Re-evaluation of P-Chiral, N-Phosphoryl Sulfonamide Brønsted Acids in the Asymmetric Synthesis of 1,2,3,4-Tetrahydroquinoline-2-carboxylate Esters via Biomimetic Transfer Hydrogenation

Abstract

Enantioenriched heterocyclic and rigidified bioisosteres of amino acids are valuable building blocks in drug discovery, particularly in the design of peptidomimetic drugs. The rigidified bioisostere of phenylalanine, 1,2,3,4-tetrahydroquinoline-2-carboxylic acid, is found in a number of biologically active compounds. However, only a small number of successful methodologies have been reported for its asymmetric synthesis. In an effort to develop an environmentally benign and metal-free organocatalytic process for the preparation of this compound, a number of novel P-chiral, N-phosphoryl sulfonamide Brønsted acids were synthesized and evaluated in a biomimetic transfer hydrogenation reaction of quinoline-2-carboxylates to give the (R)-1,2,3,4-tetrahydroquinoline-2-carboxylates.

A Powerful P−N Connection: Preparative Approaches, Reactivity, and Applications of P‐Stereogenic Aminophosphines

“…In this context, dibenzylaminoesters (60) with electron-deficient aryl groups such as 3,5-(CF 3 ) 2 -C 6 H 3 were found to increase both yield and stereoselectivity. The same is true for diarylphosphine substrates (61) with sterically hindered aryl substituents. The best result for substrates with PO entities [product (S P )-63-O] in terms of enantiomeric excess (90 %) was obtained with mesityl-substituted phosphines (61-Mes) (Table 2, entry 1), as determined by HPLC on a chiral stationary phase.…”

“…[60] In a subsequent publication, the scope of catalysts and substrates was expanded and it was shown that such catalysts are limited in application at temperatures higher than room temperature, as they tend to racemize upon heating. [61] Nevertheless, this class of organocatalysts Scheme 15. Top: Palladium(II)-catalyzed synthesis of (S P )-93 starting from a P,P-diarylaminophosphine oxide (90) by selective ortho-arylation of one of the Paryl substituents (Ar F = 2,3,5,6-tetrafluorobenzonitrile, BPin = pinacolborane, DMF = dimethylformamide).…”

“…The best result was achieved for the conversation of compound 110 into product ( S C )‐ 112 using cyclohexane as solvent at 22 °C [60] . In a subsequent publication, the scope of catalysts and substrates was expanded and it was shown that such catalysts are limited in application at temperatures higher than room temperature, as they tend to racemize upon heating [61] . Nevertheless, this class of organocatalysts provided short reaction times and good enantioselectivities, which could possibly be further enhanced upon crystallization.…”