Lactones dehydrative cyclization

Viridifloric /3-lactone, 143, has been identified as one of the pheromone components of a complex mixture of volatiles released by the pheromone glands of the male Idea leuconoe butterfly during courtship <1996BMC341>. A racemic mixture of both diastereoisomers was synthesized in four steps from the dilithio salt of 3-methylbutyric acid 144 alkylation with ethanal, dehydration of the secondary alcohol with phosphorus pentoxide, dihydroxylation of the C-C double bond with osmium tetraoxide, and finally formation of the /3-lactone by cyclization with sulfonyl chloride. By comparison with the sample isolated from I. leuconoe, the absolute configuration was established to be (2V,3V)-2-hydroxy-2-(l-methylethyl)-3-butanolide 143. 

The role of acid-catalyzed reactions in bicyclo[3.3.0]octane synthesis has also been a major one. It is now well established that 6-lactones (e. g., 14)41 and certain 7-lactones (7J)42) undergo dehydrative cyclization when heated with polyphosphoric... 

In a related process, Dixon and co-woricers reported a cascade process with the same chiral phosphoric acid in the reaction between tryptamine 134 and enol lactone 133 (Scheme 1.33) [43]. In this reaction, it is postulated that the primary amine of the tryptamine ring-opens the lactone which is then followed by chiral Brpnsted acid catalyzed dehydrative cyclization to give an N-acyliminium ion intermediate 136. Presumably as with the other reactions of this class described above, there is an association between the conjugate base of the chiral acid and the acyl iminium species, allowing the subsequent cyclization onto the indole to be asymmetrically controlled and generate enanliopure product 137. 

Adam and his co-workers have shown that sterically congested E-olefins are conveniently prepared by the lactone route shown in Scheme 7. Stereocontrol is achieved because a-lithiocarboxylates condense with aldehydes and ketones to give -hydroxy acids of predominantly r/ireo-configuration once formed, dehydrative cyclization is straightforward because the bulky substituents force the carboxy and hydroxy groups into juxtaposition. 

Scheme 10.8 Biosynthesis of epothilone. Individual PKS domains are represented as circles and individual NRPS domains as hexagons. Acyl carrier proteins (ACPs) and thiola-tion domains (T) are posttranslationally modified by a phos-phopantetheinyl group to which the biosynthetic intermediates are covalently bound throughout the chain assembly. The thioesterase domain (TE) cyclizes the fully assembled carbon chain to give the 16-membered lactone. Following dehydration of Cl 2—Cl 3 to give epothilones C and D, the final step in epothilone biosynthesis is the epoxidation of the C12=C13 double bond by the cytochrome P450 enzyme P450epol<. KS ketosyn-thase KS(Y) active-site tyrosine mutant of KS AT acyltransfer-ase C condensation domain A adenylation domain ...

Cyclic tetrafluoro ethers are also the main or sole products of the sulfur tctrafluoridc fluorination of phthalic and pyromellitic acids, or their anhydrides, possessing two bulky ortho substituents (e.g., CF3. N02, Br. Cl or even Me). These substituents create steric crowding which pushes two neighboring carboxylic acid groups towards each other and forces cyclization acid anhydrides and difluoro lactones are the intermediates and they may be isolated from reactions carried out under sufficiently mild conditions. Thus, reaction of 3,6-bis(trifluoromcthyl)bcn-zcnc-1,2-dicarboxylic acid (4) with sulfur tctrafluoridc at ambient temperature results in dehydration to give exclusively the corresponding cyclic anhydride 5 at 60"C a mixture of the anhydride 5, 3,6-bis(trifluoromethyl)phthaloyI difluoride (6) and 3,3-difluoro-4,7-bis(trifluoro-methyl)isobenzofuran-l(3//)-one (7) is obtained, but at 200"C the final product, 1,1,3,3-tct-rafluoro-4,7-bis(trifluoromethyl)-l,3-dihydroisobenzofuran (8), is formed as the sole product.137... 

Esters formed from lactobionic acid are not stable. However, lactobionic acid may be cyclized by dehydration to form a lactone which is reactive with amines to form stable amides (Scholnick and Pfeffer 1980). An extensive examination of the characteristics of nitrogenous derivatives such as N-dodecyl-lactobionamide or 1,6-dilactobionamido hexane was conducted, but no antimicrobial activity or other special use for these derivatives was identified. 

Hydroxyalkanoic acids are easily dehydrated to either spiro or fused /3-lactones. Sulfonyl chlorides have been the traditional reagents employed for this transformation <1996S586, 2001CC753>. However, as illustrated in Equation (38) for a cyclization used as part of a synthesis of lactacystin/omuralide (see also Section 2.06.12.4), bis(oxazolidi-none) phosphinyl chloride (BOP-C1) has proven an effective agent for application in sensitive structures note also the selectivity for introduction of the fused (vs. spiro) lactone <2006JOC1220>. 

An improved synthesis of the Cn-terpenic lactone Dihydroactinidiolide was described by A.K. Bose et al. [35]. The synthesis started from a commercially available aldehyde that was subjected to treatment with m-CPBA and a catalytic amount of PTSA (Scheme 10). The intermediate epoxy acid underwent cyclization resulting in the formation of Aeginetolide. Dehydration has been reported earlier by heating of this compound with aqueous NaOH, at 60 °C for 24 h, or with SOCI2 and pyridine at room temperature for 5 h. The authors observed expeditious and convenient dehydration of this compound supported on silica gel, under microwave irradiation for 5 -10 min (domestic oven), yielding Dihydroactinidiolide in 80% yield. 

Fig (20) Bromide (172), prepared from alcohol (171) on alkylation yields (173) which is converted to (174) without any difficulty. Conversion of (174) to homoallylic bromide (175) is accomplished by the method of Julia. On alkylation followed by cyclization generated the tricyclic alcohol which undergoes dehydration to yield unsaturated ester (177) which is converted to unsaturated lactone (146) by epoxidation and elimination. 

While the condensation of enamine 37 with methyl OY7 s-2-butenoate, followed by acid hydrolysis and sodium borohydride reduction affords lactone 38 with reasonable efficiency, the cyclodehydrative ring contraction of this intermediate with PPA gives a mixture of bicyclo[3.3.0]octenones in abysmal (< 5 %) yield.66 To circumvent this difficulty and enable the large scale production of 39,2-carbo-methoxy-4,4-dimethylcyclohexanone was initially transformed to tram diacid 40 under Favoiskii conditions (Scheme 14). Conversion to the diacid chloride and condensation with lithium dimethylcuprate resulted in formation of the diacetyl derivative. In basic solution, the latter is reported to experience epimerization and aldol cyclization with dehydration in 82 % yield. With hydrogen and palladium on charcoal, the essentially quantitative production of 39 was achieved.66 ... 

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. 

Multisubstituted five-membered aromatic heterocycles are synthesized via this cascade protocol (equation 34). The cycloadditions of a-acyloxyketones 78a with lithium ynolates afford /3-lactone lithium enolates 79a, which spontaneously cyclize to give bicyclic compounds 80a. These intermediates, which are stable enough to be isolated, are treated with TsOH under heating to provide substituted furans 81a via decarboxylation and dehydration. Thiophenes (e.g. 81b) are also synthesized by the analogous scheme via intermediate 80b using a-acylthioketones (78b) as a substrate. In the synthesis of pyrroles using a-acylaminoketones as a substrate, the cyclization proceeded at —20 °C, and the -lactone was subsequently ring-opened via /3-elimination to furnish pyrroles in one-pot (equation 35). ... 

Noteworthy among these conversions are the first successful cyclizations of lactone and furan secolactaranes to the corresponding lactarane sesquiterpenes, which were obtained by a Me2AlCl catalysed ene reaction (60). Under these conditions lactaral (19.1) yielded directly the diene 18.1, identical with the dehydration product of furosardonin A (18.8), while smooth cyclization of aldehyde 14.3 gave the lactone 11.8 in which the protons H-8 and H-9 have the "unnatural" cis stereochemistry. This result could be anticipated by examination of the Dreiding models of the two possible transition states 11.8 A and 11.8 B, which showed that unfavourable steric interactions developing between the C-3 methyl group and the bulky >C=0-—AI J complex are minimized in the... 

Construction of the suitably substituted geranic acid for making the furan ring has been effected too. For example, Poulter et al. have prepared the substituted geranate 865 by reaction of 4-methyl-3-pentenylcopper with the acetylenic ester 866. The ester 865 then underwent cyclization in the presence of acid to the lactone 867, related to scobinolide (161), and the action of acid on the lactol produced from 867 with diisobutylaluminum hydride gave perillene (849). The lactone 867 has also been prepared by a slightly different method the C9 alcohol 868 was made (in poor yield) from isobutenol and prenyl chloride with butyllithium. The extra carbon atom was introduced by the action of sodium cyanide on the epoxide of 868, and hydrolysis of the cyano group followed by dehydration yielded the lactone 867. The dimethylthioacetal of 867 has been used to synthesize perillene (849). This thioacetal was made from the suitably substituted ketene thioacetal 869 and dimethylsulfonium methylide. Thus the ketene thioacetal 870 (readily prepared from acetone, carbon disulfide, and sodium amylate, followed by methylation °) can be prenylated with lithium... 

If R has between five and seven methylene groups then there will be intramolecular dehydration, leading to lactones that will compete with polyesterification. This is an example of the cyclization reaction that competes with linear polymerization and is discussed in Section 1.2.2 ... 

Formation of Pyrazoles from Bis(hydrazones).—Mesoxaldehyde bis(phenylhydrazone) (193), obtained by periodate oxidation of saccharide osazones (192) is readily cyclized in the presence of acids to give l-phenyl-4-phenylazo-pyrazole (195).162 365 Hexulose phenylosazones (192) are also disproportionaled in the presence of acidic salts of carbonyl reagents, such as hydroxylamine hydrochloride, to give l-phenyl-4-phenylazo-pyrazolin-5-one (196). The reaction probably proceeds via mesoxalic acid 1,2-bis(phenylhydrazone) (194).365 The hydroxalkyl derivatives of 196 are produced from dehydroascorbic acid bis(phenylhydrazone) by treatment with base to open the lactone ring and permit the conversion of 197 to 199.351,366 Another type of pyrazole that is formed by dehydrating osazones with acetic anhydride is discussed later under anhydroosazones (see Schemes 45,53). 

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