Short Articles
Bull. Chem. Soc. Jpn. Vol. 83, No. 12, 1545–1547 (2010) 1545
one.6 However, efficient procedures for the preparation of ¢-amino
acids are of continuous interest,7 because of increasing importance
of ¢-amino acid moieties in bioactive molecules.8,9
Diastereoselective Michael Addition
of Magnesium Amide to
O-(2-Alkenoyl)TEMPOs
and Comparison of Reactivity
with Acyl Substituent-Modified
Carboxylic Analogues
As far as the 1,4-addition of amide anion is concerned, we have
shown in a previous paper that the conjugate addition of the
lithium amide from secondary amine to O-(2-alkenoyl)TEMPO
(TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl) followed by aldol
reaction of the resulting enolate with aldehyde proceeded to give
the three-component combined products in good yields.10 We
therefore examined the diastereoselective addition of optically
active amides to O-(2-alkenoyl)TEMPOs I to produce the optically
pure ¢-amino acid derivatives II (E = H). Meanwhile, we also
studied the effect of TEMPO as the acyl substituent11 in
comparison with other acyl substituent-modified analogs such as
Weinreb amides. Furthermore, we attempted to introduce a
hydroxy group or its equivalent at the C2 position by trapping
the resulting enolate, after the amide anion addition, with the N-O
double bond of the N-oxoammonium salt, forming II (E =
TEMPO) (Scheme 1).
Li-Jian Ma,1 Zhen-Wu Mei,1 Keisuke Toyohara,1
Hiroyuki Kawafuchi,2 Junzo Nokami,3 and
Tsutomu Inokuchi*1
1Department of Medicinal and Bioengineering Science,
Graduate School of Natural Science and Technology,
Okayama University, Tsushima-naka, Kita-ku,
Okayama 700-8530
1) R1R2N–Mtl+
2) "E+"
R1R2N
R
O
O
N
N
O
R
O
2Department of Chemical and Biochemical Engineerings,
Toyama National College of Technology, Hongo-machi,
Toyama 939-8630
E
I
II
E = H, TEMPO
"E+" =
N O
3Department of Applied Chemistry, Faculty of Engineering,
Okayama University of Science, Ridai-cho, Kita-ku,
Okayama 700-0005
Scheme 1. Addition of amide anion to O-(2-alkenoyl)-
TEMPOs and reaction with electrophiles.
Results and Discussion
Received June 28, 2010
Prior to executing the 1,4-addition of amide anions, we
reinvestigated the electronic structure of the carbonyl function of
O-(2-butenoyl)TEMPO (1c) in comparison with analogs bearing
different hetero-hetero atom bonds such as Weinreb amide 1d,12
E-mail: inokuchi@cc.okayama-u.ac.jp
O-(2-Alkenoyl)TEMPOs bearing an O-N bond in the acyl
substituent are highly reactive in Michael addition of magnesium
amide compared with their acyl substituent-modified analogs.
Highly diastereoselective addition is achieved to the AlMe3-
treated O-(2-alkenoyl)TEMPO as an acceptor with the Mg amide
generated from optically active secondary amine.
peroxy ester 1e, and carbazide 1f.13
¹1
As shown in Table 1, 1c shows IR absorption at 1752 cm
,
which is much higher than Weinreb amide 1d (1668 cm¹1) and
carbazides 1f (1662 cm¹1). Accordingly, 1c has a stronger carbonyl
vibration than Weinreb amide 1d. This implies that contribution of
the charged resonance structure of 1c is less important for O-(2-
alkenoyl)TEMPOs, in contrast to Weinreb amide 1d, in which the
amide-resonance structure is most important. Therefore, it is
expected that O-(2-alkenoyl)TEMPOs would be more reactive as a
Michael acceptor of various amide nucleophiles than other acyl
substituent-modified derivatives, 1d and 1f.
¢-Amino acids show interesting pharmacological properties and
are found in free form or as components of naturally occurring
biologically active peptides, and ¡-hydroxy-¢-amino acids are
also found in various peptidic enzyme inhibitors and constitute the
side chain of the anticancer drug taxolµ.1,2 Although many
approaches to this class of amino acid are developed by
homologation of ¡-amino acids, hydrogenation of 3-aminoacry-
lates, derivatization of aspartic derivatives, and others,1a,1c,1d the
most direct access to this structural unit must be Michael addition
of amines or amide anions to acrylates and derivatives.3
With respect to 1,4-addition of amide anion, Yamamoto and co-
workers devised a silylated amide anion to improve the yield and
selectivity.4 Davies et al. reported later that addition of a lithium
amide from optically active secondary amines to 2-alkenoates pro-
ceeded with high diastereoselectivity.3 Furthermore, Tomioka et al.
developed the ligand-controlled asymmetric conjugate addition of
lithium amides to enoates by employing C2-symmetry diether,5 and
Sodeoka et al. reported Pd-catalyzed asymmetric conjugate addition
of various amines toward 3-(2-alkenoyl)-2,3-dihydroisoxazole-2-
With this knowledge in hand, we examined the Michael
addition of lithium benzylamide from the amine 6a to 1c, and
results were compared with those of alkyl butenoates 1a and 1b,
butenoic Weinreb amide 1d, and the peroxy ester 1e (Table 2).
Thus, the reaction of lithium benzylamide and 1c proceeds at
¹78- ¹70 °C to give the corresponding adduct 2c in 94% yield
(Entry 3). Neither of the nucleophilic acyl substitutions were
found except for a small amount of the deconjugated 5 due to £-
deprotonation. In contrast, the reaction of crotonates 1a and 1b
with lithium benzylamide suffers from low yield (Entry 2) and
considerable amount of acyl substitution, forming 3 (Entry 1).4
Furthermore, the reaction of Weinreb amide 1d with lithium
benzylamide produces the acyl substitution 4 as a major product,
without forming 1,4-addition products (Entry 4). In addition, the
reaction of the peroxy ester 1e produces no desired amination, but
the acyl group substitution product 4 as a major product. Thus,