Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity.

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy-directed ruthenium catalyzed trans-hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non-natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The "northern" allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.

Scalable synthesis and structural characterization of reversible KLK6 inhibitors.

Scalable asymmetric syntheses of two kallikrein-related protease 6 (KLK6) inhibitors are reported. The inhibitors are assembled by linking enantiomerically enriched fragments via amide bond formation, followed by conversion of a cyano group to an amidine. One fragment, an amine, was prepared using the Ellman auxiliary, and a lack of clarity in the literature regarding the stereochemical outcome of this reaction was solved via X-ray crystallographic analysis of two derivatives. Complexes of the inhibitors bound to human KLK6 were solved by X-ray crystallography, revealing the binding poses.

Correction: Scalable synthesis and structural characterization of reversible KLK6 inhibitors.

[This corrects the article DOI: 10.1039/D2RA04670A.].

Bioinspired Asymmetric Total Synthesis of Emeriones†A-C.

We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A-C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The anti-aldol side chain is made using a Paterson-aldol addition, and the epoxide of the dioxabicyclo[3.1.0]hexane side chain via ring-closure onto an oxidized acetal. Our work has enabled the structural revision of emerione C, and resulted in the synthesis of a "missing" family member, which we call emerione D. DFT calculations identified two methyl groups that govern torquoselectivity in the 8π/6π cascade.

Single or Paired? Structure and Reactivity of PNP-Chromium(II) Hydrides.

The preparation and reactivity of a range of novel paramagnetic chromium(II) complexes supported by a carbazole-based PNP pincer ligand is reported. Deprotonation of the ligand precursors R(PNP)H (1R) and subsequent reaction with chromium(II) chloride led to the formation of square-planar chlorido complexes R(PNP)CrCl (2R). Further reaction with various alkylating agents resulted in the isolation of chromium alkyl complexes R(PNP)CrR' (3R-R') which were then hydrogenated to yield two rare examples of paramagnetic chromium(II) hydrides 4iPr and 4tBu. Both compounds were characterized by X-ray diffraction and paramagnetic NMR spectroscopy supported by a comprehensive DFT-supported assignment of the resonances. While the di(tert-butyl)phosphino PNP substituted complex 4tBu was found to exhibit a monomeric square-planar molecular structure, its isopropyl-substituted analog 4iPr forms a dimer, also indicated by a strong antiferromagnetic coupling of the chromium centers. The pronounced reactivity of these compounds toward C═X double bonds was demonstrated by reaction with benzophenone, N,N'-dicyclohexylcarbodiimide, and carbon dioxide, which gave the corresponding insertion products. The alkoxido complex 5iPr, the amidinato complex 6iPr, and the formato compound 7tBu were also characterized by X-ray diffraction.