On the Chemistry of Latrunculins A and B

Blasberger, D.; Carmely, S.; Kashman, Yoel; Cojocaru, Miriam; Spector, Ilan; Shochet, Nava R.

doi:10.1002/jlac.198919890289

Cited by 27 publications

(50 citation statements)

References 13 publications

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“…[5, 42,59] In line with the results discussed above, it is reasonable to assume that this cleavage is en- thalpically driven by relief of the 1,3-transannular interaction between the anomeric -OH group and the lactone moiety on the tetrahydropyran ring.…”

Section: A Novel Degradation Pathwaymentioning

confidence: 73%

“…[42] It is assumed that hemiacetal 30 with an axially oriented -OH group at C13 (Lat-B numbering) is predisposed to eliminate H 2 O to relieve the strain resulting from the unfavorable 1,3-transannular interaction with the anomeric hydroxyl group. The loss of a second molecule of H 2 O will then rapidly ensue under the acidic conditions due to the stabilized character of the incipient oxocarbenium cation 32.…”

Section: Resultsmentioning

confidence: 99%

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Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Fürstner

Souza

Turet

et al. 2006

Chemistry A European J

125

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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)(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

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Section: A Novel Degradation Pathwaymentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Fürstner

Souza

Turet

et al. 2006

Chemistry A European J

125

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“…Whereas essentially all post facto chemical derivatizations of latrunculin A or B reported in the literature led to a complete loss of the actin-binding capacity of these marine natural products (24)(25)(26), a series of fully functional synthetic analogues is now presented, some members of which even surpass the natural lead compounds in terms of bioactivity. Because none of the synthetic analogues is available from the natural products without unreasonable effort, this study highlights the enabling power of the concept of ''total synthesis-driven'' searches for SAR profiles of complex bioactive molecules.…”

Section: Resultsmentioning

confidence: 99%

“…Despite these truly remarkable physiological properties of the latrunculins and their widespread use as biochemical tools, the present understanding of the structure͞activity relationship (SAR) of these exquisite actin binders is fairly limited (24)(25)(26). While derivatizations of the natural products showed that a free hemiacetal moiety at C.17 (Lat-A numbering) and an unprotected N-atom of the thiazolidinone ring are pivotal for eliciting a biological response, ʈ a more detailed mapping of the SAR is warranted.…”

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confidence: 99%

Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

Fürstner

Kirk

Fenster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Two largely catalysis-based and highly convergent total syntheses of latrunculin A (1) and B (2) were diverted to the preparation of a focused library of analogues of these potent actin-binding macrolides that enjoy widespread use in chemical biology. Because the chosen route allows for structural variations of all characteristic parts of the natural leads, it was possible to map the previously largely unknown structure͞activity profile of this class of bioactive natural products. This led to the discovery that the removal of the methyl branches decorating the macrocycle in 2 engenders a significant increase in potency, while streamlining the synthesis to a considerable extent. Moreover, compelling evidence is provided that the conspicuous 2-thiazolidinone ring present in all naturally occurring latrunculins may be an optimal but not an essential structural motif for actin binding because it can be replaced by an oxazolidinone moiety with only slight loss in efficacy. Likewise, the inversion of the absolute configuration of the chiral center at C.16 is well accommodated. From the purely chemical perspective, this investigation attests to the maturity of alkyne metathesis, a method that has received attention as efficient means for the formation of macrocycles only recently.alkyne metathesis ͉ natural products

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“…[4,5] Despite the truly remarkable properties of the latrunculins and their widespread use as biochemical tools, the understanding of the structure-activity relationships (SAR) of these exquisite actin binders is fairly limited. [6] As a first step towards a synthesis-driven mapping of the structural elements essential for biological activity, a concise total synthesis of latrunculin B (1) was devised which is flexible enough to allow structural variations at a later stage. This flexibility was ensured by disconnecting 1 into three simple building blocks (Scheme 1) that are easy to modify and can be efficiently assembled through aldol chemistry, esterification, and formation of the macrocycle by the novel ring-closing alkyne metathesis (RCAM)/Lindlar reduction manifold.…”

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confidence: 99%