SignificanceOnchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Current control efforts are hindered by the lack of a safe macrofilaricidal drug that can eliminate the parasitic adult nematodes safely. A clinically validated approach for delivering macrofilaricidal activity is to target the Wolbachia bacterial endosymbiont of the causative nematodes. This first-in-class and highly potent and specific anti-Wolbachia preclinical candidate molecule, AWZ1066S, has the potential to significantly impact current global onchocerciasis and lymphatic filariasis elimination programs and reduce elimination time frames from decades to years.

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[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.

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Multikilogram manufacturing process of the Halaven ® C14-C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment. Halaven ® (1; E7389, INN eribulin mesylate) is a fully synthetic analogue of the structurally complex marine natural product halichondrin B. 1 Eribulin has been recently approved by the FDA for the treatment of certain patients with metastatic breast cancer. 2,3 The Halaven ® C14-C35 fragment 2 constitutes a major structural element of 1, in which 10 of the 19 stereogenic centers contained in Halaven ® are incorporated. 4 The overall approach toward 2 mirrors that used by Kishi and co-workers to construct the halichondrin C14-C38 fragment: 3a Namely, Ni(II)/Cr(II)-mediated coupling (Nozaki-Hiyama-Kishi reaction) of the C27-C35 aldehyde 3 and the sulfonate-containing nucleophile 4 followed by Williamson cyclic etherification was anticipated to form the pyran-containing C14-C35 subunit (Scheme 1). 5 The conciseness of this approach and the functional-group tolerance of the Ni/Cr process were attractive features for future manufacturing. Nevertheless, there were concerns about scaling up the overall process due to the somewhat labile nature of the C23 sulfonate substrate 4 and the fact that a Ni/Cr coupling had not previously been demonstrated on kilogram scale in fixed equipment. At the same time, we considered that in principle a similar strategy could be employed to construct the tetrahydrofuran-containing C14-C26 subunit. A strategic advantage of utilizing a Ni/Cr C19-C20 coupling-cyclic etherification sequence for the preparation of 4 would be the opportunity to demonstrate the feasibility of the Nozaki-Hiyama-Kishi reaction in fixed equipment on a much less costly and presumably more stabile system. Thus, establishment of a firm foundation for the overall synthesis of eribulin which used not only a C26-C27 Ni/Cr-mediated coupling, but also a later-stage C13-C14 Ni/Cr-mediated macrocyclization could be accomplished by carefully studying and then demonstrating the viability of C19-C20 Ni/Cr 'model system' on kilogram scale in our pilot plant.