Myers, pseudoephedrine chiral auxiliary

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. 

Two other alkylations were based on readily-available chiral auxiharies. PhUippe Karoyan of the Universite Pierre et Marie Curie observed Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established J. Am. Chem. Soc. 2008,130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. 

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. 

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). 

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. 

With this piece synthesized, the opportunity to install the stereo-genic center in 27 selectively through a diastereoselective alkylation reaction was now at hand. For this purpose, the Winkler group decided to enlist a widely applicable and useful method developed by Andrew Myers and co-workers at Harvard University for the synthesis of a-amino acids in which pseudoephedrine glycinamide (41), an inexpensive and commercially available material, serves as a chiral auxiliary capable of controlling the selectivity of nucleophile addition. Indeed, this synthetic technology proved highly efficacious as treatment of 41 with two equivalents of LDA in the presence of LiCl in THF at — 78°C, followed by the slow addition... 

Myers AG, Yang BH, Chen H, Gleason JL (1994) Use of Pseudoephedrine as a Practical Chiral Auxiliary for Asymmetric Synthesis. J Am Chem Soc 116 9361... 

Scheme 12.62. A generalized scheme for the preparation of any amino acid whose alkyl side chain can be introduced by nucleophilic substitution. The synthesis, after Myers, A. G. Gleason, J. L. Yoon,T. /. Am. Chem. Soc., 1995,117,8488, makes use of pseudoephedrine as a chiral auxiliary group to guide in the placement of the incoming group.

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... 

Myers-Type Alkylations with Different Carboxamides In 2012, Myers described the diastereoselective alkylation of (1S,2S)- and (lR,2R)-2-methylamino-l,2-diphenylethanol carboxamides 29 and 30 [43] (Scheme 2.39). This study unveiled several advantages of these chiral auxiliaries over the more traditional pseudoephedrine carboxamides ... 

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