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 ß-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 ß-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.

Asymmetric Synthesis of a Bacteriochlorophyll Model Compound Containing trans-Dialkyl Substituents in Ring D.

Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include creating the macrocycle along with the trans-dialkyl substituents in both pyrroline rings (B and D). A known route to a model bacteriochlorophyll with a gem-dimethyl group in each pyrroline ring has been probed for utility in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1), which contains a trans-dialkyl group in ring D and a gem-dimethyl group in ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl, ß-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z, 3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions) gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the desired trans-dialkyl stereochemistry in ring D and was obtained as a 7:1 mixture of (expected) epimers owing to the configuration of the 132-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.