Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

Abstract

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)-2-aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P(V) oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring-opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P-O bond. Interestingly, the use of a P(III) phosphine precursor afforded a P-epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P(V) or a P(III) phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.

d-Glucosamine as a novel chiral auxiliary for the stereoselective synthesis of P-stereogenic phosphine oxides

“…and analyzed by X-Ray diffraction. It appeared that the inversion of configuration at the phosphorus atom, already observed during our previous study, 16 was also confirmed in the ring opening of oxazaphospholidine R P -3. 27 In addition, the The same methodology was applied to the β-anomer (Table 1, entry 3) but the desired phosphinate 7 was formed with a low selectivity (d.e.…”

“…We were pleased to observe that the previously optimized conditions 16 proved once again successful on glucopyranoside derivatives S P -5 and R P -6. Indeed, 6.0 equiv.…”

“…26 Scheme 1. Diastereoselective formation of oxazaphospholidine starting from a phosphine oxide precursor (P(V) strategy) As these cyclized products appeared difficult to purify, 16 crude oxazaphospholidines R P -3 and 4 were directly engaged into the selective cleavage of P-N bond. The conditions previously optimized 16 were thus applied, and upon treatment with 3.3 equiv.…”

“…Diastereoselective formation of oxazaphospholidine starting from a phosphine oxide precursor (P(V) strategy) As these cyclized products appeared difficult to purify, 16 crude oxazaphospholidines R P -3 and 4 were directly engaged into the selective cleavage of P-N bond. The conditions previously optimized 16 were thus applied, and upon treatment with 3.3 equiv. of Grignard reagents (o-anisylmagnesium bromide and methylmagnesium chloride) at -78 °C in DCM, the expected phosphinates were both formed in 83% yield with satisfying diastereoselectivities (90% and 94% respectively - Table 1, entries 1 and 2).…”

“…16 This method was then applied to glucopyranoside 1 (Scheme 2). Chiral auxiliary 1 was then reacted with dichlorophenylphosphine in the presence of N-methylimidazole.…”