Lactone synthesis palladium® reactions

Various methods have been explored for the synthesis of lactones by cycloaddition reactions. The most common of these types of reaction is the [2+2] cycloaddition of aldehydes and ketene. Palladium(ll) complexes, [Pd(dppb)2(PhCN)2](BF4)2, have been shown to be efficient catalysts for this reaction (Equation 34) <2000CC73>. 

A reported diastereoselective synthesis of precursor A of vitamin D3 involved the use of 2-methylcyclopent-2-enone as starting material. The Mukaiyama-Michael conjugate addition of ketene acetal 269 in the presence of trityl hexachloroaniimonate afforded the adduct 270. The lateral chain was introduced, according the procedure of Tsuji, by the treatment of crude 270 with allyl carbonate and palladium dibenzylideneacetone " (Scheme 63). The expected product 271 was obtained in 63% yield from 269. Reduction of 271 with LAH afforded a mixture of diols that was selectively tosylated at the primary hydroxy group. The secondary hydroxy group was protected with the methoxymethyl group and further functional modifications afforded the lactone 272. The reaction of lithium dimethyl methylphosphonate with the lactone 272 completed the synthesis of the AB-des-cholestane derivative 273. 

Palladium-catalyzed cyclic carboxylation of dienes can be utilized for the synthesis of lactones.2 Polymer-supported Pd catalyst could also be used for this reaction (Scheme 42).61 The reaction is initiated by dimerization of two molecules of diene to give a bis-7r-allylpalladium intermediate such as 123. The incorporation of C02 takes place at the internal position of an allyl unit to afford the 7r-allylpalladium carboxylate 124 which, after reductive elimination/ cyclization, yields the (5-lactone 121 (Scheme 43). 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

A very promising synthesis of /3-lactones has been recently reported, involving the palladium-catalyzed carbonylation reaction of halogeno alcohols. For example, 3-phenyl-2-oxetanone was obtained in 63% yield from 2-phenyl-2-bromoethanol in DMF solution at room temperature under 1 atmosphere pressure of carbon monoxide (equation 115). A proposed mechanism, in which palladium metal inserts into the carbon-halogen bond, followed by insertion of a molecule of carbon monoxide into the carbon-palladium bond and then ring closure, fits kinetics data (80JA4193). 

In certain other systems, there is compelling evidence for the insertion into a metal-caiboxylate complex (equation 37). For example, in the synthesis of a-methylene-y-lactones from alkynic alcohols,70,71 no double bond rearrangement to a butenolide occurs, a reaction shown to take place in the presence of transition metal hydrides. The source of the vinyl proton (deuterium) on the a-methylene group is indeed the alcohol function. Finally, palladium carboxylate complexes containing alkynic (equation 40) or vinyl tails (equation 41) can be isolated and the corresponding insertion reaction can be observed. 

Tsuji-Trost allylation reactions offer multiple pathways to tetrahydrofuran synthesis including C-C bond-formation steps. A palladium-catalyzed sequence of allylic alkylation and Hiyama cross-coupling provides a convenient synthesis of 4-(styryl)-lactones (Scheme 67) <2006SL2231>. 

There is an ongoing interest in catalytic C-C bond-forming reactions of CO2 [3] and much work has been invested in palladium-catalyzed synthesis of 5-lactone 2 from butadiene 1 and CO2 [3 e, 3 f, 4]. Table 1 presents the catalyst development for this catalytic coupling reaction, and the optimum conditions as known up to now are summarized in eq. (1). 

Preparation of the lactone fragment started with a mixture of (2 ,45) and (25,4S)-4-methyl-2-phenylsulfenyl-y-butyrolactone (53) which was alkylated with ( )-l,9-diiodo-l-nonene. The corresponding iodo compound 100 so obtained was then coupled with the alkyne 99 through the efficient palladium catalyzed reaction (Pd(PPh3)4, Cul, Et3N, room temperature) in 86 % yield. Enyne reduction of 101 with Wilkinson s catalyst, then oxidation of the sulfide into sulfoxide and subsequent thermal elimination gave rise to the title compound 90. The synthesis was achieved in 20 steps and in 0.36 % yield. 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

Bringman et al. have described a synthesis of the unusual isoquinoline alkaloid ancistrocladine (82) starting from the chiral tetrahydroisoquinoline (79). Conversion of (79) to the ester (80), followed by a palladium catalysed coupling reaction led to the helicene-type lactone (81) which was then easily converted to (82). In a new route to the morphine ring system, Ludwig and Schafer have developed the intramolecular Lewis acid catalysed coupling of the tetrahydroisoquinoline (83) to (84) as a key step.26 The tetracycle... 

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