Versatile Configuration-Encoded Strategy for Rapid Synthesis of 1,5-Polyol Stereoisomers

The isolated stereogenic centers of 1,5-polyol-containing natural products present challenges to synthesis and structure determination. To address this problem, a configuration-encoded strategy defines each configuration within a simple 4-(arylsulfonyl)butyronitrile building block, a repeat unit that is reliably and efficiently coupled in iterative fashion to afford 1,5-polyols of defined stereochemistry. For example, the C27−C40 subunit of tetrafibricin is prepared in five steps and 42% yield. This strategy is amenable to rapid and unambiguous preparation of all configurational permutations of 1,5-polyols with equal facility

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ‑Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia–Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia–Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ‑Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia–Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia–Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin

Enantioselective Synthesis of α‑Trifluoromethyl Amines via Biocatalytic N–H Bond Insertion with Acceptor-Acceptor Carbene Donors

The biocatalytic toolbox has recently been expanded to include enzyme-catalyzed carbene transfer reactions not occurring in Nature. Herein, we report the development of a biocatalytic strategy for the synthesis of enantioenriched α-trifluoromethyl amines through an asymmetric N–H carbene insertion reaction catalyzed by engineered variants of cytochrome c552 from Hydrogenobacter thermophilus. Using a combination of protein and substrate engineering, this metalloprotein scaffold was redesigned to enable the synthesis of chiral α-trifluoromethyl amino esters with up to >99% yield and 95:5 er using benzyl 2-diazotrifluoropropanoate as the carbene donor. When the diazo reagent was varied, the enantioselectivity of the enzyme could be inverted to produce the opposite enantiomers of these products with up to 99.5:0.5 er. This methodology is applicable to a broad range of aryl amine substrates, and it can be leveraged to obtain chemoenzymatic access to enantioenriched β-trifluoromethyl-β-amino alcohols and halides. Computational analyses provide insights into the interplay of protein- and reagent-mediated control on the enantioselectivity of this reaction. This work introduces the first example of a biocatalytic N–H carbenoid insertion with an acceptor–acceptor carbene donor, and it offers a biocatalytic solution for the enantioselective synthesis of α-trifluoromethylated amines as valuable synthons for medicinal chemistry and the synthesis of bioactive molecules