Diastereo- and enantioselective conjugate addition of α-substituted nitroacetates to maleimides under base-free neutral phase-transfer conditions

Article abstract of DOI:10.1039/c1cc14043d

Highly diastereo- and enantioselective conjugate addition of α-substituted nitroacetates to maleimides under base-free neutral phase-transfer conditions was developed for the synthesis of α,α-disubstituted α-amino acid derivatives.

Full text of DOI:10.1039/c1cc14043d

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Diastereo- and enantioselective conjugate addition of a-substituted
nitroacetates to maleimides under base-free neutral phase-transfer
conditionswz
Seiji Shirakawa, Shogo J. Terao, Rongjun He and Keiji Maruoka*
Received 6th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1cc14043d
Highly diastereo- and enantioselective conjugate addition of
a-substituted nitroacetates to maleimides under base-free
neutral phase-transfer conditions was developed for the synthesis
of a,a-disubstituted a-amino acid derivatives.
The structural motif of a,a-disubstituted a-amino acids is
widely observed in important biologically active compounds
and natural products. Accordingly, numerous synthetic efforts
have been devoted to build up this structure in a highly
stereoselective manner, and hence various efficient catalytic
asymmetric methods have been developed.1 Among them,
enantioselective phase-transfer catalyzed reactions2 of aldimine
Schiff bases of type 1, which are derived from a-substituted
a-amino acids, with appropriate electrophiles (E+) represent
one of the most practical protocols for the synthesis of
a,a-disubstituted a-amino acids 3 (Scheme 1, left equation).2,3
The drawback of this method in the reported literature from
an atom-economic point of view is that it often needs more
than stoichiometric amounts of a base additive for asymmetric
alkylation and conjugate addition.3 As an alternative approach
to solve this problem, we are interested in the possibility of
developing base-free reaction of a-substituted nitroacetates 2
as a-amino acid equivalents under neutral phase-transfer
conditions (Scheme 1, right equation).4 The strong electron-
withdrawing nature of the nitro group in compound 2 offers
appropriate reactivity for neutral phase-transfer reactions.
Scheme 2 Conjugate addition of a-substituted nitroacetate to
maleimide.
As a model reaction for the synthesis of a,a-disubstituted
a-amino acid derivatives under neutral phase-transfer conditions,
we have been interested in the development of asymmetric
conjugate addition of a-substituted nitroacetates to maleimides
(Scheme 2). The product of this reaction offers an attractive
structure in natural product chemistry and medicinal chemistry,
because structures similar to product 4 are observed in biologically
active natural products such as penmacric acid5 and deal-
anylalahopcin.6 It should be noted that the reaction using
aldimine Schiff base 1 with maleimide generally gives the
cycloaddition product 5,7 hence making it difficult to construct
the structures of type 4. Here we wish to report a novel
environmentally benign approach for the asymmetric synthesis
of a,a-disubstituted a-amino acids based on the base-free
neutral phase-transfer conditions in water-rich biphasic
solvents. The present reaction is only achieved when the reaction
is performed under the base-free neutral phase-transfer conditions.
We first examined the screening of binaphthyl-modified
chiral ammonium salts as phase-transfer catalysts for conjugate
addition of methyl 2-nitrohexanoate 2a under base-free neutral
conditions in water-rich biphasic solvents (Table 1). Attempted
reaction of methyl 2-nitrohexanoate 2a and N-benzylmaleimide
in H2O/toluene (10 : 1 ratio) with 3 mol% of (S)-6a or (S)-6b3e,8
as chiral phase-transfer catalyst at room temperature (25 1C) for
24 h afforded conjugate adduct 4a (R = Bn) in very low yield
(Table 1, entries 1 and 2). The use of a morpholine-derived
catalyst (S)-6c gave the product in low yield with low
stereoselectivity (entry 3). To our delight, an improvement in
both yield and enantioselectivity was attained by using a
bifunctional catalyst (S)-7a4,9 possessing diarylhydroxymethyl
groups (56% yield, dr 1.4: 1, 33% ee; entry 4). Exchange of the
morpholine-derived catalyst (S)-7a for piperidine-derived catalyst
(S)-7b improved the diastereoselectivity (dr 4.9 : 1; entry 5).
Scheme 1 Asymmetric synthesis of a,a-disubstituted a-amino acids
under phase-transfer conditions.
Laboratory of Synthetic Organic Chemistry and Special Laboratory
of Organocatalytic Chemistry, Department of Chemistry, Graduate
School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-4041;
Tel: +81-75-753-4041
w This article is part of a ChemComm ‘Organocatalysis’ web-theme
issue.
z Electronic supplementary information (ESI) available. CCDC
805745 and 805746. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc14043d
c
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Chem. Commun., 2011, 47, 10557–10559 10557

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Table 1 Optimization of the reaction conditionsa
The effect of counter anions of the chiral ammonium salt (S)-7c
was also examined. Exchange of the bromide anions of (S)-7c
with hydroxide and phenoxide anions,11 which showed basic
property, caused the decrease of diastereo- and enantioselectivities
(Scheme S1, ESIz). These results clearly indicate that the neutral
property of the chiral ammonium bromide is very important to
obtain high diastereo- and enantioselectivities.
With optimal reaction conditions in hand, we further
studied the generality of the enantioselective conjugate
addition of a-substituted nitroacetates to N-benzylmaleimide
under the neutral conditions in the presence of chiral bifunctional
ammonium bromide (S)-7c (Table 2). Various types of
nitroacetates were found to be employable for the reaction.
The reactions of nitroacetates having a simple alkyl chain such
as n-butyl and n-hexyl groups gave the corresponding
conjugate adducts 4a and 4b in good diastereo- and enantios-
electivities at 10 1C (dr 13 : 1–19 : 1, 88% ee; entries 1 and 3).
The reaction at lower temperature (0 1C) improved both these
selectivities and gave the products with high stereoselectivities
(dr 420 : 1, 91% ee; entries 2 and 4). The nitroacetates
possessing various benzylic groups were employable for the
reaction. Although electronic properties on the aromatic ring of
benzylic groups slightly affected the stereoselectivity, the
reactions gave the products 4c–e in good to high diastereo-
and enantioselectivities (dr 12 : 1–420 : 1, 84–90% ee; entries 5–7).
The reaction of nitroacetates possessing cinnamyl and propargyl
groups also gave the products in good to high diastereo- and
enantioselectivities (dr 10 : 1, 83–90% ee; entries 8 and 9).
Entry
Catalyst
R
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
(S)-6a
(S)-6b
(S)-6c
(S)-7a
(S)-7b
(S)-7c
(S)-7c
(S)-7c
(S)-7c
(S)-7c
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Ph
o5
o5
7
56
33
86
70
51
43
36
—
—
–
–
1 : 2.2
1.4 : 1
4.9 : 1
9.0 : 1
13 : 1
420 : 1
2.0 : 1
16 : 1
10e
33
33
80
88
91
64
63
7f
8g
9
10
The nitro group of resulting products 4 can be readily
reduced to obtain a,a-disubstituted a-amino acid derivatives.
For example, treatment of conjugate adduct 4a with acetic
acid in iso-propanol in the presence of zinc12 gave the
corresponding a,a-disubstituted a-amino acid 8 in 88% yield
with almost no loss of stereo information (Scheme 3).
a
Reaction conditions: 2a (0.050 mmol) and maleimide (0.060 mmol)
in the presence of 3 mol% of chiral phase-transfer catalyst in H2O
b
(2.0 mL)/toluene (0.20 mL) at room temperature for 24 h. Yield of
isolated products. Determined by 1H NMR and HPLC analyses.
c
d
e
Determined by chiral HPLC analysis. Enantiomeric excess of
f
g
minor diastereomer. Reaction was performed at 10 1C. Reaction
was performed at 0 1C.
Table
2 Diastereo- and enantioselective conjugate addition of
a-substituted nitroacetates to N-benzylmaleimide under neutral
phase-transfer conditionsa
Furthermore, switching the catalyst to (S)-7c possessing a
4-methylpiperidine skeleton dramatically enhanced the yield and
stereoselectivity (86% yield, dr 9.0 : 1, 80% ee; entry 6).10 The
reaction at lower temperature (10 1C) further improved the
stereoselectivity (dr 13 : 1, 88% ee; entry 7), and the highest
diastereo- and enantioselectivity was attained when the reaction
was performed at 0 1C with catalyst (S)-7c (dr 420 : 1, 91% ee;
entry 8). The reactions with N-methyl- and N-phenylmaleimide
gave moderate enantioselectivities (entries 9 and 10).
Entry R1
R2 Yieldb (%) drc
eed (%)
88
1
n-Bu
Me 70 (4a)
Me 51 (4a)
Me 63 (4b)
Me 42 (4b)
13 : 1
420 : 1 91
19 : 1 88
420 : 1 91
420 : 1 87
12 : 1
420 : 1 90
10 : 1
10 : 1
It should be noted that the present reaction does not work
well under the ordinary phase-transfer conditions using
aqueous base solutions, such as those of KOH and K2CO3,
which primarily caused the partial decomposition of substrates
and the product under the basic conditions (Scheme S1, ESIz).
Even in the reaction using PhCO2K as a relatively mild base,
almost no conjugate adduct 4a was obtained. Furthermore, the
reaction under homogeneous conditions without aqueous solution
does not proceed at all. Hence, the diastereo- and enantioselective
conjugate addition of a-substituted nitroacetate to maleimide
was only achieved when the reaction was performed under
the base-free neutral phase-transfer conditions in water-rich
biphasic solvents.
2e
3
n-Hex
4e
5
PhCH2
4-Br-C6H4CH2
4-Me-C6H4CH2
(E)-PhCHQCHCH2 Et
CHRCCH2 Et
Et
Et
Et
54 (4c)
72 (4d)
72 (4e)
92 (4f)
71 (4g)
6f
7
84
8g
9
83
90
a
Reaction conditions:
(0.060 mmol) in the presence of 3 mol% of catalyst (S)-7c in H2O
2 (0.050 mmol) and N-benzylmaleimide
b
(2.0 mL)/toluene (0.20 mL) at 10 1C for 24 h. Yield of isolated
c
d
products. Determined by 1H NMR and HPLC analyses. Determined
e
f
by chiral HPLC analysis. Reaction was performed at 0 1C. Reaction
was performed for 120 h. Reaction was performed for 48 h.
g
c
10558 Chem. Commun., 2011, 47, 10557–10559
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The observed diastereoselectivity may also be explained by the
steric repulsion between one of the diarylhydroxymethyl
groups of (S)-7c and N-benzylmaleimide (A 4 B in Fig. 1).
This explanation of steric repulsion being responsible for the
high diastereoselectivity was supported by the result of
reaction using less hindered N-methylmaleimide, which gave
low diastereoselectivity (dr 2.0 : 1; Table 1, entry 9).
This work was partially supported by a Grant-in-Aid for
Scientific Research from JSPS, MEXT (Japan) and The
Association for the Progress of New Chemistry.
Scheme 3 Reduction of the nitro group on product 4a.
To obtain insight into the transition state structure for the
present enantioselective conjugate addition, we tried X-ray
diffraction analysis of ammonium nitronate prepared from the
chiral bifunctional ammonium bromide of type 7 and nitroacetate.
Several kinds of ammonium nitronates were prepared to obtain
crystals suitable for X-ray diffraction analysis, and we finally
succeeded in obtaining a single-crystal X-ray structure of
(S)-7d (Fig. 1),13 which was prepared from an ammonium
bromide of type 7 possessing diphenylhydroxymethyl groups
(Ar = Ph, X = CH–Me in Table 1, (S)-7) and methyl
2-nitropropanoate. Very importantly, the hydrogen bonding
interaction between the hydroxy group in the binaphthyl unit
and the oxygen of the nitro group is clearly observable in the
crystal structure of (S)-7d.
We are grateful to Dr Hiroyasu Sato (Rigaku Corporation)
for X-ray crystallographic analysis.
Notes and references
1 For reviews on asymmetric synthesis of a,a-disubstituted a-amino
acids, see: (a) C. Cativiela and M. D. Dı
Tetrahedron: Asymmetry, 1998, 9, 3517; (b) C. Cativiela and
M. D. Dıaz-de-Villegas, Tetrahedron: Asymmetry, 2000, 11, 645;
(c) Y. Ohfune and T. Shinada, Eur. J. Org. Chem., 2005, 5125;
(d) H. Vogt and S. Brase, Org. Biomol. Chem., 2007, 5, 406.
´
az-de-Villegas,
´
¨
2 For recent reviews on asymmetric phase-transfer catalysis, see:
(a) T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2007,
46, 4222; (b) T. Hashimoto and K. Maruoka, Chem. Rev., 2007,
107, 5656.
3 For representative examples, see: (a) M. J. O’Donnell and S. Wu,
Tetrahedron: Asymmetry, 1992, 3, 591; (b) B. Lygo, J. Crosby and
J. A. Peterson, Tetrahedron Lett., 1999, 40, 8671; (c) T. Ooi,
M. Takeuchi, M. Kameda and K. Maruoka, J. Am. Chem. Soc.,
2000, 122, 5228; (d) T. Ohshima, T. Shibuguchi, Y. Fukuta and
M. Shibasaki, Tetrahedron, 2004, 60, 7743; (e) M. Kitamura,
S. Shirakawa and K. Maruoka, Angew. Chem., Int. Ed., 2005,
44, 1549; (f) S. Arai, F. Takahashi, R. Tsuji and A. Nishida,
Heterocycles, 2006, 67, 495; (g) T. Kano, T. Kumano and
K. Maruoka, Org. Lett., 2009, 11, 2023; (h) T. Kano, T. Kumano,
R. Sakamoto and K. Maruoka, Chem. Sci., 2010, 1, 499.
Based on the X-ray structure of (S)-7d, plausible transition-state
models have been proposed to account for the observed absolute
configuration of conjugate adducts 4 (Fig. 1). In the generation of a
chiral ammonium nitronate derived from a-substituted nitroacetate
and the catalyst (S)-7c under neutral conditions, the nitronate
anion would be stabilized by both the ionic interaction of
ammonium nitronate and the hydrogen bond between the
hydroxy group in catalyst (S)-7c and the nitro group. Then,
N-benzylmaleimide might approach from the front leading to
conjugate adduct 4 with the observed absolute configuration,
which was determined by X-ray analysis of the product 4d.14
4 (a) R. He, S. Shirakawa and K. Maruoka, J. Am. Chem. Soc., 2009,
131, 16620; (b) L. Wang, S. Shirakawa and K. Maruoka, Angew.
Chem., Int. Ed., 2011, 50, 5327.
5 (a) M. Ueda, A. Ono, D. Nakao, O. Miyata and T. Naito,
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J. Antibiot., 1985, 38, 296; (b) J. E. Baldwin, R. M. Adlington,
D. W. Gollins and C. J. Schofield, Tetrahedron, 1990, 46, 4733.
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53, 1384; (b) C. Najera, M. G. Retamosa and J. M. Sansano, Org.
´
Lett., 2007, 9, 4025; (c) K. V. Kudryavtsev and A. A. Zagulyaeva,
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2009, 2905.
8 (a) X. Wang, M. Kitamura and K. Maruoka, J. Am. Chem. Soc.,
2007, 129, 1038; (b) M. Kitamura, S. Shirakawa, Y. Arimura,
X. Wang and K. Maruoka, Chem.–Asian J., 2008, 3, 1702.
9 X. Wang, Q. Lan, S. Shirakawa and K. Maruoka, Chem.
Commun., 2010, 46, 321.
10 The reason for the positive effect of 4-methylpiperidine skeleton of
(S)-7c is not clear at this stage.
11 Chiral ammonium phenoxides as chiral base catalysts, see:
(a) H. Nagao, Y. Kawano and T. Mukaiyama, Bull. Chem. Soc.
Jpn., 2007, 80, 2406; (b) T. Tozawa, H. Nagao, Y. Yamane and
T. Mukaiyama, Chem.–Asian J., 2007, 2, 123. See also:
(c) D. Uraguchi, K. Koshimoto and T. Ooi, J. Am. Chem. Soc.,
2008, 130, 10878; (d) D. Uraguchi, K. Koshimoto and T. Ooi,
Chem. Commun., 2010, 46, 300.
12 N. V. Yashin, E. B. Averina, Y. K. Grishin, T. S. Kuznetsova and
N. S. Zefirov, Synlett, 2006, 279.
Fig. 1 X-Ray crystal structure of (S)-7d and plausible transition-state
13 CCDC 805745z.
models.
14 CCDC 805746z.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10557–10559 10559