2-Methyl-2-propanesulfinamide (Ellman’s Sulfinamide): A Versatile Chiral Reagent

Biographical Sketches

Xiao-Yu Guan was born in Henan, P. R. of China in 1980. He received a B.Sc. in Chemistry from Southwest Normal University in 2003, and is now working towards his Ph.D. under the supervision of Prof. Wen-hao Hu at the Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences. His current research is focused on multi-component reaction and asymmetric synthesis.

Introduction

Enantiopure 2-methyl-2-propanesulfinamide (tert-butane­sulfinamide) was introduced by Ellman in 1997. [¹] As a chiral ammonia equivalent, it can easily condense with aldehydes and ketones to afford tert-butanesulfinyl imines in high yields (Scheme 1). [²] The tert-butanesulfinyl group activates these imines for the addition of many different classes of nucleophiles and serves as a powerful chiral ­directing group to provide products with generally high diastereoselectivity. Subsequent removal of the tert-butanesulfinyl group under mild conditions cleanly provides the amine products. Many versatile building blocks [³] including syn- and anti-1,2- or 1,3-amino alcohols, [4] [5] α-branched and α,α-dibranched amines, [6] α- or β-amino acids and esters [7] [8] can be efficiently synthesized by using this methodology. In addition, this methodology can also be used in the synthesis of antibiotics, biologically active compounds, and other complex natural products. [9] Furthermore, tert-butanesulfinamide has been used in the synthesis of asymmetric ligands [¹0] or catalysts [¹¹] , and in a few cases, appears as the chirality-bearing component. [¹²]

Scheme 1 Synthesis of sulfinyl aldimines or ketimines

Each configuration of 2-methyl-2-propanesulfinamid is readily available in a two-step process of catalytic asymmetric oxidation of tert-butyl disulfide, followed by the reaction of the tert-butanethiosulfinate product 4 with an amide anion (Scheme 2). [¹³]

Scheme 2 Preparation of (R)-tert-butanesulfinamide

Abstracts

(A) Ellman and co-workers have demonstrated the facile synthesis of chiral α,α-dibranched amines through 1,2-addition of organolithium reagents to N-tert-butanesulfinyl ketimines, which proceeds with high yields and diastereoselectivities. [6b]
(B) N-tert-Butylsulfinyl imines have been used in a highly diastereo­selective multi-component reaction of phenyldiazoacetates, alcohols, and imines, which provides readily access to β-amino-α-hydroxyesters in high optical purity. [4d]
(C) Ellman and co-workers have reported the copper-catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl aldimines with excellent diastereoselectivity for diverse chiral α-amino boronic acids. [¹4] Furthermore, the N-sulfinyl α-amino boronate ester addition products can be used as intermediates in the asymmetric synthesis of bortezomib.
(D) Morton and co-workers synthesized chiral aziridines using tri­methylsulfonium iodide with good yields and diastereoselectivities. [¹5a] Chemla and Ferreira reacted a racemic allenylzinc substrate with various N-tert-butanesulfinyl imines to achieve trans-ethynyl­aziridines as diastereomerically and enantiomerically pure compounds in good yields. [¹5b]
(E) Using N-tert-butanesulfinamide as staring material, Ellman and co-workers have synthesized a novel bis(sulfinyl)imidoamidine (siam) ligand 5 in three straightforward steps. [¹0b] The complex of bis(sulfinyl)imidoamidine 5 with copper(II) catalyzes the Diels-­Alder reaction with exceptional levels of enantio- and diastereo­selectivity.
(F) Ellman and co-workers have developed a new class of organocatalysts that incorporate the N-sulfinyl urea substituent, which is acidifying and serves as a chiral controlling element. [¹¹] The condensation of tert-butanesulfinamide with the appropriate isocyanate in one step provids urea 6, which is proven to be an efficient organocatalyst in the enantioselective aza-Henry reaction.

References

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• 2 Liu G. Cogan DA. Owens TD. Tang TP. Ellman JA. J. Org. Chem.  1999,  64:  1278 
• 3For a recent review, see:
• 3 Ellman JA. Owens TD. Tang TP. Acc. Chem. Res.  2002,  35:  984 
• 1,2-amino alcohols:
• 4a Zhong Y.-W. Dong Y.-Z. Fang K. Izumi K. Xu M.-H. Lin G.-Q. J. Am. Chem. Soc.  2005,  127:  11956 
• 4b Evans JW. Ellman JA. J. Org. Chem.  2003,  68:  9948 
• 4c Tang TP. Volkman SK. Ellman JA. J. Org. Chem.  2001,  66:  3707 
• 4d Huang H.-X. Guo X. Hu W.-H. Angew. Chem. Int. Ed.  2007,  46:  1337 
• 1,3-amino alcohols:
• 5a Kochi T. Tang TP. Ellman JA. J. Am. Chem. Soc.  2003,  125:  11276 
• 5b Kochi T. Tang TP. Ellman JA. J. Am. Chem. Soc.  2002,  124:  6518 
• 6a Cogan DA. Liu G. Ellman JA. Tetrahedron  1999,  55:  8883 
• 6b Cogan DA. Ellman JA. J. Am. Chem. Soc.  1999,  121:  268 
• 6c   , 
• α-amino acids:
• 7a Avenoza A. Busto JH. Corzana F. Peregrina JM. Sucunza D. Zurbano MM. Synthesis  2005,  575 
• 7b Naskar D. Roy A. Seibel WL. Portlock DE. Tetrahedron Lett.  2003,  44:  8865 
• β-amino acids and esters:
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• 8c Tang TP. Ellman JA. J. Org. Chem.  1999,  64:  12 
• Some recent examples:
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