Stereodivergent Synthesis of rac-cis - and rac-trans-4-Hydroxyphosphopipecolic Acids

We report herein the first stereodivergent synthesis of rac- cis- and rac-trans-4-hydroxyphosphopipecolic acids. The main feature of this methodology is the controlled cis or trans reduction of 4-oxophosphopipecolates by exclusively varying the size of the hydride reagents. Thus, a small hydride reagent (NaBH4) adds selectively from the axial side of the carbonyl group to give the equatorial hydroxyl group (cis -product), whereas a bulky hydride reagent such as LiBH(sec-Bu)(3) (L-Selectride (R)) preferentially attacks from the equatorial side, giving the hydroxyl group in the axial position (trans -product). In the last step, hydrolysis of the diethyl phosphonate and ethyl phenylphosphinate groups with bromotrimethylsilane, followed by methanolysis, led to the target compounds.