Cyclic Sulfonimidates by Dynamic Diastereomer-Differentiating Cyclisation: Large-Scale Synthesis and Mechanistic Studies

Abstract

A dynamic diastereomer differentiating cyclisation is the key step in a new large-scale synthesis of both enantiomers of the cyclic sulfonimidates 1 (Aldrich no. 54099-4) and ent-1 (Aldrich no. 54412-4). These are valuable starting materials in the asymmetric synthesis of chiral oxa- and azaheterocyclic compounds. NMR spectroscopic studies on the reacting system reveal N-chloro sulfinamides to be reactive intermediates in the oxidative chlorination of sulfinamides with tert-butyl hypochlorite and allow for the inspection of the configurational behaviour of the involved sulfonimidoyl chlorides and sulfonimidoyl bromides.

Synthesis of Enantiopure Sulfonimidamides and Elucidation of Their Absolute Configuration by Comparison of Measured and Calculated CD Spectra and X‐Ray Crystal Structure Determination

“…The findings of Johnson7d and Reggelin13 on related systems suggested that the nucleophilic chloride displacement of sulfonimidoyl chlorides 6 and 7 with ammonia occurred with inversion of configuration. In order to confirm this hypothesis and to ensure the stereochemistry of the products it was decided to determine their absolute configuration by experimental and theoretical CD spectroscopy, which allowed establishing the spatial arrangement of the substituents at the chiral sulfur atom with a high degree of probability.…”

Synthetic approaches and applications of sulfonimidates

“…A rearrangement of 53 via a 6-electron transition state allowed access to sulfonimidates 54 with retention of configuration (Scheme 13a). However, from intermediate 53, an alternative route via an three-atom rearrangement (first reported by Reggelin and co-workers) 34 would afford a sulfonimidoyl iodonium 55a species that could be responsible for loss in enantiomeric excess during the transformation, yielding sulfonimidate 56 (Scheme 13b).…”

“…Nearly two decades ago, Reggelin shed light on the mechanism believed to be in operation during the synthesis of cyclic sulfonimidates. 34 He found through optimisation reactions that two particular pathways were in operation, depending on the base used in the reaction (Scheme 20). Oxidative cyclisation of an enantiomer of sulfinamide involved two key stereoselective steps; the first process is an oxidative chlorination reaction to afford sulfonimidoyl chloride intermediate 81, that proceeds with retention of configuration at sulfur.…”

Synthesis of Bis(4-methylphenylsulfonimidoyl)methane - The First ‘Free' Geminal Bis(sulfoximine)

“…Its reduction and O-protection delivered the TMS-protected amino alcohol rac-6 in good yields. Following the established synthetic procedure developed in our group, 23,24 the cyclic sulfonimidate rac-8 was obtained by sulfinylation and diastereoselective cyclization via the epimers rac-7 in good yield and diastereomeric ratio. After removal of the minor diastereomer by crystallization, the sulfonimidate was opened by methyllithium, the product deprotonated with LiHMDS and treated with another equivalent of rac-8.…”