been devised for the synthesis of THQs,1b,6 the partial
reduction of the heteroaromatic ring system has emerged as
one of the most useful routes.7 In contrast, only a few
methods exist in the literature for the asymmetric synthesis
of 3-substituted THQs, including strategies involving oxida-
tive aza-annulation of chiral amino acids,8 Rh-catalyzed
reduction of R-amino cinnamate,9 and asymmetric dihy-
droxylation10 and epoxidation9 of olefins followed by cy-
clization with an aromatic amino group. However, use of
chiral starting materials, lengthy reaction sequence, and use
of protection and deprotection of various functional groups
are some of the drawbacks of the existing routes. Hence,
there has been considerable interest in the development of
elegant and efficient protocols for the asymmetric synthesis
of 3-substituted THQs.11
reduction with CoCl2 (1 mol %) and NaBH4 (4 equiv),
compound 3a underwent reductive cyclization smoothly to
provide (R)-3-hydroxytetrahydroquinoline (5a) exclusively,
in 81% yield and 94% ee, instead of the expected ester 4.
This unexpected transformation was comprised of simulta-
neous reduction of multifunctional groups all occurring in a
single step leading to the cyclized 3-substituted THQ 5a in
high optical purity (Scheme 1).
Scheme 1. Synthesis of (R)-3-Hydroxytetrahydroquinoline (5a)
In continuation with our studies on simultaneous reduction
of multifunctional moieties,12 we report in this communica-
tion a novel method for the construction of 3-substituted
tetrahydroquinoline derivatives 5a-f using CoCl2 as catalyst
and NaBH4 as hydride source, demonstrating its effectiveness
in the asymmetric synthesis of PNU 95666 E (1) and
anachelin H chromophore (2).
As part of our program on asymmetric synthesis of
bioactive molecules,12 we sought a new enantioselective
synthetic route to (S)-ethyl indole-2-carboxylate (4), a key
intermediate required in the synthesis of perindopril,13 an
orally active pharmaceutical for the treatment of hyperten-
sion. For this, we reasoned that the required carboxylate 4
could be prepared by Co-catalyzed reductive cyclization of
nitro cyclic sulfite 3a. Surprisingly, when subjected to
Encouraged by this result, we examined the scope of this
reaction by subjecting several chiral nitro cyclic sulfites 3b-f
to reductive cyclization. While compound 3a was prepared
from o-nitrobenzaldehyde (Wittig followed by AD-mix-R),
other substrates 3b-f were efficiently prepared in three steps
starting from the corresponding R,ꢀ-unsaturated esters 6b-f:
(i) Os-catalyzed asymmetric dihydroxylation (AD-mix-R) of
cinnamates 6b-f using (DHQ)2-PHAL ligand;15 (ii) re-
giospecific aromatic nitration of diols 7b-f using HNO3,2a
and (iii) protection of diols 8a-f with SOCl216 (Scheme 2).
(6) (a) Zhu, G.; Pang, K.; Parkin, G. J. Am. Chem. Soc. 2008, 130, 1564–
1565. (b) Kinney, W. A.; Teleha, C. A.; Thompson, A. S.; Newport, M.;
Hansen, R.; Ballentine, S.; Ghosh, S.; Mahan, A.; Grasa, G.; Zanotti-Gerosa,
A.; Dingenen, J.; Schubert, C.; Zhou, Y.; Leo, G. C.; McComsey, D. F.;
Santulli, R. J; Maryanoff, B. E. J. Org. Chem. 2008, 73, 2302–2310. (c)
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Tochilkin, A. I. Chem. Heterocycl. Comp. (Eng. Trans.) 1988, 65–67. (g)
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Scheme 2. Synthesis of Nitro Cyclic Sulfites 3b-f
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When subjected to the CoCl2-catalyzed reduction14 with
4 equiv of NaBH4, chiral nitro cyclic sulfites 3a-f gave the
corresponding (R)-3-hydroxytetrahydro-quinoline derivatives
5a-f in 78-86% yields with excellent enantioselectivities.
Results of such studies are presented in Table 1. As can be
seen, various cyclic sulfites underwent reductive cyclization
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