Nicolaou Taxol Total Synthesis - D Ring Synthesis

D Ring Synthesis

The desired enantiomer from resolution, allylic alcohol 5.1 (Scheme 5) was acetylated with acetic anhydride and 4-(dimethylamino)pyridine in methylene chloride to yield monoacetate 5.2. It is noteworthy that this reaction was exclusive for the allylic alcohol, and the adjacent hydroxyl group was not acetylated. Alcohol 5.2 was oxidized with tetrapropylammonium perruthenate and N-methylmorpholine N-oxide to give ketone 5.3. Alkene 5.3 underwent hydroboration in tetrahydrofuran. Oxidation with basic hydrogen peroxide and sodium bicarbonate gave alcohol 5.4 in 35% yield, with 15% yield of a regioisomer. The acetonide was removed, giving triol 5.5. This alcohol was monoacetylated, to give acetate 5.6. The benzyl group was removed and replaced with a triethylsilyl group. Diol 5.7 was selectively activated using methanesulfonyl chloride and 4-(dimethylamino)pyridine to give mesylate 5.8, in 78% yield.

The acetyl group in 6.1 (Scheme 6) was removed to give primary alcohol 6.2. The Taxol ring (D) was added by an intramolecular nucleophilic substitution involving this hydroxyl group to give oxetane 6.3. After acetylation, phenyllithium was used to open the carbonate ester ring to give alcohol 6.5. Allylic oxidation with pyridinium chlorochromate, sodium acetate, and celite gave ketone 6.6, which was subsequently reduced using sodium borohydride to give secondary alcohol 6.7. This was the last compound before the addition of the amide tail.