A novel C2-symmetric bisphosphane ligand with a chiral cyclopropane backbone: Synthesis and application in the Rh(I)-catalyzed asymmetric 1,4-addition of arylboronic acids

Article abstract of DOI:10.1016/j.tetasy.2010.10.027

The synthesis of a novel C₂-symmetric bisphosphane ligand was accomplished starting from trans-(2R,3R)-bis(3′,5′-diphenylphenyl) cyclopropane-1,1-dimethanol as a key intermediate. This ligand was tested in the asymmetric rhodium(I)-catalyzed 1,

Full text of DOI:10.1016/j.tetasy.2010.10.027

Tetrahedron: Asymmetry 21 (2010) 2768–2774
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Tetrahedron: Asymmetry
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A novel C2-symmetric bisphosphane ligand with a chiral cyclopropane
backbone: synthesis and application in the Rh(I)-catalyzed asymmetric
1,4-addition of arylboronic acids
⇑
Yaßsar Gök, Timothy Noël, Johan Van der Eycken
Laboratory for Organic and Bioorganic Synthesis, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S.4), B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel C2-symmetric bisphosphane ligand was accomplished starting from trans-
(2R,3R)-bis(30,50-diphenylphenyl)cyclopropane-1,1-dimethanol as a key intermediate. This ligand was
tested in the asymmetric rhodium(I)-catalyzed 1,4-addition to cyclic enones. We also compared the
new ligand with a similar phosphane ligand with a less bulky cyclopropane backbone. Good yields (up
to 99%) and enantioselectivities (up to 89% ee) were observed. We demonstrated that the presence of
a more bulky cyclopropane backbone resulted in a less effective ligand.
Received 8 September 2010
Accepted 28 October 2010
Available online 20 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
n
n = 0, 1, 2
R
R
R = alkyl, aryl
X = oxygen, phosphorus
nitrogen donor atoms
Carbon–carbon bond-forming reactions are one of the most
interesting transformations for constructing an organic molecule.1
As a result, the use of transition metal-catalyzed reactions to form
new C–C bonds in an enantioselective way is a topic of great inter-
X
X
Figure 1. A C2-symmetric modular ligand structure.
est. The asymmetric Rh(I)-catalyzed 1,4-addition to
a,b-unsatu-
rated enones has recently received much attention2 and, thus a
wide variety of ligands have been developed, for example, bisphos-
phanes,3 amidomonophosphane,4 bisphosphonites,5 phosporami-
dites,6 N-heterocyclic carbenes (NHC),7 chiral dienes,8,9 and hybrid
phosphane-olefins.10
Herein we report the synthesis of the novel bisphosphane
ligand 2 (Fig. 2) with an increased steric bulk of the backbone
(n = 0, R = 3,5-diphenylphenyl). This new bisphosphane ligand 2,
together with bisphosphane ligand 1 (n = 0, R = phenyl)13 was
tested and compared in the asymmetric Rh(I)-catalyzed 1,4-addi-
tion of several arylboronic acids to cyclic enones.
The choice of an appropriate ligand is crucial for the success of
an asymmetric transition metal-catalyzed reaction. Given the com-
plexity of most catalytic processes, the rational design of a chiral
ligand is seldom straightforward. Therefore, we designed a C2-sym-
metric ligand structure, shown in Figure 1, in order to address this
problem. Variation of the bulkiness of the R substituents on the
cycloalkane ring allows us to determine the optimal transfer of chi-
rality from the backbone to the reaction center. The electronic and
steric properties of the chelating atoms can also be tuned,11 as well
as their bite angle12 by changing the ring size of the backbone
(n = 0, 1, 2). Recently, we reported on a first set of diphenyl-
substituted cyclopropane-based ligands (R = Ph, n = 0) with P or
N as donor atoms.13 Bisphosphane 1 (Fig. 2) showed some promis-
ing results in asymmetric Pd(0)-catalyzed allylic alkylation reac-
tions and asymmetric Rh(I)-catalyzed hydrogenations.
Ph
Ph
Ph
PPh2 PPh2
Ph
PPh2 PPh2
1
2
Figure 2. C2-Symmetric bisphosphane ligands 1 and 2.
2. Results and discussion
The synthesis of ligand 2 is analogous to our previously de-
scribed synthesis of ligand 1.13 However, tetra-bromo-substituted
(E)-stilbene 5 is not commercially available and needs to be syn-
thesized. This product can be accessed via two different routes
⇑
Corresponding author. Tel.: +32 9 264 44 80; fax: +32 9 264 49 98.
E-mail address: Johan.Vandereycken@UGent.be (Johan Van der Eycken).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.027

Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
2769
O
obtained via an Arbuzov reaction and further used in a Wittig-type
reaction in order to afford the substituted (E)-stilbene 5 in good
overall yield. The latter route could be easily scaled up.
MePPh3Br
tBuOK, THF,
Next, tetrabromo-substituted (E)-stilbene 5 was used in the
synthesis of bisphosphane ligand 2 (Scheme 2). Diol 9 was pre-
pared via a Sharpless asymmetric dihydroxylation (>99% ee). Next,
THF was added as a co-solvent in order to increase the solubility of
5. This diol 9 was further converted into cyclic sulfate 10 in two
high yielding steps. The cyclopropane moiety in 11 was obtained
via a stereocontrolled double substitution of the cyclic sulfate 10
with the anion of diethyl glutaconate. Subsequent oxidative cleav-
age of 11 afforded monoester 12, which was finally reduced to piv-
otal diol 13 with NaBH4 in the presence of BF3ꢀOEt2. From a Suzuki
cross coupling, four phenyl groups could be simultaneously intro-
duced to afford 14 in excellent yield. Next, diol 14 was converted
into dichloride 15. A nucleophilic substitution with potassium
diphenylphosphide in THF and subsequent in situ protection
with BH3ꢀSMe2 afforded the protected phosphane ligand 16 in high
yield. Normally, cleavage of the BH3-protecting group can be
achieved by treatment with strong acids15 or an excess of
amines.16 However, we recently discovered that phosphane depro-
tection can be conveniently carried out under very mild neutral
conditions by simply refluxing in ethanol for 16 h, to afford bis-
phosphane ligand 2 in 87% yield.17 It is noteworthy that free bis-
phosphane ligand 2 appeared to be stable enough to be handled
in air.
The efficiency of bisphosphane ligands 1 and 2 was evaluated in
the rhodium(I)-catalyzed asymmetric 1,4-addition of boronic acids
to cyclic enones (Table 1). In accordance with our earlier findings,
the best results were obtained when the catalyst was generated
in situ from [Rh(C2H4)2Cl]2 and bisphosphane 1 or 2 in the presence
of KOH.3a,9i,9n In the 1,4-addition of PhB(OH)2 18a to cyclohexenone
17A in the presence of ligand 1, a good conversion and enantioselec-
tivity were obtained (Table 1, entry 1). When the more bulky bisphos-
phane ligand 2 was used, a comparable enantioselectivity but a
higher yield was observed (Table 1, entry 2) in only 3 h reaction time.
Next, other substituted arylboronic acids were used in this transfor-
mation. We observed the highest enantioselectivity (up to 89% ee)
and yield with the electron-poor 4-trifluoromethyl-phenylboronic
r.t., 24 h.
Br
Br
Br
Br
4
3
(70%)
Grubbs 2nd generation
toluene, reflux, 24 h.
83%
Br
Br
5
Br
Br
3,5-dibromobenzaldehyde,
93%
tBuOK, THF, r.t., 3 h.
O
Br
(EtO)2P
P(OEt)3,
NBS, BPO,
CCl4, reflux, 5 h.
reflux, 5 h.
Br Br
Br
Br
Br
Br
6
7
8
(50%)
(93%)
Scheme 1. Synthesis of bromo-substituted (E)-stilbene 5.
(Scheme 1). The first route started with a Wittig reaction in order
to obtain 3,5-dibromostyrene 4. Next, 5 was obtained in good yield
via a self-cross metathesis reaction. Although the overall yield was
quite good, this route was not pursued because of the requirement
of a rather large amount of the very expensive second generation
Grubbs catalyst (20 mol %). Therefore, a second route was devised
(Scheme 1). Hereby, 3,5-dibromotoluene 6 was monobrominated
in a Wohl–Ziegler reaction with NBS.14 Next, phosphonate 8 was
O
O
O
O
Ar1
O
AD-mix β, MeSO2NH2,
Ar1
Ar1
HO
Ar1
OH
Ar1
S
tBuOH/H2O/THF, 0°C,
i) SOCl2, CCl4, reflux, 4 h.
diethylglutaconate
NaH, DME, r.t., 7 h.
5 days.
Ar1
ii) NaIO4, RuCl3,
Ar1
Ar1
O
OEt
11
5
CH3CN/H2O, 0°C to r.t., 3 h.
10
9
OEt
Ar2
(93%)
(63%, >99% ee)
(49%)
Ar2
Ar1
O
Ar1
Ar1
O
Ar1
Pd(PPh3)4, PhB(OH)2
K2CO3, toluene,
reflux, 4 h.
NaIO4, RuCl3,
NaBH4, BF3.OEt2
THF, r.t., 3 h.
CCl4, CH3CN, H2O,
r.t., 24 h.
OH OH
OH OEt
OH OH
14
12
13
(96%)
(69%)
(90%)
Ar2
Ar2
Ar2
Ar2
Ar2
Ar2
i) KPPh2, THF,
0°C to r.t., 3 h.
EtOH, reflux, 24 h.
SOCl2
DMF, 0°C to refux,
24 h.
ii) BH3.SMe2, r.t., 2 h.
PPh2 PPh2
Cl
Cl
PPh2 PPh2
BH3 BH3
2
15
(87%)
(49%)
16
(96%)
Ar1= 3,5-dibromophenyl
Ar2= 3,5-diphenylphenyl
Scheme 2. Synthesis of bisphosphane 2.

2770
Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
Table 1
bisphosphane ligand 1 was the most effective (up to 99% yield
and up to 89% ee). An increase in the steric bulk of the chiral back-
bone generally led to a less efficient transfer of chirality from the
backbone to the reaction center and to lower yields.
Rh(I)-catalyzed asymmetric 1,4-addition of boronic acids 18a–f to cyclic enones 17A–
C using bisphosphane ligands 1 and 2
O
O
[RhCl(C2H4)2]2 / ligand 1 or 2
+
ArB(OH)2
4. Experimental
4.1. General
dioxane / 1.5 M aq KOH (10:1.3)
T= 50°C, 18 h.
n
Ar
n
n = 1: 17A
n = 0: 17B
n = 2: 17C
19
18a Ar = Ph
18b Ar = 4-CF3Ph
18c Ar = 4-MeOPh
18d Ar = 1-naphthyl
18e Ar = 2-CH3Ph
18f Ar = 2,6-(CH3)2-Ph
All reactions were carried out under an argon atmosphere in dry
solvents under anhydrous conditions, unless otherwise stated.
Phosphane ligand 1 was synthesized according to our earlier de-
scribed method.13 All reagents were purchased and used without
purification, unless otherwise noted. Analytical TLC was performed
using Macherey-Nagel SIL G-25 UV254 plates. Flash chromatogra-
phy was carried out with Rocc silica gel (0.040–0.063 mm). 1H
NMR, 13C NMR and 31P NMR were recorded on a Bruker Avance
300 or a Bruker DRX 500 spectrometer as indicated, with chemical
shifts reported in ppm relative to TMS (for 1H and 13C), and relative
to 85% aqueous phosphoric acid (for 31P), using the residual solvent
signal as a standard. 13C NMR spectra were recorded using the at-
tached proton test. IR-spectra were recorded on a Perkin–Elmer
SPECTRUM-1000 FT-IR spectrometer with a Pike Miracle Horizon-
tal Attenuated Total Reflectance (HATR) module. EI Mass spectra
were recorded with a Hewlett–Packard 5988A mass spectrometer.
LC–MS analysis was performed on an Agilent 1100 series HPLC
with quaternary pump, DAD, and single quadrupole MS detector
type VL with an API-ES source, using a Phenomenex Luna C18(2)
Entry
Ligand
Cyclic enone
Arylboronic acid
Yielda (%)
eeb,c (%)
1
2d
3
4
5
6
7
8
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
17A
17A
17A
17A
17A
17A
17A
17A
17A
17A
17A
17A
17B
17B
17C
17C
18a
18a
18b
18b
18c
18c
18d
18d
18e
18e
18f
71
84
99
70
64
16
46
16
58
78
nc
nc
68
25
9
83 (S)
81 (S)
89 (S)
76 (S)
71 (S)
45 (S)
83 (S)
<5 (nd)
63 (S)
59 (S)
—
9e
10e
11
12
13
14
15
16
18f
—
18a
18a
18a
18a
<5 (nd)
<5 (nd)
67 (S)
53 (S)
36
a
column (250 ꢁ 4.6 mm, particle size 5
lm). Analytical chiral HPLC
Isolated yield.
b
separations were performed on an Agilent 1100 series HPLC sys-
tem with DAD detection. Exact molecular masses were measured
on a quadrupole/orthogonal—acceleration time-of-flight (Q/oaTOF)
tandem mass spectrometer (qTof 2, Micromass, Manchester, UK)
equipped with a standard electrospray ionization (ESI) interface.
HRMS-EI masses were measured on a Kratos MS50TC mass spec-
trometer. Optical rotations were measured with a Perkin–Elmer
241 polarimeter. Melting points were measured with a Kofler melt-
ing point apparatus.
Determined by HPLC analysis with a chiral stationary phase column (Chiracel
OD-H, Chiralpak AS-H or Chiralpak AD-H).
c
The absolute configuration was assigned by the sign of the specific rotation.
Reaction time = 3 h.
Determined by GC analysis with a chiral stationary phase column (Cyclosil B).
d
e
acid 18b and ligand 1 (Table 1, entry 3). With the more bulky ligand 2,
a significantly lower enantioselectivity and conversion were obtained
(Table 1, entry 4). The same trend was also observed for 18c (Table 1,
entries 5 and 6). With the bulky 1-naphthylboronic acid 18d, a good
enantioselectivity was observed with ligand 1, however, the reaction
was much slower due to the steric bulk of the reagent (Table 1, entry
7). With the more bulky ligand 2, almost no conversion was observed
with 18d, and the selectivity was very low (Table 1, entry 8). The hin-
dered o-tolylboronic acid 18e gave a lower selectivity and yield
(especially for ligand 1 (Table 1, entries 9 and 10), whereas no reac-
tion was observed for the bulky 2,6-dimethylphenylboronic acid
18f (Table 1, entries 11 and 12). Except for 18a and 18e, an increase
in the steric bulk of the chiral ligand backbone leads in general to
lower yields and to a less effective transfer of chirality from the back-
bone to the reaction center.
The rhodium(I)/bisphosphane catalyst system was also applied
to 2-cyclopentenone 17B and 2-cycloheptenone 17C as acceptors
(Table 1, entries 13–16). With 2-cyclopentenone 17B, which can
be considered as a more difficult substrate, rather poor conversions
(especially with ligand 2) and very low enantioselectivities were
obtained (Table 1, entries 13 and 14). Similarly, poor results were
observed with 2-cycloheptenone 17C as a substrate (Table 1, en-
tries 15 and 16).
4.2. 5-Bromomethyl-1,3-dibromobenzene 7
3,5-Dibromotoluene
6
(9.5 g, 36.8 mmol), NBS (6.6 g,
36.8 mmol) and a catalytic amount of benzoyl peroxide (266 mg,
1.1 mmol) were refluxed in CCl4 (300 mL) for 5 h. The insoluble
succinimide was removed via filtration and was washed with
CCl4. The filtrate was concentrated in vacuo and purified by flash
chromatography over silica gel (Hexane/EtOAc, 99:1) resulting in
6.7 g of a mixture of 5-bromomethyl-1,3-dibromobenzene and 5-
dibromomethyl-1,3-dibromobenzene. Recrystallization from etha-
nol gave 5.9 g (50%) of 7 as a pure white solid. 1H NMR (300 MHz,
CDCl3): d 4.40 (s, 2H), 7.52 (d, J = 1.6 Hz, 2H), 7.64 (t, J = 1.6 Hz, 1H)
ppm. 13C NMR (75.4 MHz, CDCl3): d 30.8 (CH2), 123.1 (C), 130.8
(CH), 134.1 (CH), 141.3 (C) ppm. IR (HATR): 3061, 1772, 1745,
1580, 1552, 1421, 1370, 1223, 1207, 1097, 861, 741, 685,
627 cmꢂ1. EI-MS m/z (rel. intensity%): 328 (M+, 25), 249 (89), 168
(39), 89 (100). Mp: 91–93 °C. HRMS (EI): calcd for C7H579Br3:
325.7941; found: 325.7935.
4.3. 1,3-Dibromo-5-(diethylphosphonyl)methyl-benzene 8
3. Conclusion
A mixture of 5-bromomethyl-1,3-dibromobenzene 7 (5.0 g,
15 mmol) and triethyl phosphite (5.325 g, 30 mmol) was refluxed
at 140 °C for 5 h. The excess reagent was removed in vacuo. The
crude product was purified by flash chromatography over silica
gel (Pentane/EtOAc, 30:70) resulting in 5.40 g (93%) of pure 8 as
a yellow oil. 1H NMR (300 MHz, CDCl3): d 1.15 (t, J = 7.1 Hz, 6H),
In conclusion, we have synthesized a new bisphosphane ligand
2 with a more bulky cyclopropane backbone than our previously
reported bisphosphane ligand 1. We compared the efficiency of 1
and 2 in the Rh(I)-catalyzed asymmetric 1,4-addition to cyclic
enones. In almost all cases, we observed that the less bulky

Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
2771
2.94 (d, J = 21.8 Hz, 2H), 3.87–3.97 (m, 4H), 7.24–7.28 (m, 2H),
7.41–7.45 (m, 1H) ppm. 13C NMR (75.4 MHz, CDCl3): d 16.3
(d, JC–P = 7.0 Hz, 2 ꢁ CH3), 33.2 (d, JC–P = 35.0 Hz, CH2), 62.4
(d, JC–P = 7.1 Hz, 2 ꢁ CH2), 122.8 (d, JC–P = 3.3 Hz, C), 131.5
(d, JC–P = 6.6 Hz, CH), 132.6 (d, JC–P = 3.3 Hz, CH), 135.7
(d, JC–P = 8.8 Hz, C) ppm. 31P NMR (121.4 MHz, CDCl3):
d +24.4 ppm. IR (HATR): 2919, 1583, 1554, 1427, 1212, 1102,
859, 841, 742, 692, 666 cmꢂ1. ES-MS: 386.9 [M+H]+.
reaction mixture was cooled to 0 °C, whereupon the inorganic salts
were partially precipitated. (E)-3,30,5,50-Tetrabromostilbene
5
(23.5 g, 47.0 mmol) was added in one portion and the heteroge-
neous slurry was stirred vigorously at 0 °C for 5 days. The mixture
was allowed to warm to room temperature and Na2SO3 (80 g,
639.0 mmol) was added. The reaction mixture was stirred at room
temperature for another 24 h. Next, EtOAc (300 mL) was added and
the organic phase was separated, whereupon the aqueous phase
was further extracted with EtOAc (2 ꢁ 300 mL). The combined or-
ganic phases were washed with 2 M KOH and dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography over silica gel (Toluene/EtOH, 97:3)
resulting in 15.6 g (>99% ee, 63% yield) pure diol 9 as a white solid.
1H NMR (300 MHz, C6D6): d 1.65 (br s, 2H), 3.72 (s, 2H), 6.95 (d,
J = 1.7 Hz, 4H), 7.35 (t, J = 1.7 Hz, 2H) ppm. 13C NMR (75.4 MHz,
C6D6): d 75.2 (CH), 121.6 (C), 127.5 (CH), 132.3 (CH), 143.0 (C)
ppm. IR (HATR): 3457, 3289, 3085, 2914, 1737, 1585, 1557, 1419,
1371, 1241, 1192, 1105, 1038, 856, 760, 745, 673 cmꢂ1. EI-MS
(m/z, rel. intensity%): 530 (M+, 2), 513 (5), 156 (40), 266 (60).
4.4. 3,5-Dibromostyrene 4
3,5-Dibromobenzaldehyde 3 (2.0 g, 7.57 mmol) was added to a
mixture of t-BuOK (0.927 g, 8.26 mmol) and methyltriphenylphos-
phonium bromide (3.01 g, 8.26 mmol) in dry THF (35 mL). The
reaction mixture was stirred at room temperature for 4 h. A satu-
rated aqueous NH4Cl solution (10 mL) was added and the resulting
mixture was concentrated in vacuo. The aqueous layer was ex-
tracted with CH2Cl2 (2 ꢁ 100 mL). The combined organic phases
were washed with water (10 mL) and dried over MgSO4, filtered
off, and concentrated in vacuo. The crude product was purified
by flash chromatography over silica gel (Pentane/EtOAc, 98:2)
resulting in 1.390 g (70%) pure 4 as a yellow oil. 1H NMR
(300 MHz, CDCl3): d 5.15 (d, J = 10.9 Hz, 1H), 5.55 (d, J = 17.6 Hz,
1H), 6.30–6.42 (dd, J = 10.9 Hz and J = 17.6 Hz, 1H), 7.25 (d,
J = 1.7 Hz 2H), 7.33 (t, J = 1.7 Hz, 1H) ppm. 13C NMR (75.4 MHz,
CDCl3): d 116.9 (CH2), 123.1 (C), 128.0 (CH), 133.0 (CH), 134.3
(CH), 141.1 (C) ppm. IR (HATR): 3066, 2981, 1841, 1583, 1543,
1431, 1391, 1201, 1099, 988, 913, 847, 741, 635 cmꢂ1. EI-MS m/z
(rel. intensity%): 262 (M+, 53), 183 (30), 102 (100). HRMS (EI): calcd
for C8H679Br2: 259.8836; found: 259.8846.
½
a 2D0
C
ꢃ
¼ ꢂ119:0 (c 1.0, EtOH). Mp: 54–56 °C. HRMS (EI): calcd for
17H14O279Br4: 565.7727; found: 565.7708. Conditions for HPLC:
Chiralpak AD-H column, solvent: n-hexane/EtOH (95:5), flow
rate = 1 mL/min, T = 35 °C, retention times: 13.2 min for (1R,2R)-
9, 15.3 min for (1S,2S)-9.
4.7. (4R,5R)-4,5-Bis(30,50-dibromophenyl)-(1,3,2)-dioxathiolane-
(2,2)-dioxide 10
A dried 1 L three-neck flask was equipped with a reflux con-
denser carrying a drying tube with an HCl trap. (1R,2R)-1,2-
bis(3,5-dibromophenyl)-ethane-1,2-diol 9 (15.5 g, 29 mmol) and
CCl4 (100 mL) were added under an argon atmosphere. Thionyl
chloride (2.58 mL, 35 mmol) was added dropwise over 40 min.
The resulting reaction mixture was refluxed for 4 h. The solution
was cooled in an ice-water bath and then diluted with acetonitrile
(100 mL). NaIO4 (9.3 g, 43.5 mmol), RuCl3ꢀxH2O (0.031 g,
0.116 mmol), and water (140 mL) were added. The resulting bipha-
sic mixture was rapidly stirred at room temperature for 3 h. The
mixture was diluted with diethyl ether (500 mL) and the two
phases were separated. The organic phase was washed with H2O
(50 mL), saturated aqueous NaHCO3 (2 ꢁ 50 mL), and brine
(50 mL). After drying over Na2SO4, the organic phase was filtered
through a small pad of silica to remove the dark color and concen-
trated to give 16.0 g (93%) of 10 as a colorless oil. This product
decomposes at room temperature but is stable under an argon
atmosphere at ꢂ20 °C. 1H NMR (300 MHz, CDCl3): d 5.50 (s, 2H),
7.40 (d, J = 1.7 Hz, 4H), 7.80 (t, J = 1.7 Hz, 2H) ppm. 13C NMR
(75.4 MHz, CDCl3): d 87.0 (CH), 124.2 (C), 128.7 (CH), 134.0 (C),
136.9 (CH) ppm. IR (HATR): 3302, 3074, 1736, 1586, 1559, 1426,
1396, 1201, 1105, 957, 858, 804, 742, 677, 649 cmꢂ1. EI-MS m/z
4.5. (E)-3,30,5,50-Tetrabromostilbene 5
4.5.1. Method 1 (methathesis reaction)
Grubbs catalyst (2nd generation) (0.194 g, 0.229 mmol) dis-
solved in dry toluene (40 mL) was added in three portions to a
solution of 3,5-dibromostyrene 8 (1.2 g, 4.58 mmol) in dry toluene
(10 mL) under an argon atmosphere. The mixture was refluxed for
24 h. Subsequently, the reaction mixture was concentrated and the
crude product was purified by flash chromatography over silica gel
(Pentane/CH2Cl2/EtOH, 98:1.9:0.1) resulting in 1.0 g (83%) of pure
(E)-5 as a white solid.
4.5.2. Method 2 (Wittig reaction)
1,3-Dibromo-5-(diethylphosphonyl)methyl-benzene
8 (5.0 g,
13.0 mmol) dissolved in dry THF (100 mL) was added to a solution
of 3,5-dibromobenzaldehyde (6.85 g, 26.0 mmol) in dry THF
(380 mL) under an argon atmosphere at room temperature. Next,
t-BuOK (2.184 g, 19.5 mmol) was added to the reaction mixture.
The resulting reaction mixture was stirred at room temperature
for an additional 3 h. After hydrolysis with water, the mixture
was stirred for a further 30 min and the precipitated solid was fil-
tered off, resulting in 6 g (93%) of 5 as a pure white solid. 1H NMR
(300 MHz, C6D6): d 5.70 (s, 2H), 6.83 (d, J = 1.7 Hz, 4H), 7.08 (t,
J = 1.7 Hz, 2H) ppm. 13C NMR (75.4 MHz, C6D6): d 123.4 (C), 128.1
(CH), 128.5 (CH), 133.3 (CH), 140.0 (C) ppm. IR (HATR): 3062,
2917, 2852, 1705, 1580, 1548, 1419, 1241, 1216, 1101, 961, 906,
846, 745, 675 cmꢂ1. EI-MS m/z (rel. intensity%): 496 (M+, 100),
336 (91), 176 (95). Mp: 218–220 °C. HRMS (EI): calcd for
(rel. intensity%): 592 (M+, 5), 496 (2) 336 (7). ½a 2D0
¼ þ79:1 (c 1.0,
ꢃ
CHCl3). HRMS (EI): calcd for C14H8O4S79Br4: 587.6877; found:
587.6899.
4.8. (2R,3R)-1-(Ethoxycarbonyl)-1-(20-ethoxycarbonyl-vinyl)-
2,3-bis(300,500-dibromophenyl)-cyclopropane 11
At first, NaH (95% powder, 700.0 mg, 15.67 mmol) was sus-
pended in dry DME (25 mL) in a dried 250 mL two-neck flask fitted
with a reflux condenser under argon. Next, diethyl glutaconate
(1.3 mL, 6.48 mmol) was added dropwise over 40 min. Compound
10 (3.2 g, 5.4 mmol) was dissolved in dry DME (50 mL) and added
dropwise to the anion mixture. The resulting orange solution was
stirred at room temperature for 7 h. The reaction mixture was
quenched by adding saturated aqueous NH4Cl (60 mL) and the
water phase was extracted with EtOAc (2 ꢁ 250 mL). The
C
14H879Br4: 491.7359; found: 491.7371.
4.6. (1R,2R)-1,2-Bis(3,5-dibromophenyl)-ethane-1,2-diol 9
At first, AD-mix-b (125 g) was dissolved in a mixture of tert-
butyl alcohol (300 mL), THF (300 mL), and water (300 mL). Next,
methanesulfonamide (5.8 g, 61.0 mmol) was added and the

2772
Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
combined organic phases were dried over Na2SO4, filtered off, and
concentrated in vacuo. The crude product was purified by flash
chromatography over silica gel (pentane/EtOAc, 92:8), resulting
in 1.75 g (49%) of pure product 11 as a yellow oil. 1H NMR
(500 MHz, CDCl3): d 1.10 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H),
3.20 (d, J = 8.1 Hz, 1H), 3.85 (d, J = 8.1 Hz, 1H), 4.10 (dq, J = 12.8,
7.1 Hz, 1H), 4.15 (dq, J = 12.8, 7.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H),
5.97 (d, J = 15.9 Hz, 1H), 6.70 (d, J = 15.9 Hz, 1H), 7.37 (dd, J = 1.7,
0.7 Hz, 2H), 7.41 (dd, J = 1.7, 0.7 Hz, 2H), 7.63 (app. t, J = 1.7 Hz,
1H), 7.64 (app. t, J = 1.7 Hz, 1H) ppm. 13C NMR (125.7 MHz, CDCl3):
d 14.0 (CH3), 14.2 (CH3), 35.8 (CH), 37.1 (CH), 40.9 (C), 60.7 (CH2),
62.0 (CH2), 122.9 (C), 123.2 (C), 123.5 (CH), 130.8 (CH), 131.0 (CH),
133.4 (CH), 133.6 (CH), 138.2 (C), 138.4 (C), 141.5 (CH), 165.6 (C),
167.5 (C) ppm. IR (HATR): 2978, 1711, 1644, 1583, 1551, 1411,
1366, 1266, 1179, 1031, 977, 853, 741, 680, 675 cmꢂ1. ES-MS:
[MꢂH2O+H]+, 534.7 [Mꢂ2 ꢁ H2O+H]+. ½a 2D0
¼ ꢂ81:1 (c 1.0, CHCl3).
ꢃ
Mp: 148–150 °C.
4.11. (R,R)-2,3-Bis(30,50-diphenylphenyl)-cyclopropane-1,1-
dimethanol 14
To a solution of 13 (0.2 g, 0.351 mmol) and Pd(PPh3)4 (0.1 g,
0.084 mmol) in toluene (22 mL) were added phenylboronic acid
(524.0 g, 4.21 mmol), EtOH (5.5 mL), and aq K2CO3 (2 M, 11 mL).
The resulting reaction mixture was refluxed for 4 h. To the reaction
mixture was added water (100 mL). The aqueous layer was further
extracted with CH2Cl2 (3 ꢁ 100 mL) and the combined organic
phases were washed with brine (20 mL), dried over MgSO4, and
concentrated in vacuo. The crude product was passed through a
short pad of silica gel to remove the dark color and concentrated
in vacuo to give 0.188 g (96%) of pure 14 as a gray-white solid.
1H NMR (300 MHz, CDCl3): d 3.10 (s, 2H), 4.05 (d, J = 11.5 Hz,
2H), 4.15 (d, J = 11.5 Hz, 2H), 7.35–7.50 (m, 12H), 7.55–7.85 (m,
14H) ppm. 13C NMR (75.4 MHz, CDCl3): d 31.8 (CH), 32.1 (C), 66.7
(CH2), 124.9 (CH), 126.9 (CH), 127.3 (CH), 127.6 (CH), 128.8 (CH),
137.4 (C), 140.8 (C), 142.2 (C) ppm. IR (HATR): 3272, 3059, 2940,
2162, 1633, 1586, 1551, 1413, 1309, 1292, 1253, 1128, 1066,
681 [M+H]+. ½a 2D0
¼ þ75:3 (c 1.0, CHCl3). HRMS (EI): calcd for
ꢃ
C21H15O3Br4 [M – EtO]: 634.7714; found: 634.7700.
4.9. (2R,3R)-1-(Ethoxycarbonyl)-2,3-bis(30,50-dibromophenyl)-
cyclopropane-1-carboxylic acid 12
Compound 11 (1.40 g, 2.06 mmol) and NaIO4 (3.55 g,
16.47 mmol) were dissolved in a mixture of CH3CN (12 mL), CCl4
(12 mL), and H2O (18 mL). Next, RuCl3ꢀxH2O (0.032 g, 0.164 mmol)
was added to the reaction mixture, which was stirred at room tem-
perature for 24 h. The solids were filtered over Celite and washed
with water and CH2Cl2. The aqueous phase was extracted with
CH2Cl2 (2 ꢁ 200 mL). The combined organic phases were dried over
Na2SO4, filtered off, and concentrated in vacuo. The crude product
was purified by flash chromatography over silica gel (CH2Cl2/
MeOH/AcOH, 98.9:1:0.1) resulting in 0.893 g (69%) of pure 12 as
854, 756, 738, 693, 640 cmꢂ1
.
ES-MS: 576 [M+NH4]+, 523
[Mꢂ2 ꢁ H2O+H]+, 541 [MꢂH2O+H]+. ½a D20
ꢃ
¼ ꢂ76:8 (c 1.0, CHCl3).
Mp: 240–242 °C. HRMS (EI): calcd for
522.2347; found: 522.2334.
C
41H30 [Mꢂ2 ꢁ H2O]:
4.12. (2R,3R)-1,1-Bis(chloromethyl)-2,3-bis(30,50-diphenylphenyl)-
cyclopropane 15
Diol 14 (390.0 mg, 0.698 mmol) was dissolved in dry DMF
(4 mL) in an oven-dried 10 mL flask. The solution was cooled to
0 °C. Next, SOCl2 (0.249 g, 2.09 mmol) was added dropwise to the
solution and the resulting mixture was refluxed for 24 h. Water
(10 mL) was added to the reaction mixture, which was extracted
with CH2Cl2 (3 ꢁ 50 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
over silica gel (hexane/CH2Cl2, 70:30) resulting in 205.0 mg pure
15 as a pale yellow oil. 1H NMR (300 MHz, CDCl3): d 3.15 (s, 2H),
3.20 (d, J = 11.5 Hz, 2H), 3.90 (d, J = 11.5 Hz, 2H), 7.40–7.50 (m,
12H), 7.50–7.60 (m, 14H) ppm. 13C NMR (75.4 MHz, CDCl3): d
36.6 (CH), 36.8 (C), 47.7 (CH2), 125.3 (CH), 126.9 (CH), 127.3
(CH), 127.7 (CH), 128.9 (CH), 136.7 (C), 140.7 (C), 142.3 (C) ppm.
IR (HATR): 3043, 1594, 1576, 1496, 1426, 1333, 1264, 1178,
a
colorless oil. 1H NMR (500 MHz, acetone-d6):
d 1.02 (t,
J = 7.1 Hz, 3H), 3.86 (d, J = 8.2 Hz, 1H), 3.89 (d, J = 8.2 Hz, 1H),
4.00 (dq, J = 10.8, 7.1 Hz, 1H), 4.08 (dq, J = 10.8, 7.1 Hz, 1H), 7.59
(d, J = 1.6 Hz, 2H), 7.62 (d, J = 1.6 Hz, 2H), 7.67 (t, J = 1.6 Hz, 1H),
7.69 (t, J = 1.6 Hz, 1H) ppm. 13C NMR (125.7 MHz, acetone-d6): d
13.4 (CH3), 33.1 (CH), 33.3 (CH), 46.0 (C), 61.4 (CH2), 122.3 (C),
122.3 (C), 131.0 (CH), 131.1 (CH), 132.7 (CH), 139.6 (C), 165.9 (C),
166.2 (C) ppm. IR (HATR): 1706, 1584, 1552, 1412, 1369, 1263,
1218, 1178, 1134, 1100, 1029, 856, 734, 703, 678 cmꢂ1. ES-MS:
626.7 [M+H]+. ½a D20
¼ þ27:3 (c 1.0, CHCl3). HRMS (EI): calcd for
ꢃ
C
19H14O479Br4: 621.7626; found: 621.7624.
4.10. (2R,3R)-2,3-Bis(30,50-dibromophenyl)-cyclopropane-1,1-
dimethanol (13)
1075, 1029, 1005, 909, 876, 755, 694 cmꢂ1
. ES-MS: 523.2
[Mꢂ2Cl+H]+, 559.2 [MꢂCl+H]+. ½a 2D0
¼ ꢂ88:6 (c 1.0, CHCl3). HRMS
ꢃ
Compound 12 (1.0 g, 1.60 mmol) in THF (50 mL) was placed in
an oven-dried 100 mL two-neck flask under an argon atmosphere
and cooled to 0 °C. Next, NaBH4 (575.0 mg, 14.38 mmol) was added
to the solution and the resulting suspension was stirred for 20 min.
Subsequently, BF3ꢀOEt2 (2.50 g, 17.58 mmol) was added dropwise
to the resulting mixture at 0 °C. The reaction mixture was stirred
at room temperature for another 3 h. The reaction was neutralized
with aq 2 M NaOH (5 mL) until the pH of the mixture was around
8–9. Next, THF was evaporated in vacuo and the residue was ex-
tracted with Et2O (3 ꢁ 150 mL). The combined organic phases were
washed with H2O (10 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
over silica gel (CH2Cl2/EtOAc, 9:1), resulting in 0.821 g (90%) of
pure 13 as a white solid. 1H NMR (300 MHz, CDCl3): d 2.05 (br s,
2H), 2.60 (s, 2H), 3.52 (d, J = 10.8 Hz, 2H), 3.58 (d, J = 10.8 Hz,
2H), 7.35 (s, 4H), 7.50 (s, 2H) ppm. 13C NMR (75.4 MHz, CDCl3): d
30.8 (CH), 37.4 (C), 65.5 (CH2), 123.1 (C), 130.9 (CH), 132.8 (CH),
140.6 (C) ppm. IR (HATR): 3349, 2933, 2884, 2356, 2012, 1581,
1549, 1429, 1405, 1288, 1170, 1071, 1021, 1013, 933, 859, 851,
(EI): calcd for C41H3235Cl2: 594.1881; found: 594.1884.
4.13. (2R,3R)-1,1-Bis[(boratodiphenylphosphanyl) methyl]-2,3-
bis(30,50-diphenylphenyl)-cyclopropane 16
At first, KPPh2 in THF (0.5 M, 2.20 mL, 1.18 mmol) was placed in
an oven-dried Schlenk tube under an argon atmosphere at 0 °C.
Next, 15 (0.15 g, 0.252 mmol) in dry THF (2.40 mL) was added
dropwise to the solution. The resulting mixture was stirred at room
temperature for 3 h. Subsequently, BH3ꢀSMe2 (0.109 g, 1.429
mmol) was added dropwise to the reaction mixture at room tem-
perature, followed by stirring for 2 h. After the addition of aq
NH4Cl, the reaction mixture was diluted with CH2Cl2 (20 mL) and
the water phase was extracted with CH2Cl2 (3 ꢁ 20 mL). The com-
bined organic phases were dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash chromatography
over silica gel (hexane/EtOAc, 90:10) resulting in 224 mg (96%) of
pure product 16 as a colorless oil. 1H NMR (300 MHz, CDCl3): d
1.40–1.55 (br s, 6H, BH3), 2.00 (dd (app. t), J = 15.7 Hz, 2H), 2.32
(s, 2H), 3.50 (dd, J = 6.2, 15.7 Hz, 2H), 7.05–7.75 (m, 46H) ppm.
743, 738, 700, 686 cmꢂ1
.
ES-MS: 587.8 [M+NH4]+, 552.7

Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
2773
13C NMR (75.4 MHz, CDCl3): d 28.3 (C), 28.8 (CH2), 30.8 (dd,
JC–P = 4.9, 10.4 Hz, CH), 124.7 (CH), 127.3 (CH), 127.4 (CH), 128.6
(CH), 128.2 (C), 128.7 (d, JC–P = 9.0 Hz, CH), 128.9 (CH), 129.1 (d,
JC–P = 9.0 Hz, CH), 130.7 (d, JC–P = 2.2 Hz, CH), 130.9 (C), 131.6 (d,
JC–P = 9.0 Hz, CH), 132.1 (d, JC–P = 2.2 Hz, CH), 133.7 (d,
JC–P = 9.0 Hz, CH), 137.4 (C), 140.8 (C), 141.8 (C) ppm. 31P NMR
(121.4 MHz, CDCl3): d +14.1 ppm. IR (HATR): 3049, 2392, 1595,
1576, 1496, 1435, 1105, 1059, 878, 853, 757, 694 cmꢂ1. ES-MS:
For 3-(1-naphthyl)cyclohexanone 19Ad: The enantiomeric ex-
cess was determined by chiral HPLC analysis: Chiralcel AD-H col-
umn (250 ꢁ 4.6 mm, particle size 10
lm), solvent: n-hexane/
iPrOH (98:2), flow rate = 1 mL/min, T = 35 °C, retention times:
12.1 min for (ꢂ) and 13.5 min for (+).
For 3-(o-tolyl)cyclohexanone 19Ae: The enantiomeric excess
was determined by chiral GC analysis: Cyclosil
B
120
(30 m ꢁ 0.25 mm ꢁ 0.25
l
m); carrier gas: H2; temperature pro-
940.3 [M+NH4]+. ½a D20
ꢃ
¼ þ82:4 (c 1.0, CHCl3). HRMS (EI): calcd for
gram: 50 °C for 3 min; increase to 200 °C (20 °C/min); 200 °C for
3 min; increase to 240 °C (20 °C/min); 240 °C for 5 min; retention
times: 14.86 min for R and 14.93 min for S.
C
65H58B2P2: 922.4200; found: 922.4198.
4.14. (2R,3R)-1,1-Bis[(diphenylphosphanyl)methyl]-2,3-
For 3-phenylcycloheptanone 19Ca: The enantiomeric excess
was determined by chiral HPLC analysis: Chiralcel OD-H column
bis(30,50-diphenylphenyl)-cyclopropane 2
(250 ꢁ 4.6 mm, particle size 10
lm), solvent: n-hexane/iPrOH
(98:2), flow rate = 1 mL/min, T = 35 °C, retention times: 11.7 min
for (ꢂ) and 13.3 min for (+).
Compound 16 (180.0 mg, 0.195 mmol) was dissolved in de-
gassed EtOH (6 mL) in an oven-dried Schlenk tube under argon
atmosphere. The solution was refluxed for 24 h, subsequently di-
luted with degassed CH2Cl2 (15 mL), and concentrated in vacuo.
The crude product was purified by flash chromatography over sil-
ica gel with degassed solvents (hexane/EtOAc, 95:5) resulting in
152 mg of pure 2 as a colorless oil. 1H NMR (300 MHz, CDCl3): d
2.05 (dd, J = 2.8, 14.4 Hz, 2H), 2.6 (s, 2H), 2.8 (dd (app. d),
J = 14.4 Hz, 2H), 7.15–7.70 (m, 46H) ppm. 13C NMR (125.7 MHz,
CDCl3): d 32.5 (t, JC–P = 17.4 Hz, C), 33.1 (dd, JC–P = 10.1, 13.7 Hz,
CH2), 33.6 (t, JC–P = 7.3 Hz, CH), 124.2 (CH), 127.0 (CH), 127.4
(CH), 127.5 (CH) 127.9 (CH), 128.3 (d, JC–P = 6.4 Hz, CH), 128.7
(CH), 128.8 (d, JC–P = 8.2 Hz, CH), 129.7 (CH), 132.0 (d,
JC–P = 17.4 Hz, CH), 134.6 (d, JC–P = 22.0 Hz, CH), 137.8 (d,
JC–P = 14.7 Hz, C), 139.0 (C), 139.8 (d, JC–P = 13.8 Hz, C), 141.1 (C),
141.7 (C) ppm. 31P NMR (121.4 MHz, CDCl3): d ꢂ20.5 ppm. IR
(HATR): 3054, 2165, 1593, 1496, 1432, 1070, 1028, 909, 881,
Acknowledgments
Y.G., T.N. and J.V.D.E wish to thank Ghent University and COST-
Chemistry (Action D.40-‘Innovative Catalysis’) for financial sup-
port. Professor Dr. Erik Van der Eycken (Laboratory for Organic &
Microwave-Assisted Chemistry (LOMAC), Department of Chemis-
try, Katholieke Universiteit Leuven) is kindly acknowledged for
performing the HRMS-measurements.
References
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1,4-addition of arylboronic acids to cyclic enones
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were dissolved in dry and degassed dioxane (1 mL) and stirred for
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through a short pad of silica gel and was eluted with EtOAc. The
crude product was purified by flash chromatography over silica
gel (hexane/Et2O, 85:15), resulting in pure 19.
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For 3-phenylcyclohexanone 19Aa: The enantiomeric excess was
determined by chiral HPLC analysis: Chiralpak AS-H column
(250 ꢁ 4.6 mm, particle size 10
lm), solvent: n-hexane/iPrOH
(98:2), flow rate = 1 mL/min, T = 35 °C, retention times: 18.3 min
for S and 21.4 min for R.
For 3-(4-trifluoromethylphenyl)cyclohexanone 19Ab: The
enantiomeric excess was determined by chiral HPLC analysis: Chir-
alpak AD-H column (250 ꢁ 4.6 mm, particle size 10
lm), solvent:
n-hexane/iPrOH (99:1), flow rate = 1 mL/min, T = 35 °C, retention
times: 14.0 min for (+) and 15.1 min for (ꢂ).
For 3-(4-methoxyphenyl)cyclohexanone 19Ac: The enantio-
meric excess was determined by chiral HPLC analysis: Chiralcel
OD-H column (250 ꢁ 4.6 mm, particle size 10
lm), solvent: n-hex-
ane/iPrOH (98:2), flow rate = 1 mL/min, T = 35 °C, retention times:
13.0 min for (+) and 13.6 min for (ꢂ).

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Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2768–2774
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