Chelated ester enolate

The lithium enolates of a-alkoxy esters exhibit high stereoselectivity, which is consistent with involvement of a chelated enolate.374 39 The chelated ester enolate is approached by the aldehyde in such a manner that the aldehyde R group avoids being between the a-alkoxy and methyl groups in the ester enolate. A syn product is favored for most ester groups, but this shifts to anti with extremely bulky groups. 

The lithium enolates of a-alkoxy esters have been extensively explored, and several cases in which high stereoselectivity is observed have been documented.14 This stereoselectivity can be explained in terms of a chelated ester enolate which is approached by the... 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

The chelated ester enolate Claisen rearrangement of allylic glycinates 9 is carried out with zinc(II) chloride, which is added to the enolate at — 78 C (Table 19). The rearrangement occurs as the reaction mixture is allowed to warm to room temperature over 1 hour. The 2-amino-3,3-difluoro-4-[(2-methoxyethoxy)methoxy] alk-4-enoic acids 10 arc converted directly into the corresponding methyl esters, which can be hydrolyzed to the methyl 2-amino-3,3-difluoro-4-oxoal-kanoates. 

Table 19. Synthesis of 2-Amino-3,3-difluoro-4-[(2-methoxyethoxy)meth-oxy]alk-4-cnoic Acids 10 by the Chelated Ester Enolate Claisen Rearrangement of Allylic Glycinates 943...

The six amino acids 63 were prepared individually, and mixed to give acids M-64 (see Scheme 13.15) [51]. Esterification of M-64, zinc-chelated ester enolate Claisen rearrangement of M-65, tert-butyl esterification, and removal of the Me3Si group yielded M-66. The alkynyl allenes M-67 were obtained by Af-propargylation. The allenic Pauson-Khand reaction of M-67 afforded three products (/ )-alkylidenecyclopentenone... 

Recently, the enolate method has emerged as a widely and frequently employed method in the synthesis for reasons like the easy access to the starting materials, simplicity and mildness of the experimental procedures, accurate predictability of the stereochemistry of the products and good to excellent realization of the stereoselection. This method can be further sub-divided into sub-topics like the simple enolate method [11], the Ireland silyl ketene acetal method, the chelated ester enolate method, imidate method, and the N,0- and N,S-acetal method. The present discussion will be restricted to simple enolate method as the remaining sub-topics are covered separately in this book. 

Like a-aUcoxy substituted allylic esters, the a-amido substituted analogues are also able to form chelated ester enolates such as 122 (Fig. 5.2.3). 

Because of the good results obtained with acyclic substrates, the chelate ester enolate rearrangement was also applied by Kazmaier et al. [80] to the rearrangement of cycloalkenyl glycinates 144 (Scheme 5.2.45). The influence of the ring size as well as the metal salt used for chelation of the ester enolate was investigated and the results are listed in Table 5.2.16. The crude amino acids, obtained by... 

Exceptions can only be observed if steric interactions either between the substituents in the allyl substrate [14] or between the allyl moiety and the ligands [15] destabilize the syn,syn-complex. However, selective palladiumotalyzed conversions of (Z)-allyl substrates with retention of the alkene geometry is not a trivial issue. A transfer of the (Z)-configuration from the allyl substrate to the product would only be possible, if the reaction could be carried out at low temperatures (below —60 °C) at which isomerization reactions do not yet take place. This can only be achieved with highly reactive nucleophiles such as chelated ester enolates, but not with the generally used stabilized soft C-nucleophiles [16]. 

Scheme 12.15 Regio- and stereoselective allylic alkylation of a chelated ester enolate [16].

Scheme 12.50 Allylic alkylation of chelated ester enolates [117].

Scheme 2.44 Chelate-controlled Claisen rearrangement of zinc ester enolates 136. Cbz = benzyloxycarbonyl Boc = tert-butoxycarbonyl.

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

As with other ester enolate rearrangements, the presence of chiral ligands can render the reaction enantioselective. Use of quinine or quinidine with the chelating metal leads to enantioselectivity (see entry 21 in Scheme 6.12). 

The stereoselectivity of ester enolate Claisen rearrangements can also be controlled by specific intramolecular interactions.168 169 The enolates of a-alkoxy esters give the Z-silyl derivatives because of chelation by the alkoxy substituent. 

When the lithium dianion was prepared in a completely different manner, viz from an a,j -epoxy ester 8 by treatment of the latter with lithium in liquid ammonia and tetrahydrofuran at - 78 C, alkylation experiments (CH3I, — 40 °C) gave the expected a-alkyl- -hydroxy ester 10, but in a ratio of only 4 1 in favor of the anti-isomer and not in the usual 19 1 ratio15. This result could be interpreted as a direct consequence of the participation of an intermolecularly chelated dianionic enolate such as 7 which gains importance because of the use of ammonia as a cosolvent. 

Thus, the methanolysis of the lactone 35 by MeONa or (MeO)2Mg produces initially the triketoester 36, which is subsequently deacylated in situ to give after hydrolysis the diketone ester 38. The yield of 38 is considerably better with (MeO)2Mg, as the result of the formation in the reaction medium of a chelated bis-enolate 37 which protects 38 from degradation. Extensive degradation is observed with the sodium enolate analogue of 37 which is unstable in these conditions (equation 56). ... 

Asymmetric hydraxylation of lithium enolates of esters and amides.2 Hydroxylation of typical enolates of esters with ( + )- and (-)-l is effected in 75-90% yield and with 55-85% ee. The reaction with amide enolates with ( + )- and ( — )-l results in the opposite configuration to that obtained with ester enolates and with less enantioselectivity. Steric factors appear to predominate over metal chelation. 

Sn-chelated glycine ester enolates have been proved efficient nucleophiles for highly stereoselective 1,4-additions toward nitroalkenes.37 In the presence of acyl halides the tin also acts as a reducing agent of the nitronate intermediates, giving direct access to nitriles in a one-pot protocol. 

Tin(II)- and zinc(II)-chelated glycine ester enolates have been found to act as efficient nucleophiles for highly diastereoselective 1,4-additions toward nitroalkenes, such as PhC H(Me)=CHN02 (<99% ds) or RCH=CHN02.195 196... 

An aromatic Claisen rearrangement has been used as a key step in a total synthesis of racemic heliannuols C and E.18 A formal synthesis of (-)-perhydrohistrionicotoxin has used Claisen rearrangement of an amino acid ester enolate as the key step, in which almost total chirality transfer was observed from (S, )-oct-3-en-2-ol in the sense predicted by a chair-shaped transition state with chelation control of enolate geometry.19 Treatment of 1-(cyclohex-l-enyl)-6-methoxy-2-propargylindanol derivatives with base... 

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