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)(Me₂C₆H₃)N]₃Mo (37) as precatalyst activated in situ with CH₂Cl₂, 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)₃WCΞCMe₃] (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[BOND]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

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

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Selektives Binden von Actin ist die auffälligste biochemische Eigenschaft des seltenen marinen Naturstoffs Latrunculin A (siehe Formel). Moderne metallkatalysierte C‐C‐Bindungsbildungen, darunter eine Enin‐In‐Ringschlussmetathese (in Rot wiedergegeben), eröffnen nun einen bequemen, flexiblen und produktiven Zugang zu diesem wichtigen Sondenmolekül für die chemische Biologie.

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