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Studies On The Asymmetric Total Synthesis Of Marine Natural Products Ypaoamide And Awajanomycin; Applications Of Carbohydrates In The Synthesis Of Chiral Ligands And Polymers

Posted on:2010-11-27Degree:DoctorType:Dissertation
Country:ChinaCandidate:J ChenFull Text:PDF
GTID:1101360275488112Subject:Organic Chemistry
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Pyrrolin-2-one and piperidin-2-one containing natural products possess a varietyof important bioactivities and show high potential for medical and biologicalapplications. The synthesis of such compounds represent a worthwhile andchallenging goal for the organic chemists particularly as most of the target moleculesare comprised of complex architechtural framework with several stereogenic centers.One aim of this thesis is to further study on the important building blocks,protected malimides and glutarimides which were previously developed in ourlaboratory, as well as their application in the asymmetric synthesis of marine naturalproducts ypaoamide (3) and awajanomycin (4).Ypaoamide (3) was isolated in 1996 from the marine cyanobacterium Lyngbyamajuscula at Ypao Beach on Guam and shown to be a new broadly acting feedingdeterrent. Its ecological significance has been studied. The enantioselective synthesisof ypaoamide (3) presents several challenges because that its structure contains a5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which is subjected to racemizationunder basic condition and Z-β-methoxy-α,β-unsaturated imide moiety which isunstable under acidic condition.Awajanomycin (4) was isolated in 2006 from the marine-derived fungusAcremonium sp. AWA16-1,collected from sea mud off Awajishima Island in Japan.Awajanomycin exhibited cytotoxic activity against the A549 cells with IC50 value of27.5μg/mL. It possesses a characteristicγ-lactone-δ-lactam core structure with a fullysubstituted 2-piperidinone ring bearing four chiral centers including a quaternarycarbon.The intriguing structural features, in addition to the undeterminedstereochemistry and significant sytotoxicity make ypaoamide (3) and awajanomycin(4) attractive and challenging synthetic targets. To date no total synthesis of them hasbeen reported. The main results and observations from these studies are listed as follows:1.The first asymmetric total synthesis of ypaoamide (3) has been achieved.(1) The unusual t-butyl lipid side chain of ypaoamide 53 was prepared in 9 stepsincluding Wittig reaction and cross-Claisen condensation with 9.7% overall yieldstarting from ethyl 4-bromobutyrate.(2) The building block N-allyl malimide 5b was obtained starting from (S)-malic acid.Employing a highly chemo-, regio-, and stereoselective stepwise reductivep-benzyloxybenzylation of 5b, the 5-(p-benzyloxyphenylmethyl)-3-pyrrolin-2-oneportion 54b was prepared in 6 steps with 46% overall yield starting from malic acid.(3) The key intermediate 89 was obtained through the coupling of pyrrolin-2-oneportion 54b with side chain segment 53. After a one-pot tandem hydroxyl Bocprotection-β-elimination process of 89, O-Boc protected ypaoamide 52a was obtainedAfter a selective acetylation-β-elimination process of 89, O-Ac ypaoamide 52b wasobtained. (4) Studies on the deprotection of the phenolic hydroxyl group of ypaoamide. Becausethat its structure contains a 5-alkyl-α,β-unsaturated-pyrrolin-2-one portion which issubjected to racemization under basic condition and E-β-methoxy-α,β-unsaturatedimide moiety which is unstable under acidic condition, the deprotection was proved agreat challenge. Deacetylation of O-Ac ypaoamide 52b catalyzed by CCL (lipasefrom Candida cylindracea) gave (R)-3. Thus, the first asymmetric total synthesis of(R)-3 was achieved in 19 steps with 1.0% overall yield starting from ethyl4-bromobutyrate and N-allyl malimide 5b. The absolute configuration of the naturalypaoamide was determined as S.(5) On the basis of the total synthesis of (R)-ypaoamide, the asymmetric synthesis ofthe key segment of marine natural product Microcolin B 97 was achieved. 2. Studies on the asymmetric synthesis of awajanomycin (4).(1) The building block protected(S)-3-hydroxyl-glutarimide 6b was obtained startingfrom(S)-glutamic acid. Employing a stepwise reductive methylation of 6b, theintroduction of O-methoxycarbonyl group and an epoxidation, the piperidin-2-oneportion 192b was prepared in 9 steps starting from 6b.(2) The asymmetric synthesis of (R)-215 was studied. Asymmetric catalytic transferhydrogenation of 222 catalyzed by the Ru catalyst 221 gave (R)-215 in 90% yield and98% ee. The chain side of awajanomycin (R)-114a was obtained from (R)-215 though2 steps. The synthesis of the two key segments founded the basis of the asymmetrictotal synthesis of awajanomycin. 3. The other part of this thesis is applications of carbohydrates in the synthesis ofchiral ligands and polymers.(1) Based on the previous work of our laboratory, three types of azide derivativeswere prepared from natural carbohydrates. Employing Staudinger-Vilarrasa reaction,the coupling of primary azide 243 with 2,2'-bypyridine-3,3'-dicarboxylic acid wasachieved to give diamide 255 which can be used as a chiral ligand for enantioselectivefluorination. This work expanded the application of carbohydrates in chiral catalysis.(2) Two glycomonomers 287 and 290 both with azido group and ynyl group wereobtained from isomaltulose. Employing Huisgen 1,3-dipolar cycloaddition, theformation and characters of the glycopolymer were studied. This work expanded theapplication of carbohydrates in glycopolymer synthesis.
Keywords/Search Tags:Pyrrolin-2-one, Piperidin-2-one, Marine natural product, Ypaoamide, Awajanomycin, Asymmetric synthesis, Carbohydrate, Chiral ligand, glycopolymer
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