Permethyl analog of the pyrrolic antibiotic distamycin A

Abstract

The synthesis of an analogue of distamycin A, a pyrrolic oligopeptide possessing antiviral and antibiotic activity, is described in which each of the three pyrrole rings is fully methylated. This structural modification results in pyrrole rings which are extraordinarily electron rich and required the development of a new synthetic approach to these polypyrrolic amides. The key reactions involved development of a general method for the synthesis of 3-aminopyrroles and for formation of an amide bond between a pyrrole-2-carboxylic acid and these 3-aminopyrroles. Since the acid is hindered, a poor electrophile, and acid sensitive, while the amine is unstable and a hindered, weak nucleophile, amide bond formation under the usual conditions was poor. A very efficient method, however, was developed involving the isolation of 1-hydroxybenzotriazole active ester prepared in situ from another active ester. Neither the mono-, di-, nor tripyrrolic permethyl analogues were effective antimalarials, and none showed anticancer activity.

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

“…Based on this previously developed methodology,20,21 we prepared a set of pyrrole-type lexitropsin oligopeptides possessing at least one moiety which would be protonated at physiological pH.…”

Practical Synthesis of Active Esters of 4-Alkoxycarbonylamino-3-methoxypyrrole-2-carboxylic Acid

“…8 Attempted reaction of 4 with t-BuOH gave a complex mixture containing at best trace amounts of the desired Boc product, even when capture of the isocyanate with t-BuOH was attempted in the presence of catalysts such as CuCl. 9 In complete accord with Dervan, 5 more reactive allyl alcohol did combine with the isocyanate to produce the corresponding allyl carbamate, but only in 30-40% yield. A compound tentatively identified as 5 was also obtained from this reaction, raising questions about the viability of a free OH group during the Yamada step.…”

Predicting experimental yields as an index to rank synthesis routes II: application to the Curtius rearrangement

“…Because it is better to use more than 20 data for the PLS regression to have meaningful results, we gathered 91 papers describing synthesis experiments of the Curtius rearrangement. However, only 16 examples listed in Table included all the experimental data required for the PLS regression. Figure displays all the acyl azides used to generate a model equation between yields, E a values, and experimental conditions.…”