Trans-(2R,3R)-2,3-Diphenylcyclopropane-1,1-dimethanol: A pivotal diol for the synthesis of novel C2-symmetric ligands for asymmetric transition metal catalysis

Article abstract of DOI:10.1016/j.tetasy.2010.08.007

Various chiral ligands bearing phosphorus or nitrogen donor atoms were obtained in a straightforward manner starting from trans-(2R,3R)- diphenylcyclopropane-1,1-dimethanol as a key structure. These chiral ligands were tested and compared in palladium(0)-

Full text of DOI:10.1016/j.tetasy.2010.08.007

Tetrahedron: Asymmetry 21 (2010) 2321–2328
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
trans-(2R,3R)-2,3-Diphenylcyclopropane-1,1-dimethanol: a pivotal diol for
the synthesis of novel C2-symmetric ligands for asymmetric transition
metal catalysis
Elias Vervecken, Michel Van Overschelde, Timothy Noël, Yasßar Gök, Susana Alvárez Rodríguez,
⇑
Simon Cogen, 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:
Various chiral ligands bearing phosphorus or nitrogen donor atoms were obtained in a straightforward
manner starting from trans-(2R,3R)-diphenylcyclopropane-1,1-dimethanol as a key structure. These chi-
ral ligands were tested and compared in palladium(0)-catalyzed asymmetric allylic alkylation reactions
(up to 71% ee) and rhodium(I)-catalyzed asymmetric hydrogenations (up to 88% ee). Moreover, in the
asymmetric allylic alkylation, we observed excellent activity with a diphosphinite ligand (TOF = 600 mol
17 ꢀ [mol Pd ꢀ h)ꢁ1].
Received 4 May 2010
Revised 11 August 2010
Accepted 12 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
and broaden the scope of this new ligand architecture in transition
metal catalysis.
Today, asymmetric transition metal catalysis has become one of
the most efficient and interesting approaches for the synthesis of
optically active compounds.1,2 For a successful asymmetric catalytic
reaction, a careful combination of a metal with an appropriate ligand
is a key requisite. Given the complexity of most catalytic processes,
the rigorous prediction of the electronic and steric needs of a ligand
in order to obtain high enantioselective inductions remains a
difficult task.3 To cope rationally with this problem, a modular li-
gand structure is required, which allows rapid diversification.4 The
C2-symmetric5 ligand, shown in Figure 1, contains this feature.
Herein, we report on a first set of diphenyl-substituted cyclo-
propane-based ligands (R = Ph, n = 0) with P or N as donor atoms.
These ligands can all be derived directly from a pivotal diol 6
(Scheme 1). The newly synthesized ligands were tested and com-
pared in the asymmetric rhodium(I)-catalyzed hydrogenation
and the palladium(0)-catalyzed asymmetric allylic alkylation.
2. Results and discussion
Our approach is based on an earlier described synthesis of
monomalonate ester 5 for the preparation of cyclopropyl amino
acids.8 As shown in Scheme 1, diol 2 can be efficiently prepared
via a Sharpless asymmetric dihydroxylation (>99% ee).9 This diol
was converted to cyclic sulfate 3 in two high yielding steps. A ste-
reocontrolled double substitution of the cyclic sulfate 3 with
diethyl glutaconate anion in the presence of 2.3 equiv of base affor-
ded cyclopropane 4 in good yield. Subsequent oxidative cleavage of
4 yielded monomalonate ester 5, which was finally reduced to the
desired pivotal diol 6 with LiAlH4.
n
n = 0, 1, 2
R = alkyl, aryl
R
R
X = oxygen-, phosphorus- or
nitrogen-based donor groups
X
X
Figure 1. A C2-symmetrical modular ligand structure.
Variation of the bulk of the R substituents on the cycloalkane
ring should allow us to determine the optimal transfer of chirality
from the backbone to the reaction center. The electronic and steric
properties of the chelating atoms can also be tuned,6 as well as
their bite angle7 by changing the ring size of the backbone (n = 0,
1, 2). Both phosphorus- and nitrogen-based ligands are accessible
Pivotal diol 6 is a key structure in our synthesis of new diphos-
phane, diphosphinite, bisimine, and bisamine ligands.
The synthesis of chiral diphosphane ligands can be performed
efficiently in three steps starting from diol 6, as shown in Scheme 2.
Diol 6 was converted into dimesylate 7. Next, a nucleophilic substi-
tution with 4 equiv of potassium diphenyl phosphide in THF and
subsequent in situ protection with BH3ꢂSMe2 afforded the pro-
tected phosphane ligand 8 in high yield.10 Normally, cleavage of
the BH3-protecting group can be achieved by treatment with
⇑
Corresponding author. Tel.: +32 9 264 44 80; fax: +32 9 264 49 98.
E-mail address: Johan.Vandereycken@UGent.be (J. Van der Eycken).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.007

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E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
O
O
Ph
O
S
i) AD-mix beta, MeSO NH ,
tert-BuOH/H2O, 0ºC, 3 days.
Ph
HO
Ph
OH
Ph
Ph
2
2
O
O
i) SOCl2, CCl4, reflux, 30 min.
diethylglutaconate
NaH, DME, rt, 7h
ii) NaIO4, RuCl3, CH3CN/H2O,
0ºC to rt.
ii) recrystallization
Ph
Ph
Ph
O
OEt
1
2
3
(89%, >99% ee)
(89%)
OEt
4
(84%)
Ph
Ph
Ph
O
Ph
NaIO4, RuCl3,
LiAlH4
O
CCl4, CH3CN, H2O,
rt, 17h
Et2O, rt, 1h
OH
OH
OH
OEt
5
6
(97%)
(58%)
pivotal diol
Scheme 1. Synthesis of pivotal diol 6.
Ph
Ph
Ph
Ph
i) KPPh2, THF,
0ºC to RT, 1.5h
MsCl, Et3N
6
CH2Cl2, 0ºC, 1.5h
ii) BH3.SMe2, rt, 2h
PPh2 PPh2
BH3 BH3
OMs OMs
7
8
(97%)
(95%)
Ph
Ph
EtOH, reflux, 16h
PPh2 PPh2
9
(99%)
Scheme 2. Synthesis of diphosphane ligand 9.
strong acids11 or an excess of amine.12 However, we recently dis-
covered that phosphane deprotection can be conveniently carried
out under very mild neutral conditions by simply refluxing in eth-
anol for 16 h, to afford diphosphane ligand 9 in 99% yield.13 Fur-
thermore, the unprotected solid diphosphane 9 appeared to be
air-stable at room temperature for at least 3 weeks.
complete solvolysis of 11. Although diphosphinite 11 appeared to
be susceptible to decomposition, fast flash chromatography on
neutral dry alumina, and eluting with dry ether afforded 11 as a
white crystalline product in good yield. It should be noted that this
solid diphosphinite 11 is stable in air at room temperature for at
least 8 days.
Phosphinite ligands can also be easily derived from this versa-
tile diol 6, as demonstrated in Scheme 3. When diol 6 was treated
with chlorodiphenylphosphane (3.5 equiv) in the presence of tri-
ethylamine, and subsequently protected in situ with BH3ꢂSMe2,
diphosphinite borane 10 was obtained in excellent yield. Deprotec-
tion could be accomplished by treatment with DABCO (4.5 equiv)
in benzene at 50 °C. Not unexpectedly, our alternative deprotection
method by refluxing 10 in ethanol was unsuccessful and led to
Finally, we wanted to synthesize some nitrogen-containing li-
gands derived from chiral diol 6. Although phosphane ligands are
the most widely used ligands, nitrogen-containing ligands have
some interesting advantages.14 Firstly, they can be used in
asymmetric catalysis with other transition metals, and are less
expensive than noble metals, for example, cobalt complexes.15
Secondly, they are also suitable for heterogeneous catalysis, which
is one of their main advantages over phosphane ligands.14c
Ph
Ph
Ph
Ph
i) PPh2Cl, Et3N,
DABCO, benzene,
50ºC, 8h
rt, CH2Cl2, 2h
6
ii) BH3.SMe2, rt, 2h
O
O
O
O
Ph2P
H3B
PPh2
BH3
Ph2P
PPh2
11
(79%)
10
(92%)
Scheme 3. Synthesis of diphosphinite ligand 11.

E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
2323
Ph
Ph
Ph
Ph
i) PPh3, THF,
RT, 1 h
NaN3
7
ii) aq. HCl, rt, 16h
DMSO, 35ºC, 3.5h
NH3Cl NH3Cl
N3
N3
12
(89%)
13
(99%)
benzaldehyde
Ph
Ar
Ph
Ph
or
Ph
NaBH4, MeOH,
toluene, 16h
2,6-dichlorobenzaldehyde
Et3N, Na2SO4,
CH2Cl2, 3h.
N
N
NH HN
Ar
Ar = Ph: 14 (91%)
Ar = 2,6-dichloro-Ph: 15 (88%)
Ar
Ar
16 (73%)
Ar = 2,6-dichloro-Ph
Scheme 4. Synthesis of bisimine and bisamine ligands.
Table 1
The synthesis of bisimine and bisamine ligands is shown in
Pd(0)-catalyzed asymmetric allylic alkylation of 17 using ligands 9, 11, 14–16
Scheme 4. Reaction of dimesylate 7 with sodium azide in DMSO
at 35 °C afforded diazide 12 in 89% yield. Higher temperatures
led to more complex reaction mixtures due to decomposition of
12. Diazide 12 should be handled with care, as it decomposes
slowly even at ꢁ20 °C. Our attempts to synthesize bis(ammonium
chloride) 13 through hydrogenation of 12 with Pd/C or PtO2 were
unsuccessful. However, Staudinger reduction, which is known to
be a very mild method for reducing azides16 afforded the HCl salt
of bisamine 13 in excellent yield. The latter can be easily purified
via recrystallization from isopropanol/ether. As a result, purifica-
tion of the very sensitive diazide 12 can be avoided. The free bis-
amine can be obtained by careful treatment of 13 with aqueous
NaOH (10%, 2 equiv) in dichloromethane. However, concentrating
a solution of the free bisamine base, as well as flash chromatogra-
phy led to decomposition. Therefore, whenever the free bisamine is
needed, it is more convenient to liberate it from its salt in situ.
Hence, bisimine ligands 14 and 15 are readily obtained by the
reaction of bis(ammonium chloride) 13 with the corresponding
aldehyde in the presence of triethylamine and Na2SO4. The corre-
sponding bisamine ligand 16 could be obtained upon treatment
of 15 with NaBH4 in MeOH.
[Pd(π-C3H5)Cl]2/
OAc
Ph
CH(COOMe)2
Ph
Ligand
CH2(COOCH3)2/BSA
BSA-activator
Ph
Ph
CH2Cl2, RT.
17
18
Entry
Ligand
BSA-activatora
Reaction time
Yieldb (%)
eec,d (%)
1
9
9
11
14
15
16
LiOAc
KOAc
LiOAc
LiOAc
LiOAc
LiOAc
2 h
1 h
5 min
6 days
45 h
n.r.
100
100
100
14
100
—
61 (R)
71 (R)
34 (R)
23 (R)
45 (R)
—
2e
3f,g
4
5
6h
a
b
c
BSA = N,O-bis-(trimethylsilyl)acetamide.
Isolated yield.
Determined by HPLC analysis with a chiral stationary phase column (Chiralpak
AD-H).
d
Absolute configuration was assigned by the sign of the specific rotation.
The reaction was performed with acetylacetone as a nucleophile.
Reaction temperature = 0 °C.
The reaction was performed in acetone as a solvent.
No reaction occurred, even after prolonged reaction times.
e
f
g
h
Preliminary experiments demonstrated that this novel ligand
backbone holds the potential for application in asymmetric transi-
tion metal catalysis. The Pd(0)-catalyzed allylic alkylation of rac-
1,3-diphenyl-3-acetoxyprop-1-ene 17 with dimethylmalonate
could be performed with 61% ee and in quantitative yield in the
presence of diphosphane 9 (Table 1, entry 1).17 The use of acetyl-
acetone as a nucleophile and KOAc as a BSA-activator afforded
the corresponding adduct in excellent yield with an enantioselec-
tivity of 71% ee (Table 1, entry 2). To our delight, with diphosphi-
nite 11 as a ligand, full conversion was obtained in less than
5 min even at 0 °C (Table 1, entry 3). Although the enantioselectiv-
ity was rather poor, the high activity of this ligand is noteworthy
[TOF = 600 mol 17 ꢀ (mol Pd ꢀ h)ꢁ1].18 Poor results were obtained
in the presence of nitrogen ligands 14–16 (Table 1, entries 4–6).
With bisimine 15, full conversion was obtained in 45 h with mod-
erate enantioselectivity (Table 1, entry 5).
The Rh(I)-catalyzed asymmetric hydrogenation of methyl-2-
acetamido-3-phenylacrylate 19 was selected as a second bench-
mark test reaction (Table 2). With diphosphane ligand 9, full con-
version was obtained in 3 h and a very good selectivity of 88% ee
was observed (Table 2, entry 1). Also, with diphosphinite 11 full
conversion was reached in 3 h and a good enantioselectivity of
72% ee was obtained (Table 2, entry 2).
Table 2
Rh(I)-catalyzed asymmetric hydrogenation of 19 using ligands 9 and 11
COOCH3
COOCH3
Rh(COD)2BF4/
Ligand
NHAc
NHAc
solvent, RT.
19
20
Yielda
Entry Ligand Solvent
H2
(bar)
Reaction time
(h)
eeb,c
(%)
(%)
1
2
9
11
Acetone 15
EtOAc
3
3
100
100
88 (R)
72 (R)
6
a
Isolated yield.
b
Determined by GC analysis with a chiral stationary phase column (Chirasil-Val
column).
c
Absolute configuration was assigned by the sign of the specific rotation.
3. Conclusion
In conclusion, we have successfully developed new nitrogen-
and phosphorus-based ligands derived from trans-(2R,3R)-2,3-

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E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
diphenylcyclopropane-1,1-dimethanol 6, as a pivotal key structure
in their synthesis. As proof of their potential in asymmetric transi-
tion metal catalysis, these ligands were tested in Pd(0)-catalyzed
asymmetric alkylations (up to 71% ee) and Rh(I)-catalyzed asym-
refluxing ethanol afforded 29.5 g (89%) of enantiopure diol 2
(>99.9% ee). 1H NMR (500 MHz, CDCl3): d 4.70 [s, 2H, H1 and H2],
2.91 [s, 2H, OH], and 7.05–7.27 [m, 10H, H arom.] ppm. 13C NMR
(125.72 MHz, CDCl3): d 78.9 [CH, C1 and C2], 126.7 [CH, C arom.],
127.7 [CH, C arom.], 127.9 [CH, C arom.], and 139.6 [C, C arom.]
metric hydrogenations (up to 88% ee). Remarkably, with
a
diphosphinite ligand, high activities were observed in the Pd(0)-
catalyzed asymmetric allylic alkylation reaction (TOF = 600 mol
17 ꢀ (mol Pd ꢀ h)ꢁ1). Current studies are focused upon expanding
the scope of this novel ligand backbone by variation of its steric
and electronic properties. These results will be reported in due
course.
ppm. IR mmax (KBr): 3498 [vs,
[m], 1603 [w, mc@c Ph], 1584 [vw, mc@c Ph], 1493 [w, mc@c Ph],
1451 [m, mc@c Ph], 1046 [s, C–O], 777 [m, cC–H Ph], 695 [s, cPh
mO–H], br 3390 [s, mO–Hꢂ ꢂ ꢂH], 2895
m
]
cmꢁ1. EI-MS m/z [rel intensity%]: 214 [2, M+], 108 [93], 107 [100,
M+/2 or M++], 79 [88], and 77 [59, Ph+]. ½a 2D0
¼ þ90:8 (c 1.0, EtOH).
ꢃ
Mp 147.5 °C. HRMS (EI) calcd for C14H14O2 [M+]: 214.0994; found
214.1005. Conditions for chiral HPLC analysis: Chiralpak AD-H col-
umn, solvent: n-hexane/EtOH (97:3), flow rate = 1 mL/min,
T = 35 °C, and retention times: 51.2 min for (1S,2S)-(ꢁ)-2 and
59.0 min for (1R,2R)-(+)-2.
4. Experimental
4.1. General
4.3. Synthesis of (4R,5R)-4,5-diphenyl-(1,3,2)-dioxathiolane-
All reactions were carried out under an argon atmosphere in dry
solvents under anhydrous conditions, unless otherwise stated. All
reagents were purchased and used without purification, unless
otherwise noted. Analytical TLC was performed using Macherey-
Nagel SIL G-25 UV254 plates. Flash chromatography was carried
out with Rocc silica gel (0.040–0.063 mm). 1H NMR and 13C NMR
were recorded on a Bruker Avance 300 or a Bruker DRX 500 spec-
trometer as indicated, with chemical shifts reported in ppm rela-
tive to TMS, using the residual solvent signal as a standard and
relative to 85% aqueous phosphoric acid for 31P. 13C NMR spectra
were recorded using the attached proton test. IR-spectra were re-
corded on a Perkin–Elmer SPECTRUM-1000 FT-IR spectrometer
(2,2)-dioxide 3
A 1 L two-necked round-bottomed flask was fitted with a reflux
condenser carrying a drying tube with an HCl trap, and filled with
1,2-diphenyl-1,2-ethanediol 2 (36.05 g, 168.25 mmol). The flask
was flushed with argon, and dry CCl4 (178 mL) was added via syr-
inge, followed by thionyl chloride (14.8 mL, 201.9 mmol). The
resulting mixture was refluxed for 1.5 h. The solution was cooled
in an ice bath and then diluted with acetonitrile (178 mL). Solid
NaIO4 (54.5 g, 252.38 mmol) and RuCl3ꢂH2O (35–42% Ru, 89 mg,
0.337 mmol) were added, followed by H2O (250 mL), and the
resulting biphasic mixture was vigorously stirred at room temper-
ature for 2 h. The mixture was poured into a separation funnel con-
taining diethyl ether (1 L). The organic layer was washed with H2O
(100 mL), saturated aqueous NaHCO3 solution (2 ꢀ 100 mL), and
brine (100 mL), and was finally dried over Na2SO4. The solution
was filtered through a pad of silica, and concentrated in vacuo to
give 41.4 g of 3 as white crystals covered with a yellow oil. The
product decomposes at room temperature but is stable for several
months upon storage in the freezer (ꢁ20 °C) under argon. The
crude product was used without further purification. A small
amount of 3 could be purified for spectroscopic data, by washing
with dry diethyl ether, giving white crystals. 1H NMR (500 MHz,
CDCl3): d 5.72 [s, 2H, H4 and H5], 7.24–7.33 [m, 4H, H arom.], and
7.38–7.48 [m, 6H, H arom] ppm. 13C NMR (125.72 MHz, CDCl3): d
89.55 [CH, C4 and C5], 126.99 [CH, C arom.], 129.03 [CH, C arom.],
130.44 [CH, C arom.], and 130.57 [C, C arom.] ppm. IR mmax (KBr):
1616 [m, mc@c Ph], 1496 [m, mc@c Ph], 1461 [m, mc@c Ph], 1382 [s,
with
a Pike Miracle Horizontal 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) column (250 ꢀ 4.6 mm, particle
size 5 lm). Analytical chiral HPLC separations were performed on
an Agilent 1100 series HPLC system with DAD detection. Exact ES
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. Exact EI molecular masses
were measured on a Kratos MS50TC mass spectrometer with stan-
dard electron impact ionization (EI). Melting points were measured
with a Kofler melting point apparatus. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter at 589 nm.
m
asS@O], 1261 and [vs, m
sS@O] cmꢁ1. EI-MS m/z [rel intensity%]:
276 [2, M+], 107 [41], 105 [100], and 77 [19, Ph+]. HRMS (EI) calcd
for C14H12O4S [M+]: 276.0456; found 276.0458.
4.2. Synthesis of (1R,2R)-1,2-diphenyl-1,2-ethanediol 2
A 4 L two-necked round-bottomed flask, equipped with a
mechanical stirrer, was charged with water (772 mL), tert-butyl
alcohol (772 mL), and AD-mix-b (216.37 g). Stirring at room tem-
perature produced two clear phases; the lower aqueous phase ap-
peared bright yellow. Methanesulfonamide (15.14 g, 153.36 mmol)
was then added at this point. The mixture was cooled to 0 °C
whereupon some of the dissolved salts precipitated. trans-Stilbene
(28.68 g, 154.36 mmol) was added in one portion, and the hetero-
geneous slurry was stirred vigorously at 0 °C for 3 days. Next, solid
sodium sulfite (232 g, 1.84 mol) was added and the mixture was al-
lowed to warm to room temperature and was stirred for another
hour. Ethyl acetate (600 mL) was added to the reaction mixture,
and after separation of the layers, the aqueous phase was further
extracted with ethyl acetate (3 ꢀ 800 mL). The combined organic
phases were washed with 2 M aqueous KOH, dried over anhydrous
sodium sulfate, and concentrated in vacuo to give 47 g of crude diol
2. Purification by flash chromatography over silica gel (iso-octane/
EtOAc, 65:35) resulted in 33 g of diol 2. One recrystallization from
4.4. Synthesis of (2R,3R)-1-(ethoxycarbonyl)-1-(E-20-ethoxy-
carbonyl-vinyl)-2,3-diphenylcyclopropane 4
To a 250 mL two-necked round-bottomed flask, equipped with a
reflux condenser and a magnetic stirrer, were added NaH (95% pow-
der, 9.25 g, 366.25 mmol) and freshly distilled DME (366 mL). Next,
diethyl glutaconate (29.1 mL, 161.15 mmol) was added carefully to
the NaH suspension. Cyclic sulfate 3 (40.48 g crude, 146.50 mmol)
was dissolved in DME (698 mL) and added dropwise to the anion
mixture. The resulting orange solution was stirred at room temper-
ature for 2 h. The solution was diluted with saturated NH4Cl
(300 mL) and extracted with ethyl acetate (3 ꢀ 800 mL). The com-
bined organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography over silica
gel (iso-octane/toluene/EtOAc, 50:48:2) resulted in diester
4
(45.63 g, 85%) as a dark yellow oil. 1H NMR (500 MHz, CDCl3): d
0.91 [t, J = 7.1 Hz, 3H, OCH2CH3], 1.22 [t, J = 7.1 Hz, 3H, OCH2CH3],

E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
2325
3.35 [d, J = 8.3 Hz, 1H, H2 or H3], 3.88 [dq, J = 10.7 and 7.1 Hz, 1H,
OCH2CH3], 3.95 [dq, J = 10.7 and 7.1 Hz, 1H, OCH2CH3], 4.05 [d,
J = 8.3 Hz, 1H, H2 or H3], 4.11 [q, J = 7.1 Hz, 2H, OCH2CH3], 5.88 [d,
wise. After stirring overnight, an aqueous 2 M KOH solution was
carefully added to the reaction mixture causing precipitation of
the Al-salts, which were subsequently dissolved by adding care-
fully a 2 M aqueous H2SO4 solution. Subsequently, the phases were
separated and the water phase was extracted with Et2O/CH2Cl2
(7:3). The combined organic phases were dried over Na2SO4 and
concentrated in vacuo. Purification of the pale yellow crystals
was effected by refluxing in Et2O (0.7 L), and subsequently concen-
trating the solution to a volume of about 200 mL. This yielded, after
filtration, 10.94 g of pure diol 6 as white crystals. The filtrate was
subjected a second time to refluxing Et2O and yielded another
2.36 g of pure diol 6. The filtrate was further purified by flash chro-
matography over silica gel (CH2Cl2/EtOAc, 8:2) to yield another
3.93 g of pure diol 6. In total, an overall yield of 17.23 g diol 6
was obtained as white crystals (58%). 1H NMR (500 MHz, DMSO-
d6): d 2.74 [s, 2H, H2 and H3], 2.84 [dd, J = 4.7 and 11.2 Hz, 2H,
CH2OH], 3.55 [dd, J = 6.2 and 11.2 Hz, 2H, CH2OH], 4.43 [dd,
J = 4.7 and 6.2 Hz, 2H, OH], and 7.17–7.35 [m, 10H, H arom.]
ppm. 13C NMR (125.72 MHz, CDCl3): d 31.4 [CH, C2 and C3], 37.7
[C, C1], 61.7 [CH2, 2 ꢀ CH2OH], 126.2 [CH, C arom.], 128.2 [CH, C
arom.], 129.1 [CH, C arom.], and 138.6 [C, C arom.] ppm. IR mmax
0
0
J = 16.0 Hz, 1H, H2 ], 6.78 [d, J = 16.0 Hz, 1H, H3 ], and 7.25–7.36 [m,
10H, H arom.] ppm. 13C NMR (125.72 MHz, CDCl3): d 13.9 [CH3,
OCH2CH3], 14.3 [CH3, OCH2CH3], 37.4 [CH, C2 or C3], 39.6 [CH, C2 or
C3], 40.9 [CH2, C1], 60.4 [CH2, OCH2CH3], 61.4 [CH2, OCH2CH3],
0
121.5 [CH, C2 ], 127.5 [CH, C arom.], 128.4 [CH, C arom.], 128.7 [CH,
C arom.], 129.1 [CH, C arom.], 129.5 [CH, C arom.], 135.1 [C, C arom.],
0
0
00
135.3 [C, C arom.], 144.0 [CH, C1 ], 166.3 [C, C3 ], and 168.6 [C, C1
]
ppm. IR mmax (KBr): 1725 [vs,
Ph], 1584 [w, mC@C Ph], 1498 [m, mC@C Ph], 1458 [m, das Me], 1448
[m, mC@C Ph], 1392 [m, ds Me], 1369 [m, CH2], 1307 [s, CH2],
1268 [s, mC–O conj. ester], 1258 [s, mC–O sat. ester], 1036 [s, O–C],
mC@O], 1714 [vs, mC@O], 1604 [m, mC@C
x
s
m
755 [m, cC–H Ph], 698 [s, c
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 364
[2, M+], 319 [14, MꢁEtO], 318 [29, MꢁEtOH], 290 [6%, 318ꢁCO],
272 [100, 318ꢁEtOH], 244 [60, 290ꢁEtOH], 217 [65, 290ꢁEtOCO],
216 [48, 244ꢁCO], 91 [70, trop.], and 77 [42, Ph+]. ½a D20
¼ þ124:9 (c
ꢃ
1.4, CHCl3). HRMS (EI) calcd for C21H19O3 [MꢁEtO]: 319.1334; found
319.1328.
4.5. Synthesis of (2R,3R)-1-(ethoxycarbonyl)-2,3-diphenylcyclo-
propane-1-carboxylic acid 5
(KBr): 3304 [br, m,
Ph], 1445 [m, mC@C Ph], 1058 [s], 1011 [vs,
and 696 [vs,
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 254 [1, M+],
m
O–Hꢂ ꢂ ꢂH], 1600 [w, mC@C Ph], 1494 [w, mC@C
mC–O], 737 [m, cC–H Ph],
c
To
a
rapidly stirred mixture of compound
4
(45.63 g,
223 [3, MꢁCH2OH], 207 [51], 205 [100, 223ꢁH2O], 108 [25], 179
125.21 mmol), NaIO4 (216.4 g, 1002 mmol), acetonitrile (243 mL),
CCl4 (243 mL), and H2O (373 mL) was added RuCl3ꢂH2O (35–42%
Ru, 0.663 g, 2.504 mmol). The resulting slurry was stirred at room
temperature for 17 h. The mixture was filtered and the residue was
washed with H2O and CH2Cl2. The aqueous layer was extracted
with CH2Cl2. The combined organic phases were dried on Na2SO4
and evaporated in vacuo, to give 5 (37.7 g, 97%) as a brown oil.
The crude acid was used in the next step without purification. A
small amount of 5 could be purified by flash chromatography over
silica gel (CH2Cl2/MeOH/AcOH, 98.9:1:0.1) resulting in pure 5 as a
pale yellow oil. 1H NMR (500 MHz, acetone-d6): d 0.91 [t, J = 7.1 Hz,
3H, OCH2CH3], 3.76 [d, J = 8.5 Hz, 1H, H2 or H3], 3.80 [d, J = 8.5 Hz,
1H, H2 or H3], 3.90 [dq, J = 7.1 and 10.8 Hz, 1H, OCH2], 3.93 [dq,
J = 7.1 and 10.8 Hz, 1H, OCH2], and 7.23–7.4 [m, 10H, H arom.]
ppm. 13C NMR (125.72 MHz, CDCl3): d 14.1 [CH3, OCH2CH3],
35.01 [CH, C2 or C3], 35.10 [CH, C2 or C3], 46.40 [C, C1], 61.72
[CH2, COOCH2], 128.01 [CH, C arom.], 128.06 [CH, C arom.],
[32], 166 [23], 148 [7], 128 [13], 115 [35], 91 [99, trop.], and 77
[26, Ph+]. ½a 2D0
¼ ꢁ118:9 (c 1.0, CHCl3). Mp 157 °C. HRMS (EI) calcd
ꢃ
for C17H18O2 [M+]: 254.1307; found 254.1325.
4.7. Synthesis of (2R,3R)-1,1-bis(methanesulfonyl oxymethyl)-
2,3-diphenylcyclopropane 7
A dry 500 mL two-necked round-bottomed flask with stirring
bar was charged with diol 6 (4.0 g, 15.73 mmol) and dry CH2Cl2
(160 mL). The suspension was cooled to 0 °C and dry Et3N
(7.67 mL, 55.05 mmol) was added. After stirring for 15 min, mesyl-
chloride (3.73 mL, 47.18 mmol) was added. The reaction was com-
plete in 1.5 h, and the reaction mixture was poured into 600 mL of
Et2O. The organic layer was washed four times with 160 mL of ice
cold water and subsequently with 160 mL of brine, and dried over
Na2SO4. Concentration in vacuo afforded 8 g of a yellow oil, which
was purified by flash chromatography over silica gel (cyclo-hexane/
acetone, 75:25), yielding 6.28 g of pure 7 as white crystals (97%).
This compound decomposes overnight at room temperature, but
is stable for several months upon storage in the fridge (ꢁ20 °C) un-
der argon. 1H NMR (500 MHz, CDCl3): d 2.85 [s, 6H, CH3SO3], 3.09
[s, 2H, H2 and H3], 3.96 [d, J = 11.0 Hz, 2H, CH2O], 4.22 [d,
J = 11.0 Hz, 2H, CH2O], and 7.27–7.40 [m, 10H, H arom.] ppm. 13C
NMR (125.72 MHz, CDCl3): d 31.54 [C, C1], 32.41 [CH3, CH3SO3],
37.20 [CH, C2 and C3], 70.84 [CH2, 2 ꢀ CH2O], 127.71 [CH, C arom.],
128.89 [CH, C arom.], 129.16 [CH, C arom.], and 134.83 [C, C arom.]
129.00 [CH, C arom.], 129.61 [CH, C arom.], 135.97 [C, C arom.],
0
167.18 [C, C1 ], and 167.55 [C, COOH] ppm. IR mmax (KBr): 3100
[m, br, mOHꢂꢂꢂO], 1731 [vs, mC@O ester], 1698 [vs, mC@O acid], 1604
[m, mC@C Ph], 1584 [m, mC@C Ph], 1498 [m, mC@C Ph], 1460 [m, dbr
Me], 1449 [m, mC@C Ph], 1428 [m, coupling db OH–mC@O dimer],
1390 [m, ds Me], 1370 [m,
CH2, 1227 [m,
x
CH2], 1299 [s, mC–O acid] + shoulder
C–O], 1176 [m, b Me], 1130 [m, q0 Me], 1026 [m,
Ph] cmꢁ1. EI-MS m/z [rel inten-
s
m
m
O–C], 745 [m, cC–H Ph], 697 [s,
c
sity%]: 310 [2, M+], 293 [6, MꢁOH], 292 [24, MꢁH2O], 265 [5,
MꢁCOOH], 264 [21, MꢁEtOH], 247 [34, 293ꢁEtOH or 264ꢁOH],
246 [100, 264ꢁH2O], 236 [5, 264ꢁCO], 220 [8, 265ꢁOEt], 219
[17, 236ꢁOH], 218 [18, 236ꢁH2O], 192 [29, 220ꢁCO], 191 [70,
ppm. IR
C@C Ph], 1448 [m,
[m, cC–H Ph], 937 [s, cC–H Ph], 841 [m, cC–H Ph], 734 [m, cC–H Ph],
and 700 [m,
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 410 [2, M+],
mmax (KBr): 1602 [m,
mC@C Ph], 1581 [w,
m
C@C Ph], 1498 [m,
m
mC@C Ph], 1356 [s,
m
as SO2], 1174 [vs,
m
s SO2], 974
236ꢁCOOH], 165 [23], 115 [28], and 77 [31, Ph+]. ½a D20
ꢃ
¼ þ52:7 (c
c
1.0, CHCl3). HRMS (EI) calcd for C17H12O3 [MꢁEtOH]: 264.0786;
314 [2, MꢁHOSO2Me], 319 [20, 314ꢁOSO2Me], 218 [64,
found 264.0794.
314ꢁHOSO2Me], 205 [21], 129 [41], 91 [trop.], and 77 [45, Ph+].
½
a 2D0
ꢃ
¼ ꢁ22:9 (c 1.0, CHCl3). Mp 78 °C (decomp.). HRMS (EI) calcd
4.6. Synthesis of (2R,3R)-2,3-diphenylcyclopropane-1,1-
dimethanol 6
for C18H18O3S [MꢁHOSO2Me]: 314.0977; found 314.0994.
4.8. Synthesis of {[(2R,3R)-2,3-diphenylcyclopropane-1,1-diyl]-
A dry 1 L two-necked round-bottomed flask with a stirring bar
was fitted with a reflux condenser, and charged with LiAlH4
(95%, 11.57 g, 289.75 mmol). Next, dry THF (965 mL) was added.
The suspension was stirred for 10 min and then a solution of 5
(35.97 g crude, 115.90 mmol) in THF (580 mL) was added drop-
bis(methyl)}-bisdiphenylphosphane (P–B) borane 8
A 0.5 M solution of KPPh2 in THF (1.95 mL, 0.974 mmol) was
cooled to 0 °C. Next, a solution of 7 (100 mg, 0.244 mmol) in dry
THF (2.44 mL, 0.1 M) was added. The reaction mixture was allowed

2326
E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
to warm up to room temperature and was stirred for another 1.5 h.
Then BH3ꢂSMe2 (0.146 mL, 1.462 mmol) was carefully added,
whereupon the red solution turned colorless. Stirring was contin-
ued for 2 h, after which the reaction mixture was poured into a
saturated aqueous solution of NH4Cl (25 mL), and diluted with
CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2
(2 ꢀ 25 mL). The combined organic phases were dried over Na2SO4
and concentrated in vacuo, giving 215 mg of a white foam. Crude 8
was purified by flash chromatography over silica gel (iso-octane/
toluene/EtOAc, 50:49:1) affording 143 mg pure 8 as white crystals
(95%). 1H NMR (500 MHz, CDCl3): d 0.9–1.7 [br s, 6H, BH3], 1.90 [dd
(app. t), J = 15.4 Hz, CH2P], 2.19 [s, 2H, H2 and H3], 3.35 [dd, J = 6.8
and 15.4 Hz, CH2P], and 7.05–7.8 [m, 30H, H arom.] ppm. 13C NMR
(125.72 MHz, CDCl3): d 27.7 [C, C1], 28.5 [d, Jcp = 34.8 Hz, CH2,
2 ꢀ CH2P], 30.6 [dd, Jcp = 5 and 10 Hz, CH, C2 and C3], 126.5 [CH,
C arom.], 127.9 [CH, C arom.], 128.4 [d, Jcp = 55.3 Hz, C, C arom.],
128.4 [d, Jcp = 10.0 Hz, CH, C arom.], 128.7 [d, Jcp = 10.0 Hz, CH, C
arom.], 129.5 [CH, C arom.], 130.3 [CH, C arom.], 130.8 [d,
Jcp = 55.3 Hz, C, C arom.], 131.3 [d, Jcp = 10.0 Hz, CH, C arom.],
131.6 [CH, C arom.], 133.3 [d, Jcp = 9.0 Hz, CH, C arom.], and 136.3
[C, C arom.] ppm. 31P NMR (202.45 MHz, CDCl3): d 14.11 ppm [br
ture was stirred for 2 h at room temperature. Then, BH3ꢂSMe2
(0.402 mL, 4.18 mmol) was carefully added, and stirring was con-
tinued for 2 h. Evaporation in vacuo and purification by flash chro-
matography over silica gel (iso-octane/acetone, 8:2) resulted in 10
as a pure white foam, 118 mg (92%). 1H NMR (500 MHz, CDCl3): d
0.57–1.36 [br m, 6H, BH3], 2.92 [s 2H, H2 and H3], 3.90 [dd, J = 5.6
and 10.6 Hz, 2H, CH2O], 4.04 [dd, J = 5.6 and 10.6 Hz, 2H, CH2O],
and 7.20–7.66 [m, 30H, H arom.] ppm. 13C NMR (125.72 MHz,
CDCl3): d 31.9 [CH, C2 and C3], 35.7 [t, Jcp = 9.4 Hz, C, C1], 127.1
[CH, C arom.], 128.6 [CH, C arom.], 128.7 [d, Jcp = 6.5 Hz, CH, C
arom.], 128.8 [d, Jcp = 6.5 Hz, CH, C arom.], 129.1 [CH, C arom.],
131.3 [d, Jcp = 10.5 Hz, CH, C arom.], 131.3 [d, Jcp = 10.5 Hz, CH, C
arom.], 131.8 [d, Jcp = 35.6 Hz, C, C arom.], 131.8 [CH, C arom.],
131.9 [CH, C arom.], 132.3 [d, Jcp = 35.6 Hz, C, C arom.], and 136.0
[C, C arom.] ppm. 31P NMR (202.45 MHz, CDCl3): d 105.65 [br s,
Dm1/2 = 172 Hz] ppm. IR mmax (KBr): 2384 [m, mB–H], 1438 [m, mC@C
Ph], 1114 [m], 1064 [m], 1008 [m], 996 [m], 735 [vs, cC–H Ph],
696 [s,
c
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 635 [2, Mꢁ2ꢀ BH3],
421 [18], 254 [9, diol 6], 201 [100], 185 [98], 108 [44], 91 [84,
trop.], and 77 [49, Ph+]. ES-MS: 668 [M+NH4]+. ½a 2D0
¼ þ15:6 (c
ꢃ
1.0, CH2Cl2). Mp 49 °C. HRMS (ES) calcd for C41H46B2NO2P2
s,
[w, mC@C Ph], 1495 [m, mC@C Ph], 1436 [m, mC@C Ph], 737 [s, cC–H
Ph], and 697 [s,
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 604 [2,
D
m
1/2 = 105 Hz]. IR mmax (KBr): 2385 + shoulder [m,
m
B–H], 1601
[M+NH4þ]: 668.3190; found 668.3200.
c
4.11. Synthesis of {[(2R,3R)-2,3-diphenylcyclopropane-1,1-diyl]-
MꢁBH3], 513 [3, 8-Ph], 405 [4, 8-PPh2], 183 [100], 91 [21, trop.],
bis(methylene)}-bisdiphenylphosphinite 11
and 77 [10, Ph+]. ½a D20
¼ þ36:1 (c 1.0, CHCl3). Mp 171 °C. HRMS
ꢃ
(EI) calcd for C41H39P211B [MꢁBH3]: 604.2620; found 604.2605.
A mixture of diphosphinite borane 10 (250.0 mg, 0.384 mmol)
and DABCO (194.0 mg, 1.730 mmol) in dry benzene (6.25 mL)
was heated to 60 °C for 8 h under argon. Evaporation in vacuo
and purification by flash chromatography over dry Al2O3 (dry
ether) resulted in 11 as white crystals, 188 mg (79%). 1H NMR
(500 MHz, CDCl3): d 2.84 [s, 2H, H2and H3], 3.64 [dd, J = 7.0 and
10.6 Hz, 2H, OCH2], 3.95 [dd, J = 7.0 and 10.6 Hz, 2H, OCH2] 7.20–
7.36 [m, 26H, H arom.], and 7.43–7.49 [m, 4H, H arom.] ppm. 13C
NMR (125.72 MHz, CDCl3): d 31.7 [CH, C2 and C3], 36.4 [t,
Jcp = 10.1 Hz, C, C1], 70.4 [d, Jcp = 20.0 Hz, CH2, CH2O], 126.2 [CH,
C arom.], 127.9 [d, Jcp = 6.0 Hz, CH, C arom.], 127.9 [CH, C arom.],
128.7 [d, Jcp = 6.0 Hz, CH, C arom.], 128.9 [CH, C arom.], 129.8 [d,
Jcp = 7.5 Hz, CH, C arom.], 129.9 [d, Jcp = 7.5 Hz, CH, C arom.],
136.8 [C, C arom.], 141.9 [d, Jcp = 18.8 Hz, C, C arom.], and 142.0
[d, Jcp = 18.8 Hz, C, C arom.] ppm. 31P NMR (202.45 MHz, CDCl3):
d 127,4 [br s] ppm. IR mmax (KBr): 1434 [m, P–O], 1012 [s], 996
4.9. Synthesis of (2R,3R)-1,1-bis[(diphenylphosphanyl)methyl]-
2,3-diphenylcyclopropane 9
A dry 30 mL pressure tube with a stirring bar was charged with
diphenylphosphine borane 8 (300 mg, 0.485 mmol). The tube was
flushed with argon, followed by dry and degassed EtOH (15 mL).
The tube was sealed and the mixture was refluxed overnight. The
crude reaction mixture was transferred with CH2Cl2 to a 50 mL
flask and concentrated in vacuo. Purification was done by a fast fil-
tration over silica gel, eluting with 100 mL of CH2Cl2 under argon
atmosphere. In this way, 283 mg of pure diphosphane 9 were ob-
tained as a solid white foam (99%). Diphosphane 9 appeared to
be insensitive to air at room temperature for at least 3 weeks. 1H
NMR (500 MHz, CDCl3): d 1.81 [dd, J = 4.2 and 14.4 Hz, 2H, CH2P],
2.34 [s, 2H, H2and H3], 2.69 [d, J = 14.4 Hz, 2H, CH2P], and 6.9–7.6
[m, 30H, H arom.] ppm. 13C NMR (125.72 MHz, CDCl3): d 31.6 [t,
Jcp = 16.1 Hz, C, C1], 33.0 [dd, Jcp = 11.0 and 15.0 Hz, CH2, 2 ꢀ CH2P],
33.8 [t, Jcp = 6.8 Hz, C2 and C3], 126.3 [CH, C arom.], 128.0 [CH, C
arom.], 128.2 [CH, C arom.], 128.4 [d, Jcp = 5.1 Hz, CH, C arom.],
128.8 [d, Jcp = 6.8 Hz, CH, C arom.], 129.4 [CH, C arom.], 129.5
[CH, C arom.], 132.2 [d, Jcp = 18.6 Hz, CH, C arom.], 134.5 [d,
Jcp = 22 Hz, CH, C arom.], 137.9 [d, Jcp = 14.4 Hz, C, C arom.], 138.2
[C, C arom.], and 140.0 [d, Jcp = 12.7 Hz, C, C arom.] ppm. 31P
[m], 737 [s, c
Ph], 696 [vs] cmꢁ1. ES-MS: 640 [27, M+NH4þ], 623
[100, M+H+]. ½a 2D0
¼ þ15:6 (c 1.0, CH2Cl2). Mp 92 °C. HRMS (ES)
ꢃ
calcd for C41H37O2P2: 623.2269 [M+H+]; found 623.2283.
4.12. Synthesis of (2R,3R)-1,1-bisazidomethyl-2,3-diphenyl-
cyclopropane 12
To a solution of dimesylate 7 (1.575 g, 3.837 mmol) in dry
DMSO (22 mL) was added sodium azide (1.008 g, 15.35 mmol).
The reaction mixture was stirred for 3.5 h at 35 °C. The reaction
mixture was poured into H2O (50 mL) and extracted with CH2Cl2
(3 ꢀ 60 mL). The organic phases were washed with H2O
(2 ꢀ 30 mL), dried over Na2SO4, and evaporated in vacuo. Purifica-
tion by flash chromatography over silica gel (iso-octane/Et2O/Et3N,
99:0.5:0.5) resulted in 12 as a transparent oil, 1.044 g (89%). 1H
NMR (500 MHz, CDCl3): d 2.80 [s, 2H, H2 and H3], 3.05 [d,
J = 13.0 Hz, 2H, CH2N3], 3.38 [d, J = 13.0 Hz, 2H, CH2 N3], and
7.20–7.40 [m, 10H, H arom.] ppm. 13C NMR (125.72 MHz, CDCl3):
d 32.0 [CH, C2 and C3], 32.9 [C, C1], 53.5 [CH2, 2 ꢀ CH2N3], 127.2
[CH, C arom.], 128.7 [CH, C arom.], 129.1 [CH, C arom.], and 136.0
[C, C arom.] ppm. IR mmax (KBr): 2096 [vs, N3], 1602 [m, mC@C Ph],
1496 [m, mC@C Ph], 1447 [m, mC@C Ph], 1264 [s, N3], 742 [s, cC–H
NMR (202.45 MHz, CDCl3): d ꢁ19.84 [br s,
Dm1/2 = 24 Hz] ppm. IR
mmax (KBr): 1600 [m, mC@C Ph], 1585 [m, mC@C Ph], 1498 [m, mC@C
Ph], 1446 [m, mC@C Ph], 1433 [m, P–Ph], 738 [s, cC–H Ph], and 698
[vs, c
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 590 [5, M+], 513 [59,
MꢁPh], 405 [33, MꢁPPh2], 262 [12%], 183 [100], 152 [15], 91
[48, trop.], and 77 [11; Ph+]. ½a D20
¼ þ108:8 (c 1.0, CH2Cl2). Mp
ꢃ
61 °C. HRMS (EI) calcd for
C
41H36P2 [M+]: 590.2292; found
590.2300.
4.10. Synthesis of {[(2R,3R)-2,3-diphenylcyclopropane-1,1-diyl]-
bis(methyl)}-bisdiphenylphosphinite (P–B) borane 10
To a suspension of diol (2R,3R)-6 (50 mg, 0.197 mmol), and Et3N
(124
l
l, 0.885 mmol) in dry CH2Cl2 (0.5 mL) was added Ph2PCl
Ph], 699 [s,
c
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 304 [1, M+],
(1 mL, 0.688 M in CH2Cl2, 0.688 mmol). The resulting reaction mix-
276 [2, MꢁN2], 248 [4, Mꢁ2ꢀ N2], 220 [37, Mꢁ2ꢀ N3], 205 [27],

E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
2327
178 [37], 165 [27], 144 [25], 115 [100], 91 [98, trop.], and 77 [47,
arom.], 128.1 [CH, C arom.], 128.9 [CH, C arom.], 129.1 [CH, C
arom.], 131.2 [CH, C arom.], 132.6 [C, C arom.], 133.5 [C, C arom.],
137.7 [C, C arom.], 157.6 [CH, C@N]. IR mmax (KBr): 3025 [w], 2884
Ph+]. ½a 2D0
¼ ꢁ50:4 (c 1.0, CH2Cl2).
ꢃ
4.13. Synthesis of (2R,3R)-1,1-bisaminomethyl-2,3-diphenyl-
cyclopropane dihydrochloride 13
[w], 2844 [w], 1649 [s,
m
C@N], 1602 [m,
m
C@C Ph], 1580 [m,
C@C Ph], 1310 [w], 1189 [m],
C–H Ph], and 698 [vs,
mC@C Ph],
1558 [m], 1496 [m, C@C Ph], 1429 [s, m
m
1093 [m], 966 [w], 860 [w], 773 [vs], 741 [s,
c
To a solution of bisazide 12 (1.650 g, 5.42 mmol) in dry THF
(30 mL) was added triphenylphosphine (4.27 g, 16.26 mmol). The
reaction mixture was stirred for 1 h at room temperature. Subse-
quently, water (20 mL) and a few drops of a 10% HCl-solution were
added, and the resulting solution was stirred overnight. Next, the
reaction mixture was concentrated in vacuo and CH2Cl2 (40 mL)
was added. Extraction of the organic phase with 10% HCl-solution
(2 ꢀ 40 mL) and freeze drying of the water phase resulted in 13 as
a white crystalline solid, 1.75 g (99%). 1H NMR (500 MHz, D2O): d
2.53 [d, J = 14.6 Hz, 2H, CH2N], 3.25 [s, 2H, H2 and H3], 3.44 [d,
J = 14.6 Hz, 2H, CH2N], and 7.35–7.50 [m, 10H, H arom.] ppm. 13C
NMR (125.72 MHz, D2O): d 28.9 [C, C1], 32.9 [CH, C2 and C3], 40.7
[CH2, 2 ꢀ CH2N], 128.0 [CH, C arom.], 129.2 [CH, C arom.], 129.4
[CH, C arom.], and 134.7 [C, C arom.] ppm. IR mmax (KBr): 3408 br
c
Ph] cmꢁ1. ES-MS: 567 [M+H]+. ½a 2D0
¼ ꢁ69:3 (c 1.0, DMSO). HRMS
ꢃ
(ES) calcd for C31H2535Cl4N2 [M+H+]: 565.0772; found 565.0786.
4.16. Synthesis of (2R,3R)-1,1-bis-[(2,6-dichlorobenzylamino)-
methyl]-2,3-diphenylcyclopropane 16
To a solution of 15 (50.0 mg, 0.0883 mmol) in dry toluene
(0.9 mL) and dry MeOH (0.9 mL) was added NaBH4 (20.0 mg,
0.530 mmol). The reaction mixture was stirred overnight at room
temperature. The reaction mixture was poured into sat. NH4Cl
solution (25 mL) and extracted with CH2Cl2 (3 ꢀ 25 mL). The or-
ganic phases were dried over Na2SO4 and concentrated in vacuo.
Purification by flash chromatography over neutral alumina
(CH2Cl2/cyclo-hexane, 80:20) resulted in 15 as a white foam,
36.9 mg (73%). 1H NMR (500 MHz, CDCl3): d 1.65 [br s, 2H, NH],
2.50 [d, J = 12.1 Hz, 2H, CH2N], 2.59 [s, 2H, H2 and H3], 2.78 [d,
J = 12.1 Hz, 2H, CH2N], 3.83 [d, J = 13.0 Hz, 2H, NCH2Ar], 3.88 [d,
J = 13.0 Hz, 2H, NCH2Ar], and 7.04–7.25 [m, 16H, H arom.] ppm.
13C NMR (125.72 MHz, CDCl3): d 32.0 [CH, C2 and C3], 48.8 [CH2,
NCH2Ar], 51.5 [CH2, CCH2N], 126.4 [CH, C arom.], 128.3 [CH, C
arom.], 128.4 [CH, C arom.], 128.6 [CH, C arom.], 128.8 [CH, C
arom.], 129.2 [CH, C arom.], 136.1 [C, C arom.], and 137.9 [C, C
[s,
m
N–H], 2968 [br s] 1603 [m, mC@C Ph], 1496 [m, mC@C Ph], 1446
[m, mC@C Ph], 741 [s, cC–H Ph], and 698 [s,
c
Ph] cmꢁ1. EI-MS m/z
[rel intensity%]: 235 [37, MꢁNH3], 206 [20], 179 [40], 144 [12],
115 [27], 91 [66, trop.], and 77 [76, Ph+], 49 [100]. ES-MS: 253
[M+H]+. ½a 2D0
¼ ꢁ56:9 (c 1.0, MeOH). Mp 215 °C. HRMS (ES) calcd
ꢃ
for C17H21N2 [M+H+]: 253.1705; found 253.1710.
4.14. Synthesis of (2R,3R)-1,1-bis-(benzylideneaminomethyl)-
2,3-diphenylcyclopropane 14
arom.] ppm. IR mmax (KBr): 3303 [m, mN–H], 3057 [w], 2935 [w],
2843 [w], 1601 [m, mC@C Ph], 1580 [m, mC@C Ph], 1561 [m], 1496
[m, mC@C Ph], 1435 [vs, mC@C Ph], 1104 [m], 1084 [m], 775 [s], and
To a suspension of 13 (120.0 mg, 0.369 mmol) and anhydrous
Na2SO4 (213.0 mg, 1.476 mmol) in dry CH2Cl2 (3 mL) were added
benzaldehyde (0.075 mL, 0.738 mmol) and dry Et3N (0.105 mL,
0.738 mmol). The reaction mixture was stirred overnight at room
temperature. Evaporation in vacuo and purification by flash chro-
matography over basic alumina (dry ether) resulted in 14 as a pale
yellow oil, 140.7 mg (91%). 1H NMR (500 MHz, DMSO-d6): d 2.95 [s,
2H, H2 and H3], 3.16 [d, J = 12.4 Hz, 2H, CH2N], 3.65 [d, J = 12.4 Hz,
2H, CH2N], 7.35–7.50 [m, 16H, H arom.], 7.70–7.80 [m, 4H, H
arom.], and 8.10 [s, 2H, CH2NCH] ppm. 13C NMR (125.72 MHz,
DMSO-d6): d 31.8 [CH, C2 and C3], 35.4 [C, C1], 62.0 [CH2, 2 ꢀ CH2N],
126.2 [CH, C arom.], 127.7 [CH, C arom.], 128.1 [CH, C arom.], 128.6
[CH, C arom.], 129.0 [CH, C arom.], 130.5 [CH, C arom.], 136.2 [C, C
698 [s, c
Ph] cmꢁ1. EI-MS m/z [rel intensity%]: 570 [1, M+], 292 [3],
235 [20, 13-NH3], 234 [100], 178 [17], 159 [47, CH2Ar] 91 [18,
trop.], and 49 [22]. ES-MS: 571 [M+H]+. ½a D20
¼ þ17:5 (c 1.0, CHCl3).
ꢃ
HRMS (ES) calcd for C31H2935Cl4N2 [M+H+]: 569.1085; found
569.1086.
4.17. General procedure for the palladium(0)-catalyzed
asymmetric allylic alkylation
The ligands (0.0297 mmol) and [(g
3-C3H5)PdCl]2 (0.0119 mmol)
were dissolved in degassed CH2Cl2 (1 mL) under argon atmosphere
using Schlenk techniques. The reaction mixture was stirred for 2 h
at 50 °C and cooled to room temperature. Then rac-1,3-diphenyl-3-
acetoxyprop-1-ene 17 (0.5945 mmol) in CH2Cl2 (0.7 mL) was added
and stirred at room temperature for 30 min. Finally, a solution of BSA
(1.783 mmol), LiOAc (0.0238 mmol) and dimethylmalonate
(1.783 mmol) in CH2Cl2 (0.3 mL) was added to the mixture. The reac-
tion mixture was stirred for the appropriate time at room tempera-
ture. Next, diethylether was added, the organic phase washed with
saturated NH4Cl, dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel
(hexane/EtOAc, 90:10) to afford the target compound. The enantio-
meric excess was determined by chiral HPLC analysis: Chiralpak
arom.], 138.0 [C, C arom.], and 161.4 [CH, C@N] ppm. IR
mmax (KBr):
3057 [w], 3024 [w], 2840 [w], 1643 [s, C@N], 1601 [m, mC@C Ph],
m
1579 [m, mC@C Ph], 1496 [s, mC@C Ph], 1446 [s, mC@C Ph], 1430 [m],
1374 [w], 1308 [w], 1292 [w], 1217 [w], 1074 [w], 1056 [w],
1026 [w], 1007 [w], 772 [m], 754 [s, cC–H Ph], 739 [s, cC–H Ph],
and 693 [vs,
c
Ph] cmꢁ1. ES-MS: 429 [M+H]+. ½a 2D0
¼ ꢁ22:1 (c 1.0,
ꢃ
DMSO). HRMS (ES) calcd for C31H29N2 [M+H+]: 429.2331; found
429.2350.
4.15. Synthesis of (2R,3R)-1,1-bis-[(2,6-dichlorobenzylidene)-
aminomethyl]-2,3-diphenylcyclopropane 15
AD-H column (250 ꢀ 4.6 mm, particle size 10
lm), solvent: n-hex-
To a suspension of 13 (610.0 mg, 1.88 mmol) and anhydrous
Na2SO4 (1.08 g, 7.5 mmol) in dry CH2Cl2 (23 mL) was added 2,6-
dichlorobenzaldehyde (663 mg, 3.75 mmol) and dry Et3N
(0.530 mL, 3.75 mmol). The reaction mixture was stirred overnight
at room temperature. Evaporation in vacuo and purification by
flash chromatography over basic alumina (dry ether) resulted in
15 as a white foam, 936.0 mg (88%). 1H NMR (500 MHz, DMSO-
d6): d 3.08 [s, 2H, H2 and H3], 3.16 [d, J = 12.5 Hz, 2H, CH2N], 3.80
[d, J = 12.5 Hz, 2H, CH2N], 7.20–7.55 [m, 16H, H arom.], and 8.35
[s, 2H, CH2NCH] ppm. 13C NMR (125.72 MHz, DMSO-d6) d 31.9
[CH, C2 and C3], 34.6 [C, C1], 62.9 [CH2, 2 ꢀ CH2N], 126.2 [CH, C
ane/EtOH (70:30), flow rate = 1 mL/min, T = 35 °C, retention times:
9.2 minfor (S)-(ꢁ)and 13.9 minfor (R)-(+). Adduct 18was fullychar-
acterized by comparison of its spectroscopic data with those re-
ported in the literature. The absolute configuration was assigned
via the correlation of its specific rotation with the literature values.19
4.18. General procedure for the rhodium(I)-catalyzed
asymmetric hydrogenation
The ligands (7.53
lmol) and Rh(COD)2BF4 (6.84 lmol) were dis-
solved in degassed solvent (2 mL) under an argon atmosphere

2328
E. Vervecken et al. / Tetrahedron: Asymmetry 21 (2010) 2321–2328
K.; Calabrese, J. C. J. Org. Chem. 1997, 62, 6012–6028; (d) Nomura, N.; Mermet-
Bouvier, Y. C.; RajanBabu, T. V. Synlett 1996, 745–746.
7. van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev.
2000, 100, 2741–2769.
8. Moye-Sherman, D.; Jin, S.; Ham, I.; Lim, D.; Sholtz, J. M.; Burgess, K. J. Am. Chem.
Soc. 1998, 120, 9435–9443.
9. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.
S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem.
1992, 57, 2768–2771.
using Schlenk techniques, and the solution was stirred for 30 min.
Next, methyl Z-2-acetamido-3-phenylacrylate 19 (0.684 mmol),
dissolved in a suitable solvent (1.4 mL) was added to the catalyst
mixture. The reaction mixture was placed in an autoclave, purged
with H2 (4ꢀ) and pressurized until the appropriate pressure of H2
was reached. After 3 h, the reaction mixture was filtered over a
short pad of silica gel and eluted with EtOAc. Evaporation in vacuo
resulted in 20 as a pure product. The enantiomeric excess was
10. Treatment of the ‘harder’ dimesylate
7
with the ‘softer’ lithium
diphenylphosphide borane complex, gave no reaction.
determined by chiral GC analysis on
a Chirasil-Val column
11. (a) McKinstry, L.; Overberg, J. J.; Soubra-Ghaoui, C.; Walsh, D. S.; Robins, K. A. J.
J. Org. Chem. 2000, 65, 2261–2263; (b) McKinstry, L.; Livinghouse, T.
Tetrahedron 1995, 51, 7655–7666.
12. (a) Bradley, D.; Williams, G.; Lombard, H.; Van Niekerk, M.; Coetzee, P. P.
Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 2799–2803; (b) Bradley, D.;
Williams, G.; Lombard, H.; Van Niekerk, M.; Coetzee, P. P. Phosphorus, Sulfur
Silicon Relat. Elem. 2002, 177, 2115–2116; (c) Brisset, H.; Gourdel, Y.; Pelon, P.;
Le Corre, M. Tetrahedron Lett. 1993, 34, 4523–4526.
(30 m ꢀ 0.25 mm ꢀ 0.25 m); temperature program: 150 °C for
l
11 min, then increasing to 190 °C (40 °C/min), retention times:
9.1 min for (R)-20, 9.4 min for (S)-20, 14.6 min for 19. The absolute
configuration of 20 was assigned via correlation of its specific rota-
tion with literature values.20
13. Van Overschelde, M.; Vervecken, E.; Modha, S. G.; Cogen, S.; Van der Eycken, E.;
Van der Eycken, J. Tetrahedron 2009, 65, 6410–6415.
Acknowledgments
14. (a) Caputo, C. A.; Jones, N. D. Dalton Trans. 2007, 4627–4640; (b) Fache,
F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159–
2231; (c) Fache, F.; Dunjic, B.; Gamez, P.; Lemaire, M. Top. Catal. 1997, 4,
201–209; (d) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994,
33, 497–526.
15. (a) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1989, 28,
60–61; (b) Nagata, T.; Yorozy, K.; Yamada, T.; Mukaiyama, T. Angew. Chem., Int.
Ed. Engl. 1995, 34, 2145–2147.
E.V., M.V.O., T.N., Y.G., S.C. and J.V.D.E. wish to thank Ghent Uni-
versity and COST-Chemistry (Action D.40—‘Innovative Catalysis’)
for the financial support. M.V.O. and S.C. thank the IWT (‘Agent-
schap voor Innovatie door Wetenschap en Technologie’) for a doc-
toral Grant. S.A.R. thanks the EC for the Socrates Grant. Professor
Erik Van der Eycken (LOMAC, Dept. of Chemistry, KULeuven) and
Professor Serge Van Calenbergh (Faculty of Pharmaceutical Sci-
ences, UGent) are gratefully acknowledged for providing the EI-
HRMS, respectively, ES-HRMS-spectra.
16. (a) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406; (b)
Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297–368.
17. For reviews of asymmetric allylic substitutions: (a) Lu, Z.; Ma, S. Angew. Chem.,
Int. Ed. 2008, 47, 258–297; (b) Rovis, T. In New Frontiers in Asymmetric Catalysis;
Mikami, K., Lautens, M., Eds.; Wiley-VCH: Weinheim, 2007; pp 276–278; (c)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2943; (d) Trost, B. M.;
Lee, C. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim,
2000; pp 593–650; (e) Pfaltz, A.; Lautens, M.. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, pp 833–886; (f) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395–422.
18. Diphosphite ligands have also provided high TOF’s in the asymmetric allylic
alkylation: (a) Diéguez, M.; Pàmies, O.; Claver, C. J. Org. Chem. 2005, 70, 3363–
3368; (b) Diéguez, M.; Pàmies, O.; Claver, C. Adv. Synth. Catal. 2005, 347, 1257–
1266; (c) Diéguez, M.; Jansat, S.; Gomez, M.; Ruiz, A.; Muller, G.; Claver, C.
Chem. Commun. 2001, 1132–1133.
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