Total synthesis of prostaglandin J natural products and their intermediates

Patent metadata

Field	Value
Publication number	US-10995049-B2
Application number	US-202016922290-A
Country	US
Kind code	B2
Filing date	Jul 7, 2020
Priority date	Jul 19, 2019
Publication date	May 4, 2021
Grant date	May 4, 2021

Abstract

The present disclosure is directed to methods of preparing prostaglandin J natural products by stereoretentive metatheses reactions and intermediates used in the synthesis of these natural products, including the use of intermediates of Formula (I-A), where R 1 is defined in the specification

First claim

What is claimed:

1. A compound of Formula (I):

wherein: R 1 is one of (P-1), (P-2), (P-3), or (P-4)

R 2 is H or an alcohol protecting group; and
at least one carbon-carbon double bond has a Z/E-selectivity of 95/5 or higher.

2. The compound of claim 1 , having a structure of Formula (I-A) or (I-B):

and exhibiting an enantiomeric excess of 95% or higher.

3. A method of making a compound of Formula (I) of claim 1 by coupling an allyl group and an ω-chain to a compound of Formula (II),

the method comprising adding to the compound of Formula (II):
(a) an organocopper allyl source and
(b) an aldehyde of Formula (O-1), (O-2), (O-3), or (O-4), respectively:

the reaction of the coupling of the compound of Formula (II), organocopper allyl source, and the aldehyde resulting in the formation of an aldol intermediate; and then
(c) oxidizing the aldol intermediate to form the compound of Formula (I) of claim 1 .

4. The method of claim 3 , wherein the compound Formula (II) has a structure of:

that exhibits an enantiomeric excess of 95% or higher, wherein the method results in the formation of a compound having a structure of Formula (I-A) or (I-B):

that exhibits an enantiomeric excess of 95% or higher.

5. The method of claim 4 , wherein the compound of Formula (I-A) or (I-B) has an enantiomeric purity corresponding to that of the compound of Formula (II-A) or (II-B), respectively.

6. The method of claim 4 , wherein the organocopper allyl source is derived from the admixture of a copper halide and an allyl Grignard reagent, optionally in the presence of an alkyl sulfide and alkali metal halide.

7. The method of claim 4 , wherein oxidizing the aldol intermediate to the compound having a structure of Formula (I-A) or (I-B) comprises reacting the aldol intermediate with a sulfonylating agent and a base to form the compound of Formula (I-A) or (I-B).

8. A method of preparing a compound of Formula (VI-A) or Formula (VI-B):

wherein R 1 is one of (P-1), (P-2), (P-3), or (P-4)

and
R 1 is H or an alcohol protecting group;
the method comprising:
(a) subjecting a compound of Formula (I-A) or (I-B)

to conditions suitable for effecting a retro-Diels Alder reaction to form compounds corresponding to:

respectively.

9. The method of claim 8 , wherein the conditions suitable for effecting a retro-Diels Alder reaction comprise treating the compounds of Formula (I-A) and (IB) with a Lewis acid catalyst in the optional presence of an olefin.

10. The method of claim 8 further comprising:
(b) reacting the compound of Formula (III-A) or (III-B) with a compound of Formula (ZO-1), or (ZO-2), in the presence of a Z-selective or stereoretentive olefin metathesis catalyst:

where R 3 is H or a C 1-3 alkyl;
R 4 is CH 2 —OR 2 , an optionally protected carboxylato (—COOH), optionally protected aldehyde (—CHO), or a cyano (—CN);

under conditions effective to cross-metathesize the compound of compound (I-A) or (I-B) with the compound of Formula (IV) to form a compound of Formula (IV-A) or (IV-B)

11. The method of claim 10 , wherein the Z-selective or stereoretentive olefin metathesis catalyst is a Grubbs metathesis catalyst.

12. The method of claim 10 further comprising:
(c) subjecting the compound of Formula (IVA) or Formula (IV-B) to conditions sufficient to convert R 4 to a carboxylic acid group, —COOH to form the compounds of Formula (VI-A) or (VI-B), respectively

Assignees

• California Inst Of Techn

Inventors

• Li Jiaming
• Xu Chen
• Ahmed Tonia S
• Grubbs Robert H
• Stoltz Brian M

Classifications

• C07C49/577

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C405/00

  Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins {; Analogues or derivatives thereof} · CPC title

• C07C45/72

  by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups · CPC title

• C07C49/557

  having unsaturation outside the rings · CPC title

• C07C45/29 Primary

  of hydroxy groups · CPC title