Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions

Abstract

Conspectus The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C–H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of β-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide–Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to β-oxo acid derivatives. While the enantioconvergent hydrogenation of β-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electro...

Enantioselective, Stereoconvergent Resolution Copolymerization of Racemic cis‐Internal Epoxides and Anhydrides

“…Although enantioconvergent catalysis is emerging as a powerful method for synthesizing single enantiomerically‐enriched organic compounds from the racemic substrates with a maximum yield of 100 %, [31–35] such a strategy has not been applied to the preparation of optically active polymers from a racemic starting material. The present study is the first report of the enantioselective, stereoconvergent copolymerization of racemic cis ‐internal epoxides with anhydrides to afford enantioenriched semi‐crystalline polyesters with high enantioselectivities of up to 99 % ee at more than 50 % conversion.…”

Dynamics in Catalytic Asymmetric Diastereoconvergent (3 + 2) Cycloadditions with Isomerizable Nitrones and α-Keto Ester Enolates

“…32 Building on these precedents, we aimed at precisely regulating the geometry of prochiral double bonds 33,34 in nitrones (1,3-dipoles) and Ni(II)-enolates (formal 1,3dipolarophiles) to achieve stereoconvergent (3 + 2) cycloaddition. 35 A consideration of the reaction sequence of the formal (3 + 2) cycloaddition, comprising addition 36 and cyclization, led to two queries: (1) whether our bifunctional activation mechanism 37,38 can be applied to synthesize other diastereomers of the (3 + 2) adduct and (2) if the enantio-and diastereoselectivity in the reaction with two isomerizable substrates can be explained by the Curtin−Hammett principle. 39 The aforementioned model was supported by various spectroscopic analyses of the Ni(II) complex in the ground state, on the basis of the electron density distribution (EDD) analysis 40−42 of the Ni(II)-diamine-acetate complex (CCDC 1482741).…”

Enantioselective, Stereoconvergent Resolution Copolymerization of Racemic cis‐Internal Epoxides and Anhydrides

“…Although enantioconvergent catalysis is emerging as ap owerful method for synthesizing single enantiomericallyenriched organic compounds from the racemic substrates with amaximum yield of 100 %, [31][32][33][34][35] such astrategy has not been applied to the preparation of optically active polymers from ar acemic starting material. Thep resent study is the first report of the enantioselective,s tereoconvergent copolymerization of racemic cis-internal epoxides with anhydrides to [a] Conditions:The reaction was performed in toluene in a20mLflask;toluene/epoxides/anhydride/catalyst/PPNCl = 500:250:125:1:2 (molar ratio), except for entries 6and 8.…”