Research Article

Delayed catalyst function enables direct enantioselective conversion of nitriles to NH2-amines

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Science  05 Apr 2019:
Vol. 364, Issue 6435, pp. 45-51
DOI: 10.1126/science.aaw4029

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Amines emerge, as copper bides its time

Concurrent operation of two or more catalytic cycles requires a delicate balance of relative rates. Zhang et al. developed an amine synthesis in which allenes and nitriles are coupled under reductive conditions. A copper catalyst was charged with successively borylating the allene, coupling the intermediate to the nitrile, and then enantioselectively reducing that next intermediate to the amine. However, formation and reaction of the copper-boryl complex were too slow relative to a competing copper hydride. By adding an innovative delay cycle, the authors succeeded in keeping the fast-reacting hydride at bay until needed.

Science, this issue p. 45

Abstract

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.

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