AmericanChemicalSociety.com

Enantiopure phosphonic acids and their derivatives are important compounds in medicinal and biological chemistry.  Several ways to synthesize chiral phosphonic acids have been described, including the phosphonylation of aldehydes, the hydrophosphonylation of cyclic imines, the hydrogenation of a,b-unsaturated phosphonates, the enantioselective catecholborane reduction of a-ketophosphonates, and the alkylation of lithium-stabilized phosphonate anions.  Among the chiral auxiliaries used in these syntheses (Scheme 1) are (-) ephedrine and other substituted N-alkyl-b-amino alcohols, and trans-N,N’-dialkyl-1,2-diaminoalkanes.  The reaction chemistry of these chiral auxiliaries has been studied extensively.

We have devised an alternative synthetic approach to chiral phosphonic acids that employs air- and water- stable starting materials, uses an inexpensive and easily resolvable C₂-symmetric chiral auxiliary, and affords good yields and diastereoselectivities.  In addition, the diastereomeric excess can easily be determined by NMR spectroscopy, and the diastereomers can be separated and the chiral auxiliary removed to afford enantiopure phosphonic acids.  Although previous approaches produce both good yields and selectivities, many of the previously employed auxiliaries are either expensive, require several steps to prepare, are moisture sensitive, or use non C₂ symmetric ligands that result in the production of multiple diastereomers.  The approach described herein has none of these drawbacks.
We have prepared enantiopure (1-phenylalkyl)phosphonic acids by using 1,1’-binaphthyl-2,2’-diol, (BINOL), as a chiral auxiliary.  Deprotonation of enantiopure [S(-)(1,1’-binaphthyl-2,2’-dioxo)benzylphosphonate, [S(-)BINOL]PO(CH₂Ph), followed by addition of an alkyl halide, RX, where R = methyl, ethyl, allyl, or benzyl, at -72°C affords diastereoenriched (1-phenylalkyl)phosphonates (S(-)BINOL)PO(CHRPh) in 16% to 84% yield and 64% to 84% diastereomeric excess.  After the diastereomers were separated by flash column chromatography and the chiral auxiliary was removed, enantiopure (1-phenylalkyl)phosphonic acids (HO)₂P(O)(CHRPh) can be isolated.

We are currently investigating the use of these chiral phosphonic acids to prepare chiral solids useful as catalysts for asymmetric oxidation reactions.