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

Abstract

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, β-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.

Synthesis of AD-Dihydrodipyrrins Equipped with Latent Substituents of Native Chlorophylls and Bacteriochlorophylls

“…The coupling constant values are consistent with the trans configuration of the vicinal protons. 9,11,55 Moreover, 2D NOESY spectroscopy of 26 showed a correlation between the 3-proton and the 2aprotons (first methylene of the propanol substituent), and the 3-methyl and the 2-proton without observing a correlation between the 2-and the 3-protons (see Scheme 9 for numbering). For 28-Br, a correlation was observed between the 3-and 2a-/2b-protons (first/second methylenes of the propanol substituent), but not between the 2-and 3-protons of 28-Br (Supporting Information).…”

“…A current objective is to adapt the general synthesis to accommodate the substituents characteristic of the native macrocycles. To date, we have synthesized the ring C pyrrole, 8 shown that stereodefined model substituents (17-methyl, 18-ethyl) in ring D can be incorporated at an early stage of the synthesis and carried through Knoevenagel and double-ring closure processes to form the macrocycle without loss of stereochemical integrity, 9 refined the conditions for the double-ring closure, 10 compounds containing a 3-acetyl as well as other substituents. 11 The prior incorporation of an acetyl 11 or carboethoxy 9,10 group at the 3-position in each case required independent synthesis beginning with the corresponding substituted pyrrole.…”

“…The trans-dialkyl-substituted dihydrodipyrrins, by contrast, are constructed via Pd-mediated joining of a 2-iodopyrrole and a trans-dialkylsubstituted pentynoic acid. 9,11 While the opportunity for latestage diversification of bacteriochlorophyll macrocycles afforded by the presence of a 3-bromine atom is tantalizing, we anticipated challenges in accommodating the bromine in the route to trans-dialkyl-substituted dihydrodipyrrins.…”

“…The prior incorporation of an acetyl or carboethoxy , group at the 3-position in each case required independent synthesis beginning with the corresponding substituted pyrrole. Bacteriochlorophyll a contains a 3-acetyl group.…”

“…The acetyl group and many other auxochromes have been installed via Pd-mediated coupling of synthetic 3-bromobacteriochlorins, which were equipped with a gem -dimethyl substituent in each pyrroline ring and did not include ring E. The corresponding gem -dimethyl-substituted dihydrodipyrrin precursors were prepared via a route that did not entail any Pd-mediated coupling steps. The trans -dialkyl-substituted dihydrodipyrrins, by contrast, are constructed via Pd-mediated joining of a 2-iodopyrrole and a trans -dialkyl-substituted pentynoic acid. , While the opportunity for late-stage diversification of bacteriochlorophyll macrocycles afforded by the presence of a 3-bromine atom is tantalizing, we anticipated challenges in accommodating the bromine in the route to trans -dialkyl-substituted dihydrodipyrrins.…”