Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

Abstract

Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80-90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]-spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right-half precursor.

A landmark in drug discovery based on complex natural product synthesis

“…These developments have been incorporated to this project. Thus, C52-halichondrin-B alcohol (E7130 precursor) was synthesized from the left and right halves via a C37-C38 bond formation in the new synthesis 14–16 , whereas the previous synthesis used a C38-C39 bond formation as a key step 13 (Fig. 1b, and the relevant parts of E7130 synthesis are paragraph numbers [00868]-[00909] in WO2019/010363 and paragraph numbers [00387]-[00417], [00428]-[00432] and [00544]-[00547] in WO2016/176560).…”

“…Third, a practical and scalable synthesis was developed by selecting the appropriate coupling conditions for four catalytic, asymmetric Ni/Cr-mediated coupling reactions as well as for other transformations 17 . Overall, we successfully synthesized 19.5 g of C52-halichondrin-B alcohol with 99.84% purity via a total synthesis 14 . From 15.0 g of this material, we obtained 11.5 g of E7130 with 99.81% purity, and the material was isolated by reverse-phase medium-pressure chromatography (Fig.…”

Marine natural products

“…In addition, the X-ray structure of halichondrin C was solved during this epic process. 518 A chemo-ecological study explored chemical defence strategies within the "symbiotic" two sponge association between Xestospongia deweerdtae and Plakortis simplex. The feeding deterrent activity of extracts of each sponge was measured against three common coral reef predator sh species.…”

Metal‐Catalyzed Synthesis and Use of Thioesters: Recent Developments

“…However, (super‐)stoichiometric amounts of Pd, ligand and additives were required for attaining an acceptable yield . Other catalytic (Fe, Ni) variants of this cross‐electrophile coupling have been published by Kishi using S ‐(2‐pyridyl)thioesters and subsequently applied in the total synthesis to some members of the halichondrin natural product series …”

“…[63] Other catalytic (Fe, Ni)v ariants of this cross-electrophile coupling have been published by Kishi using S-(2-pyridyl)thioesters [64] and subsequently applied in the total synthesis to some members of the halichondrin natural product series. [65] Another milestone in this area is the Liebeskind-Srogl coupling, which was disclosed in 2000 (Scheme 19). [66] Here, aryl boronic acids were employed to render the transformation especially facile with respectt ot he stoichiometricc ouplingp artner.Inthis case however,Pd ÀSbond activation in the transmetalation (or maybe CÀSa ctivation in the oxidative addition) step must be facilitated by an additional stoichiometric Cu I source ( 39).…”