Total Synthesis of (+)-Zampanolide

Abstract

In 1996 Tanaka and Higa reported the isolation, partial structure elucidation, and biological activity of (-)-zampanolide, an architecturally novel macrolide from the Okinawan sponge Fasciospongia rimosa (Scheme 1). 1 Key structural elements include the highly unsaturated framework and the uncommon N-acyl hemiaminal side chain. 2 Adding to the structural complexity, only the relative stereochemistry between C(11), C(15), and C(19) had been assigned. Although the extreme scarcity of (-)-zampanolide precluded a comprehensive evaluation of the biological profile, the impressive cytotoxicity against P388, HT29, A549, and MEL28 cell lines (IC 50 1-5 ng/mL), in conjunction with the interesting architecture, prompted us to launch a synthetic program targeting this metabolite. Herein, we disclose the first total synthesis and tentative stereochemical assignment of the nonnaturally occurring antipode, (+)-zampanolide (1).Retrosynthetically, disconnections of 1 at the amide, the macrolide, and the C(2-3), C(8-9), and C(17-18) linkages gave rise to fragments C(3-8) A, C(9-17) B, C(18-20) C, and C(1′-6′) D. In the forward direction, we envisioned construction of the macrolide via Kocienski-Julia olefination 3 of aldehyde A with sulfone B, followed in turn by nucleophilic opening of epoxide C with a higher-order cuprate 4 derived from AB, incorporation of a C(1-2) acyl phosphonate, and intramolecular HornerEmmons macrocyclization. 5 Highlights of the closing stage of the synthesis would then entail installation of the N-acyl hemiaminal moiety via a stereospecific Curtius rearrangement 6 of R-alkoxy acid 2 followed by acylation with acid chloride D.To assemble fragment B we elected the Petasis-Ferrier rearrangement, 7 recently established in our laboratory as a powerful, stereocontrolled entry to cis-2,6-disubstituted tetrahydropyrans. 8 Toward this end, Brown asymmetric allylation 9 of aldehyde 3 10 (Scheme 2) followed in turn by TES protection of the hydroxyl and ozonolysis afforded (+)-4, which upon oxidation 11 and desilylation led to -hydroxy acid (-)-5 (57% yield, five steps). Bis-silylation 12 followed by union with (2E)-3-bromobut-2-enal 13 promoted by TMSOTf 14 furnished dioxanone (+)-6 in 82% overall yield [10:1 at C(15)]. Methylenation with the Petasis-Tebbe reagent 15 then furnished the corresponding enol ethers [72% yield, 6:1 at C(15)], which upon treatment with Me 2 AlCl 8 underwent the desired Petasis-Ferrier rearrangement 7 to deliver cis-pyranone (+)-7 in 59% yield. 16 Ketone methylenation, desilylation, incorporation of the thiotetrazole via Mitsunobu reaction, 17 and oxidation 18 proceeded smoothly to afford sulfone (-)-B (62% yield, 4 steps).Construction of subunits A and C was achieved as outlined in Scheme 3. 19 Noteworthy is the stereoselective 20 installation of the C(4-5) olefin in subtarget A.With the requisite subtargets in hand, assembly of the macrolide began with the Kocienski-modified 3 Julia olefination 21 of aldehyde (1) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535. (b) For a related...

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Organometallic Tetrazole Derivatives: Preparation and Application to Organic Synthesis

“…Alongside the high yields (up to 100%) of alkenes 62 the process is characterized by a high streoselectivity. Therefore compounds 61 were recently extensively used in Julia olefination instead of aryl and hetaryl sulfones [5,54] for stereoselective prepara-tion of naturally occurring compounds containing in their structure a fragment of trans-1,2-disubstituted alkene, for instance, Hennoxazole A [55], Herboxidiene [56], Thiazinotrienomycin E [57], Cylindrocyclophanes A and F [58], Zampanolide [59], Ambruticin [60], Laulimalide [61], Nafuredin [62], Callystatin A [63], Plakortone D [64], Brefeldin A [65], Lasonolide A [66,67], Amphidino-lide A [68], Zampanolide, Dactylolide…”

Synthesis, X-ray crystal structure and antimycobacterial activity of enantiomerically pure 1-ethyl-2,3-dicyano-5-(het)aryl-6-hetaryl-1,6-dihydropyrazines

“…[27][28][29][30][31][32][33][34] The reaction proceeds via the formation of aminal intermediate 4 (Scheme 1). The reaction has also been applied to the synthesis of heterocyclic systems [35][36][37][38][39][40] and solid phase synthesis of peptides. [41][42][43] The reaction is a very efficient with alkenyl and electron-rich aromatic boronic acids.…”