Quinine Synthesis Studies:  A Radical−Ionic Annulation via Mn-Mediated Addition to Chiral N-Acylhydrazones

Abstract

A radical-ionic annulation approach to functionalized perhydroisoquinolines involving Mn-mediated coupling of alkyl iodides and chiral N-acylhydrazones was achieved using only 1.25 equiv of the alkyl iodide. Application of this reaction to alkene-containing substrates en route to quinine offered modest yields, decreasing on scaleup. Control experiments revealed that the alkene interfered with the coupling reaction. A revised approach involving prior oxidation of the alkene offered 93% yield in the Mn-mediated coupling, with the adduct obtained as a single diastereomer.

Asymmetric Methods for Radical Addition to Imino Compounds

“…Clearly, this would be a prohibitive stoichiometric requirement for an iodide such as 41, prepared through several synthetic steps. To our great delight, the Mn-mediated coupling of 40 with only 1.25 equiv 41 proceeded in 93% yield in 1 mmol scale, giving 42 as a single diastereomer [34]. The low stoichiometric requirement in the coupling of the multifunctional alkyl group of 41 to an imino compound is quite attractive and should enable broader applications of this Mn-mediated coupling process in complex target synthesis.…”

Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine

“…As an alkaloid of some complexity and synthetic challenge, quinine presented a worthy adversary against which to test the limits of this reaction in a multifunctional molecular setting in natural product synthesis. 22 …”

“…Its proposed coupling partner, radical precursor 5a , was prepared as previously described. 22 The stage was set to attempt the key Mn-mediated coupling. A mixture of hydrazone 1 , iodide 5a , and Mn 2 (CO) 10 was subjected to photolysis (Rayonet, 300 nm) in the presence of InCl 3 , but to our dismay no coupling product was observed.…”

“…The findings above, taken together with a separate series of experiments demonstrating the detrimental effect of the alkene functionality on yield, 22 led to a revision of the strategy which entailed two main changes (Scheme 4). First, the 6-methoxyquinoline would need to be introduced during a later stage in the synthesis, perhaps using an organometallic reagent prepared from 4-bromo-6-methoxyquinoline, 28 Second, the original late-stage C6–C7 bond cleavage tactic (e.g., alkene ozonolysis) was changed to oxidative cleavage of a vicinal diol, which would require oxidation of the C6–C7 alkene prior to the radical addition.…”

“…First, the radical–ionic annulation was completed in a stepwise fashion. The S N 2-type cyclization of a tosylate derived from 11 proceeded to a piperidine structure analogous to 12 , 22 but that material could not be advanced due to difficulties in N–N bond cleavage. After some experimentation, it was found that cleavage of the N–N bond prior to piperidine ring construction led to an efficient overall process (Scheme 5).…”