Efficient Catalytic Methods for Asymmetric Cross‐Aldol Reaction of Aldehydes

Abstract The aldol reaction is one of the oldest and important C−C bond‐forming reactions between two carbonyl compounds where one carbonyl compound with a α‐hydrogen acts as a nucleophile (donor) and the second carbonyl compound acts as an electrophile (acceptor) leading to a β‐hydroxycarbonyl compound. Out of various possibilities with carbonyl compounds as donors and acceptors, the direct cross‐aldol reaction of two aldehydes is problematic because of several issues. Undesired side reactions such as donor acceptor pair reversal, self‐aldol reaction of the partner aldehyde(s) having α‐hydrogen atom(s), overreaction by further aldolization of the product β‐hydroxyaldehyde, aldol condensation followed by Michael‐type additions, and Tischenko‐type reactions are the other challenging issues. Generation of up to two stereogenic centres is common during the C−C bond formation. Hence, diastereoselectivity and enantioselectivity are additional concerns. To resolve the said problems, two approaches are in practice involving an unmodified aldehyde as acceptor (electrophile) and either an unmodified aldehyde or an aldehyde modified to its ene‐form (enolate/enamine) as the donor (nucleophile). This review highlights the selected methods for efficient asymmetric cross‐aldol reactions of aldehydes mediated by organocatalysts.