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Multistep Chemoenzymatic Cascade for the Synthesis of Chiral N-Heterocycles
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DOI：10.1002/cctc.70902.png)
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Abstract
En 中文
Multistep cascade reactions offer a powerful synthetic strategy to build significant molecular complexity without the reliance on protecting group chemistry and the isolation and purification of intermediates following each transformation. Herein, we describe novel multistep one-pot bio-organocatalytic methodology to access quinolizidine and indolizidine containing compounds with multiple chiral centers. The cascade incorporates a transaminase to generate a reactive intermediate in situ and a subsequent proline-mediated Mannich-aza-Michael reaction for the construction of privileged aza-bicyclic scaffolds. The addition of further biocatalysts enables the late-stage functionalization of these molecules, affording a panel of natural products and novel N-heterocycle derivatives. Notably, we report a three-step cascade, involving a transaminase, L-proline, and an alcohol dehydrogenase, to transform the linear diamine, cadaverine, and a β-aryl enone, to the sp3-rich natural product, (−)-lasubine II, isolated as a single diastereoisomer. The methodology showcases the synthetic capabilities of enzymes for the generation of reactive intermediates in situ, the resolution of stereoisomers and the selective installation of multiple chiral centers, all while operating under ambient aqueous reaction conditions.
Keywords:
alcohol dehydrogenase
biocatalysis
chemoenzymatic cascade
quinolizidine
transaminase
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