Enantioselective phase-transfer catalytic α-alkylation of benzylideneamino tert-butyl malonate
Benzylideneamino tert-butyl malonate의 상전이 촉매 알킬화 반응을 이용한 α,α-dialkylmalonate의 입체선택적 합성에 대한 연구
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- asymmetric synthesis; phase-transfer catalytic alkylation; benzylideneamino; α; α-dialkylmalonates; selective hydrolysis; quaternary carbon center
- 학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과 약품제조화학전공, 2016. 2. 박형근.
- Phase-transfer catalysis is to facilitate the migration of a reactant from one phase into another phase where reaction occurs. Generally, one phase is aqueous and the other is organic. Phase-transfer catalyst, usually called PTC, promotes the reaction shuttling between two phase. So PTC involves a hydrophilic part like ammonium, phosphonium and crown ether for metal ion capture and a liphophilic part like hydrocarbon. According to the PTC concept, reactions are performed in heterogeneous two phase systems, that offers numerous advantages over traditional methodologies, which use homogeneous media, and finds extremely wide application in laboratory organic synthesis and industrial processes. Malonates are the structure in that the both ends carbon are in oxidation state of +3 and middle carbon in -2 at linear three carbon. Thanks to inherent nature, various reactions – Michael addition, Friedel-crafts alkylation, cyclization, Knoevenagel condensation, cyclopropanation, cycloaddition and Diels-Alder reaction can be available to malonate, which are one of the most fundamental starting materials in diverse research areas such as total synthesis, methodology and medicinal chemistry etc. Especially in case chirality is added to α-position of malonate, it can become useful building blocks.
In 2011, our research team reported highly enantioselective synthesis of α,α-dialkylmalonates by phase-transfer catalytic alkylation using diphenylmethyl tert-butyl malonate as a substrate. The results showed excellent yield and ee. By the way, there were some problem while hydrolysis for an application. In acidic condition, both esters were hydrolyzed and α-chirality was lost. In basic condition, no reaction occurred. We developed 2-methylbenzyl tert-butyl malonate as an improved substrate in selective hydrolysis. In case of the substrate selective hydrolysis was possible in basic condition, but still both esters were hydrolyzed in acidic condition. And the alkylation results showed relatively low enantioselectivity while reactions took long time. For satisfying selective hydrolysis in both conditions, excellent reactivity and enantioselectivity, we designed benzylideneamino tert-butyl malonate bearing diphenylmethylimine, which is originated from the structure of Odonnell substrate. After optimization, we could obtain α,α-dialkylmalonates in high chemical (up to 97%) and optical (up to 98% ee) yields using (E)-4-bromobenzylideneamino tert-butyl malonate as a final substrate. As an application, chiral ε-caprolactone was synthesized and selective hydrolysis in acidic, basic and catalytic hydrogenation condition. Also, the enantioselective phase-transfer catalytic α-sulfenylation was achieved in high chemical (90%) and optical (92% ee) yields using beznhydrylideneamino tert-butyl malonate as a substrate. And the change of chiral induction in the asymmetric phase-transfer catalytic alkylation of modified substrates through simplification of representative benzylideneamino malonates and carbon length-varied malonates was observed.
Our new catalytic system provided an attractive synthetic method for various chiral building blocks that could be readily converted en route to the synthesis of versatile chiral target molecules with the involvement of quaternary carbon centers.