Auxiliaries, chiral with conjugated esters

The first report of an enantioselective photocycloaddition of prochiral conjugated esters involved the introduction of (+ )-2,3-di-0-methyl-erythritol as chiral auxiliary in a diastereoselective and intramolecular photocycloaddition of the bis cinnamate 78 (Scheme 18). Among the isolated isomers, the chiral 8-truxinate (+ )-79 could be obtained as the major product with a de up to 86% [59] (Scheme 18). 

Sakai and co-workers [38] studied the additions to conjugate esters protected with a cyclic diol as a chiral auxiliary. The ester is protected with enantiomerically pure ( R2R) rrfl/js-cyclohexane diol (see Table 4, entry 7). Addition of phenyl Grignard reagent, catalyzed by Cul, produced a moderate yield (50%) of a mixture of the two diastereomers (prochiral carbon R/5 = 78% 22%) with a d.e. of 55%. In contrast, the authors also reported that addition of the phenyl lithium cuprate gave 94 6 ratio with the major product having the S-configuration for the prochiral carbon. Because of the differences in the structures of the complexes, attack from the lithium cuprate comes from the Re-face, whereas attack from the copper-Grignard comes from the Si-face. 

Several conjugate addition reactions have been used for the synthesis of amino acids, as seen in chapter three. It is easy to prepare conjugated esters and using chiral auxiliary or a chiral template, conjugate addition can lead to amino acids with high diastereoselectivity and enantioselectivity. 

Chiral /3,/3-diaryIpropionic acid moieties are often found in compounds showing biological activities, such as antiarrhythmics vasodilators antidepressives " , antihistamines and controllers of cerebral insufficiency ". In the course of synthetic studies of chiral -diaryIpropionic acid derivatives, Merck researchers developed stereoselective conjugate addition of aryllithium reagents to the a,/ -unsaturated fert-butyl esters 18 bearing a chiral imidazolidine or oxazolidine auxiliary at the ortho position of an aryl group. The addition furnished chiral -diaryIpropionic acid derivatives 19 with... 

Using these optimized conditions, the conjugate addition of 45 to the malonates 49 in the presence of the solid base provided access to the Michael adducts in good yields and high diastereoselectivities. The removal of the chiral TADDOL auxiliary could be accomplished without epimerization or racemization in this case, too. After esterification of the very polar acid intermediates with diazomethane the corresponding dimethyl esters 52 were obtained with yields of 72-94% and enantiomeric excesses ee of 84-94% (Scheme 1.1.13). 

Asymmetric Michael additions The anions of hydrazones (2), obtained from 1 and methyl ketones, undergo conjugate addition to a,p-unsaturated esters with virtually complete 1,6-asymmetric induction to give the adducts (S,R)-3. Ozonolysis converts these products into P-substituted 8-keto esters, (R)-4, obtained in optical yields of 96-l(X)%, with recovery of the chiral auxiliary as the nitrosamine (S)-5. The overall chemical yields of 4 are 45-62%. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

The following transformations demonstrate the characteristie feature of titanium alk-oxide-catalyzed transesterification. The isolated double bond does not enter into conjugation with the active methylene moiety (Eq. 218) [515]. Removal of a sterically demanding chiral auxiliary was possible without affecting the ketoester moiety (Eq. 219) [516,517]. Preparation of an allyl ester was achieved in good yield with retention of the nitrone moiety essential for subsequent cycloaddition (Eq. 220) [518]. 

Using a chiral auxiliary via an amide or ester leads to asymmetric induction. Aryl aldehydes and conjugated ketones were condensed using proline, leading to modest enantioselectivity. °° Chiral biaryl catalysts have been used with trialkyl-phosphines, giving good enantioselectivity. ° Chiral quinuclidine catalysts lead to... 

Methyl-a-D-mannopyranoside and methyl-a-D-galactopyranoside have also been used as chiral auxiliaries for conjugate additions of organocuprates to crotonyl esters. For the galactosyl derivative, the crotonyl ester was attached to the 3-hydroxyl group of the galactopyranoside. The addition of vinyl cuprate to ester 191 proceeded with high yield and stereoselectivity (Scheme 10.63). In this case, the diastereomeric esters 192 and 193 delivered the enantiomeric benzyl esters 194 and 195 with 96% ee. 

In some examples, the stereochemistry of radical reactions was controlled by chiral carbohydrate auxiliaries. As a radical counterpart to the ionic conjugate additions discussed above, Garner et al. [169] prepared carbohydrate linked radicals that were reacted with a,P-unsaturated esters. The radical precursor, the carboxylic acid 256, generated by the addition of ( Sj-methyl lactate to tri-O-benzyl-D-glucal and subsequent ester hydrolysis, was decarboxylated by Barton s procedure (Scheme 10.84) [170]. Trapping of the chiral radical 258 with methyl acrylate furnished the saturated ester 259 in 61% yield and with high diastereoselectivity (11 1). The auxiliary caused a preferential addition to the si-facQ of radical 258, probably due to entropic effects. The ester 259 was transformed in acceptable yield to the y-butyrolactone 261 by reductive removal of the thiopyridyl group followed by acid hydrolysis. 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

If no component has stereochemistry, asymmetric conjugate addition can be ensured by a C2 symmetric chiral auxiliary attached to the enolate partner. Addition of the lithium enolate of the amide 31 to the unsaturated ester 32 gives the lithium enolate 33 with good stereochemical control at both the new centres.8... 

Limitations of this method are the poor selectivity observed with 2-cyclo-hexencne and the lack of reactivity of these enolates toward (3-alkyl-a,p-un-saturated esters [413], Conjugate addition of the sodium enolate of 530 (R = H) to a substituted nitrostyrene 7.96 is the first step of the synthesis of an antidepres-sive drug [1448], The chiral auxiliary is excised by lactam formation induced by hydrogenation of the nitro group. This leads to pyrrolidine 7.97 (Figure 7.62). 

There are many synthetic examples that use radical cyclization as a key step, and the radical precursor is not limited to iodides or bromides. In Pattenden s synthesis of pentalenene, conjugated selenyl ester 156 was treated with Bu3SnH and AIBN to give a 45% yield of tricyclic ketone 159. Loss of PhSe generated the acyl radical 157, which exists in equilibrium with the ketene radical 156. Radical cyclization via the latter intermediate leads to 159. Cyclization via aryl radicals is also possible. In Schultz s synthesis of hexahydro-phenanthren-2-one derivatives, " aryl bromide 160 was cyclized to 161 in 78% yield under standard conditions. Radical cascade reactions have become quite popular for the synthesis of polycyclic ring systems. In these reaction, polyenes are subjected to radical cyclization, generating tricyclic or even tetracyclic ring systems. 5 Chiral auxiliaries have been used effectively in radical cyclization reactions. ... 

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