Catalytic enantioselective aldol reactions

Abstract

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize β-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

“…The a-OPMB amide 1d was transformed successfully as expected (entries 7a nd 8), and amides with an a-Oallyl or a-OMOM and a-OBOM substituents were also incorporated in the present direct aldol reaction (entries 9-14), allowing for flexibility in choosing the appropriate amide pronucleophiles to deliver enantioenriched syn-a nd anti-diols with the protecting group of interest. Other fluoroalkyl ketones without an a-hydrogen atom showed the identical stereoselectivity trend described above,although anti-selective conditions using ligand L8 gave lower diastereoselectivity (entries [3][4][5][6][7][8]. Nonetheless, those with meta or para substituents delivered the corresponding aldol adducts in ad iastereodivergent fashion (entries 1-18), while relatively sterically hindered b-naph- [b] syn/anti [c] ee thyl-substituted ketone 2e exhibited lower diastereoselectivity (entries 7and 8).…”

“…[2] Methods for optically active fluorinated motifs offer apromising opportunity to expand the chemical space of fluorinated active pharmaceutical ingredients (APIs). Surprisingly,t he direct catalytic enantioselective aldol reaction [3,4] engaging a-fluorinated ketones and a-oxygenated carbonyl compounds is little explored. Surprisingly,t he direct catalytic enantioselective aldol reaction [3,4] engaging a-fluorinated ketones and a-oxygenated carbonyl compounds is little explored.…”

Direct anti Glycolate Aldol Reaction of Protected Chiral N‐Hydroxyacetyl Thiazolidinethiones with Acetals Catalyzed by a Nickel(II) Complex

“…In this context, organocatalysis leads the way and mono‐ and dihydroxyacetone have become excellent platforms from which to carry out enantioselective aldol reactions under mild conditions . Surprisingly, there is a lack of parallel reactions proceeding through metal enolates that, in principle, might give access to a broader range of trioxygenated motifs . Pioneering studies by Shibasaki established that the direct aldol reaction of hydroxyacetophenone, catalyzed by heterobimetallic and zinc BINOL‐derived complexes, afforded anti or syn glycolate aldol derivatives respectively in high yields with a remarkable stereocontrol .…”

Feedstock Reagents in Metal‐Catalyzed Carbonyl Reductive Coupling: Minimizing Preactivation for Efficiency in Target‐Oriented Synthesis

“…[9,12] However,w ith the exception of eribulin, [3] all commercial polyketides are manufactured by either fermentation or semisynthesis,suggesting the present lexicon of synthetic methods does not adequately address the challenges posed by the construction of such complex structures.A symmetric aldol additions [13] and carbonyl allylations [14] are among the most commonly utilized methods for polyketide construction. [9,12] However,w ith the exception of eribulin, [3] all commercial polyketides are manufactured by either fermentation or semisynthesis,suggesting the present lexicon of synthetic methods does not adequately address the challenges posed by the construction of such complex structures.A symmetric aldol additions [13] and carbonyl allylations [14] are among the most commonly utilized methods for polyketide construction.…”