Cinchona catalyst를 매개한 aza Diels-Alder reaction과 적용
- Issue Date
- 서울대학교 대학원
- 학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2012. 2. 박형근.
- 1970년대 후반부터, 다양한 cinchona-derived catalyst들이 개발되었고, 유용한 catalyst로서 다양한 chemical reaction에 사용되었다. 본 연구에서 cinchona-derived catalyst들은 Danishefskys diene의 aza Diels-Alder reaction에 적용되었다. 그 결과, 9개의 cinchonidine-derived quaternary ammonium catalyst들이 합성되었고, Danishefskys diene과 imine, 그리고 cyclic imine의 aza Diels-Alder reaction에 촉매로 사용되어 각각 1,2-dialkyl-2,3-dihydro-4-pyridinone과 cyclic dihydropyridone들을 생성하였다. Catalyst들 중에서는 N-2,3,4-trifluorobenzyl-O-benzylcinchonidium bromide가 최대 99%로 가장 높은 chemical yield를 보였다. 비록 반응에서 enantioselectivity를 유도하지 못했으나, 개발한 catalyst를 성공적으로 aza Diels-Alder reaction을 통한 polycyclicdihydropyridone 합성에 도입 할 수 있었다. 이는 생물학적으로 활성이 있는 aza polycyclic natural product의 합성에 응용될 수 있을 것이다.
이 methodology의 응용으로 tetrabenazine의 합성이 연구되었다. 6,7-dimethoxy-3,4-dihydroisoquinoline과 Danishefskys diene의 aza Diels-Alder 반응으로 Tetrabenazine의 polycyclic 구조를 얻었고, 3-bromo-2-methyl propene으로 alkylation한 뒤, 환원하여 tetrabenzaine을 얻을 수 있다. Aza Diels-Alder product는 구조적 변형을 통하여 다양한 tetrabenazine 유도체를 합성하는 데 응용될 수 있다.
Since late 1970s, various cinchona-derived ammonium salt catalysts have been developed, and applied to diverse chemical reactions usefully. In this research, cinchona-derived catalysts were applied to aza Diels-Alder reaction of Danishefskys diene with imine. As a result, 9 of cinchonidine-derived quaternary ammonium catalysts were synthesized. Those catalysts promoted aza Diels-Alder reaction of Danishefskys diene with imine, and cyclic imine, which produced 1,2-dialkyl-2,3-dihydro-4-pyridinone, and cyclic dihydropyridone, respectively. Among catalysts synthesized, N-2,3,4-trifluorobenzyl-O-benzylcinchonidium bromide showed the best chemical yield. (up to 99%) Although, enantioselectivity was not induced in this reaction, developed catalyst could be successfully applied to synthesis of polycyclicdihydropyridone via aza Diels-Alder reaction. This suggests the possibility of applying to synthesis of various aza polycyclic natural products which are biologically active.
As application, synthesis of tetrabenazine was studied. The polycyclic structure of tetrabenazine was obtained via aza Diels-Alder reaction of Danishefskys diene with 6,7-dimethoxy-3,4-dihydroisoquinoline. Then, allylation with 3-bromo-2-methylpropene was carried out. Reduction of the allylated product would produce tetrabenazine, and screening of reduction condition is ongoing. Aza Diels-Alder products could be applied to synthesis of tetrabenazine derivatives by structural modification.
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