Bromolactonizations bromine

Several a-btomo-a,/3-olefinic ketones and esters have been prepared by an interesting cleavage of S-acyl or )3-carbethoxy-a-ketolactones. It is unnecessary to isolate the bromolactone. Bromination and cleavage take place readily at 0-20° over-all yields are 60-85%. The /6-acyl and /6-catbethoxy-a-ketolactones are prepared by aldol-type condensations of aldehydes with the active methylene groups of ethyl )3-acetyl-pyruvate, CHjCOCHjCOCO CjHs, and ethyl oxalacetate,... 

Synthesis of (A) started with the combination of 2,4,6-trimethylphenol and allyl bromide to give the or/Ao-allyl dienone. Acid-catalyzed rearrangement and oxidative bydroboration yielded the dienone with a propanol group in porlactone ring were irons in the product as expected (see p. 275). Treatment with aqueous potassium hydroxide gave the epoxy acid, which formed a crystalline salt with (R)-l-(or-naphthyl)ethylamine. This was recrystallized to constant rotation. 

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. 

Bromolactonization of /3,y-unsaturated acids has proven to be a much more satisfactory method of synthesis of /3-lactones, giving good yields of stable crystalline -y-bromo-/3-lactones, except when the substitution at the -y-carbon atom can favor development of carbonium character there. Thus 1,4-dihydrobenzoic acid and 2-methyl-l,4-dihydrobenzoic acid form /3-lactones (equation 95), while 3-methyl-l,4-dihydrobenzoic acid forms the -y-lactone (75JOC2843). The reaction of the sodium salt of a-methylcinnamic acid with bromine in water or methanol also gives /3-lactone, but the yield is low (78JOC3131). 

Having the 2-alkylated 5-bromolactones in hand, the conversion to isoiminosugars were performed by transforming the bromine to an amino group via an azide displacement followed by reduction. This gave directly the optically pure lactams by ciystallisation. Reduction of the lactam function gave... 

Variations on this cyclization methodology include the use of bromine, rather than iodine again, both lactones and ethers can be prepared.1,47,54-57 An asymmetric bromolactonization procedure affords a-hydroxy acids with good asymmetric induction.57-62... 

Bromolactonization.1 Reaction of unsaturated acids with Br2 and thallium(I) carbonate results in bromine-substituted lactones in moderate yield. Yields generally are higher than those obtained with NBS in CH2C12, THF, or DMF. 

It is noteworthy, however, that by bromolactonization of a methyl 4-C-(aminocarbonylmethyl)-2-hexenopyranoside with bromonium collidine perchlorate in chloroform, an unexpected a-bromination in the C-4 side chain is observed43. 

The halocyclization of ( )-2-methyl-3-pentenoic acid occurs with high stereoselectivity under various conditions affording the y-iodo- and y-bromolactones20. (/ )-( )-2-Methyl-3-pentenoic acid (5), easily obtained by separation of the racemic acid with (R)- or (S)-a-methylbenzyl-amine, affords the (37 ,47 ,5,S )-y-lactone 6 susceptible to further transformation. The iodolac-tonc is obtained in 95% yield by reaction of the sodium salt of the unsaturated acid with iodine in methanol/water (85 15) containing sodium hydrogen carbonate at — 78 °C for 6 h. The IR spectrum confirms the presence of the y-lactone functionality while the H-NMR data is consistent with a trans,trans-arrangement21 of the substituents. The bromolactone can be obtained in 85-90% yield (mp 45-46°C) by treatment of the thallium salt of (E)-5 with bromine in dichloromethane at — 78 °C20. 

Under similar cyclization conditions (2S, 3R)-2-/< r/-butoxycarbonylamino-3-hydroxy-4-pentenoic acid (32) gives the corresponding (3S, 4S, 5.R)-bromolactone in low yield. On the contrary, the lactonization performed with mercury(Il) acetate in tetrahydrofuran, followed by treatment with bromine, exclusively produces the (SS S /Q-lactone 33 in 56% yield. The (35,45,5/ )-lactone was converted into (25,3S,4S )-3,4-dihydroxyproline (34), a compound isolated from diatom cell walls. These transformations thus provide an effective method for the synthesis of substituted prolines35. 

Diphenyldibromoselenurane (142) and the ionic derivative 143 were found [70] to be efficient sources of positive bromine for bromolactonization of 4-pentanoic acid (144), bromocyclization of unsaturated alcohols and bromi-nation of 1,3,5-trimethoxybenzene (147) (Eqs. 34 and 35). 

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. 

Three organocatalysts, DMF, DMA and TMG (1), were examined for their catalytic roles for the bromolactonization of y,8- and 8,E-unsaturated carboxylic acids with A-bromo-succinimide (NBS). TMG (1) was found to be a superior catalyst for this bromination (1-10 mol% loading, 100% conversion after 15 min) and to catalyse an intermolecular bromoacetoxylation of alkenes with acetic acid and NBS. The catalytic cycle is proposed (Scheme 4.13) [38]. 

The synthesis consisted of the reaction of 90 with N-bromosuccinimide (NBS) to give the bromolactone 91, substitution of the bromine atom for a hydroxyl group to form 92 and reduction of the lactone grouping in 92 with bis[2-(3-methylbutyl)] borane to give the desired product. Optic ly active forms of the acid 90, which served for the synthesis of enantiomeric 2-deoxy-erythro-pentoses, were readily obtained by resolution of the racemate with quinine. 

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