The first total synthesis of ipomoeassin F was carried out using a convergent approach that relied upon the use of Schmidt glycosidation technology for the coupling of two suitably protected monosaccharide fragments. After two steps, ring-closing metathesis was used to form the macrocyclic ring, and seven more steps then furnished ipomoeassin F. In vitro inhibitory activity against a four-panel cell line showed low nanomolar inhibitory activity.

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.

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