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Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study
Author(s) -
Boyd Derek R.,
Sharma Narain D.,
Belhocine Tayeb,
Malone John F.,
McGregor Stuart T.,
Atchison Jordan,
McIntyre Peter A. B.,
Stevenson Paul J.
Publication year - 2013
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.3183
Subject(s) - chemistry , enantiopure drug , allylic rearrangement , sigmatropic reaction , azide , nucleophile , sodium azide , substitution reaction , lewis acids and bases , sodium ethoxide , cyclohexene , electrophile , stereochemistry , nucleophilic substitution , cis–trans isomerism , stereoselectivity , medicinal chemistry , organic chemistry , enantioselective synthesis , catalysis , ethanol
The reactions of enantiopure cyclohexene epoxides and trans ‐1,2‐bromoacetates, derived from the corresponding substituted benzene cis ‐dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2‐aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans ‐1,2‐azidohydrins were prepared by Lewis acid‐catalysed ring‐opening of cyclic vinyl epoxides with sodium azide via an S N 2 mechanism. On heating, these trans ‐1,2‐azidohydrins isomerized to the corresponding trans ‐1,4‐azidohydrins via a suprafacial allyl azide [3,3]‐sigmatropic rearrangement mechanism. Conversion of a 1,2‐azidohydrin to a 1,2‐azidoacetate moved the equilibrium position in favour of the 1,4‐substitution product. Allylic trans ‐1,2‐bromoacetates reacted with sodium azide at room temperature to give C‐2 and C‐4 substituted products. A clean inversion of configuration at C‐2 was found, as expected, from a concerted S N 2‐pathway. However, substitution at C‐4 was not stereoselective and resulted in mixtures of 1,4‐ cis and 1,4‐ trans products. This observation can be rationalized in terms of competitive S N 2 and S N 2′ reactions allied to a [3,3]‐sigmatropic rearrangement . cis ‐1,2‐Azidohydrins and cis ‐1,2‐azidoacetates were much more prone to rearrange than the corresponding trans ‐isomers. Reaction of the softer tosamide nucleophile with trans ‐1,2‐bromoacetates resulted, predominantly, in C‐4 substitution via a syn ‐S N 2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans ‐1,2‐aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S N 2 mechanism. Copyright © 2013 John Wiley & Sons, Ltd.