Diastereoselectivity of enolates

It has been demonstrated that excellent diastereoselectivities for enolate alkylation also are obtained when alkyl substituents are positioned at C(4), C(5) or C(6) of benzamide 5. AryE and methoxy substituents at C(5) also are compatible, but a methyl group at C(3) leads to an inversion of the diastereoselectivity of enolate alkylation. The inverted sense of stereoselection is thought to be a result of a disruption of the internal chelation shown in enolate 6 by steric effects of the neighboring methyl substituent. 5... 

Steric influences of enolate substituents (Ri R2) play a dominent role in kinetic diastereoselection. 

Benzyloxy-2-fluoro-2-methylpropionaIdehyde was prepared in optically active form from (5)-monoethyl 2-fluoro-2-methylmalonate, which had itself been prepared by enzymatic hydrolysis A number of enol silyl ethers or enolates were added to the aldehyde in processes that occur with fair to good diastereoselectivity [6] (equation 6) (Table 2)... 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

The chlorotitanium enolate, generated by treatment of (S )-l-tm-butyldimethylsiloxy-l-cyclohexyl-2-butanone with titanium(iv) chloride and diisopropylethylamine, provides the syn-product upon reaction with benzaldehyde. The diastereoselectivity of 99 1 is defined as the ratio of the major isomer to the sum of all other isomers47bc. 

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

The diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

The diastereoselectivity of the copper enolate 2b may be rationalized by suggesting that the chair-like cyclic transition state J is preferred which leads to the major diastereomer 4. The usual antiperiplanar enolate geometry and equatorial disposition of the aldehyde substituent are incorporated into this model. Possible transition states consistent with the stereochemistries of the observed minor aldol products are also illustrated. 

The addition of boron enolates to imincs is useful for the construction of anti-fi-amino acid derivatives8. On the other hand, it is possible to control the direction of the diastereoselective addition of enolates from (A)-phenyl alkanethioates with imines9. 

The diastereoselectivity of the zinc iodide catalyzed reaction of the azetidinone I with the trimethylsilyl enolate derivatives of the chiral 3-(l-oxopropyI)oxazolidinones 6 was considerably lower (about 60 40), although independent generation of the zinc enolate, via exchange of the lithium enolate with zinc bromide, afforded the /9-Iactam carboximide derivatives in a ratio (RIS) 80 20177. 

For amide enolates (X = NR2), with Z geometry, model transition state D is intrinsically favored, but, again, large X substituents favor the formation of nt/-adducts via C. Factors that influence the diastereoselectivity include the solvent, the enolate counterion and the substituent pattern of enolate and enonc. In some cases either syn- or unh-products are obtained preferentially by varying the nature of the solvent, donor atom (enolate versus thioeno-late), or counterion. Most Michael additions listed in this section have not been examined systematically in terms of diastereoselectivity and coherent transition stale models are currently not available. Similar models to those shown in A-D can be used, however all the previously mentioned factors (among others) may be critical to the stereochemical outcome of the reaction. 

Q Chiral racemic y-alkyl-substituted enones the titanium(IV) chloride mediated addition of enol silanes and silylketene acetals to 7 shows high induced diastereoselection (diastereomeric ratios from 89 11 to more than 97 3) and the major isomer 8 results from addition of the enolsilane with ul topicity288. Re face attack on the S enantiomer of 7.)... 

The Lewis acid catalyzed reactions of silyl enol ethers with nitroalkenes have been reviewed, however the diastereoselectivity of these reactions has not been addressed17. 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

The addition of enolate anions to (E)- and (Z)-3,3,3-trifluoro-l-[(4-methylphenyl)sulfinyl]-1 -propene has been investigated (E)- and (Z)-a,/(-unsaturated sulfoxides undergo addition in the opposite stereochemical sense3,4. In general, yields and product diastereoselection are high. When the -position of the double bond of the enolate is substituted then all four diastereomer-ic products result. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Rovis and co-workers further extended the scope of the reaction to the enantio-and diastereoselective cyclisation of a,P-disubstituted Michael acceptors 137. The high diastereoselectivity of the process relies on selective protonation of the resnltant enolate after conjugate addition. It was found that HMDS (formed dnring deprotonation of the triazolium salt pre-catalyst) was detrimental to the... 

A comparison of the anti.syn diastereoselectivity of the lithium, dibutylboron, and (Cp)2Zr enolates of 3-methyl-2-hexanone with benzaldehyde has been reported.34d The order of stereoselectivity is Bu2B > (Cp)2Zr > Li. These results suggest that the reactions of the zirconium enolates proceed through a cyclic TS. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

If HMPA is included in the solvent, the Z-enolate predominates.236,238 DMPU also favors the Z-enolate. The switch to the Z-enolate with HMPA or DMPU is attributed to a looser, perhaps acyclic TS being favored as the result of strong solvation of the lithium ion. The steric factors favoring the -TS are therefore diminished.239 These general principles of solvent control of enolate stereochemistry are applicable to other systems.240 For example, by changing the conditions for silyl ketene acetal formation, the diastereomeric compounds 17a and 17b can be converted to the same product with high diastereoselectivity.241... 

The synthesis of the C(17)-C(24) segment also began with a diastereoselective boron enolate aldol addition. The adduct was protected and converted to an aldehyde in sequence H. The terminal diene unit was installed using a y-silylallyl chromium reagent, which generates a (3-hydroxysilane. Peterson elimination using KH then gave the Z-diene. 

Diastereoselective hydroxylation of enolates of chiral amides. Davis and coworkers1 have examined the asymmetric hydroxylation of the tetrasubstituted enolates of a chiral amide (2) with these chiral camphoryloxaziridines. Oxidation of the lithium enolate of 2 with (+ )-l proceeds with only moderate diastereoselectivity (48.4% de), which is somewhat less than that observed on hydroxylation with the achiral 2-(phenylsulfonyl)-3-phenyloxaziridine (4). Oxidation of the enolate of 2... 

Reipig (39,40), Pfaltz (41), and Andersson and their co-workers (42) independently showed that these catalysts are capable of effecting the selective cyclopropanation of enol ethers and enolsilanes. Methyl vinyl ketone and acetophenone enolsilanes provide high selectivities in the cyclopropane products, but both isomers are formed equally. The trisubstituted dihydropyran 65 leads to cyclopropane adducts in high diastereoselectivities and enantioselectivities using 55c CuOTf as catalyst. 

Several applications of this methodology are known. For the determination of the relative configuration of the stereocenter and the axial chiral unit of 71, the product of a diastereoselective ester enolate Claisen rearrangement of 70, with AgBF4 a cycli-zation to 72 was initiated. Then the carboxylic acid was reduced to alcohol 73 and the position of the substituents was investigated by NMR and by the use of NMR shift-reagents (Scheme 15.16) [32], Control experiments ensured the stereospecifi-city of the cyclization and the reduction step. There are further examples of this strategy [33]. 

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