Cyclization-elimination, reaction

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

Fig. 8.12. Activation of hemiester prodrugs of phenols by acid-catalyzed hydrolysis (Reaction a), base-catalyzed hydrolysis (Reaction b), and cyclization-elimination (Reaction c). Enzymatic hydrolysis not shown (adapted from [174]). 

Fig. 11.18. Cyclization-elimination reactions in the in vitro and in vivo metabolism of nephrotoxic 2-haloethylamines (11.133). Aziridine (11.134) formation is probably a reaction of tox-ification, whereas oxazolidin-2-one (11.136) is clearly a reaction of detoxification [155][156].

Fig. 6 Activation of hemiester prodrugs of phenols by proton-catalyzed hydrolysis (reaction a), hydroxyl-catalyzed hydrolysis (reaction b), or cyclization-elimination (reaction c). Enzymatic hydrolysis is not represented. (Adapted from Ref.. )...

Very different classes of organic compounds are able to yield 6-membered heterocyclic products upon electron impact induced cyclization/elimination reactions. In spite of the formal similarity of these processes with (19), it cannot be ruled out that the reaction mechanism of these decompositions is quite distinct. The structurally important parameters are the nature of the leaving group X as well as the ring forming heteroatom. The examples 99-103 may give a small impression of which structural features may be involved in the formation of (M—X)+ fragments. 

The preparation of the quinoline system by pericyclic reactions is less important than the previous syntheses. Some cyclization/elimination reactions of iV-phenylimines 95 and 96 with alkynes, enol ethers or enamines are of preparative interest. Although they correspond to [4+2] cycloadditions, they are likely to proceed by SeAt mechanisms and are usually catalysed by Lewis acids. In the enolether cycloaddition to imines 95 ytterbium(III)triflate proved to be particularly effective [104]. 

Miyata, O., Ozawa, Y., Ninomiya, L, and Naito, T. (1997) An enantioselective synthesis of (—)-a-kainic acid via thiyl radical addition-cyclization-elimination reaction. Synlett, 275-276. 

Barrelene was obtained via a double Diels-Alder reaction from a-pyrone with methyl acrylate (H.E. Zimmerman, I969A). The primarily forming bicyclic lactone decarboxylates in the heat, and the resulting cyclohexadiene rapidly undergoes another Diels-Alder cyclization. Standard reactions have then been used to eliminate the methoxycarbonyl groups and to introduce C—C double bonds. Irradiation of barrelene produces semibullvalene and cyclooctatetraene (H.E. Zimmerman. 1969B). 

A polyfluorinated P,y-unsaturated ketone is formed m situ from tributylamine and 3,4-bis(tnfluoromethyl)-3-(pentafluoroethyl)-5,5,6,6,6-pentafluoro-2-hex-anone. The enol form of the unsaturated ketone cyclizes via an intermolecular addition-elimination reaction that involves exclusive attack by oxygen rather than by carbon. This reaction demonstrates the hardness of a F-C= site toward... 

The reactions of (174) with various amines has been studied." " Hydrolysis of the hexamine salt of (174) gave not the symmetric diamine but (184) via a cyclic intermediate. The pyrolysis of 5-methyl-2-thenyltrimethyl ammonium hydroxide (185) is claimed to give (186) through a 1,6 Hofmann elimination reaction. The Bischler-Napieralski cyclization has been applied to acetyl derivatives of 2-(2-thienyl) ethylamine and 2-(3-thienyl) ethylamine for the preparation of sulfur analogs of isoquinoline. ... 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Cyclization of 148 with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a subsequent elimination reaction with acetic anhydride and pyridine furnished compound 149. °- Compound 149 was found to be an important key compound for the following synthesis of carba-sugars of the a-L-altro, fi-D-gluco, P-h-allo, and a-D manno modifications. 

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

In a reaction similar to the (>-alkoxide elimination reactions seen with zir-conocenes, catalytic Rh(OH)(cod)2 and 2 eq. of arylboronic acids gave cyclic products 165 from enynes 166 (Scheme 35) [100]. In this reaction, transmet-allation of Rh - OR with B - Ph gave Rh - Ph species 167, which inserted into the alkyne, cyclized to 168, and finally underwent [>-alkoxidc elimination to provide Rh-OCH3. This reaction is limited to the formation of five-membered rings, but it can also undergo cascade type reactions of enediynes to give multicyclic products [100]. 

This section presents selected examples of the use of zeolites and related porous materials for transformations of carbohydrates, that fall beyond the scope of the previous paragraphs. They include the use of zeolites in click chemistry and in a variety of reactions, including the synthesis of anhydro sugars, cyclization, elimination, and addition reactions to the carbonyl group. 

A detailed review of the ortho-effect in mass spectrometry was published by H. Schwarz [22]. He classified the processes related to the ortho-effect, gave examples of unusual elimination reactions, processes of intramolecular cyclization, exchange and reduction processes. 

An unusual one-pot intramolecular sulfoxide alkylation-elimination reaction was found by Gibson et al. <2001SL712>. These authors found that treatment of 459 with potassium bis-trimethylsilylamide resulted in a ring closure to 460 in acceptable yield. Furthermore, Batori and Messmer found an effective method for preparation of [l,2,3]triazolo[l,5- ]pyrimidinium salts <1994JHC1041> oxidative cyclization of hydrazones 461 by 2,4,4,6-tetrabromo-2,5-cyclohexadienone gave rise to the quaternary salts 462. Under certain reaction conditions, the formation of 6-bromo-salts 462 (R6 = Br) was also experienced. As neither the starting compound nor the quaternary triazolopyridinium salt underwent bromination in this position, the authors assumed that this bromination process occurred on one of the intermediates in the course of the above-mentioned cyclization reaction. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Methyleneazetidones have been obtained [39, 40] under liquiddiquid and solidrliquid basic conditions (Table 5.19) from an intramolecular cyclization and elimination reaction of 3-bromo-2-(bromomethyl)propionamides (Scheme 5.9). Traditional methods for the preparation of such compounds are either not particularly adaptable for general use, or involve lengthy and vigorous reaction conditions. In... 

Prodrug activation occurs enzymatically, nonenzymatically, or, also, sequentially (an enzymatic step followed by a nonenzymatic rearrangement). As much as possible, it is desirable to reduce biological variability, hence the particular interest currently received by nonenzymatic reactions of hydrolysis or intramolecular catalysis [18][20], Reactions of cyclization-elimination appear quite promising and are being explored in a number of studies. 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

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