Cyclization in Water

SCHEME 4.43 Jamison s approach to the gymnocin tetrahydropyran core. 

Advances in applying these studies to stereoselective oxacycle synthesis have been critically dependent upon the development of enantioselective epoxidation methods. Extensive research into designing these reactions has resulted in a wide range of structurally distinct epoxides being available in enantiomerically pure form through experimentally facile methods that utilize easily accessible catalysts. These enabling methods assure that substrate synthesis will not limit further exploration in epoxide-based cyclization reaction development. 

The understanding of epoxide reactivity patterns and the availability of stereochemicaUy defined epoxides has made complex natural products accessible through often shockingly short sequences. These efforts have resulted in the capacity to prepare analogs and probes that provide greater insight into the biological activities that these compounds effect. 

Challenges still remain in this area despite the dramatic advances that have been detailed. Definitive proof of the epoxide cascade route to the marine ladder toxins has yet to be 

FROM ACETATE TO ME VALONATE AND DEOXYXYLULOSE PHOSPHATE BIOSYNTHETIC PATHWAYS AN INTRODUCTION TO TERPENOIDS 

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Mandolini and Masci provided further information on this question quite recently by demonstrating that polyethylene glycol dibromides undergo partial hydrolysis and then cyclization in water containing Ba ions. According to the report, yields were higher in this reaction when barium cation was present than when it was absent. 

This is a general method, leading to either 3-hydroxypiperazine-2,5-diones, or to the corresponding alkylidene derivatives (74CB2804). Thus A-pyruvoylproline methylamide cyclizes in water at pH 7.5 to yield the piperazinedione the cyclization appears to be highly stereoselective, leading to the kinetically controlled product (26). The scope of the method has been considerably expanded by Dutch workers, who have used it for the synthesis of l-hydroxypiperazine-2,5-dione derivatives (see Section VI). 

Scheme 30. EtjB-induced atom transfer radical cyclization in water...

Two possible explanations were offered for the apparent curvature of the Br0nsted plot (Fig. 2). It was suggested that the cyclization in water may represent the rather abrupt onset of an uncatalyzed reaction [i.e., similar to Eq. (47)]. We believe that the curvature is too gradual to be called abrupt. Thus, the alternative explanation of a gradually changing response in rate to the difference in pK between the base and alcohol appears to be more reasonable, yet it awaits verification. 

A. Keivanloo, M. Bakherad, H. Nasr-Isfahani, S. Esmaily, Highly efficient synthesis of 5,6-disubstituted 5H-pyrrolo-[2,3-l ]-pyrazine-2,3-di-carbonitriles through a one-pot palladium-catalyzed coupling reaction/cyclization in water. Tetrahedron Lett. 53 (2012) 3126-3130. 

A [4 + 2 +1] domino cyclization in water involving condensation of 2,2-dihydroxy-indene-l,3-dione (149), tetronic acid 150 and OPD catalyzed by acetic acid has been developed for the synthesis of spiro-substituted benzofurodiaz-epine derivatives 152 and 153 (Scheme 32) in a one-pot manner xmder MW proceeding within few minutes [102]. The authors observed that the outcome of tiie process was dependent on the ratio of reactants as well as on the electronic effects of the substituent in the aromatic ring of the diamine. 

SCHEME 32 A domino cyclization in water leading to benzofurodiazepine derivatives. 

C. Cheng, B. Jiang, S.-J. Tu, G. Li, [4+2+1] Domino cyclization in water for chemo- and regioselective synthesis of spiro-substituted benzo[i ] furo[3,4-e][l,4]diazepine derivatives. Green Chem. 13 (2011) 2107-2115. 

Yorimitsu H, Nakamura T, Shinokuho H, Oshima K, Omoto K, Fujimoto H. Powerful solvent effect of water in radical reaction triethylborane-induced atom-transfer radical cyclization in water. J. Am. Chem. Soc. 2000 122(45) 11041-11047. 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

The cyclization of a-thiocyanatoketones (183) in aqueous acid, concentrated sulfuric acid in acetic acid and water, or alkaline solution leads to 2-hydroxythiazoles after dilution in water. 

In a similar reaction, bromosuccinic acid and thiobenzamide in ethyl-acetate yielded an acyclic intermediate (229), Ri = Ph, R2 = CH2C02H, which by heating in water cyclizes to the thiazole (230), Rj = Ph and R2 = CH2C02H. (260). 

Cationic monomers are used to enhance adsorption on waste soHds and faciHtate flocculation (31). One of the first used in water treatment processes (10) is obtained by the cyclization of dimethyldiallylammonium chloride in 60—70 wt % aqueous solution (43) (see Water). Another cationic water-soluble polymer, poly(dimethylarnine-fi9-epichlorohydrin) (11), prepared by the step-growth... 

The mechanism of cyclization of diaminopyrimidines by nitrous acid appears not to have been studied in detail. For the preparative procedure an aqueous solution of alkaline nitrite is treated with the diaminopyrimidine either in the form of a salt or with simultaneous addition of hydrochloric or acetic acid. The first phase of the reaction is usually carried out at 0°C, in some cases the reaction being terminated by heating to 50-60°C. With diaminopyrimidines which are sparingly soluble in water, the reaction was carried out in an organic solvent using amylnitrite. Excess nitrous acid can possibly attack the amino groups present. This was employed in some cases for the preparation of the hydroxy derivatives. ... 

N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homo-chiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0°C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and tranx-l,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCI3 solution, the reaction is poorly diastereo-selective. In water, a considerable enhancement in favor of the trans adduct is observed. 

Cationic polymerization of alkenes and alkene derivatives has been carried out frequently in aqueous media.107 On the other hand, the reaction of simple olefins with aldehydes in the presence of an acid catalyst is referred to as the Prins reaction.108 The reaction can be carried out by using an aqueous solution of the aldehyde, often resulting in a mixture of carbon-carbon bond formation products.109 Recently, Li and co-workers reported a direct formation of tetrahydropyranol derivatives in water using a cerium-salt catalyzed cyclization in aqueous ionic liquids (Eq. 3.24).110... 

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

Radical addition to alkenes has been used in cyclizations in aqueous media. Oshima and co-worker studied triethylborane-induced atom-transfer radical cyclization of iodoacetals and iodoacetates in water.121 Radical cyclization of the iodoacetal proceeded smoothly both in aqueous methanol and in water. Atom-transfer radical cyclization of allyl iodoacetate is much more efficient in water than in benzene or hexane. For instance, treatment of allyl iodoacetate with triethylborane in benzene or hexane at room temperature did not yield the desired lactone. In contrast, the compound cyclized much more smoothly in water and yielded the corresponding y-lactone in high yield (Eq. 3.31). 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

In water alone, the cyclization proceeded in 20% yield with an epimeric selectivity of 1 2 (A B) at 89°C after 6 h. The same reaction gave 91% of the cyclized product when one equivalent of 6-cyclodextrin was present. In this case, the epimeric selectivity was also changed to 1 1.5 (A B). However, no significant change of reactivity was observed with either a-cyclodextrin or the nonionic detergent, Brij-35, present. A similar enhancement of reactivity by (i-cyclodextrin was observed in the cyclization of the amine derivative. 

Roskamp reported29 a similar intramolecular Diels-Alder reaction accelerated by silica gel saturated with water. The reaction led to the ready construction of the 11-oxabicyclo [6,2,1] ring systems (Eq. 12.4). The intramolecular Diels-Alder reaction has also been investigated by Keay.30 The Diels-Alder reaction of 2,5-dimethylpyrrole derivatives with dimethyl acetylenedicarboxylate in water generated the corresponding cyclization products.31... 

Kobayashi has found that scandium triflate, Sc(OTf)3,36 and lanthanide triflate, Ln(OTf)3, are stable and can be used as Lewis catalysts under aqueous conditions. Many other Lewis acids have also been reported to catalyze Diels-Alder reactions in aqueous media. For example, Engberts reported37 that the cyclization reaction in Eq. 12.7 in an aqueous solution containing 0.010 M Cu(N03)2 is 250,000 times faster than that in acetonitrile and about 1,000 times faster than that in water alone. Other salts, such as Co2+, Ni2+, and Zn2+, also catalyze the reaction, but not as effectively as Cu2+. However, water has no effect on the endo-exo selectivity for the Lewis-acid catalyzed reaction. 

The a-ketoacid-dependent enzymes are distinguished from other non-haem iron enzymes by their absolute requirement for an a-ketoacid cofactor as well as Fe(II) and O2 for activity. They catalyse two types of reaction (Table 2.3), hydroxyla-tion and oxidation. In both, the a-ketoglutarate is decarboxylated and one oxygen atom introduced into the succinate formed in the hydroxylases, the other oxygen atom is introduced into the substrate, while in the oxidases it is found in water, together with the cyclized product. In general these enzymes require one equivalent of Fe(II) an a-ketoacid, usually a-ketoglutarate and ascorbate. Examples of these enzymes include proline 4-hydroxylase, prolyl and lysyl hydroxylase, which... 

It was suggested that the reaction of 3-methyl-1,2-butadienephosphinic acid with bromine in water involved oxaphospholic cyclization and oxidation of the substrate (Scheme 18) [58],... 

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