3,3′-oxazolidinyl-substituted 2,2′-biphenyldiols: Novel tropos ligands with a large induction on the chiral axis

Article abstract of DOI:10.1021/ol060528u

A novel type of bisphenol ligand is presented which provides high modularity. Chiral information is introduced in the 3,3′-positions as N-arenesulfonyl-1,3-oxazolidines inducing an unexpectedly high diastereoselectivity of up to 98:2 onto the chiral axis.

Full text of DOI:10.1021/ol060528u

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2455-2458
3,3
2,2
′
′
-Oxazolidinyl-Substituted
-Biphenyldiols: Novel Tropos
Ligands with a Large Induction on the
Chiral Axis
Stefan Wu1nnemann, Roland Fro1
hlich,† and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received March 3, 2006
ABSTRACT
A novel type of bisphenol ligand is presented which provides high modularity. Chiral information is introduced in the 3,3′-positions as
N-arenesulfonyl-1,3-oxazolidines inducing an unexpectedly high diastereoselectivity of up to 98:2 onto the chiral axis. The impact of each part
of the molecule on the diastereomeric ratio is evaluated with extended variable-temperature (VT) NMR studies. A first example of application
in asymmetric catalysis is given.
In asymmetric catalysis, enantiomerically pure BINOLs play
an important role for ligand design. However, substantially
less work is published using the related but flexible 2,2′-
dihydroxybiphenyl as a ligand backbone.1 In the design of
such phosphite and phosphoramidite ligands, the use of chiral
alcohols or amines or asymmetric activation by additional
chiral ligands has been a popular approach.2 Within these,
little attention has been dedicated to the examination of
asymmetric induction onto the chiral axis of the backbone,3
whereas many researchers report rapid ring inversion of the
dibenzo[d,f][1,3,2]dioxaphosphepine moiety (Scheme 1).
Scheme 1. Ring Inversion
† To whom correspondence regarding X-ray structure analysis should
be addressed.
(1) For a review on atropisomerism see: Mikami, K.; Aikawa, K.; Yusa,
Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, 1561.
(2) See, for example: (a) Mata, Y.; Die´guez, M.; Pa`mies, O.; Claver,
C. Org. Lett. 2005, 7, 5597. (b) Alexakis, A.; Polet, D. Org. Lett. 2004, 6,
3529. (c) Reetz, M. T.; Li, X. Angew. Chem., Int. Ed. 2005, 44, 2959. (d)
Duursma, A.; Pen˜a, D.; Minnaard, A. J.; Feringa, B. L. Tetrahedron:
Asymmetry 2005, 16, 1901.
In our laboratories, chiral N-arenesulfonyl-1,3-oxazolidines
have played an important role as chiral auxiliaries, and we
have demonstrated their utility in total synthesis.4 Their
formation from aldehydes and N-arenesulfonyl-2-amino-1-
(3) See, for example: (a) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig,
J. F. J. Am. Chem. Soc. 2005, 127, 15506. (b) Shum, S. P.; Pastor, S. D.;
DeBellis, A. D.; Odorisio, P. A.; Burke, L.; Clarke, F. H.; Rihs, G.; Piatek,
B.; Rodebaugh, R. K. Inorg. Chem. 2003, 42, 5097. (c) Pastor, S. D.; Shum,
S. P.; Rodebaugh, R. K.; DeBellis, A. D. HelV. Chim. Acta 1993, 76, 900.
(4) (a) Hoppe, I.; Hoppe, D.; Wolff, C.; Egert, E.; Herbst, R. Angew.
Chem., Int. Ed. Engl. 1989, 28, 67. (b) Hoppe, I.; Hoffmann, H.; Ga¨rtner,
I.; Krettek, T.; Hoppe, D. Synthesis 1991, 1157. (c) Bru¨ggemann, M.; Holst,
C.; Hoppe, D. Eur. J. Org. Chem. 2001, 647. (d) Winter, E.; Hoppe, D.
Tetrahedron 1998, 54, 10329.
10.1021/ol060528u CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/18/2006

alkanols proceeds with exclusive 2,4-cis selectivity (Scheme
2). We decided to apply this excellent selectivity as source
the hydroxy groups into more electron-poor acetates. Bis-
acetylated bisphenol 5 reacts with N-arenesulfonylamino
alcohols 6 in the presence of dichlorodimethylsilane in
refluxing toluene to give the desired bis-1,3-oxazolidines 7
in excellent yields. Finally, after hydrolysis of the acetates,
the oxazolidines 8 were converted into phosphites 9 using
phosphorus trichloride and alcohols.
Scheme 2. Formation of 2,4-cis-1,3-Oxazolidines
To demonstrate the high modularity of our approach, we
synthesized a number of ligands in good to excellent yields.
Variations at three sites in the molecule can easily be
performed: (i) a number of amino alcohols (available from
cheap natural sources) can readily react with dialdehyde 5,
(ii) different arenesulfonyl groups are tolerated (Table 1),
of chirality in our ligand design. The synthesis of our novel
ligands is depicted in Scheme 3. Starting from phenol 1,
Scheme 3. Synthesis of Ligands 9a
Table 1. Synthesis of 1,3-Oxazolidines 7 and 8
product 7
(% yield)
product 8
(% yield)
entry
R1, R2
R3
1
2
3
4
5
6
Et, H
Tola
Tol
Tol
Tol
Asb
Mesc
ent-7a (83)
7b (90)
7c (90)
7d (84)
7e (37)
ent-8a (99)
8b (99)
8c (95)
8d (94)
8e (72)
i-Pr, H
s-Bu, H
Bn, H
Me, Ph
Et, H
ent-7f (50)
ent-8f (88)
a Tol ) 4-methylphenyl. b As ) 4-methoxyphenyl. c Mes ) 2,4,6-
trimethylphenyl
and (iii) a broad range of alcohols can be reacted to give the
desired phosphites 9 (Table 2).
Table 2. Synthesis of Phosphites 9, Diastereomeric Ratio in
Toluene-d8, and Enantiomeric Excess in Model Reaction
(Scheme 4)
product 9
(% yield)
TC ee of
(K) 12 (%)
entry R1, R2 R3
R4
dr
1
2
3
4
5
6
7
8
9
Et, H
Tol Ph
ent-9a (86) 87:13 243
68
78
39
68
2
i-Pr, H Tol Ph
s-Bu, H Tol Ph
Bn, H Tol Ph
Me, Ph As Ph
Et, H
Et, H
9b (90)
9c (69)
88:12 243
89:11 243
88:12 243
73:27 223
98:2 233
a In a few cases, the opposite enantiomers, ent-7 to ent-9, have
been prepared (see Tables 1 and 2 for substituent key).
9d (98)
9e (67)
Mes Ph
Tol i-Pr
ent-9f (72)
9
ent-9g (49) >95:5
9h (66) >95:5
Tol CH(i-Pr)2 ent-9i (74) 95:5 243
94:6 253
83
67
68
70
bisphenol 2 is obtained using a literature protocol5 and is
subsequently converted into the bis-carbamate 3.
i-Pr, H Tol i-Pr
Et, H
10 i-Pr, H Tol CH(i-Pr)2 9j (60)
Double ortho-lithiation by a carefully optimized method
developed in our group6 and subsequent DMF quench and
deprotection in a one-pot operation furnished bis-salicylal-
dehyde 4. The key stepsoxazolidine formationsturned out
to be problematic. In contrast to simple benzaldehyde, a
number of protocols4 led to failure in the transformation of
4, presumably for electronic reasons. Thus, we converted
As can be seen from Table 1, the formation of 1,3-
oxazolidines was performed in fair to very good yields.
Hydrolysis of the acetyl groups mostly occurred in excellent
yield. Introduction of sterically more demanding groups
(entries 5 and 6, Table 1) resulted in a decrease of the yield.
In particular, the nor-pseudoephedrine-derived compounds
7e and 8e could only be obtained bearing the anisylsulfonyl
group; other arenesulfonyl groups failed. Importantly, all
oxazolidines were synthesized on a gram scale.
(5) (a) Buisman, G. J. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Tetrahedron: Asymmetry 1993, 4, 1625. (b) Yamato, T.; Hasegawa, K.;
Saruwatari, Y.; Doamekpor, L. Chem. Ber. 1993, 126, 1435.
(6) (a) Kauch, M.; Hoppe, D. Can. J. Chem 2001, 79, 1736. (b) Kauch,
M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005, 70, 7149.
2456
Org. Lett., Vol. 8, No. 12, 2006

In the final step, oxazolidines 8 were reacted with
phosphorus trichloride and phenol or aliphatic alcohols,
respectively (Table 2). Systematic variation of each inter-
changeable substituent allowed investigation of the impact
of each residue on the diastereomeric ratio concerning the
chiral axis (vide infra). Therefore, all oxazolidines 8 were
converted into the corresponding 2-phenoxydibenzo[d,f]-
[1,3,2]dioxaphosphepines 9a-f (entries 1-6), and a subset
was reacted with branched aliphatic alcohols to vary the steric
bulk of substituent R4 in phosphites 9. The yields for that
step range from moderate to excellent. Again, the nor-
pseudoephedrine derivative afforded a lower yield. As a
general trend, phenol seems to furnish higher yields.
It is worth noting that all phosphites 9 are reasonably stable
toward oxidation to the corresponding phosphate and can
be chromatographed on silica. However, during crystalliza-
tion attempts, compound 9f was oxidized and a single crystal
of phosphate 10f (Figure 1) was obtained; nevertheless the
Figure 2. VT 31P NMR-spectra of phosphite 9d in toluene-d8.
to compounds 9 in 39% overall yield. This showed no
dynamic behavior in the VT NMR experiment. Hence, it can
be concluded that the dynamic interconversion does not occur
within the chiral 1,3-oxazolidine moieties.
Figure 3. BINOL-derived phosphite 11.
Figure 1. X-ray structure of phosphate 10f.
Most of the phosphites show coalescence around TC )
243 K. Again, the nor-pseudoephedrine derived com-
pound 9e (entry 5) behaves differently with a lower tem-
perature of coalescence at 223 K. The other exceptions, the
mesitylenesulfonyl compound 9f and the highly branched
phosphite 9j (entries 6 and 10), do not differ significantly.
In nearly all cases, we observe the typical broadening of the
signals which form two distinct signals upon further cooling.
This is the case, even for those phosphites which display a
strong difference in the population of both diastereomers
(entries 6, 9, and 10). Further cooling again leads to broad-
ening of the signals which is due to slower conformational
dynamic in all parts of the molecule. In contrast, compounds
9g and 9h (entries 7 and 8) show slightly broadened signals
around 243 K which neither become sharpened at lowered
temperature nor form a second signal. We therefore cannot
quote a well-defined coalescence temperature TC. Further-
more, we expect the diasteromeric ratio to be higher than
95:5, but we cannot give exact values.
desired information remains untouched: the absolute con-
figuration of the chiral axis is (aS) with (2R,4R)-configured
1,3-oxazolidines. We assume that this should also be the
configuration of the major isomer in solution.7
For the determination of diastereomeric ratios, the phos-
phites were subjected to VT 31P NMR-spectroscopic studies.
The results are shown in Table 2, and a representative plot
showing coalescence and resolution of two distinct reso-
nances is depicted in Figure 2.
The dynamic behavior found in the temperature-dependent
31P NMR spectra clearly results from the interchange of both
atropisomers of 9 by rotation around the chiral biaryl axis,
as evidenced by two further experiments. First, irradiation
experiments at low temperature showed correspondence of
both signals observed. Second, the related oxazolidine 11
(Figure 3) derived from (S)-BINOL was synthesized similarly
(7) CD-spectroscopic and quantum chemical investigations on a related
compound support this assumption; in cooperation with C. Diedrich and S.
Grimme. To be published.
We first examined the impact of substituent R1 on the
diasteromeric ratio (entries 1-4, Table 2). Increasing the size
Org. Lett., Vol. 8, No. 12, 2006
2457

of R1 slightly enhances the energy difference between both
configurations, whereas introduction of aromatic side groups
in 9d has no influence. We then turned our attention on the
effect of further substitution of the 1,3-oxazolidine moiety
(entry 5). It is necessary that substituents at carbons 4 and 5
of the heterocycle are in a trans relationship.8 However, this
variation only led to dramaticly less selectivity in combina-
tion with a lowered rotational barrier as can be seen from
the lower coalescence temperature of 9e. To our delight,
increasing the steric bulk of the arenesulfonyl group shows
substantial impact on the diastereoselectivity; a ratio of 98:2
is observed in ent-9f.
We finally varied the size of the substituent at the
phosphorus atom (entries 7-10). On going from flat phenol
to branched alcohols we expected stronger steric interaction
of the heterocycles with the residue at the P-atom. Introduc-
tion of an isopropoxy group led to the described behavior
of compound 9g in the VT NMR spectra (vide supra). With
this strongly enhanced selectivity of more than 95:5 in hand,
we hoped that an even more branched substituent (compound
9i) would lead to higher selectivity and clear spectra. In
contrast, we obtained spectra with a more developed
coalescence phenomenon (more equal populations of the
interchanging signals furnishes more broadened signals at
TC) and a selectivity below our expectations of 95:5. We
therefore further investigated this behavior by slightly
increasing the size of the alkyl residues R1 in the hetero-
cycles. Isopropoxy compound 9h (entry 8) showed spectra
comparable to phosphite 9g. Finally, the highly branched
phosphite 9j again displayed a decrease in selectivity.
Interestingly, the ratio of 94:6 is slightly lower than that of
compound 9i bearing a sterically less demanding alkyl group
R1. This makes us assume that in phosphites 9i and 9j the
molecule might be somewhat sterically overcrowded, leading
to a decrease in selectivity.
Scheme 4. Michael Addition of Diethylzinc to
2-Cyclohexenone
The enantioselectivities obtained are found in Table 2. In
general, (2R,4R)-configured ligands furnish (R)-12.10 On one
hand, ligand 9g, which displays one of the best ratios
concerning the chiral axis, delivers the best result in the
model reaction, but on the other hand, there is no general
trend between the diastereoselectivity within the free ligand
and the ee in the Michael product 12. Nevertheless, these
results demonstrate the potential that lies within our highly
modular ligands.
In conclusion, we presented the synthesis of novel and
highly modular (four variable sites) bisphenol-based ligands.
All synthetic steps proceed in good to excellent yield and
can be performed on a gram scale. To the best of our
knowledge, this is the first bisphenol-based phosphorus
ligand reported that bears the chiral information at the 3,3′-
positions. The 1,3-oxazolidinyl substituents are relatively far
away from the chiral biaryl axis and have an unexpectedly
high impact on the diastereomeric ratio. The selectivity of
up to 98:2 for this type of compounds is the best so far
reported. The strong influence of the arenesulfonyl group
on the diastereomeric ratio renders the free hydroxy oxazo-
lidines 8 an interesting subject of research suitable for the
use as diol ligands, complementing BINOL compounds. This
project is currently under way, as well as further investiga-
tions in the field of phosphites 9.
Acknowledgment. Generous support by the Fonds der
Chemischen Industrie is gratefully acknowledged.
To demonstrate the potential use of our novel bisphenol
compounds as ligands in asymmetric catalysis, we applied
them in the copper-mediated Michael-type addition of
diethylzinc to 2-cyclohexenone (Scheme 4).9
Supporting Information Available: Representative pro-
cedures, spectral data of new compounds, and crystal-
lographic data (CIF) for compound 10f. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) In our work using chiral N-arenesulfonyl-1,3-oxazolidines as chiral
auxiliaries, nor-pseudoephedrine derivatives often provided superior selec-
tivity; see, for example: Bru¨ggemann, M.; Fro¨hlich, R.; Wibbeling, B.;
Holst, C.; Hoppe, D. Tetrahedron 2002, 58, 321.
OL060528U
(9) For reviews on copper-catalyzed Michael additions, see: (a) Alexakis,
A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (b) Krause, N.; Hoffmann-
Ro¨der, A. Synthesis 2001, 171.
(10) The absolute configuration of 12 was determined by derivatiza-
tion: Alexakis, A.; Frutos, J. C.; Mangeney, P. Tetrahedron: Asymmetry
1993, 4, 2431.
2458
Org. Lett., Vol. 8, No. 12, 2006