Lactones production

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

Structural changes within the elongation/cyclization pocket of CHS affect the ratio of Claisen-derived products versus lactone products, with both physiological, .e., p-coumaroyl-CoA, and non-physiological starter molecules. The product profiles of the G256A and G256V mutants with p-coumaroyl-CoA show an increase in the... 

Succinic anhydride is clearly hydrogenated more readily than the acid, as was the case with phthalic acid (Scheme 15.17), but faster absolute rates were observed in the hydrogenation of o-phthalic acid and phthalic anhydride to phtha-lide. In these reactions, the problem of anhydride hydrolysis is less significant as the acid can also be reduced to the same lactone product... 

A magnesium enolate of 99 is susceptible to aldol condensation with 4-pentenal, and the crude product can be directly protected to give its ethyl carbonate 100. a-Hydroxylation of the carbonyl group yields the hydroxyl carbonate 101. Reduction of the carbonyl group generates a triol, and this compound can be simultaneously converted to carbonate 102. Swern oxidation of 102 gives ketone 103, which can be rearranged25 to produce lactone product 104 (Scheme 7-32). 

Lactone product 104 is now susceptible to reductive C-3 hydroxyl removal, providing an enol product 105 that can be converted to the ketone 106 upon silica gel treatment. C-l a-hydroxylation of compound 106 provides compound 107. Compound 108 is then produced via Red-Al reduction of 107 and subsequent formation of the cyclic carbonate upon phosgene treatment (Scheme 7-33). 

Cyclobutanones were found to be much more reactive under these conditions, presumably due to relief of ring strain (131). Racemic cyclobutanone (192) is oxidized under the conditions described above to provide lactones 193 and 194 in a ratio of 55 45, Eq. 111. The expected lactone product 193 is formed in 67% ee while the abnormal product 194 is formed in 92% ee. The major enantiomers of the two products are complementary, resulting from enantiomeric ketones. 

Cyclic alkynyl carbonates undergo carbonylation in the presence of a palladium catalyst and carbon monoxide (5 MPa) in MeOH to give allenic carboxylates (Eq. 9.118) [92], Bu3P proved superior to Ph3P as the catalyst ligand. An enynyl cyclic carbonate underwent double vicinal carbonylation at 80 °C to produce a five-membered lactone product in 52% yield (Eq. 9.119). When the reaction was performed at 50 °C, the bicyclic enone lactone was produced in 75% yield along with 10% of the y-lactone. 

The checkers found that comparable yields could be obtained at -78°C. The submitters confirm this finding, but recommend the lower temperature especially when the p-lactone product is a liquid. Purification to remove small amounts of a p-keto ester by-product that forms at the higher temperature is more difficult with liquid products. 

Analysis of product distributions has often been used to evince the presence of 774-vinylketenes in the Dotz reaction. Wulff has studied the reactions of a wide variety of substituted aryl chromiumcarbenes and drawn conclusions from the data that point directly toward i74-vinylketene complexes as key intermediates.13 He has also isolated40 bicyclic lactone products (e.g., 23) characteristic of a van Halban-White cyclization41-44 from the reaction of vinylcarbenes and ketoalkynes. These bicyclic lactones are not generally... 

Show the structures, including stereochemistry, of two possible lactone products. 

The oxidation potential for the alkene bond is close to that for a carboxylate ion. In tlie styrene derivative 19, the alkene moiety is preferentially oxidised and intramolecular capture of a carbocation leads to a lactone product [35]. The tetrasub-... 

Ester-tethered enyne systems cycloisomerized to give lactone products (Eq. 11) [24]. Eor example, enyne 6 reacted under the Alder-ene conditions of [Rh(COD)Cl]2/BlNAP/ AgSbEg to give the corresponding lactone (Eq. 11). Once again free hydroxyl groups on the allylic terminus were incorporated into the cyclization precursors and subjected to the Alder-ene conditions, which led to the exclusive formation of the tautomerized products in good yields and enantioselectivities (Eq. 12). 

Cyanopyridine-4-carboxylate salts can be reduced to give dihydrofuro[3,4-f]pyridines (Equation 51) <2005RJ0279>. Under acidic conditions, the imine fragment can be hydrolyzed to generate lactone product. 

Results are consistent with the initial formation of an adduct which is transformed during the acidic workup into the observed a,a-disubstituted crossover experiments have shown that under the reaction conditions, the formation of the adduct is not reversible23. 

A recently described method for insertion of a carbon monoxide molecule into the monoepoxide of a conjugated diene gives /3-lactones in high yield. This is achieved by reaction of iron pentacarbonyl with the starting vinyloxirane to give the 7r-allyl iron complex (66), which on oxidation with cerium(IV) ammonium nitrate gives the /3-lactone. In some cases, y-lactone products can also be obtained from this reaction (8lJCS(Pl)27o). 

The reactions described here do not cause any racemization of the readily epimerizable aldehyde starting material. No 5/ -isomers were detected by chiral HPLC of the final lactone product. In addition, these conditions are suitable for large-scale reactions. DeCamp et al.[19] mentioned that they converted 600 g of a-amino aldehyde derivatives into the desired lactone. 

A recent study of group selectivity in iodocyclizations which could form either ds-fused tetrahydrofu-ran or 7-lactone products (equation IS) has shown that the observed selectivity correlates with the conformational bias of each isomeric substrate.62 One isomer, with no significant conformational bias, produced a mixture of the products upon cyclization of the ester, but gave only the 7-lactone upon cyclization of the carboxylic acid. 

We were eager to apply this reaction to the real synthesis, but since the lactone product of the Baeyer-Villiger reaction, and each intermediate... 

Ginkgo biloba dried leaf extract should be standardized to contain 24% flavone glycosides and 6% terpene lactones. Products should be concentrated to a 50 1 ratio. The daily dose ranges from 120-240 mg of the dried extract in two or three divided doses. Onset of effect may require 2-4 weeks. 

Although cell-free synthesis of 6-dEB was achieved, kinetic studies demonstrated that the process was very inefficient [34], The low rate of biosynthesis was likely due to the fact that the association of the three DEBS proteins in vitro was suboptimal. To simplify in vitro synthesis and to facilitate mechanistic analysis, a truncated version of the erythromycin PKS was created. The protein, DEBS 1-TE, was engineered by relocating the thioesterase (TE) from the end of DEBS 3 to the terminus of DEBS 1 (Fig. 9a,b) [35], In vivo, this bimodular construct synthesizes two triketide lactone products, one derived from propionate as a starter unit, and the other from acetate. 

The DEBS 1-TE mini-PKS offers several advantages over the complete three-protein DEBS system for studies in vitro. Most importantly, it is a single protein whose size (MW —390 kDa) makes it amenable to purification by size-exclusion chromatography. And unlike the three DEBS proteins, purified DEBS 1-TE can function autonomously to catalyze two complete condensation cycles to give a lactone product. Finally, the lactone incorporates much of the functionality and stereochemistry present in the macrolide, but is significantly easier to analyze than 6-dEB by various techniques such as GC-MS and H NMR. DEBS 1 -TE can therefore serve as a convenient model system for the far more elaborate... 

Figure 13 Stereochemistry of chain extension in erythromycin biosynthesis. DEBS 1-TE uses only the (25)-isomer of methylmalonyl-CoA to generate both a D- and an L-center in its lactone product. The D-methyl stereochemistry corresponds to condensation of (25)-methylmalonyl-CoA with retention of configuration, while the L-methyl corresponds to condensation with inversion.

Figure 14 Four plausible mechanisms by which one configuration (S) in the chainextending methylmalonyl-CoA can become two in the propionyl lactone product. The methyl stereochemistry generated by module 1 (C-4 center) corresponds to condensation with retention of configuration. Therefore, any mechanism incorporating inversion in that module (e.g., Ill) must necessarily include an essential epimerization at that center. Similarly, the methyl stereochemistry generated in module 2 (C-2 center) corresponds to condensation with inversion of configuration. Therefore, any mechanism including retention of configuration in that module (e.g., II) must include an epimerization at that center.

An experiment was designed to discriminate between the possible mechanisms. Biosynthesis of ra-butyryl lactone was carried out in the presence of (2/iV)- [2-2H]methy 1 ma-lonyl-CoA and NADPH. In the absence of spontaneous loss of the deuterium, the resulting labeling pattern in the ra-butyryl lactone was diagnostic for a particular mechanism. Any epimerization step in a mechanism acted to remove the label from the corresponding center. Structural analysis of the lactone product demonstrated labeling consistent with mechanism in. 

Figure 27 Altering chain extension by DEBS 1 +module 3+TE. (a) DEBS 1 +module 3+TE makes two products in vivo, (b) KRS from DEBS was introduced in place of KR2. The resultant hybrid PKS produced the expected tetraketide products, (c) The KR domains from RAPS modules 2 and 4 were introduced in place of DEBS KR2. The resultant hybrid PKSs both produced a triketide lactone product incorporating novel (R)-hydroxyl stereochemistry at C-3.

Propynyl alcohols have been converted into (Z)-a-(alkoxycarbonyl)methylene /3-lactones by dialkoxycarbonylation in alcoholic media, under a carbon monoxide-air (3 1) atmosphere, using a PdVKI catalyst (Equation 37) <1997J(P1)147>. The (Z)-stereochemistry of the products was attributed to the syn nature of the carbon monoxide insertion. Substitution at the ct-alkyl position was essential to generate the lactone products in good yields. When the propynyl alcohols were cr-alkyl-unsubstituted, no /3-lactone formation was observed instead, a maleic diester and its cyclic isomer were the predominant products. Where substrates were mono-a-alkyl-substituted, yields of the /3-lactone were low, unless the alkyl group was sufficiently sterically bulky. 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

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