Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

Abstract

In recent years, the synthesis of axially chiral compounds has received considerable attention due to their extensive application as biologically active compounds in medicinal chemistry and as chiral ligands in asymmetric catalysis. Chiral phosphoric acids are recognized as efficient organocatalysts for a variety of enantioselective transformations. In this review, we summarize the recent development of chiral phosphoric acid-catalyzed synthesis of a wide range of axially chiral biaryls, heterobiaryls, vinylarenes, N-arylamines, spiranes, and allenes with high efficiency and excellent stereoselectivity.

Enantioselective synthesis of α-tetrasubstituted (3-indolizinyl) (diaryl)methanamines via chiral phosphoric acid catalysis

“…7 f Although these strategies enable direct access to asymmetric synthesis of chiral indolizine derivatives, development of new class indolizines is still a formidable target. To continue our efforts 8 on the advancement of chiral phosphoric acid catalysis, 9 we here present the chiral spirocyclic phosphoric acid (SPINOL-PA) catalyzed enantioselective Friedel–Crafts of indolizines with in situ generated cyclic α-diaryl N -acyl imines 10 for the synthesis of chiral α-(3-indolizinyl)(diaryl) methanamines.…”

Enantioselective synthesis of indole‐based unnaturalβ‐Alkynylα‐amino acid derivatives via chiral phosphoric acid catalysis

“…To test the feasibility of our design, we began our studies with the enantioselective C-3 functionalization of indole substrate 1a with the β,γ-alkynyl-α-imino ester 2a (see the supporting information) in the presence of 10 mol% chiral spirocyclic phosphoric acid (S)-A1 developed by our group [41][42][43][44][45][46][47][48] in dichloromethane at room temperature. Fortunately, the transformation proceeded smoothly and the corresponding product, a chiral indole-β-alkynylα-amino acid derivative, was obtained in 61% yield with 35% ee within 4 h (Table 1, entry 1).…”

“…37 Moreover, in 2010, the Bolm group reported an enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a -CF 3 unit via chiral Brønsted acid catalysis. 38 Here, we envisioned to develop an organocatalytic asymmetric synthesis of indole-based unnatural β-alkynyl-α-amino acid derivatives with the chiral phosphoric acid [39][40][41][42][43][44][45][46][47][48] as a catalyst (Scheme 1D), and the strategy is atom-economical and the reaction proceeds without any additives. The significant challenge is to select suitable chiral catalysts to control regioselectivity and stereoselectivity during this asymmetric transformation.…”

An update on chiral phosphoric acid organocatalyzed stereoselective reactions

“…Atropisomerism is another type of enantiomerism that is currently receiving a lot of attention in drug discovery, [63][64][65][66] as well as in asymmetric synthesis, including CPA organocatalysis. [20][21][22][67][68][69] In 2019, Zhang, Shi, and co-workers reported the synthesis of axially chiral naphthyl-indoles (Scheme 12). 70 Their strategy involved the addition of bulky electrophiles at the C2-position of the indole of axially unstable naphthyl-indole compounds in order to hamper the free rotation around the axis and generate a stable axial chiral compound.…”

“…12,13 This kind of catalyst has a well-defined chiral environment around the active site and represents a powerful instrument for asymmetric transformations. Phosphoric acids based on chiral BINOL, H 8 -BINOL, or SPINOL 14,15 backbones proved to be useful in the formation of all-carbon quaternary stereocenters, [16][17][18][19] chiral axes, [20][21][22] and compounds with planar chirality. 23 A few applications of CPAs include asymmetric transfer hydrogenations, 24 dynamic kinetic resolutions and desymmetrization, 25,26 cycloaddition and annulation reactions, 27 and S N 1 substitutions, 28,29 and they have emerged as promising molecules in photoredox transformations.…”