A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.
A 4-component Ugi reaction with a suitable isocyanide, followed by a novel secondary transformation involving a Pd(II)-mediated (R5 = H) or a Pd(0)-mediated (R5 = CO2Me) SN2' cyclization to give highly functionalized N-acyl-2-vinylpyrrolidines, is reported. The overall yields are usually good and in most cases the Pd(0)-catalyzed reaction gave the final product in almost quantitative yield.
A small library of natural product-like compounds has been assembled by coupling an Ugi multicomponent reaction with two postcondensation transformations, carried out in one-pot fashion: a S(N)2' cyclization followed by an intramolecular Heck reaction.
SummaryThe Ugi reaction of 2-substituted dihydrobenzoxazepines was found to proceed with unexpectedly good diastereoselectivitiy (diastereoisomeric ratios up to 9:1), despite the large distance between the pre-existing stereogenic centre and the newly generated one. This result represents the first good 1,4 asymmetric induction in an Ugi reaction as well as the first example of diastereoselective Ugi reaction of seven membered cyclic imines. It allows the diversity-oriented synthesis of various tetrahydro[f][1,4]benzoxazepines.
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