Catalysis-Based Total Synthesis of Putative Mandelalide A

A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A (1) is disclosed. Specifically, an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal-acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11-epi-1 deviate from those of the natural product, which implies a subtle but deep-seated error in the original structure assignment

Divergent Total Synthesis of the Antimitotic Agent Leiodermatolide

Subtle but distinctive: The stereostructure of the biologically highly promising antimitotic agent leiodermatolide was uncertain. A short, efficient, and flexible total synthesis based on ring-closing alkyne metathesis as the key step has now solved the puzzle. Subtle differences in the 1H NMR spectra of the structure shown and the conceivable isomer proved invaluable for the assignment

Grothendieck-Teichm\"uller and Batalin-Vilkovisky

It is proven that, for any affine supermanifold $M$ equipped with a constant odd symplectic structure, there is a universal action (up to homotopy) of the Grothendieck-Teichm\"uller Lie algebra $\mathfrak{grt}_1$ on the set of quantum BV structures (i. e.\ solutions of the quantum master equation) on $M$

Lower limb joint kinetics during the first stance phase in athletics sprinting: three elite athlete case-studies

This study analysed the first stance phase joint kinetics of three elite sprinters to improve the understanding of technique and investigate how individual differences in technique could influence the resulting levels of performance. Force (1000 Hz) and video (200 Hz) data were collected and resultant moments, power and work at the stance leg metatarsal-phalangeal (MTP), ankle, knee and hip joints were calculated. The MTP and ankle joints both exhibited resultant plantarflexor moments throughout stance. Whilst the ankle joint generated up to four times more energy than it absorbed, the MTP joint was primarily an energy absorber. Knee extensor resultant moments and power were produced throughout the majority of stance, and the best-performing sprinter generated double and four times the amount of knee joint energy compared to the other two sprinters. The hip joint extended throughout stance. Positive hip extensor energy was generated during early stance before energy was absorbed at the hip as the resultant moment became flexor-dominant towards toe-off. The generation of energy at the ankle appears to be of greater importance than in later phases of a sprint, whilst knee joint energy generation may be vital for early acceleration and is potentially facilitated by favourable kinematics at touchdown

Sprint start kinetics of amputee and non-amputee sprinters

The purpose of this study was to explore the relationship between the forces applied to the starting blocks and the start performances (SPs) of amputee sprinters (ASs) and non-amputee sprinters (NASs). SPs of 154 male and female NASs (100-m personal records [PRs], 9.58–14.00 s) and 7 male ASs (3 unilateral above knee, 3 unilateral below knee, 1 bilateral below knee; 100 m PRs, 11.70–12.70 s) with running specific prostheses (RSPs) were analysed during full-effort sprint starts using instrumented starting blocks that measured the applied forces in 3D. Using the NAS dataset and a combination of factor analysis and multiple regression techniques, we explored the relationship between force characteristics and SP (quantified by normalized average horizontal block power). Start kinetics were subsequently compared between ASs and NASs who were matched based on their absolute 100 m PR and their 100 m PR relative to the world record in their starting class. In NASs, 86% of the variance in SP was shared with five latent factors on which measured parameters related to force application to the rear and front blocks and the respective push-off directions in the sagittal plane of motion were loaded. Mediolateral force application had little influence on SP. The SP of ASs was significantly reduced compared to that of NASs matched on the basis of relative 100-m PR (−33.8%; d = 2.11, p < 0.001), while a non-significant performance reduction was observed when absolute 100-m PRs were used (−17.7%; d = 0.79, p = 0.09). These results are at least partially explained by the fact that force application to the rear block was clearly impaired in the affected legs of ASs

Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Mandelalide A and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure 1 as the purported representation of mandelalide A. The sequence involves an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal acetylene metathesis into natural product total synthesis, which is remarkable in that this class of substrates had been beyond the reach of alkyne metathesis for decades. Synthetic 1, however, proved not to be identical with the natural product. In an attempt to clarify this issue, NMR spectra were simulated for 20 conceivable diastereomers by using DFT followed by DP4 analysis; however, this did not provide a reliable assignment either. The puzzle was ultimately solved by the preparation of three diastereomers, of which compound 6 proved identical with mandelalide A in all analytical and spectroscopic regards. As the entire “northern sector” about the tetrahydrofuran ring in 6 shows the opposite configuration of what had originally been assigned, it is highly likely that the stereostructures of the sister compounds mandelalides B–D must be corrected analogously; we propose that these natural products are accurately represented by structures 68–70. In an attempt to prove this reassignment, an entry into mandelalides C and D was sought by subjecting an advanced intermediate of the synthesis of 6 to a largely unprecedented intramolecular Morita–Baylis–Hillman reaction, which furnished the γ-lactone derivative 74 as a mixture of diastereomers. Whereas (24R)-74 was amenable to a hydroxyl-directed dihydroxylation by using OsO4/TMEDA as the reagent, the sister compound (24S)-74 did not follow a directed path but simply obeyed Kishi’s rule; only this unexpected escape precluded the preparation of mandelalides C and D by this route. A combined spectroscopic and computational (DFT) study showed that the reasons for this strikingly different behavior of the two diastereomers of 74 are rooted in their conformational peculiarities. This aspect apart, our results show that the OsO4/TMEDA complex reacts preferentially with electron deficient double bonds even if other alkenes are present that are more electron rich and less encumbered. Finally, in a brief biological survey authentic mandelalide A (6) was found to exhibit appreciable cytotoxicity only against one out of three tested human cancer cell lines and all synthetic congeners were hardly active. No significant fungicidal properties were observed