Pseudoephedrine auxiliary

A useful mnemonic for deriving the preferred diastereomer formed in the alkylation reaction of pseudoephedrine amide eno-lates with alkyl halides is as follows the alkyl halide enters from the same face as the methyl group of the pseudoephedrine auxiliary when the (putative) ( -enolate is drawn in a planar, extended conformation (eq 1). ... 

Ephedrine and pseudoephedrine auxiliaries have the advantage of being commercially available and cheap. In addition, no further modification is necessary prior to their use. 

Following the successful cross-coupling of trifluoroboratoamide 11 and bromide 28, displacement of the pseudoephedrine auxiliary with mefhyllithium was required in order to conduct the aldol reaction (Scheme 11). Treatment of amide 34 with methyllithium afforded methyl ketone 27 in a pleasing 85% yield. 

Other auxiliaries are also used, and the choice of auxiliary may depend not only on the selectivity of the reaction under investigation but also on the physical properties of the products. The camphor-based auxiliary of Oppolzer is reputed to confer crystallinity on its derivatives, while the pseudoephedrine auxiliary of Myers is cheap, readily available, and very easy to introduce. More bulky auxiliaries such as 8-phenylmenthol work well where control over long-range interactions, such as conjugate additions, are required. 

Ephedrine and pseudoephedrine auxiliaries are cheap commercially available compounds and readily accessible without any further modification. Procter and coworkers developed a polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase." The resin-bound amide 109 is deprotonated and alkylated with benzyl bromide to provide enantiopure 110. Treating later with different reagents resulted in the enantioselective formation of various alcohols, acids, and amide in 31-55% yield (overall yields), with ee ranging from 78% to 92% (Scheme 7.23). 

Scheme 7.23. Polymer-supported pseudoephedrine auxiliary for asymmetric alkylation.

Cleavage of Pseudoephedrine Auxiliary In contrast to the ephedrine auxiliary, which is difficult to cleave once the alkylation is performed, the pseudoephedrine moiety can be readily removed under various conditions with a limited impact on the ees [36]. 

Asymmetric Michael additions developed at Merck using a pseudoephedrine auxiliary [22]... 

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 introduction of various metal-catalyzed reactions, however, remarkably expanded the scope of the epoxidation of Q,.3-unsaturatcd ketones. Enders et al. have reported that a combination of diethylzinc and A-methyl-pseudoephedrine epoxidizes various o,. j-unsaturatcd ketones, under an oxygen atmosphere, with good to high enantioselectivity (Scheme 23).126 In this reaction, diethylzinc first reacts with the chiral alcohol, and the resulting ethylzinc alkoxide is converted by oxygen to an ethylperoxo-zinc species that epoxidizes the a,/3-unsaturated ketones enantioselectively. Although a stoichiometric chiral auxiliary is needed for this reaction, it can be recovered in almost quantitative yield. 

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. 

S,S)-(+)-pseudoephedrine propionamide as chiral auxiliary. The obtained p-amino esters were subjected to a reported base-promoted cyclization [182, 183] affording the p-lactams in good yields and as unique detectable stereoisomer (Scheme 82). 

B. A. Synthesis of a-substituted / -amino acids using pseudoephedrine as a chiral auxiliary. Org. Lett. 2000, 2, 3527-3529. 

Pseudoephedrine proprionamide (39) has been employed as a chiral auxiliary in asymmetric acetate aldol reactions.135... 

In a separate step of the process, either (IS, 2S)-(+)-pseudoephedrine (37) or /V-methyl-( IS, 2K)-cisA -amino-2-indanol (38) was successfully used as auxiliaries for the chiral Michael addition of an aryllithium to give compound 39 (Scheme 23.11).57... 

Ramamurthy et al. have examined enantioselective and diastereoselective ODPM rearrangements of cyclohexadienone and naphthalenone derivatives within MY zeolites, where M is an alkali ion [38, 39]. For example, in Scheme 4.27, in NaY in the presence of several chiral inductors such as ephedrine, pseudoephedrine, and camphorquinone-3-oxime, an enantioselective ODPM rearrangement of 65 and 66 took place to afford 68 in 30% ee yield. In the frame of the chiral auxiliary approach, the compound 67 linked to (S)-ephedrine was irradiated within NaY to give 68 in moderate diastereoselective excess (de) (59%). Interestingly, the reaction media of KY, RbY, and CsY reverse the diastereoselectivities. The cation-dependent diastereo-meric switch has been discussed with respect to the N- or O-functional group in 67 [39]. Recently, Arumugan reported that the irradiation of naphthalenones 65 linked chiral auxiliaries (R3 = COO(—)-Ment or (S)-NHCH(Me)Ph) in Li+ or Na + Nafion resulted in chiral products ( 14% de) [40],... 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

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. 

Unsaturated pseudoephedrine amides are efficiently converted into y-lactones by cleavage of the auxiliary through halo-lactonization reactions (eqs 13 and 14). - ... 

Amino Acids. Pseudoephedrine has been used as a chiral auxiliary for the preparation of both a-substituted and a,p-disubstituted p-amino acids. Alkylation of p-alanine was shown to furnish an efficient, inexpensive, and enantioselective route to a-alkyl p-amino acids (eq 23). ... 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

Myers, A. G., Yang, B. H., Chen, H., McKinstry, L., Kopecky, D. J., Gleason, J. L. Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc. 1997, 119, 6496-6511. 

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... 

To explore the viability of chiral auxiliaries in the vinyl phosphate-p-ketophosphonate rearrangement, a series of vinyl phosphates derived from ephedrine, pseudoephedrine, (lR,2S,5R)-(-)-menthol, (15,25,35,57 )-(-i-)-isopinocampheol, (5)-(-)-2-methylbutanol, binaphtol, and (2R,4R)- or (25,45)-pentane-2,4-diol have been examined. (5)-(-)-2-methylbutanol and 2,4-pentane-2,4-diol derivatives appear as the most attractive chiral auxiliaries. 

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