Experimental details for the first general methods for the one-step preparation of N-tert-butanesulfinyl imines (tert-butanesulfinimines) (2) from aldehydes and ketones is described. To effect the condensations of tert-butanesulfinamide (1) with aldehydes, the Lewis acidic dehydrating agents MgSO4, CuSO4, or Ti(OEt)4 are employed. Aldehyde condensations mediated by MgSO4 proceed in high yields (84−96%) when an excess of aldehyde is used. In contrast, only a slight excess of aldehyde (1.1 equiv) relative to tert-butanesulfinamide provides sulfinimines in high yields when the more Lewis acidic dehydrating agent CuSO4 is used. The CuSO4-mediated procedure is effective for a wide range of aldehydes, including sterically demanding aldehydes, such as isobutyraldehyde (90%), and electron-rich aldehydes, such as p-anisaldehyde (81%). The still more Lewis acidic Ti(OEt)4 and Ti(O-i-Pr)4 also afford N-tert-butanesulfinyl aldimines from especially unreactive aldehydes, such as pivaldehyde (82%). In addition, Ti(OEt)4 is effective for the condensation of 1 with ketones to afford a wide range of N-tert-butanesulfinyl ketimines in good yields (77−91%). For sulfinyl ketimines derived from methyl or n-alkyl phenyl ketones and methyl or n-alkyl isopropyl ketones, only the E isomer is detected by 1H and 13C NMR in CDCl3. For those cases where the difference in steric demand about the imine is very small, such as for 2-hexanone, high E/Z ratios are still observed (5:1).

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The first example of the catalytic asymmetric oxidation of tert-butyl disulfide (1) is described. The product, tert-butyl tert-butanethiosulfinate (2) is obtained with 91% enantiomeric excess in yields of ≥92% on scales as large as 1 mol. The application of H2O2 as stoichiometric oxidant in the presence of 0.25 mol % of VO(acac)2 and 0.26 mol % of a chiral Schiff base ligand, 6a, is both convenient and cost-effective. Thiosulfinate ester 2 is chemically and optically stable and serves as an excellent precursor to chiral tert-butanesulfinyl compounds by the stereospecific nucleophilic displacement of tert-butyl thiolate. Addition of LiNH2 in liquid ammonia and THF provides tert-butanesulfinamide (3; 91% yield). A single recrystallization provides enantiomerically pure 3 in 71−75% overall yield from disulfide 1. Enantiomerically pure thiosulfinate ester 2 also reacts readily and stereospecifically with Grignard reagents, organolithiums, lithium amides, and lithium imine salts to provide enantiomerically pure chiral sulfoxides, sulfinamides, and sulfinimines in good yield.

The success of these studies clearly demonstrates the power of coupling the complementary methods of combinatorial chemistry and structure-based design. We anticipate that the general approaches described here will be successful for other members of the aspartyl protease class and for many other enzyme classes.