Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of “latrunculin‐like” compounds, in which all characteristic structural elements of these macrolides were subject to pertinent molecular editing. Although all previously reported derivatives of 1 and 2 were essentially devoid of any actin‐binding capacity, the synthetic compounds presented herein remain fully functional. One of the designer molecules with a relaxed macrocyclic backbone, that is compound 44, even surpasses latrunculin B in its effect on actin while being much easier to prepare. This favorable result highlights the power of “diverted total synthesis” as compared to the much more widely practiced chemical modification of a given lead compound by conventional functional group interconversion. A computational study was carried out to rationalize the observed effects. The analysis of the structure of the binding site occupied by the individual ligands on the G‐actin host shows that latrunculin A and 44 both have similar hydrogen‐bond network strengths and present similar ligand distortion. In contrast, the H‐bond network is weaker for latrunculin B and the distortion of the ligand from its optimum geometry is larger. From this, one may expect that the binding ability follows the order 1 ≥ 44 > 2, which is in accord with the experimental data. Furthermore, the biological results provide detailed insights into structure/activity relationships characteristic for the latrunculin family. Thus, it is demonstrated that the highly conserved thiazolidinone ring of the natural products can be replaced by an oxazolidinone moiety, and that inversion of the configuration at C16 (latrunculin B numbering) is also well accommodated. From a purely chemical perspective, this study attests to the maturity of ring‐closing alkyne metathesis (RCAM) catalyzed by a molybdenum alkylidyne complex generated in situ, which constitutes a valuable tool for advanced organic synthesis and natural product chemistry.

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

The viability of bridgehead lithiation-substitution of bridged carbonyl compounds has been tested in the laboratory, and the results were rationalized with the aid of a computational study. Lithiation-substitution was found to be possible for ketones, lactones, lactams, and imides having small bridges, including examples having [3.2.1], [3.2.2], [3.3.1], [4.2.1], and [4.3.1] skeletons. Smaller systems, where the sum of the bridging atoms (S) was 5, for example [2.2.1] or [3.1.1] ketones or [2.2.1] lactams, did not undergo controlled bridgehead substitution. Ketones or lactams having a [2.2.2] structure also did not give bridgehead substitution. B3LYP calculations accurately predict this behavior with negative DeltaE(rxn) values being calculated for the successful deprotonations and positive DeltaE(rxn) values being calculated for the unsuccessful ones. NBO calculations were also performed on the anionic deprotonated species, and these show that some structures are best represented as bridgehead enolates and some are best represented as alpha-keto carbanions.

[reaction: see text] Contrary to expectations, a number of bridged carbonyl compounds undergo facile bridgehead metalation with lithium amide bases. Diketone, lactone, lactam, and imide functions are all demonstrated to participate in this type of "bridgehead enolate" chemistry, leading to a range of substituted products. Meso compounds can also be desymmetrized in very high ee by asymmetric bridgehead metalation.