Rh-Catalyzed Enantioselective Hydrogenation of Di- and Tri-Substituted Enamides Enabled by Easily Tunable P-Stereogenic N-Phosphinyl Phosphoramidite Ligands

Abstract

A modular mixed donor P-stereogenic narrow bite angle N-phosphinyl phosphoramidite ligand library (JoSoPhos) was synthesized. The JoSoPhos ligand library was applied to the asymmetric synthesis of the anti-Parkinson therapeutic Rasagiline in >99% ee and 79% yield via the Rh-catalyzed asymmetric hydrogenation of 1-indanone derived enamide as the key step. The Rh/ JoSoPhos catalyst also demonstrated high catalytic performance in the asymmetric hydrogenation of vinyl enamides with a broad functional group tolerance up to >99% ee. Other challenging trisubstituted vinylic olefins were also reduced with excellent enantioselection. A range of trisubstituted carbocyclic olefins bearing different functional groups were also reduced delivering products with >99% ee's. Pharmaceutically important chiral primary amines have also been prepared using the hydrogenation/ hydrolysis method in close to enantiopure form. Isotope labeling studies showed the Rh/JoSoPhos catalyzed enantioselective hydrogenation of di-and trisubstituted enamide is an isomerization-free direct asymmetric hydrogenation process.

P-Stereogenic Phosphorus Ligands in Asymmetric Catalysis

“…320,325,331 Simple disubstituted enamides such as 1acetylamino-1-arylethenes have been often used as the standard substrates for the evaluation of P-stereogenic phosphorus ligands (BisP*, 356 MiniPHOS, 356 TangPhos, 40 DiSquareP*, 171 DuanPhos, 42 QuinoxP*, 43,189 PingFer, 229 L41, 175 L77, 233 Trichickenfootphos (TCFP), 360 SMS-Phos, 183,184,338 ZhangPhos, 186 BIBOP, 44 BenzP*, 46,189 Dioxy-BenzP*, 189 3H-QuinoxP*, 239 3H-BenzP*, 239 L88, 259 TMB-QuinoxP*, 196 L81, 243 BulkyP*, 252 and JoSoPhos). 260 In most cases, a very high enantioselectivity of higher than 95% ee was observed. Some of these reactions have been applied to the practical synthesis of the building blocks of chiral drugs, as exemplified by the reactions shown in Schemes 12 and 13.…”

“…The excellent hydrogenation results and the potential utility for the large-scale production of pregabalin, a medicine to treat epilepsy and anxiety, have attracted the attention of researchers in this field to fuel the synthesis of analogous ligands L77, 233 POP, 235 L79, 236 MaxPHOS, 237 3H-QuinoxP*, 239 3H-BenzP*, 239 t-Bu-Wudaphos, 247,248 L82, 251 BulkyP*, 252 and 5,8-Si-Quinox-t Bu 3 . 257 Most of these ligands have been used for the Rh-catalyzed asymmetric hydrogenation of functionalized alkenes, and 5,8-Si-Quinox-t Bu 3 , a silyl-modified three-hindered quadrant QuinoxP*-type ligand, has been recently used in the Cu- 258 and JoSoPhos, 260 which consist of phosphine, aminophosphine, phosphite, phosphoramide, or phosphorodiamidite moieties, have been used in the Rh-catalyzed asymmetric hydrogenation of enamides and the Rh-catalyzed hydroformylation reaction. Verdaguer, Riera, and co-workers have synthesized novel nitrogen atom-bridged mixed bisphosphorus ligands called ThaxPHOS from enantiopure cis-1-amino-2-indanol.…”

“…Figure shows C 1 -symmetric bisphosphorus ligands reported from 2001 to 2023. ,− Among these, the three-hindered quadrant bisphosphorus ligands are typical C 1 -symmetric ligands. In 2004, Hoge and co-workers reported the first distinct three-hindered quadrant bisphosphine ligand, Trichickenfootphos (TCFP) .…”

“…P-Stereogenic bisphosphorus hybrid ligands L70 , L71 , L74 , L80 , BettiPhos, L83 , L86 , L87 , and JoSoPhos, which consist of phosphine, aminophosphine, phosphite, phosphoramide, or phosphorodiamidite moieties, have been used in the Rh-catalyzed asymmetric hydrogenation of enamides and the Rh-catalyzed hydroformylation reaction. Verdaguer, Riera, and co-workers have synthesized novel nitrogen atom-bridged mixed bisphosphorus ligands called ThaxPHOS from enantiopure cis -1-amino-2-indanol.…”

Concise synthesis of Azilect via cobalt-catalyzed enantioselective hydrogenation in a bio-based solvent

“…The use of readily available cobalt precursors and enantiopure ligands have generated highly active catalysts for the synthesis of levetiracetam, 36 hydrogenation of N-functionalized imines, 37 α,β-unsaturated carboxylic acids, [38][39][40] E/Z alkenes, 41 functionalized alkynes, 42,43 enynes, 44 minimally functionalized alkenes, [45][46][47][48] azole derived tri-substituted alkene, 49 and other unsaturated compounds. 13,34,[50][51][52][53] A handful of Rh-based homogeneous catalysts are known for the preparation of chiral N-(indan-1yl)-acetamide (1b) [54][55][56][57] or, 1-indanamine (1c). 58 Construction of such chiral N-building blocks is essential for the preparation of active pharmaceuticals, such as rasagiline (anti Parkinson's therapeutic), ladostigil (treatment for neurodegenerative disorders), indatraline (antidepressive agent) or Aficamten (CK-274, ph.…”