Lactone annulation reaction

The total synthesis of the immunosuppressant (-)-pironetin (PA48153C) was accomplished by G.E. Keck and co-workers. The six-membered a,(3-unsaturated lactone moiety was installed using a lactone annulation reaction by reacting the advanced aldehyde intermediate with the lithium enolate of methyl acetate. The aldehyde was prepared by the Ley oxidation of the corresponding primary alcohol and was used without purification in the subsequent annulation step. 

Heterocyclic secondary enamines and dicarboxylic acid dichlorides undergo complex, ring-size-dependent annulation reactions that, in the case of ester 238 and phthaloyl chloride (Scheme 57), lead to lactone-containing derivative 239 (02T2821). 

A multicomponent one-pot annulation reaction, such as the one described in Chapter VII. 1, can also be used to synthesize lactones with enlarged rings. [74] [108],... 

Keck et al. have used the lactone annulation procedure developed in their laboratory to install the lactone moiety by reaction of the lithium enolate of methylacetate with a (3-acetoxy aldehyde [108]. The other key steps include a diastereoselective Lewis acid mediated (Z)-crotylstannane aldehyde addition, a highly selective Lewis acid promoted Mukaiyama aldol reaction and an arari-selective Sml2 reduction of a p-hydroxyketone. The preparation of the C8-C15 fragment of (-)-pironetin started with the chelation-controlled addition of (Z)-crotyl tri-n-butylstannane to the (3-benzyloxy-aldehyde 153 in the presence of TiCU [109] to give the... 

The Ye group have established an unprecedented NHC-catalyzed [3 + 4] annulation of enals with o-quinone methides to give the corresponding benzo-e-lactones. The reaction worked well for both p-aryl enals and p-alkyl enals, giving the corresponding benzo-e-lactones in high yields with moderate (for p-aryl enals, 3 1-5 1 dr, 81-95% ee) to excellent (for p-alkyl... 

In 2012, Alexakis and co orkers disclosed the first stereoselective annulation reaction between ynals and a-cyano-l,4-diketones which is mediated by a catalytic amount of a triazolium salt precatalyst and a weak carboxylate base. This transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon, and affords privileged bicyclic scaffolds in 61-90% yields with up to 20 1 diastereomeric preference. A mechanistic rationalization for the NHC-catalyzed annulation of a-cyano-l,4-diketones with ynals is proposed as the following. Initially, the free carbene condenses with a molecule of ynal to form the key d,p-unsaturated acylazolium intermediate followed by a direct nucleophilic conjugate addition of 1,4-diketone. Subsequent intramolecular H-migration and an irreversible lactonization furnish the observed bicyclic product and liberate free carbene for the next catalytic cycle (Scheme 7.98). 

Cyclizations of enediynes under the action of electrophiles 13KGS129. Cyclization reactions of l,l-bis(trimethylsilyloxy)ketene acetals (synthesis of lactones, cyclic anhydrides, lactone-bridged N-heterocycles, lactone-annulated N-heterocycles) 12SL1283. 

Eurthermore, in alkenylation reactions with phenyl carboxylic acid as the substrate, a similar annulation reaction proceeds to give a lactone by cyclization reaction via the alkenylation of the cyclometalation product, as shown in Eq. (7.80) [156],... 

Treatment of M(C0)5[C(0Me)(CsCPh)] (M = Cr, W) with CpH modifies the carbene by Diels-Alder type addition of the alkyne across CpH. " Carbenes Cr(CO)5(carbene) react with 1-alkynols to form hydroquinone and/or vinyl lactone derivatives via vinyl ketene intermediates. Annulation reactions of Cr carbene complexes with 3-carbomethoxy-5-hexynoate and CO form part of a new regiospecific route relevant to the synthesis of... 

This strategy [20b] has been applied, for instance, in a total synthesis of pentalenolactone E methyl ester (27) (Scheme 5.17), and more recently Marino and Long [20c] have described the intramolecular version of this annulation procedure to synthesise an octahydronaphthalene derivative (28) which is a key intermediate for a new synthesis of dihydrocompactin (Scheme 5.18). However, the reaction with aldehydes affords only very low yields of a mixture of lactones. 

The synthesis was initiated with the stereoselective introduction of two methyl groups onto the tritylated butenolide 1 to give the dimethylated lactone 2 (67%) along with the C-2 epimer (13%). As this stereocenter will be lost in the Stork annulation vide post), both epimers could be used in the total synthesis of 12. Their structures were confirmed by the NOE enhancement in 2. After detritylation, the resulting alcohol was transformed to the dimethyl acetal 3. Reaction with the lithiated MeS02Ph gave the lactol 4, which was silylated to the open chain having the enol silyl ether 5 (91%). These reactions seem to depend on the readiness of the enol silyl ether formation. 

Doubly activated imines undergo intramolecular electrophilic cyclization reactions in the presence of Lewis acids and this provides an efficient route to annulated pyrrolidine, piperidine and azepine lactones (Sch. 32) [143]. TMSOTf and GaCls give different product ratios and yields. 

An interesting and potentially useful sequence is shown in equation (107). Cyclopropane esters (305) may be prepared by the addition of diazo esters (304) to double bonds under elimination of nitrogen. After saponification the acid is 0-protonated to open the cyclopropane ring, and the resulting carbenium ion (306) is trapped by lactonization. In effect a "y-lactone has been annulated to a double bond in a re-giodefined manner.Examples are given in Scheme 10. A related reaction involves the conversion of the cyclopropane ester (307) into the lactone (308 equation 108). ... 

A simple one-pot synthesis under phase-transfer conditions using two moles of base and one mole of iodine per mol alkene gave geminally substituted cyclopropanes 6. If an ester moiety is incorporated into the starting alkene at a suitable position, an intramolecular reaction may occur resulting in the formation of cyclopropanes 7 with an annulated lactone ring. "... 

Annulated tetrahydropyranones 37 and oxepans 38 can be prepared in moderate to high yields when lactones of increased ring size are employed in this type of reaction. The c/i-fused isomer predominates in these cases. 

As depicted below, a procedure for the iodocyclization of acetoxy-containing 2-(l-alkynyl)anisole and subsequent direct palladium-catalyzed earbonylatiori/lactonization was reported as an efficient entry to naturally occurring eoumestan and coumestrol <05IOC9985>. A novel Pd(II)-mediated cascade carbonylative annulation of substituted o-hydroxyphenylacetylenes to give benzo[fo]furan-3-carboxylie adds was achieved in a one-pot reaction <050L2707>. 

The stereoselective five-ring annulation is the cornerstone in a synthesis of Corey s lactone, starting from readily available 3-deoxy-1.2 5,6-di-0-isopropylidene-a-D- v7)o-hexofuranose (8)54. Treatment of the intermediate 5-hexenol with thiocarbonylbis(iniidazole) followed by reaction with tributyltin hydride (Barton deoxygenation) gives exclusively the bicyclic compound 9 with the /i-orientated methoxymcthvl substituent. The cyelization product has the correct absolute configuration for the Corey lactone, to which it can be converted in four additional steps. 

Similar to the selectivities observed in five-ring annulations of carbocyclic systems (see previous section), cyclic 3-oxa-5-hexenyl radicals exhibit a distinct preference for the formation of l,5-c( s-configurated products. This is illustrated by the reaction of five- and six-membered /i-phenylselenocrotonates with triphenyltin hydride59. The intermediate cyclopentyl or cyclohexyl radicals cyclize exclusively in the 5-exo mode to yield the corresponding c -fused "/-lactones. 

Besides the intermolecular versions of this [3+2] annulation, intramolecular reactions are also possible. The first example of this transformation was reported by Oshima as early as 1988 in a synthesis of vinyl cylopentenes [8]. More recently this methodology was applied to the preparation of bicyclo[3.3.0]lactams and lactones... 

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