3154
J . Org. Chem. 1998, 63, 3154-3155
Communications
Dyn a m ic Kin etic Resolu tion s Ca ta lyzed by a
P la n a r -Ch ir a l Der iva tive of DMAP :
En a n tioselective Syn th esis of P r otected
r-Am in o Acid s fr om Ra cem ic Azla cton es
J ack Liang, J . Craig Ruble, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received February 25, 1998
Due to the widespread occurrence of R-amino acids in
biologically active compounds, the development of efficient
methods for their enantioselective synthesis is a challenge
of considerable practical importance.1 To date, approaches
that employ stoichiometric chiral auxiliaries have been the
primary focus of attention, although several effective cata-
lytic methods have also been reported, perhaps most notably
the metal-catalyzed asymmetric hydrogenation of dehy-
droamino acids.2
F igu r e 1. Dynamic kinetic resolution in the ring opening of
azlactones.
Ta ble 1. Dyn a m ic Kin etic Resolu tion : Solven t Effect on
En a n tioselectivity
One straightforward route to the synthesis of protected
R-amino acids involves the ring opening of azlactones by
alcohols or by water. Because of the propensity of azlactones
to racemize (pKa ∼9),3 this process is especially interesting
from the standpoint of asymmetric catalysis, since a dynamic
kinetic resolution (deracemization)4 should be possible (Fig-
ure 1). Indeed, proof-of-principle for this strategy has been
established using enzymes.5
4-(Dimethylamino)pyridine (DMAP) is an effective cata-
lyst for the ring opening of azlactones by alcohols. We
recently described the synthesis and resolution of two
planar-chiral derivatives of DMAP (1 and 2), and we
demonstrated the efficiency of enantiopure 1 as a catalyst
for the kinetic resolution of secondary alcohols.6 In this
paper, we report the application of enantiopure 2 to the
deracemization/ring opening of azlactones.
In initial studies, we determined that, like DMAP itself,
planar-chiral DMAP analogue 2 catalyzes the addition of
alcohols to azlactones and that racemization occurs rapidly
relative to ring opening (eq 1).7 With regard to the central
issue of stereoselectivity, we investigated the methanolysis
of (()-3, and we established that enantiopure (-)-2 catalyzes
the dynamic kinetic resolution of this azlactone, preferen-
tially affording the L-alanine derivative (Table 1). The level
of enantioselectivity is solvent-dependent, with toluene
furnishing the highest ee (entry 8, 49% ee).
(1) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (b) Williams,
R. M. Synthesis of Optically Active R-Amino Acids; Pergamon: New York,
1989.
(2) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112. (b) Takaya,
H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH: New York, 1993; Chapter 1. (c) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994; Chapter 2.
(3) (a) de J ersey, J .; Zerner, B. Biochemistry 1969, 8, 1967-1974. (b)
Goodman, M.; Levine, L. J . Am. Chem. Soc. 1964, 86, 2918-2922. (c)
Benoiton, N. L. The Peptides; Academic: New York, 1983; Vol. 5, Chapter
4.
(4) (a) Stecher, H.; Faber, K. Synthesis 1997, 1-69. (b) Caddick, S.;
J enkins, K. Chem. Soc. Rev. 1996, 25, 447-456. (c) Ward, R. S. Tetrahe-
dron: Asymmetry 1995, 6, 1475-1490. (d) Noyori, R.; Tokunaga, M.;
Kitamura, M. Bull. Chem. Soc. J pn. 1995, 68, 36-56.
(5) (a) Pugniere, M.; Kraicsovits, F.; Coletti-Previero, M.-A.; Previero,
A. Biotech. Lett. 1985, 7, 641-646. (b) Bevinakatti, H. S.; Newadkar, R. V.;
Banerji, A. A. J . Chem. Soc., Chem. Commun. 1990, 1091-1092. (c) Crich,
J . Z.; Brieva, R.; Marquart, P.; Gu, R.-L.; Flemming, S.; Sih, C. J . J . Org.
Chem. 1993, 58, 3252-3258. (d) Turner, N. J .; Winterman, J . R.; McCague,
R.; Parratt, J . S.; Taylor, S. J . C. Tetrahedron Lett. 1995, 36, 1113-1116.
(6) (a) Ruble, J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc. 1997,
119, 1492-1493. (b) Ruble, J . C.; Tweddell, J .; Fu, G. C. In press. See also:
Ruble, J . C.; Fu, G. C. J . Org. Chem. 1996, 61, 7230-7231.
(7) We inadvertently discovered that the presence of benzoic acid leads
to ring opening of the azlactone at a faster rate and with higher enanti-
oselectivity than in the absence of benzoic acid (with no benzoic acid: <2%
ee for the ring opening of (()-3 with MeOH catalyzed by (-)-2).
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