Ellman's Sulfinamides

Since its introduction by Ellman in 1997 as a chiral ammonia equivalent,¹ enantiopure 2-methyl-2-propanesulfinamide (tert-butanesulfinamide) has been demonstrated to be a versatile chiral auxiliary and has found extensive use both in academics and industry. Condensation of tert-butanesulfinamide with aldehydes and ketones proceeds under mild conditions and provides tert-butanesulfinyl imines in high yields. 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.

These tert-butanesulfinyl imines have been used as intermediates in the asymmetric synthesis of many versatile building blocks² including syn- and anti- 1,2- or 1,3-amino alcohols,^3,4 α-branched and α,α-dibranched amines,⁵ and α- or β-amino acids and esters^6,7 (Scheme 1). Several researchers have taken advantage of the robust chemistry of tert-butanesulfinyl imines in the synthesis of antibiotics, biologically active compounds and other complex natural products.⁸ Furthermore, tert-butanesulfinyl imines have been used in the synthesis of asymmetric ligands,⁹ and in a few cases, appears as the chirality-bearing component.¹⁰

Scheme 1. Asymmetric synthesis of many versatile building blocks using tert-butanesulfinyl imines

Recently, tert-butanesulfinyl imines have been employed in the synthesis of chiral heterocycles. A few groups have synthesized chiral aziridines through a common tert-butanesulfinyl imine intermediate (Scheme 2). Morton and co-workers synthesized chiral aziridines using trimethylsulfonium iodide with good yields and diastereoselectivities.^11a Chemla and Ferreira reacted a racemic allenylzinc substrate with various tert-butanesulfinyl imines to achieve trans-ethynylaziridines as diastereomerically and enantiomerically pure compounds in good yields.^11b

Scheme 2. synthesis of chiral aziridines through a common tert-butanesulfinyl imine intermediate

Additionally, Dondas and De Kimpe devised an efficient route to pyrrolidines and piperidines using a common racemic tert-butanesulfinyl amine (Scheme 3), which is easily achieved from the sulfinyl imine by reduction with NaBH₄.¹² Their synthesis highlights a one-pot cascade cyclization and fragmentation, which allows for very high yields and purity of the cyclized product.

Scheme 3. Pyrrolidines and piperidines using a common racemic tert-butanesulfinyl amine

Ellman’s research group has also reported the synthesis of chiral heterocycles. In an extension of their work on synthesis of 1,3-amino-alcohols,^4a Ellman carried out the asymmetric syntheses of (-)-halosaline and (-)-8-epihalosaline (Scheme 4).

Scheme 4. Asymmetric syntheses of (-)-halosaline and (-)-8-epihalosaline

Another recent report describes the intermolecular self-condensation of chiral tert-butanesulfinyl imines in a synthesis for the pyrrolizidine alkaloid SC-53116 (Scheme 5).¹³ In a later report, Ellman demonstrated the facile synthesis of chiral 2-substituted pyrrolidines (Scheme 6) that proceeds with high yields and diastereoselectivities.¹⁴

Scheme 5. Self-condensation of chiral tert-butanesulfinyl imines to form pyrrolizidine alkaloid

Scheme 6. Facile synthesis of chiral 2-substituted pyrrolidines

We are pleased to be able to offer this versatile and useful auxiliary in both enantiomeric and racemic forms for your research.

References

1. Liu G, Cogan DA, Ellman JA. 1997. Catalytic Asymmetric Synthesis oftert-Butanesulfinamide. Application to the Asymmetric Synthesis of Amines. J. Am. Chem. Soc.. 119(41):9913-9914. https://doi.org/10.1021/ja972012z

2. Ellman JA, Owens TD, Tang TP. 2002. N-tert-Butanesulfinyl Imines:  Versatile Intermediates for the Asymmetric Synthesis of Amines. Acc. Chem. Res.. 35(11):984-995. https://doi.org/10.1021/ar020066u

3. NA. NA.

4. Evans JW, Ellman JA. 2003. Stereoselective Synthesis of 1,2-Disubstituted ?-Amino Alcohols by Nucleophilic Addition toN-tert-Butanesulfinyl ?-Alkoxyaldimines. J. Org. Chem.. 68(26):9948-9957. https://doi.org/10.1021/jo035224p

5. Tang TP, Volkman SK, Ellman JA. 2001. Asymmetric Synthesis of Protected 1,2-Amino Alcohols Usingtert-Butanesulfinyl Aldimines and Ketimines. J. Org. Chem.. 66(26):8772-8778. https://doi.org/10.1021/jo0156868

6. Barrow JC, Ngo PL, Pellicore JM, Selnick HG, Nantermet PG. 2001. A facile three-step synthesis of 1,2-amino alcohols using the Ellman homochiral tert-butylsulfinamide. Tetrahedron Letters. 42(11):2051-2054. https://doi.org/10.1016/s0040-4039(01)00122-8

7. Kochi T, Tang TP, Ellman JA. 2003. Development and Application of a New General Method for the Asymmetric Synthesis ofsyn- andanti-1,3-Amino Alcohols. J. Am. Chem. Soc.. 125(37):11276-11282. https://doi.org/10.1021/ja0363462

8. Kochi T, Tang TP, Ellman JA. 2002. Asymmetric Synthesis ofsyn- andanti-1,3-Amino Alcohols. J. Am. Chem. Soc.. 124(23):6518-6519. https://doi.org/10.1021/ja026292g

9. Cogan DA, Liu G, Ellman J. 1999. Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines. Tetrahedron. 55(29):8883-8904. https://doi.org/10.1016/s0040-4020(99)00451-2

10. Cogan DA, Ellman JA. 1999. Asymmetric Synthesis of ?,?-Dibranched Amines by the Trimethylaluminum-Mediated 1,2-Addition of Organolithiums totert-Butanesulfinyl Ketimines. J. Am. Chem. Soc.. 121(1):268-269. https://doi.org/10.1021/ja983217q

11. Avenoza A, Peregrina J, Busto J, Corzana F, Sucunza D, Zurbano M. Diastereoselective Synthesis of (S)- and (R)-?-Phenylserine by a Sulfinimine-Mediated Strecker Reaction. Synthesis. 2005(04):575-578. https://doi.org/10.1055/s-2004-837308

12. Naskar D, Roy A, Seibel WL, Portlock DE. 2003. Hydroxylamines and sulfinamide as amine components in the Petasis boronic acid?Mannich reaction: synthesis of N-hydroxy or alkoxy-?-aminocarboxylicacids and N-(tert-butyl sulfinyl)-?-amino carboxylicacids. Tetrahedron Letters. 44(49):8865-8868. https://doi.org/10.1016/j.tetlet.2003.09.179

13. Jacobsen MF, Skrydstrup T. 2003. Asymmetric Mannich-Type Reactions for the Synthesis of Aspartic Acid Derivatives from ChiralN-tert-Butanesulfinylimino Esters. J. Org. Chem.. 68(18):7112-7114. https://doi.org/10.1021/jo034436j

14. Tang TP, Ellman JA. 2002. Asymmetric Synthesis of ?-Amino Acid Derivatives Incorporating a Broad Range of Substitution Patterns by Enolate Additions totert-Butanesulfinyl Imines. J. Org. Chem.. 67(22):7819-7832. https://doi.org/10.1021/jo025957u

15. Tang TP, Ellman JA. 1999. Thetert-Butanesulfinyl Group:  An Ideal Chiral Directing Group and Boc-Surrogate for the Asymmetric Synthesis and Applications of ?-Amino Acids. J. Org. Chem.. 64(1):12-13. https://doi.org/10.1021/jo9820824

16. Lu BZ, Senanayake C, Li N, Han Z, Bakale RP, Wald SA. 2005. Control of Diastereoselectivity by Solvent Effects in the Addition of Grignard Reagents to Enantiopuret-Butylsulfinimine:? Syntheses of the Stereoisomers of the Hydroxyl Derivatives of Sibutramine. Org. Lett.. 7(13):2599-2602. https://doi.org/10.1021/ol0507017

17. Kochi T, Ellman JA. 2004. Asymmetric ?-Alkylation ofN?-tert-Butanesulfinyl Amidines. Application to the Total Synthesis of (6R,7S)-7-Amino-7,8-dihydro-?-bisabolene. J. Am. Chem. Soc.. 126(48):15652-15653. https://doi.org/10.1021/ja044753n

18. Kochi T, Ellman JA. 2004. Asymmetric ?-Alkylation ofN?-tert-Butanesulfinyl Amidines. Application to the Total Synthesis of (6R,7S)-7-Amino-7,8-dihydro-?-bisabolene. J. Am. Chem. Soc.. 126(48):15652-15653. https://doi.org/10.1021/ja044753n

19. Kato T, Marubayashi K, Takizawa S, Sasai H. 2004. Development of a novel chiral spiro ligand bearing oxazoline. Tetrahedron: Asymmetry. 15(23):3693-3697. https://doi.org/10.1016/j.tetasy.2004.09.037

20. Schenkel LB, Ellman JA. 2004. Application ofP,N-Sulfinyl Imine Ligands to Iridium-Catalyzed Asymmetric Hydrogenation of Olefins. J. Org. Chem.. 69(6):1800-1802. https://doi.org/10.1021/jo035675+

21. Schenkel LB, Ellman JA. 2003. Novel Sulfinyl Imine Ligands for Asymmetric Catalysis. Org. Lett.. 5(4):545-548. https://doi.org/10.1021/ol027468m

22. Owens TD, Souers AJ, Ellman JA. 2003. The Preparation and Utility of Bis(sulfinyl)imidoamidine Ligands for the Copper-Catalyzed Diels?Alder Reaction. J. Org. Chem.. 68(1):3-10. https://doi.org/10.1021/jo020524c

23. Chemla F, Ferreira F. 2004. High Kinetic Resolution in the Addition of a Racemic Allenylzinc onto EnantiopureN-tert-Butanesulfinimines:  Concise Synthesis of Enantiopuretrans-2-Ethynylaziridines1. J. Org. Chem.. 69(24):8244-8250. https://doi.org/10.1021/jo0490696

24. Dondas HA, De Kimpe N. 2005. A sequence of electrophile induced cyclisation and concomitant N-deprotection of alkenylsulfinimines and alkenylsulfinamides as a direct route to cyclic or spirocyclic imines, pyrrolidines and piperidines. Tetrahedron Letters. 46(24):4179-4182. https://doi.org/10.1016/j.tetlet.2005.04.060

25. Schenkel LB, Ellman JA. 2004. Self-Condensation ofN-tert-Butanesulfinyl Aldimines:? Application to the Rapid Asymmetric Synthesis of Biologically Important Amine-Containing Compounds. Org. Lett.. 6(20):3621-3624. https://doi.org/10.1021/ol048458j

26. Brinner KM, Ellman JA. 2005. A rapid and general method for the asymmetric synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide. Org. Biomol. Chem.. 3(11):2109. https://doi.org/10.1039/b502080h