Alkylation using chiral auxiliaries

Scheme 1.9. Diastereoselective Enolate Alkylation Using Chiral Auxiliaries...

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

Table 2-13 summarizes some useful chiral auxiliaries for a-alkylation of a carbonyl compound. 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

A special case of asymmetric induction using chiral auxiliaries has been reported for the alkylation of /1-keto esters94,106. In this approach the reaction proceeds in a diastereoselective manner via a base-catalyzed opening of the corresponding chiral 1.2-cyclohexanedioxy or 1,2-cyclohep-tanedioxy acetal, e g., acetal 50. 

Chiral enamines may be prepared by condensation of ketones with enantioenriched 5ec-amines. The C2-symmetric rran5-2,5-dimethylpyrrolidine is a frequently used chiral auxiliary for the preparation of enantiomeric enamines. Alkylation of chiral enamines followed by hydrolysis is an effective method for the enantioselective alkylation of ketones. ... 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Stereoselective alkylation C-C bond 41% (ee 82%) Using chiral auxiliary 2004/[46]... 

In conclusion, the asymmetric alkylation of chiral enolates and enamines can be completed with high stereoselectivity affording final products with high optical purity [17], The chiral economy of this and other noncatalytic methods that use chiral auxiliary agents in a stoichiometric quantity depends on their availability and effective recycling in the process. 

Some of the early asymmetric alkylation processes using chiral auxiliaries involved weakly nucleophilic enolates and thus provided access to a limited set of products, because only reactive electrophiles such as methyl, benzyl, and allyl halides could be employed. Nevertheless, it is interesting to note that despite the evolution in the field, some of these traditional methods continue to be used extensively both in academia and industry for the convenient preparation of specific product classes. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

Cyclic dithioketals and acetals represent another important class of sulfur containing chiral auxiliaries, which are available in chiral form by biooxidation. Biotransformations were performed on a preparative scale using whole-cells (wild type and recombinant) and isolated enzyme. Again, enantiocomplementary oxidation of unsubstituted dithianes (linear and cyclic, R = H) was observed when using and CPMOcomo (Scheme 9.28) [211,212]. Oxygenation of functionalized substrates (R = substituted alkyl) with gave preferably trans... 

A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occurs anti to the a-oxybenzyl group.93 The reactions involve the Z-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94... 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Chapter 1 deals with alkylation of carbon nucleophiles by alkyl halides and tosylates. We discuss the major factors affecting stereoselectivity in both cyclic and acyclic compounds and consider intramolecular alkylation and the use of chiral auxiliaries. 

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

Model (1) further suggests that, if the substrate is a secondary allylic alcohol (R4 / 11, R5 = H or r4=h, rVh), enantiomeric alcohols are epoxidized at different rates when (R,R)-DAT is used as the chiral auxiliary, (5)-allylic alcohol (R4 f H, R5 = H) suffers less steric hindrance from the tartrate ligand and is oxidized faster than (R)-allylic alcohol (R4 = H, R5 f H).37 As the ester alkyl group of DAT becomes bulkier, the hindrance becomes more intense and the relative... 

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