Bicyclic carboxylic acid

This [3,3] sigmatropic rearrangement process, which represents a variant of the well-known Biichi reaction, does proceed through a transition state geometry which is boatlike in character. The rearrangement reaction has been applied to other lactones as well. One rather interesting example is provided by the rearrangement of the cls-fused lactone (646) to the bicyclic carboxylic acid (647 Scheme 148). 

A two step process involving an intermediate radical or carbonium ion has been suggested as mechanism because of the fact that both meso- and d,7-2,3 -di-phenylsuccinic acid yield 35-40% trans-stilbene 314 A cationic intermediate however seems improbable for the bisdecarboxylations of aliphatic bicyclic carboxylic acids (Eq. (139-144) ), since no products with reananged carbon skeleton, as expected from carbonium ions, have been isolated. 

In order to determine the structure of the photochemical rearrangement product of carvone camphor in methanol, and to prove its structure, the research team of T. Gibson subjected the bicyclic carboxylic acid product to a degradation sequence, which commenced with the HVZ reaction, followed by dehydrohalogenation, dihydroxylation and glycol cleavage. 

The rates and equilibrium constants for isomerization of various [2,2,1] and [2,2,2] alkenes are reported. For example methylenenorbornane is more stable than 2-methyl-norbornene, but in the [2,2,2] series the endocyclic alkene is the more stable. The Pb(OAc)4 decarboxylation of a variety of [3,2,1] and [2,2,2] bicyclic carboxylic acids seems to proceed by two competing routes. ... 

In the electrochemical oxidation, 2,6-diamino-8-purinol (II) is further oxidized in a 2e, 2H+ reaction to an unstable product which was proposed to be a diimine (III). This product has not been identified directly, but its formation is strongly supported by the identification of a diol (VI, Fig. 1) which must form through hydrolysis of the diimine intermediate (III VI, Fig. 1). The diol decomposes to the final product which was identified as the bicyclic carboxylic acid (IX, Fig. IB). In the identification, separations were used to isolate intermediates and products, and their chemical identity was confirmed by gas chromatography/ mass spectrometry. Volatile derivatives were formed before GC/MS analysis. The off-line measurements have drawbacks associated with necessary manipulation of samples i. ... 

The feasibility of on-line electrochemistry mass spectrometry in the study of electrode processes has recently been demonstrated by Heitbaum et al. . We have tested the potential of on-line mass spectrometry in the study of redox reactivity of biological compounds with uric acid as a probe. Electrochemical oxidation of uric acid has been studied extensively . The scheme in Figure 6 shows the electrochemical oxidation pathway of uric acid and indicates intermediates and products which were identified by on-line electrochemistry thermospray mass spectrometry (EC/TSP/MS/MS) . In our studies, tandem mass spectrometry (MS/MS) was used to obtain structurally informative fragmentation patterns (daughter spectra) of standards for comparison to the mass spectra of intermediates and products obtained by EC/TSP/MS/MS. This, for example, allowed identification of allantoin through its characteristic daughter spectrum. It also allowed confirmation of the structural features of the intermediate, bicyclic carboxylic acid, which apparently forms from the imine alcohol in the oxidation of uric acid. The intermediates and products which were identified in this way are indicated in the scheme, and mass spectral results are summarized in Table 1. 

Polarization that occurs through space or is transmitted by solvent molecules rather than through bonds is known as zjteld ejfect.This effect, like the inductive effect, drops off substantially with distance. A good example of a field effect is seen with the two bicyclic carboxylic acids shown in Figure 3.8. The chlorines in each isomer are exactly the same number of... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Alkylation of 28 with acrolein gives the bicyclic ketone (65), which can be converted to 4-cyclooctene-l-carboxylic acid by the action of base on its methiodide (55a). 

Interaction between CuC=CPh and iodamide with the reverse arrangement of the functions (amide of 3-iodo-l,5-dimethylpyrazole-4-carboxylic acid) gave a similar result. Formation of the bicyclic compound was not observed. The yield of the acetylenylpyrazole was 62% (Scheme 127). 

Bond-Huper [69JCS(C)2453] synthesis, no traces of the described high-melting dark red substance were found. Only tolane-2-carboxylic acid amide (yield 65%) was obtained—the white crystals with a melting temperature of 156-157°C— which coincided with the results of Castro et al. (66JOC4071). Thus, in conditions of acetylide synthesis, o-iodobenzamide forms no bicyclic product. 

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

The same nonpolar conformation can be achieved by conversion to bicyclic structures. 1,4-Cyclo-addition of ethylene to anthracene-9-carboxylic acid gives acid 68. Successive conversion to the N-methylamide, via the acid chloride, followed by reduction with lithium aluminum hydride produced... 

A xanthine series (I) exemplified by 33 and 34 is another important class of GPR109A agonists [83-88], It is worth noting that members of this series lack the carboxylic acid to interact with Arglll of GPR109A, unlike compounds in the aforementioned series. However, it is conceivable that the N-H present in the bicyclic core of this class of compounds is sufficiently acidic (pKa 5.6) [82] to mimic the function of a carboxylic acid present in the anthranilide class. 

---