Sulfondiiminesthe double aza-analogues of sulfoneshold significant potential as leads in discovery chemistry, yet their application in this arena has been held back by the scarcity of appropriate synthetic routes. Existing methods employ sulfides as substrates, and rely on consecutive imination reactions using the hazardous reagent O-mesitylenesulfonyl hydroxylamine.Here we report a method for sulfondiimine synthesis that does not begin with a sulfide or a thiol, and instead employs two Grignard reagents and a bespoke sulfinylamine (RNSO) reagent as starting materials. Lewis acid-mediated assembly of these three components provides efficient access to a series of sulfilimine intermediates. A novel rhodium-catalyzed imination of these electron-rich sulfilimines then delivers a varied range of sulfondiimines featuring orthogonal N-functionalization. Conditions for the selective manipulation of both Natoms of the sulfondiimines are reported, allowing access to a broad range of mono-and difunctionalized products. The oxidation of the sulfilimine intermediates is also described, and provides a complementary route to sulfoximines.

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A new method for one-step construction of the tetracyclic core structure of the indole alkaloid (+)-minfiensine was developed utilizing a palladium-catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)-minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.

A new N -silyl sulfinylamine reagent allows the rapid preparation of a broad range of (hetero)aryl, alkenyl, and alkyl primary sulfinamides, using Grignard, organolithium, or organozinc reagents to introduce the carbon fragment. Treatment of these primary sulfinamides with an amine in the presence of a hypervalent iodine reagent leads directly to NH-sulfonimidamides. This two-step sequence is straightforward to perform and provides a modular approach to sulfonimidamides, allowing ready variation of both reaction components, including primary and secondary amines.

Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.

The Strychnos alkaloid minfiensine and a series of akuammiline alkaloids, such as vincorine, aspidophylline A, and picrinine, possess a common core skeleton, a 4a,9a-heterocycle-fused tetrahydrocarbazole. Efficient construction of this core structure in a highly enantioselective manner would facilitate the total synthesis of these alkaloids. In this article, we briefly summarize the established strategies for obtaining this core structure, together with the corresponding total-synthesis routes, and we describe our own effort on the development of a new strategy, the asymmetric cascade dearomative cyclization, for the efficient total synthesis of (+)-minfiensine.