Trehazolin (2) is a specific inhibitor of trehalase, an enzyme that cleaves the reserve carbohydrates of many insects. We describe a short and efficient synthesis of trehazolin (2) and trehazolamine (5) that mimics its hypothetical biosynthesis. Starting molecule for the synthesis of trehazolamine (5) is glucose from which three chiral centers are conserved during the reaction sequence. The remaining two chiral centers of trehazolamine (5) are formed stereoselectively in a reductive cyclization of ketooxime ether 16 and the reduction of oxime ether 18. The overall yield of trehazolamine (5) is 22% over 8 steps from 15. The synthesis of trehazolin (2) from trehazolamine (5) follows a known procedure and is achieved in 63% over 3 steps.
The syntheses of all four imidazolo-piperidino-pentoses in the L-series ent-2 to ent-5, and of three out of the four possible stereomers in the D-series 3, 4, and 5, are reported. The linear imidazolo sugar precursors were prepared, either by double condensation of formamidine with protected aldohexoses, or by nucleophilic addition of a lithiated imidazole derivative to protected aldotetroses. Cyclisation of these linear imidazolo-carbohydrates was performed by intramolecular S N 2 reactions. These were followed by deprotection to
Asymmetric methylation and phenylation of the chiral pyridinium salt 7, as well as methylation of chiral pyridinium salt 18, with Grignard reagents occurred in good yield and with good‐to‐excellent diastereoselectivities (Schemes 2 and 3, resp.). These results are best explained by assuming chelate control to govern the asymmetric alkylation/arylation process. The minimum‐energy conformations of the out‐of‐plane twisted pyridinium salts 7 and 18, as determined by the ‘Molecular Simulations Cerius‐Dreiding II’ program, are in good agreement with the postulated asymmetric chelate‐control mechanism.
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