The iso-VAPOL ligand: Synthesis, solid-state structure and its evaluation as a BOROX catalyst

Article abstract of DOI:10.1039/c4cy00742e

The new vaulted biaryl ligand iso-VAPOL is an isomer of VAPOL but has the chiral pocket of VANOL. The synthesis of iso-VAPOL involves a cycloaddition/electrocyclization cascade (CAEC) similar to one that is used for VAPOL except that the starting material

Full text of DOI:10.1039/c4cy00742e

Catalysis
Science &
Technology
View Article Online
View Journal | View Issue
PAPER
The iso-VAPOL ligand: synthesis, solid-state
structure and its evaluation as a BOROX catalyst†
Cite this: Catal. Sci. Technol., 2014,
4, 4406
*
Anil K. Gupta, Xin Zhang, Richard J. Staples and William D. Wulff
The new vaulted biaryl ligand iso-VAPOL is an isomer of VAPOL but has the chiral pocket of VANOL. The
synthesis of iso-VAPOL involves a cycloaddition/electrocyclization cascade (CAEC) similar to one that is
used for VAPOL except that the starting material for iso-VAPOL is less than one-tenth the cost. The solid-
state structure of iso-VAPOL was determined as well as that of VANOL since it had not been previously
reported. The structures of iso-VAPOL and VANOL are compared to the known solid-state structure of
VAPOL and it is found that all three ligands have the cisoid conformations in the solid-state; the dihedral
angle between the two aryl groups is less than 90°. In addition, all three ligands pack in the solid-state with
no inter-molecular hydrogen bonds. This is the opposite to what has been reported for BINOL where all
known structures exist with transoid conformations where the dihedral angle is >90° and where the BINOL
units pack with hydrogen bonds between neighboring BINOL units. Spectroscopic evidence including
1H and 11B NMR spectra are presented which indicate that the iso-VAPOL ligand will form BOROX catalysts
with B(OPh)3 in much the same way as VAPOL catalysts which have previously reported and characterized
both by spectroscopy and X-ray crystallography. Support for the BOROX catalysts can also be taken from
the fact that iso-VAPOL BOROX catalysts give essentially the same asymmetric inductions as the VAPOL
BOROX catalyst over a range of substrates.
Received 5th June 2014,
Accepted 13th August 2014
DOI: 10.1039/c4cy00742e
www.rsc.org/catalysis
hydrogenation.4 For those reactions in which there is turnover
of the free ligand, VAPOL proved paramount in a boron
1. Introduction
We first introduced the vaulted biaryl ligands VANOL and
VAPOL in 1993 as ligands for an aluminium catalyst in an
asymmetric catalytic Diels–Alder reaction.1 In that particular
system, an aluminum Lewis acid derived from VAPOL gave
much higher asymmetric inductions than did the correspond-
ing VANOL catalyst. Since that time these ligands have been
incorporated into a variety of catalysts whose effectiveness
has been evaluated in over two-dozen different catalytic
asymmetric reactions. Given the deeper chiral pocket of the
VAPOL ligand it might have been expected that VAPOL would
be superior to VANOL in all applications. This is not the
case as VANOL catalysts have proven dominant in a sub-
stantial fraction of these applications. While VAPOL was the
optimal ligand for an aluminum catalyst in the Diels–Alder
reaction,1 a VANOL aluminum catalyst proved preeminent in a
Baeyer–Villiger reaction.2 VAPOL was the ligand of choice in a
Mannich reaction with a zirconium catalyst,3 whereas, VANOL
was found optimal in a titanium catalyst for asymmetric
mediated Petassis reaction,5 while VANOL proved the most
viable in a boron mediated propargylation of ketones6 and
also in a zinc mediated Michael addition of alkynes.7 The
deeper chiral pocket of VAPOL does seem to have won out
for hydrogen phosphate derivatives of VANOL and VAPOL
since all twelve of the applications reported to date with
these Brønsted acid catalysts have faired better with VAPOL.
These include the amidation8 and imidation9 of imines,
the asymmetric reduction of imines,10 desymmetrization of
aziridines,11 benzoyloxylation of aryloxindoles,12 aza-Darzens
reaction,13 chlorination and Michael reactions of oxindoles,14
pinacol rearrangement,15 and reduction of aminals.16 This is
not the case for phosphoramidite derivatives since a VAPOL
derivative was superior for hydroarylation of alkenes17 and a
VANOL derivative for a hydroacylation of alkenes.18 The other
major class of catalysts that are known for VANOL and VAPOL
are the BOROX catalysts which are chiral anionic species com-
prised of a boroxinate core (Fig. 1). These catalysts can function
as chiral anion catalysts as in the Ugi reaction where there is
an ion-pair with an iminium ion and the VAPOL boroxinate
functions far better than the VANOL analog.19 Alternatively, the
BOROX catalysts can function as a Brønsted acid in heteroatom
Diels–Alder reactions where the VAPOL BOROX catalyst is
superior to that of VANOL,20 and in 2-aza-Cope rearrangements
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
E-mail: wulff@chemistry.msu.edu
† Electronic supplementary information (ESI) available. CCDC 1006298 and
1006299. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cy00742e
4406 | Catal. Sci. Technol., 2014, 4, 4406–4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Catalysis Science & Technology
Paper
Fig. 1 (A) Different chiral diols from the vaulted biaryl ligands. (B) Different catalysts derived from VAPOL and VANOL.
where the VANOL BOROX catalyst is superior to that of
VAPOL.21 The VANOL and VAPOL BOROX catalysts also serve
as highly efficient chiral catalytic asymmetric aziridination of
imines with diazo compounds. In contrast to nearly all of the
known reactions mediated by VANOL and VAPOL catalysts, the
catalytic asymmetric aziridination reaction is equally effective
with each ligand. This is true of the reactions of imines with
diazo compounds (two component),22 or of the reactions of
aldehydes, amines and diazo compounds (three component)23
with BOROX derivatives which give essentially the same asym-
metric induction with VANOL and VAPOL ( 1% ee) averaged
over nearly a dozen imine substrates.22,24 We have recently
reported the preparation of 44 new VANOL ligands as a result
of introduction of substituents in all five of the open positions
in VANOL (positions 4 to 8). The BOROX catalysts from these
ligands were screened in the catalytic asymmetric aziridination
reaction with the hot spots found at positions 5, 6 and 7 with
the highest inductions favoring substitution at position 7.25
The vaulted biaryl 3 is an isomer of VAPOL and would be
expected to have a distinct profile from either VAPOL or VANOL
in catalysts for the many reactions described above that have
been documented for VANOL and VAPOL. This ligand would
formally result from moving the benzene ring that is fused
to the 7,8-positions of VANOL to the 5,6-positions of VANOL. We
were attracted to compound 3, or iso-VAPOL, since it could
potentially be prepared in a manner that would be less expensive
than VAPOL by a substantial margin. We describe herein, a
successful synthesis of (S)-iso-VAPOL 3 in an overall yield similar
to that reported for VAPOL and from starting materials that are
more than a factor of ten cheaper than those for VAPOL.
Thereafter, the solid-state structures of the (R)-VANOL 2 and
(S)-iso-VAPOL 3 were compared. Finally, the BOROX catalysts
of (S)-iso-VAPOL and (R)-VANOL 2 were evaluated and com-
pared for the catalytic asymmetric aziridination reaction and it
was found that results using (S)-iso-VAPOL 3 were comparable
to the same catalysts prepared from VANOL and VAPOL.
2. Background
The original method for the synthesis of VANOL and VAPOL
involved the benzannulation of a Fischer carbene complex.26
While this method is highly efficient giving racemic VAPOL
in ~45% overall yield in four steps and since no chromato-
graphy was required until the final step, this reaction could
be readily adapted to large scale. Unfortunately, the cost of
chromium hexacarbonyl greatly hampers the utilization
of this method on large scale. We have also developed a
synthesis of VAPOL based on the Snieckus phenol synthesis
but this has not been evaluated on large scale.27 We
have also developed a very efficient method for the large
scale synthesis of VANOL based on a dienone–phenol
rearrangement but this method is not applicable to VAPOL or
iso-VAPOL.28 The most efficient route for the synthesis of
VANOL and VAPOL that is both scalable and flexible for access
to derivatives involves a cycloaddition/electrocyclization
cascade (CAEC).29 In the case of VAPOL, this begins with
2-naphthyl acetic acid, and after conversion to the corre-
sponding acid chloride, thermolysis with phenyl acetylene
This journal is © The Royal Society of Chemistry 2014
Catal. Sci. Technol., 2014, 4, 4406–4415 | 4407

View Article Online
Paper
Catalysis Science & Technology
initiates the cycloaddition/electrocyclization cascade (CAEC)
that concludes in the formation of 2-phenyl-4-phenanthrol
12 in 74% yield (Scheme 1).29 Approximately ten percent of
the flux in this reaction proceeds to the naphthyl-substituted
phenol 11 which has incorporated two molecules of phenyl
acetylene. An oxidative phenol coupling reaction of 12 gives
rise to racemic VAPOL in 81% yield. All the steps to racemic
VAPOL can be performed on large scale with purification
by crystallization thus avoiding chromatography.29 This
includes the ability to separate the phenanthrol 12 from the
side-product 11 since the latter is ~100 times less soluble in
iso-propanol than the former. A combination of crystalliza-
tion and quick filtration through silica gel to remove colored
impurities allows for the isolation of phenanthrol 12 in 64%
yield from 57 g of the acid 10. The overall yield of 12 varies
with the commercial source of 2-naphthyl acetic acid and
can range from 57 to 75%. Optically pure VAPOL can be
obtained on large scale via its hydrogen phosphate and a
classical resolution with (−)-cinchonidine.29 On small scale,
the most convenient way to secure optically pure VAPOL is
via a deracemization with a copper complex of either (+)- or
(−)-sparteine (Scheme 1).25,30
The cycloaddition/electrocyclization cascade involves a
[2 + 2] cycloaddition of 2-naphthyl ketene 13 with phenyl acety-
lene to give the cyclobutenone 14 (Scheme 2). At the tempera-
ture of the reaction (190 °C), the cyclobutenone 14 will
undergo a 4π e− electrocyclic ring opening to give the
β-naphthyl vinyl ketene 15 which is readily transformed by a
6π e− electrocyclic ring closure to generate the cyclo-
hexadienone 16 that upon tautomerization gives 2-phenyl-4-
phenanthrol 12. iso-Butyric anhydride is added to the reaction
to trap the phenol function in 12 to give the iso-butyrate ester
17. If this is not done, the phenanthrol 12 is trapped by the
ketene 13 to give a 2-naphthyl acetic ester which diverts half of
the starting 2-naphthyl acetic acid to an unproductive course
and drops the yield of phenanthrol 12 by a factor of two.29
3. Results and discussion
Synthesis of iso-VAPOL
The synthesis of iso-VAPOL 3 was envisioned via a cycloaddition/
electrocyclization cascade (CAEC) akin to that developed for
VAPOL shown in Scheme 1. The extension of this strategy for
the synthesis of iso-VAPOL did in fact prove viable and the
Scheme 1
Scheme 2
4408 | Catal. Sci. Technol., 2014, 4, 4406–4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Catalysis Science & Technology
Paper
18 is subjected to thermolysis with phenyl acetylene the desired
3-phenyl-1-phenanthrol 20 was isolated in 54% yield on a
9.4 g scale which is accompanied by the formation of the side-
product 19 in 7% yield. The success of the synthesis depends
on the quality of the 1-naphthyl acetic acid. Some technical
grade samples of 1-naphthyl acetic acid were found to contain
up to 7% of 2-naphthyl acetic acid. The use of technical grade
quality leads to a reaction mixture that contains the VAPOL
monomer 12 and the isolation of compound 20 in pure form
from this mixture proved to be tedious. Thus it is best to use
commercial 1-naphthyl acetic acid that is devoid of its
2-naphthyl isomer which we find is the case with material that
is rated as plant cell culture tested (≥95%). As in the VAPOL
synthesis with 2-naphthyl acetic acid, the side product in the
reaction of 1-naphthyl acetic acid resulted from the incorpora-
tion of two molecules of phenyl acetylene. The completion
of the synthesis of racemic ( )-iso-VAPOL 3 followed from the
oxidative phenol coupling of 3-phenyl-1-phenanthrol 20 which
was effected by heating in mineral oil in the presence of air
at 190 °C to give ( )-3 in 70% yield. Deracemization with a
copper-(−)-sparteine complex gave (S)-iso-VAPOL 3 in 95% yield
and >99% optically purity (Scheme 3).25,30
Scheme 3
details of the synthesis are shown in Scheme 3. The difference
is that while the synthesis of VAPOL begins with 2-naphthyl
acetic acid 10, the synthesis of iso-VAPOL begins with
1-naphthyl acetic acid 18. While both acids are commercially
available, 1-naphthyl acetic acid is more than an order of
magnitude less costly than its 2-naphthyl isomer. 1-Naphthyl
acetic acid 18 is a plant hormone and it is used in agriculture
for a variety of purposes. When the acid chloride derived from
A mechanistic accounting of the products produced in the
cycloaddition/electrocyclization cascade with the acid halide
from 1-naphthyl acetic acid 18 and phenyl acetylene is
presented in Scheme 4. The [2 + 2] cycloaddition of the
1-naphthyl ketene 21 and phenyl acetylene is highly
Scheme 4
This journal is © The Royal Society of Chemistry 2014
Catal. Sci. Technol., 2014, 4, 4406–4415 | 4409

View Article Online
Paper
Catalysis Science & Technology
regioselective giving only the cyclobutene 22 and none of the
regioisomer 27. If the regioisomer 27 had been formed, this
would have lead to the formation of 2-phenyl-1-phenanthrol
29 but this was not observed in the reaction. Electrocyclic
ring opening of the cyclobutene 22 gives the ketene 23 which
can undergo electrocyclic ring closure and tautomerization to
give the desired product 20. The second alkyne in the side-
product 19 is presumed to result from a [2 + 2] cycloaddition
of phenyl acetylene with the β-naphthyl vinyl ketene 23 to
give the cyclobutenone 24 and then a 4π e− electrocyclic ring
opening to ketene 25 followed a 6π e− electrocyclic ring closure
to dienone 26 and finally a tautomerization.
structure of (S)-VAPOL 1,31 the solid-state form of (S)-iso-VAPOL
3 lacks intermolecular hydrogen bonding that prevails for
BINOL. The dihedral angle between the phenanthrene rings of
the (S)-3 is 70.6°. It varies from 80.1° to 88.5° in the case of the
VAPOL ligand.31 The dihedral angle is <90° and corresponds
to the cisoid conformation,32,33 which alters the preferred pack-
ing motif. Also, as in the case of VAPOL,31 the hydroxyl groups
are buried in the pocket created by the phenanthrene rings of
the iso-VAPOL ligand (S)-3. The steric repulsion of these
inverted phenanthrene groups inhibits intermolecular hydro-
gen bonding. Although the VANOL ligand has been reported
and used in many asymmetric reactions, its solid-state struc-
ture has not been studied yet. White needles were obtained
when (R)-VANOL 2 was crystallized from dichloromethane. In
the case of (R)-VANOL 2, three conformations of the unit cell
were observed with the dihedral angles of 69.6°, 74.6°, 76.9°
respectively (Fig. 2B). Thus (R)-VANOL 2 exists in a cisoid con-
formation and surprisingly, it lacks inter molecular hydrogen
bonding. It must be noted that in the case of the BINOL ligand,
intermolecular hydrogen bonding occurs in both the enantio-
pure and racemic crystal structures.34 The dihedral angle
between the naphthalenes of all known solid-state forms
of BINOL is >90° and thus exists in transoid conformations.33
Comparison of the solid-state structures of iso-VAPOL
and VANOL
In the past, the solid-state structure of the VAPOL ligand
has been reported by Matzger and coworkers.31 During the
purification of (S)-iso-VAPOL 3 by silica gel chromatography, a
few crystals were formed serendipitously in one of the fractions
collected. The crystals were then subjected to the X-ray diffrac-
tion analysis and the resulting ORTEP diagram of the crystal
structure is shown in Fig. 2A. As was the case in the crystal
Fig. 2 (A) ORTEP drawing of X-ray crystal structure of (S)-3 and ORTEP drawing of crystal packing of (S)-3 along b-axis. (B) ORTEP drawing of
X-ray crystal structure of all three conformations (in the unit cell) of (R)-2 and ORTEP drawing of crystal packing of (R)-2 along b-axis.
4410 | Catal. Sci. Technol., 2014, 4, 4406–4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Catalysis Science & Technology
Paper
Evaluation of the BOROX catalyst of iso-VAPOL and VANOL
in the aziridination reaction
ligand, B(OPh)3 and H2O in toluene at 80 °C for 1 h and
then removal of all of the volatiles at this temperature under
vacuum (0.1 mm Hg). Addition of the imine 30 should then
initiate the assembly of the BOROX catalyst species 31 and
then finally addition of the ethyl diazoacetate should allow
for aziridine formation to begin. The catalytic asymmetric
aziridination reaction (AZ reaction) was originally developed
with a benzhydryl group (Bh)22c on the imine 30 but later
it was found that the diaryl methyl groups DAM, MEDAM
and BUDAM were much easier to remove from the nitrogen
to give N–H aziridines,35 and in addition, that these groups
gave much higher asymmetric induction in the aziridination
reaction.22e Thus, all four nitrogen protecting groups were
investigated in aziridination reactions catalyzed by the
iso-VAPOL BOROX catalyst and the results are presented
in Table 1.
The generation of the iso-VAPOL BOROX catalyst 31 was
undertaken with the protocol shown in Scheme 5 that is one
of the protocols that has been established for the correspond-
ing VANOL and VAPOL BOROX catalysts.22c,e This protocol
involves the generation of a pre-catalyst by heating the
The initial evaluation of iso-VAPOL ligand was performed
with the four imines 30a–30d prepared from benzaldehyde
and ethyl diazoacetate 32. Each reaction was performed with
5 mol% catalyst in toluene at room temperature for 24 h
although undoubtedly most of the reactions were complete
in far less time. The catalyst was prepared by heating 1 equiv.
of the ligand with 4 equiv. of B(OPh)3 and 1 equiv. H2O in
toluene at 80 °C for 1 h followed by removing all volatiles
under vacuum at this temperature for 0.5 h. The imine
(20 equiv.) was added to assemble the BOROX catalyst and
then ethyl diazoacetate (24 equiv.) was added to start the
reaction. Each of the imines has been previously examined in
the aziridination reaction with ethyl diazo acetate with both
VANOL and VAPOL ligands. However, in the present study
Scheme 5
Table 1 Comparison of vaulted biaryl ligands with different imine protecting groupsa
% yield
% ee
% yield
Entry
Imine
PG
Bh
Ligand
cis-33b
cis-33c
A (B)d
1e
2
30a
(S)-iso-VAPOL
(R)-VANOL
(S)-VAPOLf
(S)-iso-VAPOL
(R)-VANOL
(R)-VAPOLf
(S)-iso-VAPOL
(R)-VANOL
(S)-VAPOLf
(S)-iso-VAPOL
(R)-VANOL
(S)-VAPOLf
82
87
89
91
89
95
96
98
98
97
98
98
92
−89
93
3(7)
<1(<1)
4(3)
6(<1)
1(<1)
1(<1)
2(1)
1(1)
2(2)
<1(<1)
<1(<1)
<1(<1)
3
4e
5
30b
30c
30d
DAM
96
−92
−92
98
6
7
8
9
10
11
12
MEDAM
BUDAM
−97
99
96
−96
99
a
Unless otherwise specified, all reactions were performed with 1 mmol of imine 30 in toluene (0.5 M) with 1.2 equiv. 32 and 5 mol% catalyst
at 25 °C for 24 h and went to 100% completion. In all cases the cis : trans ratio for 33 was 50 : 1. The pre-catalyst was prepared by heating ligand
(1 equiv.) with commercial B(OPh)3 (4 equiv.) and H2O (1 equiv.) in toluene at 80 °C for 1 h, followed by removal of all volatiles under vacuum
b
c
d
(0.1 mm Hg) for 0.5 h at 80 °C. Isolated yield after chromatography on silica gel. Determined by HPLC. Determined by integration of the
e
NH signals of the enamines relative to the methine proton on aziridine ring in cis-33 in the crude reaction mixture. 94% and 96% conversion
f
for entries 1 and 4, respectively. Data from ref. 22e.
This journal is © The Royal Society of Chemistry 2014
Catal. Sci. Technol., 2014, 4, 4406–4415 | 4411

View Article Online
Paper
Catalysis Science & Technology
the reaction of each imine was carried out with iso-VAPOL
and with VANOL where the latter serves as the control. The
data for VAPOL from the literature is also included in Table 1.
In all cases, only the cis-isomer of the aziridine 33 is observed
with a cis : trans ratio of ≥50 : 1. The error is these reactions
is usually larger for the yields than it is for the asymmetric
induction and for the latter it has been found that the
measurements are usually within 1% ee.22c,e Even with
that caveat the differences between the VANOL, VAPOL and
iso-VAPOL ligand are quite small. The iso-VAPOL ligand is
more like the VAPOL ligand with the benzhydryl imine 30a
and slightly better that either VANOL or VAPOL with the DAM
imine 30b. All the ligands perform about the same with the
MEDAM imine and with the BUDAM imine the iso-VAPOL
ligand behaves more like the VANOL ligand.
The effect of solvent on the aziridination of imine 30a
with the iso-VAPOL BOROX catalyst 31 was also examined
and the results are presented in Table 2. There is a signifi-
cant drop in asymmetric induction (~10% ee) in diethyl ether
and ethyl acetate compared to toluene but the cis : trans selec-
tivity is not effected. The drop in asymmetric induction for
the VANOL catalyst in these solvents was only about half as
much. Methylene chloride and 1,2-dichloroethane proved to
be suitable solvents for the iso-VAPOL catalyst giving essen-
tially equivalent results to those in toluene.
be seen from the data in Table 3, there is very little difference
between the inductions observed for the iso-VAPOL and
VANOL BOROX catalysts. This is true for imines derived from
both electron-rich and electron-poor aromatic aldehydes. If
there is any difference, it would be in favor of iso-VAPOL
which gives higher inductions for four substrates and a lower
induction for only one substrate. The cis : trans ratio is ≥50 : 1
in all cases except for the p-methoxyphenyl imine 36a where
the selectivity falls to ~10 : 1, but this happens for both the
iso-VAPOL and VANOL catalysts (entries 7 and 8).
Investigation of the VANOL BOROX catalyst 8 and iso-VAPOL
BOROX catalyst 31 using NMR spectroscopy
We have reported a detailed NMR and crystallographic study
of the VAPOL BOROX catalyst in 2010.22f The structure of the
VANOL BOROX catalyst has been supported by calculations
and NMR experiments and the very characteristic 11B NMR
spectra of the BOROX VAPOL catalyst is also observed for the
VANOL BOROX catalyst.22h In order to gain the evidence for
the generation of the BOROX catalyst 31 from the iso-VAPOL
ligand, a series of NMR experiments was performed (Fig. 3).
Various species were identified based on the characteristic
peaks obtained from
and
for VANOL 2 and iso-VAPOL 3
respectively (Fig. 3A).
The scope of the aziridination reaction for the iso-VAPOL
BOROX catalyst with imines derived from various aldehydes
was carried out on the benzhydryl series since it gives the
lowest asymmetric induction of the four imines and thus
would more likely lead to a difference that would distinguish
between the iso-VAPOL and VANOL ligands. However, as can
The chemical shift of the proton in the 8,8′-positions in
VANOL 2 is assigned as δ = 8.35 ppm (d, CDCl3). This assign-
ment is based on the fact that the most downfield absorption
in VANOL is missing in the 1H NMR spectrum of 8,8-dimethyl-
VANOL for which the most downfield signal is a doublet at
δ = 7.57 ppm.30 The method for pre-catalyst formation involves
Table 2 Effect of solvent on aziridination with VANOL and iso-VAPOL catalystsa
% yield
% ee
Cis : trans
% yield
Entry
Solvent
EtOAc
Ligand
% convb
cis-33ac
cis-33ad
33ae
A (B)f
1
2
3
4
5
6
7
8
9
10
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
45
55
95
96
94
100
94
100
94
100
36
43
83
83
79
83
81
83
82
87
81
−84
80
20 : 1
>50 : 1
50 : 1
50 : 1
25 : 1
50 : 1
50 : 1
50 : 1
50 : 1
50 : 1
5(4)
7(4)
5(6)
4(5)
4(9)
4(8)
4(8)
4(8)
3(7)
Et2O
−84
CH2Cl2
91
−89
91
ClCH2CH2Cl
Toluene
−90
(S)-iso-VAPOL
(R)-VANOL
92
−89
<1(<1)
a
Unless otherwise specified, all reactions were performed with 1 mmol of imine 30a in toluene (0.5 M) with 1.2 equiv. 32 and 5 mol% catalyst at
25 °C for 24 h. The pre-catalyst was prepared as indicated in Table 1. Determined from the 1H NMR spectrum of the crude reaction mixture.
b
c
d
e
Isolated yield after chromatography on silica gel. Determined by HPLC. Determined by integration of the methine protons of the aziridine
ring for the cis and trans isomers of 33a in the 1H NMR spectrum of the crude reaction mixture. f Determined from the 1H NMR spectrum of the
crude reaction mixture by integration of the NH signals of the enamines relative to the methine proton on the aziridine ring in cis-33a.
4412 | Catal. Sci. Technol., 2014, 4, 4406–4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Catalysis Science & Technology
Paper
Table 3 Comparing VANOL and iso-VAPOL and VAPOL with various iminesa
% yield
Azirb
% ee
Azirc
% yield
Entry
Imine
R
Ligand
Aziridine
A (B)d
1
2
3
4
30a
30a
34a
34a
35a
35a
36a
36a
37a
37a
38a
38a
C6H5
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
(S)-iso-VAPOL
(R)-VANOL
33a
33a
39a
39a
40a
40a
41a
41a
42a
42a
43a
43a
82
87
80
83
82
79
62
62
72
70
83
86
92
−89
94
3(7)
<1(<1)
2(6)
4(6)
3(7)
4-BrC6H4
4-MeC6H4
4-MeOC6H4
Cyclohexyl
t-Butyl
−91
5
94
6
−92
89
3(6)
7e
8f
9
<1(6)
<1(3)
9(4)
5(4)
6(<1)
<1(8)
−91
79
10
11
12
−77
84
−84
a
Unless otherwise specified, all reactions were performed with 1 mmol of the imine in toluene (0.5 M) with 1.2 equiv. 32 and 5 mol% catalyst
at 25 °C for 24 h and gave 50 : 1 cis : trans selectivity and went to 94–100% completion. The pre-catalyst was prepared as indicated in Table 1.
b
Isolated yield after chromatography on silica gel. c Determined by HPLC. d Determined from the 1H NMR spectrum of the crude reaction mixture
by integration of the NH signals of the enamines relative to the methine proton on the aziridine ring. Cis/trans = 9 : 1. f Cis/trans = 10 : 1.
e
heating (S)-VANOL with 4 equiv. of commercial B(OPh)3 and
1 equiv. of H2O of at 80 °C. This resulted in the generation of
two species which have been previously tentatively identified as
the pyro-borate B2 45 and the meso-borate 44.22c It is also possi-
ble that one of the two observed species could be the cyclic
pyro-borate 46; further elucidation of the structure of these two
species will have to await additional studies. Treatment of this
mixture with 1 equiv. of the imine 30c at room temperature
within a few minutes results in the conversion of the colorless
solution of 44 and 45 (or 46) to a red solution of boroxinate 8c
11B NMR spectrum for the tetra-coordinate boron where the
ratio of the 3-coordinate to 4-coordinate borons = 2.3 : 1
(entry 4, Fig. 3D, integration not shown). Nearly identical 11B
NMR spectra are observed for the VANOL BOROX22h and
VAPOL BOROX22f catalysts. The presence of a single doublet
at δ
= 8.55 ppm and at δ
= 8.58 ppm for both the
boroxinate complexes 8c and 31c respectively, indicates
that the exchange of the iminium ion from the top face of the
catalyst to the bottom is fast on the NMR time scale in both
the cases. A striking difference between the two boroxinates
8c and 31c was that the splitting in the methyl and methoxy
region of the MEDAM group was absent in the case of the
VANOL ligand derived catalyst 8c (Fig. 3C). The splitting of
methyl and methoxy into two singlets has been observed for
VAPOL derived catalysts.22f This may be due to differentiation
of the two dimethylmethoxyphenyl groups in the catalyst
bound iminium. The chemical shifts of the protons associ-
ated with the nitrogen of the protonated imines in the
complexes 8c and 31c are δ = 13.74 ppm and δ = 13.67 ppm
respectively.
(δ
= 8.55 ppm, d, J = 9.0 Hz, CDCl3) (entry 3, Fig. 3B).
It is well known that most three coordinate aryl borate
esters show very broad absorptions at 16–18 ppm in the
11B NMR. The VANOL BOROX catalyst 8c has a sharp absorp-
tion at δ = 6.09 ppm in 11B NMR (entry 2, Fig. 3D).22h This is
due to the increased spherical symmetry of a four coordinate
boron in the BOROX catalyst. Additionally, a very broad
absorption was also observed at δ = 16.10 ppm, which can be
attributed to the two 3-coordinate borons present in the cata-
lyst. The ratio of the 3-coordinate : 4-coordinate borons is 2 : 1
which is in perfect agreement of the structure of the catalyst
(integration not shown).
The formation of the pre-catalyst from the reaction of iso-
VAPOL 3 seemed to be little cleaner giving a major species
with a doublet at δ = 8.65 ppm (entry 5, Fig. 3B). This species
is tentatively identified as the pyro-borate 45′ but additional
studies will be needed to rule out 44′ or 46′ as the structure
of this species. A new doublet is observed at δ = 8.58 ppm
4. Conclusions
Iso-VAPOL is a new member of the vaulted biaryl family of
atropisomeric ligands and its syntheses and characterization
is described. This ligand is prepared by a cycloaddition/
electrocyclization cascade similar to that reported for VAPOL,
however, the starting material is an order of magnitude
cheaper than that for VAPOL. The solid-state structures of
iso-VAPOL and VANOL were determined and it was found that
(J = 8.8 Hz, CDCl3) for proton
for the boroxinate 31c when
1 equiv. of imine 30c was added (entry 6, Fig. 3B). In support
of the formation of 31c, a peak at δ = 5.72 ppm in the
This journal is © The Royal Society of Chemistry 2014
Catal. Sci. Technol., 2014, 4, 4406–4415 | 4413

View Article Online
Paper
Catalysis Science & Technology
Fig. 3 (A) Treatment of (S)-2 and (S)-3 with B(OPh)3 and imine 30c. (B) 1H NMR spectra of the reaction mixture in CDCl3. Entry 1: pure (S)-2.
Entry 2: (S)-2 (0.1 mmol) plus 4 equiv. B(OPh)3 and 1 equiv. H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum
for 0.5 h. Entry 3: 1.0 equiv. of imine 30c was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. Entry 4: pure (S)-3. Entry 5: (S)-3 (0.1 mmol) plus
4 equiv. B(OPh)3 and 1 equiv. H2O were heated at 80 °C in toluene for 1 h followed by removal of volatiles under vacuum for 0.5 h. Entry 6: 1.0 equiv.
of imine 30c was added to the entry 2 (pre-catalyst) for 10 min at 25 °C. (C) 1H NMR spectra (methyl and methoxy region) corresponding to the entries
3 and 6 in 1H NMR spectra in Fig. 3B. (D) 11B NMR spectra corresponding to entries 2, 3, 5 and 6 in the 1H NMR spectra in Fig. 3B.
both do not display intermolecular H-bonds and both have
cisoid conformations. These two characteristics are shared with
References
the vaulted biaryl VAPOL which is in contrast to linear biaryl
ligands such as BINOL which exists in a transoid conformation
and has intermolecular H-bonds in the solid state. It was shown
that iso-VAPOL can form a BOROX catalyst with B(OPh)3 and
that this species is capable of catalyzing the aziridination
of imines with ethyl diazo acetate to give aziridine-
2-carboxylates in high yield and with high enantio- and
diastereo-selectivity. Iso-VAPOL is an isomer of VAPOL but
has a chiral pocket similar to that of VANOL. This fact will be
expected to play out and its value to be defined in the differ-
ences in asymmetric inductions between it and VANOL and
VAPOL in a variety of catalysts for a number of different
asymmetric reactions.
1 (a) J. Bao, W. D. Wulff and A. L. Rheingold, J. Am. Chem.
Soc., 1993, 115, 3814; (b) D. P. Heller, D. R. Goldberg and
W. D. Wulff, J. Am. Chem. Soc., 1997, 119, 10551–10552; (c)
D. P. Heller, D. R. Goldberg, H. Wu and W. D. Wulff,
Can. J. Chem., 2006, 84, 1487–1503.
2 C. Bolm, J.-C. Frison, Y. Zhang and W. D. Wulff, Synlett,
2004, 1619–1621.
3 S. Xue, S. Yu, Y. Deng and W. D. Wulff, Angew. Chem.,
Int. Ed., 2001, 40, 2271–2774.
4 P. W. N. M. Van Leeuwen, D. Rivillo, M. Raynal and
Z. Freixa, J. Am. Chem. Soc., 2011, 133, 18562.
5 S. Lou and S. E. Schaus, J. Am. Chem. Soc., 2008, 130, 6922–6923.
6 D. S. Barnett and S. E. Schaus, Org. Lett., 2011, 13, 4020.
7 G. Blay, L. Cardona, J. R. Pedro and A. Sanz-Marco,
Chem. – Eur. J., 2012, 18, 12966–12969.
8 G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadhavuni,
Y. Wang and J. C. Antilla, J. Am. Chem. Soc., 2005, 127,
15696–15697.
Acknowledgements
This work was supported by a grant from the National Institute
of General Medical Sciences (GM094478).
4414 | Catal. Sci. Technol., 2014, 4, 4406–4415
This journal is © The Royal Society of Chemistry 2014

View Article Online
Catalysis Science & Technology
Paper
9 Y. Liang, E. B. Rowland, G. R. Rowland, J. A. Perman and
J. C. Antilla, Chem. Commun., 2007, 4477–4479.
10 (a) G. Li, Y. Liang and J. C. Antilla, J. Am. Chem. Soc.,
2007, 129, 5830–5831; (b) I. A. Khan and A. K. Saxena, J. Org.
Chem., 2013, 78, 11656.
11 (a) E. B. Rowland, G. B. Rowland, E. Rivera-Otero and
J. C. Antilla, J. Am. Chem. Soc., 2007, 129, 12084–12085; (b)
G. Della Sala and A. Lattanzi, Org. Lett., 2009, 11, 3330–3333;
(c) S. E. Larson, J. C. Baso, G. Li and J. C. Antilla, Org. Lett.,
2009, 11, 5186–5189; (d) M. Senatore, A. Lattanzi, S. Santoro,
C. Santi and G. Della Sala, Org. Biomol. Chem., 2011, 9,
6205–6207; (e) G. Della Sala, Tetrahedron, 2013, 69, 50.
12 Z. Zhang, W. Zheng and J. C. Antilla, Angew. Chem., Int. Ed.,
2011, 50, 1135–1138.
W. D. Wulff, Synlett, 2009, 2715–2739; (e) M. Mukherjee,
A. K. Gupta, Z. Lu, Y. Zhang and W. D. Wulff, J. Org. Chem.,
2010, 75, 5643; ( f ) G. Hu, A. K. Gupta, R. H. Huang,
M. Mukherjee and W. D. Wulff, J. Am. Chem. Soc., 2010, 132,
14669–14675; For trans-aziridination: (g) A. A. Desai and
W. D. Wulff, J. Am. Chem. Soc., 2010, 132, 13100–13103; (h)
M. J. Vetticatt, A. A. Desai and W. D. Wulff, J. Am. Chem.
Soc., 2010, 132, 13104–13107.
23 (a) A. K. Gupta, M. Mukherjee and W. D. Wulff, Org. Lett.,
2011, 13, 5866–5869; (b) A. K. Gupta, M. Mukherjee, G. Hu
and W. D. Wulff, J. Org. Chem., 2012, 77, 7932.
24 See pages S26 to S28 in the ESI† of footnote 22e.
25 Y. Guan, Z. Ding and W. D. Wulff, Chem. – Eur. J., 2013, 19,
15565–15571.
13 S. E. Larson, G. Li, G. B. Rowland, D. Junge, R. Huang,
H. Woodcock and J. C. Antilla, Org. Lett., 2011, 13, 2188.
14 W. Zheng, Z. Zhang, M. J. Kaplan and J. C. Antilla, J. Am.
Chem. Soc., 2011, 133, 3339–3341.
26 J. Bao, W. D. Wulff, J. B. Dominy, M. J. Fumo, E. B. Grant,
A. C. Rob, M. C. Whitcomb, S.-M. Yeung, R. L. Ostrander
and A. L. Rheingold, J. Am. Chem. Soc., 1996, 118,
3392–3405.
15 S. A. Snyder, S. B. Thomas, A. C. Mayer and S. P. Breazzano,
Angew. Chem., Int. Ed., 2012, 51, 4080–4084.
27 S. Yu, C. Rabalakos, W. D. Mitchell and W. D. Wulff, Org.
Lett., 2005, 7, 367–369.
16 M.-W. Chen, Q.-A. Chen, Y. Duan, Z.-S. Ye and Y.-G. Zhou,
Chem. Commun., 2012, 48, 1698–1700.
28 Z. Ding, S. Xue and W. D. Wulff, Chem. – Asian J., 2011, 6,
2130–2146.
17 H. Harada, R. K. Thalji, R. G. Bergman and J. A. Ellman,
J. Org. Chem., 2008, 73, 6772–6779.
29 Z. Ding, W. E. G. Osminski, H. Ren and W. D. Wulff, Org.
Process Res. Dev., 2011, 15, 1089–1107.
18 T. J. Hoffman and E. M. Carreira, Angew. Chem., Int. Ed.,
2011, 50, 10670–10674.
30 G. Hu, D. Holmes, B. F. Gendhar and W. D. Wulff, J. Am.
Chem. Soc., 2009, 131, 14355.
19 W. Zhao, L. Huang, Y. Guan and W. D. Wulff, Angew. Chem.,
Int. Ed., 2014, 53, 3436–3441.
20 C. A. Newman, J. C. Antilla, P. Chen, A. V. Predeus,
L. Fielding and W. D. Wulff, J. Am. Chem. Soc., 2007, 129,
7216–7217.
21 (a) H. Ren and W. D. Wulff, J. Am. Chem. Soc., 2011, 133,
5656–5659; (b) H. Ren and W. D. Wulff, Org. Lett., 2013, 15,
242–245.
22 For cis-aziridination: (a) J. C. Antilla and W. D. Wulff, J. Am.
Chem. Soc., 1999, 121, 5099–5100; (b) J. C. Antilla and
W. D. Wulff, Angew. Chem., Int. Ed., 2000, 39, 4518–4521; (c)
Y. Zhang, A. Desai, Z. Lu, G. Hu, Z. Ding and W. D. Wulff,
Chem. – Eur. J., 2008, 14, 3785–3803; (d) Y. Zhang, Z. Lu and
31 C. P. Price and A. J. Matzger, J. Org. Chem., 2005, 70, 1–6.
32 The terms cisoid and transoid describe biaryl dihedral
angles of <90° and >90°, respectively.
33 (a) K. A. Kerr and J. M. Robertso, J. Chem. Soc. B, 1969,
1146–1149; (b) R. B. Kress, E. N. Duesler, M. C. Etter, I. C. Paul
and D. Y. Curtin, J. Am. Chem. Soc., 1980, 102, 7709–7714.
34 (a) K. Mori, Y. Masuda and S. Kashino, Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun., 1993, 49, 1224–1227; (b)
F. Toda, K. Tanaka, H. Miyamoto, H. Koshima, I. Miyahara
and K. Hirotsu, J. Chem. Soc., Perkin Trans. 2, 1997,
1877–1885.
35 Z. Lu, Y. Zhang and W. D. Wulff, J. Am. Chem. Soc.,
2007, 129, 7185–7194.
This journal is © The Royal Society of Chemistry 2014
Catal. Sci. Technol., 2014, 4, 4406–4415 | 4415