ˇ
´
A. V. Malkov, P. Kocovsky et al.
erating in the case of the a-aryl and a-alkyl derivatives, pro-
vided a set of highly diastereoisomerically enriched b2,3
-
amino acid derivatives 6l–n, 6p–r, and 7l–n (syn/antiꢄ95:5)
with good enantioselectivity (76-86% ee).
Experimental Section
General procedure[7] for the synthesis of enamines 3a–j and3l–r : A solu-
tion of ketoester 1 (5 mmol), p-anisidine (677 mg, 5.5 mmol), and p-tolu-
AHCTREeUNG nesulfonic acid monohydrate (95 mg, 0.5 mmol) in dry ethanol (5 mL)
was heated at reflux for 24–48 h under argon, then cooled and evaporat-
ed. Solid residues were directly purified by crystallization. Oily residues
were dissolved in CH2Cl2 (20 mL) and washed with water (10 mL), the
organic phase was dried (MgSO4), filtered, and evaporated. The residue
was purified by column chromatography on silica gel.
Enamine 3k: A mixture of ketoester 1k (791 mg, 5 mmol), p-anisidine
(677 mg, 5.5 mmol), and acetic acid (29 mL) was placed in an ultrasound
bath for 3 h, then acetic acid was evaporated in vacuo. The residue was
purified by column chromatography on silica gel with a petroleum ether/
ethyl acetate mixture (95:5, Rf =0.36). Yields and spectral data are given
in the Supporting Information.
General procedure[19] for the synthesis of enamines 4a, 4l–n, 4s: A solu-
tion of ketonitrile 2 (5 mmol) and p-anisidine (800 mg, 6.5 mmol) or ani-
line (605 mg, 6.5 mmol) in glacial acetic acid (2.9 mL) was stirred at 808C
for 6 h under argon. The mixture was then cooled to room temperature
and the precipitated solid was filtered off, washed with glacial acetic acid,
vacuum dried, and used without further purification (4n, 4s) or after ad-
ditional recrystallization (4a). In the cases in which no solid precipitated
(4l, 4m), the reaction mixture was diluted with water (50 mL) and ex-
tracted with CH2Cl2 (325 mL). The organic phase was washed with
0.5m HCl (25 mL) and brine (25 mL), dried (MgSO4), filtered, and
evaporated. The residue was purified by column chromatography on
silica gel (4l) or by recrystallization (4m). Yields and spectral data are
given in Supporting Information.
Scheme 2. Determination of the relative and absolute configuration of
amino ester 6l and the relative configuration of amino ester 6o.
formed from the a-unsubstituted enamines 3a and 4a. Anal-
ogous experiments, carried out with the a-benzyl derivative
(6o), that is, reduction and cyclization (6o!11o!12o), re-
vealed the anti-configuration for the major diastereoisomer.
The observed DKR in the reduction of (ꢂ)-5l,p–r is con-
sistent with the model, in which the ester carbonyl and the
imine group are held together either by hydrogen bonding
(in the protonated form) or by chelation to silicon (A,
Scheme 3). In the case of a-aryl derivatives 5l–n, featuring
General procedure for the asymmetric reduction of enamines 3 and 4
with trichlorosilane: A solution of enamine 3 or 4 (0.2mmol) in dry tolu-
ene (2mL) was precooled to 0 8C and a 0.1m solution of catalyst 8 in dry
toluene (100 mL, 5 mol%) was added, followed by glacial acetic acid
(11.5 mL, 1.0 equiv) and freshly distilled trichlorosilane (40 mL, 0.4 mmol,
2.0 equiv). The reaction mixture was stirred at room temperature for
48 h, after which time a saturated aqueous solution of NaHCO3 (5 mL)
was added to quench the reaction. The mixture was diluted with brine
(10 mL), extracted with EtOAc (220 mL) and the combined organic
Scheme 3. Preferred directions of the nucleophilic attack at the C=N
bond.
fractions were dried over MgSO4. Concentration in vacuo, followed
flash chromatography on silica gel, afforded products and 7,
respectively.
ACHTREUNGby
6
high diastereoselectivity, both the chelation and the Felkin–
Anh model, in which Ph assumes a perpendicular orienta-
tion to the C=N bond (B, Scheme 3), predict the formation
of the same syn diastereoisomer. Predominant formation of
the anti isomer in the case of 3o (in ꢃ3:1 ratio) is consistent
with conformation C (Scheme 3) of the imine intermediate
(ꢂ)-5 in the catalytic reduction, which suggests a small rela-
tive difference in the conformational energies of the transi-
tion state.[18]
AHCTREUNG
Acknowledgements
We thank the EPSRC for grant no. GR/S87294/01, the European Socra-
tes-Erasmus Exchange Program for a fellowship to M.A., and the Uni-
versity of Glasgow for a fellowship to K.V.
In summary, we have developed a new, expedient protocol
for the enantioselective synthesis of b3- and b2,3-amino acid
derivatives 6 and 7 from the enamine precursors 3/4. The
method relies on fast equilibration between the enamine
and imine forms (3/4Q5). Reduction of the equilibrated
mixture with Cl3SiH, catalyzed by the l-valine-derived form-
Keywords: amino acids · asymmetric synthesis · imines ·
organocatalysis · reduction
[1] For an overview, see: D. L. Steer, R. A. Lew, P. Perlmutter, A. I.
ACHTREUNGamide 8 (5 mol%), afforded the corresponding amino esters
(S)-6a–k and amino nitriles (S)-7a,s in excellent yields and
with high enantioselectivity (ꢀ90% ee). Efficient DKR, op-
[2] For overviews, see: a) D. C. Cole, Tetrahedron 1994, 50, 9517–9582;
b) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1999, 118–128; c) M.
8084
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8082– 8085