Lactones, from alkene-acids

Before we move on, we leave you with one final example. Stereoselectivity in the epoxidation of lactone-bridged alkenes related to those we saw earlier (p. 874) can be completely reversed if the lactone is hydrolysed, revealing a hydroxyl group. In this bicyclic example, the hydroxyl group delivers the peroxy-acid from the bottom face of the alkene. First, the lactone bridge is used to introduce the alkene as before. 

A useful extension of the alkoxycarbonylation reaction has been devised in order to obtain 3,4-dihydro-4-hydroxy-l//-2-benzopyran-3-acetic acid lactones from 5-alkene-l,4-diols. The intramolecular cyclization of 7, carried out with palladium(II) acetate and copper(II) chloride under a carbon monoxide atmosphere, affords the m-lactone 8 in 68% yield. The configuration is assigned on the basis of H-NMR double resonance methods86. 

Good yields of 1 1 adducts have also been obtained from Lewis acid catalyzed reactions of methyl chloropropiolate or DMAD with alkenes. With methyl chloropropiolate, cyclobutenes are obtained exclusively from mono- and 1,2-di-substituted alkenes and mixtures of ene adducts and cyclobutenes are obtained with 1,1-di-, tri- and tetra-substituted alkenes. With DMAD, ene adducts are obtained exclusively from 1,1-di-, tri- and tetra-substituted alkenes and mixtures of ene adducts and cyclobutenes are obtained hrom 1,2-disubstituted alkenes. EtAlCb is a more effective catalyst than AlCb since it is a proton scavenger as well as a Lewis acid. With AlCb, lactone byproducts are also formed. - The relative reactivity of alkenes in these Lewis acid catalyzed reactions was found to be 1,1-di- > tri- > tetra- mono- > 1,2-di-substituted. With reactive ene components such as methylenecyclohexane, ethyl-idenecyclohexane and -pinene, good yields of ene adducts can be obtained with DMAD by thermal reaction at 110-130 "C for 0.25-6 d. ... 

Manganic acetate (manganese triacetate), Mn(OCOCH3)3, is prepared by refluxing a solution of manganese acetate tetrahydrate in acetic acid with potassium permanganate [S03]. This oxidant hydroxylates ben-zylic methylene groups [416] and forms lactones from terminal alkenes [803, 804] (see equation 88). 

We can use sulfenyl-lactonisation to illustrate the stereospecificity of the process when the alkene differs in geometry. Rokach28 has shown that the geometrical isomers of the unsaturated acid E-and Z-182 give the correct diastereoisomers of the lactones from anti addition of Cl and R S. 

A series of alkenes 20, derived from amino acids, react with the dienol 21a to give adducts 22. Formation of the additional lactone and lactam rings occurs prior to isolation of the product. A complete facial selectivity, but only moderate (22a) to low (22b and 22c) yields are obtained9. To prevent lactone ring formation several protected derivatives of dienol 21 were reacted with alkylidene malonic ester 20a. Only diene 21g reacts in an acceptable yield and selectivity10. 

Oxone in conjunction with OSO4 cleaves alkenes to ketones or carboxylic acids (eq 43). This protocol has the advantage over traditional methods in that there is no need for intermediate 1,2-diols. This method has been exploited in the direct synthesis of lactones from alkenols (eq 44) and tetrahydrofuran-diols from 1,4-dienes as well. ... 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

A y-lactone was formed in excellent yield by the nucleophilic cyclization of a carboxylic acid onto an alkene radical cation generated from a (i-nilrophosphale under tin hydride conditions (Scheme 21) [139]. Related experiments employing the acetate group and an internal carboxylate nucleophile failed, emphasizing the very rapid collapse of the alkene radical cation/acetate ion pair [127]. 

With respect to the biosynthesis of the solvents it has been speculated on the basis of quantitative data and the identification of (3,y-unsaturated acids in primitive oxytelid beetles that pairs of 1-alkenes and y-lactones are synthesized from corresponding 3-alkenoic acids by either lactonization or by decarboxylation [118]. 

Oxazine derivatives are formed from unsaturated AAs. Vinylglycine, after epoxidation at the double bond, yielded methyl l,3-oxazin-2-one-4-carboxylate after treatment with sodium methoxide or p-chlorophenol (90TL2291). Similarly, some alkenes react with methyl a-methoxyhippurate and cyclization occurs with BF3-Et20 (75TL3737). In sulfuric acid butyro-lactones are formed. 

The enantiomerically-pure intermediate 1 was prepared from the dioxolanone 4, available in three steps from L-malic acid. Lewis acid-mediated homologation converted 4, a 4 1 mixture of diastereomers, into 5 as a single diastereomer. After establishment of the alkenyl iodide, it necessary to maintain the lactone in its open form. A solution was found in the formation of the Weinreb amide. The final stereogenic center was established by Brown allylation of the derived aldehyde. The alkene metathesis to form 1 was carried out with the commercially-available Schrock Mo catalyst. The authors did not comment on the relative efficacy of alternative alkene metathesis catalysts. 

Alkenes from p-oxygenated selenidesS /J-Phenylseleno lactones, ethers, and alcohols are converted into alkenes on treatment with ClSi(CHj)j and Nal in C HiCN. Hydriodic acid (formed by inadvertent hydrolysis) may play a role this acid cun effect this reaction, but in lower yield. This elimination thus reverses cyclo-(unclionali/ations induced by C6H5ScX (cf Na-NH3, 9, 26), and in addition provides a stereospecific route to alkenes by way of/l-hydroxv selenides. lixnmplc ... 

Dondoni et al. prepared a 1-hydroxyethylene peptide using a thiazole-aldehyde synthesis starting from an amino acid.[38] The aldehyde is converted into an alkanoate by Wittig alkenation and reduction of the double bond (Scheme 18). Then, removal of the tert-bu-tyldimethylsilyl group gives the unsubstituted lactone. In the last step, the lactone is alkylated using the method reported by Kleinman and co-workers. 20 ... 

A large part of the usefulness of the Michael reaction in organic synthesis derives from the fact that almost any activated alkene can serve as an acceptor7—a, 3-unsaturated ketones, esters, aldehydes, amides, acids, lactones, nitriles, sulfoxides, sulfones, nitro compounds, phosphonates, phosphoranes, quinones,... 

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