Spirocyclic scaffolds are embedded in many biologically active natural compounds, including candidates for medicines, perfumes and agricultural chemicals. Therefore, a development of efficient synthetic methods directed at those structures is strongly demanded. To this end, we have recently developed synthetic methodologies for two different spirocyclic frameworks based on Claisen rearrangement; (1) multifunctionalized spiro[4.5]decanes through Claisen rearrangement of bicyclic 2-(alkenyl)dihydropyrans, and (2) spirocyclic oxindoles through a sequential intramolecular Ullmann coupling (IUC) and Claisen rearrangement of 2-iodoindoles bearing allylic alcohol moiety. We have developed the Claisen rearrangement protocol by which bicyclic 2-(alkenyl)dihydropyrans bearing a functional group at the C4 position can be transformed to the corresponding spiro[4.5]decanes in good-to-excellent yields with excellent stereoselectivities. We applied this method to a concise total synthesis of (-)-Gleenol (3), from hindered dihydropyran 9 bearing all requisite functional groups with proper stereochemistry. The most striking features of this synthesis are that remarkable solvent effects in the key Claisen rearrangement has been observed, and that the rearrangement of 9 led to the fully functionalized spiro[4.5]decane 10 in a single step. Related Claisen rearrangement in (alkenyl)pyranoindole systems can be also achieved. Thus, a one-pot IUC/Claisen rearrangement sequence from 2-iodoindoles 14 was found to provide spirocyclic oxindoles 16 in good yields with excellent stereoselectivities. We applied this sequence to the asymmetric synthesis of pyrrolidinoindoline alkaloids, (-)-debromoflustramine B (22). Enantiomerically pure 2-lodoindole 17 was subjected to the IUC/Claisen rearrangement conditions to furnish spirocyclic oxindole (+)-16 in good yield with perfect asymmetric transmission. Further transformations including oxidative cleavage of the olefin in (+)-16 provided the pyrrolo[2,3-b]indoline 20. Finally, the total synthesis of 22 was accomplished via a two-step sequence.
