Enol lactones synthesis

Alper and Yu in 2007 developed the palladium-catalyzed highly substituted endocyclic enol lactone synthesis via the carbonylation of terminal alkyne and 1,3-diketones in an ionic hquid system (Table 15.21) [29]. Thirteen examples have been isolated under this process. It should be noted that this catalytic system can be recycled five times with only modest loss of its catalytic activity. 

Dimethyldioxirane DMDO discovered by Murray and coworkers, is a superior choice for the epoxidation of most olefins, giving comparable or higher yields than m-CPBA-based epoxidation [21]. Proceeding rapidly under neutral and mild conditions, it is especially well suited for the synthesis of sensitive epoxides of enol esters, enol lactones [22], and enol ethers [23]. The reaction is stereospecific, gen-... 

In this chapter the proposed (5) division of secophthalideisoquinolines into the four subgroups and the nomenclature have been preserved. Since the publication of the most recent review (5), information about the synthesis of the missing ( )-narceine enol lactone (102) (87), the isolation of ( )-fumaramine (112) from Fumaria vailanti (88), and the discovery of a new seco alkaloid, coryrutine (118), from Corydalis rutifolia (89) has appeared. In the former plant fumaramine (111) (55) and in the latter N-methylhydrasteine... 

Secophthalideisoquinoline enol lactones of type 128 were used by Klotzer et al. (95,103-105) for the synthesis of benzazepine system 129 which was further transformed to alkaloids of rhoeadine type. 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

Scheme 14.12 Diastereoselective synthesis of ketoester from an enol lactone.

The procedure that Kuhn and Baschang99 had reported for the synthesis of NeuAc was extended by Hershberger and Binkley100 to a synthesis of KDO, as follows. Condensation of di-ter -butyl oxalacetate (85 see Scheme 25) with D-arabinose gave the epimeric mixture of lactone esters, 86 and 87, which was separated by fractional recrystallization. When 86 was heated in aqueous solution, the enol lactone, 88, was produced from 87, an enol lactone diastereomeric with 88 was obtained under these conditions. Compound 88 was converted into ammonium KDO by treatment with aqueous ammonia. 

Halo-lactonization of ketophosphoranes has been achieved via reaction with cyclic anhydrides and subsequent halogenation. " The products, halo enol lactones (75), are synthetically useful compounds, and an alternative synthesis via incorporation of the halogen at the ylid stage is also described. Mechanistic investigation of the Wittig reactions involved reveals subtle variations in pathway, allowing optimum experimental conditions to be selected to allow for the variation in reactivity of different anhydrides and halides. 

Under the same conditions, pent-4-ynoic acids 412 afford y-methylenefuranones 413 in excellent yields (Scheme 120).340 342 Whereas the reaction proceeds rather slowly in the absence of an additional alcohol group (R1 = H), substrates bearing a hydroxy function are smoothly cyclized within a few minutes. The first total synthesis of the naturally occurring m-2-hexadecyl-3-hydroxy-4-methylenefuranone was achieved in four steps with an overall yield of 64% by this procedure. The corresponding 3-ynoic acids 414 are cleanly converted into the labile enol lactones 415 in the presence of 0.2 equiv. of AgN03.329... 

In recent work Coates, Mason and Shah have successfully achieved the synthesis of gymnomitrol (29Ja).280) Since intramolecular aldol condensation of the aldehyde obtained by hydrolysis of 291 (Scheme 45) was unfavorable, conversion to enol lactone 292 was effected. Dibal-H reduction of 292 resulted directly in aldoli-zation of the intermediate lactol, oxidation of which afforded 293. The latter was converted successfully to keto alcohol 294 by capitalizing on the different steric environments about the carbonyl groups. Sequential dehydration and hydride reduction of 294 gave a 45 55 mixture of exo and endocyclic isomers 295a and295 b which were separated by TLC. 

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

Enol lactonization. The last step in a synthesis of ( )-cyanobacterin (2), an antibiotic isolated from a cyanobacterium, is the enol lactonization of the y,8-acetylenic carboxylic acid 1. Cyclization catalyzed by AgNO, results in the desired exocyclic y-... 

Aldol cyclization. Although the keto aldehyde 1 is resistant to aldol cyclization under normal, alkaline conditions, this reaction can be accomplished by a method originally developed by Raphael et Reduction of the enol lactone (2), derived from 1, with DIBAH produces a bridged ketol, which is oxidized to 3 with chromic add. This diketone was employed as an intermediate in a synthesis of the sesquiterpene gymnomitrol (4). 

A facile synthesis of enol lactones was achieved by a process dependent upon successful rDA decomposition. The tricyclic ( >enol lactones (61) thermally decomposed to the corresponding ( )-enol lactones (62) in excellent yield as shown in equation (33). Tricyclic ( )-enol lactones (61) could be photoisomerized to the corresponding (Z)-enol lactones, which were also thermally cleaved to the (Z)-enol lactones (62). 

Enol lactones have been used to construct cyclopentenones [341], which have been used to prepare mannostatin A [342]. More recently, a related strategy was applied to the synthesis of trehazolin analogs [343]. 

J.A. Katzenellenbogen et al. developed an efficient method for the synthesis of alkyl-substituted enol lactones that are potent inhibitors of the serine protease elastase. The precursors for the enol lactones were a- and 3-alkyl-substituted 5-hexynoic acids, which were prepared by the bromoform reaction of the corresponding alkynoic methyl... 

Dai, W., Katzenellenbogen, J. A. New approaches to the synthesis of alkyl-substituted enol lactone systems, inhibitors of the serine protease elastase. J. Org. Chem. 1993, 58, 1900-1908. 

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