A, jS-unsaturated esters

J-unsaturated ester is formed from a terminal alkyne by the reaction of alkyl formate and oxalate. The linear a, /J-unsaturated ester 5 is obtained from the terminal alkyne using dppb as a ligand by the reaction of alkyl formate under CO pressure. On the other hand, a branehed ester, t-butyl atropate (6), is obtained exclusively by the carbonylation of phenylacetylene in t-BuOH even by using dppb[10]. Reaction of alkynes and oxalate under CO pressure also gives linear a, /J-unsaturated esters 7 and dialkynes. The use of dppb is essen-tial[l 1]. Carbonylation of 1-octyne in the presence of oxalic acid or formic acid using PhiP-dppb (2 I) and Pd on carbon affords the branched q, /J-unsatu-rated acid 8 as the main product. Formic acid is regarded as a source of H and OH in the carboxylic acids[l2]. 

The anions derived from racemic alkyl and benzyl tert-butyl sulfoxides undergo 1,4-addition to a,/J-unsaturated esters to give adducts with high product diastereoselection (>5 1)10,11. Alkyl 4-methylphenyl sulfoxides were found to be less diastereoselective. In the case of 2-methyl-2-(methylsulfinyl)propanc the highly hindered 2,6-di-rer7-butyl-4-methylphenyl ester was required to prevent a competing acylation reaction. 

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

A mixture of the a/J-unsaturated ester (14mmol), t-butyldimethylsilane (18 mmol) and tris(triphenylphosphine)rhodium(i) chloride (0.56 mmol) was placed in a pre-heated (100°C) oil bath, and the course of reaction monitored by i.r. spectroscopy. On completion (ca. 30 min) the product was isolated by direct distillation (60-88%). 

Reaction of a-phenylsulfinyl 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 / -hydroxycarboxylates 130167, jS-keto esters 131168, a,/J-unsaturated esters 133169 and other derivatives by this method. 

Photolysis of alkoxycarbene complexes in the presence of stabilized ylides produced allenes having a donating group at one terminus and an accepting group at the other. These were highly reactive and rearranged to 1,3-dienes under mildly acidic conditions and hydrolyzed to y-keto-a,/J-unsaturated esters (Eq.31) [117]. 

A different task was pursued by the CM of CsA with various maleates 339 [ 148]. The CM demanded in this case the highly active Hoveyda catalyst D, that exhibits potency not reached by the phosphine-containing catalysts C and E. Under the conditions given in Scheme 65, metathesis with maleates 339 led (E)-selectively to the a,/J-unsaturated ester derivatives 340 in high yield. Compounds 340 still demonstrated activity comparable to that of CsA and are thus potential soft drugs via esterase-mediated biotransformation to the corresponding inactive carboxylic acids 341. 

The conversion of 27 to chiral hydroxy acid 26 was envisioned to arise via a sequential reduction protocol where the ketone moiety of 27 would enantioselectively be reduced to give chiral allylic cyclopentenol 46 (Scheme 7.11). Subsequent 1,4-addition of hydride to the a,/J-unsaturated ester of 46, presumably assisted by... 

An alternative method to prepare (Mormyl esters uses different building blocks to assemble the 1,4-dicarbonyl system and is complementary in many cases.10 Base-catalyzed addition of nitromefhane to a, J-unsaturated esters, followed by a variation of the Nef reaction, provides y-dialkoxy-substituted esters. The scope of this sequence has not yet been explored. Another approach involves cuprate additions to norephedrine-derived 2-alkenyloxazolidines this process allows small-scale synthesis of several p-formyl esters in optically active form (ee up to 95%).11... 

The trialkylstannyl intermediates required in this synthetic sceme to prepare labelled compounds can be obtained in several ways. One method is the addition of the organotin hydride to the carbon-carbon triple bond of an alkyne (equation 93). These reactions have already been discussed in detail above. A second approach is to add a trialkylstan-nylvinyllithium to a ketone (equation 95), and a third method involves adding trialkylstan-nyllithium to a /J-halo, a, /J-unsaturated ester (equation 96). Although this last reaction gives a suitable trialkylstannane, these stannanes have proven to be inert in the destanny-lation reaction and, therefore, have not been used extensively to prepare radiolabelled compounds. 

The discovery of the ethylidenecarbapenems, the asparenomycins, as naturally occurring /J-lactamase inactivators in the early 1980s was another striking point in /J-lactamase inhibitor research. The substituted exomethylene function in asparenomycins is a distinctive feature of this class of compounds, which many scientists recognized could be a key factor for /J-lactamase inhibition. The exo cyclic methylene is expected to increase the acylation ability, and form an a,/J-unsaturated ester of the active site serine residue as an acyl-enzyme complex. This ester will be similar in structure to the acyl-enzymes formed from clavulanate and sulfone fragmentation, and will be quite resistant to hydrolytic deacylation. Thus, the exocyclic methylene promotes acylation by the enzyme and subsequently represses deacylation. Based on... 

A wide range of organic substrates can undergo an oxidative carbonylation reaction. Depending on reaction conditions, alkenes have been converted into -chloroalkanoyl chlorides (oxidative chloro-chlorocarbonylation) [1,2], succinic diesters (oxidative dialkoxycarbonylation) [3-20], a,/J-unsaturated esters [21,22] (oxidative monoalkoxycarbonylation), or /J-alkoxyalkanoic esters [11] (oxidative alkoxy-alkoxycarbonylation), according to Eqs. 10-13. 

Sattelkau and Eilbracht90 have exploited the Claisen rearrangement of allyl vinyl ethers in their synthesis of several spiro compounds. As shown below in equation 62, 7,9-dimethyl-l,4-dioxa-spiro[4,5]decan-8-one, 118, was converted to a ,/J-unsaturated ester 119 which was reduced to allyl alcohol 120906. Allyl vinyl ether 121 underwent a rhodium-catalyzed Claisen rearrangement to afford 7r,13r-dimethyl-l,4-dioxa-(8rC9)-dispiro[4.2.4.2]tetradecan-10-one (122) in 36% yield. 

Reactions of chiral a, J-unsaturated esters or amides 3 little is reported, however, tor the... 

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,/J-unsaturated esters (entry 5, Scheme 1.12). 

This reaction is one step in an annulation sequence that also features two Michael (5 17) steps. An a,(J-unsaturated ester is treated with a lithium enolate ... 

The reaction of the enol diethylphosphate of a p-keto ester with a primary dialkyl cuprate provides a useful stereoselective synthesis of / -alkyl-a,j -unsaturated esters (equation II).3 This coupling was used in two steps in a recent synthesis of mokupalide, a novel C30-isoprenoid.A... 

Various activated olefins can also be employed instead of organic halide for the formation of a carbon-silicon bond. Thus, cathodic reduction of a,j -unsaturated esters, nitriles... 

Deconjugation of a,fi-unsaturated esters. It has been known for some time that deprotonation and reprotonation (or alkylation) of a,/J-unsaturated esters is accompanied by migration of the double bond to the /l,y-position (thermodynamically the less stable position). The stereochemistry of the isomerization has now been elucidated by two groups.4,5 A (Z)-2-alkenoate isomerizes almost exclusively to the (E)-3-alkenoate. The (E)-2-alkenoate isomerizes to (Z)- and (E)-3-alkenoates in a ratio of ubout 85 15. Both the (E)- and (Z)-3-alkenoates are unchanged on re-exposure to this sequence. Both papers suggest possible reasons for this stereochemical outcome. 

Succinic diesters and acrylic esters are formed through insertion of the olefin into the Pd-C bond of an alkoxycarbonylpalladium species X - Pd - C02R (ensuing from the reaction between PdX2, CO and an alcohol R OH used as an external nucleophile, Scheme 3). Further carbon monoxide insertion, followed by nucleophilic displacement by R OH, then leads to the succinic diester (Scheme 3, path a). /MI elimination may also take place to give the a,/J-unsaturated ester (Scheme 3, path b). This latter pathway is followed at low carbon monoxide partial pressures. 

The initial product is a (J-hydrOxy ester, which may be dehydrated to an a./J-unsaturated ester. 

A stereoselective intramolecular Michael addition of semiacetals to a,/j-unsaturated esters and amides has been utilized in order to prepare syw-l,3-diols. Thus, the alcohol 1 reacts with benzaldehyde in the presence of potassium fer/-butoxide in tetrahydrofuran at 0 °C to give the corresponding benzylidene acetals 2 in good yield and very high diastereoselectivity155. 

Oxidation of the <5-dibenzylamino-a,/J-unsaturated esters 4, prepared in enantiomerically pure form from the corresponding amino acids, with 3-chloroperbenzoic acid gave the hydroxyl-amines 6 in 70-80% yields63. The optical purity of the a-hydroxy esters 7, obtained from 6 by reduction with H2/Pd(OH)2, was determined to be higher than 95% by the Mosher procedure. Thus, the sigmatropic rearrangement of the intermediate amine oxides 5 proceeds with essentially complete transfer of chirality. 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

The ate complex of 1, (CH3)3A1 SC6H5Li +, is necessary for aldol condensations with a,/J-unsaturated esters. 

Substrate-controlled diastereoselectivity is also apparent in the intermolecular addition of carbon-centered radicals to the double bond of chiral nonracemic a,/J-unsaturated esters derived from glyceraldehyde acetonide28, Different levels of selectivity arc observed starting from the (Z)- or the ( )-isomer. respectively,... 

Cerfontain and van Noort have reported a photosynthesis of 4-oxo-alkanoic acids and esters (90). The reaction is achieved by the benzophenone-sensitized addition of aldehydes (91) to a,j -unsaturated esters (92). The yields obtained from... 

Mention should also be made of the addition of tervalent phosphorus compounds to alkynylphosphonic and to (alka-l,2-dienyl)phosphonic derivatives [in which addition occurs across the C(i)—C(2) bond]. The main product is of type 521 (X = Ph, OR or NR2), but is normally accompanied by smaller amounts of the isomers 522. Although this process is formally of a [3 + 2] format, a P NMR study of the kinetics suggests that the addition is not a synchronous addition but rather occurs in a stepwise manner . On the other hand, the phosphorylated Schiff base 523 undergoes regioselective and stereospecific reaction with a,j -unsaturated esters which, a kinetic study has shown, appears to be concerted. ... 

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