5130
J. Am. Chem. Soc. 2001, 123, 5130-5131
Ortho-anilide 6 was synthesized from rac-3 as shown in eq 2.
O-Methylation of rac-3 with methyl trifluoromethanesulfonate
Synthesis of Enantioenriched Axially Chiral Anilides
from Atropisomerically Enriched Tartarate
Ortho-Anilides
Ali Ates and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh
Pittsburgh, PennsylVania, 15260
ReceiVed February 21, 2001
Anilides such as 1 and 2 bearing appropriate ortho-substituents
exist as stable atropisomers at room temperature and above,1 and
these axially chiral anilides undergo an assortment of diastereo-
selective reactions.1,2 Barriers to racemization of 1, 2, and related
analogues are in the range of 28-30 kcal/mol.1b,3
provided an intermediate alkoxy imminium salt rac-4 that was
quenched with sodium methoxide to provide ortho-anilide 5.
Trans-ketalization of 5 with (+)-dimethyl L-tartrate then provided
ortho-anilide 6. At the onset, we hypothesized that the conversion
of the sp2 amide carbonyl carbon to an sp3 anilide ketal carbon
would significantly lower the C-N rotation barrier and allow an
asymmetric hydrolysis of 6 to occur under conditions of dynamic
1
kinetic resolution. However, the H and 13C NMR spectra of 6
showed pairs of resonances (ratio 1.1/1) for most peaks, suggesting
that C-N bond rotation was not especially rapid. In addition, all
attempts to conduct asymmetric acidic hydrolysis of 6,8 both with
and without chiral additives, consistently occurred in poor yields
to give product 3 of about 15-20% ee. The rough correspondence
of the low ee of 3 to the diastereomer ratio of 6 and the inability
to influence the ee with additives led us to speculate that the
hydrolysis was faster than interconversion of the rotamers of 6.
If this is true, then hydrolysis of one isomer of 6 might give one
enantiomer of 3.
Limiting the usefulness of these and related transformations is
the lack of general methods that provide single enantiomers of
anilide atropisomers.4 Most current methods involve nonselective
synthesis of isomers followed by physical or chromatographic
separation.1,2,5,6 We report herein a new approach to enantiomeri-
cally enriched anilide atropisomers through the selective cleavage
of ortho-anilide diastereomers. These ortho-anilides belong to a
rare class of atropisomers originating from restricted rotation about
an sp2-sp3 C-N bond.7 The configuration of the ortho-anilide
precursor determines the configuration of the resulting anilide in
an unusual cleavage reaction that changes one type of axial
chirality (sp2-sp3) into another (sp2-sp2). In turn, the configu-
ration of the ortho-anilide is controlled either by a crystallization-
induced asymmetric transformation or by a thermodynamic
equilibrium.
In an important breakthrough, we discovered that isomer 6a
(eq 3) selectively crystallizes (20/1 ratio, mp 84-86 °C) in 95%
(1) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131. (b) Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.;
Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron
Asymmetry 1997, 8, 3955.
(2) (a) Hughes, A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S.
Tetrahedron Lett. 1996, 37, 7607. (b) Hughes, A. D.; Price, D. A.; Simpkins,
N. S. J. Chem. Soc., Perkin Trans. 1 1999, 1295.
(3) Curran, D. P.; Liu, W. D.; Chen, C. H.-T. J. Am. Chem. Soc. 1999,
121, 11012.
(4) Benzamides with a chiral C-C axis have been resolved by a number
of dynamic methods: (a) Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. Engl.
1999, 38, 2556. (b) Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron
Lett. 2000, 41, 3279.
(5) (a) Cass, Q. B.; Degani, A. L. G.; Tiritan, M. E.; Matlin, S. A.; Curran,
D. P.; Balog, A. Chirality 1997, 9, 109. (b) Hughes, A. D.; Simpkins, N. S.
Synlett 1998, 967. (c) Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M.
Tetrahedron Lett. 1997, 38, 4447. (d) Kitagawa, O.; Izawa, H.; Sato, K.;
Dobashi, A.; Taguchi, T.; Shiro, M. J. Org. Chem. 1998, 63, 2634. (e)
Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett. 1999,
40, 8827.
(6) Uemura has recently reported a highly enantioselective synthesis of
2-methyl-6-alkyl-substituted anilides by selective deprotonation of prochiral
chromium carbene complexes with chiral bases, but this method is not
applicable to either of the classes of compounds shown in eq 1. Hata, T.;
Koide, H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2, 1907.
(7) (a) Eliel, E. L.; Wilen, S. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994; pp 1150-1153. (b) Oki, M. Applications
of Dynamic NMR Spectroscopy to Organic Chemistry; VCH: Deefield Beach,
1986; pp 195-206.
yield from hexane under conditions where the two atropisomers
6a,b are in equilibrium. This process shows all the hallmarks of
a crystallization-induced asymmetric transformation.7a,9 If crystal-
lization occurs too rapidly, then the diastereoisomer ratio is greatly
reduced. Crystals of the enriched 20/1 mixture retain the ratio
for weeks, but equilibration to the starting 1.1/1 mixture occurs
in a matter of hours at ambient temperature in solution. Attempts
(8) Under acidic conditions, hydroylsis with C-N bond cleavage competes.
Hydrolyses under both acidic and basic conditions probably go through imidate
salts. See: Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: Oxford, 1983; pp 101-162.
(9) (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and
Resolutions; Wiley: New York, 1981; pp 369-377. (b) Vedejs, E.; Donde,
Y. J. Org. Chem. 2000, 65, 2337.
10.1021/ja010467p CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001