Stereoselective substitution of the hydroxyl group in chiral cyanohydrins

The synthetic potential of non-racemic cyanohydrins can be extended considerably by converting the hydroxyl group into a good leaving group, which could be exchanged stereoselectively with any kind of nucleophile.

Nucleophilic substitutions of O-activated 2-hydroxy carboxylic acids and esters, respectively, are well established,2021 but little is known about the analogous reactions of activated cyanohydrins. Chiral 2-sulfonyloxynitriles, accessible from non-racemic cyanohydrins, have a relatively high configurational stability.29 They react with nucleophiles under very mild conditions under inversion of configuration (Scheme 8).30-31

Scheme 8: Stereoselective reactions of non-racemic 2-sulfonyloxy nitriles with nucleophiles.

The chemical yields in all substitution reactions are normally higher than 80%. The optical yields in case of 2-sulfonyloxy nitriles derived from aliphatic aldehydes (R = aliphatic) are very high (ee 94-99%), whereas in case of aromatic derivatives (R = Ar) partly racemization occurs (ee ~ 80%). For these substrates, the Mitsunobu reaction represents an alternative to the O-activation combined with nucleophilic substitution.32 The (S)-configurated products obtained by nucleophilic substitution of (R)-2-sulfonyloxynitriles (Scheme 8) can be transformed stereoselectively into other interesting compounds. (S)-2-azidonitriles can be hydrogenated to give (S)-2-aminonitriles or chiral 1,2-diamines.30b Optically active 2-aminothiols are accessible from the substitution product with thioacetate by hydrogenation of the nitrile function.31 Chiral 2-aminothiols could be of interest as complexing agents for metal ions in chiral catalysts or as educts for the synthesis of optically active heterocycles.

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