N-alkenyl nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 7. Hydroxylamine–alkyne cyclisations. Formation of cyclic nitrones and application to the synthesis of the proposed structure for (±)-acacialactam

Abstract

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The reverse Cope cyclisation: a classical reaction goes backwards

“…Scheme 31) This does not apply to 1-trialkylsilyl-1-alkynes: such a derivative of the hydroxylamine 288 undergoes rapid reverse Cope cyclisation to give cyclic nitrone 289 with loss of the silyl group after the reverse Cope step. 63,64 Remarkably, however, the hydroxylamine-alkene version of the reverse Cope cyclisation wins out in the case of the 2-alkyne analogue 293 of the terminal alkyne 288 (Scheme 81), with the isomeric pyrrolidines 294 being formed instead in a combined yield of 83%. 63,64 In the absence of a competing mode of cyclisation, internal alkynes will then undergo alkyne-hydroxylamine cyclisations successfully [cf.…”

“…63,64 Remarkably, however, the hydroxylamine-alkene version of the reverse Cope cyclisation wins out in the case of the 2-alkyne analogue 293 of the terminal alkyne 288 (Scheme 81), with the isomeric pyrrolidines 294 being formed instead in a combined yield of 83%. 63,64 In the absence of a competing mode of cyclisation, internal alkynes will then undergo alkyne-hydroxylamine cyclisations successfully [cf. 291b], a further example being the conversion of the simpler hydroxylamine 295 into nitrone 296.…”

“…291b], a further example being the conversion of the simpler hydroxylamine 295 into nitrone 296. 64 can be obtained using this chemistry, but their formation is clearly not especially favoured and hence the yields are rather lower from the more vigorous reaction conditions required. What is remarkable about these cyclisations is the often extreme ease with which they proceed, in the absence of activating substituent effects such as Thorpe -Ingold compression.…”

“…64 emerging as the optimum solvents; carbon tetrachloride or acetonitrile, while seemingly effective for the cyclisation step, proved to be too reactive and extensive decomposition resulted. Subsequent addition of vinylmagnesium bromide led exclusively to the N-hydroxyazepine 304 and thence to the proposed structure 305 for the natural product, acacialactam, which this work showed to be incorrect.…”

Site selectivity in the addition of ketoximes to activated allenes and alkynes; N- versus O-alkylation

“…7 Further, Holmes and co-workers have reported that an enynylhydroxylamine preferentially cyclises on the alkyne moiety to give an alkenyl substituted dipole. 8 Thus it was anticipated that methyl propiolate and dimethyl acetylenedicarboxylate may be potent substrates in an intermolecular APT reaction and that the N-vinyl nitrones 2 may thus be readily accessible.…”