Enantiopure organic synthesis with hydrogen bond donor catalysts
Over the last 20 years, small molecule hydrogen bond donors have emerged as important catalysts in enantioselective organic synthesis. 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.
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).
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.
- Angew Chem Int Ed Engl., 2004, 43, 5138-5175.
- Org. Lett., 2016, 18, 760-763.
- ACS Cent. Sci., 2015, 1, 50-56.
- U.S. Patent No. 9446393 B2.
- 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]