Y-Lactones, bicyclic

The domino process can be catalyzed by a Cu-complex with (S.S)-tBu-bis(oxazo-line) to give 2-616 with excellent enantioselectivity (97-98% ee) [320b,c]. The use of 5 A molecular sieves turned out to be obligatory. Wada and coworkers also reported on a related transetherification/l,3-dipolar cycloaddition procedure to give access to trans-fused bicyclic y-lactones [321]. 

Addition of halocarbons to alkenes in the presence of transition metals is a well-known radical reaction. Weinreb etal. have now reported an intramolecular version leading to cyclic esters or bicyclic lactones. Typical substrates are the a,a-dichloro ester 1 or the a,a-dichloro acid 2, readily available by reaction of ethyl lithiodi-chloroacetate with 5-bromo-l-pentene. When 1 is heated in benzene at 160° with a metal catalyst, mixtures of epimeric ot,w-dichloro esters 3 and 4 are obtained. The ratio and yields of 3 and 4 are dependent on the catalyst and concentration of 1, but 3 and 4 are the major products formed in the presence of Ru(II) and Fe(II) catalysts. In contrast cyclization of 2 under the same conditions gives the bicyclic y-lactone 5 in high yield. 

Bicyclic y-lactones,7 These lactones can be obtained by intramolecular reductive cyclization of unsaturated keto esters with Sml2 in THF-HMPT. Example ... 

These add to aldehydes providing the homoaldol products 351 with high stereoselectivity following the expected stereochemical course, as could be elucidated by several X-ray crystal structure analyses under anomalous dispersion (equation 93). It is currently unknown why the yields are relatively low (21-35%), since we could not detect side products besides traces of starting material. The corresponding lithium-TMEDA complexes, after titanation, deliver good yields (71-79%). The homoaldol products are easily converted to enantioenriched bicyclic y-lactones of type 352 °. 

The first report of a successful a-alkylation of a lactone enolate was the high yielding conversion of the bicyclic y-lactone 1 into the stereoselectively methylated derivative 21. 

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and <5-lactones, respectively (equations 137 and 138)198 205. The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of E-alkenes in bicyclic y-lactone formation198. Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enandoselectivity in intramolecular cyclopropanation (equation 139)194. On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations201. In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140)206. 

Trani-fused bicyclic y-lactones (7) have been conveniently prepared, in a one-pot process, from conjugated nitroalkenes, by way of the expected transesterihcation-intramolecular hetero Diels-Alder (HAD) reaction, followed by the transformation of a functional group using ( )-l-ethoxy-2-nitroethylene (5) and prim-, sec-, and tert-y,e-unsaturated alcohols (6) having two methyl substituents at the terminal position as illustrated in Figure 2.2 (Wada and Yoshinaga, 2003). 

Several triflates and metal salt hydrates were tested as Lewis acid catalysts (each 10 mol%) and the best results were obtained using Yb(OTf or Ni(C104)2-6H20. The stereoselective formation of bicyclic y-lactones (7) could be obtained from bicyclic nitronate (9) via the hydrolytic process by the action of a strong acid generated from Lewis acid with a small amount of water in both nitroalkene (5) and the Lewis acid. This new methodology of one-pot reaction also involves a new type of intramolecular HAD reaction of nitroalkenes as heterodienes, which provides stereochemically defined bicyclic nitronates. 

Wada, E. and Yoshinaga, M. 2003. A new methodology of intramolecular hetero-Diels-Alder reaction with (3-alkoxy-snbstituted conjugated nitroalkenes as heterodienes Stereoselective one-pot synthesis of tra -fused bicyclic y-lactones. Tetrahedron letters, 44(43) 7953-6. 

Lactonization. Lactonization of -y-hydroxy acids to rrans-fused bicyclic y-lactones generally requires acidic conditions or DCC. Cyclization of hydroxy acids of structure 2 is difficult because of dehydration, but is effected in >95% yield by treatment with excess I and NfCaHs), in refluxing CHjClj. 

Polycyclic y-lactones. An intramolecular v. .rsion of the formation of y-lactones by reaction of an alkene with acetic acid and mangane, e(lll) acetate (1) (6, 355-356) provides a general route to polycyclic y-lactones. Thus th unsaturated -keto acid 2 cyclizes to the r/.v-bicyclic y-lactone 3 when warmed in acei c acid with 1 (1.3 cquiv.) ... 

As noted for simple /1-lactones, these bicyclic compounds can also be converted into the thermodynamically more stable y-isomers, with the ring expansion representing a useful access to derivatized bicyclic y-lactones. 

The low yield in this reaction might be caused by a number of reasons. First, the overall reaction is only rapid for readily enolizable compounds. 1,3-Dicarbonyl compounds will therefore be a better choice as compared to acetic acid. Second, to prevent oxidation of radical 54, it is advantageous to work with excess diene and therefore speed up trapping of 54 through diene addition. Finally, lactone 55 can, as an enolizable compound itself, also be oxidized by manganese(III) acetate and form various oxidation products. Shorter reaction time and the use of understoichiometric amounts of oxidant might therefore benefit the overall result. All these factors have been taken into account in the synthesis of bicyclic y-lactone 56, which has been obtained from cyanoacetic acid and 1,3-cyclohexadiene in 78% yield within 15 min reaction time (equation 25) . ... 

Investigations by J. Oh showed that the cycloaddition of dichloroketene to glucal followed by Baeyer-Villiger oxidation afforded a bicyclic y-lactone, an a-D-C-glucoside, which was further transformed to a C1-methyl glucitol derivative. ... 

Cyclic a -nucleofuge-a,)S-unsaturated ketones 35 (X = Cl, Br, OMs) similarly condensed with dimethyl sodiomalonate but the yields of cyclopropanols were poorer (14-20%). The cyclopropanols 36 were obtained as mixtures of diastereomers, which were accompanied by bicyclic y-lactones 37 in 15-22% yield. ° ... 

A remarkable observation is the cyclization of biscarbamate (194) to y-lactone (195) mediated by methanesulfonic acid (equation 133). No trace of the expected 8-lactone is formed, presumably because of the unfavorable ester geometry in the transition state required for six-membered ring formation. Such problems with 8-lactone formation have been observed also in Diels-Alder chemistry. A nice example related to A-acyliminium chemistry is the thermal hetero Diels-Alder reaction of acylimine precursor (196) to bicyclic -y-lactone (197) in good yield. The corresponding intramolecular cycloaddition of (198) fails. Finally, Lewis acid mediated cyclization of allylsilane (199) is unsuccessful, although lactonization of (200) proceeds very well (equation 135, cf. equation 119). ... 

This type of stereoselection has been exploited in the construction of intermediates for alka-loid48,49 and prostaglandin50 syntheses. Thus, the (Z)- and ( )-olefins 16 selectively provided bicyclic y-lactones which were transformed into ( + )-hastenecine and ( + )-dihydroxyheliotri-dane, respectively48. 

Independently, Fukuzawa and co-workers [39] reported intramolecular reactions leading to bicyclic y-lactones from keto or aldo a, 3-unsaturated esters (Scheme 9). The reaction was mediated by Sml2 in the presence of HMPA (THF/HMPA=10/1) but the beneficial effect of HMPA was less obvious in that case. 

Bicyclic y-lactones 14 are readily prepared by treatment of 2-cycloalkcn-1,4-diols 13 with triethyl orthoacetate406. For a similar reaction sequence used in the synthesis of optically active compound 14 starting from mm>-diols see ref 407. 

Carboxylic ester 194b was converted to the bicyclic y-lactone 197 [Eq. (51)]... 

The synthesis of verrucarol (454) started with the a-methylated bicyclic y-lactone 437, which was synthesized in 23 steps from commercially available diacetone glucose 435 (328, 329) (Scheme 8.10). 

Bicyclic y-lactones have been prepared from cycloalk-2-ene-l,4-diols using ethyl orthoacetate and acid, e.g. lactone (324) was obtained from cyclohept-2-ene-l,4-diol (83%). The enolate anion (325) cyclizes by Cl" displacement to give the corresponding benzofuran. Epoxyalcohol (326) dehydrates when treated with BFj-... 

Unsaturated alicyclic alcohols also give lactones. The reaction of (3-cyclohexenyl)methanol leads not to the expected bicyclic 8-lactone but to the isomeric bicyclic y-lactone, probably again by isomerization of an intermediate cobalt complex. 

Intramolecular radical cyclization was reported by Burton et al. [67]. The reaction of 4-pentenylmalonates with Mn(OAc)3, which is well used as a one-electron oxidant, gave bicyclic y-lactones. For example, the reactions of 98 gave the corresponding lactone 99 in 88% yield (Scheme 44). 

Paddon-Jones GC, McErlean CSP, Hayes P, Moore CJ, Konig WA, Kitching W. Synthesis and stereochemistry of some bicyclic y-lactones from parasitic wasps (Hymenop-tera Braconidae). Utility of hydrolytic kinetic resolution of epoxides and palladium(II)-catalyzed hydroxycycliza-tion-carbonylation-lactonization of ene-diols. J. Org. Chem. 2001 66 7487-7495. 

Cyclization of sensitive /rans-y-hydroxy acids to give strained mons-bicyclic y-lactones of the type (5) is often problematic due to dehydration of the tertiary alcohol. A study showed (1) to be the reagent of choice for this transformation (eq 4). Other reagents, such as 1,3-DicyclohexylcarbodumidelPyridine OT2,2 -Dipyri l Disulfide/Triphenylphosphine, give far lower yields. 

To introduce the methyl group at C-1, the chiral monoester 197 was treated with LDA and methyl iodide to afford die methylated monoester 198. In a separate experiment, the chiral monc ster 197 was transformed to the terr-butyl monc ster and was reacted with LDA and Mel in the same manner as for 197 to obtain the methylated product 201. The conversion of these monoesters 198 and W1 to the bicyclic y-lactone derivatives was examined. Reaction of the monoester 198 with LiBHj and methanol resulted in the reduction of the methoxycaibonyl group, and the subsequent treatment of the crude hydroxy acid with p-toluenesulfonic acid (TsOH) afforded the y-lactone 199. On the other hand, reduction of the carboxyl group of 198 and acid treatment of the hydroxy ester afforded the isomeric 7-lactone 200. The chiral monoester 201 was similarly converted to the enantiomeric 7-lactones 202 and 203. 

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