Chiral N-Acyl-tert-butanesulfinamides:  The “Safety-Catch” Principle Applied to Diastereoselective Enolate Alkylations

Abstract

Diastereoselective enolate alkylation reactions of N-acylsulfinamides and conversion of the alkylation products to a variety of enantiopure products are reported. Several sulfinamides were prepared in solution followed by acylation to provide N-acylsulfinamides. The N-acylsulfinamides were then evaluated in diastereoselective enolate alkylation reactions. Of the sulfinamides evaluated, tert-butanesulfinamide provided the highest diastereoselectivity. To establish the potential utility of sulfinamides as versatile auxiliaries, methods were developed for (1) the racemization-free acylation of tert-butanesulfinamide to prepare optically pure N-acyl-tert-butanesulfinamides, (2) the diastereoselective C-alkylation of N-acyl-tert-butanesulfinamides, (3) the conversion of the N-acyl-tert-butanesulfinamides to the active ester equivalent by N-alkylation and S-oxidation, and (4) the cleavage of the N-alkyl-N-acyl-tert-butanesulfonamides to give chiral alcohol, ester, amide, and carboxylic acid target compounds. These studies provide the groundwork for the development of sulfinamides as dual chiral auxiliaries and linkers for the multistep solid-phase synthesis of enantioenriched compounds.

The 3‐(3‐Pyridine)propionyl Anchor Group for Protease‐Catalyzed Resolutions: p‐Toluenesulfinamide and Sterically Hindered Secondary Alcohols

“…[17] After 1 h at room temperature, the reaction mixture was added to a biphasic mixture of NH 4 OH (500 mL) and EtOAc (500 mL) at 0 8C and then stirred at room temperature. After 1 h, the reaction mixture was diluted with EtOAc (500 mL) and the two layers were separated.…”

“…The combined organic layers were concentrated under vacuum to give a white powder; yield: 66.7 g (86 %); mp 115-117 8C (lit. [17] …”

“…[17] Acylation using a mixed anhydride prepared from isobutyl chloroformate and 3-(3-pyridine)propionic acid gave < 10 % yield, [17] so we used the symmetrical anhydride of 3-(3-pyridine)propionic acid. This symmetrical anhydride was prepared by KMnO 4 oxidation [18] of 3-(3-pyridine)propanol and coupling of the resulting acid using carbodiimide.…”

“…This symmetrical anhydride was prepared by KMnO 4 oxidation [18] of 3-(3-pyridine)propanol and coupling of the resulting acid using carbodiimide. [17] Thus, treating p-toluenesulfinamide with NaH, followed by addition of the symmetrical anhydride of 3-(3-pyridine)propionic acid yielded the crude 1a. Trituration with hexanes/ethyl acetate removed unreacted p-toluenesulfinamide 1 and gave 1a in 73 % yield.…”

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…Lithium or potassium anions of tert-butanesulfinamide (1) have been reported to react with carboxylic anhydrides [41] and esters [42,43] to provide the corresponding N-tert-butanesulfinyl amides, and with isocyanates [44] and 1,1'-carbonyldiimidazole [45] to give N-tert-butanesulfinyl ureas. Even though it has been an issue in certain cases, [41] these reactions have been usually carried groups in the presence of either tBuOK, as for the formation of 8, or NaH.…”