Search

Author(s): Aaron Trowbridge [sup.1] , Dominik Reich [sup.1] , Matthew J. Gaunt [sup.1] Author Affiliations:(1) Department of Chemistry, University of Cambridge, Cambridge, UKMain The physiological properties of tertiary aliphatic amines [...], There is evidence to suggest that increasing the level of saturation (that is, the number of sp.sup.3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline.sup.1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates.sup.2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination.sup.3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines.sup.4-7. In particular, processes that transform accessible feedstocks into sp.sup.3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted [alpha]-amino radicals, which subsequently react with alkenes to form C(sp.sup.3)-C(sp.sup.3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.Complex tertiary alkylamines are prepared in one step from readily available amines, carbonyls and alkenes, via the visible-light-mediated reduction of in-situ-generated iminium ions to form alkyl-substituted [alpha]-amino radicals.

The chemistry of low‐valent intermediates continues to inspire new modes of reactivity across synthetic chemistry. But while the generation and reactivity of both carbenes and nitrenes are well‐established, difficulties in accessing oxene, their oxygen‐based congener, has severely hampered its application in synthesis. Here, we report a conceptually novel approach towards oxenoid reactivity through the violet‐light photolysis of tetrabutylammonium periodate. Computational studies reveal an unexpected geometric change upon periodate photoexcitation that facilitates intersystem crossing and near‐barrierless dissociation of triplet periodate into oxene. Under these operationally simple conditions, we have demonstrated the epoxidation of a wide range of substituted olefins, revealing unprecedented functional group compatibility. By overcoming the historic challenges associated with employing oxene as an intermediate in organic chemistry, we believe that this platform will inspire the development of new reactive oxygen‐based methodologies across industry and academia. [ABSTRACT FROM AUTHOR]

We report a common strategy to facilitate the syntheses of the polycyclic alkaloids (-)-FR901483 (1) and (+)-TAN1251C (2). A divergent synthetic strategy provides access to both natural products through a pivotal spirolactam intermediate (3), which can be accessed on a gram-scale. A photocatalytic olefin hydroaminoalkylation brings together three readily available building blocks and forges the majority of the carbon framework present in 1 and 2 in a single operation, leading to concise total syntheses. The complexity-generating photocatalytic process also provides direct access to novel non-racemic spirolactam scaffolds that are likely to be of interest to early-stage drug discovery programs., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a general visible-light-mediated strategy that enables the construction of complex C(sp 3 )-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp 3 )-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.