Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments.  However, their complexity creates synthetic challenges in devising efficient methods to make analogs and to make quantities necessary for biological testing.  One particular challenge is the enantioselective synthesis of carbocyclic quaternary stereogenic centers.   Synthetic chemistry tools are being developed which will allow the efficient, enantioselective construction of carbocyclic quaternary stereocenters.  The methods combine the previously reported asymmetric Birch reduction-alkylation with the stereospecific Cope rearrangement (Scheme 1).  In sequence, the two reactions permit the efficient transfer of chiral information to enantioselectively create a new carbocyclic quaternary stereogenic center.  Modifications of the o-anisic acid Birch reduction substrate or the alkylation group will allow access to a range of carbocyclic quaternary centers with extremely high levels of stereocontrol.  Vicinal stereocenters, either quaternary-tertiary or quaternary-quaternary, are accessible by performing the alkylation with di- or trisubstituted alkenes, respectively. 

To demonstrate the potential for the Birch reduction-allylation/Cope rearrangement sequence to address challenges in natural product synthesis, an enantioselective total synthesis of (+)-lycoramine (Figure 1) is being undertaken.  There are currently no reported enantioselective syntheses of (+)-lycoramine, which is the dihydro derivative of (-)-galanthamine, a drug that has recently been approved for the treatment of Alzheimer's disease. 

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