Synthesis of the chiral 4-substituted 1-phenylcyclohexene PD137789 via intramolecular Wittig reaction

We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA y . This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-g g. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARg g. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARg g, were tested using KKA y mice. Among these compounds, (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.

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“…a,a-Dimethylester (11k) was synthesized from 21 41) (Chart 6). Reduction of 21 with lithium aluminum hydride gave alcohol (22).…”

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confidence: 99%

Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.

Sugiyama

Kimura

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…These groups are both oriented "vertically" such that the C(10)−C(2)−C(3)− C(12) dihedral angle is nearly zero (2.1°), and the phenyl and carbomethoxy groups are oriented approximately parallel such that planar faces of the carbomethoxy and the phenyl group are oriented toward one another. The angle between the leastsquares fitted planes defined by the phenyl ring and by the carbomethoxy group is 41.6°and is entirely the result of the angle between the C(3)−C (12) and C(2)−C(10) bond vectors. The planes defined by the phenyl and carbomethoxy groups are nearly perpendicular to the C(2)−C(3) bond vector (82.2°and 82.0°, respectively).…”

Section: ■ Results and Discussionmentioning

confidence: 96%

“…14 To overcome the longer reaction times, βamino aldehyde (+)-14a (R = Me) was subjected to the Roush−Masamune modification of the Horner−Wadsworth− Emmons (HWE) reaction with nucleophilic trimethylphosphonoacetate and DBU-LiCl. 12 However, these conditions resulted in the formation of (S s ,5S)-(+)-16a as an inseparable 9:1 E:Z mixture of isomers in 80% yield within 5−6 h. Prolonged reaction times and the presence of LiCl were thought to be causing isomerization of olefin geometry. Importantly, only the (E)-isomer (+)-16a was obtained in >90% yield when LiCl was omitted from the HWE reaction.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our new methodology has the potential for the enantioselective syntheses of a wide variety of new and novel cocaine analogues not only having varied substituents at the C-1 position, but at other positions as well because of the diverse groups that can be introduced using sulfinimine chemistry. 28 3-(2-phenyl-1,3-dioxolan-2yl)propanal (3e), 12 and (S S )-(+)-3-(2-methyl-1,3-dioxolan-2-yl)propylidene-p-toluenesulfinamide (6a) 11c were prepared as previously described.…”

Section: ■ Summary and Conclusionmentioning

confidence: 99%

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Enantioselective Synthesis of Cocaine C-1 Analogues using Sulfinimines (N-Sulfinyl Imines)

et al. 2012

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The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,β-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O(t)Bu)(3) the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.

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“…The protecting regimen of choice appeared to be ketal protection, which is presented in Scheme . Normal, acid-catalyzed dimethyl or ethylene ketal formation was poor, but 2-methoxy-1,3-dioxolane with catalytic triflic acid gave 75−79% yields of the ethylene ketals 12 . Problems then arose in utilizing 12 in peptide synthesize.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Anisolylated Aspartyl and Glutamyl Tripeptides

et al. 1996

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A process has been developed for transforming the beta-carboxyl of aspartate and the gamma-carboxyl of glutamate into anisolyl ketones. These ketones are occasional byproducts in peptide synthesis, resulting from deprotection or resin-removal processes in the presence of anisole as a scavenger. The ketone amino acids have been incorporated in a tripeptide by coupling with CBMIT. During peptide bond formation the keto group of the glutamyl residue required protection, which was provided as the ethylene dithioketal.

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Synthesis of the chiral 4-substituted 1-phenylcyclohexene PD137789 via intramolecular Wittig reaction

Cited by 10 publications

References 7 publications

Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.

Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.

Enantioselective Synthesis of Cocaine C-1 Analogues using Sulfinimines (N-Sulfinyl Imines)

Synthesis of Anisolylated Aspartyl and Glutamyl Tripeptides

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