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 100 chemical supply companies market 1 with virtually all using the practical two-step catalytic enantioselective route developed for its synthesis 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.

  

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

Chiral reagent 1 has been employed on metric ton scales, and >5000 publications including >2500 patents and patent applications cite its use primarily for the discovery and/or production of drugs, agrochemicals or fine chemicals. In a recent SciFinder sub-structure search of patents, 1 is currently used much more frequently than other chiral reagent, auxiliary or catalyst. Indeed, numerous clinical candidates and approved drugs have been discovered and produced using tert-butanesulfinamide chemistry, including the kinase inhibitors avopritinib and larotrectinib approved for the treatment of different types of cancers and Gilead’s first in class long-acting HIV-1 capsid inhibitor lenacapavir, which was recently approved for the treatment of AIDS. 

Sulfinamide functionality has proven to be an essential feature of an increasingly large number of asymmetric catalysts for a range of transformations (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 at suifur 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 continues to develop sustainable and highly functional group compatible approaches for the synthesis of diverse classes of amines from readily available starting materials. In one major approach, the lab utilizes catalytic C-H bond functionalization (discussed in the C-H Functionalization research section). In a second major approach, the lab is developing new catalytic reactions, including enantioselective transformations, of N-acyl sulfenamides that proceed by C-S bond formation to provide high oxidation state sulfur compounds incorporating nitrogen. This general class of compounds, as exemplified by sulfoximines, have become highly valued motifs in drug discovery and development. 

Relevant Publications

Chu, D.; Zoll, A. J.; Ellman, J. A.
Copper-Catalyzed Three-Component Synthesis of Highly Substituted Morpholines
Org. Lett.  202426, 4803–4807.  
Greenwood, N. S.; Cerny, N. P.; Deziel, A. P.; Ellman, J. A.
Synthesis of N-Acylsulfenamides from (Hetero)Aryl Iodides and Boronic Acids by One-Pot Sulfur-Arylation and Dealkylation
Angew. Chem. Int. Ed.  202463, e202315701.  
Greenwood, N. S.; Ellman, J. A.
Sulfur-Arylation of Sulfenamides via Ullmann-Type Coupling with (Hetero)aryl Iodides
Org. Lett.  202325, 4759–4764.  
Champlin, A. T.; Ellman, J. A.
Preparation of Sulfilimines by Sulfur-Alkylation of N-Acyl Sulfenamides with Alkyl Halides
J. Org. Chem.  202388, 7607–7614.  
Greenwood, N. S.; Ellman, J. A.
Sulfur-Arylation of Sulfenamides via Chan–Lam Coupling with Boronic Acids: Access to High Oxidation State Sulfur Pharmacophores
Org. Lett.  202325, 2830–2834.  
Liu, J. T.; Brandes, D. S.; Greenwood, N. S.; Ellman, J. A.
Synthesis of N-Acylsulfenamides from Amides and N-Thiosuccinimides
Synthesis  202355, 2353–2360 [Special Issue dedicated to Prof. David A. Evans].  
Greenwood, N. S.; Champlin, A. T.; Ellman, J. A.
Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines
J. Am. Chem. Soc.  2022144, 17808–17814.  
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.  
Xu, H. C.; Chowdhury, S.; Ellman, J. A.
Asymmetric Synthesis of Amines Using tert-Butanesulfinamide
Nat. Protoc.  20138, 2271-2280.  
Khan, H. A.; Ellman, J. A.
Asymmetric Synthesis of α-Aminophosphonate Esters by the Addition of Dialkyl Phosphites to tert-Butanesulfinyl Imines
Synthesis  201345, 3147–3150.  
Jung, H. H.; Buesking, A. W.; Ellman, J. A.
Rh-Catalyzed Addition of Arylboroxines to Cyclic N-(Isopropanesulfinyl)ketimines
J. Org. Chem.  201277, 9593-9600.  
Kimmel, K. L.; Weaver, J. D.; Lee, M.; Ellman, J. A.
Enantio- and Diastereoselective Addition of Cyclohexyl Meldrum’s Acid to β- and α,β-Disubstituted Nitroalkenes via N-Sulfinyl Urea Catalysis
J. Am. Chem. Soc.  2012134, 9058-9061.  
Kimmel, K. K.; Robak, M. T.; Thomas, S.; Lee, M.
Enantio- and Diastereoselective Addition of Thioacetic Acid to Nitroalkenes via N-Sulfinyl Urea Catalysis
Tetrahedron  201268, 2704-2712.  
Kimmel, K.L.; Weaver, J.D.; Ellman, J.A.
Enantio- and Diastereoselective Addition of Cyclohexyl Meldrum’s Acid to β- and α,β-Disubstituted Nitroalkenes via N-Sulfinyl Urea Catalysis
Chem. Sci.  20123, 121-125.  
Buesking, A. W.; Baguley, T. D.; Ellman, J. A.
Asymmetric Synthesis of Amines by the Knochel-Type MgCl2-Enhanced Addition of Benzyl Zinc Reagents to N-tert-Butanesulfinyl Aldimines
Org. Lett.   201113, 964-967.  
Datta, G. K.; Ellman, J. A.
Racemization Free Protocol for the Synthesis of N-tert-Butanesulfinyl Ketimimes
J. Org. Chem.  201075, 6283-6285.  
Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Synthesis and Applications of tert-Butanesulfinamide
Chem. Rev.  2010110, 3600–3740 [most read ACS article of 2011].  
Brak, K.; Ellman, J. A.
Total Synthesis of (-)-Aurantioclavine
Org. Lett.  201012, 2004–2007.  
Storgaard, M.; Ellman, J. A.
Rhodium-Catalyzed Enantioselective Addition of Arylboronic Acids to In Situ Generated N-Boc Arylimines. Preparation of (S)-tert-Butyl (4-Chlorophenyl)(Thiophen-2-yl-MethyylCarbamate
Org. Synth.  200986, 360-373.  
Kimmel, K. L.; Robak, M. T.; Ellman, J. A.
Enantioselective Addition of Thioacetic Acid to Nitroalkenes via N-Sulfinyl Urea Organocatalysis
J. Am. Chem. Soc.  2009131, 8754–8755.  
Brak, K.; Harris, K. ; Ellman, J. A.
General One-pot Method for the Preparation of N-tert-Butanesulfinyl Amine Diastereomer Mixtures as Standards for Stereoselectivity Determinations
J. Org. Chem.  200974, 3606-3608.  
Brak, K.; Ellman, J. A.
Asymmetric Synthesis of α–Branched Allylic Amines by the Rh(I)-Catalyzed Addition of Alkenyltrifluoroborates to N-tert-Butanesulfinyl Aldimines
J. Am. Chem. Soc.  2009131, 3850–3851.  
Wakayama , M.; Ellman, J. A.
Recycling the tert-Butanesulfinyl Group in the Synthesis of Amines Using tert-ButanesulfinamideRecycling the tert-Butanesulfinyl Group in the Synthesis of Amines Using tert-Butanesulfinamide
J. Org. Chem.   200974, 2646–2650.  

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