Asymmetric synthesis of β-amino acid derivatives via catalytic conjugate addition of hydrazoic acid to unsaturated imides [10]

Full text of DOI:10.1021/ja991621z

J. Am. Chem. Soc. 1999, 121, 8959-8960
8959
Asymmetric Synthesis of â-Amino Acid Derivatives
via Catalytic Conjugate Addition of Hydrazoic Acid
to Unsaturated Imides
Jason K. Myers and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology
HarVard UniVersity
Cambridge, Massachusetts
ReceiVed May 14, 1999
Interest in synthetic routes to â-amino acids can be traced to
the presence of these building blocks in a variety of biologically-
interesting natural products,1 and to the recent revelation that
derived peptides show well-defined secondary structures.2 While
several methods for the construction of enantiomerically enriched
â-amino acid derivatives have been developed utilizing either
chiral substrates or chiral auxiliaries,1a,3 the enantioselective
catalytic synthesis of these targets from achiral precursors remains
a significant challenge.4 The conjugate addition of amines or their
synthetic equivalents to R,â-unsaturated carbonyl compounds
constitutes one of the most direct and attractive strategies for the
construction of â-amino acid derivatives.4a,c In this paper, we
describe a significant advance in this direction, with the highly
enantioselective conjugate addition of hydrazoic acid (HN3) to
R,â-unsaturated imides catalyzed by a readily available chiral
(salen)Al(III) complex.
and diethylaluminum azide;13 alternatively, the shelf-stable (salen)
Al(III)Me complex 1c could be employed as precatalyst. Complex
1c undergoes rapid conversion to azide complex 1b under the
conditions of catalysis, and identical results were obtained in
reactions employing either of the two complexes.
Pursuant to this encouraging preliminary result, we evaluated
a wide variety of easily accessible conjugate acceptors for the
addition of HN3 catalyzed by 1b. Of these, N-alkylmaleimides
displayed both excellent reactivity and enantioselectivity in the
conjugate addition reaction. Under optimal conditions, N-ethyl-
maleimide (4) underwent clean conversion to afford the azide
adduct 5 in 94% ee and 93% yield (eq 2).
Metal complexes of the salen ligand 1a have been shown to
be effective for a wide variety of asymmetric nucleophile-
electrophile reactions, including the opening of epoxides by azide,5
water,6 carboxylic acids,7 and phenols,8 the addition of HCN to
imines,9 and hetero-Diels-Alder reactions between electron-rich
dienes and aldehydes.10 In a preliminary screen of conjugate
addition reactions using nitrogen-based nucleophiles, we evaluated
this chiral template for catalysis of the addition of hydrazoic acid11
to oxazolidinone 2 (eq 1). The best results were obtained with
aluminum azide complex 1b, which afforded the azide adduct 3
in 34% ee and 50% conversion after 48 h.12 Although complex
1b displayed irreproducible activity after prolonged storage, it
could be generated conveniently in situ from the salen ligand 1a
It appeared that the imide group common to 2 and maleimide
4 was critical for effective catalytic conjugate addition of HN3 in
the presence of the (salen)Al catalyst. On that basis, we examined
a series of acyclic R,â-unsaturated imides as potential substrates
(Table 1). Imide 6 displayed a higher level of reactivity than
oxazolidinone 2, undergoing complete conversion within 6 h at
ambient temperature; however, only modest (31%) enantioselec-
tivity was obtained. The unsubstituted imides 7 and 8a were
equally reactive, but afforded substantially higher enantioselec-
tivity (60-68% ee at rt). Reducing the reaction temperature to
-40 °C led to formation of the azide adduct 9a in excellent yield
and enantioselectivity (96% yield, 96% ee).
Encouraged by the excellent results obtained with the N-benzoyl
imide derivative 8a, we prepared a series of analogs (8b-h)
varying in the identity of the â-substituent. These imide derivatives
were prepared conveniently in a single step via a Horner-
Emmons reaction of the appropriate aldehyde with phosphonate
10 (eq 3). This modular approach allowed rapid access to a wide
(1) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997. (b) Cephalosporins and Penicillins Chemistry and
Biology; Flynn, E. H., Ed.; Academic Press: New York and London, 1972.
(c) Rzasa, R. M.; Shea, H. A.; Romo, D. J. Am. Chem. Soc. 1998, 120, 591.
(d) Bewley, C. A.; Faulkner, D. J. Angew. Chem., Int. Ed. 1998, 37, 2162.
(2) For reviews, see: (a) Seebach, D.; Matthews, J. L. Chem. Commun.
1997, 2015. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) (a) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27,
3. (b) Cole, D. C. Tetrahedron 1994, 32, 9517. (c) Cardillo, G.; Tomasini, C.
Chem. Soc. ReV. 1996, 117. (d) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.;
Gramain, J.; Canet, I. Tetrahedron Lett. 1999, 40, 1661. (e) Lakshmipathi,
P.; Rao, A. V. R. Tetrahedron Lett. 1997, 38, 2551.
(4) For recent advances, see: (a) Falborg, L.; Jørgensen, K. A. J. Chem.
Soc., Perkin Trans. 1 1996, 2823. (b) Kobayashi, S.; Ishitani, H.; Ueno, M.
J. Am. Chem. Soc. 1998, 120, 431. (c) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse,
C. P. J. Am. Chem. Soc. 1998, 120, 6615. (d) While this manuscript was in
preparation, the Detty group reported moderate (up to 46%) enantioselectivity
in the conjugate addition of amines with chiral (salen)Cu(II) complexes: Zhou,
F.; Detty, M. R.; Lachicotte, R. J. Tetrahedron Lett. 1999, 40, 585.
(5) (a) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J.
Am. Chem. Soc. 1995, 117, 5897. (b) Larrow, J. F.; Schaus, S. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 1996, 118, 7420.
variety of unsaturated imides in high yield, and appeared to be
limited only by the availability of the requisite aldehyde.
As illustrated in Table 2, imides 8a-g underwent conjugate
addition of HN3 in the presence of catalyst 1c in excellent yield
(6) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936.
(7) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.; Tokunaga,
F. Tetrahedron Lett. 1997, 38, 773.
(8) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 6086.
(9) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315.
(10) Schaus, S. E.; Bra˚nalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
403.
(11) The preparation and handling of hydrazoic acid solutions are described
H. Wolff (Org. React. 1946, 3, 307).
(12) Of the complexes screened under these conditions (5 mol % catalyst,
rt, 48 h), only the corresponding (salen)Al(III) chloride (31% conversion, 28%
ee), (salen)Cr(III) azide (23% conversion, 9% ee), and (salen)Ru(III) chloride
(46% conversion, 4% ee) proved catalytically active.
(13) Chung, B. Y.; Park, Y. S.; Cho, I. S.; Hyun, B. C. Bull. Korean Chem.
Soc. 1988, 9, 269.
10.1021/ja991621z CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/11/1999

8960 J. Am. Chem. Soc., Vol. 121, No. 38, 1999
Communications to the Editor
Table 1. Asymmetric Conjugate Addition of HN3 to Imides 6-8a
Catalyzed by (R,R)-1c
serves both as a Lewis acid activator of electrophile and as a
nucleophile-delivery agent. The kinetic data obtained in the
reactions of 1b suggest that the aluminum catalyst is fulfilling
only one of those functionsseither as Lewis acid or as mediator
of azide transfersin the conjugate addition to unsaturated imides.15
The utility of â-azido imide adducts 9 as precursors to â-amino
acid derivatives was illustrated through the transformation of azide
9a into N-Boc-â-aminobutyric acid16 (eq 4). The azide group of
R1
R2
ee (%)a
conv (%)
6
7
8a
Me
Me
Ph
Me
H
H
31
62
68
100
100
100
a Full experimental details and ee analyses are provided in the
Supporting Information.
9a was hydrogenated and protected as the tert-butyl carbamate
11 in one operation in 90% yield.17 The imide group underwent
regioselective cleavage with aqueous sodium hydroxide to provide
N-Boc-protected carboxylic acid 12 in 84% yield.
Table 2. Conjugate Addition of HN3 to Unsaturated Imides 8a-h
Catalyzed by (S,S)-1ca
There are several interesting implications to the finding that
(salen)Al complexes are effective catalysts for the enantioselective
addition of azide to unsaturated imides. The reaction itself
employs an inexpensive and easily accessed catalyst, and it
involves a simple experimental protocol. Coupled with the
straightforward reduction and hydrolysis of the â-azido imide
products, this constitutes a useful and general method for the
synthesis of highly enantioenriched â-amino acids. In addition,
unsaturated imides such as 6-8 are easily accessible but have
rarely been used in organic synthesis. Their utility in the conjugate
addition chemistry suggests that they may be interesting substrates
for other asymmetric catalytic reactions. Finally, the results
summarized here constitute the first example of highly enanti-
oselective 1,4-addition catalyzed by chiral (salen)metal complexes,4d
and therefore they expand the chemistry of these versatile catalyst
systems to an important new reaction class. The full scope of
this conjugate addition chemistry remains to be established.
R
ee (%)d yield (%)e
R
ee (%)d yield (%)e
8a Me
8b Et
8c n-Pr
8d i-Pr
96
97
95
97
96
97
97
98
8e t-Bub
8f Bn
8g CH2OBn
97
95
96
58
99
97
93
60
8h Phc
a Unless noted otherwise, reactions were carried out on a 0.5 mmol
scale at -40 °C with 5 mol % catalyst and 6.6 equiv of HN3. b -30
°C. c 23 °C, 10 mol % catalyst. d Enantiomeric excesses were measured
by chiral HPLC on a Pirkle L-leucine column (Regis). The absolute
stereochemistry of 9a was established by conversion to the known
N-Boc amino acid 11. All other assignments were made by analogy.
e Isolated yield after silica gel chromatography.
and ee. The reaction was largely insensitive to the steric properties
of the â-substituent, with alkyl groups ranging from methyl to
tert-butyl all providing products in 95-97% ee.11 However, the
rate of the reaction was somewhat lower for 8e (R ) tert-butyl),
and a slightly higher temperature was required to achieve complete
conversion. The benzyl ether-containing substrate 8g underwent
clean reaction as well, suggesting that a fair level of tolerance
toward Lewis basic functionalities is to be anticipated for this
reaction. Cinnamate derivative 8h was considerably less reactive
than the alkyl-substituted substrates, undergoing incomplete
conversion after 24 h at room temperature. It is worth noting that
the ee of the product was similar to that obtained with 8a under
the same conditions, suggesting that the problem for this important
substrate subclass is one of reactivity and not enantioselectivity.
Acknowledgment. We are grateful to Professor David A. Evans for
helpful discussions. This work was supported by the NIH through Grant
GM43214 and a postdoctoral fellowship to J.K.M.
Supporting Information Available: Complete experimental proce-
dures, analytical data, and chiral chromatographic analyses of racemic
and enantiomerically enriched conjugate addition products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA991621Z
(15) The similarly high enantioselectivities obtained with maleimide 4 and
acyclic substrates 8a-g suggest a reactive s-trans conformation of the
unsaturated imide in the conjugate addition reaction. If a Lewis acid mode of
activation involving one-point binding is assumed, a simplified stereochemical
model can be devised, such as the one below, that accounts for the observed
facial selectivity.
In preliminary kinetic studies, it has been established that the
rate of the conjugate addition reaction displays a first-order
dependence on catalyst 1b. This stands in contrast to the
enantioselective addition of azide to epoxides catalyzed by the
chromium analog of 1b, which displays a second-order depen-
dence on the metal complex.14 In the latter case, a dual role for
the catalyst is indicated wherein the chiral chromium complex
(16) (a) Alco´n, M.; Canas, M.; Poch, M.; Moyano, A.; Perica`s, M. A.;
Riera, A. Tetrahedron Lett. 1994, 35, 1589. (b) Seebach, D.; Circeri, P. E.;
Overhand, M.; Juan, B.; Rigo, D.; Oberer, L.; Hommel, U.; Amstutz, R.;
Widmer, H. HelV. Chim. Acta 1996, 79, 2043.
(17) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett.
1989, 30, 837.
(14) Hansen, K. B., Leighton, J. L., Jacobsen, E. N. J. Am. Chem. Soc.
1996, 118, 10924.