Phosphine-mediated selective synthesis

Phosphine-mediated selective synthesis of tetra-substituted furans was developed directly from 1,4-enediones in anhydrous 1,2-dichloroethane (14T6733). 

The completion of the total synthesis of FK506 (1) is described in Scheme 34. The coupling of the two segments 222 and 230 was accomplished by phosphine oxide-mediated HW olefination. The addition of 222 to 230 afforded a separable 1 1 mixture, and the less polar diastereomer yielded ( )-olefin 231. After selective removal of the TES group, esterification of 231 with (S)-A-Boc-pipecolic acid (232) under DCC-DMAP conditions followed by dethioacetalization afforded aldehyde 233. The Evans aldol reaction of 233 with 218d installed a glycolate unit, and hydrolysis of the chiral auxiliary followed by TES protection provided 234 ready for macrocyclization. The macrolactamization of 234 was effectively... 

Synthesis of the modified triphosphate subunit was accomplished starting from ethyl bis(bromomethyl)phosphinate 253 (Scheme 51). An Arbusov reaction with triethyl phosphite and trimethyl phosphite, respectively, produced bis (phosphonomethyl)phosphjnate 255 in 40% overall yield. A selective monodemethylation by cyanide and acidificaticHi led to monophosphonic acid 256. Bismethylene triphosphate (BMT) 258 analogues of nucleosides were obtained by coupling of the 5 -free OH nucleosides 257 with phosphonate 256 under Mitsunobu conditions [181,182]. TMSBr mediated deprotection followed by treatment with aqueous anmumia and cation exchange afforded bismethylene analogues 259 of nucleoside triphosphate in yields up to 62%. 

---