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Enantiopure Organic Synthesis with Hydrogen Bond Donor Catalysts

High Enantioselectivities in Carbon-Carbon, Carbon-Heteroatom and Carbon-Hydrogen Bond Formations

Over the last 20 years, small molecule hydrogen bond donors have emerged as important catalysts in enantioselective organic synthesis.[1] During this time, chiral organocatalysts dominated the landscape of H-bond donor catalysis.  Noting that certain chiral motifs are difficult to access in organic catalysts, Gladysz and his co-workers at Texas A&M sought to expand the chiral pool to include inorganic transition metal complexes.  Inspired by the helically chiral surface of D3-symmetric Werner complexes [Co(en)3]3+, the team utilized the classic structural motif with the added stereochemical enforcement of chiral (S,S)-1,2-diphenylethylenediamine ligands (dpen).[2-4]  Accordingly, 27-4010 and 27-4011 (Figure 1) represent two diastereomeric isomers of the [Co((S,S)-dpen)3]3+ enantiomers—symbolized as Λ and Δ, respectively.  In these complexes, metal-centered chirality is effectively anchored by N-coordination of the amine groups with Co3+.  Notwithstanding, primary coordination of the amine does not prevent substrates from organizing at the catalyst surface through [N-H ∙ ∙ ∙ substrate] hydrogen bonding interactions.[2-4]  


Figure 1.  H-bond donor catalysts with axial symmetry (each of the twelve H-bond donating groups in blue). 

Hydrogen bonding of the catalysts with various substrates has been shown to promote a diverse range of enantioselective transformations including C-C, C-heteroatom and C-H bond formation.  As shown in Figure 2, L-[Co((S,S)-dpen)3]3Cl2BArF4 (27-4010) was found to catalyze enantioselective Michael reaction between malonate esters and nitroalkenes.[3]



Figure 2. Enantioselective Michael addition of malonate esters with nitroalkenes catalyzed by 27-4010.

The diastereomer Δ-[Co((S,S)-dpen)3]3Cl2BArF20 (27-4011) was found to serve as an efficient catalyst in enantioselective α-aminations of 1,3-dicarbonyl compounds with di-tert-butyl azodicarboxylate in the presence of N-methylmorpholine (NNM).  Evaluation of a variety of substrates showed efficient conversion of five- and six-membered ring ketones (99-88% yields, >99-91% ee), 2-cyanocyclopentanone (92%, 45% ee), and an acyclic oxybutanoate (98%, >99% ee).[2]



Figure 3.  Enantioselective α-aminations catalyzed by 27-4011.

Gladysz’s [Co(dpen)3][2Cl][BAr4] catalysts are readily soluble in organic solvents and offer excellent functional group tolerance while delivering high levels of enantioselectivity for a diverse range of applications.  The catalysts are not air-sensitive and can be used under ambient conditions.  In addition to applications in catalysis, [Co(en)3]3+ complexes have been used to resolve enantiomers for analysis by NMR.[5]   



  1. Angew Chem Int Ed Engl., 2004, 43, 5138-5175.
  2. Org. Lett., 2016, 18, 760-763.
  3. ACS Cent. Sci., 2015, 1, 50-56.
  4. U.S. Patent No. 9446393 B2.
  5. Chem. Sci., 2018, 9, 5087–5099.


Products mentioned in this blog:

27-4010: lambda-Tris[(1S,2S)-1,2-diphenyl-1,2-ethanediamine]cobalt(III) chloride tetrakis[3,5-bis(trifluoromethyl)phenyl]borate dihydrate SKJ-1 [1542135-29-4]

27-4011: delta-Tris[(1S,2S)-1,2-diphenyl-1,2-ethanediamine]cobalt(III) chloride tetrakis(2,3,4,5,6-pentafluorophenyl)borate trihydrate SKJ-3 [1867120-15-7]




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