Configuration-guided reactions: the case of highly decorated spiro[cyclopropane-1,2′(3′H)-pyrrolo[1,2-b]isoxazole] derivatives en route to polyhydroxyindolizidines

In the course of studies directed toward the synthesis of 7,8-disubstituted 1,2-dihydroxyindolizidines as analogues of the proapoptotic iminosugar lentiginosine, marked reactivity differences of diastereomeric spiro[cyclopropane-1,2’(3H)-pyrrolo[1,2-b]isoxazolidines] precursors were observed. While one minor diastereoisomer gives the Brandi–Guarna rearrangement to indolizidinone very smoothly, and also easily undergoes fluorination of the primary alcohol, the main diastereoisomer behaves in a rather different way. The thermal rearrangement is less efficient and fluorinating agents mainly induce an unexpected cyclization to a highly strained tetracyclic derivative that, in turn, rearranges to form the uncommon 2-oxa-8- azatricyclo[6.2.1.04,9]undecan-5-one system with good yield. In this last process a remarkable macrocyclic dimer has been isolated that sheds light on an unprecedented different aspect of the Brandi– Guarna rearrangement.