Ivan L. Pinto

A hetero Diels-Alder approach to novel thiopyran analogues of aprikalim, A potassium channel activator

Abstract α-Thioketo-ester (6) derived from Bunte salt (5) has been shown to undergo a hetero Diels-Alder reaction with a variety of dienes to form the basis of a concise synthesis of dihydrothiopyran analogues of the potassium channel activator aprikalim.

An unusual hydroxyl inversion mediated by dast

Abstract Trans -3-hydroxy-4-(2-oxopyrrolidin-1-yl) benzopyrans have been shown to undergo inversion to cis -3-hydroxy-4-(2-oxopyrrolidin-1-yl) benzopyrans in moderate yield on treatment with diethylaminosulphur trifluoride (DAST).

An unusual base-mediated ring contraction reaction of benzopyrans to benzofurans

Abstract The reaction of electron deficient pyrroles and pyrazoles with trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol under basic conditions results in the formation of 2-isopropylbenzofurans by a mechanism which appears to be dependent on the rate of the competitive dehydration reaction leading to the corresponding benzopyrans.

Conformational and steric modifications of the pyran ring of the potassium-channel activator cromakalim

The syntheses of analogues of the novel smooth muscle relaxant cromakalim, in which the C-2 methyl groups have been successively replaced by hydrogen, are described and the relative stereochemistry of the two corresponding, isomeric monomethyl compounds, unambiguously assigned by 1H NMR spectroscopic techniques. Single-crystal X-ray analysis of the 2α-monomethyl compound showed that it existed in a distorted half-chair conformation in the solid state and confirmed the relative orientation of the C-2, C-3 and C-4 substituents. The 2β-Me isomer appeared to exist in a single conformation in solution, with the pyran ring adopting a half-chair conformation and with all the substituents in this ring occupying a pseudoequatorial position. The solution behaviour of the 2α-Me isomer is more complex, however, although it seems likely to exist as a distorted half-chair conformer similar to that found in the solid state. The syntheses of two related benzoxepines are also described. All compounds were less potent than cromakalim itself, which is consistent with the view that dimethyl substitution at C-2 is essential for optimal activity.

An efficient synthesis of (±) 7-oxo-3-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-3,3-dioxide

The title compound was prepared in good yield via intramolecular insertion of an α-alkoxycarbonyl, α-sulphonyl carbene into the Nue5f8H bond of an azetidinone.

Structural modifications of the potassium channel activator cromakalim: the C-3 position

The syntheses of a selection of C-3 analogues of 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol, the potassium channel activator cromakalim 1, are described. Particular interest has focused on the corresponding 3-ketone 2 and compounds in which the hydroxy group of 1 has been replaced by fluorine, carbon and nitrogen containing residues. The hindered neopentylic nature of the C-3 hydroxy group in 1 has a marked effect on its reactivity and has necessitated the independent synthesis of many of these analogues from simpler precursors rather than from the direct modification of compound 1 itself.

Novel redox cyclisation products derived from 2-acylpyrroles and trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-chromene-6-carbonitrile

The reaction of 2-(trifluoroacetyl)pyrrole with trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-chromene-6-carbonitrile under basic conditions has been shown to afford high yields of (4R*, 5aS*,11 bS*)-5a-hydroxy-6,6-dimethyl-4-trifluoromethyl-5a,11 b-dihydro-4H,6H-pyrrolo[1′,2′:4,5]-oxazino[2,3-c]chromene-10-carbonitrile rather than the anticipated amino alcohol. The unequivocal structural assignment of this unusual tetracyclic product by spectroscopic and X-ray crystallographic techniques is described and possible mechanistic explanations for its formation are discussed. Analogous reactions of pyrroles substituted in the 2-position by formyl, acetyl and benzoyl moieties have been shown to behave in an essentially similar manner, suggesting that the reaction is general for 2-acylpyrroles.