4-Alkynoic Acids in the Synthesis of Biologically Important Tetrapyrroles

Jacobi, Peter A.; Brielmann, Harry; Chiu, Melanie; Ghosh, Indranath; Hauck, Sheila I.; Lanz, Sandra; Leung, Sam H.; Li, Yongkai; Liu, Hui; Löwer, Franzisca; O’Neal, William G.; Pippin, Douglas; Pollina, Elizabeth; Pratt, Benjamin A.; Robert, Frédéric; Roberts, William P.; Tassa, Carlos; Wang, Hui

doi:10.3987/rev-10-sr(e)6

Cited by 17 publications

(15 citation statements)

References 101 publications

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“…The pattern of substituents that can be introduced to a bacteriochlorin in a de novo synthesis depends in large part on methods for preparing the corresponding dihydrodipyrrin (or other precursors). In contemplating a new route to bacteriochlorins that complements the existing approach (Scheme ), we were struck by the powerful chemistry of Jacobi and co-workers, − who developed methodology − ,, supporting a new route to dihydrodipyrrins ,− with application of the latter to the synthesis of chlorins ,, (Scheme ). For extension to bacteriochlorin chemistry, there are two notable features of the Jacobi route: (1) the starting reactants, a pent-4-ynoic acid ( J1 ) and an iodopyrrole ( J2 ), are joined via a Pd-coupling reaction to give a lactone–pyrrole ( J3 ), ,, a precursor via ene–lactone–pyrrole ( J4 ) to the dihydrodipyrrin ( J5 ); (2) the corresponding dihydrodipyrrin–carboxaldehyde ( J6 ) has the gem -dimethyl group and carboxaldehyde at the respective 2- and 1-positions of the pyrroline unit.…”

Section: Results and Dicussionmentioning

confidence: 99%

Northern–Southern Route to Synthetic Bacteriochlorins

Liu

Lindsey

2016

J. Org. Chem.

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A new route to bacteriochlorins via Northern-Southern (N-S) self-condensation of a dihydrodipyrrin-acetal complements a prior Eastern-Western (E-W) route. Each bacteriochlorin was prepared in five steps from an α-halopyrrole and a 2,2-dimethylpent-4-ynoic acid. The first three steps follow Jacobi's synthesis of dihydrodipyrrins: Pd-mediated coupling to form a lactone-pyrrole, Petasis reagent treatment for methenylation, and Paal-Knorr type ring closure to form the 1,2,2-trimethyl-substituted dihydrodipyrrin. Subsequent steps entail conversion of the 1-methyl group to the 1-(dimethoxymethyl) unit and acid-catalyzed self-condensation of the resulting dihydrodipyrrin-acetal. The essential differences between the N-S and E-W routes lie in (1) the location of the gem-dimethyl group (with respect to the 1-acetal unit) at the 2- versus 3-position in the dihydrodipyrrin-acetals, respectively, (2) the method of synthesis of the dihydrodipyrrins, and consequently (3) access to diverse substituted bacteriochlorins including those with substituents at the meso-positions. Ten new bacteriochlorins bearing 0-6 total aryl, alkyl, and carboethoxy substituents at the β-pyrrole and/or meso-positions have been prepared, with yields of macrocycle formation of up to 39%. Four single-crystal X-ray structures (two intermediates, two bacteriochlorins) were determined. The bacteriochlorins exhibit characteristic bacteriochlorophyll-like absorption spectra, including a Q band in the region 713-760 nm.

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Section: Results and Dicussionmentioning

confidence: 99%

Northern–Southern Route to Synthetic Bacteriochlorins

Liu

Lindsey

2016

J. Org. Chem.

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“…As with all de novo syntheses of chlorins, much methodology development was required for the preparation of the critical pyrroline-containing precursors. 228,230–232,234,235 …”

Section: Development Of De Novo Syntheses Of Gem-dialkylchlorinsmentioning

confidence: 99%

De NovoSynthesis of Gem-Dialkyl Chlorophyll Analogues for Probing and Emulating Our Green World

2015

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Woodward reported his infamous synthesis of chlorin e 6 trimethyl ester, a known synthetic precursor to chlorophyll a. [59][60][61][62][63][64]124 The work was posited on a half-century of intensive studies by many investigators in tetrapyrrole chemistry and began a decade after the close of Fischer's lifetime of research 125−128 (which included an uncompleted synthetic program directed toward chlorophylls 15 ). Indeed, "he read all the umpteen papers on the chlorophylls written by Willstaẗter and Fischer, including the experimental parts." 129 The Woodward synthesis of chlorin e 6 trimethyl ester required 46 steps, of which 24 were spent on converting the sole precursor, Knorr's pyrrole, to the four pyrroles destined to form rings A−D; 7 additional steps accrued to obtain the dipyrromethanes that constitute the Eastern and Western halves (Scheme 13, the step numbers are identical to those shown in ref 64.). The first step formed the Knorr pyrrole (in several kg quantities), the next 24 steps were divided into four parallel paths, whereas the remaining 21 steps proceeded in linear fashion. Remarkable features of the synthesis include the directed intramolecular joining (via an imine) of the Eastern and Western halves (step 33), construction of the acrylate Scheme 10. Hydrogenation of a Porphyrin to Form a Chlorin Scheme 11. Representative meso-Tetraarylchlorins Scheme 12. Methyl Pyropheophorbide a

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“…The formation of the AD half relies on the 2-halo-pyrrole plus 5-pentynoic acid coupling strategy that has been used previously. − ,,− Before embarking on the use of the valuable compound 17 , we carried out three short model studies (Scheme ). The objectives of the model studies were to identify suitable Pd-mediated coupling conditions and also to explore how to gain access to (bacterio)chlorophylls bearing 3-substituents.…”

Section: Resultsmentioning

confidence: 99%

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

Wang

Lindsey

2021

J. Org. Chem.

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Native chlorophylls and bacteriochlorophylls share a common trans-substituted pyrroline ring D (17-propionic acid, 18-methyl), whereas diversity occurs in ring A particularly at the 3-position. Two dihydrodipyrrins equipped with native-like D-ring substituents and tailorable A-ring substituents have been synthesized. The synthesis relies on a Schreiber-modified Nicholas reaction to construct the stereochemically defined precursor to ring D, a dialkyl-substituted pent-4-ynoic acid. The carboxylic acid group of the intact propionic acid proved unworkable, whereupon protected propionate (−CO2 tBu) and several latent propyl ethers were examined. The tert-butyldiphenylsilyl-protected propanol substituent proved satisfactory for reaction of the chiral N-acylated oxazolidinone, affording (2S,3S)-2-(3-((tert-butyldiphenylsilyl)oxy)propyl)-3-methylpent-4-ynoic acid in ∼30% yield over 8 steps. Two variants for ring A, 2-tert-butoxycarbonyl-3-Br/H-5-iodo-4-methylpyrrole, were prepared via the Barton–Zard route. Dihydrodipyrrin formation from the pyrrole and pentynoic acid entailed Jacobi Pd-mediated lactone formation, Petasis methenylation, and Paal–Knorr-type pyrroline formation. The two AD-dihydrodipyrrins bear the D-ring methyl and protected propanol groups with a stereochemical configuration identical to that of native (bacterio)chlorophylls, and a bromine or no substitution in ring A corresponding to the 3-position of (bacterio)chlorophylls. The analogous β-position of a lactone–pyrrole intermediate on the path to the dihydrodipyrrin also was successfully brominated, opening opportunities for late-stage diversification in the synthesis of (bacterio)chlorophylls.

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4-Alkynoic Acids in the Synthesis of Biologically Important Tetrapyrroles

Cited by 17 publications

References 101 publications

Northern–Southern Route to Synthetic Bacteriochlorins

Northern–Southern Route to Synthetic Bacteriochlorins

De NovoSynthesis of Gem-Dialkyl Chlorophyll Analogues for Probing and Emulating Our Green World

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

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