Hydrogenation of lactones

The conditions required for the hydrogenation of lactones are always severe and the reaction is often realized in three phase systems. Copper chromite promoted by barium oxide is the preferred catalyst. 

The first enantioselective synthesis of 4-aza-podophyllotoxin derivatives (211) has been achieved using a chiral biphenyl phosphoric acid catalyst (212) through a partial transfer hydrogenation of lactone-fused quinolines (210) (Scheme 56)7 ... 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

The rhodium catalyst previously discussed is employed in the hydrogenation of / -hydroxybenzoic acid. The resulting mixture of cis and trans products is separated by virtue of the ready formation of the lactone of the cis product, which is then hydrolized to the hydroxy acid. 

Unsaturated -lactone 34 adopts a well-defined conformation and provides a suitable platform for the introduction of the stereogenic center at C-24 (monensin numbering). Catalytic hydrogenation of the carbon-carbon double bond in 34 takes place preferentially from the less hindered side of the molecule and provides an 8 1 mixture of stereoisomers in favor of 35 (100% yield). Cleavage of -lactone 35 with concentrated hydriodic acid at 130°C, followed by treatment of the resultant iodide 36 with triphenylphosphine, completes the synthesis of intermediate 19. 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

The results of the series of reactions shown in eq. 2 are listed in Table 1 together with our early reported data on the hydrogenation of 2-octanone (Z) [4]. The hydrogenation on all substrates proceeded smoothly and gave the corresponding chiral secondary alcohol. In the case of 3, 4, S, and 6, some amounts of lactone were produced as by-product. From this study, quite interesting stereochemical behavior... 

As might be expected, a complex mixture of lactones corresponding to abstraction of a hydrogen atom from various sites along the methylene chain was obtained from the photolysis. The mixture of lactones was converted by dehydration, ozonolysis, and hydrolysis to a mixture of ketones. It was found that no functionalization occurs with ester side chains of less than nine carbon atoms. This is probably due to the inability of the carbonyl to approach any methylene closely enough to abstract a hydrogen. The data for side chains of nine carbons or greater is presented in Table 3.11. 

The hydrogenolysis proceeds usually with inversion on Pd. This ability of Pd was used for stereospecific hydrogenation of a lactone during the synthesis of a phenyl kainoid on 10% Pd(OH2)/C in AcOEt at 40°C (Scheme 4.44).214... 

The cobalt-catalyzed reaction was studied by isolation of the lactones formed by hydrogenation and lactonization at higher temperatures (73). The hydroformylation was conducted at 140°C and 300 atm, followed by hydrogenation and cyclization at 200°-240°C, Eq. (33). 

Hydrogenation of derivatives of glycurononitriles, readily accessible by lactone ammonolysis, and dehydration of the intermediate... 

Catalytic hydrogenation of the oxime of D-glucurono-6,3-lactone leads179 to simultaneous isomerization with formation of L-gulono-... 

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