RESEARCH PROPOSAL
Asymmetric Counteranion Directed Enantioselective Radical Cyclizations
Ziqing Qian
Abstract: This research proposal summarizes scientific context of enantioselective radical reactions,
especially chiral Lewis acid mediated enantioselective radical cyclizations. This proposal based on Prof. Dan
Yang’s research of enantioselective group-transfer tandem radical cyclization reactions, aims at employing
Asymmetric Counteranion Directed Catalysis (ACDC) concept to study some unsolved problems in this area.
Keywords: asymmetric counteranion directed catalysis·radical cyclization. Lewis acid catalysis
Introduction
molecular construction (cyclizations) have been
reported.[5-9] These reactions can be classified into
For the requirement of pharmaceutical and
two types by the nature of coordination with a
agrochemical synthesis, asymmetric synthesis has
Lewis acid (Type A and B, ML* = chiral Lewis
attracted much attention. Chiral compounds are
acid).
typically accessed from either Nature’s “chiral
pool,” by resolution of a racemate or by means of
an enantioselective transformation mediated by a
chiral catalyst.[1] Radicals, as one major kind of
intermediates, have been recognized as highly
reactive short-lived species that are difficult to tame.
This misconception, which hindered their use in
stereoselective reactions, has long since been
Enantioselective Radical Cyclizations
negated, and the synthetic utility of radicals has
been properly recognized. There are many good
A recent work on enantioselective type A radical
sources of literature discussing radical chemistry
cyclizations was reported by Takemoto’s group
and the appropriate methods for its application in
(Scheme 1).[9] A suitable combination of a chiral
organic synthesis.[2] The study of stereochemistry in
radical-mediated reactions has been of great
importance to organic synthesis.[3]
Enantioselective Radical Reactions
Researchers achieved success in different types of
asymmetric radical reactions: atom/group- transfer
reactions, reductive alkylations, tandem reactions,
oxidations, polymerizations, etc.[4-5] Particularly
chiral Lewis acids promoted
enantioselective
carbon-carbon bond construction from radical
intermediates
have
attracted
much
interests.
Stereocontrol in both intermolecular reactions
(addition reactions, allylation, etc.) and intra-
Ziqing Qian
Department of Chemistry, East China Normal University
Shanghai, China
RESEARCH PROPOSAL
Lewis acid and hydroxamate ester leads to highly
cyclization of 6 proceeded smoothly to give
enantioselective reactions of 1. Although this new
cyclized product 8 in good enantioselectivity when
approach of utilizing hydroxamate esters has
chiral ligand 7 and Mg(ClO4)2 were employed.[7b]
achieved
PhSe-group-transfer radical cyclization of 9 also
highly
enantioselective
additiona
proceeded with 89% ee and better yield.[8a] In some
powerful synthetic approach to γ-latams, prepare of
cases, high enantioselectivity was achieved using
hydroxamate esters is difficult. Some other enantio-
0.3 equivalents of the chiral Lewis acid catalyst, but
selective cyclizations have been achieved by
it is still not a perfect methodology, considering
Nishida’s group, Yang’s group, Ishii’s group,
limited substrate scope, large catalyst load, toxicity
Curran’s group, Bach’s group, and Takemoto’s
of PhSe-substituents, and reaction temperature
cyclization-trapping
group.
reaction
that
provides
[6-8, 10-11]
(-78℃) in this system.
From 2002 to 2006, Yang and coworkers focused
on the asymmetric Lewis acid-catalyzed
Enantioselective
tandem
or
cascade
radical
bromo-
cyclizations attract much interest, since highly
and phenylseleno- transfer radical cyclizations of a
functionalized compounds with multiple stereo-
serious of α-substituted β-keto esters.
Using
centers are provided, and multiple carbon–carbon
β-keto esters bidentate coordinating substrates for
bonds and some tertiary chiral centers are formed in
the design of enantioselective radical cyclization,
a single operation; thus, a number of extensive
they
of
investigations into sequential radical reactions were
α-substituents of β-keto esters, and found that
reported in recent years.[12] Yang’s group also
although high enantioselectivity (up to 94% ee)
reported Lewis acid-catalyzed atom-/group-transfer
could be achieved both in the case of bromo- and
tandem radical processes of α-radical species β-keto
phenylseleno- β-keto esters in type B cyclization
esters to give monocyclic or bicyclic products in a
(Scheme 2), the use of bromide unfortunately
high efficient, regioselective, and stereoselective
[7b, 8a,b]
manner.[8] For instance, the type B cyclization has
systematically
afforded lower yield.
studied
the
[7-8]
effect
Atom-/group- transfer
been applied to tandem cyclization (Scheme 3) by
Yang and co-workers.[8b] Tandem reaction of 11
could be performed with ligand 7 and Mg(ClO 4)2.
Good
enantioselectivity
was
observed
when
reaction was carried out in toluene at -20℃, but the
yield of the product 12 was low. Recently, Yang’s
group
also
reported
that
the
phenylseleno-
group-transfer reaction was ideal in terms of both
reaction efficiency and enantioselectivity for the
tandem cyclization (Scheme 4).[8a] However, yield
is still low, and introduction of PhSe-group, low
Ziqing Qian
Department of Chemistry, East China Normal University
Shanghai, China
RESEARCH PROPOSAL
My Strategy
As introduced above, ACDC strategy has emerged
as a promising strategy in Lewis acids-mediated
asymmetric catalysis. However, it has not been
employed in catalytic asymmetric radical reactions.
In this light, I wish to introduce ACDC strategy into
enantioselective radical reactions (Scheme 5).
temperature (-78℃), high catalyst load, and add of
activated molecular sieves are necessary to obtain
the enantioselectivity.
Chiral Counteranion Strategy
In general, chiral catalysts rely on covalent (dative
or nondative) bonds between the reactive site and
the chiral moiety. An alternative approach is the
induction of asymmetry by interaction of the
cationic catalyst with a chiral counteranion. Highly
efficient chiral catalytic transformations involving
chiral anionic catalysts have been reported in
phase-transfer catalysis, Brønsted acid catalysis,
organocatalysis,
catalysis
As can be expected, chiral counteranions could tune
Intramolecular hydroalkoxylation of
the chiral space around Lewis acids, either used
allenes proceeded with a high level of enantio-
alone or in combination with chiral ligand, just like
selectivity to give pyrrolidine products with a
its applications in transition-metal asymmetric
(Scheme 5).
[13]
and
transition-metal
synthesis.
It is interesting to examine if the introduction of
ACDC concept, using chiral counteranion alone or
in combination with chiral Lewis acid, will decrease
the catalyst loading, achieve high enantioselectivity
and high yield under mild conditions, or expand the
substrate scope, for example, using monodentate
substrates instead of bidentate substrates. .
My Aims in PhD Research
a cationic gold complex and the chiral phosphate
counteranion
example
provides
To develop novel transition metal promoted
asymmetric radical reactions directed towards
promising method towards introducing asymmetric
polycyclic units based on chiral counteranion
counteranion strategy into Lewis acid catalyzed
strategy.
Ziqing Qian
This
A.
a
reactions.
15.
B.
To study the applications of the methodology
Department of Chemistry, East China Normal University
Shanghai, China
RESEARCH PROPOSAL
Conclusion
in natural products and bio-active molecules
synthesis.
C.
To study reaction mechanisms, which benefit
the development of .new reactions or catalysts.
To sum up, since my initial interests towards
enantioselective
radical
reactions
and
chiral
counteranion strategy, I would very like to try my
My Academic Background
proposal in Prof. Yang Dan’s laboratory for my
PhD research period. As a PhD applicant this year, I
I
have
achieved
an
outstanding
academic
would like to devote myself to challenging and
performance of 3.75 major GPA, and ranked top
pioneer work – do best research in my PhD life. In
3% in our department. Combining with extensive
this light, working in your eminent program is no
research experiences in organic chemistry, I have
doubt the best way to turn my dream into reality.
prepared myself to challenging and pioneer work in
my PhD life.
My present
research
focus
on
asymmetric
References and Notes
transition metal catalysis: asymmetric nucleophile-
1. J. Mulzer, in Comprehensive Asymmetric Catalysis, E. N.
assisted cyclization of enynones. I synthesized
Jacobsen, A. Pfaltz, H. Yamamoto, Eds. (Springer, Berlin,
cationic Au (Ⅰ) and Au (Ⅲ) complexes with chiral
1999), vol. I, chap. 3.
binaphthol-derived phosphate chiral anions, tested
2. For selected examples of radical reactions, see: a) Renaud, P.,
their performance, and achieved moderate enantio-
Sibi, M. P., Eds. Radicals in Organic Synthesis; Wiley-VCH:
selectivity. From the practice, I noticed the
New York, 2001; Vols. 1 and 2. b) Parsons, A. F. An
importance of chiral counteranion strategy in
Introduction to Free Radical Chemistry; Blackwell Science:
asymmetric synthesis because of the importance of
Oxford, 2000. c) Alfassi, Z. B. General Aspects of the
anions in organic reactions and high efficiency of
Chemistry of Radicals; Wiley: New York, 1999. d) Fossey, J.;
chiral counteranion's chiral induction. I also
Lefort, D.; Sorba, J. Free Radical in Organic Chemistry;
believed the combination of transition metal
Wiley: New York, 1995. e) Curran, D. P. In Comprehensive
catalysis and organocatalysis is the future trend of
Organic Synthesis; Trost, B. M., Fleming, I., Semmelheck, M.
asymmetric synthesis. This practice equipped me
F., Eds.; Pergamon: Oxford, 1991; Vol. 4, p 715. f) Giese, B.
with a
Radicals in Organic Synthesis. Formation of Carbon-Carbon
deeper understanding of asymmetric
synthesis from perspectives of stereochemistry,
which is critical in my future research of chiral
counteranion directed asymmetric radical reactions.
Bonds; Pergamon: Oxford, 1986.
3. For selected examples of stereochemistry of radical reactions,
see: a) Radicals in Organic Synthesis, Vols. 1 and 2 (Eds.: P.
I also performed some other organic chemistry
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001; b) B.
research projects: “Synthesis of truxene-derived
Giese, B. Kopping, T. Gçbel, J. Dickhaut, G. Thoma, K. J.
derivatives for nanosized π-conjugated molecules”,
Kulicke, F. Trach, Org. React. 1996, 48, 301; c) D. P. Curran,
“Development of novel reactions of enynones with
N. A. Porter, B. Giese, in Stereochemistry of Radical
different nucleophiles” (Please refer to my CV).
Reactions: Concepts, Guidelines, and Synthetic Applications,
From these experiences, I got to know how to
identify reaction conditions from analysis of
reaction
mechanisms,
and
reactions, see: a) Sibi, M. P.; Rheault, T. R. In Radicals in
electronic effects. I also obtained
evaluated
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
hands-on
synthesis:
Weinheim, 2001; Vol. 1, pp 461. b) Porter, N. A.; Giese, B.;
experiences
especially
in
organic
functional group transformations.
steric
VCH, Weinheim, 1996.
4. For general information details for enantioselective radical
Curran, D. P. Acc. Chem. Res. 1991, 24, 296.
5. For selected examples of intramolecular carbon-carbon
Ziqing Qian
Department of Chemistry, East China Normal University
Shanghai, China
RESEARCH PROPOSAL
construction radical reactions, see: a) Sibi, M. P., Manyem, S.,
Synthesis, I. Ojima, Ed. (Wiley-VCH, New York, ed. 2, 2000),
Zimmerman, Chem. Rev. 2003, 103. 3263. b) G. Bar, A. F.
chap. 10, pp. 727–755. b) G. Lelais, D. W. C. MacMillan,
Parsons, Chem. Soc. Rev. 2003, 32, 251; c) Sibi, M. P.; Porter,
Aldrichim. Acta. 2006, 39, 79. c) M. S. Taylor, E. N. Jacobsen,
N. A. Acc. Chem. Res. 1999, 32, 163. d) M. P. Sibi, N. A.
Angew. Chem. Int. Ed. 2006, 45, 1520. d) S. Mayer, B. List,
Porter, Acc. Chem. Res. 1999, 32 163; e) P. Renaud, M.
Angew. Chem. Int. Ed. 2006, 45, 4193. e) G. L. Hamilton, E. J.
Gerster, Angew. Chem. 1998, 110, 2704; Angew. Chem. Int.
Kang, M. Mba, F. D. Toste, Science 2007. 317, 496. f) S.
Ed. 1998, 37, 2562;
Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336. g)
6. M. Nishida, H. Hayashi, A. Nishida, N. Kawahara, Chem.
Commun. 1996, 579.
M. Rueping, A. P. Antonchick, C. Brickmann, Angew. Chem.
Int. Ed. 2007, 46, 6903. h) N. J. A. Martin, B. List, J. Am.
7. For a selected examples of enantioselective radical reactions
Chem. Soc. 2006, 128, 13368. i) T. Akiyama, J. Itoh, K.
reported by Yang et al., see: (a) D. Yang, Q. Gao, B.-F. Zheng,
Fuchibe, Adv. Synth. Catal. 2006, 348, 999. j) D. B.
and N.-Y. Zhu, J. Org. Chem. 2004, 69, 8821. b)Yang, D.; Gu,
Llewellyn, D. Adamson, B. A. Arndtsen, Org. Lett. 2000, 2,
S.; Yan, Y. L.; Zhu, N. Y.; Cheung, K. K. J. Am. Chem. Soc.
4165.
2001, 123, 8612;
8. For selected examples of enantioselective tandem radical
reactions reported by Yang et al., see: a) D. Yang, B.-F. Zheng,
Q. Gao, S. Gu, N.-Y. Zhu, Angew. Chem. 2006, 118, 261;
Angew. Chem. Int. Ed.2006, 45, 255.b) Yang, D.; Gu, S.; Yan,
Y. L.; Zhao, H. W.; Zhu, N. Y. Angew. Chem. 2002, 114, 3143;
Angew. Chem., Int. Ed. 2002, 41, 3014. c) D. Yang, Q. Gao,
O-Y. Org. Lett. 2002, 4, 1239-1241.
9. K. Hiroi, M. Ishii, Tetrahedron Lett. 2000, 41, 7071.
10. a) H. Miyabe, R. Asada, A. Toyoda, Y. Takemoto, Angew.
Chem. 2006, 118, 5995; Angew. Chem. Int. Ed. 2006, 45,
5863. b) H. Miyabe, Y. Takemoto, Chem. Eur. J. 2007, 13,
7280.
11. Transfer of chirality in radical cyclization was reported. See:
D. P. Curran, W. Liu, C. H.-T. Chen, J. Am. Chem. Soc. 1999,
121, 11012.
12. a) T. Aechtner, M. Dressel, T. Bach, Angew. Chem. 2004, 116,
5974; Angew. Chem. Int. Ed. 2004, 43, 5849; b) M. Dressel, T.
Aechtner, T. Bach, Synthesis 2006, 2206.
13. For selected recent examples of tandem or cascade radical
reactions, see: a) K. Miura, M. Tojino, N. Fujisawa, A.
Hosomi, I. Ryu, Angew. Chem. 2004, 116, 2477; Angew.
Chem. Int. Ed. 2004, 43, 2423; b) M. Tojino, Y. Uenoyama, T.
Fukuyama, I. Ryu, Chem. Commun. 2004, 2482; c) Y.
Uenoyama, T. Fukuyama, O. Nobuta, H. Matsubara, I. Ryu,
Angew. Chem. 2005, 117, 1099; Angew. Chem. Int. Ed. 2005,
44, 1075.
14. For selected examples of chiral counteranion strategy in
phase-transfer catalysis, organocatalysis, and transition-metal
catalysis, see: a) M. J. O’Donnell, in Catalytic Asymmetric
Ziqing Qian
Department of Chemistry, East China Normal University
Shanghai, China