Total Synthesis Of Autolytimycin And Its Analogues Studies On Fragment Syntheses And Olefin Matathesis

Autolytimycin are polyketide anti-biotics that exhibit promising antitumor activity, acting as inhibitors of Hsp 90. Like many of the ansamycins, autolytimycin’s chemical structure is comprised of a 19-membered lactam joined at the meta positions of a phenol ring. The ansa chain of this natural product contains six stereogenic centers, two (E)-trisubstituted double bonds, and a C7-carbamate functionality. The architectural similarities to geldanamycin and other members of the ansamycin family provided incentive to explore these molecules as potential Hsp 90 inhibitors.Heat shock protein 90 (Hsp 90) is a protein chaperone responsible for regulation of proteins in cell signaling, pro-liferation, and survival processes, including client proteins involved inmultiple oncogenic signaling (signal transduction and transcription) pathways.This these work describes the C1-C7 fragment of autolytimycin and its analogues, a highly diastereoselective chelation-controlled diisopropenylzinc addtion to a-methoxy aldehyde was developed as a key step in order to built the C7 chiral center of autolytimycin. In addition, we try to conduct preliminary exploration for assembling the congested trisubstituted (E)-double bond at C8-C9 by using olefin metathesis strategy.The major contents of this thesis are follows:1. Synthesis of the C1-C8 fragments of autolytimycin in 24.5% overall yield via 12-step sequence. After extensive screening on the condition, a highly diastereoselective chelation-controlled diisopropenylzinc addtion to a-methoxy aldehyde was developed as a key step in order to built the C7 chiral center of autolytimycin. It is followed by a concise sythesis of the 6-Me C1-C7 fragment of autolytimycin analogues in a 3.2% overall yield via 12-step sequence. These works provided the foundation for studying on the structure-activity relationship of autolytimycin and its analogues and further pharmacological actiivity research.2. discloses the preliminary exploration for assembling the congested trisubstituted (E):2,4-Dimethyl-3(E)-penten-1,5-diol subunits by using olefin metathesis strategy including Cross Metathesis (CM), Ring-Closing Metathesis (RCM), and account for the problem and scheme in this reserch. We designed some model to explor the reactivity of CM and RCM. There are some interesting phenomenons which can make us understand that the allyl alcohol is the restraining factor. We also designed some model of RCM to explor the reactivity and get some valuable clues.The main experimental section complies the synthetic procedures and the full characterization data for all key intermediates and final product, and the cited references arefound at the end of thesis. Copies of original 1H,13C NMR and MS are given in the appendix.