15 research outputs found
Genetically programmed chiral organoborane synthesis
Recent advances in enzyme engineering and design have expanded natureâs catalytic repertoire to functions that are new to biology. However, only a subset of these engineered enzymes can function in living systems. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus8 (Rma cyt c) were found to form carbonâboron bonds in the presence of boraneâLewis base complexes, through carbene insertion into boronâhydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100âh^(â1), a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems
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An Expedient Total Synthesis of Chivosazoleâ F: an Actin-Binding Antimitotic Macrolide from the Myxobacterium
A unified strategy for the chemical synthesis of the chivosazoles is described. This strategy is based on two closely related approaches involving the late-stage installation of the isomerization-prone (2Z,4E,6Z,8E)-tetraenoate motif, and an expedient fragment-assembly procedure. The result is a highly convergent total synthesis of chivosazoleâ
F through the orchestration of three mild Pd/Cu-mediated Stille cross-coupling reactions, including the use of a one-pot, site-selective, three-component process, in combination with controlled installation of the requisite alkene geometry.We thank Sidney Sussex College Cambridge (C.T. So Studentship to J.J.), the Cambridge Overseas Trust (M.L., L.J.G.), the EPSRC (S.B.J.K. EP/F025734/1)) and Prof. David Spring for support, and the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectra
Direct allylic CâH alkylation of enol silyl ethers enabled by photoredoxâBrĂžnsted base hybrid catalysis
Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon-carbon bond forming reaction
The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon-carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counter-anion-directed Lewis acid catalysis mechanism