Asymmetric Synthesis Of Alkaloid Haliclorensin, Isohaliclorensin And Stellettamide C

Alkaloids are widespread in nature. Many of them possess a variety of important bioactivities and show high potential for medical and biological applications. The asymmetric synthesis of these compounds continues to attract much attention, In recent years, many alkaloids with novel structure were isolated from marine creature and microorganism and attract many groups to synthesize them.The aim of this thesis was the asymmetric synthesis of cytotoxic marine alkaloid haliclorensin and isohaliclorensin, a constituent of halitulin, based on a ring-expansion reaction. Besides, further studies on the reductive alkylation of (S)-malimide were undertaken. The main results and observations from these studies are listed as follows.1. Based on the addition of vinyl magnesium bromide to the chiral non-racemic synthon 2 derived from (R)-1, an enantioselective total synthesis of (R)-3, the antipode of marine alkaloid halitulin (10 steps, overall yield: 5.3% from (R)-1) was achieved using aza-Claisen rearrangement as a key step.Based on (R)-4, the intermediate in the total synthesis of (R)-3, an enantioselective total synthesis of the anti-tumor marine alkaloid haliclorensin (R)-l (12 steps, overall yield 2.7% from (R)-1) was achieved using Zip rearrangement as a key step.2. Based on the addition of vinyl magnesium bromide to the chiral non-racemic synthon 6 derived from (R)-1, an enantioselective total synthesis of (S)-3, aconstituent of marine alkaloid hulitulin (10 steps, overall yield 5.9% from was achieved using aza-Claisen rearrangement as a key step.Based on the intermediate (S)-4 in the total synthesis of (S)-3, an enantioselective total synthesis of an anti-tumor marine alkaloid haliclorensin (S)-l (12 steps, overall yield 3.0% from (R)-1) was achieved using Zip rearrangement as a key step.3. Detailed studies on:(1) The transformation of (R)-2-amino-2-phenyl ethanol 1 into the desired(3R,8aR)-3-phenyl-hexahydro-2H-oxazolo [3,2-a] pyridine 2 (with 51% overall yield from (R)-l) resulted in a new two-step procedure. The thus developed method is milder in comparison with a known method.(2) The diastereoselective addition of vinyl magnesium bromide to (3R,8aR)-3-phenyl-hexahydro-2H-oxazolo[3,2-a]pyridine 2 was undertaken. The results showed that the addition leading to (R)-2-phenyl-2-(2-vinylpiperidin-l-yl) ethanol 7 could proceed with good diastereoselectivity and excellent yield (95%).(3) The selective N-deprotection of (R)-2-phenyl-2-(2-vinylpiperidin-l-yl) ethanol 2 without affecting the vinyl group in the substrate were untaken.(4) The Zip reaction for the transformation of (R)-1-(3-aminopropyl)-3-methylazecan-2-one 8 to (R)-7-Methyl-l,5diaza-cyclotetradecan-6-one 9 were undertaken. The results showed that, under controlled conditions, acceptable yields (43%) could be achieved and racemization can be minimized during the ring expansion reaction.4. Further studies on the reductive alkylation of (S)-malimide 11 (which was derived from (S)-malid acid 10) were undertaken. The addition to 11 showed nearly 100% regioselectivity at C2 The reductive alkylation product was then converted to known (lS,8aR)-octahydroindolizin-l-ol 12 (5 steps, overall yield 46% from malimide 11).5. Finally, the asymmetric synthesis of indolizidine alkaloid stellettamide C 15 was studied. The precursor of indolizidine 13, indolizidine 14 was prepared from (S)-N, O-dibenzyl malimide 11. The present work founded the basis for theasymmetric total synthesis of stellettamide C 15.