Easily accessible and highly tunable bisphosphine ligands for asymmetric hydroformylation of terminal and internal alkenes

Article abstract of DOI:10.1002/chem.201304684

An efficient methodology for synthesizing a small library of easily tunable and sterically bulky ligands for asymmetric hydroformylation (AHF) has been reported. Five groups of alkene substrates have been tested with excellent conversions, moderate-to-excellent regio- and enantioselectivities. Among the best result of the reported literature, application of ligand 1 c in the highly selective AHF of the challenging substrate 2,5-dihydrofuran yielded almost one isomer in up to 99 % conversion along with enantiomeric excesses (ee) of up to 92 %. Highly enantioselective AHF of dihydropyrrole substrates is achieved using the same ligand, with up to 95 % ee and up to >1:50 β-isomer/α- isomer ratio. The simpler the better! An efficient method for the easy and tunable synthesis of a series of asymmetric hydroformylation (AHF) ligands from low-cost, commercially available starting materials has been reported. These ligands can give excellent conversions and moderate to excellent regio- and enantioselectivities for a broad range of mono- and disubstituted alkenes with a low catalyst loading (substrate-to-catalyst ratios (S/C) of 1000:1 to 3000:1).

Full text of DOI:10.1002/chem.201304684

DOI: 10.1002/chem.201304684
Full Paper
&
Ligands
Easily Accessible and Highly Tunable Bisphosphine Ligands for
Asymmetric Hydroformylation of Terminal and Internal Alkenes
Kun Xu,[a, b] Xin Zheng,[b] Zhiyong Wang,*[a] and Xumu Zhang*[b]
Abstract: An efficient methodology for synthesizing a small
library of easily tunable and sterically bulky ligands for asym-
metric hydroformylation (AHF) has been reported. Five
groups of alkene substrates have been tested with excellent
conversions, moderate-to-excellent regio- and enantioselec-
tivities. Among the best result of the reported literature, ap-
plication of ligand 1c in the highly selective AHF of the chal-
lenging substrate 2,5-dihydrofuran yielded almost one
isomer in up to 99% conversion along with enantiomeric ex-
cesses (ee) of up to 92%. Highly enantioselective AHF of di-
hydropyrrole substrates is achieved using the same ligand,
with up to 95% ee and up to >1:50 b-isomer/a-isomer ratio.
Introduction
Although significant progress has been made, the following
challenges restrict the wide application of AHF: 1) Limited sub-
strate scope; 2) high catalyst loading; 3) requires multiple
steps to synthesize the ligand. Recently, Landis and co-workers
successfully developed an elegant bis(diazaphospholane) (BDP)
ligand through a highly efficient method.[18] Due to the confor-
mational rigidity and electron-deficient property, these BDP li-
gands are highly efficient for a broad range of substrates. Li-
gands developed by Landis and co-workers set a new bench-
mark in the field of AHF. A drawback associated with BDP
ligand synthesis stem not from the reaction, but rather from
the step involving HPLC separation. Due to the limitation of
the starting material, only electron-withdrawing amide groups
can be introduced to the ortho positions of phenyl moieties
(Scheme 1, [Eq. (1)]). Giving that there are few chiral phos-
phines available and tunable for AHF, an advance in ligand
preparation will have a major impact in this field.
Among intensive research in olefin functionalization,[1] hydro-
formylation of alkenes is attractive for its high atom economy,
thus rendering this method to be an outstanding example of
the application of homogeneous catalysis on an industrial
scale.[2] Compared with the well-studied hydroformylation for
linear selectivity, AHF is underdeveloped due to the difficulty
in simultaneously controlling regio- and enantioselectivities at
high temperature.[3] However, AHF can offer a series of synthet-
ically useful chiral aldehydes, some of which are inaccessible
by other methods.[4] In the field of AHF, a significant break-
through was the introduction of BINAPHOS by Takaya, Nozaki,
and co-workers.[5] Later on, a variety of bisphosphite and phos-
phine--phosphite ligands developed by the groups of White-
ker,[6] Will,[7] van Leeuwen,[8] Claver,[9] Reek,[10] Tan,[11] Buch-
wald,[12] Clark,[13] Ding,[14] Zhang,[15] and others[16] brought the
research on AHF to a new level. Meanwhile, Klosin and co-
workers showed that bisphosphine ligand 1,2-bis(2,5-diphenyl-
phospholano)ethane (Ph-BPE) can also give good results for
the AHF, even though the conversion is low-to-moderate.[17]
In asymmetric catalysis, a subtle change in the ligand can
bring significantly affect the yields and the regio- and enantio-
selectivities. However, to the best of our knowledge, examples
on the systematically varying the steric and electronic proper-
ties of the ligands for AHF are very limited. With the aim to-
wards a tunable synthesis of a series of highly efficient AHF
catalysts without involving the HPLC separation, we devised
an effective strategy (Scheme 1, [Eq. (2)]. With the participation
of a commercially available and cheap chiral scaffold, a series
of electronically and sterically varied ligands can be synthe-
sized in one pot and separated through silica gel column
easily. Moreover, the easily synthesized ligands can give good-
to-excellent conversions, regio- and enantioselectivities for
a broad range of mono- and disubstituted alkenes. For some
substrates such as cyclic alkenes, results in this paper are
among the best in the current literature. In addition, mechanis-
tic studies on the precatalyst and catalytic resting-state species
were also carried out.
[a] K. Xu,+ Prof. Z. Wang
Hefei National Laboratory for Physical Sciences
at Microscale CAS Key Laboratory of
Soft Matter Chemistry and Department of Chemistry
University of Science and Technology of China
Hefei, Anhui, 230026 (P.R. China)
Fax: (+86)551-63603185
E-mail: zwang3@ustc.edu.cn
[b] K. Xu,+ X. Zheng,+ Prof. X. Zhang
Department of Chemistry and Chemical Biology
and Department of Medicinal Chemistry, Rutgers
The State University of New Jersey Piscataway
New Jersey 08854 (USA)
Fax: (+1)732-4456312
E-mail: xumu@rci.rutgers.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304684.
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Scheme 1. Different approaches to the bis-diazaphospholate ligands.
Results and Discussion
Table 1. Ligand screening for AHF of styrene.
With the hypothesis in mind, initial experiments were carried
out to synthesize ligand 1 (see the Supporting Information for
details). In most cases, both of the two diastereomers can be
synthesized in one pot and separated by flash column chroma-
tography; however, when the R group was replaced by 4-F
and 4-Cl, only one isomer of 2g and 2h were obtained respec-
tively, and the exact reason is not yet clear. The absolute con-
figuration of ligand 1c was determined by single-crystal X-ray
diffraction analysis.[24] The stereochemistry of all other products
(1a–f, 1i) is assigned by analogy.[19]
These easily synthesized ligands were then examined for the
AHF of styrene (Table 1). First, the combination of ligand 1a/
[Rh(CO)2(acac)] (acac=acetylacetonate) was employed as the
catalyst, which can give excellent conversion with a low cata-
lyst loading (substrate-to-catalyst ratios (S/C)=3000, Table 1,
entry 1). Encouraged by the preliminary results, a variety of
electronically and sterically different ligands were examined.
When the fluoride, chloride, bromide, and methyl groups were
attached to the ortho positions of phenyl moieties, better
regio- and enantioselectivities were obtained (Table 1, en-
tries 2,3,5 vs. 1). It is known that the flexible ligand is not effi-
cient for the asymmetric induction under high temperature;
the introduction of a suitable group to the ortho position of
phenyl moiety can possibly make the ligand more rigid, which
has a benefit effect for the asymmetric induction. However,
a substituent that is too bulky (e.g., 2-Br) has a negative effect
on the enantioselectivity (Table 1, entries 2, 3 vs. 5). In terms of
electronic properties of the substituents, the moderate electro-
withdrawing group can increase the regio- and enantioselectiv-
ities (Table 1, entries 3 vs. 6). To investigate the steric effect of
the ligand, the ortho chloride was replaced by meta chloride,
lower regio- and enantioselectivities were obtained (Table 1,
Entry[a]
Ligand
Conversion
[%][b]
b/l[c]
ee
[%][d]
1
2
3
4[e]
5
6
7
8
9
10
11
12
13[f]
1a
1b
1c
1c
1d
1e
1 f
1i
2g
2h
2j
2c
1c
99
99
99
99
99
99
99
99
99
99
99
99
98
16
20
24
14
17
19
13
16
9
9
4
19
11
70
81
85
84
75
82
61
73
30(S)
52(S)
20(S)
24(S)
81
[a] All reactions were performed on a 1.0 mmol scale at 608C in toluene
(0.5 mL) with 20 bar syngas (CO/H2 =3:1) with L/Rh=3:1, S/C=3000, and
8 h reaction time. [b] Determined by GC (b-DEX 225) with dodecane as in-
ternal standard. [c] Determined by 1H NMR spectroscopic analysis. [d] De-
termined by Chiral GC (b-DEX 225). [e] The ratio of L/Rh was changed to
2:1. [f] 808C, 150 psi of syngas (CO/H2 =1:1), S/C=5000.
entry 7). Subsequently, the cooperative effect between the ste-
reogenic centers of the cyclohexane backbone and the stereo-
genic phenyl moieties was demonstrated. Comparison of alde-
hyde configurations obtained with the diastereomers (Table 1,
entries 3 vs. 12) indicated that the chirality of the product was
predominantly controlled by the configuration of the aryl moi-
eties, rather than the stereochemistry of the cyclohexane back-
bone. When ligand 1c was evaluated under the standard AHF
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Table 2. Asymmetric hydroformylation of styrene derivatives.
Table 3. Asymmetric hydroformylation of vinyl esters.
Entry[a]
R
Conversion
[%][b]
b/l[c]
ee
[%][d]
Entry[a]
R
Conversion
[%][b]
b/l[c]
ee
[%][d]
1
2
3
4
5
CH3
tBu
n-C7H15
n-C9H19
Ph
99
99
87
85
80
53
24
45
34
240
91
91
93
93
91
1
2
3
4
5
H
99
98
93
99
99
24
20
20
19
58
85
80
77
83
88
4-Me
4-OMe
4-F
2-F
[a] All reactions were performed on a 1.0 mmol scale at 608C in toluene
(0.5 mL) with 20 bar syngas (CO/H2 =1:1) with 1c/Rh=3:1, S/C=3000,
and 12 h reaction time. [b] Determined by GC (b-DEX 225) with dodecane
as internal standard. [c] Determined by 1H NMR spectroscopic analysis.
[d] Determined by Chiral GC (b-DEX 225).
[a] All reactions were performed on a 1.0 mmol scale at 608C in toluene
(0.5 mL) with 20 bar syngas (CO/H2 =3:1) with 1c/Rh=3:1, S/C=3000,
and 8 h reaction time. [b] Determined by GC (b-DEX 225) with dodecane
as internal standard. [c] Determined by 1H NMR spectroscopic analysis.
[d] Determined by Chiral GC (b-DEX 225).
conditions reported by Landis (808C, 150 psi syngas, S/C=
5000),[18a] 11:1 branched/linear (b/l) ratio and 81% ee value
were obtained (Table 1, entry 13, Landis’s result: 6.6:1 b/l ratio,
82% ee).
Table 4. AHF of N-allylsulfonamides and N-allylamides.
Application of optimized conditions to the AHF of other sty-
rene derivatives also gave the desired products with excellent
conversions, regio- and enantioselectivities (Table 2). In general,
the electron-rich styrene derivatives have a negative effect on
the conversion and stereoselectivities (Table 2, entries 2 and 3
vs. 1). The ortho substituents on the phenyl moiety have a posi-
tive effect on the asymmetric induction and regioselectivity
(Table 2, entry 5).
Entry[a]
R
Conversion
[%][b]
b/l[b]
ee
[%][d]
1
2
3
4
5
6
MeC6H5SO2
MeOC6H5SO2
NO2C6H5SO2
Bz
Cbz
Boc
92
92
99
99
93
95
9
6
6.5
18
9.5
10
88
88
91
92
92
85
Then, the efficient catalyst was applied to the AHF of vinyl
esters (for the effects of different ligands on the AHF reaction,
see the Supporting Information for details). As illustrated in
Table 3, both alkyl and aromatic groups attached to the ester
group were well-tolerated under the standard conditions. For
the alkyl-chain-substituted substrates, the longer chain is bene-
ficial for enantioselectivity, but has a negative effect on the
conversion (C7 and C9, Table 3, entries 3 and 4). It is worth
noting that a high regioselectivity (240 b/l ratio) and excellent
enantioselectivity (91% ee) were achieved for the AHF of vinyl
benzoate 6e.
[a] All reactions were performed on a 1.0 mmol scale at 408C in toluene
(0.5 mL) with 20 bar syngas (CO/H2 =3:1) with 1c/Rh=3:1, S/C=1000,
and 20 h reaction time. [b] Determined by H NMR spectroscopic analysis.
1
[d] Determined by HPLC or chiral GC (b-DEX 225).
tant molecules. A prominent example is the promising cancer
drug cryptophycin C and D, which can be obtained by utilizing
this unit with the improved overall synthetic efficiency
(Scheme 2).[20]
To further explore the application of the ligand, a series of
N-allylsulfonamides and N-allylamides were tested for AHF
(Table 4). For benzoyl (Bz)- and carbobenzyloxy (Cbz)-protected
allylic amines 9d and 9e, excellent conversions and enantiose-
lectivities were obtained (Table 4, entries 4 and 5). The protect-
ing group in the resulting products can be easily deprotected,
affording the synthetically useful chiral 1, 3-aminoaldehyde in
short synthetic steps. More importantly, tert-butoxycarbonyl
(Boc)-protected allylic amine 9 f can be hydroformylated under
the standard conditions, providing the N-Boc-protected b2-
amino aldehyde 10 f with good conversion and stereoselectiv-
ity (Table 4, entry 6).
Encouraged by the success of AHF of N-functionalized allyl
substrates, O-, Si-functionalized and unfunctionalized allylic
substrates were also tested. To our delight, various allylic sub-
strates could undergo the AHF reaction to give the chiral alde-
N-Boc-protected b2-amino aldehyde is a valuable structural
motif, which can be transformed into many biologically impor-
Scheme 2. Application of b2-amino aldehyde to the synthesis.
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on the AHF reaction, see the Supporting Information for de-
tails). It was found that dihydrofuran and dihydropyrrole are
ideal substrates under the standard conditions, which gave
good-to-excellent conversions (70–99%) and enantioselectivi-
ties (91–95%) under mild conditions. When 2,3-dihydrofuran
15a and 2,3-dihydropyrrole 15c were employed as the sub-
strates, the configurations of 2-formyl products 17a and 17c
were determined to be R (Table 6, entries 1 and 3); whereas
2,5-dihydrofuran 15b and 2,5-dihydropyrrole 15d gave S-con-
figured 2-formyl products 17b and 17d (Table 6, entries 2 and
4). The similar behavior of inverted stereochemistry for AHF of
dihydrofuran substrate has been observed and explained by
Landis and co-workers.[18e] Notably, the AHF of 2,5-dihydrofuran
15b gave a ratio of 166:1 of 2-formyl/1-formyl and 92% ee,
which represents the highest selectivities reported so far with
the lowest catalyst loading (Table 6, entry 2).[9b,10b,18e]
Table 5. Asymmetric hydroformylation of other allylic substrates.
Entry[a]
R
Conversion
[%][b]
b/l[b]
ee
[%][c]
1
2
3
4
5
6[d]
TMSO
TBSO
PhO
AcO
TMS
Ph
99
99
99
67
83
99
2.4
2
3
3
0.5
1.1
94
83
90
92
91
90
[a] All reactions were carried out on a 1.0 mmol scale at 408C in toluene
(0.5 mL) with 20 bar syngas (CO/H2 =3:1) with 1c/Rh=3:1, S/C=1000,
and 20 h reaction time. TBSO=tert-Butyldimethylsilyl ether. [b] Deter-
mined by 1H NMR spectroscopic analysis. [c] Determined by HPLC or
chiral GC (b-DEX 225). [d] The reaction temperature is 808C.
The resulting chiral 3-(S)-carbaldehyde 17b (Scheme 3) is
a useful synthetic intermediate. 3-(S)-hydroxytetrahydrofuran
18 can be afforded through a Baeyer–Villiger oxidation from 3-
(S)-carbaldehyde 17b.[21] With 3-(S)-hydroxytetrahydrofuran 18
as a key intermediate, HIV protease inhibitor Amprenavir can
be synthesized easily according to the literature.[22]
hyde with good conversion, moderate branch/linear ratio, and
excellent ee values (up to 94% ee, Table 5). For O-functional-
ized substrates, moderate regioselectivity and good-to-excel-
lent enantioselectivities were obtained (Table 5, entries 1–4).
For the Si-functionalized and unfunctionalized allyl substrates
allyltrimethylsilane 12e and allylbenzene 12 f, good-to-excel-
lent conversion and enantioselectivities were obtained, but
showed preference for linear selectivity (Table 5, entries 5 and
6).
After investigating the reactivity of monosubstituted al-
kenes, the AHF of more challenging 1, 2-disubstituted olefins
was then examined (Table 6, for the effects of different ligands
Scheme 3. Application of 3-carbaldehyde to the total synthesis.
After exploring the application of the present catalytic
system for asymmetric hydroformylation, a series of experi-
ments were performed to investigate the mechanism of the
catalytic system. First, ligand 1c was mixed with [Rh(CO)2-
(acac)] at room temperature, displacement of the two carbon
monoxide ligands by the bidentate ligand afforded the square-
planar complex A [Rh(acac)(P^P)], which was demonstrated
by single-crystal X-ray diffraction analysis[24] (bite-angle: 84.9,
Figure 1).
Table 6. AHF of cyclic 1,2-disubstituted olefins.
Entry[a] 15
S/C
Conversion 16/17[b] ee
[%][b] [%][c] (16) [%][c] (17)
ee
1[d]
2
3000 99
3000 99
1.2:1
92(R)
71(R)
92(S)
[e]
1:166
–
3[f]
1000 70
1000 83
6:1
95(R)
71(R)
91(S)
4[f]
1:>50
–
[e]
[a] All reactions were carried out on a 0.5 mmol scale at 608C in toluene
(0.25 mL) with 20 bar syngas (CO/H2 =3:1) with 1c/Rh=3:1, and 20 h re-
action time. [b] Determined by 1H NMR spectroscopic analysis. [c] Deter-
mined by Chiral GC (b-DEX 225). [d] The pressure of the syngas is 20 bar
(CO/H2 =1:1). [e] The percent of this isomer is too low to determine the
ee value. [f] The reaction temperature is 408C.
Figure 1. X-ray structure of complex A [Rh(1c)(acac)].
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was carefully released in a well-ventilated hood. The conversion
and branch/linear ratio were determined by 1H NMR spectroscopy
from the crude reaction mixture. The enantiomeric excesses of the
products were determined by chiral GC analysis with a Supelco’s
Beta Dex 225 column from the crude reaction mixture, or by re-
ducing them into alcohol with NaBH4 and analyzing by using
HPLC.
Next, the resting-state species (complex B [Rh(H)(CO)2(P^P)])
was prepared in situ by mixing one equivalent of ligand 1c
with the metal precursor [Rh(CO)2(acac)] in [D8]toluene, and re-
acted under the same hydroformylation conditions (20 bar
syngas (CO/H2 =3:1) at 608C for 10 h, without the existence of
the substrate). The formation of the rhodium complex B was
characterized by using NMR spectroscopy (Scheme 4).[23]
Acknowledgements
This research was supported by the NSF (CHE0956784); the au-
thors are also grateful to National Nature Science Foundation
of China (21272222).
Keywords: alkenes · enantioselectivity · hydroformylation ·
ligands · synthetic methods
Scheme 4. NMR spectroscopic data of complex B [RhH(CO)2(P^P)] obtained
at 298 K.
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signal was detected at high field (d=À8.3 ppm). It was found
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indicated that one of the phosphane atoms in ligand 1c is in
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isomer is more favored by 1.76 kJmolÀ1
.
Conclusion
We have reported an efficient method for the easy and tunable
synthesis of a series of AHF ligands from low-cost, commercial-
ly available starting materials. A systematic screening of the li-
brary of ligands on AHF showed that an appropriate electron-
withdrawing group attached to the ortho position of phenyl
moieties in the ligand is essential to achieve the high regio-
and enantioselectivities; however, too bulky substituent led to
the decrease in enantioselectivities. With a low catalyst loading
(S/C=1000:1 to 3000:1), a wide range of terminal and internal
olefins, especially the challenging dihydrofuran and N-Boc-pyr-
roline substrates, underwent the hydroformylation reaction to
give the synthetically useful chiral aldehydes with good to ex-
cellent regio- and enantioselectivities. We believe the findings
reported herein together with the previously relevant works
should assist in further research on AHF reactions.
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Experimental Section
In a glovebox filled with nitrogen, the ligand (0.003 mmol) and
[Rh(CO)2(acac)] (0.001 mmol in toluene (0.2 mL) were added to
a vial (5 mL) equipped with a magnetic bar. After stirring for
10 min, the substrate (1.0 mmol) and additional toluene were
charged to bring the total volume of the reaction mixture to
0.5 mL. The vial was transferred into an autoclave and taken out of
the glovebox. Carbon monoxide (15 bar) and hydrogen (5 bar)
were charged in sequence. The reaction mixture was stirred at
608C (oil bath) for 20 h. The reaction was cooled and the pressure
Chem. Eur. J. 2014, 20, 4357 – 4362
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Full Paper
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31
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however, only one P atom and one C atom were observed from NMR
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[24] CCDC-955452 (1c) and CCDC-955453 (complex A, [Rh(1c)(acac)]) con-
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Received: November 29, 2013
Revised: December 19, 2013
Published online on February 26, 2014
Chem. Eur. J. 2014, 20, 4357 – 4362
www.chemeurj.org
4362
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim