Siloxy Esters as Traceless Activators of Carboxylic Acids: Boron‐Catalyzed Chemoselective Asymmetric Aldol Reaction**

Abstract

The catalytic asymmetric aldol reaction is among the most useful reactions in organic synthesis.Despite the existence of many prominent reports,h owever,t he late-stage,c hemoselective,c atalytic, asymmetric aldol reaction of multifunctional substrates is still difficult to achieve.H erein, we identified that in situ pre-conversion of carboxylic acids to siloxy esters facilitated the boron-catalyzed direct aldol reaction, leading to the development of carboxylic acidselective,c atalytic, asymmetric aldol reaction applicable to multifunctional substrates.Combining experimental and computational studies rationalized the reaction mechanismand led to the proposal of Si/B enediolates as the active species.T he silyl ester formation facilitated both enolization and catalyst turnover by acidifying the a-proton of substrates and attenuating poisonous Lewis bases to the boron catalyst.

Diastereo‐ and Enantioselective Reductive Mannich‐type Reaction of α,β‐Unsaturated Carboxylic Acids to Ketimines: A Direct Entry to Unprotected β2,3,3‐Amino Acids

“…Although most alkenes did not affect the reactivity of this reaction, [20] the yield of the desired product decreased in the presence of ethyl acrylate ( 4 e ): a small amount of the coupling product with ethyl acrylate was observed (Scheme 2, see Supporting Information for results of other alkenes). However, this result still indicates that the silyl‐protected acrylic acid is more reactive than the corresponding acrylates [10d] . The observed tendency can be accounted for by assuming the formation of a bidentate carboxylate species with a hypervalent silicon atom, as Yamamoto observed in 29 Si NMR [21] …”

The Enediolate Chemistry of Free Carboxylic Acids

“…Most recently, Mitsunuma and Kanai developed a (AcO) 4 B 2 O catalyzed enantioselective aldol reaction of carboxylic acids using (EtO) 3 SiCl as activator (Scheme 23). [38] In this reaction, both (AcO) 4 B 2 O and (EtO) 3 SiCl are indispensable for achieving any activity, and an enediolate intermediate was proposed as the active species. A broad scope of the substrates was shown with high yields and enantioselectivities including the late‐stage transformations of several complex molecules.…”

Boron Catalysis in the Transformation of Carboxylic Acids and Carboxylic Acid Derivatives

“…In 2021, Mitsunuma, Kanai, and co‐workers found that in situ formation of siloxy esters was quite powerful to realize boron‐catalyzed enantioselective aldol reactions of carboxylic acids with aldehydes via proposed Si/B enediolates 76 (Scheme 18). [37] Addition of two equivalents of triethoxysilylchloride was optimal for the reaction, and a chiral boron catalyst comprising (AcO) 4 B 2 O pre‐catalyst and valine‐derived chiral ligand 75 bearing a perfluorosulfonyl group on the nitrogen atom induced high diastereo‐ and enantio‐selectivities. Three main roles of the siloxy ester formation were mentioned based on several mechanistic investigations and computational studies.…”

“…The binaphthol (BINOL) scaffold was revealed to be effective to induce the chirality, with ( R )‐3,3’‐I 2 ‐BINOL 66 being the best ligand, affording the product with up to 98 % ee. Since the investigation of the relationship between the enantiomeric excess of the product and the enantiomeric excess of the ligand showed a positive non‐linear effect, [37] diboron enediolate 68 was proposed to be the active species of the enantioselective Mannich reaction.…”