Asymmetric Synthesis of Amines

  • The 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 has developed tert-butanesulfinamide 1 as a versatile and extensively used chiral reagent (Figure 1) and key component in organocatalysts and ligands for transition metal catalysis.  Over 125 chemical supply companies market with virtually all using the practical two-step catalytic enantioselective route developed by the Ellman lab. Many researchers regularly use 1 for the asymmetric synthesis of a very large variety of amine containing compounds 2. Indeed, this compound has been employed on metric ton scales, and more than 1300 patents or patent applications cite its use for the discovery or production of drug candidates, 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 amine structures that can be prepared

We are very interested in exploring 1 in powerful new bond connections. For example, we have developed efficient methods for the asymmetric synthesis of N-sulfinyl α-aminoboron reagents 3 that through Rh-catalysis can be coupled with electrophiles such as carbonyl compounds to provide access to highly functionalized amines (Figure 2). The lab is also developing C-H bond functionalization-based approaches for using sulfinamide chemistry for the rapid and versatile asymmetric synthesis of amines.

                     

Figure 2. Asymmetric synthesis of α-amino boron reagents 3 and their Rh-catalyzed reactions

The sulfinamide functionality has proven to be an essential feature of a number of asymmetric catalysts.  For example,we have recently developed a new class of hydrogen bonding organo­catalysts for asymmetric synthesis based upon the sulfinyl group’s unique ability to enhance the acidity of the urea while at the same time providing a chiral environment (Figure 3). It is notable that catalyst 4, which has enabled the first example of catalytic asymmetric nitronate protonation, has sole chirality on the sulfinyl group. We have also applied catalyst 5 on mole scale at 0.2 mol % catalyst loading to the enantioselective synthesis of a key intermediate to Lyrica, which is a γ-amino acid blockbuster drug for the treatment of neuropathic pain.

   

Figure 3. The unique properties and examples of N-sulfinyl H-bonding organocatalysts

The Ellman lab has applied the methods and catalysts that they have developed to the efficient synthesis of a number of bioactive natural products and drug candidates (Figure 4). 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 potent and selective cathepsin S inhibitors that were developed in the Ellman labs. 

    

Figure 4. Representative compounds synthesized using sulfinamide chemistry

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.