Palladium-mediated ketolization
AssigneePresident and Fellows of Harvard College
InventorsJung Hwa Lee, Yoshito Kishi, Ayumi Osawa, Zhanjie Li
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Abstract
Provided herein are palladium-mediated coupling reactions useful in the preparation of ketone-containing organic molecules. The provided methods can be used for the preparation of natural products and pharmaceutical agents, including Eribulin, halichondrins, and analogs thereof. The present invention also provides novel halichondrin analogs which can be prepared via the palladium-mediated coupling reactions. The novel halichondrin analogs can be used in the prevention and/or treatment of diseases or conditions (e.g., proliferative diseases such as cancer).
Claims30
1-111. (canceled)
A compound of Formula (HH-1):
- or a pharmaceutically acceptable salt thereof, wherein:
- RP5 and RP6 are independently hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- each instance of R4 is independently hydrogen, halogen, optionally substituted alkyl, or two R4 groups are taken together to form:
- each instance of R6 is independently hydrogen, halogen, optionally substituted alkyl, or two R6 groups are taken together to form:
- R5, R8, R9, and R10 are hydrogen, halogen, or optionally substituted alkyl;
- RX is hydrogen or —ORXa, wherein RXa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- and
- RY is hydrogen or —ORYa, wherein RYa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- optionally wherein RXa and RYa are joined together with their intervening atoms to form optionally substituted heterocyclyl;
- and
- optionally wherein RP5 and RP6 are joined together with the intervening atoms to form optionally substituted heterocyclyl.
114-144. (canceled)
150-153. (canceled)
156-159. (canceled)
(canceled)
169-174. (canceled)
A method of preparing a compound of Formula (H-2), or a salt thereof, the method comprising reacting a compound Formula (H-3):
- or salt thereof, in the presence of palladium, zinc, and a single electron transfer initiator to yield a compound of Formula (H-2):
- or a salt thereof, wherein:
- X1 is halogen or a leaving group;
- R1 is optionally substituted alkyl;
- RP1 is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- each instance of R4 is independently hydrogen, halogen, optionally substituted alkyl, or two R4 groups are taken together to form:
- each instance of R6 is independently hydrogen, halogen, optionally substituted alkyl, or two R6 groups are taken together to form:
- R5 is hydrogen, halogen, or optionally substituted alkyl;
- R7 is —CH2OR7a, —CO2R7a, or —C(O)H;
- R8 is hydrogen, halogen, or optionally substituted alkyl;
- RX is hydrogen or —ORXa, wherein RXa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- and
- RY is hydrogen or —ORYa, wherein RYa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- optionally wherein RXa and RYa are joined together with their intervening atoms to form optionally substituted heterocyclyl;
- and
- optionally wherein RP1 and R7a are taken together with the intervening atoms to form optionally substituted heterocyclyl.
A compound of Formula (H-2):
- or a salt thereof, wherein:
- RP1 is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- each instance of R4 is independently hydrogen, halogen, optionally substituted alkyl, or two R4 groups are taken together to form:
- each instance of R6 is independently hydrogen, halogen, optionally substituted alkyl, or two R6 groups are taken together to form:
- R5 is hydrogen, halogen, or optionally substituted alkyl;
- R7 is —CH2OR7a, —CO2R7a, or —C(O)H;
- R8 is hydrogen, halogen, or optionally substituted alkyl;
- RX is hydrogen or —ORXa, wherein RXa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- and
- RY is hydrogen or —ORYa, wherein RYa is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
- optionally wherein RXa and RYa are joined together with their intervening atoms to form optionally substituted heterocyclyl;
- and
- optionally wherein R7a and RP1 are joined together with the intervening atoms to form optionally substituted heterocyclyl.
Dependencies are inferred from the claim text.