Medium-sized lactones

The chemical properties of cycHc ketones also vary with ring size. Lower members (addition reactions, than corresponding acycHc ketones. The Cg—C 2 ketones are unreactive, reflecting the strain and high enol content of medium-sized ring systems. Lactones are prepared from cycHc ketones by the Bayer-ViUiger oxidation reaction with peracids. S-Caprolactone is manufactured from cyclohexane by this process ... 

CO-Hydroxycarboxylic acids give, after silylation to bis(trimethylsilylated) intermediates and subsequent treatment with mild Lewis acdds, small- and large-ring lactones in high yields. Thus co-hydroxytridecanoic acid 332 (n= 12) affords, via 333 n= 12), at room temperature, the macrolide 334 in 89% yield [115]. The medium-sized 8- and 9-membered lactones are, however, not formed, only diolides. Likewise, trimethylsilyl 6-trimethylsilyloxyhexanoate 333 is readily lactonized in the presence of 4-trifluoro-... 

Various cyclic esters have been subjected to hpase-catalyzed ring-opening polymerization. Lipase catalyzed the ring-opening polymerization of 4- to 17-membered non-substituted lactones.In 1993, it was first demonstrated that medium-size lactones, 8-valerolactone (8-VL, six-membered) and e-caprolactone (e-CL, seven-membered), were polymerized by lipases derived from Candida cylindracea, Burkholderia cepacia (lipase BC), Pseudomonas fluorescens (lipase PF), and porcine pancreas (PPL). °... 

Similarly, bicyclic hemiacetals fragment to medium-size lactones. 

Lipase catalyzed the ring-opening polymerization of medium-size lactones, d-valerolactone (<5-VL, six-membered) and -caprolactone (c-CL, seven-mem-bered). Lipases CC, PF and PPL showed high catalytic activity for the polymerization of <5-VL [74,75]. The molecular weight of the polymer obtained in bulk at 60 °C was relatively low (less than 2000). 

Ring-opening polymerization of a-methyl-substituted medium-size lactones, a-methyl-y-valerolactone and a-methyl-c-caprolactone, proceeded by using lipase CA catalyst in bulk [82]. As to (R)- and (S)-3-methyl-4-oxa-6-hexa-nolides (MOHELs), lipase PC induced the polymerization of both isomers. The apparent initial rate of the S-isomer was seven times larger than that of the R-isomer, indicating that the enantioselective polymerization of MOHEL took place through lipase catalysis [83]. 

Medium-ring acetylenic lactones,2 Cyclization to medium size acetylenic lactones is difficult because of geometric constraint imposed by the triple bond, and has been considered practicable only for at least fifteen-membered rings. Surprisingly, the acetylenic w-hydroxy acid 1 when complexed with Co2(CO), is cyclized in 28% yield to the seven-membered complexed acetylenic lactone 2 by Mukai-yama s reagent, 2-chloro-l-methylpyridinium chloride (8, 95-96). The yield is essentially the same as that observed in lactonizaton to a complexed 10-membered... 

Lactones by ring expansion of lactols. Medium-sized lactones can be obtained in reasonable yield by photolysis of the hypoiodites of catacondensed lactols, which results in regioselective cleavage of the bridging bond. The substrates are available by the general route shown for the 6/6 lactol 1, which is cleaved to the 10-membered lactone 2. This cleavage can be used for preparation of 9-membered... 

A highly efficient method for the synthesis of medium-sized rings (examples of 17-, 15-, 10- and 5-membered carbocycles, lactones and lactams) without high-dilu-tion conditions was developed by Trost et al. for example, precursor 204 with a palladium catalyst led to an E-Z mixture of 205 in 86% yield, and subsequent hydrogenation then provided the 10-membered lactam ring 206 in 85% yield (Scheme 15.66) [132],... 

Macrolides. Steliou, Hanessian, and co-workers- have prepared lactones and lactams in moderate to excellent yield by treatment of ro-hydroxy or ru-amino carboxylic acids with catalytic amounts of di-r -butyltin oxide in refluxing mesitylcne or xylene in a Dean-Stark apparatus for 12 24 hours. The method has the advantage of high dilution, since the tin reagent is regenerated continuously. As expected, yields arc low for medium-sized rings. 

Medium-sized lactones A new method for synthesis of lactones that is particularly useful in the case of medium sized ones involves the hypoiodite reaction with a catacondensed lactol such as 1, which results in cleavage to the ten-membered isomeric iodo lactone 2. Phoracantholide I (3) is obtained on reductive removal of iodine. 

Medium-sized lactones have become significant targets of synthesis due to their regular occurrence as biologically active natural products701-703. Various synthetic methods utilizing the alkene moiety have been developed recently for the preparation of these compounds. Medium-sized lactones have also been very successfully prepared, with... 

Further, medium-sized lactones have been prepared by a thermal elimination-Claisen rearrangement sequence, of unsaturated selenoxide cyclic acetals (equation 198)710. The reaction affords reasonable yields of these useful lactones upon treatment with DBU and a siloxy species at 185 °C. The reaction has been used as the key step in the synthesis of (-l-)-laurencin, which contains an 8-membered cyclic ether moiety711. 

An intramolecular lactonization reaction with extremely low catalyst loadings was reported in 1998 [77]. This development led to milder reaction conditions without concomitant loss of product yield. Thus, medium-sized lactones were accessible with a combination of as little as 0.03 mol% of FeCl2 and 0.03 mol% of a multidentate nitrogen-based ligand (Scheme 3.13). 

Conventional ring-opening polymerization of cyclic anhydrides, carbonates, lactones, and lactides require extremely pure monomers and anhydrous conditions as well as metallic catalysts, which must be completely removed before use, particularly for medical applications. To avoid these difficult restrictions, an enzymatic polymerization may be one of the more feasible methods to obtain the polyesters. This method was first reported by two independent groups (Kobayashi [152] and Gutman [153]) who showed that lipases, enzymes capable of catalyzing the hydrolysis of fatty acid esters, can polymerize various medium-sized lactones. 

It has also been found that in medium-sized (8- to 12-membered) lactones containing a single chiral center at a remote position, highly stereoselective formation of a new chiral center adjacent to the carbonyl group occur (equation 79). This effect falls off as the distance between the enolate and the controlling asymmetric center increases561. Such stereocontrol is caused by the conformational properties of the particular lactone being alkylated. 

As an alternative to the lead tetraacetate oxidation, (diacetoxyiodo)benzene can be used to initiate a fragmentation reaction which leads to unsaturated medium-sized lactones [110]. The structures of the starting materials are similar to those of compounds VII/157, VII/160, and VII/163. The same stereochemical consequences are observed as mentioned above. 

Both materials were isolated in approximately 30 % yield. The iodo compound VII/175 was then reduced photochemically with tributyltinhydride to give 15-pentadecanolide [114]. Experiments with different cycloalkanones (five- to eight-membered) and different lengths of the side chain (two and three methylene groups) showed that this reaction can be used for the synthesis of several medium sized lactones [75] [80] [114]. Under similar reaction conditions, lactols can also undergo ring expansion reaction [115]. The substrates (steroidal lac-... 

The formation of the twelve-membered lactone, IX/52, from the eight-mem-bered ketone, IX/51, prepared by alkylation of the aldehyde, IX/50, can be explained as an enlargement of a medium-sized ring. The driving force is probably the resonance stabilisation of the secondary nitro group in base (nitro-nate), compared to the tertiary nitro group in the starting material (Scheme IX/9) [29],... 

---