a review, see: (a) L.-W. Xu and Y. Lu, Org. Biomol. Chem.,
2008, 6, 2047. For selected examples, see: (b) S. Danishefsky and
P. Cain, J. Am. Chem. Soc., 1976, 98, 4975; (c) A. Cordova,
´
W. Zou, I. Ibrahem, E. Reyes, M. Engqvist and W. W. Liao, Chem.
Commun., 2005, 3586; (d) H. Huang and E. N. Jacobsen, J. Am.
Chem. Soc., 2006, 128, 7170; (e) S. S. V. Ramasastry, H. Zhang,
F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2007, 129, 288;
(f) S. Luo, H. Xu, J. Li, L. Zhang and J.-P. Cheng, J. Am. Chem.
Soc., 2007, 129, 3074; (g) K. Ishihara and K. Nakano, J. Am. Chem.
Soc., 2005, 127, 10504; (h) N. J. A. Martin and B. List, J. Am.
Chem. Soc., 2006, 128, 13368; (i) J.-W. Xie, W. Chen, R. Li,
M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu and
J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389; (j) R. P. Singh,
K. Bartelson, Y. Wang, H. Su, X. Lu and L. Deng, J. Am. Chem.
Soc., 2008, 130, 2422; (k) X. Wang, C. M. Reisinger and B. List,
J. Am. Chem. Soc., 2008, 130, 6070.
Scheme 2 A synthesis of (S,S)-sodium cyclamate.
We thank the National University of Singapore and the
Ministry of Education (MOE) of Singapore (R-143-000-362-112)
for generous financial support.
Notes and references
1 N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon Press,
Oxford, 1993.
a review on the chemistry of vinyl sulfones, see:
N. S. Simpkins, Tetrahedron, 1990, 46, 6951.
3 For examples of non-stereoselective Michael additions to vinyl
sulfones, see: (a) A. Risaliti, S. Fatutta and M. Forchiassin,
Tetrahedron, 1967, 23, 1451; (b) F. Benedetti, S. Fabrissin and
A. Risaliti, Tetrahedron, 1984, 40, 977; (c) O. D. Lucchi,
L. Pasquato and G. Modena, Tetrahedron Lett., 1984, 25, 3643.
2 For
11 Z. Jiang, Z. Liang, X. Wu and Y. Lu, Chem. Commun., 2006, 2801.
12 (a) L. Cheng, X. Wu and Y. Lu, Org. Biomol. Chem., 2007, 5, 1018;
(b) X. Wu, Z. Jiang, H. M. Shen and Y. Lu, Adv. Synth. Catal.,
2007, 349, 812; (c) L. Cheng, X. Han, H. Huang, M. W. Wong and
Y. Lu, Chem. Commun., 2007, 4143.
13 See supporting information for the details.
4 (a) S. Pinheiro, A. Guingant, D. Desmaele and J. d’Angelo,
¨
S. Delarue-Cochin, C. Cave, J. d’Angelo and G. Morgant, Org.
Lett., 2004, 6, 2421.
14 When 3-pentanone was used as the donor, the yield of the reaction
was below 30%. The Michael reaction of O-benzyl-hydroxyacetone
with vinyl sulfone gave the adduct in 61% yield and with only
27% ee.
¨
Tetrahedron: Asymmetry, 1992, 3, 1003; (b) D. Desmaele,
5 For general reviews on organocatalysis, see: (a) P. I. Dalko and
L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (b) A. Berkessel
and H. Groger, Asymmetric Organocatalysis, Wiley-VCH,
Weinheim, 2005; (c) Enantioselective Organocatalysis, Reactions
15 C. Najera and M. Yus, Tetrahedron, 1999, 55, 10547.
16 R. A. Wiley, D. A. Pearson, V. Schmidt, S. B. Wesche and
J. J. Roxon, J. Med. Chem., 1983, 26, 1077.
17 See supporting information for the synthesis of trans-alcohol 10.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 6315–6317 | 6317