Liebeskind variation

Chemistry conceptually similar to that described for tamoxifen analogs 218 has been applied to the synthesis of CDP840 222, a phosphodiesterase (PDE) IV inhibitor for the treatment of asthma [78]. In combination with the Liebeskind-variation of the Suzuki reaction, thiopyrimidine ether 220 was cross-coupled to pyridyl-4-boronic acid 210 to afford 221. Catalytic hydrogenation of the olefin gave rise to 222. 

The key step in the synthesis of CDP840 ( 108), a phosphodiesterase IV (PDE IV) inhibitor for the treatment of asthma included the Liebeskind variation of the Suzuki reaction i.e., the thiopyrimidine ether 106 was cross-coupled with pyridyl-4-boronic acid to afford 107. Catalytic hydrogenation of 107 then afforded racemic 108. 

The 2-indolinone pharmacophore is present in a large number of pharmaceutically active compounds and could be constructed by a tandem Heck-Suzuki reaction sequence. Intramolecular Heck reaction of 133 afforded a cyclized intermediate that, in situ, reacted with boronic acid 134 to produce 135 in a single-pot sequence. The reaction used the Liebeskind variation of the Suzuki reaction (CuTC). 

Liebeskind and Welker reacted 720 with lithium diisopropylamide (sec. 9.2.A) and propanal, showing the enantioselectivity in the final P-hydroxy acids (722 and 723) to be dependent on the conditions used to form the enolate. If diisobutylaluminum chloride (i-Bu2AlCl) was used, a 5.2 1 mixture of 722 and 723 was reversed (to 1 11.6) in 66% yield. Good enantioselectivity was observed in this reaction also. The acyl iron derivative behaves essentially as a protected acid, where the iron group is a chiral auxiliaryThe chiral iron moieties are useful variation of enolate condensation chemistry (sec. 9.4.B). In addition to the formation of the condensation product, the high asymmetric induction will prove valuable. 

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