Enantioselective synthesis of cis-1,2-disubstituted cyclopentanes and cyclohexanes by Suzuki-Miyaura cross-coupling and iridium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/chem.201102650

A series of 1,2-disubstituted cyclohexene derivatives was prepared through Suzuki-Miyaura cross-coupling of 2-bromo-1-cyclohexenecarbaldehyde or 2-carbomethoxy-1-cyclohexen-1-yl triflate with arylboronates. These tetra-substituted cyclic alkenes were subjected to Ir-catalyzed asymmetric hydrogenation. In this way cis-1-methoxymethyl-2-arylcyclohexanes were obtained in high yield with excellent enantio- and diastereoselectivities (up to >99%ee, >99%cis) by using phosphinomethyloxazolines as ligands. Asymmetric hydrogenation of analogous cyclopentene derivatives, prepared by Suzuki-Miyaura cross-coupling, proved to be more difficult and proceeded with lower enantioselectivities of up to 88%ee. The synthetic potential of this cross-coupling/asymmetric-hydrogenation strategy was demonstrated by an enantioselective route to chiral hexahydrofluorenones. Alkene interest: Starting from arylboronates, a variety of cyclic, tetra-substituted olefins was prepared by Suzuki-Miyaura cross-coupling (see scheme). Subsequent Ir-catalyzed asymmetric hydrogenation with phosphanylmethyloxazoline ligand complexes led to cis-disubstituted cycloalkane derivatives in high yield and excellent enantio- and distereoselectivities. Copyright

Full text of DOI:10.1002/chem.201102650

DOI: 10.1002/chem.201102650
Enantioselective Synthesis of cis-1,2-Disubstituted Cyclopentanes and
Cyclohexanes by Suzuki–Miyaura Cross-Coupling and Iridium-Catalyzed
Asymmetric Hydrogenation
Andreas Schumacher, Marcus G. Schrems, and Andreas Pfaltz*[a]
Abstract: A series of 1,2-disubstituted
cyclohexene derivatives was prepared
through Suzuki–Miyaura cross-coupling
of 2-bromo-1-cyclohexenecarbaldehyde
or 2-carbomethoxy-1-cyclohexen-1-yl
triflate with arylboronates. These tetra-
substituted cyclic alkenes were subject-
ed to Ir-catalyzed asymmetric hydroge-
nation. In this way cis-1-methoxymeth-
yl-2-arylcyclohexanes were obtained in
high yield with excellent enantio- and
diastereoselectivities (up to >99% ee,
>99% cis) by using phosphino-
pentene derivatives, prepared by
Suzuki–Miyaura cross-coupling, proved
to be more difficult and proceeded
with lower enantioselectivities of up to
88% ee. The synthetic potential of this
cross-coupling/asymmetric-hydrogena-
tion strategy was demonstrated by an
enantioselective route to chiral hexahy-
drofluorenones.
AHCTUNGTRENNUNG
Keywords: alkenes
·
asymmetric
synthesis · enantioselectivity · hy-
drogenation · iridium · palladium
Introduction
Asymmetric hydrogenation of prochiral olefins is one of the
most efficient and reliable methods for the enantioselective
introduction of stereogenic centers. Although Rh– and Ru–
diphosphane complexes have been widely used for the enan-
tioselective hydrogenation of suitably functionalized olefins
that bind to the catalyst through heteroatom substituents,[1]
iridium complexes, particularly those with chiral P,N ligands,
have proved to be the catalysts of choice for the asymmetric
hydrogenation of olefins lacking coordinating groups.[2] Re-
cently, we have shown that even tetra-substituted, unfunc-
tionalized olefins can be hydrogenated with high efficiency
and enantioselectivity by using chiral iridium catalysts.[3] In
this way two adjacent stereogenic centers can be introduced
enantio- and diastereoselectively in a single step. However,
tetra-substituted olefins are often difficult to synthesize.[4]
Herein, we report an efficient two-step sequence for the in-
troduction of two stereogenic centers in cyclopentanes and
cyclohexanes, involving a Suzuki–Miyaura cross-coupling re-
action, leading to a tetra-substituted C=C bond, followed by
an Ir-catalyzed asymmetric hydrogenation.
Scheme 1. Enantioselective hydrogenation of compound 1.
quent studies showed that a range of tetra-substituted al-
kenes could be hydrogenated with Ir complexes based on
these ligands. In many cases high enantioselectivities were
achieved, often under surprisingly mild conditions at only 1–
5 bar hydrogen pressure.
In connection with this work, tricyclic olefins, like com-
pound 4, attracted our interest (Scheme 2) because the cor-
Scheme 2. Synthesis and subsequent asymmetric hydrogenation of tetra-
hydrofluorene 4.
In our initial work on the iridium-catalyzed asymmetric
hydrogenation of tetra-substituted olefins by using alkene 1
as a test substrate, 2-(phosphanylmethyl)oxazolines were
found to be the most efficient ligands (Scheme 1).[3] Subse-
responding hexahydrofluorene motif
carbon skeleton of various natural products, for example,
taiwaniaquinol B[5a]
Furthermore, Banwell et al. have
5 forms the core
.
[a] A. Schumacher, Dr. M. G. Schrems, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
shown that methoxy-substituted derivative 10 (Scheme 3)
can be used as a precursor for the construction of the carbo-
cyclic framework of the gibberilins.[5b]
Initially, we used a procedure described by Colonge and
Sibeud to synthesize olefin 4.[6] The key step in this method
is an intramolecular Friedel–Crafts-type reaction of 2-ben-
E-mail: andreas.pfaltz@unibas.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102650.
13502
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Chem. Eur. J. 2011, 17, 13502 – 13509

FULL PAPER
Scheme 4. Synthesis of 1 by using Pd-catalyzed cross-coupling.
into a wide range of functionalized tetra-substituted olefins,
which give access to synthetically useful classes of chiral
compounds by enantioselective iridium-catalyzed hydroge-
nation.
Results and Discussion
Synthesis of cyclic, tetra-substituted olefins through phos-
phine-free Suzuki–Miyaura cross-coupling: Since traces of
phosphine contaminants may act as inhibitors in the iridi-
um-catalyzed asymmetric hydrogenation and could lead to a
reduction in the turnover number of the catalyst and the
enantioselectivity, we searched for a phosphine-free Suzuki–
Miyaura cross-coupling procedure.[11] Two general routes to
1,2-disubstituted cyclohexenes and cyclopentenes are shown
in Scheme 5. An initial set of 1,2-disubstituted cyclohexenes
was obtained from bromoaldehyde 13.[12,13] However, this
approach was not suited for the synthesis of 1,2-disubstitut-
ed cyclopentenes because 2-bromocyclopent-1-enecarbalde-
hyde proved to be too unstable under the reaction condi-
tions. However, trifluoromethanesulfonate 20 was success-
fully used under similar reaction conditions for the synthesis
of esters 21 and 22.
Scheme 3. General route to tetrahydrofluorene 9. See the Supporting In-
formation for details (Ts=tosyl; cod=1,5-cyclooctadiene; BArF =
tetrakisACHTUNGTRENNUNG(3,5-bis(trifluoromethyl)phenyl)borate.
zylcyclohexanone, which gives the tetra-substituted olefin di-
rectly (Scheme 2). However, because this method shows low
functional-group tolerance, it is not suitable for the synthesis
of olefins like 9. An alternative route to this class of tricyclic
olefins has been described by House et al.,[7] starting from
tetrahydrofluorenones, which can be converted into the cor-
responding tetra-substituted olefins by a reduction/elimina-
tion/isomerization sequence (Scheme 3). We used this
method for the synthesis of 9 and obtained the tetra-substi-
tuted olefin in high overall yield (80%) starting from the
known hexahydrofluorenone 6.[5b] When we applied com-
pound 9 in the iridium-catalyzed asymmetric hydrogenation,
the results were similar to those obtained for olefin 4. Thus,
compound 10 was obtained in up to 93% ee with full con-
version by using ligand L1a.
Although we were pleased to have a reliable method for
the synthesis of this class of tricyclic olefin in hand, the
detour of dehydration and subsequent isomerization is only
applicable for a limited range of substrates, such as indenes
or dihydronaphthalenes. In many other cases elimination of
water from a tertiary alcohol gives an isomeric mixture of
olefins. As even small amounts of undesired double-bond
isomers can lead to a significant decrease in enantioselectivi-
ty, a more general approach was required. For this purpose,
we evaluated an alternative route through Suzuki–Miyaura
cross-coupling by using a Pd/N-heterocyclic carbene (NHC)
system described by Trudell, Nolan et al.[8] This method
worked well for olefin 1, which was obtained in 70% yield
(Scheme 4).
Initially, we used
a relatively high catalyst loading
(2 mol% Pd) with IMes (1,3-bis(2,4,6-trimethylphenyl)imi-
dazol-2-ylidene) as the ligand precursor for the Suzuki–
Miyaura cross-coupling of boronate 11a with bromoalde-
hyde 13.[8] An initial test reaction with dioxane as the sol-
vent gave desired 1,2-disubstituted cyclohexene 14a in es-
sentially quantitative yield (98%). The catalyst loading
could be reduced to 0.2 mol% when IMes was used as the
ligand, whereas without the ligand the product was obtained
in only 55% yield. Further test reactions showed that no
ligand is needed if the reaction is carried out in a THF/H2O
solvent mixture. Under these conditions the product was
formed in up to 89% yield by using only 0.1 mol% [Pd2-
AHCTUNGTRENNUNG
the scope of the reaction. We found that replacing the elec-
tron-donating methoxy group with a hydrogen atom or with
an electron-withdrawing trifluoromethyl group resulted in
diminished reactivity under the conditions used previously.
In the reaction with (trifluoromethylphenyl)borate 11b only
24% of product 14b was isolated and the corresponding un-
substituted phenylborate 11c gave only traces of the desired
product. However, the yields could be significantly im-
proved by changing the solvent. In dibutyl ether trifluoro-
methyl-substituted borate 11b was converted into product
Encouraged by this result, we decided to extend the
method to cyclic bromoolefins, such as readily available 2-
bromo-1-cyclohexenecarbaldehyde 13.[9] The resulting aryl-
substituted cyclohexenecarbaldehydes[10] can be transformed
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A. Pfaltz et al.
yields were still much lower
than in the cross-coupling with
methoxy-substituted
borate
11a.
Similar conditions were ap-
plied for the cross-coupling of
trifluoromethanesulfonate 20a
with boronates 11a and 11b.
The yields of cross-coupling
products were optimal when no
ligand was used (Table 2). With
only 0.1 mol% [Pd2ACHTUNGTRENNUNG(dba)3],
olefin 21a was obtained in
quantitative yield and even p-
CF3-substituted
olefin
21b
could be obtained in 72%
yield.
However, this method proved
to be inefficient for triflate 20b
(Scheme 6). By using the condi-
tions established for the reac-
tion of 20a, no product was ob-
tained with borate 11a. Further
investigation of the reaction
Scheme 5. Suzuki–Miyaura cross-coupling reactions starting from bromoaldehyde 13 or triflates 20a and
20b.Reagents and conditions: i) Pd2A
16a-c: NaH, MeI, THF, RT, 2 h; 17a: Et3N, TMSCl, CH2Cl2, RT, 1 h; 18a: Imidazol, TBDMSCl, DMF, RT, 14
h; 19a: NaH, (nBu)4NI, BnBr, THF, RT, 14 h; iii) 21a–b: Pd2A(dba)3, THF, 66 8C, 4 h; 22a-b: Pd2A(dba)3, THF/
H2O, 66 8C, 14 h; iv) 23a: LiAlH4, THF, 0 8C - RT, 10 min.; 24a: NaH, MeI, THF, RT, 2 h.
(dba)3, THF/H2O, 66 8C, 2 h; ii) 15a–c: NaBH4, MeOH, 0 8C - RT, 1 h; conditions showed that catalytic
amounts of both the IMes
ligand and water had to be
G
CHTUNGTRENNUNG
Table 1. Suzuki–Miyaura cross-coupling by using bromoaldehyde 13.[a]
Table 2. Suzuki–Miyaura cross-coupling by using trifluoromethanesulfo-
nate 20a.[a]
R
Solvent
T
Catalyst loading
Ligand loading Yield
A
R
Solvent
T
[8C]
Catalyst loading
Ligand loading
ACHTUNGTRENNUNG
[mol%][b]
Yield
[%][c]
[8C] [mol% Pd
(dba)3]
[mol%][b]
[%][d]
[mol% Pd
2A
OMe dioxane
OMe dioxane
OMe dioxane
90 1.0
90 0.1
90 0.1
66 1.0
66 0.1
66 0.1
66 1.0
66 0.1
66 0.1
66 0.1
120 0.1
66 0.1
90 0.1
2.0
0.2
–
2.0
0.2
–
2.0
0.2
–
–
–
–
–
98
99
55
86
90
89
54
60
57
24
40
<5
47
OMe
OMe
CF3
THF
THF
THF
THF
66
66
66
66
1.0
0.1
1.0
0.1
2.0
–
2.0
–
92
99
39
72
OMe THF/H2O[d]
OMe THF/H2O[d]
OMe THF/H2O[d]
OMe EtOH/H2O[e]
OMe EtOH/H2O[e]
OMe EtOH/H2O[e]
CF3
[a] Full experimental conditions are given in the Supporting Information.
[b] IMes was used as the ligand. [c] Determined by GC.
CF3
CF3
H
THF/H2O[d]
butylether
THF/H2O[d]
dioxane
H
[a] Full experimental conditions are given in the Supporting Information.
[b] IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) was used as
the ligand. [c] Determined by GC. [d] Ratio of 2:1. [e] Ratio of 1:1.
14b in up to 40% yield. For the synthesis of 14c the best re-
Scheme 6. Optimized reaction conditions for the Suzuki–Miyaura cross-
sults were obtained in dioxane (47% yield). Nevertheless,
coupling by using trifluoromethanesulfonate 20b.
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Synthesis of cis-1,2-Disustituted Cyclopentanes and Cyclohexanes
FULL PAPER
added to obtain ester 22a (up to 60% yield). It appears that
these coupling reactions are quite sensitive to the conditions
applied and careful optimization is often necessary to obtain
satisfying results.
Other 1,2-disubstituted cyclohexenes were obtained by
functional-group interconversion of aldehydes 14a–14c
(Scheme 7). Thus, allylic alcohols 15a–15c, for example,
Scheme 8. P,N ligands used in the Ir-catalyzed hydrogenation reaction
(Cy=cyclohexyl; o-Tol=ortho-tolyl; Xyl=xylyl).[2a,14]
Scheme 7. Substrates applied in the Ir-catalyzed asymmetric hydrogena-
tion reaction (TMS=trimethyl silyl; TBDMS=tert-butyl dimethyl silyl;
Bn=benzyl).
(Scheme 9). We assume that this undesired reaction was
caused by acidic Ir hydrides, which are formed during the
hydrogenation reaction.[15] To verify this assumption, we in-
were generated by reduction of the corresponding aldehydes
with NaBH4 (>99%). Protection of these alcohols gave
methyl ethers 16a–16c (>95%), TMS ether 17a (88%),
TBDMS ether 18a (92%), and benzyl ether 19a (97%).
The 1,2-disubstituted allylic alcohol 23a was generated from
methyl ester 21a by reduction with LiAlH4 (>99%) and
converted into methyl ether 24a (95%).
Ir-catalyzed hydrogenation of cyclic tetra-substituted olefins:
The set of tetra-substituted cyclic olefins described in the
previous section (Scheme 7) was subjected to hydrogenation
with a range of different Ir catalysts (Scheme 8), including
the Ir–phosphanylmethyl complexes (Ir–L4) that were
found to be particularly efficient for the hydrogenation of
tetra-substituted C=C bonds.[3] The enantioselectivity and
reactivity of these substrates strongly depended on the func-
tional group next to the C=C bond. Aldehyde 14a, for ex-
ample, which was directly accessible from the Suzuki–
Miyaura cross-coupling, showed no reactivity; even at a H2
pressure of 100 bar with an extended reaction time of 14 h
at 408C no reduction occurred. For methyl esters 22a and
22b, on the other hand, full conversion was achieved after
14 h. However, the products were obtained as cis/trans mix-
tures in low enantiomeric excess. When allylic alcohol 15a
was used as the substrate, the desired product was not ob-
tained. Instead, a cis/trans mixture of the methyl-substituted
cyclohexane 25 was obtained, presumably by elimination of
water followed by reduction of the resulting dienes
Scheme 9. Hydrogenation of 15a, 17a, and 19a.
vestigated the reaction of allylic alcohol 15a with several
Lewis and Brønsted acids. As expected, elimination of water
was observed, giving several isomeric dienes that could be
converted into methylcyclohexane 25 under hydrogenation
conditions.
We hoped to circumvent this problem by using a suitable
protecting group. First, silyl protecting groups were tested.
Trimethylsilyl ether 17a was cleaved under the reaction con-
ditions, so the more acid-stable tert-butyldimethylsilyl ether
was used instead. The resulting olefin (18a) could be hydro-
genated without any side reactions, however, the product
was obtained as a cis/trans mixture, as previously observed
in the hydrogenation of methyl esters 22a and 22b. As an
alternative, the benzyl protecting group was tested (19a),
but proved to be unsuitable, since it was also cleaved under
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13505

A. Pfaltz et al.
the reaction conditions and water was subsequently elimi-
nated from the resulting allylic alcohol.
A solution to this problem was found by protecting allylic
alcohol 15a as the methyl ether (16a). Its stability against
Brønsted acids and low steric demand resulted in excellent
results by using Ir complexes with ligands L4 (Table 3). Sur-
obtained with most phosphanylmethyloxazoline ligands
(L4), only ligands L4j, L4k, and L4m gave desired product
27 in more than 90% ee. The most efficient catalyst in this
case was the Ir complex with ligand L4j, leading to com-
pound 27 in >98% ee and 92% yield (Table 4).
Table 4. Ir-catalyzed hydrogenation of substrate 16c.[a]
Table 3. Ir-catalyzed hydrogenation of substrate 16a.[a]
Ligand L
Conversion [%][b]
Yield 27 [%][b]
ee [%][c]
71 (1R,2S)
(S)-L4a
(S)-L4b
(S)-L4d
(S)-L4e
(S)-L4 f
(S)-L4g
(S)-L4h
(S)-L4i
(S)-L4j
(R)-L4k
(S)-L4m
(S)-L4n
(S)-L4p
98
>99
>99
76
>99
>99
>99
97
>99
>99
>99
90
46
6
18
25
6
2
6
2
92
96
69
80
56
Ligand L
Conversion [%][b]
Yield 26 [%][b]
ee [%][c]
36 (1R,2S)
72 (1R,2S)
71 (1R,2S)
55 (1R,2S)
50 (1R,2S)
32 (1R,2S)
29 (1R,2S)
>98 (1R,2S)
94 (1S,2R)
>98 (1R,2S)
79 (1R,2S)
79 (1R,2S)
[d]
(S)-L1b
(S)-L1c
(S)-L1d
(S)-L1e
>99
>99
28
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
[d]
[d]
[d]
18
[d]
A
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
[d]
N
[d]
(S)-L3a
(S)-L3b
(S)-L4a
(S)-L4b
(S)-L4c
(S)-L4d
(S)-L4 f
(S)-L4g
(R)-L4k
(R)-L4l
(S)-L4m
(R)-L4m
(S)-L4n
(S)-L4o
(S)-L4p
(R)-L5
[d]
92
74
56
81
58
28
97
>99
99
99
75 (1R,2S)
75 (1R,2S)
69 (1R,2S)
80 (1R,2S)
78 (1R,2S)
86 (1R,2S)
95 (1S,2R)
96 (1S,2R)
>99 (1R,2S)
>99 (1S,2R)
80 (1R,2S)
78 (1R,2S)
87 (1R,2S)
–
>99
[a] Full experimental conditions are given in the Supporting Information.
[b] Conversions and yields were determined by GC. [c] Determined by
GC on a chiral stationary phase (OV1701); assignment of absolute con-
figuration in analogy to 26.
Changing the substituent at the para position of the
phenyl ring to CF3 (16b) led to decreased conversion and
enantioselectivity for most of the L4 ligands. Interestingly,
with ligand L4j, full conversion and a yield of 92% of the
desired product with an ee of 96% was obtained (Table 5).
98
64
94
–
[d]
[a] Full experimental conditions are given in the Supporting Information.
[b] Conversions and yields were determined by GC. [c] The ee value was
determined by GC on a chiral stationary phase (DiMeTBuSil-b-cyclodex-
trin (OV1701)); the absolute configuration is based on X-ray analysis.
[d] Formation of 25 occurred.
Table 5. Ir-catalyzed hydrogenation of substrate 16b.[a]
prisingly, all other ligand classes led to an elimination reac-
tion, as previously observed for allylic alcohol 15a, TMS
ether 17a, and benzyl ether 19a. Hydrogenation of methyl
ether 16a with various Ir–L4 complexes gave good to excel-
lent enantioselectivities (up to >99% ee) and full conver-
sion into desired cyclohexane 26. In general, ligands with
phenyl substituents at the oxazoline ring proved to be best
suited for this substrate. Both conversion and enantioselec-
tivity were significantly higher when complexes with ligands
L4k–L4m were used. Neither the enantioselectivity nor the
conversion changed if the amount of catalyst L4m was re-
duced from 2.0 to 1.0 mol%, although at 0.5 mol% catalyst
loading the conversion decreased significantly to 4% after a
reaction time of 4 h. With a catalyst loading of 0.1 mol% no
product was formed.
Ligand L
Conversion [%][b]
Yield 28 [%][b]
ee [%][c]
(S)-L4a
(S)-L4d
(S)-L4g
(S)-L4h
(S)-L4i
(S)-L4j
(R)-L4k
(S)-L4m
(R)-L4n
(S)-L4p
22
45
77
40
35
>99
34
75
>99
59
2
7
1
1
1
92
26
40
71
33
58 (1R,2S)
56 (1R,2S)
20 (1R,2S)
12 (1R,2S)
14 (1R,2S)
96 (1R,2S)
89 (1S,2R)
95 (1R,2S)
48 (1S,2R)
70 (1R,2S)
[a] Full experimental conditions are given in the Supporting Information.
[b] Conversions and yields were determined by GC. [c] Determined by
GC on a chiral stationary phase (OV1701); assignment of absolute con-
figuration in analogy to 26.
The analogous phenyl-substituted alkene 16c proved to
be a more difficult substrate. Although full conversion was
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Chem. Eur. J. 2011, 17, 13502 – 13509

Synthesis of cis-1,2-Disustituted Cyclopentanes and Cyclohexanes
FULL PAPER
Table 7. Pressure, temperature, and catalyst-loading dependence in the
Next, we explored the hydrogenation of 1,2-disubstituted
cyclopentenes. As observed for methyl esters 22a and 22b, a
cis/trans mixture was obtained after hydrogenation of
methyl esters 21a and 21b. Allylic alcohol 23a showed simi-
lar reactivity to the cyclohexene analogue 15a, resulting in a
cis/trans mixture of 4-methoxyphenyl-2-methylcyclopentane.
For the hydrogenation of methyl ether 24a, full conversion
into desired product 29 was obtained with all ligands ap-
plied. Compared with previous results from the hydrogena-
tion of 1,2-disubstituted cyclohexenes, the enantioselectivi-
ties were rather low (Table 6). The highest enantiomeric
Ir-catalyzed hydrogenation of substrate 24a.[a]
Pressure
H2 [bar]
T
[8C]
Catalyst loading
[mol%]
Conversion
[%][b]
Yield 29
ee (ꢀ)
G
[%][b]
[%][c]
1
1
1
5
5
5
5
5
5
5
5
5
50
50
50
50
25
25
25
25
25
25
0
0
0
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
2.0
1.0
0.5
2.0
1.0
0.5
2.0
1.0
0.5
2.0
1.0
0.5
2.0
1.0
0.5
0.1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
53
55
59
63
65
69
75
78
79
81
82
83
88
86
78
74
Table 6. Ir-catalyzed hydrogenation of substrate 24a.[a]
Ligand L
(S)-L1a
Conversion [%][b]
Yield 29 [%][b]
ee [%][c]
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
89
33 (+)
25 (ꢀ)
40 (+)
16 (+)
34 (+)
28 (+)
57 (+)
0 (+)
57 (ꢀ)
77 (+)
1 (+)
1 (+)
1 (ꢀ)
ACHTUNGTRENNUNG(R,R)-L2a
(S)-L3a
(S)-L4a
(S)-L4b
(S)-L4d
(S)-L4 f
(S)-L4j
(R)-L4k
(S)-L4m
(S)-L4n
(S)-L4p
(R)-L5
[a] Full experimental conditions are given in the Supporting Information.
[b] Conversions and yields were determined by GC. [c] Determined by
GC on a chiral stationary phase (SE54).
structural elements in various natural products. To demon-
strate the potential of the Suzuki–Miyaura cross-coupling/Ir-
catalyzed asymmetric hydrogenation sequence for accessing
tricyclic ring systems of this type, we chose hexahydrofluore-
none 32 as our target structure.
[a] Full experimental conditions are given in the Supporting Information.
[b] Conversions and yields were determined by GC. [c] Determined by
GC on a chiral stationary phase (DEtTBuSil-b-cyclodextrin (SE54)).
The synthetic sequence leading to compound 32 is shown
in Scheme 10. Asymmetric hydrogenation of allyl methyl
excess was obtained with ligand L4m (77% ee), which was
subsequently used for further optimization of the reaction
conditions. Lowering the hydrogen pressure from 50 to 5 to
1 bar caused a significant decrease in enantioselectivity, but
still gave full conversion to desired product 29 (Table 7).
Slightly higher enantiomeric excesses were obtained by re-
ducing the catalyst loading at low hydrogen pressure (5 and
1 bar). On the other hand, this behavior was not observed at
higher hydrogen pressure. At 50 bar, enantioselectivities de-
creased when the catalyst loading was reduced. At 5 bar,
lower temperatures had a positive effect on the enantiose-
lectivity, although the conversion was unaffected. Under the
optimized conditions for conversion of 24a (ꢀ208C, hydro-
gen (50 bar), catalyst (2.0 mol%)), the desired product was
obtained quantitatively with an enantiomeric excess of
88%.
Scheme 10. Reaction conditions: i) [Ir((R)-L4m)cod]ACTHUNTRGNE[UNG BArF] (1 mol%), H2
(50 bar), RT, 4 h; ii) BBr3 (1.0 equiv), CH2Cl2, ꢀ78!258C, 30 min then
H2O; iii) Dess–Martin periodinane (DMP; 1.2 equiv), CH2Cl2, RT, 2 h;
iv) H3NSO3 (1.8 equiv), sodium chlorite (1.8 equiv), THF/H2O, RT, 1.5 h;
v) oxalyl chloride (1.0 equiv) then AlCl3 (2.5 equiv), CH2Cl2, 08C
(30 min)!258C, 2 h.
Synthesis of hexahydrofluorenone 32: As mentioned in the
introduction, enantioselective routes to chiral hexahydro-
fluorenes are of interest because these compounds occur as
Chem. Eur. J. 2011, 17, 13502 – 13509
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13507

A. Pfaltz et al.
ether 16a with [Ir((R)-L4m)cod]
G
Conclusion
cyclohexane 26 in 93% yield and >99% ee. Chemoselective
O-demethylation with boron tribromide (70% yield,
>99% ee) gave alcohol 30, which was oxidized with DMP[16]
to afford the corresponding aldehyde (95% yield,
>99% ee). Oxidation to carboxylic acid 31a was accom-
plished by using sodium chlorite and sulfamic acid (95%,
>99% ee).[17] Finally, an intramolecular Friedel–Crafts-type
reaction gave desired hexahydrofluorenone 32 in 95% yield
and a very high enantiomeric purity of >99% ee. The abso-
lute configuration of alcohol 30 was determined to be
(1R,2S) by X-ray analysis of the corresponding para-bromo-
benzoic ester (see the Supporting Information). The abso-
lute configuration of all cyclohexane products was assigned
based on this analysis.
We have shown that cis-1,2-disubstituted cyclohexane deriv-
atives are readily accessible in a high enantiomeric purity of
up to 99% ee through a sequence involving Suzuki–Miyaura
cross-coupling and Ir-catalyzed asymmetric hydrogenation.
Asymmetric hydrogenation of the cyclopentene series
proved to be more difficult, giving lower enantioselectivities
of up to 88% ee. The utility of this synthetic strategy was
further demonstrated by an enantioselective route to chiral
hexahydrofluorenones.
Experimental Section
As shown in Scheme 11, cis compound 31a also gives
access to the trans isomer by epimerization of the corre-
General: All chemicals were purchased from commercial sources and
used as received. Anhydrous solvents were obtained in sure-seal bottles
from Fluka or purified by using standard methods.[19] Air-sensitive reac-
tions were carried out in an atmosphere of purified nitrogen by using a
glove box or standard Schlenk techniques under an argon atmosphere.
General procedure for Suzuki–Miyaura cross-coupling reactions by using
bromoaldehyde 13: Under an argon atmosphere the appropriate boro-
nate (11a–11c; 25.0 mmol, 1.20 equiv), bromoaldehyde 13 (20.9 mmol,
1.00 equiv), [Pd2ACTHNUTRGNE(UNG dba)3] (0.1 mol%), and a mixture of THF/H2O (2:1)
were added to a vial containing a stirring bar and the system was sealed
with a screw cap. After stirring for 2 h at 668C, the reaction mixture was
cooled to room temperature and saturated NaHCO3 was added. The
aqueous layer was extracted with tert-butyl methyl ether (3ꢁ10 mL) and
the combined organic extracts were washed with brine, dried over
MgSO4, and filtered. Removal of the solvent in vacuo and purification of
the brown residue by column chromatography (silica gel, hꢁd: 11ꢁ2 cm,
hexane/ethyl acetate 20:1) gave an orange solid. Residual traces of palla-
dium were removed by sublimation to afford the desired product.
Scheme 11. Reaction conditions: i) MeOH, H2SO4 (catalytic), reflux, 5 h;
ii) NaOMe, MeOH, 808C, 4 h then HCl (1m).
sponding ester (33). This was demonstrated in the racemic
series starting from rac-31a, which was converted into
methyl ester rac-33. Subsequent treatment with NaOMe in
refluxing MeOH afforded, after acidic workup, the trans-
configured carboxylic acid rac-31b in 95% overall yield (d.r.
>20:1 by NMR spectroscopy).
In connection with the synthesis of hexahydrofluorenone
32, an alternative oxidation method for alcohol 30 was
tested by using iodine and K2CO3 in refluxing toluene
(Scheme 12).[18] Surprisingly, under these conditions rac-30
General procedure for Suzuki–Miyaura cross-coupling reactions by using
trifluoromethylsulfonate 20a: Under an argon atmosphere the appropri-
ate boronate (11a or 11b; 1.30 equiv) and [Pd2ACTHNUTRGNEU(NG dba)3] (0.1 mol%) were
added to a vial containing a stirring bar and dissolved in THF (1 mL).
Triflate 20a (100 mg, 0.37 mmol, 1.00 equiv) was dissolved in THF
(1 mL) and added to the vial. The degassed system was sealed with a
screw cap and stirred for 4 h at 668C. The reaction mixture was then
cooled to room temperature and saturated NaHCO3 was added. The
aqueous layer was extracted with tert-butyl methyl ether (3ꢁ5 mL) and
the combined organic extracts were washed with brine, dried over
MgSO4, and filtered. Removal of the solvent in vacuo and purification of
the residue by column chromatography (silica gel, hꢁd: 10ꢁ2 cm,
hexane/ethyl acetate 20:1) afforded the desired product.
General procedure for Suzuki–Miyaura cross-coupling reaction by using
trifluoromethylsulfonate 20b: Under an argon atmosphere the appropri-
ate boronate (11a or 11b; 1.30 equiv), [Pd2ACTHNUTRGNEUNG(dba)3] (1.00 mol%), 1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes, 2.40 mg, 2.00 mol%),
and water (3.00 mol%) were added to a vial containing a stirring bar and
dissolved in THF (1 mL). Triflate 20b (1.00 equiv) was dissolved in THF
(1 mL) and added to the vial. The degassed system was sealed with a
screw cap and stirred for 14 h at 668C. The reaction mixture was then
cooled to room temperature and saturated NaHCO3 was added. The
aqueous layer was extracted with tert-butyl methyl ether (3ꢁ5 mL). The
combined organic extracts were washed with brine, dried over MgSO4,
and filtered. Removal of the solvent in vacuo and purification of the resi-
due by column chromatography (silica gel, hꢁd: 10ꢁ2 cm, hexane/ethyl
acetate 20:1) afforded the desired product.
Scheme 12. Synthesis of the O-heterocycle rac-34.
was converted into O-heterocycle rac-34 in 53% yield. The
structure of this compound was established by 2D NMR
spectroscopy. It appears that an ortho or para iodination oc-
curred with subsequent intramolecular addition of the hy-
droxy group to the oxonium intermediate, followed by elimi-
nation of HI. Further investigations into the scope of the re-
action showed this cyclization to be limited to compound
rac-30 (see the Supporting Information).
General asymmetric hydrogenation procedure: A high pressure steel au-
toclave (Premex Reactor AG; Lengnau, Switzerland; Model HPM-005)
with a dry glass insert and a magnetic stirring bar was taken into a glove
box. The glass insert was charged with the appropriate catalyst (1–
2 mol%; see Table 7) and the degassed substrate solution (10 mL, 0.22m)
13508
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Chem. Eur. J. 2011, 17, 13502 – 13509

Synthesis of cis-1,2-Disustituted Cyclopentanes and Cyclohexanes
FULL PAPER
freshly prepared from the corresponding substrate and dichloromethane
(stirred over basic alumina and filtered). The autoclave was sealed, taken
out of the glove box, attached to a high-pressure hydrogen line and
purged with H2. The autoclave was sealed under the appropriate H2 pres-
sure (see Table 7) and the mixture was stirred for 4–12 h at the appropri-
ate temperature. After release of H2, the solution was concentrated in a
stream of nitrogen, dissolved in a mixture of n-hexanes/methyl tert-butyl
ether (4:1; 30 mL) as an eluent and passed through a silica gel plug. The
filtrate was concentrated in vacuo and analyzed without further purifica-
tion for conversion (GC) and ee (GC or HPLC).
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Acknowledgements
Financial support from the Swiss National Science Foundation and the
Federal Commission for Technology and Innovation (KTI) is gratefully
acknowledged. We thank Wei Liu for experimental assistance.
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Received: August 25, 2011
Published online: November 3, 2011
Chem. Eur. J. 2011, 17, 13502 – 13509
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13509