Benzyl diastereoselective alkylation with

N-propionyloxazolidinone and the subsequent diastereoselective alkylation with benzyl bromide at —100 °C. The observed diastereomeric ratio of 91 9 was superior to that of 85 15 observed in a batch reactor (Scheme 4.9) [11,13],... 

Charlton [57] demonstrated the use of oxazolidinones as effective chiral auxiliaries the commercially available (4i )-benzyl and (4S)-isopropyl-2-oxazolidinones were /V-acylated with dihydrocinnamic acid to give N-acyloxazolidinones (54 and 55) in yields greater than 80%, Scheme (10). Diastereoselective alkylation with tert-butylbromoacetate gave in each case principally only one diastereomer (56 and 57, respectively) (de>95%). The oxazolidinone moiety could be removed by utilizing LiOH-H2C>2 without affecting the tert-butyl ester. The crude acid was reduced to the corresponding primary alcohol with BH3THF, then... 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

Diastereoselectivities for alkylation of enolate 6 are outstanding. Alkylation with Mel gives 7 (R = Me) as the major product diastereomer in a ratio of 260 1 with respect to the minor diastereomer 8. A wide range of alkylation reagents have been examined including allylic, benzylic, homoallylic, alkoxymethyl, cyanomethyl, and arylethyl halides. 

The diastereoselective alkylation of dialkyl malates has been frequently used in the past [65]. However, according to the original procedure [63] (dialkyl malate, base, -78 -20 °C, then -78 °C, electrophile, then -78 0 °C, 16 h), the alkylation proceeded in average yields of about 50-60% and in diastereoselectivities in the range of 9 1 anti / syn. In our hands, application of this procedure to the reaction of benzyl bromide 23 with dimethyl malate 106 produced the alkylated compounds in only 20% yield. The yield of the alkylation was easily improved (>75%) when the ester was deprotonated with LHMDS in the presence of the electrophile at -78 °C and the reaction mixture was allowed to warm to 10 °C (Scheme 26 and Table 2). 

The phosphine oxide (-)-(5 )-[2-(dimethylamino)ethyl]methyloxophenylphosphorane85 was treated with butyllithium or LDA to give, via directed lithiation, the methylene-deprotonated compound regioselectively. Alkylation with bromomethylbenzene gave (S)-[l-benzyl-2-(di-methylamino)ethyl]methyloxophenylphosphorane with low diastereoselectivity (d.r. 55 45)86. 

Contrary to the above findings, the alkylation of O-benzyl glycolates 16a and 17a proceeds in the same sense in both solvent systems (THF and THF/HMPA)122. Both 16a and 17a are alkylated with ca. 90% diastereoselectivity to give 16b, 16c and 17b, 17c, respectively, in both... 

The bicyclic / -lactam 8 is alkylated with excellent diastereoselectivity (d.r. >97 3) to give 9 (yield 50-80 %)18. Best yields are obtained with iodomethane (80%), whereas ally or benzyl bromide give 69% and 51 % yield, respectively18. 

When treated with a strong base such as butyllithium or potassium tert-butoxide, 2-isocyano-tV[(S)-l-phenylethyl]propanamide (1) forms an enolate 2 which is not alkylated at low temperatures. Instead it rearranges on warming and cyclizes to give the enolate of 3,5-dihydro-5-methyl-3-[(,3 )-1-phenylctbylJ-4//-imidazol-4-onc (3) which can be alkylated with benzylic halides with excellent diastereoselectivities4,13. 3-Halopropenes or haloalkanes give much lower diastereoselectivities. 

Diastereoselective alkylation of tartaric acid. The enolate (2) of the acetonide of dimethyl (R, R)-tartrate (1) can be generated with LDA in THF-HMPT at — 70° and is sufficiently stable for alkylation with allyl and benzyl halides, but not with other simple alkyl halides, and for addition to acetone (60% yield). The main products (3) of allylation and benzylation have the /ranr-configuration, and thus the substitution occurs with retention of configuration.7... 

It is assumed that the preferred conformation of the substructure C=C—O—C of the configured ester enolate in the preferred transition state of the alkylation is that depicted in the center of the left-hand column of Figure 13.42. In the projection shown, the alkylating reagent reacts with the enolate from the front side for the reasons just stated. The reaction occurs with a diastereoselectivity of 97 3. Chromatography allows for the complete separation of the main diastereoisomer from the minor diastereoisomer. Reduction of the main diastereoisomer (for the mechanism, see Section 17.4.3) affords the alcohol B, a derivative of. S -a-benzyl propionic acid, with 100% ee. Hydrolysis of the benzylated esters without iso-... 

Why are the benzylated esters of Figure 10.37 not obtained with higher diastereose-lectivities than 95 or 97%, respectively One of the reasons, and perhaps the only reason, lies in the failure of both the E - and the Z"-enolate to form with perfect stereocontrol. Small contaminations of these enolates by just 5 or 3% of the corresponding enolate with the opposite configuration would explain the observed amounts of the minor diastereoisomers, even if every enolate were alkylated with 100% diastereoselectivity. 

Stereoselective Alkylation. Chiral tricyclic lactams can be prepared from (l/ ,2/ ,35,5/ )-ATBH and y-keto acids by heating in toluene with a catalytic amount of p-toluenesulfonic acid (eq 7). Enolization of the resulting lactams with sec-butyllithium, followed by trapping with methyl iodide, furnishes the methylated products in high diastereoselectivity. Subsequent enolization and alkylation with benzyl bromide affords a single diastereomer in 82% yield. Further acidic hydrolysis in butanol provides the desired ester with a quaternary asymmetric center (eq 7). ... 

Scheme 3.15 illustrates a different auxiliary derived from camphor, and which has similar design features, but which affords higher diastereoselectivity [75]. Additionally, Scheme 3.15 illustrates the selective formation of either an E(0)- or Z(0)-enoIate based on the presence or absence of HMPA in the reaction mixture. Thus, deprotonation of the ester with LICA is 98% selective for the fO>enolate and deprotonation in the presence of HMPA is 96% selective for the ZfO]-enolate. Alkylation with benzyl bromide is more selective for the E(0)-enolate than for the Z(0), but after diastereomer separation, reduction gives enantiomerically pure R-or S-2-methyl-3-phenylpropanol, opposite enantiomers from the same auxiliary... 

Several dialkyl malate esters were alkylated with a benzylic bromide. The dimethyl and diethyl esters show a 8 1 and 9 1 selectivity for 26-A si face, respectively). The diastereoselectivities are shown for several more bulky esters. Figure 6.P26 gives the HF/6-31G structures of the corresponding enolates. Explain the observed stereoselectivity on the basis of structural features present in these enolates. 

Beak et al. reported that chiral homoenolate equivalents can be formed by di-lithiation of an amide and highly diastereoselective reaction with electrophiles to provide the benzylically substituted products [76]. Treatment of (S)-N-(T-phenylethyl)-3-phenylpropionamide 95 with 2.2 equivalents of sec-BuLi and TMEDA followed by addition of an electrophile affords the alkylated products 96 in 46-55% yield with 90 10-94 6 drs (Scheme 27). 

Lithium A number of Michael-type additions of organolithiums have been described. This is also the case of the reaction of aryllithiums with nitroalkene (389). Deprotonation of the benzylic fluoride (455) with LDA, directed by the neighbouring sulfoxide group, generated the benzyllithium intermediate (456), which underwent addition to the Michael acceptor R CH=CHY (Y = CO2BU, S02Ph R = Ar, alkyl, alkenyl) in a diastereoselective manner controlled by the chiral sulfur to afford the 5yn-configured product (457) with <99 1 dr ... 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

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. 

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. 

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