Study of conditions for streamlined assembly of a model bacteriochlorophyll from two dihydrodipyrrin halves

Abstract

A long-term goal is to gain synthetic access to native photosynthetic bacteriochlorophylls. A recently developed route entails Knoevenagel condensation of an AD dihydrodipyrrin (I, bearing a carboxaldehyde attached to pyrroline ring D) and a BC dihydrodipyrrin (II, bearing a β-ketoester attached to pyrrole ring C) to form the Z/E-enone. Acid-mediated double-ring closure of the E-enone III-E (Nazarov cyclization, electrophilic aromatic substitution, and elimination of methanol) affords the bacteriochlorophyll skeleton BC-1 containing the isocyclic ring (ring E), a trans-dialkyl group in ring D, and a gem-dimethyl group in ring B. Prior work established the synthesis and the integrity of the resulting trans-dialkyl groups and bacteriochlorin chromophore. The counterpart report here concerns an in-depth study of conditions for the double-ring closure: catalyst/solvent surveys; grid search including time courses of [III-E] versus [acid] concentrations emphasizing equimolar, inverse molar, and variable acid lines of inquiry; and chlorin byproduct quantitation. Key findings are that (1) the double-ring closure can be carried out in 4 h (t_1/2 ∼ 40 min) instead of 20 h, affording ∼1/5th the chlorin byproduct (0.16%) while maintaining the yield of BC-1 (up to 77%); (2) the separate Z/E-enones of III have comparable reactivity; (3) sub-stoichiometric quantities of acid are ineffective; (4) the Knoevenagel condensation (40 mM, room temperature, piperidine/acetic acid in acetonitrile) and the acid-mediated double-ring closure (0.20 mM, 80 °C, Yb(OTf)₃ in acetonitrile) can be carried out in a two-step process; and (5) zinc insertion to form ZnBC-1 is straightforward. Together, the results enable streamlined conversion of dihydrodipyrrin reactants to the bacteriochlorophyll model compounds.