DOI: 10.1002/anie.201006422
Amino Acid Synthesis
One-Pot Synthesis of a-Amino Acids from Imines through CO2
Incorporation: An Alternative Method for Strecker Synthesis**
Tsuyoshi Mita,* Jianyang Chen, Masumi Sugawara, and Yoshihiro Sato*
Carbon dioxide is an abundant and inexpensive carbon source
(C1 unit); however, its inertness and gaseous character
amino acid synthesis from imines 2.[8] Nevertheless, this
classical method has some practical drawbacks including:
1) the use of highly toxic hydrogen cyanide or an equivalent,
such as an alkali metal cyanide or TMSCN, and 2) the need
for hydrolysis of a-amino nitrile intermediate 5 in strongly
acidic media such as aqueous HCl and H2SO4 at a high
temperature. Replacement of cyanide by CO2 in the Strecker
reaction would lead to direct carboxylation of imines while
avoiding the hydrolysis of nitrile 5. Although the cyanide ion
is a strong nucleophile that readily attacks imine groups, the
central carbon atom of CO2 behaves as an electrophile.
Therefore, reversal of polarity (umpolung[9]) on the imino
carbon atom is a key to the success of the proposed
transformation. For this purpose, we considered the use of a
stannyl anion,[10] which is known to react with imine 2[11] so
that the resulting a-amino stannane 3 would act as a
nucleophile towards CO2 after metal exchange with Sn.[12]
Our a-amino acid synthesis from imine 2 and CO2 is based
on several assumptions [Eq. (2), Scheme 1]: 1) imine 2 can be
generated in situ from a readily available and stable synthetic
precursor of imines, a-amino sulfone 1,[13] by treatment with a
base, 2) imine 2 can be converted into a-amino stannane 3[11]
À
sometimes hamper its use for efficient C C bond-forming
reactions in organic synthesis. To overcome this problem,
strongly nucleophilic organometallic regents, such as RLi and
À
RMgX, are often used for C C bond construction that
incorporates CO2.[1] Recently, transition-metal-promoted
CO2 fixation reactions, especially those involving metal-
activated/attached unsaturated bonds,[2–5] have been reported.
However, there have been relatively few examples of robust
C C bond-forming reactions between CO2 and an sp3-
À
hybridized carbon center under mild reaction condition-
s.[1,3a,b,6]
In 1850, Strecker pioneered the use of imine hydro-
cyanation with HCN and subsequent hydrolysis of the
resulting a-amino nitrile 5 under a acidic conditions to
prepare a-amino acids 4 [Eq. (1), Scheme 1].[7] This remark-
able transformation is one of the most reliable methods for a-
by attack of the tributylstannyl anion generated from
[10,14]
TMSSnBu3
in the presence of an appropriate fluoride
source,[15] and 3) the fluoride ion can further activate a-amino
stannane 3 by attack on the tin atom to exhibit carbanion-like
reactivity at the sp3-hybridized carbon atom, thus leading to a
À
C C bond-forming process with CO2 and affording a-amino
acid derivative 4.[12] Ideally, this series of steps could be
carried out in one pot with a single fluoride base. The
proposed process is complementary to the Strecker amino
acid synthesis because readily available and nontoxic CO2 gas
can be employed instead of cyanide as a C1 unit, and also
acid-labile substrates would be applicable owing to the
avoidance of acid hydrolysis.
Scheme 1. Synthetic strategies for a-amino acids from imines.
TMS=trimethylsilyl.
For maximum synthetic utility, the tert-butoxycarbonyl
(Boc) group was chosen as the protecting group for the imino
nitrogen atom of the starting imine 2. N-Boc-a-amido
stannane 3a was prepared by a reported procedure[11] to
evaluate the desired fluoride-promoted carboxylation step at
100–1108C under CO2 (Table 1). During this process, the
desired carboxylate 6a, which was isolated after methyl
esterification, and protiodestannylation product 7a were both
obtained. The 6a/7a ratio depended on the fluoride source
employed and the pressure of CO2. Alkali metal fluorides
other than CsF did not mediate carboxylation well, even in
combination with a crown ether (Table 1, entries 1–4). In
contrast, carboxylation proceeded readily in the presence of
CsF. The ratio of 6a/7a could be further improved by
increasing the pressure of CO2 (Table 1, entries 5–7). When
[*] Dr. T. Mita, J. Chen, M. Sugawara, Prof. Dr. Y. Sato
Faculty of Pharmaceutical Sciences, Hokkaido University
Nishi 6, Kita 12, Kita-ku
Sapporo 060-0812 (Japan)
Fax: (+81)11-706-4982
E-mail: biyo@pharm.hokudai.ac.jp
top_page.htm
[**] This work was financially supported by a Grant-in-Aid for Young
Scientists (B) from the Japan Society for the Promotion of Science
(JSPS; grant no. 22750081) and the Tosoh Corporation. Dr. Kousuke
Sato (Hokkaido University) is greatly acknowledged for support in
calculation of pKa values.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 1393 –1396
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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