Research on antibacterial and antifungal agents. 16. Synthesis and antifungal activities of 1-[α-(1-naphthyl)benzyl]imidazole derivatives and related 2-naphthyl isomers
“…(S)-(1-Naphthyl)-(4'-methylphenyl)methanol (3d) [12] The title compound was obtained from 1-naphthylboronic acid (1e) (103 mg, 0.6 mmol) and 4-methylbenzaldehyde (2d) (29.5 mL, 0.25 mmol) according to the general procedure after column chromatography (silica gel, eluents: pentane/diethyl ether = 8:2) as a colorless oil; yield: 0. (R)-(1-Naphthyl)-(4'-methylphenyl)methanol (ent-3d)…”
Using a planar-chiral ferrocene as catalyst and combinations of functionalized aldehydes and substituted arylboronic acids as starting materials, asymmetric aryl transfer reactions give access to structurally diverse, optically active diarylmethanols in high yields and enantioselectivities.Keywords: arylboronic acids; C À C bond formation; diarylmethanols; enantioselective catalysis; organozinc reagents Diarylmethanols 3 with defined stereochemistry at the hydroxy-bearing carbon are important intermediates for the synthesis of numerous compounds with high biological and/or physiological activity.[1] For example, neobenodine and orphenandrine show anticholinergic as well as anthihistaminic properties.[2] Recently, diarylmethanols have been used in the synthesis of pharmaceuticals containing asymmetrical 1,1'-diarylalkyl subunits.[3] The most common routes towards diarylmethanols are either enantioselective reductions of prochiral benzophenone derivatives [4] or asymmetric carbon-carbon bond formations starting from aromatic aldehydes and appropriate organometallic compounds. [5,6] Despite the fact that the latter strategy has attracted considerable attention due to its enormous synthetic potential, the so far evaluated substrate range appears rather limited. Thus mostly, aryl transfer reactions onto (unsubstituted) benzaldehyde (Scheme 1, Ar 2 = Ph) or phenyl-to-aldehyde transfers have been studied leading to arylphenylmethanols. The synthesis of diarylmethanols with two differently substituted aryl groups via zinc reagents has, to the best of our knowledge, never been in the focus of an intensive study. [7] In 2002, we described a general approach for aryl transfer reactions to aromatic aldehydes involving arylzinc species formed in situ from arylboronic acids 1 and diethylzinc. Ferrrocene 4 served as catalyst (Scheme 1). [8] Noteworthy is the fact that with a single catalyst both enantiomers of 3 became accessible by choosing the appropriate combination of arylboronic acid 1 and aldehyde 2. Also in this case, only arylphenylmethanols were prepared.Wondering about the flexibility of this method and with the goal to investigate the applicability of the approach in the preparation of more functionalized molecules, we have now studied the catalytic synthesis of 1,1'-disubstituted diarylmethanols (e.g., products with aryls other than phenyl). This involved structural variations of both the arylboronic acids 1 as well as the aldehydes 2. The results are summarized in Table 1.To our delight we found that most diarylmethanols 3 were formed in good yields and high enantioselectivities (Figure 1). For example, 4-chlorophenyl-2'-methylphenylmethanol (3a) was obtained with 91 % ee in 71 % yield (Table 1, entry 1). In the catalysis starting from 2-bromobenzaldehyde (2c) and 3-methoxyphenylboronic acid (1c) diarylmethanol ent-3b was formed with 88 % ee in 66 % yield (entry 3). Using the "reverse combination" of substrates, the enantiomeric product 3b was obtained by aryl transfer from 2-bromophenylboronic acid (1b) ...
“…(S)-(1-Naphthyl)-(4'-methylphenyl)methanol (3d) [12] The title compound was obtained from 1-naphthylboronic acid (1e) (103 mg, 0.6 mmol) and 4-methylbenzaldehyde (2d) (29.5 mL, 0.25 mmol) according to the general procedure after column chromatography (silica gel, eluents: pentane/diethyl ether = 8:2) as a colorless oil; yield: 0. (R)-(1-Naphthyl)-(4'-methylphenyl)methanol (ent-3d)…”
Using a planar-chiral ferrocene as catalyst and combinations of functionalized aldehydes and substituted arylboronic acids as starting materials, asymmetric aryl transfer reactions give access to structurally diverse, optically active diarylmethanols in high yields and enantioselectivities.Keywords: arylboronic acids; C À C bond formation; diarylmethanols; enantioselective catalysis; organozinc reagents Diarylmethanols 3 with defined stereochemistry at the hydroxy-bearing carbon are important intermediates for the synthesis of numerous compounds with high biological and/or physiological activity.[1] For example, neobenodine and orphenandrine show anticholinergic as well as anthihistaminic properties.[2] Recently, diarylmethanols have been used in the synthesis of pharmaceuticals containing asymmetrical 1,1'-diarylalkyl subunits.[3] The most common routes towards diarylmethanols are either enantioselective reductions of prochiral benzophenone derivatives [4] or asymmetric carbon-carbon bond formations starting from aromatic aldehydes and appropriate organometallic compounds. [5,6] Despite the fact that the latter strategy has attracted considerable attention due to its enormous synthetic potential, the so far evaluated substrate range appears rather limited. Thus mostly, aryl transfer reactions onto (unsubstituted) benzaldehyde (Scheme 1, Ar 2 = Ph) or phenyl-to-aldehyde transfers have been studied leading to arylphenylmethanols. The synthesis of diarylmethanols with two differently substituted aryl groups via zinc reagents has, to the best of our knowledge, never been in the focus of an intensive study. [7] In 2002, we described a general approach for aryl transfer reactions to aromatic aldehydes involving arylzinc species formed in situ from arylboronic acids 1 and diethylzinc. Ferrrocene 4 served as catalyst (Scheme 1). [8] Noteworthy is the fact that with a single catalyst both enantiomers of 3 became accessible by choosing the appropriate combination of arylboronic acid 1 and aldehyde 2. Also in this case, only arylphenylmethanols were prepared.Wondering about the flexibility of this method and with the goal to investigate the applicability of the approach in the preparation of more functionalized molecules, we have now studied the catalytic synthesis of 1,1'-disubstituted diarylmethanols (e.g., products with aryls other than phenyl). This involved structural variations of both the arylboronic acids 1 as well as the aldehydes 2. The results are summarized in Table 1.To our delight we found that most diarylmethanols 3 were formed in good yields and high enantioselectivities (Figure 1). For example, 4-chlorophenyl-2'-methylphenylmethanol (3a) was obtained with 91 % ee in 71 % yield (Table 1, entry 1). In the catalysis starting from 2-bromobenzaldehyde (2c) and 3-methoxyphenylboronic acid (1c) diarylmethanol ent-3b was formed with 88 % ee in 66 % yield (entry 3). Using the "reverse combination" of substrates, the enantiomeric product 3b was obtained by aryl transfer from 2-bromophenylboronic acid (1b) ...
“…Botta, Corelli and coworkers [17] described the first synthesis, the full stereochemical characterization, and the biological evaluation of both enantiomers of bifonazole (18) and related compounds (19), (20) and (21) (Fig. 8).…”
Imidazoles are an important class of heterocycles and include many substances of both biological and chemical interest. They are part of a large number of highly significant biomolecules such as the essential amino acid histidine and related compounds, biotin, and the imidazole alkaloids. Insertion of the imidazole nucleus is an important synthetic strategy in drug discovery. Imidazole drugs have broad applications in many areas of clinical medicine. The imidazoles are a class of antifungal azole derivatives and have a broad spectrum of activities both in vitro and in vivo. The imidazole moiety is also contained in many histaminergic ligands for histamine H1, H2, and H3 receptors. These are currently used as tools in pharmacological studies. The important therapeutic properties of imidazole related drugs have encouraged the medicinal chemists to synthesize and test a large number of novel molecules. Some of these have chemotherapeutic properties, such as for example several FTase inhibitors with an imidazole moiety. Imidazole derivatives have also been shown to have antibacterial activity and recently several P38 MAP Kinase inhibitors and 5-Lipoxygenase inhibitors containing the imidazole moiety have been synthesized. This review reports current progress in the area of new biologically active imidazoles and recently discovered naturally occurring imidazole.
“…During the course of our studies on antifungal agents, we became interested in developing methodologies for the preparation of these compounds in homochiral form for subsequent biological evaluation following the new regulatory guidelines. We describe herein the first synthesis, the full stereochemical characterization, and the biological evaluation of both enantiomers of bifonazole ( 1a ) and related compounds 1b − d (Figure ), which have been previously synthesized and tested for their antifungal and/or aromatase inhibiting activity in racemic form. − 1 …”
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