Synthesis of a BC-Dihydrodipyrrin Building Block of Bacteriochlorophyll a

A strategy for the synthesis of bacteriochlorophyll a relies on joining AD and BC halves that contain the requisite stereochemical configurations of the target macrocycle. The BC half (1) is a dihydrodipyrrin bearing a dimethoxymethyl group at the 1-position, a β-ketoester at the 8-position, and (R)-2-methyl and (R)-3-ethyl substituents in the pyrroline ring. An established route to AD-dihydrodipyrrins (Pd-mediated coupling of a 2-halopyrrole with a chiral 4-pentynoic acid followed by Petasis methenylation, acidic hydrolysis, Paal-Knorr ring closure, and Riley oxidation) proved to be unviable for BC-dihydrodipyrrins given the presence of the β-ketoester unit. A route presented here entails Pd-mediated coupling of a 2-halopyrrole (2) with (3R,4R)-4-ethyl-1,1-dimethoxy-3-methylhex-5-yn-2-one (3), anti-Markovnikov hydration of the alkyne to give the 1,4-diketone, and Paal-Knorr ring closure. Compound 3 was prepared by Schreiber-modified Nicholas reaction beginning with (S)-4-isopropyl-3-propionyloxazolidin-2-one and the hexacarbonyldicobalt complex of (±) 3-methoxy-1-(trimethylsilyl)pentyne followed by transformation of the aldehyde derived therefrom to the 1,1-dimethoxymethylcarbonyl motif. The absolute stereochemical configuration of the Schreiber-Nicholas alkylation product was confirmed by single-crystal X-ray diffraction, whereas the BC half (1) by ¹H NMR spectroscopy showed a J value of 2.9 Hz consistent with the trans-configuration. Taken together, the route provides a key chiral building block for the synthesis of photosynthetic tetrapyrroles and analogues.