Total Synthesis of the Galbulimima Alkaloid GB

Lew Mander of the Australian National University recently reported (J. Am. Chem. Soc. 2003, 125, 2400) the total synthesis of the pentacyclic alkaloid GB 13 3, which had been isolated from the bark of the rain forest tree Galbulimima belgraveana. In the course of the synthesis, he took full advantage of benzene precursors, while at the same time carefully establishing each of the eight stereogenic centers of 3. 

The core tricyclic ketone 1 was assembled by Birch reduction of 2,5-dimethoxybenzoic acid, followed by alkylation with 3-methoxybenzyl bromide, to give 4. Acid-catalyzed electrophilic cyclization of 4 gave the tricyclic ketone 5, which on decarboxylation and protection gave 1. 

Diazo transfer to 1 followed by irradiation in the presence of bis-(trimethylsilyl)amide led to ring contraction with concomitant carbonyl extrusion, to give 7. Dehydration to the nitrile followed by selenation then set the stage for a highly diastereoselective ytterbium-catalyzed Diels-Alder reaction, to give, after reduction and protection, the pentacyclic intermediate 2. 

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The total synthesis of galbulimima alkaloid GB 13 was accomplished by L.N. Mander and co-workers. The Birch reduction of a complex intermediate was necessary in order to prepare a cyclic a,p-unsaturated ketone. The treatment of the substrate with lithium metal in liquid ammonia first resulted in a quantitative reductive decyanation of the C6a cyano group. The addition of excess ethanol to the reaction mixture reduced the aromatic ring to the corresponding enol ether that was hydrolyzed in a subsequent step to afford the unsaturated ketone. 

The enone formation has been applied to a number of natural product syntheses. The enone 524 was prepared from the complex molecule 523 and successfully applied to the total synthesis of pallescensin [212], Even the phenolic OH in 525 was converted to the conjugated ketone. The reaction was utilized as a key step in hypoxyxylerone synthesis [213]. In the total synthesis of galbulimima alkaloid GB 13, Mander converted a cyclohexanone in the complicated molecule 526 to the corresponding cyclohexenone via silyl enol ether in 82% yield [214]. 

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