- Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B
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The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne-yne metathesis of suitable diyne or enyne-yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me2C6H 3)N]3Mo (37) as precatalyst activated in situ with CH 2Cl2, as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)3 W≡CMe3] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine. and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner-Wadsworth-Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C-C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography.
- Fuerstner, Alois,De Souza, Dominic,Turet, Laurent,Fenster, Michael D. B.,Parra-Rapado, Liliana,Wirtz, Conny,Mynott, Richard,Lehmann, Christian W.
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p. 115 - 134
(2007/10/03)
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- Concise and practical synthesis of latrunculin A by ring-closing enyne-yne metathesis
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(Chemical Equation Presented) Selective actin-binding is the most prominent biochemical property of the scarce marine natural product latrunculin A (see formula). Modern metal-catalyzed C-C bond-formation reactions, including a ring-closing enyne-yne metathesis (shown in red), now open a convenient, flexible, and productive entry to this important probe molecule for chemical biology.
- Fuerstner, Alois,Turet, Laurent
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p. 3462 - 3466
(2007/10/03)
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- Total Synthesis of (+)-Latrunculin A, an Ichthyotoxic Metabolite of the Sponge Latrunculia magnifica, and Its C-15 Epimer
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Latrunculin A (1), an ichthyotoxic metabolite of the sponge Latrunculia magnifica with potent inhibitory action on microfilament-mediated processes involved in cell division, was synthesized via a convergent approach.Construction of a major segment of the latrunculin backbone was accomplished by means of a three-component coupling of aldehyde 24, β-keto ester 27, and phosphonium salt 26, which established the conjugated E,Z-diene moiety of 31.The thiazolidinone subunit of 1 was elaborated in the form of 39 from L-cysteine and was linked to 35 without nitrogen protection.Final lactonization of 47 was carried out using the Mitsunobu protocol.A parallel sequence employing the epimeric seco acid 48 produced 15-epilatrunculin A.
- White, James D.,Kawasaki, Motoji
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p. 5292 - 5300
(2007/10/02)
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- Total synthesis of the latrunculins
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The total syntheses of (+)-latrunculin A (1) and (+)-latrunculin B (2), two architecturally novel toxins isolated from the Red Sea sponge Latrunculia magnifica (Keller), have been achieved via highly convergent and stereocontrolled routes (longest linear sequences, 16 and 12 steps, respectively). Formal syntheses of scalemic latrunculins C (3) and M (5) also derive from the construction of 2. Central features of the unified synthetic strategy include the aldol reaction of aldehyde (-)-12 with methyl ketone (-)-13, a novel acid-catalyzed reorganization-equilibration of ortho ester (-)-11, and Mitsunobu macrolide cyclization.
- Smith III, Amos B.,Leahy, James W.,Noda, Ichio,Remiszewski, Stacy W.,Liverton, Nigel J.,Zibuck, Regina
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p. 2995 - 3007
(2007/10/02)
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- Total Synthesis of (+)-Latrunculin A
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The total synthesis of (+)-latrunculin A (1) has been achieved by a highly convergent and stereocontrolled route (longest linear sequence, 17 steps).
- Smith, Amos B.,Noda, Ichio,Remiszewski, Stacy W.,Liverton, Nigel J.,Zibuck, Regina
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p. 3977 - 3979
(2007/10/02)
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