Lactone synthesis cycloadditions

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>. 

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). ... 

Although much less prevalent than the use of CO in lactone synthesis, direct incorporation of CO2 for the synthesis of lactones is advantageous due to lower toxicity while maintaining high atom efficiency. Louie and coworkers demonstrated that a formal [2 + 2 + 2] cycloaddition of bis-alkynes with CO2 yields pyrone derivatives under Ni(0) catalysis (Scheme 2.62) [117]. It is proposed that an initial cydometallation of one alkyne and CO2 yields a Ni(II) metallacycle, followed by insertion of the other alkyne and reductive elimination. Pd(0) has also demonstrated catalytic activity in carboxylations of methoxyallene [118] and 1,3-butadiene [119]. 

Arylalkylketenes react with P,y-unsaturated a-ketophosphonates with chiral catalysis by N-heterocyclic carbenes giving enantioselective formation of products of formal [4 + 2] cycloaddition (Eqn (4.103)). ° These ketenes react similarly with acylcarboxylates forming the corresponding esters and amides with high enantioselectivity (Eqn (4.104)). ° A similar lactone synthesis by [4 + 2] cycloaddition is shown in Eqn (4.99), and such ketene reactions catalyzed by N-heterocycHc carbenes have been recently reviewed. 

Bicyclic lactone synthesis by Rh-catalyzed cycloisomerization reactions of ester-tethered substrates was well studied by Saito et al. [49]. For instance, formal (5-f2) cycloaddition reaction of alkyne 75 bearing vinyl cyclopropane moiety smoothly proceeded to give oxa-bicyclo[5,3,0]octene compoxmd 76 in good yield (Scheme 34). 

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. 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

Intramolecular cycloadditions of a,p-unsaturated lactones to alkenes have been used as key step in the synthesis of a precursor of the terpene reserpine 480) (4.68) and of fused cyclooctanes (4.69) 481 ... 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

Dideoxyhex-2-enono-1,5-lactone derivatives (penten-5-olides) have been prepared (255-258) and employed as starting compounds in synthesis. Thus, Michael addition of benzylhydroxylamine to racemic 6-0-acetyl-2,3,4-trideoxy-D,L-g/ycerohex-2-enono-1,5-lactone (267) took place ster-eoselectively to give the unstable benzyloxyamino-2-pyrone 268, which was readily converted into the /Mactam derivative 269, a precursor of thienamy-cin (259). / -Lactams were also obtained (260) by 1,3-dipolar cycloaddition of nitrone 270 to the unsaturated 1,5-lactone 267, followed by hydrogenoly-sis and subsequent cyclization to the /Mactam 271, having a polyol side-chain at the C-3 position. 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

Tricyclic lactone systems were synthesized by the analogous intramolecular [4+ 2]-reaction followed by hydration and oxidation of the resulting dihydropyran ring. This isomerization-cycloaddition sequence was successfully applied to the synthesis of (+)-platyphyllide [134]. 

Alternatively, some of the desired amino acid functionality may be contained within the nitrone fragment, as in the synthesis of homochiral allyl glycines by Katagiri et al. (151), which reveals the carboxylate by hydrolysis of a lactone in the dipole (Scheme 1.24). Here, thermolysis of nitroso Meldrum s acid (112) via a nitrosoketene intermediate 113 and reaction with 1-menthone gave the separable nitrones 114a (26%) and 114b (28%) by a [3 + 2] cycloaddition, although a... 

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