Spin States Matter─from Fundamentals toward Synthetic Methodology Development and Drug Discovery.

ConspectusThe potent reactivity of carbenes and nitrenes has been traditionally harnessed by the employment of a transition-metal catalyst in which the reactivity of the metal carbene/nitrene intermediates can be controlled via the judicious tuning of the metal catalyst. In recent years, progress made in this research area has unveiled novel strategies to directly access free carbenes or nitrenes under visible-light-mediated conditions without the necessity of a metal catalyst for stabilization of the carbene/nitrene intermediate. Such photochemical approaches present new opportunities to leverage orthogonal reactions with classic metal-catalyzed transformations.

Palladium-Catalyzed (3+2) and (4+2) Cycloaddition Reactions of Sulfamidate Imine-Derived Azadienes: Synthesis of Spirocyclic Pyrrolidines and Tetrahydroquinolines.

Diastereoselective Pd-catalyzed (3+2) and (4+2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes with zwitterionic N-dipoles derived from 1-tosyl-2-vinylaziridine and 4-vinylbenzoxazinone have been developed. These reactions provide highly functionalized azaspirocycles featuring three contiguous stereocenters. The sulfonyl imine moiety of the cycloadducts can be fully reduced to access valuable β-amino alcohols.

Diastereoselective Pd-catalyzed Decarboxylative (4+2) Cycloaddition Reactions of 4-Vinylbenzoxazinanones and 2-Nitro-1,3-enynes.

A formal palladium-catalyzed decarboxylative (4+2) cycloaddition reaction between 4-vinylbenzoxazinanones and 2-nitro-1,3-enynes has been developed to produce highly valuable, densely functionalized tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2-nitro-1,3-enynes, which represent an under-utilized class of dipolarophile for transition-metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N-H- and N-Ts-4-vinylbenzoxazinanone dipole precursors.

Palladium-catalysed enantio- and regioselective (3 + 2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes towards spirocyclic cyclopentanes.

An enantio- and diastereoselective Pd-catalysed (3 + 2) cycloaddition of bis(trifluoroethyl) 2-vinyl-cyclopropane-1,1-dicarboxylate (VCP) with cyclic sulfamidate imine-derived 1-azadienes (SDAs) has been developed. These reactions provide highly functionalized spiroheterocycles having three contiguous stereocentres, including a tetrasubstituted carbon bearing an oxygen functionality. The two geminal trifluoroethyl ester moieties can be manipulated in a facially selective manner to afford more diversely decorated spirocycles with four contiguous stereocentres.

The Pd-catalysed asymmetric allylic alkylation reactions of sulfamidate imines.

The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5-oxathiazole 2,2-dioxides has been developed. Various 4,5-disubstituted and 4-substituted cyclic sulfamidate imines have participated in the transformation with a range of allyl carbonates-as well as 2-vinyl oxirane, 2-vinyl--tosylaziridine, and 2-vinyl-1,1-cyclopropane dicarboxylate-to furnish the desired -allylated products in moderate to high yields, with high regioselectivites and generally high enantioselectivities. Conversion between - and -allyl products was observed, with the -allylated products converting to the -allylated products over time.

Five-membered cyclic sulfamidate imines: versatile scaffolds for organic synthesis.

In recent years, five-membered ring cyclic sulfamidate imines (5H-1,2,3-oxathiazole 2,2-dioxides) have received increasing attention as useful precursors for the stereoselective synthesis of many valuable heterocycles. Bearing a reactive N-sulfonyl imine moiety as part of the stereodefined skeleton, this sulfamidate imine platform has been utilised as a substrate in many reactions, including nucleophilic additions and reductions, to prepare highly functionalised cyclic sulfamidates. In addition, cyclic sulfamidate imines can also readily participate as nucleophiles in many chemical transformations, owing to the acidic proton(s) adjacent to the imine moiety.