Catalytic asymmetric synthesis of aromatic spiroketals by spinphox/iridium(I)-catalyzed hydrogenation and spiroketalization of α,α′-Bis(2-hydroxyarylidene) ketones

Article abstract of DOI:10.1002/anie.201106488

From spiro to spiro: An iridium(I) complex with a spiral P,N ligand (SpinPhox) is highly efficient in the catalytic asymmetric hydrogenation of α,α′-bis(2-hydroxyarylidene) ketones to afford the corresponding aromatic spiroketals in high yields with excellent diastereo- and enantioselectivities (see scheme). The complex plays a dual role in the reaction, acting as catalyst for both the hydrogenation of C=C bonds and the subsequent spiroketalization of bisphenolic ketones. Copyright

Full text of DOI:10.1002/anie.201106488

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DOI: 10.1002/anie.201106488
Asymmetric Synthesis
Catalytic Asymmetric Synthesis of Aromatic Spiroketals by SpinPhox/
Iridium(I)-Catalyzed Hydrogenation and Spiroketalization of a,a’-
Bis(2-hydroxyarylidene) Ketones**
Xiaoming Wang, Zhaobin Han, Zheng Wang,* and Kuiling Ding*
Recently, the chemistry of chiral aromatic spiroketals has
received much attention because they are key substructures in
biologically active natural products,[1] pharmaceuticals,[2] and
chiral ligands in transition-metal-catalyzed reactions.[3]
Although several methods for the preparation of aromatic
spiroketals have been reported,[4–8] the direct catalytic,
enantioselective synthesis of aromatic spiroketals has not
yet been achieved. On the other hand, transition-metal-
catalyzed asymmetric hydrogenations have long held a
respected position in modern organic synthesis.[9] In partic-
ular, the iridium-catalyzed asymmetric hydrogenation of the
rated ketones independently reported by the groups of
Bolm[12a] and Hou[12b]. We also found that SpinPHOX/IrI
demonstrated excellent enantioselectivity and catalytic activ-
ity in the hydrogenation of a,a’-bis(2-methoxybenzylidene)-
cyclohexanone (> 99% ee, d.r. = 92:8).[13] This result encour-
aged us to attempt the catalytic asymmetric synthesis of
aromatic spiroketals 2 by sequential hydrogenation of a,a’-
bis(2-hydroxyarylidene) ketones followed by spontaneous
spiroketalization of the optically active hydrogenation prod-
ucts. After screening a variety of IrI catalysts to check the
viability of this transformation,[14] we decided to employ chiral
IrI complexes of phosphine–oxazoline ligands to catalyze the
hydrogenation of prochiral a,b-unsaturated ketone 3a, which
bears two hydroxy groups. In principle, three diastereomeric
spiroketals might be formed (cis-2a, trans-2a, and trans-2a’;
Table 1). As shown in entry 1, we were pleased to find that the
hydrogenation of 3a, in the presence of 1 mol% of IrI-(R,S)-
1a, proceeded smoothly to give the corresponding, optically
active spiroketal trans-2a in 83% yield, with a d.r. of 87:13
(trans-2a/cis-2a) and 87% ee for the trans isomer, thus
demonstrating the feasibility of this catalytic, asymmetric
hydrogenation strategy for the synthesis of optically active
spiroketals. The structures of both cis-2a and trans-2a were
confirmed by X-ray diffraction analysis (Figure 1).[20] How-
ever, trans-2a’ was not observed in the 1H NMR spectrum of
the crude product mixture, indicating that the diastereoselec-
tivity of the spiroketalization is completely controlled by the
chirality of the trans-hydrogenated intermediate.
=
C C bonds of either functionalized or unfunctionalized olefin
derivatives has lately been an important topic in asymmetric
catalysis.[10] We have recently reported a class of highly
efficient iridium(I) catalyst complexes with spiro[4.4]-1,6-
nonadiene-based chiral phosphine–oxazoline ligands (Spin-
PHOX, 1) for the enantioselective hydrogenation of N-aryl or
alkyl imines and a-aryl-b-substituted acrylic acids.[11] Herein,
we report the first catalytic enantioselective synthesis of
aromatic spiroketals 2 through the SpinPHOX/IrI-promoted
asymmetric hydrogenation of a,a’-bis(2-hydroxyarylidene)
ketones and spiroketalization of hydrogenation products.
With these initial results in hand, we turned to optimiza-
tion of the IrI catalysts by screening a list of chiral phosphine–
oxazoline ligands, including PHOX and SpinPHOX. As
summarized in Table 1, the chirality of the spiro backbone
of the SpinPHOX ligands plays a dominant role in determin-
ing the sense of the asymmetric induction (entries 1–10).
Moreover, the substituent on the oxazoline fragment also has
a substantial impact on the levels of asymmetric induction and
catalytic activity. IrI/(S,S)-1c turned out to be optimal among
the catalysts screened, in terms of the efficiency and
selectivity of the reaction, leading to formation of (À)-2a in
92% yield with 98:2 d.r. and greater than 99% ee (entry 6).
On the other hand, hydrogenation with catalyst IrI/(R,S)-1e
afforded (+)-2a with 96:4 d.r. and greater than 99% ee of the
major isomer, albeit with a lower yield (79%; entry 9). When
Pfaltzꢀs IrI/PHOX catalysts (R = tBu, iPr; entries 11, 12) were
applied, IrI/iPr-PHOX was found to be ineffective under the
reaction conditions (entry 12), while IrI/tBu-PHOX afforded
excellent enantioselectivity (> 99% ee), but with only modest
activity (entry 11).
This research was inspired by the excellent performance
of IrI complexes of phosphine-oxazoline ligands in the
=
asymmetric hydrogenation of the C C bond of a,b-unsatu-
[*] X. M. Wang, Dr. Z. B. Han, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: kding@mail.sioc.ac.cn
[**] We thank the National Natural Science Foundation of China (grant
nos. 20821002, 20923005, 20972176), the Major Basic Research
Development Program of China (grant no. 2010CB833300), the
Chinese Academy of Sciences, and the Science and Technology
Commission of Shanghai Municipality for the financial support of
this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106488.
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Table 1: Asymmetric hydrogenation and spiroketalization of 3a in the
Table 2: Sequential asymmetric hydrogenation and spiroketalization of 3
presence of IrI complexes of chiral phosphine–oxazoline ligands.[a]
in the presence of IrI/(S,S)-1c.[a]
Entry Product
y
Yield [%][b] d.r.[c]
ee [%][d]
>99
1
1
92
94
98:2
95:5
2
3
1
1
98
92
93:7
>99
Entry
Catalyst
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
IrI/(R,S)-1a
IrI/(S,S)-1a
IrI/(R,S)-1b
IrI/(S,S)-1b
IrI/(R,S)-1c
IrI/(S,S)-1c
IrI/(R,S)-1d
IrI/(S,S)-1d
IrI/(R,S)-1e
IrI/(S,S)-1e
IrI/tBuPHOX
IrI/iPrPHOX
83
14
91
80
91
92
0
73
79
31
24
0
87:13
54:46
95:5
83:17
91:9
98:2
–
75:25
96:4
75:25
93:7
–
87(+) (15)
60(À) (1)
84(+)
84(À) (4)
75(+) (12)
>99(À)
–
81(À) (3)
>99(+)
98(À) (5)
>99(+)
–
4
5
6
2
3
3
90
81
90
92:8
97:3
97:3
>99
98
9
10
11
12
95
[a] Reaction conditions: 3a (0.1 mmol), IrI catalyst (0.001 mmol,
1 mol%), H2 (50 atm), CH2Cl2 (2 mL), room temperature for 24 h.
[b] Yield of isolated trans-2a. [c] Determined by 1H NMR. [d] Determined
by chiral HPLC for trans-2a. The ee values of the corresponding cis-2a are
given in parentheses.
7
8
2
1
88
93
98:2
94:6
>99
>99
9
1
5
3
96
92
86
98:2
94:6
98:2
>99
>99
>99
Figure 1. X-ray structures of trans-2a (left) and cis-2a (right). C gray,
H blue, O red.
10
11
Having established complex IrI/(S,S)-1c as the optimal
catalyst, we next examined its adaptability in the asymmetric
hydrogenation of various a,a’-bis(2-hydroxyarylidene)
ketones. As shown in Table 2, a number of a,a’-bis(2-
hydroxyarylidene) cyclohexanones (3a–3o) can be readily
hydrogenated, followed by spiroketalization, to afford the
corresponding optically active, aromatic spiroketals in high
yields with excellent diastereo- and enantioselectivities. The
reaction proceeded well with substrates having ortho-, meta-,
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Table 2: (Continued)
Entry Product
showed moderate activity in the hydrogenation of 3q (with a
tetrahydropyran-4-one skeleton) to give 2q in 85% yield.
Although the diastereoselectivity was only modest (75:25),
the enantiomeric excess of the major diastereomer still
remained high (96% ee). Similarly, the hydrogenation of 3r
(with a cycloheptanone backbone) gave the corresponding
spiroketal (+)-2r in 80% yield with a 17:83 d.r. and 98% ee of
the minor trans isomer. Alternatively, the use of catalyst
IrI/(R,S)-1a afforded (À)-2r in 81% yield with a 66:34 d.r.
and more than 99% ee of the major trans isomer. Although no
reaction occurred in the hydrogenation of cyclopentanone
derivative 3p with catalyst IrI/(S,S)-1c (3 mol%), catalyst
IrI/(R,S)-1a was effective, affording the corresponding spi-
roketal (+)-2p in 83% yield, albeit with poor diastereo- and
enantioselectivity.
y
Yield [%][b] d.r.[c]
ee [%][d]
>99
12
3
85
91
95
95:5
95:5
98:2
13
14
1
1
98
>99
To demonstrate the potential of this highly efficient
catalytic asymmetric reaction, product 2h was employed for
the preparation of a new type of spiroketal-based diphosphine
ligand 4. As showed in Scheme 1, enantiopure (R,R,R)-(+)-4
could be readily obtained in 73% yield by a one-step
transformation from (R,R,R)-(À)-2h, providing a facile and
practical approach to the access of chiral diphosphine ligands,
which might be useful for asymmetric catalysis.[15]
15
3
3
3
3
85
89:11
66:34
75:25
96
26
96
16[e]
83[f]
85[f]
81[f]
17
18[e]
66:34 >99
Scheme 1. Preparation of the chiral diphosphine ligand 4.
[a] Reaction conditions, unless otherwise stated: substrate (0.1 mmol),
catalyst IrI/(S,S)-1c (1–5 mol%), CH2Cl2 (2 mL), room temperature for
24 h. [b] Yield of isolated trans product. [c] d.r.=trans/cis, determined by
1H NMR spectroscopy. [d] The ee value of the trans isomer was
determined by chiral HPLC. [e] Catalyst IrI/(R,S)-1a was used. [f] The
total yield of cis and trans products.
To gain more information on the catalytic process, bis-
(phenol) product 6, obtained by hydrogenation of 5 using Pd/
C as catalyst, was further treated with 1 mol% of catalyst
IrI/(R,S)-1a in CH2Cl2 at room temperature for 16 h in the
absence of H2 (Scheme 2).[16] No spiroketalization was
observed under these conditions. However, 18 h after intro-
duction of H2 (50 atm) to the reaction system, spiroketaliza-
or para-methyl groups on the phenyl rings and gave the
corresponding products 2b–d in 90–94% yield with 98–
> 99% ee, indicating the high adaptability of the catalyst to
variation in the steric environment of the substrates.
Electron-donating or -withdrawing substituents on the
phenyl ring of the substrates have little impact on the yield
and enantioselectivity of the reaction. The introduction of
halogen substituents, in particular chloro or bromo variants,
onto the substrates allows for direct construction of the
corresponding halogen-substituted, enantioenriched, aro-
matic spiroketals 2 f–o (95– > 99% ee), thus providing an
excellent opportunity for further modification of the spiro-
ketal motifs. The absolute configuration of (À)-2h was
established to be (R,R,R) by X-ray crystal diffraction analysis.
The absolute configurations of the analogous products were
deduced by comparing their CD spectra with that of (R,R,R)-
(À)-2h.[13] Finally, the effect of the cycloketone moiety of the
substrates on the catalytic reaction was investigated for
cyclopentanone, tetrahydropyran-4-one, and cycloheptanone
derivatives 3p–r. As shown in Table 2, catalyst IrI/(S,S)-1c
Scheme 2. Experimental studies on plausible reaction pathways in the
catalytic synthesis of aromatic spiroketals.
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Xing, H. Huang, X. Liu, J. Su, W. Zhang, J. Pharm. Biomed.
tion product 7 was isolated in 71% yield, which is close to the
results obtained from direct hydrogenation of 5 using
IrI/(R,S)-1a as catalyst. On the other hand, the direct use of
IrCl3·3H2O (10 mol%) as a catalyst for the spiroketalization
of 6, in the absence of hydrogen, afforded 7 in 95% yield
(Scheme 2). These results imply that the spiroketalization was
probably promoted by an IrIII species resulting from a
reaction between H2 and the IrI precatalyst. It is well known
that chiral dihydroxy ketones can be readily cyclized in the
presence of Lewis or Brønsted acids to form spiroketals.[17]
However, the chiral a carbon atoms of the ketone will easily
undergo racemization under acidic conditions. In fact, this
racemization did occur when the cyclization of the hydro-
genation product (with > 99% ee) of a,a’-bis(2-methoxyben-
zylidene)cyclohexanone was carried out by demethylation
with BBr3, which was followed by spontaneous spiroketaliza-
tion. The major spiroketalization product isolated was
racemic cis-2a (71%), while the expected, optically active
trans-2a, with an enantiomeric excess of 15%, constitutes
only 10% of the product mixture.[13] Although we cannot rule
out the possibility of Brønsted acid promotion of the
diastereoselective spiroketalization of diphenolic ketones,
some kind of high-valent iridium species seems more likely to
be involved; both the use of various IrI or IrIII species as Lewis
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À
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hydrogenation of 3a, has an ee value of 15%. This result is
evidence for the involvement of a chiral iridium species in the
spiroketalization reaction.
In conclusion, we have developed the first catalytic,
enantioselective synthesis of aromatic spiroketals 2 through
the asymmetric hydrogenation of a,a’-bis(2-hydroxyaryli-
dene) ketones and subsequent spiroketalization of the
resulting hydrogenated, bisphenolic ketones using IrI/Spin-
PHOX as catalyst. The iridium complexes were found to play
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=
the hydrogenation of C C bonds and the spiroketalization of
the hydrogenated ketone-bearing bis(phenol) moieties with-
out racemization of the chiral a-carbon centers. The present
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Received: September 13, 2011
Published online: December 14, 2011
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Keywords: asymmetric catalysis · hydrogenation · iridium ·
P,N ligands · spiroketals
.
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[20] CCDC-832586 (trans-2a) and CCDC-832585 (cis-2a) contain
the supplementary crystallographic data for this paper. These
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