Sulfenate Substitution as a Complement and Alternative to Sulfoxidation in the Diastereoselective Preparation of Chiral β-Substituted β-Amino Sulfoxides

Abstract

Building from a previous communication, the reaction of sulfenate anions with chiral N-Boc-protected β-substituted β-amino iodides was evaluated as a conceptually different synthetic approach to chiral β-substituted β-amino sulfoxides. Using arenesulfenates, yields typically ranged from 71% to 92%, and dr's were often near 9:1. Alkanesulfenates proved less reactive, delivering lower yields and dr's. 1-Alkenesulfenates demonstrated high reactivity, returning chemical yields of 60-86% and dr's often close to 9:1 and as high as 95:5. (S)-β-Amino iodide electrophiles yielded (R(S),S(C))-β-amino sulfoxides, whereas (R)-amino iodides afford (S(S),R(C))-β-amino sulfoxides. The absolute configuration of the products makes the sulfenate protocol complementary to other existing preparations, including the commonly employed sulfoxidation of β-amino sulfides. The reactivity of N-Boc-protected 2-benzyl-2-aminoethyl iodide was found to be superior to the less sterically encumbered n-butyl iodide. A transition state model is proposed to account for the stereochemistry of the products and also for the high reactivity of the electrophile. Overall, the chemistry represents a new means of introducing sulfur stereogenicity in a molecule.

N‐Sulfanylimides as the Sulfur Source for Alkyl Allenyl Sulfoxides via [2,3]‐Sigmatropic Rearrangement

“…Initial studies focused on the generation and capture of sulfenyl chlorides 1 a/b/c (Scheme 2), as the allenyl sulfoxide products of [2,3]‐sigmatropic rearrangement could generate sulfenate anion precursors [12b,13] . A preparation of sulfenyl chloride 1 a already has been introduced by our group, [14] and several attempts were made to prepare allene 2 a through capture of 1 a with 3‐phenyl‐2‐propynol.…”

Sulfenate anions as organocatalysts for benzylic chloromethyl coupling polymerization via C=C bond formation

“…Sulfenate anions (ArSO – ) are highly reactive intermediates in biological chemistry and in organic reactions 7 – 10 . We recently disclosed that sulfenate anions can act as organocatalysts and reported their ability to catalytically dehydrocouple benzyl halides under basic conditions to yield trans -stilbenes (Fig.…”

A Computational Determination of the Origins of Diastereoselective Alkylations of a Cysteinesulfenate Anion

“…If the sulfenate contains a stereogenic character in its backbone, the structural parameters within the stabilized sulfenate conformation could create an environment to deliver stereoselective S‐alkylation and possibly S‐arylation reactions. The computational model established here may also assist in the understanding of the diastereoselectivity observed when a chiral electrophile holds the appropriate coordinating functional groups,[11a] and an assessment of that experimental work is currently underway.…”

“…The latter grouping includes enantioselective substitutions in the presence of chiral phase transfer reagents or chiral chelating agents . Diastereoselective alkylation can be induced by chirality in the sulfenate or in the electrophile . Often, diastereoselective sulfoxide formation achieved through sulfenate intermediacy is superior or complementary to that arising from sulfide monoxidation.…”