[ 64715-80-6]  · C10H15NO  · Benzyl(methoxymethyl)methylamine  · (MW 165.23) (R)


(chiral auxiliary for the enantioselective alkylation of ketones1 and aldehydes;2 can form chiral cuprate reagents3)

Physical Data: (S) bp 55-59 °C/0.1 mmHg; mp HCl salt 151-152 °C; [a]D25 -14.4° (c 5.7, benzene); HCl salt [a]D25 +19.7° (c 2.5, EtOH).

Preparative Method: these chiral methoxy amines are readily prepared from (S)- or (R)-phenylalanine via reduction followed by methylation.2

Handling, Storage, and Precautions: conversion of the freshly distilled amine to its hydrochloride salt is a convenient way to store and handle the compound. The free amine reacts with atmospheric carbon dioxide to produce the respective carbonate. The free amine should be stored tightly sealed under argon or nitrogen immediately after distillation to avoid CO2 adsorption.

Enantioselective Alkylation.

Both antipodes of this chiral amine have been used in the enantioselective alkylation of ketones and aldehydes via their respective chiral, nonracemic lithioenamines (eq 1). The enantioselectivity in alkylation results from the induced rigidity of the lithioenamine upon chelation with the methoxy group, providing the bias necessary to influence the direction and rate of entry of the electrophile.

Medium-sized cyclic ketones have been enantioselectively alkylated via their chiral lithioenamines to yield 2-alkylcycloalkanones in 80-100% ee.4 This procedure has also furnished a,a-dialkyl cyclohexanones in good enantiomeric excess (eq 2).4 Based on this protocol, regiospecific deuteration of 3-methylcyclohexanones has been achieved with good enantioselectivity.5

In contrast with medium-sized cyclic ketones, alkylation of macrocyclic ketones can afford either optical antipode depending on whether the lithioenamine is formed via kinetic (E-) or thermodynamic conditions (Z-enamine) (eq 3).6 Optically active a-alkyl macrocyclic ketones have been formed in 30-82% enantiomeric excess, with chemical yields of 62-90%.

In a similar manner, aldehydes can also be enantioselectively alkylated by this procedure. However, the enantiomeric excess obtained is much lower (47%).2 A special application of this method is the enantioselective alkylation of aldehydes for the construction of quaternary stereogenic centers. An example is the formation of the chiral quaternary carbon in 4-methyl-4-phenylcyclohex-2-en-1-one in high enantiomeric excess using this methodology (eq 4).7

Chiral Cuprate Reagents.

This chiral amine has also found application in asymmetric conjugate addition of copper azaenolates to cyclic enones. Lithium azaenolates of optically active acetone imines have been used in the preparation of chiral cuprate reagents. However, the asymmetric induction is low (17-28% ee) when this amine is employed (eq 5).3

Enantioselective alkylation of aldehydes and ketones can also be accomplished using Enders' reagents SAMP and RAMP.8 In contrast with Meyer's chiral auxiliary, the synthesis of Enders' reagents is lengthy and the recovery is inconvenient because cleavage of the auxiliary does not afford back the reagent. It also generates nitrosoamines (via ozonolysis) which are considered carcinogenic compounds. Therefore, the ease of preparation, availability of the starting material, and efficient cleavage and recovery of this chiral amine make it a convenient chiral auxiliary.

1. Meyers, A. I.; Williams, D. R.; Druelinger, M. JACS 1976, 98, 3032.
2. Meyers, A. I.; Poindexter, G. S.; Brich, Z. JOC 1978, 43, 892.
3. Yamamoto, K.; Iijima, M.; Ogimura, Y. TL 1982, 23, 3711.
4. Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. JACS 1981, 103, 3081.
5. Kallmerten, J.; Knopp, M. A.; Durham, L. L.; Holak, I. J. Label. Compound Radiopharm. 1986, 23, 329.
6. Meyers, A. I.; Williams, D. R.; White, S.; Erickson, G. W. JACS 1981, 103, 3088.
7. Marron, B. E.; Schlicksupp, L.; Natale, N. R. JHC 1988, 25, 1067.
8. Enders, D.; Eichenauer, H. AG 1976, 88, 579; AG(E) 1976, 15, 549.

Eduardo A. Véliz & Joseph P. Konopelski

University of California, Santa Cruz, CA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.