Non-linear effects operate and dynamic ligand exchange occurs when chiral BINOL-boron Lewis acids are used for asymmetric catalysis

Article abstract of DOI:10.1016/S0957-4166(03)00352-5

Non-linear effects reveal that the use of chiral BINOL-boron reagents for aza-Diels-Alder reactions results in an enantioselective catalytic species containing at least 2 equiv. of BINOL. Dynamic ligand exchange and ligand accelerated catalysis occurs in these reactions, consistent with the formation of a cyclic borate ester of BINOL with enhanced Lewis acidity.

Full text of DOI:10.1016/S0957-4166(03)00352-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1965–1968
Non-linear effects operate and dynamic ligand exchange occurs
when chiral BINOL–boron Lewis acids are used for asymmetric
catalysis
Jean Philippe Cros, Yolanda Pe´rez-Fuertes, Michael J. Thatcher, Susumu Arimori, Steven D. Bull*
and Tony D. James*
Department of Chemistry, University of Bath, Bath BA2 7AY, UK
Received 1 April 2003; accepted 24 April 2003
Abstract—Non-linear effects reveal that the use of chiral BINOL–boron reagents for aza-Diels–Alder reactions results in an
enantioselective catalytic species containing at least 2 equiv. of BINOL. Dynamic ligand exchange and ligand accelerated catalysis
occurs in these reactions, consistent with the formation of a cyclic borate ester of BINOL with enhanced Lewis acidity. © 2003
Elsevier Science Ltd. All rights reserved.
It is well known that boron–ligand complexes contain-
ing aryloxy ligands can undergo dynamic ligand
exchange in solution,1 and this fact has been exploited
by Yamamoto et al., and others, in developing a range
of boron complexes containing enantiopure 1,1%-
binaphthol [BINOL] (and its derivatives) as chiral
Lewis acids for asymmetric catalysis.2–7 Their first
report on the use of chiral boron reagents derived from
BINOL described that mixing 1 equiv. of (PhO)3B 1
with 1 equiv. of BINOL (R)-2 in dry CH2Cl2 resulted in
a self-assembled chiral boron reagent (R)-3a that
catalysed formal asymmetric aza-Diels–Alder reactions8
in good e.e. (Scheme 1). Thus, treatment of a range of
N-benzylaldimines 4a–e and Danishefsky’s diene 5 with
a stoichiometric amount of chiral boron reagent (R)-3a
in CH2Cl2 at −78°C gave a range of chiral N-benzyl-
2,3-dihydro-1H-pyridin-4-ones (R)-6a–e in 74–90% e.e.
(Scheme 2).2
diastereoselective aza-Diels–Alder,2b,3 and aldimine–
aldol reactions,4 with complex (R)-7 being invoked as
the catalytically active species in each case.
Yamamoto et al. subsequently introduced an alterna-
tive protocol for the preparation of this type of chiral
boron–BINOL reagent by refluxing 2 equiv. of (R)-
Scheme 1.
Yamamoto et al. proposed that monomeric BINOL–
boron complex (R)-7 was the most likely active cata-
lytic species in these reactions,2a however the possibility
that other BINOL–boron species might be responsible
for the observed enantioselectivity was not excluded.9
Subsequently, this chiral boron reagent (R)-3a was
employed as a stoichiometric chiral Lewis acid for
* Corresponding authors. Tel.: +44-1225-383551; fax: +44-1225-
386231 (S.D.B.); Tel.: +44-1225-383810; fax: +44-1225-386231
(T.D.J.); e-mail: s.d.bull@bath.ac.uk; t.d.james@bath.ac.uk
Scheme 2.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00352-5

1966
J. P. Cros et al. / Tetrahedron: Asymmetry 14 (2003) 1965–1968
BINOL with 1 equiv. of (MeO)3B in CH2Cl2 in the
6
,
presence of 4 A molecular sieves. A crystalline precata-
lyst was isolated and characterised via spectroscopic and
crystallographic analysis as a dimeric ‘ate’ species
(R,R)-8 that contained 2 equiv. of (R)-BINOL.6 Chiral
boron reagent (R,R)-87 was shown to demonstrate sim-
ilar reactivity to chiral boron reagent (R)-3a catalysing
the formation of (R)-6a in 86% e.e.6 (compare with 82%
e.e.2 for formation of (R)-6a using (R)-3a).
Non-linear effects in asymmetric catalysis have previ-
ously been employed to probe whether enantioselective
catalytic species contain 2 or more equiv. of chiral
ligand.10 Consequently, we chose to investigate whether
the use of (R)-3a for formal aza-Diels–Alder reactions
using scalemic BINOL would result in a non-linear
effect, since the existence of this phenomena would
establish that a complex containing 2 equiv. of (R)-
BINOL was responsible for the high enantioselectivity
in these reactions. The formal aza-Diels–Alder reaction
between N-benzylphenylimine 4a and Danishefsky’s
diene 5 for the formation of (R)-6a (R=Ph) was chosen
as our model reaction and carried out using chiral
boron reagent (R)-3a which was prepared via premixing
(R)-BINOL (1 equiv.) and (PhO)3B (1 equiv.) in CH2Cl2
under anhydrous conditions at room temperature.2 In
our hands, this formal aza-Diels–Alder reaction at −
78°C reproducibly gave (R)-6a in 77% e.e.,11 which was
inferior to the value of 82% e.e. previously reported for
the formation of (R)-6a using (R)-3a under these condi-
tions.2
Figure 1. Graph of non-linear effects for conversion of 4a+5
into (R)-6a using chiral reagents (R)-3a and (R)-3b. (R)-3a
prepared using 1 equiv. of (R)-BINOL (ꢀ) and (R)-3b pre-
pared using 2 equiv. of (R)-BINOL (ꢁ).
Nevertheless, this formal aza-Diels–Alder reaction was
repeated four times at −78°C using a chiral boron
reagent (R)-3a derived from 1 equiv. of BINOL of
varying enantiopurity (ranging from 0 to 80% e.e.)
under otherwise identical conditions, and the enan-
tiomeric excess of (R)-6a determined in each case.
Analysis of the enantiomeric excess obtained for (R)-6a
in these reactions clearly revealed the presence of a small
but significant positive non-linear effect (Fig. 1), thus
providing clear experimental evidence that the active
catalyst responsible for asymmetric induction in this
reaction contained more than 1 equiv. of (R)-BINOL.
(PhO)3B. This implied that the chiral catalyst generated
in this reaction must catalyse the formation of (R)-6a at
a significantly faster rate than (PhO)3B catalysed the
background racemic reaction to afford (rac)-6a.
Consequently, we next carried out the same formal
aza-Diels–Alder reaction at −78°C using a chiral boron
reagent (R)-3b prepared from (PhO)3B and 2 equiv. of
(R)-BINOL, which reproducibly gave (R)-6a in an
improved 81% e.e. Unsurprisingly, the use of scalemic
BINOL for the preparation of (R)-3b resulted in the
formation of (R)-6a with an even greater positive non-
linear effect than that observed for (R)-3a (Fig. 1), thus
providing compelling evidence that the enantioselective
catalytic species present in both these reactions contains
at least 2 equiv. of (R)-BINOL.12
A potential explanation for the observed rate accelera-
tion for (R)-3a and (R)-3b is the fact that cyclic borate
esters are known to be stronger Lewis acids than the
corresponding acyclic borate esters.1b Thus, if (R)-3a
and (R)-3b afford an enantioselective catalytic species
that contains a cyclic borate ester of (R)-BINOL then it
would display enhanced Lewis acidity relative to acyclic
(PhO)3B, thus explaining both the rate enhancement
and good enantioselectivity observed in this reaction.
Since the enantioselective catalytic species in these reac-
tions must contain either a trivalent or tetravalent boron
species and at least 2 equiv. of (R)-BINOL, we reasoned
that the use of (R)-3a for catalysis must occur in the
presence of significant amounts of unreacted achiral
Given the similar non-linear effects, enantioselectivity,
and ligand acceleration effects13 observed for the
formation of (R)-6a using (R)-3a or (R)-3b in
this reaction, it is reasonable to propose that the same

J. P. Cros et al. / Tetrahedron: Asymmetry 14 (2003) 1965–1968
1967
enantioselective catalytic species is operating to control
stereoselectivity in both cases. The fact that (R)-3b (2
equiv. (R)-BINOL) affords (R)-6a in higher e.e. than
(R)-3a (1 equiv. (R)-BINOL) would then simply be due
to a higher concentration of the enantioselective cata-
lytic species (2 equiv. (R)-BINOL) being present when
(R)-3b is employed for reaction.
Potential catalytically active species that have been
proposed previously that satisfy this criteria include
(R,R)-8 derived from 2 equiv. of (R)-BINOL and 1
equiv. of boron;6 or (R,R,R)-9 containing 3 equiv. of
(R)-BINOL and 2 equiv. of boron.5f Secondly, the need
for stoichiometric amounts of boron reagent in these
reactions suggest that boron is coordinated to reactants
or products (or both) throughout the course of the
reaction.16 Thirdly, a cyclic chiral boron–BINOL com-
plex with enhanced Lewis acidity affords (R)-6a at a
significantly faster rate than the corresponding acyclic
complex (PhO)3B affords (rac)-6a. Finally, rapid
dynamic ligand exchange of aryloxy ligands occurs
between all of the aryloxy–boron complexes present in
solution, thus ensuring that (R)-BINOL is always avail-
able for the competing formation of the more reactive
enantioselective complex, even when (R)-BINOL is
employed as a chiral ligand in sub-stoichiometric
amounts.
In order to probe how effectively dynamic ligand
exchange was occurring in these reactions, we carried
out a series of aza-Diels–Alder reactions using chiral
boron reagents prepared from 1 equiv. of (PhO)3B and
sub-stoichiometric quantities of (R)-BINOL. We rea-
soned that if dynamic ligand exchange was occurring,
then turnover of (R)-BINOL between the different
chiral and achiral boron–aryloxy complexes would
occur in these reactions. Since chiral BINOL–boron
complexes afford (R)-6a at a significantly faster rate
than achiral (Ph3O)B complexes afford (rac)-6a then
aryloxy ligand turnover should result in (R)-6a being
formed in a significantly higher e.e. than expected if a
simple linear relationship relating the concentration of
(R)-BINOL to the e.e. of (R)-6a was in operation.
It is likely that similar non-linear effects, dynamic
ligand exchange and ligand accelerated catalysis are
operating in other reaction scenarios where these type
of chiral boron–BINOL reagents have been employed
for asymmetric catalysis. Further investigations are cur-
rently underway in our laboratory to further delineate
the mechanism of these reactions.
Consequently, the aza-Diels–Alder reaction between N-
benzylphenylimine 4a and 5 was carried out using 1
equiv. of a new chiral boron reagent prepared from 1
equiv. of (PhO)3B and 0.1 equiv. of (R)-BINOL (10
mol%) which resulted in formation of (R)-6a in 15%
e.e. This value was clearly greater than the 7.7% e.e.14
for (R)-6a that would have been expected if a linear
relationship relating the concentration of (R)-BINOL
to the e.e. of (R)-6a had occurred. We next carried out
an inverse addition protocol in an attempt to minimise
the background racemic reaction catalysed by (PhO)3B,
whereby dropwise addition of 1 equiv. of (PhO)3B in
CH2Cl2 to a solution of (R)-BINOL (10 mol%), 4a (1
equiv.) and 5 (1 equiv.) in CH2Cl2 at −78°C, over a
period of 5 h, gave (R)-6a in an improved 42.5% e.e.
Finally, use of a syringe pump enabled us to increase
the length of time of inverse addition of PhO3B to 16 h
resulting in a further increase in the enantioselectivity
of (R)-6a to 47% e.e. Thus, it was concluded that
dynamic ligand exchange of (R)-BINOL between chiral
and achiral boron–aryloxy complexes was occurring in
solution, with (R)-6a being formed in an enhanced e.e.
due to the increased rate of the enantioselective
reaction.
Acknowledgements
We would like to thank the Royal Society (T.D.J.,
S.D.B.) and the University of Bath (Y.P.F.) for finan-
cial support.
References
1. (a) James, T. D.; Shinkai, S. Top. Curr. Chem. 2002, 218,
159; (b) The increase in boron Lewis acidity for cyclic
boronate esters over their corresponding acyclic ana-
logues has been ascribed to the change in the OꢀBꢀO
bond angle from 120° to around 108° for the cyclic
system. For detailed discussion of this phenomenon, see:
Ref. 1(a).
2. (a) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57,
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49, 1749.
Clearly, the principle of employing sub-stoichiometric
amounts of a chiral ligand to amplify stereoselectivity
in this manner is a potentially powerful atom efficient
strategy,15 that may be applicable in alternative reac-
tion scenarios where other stoichiometric chiral
reagents that undergo dynamic ligand exchange are
employed for asymmetric synthesis.
3. (a) Hattori, K.; Yamamoto, H. Synlett 1993, 129; (b)
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Bioorg. Med. Chem. Lett. 1993, 3, 2337; (d) Hattori, K.;
Yamamoto, H. Tetrahedron 1994, 50, 2785.
5. For selected examples of other chiral boron reagents
derived from enantiopure BINOL (and its derivatives) for
asymmetric catalysis, see: (a) Kelly, T. R.; Whiting, A.;
Chandrakumar, N. S. J. Am. Chem. Soc. 1986, 108, 3510;
(b) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994,
In conclusion, we propose that the results described
herein, and elsewhere,2,3 are consistent with the follow-
ing reaction mechanism. Firstly, non-linear effects
obtained using scalemic BINOL demonstrate that the
enantioselective species responsible for asymmetric
induction contains at least 2 equiv. of (R)-BINOL.

1968
J. P. Cros et al. / Tetrahedron: Asymmetry 14 (2003) 1965–1968
116, 1561; (c) Umemoto, T.; Adachi, K. J. Org. Chem.
CH2Cl2 (10 ml) and the resulting suspension stirred under
N2 for 1 h at rt. The reaction mixture was cooled to 0°C
and a solution of N-benzyl-a-phenylimine 4a (68 mg, 0.35
mmol) in CH2Cl2 (1 ml) was then added and the reaction
stirred for a further 10 min at 0°C, before cooling to
−78°C followed by dropwise addition of diene 5 (0.084
ml, 0.42 mmol) in CH2Cl2 (1 ml). The reaction was
stirred at −78°C for a further 5 h, before quenching with
water and NaHCO3(aq), dried (MgSO4), and the solvent
removed in vacuo to afford a crude product which was
purified by chromatography over silica gel to afford pure
dihydropyridone (R)-6a in 50–63% yield. The enan-
tiomeric excess of (R)-6a was determined in each case via
chiral HPLC analysis over a Daicel CHIRALPAK AD
column using a mixed hexane/isopropanol (95:5) solvent
at a flow rate of 1.0 ml min−1, which gave baseline
resolution with elution times for (R)-6a of 33 min, and
(S)-6a of 36 min.
1994, 59, 5692; (d) Ishihara, K.; Kurihara, H.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049; (e)
Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H. J.
Org. Chem. 1997, 62, 3026; (f) Thormeier, S.; Carboni,
B.; Kaufmann, D. E. J. Organomet. Chem. 2002, 657,
136.
6. Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520.
7. For other examples where BLA complex (R,R)-8 (and
structural analogues) have been employed as chiral Lewis
acids for asymmetric catalysis, see: (a) Ishihara, K.;
Kuroki, Y.; Yamamoto, H. Synlett 1995, 41; (b) Kawate,
T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Naka-
gawa, M. Synlett 1997, 761; (c) Yamada, H.; Kawate, T.;
Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa,
M. J. Org. Chem. 1998, 63, 6348.
8. Formation of (R)-6a–e may occur via an alternative
tandem Mannich-conjugate addition pathway, however
these reactions are described as formal aza-Diels–Alder
reactions for clarity and consistency with the terminology
used in Refs. 2a,b. For a fuller discussion on the mecha-
nism of these reactions, see: (a) Waldmann, H.; Braun,
M. J. Org. Chem. 1992, 57, 4444; (b) Yuan, Y.; Li, X.;
Ding, K. Org. Lett. 2002, 4, 3309 and references cited
therein.
12. For a previous example where addition of scalemic (R)-
BINOL to borane resulted in kinetic resolution via selec-
tive formation of homochiral 3:2 BINOL–boron complex
(R,R,R)-9 in enantiomerically enriched form, see: Ref. 5f.
13. For a review on ligand accelerated catalysis, see: Berris-
ford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
14. The theoretical value of 7.7% e.e. for (R)-6a is calculated
from 10% of 77% e.e. obtained for (R)-6a using a chiral
boron reagent (R)-3a derived from (R)-BINOL (100%
e.e.).
15. For an overview on the concept of atom-efficiency in
chemical reactions, see: Trost, B. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 259.
16. Use of 10 mol% of (R)-3a as catalyst for the aza-Diels–
Alder reaction between 4a and 5 resulted in formation of
(R)-6a in less than 5% yield.
9. See Ref. 4 in Ref. 2a.
10. For recent reviews on non-linear effects in asymmetric
catalysis, see: (a) Kagan, H. B. Synlett 2001, 888; (b)
Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl.
1998, 37, 2922.
11. Reactions were carried out according to the experimental
protocol described in Refs. 2a and 2b. Thus, BINOL
(R)-2 (100 mg, 0.35 mmol, ranging from 0 to 100% e.e.)
and (PhO)3B (101 mg, 0.35 mmol) were added to a
,
suspension of powdered 4 A molecular sieves (1.0 g) in