Pseudoephedrine amide, chiral

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary Unexpected Influence of Additives ... 

A wide repertoire of cleavage reactions demonstrates the synthetic potential of the pseudoephedrine amides, providing access to chiral a-branched carboxylic acids, aldehydes, ketones or primary alcohols with recovery of the auxiliary (Scheme 2). Moreover, efficient alkylation reactions utilizing epoxides and epoxide-derived electrophiles open up a route to chiral y-lactones and y-hydroxy ketones. [7]... 

A. G. Myers, L. McKinstry, J. Org. Chem. 1996, 61, 2428. Interestingly, attack from opposite r-faces of the pseudoephedrine amide enolates is found for epoxides and alkyl halides. In this context, the lithium alko-xide function of the chiral auxiliary, seems to be the crucial moiety, directing the addition of epoxides and operating as a screen in the case of alkyl halides. 

Alkylations. The alkylation of pseudoephedrine amides with epoxides is a practical method for gaining access to chiral y-lactones. Reaction of the alkylation products with alkyllithiums leads to y-hydroxy ketones. 

In the last entry of Table I, it is noted that the reduction had to be done with lithium aminoborohydride (LiH3BNH2). Myers further expanded the utility of this reagent with additional examples of the reduction of alkylated pseudoephedrine amides to chiral alcohols of high ee (Table II), and the reduction of iV,iV-disubstituted dodecanecarboxamides and 1-adamantanecarbox-amides to the corresponding alcohols, respectively (Table III) (5). 

Pseudoephedrine was used as a chiral auxiliary in Merck s synthesis of neurokinin-1 (NKj receptor antagonists 226. NKi receptor antagonists have been shown to prevent acute delayed chemotherapy-induced nausea and vomiting. The enolate of (f ,f )-pseudoephedrine amide 222 was formed by reaction with LiHMDS in the presence of TMEDA, and subsequent reaction with ot,p-unsaturated ester afforded the desired product 224 in 56% yield with the required diastereoisomer as the major product. Following reduction of the ester functionality, the chiral auxiliary was removed via acid induced cyclisation to afford lactone 225. This was transformed into NKi receptor antagonist 226 in eight steps (Scheme 14.77). 

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... 

Asymmetric Alkylation. 4-Pseudoephedrine ([IS, 2S]-(+)) is a commodity chemical employed in over-the-counter medications with annual worldwide production in excess of 300 metric tons. The enantiomer, /-pseudoephedrine, is also readily available in bulk and is inexpensive. Pseudoephedrine has been shown to be highly effective as a chiral auxiliary in asymmetric alkylation reactions. Treatment of either enantiomer of pseudoephedrine with carboxylic acid chlorides and anhydrides leads to efficient and selective iV-acylation to form the corresponding tertiary amide derivatives (Table 1). Typically, the only by-product in the acylation reactions is a small amount (<5%) of the A,0-diacylated product, which is easily removed by crystallization or flash column chromatography. Because intramolecular 0- -N acyl transfer within pseudoephedrine 3-amino esters occurs rapidly, and because the A-acyl form is strongly favored under neutral or basic conditions, products arising from (mono)acylation on oxygen rather than nitrogen are not observed. 

Amides bearing chirality at the a-position are available from the chiral pyrrolidinone 13 through iV-acylation, alkylation, and aminolysis. Pseudoephedrine has been developed into a practical chiral auxiliary for the synthesis of a-branched carboxylic acids (and other... 

Schill, G. Wainer, I.W. Barkan, S.A. Chiral separation of cationic drugs on rm al-acid glycoprotein bonded stationary phase. J.Liq.Chromatogr., 1986, 9, 641—666 [chiral also atropine, bromdiphen-hydramine, brompheniramine, bupivacaine, butorphanol, cru-binoxamine, chlorpheniramine, clidi-nium, cocaine, cyclopentolate, dimethindene, diperidone, disop3n-amide, doxylamine, ephedrine, hom-atropine, labetalol, labetalol A, labetalol B, mepensolate, mepivacaine, methadone, methorphan, methylatropine, methylhomatropine, methylphenidate, metoprolol, nadolol, nadolol A, nadolol B, ox-prenolol, oxyphencyclimine, phenmetrazine, phenoxybenzamine, promethazine, pronethalol, propranolol, pseudoephedrine, terbutaline, tocainide, tridihexethyl]... 

Recently, Myers et al. described a method for alkylation of amide enolates having d-(+)-pseudoephedrine, an industrial product manufactured worldwide in ton quantities, as a chiral auxiliary. [6] Upon treatment with LDA (2 equiv), N-acyl-pseudoephedrine derivatives 1 react with alkyl bromides or iodides efficiently and with high stereoselectivity in the presence of LiCl (6 equiv) (Scheme 1). 

The series on asymmetric synthesis then concludes with procedures for the preparation of enantiomerically pure products. The asymmetric syntheses of unnatural a-amino acids by the alkylation of pseudoephedrine glycin-amide is nicely exemplified by the preparation of l-ALLYLGLYCINE and N-BOC-i.-ALLYLGLYCINE. One of the advantages of this method is the ready availability of the chiral auxiliary and the mildness of the conditions required for the hydrolysis of the pseudophedrine amide to provide the a-amino acid. Biocatalytic transformations are also gaining importance in asymmetric synthesis as illustrated by the preparation of... 

Before embarking on a discussion of new reactions, it will be useful to describe recently reported examples of the synthetic utility of the reducing capabilities of the LABs. Myers has recently described a practical synthesis of chiral alcohols employing pseudoephedrine as a chiral auxiliary (4). An amide of pseudoephedrine is first deprotonated with LDA and then alkylated with the appropriate alkyl halide to give the substituted amide with 97-99% de. The amide is then reduced to the alcohol with lithium pyrrolidinoborohydride to give... 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

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