Angewandte
Communications
Chemie
Asymmetric Catalysis
Enantioselective Silver and Amine Co-catalyzed Desymmetrizing
Cycloisomerization of Alkyne-linked Cyclohexanones
Abstract: A silver(I) and amine co-catalyzed desymmetriza-
tion of 4-propargylamino cyclohexanones for the direct
enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is
described. Exploiting reactivity arising from dual activation
of the pendant terminal alkyne by silver(I) and the ketone
moiety through transient enamine formation, this synthetically
relevant transformation is easy to perform, efficient and broad
in scope. High enantioselectivity (up to 96% ee) was achieved
by exploiting a significant matching effect between the chirality
of a cinchona alkaloid-derived aminophosphine ligand for the
silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst
which was rationalized by DFT calculations. This allowed
for the preparation of both enantiomers of the bicyclic product
with near-identical stereocontrol.
formations we took inspiration from nature. A wide variety of
natural products and biologically relevant molecules contain
the morphan core (2-azabicyclo[3.3.1]nonane) in their struc-
tures, including the daphniphyllum and strychnos alkaloid
families,[7] and accordingly the development of new, efficient
and stereoselective methods for the construction of this motif
is highly desirable. In this context, an organocatalyzed
intramolecular Michael addition to a,b-unsaturated esters[8a]
and an enantioselective arylation of cyclohexanones have
been reported.[8b]
We envisaged that an enantioselective desymmetrizing[9]
cycloisomerization of prochiral scaffold I (Scheme 1) to
afford the 6,6-bicyclic morphan skeleton II could possibly
I
n recent years, the demand for ever-increasing efficiency in
the synthesis of structurally complex and stereochemically
defined molecular constructs has spawned numerous lines of
research in the field of enantioselective catalysis. One
particular strand, where multiple catalytically competent
and compatible species are employed simultaneously to
achieve reactivity unattainable by a single catalytic entity
alone, has been particularly successful.[1] In this regard, the co-
operative combination of aminocatalysis and transition metal
catalysis has been demonstrated to be a powerful and
Scheme 1. Metal and amine co-catalyzed desymmetrization concept.
versatile catalytic strategy for the enantioselective construc-
[2]
À
tion of C C bonds, which has found applications in both
library synthesis and natural product synthesis alike.[3]
The use of terminal alkynes as electrophilic partners for
carbonyl compounds in co-operative metal and amine co-
catalysis was first reported independently by the Kirsch group
and our group in 2008.[4] Racemic cyclopentane derivatives
were prepared by a gold-catalyzed intramolecular cyclization
of 1,7-ynals in the former case, and by a copper-catalyzed
cascade reaction between a,b-unsaturated ketones and prop-
argylmalonates in the latter. Enantioselective variants of both
5-exo-dig cyclizations with aldehydes as starting materials
were later disclosed.[5,6]
be realized using a co-operative metal and amine co-catalyst
system. Under appropriate reaction conditions, the amino-
catalyst would generate in situ a nucleophilic enamine
intermediate, which would be poised to react intramolecularly
with the pendant alkyne when suitably activated by a “soft”
late transition metal ion, such as a copper or silver species.[10]
Such an enantioselective transformation to a strained 6,6-
bicyclic morphan core has not previously been described
despite its potential use in synthesis and herein we wish to
disclose our findings.
Our hypothesis was validated following a series of experi-
ments with substrate 1a, which was accessible on scale from
simple commercial starting materials. Treatment of 1a with
catalytic amounts of pyrrolidine, Cu(OTf)2 and triphenyl-
phosphine (as a reducing agent and ligand for copper) in
DMF at 708C for 12 hours provided the racemic morphan
product 2a in good yield (Scheme 2). Control experiments
omitting any one of these three components produced no or
insignificant amounts of 2a (see the Supporting Information
(SI) for details). Additionally, N-methylpyrrolidine was found
to be catalytically incompetent in the reaction. Taken
together these preliminary studies suggested that both
enamine activation of the ketone group and transition metal
In a continuation of our research program into expanding
the synthetic possibilities of co-operative co-catalytic trans-
[*] Dr. R. Manzano, Dr. S. Datta, Prof. Dr. R. S. Paton,
Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
Mansfield Road, Oxford OX1 3TA (UK)
E-mail: robert.paton@chem.ox.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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