Processes for the synthesis of chiral 1-alkanols

Patent metadata

Field	Value
Publication number	US-10000432-B2
Application number	US-201515111449-A
Country	US
Kind code	B2
Filing date	Jan 9, 2015
Priority date	Jan 13, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

The invention relates to highly enantioselective processes for the synthesis of chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes.

First claim

What is claimed is:

1. A process of preparing a compound of formula I,

wherein
R 1 is alkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, or aryl-alkyl;
R 2 is H, D, CD 3 , CH 2 CD 3 , CD 2 CH 3 , CD 2 CD 3 , alkyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, or heteroaryl, wherein each of alkyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, and heteroaryl is optionally mono- or polysubstituted with substituents independently selected from halo, O-alkyl, cyano, amino, nitro, COOMe, and COOEt; and
n is an integer selected from 2-8

the process comprising treating a compound of formula (IV) having a high enantiomeric purity of ee≥99%:

wherein X is OR x , R x is a protective group, and Z is H or a protective group; under a reduction condition or a cross-coupling condition to prepare said compound of formula (I), wherein said compound of formula (I) has a high enantiomeric purity (ee≥99%).

2. The process of claim 1 , wherein said compound of formula (IV) is prepared by
(a) treating a compound of formula (III)

under a Zr-catalyzed asymmetric carboalumination condition to prepare intermediate (I);
(b) treating said intermediate (I) with a reagent to prepare said compound of formula (IV) having a low enantiomeric purity of ee<99%; and
(c) purifying the compound of formula (IV) having a low enantiomeric purity under a lipase-catalyzed acetylation reaction condition to prepare said compound of formula (IV) having a high enantiomeric purity of ee≥99%; wherein Z and n in formula (III) have the same meanings as in claim 1 .

3. The process of claim 1 , wherein said reduction condition comprises LiAlH 4 .

4. The process of claim 1 , wherein said cross-coupling condition is a Cu-, Ni-, or Pd-catalyzed cross-coupling reaction.

5. A process of preparing a compound of formula (I),

wherein
R 1 is alkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, or aryl-alkyl;
R 2 is H, D, CD 3 , CH 2 CD 3 , CD 2 CH 3 , CD 2 CD 3 , allyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, or heteroaryl, wherein each of alkyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, and heteroaryl is optionally mono- or polysubstituted with substituents independently selected from halo, O-alkyl, cyano, amino, nitro, COOMe, and COOEt; and
n is an integer selected from 2-8
the process comprising
(a) treating a compound of formula (III)

where n and Z have the same meanings as for formula (I);
under a Zr-catalyzed asymmetric carboalumination condition to prepare intermediate (I);
(b) treating said intermediate (I) with a reagent to prepare said compound of formula (IV) having a low enantiomeric purity of ee<99%

wherein X is OR x wherein R x is a protective group; and Z is H or a protective group and wherein n and Z have the same meanings as for formula (I);
(c) purifying the compound of formula (IV) having said low enantiomeric purity under a lipase-catalyzed acetylation reaction condition to prepare a compound of formula (IV) having an enantiomeric excess of 99% or above; and
(d) treating said compound of formula (IV) having a high enantiomeric purity of ee≥99% under a reduction condition or a cross-coupling condition to prepare said compound of formula (I).

6. A process of preparing a compound of formula (II),

wherein
R 1 is alkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, or aryl-alkyl;
R 2 is H, D, CD 3 , CH 2 CD 3 , CD 2 CH 3 , CD 2 CD 3 , alkyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, or heteroaryl, wherein each of alkyl, cycloalkyl, cycloalkyl-alkyl, cyclo(hetero)alkyl-alkyl, aryl-alkyl, alkenyl, aryl, and heteroaryl is optionally mono- or polysubstituted with substituents independently selected from halo, O-alkyl, cyano, amino, nitro, COOMe, and COOEt;
and n is an integer selected from 2-8;

the process comprising treating a compound of formula (V) having a high enantiomeric purity of ee≥9%:

wherein X is OR x , R x is a protective group, and Z is H or a protective group and n is an integer selected from 2-8; under a reduction condition or a cross-coupling condition to prepare said compound of formula (II), wherein said compound of formula (H) has a high enantiomeric purity of ee≥99%.

7. The process of claim 6 , wherein said compound of formula (V) is prepared by
(a) treating a compound of formula (III)

where n and Z have the same meanings as for formula (V);
under a Zr-catalyzed asymmetric carboalumination condition to prepare intermediate (II);
(b) treating said intermediate (H) with a reagent to prepare said compound of formula (V) having a low enantiomeric purity of ee<99%; and
(c) purifying the compound of formula (V) having said low enantiomeric purity under a lipase-catalyzed acetylation reaction condition to prepare said compound of formula (V) having a high enantiomeric purity of ee≥99%.

8. The process of claim 6 , wherein said reduction condition comprises LiAlH 4 .

9. The process of claim 6 , wherein said cross-coupling condition is a Cu-, Ni-, or Pd-catalyzed cross-coupling reaction.

10. The process of claim 6 , wherein said cross-coupling condition is a Cu-catalyzed cross-coupling reaction with an alkylmagnesium halide reagent.

11. The process of claim 10 , wherein said cross-coupling condition comprises MeMgBr and Li 2 CuCl 4 .

12. The process of claim 10 , wherein said cross-coupling condition comprises EtMgCl, CuCl 2 , and 1-phenylpropyne.

13. The process of claim 6 , wherein said cross-coupling condition is a Pd-catalyzed Negishi coupling reaction condition.

14. The process of claim 13 , wherein said Pd-catalyzed Negishi coupling reaction condition comprises vinyl bromide and Pd(DPEphos)Cl 2 .

15. The process of claim 2 , wherein said Zr-catalyzed asymmetric carboalumination condition comprises a trialkylaluminium reagent, an aluminoxane, and (−)-(NMI) 2 ZrCl 2 in a solvent.

16. The process of claim 15 , wherein said aluminoxane is methylaluminoxane.

17. The process of claim 16 , wherein said trialkylaluminium is Me 3 Al.

18. The process of claim 15 , wherein said aluminoxane is isobutylaluminoxane.

19. The process of claim 18 , wherein said trialkylaluminium is Et 3 Al or n Pr 3 Al.

20. The process of claim 12 , wherein said solvent is CH 2 Cl 2 .

Assignees

• Purdue Research Foundation

Inventors

• Negishi Ei-Ichi

Classifications

• C07C41/26

  by introduction of hydroxy or O-metal groups · CPC title

• C07C31/1355

  with a six-membered ring · CPC title

• C07C31/12

  containing four carbon atoms · CPC title

• C07C29/44 Primary

  increasing the number of carbon atoms by addition reactions, i.e. reactions involving at least one carbon-to-carbon double or triple bond (C07C29/16 takes precedence) · CPC title

• C12P7/62

  Carboxylic acid esters · CPC title