| Popis: |
Part I. Studies on the total synthesis of halichondrin B. Halichondrin B is a remarkably effective antitumor agent in vivo. A practical synthesis of an F-ring intermediate 91 for halichondrin B was accomplished starting from D-glucose. In the presence of HCl and methanol, glucose-derived 33 was rearranged to furan 32. Activation of alcohol 32 to phenylthiocarbonate derivative 40 followed by deoxygenation provided 39. The stereocenter at C17 (halichondrin numbering) of 32 was provided by C5 of D-glucose after inversion of the configuration, and C20 of 32 was from C2 of D-glucose. Activation of tosylate 32 to iodide 43 followed by treatment with lithio trimethylsilylacetonitrile gave nitrile 51, which was converted to ylide 62 via an imidazolide intermediate 63. Completion of the F-ring was achieved by conversion of acetal 39 to TBDMS ether 89 followed by Swern oxidation and subsequent treatment with Tebbe's reagent delivering methylenation product 91. In the synthesis of an ABCDEF-ring fragment, the use of Dowex-50 instead of H2SO4 increased the yield of acetonide 98. Preparation of p-methoxy benzyl ether 99 was improved by the use of a catalytic amount of NBu4I and conversion of di-p-methoxy benzyl e ther 100 to 99 with CAN. Synthesis of a JK-ring intermediate was explored with a model compound. Reaction of lactone 105 with lithio acetylide 106 followed by acylation gave an acyclic ketone 110. Compound 109 was protected with TBDMS followed by regio selective removal of TES using PPTS, and finally, oxidized to dione 117 using PCC. Part II. Total synthesis of a CD-ring intermediate for isolaulimalide: Model study. Isolaulimalide, an antitumor agent, was isolated from a sponge called Hyattella. Diol 130 is a degredation product of isolaulimalide. A model study for a practical synthesis of diol 130 was performed starting from D-glucose. Coupling of ylide 8 with aldehyde 67 afforded 131. Under photochemical conditions, compound 131 underwent both detosylation and debenzylation to deliver cis diol 145a, which was protected as dibenzoate 149. Alternatively, treatment of ethyl acetoacetate with propargyl zinc bromide gave alcohol 155. Protection of alcohol 155 with TESCl followed by cis addition of n-Bu3SnH to alkyne 36 delivered n-tributyl vinyltin product 162. Coupling of vinyltin compound with benzaldehyde followed by ring closure and elimination gave 163, a model compound for 130. |
