Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same

Patent metadata

Field	Value
Publication number	US-11214568-B2
Application number	US-201916657672-A
Country	US
Kind code	B2
Filing date	Oct 18, 2019
Priority date	Oct 18, 2018
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

Described here are transition metal-catalyzed enantioselective arylation and vinylation reactions of α-substituted lactams, such as γ-lactams. The use of various electrophiles and ligands are described, and result in the construction of α-quaternary centers in good yields (up to 91% yield) and high enantioselectivities (up to 97% ee).

First claim

The invention claimed is:

1. A compound of formula (III) or formula (IV):

wherein, as valence and stability permit,
R 21 is —C(O)aryl or —C(O)heteroaryl, each optionally substituted with alkoxy, alkyl, or haloalkyl;
R 22 is —C(O)OR 22a , —C(O)aryl, or —C(O)heteroaryl, wherein each of aryl and heteroaryl are optionally substituted with alkoxy, alkyl, or haloalkyl;
R 22a is C 1-6 alkyl, C 6-10 aryl, or C 5-9 heteroaryl, wherein each of aryl and heteroaryl are optionally substituted with alkoxy, alkyl, or haloalkyl;
R 23 is H, halogen, alkynyl, alkenyl, or C 1-6 alkyl, each optionally substituted with OH, cyano, alkoxy, aryloxy, acyl, alkoxycarbonyl, halogen, aryl, or —NHC(O)OR 23a ;
R 23a is C 1-6 alkyl, (C 6-10 aryl)alkyl, or (C 5-9 heteroaryl)alkyl;
R 24 is H or halogen; and
p is 1,
or
a compound of formula (E):

or a salt thereof,
wherein, as valence and stability permit,
R 23 is halogen, alkynyl, alkenyl, or C 1-6 alkyl, each optionally substituted with halogen, OH, cyano, alkoxy, aryloxy, alkoxycarbonyl, or —NHC(O)OR 23a ;
R 23a is C 1-6 alkyl; and
R 24 is H.

2. A compound selected from:

3. A method comprising preparing a compound of formula (IV):

by treating a compound of formula (III)

or a salt thereof,
with a Pd(0) catalyst and a ligand L under alkylation conditions,
wherein, as valence and stability permit,
R 21 is —C(O)aryl or —C(O)heteroaryl, optionally substituted with alkoxy, alkyl, or haloalkyl;
R 22 is —C(O)OR 22a , —C(O)aryl, or —C(O)heteroaryl, wherein each of aryl and heteroaryl is optionally substituted with alkoxy, alkyl, or haloalkyl;
R 22a is C 1-6 alkyl, C 6-10 aryl, or C 5-9 heteroaryl;
R 23 is H, halogen, alkynyl, alkenyl, or C 1-6 alkyl, each optionally substituted with cyano, OH, alkoxy, aryloxy, acyl, alkoxycarbonyl, halogen, aryl, or —NHC(O)OR 23a ;
R 23a is C 1-6 alkyl, (C 6-10 aryl)alkyl, or (C 5-9 heteroaryl)alkyl;
R 24 is H or halogen; and
p is 1.

4. The method of claim 3 , wherein:
the compound of formula (IV) is a compound of formula (IVb)

and
the compound of formula (III) is a compound of formula (IIIb)

or a salt thereof,
wherein, as valence and stability permit,
R 22 is —C(O)OR 22a ;
R 22a is C 1-6 alkyl;
R 23 is halogen, alkynyl, alkenyl, or C 1-6 alkyl, each optionally substituted with halogen, OH, cyano, alkoxy, aryloxy, alkoxycarbonyl, or —NHC(O)OR 23a ;
R 23a is C 1-6 alkyl; and
R 24 is H.

5. The method of claim 3 , wherein the Pd(0) catalyst is Pd(dmdba) 2 or Pd 2 (dmdba) 3 .

6. The method of claim 3 , wherein:
ligand L is an enantioenriched ferrocelane ligand, wherein the enantioenriched ferrocelane ligand is 1,1′-bis[(2S,5S)-2,5-diethyl-1-phospholanyl]ferrocene, 1,1′-bis[(2S,5S)-2,5-dimethyl-1-phospholanyl]ferrocene, or 1,1′-bis[(2S,5S)-2,5-diisopropyl-1-phospholanyl]ferrocene.

7. The method of claim 3 , wherein the ligand L is

8. The method of claim 4 , whereby the compound of formula (IVb) is enantioenriched.

9. The method of claim 4 , wherein a medicinal product is prepared.

10. The method of claim 9 , wherein preparing the medicinal product comprises:
treating the compound of formula (IVb)

with lithium hydroxide and subsequently with lithium aluminum hydride, to form a product of formula (A)

treating the compound of formula (A) with a compound of formula (B)

and subsequently with acetyl chloride in methanol, to form a product of formula (C)

treating the compound of formula (C) with a compound of formula (D)

to form a medicinal product of formula (E)

11. The method of claim 4 , wherein:
R 21 is Bz, An, or pCF 3 Bz;
R 22 is Boc; and
R 23 is CH 3 , CH 2 Ph, CH 2 CCl═CH 2 , F, CH 2 CCH, CH 2 CH 2 CO 2 CH 3 , CH 2 CH 2 CN, or CH 2 NHBoc.

12. The method of claim 4 , wherein the compound of formula (IIIb) is:

13. The method of claim 4 , wherein the compound of formula (IVb) is:

14. The method of claim 4 , wherein the compound of formula (IVb) is

Assignees

• California Inst Of Techn

Inventors

• Stoltz Brian M
• Sun Alexander W
• Hess Stephan N
• Jette Carina I
• Geibel Irina
• Bachman Shoshana
• Hayashi Masaki
• Shimizu Hideki
• Morgan Jeremy B
• Sakurai Shunya
• Sercel Zachary P

Classifications

• C07D243/08

  not condensed with other rings · CPC title

• C07D207/26

  2-Pyrrolidones · CPC title

• C07D241/08

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• C07D507/00

  Heterocyclic compounds containing a condensed beta-lactam ring system, not provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D505/00; Such ring systems being further condensed · CPC title

• C07D239/06

  having one double bond between ring members or between a ring member and a non-ring member · CPC title