A catalytic enantioselective stereodivergent aldol reaction

Abstract

The aldol reaction is among the most powerful and strategically important carbon–carbon bond–forming transformations in organic chemistry. The importance of the aldol reaction in constructing chiral building blocks for complex small-molecule synthesis has spurred continuous efforts toward the development of direct catalytic variants. The realization of a general catalytic aldol reaction with control over both the relative and absolute configurations of the newly formed stereogenic centers has been a longstanding goal in the field. Here, we report a decarboxylative aldol reaction that provides access to all four possible stereoisomers of the aldol product in one step from identical reactants. The mild reaction can be carried out on a large scale in an open flask, and generates CO 2 as the only by-product. The method tolerates a broad substrate scope and generates chiral β-hydroxy thioester products with substantial downstream utility.

Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,β‐Unsaturated Aldehydes – Total Synthesis of Tapentadol

“…Considering the benefits of a process with a wider scope and the lack of regio‐ and stereoselective Michael additions of metal enolates to α,β‐unsaturated aldehydes, we envisaged that a close, but less stringent version, of the aforementioned stereodivergent dual catalytic model might be successful. This would entail a single transition‐metal catalytic model in such a way that the simple change of the chiral ligand would give access to all the potential stereoisomers in a highly regio‐ and stereocontrolled manner [16,23] …”

Stereodivergent Carbon–Carbon Bond-Forming Reactions

“…Despite the substantial attention devoted to this pursuit, the realization of a catalytic stereodivergent aldol reaction was achieved only recently (vide infra). 10 The aldol reaction unites two carbonyl compounds (A and B) to generate a -hydroxy carbonyl compound (C) with two vicinal stereocenters (Figure 1). An extensive array of enantioselective aldol methods has been reported in which a single catalyst controls the absolute configuration of the new stereocenters in the bond-forming reaction to give a single enantiomer of the product (e.g., (S,S)-C).…”

“…Despite the substantial attention devoted to this pursuit, the realization of a catalytic stereodivergent aldol reaction was achieved only recently ( vide infra ). 10…”

Harnessing Dpp-Imine as a Powerful Achiral Cocatalyst to Dramatically Increase the Efficiency and Stereoselectivity in a Magnesium-Mediated Oxa-Michael Reaction

“…Imines are important and basic synthetic feedstocks in chemical synthesis and are widely utilized as model substrates in many classic reactions, including under catalytic asymmetric patterns (Scheme , A). − On the other hand, the nonactive imine, usually called Schiff base, represents one of the mainstream ligands that are employed in a series of metal-catalyzed transformations. It is well-known that the usual Schiff base ligands possessing multiple coordination sites are always generated from primary aromatic or aliphatic amines. − However, attempts of applying active and easily accessed imines, including Boc-, Ts-, or Dpp-imine, as ligands in metal catalysis is still elusive, given that these imines are often utilized as model substrates in asymmetric reactions. − There exist several potential challenges for utilizing these active monoimines as ligands in metal catalysis: (a) active monoimines might not be as enough as ligands; (b) these active imines are typically electrophiles which are prone to react with a wide scope of given nucleophiles; (c) in the situation of asymmetric reactions, it might be hard to introduce valid chiral elements in the classic structure of active monoimines; and (d) the inflexible impression of these types of imines as “classic model substrates”. On consideration of these above reasons, we wondered whether it is possible to explore these active imines as ligands or coligands in metal-catalyzed reactions, which might benefit the discovery of new types of active imine ligands in organic synthesis.…”

“…It is well-known that the usual Schiff base ligands possessing multiple coordination sites are always generated from primary aromatic or aliphatic amines. 13 − 23 However, attempts of applying active and easily accessed imines, including Boc-, Ts-, or Dpp-imine, as ligands in metal catalysis is still elusive, given that these imines are often utilized as model substrates in asymmetric reactions. 24 − 39 There exist several potential challenges for utilizing these active monoimines as ligands in metal catalysis: (a) active monoimines might not be as enough as ligands; (b) these active imines are typically electrophiles which are prone to react with a wide scope of given nucleophiles; (c) in the situation of asymmetric reactions, it might be hard to introduce valid chiral elements in the classic structure of active monoimines; and (d) the inflexible impression of these types of imines as “classic model substrates”.…”