Carbamate-based P,O-ligands for asymmetric allylic alkylations

Article abstract of DOI:10.1016/j.tet.2020.131246

Herein we report the design and successful catalytic application of modified Trost-ligands in asymmetric allylic alkylation (AAA) reactions. A small set of carbamate-monophosphine P,O-ligands has been prepared in a straightforward two-step synthetic procedure. After optimization of the reaction conditions, high catalytic activities and excellent enantioselectivity up to >99% have been attained.

Full text of DOI:10.1016/j.tet.2020.131246

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Carbamate-based P,O-ligands for asymmetric allylic alkylations
Ádám Márk Pálvölgyi, Michael Schnürch, Katharina Bica-Schröder
PII:
S0040-4020(20)30388-4
https://doi.org/10.1016/j.tet.2020.131246
TET 131246
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 March 2020
Revised Date: 22 April 2020
Accepted Date: 25 April 2020
Please cite this article as: Pálvölgyi ÁáMá, Schnürch M, Bica-Schröder K, Carbamate-based P,O-ligands
for asymmetric allylic alkylations, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131246.
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Graphical Abstract
Carbamate-based P,O-ligands for
Leave this area blank for abstract info.
asymmetric allylic alkylations
Ádám Márk Pálvölgyi, Michael Schnürch and Katharina Bica-Schröder*
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060,
Vienna, Austria

Tetrahedron
journal homepage: www.elsevier.com
Carbamate-based P,O-ligands for asymmetric allylic alkylations
Ádám Márk Pálvölgyia, Michael Schnürcha and Katharina Bica-Schrödera
aInstitute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060, Vienna, Austria
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the design and successful catalytic application of modified Trost-ligands in
asymmetric allylic alkylation (AAA) reactions. A small set of carbamate-monophosphine P,O-
ligands has been prepared in a straightforward two-step synthetic procedure. After optimization
of the reaction conditions, high catalytic activities and excellent enantioselectivity up to >99%
have been attained.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Chiral P,O-ligands
Tsuji-Trost reaction
Asymmetric synthesis
Palladium-catalyzed allylation
———
Corresponding author. e-mail: katharina.schroeder@tuwien.ac.at
1

1. Introduction
two-step procedure (Scheme 1). At first, the chiral diamines have
been reacted with the corresponding anhydride or chloroformate
by using a temporary masking on one of the amino groups by
means of HCl salt, resulting in the corresponding mono
carbamate-protected intermediates as major products. These
intermediates (5-10) have then been coupled with 2-
(diphenylphosphino)-benzoic acid via simple DCC/DMAP
coupling procedure, affording the chiral ligand 11-16 in good
overall yields (Scheme 1).
Highly functionalized and optically active allylic
intermediates are invaluable building blocks for the total
synthesis of numerous biologically active compounds.1,2,3,4 In this
field, palladium-catalyzed asymmetric allylic alkylation (AAA)
provides a useful synthetic tool and thanks to its indisputable
advantages, such as mild reaction conditions and operational
simplicity, it is still one of the most relevant strategies for the
synthesis of substituted allylic compounds.5 The class of C2-
symmetric diamine-based chiral diphosphines, such as 1 and 2
have been already proven to be really efficient ligands for
asymmetric allylic alkylation, resulting in high catalytic activities
and excellent stereocontrol.6
Scheme 1. Design of carbamate-based P,O-ligands. Reagents and conditions: (a) HCl,
anhydride or chloroformate, anhydrous MeOH or EtOH, 0-25˚C (b) 2-PPh2-PhCOOH,
DCC/DMAP, anhydrous CH2Cl2, 0-25˚C.
In order to investigate whether the carbamate carbonyl group
plays an important role in the complexation, the unprotected
analogues of ligand 11 and 14 have also been synthesized
(Scheme 2).
Figure 1. Typical Trost-type bidentate P,P-ligands for AAA reactions.
Despite the wide variety of other available chiral ligands
including (bis)oxazolines,7,8 amino acid-derived ligands,9,10 or
diphosphines featuring axial and planar chirality,11,12,13,14 the
Trost-type chiral diamine-based P,P-ligands still remain one of
the most important tools in the field of asymmetric allylic
alkylation. While such ligands have been already quite well
studied, the chiral diamine-based monophosphine-analogues did
not gain too much of attention. In 1994, Trost reported the first
application of chiral diamine-based analogues bearing only one
phosphine unit for asymmetric allylations, however low
reactivities (20-50% yield) and poor enantioselectivity (< 20%
ee) were observed.15 Since then, only a few examples in the area
of chiral diamine-based monophoshine ligands have been
reported, but the enantio-selectivity could not be improved
significantly in any case. In 2000, Kim et al. reported the
synthesis of novel P,N-mono-phosphine ligands based on an
(R,R)-1,2-diaminocyclohexane (R,R-DACH) core and in the
absence of the second phosphine unit, they observed strong P,N-
and P,O-chelation.16 In contrast with the previous results, they
could reach significantly higher enantio-selectivity (up to 75%
ee), indicating that there is still potential in such diamine-based
P,N and P,O-ligands for asymmetric allylic allylations.
Scheme 2. Deprotection of carbamate ligands 11 and 14
After the successful synthesis and characterization of the
ligands, we investigated the asymmetric allylic alkylation of
racemic (E)-1,3-diphenylallyl acetate (19) with dimethyl
malonate as a benchmark reaction (Table 1). The initial screening
aiming to find the most suitable solvent and base has been carried
out by using 1.0 mol% of Pd-precursor and 2.2 mol% chiral
ligand (11) at room temperature for 24 hours. As it can be seen
from Table 1, ether-type solvents like THF and MTBE afforded
the desired product 20a with higher enantioselectivity than
dichloromethane, without significantly effecting the catalytic
activity (Table 1, entries 1 vs. 4-5.). To our delight, the product
20a could be obtained in 93% isolated yield and excellent
enantioselectivity
Inspired by these results and based on our previous success
with carbamate-based ligands in asymmetric transfer
hydrogenations,17 herein we report the synthesis and application
of chiral diamine-based, carbamate-derived monophosphine
ligands for asymmetric allylic allylations.
(> 99% ee) by using diethyl ether as solvent in the presence of
the chiral ligand 11 at room temperature (Table 1, entry 6.).
Moreover, the reaction time could be also reduced to 6 hours
2. Results and Discussion
Starting from the cheap and easily accessible chiral pool of
diamines 3-4, a small library of carbamate-monophosphine
ligands (11-16) has been prepared according to a straightforward
without
in
any loss
catalytic
activity
entries 6
(Table 1,
vs. 7.).
Similarly, high enantioselectivity was observed in toluene albeit
the catalytic activity was significantly decreased compared to
those reactions in other solvents (Table 1, entries 6-7 vs. 8).
2

Table 1. Parameter optimization for the AAA reaction of the allylic acetate 19.
alkylation of the racemic (E)-1,3-diphenylallyl acetate (19) under
the previously optimized reaction conditions. As it can be seen
from Scheme 3, the corresponding products could be obtained
with high isolated yields (87-98%) and excellent stereocontrol
(84 - >99%). While the C-allylated products have been formed
mainly in (R)-configuration, interestingly the reaction with
a
Performed with 0.50 mmol rac-(E)-1,3-diphenylallyl acetate (19) using 0.011
Entrya
Solvent
CH2Cl2
CH2Cl2
EtOAc
THF
Conversion (%)b
Yield (%)b
ee (%)c
49 (R)
48 (R)
70 (R)
73 (R)
75 (R)
>99 (R)
>99 (R)
>99 (R)
mmol (2.2 mol%) chiral ligand 11, 0.005 mmol (1.0 mol%) [Pd(C3H5)Cl]2, 0.60 mmol
(1.2 equiv.) dimethyl malonate, 1.0 mmol (2.0 equiv.) BSA and 2 mg (2 mol%) KOAc in
1 mL solvent at 25°C for 24 hours.
1
2d
3
98
75
85
91
96
95
95
60
95
70
b Determined by GC analysis. Isolated yield in parenthesis.
c Determined by chiral HPLC analysis using Diacel Chiralcel IB column.
d Cs2CO3 instead of BSA/KOAc.
55
4
89
e Reaction time was 6 hours.
5
MTBE
Et2O
93
After determining the optimal reaction conditions, the
catalytic efficiency of the chiral ligands was also evaluated
6
94 (93)
94 (93)
57
7e
Et2O
8
Toluene
Effect of ligand structure on the yield and enantioselectivity
100
diethyl-acetamido-malonate resulted in the formation of the (S)-
20d as a major product, indicating that the -NHAc group might
alter the chelation mode during the reaction. The high catalytic
activity and selectivity were eventually retained by using N-
nucleophiles as well, affording the amines 20g-i in high yields
and 84-92% ee. For all amine products, the (S)-enantiomer has
been predominantly formed.
Yield
Enantioselectivity
80
60
40
20
0
Scheme 3. Screening of different nucleophiles for the AAA reaction of allylic acetate 19
by using 0.50 mmol substrate, 0.011 mmol (2.2 mol%) chiral ligand 11, 0.005 mmol (1.0
mol%) [Pd(C3H5)Cl]2, 0.60 mmol (1.2 equiv.) nucleophile, 1.0 mmol (2.0 equiv.) BSA
and 2 mg (2 mol%) KOAc in 1 mL Et2O at 25°C for 6 hours. Yields refer to the pure
products after preparative TLC/column chromatography. Enantiomeric excess values
have been determined by chiral HPLC analysis. Absolute configuration was determined
by comparison of the optical rotation with literature data. a Without BSA/KOAc.
11
12
13
14
15
16
17
18
Chiral ligand
(Figure 2).
Figure 2. Catalyst screening for the AAA reaction of allylic acetate 19. The reaction
conditions and monitoring were identical to those used in Table 1, entry 7.
Eventually, we further expanded our reaction scope with the
asymmetric allylic alkylation of racemic 3-acetoxy-1-
cyclohexene (21). By using diphenyl malonate as nucleophile,
the product 22c could be isolated in high yield and excellent
enantiopurity (>99% ee), while the other products could be also
obtained in good yields and moderate to good enantioselectivity
(Scheme 4).
The catalyst screening revealed that the (R,R)-1,2-diamino-
cyclohexane based ligands are in general superior over the (R,R)-
1,2-diphenylethylenediamine analogues yielding the desired
product 20a with slightly higher yields and significantly higher
enantiomeric excess (ligand 11-13 vs. 14-16). Moreover, the
presence of the bulky Boc-group was also found to be beneficial.
Importantly, the compound 17 and 18 – the corresponding
amino-monophosphine analogues of ligand 11 and 14 – gave
basically no product under identical conditions, indicating that
the presence of the carbamate unit is indeed crucial for the
complex formation.
Pd[(C3H5)Cl]2 (1.0 mol%)
OAc
Chiral ligand 11 (2.2 mol%)
Nu
NuH
(+BSA/KOAc)
Et2O
21
22a-d
Encouraged by these results, a series of different nucleophiles
have been successfully applied for the asymmetric allylic
Sche
me 4.
Screen
ing of
differe
nt
COOMe
COOMe
COOBn
COOBn
COOEt
COOEt
H
N
Pd[(C3H5)Cl]2 (1.0 mol%)
Ph
Chiral ligand 11 (2.2 mol%)
Nu
Ph
OAc
Ph
NuH
(+BSA/KOAc)
Et2O
22da
Ph
Ph
22a
86% yield
86% ee (R)
22b
88% yield
83% ee (R)
22c
90% yield
>99% ee (R)
89% yield
19
20a-i
60% ee (S)
MeOOC
COOMe
EtOOC
Ph
COOEt
Ph
BnOOC
COOBn
Ph
Ph
Ph
Ph
20a
20b
20c
93% yield
94% yield
98% yield
>99% ee (R)
99 ee (R)
>99 ee (R)
NHAc
EtOOC
MeOC
Ph
COMe
Ph
MeOOC
Ph
COOMe
COOEt
Ph
Ph
Ph
20d
20e
20f
98% yield
89% yield
91% yield
92% ee (S)
92% ee (R)
>99 ee (R)
N
N
Ph
Ph
NH
Ph
3
Ph
Ph
Ph
Ph
20ga
20ha
20ia
98% yield
92% ee (S)
96% yield
84% ee (S)
87% yield
92% ee (S)

nucleophiles for the AAA reaction of allylic acetate 21 by using 0.50 mmol substrate,
0.011 mmol (2.2 mol%) chiral ligand 11, 0.005 mmol (1.0 mol%) [Pd(C3H5)Cl]2, 0.60
mmol (1.2 equiv.) nucleophile, 1.0 mmol (2 equiv.) BSA and 2 mg (2 mol%) KOAc in 1
mL Et2O at 25 °C for 24 hours. Yields refer to the pure products after column
chromatography. Enantiomeric excess values have been determined by chiral HPLC
analysis. Absolute configuration was determined by comparison of the optical rotation
with literature data. a Without BSA/KOAc.
reported in Hertz (Hz). The following abbrevia-tions were used
to explain the multiplicities: s = singlet, d = doublet, t = triplet, q
= quartet, qvin. = qvintett, sex = sextet, m = multiplet, brs =
broad singlet. Melting points above room tempe-rature were
measured on an automated melting point system OPTI MELT of
Stanford ResearchSystems and are uncorrected. Infrared spectra
were recorded on
a Perkin-Elmer Spectrum 65 FT IR
spectrometer equipped with a specac MK II Golden Gate Single
Reflection ATR unit. HR-MS analysis was carried out from
methanol solutions (c = 10 ppm) by using an HTCPAL system
auto sampler (CTC Analytics AG), an Agilent 1100/1200 HPLC
with binary pumps, a degasser and a column thermostat (Agilent
Technologies) and an Agilent 6230 AJS ESI-TOF mass
spectrometer. Chiral HPLC analysis were carried out on a
DIONEX UPLC, equipped with a PDA plus detector (190-360
nm) using Chiralcel Diacel IB, AS-H, OJ and OD columns (250
x 4.60 mm) as stationary phases. GC measurements have been
performed on a Thermo Scientific Focus instrument, equipped
with an FID detector using a BGB5 column. Optical rotation was
measured on an Anton Paar MCP500 polarimeter at the specific
conditions and the results have been compared to literature
values. Concentrations are given in g / 100 ml.
In order to get more insight into the chelation mode, 31P{1H}
NMR analysis of the in-situ formed (π-allyl)Pd complex 11* was
carried out by using 1.0 equivalent of [Pd(C3H5)Cl]2 and 2.0
equivalents of chiral ligand 11 (Pd/L* = 1). As shown in Figure 3,
only one doublet of the complex at δ = 25.6 ppm with a coupling
constant of 2J(P,O) = 37.1 Hz was formed. This indicates, that
basically only one type of chelation takes place and there is no
competition between the different complexation modes which can be
sometimes observed with the P,P-bidentate Trost ligands.18 Based on
the literature, the major complex should have a P,O-chelation motif
in which the carboxamide oxygen acts as an O-ligand. While there is
no direct proof for the carbamate unit participating in the chelation
mode; based on the results, its presence is certainly crucial in order
to reach high enantioselectivity.
4.2. Synthesis of mono-protected carbamates (5-10)
4.2.1. tert-Butyl ((1R,2R)-2-aminocyclohexyl)carbamate (5)
Figure 3. 31P {1H} NMR spectra of the pure chiral
ligand 11 (top, green), and the in-situ formed (π-
allyl)Pd complex 11* (bottom, red) showing only one
major chelation mode.
Prepared according to the modified literature procedure.19
(1R,2R)-DACH (780 mg, 6.83 mmol, 1.0 equiv.) was dissolved
in anhydrous MeOH (15 mL) and cooled via ice bath. 37% HCl
(600 µL, 7.18 mmol, 1.05 equiv.) was diluted with 5 mL
anhydrous MeOH, and it was added to the reaction mixture
dropwise at 0 ˚C. The mixture was allowed to warm up, and it
was stirred for 30 minutes. Then, di-tert-butyl dicarbonate (2.22
g, 10.25 mmol, 1.50 equiv.) in anhydrous MeOH (10 mL) was
added dropwise at 0 ˚C. The mixture was stirred at room
temperature for 4 hours. After evaporation of the MeOH, water
was added, and the insoluble byproduct was filtered off. The
aqueous layer was basified with 2 M NaOH, extracted with
CH2Cl2 (4×), dried over Na2SO4 and concentrated in vacuo,
affording compound 5 as a white solid, which was found to be
3. Conclusion
Herein, we have reported the synthesis and application of
carbamate-based
P,O-ligands
for
palladium-catalyzed
asymmetric allylic alkylation. After optimization of the catalyst
structure and reaction conditions, the chiral ligand 11 bearing a
bulky Boc-protecting group could be successfully applied for the
AAA reaction of an aromatic and an aliphatic model substrate by
using a series of different C- and N-nucleophiles. High isolated
yields and excellent stereocontrol could be attained for all
products of racemic (E)-1,3-diphenylallyl acetate (19), while
moderate to excellent enantioselectivities were obtained in the
AAA reaction of racemic 3-acetoxy-1-cylohexene (21).
1
pure without further purification (1.29 g, 88% yield). H NMR
(400 MHz, CDCl3)δ: 4.43 (brs, 1H, NHCOO), 3.13 (brs, 1H,
CH-NHCOO), 2.32 (td, J = 10.2 Hz, 1H, CH-NH2), 1.98 (t, J =
6.0 Hz, 2H, CH2-CH), 1.70 (d, J = 6.02 Hz, 2H, CH2-CH), 1.45–
1.40 (m, 11H, C-(CH3)3, CH-NH2), 1.28–1.07 (m, 4H, CH2-CH2);
13C NMR (100 MHz, CDCl3)δ: 156.3 (NHCOO), 79.4 (C-
(CH3)3), 57.9 (CH-NHCOO), 55.8 (CH-NH2), 35.4 (CH2-CH),
33.0 (CH2-CH), 28.5 (C-(CH3)3), 25.3 (CH2-CH2), 25.2 (CH2-
CH2).
4. Experimental section
4.1. General remarks
4.2.2. Isobutyl ((1R,2R)-2-aminocyclohexyl)carbamate (6)
All reagents were purchased from commercial suppliers and
used without further purification unless noted otherwise. Solvents
intended for anhydrous reactions were pre-distilled and
desiccated on Al2O3 columns (PURESOLV, Innovative
Technology). Chromatography solvents were distilled prior to
use. Column chromatography was performed on standard manual
glass columns using silica gel from Merck (40-63 μm). TLC-
analysis was carried out using precoated and aluminum-backed
plates purchased from Merck (silica gel 60 F254). UV active
compounds were detected at 254 nm, while non-UV active
compounds were detected by using potassium permanganate
Prepared according to the procedure for the synthesis of
compound 5 by using (1R,2R)-DACH (456 mg, 4.0 mmol, 1.0
equiv.), 37% HCl (351 µL, 4.2 mmol, 1.05 equiv.), isobutyl
chloroformate (778 µL, 6.0 mmol, 1.50 equiv.) and anhydrous
MeOH (10 + 5 + 10 mL) to afford product 6 as a light brown
solid, which was found to be pure without further purification
(705 mg, 82% yield). M.p.: 100-101 °C; HRMS (ESI-TOF)
m/z: [M+H]+ calculated for C11H23N2O2 215.1760, found
215.1762; ꢀꢂꢁꢃ: +10.5 (c 1.0, CHCl3); IR (νmax/cm-1): 3358 (N-H
ν), 2904 (C-H ν), 16852 (C=O ν), 1607 (C-C ν), 1511 (N-H δ),
1437 (CH2 δ); 1242 (C-O ν); 1H NMR (400 MHz, CDCl3)δ:
4.65 (brs, 1H, NHCOO), 3.82 (d, J = 8.0 Hz, 2H, CH2-
CH(CH3)2), 3.15 (brs, 1H, CH-NHCOO), 2.33 (td, J = 10.2 Hz,
1H, CH-NH2), 2.00–1.92 (m, 3H, CH2-CH, CH2-CH(CH3)2),
1.71–1.68 (m, 2H, CH2-CH), 1.24–1.02 (m, 6H, CH2-CH2, CH-
1
solution as staining agent. H, 13C and 31P NMR spectra were
recorded from CDCl3 and MeOD solutions on a Bruker AC 200
(200 MHz) or Bruker Advance UltraShield 400 (400 MHz)
spectrometer and chemical shifts (δ) are reported in ppm, using
tetramethylsilane as internal standard. Coupling constants (J) are
4

NH2), 0.85 (d, J = 4.0 Hz, 6H, CH2-CH(CH3)2); 13C NMR (100
MHz, CDCl3)δ: 157.0 (NHCOO), 71.0 (CH2-CH(CH3)2), 57.9
(CH-NHCOO), 55.4 (CH-NH2), 35.2 (CH2-CH), 32.9 (CH2-CH),
28.0 (CH2-CH(CH3)2), 25.2 (CH2-CH2), 19.1 (CH2-CH(CH3)2).
4.2.6. Benzyl ((1R,2R)-2-amino-1,2-diphenylethyl)carbamate
(10)
Prepared according to the synthesis of compound 7 by using
(1R,2R)-DPEN (2.36 mmol, 500 mg), 10 mL anhydrous EtOH,
and benzyl-phenyl-carbonate (2.36 mmol, 540 mg, 1.0 equiv.),
affording the product 10 as an off-white solid (570 mg, 70%
yield). 1H NMR (400 MHz, CDCl3)δ: 7.29–7.20 (m, 15H, H-
arom), 6.05 (d, J = 7.24 Hz, 1H, CH-NHCOO), 4.91 (s, 2H, CH2-
arom), 4.83 (brs, 1H, NHCOO), 4.29 (s, 1H, CH-NH2), 1.32 (brs,
2H, CH-NH2); 13C NMR (100 MHz, CDCl3)δ: 156.3 (NHCOO),
142.3
(C-arom), 141.0 (C-arom), 136.9 (C-arom), 128.8 (C-
arom),128.7 (C-arom) 128.2 (C-arom), 127.8 (C-arom), 127.6
(C-arom), 126.9 (C-arom), 126.6 (C-arom), 66.8 (CH2-arom),
60.6 (CH-NHCOO), 60.0 (CH-NH2).
4.2.3. Benzyl ((1R,2R)-2-aminocyclohexyl)carbamate (7)
Prepared according to the literature procedure.20 (1R,2R)-DACH
(456 mg, 4.0 mmol, 1.0 equiv.) was dissolved in 10 mL
anhydrous EtOH, and the solution of benzyl-phenyl-carbonate
(790 µL, 4.0 mmol, 1.0 equiv.) in anhydrous EtOH (10 mL) was
added dropwise at room temperature. The reaction mixture was
stirred for 24 hours and the EtOH was removed in vacuo. 10 M
HCl (960 µL) was added, the formed precipitate was filtered off
and it was successively washed with diethyl ether (2×) and H2O
(2×). Then, it was treated with a solution of NaOH (355 mg) in
H2O (2.40 mL). In a few minutes, the precipitate was filtered off,
and it was washed with H2O (3×10 mL), affording compound 7
as an off-white solid, which was found to be pure without further
purifications (655 mg, 66% yield). 1H NMR (200 MHz,
CDCl3)δ: 7.26–7.18 (m, 5H, H-arom), 4.99 (brs, 3H, arom-CH2,
CH-NHCOO), 3.11–3.01 (m, 1H, NHCOO), 2.28 (td, J = 10.2
Hz, 1H, CH-NH2), 1.91–1.78 (m, 2H, CH2-CH), 1.60–1.57 (m,
2H, CH2-CH), 1.26–0.95 (m, 6H, CH2-CH2, CH-NH2);13C NMR
(100 MHz, CDCl3)δ: 156.7 (NHCOO), 136.6 (C-arom), 128.5
(C-arom), 128.1 (C-arom), 66.7 (arom-CH2), 58.2 (CH-
NHCOO), 55.4 (CH-NH2), 35.3 (CH2-CH), 32.8 (CH2-CH), 25.1
(CH2-CH2), 25.0 (CH2-CH2).
4.3. General procedure for the ligand synthesis (11-16)
Compound 11-16 have been prepared according to the literature
procedure.16 To the solution of 2-(diphenylphosphino)benzoic
acid (1.05 equiv.) in anhydrous CH2Cl2 at 0°C, DCC (2.0 mmol,
1.05 equiv.) was added and the mixture was stirred at 0˚C for 15
minutes. To this, the solution of monoprotected carbamate 5-10
(1.0 equiv.) and DMAP (0.1 equiv.) in anhydrous CH2Cl2 was
slowly added at 0 °C. The mixture was allowed to warm up to
room temperature and it was stirred overnight. The reaction
mixture was cooled at 5˚C for 1 hour, filtered and washed with
cold CH2Cl2 to remove the majority of the dicyclohexyl urea. The
filtrate was successively washed with 0.5 M HCl (3×), sat.
NaHCO3 (3×) and water (2×). After evaporation of the solvent,
the crude products were purified by column chromatography.
4.2.4. tert-Butyl ((1R,2R)-2-amino-1,2-diphenylethyl)carbamate
(8)
Prepared according to the procedure for the synthesis of
compound 5 by using (1R,2R)-DPEN (1.93 g, 9.1 mmol, 1.0
equiv.), 37% HCl (900 µL, 10.8 mmol, 1.05 equiv.), di-tert-butyl
dicarbonate (2.93 g, 13.5 mmol, 1.50 equiv.) and anhydrous
MeOH (30 + 15 + 15 mL). After the work-up, the obtained crude
product was dissolved in ethyl acetate and the solid residue was
removed over a patch of silica. The solvent was removed under
reduced pressure to yield 8 as a white solid (2.18 g, 77% yield).
1H NMR (400 MHz, CDCl3)δ: 7.28–7.14 (m, 10H, H-arom),
5.80 (d, J = 8.51 Hz, 1H, CH-NHCOO), 4.77 (brs, 1H, NHCOO),
4.24 (s, 1H, CH-NH2), 1.37 (s, 2H, CH-NH2), 1.22 (s, 9H, C-
(CH3)3); 13C NMR (100 MHz, CDCl3)δ: 155.9 (NHCOO), 142.4
(C-arom), 141.2 (C-arom), 128.7 (C-arom), 128.5 (C-arom),
127.6 (C-arom), 127.4 (C-arom), 127.0 (C-arom), 126.6 (C-
arom), 79.4 (C-(CH3)3), 60.0 (CH-NHCOO, CH-NH2), 28.5 (C-
(CH3)3).
4.3.1. tert-Butyl ((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)
-cyclohexyl)carbamate (11)
Prepared from compound 5 following the general procedure on a
1.9 mmol scale. Flash column chromatography (silica gel, light
petrol:ethyl-acetate 4:1) afforded 11 as a white solid (870 mg,
91% yield). 1H NMR (400 MHz, CDCl3)δ: 7.51 (brs, 1H,
NHCO), 7.25–7.20 (m, 12H, H-arom), 6.86 (brs, 1H, H-arom),
6.38 (brs, 1H, H-arom), 4.74 (d, J = 8.0 Hz, 1H, NHCOO), 3.61–
3.58 (m, 1H, CH-NHCO), 3.29–3.26 (m, 1H, CH-NHCOO), 1.93
(d, J = 8.0 Hz, 1H, CH2a-CH), 1.82 (d, J = 8.0 Hz, 1H, CH2b-
CH), 1.63 (brs, 1H, CH2a-CH), 1.55 (brs 1H, CH2b-CH), 1.31 (s,
9H, C-(CH3)3), 1.20–1.12 (m, 3H, CH2-CH2a), 0.92–0.88 (m, 1H,
CH2- CH2b); 31P NMR (167 MHz, CDCl3)δ: −9.15; 13C NMR
(100 MHz, CDCl3)δ: 169.2 (NHCO), 156.9 (NHCOO), 141.1
(C-arom), 140.9 (C-arom), 137.8 (C-arom), 134.5 (C-arom),
134.2 (C-arom), 130.3 (C-arom), 128.7 (C-arom), 127.6 (C-
arom), 79.7 (C-(CH3)3), 55.1 (CH-NHCO), 54.3 (CH-NHCOO),
33.0 (CH2-CH), 32.4 (CH2-CH), 28.6 (C-(CH3)3), 25.2 (CH2-
CH2), 24.7 (CH2-CH2).
4.2.5. Isobutyl ((1R,2R)-2-amino-1,2-diphenylethyl)carbamate
(9)
Prepared according to the procedure for the synthesis of
compound 5 by using (1R,2R)-DPEN (2.36 mmol, 500 mg), 37%
HCl (207 µL 2.48 mmol, 1.05 equiv.) and isobutyl chloroformate
(460 µL, 3.54 mmol, 1.50 equiv.) and anhydrous MeOH (10 + 5
+ 5 mL). After the work-up, the obtained crude product was
purified by column chromatography (15 g silica, light petrol:
ethyl acetate 1:1 + 1 V/V % Et3N), affording 9 as a white powder
4.3.2. Isobutyl ((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)-
cyclohexyl)carbamate (12)
Prepared from compound 6 following the general procedure on a
1.4 mmol scale. Flash column chromatography (silica gel, light
petrol: ethyl-acetate 4:1) afforded 12 as a white solid (610 mg,
87% yield). M.p.: 90-92 °C; HRMS (ESI-TOF) m/z: [M+H]+
1
(479 mg, 65% yield). H NMR (400 MHz, CDCl3)δ: 7.31–7.18
(m, 10H, H-arom), 5.91 (d, J = 7.84 Hz, 1H, CH-NHCOO), 4.80
(brs, 1H, NHCOO), 4.29 (s, 1H, CH-NH2), 3.64 (s, 2H, CH2-
CH(CH3)2), 1.74 (s, 1H, CH2-CH(CH3)2), 1.46 (brs, 2H, CH-
NH2), 0.78 (s, 5H, CH2-CH(CH3)2), 0.52 (s, 1H, CH2-CH(CH3)2);
13C NMR (100 MHz, CDCl3)δ: 156.7 (NHCOO), 142.3 (C-
arom), 141.1 (C-arom), 128.8 (C-arom), 128.7 (C-arom), 127.8
(C-arom), 127.6 (C-arom), 127.0 (C-arom), 126.6 (C-arom), 71.2
(CH2-CH(CH3)2), 60.4 (CH-NHCOO), 60.0 (CH-NH2), 28.2
(CH2-CH(CH3)2), 19.2 (CH2-CH(CH3)2).
Calculated for C30H36N2O3P 503.2464, found 503.2463; ꢀꢁꢂꢃ
:
+35.5 (c 1.0, CHCl3); IR (νmax/cm-1): 3332 (N-H ν), 2930 (C-H
ν), 1680 (C=O ν), 1635 (C=O ν), 1526 (N-H δ), 1452 (C=C ν),
1432 (CH2 δ); 1240 (C-O ν), 1150 (C-N ν), 743 (C-H arom δ),
695 (C-H arom δ); 1H NMR (400 MHz, CDCl3)δ: 7.48 (brs, 1H,
NHCO), 7.25–7.20 (m, 12H, H-arom), 6.88 (brs, 1H, H-arom),
6.16 (brs, 1H, H-arom), 5.01 (d, J = 8.0 Hz, 1H, NHCOO), 3.73–
5

3.63
78% yield). M.p.: 106-108 °C HRMS (ESI-TOF) m/z: [M+H]+
calculated for C38H38N2O3P 601.2620, found 601.2619 ꢀꢁꢂꢃ
(m, 3H, CH-NHCO, CH2-CH(CH3)2), 3.34–3.32 (m, 1H, CH-
NHCOO), 1.87–1.85 (m, 1H, CH2-CH(CH3)2), 1.82–1.80 (m, 2H,
CH2-CH), 1.65–1.50 (m, 2H, CH2-CH), 1.26–1.11 (m, 4H, CH2-
CH2), 0.81 (d, J = 8.0 Hz, 6H, CH2-CH(CH3)2); 31P NMR (167
MHz, CDCl3)δ: −9.78; 13C NMR (100 MHz, CDCl3)δ: 169.2
(NHCO), 157.3 (NHCOO), 141.2 (C-arom), 140.9 (C-arom),
137.6 (C-arom), 137.3 (C-arom), 136.4 (C-arom), 136.2 (C-
arom), 133.7 (C-arom), 130.2 (C-arom), 128.4 (C-arom), 127.3
(C-arom), 71.0 (CH2-CH(CH3)2), 55.0 (CH-NHCO), 54.0 (CH-
NHCOO), 32.7 (CH2-CH), 32.0 (CH2-CH), 27.9 (CH2-
CH(CH3)2), 24.7 (CH2-CH2), 24.5 (CH2-CH2), 19.0 (CH2-
CH(CH3)2).
:
+43.4 (c 1.0, CHCl3); IR (νmax/cm-1): 3321 (N-H ν), 2930 (C-H
ν), 1680 (C=O ν), 1641 (C=O ν), 1530 (N-H δ), 1451 (C=C ν),
1243 (C-O ν), 1173 (C-N ν), 740 (C-H arom δ), 696 (C-H arom
δ); 1H NMR (400 MHz, CDCl3)δ: 7.74 (brs, 1H, NHCO), 7.49–
7.33 (m, 20H, H-arom), 7.12–7.08 (m, 1H, H-arom), 7.08–6.89
(m, 3H, H-arom), 6.25 (d, J = 8.0 Hz, 1H, CH-NHCO), 5.45 (t, J
= 8.0 Hz, 1H, CH-NHCOO), 5.09 (t, J = 12.0 Hz, 1H, NHCOO),
3.91 (d, J = 6.0 Hz, 2H, CH2-CH(CH3)2), 1.93 (brs, 1H, CH2-
CH(CH3)2), 1.38–1.34 (m, 1H, CH2-CH(CH3)2), 0.99–0.96 (m,
5H,
CH2-CH(CH3)2);
31P NMR (167 MHz, CDCl3)δ: −11.22; 13C NMR (100 MHz,
CDCl3) δ: 169.9 (NHCO), 157.3 (NHCOO), 141.4 (C-arom)
139.7 (C-arom), 138.2 (C-arom), 134.5 (C-arom), 134.1 (C-
arom), 134.0 (C-arom), 133.8 (C-arom), 130.6 (C-arom), 128.9
(C-arom), 128.5 (C-arom), 127.8 (C-arom), 127.6 (C-arom) 71.5
(CH2-CH(CH3)2), 61.7 (CH-NHCO), 59.4 (CH-NHCOO), 28.2
(CH2-CH(CH3)2), 19.3 (CH2-CH(CH3)2).
4.3.3. Benzyl ((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)-
cyclohexyl)carbamate (13)
Prepared from compound 7 following the general procedure on a
1.27 mmol scale. Flash column chromatography (silica gel, light
petrol: ethyl-acetate 4:1) afforded 13 as a white solid (540 mg,
83% yield). M.p.: 101-103 °C; HRMS (ESI-TOF) m/z: [M+H]+
4.3.6. Benzyl ((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)-
1,2-diphenylethyl)carbamate (16)
calculated for C33H34N2O3P 537.2307, found 537.2310; ꢀꢁꢂꢃ
:
+30.1 (c 1.0, CHCl3); IR (νmax/cm-1): 3301 (N-H ν), 2923 (C-H
ν), 1691 (C=O ν), 1637 (C=O ν), 1529 (N-H δ), 1450 (C=C ν),
1436 (CH2 δ); 1250 (C-O ν), 1158 (C-N ν), 743 (C-H arom δ),
694 (C-H arom δ); 1H NMR (400 MHz, CDCl3)δ: 7.45 (brs, 1H,
NHCO), 7.31–7.21 (m, 17H, H-arom), 6.94–6.92 (m, 1H, H-
arom), 6.27 (d, J = 8.0 Hz, 1H, H-arom), 5.33 (d, J = 8.0 Hz, 1H,
NHCOO), 5.05 (s, 2H, arom-CH2) 3.79–3.68 (m, 1H, CH-
NHCO), 3.38–3.36 (m, 1H, CH-NHCOO), 2.05 (m, 1H, CH2a-
CH), 1.88–1.86 (m, 1H, CH2b-CH), 1.71–1.69 (m, 2H, CH2-CH),
1.25–1.22 (m, 3H, CH2-CH2a), 0.96–0.89 (m, 1H, CH2-CH2b); 31P
NMR (167 MHz, CDCl3)δ: −9.34; 13C NMR (100 MHz,
CDCl3)δ: 169.5 (NHCO), 157.1 (NHCOO), 141.5 (C-arom),
141.0 (C-arom), 137.9 (C-arom), 136.7 (C-arom), 134.4 (C-
arom), 134.2 (C-arom), 133.9 (C-arom), 133.8 (C-arom), 130.3
(C-arom), 128.8 (C-arom), 128.1 (C-arom), 127.5 (C-arom), 66.7
(arom-CH2), 55.6 (CH-NHCO), 54.0 (CH-NHCOO), 32.9 (CH2-
CH), 32.2 (CH2-CH), 24.9 (CH2-CH2), 24.8 (CH2-CH2).
Prepared from compound 10 following the general procedure on
a 1.0 mmol scale. Flash column chromatography (silica gel, light
petrol: ethyl-acetate 4:1) afforded 16 as a white solid (505 mg,
75% yield). M.p.: 100-104 °C; HRMS (ESI-TOF) m/z: [M+H]+
calculated for C41H36N2O3P 635.2464, found 635.2466; ꢀꢁꢂꢃ
:
+47.8 (c 1.0, CHCl3); IR (νmax/cm-1): 3311 (N-H ν), 3010 (C-H
ν), 1695 (C=O ν), 1630 (C-C ν), 1525 (N-H δ), 1450 (C=C ν),
1
1170 (C-N ν), 742 (C-H arom δ), 696 (C-H arom δ); H NMR
(400 MHz, CDCl3)δ: 7.44 (brs, 1H, NHCO), 7.21–7.03 (m, 26H,
H-arom), 6.86 (brs, 1H, H-arom), 6.71 (d, J = 8.0 Hz, 2H, H-
arom), 6.28 (d, J = 8.0 Hz, 1H, CH-NHCO), 5.24 (t, J = 8.0 Hz,
1H, CH-NHCOO), 4.99–4.85 (m, 3H, NHCOO, CH2-arom); 31P
NMR (167 MHz, CDCl3)δ: −11.16; 13C NMR (100 MHz,
CDCl3) δ: 169.8 (NHCO), 156.7 (NHCOO), 141.4 (C-arom)
139.4 (C-arom), 137.3 (C-arom), 136.8 (C-arom), 136.5 (C-
arom), 134.3 (C-arom), 134.0 (C-arom), 133.8 (C-arom), 133.5
(C-arom), 130.4 (C-arom), 128.8 (C-arom), 128.6 (C-arom),
128.5 (C-arom), 128.3 (C-arom), 127.9 (C-arom), 127.8 (C-
arom), 127.6 (C-arom), 127.5 (C-arom), 66.7 (CH2-arom), 61.8
(CH-NHCO), 59.2 (CH-NHCOO).
4.3.4. tert-Butyl((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)-
1,2-diphenylethyl)carbamate (14)
Prepared from compound 8 following the general procedure on a
1.0 mmol scale. Flash column chromatography (silica gel, light
petrol: ethyl-acetate 4:1) afforded 14 as a white solid (540 mg,
83% yield). M.p.: 110-112 °C; HRMS (ESI-TOF) m/z: [M+H]+
4.4. General procedure for ligand deprotection (17-18)
Prepared according to the literature procedure.16 To a solution of
17 or 18 (0.5 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (1.5 mL),
trifluoroacetic acid (765 µL, 10.0 mmol, 20.0 equiv.) was added,
and the reaction mixture was stirred at room temperature for 4
hours. Then, the mixture was poured onto saturated NaHCO3
solution, and it was extracted with CH2Cl2 (4×). The crude
product was purified by flash column chromatography. All data
were in accordance with the literature.16,21
calculated for C38H38N2O3P 601.2620, found 601.2615; ꢀꢁꢂꢃ
:
+44.7 (c 1.0, CHCl3); IR (νmax/cm-1): 3318 (N-H ν), 2933 (C-H
ν), 1682 (C=O ν), 1639 (C=O ν), 1526 (N-H δ), 1450 (C=C ν),
1241 (C-O ν), 1170 (C-N ν), 742 (C-H arom δ), 695 (C-H arom
δ); 1H NMR (400 MHz, CDCl3)δ: 7.67 (brs, 1H, NHCO), 7.34–
6.90 (m, 25H, H-arom), 5.75 (d, J = 8.0 Hz, 1H, CH-NHCO),
5.26 (t, J = 8.0 Hz, 1H, CH-NHCOO), 4.92 (t, J = 12.0 Hz, 1H,
NHCOO), 1.36 (s, 9H, C-(CH3)3); 31P NMR (167 MHz,
CDCl3)δ: −11.15; 13C NMR (100 MHz, CDCl3)δ: 169.2
(NHCO), 156.4 (NHCOO), 141.1 (C-arom) 139.4 (C-arom),
138.4 (C-arom), 134.3 (C-arom), 134.2 (C-arom), 133.8 (C-
arom), 133.5 (C-arom), 130.3 (C-arom), 128.7 (C-arom), 128.5
(C-arom), 128.4 (C-arom), 128.1 (C-arom), 127.6 (C-arom),
127.5 (C-arom), 79.8 (C-(CH3)3), 60.8 (CH-NHCO), 59.6 (CH-
NHCOO), 28.4 (C-(CH3)3).
4.4.1 N-((1R,2R)-2-aminocyclohexyl)-2-(diphenylphosphaneyl)-
benzamide (17)
The crude product was purified by column chromatography
(silica gel, CH2Cl2: MeOH 30:1) affording 17 as a white solid
1
(197 mg, 98% yield). H NMR (400 MHz, CDCl3)δ: 7.32 (brs,
1H, NHCO), 7.28–7.21 (m, 13H, H-arom), 6.92 (m, 1H, H-arom)
5.76 (d, J = 8.0 Hz, 1H, CH-NHCO), 3.59 (m, 1H, CH-NH2),
2.19–2.14 (m, 1H, CH2a-CH), 1.90–1.86 (m, 2H, CH2-CH), 1.69–
1.63 (m, 3H, CH2b-CH, CH-NH2), 1.26–1.21 (m, 3H, CH2a-CH2),
0.89–0.86 (m, 1H, CH2b-CH2).
4.3.5. Isobutyl ((1R,2R)-2-(2-(diphenylphosphaneyl)benzamido)-
1,2-diphenylethyl)carbamate (15)
Prepared from compound 9 following the general procedure on a
1.0 mmol scale. Flash column chromatography (silica gel, light
petrol: ethyl-acetate 4:1) afforded 15 as a white solid (505 mg,
4.4.2 N-((1R,2R)-2-amino-1,2-diphenylethyl)-2-(diphenyl-
phosphaneyl)benzamide (18)
6

The crude product was purified by column chromatography
temperature. After completion, 5 mL diethyl ether was added. In
case of C-allylation reactions the organic layer was washed with
saturated NH4Cl solution and water, dried over Na2SO4 and
concentrated under reduced pressure. For the N-allylations, the
reaction mixtures were simply concentrated in vacuo. The crude
products were purified by column chromatography or preparative
TLC.
(silica gel, CH2Cl2: MeOH 30:1) affording 18 as a white solid
1
(240 mg, 96% yield). H NMR (400 MHz, CDCl3)δ: 7.45 (brs,
1H, NHCO), 7.31–7.18 (m, 21H, H-arom), 7.05 (d, J = 8.0 Hz,
2H, H-arom), 6.96 (brs, 1H, H-arom), 5.25 (dd, J = 8.0 Hz, 4.0
Hz, 1H, CH-NHCO), 4.28 (d, J = 4.0 Hz, 1H, CH-NH2), 1.69
(brs, 2H, CH-NH2).
4.5. Synthesis of the allylic acetates
4.6.1. Dimethyl-(R,E)-2-(1,3-diphenylallyl)malonate (20a)24
4.5.1. (±)-(E)-1,3-Diphenylallyl acetate (19)
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a colorless liquid
Prepared according to the literature procedure.22 (±)-(E)-1,3-
Diphenylallyl alcohol (28.6 mmol, 6.0 g, 1.0 equiv.) was
dissolved in anhydrous CH2Cl2 (70 mL) and Et3N (34.8 mmol,
4.83 mL, 1.22 equiv.) was added. The mixture was cooled to 0
°C via ice bath, and a solution of acetyl chloride (34.3 mmol,
2.46 mL, 1.20 equiv.) in anhydrous CH2Cl2 was slowly added.
Then, the solution was allowed to warm up to room temperature
and it was stirred for 4 hours. The reaction mixture was washed
with 2 M NaOH (3×), water (2×) and brine (2×) successively,
dried over Na2SO4, filtered and evaporated. The crude product
was purified by Kugelrohr distillation (0.35 mBar, 150-170 °C)
to obtain the product 19 as a light-yellow oil (6.84 g, 95% yield).
1H NMR (400 MHz, CDCl3)δ: 7.37–7.21 (m, 10H, H-arom),
6.56 (d, J = 16.0 Hz, 1H, arom-CH=CH), 6.37 (d, J = 8.0 Hz, 1H,
arom-CH=CH), 6.27 (dd, J = 16.0 Hz, 4.0 Hz, 1H, arom-CH),
1
(151 mg, 93% yield; >99% ee). ꢀꢂꢁꢃ: +12.4 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3)δ: 7.29–7.17 (m, 10H, H-arom), 6.45
(d, J = 16.0 Hz, 1H, arom-CH=CH), 6.30 (dd, J = 16.0 Hz, 8.0
Hz, 1H, arom-CH=CH), 4.24 (dd, J = 12.0 Hz, 8.0 Hz, 1H, arom-
CH), 3.91 (d, J = 12.0 Hz, 1H, CH(COOCH3)), 3.66 (s, 3H,
COOCH3), 3.47 (s, 3H, COOCH3); Chiral HPLC analysis:
n
(chiralcel IB column, hexane : EtOH 99:1 V/V, 1.0 mL/min, 25
ºC, UV 254 nm) tR = 7.71 min (R).
4.6.2. Diethyl-(R,E)-2-(1,3-diphenylallyl)malonate (20b)24
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a colorless oil
1
(166 mg, 94% yield; 99% ee). ꢀꢂꢁꢃ: +17.0 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3)δ: 7.23–7.16 (m, 10H, H-arom), 6.44
(d, J = 16.0 Hz, 1H, arom-CH=CH), 6.28 (dd, J = 16.0 Hz, 8.0
Hz, 1H, arom-CH=CH), 4.28–4.08 (m, 3H, arom-CH,
2.09
(s,
3H,
CH3-CO);
13C NMR (100 MHz, CDCl3)δ: 170.3 (CH3-CO), 139.5 (C-
arom), 136.4 (arom-CH), 132.8 (arom-CH=CH), 128.9 (C-arom),
128.8 (C-arom), 128.4 (C-arom), 128.3 (C-arom), 127.7 (C-
arom), 127.3 (arom-CH=CH), 126.9 (C-arom), 76.4 (arom-CH),
21.6 (CH3-CO).
COOCH2CH3),
3.91–3.85
(m,
3H,
COOCH2CH3,
CH(COOCH2CH3)), 1.20 (t, J = 8.0 Hz, 3H, COOCH2CH3), 0.97
(t, J = 8.0 Hz, 3H, COOCH2CH3); Chiral HPLC analysis:
(chiralcel IA column, nhexane : 2-propanol 90:10 V/V, 0.5
mL/min, 25 ºC, UV 254 nm) tR = 11.3 min (R), tR = 13.5 min (S).
4.5.2. (±)-3-Acetoxy-1-cyclohexene (21)
4.6.3. Dibenzyl-(R,E)-2-(1,3-diphenylallyl)malonate (20c)24
Prepared according to literature procedure.23 Freshly distilled
3-bromo-1-cyclohexene (30.3 mmol, 3.5 mL, 1.0 equiv.) was
dissolved in acetone (60 mL). Glacial acetic acid (0.3 mol, 17.5
mL, 10.0 equiv.) was added, followed by the dropwise addition
of Et3N (0.31 mol, 43 mL, 10.2 equiv.) at 0 °C. The mixture was
allowed to warm up and it was subsequently stirred at room
temperature overnight. The solvent was removed in vacuo and
the residue was dissolved in diethyl-ether. The organic layer was
washed with 0.5 M HCl (3×), saturated NaHCO3-solution (3×),
brine (1×) and water (1×) successively, dried over Na2SO4 and
concentrated in vacuo. Vacuum distillation (20 mBar, 85 °C)
afforded product 21 as a colourless liquid (3.56 g, 84% yield).
1H NMR (400 MHz, CDCl3)δ: 5.96–5.93 (m, 1H, CH-CH=CH),
5.71–5.67 (m, 1H, CH-CH=CH), 5.26–5.23 (m, 1H, CH-
CH=CH), 2.12–2.09 (m, 1H, CH2-CH2a-CH), 2.04 (s, 3H, CH3-
CO), 2.01–1.98 (m, 1H, CH2-CH2b-CH), 1.89–1.83 (m, 1H,
CH2a-CH2-CH), 1.77–1.68 (m, 1H, CH2-CH=CH), 1.66–1.60 (m,
1H, CH2b-CH2-CH); 13C NMR (100 MHz, CDCl3)δ: 170.9
(CH3-CO), 132.8 (CH-CH=CH), 125.8 (CH-CH=CH), 68.2 (CH-
CH=CH), 28.4 (CH-CH2-CH2), 25.0 (CH2-CH=CH), 21.5 (CH3-
CO), 19.0 (CH-CH2-CH2).
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a colorless oil
1
(233 mg, 98% yield; >99% ee). ꢀꢂꢁꢃ: +7.0 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3)δ: 7.27–7.22 (m, 18H, H-arom), 7.05
(d, J = 8.0 Hz, 2H, H-arom), 6.42 (d, J = 16.0 Hz, 1H, arom-
CH=CH), 6.31 (dd, J = 16.0 Hz, 8.0 Hz, 1H, arom-CH=CH),
5.11 (dd, J = 16.0 Hz, 12.0 Hz, CH2-arom), 4.94 (dd, J = 16.0
Hz, 12.0 Hz, CH2-arom), 4.30 (dd, J = 12.0 Hz, 8.0 Hz, 1H,
arom-CH), 4.05 (d, J = 12.0 Hz, 1H, CH(COOCH2Ph); Chiral
HPLC analysis: (chiralcel IA column, nhexane : 2-propanol
90:10 V/V, 0.5 mL/min, 25 ºC, UV 254 nm) tR = 21.0 min (R).
4.6.4. Diethyl-(S,E)-2-acetamido-2-(1,3-diphenylallyl)malonate
(20d)25
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a white solid (200
1
mg, 98% yield; 92% ee). ꢀꢂꢁꢃ: +44.0 (c 1.0, EtOH); H NMR
(400 MHz, CDCl3)δ: 7.29–7.21 (m, 9H, H-arom), 7.16–7.12 (m,
1H, H-arom), 6.74 (dd, J = 16.0 Hz, 8.0 Hz, 1H, arom-CH=CH),
6.56 (brs, 1H, NH), 6.27 (d, J = 16.0 Hz, 1H, arom-CH=CH),
4.75 (d, J = 12.0 Hz, 1H, arom-CH), 4.29–4.20 (m, 2H,
COOCH2CH3), 4.13–3.99 (m, 2H, COOCH2CH3), 1.94 (s, 3H,
CH3-CO), 1.23 (t, J = 8.0 Hz, 1H, COOCH2CH3), 1.14 (t, J = 8.0
Hz, 3H, COOCH2CH3); Chiral HPLC analysis: (chiralcel IA
column, nhexane : 2-propanol 90:10 V/V, 0.5 mL/min, 25 ºC, UV
254 nm) tR = 12.9 min (S), tR = 15.1 min (R).
4.6. General procedure for the asymmetric allylic alkylation
A mixture of [Pd(C2H5)Cl)]2 (1.83 mg, 0.005 mmol, 1.0 mol%)
and the chiral ligand (0.011 mmol, 2.2 mol%) in 0.5 mL solvent
was stirred for 30 minutes under argon atmosphere to form the
active catalyst species. The allylic acetate (0.5 mmol, 1.0 equiv.)
was dissolved in 0.5 mL solvent, and it was added to the reaction
mixture. After an additional 10 minutes of stirring, the
corresponding malonate or amine (0.60 mmol, 1.2 equiv.), and
optionally BSA (250 µL, 1.0 mmol, 2.0 equiv.) and KOAc (2 mg,
2.0 mol%) were added. The mixture was stirred at room
4.6.5. (R,E)-3-(1,3-Diphenylallyl)pentane-2,4-dione (20e)26
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a white solid (130
1
mg, 95% yield; 92% ee). ꢀꢂꢁꢃ: −11.0 (c 1.0, CHCl3); H NMR
7

(400 MHz, CDCl3)δ: 7.32–7.18 (m, 10H, H-arom), 6.41 (d, J =
16.0 Hz, 1H, arom-CH=CH), 6.19–6.15 (m, 1H, arom-CH=CH),
4.33–4.31 (m, 2H, arom-CH, CH(COCH3)), 2.23 (s, 3H,
COCH3), 1.91 (s, 3H, COCH3); Chiral HPLC analysis:
(chiralcel OJ column, nhexane : 2-propanol 98:2 V/V, 0.5
mL/min, 25 ºC, UV 254 nm) tR (major) = 37.3 min (R), tR (minor)
= 47.5 min (S).
86% ee). ꢀꢂꢁꢃ: +35.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3)δ: 5.80–5.76 (m, 1H, CH-CH=CH), 5.51 (d, J = 12.0 Hz,
1H CH-CH=CH), 3.73 (s, 6H, 2 x COOCH3), 3.29 (d, J = 8.0 Hz,
1H, CH-CH=CH), 2.93–2.87 (m, 1H, CH(COOCH3)2), 2.00–1.97
(m, 2H, CH2-CH), 1.79–1.73 (m, 2H, CH2-CH2-CH), 1.60–1.54
(m, 1H, CH2a-(CH2)2-CH), 1.40–1.33 (m, 1H, CH2b-(CH2)2-CH);
n
Chiral HPLC analysis: (chiralcel AS-H column, hexane : 2-
propanol 95:5 V/V, 1.0 mL/min, 25 ºC, UV 220 nm) tR = 6.6 min
(R), tR = 7.7 min (S).
4.6.11. Diethyl 2-(cyclohex-2-en-1-yl)malonate (22b)28
4.6.6. Dimethyl (R,E)-2-(1,3-diphenylallyl)-2-(prop-2-yn-1-
yl)malonate (20f)
Purification by preparative TLC (light petrol : ethyl-acetate 10:1,
UV visualization) afforded the pure product as a light-yellow oil
Purification by column chromatography (light petrol : diethyl-
ether 10:1, visualization by potassium permanganate stain)
afforded the pure product as a colorless oil (106 mg, 88% yield;
83% ee). ꢀꢂꢁꢃ: +23.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3)δ: 5.73–5.65 (m, 1H, CH-CH=CH), 5.48 (d, J = 12.0 Hz,
1H, CH-CH=CH), 4.13 (q, 4H, 2 x COOCH2H3), 3.17 (d, J = 8.0
Hz, 1H, CH-CH=CH),2.87–2.77 (m, 1H, CH(COOCH2CH3)2),
1.95–1.91 (m, 2H, CH2-CH), 1.75–1.35 (m, 4H, CH2-CH2-CH,
CH2a-(CH2)2-CH, CH2b-(CH2)2-CH), 1.20 (t, J = 12.0 Hz, 2 x
COOCH2CH3)2); Chiral HPLC analysis: (chiralcel OJ column,
nhexane : 2-propanol 98:2 V/V, 0.5 mL/min, 25 ºC, UV 220 nm)
tR = 10.5 min (R), tR = 10.9 min (S).
1
(165 mg, 94% yield; 99% ee). ꢀꢂꢁꢃ: +15.2 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3)δ: 7.34–7.19 (m, 10H, H-arom), 6.76
(dd, J = 16.0 Hz. 8.0 Hz, 1H, arom-CH=CH), 6.43 (d, J = 16.0
Hz, 1H, arom-CH=CH), 4.42 (d, J = 12.0 Hz, 1H, arom-CH),
3.76 (s, 3H, COOCH3), 3.69 (s, 3H, COOCH3), 2.80 (d, J = 20.0
Hz, 1H, CHCCH2a), 2.62 (d, J = 20.0 Hz, 1H, CHCCH2b), 2.11–
2.09 (m, 1H, CHCCH2); Chiral HPLC analysis: (chiralcel IA
n
column, hexane : 2-propanol 99:1 V/V, 0.5 mL/min, 25 ºC, UV
254 nm) tR = 20.1 min (R).
4.6.7. (S,E)-1-(1,3-diphenylallyl)pyrrolidine (20g)27
Purification by preparative TLC (light petrol : ethyl-acetate 7:1,
UV visualization) afforded the pure product as a yellow oil (129
4.6.12. Dibenzyl 2-(cyclohex-2-en-1-yl)malonate (22c)
1
mg, 98% yield; 92% ee). ꢀꢂꢁꢃ: +4.1 (c 1.0, CHCl3); H NMR
Purification by column chromatography (light petrol : diethyl-
ether 10:1, visualization by potassium permanganate stain)
afforded the pure product (90% yield; 99% ee). ꢀꢂꢁꢃ: +17.8 (c 1.0,
(400 MHz, CDCl3)δ: 7.35–7.12 (m, 10H, H-arom), 6.49 (d, J =
16.0 Hz, 1H, arom-CH=CH), 6.34 (dd, J = 16.0 Hz, 8.0 Hz,
arom-CH=CH), 3.69 (d, J = 8.0 Hz, 1H, arom-CH), 2.50–2.49
(m, 2H, N-CH2), 2.37–2.35 (m, 2H, N-CH2), 1.73–1.69 (m, 2H,
N-CH2-CH2), 1.51 (brs, 2H, N-CH2-CH2); Chiral HPLC
1
CHCl3); H NMR (400 MHz, CDCl3)δ: 7.34–7.29 (m, 10H, H-
arom), 5.77–5.72 (m, 1H, CH-CH=CH), 5.53 (d, J = 12.0 Hz, 1H,
CH-CH=CH), 5.15 (dd, J = 16. 0 Hz, 8.0 Hz, 4H, 2 x CH2-arom),
3.39 (d, J = 8.0 Hz, 1H, CH-CH=CH), 2.99–2.91 (m, 1H,
CH(COOCH2Ph)2), 1.98–1.94 (m, 2H, CH2-CH), 1.77–1.66 (m,
2H, CH2-CH2-CH), 1.51–1.47 (m, 1H, CH2a-(CH2)2-CH), 1.39–
1.34 (m, 1H, CH2b-(CH2)2-CH); Chiral HPLC analysis:
(chiralcel IA column, nhexane : 2-propanol 90:10 V/V, 0.5
mL/min, 25 ºC, UV 254 nm) tR = 10.8 min (R).
n
analysis: (chirlacel OD column, hexane : 2-propanol 99.5:0.5
V/V, 0.5 mL/min, 25 ºC, UV 254 nm) tR = 10.1 min (R), tR = 10.9
min (S).
4.6.8. (S,E)-1-(1,3-diphenylallyl)piperidine (20h)27
Purification by preparative TLC (light petrol : ethyl-acetate 7:1,
UV visualization) afforded the pure product as a yellow oil (133
mg, 98% yield; 84% ee). ꢀꢂꢁꢃ: +5.2 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3)δ: 7.33–7.12 (m, 10H, H-arom), 6.45 (d, J =
16.0 Hz, 1H, arom-CH=CH), 6.26 (dd, J = 16.0 Hz, 8.0 Hz,
arom-CH=CH), 3.74 (d, J = 8.0 Hz, 1H, arom-CH), 2.43–2.38
(m, 2H, N-CH2), 2.30–2.25 (m, 2H, N-CH2), 1.51–1.47 (m, 4H,
N-CH2-CH2), 1.39–1.35 (m, 2H, N-(CH2)2-CH2); Chiral HPLC
4.6.13. (S)-N-Benzylcyclohex-2-en-1-amine (22d)
Purification by column chromatography (light petrol: diethyl-
ether 5:1, visualization by potassium permanganate stain)
afforded the pure product as a light-yellow oil (84 mg, 89%
1
yield; 60% ee). ꢀꢂꢁꢃ: +1.8 (c 0.5, CHCl3); H NMR (400 MHz,
CDCl3)δ: 7.25–7.17 (m, 5H, H-arom) 5.73–5.65 (m, 2H, CH-
CH=CH, CH-CH=CH), 3.78 (dd, J = 16.0 Hz J = 8.0 Hz, 2H,
CH2-arom), 3.17–3.14 (m, 1H, CH-NH), 1.94–1.92 (m, 2H, CH2-
CH), 1.84–1.72 (m, 2H, CH2-CH2-CH), 1.70–1.65 (m, 1H, CH2a-
(CH2)2-CH), 1.52–1.40 (m, 1H, CH2b-(CH2)2-CH); Chiral HPLC
n
analysis: (chiralcel OD column, hexane : 2-propanol 99.5:0.5
V/V, 0.5 mL/min, 25 ºC, UV 254 nm) tR = 9.6 min (R), tR = 10.5
min (S).
4.6.9. (S,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (20i)27
n
analysis: (chiralcel OD column, hexane : 2-propanol 99.5:0.5
V/V, 1.0 mL/min, 25 ºC, UV 220 nm) tR = 19.1 min (S), tR = 21.1
min (R).
Purification by preparative TLC (light petrol : ethyl-acetate 7:1,
UV visualization) afforded the pure product as a light-yellow oil
1
(131 mg, 87% yield; 92% ee). ꢀꢂꢁꢃ: +29.5 (c 1.5, CHCl3); H
Acknowledge
NMR (400 MHz, CDCl3)δ: 7.36 (d, J = 8.0 Hz, 2H, H-arom),
7.29–7.10 (m, 13H, H-arom), 6.50 (d, J = 16.0 Hz, 1H, arom-
CH=CH), 6.24 (dd, J = 16.0 Hz, 8.0 Hz, 1H, arom-CH=CH),
4.32 (d, J = 8.0 Hz, 1H, arom-CH), 3.71 (dd, J = 16.0 Hz, 12.0
Hz, 2H, arom-CH2), 1.63 (brs, 1H, NH); Chiral HPLC analysis:
Financial support by the Austrian Science Fund (project P29146-
N34) is gratefully acknowledged.
Appendix A. Supplementary data
n
(chirlacel OD column, hexane: 2-propanol 99.5:0.5 V/V, 0.5
mL/min, 25 ºC, UV 254 nm) tR = 24.66 min (R), tR = 27.4 min
(S).
NMR spectra of all new and known chiral ligands and allylation
products, chiral HPLC traces.
4.6.10. Dimethyl 2-(cyclohex-2-en-1-yl)malonate (22a)28
Purification by column chromatography (light petrol : diethyl-
ether 10:1, visualization by potassium permanganate stain)
afforded the pure product as a colorless oil (91 mg, 86% yield;
8

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9

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: