With Lactones and Lactams

Morita, S. Kobayashi, H. Shimadzu, and M. Ochai, Tetrahedron Lett., 861 (1970). 

A more aromatic type of lactam, 3-methoxycarbonyl-l-methyl-5,6-diphenylpyrazin-2-one (53), when fused with guanidine carbonate, gave an excellent yield of 2-imino-8-methyl-6,7-diphenylpteridin-4-one (see 10).36 

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The dehydrogenation of steroidal and other ketones can be accomplished with (43) at elevated temperatures. Similar reactions with lactones and lactams have also been reported. Other interesting oxidations include the angular hydroxylation of ketones and the oxidation of benzylic hydrocarbons, as shown in Scheme 14. In some cases, the selenium reagent may be employed catalytically in the presence of a less expensive cooxidant that reoxidizes Se by-products back to the required Se oxidation state. 

TV-fluorobenzenesulfonimlde also reacts with lactone and lactam enolates to afford the corresponding a-fluoro deiivatlve. Glutamates can be monofluoiinated in the 4-posItion by this method. Repeating the reaction sequence affords the corresponding difluorinated product (eq 15). ... 

Thermal fragmentation of l,3-dioxin-4-ones or acylated Meldrum acids with generation of a-oxoketenes, hetero Diels-Alder reactions of the latter, and their transformations into lactones and lactams, among them macrocyclic 99YGK76. 

Entries 10 and 11 involve lactones and lactams, respectively. The catalyst used in Entry 10 is thought to be capable of interaction with both the carbonyl and ether oxygens. 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

Organo copper and lithium enolates of cyclic ketones, lactones, and lactams or acyclic ketones are converted with acylimidazoles or imidazole-N-carboxylates into the corresponding / -diketones or / -ketoesters ... 

A highly efficient method for the synthesis of medium-sized rings (examples of 17-, 15-, 10- and 5-membered carbocycles, lactones and lactams) without high-dilu-tion conditions was developed by Trost et al. for example, precursor 204 with a palladium catalyst led to an E-Z mixture of 205 in 86% yield, and subsequent hydrogenation then provided the 10-membered lactam ring 206 in 85% yield (Scheme 15.66) [132],... 

The following data are closely related to the results of a Russian team, who synthesized lactone- and lactam-bridged photochromes and studied their transformations. 2,5-Dimethyl-3-thienylacetic acid with a-chloro ketone in base gives ester 206, which undergoes cyclization when heated with K2CO3 in DMF under an inert atmosphere to give lactone 207 in 70-75% yields (Scheme 61). The reaction can be performed in situ without isolation of the ester (06ZOR1827)... 

The antifungal antibiotic (—)-PF1163B 297 isolated from Streptomyces sp., which features a 13-membered macrocycle incorporating both lactone and lactam units, was synthesized by an RCM route too (Scheme 58). While only poor results were obtained by treatment of diene 296 (containing 8% of an unidentified epimer) with catalyst B, the use of NHC catalyst G led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimerization in a previous step. 

For a review of the synthesis of lactones and lactams, see Wolfe Ogliaruso, in Palai The Chemistry of Acid Derivatives, pt. 2 Wiley New York, 1979, pp. 1062-1330. For a list of methods for converting hydroxy acids to lactones, with references, see Ref. 508, pp. 941-943. 

BC13 convert 0=0 groups of ketones, lactones, and lactams to G=S groups119 and H2S-Me3SiCl-i-Pr2NLi converts carboxylic esters to thiono esters.120 Carboxylic acids RCOOH can be converted directly to dithiocarboxylic esters RCSSR, 120a in moderate yield, with P4S, and a primary alcohol R OH.121 Thioketones can also be prepared by treatment of ketones with P4SI0,122 and from oximes or various types of hydrazone (overall conversion C=N------> C=S).123... 

Macrolides. Steliou, Hanessian, and co-workers- have prepared lactones and lactams in moderate to excellent yield by treatment of ro-hydroxy or ru-amino carboxylic acids with catalytic amounts of di-r -butyltin oxide in refluxing mesitylcne or xylene in a Dean-Stark apparatus for 12 24 hours. The method has the advantage of high dilution, since the tin reagent is regenerated continuously. As expected, yields arc low for medium-sized rings. 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

Lactones and Lactams Unstrained lactones (cyclic esters) and lactams (cyclic amides) absorb at typical frequencies for esters and amides. Ring strain raises the carbonyl absorption frequency, however. Recall that cyclic ketones with five-membered or smaller rings show a similar increase in carbonyl stretching frequency (Section 18-5A). Figure 21-5 shows the effect of ring strain on the C=0 stretching frequencies of lactones and lactams. 

Variation of the ligands at titanium can lead to improvements. For example, enolates 197a b react with benzaldehyde to afford 92 8 and 97 3 mixtures of 195 a and 196a, respectively 25). Enolates 199-202, derived from ketones, lactones and lactams, add erythro-selectively to benzaldehyde to yield the corresponding aldols (erythro threo as 85 15, 91 9, 92 8, 58 42 and 88 12, respectively) 25,77). 

Selenenylations of ketones, esters, lactones and lactams are usually effected by the reaction of the corresponding lithium enolates with PhSeCl, PhSeBr and PhSeSePh (with the exception of ketones) at low temperature. Aldehydes have not been selenenylated in this manner. Table 4 illustrates some typical products that have been made in this way. Selenenylation has been especially useful in natural piquet synthesis for the formation of a-methylenelactones from the parent a-methyl compounds (Scheme 15 and Table 4), and has significant advantages over the more traditional methods for ef-... 

F. Formal [3 + 2] Cycloaddition of Metal Ynolates with Oxiranes and Aziridines to Give Lactones and Lactams... 

A strategy for the assembly of various carbasugars and aminoc-arbasugars employed condensation of the reagent with 2-silyloxy-furans and 2-silyloxy-Af-protected pyrroles. The additions proceed in high yield and stereoselectivity to afford a,(3-unsaturated lactones and lactams, respectively, which were parlayed into pseu-do-D-gulopyranose, pseudo-o-xylofuranose, pseudo-o-gulopyra-nosylamine, and psuedo-o-xylofuranosylamine (eq 11). ... 

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