The
development of non-natural reaction mechanisms is an attractive
strategy for expanding the synthetic capabilities of substrate promiscuous
enzymes. Here, we report an “ene”-reductase catalyzed
asymmetric hydroalkylation of olefins using α-bromoketones as
radical precursors. Radical initiation occurs via ground-state electron
transfer from the flavin cofactor located within the enzyme active
site, an underrepresented mechanism in flavin biocatalysis. Four rounds
of site saturation mutagenesis were used to access a variant of the
“ene”-reductase nicotinamide-dependent cyclohexanone
reductase (NCR) from Zymomonas mobiles capable of catalyzing a cyclization to furnish β-chiral cyclopentanones
with high levels of enantioselectivity. Additionally, wild-type NCR
can catalyze intermolecular couplings with precise stereochemical
control over the radical termination step. This report highlights
the utility for ground-state electron transfers to enable non-natural
biocatalytic C–C bond forming reactions.
Cycloadditions are powerful processes to synthesize complex polycyclic scaffolds. Herein, we disclose a [4+3]‐cycloaddition between an in situ generated ortho‐quinone methide and an isomünchnone to yield oxa‐bridged oxazocine cores, generating N2 and H2O as the sole by‐products. Using only catalytic amounts of camphorsulfonic acid, it is possible to generate both reactive intermediates in one step, eliminating the need for rhodium catalysts generally employed for isomünchnone formation. Spectroscopic data and X‐ray crystallography indicate the formation of the syn diastereomer, with the main side‐product arising from a hydrate participating in a competing [4+2]‐cycloaddition pathway.
A robust method for the dual-metal-catalyzed
combination of organic
azides, terminal alkynes, and internal alkynes is reported. The reaction
is initiated with a chemoselective copper-catalyzed azide alkyne cycloaddition
(CuAAC) followed by a palladium-catalyzed incorporation of an internal
alkyne. The simple one-pot procedure introduces C–H functionalization
to the growing field of multicomponent multicatalytic reactions ((MC)2R). With inexpensive CuI and the Herrmann–Beller palladacycle
as catalysts, four bonds and two heterocyclic rings are created with
HI as the sole byproduct. The broad scope with respect to all components
showcases this versatile transformation, leading to a new class of
fully substituted polycyclic triazoles. 1H NMR and deuterium-labeling
studies provide insight into the rate differences of the copper and
palladium steps.
Abstract(4+3)-Annulations are incredibly versatile reactions which combine a 4-atom synthon and a 3-atom synthon to form both 7-membered carbocycles as well as heterocycles. We have previously reviewed transition-metal-catalyzed (4+3)-annulations. In this review, we will cover examples involving bases, NHCs, phosphines, Lewis and Brønsted acids as well as some rare examples of boronic acid catalysis and photocatalysis. In analogy to our previous review, we exclude annulations involving cyclic dienes like furan, pyrrole, cyclohexadiene or cyclopentadiene, as Chiu, Harmata, Fernándes and others have recently published reviews encompassing such substrates. We will however discuss the recent additions (2010–2020) to the literature on (4+3)-annulations involving other types of 4-atom-synthons.1 Introduction2 Bases3 Annulations Using N-Heterocyclic Carbenes3.1 N-Heterocyclic Carbenes (NHCs)3.2 N-Heterocyclic Carbenes and Base Dual-Activation4 Phosphines5 Acids5.1 Lewis Acids5.2 Brønsted Acids6 Boronic Acid Catalysis and Photocatalysis7 Conclusion
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