Benzyl amine diastereoselective hydrogenation

Modification of the products that resulted from the aza-annulation of tetrasubstituted enamine substrates with acrylate derivatives was very limited. The aza-annulation of benzyl ester 496 with the mixed anhydride, a mixture (497) preformed from EtC CCl and sodium acrylate, provided a route to 498 in >98 2 diastereoselectivity (eq. 100), which allowed access to the carboxylic acid derivative 499 through catalytic hydrogenation.1 Further elaboration of either the ester or the acid derivative was unsuccessful, possibly due to the steric congestion around the reactive functionality. Extended hydrogenation did not reduce the enamine functionality, as observed in related substrates, and 498 was relatively stable to acidic hydrolysis conditions. In addition, DCC (N,N -dicyclohexylcarbodiimide) coupling of acid 499 with either benzyl amine or glycine ethyl ester was unsuccessful. 

A second-generation process ronte was developed that improves upon the initial process route (Scheme 6). - - In this simplified process approach, the molecular symmetry of the starting caronic anhydride was maintained to the latest stage possible. Caronic anhydride (30) was initially converted directly to imide 40 by heating with either ammonium hydroxide or formamide with DMAP under Dean-Stark conditions. In an alternative two-step protocol, heating of 30 with benzyl amine produced an intermediate benzyl imide, which was deprotected to 40 under catalytic hydrogenation conditions. Reduction of imide 40 with lithium aluminum hydride afforded 41, which was desymmetrized under oxidative conditions to produce racemic imine 42. Diastereoselective cyanation favored trans-43, which underwent methanolysis under Pinner conditions. Finally, classical resolution by crystallization with D-DTTA afforded 24 as the D-DTTA salt with >95% ee. 

Hydrogenation of 25 was accomplished using Pearlman s catalyst to provide amino-ester 28 as a 10 1 mixture of diastereoisomers favoring the desired cis isomer.Excess acid (>1 equiv of p-toluensulfonic or sulfuric acid) was necessary to facilitate the hydrogenation by promoting relatively rapid nitrile reduction to protonated amine 26. This protocol prevents catalyst deactivation. Acid also catalyzes the subsequent benzylic alcohol dehydration and the final reduction to 28. The observed increase in diastereoselectivity during the hydrogenation is consistent with acid-catalyzed elimination of water to form intermediate indene 27 followed by reduction from the least hindered face of 27 to afford the cis isomer of 28 as the major product. We did not observe elimination of water prior to nitrile reduction. ... 

---