Date of Award
Doctor of Philosophy (PhD)
Robert P. Hammer
A general method for the preparation of a wide variety of phosphonate derivatives, including phosphonamides, thiophosphonamides, thiosphonates, and dithiophosphonates, from reduced phosphorus intermediates has been developed. Esters (or thioesters) of H-phosphinates are converted to the highly reactive phosphonochloridites by non-oxidative activation with dichlorotriphenylphosphorane. The phosphonochloridites react readily with alcohols, amines and thiols and after in situ oxidation or sulfurization, phosphonate derivatives can be isolated in moderate to very good yields (47-85%). This method was used to synthesize a thiophosphonate dipeptide, Boc-Val-$\Psi$(P(S)(OtBu)O) Ala-OCH$\sb3$ (15b), two thiophosphonamide dipeptides, Boc-Val-$\Psi$ (P(S)(OtBu)NH) Gly-OCH$\rm\sb2CH\sb3$ (16b) and Fmoc-Aib-$\Psi$ (P(S)(OBn)NH) Gly-OCH$\rm\sb2CH\sb3$ (20), and two phosphonate dipeptides, Fmoc-Aib-$\Psi$ (P(O)(OBn)NH) Gly-OCH$\rm\sb2CH\sb3$ (19) and Fmoc-Phe-$\Psi$ (P(S)(OBn)NH) Gly-OCH$\rm\sb2CH\sb3$ (21). Compounds 15b,16b and 20 represent the first five examples of such monothiophosphonopeptide analogues and compounds 19 and 20 the first incorporation of a highly sterically hindered Aib-phosphonate amino acid into a phosphonopeptide. The successful preparation of 15b, 16b, 19, 20 and 21 demonstrates the compatability of this method with a variety of potentially sensitive functionalities and applicability to easy preparation of new classes of peptide mimics. To test our chemistry on the solid-phase we prepared known and potential inhibitors. The phosphonoamidate peptides Z-Aib$\Psi$ ((POOBn)NH) -Phe-OH (25), Z-Aib$\Psi$ ((POO$\sp-$)NH) -Phe-OH (26) and Z-Gly$\Psi$ ((POO$\sp-$)NH) -Phe-OH (27) synthesized could not be isolated or purified due to instability factors, but we could isolate and characterize the phosphonate peptide Z-Phe-$\Psi$ ((POO$\sp-$)O) Phe-Ala-NH$\sb2$ (29).
Fernandez, Maria De fatima, "Synthesis of Phosphonate Derivatives and Phosphonate Peptide Analogues." (1996). LSU Historical Dissertations and Theses. 6338.