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Catalysis of Sterically Demanding Cross Couplings Using Ligands which are Chiral at Phosphorus

Strem Has Added BI-DIME, A Family Of Stable Chiral Biaryl Phosphine Ligands

Trivalent phosphines, which are chiral at the phosphorus, are generally stable.  Temperatures of over 100°C are required to initiate racemization. The development of bis-cyclopentanes, each ring substituted by one chiral phosphorus, led to the 1,2-bisphospholane known as TangPhos which is difficult to synthesize.  Wenjun Tang developed this molecule as a graduate student with Xumu Zhang of ChiralQuest/Penn State University.  Later, Dr. Tang and coworkers from Boehringer Ingelheim and the Chinese Academy of Sciences, Shanghai, developed more accessible structures with both an oxygen and phosphorus atom in the five-membered ring of a bisdihydrobenzooxaphosphole.  This molecule could be resolved as stereoisomers by temporarily linking them to an enantiomeric derivative of menthol,1  and then through a Suzuki coupling with 2,6-dimethoxyphenylboronic acid forms the novel P-chiral monophosphorus biaryl ligands BI-DIME.2   The acronym BI-DIME was originally derived from the words “biaryl” and “dimethoxy”.

Structures

Applications of BI-DIME as ligands with Pd, Ni and Rh, are reported for catalysis in asymmetric Suzuki Miyaura Coupling Reactions,2 the Miyaura Borylation,3 enantioselective nickel-catalyzed alkylative alkyne–aldehyde cross-couplings,4 aminations of heteroaromatic halides and asymmetric hydroborations.

Examples are listed below:

Suzuki Miyaura Coupling

Suzuki Miyaura Coupling

 

 

Enantioselective nickel-catalyzed alkylative alkyne–aldehyde cross-couplings

Enantioselective

 

For a commercial example, Boehringer Ingelheim Pharmaceuticals scientists have used the BI-DIME (i-Pr) ligand  (15-6230) to produce a complex chiral HIV integrase inhibitor in 4.7:1 d.r. atropisomeric ratio purity, increased to >95:5 by crystallization. This complex was created via the diastereoselective Suzuki coupling of two heteropolyaromatic fragments.  The process is said to have been conducted on a multi-kilogram scale.5

References

1.      Org. Lett., 2010, 12, 176.

2.      Org. Lett., 2012, 14, 2258.

3.      Org. Lett., 2011, I3, 1366.

4.      Organic Chemistry Frontiers, 2015, 2, 1322.

5.      Angew. Chem., 2015, 54, 1.

 

 

Products mentioned in this blog:

15-6205:3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% rac-BI-DIME (1246888-90-3)

15-6210: (S)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (S)-BI-DIME (1373432-09-7)

15-6211:(R)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (R)-BI-DIME (1373432-03-7)

15-6220:(2S,3S)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2-methyl-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (S,S)-Me-BI-DIME (1373432-11-1)

15-6225:(2R,3R)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2-methyl-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (R,R)-Me-BI-DIME (1477517-18-2)

15-6230: (2S,3S)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2-i-propyl-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (S,S)-iPr-BI-DIME (1477517-21-7)

15-6235:(2R,3R)-3-(t-Butyl)-4-(2,6-dimethoxyphenyl)-2-i-propyl-2,3-dihydrobenzo[d][1,3]oxaphosphole, min. 97% (R,R)-iPr-BI-DIME (1477517-19-3)

 

We also offer a kit composed of each of the above-mentioned ligands.

BI-DIME Ligand Kit (96-0650)

 

 

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