Strain-Promoted 1,3-Dithiolium-4-olates-Alkyne Cycloaddition.

Reported here is the reactivity of mesoionic 1,3-dithiolium-4-olates towards strained alkynes, leading to thiophene cycloaddition products. In the process, the potential of these dipoles towards orthogonal reaction with azides, allowing efficient double ligation reactions, was discovered. A versatile process to access benzo[c]thiophenes, in an unprecedented divergent fashion, was developed and provides a new entry to unconventional polyaromatic thiophenes.

Sydnone-based turn-on fluorogenic probes for no-wash protein labeling and in-cell imaging.

We report the synthesis and use of sydnone-based profluorophores as tools for imaging applications. These new probes display exquisite reactivity towards strain promoted cycloaddition reactions with cycloalkynes allowing fast, efficient and selective labeling in biological media. Styryl-pyridinium sydnone probes were found particularly interesting for click reactions to proceed selectively inside cells.

Total Synthesis of Thailanstatin A.

The total synthesis of the spliceosome inhibitor thailanstatin A has been achieved in a longest linear sequence of nine steps from readily available starting materials. A key feature of the developed synthetic strategy is the implementation of a unique, biomimetic asymmetric intramolecular oxa-Michael reaction/hydrogenation sequence that allows diastereodivergent access to highly functionalized tetrahydropyrans, which can be used for the synthesis of designed analogues of this bioactive molecule.

Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations.

From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.

Total synthesis of myceliothermophins†C, D, and E.

The total synthesis of cytotoxic polyketides myceliothermophins E (1), C (2), and D (3) through a cascade-based cyclization to form the trans-fused decalin system is described. The convergent synthesis delivered all three natural products through late-stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X-ray crystallographic analysis, which revealed an interesting dimeric structure between its enantiomeric forms.

Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A.

A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichlorohydrin and (R)-2,3-O-isopropylidene glyceraldehyde, respectively.

Iodocyclization and Prins-type macrocyclization: an efficient formal synthesis of leucascandrolide A.

The formal total synthesis of leucascandrolide A has been achieved in 20 steps from a known epoxide with an overall yield of 11.5% following a recently developed strategy for the construction of trans-2,6-disubstituted-3,4-dihydropyrans and a Lewis acid catalyzed intramolecular Prins-cyclization of an aldehydic homoallylic alcohol to generate the tetrahydropyran ring with three stereogenic centers and macrocycle concomitantly.