Exo-enol lactone

The Pd-catalyzed coupling reaction of the propargyl acetate 53 and 4-pentynoic acid (54) in the presence of potassium bromide produced the unsaturated exo-enol lactone 55 [66], The reaction proceeded via oxypalladation of the triple bond of 54 with an allenylpalladium intermediate, which was formed from Pd(0) and 53 and the carboxylate as shown in Scheme 3.30. 

Compounds which have an unsaturated y- or 5-lactone ring are reported to have carcinogenic and antitumour activity as well as other biological properties (72ABC2505). Many naturally occurring y-exo-enol lactones have been reported the mould metabolites... 

Scheme 11.47 Formation of unsaturated exo-enol lactone from 4-pentynoic acid.

The unsaturated exo-enol lactone 175 was obtained by the coupling of the propargylic acetate 172 with 4-pentynoic acid (173) in the presence of potassium bromide using tris(2-furyl)phosphine (TFP) as a ligand (Scheme 11-47). Oxypalladation of the triple bond of 4-pentynoic acid (173) with allenylpalladium and the carboxylate as shown by 174 is the first step, and the subsequent reductive elimination affords the lactone 175. The E olefinic bond is formed because the oxypalladation is a trans addition [42]. 

The Pd(II) species on an allenylpalladium complex A has ample Lewis acidity to activate a triple bond, on which a suitably arranged carboxylate anion attacks intramolecularly. Reductive elimination of Pd(0) species completes the formation of exo-enol lactones (Scheme The Pd-catalyzed coupling of the propargylic acetates with 4-pentynoic acids proceeds very smoothly in the presence of potassium bromide using tris(2-furyOphosphine (TFP) as the ligand (Scheme 10). 

Catalytic reduction of bridgehead enol lactone over Pd/C indicates that, indeed, the syn addition from the exo face of the bridgehead double bound establishes the relative configuration of all substituents [264], Equilibration studies performed in EtONa/EtOH also established that the ratio of the epimers corresponds to an equilibrium mixture. Under mild basic conditions (NajCOj/ EtOH), the product isomerization occurs to a very small extent. The product distribution is best understood by rapid conformational relaxation to one of the two low-eneigy half-chair conformations. The stereochemistry is established at the subsequent protonation step. This takes place with a strong preference for axial protonation from the /I face at carbon 2 to produce the most stable chair conformation (Scheme 14.12). 

In recent work Coates, Mason and Shah have successfully achieved the synthesis of gymnomitrol (29Ja).280) Since intramolecular aldol condensation of the aldehyde obtained by hydrolysis of 291 (Scheme 45) was unfavorable, conversion to enol lactone 292 was effected. Dibal-H reduction of 292 resulted directly in aldoli-zation of the intermediate lactol, oxidation of which afforded 293. The latter was converted successfully to keto alcohol 294 by capitalizing on the different steric environments about the carbonyl groups. Sequential dehydration and hydride reduction of 294 gave a 45 55 mixture of exo and endocyclic isomers 295a and295 b which were separated by TLC. 

Silverstein and coworkers have used the peroxy add oxidation of exo-all lidene cycloalkanones as a route to keto acids (Scheme 23). Oxidation of pulegone (72) and hydrolysis of the derived enol lactone led to the keto acid 3). 

They even react cleanly with formaldehyde, thus solving the problem that the Mannich reaction is not applicable to esters. The synthesis of the exo-methylene lactone 80 can be accomplished this way. Enone disconnection13 reveals formaldehyde as the electrophilic component in a crossed aldol reaction, realised with a lithium enolate 82.14 The mono-adduct 83 of formaldehyde and the lactone 81 can be isolated and the cautious dehydration step is to avoid migration of the double bond into the ring. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

The key reaction in Jung et al. s proposed assembly of Plaunol B (81a) and C (81b) was an intermolecular Diels-Alder reaction between a diene and an allenic lactone that should give the exo-methylene group in the natural product (Scheme 19.16) [20], The phenyl-substituted lactone 83 was prepared as a model for the eventual furan lactone of the plaunols. Cydoaddition of 82 possessing a TBS enol ether and... 

The norbornene derivative 16, obtained exclusively as the exo adduct via a Diels-Alder reaction of itaconic anhydride with cyclopentadiene followed by hydrolysis and esterification [7], was found to be a suitable precursor for an enolate of type 14 (Scheme 2). Due to the quaternary center at C-3 eno-lization with base proceeded unambiguously, giving rise to a diastereomeric mixture of lactones 17/18 after reaction with hexanal. Retro-Diels-Alder reaction led to the monocyclic lactones 19/20 (2 1), elegantly unmasking the cxo-methylene group found in so many paraconic acids [8]. Hydrolysis of this mixture in refluxing butanone with 6 N HCl [9] effected epimerization... 

The bicyclic 5-lactone ( — )-( / .5/ )-16 furnished an apparently quite stable enolate upon treatment with LDA between - 30 C and —10 C61. Alkylation of the enolate gave high yields of exclusively the exo-products 17. 

The fluoro-lactonization of alk-4-enoic acids and the fluoro-etherification of alk-4-enols with pentachloro-l-fluoropyridinium triflate (lo) proceed smoothly in a regioselective manner when the substrates contain an aryl substituent on the double bond.63 Some stereospecificity is observed in the case of 5-exo ring closure, possibly due to participation of the oxygen atom in the aryl-stabilized cationic intermediate. 

The Ferrier carbocyclization reaction of an enol-acetate substrate gives an a,p-dihydroxy-cyclohexanol derivative (see Schemes 12.7 and 12.81. This transformation would be effective for the chiral synthesis of inositol derivatives. A retrosynthetic plan for the marine natural product tetrodotoxin 88 based on the enol-acetate version of Ferrier carbocyclization is shown in Scheme 12.22. Tetrodotoxin 88 was planned to be synthesized from lactone 89, the precursor of which would be highly functionalized cyclohexane 90. Cyclohexane 90 was envisioned to arise from cyclohexanone 91. For the preparation of 91, Ferrier carbocyclization of enol acetate 92 would be a suitable transformation. d-Glucose derivative 93 possessing an exo-methylene at C-3 would serve as a promising precursor of 92. 

In 1992 Burke et al. reported the selective enolization of a glycolate in the presence of a butenoUde (Scheme 4.47) [50]. The rearrangement of the Z-silyl ketene acetal occurred via a chair-Hke transition state to afford the exo methylene butyro-lactone. The pentenoic add products were transformed into isoavenaciolide and... 

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