Chiral imidazoline nitrones for cycloaddition reactions

Martin, Jason Neil (2000). Chiral imidazoline nitrones for cycloaddition reactions. PhD thesis The Open University.



Previous work in this group has demonstrated that azomethine ylide 1,3-dipoles based on the 2-imidazoline chiral template show high regio- and enantioselectivity in their 1,3-dipolar cycloaddition reactions with a range of dipolarophiles. We proposed to synthesise nitrone 1,3-dipoles based on this 2-imidazoline template in order to investigate their utility in 1,3-dipolar cycloaddition chemistry.

We have developed the synthesis of chiral 4-phenyl-2-imidazoline nitrones 126a-c via a key hydroxylamino amine dihydrochloride intermediate 140a, available in four steps (61% overall yield) from commercial 2-chloroacetophenone. Nitrones 126a & 126b are generated rapidly and quantitatively from 140a by treatment with the appropriate triethyl orthoester. 2-Methyl nitrone 126b does not undergo a 1,3-dipolar cycloaddition reaction with common dipolarophiles, suggesting C-2 substitution is not tolerated in the transition state. On the other hand, we have shown 2-H nitrone 126a to react with many mono- and disubstituted alkynes and alkenes. The relative stereochemistry of the cycloadducts formed with 126a has been assigned by NOESY and X-ray crystallography. In each case, the dipole shows total diastereofacial selectivity in which the incoming dipolarophile is directed to the less hindered face of 126a by the bulky 4-phenyl group. The isolated cycloadducts are, almost without exception, formed via the exo transition state.

The cycloadduct of 126a with dimethyl maleate has been the focus of our efforts towards cleavage of the 2-imidazoline template. It is unreactive towards the conditions developed for template removal in the analogous azomethine ylides, despite many modifications. Cleavage of the isoxazolidine N-0 bond followed by spontaneous lactamisation afforded the lactam 271. Reduction of the lactam carbonyl would afford the pyrroloimidazole ring system, for which a template removal strategy is in place, but 271 has not to date afforded the desired material under a number of reaction conditions. For example, borane-complexed reagents gave a partially aromatised system in which three chiral centres are lost.

Thus, we have illustrated that these reagents, available from cheap commercial materials, are viable 1,3-dipoles capable of generating multiple chiral centres in a single step with total facial selectivity and have made progress towards the synthesis of chiral pyrrolidines.

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