聚雜環和有機磷結構物的設計、合成及其多樣性

Design, Synthesis and Diversification of Poly-heterocyclic and Organophosphorus Compounds

戴柏強(Prashant B. Dalvi)

指導教授 ： 孫仲銘

國立交通大學/理學院/應用化學系所/博士(2017年)

摘要

ABSTRACT
First chapter deals with a mild and efficient stereoselective synthesis of indole alkaloids with tetrahydro-β-carboline motif, utilizing Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, diene unit was installed in the tetrahedro-β-carboline skeleton through Pictet-Spengler cyclization of corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in-situ, [4+2] intramolecular Diels-Alder cycloaddition of activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds and five new chiral centers with excellent stereoselectivity are the key features of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies.
The second chapter describes an efficient synthesis of dihydroquinoxalinones utilizing a one-pot and two-step reaction of four components including aldehydes, F-moc protected α-amino acid, isocyanide and soluble polymer supported 4-fluoro-3-amino benzoate ester under microwave irradiation. F-moc deprotection followed by intramolecular cyclization of diamide gave a facile access to novel bicyclic quinoxalin-2-ones. Based on this approach, a new route to synthesize this privileged scaffold from diamide intermediate was designed and accomplished with high yields. The use of multicomponent reactions (MCRs) has been shown to display a good functional group tolerance, while the product isolation and purification is straightforward by precipitation and washings. Current library discusses synthesis and diversification of 21 compounds produced using this strategy.
Third chapter consists of an efficient and facile synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4, 5-b]indoles. Naturally occurring iboga class alkaloid inspired seven-member azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of aziridine ring. To improve the
efficiency of the synthetic route, the double bond of the rearranged olefinic product was reduced (path B) and privileged hydantoin moiety was constructed on the core system through urea formation using a variety of isocyanates, isothiocyanates and isoselenocyanates followed by an intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond in the final step afforded hydantoin-fused tetrahydroazepino [4, 5-b]indoles.
Fourth chapter reveals an unprecedented two-step, one-pot synthesis of benzimidazothiadiazine 5, 5 dioxides for the first time. The reaction condition-based regioselectivity has been described, where fused benzimidazo[1,2-b][1,2,4]thiadiazines are exclusively formed under thermal conditions, whereas benzimidazo[2,1-c][1,2,4]thiadiazines
were created only under microwave (MW) irradiation. The salient features of this chapter include a regioselective sulfonylation of 2-aminobenzimidazole with ortho halo sulfonyl chlorides followed by N-C bond formation. The acid forms of these fused regioisomers have used further to introduce novel guanidine-containing isocoumarin frameworks.
The final chapter reports a straightforward, practical method for the ‘P-S’ bond formation. This unprecedented synthesis of diverse organo phosphorous compounds has involved the use of phosphenes/phosphites/phosphonites with iodine and benzyl mercaptan as a sulphur
transfer reagent. The application of iodine in the present strategy is to form an intermediary salt with trisubstituted phosphenes/phosphites/phosphonites prior to nucleophilic attack of sulphur transfer reagent. The key feature of this protocol is the use of readily available thiols with high efficiency to installation of sulphur atom.

關鍵字

吲哚生物鹼 ； 烏吉去保護/合環反應 ； 微波輔助反應 ； 多重成分反應 ； 位置選擇性合成 ； 有機磷化學

並列摘要

ABSTRACT
First chapter deals with a mild and efficient stereoselective synthesis of indole alkaloids with tetrahydro-β-carboline motif, utilizing Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, diene unit was installed in the tetrahedro-β-carboline skeleton through Pictet-Spengler cyclization of corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in-situ, [4+2] intramolecular Diels-Alder cycloaddition of activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds and five new chiral centers with excellent stereoselectivity are the key features of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies.
The second chapter describes an efficient synthesis of dihydroquinoxalinones utilizing a one-pot and two-step reaction of four components including aldehydes, F-moc protected α-amino acid, isocyanide and soluble polymer supported 4-fluoro-3-amino benzoate ester under microwave irradiation. F-moc deprotection followed by intramolecular cyclization of diamide gave a facile access to novel bicyclic quinoxalin-2-ones. Based on this approach, a new route to synthesize this privileged scaffold from diamide intermediate was designed and accomplished with high yields. The use of multicomponent reactions (MCRs) has been shown to display a good functional group tolerance, while the product isolation and purification is straightforward by precipitation and washings. Current library discusses synthesis and diversification of 21 compounds produced using this strategy.
Third chapter consists of an efficient and facile synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4, 5-b]indoles. Naturally occurring iboga class alkaloid inspired seven-member azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of aziridine ring. To improve the
efficiency of the synthetic route, the double bond of the rearranged olefinic product was reduced (path B) and privileged hydantoin moiety was constructed on the core system through urea formation using a variety of isocyanates, isothiocyanates and isoselenocyanates followed by an intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond in the final step afforded hydantoin-fused tetrahydroazepino [4, 5-b]indoles.
Fourth chapter reveals an unprecedented two-step, one-pot synthesis of benzimidazothiadiazine 5, 5 dioxides for the first time. The reaction condition-based regioselectivity has been described, where fused benzimidazo[1,2-b][1,2,4]thiadiazines are exclusively formed under thermal conditions, whereas benzimidazo[2,1-c][1,2,4]thiadiazines
were created only under microwave (MW) irradiation. The salient features of this chapter include a regioselective sulfonylation of 2-aminobenzimidazole with ortho halo sulfonyl chlorides followed by N-C bond formation. The acid forms of these fused regioisomers have used further to introduce novel guanidine-containing isocoumarin frameworks.
The final chapter reports a straightforward, practical method for the ‘P-S’ bond formation. This unprecedented synthesis of diverse organo phosphorous compounds has involved the use of phosphenes/phosphites/phosphonites with iodine and benzyl mercaptan as a sulphur
transfer reagent. The application of iodine in the present strategy is to form an intermediary salt with trisubstituted phosphenes/phosphites/phosphonites prior to nucleophilic attack of sulphur transfer reagent. The key feature of this protocol is the use of readily available thiols with high efficiency to installation of sulphur atom.

並列關鍵字

Indole alkaloids ； Ugi/Deprotection/Cyclization ； Miicrowave assisted reaction ； Multicomponent reaction ； Regioselective synthesis ； Organophosphorus compounds

參考文獻

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