Alkylation with lactones

Stereoselective All lations. Ben2ene is stereoselectively alkylated with chiral 4-valerolactone in the presence of aluminum chloride with 50% net inversion of configuration (32). The stereoselectivity is explained by the coordination of the Lewis acid with the carbonyl oxygen of the lactone, resulting in the typ displacement at the C—O bond. Partial racemi2ation of the substrate (incomplete inversion of configuration) results by internal... 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Therefore, taking into account the potentialities of such lactones as carbohydrate delivery synthons (vide infra), several routes leading to carboxymethyl glycosides (and thus subsequently to the lactones) were investigated, in order to get as many structural variations as possible for widening the scope of their use in synthesis. In addition to the isomaltulose oxidation method (route a), the oxidation of allyl glycosides (route b), and the anomeric alkylation with tert-butylbromoacetate (route c) were studied (Scheme 11). These three methods are detailed in the following sections. 

The a-acetylenic alcohols were used in a synthesis of optically active 4-alkyl- y-lactones (80) (90), as shown in Scheme 11. Lactones with optical purity >... 

The allylic alkylation products represent useful synthons, as exemplified by the reaction sequence outlined in Scheme 10.4. For example, reductive ozonolysis of the allylic alkylation product 15 afforded the y-lactone 16 as a single diastereoisomer. Sequential alkylation with methyl iodide, and reductive alkylation using lithium naphthalenide with allyl iodide furnished the ternary-quaternary substituted y-lactones 17a/17b in 72% overall yield, as a 10 1 mixture of diastereomers favoring 17a [18]. This method provides a versatile approach to the construction of a variety of a-quaternary-/9-ternary stereogenic centers. 

As will be seen in the following section the most widespread use of the alkylation of lactones is that of y-lactones. Clearly the need for a-substitution of y-lactones was present before the advent of Creger s non-nucleophilic base. The most versatile method was the reaction of a-substitutcd malonic or acetoacetic esters with epoxyethane or 2-chloroethanol, followed by hydrolysis and decarboxylation or ketonic cleavage5. Another common approach was the condensation of butyrolactones (y-lactones) with aldehydes and subsequent hydrogenation5,s. It should be mentioned at this point that these older methods still have their merits, especially for large scale production. 

The e-lactone 1 was alkylated with 100% diastereoselectivity to form 271 giving an example of 1,4-induction. 

The enolates of l,3-dioxolan-4-ones 1 and l,3-oxathiolan-4-ones2, which are y-lactones substituted with a heteroatom, can be prepared using normal conditions (LDA, THF) and subsequently alkylated. If one takes, e.g.. a nonracemic a-hydroxy acid such as lactic acid 3, then on formation of the heterocycles 1 (R1 = CH3 R2 = alkyl) chirality is transferred from the a-po-sition (C-5) in the starting acid to C-2 in 1, forming (2R,5R)-4 and (2S,5R)-5. If 4 and 5 are easily separable or, even better, if one of them is formed diastereoselectively from 3 then 4 and/or 5 can be transformed to the respective enolates 6 and 7 and alkylated with R X. 

Each desired enantiomer of 3-substituted dihydro-2(3.//)-furanones and 3-substituted tetrahydro-2//-pyran-2-ones was prepared starting either from 4,5-dihydro-2-(m-trimethylsilyloxy)oxazoles and alkylating with the corresponding alkyl halide, or by reversing the order of alkyl group introduction. Upon hydrolysis with dilute hydrochloric or sulfuric acid, 2-substituted cyclic lactones were obtained in 40-75% overall yield and 60-86% enantiomeric excess20. 

Thionolactones.1 Lactones can be converted into thionolactones by O-alkylation with Meerwein s salt followed by reaction with sodium hydrosulfide in acetonitrile. Hydroxy thionoesters are usually formed as by-products. 

Chiral oxazolines have been used in the chiral-selective assembly of carboxylic acids and lactones. The chiral oxazoline (407) was prepared using a commercially available chiral aminodiol. Metallation at -78 °C gave a lithiooxazoline which was alkylated with a variety of alkyl halides to afford on acid hydrolysis a-alkylalkanoic acids (409) of the (S)-configuration (72-82% e.e.). The methoxyamino alcohol released during the hydrolysis could be recycled to produce again the chiral oxazoline (Scheme 91) (79PAC1255). 

A new synthesis of ( )-menthofuran (155) has been described which involves a three-step reaction sequence from the cyclohexanone (152) via direct C-alkylation with ethyl 2-iodopropionate to give (153) (Scheme 35). Hydrolysis of the diester (153) with hydrochloric acid afforded 3,6-dimethyl-2,4,5,6,7,7a-hexahydrobenzofuran-2-one (154). The final step in the sequence was the conversion of the a,/3-unsaturated y-lactone ring into the furan ring by reduction with lithium aluminum hydride and 2-propanol to afford (i)-menthofuran (155) in satisfactory yield (80JOC1517). 

Kleinman and co-workers 20 synthesized a lactone precursor to the (2/ ,46, 56 )- -hydroxy-ethylene dipeptide stereoselectively in four steps using the lithium salt of ethyl propiolate as a homoenolate equivalent. As summarized in Scheme 11, addition of ethyl lithiopropiolate to a protected a-amino aldehyde affords hydroxy acetylenic esters as a mixture of dia-stereomers. Reduction of the acetylene group and subsequent lactonization gives a readily separable (4S)-lactone-enriched mixture. Direct alkylation with alkyl halide and lithium hexamethyldisilanazide yields the tram-lactone as the major stereoisomer. 

Resonance, similar to that in pyrylium salts, was shown594,595 to exist between oxonium ion (299a) and carbenium ion (299b) forms in alkylated ketones, esters, and lactones that were obtained via alkylation with trimethyl- or triethyloxonium tetra-fluoroborates596 [Eq. (3.78)]. Ramsey and Taft597 used H NMR spectroscopy to investigate the nature of a series of secondary and tertiary carboxonium ions (300-302). 

Phenolic methyl ethers were usually prepared by treatment of the alkaloid with dimethyl sulfate and sodium hydroxide or with diazomethane 17). In the first case a side reaction was N-methylation or even cleavage of the lactone (3). In decodine (6) the C-17 OH group was methylated on treatment with ethereal diazomethane. The hindered C-21 OH group was alkylated with methanolic CH2N2 (77). 

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. 

As lactones can be alkylated with powerful alkylating agents, it is possible to study the addition of nucleophiles to dioxocarbonium ions directly. The attack of nucleophiles on conformationally restricted dioxocarbonium ion... 

Finally, acetylide anions have been alkylated with propargyl halides to give excellent yields of dialkynes643,644. Similar reactions have been used in the synthesis of a wide variety of natural products including lactones and macrolides645,646 and leukotrienes647-651. With many halides, reaction with acetylide anions is not useful however, due to elimination side-reactions caused by the significant basicity of the carbanion. 

If the p-lactone has a substituent already then there may be a choice as to which face of the enolate is attacked by an electrophile. Simple alkylation with a variety of alkyl halides gives essentially only one diastereoisomer of the product. 

The end result is that the larger of the two groups is on the inside There are other ways to do this too. If we alkylate the enolate of a bicyclic lactone, the alkyl group (black) goes on the outside as expected. But wha t will happen if we repeat the alkylation with a different alkyl group The new enolate will be flat and the stereochemistry at the enolate carbon will be lost. When the new alkyl halide comes in, it will approach from the outside (green) and push the alkyl group already there into the inside. 

Enediamine 93 undergoes an easy C-alkylation with a,/ -unsaturated ketones under comparable conditions and no cyclocondensation products are observed36. Similar C-alkylations with other electrophilic olefins such as unsaturated lactones, propenonitrile, vinyl sulfoxide, sulfone and phenylphosphonium bromide have been achieved36. All the adducts 135 exist predominantly as the imine form (see Section II.A). Treatment with organometallic reagents transforms the C-alkylated products into... 

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