Communications
DOI: 10.1002/anie.200803338
Asymmetric Catalysis
Helical Chiral Pyridine N-Oxides: A New Family of Asymmetric
Catalysts**
Norito Takenaka,* Robindro Singh Sarangthem, and Burjor Captain
The design, synthesis, and study of new catalyst structures
have had an enormous impact on chemical synthesis, and
continue to be a central challenge in asymmetric catalysis.[1]
We recently described that a 2-aminopyridinium ion might be
a promising catalaphore[2] for the design of new asymmetric
hydrogen-bond donor catalysts.[3] In that connection, we
became interested in 1-aza[6]helicene[4] 1 as a chiraphore[2]
because a first-order analysis of the crystal structure of an
analogous 1,16-diaza[6]helicene[5] suggests that its pyridine
Scheme 1. Synthesis design.
ring is well-desymmetrized in terms of both top-from-bottom
and left-from-right differentiations. To our knowledge, the
application of 1 and analogous helical chiral pyridines[5–7] in
asymmetric catalysis has not been studied, even though 1 has
been known in the literature since 1975.[4d] In this context, we
were prompted to develop an efficient synthesis of
1-azahelicenes, which allows systematic structural varia-
tion—important for the elucidation of the relationship
between catalyst structure, reactivity, and selectivity—and
to exploit them as chiraphores. In view of the utility of helical
chiral pyridines such as 1, it occurred to us that the
corresponding pyridine N-oxides might prove to be effective
asymmetric catalysts.[8] Herein, we describe the scalable
synthesis of 1-azahelicenes and the structural characterization
of the corresponding N-oxides, and we apply this new family
of compounds to the catalytic enantioselective desymmetri-
zation of meso epoxides (see Table 1). This study provides the
first report of the application of azahelicenes in asymmetric
catalysis.[9]
An examination of the structure of 1 suggests that the
chiral environment in the vicinity of the nitrogen atom can be
tuned by structural modification at cabon atoms 11–16.
Scheme 2. Syntheses of 1-azahelicenes: a) NaHMDS, DMF, 78%;
Therefore, we devised a convergent synthetic route to 1 in
which benzoquinoline unit 2 and C11–C16 unit 3 could be
expeditiously united (Scheme 1). This strategy would allow
ready access to the necessary 1-azahelicene derivatives by
simply replacing 3 with its readily available structural
analogues, such as 9 and 12 (Scheme 2). Preparation of key
b) [PdCl2(Ph3P)2], (Me3Sn-)2, PhMe, 77%; c) Pd(II) catalyst,[12] NBS,
CH3CN, 84%; d) benzoyl peroxide, NBS, PhH, 71%; e) 2-nitropropane,
NaOEt, EtOH, DMF, 86%; f) NaHMDS, DMF, 79% for 9, 76% for 11,
62% for 12; g) [PdCl2(Ph3P)2], (Me3Sn-)2, PhMe, 70% for 10, 61% for
1, 55% for 13. HMDS=1,1,1,3,3,3-hexamethyldisilazane; DMF=N,N-
dimethylformamide; NBS=N-bromosuccinimide.
[*] Prof. N. Takenaka, Dr. R. S. Sarangthem, Prof. B. Captain
Department of Chemistry, University of Miami
1301 Memorial Drive, Coral Gables, FL 33146-0431 (USA)
Fax: (+1)305-284-4571
unit 8 starts from commercially available pyridine 4 and
phosphonium salt 5, which was readily synthesized in three
steps from commercially available 2-bromo-4-methyl benzal-
dehyde. The highly Z-selective Wittig reaction[6b,10] of 4 and 5
and subsequent Stille–Kelly reaction[5,11] provided benzoqui-
E-mail: n.takenaka@miami.edu
[**] We thank the Florida Department of Health (07KN-12), the
American Cancer Society (IRG-98-277-07), the Sylvester Compre-
hensive Cancer Center, and the University of Miami for support. We
also thank Prof. Stanislaw Wnuk (Florida International University)
for the use of their polarimeter, and Prof. Roger LeBlanc and Charles
H. Vannoy for the CD spectral measurements.
À
noline 6. The catalytic C H functionalization method devel-
oped by Sanford and co-workers[12] readily converted 6 into 7
from which 8 was obtained in an ordinary way. The second
sequence of the highly Z-selective Wittig reaction and the
Stille–Kelly reaction of 8 with 9, 11, or 12 provided 1-
azahelicenes 10, 1, or 13, respectively. The scalability of this
Supporting information for this article is available on the WWW
9708
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 9708 –9710