Ir-SpinPHOX Catalyzed Enantioselective Hydrogenation of 3-Ylidenephthalides

Article abstract of DOI:10.1002/anie.201807639

The first asymmetric hydrogenation of 3-ylidenephthalides has been developed using the Ir^I complex of a spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline ligand (SpinPHOX) as the catalyst, affording a wide variety of chiral 3-substituted phthalides in excellent enantiomeric excesses (up to 98 % ee). The utility of the protocol has been demonstrated in the asymmetric synthesis of chiral drugs NBP and BZP precursor, as well as the natural products chuangxinol and typhaphthalide.

Full text of DOI:10.1002/anie.201807639

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Accepted Article
Title: Ir-SpinPHOX Catalyzed Enantioselective Hydrogenation of 3-
Ylidenephthalides
Authors: Kuiling Ding, Yao Ge, Zhaobin Han, Zheng Wang, Chen-Guo
Feng, Qian Zhao, and Guo-Qiang Lin
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10.1002/anie.201807639
Angewandte Chemie International Edition
COMMUNICATION
Ir-SpinPHOX Catalyzed Enantioselective Hydrogenation of 3-
Ylidenephthalides
*
Yao Ge,a,b Zhaobin Han,a Zheng Wang,a Chen-Guo Feng,a Qian Zhao,c Guo-Qiang Lin,a and Kuiling
Dinga,b,d*
Dedication ((optional))
Abstract: The first asymmetric hydrogenation of 3-ylidenephthalides
has been developed using the IrI complex of a spiro[4,4]-1,6-
nonadiene-based phosphine–oxazoline ligand (SpinPHOX) as the
catalyst, affording a wide variety of chiral 3-substituted phthalides in
excellent enantiomeric excesses (up to 98% ee). The utility of the
protocol has been demonstrated in the asymmetric synthesis of
chiral drugs NBP and BZP precursor, as well as the natural products
chuangxinol and typhaphthalide.
have been devoted to access these important architectures.[5] In this
context, conventional methods usually involved multistep synthesis
using chiral auxiliaries,[6] or optical resolution in a few cases.[7]
The asymmetric catalytic strategies developed for 3-substituted
chiral phthalides were mostly based on the conversion of 2-
acylarylcarboxylates into the enantioenriched 2-(hydroxymethyl)
arylcarboxylates via asymmetric hydrogenation (AH),[8] transfer
hydrogenation,[9] or organometallic addition,[10] followed by an in
situ lactonization (Scheme 2a). Alternative asymmetric catalytic
methods via dihydroxylation and lactonization,[11] ketone
hydroacylation,[12] or redox allylation[13] have also been explored.
The
phthalide[1(3H)-isobenzofuranone]
frameworks,
in
particular chiral 3-substituted phthalides, are structural subunits in
numerous natural products with remarkable pharmaceutical
interests (Scheme 1).[1] For examples, (S)-3-n-butylphthalide
(NBP), a constituent of celery seed oil, and its derivative BZP
demonstrate diverse pharmacological effects for anti-tumor, anti-
asthmatic, anti-convulsant, anesthesia prolongation, and have been
clinically approved as anti-ischemic agents by CFDA.[2]
Cytosporone E[3] and alcyopterosin E[4] exhibit antibacterial
activity and cytotoxicity against wild Hep-2 cell line, respectively.
Scheme 2. Asymmetric catalytic synthesis of phthalide derivatives.
We envisioned that the AH of readily accessible 3-
ylidenephthalides,[14] which are synthetic precursors for 2-
acylarylcarboxylates, might constitute a more straightforward
approach to enantioenriched 3-substituted phthalides (Scheme 2b).
Although there have been a few literature precedents on the AH of
several simple lactones bearing an exocyclic methylene moiety
(e.g., 5-methylideneoxolan-2-one, 5-methylene-1,3-dioxolan-2-one,
Scheme 1. Representative phthalide natural products and derivatives with
pharmacological interests.
and
6-methylene-tetrahydropyran-2-one),[15]
AH
of
3-
ylidenephthalide derivatives has not been reported so far, probably
due to the difficulty associated with chelation of exocyclic C=C
bond to the catalyst metal, which is often crucial for effective
chirality transfer especially in Rh or Ru catalyzed AH of olefins.[16]
On the other hand, AH of minimally functionalized olefins with
various chiral Ir-P^N catalysts has received considerable
attention[17] since the pioneering work reported by Pfaltz and
coworkers.[18] We previously reported a class of chiral iridium(I)
complexes with spiro P^N ligands, SpinPHOX/Ir(I), for efficient
AH of ketimines and several types of α,β-unsaturated carbonyl
compounds.[19] In continuation of our work along this vein, herein
we communicate the AH of 3-alkylidene- and 3-
arylidenephthalides with a SpinPHOX/Ir(I) catalyst, providing a
direct access to chiral 3-substituted phthalides in excellent
enantiopurities.
Such broad spectra of biological activities made chiral 3-
substituted phthalides attractive synthetic targets, and much efforts
[a]
Y. Ge, Dr. Z. Han, Dr. Z. Wang, Prof. Dr. K. Ding , State Key
Laboratory of Organometallic Chemistry, and CAS Key Laboratory
of Synthetic Chemistry of Natural Substances, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
Fax: Int. code + (21)-6416-6128
E-mail: kding@mail.sioc.ac.cn
[b]
[c]
University of Chinese Academy of Sciences, Beijing 100049 (China)
Jiangsu Key Laboratory of Chiral Drug Development, Jiangsu
Aosaikang Parmaceutical CO., LTD., Nanjing, 211112 (China)
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin 300071 (China)
[d]
Our initial evaluation began with AH of 5a as the model
substrate. The reaction was performed in CH2Cl2 at rt under 50 atm
H2 in the presence of 1 mol% (R,S)-1a as the catalyst. Full
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807639
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COMMUNICATION
19
(R,S)-4
30
0
-
conversion to 6a with 88% ee was observed in 24 h (Table 1, entry
1), which encouraged us to further screen the SpinPHOX/Ir(I)
series [(R,S)-1a-g, (S,S)-1a-d] under identical conditions. The axial
chirality of the SpinPHOX ligands seems to play a dominant role in
the sense of the asymmetric induction (entries 1-10), and the (R,S)-
1 (entries 1, 3, 5, 7) gave much higher enantioselectivities than
their corresponding mismatched diastereomeric (S,S)-counterparts
(entries 2, 4, 6, 8). Moreover, the oxazoline substituent also has an
impact on the asymmetric induction and/or catalytic activity.
[a] Conditions: 5a (0.25 mmol), Ir cat. (0.0025 mmol), dichloromethane
(2.5 mL), 25°C, 24 h. [b] Determined by 1H NMR spectroscopy. [c]
Determined by HPLC analysis on a chiral stationary phase. [d] 0.5 mol% of
(R,S)-1f or (R,S)-1g, 4 h. [e] 0.5 mol% (R,S)-1g, 24 h.
With the optimal catalyst (R,S)-1g at hand, we proceeded to
examine the substrate scope of the protocol. The 3-
ylidenephthalide substrates bearing aliphatic (5a-q) or aromatic
side moieties (7a-q) were readily obtained via one-step
synthesis from cheap starting materials (SI). AH of these 3-
ylidenephthalides proceeded smoothly with (R,S)-1g as the
catalyst, and the results were summarized in Tables 2 and 3. The
protocol proved to be versatile for AH of 5a-q (Table 2), where
the corresponding phthalides 6a-q were generally obtained in
high yields (86->99%) and good to excellent enantioselectivities
(86-96% ee), irrespective of the side chain lengths (alkyl = H,
Me, Et, Pr, Bu) or stereoelectronic nature of the substituent
(MeO, naphthyl, m-Br, m-F, o-CF3, o-OMe, o-Ph, o-Me ) on the
phthalide phenyl ring. An intriguing behavior was found in the
AH of 5p bearing an isopropyl group, where the phthalide 6p
was obtained in moderate ee (68%). Remarkably, AH of 5q with
a tetra-substituted C=C bond also proceeded smoothly to afford
6q in > 99% yield with 92% ee.
s
i
Catalysts (R,S)-1a, (R,S)-1d and (R,S)-1f bearing a Bn, Bu or Bu
group on their oxazoline moieties, respectively, were superior in
terms of both reactivity and enantioselectivity, affording a full
conversion to 6a with 87-88% ee (entries 1, 7, 10). With 0.5 mol%
of (R,S)-1f as the catalyst, AH of 5a under 30 atm of H2 proceeded
to completion in 4 h with 91% ee for 6a (entry 11). Using (R,S)-1g
as the catalyst in AH of 5a gave 6a in 93% ee (entry 12), which
was improved to 95% under a lower pressure of H2 (10 atm, entry
13). Remarkably, AH of 5a under 2 atm H2 with 0.5 mol% (R,S)-
1g still proceeded to full conversion and afforded 95% ee of (R)-
6a (entry 14). Several well-established chiral iridium phosphine-
oxazoline catalysts, including PHOX-Ir [(S)-2],[18] ThrePHOX-Ir
[(R,R)-3a-b],[20] and SIPHOX [(S,S)- or (R,S)-4],[21] were also
examined in this reaction under otherwise identical conditions as in
entry 11. Unfortunately, lower reactivity and/or enantioselectivity
was observed in these cases (entries 15-19).
n
n
Table 2. AH of the 3-alkylidenephthalides (5a-q)[a]
Table 1. Ir(I)-catalyzed AH of the 3-butylidenephthalide (5a)[a]
Entry
1
Ir Cat.
(R,S)-1a
(S,S)-1a
(R,S)-1b
(S,S)-1b
(R,S)-1c
(S,S)-1c
(R,S)-1d
(S,S)-1d
(R,S)-1e
(R,S)-1f
(R,S)-1f
(R,S)-1g
(R,S)-1g
(R,S)-1g
(S)-2
p(H2)(atm)
50
Conv.[%][b]
> 99
92
Ee[%] [c]
88 (R)
11 (S)
67 (R)
33 (S)
87 (R)
7 (R)
2
50
3
50
> 99
33
4
50
5
50
80
6
50
93
7
50
> 99
91
87 (R)
3 (R)
8
50
9
50
47
73 (R)
88 (R)
91 (R)
93 (R)
95 (R)
95 (R)
33 (R)
81 (S)
rac
[a] Conditions: 5 (0.2 mmol), (R,S)-1g (0.002 mmol), CH2Cl2 (2.0 mL),
p(H2) (10 atm), 25°C, 24 h. The yields are for the isolated products 6a-q,
and the ee values were determined by HPLC analysis on a chiral
stationary phase. The absolute configurations of 6a-q were assigned to be
(R) by comparison of their optical rotations with the literature reported
values or based on their CD spectra (see SI).
10
11[d]
12[d]
13[d]
14[e]
15
16
17
18
50
> 99
> 99
> 99
> 99
> 99
58
30
30
10
2
3-Arylidenephthalides 7a-q turned out to be less reactive for
this AH system, probably owing to the electronic stabilization
of C=C bond by two conjugated aryl rings. A survey of the
reaction conditions for AH of 3-benzalphthalide 7a revealed that
30
(R,R)-3a
(R,R)-3b
(S,S)-4
30
76
30
89
30
14
23 (R)
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10.1002/anie.201807639
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elevated H2 pressure (80 atm) and higher loading of (R,S)-1g (2
quantitative yield with 95% ee. Under identical reaction conditions,
mol%) were necessary for smooth conversion (see SI). Under
AH of 3-ylidenephthalide 5r gave 95% ee of (R)-6r, which is an
these optimized conditions, AH of
a
variety of 3-
immediate synthetic precursor to BZP,[2b-c]
a
potential
arylidenephthalides (7a-p) were examined and the results were
shown in Table 3. In all cases, the corresponding products 8a-p
were obtained with excellent enantioselectivities (92-98% ee),
albeit incomplete conversions were observed for reactions of
several substrates. Finally, the AH of 3-ylidenephthalide 7q
with a vinyl phenoxy ether moiety also proceeded well to afford
8q in excellent yield (98%) with good ee value (80%).
cardiovascular drug. Finally, AH of phenoxy-bearing 3-
ylidenephthalides 9 and 10 with (R, S)-1g as the catalyst provided
ready access to optically active natural products (R)-chuangxinol[22]
and (R)-typhaphthalide,[23] respectively, in high yields and
excellent ee values.
O
O
(R,S)-1g (0.5 mol%)
+
H2
O
O
CH2Cl2, 50oC, 24 h
100% conv.
Table 3. AH of the 3-arylidenephthalides (7a-q)[a]
10 atm
nBu
(R)-6a, NBP
nPr
5a
1 gram
98% yield, 95% ee
O
O
Br
Br
(R,S)-1g (1 mol%)
O
H2
O
+
CH2Cl2, rt, 24 h
>99% conv.
10 atm
nPr
nBu
5r
(R)-6r, BZP precursor
97% yield, 95% ee
O
O
O
(R,S)-1g (1 mol%)
O
+
H2
CH2Cl2, rt, 24 h
> 99% conv.
nPr
10 atm
nBu
OH
OH
9
(R)-chuangxinol
96% yield, 92% ee
OH
OH
O
O
(R,S)-1g (2 mol%)
H2
O
O
+
CH2Cl2, rt, 24 h
> 99% conv.
80 atm
Ph
Bn
10
(R)-typhaphthalide
96% yield, 94% ee
Scheme 3. Synthesis of chiral drugs NBP and BZP precursor, as well as the
natural products (R)-chuangxinol and (R)-typhaphthalide with AH of 3-
ylidenephthalides as the key steps
We have determined the solid structure of catalyst precursor
(R,S)-1g (Figure 1a). Inspired by the elegant theoretical study of
Andersson and coworkers on Ir/P^N catalyzed AH of
unfunctionalized olefins,[24] we tentatively proposed a schematic
model for stereoselection in the titled reaction. As shown in Figure
1b, the oxazolyl substituent R’ is situated above the N–Ir–P plane
of intermediate {[(R,S)-1]Ir(H)2(H2)(5)}+, as a result of constraints
by the rigid ligand backbone. As a trisubstituted olefin, 3-
ylidenephthalide is coordinated trans to P and oriented with its
smallest substituent (H) pointing towards the oxazoline fragment,
hence leading to preferential formation of (R)-phthalides.
[a] Conditions: 7 (0.1 mmol), (R,S)-1g (0.002 mmol), CH2Cl2 (4.0 mL), p(H2)
(80 atm), 25°C, 24 h. The substrate conversions (values before the
parentheses) were determined by 1H NMR analyses, and the values within the
parentheses are yields of the isolated products 8a-q. The ee values were
determined by HPLC analysis on a chiral stationary phase. The absolute
configurations of the products were assigned to be (R) by comparison of their
optical rotations with the literature reported values or based on their CD
spectra (see SI).

Figure 1. (a) X-Ray structures of (R,S)-1g, H atoms and BArF anion are
omitted for clarity. (b) Schematic model for enantioselection of (R,S)-1.
In summary, we have developed the first enantioselective
hydrogenation of 3-ylidenephthalides using a SpinPHOX/Ir(I)
catalyst, providing a straightforward approach to a wide variety of
3-substituted chiral phthalides in high yields with excellent optical
purities (up to 98 % ee). Synthetic utilities of the protocol have also
been demonstrated in the asymmetric synthesis of chiral drugs (R)-
NBP and a (R)-BZP precursor, as well as the natural products (R)-
chuangxinol and (R)-typhaphthalide. Given the considerable
biological importance, the protocol might find broader applications
The synthetic utilities of the protocol were demonstrated in the
synthesis of several chiral drugs and natural products with AH of
the corresponding 3-ylidenephthalides as the key steps (Scheme 3).
Under standard reaction conditions, (R,S)-1g catalyzed AH of 5a
was performed on gram-scale to afford (R)-NBP (6a) in nearly
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We are grateful for financial support from MOST
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Keywords: asymmetric catalysis • hydrogenation • iridium •
phthalides • P, N ligand
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Yao Ge, Zhaobin Han,* Zheng Wang,
Chen-Guo Feng, Qian Zhao, Guo-Qiang
Lin, and Kuiling Ding*
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Ir-SpinPHOX Catalyzed
Enantioselective Hydrogenation of 3-
Ylidenephthalides
A Shortcut to a wide variety of chiral 3-substituted phthalides with pharmacological
interests has been realized by SpinPHOX/Ir catalyzed asymmetric hydrogenation of
3-ylidenephthalides in high enantioselectivities (up to 98% ee).
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