Lactones, absolute configuration

The absolute configuration of the cycloaddition products 54a,b was assigned by transformation to the lactones 66a,b with known configuration (Scheme 4.35)... 

The significance, reversibility, and mechanisms of nonenzymatic lactone hydration may be aptly illustrated with pilocarpine, an extensively investigated drug whose stability in aqueous solution is of great pharmaceutical relevance. Pilocarpine (7.76, Fig. 7.13), whose absolute configuration is... 

Lactones of larger ring size, however, deviate considerably from planarity, and the consequences of their conformations must be taken into consideration in any assignment of absolute configuration. Few 5-lactones have been examined. Although several 5-lactones are asserted to show nonequivalence in accord with the 7-lactone model (38, 39), we recommend that this model not be used for assignment of absolute configuration to 5-lactones. 

Fluoroalcohols 1 have been employed in assigning absolute configuration of amines (30), benzothiophene oxides (45), lactones (33,46), oxaziridines (41), and an amine oxide (47). 

Diastereomeric secondary amides and lactones have been investigated and a simple model developed to predict relative configurations on the basis of an assumed preferred conformation396,397. The substituents A1 and A2 belong to the amine and C1 and C2 to the acyl part of the molecule 15. Thus, the relative configuration can be derived, and even the absolute configuration, when one part of the molecule is known. Four different situations are described. 

For example, the two carbonyl groups in methyl l-methyl-2,5-dioxocyclopentane acetate are enantiotopic and the two faces of each carbonyl group are diastereotopic. Yeast reduction furnished 1 (albeit in low chemical yield), by attack of the pro-R carbonyl group from its sterically less hindered Re-face. The immediate lactone formation indicates the relative configuration at the two stereogenic centers, while the absolute configuration of the yeast reduction product had to be determined (see p 437)133. 

In toluene with 4 equiv methanol and a catalytic amount of the alkaloid. b ee values are determined by conversion of the monoesters to the (R)-l-(l-naphthalenyl)ethylamides (entries 1-14) and analysis by HPLC, by salt formation with (R)-l-phenylethylamine (entries 15-20) or by H-NMR spectroscopy in the presence of Eu(hfc)3. Absolute configurations are determined by chemical correlation or by X-ray analysis of the Mosher ester of the lactone alcohol (entry 21). With 20 equiv of methanol. d With 4 equiv of methanol. With 10 equiv of methanol. f With 3 equiv of methanol. 

A different approach to enantiotopic group differentiation in bicyclic anhydrides consists of their two-step conversion, first with (/ )-2-amino-2-phcnylethanol to chiral imides 3, then by diastereoselective reduction with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to the corresponding chiral hydroxy lactames 4, which may be converted to the corresponding lactones 5 via reduction with sodium borohydride and cyclization of the hydroxyalkyl amides 101 The overall yield is good and the enantioselectivity ranges from moderate to good. Absolute configurations of the lactones are based on chemical correlation. 

Enantioselective reduction of prostereogenic anhydrides la-g with 4 equivalents of chiral reducing reagent, obtained from lithium aluminum hydride, enantiomerically pure (M)-, 1 -bi-2-naph-thol and ethanol, provides easier access to chiral lactones as exemplified by 3a-g.10 la. Absolute configurations of lactones 3 are based on chemical correlation and the ee value for 3b is determined by HPLC on the chiral column Chiralcel OB-H (Daicel Chemical Industries, Ltd.)101b. 

In 1997 (-)-callystatin A (Fig. 1.2.2), a potent cytotoxic polyketide, was isolated from the marine sponge Callyspongia truncata and structurally elucidated by Ko-bayashi et al. [20] shortly afterward its absolute configuration was confirmed by the same authors by total synthesis [21]. The structure of (-)-callystatin A shows a polypropionate chain and a lactone ring connected to each other by two diene systems separated by two sp carbon atoms (Fig. 1.2.2). Since this arrangement is structurally related to several antitumor antibiotics and due to the fact that only very small amounts can be isolated from natural sources, callistatin A has been... 

Neonepetalactone, 61 (Fig. 1.2.3), a bioactive compound found to be quite attractive to cats [41], was isolated in 1965 from the leaves and galls of Actinidia polygama by T. Sakan et al. and its absolute configuration was determined in 1980 [41b]. As some syntheses of the racemic mixture or ex-chiral-pool syntheses had already been reported, we realized that our SAMP/RAMP hydrazone methodology would make it possible to develop a very short asymmetric synthesis of this bioactive 8-lactone. 

Two thioacetates, thiofurodysin acetate (320) and thiofurodysinin acetate (209) were isolated from a Dysidea species from Sydney, Australia. They were converted by treatment with Raney nickel to a mixture containing furodysin and furodysinin respectively [214], These were the first thiol acetates isolated from natural sources. The absolute configurations of (-)-(6/ ,ll/ )-thiofurodysinin acetate (209), (-)-(6/ ,ll/ )-furodysinin disulfide (208) and (+)-(6/ ,ll/ )-methoxythiofurodysinin acetate lactone (321), isolated from a Fijian specimen of D. herbacea were determined by chemical interconversion [292]. 

A Palauan species of Dysidea contained 15-acetylthioxyfurodysinin lactone (327), that binds to human leukotriene B4 (LTB4) receptor. The structure was determined by spectral data analysis and confirmed by synthesis involving photo-oxidation of 15-acetylthioxyfurodysinin (328), which co-occurs with it in the sponge [297,298]. An Australian species of Euryspongia also contained 15-acetylthioxyfurodysin (329) and 15-acetylthioxyfurodysinin (328) [299]. A sample of D. herbacea from the Great Barrier Reef contained (-)-neodysidenin (330) and the absolute configuration was determined by capillary electrophoresis of Marfey s derivatives [300]. 

Azetidine-2-carboxylic acid (2) like proline gives an intense blue color with sodium nitroprusside in 10% acetaldehyde solution in the presence of sodium carbonate. 98,99 Upon usual acid hydrolysis (6M HC1, 110 °C, 24 h or more) as required for amino acid analysis, azetidine-2-carboxylic acid is completely decomposed, yielding mainly homoserine lactone, as well as other ninhydrin-positive compounds. 87,89,99 To enable an accurate quantification of this imino acid, azetidine-2-carboxylic acid peptides should be hydrolyzed by alkali (5M barium hydroxide, at 100 °C for 18 h 89 or 2 M sodium hydroxide at 110°C for 22h 100 ). There are extensive NMR spectroscopic data available 100-104 and the absolute configurations of A-acetyl-L-azetidine-2-carboxylic acid 105 and A-terf-butoxycarbonyl-L-azetidine-2-car-boxylic acid 106 have been determined by X-ray analysis. 

Optical rotatory dispersion studies on lactones of aldonic acids and other carbohydrate acids were made by Hirst et al.11 and later by Okuda et al.7S The latter workers related the absolute configuration at C-2 of aldono-1,4-lactones to the sign of the Cotton effect. 

Bulgarsenine (61) has also been isolated from Senecio doronicum L. together with a new alkaloid, doronenine (62).28 The structure and absolute configuration of doronenine were established by X-ray structure analysis.29 The structure (63) of the saturated y-lactone (ds-nemorensic acid) that was obtained on alkaline hydrolysis of doronenine was also determined by X-ray crystallography.30... 

Viridifloric /3-lactone, 143, has been identified as one of the pheromone components of a complex mixture of volatiles released by the pheromone glands of the male Idea leuconoe butterfly during courtship <1996BMC341>. A racemic mixture of both diastereoisomers was synthesized in four steps from the dilithio salt of 3-methylbutyric acid 144 alkylation with ethanal, dehydration of the secondary alcohol with phosphorus pentoxide, dihydroxylation of the C-C double bond with osmium tetraoxide, and finally formation of the /3-lactone by cyclization with sulfonyl chloride. By comparison with the sample isolated from I. leuconoe, the absolute configuration was established to be (2V,3V)-2-hydroxy-2-(l-methylethyl)-3-butanolide 143. 

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