Tetrahydroisoquinoline asymmetric protonation

The first method using the j-BuLi-sparteine aggregate was successfully applied to the asymmetric protonation of 2-(l-phenylethyl)pyridine 5 to afford (S)-5 in good yield with 50% ee. The 4-aryl-tetrahydroisoquinoline backbone 6, which is of considerable interest because of its presence in several natural or bioactive products such as sertraline or nomifensine, was obtained in good yield with 88% ee. Although the backbone of bioactive compounds was synthesized in an asymmetric fashion, the total synthesis of the corresponding drugs or natural products has not yet been achieved to date. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

Use of a chiral proton source, a chiral base or base/chiral ligand complex circumvents the problem of incorporation and removal of a chiral auxiliary. Simpkins and coworkers opened the possibility of enantioselective protonation as a method for the asymmetric syntheses of 1-substituted tetrahydroisoquinolines [77]. Using the chiral amine 98 as a proton source, deracemization of 97 proceeded in up to 93 7 er, alleviating the requirement for a chiral auxiliary (Scheme 28). 

SCHEME 31.4. Enantioselective protonation of 1-substituted tetrahydroisoquinoline and asymmetric synthesis of (-)-salsolidine 9. 

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