Novel Aza‐Michael Addition‐Asymmetric Protonation to α,β‐Unsaturated Carboxylic Acids with Chiral Thiourea‐Boronic Acid Hybrid Catalysts

Abstract

Novel aza-michael addition-asymmetric protonation to unsaturated carboxylic acids with chiral thioureaboronic acid hybrid catalysts. #asymmetric protonationIn this study, an efficient method has been developed for controlling carbonyl α-chirality with functionalizing βposition by the conjugate addition-asymmetric protonation (CAAP) of α,β-unsaturated carboxylic acids using chiral thiourea-amino boronic acid hybrid catalysts. In addition, the method is applied to the asymmetric synthesis of biologically active compounds.Carbonyl compounds that are adjacent to a chiral tertiary carbon center are common structures in pharmaceuticals and natural products. Due to their ubiquity, numerous studies have analyzed the asymmetric synthesis of this important substructure. Asymmetric protonation of enolates is one of the most versatile methods for fabricating chiral carbonyl α-carbon centers. Thus, the enantioselective protonation of preformed enolates, such as metal enolate or silyl enol ether, has been investigated using stoichiometric amounts of chiral proton sources or chiral catalysts (Scheme 1-1). [1,2] Furthermore, another attractive approach with β-functionalization is the combination of the Michael addition and the enantioselective α-protonation of the resulting enolates (Scheme 1-2). To date, such transformation using unsaturated aldehyde, ketone, ester, amide, and others as Michael acceptors has been successfully studied. [3,4] However, to the best of our knowledge, the CAAP reaction of α,β-unsaturated carboxylic acids has not yet been reported, despite their chemical stability and availability as starting materials.Due to their improved stability to enzymatic hydrolysis, peptides containing β-amino acids are commonly found in pharmaceuticals and biopolymers. [5] β-Amino acids are mainly classified as five categories: β 2 , β 2,2 β 2,3 , β 3 , and β 3,3 -amino acids. Although catalytic asymmetric synthesis of β-amino acid derivatives has been well developed, the direct transformation of α,β-unsaturated carboxylic acids into chiral β 2 -amino acids is [a

Emergent Organoboron Acid Catalysts

“…Takemoto has developed hybrid thiourea–boronic acid catalysts for the aza-Michael addition (Scheme ). − These bifunctional catalysts form ordered complexes through both hydrogen bonding and complexation of the carboxylic acid substrate to the boronic acid to activate and deliver the amine nucleophile selectively to a single face of the alkene . Similar enantioselective Michael addition through hydrogen-bond direction of the nucleophile was reported by Toste and co-workers for desymmetrization of para -quinols using a combination of an arylboronic acid catalyst and a chiral phosphoric acid .…”

Progress in (Thio)urea‐ and Squaramide‐Based Brønsted Base Catalysts with Multiple H‐Bond Donors

“…Conjugate addition of hydroxylamines to α-aryl acrylic acids promoted by C59, and subsequent transformation of the obtained chiral product into (-)-nakinadine B. Takemoto, 2021. [81] Scheme 44. Design of the new guanidinium/bis-thiourea catalyst subfamily J and its application in the asymmetric Michael addition of phenols to naphthols.…”

“…The usefulness of this catalyst system has been extended to the protonation of in situ generated enolate species, such as those formed upon conjugate addition of hydroxylamines to α‐aryl acrylic acids (Scheme 43). [81] This reaction could be triggered by the thiourea‐boronic acid catalyst C59 in p ‐chlorotrifluoromethylbenzene with variable levels of enantioselectivity. Here, while the rate‐limiting step appears to be the C−N bond forming step, product configuration is set during the subsequent protonation.…”

“… Conjugate addition of hydroxylamines to α‐aryl acrylic acids promoted by C59 , and subsequent transformation of the obtained chiral product into (‐)‐nakinadine B. Takemoto, 2021 [81] …”

Recent Advances on Catalytic Enantioselective Protonation for Construction of α-Tertiary Carbonyl Compounds

“…手性 β-氨基酸广泛存在于药物等生物活性分子中. Takemoto 课题组在他们之前工作的基础上 [28][29] , 利用硫 脲衍生的氨基硼酸类催化剂 C6, 实现了 α-芳基丙烯酸 35 与羟胺衍生物 36 之间的氮杂 Michael 加成/不对称质 子化串联反应(Scheme 11) [30] . 尽管肉桂酸的加入显著 提高了该反应的活性和选择性, 但大多数底物只能得到 中等的结果, 最高以 80%的收率和 79% ee 的对映选择 性得到含 α-叔碳立体中心的手性 β-氨基酸酯.…”