Novel biferrocene-based phosphoramidite ligands: The combination of a rather unexplored chiral backbone and a privileged ligand scaffold

Article abstract of DOI:10.1016/j.tet.2019.06.024

A small library of novel chiral monodentate phosphoramidite ligands, characterized by a dihydroazepine-biferrocene backbone was prepared. In order to obtain this biferrocene substructure, a mild and efficient homocoupling was developed. This allowed to synthesize the dihydroazepine ligand precursor and the phosphoramidite ligands with good overall yields and high enantiomeric excess. These ligands were successfully tested in a rhodium(I)-catalyzed hydrogenation of activated olefins.

Full text of DOI:10.1016/j.tet.2019.06.024

Accepted Manuscript
Novel biferrocene-based phosphoramidite ligands: The combination of a rather
unexplored chiral backbone and a privileged ligand scaffold
W. Kimpe, P. Janssens, K. Bert, S. Wackens, J.L. Goeman, J. Van der Eycken
PII:
S0040-4020(19)30686-6
https://doi.org/10.1016/j.tet.2019.06.024
TET 30416
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2019
Revised Date: 6 June 2019
Accepted Date: 17 June 2019
Please cite this article as: Kimpe W, Janssens P, Bert K, Wackens S, Goeman JL, Van der Eycken
J, Novel biferrocene-based phosphoramidite ligands: The combination of a rather unexplored
chiral backbone and a privileged ligand scaffold, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.06.024.
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ACCEPTED MANUSCRIPT
Novel biferrocene-based phosphoramidite ligands: the combination of a
rather unexplored chiral backbone and a privileged ligand scaffold
W. Kimpea, P. Janssensa, K. Berta, S. Wackensa, J. L. Goemana and J. Van der Eyckena*
a
Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent
University, Krijgslaan 281 (S.4), B-9000 Ghent, Belgium, E-mail: Johan.VanderEycken@UGent.be, Fax: +32-9-264-49-98
*Corresponding author
Keywords: Asymmetric catalysis – Ligand synthesis - Phosphoramidites – Biferrocene-based ligands – Rhodium-catalyzed
hydrogenation
Abstract A small library of novel chiral monodentate phosphoramidite ligands, characterized by a dihydroazepine-
biferrocene backbone was prepared. In order to obtain this biferrocene substructure, a mild and efficient homocoupling
was developed. This allowed to synthesize the dihydroazepine ligand precursor and the phosphoramidite ligands with
good overall yields and high enantiomeric excess. These ligands were successfully tested in a rhodium(I)-catalyzed
hydrogenation of activated olefins.
extra chiral moiety allows to replace the axially chiral binol
ligand backbone, which is mostly used for the
phosphoramidite ligand family, by an achiral biphenol.
Consequently, the influence of the axial chirality of the
dihydroazepine moiety as well as the ‘matched’ and
‘mismatched’ combinations of the axially chiral binol and
axially chiral dihydroazepine ligand substructures were
explored in the enantioselective rhodium(I)-catalyzed
1. Introduction
During last decades, there has been a tremendous
interest in the production of optically active compounds for
specialty materials, food and agrochemical industries,
fragrancy industry and especially for the pharmaceutical
industry.[1-3] Today, asymmetric transition metal catalysis
has become one of the most efficient and interesting
approaches for the synthesis of enantiopure compounds.[4-6]
This growth of enantioselective catalysis calls for
a
permanent research for new and improved chiral ligands.[7]
Given the complexity of most catalytic processes, the
rigorous prediction of the required electronic and steric
properties of
a
ligand in order to obtain high
enantioselective inductions remains a difficult task.[8] The
finetuning of reported ligands by modification of a ligand
substructure, e.g. by introducing more bulky groups such as
ferrocene, is one of the most straightforward promising
strategies. A highly successful ligand family that allows for
this type of modification is the family of phosphoramidites
(represented as 1 in Figure 1). The first examples of these
ligands were reported by Feringa in 1996 and since then,
many phosphoramidites have been used in different types of
transformations.[9-10] A general modification of these ligands
involves the installation of different amines on the central
phosphorus atom.[11] Phosphoramidite ligand 2 (Figure 1) is
often used by the research group of Carreira in many
enantioselective iridium-catalyzed reactions such as allylic
substitutions[12] and vinylations[13] among others. In contrast
to the monodentate phosphoramidites of Feringa, the olefin
functional group coordinates to the iridium metal as well
with the formation of a bidentate transition metal ligand
complex. Other interesting monodentate phosphoramidite
ligands have been reported by Matt et. al. (represented as 3
in Figure 1).[14] These ligands are characterized by the
presence of an axially chiral binapthyl-based dihydroazepine
substructure as the amine part of the phosphoramidite. This
Figure 1. Interesting examples of the phosphoramidite
ligand family.
hydrogenation of activated olefins/esters of α-dehydroamino
acids. Another interesting privileged ligand family is the
well-known Josiphos family.[15] Among others, these are
characterized by the presence of a planar chiral ferrocene
1

ACCEPTED MANUSCRIPT
ligand scaffold.[16,17] The easy derivatization, the rigidity, the
steric bulkiness and the possibility to introduce planar
chirality are some interesting properties rendering the
ferrocene backbone suitable as chiral scaffold for ligand
design.[18] Consequently, it is often used for the development
of novel chiral ligands.[15-18] In contrast, the biferrocene
scaffold is significantly less explored as a ligand backbone
in the field of asymmetric transition metal catalysis.
Nevertheless, its extraordinary conformational behavior, due
to the combination of planar as well as axial chirality
elements, makes it an ideal structural ligand motive, very
attractive for designing new chiral ligands.[17,19] Some
interesting biferrocene-based ligands already known in
literature are shown in Figure 2. The first one, 4, is known
as BIFEP (or 2,2"-bis(dipheny1phosphino)-1,l"-biferrocene)
and represents the biferrocene analog of Noyori’s highly
successful BINAP ligand. Its enantioselective synthesis was
described by the group of Weissensteiner in 2001.[20] This
ligand has been tested in a range of transition metal
catalyzed hydrogenation reactions of different substrates
(olefins, ketones and imines).[20,21] Biferrocene-based
bidentate P,N-type ligands 5, characterized by the presence
of a dihydroazepine heterocycle, were reported by Widhalm
Figure 3. Novel biferrocene-based dihydroazepine
phosphoramidite ligands 6a-6c.
2. Results and Discussion
2.1. Ligand Synthesis
et. al.[22]
, discussing their multistep synthesis, their
The synthesis of an optically pure biferrocene backbone
theoretically requires the synthesis of an enantiomerically
pure planar chiral ferrocene compound. A variety of
methods to prepare this type of structures have already been
reported by different research groups.[17,23] One of these is
the Kagan’s general approach, based on a chiral acetal,
obtained from malic acid.[24] This approach allowed to
prepare planar chiral α-iodoferrocenecarboxaldehyde (Sp)-8
in high enantiomeric excess (Scheme 1).
conformational behavior and their application in palladium-
catalyzed asymmetric allylic substitution reactions. As
shown in Figure 2, the aryl group is representing classical
aromatic phenyl rings as well as both enantiomers of planar
chiral diphenylphosphinoferrocene substructures.
Conditions: (a) H(COMe)3, PTSA.H2O, MeOH, 80°C; (b)
(S)-1,2,4-butanetriol, CSA, 4 Å Mol. Sieves, CHCl3, rt; (c) 1.
NaH, THF, 0°C; 2. MeI, 0°C to rt; (d) 1. t-BuLi, Et2O, -78°C
to rt; 2. (CH2I)2, THF, -78°C to rt; (e) PTSA.H2O, CH2Cl2,
H2O, rt.
Figure 2. Interesting biferrocene-based ligands.
Scheme 1. Synthesis of (Sp)-8 via Kagan’s general
approach.
In this paper we wish to report on the synthesis and
screening of a small library of novel phosphoramidite
ligands, characterized by the presence of a biferrocene-
based dihydroazepine substructure (represented as 6 in
Figure 3). The ligands we propose in this study are
considered as the biferrocene analogs of the dihydroazepine
phosphoramidite ligands published by Matt and co-
workers.[14]
For our study, planar chiral aldehyde (Sp)-8 was chosen as
an important intermediate for the synthesis of the
biferrocene ligand backbone. Indeed, the Ullmann
homocoupling reaction, with metallic copper at 105°C
allowed to synthesize dialdehyde (Sp,Sp)-9 (Scheme 2) in a
yield of 67%. The latter turned out to be a very light
sensitive compound requiring some practical precautions
(see experimental part for more details). However, a novel
method, based on a procedure reported by Liebeskind et.al.
for the coupling of aryl halides at lower temperatures, using
copper(I) thiophene-2-carboxylate (CuTC) in NMP, was
developed during our study, as shown in Scheme 2.[25]
Yields of 59% and 50% were obtained when the
temperature was set at respectively 70°C and room
2

ACCEPTED MANUSCRIPT
temperature. For both methods using metallic copper and
3). Removal of the benzyl group ((Sp,Sp)-14) via a Pd/C
reduction with hydrogen gas and removal of the para-
methoxybenzyl group ((Sp,Sp)-15) using DDQ did not lead
to the formation of the target ligand precursor (Sp,Sp)-11.
However, as shown in Scheme 3, the allyl protected
dihydroazepine biferrocene (Sp,Sp)-10 allowed to efficiently
synthesize (Sp,Sp)-11. The latter was prepared with a yield of
96% after removal of the allyl protecting group with KO-
tBu in DMSO at 100°C and subsequent mild acidic work-up
with a saturated NH4Cl solution.
CuTC, it was possible to prepare enantiopure dialdehyde
(Sp,Sp)-9, starting from highly enantiopure α-iodoaldehyde
(Sp)-8 (96% ee). More interestingly, it was possible to obtain
enantiopure (Sp,Sp)-9 starting from a scalemic mixture of
(Sp)- and (Rp)-α-iodoaldehyde of only 68% ee. When this
scalemic mixture was homocoupled, meso-compound
(Rp,Sp)-9 was formed and could be observed on TLC as a
separate spot. This meso-compound could be separated by
flash chromatography from its diastereomer (Sp,Sp)-9.
Several protocols have been developed for the preparation
of phosphoramidite ligands.[26] In initial experiments, the
procedure applied by Matt et. al was tested.[14] This consists
of a two-step reaction in which the diol is first reacted with
phosphorus trichloride (PCl3), followed by reaction with the
secondary amine, both steps in the presence of a tertiary
amine as a base. Unfortunately, this protocol gave no
conversion. However, the most frequently used procedure
for the synthesis of bulky phosphoramidite ligands consists
of a two-step reaction in which the secondary amine is first
reacted with PCl3, followed by reaction with a diol, both
steps in the presence of a base.[26c,27] Because the chiral
biferrocene is generally considered to be (very) bulky, this
protocol was subsequently applied for the preparation of the
target biferrocene-based phosphoramidite ligands (Scheme
4). This procedure afforded the proposed ligands only in
rather low yields varying between 29-44%.
Scheme 2. Ullmann homo coupling of planar-chiral
ferrocenecarboxaldehyde (Sp,Sp)-9.
Dialdehyde (Sp,Sp)-9 allowed to install the dihydroazepine
very efficiently via reductive amination. Reactions with
liquid ammonia and NaBH3CN or NaBH(OAc)3 did not lead
to any successful results. Therefore, three primary amines,
benzylamine, para-methoxybenzylamine and allylamine,
each containing a removable protecting alkyl group, were
introduced using NaBH3CN as reducing agent. Good yields
of 76-88% were obtained for these transformations (Scheme
Scheme 3. Preparation of biferrocene dihydroazepine ligand precursor 11.
3

ACCEPTED MANUSCRIPT
2.2. Catalytic Asymmetric Hydrogenation Reaction
transition metals such as rhodium, ruthenium, iridium and
palladium are frequently used in combination with different
types of chiral ligands. Moreover, for many years now, the
Catalytic asymmetric hydrogenation reactions of
prochiral substrates such as olefins, ketones and imines are
one of the most powerful and most studied transformations
in the field of asymmetric catalysis.[28] A variety of
rhodium(I)-catalyzed
activated olefins,
asymmetric
such as
hydrogenation
itaconic
of
acids,
Scheme 4. Synthesis of a small library of biferrocene-based dihydroazepine phosphoramidite ligands 6a-6c.
dehydroamino acids and derivatives of both, is a benchmark
test reaction for novel monodentate ligands.[10,11,14,29]
Therefore, substrate 12 was chosen for our preliminary
experiments, in order to demonstrate the potential of the
novel biferrocene-based monodentate phosphoramidite
ligands. The results of these test reactions are shown in
Table 1. Standard reaction conditions were chosen for the
test reactions. These involve a hydrogen pressure of 1
obtained for ligand 6b, which was therefore identified as the
‘matched’ combination. On the other hand, a lower
conversion of 84% and a significantly lower enantiomeric
excess of only 4.0% in favor of the (R)-enantiomer was
observed for ligand 6c. Therefore, the latter was assigned to
have the mismatched combination. Based on these
experiments it can be concluded that the asymmetric
induction of the chiral biferrocene backbone is overruled by
the axial chirality of the binapthyl group of the diol.
However, the biferrocene ligand backbone definitely has a
potential as a ligand scaffold.
atmosphere using
a
balloon, room temperature,
dichloromethane as solvent, 24 h reaction time and a
catalyst loading of 5 mol% rhodium as [Rh(COD)2BF4] in
combination with 10 mol% of the monodentate ligands. Full
conversion in combination with a rather low ee-value of
26.2% in favor of the (S)-enantiomer was obtained for
ligand 6a, characterized by the presence of a chiral
biferrocene backbone and an achiral biphenol ligand
substructure. Therefore, this experiment indicates the
potential of the chiral biferrocene ligand backbone as such
for asymmetric induction in this hydrogenation reaction.
Ligands 6b and 6c, characterized by a chiral biferrocene
backbone in combination with axially chiral (R)-binol or
(S)-binol respectively, were synthesized in order to explore
the effect of a ‘matched’ and ‘mismatched’ combination.
Indeed, an excellent conversion of 95% in combination with
a significantly higher enantiomeric excess of 67.6% was
Table 1. Results for the Rh(I)-catalyzed asymmetric
hydrogenation of enamide 12 using novel biferrocene-based
phosphoramidite ligands 6a-6c.
Substrate Ligand Time (h)
24
Conv (%)
ee (%)
100
26.2 (S)
12
6a
4

ACCEPTED MANUSCRIPT
TOF-MS detector equipped with an APCI-ESI multimode
24
24
95
84
67.6 (S)
4.0 (R)
12
12
6b
6c
source or a Kratos MS50TC mass spectrometer (EI). For all
MS-analysis the standard solvent was a 50:50 mixture of
MeOH:5mM aqueous NH4OAc and a sample volume of
5µL was injected. LC-MS analyses were performed on an
Agilent 1100 series HPLC connected to a UV-DAD detector
and a single quadrupole MS detector G1946C (type VL)
equipped with an API-ESI source by using a Phenomenex
Kinetex C18 column (150 x 4.6 mm, 5 µm particle size). All
measurements were performed at 35°C, a flow rate of 1
mL/min and sample volume of 15 µL was injected. Mili-Q
water and HPLC quality grade CH3CN were used.
Analytical chiral separations were performed on an Agilent
1100 series HPLC system using a Chiralcel OD-H column
(250 x 4.6 mm, 5 µm particle size) or a Chiralpak AS-H
column (250 x 4.6 mm, 5 µm particle size), connected to a
UV-DAD detector. All measurements were performed at
35°C, a flow rate of 1 mL/min and a sample volume of 20
µL. HPLC quality grade solvents were used for all
measurements. Optical rotations were measured using a
Perkin-Elmer 214 polarimeter at 589 nm.
3. Conclusion
In conclusion, we have disclosed the synthesis of three
novel chiral monodentate biferrocene-based
phosphoramidite ligands. Therefore we started from
enantioenriched planar chiral α-iodoferrocenecarboxaldhyde
(Sp)-8, obtained via the Kagan approach.[24] Afterwards, we
developed a novel very mild Ullmann homocoupling
reaction with CuTC at room temperature. This allowed to
efficiently synthesize the biferrocene dihydroazepine ligand
precursor in a few steps and a high yield. The final step
towards the desired ligands, however was rather
cumbersome and yields between 29-44% were obtained.
Nevertheless, this allowed to test these ligands in a
benchmark
testreaction,
the
rhodium(I)-catalyzed
hydrogenation of enamide 12. To explore the influence of
the biferrocene backone as well as ‘matched’ and
‘mismatched’ effects, biphenol as wel as both enantiomers
of axial chiral binol were applied as the diol substructure of
the phosphoramidite ligands. Very good conversions and an
ee-value up to 67.6% were observed, indicating the potential
of the novel chiral phosphoramidite ligands and the
corresponding biferrocene ligand backbone.
Despite different attempts, we were unfortunately not able
to grow crystals from the ligands nor from a rhodium
complex, suitable for X-ray analysis. These attempts involve
dissolving minimal amounts of the ligands in CH2Cl2 or
toluene and slow evaporation of the solvents. For the
attempts towards the rhodium complexes, [Rh(COD)2BF4]
was added to the mixture which was stirred properly before
slow evaporation of the solvents.
4.2. Metallic copper based synthesis of (Sp,Sp)-[1,1’-
biferrocenyl]-2,2’-dicarboxaldehyde (Sp,Sp-9): An oven-
dried, 50 mL round-bottom flask was charged with (Sp)-8
(2.610 g, 7.68 mmol). Metallic copper (1.950 g, 30.71 mmol,
4 eq) was carefully added in such way that all of the starting
material was covered with copper. A heavy, egg-shaped
stirring bar was carefully added and the reaction flask was
wrapped in aluminum foil. The reaction was stirred
overnight at 105°C. The crude reaction mixture was taken
up in CH2Cl2 and filtered over Celite, while the filtrate was
collected in a round-bottom flask which was wrapped in
aluminum foil. The solvent was removed under reduced
pressure and the resulting residue was purified by flash
chromatography 1 (gradient n-hexane/EtOAC: 8/2 to 6/4)
affording (Sp,Sp)-9, with a yield of 66.8%, as a red solid. Rf
(n-hexane/EtOAc: 7/3): 0.25. 1H-NMR: (500 MHz, CDCl3):
δ = 4.31 (s, 10H), 4.74 (dd, J = 2.8 Hz, J = 2.4 Hz, 2H), 4.94
(dd, J = 2.4 Hz, J = 1.6, 2H), 4.95 (dd, J = 2.8 Hz, J = 1.6,
2H), 9.94 (s, 2H) ppm. 13C-NMR: (125 MHz, CDCl3): δ =
68.8 (CH x2), 71.0 (CH x10), 71.9 (CH x2), 76.6 (CH x2),
78.6 (C x2), 85.3 (C x2), 192.2 (CH x2) ppm. IR (HATR):
υmax = 3921, 3561, 3315, 3101, 3009, 2941, 2840, 2778,
2764, 1661, 1652, 1426, 1409, 1395, 1289, 1208, 1106, 998,
990, 825, 774, 733, 679 cm-1. HRMS (ESI): calculated for
C22H19Fe2O2 [M+H]+: 427.0078; found: 427.0079. Optical
4. Experimental
4.1. General Experimental Methods
Unless otherwise stated, all reagents were obtained
commercially and used without further purification. All
reactions were carried out under an argon atmosphere in dry
solvents under anhydrous conditions, unless otherwise noted.
Dichloroethane, Et3N and DIPEA were dried via distillation
over CaH2. Toluene was dried via distillation over sodium
with benzophenone as indicator. Other anhydrous solvents
were purchased as such. Analytical TLC was performed by
using Machery-Nagel SIL G-25 UV254 plates. Flash
chromatography was carried out with Rocc silica gel (0.040-
ꢀ ꢂꢄꢅ
rotation: ꢁ = -257 (c 0.1, CH2Cl2).
ꢃ
0.063 mm). H NMR and 13C NMR spectra were recorded
1
4.3. CuTC based synthesis of (Sp,Sp)-[1,1’-biferrocenyl]-
with a Bruker avance 300 or a Bruker Avance 400 or a
Bruker AM 500 spectrometer as indicated, with chemical
shifts reported in ppm relative to TMS, by using the residual
solvent signal as a standard, and relative to 85% aqueous
phosphoric acid for 31P NMR spectra. IR spectra were
recorded with a Perkin-Elmer SPECTRUM-1000 FTIR
spectrometer with a Pike Miracle Horizontal Attenuated
Total Reflectance (HATR) module. ESI-MS was performed
on an Agilent 1100 series with a single quadrupole MS
detector G1946C (type VL) equipped with an API-ESI
source. High Resolution Mass Spectrometry (HRMS) was
performed on an Agilent 1100 series connected to a 6220A
2,2’-dicarboxaldehyde (Sp,Sp-9): An oven-dried
round-bottom flask was charged with a magnetic stirring bar,
(Sp)-8 (68 mg, 0.20 mmol) and CuTC (114 mg, 0.60 mmol,
5 mL
1Because 9 is light sensitive, the column was wrapped in aluminum foil
as well. First a mixed fraction of ferrocenecarboxaldehyde 7 and α-
iodoferrocenecarboxaldehyde (Sp)-8 was collected. The polarity of the
eluent system was raised to n-hexane/EtOAC: 7/3 and the meso form
(Rp,Sp)-9 was collected. The polarity of the eluent system was raised to
n-hexane/EtOAC:
6/4
and
(Sp,Sp)-[1,1’-bifferrocenyl]-2,2’-
dicarboxaldehyde (Sp,Sp)-9 was collected in a round bottom flask which
was wrapped in aluminum foil.
5

ACCEPTED MANUSCRIPT
3 eq). Anhydrous NMP (1.0 mL) was added and the reaction
(Sp,Sp)-15, with a yield of 88.2%. Rf (n-hexane/EtOAc: 7/3):
0.14. 1H-NMR: (500 MHz, CDCl3): δ = 3.70 (d, J = 14.9 Hz,
2H), 3.80-3.82 (m, 2H), 3.83 (s, 3H), 3.86 (d, J = 14.9 Hz,
2H), 3.95 (s, 10H), 3.98-4.01 (m, 2H), 4.10 (dd, J = 2.4 Hz,
J = 2.2 Hz, 2H), 4.38 (dd, J = 2.2 Hz, J = 1.4 Hz, 2H), 6.89
(br d, J = 8.5 Hz, 2H), 7.3 (br d, J = 8.5 Hz, 2H) ppm. 13C-
NMR: (125 MHz, CDCl3): δ = 55.3 (CH3), 56.2 (CH2 x2),
59.8 (CH2), 65.8 (CH x2), 66.2 (CH x2), 67.7 (CH x2), 70.0
(CH x10), 82.6 (C x2), 84.5 (C x2), 113.7 (CH), 130.1 (CH),
158.7 (C) ppm. 1 C not observed. IR (HATR): υmax = 3916,
3090, 2925, 2833, 1610, 1584, 1455, 1440, 1357, 1300,
1170, 1130, 1104, 1031, 999, 814, 733, 703 cm-1. HRMS
(ESI): calculated for C30H30Fe2NO [M+H]+: 532.1021;
ꢀ ꢂꢄꢅ
flask was wrapped in aluminum foil. The reaction mixture
was heated to 70°C and stirred overnight. Then, the reaction
mixture was allowed to cool to room temperature, diluted
with Et2O and filtered over Celite. Et2O was removed under
reduced pressure. The residu was taken up in Et2O (10 mL)
and washed 3 times with water (10 mL). The organic phase
was dried over anhydrous MgSO4 and filtered. Et2O was
removed under reduced pressure and the resulting residue
1
was purified by flash chromatography (gradient: n-
hexane/EtOAC: 8/2 to 6/4) affording (Sp,Sp)-9, with a yield
of 59.0%, as a red solid.
4.4. Synthesis
of
(Sp,Sp)-N-benzyl-3,5-dihydro-4H-
found: 532.1032. Optical rotation:
CHCl3)
ꢁ
= -454 (c 1.0,
ꢃ
diferrocenyl-[c,e]-azepine (Sp,Sp-14): An oven-dried, 25 mL
two-neck round-bottom flask was charged with a magnetic
stirring bar, (Sp,Sp)-9 (118 mg, 0.28 mmol). Freshly distilled
dichloroethane (8.0 mL) was added followed by a solution
of benzylamine in dichloroethane (1.3 M, 850 µL, 1.1 mmol,
4 eq). The reaction mixture was stirred for 5 min at room
temperature and NaBH3CN (609 mg, 9.69 mmol, 35 eq) and
anhydrous K2CO3 (153 mg, 1.11 mmol, 4 eq) were added.
The reaction was stirred overnight at room temperature and
quenched with a saturated solution of NaHCO3 (30 mL). The
aqueous phase was extracted 3 times with CH2Cl2 (30 mL).
The combined organic phases were dried over anhydrous
MgSO4 and filtered. The solvents were removed under
reduced pressure and the resulting residue was purified by
flash chromatography (n-hexane/EtOAc/Et3N: 8/2/0.2)
4.6. Synthesis
of
(Sp,Sp)-N-allyl-3,5-dihydro-4H-
diferrocenyl-[c,e]-azepine (Sp,Sp-10): An oven-dried, 25 mL
two-neck round-bottom flask was charged with a magnetic
stirring bar, (Sp,Sp)-9 (118 mg, 0.28 mmol). Freshly distilled
dichloroethane (8.0 mL) was added followed by a solution
of allylamine in dichloroethane (1.3 M, 850 µL, 1.1 mmol, 4
eq). The reaction mixture was stirred for 5 min at room
temperature and NaBH3CN (609 mg, 9.69 mmol, 35 eq) and
anhydrous K2CO3 (153 mg, 1.11 mmol, 4 eq) were added.
The reaction was stirred overnight at room temperature and
quenched with a saturated solution of NaHCO3 (30 mL). The
aqueous phase was extracted 3 times with CH2Cl2 (30 mL).
The combined organic phases were dried over anhydrous
MgSO4 and filtered. The solvents were removed under
reduced pressure and the resulting residue was purified by
flash chromatography (n-hexane/EtOAc/Et3N: 8.5/1.5/0.2)
affording (Sp,Sp)-14, with
a yield of 79.9%. Rf (n-
hexane/EtOAc 7/3): 0.14. 1H-NMR: (500 MHz, CDCl3): δ =
3.72 (d, J = 15.0 Hz, 2H), 3.88-3.89 (m, 2H), 3.89 (d, J =
15.0 Hz, 2H), 3.95 (s, 10H), 3.99-4.00 (m, 2H), 4.11 (dd, J =
2.4 Hz, J = 2.2 Hz, 2H), 4.39 (dd, J = 2.4 Hz, J = 1.4 Hz,
2H), 7.36 (m, 5H) ppm. 13C-NMR: (125 MHz, CDCl3): δ =
56.4 (CH2 x2), 60.4 (CH2), 65.8 (CH x2), 66.3 (CH x2), 67.7
(CH x2), 69.9 (CH x10), 82.6 (C x2), 84.5 (C x2), 127.0
(CH), 128.3 (CH), 128.9 (CH), 139.3 (C) ppm. IR (HATR):
υmax = 3920, 3087, 2923, 2852, 1731, 1493, 1453, 1357,
1265, 1130, 1104, 1028, 999, 815, 804, 734, 698 cm-1.
HRMS (ESI): calculated for C29H28Fe2N [M+H]+: 502.0915;
ꢀ ꢂꢄꢅ
affording (Sp,Sp)-10, with
a yield of 75.6%. Rf (n-
1
hexane/EtOAc: 7/3): 0.19. H-NMR: (400 MHz, CDCl3): δ
= 3.31 (dd, J = 13.7 Hz, J = 6.8 Hz, 1H), 3.37 (dd, J = 13.7
Hz, J = 5.8 Hz, 1H), 3.72 (d, J = 14.9 Hz, 2H), 3.96 (d, J =
14.9 Hz, 2H), 4.06 (br dd, J = 2.3 Hz, J = 1.3 Hz, 2H), 4.1
(br dd, J = 2.3 Hz, J = 2.1 Hz, 2H), 4.36 (br dd, J = 2.1 Hz,
J = 1.3 Hz, 2H), 5.20 (dd, J = 10.3 Hz, J = 1.4 Hz, 1H), 5.21
(dd, J = 17.1 Hz, 1.4 Hz, 1H), 5.96 (dddd, J = 17.1 Hz, J =
10.3 Hz, J = 6.8 Hz, J = 5.8 Hz, 1H) ppm. 13C-NMR: (100
MHz, CDCl3): δ = 56.3 (CH2 x2), 59.4 (CH2), 65.7 (CH x2),
66.2 (CH x2), 67.6 (CH x2), 69.9 (CH x10), 82.2 (C x2),
84.6 (C x2), 117.5 (CH2), 136.3 (CH) ppm. IR (HATR): υmax
= 3081, 2928, 2797, 2362, 2336, 1636, 1452, 1432, 1406,
1316, 1219, 1130, 1102, 1076, 1026, 997, 975, 922, 846,
810, 804, 757 cm-1. HRMS (ESI): calculated for C25H26Fe2N
[M+H]+: 452.0759; found: 452.0751. Optical rotation:
found: 502.0917. Optical rotation:
CHCl3).
ꢁ
= -508 (c 1.2,
ꢃ
4.5. Synthesis of (Sp,Sp)-N-4-methoxybenzyl-3,5-dihydro-
4H-diferrocenyl-[c,e]-azepine (Sp,Sp-15): An oven-dried, 25
mL two-neck round-bottom flask was charged with a
magnetic stirring bar, (Sp,Sp)-9 (118 mg, 0.28 mmol).
Freshly distilled dichloroethane (8.0 mL) was added
followed by a solution of para-methoxybenzylamine in
dichloroethane (1.3 M, 850 µL, 1.1 mmol, 4 eq). The
reaction mixture was stirred for 5 min at room temperature
and NaBH3CN (609 mg, 9.69 mmol, 35 eq) and anhydrous
K2CO3 (153 mg, 1.11 mmol, 4 eq) were added. The reaction
was stirred overnight at room temperature and quenched
with a saturated solution of NaHCO3 (30 mL). The aqueous
phase was extracted 3 times with CH2Cl2 (30 mL). The
combined organic phases were dried over anhydrous MgSO4
and filtered. The solvents were removed under reduced
pressure and the resulting residue was purified by flash
chromatography (n-hexane/EtOAc/Et3N: 8/2/0.2) affording
ꢀ ꢂꢄꢅ
ꢁ
= -659 (c 1.7, CHCl3).
ꢃ
4.7. Synthesis of (Sp,Sp)-N-H-3,5-dihydro-4H-diferrocenyl-
[c,e]-azepine (Sp,Sp-11): An oven-dried pressure tube was
charged with a magnetic stirring bar, (Sp,Sp)-10 (90 mg, 0.20
mmol) and KOt-Bu (112 mg, 1.00 mmol, 5 eq). Anhydrous
DMSO (7.0 mL) was added and the pressure tube was
closed with a stopper. The reaction mixture was heated up to
100°C for 2 h. The reaction was allowed to cool to room
temperature. The dark suspension was diluted with Et2O (30
mL) and carefully quenched with a saturated solution of
NH4Cl (30 mL). The organic phase was separated and
washed 3 times with water (30 mL) and once with brine (30
6

ACCEPTED MANUSCRIPT
mL). The organic phase was dried over anhydrous MgSO4
to 0°C using an ice-water bath. A solution of Et3N in toluene
(0.36 M, 2.0 mL, 0.73 mmol, 10 eq) was added, followed by
dropwise addition of a solution of freshly distilled PCl3 in
toluene (0.57 M, 128 µL, 0.073 mmol, 1 eq). The reaction
mixture was stirred for 10 min at 0°C, allowed to warm up
to room temperature and stirred for an additional 2 h. The
reaction was cooled again to 0°C and a suspension of (R)-
binol (21 mg, 0.073 mmol, 1.0 eq) in toluene (1.0 mL) was
added, followed by addition of a solution of Et3N in toluene
(0.36 M, 0.5 mL, 0.18 mmol, 2.5 eq). The reaction mixture
was stirred for 10 min at 0°C, allowed to warm up to room
temperature and stirred overnight. The reaction was
quenched with water (25 mL) and extracted 3 times with
CH2Cl2 (25 mL). The combined organic phases were washed
with brine (40 mL), dried over anhydrous MgSO4 and
filtered. The organic solvents were removed under reduced
pressure and the resulting residue was purified by flash
chromatography (n-hexane/EtOAc: 98/2) affording 6b, with
a yield of 28.7%, as a yellow solid. Rf (n-hexane/EtOAc:
and filtered. Et2O was removed under reduced pressure and
pure (Sp,Sp)-11 was obtained as a yellow solid with a yield
of 96.2%. Rf (n-hexane/EtOAc/Et3N: 2/7/1): 0.33. 1H-NMR:
(500 MHz, CDCl3): δ = 3.92 (d, J = 16.0 Hz, 2H), 3.96 (s,
10H), 4.05 (d, J = 16.0 Hz, 2H), 4.11-4.13 (m, 4H), 4.30
(app t, J = 1.9 Hz, 2H) ppm. 13C-NMR: (125 MHz, CDCl3):
δ = 51.6 (CH2 x2), 65.4 (CH x2), 66.4 (CH x2), 67.6 (CH
x2), 69.6 (CH x10), 82.0 (C x2), 88.0 (C x2) ppm. IR
(HATR): υmax = 3075, 2909, 2851, 2359, 2331, 1616, 1442,
1406, 1354, 1307, 1212, 1115, 1102, 1030, 998, 809, 780,
737, 674 cm-1. HRMS (ESI): calculated for C22H22Fe2N
[M+H]+: 412.0446; found: 412.0448. Optical rotation:
ꢀ ꢂꢄꢅ
ꢁ
= -399 (c 0.09, CHCl3).
ꢃ
4.8. Synthesis of biphenol-based phosphoramidite ligand
(6a): An oven-dried Schlenk tube charged with a magnetic
stirring bar and (Sp,Sp)-11 (73 mg, 0.18 mmol) was cooled to
0°C using an ice-water bath. A solution of Et3N in toluene
(0.36 M, 5.0 mL, 1.80 mmol, 10 eq) was added, followed by
dropwise addition of a solution of freshly distilled PCl3 in
toluene (0.57 M, 316 µL, 0.18 mmol, 1 eq). The reaction
mixture was stirred for 10 min at 0°C, allowed to warm up
to room temperature and stirred for an additional 2 h. The
reaction was cooled again to 0°C and a suspension of 2,2’-
biphenol (33 mg, 0.18 mmol, 1.0 eq) in toluene (3.0 mL)
was added, followed by addition of a solution of Et3N in
toluene (0.36 M, 1.2 mL, 0.44 mmol, 2.5 eq). The reaction
mixture was stirred for 10 min at 0°C, allowed to warm up
to room temperature and stirred overnight. The reaction was
quenched with water (70 mL) and extracted 3 times with
CH2Cl2 (70 mL). The combined organic phases were washed
with brine (100 mL), dried over anhydrous MgSO4 and
filtered. The organic solvents were removed under reduced
pressure and the resulting residue was purified by flash
chromatography (n-hexane/EtOAc: 98/2) affording 6a, with
a yield of 30.2%, as a yellow solid. Rf (n-hexane/EtOAc:
1
7/3): 0.75. H-NMR: (500 MHz, CDCl3): δ = 3.79 (dd, J =
2.3 Hz, J = 1.5 Hz, 2H), 3.97-4.01 (m, 2H), 3.98 (s, 10H),
2
3
4.00-4.02 (m, 2H), 4.26 (dd, JHH = 15.7 Hz, JPH = 8.7 Hz,
2H), 4.29 (dd, J = 2.4 Hz, J = 1.5 Hz, 2H), 7.24-7.28 (m,
1H), 7.32-7.37 (m, 2H), 7.39-7.52 (m, 5H), 7.89-7.91 (m,
2H), 7.99-8.03 (m, 2H) ppm. 13C-NMR: (125 MHz, CDCl3):
δ = 49.6 (CH2 x2, d, JCP = 21.8 Hz), 65.5 (CH x2), 66.3 (CH
x2), 67.4 (CH x2), 69.8 (CH x10), 81.9 (C x2), 86.4 (C x2, d,
JCP = 3.6Hz), 121.9 (CH), 122.1 (CH), 123.9 (C, d, JCP = 5.5
Hz), 124.6 (CH), 124.8 (CH), 126.1 (CH), 126.1 (CH),
127.0 (CH x2), 128.3 (CH), 128.3 (CH), 130.1 (CH), 130.2
(CH), 130.7 (C), 131.4 (C), 132.7 (C), 132.8 (C), 132.8 (C),
149.6 (C), 150.1 (C, d, JCP = 4.5 Hz) ppm. 31P-NMR: (162
MHz, CDCl3): 145.23 ppm. IR (HATR): υmax = 3088, 2954,
2921, 2852, 1589, 1506, 1463, 1431, 1326, 1227, 1202,
1124, 1103, 1061, 1039, 1004, 951, 932, 913, 820, 799, 747,
697, 683, 626 cm-1. HRMS (ESI): calculated for
C42H33Fe2NO2P [M+H]+: 726.0942, found: 726.0922;
calculated for C42H32Fe2NO2P [M]·+: 725.0864, found:
1
7/3): 0.78. H-NMR: (400 MHz, CDCl3): δ = 3.90 (dd, J =
ꢀ ꢂꢄꢅ
725.0862. Optical rotation: ꢁ = -549 (c 0.10, CHCl3).
2.3 Hz, J = 1.5 Hz, 2H), 4.01 (s, 10H), 4.09 (app t, J = 2.3
ꢃ
3
Hz, 2H), 4.22 (dd, 2JHH = 15.8 Hz, JPH = 7.4 Hz, 2H), 4.36
2
(dd, J = 2.3 Hz, J = 1.5 Hz, 2H), 4.37 (dd, JHH = 15.8 Hz,
4.10.Synthesis of (S)-binol-based phosphoramidite ligand
(6c): An oven-dried Schlenk tube charged with a magnetic
stirring bar and (Sp,Sp)-11 (60 mg, 0.15 mmol) was cooled to
0°C using an ice-water bath. A solution of Et3N in toluene
(0.36 M, 4.1 mL, 1.46 mmol, 10 eq) was added, followed by
dropwise addition of a solution of freshly distilled PCl3 in
toluene (0.57 M, 256 µL, 0.15 mmol, 1 eq). The reaction
mixture was stirred for 10 min at 0°C, allowed to warm up
to room temperature and stirred for an additional 2 h. The
reaction was cooled again to 0°C and a suspension of (S)-
binol (42 mg, 0.15 mmol, 1.0 eq) in toluene (2.0 mL) was
added, followed by addition of a solution of Et3N in toluene
(0.36 M, 1.0 mL, 0.36 mmol, 2.5 eq). The reaction mixture
was stirred for 10 min at 0°C, allowed to warm up to room
temperature and stirred overnight. The reaction was
quenched with water (50 mL) and extracted 3 times with
CH2Cl2 (50 mL). The combined organic phases were washed
with brine (80 mL), dried over anhydrous MgSO4 and
filtered. The organic solvents were removed under reduced
pressure and the resulting residue was purified by flash
chromatography (n-hexane/EtOAc: 98/2) affording 6c, with
3JPH = 8.4 Hz, 2H), 6.87-6.92 (m, 1H), 7.24-7.33 (m, 4H),
7.41 (td, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.48-7.53 (m, 2H) ppm.
13C-NMR: (100 MHz, CDCl3): δ = 49.6 (CH2 x2, d, JCP
=
22.7 Hz), 65.6 (CH x2), 66.2 (CH x2), 67.8 (CH x2), 69.8
(CH x10), 81.9 (C x2), 86.3 (C x2, d, JCP = 4.4 Hz), 122.0
(CH), 122.6 (CH), 124.3 (CH), 124.7 (CH), 129.2 (CH),
129.3 (CH), 129.5 (CH), 129.7 (CH), 130.5 (C, d, JCP = 2.9
Hz), 131.2 (C, d, JCP = 3.7 Hz), 151.0 (C, d, JCP = 6.6 Hz),
151.2 (C, d, JCP = 3.7 Hz) ppm. 31P-NMR: (162 MHz,
CDCl3): 144.57 ppm. IR (HATR): υmax = 3083, 2953, 2922,
2854, 1474, 1433, 1365, 1245, 1225, 1189, 1123, 1097,
1042, 1031, 1005, 882, 846, 818, 793, 762, 732, 702, 676
cm-1. HRMS (ESI): calculated for C34H29Fe2NO2P [M+H]+:
626.0629, found: 626.0617; calculated for C34H28Fe2NO2P
+
ꢀ ꢂꢄꢅ
[M]· : 625.0551, found: 625.0527. Optical rotation: ꢁ
=
ꢃ
-396 (c 0.10, CHCl3).
4.9. Synthesis of (R)-binol-based phosphoramidite ligand
(6b): An oven-dried Schlenk tube charged with a magnetic
stirring bar and (Sp,Sp)-11 (30 mg, 0.073 mmol) was cooled
7

ACCEPTED MANUSCRIPT
a yield of 43.6%, as a yellow solid. Rf (n-hexane/EtOAc:
balloon. The reaction mixture was filtered over a short plug
of silica gel and eluted with EtOAc. The solvents were
removed under reduced pressure and 13 was obtained as a
white solid. Conversion and enantiomeric excess were
determined by chiral LC analysis on a Chiralcel OD-H
column (250 x 4.6 mm, particle size 5 µm), solvent: n-
hexane/EtOH (95:5), flow rate = 1 mL/min, t = 30 min, T =
35°C, retention times: 11.20 min for (R)-13, 12.80 min for
(S)-13 and 20.81 min for starting material 12. The absolute
configuration of 13 was assigned via correlation of its
1
7/3): 0.71. H-NMR: (400 MHz, CDCl3): δ = 3.83 (m, 2H),
4.00 (s, 10H), 4.12 (app t, J = 2.4 Hz, 2H), 4.14 (dd, 2JHH
15.9 Hz, 3JPH = 7.5 Hz, 2H), 4.35 (dd, 2JHH = 16.0 Hz, 3JPH
=
=
8.3 Hz, 2H), 4.39 (dd, J = 2.4 Hz, J = 1.5 Hz, 2H), 7.05 (d, J
= 8.7 Hz, 1H), 7.22-7.26 (m, 1H), 7.28-7.36 (m, 2H), 7.40-
7.50 (m, 3H), 7.55 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.7 Hz,
1H), 7.90-7.97 (m, 2H), 7.99 (d, J = 8.8 Hz, 1H) ppm. 13C-
NMR: (100 MHz, CDCl3): δ = 49.7 (CH2 x2, d, JCP = 23.5
Hz), 65.5 (CH x2), 66.1 (CH x2), 68.2 (CH x2), 69.9 (CH
x10), 82.0 (C x2), 85.9 (C x2, JCP = 4.4 Hz), 121.9 (CH),
122.9 (CH), 124.0 (C, JCP = 5.1 Hz), 124.5 (CH), 124.9
(CH), 125.9 (CH), 126.1 (CH), 127.1 (CH x2), 128.3 (CH),
128.3 (CH), 130.2 (CH), 130.4 (CH), 130.6 (C), 131.4 (C),
132.5 (C), 132.8 (C), 132.8 (C), 149.1 (C), 149.3 (C), 149.3
(C) ppm. 31P-NMR: (162 MHz, CDCl3): 143.47 ppm. IR
(HATR): υmax = 3089, 3054, 2958, 2923, 2853, 2359, 2341,
1619, 1590, 1506, 1462, 1431, 1366, 1328, 1261, 1229,
1204, 1124, 1104, 1043, 1066, 1031, 1007, 982, 951, 927,
820, 800, 750, 737, 696 cm-1. HRMS (ESI): calculated for
C42H33Fe2NO2P [M+H]+: 726.0942, found: 726.0899;
calculated for C42H32Fe2NO2P [M]·+: 725.0864, found:
ꢀ ꢂꢄꢅ
specific
rotation
with
literature
values.[30]
Rf
(CH2Cl2/EtOAc: 90/10): 0.18. 1H-NMR: (500 MHz, CDCl3):
δ = 1.98 (s, 3H), 3.09 (dd, J = 13.9 Hz, J = 5.8 Hz, 1H), 3.14
(dd, J = 13.9 Hz, J = 5.8 Hz, 1H), 3.73 (s, 3H), 4.83 (app dt,
J = 7.8 Hz, J = 5.8 Hz, 1H), 5.95 (br s, 1H), 7.07-7.11 (m,
2H), 7.22-7.32 (m, 3H) ppm. 13C-NMR: (125 MHz, CDCl3):
δ = 23.3 (CH3), 38.0 (CH2), 52.5 (CH), 53.2 (CH3), 127.3
(CH), 128.4 (CH), 128.8 (CH), 135.9 (C), 169.8 (C), 172.2
(C) ppm. ESI-MS m/z (rel. intensity %): 222.1 (74) [M+H]+,
180.1 (92), 162.1 (100), 120.1 (50).
Acknowledgments
725.0867. Optical rotation: ꢁ
= -60.7 (c 0.14, CHCl3).
ꢃ
The authors wish to thank Ghent University and the Agency
for Innovation by Science and Technology in Flanders for
financial support. Timothy Noël is gratefully acknowledged
for scientific advice.
4.11.Synthesis of methyl Z-2-acetamido-3-phenylacrylate
(12): An oven-dried 50 mL round-bottom flask was charged
with a magnetic stirring bar and α-acetamidocinnamic acid
(2.21 g, 10.7 mmol). Anhydrous DMF (20 mL), anhydrous
DIPEA (3.7 mL, 21.5 mol, 2 eq) and iodomethane (2.7 mL,
43.1 mmol, 4 eq) were added. The reaction mixture was
stirred overnight at room temperature, quenched with a
saturated solution of NH4Cl (100 mL) and extracted three
times with EtOAc (100 mL). The combined organic phases
were washed with a 10 mol% solution of KHCO3 (100 mL)
and a 10 mol% solution of citric acid (100 mL) and dried
over Na2SO4. After filtration and removal of the organic
solvents under reduced pressure, the obtained solid was
washed with Et2O and n-hexane. Methyl Z-2-acetamido-3-
phenylacrylate 12 was obtained as a white solid with a yield
References and notes
[1] Lorenz, H.; Seidel-Morgenstern, A., Angew. Chem. Int. Ed.,
2014, 53, 1218-1251.
[2] (a) Rouhi, A. M., Chem. Eng. News, 2003, 81, 56-61. (b) Jeschke,
P., Pest. Manag. Sci., 2018, 74, 2389-2404. (c) Blaser, H.-U.,
Hoge, G., Lotz, M., Nettekoven U., Schnyder, A. Spindler, F.,
Chimia, 2008, 62, 476-481.
[3] (a) Sheldon, R. A., Chirotechnology: Industrial Synthesis of
Optically Active Compounds, Marcel Dekker, New York, 1993.
(b) Chiral Drugs: Chemistry and Biological Action, Eds: G.-Q.
Lin, Q.-D. You, J.-F. Cheng, Wiley, Hoboken, 2011.
[4] Vervecken, E.; Van Overschelde, M.; Noël, T.; Gök, T.;
Rodríguez, S. A.; Cogen, S.; Van der Eycken, J.; Tetrahedron:
Asymmetry, 2010, 21, 2321-2328.
[5] (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H., Eds.; Springer: Berlin, 1999; (b) Catalytic
Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.; Wiley-VCH: New
York, 2000; (c) New Frontiers in Asymmetric Catalysis; Mikami,
K.; Lautens, M., Eds.; Wiley-Interscience, 2007.
[6] (a) Federsel, H.-J., Nat. Rev. Drug. Disc., 2005, 4, 685-697; (b)
Taylor, M.S.; Jacobsen, E.N., Proc. Natl. Acad. Sci. U.S.A., 2004,
101, 5368-5373.
1
of 82.3%. Rf (CH2Cl2/EtOAc: 85/15): 0.19. H-NMR: (400
MHz, CDCl3): δ = 2.15 (s, 3H), 3.86 (s, 3H), 6.98 (br s, 1H),
7.10-7.85 (m, 6H) ppm. 13C-NMR: (100 MHz, CDCl3): δ =
23.5 (CH3), 52.7 (CH3), 124.2 (C), 128.6 (CH x2), 129.5
(CH), 129.6 (CH x2), 132.2 (CH), 133.7 (C), 165.7 (C),
168.7 (C) ppm. ESI-MS m/z (rel. intensity %): 242.1 (100)
[M+Na]+, 220.1 (25) [M+H]+.
[7] (a) Noël, T.; Bert, K.; Van der Eycken, E.; Van der Eycken, J.,
Eur. J. Org. Chem., 2010, 4056-4061. (b) Mahatthananchai, J.,
Dumas, A. M., Bode, J. W., Angew. Chem. Int. Ed., 2012, 51,
10954-10990.
[8] Inoguchi, K.; Sakuraba, S.; Achiwa, K., Synlett, 1992, 169-178.
[9] de Vries, A. H. M.; Meetsma, A.; Feringa, B. L., Angew. Chem.
Int. Ed., 1996, 35, 2374-2375.
[10] Teichert, J. F.; Feringa, B. L., Angew. Chem. Int. Ed., 2010, 49,
2486-2528.
[11] Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G., Acc.
Chem. Res., 2007, 40, 1267-1277.
4.12.General procedure for the Rhodium(I)-catalyzed
asymmetric hydrogenation of 12: An oven-dried Schlenk
tube was connected to an argon Schlenk line, charged with a
magnetic stirring bar, Rh(COD)2BF4 (2.8 mg, 6.89 µmol, 1
mol%) and a ligand (6a, 6b or 6c) (13.8 µmol, 2 mol%).
Degassed2 CH2Cl2 (3 mL) was added to the catalyst mixture,
which was stirred for 30 min at room temperature. Methyl
Z-2-acetamido-3-phenylacrylate 12 (151 mg, 689 µmol) was
added, and hydrogen gas was bubbled through the reaction
mixture for 10 min. The reaction was stirred overnight at
room temperature under a hydrogen atmosphere using a
[12] C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira, Angew.
Chem. Int. Ed., 2007, 46, 3139-3143.
[13] Hamilton, J. Y.; Sarlah, D.; Carreira, E. M., J. Am. Chem. Soc.,
2013, 135, 994-997.
[14] Eberhardt, L.; Armspach, D.; Matt, D.; Toupet, L.; Oswald, B.,
Eur. J. Org. Chem., 2007, 5395-5403.
2 Degassing was accomplished by bubbling of H2-gas through the
solvent for 10 min. using a balloon.
8

ACCEPTED MANUSCRIPT
[15] (a) Blaser, H. U.; Brieden, W.; Pugin B.; Spindler, F.; Studer, M.;
Comprehensive Organic Chemistry, Barton, D. H. R., Ollis, W.
D., Pergamon Press., Oxford, 1979, Vol. 2, part 10.3; (c) Van
Rooy, A.; Burgers, D.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M., Recl. Trav. Chim. Pays-Bas, 1996, 115, 492-498.
Togni, A., Top. Catal., 2002, 19, 3-16; (b) Blaser, H. U. ;
Spindler F.; Studer, M.; Appl. Catal., A., 2001, 221, 119-143; (c)
Blaser H. U., Adv. Synth. Catal., 2002, 344, 17-31.
[16] (a) Arrayás, R. G.; Adrio, J.; Carretero, J. C., Angew. Chem. Int.
Ed., 2006, 45, 7674-7715; (b) Colacot, T. J., Chem. Rev., 2003,
103, 3101-3118; (c) Barbaro, P.; Bianchini, C.; Giambastiani, G.;
Parisel, S. L., Coord. Chem. Rev., 2004, 248, 2131-2150; (d)
Atkinson, R. C. J.; Gibson, V. C.; Long, N. J., Chem. Soc. Rev.,
2004, 33, 313-328. (e) Noël, T.; Van der Eycken J., Green
Process. Synth, 2013, 2, 297-309
[17] Chiral Ferrocenes in Asymmetric Catalysis, Dai, L.-X.; Hou X.-
L., Eds, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim,
2010
[27] Choi, Y. H.; Choi, J. Y.; Yang, H. Y.; Kim, Y. H., Tetrahedron:
Asymmetry, 2002, 13, 801-804.
[28] Tang, W.; Zhang, X., Chem. Rev., 2003, 103, 3029-3063.
[29] (a) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C., Tetrahedron:
Asymmetry, 2004, 15, 2101-2111; (b) Peña, D.; Minnaard, A. J.;
de Vries, J. G.; Feringa, B. L., J. Am. Chem. Soc., 2002, 124,
14552-14553; (c) Reetz, M. T.; Sell, T., Tetrahedron Lett., 2000,
41, 6333-6336. (d) Claver C.; Fernandez, E.; Gillon, A.; Heslop,
K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G.,
Chem. Commun., 2000, 961-962; (e) van den Berg, M.;
Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.;
de Vries, J. G.; Feringa, B. L., J. Am. Chem. Soc., 2000, 122,
11539-11540; (f) van den Berg, M.; Haak, R. M.; Minnaard, A.
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L., Adv. Synth.
Catal., 2002, 344, 1003-1007; (g) van den Berg, M.; Minnaard,
A. J.; Haak. R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.;
Feringa, B. L.; de Vries. A. H. M.; Maljaars, C. E. P.; Willans, C.
E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J.
G., Adv. Synt. Catal., 2003, 345, 308-325.
[18] Dai, L.-X.; Tu, T.; You, S.-L.; Deng W.-P.; Hou, X.-L., Acc.
Chem. Res., 2003, 36, 659-667.
[19] Krajnik, P.; Kratky, C.; Schlögl, K. Widhalm, M., Monatsch.
Chem., 1990, 121, 945-953.
[20] Xiao, L.; Mereiter, K.; Spindler F.; Weissensteiner, W.,
Tetrahedron: Asymmetry, 2001, 12, 1105-1108.
[21] Espino, G.; Xiao, L.; Puchberger, M.; Mereiter, K.; Spindler F.;
Manzanno, B. R.; Jalόn, F. A.; Weissensteiner, W., Dalton Trans.,
2009, 2751-2763.
[22] Xia, L.; Weissensteiner, W.; Mereiter, K.; Widhalm, M., J. Org.
Chem., 2002, 67, 2206-2214.
[30] (a) Vineyard, B. D.; Knowles, W.S.; Sabacky, M. J.; Bachman,
G. L.; Weinkauff, D. J., J. Am. Chem. Soc., 1977, 99, 5946-5952;
(b) Togni, A.; Breutel, B.; Schnyder, A.; Spindler, F.; Landert,
H.; Tijani, A., J. Am. Chem. Soc., 1994, 116, 4062-4066 (c) Pye,
J. P.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.;
Reider, P. J., J. Am. Chem. Soc., 1997, 119, 6207-6208.
[23] Schaarsmidt, D.; Lang H., Organometallics, 2013, 32, 5668-5704.
[24] (a) Riant, O.; Samuel, O.; Kagan, H. B.; J. Am. Chem. Soc., 1993,
115, 5835-5836; (b) Riant, O.; Samuel, O.; Flessner, T.; Taudine,
S.; Kagan, H. B., J. Org. Chem., 1997, 62, 6733-6745.
[25] Zhang, S.; Zhang, D.; Liebeskind L. S., J. Org. Chem., 1997, 62,
2312-2313.
[26] (a) Weyl, H., Methoden der Organischen Chemie, Müler, E., Ed,
Thieme, Stuttgart, 1964, Vol XII/2; (b) Edmundson, R. S., in
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