Reductive coupling reactions, viii

Formation of this product, in the Heck coupling reaction, is the consequence of the migration of the C=C bond repeatedly observed in this catalytic reaction [21], and transitory formation of the enol form of ketone 15. Reduction of this ketone to the S-enantiomer of benzylic alcohol 16 is the key step on the path to the (R)-enantiomer of montelukast 1. The second Grignard reaction (vi), with subsequent activation of the benzylic OH group (vii) and protection of ferf-OH group (viii) afforded the first key intermediate 18. 

The large value of / 59, and its similarity to the reactions of Craq002 + with two other radicals of widely different reduction and oxidation potentials, Table VIII, strongly supports radical coupling as the mechanism for reaction 59. 

An obvious means by which to increase the affinity of a molecule for DNA is to link the molecule to a short segment of nucleic acid. Such a plan has been pursued by Paoletti and co-workers (129,130). To prepare the tetrathymidylate-ellipticine conjugate 348, these workers synthesized the appropriate ox-azolopyridocarbazole carboxylic acid, as described previously (i.e., 267), and coupled it to the appropriate tetradeoxynucleotide. A second method of linking ellipticine to a nucleic acid involves condensation of the aldehyde moiety of 3 -apurinic octathymidylate with 9-aminoellipticine, followed by reduction of the imine with sodium cyanoborohydride (130). This reaction is depicted in a different context in Scheme 66 (see Section VIII). 

The importance of the reaction rates of the different possible reactions has been vividly demonstrated by experiments, soon to be published, in which it was shown that osmium tetroxide, OSO4, so rapidly and completely passivates iron that an iron electrode in such a solution indicates the reversible potential of the Os-(IV)-Os(VIII) couple, exactly as registered by an indicating platinum electrode. In this case, the passivator itself is definitely the principal source of oxide ions because of the rapidity of its reduction. The reduction product is not reoxidized, however, and adsorption of unreduced inhibitor is apparently still required for permanent inhibition. 

Following the identification of the benzophenones (Fig. 2, IX, X and XII) as metabolic products of P. patulum, the reasonable and attractive hypothesis was advanced that griseofulvin biosynthesis proceeded by the pathway acetate-malonate -> (VIII) -> (IX) (X) -> (XII) (XIV) -> (XI) -> (I R = Cl) it received some support from the fact that the reactions (XII) -> (XIV) -> (XI) and (XI) -> (I R = Cl) had already been achieved in vitro by oxidative phenol radical coupling and stereospecific selective catal)d ic reduction respectively for review see Grove (1964). 

---