Organocatalytic Enantioselective Synthesis of Both Diastereomers of α-Hydroxyphosphinates

Abstract

Racemic α-acylphosphinates and formylphosphinate hydrate were used directly as the substrates in a proline derivative-catalyzed cross aldol reaction with ketones. Because of the preexisting the phosphorus stereogenic center, a mixture of two diastereomers of the corresponding α-hydroxyphosphinates were obtained in this reaction. Good to high enantioselectivities (up to 99% ee) were obtained simultaneously for both of these two diastereomers in good yields. Good diastereoselectivities were also obtained when the reaction generates an additional carbon stereogenic center.

Quinidine Thiourea‐Catalyzed Aldol Reaction of Unactivated Ketones: Highly Enantioselective Synthesis of 3‐Alkyl‐3‐hydroxyindolin‐2‐ones

“…5,6,7 Nevertheless, the enolate mechanism does have certain advantages, especially when the formation of an enamine is difficult. During our study of using activated ketone compounds as the enamine acceptors for the organocatalyzed aldol reactions, 8 we envisioned such an organocatalyzed enolate-mediated aldol reaction should be possible if the enolate acceptor is sufficiently activated, because the equilibrium favors the formation of the product with such a substrate. Herein we wish to report the first enantioselective aldol reaction of unactivated ketones involving the enolate mechanism, which may be used for the high enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones.…”

Developing Novel Organocatalyzed Aldol Reactions for the Enantioselective Synthesis of Biologically Active Molecules

“…42 All the catalyst exhibited high reactivity and led to the formation of the expected diastereomeric mixture of 60a and 61a (due to the phosphorus chirality) in roughly 50:50 ratio and good yields. Although moderate enantioselectivities were obtained for the rest of these catalysts, L-proline ( 4 ) was found to yield good enantioselectivities for both diastereomers.…”

“…This would allow the synthesis of both diastereomers of α-hydroxyphosphinates in good enantioselectivities simultaneously. 42 …”

Proline Sulfonamide Based Organocatalysis: Better Late than Never

“…In addition, there were several examples of transformations in which other catalysts such as the proline tetrazole 18 xx,xxxviii or proline itselfxxvii,xxxix,xl,xli prove superior. It became clear to us that while preliminary work demonstrated the viability of proline sulfonamides as organcatalysts, the unique reactivity of these catalysts had not been fully realized.…”

“…These compounds have generated considerable synthetic attention due to their presence in numerous alkaloid natural products,xlv,xlvi including the pharmaceutically relevant iboga alkaloids xlvii. Prior asymmetric work in the field had primarily focused on using enantioenriched BINOL-derived, phosphoric Brønsted acids with modestly endo -selective products (typically 3–4:1 endo:exo selectivity) and reasonable enantioselectivities (typically 76–88% ee) xlviii,xlix,l,liScheme 14 xlviiia…”