Catalytic enantioselective synthesis of glutamic acid derivatives via tandem conjugate addition - Elimination of activated allylic acetates under chiral PTC conditions

Article abstract of DOI:10.1021/ja052638m

A new, general, and practical procedure for the asymmetric synthesis of 4-alkylidenyl glutamic acid derivatives via a catalytic enantioselective tandem conjugate addition-elimination on allylic acetates under chiral phase-transfer conditions is reported.

Full text of DOI:10.1021/ja052638m

Published on Web 09/13/2005
Catalytic Enantioselective Synthesis of Glutamic Acid Derivatives via Tandem
Conjugate Addition-Elimination of Activated Allylic Acetates under Chiral
PTC Conditions
P. Veeraraghavan Ramachandran,*,† Sateesh Madhi,† Layla Bland-Berry,†
M. Venkat Ram Reddy,† and Martin J. O’Donnell‡
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907-2084, and
Department of Chemistry and Chemical Biology, Indiana UniVersity Purdue UniVersity Indianapolis,
Indianapolis, Indiana 46202-3274
Received April 22, 2005; E-mail: chandran@purdue.edu
Table 1. Enantioselective Alkylation of the Benzophenone Imine
of Glycine tert-Butyl Ester Using Various Phase-Transfer
Catalystsa
Glutamic acid is the main excitatory amino acid in the central
nervous system. The design of ligands for the various types of
glutamate receptors as potential therapeutic agents has attracted the
attention of numerous groups.1 4-Substituted glutamate analogues,
such as 4-substituted alkylidene glutamic acids, have been the
targets of several synthetic and pharmacological studies.2
The enantioselective synthesis of R-amino acid derivatives
employing chiral phase-transfer catalysts (PTC) represents an
important synthetic advancement.3 Enantioselective reactions of the
Schiff bases of amino esters, using PTC conditions catalyzed by
quaternized Cinchona alkaloids by O’Donnell,4 Corey,5 Lygo,6 and
related systems by others,7 have been used to obtain a variety of
amino acid products with impressive levels of enantioselection using
simple procedures. However, to the best of our knowledge, there
have been no reports on the tandem conjugate addition-elimina-
tion8,9 under phase-transfer conditions for the enantioselective
preparation of amino acids.10 Herein we report a new, general, and
practical method for the preparation of 4-alkylidenyl glutamic acids
via tandem conjugate addition-elimination under PTC.
entry
catalyst
temp,
°
C
time, h
yield, %b
ee, %c
1
2
3
4
5
4a
4b
4c
4d
4e
-78
25
-78
-78
-78
30
24
36
36
36
92
72
78
82
78
92
60
86
85
84
a The reaction was conducted with the benzophenone imine of glycine
tert-butyl ester 1 (1 mmol), allylic acetate 2 (1 mmol), CsOH‚H2O (10
equiv), and PTC (10 mol %) in CH2Cl2 for the given time. b Isolated yield.
c The enantiopurity of model product (S)-3a was determined by chiral HPLC
analysis of the product using a (S,S)-Whelk-O1 column (Regis Technologies)
with hexane:2-propanol as the solvent system; the resolution of the
enantiomers was confirmed by analysis of racemic glutamate (3a); see
Supporting Information.
Targets for initial studies, which focused on standardizing the
reaction conditions and determining the scope of the methodology,
were the racemic glutamate derivatives 3 (Scheme 1).
Scheme 1. Synthesis of the 4-Alkylidenyl Glutamic Acid
Derivatives
Figure 1. Structure of the phase-transfer catalysts.
2a using O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide
(4a) as the PTC (CsOH‚H2O, CH2Cl2, -78 °C) gave the model
product (S)-3a in 92% yield and 92% ee (Table 1 and Figure 1).
Use of homogeneous reaction conditions (catalyst 4a, Schwesing-
er base BEMP, CH2Cl2, -78 °C, 24 h)4c,d afforded (S)-3a in 90%
yield and 79% ee. Similarly, liquid-liquid PTC (4b, 50% KOH,
PhMe, 25 °C, 24 h)6a also gave poorer results. Variation in the
N-alkyl group on the quinuclidine core of the quaternary ammonium
salt (4c-4e) also resulted in decreased yields and enantioselec-
tivities (Table 1). As expected from literature reports, the anthra-
cenylmethyl-derived catalyst (4a) gave the best enantioselectivity
(92% ee) and yield. N-Benzyl cinchonidinium bromide (4e) was
the least effective catalyst of those studied (84% ee), while the 2-
and 1-naphthylmethyl-derived catalysts (4c and 4d, respectively)
gave intermediate results.
Reaction of the lithium enolate of the benzophenone imine of
glycine tert-butyl ester (1) with allylic acetates 2, prepared via
vinylalumination11 or Baylis-Hillman reaction,9 in THF at -78
°C for 1.5-4.5 h, gave the racemic products 3.12 A variety of types
of allylic acetates, including aromatic, aliphatic, heterocyclic, and
fluoroaromatic, smoothly undergo the tandem conjugate addition-
elimination (see Supporting Information). It is noteworthy that, with
allylic acetates that are not activated with an ester group at the
2-position, palladium catalysis is required in similar reactions.13
We then investigated the enantioselective version of the tandem
conjugate addition-elimination to prepare optically active 4-alkyl-
idenyl glutamates 3 using chiral PTC. Catalysts derived from the
Cinchona alkaloids were chosen because of their demonstrated
applicability in phase-transfer catalysis and their facile preparation
from inexpensive and available sources.3-6 The reaction of 1 with
A number of optically active 4-alkylidene glutamates were
prepared using the optimized conditions developed for the model
phenyl-substituted product 3a using 4a as the PTC (Table 2).
Product 3b, derived from the electron-poor allylic acetate 2b, gave
† Purdue University.
‡ Indiana University Purdue University Indianapolis.
9
13450
J. AM. CHEM. SOC. 2005, 127, 13450-13451
10.1021/ja052638m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of 4-Substituted Pyroglutamates
Table 2. Enantioselective Synthesis of 4-Alkylidenyl Glutamic Acid
Derivatives under Phase-Transfer Conditionsa
allyl
glutamic acid
derivative
acid derivatives, which is based on the catalytic enantioselective
tandem conjugate addition-elimination of the Schiff base of glycine
tert-butyl ester with activated allylic acetates under phase-transfer
conditions. The simple procedure and high enantioselectivity of the
process offer a practical route to these important targets.
entry
acetate
R
time, h
yield, %b
ee, %c
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
30
48
48
48
34
48
34
40
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
(S)-3g
(S)-3h
92
72
63
90
72
68
82
63
92
97
89
86
82
80
82
85
4-NO2-Ph
4-MeO-Ph
2-thienyl
2-pyridinyl
2,6-F2Ph
nPr
2g
2h
Acknowledgment. Dedicated to the memory of Professor
Herbert C. Brown.We gratefully acknowledge the National Institutes
of Health (GM 28193) for support of this research.
tBu
a The reaction was conducted with the benzophenone imine of glycine
tert-butyl ester 1 (1 mmol), allylic acetate 2 (1 mmol), CsOH‚H2O (10
equiv), and 4a (10 mol %) in CH2Cl2 for the given time. b Isolated yield.
c Enantiopurities of the products (S)-3 were determined by chiral HPLC
analysis of the product using a (S,S)-Whelk-O1 column (Regis Technologies)
with hexane:2-propanol as the solvent system; in each case, the resolution
of the enantiomers was confirmed by analysis of racemic glutamates (3);
see Supporting Information.
Supporting Information Available: Experimental details, spectral
data, and X-ray crystal data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Moloney, M. G. Nat. Prod. Rep. 1998, 205. (b) Brauner-Osborne, H.;
Egebjerg, J.; Nielsen, E. Ø.; Madsen, U.; Krogsgaard-Larsen, P. J. Med.
Chem. 2000, 43, 2609. (c) Augelli-Szafran, C. E.; Schwarz, R. D. Ann.
Rep. Med. Chem. 2003, 38, 21.
(2) (a) Baker, S. R.; Bleakman, D.; Ezquerra, J.; Ballyk, B. A.; Deverill, M.;
Ho, K.; Kamboj, R. K.; Collado, I.; Dom´ınguez, C.; Escribano, A.; Mateo,
A. I.; Pedregal, C.; Rubio, A. Bioorg. Med. Chem. Lett. 2000, 10, 1807.
(b) Wehbe, J.; Rolland, V.; Fruchier, A.; Roumestant, M.; Martinez, J.
Tetrahedron: Asymmetry 2004, 15, 851.
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Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
Figure 2. X-ray crystal structure of glutamate product (S)-3d.
(7) (a) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Vyskocil, S.; Kagan, H. B. Tetrahedron: Asymmetry 1999, 10, 1723. (b)
Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g. Org. Lett.
2002, 4, 4245. (c) Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002,
43, 9535. (d) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.;
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Chem. ReV. 2003, 103, 3013. (f) Chinchilla, R.; Mazo´n, P.; Na´jera, C.;
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Shibuguchi, T.; Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743.
(8) This reaction is referred to as an SN2′ reaction in the literature; see ref 9.
However, this is a conjugate addition-elimination that yields an SN2′-
type product.
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and 7g.
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J. Tetrahedron 2001, 57, 9711.
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(15) The hydrogenation of (S)-4 yields the cis-diastereomer selectively:
Ezquerra, J.; Pedregal, C.; Yruretagoyena, B.; Rubio, A.; Carreno, M.
C.; Escribano, A.; Ruano, J. L. G. J. Org. Chem. 1995, 60, 2925 and
cited references. For the X-ray crystal structure of the N-Boc-protected
(2S,4S-5), see the Supporting Information.
the highest enantioselectivity (97% ee, entry 2), while the deacti-
vated electron-rich allylic acetate 2c gave a lower % ee of product
3c (89% ee, entry 3). In the case of heterocyclic, fluoroaromatic,
and aliphatic allylic acetates, slightly lower enantioselectivities (80-
86%) were obtained.
The structure of product 3d, including the E-double bond
geometry, was elucidated by spectroscopic and X-ray crystal-
lographic techniques (Figure 2). The absolute configuration (2S)
of the stereogenic center resulting from the enantioselective
alkylation was assigned by analogy with earlier studies, which have
shown that 2S products result when cinchonidine-derived catalysts
are used in the PTC alkylation.3-6,7f This assignment was confirmed
by conversion of (S)-3d to the known 4-oxo glutamic acid via the
dihydroxylation-periodate cleavage of the double bond, followed
by hydrolysis14 (see Supporting Information).
The utility of this process was demonstrated by transforming a
representative 4-alkylidene glutamate (S)-3a into 4-oxo glutamates
and 4-substituted pyroglutamates (Scheme 2), which can be readily
converted to 4-substituted glutamic acids15 (see Supporting Infor-
mation).
In conclusion, we have presented a new, general, and practical
procedure for the asymmetric synthesis of 4-alkylidenyl glutamic
JA052638M
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