Angewandte
Chemie
DOI: 10.1002/anie.201403587
Vicinal Quaternary Stereocenters Very Important Paper
Catalytic Enantioselective Nazarov Cyclization: Construction of
Vicinal All-Carbon-Atom Quaternary Stereocenters**
Anais Jolit, Patrick M. Walleser, Glenn P. A. Yap, and Marcus A. Tius*
Dedicated to Professor E. J. Corey
Abstract: The diastereoselective asymmetric synthesis of
vicinal all-carbon-atom quaternary stereocenters is a challeng-
ing problem in organic synthesis for which only few solutions
have been described. A catalytic asymmetric Nazarov cycliza-
tion of fully substituted dienones that provides cyclopentenone
derivatives with vicinal quaternary stereocenters in high optical
purity and as single diastereoisomers is now reported.
rapid termination process that is enabled through loss of the
2-(trimethylsilyl)ethoxymethyl (SEM) group contribute to
the success of this cyclization, which results in the formation
of vicinal all-carbon-atom quaternary stereocenters. Rapid
termination is especially important in the case of Nazarov
cyclizations that lead to sterically congested products as
Wagner–Meerwein rearrangements of the intermediate cyclic
cation, which would be driven by relief of steric compression,
have to be suppressed.[7] Herein, we report the first catalytic
asymmetric Nazarov cyclization of fully substituted dienones
for the construction of vicinal all-carbon-atom stereocenters.
We had confidence that an asymmetric version of the
cyclization that is shown in Equation (1) could be developed
through systematic variation of the enol ether and ester
groups, which could serve as recognition elements for
a catalyst. The process could be optimized through iterative
changes in catalyst, solvent, and additive(s). As the enol ether
moiety must depart as a stable cation following the cycliza-
tion, its choice does not restrict the structural types of
cyclopentenones that might be accessed by this reaction.
We chose the (R)-BINOL scaffold for our screen of chiral
Brønsted acids.[8] The broad utility of this class of compounds
for a variety of catalytic asymmetric reactions is related to the
ease with which substituents at the C3 and C3’ positions can
be introduced to quickly assemble a library of catalysts.[9]
Catalyst optimization is summarized in Table 1. The phenyl
ester group in 3 strongly influenced the enantioselectivity of
the reaction. The ethyl ester analogue of 3 led to the desired
product 5 with an enantioselectivity of 80:20 e.r. in the
presence of catalyst 4e, whereas the cyclization of 3 under the
same conditions led to 5 in 90:10 e.r. (Table 1, entry 5). The
cyclization of dienone 3 was subsequently used to evaluate all
catalysts. The diphenylmethyl enol ether was chosen as
a sterically demanding group that would be rapidly lost
from the cyclic cation intermediate as a very stable cation.[10]
Phosphoric acid 4a was not an effective catalyst, presumably
because of its weak acidity (pKa ꢀ 12, CH3CN), and no
reaction took place.[11] Rueping and co-workers have demon-
strated that N-triflyl phosphoramides are more acidic (pKa
ꢀ 6, CH3CN) and have used these acids to catalyze asym-
metric Nazarov cyclizations.[2b,i] Indeed, exposure of 3 to
10 mol% of N-triflyl phosphoramide 4b (Ar= Ph) for
24 hours led to complete conversion of 3 into 5 in 85:15 e.r.
A small improvement in the optical purity of 5 was observed
with catalyst 4c (Ar= 4-tolyl), and a much larger improve-
ment to 96:4 e.r. was achieved with catalyst 4d (Ar= 4-tert-
butylphenyl). Phenyl (4e) or 9-phenanthryl (4 f) substituents
in the para position led to inferior catalyst performance.
T
he catalytic asymmetric synthesis of vicinal, all-carbon-
atom quaternary stereocenters presents a difficult challenge
for which only a small number of solutions, none of which are
completely general, have been described to date.[1] The
enantioselective version of the reaction that is shown in
Equation (1) would constitute a new solution to this problem.
None of the asymmetric Nazarov cyclizations that have been
described thus far[2] form vicinal quaternary stereocenters. At
best, vicinal quaternary and tertiary stereocenters could be
generated.[3]
Polarization of the acyclic dienone precursor[4] accelerates
the Nazarov cyclization.[5] We have previously disclosed the
highly diastereoselective triflimide-catalyzed cyclization that
converts dienone 1 into cyclopentenone 2 in 80% yield
[Eq. (1)].[6] The stereochemistry of 2 reveals that a conrotatory
process, which is required to conserve orbital symmetry, has
occurred. The polarization of “push–pull” dienone 1 and the
[*] A. Jolit,[+] Dr. P. M. Walleser,[+] Prof. Dr. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
E-mail: tius@hawaii.edu
Dr. G. P. A. Yap
Department of Chemistry and Biochemistry, University of Delaware
236 Brown Laboratory, Newark, DE 19716 (USA)
Prof. Dr. M. A. Tius
University of Hawaii Cancer Center
701 Ilalo Street, Honolulu HI 96813 (USA)
[+] These authors contributed equally to this work.
[**] G.P.A.Y. thanks the NSF (CRIF-MRI 1048367). Jonathan Congmon is
acknowledged for experimental assistance.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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