Studies Directed Towards The Total Synthesis Of Ionomycin - Synthesis Of Optically Active C17-c22 And C23-c32 Segments (asymmetric Epoxidation, Geraniol, Phase Transfer Agent, Payne Rearrangement, Pummerer, Carbons).

Polyether antibiotics belonging to the class of ionophores are emerging as interesting new compounds in terms of both biological activity and scope for synthetic challenge. Ionomycin, possessing a 32 carbon backbone and 14 asymmetric centres is an interesting new member of this class that demonstrates remarkable Ca('2-) selectivity in biological transport. In the endeavor towards its total synthesis ionomycin has been divided into four substructures with bond disconnections at C22-C23, C16-C17 and C10-C11. In the presently described synthesis of the C23-C32 fragment, the Sharpless asymmetric epoxidation has been used as a valuable tool. The 10 carbon backbone of geraniol was used as the starting point and converted in nine steps to the acyclic precursor 67 viz 10-benzyloxy-3.7-dimethyl-2(E),6(E)-decadiene-1-ol. Synthetic maneuvers on the corresponding 2(S),3(S) epoxide 39 to arrive at the appropriately designed 2(R),3(S) dihydroxy intermediate I proved cumbersome. However, success was achieved when epoxide 39 was opened by NaBH(,4) under Payne rearrangement conditions (1N NaOH/Dioxane 1:1, 100(DEGREES)). It was also discovered that phase transfer agents viz CTAB (Cetyl trimethyl ammonium bromide) and DMEB (N,N-Dodecyl N-methyl ephedrinium bromide) influence this reaction remarkably, the former increases the yield while the later increases the C-1 selectivity by a factor of 5-10 for the nerol and geraniol epoxides. The 10-benzyloxy-3,7-dimethyl-6(E)-decene-2R,3S-diol 42a was subjected to oxidative cyclisation to give (2R,5S)-2- 2S)-2-Hydroxy-5-benzylozy-2-pentyl -5-methyl-5- (1R)-1-hydroxyethyl -tetrahydrofuran 90a and its diastereomer 90b. After silylation the isomers were separated and functional group transformations on the correct cis-furanoid gave the phosphonium salt AA. Correct spectroscopic characterisation was obtained for all intermediates. The centre left quarter segment B (C17-C22) was synthesised by way of a crotyl-chromium coupling with R-(-)-3-benzyloxy-2-methylpropanal 96. The antiCramthreo isomer obtained in this reaction was functionalised by epoxidation and subsequent opening by thiophenol. This intermediate after hydroxy protection was oxidised and transformed to 6-Benzyloxy-3S,5R-dimethyl-hexane-1-al-2R,4S-acetonide B via a Pummerer rearrangement-equilibration step in high overall yield. Results on the Wittig couplings of AA and B with model substrates and themselves, using a variety of bases has also been described.PhDOrganic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127928/2/8621369.pd