Using amide conformation to 'project' the stereochemistry of an (-)-ephedrine-derived oxazolidine: A pair of pseudoenantiomeric chiral amido-phosphine ligands

Article abstract of DOI:10.1016/S0957-4166(01)00110-0

Protection of a tertiary 2-formylbenzamide as an (-)-ephedrine-derived oxazolidine both forces the amide's stereogenic Ar-CO axis to adopt one of two possible diastereoisomeric conformations and protects the formyl group from attack during amide ortho-lit

Full text of DOI:10.1016/S0957-4166(01)00110-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 695–698
Using amide conformation to ‘project’ the stereochemistry of an
(−)-ephedrine-derived oxazolidine: a pair of pseudoenantiomeric
chiral amido-phosphine ligands
Jonathan Clayden,* Lai Wah Lai and Madeleine Helliwell
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 5 February 2001; accepted 2 March 2001
Abstract—Protection of a tertiary 2-formylbenzamide as an (−)-ephedrine-derived oxazolidine both forces the amide’s stereogenic
Ar–CO axis to adopt one of two possible diastereoisomeric conformations and protects the formyl group from attack during
amide ortho-lithiation. By functionalising the amide in the 6-position, reactive sites (such as –CHO, –SR, –PR2 groups) may be
introduced which fall under the stereochemical influence, relayed by the amide, of the (−)-ephedrine-derived oxazolidine. This
‘projection’ of stereochemistry is exemplified by a pair of amido-phosphines, members of the first ever class of non-biaryl
atropisomeric ligands, which are made functionally pseudoenantiomeric by the intervention of either one or two amide groups
between the (−)-ephedrine-derived oxazolidine and the PPh2 group. The pseudoenantiomeric amido-phosphines promote the
palladium-catalysed asymmetric allylation of dimethyl malonate in 82 and −53% e.e., respectively. © 2001 Published by Elsevier
Science Ltd.
We recently introduced1 the use of (−)-ephedrine as a
resolving agent for the dynamic resolution of atropiso-
mers. Formation of an (−)-ephedrine-derived oxazo-
lidine adjacent to the stereogenic ArꢀCO axis of a
tertiary aromatic amide gives the oxazolidine thermo-
dynamic control over the conformation of the amide.
We now expand upon this finding, exploiting the appar-
ent compatibility of the ephedrine-derived oxazolidine
with ortho-lithiation chemistry2 to make enantiomeri-
cally pure functionalised atropisomeric amides by a
short sequence of lithiation/electrophilic quench steps.
We also demonstrate that the conformation of the
amide, itself under the influence of (−)-ephedrine, is
able to control further stereoselective reactions, relaying
(or ‘projecting’) the stereochemistry of the (−)-
ephedrine-derived oxazolidine onto reaction sites both
within the amide molecule and in other molecules.
Oxazolidines 1 and 2, which are apparently single
ArꢀCO conformers in solution,1 were made from the
aldehydes and (−)-ephedrine, as described previously.
Lithiation with s-BuLi (1.3 equiv.) gave organolithiums
3 and 4, which reacted cleanly with methyl iodide to
yield 5a (E=Me) and 6a (E=Me) as single atropiso-
mers (by 1H NMR), with the preferred conformation of
the amide now locked in place by the second ortho-sub-
stituent (Scheme 1).3 An X-ray crystal structure of 5a
(E=Me) (Fig. 1) confirmed the stereochemistry of the
product, and hence the conformational preference of
the starting material 1. The ephedrine-derived oxaz-
Scheme 1. Ortholithiation of ephedrine-protected amido-aldehydes.
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00110-0

696
J. Clayden et al. / Tetrahedron: Asymmetry 12 (2001) 695–698
Figure 1. X-Ray crystal structures of 5a, 5e, 5f and 5g.
olidine functions both as a source of stereocontrol and
as a useful protecting group during the lithiation step.4
amide to relay, or project,9 a stereochemical influence
from the oxazolidine onto the new ortho-substituent.
To demonstrate this effect, we treated the aldehyde 5d
with phenylmagnesium bromide, a reaction similar to a
known10,11 atroposelective transformation of 2-formyl-
1-naphthamides, and obtained a single diastereoisomer
(>95:5 by NMR) of the alcohol 7 in quantitative yield
(Scheme 2).12 In essence, this is an instance of 1,7-stereo-
control, in which stereochemistry is relayed from
ephedrine to the new stereogenic centre via the configu-
ration at the stereogenic centre in the oxazolidine ring
and the conformational preference of the amide axis.
We repeated the lithiation–quench sequence of Scheme
1 with a series of electrophiles (Table 1). In each case,
a single atropisomer (by NMR) of the products 5 or 6
was obtained, and the structure and stereochemistry of
the sulfides 5e and 5f and phosphine 5g were confirmed
by X-ray crystallography (Fig. 1). This atroposelective
synthesis of amides 5 and 6 is conceptually similar to
our published use of a 1-silylethyl group as a source of
stereocontrol,5 but it is easier to construct an (−)-
ephedrine derived oxazolidine than to carry out an
enantioselective silylation reaction.6,7
In 5e–5g, a potential metal-coordinating site (the sulfide
or phosphine) should similarly be under the projected
stereochemical influence of the (−)-ephedrine-derived
oxazolidine. The ortho-lithiation route to these com-
pounds (Scheme 1) represents a highly efficient synthe-
sis of a series of potential chiral ligands for metals, and
we set out to establish the utility of phosphine 5g by
employing it in a palladium-catalysed allylic substitu-
tion reaction.13 Racemic 1,3-diphenylallyl acetate 8 was
treated with dimethylmalonate, allylpalladium chloride
The new substituents ortho to the amide group in 5 and
6, while relatively remote from the chirality of the
oxazolidine, still fall under the oxazolidine’s stereo-
chemical influence because of the control the oxazo-
lidine exerts over amide conformation. We have shown,
in a series of papers,8 that the stereogenic axis of
tertiary aromatic amides is a powerful director of
stereoselective reactions, and in 5 and 6 we expected the
Table 1. Functionalised atropisomeric amido-oxazolidines produced by the method of Scheme 1
Entry
R
E+
E
Oxazolidine product
Yield (%)
1
2
3
4
5
6
7
8
9
i-Pr
Et
i-Pr
Et
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
MeI
MeI
EtI
EtI
Me2CO
Me2NCHO
Me2S2
Ph2S2
ClPPh2
Me
Me
Et
Et
C(OH)Me2
CHO
SMe
SPh
5a
6a
5b
6b
5c
5d
5e
5f
55
58
69
58
89
89
39
53
44
PPh2
5g

J. Clayden et al. / Tetrahedron: Asymmetry 12 (2001) 695–698
697
Scheme 2. Projecting the stereochemistry of the oxazolidine onto a new stereogenic centre.
assume PdꢀP complexation is involved, with the amide
system projecting the stereochemistry of the ephedrine-
derived oxazolidine onto the phosphorus atom.
Nonetheless, it seems conceivable that the asymmetric
induction observed in these reactions arises not from
the stereochemistry of the rotationally restricted amide
group but from direct complexation of palladium by
the oxazolidine ring. To rule out this possibility, we
made a ligand still containing ephedrine, but whose
phosphorus atom is in a local environment pseudo-
enantiomeric with that of 5g.
Scheme 3. Allylic substitution reactions with atropisomeric
amido-phosphine ligands.
We know that ortho-disposed tertiary carboxamides
align their carbonyl groups anti, presumably to avoid
steric interactions between the NR2 groups, and we
have used such conformational interlocking of two
amide groups to relay stereochemistry around an aro-
matic ring14 or from one ring to another.15 The stereo-
chemistry of the second amide is inverted relative to
that of the first. We ortho-lithiated N,N,N%,N%-tetra-
isopropylbenzene-1,2-dicarboxamide 1016 and con-
verted it to the aldehyde 11. This aldehyde reacted with
ephedrine under the usual conditions to give the oxazo-
lidine 12 which was isolated in 83% yield, and whose
X-ray crystal structure (Fig. 2) clearly displays an anti
arrangement between the two amide groups. The oxa-
zolidine-containing diamide 12 was lithiated and
quenched with chlorodiphenylphosphine to give, in low
yield, but as an easily purified white solid, the
bis(amido)phosphine 13 (Scheme 4).
Figure 2. X-Ray crystal structure of 12.
dimer (1 mol%), phosphine 5g (3 mol%) and N,O-
bis(trimethylsilyl)acetamide (3 equiv.) and the mixture
stirred at 20°C for 24 hours. The product (S)-(−)-9 was
obtained in 93% yield, with an enantiomeric excess of
82% (HPLC on chiral stationary phase: Whelk-O1)
(Scheme 3).
The allylic substitution reaction (Scheme 3) was
repeated with the phosphine 13 and gave, as expected,
the (R)-(+) enantiomer of the product 9, with an e.e. of
53%. The local environment at the oxazolidine is the
It is not yet possible to be precise about the mode of
coordination between palladium and the ligand, but we
Scheme 4. Asymmetric synthesis of a chiral bis(amido)phosphine.

698
J. Clayden et al. / Tetrahedron: Asymmetry 12 (2001) 695–698
same in both ligands, while the environment at phos-
phorus is pseudoenantiomeric, so we are confident that
the asymmetric induction observed with atropisomeric
amido-phosphine ligands is due to the stereochemistry
of the ArꢀCO axis.17
Ref. 16 and Clayden, J.; Westlund, N.; Beddoes, R. L.;
Helliwell, M. J. Chem. Soc., Perkin Trans. 1 2000, 1351.
8. For a review, see: Clayden, J. Synlett 1998, 810. For
further leading references, see: Clayden, J.; Westlund, N.;
Frampton, C. S. J. Chem. Soc., Perkin Trans. 1 2000,
1379; Clayden, J.; Helliwell, M.; McCarthy, C.; West-
lund, N. J. Chem. Soc., Perkin Trans. 1 2000, 3232;
Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron
Lett. 1999, 40, 3329; Clayden, J.; Westlund, N.; Wilson,
F. X. Tetrahedron Lett. 1999, 40, 3331; Ahmed, A.;
Clayden, J.; Rowley, M. Tetrahedron Lett. 1998, 39,
6103; Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38,
2561.
9. We feel that the term ‘projecting stereochemistry’ carries
some useful implications absent from ‘relaying stereo-
chemistry’. Projection implies the representation, at a
distance, of a three-dimensional object on a two dimen-
sional surface. It also implies inversion (by use of a lens).
These three features—distance, planarity, inversion—are
all aspects of the amide’s role in these reactions: the
essential steric features of the gross, three-dimensional
stereochemistry of the oxazolidine are reproduced, with
inversion, in the conformation of the amide in the two-
dimensional plane perpendicular to the aromatic ring.
Inversion occurs because the amide places its bulk anti to
the bulk of the oxazolidine, and a second inversion is
apparent when two amides are placed in sequence, con-
tinuing the lens analogy.
Acknowledgements
We are grateful to the EPSRC and to GlaxoWellcome
for a CASE award (to L.W.L.), to Dr. Paul Johnson
for carrying out the synthesis of 5d and 9 and to Dr.
Andrew Craven for many helpful discussions.
References
1. Snieckus, V. Chem. Rev. 1990, 90, 879.
2. Clayden, J.; Lai, L. W. Tetrahedron Lett., submitted.
3. On addition of a second ortho substituent, the thermody-
namically stable but kinetically labile ArꢀCO axis of 1 or
2 becomes both thermodynamically and kinetically stable
in 5 and 6. For discussion of this matter, see Ref. 5.
4. We had previously had difficulties ortho-lithiating amides
bearing aldehydes protected as lithiohemiaminals
(Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49,
1078), acetals, or aminals (Clayden, J.; Lai, L. W.; West-
lund, N.; Youssef, L. H., unpublished observations),
presumably due to competing complexation of s-BuLi to
the protected aldehyde. Irrespective of stereochemical
features, condensation with (−)-ephedrine is currently our
favoured method for protecting aldehydes during ortho-
lithiation.
10. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron
Lett. 1996, 37, 5577.
11. Clayden, J.; McCarthy, C.; Westlund, N.; Frampton, C.
S. J. Chem. Soc., Perkin Trans. 1 2000, 1363.
12. Stereochemistry assigned by analogy with precedent, see:
Refs. 10 and 11.
5. Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J.
13. Trost, B. M.; van Vranke, D. L. Chem. Rev. 1996, 96,
395.
Org. Chem. 2000, 65, 7033.
6. Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am.
Chem. Soc. 1994, 116, 9755.
14. Clayden, J.; Pink, J. H.; Yasin, S. A. Tetrahedron Lett.
1998, 39, 105.
7. Removal of (−)-ephedrine from the amide as though it
were an auxiliary (by the method of Ref. 1) was not
successful: oxazolidines 5a, 5b, or 5e were hydrolysed
(CF3CO2H) and reduced immediately at low temperature
to alcohols, but the enantiomeric excesses obtained were
only 8, 28 and 0%, respectively. Presumably, racemisation
of a configurationally unstable intermediate aldehyde is
responsible: atropisomeric amides with trigonal 2-sub-
stituents (2-formyl or 2-acyl, in particular) have very
poor resistance to racemisation by bond rotation: see
15. Clayden, J.; Kenworthy, M. N.; Youssef, L. H. Tetra-
hedron Lett. 2000, 41, 5171.
16. Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.;
McCarthy, C.; Pink, J. H.; Westlund, N.; Yasin, S. A.
Tetrahedron 1998, 54, 13277.
17. The local environment of the phosphorus atom in 5g is
homochiral with that of the phosphorus atom in our
previously published amido-phosphine ligand (Ref. 5),
and a similar degree and sense of enantioselectivity arise
from both ligands.
.
.