Malonic Ester Synthesis - University of Calgary
Choice of base for malonic ester synthesis
The diester was then treated with (freshly distilled) hydrogen cyanide and triethylamine to form the corresponding cyanolactone that was then reductively opened by cleavage of the C-O bond using Zinc dust in acetic acid. This represents a most unusual method for increasing the length of the sidechain by one carbon atom, and although the yield is dire the reaction was at least consistent, giving the same yield on 20 to 115 mg. Finally, with a simple hydrolysis of the nitrile group to the third methyl ester, chlorine e6 trimethyl ester was isolated, completing the formal total synthesis of chlorophyll a.
27/06/2011 · Malonic Ester Synthesis May 24, 2011 #1
Comparison of this oxidation product with chlorin e6 trimethyl ester reveals that only three transformations were now required to react the target: excision of the methoxalyl group, resolution and homologation of the aldehyde to the longer chain ester. The first of these operations, a retro-Claisen condensation, was performed in fairly low yield by treatment with methanolic KOH (followed by regeneration of the other esters with diazomethane), to give the trans disposed D-ring ring isomer. These conditions also caused cyclisation of the C-ring ester onto the nearby aldehyde to give the methoxylactone. This slightly unexpected transformation was explained by the fact that cyclisation at this position had the effect of reducing the afore mentioned peripheral overcrowding at this part of the ring. In any case, the this compound was treated with aqueous sodium hydroxide in dioxane to hydrolyse the one remaining methyl ester (and incidentally convert the methoxylactone to the hydroxylactone), in order to provide a handle for resolution. Unfortunately, although resolution (via the quinine salt) could be successfully carried out (under entirely non-obvious conditions), it proved exceptionally difficult and the yield of optically pure material obtained was only 4% from the acid. Finally, treatment of this compound with yet more diazomethane gave the corresponding purpurin dimethyl ester in a surprisingly poor yield for this step. Crucially for the group, the disappointment of the resolution could now be put behind them because this compound could easily be derived from natural material (methyl pheophorbide a). Thus, a relay point had been reached and they were able to replenish their supply of material before pushing on for the finish. Comparison of various synthetic compounds at this points showed identity with naturally derived material, confirming the success of the route so far.