New derivatives of VAPOL and VANOL: Structurally distinct vaulted chiral ligands and bronsted acid catalysts

Article abstract of DOI:10.1055/s-0030-1258231

Lean and efficient multi-gram scale syntheses of a number of new derivatives of VAPOL and VANOL are described. These are structurally novel chiral ligands and Bronsted acid catalysts, and could provide singular profiles for reactivity and asymmetric inductions in catalysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258231

3670
PAPER
New Derivatives of VAPOL and VANOL: Structurally Distinct Vaulted Chiral
Ligands and Brønsted Acid Catalysts
New
Derivatives
o
m
f
V
APOL and
V
A
N
a
OL n A. Desai, William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Fax +1(517)3531793; E-mail: wulff@chemistry.msu.edu
Received 8 June 2010; revised 23 July 2010
considerable success in asymmetric organocatalysis in re-
Abstract: Lean and efficient multi-gram scale syntheses of a num-
ber of new derivatives of VAPOL and VANOL are described.
These are structurally novel chiral ligands and Brønsted acid cata-
lysts, and could provide singular profiles for reactivity and asym-
metric inductions in catalysis.
cent years.7
The vaulted biaryl diol ligands VAPOL (4) and VANOL
(5) were introduced by our group in 1993 (Figure 1).8,9
These ligands possess a unique vaulted backbone, and are
thus structurally distinct from the BINOL ligands. Since
their introduction, VAPOL and VANOL have served as
the basis for a number of successful catalytic asymmetric
systems from several research groups. Catalysts prepared
from VAPOL/VANOL and various boron compounds
have been shown to mediate efficient and general asym-
metric aziridinations,10,11 as well as asymmetric hetero-
Diels–Alder cycloadditions.12 VAPOL/VANOL catalysts
containing aluminum or zirconium have successfully cat-
alyzed asymmetric Diels–Alder reactions,8,13 imino-aldol
reactions,14 and Baeyer–Villiger reactions.15 Phosphora-
midite derivatives of VAPOL and VANOL have been
shown to be effective ligands in rhodium-catalyzed enan-
tioselective intramolecular hydroarylation of alkenes.16
VAPOL as a standalone species can mediate asymmetric
Petasis reactions, affording chiral a-amino acid esters
with high asymmetric inductions.17 An increasing number
of systems in recent years have showcased the use of the
chiral phosphoric acid catalysts prepared from VAPOL
and VANOL. Imine amidations,18 imino ester reduc-
tions,19 imine imidations,20 as well as desymmetrization of
meso-aziridines to afford vicinal diamines21 and vicinal
amidophenylthioethers22 have been all shown to proceed
with excellent levels of asymmetric inductions under their
catalysis.
Key words: VAPOL, VANOL, ligand, Brønsted acid, asymmetric
catalysis
The field of chiral Brønsted acid catalysis has witnessed
an exponential growth in the last decade.1 Countless effi-
cient asymmetric reaction systems mediated by these or-
ganocatalysts have been developed by numerous research
groups around the world, and this growth continues un-
abated till date. The BINOL ligand scaffold has been
ubiquitous in the realm of organocatalysis, and is entitled
to the label of a ‘privileged’ ligand.2
Shown in Scheme 1 are the three most extensively utilized
groups of chiral Brønsted acids derived from the BINOL
scaffold. As weakly acidic Brønsted acids, a variety of
BINOL derivatives 1 have been prepared and utilized in
asymmetric organocatalysis.3 In 2004, the research groups
of Akiyama4a and Terada4b independently introduced the
3,3¢-disubstituted BINOL phosphoric acids 2 for asym-
metric Mannich-type reactions. These phosphoric acids
have since then proven to be versatile chiral Brønsted acid
catalysts, and a multitude of successful catalytic asym-
metric systems have been developed under their aegis.5
Chiral BINOL N-triflyl phosphoramide catalysts 3 were
subsequently introduced by Yamamoto in 2006 for an
asymmetric Diels–Alder reaction.6 These are stronger
Brønsted acids (pKa of –3 in water)1c as compared to the
corresponding BINOL phosphoric acids (pKa of 1 in wa-
ter);1c these N-triflyl phosphoramides have also found
The utility of VAPOL and VANOL is poised to increase
as both antipodes of these ligands are now commercially
available.9,23 Despite the significant use of catalysts de-
rived from VAPOL and VANOL in asymmetric catalysis,
X
X
X
O
O
OH
OH
OH
OH
O
O
O
O
P
P
OH
NHTf
X
X
X
‘privileged’ BINOL
scaffold
1
2
3
Scheme 1 Chiral Brønsted acid catalysts from the BINOL scaffold
SYNTHESIS 2010, No. 21, pp 3670–3680
x
x.
x
x
.
2
0
1
0
Advanced online publication: 25.08.2010
DOI: 10.1055/s-0030-1258231; Art ID: M04110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Derivatives of VAPOL and VANOL
3671
would be unique ligands, and could again be completely
orthogonal in their reaction profiles as compared to the
3,3¢-diaryl BINOL ligands. Not only would they be inter-
esting chiral scaffolds for standalone weak Brønsted acid
catalysis, but their phosphoric acid and phosphoramide
derivatives would be attractive in the realm of strong
Brønsted acid catalysis as well.
Ph
Ph
OH
OH
Ph
Ph
OH
OH
We have previously reported the synthesis of one such
family member, the 8,8¢-Ph2VANOL 6.9b A linear route
was adopted in that study (pathway a in Scheme 2), that
is, to prepare each new family member 16 with a different
aryl group on the 8 and 8¢ position of the ligand backbone,
one would be required to begin from the very start of the
synthetic route, with a different ortho-bromobiaryl 21,
which in turn would have to be prepared from the corre-
sponding aromatic coupling precursors. Such a pathway
thus becomes cumbersome and un-amenable for the prep-
aration of an entire family of these ligands.
4
5
(S)-VAPOL
(S)-VANOL
Figure 1 Structurally distinct vaulted biaryl diol ligands
a dearth of information exists in the literature for the prep-
aration of derivatives of these ligands. In the present
study, we thus wish to report efficient and reproducible
multi-gram scale syntheses of several new derivatives of
VAPOL and VANOL. Shown in Figure 2 are the deriva-
tives prepared in the present study, these are structurally
novel chiral ligands and Brønsted acid catalysts; the
asymmetric active sites created by these derivatives will
be electronically and sterically distinct from those created
from the corresponding BINOL derivatives, thus resulting
in a profile for reactivity and asymmetric inductions that
could be quite singular.
At the outset of the present study, it was desired to have a
general and nonlinear route towards these new deriva-
tives, which should make it possible to generate a large
number of family members using similar reaction condi-
tions. The ideal retrosynthetic analysis for the preparation
of a large family of these ligands is presented by pathway
b in Scheme 2. The syntheses would start from compound
18, which is the monomer used for the synthesis of the
VANOL ligand. We have already reported an efficient
multi-gram scale synthesis for this compound,9 and this
was thus thought to be an attractive starting point for the
present work. A transition-metal-catalyzed C–H activa-
tion and coupling reaction should then be able to install
sterically and electronically different aromatic substitu-
ents on the 8-position of the VANOL monomer, thereby
providing the requisite monomers 17 for the new ligands.
Subsequent dimerization and deracemization, in a similar
fashion as done during our previous syntheses of these
We believe that the uniqueness of their structure, and the
subsequent promise of radically different reactivity pro-
files, warrants the inclusion of these derivatives in any
screen comprised of chiral Brønsted acid catalysts.
A New Family of Vaulted Ligands – 8,8¢-Diaryl
VANOL Derivatives
Gaining inspiration from the enormous success associated
with the 3,3¢-diaryl BINOL derivatives 1 in asymmetric
catalysis, we were drawn towards the prospect of creating
a new family of structurally distinct vaulted ligands, the
8,8¢-diaryl VANOL derivatives 16 (Scheme 2). These
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
Ph
Ph
OH
OH
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
O
O
P
P
P
P
P
Cl
OH
OH
OH
NHTf
Ph
Ph
Ph
6
7
8
9
10
11
i-Pr
O
O
O
O
O
O
O
Ph
Ph
O
Ph
Ph
O
O
Ph
O
O
Ph
Ph
O
O
O
P
P
S
P
S
P
NHTf
N
N
O
Ph
NHTf
H
H
i-Pr
i-Pr
NO2
12
13
14
15
Figure 2 New derivatives of VAPOL and VANOL available from the present study
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

3672
A. A. Desai, W. D. Wulff
PAPER
vaulted ligands,9 should then afford the new family of yield, again at a multi-gram scale. The monomer was
8,8¢-diaryl VANOL ligands 16.
dimerized in air with acceptable yields; the dimer was
then subjected to a deracemization protocol with CuCl
and (–)-sparteine to afford the optically pure (S)-8,8¢-
Ph2VANOL ligand 6 in good yields in multi-gram quanti-
ties.
The expectations from this retrosynthetic analysis were
borne out quite satisfyingly when the multi-gram synthe-
sis of (S)-8,8¢-Ph2VANOL 6 was carried out as a proof of
principle (Scheme 3). All reactions were optimized on a
small scale first, and then demonstrated on larger scales Thus, a lean, efficient and multi-gram scale synthesis of 6
for multiple times. The yields reported are the average of could be developed, and a proof of principle demonstrated
all runs on larger scales. The initial transition-metal-cata- for the synthesis of a new family of biaryl diol ligands in
lyzed C–H activation/coupling step was the key for the the future; this should in principle be easily achieved by
synthesis; it was our synthetic handle to be able to rapidly simply substituting iodobenzene in the initial Pd-cata-
prepare the entire family of these new ligands. To our lyzed C–H activation/coupling reaction in the above syn-
pleasure, a phenoxy-directed palladium-mediated C–H thetic route with a variety of electronically and sterically
activation/coupling protocol developed by Miura and co- distinct aryl iodides, and the rest of the synthesis should
workers24 worked smoothly from the VANOL monomer be identical as for 6.
18 to afford the corresponding new acetylated monomer
23, in 75% isolated yield over 2 steps at a multi-gram
scale. Attempts to isolate the monomer 24 after the initial
Brønsted Acid Derivatives of 8,8¢-Ph2VANOL
We were subsequently interested in demonstrating the
preparation of the phosphoric acid 8 and the N-triflyl
Pd-coupling reaction by silica gel chromatography
phosphoramide 9 derivatives of the new 8,8¢-Ph2VANOL
ligand 6. This was done in acceptable yields, and is pre-
sented in Scheme 4. An interesting and unexpected out-
come during the optimization of these syntheses was that
the phosphorous chloride intermediate 7 could be isolated
by silica gel chromatography in good yields (Scheme 4).
failed,24 thus requiring the subsequent acetylation of the
crude material to afford the acetylated monomer 23. This
could then be isolated as a pure compound after silica gel
column chromatography, and a simple deacetylation was
then optimized to afford the pure monomer 24 in excellent
Ar
Ar
Ph
Ph
OH
OH
OH
OH
Ar
Ar
widely used
3,3'-diaryl BINOL ligands
a new family of
8,8'-diaryl VANOL ligands
transition-metal-
catalyzed C–H
activation
Ar
OH
Ar
OH
dimerization/
deracemization
and coupling
Ph
Ph
OH
OH
pathway b
‘non linear’
Ph
Ph
Ar
18
17
VANOL monomer
pathway a
‘linear’
16
OMe
OMe
(OC)5Cr
Ar
(OC)5Cr
19
20
Br
Br
Br
ArX
+
Ar
X
21
22
Scheme 2 A new family of structurally distinct vaulted ligands
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

PAPER
New Derivatives of VAPOL and VANOL
3673
a) PhI (1.2 equiv)
Pd(OAc)2 (2.5 mol%)
Cs2CO3, DMF, 110 °C, 24 h
Ph
OAc
OH
b) Ac2O, pyridine
25 °C, overnight
Ph
Ph
18
23
75% (over 2 steps, 6 g product)
average of 3 runs
Ph
Ph
K2CO3
CH2Cl2–H2O–MeOH
25 °C, overnight
Ph
OH
neat, air
200 °C, 60 h
Ph
Ph
OH
OH
Ph
24
92% (5 g product)
average of 3 runs
6
53% (2.5 g product)
average of 3 runs
Ph
CuCl (1.7 equiv)
(–)-sparteine (3.5 equiv)
MeOH, CH2Cl2, 25 °C
Ph
Ph
OH
OH
Ph
6
(S)-8,8'-Ph2VANOL
62% (3 g product), >99.9% ee
average of 2 runs
Scheme 3 Multi-gram scale synthesis of (S)-8,8¢-Ph2VANOL 6
Ph
Ph
Ph
OH
OH
Ph
6
a) Et3N, DMAP
CH2Cl2, POCl3
0–25 °C, 1 h
b) TfNH2, EtCN
reflux, 24 h
a) POCl3, pyridine
25 °C, 24 h
b) H2O, 25 °C, 24 h
POCl3, pyridine
25 °C, 24 h
Ph
O
Ph
O
Ph
O
O
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
P
P
P
O
Cl
OH
NHTf
Ph
Ph
Ph
7
56%
8
69%
9
55%
Scheme 4 Brønsted acid derivatives of 8,8¢-Ph2VANOL 6
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

3674
A. A. Desai, W. D. Wulff
PAPER
Displacement of chloride from this intermediate should be
facile, to introduce other functionality such as urea/thio-
urea groups, thus paving the way towards other novel
Brønsted acid catalysts or H-bonding ligands for use in
asymmetric catalysis.
a) POCl3, pyridine
0–25 °C, 6 h
b) H2O
0–25 °C, 2 h
O
Ph
Ph
OH
OH
Ph
Ph
O
O
P
84–90% yield
(~ 6 g product)
OH
Brønsted Acid Derivatives of VANOL
VANOL phosphoric acid 10 was prepared at a multi-gram
scale from VANOL (5), in an excellent yield and under
mild conditions (Scheme 5). Thus, VANOL was reacted
with POCl3 at room temperature, followed by the addition
of water, which upon workup and purification afforded
pure VANOL phosphoric acid 10 in 92% isolated yield
(2.1 g product). While the synthesis of optically active 10
has never been reported before, we have previously re-
ported the synthesis of racemic 10, via a route that in-
volved significantly harsher conditions than those that
have been developed for the present study.9a,25 We find
that these milder conditions lead to cleaner reaction mix-
tures and higher yields.
4
11
(R)-VAPOL
(R)-VAPOL phosphoric acid
Scheme 7 Multi-gram scale synthesis of VAPOL phosphoric acid
11
asymmetric active sites of these catalysts – the triflate side
chain. If the trifluoromethyl group in these derivatives
was to be replaced with a bulky aromatic group, it would
add yet another element of steric bulk into the system.
Thus, the N-TRIP-benzenesulfonyl VAPOL phosphor-
amide 14 and the N-nitrobenzenesulfonyl VAPOL phos-
phoramide 15 Brønsted acids were also prepared using
similar procedures as before (Scheme 9).
By virtue of their unique vaulted structure, the biaryl diol
ligands VAPOL and VANOL have carved a special niche
for themselves in asymmetric catalysis. A multitude of
different catalytic asymmetric reactions have been medi-
ated by the catalysts prepared from these ligands, afford-
ing excellent selectivities, yields and asymmetric
inductions.8,10–22 The use of these ligands in the future will
be further facilitated by that they are now commercially
available.9,23
a) POCl3, pyridine, 6 h, 25 °C
O
Ph
Ph
OH b) H2O, 2 h, 25 °C
OH
Ph
Ph
O
O
P
92% (2.1 g product)
OH
5
10
(S)-VANOL phosphoric acid
(S)-VANOL
Scheme 5 Multi-gram scale synthesis of VANOL phosphoric acid
10
Anticipating an increased use of these ligands in asym-
metric catalysis in the near future, we have initiated a pro-
gram to prepare novel derivatives of these ligands. Herein,
we have reported our preliminary results from this study;
efficient and reproducible multi-gram scale syntheses of
several new chiral ligands and Brønsted acid catalysts
based on the framework of VAPOL and VANOL have
been presented. These are structurally distinct as com-
pared to the traditional BINOL scaffolds, and should gen-
erate singular profiles for reactivity and asymmetric
inductions. We hope that this expectation gets borne out
in our laboratories in the near future, and in those of others
actively engaged in the science of asymmetric catalysis.
The stronger Brønsted acid, N-triflyl VANOL phosphor-
amide 12, was prepared in 76% isolated yield (2.2 g prod-
uct) in a one-pot two-step sequence6 starting from
VANOL 5 (Scheme 6).
Brønsted Acid Derivatives of VAPOL
As with VANOL, the phosphoric acid 1125 (Scheme 7)
and the N-triflyl phosphoramide 13 (Scheme 8) Brønsted
acid derivatives of VAPOL were also prepared at multi-
gram scales, and with excellent yields.
It was realized that the N-triflyl phosphoramide deriva-
tives offered yet another handle with which to tune the
CH2Cl2, Et3N
POCl3
TfNH2, EtCN
100 °C, 12 h
O
0 to 25 °C, 2 h
Ph
Ph
OH
OH
Ph
Ph
O
O
P
NHTf
76% (2.2 g product)
12
(S)-N-triflyl VANOL phosphoramide
5
(S)-VANOL
Scheme 6 Multi-gram scale synthesis of N-triflyl VANOL phosphoramide 12
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

PAPER
New Derivatives of VAPOL and VANOL
3675
CH2Cl2, Et3N
POCl3, DMAP
0 to 25 °C, 2 h
TfNH2, EtCN
100 °C, 12 h
O
Ph
Ph
OH
OH
Ph
Ph
O
O
P
NHTf
70% (1.9 g product)
4
13
(R)-VAPOL
(R)-N-triflyl VAPOL phosphoramide
Scheme 8 Multi-gram scale synthesis of N-triflyl VAPOL phosphoramide 13
i-Pr
H2NO2S
i-Pr
i-Pr
EtCN
100 °C, 12 h
CH2Cl2, Et3N
POCl3, DMAP
0 to 25 °C, 2 h
O
S
O
O
Ph
Ph
OH
OH
Ph
Ph
O
O
P
N
Ar
H
73%
4
14
(S)-VAPOL
N-TRIP-benzenesulfonyl
VAPOL phosphoramide
(Ar = 2,4,6-i-Pr3C6H2)
H2NO2S
NO2
CH2Cl2, Et3N
POCl3, DMAP
0 to 25 °C, 2 h
EtCN
100 °C, 12 h
O
S
O
O
Ph
Ph
OH
OH
Ph
Ph
O
O
P
N
Ar
H
37%
4
15
(S)-VAPOL
N-nitrobenzenesulfonyl
VAPOL phosphoramide
(Ar = 4-O2NC6H4)
Scheme 9 N-Benzenesulfonyl VAPOL phosphoramide Brønsted acid catalysts
erwise noted, wherein either DMSO-d5 was used as the internal
Both antipodes of VAPOL and VANOL are commercially available
from Aldrich and Strem Chemicals, Inc. Alternatively, they can be
prepared according to a procedure described in literature.9 If de-
sired, they could be purified using column chromatography on reg-
ular silica gel using an eluent mixture of 2:1 CH2Cl2–hexanes.
POCl3 was purchased from Aldrich, and pyridine from Jade Scien-
tific, and both were used as obtained. Other reagents were used as
purchased from commercial sources. CH2Cl2 and Et3N were dried
from CaH2 under N2. Propionitrile and DMF were distilled appro-
priately before use. The VANOL monomer 18 can be prepared on a
multi-gram scale according to a procedure described in literature.9
For the synthesis of VAPOL phosphoric acid 11, see reference 25.
1
standard for both H NMR (d = 2.49) and 13C NMR (d = 39.5) or
CHCl3 was used as the internal standard for both 1H NMR
(d = 7.24) and 13C NMR (d = 77), respectively. Low-resolution
mass spectra analysis was performed at the Department of Chemis-
try at Michigan State University. High-resolution mass spectra anal-
ysis was performed at the Department of Biochemistry at Michigan
State University. Analytical TLC was performed on Silicycle silica
gel plates with F-254 indicator. Visualization was by short wave
(254 nm) and long wave (365 nm) ultraviolet light, or by staining
with phosphomolybdic acid reagent (20% wt in EtOH, Aldrich).
HPLC was carried out using a Varian Prostar 210 Solvent Delivery
Module with a Prostar 330 PDA Detector and a Prostar Worksta-
tion. Optical rotations were obtained on a PerkinElmer 341 polarim-
eter at a wavelength of 589 nm (sodium D line) using a 1.0
decimeter cell with a total volume of 1.0 mL. Specific rotations are
reported in degrees per decimeter at 25 °C and the concentrations
are given in grams per 100 mL of the solvent indicated.
The silica gel for column chromatography was purchased from
Sorbent Technologies with the following specifications: standard
grade, 60 Å porosity, 230 × 400 mesh particle size, 500–600 m2/g
surface area and 0.4 g/mL bulk density. IR spectra were taken on a
Nicolet IR/42 spectrometer. 1H and 13C NMR spectra were recorded
on a VXR-500 MHz instrument in DMSO-d6 or CDCl3 unless oth-
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

3676
A. A. Desai, W. D. Wulff
PAPER
3,8-Diphenylnaphthalen-1-yl Acetate (23)
1H NMR (500 MHz, CDCl3): d = 5.47 (s, 1 H), 7.18–7.20 (m, 2 H),
7.36 (tt, J = 1.2, 7.4 Hz, 1 H), 7.44–7.48 (m, 3 H), 7.50–7.54 (m, 5
H), 7.70–7.72 (m, 3 H), 7.90 (dd, J = 1.0, 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 111.2, 118.9, 120.5, 125.3, 127.2,
127.5, 128.4, 128.7, 128.8, 129.0, 129.0, 129.5, 135.9, 136.1, 139.6,
140.4, 141.1, 153.3.
A 250 mL round-bottom flask, equipped with a magnetic stir bar
and a water condenser, was flame dried and cooled under argon. To
the flask was added Cs2CO3 (14.81 g, 45.45 mmol, 2 equiv), and the
assembly was then heated at 150 °C for 2 h under high vacuum (0.1
mmHg). This was subsequently cooled to r.t., and the VANOL
monomer 18 (5.00 g, 22.73 mmol, 1 equiv) was added, which was
followed by the addition of Pd(OAc)2 (127.5 mg, 0.57 mmol, 0.025
equiv), DMF (120 mL), and iodobenzene (3.04 mL, 27.28 mmol,
1.2 equiv). The assembly was then fitted with a rubber septum and
an argon balloon, and stirred in an oil bath at 110 °C for 24 h. The
reaction mixture was subsequently cooled to r.t., and added to a sep-
aratory funnel. Also added to the funnel were EtOAc (200 mL),
H2O (200 mL), and brine (50 mL). The layers were separated, the
aqueous layer extracted with EtOAc (4 × 200 mL), the organic lay-
ers were combined, and washed with H2O (2 × 500 mL), aq 0.5 N
HCl (2 × 500 mL), and brine. The organic layer was dried (Na2SO4),
filtered through a pad of Celite, subjected to rotary evaporation till
dryness, and finally to high vacuum (0.1 mm Hg) overnight to af-
ford the crude intermediate product. To the flask containing the
crude product was then added pyridine (120 mL) to dissolve the
crude product. The flask was equipped with a rubber septum and an
argon balloon. Ac2O (11.00 mL, 113.65 mmol, 5 equiv) was then
added slowly via a syringe and the reaction mixture stirred at r.t. for
12 h. The mixture was added to a separatory funnel, with CH2Cl2
(700 mL). This was then washed with aq 1 N HCl (4 × 700 mL), the
organic layers combined, washed with brine, dried (Na2SO4), fil-
tered through a pad of Celite, subjected to rotary evaporation till
dryness, and finally to high vacuum to afford crude product 23. Col-
umn chromatography with regular silica gel and an eluent system of
1:19 EtOAc–hexanes afforded pure 23 as a light yellow solid in
76% isolated yield (5.86 g, 17.34 mmol); light yellow solid; mp
117–119 °C; Rf = 0.24 (1:19 EtOAc–hexanes).
MS: m/z (%) = 296 (100, M+).
HRMS (ESI+): m/z calcd for C22H17O (M + H): 297.1279; found:
297.1274.
3,3¢,8,8¢-Tetraphenyl-2,2¢-binaphthyl-1,1¢-diol (rac-8,8¢-
Ph2VANOL, 6)
The monomer 24 (4.65 g, 15.71 mmol) was dissolved in Et2O and
divided equally into 5 glass test tubes (18 d × 150 h mm). The Et2O
in all test tubes was then evaporated by heating slightly on a water
bath in a fume hood. All test tubes were fitted with magnetic stir
bars, and subsequently heated in an oil bath at 200 °C with rapid
stirring for 60 h. The test tubes were then allowed to cool down to
r.t., the crude product in the test tubes dissolved in CH2Cl2, com-
bined, and subjected to rotary evaporation till dryness and finally to
high vacuum to afford crude product 6. Careful column chroma-
tography with regular silica gel and an eluent mixture of 1:19
EtOAc–hexanes afforded pure 6 as a light yellow solid in 54% iso-
lated yield (2.50 g, 4.24 mmol); light yellow solid; mp 222–226 °C;
Rf = 0.15 (1:19 EtOAc–hexanes).
IR (thin film): 3524s, 3053w, 1568m, 1493m, 1348s cm–1.
1H NMR (500 MHz, CDCl3): d = 5.46 (s, 2 H), 6.98 (d, J = 7.2 Hz,
2 H), 7.00–7.02 (m, 4 H), 7.11 (t, J = 7.5 Hz, 4 H), 7.14–7.17 (m, 4
H), 7.30–7.45 (m, 12 H), 7.74 (d, J = 8.4 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 117.5, 120.6, 121.2, 125.2,
125.8, 126.3, 126.9, 127.1, 127.6, 128.6, 128.6, 129.4, 135.0, 138.5,
140.9, 141.2, 144.2, 152.2.
IR (thin film): 3055w, 3028w, 1785s, 1367m, 1203s cm–1.
MS: m/z (%) = 590 (100, M+), 295 (44).
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 3 H), 7.25 (dd, J = 1.2, 7.1
Hz, 1 H), 7.34–7.51 (m, 10 H), 7.68–7.70 (m, 2 H), 7.93 (d, J = 8.3
Hz, 1 H), 8.02 (d, J = 1.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.7, 119.8, 123.8, 124.7, 125.9,
126.6, 127.3, 127.6, 127.7, 128.6, 128.9, 129.5, 130.2, 136.0, 137.3,
138.4, 139.7, 143.4, 147.2, 169.9.
HRMS (ESI+): m/z calcd for C44H31O2 (M + H): 591.2324; found:
591.2309.
(S)-3,3¢,8,8¢-Tetraphenyl-2,2¢-binaphthyl-1,1¢-diol 6
A 250 mL round-bottom flask was flame-dried and cooled under ar-
gon. After the flask had cooled to r.t., it was opened to air. To the
flask were then added CuCl (1.38 g, 13.9 mmol, 1.7 equiv), MeOH
(125 mL), and (–)-sparteine (6.64 mL, 28.88 mmol, 3.5 equiv), and
this mixture was sonicated open to air in an ultrasound water bath at
r.t. for 1 h. A dark green solution was obtained at this stage; the flask
was then fitted with a rubber septum, and the solution was deoxy-
genated by bubbling in argon via a metallic needle (1 h inside the
solution and 0.5 h above the solution). A different 1 L round-bottom
flask fitted with a magnetic stir bar was flame dried and cooled un-
der argon. To this flask was added the racemic ligand 6 (4.9 g, 8.3
mmol, 1 equiv), which was dissolved in anhyd CH2Cl2 (400 mL) to
obtain a clear yellow solution. The flask was then fitted with a rub-
ber septum, and the solution was deoxygenated with argon in a sim-
ilar way as above. The copper-sparteine complex prepared above
was added to this 1 L reaction flask via a cannula under argon pres-
sure. The cannula was replaced with an argon balloon; the flask was
sonicated in an ultrasound water bath for 15 min, covered with alu-
minum foil, and subsequently stirred at r.t. with a magnetic stirrer
for 3 h. The reaction mixture was then quenched with sat. aq
NaHCO3 (70 mL), stirred for 10 min, and then added to a separatory
funnel, which was followed by the addition of H2O (200 mL). The
layers were separated, the aqueous layer extracted with CH2Cl2 (3 ×
200 mL), the organic layers combined, dried (Na2SO4), filtered
through a pad of Celite, subjected to rotary evaporation till dryness
and finally to high vacuum to afford a dark green crude product.
This was dissolved in a minimum amount of CH2Cl2, and subjected
MS: m/z (%) = 338 (10, M+), 297 (28), 296 (100).
HRMS (ESI+): m/z calcd for C24H19O2 (M + H): 339.1385; found:
339.1393.
3,8-Diphenylnaphthalen-1-ol (24)
To a 500 mL round-bottom flask, fitted with a magnetic stir bar, was
added compound 23 (5.76 g, 17.04 mmol, 1 equiv) and anhyd
CH2Cl2 (25 mL) to obtain a clear yellow solution. To this was added
slowly a clear solution of K2CO3 (4.71 g, 34.08 mmol, 2 equiv) in
H2O (18 mL). To the reaction flask was then added MeOH (110
mL), and the reaction mixture was stirred at r.t. for 15 h. During the
course of the reaction, the color of the solution changed from yellow
to an intense green and finally to light brown/orange, and salts pre-
cipitated out. For the workup, the reaction mixture was added to a
separatory funnel, and H2O (150 mL) and CH2Cl2 (150 mL) were
also added. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 150 mL) and Et2O (2 × 150 mL). The
organic layers were combined, washed with brine, dried (Na2SO4),
filtered through a pad of Celite, subjected to rotary evaporation till
dryness, and finally to high vacuum to afford crude product 24. Col-
umn chromatography with regular silica gel and an eluent mixture
of 1:19 EtOAc–hexanes afforded pure 24 as a colorless oil in 94%
isolated yield (4.80 g, 16.22 mmol); Rf = 0.22 (1:19 EtOAc–hex-
anes).
IR (thin film): 3490s, 3055w, 1628m, 1496m, 1373m cm–1.
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

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New Derivatives of VAPOL and VANOL
3677
to flash column chromatography with regular silica gel and CH2Cl2
as the eluent, to separate the copper salts and other baseline impuri-
ties. This afforded again the crude product 6, which was subjected
to careful column chromatography with regular silica gel and an
eluent mixture of 1:9 EtOAc–hexanes to afford pure 6 as a light yel-
low solid in 60% isolated yield (2.92 g, 4.95 mmol); mp 130–134
°C.
product fractions were collected, subjected to rotary evaporation till
dryness and finally to high vacuum to afford product 8. This was
dissolved in a minimum amount of CH2Cl2, and precipitated with
the addition of excess pentane. Filtration off a Büchner funnel af-
forded product 8 again. This was again dissolved in CH2Cl2, washed
with aq 1 N HCl (4 × 100 mL), dried (Na2SO4), filtered through a
pad of Celite, subjected to rotary evaporation till dryness and finally
to high vacuum. The solid 8 thus obtained was again dissolved in a
minimum amount of CH2Cl2, and precipitated with the addition of
excess pentane. Filtration once again off a Büchner funnel afforded
the final pure product 8 as a white solid in 69% isolated yield (335
mg, 0.51 mmol); Rf = 0.3 (streak, 1:9 MeOH–CH2Cl2); white solid;
mp >230 °C (dec.); [a]D23 +362.4 (c 1.0, CH2Cl2).
The optical purity of the product, (S)-6, was determined to be
>99.9% ee by chiral HPLC analysis [Chiralcel OD-H column, hex-
anes–i-PrOH (99:1), flow rate 0.5 mL/min, 222 nm]; tR = 12.15 min
23
(major enantiomer); tR = 19.37 min (minor enantiomer); [a]D
–43.2 (c 1.0, CH2Cl2); >99.9% ee.
(S)-8,8¢-Ph2VANOL Phosphorus Oxychloride 7
IR (thin film): 3446s, 3055w, 1495m, 1334s, 1263s cm–1.
A 10 mL round-bottom flask, fitted with a magnetic stir bar, was
flame-dried and cooled under argon. To this flask was then added
the ligand 6 (100 mg, 0.17 mmol), which was followed by the addi-
tion of pyridine (1 mL) and POCl3 (32 mL, 0.34 mmol). The flask
was fitted with a rubber septum and an argon balloon, and stirred at
r.t. for 24 h, at which the reaction was judged complete by TLC. The
reaction mixture was then diluted with CH2Cl2, filtered through a
pad of Celite, subjected to rotary evaporation till dryness and finally
to high vacuum overnight. CH2Cl2 was added to the thus obtained
solid crude product to get a slurry, which was again filtered through
a pad of Celite. The resulting solution was subjected to rotary evap-
oration till dryness and finally to high vacuum to afford the crude
product 7. This was then subjected to column chromatography with
regular silica gel and an eluent mixture of 1:9 EtOAc–hexanes to af-
ford pure product 7 as a white foamy solid in 56% isolated yield (64
mg, 0.095 mmol); white foamy solid; mp 180–200 °C (dec.);
Rf = 0.17 (1:9 EtOAc–hexanes); [a]D23 +313.7 (c 1.0, CH2Cl2).
1H NMR (500 MHz, CDCl3): d = 6.50 (d, J = 7.2 Hz, 4 H), 6.96 (t,
J = 7.8 Hz, 4 H), 7.11 (t, J = 7.4 Hz, 2 H), 7.19 (t, J = 7.2 Hz, 2 H),
7.25–7.30 (m, 6 H), 7.36–7.37 (m, 4 H), 7.43–7.47 (m, 4 H), 7.73
(d, J = 7.6 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 123.2, 124.5, 125.7, 125.9,
126.1, 126.5, 127.5, 127.7, 128.1, 128.6, 130.0, 130.2, 135.0, 138.3,
139.4, 139.5, 142.9, 146.5.
31P NMR (121 MHz, DMSO-d6): d = 0.91 (s).
MS: m/z (%) = 652 (100, M+).
HRMS (ESI+): m/z calcd for C44H30O4P (M + H): 653.1882; found:
653.1863.
(S)-8,8¢-Ph2VANOL N-Triflyl Phosphoramide 9
A 25 mL round-bottom flask, fitted with a magnetic stir bar, was
flame dried and cooled under argon. To the flask was added the
ligand 6 (100 mg, 0.17 mmol, 1 equiv) and anhyd CH2Cl2 (2 mL) to
obtain a clear yellow solution. The flask was fitted with a rubber
septum and an argon balloon, and cooled to 0 °C in an ice bath. Et3N
(165 mL, 1.19 mmol, 7 equiv) and POCl3 (19 mL, 0.20 mmol, 1.2
equiv) were added via a syringe, followed by the addition of DMAP
(42 mg, 0.34 mmol, 2 equiv). The reaction was then allowed to
warm up to r.t., and stirred at r.t. for 1 h; TLC at this stage indicated
complete consumption of 6. EtCN (2 mL) was added to the reaction
flask, followed by the addition of TfNH2 (50 mg, 0.34 mmol, 2
equiv). A water condenser, separately flame dried and cooled under
argon, was then attached to the reaction flask, and the mixture heat-
ed at 100 °C in an oil bath for 24 h. The reaction mixture was al-
lowed to cool to r.t., and stirred at r.t. for an additional 12 h. For the
workup, the mixture was diluted with H2O and CH2Cl2, and the lay-
ers were separated. The aqueous layer was extracted with CH2Cl2,
the organic layers were combined, washed with sat. aq NaHCO3, aq
4 N HCl (2 ×), dried (Na2SO4), filtered through a pad of Celite, sub-
jected to rotary evaporation till dryness, and finally to high vacuum
to afford crude product 9. This crude product was subjected to col-
umn chromatography with regular silica gel and an eluent mixture
of 1:9 MeOH–CH2Cl2. The product fractions were collected, sub-
jected to rotary evaporation till dryness and finally to high vacuum
to afford 9 again, which was subsequently subjected to yet another
round of column chromatography with regular silica gel and an elu-
ent mixture of 5:1 EtOAc–hexanes to afford product 9. The solid
product obtained was dissolved in CH2Cl2, washed with aq 4 N HCl
(2 ×), dried (Na2SO4), filtered through a pad of Celite, subjected to
rotary evaporation till dryness, and finally to high vacuum to afford
solid product 9. This was finally dissolved in a minimum amount of
CH2Cl2, and precipitated with excess pentane, which upon filtration
off a Büchner funnel afforded the final pure product 9 as a white sol-
id in 55% isolated yield (72 mg, 0.092 mmol); white solid; mp >255
°C (dec.); Rf = 0.3 (streak, 1:9 MeOH–CH2Cl2 as well as 5:1
EtOAc–hexanes); [a]D23 +309.5 (c 1.0, CH2Cl2).
IR (thin film): 3057w, 1314s, 760s cm–1.
1H NMR (500 MHz, CDCl3): d = 6.54 (dd, 4 H, J = 7.3, 11.4 Hz),
7.02 (q, 4 H, J = 7.6 Hz), 7.17 (q, 2 H, J = 7.5 Hz), 7.27–7.39 (m, 6
H), 7.47–7.54 (m, 5 H), 7.57–7.65 (m, 5 H), 7.84 (t, 2 H, J = 7.7
Hz).
13C NMR (75 MHz, CDCl3): d = 122.6 (d, J = 3.4 Hz, 1 C), 123.4
(d, J = 2.9 Hz, 1 C), 124.5 (d, J = 2.9 Hz, 1 C), 124.6 (d, J = 3.4 Hz,
1 C), 126.4, 126.6, 126.8, 126.9, 127.2, 127.7, 127.8, 127.9, 127.9,
128.1, 128.2, 128.5, 128.5, 128.5, 129.0, 129.1, 129.3, 129.9, 130.6,
130.9, 131.2, 135.5, 135.5, 135.6, 135.6, 138.1, 138.2, 138.3, 138.3,
139.2, 139.9, 139.9, 140.1, 140.1, 142.0, 142.5, 144.6 (d, J = 11.5
Hz, 1 C), 144.9 (d, J = 13.2 Hz, 1 C) (2 sp2 carbons missing).
31P NMR (121 MHz, CDCl3): d = 7.30 (s).
MS: m/z (%) = 673 (15, 37Cl, M+), 672 (40, 37Cl), 671 (42, 35Cl, M+),
670 (100, 35Cl).
HRMS (ESI+): m/z calcd for C44H29ClO3P (M + H): 671.1543;
found: 671.1572.
(S)-8,8¢-Ph2VANOL Phosphoric Acid 8
A 50 mL round-bottom flask, fitted with a magnetic stir bar, was
flame dried and cooled under argon. To this flask was added the
ligand 6 (442 mg, 0.75 mmol) and pyridine (3 mL) to obtain a clear
solution. The flask was then fitted with a rubber septum and an ar-
gon balloon. POCl3 (140 mL, 1.5 mmol) was then added dropwise
via a syringe, and the resulting reaction mixture was stirred at r.t. for
24 h. H2O (3 mL) was then added dropwise via a syringe, and the
mixture stirred at r.t. for an additional 24 h. The mixture was then
added to a separatory funnel, along with CH2Cl2 (75 mL). This was
washed with aq 1 N HCl (7 × 75 mL), brine, dried (Na2SO4), filtered
through a pad of Celite, subjected to rotary evaporation till dryness,
and finally to high vacuum to afford crude 8.
The crude product was subjected to column chromatography with
regular silica gel and an eluent mixture of 1:9 MeOH–CH2Cl2. The
IR (thin film): 3435s, 3055w, 1215s cm–1.
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

3678
A. A. Desai, W. D. Wulff
PAPER
1H NMR (500 MHz, CDCl3): d = 5.46 (br s, 1 H), 5.71 (br s, 1 H),
6.47 (d, J = 7.3 Hz, 2 H), 6.62 (d, J = 7.3 Hz, 2 H), 6.84 (br s, 1 H),
6.96 (t, J = 7.9 Hz, 2 H), 7.02 (t, J = 7.9 Hz, 3 H), 7.10–7.16 (m, 2
H), 7.19 (d, J = 6.9 Hz, 1 H), 7.31–7.53 (m, 8 H), 7.61 (s, 1 H),
7.65–7.70 (m, 2 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.4 Hz, 1
H).
13C NMR (125 MHz, CDCl3): d = 117.9, 118.0, 120.4, 120.5, 123.0,
124.3, 124.3, 124.7, 125.2, 126.2, 126.5, 126.8, 126.8, 126.9, 127.2,
127.7, 127.8, 127.8, 127.9, 128.0, 128.3, 128.8, 129.4, 129.6, 130.5,
131.5, 132.7, 135.5, 135.6, 136.4, 138.6, 139.3, 139.6, 140.1, 142.8,
145.1, 145.3, 145.4, 145.6, 145.6 (4 sp2 carbons and CF3 missing).
(2.2 g, 3.49 mmol); mp >250 °C (dec.); [a]D23 +137.3 (c 1.0,
CH2Cl2).
IR (thin film): 3430s, 3055w, 1284m, 1217s, 1084s, 760m cm–1.
1H NMR (500 MHz, DMSO-d6): d = 6.38–6.40 (m, 4 H), 6.96 (dt,
J = 2.6, 5.6 Hz, 4 H), 7.12 (t, J = 7.4 Hz, 2 H), 7.56 (d, J = 8.3 Hz,
2 H), 7.60–7.70 (m, 4 H), 7.95–7.99 (m, 2 H), 8.27 (d, J = 8.3 Hz,
1 H), 8.35–8.37 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 120.1 (q, J = 318.2 Hz, CF3),
122.1, 122.5, 122.9, 123.2, 125.6, 125.7, 125.7, 126.2, 126.5, 126.5,
126.7, 126.8, 127.1, 127.3, 127.4, 127.6, 127.7, 127.6, 128.8, 128.9,
133.8, 134.2, 139.8, 139.9, 140.0, 140.1, 145.3 (d, J = 8.7 Hz, 1 C),
146.3 (d, J = 9.7 Hz, 1 C).
19F NMR (283 MHz, CDCl3): d = –78.69 (s).
31P NMR (121 MHz, CDCl3): d = 0.75 (s).
MS: m/z (%) = 631 (11, M+), 420 (14), 170 (17), 80 (81), 79 (48),
19F NMR (283 MHz, CDCl3): d = –79.18 (s).
31P NMR (121 MHz, CDCl3): d = 2.82 (s).
MS: m/z (%) = 783 (<1, M+), 572 (90), 246 (33), 39 (100).
HRMS (ESI–): m/z calcd for C45H28F3NO5PS (M – H): 782.1378;
found: 782.1374.
44 (100).
HRMS (ESI–): m/z calcd for C33H20F3NO5PS (M – H): 630.0752;
found: 630.0785.
(S)-VANOL Phosphoric Acid 10
To a 50 mL round-bottom flask, flame-dried and cooled under ar-
gon, was added (S)-VANOL (2 g, 4.57 mmol, 1 equiv) and pyridine
(8 mL) to obtain a clear yellow solution. The round-bottom flask
was fitted with a rubber septum and an argon balloon. Thereafter,
POCl3 (0.85 mL, 9.13 mmol, 2 equiv) was added slowly via a sy-
ringe. The reaction mixture was then stirred at r.t. for 6 h, in which
time salts started precipitating out. Thereafter, H2O (8 mL) was add-
ed via a syringe, and the mixture was stirred at r.t. for 2 h. For the
workup, the mixture was taken in a separatory funnel and CH2Cl2
(350 mL) was added. This was then washed with aq 1 N HCl (4 ×
350 mL). The organic layer was collected, dried (Na2SO4), filtered
through a pad of Celite, subjected to rotary evaporation, and finally
high vacuum to afford the crude product 10 as a white solid. The pu-
rification was a simple precipitation. The crude solid was dissolved
in a minimum amount of CH2Cl2 to obtain a clear yellow solution,
which was followed by the addition of excess pentane to precipitate
the product as a white solid in the solution. Filtration off a Buchner
funnel then provided the pure (S)-VANOL phosphoric acid product
10, which was subjected to high vacuum to completely remove all
organic volatiles. Thus, (S)-VANOL phosphoric acid 10 was ob-
tained as a white solid in 92% yield (2.1 g, 4.2 mmol); mp >250 °C
(dec.); [a]D23 +43.0 (c 1.0, CH2Cl2).
(R)-N-Triflyl VAPOL Phosphoramide 13
To a 100 mL round-bottom flask, flame-dried and cooled under ar-
gon, was added (R)-VAPOL (2 g, 3.72 mmol) and anhyd CH2Cl2
(20 mL) to obtain a clear solution. The round-bottom flask was fit-
ted with a rubber septum and an argon balloon. It was then cooled
to 0 °C in an ice-bath. Thereafter, anhyd Et3N (3.62 mL, 26 mmol)
and POCl3 (0.42 mL, 4.46 mmol) were added sequentially via a sy-
ringe, which was followed by the addition of DMAP (0.91 g, 7.44
mmol), all at 0 °C. The reaction flask was then warmed up to r.t.,
and the mixture stirred for 2 h. Thereafter, TfNH2 (1.11 g, 7.44
mmol) and distilled EtCN (20 mL) were added, and a water con-
denser (flame-dried and cooled under argon separately) was at-
tached. The reaction mixture was then heated at 100 °C for 12 h and
cooled down to r.t. thereafter. For the workup, H2O (100 mL) and
Et2O (150 mL) were then added, stirred, and the layers were sepa-
rated. The aqueous layer was extracted with Et2O (2 × 100 mL), the
organic layers combined and washed with sat. aq NaHCO3 (300
mL) and aq 4 N HCl (2 × 300 mL), dried (Na2SO4), filtered through
a pad of Celite and subjected to rotary evaporation and high vacuum
(0.1 mmHg) to afford the crude product 13 as a light brown solid.
Crude TLC (EtOAc) showed a long product streak in the middle of
the TLC plate and a baseline impurity spot. For purification, the
crude product was dissolved in EtOAc, flushed through a glass frit
packed with 1:1 Celite/silica gel and rinsed with EtOAc. Different
fractions were collected and analyzed by TLC. All product fractions
showed absence of the baseline impurity. This process was repeated
if the fractions were not pure and contained the baseline impurity.
All fractions were collected, subjected to rotary evaporation and
high vacuum. The pure product was then subjected to precipitation.
It was dissolved in a minimum amount of CH2Cl2 and an excess of
pentane was added to precipitate the product. It was then filtered off
a Büchner funnel; the solid product was collected and subjected to
high vacuum. This precipitation cycle was repeated until 1H NMR
analysis indicated complete (or almost complete) removal of all re-
sidual solvent peaks.This process thus afforded the pure product 13
as a white solid in 70% isolated yield (1.9 g, 2.60 mmol); mp >250
°C (dec.); [a]D23 –476.1 (c 1.0, CH2Cl2).
It was found that (S)-VANOL phosphoric acid 10 decomposed on
regular silica gel column chromatography.
IR (thin film): 3435s, 3057w, 1634m, 1489m, 1026m cm–1.
1H NMR (500 MHz, THF-d8): d = 6.50 (d, J = 8.2 Hz, 4 H), 6.92 (t,
J = 7.7 Hz, 4 H), 7.07 (t, J = 7.4 Hz, 2 H), 7.53 (s, 2 H), 7.54–7.61
(m, 4 H), 7.86 (d, J = 7.6 Hz, 2 H), 8.46 (d, J = 8.2 Hz, 2 H).
13C NMR (125 MHz, THF-d8): d = 123.7, 123.8 (d, J = 2.0 Hz, 1 C),
127.0 (d, J = 2.6 Hz, 1 C), 127.1, 127.2, 127.3, 128.1, 128.4, 128.4,
129.8, 135.3, 141.1, 141.2, 147.4 (d, J = 9.8 Hz, 1 C).
31P NMR (CDCl3, 121 MHz): d = 7.03 (s).
MS: m/z (%) = 500 (13, M+), 83 (14), 73 (20), 57 (22), 44 (100), 41
(25).
HRMS (ESI–): m/z calcd for C32H20O4P (M – H): 499.1099; found:
499.1118.
IR (thin film): 3424s, 1653m, 1635m, 1213w cm–1.
(S)-N-Triflyl VANOL Phosphoramide 12
1H NMR (500 MHz, DMSO-d6): d = 6.43 (t, J = 7.8 Hz, 4 H), 6.96
(t, J = 7.6 Hz, 4 H), 7.11 (t, J = 7.5 Hz, 2 H), 7.62–7.73 (m, 6 H),
7.88–7.96 (m, 4 H), 8.03–8.06 (m, 2 H), 9.67–9.69 (m, 1 H), 9.91
(d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 120.2 (q, J = 323.6 Hz, CF3),
121.4, 121.1, 121.4, 121.4, 125.9, 125.9, 126.4, 126.4, 126.5, 126.5,
This was prepared in the same manner as for the (R)-N-triflyl
VAPOL phosphoramide 13 described below. The entire process
was similar, except that DMAP was not utilized in the synthesis of
12. Thus, (S)-VANOL (2 g, 4.57 mmol) was reacted accordingly to
afford crude 12. This was also purified and precipitated accordingly
to afford the pure product 12 as a white solid in 76% isolated yield
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

PAPER
New Derivatives of VAPOL and VANOL
3679
126.6, 126.6, 126.7, 126.7, 126.9, 126.9, 126.9, 127.5, 127.5, 128.2,
128.3, 128.4, 128.6, 128.7, 128.8, 128.9, 128.9, 132.7, 133.9, 134.0,
139.1, 139.3, 140.5, 140.5, 147.9 (d, J = 8.7 Hz, 1 C), 148.9 (d,
J = 11 Hz, 1 C).
19F NMR (283 MHz, CDCl3): d = –79.69 (s).
31P NMR (121 MHz, CDCl3): d = 1.07 (s).
MS: m/z (%) = 730 [100, (M – 1)–], 630 (3).
140.4, 140.4, 147.3, 148.3 (d, J = 9.9 Hz, 1 C), 149.1 (d, J = 10.8
Hz, 1 C), 153.1.
31P NMR (CDCl3, 121 MHz): d = –0.11 (s).
MS: m/z (%) = 783 [100, (M – 1)–], 771 (7).
HRMS (ESI–): m/z calcd for C46H28N2O7PS (M – H): 783.1355;
found: 783.1342.
HRMS (ESI–): m/z calcd for C41H24F3NO5PS (M – H): 730.1065;
found: 730.1080.
Acknowledgment
This work was supported by NSF Grant CHE-0750319.
(S)-N-(2,4,6-Triisopropylbenzenesulfonyl) VAPOL Phosphor-
amide 14
References
This was prepared in the same manner as for the (R)-N-triflyl
VAPOL phosphoramide 13 described above. The reaction and
workup were identical, but the purification was different. Thus, (S)-
VAPOL (0.30 g, 0.56 mmol) was reacted and worked up according-
ly to afford crude 14. After workup, crude TLC showed the pres-
ence of 2,4,6-triisopropylbenzenesulfonamide. Thus, the crude
solid product 14 was subjected to column chromatography with an
eluent system of 1:3 EtOAc–hexanes to elute the sulfonamide first
(Rf = 0.3). Once the sulfonamide was completely eluted from the
column (as judged by TLC), the column was flushed with EtOAc to
elute the product 14. This afforded the pure product 14 as a light
brown solid in 73% isolated yield (0.35 g, 0.41 mmol); mp >250 °C
(dec.); [a]D23 +270.5 (c 1.0, CH2Cl2).
(1) For selected reviews on chiral Brønsted acid catalysis, see:
(a) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101.
(b) Terada, M. Chem. Commun. 2008, 4097. (c) Doyle, A.
G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
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(g) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
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IR (thin film): 3414s, 3057w, 2961m, 1626s, 1599s, 1226s, 1126s
cm–1.
(2) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
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Org. Biomol. Chem. 2007, 5, 606. (b) Momiyama, N.;
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2005, 127, 3680. (f) Dixon, D. J.; Tillman, A. L. Synlett
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1H NMR (500 MHz, DMSO-d6): d = 0.91 (t, J = 7.1 Hz, 12 H), 1.20
(t, J = 6.8 Hz, 6 H), 2.81–2.87 (m, 1 H), 4.42–4.50 (m, 2 H), 6.37
(d, J = 7.1 Hz, 2 H), 6.44 (d, J = 7.1 Hz, 2 H), 7.52 (t, J = 7.1 Hz, 1
H), 7.56 (d, J = 3.4 Hz, 2 H), 7.64–7.68 (m, 2 H), 6.93 (t, J = 7.3 Hz,
4 H), 6.97–7.02 (m, 3 H), 7.06–7.10 (m, 2 H), 7.81–7.87 (m, 3 H),
7.89–7.94 (m, 2 H), 8.00–8.02 (m, 1 H), 9.55 (d, J = 8.8 Hz, 1 H),
9.90–9.92 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 23.7, 23.7, 24.5, 24.8, 28.0,
33.3, 121.4, 121.5, 121.6, 121.6, 122.2, 125.6, 125.9, 126.0, 126.1,
126.4, 126.6, 126.6, 126.8, 126.9, 127.0, 127.0, 127.3, 127.4, 127.9,
128.1, 128.3, 128.8, 128.9, 129.0, 129.3, 132.5, 132.7, 133.7, 133.7,
139.5, 139.6, 140.5, 140.5, 142.1, 142.2, 147.6, 148.3, 148.9, 148.9,
148.9 (d, J = 9.2 Hz, 1 C), 150.0 (d, J = 10.9 Hz, 1 C) (1 sp2 carbon
missing).
(4) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356.
(5) For a selection of reports from 2009, see: (a) Mori, K.;
Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T.
Angew. Chem. Int. Ed. 2009, 48, 9652. (b) Dagousset, G.;
Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546.
(c) Li, N.; Chen, X.-H.; Song, J.; Luo, S.-W.; Fan, W.; Gong,
L.-Z. J. Am. Chem. Soc. 2009, 131, 15301. (d) Chen, X.-H.;
Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem.
Soc. 2009, 131, 13819. (e) Yue, T.; Wang, M.-X.; Wang,
D.-X.; Masson, G.; Zhu, J. Angew. Chem. Int. Ed. 2009, 48,
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Chem. Soc. 2009, 131, 12882. (g) Zhu, C.; Akiyama, T.
Org. Lett. 2009, 11, 4180. (h) Muratore, M. E.; Holloway,
C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 10796. (i) Zeng, X.; Zeng, X.;
Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036.
(j) Akiyama, T.; Katoh, T.; Mori, K. Angew. Chem. Int. Ed.
2009, 48, 4226. (k) Akiyama, T.; Suzuki, T.; Mori, K. Org.
Lett. 2009, 11, 2445. (l) Liu, H.; Dagousset, G.; Masson, G.;
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(m) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem.
Soc. 2009, 131, 3430. (n) Li, G.; Antilla, J. C. Org. Lett.
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31P NMR (121 MHz, CDCl3): d = 0.78 (s).
MS: m/z (%) = 866 [100, (M + 1)+], 301 (60).
HRMS (ESI–): m/z calcd for C55H47NO5PS (M – H): 864.2913;
found: 864.2951.
(S)-N-(4-Nitrobenenesulfonyl) VAPOL Phosphoramide 15
This was prepared in the same manner as for the (R)-N-triflyl
VAPOL phosphoramide 13 described above. The entire process
was similar, except that the precipitation was not done. Thus, (S)-
VAPOL (0.30 g, 0.56 mmol) was reacted and purified accordingly
to afford the pure product 15 as a yellow solid in 37% isolated yield
(0.16 g, 0.21 mmol); mp >250 °C (dec.); [a]D23 +257.4 (c 1.0,
MeOH).
1H NMR (500 MHz, DMSO-d6): d = 6.29 (d, J = 7.3 Hz, 2 H), 6.36
(d, J = 7.3 Hz, 2 H), 6.91 (q, J = 7.9 Hz, 4 H), 7.06–7.09 (m, 2 H),
7.48 (d, J = 8.8 Hz, 2 H), 7.54 (s, 1 H), 7.58 (s, 1 H), 7.61–7.72 (m,
4 H), 7.84–7.94 (m, 6 H), 8.02–8.06 (m, 2 H), 9.67 (d, J = 8.1 Hz, 1
H), 10.05 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 121.2, 121.4, 122.9, 124.4,
126.0, 126.0, 126.1, 126.3, 126.5, 126.5, 126.6, 126.6, 126.7, 126.7,
126.8, 127.0, 127.1, 127.3, 127.4, 128.1, 128.4, 128.5, 128.5, 128.8,
128.8, 128.9, 129.0, 129.3, 132.6, 132.7, 133.7, 133.8, 139.1, 139.2,
(6) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626.
Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York

3680
A. A. Desai, W. D. Wulff
PAPER
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Dissertation; Department of Chemistry, Michigan State
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(23) Both the vaulted ligands VANOL and VAPOL are
commercially available from Sigma-Aldrich as well as
Strem Chemicals, Inc.
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(25) The multi-gram scale preparation of VAPOL phosphoric
acid 11 has recently been communicated by us as a ‘Practical
Synthetic Procedure (PSP)’, see: Desai, A. A.; Huang, L.;
Wulff, W. D.; Rowland, G. B.; Antilla, J. C. Synthesis 2010,
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Synthesis 2010, No. 21, 3670–3680 © Thieme Stuttgart · New York