Synthesis of Nonracemic Dimethyl α-(Hydroxyfarnesyl)phosphonates via Oxidation of Dimethyl Farnesylphosphonate with (Camphorsulfonyl)oxaziridines

Abstract

Several strategies for synthesis of nonracemic dimethyl α-(hydroxyfarnesyl)phosphonate and the parent phosphonic acid have been explored. Separation of diastereomeric derivatives prepared by esterification of racemic α-hydroxy phosphonate with (S)-(+)-O-methylmandelic acid was possible, and these diastereomers could be assigned absolute stereochemistry on the basis of literature precedent. However, hydrolysis to the α-hydroxy phosphonic acid was accompanied by extensive isomerization. Addition of a nonracemic phosphonamidite to farnesal also gave nonracemic material, but again hydrolysis was problematic. Oxidation of dimethyl farnesylphosphonate anion with nonracemic (camphorsulfonyl)oxaziridines was shown to be regio- and stereoselective for formation of the α-hydroxy phosphonate. Enantiomeric excess of ∼70% ee was established by conversion of the oxidation products to their (S)-(+)-O-methylmandelate derivatives. Although hydrolysis of these methyl esters was accompanied by extensive racemization, both enantiomers of α-(hydroxyfarnesyl)phosphonic acid were obtained in low ee by this strategy.

Understanding the π-facial diastereoselectivity in the addition of chiral diaminophosphino(silyl)carbenes to activated olefins

“…On the basis of a previously described methodology, 12 DMAP to afford diamide 6 in 98% yield. Reduction of the diamide was carried out by reaction with BH 3 ÁTHF for 3 days at room temperature followed by stirring in the presence of HCl (pH 2) to destroy the amine-boron complex.…”

“…Freshly distilled PCl 3 (0.28 mL, 3.2 mmol) and TEA (1.3 mL, 9.5 mmol) were successively added to an ice-cooled solution containing diamine 7 (0.8 g, 3.2 mmol), prepared according to the literature, 12 in dry THF (10 mL) under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 h. Solvent was removed under reduced pressure and pentane (15 mL) was added to the residue.…”

Direct Conversion of Benzylic and Allylic Alcohols to Phosphonates

“…Several isoprenoid phosphonates have been studied as inhibitors of isoprenoid metabolism, 32 and so the first examples examined in this reaction were terpenoid allylic alcohols (Table 2). Geraniol ( 21 ) reacted smoothly under the standard reaction conditions to afford diethyl geranylphosphonate ( 22 ).…”

Enantiodifferentiation of α‐hydroxyalkanephosphonic acids in 31P NMR with application of α‐cyclodextrin as chiral discriminating agent

“…[8][9][10] Thus, the chemistry of these compounds is continuously developing and providing many novel routes of their synthesis. 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] As the absolute configuration of the stereogenic a-carbon atom in substituted phosphonic acids has been shown to be important feature for the biological activity, 6 a significant number of methods allowing preparation of hydroxy analogues in the optically pure forms have been elaborated. They include kinetic resolution, as well as chemoenzymatic and asymmetric syntheses.…”

“…They include kinetic resolution, as well as chemoenzymatic and asymmetric syntheses. 1,[17][18][19][20][21][22][23][24][25][26][27][28] Therefore, there is a demand for fast and accurate methods for the determination of the enantiomeric composition of these compounds. NMR spectroscopy (particularly 31 P NMR which uses the characteristic feature of organophosphorus molecules) represents a powerful tool for determination of the enantiomeric purity of substituted alkanephosphonates.…”