Communications
[2] For reviews on the asymmetric synthesis of b-amino acids, see:
[3] For recent reviews on the asymmetric Mannich Reaction, see:
a) R. G. Arrayꢁs, J. C. Carretero, Chem. Soc. Rev. 2009, 38, 1940;
b) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
[4] a) I. Ojima, S. Lin, T. Wang, Curr. Med. Chem. 1999, 6, 927; b) I.
c) J. Kant, W. S. Schwartz, C. Fairchild, Q. Gao, S. Huang, B. H.
Long, J. F. Kadow, D. R. Langley, V. Farina, D. Vyas, Tetrahe-
Aoyoagi, S. Yoshida, N. Matsuda, T. Ikeda, M. Hamada, T.
Takeuchi, J. Antibiot. 1991, 44, 573; c) B. Bauvois, D. Dauzonne,
Scheme 1. Stereochemical hypothesis.
In conclusion, we have developed a new, highly stereose-
lective synthesis of enantiomerically enriched a-alkyl-a-
hydroxy-b-amino esters through tandem asymmetric Wittig
rearrangement/Mannich reactions. This method provides
access to a range of syn- and anti-amino alcohol products
from simple starting materials, and further illustrates the
utility of Wittig rearrangements for stereoselective generation
of enolates derived from a-alkyl-a-hydroxy esters.
references therein.
[7] a) A. Guerrini, G. Varchi, R. Daniele, C. Samori, A. Battaglia,
[8] For multistep approaches involving b-lactam, epoxide, or
aziridine ring-opening, see: a) J. L. Garcꢂa Ruano, C. G. Paredes,
Tetrahedron Lett. 2000, 41, 5357; b) C. Papa, C. Tomasini, Eur. J.
Experimental Section
Representative procedure for tandem Wittig rearrangement/Mannich
reactions: A flame-dried flask was cooled under a stream of nitrogen
and charged with a 1m solution of dibutylboron triflate in dichloro-
methane (0.56 mL, 0.56 mmol). The pale yellow solution was cooled
to 08C, and triethylamine (62 mL, 0.45 mmol) was added dropwise to
afford a colorless solution. A solution of ester 3a (47 mg, 0.14 mmol)
in CH2Cl2 (0.14 mL) was then added dropwise, and the reaction
mixture was warmed to room temperature, stirred for 15 min, and
then cooled to 08C. A solution of N-(benzylidene)benzylamine
(42 mg, 0.22 mmol) in CH2Cl2 (0.22 mL) was added dropwise, and the
reaction mixture was warmed to room temperature and stirred for
3 h. The reaction vessel was then opened to air, and pH 7 buffer
(1.4 mL), and methanol (2.8 mL) were added. The resulting mixture
was cooled to 08C, 30% aqueous H2O2 (2.8 mL) was added slowly,
and the reaction mixture was warmed to room temperature and
stirred for 1 h. The mixture was diluted with ether (14 mL) and water
(7 mL), then was transferred to a separatory funnel. The layers were
separated, and the organic layer was washed with a saturated aqueous
solution of FeSO4 (4 ꢀ 7 mL) until a red-orange aqueous phase no
longer persisted in order to quench any remaining peroxide. Caution!
This procedure is exothermic. The FeSO4 solution should be added
through a glass pipette SLOWLY DROPWISE. The organic layer was
then washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel to afford 54 mg (72%) of
(À)-(1R,2S,2’R,3’S)-2-phenylcyclohexyl-2’-benzyl-3’-benzylamino-2’-
hydroxy-3’-phenylpropanoate (4) as a white foam.
[10] For conjugate addition reactions between enantiopure chiral
amines and a,b-unsaturated esters bearing chiral auxiliaries, see:
a) M. E. Bunnage, A. N. Chernega, S. G. Davies, C. J. Goodwin,
Epstein, A. C. Garner, O. Ichihara, A. D. Smith, Tetrahedron:
[12] The configuration of 4 was determined by X-ray crystallographic
analysis. CCDC 763869 (4) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
[13] For reviews on the 1,2-Wittig rearrangement, see: a) J. P. Wolfe,
N. J. Guthrie in Name Reactions for Homologations Part II (Ed.:
J. J. Li), Wiley, Hoboken, 2009, p. 226; b) K. Tomooka in The
Chemistry of Organolithium Compounds, Vol. 2 (Eds.: Z.
Rappoport, I. Marek), Wiley, London, 2004, p. 749; c) K.
[14] For other examples of enolate 1,2-Wittig rearrangements, see:
Vilotijevic, J. Yang, D. Hilmey, L. A. Paquette, Synthesis 2003,
1872; d) A. Garbi, L. Allain, F. Chorki, M. Ourevitch, B.
Crousse, D. Bonnet-Delpon, T. Nakai, J. P. Begue, Org. Lett.
2001, 3, 2529; e) T. Hameury, J. Guillemont, L. Van Hijfte, V.
Bellosta, J. Cossy, Synlett 2008, 2345.
Received: February 1, 2010
Published online: March 15, 2010
Keywords: asymmetric synthesis · imines · Mannich reaction ·
.
rearrangements · stereoselectivity
[15] The syn-amino alcohol products could also be formed by
reaction of the minor Z-imine stereoisomers through chair-like
transition states. For further discussion, see: C. Gennari, A.
therein.
[1] For general reviews on the Mannich reaction, see: a) P. Galatsis
in Name Reactions for Homologations Part II (Ed.: J. J. Li),
Wiley, Hoboken, 2009, p. 653; b) M. Arend, B. Westermann, N.
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2922 –2924