Angewandte
Research Articles
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 7412–7417
International Edition:
German Edition:
Asymmetric Catalysis
Palladium-Catalyzed Enantioselective Heteroarenyne
Cycloisomerization Reaction
Ren-Xiao Liang, Ling-Jie Song, Jin-Bo Lu, Wei-Yan Xu, Chao Ding, and Yi-Xia Jia*
Dedicated to Professor Peter Kündig on the occasion of his 75th birthday
Abstract: The extensively developed ene-type enantioselective
cycloisomerization of classical 1,n-enynes provides an efficient
approach to chiral cyclic 1,4-dienes. In contrast, the catalytic
asymmetric heteroarenyne (heteroarene–alkyne) cycloisome-
rization involving the dearomative transformation of endocy-
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clic aromatic C C bonds remains unknown. Herein, we
communicate a PdH-catalyzed enantioselective heteroarenyne
cycloisomerization reaction of alkyne-tethered indole sub-
strates (formal 1,5- and 1,6-enynes). Based on this strategy,
a variety of structurally diverse chiral spiro and fused indoline
derivatives bearing quaternary stereocenters and exocyclic
Scheme 1. Ene-type enantioselective enyne and heteroarenyne cyclo-
isomerization.
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C C bonds are afforded in moderate to excellent yields and
excellent enantioselectivities (up to 98% ee). The classical ene-
type enantioselective 1,5-enyne cycloisomerization of N-vinyl-
propiolamides is also developed to afford chiral 2-pyrrolones
in good to excellent ee values.
1b).[8] Exploration of new catalytic asymmetric ene-type
cycloisomerization reaction is highly desirable towards the
construction of ring molecules with structural complexity.
Recently, asymmetric dearomatization reaction based on
dearomative migratory insertion strategy has received con-
siderable attention.[9,10] By employing endocyclic aromatic
Introduction
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Ene-type cycloisomerization of 1,n-enynes represents
a synthetically appealing approach for the synthesis of cyclic
1,4-diene molecules in a high atom-economy fashion.[1] Since
Trostꢀs seminal report of 1,6-enyne cycloisomerization,[2]
transition-metal-catalyzed enyne cycloisomerization reaction
has been extensively developed. Enantioselective versions are
also well-established by using the complexes of palladium,[3]
rhodium,[4] cobalt,[5] and gold[6] as chiral catalysts, rendering
the conversion of 1,n-enynes to optically active five- or six-
membered carbo- and hetero- cyclic compounds straightfor-
ward and efficient (Scheme 1a).[7] As a sharp comparison,
enantioselective heteroarenyne cycloisomerization, the reac-
tion of heteroarene-alkyne substrates, involving dearomative
C C bonds as coupling partners, enantioselective or racemic
Heck reactions,[11] reductive Heck reactions,[12] and domino
Heck/alkyl-metal termination sequences[13] have been exten-
sively studied. Relying on these transformations, a range of
structurally unique hetero- or carbocyclic molecules as well as
natural products have been efficiently synthesized.[11a,14] We
envisioned that a PdH-catalyzed enantioselective heteroar-
enyne cycloisomerization reaction might be possible through
intermolecular alkyne hydropalladation[15] and subsequent
intramolecular dearomative Heck vinylation.[11] Herein, we
communicate our primary results of catalytic enantioselective
cycloisomerization of alkyne-tethered indoles. As shown in
Scheme 2a, PdH-catalyzed cycloisomerization of C2-alkyne-
tethered indole, a formal 1,6-enyne substrate, in the presence
of chiral phosphoramidite ligand and Ph3CCO2H afforded
spirocyclic indolines in 80–98% ee. Note that chiral spirohe-
terocycle could also be afforded by classical 1,7-enyne
cycloisomerization.[3e, f] Further, heteroarenyne cycloisomeri-
zation of N-alkyne-tethered indole, a formal 1,5-enyne
substrate, proceeds smoothly through a possible E-to-Z
isomerization of vinyl-Pd species (Scheme 2b).[16] In this case,
polycyclic indolines bearing tetrasubstituted stereocenters are
afforded in excellent enantioselectivities (up to 98% ee) with
(S)-tBu-PHOX as the chiral ligand and NEt3·HOTf as the
hydride donor. The resulting fused indolines constitute the
core structures of a number of natural products (Scheme
2c).[17] Asymmetric ene-type cycloisomerization of classical
1,5-enyne substrates is also developed to deliver chiral 2-
pyrrolones in good to excellent enantioselectivities.
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transformation of endocyclic aromatic C C bond via a mi-
gratory insertion/b-H elimination sequence under the PdH
catalysis, is very challenging and remains unknown (Scheme
[*] Dr. R.-X. Liang, L.-J. Song, J.-B. Lu, W.-Y. Xu, C. Ding, Prof. Dr. Y.-X. Jia
College of Chemical Engineering, State Key Laboratory Breeding Base
of Green-Chemical Synthesis Technology
Zhejiang University of Technology
Chaowang Road #18, Hangzhou 310014 (China)
E-mail: yxjia@zjut.edu.cn
Prof. Dr. Y.-X. Jia
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
7412
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 7412 –7417