De Novo Synthesis of Bacteriochlorins Bearing Four Trideuteriomethyl Groups

Abstract

Site-specific introduction of isotopes in tetrapyrrole macrocycles provides the foundation for probing physicochemical features germane to photosynthetic energy-transduction processes, but has chiefly been done with porphyrins rather than the more biologically relevant hydroporphyrin analogues of native photosynthetic pigments. A prior study incorporated pairwise 13C or 15N atoms in the skeleton of a bacteriochlorin containing a gem-dimethyl group in each pyrroline ring. Here, a complementary effort is reported that installs deuterium atoms in substituents at the perimeter of a bacteriochlorin. Thus, perdeuteriated 3-methyl-2,4-pentanedione was converted in an 8-step synthesis via the intermediacy of tert-butyl 5-formyl-3,4-bis(trideuteriomethyl)pyrrole-2-carboxylate to the 2,3,12,13-tetrakis(trideuteriomethyl)-8,8,18,18-tetramethylbacteriochlorin (BC-2). The fidelity of isotope substitution was maintained throughout the synthesis. Resonance Raman spectroscopy of the copper chelate (CuBC-2) revealed that addition of the four β-pyrrolic substituents alone is not sufficient to account for the vibronic complexity observed for the copper chelate of bacteriochlorophyll a (CuBChl a). The increased vibronic activity exhibited by the natural pigments and CuBChl a must arise from the increased structural complexity of the macrocycle.

Development and Validation of Nerve-Targeted Bacteriochlorin Sensors

“…While multistep synthesis of bacteriochlorins was performed by the Lindsey group, ,, and enhanced, photostable, and soluble porphyrinoid derivatives were developed by the groups of Drain and Tome (Scheme S1A, S1B), no clinical evaluations have been reported. ,, In 2008, Foster and colleagues reported the use of a chlorin agent, NPe6, for the fluorescent visualization of breast cancer cells/tumors; they demonstrated rapid chlorin accumulation in the vasculature and extra-vasculature, generating some contrast between the tumor and surrounding tissue in vivo. , In 2011, Takashi and co-workers reported a chlorin-sugar conjugate for the detection and therapy of gastric and colon cancers, but no biomarker was presented for targeting . In 2021, Spingler and colleagues reported the use of bacteriochlorins with anticancer activities in cervical cancer cells .…”

“…22 Thus, conjugates of bacteriochlorins with a cell/tissue targeting moiety should be ideal in vivo imaging agents for use in the clinic. 16 While multistep synthesis of bacteriochlorins was performed by the Lindsey group, 9,13,23 and enhanced, photostable, and soluble porphyrinoid derivatives were developed by the groups of Drain and Tome (Scheme S1A, S1B), no clinical evaluations have been reported. 14,24,25 In 2008, Foster and colleagues reported the use of a chlorin agent, NPe6, for the fluorescent visualization of breast cancer cells/tumors; they demonstrated rapid chlorin accumulation in the vasculature and extravasculature, generating some contrast between the tumor and surrounding tissue in vivo.…”

“…Although bacteriochlorins present superior chemo-photophysical properties for exploration as an optical tracer, they have not been widely adopted by the imaging field. , Several in situ challenges have prevented their use as tracers in the trials and the clinic . So far, most research has focused on bacteriochlorins’ energy transfer, incorporation of isotopic atoms, and light harvesting, leaving their practical electromagnetic properties and imaging attributes understudied . There has been no strategic development of bacteriochlorins for use in the bio-imaging field: after Woodward first described their synthesis, research for in vivo use has been markedly slow.…”