Asymmetric Hydrogenation of Tetrasubstituted Cyclic Enones to Chiral Cycloalkanols with Three Contiguous Stereocenters

Article abstract of DOI:10.1021/acs.orglett.7b01343

A highly efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted cyclic enones has been developed for the enantioselective synthesis of chiral cycloalkanols with three contiguous stereocenters. The C=O and C=C bonds of the enone substrate

Full text of DOI:10.1021/acs.orglett.7b01343

Letter
pubs.acs.org/OrgLett
Asymmetric Hydrogenation of Tetrasubstituted Cyclic Enones to
Chiral Cycloalkanols with Three Contiguous Stereocenters
Yun-Ting Liu,† Ji-Qiang Chen,† Lin-Ping Li,† Xin-Yang Shao,† Jian-Hua Xie,*,† and Qi-Lin Zhou†,‡
†State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, and ‡Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A highly efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted cyclic enones has been
developed for the enantioselective synthesis of chiral cycloalkanols with three contiguous stereocenters. The CO and CC
bonds of the enone substrates were hydrogenated sequentially in one pot with excellent enantioselectivity (92 to >99% ee) and
diastereoselectivity (dr 95:5 to >99:1). The reaction provided a practical approach to all of the stereoisomers of the antiulcer
drug rosaprostol.
ulcers),6 which are widely used as pharmaceuticals,7 are the
hiral cycloalkanols, particularly chiral cyclopentanols with
Ccontiguous stereocenters, are prevalent structural motifs
most prominent examples of compounds with chiral core
cyclopentanol structures with three or four contiguous
stereocenters, in which the β-tertiary stereocenter linked with
an alkyl group. Thus, the enantioselective synthesis of chiral
cycloalkanols with contiguous stereocenters including a β-alkyl-
substituted tertiary stereocenter have been the focus of study in
organic synthesis.8
in natural products, pharmaceuticals, and other bioactive
molecules. Estradiol (1, the primary female sex hormone),1
longeracemine (2, a daphniphyllum alkaloid),2 and dipulchellin
A (3, a sesquiterpene lactone dimer)3 contain a chiral
cyclopentanol unit with three contiguous stereocenters, one
of which is an alkyl-substituted tertiary stereocenter (Figure 1).
Prostaglandins and their analogues such as prostaglandin F2α
(4, PGF2α, used to induce labor and as an abortifacient),4
lantanoprost (5, used to treat increased pressure inside the
eye),5 and rosaprostol (6, used to treat gastric and duodenal
Undoubtedly, transition-metal-catalyzed asymmetric hydro-
genation of configurationally labile α-substituted ketones via
dynamic kinetic resolution (DKR) is a reliable method for the
syntheses of optically active chiral alcohols with contiguous
stereocenters.9 However, the asymmetric hydrogenation of
cyclic ketones to chiral alcohols with three contiguous
stereocenters remains a challenge. Recently, we have found
that asymmetric hydrogenations of racemic disubstituted
cyclohexanones and cyclopentanones with two configuration-
ally labile α- or β-stereocenters catalyzed by chiral spiro
ruthenium or iridium catalysts via DKR produce chiral alcohols
with three contiguous stereocenters in high yield with high
enantioselectivity and diastereoselectivity.10 However, those
reactions cannot be used to direct prepare chiral cyclic alcohols
with a β-alkyl-substituted tertiary stereocenter because the β-
C−H of the tertiary stereocenter of the ketone substrates is not
Figure 1. Representative natural products and pharmaceuticals
containing cyclopentanol units with contiguous stereocenters.
Received: May 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01343
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Letter
acidic enough to be epimerized under the DKR reaction
conditions.
Table 1. Asymmetric Hydrogenation of β-Alkyl-α-
ethoxycarbonylcyclopentenones 8a−g with (R)-7
a
To develop an efficient method for the enantioselective
synthesis of chiral cycloalkanols, especially those containing a β-
alkyl-substituted tertiary stereocenter, we studied the catalytic
asymmetric hydrogenation of β-alkyl-α-ethoxycarbonylcycloal-
kenones 8 to obtain chiral cycloalkanols 9 with three
contiguous stereocenters (Scheme 1). We envisioned that the
b
c
time
(h)
yield
ee
entry
R
(R)-7
9
(%)
(%)
Scheme 1. Our Envisioned One-Pot Sequential Asymmetric
Hydrogenation Strategy for the Synthesis of Chiral
Cycloalkanols with Three Contiguous Stereocenters
1
2
3
4
5
6
Me (8a)
Me (8a)
Me (8a)
Me (8a)
Et (8b)
(R)-7a
(R)-7b
(R)-7c
(R)-7d
(R)-7a
(R)-7a
(R)-7a
(R)-7a
9a
9a
9a
9a
9b
9c
9d
9e
9f
0.5
0.5
0.5
0.5
0.5
2
93
91
92
92
92
90
92
94
95
90
97
97
97
97
98
n-Pr (8c)
i-Pr (8d)
n-Hex (8e)
93
d
7
0.5
0.5
0.5
16
>99
97
8
9
C6H5CH2CH2 (8f) (R)-7a
EtOC(O)CH2 (8g) (R)-7a
>99
92
e
10
9g
a
Reaction conditions: 1.0 mmol scale, (R)-7/8/t-BuOK = 1/1000/
100, [8] = 0.2 M, 10 atm H2, EtOH, room temperature (25−30 °C),
0.5−16 h, 100% conversion, cis,trans-selectivity is >99:1 determined by
b
c
HPLC. Isolated yield. Determined by HPLC on a chiral stationary
d
phase (see the Supporting Information). cis,trans/trans,cis = 95:5
(cis,cis-isomer was not observed). 50 atm H2, 40 °C.
e
asymmetric hydrogenation of the CC bond of cyclo-
alkenones 8 could install the β-alkyl-substituted tertiary
stereocenter and followed by asymmetric hydrogenation of
the CO bond of the resulting β-ketoesters 10 via DKR chiral
cycloalkanols 9 with three contiguous stereocenters could be
achieved. Thus, a one-pot sequential asymmetric hydrogenation
of tetrasubstituted cyclic enones could provide an efficient
approach to chiral cycloalkanols with three contiguous
stereocenters. Herein, we report our detailed investigations
on the catalytic asymmetric hydrogenation of 8 to chiral cyclic
alkanols 9 with excellent enantioselectivity and diastereoselec-
tivity and the application of this method for the enantioselective
syntheses of the stereoisomers of rosaprostol (6). It should be
mentioned that, although the asymmetric hydrogenations of
separated ketones and olefins have been well-explored, the
asymmetric hydrogenation of α,β-unsaturated enones, espe-
cially the enones with tetrasubstituted olefin to saturated chiral
alcohols, is still an unrealized goal in asymmetric catalysis.11
We chose β-methyl-α-ethoxycarbonylcyclopentenone (8a)
prepared from a γ-ketoacid12 as a model substrate to evaluate
various chiral spiro iridium catalysts Ir-(R)-SpiroPAP, (R)-7.13
The reaction was carried out under mild conditions: 0.1 mol %
of catalyst and 10 mol % of t-BuOK as the base in EtOH under
10 atm of H2 at room temperature (Table 1). When the catalyst
(R)-7a was used, the hydrogenation of 8a for 0.5 h afforded
chiral alcohol β-methyl-α-ethoxycarbonylcyclopentanol (9a) in
93% yield with 97% ee and >99% cis,trans-selectivity (entry 1).
The absolute configuration of 9a was determined to be
1R,2S,5S by X-ray diffraction analysis of the crystal structure of
its 3,5-dinitrobenzoyl derivative (Figure 2, left). This result
shows that both the CO and CC bonds of the substrate
were hydrogenated by catalyst (R)-7a. Thus, this reaction
constitutes a one-step procedure for hydrogenation of two
different functional groups, generating three contiguous
stereocenters with excellent enantioselectivity and diastereose-
lectivity. Catalysts (R)-7b−d gave almost the same results as
(R)-7a (entries 2−4). By using catalyst (R)-7a, a variety of
cyclopentenones 8b−g with different β-alkyl groups were
Figure 2. Crystal structures of the 3,5-dinitrobenzoyl derivative of 9a
(left) and the product 9m (right).
hydrogenated to the corresponding cyclopentanols 9b−g in
high yield, excellent enantioselectivity, and diastereoselectivity
(entries 5−10).
Encouraged by these results, we investigated the asymmetric
hydrogenation of β-alkyl-substituted cyclohexenones 8h−n
with Ir-(R)-SpiroPAP catalysts. When the catalyst (R)-7a was
used, the β-methyl-α-ethoxycarbonylcyclohexanone (8h) was
hydrogenated to the cyclohexanol 9h in 0.5 h in 94% yield with
99% ee and >99% cis,cis-selectivity (Table 2, entry 1). The
cis,cis-(1S,2R,6S) configuration of 9h was determined by
1HNMR spectroscopy and optical rotation compared with the
literature data.14 The catalysts (R)-7b−d were evaluated, and
also, almost the same results were observed (entries 2−4). With
catalyst (R)-7a, other cyclohexenones 8i−n with different β-
alkyl groups were hydrogenated, producing cyclohexanols 9i−n
in high yields (90−98%) with excellent enantioselectivity (96 to
>99% ee) and excellent diastereoselectivity (cis,cis-isomer: >
99%) (entries 5−10). A crystal of 9m was grown, and the
single-crystal X-ray diffraction analyses showed that the
absolute configuration of 9m is 1S,2R,6R (Figure 2, right).
To rationalize the stereochemistry of the reaction, we
monitored the progress of the hydrogenation of 8a by gas
chromatography (Scheme 2). The product of CC bond
hydrogenation, trans-10a, predominated during the early stage
of the reaction (Figure 3). Fully hydrogenated product
(1R,2S,5S)-9a formed slowly at the beginning of the reaction
B
DOI: 10.1021/acs.orglett.7b01343
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Letter
progress was also observed for the asymmetric hydrogenation
of cyclohexanone 8h (see the Supporting Information).
Table 2. Asymmetric Hydrogenation of β-Alkyl-α-
ethoxycarbonylcyclohexenones 8h−n with (R)-7
a
With this highly efficient, selective method for construction
of chiral cyclic alcohols with three contiguous stereocenters in
hand, we investigated the catalytic enantioselective synthesis of
the stereoisomers of rosaprostol (6), which exhibit gastric
antisecretory activity and cytoprotective action without the
undesired side effects common to other prostanoids (e.g.,
diarrhea, hypotension, and uterine stimulation15) and is used to
treat gastric and duodenal ulcers under the brand name Rosal.6
However, owing to the lack of efficient methods for
enantioselective construction of the chiral core cyclopentanol
structure of rosaprostol,16 the drug is used as a racemic sodium
salt (that is, a mixture of racemic trans,cis and trans,trans
diastereomers), and the active stereoisomer remains unknown.
Using catalyst (R)-7a, the cyclopentenone 8e was hydrogenated
to cyclopentanol (+)-9e in 92% yield with 97% ee on a gram
scale (Scheme 3). Protection of the hydroxyl group of (+)-9e
b
c
time
(h)
yield
ee
entry
R
(R)-7
9
(%)
(%)
1
2
Me (8h)
Me (8h)
Me (8h)
Me (8h)
Et (8i)
(R)-7a 9h
(R)-7b 9h
(R)-7c 9h
(R)-7d 9h
(R)-7a 9i
(R)-7a 9j
(R)-7a 9k
(R)-7a 9l
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
94
92
93
94
92
98
98
96
95
90
99
99
3
99
4
99
5
>99
>99
98
6
n-Pr (8j)
7
n-Bu (8k)
i-Bu (8l)
8
96
9
C6H5CH2CH2 (8m) (R)-7a 9m
EtOC(O)CH2 (8n) (R)-7a 9n
99
10
16
99
a
Scheme 3. Enantioselective Syntheses of the Stereoisomers
of Rosaprostol
Reaction conditions: 1.0 mmol scale, (R)-7/8/t-BuOK = 1/1000/
100, [8] = 0.2 M, 10 atm H2, EtOH, 25−30 °C, 0.5−16 h, 100%
conversions, cis,cis-isomer is >99% determined by HPLC. Isolated
yield. Determined by GC or HPLC on a chiral stationary phase (see
b
c
the Supporting Information).
Scheme 2. Process of Hydrogenation of 8a with (R)-7a
Figure 3. Plots of the process of hydrogenation of 8a with (R)-7b
(reaction conditions: 1.0 mmol scale, (R)-7b/8a/t-BuOK = 1/500/50,
[8a] = 0.2 M, 1 atm of H2, EtOH, 35 °C, conversions determined by
GC).
with benzyl 2,2,2-trichloroacetimidate (BTCA) yielded (+)-11
in 90% yield. Reduction of (+)-12 with LiAlH4, followed by
oxidation with Dess−Martin periodinane (DMP), afforded
aldehyde (+)-13 in 82% yield for two steps. Reaction of (+)-13
with Wittig reagent 14 provided the acid (+)-15 in 80% yield
without epimerization at C-1. Finally, hydrogenation of (+)-15
over Pd(OH)2/C yielded target molecule (+)-6a in 92% yield.
Because no change in configuration occurs during the
transformation of (+)-9e to (+)-6a, we synthesized
but eventually became the major product and finally the only
product. We isolated trans-10a from the reaction mixture and
found it to have the same ee as the final product (1R,2S,5S)-9a.
These results suggested that the hydrogenation proceeds
through hydrogenation of the CC bond of 8a to form β-
ketoester (1R,2S)-10a, followed by hydrogenation of the CO
bond of (1R,2S)-10a via DKR to afford (1R,2S,5S)-9a. Similar
C
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Letter
(+)-(1R,2S,5S)-rosaprostol from cyclopentenone 8e in six steps
in 50% overall yield on a gram scale.
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With (+)-(1R,2S,5S)-6a as a chiral starting material, we then
synthesized the (1R,2S,5R)-isomer of rosaprostol,
(+)-(1R,2S,5R)-6b (Scheme 3). Esterification of
(+)-(1R,2S,5S)-6a with MeOH in the presence of BF3·Et2O
furnished the corresponding methyl ester (+)-16 in 91% yield.
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stereoisomer (+)-(1R,2S,5R)-6b was obtained in 70% yield
over three steps including a Mitsunobu inversion of the
configuration of the C-5 hydroxyl group. In addition, we also
carried out (S)-7a-catalyzed asymmetric hydrogenation of 8e
and obtained (−)-9e in 91% yield with 97% ee (Scheme 3). By
using the same procedure as that for the syntheses of the
rosaprostol stereoisomers (+)-(1R,2S,5S)-6a and
(+)-(1R,2S,5R)-6b, the other two stereoisomers of rosaprostol,
(−)-(1S,2R,5R)-6c and (−)-(1S,2R,5S)-6d, can undoubtedly be
obtained from (−)-9e. Thus, we have established an efficient
catalytic method for the enantioselective syntheses of all
stereoisomers of rosaprostol. This represents the first example
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rosaprostol.
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In conclusion, we have developed a highly efficient iridium-
catalyzed asymmetric hydrogenation of β-alkyl cyclic enones for
the synthesis of chiral cyclic alcohols with three contiguous
stereocenters. During the reaction, the CO and CC bonds
of the enone substrates were hydrogenated sequentially in a
single step with excellent enantioselectivity and diastereose-
lectivity. This practical protocol served as the key step in the
syntheses of the stereoisomers of the antiulcer drug rosaprostol.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01343.
(13) (a) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2011, 50, 7329. (b) Xie, J.-H.; Liu, X.-Y.; Yang,
X.-H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2012,
51, 201.
Experimental procedures and characterization of the
substrates and products (PDF)
X-ray data for compound 9m (CIF)
(14) The optical rotation of the product 9h is [α]20 −8.2 (c 1.0,
D
CHCl3) [lit. [α]20 −2.29 (c 1.0, CHCl3), 28% ee]; see: Frat
́
er, G.;
D
Gunther, W.; Muller, U. Helv. Chim. Acta 1989, 72, 1846.
̈
̈
X-ray data for the dibitrobenzoyl derivative of 9a (CIF)
̇
́
(15) Perlikowska, W.; Zurawinski, R.; Mikołajczyk, M. Beilstein J. Org.
Chem. 2016, 12, 2234.
AUTHOR INFORMATION
■
(16) For selected recent papers for the synthesis of rosaprostol in
racemic form, see: (a) Mikołajczyk, M.; Zurawin
̇
Corresponding Author
*E-mail: jhxie@nankai.edu.cn.
ORCID
ski, R. J. Org. Chem.
1998, 63, 8894. (b) Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2,
1601. (c) Mikołajczyk, M.; Mikina, M.; Jankowiak, A.; Mphahlele, M.
Synthesis 2000, 2000, 1075. (d) Trost, B. M.; Pinkerton, A. B. J. Org.
Chem. 2001, 66, 7714. For papers for the enantioselective synthesis of
rosaprostol, see: (e) Murcia, M. C.; de la Herran, G.; Plumet, J.; Csaky,
Jian-Hua Xie: 0000-0003-3907-2530
Qi-Lin Zhou: 0000-0002-4700-3765
Notes
A. G. Synlett 2007, 2007, 1553. (f) Łukasik, B.; Perlikowska, W.;
̇
Zurawin
́
15.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21325207, 21532003, and 21421062) and the “111”
project (B06005) of the Ministry of Education of China for
financial support.
D
DOI: 10.1021/acs.orglett.7b01343
Org. Lett. XXXX, XXX, XXX−XXX