poses important problems to be addressed particularly when
large-scale applications are considered. In this regard the
possibility of employing KCN as a cyanide source has also been
taken into consideration and very recently successfully applied,
among the others, to an organocatalyzed asymmetric Strecker
reaction.5
Herein we disclose the first example of the use of cyanohy-
drins as a CN- source in a organocatalyzed Strecker reaction
performed under phase transfer conditions and employing N-Boc
protected R-amido sulfones as imine precursors.6
Acetone cyanohydrin is one of the simplest, most soluble,
cheap, and on large-scale commercially available cyanide
sources.7 To date its use as cyanide source has been described
for the regiospecific opening of 1,2-epoxides under mild basic
conditions8 and as a new Mitsunobu reagent in the cyanation
of alcohols.9 Furthermore, more recently a convenient procedure
for the Pd-catalyzed cyanation of aryl halides has been
reported.10
Phase Transfer Catalyzed Enantioselective
Strecker Reactions of r-Amido Sulfones with
Cyanohydrins
Raquel P. Herrera,*,† Valentina Sgarzani,‡ Luca Bernardi,‡
Francesco Fini,‡ Daniel Pettersen,‡ and Alfredo Ricci*,‡
Department of Organic Chemistry “A. Mangini”, UniVersity of
Bologna, V. Risorgimento 4, 40136 Bologna, Italy, and Instituto
de InVestigaciones Quimicas (CSIC-Use), Isla de la Cartuja,
Americo Vespucio s/n, 41092 SeVille, Spain
rph@alu.ua.es; ricci@ms.fci.unibo.it
ReceiVed July 28, 2006
We initiated our search for an appropriate reaction system
(see Table 1) with the R-amido sulfone of 3-phenylpropional-
dehyde 2a11 and acetone cyanohydrin 3a as model substrates
in order to develop the cyanation under biphasic conditions (K2-
CO3, organic solvent). Several chiral quaternary ammonium salts
derived from cinchona alkaloids were screened as potential
organocatalysts together with the effects of the imine nitrogen
substituent and of the addition of water.
The key elements for the success of the reaction were the
easily available quinine-derived catalyst 1a and the presence
in it of an electron withdrawing group such as CF3 at ortho
position of the benzyl group, which afforded the expected
product 4a in excellent yield and 60% ee (entry 1 in Table 1).
On the contrary, 1b, in which the same functional group was
installed at the para position, had significantly less efficient
results (16% ee, entry 2). Also the free hydroxyl group at the
position 9 plays a significant role in substrate activation since
the corresponding catalyst 1c, whose OH group had been
protected in the form of benzyl ether, led to a racemic mixture
(entry 3).
Increasing steric hindrance in the cyanide source, such as in
benzophenone (3b) and fluorenone (3c) cyanohydrins, was
detrimental for the enantioselection (compare entries 1, 4, and
5 in Table 1). Finally it was possible to further improve the
enantioselectivity of the reaction by careful optimization of the
reaction conditions. For example, the ee of product 4a could
be enhanced to 68% ee (entry 6) by simply using more dilute
conditions in conjunction with aqueous base and lower tem-
perature (-20 °C). The occurrence of an effective catalytic
A study into the use of a chiral phase-transfer catalyst in
conjunction with acetone cyanohydrin to effect the enanti-
oselective formation of R-amino nitriles from R-amido
sulfones is described. This novel catalytic asymmetric
Strecker reaction is analyzed with regard to the possible
mechanistic basis.
The Strecker hydrocyanation of imines1 is the oldest known
synthesis for the preparation of R-amino acids in an economical
manner and under simple operational conditions.
Since R-amino acid derivatives are broadly used as chiral
building blocks with important applications in complex natural
products,2 the enantioselective variants of this reaction have been
intensively studied over the past years. Several successful
achievements in catalytic asymmetric Strecker reactions were
reported by different groups within the past few years.3
Noteworthy, the range of suitable catalysts is broad, covering
metal catalysts and, more recently, organocatalysts.4 However
most of the previously elaborated catalytic asymmetric meth-
odologies rely on the use of anhydrous hydrogen cyanide which
(5) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006, 128,
2548-2549.
(6) During the preparation of this manuscript a paper on the use of an
NEt3/acetone cyanohydrin as a catalytic system for the three-component
Strecker-type, R-amino nitrile synthesis appeared: Paraskar, A. S.; Sudalai,
A. Tetrahedron Lett. 2006, 47, 5759-5762.
(7) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682.
(8) Mitchell, D; Koenig, T. M. Tetrahedron Lett. 1992, 33, 3281-3284.
(9) Tsunoda, T.; Uemoto, K.; Nagino, C.; Kawamura, M.; Kaku, H.;
Ito, S. Tetrahedron Lett. 1999, 40, 7355-7358.
(10) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003,
42, 1661-1664.
(11) For the preparation of R-amido sulfones see (a) Pearson, W. H.;
Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622-2636.
(b) Mecozzi, T; Petrini, M. J. Org. Chem. 1999, 64, 8970-8972.
* To whom correspondence should be addressed. (A.R.) Phone: +39(051)-
2093635. Fax: +39(051)2093654.
† Instituto de Investigaciones Quimicas.
‡ University of Bologna.
(1) Strecker, V. A. Liebigs. Ann. Chem. 1850, 75, 27-51.
(2) (a) Schultz, P. G.; Ellman, J. A.; Mendel, D. J. Am. Chem. Soc. 1991,
113, 2758-2760. (b) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992,
92, 889-917.
(3) (a) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875-877 and references
cited therein. (b) Kobayashi, S; Ishitani, H. Chem. ReV. 1999, 99, 1069-
1094.
(4) (a) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2828. (b) Corey, E. J.;
Grogan, M. J. Org. Lett. 1999, 1, 157-160. (c) Vachal, P.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 10012-10014. (d) Huang, J.; Corey, E. J.
Org. Lett. 2004, 6, 5027-5029.
10.1021/jo061566u CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/21/2006
J. Org. Chem. 2006, 71, 9869-9872
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