Lactone annelation

Lactone annelatlon. Enolates of 1,3-dicarbonyl compounds undergo 1,6-Michael addition to 1 subsequent cyclization results in lactone annelation (equation... 

Epoxy-5,5-dimethylcyclohexanone allowed to react 2 hrs. at 25 with 1.25 equivalents cyclopropyldiphenylsulfonium fluoroborate and 2 equivalents KOH in dimethyl sulfoxide -> diepoxide (Y 96%) dissolved in pentane and washed with aq. 1 M fluoroboric acid epoxycyclobutanone deriv. (Y ca. 100%) (startg. m. f. 101). - This sequence can be used as part of an annelation process complimentary to the normal Robinson method. F. e., rearrangement also with oxalic acid, s. B. M. Trost and M. J. Bogdanowicz, Am. Soc. 94, Mil (1972) lactone annelation cf. Tetrah. Let. 1973, 923 Am. Soc. 95, 5321 (1973) replacement of carbonyl oxygen by 2 functionalized carbon substituents cf. Am. Soc. 95, 2038, 7862 (1973). 

A further report has appeared on the use of j8-vinyl-butenolide in lactone annelation by condensation with jS-keto-esters, in this case 2-ethoxycarbonyl-cyclohexanones. Although yields of the desired products (58) are only moderate, the method clearly has considerable potential. 

Camptothecin, the potent antitumor and antileukemic agent isolated from the stem wood of the Chinese tree Camptotheca acuminata Nyssaceae, has been the target of numerous chemical syntheses. The first successful synthesis of this unusual alkaloid, characterized by an a-hydroxy-lactone and a pyridone system fused to a five-membered ring, was reported by Stork and Schultz in 1971. A key feature of this synthesis is construction of ring E by a novel lactone annelation involving addition-cyclization of the carbonate of an 0 -hydroxy ester to the tetracyclic Q ,/3-unsaturated lactam (B). 

Content and composition of essential oils from Nepeta L. species, most of them containing diastereomeric nepetalactones, unsaturated 8-lactones with annelated cyclopentane ring 98KPS84. 

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

Four-component annelation to alkenolides. Posner et al. have reported a one-pot three-step annelation of cycloalkenones to provide, after oxidation, four-atom enlarged macrolides. Thus Michael addition of tributyltinlithium to cyclo-hexenone (1) and Michael addition of the resulting enolate to ethyl vinyl ketone followed by an aldol reaction results in cyclization to a bicyclic hemiketal (2), which is oxidized by Pb(OAc)4 to an unsaturated 10-membered lactone (3). 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

When /3-vinylbutenolide (158), prepared from /3-vinylbutyrolactone by a sulfenylation-sulfoxide elimination process, was reacted with the anion of a-methylcyclohexane-1,3-dione, two products (159) and (160) were produced in an 11 1 ratio (47% combined yield) (75CC337). Dehydration of these compounds with thionyl chloride in pyridine yielded (161) and (162), respectively (Scheme 35). The annelation products are useful intermediates for sesquiterpene lactone construction. 

I.actone annelation. A new lactone synthesis from an allylic alcohol such as 1 involves a Cluiscn rearrangement (4, 234 235) followed by an intramolecular Michael addition, as formulated in equation (I). 

This novel annelation not only provides a route to chiral lactones, but was applied to a synthesis of a diol (8) from the acetal 7 as a precursor to (- )-lardolure (9). 

A fascinating synthesis of the twelve-membered lactone 5(E),8(Z)-6-methyl-5,8-undecadien-ll-olide (VIII/60) is shown in Scheme VIII/11. The tricyclic system VIII/58 and its isomer, VIII/59, starting materials for this reaction, were built up from three annelated six-membered rings. When both compounds were heated to their melting points, 180° and 220°, respectively, the evolution of car-bondioxide and the formation of p-toluenesulfonic acid was observed [33]. In... 

An alternative procedure, starting with the enamine VIII/168, gave the twelve-membered oxolactone VIII/171 via VIII/169 and VIII/170 in a yield of 4% (from VIII/168, Scheme VIII/31), [97]. Syntheses of macrocyclic lactones with an annelated aromatic ring are described by various authors. Oxidations of compounds of type VIII/172 have been investigated in order to prepare aromatic oxolactones of type VIII/173, [99], Scheme VIII/3210). 

Scheme VIII/32. Synthesis of macrocyclic lactones with an annelated aromatic ring by ring enlargement [100] [101].

Trimethylsiloxy cyanohydrins (9) derived from an a,3-unsaturatied aldehyde form ambident anions (9a) on deprotonation. The latter can react with electrophiles at the a-position as an acyl anion equivalent (at -78 C) or at the -y-position as a homoenolate equivalent (at 0 C). The lithium salt of (9) reacts exclusively at the a-position with aldehydes and ketones. The initial kinetic product (10) formed at -78 C undergoes an intramolecular 1,4-silyl rearrangement at higher temperature to give (11). Thus the initial kinetic product is trapped and only products resulting from a-attack are observed (see Scheme 11). The a-hydroxyenones (12), -y-lactones (13) and a-trimethylsiloxyenones (11) formed are useful precursors to cyclopentenones and the overall reaction sequence constitutes a three-carbon annelation procedure. 

The Stork-Dolfini synthesis of the amino ketone 458 requires some 11 steps clearly, this is an area for improvement. One method used has been that of methyl vinyl ketone annelation (237). This procedure had been used previously in a synthesis of mesembrine (238) involving 2- -rolines. Stevens hoped to extend this technique to endocyclic enamines to give compounds in the octahydroquinolone series. 3-Ethylpiperid-2-one (549) was prepared from the y-lactone 550 according to standard procedures (239). N-Benzylation followed by reduction with diisobutyl-aluminum hydride (DIBAL) gave enamine 473. Addition of the enamine to methyl vinyl ketone (551) gave an almost quantitative yield of a hydroquinoline 552, which could be readily debenzylated to the known amino ketone 458. As with the Stork method of synthesis, this route to the Aspidosperma nucleus is efficient for the parent compounds but appears to lack the potential for diversification required to synthesize the more complex alkaloids such as vindoline (101) or even tabersonine (28). 

Schreiber et al. have been able to apply their enediyne intramolecular Diels-Alder approach to the synthesis of dynemicin model systems [268-270], culminating in the total synthesis of di- and tri-O-methyl dynemicin A methyl esters 388 and 389 (Scheme 7-78) [271], derivatives of the natural product itself. Highlights of this synthetic approach include (a) intramolecular lactonization and concomitant Diels-Alder cyclization (380- 381) (b) allylic hydroxylation followed by an allylic diazene rearrangement in order to regiospecifically isomerize a double bond (381 - 382) (c) a-hydroxylation of the lactone 381 and subsequent conversion to the P-ketoester 383 (d) annelation of the anthraquinone unit (383- 384- 385- 386) (e) mild base-induced P-elimination of the N-protecting group of 386 to give the free amine 387 and (f) a final oxidation to complete the anthraquinone (387 - 388). 

Much of the work carried out with carbohydrates is an extension of the strategies initiated in the earlier period. The use of chiral fragments derived from D-glucose, a-D-isosaccharino-l,4-lactone and D-glucosaccharinolactone, continues in the synthesis of enantiopure AB building blocks as well as for annelation to leucoquinizarine, resulting in an anthracyclinone tetracycUc moiety with defined ring A stereochemistry. 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

The annelation of phenols with 2,3-epoxycycloalkanones via a Lewis acid-promoted intramolecular acylation-rearrangement of a lactone intermediate, e.g. (184), has been shown to give tricyclic benzofurans, e.g. (183), in excellent yields (Scheme 38). The methyl-substituted furan double bond in (183) is effectively a masked ketone carbonyl that is easily liberated by ozonolysis, producing the diketone (182). 

The stereogenic centers were then introduced by palladium-catalyzed dynamic kinetic asymmetric transformatitHi. ITierefore, 41 was coupled with lactone 42 in the presence of chiral ligand (RJt)-43 and gave 44 in 89% yield. The synthesis of 42 is shown below in Scheme 2.6. Compound 44 was subjected to an intramolecular Heck reaction followed by acidic cleavage of the ester function 45). The intramolecular Heck reaction only produced one diastereomer, because the c/s-annelated rings are favored. Scandium(lll)-mediated cyclizatitMi and reduction of the lactone with DIB ALII yielded (-)-aflatoxin Baa (46). It was acetoxylated and then pyiolyzed to give (-)-aflatoxin Bi (1) in 1.6% overall yield and nine linear steps from catechol (40). 

Other annellated tetrahydropyranes have been prepared by a hydroformylation-allylboration-hydroformylation sequence (Scheme 5.84) [76]. By treatment of an allyl amine derivative with syngas, a cascade reaction was initiated consisting of hydroformylation and hemiacetal formation, followed by a second hydroformylation-hemiacetal formation step. The product was converted via Ley-Griffith oxidation into the corresponding lactone. 

Among the bicyciic y-lactones having an annelated cyclohexane ring, compounds of the general formula (62) constitute outstanding aroma... 

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