Organocatalytic Michael addition of aldehydes to vinyl sulfones: Enantioselective α-alkylations of aldehydes and their derivatives

Article abstract of DOI:10.1021/ol8019296

(Equation Presented) Organocatalytic asymmetric Michael reaction of unmodified aldehydes to vinyl sulfones catalyzed by silylated biarylprolinol afforded the desired Michael products with exceptional enantioselectivity. The described enantioselective addition to vinyl sulfones, in combination with desulfonation, offers a unique, asymmetric entry to α-alkylated aldehydes and their derivatives.

Full text of DOI:10.1021/ol8019296

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4803-4806
Organocatalytic Michael Addition of
Aldehydes to Vinyl Sulfones:
Enantioselective r-Alkylations of
Aldehydes and Their Derivatives
Qiang Zhu and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore 117543
chmlyx@nus.edu.sg
Received August 18, 2008
ABSTRACT
Organocatalytic asymmetric Michael reaction of unmodified aldehydes to vinyl sulfones catalyzed by silylated biarylprolinol afforded the
desired Michael products with exceptional enantioselectivity. The described enantioselective addition to vinyl sulfones, in combination with
desulfonation, offers a unique, asymmetric entry to r-alkylated aldehydes and their derivatives.
Sulfones are widely employed as valuable intermediates in
organic synthesis.1 Asymmetric Michael addition of carbon
nucleophiles to vinyl sulfones represents an important
carbon-carbon bond-forming reaction and provides an easy
access to various optically pure sulfones. In a number of
early reports,2 enamines preformed from ketones were
successfully added to vinyl sulfones; however, the additions
were nonstereoselective. D’Angelo and co-workers later
developed enantioselective additions of imines derived from
cyclic ketones and chiral 1-phenyethylamine to vinyl sul-
fones.3 Deng et al. reported elegant cinchona alkaloid-
mediated enantioselective conjugate additions to vinyl sul-
fones for the construction of all-carbon quaternary
stereocenters.4 Recently, Alexakis and his co-workers de-
scribed an asymmetric organocatalytic Michael addition of
aldehydes to vinyl sulfones.5 These reactions were promoted
by their well-designed N-iPr-2,2′-bipyrrolidine catalysts, and
the adducts were obtained with modest to good enantiose-
lectivity. Despite all the aforementioned excellent advances,
highly enantioselective catalytic Michael addition of carbonyl
substrates to vinyl sulfones remains a challenging task,
particularly with aldehyde substrates.
(3) (a) Pinheiro, S.; Guingant, A.; Desmae¨le, D.; d’Angelo, J. Tetrahe-
dron: Asymmetry 1992, 3, 1003. (b) Desmae¨le, D.; Delarue-Cochin, S.; Cave,
C.; d’Angelo, J.; Morgant, G. Org. Lett. 2004, 6, 2421.
(1) (a) Simpkins, N. S. Tetrahedron 1990, 46, 6951. (b) Simpkins, N. S.
Sulfones in Organic Synthesis; Pergamon Press: Oxford, 1993.
(2) (a) Risaliti, A.; Fatutta, S.; Forchiassin, M. Tetrahedron 1967, 23,
1451. (b) Benedetti, F.; Fabrissin, S.; Risaliti, A. Tetrahedron 1984, 40,
977. (c) Lucchi, O. D.; Pasquato, L.; Modena, G. Tetrahedron Lett. 1984,
25, 3643.
(4) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127,
8948.
(5) (a) Mosse, S.; Alexakis, A. Org. Lett. 2005, 7, 4361. For an excellent
recent report on organocatalytic addition of aldehyde to vinyl phosphonate,
see: (b) Sulzer-Mosse, S.; Tissot, M.; Alexakis, A. Org. Lett. 2007, 9, 3749.
10.1021/ol8019296 CCC: $40.75
Published on Web 10/04/2008
2008 American Chemical Society

Asymmetric organocatalysis has attracted much attention
in recent years.6 In particular, proline and its various
structural analogues have been shown to be efficient catalysts
for a wide range of organic reactions. We became interested
in developing an efficient and practical organocatalytic
approach to access chiral sulfones. Herein, we disclose that
silylated biarylprolinols promote addition of aldehydes to
various vinyl sulfones with exceptional enantioselectivity.
The Michael addition of isovaleraldehyde 1 to vinyl
sulfone 2 was selected as our model reaction, and a few
common organocatalysts were screened (Table 1). Proline
effective than the diphenylprolinol silyl ether 7 (entries 4
and 5). Solvent screening revealed that a number of solvents
were suitable (entries 6-11), and chloroform was chosen
for synthetic convenience. When the reaction was carried
out at 0 °C, essentially enantiomerically pure adduct was
obtained (entry 12).
After the reaction conditions were optimized, the generality
of the reaction was then examined, and the results are
summarized in Table 2. A wide range of aliphatic aldehydes
Table 2. Addition of Various Aldehydes to Vinyl Sulfone 2
Catalyzed by Prolinol Silyl Ether 8a
Table 1. Screening of Organocatalysts for the Asymmetric
Michael Addition of Isovaleraldehyde to Vinyl Sulfonea
entry
catalyst
solvent
T (°C)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
4
5
6
7
8
8
8
8
8
8
8
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
CH2Cl2
Toluene
DMSO
CH3OH
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
56
41
76
92
93
87
94
95
71
88
95
94
2
31
9
89
98
79
96
98
79
91
96
>99
10
11
12
CHCl3
a The reactions were performed with isovaleraldehyde (0.5 mmol), vinyl
sulfone (0.05 mmol), and catalyst (0.005 mmol) in anhydrous solvent (0.1
mL) at room temperature, unless otherwise specified. b Isolated yield. c The
ee value was determined by chiral HPLC analysis.
4, tetrazole 5, and proline derivative 6 were not very
effective, affording the desired adducts with poor enanti-
oselectivites (entries 1-3). Prolinol silyl ethers,7 indepen-
dently developed by the groups of Hayashi and Jørgensen,
were found to be very effective. The trifluoromethyl-
substituted silylated diphenylprolinol catalyst 8 was more
a The reactions were performed with aldehyde (0.5 mmol), vinyl sulfone
(0.05 mmol), and catalyst (0.005 mmol) in anhydrous CHCl3 (0.1 mL) at
0 °C. b Isolated yield. c The ee value was determined by chiral HPLC
analysis.
(6) (a) Dalko, P. I.; Moisan, L. Angew. Chem. 2004, 116, 5248; Angew.
Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Groger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005. (c) EnantioselectiVe Or-
ganocatalysis, Reactions and Experimental Procedures; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, 2007.
were tested as Michael donors. In all the examples studied,
very high yield and excellent enantioselectivity were attain-
able.
To make our methodology synthetically more useful, we
extended our reactions to include 2-aryl-substituted vinyl
(7) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.
2005, 117, 42824; Angew. Chem., Int. Ed. 2005, 44, 4212. (b) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. 2005, 117,
804; Angew. Chem., Int. Ed. 2005, 44, 794. (c) Palomo, C.; Mielgo, A.
Angew. Chem. 2006, 118, 8042; Angew. Chem., Int. Ed. 2006, 45, 7876.
4804
Org. Lett., Vol. 10, No. 21, 2008

sulfones 118 as acceptors (Table 3). The aryl component of
vinyl sulfone can be either electron rich or neutral; however,
electron-poor aryl-substituted vinyl sulfones were too un-
stable to be prepared. The addition of aldehydes to various
vinyl sulfones proceeded very efficiently, yielding the desired
adducts in excellent yield, good diastereoselectivity, and
nearly perfect enantioselectivity.
Table 3. Organocatalytic Michael Addition of Aldehydes to
2-Aryl-Substituted Vinyl Sulfonesa
The Michael adduct of an aldehyde to vinyl sulfone is a
versatile intermediate in organic synthesis. The facile conver-
sion of aldehyde into a number of important functional
groups, in combination with well-established desulfonylation
methods,9 offers a unique asymmetric entry to R-alkylated
aldehydes and their derivatives. To illustrate the value of
our highly enantioselective Michael additions of aldehydes
to vinyl sulfones, we prepared a number of chiral building
blocks, as shown in Scheme 1. Following the prolinol silyl
Scheme 1
.
Conversion of the Michael Adduct into Synthetically
Useful Chiral Building Blocks
ether 8-medicated Michael addition, reduction with NaBH4
then afforded 13, and the subsequent reductive removal of
the sulfone groups yielded chiral alcohol 1410 in high yield
and with 95% ee. Chiral acid 16 and amine 17 could also
be readily prepared, in overall good yield and with excellent
enantioselectivity.
Figure 1. Proposed transition-state model.
Based on the observed stereochemistry of the Michael
product, a plausible transition-state model is proposed in
a The reactions were performed with aldehyde (0.5 mmol), vinyl sulfone
(0.05 mmol), and catalyst (0.005 mmol) in anhydrous CHCl3 (0.1 mL) at
0 °C. b Isolated yield. c Determined by 1H NMR analysis of the crude
product. d The ee value of the syn-isomer was determined by chiral HPLC
analysis.
(8) Ziegler, E.; Ruef, W.; Zwainz, J. G. Anorg. Chem., Org. Chem. 1975,
30, 755.
(9) (a) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547. (b) Kundig,
E. P.; Cunningham, A. F., Jr. Tetrahedron 1988, 44, 6855.
Org. Lett., Vol. 10, No. 21, 2008
4805

Figure 1. The bulky biaryl silyl ether moiety exerts steric
shielding, resulting in the formation of observed stereoisomer.
In conclusion, we have disclosed highly efficient organo-
catalytic Michael additions of aldehydes to vinyl sulfones
mediated by trifluoromethyl-substituted diphenylprolinol silyl
ether. Our results represent the only example in the literature
showing that remarkable enantioselectivity can be achieved
for this type of reaction. The excellent enantioselectivity
described in this report makes the utilization of vinyl sulfone
as valuable synthetic intermediates highly practical and
desirable, and we anticipate that these synthetic methods will
find wide application in organic synthesis.
Acknowledgment. We thank the National University of
Singapore and the Ministry of Education (MOE) of Sin-
gapore (R-143-000-362-112) for generous financial support.
Supporting Information Available: Representative ex-
perimental procedure for Michael addition to vinyl sulfone,
procedures to convert Michael adduct into chiral alcohol,
acid, and amine, determination of absolute configurations of
Michael products, HPLC chromatogram, and analytical data
and NMR spectra of the Michael adducts. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) (a) Absolute configuration of the Michael adduct 10g was assigned
by comparing the optical rotation of its derivative 14 with the literature
data; see: Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577.
(b) For the assignment of absolute configurations of 12a-I, see the
Supporting Information.
OL8019296
4806
Org. Lett., Vol. 10, No. 21, 2008