Enantioselective Desymmetrization of Diphenylphosphinamides via (−)-Sparteine-Mediated Ortho-Lithiation. Synthesis of P-Chiral Ligands

Abstract

Asymmetric ortho-lithiation of N-dialkyl-P,P-diphenylphosphinamides using [n-BuLi.(-)-sparteine] is described as an efficient method for the synthesis of P-chiral ortho-functionalized derivatives in high yields and ee's from 45 to >99%. The method allows access to new enantiomerically pure P-chiral phosphine and diimine ligands.

Synthesis of P-stereogenic compounds based on the diastereoselective ortho-lithiation of phosphinimidic amides

“…(R P )-P-(2-((R)-4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phos-phinic amide 23b. J PC 2.5 Hz, C-5), 18.6 (C-25), 19.1 (C-25 0 ), 28.0 (d, 2 J PC 4.6 Hz, C-3), 32.7 (C-24), 52.7 (d, 2 J PC 3.6 Hz, C-4), 70.9 (C-23), 72.8 (C-22), 127.0 (C-9), 127. 7 (C-8), 128.2 (C-7), 128.2 (d, 3 J PC 13.2 Hz, C-18), 129.9 (d,3 J PC 11.6 Hz,, 131.0 (d,4 J PC 2.5 Hz,, 131.1 (d, 2 J PC 9.2 Hz, C-17), 131.4 (d, 4 J PC 2.5 Hz, C-13), 132.1 (d, 3 J PC 9.7 Hz, C-12), 131.4 (d, 4 J PC 2.8 Hz, C-13), 131.0 (d, 1 J PC 127.7 Hz, C-10/16), 133.3 (d, 2 J PC 8.1 Hz, C-15), 133.1 (d, 1 J PC 117.0 Hz, C-10/16), 138.8 (d, 2 J PC 13.4 Hz, C-11), 141.5 (d, 3 J PC 4.6 Hz, C-6), 162.9 (d, 3 4.2.11.…”

“…In this context, we have reported on the enantioselective deprotonation of N,N-diisopropyl-P,P-diphenylphosphinic amide 5a using [ n BuLiÁ(À)-sparteine] as a chiral base (Scheme 2). 19 Electrophilic trapping of the anion afforded P-stereogenic ortho-functionalized phosphinimic amides (S P )-6 with modest ee (60%). Enantiopure compounds could be obtained after three recrystallization cycles.…”

Phosphorus‐Bearing Lithium Compounds in Modern Synthesis

“…Further applications of bidentate copper-catalyzed peroxide oxidation (CCPO) pincer ligand 108 include the synthesis of the tridentate mixed P(O)N/P(O) ligand whose complexating ability toward lanthanides [46] was the basis for the development of a sensing film highly selective and sensitive toward Eu(III) ion [47]. Very recently, this desymmetrization has been achieved in an asymmetric manner for the first time using [n-BuLi⋅(−)-14] as the chiral base in toluene at −90 • C. The ortho-lithiated species is configurationally stable and by treatment with a variety of electrophiles afforded products (S P )-112 in good yields and enantiomeric excesses in the range of 45-63% [48]. Although the enantiomeric excesses obtained are low, simple recrystallization allowed isolating enantiopure compounds.…”

General Principles ofortho-Lithiation in Arylphosphinamides

“…Adicionalmente, quando se efetua a litiação benzílica em presença de agentes de solvatação, tais como HMPA ou DMPU (N,N'-dimetilpropilenoureia), o ânion formado propicia um ataque intramolecular na posição orto de um dos anéis p-fenila, originando-se um novo ânion, neste caso, desaromatizado, o qual acopla com um amplo número de eletrófilos com excelente estereocontrole (Esquema 6a). 30 As fosfinamidas litiadas em posição orto, foram utilizadas como ligantes na preparação de complexos de estanho(IV), ouro(I) e ouro(III 38 Os produtos desaromatizados apresentam atividades antitumorais e, mediante hidrólise em meio ácido, levam à obtenção de ácidos -aminofosfínicos quirais, valiosos na síntese de novos peptídeos fosforados. O estudo do mecanismo de reação revelou que em ausência de cosolvente a litiação orto (aproximadamente 30%) compete com a benzílica, 39 o que sugere que com a seleção cuidadosa das condições de reação, a desprotonação orto pode converter-se no processo majoritário.…”