Enolates acyclic

The coupling reaction between lithium dimethylcuprate and acyclic enol phosphates must be carried out between -47 and -98 C for stereoselective formation of g-methyl-a,g-unsaturated esters. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The addition of sulphinyl chlorides to trimethylsilyl enol ether 138 affording a-ketosulphoxides 139 (equation 76) represents an extension of the reaction of sulphinyl chlorides with ketones. This reaction has attracted attention only recently. Sergeev and coworkers192 reported that treatment of sulphinyl chlorides with acyclic enol ethers afforded a-ketosulphoxides 139 in good to excellent yields. Meanwell and Johnson193 observed that in the case of cyclic enol ethers the corresponding sulphoxides were formed only in very low yields. They found, however, that the introduction of an equivalent amount of a Lewis acid into the reaction mixture markedly promotes the desired reaction, whereas the use of catalytic amounts of a Lewis acid led to a substantial reduction in the yield. This is most probably due to the formation of a complex, between the a-ketosulphoxide and the Lewis acid. 

These examples illustrate the issues that must be considered in analyzing the stereoselectivity of enolate alkylation. The major factors are the conformation of the enolate, the stereoelectronic requirement for an approximately perpendicular trajectory, the steric preference for the least hindered path of approach, and minimization of torsional strain. In cyclic systems the ring geometry and positioning of substituents are often the dominant factors. For acyclic enolates, the conformation and the degree of steric discrimination govern the stereoselectivity. 

The described approach to this pharmaceutically important class of compounds [324] was also utilized by Bonnet-Delpon and coworkers one year later [325]. Interestingly, these authors employed hexafluoroisopropanol (HFIP) as solvent and were able to perform the domino process without adding any extra Lewis acid catalyst such as InCl3 due to the acidic properties of HFIP (pKa = 9.3) [326]. Besides di-hydrofuran or dihydropyran, they have also used acyclic enol ethers. 

An alternative approach involves a two-step procedure, in which carbonyl olefination, using the Tebbe reagent 93, generates an acyclic enol ether-olefin (Scheme 16). In this case, subsequent RCM using molybdenum alkylidene 1 proceeds to give cyclic enol ethers. An efficient, one-pot carbonyl olefination-RCM approach has been developed by Nicolaou et al. for the formation of cyclic enol... 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

While Rh-DuPhos mediated asymmetric hydrogenation of acyclic enol esters shows high levels of enantioselectivity, it does not provide the same high... 

Cyclic enol ethers are reductively cleaved to produce a,to-diols using a stoichiometric amount of benzyltriethylammonium borohydride and chlorotrimethylsilane [30] acyclic enol ethers give saturated alcohols. 

The chemistry of chiral 1,3-dithiane 1-oxides, in particular their use as chiral auxiliaries, has been reviewed <19980PP145>. Some further developments in this field are the stereoselective a-alkylation with alkyl halides <1997T13149> or a-hydrazination with di-fert-butyl azodicarboxylate (DBAD) <2000T9683>. The carbonyl group of 2-acyl-l,3-dithiane 1-oxides was also used as an electrophile (Scheme 82). Interestingly, acyclic enolates react with these substrates to give a 95 5 mixture of anti- and ry -adduct, whereas cyclic enolates produce a mixture of anti- and ry -adduct in 8 92 ratio <2000JOC6027>. 

The acyclic, enolic compounds 7 and 9 may exist in either cis or trans forms. Methyl ethers of 7 have been isolated in the cis form,8 but it is not known whether the trans forms, which must be acyclic, exist. The relative proportion of isomers is controlled by the geometry of the parent sugar enediol. Although the acyclic forms are readily interconvertible tautomers, it appears that, in acidic medium, further reaction occurs much more rapidly than any equilibrating reactions. Compound 7 undergoes rapid elimination of a second hydroxyl group to give 11. This acyclic product, also, may exist as either a cis or a trans isomer, both forms of which have been isolated.8 The loss of a third molecule of water per molecule occurs after, or simultaneously with, the cyclization of 11 (see Section II, 3 p. 171), and results in formation of 5-(hydroxymethyl)-2-furaldehyde (5). 

As expected, enol triflates also couple under these conditions (Scheme 28). Thus, Furstner and coworkers have recently shown that various cyclic and acyclic enol triflates can be used successfully. 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

Moreover, fermentation of various a-substituted cycloalkanone enol esters results in optically active six-, eight-, ten-, and twelve-membered ring ketones with 70-96% ee (84). Isolated enzymes catalyze similar transformations. Bacillus coagubns and Candida cyBndmceahpase OF (Meito Sangyo) hydrolyze a number of cyclic and acyclic enol esters, giving ketones in 40—80% yield and 14—85% ee (85,86). 

The yields from aldehyde alkylidenation is somewhat lower due to the reductive dimerization of aldehydes with low-valent Ti. Alkylidenation of esters is possible by the reaction of 1,1 -dibromoalkane. TiCU and Zn in the presence of TMEDA to give (Z) vinyl ethers [60], Cyclic vinyl ethers are prepared from unsaturated esters in two steps. The first step is formation of the acyclic enol ethers using a stoichiometric amount of the Ti reagent, and the second step is ring-closing alkene metathesis catalysed by Mo complex 19. Thus the benzofiiran moiety of sophora compound I (199, R = H) was synthesized by the carbonyl alkenation of ester in 197 with the Ti reagent prepared in situ, and the subsequent catalytic RCM of the resulting enol ether 198 catalysed by 19 [61]. 

The regioselectivity of the Paterno-Biichi reaction with acyclic enol ethers is substantially higher than with the corresponding unsymmetrically alkyl-substituted olefins. This effect was used for the synthesis of a variety of 3-alkoxyoxetanes and a series of derivatives [55]. The diastereoisomeric cis-and tnms-l-methoxy-l-butenes were used as substrates for the investigation of the spin state influence on reactivity, regio- and stereoselectivity [56]. The use of trimethylsilyloxyethene 62 as electron rich alkene is advantageous and several 1,3-anhydroapiitol derivatives such as 63 could be synthesized via photocycloaddition with l,3-diacetoxy-2-propanone 61 (Sch. 17) [57]. 

Photoinduced [2+2] cycloaddition (the Paterno-Buchi reaction) of 1-acetylisatin with acyclic enol ethers afford the spiro(3f/-indole-3,2 -oxetane)s 43 with moderate regio- and diastereoselectivity via the mi triplet state of the isatin derivative without involvement of single electron transfer <02JCS(P1)345>. 

ACRYLIC ACID, 2-(BROMOMETHYL)-, METHYL ESTER [4224-69-5], 61, 77 Acyclic enol phosphates, 62, 19... 

For the first example, we chose to acylate olefin alcohol la. This was readily accomplished using acetic anhydride and 4-DMAP in pyridine to provide ester 17. Methylenation, using Takai s (10) protocol, yielded the acyclic enol ether 18 which was subsequently cyclized with 15 mol % of the Schrock catalyst 6 in hot toluene to afford the glycal 19 in good yield. Hydroboration and oxidative work-up led to the methyl-C-glycoside 20 (Scheme 4). With this proof of principle in hand, we then set out to prepare a number of additional examples as shown in Table 1 (11). 

Entry Ester/Acyclic Enol Ether Glycal, (% Yield)3, b... 

The reaction was carried out in a few different ways as summarized below in Table 5. We found that material was being lost at the methylenation stage and that purification of the acyclic enol ether was causing a drop in the overall yield. If no purification was carried out until after the hydroboration step, then good overall yields (over 3 steps) of product could be obtained (Table 5) 18). To obtain reproducible yields, each of the individual reactions had to be pushed to completion. 

The acyclic enol ether was purified by flash chromatography. The product glycal was not isolated, but rather the one-pot protocol was employed. cYield is over two steps. dThe acyclic enol ether was not purified by flash chromatography, but the crude reaction mixture filtered through a pad of basic alumina. The glycal was not isolated, but carried on crude to the next step. Yield is over three steps. 

For the E(O) enolate, the stereoselection is best understood in terms of stereoelectronic effect. The most stable conformation of the 2,3-allylic bond of an acyclic enolate corresponds to the smallest substituent eclipsing the double bond whatever the geometry of the enolate (A1,3 strain)459. Then, in the transition state, the maximum overlap of the better ally lie a-donor and the n -orbital of the enolate directs the antiperiplanar attack of the electrophile (Scheme 95). 

Cyclic and acyclic enol derivatives 480 can be asymmetrically aziridinated with (A -tosylimino)iodobenzene 481 using a chiral copper catalyst prepared in situ from [Cu(MeCN)4]PF6 and the optically active ligand 479. Collapse of the aminal (i.e., 482) leads to the formation of enantiomerically enriched Q-amino carbonyl compounds 483, although ee s to date are modest <2000EJ0557>. Similarly, dienes can be selectively aziridinated using the chiral Mn-salen complex 484 to give vinyl aziridines 486 in scalemic form (Scheme 124) <2000TL7089>. 

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