Reactions bromolactonization

The classic method for controlling stereochemistry is to perform reactions on cyclic substrates. A rather lengthy but nonetheless efficient example in the prostaglandin field uses bicyclic structures for this purpose. Bisacetic acid derivative S is available in five steps from Diels-Alder reaction of trans-piperylene and maleic anhydride followed by side-chain homologation. Bromolactonization locks the molecule as bicyclic intermediate Esterification, reductive dehalogen-... 

As seen in Table 1, (S)-4 are obtained in excellent chemical and optical yields by using the neutral and mild key reaction, the bromolactonization, followed by simple treatment with HCl. 

To a solution of 2a (1.00 g, 5.46 mmol), (ref. 4) in 10 ml of DMF, a solution of NBS (1.95 g, 10.9 mmol) was added at 0°C and then for 24 hours at room temperature. It was diluted with 400 ml of EtOAc and partitioned. The EtOAc solution was washed with sat. NaHC03 solution (50 x 3 ml), and sat. NaCl solution (50 X 2 ml), and dried over anhyd. MgS04. Filtration and evaporation gave crude bromolactones to which 55 ml of 6N-HC1 was added. After the reaction mixture was refluxed for 24 hours, it was diluted with 55 ml of sat. NaCl solution and extracted with EtOAc (55 x 3 ml). The combined EtOAc solution was washed with... 

The bromolactonization product 470 was obtained by the reaction of y-monoalkyl-substituted allenoates 467 with NBS in H20 or Br2 at room temperature. Here the carbonyl oxygen served as an intramolecular nucleophile. The Z-isomer of the bro-mohydroxylation product was also formed in 4% yield (R Me, R2 = H) [211, 213, 214], The absence of the Z-isomer may be ascribed to the easy conversion of the E-isomer to butenolide 470. 

Ring closure of the amino-bromolactones 34 and 39 was now performed. Based on our experience with the reaction of bromolactones with different... 

In the total synthesis of an anthracycline antibiotic, the key step was an asymmetric halolactonization reaction. The corresponding bromolactones were formed with high stereoselectivity (d.s. > 90%). (S)-Proline was used as chiral auxiliary. 

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). 

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). 

Most recently in 2003, McLeod s group obtained the 3-lactone motif of orlistat (1) using a bromolactonization reaction.3,Y-Unsaturated acid 38 was prepared from a diene-ester, hexadeca-2,4-dienoic acid methyl ester. McLeod et al discovered that conducting the bromolactonization in methanol and 10% aqueous sodium bicarbonate solution afforded predominantly rrany-39, which was then transformed to orlistat (1). 

Reaction of the bromolactone 90, the product of photobromination of methyl tetra-0-benzoyl-/ -D-glucopyranoside, with sodium iodide in acetone affords63 2,4,6-tri-0-benzoyl-3-deoxy-D-er)y/i/r>hex-2-enono-1,5-lactone (176) in good yield (see Scheme 30). 

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. 

In a different sequence of reactions, N-acetylation of 274 and exposure of the intermediate imide 275 to ethanolic KOH gave a mixture (about 2 1) of the desired carboxylic acid 276 together with the starting lactam 274 via the non-selective hydrolysis of the imide moiety of 275 (148a,c). When 276 was treated with /V-bromosuccinimide (NBS), an intermediate bromolactone was produced which was heated at reflux in pyridine in the presence of DBU to give 277. The conversion of the lactone 277 to the lactam 278 was effected by heating 277 in aqueous NaOH followed by protection of the resulting allylic alcohol function as a tetrahydropyranyl ether. 

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. 

To finish our discussion of bromonium ions, you need to know about one more important class of reactions, those in which the nucleophile is located within the same molecule as the bromonium ion. Here is an example the nucleophile is a carboxylate, and the product is a lactone (a cyclic ester). This type of reaction—the cyclization of an unsaturated acid—is known as a bromolactonization. Intermolecular attack on the bromonium ion by bromide ion does not compete with the intramolecular cyclization step. 

Asymmetric bromolactonization (8, 421-423). Detailed papers concerning this reaction have been published. For this reaction L-proline is definitely superior to open-chain L-amino acid derivatives where free rotation of the bond between the asymmetric center and the N atom is possible. 

---