Chiral Amines in Asymmetric Synthesis

Chiral amines have found widespread application in asymmetric synthesis serving, for instance, as chiral bases in enantioselective deprotonation reactions^1,2 or being valuable substances for resolving racemic mixtures of acids. Additionally, chiral amines are prevalent, essential parts of many drugs and drug candidates.

α-Ethylbenzylamine

Alexakis has reported on a practical solvent-free reductive amination reaction. In a one-pot synthesis, C₂-symmetrical secondary amines could be obtained in high diastereoselectivities starting from (R)-α-ethylbenzylamine or (S)-α-ethylbenzylamine, respectively (Figure 1).

Figure 1. α-Ethylbenzylamine

These secondary amines also serve as valuable chiral building blocks for the synthesis of atropisomeric phosphoramidites used in highly enantioselective copper-catalyzed conjugate additions^3,4 or in iridium-catalyzed allylic substitutions.⁵

2-Amino-3-methylbutane

Diazoxide BPDZ-44 was found to be a tissue selective ATP-sensitive potassium channel opener, resulting in inhibition of important physiological processes such as insulin release or muscle tone and contractility. The straightforward synthesis of BPDZ-44 used (S)-2-amino-3-methylbutane as a chiral building block in a key step (Figure 2).⁶

Figure 2. 2-Amino-3-methylbutane

Materials

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References

1. Cox PJ, Simpkins NS. 1991. Asymmetric synthesis using homochiral lithium amide bases. Tetrahedron: Asymmetry. 2(1):1-26. https://doi.org/10.1016/s0957-4166(00)82150-3

2. O'Brien P. 2002. Recent developments in chiral lithium amide base chemistry. Tetrahedron. 58(23):xi. https://doi.org/10.1016/s0040-4020(02)00362-9

3. Alexakis A, Polet D, Rosset S, March S. 2004. Biphenol-Based Phosphoramidite Ligands for the Enantioselective Copper-Catalyzed Conjugate Addition of Diethylzinc. J. Org. Chem.. 69(17):5660-5667. https://doi.org/10.1021/jo049359m

4. Alexakis A, Benhaim C. 2002. Eur.. J. Org. Chem.3221.

5. Alexakis A, Polet D. 2004. Very Efficient Phosphoramidite Ligand for Asymmetric Iridium-Catalyzed Allylic Alkylation. Org. Lett.. 6(20):3529-3532. https://doi.org/10.1021/ol048607y

6. Khelili S, de Tullio P, Lebrun P, Fillet M, Antoine M, Ouedraogo R, Dupont L, Fontaine J, Felekidis A, Leclerc G, et al. 1999. Preparation and pharmacological evaluation of the R - and S -enantiomers of 3-(2?-butylamino)-4 H - and 3-(3?-methyl-2?-butylamino)-4 H -pyrido[4,3- e ]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorganic & Medicinal Chemistry. 7(8):1513-1520. https://doi.org/10.1016/s0968-0896(99)00082-6