Palladium catalyzed asymmetric reactions assisted by P*,P*-bidentate bisdiamidophosphites based on 1,4-diols

Article abstract of DOI:10.1016/j.tet.2016.12.023

A small series of P*,P*-bidentate bisdiamidophosphite ligands containing 1,3,2-diazaphospholidine rings have been prepared. The cationic [Pd(allyl)(P*,P*)]BF₄and neutral [Pd(P*,P*)Cl₂] palladium(II) complexes were synthesized with on

Full text of DOI:10.1016/j.tet.2016.12.023

Accepted Manuscript
Palladium catalyzed asymmetric reactions assisted by P*,P*-bidentate
bisdiamidophosphites based on 1,4-diols
Konstantin N. Gavrilov, Sergey V. Zheglov, Vladislav K. Gavrilov, Marina G.
Maksimova, Viktor A. Tafeenko, Vladimir V. Chernyshev, Kirill P. Birin, Igor S. Mikhel
PII:
S0040-4020(16)31301-1
10.1016/j.tet.2016.12.023
TET 28315
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 July 2016
Revised Date: 17 November 2016
Accepted Date: 12 December 2016
Please cite this article as: Gavrilov KN, Zheglov SV, Gavrilov VK, Maksimova MG, Tafeenko VA,
Chernyshev VV, Birin KP, Mikhel IS, Palladium catalyzed asymmetric reactions assisted by P*,P*-
bidentate bisdiamidophosphites based on 1,4-diols, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.023.
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ACCEPTED MANUSCRIPT
Graphical abstract.
Palladium catalyzed asymmetric reactions assisted by
-
P*,P*
bidentate bisdiamidophosphites based on 1,4-diols
Konstantin N. Gavrilov, Sergey V. Zheglov, Vladislav K. Gavrilov,
Marina G. Maksimova, Viktor A. Tafeenko, Vladimir V. Chernyshev,
Kirill P. Birin, Igor S. Mikhel
Nu
EtO
O
Ph
* Ph
up to 98% ee
Ph
*
O
Ph
O
O
O
N
P
Ts
O
O
*
Ph
up to 72%
ee
O
*
P
N
N
P
N
N
P
N
O
N
*
*
N
N
O
up to 94% ee
O
(S,S)- or (R,R)-
up to 94% ee
1

ACCEPTED MANUSCRIPT
Palladium catalyzed asymmetric reactions assisted by P*,P*-bidentate
bisdiamidophosphites based on 1,4-diols
Konstantin N. Gavrilov a,1, Sergey V. Zheglov a, Vladislav K. Gavrilov a, Marina G.
Maksimova a, Viktor A. Tafeenko b, Vladimir V. Chernyshev b,c, Kirill P. Birin c, Igor S.
Mikhel c
a Department of Chemistry, S. A. Esenin Ryazan State University, 46 Svoboda Street, 390000
Ryazan, Russian Federation
b Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1-3,
119991 Moscow, Russian Federation
c A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of
Sciences, Leninskiy prospect 31, 119071 Moscow, Russian Federation
Abstract: A small series of P*,P*-bidentate bisdiamidophosphite ligands containing 1,3,2-
diazaphospholidine rings have been prepared. The cationic [Pd(allyl)(P*,P*)]BF4 and neutral
[Pd(P*,P*)Cl2] palladium(II) complexes were synthesized with one of the new ligands. The use of
these ligands provides up to 98% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-
diphenylallyl acetate, up to 72% ee in Pd-catalyzed asymmetric alkylation of cinnamyl acetate
with ethyl 2-oxocyclohexane-1-carboxylate and up to 94% ee in Pd-catalyzed desymmetrization of
N,N'-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate. The influence of the nature of the
bridging ligand fragments of the bisdiamidophosphites on asymmetric induction is discussed.
Keywords:
Asymmetric
allylic
substitution;
Desymmetrization;
Palladium;
Bisdiamidophosphites.
1. Introduction
Transition-metal-complex-promoted asymmetric catalysis is one of the leading
approaches to single enantiomers of chiral compounds. The demand for enantiopure or in general
case enantioenriched organic and organoelement compounds for a range of applications from
medical chemistry to materials science continues unabated. In turn, the activity and
stereoselectivity of metal-complex catalysts strongly depend on the successful strategy of design
1 Corresponding author. Tel.: +7-4912-280580; fax +7-4912-281435; e-mail: k.gavrilov@rsu.edu.ru
2

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and synthesis of appropriate chiral ligands, among which phosphorus-containing asymmetric
inductors are worth noting.1
P,P-bidentate ligands are extremely powerful and versatile stereoselectors for metal-
mediated asymmetric reactions.1b,d,l,m,2 To embark on the synthesis of any efficient P,P-ligands,
it is necessary to carefully select the optimal chiral backbone. For instance, a number of
publications have dealt with the utility of (4S,5S)- and (4R,5R)-4,5-di-(hydroxymethyl)-2,2-
dimethyl-1,3-dioxolane as a valuable starting material for the synthesis of the historically
important diphosphine DIOP ligand and of a various P,P-bidentate phosphite-type ligands LA-C
(Fig. 1).3 This starting diol is easily prepared from both enantiomers of tartaric acid, a simple and
readily available chiral source.4 Note that these interesting ligands showed low to moderate
enantioselectivity in palladium-catalyzed allylic substitution.3b,c,e,5
Fig. 1. Structures of reported P,P-bidentate ligands derived from (R,R)- or (S,S)-tartaric acid.
In the last few years, we have reported the synthesis of several P*,P*-bidentate
bisdiamidophosphites with 1,3,2-diazaphospholidine rings and demonstrated that they can
promote a wide range of catalytic enantioselective transformations.6 Encouraged by these
observations and motivated by our continuing efforts in the design and application of novel P*-
chiral ligands for use in asymmetric catalysis, we have prepared P*,P*-bidentate
bisdiamidophosphite compounds (S,S)-4 and (R,R)-4 with (4S,5S)- or (4R,5R)-4,5-di-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane
backbone
and
1,3-diaza-2-
phosphabicyclo[3.3.0]octane cores as ligands for Pd-catalyzed asymmetric reactions. For
comparative purposes, ligand 5, with a non-chiral 1,4-diol link, has also been synthesized. It
should be noted that the presence of stereogenic donor phosphorus atoms substantially promotes
3

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the successful asymmetric induction in the catalytic cycle. Since these atoms bind directly to the
metal atom, they are positioned close to the coordinated substrate, that eliminates potentially
inefficient secondary transfer of chirality from the ligand framework and, thus, provides a more
efficient chiral environment at the site where the enantioselection originates from.1b,2a,6b,7
The novel P*,P*-bidentate bisdiamidophosphites were employed in Pd-catalyzed
asymmetric allylic substitution and desymmetrization reactions. Pd-mediated allylic substitutions
represent a versatile, highly efficient and practically-oriented tool for the stereoselective
formation of carbon–carbon and carbon–heteroatom bonds.1c,2b,7a,8 Thus, products of alkylation
with dimethyl malonate can be readily converted to esters and amides of chiral unsaturated
carboxylic acids under mild conditions and without involvement of the C*-stereocenter.8h The
Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate with 1-cyclohexenylpyrrolidine
has been used as a key step in the synthesis of a selective antimuscarinic agent.9 Also, Pd-
catalyzed enantioselective synthesis of a quaternary carbon center is highly challenging.1c,10
From a natural product synthesis and a drug discovery perspective, this approach provides access
to useful building blocks with a single quaternary stereocenter.11 Both enantiomers of the
desymmetrization product of N,N'-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate are key
precursors of pharmacologically active compounds mannostatin A and (–)-swainsonine.1c,8b
Finally, these reactions are the reliable methods for ligand benchmark testing and the
enantiomeric excesses obtained are the simplest scale for the evaluating new chiral
inductors.2b,8f,12
2. Results and discussion
2.1. Synthesis of bisdiamidophosphite ligands and palladium complexes
Bisdiamidophosphites (S,S)-4, (R,R)-4 and 5 were synthesized in one step by condensing
the phosphorylating reagent 1 (2 equiv) with the corresponding diol (S,S)-2, (R,R)-2 or 3 in THF
in the presence of an excess of NEt3 as a base (Scheme 1). The new ligands were purified by
flash chromatography on Al2O3 and isolated in good yields (75-83%) as white solids for (S,S)-4
and (R,R)-4 and as colorless viscous oil for 5. They can be stored under dry conditions at room
temperature for at least a few months with minimal degradation. All these compounds could be
prepared on a gram scale. It should be added that the phosphorylating reagent 1 can be
13
synthesized in high yield from readily accessible (S)-glutamic acid anilide.14 The elemental
1
analyses, H, 13C, and 31P NMR spectra, IR spectra and MALDI TOF/TOF mass spectra, are
consistent with the expectation for these bisdiamidophosphites.
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Scheme 1. Synthesis of P*,P*-bidentate bisdiamidophosphites (S,S)-4, (R,R)-4 and 5.
During the phosphorylation, the exclusive formation of the stereoindividual
bisdiamidophosphites (S,S)-4, (R,R)-4 and 5 with an (R)-configuration at the asymmetric
31
phosphorus atoms occurred. The P NMR spectra of their solutions in CDCl3 exhibited narrow
13
singlets at δР 121.1, 122.5 and 121.6 ppm, respectively. The C NMR spectra of these ligands
2
are characterized by large spin–spin coupling constants JC(8),P (38.3 Hz, see Experimental
section), which are indicative of the syn-orientation of the phosphorus lone pair with respect to
the C(8) atom. The pseudoequatorial exocyclic substituent at the phosphorus atom and the –
(CH2)3– part of the pyrrolidine fragment of the phosphabicyclic skeleton are in the anti-
arrangement (Fig. 2).6,13-15
Fig. 2. Stereochemistry of the phosphabicyclic part in ligands (S,S)-4, (R,R)-4 and 5 (X =
exocyclic substituent).
To examine the complexing capacity of the bisdiamidophosphite ligands, two
palladium(II) coordination compounds were prepared. In particular, reaction of (S,S)-4 with
[Pd(allyl)Cl]2 proceeded smoothly in CH2Cl2/THF mixture in the presence of AgBF4 as a
chloride scavenger and resulted in chelate cationic complex 6 (Scheme 2). In the 31P NMR
spectrum of the solution of complex 6 in CDCl3 one can see a narrow symmetric singlets at δР
121.11 and 121.06 ppm indicating that 6 exists as a mixture of exo- and endo-isomers about the
1
π-allyl-Pd-species.3e,16 Severe overlap in the H NMR spectrum as well as the line widths for
5

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almost all proton resonances in the aliphatic region of 6 precluded the assignment of the signals.
The MALDI TOF/TOF mass spectrometry and elemental analysis data (see Experimental
section) were also in good agreement with the proposed structure of 6. Note that analogous
cationic metallochelates [Pd(1,3-Ph-allyl)(LB)]PF6 and Pd(2-Me-allyl)(LC)]PF6 were formed on
the base of known P,P-bidentate ligands LB and LC.3c,e The complexation of (S,S)-4 with
31
Pd(Cod)Cl2 in CH2Cl2 leads to neutral palladium chelate 7 (Scheme 2). P analyses confirmed
this coordination mode. Thus, the resonance at δР 102.5 ppm and the considerable coordination
shift (∆δР = −18.6 ppm) are observed in 31P NMR spectrum of 7 in CDCl3. The magnitude of the
δP is typical for the PdCl2 complexes with two coordinated diamidophosphite centers.17
Scheme 2. Synthesis of cationic and neutral palladium complexes 6 and 7.
The molecular structures of ligand (S,S)-4 and complex 7 in the solid state were
confirmed by X-ray structure determination (Fig. 3 and 4). Compound (S,S)-4 was obtained as
crystalline powder, so its crystal structure was determined by powder diffraction method. Single
crystals suitable for X-ray crystal structure analysis were obtained for 7 by crystallization from
heptane/CH2Cl2 at -20 °C. All bond lengths and angles in (S,S)-4 and 7 are normal and
comparable with those observed in the Cambridge Structural Database18 for related compounds.
In (S,S)-4, the P–O bond lengths are 1.697(8) and 1.681(6) Å, and the P–N bond lengths lie in
the range 1.694(10) – 1.754(9) Å. The N–P–N bond angles are 86.8(4) and 93.5(5)o, and the N–
P–O bond angles cover the range 99.8(4) - 111.1(3)o. The crystal packing is consolidated by the
weak Van der Waals interactions proved by the relatively short intermolecular C…O and C…C
distances of 3.52(2) and 3.62(2) Å, respectively.
6

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Fig. 3. The molecular structure of ligand (S,S)-4 showing the atomic numbering and 50%
probability displacement spheres. H atoms omitted for clarity.
7

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Fig. 4. The molecular structure of complex 7 showing the atomic numbering and 40%
probability displacement ellipsoids. H atoms and solvent molecule omitted for clarity.
In complex 7, the Pd1(II) ion is coordinated by two chloro ligands and two phosphorus
atoms in a highly distorted square-planar geometry, where atoms Cl1 and Cl2 deviate from the
8

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plane Pd1/P1/P1A at 0.219(3) and -0.219(3) Å, respectively. The selected coordination bond
lengths and angles around Pd1 are presented in Table 1.
Table 1. Coordination geometry of Pd1 in complex 7 – selected bond lengths (Å) and angles (o).
Pd1 – Cl1
Pd1 – Cl2
Pd1 – P1
2.363(4)
2.329(4)
2.243(4)
2.235(3)
Cl1 – Pd1 – Cl2
Cl1 – Pd1 – P1
Cl1 – Pd1 – P1A
Cl2 – Pd1 – P1
Cl2 – Pd1 – P1A
P1 – Pd1 – P1A
93.6(2)
174.5(2)
87.3(2)
88.1(2)
174.6(2)
91.4(2)
Pd1 – P1A
In the bonded bisdiamidophosphite ligand, the P–O bond lengths [1.588(8) and 1.590(7)
Å] are shorter than those in the free (S,S)-4, and the same is valid for the P–N bond lengths,
which lie in the range 1.615(9) – 1.676(10) Å. In the crystal, weak intermolecular C–H…Cl
interactions (Table 2) link the molecules into chains running along the axis b. Comparing the
overall conformations of bisdiamidophosphite molecule in free and bound states, which can be
quantified by the distance between the atoms P1 and P1A – 5.927(11) and 3.205(9) Å in (S,S)-4
and 7, respectively, one can see its high flexibility.
Table 2. Weak C-H…Cl interactions (Å, °) in complex 7.
D−H…A
D−H
0.98
0.98
H…A
2.75
2.82
D…A
3.558(12)
3.617(12)
D−H…A
140
C2−H2…Cl2 a
C8−H8…Cl1 a
139
a Symmetry code: (i) 1-x, -1/2+y, 1/2-z.
In both crystal structures, all five-membered cycles exhibit an envelope conformation. In
ligand (S,S)-4, the phosphorous P1/N1/C7/C8/N2 (with C8 as a flap) and pyrrolidine
N2/C8/C9/C10/C11 (N2) cycles form a dihedral angle of 41(1)o, while dihedral angle between
the cycles P1A/N1A/C7A/C8A/N2A (C7A) and N2A/C8A/C9A/C10A/C11A (C10A) is 56(1)o.
In complex 7, the corresponding dihedral angles are 49.8(2)o [between the P1/N1/C7/C8/N2 (C7)
and N2/C8/C9/C10/C11 (C10)] and 51.0(2)o [between the P1A/N1A/C7A/C8A/N2A (C7A) and
N2A/C8A/C9A/C10A/C11A (C10A)].
We have found that after storing several hours in solution, complex 7 exists as an almost
equimolar mixture of two isomers - 7 and 7`. A second isomer 7` (δP 104.7) evolves until an
isomer equilibrium is reached (Scheme 3).
9

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P
P
Cl
P
Cl Pd Cl Cl Pd Cl
2
Pd
P
Cl
P
P
7
7`
Scheme 3. The equilibrium between complexes 7 and 7` in CDCl3.
1
13
All H and C NMR signals of 7 and 7` were located by a combination of NMR spectroscopic
methods (13C-1H HSQC, 13C-1H HMBC, 1H-1H COSY, and 1H-1H ROESY) (Fig. 5 and 6).
122.56
129.16
118.47, vt, J = 2.6
142.25, vt, J = 4.5
26.85
N
56.58, vt, J = 2.9
O P
1.44, s
O
77.34
61.71
30.66
26.88, vt, J = 2.4
112.09
N
66.69, vt,
J = 5.6
4.36-
O
4.39, m
50.24,
vt, J = 10.0
3.56-3.64, m
4.50-4.57, m
O
4.39-4.47, m
3.28-3.33, m
7.27, d,
J = 7.2
P
N
2.25-2.33, m
1.99-2.05, m
7.04, t,
J = 7.2
N
4.15-
4.20, m
2.10-2.16, m
1.89-1.94, m
7.27-7.31, m
3.82-3.87,
m
3.76-3.82,
m
Fig. 5. Full assignment of all C-13 and H-1 resonances for complex 7.
10

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122.19
129.15
116.91, vt, J = 2.6
141.77, vt, J = 4.5
25.92
N
56.71, br.
O P
74.32,
br.
1.22, s
O
62.05
30.90
110.31
N
64.62, br.
4.33-
4.35, m
O
50.79,
vt, J = 9.8
26.45, vt, J = 2.1
4.21-4.28, m
O
4.43-4.48, m
3.32-3.37, m
7.28-7.31
m
P
N
2.34-2.41, m
1.93-1.99, m
6.98, t,
J = 7.2
N
4.13-
4.19, m
2.05-2.10, m
1.98-2.04, m
7.23, t,
J = 7.8
3.87-3.93,
m
3.82-3.87,
m
Fig. 6. Full assignment of all C-13 and H-1 resonances for complex 7`.
Surprisingly, for both isomers 7 and 7` the trans geometry should be assigned on the basis of the
presence of virtual triplets for some of the 13C signals.19 Finally, molecular volume data obtained
by DOSY NMR spectroscopy confirm that 7 and 7` are monomer and dimer complexes,
respectively, as their hydrodynamic radii are quite different: rh = 6.45 Å (7) and 8.9 Å (7`). It
should be noted, that trans - complexes containing a nine - membered chelate ring are well
known.19a,20 The X-ray structure of several metal complexes has been determined and show that
the major isomer has indeed trans-configuration. However, NMR experiments have shown that
cis-isomers are also present.20 Summarizing, NMR and X-ray diffraction data clearly indicate
that 7 have different structures in solution and in the solid state.
11

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2.2. Pd-catalyzed asymmetric reactions
Our initial studies on the application of new bisdiamidophosphites and the obtained
palladium complexes in catalysis were focused on the Pd-catalyzed asymmetric allylic
substitution of (E)-1,3-diphenylallyl acetate 8 as a model transformation. In the first set of
experiments, we chose NaSO2pTol as the S-nucleophile, using standard conditions and THF as
the solvent (Table 3). Both diastereomers (S,S)-4 and (R,R)-4 perform the Pd-catalyzed synthesis
of the (R)-9a with good enantioselectivity (Table 3, entries 1, 2 and 5, 6). The “natural”
diastereomer (S,S)-4 (derived from natural (R,R)-tartaric acid) is most efficient, and sulfone (R)-
9a is formed with 96% yield and 92% ee in the reaction (Table 3, entry 1). The use of complexes
6 and 7 makes it possible to obtain product 9a with the opposite absolute configurations, but with
lower asymmetric induction and, in the case of 7, with lower chemical yield. Moderate
enantioselectivity of 46–52% ee (S) was obtained with butane-1,4-diol-based
bisdiamidophosphite 5, the molar ratio L/Pd = 2 is slightly preferable (Table 3, entries 7 and 8).
Table 3. Pd-catalyzed allylic sulfonylation of (E)-1,3-diphenylallyl acetate 8 with sodium para-
toluene sulfinate a
Entry Compound L/Pd
Yield (%)
ee (%) b,c
1
2
3
4
5
6
7
8
1
2
1
1
1
2
1
2
96
95
92
29
52
42
84
95
92 (R)
86 (R)
50 (R)
49 (S)
82 (R)
85 (R)
46 (S)
52 (S)
(S,S)-4
(S,S)-4
6
7
(R,R)-4
(R,R)-4
5
5
a Reactions were carried out with 2 mol% of [Pd(allyl)Cl]2.
b The enantiomeric excess of 9a was determined by HPLC (Kromasil 5-CelluCoat, C6H14/i-PrOH
= 4/1, 0.5 mL/min, 254 nm, t(R) = 18.2 min, t(S) = 20.0 min).
c The absolute configuration was assigned by comparison of the HPLC retention times reported
in the literature.2c,21
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In the next step, the novel bisdiamidophosphites were evaluated in the traditional Pd-
catalyzed allylic alkylation reaction of (E)-1,3-diphenylallyl acetate 8 with dimethyl malonate in
CH2Cl2 or THF medium (Table 4). The C-nucleophile was generated in situ using N,O-
bis(trimethylsilyl) acetamide (BSA) and a catalytic amount of KOAc.22a,b As seen from Table 4,
ligands (S,S)-4, (R,R)-4 and 5 induced excellent enantioselectivity (up to 98%, 97%, and 96% ee
for (S)-9b, respectively, entries 1-4 and 9-16) practically regardless of the L/Pd molar ratio and
solvent nature. On the contrary, the catalytic activity depended on the solvent used: in most cases
quantitative conversion was achieved in CH2Cl2. Notably, cationic palladium complex 6
provides higher ee values of product (S)-9b and the conversion of starting substrate 8 than
neutral complex 7 (Table 4, entries 5-8).
Table 4. Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with dimethyl
malonate a
Entry Compound L/Pd
Solvent
Conversion (%)
ee (%) b,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
2
1
2
1
1
1
1
1
2
1
2
1
2
1
2
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
100
100
100
100
100
100
72
98 (S)
97 (S)
97 (S)
86 (S)
97 (S)
96 (S)
85 (S)
90 (S)
97 (S)
97 (S)
96 (S)
94 (S)
95 (S)
96 (S)
95 (S)
94 (S)
(S,S)-4
(S,S)-4
(S,S)-4
(S,S)-4
6
6
7
7
28
100
100
43
67
99
100
70
56
(R,R)-4
(R,R)-4
(R,R)-4
(R,R)-4
THF
CH2Cl2
CH2Cl2
THF
5
5
5
5
THF
a Reactions were carried out with 2 mol% of [Pd(allyl)Cl]2.
b The conversion of substrate 8 and enantiomeric excess of 9b were determined by HPLC
(Kromasil 5-CelluCoat, C6H14/i-PrOH = 99/1, 0.6 mL/min, 254 nm, t(R) = 18.6 min, t(S) = 20.7
min).
c The absolute configuration was assigned by comparison of the HPLC retention times reported
in the literature.21,22c,d
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Allylic amination of compound 8 with pyrrolidine as the N-nucleophile in presence of
(S,S)-4, (R,R)-4 and 5 afforded the reaction product 9c having a (R)-configuration. On the whole
the “natural” ligand (S,S)-4 displayed higher catalytic activity and enantioselectivity (74–96%
ee) than “unnatural” diastereomer (R,R)-4 (65–90% ee, Table 5, entries 1-4 and 9-12). Cationic
palladium complex 6 provided up to 82% ee and quantitative conversion (Table 5, entries 5, 6).
Similar asymmetric induction, but lower activity in THF medium was demonstrated by neutral
complex 7 (Table 5, entries 7, 8). The catalytic systems based on ligand 5 induced high reaction
rate and good ee values (87–93% ee, Table 5, entries 13-16). In general, the enantioselectivity
was poorly sensitive to the L/Pd molar ratio and nature of the solvent. At the same time, the
conversion of substrate 8 decreases from the quantitative one in CH2Cl2 to moderate in THF in
some cases.
Table 5. Pd-catalyzed allylic amination of (E)-1,3-diphenylallyl acetate 8 with pyrrolidine a
Entry Compound L/Pd
Solvent
Conversion (%)
ee (%) b,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
2
1
2
1
1
1
1
1
2
1
2
1
2
1
2
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
100
100
100
100
100
100
100
60
89 (R)
96 (R)
94 (R)
74 (R)
72 (R)
82 (R)
75 (R)
86 (R)
90 (R)
84 (R)
79 (R)
65 (R)
93 (R)
89 (R)
87 (R)
89 (R)
(S,S)-4
(S,S)-4
(S,S)-4
(S,S)-4
6
6
7
7
100
100
91
(R,R)-4
(R,R)-4
(R,R)-4
(R,R)-4
THF
72
CH2Cl2
CH2Cl2
THF
100
100
99
5
5
5
5
THF
94
a Reactions were carried out with 2 mol% of [Pd(allyl)Cl].
b The conversion of substrate 8 and enantiomeric excess of 9c were determined by HPLC
(Kromasil 5-AmiCoat, C6H14/i-PrOH = 200/1, 1.0 mL/min, 254 nm, t(R) = 5.5 min, t(S) = 6.0
min).
c The absolute configuration was assigned based on the literature data.23
14

ACCEPTED MANUSCRIPT
The novel P*,P*-bidentate bisdiamidophosphites were also involved in the Pd-catalyzed
allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with 1-cyclohexenylpyrrolidine 10 (Table 6).
It is rather important that enamines are convenient nucleophiles for Pd-catalyzed asymmetric
allylic alkylations, avoiding the need to generate unstabilized ketone enolates using strong bases.
However, successful examples of Pd-catalyzed asymmetric allylic substitution with enamines are
scarce, and this process remains a challenge.9a,24 Taken as a whole, the new catalysts based on
(S,S)-4, (R,R)-4 and 5 led to the desired product as a mixture of anti- and syn-diastereomers 11a
and 11b with excellent conversion, good enantioselectivity (up to 94% ee in both cases, Table 6,
entries 3 and 13) and mediocre diastereomeric ratio. Bisdiamidophosphite (S,S)-4 demonstrated
higher anti/syn-ratio and asymmetric induction than its diastereomer (R,R)-4 practically in all
cases (Table 6, entries 1-4 and 7-10). Neutral cationic complex 7 gave no conversion in this
reaction, while cationic complex 6 afforded up to 76% ee and quantitative conversion (Table 6,
entries 5, 6). Ligands (S,S)-4 and 5 provided virtually equal enantioselectivity, but the
diastereoselectivity was higher with (S,S)-4 (Table 6, entries 1-4 and 11-14). We found that there
was no obvious trend in the influence of the nature of the solvent and the L/Pd molar ratio on the
reaction outcome.
Table 6. Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with 1-
cyclohexenylpyrrolidine 10 a
Conversion
(%) b
99
ee (%)
11a/11b
90/86
76/62
94/93
88/85
74/70
72/76
74/76
88/88
78/82
74/78
92/90
88/87
88/94
90/82
Entry
Compound
L/Pd
Solvent
anti/syn c,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
2
1
2
1
1
1
2
1
2
1
2
1
2
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
58/42
60/40
63/37
61/39
52/48
58/42
51/49
50/50
55/45
55/45
57/43
55/45
58/42
54/46
(S,S)-4
(S,S)-4
(S,S)-4
(S,S)-4
6
99
97
96
100
100
100
100
100
100
100
100
100
100
6
(R,R)-4
(R,R)-4
(R,R)-4
(R,R)-4
5
THF
CH2Cl2
CH2Cl2
THF
5
5
5
THF
15

ACCEPTED MANUSCRIPT
a Reactions were carried out with 2 mol% of [Pd(allyl)Cl]2.
b The conversion of substrate 8 and enantiomeric excess of 11a and 11b were determined by
HPLC (Kromasil 5-AmyCoat, C6H14/i-PrOH = 96/4, 0.5 mL/min, 254 nm, t(S,R)-11b = 19.0
min, t(R,S)-11b = 20.0 min; t(S,S)-11a = 20.6 min, t(R,R)-11a = 24.1 min).
c Determined by 1H NMR based on the literature protocol.24c
d The absolute configuration of the predominant enantiomers of the anti- and syn-products was
assigned by comparison of the HPLC retention times reported in the literature.24b,c
Table 7 shows the results obtained in the Pd-catalyzed asymmetric alkylation of cinnamyl
acetate 12 with ethyl 2-oxocyclohexane-1-carboxylate 13 in toluene as the reaction medium; in
this process a quaternary C*-stereocenter formed on a carbon atom belonging to the nucleophile.
Bisdiamidophosphites (S,S)-4, (R,R)-4 and 5 have allowed the synthesis of quaternary-
substituted β-keto ether (S)-14 with quantitative conversion and enantioselectivity up to 62 %, 56
% and 72% ee, respectively (Table 7, entries 1, 2 and 5-8). It is clear that for all ligands the
optimal L/Pd molar ratio is 1. Both cationic 6 and neutral 7 palladium complexes gave
practically equal ee values, but substantially different conversion (Table 7, entries 3, 4). In all
cases, (S)-enantiomer of the resulting product 14 predominates.
Table 7. Pd-catalyzed allylic alkylation of cinnamyl acetate 12 with ethyl 2-oxocyclohexane-1-
carboxylate 13 a
Entry Compound L/Pd
Conversion (%)
ee (%) b,c
1
2
3
4
5
6
7
8
1
2
1
1
1
2
1
2
100
100
100
21
100
98
62 (S)
46 (S)
64 (S)
66 (S)
56 (S)
54 (S)
72 (S)
67 (S)
(S,S)-4
(S,S)-4
6
7
(R,R)-4
(R,R)-4
5
100
100
5
a Reactions were carried out with 2 mol% of [Pd(allyl)Cl]2.
b The conversion of substrate 12 and enantiomeric excess of 14 were determined by HPLC
(Kromasil 5-CelluCoat, C6H14/i-PrOH = 95/5, 0.4 mL/min, 254 nm, t(R) = 14.3 min, t(S) = 16.4
min).
c The absolute configuration was assigned by comparison of the HPLC retention times reported
in the literature.10
16

ACCEPTED MANUSCRIPT
Finally, we also examined the Pd-catalyzed desymmetrization of N,N'-ditosyl-meso-
cyclopent-4-ene-1,3-diol biscarbamate 16 (Table 8); this transformation is formally an
intramolecular allylic substitution reaction of a meso-substrate with two enantiotopic leaving
groups. The catalytic systems were generated in situ from [Pd2(dba)3]·CHCl3, the corresponding
ligand and using Et3N as a base in THF medium, which are used as the standard conditions.25
Higher enantiomeric excess and chemical yield were obtained in the order (R,R)-4 (up to 60%
ee, 39% Table 8, entry 4) < (S,S)-4 (up to 92% ee, 54%, entry 1) < 5 (up to 94% ee, 68%, entry
6). Note that the desired compound 17 proved to have the same (S,R)-configuration in all
experiments. The results in Table 8 showed that “natural” ligand (S,S)-4 provided better
chemical yields and enantioselectivities than “unnatural” diastereomer (R,R)-4 (entries 1, 2 vs 3,
4). As a whole the L/Pd molar ratio do not have a clear impact on the efficiency of the catalytic
process.
Table 8. Pd-catalyzed desymmetrization of N,N'-ditosyl-meso-cyclopent-4-ene-1,3-diol
biscarbamate 16 a
Entry
Ligand
L/Pd
Yield (%)
ee (%) b,c
1
2
3
4
5
6
1
2
1
2
1
2
54
49
43
39
62
68
92 (S,R)
88 (S,R)
58 (S,R)
60 (S,R)
88 (S,R)
94 (S,R)
(S,S)-4
(S,S)-4
(R,R)-4
(R,R)-4
5
5
a Reactions were carried out with 5 mol% of [Pd2(dba)3]·CHCl3.
b The enantiomeric excess of 17 was determined by HPLC (Knauer AG 250, C6H14/i-PrOH =
1/1, 1.0 mL/min, 245 nm, t(R,S) = 16.0 min, t(S,R) = 23.0 min).
с The absolute configuration was assigned by comparison of the HPLC retention times reported
in the literature.25b
3. Conclusion
17

ACCEPTED MANUSCRIPT
The following conclusions can be drawn: (i) novel P*,P*-bidentate bisdiamidophosphites
(S,S)-4, (R,R)-4 and 5 with 1,3-diaza-2-phosphabicyclo[3.3.0]octane cores and 1,4-diol
backbone have been successfully designed and synthesized; (ii) overall, these compounds are
rather efficient chiral inductors for Pd-catalyzed asymmetric transformations. Taking the Pd-
mediated allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with dimethyl malonate as a test
case, it has been demonstrated that the new ligands out-perform the related P,P-bidentate
organophosphorus stereoselectors DIOP and LA-C. Indeed, these compounds gave maximum ee
values of 6%, 3%, 15% and 50%, respectively.3b,c,e,5c This is substantially lower than those
obtained with (S,S)-4, (R,R)-4 and 5 (96–98% ee); (iii) on the whole, the enanioselectivities and
activities achieved with “natural” ligand (S,S)-4 were higher than those attained with its
“unnatural” diastereomeric counterpart (R,R)-4. With exception of the allylic sulfonylation,
ligand 5 provided practically equal or even somewhat higher asymmetric induction than (S,S)-4
in spite that the backbone of 5 is achiral and more flexible; (iv) cationic 6 and neutral 7
palladium complexes showed comparable enantioselectivity, but 6 is significantly superior to 7
in catalytic activity; (v) phosphabicyclic moieties with P*-chirogenic phosphorus atoms have a
dominating steering effect determining the preferred configuration of the product formed. An
exception to this is the allylic sulfonylation, however the stereochemical outcome of this reaction
strongly depends on subtle differences in the structure of the phosphorus-containing ligands.26
Additional studies highlighting the potential of these bisdiamidophosphite ligands in
other transition-metal- mediated enantioselective processes are currently underway.
4. Experimental section
4.1. General comments
13
1
31
31P, C and H NMR spectra were recorded on a Bruker AMX 400 (162.0 MHz for P, 100.6
13
1
31
MHz for C and 400.13 MHz for H) and a Bruker Avance III 600 (242.9 MHz for P, 150.9
MHz for 13C and 600.13 MHz for 1H) instruments. Complete assignment of all the resonances in
1
13
the H and C NMR spectra was achieved by the use of APT and DEPT techniques (together
with COSY, NOESY, ROESY, HSQC and HMBC techniques) and published data.13,14 Chemical
13
shifts (parts per million, ppm) were given relative to Me4Si (1H and C) and 85% H3PO4 (31P
NMR). Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d =
doublet, t = triplet, m = multiplet); coupling constants nJ in Hertz (Hz), ”n” values are reported in
18

ACCEPTED MANUSCRIPT
the case of their unambiguous determination. DOSY diffusion experiments were performed with
double-stimulated echo dstegp3s pulse sequence from TopSpin 3.2 program package.
X-ray powder diffraction data were collected using a Panalytical EMPYREAN
instrument with a linear X’celerator detector using nonmonochromated Cu Ka radiation. The
single-crystal X-ray diffraction experiments were carried out on a STOE diffractometer
Pilatus100K detector, focusing mirror collimation Cu Kα (1.54086Å) radiation, in rotation
method mode. IR spectra were recorded on an IFS-113V instrument. Mass spectra were recorded
on a Bruker Daltonics Ultraflex spectrometer (MALDI TOF/TOF). Optical rotations were
measured on an Atago AP-300 polarimeter. HPLC analyses were performed on a Stayer
instrument using Kromasil® and Knauer® columns. Elemental analyses were performed on a
CHN-microanalyzer Carlo Erba EA1108 CHNS-O.
All reactions were carried out under a dry argon atmosphere in flame-dried glassware and
in freshly dried and distilled solvents. For example, toluene and tetrahydrofuran were freshly
distilled from sodium benzophenone ketyl before use; dichloromethane was distilled from NaH.
Triethylamine and pyrrolidine were distilled over KOH and then over a small amount of LiAlH4
before use. Thin-layer chromatography was performed on E. Merck pre-coated silica gel 60 F254
and Macherey-Nagel Alugram Alox N/UV254 plates. Column chromatography was performed
using silica gel MN Kieselgel 60 (230 – 400 mesh) and MN-Aluminum oxide, basic, Brockmann
Activity
1.
Phosphorylating
reagent
(5S)-2-chloro-3-phenyl-1,3-diaza-2-
phosphabicyclo[3.3.0]octane 1, (4S,5S)- and ((4R,5R)-4,5-di-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolane ((S,S)-2 and (R,R)-2) were prepared analogously to known procedures.13,4 The
[Pd(allyl)Cl]2, (E)-1,3-diphenylallyl acetate 8, Pd(Cod)Cl2 and [Pd2(dba)3]·CHCl3 were obtained
as published.27 Pd-catalyzed reactions: allylic sulfonylation of (E)-1,3-diphenylallyl acetate 8
with sodium para-toluene sulfinate, alkylation with dimethyl malonate and 1-
cyclohexenylpyrrolidine 10, amination with pyrrolidine, allylic alkylation of cinnamyl acetate
12 with ethyl 2-oxocyclohexane-1-carboxylate 13 and desymmetrization of N,N'-ditosyl-meso-
cyclopent-4-ene-1,3-diol biscarbamate 16 were performed according to the appropriate
procedures.13,24,28,10,25,2c
Butane-1,4-diol 3, sodium para-toluene sulfinate, dimethyl malonate, N,O-
bis(trimethylsilyl) acetamide (BSA), 1-cyclohexenylpyrrolidine 10, cinnamyl acetate 12, ethyl 2-
oxocyclohexane-1-carboxylate 13, meso-cyclopent-4-ene-1,3-diol 15 and tosyl isocyanate were
purchased from Aldrich and Acros Organics and used without further purification.
4.2. General procedure for the preparation of ligands (S,S)-4, (R,R)-4 and 5
19

ACCEPTED MANUSCRIPT
A solution of the appropriate diol (S,S)-2, (R,R)-2 or 3 (1 mmol) in THF (5 mL) was
added dropwise to a vigorously stirred solution of the phosphorylating reagent 1 (0.49 g, 2
mmol) and Et3N (0.42 mL, 3 mmol) in THF (10 mL). The mixture obtained was stirred for 24 h
at 20 °C, then heated to 45 °C, and stirred at this temperature for 30 min, and then cooled to
20oC. The resulting suspension was filtered through a short plug of Al2O3/SiO2, the column was
washed twice with THF (6 mL), and the solvent was evaporated under reduced pressure (40
Torr). The residue was purified by flash chromatography on Al2O3 (toluene/Et3N, 97:3). The
product was dried in vacuum (1 Torr) for 1 h.
4.2.1.
(4S,5S)-4,5-Bis[((2R,5S)-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octyloxy)methyl]-
2,2-dimethyl-1,3-dioxolane ((S,S)-4). Yield: 0.47 g (83%) as white solid, mp 48-50 °C. [α]D24 = -
300.1o (c 1.0, THF). IR: νmax (KBr) 3035, 2938, 2867, 1598, 1499, 1306, 1118, 1016, 751, 691
1
cm-1. H NMR (600.03 MHz, CDCl3, 30 °C): δ = 1.37 (s, 6H, СH3), 1.58-1.65 (m, 2H,
NCHCH2), 1.71-1.80 (m, 2H, NCH2CH2), 1.81-1.88 (m, 2H, NCH2CH2), 1.99-2.07 (m, 2H,
NCHCH2), 3.09-3.13 (m, 2H, PNCH2), 3.13-3.20 (m, 2H, NCH2CH2), 3.36-3.41 (m, 2H,
POCH2), 3.52-3.58 (m, 2H, NCH2CH2), 3.60 (t, JH,H = 8.4, 2H, PNCH2), 3.74-3.79 (m, 2H,
3
POCH2), 3.91-3.95 (m, 2H, POCH2CH), 3.99-4.05 (m, 2H, PNCH), 6.84 (t, JH,H = 7.8, 2H,
CHpara), 6.97 (d, 3JH,H = 7.8, 4H, CHotho), 7.23 (t, 3JH,H = 7.8, 4H, CHmeta). 13C NMR (150.9 MHz,
3
CDCl3, 30 °C): δ = 26.3 (d, JC,P = 3.8, NCH2CH2), 27.0 (s, CH3), 32.1 (s, NCHCH2), 48.6 (d,
2JC,P = 38.3, NCH2CH2), 55.0 (d, 2JC,P = 6.9, PNCH2), 61.2 (d, 2JC,P = 5.6, POCH2), 63.1 (d, 2JC,P
3
3
= 8.8, PNCH), 77.2 (d, JC,P = 2.8, POCH2CH), 109.1 (s, C(CH3)2), 114.8 (d, JC,P = 12.1,
2
CHotho), 118.8 (s, CHpara), 129.1 (s, CHmeta), 145.6 (d, JC,P = 15.7, PNC). MS (MALDI
TOF/TOF): m/z (%) = 609 (15) [M + K]+, 589 (21) [M + H2O + H]+, 181 (100)
[HOCH2(CHOCMe2OCH)CH2OH + H2O + H]+. Anal. Calcd for C29H40N4O4P2: C, 61.04; H,
7.07; N, 9.82. Found: C, 61.28; H, 7.13; N, 9.67.
4.2.2. (4R,5R)-4,5-Bis[((2R,5S)-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octyloxy)methyl]-
24
2,2-dimethyl-1,3-dioxolane ((R,R)-4). Yield: 0.46 g (80%) as white solid, mp 62-64 °C. [α]D
=
- 293.8o (c 1.0, THF). IR: νmax (KBr) 3036, 2945, 2870, 1599, 1500, 1304, 1119, 1005, 750, 688
1
cm-1. H NMR (400.13 MHz, CDCl3, 27 °C): δ = 1.35 (s, 6H, СH3), 1.55-1.66 (m, 2H, CH2),
1.68-1.89 (m, 4H, CH2), 1.95-2.07 (m, 2H, CH2), 3.08-3.21 (m, 4H, NCH2), 3.50-3.60 (m, 4H,
POCH2 + NCH2), 3.65 (t, J = 8.2, 2H, PNCH2), 3.74-3.85 (m, 4H, POCH2 + POCH2CH), 4.00-
3
3
4.09 (m, 2H, PNCH), 6.84 (br. t, JH,H = 7.6, 2H, CHpara), 6.99 (br. d, JH,H = 7.6, 4H, CHotho),
3
7.19-7.26 (m, 4H, CHmeta). 13C NMR (100.6 MHz, CDCl3, 27 °C): δ = 26.1 (d, JC,P = 3.0,
2
2
NCH2CH2), 26.9 (s, CH3), 31.9 (s, NCHCH2), 48.5 (d, JC,P = 38.3, NCH2CH2), 54.8 (d, JC,P
=
20

ACCEPTED MANUSCRIPT
2
2
3
6.9, PNCH2), 62.6 (d, JC,P = 3.8, POCH2), 63.0 (d, JC,P = 8.9, PNCH), 77.7 (d, JC,P = 2.6,
3
POCH2CH), 109.5 (s, C(CH3)2), 114.7 (d, JC,P = 11.6, CHotho), 118.8 (s, CHpara), 129.0 (s,
2
CHmeta), 145.5 (d, JC,P = 16.5, PNC). MS (MALDI TOF/TOF): m/z (%) = 609 (11) [M + K]+,
589 (19) [M + H2O + H]+, 181 (100) [HOCH2(CHOCMe2OCH)CH2OH + H2O + H]+. Anal.
Calcd for C29H40N4O4P2: C, 61.04; H, 7.07; N, 9.82. Found: C, 61.33; H, 7.17; N, 9.87.
4.2.3. 1,4-Bis((2R,5S)-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octyloxy)butane (5). Yield:
0.37 g (75%) as colorless viscous oil that solidified on standing, mp 74-76 °C. [α]D24 = - 315.6o
(c 1.0, THF). IR: νmax (KBr) 3033, 2943, 2867, 1597, 1501, 1309, 1117, 1001, 756, 692 cm-1. 1H
NMR (600.03 MHz, CDCl3, 30 °C): δ = 1.53-1.59 (m, 4H, POCH2СH2), 1.58-1.65 (m, 2H,
NCHCH2), 1.70-1.79 (m, 2H, NCH2CH2), 1.80-1.87 (m, 2H, NCH2CH2), 1.98-2.06 (m, 2H,
NCHCH2), 3.09-3.13 (m, 2H, PNCH2), 3.13-3.20 (m, 2H, NCH2CH2), 3.40-3.47 (m, 2H,
POCH2), 3.51-3.58 (m, 2H, NCH2CH2), 3.57-3.63 (m, 2H, POCH2), 3.59 (t, JH,H = 8.1, 2H,
3
3
PNCH2), 3.97-4.03 (m, 2H, PNCH), 6.84 (t, JH,H = 7.8, 2H, CHpara), 6.99 (d, JH,H = 7.2, 4H,
CHotho), 7.23 (t, 3JH,H = 7.8, 4H, CHmeta). 13C NMR (100.6 MHz, CDCl3, 27 °C): δ = 26.0 (d, 3JC,P
3
2
= 3.4, NCH2CH2), 26.7 (d, JC,P = 3.1, POCH2CH2), 31.9 (s, NCHCH2), 48.6 (d, JC,P = 38.3,
2
2
2
NCH2CH2), 54.8 (d, JC,P = 6.8, PNCH2), 60.7 (d, JC,P = 3.9, POCH2), 63.1 (d, JC,P = 8.9,
PNCH), 114.6 (d, 3JC,P = 11.9, CHotho), 118.5 (s, CHpara), 128.9 (s, CHmeta), 145.7 (d, 2JC,P = 16.1,
PNC). MS (MALDI TOF/TOF): m/z (%) = 537 (100) [M + K]+. Anal. Calcd for C26H36N4O2P2:
C, 62.64; H, 7.28; N, 11.24. Found: C, 62.83; H, 7.35; N, 11.10.
4.3. Procedure for the synthesis of the cationic palladium complex 6
A solution of the ligand (S,S)-4 (0.114 g, 0.2 mmol) in CH2Cl2 (2 mL) was added
dropwise over 30 min to a stirred solution of [Pd(allyl)Cl]2 (0.037 g, 0.1 mmol) in CH2Cl2 (1
mL) at 20 °C. The reaction mixture was stirred for a further 1 h at 20 °C. A solution of AgBF4
(0.039 g, 0.2 mmol) in THF (2 mL) was added dropwise over 30 min to the resulting solution,
and the reaction mixture was stirred for 1.5 h at 20 °C. The precipitate of AgCl formed was
separated by filtration. Solvent excess was removed in vacuum (40 Torr) to a volume of ~0.3
mL, and ether (7 mL) was added. The precipitate formed was separated by centrifugation,
washed with ether (2 × 5 mL), and dried in air and in vacuum (1 Torr).
4.3.1. [Pd(allyl)((S,S)-4)]BF4 (6). Yield: 0.145 g (90%) as sand-colored powder. MS (MALDI
TOF/TOF): m/z (%) = 717 (100) [M – BF4]+, 676 (8) [M – BF4 – allyl ]+. Anal. Calcd for
C32H45BF4N4O4P2Pd: C, 47.75; H, 5.64; N, 6.96. Found: C, 48.05; H, 5.55; N, 6.87.
21

ACCEPTED MANUSCRIPT
4.4. Procedure for the synthesis of the neutral palladium complex 7
A solution of the ligand (S,S)-4 (0.114 g, 0.2 mmol) in CH2Cl2 (2 mL) was added
dropwise over 30 min to a stirred suspension of Pd(Cod)Cl2 (0.057 g, 0.2 mmol) in CH2Cl2 (2
mL) at 20 °C. The reaction mixture was stirred for a further 1 h at 20 °C. Solvent excess was
removed in vacuum (40 Torr) to a volume of ~0.3 mL, and ether (7 mL) was added. The
precipitate formed was separated by centrifugation, washed with ether (2 × 5 mL), and dried in
air and in vacuum (1 Torr).
1
4.4.1. [Pd((S,S)-4)Cl2] (7). Yield: 0.139 g (93%) as yellow powder. H NMR for 7 (600.03
MHz, CDCl3, 23 °C): δ = 1.44 (s, 6H, СH3), 1.89-1.94 (m, 2H, NCHCH2), 1.99-2.05 (m, 2H,
NCH2CH2), 2.10-2.16 (m, 2H, NCHCH2), 2.25-2.33 (m, 2H, NCH2CH2), 3.28-3.33 (m, 2H,
NCH2CH2), 3.56-3.64 (m, 2H, POCH2), 3.76-3.82 (m, 2H, PNCH2), 3.82-3.87 (m, 2H, PNCH2),
4.15-4.20 (m, 2H, PNCH), 4.36-4.39 (m, 2H, POCH2CH), 4.39-4.47 (m, 2H, NCH2CH2), 4.50-
3
3
4.57 (m, 2H, POCH2), 7.04 (t, JH,H = 7.2, 2H, CHpara), 7.27 (d, JH,H = 7.2, 4H, CHotho), 7.27-
7.31 (m, 4H, CHmeta). 1H NMR for 7` (600.03 MHz, CDCl3, 23 °C): δ = 1.22 (s, 6H, СH3), 1.93-
1.99 (m, 2H, NCH2CH2), 1.98-2.04 (m, 2H, NCHCH2), 2.05-2.10 (m, 2H, NCHCH2), 2.34-2.41
(m, 2H, NCH2CH2), 3.32-3.37 (m, 2H, NCH2CH2), 3.82-3.87 (m, 2H, PNCH2), 3.87-3.93 (m,
2H, PNCH2), 4.13-4.19 (m, 2H, PNCH), 4.21-4.28 (m, 4H, POCH2), 4.33-4.35 (m, 2H,
3
3
POCH2CH), 4.43-4.48 (m, 2H, NCH2CH2), 6.98 (t, JH,H = 7.2, 2H, CHpara), 7.23 (t, JH,H = 7.8,
4H, CHmeta), 7.28-7.31 (m, 4H, CHortho). 13C NMR for 7 (150.9 MHz, CDCl3, 24 °C): δ = 26.85
(s, CH3), 26.88 (vt, JC,P = 2.4, NCH2CH2), 30.66 (s, NCHCH2), 50.24 (vt, JC,P = 10.0,
NCH2CH2), 56.58 (vt, JC,P = 2.9, PNCH2), 61.71 (s, PNCH), 66.69 (vt, JC,P = 5.6, POCH2), 77.34
(s, POCH2CH), 112.09 (s, C(CH3)2), 118.47 (vt, JC,P = 2.6, CHotho), 122.56 (s, CHpara), 129.16 (s,
CHmeta), 142.25 (vt, JC,P = 4.5, PNC). 13C NMR for 7` (150.9 MHz, CDCl3, 24 °C): δ = 25.92 (s,
CH3), 26.45 (vt, JC,P = 2.1, NCH2CH2), 30.90 (s, NCHCH2), 50.79 (vt, JC,P = 9.8, NCH2CH2),
56.71 (br. s, PNCH2), 62.05 (s, PNCH), 64.62 (br. s, POCH2), 74.32 (br. s, POCH2CH), 110.31
(s, C(CH3)2), 116.91 (vt, JC,P = 2.6, CHotho), 122.19 (s, CHpara), 129.15 (s, CHmeta), 141.77 (vt,
JC,P = 4.5, PNC). Anal. Calcd for C29H40Cl2N4O4P2Pd: C, 46.57; H, 5.39; N, 7.49. Found: C,
46.82; H, 5.50; N, 7.69.
4.5. Catalytic reactions
22

ACCEPTED MANUSCRIPT
4.5.1. Pd-catalyzed allylic sulfonylation of (E)-1,3-diphenylallyl acetate 8 with sodium para-
toluene sulfinate. A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the appropriate ligand
(0.01 mmol or 0.02 mmol) in THF (1.5 mL) was stirred for 40 min at 20 °C or the appropriate
complex 6 or 7 (0.01 mmol) was dissolved in THF (1.5 mL). (E)-1,3-Diphenylallyl acetate (0.05
mL, 0.25 mmol) was added and the solution stirred for 15 min, then sodium para-toluene
sulfinate (0.089 g, 0.5 mmol) was added and the reaction mixture stirred for a further 48 h,
quenched with brine (3 mL), and extracted with THF (3 × 2 mL). The organic layer was washed
with brine (2 × 2 mL), dried over MgSO4 and filtered. The solvent was evaporated at reduced
pressure (40 Torr). Crystallization of the residue from EtOH, followed by desiccation in vacuum
(10 Torr, 12 h), gave (E)-1,3-diphenyl-3-tosylprop-1-ene 9a as white crystals.26,29 The
enantiomeric excess of 9a was determined by HPLC (Kromasil 5-CelluCoat, C6H14/i-PrOH =
4/1, 0.5 mL/min, 254 nm, t(R) = 18.2 min, t(S) = 20.0 min).
4.5.2. Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with dimethyl malonate.
A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the appropriate ligand (0.01 mmol or
0.02 mmol) in the appropriate solvent (1.5 mL) was stirred for 40 min at 20 °C or the appropriate
complex 6 or 7 (0.01 mmol) was dissolved in the corresponding solvent (1.5 mL). (E)-1,3-
Diphenylallyl acetate (0.05 mL, 0.25 mmol) was added and the solution stirred for 15 min.
Dimethyl malonate (0.05 mL, 0.44 mmol), BSA (0.11 mL, 0.44 mmol), and potassium acetate
(0.002 g) were added. The reaction mixture was stirred for 48 h, diluted with CH2Cl2 or THF (2
mL), and filtered through a thin layer of SiO2. The filtrate was evaporated at reduced pressure
(40 Torr) and dried in vacuum (10 Torr, 12 h) affording a residue containing (E)-dimethyl 2-
(1,3-diphenylallyl)malonate 9b.30 In order to evaluate ee and conversion, the obtained residue
was dissolved in an appropriate eluant mixture (8 mL) and a sample was taken for HPLC
analysis (Kromasil 5-CelluCoat, C6H14/i-PrOH = 99/1, 0.6 mL/min, 254 nm, t(R) = 18.6 min,
t(S) = 20.7 min).
4.5.3. Pd-catalyzed allylic amination of (E)-1,3-diphenylallyl acetate 8 with pyrrolidine. A
solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the appropriate ligand (0.01 mmol or 0.02
mmol) in the appropriate solvent (1.5 mL) was stirred for 40 min at 20 °C or the appropriate
complex 6 or 7 (0.01 mmol) was dissolved in the corresponding solvent (1.5 mL). (E)-1,3-
Diphenylallyl acetate (0.05 mL, 0.25 mmol) was added and the solution stirred for 15 min, then
freshly distilled pyrrolidine (0.06 mL, 0.75 mmol) was added. The reaction mixture was stirred
for 48 h, diluted with CH2Cl2 or THF (2 mL), and filtered through a thin layer of SiO2. The
filtrate was evaporated at reduced pressure (40 Torr) and dried in vacuum (10 Torr, 12 h)
23

ACCEPTED MANUSCRIPT
affording a residue containing (E)-1-(1,3-diphenylallyl)pyrrolidine 9c.23,31 In order to evaluate ee
and conversion, the obtained residue was dissolved in an appropriate eluant mixture (8 mL) and
a sample was taken for HPLC analysis (Kromasil 5-AmiCoat, C6H14/i-PrOH = 200/1, 1.0
mL/min, 254 nm, t(R) = 5.5 min, t(S) = 6.0 min).
4.5.4. Pd-catalyzed allylic alkylation of (E)-1,3-diphenylallyl acetate 8 with 1-
cyclohexenylpyrrolidine 10. A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the
appropriate ligand (0.01 mmol or 0.02 mmol) in the appropriate solvent (1.5 mL) was stirred for
40 min at 20 °C or the appropriate complex 6 or 7 (0.01 mmol) was dissolved in the
corresponding solvent (1.5 mL). (E)-1,3-Diphenylallyl acetate (0.05 mL, 0.25 mmol) was added
and the solution stirred for 15 min, then 1-cyclohexenylpyrrolidine (0.115 g, 0.75 mmol) was
added and the reaction mixture was stirred for further 48 h, quenched with saturated NH4Cl
solution (5 mL) for 2 h and extracted with CH2Cl2 (3 x 3 mL). The combined organic extracts
were washed with water (3 mL), brine (3 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure (40 Torr) after filtration. The residue was dissolved in EtOAc/hexane
(1:10) and filtered through a thin layer of SiO2. The filtrate was evaporated at reduced pressure
(40 Torr) and dried in vacuum (10 Torr, 12 h) affording a residue containing (E)-2-(1,3-
diphenylallyl)cyclohexanone of anti-configuration (11a) and syn-configuration (11b).24b,c The
1
ratio of anti- and syn-configuration was determined by H NMR. In order to evaluate ee and
conversion, the obtained residue was dissolved in an appropriate eluent mixture (8 mL) and a
sample was taken for HPLC analysis (Kromasil 5-AmyCoat, C6H14/i-PrOH = 96/4, 0.5 mL/min,
254 nm, t(S,R)-11b = 19.0 min, t(R,S)-11b = 20.0 min; t(S,S)-11a = 20.6 min, t(R,R)-11a = 24.1
min).
4.5.5. Pd-catalyzed allylic alkylation of cinnamyl acetate 12 with ethyl 2-oxocyclohexane-1-
carboxylate 13. A solution of [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) and the appropriate ligand
(0.01 mmol or 0.02 mmol) in toluene (1.5 mL) was stirred for 40 min at 20 °C or the appropriate
complex 6 or 7 (0.01 mmol) was dissolved in toluene (1.5 mL). Cinnamyl acetate (0.04 mL, 0.25
mmol) was added and the solution stirred for 15 min. Ethyl 2-oxocyclohexane-1-carboxylate
(0.06 mL, 0.375 mmol), BSA (0.25 mL, 1 mmol) and Zn(OAc)2 (0.005 g) were added. The
reaction mixture was stirred for 48 h, diluted with toluene (2 mL) and filtered through a thin
layer of SiO2. The filtrate was evaporated at reduced pressure (40 Torr) and dried in vacuum (10
Torr, 12 h) affording a residue containing ethyl 1-cinnamyl-2-oxocyclohexanecarboxylate 14.10
In order to evaluate ee and conversion, the obtained residue was dissolved in an appropriate
24

ACCEPTED MANUSCRIPT
eluent mixture (8 mL) and a sample was taken for HPLC analysis (Kromasil 5-CelluCoat,
C6H14/i-PrOH = 95/5, 0.4 mL/min, 254 nm, t(R) = 14.3 min, t(S) = 16.4 min).
4.5.6.
Pd-catalyzed
desymmetrization
of
N,N'-ditosyl-meso-cyclopent-4-ene-1,3-diol
biscarbamate 16. A solution of [Pd2(dba)3]·CHCl3 (0.005 g, 0.005 mmol) and the appropriate
ligand (0.01 mmol or 0.02 mmol) in THF (1 mL) was stirred for 40 min at 20 °C. A solution of
N,N’-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate 16 and Et3N (14 µL, 0.099 mmol) in
THF (0.5 mL) was added (compound 16 was prepared in situ as follows: to a solution of the
meso-cyclopent-4-ene-1,3-diol 15 (0.01 g, 0.099 mmol) in THF (0.5 mL), tosyl isocyanate (35
µL, 0.232 mmol) was added; the mixture was stirred at 20 °C for 15 min, heated to 55 °C for 1 h,
and cooled down to 20 °C). The reaction mixture was stirred for 24 h. The solvent was removed
at reduced pressure (40 Torr) and the residue was purified by flash chromatography on a short
pad of SiO2 (EtOAc/hexane, 1:4). The residue was suspended in boiling mixture CH2Cl2/hexane
(1:10) and filtered. The filtrate was evaporated at reduced pressure (40 Torr) and dried in
vacuum (1 Torr, 2 h) gave the desired product 17 as a slightly yellow oil that solidified on
standing.25c,32 The enantiomeric excess of 17 was determined by HPLC (Knauer AG 250,
C6H14/i-PrOH = 1/1, 1.0 mL/min, 245 nm, t(R,S) = 16.0 min, t(S,R) = 23.0 min).
Crystallographic data (excluding powder pattern) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supplementary publication
nos. CCDC 1479708 ((S,S)-4) and 1479709 (7). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Acknowledgments
The reported study was supported by Russian Foundation for Basic Research, research
Project No. 14-03-00396-a.
Supplementary data
Supplementary data associated with this article can be found in the online version, at
References and notes
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