Stereoselective Routes to -Sertraline

Enantioselective synthesis of (+)-sertraline, (15,45)-TM 9.3, can be completed starting from either achiral building blocks, completing the key reaction in an enantioselective fashion, or starting from chiral raw materials, available from the chiral pool of nature, and completing the key reaction in a diastereoselective mode. 

Diastereoselective reduction of optically pure imine (45)-TM 9.3b to (-i-)-ier-traline (1S,4S)-TM 9.3 is completed with achiral heterogeneous catalysts for hydrogenation, RaNi/Ha or Pd/C/Ha. 

Note Mew-compounds are prochiral strucmres possessing an internal symmetry plane and hence two enantiotopic groups. Two chiral centers separated by a symmetry plane are of the opposite configurations. Modification of one of the 

Addition of bromine is promoted by tert-ssmae, but elimination of hydrogen bromide requires a strong organic base, DBU. Regioselective elimination of HBr deserves comment. The kinetically preferred product is formed on the elimination of bromine from the benzylic C atom and hydrogen from the vicinal position. Then, the 1,2-shift of bromine leads to (R)-IO with the Br atom in the benzylic position. 

Coupling of (R)-IO and (R)-ll to (R)-12 is completed by the well-known Suzuki-Miyaura reaction where Pd(0) complex catalyzes the formation of the C-C bond (Sect. 6.3, Example 6.4). In the next step, the protecting group is eliminated and the C=C bond reduced by achiral Ir(I) complex to trans-(lR,4S)-14. It is important to note the wrong R configuration at the C(l) atom in this and the previous intermediate. Inversion of the configuration in (15,45)-15 is achieved by the Mitunobu reaction with diphenylphosphorylazide (dppa) as the source of nucleophilic azide ions in the presence of DBU. This reaction is the method of choice for the transformation of alcohols in many other functionalities, azides, esters, alkyl-aryl ethers, imides, sulfonamides, etc., and its mechanism is explained in considerable detail [21, 22]. 

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