Hydroxy ester enantioselective lactonization

The enantioselective hydrogenation of a,fj- or / ,y-unsaturated acid derivatives and ester substrates including itaconic acids, acrylic acid derivatives, buteno-lides, and dehydrojasmonates, is a practical and efficient methodology for accessing, amongst others, chiral acids, chiral a-hydroxy acids, chiral lactones and chiral amides. These are of particular importance across the pharmaceutical and the flavors and fragrances industries. 

Capillary gas chromatographic determination of optical purities, investigation of the conversion of potential precursors, and characterization of enzymes catalyzing these reactions were applied to study the biogenesis of chiral volatiles in plants and microorganisms. Major pineapple constituents are present as mixtures of enantiomers. Reductions, chain elongation, and hydration were shown to be involved in the biosynthesis of hydroxy acid esters and lactones. Reduction of methyl ketones and subsequent enantioselective metabolization by Penicillium citrinum were studied as model reactions to rationalize ratios of enantiomers of secondary alcohols in natural systems. The formation of optically pure enantiomers of aliphatic secondary alcohols and hydroxy acid esters using oxidoreductases from baker s yeast was demonstrated. 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

Enantioselective Addition of Dialkylzincs to Aldehydes with Functional Groups. Enantioselective and chemoselective addition of dialkylzincs to formyl esters using (15,2R)-DBNE as a catalyst affords optically active hydroxy esters. The subsequent hydrolysis of the esters affords the corresponding optically active alkyl substituted lactones with up to 95% ee (eq 13). ... 

This zinc-promoted reaction has been used with a variety of carbonyl compounds. Thus, the Luche conditions were applied in a synthesis of (-1-)-muscarine using an aldehyde derived from ethyl lactate [109]. Allyl halide condensation onto a-ketoamides of proline benzyl ester gave good diastereoselec-tivity when performed in the presence of zinc dust and pyridinium p-toluene-sulfonate in a water/THF mixture. In this way, a-hydroxy ketones were obtained with good enantioselectivity after removal of the chiral auxiliary [110]. Reactions of allyl bromide under the Luche conditions with y-aldo esters afforded y-hydroxy esters, which were converted in a one-pot reaction to y-allyl-y-butyro-lactones (Scheme 22) [111]. 

Bonini, C., R Pucci, R. Racioppi, and L. Viggiani Enzyme Catalysed Lactonization of 3,5-Dihydroxy Esters Enantioselective Synthesis of Naturally Occurring 3-Hydroxy-5-decanolide, (-)-Massoialactone and 3-Hydroxy-5-eicosanolide. Tetrahedron Asymmetry, 3, 29 (1992). 

The use of isolated enzymes in organic solvents has already found its niche in organic synthetic laboratories, both in academia and industry (14, 75). Enzymes have emerged as very useful tools for the synthesis of optically active lactones by enantioselective lactonization of racemic yhydroxy esters, cohydroxy esters, and 5-hydroxy esters into enantioenriched y-butyrolactones, colactones, and 5-lactones, respectively (76,77,78). Isolated enzymes, such as lipases (20) and esterases (27) have also been exploited for preparing optically active four-, five- and six-membered lactones by enantioselective ring-opening... 

The 2b-catalyzed reduction of j or 8-keto esters provided the corresponding hydroxy esters with high enantioselectivity (Scheme 11.9) [5b], while the reduction of a-keto esters was less effective [6b, 44b, 59]. Desymmetrization of meso-imides 31 via stereoselective reduction is one of the most powerful transformations to provide products with three new chiral centers. Such transformations with good enantioselectivities were achieved by OABs-catalyzed reductions (Scheme 11.10) [60-62], The hydroxy lactams 32 obtained were easily converted into ethoxy lactams 33 by acidic ethanoly-sis, and were transformed into chiral lactones 34 by sodium borohydride reduction. 

Honda et al. have utilized acid-catalyzed lactonization of a 5-hydroxy ester in an enantioselective synthesis of the lactone moiety of HMG CoA reductase inhibitor [52] (Scheme 15). An enantioselective deprotonation reaction of meso-ketone 75 with lithium (5,5)-a,a -dimethyldibenzylamide as the chiral base in the presence of... 

Sibi and He have described the formation of 8-lactone from an in situ formed 5-hydroxy ester in the synthesis of ricciocarpins A and B [65] (Scheme 25). Enantioselective conjugate addition of the tertiary radical derived from 133 onto... 

The enzymatic lactonization of hydroxy acids has been used mainly as a method for the synthesis of macrocyclic lactones [94,95] and the synthetic application of enzymatic lactonization for the purpose of enantioselective preparations refers almost exclusively to the cyclization of hydroxy esters. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

The biotechnological synthesis of lactones has reached a high standard. Besides microbial production, lactones can also be enzymatically produced. For instance, a lipase-catalysed intramolecular transesterification of 4-hydroxy-carboxylic esters leads enantioselectively (ee>80%) to (S)-y-lactones the chain length may vary from C5 to Cl 1 [13]. y-Butyrolactone can be produced in that way with lipase from Mucor miehei [30]. 

In the actual implementation of this concept, Bode and coworkers used 3-hydroxy-2-pyranone derivatives (kojic acids) as the enol components, and the lactone product was submitted in situ to ring-opening with methanol to afford the more stable methyl esters. Both the yields and the enantioselectivities were excellent, using the chiral triazolium salt 26 as the preotalyst (Scheme 40.40). 

Hiyama et al. have reported an enantioselective synthesis of p-hydroxy 5-lactones as simplified analogs of compactin and mevinolin [47] (Scheme 10). The p,5-diketo ester 54 derived from Taber s chiral alcohol 57 was subjected to a stereoselective reduction with sodium borohydride in the presence of Et2BOMe to afford a syn diol, which upon saponification and then heating in dry toluene led to the chiral lactone 56. 

---