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Asymmetric synthesis of amines using tert-butanesulfinamide

Nature Protocols volume 8, pages 2271–2280 (2013)Cite this article

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Abstract

Chiral amines are prevalent in many bioactive molecules, including amino acids and pharmaceutical agents. tert-Butanesulfinamide (tBS) is a chiral amine reagent that has enabled the reliable asymmetric synthesis of a very broad range of different amine structures from simple, readily available starting materials. Three steps are commonly applied to the asymmetric synthesis of amines: (i) condensation of tBS with a carbonyl compound, (ii) nucleophile addition and (iii) tert-butanesulfinyl group cleavage. Here we demonstrate these steps with the preparation of a propargylic tertiary carbinamine, one of a class of amines that have been used for many different biological purposes, including click chemistry applications, diversity-oriented synthesis, the preparation of peptide isosteres and the development of protease inhibitors as drug candidates and imaging agents. The process described here can be performed in 3–4 d.

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Figure 1
Figure 2
Figure 3: Three common steps in the asymmetric synthesis of amines with tBS.
Figure 4: Four-step procedure for the asymmetric synthesis of propargylic tertiary carbinamine 19.
Figure 5
Figure 6: Reactions of sulfinyl ketimines with acetylides.
Figure 7
Figure 8
Figure 9

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References

  1. Nugent, T.C. Chiral Amine Synthesis: Methods, Developments and Applications 494 (Wiley, 2010).

  2. Okamoto, Y. & Ikai, T. Chiral HPLC for efficient resolution of enantiomers. Chem. Soc. Rev. 37, 2593–2608 (2008).

    Article  CAS  Google Scholar 

  3. Noyori, R. Asymmetric catalysis: science and opportunities (Nobel lecture). Angew. Chem Intl. Edn. 41, 2008–2022 (2002).

    Article  CAS  Google Scholar 

  4. Savile, C.K. et al. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329, 305–309 (2010).

    Article  CAS  Google Scholar 

  5. Kroutil, W. et al. Asymmetric preparation of prim-, sec-, and tert-amines employing selected biocatalysts. Org. Process Res. Dev. 17, 751–759 (2013).

    Article  CAS  Google Scholar 

  6. Friestad, G.K. & Mathies, A.K. Recent developments in asymmetric catalytic addition to C=N bonds. Tetrahedron 63, 2541–2569 (2007).

    Article  CAS  Google Scholar 

  7. Kobayashi, S., Mori, Y., Fossey, J.S. & Salter, M.M. Catalytic enantioselective formation of C-C bonds by addition to imines and hydrazones: a ten-year update. Chem. Rev. 111, 2626–2704 (2011).

    Article  CAS  Google Scholar 

  8. Enders, D. & Reinhold, U. Asymmetric synthesis of amines by nucleophilic 1,2-addition of organometallic reagents to the CN-double bond. Tetrahedron Asymmetry 8, 1895–1946 (1997).

    Article  CAS  Google Scholar 

  9. Robak, M.T., Herbage, M.A. & Ellman, J.A. Synthesis and applications of tert-butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010).

    Article  CAS  Google Scholar 

  10. Ferreira, F., Botuha, C., Chemla, F. & Perez-Luna, A. tert-Butanesulfinimines: structure, synthesis and synthetic applications. Chem. Soc. Rev. 38, 1162–1186 (2009).

    Article  CAS  Google Scholar 

  11. Lin, G.-Q., Xu, M.-H., Zhong, Y.-W. & Sun, X.-W. An advance on exploring N-tert-butanesulfinyl imines in asymmetric synthesis of chiral amines. Acc. Chem. Res. 41, 831–840 (2008).

    Article  CAS  Google Scholar 

  12. Morton, D. & Stockman, R.A. Chiral non-racemic sulfinimines: versatile reagents for asymmetric synthesis. Tetrahedron 62, 8869–8905 (2006).

    Article  CAS  Google Scholar 

  13. Senanayake, C.H., Han, Z. & Krishnamurthy, D. Organosulfur chemistry in asymmetric synthesis. (Wiley, 2008).

  14. Senanayake, C.H., Krishnamurthy, D., Lu, Z.-H., Han, Z. & Gallon, E. Enantiopure sulfoxides and sulfinamides: recent developments in their stereoselective synthesis and application to asymmetric synthesis. Aldrichim. Acta 38, 93–103 (2005).

    CAS  Google Scholar 

  15. Liu, G., Cogan, D.A., Owens, T.D., Tang, T.P. & Ellman, J.A. Synthesis of enantiomerically pure N-tert-butanesulfinyl imines (tert-butanesulfinimines) by the direct condensation of tert-butanesulfinamide with aldehydes and ketones. J. Org. Chem. 64, 1278–1284 (1999).

    Article  CAS  Google Scholar 

  16. Datta, G.K. & Ellman, J.A. Racemization free protocol for the synthesis of N-tert-butanesulfinyl ketimines. J. Org. Chem. 75, 6283–6285 (2010).

    Article  CAS  Google Scholar 

  17. Higashibayashi, S., Tohmiya, H., Mori, T., Hashimoto, K. & Nakata, M. Synthesis of sulfinimines by direct condensation of sulfinamides with aldehydes using Cs2CO3 as an activating and dehydrating reagent. Synlett 2004, 457–460 (2004).

    Google Scholar 

  18. Huang, Z., Zhang, M., Wang, Y. & Qin, Y. KHSO4-mediated condensation reactions of tert-butanesulfinamide with aldehydes. Preparation of tert-butanesulfinyl aldimines. Synlett 2005, 1334–1336 (2005).

    Article  Google Scholar 

  19. Collados, J.F., Toledano, E., Guijarro, D. & Yus, M. Microwave-assisted solvent-free synthesis of enantiomerically pure N-(tert-butylsulfinyl)imines. J. Org. Chem. 77, 5744–5750 (2012).

    Article  CAS  Google Scholar 

  20. Guijarro, D., Pablo, Ó. & Yus, M. Ruthenium-catalysed asymmetric transfer hydrogenation of N-(tert-butanesulfinyl)imines. Tetrahedron Lett. 50, 5386–5388 (2009).

    Article  CAS  Google Scholar 

  21. Weix, D.J., Shi, Y. & Ellman, J.A. Diastereoselective and enantioselective Rh(I)-catalyzed additions of arylboronic acids to N-tert-butanesulfinyl and N-diphenylphosphinoyl aldimines. J. Am. Chem. Soc. 127, 1092–1093 (2005).

    Article  CAS  Google Scholar 

  22. Beenen, M.A., Weix, D.J. & Ellman, J.A. Asymmetric synthesis of protected arylglycines by rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters. J. Am. Chem. Soc. 128, 6304–6305 (2006).

    Article  CAS  Google Scholar 

  23. Dai, H. & Lu, X. Diastereoselective synthesis of arylglycine derivatives by cationic palladium(II)-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters. Org. Lett. 9, 3077–3080 (2007).

    Article  CAS  Google Scholar 

  24. Xiao, X. et al. Selective diethylzinc reduction of imines in the presence of ketones catalyzed by Ni(acac)2 . Org. Lett. 8, 139–142 (2005).

    Article  Google Scholar 

  25. Bolshan, Y. & Batey, R.A. A room-temperature protocol for the Rhodium(I)-catalyzed addition of arylboron compounds to sulfinimines. Org. Lett. 7, 1481–1484 (2005).

    Article  CAS  Google Scholar 

  26. Boebel, T.A. & Hartwig, J.F. Conversion of 1,3-disubstituted arenes to chiral α,α-diaryl methylammonium chlorides using arene borylation. Tetrahedron 64, 6824–6830 (2008).

    Article  CAS  Google Scholar 

  27. Beenen, M.A., An, C. & Ellman, J.A. Asymmetric copper-catalyzed synthesis of α-amino boronate esters from N-tert-butanesulfinyl aldimines. J. Am. Chem. Soc. 130, 6910–6911 (2008).

    Article  CAS  Google Scholar 

  28. Liu, G.C., Cogan, D.A. & Ellman, J.A. Catalytic asymmetric synthesis of tert-butanesulfinamide. Application to the asymmetric synthesis of amines. J. Am. Chem. Soc. 119, 9913–9914 (1997).

    Article  CAS  Google Scholar 

  29. Patterson, A.W. & Ellman, J.A. Asymmetric synthesis of α,α-dibranched propargylamines by acetylide additions to N-tert-butanesulfinyl ketimines. J. Org. Chem. 71, 7110–7112 (2006).

    Article  CAS  Google Scholar 

  30. Lo, V.K.-Y., Zhou, C.-Y., Wong, M.-K. & Che, C.-M. Silver(i)-mediated highly enantioselective synthesis of axially chiral allenes under thermal and microwave-assisted conditions. Chem. Commun. 46, 213–215 (2010).

    Article  CAS  Google Scholar 

  31. Corbett, J.W. et al. Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J. Med. Chem. 43, 2019–2030 (2000).

    Article  CAS  Google Scholar 

  32. Trost, B.M., Chung, C.K. & Pinkerton, A.B. Stereocontrolled total synthesis of (+)-streptazolin by a palladium-catalyzed reductive diyne cyclization. Angew. Chem. Intl. Edn. 43, 4327–4329 (2004).

    Article  CAS  Google Scholar 

  33. Davidson, M.H. & McDonald, F.E. Stereoselective synthesis of D-desosamine and related glycals via tungsten-catalyzed alkynol cycloisomerization. Org. Lett. 6, 1601–1603 (2004).

    Article  CAS  Google Scholar 

  34. Brennan, C.J., Pattenden, G. & Rescourio, G. Formal synthesis of (+)-lactacystin based on a novel radical cyclisation of an α-ethynyl substituted serine. Tetrahedron Lett. 44, 8757–8760 (2003).

    Article  CAS  Google Scholar 

  35. Cantel, S. et al. Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition. J. Org. Chem. 73, 5663–5674 (2008).

    Article  CAS  Google Scholar 

  36. Brak, K., Doyle, P.S., McKerrow, J.H. & Ellman, J.A. Identification of a new class of nonpeptidic inhibitors of cruzain. J. Am. Chem. Soc. 130, 6404–6410 (2008).

    Article  CAS  Google Scholar 

  37. Brak, K. et al. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy. J. Med. Chem. 53, 1763–1773 (2010).

    Article  CAS  Google Scholar 

  38. Verdoes, M. et al. A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages. Chem. Biol. 19, 619–628 (2012).

    Article  CAS  Google Scholar 

  39. Leyva, M.J. et al. Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models. Chem. Biol. 17, 1189–1200 (2010).

    Article  CAS  Google Scholar 

  40. Deu, E. et al. Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes. Chem. Biol. 17, 808–819 (2010).

    Article  CAS  Google Scholar 

  41. Wood, W.J., Patterson, A.W., Tsuruoka, H., Jain, R.K. & Ellman, J.A. Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors. J. Am. Chem. Soc. 127, 15521–15527 (2005).

    Article  CAS  Google Scholar 

  42. Patterson, A.W. et al. Identification of selective, nonpeptidic nitrile inhibitors of cathepsin S using the substrate activity screening method. J. Med. Chem. 49, 6298–6307 (2006).

    Article  CAS  Google Scholar 

  43. Inagaki, H. et al. Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode. J. Med. Chem. 50, 2693–2699 (2007).

    Article  CAS  Google Scholar 

  44. Moss, N. et al. Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement. Bioorg. Med. Chem. Lett. 22, 7189–7193 (2012).

    Article  CAS  Google Scholar 

  45. Moura-Letts, G., Diblasi, C.M., Bauer, R.A. & Tan, D.S. Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library. Proc. Natl. Acad. Sci. USA 108, 6745–6750 (2011).

    Article  CAS  Google Scholar 

  46. Cogan, D.A., Liu, G. & Ellman, J. Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines. Tetrahedron 55, 8883–8904 (1999).

    Article  CAS  Google Scholar 

  47. Shaw, A.W. & deSolms, S.J. Asymmetric synthesis of α,α-diaryl and α-aryl-α-heteroaryl alkylamines by organometallic additions to N-tert-butanesulfinyl ketimines. Tetrahedron Lett. 42, 7173–7176 (2001).

    Article  CAS  Google Scholar 

  48. Chen, B.-L., Wang, B. & Lin, G.-Q. Highly diastereoselective addition of alkynylmagnesium chlorides to N-tert-butanesulfinyl aldimines: a practical and general access to chiral α-branched amines. J. Org. Chem. 75, 941–944 (2009).

    Article  Google Scholar 

  49. Ding, C.-H., Chen, D.-D., Luo, Z.-B., Dai, L.-X. & Hou, X.-L. Highly diastereoselective synthesis of N-tert-butylsulfinylpropargylamines through direct addition of alkynes to N-tert-butanesulfinimines. Synlett 2006, 1272–1274 (2006).

    Article  Google Scholar 

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Acknowledgements

This work was supported by the US National Science Foundation (CHE-1049571).

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Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, Connecticut, USA

    Hai-Chao Xu, Somenath Chowdhury & Jonathan A Ellman

  2. Department of Chemistry, Xiamen University, Xiamen, China

    Hai-Chao Xu

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  1. Hai-Chao Xu
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Contributions

H.-C.X. and S.C. carried out the experiments; J.A.E. designed the protocol and supervised the project; and H.-C.X. and J.A.E. assembled the manuscript.

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Correspondence to Jonathan A Ellman.

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The authors declare no competing financial interests.

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Supplementary Data

1H NMR and 13C NMR spectra of products 16–19 (PDF 515 kb)

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Xu, HC., Chowdhury, S. & Ellman, J. Asymmetric synthesis of amines using tert-butanesulfinamide. Nat Protoc 8, 2271–2280 (2013). https://doi.org/10.1038/nprot.2013.134

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