Angewandte
Chemie
DOI: 10.1002/anie.201405381
Asymmetric Organocatalysis
Hot Paper
N-Heterocyclic Carbene Catalyzed Formal [3+2] Annulation Reaction
of Enals: An Efficient Enantioselective Access to Spiro-Heterocycles**
Chang Guo, Michael Schedler, Constantin G. Daniliuc, and Frank Glorius*
Abstract: A highly enantioselective N-heterocyclic carbene
(NHC) catalyzed formal [3+2] annulation of a,b-unsaturated
aldehydes with azaaurones or aurone generating spiro-hetero-
cycles has been developed. The protocol represents a unique
NHC-activation-based approach to access spiro-heterocyclic
derivatives bearing a quaternary stereogenic center with high
optical purity (up to 95% ee).
the most effective ways to construct the racemic spiro-
pseudoindoxyl framework.[16] Despite extensive efforts, cata-
lytic asymmetric syntheses of substituted spiro-heterocyclic
derivatives by direct synthetic approaches are still rare.[1l]
Therefore, the development of a catalytic asymmetric syn-
thesis of optically active spiro-pseudoindoxyl moieties has
been a highly desirable yet challenging subject.
Based on the importance of the spiro-heterocycle syn-
thesis and our interest in NHC chemistry, we envisioned that
novel methods for spiro-heterocycles might be achieved by
NHC-catalyzed annulation via an NHC-generated homoeno-
late (Scheme 1). Herein, we report our results on this NHC-
catalyzed highly enantioselective formal [3+2] annulation of
enals with azaaurones or aurone, thus providing an alternative
route to valuable enantioenriched substituted spiro-hetero-
cycles.
N
-Heterocyclic carbene (NHC) catalysis has become well
known for the development of unique transformations based
on the umpolung of aldehydes.[1] In particular, the Bode
group[2] and the Glorius group[3] have independently reported
the NHC-catalyzed formal [3+2] annulation of enals with
aldehydes via homoenolate intermediates affording g-butyro-
lactones. Later, the NHC–homoenolate pathway was
explored with various types of reactive electrophiles to
prepare synthetically valuable cyclic[4–7] as well as acyclic[8]
molecular scaffolds. The Nair group and the Bode group
reported a formal [3+2] annulation of enals with cyclic
dienones by a conjugate addition–cyclization sequence gen-
erating cyclopentanones.[9] Recently, the Scheidt group[10] and
the Ye group[11] described the highly enantioselective formal
[4+3] annulation of enals with o-quinone methides to access
benzoxopinones. However, to the best of our knowledge, no
highly enantioselective variant of the cyclopentanone annu-
lation[9] to generate spiro-pseudoindoxyl moieties has been
available.
Scheme 1. The synthesis of spiro-heterocycles by the NHC-catalyzed
annulation reaction.
The spiro-heterocyclic moiety constitutes the core struc-
ture of numerous natural alkaloids and pharmaceuticals
exhibiting significant biological activities.[12] For example,
brevianamide A, isolated as the major fluorescent metabolite
from Penicillium brevicompactum by Birch and Wright,[13]
was found to exhibit insecticidal activity.[14] In addition to its
interesting biological activity, this unique structural motif
contains a spirocyclic quaternary stereogenic carbon center at
the C2 position of indole, a structural unit that has long
challenged synthetic organic chemists.[15] Oxidative rear-
rangement of indole derivatives has been considered one of
We started the evaluation of our hypothesis by combining
cinnamaldehyde (1a) with azaaurone[17] 2a using azolium salt
4a as the NHC precatalyst and DBU as the base in THF at
508C (Table 1, entry 1). To our delight, the reaction pro-
ceeded smoothly and afforded the desired product 3aa in
18% yield with 23% ee. Encouraged by this result, we
conducted a vigorous screening with different NHC catalysts,
which displayed remarkable effects on the outcome of the
reaction (entries 1–5). Gratifyingly, the desired spiro-pseu-
doindoxyl 3aa could be obtained in 77% yield with 91% ee
when the precatalyst 4d was employed (entry 4). The NH
variant of the azaaurone generated no product at all (entry 6).
When 5 mol% catalyst was employed the yield and enantio-
selectivity were lower than with 10 mol% catalyst (entries 4
and 7). The use of other bases, such as NaOAc and Et3N,
resulted in no formation of the desired product (entries 8 and
9). Varying the solvents led to no improvement in the reaction
performance and THF was proven to be the solvent of choice
(entries 4 and 10–12). Naturally, the opposite configuration of
3aa can be accessed in the same yield and enantioselectivity
by using the opposite enantiomer of the NHC precatalyst 4d’;
in this way both spiro-pseudoindoxyl enantiomers can be
[*] Dr. C. Guo, M. Schedler, C. G. Daniliuc, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
[**] Generous financial support by the Alexander von Humboldt
Foundation (C.G.), the Fonds der Chemischen Industrie (M.S.), and
the Deutsche Forschungsgemeinschaft (SPP 1179) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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