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.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring by varying the MDOs (Scheme ). The enantiomers of 767 and 768 could also be obtained in similar stereoselectivities by using the pseudo‐enantiomeric MDOs 438 /( R )‐ 764 and 770 /( R )‐ 764 , respectively . Control experiments clearly indicated that the observed catalytic activity of the MDO was the direct result of a cooperative action of both precatalyst modules …”

“…Using a similar strategy, most recently we have synthesized cis ‐ and trans ‐fused pyrano[2,3‐ b ]pyrans ( 767 and 768 , respectively) in high diastereoselectivities and enantioselectivities from the same initial substrates ( 123 and 541 ) using a domino inverse electron‐demand hetero‐Diels–Alder/oxa‐Michael reaction catalyzed by MDOs self‐assembled from l ‐proline [( S )‐ 764 ] and Cinchona alkaloid thiourea derivatives 447 and 769 . Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring by varying the MDOs (Scheme ).…”

Advances in Asymmetric Diastereodivergent Catalysis

“…Most recently, we further explored the utility of MDOs in enantio‐ and diastereodivergent catalysis, and synthesized both enantiomers of the cis ‐ and trans ‐fused pyrano[2,3‐ b ]pyrans 114 using a tandem inverse‐electron‐demand hetero‐Diels–Alder/oxa‐Michael reaction between compounds 106 and 113 (Scheme ) . The MDO self‐assembled from quinidine thiourea ( 7 ) and l ‐proline [( S )‐ 33 ] gave cis ‐ 114 in high dr and ee values (up to 99:1 and >99% ee ), while the MDO self‐assembled from 115 and ( S )‐ 33 yielded the trans ‐ 114 in a similar level of dr and ee values (up to 98:2 and >99% ee ).…”

“…The MDO self‐assembled from quinidine thiourea ( 7 ) and l ‐proline [( S )‐ 33 ] gave cis ‐ 114 in high dr and ee values (up to 99:1 and >99% ee ), while the MDO self‐assembled from 115 and ( S )‐ 33 yielded the trans ‐ 114 in a similar level of dr and ee values (up to 98:2 and >99% ee ). Again, the enantiomers of both cis ‐ and trans ‐ 114 could be obtained by using the pseudo‐enantiomers of these two MDOs as the catalyst [ 5 /( R )‐ 33 and 116 /( R )‐ 33 , respectively] …”

“…During a study of the MDO‐catalyzed diastereodivergent tandem reactions, in order to understand the catalytic mechanisms, we evaluated the effects of the catalysts on the proposed reaction intermediates ,. As shown in Scheme , diastereodivergence could be achieved from the optically enriched compound 253 , which was the intermediate of the tandem Michael–Michael reaction, by using quinine thiourea ( 5 ) or quinidine thiourea ( 7 ) as the catalyst, and the diastereomers 107a and 108a were obtained in high dr and ee values from these two catalysts, respectively .…”