Lactones hydroxy, formation

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

Chiral Lactones and Polyesters. Similar to intermolecular reactions described previously. Upases also catalyze intramolecular acylations of hydroxy acids the reactionsults in the formation of lactones. 

Bicucine, C20H19O7N, H2O. This alkaloid has m.. 222° (dec.) and — 115 4° (N/10, KHO) but in N/HCl it shows mutarotation — 145° to — 100°,due to the formation of an equilibrium mixture of bicucine and bicuculline. Alkaline permanganate oxidises it to 3 4-methylene-dioxyphthalic acid, isolated as the ethylimide. In view of its formation from bicuculline by the action of alkali, Manske has suggested for its formula (II) or (III), the former representing it as the nomarceine (p. 208) analogue of bicuculline, whilst (III) makes it the hydroxy-acid corresponding to the lactone, bicuculline and is preferred. 

The rhodium catalyst previously discussed is employed in the hydrogenation of / -hydroxybenzoic acid. The resulting mixture of cis and trans products is separated by virtue of the ready formation of the lactone of the cis product, which is then hydrolized to the hydroxy acid. 

The addition of the dianion of /j-sulfmylcarboxylic acids to carbonyl compounds leads to the formation of the corresponding hydroxy derivatives which undergo spontaneous eyclization to give y-lactones. It was found that when optically active ( + )-(/ )-3-(4-methylphenylsulfinyl)pro-panoic acid is used for the reaction, the corresponding diastereomeric /i-sulfinyl-y-lactones are formed in a ratio which is dependent on the substituents of the carbonyl component. However, the diastereoselectivity was always moderate. 

The initial results of an early directed evolution study are all the more significant, because no X-ray data or homology models were available then to serve as a possible guide [89]. In a model study using whole E. coU cells containing the CHMO from Adnetohacter sp. NCIM B9871,4-hydroxy-cydohexanone (3 5) was used as the substrate. The WT leads to the preferential formation of the primary product (i )-36, which spontaneously rearranges to the thermodynamically more stable lactone (R)-37. The enantiomeric excess of this desymmetrization is only 9%, and the sense of enantioselectivity (R) is opposite to the usually observed (S)-preference displayed by simple 4-alkyl-substituted cydohexanone derivatives (see Scheme 2.10) [84—87]. 

Polyfunctionality of the reactants is not sufficient in itself to assure formation of polymer the reaction may proceed intramolecularly with the formation of cyclic products. For example, hydroxy acids when heated yield either lactone or linear polymer (or both),... 

The principles set forth above account reasonably well for the course of bifunctional condensations under ordinary conditions and for the relative difficulty of ring formation with units of less than five or more than seven members. They do not explain the formation of cyclic monomers from five-atom units to the total exclusion of linear polymers. Thus 7-hydroxy acids condense exclusively to lactones such as I, 7-amino acids give the lactams II, succinic acid yields the cyclic anhydride III, and ethylene carbonate and ethylene formal occur only in the cyclic forms IV and V. 

Application of the carbonylation reaction to halides with appropriately placed hydroxy groups leads to lactone formation. In this case the acylpalladium intermediate is trapped intramolecularly. 

In aqueous acid cross-conjugated cyclohexadienones are principally photoconverted to one or more hydroxy ketones. In the case of a-santonin (1), isophotosantonic lactone (5) is formed in about 50% yield. A series of papers by Kropp and co-workers has aided in understanding this reaction/32-39-411 They have shown that the presence of a 4-methyl group (steroid numbering) results in the preferential formation of the 5-7 fused ring system (isophoto-... 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

The formation of this analog CXI of L-ascorbic acid containing one enolic hydroxy group is therefore responsible for the reducing properties displayed by the two dilactones CIX and CX and the two ester lactones CVII and CVIII of D-glucosaccharic acid. 

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