Article
Ir-Catalyzed Regio- and Enantioselective Hydroalkynylation of
Trisubstituted Alkene to Access All-Carbon Quaternary
Stereocenters
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ABSTRACT: The stereoselective construction of all-carbon quater-
nary stereocenters, especially acyclic ones, represents an important
challenge in organic synthesis. In particular, homopropargyl amides
with a quaternary stereocenter β to a nitrogen atom are valuable
synthetic intermediates, which could be transformed to diverse chiral
structures through alkyne transformations. However, highly enantio-
selective synthetic methods for homopropargyl amides with a β quaternary stereocenter are extremely rare. We report here
unprecedented substrate-directed, iridium-catalyzed enantioselective hydroalkynylations of trisubstituted alkenes to form an acyclic
all-carbon quaternary stereocenter β to a nitrogen atom. The hydroalkynylation of enamide occurred with unconventional selectivity,
favoring the more hindered reaction site. Homopropargyl amides with β-stereocenters were prepared in high regio- and
enantioselectivities. Combined experimental and computational studies revealed the origin of the regio- and enantioselectivities.
preinstalled into the prochiral carbon of the substrate to
facilitate subsequent formation of the alkynylated stereocenter.
Modular catalytic asymmetric synthesis of homopropargyl
amine with a β all-carbon quaternary center through alkynyl
addition remains an unsolved task.
1. INTRODUCTION
All-carbon quaternary stereogenic centers occur frequently in
natural products and pharmaceutical and agrochemical
compounds (Scheme 1).1 In drug discovery, increasing
emphasis has been placed on the building of C(sp3)-rich
molecules to escape from flatland.2 All-carbon quaternary
stereogenic centers offer a unique opportunity to increase
molecular complexity by the three-dimensional orientation of
substituents at the carbon stereocenters. However, the
construction of a single configuration of an all-carbon
quaternary center poses a significant challenge to chemical
synthesis due to its congested nature and the control of
stereochemistry.3 In acyclic systems, the challenge is further
complicated by the additional conformational mobility.4
On the other hand, heteroatoms such as nitrogen also play a
key role in drug design.5 Therefore, the synthesis of nitrogen
compounds with all-carbon quaternary stereogenic centers is
highly desirable.6 Homopropargyl amines with an alkynylated
stereocenter are particularly attractive because the rich
chemistry associated with the alkyne would enable facile
product diversification through alkyne modification.7 Current
enantioselective synthesis of homopropargyl amines usually
relies on the propargylation of imines with functionalized metal
reagents or phase-transfer-catalyzed propargylation of glyci-
nate.8 These methods generate a stereocenter α to the nitrogen
atom. In contrast, very few catalytic methods have emerged
only recently to prepare homopropargyl amine with a β-
stereogenic center.9,10 Hu and co-workers reported the
construction of acyclic homopropargyl amine with a β
quaternary stereocenter through an elegant multicomponent
strategy.11 In these methods,9,11c the alkynyl group needs to be
In 2016, we devised a hydroalkynylation strategy to access
homopropargyl amide with a β-stereogenic center.12 This
reactivity pattern provided notable structural flexibility that was
otherwise difficult to access. Based on this finding, we surmised
that an enantioselective hydroalkynylation of a trisubstituted
alkene would enable the construction of homopropargyl amide
with a β all-carbon quaternary center. If successful, this method
would provide direct access to acyclic all-carbon quaternary
stereocenters from easily available alkene and alkyne
substrates. However, this design faces several challenges.
First, the reactivity of a trisubstituted alkene is significantly
lower than that of a disubstituted alkene due to the increased
steric hindrance. Second, the β position of the enamide is both
more electron-rich and more hindered. Thus, the catalyst must
exert substantial control to reverse the electronically and
sterically favored alkynylation at the α position.4c,12d Third, the
alkene isomerization must be minimized because it could lead
to decreased reactivity and enantioselectivity.13 Despite the
recent advances in enantioselective alkynyl addition to
Received: April 29, 2021
Published: June 21, 2021
J. Am. Chem. Soc. 2021, 143, 9639−9647
© 2021 American Chemical Society
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