Lactone stabilizer

Karenitedn (11, Figure 2.2) is a very lipophilic compound that exhibits more potent cytotoxic activity than camptothecin with both in vitro and in vivo scenarios. In addition to superior in vitro potency, its increased lactone stability and enhanced oral bioavailability are potential clinical advantages [108]. Karenitecin showed significant activity in metastatic melanoma and the dose-limiting toxicity consisted of neutropenia and thrombocytopenia [109]. 

Lesueur-Ginot, L., et al. Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res. 1999, 59, 2939-2943. 

Lactone stabilizers are a new class of materials that are reputed to stop the autoxidation process before it starts. These products, which... 

Lactone stabilizers are a new class of materials that are reputed to stop the autoxidation process before it starts. These products are derivatives of the benzofu-ranone family. Some blends (Ciba Giegy s HP) claim to be particularly effective in high-temperature and high-shear processing. 

Scheme 17. Chain-breaking reactions involved in the antioxidant action of benzofuranes (lactone stabilizers).

From their structures, it appears that the hydrolytic stability of macrocyclic lactones must necessarily be inferior to macrocyclic polyethers. Ease of synthesis of the cyclic esters is therefore one of the aspects which commend them to interest. It is probably for this reason that such lactones have not been made more often by the interesting approach of Kdgel and Schroder . These workers report the ozonolysis of dibenzo-18-crown-6 in a mixture of methanol and dichloromethane at —20°. Reduction of the ozon-ide at —75° using dimethylsulfide followed by warming and addition of acetone led to formation of 6 in 14% yield. The bis-oxalate had mp 164—165° from acetone, very similar to that of the starting crown. The transformation is illustrated below in Eq. (5.9). 

The use of an ester as an anion-stabilizing group for a lithiated epoxide was demonstrated by Eisch and Galle (Table 5.5, Entry 11). This strategy has been extended to a,P-epoxy-y-butyrolactone 191, which could be deprotonated with LDA and trapped in situ with chlorotrimethylsilane to give 192, which was used in a total synthesis of epolactaene (Scheme 5.45) [69], The use of a lactone rather than a... 

In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to epoxides are not widely used in the synthesis of complex molecules. Following the seminal work of Danishefsky [64], who introduced the use of Et2AlCl as an efficient catalyst for the reaction, Taylor obtained valuable spiro lactones through the addition reaction of the lithium eno-late of tert-butyl acetate to spiro-epoxides, upon treatment of the corresponding y-... 

Another possibility is that the intermediate may be stable or may find some other way to stabilize itself. In such cases, Y never attacks at all and the product is cyclic. These are simple internal Sn2 reactions. Two examples are formation of epoxides and lactones ... 

The y-lactone ring of the steroid skeleton forms an intermediate cardenohde anion in alkaline medium that nucleophilically adds to the 3,5-dinitrobenzoic acid in the position ortho to the two nitro groups. A mesomerically stabilized red-violet anion is produced (Meisenheimer complex). 

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

While wild-type PAMO was unable to convert 2-phenylcyclohexanone efficiently, all deletion mutants readily accepted this ketone as substrate. All mutants also displayed a similar thermostability when compared with the parent enzyme. The most active mutant (deletion of S441 and A442) was used for examining its enantioselective properties. It was found that the mutant preferably formed the (/ )-enantiomer of the corresponding lactone E = 100). While CHMO also shows a similar enantioselective behavior, this PAMO deletion mutant is a better candidate for future applications due to its superior stability. This clearly demonstrates that PAMO can be used as parent enzyme to design thermostable BVMO variants. It also illustrates that the available crystal structure of PAMO will be of great help for BVMO redesign efforts. ... 

The pH of the reconstituted milks was adjusted to 6.4 with 1 N HCL. First, the acidification phase was carried out with glucono(5)lactone (2 g/L) at 30°C in order to exponentially decrease the pH and obtain a stabilized value corresponding to pH = 6.0 after 2 h incubation. Then, rennet was added to the acidified reconstituted milks at a final concentration of 19.5 mg/L and the coagulation phase was performed at 30°C for 3h. 

The most widely used reagent for partial reduction of esters and lactones at the present time is diisobutylaluminum hydride (DiBAlH).83 By use of a controlled amount of the reagent at low temperature, partial reduction can be reliably achieved. The selectivity results from the relative stability of the hemiacetal intermediate that is formed. The aldehyde is not liberated until the hydrolytic workup and is therefore not... 

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