ance of two doublets centered at the same frequency, one
for each enantiomer, in the H NMR spectrum. As the
enantiomeric analysis. Therefore, amino acids were quanti-
tatively doubly derivatized in two steps: esterification using
2
enantiomeric discrimination depends on sole interactions with
the chiral solvent but requires isotopic labeling, we subse-
quently proposed an improved method for enantiomeric
analysis, using deuterated nonchiral derivatizing agents as a
methanol-d
followed by reaction with acetyl-d
triethylamine (2.2 equiv) in dichloromethane (Scheme 2).
4
in the presence of thionyl chloride (1.2 equiv)
chloride (1.1 equiv) and
3
5
simple way of incorporating deuterium in the substrates.
The first application concerned amino acids, on which
esterification by methanol-d allowed enantiomeric analysis.
4
Scheme 2
However, this procedure required the stabilization of the
amino ester derivative as an iminoester by a second reaction
step with benzophenone imine.5 More recently, we dem-
onstrated the enantiomeric analysis of primary and secondary
a
amines, using acetyl-d
time, Courtieu et al. used perdeuterated benzoyl chloride as
chloride as NCDA.5b At the same
3
5c
the derivatizing agent for alcohols, amines, and amino acids.
As spectral discrimination between enantiomers of acet-
amides-d was particularly pronounced and therefore suitable
3
for enantiomeric analysis, we decided to extend the use of
acetyl chloride to amino acids and to evaluate the ability of
this technique to establish the absolute configuration of these
substrates, together with amines.
For natural amino acids, optically active mixtures were
prepared by weighing racemic and L-compounds. For non-
natural ones, enrichment in the D-isomer was performed from
the racemic amido esters using R-chymotrypsin: hydrolysis,
monitored by 0.1 M NaOH addition, was stopped after half-
Racemic primary amines, if not commercially available,
were synthesized from the corresponding ketones by reduc-
tive amination using sodium cyanoborohydride and am-
9
consumption of the L-ester, to obtain 33% ee. Synthesis of
6
monium acetate (Scheme 1). Optically active amines were
10
â-amino acids is described elsewhere.
We recorded the proton-decoupled deuterium NMR spectra
of amides 1-6 and of amido esters 7-19, dissolved in
1
1
2 2
PBLG-CH Cl solvent.
Scheme 1
The results obtained for amides are listed in Table 1. As
amides contain one type of deuterium, NMR spectra are
Table 1. Values of Quadrupolar Splittings for Enantiomers of
Amides 1-6
synthesized in three steps from the ketones by subsequent
7
bakers’ yeast reduction, Mitsunobu reaction with phthal-
8
imide, and then hydrazinolysis. Derivatization of racemic
and optically active amines (ee created by weight of both
components) was achieved using acetyl-d chloride in the
3
presence of triethylamine in ether.5b In the case of amino
acids, we decided to perform a double derivatization,
esterification and N-acetylation, to compare the ability of
a
Absolute configurations were determined by comparison of the optical
rotation of alcohols and amines with those reported in the litterature.
Volumic absolute configurations were defined following Cahn-Ingold-
Prelog rules, using substituent hierarchy based on the van der Waals volumes
b
methanol-d
4
and acetyl-d
3
chloride to act as NCDA for
(
ref 13) instead of the atomic numbers.
(5) (a) Canet, I.; Meddour, A.; Courtieu, J.; Canet, J. L.; Sala u¨ n, J. J.
Am. Chem. Soc. 1994, 116, 2155-2156. (b) Canet, J. L.; Canet, I.; Courtieu,
J.; Da Silva, S.; Gelas, J.; Troin, Y. J. Org. Chem. 1996, 61, 9035-9037.
composed of two doublets, corresponding to the differentia-
tion of enantiomers (Figure 1). For all the amides, enanti-
(c) Meddour, A.; Loewenstein, A.; P e´ chin e´ , J. M.; Courtieu, J. Tetrahe-
dron: Asymmetry 1997, 8, 485-494.
6) Borch, R. F.; Bernstein, M. D.; Dupont Durst, H. J. Am. Chem. Soc.
971, 93, 2897.
7) Besse, P.; Bolte, J.; Fauve, A.; Veschambre, H. Bioorg. Chem. 1993,
1, 342-353.
8) Roush, W. R.; Straub, J. A.; Brown, R. J. J. Org. Chem. 1987, 52,
127-5136. Heatcock, C. H.; Davidsen, S. K.; Mills, S. G.; Sanner, M. A.
(
1
2
5
(9) Bernasconi, S.; Corbella, A.; Gariboldi, P.; Jommi, G. Gazz. Chim.
Ital. 1977, 107, 95-99.
(10) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J. C.
Tetrahedron: Asymmetry 1998, 24, 4361-4368. Chalard, P.; Remuson, R.;
Gelas-Mialhe, Y.; Gramain, J. C.; Canet, I. Tetrahedron Lett. 1999, 40,
1661-1664.
(
(
J. Org. Chem. 1992, 57, 2531-2544.
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Org. Lett., Vol. 2, No. 16, 2000