Racemic lactones

Lipase catalysis is often used for enantioselective production of chiral compounds. Lipase induced the enantioselective ring-opening polymerization of racemic lactones. In the lipase-catalyzed polymerization of racemic (3-BL, the enantioselec-tivity was low an enantioselective polymerization of (3-BL occurred by using thermophilic lipase to give (/ )-enriched PHB with 20-37% enantiomeric excess (ee). ... 

L. Blanco, E. Guibe-Jampel, G. Rousseau, Enzymatic Resolution of Racemic Lactones , Tetrahedron Lett. 1988, 29, 1915-1918. 

In recent work, Chmielewski and co-workers (174) reported the highly stereoselective reaction of ene-lactones with chiral pyrrolidine nitrone (141) to afford tricyclic adducts (Scheme 1.31). A 1 1 mixture of ene-lactone 142 and nitrone 141 provided adduct 143 with an uncharacterized isomer (97 3) (91%) whUe homo-chiral D-glycero (138) gave the adduct 144 as a single diastereomer (88%). A 2 1 mixture of racemic 138 and nitrone 141 afforded a 91 1 mixture of the two possible adducts, representing an effective kinetic resolution of the racemic lactone. 

Langlois and co-workers (179) found the same exo stereochemical preference through double asymmetric induction of a related ene-lactone (1 )-145 with their well-explored and efficient camphor-derived oxazoline nitrone (150-146 (Scheme 1.32). They found the cycloaddition components form a matched pair and allowed kinetic resolution of the racemic lactone in up to 70% enantiomeric excess (ee). They suggest the selectivity for exo adduct 147 arises through destabilization of the endo transition state by a steric clash between dipolarophile ring hydrogens and the bornane moiety. 

Such racemic lactones as substituted -butyrolactones and -valerolactones are resolved by means of the diastereomeric salt formation or the diastereomeric amide formation method.24,25 For example, -decalactone is successfully resolved in the form of its diastereomeric amides derived from a-methylbenzylamine (Figure ll).24... 

Chemical oxidations of diols to racemic lactones can be achieved by a broad spectrum of oxidizing agents. However, at the present time, only the enzymic route described can provide a versatile, one-step, access to such a wide range of highly enantiomerically enriched y-lactones, useful as chiral building blocks for syntheses. 

An interesting application of the esterase activity of horse liver acetone powder (HLE) has been the enantioselective hydrolysis of racemic lactones. The powder proved to be more effective than PLE in this hydrolysis, from which the unreacted lactone was recovered with high enantiomeric excess. The process seems more effective for S and medium size lactones (eq 13). ... 

Optically active lactones are also readily available through this classical resolution technique. The racemic lactone is hydrolyzed to the hydroxy acid and resolved with (S)-(-)-NEA (eq 3). After crystallization, the dextro (+)-lactone is regenerated upon acidi-... 

Reduction of the achiral ketodiester 139 gives the racemic lactone 140. Hydrolysis of both ester groups then gives the again achiral hydroxydicarboxylate 141. This compound is prochiral and the two C02 groups are enantiotopic. If one could be protonated selectively by an enantiomerically pure acid, one enantiomer of the monoacid would be formed. This sounds like an improbable event. 

The racemic lactone ( )-18 was obtained as a pure and crystalline compound, and its relative stereochemistry had to be determined. I thought, in 1960, XH NMR analysis to be the most appropriate method to solve the problem, because it had already been known to use a vicinal coupling constant for the stereochemical studies of cyclohexane compounds including terpenoids and steroids. Figures 1.13(a) and (b)... 

Figure 2.3 shows the structures of racemic lactones synthesized by myself as the model compounds of the ring A of the gibberellins.11 12 Infrared absorptions due to the lactonic carbonyl group of each of the lactones are also shown in the figure. Infrared spectra of these lactones were measured as nujol pastes and also as solutions in dioxane. 1,4-Dioxane was the solvent that could dissolve the gibberellins, while chloroform could not. 

Equally successful stereocontrol has been achieved with secondary cycloalkyl diazoacetates where diastereoselectivity is associated with the formation of cis-and trans-fused bicyclic lactones. With cyclohexyl diazoacetate, Eq. (44) and Rh2(OAc)4 racemic lactones with only a small preference for the trans-isomer are formed (60 40). Use of chiral Rh2(5S-MEPY)4 led to diastereocontrol of only 3 1, but enantiocontrol was nearly complete (97% ee) in the cis-lactone. However, both high enantio control and nearly full diastereocontrol were realized with Rh2(4S-MACIM)4. Rh2(4S-MEOX)4, the oxazolinidinone analog of Rh2(5S-MEPY)4, catalyzed high enantio control, but little diastereocontrol [63]. Similarly high enantio- and diastereoselectivities have been observed with cyclopentyl, cycloheptyl, and cyclooctyl diazoacetates, with cis- or fra s-4-methylcyclohexyl diazoacetate (where preferential insertion into equatorial bonds leads to lactones (36) and (37) in Fig. 14) has been demonstrated [63,64] and with 2-ada-mantyl diazoacetate (Fig. 14, (38)) [21]. With these substrates Rh2(MEOX)4 catalysts achieved the highest levels of enantio control. 

In Baeyer-Villiger oxidations catalyzed by (achiral) copper or nickel salts substituted cyclohexanones like 4 (Eq. 3) had been shown to be reactive substrates for the conversion to the corresponding (racemic) lactones in the presence of aldehyde and molecular oxygen [22]. The next step was to develop a chiral catalyst in order to make this reaction proceed in an enantioselective manner, giving optically active oxepanones. Various copper complexes were screened in a search for asymmetric induction in the aerobic Baeyer-Villiger oxidation. The most active and selective catalyst that was eventually found was the copper complex... 

A large number of mono- and bicyclic lactones (73-91) have been obtained by using pig liver esterase in combination with horse liver esterase for the enantiomer-differentiating hydrolysis of the corresponding racemic lactones. Interestingly, in the series of methyl-substituted lactones (85-89), both enzymes show toward the seven-membered lactone (86) the opposite enantiomer selectivity as compared to the other lactones. 

Warm, sweet, hay- and tobacco-like, herbaceous odor of moderate tenacity (Arctander, 1967). The sensory properties mentioned by Dufosse et al. (1994) are sweet, herbaceous, fatty, coconut-like, woody, resinous. The (R)- enantiomer has a faint, sweet odor, and the (S) is nearly odorless according to Mosandl and Gunther (1989). The flavor is milky, fatty, weak for the racemic lactone (Chemisis, 1996). 

With this new approach in mind, the revised retrosynthetic analysis would utilize two different Wittig reactions to homologate the carbon side chains, providing ketoolefm (+)-16 (Scheme 13). Further disconnection revealed hydroxy aldehyde (+)-27 which could arise from a selective DIBALH reaction of lactone (+)-28. Applying Bringmann s method, lactone (+)-28 would be enantiomerically enriched via a kinetic resolution of a racemic lactone mixture. Racemic lactone ( )-28 could arise from a... 

The undesired diol (-)-32 was recycled by first oxidizing to the dialdehyde with Dess-Martin s reagent (Scheme 15). After heating the dialdehyde in acid to racemize the material, ( )-29 was subjected to the Cannizarro/DCC conditions providing racemic lactone ( )-28 in a 60% yield. Performing this kinetic resolution/recycling process provided (+)-28 in an overall yield of 61% (98% ee). 

Third, the diastereotopic facial selectivity between the olefin and the ketyl is determined by the biaryl stereochemistry. This stereocontrol element, set earlier via a kinetic resolution of racemic lactone ( )-28, provided an enantiomerically enriched atropisomer (98% ee) that was carried throughout the synthesis without loss of stereochemical integrity. 

The synthetic scheme used by Woodward in his famous reserpine synthesis has been adapted for a synthesis of racemic apoyohimbine (Chart IV). The aldehyde LIXa, precursor of rings D-E of apoyohimbine, was prepared together with its epimer (LIXb) by 0s04/Ba(C103)2 oxidation of the key intermediate (LVIII) (cf. reserpine synthesis. Volume VIII, p. 316). Condensation of LIXa with tryptamine, followed by the conventional steps, yielded the racemic lactone LXIV, which was subsequently hydrolyzed and esterified to LXV, isomeric with corynan-thine. Racemic apoyohimbine (LXVI) was then secured by tosylation of LXV followed by basic treatment of the 18-tosylate (39a). 

Pseudomonas cepacia (Amano PS-30) lipase immobilized on polypropylene beads was the key enzyme in a Bristol-Meyers Squibb process for the production of a HMG-CoA reductase inhibitor (Scheme 9) [68]. Racemic lactone rac-... 

Lipase catalysis is often used for the enantioselective production of chiral compounds indeed, lipase has been known to induce an enantioselective ROP of racemic lactones. In the lipase-catalyzed polymerization of racemic j8-butyrolactone (/3-BL), the enantioselectivity was low rather, an enantioselective polymerization of /3-BL occurred by employing a thermophilic lipase to yield the (R)-enriched polymer with 20-37% enantiomeric excess (e.e.) [101]. The enantioselectivity was greatly improved by copolymerization with seven- or 13-membered nonsubstituted lactones, using the lipase CA catalyst, whereby the e.e.-value reached almost 70% for the copolymerization of /3-BL with DDL [102]. It should be noted that, in the case of the lipase CA catalyst, the (S)-isomer was reacted preferentially to produce the (S)-enriched, optically active copolymer. The lipase CA-catalyzed copolymerization of i5-CL (six-membered) with DDL proceeded enantioselectively, to yield the (R)-enriched optically active polyester with an e.e.-value of 76%. 

Helmchen ef /. [63] used S( —)-l-phenylethylamine (23) to form amides of racemic lactones, which were separated directly on a silica Lobar column using petroleum ether/ethyl acetate. The enantiomeric lactones were recovered using acid hydrolysis (1 M sulphuric acid at 80 °C overnight). 

The nitrone 61b underwent stereoselective 1,3-dipolar addition to the sugar-derived racemic lactone 65, to give the adduct 66 (82% de). The unreacted 65 was recovered in 77% ee [60]. See Scheme 6.34 for a similar system used in an enantiodivergent reaction. 

Effective KR of the racemic lactone 72 was performed upon [2+3] cycloaddition with 2 equiv of enantiomericaUy pure oxazohne N-oxide 71 derived from (—[-camphor [62]. Exo-adduct 73 was obtained as the major diastereomer and (R)-72 recovered in 69% ee. 

The racemic lactone was prepared in five steps from 1,4-butanediol 22 (Figure 3). The symmetrical diol 22 was mono-protected as a tetrahydropyranyl (THP) ether 23, using a biphasic mixture containing 1,4-butanediol, 3,4-dihydro-2//-pyran (DHP), CH2CI2, and a catalytic amount of 0.1 N aqueous HCl (22), Compound 23 migrates from the aqueous phase as it is formed, thus reducing the chance of further derivatization to the diether (22),... 

Optically active lactones are valuable building blocks in organic synthesis (4) and in the preparation of optically active biodegradable polymers (7,5). Several chemical methods for producing these compounds and their corresponding polymers have been explored (6) but unfortunately all of these methods are either experimentally cumbersome or afford the lactones with only modest enantioselectivities. Examples of chemically prepared optically active polyesters include poly(a-phenyl-P-propiolactone) (7), poly(a-ethy(-a-phenyl-P -propiolactone) (S, 9), poly(a-methyl-a-ethyl-P-propiolactone) (70) and poly(lactic acid) (77, 72). Use of enantioselective polymerization catalysts to carry out stereoelective polymerizations of racemic lactones has produced mixed results. For example, stereoelective polymerization of [/ ,S]- P-methyl-P-propiolactone with a catalyst from Zn ( 2115)2 and [7 ]-(-)-3,3-dimethyl-l,2-butanediol showed only a small enantiomeric enrichment in the final polymer (75). Stereoselective copolymerizations of racemic (LL/DD monomers) and meso (LD monomer) lactides using chiral catalyst that gives heterotactic and syndiotactic PLA, respectively have also been studied (77). 

The analytical separation of the two enantiomers of the racemic lactones was achieved by carefully adjusting the analysis parameters of the gas chromatograph equipped with a Cyclodex-B (J W Scientific) chiral phase... 

---