Abstract
Diastereodivergent heterocycle synthesis has been recognized as an important tool for drug discovery in recent years, yet strategies based on nickelacycle formation have not been established. Here, we report a NHC-Ni catalyzed highly 1,3- and 1,4-diastereodivergent heterocycle synthesis from enyne, which is achieved by manipulating the enyne N-substituent (allowing switching of selectivity from up to 2:98 to 98:2). The key to success is the efficient diastereodivergent formation of a nickelacyclopentene, with broad enyne scope at mild conditions, which subsequently provides reductive hydroalkenylation, acylation and silylation products on demand. Diastereoisomers which are sterically hard to distinguish or difficult to access by conventional routes are now accessible easily, including those with very similar 4°, contiguous and skipped stereocenters.
Highlights
Diastereodivergent heterocycle synthesis has been recognized as an important tool for drug discovery in recent years, yet strategies based on nickelacycle formation have not been established
Unlike a few examples noted in intramolecular hydroalkenylation of diene (Fig. 2c)[28,29], the scope is mostly limited to those equipped with cyclic template, some requires Thorpe-Ingold effect assistance, and no efficient diastereodivergent example has been developed
The condition employed is as simple as an NHC-Ni(0) catalyzed enyne cycloaddition reported in the literature with shorter tethers[24], except 1-phenylethanol is used as terminal reductant to complete the desired catalytic cycle by reductive hydroalkenylation under mild condition (Supplementary Table 1)
Summary
Diastereodivergent heterocycle synthesis has been recognized as an important tool for drug discovery in recent years, yet strategies based on nickelacycle formation have not been established. The key to success is the efficient diastereodivergent formation of a nickelacyclopentene, with broad enyne scope at mild conditions, which subsequently provides reductive hydroalkenylation, acylation and silylation products on demand. Multi-substituted hydropyran and piperidine skeletons with exocyclic olefin are key core structures or precursors in many biologically active natural products and drug molecules (Fig. 1)[2,3,4,5,6,7]. Undesired steric repulsion among substituents (mismatch) as well as the high demands of functional groups often limited the scope and the efficiency of the process. 1,3-syn-diastereoselective synthesis has been achieved in a few examples according to the steric demands of enyne substituents and metallacycle formation (Fig. 2b)[25,26,27], other possible combinations were explored rarely (e.g., 1,3- 1,4-diastereodivergent, and in higher substituted cases). By trapping the NHC-nickelacyclopentenes with alcohol, silane and aldehyde, 1,3- and 1,4-diastereodivergent reductive hydroalkenylation[30,31,32], silylation and acylation products are obtained[26,33]
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