Stereoselektywna addycja pochodnych orto-toluiloamidów do imin jako metoda syntezy alkaloidów protoberberynowych
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2011-09-12T09:31:46Z
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Stereoselective addition of ortho-toluamide derivatives to imines as the method of protoberberine alkaloids synthesis
Abstract
Problematyka badawcza rozprawy doktorskiej związana była z asymetryczną syntezą alkaloidów protoberberynowych, wykorzystującą metodę stereoselektywnej addycji nukleofili węglowych do imin. Badania obejmowały dwie metody syntezy asymetrycznej: z udziałem nukleofili węglowych zawierających pomocnik chiralny oraz z udziałem achiralnych substratów prowadzoną wobec zewnętrznych induktorów chiralności. Związkami modelowymi były: 8-oksoksylopinina i 2,3-dimetoksy-8-oksoberbina. W syntezie 8-oksoksylopininy, jako pomocniki chiralne wykorzystane zostały handlowo dostępne aminoalkohole: (S)- (+)-alaninol oraz (S)-(-)-fenyloalaninol. Otrzymano pochodne o-toluiloamidów zawierające podstawniki metoksylowe w pierścieniu aromatycznym i pomocnik chiralny pochodzący z odpowiedniego aminoalkoholu. W reakcji addycji anionu benzylowego wygenerowanego metodą bocznego litowania z o-toluiloamidu z pomocnikiem chiralnym pochodzącym z (S)-(+)-alaninolu do 6,7-dimetoksy-3,4-dihydroizochinoliny uzyskano (S)-(-)-8-oksoksylopininę z 99,0% ee. Zastosowanie (S)-(-)-fenyloalaninolu jako pomocnika chiralnego prowadziło do uzyskania 8-oskoksylopininy z 74% ee. Drugi nurt badań dotyczył syntezy enancjoselektywnej 2,3-dimetoksy-8-oksoberbiny. W reakcja addycji anionu wygenerowanego z achiralnej 2,2-dimetylo-3-o-toluilooksazolidyny do 6,7-dimetoksy-3,4-dihydroizochinoliny prowadzonej wobec (-)-sparteiny uzyskano (S)-(-)-2,3-dimetoksy-8-oksoberbinę z 58% ee. Zastosowanie (+) -surogatu sparteiny jako chiralnego liganda dało produkt o konfiguracji (R) z 60% ee.
The subject of undertaken studies was asymmetric synthesis of protoberberine alkaloids via carbon nucleophile addition to imines. Carbon nucleophiles were derived from o-toluamides. Two pathways of asymmetric synthesis were investigated: synthesis employing o-toluamide with chiral auxiliary and enantioselective one where nonchiral amide was applied in the presence of external chiral auxiliary/ligand. As model compounds 8-oxoxylopinine and 2,3-dimethoxy-8-oxoberbine were chosen. The key step of the synthesis was the addition of the carbanion generated from o-toluamide by lateral lithiation methodology to imine’s double bound and simultaneous cyclization to protoberberine system. In order to obtain 8-oxoxylopinine two optically active amides containing methoxyl substituents in aromatic ring were synthetized. Commercially available aminoalcohols: (S)-(-)-phenylalaninol and (S)-(+)-alaninol were used as chiral auxiliaries. The addition reaction of benzyl anion formed by lateral lithiation methodology from o-toluamide with (S)-(-)- alaninol as chiral auxiliary gave (S)-(-)-8-oxoxylopinine with 99% ee. Applying (S)-(-)-phenylalaninole as chiral auxiliary led to the same product with 74% ee. In synthesis of 2,3-dimethoxy-8-oxoberberine nonchiral 2,2-dimethyl-o-toluoyloxasolidine was used in the presence of chiral ligands. Addition/cyclization of benzyl anion to 6,7-dimethoxy-3,4-dihydroisoquinoline in presence of (-)-sparteine led to 2,3-dimethoxy-8-oxoberberine with 58% ee. The reaction employing (+)-sparteine surrogate led to enantiomeric (R) product with 60% ee.
The subject of undertaken studies was asymmetric synthesis of protoberberine alkaloids via carbon nucleophile addition to imines. Carbon nucleophiles were derived from o-toluamides. Two pathways of asymmetric synthesis were investigated: synthesis employing o-toluamide with chiral auxiliary and enantioselective one where nonchiral amide was applied in the presence of external chiral auxiliary/ligand. As model compounds 8-oxoxylopinine and 2,3-dimethoxy-8-oxoberbine were chosen. The key step of the synthesis was the addition of the carbanion generated from o-toluamide by lateral lithiation methodology to imine’s double bound and simultaneous cyclization to protoberberine system. In order to obtain 8-oxoxylopinine two optically active amides containing methoxyl substituents in aromatic ring were synthetized. Commercially available aminoalcohols: (S)-(-)-phenylalaninol and (S)-(+)-alaninol were used as chiral auxiliaries. The addition reaction of benzyl anion formed by lateral lithiation methodology from o-toluamide with (S)-(-)- alaninol as chiral auxiliary gave (S)-(-)-8-oxoxylopinine with 99% ee. Applying (S)-(-)-phenylalaninole as chiral auxiliary led to the same product with 74% ee. In synthesis of 2,3-dimethoxy-8-oxoberberine nonchiral 2,2-dimethyl-o-toluoyloxasolidine was used in the presence of chiral ligands. Addition/cyclization of benzyl anion to 6,7-dimethoxy-3,4-dihydroisoquinoline in presence of (-)-sparteine led to 2,3-dimethoxy-8-oxoberberine with 58% ee. The reaction employing (+)-sparteine surrogate led to enantiomeric (R) product with 60% ee.
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Wydział Chemii: Pracownia Spektrochemii Organicznej
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synteza asymetryczna, asymmetric synthesis, protoberberyny, protoberberines, pomocnik chiralny, Chiral auxiliary, 8-oksoksylopinina, 8-oxoxylopinine, 2,3-dimetoksy-8-oksoberbina, 2,3-dimetoxy-8-oxoberberine