Synthesis of Chiral N‐Sulfonyl and N‐Phosphinoyl α‐Halo Aldimine Precursors

Abstract

a-Halogenated aldimines have emerged as an important class of synthetic intermediates. The stability and reactivity of a-halo aldimines can vary greatly depending on the nitrogen protecting group. A general synthesis of stable, chiral a-halo-N-sulfonimines can be isolated upon treatment with a mild base. Enantioenriched a-chloro aldehydes can be employed to afford aldimine precursors with no erosion of optical purity. Both the enantioenriched aldi-mine precursor and the isolated aldimine can react with an alkynyllithium nucleophile to give trans-bchloroamine products with excellent dr. Ring closure affords the enantioenriched trans-aziridine, demonstrating the potential for this approach in complex molecule synthesis. Scheme 1. Formation of a-amido sulfone 1.

Acyclic Stereocontrol in the Additions of Nucleophilic Alkenes to α‐Chiral N‐Sulfonyl Imines

“…[15À17] Diastereoselective additions to N-sulfonyl imines are limited to six reports. Walsh has reported remarkable syn-selectivity in the addition of organozinc reagents [20,21] to a-chloro N-sulfonyl imines, and as ingle occurrence [21] of an anti-addition using alkynyllithium. Walsh has reported remarkable syn-selectivity in the addition of organozinc reagents [20,21] to a-chloro N-sulfonyl imines, and as ingle occurrence [21] of an anti-addition using alkynyllithium.…”

“…Reetz has presented the anti ‐selective additions of Grignard reagents and cyanide to α‐amino N‐tosyl imines. Walsh has reported remarkable syn ‐selectivity in the addition of organozinc reagents to α‐chloro N ‐sulfonyl imines, and a single occurrence of an anti ‐addition using alkynyllithium. Marek expanded Walsh's additions of organozincs to α‐chloro N‐tosyl imines to produce more stereochemically complex addition products through acyclic stereocontrol …”

Diastereoselective Base-Catalyzed Formal [4 + 2] Cycloadditions of N-Sulfonyl Imines and Cyclic Anhydrides

“…We initially predicted that the addition would be governed by the polar Felkin–Anh model, 26–30 consistent with two reports of homophthalic anhydride enolate additions to alkyl imines. 31,32 However, we know of only two examples of nucleophilic addition to α -chiral N -sulfonyl imines without addition of exogenous chelating agent; one was governed by the Cornforth–Evans model, 33 and the other, a Grignard addition, did not give the expected chelation-controlled product. 34 With the steric bulk of the sulfonyl group in play, the classic polar Felkin–Anh and Cram chelation addition models may not adequately describe additions to N -sulfonyl imines.…”

Recent Functionalizations of Primary Sulfonamides

“…Walsh and co-workers explored a practical approach to storable, enantioenriched α-chloro aldimine precursors 54.1, via α-amido sulfones. 123 The chemistry can be performed either under aqueous conditions or in dichloromethane, which certainly broadens the reaction scope (Scheme 54). The authors demonstrated that under basic conditions, the α-chloro aldimine 55.1 could be generated in situ, and further reacted with lithium trimethylsilylacetylide to achieve β-chloroamine 55.2 in 85% yield as a single diastereomer.…”