Synthesis of enantioenriched axially chiral anilides from atropisomerically enriched tartarate ortho-anilides

Full text of DOI:10.1021/ja010467p

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

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5131
We next prepared ortho-anilide 7 (eq 4) by a similar sequence
to the one in eq 2 (not shown). To our surprise, this ortho-amide
existed as a 10/1 mixture of atropisomers according to 1H NMR
analysis. The oily mixture could not be crystallized and was a
single peak on HPLC, so we have not yet been able to obtain a
sample with a different isomer ratio. Prolonged heating of 7 at
50 °C did not change the 10/1 ratio and we assume that this is
the thermodynamic ratio. Cleavage of 7 with samarium iodide is
not applicable because of the presence of the iodide, but hydrolysis
under basic conditions provided (M)-8 in 99% yield and 77% ee
(eq 4). Once again, the ee of the product 8 roughly corresponds
to the de of the precursor 7. The configuration of (M)-8 has been
assigned by X-ray crystallography (see Supporting Information),
and that of 7a is assigned accordingly.
These results show that ortho-anilides bearing either one large
and one small ortho substituent 6 or two medium ortho substit-
uents 7 comprise a new class of atropisomers with restricted
rotation imparted by the sp2-sp3 C-N bond. The rate of many
reactions occurring at room temperature or below will typically
exceed the rate of rotation. When reactions convert the ketal to
an amide, the rotation barrier increases significantly (∼6 kcal/
mol) so the ratio of the precursor ortho-anilide can be locked in.
The needed high diastereomer ratio of the ortho-anilides may
occur naturally due to the thermodynamic stability of the isomers,
or it may be secured kinetically through a crystallization-induced
asymmetric transformation. Neither of these approaches is neces-
sarily predictable or general, so the acetate derivatives 3 and 8
made in this paper are especially important since they can readily
be converted into more complex amides by alkylation or related
reactions.1-3,5
Even though a stoichiometric quantity of tartrate has been used,
this work has two important implications for future efforts directed
at the catalytic asymmetric synthesis of axially chiral amides. First,
the development of an asymmetric hydrolysis of an ortho-anilide
or related intermediate (for example, treatment of 5 with a chiral
Lewis acid) may be difficult since the rate of hydrolysis must
exceed the rate of rotation of the ortho-anilide but be slower than
the rate of rotation of the anilide product. Second, a projected
asymmetric acylation reaction to make an axially chiral anilide
(for example, reaction of an acid chloride and an aniline with a
chiral catalyst) will likely require selective formation of a
tetrahedral intermediate since atropisomers of that intermediate
(which resemble amide ketals) would not interconvert under the
reaction conditions and would collapse to give enantiomeric
products. Thus, design of chiral acylation catalysts should focus
on the first (addition) not the second (elimination) step.
Figure 1. Crystal Structure of Anilide Ketal 8a.
Table 1. Cleavage of an Anilide Ketal Mixture 8a/b To Give
Enantiomerically Enriched 5
ratio
temp, % yield obsd ee,b calcd ee,c
entry 8a/8b conditionsa
°C
M/P-5
%
%
1
2
3
4
5
6
7
1.1/1
1.1/1
7.5/1
20/1
20/1
1.1/1
20/1
SmI2
SmI2
SmI2
SmI2
SmI2
NaOH
NaOH
25
0
25
25
0
25
25
99d
99d
84e
68e
86e
99e
99e
18
18
88
92
93
13
87
7
7
77
91
91
7
91
a SmI2 ) 4.5 equiv of SmI2, THF, 20 equiv of ethylene glycol, 30
min; NaOH ) 0.05 M NaOH/THF, 5 h. b M-5 is the major enantiomer
in all cases. c This is the diastereomeric excess (de) % 8a - % 8b.
d Crude yield. e Isolated yield.
to increase the isomer ratio by recrystallizing the 20/1 mixture
failed, presumably because return to the equilibrium ratio is faster
than crystallization.
The barrier to interconversion of the atropisomers 6a,b was
measured to be about 23 kcal/mol by a standard NMR experiment
(see Supporting Information). The structure of 6a as determined
by X-ray crystallography is shown in Figure 1. As expected, the
nitrogen atom of the ortho-anilide is now pyramidal, and the
o-tert-butyl group adopts an orientation that is roughly syn to
the vicinal nitrogen lone pair. We suggest that the sp2-sp3 C-N
bond is the source of the restricted rotation in 6a and that its
isomer 6b (eq 3) has the C-N bond rotated roughly 180° with
the nitrogen inverted to again be pyramidalized away from the
tert-butyl group. Accordingly, formation of 6a may be the first
example of a crystallization-induced asymmetric transformation
that involves atroposelectivity about an sp2-sp3 bond.
Given the poor yields of acidic hydrolysis, we initially cleaved
6 with samarium iodide10 to provide 3 in good yield. As shown
in Table 1, the ee of 3 (in favor of the M-isomer) depends directly
on the diastereomeric ratio of 6a/b. The 1.1/1 equilibrium mixture
again gave 5 with about 18% ee (entry 1), while the 20/1 mixture
gave 3 in 92% ee (entry 4). The ratios were not dependent on
temperature (compare entries 1/2 and 4/5). An intermediate 7.5/1
mixture (obtained by partial isomerization of the 20/1 prior to
quenching with SmI2) gave product of intermediate ee (88%, entry
3). We subsequently discovered that hydrolysis under basic
conditions occurred in high yield.8 Once again, the ee of the
product 3 depended directly on the diastereomer ratio of the
precursor 6 (entries 6 and 7). These results suggest that the
reactions (reduction or hydrolysis) are fast relative to C-N bond
rotation, and that the ee of the product 5 is determined
predominately by the de of the precursor 6.
Acknowledgment. We thank the National Science Foundation and
the Universite´ Catholique de Louvain-La-Neuve (Belgium) for funding
this work. We thank Dr. Steven Geib for solving the X-ray crystal
structures.
Supporting Information Available: Complete experimental and
characterization details for all new compounds and details for the crystal
structures of 6a and 7a (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Molander, G. A. Org. React. 1994, 46, 211.
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