Synthesis and antiinflammatory activity of some 1,6-methano[10]annuleneacetic acids

Nelson, Peter H.; Bartsch, G. A.; Untch, Karl G.; Fried, J. H.

doi:10.1021/jm00240a012

Cited by 7 publications

(5 citation statements)

References 2 publications

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“…1,6-Methano[10]annulenyl Cations. The 2-substituted chloride 8 was prepared as previously described , from the corresponding alcohol 7 , and the isomeric 3-substituted chloride 10 was prepared in an analogous fashion from alcohol 9 . These chlorides were solvolyzed in methanol at 25.0 °C, where both of these substrates readily react.…”

Section: Resultsmentioning

confidence: 99%

“…Preparation of 3-Chloromethyl-1,6-methano[10]annulene (10). , A solution of 31 mg of 3-hydroxymethyl-1,6-methano[10]annulene ( 9 ). , in 1 mL of anhydrous ether containing 50 mg of Na 2 CO 3 was stirred as 54 mg of SOCl 2 was added. After 1.5 h the mixture was filtered, and the solvent was removed using a rotary evaporator.…”

Section: Methodsmentioning

confidence: 99%

“…The crude 2-chloromethyl-1,6-methano [10] Preparation of 3-Chloromethyl-1,6-methano [10]annulene (10). 6,7 A solution of 31 mg of 3-hydroxymethyl-1,6methano [10]annulene (9). 7,20 in 1 mL of anhydrous ether containing 50 mg of Na2CO3 was stirred as 54 mg of SOCl2 was added.…”

Section: Methodsmentioning

confidence: 99%

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Stabilized and Destabilized Carbocations in the 1,6-Methano[10]annulene Series

Creary

Miller

2003

J. Org. Chem.

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2-Chloromethyl and 3-chloromethyl-1,6-methano[10]annulene systems solvolyze in methanol to give simple substitution products. Solvent effect studies and the special salt effect support the involvement of cationic intermediates stabilized by the 1,6-methano[10]annulene group. Rate data indicate that the degree of cation stabilization greatly exceeds that of naphthyl groups. B3LYP/6-31G computational studies also suggest that the cationic intermediates are greatly stabilized by the 1,6-methano[10]annulene. By way of contrast to these findings, solvolytic and computational studies indicate that the 11-(1,6-methano[10]annulenyl) cation is a destabilized analogue of the cycloheptatrienyl cation. There are no favorable interactions with the annulene ring. Distortions from planarity prevent charge delocalization as in the analogous aromatic cycloheptatrienyl cation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Stabilized and Destabilized Carbocations in the 1,6-Methano[10]annulene Series

Creary

Miller

2003

J. Org. Chem.

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“…Alternatively, the alkene may be functionalized with a pendant diazocarbonyl substituent which, after treatment with the appropriate metal catalyst, leads to intramolecular methylene addition. One of these examples was published by Nelson et al 30 Here, the authors report moderate to high yields of cyclopropanated tetrasubstituted double bonds which could be attributed to the assistance of hydroxyl and carboxylic acid functionalization of the alkyl chain (Scheme 1.12). Scheme 1.12 Intramolecular cyclopropanation assisted by hydroxyl and carboxyl moieties.…”

Section: Methylene Addition Mediated By Zn-carbenoidmentioning

confidence: 96%

“…Due to the difficulties encountered in trying the epimerize the 7-OH, an alternative strategy to cyclopropanate the convex face of substrate 23 stereoselectively was scoped. In a publication reported by Nelson et al, 30 the authors compare the directing capacity of alkoxy-and carboxylic-alkyl chains towards cyclopropanation of tetrasubstituted double bonds in an intramolecular manner. For these substrates (Scheme 1.12, substrate 49) a carboxylic acid moiety greatly improves the yield in obtaining the cyclopropane.…”

Section: Attempted Cyclopropanation Of the Convex -Face Of Alkene 24...mentioning

confidence: 99%

Synthesis of Novel Bile Acids

Aponte¹

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Bile acids are steroid structures with a carboxylic acid alkyl chain that are synthesised from cholesterol in the liver and function to regulate metabolism. They are mainly used as surfactants in the solubilization of lipids but they can also be used as cell signalling molecules targeting TGR5 and FXR receptors which have been implicated as important targets for the potential treatment of diseases such as inflammatory bowel disease, colorectal cancer and type 2 diabetes.1 Modifications to the structure of primary bile acids result in the selective activation of different receptors. 2 To further probe structure activity relationships, a library of new bile acid derivatives has been prepared. The focus of this research is the exploration of cyclopropanation reactions of unsaturated C/D-ring alkenes resulting from a novel bile acid rearrangement. Stereoselective cyclopropanation has been achieved on a highly hindered, tetrasubstituted alkene using Furukawa’s method (EtZnCH2I)3, while Shi’s method (CF3CO2ZnCH2I)4 unexpectedly furnished a novel spiro-bile acid motif from the same alkene in an apparent skeletal rearrangement. Intermolecular carbene additions to the double bond of tetrasubstituted alkenes were attempted using a range of transition metal-catalysed decompositions of ethyl diazoacetate (EDA), dichlorocarbene and difluorocarbene. The substrate proved to be too hindered for reaction with EDA; dichlorocarbene promoted CH insertion in allylic position to the double bond while reactions generating difluorocarbene effected double bond migration product. Selective diazoacetylation of the bile acid alkene 7α-hydroxy substituent enabled the intermolecular decompositions to be probed using transition metal-catalysed and violet light (385 nm) mediated decompositions. A custom-built monochromatic LED reactor was designed and used for this purpose. Both light mediated reactions and a range of Cu(I), Cu(II) and Rh(II) and Re(VI) complexes effectively decomposed the diazo functionality but no intramolecular cyclopropanations were detected. As an extension to attempting cyclopropanations, cheno- and urso-deoxycholic acids were selectively diazoacetylated at the 7α-hydroxy substituent using the successfully developed method above. Towards analogues of obeticholic acid a number of Doyle’s asymmetric Rh(II) catalysts were then probed in an attempt to effect C-H insertion by diazodecomposition. Finally, a novel route for the synthesis of the A-ring 3-aza-bile acid starting from Chenodeoxycholic acid is presented. This route allowed us to synthesise the two isomeric intermediates tert-Butyl-2-hydroxy-7a-(benzyloxymethyl)oxy-4-amino-3-nor-3,4-seco-5b-cholan-24-oate and tert-Butyl-2-amino-4-hydroxy-7a-(benzyloxymethyl)oxy-3-nor-3,4-seco-5b-cholan-24-oate which could both be converted, by different methods, to the desired aza-bile acid. Interestingly, a novel tetrohydrofuran bile acid product and the 5α-H (allo) bile acid analogue was afforded from one of these isomers by these synthetic endeavours.

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Simmons‐Smith Cyclopropanation Reaction

2001

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Almost 30 years after Emschwiller prepared IZnCH 2 I, Simmons and Smith discovered that the reagent formed by mixing a zinc‐copper couple with CH 2 I 2 in ether could be used for the stereospecific conversion of alkenes to cyclopropanes. Nowadays, the Simmons‐Smith cyclopropanation reaction is one of the most widely used reactions in the organic chemist's arsenal for the conversion of olefins into cyclopropanes. This popularity is mainly due to the stereospecificity of the reaction with respect to the double bond geometry and its compatibility with a wide range of functional groups. The chemoselectivity of the reaction toward some olefins is excellent and very few side reactions are observed with functionalized substrates. The metal carbenoid is electrophilic in nature and electron‐rich alkenes usually react much faster than electron‐poor alkenes. Furthermore, the ability to use proximal hydroxy or ether groups to dictate the stereochemical outcome of the CC bond forming process was recognized early on, and this unique property has been successfully exploited on numerous occasions. It has been recognized that halomethylmetal reagents are powerful synthetic tools for the stereoselective addition of a methylene unit to chiral acyclic allylic alcohols and allylic ethers. In addition, the use of halomethylzinc reagents in the presence of chiral additives is one of the few ways to cyclopropanate allylic alcohols efficiently and with good enantiocontrol. Carbenoids can be divided into the following two classes: (1) those of general structure MCH 2 X and (2) those corresponding to M = CH 2 . This chapter is focussed exclusively on the first class in which M = Zn, Sm, or Al. Although other metal carbenoids of type MCH 2 X, such as those derived from Cu, Cd, Hg, and In, have been reported to be effective reagents for the cyclopropanation of some olefins, they have been used only sporadically, and this review does not highlight these reactions. This chapter covers cyclopropanation reactions involving haloalkylzinc, aluminum, and samarium reagents published since the comprehensive chapter in Organic Reactions by Simmons that surveyed the literature up to 1973.

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Synthesis and antiinflammatory activity of some 1,6-methano[10]annuleneacetic acids

Cited by 7 publications

References 2 publications

Stabilized and Destabilized Carbocations in the 1,6-Methano[10]annulene Series

Stabilized and Destabilized Carbocations in the 1,6-Methano[10]annulene Series

Synthesis of Novel Bile Acids

Simmons‐Smith Cyclopropanation Reaction

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