The preparation and reactions of allylic hydroxy phosphonates: A study toward the synthesis of sphingomyelin phosphonate analogs

This study involved a development of catalyst systems for the asymmetric hydrophosphonylation of aldehyes. Titanium alkoxide complexes with a series of ligands derived from L-tartaric acid were investigated. Using combinatorial techniques and medium throughput screening accelerated the catalyst discovery. Dimethyl-L-tartrate was found to be the most effective ligand for this system. With the optimized reaction conditions, 20 mol% catalyst, 2 equivalent of dimethyl phosphite in ether at -15°C, the enantioselectivity of the obtained product, allylic-alpha-hydroxy phosphonate, increased 15--20% from the initial screening reaction. Sequential asymmetric Pudovik and CM reactions utilizing Grubbs catalyst provided various allylic hydroxy phosphonates with excellent enantioselectivity.; Allylic hydroxy phosphonates are useful precursors for many organic reactions. Structural elaboration of allylic hydroxy phosphonates can lead to the preparation of many important biologically active molecules. Introduction of oxygen to allylic phosphonates was accomplished by asymmetric epoxidation utilizing the achiral Sharpless catalyst Ti(iPrO 4) and t-BuOOH. Addition of oxygen to allylic hydroxy phosphonates was also be achieved by oxymercuration providing five- and six-membered cyclic acetals with high diastereoselectivity. However, due to the toxicity of mercury waste, alternative approaches utilizing other electrophiles such as halogens and palladium to effect the cyclization was explored. Palladium-catalyzed reactions of the allylic carbamates, which were easily prepared from allylic hydroxy phosphonates, provided divergent routes for the synthesis of isosteric and non-isosteric phosphonate analogs of sphingomyelin. Reaction of the allylic carbamate derived from dimethyl(1-hydroxy-4-acetoxy-2-butenyl) phosphonate with Pd2(dba)3/P(OiPr) 3 resulted in 1,3-transposition with loss of CO2 to provide the corresponding vinyl gamma-amino phosphonate. In contrast, treatment of the allylic carbamate with Pd(II) provided the cyclized product, alpha-hydroxy-beta-amino phosphonate. Structural elaboration of these products may provide the desired analogs.