Lactone synthesis carbonylation

Lactone synthesis.2 Carbonylation of simple organic halides can be carried out readily with several palladium catalysts such as bis(diphenylphosphinoethane)-his(triphenylphosphine)palladium(0) and dichlorobis(triphenylphosphinc)pal-ludium(ll). The latter catalyst is preferred because it is stable and easily converted to Pd(0) in situ. Carbonylation of halo alcohols provides a useful synthesis of various lactones. 

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]. 

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

Lactone synthesis. This Ti(II) complex can serve as catalyst for hydro-magnesiation of allylic or homoallylic alcohols, prepared by addition of vinyl- or allyl-Grignard reagents to ketones. Ethylmagnesium bromide is used as the source of magnesium hydride. The carbonylation of the organomagnesium intermediate results in a -y- or a 5-lactone (equation I). 

One of the earliest examples of the synthetic promise of radical reactions for preparing polycyclic products was provided by Corey s y-lactone synthesis. This approach was actually based on a well-known reaction of a-carbonyl radicals, generated by manganese(iii) oxidation of carboxylic acids, with unsaturated substrates. The mechanism of the basic steps shown for the preparation of lactone 418 (Scheme 2.140) involves initial addition of the a-carbonyl radical 419 to the double bond of styrene, followed by oxidation of the radical intermediate 419a to carbocation 419b, and subsequent intramolecular reaction with the carboxyl nucleophile to yield the lactone product. 

Unsaturated lactones lacking substitution at C-4 are the simi est ones available via this general type of cycloaddition. Several syntheses of these lactones are of practical value, including two Pd-based meth-ods. However, the considerable utility of metal carbonyl anions in lactone synthesis is illustrated by a rhodium carbonyl anion catalyst system which gives very high yields upon reaction with a variety of internal alkynes under weakly basic aqueous conditions, essentially water-gas shift conditions. These conditions were established to maximize chemoselectivity with respect to other possible alkyne carbonylation products. Regioselectivity is modest in this process, but was not examined systematic ly (equation 13). ... 

Scheme 9. Lactone synthesis by <5-carbonylation of alcohols under oxidative conditions...

One alternative approach to lactone synthesis with CO in the absence of C—X and C—M bonds involves the decarboxylation of cyclic carbonates where lactone formation occurs with concomitant loss of CO2 (Scheme 2.22) [48-50]. Since CO2 is the sole byproduct, this process is considerably more green than carbonylation of C—X and C—M bonds. 

Surprisingly, methyl esters are also suitable substrates whereby intramolecular cyclization occurs with concomitant loss of methyl iodide. Larock used internal alkynes as coupling partners for lactone synthesis (Scheme 2.33) [74]. The proposed mechanism involves oxidative addition of Pd(0) to the aryl iodide, followed by addition across the alkyne and cyclization of the carbonyl O of the ester to form an oxonium ion. Reductive elimination followed by loss of the methyl group then yields the product [74]. Shen and coworkers also reported a variant utilizing o-2,2-dibromovinylbenzoates (Scheme 2.34) [79]. 

A catalytic asymmetric synthesis of a-methylene lactones by carbonylation of a meso substrate (Scheme 10) was developed by Shibasaki and co-workersJ The combination of Pd(OAc)2, (1 )-BINAP, and Ag20 gave 44% yield of lactone with a modest ee. No asymmetric induction occurred in the absence of Ag20. Presumably the role of Ag20 is to promote formation of an intermediate cationic palladium species, which could retain bidet tate coordination of the chiral ligand throughout the catalytic process. 

This lactone synthesis therefore involves a double carbonylation of the multiple bond and is therefore a very powerful and useful strategy in organic synthesis (Scheme... 

Numerous examples of lactone synthesis have been reported [57, 94], particularly as applications of transition metal-catalyzed carbonylation [95, 96] reactions and as appUcations of CO2 [97]. 

The influence of the functional groups of the substrate in the course of an allylsilane addition to a carbonyl group are exempHfied in the enantiodivergent synthesis of the Geissman-Waiss lactone [63]. The Geissman-Waiss [64] lactone 200 and 202 serves as a versatile intermediate for the synthesis of pyrroUzidine alkaloids. For this reason, there are a variety of different syntheses to this building block [65]. The Geissmann-Waiss lactone synthesis of Wistrand and coworkers not only provides a short access to one enantiomer but also enables the synthesis of both enantiomeric forms. The synthesis is depicted in Scheme 3.40. 

Lactone synthesis through the reaction of 2-(alkoxycarbonyl)allyl metal species to carbonyl substrates holds a main position for the synthesis of the a-methylene derivatives. In 2(X)5, Hall et al. [30] obtained an interesting result in a TfOH-catalyzed reaction of a benzaldehyde derivative bearing electronically rich arene structure with (E)-crotyl boron reagent (E)-39 (Scheme 16). In this case, if the reaction proceeds via normal cyclic six-membered transition... 

Alper and Yu in 2007 developed the palladium-catalyzed highly substituted endocyclic enol lactone synthesis via the carbonylation of terminal alkyne and 1,3-diketones in an ionic hquid system (Table 15.21) [29]. Thirteen examples have been isolated under this process. It should be noted that this catalytic system can be recycled five times with only modest loss of its catalytic activity. 

As [2 + 2]cycloaddition, carbo[2 + 2] cycloaddition of a, P-unsaturated carbonyls with vinyl ethers and P-lactone synthesis through [2 + 2]cycloaddition of ketenes with aldehydes were examined. As shown in Scheme 6.99, since under nonpho-tochemical conditions the concerted mechanism for both reactions are disallowed by Woodward-Hoffmann rules, ground-state catalytic reactions must proceed through a stepwise mechanism. 

Scheme 66 Synthesis of 3-hydroxy-5-lactones via carbonylation of homoglycidols...

The carbonylation of COD PdCl2 complex in aqueous sodium acetate produces /rui7x-2-hydroxy-5-cyclooctenecarboxylic acid /i-lactone (240). The lactone is obtained in 79% yield directly by the carbonylation of the COD complex in aqueous sodium acetate solution[220]. /i-Propiolactone (241) is obtained in 72% yield by the reaction of the PdCC complex of ethylene with CO and water in MeCN at —20 " C. /3-Propiolactone synthesis can be carried out with a catalytic amount of PdCC and a stoichiometric amount of CuCl2[221]. 

The intramolecular oxidative earbonylation has wide synthetie applieation. The 7-lactone 247 is prepared by intramolecular oxycarbonylation of the alke-nediol 244 with a stoichiometric amount of Pd(OAc)2 under atmospheric pres-sure[223]. The intermediate 245 is formed by oxypalladation, and subsequent CO insertion gives the acylpalladium 246. The oxycarbonylation of alkenols and alkanediols can be carried out with a catalytic amount of PdCl2 and a stoichiometric amount of CuCb, and has been applied to the synthesis of frenolicin(224] and frendicin B (249) from 248[225]. The carbonylation of the 4-penten-l,3-diol 250, catalyzed by PdCl2 and CuCl2, afforded in the c -3-hydroxytetrahydrofuran-2-aeetie acid lactone 251[226J. The cyclic acetal 253 is prepared from the dienone 252 in the presence of trimethyl orthoformate as an accepter of water formed by the oxidative reaction[227]. 

Alkynes undergo stoichiometric oxidative reactions with Pd(II). A useful reaction is oxidative carboiiyiation. Two types of the oxidative carbonyla-tion of alkynes are known. The first is a synthesis of the alkynic carbox-ylates 524 by oxidative carbonylation of terminal alkynes using PdCN and CuCh in the presence of a base[469], Dropwise addition of alkynes is recommended as a preparative-scale procedure of this reation in order to minimize the oxidative dimerization of alkynes as a competitive reaction[470]. Also efficient carbonylation of terminal alkynes using PdCU, CuCI and LiCi under CO-O2 (1 I) was reported[471]. The reaction has been applied to the synthesis of the carbapenem intermediate 525[472], The steroidal acetylenic ester 526 formed by this reaction undergoes the hydroarylalion of the triple bond (see Chapter 4, Section 1) with aryl iodide and formic acid to give the lactone 527(473],... 

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