Reduction, and Lactonization

Although we were able to obtain the desired 29 in this way, there were several aspects of the last few steps that troubled us. One flaw was the requirement for azeotropic removal of H20 in two consecutive steps the dehydration of 26 to 5 and the acetalization of 5 to 27. Another flaw was that the acetal protecting group, discarded immediately after its use here, needed to be reinstalled before the last step of the synthesis (see below). Although ethylene glycol was very inexpensive, it seemed that this duplication of effort should have been avoided, if possible. 

With the implementation of this improvement, the synthesis at this point stood at seven steps with no protecting groups and only two chromatographic purifications (6 and 29). 

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The Mannich adducts are readily transformed to optically active a-amino-y-lac-tones via a one-pot diastereoselective reduction and lactonization sequence and the tosyl group exchanged for a Boc group via a two-step procedure. The cop-per(II) ion is crucial for the success of this reaction [21]. It has the properties necessary both to generate the enol species in situ and, in combination with the C2-symmetric ligand, coordinate it as well as the imine in a bidentate fashion. The reaction proceeds via a cyclohexane-like transition state with the R substituent of the enol in the less sterically crowded equatorial position, which is required to obtain the observed diastereoselectivity (Fig. 5). 

Lactones. Photosensitized (methylene blue) oxidation of 3-alkyl-1,2-cyclohex-anediones (1) results in 8-kcto carboxylic acids (2) in high yield. They are converted by reduction and lactonization into 8-lactones (3). The method is attractive for substrates bearing labile, unsaturated side chains. 

Butenolides [e.g. (435)] have been synthesized from /8-keto-sulphoxides by alkylation with methyl bromoacetate, followed by reduction and lactonization (Scheme 14). The required /3-keto-sulphoxide (432) was prepared by reaction between the methyl etienate and dimsyl potassium (MeSOCHiK ). ... 

Chromatographic methods have also been developed for quantitative determination of the AUC of pectin. Uronic acids have been analyzed using gas-liquid chromatography (GLC) after conversion to L-galactono-1,4-lactone via potassium borohydride reduction and lactonization using methanolic hydrogen chloride. The derived lactone was then analyzed by GLC as the trimethylsilyl derivative (Perry... 

The chiral source for our synthesis of (+)-52 was methyl (.S )-citronellate, which was converted to acetylenic phenylselenyl ester A. Radical-mediated cyclization of A afforded B. Further conversion of B to C was followed by its reduction and lactonization to give lactones D and E. Formylation of D gave F, which was coupled with bromolactone ( )-G to give (-l-)-sorgolactone (52) and its diastereomer 52. Similarly, E yielded two additional diastereomers, 52" and 52". ... 

Reduction of minovincine (11) with sodium borohydride gave a mixture of the 19-epimers of minovincinine, (12) and (13). When each of these compounds was treated with zinc in methanolic sulfuric acid, 2,16-reduction and lactonization occurred to afford 14 and 15, respectively. From molecular models, once the stereochemistry of the tryptamine bridge and of C-20 are described, only the stereochemistry in which the C/D ring junction is cis will permit lactonization. Further work indicated that in 14 C-19 had the R configuration whereas in 15 this center was S. Interestingly, there was quite a substantial difference in the [< ]d of these two compounds (11). 

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 mechanism of ester (and lactone) reduction is similar to that of acid chloride reduction in that a hydride ion first adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde. Further reduction of the aldehyde gives the primary alcohol. 

The most widely used reagent for partial reduction of esters and lactones at the present time is diisobutylaluminum hydride (DiBAlH).83 By use of a controlled amount of the reagent at low temperature, partial reduction can be reliably achieved. The selectivity results from the relative stability of the hemiacetal intermediate that is formed. The aldehyde is not liberated until the hydrolytic workup and is therefore not... 

The two major subunits were coupled by a Suzuki reaction in Step H-3. The Multistep Syntheses synthesis was then completed by reductive opening of the 1,3-dioxane ring, oxidation of the terminal alcohol to the carboxylic acid, carbamoylation, deprotection, and lactonization. 

The structure of narlumidine (119) was established by Dasgupta et al. (117,119) on the basis of spectral data, particularly by comparison with spectra of bicucullinine (108), and also on chemical grounds. On hydrolysis followed by oxidation-methylation, narlumidine (119) was converted to ester 147, which was also obtained from 108 by N.O-methylation. Sodium borohydride reduction gave lactone 145, identical to the lactone obtained from 108. 

Table 10. organosilane reduction of Esters and Lactones (continued)... 

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