Synthesis and applications of diphosphine ligands derived from the lignan hydroxymatairesinol

Article abstract of DOI:10.1016/j.cattod.2014.02.032

Highly efficient methods for synthetic modifications of the natural lignan hydroxymatairesinol into chiral diphosphines similar to DIOP were developed. Catalytic activity and induction of enantioselectivity for the prepared phosphines were evaluated in rh

Full text of DOI:10.1016/j.cattod.2014.02.032

G Model
CATTOD-8924; No. of Pages4
ARTICLE IN PRESS
Catalysis Today xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Catalysis Today
journal homepage: www.elsevier.com/locate/cattod
Synthesis and applications of diphosphine ligands derived from
the lignan hydroxymatairesinol
Yury Brusentsev, Patrik Eklund∗
Laboratory of Organic Chemistry, Åbo Akademi University, Biskopsgatan 8, 20500 Åbo (Turku), Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly efficient methods for synthetic modifications of the natural lignan hydroxymatairesinol into chiral
diphosphines similar to DIOP were developed. Catalytic activity and induction of enantioselectivity for
the prepared phosphines were evaluated in rhodium catalyzed hydrogenations of different functionalized
alkenes. High catalytic activities were observed with low catalyst loading at atmospheric pressure. The
phosphines showed moderate to high enantioselectivity depending on the substrate used. Hydrogenation
of 1-acetamidostyrene gave 84% ee of the S-enantiomer.
Received 10 October 2013
Received in revised form 4 December 2013
Accepted 12 February 2014
Available online xxx
Keywords:
© 2014 Elsevier B.V. All rights reserved.
Hydroxymatairesinol
Chiral phosphine
DIOP
Lignans
Asymmetric catalysis
Rhodium catalyzed hydrogenation
1. Introduction
environment and to stabilize the metal complex. Phosphine ligand
has been proven to be the most suitable for this purpose.
The increasing demand to produce enantiomerically pure
pharmaceuticals, agrochemicals, flavors, and other fine chemicals
requires the development of new, more effective and cheaper
methods of asymmetric catalysis. Utilization of natural chiral
molecules as ligands in asymmetric catalysis is one way to increase
the efficiency. Recent development in the field of biorefinery has
made several wood-based natural products available in large-scale.
The isolation and purification of lignans from knotwood of conifer-
ous species has received much attention. For example, separation of
hydroxymatairesinol from knotwood of Norway spruce has made
it possible to study this lignan more in detail. Hydroxymatairesinol
has been shown to have interesting biological activity such as anti-
cancer and antioxidant activity and new application areas for its
utilization are of great interest. Here we report the transformation
of hydroxymatairesinol to chiral diphosphines for applications in
chiral catalysis.
(4R,5R)-4,5-Bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-
dioxolane (DIOP) was one of the first chiral ligands used for
asymmetric catalysis [1]. However, DIOP itself provided only mod-
erate to good enantioselectivities in asymmetric hydrogenations
of dehydroamino acid derivatives. Tang at al. [2] proposed as a
possible reason that the seven-membered chelate ring of the DIOP
metal complex is conformationally flexible. Indeed introduction
of the substituent into -CH2-P arm significantly improves the
selectivity (DIOP*) [3]. On the other hand, similar diphosphines
with more rigid 6-membered ring in their backbone like sk-Phos,
provides excellent selectivity in a number of reactions [4]. Nev-
ertheless, only a few chirally pure diphosphines similar to DIOP,
not derived from tartaric acid, has been described in literature
[5–7].
We recently reported that the readily available lignan hydroxy-
matairesinol from knotwood of Norway Spruce can be transformed
to chiral 1,4-diols [8,9]. Here we present the concept of using
hydroxymatairesinol for preparation of different (similar to DIOP)
diphosphine ligands and their application in asymmetric hydro-
genations. The use of hydroxymatairesinol as a starting material,
gives an access to the enantiopure butyrolactone with the 8R,8ꢀR
configuration similar to DIOP (Fig. 1). The structure of hydrox-
ymatairesinol allows modifications of the phenolic functions,
electron rich aromatic rings, the benzylic alcohol group and the
One of the most important reactions in this field of cataly-
sis is the transition metal catalyzed asymmetric hydrogenation.
This reaction requires a chiral ligand to create the asymmetric
∗
Corresponding author. Tel.: +358 2215 4720.
E-mail address: paeklund@abo.fi (P. Eklund).
http://dx.doi.org/10.1016/j.cattod.2014.02.032
0920-5861/© 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: Y. Brusentsev, P. Eklund, Synthesis and applications of diphosphine ligands derived from the lignan
hydroxymatairesinol, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.02.032

G Model
CATTOD-8924; No. of Pages4
ARTICLE IN PRESS
2
Y. Brusentsev, P. Eklund / Catalysis Today xxx (2014) xxx–xxx
to dryness. The residue was purified by flash chromatog-
O
MeO
HO
8'
8
raphy in chloroform to give product as
a
colorless solid.
O
O
Starting material (diol)
Product (dimesylate)
Yield, %
PPh2
PPh2
HO
5
6
7
8
9
10
11
12
96
62
95
97
O
OMe
OH
(-)-DIOP
2.4. Sodium diphenylphosphide
(-)-Hydroxymatairesinol
To a solution of diphenylphosphine (50 mmol, 8.7 ml) in dry THF
(30 ml) sodium metal (52 mmol, 1.2 g) was added as small pieces
over 1.5 h. The mixture was stirred for 6 h until all sodium was
dissolved and the solution of the sodium diphenylphosphide was
diluted with dry THF to 50 ml.
Fig. 1. Similarity in stereochemistry for DIOP and hydroxymatairesinol.
butyrolactone ring which provides a number of possible derivatives
and backbones.
2. Experimental
2.5. General method for preparation of the phosphines (13, 14,
15, 16) (Scheme 3)
2.1. General methods
Dimesylate (9, 10, 11 or 12) (0.5 mmol) was dissolved in
THF (30 ml) and 1 M THF solution of the sodium diphenylphos-
phide (1.5 ml, 1.5 mmol) was added dropwize. The mixture
was stirred for 18 h at room temperature and then it was
concentrated to dryness. The residue was purified by flash chro-
matography to give the target diphosphine as a colorless solid.
Unless otherwise stated, chemicals were obtained from com-
mercial suppliers and used without further purification.
A
knotwood extract containing hydroxymatairesinol was supplied by
UPM Ltd. THF and toluene were dried by the sodium-benzophenone
method immediately prior to use. DMF and DCM were dried by dis-
tilling from CaH2. NMR spectra were recorded with Bruker Avance
600 MHz NMR spectrometer using standard pulse sequences. Chi-
ral HPLC analyses were performed with a HPLC chromatograph
equipped with a Daicel HPLC column Chiralcel OD-H. Chiral GC
analyses were performed with a gas chromatograph equipped with
a Varian capillary column CP-Chirasil-Dex CB. HRMS were recorded
using a Bruker Micro Q-TOF instrument with ESI (electorspray ion-
ization) operated in positive mode. The reactions were monitored
by TLC. Aluminum based TLC plates (Merck) silicagel 60 F254 were
used.
Starting material (dimesylate)
Product (diphosphine)
Yield, %
9
10
11
12
13
14
15
16
90
87
91
88
2.6. General method for asymmetric hydrogenation reaction
2.6.1. Preparation of the stock solution of the catalyst
Dichloro-tetraethylene-dirhodium (14 mg, 0.035 mmol) was
dissolved in THF (2 ml) and phosphine (13, 14, 15 or 16)
(0.074 mmol) was added in one portion. The reaction mixture was
stirred at room temperature for 12 h. The prepared solution of the
catalyst had a concentration of 0.035 M.
Analytical data for the prepared compounds (NMR, HRMS, ele-
mental analyses) and for asymmetric reactions (chiral LC and GC
chromatograms) are presented in Supporting Information (SI).
2.2. General method for preparation of diols (5, 6, 7, 8)
(Scheme 2)
2.6.2. Catalytic reaction
Lactone (1, 2, 3 or 4) (5 mmol) was dissolved in tetrahy-
drofuran (30 ml) and the solution was cooled down to 0 ◦C.
Lithium aluminum hydride (2.5 ml of 4 M solution in Et2O,
10 mmol) was added dropwise over a period of 0.5 h. The reac-
tion mixture was stirred for 2 h at room temperature. Then 1 ml
of 10% NaOH in water was added carefully drop by drop and
the suspension was filtered and the precipitate was washed
with hot THF. The filtrates were combined and the solvent was
evaporated to give the final product (5, 6, 7 or 8) as a white powder.
Substrate 18 (0.7 mmol, 154 mg) or 20 (0.7 mmol, 114 mg) was
dissolved in methanol (2 ml) and stock solution of the catalyst was
added (0.1 ml, 0.5 mol %, or 0.2 ml, 1 mol %). Hydrogen was bubbled
through the solution for 1 h. The reaction mixture was analyzed
by GCMS and by chiral GC. All conversions were over 95%. The
selectivities of the reactions are presented in Tables 1 and 2.
3. Results and discussion
Starting material (lactone)
Product (diol)
Yield, %
To prepare a diverse scope of lignan-derived phosphines,
hydroxymatairesinol was transformed into four different lactones
by methods described in our previous publications (Scheme 1) [8,9].
In short, dimethylmatairesinol (1) was prepared from hydroxy-
matairesinol by hydrogenolysis on palladium to matairesinol [10]
followed by methylation of the phenolic hydroxyls. Dimethyl-
conidendrin (2) was obtained by methylation of the phenolic
hydroxyls of the lignan conidendrin, which forms quantitatively
in acidic conditions from hydroxymatairesinol [11]. Lactone 3 was
prepared from 1 by intramolecular oxidative coupling mediated
by vanadium oxyfluoride. For preparation of the macrocyclic com-
pound 4, the phenolic groups of matairesinol were first allylated
and then cyclized by ring-closing metathesis, followed by hydro-
genation of the double bond [9].
1
2
3
4
5
6
7
8
88
87
75
74
2.3. General method for preparation of dimesylates (9, 10, 11,
12) (Scheme 3)
Diol (5, 6, 7 or 8) (1 mmol) was dissolved in DCM (20 ml)
and TEA (0.35 ml, 2.5 mmol) was added followed by addition
of mesyl chloride (0.17 ml, 2.2 mmol). The mixture was stirred
at room temperature for 16 h and then it was washed with
water (2 × 30 ml), dried over sodium sulfate and concentrated
Please cite this article in press as: Y. Brusentsev, P. Eklund, Synthesis and applications of diphosphine ligands derived from the lignan
hydroxymatairesinol, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.02.032

G Model
CATTOD-8924; No. of Pages4
ARTICLE IN PRESS
Y. Brusentsev, P. Eklund / Catalysis Today xxx (2014) xxx–xxx
3
O
O
O
MeO
HO
MeO
MeO
MeO
MeO
O
O
O
HO
2 steps
2 steps
88% overal yield
OMe
91% overal yield
OMe
OMe
OH
OMe
OMe
Hydroxymatairesinol
1
2
4 steps
3 steps
38% overal yield
57% overal yield
MeO
MeO
O
MeO
O
O
O
O
O
MeO
MeO
MeO
3
4
Scheme 1. Preparation of different lactones from hydroxymatairesinol.
The lactones (1–4) were then reduced to the chiral diols (5–8)
by lithium aluminum hydride in good yields (Scheme 2). Racem-
ization of the Ar–Ar chiral axis was observed during the reduction
of the lactone 3 and diol 7 was obtained as a mixture of diastereo-
mers (86:14). The ratio of the isomers was not depended on the
temperature of the reaction. The ratio also remained constant after
5 h reflux in toluene. Separation of the diastereomers was not fea-
sible and all subsequent transformations were performed with the
mixture of isomers.
To transform the diols to the corresponding phosphines, the
common literature procedure via tosylates, was investigated [5].
Unfortunately, the only reaction observed was the formation of the
THF-structure 17 (Scheme 2). The bulkiness of the tosyl group prob-
ably prevented the formation of the ditosylate eventually leading
to the formation of the THF-structure.
chloride [13]. 1-acetamidostyrene (20) was prepared by
methylation of the benzonitrile with methylmagnesium bromide
and subsequent acylation of the prepared imine salt [14].
The catalytic reaction was performed at atmospheric pres-
sure in a flow of hydrogen in contrast to usual hydrogenation
conditions (1.1–50 Bars of H2, autoclave) [2]. The active catalyst
was prepared by premixing of the phosphine with dichloro-
tetraethylene-dirhodium complex. First attempts of the reaction
was made with 1% catalyst loading, but later the catalyst loading
was decreased to 0.5% with retention of reproducibility. The con-
version was monitored by HPLC or GC, and was over 95% in all
MsCl
TEA
NaPPh2
OH
OH
OMs
OMs
PPh2
PPh2
As an alternative we tried a smaller group like mesyl. Dimesy-
lates 9–12 were prepared in excellent yields from the diols 5–8 by
treatment with mesyl chloride in presence of excess of triethyl-
amine as a base (Scheme 3). Substitution of the mesylate groups
with sodium diphenylphosphinde proceeded smoothly to give the
desired phosphines in good to excellent yields.
5-8
9-12
13-16
O
-S
up to 86% overall yield
Ms =
O
To evaluate these phosphines as ligands for asymmetric
catalysis we chose two model prochiral substrates for the rhodium-
catalyzed hydrogenation, 2-acetamidocinnamic acid methyl ester
(18) and 1-acetamidostyrene (20) [2,12]. 2-acetamidocinnamic
acid methyl ester (18) was prepared from commercially available
2-acetamidocinnamic acid by esterification with methanol/thionyl
MeO
MeO
MeO
MeO
PPh2
PPh2
PPh2
PPh2
OMe
OMe
OMe
OMe
13
14
O
MeO
TosCl
TEA
LAH
MeO
O
OH
OH
OTos
OTos
O
MeO
PPh2
PPh2
PPh2
PPh2
1-4
5-8
O
O
-S
O
MeO
O
d.r. 86:14
Tos =
MeO
MeO
17
15
16
Scheme 2. Attempts to prepare diol-ditosylates.
Scheme 3. Preparation of the phosphines.
Please cite this article in press as: Y. Brusentsev, P. Eklund, Synthesis and applications of diphosphine ligands derived from the lignan
hydroxymatairesinol, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.02.032

G Model
CATTOD-8924; No. of Pages4
ARTICLE IN PRESS
4
Y. Brusentsev, P. Eklund / Catalysis Today xxx (2014) xxx–xxx
Table 1
It was interesting to notice that the best selectivity (84% ee)
was obtained using diastereomeric mixture of phosphine 15, which
could be explained if the minor diastereomer is catalytically inac-
tive.
Results of the hydrogenation of 2-acetamidocinnamic acid methyl ester
Despite only good selectivity was obtained with our phosphines,
the concept of producing phosphines from naturally occurring chi-
ral lignans is looking promising. Searching for substrates which will
be more selectively hydrogenated using the phosphines is contin-
uing in our laboratory.
Entry
1
L
Cat. loading, %
ee, % (config.)
1
0.5
1
1
1
8 (R)
9 (R)
40 (S)
15 (S)
25 (S)
13
2
3
4
14
15
16
4. Conclusions
Several highly efficient and diverse routes for the modification of
hydroxymatairesinol were developed. Four different lactones were
prepared and converted to phosphines via reduction to the diol
followed by mesylation of the hydroxyls and substitution of the
mesylates with sodium diphenylphosphide. This method could be
used for preparation of high variety of the phosphines by using
different phosphide salts.
Table 2
Results of the hydrogenation of 1-acetamidostyrene
Induction of enantioselectivity for the prepared phosphines
was evaluated by the rhodium catalyzed hydrogenation of two
unsaturated substrates. Good selectivity in the hydrogenation
of 1-acetamidostyrene was found, while hydrogenation of 2-
acetamidocinnamic acid gave only poor to moderate selectivity.
Searching of the substrates which will be more selectively hydro-
genated using the phosphines is ongoing in our laboratory.
Entry
L
Cat. loading, %
ee, % (config.)
1
2
3
4
13
14
15
16
0.5
0.5
0.5
0.5
75 (S)
62 (S)
84 (S)
81 (S)
reactions. Due to the small scale of the test reactions the isolation
of the products was not performed.
Appendix A. Supplementary data
The results of the hydrogenations are presented in
Tables 1 and 2. As clearly seen from Table 1, the selectivity
for substrate 18 was from poor to moderate, which was in
good correlation with results for DIOP (ee up to 55%)[1] and for
other ligands related to DIOP [3,4]. Only the nonsymmetrical
phosphine 14 (entry 2) gave moderate selectivity (∼40% ee).
It should be noted that the selectivity of the reaction carried
out 13 as a ligand was opposite to the reaction catalyzed with
ligands 14–16. The more flexible structure of 13 may give rise
to other effects and conformations for the catalytically active
complex compared to the more rigid structures of the phosphines
14–16.
For substrate 20 the reaction was more selective (Table 2). Good
selectivity (75–84% ee) was observed for all C2-symmetric phos-
phines (13, 15, 16), while the nonsymmetric phosphine 14 gave
only moderate selectivity (62% ee). These results were also in a
good agreement with the results for DIOP-type or similar ligands.
DIOP* and sk-Phos giving excellent selectivities with the substrate
20, while with substrate 18 the selectivity was only moderate
[3,4].
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.cattod.2014.02.032.
References
[1] H.B. Kagan, T.-P. Dang, J. Am. Chem. Soc. 94 (1972) 6429–6433.
[2] W. Tang, X. Zhang, Chem. Rev. 103 (2003) 3029–3069.
[3] W. Li, X. Zhang, J. Org. Chem. 65 (2000) 5871–5874.
[4] W. Li, J.P. Waldkirch, X. Zhang, J. Org. Chem. 67 (2002) 7618–7623.
[5] P. Aviron-Violet, Y. Colleuille, J. Varagnat, J. Mol. Catal. 5 (1979) 41–50.
[6] R. Glaser, S. Geresh, J. Blumenfeld, M. Twaik, Tetrahedron 34 (1978) 2405–2408.
[7] T.-P. Dang, J.C. Poulin, H.B. Kagan, J. Organomet. Chem. 91 (1975) 105–115.
[8] Y. Brusentsev, T. Sandberg, M. Hotokka, R. Sjöholm, P. Eklund, Tetrahedron Lett.
54 (2013) 1112–1115.
[9] Y. Brusentsev, M. Hänninen, P. Eklund, Synlett 24 (2013) 2423–2426.
[10] H. Markus, P. Mäki-Arvela, N. Kumar, N.V. Kul’kova, P. Eklund, R. Sjöholm, B.
Holmbom, T. Salmi, D.Yu. Murzin, Catal. Lett. 103 (2005) 125–131.
[11] K. Freudenberg, L. Knof, Chem. Ber. 90 (1957) 2857–2869.
[12] P. Etayo, A. Vidal-Ferran, Chem. Soc. Rev. 42 (2013) 728–754.
[13] M.P. Doyle, W.R. Winchester, M.N. Protopopova, A.P. Kazala, L.J. Westrum, Org.
Synth. 73 (1996) 13.
[14] S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. Beller, Eur. J. Org. Chem. 13 (2006)
2912–2917.
Please cite this article in press as: Y. Brusentsev, P. Eklund, Synthesis and applications of diphosphine ligands derived from the lignan
hydroxymatairesinol, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.02.032