General synthesis of P-stereogenic compounds: the menthyl phosphinate approach

Abstract

Easily prepared menthyl phosphinates of high diastereoisomeric purity provide versatile intermediates for the synthesis of P-stereogenic compounds. Previous efforts starting about fifty years ago have been hampered by a lack of generality so the menthyl route has been nearly abandoned. Herein we provide a general solution to this long-standing problem and describe a general synthesis of menthyl H-phosphinate and disubstituted phosphinate esters. The method to prepare these versatile precursors relies on a simple and inexpensive process avoiding the use of phosphorus trichloride, Grignard reagents, and complicated cryogenic crystallizations. Established protocols can then be employed to synthesize P-stereogenic secondary and tertiary phosphine oxides and therefore P-stereogenic phosphine ligands.

Palladium-Catalyzed Allylation/Benzylation of H-Phosphinate Esters with Alcohols

“…In addition to the advantages of Dean-Stark processes over the use of wasteful stoichiometric reagents, the present allylation of H -phosphinate esters can offer unique opportunities. For example (Scheme 4), the cinnamylation of optically-active menthyl hydroxymethyl- H -phosphinate proceeds with complete stereoselectivity in a nearly quantitative isolated yield [12].…”

Focusing on the Catalysts of the Pd- and Ni-Catalyzed Hirao Reactions

“…However, presence of the anion has not yet been detected [15,50,52]. Montchamp and co-workers applied solvent additives (e.g., ethylene glycol or dimethoxyethane) to facilitate the P-C coupling of H-phosphinates [15,52,53]. According to them, on the one hand, the co-solvent promotes the ligand exchange by taking part in the conversion of the pentavalent Y 2 P(O)H to the Y 2 POH tautomer, on the other hand, it stabilizes the Pd-catalyst.…”

New Developments on the Hirao Reactions, Especially from “Green” Point of View

“…Using H -phosphinates as the reactant, both bromoarenes and less reactive chloroarenes were suitable substrates in the cross-coupling (Scheme 4 ) [ 47 , 48 , 73 - 75 ]. The reactions were performed using Pd(OAc) 2 as the catalyst precursor and different ligands (PPh 3 , Xantphos, dppb, dppf, dppe, dppp, BINAP, DBFphos, PS-nixantphos), along with bases ( i Pr 2 NEt, pyridine, propylene oxide).…”

“…The reactions were performed using Pd(OAc) 2 as the catalyst precursor and different ligands (PPh 3 , Xantphos, dppb, dppf, dppe, dppp, BINAP, DBFphos, PS-nixantphos), along with bases ( i Pr 2 NEt, pyridine, propylene oxide). The best results were obtained applying Xantphos [ 47 , 48 , 73 ], dppb [ 74 ] or dppf [ 75 ] as the P -ligand, and N,N -diisopro-pylethylamine as the base. Employing a solvent/co-solvent system was beneficial, as it may support the tautomerization of the P -reagent, and thus the ligand-exchange step of the catalytic cycle.…”

“…Employing a solvent/co-solvent system was beneficial, as it may support the tautomerization of the P -reagent, and thus the ligand-exchange step of the catalytic cycle. The Hirao reaction of ( R )-menthyl(hydroxymethyl)- H -phosphinate (R 1 = menthyl, R 2 = CH 2 OH) took place with the retention of the configuration at P [ 73 ].…”