D-lactones

The (partial) description of the synthesis and coupling of the five fragments starts with the cyclohexyl moiety C —C. The first step involved the enantio- and diastereoselective harpless epoxidation of l,4-pentadien-3-ol described on p. 126f. The epoxide was converted in four steps to a d-vinyl d-lactone which gave a 3-cyclohexenecarboxylate via Ireland-CIaisen rearrangement (cf. p. 87). Uncatalysed hydroboration and oxidation (cf. p. 131) yielded the desired trans-2-methoxycyclohexanol which was protected as a silyl ether. The methyl car-... 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Koleske, J. V., and Lundberg, R. D., Lactone polymers. II. Hydrodynamic properties and unperturbed dimensions of poly-e-caprolactone, J. Polym. Sci., Part A-2. 7, 897-907, 1969. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

Another synthesis of P-D lactone that is based on an enantiomerically pure starting material is shown in Scheme 13.35. The stereocenter in the starting material is destined to become C(4) in the final product. Steps A and B served to extend the chain to provide a seven-carbon 1,5-diene. The configuration of two of the three remaining stereocenters is controlled by the hydroboration step, which is a stereospecific syn addition (Section 4.5.1). In 1,5-dienes of this type, an intramolecular hydroboration occurs and establishes the configuration of the two newly formed C—B and C—H bonds. 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

The adduct cyclized to a lactol mixture that was oxidized by TPAP-NMMO to give the corresponding lactones in an 8 1 ratio (86% yield). Hydrolysis in the presence of H202 gave the P-D lactone and recovered chiral auxiliary. 

There have been several syntheses of P-D lactone that were based on carbohydrate-derived starting materials. The starting material used in Scheme 13.42 was prepared from a carbohydrate produced in earlier work.27 The relative stereochemistry at C(4)... 

The synthesis in Scheme 13.47 was also based on use of a chiral auxiliary and provided the TBDMS-protected derivative of P-D lactone in the course of synthesis of the macrolide portion of the antibiotic 10-deoxymethymycin. The relative stereochemistry at C(2)-C(3) was obtained by addition of the dibutylboron enolate of an A-propanoyl oxazolidinone. The addition occurs with syn anti-Felkin stereochemistry. 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

The reaction was very stereoselective for the correct P-D lactone configuration. The synthesis, which is outlined in Scheme 13.51, was completed by the sequence shown in Scheme 13.49. 

Park SK, Rhee CO, Bae DH and Hettiarachchy NS. 2001. Mechanical properties and water-vapor permeability of soy-protein films affected by calcium salts and glucono-D-lactone. J Agric Food Chem 49(5) 2308-2312. 

The d-lactone (Scheme 38.11) can be efficiently obtained by the telomerization of butadiene and C02. Its biphasic hydrogenation with an in-situ-prepared Rh/ mtppts catalyst yields 2-ethylidene-6-heptenoic acid (and its isomers) [136]. Note, that the catalyst is selective for the hydrogenolysis of the lactone in the presence of two olefmic double bonds this is probably due to the relatively large [P] [Rh] ratio (10 1) which is known to inhibit C = C hydrogenations with [RhCl(wtppms)3]. The mixture of heptenoic acids can further be hydrogenated on Pd/C and Mo/Rh catalysts to 2-ethylheptanol which finds several applications in lubricants, solvents, and plasticizers. This is one of the rare examples of using C02 as a Cl building block in a transition metal-catalyzed synthetic process. 

In 2000, Knight et al. reported the 1,4-conjugate addition of Me2CuLi with 4-(T-hydroxyalkyl)-2,3-alkadienoate 492 followed by a lactonization to d-lactones 493. Here, the stereoselective introduction of the methyl group is important for the subsequent lactonization [224]. 

In aromatic compounds, potent but frustrated (their ortho positions blocked) directing groups may lead to lithiations at positions other than ortho. For example, when the carbamate 610 is treated with LDA in refluxing THE, lithiation occurs at a remote position (not peri, note) and an anionic Fries rearrangement ensues to give 611 (see Section I.B.l.d). Lactonization gives 612 (Scheme 239). ... 

The Prelog-Djerassi lactone (abbreviated as P-D-lactone) was originally isolated as a degradation product during structural investigation of antibiotics. Its open-chain precursor 1, is typical of methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. 

There have been more than 20 different syntheses of P-D-lactone.132 We will focus here on some of those which provide enantiomerically pure product, since they illustrate several of the methods for enantioselective synthesis.133... 

Owing to their pleasant odours many y-lactones and d-lactones are known to be Important flavour compounds of fruits and contribute essentially to the characteristic and distinctive notes of strawberries, peaches, apricots and many other fruits [24]. Chiral aroma compounds from fruits and other natural sources are characterised by origin-specific enantiomeric ratios, as their biogenetic pathways normally are catalysed by enzymes. 

Consequently, these intermediates are, in fruits, converted by -oxidation steps to the corresponding even-numbered y-lactones and d-lactones. 

The simultaneous stereoanalysis of y-lactones and d-lactones using enantio-MDGC has been reported (Fig. 17.7). This technique was applied to many fruits proving that enantiomeric ratios of y-lactones and d-lactones can be used as indicators of authenticity, as the genuine enantiomeric purities remain unaffected during fermentation and all other stages of fruit processing [27]. 

The preparation of optically active d-lactones is more difficult because of the lack of selectivity of most lipases. 

On acidification to pH 4.6, the caseins coagulate, which is the principle used to manufacture of a family of cheeses which represent about 25% of total cheese consumption and are the principal cheeses in some countries (Appendix 10B). Acidification is traditionally and usually achieved by in situ fermentation of lactose by a Lactococcus starter but direct acidification by acid or acidogen (gluconic acid-d-lactone) is also practised. The principal... 

The process of racemization has a number of practical application in the laboratory and in industry. Thus, in the synthesis of an optical isomer it is frequently possible to racemize the unwanted isomer and to separate additional quantities of the desired isomer. By repeating this process a number of times it is theoretically possible to approach a 100% yield of Synthetic product consisting of only one optical isomer, An example of the utilization of such a process is found in the production of pantothenic acid and its salts, In this process the mixture of D- and L-2-hydroxy-3,3-butyrolactones are separated. The D-lactone is condensed with the salt of beta-alanine to give the biologically active salt of pantothenic acid, The remaining L-lactone is racemized and recycled. 

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