Synthesis of halichondrins

Patent metadata

Field	Value
Publication number	US-11548898-B2
Application number	US-201816628504-A
Country	US
Kind code	B2
Filing date	Jul 6, 2018
Priority date	Jul 6, 2017
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

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).

First claim

What is claimed is:

1. A method of preparing a compound of Formula (H3-A):

or a salt thereof, the method comprising reducing a compound of Formula (H3-N3):

or a salt thereof, wherein:
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:

each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or

two R 6 groups are taken together to form:
R P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
optionally wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.

2. The method of claim 1 further comprising a step of reacting a compound of Formula (H3-L):

or a salt thereof, in the presence of an azide, to yield a compound of Formula (H3-N3):

or a salt thereof, wherein:
R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl;
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:

each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:

R P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
optionally wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.

3. The method of claim 2 further comprising a step of reacting a compound of Formula (H3-OH):

or a salt thereof, in the presence of a reagent of the formula X L -R L , to yield a compound of Formula (H3-L):

or a salt thereof, wherein:
R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl;
X L is halogen or a leaving group;
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:

each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:

R P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
optionally wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.

4. A method of preparing Compound (1):

or a salt thereof, the method comprising reducing Compound (B):

or a salt thereof.

5. The method of claim 4 further comprising a step of reacting a compound of Formula (A):

or a salt thereof, in the presence of an azide, to yield Compound (B):

or a salt thereof, wherein:
R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl.

6. The method of claim 5 further comprising a step of reacting Compound (2):

or a salt thereof, in the presence of a reagent of the formula X L -R L , to yield a compound of Formula (A):

or a salt thereof, wherein:
X L is halogen or a leaving group; and
R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl.

7. The method of claim 1 , wherein the step of reducing is carried out in the presence of:
(i) palladium and H2;
(ii) a hydride source; or
(iii) a phosphine reagent.

8. The method of claim 1 , wherein the step of reducing is carried out in the presence of a phosphine reagent.

9. The method of claim 8 , wherein the phosphine reagent is a trialkylphosphine or triarylphosphine.

10. The method of claim 8 , wherein the phosphine reagent is triphenylphosphine (Ph 3 P).

11. The method of claim 8 , wherein the phosphine reagent is polymer-bound triphenylphosphine (Ph 3 P).

12. The method of claim 8 , wherein at least one equivalent of the phosphine reagent is present with respect to the compound of Formula (H3-N3) or salt thereof.

13. The method of claim 8 , wherein the step of reducing is carried out in the presence of water.

14. The method of claim 1 , wherein the step of reducing is carried out in tetrahydrofuran (THF).

15. The method of claim 1 , wherein the compound of Formula (H3-A), or salt thereof, is purified and

Assignees

• Harvard College
• Eisai R&D Man Co Ltd

Inventors

• Kishi Yoshito
• Ai Yanran
• Ye Ning
• Wang Qiaoyi
• Yahata Kenzo
• ISO Kentaro
• Naini Santhosh Reddy
• Yamashita Shuji
• Lee Jihoon
• Ohashi Isao
• Fukuyama Takashi

Classifications

• C07D493/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title