Lactones route

Synthesis from carbohydrate derived 2-deoxy lactones. Routes to C-l glycals from 2-deoxy sugar pyranolactones have been described. The general strategy is outlined in Scheme 9. 

Free radical polymerization of cyclic ketene acetals has been used for the synthesis of polyfy-butyrolactone), which cannot be prepared by the usual lactone route due to the stability of the five-membered ring. The polymerization of 2-methylene-l,3-dioxalane at high temperatures (above 120 °C) gave a high molecular mass polyester [59,79]. Only 50% of the rings opened when the polymerization was carried out at 60 °C, and this led to the formation of a random copolymer. The presence of methyl substituents at the 4- or 5-position facilitated the reaction. The free radical initiators generally used in such polymerizations are ferf-butyl hydroperoxide, ferf-butyl peroxide, or cumene hydroperoxide. The various steps involved are described in Scheme 5 [59]. 

It is the second feature of the Newton-Roberts approach that is valuable from a stereocontrol point of view. In the Corey lactone approach, the synthon itself already contains C-13 of the co-sidechain, which enforces the use of a reagent containing a C-15 carbonyl, making control of the C-15 hydroxyl stereochemistry difficult, whereas in the tricycloheptanone approach the entire sidechain (C-13 to C-20) is added in one piece, which means that this sidechain can be readily introduced in the form of a reagent that has this sidechain stereochemistry already in place. Following the addition of the co-sidechain and a Baeyer-Villiger oxidation to the lactone, the later steps to add the a-chain are essentially identical to the Corey lactone route because the lactones are regioiso-meric. 

The Newton-Roberts approach, however, defines absolutely all the stereocenters. Four are held together in the tricyclic ketone intermediate manufactured in single enantiomer form, whereas because the co-sidechain component used has an extra carbon atom relative to the synthon required in the Corey lactone route, there is opportunity to predefine this center rigorously as the vinylic alcohol. There is a matter of regioisomerism in this approach as a result of the selectivity of the Baeyer-Villiger oxidation, which is discussed later, although the regioisomer is fairly easy to remove. 

The strategy described here should find considerable use as a method for the stereoselective synthesis of alkenes. Although this olefination strategy involves one more step than the classic Wittig reaction, in many cases it may prove to be the more practical method. Finally, the scope, overall efficiency, and stereoselectivity of the 0-lactone route compares favorably to the Wittig, Julia-Lythgoe, and related established strategies for the synthesis of tri- and tetrasubstituted alkenes. 

Adam and his co-workers have shown that sterically congested E-olefins are conveniently prepared by the lactone route shown in Scheme 7. Stereocontrol is achieved because a-lithiocarboxylates condense with aldehydes and ketones to give -hydroxy acids of predominantly r/ireo-configuration once formed, dehydrative cyclization is straightforward because the bulky substituents force the carboxy and hydroxy groups into juxtaposition. 

Unsubstituted coumestan and plicadin (Figure 5), a natural product whose structure is still today under discussion, were also synthesized from the appropriate diphenylacetylene derivative following this iodocyclization/car-bonylation/lactonization route [140]. 

The reductive coupling of aldehydes or ketones with 01, -unsaturated carboxylic esters by > 2 mol samarium(II) iodide (J.A. Soderquist, 1991) provides a convenient route to y-lactones (K. Otsubo, 1986). Intramolecular coupling of this type may produce trans-2-hy-droxycycloalkaneacetic esters with high stereoselectivity, if the educt is an ( )-isomer (E.J. Enholm, 1989 A, B). 

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

The use of epoxides as alkylating agents for diethyl malonate provides a useful route to y lactones Wnte equations illustrating such a sequence for styrene oxide as the starting epoxide Is the lactone formed by this reaction 3 phenylbutanohde or is it 4 phenylbutanohde ... 

Po adrninistered nifedipine is almost completely absorbed. The onset of action is 20 min and peak effects occur at 1—2 h. The principal route of elimination is through hepatic metaboHsm by oxidation to hydroxycarboxyHc acid and the corresponding lactone. These metaboHtes are pharmacologically inactive. Almost 70—80% of dmg is eliminated in the urine during the first 24 h. About 15% is excreted in the feces. The elimination half-life of nifedipine is about 1—2.5 h (1,98,99). Frequency of occurrence of side effects in patients is about 17% with about 5% requiring discontinuation of therapy (1,98,99). 

Conjugate bases of relati-.- ly strong carbon acids like esters and nitriles react with oxiranes. The former give lactones (Scheme 56) (64HC(19-1)418) while the latter provide a route to cyclobutanes (Scheme 57) (74JA5270). 

The method of synthesis described for chloropyruvic acid is essentially that reported. This procedure affords the product in excellent yields from readily available materials by a short, convenient route. Other less acceptable methods involve chlorination of pyruvic acid with sulfur dichloride or hypochlorous acid and the treatment of ethyl chloro(l-hydroxyheptyl)- or (o -hydroxybenzyl)oxalacetate 7-lactone with 50% hydrochloric acid. ... 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

Atroposelective cleavage of configurationally unstable lactone cycle in biaryl derivatives as effective route to chiral natural products and useful reagents 99S525. 

General synthetic routes to spiroketals 189 from lactones and lithiomethoxy-butenyne 184 have been described (83TL5303 88JOC652 89JOC1157 90JOC5894). Three synthetic schemes have been realized. 

Rearrangements and other side-reactions are rare. The ester pyrolysis is therefore of some synthetic value, and is used instead of the dehydration of the corresponding alcohol. The experimental procedure is simple, and yields are generally high. Numerous alkenes have been prepared by this route for the first time. For the preparation of higher alkenes (> Cio), the pyrolysis of the corresponding alcohol in the presence of acetic anhydride may be the preferable method." The pyrolysis of lactones 9 leads to unsaturated carboxylic acids 10 ... 

An alternative route to acrylic esters is via a (3-propiolactone intermediate. The lactone is obtained by the reaction of formaldehyde and ketene, a dehydration product of acetic acid ... 

A third, and more promising, route is currently under investigation. Bromine oxidation of an aqueous solution of 2-deoxy-D-nbo-hexose gave the hitherto unreported 2-deoxy-D-nbo-hexono-l,4-lactone, which was benzoylated to yield 3,5,6-tri-0-benzoyl-2-deoxy-D-nbo-hexono-l,4-lactone. Studies are in progress to effect a reduction of the benzoylated... 

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Treatment of bicyclic lactones 66, derived from Diels-Alder reaction of 3-carboxy-2-pyrone under standard radical conditions using (TMSlsSiH, leads to bridged lactones 67, which can smoothly be converted to bicyclo[3.3.0]-lactones 68 (Scheme 10). For X = CHaOMe, this cascade of rearrangements took place in a 78% overall yield, providing 68 in diastereomerically pure form. Three additional steps provided a novel route toward Corey s lactone 69. 

Scheme 9.25 Combined chemo- and biooxidative route to chiral proximal and distal lactones.

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