Polycyclic lactones

Krohn K et ai, Fusidilactones, a new group of polycyclic lactones from an endophyte, Eusidium sp., Europ J Org Chem 2002 2331-2336, 2002. 

Polycyclic lactones based on dihydroazines can be obtained in several ways. For example, trimethylsilyl ester 395 after passing through silica gel is converted to the appropriate lactone 396 [398] (Scheme 3.127). This method is a fast and facile procedure providing lactones 396 in high yields. 

I.2.2. Preparation of Fused and Bridged Bicyclic and Polycyclic Lactones... 

With the advent of the new catalysts systems that will undergo efficient reactions with electron-deficient olefins, the tandem process can be extended to the synthesis of a variety of polycyclic lactones (Eq. 6.27) [47]. 

Rhodium(II) octanoate-catalyzed decomposition of diazo esters 52, involving in the first stage a reaction of a carbenoid with the pyrrole double bond, furnishes polycyclic lactones 53 (34-79% R = H, Me R = H, Ph) (94TL5209) as shown in Scheme 18. 

If the substrate contains a nucleophile in addition to a vinylcyclopropane moiety, the halonium ion formed during the addition of bromine or iodine to the double bond, can be trapped which results in the formation of cyclization products. Examples of compounds that react in this way are 1-phosphoryl-substituted 2-vinylcyclopropanes, 2-vinylcyclopropyl-sub-stituted alkanoic acids, and 2-vinylcyclopropyl-substituted alkanols, which afford oxaphosphabicycloalkanes, bi- and polycyclic lactones and polycyclic ethers, respectively. However, 2-vinylcyclopropyl-substituted alkylamines behave differently, Very good yields have been obtained in some cases, e.g. formation of 4 from 3. ... 

The catalytic intramolecular hetero-Pauson—Khand reaction has been extensively studied by several groups.184 Kablaoui et al. reported the titanocene-catalyzed hetero-Pauson—Khand reaction of the 2-ally lphenyl ketones 382.184ab In the presence of Cp2Ti-(PMe3)2 and trimethylphosphine, the reaction of 382 with carbon monoxide gave the polycyclic lactones 383 in high yields (Scheme 121). 

An interesting method recently developed by Negishi combines cascade carbopallada-tions with termination by carbonylation, to afford fused polycyclic lactones, as exemplified in Scheme 15. 

Phenyl(chlorocarbonyl)ketene 170 reacts with N-phenylacetyknorpho-line forming 4-hydroxy-6-morpholino-3,5-diphenylpyran-2-one in a process interpreted as involving initial esterification of the acylketene with the enol of the amide followed by generation of a second acyl ketene 171 and further cyclization to 172 (Eqn (4.109)). Ketene 170 also reacts similarly with 1,3-diketones and heterocyclic 3-hydroxy-2-ene-l-ones forming polycyclic lactones. 

SCHEME 3 7 Corey s route toward polycyclic lactones. 

As shown in Scheme 37, Corey developed an effective synthetic route toward polycyclic lactones such as 83 with rigid and compact structures on the basis of tiie Cu-catalyzed intramolecular (2+1) cycloaddition of allyl diazomalonate 82 followed by the treatment of cyclopropane lactone thus obtained with MesSiOTf and a small amount of water [53]. 

Although the Diels-Alder reaction of furan-2(5H)-one itself 140b and its derivatives has been used to synthesize structurally complex polycyclic lactones, lower reactivity of such lactone dienophiles compared to the acyclic dieno-philes sometimes is problematic. Therefore, more reactive synthetic equivalents of y-butenolides were developed [114]. In addition, due to relatively strong Lewis basicity of the lactones, the reaction often requires the use of a stoichiometric amoxmt of Lewis acids [115]. As a recent elegant example of the catalytic Diels-Alder reaction, Corey demonstrated that chiral cationic oxazaborolidine 172 works as one of the effective asymmetric Lewis acid catalysts for the reaction of 140b with cyclopentadiene (Scheme 68) [116]. 

These reactions were high yielding (85-97%) and could be tuned to favor the formation of the seven-membered ring lactone (87-98%). This study employed a Pd(ll)-dppb catalytic system, and reactions were performed at 41 bar CO, 120°C. The same conditions were used to promote the reactions of allylnaphthols 29 and 30 and the 2-(l-methyl-2-propenyl) derivative of the steroid estrone, 31, to generate polycyclic lactones (Figure 14.8). 

Combined biotechnological and synthetic methods for preparation of polycyclic y-lactones, clinically important compounds 98PAC2093. 

With the polycyclic framework of the natural product intact, the completion of the total synthesis only requires a short sequence of reactions. At this juncture, the decision was made to address the problem of reconstituting the A-ring lactone. It was hoped that a selective oxidation of the A-ring allylic ether could be achieved. 

Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels Alder reactions of the dienes 44 are reported in Scheme 2.19. 

In addition to the parent compound 2, the derivatives 2a, b, the benzo-system 16, the lactone-peroxides 17, and the fused polycyclic derivatives 18 and 19 could be prepared via the singlet oxygen-diimide route. For example, the parent system 2 was obtained in ca. 40% yield by diimide reduction of the stable 1,3-cyclohexadiene endoperoxide in MeOH at 0 °C27,28). Dihydroascaridole 2a and dihydroergosterol endoperoxide... 

The conformational kinetic control of the chiral centres present in a molecule may be exemplified by the rran -diaxial opening of an epoxide i rf a polycyclic system [7]. In this case, the less stable conformation is also "frozen" by forming an auxiliary lactone bridge, which reverses temporarily the conformations of the rings and the substituents. 

Chlorine DBPs of the polycyclic musks 6-acetyl-1,1,2,4,4,7-hexamethy 1-tetraline (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-y-2-benzopyran (HHCB), which are widely used fragrances in cosmetics, daily care products, and cleaning products for household and industry, were investigated by Kuhlich et al. [123]. This study evidenced chlorination of HHCB as a potential new source of HHCB-lactone in the environment, other than biological transformation. 

Kuhlich P, Gostl R, Teichert P, Piechotta C, Nehls I (2011) Transformation of polycyclic musks AHTN and HHCB upon disinfection with hypochlorite two new chlorinated disinfection by-products (CDBP) of AHTN and a possible source for HHCB-lactone. Anal Bioanal Chem 399 3579-3588... 

Rouillard, A. Deslongchamps, P. Synthesis of a pentacyclic lactone related to quinovaic acid and emmolactone using an anionic polycyclization strategy. Tetrahedron 2002, 58, 6555-6560. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

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