C/s- -Lactones

Methyl-5-hexenoic acid (1) cyclized under conditions of kinetic control (iodine in acetonitrile in the presence of sodium hydrogen carbonate) shows the preferential formation of the less stable c /.s-lactone (d.r. 70 30). The cis or trans configuration of the product lactones is assigned on the basis of 13C chemical shifts. 

In 2004, the N-heterocyclic carbene-catalysed internal redox reaction of epo Q aldehydes and a-haloaldehydes were developed by Bode et al. and Rovis et al., respectively. In 2012, Rovis group reported that NHC catalysed [4 + 2] hetero-Diels-Alder reactions of simple aliphatic aldehydes with a,p-unsaturated ketimines and ketones under oxidative conditions, giving the fra/2s-lactams and c/s-lactones in high yields with high enantioselectivities (Scheme 20.61). ... 

Only c/s-disubstituted and trisubstituted alkenes yield l,4-dioxan-2-ones by way of a cycloaddition reaction when oxidised by dimethyl a-peroxy lactone. An open 1,6-dipolar intermediate is postulated, involving steieoelectronic control <96JA4778>. 

Scheme 41 summarizes Couladouros s synthesis of the oviposition attractant pheromone of the Southern house mosquito (Culexpipiensfatigans)y (5R,6S)-6-acetoxy-5-hexadecanolide (28) [66]. The key-steps are (i) -selective Schlosser olefination (A B), asymmetric dihydroxylation (B C), and lactonization of carbonate C to the desired 6-lactone with inversion at C-5. 

Fig. 5.12. C(6)-Epimerization of the y-lactone degradation products of cefdinir and its 7-epi-mer (5.39a and b, Fig. 5.11). The mechanism involves deprotonation of the enamine N-atom, fission of the dihydrothiazine ring at the C-S bond, followed by reclosure with inversion of... 

As Holton and his associates emphasise, it is quite remarkable that deprotonation of -cis with LTMP apparently occurs first, and perhaps only, at C(l), even though the C(3) proton should be expected to be much more acidic. Reduction of 48-c/s with Red-Al (THF, at -78 °C, 1.5 h), followed by basic workup gave C(2)a-hydroxy rra 5-fused lactone (88%), which was treated with phosgene (10 equiv., pyridine, CH2CI2, -23 °C, 0.5 h) to give quantitatively the carbonate 49. 

BC13 convert 0=0 groups of ketones, lactones, and lactams to G=S groups119 and H2S-Me3SiCl-i-Pr2NLi converts carboxylic esters to thiono esters.120 Carboxylic acids RCOOH can be converted directly to dithiocarboxylic esters RCSSR, 120a in moderate yield, with P4S, and a primary alcohol R OH.121 Thioketones can also be prepared by treatment of ketones with P4SI0,122 and from oximes or various types of hydrazone (overall conversion C=N------> C=S).123... 

Cycloaddition of a-nitroso acrylic esters (749) to alkenes followed by base hydrolysis provides a route to 5,6-dihydro-4//-l,2-oxazine-3-carboxylic acids (750). These heterocycles on heating above 150 °C decarboxylate to furnish y-hydroxynitriles (thus the overall c/s-addition of OH and CH2CN to a double bond), which can be transformed further to y-lactones (751) by treatment with methanolic hydrochloric acid (Scheme 172) (79CC1090). The adducts were also reduced to a-amino esters (752) by the action of aluminum amalgam (Scheme 173) (79CC1089). 

J. C. L6pez, A. M. G6mez, and S. Valverde, A novel entry to cyclohexanes and cyclopentanes from carbohydrates via inversion of radical reactivity in hex-2-enono-S-lactones, J Chem Soc., Chem. Commun. 613 (1992). 

N-Protected ds-4-hydroxyproline lactones react with nucleophiles to generate the corresponding c/.s-4-hydroxy pro line derivatives, e.g. the methyl ester with methanol, 141 the amide with ammonia, 141 or peptides with sterically unhindered amino acid esters. 143 ... 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

The biotransformation of linalool by Botrytis cinerea has also been described [60]. After addition of linalool to botrytised must, a series of transformation products was identified (E)- (49) and (Z)-2,6-dimethyl-2,7-octadiene-l,6-diol (48), trans- (76) and cw-furanoid linalool oxide (77), trans- (78) and c/s-pyranoid linalool oxide (79) and their acetates (80, 81), 3,9-epoxy-p-menth-1 -ene (75) and 2-methyl-2-vinyltetrahydrofuran-5-one (66) (unsaturated lactone), Fig. (11). Quantitative analysis however, showed that linalool was predominantly (> 90%) metabolised to ( )-2,6-dimethyl-2,7-octadiene-l,6-diol (49) by B. cinerea. The other compounds were only found as by-products in minor concentrations. 

It is difficult to identify the lipid moiety as a polyprenol, because of the small amounts present in tissues. Nevertheless, some information can be obtained by using glycosylated lipids labelled in the sugar moiety. The first indication of the presence of polyprenyl glycosyl phosphates comes from study of the properties just mentioned, namely, lability to mild acid, stability to mild alkali, and acidic properties. Information on the polyprenyl nature of the lipid may be obtained by labelling the lipid with radioactive 2,4-dideoxyO-C-methyl-D-g/ycero-pentono-l.S-lactone (mevalonic acid ). 

The cyclofunctionalization of cyclohexa-2,4-dieneacetic acids results in 1,4-addition to form c/s-fused 7-lactones, as shown in equation (13) and Table 4. Most reaction conditions gave products with the electrophile trans to the lactone ring (entries 1-4), but the stereochemistry of the palladium-catalyzed reaction was reversed if an excess of a complexing ligand was added to the reaction (entries 5 and 6).49>s0 Results of lactonization in cyclohepta-2,4-dieneacetic acid systems were similar, but selenolactonization produced 1,2-addition products under some conditions.31 It is possible that these products result from a 1,3-rearrangement of the initial allyl selenide.52... 

The a-oriented lactone configuration (LXVIII) was originally favored by us (8) and by Stork and Newman (33). The latter authors arrived at this conclusion from their observed molecular rotation difference between the C-2-epi-tetrahydrogibberellic acid and the corresponding dibasic acid obtained by opening the lactone ring. They interpreted this value (+75°) in a rather doubtful manner in terms of Klyne s application (24) to polycyclic compounds of Hudson s lactone rule. 

Cyclic ethers from lactones. The ready addition of RLi to the C=S group of thionolactones (14, 9) has been used to prepare functionalized cyclic ethers from lactones of the same ring size. The first step involves Lawesson thionation of lactone... 

The rather low reactivity of the 3-p-tolylsulfinyl acrylates (they do not react with furan even under forcing conditions) prompted the search for more reactive dienophiles. In this context, pyridylsulfinyl derivatives proved to be more efficient than the arylsulfinyl ones. Thus, menthyl-3-(2-pyridylsulfinyl)propenoates 14a and 14b were prepared from (+)-menthyl propiolate in low yields [34]. Their reactions with cyclopentadiene proceed smoothly in the presence of Et2AlCl at -70°C to afford just one endo diastereoisomer 15a or 15b [35] (in the absence of the catalyst the 7r-facial selectivity for the endo approach was lower than that observed for the p-tolylsulfmyl derivatives [10c]). These compounds were transformed into 16a or 16b [36] respectively (Scheme 8), both allowing the synthesis of the bicyclic lactone 17 (known as Ohno s lactone), a key intermediate in Ohno s synthesis of (-)-aristeromycin and (-)-neplanocin A [37]. 

Unpublished observations of W. T. Haskins and C. S. Hudson in this laboratory. An intermediate amide has been obtained similarly from D-gluco-L-ja/a-octonic lactone. 

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