An Expeditious Synthesis of the C(38)−C(54) Halichondrin B Subunit

Synthesis of a C(22)−C(34) Halichondrin B Precursor via Ring Opening−Double Ring Closing Metathesis

“…The synthesis of bis(dihydropyran) 1 was therefore achieved in six steps and 35% overall yield from meso diol 4 . This supplants our previous conversion of 4 to 1 , 3g,i which required 11 steps and proceeded in 14% overall yield. Moreover, the new route is operationally much simpler and serves to further validate the powerful synthetic utility of alkene metathesis.…”

“…As before, 3g,i the synthesis of 1 began with meso -2-cyclopentene-1,4-diol ( 4 ) (Scheme 1) . Although 5 could be formed in a single step by bis( O -alkylation) of 4 with (4 S )-3-(bromoacetyl)-4-isopropyl-2-oxazolidinone (e.g., Ag 2 O, acetone, 50 °C, 2 days, 47%), these and a variety of other reaction conditions gave only low conversion and forced us to employ an alternative.…”

“…It is a tubulin-interactive antimitotic agent that displays an in vitro IC 50 value of 0.3 nM against L1210 leukemia and potent in vivo activities against various chemoresistant human solid tumor xenografts . On the basis of these data, halichondrin B has been recommended by the National Cancer Institute for stage A preclinical development. 2c,d The structural complexity, biological activity, and scarcity of this natural product have stimulated several synthetic efforts, including a total synthesis by Kishi et al3d…”

Synthetic Efforts toward the C22−C36 Subunit of Halichondrin B Utilizing Local and Imposed Symmetry

“…Kishi 4,5 has published the only total synthesis of halichondrin B to date and Yonemitsu 6 and Salomon 7 have each published subunit syntheses. We have completed the synthesis of the C1−C14, C14−C21, and C37−C54 subunits, and in this Letter we describe a route to the remaining C22−C36 subunit of halichondrin B.…”

Formal Synthesis of Uvaricin via Palladium-Mediated Double Cyclization

“…Two-directional synthesis by simultaneous chain homologation and terminus differentiation 4 has been one of our main strategies in the synthesis of complex natural products . It offers not only the intrinsic efficiency in skeleton synthesis but also the possibility of higher enantio- and diastereoselectivity.…”