Bromolactones, formation

In view of the absolute configuration and their optical yields (88-96 %), it follows that the precursor of the (S)-4 should be 2a, which are formed highly diastereoselectively. It is likely that the predominant formation of 2a conforms to the mechanism of the bromolactonization, the S-trans transition state (ref. 3). 

In general, cyclization can be expected in compounds having the potential for formation of five- or six-membered rings. In addition to the more typical bromination reagents, such as those listed in Table 4.2, the combination of trimethylsilyl bromide, a tertiary amine, and DMSO can effect bromolactonization. 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

The Welch group tackles stereoselective synthesis of LL-Z1271a using Wieland-Miescher diketone 144 [82] (3% overall yield) (Scheme 4). This synthesis includes, as key steps, the stereoselective introduction of the methyl on carbon 4 in an equatorial position, the formation of the y-lactone via bromolactonization and the construction of the 5-lactone C ring through a Meyer-Schuster rearrangement. 

De Groot et al. synthesized ( )-3(3-hydroxynagilactone F (54) [85] from compound 172 [86] with an overall yield of 0.2% (13 stages). The key steps in this synthesis were the formation of the 5-lactone by nuclelophilic addition to carbonyl and subsequent treatment with p-toluensulfonic acid, the introduction of the isopropyl in an a equatorial disposition following a procedure similar to that described by Hayashi et al. and finally the formation of the y-lactone via bromolactonization. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

Barnett and Sohn (12, 13, see also 14) have discovered that the iodolactoni-zation of b,r-unsaturated carboxylic acid salts 37 yield, under kinetically controlled conditions, the Y-iodo-B-lactones 39 in preference to the more stable B-iodo-Y-lactones l. Similar results were obtained in the course of the bromolactonization reaction. Thus, here again, the formation of a four-membered ring is more facile than that of a five-membered ring. This can be rationalized on the basis of Stork s analysis, i.e. the internal opening by the carboxylate anion of the three-membered ring iodonium ion (or bromonium) 38 39 is preferred over the other mode of opening 40 41 for stereoelectronic reason. 

Bromolactonization of 450 enabled stereoselective attack of peracid at the endocyclic double bond of 451 (Scheme 54). Assistence of the benzyl ether led to tetrahydrofuran formation, debenzylation, and the secondary alcohol at C(3). Subsequently, the pentacyclic bromolactone 452 was reductively cleaved with zinc and the resulting acid was protected as methylester 453. Since lactonization by... 

A modification of the asymmetric bromolactonization leads to optically active a,p-epoxy aldehydes (18). Treatment of the bromolactone (14) with Sodium Methoxide results in the formation of the epimeric epoxy ester (17) in a ratio of 2 1 (eq 7). 

Cycloalkenes tethered with a y,5- or 5,8-unsaturated acid side chains react with Brj or I2 to furnish the corresponding halolactones. lodolactonization is more commonly used than bromolactonization since iodine is easier to handle (solid) and is more chemoselective (less reactive) than bromine. Halolactonization with aqueous base is kinetically controlled and proceeds via addition of a Br or B atom to the double bond to form a transient halonium ion. In the absence of strong directing steric effects, formation of the halonium ion may occur at either diastereoface of the double bond. However, only the halonium ion intermediate which allows trans-diaxial Sj. 2 opening by the neighboring carboxylate nucleophile leads, if the intramolecular reaction is sterically favorable, to the lactone. 

A review concerning the chemistry, biogenesis, and pharmacology of Amanita muscaria components includes a comprehensive coverage of the muscarine alkaloids. (+)-i -4-Hydroxypyrrolidin-2-one has been isolated from this source. A method for the identification of stereoisomeric muscarines by combination vacuum pyrolysis-g.c. analysis has been described. A micro method for the determination of ibotenic acid and other 3-hydroxyisoxazoles has been developed. Stereospecific syntheses for DL-muscarine and DL-a//o-muscarine have been reported. Pyrolysis of (1) yielded the carboxylic acid (2) and the bromolactone (3) which served as key compounds in the synthesis of the muscarines. The minor component (3) was shown to be an intermediate in the formation of (2) and therefore the conversion [(3)- -(2)] could be written as an intramolecular Sn2 displacement on an a-lactone (4). However, treatment of (3) with... 

Bromohydration, Bromolactonization, and Other Additions to C=C. The preferred conditions for the bromohydration of afkenes involves the portionwise addition of solid or predissolved NBS (recrystallized) to a solution of the alkene in 50-75% aqueous DME, THF, or f-butanol at 0 °C. The formation of dibromide and a-bromo ketone byproducts can be minimized by using recrystallized NBS. High selectivity for Markovrukov addition and anti stereochemistry results from attack of the bromonium ion intermediate by water. Aqueous DMSO can also be used as the solvent however, since DMSO is readily oxidized under the reaction conditions, significant amounts of the dibromide byproduct may be produced. In the bromohydration of polyalkenic compounds, high selectivity is regularly achieved for attack of the most electron-rich double bond (eq 20). With famesol acetate, squalene, and other polyisoprenes, choice of the optimum proportion of water is used to effect the selective bromohydration at the terminal double bond (eq 21), and the two-step sequence shown is often the method of choice for the preparation of the corresponding epoxides. ... 

A step in a synthesis of PGEj (prostaglandin Ej, alprostadil) is the reaction of a trisub-stituted cyclohexene with bromine to form a bromolactone. Propose a mechanism for formation of this bromolactone and accoimt for the observed stereochemistry of each substituent on the cyclohexane ring. 

Desymmetrization via bromolactonization has been attained in the case of the prochiral cyclohexadiene (19) on reaction with NBS catalysed by (DHQD)2PHAL (21) the corresponding fi- and y-bromolactones (20) were thus obtained with <93% ee. The latter reaction can also be used for the kinetic resolution of racemic cyclic ene-carboxylic acids. A catalytic asymmetric bromocyclization of trisubstituted olefinic sulfonamides (22) has been attained on reaction with iV-bromophthalimide (23), catalysed by the C2-symmetrical selenium derivative of mannitol (24) (Scheme 2). The reaction is believed to proceed via formation of the Br-Se+ species (26) that attacks the C=C bond with a subsequent 5 N) -exo-trig ring closure (27). ... 

Treatment of indole-3-propionic acid with 3 equiv. of NBS in aqueous media leads to the cyclic product 5-bromolactone (96) (295). Similar spirolactone formation has been found also with indole 3-propionyl... 

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