Aigialomycins

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. 

This ynolide strategy was applied to the synthesis of the raacrolide aigialomycin D by Geng and Danishefsky [66]. 

Aigialomycins A-E 20-24, new 14-membered resorcylic macrolides, were isolated from the mangrove fungus Aigialus parvus BCC 5311/ ... 

Scheme 21.9 Solid phase synthesis of aigialomycin D (Winssinger et al.).

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). 

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. 

After masking of the alkyne function by a dicobalthexacarbonyl complex, RCM was used to cyclize the diene 573 (Scheme 9.15). Then, decomplexation enabled a Diels-Alder reaction with the disiloxydiene 575, ensued by elimination of isobutylene. Two hydroxy groups of the resorcylic macrolide (576) obtained were protected and the TBS-ether was cleaved. Thus, dehydration with concluding deprotection of all alcohol functions furnished aigialomycin D (482), in an overall yield of 8%. 

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... 

Isaka M, Suyamsestakom C, Tanticharoen M, Kongsaeree P, Thebtaranonth Y (2002) Aigialomycins A-E, New Resorcylic Macrolodes from the Marine Mangrove Fungus... 

Barluenga S, Dakas PY, Ferandin Y, Meijer L, Winssinger, N (2006) Modular Asymmetric Synthesis of Aigialomycin D, a Kinase-Inhibitory Scaffold. Angew Chem Int Ed 45 3951... 

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 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. ... 

Aigialomycin D is a metabolite of the mangrove fungus Mgialus parvus and was shown to be a kinase inhibitor with modest antimalarial activity. The convergent synthesis showcased here assembled three fragments into the full carbon skeleton (Scheme 836). The ester-containing benzylic bromide 134 was prepared from methyl orsellinate, itself derived from methyl acetoacetate. Thioacetate 135 was formed from d-ribose as will be described, while homoallylic alcohol 136 was commercially available. 

Scheme 8.39 Unwanted truncation previously observed with aigialomycin D synthesis.

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