Involvement Of Protein Kinase C Inhibitor The Penazetidinea Synthesis And Dysprosium Barbier-type Reaction

This dissertation comprises two parts:In the first part, synthesis of penazetidine A, an alkaloid inhibitor of protein kinase C (PKC), was studied. The structure of this compound is very similar to penaresidin A and B, which are the first two sphingosine-derived alkaloid possessing an azetidine ring and a side chain with a chiral methyl. The carbon skeleton of the target molecule was established by Wittig reaction. We adopted the following stratery to synthesize the azetidine building block. The three chiral centers in the azetidine was established by Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation starting from divinylcarbinol. Regioselective ring-opening reaction of the 2,3-epoxy alcohol with NaN3 and subsequent reduction of the trinitride gave the diol compound. Then the cyclization of the diol was carried out smoothly under Mitsunobu conditions to furnish the azetidine building block. While the chiral center in the side chain was established by asymmetric alkylation of N-acylsultam. Successive treatment of acylsultam with n-BuLi and iodomethane, followed by reduction with LiAlH4 furnished the chiral alcohol. Link of the chiral alcohol and derivative of azelaic acid finished the synthesis of the chiral side chain. With the two fragments in hand, the Wittig coupling reaction was explored at -78°C and then warmed to room temperature with n-BuLi as the base. The resulting compound was reduced with diimide, followed by catalytic hydrogenation on 10% Pd/C smoothly afforded (2S, 3R, 4S,12'R)-3-hydroxy-2-hydroxymethyl-4-(12'-methyloctadecyl)-N -(p-tolylsulfonyl)-azetidine. The overall yield of this compound was 6.0% based on divinylcarbinol.In the second part, the Barbier type reaction of carbonyl compounds promoted by metallic dysprosium has been studied. Firstly we studied dysprosium promoting propargylation of ketones and aldehydes. In the presence of mercuric chloride and sodium iodide, the reactions were proceeded smoothly in anhydrous THF to afford the corresponding homopropargylic alcohols in good to excellent yields without observation of allenic alcohols. In addition, this reaction is regioselective and chemoselective. An (,(- unsaturated ketone afforded a 1,2-addition product selectively. Reactive groups (such as Cl, Br, and methoxy) of aromatic ketones and aromatic aldehydes remained unchanged under the reaction conditions. Then we studied the allylation of esters promoted by metallic dysprosium. In the presence of mercuric chloride, the reaction of esters with allyl bromide and dysprosium powder in anhydrous THF gave (,(-diallyl carbinols in good yields. When (-butyllactone was used as the substrate, the corresponding product was 4-allyl-6-heptene-1,4-diol. This reaction was also regioselective and chemoselective.