Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation

Abstract

It was found that the phosphoric acid derivatives of general structure 1 serve as highly effective catalysts for the direct addition of acetyl acetone to N-Boc-protected arylimines. The beneficial effects of the 3,3'-bisaryl substituents of the catalysts on the enantioselectivity are greatly appreciated, and thus 1d functions as an excellent catalyst. The Brønsted acid-catalyzed direct Mannich reactions presented herein provide an attractive way to construct beta-aminoketones under extremely mild conditions. The stereochemical course of this reaction was established through the synthesis of Boc-(S)-phenylglycine methylester. The transformation thus demonstrated is applicable to a useful method for the synthesis of various phenylglycine derivatives.

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

“…If the Z configuration is energetically inaccessible the reaction proceeds via a Type I  E pathway, the correct catalyst has large proximal and medium AREA(θ) 10, 11, 12, 13c, 14b, 19, 20, 21, 22, 40, 41, 42, 43, 44, 45, 46, 47. However, reactions involving displaced nucleophiles the best choice of catalyst has large proximal and small AREA(θ) 5, 8, 9, 30, 31, 48, 49, 50, 51, 52, 53. Higher enantioselectivities with small proximal bulk catalysts are not uncommon with displaced nucleophiles.…”

Organocatalysis in Total Synthesis

“…Since pioneering works reported in 2004 by Terada [63] and Akiyama [64], chiral phosphoric acids have rapidly emerged as a new potent class of Brønsted acid catalysts with remarkable synthetic power owing to its continuous application in the development of new organocatalytic methodologies and resulting in a significant expansion of this field [65] (Fig XII.5). Proof of this substantial progress is the employment of such privileged class of Brønsted acids in the total syntheses of significant compounds as, for instance: ()-arboricine A [66], (S)-anabasine [67], monastrol [68], ()-zampanolide [69], (+)-galipinine [70,71], (+)-cuspareine [70], ()-angusturine [70,72], and torcetrapib [73] (Fig XII.6).…”

Development of New Chiral Br^|^oslash;nsted Acid Catalysis

“…Since Akiyama 21 and Terada 22 independently accomplished an innovative approach to the development of chiral BINOL derived phosphoric acid catalysts in 2004, it soon became clear that they possessed tremendous potential to activate electrophiles towards nucleophilic attack in asymmetric catalysis. 23 Although many successful enantioselective addition reactions to imines have been achieved with these Brønsted acids, the utility of these acids to the activation of other functional groups are somewhat limited due to relatively lower reactivities of these Brønsted acids.…”

“…The substituents of 3,3 position of BINOL, which have been developed by many researchers, are shown in Table 6. 21,22,26,32,38 In the enantioselective Mukaiyama aldol reaction, the bulky substituent, 9 anthracenyl, at the 4 position of 3,3 aryl substituent of the BINOL improved both diastereoselectivity and enantioselectivity.…”