Tetrahydrofuran , basicity esters

The same basic strategy was applied to the synthesis of the smaller fragment benzyl ester 28 as well (Scheme 4). In this case, aldehyde 22 prepared from (S)-2-hydroxypentanoic acid [9] was allylated with ent-10 and tin(IV) chloride, and the resulting alcohol 23 was converted to epimer 24 via Mitsunobu inversion prior to phenylselenenyl-induced tetrahydrofuran formation. Reductive cleavage of the phenylselanyl group, hydrogenolysis of the benzyl ether, oxidation, carboxylate benzylation, and desilylation then furnished ester 28. 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

Table 2 also indicates that the nucleophiles effective for vinyl ethers are relatively mild, when compared with those for isobutene (cf., Section V.B.2). In fact, stronger bases lead to inhibition or severe retardation of polymerization [36,64] ketones aldehydes, amides, acid anhydrides, dimethyl sulfoxide (retardation) alcohols, aliphatic amines, pyridine (inhibition). The choice of nucleophiles is determined by their Lewis basicity (as measured by pKb, etc. [64,103]), and this factor determines the effic-tive concentrations of the nucleophiles. For example, the required amounts of esters and ethers decrease in the order of increasing basicity (i.e., a stronger base is more effective and therefore less is needed) [101,103] tetrahydrofuran < 1,4-dioxane ethyl acetate < diethyl ether. On the other hand, for amines not only basicity but also steric factors play an important role [142] thus, unsubstituted pyridine is an inhibitor, while 2,5-dimethylpyridine is an effective nucleophile for controlled/living polymerization, although the latter is more Lewis basic. 

Irrespective of the solvent the aldehyde, acid or ester 1 is first transformed into the aluminum alkoxide 5. Transfer of hydride to the C-C double bond to give 6 occurs only when electron density is delivered to aluminum by a solvent with Lewis base character. Only in solvents of strong Lewis basicity (tetrahydrofuran, 1,2-dimethoxyethane) is the carbanionic character of the C-Al bond (e.g. 7) sufficient to induce intramolecular substitution to give phenylcyclo-propane 4. " 3-Phenylpropanols 3 are byproducts in the synthesis of 4, if insufficient reflux time is applied before acidic workup. ... 

In a third Upjohn synthesis [89] the 9,15-diacetoxy derivative of PGFja methyl ester underwent ring opening with lead tetraacetate to the triacetoxy aldehyde (98) of which the dimethyl acetal afforded TXB2 after basic hydrolysis of acetate and ester groups and then hydrolysis of the acetal with phosphoric acid in aqueous tetrahydrofuran. 

Total syntheses of diterpenoid hydrokempenones have been accomplished by Paquette et al.,f using the Pd-catalyzed [3 + 2] cycloaddition methodology. One example is outlined on Scheme 43 and describes the synthesis of an isomeric compound 208 of 3/3-hydroxy-7/3-kemp-8(9)-en-6-one, a defense secretion agent of the neotropical species Nasutitermes octopilis. 3-AUcoxy-2-cyclohexenone 204 was efficiently functionalized and transformed to bicylic adduct 205 via a Robinson annulation reaction. Reduction of the double bond followed by condensation of dimethyl carbonate and oxidation gave the keto ester 206, which was treated with [2-(acetoxymethyl)-3-allyl]trimethylsilane, palladium acetate, and triisopropyl phosphite in refluxing tetrahydrofuran to afford a 98% yield of 207. Substituted methylenecyclopentane 207 was then functionalized by stereoselective reduction and protections, and final closure was done under basic conditions after an ozonolysis step. A modified Barton-McCombie reaction produced the desired tetracyclic adduct 208. 

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