The catalytic enantioselective assembly
of spirocyclic molecules
featuring a spiro quaternary carbon stereocenter is currently of great
interest because such privileged 3D structures are widely present
in natural products that exhibit a broad spectrum of biological and
pharmacological activities. This review summarizes the advances based
on six major synthetic strategies and showcases the reaction mechanisms
in detail. The advantages and limitations of each synthetic strategy
are presented, and the remaining synthetic opportunities are outlined.
Optically active spirocyclic compounds play an important role in drug discovery, and new synthetic strategies for the efficient generation of spiro stereocenters are in much demand. Here we report a catalytic enantioselective cycloaddition using spirocyclic donor–acceptor cyclopropanes as a promising approach for the generation of spiro stereocenters. A diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles with both aldonitrones and ketonitrones is developed. The key to reaction development is the activation of spirocyclopropyl oxindoles by a suitable electron-withdrawing N-protecting group. This activation approach offers the promise of a general solution to enable spirocyclopropyl oxindoles as synthons for catalytic enantioselective synthesis of spirocyclic oxindoles featuring a C3 spiro stereocenter, a prominent structural motif in drugs and pharmaceutically active compounds. This protocol also constitutes the catalytic enantioselective reaction using unactivated achiral ketonitrones to construct tetrasubstituted carbon stereocenters.
Desymmetrization of easily available disubstituted malonic esters is a rewarding strategy to access structurally diverse quaternary stereocenters. Particularly, asymmetric reduction of malonic esters would generate a functional group with a lower oxidation state than the remaining ester, thus allowing for more chemoselective derivatization. Here, we report a new set of conditions for the zinccatalyzed desymmetric hydrosilylation of malonic esters that afford aldehydes as the major product. Compared with alcohol-selective desymmetrization, the partial reduction uses a higher concentration of silanes and new pipecolinol-derived tetradentate ligands, proposedly to switch the pathway of zinc hemiacetal intermediates from elimination to silylation. As a result, high aldehyde-to-alcohol ratios and enantioselectivity of aldehydes are obtained from malonic esters with a large collection of substituents. Together with the abundant reactivity of aldehydes, the partial reduction has enabled an expeditious synthesis of bioactive compounds and natural metabolites containing a quaternary stereocenter.
A "one-pot" tandem substitution/Krapcho reaction is reported for the facile synthesis of α-fluorinated esters and sulfones, which utilizes the byproduct salt formed in the substitution step as an indispensible reagent to facilitate the Krapcho reaction step. This represents the first sustainable tandem reaction that internally recycles the waste salt formed in the upstream step as the reagent for the downstream step.
A Sc(OTf)3-catalyzed highly diastereoselective one-pot
sequential [3 + 3] dipolar cycloaddition reaction of aldehyde or ketone, N-alkyl hydroxylamine, and spirocyclopropyl oxindole is
developed, allowing facile construction of spirocyclic oxindole-tetrahydro-1,2-oxazines
with sufficient structural diversity. The corresponding catalytic
enantioselective one-pot protocol of aldehydes is also reported, affording
the desired adducts in up to 97% ee. The biological evaluation of
selected oxindole-based spirocyclic tetrahydro-1,2-oxazines revealed
that they exerted cytotoxic effects on human prostate cancer cells
with the capacity to inhibit NFκB signaling in prostate cancer
cells.
Here,
we report an unprecedented catalytic enantioselective cyanation
of ketonitrones enabled by the bifunctional cyanating reagent Me2(CH2Cl)SiCN. This approach allows facile access
to optically active N-hydroxyl-α-amino nitriles
that are of high synthetic value but difficult to acquire by other
methods. The use of bifunctional cyanating reagent Me2(CH2Cl)SiCN not only achieves an enantioselectivity higher than
that with TMSCN but also enables various diversification reactions
of the resulting silylated adducts. This represents the first enantioselective
catalytic nucleophilic addition reaction of unactivated ketone-derived
nitrones, exhibiting the potential of such tetrasubstituted CN
bonds for asymmetric synthesis of N-hydroxy α-amino
acids and other N-hydroxy tertiary amines.
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