Eisai R&d Management Co., Ltd.

Harvard College

Prism Pharma Co., Ltd.

Kentaro Iso

Satoshi Inoue

Yoshito Kishi

Yuji Yamamoto

Kenzo Yahata

Takashi Fukuyama

Isao Ohashi

Ning Ye

Yanran Ai

Qiaoyi Wang

Santhosh Reddy Naini

Shuji Yamashita

Jihoon Lee

The present invention provides methods for the synthesis of ketones involving a Ni/Zr-mediated coupling reaction. The Ni/Zr-mediated ketolization reactions can be used in the synthesis of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C), and analogs thereof. Therefore, the present invention also provides synthetic methods useful for the synthesis of halichondrins, and analogs thereof. Also provided herein are compounds (i.e., intermediates) useful in the synthesis of halichondrins, and analogs thereof. In particular, the present invention provides methods and compounds useful in the synthesis of compound of Formula (H3-A). 

Synthesis of halichondrins

A compound represented by formula (1) or pharmaceutically acceptable salt thereof: wherein Ris a Calkyl group; Rand Rare the same or different from each other and each is a hydrogen atom or a Calkyl group; X, Xand Xare the same or different from each other and each is a hydrogen atom or a halogen atom; and Xis a hydrogen atom or &#x2014;P(&#x2550;O)(OH)has a Wnt Pathway modulating activity.

(6S,9aS)-N-benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-({6-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound

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Tsukuba, Japan

Kentaro Iso