Synthesis Of A Bioactive Aminoglucoglycerolipid From A Marine Alga And Its Analogues

Due to the unique trait of the ocean ecological environment, the marine life cangenerally generate some compounds with novel structure and marked biologicalactivity, thus marine natural products are the important source for the new drugscreening. Usually, the separation yield for marine natural active constitutent is low,furthermore, though some compounds have good activity, they also have high toxicity.So it’s of vital importance to study the synthesis of those active constitutents frommarine and the structural modification, which will enormously promote the researchprogress of new drugs from marine.In this dissertation, the native aminoglycoglycerolipid1a isolated from an algaand its anologues, inhibitors of human Myt1-kinase were synthesized. The presentsynthesis provided various acyl derivatives required for the studies on thestructure-activity relationship to discover new anti-tumor potential drugs.I. Total synthesis of α-6-Dehydroxy-6-aminoglucoglycerolipid analogues.Synthetic studies on compound1a have been reported, on this basis, weintroduced an improved and efficient method for the synthesis of these compounds.(1) We devised a series of their analogues1b-h which were different from thenatural term mainly in the acyl chain. Glycosyl donors6a and6b were synthesizedthrough successive protective group manipulations from glucose.(2)Glycosylation of (S)-isopropylideneglycerol7with6a and6b was carefullyexamined, and we found employing chemically active imidate donor6b with lowsubstrate concentration could achieve excellent α-selectivitiy in glycosylation(α:β=33:1).(3)With the key intermediate5in hand, we accessed the final compounds1b-hthrough four stepsII. Total synthesis of α-6-Dehydroxy-6-aminogalactoglycerolipid analogues.(1) By substituting the glucosyl with galactosyl and altering the acy chain, another series of aminogalactoglycerolipid analogues2a-g were devised. Glycosyldonors21a,21b and33were synthesized through successive protective groupmanipulations from galactose.(2)The couplings between the accepter7and21a,21b,33were explored, andwe found the process employed4-OAc protecting group of the galactosyl donor33asremote neighboring participation group in Et2O to give34α almost as a single isomer(α:β=32:1).(3)With the key intermediate34α in hand, we accessed the final compounds2a-g through six stepsⅢ. Total synthesis of α-6-Dehydroxy-6-aminomannoglycerolipid analogues.(1)As a continuous story, by substituting the glucosyl with mannosyl andaltering the acy chain, another series of aminomannoglycerolipid analogues3a-h werealso designed. Glycosyl donors38a,38b,43a,43b and45were synthesized throughsuccessive protective group manipulations from mannose.(2)Glycosylation of (S)-isopropylideneglycerol7with five donors wasinvestigated. In the reaction of43a,46α and46β were generated in86%yield with aratio of α:β=1:1which could be easily separated through the silica columnchromatograph. In final, employing the benzoyl protected donor45to carry out thisreaction resulted in the formation of the desired product46α as a single isomer.(3)Starting form46α we accessed the final compounds3a-h throughhydrolysis of the isopropylidene, reduction, acylation and hydrogenolysis.Strategies on chemical stereoselective synthesis of the analogues of nativeaminoglycoglycerolipid were carefully investigated. And analogues ofaminoglycoglycerolipid1a-h、2a-g、3a-h with novel acyl chains were firstlysynthesized in an efficient way with high stereoselectivity. The present synthesisprovided various acyl derivatives required for the assay of activity against the enzymeMyt1-kinase to study their structure-activity relationship.