DOI: 10.1002/chem.201002071
Enantioselective Radical Addition to Ketimines: A Synthetic Route Towards
a,a-Disubstituted a-Amino Acids
Sang Yoon Kim, Sung Jun Kim, and Doo Ok Jang*[a]
The addition of organometallic nucleophiles to C=N
bonds is one of the most important reactions used for the
synthesis of amines, which are valuable synthetic building
blocks, as well as biologically active compounds.[1] However,
these reactions are limited because they employ highly basic
nucleophiles that often cause side reactions. An alternative
approach is the use of radical addition reactions to provide
neutral reaction conditions and functional-group compatibil-
ity. In the past few years, radical addition reactions to alde-
Scheme 1. Structure of some cinchonine-derivatives. Bn=benzyl; Bz=
benzoyl.
hyde-derived imine derivatives have been widely investigat-
ed.[2] However, studies into addition reactions to ketimines,
which have lower reactivity, are rare.[3]
Control of stereochemistry in radical reactions has mainly
relied on the utilization of chiral auxiliaries[4] or chiral Lewis
acids.[5,6] Recently, there have been reports of the develop-
ment of organocatalysts for enantioselective radical reac-
tions.[7,8] Offering several advantages, such as low toxicity,
low cost, and ease of manipulation, the use of organocata-
lysts in asymmetric radical reactions is an attractive ap-
proach.
Herein, we present a highly enantioselective radical addi-
tion reaction to ketimines by using protonated chiral amines
(PCAs) under tin-free conditions (Scheme 1). This reaction
results in enantioenriched chiral a,a-disubstituted a-amino
acids that are difficult to form due to their quaternary ste-
reogenic center, but desirable because of their useful prop-
erties.[9] a,a-Disubstituted a-amino acids have received con-
siderable attention because of their stability under physio-
logical conditions, their conformational rigidity, and their
biological activity as enzyme inhibitors.[10] The importance
of a,a-disubstituted a-amino acids has stimulated research
into the development of methodologies for the asymmetric
synthesis of these valuable compounds.
As a preliminary experiment, an isopropyl radical addi-
tion reaction to ethyl pyruvate-derived (E)-N-benzoylhydra-
zone 2a was performed in the presence of a catalytic
amount of protonated cinchonine-derivative 1a at À308C.
Triethylborane and diphenylsilane were employed as the
radical initiator and chain carrier, respectively. After 30 h,
the reaction mixture was analyzed, giving adduct 3a in 42%
yield and 60% ee, along with ethyl-added adduct 3’a and re-
covered starting material (Table 1, entry 1). To improve the
efficiency and enantioselectivity of the radical addition reac-
tion, ketimines 2b–d were synthesized and subjected to the
reaction conditions, with very similar results to those for 2a
(Table 1, entries 2–4). Next, we modified the structure of the
chiral amine. In PCAs 1b and c, the benzyl group of 1a was
replaced by a benzoyl and an anthracene-9-carbonyl sub-
stituent, respectively. The increase in steric bulk of the sub-
stituent results in a significant improvement in enantioselec-
tivity (Table 1, entries 5–7). Thus, 1c became the preferred
choice of PCA. Further optimization of the reaction condi-
tions was performed by varying the solvent and the ratio of
the reagents. The chemical yields were improved by switch-
ing the solvent to ClCH2CH2Cl (Table 1, entries 1 vs. 5). In-
terestingly, an increase in the amount of alkyl halide had no
effect on the enantioselectivity of the addition adduct, al-
though it provided a higher yield (Table 1, entries 7 vs. 8).
The enantioselectivity increased to 96% ee with an increase
[a] S. Y. Kim, S. J. Kim, Prof. Dr. D. O. Jang
Department of Chemistry, Yonsei Universiry
Wonju 220-710 (Korea)
Fax : (+82)33-760-2182
Supporting information for this article is available on the WWW
13046
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Chem. Eur. J. 2010, 16, 13046 – 13048