3- Hydroxy-p-lactone

Medium-ring lactonesLactones can be obtained by an intramolecular Re-formatsky-type reaction of hydroxy lactones were isolated as the acetates. Yields are high even for 8-to 14-membered lactones. 

The lessons learned from the abortive experiments in Scheme 12 were invaluable to Kozikowski and co-workers in developing a slate of do s and dont s for the final strategy (Scheme 13). Most notably, it transpired that the a,P-epoxy lactone C16 (c.f. C9, Scheme 12) underwent classical reductive elimination with zinc in acetic acid to give the P-hydroxy lactone C17, and cyclohexylidenation, followed by oxidation then led to the actinobolin skeleton in CIS. Final processing to give actinobolin hydrochloride now proved to be uneventful. 

Trost has used a,a-disulfenylated lactones as enolate precursors. As shown in equation (23), a,a-di-(phenylthio)- y-butyrolactone is treated sequentially with ethylmagnesium bromide and acetaldehyde to obtain p-hydroxy lactone (8) in virtually quantitative yield. Oxidation of the phenylthio group and subsequent elimination of the resulting sulfoxide provides the unsaturated hydroxy lactone (9). The process was employed with more complex lactones in a total synthesis of iridoids. The method fails with a,a-di-sulfenylated ketones unless a catalytic amount of copper(I) bromide is included in the reaction mixture. 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

Adam Baeza Liu J. Am. Chem. Soc. 1972, 94, 2000. For other methods of converting p-hydroxy acids to P-lactones, see Merger Chem. Ber. 1968, 101, 2413 Blume Tetrahedron Lett. 1969, 1047. 

Fragmentation of 1,3-diols 7-34 Decarbonylation of p-hydroxy carboxylic acids and of p-lactones 7-36 Elimination of CO and C02 from bridged bicydic compounds 7-43 Pyrolysis of P-hydroxy olefins 7-44 Pyrolysis of allylic ethers... 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

Another approach to the reduction in blood cholesterol levels has been the development of pravastatin (50) and its congeners as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase, the rate-limiting enzyme in cholesterol biosynthesis.52 It has also been discovered that the biological activity of such compounds is dependent largely on the P-hydroxy-8-lactone moiety within the compound.53 This led to the development of more potent compounds, such as NK-104 (51), a congener of pravastatin. 

Aroma compounds in cured vanilla beans from different countries, e.g. Madagascar, Tonga, Costa Rica, Java, Indonesia and Mexico, have been documented. Over 100 volatile compounds have been detected, including aromatic carbonyls, aromatic alcohols, aromatic acids, aromatic esters, phenols and phenol ethers, aliphatic alcohols, carbonyls, acids, esters and lactones, of which the aldehyde vanillin is the most abundant. The level of the aldehydes, e.g. vanillin and p-hydroxy-benzaldehyde and their respective acids (vanillic acid and p-hydroxybenzoic acid), in cured vanilla beans is used as an indicator of cured vanilla bean quality for commercial purposes (Klimes and Lamparsky, 1976 Adedeji et al., 1993 Ranadive, 1994). 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

The synthesis of [3-lactones has received considerable attention6 since the first representative of this class of heterocycles was prepared in 1883. Classical routes to (3-lactones generally involved the cyclization of (3-halocarboxylate salts6 and the related "deaminative cyclization that occurs upon diazotization of [3-amino acids.9 p-Hydroxy acids undergo a similar cyclization under Mitsunobu conditions,10 and the... 

Dehydrative decarboxylation. The convc sion of p-hydroxy carboxylic acids to alkenes by reaction with a DMF dialkyl acetal iirvolves an r/n/Z-elimination, and thus is complementary to the known. yv/i-elimination of these hydroxy acids via a P-lactone (5, 22 9, 504). These reactions were used to obtain both the (E)- and the (Z)-l-alkoxy-l,3-... 

SYNS 7-a-ACETYLTHIO-3-OXO-17-a-PREGN-4-ENE-21,17-P-CARBOLACTONE 7-a-ACETYLTHIO-3-OXO-17-P-PREGN-4-ENE-21,17-P-CARBOLACTONE ALDACTIDE ALDACTONE ALDACTONE A 3-(3-KETO-7-a-ACETYLTHIO-17-P-HYDROXY-4-ANDROSTEN-17-a-YL)PROPIONIC ACID LACTONE OSIREN OSYROL 3 -(3-OXO-7-a-ACETYL-THIO-17-P-HYDROXYANDROST-4-EN-17-P-YL)PRO-PIONIC ACID LACTONE 17-a-PREGN-4-ENE-21-CARBOXYLIC ACID, 1 -HYDROXY-7-a-MERCAPTO-3-OXO-a-LACTONE SC 9420 SC 15983 SPIRESIS SPIRIDON SPIROCTANIE SPIRO(17H-... 

KETO-7-a-ACETYETHIO-17-p-HYDROXY-4-ANDROSTEN-17-a-YL)PROPIONIC ACID LACTONE see AFj 500... 

Oxetanones ( -lactones) are useful synthetic intermediates which have been most often prepared by cyclization of p-halo or p-hydroxy acid derivatives or by addition of ketenes " to carbonyl compounds. They are starting materials for useful polymers and copolymers and have been used for the synthesis of alkenes and carboxylic acid derivatives. P-Lactones possessing antimicrobial activity have recently been found in bacterial cultures. ... 

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