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Synthesis of Meso-Substituted Chlorins via Tetrahydrobilene-a Intermediates

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journal contribution
posted on 09.10.2001, 00:00 by Masahiko Taniguchi, Doyoung Ra, Guoning Mo, Thiagarajan Balasubramanian, Jonathan S. Lindsey
Chlorin building blocks incorporating a geminal dimethyl group in the reduced ring and synthetic handles in specific patterns at the perimeter of the macrocycle are expected to have utility in biomimetic and materials chemistry. A prior route employed condensation of a dihydrodipyrrin (Western half) and a bromodipyrromethane-monocarbinol (Eastern half), followed by oxidative cyclization of the putative dihydrobilene-a to form the meso-substituted zinc chlorin in yields of ∼10%. The limited stability of the dihydrodipyrrin precluded study of the chlorin-forming process. We now have refined this methodology. A tetrahydrodipyrrin Western half (2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin) has been synthesized and found to be quite stable. The condensation of the Western half and an Eastern half (100 mM each) proceeded smoothly in CH3CN containing 100 mM TFA at room temperature for 30 min. The resulting linear tetrapyrrole, a 2,3,4,5-tetrahydrobilene-a, also is quite stable, enabling study of the conversion to chlorin. Refined conditions for the oxidative cyclization were found to include the following:  the tetrahydrobilene-a (10 mM), AgTf (3−5 molar equiv), Zn(OAc)2 (15 molar equiv), and 2,2,6,6-tetramethylpiperidine (15 molar equiv) in CH3CN at reflux exposed to air for 4−6 h, affording the zinc chlorin. The chlorin-forming process could be implemented in either a two-flask process or a one-flask process. The two-flask process was applied to form six zinc chlorins bearing substituents such as pentafluorophenyl, 3,5-di-tert-butylphenyl, TMS-ethyl benzoate, iodophenyl, or ethynylphenyl (deprotection of the TMS-ethynyl group occurred during the oxidative cyclization process). The stepwise yields (isolated) for the condensation and oxidative cyclization processes forming the tetrahydrobilene and zinc chlorin were 32−72% and 27−62%, respectively, giving overall yields of zinc chlorin from the Eastern and Western halves of 12−45%. Taken together, the refinements introduced enable 100-mg quantities of chlorin building blocks to be prepared in a facile and rational manner.