Highly selective bisphosphine ligands for asymmetric hydroformylation of heterocyclic olefins

Article abstract of DOI:10.1016/j.tetlet.2015.01.052

The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee. The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 β-isomer/α-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.

Full text of DOI:10.1016/j.tetlet.2015.01.052

Tetrahedron Letters 56 (2015) 1149–1152
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly selective bisphosphine ligands for asymmetric
hydroformylation of heterocyclic olefins
Xin Zheng a, , Kun Xu b, , Xumu Zhang a,
⇑
a Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
b College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The bisphosphine ligand 1c is highly efficient and selective for the asymmetric hydroformylation (AHF) of
dihydrofuran and pyrrolines. The AHF of 2,3-dihydrofuran yielded the 2-carbaldehyde in up to 93% ee.
The remarkable highest regioselectivity of 2,5-dihydrofuran was obtained to date up to 499 b-isomer/
Received 16 December 2014
Revised 4 January 2015
Accepted 6 January 2015
Available online 13 January 2015
a-isomer with ligand 1c. Furthermore, the highest 96% and 92% ee values were accomplished using
the same catalytic system in the AHF of N-Boc pyrroline 11 and 14.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Hydroformylation
Dihydrofuran
Asymmetric
Pyrroline
Asymmetric hydroformylation (AHF) is one of the most appeal-
ing methodologies to construct chiral aldehydes in only one step.1
It is challenging to build chiral carbaldehydes derived from the
AHF of dihydrofuran (DHF) and pyrrolines. Their chiral products
2- and 3-carbaldehydes can be extensively applied in the synthesis
of biologically active natural products and pharmaceuticals2
(Fig. 1). For instance, chiral 3-carbaldehyde resulted from AHF of
dihydrofuran is a potential synthetic intermediate for preparing
Terazosin,2b used as an enlarged prostate (BPH), and Amprenavir,2c
a high potent drug for the treatment of HIV protease inhibitor. Chi-
ral 2-carbaldehydes can be used to synthesize CCR5 antagonist2d
that is currently being investigated in clinical trials for the treat-
ment of HIV-1 infection. N-heterocyclic carboxylic acid, b-proline,
is a key structural element in the synthesis of peptides and pro-
teins.2e–g Limited methodologies can access to this building block
in short steps. The AHF of N-Boc pyrroline can directly access to
chiral 3-carbaldehyde, subsequently oxidized into enantioenriched
b-proline in only two steps2a (Fig. 2). Furthermore, MCH-R1 antag-
onist,2e an anti-obesity agent, is also derived from the AHF of N-Boc
pyrroline.
regio- and enantioselectivities. Recently, our group has developed
a small library of biphosphine ligands that exhibit high selectivity
and activity for a broad range of olefins.4 They are electron-
withdrawing and sterically bulky properties that make them
highly efficient in asymmetric hydroformylation reaction.
We herein describe the application of bisphosphine ligand in the
rhodium-catalyzed AHF of dihydrofuran and pyrroline substrates,
leading to unprecedented high regio- and enantioselectivities.
The AHF reactions were performed in the presence of 0.1 mol %
ligand at 60 °C under 20 bar syngas pressure (CO/H2 = 10:10). Ini-
tially, 2,3-DHF (7) was chosen as a model reaction to evaluate
To date, many groups have reported various excellent
phosphorus ligands in the AHF of dihydrofuran and pyrrolines,
such as Nozaki,3a van Leeuwen,3b Reek,3c Landis,3d,e Claver,3f,g and
others,3h–k however, more research is still needed to improve their
⇑
Corresponding author. Tel.: +1 814 880 4373; fax: +1 732 445 6312.
E-mail address: xumu@rci.rutgers.edu (X. Zhang).
These authors contributed equally to this work.
Figure 1. Structures of biologically active products.
http://dx.doi.org/10.1016/j.tetlet.2015.01.052
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1150
X. Zheng et al. / Tetrahedron Letters 56 (2015) 1149–1152
Table 1
Rh-catalyzed asymmetric hydroformylation of 7 with different ligandsa
Figure 2. Conversion of AHF of N-Boc pyrroline into b-proline.
the effects of ligands on activity and selectivity (Fig. 3). In principle,
2-carbaldehyde (9) is the desired product and 3-carbaldehyde (8)
is presented as byproduct by isomerization.2a,3e As shown in
Table 1, no reaction occurred with (R,S)-Duanphos (2) (entry 10).
The application of Tangphos (3) led to racemic carbaldehydes of
two isomers (Table 1, entry 11). Yanphos (5) and (R,R)-Ph-BPE (6)
represented quite low conversions (Table 1, entries 13 and 14).
The small library of bisphosphine ligands previously reported by
our group accomplished better conversions (up to 99%) and enan-
Entry
Ligand
Conv.b (%)
a
/b
eec (%)
eec (%)
(b)
(a)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
2
91
80
99
64
73
60
49
38
7
0.93
0.83
1.00
1.56
0.73
0.86
0.64
1.00
0.09
71 (R)
84 (R)
92 (R)
86 (R)
72 (R)
60 (R)
60 (R)
65 (R)
38 (S)
—
87 (R)
88 (R)
71 (R)
94 (R)
86 (R)
71 (R)
68 (R)
79 (R)
0
—
0
86 (R)
78 (R)
94 (S)
tioselection (up to 92% ee of a-isomer) (Table 1, entries 1–9). The
0
—
substituents on the phenyl ring strongly affected reaction activity
and selectivity. Using the ligands bearing with R groups at ortho-
position, the conversions and enantioselectivities were superior
to the ones of R groups attached on the para-position (Table 1,
entries 2–4 vs 6–8). It is assumed that suitable R group at ortho-
position could increase the sterical bulkiness of ligands and further
stabilize chiral structures under high reaction temperatures.
Among three ortho substituent ligands, ligand 1c attached with
3
4
5
6
22
37
3
0.27
0.83
0.73
0.89
0
6 (S)
65 (R)
88 (S)
1
a
Reaction conditions: 7 (1 mmol), ligand (0.1 mol %), 2 M total substrate, 3000:1
total substrate/ Rh (S/C), in toluene at 60 °C for 20 h.
Conversion determined by 1H NMR spectroscopy.
b
c
Regio- and enantioselectivities measured by chiral GC.
chloride group accomplished the highest enantioselectivity of a-carb-
hyde (8) as a minor product.3e The reaction was examined in the
presence of 0.1 mol % ligand 1c with 3000 S/C under 10:10 CO/H2
syngas pressure in toluene at 60 °C (Table 3, entry 1) affording
aldehyde 9 as high as 92% with full conversion (Table 1, entry 3).
Encouraged by preliminary results, we next varied the CO/H2
partial syngas pressure in the AHF of 2,3-DHF with optimal ligand
1c (Table 2). Increasing CO partial pressure from 10 to 15 under the
89 of b/
higher total molarity to three yielded unprecedentedly high
regioselectivity 499 of b/ ratio, along with excellent ee value
a ratio and 84% ee value of b-isomer (8). Surprisingly,
total pressure of 20 bar, the ee value of a-isomer 9 increased to 93%
with a slight drop in conversion (Table 2, entry 2) To the best of our
knowledge, this is the highest enantioselectivity of 2-carbaldehyde
(9, 93%) ever reported in the AHF of 2,3-DHF. A lower CO to H2 ratio
therefore diminished enantioselectivity (86% ee) and regioselectiv-
ity (0.30) in aldehyde 9 (Table 2, entry 3). It is generally accepted
that the competition of b-hydride elimination and CO insertion
led to isomerization. Hence, higher CO partial pressure can
suppress isomerization. Under optimal CO/H2 ratio of 15:5, neither
a decreasing temperature (40 °C) or increasing molarity has a
positive effect on both regio- and enantioselectivities (Table 2,
entries 5 and 6). The comparable result was yielded using 1000
substrate to catalyst loading (S/C) (Table 2, entries 2 vs 7).
a
(90%, 8) (Table 3, entry 5). Subsequently, varying CO to H2 pressure
ratios showed that 15:5 exhibited the highest enantioselectivity of
the desired regioisomer (8) (92%), with 166 of b/
a (Table 3,
entry 3). Decreasing the temperature to 40 °C was detrimental
to the conversion and enantioselectivity but had no effect on
regioselectivity (Table 3, entry 6).
Since few catalytic systems were efficient in the AHF of N-(tert-
butoxycarbonyl)-2-pyrroline 11 and N-(tert-butoxycarbonyl)-3-
pyrroline 14, this prompted us to employ ligand 1c in the AHF of
11 and 14. In all cases of Table 4, the AHF of 11 proceeded
smoothly at 60 °C in the presence of 3000 S/C with full conversions.
Similarly, 15:5 of CO/H2 ratio presented highest ee value (96%)
among all reported literatures (Table 4, entry 2). Further increasing
molarity has no benefit for the enantioselectivity (Table 4, entry 3).
The AHF of 14 followed basically the same trend as that of 11 under
optimal reaction conditions. Excellent enantioselectivity as high as
The excellent performance of ligand 1c encouraged and
prompted us to further explore its hydroformylation of 2,5-DHF
(10) (Table 3). The challenge of this substrate is to get high b/
a
regioselectivity and enantioselectivity of b-isomer because of
competitive olefin isomerization to 2,3-DHF, to yield 3-carbalde-
Figure 3. Structures of ligands for AHF.

X. Zheng et al. / Tetrahedron Letters 56 (2015) 1149–1152
1151
Table 2
Optimization of selected ligands for the AHF of 2,3-dihydrofuran 7a
Entry
S/C
Temp (°C)
[M]
CO/H2 (bar)
Con.b (%)
a
/b
eec (%)
-isomer)
eec (%)
(b-isomer)
(
a
1
2
3
4
5
6
7
3000
3000
3000
3000
3000
3000
1000
60
60
60
60
60
40
60
2
2
2
2
3
2
2
10:10
15:5
5:15
5:5
15:5
15:5
15:5
99
92
99
71
92
46
>99
1
92 (R)
93 (R)
86 (R)
90 (R)
88 (R)
76 (R)
91 (R)
71 (R)
53 (R)
77 (R)
57 (R)
78 (R)
33 (R)
56 (R)
0.70
0.30
1.09
0.87
0.53
0.75
a
b
c
Reaction conditions: 7 (1 mmol) catalyzed by Rh-ligand 1c in toluene at 60 °C or 40 °C for 20 h.
Conversion determined by 1H NMR spectroscopy.
Regio- and enantioselectivities measured by chiral GC.
Table 3
Optimization of selected ligands for the AHF of 2,5-dihydrofuran 10a
Entry
Temp (°C)
[M]
CO/H2 (bar)
Con.b (%)
b/
a
eec (%)
-isomer)
eec (%)
(b-isomer)
(
a
1
2
3
4
5
6
60
60
60
60
60
40
2
2
2
2
3
2
10:10
5:5
15:5
5:15
10:10
10:10
>99
47
>99
>99
93
89
9
166
76
499
443
84 (R)
47 (R)
—
88 (R)
—
84 (S)
24 (S)
92 (S)
90 (S)
90 (S)
86 (S)
67
—
a
b
c
Reaction conditions: 10 (1 mmol), ligand (0.1 mol %), 3000:1 total substrate/Rh (S/C), in toluene for 20 h.
Conversion determined by 1H NMR spectroscopy.
Regio- and enantioselectivities measured by chiral GC.
Table 4
Table 5
Optimization of selected ligands for the AHF of N-Boc pyrroline 14a
Optimization of selected ligands for the AHF of N-Boc pyrroline 11a
Con.b (%)
eec (%)
(b-isomer)
Entry
[M]
CO/H2 (bar)
Con.b (%)
b/a
eec (%)
-isomer)
eec (%)
(b-isomer)
Entry
[M]
CO/H2 (bar)
(
a
1
2
3
4
2
2
3
2
10:10
15:5
15:5
5:15
>99
>99
>99
>99
5.25
6.14
5.25
4.56
87 (R)
96 (R)
86 (R)
84 (R)
84 (R)
86 (R)
77 (R)
56 (R)
1
2
3
4
2
2
3
2
10:10
15:5
15:5
5:15
74
>99
47
88 (S)
92 (S)
84 (S)
82 (S)
23
a
a
Reaction conditions: 11 (1 mmol), ligand (0.1 mol %), 3000:1 total substrate/Rh
Reaction conditions: 14 (1 mmol), ligand (0.1 mol %), 3000:1 total substrate/Rh
(S/C), in toluene at 60 °C for 20 h.
(S/C) n toluene at 60 °C for 20 h.
b
Conversion determined by 1H NMR spectroscopy.
b
Conversion determined by 1H NMR spectroscopy.
c
c
Regio- and enantioselectivities measured by chiral GC.
Regio- and enantioselectivities measured by chiral GC.
92% with full conversion was achieved (Table 5, entry 2).
Surprisingly, in no case were isomerized products observed. It is
noteworthy that the level of enantioselection obtained in the
AHF of N-(tert-butoxycarbonyl)-3-pyrroline (14, 92%) by ligand
1c is the highest so far.
Conclusions
In summary, we have reported the highly efficient and selective
bisphosphine ligand 1c in the AHF of dihydrofuran and pyrrolines.
It outperformed among all the ligands reported to date for the AHF

1152
X. Zheng et al. / Tetrahedron Letters 56 (2015) 1149–1152
2014, 262, 1–15; (n) Torres, G. M.; Frauenlob, R.; Franke, R.; Boerner, A. Catal. Sci.
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to 93% and regioselectivity up to 499. Furthermore, the excellent
enantiomeric excesses of 96% and 92% for the AHF of N-Boc 11
and N-Boc 14, respectively, were achieved. Specifically, just one
regioisomer was produced in the AHF of N-Boc 14.
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This research was supported by the National Science Founda-
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