Total Synthesis of Aigialomycin

Afterwards, the implementation of a vinyl group as well as carboxylation of the ethynyl group resulted in carboxylic acid 571, which was esterified with chiral alcohol 572 under Mitsunobu conditions. 

Further syntheses of aigialomycin D (482) were published by the groups of Pan and Harvey 387, 388). The synthesis route of Pan et al. includes a Sharpless 

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After the isolation of the aigialomycins in 2002 (344), only two years later Danishefsky and co-workers published the first total synthesis of aigialomycin D (482) (5S5). Their synthesis strategy is denoted by a late-state aromatization via Diels-Alder cycUzation. Starting with readily available D-2-deoxyribose (568), alcohol 569 was obtained by protection of the diol, subsequent Wittig reaction, formation of the pivaloyl ether, and concluding hydroboration with oxidative workup (Scheme 9.14). Oxidation of the primary alcohol to aldehyde with a subsequent proparylation, led, after protection and deprotection, to alkyne 570. 

Baird LJ, Timmer MSM, Teesdale-Spittle PH, Harvey JE (2009) Total Synthesis of Aigialomycin D Using a Ramberg-Bdcklund/RCM Strategy. J Org Chem 74 2271... 

The first total synthesis of aigialomycin D was reported by Danishefsky and coworkers less than 2 years after the first report of isolation of this resorcyhde. The authors exploited the ynolide protocol initially developed for cycloproparadicicol [66] (Scheme 7.9) to construct aigialomycin D by a highly efficient Diels-Alder reaction of disiloxydiene (88) with the 14-membered ynolide 182 synthesized employing an RCM as key step (Scheme 7.21) [67]. 

Calo, F., Richardson, J., and Barrett, A.G.M. (2009) Total synthesis of aigialomycin D using a one-pot ketene generation-trapping-aromatization sequence. Org. Lett., 11,4910-4913. 

Other alkcnes in the substrate, and especially other alkynes, will react with the Ru catalyst. Samuel Danishefsky, of Columbia University and Sloan-Kettering Institute, recently completed (Organic Lett. 2004,6,413) the total synthesis of the antimalarial and antitumor agent aigialomycin D. For the Ru-mediated macrocyclization of 4 to 5, the alkyne in the molecule was protected as the dicobalt octacarbonyl adduct. After the cyclization, the alkyne was deprotected by brief exposure to ceric ammonium nitrate. 

Martin s sulfurane is widely used for the production of cyclic alkenes. Surprisingly, it has seen limited use in the production of macrocyclic alkenes. In the penultimate step of Danishefsky s synthesis of aigialomycin (61), Martin s sulfurane reacts with homobenzylic alcohol 59 to provide conjugated alkene 60 in 90% yield.28 The subsequent global deprotection step completed the total synthesis. Xu was unable to generate a macrocyclic... 

Resorcinylic macrolides are a family of natural products that possess a 14-membered macrolide core with a fused benzenoid subunit. A member of this family that has drawn significant scientific attention due to its antimalarial and cytotoxic activity is aigialomycin D. In one total synthesis of aigialomydn D, late-stage nickel-catalyzed macrocyclization was employed to afford the macrocyclic core [43]. Macrolide precursor 45 was cyclized in 61% yield in a 1 1 diastereoselectivity. Subsequent global deprotection and HPLC purification afforded aigialomycin D and the allylic alcohol epimer in 90% overall yield (Scheme 8.45). 

The synthetic sequence involving formation of a thioether, oxidation to the corresponding sulfone and the RBR need not be performed consecutively, although it almost invariably is when applied to the synthesis of complex targets. An example in which divorcing the sulfone preparation from the RBR was actually beneficial to the synthetic strategy is seen in the total synthesis of the resorcylic acid macrolactone (RAL) aigialomycin D by Harvey and coworkers. ... 

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