Enantioselective iron-catalysed O-H bond insertions

Article abstract of DOI:10.1038/nchem.651

The ready availability, low price and environmentally benign character of iron mean that it is an ideal alternative to precious metals in catalysis. Recent growth in the number of iron-catalysed reactions reported reflects an increasing demand for sustainable chemistry. Only a limited number of chiral iron catalysts have been reported and these have, in general, proven less enantioselective than other transition-metal catalysts, thus limiting their appeal. Here, we report that iron complexes of spiro-bisoxazoline ligands are highly efficient catalysts for asymmetric O-H bond insertion reactions. These complexes catalyse insertions into the O-H bond of a wide variety of alcohols and even water, with exceptional enantioselectivities under mild reaction conditions. The selectivities surpass those obtained with other transition-metal catalysts. This study should inspire and encourage the use of iron instead of traditional precious metals in the development of greener catalysts for catalytic asymmetric synthesis.

Full text of DOI:10.1038/nchem.651

ARTICLES
PUBLISHED ONLINE: 9 MAY 2010 | DOI: 10.1038/NCHEM.651
Enantioselective iron-catalysed O–H bond
insertions
Shou-Fei Zhu, Yan Cai, Hong-Xiang Mao, Jian-Hua Xie and Qi-Lin Zhou
*
The ready availability, low price and environmentally benign character of iron mean that it is an ideal alternative to
precious metals in catalysis. Recent growth in the number of iron-catalysed reactions reported reflects an increasing
demand for sustainable chemistry. Only a limited number of chiral iron catalysts have been reported and these have, in
general, proven less enantioselective than other transition-metal catalysts, thus limiting their appeal. Here, we report that
iron complexes of spiro-bisoxazoline ligands are highly efficient catalysts for asymmetric O–H bond insertion reactions.
These complexes catalyse insertions into the O–H bond of a wide variety of alcohols and even water, with exceptional
enantioselectivities under mild reaction conditions. The selectivities surpass those obtained with other transition-metal
catalysts. This study should inspire and encourage the use of iron instead of traditional precious metals in the
development of greener catalysts for catalytic asymmetric synthesis.
any fundamental phenomena and laws of nature result obtain reasonable selectivity in reactions involving a free carbene.
from dissymmetry, which is exemplified as chirality or Transition metals can stabilize carbenes by forming a metal–carbene
M
handedness in modern chemistry. In nature, the effective complex14. Because they are easier to handle and are more selective
forms of many biological molecules such as amino acids, sugars than free carbenes, metal–carbene complexes have been widely
or nucleic acids occur as only a single enantiomer, and the impor- applied in organic synthesis. Transition-metal-catalysed insertion
tant differences in the physiological properties of enantiomers are of diazo compounds into the X–H (X¼C, Si, O, N and so on)
now well known. To meet the rapidly increasing demand for bond is a useful carbene transfer reaction15 (Fig. 1a) and has
chiral molecules in a single enantiomeric form, catalytic asymmetric become an efficient tool for the construction of C–X bonds under
synthesis has become an important topic of research for chemists in mild reaction conditions. The most successful catalysts in asym-
both academic laboratories and industry.
metric insertion reactions have been rhodium and copper com-
Three types of chiral catalysts—enzymes, transition-metal com- plexes16–22. Although iron carbene complexes have been known
plexes and chiral organic molecules—have emerged as the most suc- for several decades23, an iron-catalysed asymmetric insertion
cessful and efficient catalysts in asymmetric synthesis. Owing to the reaction has not yet been realized24. Weak coordination between
versatile activation modes of transition-metal complexes, transition- iron and the corresponding chiral ligands may account for the
metal catalysis is still central to the investigations and applications of unsuccessful chiral induction of iron catalysts in insertion reactions.
asymmetric synthesis1. A chiral transition-metal catalyst is generally We considered that increasing the rigidity of the ligands might
composed of two parts: a chiral ligand and a central metal. The efforts increase the stability of the iron complexes and thus improve
to develop chiral transition metal catalysts have mainly focused on the chiral induction. We envisioned that the chiral bisoxazoline
design of the chiral ligands2, with the central metals being predomi- ligands 1 (Fig. 1b)25 with an unusually rigid spiro scaffold that
nately precious metals, such as palladium, platinum, rhodium, ruthe- have been developed in our laboratory might coordinate tightly
nium, osmium, iridium and so on. However, these precious metals with iron and create an efficient chiral pocket for enantioselective
are too costly and may contaminate both the products and the control. Herein, we report an iron/spiro bisoxazoline-catalysed
environment, which restricts their wide application.
asymmetric O–H bond insertion of alcohols and water with excep-
Iron, the second most abundant metal in the Earth’s crust, has tional enantioselectivities (up to 99% e.e.) (Fig. 1b). For the first
become the most common metal in everyday use3. Given its ready time, the enantioselectivities accomplished in this O–H insertion
availability, low price and environmentally benign character, iron reaction using iron catalyst unambiguously surpass those obtained
is an attractive and often advantageous alternative to other tran- with other transition-metal catalysts.
sition metals in the field of catalysis. In light of the increasing
demand for sustainable chemistry, iron-catalysed reactions have Results and discussion
drawn much attention and have undergone explosive growth4–7
.
The insertion reaction of methyl a-diazophenylacetate (2a) with
Although transition-metal-catalysed asymmetric reactions have n-butanol (3a) was performed in chloroform at 40 8C with 5 mol%
.
undergone great progress in the last several decades, only a iron catalyst prepared in situ from FeCl2 4H2O and various chiral
handful of iron-catalysed asymmetric reactions have reached an spiro bisoxazoline ligands 1 (Table 1). A preliminary investigation
enantiomeric excess (e.e.) beyond 90% (refs 4–13). Moreover, the revealed that the ligand (Sa,S,S)-1c, with 4-iso-propyl moieties on
iron-catalysed asymmetric reactions reported to date are less enan- the dihydrooxazole rings, afforded the insertion product 4awith excel-
tioselective than other metal-catalysed reactions, with the exception lent yield (93%) and extremely high enantioselectivity (98% e.e.)
of a few special substrates.
(Table 1, entry 4). Other chiral ligands, including bisoxazolines, phos-
Carbenes are among the most active and useful intermediates in phino-oxazolines and diphosphines, which were efficient in different
organic reactions. However, their great reactivity makes it difficult to catalytic asymmetric reactions, were also investigated in the O–H
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China. e-mail: qlzhou@nankai.edu.cn
*
546
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.651
ARTICLES
R1
R2
a
Table 1 | Asymmetric catalytic O–H insertion of 2a with 3a:
ligand and metal evaluation.
N2
N2
M = Transition metal
L = Ligand
X = C, Si, O, N, S, etc.
OnBu
N2
5 mol% [M]
6 mol% 1
6 mol% NaBArF
O
O
R1
R2
*
nBuOH
+
MLn
MLn
O
O
CHCl3, 40°C
3a
2a
4a
Metal carbene
Entry [M]
Ligand
(Sa,S,S)-1a 15
(Ra,S,S)-1a
(Sa,S,S)-1b 24
(Sa,S,S)-1c 15
(Sa,S,S)-1d 30
(Sa,S,S)-1c 15
Time (h) Yield (%) e.e. (%)*
R1
R2
X
.
.
.
1
FeCl2 4H2O
87
86
86
93
63
90
68
85
93
90
23
3
86
38
88
98
50
98
95
92
76
80
82
81
X
H
2
FeCl2 4H2O
8
H
3
4
FeCl2 4H2O
.
FeCl2 4H2O
.
OR3
5
FeCl2 4H2O
b
N2
6
FeCl2
[Fe]/Spirobox
O
O
R3OH
R1
R2
R1
R2
+
.
7
Fe(ClO4)2 xH2O (Sa,S,S)-1c 40
.
8
FeSO4 7H2O
(Sa,S,S)-1c 40
(Sa,S,S)-1c 15
O
O
9
FeCl3
Up to 99% e.e.
10
11
12
13
14
15
16
CuCl
CoCl2
NiCl2
AuCl
AgOTf
[RhCl(CO)2]2
[RuCl2C6H6]2
(Sa,S,S)-1c
1
(Sa,S,S)-1c 48
(Sa,S,S)-1c 48
(Sa,S,S)-1c 48
O
O
(Sa,S,S)-1a: R = Ph
(Sa,S,S)-1b: R = Bn
(Sa,S,S)-1c: R = i-Pr
(Sa,S,S)-1d: R = t-Bu
NR†
63
27
45
—
42
15
R
R
N
N
(Sa,S,S)-1c
(Sa,S,S)-1c
(Sa,S,S)-1c
4
2
2
67
Reaction conditions: [M]/1/NaBArF/2a/3a ¼ 0.015/0.018/0.018/0.3/0.45 mmol, in 4 ml CHCl3
at 40 8C. NaBArF, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
*Determined by HPLC (high-performance liquid chromatography) using a Chiralcel OD-H column.
†NR, no reaction.
Spirobox
Figure 1 | Transition-metal-catalysed insertion reactions starting with diazo
compounds. a, General catalytic cycle for transition-metal-catalysed
insertion reactions via metal carbene in situ, generated from diazo
compounds. Several transition metals, such as rhodium and copper, can
decompose diazo compounds to generate metal carbenes, which readily
undergo an insertion reaction with the X–H (X ¼ C, Si, O, N and so on) bond
to form a carbon–hydrogen bond and a carbon–carbon or carbon–
heteroatom bond. This transition-metal-catalysed insertion reaction is an
important carbene transfer reaction and has become an efficient tool
for the construction of C–X bonds under mild reaction conditions.
b, Enantioselective iron-catalysed O–H bond insertion reaction. Iron
complexes of spiro-bisoxazoline ligands are highly efficient catalysts for
asymmetric O–H bond insertion reactions. These complexes catalyse O–H
insertion into a wide variety of alcohols and even water, with exceptional
enantioselectivities under mild reaction conditions. The selectivities surpass
those obtained with other transition-metal catalysts. Ph, phenyl; Bn, benzyl;
i-Pr, isopropyl; t-Bu, tert-butyl.
and particularly high enantioselectivities (93–99% e.e.) (Table 2,
entries 1–10). The only exception was the highly sterically hindered
tert-butanol, which was unreactive. All the enantioselectivities of the
iron-catalysed O–H insertion reactions remarkably surpassed pre-
vious records (Table 2, entries 2, 3, 7, 9 and 10) of this reaction.
Compared to the saturated alcohols, allylic alcohols are trouble-
some substrates for the catalytic asymmetric O–H insertion reac-
tion. The instability of the carbon–carbon double bond of allylic
alcohols dramatically lowers the reactivity and enantioselectivity
of the O–H insertion reaction18. To our delight, the Fe/(Sa,S,S)-1c
efficiently catalysed the insertion of allylic alcohols with a-diazo-
phenylacetate (2a) to produce a-allyloxy phenylacetates (4k–4o)
in high yields (86–92%) and with excellent enantioselectivities
(89–95% e.e.) (Table 2, entries 11–15). The cyclopropanation is a
major competitive reaction in the transition-metal-catalysed
reactions of allylic alcohols with diazo compounds. However, we
insertion reaction, but very low enantioselectivities (Supplementary detected no cyclopropanation product in our reactions. The
Table S1) were observed. This result clearly revealed that the rigid carbon–carbon double bond in the chiral a-allyloxy phenylacetates
spiro scaffold of ligand 1 is crucial for a high level of chiral induction. leaves potential functionalities for further transformation in organic
Various commercially available iron(II) salts were suitable precursors synthesis. For instance, other investigators have applied the a-ally-
.
for the insertion reaction (Table 1, entries 4 and 6–8). FeCl2 4H2O loxy phenylacetates in the synthesis of densely functionalized dihy-
precursors from different sources gave the same level of reactivity dropyran derivatives, pyrazole derivatives and 3-phenyl clavams
and enantioselectivity (Supplementary Tables S5,S6). Competitive (Fig. 2a)26–29. The present reaction provides one of the most efficient
insertion of water was not detected in the reaction with FeCl2 4H2O methods for the synthesis of chiral a-allyloxy phenylacetates30.
.
as catalyst. In view of its ready availability, ease of handling and low
The use of water in catalytic asymmetric O–H bond insertion
.
price, FeCl2 4H2O was used for further investigation. It is worth reactions to produce synthetically useful alcohols is a more mean-
mentioning that FeCl3 can also catalyse the insertion reaction, ingful challenge. The iron-catalysed O–H bond insertion of water,
giving high yield and moderate enantioselectivity (Table 1, entry 9). to the best of our knowledge, has never been documented.
Other transition metals, including copper, cobalt, nickel, gold, silver, Encouraged by our success with the insertion of alcohols, we
rhodium and ruthenium, were also evaluated under the standard reac- studied the iron-catalysed asymmetric O–H insertion reaction
tion conditions and all gave markedly lower enantioselectivity between water and methyl a-diazophenylacetate (Table 3). A com-
(Table 1, entries 10–16) than the corresponding iron catalyst.
parison of ligands showed that the ligand (Sa,S,S)-1a, with phenyl
A broad range of alcohols was then investigated in the insertion groups on the dihydrooxazole rings, was the most efficient for
reaction with methyl a-diazophenylacetate (2a) under standard O–H insertion with water (Supplementary Table S4). With a
reaction conditions (Table 2). All the tested saturated alcohols 5 mol% iron complex of ligand (Sa,S,S)-1a as catalyst, the insertion
underwent the O–H insertion reaction smoothly to afford the cor- of methyl a-diazophenylacetate with water proceeded successfully
responding a-alkoxy esters (4a–4j) with excellent yields (85–95%) to give mandelate 5a in high yield (90%) with excellent
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.651
ARTICLES
Table 2 | Enantioselective iron-catalysed O–H insertion with alcohols.
R3
O
5 mol% FeCl2·4H2O
6 mol% (Sa,S,S)-1c
6 mol% NaBArF
N2
O
O
R3-OH
+
CHCl3, 40°C
O
O
3
4
2a
Time
Entry
R3OH
Product
Yield
(%)
e.e.
(%)*
Entry
R3OH
Product
Time
(h)
Yield
(%)
e.e.
(%)*
(h)
O
Ph
OH
O
1
nBuOH, 3a
15
93
98
9
15
94
98 (77)
O
O
O
3i
3j
O
O
4a
4i
Me3Si
Me3Si
O
OH
2
MeOH, 3b
EtOH, 3c
10
85
96 (69) 10
15
91
93 (90)
O
O
O
O
O
4b
4j
OH
O
O
3
10
15
88
92
95 (87) 11
48
86
92
89 (27)
O
3k
O
O
4c
4k
O
O
8
OH
4
CH3(CH2)8
CH2OH, 3d
95
94
98
12
13
14
3
93
O
3l
O
O
O
4d
O
4l
Ph
OH
5
6
20
20
90
92
12
90
88
95
95
OH
O
O
Ph
3e
O
3m
O
O
4e
4m
OH
OH
24
O
O
3f
O
O
3n
O
4f
O
4n
OH
7
8
15
10
95
95
98 (68) 15
24
91
95
OH
O
O
O
O
3o
3g
O
O
4g
4o
OH
99
O
3h
O
O
4h
Reaction conditions and analysis were the same as those in Table 1, entry 4.
*The data in parentheses are the e.e. values obtained with copper catalysts (see ref. 18).
enantioselectivity (95% e.e.) (Table 3, entry 1). The catalyst is stable gained with the catalyst Fe/(Sa,S,S)-1a were superior to those
enough to handle in air without loss of either reactivity or enantios- obtained with the copper counterpart22. In addition to a-diazoaryla-
electivity of the reaction. The catalyst Fe/(Sa,S,S)-1a was highly effi- cetate substrates, a-diazopropionate (2q) can also undergo the inser-
cient for a wide range of a-diazoesters. In all reactions of tion reaction with water to give benzyl 2-hydroxypropionate (5q) in
a-diazophenylacetate derivatives (5b–5n), a-diazo-2-naphthylace- 80% yield with 76% e.e. (Table 3, entry 18).
tate (5o) and a-diazo-3-thienylacetate (5p), high enantioselectivities
Notably, the reactions of a-diazo-(2-methoxyphenyl)acetate (5j)
(88–95% e.e.) were achieved (Table 3, entries 2–17). The results and a-diazo-(2-halophenyl)acetates (5k–5n), which have
a
548
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.651
ARTICLES
Ph
O
Ph
a
N
R2
N
O
Ref. 27
Ref. 26
HO
Ref. 28
Ref. 29
O
H
O
O
H
H
N
Ph
O
4k
O
Ph
O
O
CH2
b
N
ONs
Cl
CO2Me
N
OH
Cl
NsCl
DMAP, Et3N
2
S
O
O
7
O
O
S
CH2Cl2, 0°C
90%
Acetone, 20°C
85%
Cl
Clopidogrel 8, 93% e.e.
5l, 95% e.e.
6
Figure 2 | Synthetic applications of the O–H insertion products. a, Transformations of 2-allyloxy-2-phenylacetate (4k). The iron-catalysed asymmetric
insertion of the O–H bond of allylic alcohol provides one of the most efficient methods for the synthesis of chiral a-allyloxy phenylacetates, which have been
applied by other investigators in the synthesis of chiral densely functionalized dihydropyran derivatives, pyrazole derivatives and 3-phenyl clavams.
b, Asymmetric synthesis of clopidogrel (8). The Fe/(Sa,S,S)-1a-catalysed insertion reaction of methyl a-diazo-2-chlorophenylacetate with water produces
methyl (R)-o-chloromandelate (5l) with an excellent e.e. value at low catalyst loading. (R)-5l is a key intermediate for the preparation of clopidogrel (8), a
highly market-occupied platelet aggregation inhibitor. Iron-catalysed asymmetric insertion with water provides an efficient route for the preparation of this
important drug. Ns, nitrobenzenesulphonyl; DMAP, N,N-dimethylpyridin-4-amine.
Table 3 | Enantioselective iron-catalysed O–H insertion with water.
5 mol% FeCl2·4H2O
6 mol% (Sa,S,S)-1a
OH
N2
6 mol% NaBArF
O
O
R1
R2
R1
R2
+
H2O
CHCl3, 40°C
O
O
5
2
Entry
2
Product
Time
(h)
Yield
(%)
e.e.
(%)*
Entry
2
Product
Time
(h)
Yield
(%)
e.e.
(%)*
N2
OH
N2
OH
1
10
90
95
6
10
92
94
O
O
MeO
O
MeO
O
O
O
O
O
2a
5a
5f
2f
N2
OH
N2
OH
2
3
5
89
90
94
94
7
20
20
92
93
91
Cl
O
O
O
Cl
Br
O
O
O
O
O
O
2g
2b
5b
5g
5h
N2
OH
N2
OH
20
8
90
Br
O
O
O
O
O
O
O
Cl
Br
Cl
Br
2h
2c
5c
N2
OH
N2
OH
4
5
20
10
93
93
92
92
9
3
3
87
72
94
O
O
O
O
O
O
O
O
2i
5i
2d
5d
N2
OH
OMe
OMe OH
N2
10
92
O
O
O
O
O
O
O
O
5e
2j
2e
5j
Continued
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.651
ARTICLES
Table 3 | Continued
Entry
2
Product
Time
(h)
Yield
(%)
e.e.
(%)*
Entry
2
Product
Time
(h)
Yield
(%)
e.e.
(%)*
F
N2
F
OH
Cl
N2
Cl
OH
11
3
91
90
15
3
93
88
O
O
O
O
O
O
O
O
Cl
Cl
5k
2k
2n
5n
5o
Cl
Cl
Br
N2
Cl
Cl
Br
OH
N2
OH
12
2
6
3
92
90
94
95
92
94
16
17
18
10
12
90
66
80
91
O
O
O
O
O
O
O
O
O
O
O
O
O
O
5l
2o
2l
OH
N2
OH
N2
13†
92
76
O
O
O
O
S
S
5p
2p
2l
5l
N2
OH
N2
OH
14
20
O
O
O
Bn
Bn
O
O
O
2q
5q
2m
5m
.
Reaction conditions: FeCl2 4H2O/(Sa,S,S)-1a/NaBArF/2/H2O ¼ 0.015/0.018/0.018/0.3/1.5 mmol, in 4 ml CHCl3 at 40 8C.
*Determined by HPLC or SFC (supercritical fluid chromatography) using a chiral column.
†1 mol% catalyst was used.
coordinating group at the ortho position and were less enantioselec-
tive (,50% e.e.) in the reaction using our previously described
copper catalysts, gave high enantioselectivities with the iron catalyst
(Table 3, entries 10–15). For instance, in the insertion reaction of
methyl a-diazo-2-chlorophenylacetate with water, the catalyst
Fe/(Sa,S,S)-1a produced methyl (R)-o-chloromandelate (5l) with
95% e.e., while the analogous copper catalyst gave the same
product with only 36% e.e. (ref. 22). The activity of the catalyst
Fe/(Sa,S,S)-1a is remarkable in this reaction. The catalyst loading
can be reduced to 1 mol% without a significant reduction in yield
(90%) and enantioselectivity (92% e.e.) of the reaction (Table 3,
entry 13). The product methyl (R)-o-chloromandelate (5l) is a key
intermediate for the preparation of clopidogrel (8), a highly
market-occupied platelet aggregation inhibitor (Fig. 2b)31. The
facile conversion of 5l to clopidogrel32 demonstrated that this
iron-catalysed asymmetric insertion with water was an efficient
route for the preparation of this important drug.
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Methods
The general procedure for in situ catalyst preparation and catalytic asymmetric O–H
.
insertion reaction is as follows. The powdered FeCl2 4H2O (3.0 mg, 0.015 mmol,
5 mol%), (Sa,S,S)-1 (0.018 mmol, 6 mol%) and NaBArF (16.9 mg, 0.018 mmol,
6 mol%) were added to an oven-dried Schlenk tube in an argon-filled glovebox. After
CHCl3 (4 ml) was injected into the Schlenk tube, the solution was stirred at room
temperature under the argon atmosphere for 4 h. Alcohol (0.45 mmol) or water
(1.5 mmol) was injected into the reaction mixture at 40 8C and stirred for a few
seconds. Methyl 2-diazo-2-arylacetate (0.3 mmol) was then introduced into the
reaction mixture. The resulting mixture was stirred at 40 8C for a specified time and
the product was purified by flash chromatography. The enantiomeric purity of the
product was determined by HPLC or SFC analysis in comparison with authentic
racemic material.
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published online 9 May 2010
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Acknowledgements
The authors wish to thank the National Natural Science Foundation of China, the National
Basic Research Program of China (973 Program, nos 2006CB806106, 2010CB833300), the
Ministry of Health (grant no. 2009ZX09501-017) and the ‘111’ Project of the Ministry of
Education of China (grant no. B06005) for financial support.
Author contributions
S.-F.Z., J.-H.X. and Q.-L.Z. designed the project. C.Y. and H.-X.M. carried out the
experimental work. S.-F.Z. and Q.-L.Z. wrote the paper. All authors analysed the data,
discussed the results and commented on the manuscript.
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to Q.L.Z.
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