Asymmetric synthesis of amines using tert-butanesulfinamide

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

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DEOXYGENATIVE PHOTOCHEMICAL ALKYLATION OF SECONDARY AMIDES ENABLES A STREAMLINED SYNTHESIS OF SUBSTITUTED AMINES Article Open

access 22 January 2025 STEREOCONTROLLED 1,3-NITROGEN MIGRATION TO ACCESS CHIRAL Α-AMINO ACIDS Article 04 April 2022 STEREOSELECTIVE AMINO ALCOHOL SYNTHESIS VIA CHEMOSELECTIVE

ELECTROCATALYTIC RADICAL CROSS-COUPLINGS Article 03 January 2025 REFERENCES * Nugent, T.C. _Chiral Amine Synthesis: Methods, Developments and Applications_ 494 (Wiley, 2010). * Okamoto, Y.

& Ikai, T. Chiral HPLC for efficient resolution of enantiomers. _Chem. Soc. Rev._ 37, 2593–2608 (2008). Article  CAS  Google Scholar  * Noyori, R. Asymmetric catalysis: science and

opportunities (Nobel lecture). _Angew. Chem Intl. Edn._ 41, 2008–2022 (2002). Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Morton, D. & Stockman, R.A. Chiral non-racemic sulfinimines: versatile reagents for asymmetric synthesis. _Tetrahedron_ 62, 8869–8905 (2006). Article  CAS  Google Scholar  *

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

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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * 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  *

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  * 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  * 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  * 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  * 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  * 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  * 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 

* 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  * 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  * 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  * 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  * 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  * 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  * 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  Download

references ACKNOWLEDGEMENTS This work was supported by the US National Science Foundation (CHE-1049571). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Chemistry, Yale

University, New Haven, Connecticut, USA Hai-Chao Xu, Somenath Chowdhury & Jonathan A Ellman * Department of Chemistry, Xiamen University, Xiamen, China Hai-Chao Xu Authors * Hai-Chao Xu

View author publications You can also search for this author inPubMed Google Scholar * Somenath Chowdhury View author publications You can also search for this author inPubMed Google Scholar

* Jonathan A Ellman View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Jonathan A Ellman. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY DATA 1H NMR and 13C NMR spectra of products 16–19 (PDF 515 kb) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 24 October 2013 * Issue Date: November 2013 * DOI: https://doi.org/10.1038/nprot.2013.134 SHARE THIS ARTICLE Anyone you

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