Direct Organocatalytic Asymmetric Heterodomino Reactions:  The Knoevenagel/Diels−Alder/Epimerization Sequence for the Highly Diastereoselective Synthesis of Symmetrical and Nonsymmetrical Synthons of Benzoannelated Centropolyquinanes

Abstract

Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/Diels-Alder/epimerization reactions of readily available various precursor enones (1a-l), aldehydes (2a-p), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted, symmetrical and nonsymmetrical spiro[cyclohexane-1,2'-indan]-1',3',4-triones (5) in a highly diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation of arylaldehydes (2a-p) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3-indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine-catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans-spiranes (6ab) are excellent starting materials for the synthesis of benzoannelated centropolyquinanes. Under amino acid and amine catalysis, the topologically interesting dispirane 24 was prepared in moderate yields. Organocatalysis with pyrrolidine catalyzed a series of four reactions, namely the Michael/retro-Michael/Diels-Alder/epimerization reaction sequence to furnish cis-spirane 5ab in moderate yield from enone 1a and 1,3-indandione 3.

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…[243] Different effects have been evaluated in the enantioselective Tietze MCR. [244] Among others, the nature of the 1,3-dicarbonyl compound influences the enantioselectivity and l- proline must be used as the organocatalyst to attain good enantioselectivities. The reaction can also be performed with a phosphorane derivative, which in turn reacts with an aldehyde in a one-pot process to form the desired a,bunsaturated ketone.…”

A novel four-component reaction involving ring-opening/recyclization of 1,3-thiazolidinedione

“…To the best of our knowledge, this type of ring cleavage of thiazolidinedione has never been found before our investigation. Some related heterocyclic compounds such as 2-amino-1,3-thiazoline-5-ones and 2-thiohydantoins have been reported to show ring cleavage reaction in some cases [21][22][23][24][25][26][27][28]. Here this one-pot, multicomponent reaction clearly went through with a domino procedure.…”

2.14 Other Condensation Reactions (Knoevenagel, Perkin, Darzens)

“…52 This domino reaction involves amino acid-and amine-catalyzed epimerization reactions of trans-spiranes (32) to cis-spiranes (31) through retro-Michael reaction. The cis/trans ratios were found to be 99:1.…”