Asymmetric Synthesis of Amines

More than 80% of all drugs and drug candidates contain amine functionality. Many of these amine-containing compounds are also chiral and can be challenging to prepare. The Ellman lab developed tert-butanesulfinamide 1 as a versatile and extensively used chiral reagent (Figure 1).  Over 125 chemical supply companies market 1 with virtually all using the practical two-step catalytic enantioselective route developed by the Ellman lab. Many academic and industrial researchers heavily rely on 1 for the asymmetric synthesis of a large variety of different types of amines 2. Indeed, chiral reagent 1 has been employed on metric ton scales, and more than 2000 patents or patent applications cite its use for the discovery or production of drugs, agrochemicals or fine chemicals. In a SciFinder sub-structure search of patents, 1 is now used more frequently than other chiral reagent, auxiliary or catalyst. 

  

Figure 1. tert-Butanesulfinamide 1 and representative types of amines prepared using this reagent

Sulfinamide functionality has proven to be an essential feature of an increasingly large number of asymmetric catalysts for a range of applications (Figure 2). The first chiral sulfinamide-based ligand 3 for asymmetric transition metal catalysis was developed in the Ellman lab.  We also developed a new class of hydrogen bonding organo­catalysts for asymmetric synthesis based upon the sulfinyl group’s unique ability to enhance acidity while at the same time providing a chiral environment. For example, organocatalyst has sole chirality on the sulfinyl group and enabled the first example of catalytic asymmetric nitronate protonation.

   

Figure 2Chiral sulfinamide-based ligands and organocatalysts

The Ellman lab applies the methods and catalysts that it develops to efficient syntheses of bioactive natural products and drug candidates. These include the first total synthesis of the highly potent cytotoxic agent tubulysin D, which is actively being pursued in antibody drug conjugates for targeted chemotherapy, and syntheses of potent and selective cathepsin S inhibitors discovered in the Ellman labs (Figure 3). 

    

Figure 3. Examples of compounds synthesized in the Ellman lab using sulfinamide chemistry

The Ellman lab is currently developing a number of sustainable and highly functional group compatible approaches for the synthesis of diverse classes of amines from readily available starting materials. These methods rely primarily on catalytic C-H functionalization and are discussed in the section on C-H functionalization.

Relevant Publications

Wangweerawong, A.; Kolmar. S.; Ellman, J. A.
Preparation of (S)-Nonafluorobutanesulfinamide
Org. Synth.  201693, 319-330.  
Phelan, J. P.; Ellman, J. A.
Conjugate Addition–Enantioselective Protonation Reactions
Beilstein J. Org. Chem.  201612, 1203–1228.  
Phelan, J. P.; Ellman, J. A.
Catalytic Enantioselective Addition of Pyrazol-5-ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst
Adv. Synth. Catal.  2016358, 1713–1718.  
Wangweerawong, A.; Hummel, J. R.; Bergman, R. G.; Ellman, J. A.
Preparation of Enantiomerically Pure Perfluorobutanesulfinamide and Its Application to the Asymmetric Synthesis of α-Amino Acids
J. Org. Chem.  201681, 1547–1557.  
Phelan, J. P.; Patel, E. J.; Ellman, J. A.
Catalytic Enantioselective Addition of Thioacids to Trisubstituted Nitroalkenes
Angew. Chem. Int. Ed.  201453, 11329–11332.  
Wangweerawong, A.; Bergman, R. G.; Ellman, J. A.
Asymmetric Synthesis of α-Branched Amines via Rh(III)-Catalyzed C–H Bond Functionalization
J. Am. Chem. Soc.  2014136, 8520–8523.  
Buesking, A. W.; Bacauanu, V.; Cai, I.; Ellman, J. A.
Asymmetric Synthesis of Protected α-Amino Boronic Acid Derivatives with an Air- and Moisture-Stable Cu(II) Catalyst
J. Org. Chem.  201479, 3671–3677.  
Buesking, A. W.; Ellman, J. A.
Convergent, Asymmetric Synthesis of Vicinal Amino Alcohols via Rh-Catalyzed Addition of α-Amido Trifluoroborates to Carbonyls
Chem. Sci.  20145, 1983-1987.