Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis‐ and trans‐Fused Pyrano[2,3‐b]pyrans

Abstract

Both enantiomers of cis- and trans-fused 3,4,4a,8a-tetrahydro-2H,5H-pyrano[2,3-b]pyran-7-carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse-electron-demand hetero-Diels-Alder/oxa-Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self-assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.

Catalytic Strategies for Diastereodivergent Synthesis

“…Zhao applied in situ‐self‐assembled organocatalysts with proline and cinchona alkaloid thiourea 10 as precatalyst modules to control the diastereoselectivity of individual steps in tandem Michael/Michael reaction and an ensuing epimerization between the nitroalkenes and 7‐oxo‐5‐enal compounds . By modulating the configuration of the two modules, four 1,2‐ syn ‐diastereomers were achieved in excellent yield and ee at room temperature.…”

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…Besides, the Zhao group completed an asymmetric tandem inverse-electron-demand hetero-Diels–Alder/oxa-Michael reaction catalyzed by the modularly designed organocatalysts (MDOs) which were self-assembled from amino acids and cinchona alkaloid derivatives in the reaction medium ( Scheme 16 E) ( Huang et al., 2016a ). The reactions were derived from β,γ -unsaturated α -ketoesters 1d and the aldehydes 122.…”

Asymmetric Supramolecular Organocatalysis: A Complementary Upgrade to Organocatalysis

“…Very recently, in 2016, Zhao et al showed that both enantiomers of cis ‐ and trans ‐fused pyrano[2,3‐ b ]pyran derivatives 93 / 94 could be obtained with high diastereoselectivities and enantioselectivities from the same substrates by way of a tandem hetero‐Diels–Alder/oxa‐Michael sequence catalyzed by MDOs self‐assembled from the two enantiomers of proline and cinchona alkaloid–thiourea derivatives (Scheme ) . When l ‐proline ( 7a ) and the quinidine–thiourea 8a were used as the precatalysts in toluene at room temperature, the cis ‐fused pyrano[2,3‐ b ]pyran 93 was obtained from the substrates, aldehyde 91 , and α‐keto ester 77 in good yield, with high dr and excellent ee after 24 h. The reaction did not take place when either 7a or 8a was used alone under similar reaction conditions, which indicated that the observed catalytic activity is a cooperative action of both the components.…”