The direct catalytic asymmetric aldol reaction of α-substituted nitroacetates with aqueous formaldehyde under base-free neutral phase-transfer conditions

Article abstract of DOI:10.1039/c2ob07193b

Enantioselective direct aldol reaction of α-substituted nitroacetates with aqueous formaldehyde for the synthesis of α-alkyl serines has been achieved under base-free neutral phase-transfer conditions with a bifunctional chiral phase-transfer catalyst.

Full text of DOI:10.1039/c2ob07193b

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COMMUNICATION
The direct catalytic asymmetric aldol reaction of α-substituted nitroacetates
with aqueous formaldehyde under base-free neutral phase-transfer
conditions†‡
Seiji Shirakawa, Kensuke Ota, Shogo J. Terao and Keiji Maruoka*
Received 29th December 2011, Accepted 30th January 2012
DOI: 10.1039/c2ob07193b
loading (0.1 mol%). This reaction offers a practical synthetic
method for optically active α-alkyl serines as biologically impor-
tant compounds (Scheme 1).8
Enantioselective direct aldol reaction of α-substituted nitro-
acetates with aqueous formaldehyde for the synthesis of
α-alkyl serines has been achieved under base-free neutral
phase-transfer conditions with a bifunctional chiral phase-
transfer catalyst.
We first investigated the effect of ester moiety of 2-nitropro-
panoate in asymmetric aldol reaction with aqueous formaldehyde
under base-free neutral conditions (Table 1, entries 1–4).
Attempted reaction of methyl 2-nitropropanoate and aqueous for-
maldehyde in toluene/H2O (1 : 1) under the influence of bifunc-
tional chiral phase-transfer catalyst (S)-1 with low catalyst
loading (0.1 mol%) at room temperature (25 °C) for 24 hours
afforded an aldol product 2a in high yield with almost no enan-
tioselectivity (entry 1). Exchange of the alkyl group of ester
moiety to bulky tert-butyl group gave the aldol product 2b with
low enantioselectivity (entry 2). Pleasingly, the use of benzyl
2-nitropropanoate improved the enantioselectivity (35% ee, entry
3), and further improvement of enantioselectivity was attained
For over two decades, asymmetric phase-transfer catalysis based
on the use of structurally well-defined chiral quaternary
ammonium salts as phase-transfer catalysts has been a topic of
great scientific interest, and recent enormous efforts have resulted
in notable achievements, making it feasible to perform various
stereoselective bond formations under phase-transfer conditions
with aqueous or solid bases.1 Among them, development of
highly enantioselective direct aldol reactions,2 which are one of
the most important reactions in organic synthesis, is a formidable
challenge in phase-transfer chemistry. Although a few examples
of direct catalytic asymmetric aldol reactions under phase-trans-
fer conditions have been reported,3,4 the stereoselectivity of such
aldol products is low to moderate in most cases, except one
example.4 The main reason for modest selectivity of the reac-
tions originates from the retro-aldol reaction, which is difficult to
suppress under basic phase-transfer conditions.5 In the course of
our study on the development of asymmetric reactions under
phase-transfer conditions, we have recently discovered the
hitherto unknown base-free neutral phase-transfer reaction
system in enantioselective conjugate additions.6 In this context,
we are interested in the application of this attractive base-free
neutral reaction system to the direct aldol reaction. Here we wish
to report direct catalytic asymmetric aldol reaction of α-substi-
tuted nitroacetates with aqueous formaldehyde, which is one of
the most convenient C1 sources in organic synthesis,7 under
base-free neutral phase-transfer conditions with low catalyst
using diphenylmethyl 2-nitropropanoate as
a substrate in
toluene/H2O (68% ee, entry 4). With the diphenylmethyl 2-nitro-
propanoate as a key substrate for the reaction, solvent effect was
investigated (Table 1, entries 4–7). Although the use of di-
chloromethane and cyclopentyl methyl ether (CPME) as organic
solvents instead of toluene caused the decrease of enantioselec-
tivities (entries 5 and 6), the reaction in mesitylene/H2O
enhanced enantioselectivity (80% ee, entry 7). The highest enan-
tioselectivity was attained when lower temperature (0 °C) was
Laboratory of Synthetic Organic Chemistry and Special Laboratory of
Organocatalytic Chemistry, Department of Chemistry, Graduate School
of Science, Kyoto University, Sakyo, Kyoto606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-4041;
Tel: +81-75-753-4041
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: Experimental
details and characterization data for new compounds. See DOI: 10.1039/
c2ob07193b
Scheme 1 Direct asymmetric aldol reaction under base-free neutral
phase-transfer conditions.
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Table 1 Optimization of reaction conditionsa
Table 2 Direct asymmetric aldol reaction of α-substituted nitroacetates
with aqueous formaldehydea
Entry
R1
Solvent
Yieldb (%)
eec (%)
Entry
R2
Yieldb (%)
eec (%)
1
2
3
4
5
6
Me
t-Bu
Bn
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
Bn
Toluene
Toluene
Toluene
Toluene
91 (2a)
98 (2b)
99 (2c)
98 (2d)
55 (2d)
89 (2d)
79 (2d)
86 (2d)
98 (2c)
∼0
7
1
Me
Me
Et
n-Pr
86 (2d)
76 (2d)
70 (3a)
71 (3b)
86 (3c)
77 (3d)
70 (3e)
62 (3f)
91
91
83
81
81
82
76
74
35
68
51
29
80
91
87
2d
3
CH2Cl2
4
CPMEd
5
n-Bu
7
Mesitylene
Mesitylene
Mesitylene
6e
7
(CH3)2CHCH2CH2
CH2 = CHCH2CH2
BocNH(CH2)3CH2
8e
9e
8f
a Reaction conditions: 2-nitropropanoate (0.050 mmol) and 37%
aqueous formaldehyde (0.25 mmol) in the presence of 0.1 mol% of (S)-
1 in organic solvent (1.0 mL)/H2O (1.0 mL) at room temperature
(25 °C) for 24 h. b Yield of isolated products. c Determined by chiral
HPLC analysis. d CPME = cyclopentyl methyl ether. e Reaction was
performed at 0 °C for 60 h.
a Reaction conditions: α-substituted nitroacetate (0.050 mmol) and 37%
aqueous formaldehyde (0.25 mmol) in the presence of 0.1 mol% of (S)-
1 in mesitylene (1.0 mL)/H2O (1.0 mL) at 0 °C for 60 h. b Yield of
isolated products. c Determined by chiral HPLC analysis. d Reaction was
performed in mesitylene/H2O = 1 : 10. e Reaction was performed with
f
0.5 mol% of (S)-1 for 48 h. Reaction was performed with 0.5 mol% of
(S)-1.
Scheme 2 Effect of aqueous base solution.
Scheme 3 Reduction of the nitro group on products.
employed in mesitylene/H2O with prolonged reaction time (91%
ee, entry 8).9,10 The reaction using benzyl 2-nitropropanoate
under this optimized reaction conditions also gave the aldol
product 2c with high enantioselectivity (87% ee, entry 9).
It should be noted that the reaction under ordinary phase-
transfer conditions using aqueous base solutions, such as
aqueous K2CO3, caused a serious decrease in enantioselectivity
(Scheme 2).11 Even with PhCO2K as a relatively mild base,
decrease of enantioselectivity was observed in the reaction.
These results clearly indicate that the neutral phase-transfer con-
ditions are crucially important to obtain high enantioselectivity
in the present reaction.
With optimal reaction conditions in hand, we studied the sub-
strate generality of the direct asymmetric aldol reaction of α-sub-
stituted nitroacetates with aqueous formaldehyde under the
neutral phase-transfer conditions (Table 2). Various types of
nitroacetates were found to be employable for the reaction. The
reaction of nitroacetates with a simple alkyl chain gave the corre-
sponding aldol products in good to high enantioselectivities
(81–91% ee, entries 1–6). The nitroacetates possessing func-
tional groups were also employable for the reaction to give corre-
sponding products 3e and 3f in good enantioselectivities
(74–76% ee, entries 7 and 8). It should be noted that even in the
water-rich biphasic reaction system (mesitylene/H2O = 1 : 10),
the reaction gave the product with high enantioselectivity
(entry 2).12
The nitro group of resulting aldol products 2 and 3 can be
readily reduced to obtain α-alkyl serines. For example, treatment
of aldol products 2d and 2c with acetic acid in iso-propanol in
the presence of zinc13 gave the corresponding α-methylserinates
4 and 5, which are core structure of biologically active natural
products such as conagenin14 and piperazimycins,15 in 85 and
88% yields, respectively, without loss of enantioselectivity
(Scheme 3). The absolute configuration of product 5 was
assigned to be R by comparison of the optical rotation with the
literature value.14d
In summary, we have developed the enantioselective direct
aldol reaction of α-substituted nitroacetates with aqueous formal-
dehyde for the synthesis of α-alkyl serines as biologically impor-
tant compounds. The base-free neutral phase-transfer conditions
with a bifunctional chiral phase-transfer catalyst are indis-
pensable to obtain high enantioselectivity. The present report
demonstrates a valuable example of hitherto difficult highly
enantioselective direct aldol reactions catalyzed by tetraalkylam-
monium bromide. Further investigations on the neutral phase-
transfer reaction system using a chiral bifunctional ammonium
salt to produce important compounds are currently underway.
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5 For discussion on the retro-aldol reaction under phase-transfer conditions
see ref. 3e and 4b.
Acknowledgements
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16620; (b) L. Wang, S. Shirakawa and K. Maruoka, Angew. Chem., Int.
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K. Maruoka, Chem. Commun., 2011, 47, 10557.
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from JSPS, MEXT (Japan) and The Association
for the Progress of New Chemistry.
7 Direct asymmetric aldol reactions with aqueous formaldehyde, see:
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M. Nishio and K. Takabe, Bioorg. Med. Chem. Lett., 2009, 19, 3955;
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Tetrahedron Lett., 1988, 29, 235; (b) S.-S. Jew, Y.-J. Lee, J. Lee,
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Notes and references
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the ammonium bromide with slightly low yields [(S)-1·PhO−: 67% yield,
90% ee; (S)-1·OH−: 60% yield, 91% ee]. The effect of other catalysts
was shown in Scheme S1, ESI.‡
10 The reaction in mesitylene without addition of water except the water
in formaldehyde solution proceeded sluggishly. The same effect of
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11 Even in the absence of catalyst (S)-1, the reaction proceeded in mesity-
lene/aqueous K2CO3 by the effect of base.
12 The reaction in pure water without mesitylene proceeded sluggishly
owing to the low solubility of nitroacetate and catalyst in water.
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This journal is © The Royal Society of Chemistry 2012
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