Synthesis of chiral non racemic sulfonamides and application in asymmetric synthesis

Robert E. Boyd

doi:10.17918/00000490

The primary sulfonamide group (RSO₂NH₂) is an important building block in organic synthesis. For example, conversion to an iminoiodinane ylide (RSO₂N=IPh) activates this functional group to nitrene formation and subsequent insertion into carbon-carbon double bonds to afford N-protected aziridines. Furthermore, reaction of a sulfonamide with thionyl chloride gives the N-sulfinylsulfonamide (RSO₂N=S=O) which is capable of a number of cycloaddition reactions. While many of these reactions have been studied over the years, there has been relatively little effort aimed at the development of asymmetric versions of these synthetic transformations. (1S)-(+)-10-Camphorsulfonamide is an optically active sulfonamide which is readily available from inexpensive starting materials. An improved synthesis has been developed, which affords an 80% yield of this key intermediate with no purification. The use of a benzyl protecting group enabled the synthesis of analogues of this chiral auxilliary such as (-)-2-methoxycamphorsulfonamide. Acid catalyzed rearrangement of (1S)-(-)-camphorsulfonamide-2-ol provided (+)-trans-camphenesulfonamide, the prototype of a new class of chiral non racemic sulfonamides. Reaction conditions were optimized so as to obtain this novel chiral auxilliary in good yield with an optical purity >90%. Recrystallization from acetone/hexane increased this to >98% ee, with an isolated yield 50-55%. In addition, deuterium labeling studies were conducted and a "bridged carbocation" mechanism is postulated for this rearrangement. The use of benzyl and p-methoxybenzyl protecting groups were again employed to prepare 10-alkyl analogues of trans-camphenesulfonamide. These analogues as well as the parent compound were evaluated for asymmetric induction in the aziridination reaction and the cycloaddition of the N-sulfinyl derivitive. The iminoiodinane ylide reagents derived from trans-camphenesulfonamide and related structures were found to be significantly less stable to hydrolysis than the arylsulfonamide counterparts. The use of alkyl-substituted aryliodo-(diacetates) in this reaction produced ylides which were more stable and afforded N-(trans-camphenesulfonyl)-aziridines upon treatment with an olefin and a copper catalyst. Sulfonyl protected aziridines were also obtained from ylides which were generated in situ under anhydrous conditions, and immediately reacted with an olefin and copper catalyst. Minimal asymmetric induction was observed from either protocol and the diastereomeric products were inseparable. Reaction of N-sulfinyl-trans-camphenesulfonamide (RSO₂NSO) with cis,trans-2,4-hexadiene produced two diastereomeric cycloadducts. An endo transition state is proposed and stereodifferentiation is postulated to be the result of steric interactions. The diastereoselectivity resulting from the chiral auxilliary was essentially nill. An interesting, although prescedented, reaction of a sulfonamide with thionyl chloride and pyridine to yield a sulfonyl chloride was developed. This development led to the synthesis of trans-camphenesulfonimide by reaction of the sodium salt of trans-camphenesulfonamide with the trans-camphenesulfonylchloride. Reaction of (-)-camphorsulfonamid-2ol with benzaldehyde yielded a chiral cyclic sulfonylaminal. Attachment of achiral ligands affords the possibility of further reaction of these ligands with concurrent asymmetric induction. Finally, an active halogenating reagent is obtained upon reaction of this sulfonylaminal with NaOCl.

Synthesis of chiral non racemic sulfonamides and application in asymmetric synthesis

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Synthesis of chiral non racemic sulfonamides and application in asymmetric synthesis

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