Total synthesis of phalarine.

rearrangement were elucidated and we assumed that a total synthesis of 1would be a straightforwardmatter. As described below, we were indeed able to accomplish the inaugural total synthesis of phalarine using the rearrangement strategy, although significant obstacles had to be overcome. For a total synthesis of phalarine, it would be best if the rearrangement could be conducted on an advanced-stage arylated ketone. This would reduce the complexity in going from the rearrangement product to the desired phalarine. However, as we were to learn, the key C C bond-forming step, which would join for example, an aryl species 6 to an oxindole 5, became highly problematic if conducted with complex C4 lithiated indoles (Scheme 2). As we conceded ground in the complexity of the aryllithium species 6 in the joining step, the pathway to phalarine from the postrearrangement product became increasingly challenging. Harmonization of these competing vectors (the feasibility of coupling the aryl nucleophile to the azaspiroindolenine species versus access to the final target system from the rearrangement step) became the hallmark of the expedition. Under our first approach, we envisioned coupling the lithio species 9 (prepared from 8) with the oxindole 5 (Scheme 3). Unfortunately, yields from this coupling were very low. Given these and the other failures encountered in the coupling reactions of carbonyl electrophiles with complicated, hindered aryl lithium reagents, we decided to attempt the coupling of lithio derivative 12 (generated from bromo compound 11) with oxindole 5. Indeed, carbon–carbon coupling was realized to afford ketone 13. Fortunately, the anticipated rearrangement of azaspiroindolenine to the phalarine precursor took place under the conditions shown in Scheme 3, to provide 14 in 72% yield.