Total Synthesis Of Autolytimycin And Its Analogues

Autolytimycin was isolated from a strain of Streptomyces Autolyticus JX-47 in Yunnan soil Streptomyces.It is the novel polyketide macrolactam that exhibit anticancer activity.The structure is 19-membered ring lactam that consists of a benzene nucleus with a phenolic hydroxyl group and a 15-carbon bridge ring.Bridge ring section contains six stereogenic centers and two(E)-trisubstituted double bonds.Autolytimycin belongs to Benzenoid ansamycin on the chemical structure.Autolytimycin analogues in the security resistance,pharmacodynamic,physical and chemical properties etc have a representing an ideal result,for the further structure optimization of the Benzenoid ansamycin provides a new direction.This thesis research describes the C3-C7 fragment of autolytimycin and its analogues.Tried Ring-closing metathesis(RCM)reaction and Morita-Baylis-Hillman(MBH)reaction to construct C8-C9(E)-trisubstituted double bonds,thus completing the synthesis of C1-C15 fragment.Chapter 1 briefly introduces the autolytimycin origin,structure characteristics and pharmacological activity.Then briefly introduction of the Benzenoid ansamycin have been reported synthetic strategy and research strategy of the thesis.Chapter 2 describes the construction method of trisubstituted double bonds.Including Ring-closing metathesis(RCM)reaction,Metal reagents catalyzed alkyne-aldehyde reductive coupling reaction,Grignard reaction and Morita-Baylis-Hillman(MBH)reaction.Chapter 3 introduces model compounds and reaction substrates synthesis of Relay Ring-closing metathesis(RRCM)reaction.First-generation synthesis of C3-C7 fragment of the autolytimycin and its analogues started from the L-glutamic acid,but afforded 12%overall yield.The second-generation synthesis of C3-C7 fragment of the autolytimycin and its analogues began with 2,3-O-isopropylidene-Dglyceraldehyde,gave a satisfying 41%overall yield.Found efficient and rapid method synthesis of C3-C7 fragment.Tried Ring-closing metathesis(RCM)reaction、Morita-Baylis-Hillman(MBH)reaction and Grignard reaction to construct C8-C9(E)-trisubstituted double bonds.Used the intramolecular Horner-WadsworthEmmons(HWE)reaction and the Ring-closing metathesis(RCM)reaction synthesis of α,β-unsaturated δ-lactone in respectively,but the former was only 23%yield,the latter up to 96%.Lay the foundation for further completion of the C1-C15 fragmentChapter 4 is the experimental section lists the main experimental procedure,characterization data for the key compounds.The cited references are found at the end of the thesis.Copies of original 1H and 13C-NMR spectra are given in the Appendix.