Enantioselective Total Synthesis of (+)-Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis.

Herein we report the first enantioselective total synthesis of (+)-incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio- and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium-catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step.

Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction.

An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1-2 mol % of Vaska's complex (IrCl(CO)(PPh3)2), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF2R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N-aryl- and N-heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.

The Deazidoalkoxylation: Sequential Nucleophilic Substitutions with Diazidated Diethyl Malonate.

Diazidated malonamides derived from amines and diazidated diethyl malonate react with lithiated alcohols through nucleophilic substitution reactions where azide acts as an unconventional leaving group. This deazidoalkoxylation leads to the formal construction of N, O-acetals, and the remaining azide functionality is a useful entry point for further functionalizations through, for example, standard cycloaddition chemistry. Thus, the presented chemistry provides an easy route toward densely functionalized molecules: Amines, alcohols, and alkynes can be attached onto the small malonate core unit in a sequential manner.

Cleavage of 1,3-dicarbonyls through oxidative amidation.

A mild and convenient protocol for the oxidative cleavage of 1,3-diketone compounds is described. Under metal-free conditions, the method converts the 1,3-dicarbonyls into amides when treated with (nBu4N)N3 and iodine in the presence of an amine at room temperature. Using this method, a range of 1,3-dicarbonyls with various structural motifs including sterically demanding substituents and ordinary functional groups were easily fragmented, and it is demonstrated that cyclic 1,3-dicarbonyls can be directly transformed into acyclic diamides through ring-opening. Initial mechanistic studies show that diazidation of the enol form is followed by nucleophilic substitution with the amine.

Geminal Diazides Derived from 1,3-Dicarbonyls: A Protocol for Synthesis.

Geminal diazides constitute a rare class of compounds where only a limited number of methods are available for their synthesis. We present the reaction of 1,3-dicarbonyl compounds (as exemplified by malonates, 3-oxoesters, and 1,3-diketones) with molecular iodine and sodium azide in aqueous DMSO providing a general access to geminal diazides. A broad range of geminal diazides with various structural motifs including sterically demanding substituents and ordinary functional groups were synthesized, and it was shown that the diazidation of 1,3-dicarbonyls can be selectively achieved even in the presence of other 1,3-dicarbonyls with substituents at 2-position. Additionally, several diazides were studied regarding their thermal stability.