Ellman's Sulfinamides
Ellman's Sulfinamides, also known as tert-butylsulfinamides and 2-methyl-2-propanesulfinamides, are organosulfur compounds that are members of the sulfinamide family of compounds. Both enantiomeric forms are commercially available and are used as chiral auxiliaries in asymmetric synthesis, often as chiral ammonia equivalents for the synthesis of amines. Tert-butanesulfonamides and related synthetic methods were reported by Jonathan A. Ellman et al. in 19971. The condensation of tert-butanesulfonamides with aldehydes and ketones proceeds under mild conditions and produces tert-butylsulfoximides in high yields. The tert-butylsulfinyl groups activate these imines, allowing them to undergo electrophilic addition to many different types of nucleophilic reagents and to act as a powerful chiral auxiliary, providing products with high diastereoselectivity. Subsequent removal of the tert-butylsulfinyl groups under mild conditions gives the amine products.
These tert-butanesulfinyl imines have been used as intermediates in the asymmetric synthesis of many building blocks,2 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 esters6,7 (Scheme 1). Several researchers have taken advantage of the excellent chemical properties of tert-butanesulfinyl imines themselves in the synthesis of antibiotics, bioactive substances and other complex natural products.8 In addition, tert-butanesulfinyl imines have been used in the synthesis of asymmetric ligands, 9 and in a few cases, 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 used to synthesize chiral heterocyclic compounds. Several groups have synthesized chiral aziridines from common tert-butanesulfinyl imines intermediates (Scheme 2).Morton and his colleagues synthesized chiral aziridines using trimethylsulfonium iodide in good yields and diastereoselectivity. 11a Chemla and Ferreira reacted racemic allylzinc substrates with various tert-butanesulfinyl imines to give trans-ethynylaziridines as diastereomerically and enantiomerically pure compounds in high yields. 11b
Scheme 2.synthesis of chiral aziridines through a common tert-butanesulfinyl imine intermediate
In addition, Dondas and De Kimpe devised an efficient route for the synthesis of pyrrolidines and piperidines using the common racemic tert-butyl sulfinyl amines (Scheme 3), which can be easily produced by the reduction of sulfinyl imines with NaBH4. 12 This synthetic method highlights the "one-pot" cyclization and fragmentation, which results in very high yields and purity of the cyclized products.
Scheme 3. Synthesis of pyrrolidines and piperidines using racemic tert-butanesulfinyl amines
Ellman's group also reported on the synthesis of chiral heterocycles. In an extension of their synthetic work on 1,3-amino alcohols, [4a] Ellman performed asymmetric synthesis of (-)-halosaline and (-)-8-epihalosaline (Scheme 4).
Scheme 4.Asymmetric syntheses of (-)-halosaline and (-)-8-epihalosaline
Another recent report described the synthesis of the pyrrolidine alkaloid SC-53116 by intermolecular self-condensation of chiral tert-butanesulfinyl imines(Scheme 5). 13 Thereafter, Ellman demonstrated a facile synthesis of chiral 2-substituted pyrrolidines in high yield and high diastereoselectivity (Scheme 6). 14
Scheme 5. Self-condensation reaction of chiral tert-butanesulfinyl imines to produce pyrrolizidine alkaloid
Scheme 6. Facile synthesis of chiral 2-substituted pyrrolidines
Reference
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.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
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 Chiral N-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.