The modulation of face-face π-π Interactions in Lewis acid catalysis

Article abstract of DOI:10.1016/j.tetlet.2005.01.086

The enantiomeric excess observed for the exo-adduct from the Lewis acid catalysed Diels-Alder reaction between cyclopentadiene and methacrolein can be increased up to 21% by simple modification of the electronics of the aromatic ring in a series of stilbene-derived diol ligands, suggesting that the proposed face-face π-π interaction between the catalyst and the dienophile can be modulated by altering the electron density on the aromatic ring.

Full text of DOI:10.1016/j.tetlet.2005.01.086

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1627–1629
The modulation of face–face p–p interactions in
Lewis acid catalysis
Lisa D. Harris, Robert L. Jenkins and Nicholas C. O. Tomkinson*
School of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Received 15 November 2004; revised 13 January 2005; accepted 18 January 2005
Available online 1 February 2005
Abstract—The enantiomeric excess observed for the exo-adduct from the Lewis acid catalysed Diels–Alder reaction between cyclo-
pentadiene and methacrolein can be increased up to 21% by simple modification of the electronics of the aromatic ring in a series of
stilbene-derived diol ligands, suggesting that the proposed face–face p–p interaction between the catalyst and the dienophile can be
modulated by altering the electron density on the aromatic ring.
Ó 2005 Elsevier Ltd. All rights reserved.
The chemistÕs tool box contains a battery of catalysts
able to carry out numerous synthetic transformations
in high chemical yield and enantiomeric excess. Mech-
of the aromatic ring. Secondly, a catalyst which had pre-
viously been reported to accelerate a reaction with only
moderate ee, such that small changes in the energy of a
preferred transition state would allow for larger fluctua-
tions in the selectivities observed for the reaction. Based
1
anistic insight and structural knowledge has led to an
increasing elegance in the rational design of catalysts
and their fine tuning, to the degree, where yields and
enantiomeric excess are consistently being reported in
on these criteria we targeted the C symmetric stilbene-
2
derived diols 2 (Fig. 1). Jones and Guzel have shown
previously that the 3-methoxystyrene derived diol 1
induces asymmetry in the Diels–Alder reaction between
cyclopentadiene and methacrolein in 21% ee when
2
excess of 90%.
Many reported catalysts in the literature have attributed
a high degree of selectivity observed to a non-covalent
6
complexed to a Lewis acidic metal. In this report the
3
face–face p–p interaction. This subtle, yet highly effec-
tive interaction, has frequently been proposed with, for
asymmetric induction observed was rationalised by
invoking a face–face p–p interaction between the double
bond of the methacrolein and the aromatic ring incorpo-
rated into the structure of the catalyst. We therefore
embarked upon the synthesis of the diols 8–12 to evalu-
ate their reactivity in asymmetric Diels–Alder reactions
and discover if it was possible to modulate the proposed
face–face p–p interactions, providing a method for the
fine tuning of other catalytic systems that invoke this
non-covalent interaction as an explanation for
selectivity.
4
,13
example, phenyl or naphthyl as the aromatic partner.
As part of our research programme into novel Lewis
5
acids we were intrigued as to whether it would be pos-
sible to modulate a proposed face–face p–p interaction
by altering the electronics on an aromatic ring incorpo-
rated into the structure of a catalyst, thus adding to the
points of consideration in the design of prospective cata-
lyst architecture. Herein we report that it is possible to
alter significantly the eeÕs observed in a Diels–Alder
reaction up to 21% by simple modification of the elec-
tronics in a series of stilbene-derived diol ligands.
OH
X
OH
OH
In choosing the catalytic system to use we adopted two
initial criteria. Firstly, an easy to synthesise system that
would allow rapid preparation of a variety of analogues
OH
OMe
X
Keywords: Lewis acids; Diels–Alder reaction; p–p interactions.
Corresponding author. Tel.: +44 029 20874068; fax: +44 029
20874030; e-mail: tomkinsonnc@cardiff.ac.uk
1
2
*
Figure 1.
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.086

1628
L. D. Harris et al. / Tetrahedron Letters 46 (2005) 1627–1629
X
X
OH
CHO
(a)
(b) or (c)
X
OH
(65%)
X
X
X = OMe, Me, CF3
3
4
5
6
X = H
8
9
X = H
X = OMe (75%)
X = Me (79%)
X = CF3 (75%)
X = OMe (65%)
10 X = Me (68%)
11 X = CF3 (67%)
Br
Br
OH
OH
I
(d)
(b) or (c)
Br
Br
Br
7
(70%)
12 ( 71%)
t
Scheme 1. Reagents and conditions: (a) TiCl
, K
4
, Zn, THF, D; (b) AD-mix-b, BuOH, H
O, rt, 48 h; (d) CH CHC Br, Pd(OAc)
2
O, MeSO NH
2
2
, 0 °C, 48 h; (c) quinuclidine, K
3 6
Fe(CN) ,
t
, BuOH, H
K
2
CO
3
2
[Os(OH)
4
], MeSO
2
NH
2
2
2
6
H
4
2
, PPh , NEt
3
3
, CH
3
CN, rt, 24 h.
Both routes adopted for the synthesis of our ligands 8–
2 utilised the Sharpless asymmetric dihydroxylation as
employed within the reaction and the (S)-enantiomer
of the exo-adduct was formed preferentially as deter-
mined by HPLC analysis on the 2,4-dinitrophenylhydr-
azine derivative. Each ligand was complexed with
monobromoborane or dimethylaluminium chloride as
the Lewis acidic metal and we were delighted to see that
in both series of Lewis acids used a clear trend was
apparent indicating that it was indeed possible to modu-
late the proposed interaction.
1
a method for introduction of asymmetry. The (E)-stilb-
enes 4–6 were prepared via a McMurray type reaction of
the substituted aromatic aldehydes in the presence of
titanium tetrachloride and zinc as reported by Dyker
1
2
7
and Kellner, and the bromo-substituted stilbene 7 was
prepared via a standard Heck reaction between 4-bro-
8
moiodobenzene and 4-bromostyrene (Scheme 1). The
substituted stilbenes 4–7 along with the commercially
available unsubstituted parent system 3 were then
dihydroxylated under standard Sharpless conditions
With monobromoborane as the Lewis acid, when the
ligand contained an electron-deficient aromatic ring 11
and 12, a low ee of just 9% was observed for the
Diels–Alder adduct (entries 1 and 2). However, as the
electron density associated with the aromatic ring was
increased there was a clear increase in the ee of the prod-
uct, with the unsubstituted aromatic furnishing the
product in 24% ee (entry 3), rising to 28% ee for the
methyl substituted ligand (entry 4) and 30% for the ani-
sole derived ligand (entry 5). A similar trend was also
observed with this family of ligands when dimethylalu-
minium chloride was used within the reaction, with the
ee of the exo-Diels–Alder adduct increasing by 19%
from electron-deficient (11%) (entry 6) to electron-rich
(30%) (entry 10). Both these series suggest that in the de-
sign of a catalytic system that invokes a face–face p–p
interaction within the diastereofacial discrimination of
an electron-deficient alkene then increasing the electron
density on the aromatic ring leads to higher asymmetric
induction being observed within the transformation,
providing a more effective catalyst.
using (DHQD) PHAL as the source of asymmetry
2
followed by recrystallisation of the product to give the
corresponding (R,R)-diols 8–12 in good yields. The
enantiomeric excess of each ligand was confirmed to
be >98% by preparation of the racemic diols (±)-8–12
9
according to the method of Warren and co-workers fol-
lowed by H NMR experiments in the presence of the
1
chiral shift reagent Eu(hfc) ; in each case the proton
3
a to the hydroxyl group providing a handle with which
1
0
to determine the ee. Having prepared our family of
ligands we then sort to investigate their properties in
the Diels–Alder reaction, a fundamental bench-mark
process for testing the effectiveness of new potential
ligands in Lewis acid catalysis.
It has been well established that the method by which
the active catalytic species is prepared for the Lewis acid
catalysed Diels–Alder reaction can greatly influence the
enantiocontrol observed. For example, it has been re-
ported previously that no asymmetric induction was ob-
served for the use of one of our proposed ligands 8 in the
A possible transition state assembly consistent with
these findings is depicted in Figure 2. It has been pro-
posed by Corey and Loh that a-substituted dienophiles
prefer to adopt an s-cis conformation due to steric rea-
sons, with the metal bound trans- to the substituents
1
1
reaction between methacrolein and cyclopentadiene.
However, we found that consistent and repeatable re-
sults were obtained by preparation of the active catalytic
6
species as described by Jones and Guzel.
1
3
in a,b-unsaturated aldehydes. Although this is not
the only possible conformation that could be adopted
by the system, the effect observed suggests that the
alkene is closely associated with the aromatic ring of
The results obtained for our catalytic studies of the reac-
tion between cyclopentadiene and methacrolein are out-
lined in Table 1. In each case the (R,R) catalyst was

L. D. Harris et al. / Tetrahedron Letters 46 (2005) 1627–1629
1629
Table 1. Lewis acid catalysed Diels–Alder reaction between cyclopentadiene and methacrolein moderated by stilbene diols 8–12
O
cat (10mol%)
CH Cl , -78°C
NH NHAr,
2
H
N
+
+
isomers
+ isomers
H
CHO
EtOH, r.t.
N
Ar
2
2
2
4 h.
Ar = 2,4-dinitrophenyl
a
b
c
Entry
Ligand
Lewis acid
Endo:Exo ratio
% Ee exo-adduct
% Yield
1
2
3
4
5
6
7
8
9
11
12
8
BH
BH
BH
BH
BH
2
2
2
2
2
Br
Br
Br
Br
Br
25:75
20:80
10:90
19:81
7:93
9 (S)
9 (S)
68
68
70
73
79
69
64
73
70
81
24 (S)
28 (S)
30( S)
11 (S)
14 (S)
26 (S)
27 (S)
30( S)
10
9
11
12
8
AlMe
AlMe
AlMe
AlMe
AlMe
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
29:71
11:89
10:90
19:81
15:85
10
9
10
a
b
c
1
Determined by H NMR on the crude reaction mixtures.
12
Determined by HPLC on the 2,4-dinitrophenylhydrazine derivative.
Isolated yield of endo- and exo-isomers.
X
References and notes
O
M
1. (a) Asymmetric Catalysis, RoddÕs Chemistry of Carbon
Compounds; Sainsbury, M., Ed.; Elsevier: Amsterdam,
2001; Vol. 5; (b) Catalytic Asymmetric Synthesis; Ojima,
I., Ed., 2nd ed.; Wiley-VCH: New York, 2000; (c)
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg,
O
O
X
X = CF3 Br
H
Me OMe
BH2Br % e.e. =
9
9 24 28 30
Me2AlCl % e.e. = 11 14 26 27 30
1999; Vols. I–III; (d) Williams, J. R. Catalysis in Asym-
metric Synthesis; Academic: Sheffield, 1999.
increase in e.e.
2
. For some recent examples see: (a) Ryu, D. H.; Lee, T. W.;
Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992; (b)
Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc.
Figure 2.
2
002, 124, 5950; (c) Viton, F.; Bernardinelli, G.; Kundig,
the (R,R)-ligand with the diene approaching the re-face
of the dienophile.
E. P. J. Am. Chem. Soc. 2002, 124, 4968; (d) Corey, E. J.;
Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808;
(
1
e) Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
24, 2882.
In summary, we present evidence that it is possible to
modulate face–face p–p interactions between aromatic
rings and electron-deficient alkenes within a Lewis acid
catalysed reaction resulting in a notable influence in
the ee observed. From the results presented, it appears
that electron-rich aromatics increase the proposed
non-covalent interaction and can increase the ee ob-
served in the Diels–Alder reaction between cyclopent-
adiene and methacrolein up to 21%. We are currently
investigating whether this is a general phenomenon that
can be applied to a variety of known catalyst architec-
tures where higher levels of asymmetric induction have
been reported and thus provide a general point of con-
sideration when designing potential catalyst systems.
Our findings in these and related areas will be reported
shortly.
3
. (a) Jones, G. B. Tetrahedron 2001, 57, 7999; (b) Jones, G.
B.; Chapman, B. J. Synlett 1995, 475.
4
. For some examples of invoked face–face p–p interactions
in catalytic asymmetric synthesis see: (a) Ishihara, K.;
Gao, Q.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
10412; (b) Corey, E. J.; Loh, T.-P.; Roper, T. D.;
Azimioara, M. D.; Noe, M. C. J. Am. Chem. Soc. 1992,
1
14, 8290.
5
. (a) Harris, L. D.; Platts, J. A.; Tomkinson, N. C. O. Org.
Biomol. Chem. 2003, 1, 457; (b) Coogan, M. P.; Haigh, R.;
Hall, A.; Harris, L. D.; Hibbs, D. E.; Jenkins, R. L.; Jones,
C. L.; Tomkinson, N. C. O. Tetrahedron 2003, 59, 7389.
. Jones, G. B.; Guzel, M. Tetrahedron: Asymmetry 1998, 9, 2023.
. Dyker, G.; Kellner, A. Eur. J. Org. Chem. 1998, 1, 149.
6
7
8. Sengupta, S.; Sadhukhan, S. K.; Singh, R. S.; Pal, N.
Tetrahedron Lett. 2002, 43, 1117.
9
. Eames, J.; Mitchell, H. J.; Nelson, A.; OÕBrien, P.;
Warren, S.; Wyatt, P. J. Chem. Soc., Perkin Trans. 1
1
999, 1095.
Acknowledgements
1
1
1
0. All compounds prepared were characterised by mp, [a] ,
D
1 13
H NMR, C NMR, IR, MS and HRMS.
The authors wish to express their gratitude to the
EPSRC for a studentship GR/R41750/01 (L.D.H.) and
an advanced research fellowship GR/T04113/01
N.C.O.T.), the Royal Society and the Nuffield Founda-
tion for equipment grants and the EPSRC HRMS
service at Swansea for analyses.
1. Rebiere, F.; Riant, O.; Kagan, H. B. Tetrahedron:
Asymmetry 1990, 1, 199.
2. Harris, L. D.; Hall, A.; Jenkins, R. L.; Jones, C. L.;
Tomkinson, N. C. O. Tetrahedron Lett. 2003, 44, 111.
13. Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113,
(
8966.