Expanding the C1-symmetric bicyclo[2.2.1]heptadiene ligand family: Highly enantioselective synthesis of cyclic β-aryl-substituted carbonyl compounds

Article abstract of DOI:10.1002/ejoc.201200143

The efficient preparation of highly enantioenriched cyclic β-aryl-substituted carbonyl compounds has been achieved through the Rh ^I-catalyzed asymmetric 1,4-addition of an array of arylboronic acids to cyclic α,β-unsaturated carbonyl compounds. In the presence of 0.1 or 0.5 mol-% of the Rh^I/1g complex, the products of conjugate addition were isolated in 89 to 98%ee and in good to excellent yield.

Full text of DOI:10.1002/ejoc.201200143

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200143
Expanding the C1-Symmetric Bicyclo[2.2.1]heptadiene Ligand Family: Highly
Enantioselective Synthesis of Cyclic β-Aryl-Substituted Carbonyl Compounds
Chia-Chen Liu,[a] Damodar Janmanchi,[a] Chun-Chih Chen,[a] and Hsyueh-Liang Wu*[a]
Keywords: Asymmetric catalysis / Enantioselectivity / Conjugate addition / Diene ligands / Rhodium / Boron
The efficient preparation of highly enantioenriched cyclic β-
aryl-substituted carbonyl compounds has been achieved
through the RhI-catalyzed asymmetric 1,4-addition of an ar-
ray of arylboronic acids to cyclic α,β-unsaturated carbonyl
compounds. In the presence of 0.1 or 0.5 mol-% of the RhI/
1g complex, the products of conjugate addition were isolated
in 89 to 98%ee and in good to excellent yield.
cantly, we also observed that these are highly efficient for
mediating various Rh-catalyzed asymmetric 1,4-conjugate
addition processes.
Introduction
Enantioselective carbon–carbon bond formation is cru-
cial to the synthesis of complex organic molecules. As a
consequence, the development of efficient and highly
stereoselective asymmetric C–C bond-forming processes is
absolutely critical to the practice of modern-day synthetic
organic chemistry. The transition-metal-catalyzed asymmet-
ric conjugate addition of carbon-based nucleophiles to α,β-
unsaturated carbonyl compounds is one of the most impor-
tant reactions presently used in the preparation of chiral β-
substituted carbonyl compounds, which, in turn, can often
be converted into many biologically active compounds or
natural products of great value.[1] Chiral rhodium(I) cata-
lysts have proven especially versatile and useful and allow
various organoboron reagents to be employed as nucleo-
philes. The advantages of using such methodology are de-
rived from the high stability and ready availability of many
organoboron reagents and their high degree of compatibil-
ity with a wide range of functional groups.[2] Recent devel-
opments in this area have included the utilization of novel
chiral dienes as new chiral ligands for rhodium.[3] Their pri-
mary advantage stems from their greater catalytic activity
in these reactions and in the higher degree of enantio-
selectivity they often impart to many asymmetric rhodium-
catalyzed 1,4-addition reactions when compared with their
chiral phosphane counterparts. Hence, significant effort has
gone into the design, synthesis, and study of new chiral
diene ligands for such asymmetric transformations.[4–7] In
this connection, we recently described the synthesis of a
new set of chiral diene ligands 1 for Rh that possess a 2,5-
substituted bicyclo[2.2.1]heptadiene skeleton, and signifi-
With an overall catalyst loading as low as 0.05 mol-%,
reactions of a variety of arylboronic acids with acyclic α,β-
unsaturated ketones and esters provided 1,4-adducts with
high enantioselectivities (90Ǟ99.5%ee) at ambient tem-
peratures (Scheme 1).[8] However, cyclic α,β-unsaturated
carbonyl compounds proved unsuitable substrates under
these reaction conditions, with none of the desired product
being observed after 48 h in the reaction between 2-cyclo-
hexenone and phenylboronic acid. This limitation led us to
study the synthesis of optically active 3-arylindanones
through multistep manipulations from acyclic substrates.[8]
Scheme 1. Asymmetric conjugate addition of various arylboronic
acids to acyclic α,β-unsaturated carbonyl compounds.
Motivated by an interest in preparing chiral cyclic β-sub-
stituted carbonyl compounds as intermediates for the syn-
thesis of various natural products and biologically active
compounds and given that a family of 2,5-disubstitued bi-
cyclo[2.2.1] chiral diene ligands 1 were now at hand, the
RhI-catalyzed 1,4-addition of different cyclic enones was
studied. This report now presents the results of exploiting
ligand 1 in the enantioselective addition of arylboronic ac-
ids to cyclic α,β-unsaturated carbonyl compounds.
[a] Department of Chemistry,
National Taiwan Normal University, No. 88, Section 4,
Tinzhou Rd. Taipei, 11677, Taiwan, Republic of China
Fax: +886-229-324-249
Results and Discussion
E-mail: hlw@ntnu.edu.tw
At the outset of our work, the model reaction of 2-cyclo-
hexenone (2a) and phenylboronic acid (3a) was examined
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200143.
Eur. J. Org. Chem. 2012, 2503–2507
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C.-C. Liu, D. Janmanchi, C.-C. Chen, H.-L. Wu
SHORT COMMUNICATION
to study the effect of the loading of ligand 1a on both yield
Next, the general reaction conditions were optimized by
and ee by using aqueous potassium hydroxide as a base and screening different solvents and bases for the catalytic
dioxane as a solvent. In the presence of 1 mol-% of the RhI/ asymmetric addition of phenylboronic acid to 2-cyclohex-
1a catalyst prepared in situ, desired adduct 4aa was isolated enone by using ligand 1g (Table 2).[9] In general, the optical
in 78% yield with an unsatisfactory ee (60%), whereas when induction of the conjugate addition reactions that were car-
3 mol-% of the complex was used, this resulted in a similar ried out in ethereal solvents was generally encouraging,
level of enantioinduction but a better yield (Table 1, En- yielding (R)-3-phenylcyclohexanone (4aa) with good to ex-
tries 1 and 2). Next, the catalytic reactions of ligands 1b– cellent levels of enantioselectivity (88–93%ee) and high
g were examined. Whereas 2,5-diphenyl-substituted chiral chemical yields (Table 2, Entries 1–3). Similar results were
diene ligand 1b has been demonstrated in the addition reac- also obtained when this reaction was carried out in alcohol
tion, completed within 1 h, to give (R)-4aa in 94% yield as a solvent; the best yield (Ͼ99%) and ee (95%) were ob-
and 91%ee (Table 1, Entry 3),[8] the catalytic reaction that tained in 2-propanol (Table 2, Entry 6).[10] Subsequently, a
exploited 1c as a ligand (which bears 4-tolyl substituents on series of aqueous alkali metal hydroxide solution were ex-
the diene functionality) yielded the desired adduct with amined as bases. Generally, the isolation of 4aa in high
high ee (Table 1, Entry 4), and 4-tert-butylphenyl-substi- yield along with a 92–94%ee was achieved (Table 2, En-
tuted diene ligand 1d detrimentally affected the enantio- tries 7–9).[11] Substitution of KOH in 2-propanol for aque-
selectivity (Table 1, Entry 5). High asymmetric induction ous KOH had no positive effect on the reaction (Table 2,
also occurred when ligands with electron-withdrawing Entry 10). However, in parallel screenings aimed at identi-
groups on the benzene rings were adopted (i.e., 1e and 1f); fying an optimal combination of a solvent and base, a slight
these gave rise to compound 4aa with 91 and 92%ee increment in enantioselectivity (96%ee) was observed when
(Table 1, Entries 6 and 7, respectively). Given these obser- potassium hydroxide in ethanol was used in ethanol as the
vations, it was assumed that diene ligand 1g, with highly solvent (Table 2, Entry 11).
electron-withdrawing 4-nitrophenyl substituents, would
provide the 1,4-adduct with better enantioselectivity. Ac-
Table 2. Optimization of reaction conditions.[a]
cordingly, ligand 1g was synthesized by our reported
method, which employs a Pd-catalyzed Suzuki cross-cou-
pling reaction.[8] The asymmetric addition, in the presence
of 3 mol-% of Rh/1g, thereafter yielded 1,4-adduct 4aa with
93%ee and 92% yield (Table 1, Entry 8).
Entry
Solvent
Base
Yield
[%][b]
ee
[%][c]
Table 1. Asymmetric 1,4-addition of phenylboronic acid (3a) to 2-
cyclohexenone (2a).[a]
1
2
3
4
5
6
7
8
dioxane
THF
glyme
MeOH
EtOH
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
EtOH
aq. KOH
aq. KOH
aq. KOH
aq. KOH
aq. KOH
aq. KOH
aq. LiOH
92
72
64
Ͼ99
92
Ͼ99
Ͼ99
96
93
88
91
92
93
95
93
92
94
94
96
aq. NaOH
aq. CsOH
KOH in 2-propanol
KOH in EtOH
9
10
11
88
96
97
[a] Conditions: [RhCl(C2H4)2]2 (3 mol-% of Rh), 1g (3.6 mol-%),
2a (0.2 mmol), 3a (0.4 mmol). The reactions were carried out under
an Ar atmosphere at 30 °C for 1 h. [b] Calibrated GC yields with
the use of n-decane as an internal standard. [c] Determined by chi-
ral HPLC; see the Supporting Information.
Entry
1[d]
2
3
4
5
6
7
8
Ligand
Yield [%][b]
ee [%][c]
1a
1a
1b
1c
1d
1e
1f
78[e]
95[e]
94
91
87
84
89
92
60
62
91
92
64
91
92
93
Because a high turnover number (TON)[8,12] for the cata-
lyst is one of the key features associated with using chiral
dienes for metal-catalyzed asymmetric transformations, the
effect of the catalyst loading of RhI/1g on the reaction out-
come under the conditions specified in Entry 11 in Table 2
was studied. High catalytic reactivity and enantioselectivity
of ligand 1g were anticipated as the loading of the catalyst
was reduced. As shown in Table 3, in the presence of 2.0–
0.1 mol-% of the catalyst, the conjugate addition of phen-
ylboronic acid (3a) to 2-cyclohexenone (2a) generated de-
sired adduct 4aa without loss of high enantioselectivity and
1g
[a] Conditions: [RhCl(C2H4)2]2 (3 mol-% of Rh), 1 (3.6 mol-%), 2a
(0.2 mmol), 3a (0.4 mmol). The reactions were carried out under
an Ar atmosphere at 30 °C for 1 h. [b] Calibrated GC yields with
the use of n-decane as an internal standard. [c] Determined by chi-
ral HPLC, and the absolute configuration of 4aa was determined
by comparison of the sign of the specific rotation with that of the
known sample; see the Supporting Information. [d] 1 mol-% of cat-
alyst was used. [e] Isolated yield after 3 h.
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Eur. J. Org. Chem. 2012, 2503–2507

Enantioselective Synthesis of Cyclic β-Aryl-Substituted Carbonyls
yield (Table 3, Entries 1–5), although more time was re- 1g, the enantioselective addition of both arylboronic acids
quired for the catalytic reaction to proceed with the use of 3a and 3e gave (R)-3-phenylcycloheptanone (4ca) and (R)-
0.1 mol-% of the catalyst (Table 3, Entry 5). Notably, 3-p-tolylcycloheptanone (4ce) with high enantioselectivities
0.05 mol-% of RhI/1g promoted the asymmetric transfor- (Table 4, Entries 13 and 14). This investigation was further
mation, forming the desired adduct with 96%ee, but in an expanded to include acyclic α,β-unsaturated ketone 2e as a
unsatisfactory yield after 24 h, preventing the adoption of substrate. High yields (83–99%) and excellent enantio-
these conditions (Table 3, Entry 6).
selectivity (93–97%) were noted in the catalytic reactions of
2e with arylboronic acids in the presence of 0.1 mol-% of
the catalyst (Table 4, Entries 17–19).[13]
Table 3. Optimization of ligand loading on the model reaction.[a]
Table 4. Asymmetric addition to cyclic α,β-unsaturated carbonyl
compounds.[a]
Entry
Rh [mol-%]
Yield [%][b]
ee [%][c]
1
2
3
2.0
1.5
1.0
0.5
0.1
0.05
91
98
Ͼ99
Ͼ99
Ͼ99
14
95
93
94
95
95
96
4
5[d]
6[e]
Entry
2
Ar
Time
[h]
Yield
[%][b]
ee
[%][c]
[a] The reactions were conducted with the use of [RhCl-
(C2H4)2]2 (0.003 mmol) and the required amount of reagents were
added accordingly. All reactions were carried out under an Ar at-
mosphere at 30 °C for 1 h. [b] Calibrated GC yields with the use of
n-decane as an internal standard. [c] Determined by chiral HPLC;
see the Supporting Information. [d] The reaction was conducted
for 8 h. [e] The reaction was conducted for 24 h.
1
2
3
4
2a
2a
Ph (3a)
4-PhC6H4 (3b)
8
2.5
1
1
1
1
1
1
2
1
1
1
1.5
1.5
93 (4aa)
90 (4ab)
85 (4ac)
95 (4ad)
Ͼ99 (4ae)
Ͼ99 (4af)
Ͼ99 (4ag)
96 (4ah)
99 (4ba)
98 (4bc)
95
98
94
92
89
90
96
96
97
92
95
96
95
89
2a 4-MeOC6H4 (3c)
2a 2-MeOC6H4 (3d)
2a
2a
2a
2a
2b
5
4-MeC6H4 (3e)
2-MeC6H4 (3f)
4-FC6H4 (3g)
3-CF3C6H4 (3h)
Ph (3a)
6[d]
7[d]
8
9
The above process was extended to catalytic reactions of
a series of cyclic α,β-unsaturated carbonyl compounds with
10
2b 4-MeOC6H4 (3c)
11[d]
2b
2b
2c
2c
2d
2d
2e
2-MeC6H4 (3f)
4-FC6H4 (3g)
Ph (3a)
4-MeC6H4 (3e)
Ph (3a)
4-MeC6H4 (3e)
Ph (3a)
93 (4bf)
various arylboronic acids under the optimized general con- 12[d]
88 (4bg)
Ͼ99 (4ca)
Ͼ99 (4ce)
13[d]
ditions. Table 4 summarizes the results from which certain
trends were identified. Both 2-cyclohexenone (2a) and 2-
14[d]
15[d]
2 (7)[e] 43 (59)[e] (4da) 95 (97)[e]
cyclopentenone (2b) proved to be favorable substrates in
this study, with observed enantiomeric excess values for a
number of arylboronic acids lying in the range of 90–98%,
regardless of whether the nucleophiles bore electron-donat-
ing or electron-withdrawing substituents (Table 4, En-
tries 1–12). Whereas excellent ee values were generally ob-
served, the use of sterically hindered 2-methylphenylboronic
acid (Table 4, Entries 6 and 11) and 4-fluorophenylboronic
acid (Table 4, Entries 7 and 12) required the use of 0.5 mol-
% of the catalyst to produce a satisfactory yield. Similar
results were also encountered when a α,β-unsaturated δ-lac-
tone, 6-dihydro-2H-pyran-2-one (2d), was investigated as an
acceptor. In the presence of 0.5 mol-% of the rhodium com-
plex, addition reactions of phenylboronic acid (3a) and 4-
methylphenylboronic acid (3e) to compound 2d furnished
16[d]
17
2 (7)[e] 38 (54)[e] (4de) 85 (92)[e]
2
1
8
89 (4ea)
99 (4ec)
83 (4ef)
96
93
97
18
19
2e 4-MeOC6H4 (3c)
2e 2-MeC6H4 (3f)
[a] Reactions were carried out on a 6.0-mmol scale at 30 °C. [b] Iso-
lated yield after column chromatography. [c] Determined by chiral
HPLC; see the Supporting Information. [d] Reactions were carried
out on a 1.2-mmol scale in the presence of 0.5 mol-% of the cata-
lyst. [e] Results in the parentheses are from reactions conducted in
dioxane.
Conclusions
In summary, a highly enantioselective rhodium-catalyzed
the corresponding adducts 4da and 4de with 95 and 85%ee, conjugate addition of various arylboronic acids to cyclic
respectively, but in unsatisfactory chemical yields, mainly α,β-unsaturated carbonyl compounds has been developed.
because of the ring-opening side reaction (Table 4, En- Chiral diene 1g is a ligand that exhibits excellent catalytic
tries 15 and 16). Conducting the catalytic reactions in diox- reactivity and enantioselectivities toward cyclic and acyclic
ane not only improved the chemical yields but also the enones and lactones. In the presence of 0.1 or 0.5 mol-%
enantioselectivities up to 97%ee. 2-Cycloheptenone (2c) of the RhI/1g catalyst, generated in situ, the corresponding
was likewise found to be a good substrate for the present adducts were isolated with 89 to 98%ee and in good to
Rh complex, such that, in the presence of 0.5 mol-% of Rh/ excellent chemical yields. Future work in the authors’ labo-
Eur. J. Org. Chem. 2012, 2503–2507
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C.-C. Liu, D. Janmanchi, C.-C. Chen, H.-L. Wu
SHORT COMMUNICATION
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ratory will focus on the employment of chiral diene ligands
1 in challenging metal-catalyzed asymmetric transforma-
tions.
Experimental Section
[3]
[4]
General Procedure for the Synthesis of Chiral Diene Ligand 1g: To
a solution of corresponding bistriflate (0.6 mmol), Pd(PPh3)4
(0.06 mmol), and 4-nitrophenylboronic acid (2.35 mmol) in toluene
(9.5 mL) was added EtOH (2.4 mL) and sat. aqueous Na2CO3
(4.9 mL) at room temperature under an atmosphere of argon, and
the resulting mixture was stirred at reflux. After 90 min, sat. aque-
ous NH4Cl was added, and the aqueous layer was extracted with
ethyl acetate (3ϫ15 mL). The combined organic layer was washed
with brine and dried with Na2SO4, filtered, and evaporated to give
the crude product, which was purified by column chromatography
over silica gel to give ligand 1g (104 mg, 46%) as an orange solid.
1H NMR (500 MHz, CDCl3): δ = 8.20–8.18 (m, 4 H), 7.53–7.52
(m, 2 H), 7.39–7.37 (m, 2 H), 7.00 (d, J = 1.3 Hz, 1 H), 6.93 (d, J
= 3.5 Hz, 1 H), 3.65 (dd, J = 3.5, 1.3 Hz, 1 H), 1.34 (s, 3 H), 1.20
(s, 3 H), 1.16 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
156.8, 154.0, 146.7, 146.7, 144.6, 144.1, 142.3, 140.7, 126.7 (2 CH),
125.1 (2 CH), 124.1 (2 CH), 123.7 (2 CH), 82.9, 66.6, 61.3, 21.4,
21.2, 11.0 ppm.
General Procedure for Rhodium-Catalyzed 1,4-Addition: A mixture
of [RhCl(C2H4)]2 (1.2 mg, 0.003 mmol), chiral diene ligand 1g
(2.7 mg, 0.0072 mmol), and phenylboronic acid (1.46 g, 12 mmol)
in EtOH (20 mL) was stirred for 20 min at 30 °C. 2-Cyclohexen-1-
one (2a; 577 mg, 6 mmol) was then added. After stirring for an-
other 20 min, 1.5 m KOH in EtOH (2.0 mL) was added. After com-
pletion of the reaction, the solvent was removed under reduced
pressure to give the crude product, which was purified by column
chromatography over silica gel (hexane/ethyl acetate, 19:1) to fur-
nish 3-phenylcyclohexanone (4aa, 971 mg, 93%) as a colorless oil.
The ee was determined with a Daicel Chiralcel IA column with
hexanes/2-propanol = 99:1, flow rate = 1.0 mL/min, retention
times: 12.05 min [(S)-enantiomer], 13.57 min [(R)-enantiomer];
95%ee. [α]1D9 = +24.1 (c = 0.92 in CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.33 (m, 2 H), 7.29–7.23 (m, 3 H), 3.04 (tt, J =
11.8, 4.0 Hz, 1 H), 2.67–2.35 (m, 4 H), 2.23–2.07 (m, 2 H), 1.95–
1.74 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.9, 144.3,
128.7 (2 CH), 126.7, 126.5 (2 CH), 48.9, 44.7, 41.2, 32.8, 25.5 ppm.
[5]
[6]
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental procedures, HPLC traces, and copies of the H
[7]
and 13C NMR spectra.
Acknowledgments
This work was supported by grants from the National Science
Council (NSC 98-2113-M-003-009-MY2, NSC 99-2119-M-
003-002-MY2) and National Taiwan Normal University
(T10007000687).
[8]
[9]
W.-T. Wei, J.-Y. Yeh, T.-S. Kuo, H.-L. Wu, Chem. Eur. J. 2011,
17, 11405–11409.
Ligand 1g was chosen for the remaining studies after intensive
parallel screenings of ligands with the reaction parameters
shown in Tables 2 and 3.
When other solvents such as CH3CN, DMF, toluene, and
DCM were studied, the addition product was obtained with ee
values ranging from 89 to 94% in 13–77% yield.
[1] For reviews, see: a) R. Noyori (Ed.), Asymmetric Catalysis in
Organic Synthesis, Wiley, New York, 1994; b) E. N. Jacobsen;
A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric
Catalysis, Springer, Berlin, 1999, vol. 3; c) M. Sibi, S. Manyem,
Tetrahedron 2000, 56, 8033–8061; d) N. Krause, A. Hoffmann-
Röder, Synthesis 2001, 171–196; e) B. Heasley, Eur. J. Org.
Chem. 2009, 1477–1489; f) A. G. Schultz, Acc. Chem. Res.
1990, 23, 207–213.
[10]
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Enantioselective Synthesis of Cyclic β-Aryl-Substituted Carbonyls
[11]
chi, N. Miyaura, Chem. Lett. 2001, 722–723; b) R. Itooka, Y.
Iguchi, N. Miyaura, J. Org. Chem. 2003, 68, 6000–6004.
[13] In studies of compound 2e as a substrate, attempts to utilize
0.05 mol-% of the catalyst failed to produce the adduct in good
yields after 2 d.
When organic bases such as Et3N and DIPA (diisopropyl-
amine) were tested in the asymmetric reaction, high enantio-
selectivities (92–94%ee) of the corresponding product were ob-
served but with unsatisfactory chemical yields (2–66%).
[12] Examples of non-asymmetric versions of reactions catalyzed
by Rh–diene complexes with high TONs: a) R. Itooka, Y. Igu-
Received: February 7, 2012
Published Online: March 23, 2012
Eur. J. Org. Chem. 2012, 2503–2507
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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