Lactones conversion

A consequence of the retrosynthetic plan (Scheme 7) was that a contra-thermodynamic y-lactam 5-lactone conversion would have to be carried out at some stage of the synthesis. This challenging undertaking necessitated that the C-8/COOMe group be altered and in the interest of efficiency, this became an opportune stage for installation of a synthon for the carbonyl group required at that site in actinobolin. This synthon took the form of the phenylselenomethyl residue shown in B5c, a convenient precursor for an exocyclic methylene via selenoxide elimination, and thence a carbonyl group via ozonolysis. 

Figure 3. Plots of reaction temperature versus lactone conversion in Novozym-435-catalyzed resolution of lactones 1(A), 2 ( ) and 3( ) at 23, 40 and 60°C after 5 h. No reaction was observed at 0 C even after 24 h.

The enantiomeric ratios ( ), a measure of the enantioselectivity of the lipase (Tables 1 to 4), can be related to the extent of conversion and the enantiomeric ratio and were calculated using the following equation. Where c is the lactone conversion (determined by GC)/ H NMR, e.e.s is the enantiomeric excess (determined by GC) of the unreacted lactone. The equation is based on the assumptions that resolution proceeds irreversibly, that the two enantiomers compete for the same active site, and that there is no product inhibition (42). 

Figure 7.28 Structures of 1.4-butanediol, GHB, and GBL, the corresponding lactone. Conversion between GHB and GBL depends primarily on pH. 

Related to the water elimination from cyclohexa-l,4-diols, one can cite the intramolecular nucleophilic displacement of the 4-hydroxycylohexl-yl tosylate derived from diol 109 into 7-oxanorbomane 110 (Scheme 14) and the synthesis of rac-famesiferol C that uses an intramolecular displacement of a cyclohexa-1,4-diol-derived lactone (conversion of 45 into oxanorbomane 46, Scheme 6). 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

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. 

Another principal use of ketene is in the production of sorbic acid [110-44-1] (80,81). In this process, which requires an acidic or manganese(II) catalyst, ketene adds to crotonaldehyde [123-73-9] (8) with subsequent conversion of the P-lactone and the polyester to sorbic acid (qv) (9). 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Early attempts to apply the Sheehan penicillin synthetic strategy to the total synthesis of cephalosporins were not particularly successful. Although the key step, formation of the /3-lactam CO—N bond, could be carried out efficiently (46->47), subsequent conversion of the lactone to a free C-4 carboxyl could only be accomplished in poor yield (B-72MI51007). 

Figure 3.11 shows the relative reactivity as a function of ring size for two other intramolecular displacement reactions, namely, conversion of ethers from ca-bromoalkyl monoethers of 1,2-dihydroxyben-zene. 

The conversion of 3y5-acetoxy-5a-bromo-6y5-hydroxyandrostan-17-one to 19-norandrost-4-ene-3,17-dione via nitrite photolysis, nitrosation and oxidation to the 6)5,19-lactone results in an overall yield of about 8%, but clearly optimal yields have not been achieved. 

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

The transformation of an ester carbonyl group to a difluoromethylene group, which IS usually difficult to perform, can be accomplished by conversion to the thiaesier followed by treatment with diethylaminosulfur trifluoride (DAST). A vanety of ester types react efficiently, although the reaction fails with lactones. Remarkably, trimethylsilylmethyl esters carry through the proeedure with the silyl group intact [13] (equation 17). 

Note that this method does not work on simple esters. In addition, TMSOCH2CH2OTMS/TMSOTF has been used to effect this conversion.The same process was used to introduce the cyclohexyl version of this ortho ester in a quassinoid synthesis. Its cleavage was effected with DDQ in aqueous acetone.(R,R)-2,3-Butanediol can be used to resolve the lactone. 

Tlie isolable stable 1,2-dithietaiie, dithiatopazine (73), was prepared in 1988 and fully characterized (the name dithiatopazine was coined for its beautifully yellow-orange topazlike crystalline form) (87JA3801 88JA4856 90JA3029). Tlius, controlled photoirradiation of a dithiono-lactone (117) produced 73 in 65% yield along with an alkene 118 in 12% yield. Photolytic or thermal decomposition of 73 led to the alkene 118, a conversion that could be also carried out by a variety of reagents [m-BusShH-AIBN, Raney Ni, MCPBA, Fe2(CO)9, Mo(CO)6] in excellent yields. 

It has been reported that concentrated H2SO4 (98%) promotes conversion of 3,5-dibromolevulinic acid 47 into 4-bromo-5-(bromomethylene)-2(5// )-furanones 48 (R = Br R = H) along with minor products, while similar treatment using 20% oleum gives the isomeric 5-(dibromomethylene)-2(5// )-furanone 49 (R = H R = Br) as the major product (63AJC165). Spectroscopic data and chemical structures were not provided for the minor substances, but the formation of the major product was explained on the basis of the enol-lactonization process followed by oxidation (63AJC165). 

The proposed mechanism for the conversion of the furanone 118 to the spiro-cyclic lactones 119 and 120 involves electron transfer to the a -unsaturated methyl ester electrophore to generate an anion radical 118 which cyclizes on the /3-carbon of the furanone. The resulting radical anion 121 acquires a proton, giving rise to the neutral radical 122, which undergoes successive electron transfer and protonation to afford the lactones 119 and 120 (Scheme 38) (91T383). 

The reaction of peracids with ketones proceeds relatively slowly but allows for the conversion of ketones to esters in good yield. In particular, the conversion of cyclic ketones to lactones is synthetically useful because only a single product is to be expected. The reaction has been carried out with both percarboxylic acids and Caro s acid (formed by the combination of potassium persulfate with sulfuric acid). Examples of both procedures are given. 

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