Convenient Synthesis of Pyrrole‐ and Indolecarboxylic Acid tert‐Butylesters.

Abstract

Indole derivatives R 0140 Convenient Synthesis of Pyrrole-and Indolecarboxylic Acid tert-Butylesters. -The title reaction represents a general direct route to the required enzyme inhibitors. -(LUDWIG, J.; LEHR*, M.; Synth. Commun. 34 (2004) 20, 3691-3695; Inst. Pharm. Med. Chem., Westfael. Wilhelms-Univ., D-48149 Muenster, Germany; Eng.) -H. Toeppel 12-124

The oxygen-independent coproporphyrinogen III oxidase HemN utilizes harderoporphyrinogen as a reaction intermediate during conversion of coproporphyrinogen III to protoporphyrinogen IX

“…Harderoporphyrin trimethyl ester 7 was synthesized by condensation of pyrromethanes 3 and 5 following a modified MacDonald approach that constructs the tetrapyrrole in a convergent approach from a northern and southern segment (Figure 3) (Arsenault et al, 1960;Carr et al, 1971;Cavaleiro et al, 1973Cavaleiro et al, , 1974Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004). A slightly modified protocol was used for condensation of pyrromethanes 3 and 5 to avoid large amounts of self-condensation product 8 of the southern fragment 5.…”

“…Co-crystallization of HemN with coproporphyrinogen III would provide the necessary insight into the orientation of the substrate and its propionate side chains in the active site of the enzyme. Considering our findings that harderoporphyrinogen is a possible HemN reaction Harderoporphyrin trimethyl ester (7) was synthesized by condensation of pyrromethanes (3) and (5) following the modified MacDonald approach with some minor modifications as described in the text (Arsenault et al, 1960;Carr et al, 1971;Cavaleiro et al, 1973Cavaleiro et al, , 1974Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004). intermediate, the ring A propionate side chain of coproporphyrinogen III is expected to be found in close proximity to the w4Fe-4Sx-bound S-adenosyl-L-methionine. Further biochemical and crystallographic studies are needed to understand how the reaction intermediate harderoporphyrinogen is further decarboxylated.…”

“…Pyrromethanes (1) and (4) were synthesized as previously described (Carr et al, 1971;Chen et al, 1999;Lash et al, 1999;Ludwig and Lehr, 2004).…”

Convenient Synthesis of tert‐Butyl Esters of Indole‐5‐carboxylic Acid and Related Heterocyclic Carboxylic Acids

“…With these procedures, we did not succeed in synthesizing all isomeric tert-butyl pyrrole-and indolecarboxylates. [1] In contrast, this was possible by reacting pyrrole-and indolecarboxylic acids with an excess of N,N-dimethylformamide di-tert-butyl acetal in refluxing benzene according to a method published by Widmer. [1,2] The lowest yield of all compounds synthesized was obtained for tert-butyl indole-5-carboxylate (32%).…”

“…tert-Butyl Indole-5-carboxylate (3) [1] A solution of tert-butyl trichloroacetimidate (2) (0.66 g, 3.0 mmol) in dry cyclohexane (3 ml) was added dropwise under a nitrogen atmosphere to a solution of indole-5-carboxylic acid (1) (0.25 g, 1.5 mmol) in dry THF (1.5 ml). After addition of BF 3 -etherate (0.03 ml), the mixture was stirred at room temperature for 30 min, diluted with aqueous NaHCO 3 solution (5%), and extracted with ethyl acetate.…”