Lactones enolate Claisen rearrangement

As the ester enolate Claisen rearrangement allows for a stoichiometric combination of alcohol and acid components, it has been used for the formation of strategically important C—C bonds by esteriflcation or lactonization and subsequent rearrangement, such as is elegantly demonstrated in the synthesis of the antibiotic chlorothricolide (Scheme 24)." Radical decomposition of the selenoester of (132) leads to... 

Interesting possibilities arise when unsaturated lactones are employed in the enolate-Claisen rearrangement either ring enlargements or ring contractions can be promoted (Scheme 66). 

The ester enolate Claisen rearrangement of (Z)-crotyl /V-tm-Boc-glycinate has been applied to the synthesis of lactone hydrochloride 4, the hydrolysis product of the amanita mushroom toxins a- and / -amanitin487. The rearrangement and the iodolactonization of the A -phthaloyl derivative are the stereocontrolling steps in this reaction sequence. 

In the synthesis of the right half" of lasalocid A, the furanoid equivalent 3 is prepared from a -D-glucosaccharino-l,4-lactone. The x-butyryl side chain in 2 is attached by enolate Claisen rearrangement of the glycalyl butanoate derived from 1. Only a moderate stereocontrol of the x-ethyl group is achieved by control of the EjZ ratio of the enolates formed prior to... 

Still and Schneider have described" a total synthesis of ( )-frullanolide (82) in which the lactone ring is constructed by an enolate Claisen rearrangement of the type developed by Ireland s group, followed by iodolactonization, viz. (83) - (84). 

A one-carbon ring expansion of y-lactone (37) was used in a synthesis of the intermediate (38) required for mevinic acid syntheses. An ester enolate Claisen rearrangement of the glucose-derived bis(enol ether) (39) gave product (40). used for the synthesis of (+)-streptolic acid (41).4i... 

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

The C(9)—C(16) subunit was synthesized from the same starting material. The chain was extended by a boron enolate addition to 2-methylpropenal (Step D-2). After introduction of a double bond by selenoxide elimination in Step E-4, a Claisen rearrangement was used to generate an eight-membered lactone ring (Step E-6). 

Dehydrobromination of bromotrifluoropropene affords the more expensive trifluoropropyne [237], which was metallated in situ and trapped with an aldehyde in the TIT group s [238]synthesis of 2,6-dideoxy-6,6,6-trifluorosugars (Eq. 77). Allylic alcohols derived from adducts of this type have been transformed into trifluoromethyl lactones via [3,3] -Claisen rearrangements and subsequent iodolactonisation [239]. Relatively weak bases such as hydroxide anion can be used to perform the dehydrobromination and when the alkyne is generated in the presence of nucleophilic species, addition usually follows. Trifluoromethyl enol ethers were prepared (stereoselectively) in this way (Eq. 78) the key intermediate is presumably a transient vinyl carbanion which protonates before defluorination can occur [240]. Palladium(II)-catalysed alkenylation or aryla-tion then proceeds [241]. 

The Claisen rearrangement of lactonic enolates provides a new route to cycloalkenes. Cyclocitral was converted to the lactone (642) through a multistep sequence, the lactone deprotonated with LDA in THF at -78 °C, and the enolate quenched with f-butyldimethyl-chlorosilane (80JA6889, 6891). The crude ketene acetal (643) was heated at 110 °C for 10 h, and the product treated with fluoride ion to afford a single acid. Replacement of the quaternary carboxyl group by hydroxyl was accomplished through use of the carboxy inversion reaction (Scheme 147). The product (645) of this last reaction was identical with an authentic sample of widdrol in all respects excluding its optical rotation. 

Taking advantage of the likewise mild conditions of the Ireland version of the Claisen rearrangement, easily accessible ester or lactone bonds may be transformed via their enolates into C—C bonds. In the case of cyclic systems, the ring size may be varied by the position of the double bonds. Recently Funk et al. made use of this often applied principle for the synthesis of tricycle 76 (shown in Scheme 18) (76). 

In a series of elegant studies, Paquette and coworkers demonstrated the potential of the Claisen rearrangement for the stereocontrolled total synthesis of natural products. Dehydrative coupling of (2)-3-(trimethylsilyl)-2-propen-l-ol with cyclohexanone (51) under Kuwajima s conditions, followed by rearrangement of enol ether (52) in decalin, led in excellent stereoselectivity (>99 1) to aldehyde (53 Scheme 8). Concise construction of the eight-membered core of acetoxycrenulidine was achieved by intramolecular phenylseleno etherification of lactone (54), introduction of the exocyclic vinyl ether double bond by selenoxide elimination and subsequent Claisen rearrangement (Scheme 9, 66% from 54). ... 

The enantioselective total synthesis of the cyclooctanoid natural product (+)-epoxydictymene was accomplished in the laboratory of L.A. Paquette. The entire tricyclic framework was constructed by the application of a Claisen rerrangement via a chairlike transition state. The precursor for this / 3,37-sigmatropic rearrangement was obtained by treating a lactone precursor with the solution of the Tebbe reagent in the presence of pyridine. The corresponding enol ether was formed in almost quantitative yield, and immediately after isolation it was treated with triisobutylaluminum to effect the Claisen rearrangement. 

An ingenious synthesis of widdrol (167) has been developed98 in which a key step is the Claisen rearrangement of the vinyl lactone enolate (165) to give the acid (166) (Scheme 20). This process proceeds via a boat-like transition state thus controlling the relative stereochemistries of the two quaternary methyl groups at C-4 and C-7. 

Branched radicals can be introduced at C3 by Claisen rearrangement of enol ethers. This has been used to prepare 170 in one step of the synthesis of Mundulea lactone (107) (67CC577). Further examples can be found (88JOC5328). 

Snider has shown that thermolysis of 2,6-dimethyl-2,7-octadienal at 350°C yielded three compounds, 365-367, having the iridoid skeleton. The lactone 368 was made by cyclization of the corresponding hydroxy acid ( 8-hydroxy-citronellic acid ), and its tert-butyldimethylsilyl enol ether rearranged in an Ireland-type Claisen rearrangement, yielding the iridoid acid 369 after removal of the silyl group with HF in acetonitrile. The latter was converted (by hydrobora-tion-oxidation) into both isomers of dihydronepetalactone (370) (erroneously considered to be unsynthesized by the authors, who clearly did not read Vol. 4, p. 497). Iridomyrmecin (371) is also accessible from 369 (Scheme 30). 

Due to the boat geometry, dihydropyran rearrangements usually require temperatures >190°C176. In common with acyclic Claisen rearrangements using the Ireland variation, considerably lower temperatures are necessary for the rearrangement of lactonic silyl enolates... 

Ketene acetals obtained from unsaturated lactone enolates on mild thermolysis undergo the Claisen rearrangement leading to c/5-2-alkenylcycloalkanecarboxylic acids <82JA4030>. Starting from 4-hexenolides, substituted 2-cyclopropanecarboxylic acids, in particular, (—)-c/5-chrysanthemic acid... 

Takano et al. used the Ireland-Claisen rearrangement of an allyl lactate in the total synthesis of calcitriol lactone (Scheme 4.76) [74]. The rearrangement proceeded with a 6.7 1 diastereoselectivity via O-silylation of the intermediate li-che-lated Z-enolate. Takano noted that the corresponding benzyl ether gave significantly lower de (70%) than the PMB ether. This is presumably due to the PMB ether s greater Lewis basicity and hence its greater propensity to coordinate a lithium cation. 

Functionalized six- or seven-membered cycloalkenes with defined stereochemistry can be prepared by the Claisen rearrangement of silyl ethers of vinyl lactone enolates e.g. Scheme 32). " The stereochemical outcome of... 

Danishefsky and his collaborators have shown that Claisen rearrangement of lactonic silyl enolates provides an excellent route to functionalized cycloalkenes [(76) (77)]. This methodology has been applied to a total synthesis of... 

This method has been applied independently to the synthesis of steroid intermediates. A route to the carbocyclic acids (36), involving a Claisen rearrangement of silyl enolates obtained from the lactones (35), has been reported by which yields of between 70 and 96% were obtained for eight examples (Scheme... 

Ireland and co-workers, in their synthesis of the prostanoid skeleton, have described the use of the ester enolate modification of the aliphatic Claisen rearrangement to produce the cyclopentane ring C-8—C-12 bond, viz. (74) ->(75). Conversion of the silyl ester (75) into the lactone (76), with a trace of acid, followed by reduction with DIBAL and aldol cyclization, then led to the prostanoid (77) (Scheme 20). 

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