Synthesis of Pyrrolnitrin and Related Halogenated Phenylpyrroles

Morrison, Matthew D.; Hanthorn, Jason J.; Pratt, Derek A.

doi:10.1021/ol8026957

Cited by 42 publications

(28 citation statements)

References 26 publications

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“…Preparation of pyrrole boronic ester 48 from commercially available 3-bromo-N-triisopropylsilylpyrrole 47 has been performed using pinacolborane in the presence of a catalytic amount of bis(acetonitrile)palladium dichloride and S-Phos (dicyclohexyl(2 0 ,6 0 -dimethoxybiphenyl-2-yl) phosphine) [64]. The SuzukieMiyaura cross coupling [63,65,66] between 48 and the dihalogenated phenol 49 led only to 16% yield of biarylic compound 50 (Scheme 6). This low yield led us to consider another pathway and to perform the coupling reaction after the Click cycloaddition in order to prepare triazole T1 (Scheme 11).…”

Section: Preparation Of Azides 15e21mentioning

confidence: 99%

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Vojtíčková

Dobiáš

Hanquet

et al. 2015

European Journal of Medicinal Chemistry

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Keywords:Oxazole/1,2,3-triazole isosteric replacement Ynamide CuACC Click chemistry VEGFR2 tyrosine kinase inhibition Cytotoxic activity in Huh-7 and Mahlavu hepatocellular carcinoma cell lines PI3K/Akt pathway a b s t r a c t Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1eT7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1eT7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1eT3 and T6eT7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1eT7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1eT3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1eT3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway.

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Section: Preparation Of Azides 15e21mentioning

confidence: 99%

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Vojtíčková

Dobiáš

Hanquet

et al. 2015

European Journal of Medicinal Chemistry

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“…The thiophene, pyrrole, and tetrahydrofuran-containing allylic bromides (18, 21, and 24) were prepared in seven steps from the commercially available materials (16, 19, and 22), respectively. 12,13 Then, coupling reaction with the sulfone 15 and subsequent desulfonylation provided analogues 25e27 in good yield.…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

“…Removal of the solvent from the filtrate under reduced pressure to give a crude product, which was purified by SiO 2 column (n-hexane/Et 2 O¼1:1) to give 3-(furan-3-yl)propionaldehyde (365 mg, 81%) as a colorless oil. IR ( (13). PPh 3 (147 mg, 0.55 mmol) and CBr 4 (186 mg, 0.55 mmol) were successively added to the solution of 12 (78.0 mg, 0.46 mmol) in CH 2 Cl 2 (2.3 mL) at 0 C, and the whole mixture was stirred for 30 min.…”

Section: 23mentioning

confidence: 99%

Concise synthesis and structure–activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge

et al. 2011

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“…The key intermediate is 3‐pyrrolin‐2‐one 8b , which can help to achieve two goals: facilitating the introduction of the substituents needed for construction of rings B and D, and reducing the sensitivity of the pyrrole ring precursor (ring C). The second approach involves construction of the biaryl core of 3 by a one‐pot Ir‐catalyzed C–H borylation6 followed by Suzuki coupling 7…”

Section: Introductionmentioning

confidence: 99%

Synthetic Strategies for the Synthesis and Transformation of Substituted Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues

Kholod

Vallat²,

Buciumas³

et al. 2014

Eur J Org Chem

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The biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal, variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting a suitably substituted acetophenone with O‐methyl O‐trimethylsilyl ketene acetal gave pyrrolinones 8a and 8b in good to excellent yields. These intermediates could be transformed in four high‐yielding steps into the pyrrolic precursors 7a–c containing all the atoms necessary for the construction of rings A, B, and C of rhazinilam. Our studies illustrate a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.

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Synthesis of Pyrrolnitrin and Related Halogenated Phenylpyrroles

Abstract: A general approach to halogenated arylpyrroles, including the antifungal natural product pyrrolnitrin, is described using newly synthesized halogenated pyrroles and 2,6-disubstituted nitrobenzenes or 2,6-disubstituted anilines.

Cited by 42 publications

References 26 publications

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Concise synthesis and structure–activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge

Synthetic Strategies for the Synthesis and Transformation of Substituted Pyrrolinones as Advanced Intermediates for Rhazinilam Analogues

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