Development of New Synthetic Methods toward Bicyclic Piperidines and Pseudodistomin B Using Gold(I) Catalyst

DoctorOf all the alkaloids, piperidine natural products have received special attention. These natural products show unique bioactivities, and therefore have attracted many scientists seeking to investigate their bioactivities and develop the suitable synthetic routes to construct them. The following strategies have been used to synthesize piperidine natural products: cyclization from linear compounds, hetero Diels-Alder reactions, ring expansion, and the reduction of pyridine. However, using transition metals to catalyze the synthesis of piperidine analogues is the most attractive option due to their unique chemo- and regioselectivity. For example, regioselective nucleophiles can easily be added onto alkyne by employing gold as a transition metal catalyst. In the case of substrates bearing the MOM functional group, the methoxy in the MOM group attacks the activated alkyne to form a cyclized compound. This method is an effective way of synthesizing piperidine natural products. In the present work, this method is applied to synthesize bicyclic piperidine compounds, specifically indolizidine and quinolizidine, and pseudodistomin B triacetate. Indolizidine and quinolizidine are bicyclic products which are widely distributed in nature. These compounds show unique bioactivities, and are attractive synthetic targets. In this context, the development of a synthetic route to create indolizidine and quinolizidine core structure is becoming more important. With effective gold(I)-catalyzed cycloisomerization, a piperidine structure will be obtainedthen a, bicyclic structure will be constructed with reductive amination. To carry out this strategy, olefinic alcohol was selected as a starting materialthis was converted to homopropargylic amine with a good overall yield. The gold(I)-catalyzed cycloisomerization was successfully carried out to give excellent yield and reductive amination proceeded successfully to give indolizidine and quinolizidine. The activation of the alkyne group with the gold catalyst allows various nucleophiles to be added. These nucleophiles include the alkoxy group and carboxy group. Although there has been great effort to study these nucleophiles, there are still insufficient results on substrates bearing both nucleophiles. The gold(I)-catalyzed reaction, however, showed excellent chemoselectivity: The electron-deficient ligand tends to activate carboxycyclization, where the electron-rich ligand tends to proceed through alkoxycyclization. Using these results, the synthesis of pseudodistomin B triacetate was investigated. From 1,7-heptandiol, homopropargylic amine was synthesized with good overall yield, and the gold(I)-catalyzed cycloisomerization proceeded successfully. The produced piperidine product could be further converted to pseudodistomin B triacetate following the reported pathway.With the growing importance of homopropargylic amines, the necessity for an effective synthetic route is increasing. Prior works can be summarized as synthesis of homopropargylic amines from addition on N-substituted imines. This, however, generates protected amines that need further treatment to produce primary amines. On the other hand, the azide can be easily converted to corresponding imine simply through the liberation of nitrogen gasfree aldimine generated in situ could be modified by various nucleophilic addition reactions to directly construct unsubstituted amine compounds. Using this method, the N-unsubstituted homopropargylic amine can be produced by the addition of the allenyl group to the imine generated in situ from azide using the Ru-dimer catalyst in the photocatalytic condition. The application to various substrates gives successful results under optimized reaction conditions.Gold(I)-catalyzed cycloisomerization is an effective method of synthesizing piperidine natural products. This method was successfully applied to synthesize bicyclic piperidines, specifically indolizidine and quinolizidine, and pseudodistomin B triacetate. In addition, the effective synthesis of homopropargylic amines from azide using the Ru photocatalyst would greatly support the further application of gold(I)-catalyzed cycloisomerization