8-Lactone derivatives

Glucuronide formation appears to be a common route of clearance for the hydroxyl-acid form of statins, converting them to an inactive 8-lactone derivative [17, 25]. 

The Reformatsky reaction of 4-bromocrotonate esters with conjugated enones can conceivably give four regioisomers, as shown in equation (27). Several workers have applied such reactions to the synthesis of vitamin A and related compounds. In most cases, 8-lactones derived from 1,2-7-adducts were obtained, as exemplified by results with -cyclocitral (equation 28). ... 

Chiral 1,3-diols can be obtained, with in general modest diastereoselectivities, from aldehydes anti-29 by indium mediated aUylation reaction [73]. Also, aldehydes anti-29 can be converted in different 8-lactone derivatives by Homer-Wadworth-Emmons reaction with methyl 2-(diethoxyphosphoryl)acetate followed by dihydroxylation using osmium tetraoxide and final cyclization [74]. 

Among various a-methylene-8-lactones, derivatives with the S-lactone ring fused with the aryl ring having a structure of 3,4-dihydrocoumarins occupy prominent position and received substantial attention in the past few years. In 2007, Krawczyk and coworkers [76] demonstrated that the 3,4-dihydrocoumarin framework can be accessed by a means of Michael-type Friedel-Crafts reaction between 3-aryl-2-diethoxyphosphorylacrylic acids 181 and electron-rich hydroxyarenes 182... 

On the other hand, 22a bearing sterically demanding aromatic substituents on the binaphthyl unit and the small methyl group on the guanidine nitrogen turned out to be a catalyst of choice for the [4-e2] cycloaddition of azlactone to P.y-unsaturated a-ketoesters, which proceeded through three consecutive transformations to afford a-amino-8-lactone derivatives with high diastereo- and enanti-oselectivities (Scheme 7.40) [64]. 

Hsung and coworkers [191] have used simple y- and 8-lactone-derived acetal-tethered dienes (e.g. 398) in the RCM reaction (Scheme 96). This approach has most recently been exploited for the synthesis of (-i-)-aigialospirol 400. 

It will be recalled that lactone-derived enol triflate 102 was expected to serve as a substrate for a Murai coupling37 with the mixed cuprate reagent derived from iodo ortho ester 103 (see Scheme 17c). If successful, this C-C bond forming process would accomplish the introduction of the remaining carbon atoms needed for the annulation of the seven-membered D-ring lactone. 

The product is the lactone derived from the hydroxy acid that would result from a normal Cannizzaro reaction. 

The effect of lactone ring-size on the inhibition was studied, for N-acetyl-)3-D-glucosaminidase from bovine epididymis, with lactones and lactone derivatives unable to undeigo ring-isomerization, by Pokomy and co-workers. From a comparison of Kj values for 2-acetamido-2-deoxy-D-glu-cono-1,5-lactone (0.45 nM) with the 1,4-lactone (4.5 fiM) and of Kj for the methyl ) -furanoside with that for the pyranose (4 mM), it was concluded that the 1,4-lactone has an 10-fold lower inhibitory potency than the 1,5-lactone. The weak inhibition by the 5,6-O-isopropylidene derivative of the... 

In synthetic applications, Li et al. examined the propargylation-allenylation of carbonyl compounds by using a variety of metals including Sn, Zn, Bi, Cd, and In.203 By using the indium-mediated allenylation reaction, Li and co-workers developed the synthesis of the antiviral, antitumor compound (+)-goniofufurone (Scheme 8.22),204 a key component isolated from the Asian trees of the genus Goniothalamus,205 and other styryl lactone derivatives (Eq. 8.80). 

The grem-dibromocyclopropanes 152 bearing a hydroxyalkyl group, prepared by the addition of dibromocarbene to allylic or homoallylic alcohols, undergo an intramolecular reductive carbonylation to the bicyclic lactones 153. bicyclic lactone derived from prenyl alcohol is an important precursor for the synthesis of ris-chrysanthemic acid. (Scheme 54)... 

Add with mixing, a 300-fold molar excess of a sugar lactone derivative, such as o-b-D-galactopyranosyl-( 1 -> 4)-D-glucono-l,5-lactone (2.6 gm) dissolved in 3 ml of DMSO. 

The carboxymethyl-dextran derivative may be used to couple amine-containing molecules by the carbodiimide reaction. Heindel et al. (1994) prepared the lactone derivative of carboxymethyl-dextran by refluxing for 5 hours in toluene or other anhydrous solvents. The lactone derivative is highly reactive toward amine-containing molecules, thus creating a preactivated polymer for conjugation purposes. 

Table 2.19 y-Hydroxy-a-amino acids and lactones derived from cycloadducts 491 a-c... 

Lactone derivatives derived from glucuronic add were used as glycosyl donors by Murphy and coworkers [250], These glycosyl donors were found to react with silyl... 

A more direct confirmation that the dimethyl-L-arabinose possesses a pyranose configuration was obtained from the study of the rate with which its lactone derivative is hydrolyzed to the corresponding open chain acid.8... 

Acylation and substitution reactions on the selectively silylated aldono-lactone derivatives have been performed. 

The 7-0-silyl and 2,7-di-O-silyl derivatives (55 and 18% yields, respectively) were obtained on treatment of D-glycero-D-gulo-heplono-1,4-lactone with 1.1 eq. of rm-butylchlorodiphenylsilane (20). Sugar lactone derivatives selectively substituted with different protecting groups, which were em-... 

The Tebbe reagent [//-chloro-bis(cyclopentadienylXdimethylalumin-ium)-/r-methylenetitanium] in its pure, crystalline (70,71) or crude (72) forms has been employed for the methylenation of aldonolactones. Thus, D-ribono- 1,4-lactone derivatives 71a and 71b reacted with Tebbe s reagent to give (70,71) the exo-methylene compounds 72a and 72b. 

Difluoromethylenation (79,80) of aldonolactones may be readily accomplished by treatment of the lactone derivative with tris(dimethyl-amino)phosphine, dibromodifluoromethane, and zinc in refluxing tetrahy-... 

The lactone derivative 158 obtained from D-ribono- 1,4-lactone afforded (—)-(i )-angelica lactone (159a) upon treatment with methanolic ammonia solution (6). In a similar way, Font and coworkers (207) synthesized (+)-(S)-... 

Dideoxyhex-2-enono-1,5-lactone derivatives (penten-5-olides) have been prepared (255-258) and employed as starting compounds in synthesis. Thus, Michael addition of benzylhydroxylamine to racemic 6-0-acetyl-2,3,4-trideoxy-D,L-g/ycerohex-2-enono-1,5-lactone (267) took place ster-eoselectively to give the unstable benzyloxyamino-2-pyrone 268, which was readily converted into the /Mactam derivative 269, a precursor of thienamy-cin (259). / -Lactams were also obtained (260) by 1,3-dipolar cycloaddition of nitrone 270 to the unsaturated 1,5-lactone 267, followed by hydrogenoly-sis and subsequent cyclization to the /Mactam 271, having a polyol side-chain at the C-3 position. 

Dialkoxycarbonylation has been reported using a Pd-catalyst/oxidant system on propynols or butynols furnishing respectively /3- or y-lactone derivatives with a-(alkoxycarbonyl)ethylene chains (Scheme 24) [83,137, 138]. This reaction occurs in a stereospecific way leading exclusively to cis-dicarbonylated products in fair to excellent yields (25-97%). Noteworthy, a butynol bearing an alkyl or an aryl substituent instead of a TMS one undergoes a different course of reaction under the same conditions here frans-alkoxycarbonylation takes place selectively (Scheme 25). 

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