Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem Reactions

Abstract

Reported here are details on the discovery of a phosphine-catalyzed isomerization of hemiketals and subsequent reactions of the cyclic keto enol ether products. The new cycloisomerization complements a previously reported amine-catalyzed process that gave oxepinones from the same hemiketal starting materials. In the absence of functionality (R(2)) on the cyclic keto enol ether, a rapid and facile dimerization occurs, giving spiroketal products. When the enone is substituted (i.e., R(2) = Ph), the cyclic keto enol ether is sufficiently stable so that it can be isolated; it can then be further reacted in the same pot to provide the corresponding dihydropyrazoles. Both the spiroketal and dihydropyrazole products arise by a tandem reaction that begins with the novel cycloisomerization. The method allows for the rapid introduction of complexity in the products from relatively simple starting materials. It should find application in the synthesis of natural product-like molecules.

Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce substituted exo -glycals

“…A gold-catalyzed ring-closure reaction of alkyne F was developed for the synthesis of O-perbenzylated (Z)-phenyl-exo-glucal E [10]. Phosphine-mediated cycloisomerization of alkynyl-substituted hemiketals I resulted in acetal-protected phenyl-substituted exo-glycals E as single Zdiasteromers with a 2-keto functionality in the pyranoid ring [22].…”

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation

“…We recently reported the discovery of a phosphine‐mediated cycloisomerization of alkynyl hemiketals (e.g., 1 to 2 in Figure ). For terminal alkynes, enone intermediate 2 rapidly dimerized to give a spiroketal product, 3 . The reaction led to relatively complex spiroketals from starting materials that were readily accessible.…”

“…The structure, when compared to that of the starting material, showed that a total rearrangement of the spiroketal had occurred. The spiroketal in 3 was of the variety where both linkages contained anomeric relationships . Product 7 , in contrast, contained two spiroketals, each with one anomeric and one nonanomeric relationship.…”

“…For terminal alkynes, enone intermediate 2 rapidly dimerized to give as piroketalp roduct, 3. [13] The reaction led to relativelyc omplex spiroketals from starting materials that were readily accessible. WithDOS in mind, [14] we took the opportunity to further diversify these small molecules through subsequent reactions.…”

Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)-ones and 2,3-Dihydropyridin-4(1H)-ones from β-Substituted β-Hydroxyaminoaldehydes

“…56−58 This also ruled out the possibility that 6 -exo-trig products had formed, in which case the 1 H NMR chemical shifts for the vinyl protons would be expected at 6.7 ppm. 59 …”