Saphenic acid

Phenazines — These are dibenzopyrazine derivatives with fnnctional groups (hydroxy-, carboxy-) at C, and Cg and an oxygen or methyl gronp at Nj and N,o. There are also more complex structures, substituted phenazines, terpenoidal, and carbohydrate-containing phenazines and phenazines derived from saphenic acid. ... 

The more recently discovered and most unusual structures include the dimeric phenazine derivatives esmeraldin A (52) and esmeraldin B (53), which are produced by Streptomyces antibioticus Tii 2706 together with 49 [54]. Esmeraldins exhibit no antibacterial activity but 53 is effective against tumor cells. Much effort has been directed to the elucidation of the biosynthesis of the esmeraldins [55]. Some rare L-quinovose esters (55a-d) of saphenic acid have... 

An example of the method described is the synthesis of saphenic acid (47) that has recently been reported by Nielsen et al. [81]. Starting from properly substituted aromatic precursors 92 and 93, the naturally occurring 1,6-disub-stituted phenazine was synthesized in racemic form. Here, the first major step involves an intermolecular nucleophilic aromatic substitution that, due to the substitution pattern, has proved to be relatively unproblematic and after hydrolysis of the acetal yields the o-nitrodiphenylamine 94. Much more difficult is the ring formation leading to the final phenazine, which can best be achieved through a high excess of NaBH4, accompanied by reduction of the methyl ketone. But at 32%, the yield is still rather poor. 

So the saphenic acid (47), which has only weak biologic activity, was available as a template for the preparation of both saphenamycin (49) and saphenamycin analogs [82]. Reaction of the allylic ester 95 of the saphenic acid with the acid... 

Figure 4. Saphenic acid derived isolates from Streptomyces sp.

The biosynthesis of saphenic acid (27) and derivatives thereof is based on addition of a one-carbon unit to phenazine-1,6-carboxylic acid (Iq, Scheme 3). The transfer of a methyl group from C2 of acetate is a well-known biosynthetic transformation and occurs when the thioester of acetyl coenzyme A is converted by acetyl-CoA carboxylase to malonyl-CoA. Malonyl-CoA undergoes a decarboxylative Claisen condensation with a mono-CoA thioester of phenazine-1,6-... 

Saphenic acid derivatives Esters R = R CO (63) Carbamates R = R NHCO (64)... 

Bahnmiiller et al. have applied the Wohl—Aue procedure for the synthesis of ketal-protected natural product saphenic acid. Heating anthranilic acid and ethylene ketal-protected 3-nitroacetophenon in the presence of KOH and sand to 200 °G afforded saphenic acid (27) in very low yield (less than 5%). ... 

Observed limitations include partial decarboxylation during ring closure in the synthesis of phenazine-1,9-dicarboxylic acid as well as poor yield and very low reactivity of ketal-protected ketone diphenylamine in the cyclization step of saphenic acid synthesis. The deprotected ketone was cyclized and reduced in one step, affording the desired saphenic acid in satisfactory yields. 

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