Ring-opening carboxylative

Figure 5.17 shows the interconversion of the lactone form of a semisynthetic analogue of camptothecin to its ring-opened carboxylate form. The lactone form predominates in low pH whereas the ring-opened carboxylate form prevails at neutral and alkaline pH, as illustrated in Figure 5.18. 

The lactone form of an analogue of camptothecin converts to its ring-opened carboxylate form. Both forms are in equilibrium. The following degradation data of the lactone form were collected ... 

Because the equilibrium between the active lactone form and the ring-opened carboxylate form is pH dependent, oral alkalinization with a mixture consisting of sodium bicarbonate (2.0 g/day), magnesium oxide (2.0-4.0 g/day), water (pH over 7.2, 1.5-2 1/day), and ursodeoxycholic acid (300 mg/day), combined with controlled defecation was used in a phase II trial to reduce subacute gastrointestinal toxicity. Anticancer activity was maintained and the incidences of diarrhea and myelosuppression were significantly reduced compared with a non-randomized control group (109-111). 

When heated, cyclopropanone hemiacetals are rapidly converted into ring-opened carboxylic esters vide infra). ... 

Drug-drug interactious Linezolid is primarily metabolized by oxidation of the morpholine ring, resulting in two inactive ring-opened carboxylic acid metabolites it is not metabolized by CYP enzymes and does not inhibit their activities. 

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

Another useful route to cyciopentanes is the ring contraction of 2-bromo-cydohexanones by a Favorskii rearrangement to give csrdopcntanecarboxylic acids. If a 0 dibromoketones are used, ring opening of the intermediate cydopropanone leads selectively to, y-unsaturated carboxylic acids (S.A, Achmad, 1963, 1965 J. Wolinsky, 1965). 

Potassium t-butoxide in t-butyl alcohol requires powerful electron-attracting substituents at C-4 to effect ring opening of pyrazoles but sodamide does not (Scheme 26) (B-76MI40402). As the key to the transformation is the generation of the anion, similar results were obtained by heating some pyrazole-3-carboxylic acids with quinoline. 

Compound (122) is also obtained by decarboxylative ring-opening of l,2-benzisoxazole-3-carboxylic acid. It has also been concluded that the reaction involves an intermediateless, concerted loss of carbon dioxide via a transition state in which the negative charge is spread over the carboxyl group and the isox azole ring. 

The treatment of 4-benzoyl-3-phenylisoxazolin-5-one with KOH generated 3,5-diphenyl-isoxazole-3-carboxylic acid via a ring-opened intermediate as shown in Scheme 69 (61CB1956). 

Benzisoxazole-3-carboxylic acid decarboxylated ring opening, 6, 31 reactions, 6, 52... 

Acidic hydrolysis of 14 occurs via protonation of the nitrogen followed by attack of water on the resulting cationic intermediate. Proton transfer followed by ring-opening affords cation 15, which is trapped by a second equivalent of water. Another proton transfer followed by loss of the amino group affords protonated carboxylic acid 16, which loses to provide the carboxylic acid product. 

Ring cleavage of l-oxo-l,2,3,4-tetrahydro-jS-carboline derivatives (374) may be accomplished by base-catalyzed hydrolysis to yield tryptamine-2-carboxylic acids (375). In the case of the 1,9-dimethyl derivative decarboxylation accompanied acid-catalyzed ring-opening, and the corresponding tryptamine (376) was obtained directly. 

With tetrachloroethane as solvent, two modes of ring-opening occur, leading to the formation of 2-benzamidoindenone (20), by intramolecular acylation [Eq. (14)], and l-phenylisoquinoline-3-carboxylic acid (21), by intramolecular imidoylaiion [Eq. (15)]. 

The hetero ring in 4-(l -hydroxyalkylidene)-5-oxazolones is cleaved by alcoholic HCl to form alkyl a-acylaminoacylacetates, which cyclize to oxazole-4-carboxylates [Eq. (25)]. This rearrangement occurs directly in alkali, and a carbon-14 tracer study has substantiated a mechanism involving ring opening followed by the alternative ring closure. ... 

The oxazolone 43, prepared by reaction of 0-methylcaprolactim (42) with compound 1, undergoes a ring-opening reaction with methanolic HCl and cyclizes in alkaline medium to 1,5-pentamethyl-ene-2-phenylimidazole-4-carboxylic acid (44), which can be decar-boxylated easily. 

Azabicyclo[3.2.0]hepta-3,6-dienes are the 4 5 bicyclic valence isomers of 1//-azepines. In some cases there is an equilibrium between the bicycle and the azepine, whereas with other 1//-azepines photolysis yields an azabicycloheptadiene that can be isolated and characterized. For example, ethyl 2-azabicyclo[3.2.0]hepta-3,6-diene-2-carboxylate (1), the photoinduced valence isomer of ethyl l//-azepine-l-carboxylate (2), undergoes a clean, exothermic, first order, electrocyclic ring opening (AG = 20 kJ mol-1) to the parent 1//-azepine 2 on heating at 113-143C in an inert solvent (e.g., hexadecane).101... 

Azabicyclo[4.1.0]hept-3-enes, e. g. 13, are available from 1,4-dihydrobenzenes 12 by the route indicated, and are useful precursors for the synthesis of specifically substituted 1//-azepines free from isomeric contamination.61 For example, low temperature addition of bromine to bicycle 13 yields the dibromo derivative 14 which, with powdered sodium methoxide in tet-rahydrofuran, undergoes a double dehydrobromination followed by electrocyclic ring opening of the resulting 7-azabicyclo[4.1.0]hepta-2,4-diene 15 to give methyl l//-azepine-l-carboxylate (16). 

Treatment of ethyl 1 W-azepine-l-carboxylate with palladium(II) acetate in benzene, or in an aprotic solvent, results in ring contraction (see Section 3.1.2.4.) or ring opening (vide infra), respectively, however, with palladium(II) acetate in acetic acid ethyl 2,3-diacetoxy-2,3-dihydro-l//-azepine-l-carboxylate (6) is formed as the major product along with ( , )-hexa-2,4-dienedial.243... 

Diels-Alder cycloaddition of 3,4-bis(trifluoromethyl)furan with ethyl propynoate involved addition of two a,/3-unsaturated esters followed by acid-catalyzed ring opening, rearrangement, and elimination of ethanol to give a 6,7-bis(trifluoromethyl)isocoumarin-3-carboxylate [92JFC(56)359]. 

The C-2 proton in an aziridine-2-carboxylate is acidic, due to the adjacent carboxylic group. Upon treatment with base, such aziridines may undergo ring-opening reactions to give a-amino-a, 3-unsaturated carboxylates [74, 94, 95]. As an example, treatment of 111 (Scheme 3.39) with TMSI/Et3N gave 116 in 64% yield [74]. 

With Oxygen Nucleophiles Aziridine ring-opening of 111 (Scheme 3.42) with water in the presence of a catalytic amount of TsOH gave the corresponding (3-hydrox-yphenylalanine derivative 121 in 72% yield as the major isomer [74], Treatment of N-(p-tolylsulfmyl) aziridine-2-carboxylates with TFA and subsequent aqueous workup resulted in the formation of j3-substituted serine derivatives [62, 63, 101]. Under these reaction conditions, not only was the aziridine ring opened, but also the N-sulfmyl group was removed treatment of 122 (Scheme 3.43) with TFA at 73 °C, for example, afforded 123 in 75% yield [101],... 

Ring-opening of aziridine-2-carboxylates with alcohols has been reported to give (3-alkoxy-a-amino esters [16, 102]. Treatment of as-aziridine 127 (Scheme 3.45) with alcohol in the presence of a catalytic amount of boron trifluoride etherate afforded P-alkoxy-ot-amino esters 128 in 57-100% yields [16,102a], The reaction is both regio- and stereoselective, affording 128 as the only product. 

Carboxylic acids have also been investigated as nucleophiles in the ring-opening of aziridine-2-carboxylates [103]. Solvation of compounds 129 (Scheme 3.46) in acetic acid, for example, gave 130a and 130b in 83% and 89% yields, respectively. 

With Sulfur Nucleophiles N-Carboxy-protected aziridine-2-carboxylates react with thiols to give P-mercapto-ot-amino acid derivatives. The reaction is usually catalyzed by BF3 and the yields range from fair to excellent [15, 16, 108-111]. With N-unprotected 3-substituted aziridine-2-carboxylates, the ring-opening with thiols usually takes place with anti stereoselectivity, especially in the case of the C-3 aliphatic substituted substrates. In cases in which C-3 is aromatic, however, the stereoselectivity has been found to be a function of the substitution pattern on the aromatic ring 3-p-methoxy ph eri yl-su bs li In led aziridines 143a (Scheme 3.51) and... 

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