Highly efficient synthesis of z-macrocycles using stereoretentive, ruthenium-based metathesis catalysts

Patent metadata

Field	Value
Publication number	US-11053209-B2
Application number	US-201816611329-A
Country	US
Kind code	B2
Filing date	Apr 24, 2018
Priority date	May 8, 2017
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

A highly efficient, Z-selective ring-closing metathesis system for the formation of macrocycles using a stereoretentive, ruthenium-based catalyst supported by a dithiolate ligand is reported. This catalyst is demonstrated to be remarkably active as observed in initiation experiments showing complete catalyst initiation at −20° C. within 10 min. Using easily accessible diene starting materials bearing a Z-olefin moiety, macrocyclization reactions generated products with significantly higher Z-selectivity in appreciably shorter reaction times, in higher yield, and with much lower catalyst loadings than in previously reported systems. Macrocyclic lactones ranging in size from twelve-membered to seventeen-membered rings are synthesized in moderate to high yields (68-79% yield) with excellent Z-selectivity (95%-99% Z).

First claim

What is claimed is:

1. A method for producing at least one Z-macrocyclic product represented by Formula (VI):

wherein:
n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VI) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):

wherein:
R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; and m is 4, 5, 6, or 7;
to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):

wherein:
R is iso-propyl and R 0 is nil;
R 1 , R 5 , R 6 , and R 10 , are iso-propyl;
R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are H;
R 15 , R 16 , R 17 , and R 18 are H;
X 2 and X 3 are H;
X 1 and X 4 are chloro; and
Y is oxygen.

2. The method according to claim 1 , wherein:
R′ is methyl or ethyl;
n is 1, 3, or 4;
m is 6 or 7; and
the Z-macrocyclic product of Formula (VI) is a thirteen, fourteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95.

3. The method according to claim 1 , wherein:
R′ is methyl or ethyl;
n is 2;
m is 4 or 7; and
the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99.

4. The method according to claim 1 , wherein:
R′ is methyl or ethyl;
n is 1, 2, 3, or 4;
m is 4, 6 or 7; and
the Z-macrocyclic product of Formula (VI) is a thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95 or, in the case of a fifteen-membered ring, a Z-selectivity of 99.

5. The method according to claim 1 , wherein:
R′ is methyl;
n is 2;
m is 6; and
the Z-macrocyclic product of Formula (VI) is a fourteen-membered or a sixteen-membered ring with a Z-selectivity of 98.

6. The method according to claim 1 , wherein:
R′ is methyl or ethyl;
n is 2;
m is 4 or 7; and
the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99.

7. The method according to claim 1 , wherein:
R′ is ethyl;
n is 1;
m is 6; and
the Z-macrocyclic product of Formula (VI) is a thirteen-membered ring with a Z-selectivity of 95.

8. A method for producing at least one Z-macrocyclic product represented by Formula (VI):

comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):

to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):

wherein in Formulae (I):
R and R 0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano;
R 15 , R 16 , R 17 , and R 18 are independently H or methyl;
X 1 , X 2 , X 3 , and X 4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and
Y is oxygen, sulfur, nitrogen, or iodo,
and
wherein in Formulae (VI) and (III):
R′ is methyl or ethyl;
n is 1, 2, 3, or 4;
m is 4, 6, or 7; and
the Z-macrocyclic product of Formula (VI) is a thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95 or, in the case of a fifteen-membered ring, a Z-selectivity of 99;
or
R′ is methyl;
n is 2;
m is 6; and
the Z-macrocyclic product of Formula (VI) is a fourteen-membered or a sixteen-membered ring with a Z-selectivity of 98;
or
R′ is methyl or ethyl;
n is 2;
m is 4 or 7; and
the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99;
or
R′ is ethyl;
n is 1;
m is 6; and
the Z-macrocyclic product of Formula (VI) is a thirteen-membered ring with a Z-selectivity of 95.

9. A method for producing at least one Z-macrocyclic product represented by Formula (VI):

subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):

to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):

wherein in Formulae (VI), (III), and (I):
R′ is methyl;
n is 2;
m is 6;
the Z-macrocyclic product of Formula (VI) is a sixteen-membered ring with a Z-selectivity of 98, R is nil, iso-propyl, or butyl;
R 0 is nil;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, methyl, iso-propyl, or fluoro;
R 11 , R 12 , R 13 , and R 14 are H, phenyl, iso-propoxy, nitro, or dimethylaminosulfonate;
R 15 , R 16 , R 17 , and R 18 are H or methyl;
X 1 , X 2 , X 3 , and X 4 are H, fluoro, or chloro; and
Y is oxygen, sulfur, or iodo;
or
R′ is methyl or ethyl;
n is 2;
m is 4 or 7;
the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99;
R is nil, iso-propyl, or butyl;
R 0 is nil;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are H, methyl, iso-propyl, or fluoro;
R 11 , R 12 , R 13 , and R 14 are independently H, phenyl, iso-propoxy, nitro, or dimethylaminosulfonate;
R 15 , R 16 , R 17 , and R 18 are H or methyl;
X 1 , X 2 , X 3 , and X 4 are H, fluoro, or chloro; and
Y is oxygen, sulfur, or iodo.

10. A method for producing at least one Z-macrocyclic product represented by Formula (VI):

comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):

to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):

wherein in Formulae (VI), (III), and (I):
R is iso-propyl;

Assignees

• California Inst Of Techn

Inventors

• Ahmed Tonia S
• Grubbs Robert H

Classifications

• C08F132/08

  having condensed rings · CPC title

• B01J31/226

  Sulfur, e.g. thiocarbamates · CPC title

• B01J31/181

  Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine · CPC title

• B01J2231/543

  alkene metathesis · CPC title

• B01J2540/225

  comprising perfluoroalkyl groups or moieties · CPC title