Chiral Azole Derivatives. 4.<sup>1</sup> Enantiomers of Bifonazole and Related Antifungal Agents:  Synthesis, Configuration Assignment, and Biological Evaluation

Botta, Maurizio; Corelli, Federico; Gasparrini, Francesco; Messina, Flavia; Mugnaini, Claudia

doi:10.1021/jo991937p

Cited by 59 publications

(33 citation statements)

References 15 publications

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“…demethylase [27]. The MIC 50 amounts to 2 lg/nl and it was determinated that both enantiomers are comparably strong inhibitors [28]. According to the molecular dynamics simulations reported here (see Table 5) both enantiomers indeed behave similar at least in the active site of the C. albicans model.…”

Section: Binding Of Bifonazole Isomerssupporting

confidence: 51%

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Rupp

Raub

Marian

et al. 2005

J Comput Aided Mol Des

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Sterol 14alpha-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.

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Section: Binding Of Bifonazole Isomerssupporting

confidence: 51%

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Rupp

Raub

Marian

et al. 2005

J Comput Aided Mol Des

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“…The 1-benzofuran derivatives 1a-c are intermediates in the synthesis of chiral azoles ( 2a-c , Figure 1). Compounds 2a-c were initially examined as antifungal agents7 and have been found to be powerful nonsteroidal aromatase inhibitors 8-13. They are indicated in the treatment of hormone-dependent breast cancer 14.…”

Section: Introductionmentioning

confidence: 99%

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

2009

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Enantioenriched diaryl-, aryl heteroaryl-and diheteroarylmethanols exhibit important biological and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from readily available aryl bromides are introduced. Thus, lithium-bromide exchange with commercially available aryl bromides and n-BuLi was followed by salt metathesis with ZnCl 2 to generate ArZnCl. A second equivalent of n-BuLi was added to form the mixed organozinc, ArZnBu. In the presence of enantioenriched amino alcohol-based catalysts, ArZnBu adds to aldehydes to afford essentially racemic diarylmethanols. The low enantioselectivities were attributed to a LiCl-promoted background reaction. To inhibit this background reaction, the chelating diamine TEEDA (tetraethylethylene diamine) was introduced prior to aldehyde addition. Under these conditions, enantioenriched diarylmethanols were obtained with >90% ee. Arylations of enals generated allylic alcohols with 81-90% ee. This procedure was unsuccessful, however, when applied to heteraryl bromides, which was attributed to decomposition of the heteroaryl lithium under the salt metathesis conditions. To avoid this problem, the metathesis was conducted with EtZnCl, which enabled the salt metathesis to proceed at low temperatures. The resulting EtZn(Ar Hetero ) intermediates (Ar Hetero =2-and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were successfully added to aldehydes and heteroaryl aldehydes with enantioselectivities between 81-99%. These are the first examples of catalytic and highly enantioselective syntheses of diheteroarylmethanols. In a similar fashion, ferrocenyl bromide was used to generate FcZnEt and the ferrocenyl group added to benzaldehyde and heteroaromatic aldehydes to form ferrocene-based ligand precursors in 86-95% yield with 96-98% ee. It was also found that the arylation and heteroarylation of enals could be followed by diastereoselective epoxidations to provide epoxy alcohols with high enantio-and diastereoselectivities in a one-pot procedure.

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“…The imidazole derivative participated in the nickel-catalyzed cross-coupling to afford bifonazole, which is a drug known for its antifungal activity (Table 4, entry 35). [12] Heterocycles, such as 5-methoxyindole and 2-methoxypyridine, when combined with PhMgBr, furnished the desired arylation products in good yield (Table 4, entries 36 and 37). The combination of the enamine derived from 6-methoxy-1-tetralone and PhMgBr with [NiCl 2 (PCy 3 ) 2 ]/PCy 3 provided the biaryl derivative; thus a reactive ketone could be protected as an enamine during the course of the coupling reaction (Table 4, entry 38).…”

Section: Methodsmentioning

confidence: 99%

Nickel‐Catalyzed Cross‐Coupling of Aryl Grignard Reagents with Aromatic Alkyl Ethers: An Efficient Synthesis of Unsymmetrical Biaryls

Dankwardt¹

2004

Angew Chem Int Ed

280

102

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Transition-metal-catalyzed cross-coupling reactions play a major role in the formation of C À C bonds. As a result, the cross-coupling of aryl halides (and pseudohalides) with organometallic reagents have become a steadfast method in organic synthesis.[1] This methodology has been used to prepare biaryl compounds, which are prevalent in both natural products and drug compounds.[2] In the more challenging cross-coupling reactions unreactive substrates, such as aryl nitriles, [3] aryl fluorides, [4] and aryl carbamates [5] are coupled with an organometallic reagent and generally require nickel catalysis. Wenkert et al. reported the [NiCl 2 (PPh 3 ) 2 ]-mediated cross-coupling of anisoles with aromatic Grignard reagents.[6] The scope of this process is rather limited, and the only substrates that provide the desired biaryl products in synthetically useful yields are the more reactive 1-and 2-methoxynaphthalene derivatives. In this communication, we report a general, high-yielding nickel-catalyzed cross-coupling of nonactivated aromatic ethers with aryl Grignard reagents.Our initial attempts in cross-coupling an anisole derivative with p-TolMgBr utilized a nickel catalyst prepared in situ from [Ni(acac) 2 ] (acac = acetylacetonyl) and various phosphane ligands in THF. Unfortunately, the reaction did not proceed to completion under any of the conditions tested (Table 1). From these studies, it was found that PCy 3 (Cy = cyclohexyl), an electron-rich ligand, was the best phosphane ligand with [Ni(acac)

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Chiral Azole Derivatives. 4.¹ Enantiomers of Bifonazole and Related Antifungal Agents: Synthesis, Configuration Assignment, and Biological Evaluation

Cited by 59 publications

References 15 publications

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

Nickel‐Catalyzed Cross‐Coupling of Aryl Grignard Reagents with Aromatic Alkyl Ethers: An Efficient Synthesis of Unsymmetrical Biaryls

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Chiral Azole Derivatives. 4.1 Enantiomers of Bifonazole and Related Antifungal Agents: Synthesis, Configuration Assignment, and Biological Evaluation

Cited by 59 publications

References 15 publications

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

Nickel‐Catalyzed Cross‐Coupling of Aryl Grignard Reagents with Aromatic Alkyl Ethers: An Efficient Synthesis of Unsymmetrical Biaryls

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Chiral Azole Derivatives. 4.¹ Enantiomers of Bifonazole and Related Antifungal Agents: Synthesis, Configuration Assignment, and Biological Evaluation