Enantioselective radical addition to ketimines: A synthetic route towards α,α-disubstituted α-amino acids

Article abstract of DOI:10.1002/chem.201002071

A radical attack: In the presence of a protonated cinchonine derivative, radical addition reactions proceeded efficiently, providing a general approach to the synthesis of a diverse range of enantioenriched α,α- disubstituted α-amino acids.

Full text of DOI:10.1002/chem.201002071

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
E-mail: dojang@yonsei.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002071.
13046
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Chem. Eur. J. 2010, 16, 13046 – 13048

COMMUNICATION
Table 1. Optimization of the enantioselective radical addition reaction to
ketimine C=N bonds.
To evaluate the generality and scope of the reaction, a
wide range of ketimines were subjected to the optimized
conditions, providing a diverse range of enantioenriched
tert-alkyl amines that are not readily prepared by using or-
ganometallic nucleophiles (Table 3). The ketimines exam-
Table 3. Scope of the isopropyl radical addition reactions to ketimines.
Entry
2
PCA
([equiv])
iPrI
[equiv]
Solvent
t
Yield of 3 ee of 3
G
G
[h] [%][a]
[%][b]
1
2
3
4
5
6
7
8
9
2a 1a (0.30) 1.5
2b 1a (0.30) 1.5
2c 1a (0.30) 1.5
2d 1a (0.30) 1.5
2a 1a (0.30) 1.5
2a 1b (0.30) 1.5
2a 1c (0.30) 1.5
2a 1c (0.30) 5.0
2a 1c (0.75) 5.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C2H4Cl2 30
C2H4Cl2 30
C2H4Cl2 30
C2H4Cl2 72
C2H4Cl2 72
C2H4Cl2 72
C2H4Cl2 72
30
30
30
30
42 (13)
43 (12)
44 (13)
40 (13)
60 (14)
60 (12)
61 (14)
76 (14)
78 (14)
79 (13)
70 (19)
60
60
60
40
60
64
78
78
86
96
0
Entry
R
Product
Yield
[%][a]
ee
[%][b]
1
2
2e
2 f
2g
2h
2i
2j
2k
2l
Et
3i
3j
3k
3l
3m
3n
3o
3p
3q
–
77
81
76
62
76
80
75
77
78
–
97
96
96
40
97
97
95
96
96
–
CF3
iBu
tBu
3[c]
4
10
11
2a 1c (1.0)
2a 1d (1.0)
1.5
1.5
5[c]
6
7
Ph
(CH2)2
[a] Isolated yield. The yield in parentheses is for 3’. [b] Determined by
chiral HPLC analysis and compared with the authentic racemic material.
2-NO2PhCH2
4-OHPhCH2
EtOC(O)CH2
EtOC(O)
Ph
8
in the amount of 1c used in the reaction, showing the cata-
lytic nature of PCA 1c (Table 1, entries 9 and 10). A control
experiment was performed with unprotonated cinchonine-
derivative 1d, gaving a racemic mixture (Table 1, entry 11).
It is notable that only 1.5 equivalents of alkyl halide were
used; generally, intermolecular radical addition reactions re-
quire a large excess of either an alkyl halide or a radical ac-
ceptor to obtain a high yield of the addition product.[11]
Subsequently, we investigated the effect of radical precur-
sors on the yield and enantioselectivity of the reaction
(Table 2). The addition reaction with a secondary radical
9[c]
10
2m
2n
ACHTUGNTERN(NUNG CH2)2
[a] Isolated yield. [b] Determined by chiral HPLC analysis and compared
with the authentic racemic material. [c] Z-isomer. The other ketimines
are the E-isomers.
ined gave very high yields and extremely high enantioselec-
tivities (Table 3, entries 1–3 and 5–9) with the exception of
2h, which contains a bulky substituent (R=tBu; Table 3,
entry 4). It is notable that radical addition to phenylglyoxy-
late-derived imine 2n did not proceed under the reaction
conditions. Remarkably, functional groups such as phenols,
esters, and nitro groups were tolerated under these condi-
tions.
Even though various chiral phase-transfer catalysts (PTC)
have been developed for the synthesis of a,a-disubstituted
amino acids, only the copper(II)-salen complex[12] and Mur-
aokaꢁs catalyst[13] provide a,a-disubstituted amino acids with
two primary alkyl substituents at the a-position. However,
even those PTCs do not satisfactorily synthesize a,a-disub-
stituted amino acids possessing at least one branched sub-
stituent at the a-position. Our method affords a,a-disubsti-
tuted amino acids even with a sterically hindered substitu-
ent. Moreover, the synthesis of a,a-disubstituted amino
acids containing two branched a-substituents is possible
with a high enantioselectivity. From this point of view, the
present catalyst system is superior to previously reported
chiral PTCs.
produced
a high yield with a high enantioselectivity
(Table 2, entry 1). With tertiary alkyl halides, the addition
reactions turned out to be extremely enantioselective, even
with a substoichiometric amount of 1c (Table 2, entries 2–5).
The reaction with a primary iodide afforded moderate enan-
tioselectivity (Table 2, entry 6). When the reaction was run
with ethyl iodide, the sole product 3’a was obtained in 91%
yield and 80% ee (Table 2, entry 7).
Table 2. Various alkyl radical addition reactions to 2a in the presence of
1c.
Entry
R
Product
1c
[equiv]
Yield of 3
ee of 3
G
[%][a]
[%][b]
Sequential treatment of isopropyl adduct 3a with SmI2/
1
2
3
4
5
6
7
cyclohexyl
tBu
tBu
1-adamantyl
1-adamantyl
n-octyl
Et
3e
3 f
3 f
3g
3g
3h
3’a
1.0
0.75
1.0
0.75
1.0
1.0
74 (16)
71 (19)
73 (19)
70 (21)
71 (23)
54 (23)
– (91)
96
98
99
98
99
76
80
MeOH[14] and aqueous NaOH to cleave the N N bond and
À
hydrolyze the ester group produced the known compound
(R)-2-amino-2,3-dimethylbutanoic acid, confirming the as-
signment of the configuration.[15] Similar treatment of 3q af-
forded 2-(R)-isopropylglutamic acid,[16] showing that both E
and Z isomers provide addition products with R absolute
configuration.
1.0
[a] Isolated yield. The yield in parenthesis is for 3’a. [b] Determined by
chiral HPLC analysis and compared with the authentic racemic material.
Chem. Eur. J. 2010, 16, 13046 – 13048
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13047

D. O. Jang et al.
We hypothesize that the N+ H proton in a PCA interacts
À
Tomioka, J. Org. Chem. 2004, 69, 1531–1534; e) G. K. Friestad, Y.
Shen, E. L. Ruggles, Angew. Chem. 2003, 115, 5215–5217; Angew.
Chem. Int. Ed. 2003, 42, 5061–5068; f) M. Fernꢂndez, R. Alonso,
Org. Lett. 2003, 5, 2461–2464; g) G. K. Friestad, J. Qin, J. Am.
Chem. Soc. 2001, 123, 9922–9923.
with a ketimine through hydrogen bonding, along with p–p
stacking of the aromatic rings of the substrate and the PCA.
These two factors provide a chiral environment that leads to
the R configuration of the addition adduct. The formation
of substrate–PCA complexes
[3] a) G. K. Friestad, A. Ji, Org. Lett. 2008, 10, 2311–2313; b) H.
Miyabe, Y. Yamaoka, Y. Takemoto, Synlett 2004, 2597–2599.
[4] a) G. Bar, A. Parsons, Chem. Soc. Rev. 2003, 32, 251–263; b) B.
Guꢃrin, W. W. Ogilvie, Y. Guindon in Radicals in Organic Synthesis,
Vol. 1 (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001;
c) L. Feray, M. P. Bertrand, Eur. J. Org. Chem. 2008, 3164–3170;
d) F. Denes, F. Chemla, J. F. Normant, Angew. Chem. 2003, 115,
4177–4180; Angew. Chem. Int. Ed. 2003, 42, 4043–4096.
through hydrogen bonding and
p–p interactions is supported
by 1H NMR spectroscopy ex-
periments (see the Supporting
Information). Upon addition of
[5] For reviews, see: a) M. P. Sibi, S. Manyem, J. Zimmerman, Chem.
Rev. 2003, 103, 3263–3296; b) M. P. Sibi, N. A. Porter, Acc. Chem.
Res. 1999, 32, 163–171; c) P. Renaud, M. Gerster, Angew. Chem.
1998, 110, 2704–2722; Angew. Chem. Int. Ed. 1998, 37, 2562–2579.
[6] a) D. Yang, B.-F. Zheng, Q. Gao, S. Gu, N.-Y. Zhu, Angew. Chem.
2006, 118, 261–264; Angew. Chem. Int. Ed. 2006, 45, 255–258;
b) J. E. Hein, J. Zimmerman, M. P. Sibi, P. G. Hultin, Org. Lett.
2005, 7, 2755–2758; c) M. P. Sibi, K. Patil, Org. Lett. 2005, 7, 1453–
1456; d) L. He, G. S. C. Srikanth, S. L. Castle, J. Org. Chem. 2005,
70, 8140–8147; e) M. P. Sibi, G. Petrovic, J. Zimmerman, J. Am.
Chem. Soc. 2005, 127, 2390–2391.
[7] a) D. O. Jang, S. Y. Kim, J. Am. Chem. Soc. 2008, 130, 16152–16153;
b) M. P. Sibi, M. Hasegawa, J. Am. Chem. Soc. 2007, 129, 4124–
4125; c) S. Bertelsen, M. Nielsen, K. A. Jørgensen, Angew. Chem.
2007, 119, 7500–7503; Angew. Chem. Int. Ed. 2007, 46, 7356–7359;
d) S. Mukherjee, B. List, Nature 2007, 447, 152–153; e) D. H. Cho,
D. O. Jang, Chem. Commun. 2006, 5045–5047; f) P. Wessig, Angew.
Chem. 2006, 118, 2224–2227; Angew. Chem. Int. Ed. 2006, 45, 2168–
2171; g) A. Bauer, F. Westkçmper, S. Grimme, T. Bach, Nature 2005,
436, 1139–1140; h) T. Aechtner, M. Dressel, T. Bach, Angew. Chem.
2004, 116, 5974–5976; Angew. Chem. Int. Ed. 2004, 43, 5849–5851.
[8] For protonated chiral catalysts, see: a) A. Singh, J. N. Johnston, J.
Am. Chem. Soc. 2008, 130, 5866–5867; b) J. C. Wilt, R. M. Pink,
J. N. Johnston, Chem. Commun. 2008, 4177–4179; c) C. Bolm, T.
Rantanen, I. Schiffers, L. Zani, Angew. Chem. 2005, 117, 1788–
1793; Angew. Chem. Int. Ed. 2005, 44, 1758–1763; d) N. A. Paras,
D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123, 4370–4371;
e) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 4243–4244.
2a to a solution of 1c in CDCl3,
an upfield shift of Dd=
0.73 ppm was observed for the
[17]
N+ H hydrogen atom in 1c.
À
Furthermore, changes in the
chemical shifts (Dd=0–~0.09 ppm) of the benzene rings in
2a and 1c were observed.
In conclusion, we have developed a highly enantioselec-
tive radical addition reaction to the C=N of ketimines under
metal-free conditions. The method provides a general route
for the synthesis of a diverse range of enantioenriched a,a-
disubstituted a-amino acids. The mechanistic studies prove
that a PCA interacts with a ketimine through hydrogen
bonding and p–p stacking, providing a chiral environment
to attain the high enantioselectivity.
Experimental Section
General procedure for the enantioselective radical addition to ketimines:
A mixture of 1c (0.4 mmol) and a ketimine (0.4 mmol) in ClCH2CH2Cl
(4 mL) was stirred at room temperature under argon for 10 min. Diphe-
nylsilane (0.4 mmol) and an alkyl halide (0.6 mmol) were then added, fol-
lowed by triethylborane (1.6 mmol, 1m solution in hexane). Air (110 mL)
was added into the solution through a needle by using a syringe pump at
À308C, over 72 h. After completion of the reaction, the reaction mixture
was allowed to warm to room temperature and then washed with water.
Then, after evaporation of the solvent, the residue was purified by flash
column chromatography on silica gel, giving the corresponding addition
product. Enantiomeric excesses were determined by chiral HPLC analy-
sis (Daicel Chiralpak IA) through comparison with authentic racemic
material.
[9] For reviews on the synthesis of a,a-disubstituted a-amino acids, see:
a) S. Cabrera, E. Reyes, J. Alemꢂn, M. Milelli, S. Kobbelgaard,
K. A. Jørgensen, J. Am. Chem. Soc. 2008, 130, 12031–12037; b) H.
Vogt, S. Brꢄse, Org. Biomol. Chem. 2007, 5, 406–430; c) Y. Ohfune,
T. Shinada, Eur. J. Org. Chem. 2005, 5127–5143; d) C. Cativiela,
M. D. Dꢅaz-de-Villegas, Tetrahedron: Asymmetry 2000, 11, 645–732.
[10] a) P. Maity, B. Konig, Biopolymers 2008, 90, 8–27; b) M. Tanaka,
Chem. Pharm. Bull. 2007, 55, 349–358; c) S. Sagan, P. Karoyan, O.
Lequin, G. Chassaing, S. Lavielle, Curr. Med. Chem. 2004, 11, 2799–
2822; d) V. J. Hruby, Acc. Chem. Res. 2001, 34, 389–397.
[11] H. Miyabe, Y. Yamaoka, Y. Takemoto, J. Org. Chem. 2005, 70,
3324–3327.
[12] Y. N. Belokon, D. Bhave, D. D’Addario, E. Groaz, V. Maleev, M.
North, A. Pertrosyan, Tetrahedron Lett. 2003, 44, 2045–2048.
[13] T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem. Soc.
2000, 122, 5228–5229.
Acknowledgements
This work was supported by a Korea Research Foundation Grant, which
is funded by the Korean Government (KRF-2008-521-C00153).
[14] R. Hirabayashi, C. Ogawa, M. Sugiyra, S. Kobayashi, J. Am. Chem.
Soc. 2001, 123, 9493–9499.
[15] X. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. 2007,
119, 4445–4447; Angew. Chem. Int. Ed. 2007, 46, 4367–4369.
[16] L. M. Harwood, S. N. G. Tyler, M. G. B. Drew, A. Jahans, I. D. Mac-
Gilp, ARKIVOC 2000, 820–831.
Keywords: amino acids
enantioselectivity · organocatalysis · radical reactions
·
asymmetric synthesis
·
[1] G. K. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541–2569.
[17] O. P. Kryatova, I. V. Korendovych, E. V. Rybak-Akimova, Tetrahe-
+
À
[2] a) G. K. Friestad, J.-C. Marie, Y. Suh, J. Qin, J. Org. Chem. 2006, 71,
7016–7027; b) G. K. Friestad, C. Draghici, M. Soukri, J. Qin, J. Org.
Chem. 2005, 70, 6330–6338; c) H. Miyabe, M. Ueda, T. Naito, Syn-
lett 2004, 1140–1157; d) K. Yamada, Y. Yamamoto, M. Maekawa, K.
dron 2004, 60, 4579–4588: The proton of N H might be located in
the core of aromatic rings.
Received: July 21, 2010
Published online: October 11, 2010
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13046 – 13048