2199-64-6Relevant articles and documents
The total synthesis of chlorophyll a
Woodward, Robert Burns,Ayer, William A.,Beaton, John M.,Bickelhaupt, Friedrich,Bonnett, Raymond,Buchschacher, Paul,Closs, Gerhard L.,Dutler, Hans,Hannah, John,Hauck, Fred P.,Ito, Sho,Langemann, Albert,Le Goff, Eugene,Leimgruber, Willy,Lwowski, Walter,Sauer, Juergen,Valenta, Zdenek,Volz, Heinrich
, p. 7599 - 7659 (2007/10/02)
The total synthesis of chlorophyll a starting from Knorr's pyrrole (1) is described with full experimental detail. Forty six stages are involved to reach the target molecule, chlorin e6 trimethyl ester (46), from which the preparation of chlorophyll a has already been described. The four pyrroles which are required for rings A, B, C and D are elaborated largely by known reactions, although with considerable improvements. These pyrroles are manipulated to give two dipyrrin derivatives: a left-hand component (26, comprising rings A and D) and a right-hand component (the thioaldehyde 31, comprising rings B and C). These are brought together in a carefully controlled, stepwise, condensation to give a single porphyrin product (35) in 50% yield. This synthesis of an unsymmetrically-substituted porphyrin bearing an electron-withdrawing substituent and a meso-substituent is seen as a very considerable advance, both in conceptual and practical terms, over earlier approaches. During the course of the closure of the macrocycle, intermediates which exemplify a new group of dihydroporphyrins, the phlorins (e.g. 34), are recognised. Eleven steps remain. The porphyrin (35) is shown to undergo dehydrogenation (again via a phlorin intermediate) on brief treatment with acetic acid in air to give the meso-crylic acid derivative (36), which in acetic acid under nitrogen at 110° slowly reaches equilibrium with the purpurin (37). The introduction of the reactive vinyl group at C-3 has been delayed until this point in the synthesis. Photo-oxygenation of the product, the vinylpurpurin (38), cleaves the cyclopenteno-ring giving the methoxalylpurpurin (39). A reverse Claisen reaction now generates the methoxylactone, rac-isopurpurin 5 methyl ester (40), the first substance in this synthetic series which can be compared with a sample (albeit optically active) derived from natural chlorophyll a. rac-Isopurpurin 5 methyl ester (40) is hydrolysed to the lactol, chlorin 5 (41), which is resolved (diastereoisomeric salts with quinine). The less soluble salt gives synthetic act-chlorin 5, identical with a sample of natural provenance. Diazomethane treatment of the free acid (42) yields purpurin 5 dimethyl ester (43), again identical with the naturally-derived compound. Treatment with hydrogen cyanide in triethylamine leads to the cyanolactone (44), reductive cleavage and methylation of which give the chlorin e6 nitrile (45). Methanolysis of this furnishes synthetic crystalline chlorin e6 trimethyl ester (46), identical (mp, mixed mp, electronic spectrum, infra red spectrum) with a naturally-derived sample, so completing the total synthesis.
