(-)-Ephedrine as an auxiliary for the asymmetric synthesis of atropisomeric amides by dynamic resolution under thermodynamic control

Article abstract of DOI:10.1016/S0040-4039(01)00416-6

N,N-Dialkyl-2-formylbenzamides and N,N-dialkyl-2-formyl-1-naphthamides condense with (-)-ephedrine in refluxing toluene to give oxazolidines both as single diastereoisomers with respect to the new stereogenic centre and as single conformers with respect t

Full text of DOI:10.1016/S0040-4039(01)00416-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3163–3166
(−)-Ephedrine as an auxiliary for the asymmetric synthesis of
atropisomeric amides by dynamic resolution under
thermodynamic control
Jonathan Clayden* and Lai Wah Lai
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 20 December 2000; revised 29 January 2001; accepted 12 March 2001
Abstract—N,N-Dialkyl-2-formylbenzamides and N,N-dialkyl-2-formyl-1-naphthamides condense with (−)-ephedrine in refluxing
toluene to give oxazolidines both as single diastereoisomers with respect to the new stereogenic centre and as single conformers
with respect to the slowly-rotating ArꢀCONR2 bond. In the naphthamide series, removal of the ephedrine auxiliary by hydrolysis
returns the starting aldehyde (isolated by reduction to the more stable alcohol) in enantiomerically enriched form (up to 94% ee).
Overall, the two-step sequence amounts to a dynamic resolution under thermodynamic control. © 2001 Elsevier Science Ltd. All
rights reserved.
We1 and others,2 have recently demonstrated that non-
biaryl atropisomers (such as hindered aromatic amides
and anilides) are powerful agents of intramolecular
stereocontrol. The development of reactions employing
non-biaryl atropisomers for intermolecular control of
stereochemistry has been hampered by the shortage of
effective methods for their asymmetric synthesis. A
handful of methods for the asymmetric synthesis of
axially chiral aromatic amides (with varying degrees of
generality) have now been described,3–7 including one
involving dynamic resolution under thermodynamic
control,5 and one of these allowed us to demonstrate
for the first time a non-biaryl atropisomer acting as a
chiral ligand in an asymmetric metal-promoted
reaction.6
and directly by using (−)-ephedrine-derived oxazolidi-
nes formed in one-step by condensation of commer-
cially available (−)-ephedrine with 2-formyl benzamides
and naphthamides.8 It is well established that that
(1R,2S)-(−)-ephedrine 19 and (1S,2S)-(+)-pseudoephe-
drine 210 condense with aromatic aldehydes diastereo-
selectively (with respect to the ‘aminal’ centre) to form
oxazolidines. In order to establish the ability of
ephedrine and pseudoephedrine to control not only the
configuration of a new stereogenic centre in the ring but
also that of an adjacent stereogenic axis, we condensed
them with N,N-diisopropyl-2-formyl-1-naphthamide
311,12 in refluxing toluene under a Dean–Stark con-
denser (Scheme 1). In each case, we obtained single
diastereoisomers 4 and 5, with no trace (in the NMR
spectrum of the crude reaction mixture) of epimers at
either the new stereogenic centre in the oxazolidine ring
or at the rotationally restricted ArꢀCO axis. The oxazo-
In this Letter, we report that thermodynamic control
over amide conformation may be achieved more simply
1
1
HO
Ph
HO
Ph
2
2
MeHN 2 Me
1
(1R, 2S)-(–)-
ephedrine
MeHN
Me
N
N
N
(1S, 2S)-(+)-
pseudoephedrine
Ph
O
H
O
H
O
CHO
O
N
Ph
Me
O
N
toluene,
toluene,
Me
∆
∆
4, 74%
5 , 74%
3
Scheme 1. Condensation of (−)-ephedrine and (+)-pseudoephedrine with a 2-formyl-1-naphthamide.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00416-6

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J. Clayden, L. W. Lai / Tetrahedron Letters 42 (2001) 3163–3166
a 1:1 mixture of stereoisomeric oxazolidines 11a and
11b under these conditions.16,17 8-Heterosubstituted
naphthamides epimerise much more slowly than 8-
unsubstituted naphthamides,18 and presumably the
epimers 11a and 11b do not interconvert under the
conditions of the reaction. Thirdly, while the amides 12
and 13 form oxazolidines 14 and 15 which, without a
second aromatic ortho substituent, cannot exist as two
1
atropisomers,11,15 14 and 15 appear (by H NMR) to
exist as single conformers about the ArꢀCO bond.19
Their conformations must be under thermodynamic
control, and if one ArꢀCO conformer of 14 or 15 is
significantly more stable than the other, it seems rea-
sonable to propose the same for one atropisomer of 4,
7 or 9.
Figure 1. X-ray crystal structure of 4.
lidines were isolated in 70–80% yield after purification
by recrystallisation, and the stereochemistry of 4 was
determined by X-ray crystallography (Fig. 1).
Scheme 3 illustrates the way this dynamic resolution
under thermodynamic control (or ‘dynamic thermody-
namic resolution’20,5) is achieved with aldehyde 3. Con-
densation of 3 with (−)-ephedrine 1 gives an initial,
kinetically controlled mixture of diastereoisomers 4 and
epi-4 which rapidly equilibrate (within minutes) at the
temperature of the reaction. epi-4 Is significantly less
stable than 4, which is the only isolable product of the
reaction. The crystal structure of 4 (Fig. 1) gives an
indication of the origin of its relative stability: as
usual,6,21,22 the stereogenic centre at the ortho-position
prefers its smallest substituent (H) more or less to
eclipse the ArꢀCO bond, so that the plane of the
naphthamide ring bisects the oxazolidine ring. Steric
crowding is significantly lessened if the Ni-Pr2 group
lies anti across the ring to the N–Me group, and this is
the arrangement observed in 4.
Similar reactions of four further aldehydes 6, 8, 10 and
12 (Scheme 2) illuminate the mechanism by which
(−)-ephedrine gains control of the stereogenic ArꢀCO
axis of 4. Like 3, amides 612 and 813 reacted with
ephedrine to give single diastereoisomers of the oxazo-
lidines 7 and 9. Given that the aldehydes 3, 6 and 8 are
racemic, atropisomeric compounds,14 the formation of
4, 7 and 9 as single diastereoisomers in >50% yield can
be explained only by a dynamic resolution of some
kind. Dynamic resolution implies interconversion of
stereoisomers, and the temperature of the reaction
(110°C) provides easily enough thermal energy to
racemise 3, 6 and 8,11 so dynamic kinetic resolution
during the oxazolidine formation (one atropisomeric
enantiomer reacting faster than the other) is certainly
feasible. However, several features of the reactions of 3,
6, 8, and also 10, 12 and 13 lead us to believe that the
stereoselective formation of 4, 7 and 9 is under thermo-
dynamic control, as illustrated in Scheme 3. Firstly,
typical barriers to epimerisation of N,N-dialkyl-1-naph-
thamides bearing chiral, branched 2-substituents lie
between 105 and 115 kJ mol−1.11,15 At 110°C, a kineti-
cally-determined ratio of such products will be irrele-
vant to the outcome of a reaction lasting more than 10
min; the stereoselectivity will be determined by equili-
bration to the most stable epimer. Secondly, the amide
10, which should also racemise rapidly at 110°C, gives
In order to complete the resolution of 3 and 6, the
ephedrine auxiliary must be removed from 4 and 7. In
each case, acid-catalysed hydrolysis returned the enan-
tiomerically-enriched aldehyde, but given the low barri-
ers to racemisation of 1-naphthamides bearing carbonyl
groups in their 2-positions11,5,23 we found it necessary
to reduce the product aldehydes rapidly to alcohols 16
and 17 to prevent rapid racemisation of the products.24
Loss of enantiomeric purity, particularly from 17, is
presumably due to the ease of racemisation of the
N
N
N
N
O
H
O
H
O
O
1
1
CHO
CHO
O
N
Ph
Me
O
N
Ph
Me
toluene,
toluene,
∆
∆
7
8
6
, 87%
9, 41%
R
R
N
R
R
N
N
N
MeO O
H
O
H
MeO O
O
1
1
CHO
CHO
O
N
Ph
Me
O
N
Ph
Me
toluene,
toluene,
∆
∆
11a + 11b, 82%a
1:1 mixture of diastereoisomersa
12 (R = Et)
13 (R = i-Pr)
14 (R = Et); 34%
15 (R = i-Pr); 94%
10
one Ar–CO conformer by 1H NMR
Scheme 2. Condensation of (−)-ephedrine with amidoaldehydes. a Taken from Refs. 8 and 9.

J. Clayden, L. W. Lai / Tetrahedron Letters 42 (2001) 3163–3166
3165
view
from
here:
O
N
N
N
N
O
H
O
O
(i)
(ii), (iii)
H
O
N
Ph
Me
CHO
Me
OH
O
N
favoured
Me
4
Ph
(S)-3
(S)-16
1
89%; 94% ee
110 °C
not isolated
3
view
from
here:
N
O
N
O
N
O
H
(i)-(iii)
H
7
Me
OH
O
N
Ph
Me
O
N
disfavoured
epi-4
Me
Ph
(S)-17
85%; 74% ee
Scheme 3. Dynamic thermodynamic resolution of atropisomeric 2-formylnaphthamides. (i) CF3CO2H (20 equiv.), THF, H2O; (ii)
NaOMe (25 equiv.); (iii) NaBH4 (10 equiv.).
aldehyde intermediate. We are currently developing
new applications for enantiomerically pure non-biaryl
atropisomers, particularly as chiral ligands for metals,
and these will be reported in due course.
1997, 38, 4447; (j) Bach, T.; Schro¨der, J.; Harms, K.
Tetrahedron Lett. 1999, 40, 9003.
3. Thayumanavan, S.; Beak, P.; Curran, D. P. Tetrahedron
Lett. 1996, 37, 2899.
4. Koide, H.; Uemura, M. J. Chem. Soc., Chem. Commun.
1998, 2483.
Acknowledgements
5. Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. 1999, 38,
2556.
6. Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org.
Chem. 2000, 65, 7033.
7. Clayden, J.; Johnson, P.; Pink, J. H. J. Chem. Soc., Perkin
We are grateful to the EPSRC and to GlaxoWellcome
for a CASE award (to L.W.L.), to Dr. Andrew Craven
for many helpful discussions, and to Dr. Madeleine
Helliwell for determining the X-ray crystal structure of
4.
Trans. 1 2001, 371.
8. This ephedrine-based method has a number of advantages
over our previously-described method based on diamine-
derived aminals (Ref. 5). (−)-Ephedrine, unlike the
diamine, is cheap and commercially available as both
enantiomers, and the oxazolidines are more stable to
purification than animals.
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N
N
N
N
1. s-BuLi
2. Me2NCHO
1. s-BuLi
2. EtI
1. s-BuLi
2. Me3SiCl
O
O
Me3Si O
O
CHO
3. TBAF
24%
46%
54%
8

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J. Clayden, L. W. Lai / Tetrahedron Letters 42 (2001) 3163–3166
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on the NMR timescale: for example, 2-substituted benza-
mides containing a stereogenic centre typically display
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temperature due to the two slowly-interconverting
ArꢀCO conformers. For further discussion, see Refs. 22
and 6.
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.
.