Lactones cyclization

There are many aspects of these Rh-mediated cyclizations that are yet to be explored. What factors, for instance, govern the ratio of 25 to 26 (Scheme 1)1 Would an Rh catalyst that was more readily polarizable and so more sensitive to electronic effects give a higher proportion of 25 The enantioselective lactone cyclizations of Doyle [15] are particularly intriguing. Attempts toward enantioselective carbocyclization using a chiral rhodium catalyst have to date [16] not... 

Mesocyclic lactones. Cyclization of w-hydroxycarboxylic acids via the 0,0 -disilyl intermediates is applicable to medium-sized rings (7-membered, 35% 8- to 13-membered, 79-88%). An initial silyl carboxylate formation step is catalyzed by (Ph3P)3RhCl at room temperature which is followed by an intramolecular 0-silylation at 80°. Elimination of l,l,3,3-tetramethylbenzo-2,l,3-oxadisilazole occurs when the cyclic silylether/esters are exposed to MejSiiOTf). ... 

Lactonization. Cyclization of the thioester 1 cannot be effected with mercuric trlfluoroacetate or copper(I) trifluroacetate. The usual reagents used for this reaction (6, 582 7, 444) are ineffective, but cyclization is effected with CuOTf complexed with benzene. Two isomeric lactones (2 and 3) are obtained in 62% yield. One of thcNC is the acetate of the pyrrolizidine alkaloid crobarbatine. Unfortunately dcucctylation of these products is accompanied by further hydrolysis to the pyrrolizidine unit (retronecine). 

Cyclases are also responsible for NRP depsipeptide and PK lactone cyclization. For example, a di-domain excised from fengydn synthase was able to catalyze the formation of a macrolactone through the formation of a C—O bond [25]. Several cyclases from PK synthases have also been characterized to be functional, including the epothilone D cyclase [26, 27] (Equation 8.1). 

Glycosidic Withanolide Congeners Without Lactone Cyclization... 

Fig. 7.32 Withanolide congener without lactone cyclization prevented by an acylation of the C-22 hydroxyl group and an ester gjyco-sidation of the C-26 carboxyl group (highlighted in grey)...

Scheme 5 Keto-p-lactone cyclization to tetrahydrofurans by Romo and Mitchell [8]...

The p-lactone cyclization precursors come from Romo and Yang s tandem Mukaiyama aldol lactonization (TMAL) process (Scheme 7) [10]. As an example of this, lactone 25 was the product of the ZnCl2-mediated cyclization of a-benzyloxy aldehyde 24 with thio-ketene acetal 23. Ozonolytic cleavage of the alkene gave 26. 

Barrelene was obtained via a double Diels-Alder reaction from a-pyrone with methyl acrylate (H.E. Zimmerman, I969A). The primarily forming bicyclic lactone decarboxylates in the heat, and the resulting cyclohexadiene rapidly undergoes another Diels-Alder cyclization. Standard reactions have then been used to eliminate the methoxycarbonyl groups and to introduce C—C double bonds. Irradiation of barrelene produces semibullvalene and cyclooctatetraene (H.E. Zimmerman. 1969B). 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

COi is another molecule which reacts with conjugated dienes[10,95,96], COt undergoes cyclization with butadiene to give the five- and six-membered lactones 101. 102. and 103, accompanied by the carboxylic esters 104 and 105[97.98], Alkylphosphines such as tricyclohcxyl- and triisopropylphosphine are recommended as ligands. MeCN is a good solvent[99],... 

Alkynyl)oxiranes also react with carbon nucleophiles to afford furan derivatives. Furanes of different types are obtained depending on the structure of the substrates. 7-Methyl-2-ethynyloxirane (95) reacts with acetoacetate to give the furan 97 by the elimination of formaldehyde from the cyclized product 96. The hydroxy ester of the alkylidenefuran 98 and the corresponding lactone 99 are obtained by the reaction of i-methyl-2-(2-propynyI)oxirane[40, 42]. 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

One of the C(15) epimeric thio esters (B) cyclizes more slowly than the other (by a factor of 03. 15) due to steric repulsions involving the methyl group at C(15). After lactonization, the uncyclized diastereomer was recovered and used for the synthesis as following. 

Electrophilic cyclizations of unsaturated amides to form five- and six-member lactones 98T13681. 

The cyclization of o-halogenobenzoic acids with copper acetylides mainly leads to the formation of five-membered lactones (66JOC4071 69JA6464) (Scheme 115). Only in the case of the reaction of o-iodobenzoic with CuC=C—n-C3H7 does the formation of a mixture of y- and 5-lactones occur (Scheme 116). 

To verify the generality of the cyclization of iodopyrazolecarboxylic acids, copper p-phenylbenzoylacetylide was used in the reaction with 3-iodo-l-methylpyra-zole-4-carboxylic acid. The assumed intermediate, alkynylpyrazolylcarboxylic acid, has a distribution of the electron density which is the most favorable for closure of the five-membered cyclic ether. However, the reaction leads only to the 5-lactone (Scheme 120). 

Thus, the vic-acetylenylpyrazolecarboxylic acids are isomerized into pyranoa-zoles in boiling pyridine (20-30 min) with catalytic amounts of copper acetylide. The acetylide condensation of the corresponding iodopyrazolecarboxylic acids is followed by cyclization into the same 5-lactones but with a lower rate (2-8 h). 

The third synthetic scheme is employed when the phenylthio substituent is in the a-position of the lactone function, which interferes with the cyclization (90JOC5894). Acetylenic ketone 194 (95% yield) is readily transformed to the acetal 195 (with potassium carbonate in methanol) however, under the above conditions neither its hydrolysis nor cyclization to the spiroketal occurs. The spirocyclic pyrone 197 is formed in quantitative yield on treatment of 195 with p-toluenesulfonic acid in a 4 1 THF-H2O mixture at reflux for 12 h. 

By analogy, thermal cyclization was described also for 6-nitro-2 -hydroxy-biphenyl-2-carboxylic acids, e.g. 14, obtained by other methods. The same product 15 was also formed from lactone 17, prepared by oxidation of fluorenone 16 (Scheme 2). If the reaction was performed in DMF, the corresponding dimethylamide was isolated (82KGS703, 86KGS852, 87KGS314, 89MI1). 

The electroreductive cyclization of the furanone 118 (R = -(CH2)4CH=CH— COOMe Scheme 36) using a mercury pool cathode, a platinum anode, a saturated calomel reference electrode, and a degassed solution of dry CH3CN containing -Bu4NBr as the electrolyte, gave the spirocyclic lactones 119 and 120 in a ratio 1.0 1.1 (Scheme 37)(91T383). 

The proposed mechanism for the conversion of the furanone 118 to the spiro-cyclic lactones 119 and 120 involves electron transfer to the a -unsaturated methyl ester electrophore to generate an anion radical 118 which cyclizes on the /3-carbon of the furanone. The resulting radical anion 121 acquires a proton, giving rise to the neutral radical 122, which undergoes successive electron transfer and protonation to afford the lactones 119 and 120 (Scheme 38) (91T383). 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

Less important methods are the self condensation of w-hydroxy acid and the ring opening of lactones and cyclic esters. In self condensation of w-hydroxy acids, cyclization might compete seriously with linear polymerization, especially when the hydroxyl group is in a position to give five or six membered lactones. 

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