Antipodal lactones

The identification of a novel BVMO from Mycobacterium tuberculosis (BVMOMtbs) complements this toolbox, as this particular biocatalyst performs a classical kinetic resolution instead of a regiodivergent oxidation vith complete consumption of substrate [140]. Notably, this enzyme accepts only one ketone enantiomer and converts it selectively to the abnormal lactone while the antipodal substrate remains unchanged (Scheme 9.24) [141]. 

Within monocyclic ketones, a similar inversion of the migratory preference was only reported for the biooxidation of terpenones with CHMOAdneto- while (—)-dihydrocarvone is converted to the expected normal lactone, migration of the less substituted carbon center was observed for the biooxidation of antipodal (+)-dihydrocarvone, ultimately providing the abnormal lactone [185]. 

The same starting material can also be employed to synthesize the antipode (i )-methanophenazine [(i )-lOj, as R)-3l may easily be transformed into lactone (S)-30 by chemoselective reduction of the ester functionality [43] and subsequent cyclization. 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

C., de Ferra, L., and Sannicolo,F. 2004. Process-scale preparation of enantiomerically pure y-lactones by asymmetric hydrogenation of y-keto esters and comparative tests of the sensory properties of some antipodes. Tetrahedron Asymm., 75(14), 2289-2297. 

Preparative Methods both enantiomers of dihydro-5-(hydroxymethyl)-2(3H) furanone and their trityl derivatives are commercially available but expensive. The simplest and by far most popular method for preparing (5)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) consists of enantiospecific deamination of L-glutamic acid and subsequent selective reduction of the resulting carboxylic acid (13) (eq 1). Purification of the intermediate acid (13) by crystallization and not by distillation is recommended in order to secure an excellent optical yield (>98% ee). Likewise, (f )-dihydro-5-(hydroxymethyl)-2(3//)-furanone (1) (>98% ee) can be obtained from o-glutamic acid. As the latter is considerably more expensive than its natural antipode, an appealing option is to convert the (5)-lactone into its enantiomer (eq 2)P Also available and equally useful is an inversion route to (f )-dihydro-5-(trityloxymethyl)-2(3H)-furanone (5) by way of the Mitsunobu reaction (eq 3). ... 

The absolute configuration of 105 was established by its chemical conversion (Scheme 21) into the known lactone 107 (77JA556) and by X-ray analysis of amide 108, which was derived from 105. The stereochemistry of 106 was confirmed by its chemical conversion into the antipodal compound of 108. 

A. similar set of transformations was also done in an antipodal series w c led to (-l-)-204. Thus D-gluconic acid y-lactone (215) was converted via a straightforward protection and reduction sequence to furanoside 216. Reductive deoxygenation via the intermediate DMF acetal gave l-210 in 11% overall yield from 215. Conversion of e r-210 to a mixture of (-l-)-methyl nonactate [(+ )-204] and ( + )-8-epi methyl nonactate [(-I-)-180] was then accomplished in a manner identical to that described for the (-)-enantiomer. 

Synthesis from o-isoascorbic acid Syntheses of 2 and its antipode 37 from the commercially available D-isoascorbic acid have been reported by conversion to the enantiomerically pure acetonide lactone 29 on a large scale in 75% yield (Scheme 5). Lactone 29 was treated with amino vinylsilane 30 to give the amide 31 in 82% yield, which was used in two different ways. Mitsunobu conditions were not successful to convert 31 to 32. However, the conversion has been achieved in 88% yield by mesylation and then subjection to intramolecular cyclization. Treatment of 32 with Lawesson s reagent afforded the respective thioamide, which was treated with BFj OEtj followed by direct reduction with LiBEtjH to provide the 2-(ethylthio)pyrrolidine 35. Cyclization of 35 afforded the single stereoisomeric tetrahydroindolizine 36. Catalytic hydrogenation of 36 followed by deprotection provided 2-cp/-lentiginosine (2). 

The seminal enantioselective allylic alcohols epoxidation realized by Katsuki and Sharpless [18] to which other similarly steroselective reactions soon followed (e.g., bishydroxyla-tion, cyclopropanation, lactonization and catalytic hydrogenation) have been invaluable for this purpose. One of the most significant applications, as far as drug synthesis is concerned, of the Sharpless method from the innumerable ones which have been found in the past 20 years is the routine preparation (Fig. 6) of antipodal pairs of known chirality of (3-blockers such as propranolol (5) [19]. 

Pr(hfc)3 to give bicyclic lactone 65 in excellent yield with very good diastereocontrol (96% de). When the same chiral Lewis acid is used with the opposite pyrone ester antipode, the diastereocontrol decreases (89% de). A similar decrease in asymmetric induction was observed when achiral Pr(fod)3 is employed as the promoter species (88% de). 

Stiller and associatesin the Merck laboratories a little less than a year after the collaboration began isolated the lactone from concentrates, and determined its structure by classical methods to be -hydroxy-/5,/ -dimethyl-y-butyrolactone. This was synthesized and resolved into its optical isomers. The levo-rotatory lactone when condensed with /3-alanine by various pro-ceduresi >22>2 yields dextro-rotatory pantothenic acid with full biological activity. The antipode was found to be inactive. The biologically active form has, according to Hudson s amide rule, the D-configuration24.2s. 

Chiral compounds are frequently foimd among the flavor volatiles of fruits and, like many naturally occurring chiral compounds, one enantiomer usually exists with a greater preponderance when compared with its antipode. Chiral odor compounds may show qualitative and quantitative differences in their odor properties (7). For example, (/ )-(+)-limonene has an orange-like aroma while (5)-(-)-limonene is turpentine-like (5)-(+)-carvone is characteristic of caraway while its enantiomer has a spearmint odor (2). However, other chiral compounds, such as y 6-lactones, show very little enantioselectivity of odor perception (7). The occurrence of chiral flavor compounds in enantiomeric excess provides the analyst with a means of authenticating natural flavorings, essential oils, and other plant extracts. The advent of cyclodextrin-based gas chromatography stationary phases has resulted in considerable activity in the analysis of chiral compounds in flavor extracts of fruits, spices and other plants (i-7). 

Coke and Richon have constructed the 8-lactone framework of n-hexadecalactone, the proposed pheromone isolated from Vespa orientalis, through lactonization of a hydroxy acid intermediate [39] (Scheme 3). The optically pure amino alcohol 22 obtained by resolution was converted to the optically active epoxide 23 by quatemization, followed by Hofmaim elimination. Addition of the dianion of propiolic acid to epoxide 23, and subsequent reduction of the resulting acetylenic hydroxy acid with hydrogen and palladium, provided the saturated hydroxy acid 25, which spontaneously cycUzed to afford 8-lactone 12. In a similar way, the enantiomer of amino alcohol 22 was also transformed into the antipode of lactone 12. Furthermore, using this method, any terminal epoxide can easily be converted to the corresponding saturated 8-lactone in two steps. 

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