A ,/3-Unsaturated esters

The Asymmetric Diels-Alder Reaction of a,/ -Unsaturated Esters as Dienophiles... 

Hydrogenation of the a-unsaturated ester 32 was accompanied by extensive hydrogenolysis and NMR spectroscopy revealed that only 45% of a 3-deoxyhexose tetraacetate was present in the products and only one... 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

In order to overcome the special problems posed by brevetoxin B s tetrahydropyran systems, the decision was made to develop and test regio- and stereoselective ring closures employing two types of substrates hydroxy epoxides and hydroxy a,/ -unsaturated esters. The basic concepts of these reactions are shown in Schemes 1 and 2, respectively. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

It will be recalled that one of the key operations in the synthesis of IJK ring system 86 is the intramolecular conjugate addition reaction (see 90—>89, Scheme 17b) to form ring J. In the context of compound 90, the electrophilic a,/ -unsaturated ester moiety and the potentially nucleophilic tertiary hydroxyl group reside in proximal regions of space, a circumstance that would seem to favor the desired cyclization evept (see Scheme 19). Indeed, exposure of a solution of 90 in THFto sodium hydride (1 equiv.) for one hour at 25 °C results in the formation of compound 89 in 92% yield. In... 

Saponification of the a,/ -unsaturated ester 59, prepared by a Reforma tsky reaction on 8-chloro-5-methyl-5//-dibenz[/>,/]azepin-10(ll//)-one, is accompanied by migration of the exocyclic C —C double bond to form the 5W-dibenz[/>,/]azepine 60.72... 

Although the methodology described so far produces <5-oxo esters via diastereoselective enolate additions to enones, the same product may be obtained via an alternate sequence, i.e., addition of ketone or aldehyde enolates to a,j3-unsaturated esters or amides. Enolates of ketones are known to react with a,/ -unsaturated esters to give the Michael adducts50, however, the study of simple diastcrcoselectivity has, so far, been limited to special cases (MIMIRC reactions, Section 1.5.2.4.4.). 

Closely related to enolate additions to enones is the diastereoselective 1,4-addition of lithium enolates of esters, thioesters and amides to a,/ -unsaturated esters. These reactions provide syn-or ar /-2,3-disubstituted glutarates (pentanedioates). 

The addition of a-amino-substituted lithium enolates to a,/ -unsaturated esters is a diastereoselective route to syn- or anti-glutamic acid derivatives and also to fratw-substituted 5-oxo-2-pyrrolidinecarboxylates. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

A related stereoselective route to glutamic acid derivatives consists of the addition of the nickel complex 5 to various activated olefins, i.e., 2-propenonitrile, 2-propenal and a,/ -unsaturated esters. 

Under thermodynamically controlled conditions, using triethylamine as base for the addition of enones to 5 and sodium methoxide in methanol as base for the addition of a,/ -unsaturated esters, the diastereomeric ratios of 6 range from 95 5 to 97 3. The excellent diasteroselectivities are retained in the Michael addition of 5 to -substituted enones and esters, however, modest synjami selectivities are found212,213. 

Optically active bicyclo[2.2,2]octanes can be obtained via diastercoselective MIMIRC reaction of lithium dienolates and a,/ -unsaturated esters of various chiral alcohols. Good yields (70-90%), high endo selectivities (> 95%) and diastereomeric ratios that depend on the auxiliary alcohol are found in these additions. The highest diastereomeric ratio reached was 18 82 using a camphor derived sulfonamide. The diastereomeric ratio could be improved (up to 9 91) by titanium(IV) chloride catalyzed addition of the corresponding silylenolates with the chiral a,/J-unsaturated esters358. 

The a,a -dianions of a-ketomethyl sulphoxides 476 react with esters exclusively at the a -position547 (equation 287). With a,/(-unsaturated esters these anions afford substituted 3-oxothian-l-oxides 477 the products of annelation548 (equation 288). 

Reaction of a-sulphinyl carboxylic esters 421 with carbonyl compounds has usually been performed using a Grignard reagent as a base. No condensation products are obtained using f-butyllithium or sodium hydride - (equation 251). The condensation products formed are convenient starting materials for the synthesis of a, ) -unsaturated esters and j -ketones . ... 

Reaction of a-phenylsulfmyl acetate or ethyl a-(t-butylsulfmyl)acetate with one equivalent of ethylmagnesium bromide or iodide was shown to give the corresponding Grignard reagent 129 or 132, which upon reaction with carbonyl compounds afforded the corresponding adducts. Thus Nokami and coworkers prepared ethyl )3-hydroxycarboxylates 130 , jJ-keto esters 131 , a,/ -unsaturated esters 133 and other derivatives by this method. 

Because in this case an elimination reaction could occur to form an a,/ -unsaturated ester, use of two equivalents of the phosphorane should be avoided.1The (a-acylalk-ylidene)triphenylphosphorane can be subjected to a subsequent Wittig reaction with an aldehyde.[4] [5],[8]... 

The vinylcyclopropane 144, bearing two electron-withdrawing groups, undergoes the intermolecular palladium-catalyzed [3 + 2]cycloaddition reaction of the Jt-allylpalladium intermediate 145 with a,/ -unsaturated esters or ketones to provide a useful method for forming the cyclopentane ring of 146 [74], (Scheme 51)... 

Methoxytetralin, substituted naphthalene reduction to tetralin, 132-133 Methyl-2-(phenylcarbamoyl)butanoate, a,-unsaturated ester hydrocarbamoylation, 134 4-Methylbenzyl chloride [reductive... 

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