Communications
[3] S. Boidnard, L. Neuville, M. Bois-Choussy, J. Zhu, Org. Lett.
2000, 2, 2459.
[4] E. A. Couladouros, E. N. Pitsinos, V. I. Moutsos, G. Sarakinos,
Chem. Eur. J. 2005, 11, 406.
[5] a) J. A. McRae, R. Y. Moir, J. J. Ursprung, H. H. Gibbs, J. Org.
Chem. 1954, 19, 1500; b) M. Dahlgard, R. Q. Brewster, J. Am.
Chem. Soc. 1958, 80, 5861.
[6] H. Kessler, A. Rieker, W. Rundel, J. Chem. Soc. Chem.
Commun. 1968, 475; J. J. Bergman, W. D. Chandlwe, Can. J.
Chem. 1972, 50, 353; P. A. Lehman, Org. Magn. Reson. 1970, 2,
467.
Concerted rotation cannot interconvert the global mini-
mum of one stereoisomer with that of its mirror image for the
trisubstituted ether 19 (Figure 1b); concerted rotation from C
instead passes through local minimum y, with the methyl
group “endo”. One of the two rings must decouple and
undergo an independent rotation to racemize and yield D via
transition state z. Mirror-image minima lie separated by the
ridges on the potential-energy surface illustrated in Figure 1b,
and their interconversion must follow the pathway repre-
sented by the dotted line.
If the proposal that the huge difference in rates of
racemization between 6–8 and 9 and 10 arises from a change
in mechanism of isomerization is correct, then any diaryl
ether, whether trisubstituted or tetrasubstituted, that cannot
isomerize by a low-energy concerted pathway (namely, in
which both rings are unsymmetrically substituted) has the
potential to display atropisomerism. We tested this hypothesis
with the unsymmetrically tetrasubstituted ethers 11 and 16c
(Table 1, entries 22–25). Chromatographic separation of
atropisomers was achieved for 11d, 11e, and 16c, and
incubation of the diastereoisomers of 11d, 11e, and 16c at
raised temperatures in toluene showed only slow isomer-
ization, even over a period of weeks. We estimate that the
half-lives for epimerization of 11d and 11e at room temper-
ature reach well into millennia. Hindered 2,6,2’,6’-tetrasub-
stituted diaryl ethers with two unsymmetrically substituted
rings are stable chiral compounds.
From this data, we draw the following conclusions about
the potential for atropisomerism in acyclic diaryl ethers:
a) Atropisomerism in diaryl ethers depends less on the total
number of substituents than the substitution pattern.
b) Diaryl ethers in which one of the rings is symmetrically
substituted do not exhibit atropisomerism because their
stereoisomers may interconvert by concerted bond rota-
tion. This behavior means that even diaryl ethers with four
ortho substituents may racemize rapidly.
c) Diaryl ethers in which both rings are unsymmetrically
substituted may exhibit atropisomerism, as long as at least
one of the substituents is as large as a tert-butyl group. This
condition can hold even for diaryl ethers with only three
ortho substituents.
[7] B. M. Duggan, D. J. Craik, J. Med. Chem. 1997, 40, 2259.
[8] K. Fuji, T. Oka, T. Kawabata, T. Kinoshita, Tetrahedron Lett.
1998, 39, 1373.
[9] F. Theil, Angew. Chem. 1999, 111, 2493; Angew. Chem. Int. Ed.
1999, 38, 2345; J. S. Sawyer, Tetrahedron 2000, 56, 5045; Z. Liu,
R. C. Larock, Org. Lett. 2004, 6, 99; D. A. Evans, J. L. Katz, T. R.
West, Tetrahedron Lett. 1998, 39, 2937; D. M. T. Chan, K. L.
Monaco, R. Wang, M. P. Winters, Tetrahedron Lett. 1998, 39,
2933; G. Mann, J. F. Hartwig, Tetrahedron Lett. 1997, 38, 8005.
[10] T. D. Krizan, J. C. Martin, J. Org. Chem. 1982, 47, 2681.
[11] For the use of (ꢀ)-ephedrine-derived oxazolidines as protecting
groups for aldehydes during lithiation, see: J. Clayden, Y. J. Y.
Foricher, M. Helliwell, P. Johnson, D. Mitjans, V. Vinader, Org.
Biomol. Chem. 2006, 4, 444.
[12] J. Clayden in Chemistry of Organolithium Compounds, Vol. 1
(Eds.: Z. Rappoport, I. Marek), Wiley, Chichester, 2004, p. 495;
H. W. Gschwend, H. R. Rodriguez, Org. React. 1979, 26, 1.
[13] M. S. Betson, J. Clayden, Synlett 2006, 745.
[14] Lineshapes at a range of temperatures close to, above, and below
the Tc value were simulated by using gNMR software (Adept
Scientific).
[15] The half-lives are for the approach to the equilibrium mixture,
not half-lives for bond rotation. The bond rotation monitored in
6c, 7c, and 8c does not in fact lead to interconversion of
stereoisomers, but the half-life value is calculated in the same
way for consistency.
[16] For examples in which trigonal substituents provide low barriers
to bond rotation, see: A. I. Meyers, J. R. Flisak, R. A. Aitken, J.
Am. Chem. Soc. 1987, 109, 5446; A. Ahmed, R. A. Bragg, J.
Clayden, L. W. Lai, C. McCarthy, J. H. Pink, N. Westlund, S. A.
Yasin, Tetrahedron 1998, 54, 13277; K. Kamikawa, M. Uemura,
Synlett 2000, 938.
[17] Oki has suggested that atropisomers be defined as conformers
that interconvert with a half-life of more than 1000 sꢀ1: M. Oki,
Top. Stereochem. 1983, 14, 1.
[18] D. L. Boger, J.-H. Weng, S. Miyazaki, J. J. McAtee, S. L. Castle,
S. H. Kim, Y. Mori, O. Rogel, H. Strittmatter, Q. Jin, J. Am.
Chem. Soc. 2000, 122, 10047.
In summary, the feature most favorable to high rotational
barriers in diaryl ethers 1 is heavy, but unsymmetrical,
substitution: for stable chirality 1 requires (W,X,Y,Z ¼ H),
(W¼ X), (Y¼ Z), (Wꢁ tBu), and (Yꢁ tBu).
[19] R. Adams, H. C. Yuan, Chem. Rev. 1933, 33, 261.
[20] This estimation is made on the assumption that at least one pair
of diastereotopic or more or less equally populated diastereo-
isomeric peaks would have a peak separation of > 0.1 ppm at the
slow exchange limit.
Received: May 11, 2006
[21] Substituents attached to the symmetrical ring may show
coalescences at higher temperatures, which is indicative of
much higher barriers, but these must be barriers to nonconcerted
bond rotations; a full discussion will follow in a later report.
[22] F. Mohmadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M.
Lipton, C. Caufield, G. Chang, T. Hendrickson, W. C. Still, J.
Comput. Chem. 1990, 11, 440.
Published online: July 28, 2006
Keywords: atropisomerism · diaryl ethers · NMR spectroscopy ·
.
rotational barriers · stereochemistry
[23] P. A. Lehman, E. C. Jorgensen, Tetrahedron 1965, 21, 363; G.
Montaudo, P. Finocchiaro, E. Trivellone, F. Bottino, P. Maravi-
gna, Tetrahedron 1971, 27, 2125; J. C. Emmett, E. S. Pepper,
Nature 1975, 257, 334.
[1] K. C. Nicolaou, C. N. C. Boddy, S. Bräse, N. Winssinger, Angew.
Chem. 1999, 111, 2230; Angew. Chem. Int. Ed. 1999, 38, 2096;
B. M. Crowley, D. L. Boger, J. Am. Chem. Soc. 2006, 128, 2885,
and references therein.
[2] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994.
[24] Ground-state destabilization of tetra-ortho-substituted relative
to tri-ortho-substituted diaryl ethers may also play a role in
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5803 –5807