Asymmetric Induction at Remote Quaternary Centers of Cyclohexadienones by Rhodium-Catalyzed Conjugate Hydrosilylation

Article abstract of DOI:10.1002/anie.201601636

The enantioselective desymmetrizing conjugate hydrosilylation of prochiral differently γ,γ-disubstituted cyclohexadienone derivatives 2 to furnish the corresponding cyclohexenones 4 with a remote chiral all-carbon quaternary center at the γ position is de

Full text of DOI:10.1002/anie.201601636

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International Edition: DOI: 10.1002/anie.201601636
German Edition: DOI: 10.1002/ange.201601636
Desymmetrization
Asymmetric Induction at Remote Quaternary Centers of
Cyclohexadienones by Rhodium-Catalyzed Conjugate Hydrosilylation
Yuki Naganawa,* Mayu Kawagishi, Jun-ichi Ito, and Hisao Nishiyama*
Abstract: The enantioselective desymmetrizing conjugate
hydrosilylation of prochiral differently g,g-disubstituted cyclo-
hexadienone derivatives 2 to furnish the corresponding cyclo-
hexenones 4 with a remote chiral all-carbon quaternary center
at the g position is described. Chiral rhodium–bis(oxazolinyl)-
phenyl complexes 1 were effective catalysts for this trans-
formation. This catalytic system was extended to the asym-
metric transformation of spirocarbocyclic cyclohexadienones
5 to give the corresponding products 6 with high enantiomeric
ratios.
zation reactions have been performed successfully,[7,8]
whereas a few more challenging intermolecular variants
with high enantioselectivity were developed with several
organocatalysts.[9] We anticipated that the simplest trans-
À
formation, the desymmetrizing reduction of one C C unsa-
turated bond within the g,g-disubstituted cyclohexadienones
in an enantioselective manner, would furnish a cyclohexenone
bearing a stereogenic all-carbon quaternary center at the g-
position. We addressed this issue by applying a transition-
metal-catalyzed enantioselective conjugate hydrosilylation.[10]
Although the enantioselective conjugate hydrosilylation of
a,b-unsaturated compounds is a well-studied reaction,[11,12]
the construction of remote all-carbon quaternary centers has
rarely been investigated. The most challenging feature of this
target transformation is that the metal catalyst must show
discrimination in the steric environment of a quaternary
carbon atom that has inherently no relationship to the
reduction event.
T
he catalytic asymmetric construction of stereogenic all-
carbon quaternary centers has been recognized to be
particularly challenging.[1] Cyclohexane rings containing ste-
reogenic all-carbon quaternary centers are ubiquitous and
attractive building blocks found in pharmaceutical agents and
natural compounds.[1,2] Major approaches toward the enan-
tioselective synthesis of these structures are based on trans-
À
formations of reactive cyclohexanones. Enantioselective C C
We applied chiral rhodium–bis(oxazolinyl)phenyl com-
bond-forming processes for the a-functionalization of car-
bonyl groups are well-established.[3,4] Furthermore, enantio-
selective conjugate addition reactions to b-substituted cyclo-
hexenones are representative strategies for the synthesis of
cyclohexanones with a stereogenic all-carbon quaternary
center at the b-position.[1d] Thus, the catalytic asymmetric
preparation of cyclohexanones containing a stereogenic all-
carbon quaternary center at the a- or b-position has been
studied extensively.
plexes [Rh(Phebox-R)] (1a–d; Bn = benzyl)[13] as catalysts for
the enantioselective conjugate hydrosilylation of a,b-unsatu-
rated compounds.[14] As a model reaction, we stirred 4-
methyl-4-phenylcyclohexadienone (2a) with triethoxysilane
as a reductant in the presence of catalyst 1a (2 mol%) in
toluene at 508C (Table 1, entry 1). After 1 h, complete
formation of the corresponding 2-silyloxy diene 3a was
observed. We did not use other reductants, such as hydrogen,
as the formation of the electron-rich intermediate 3a can
One of the recent challenges in asymmetric synthesis is
the construction of remote stereogenic quaternary centers
distant from such reactive functionalities.[5,6] We aim to
develop general protocols to furnish optically active cyclo-
hexenone derivatives with a stereogenic all-carbon quater-
nary center at the g-position. The carbon atom at this position
À
=
is inherently inert, and thus it is difficult to form new C C
suppress the undesirable reduction of the second C C double
bonds at this position by the use of common transformations.
In this context, several research groups have demonstrated an
interesting asymmetric desymmetrization of achiral differ-
ently g,g-disubstituted cyclohexadienones to furnish the
corresponding six-membered rings containing a stereogenic
all-carbon quaternary center.[7] Intramolecular desymmetri-
bond. The subsequent treatment of 3a under acidic conditions
gave the desired cyclohexenone 4a with an all-carbon
quaternary center at the g-position in 52% yield (Table 1,
entry 1). Gratifyingly, nonracemic 4a was obtained with an
enantiomeric ratio of 83.5 :16.5. Next, we screened a series of
hydrosilanes as reductants. Of the alkoxyhydrosilanes tested,
the reaction with trimethoxysilane gave the best result (90%
yield, e.r. 86.5 :13.5; Table 1, entries 2 and 3). On the other
hand, the reaction with diphenylmethylsilane led to a decrease
in chemical yield and enantioselectivity (Table 1, entry 4).
The use of dihydrosilanes did not improve the result (Table 1,
entry 5). Next, we examined the effect of the substituents on
[Rh(Phebox-R)] (1; Table 1, entries 6–8). The use of
[Rh(Phebox-sBu)] (1c) led to a slight improvement in
enantioselectivity (Table 1, entry 7). Furthermore, a reaction
[*] Dr. Y. Naganawa, M. Kawagishi, Dr. J.-i. Ito, Prof. Dr. H. Nishiyama
Department of Applied Chemistry, Graduate School of Engineering
Nagoya University
Chikusa, Nagoya 464-8603 (Japan)
E-mail: yuki.n@apchem.nagoya-u.ac.jp
hnishi@apchem.nagoya-u.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601636.
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Table 1: Optimization of reaction conditions.[a]
reaction, whereas the introduction of an electron-withdraw-
ing group resulted in lower enantioselectivity. The reaction of
compound 2g with a larger aromatic substituent gave the
desired product with a similar enantiomeric ratio to that
observed for the standard product 4a (Table 2, entry 7). We
next performed the reaction of 4-ethyl-4-phenylcyclohexa-
dienone (2h) to investigate the steric importance of the alkyl
side chain of 2a (Table 2, entry 8). The enantiomeric ratio of
4h was dramatically decreased to 68.5 :31.5. Finally, the
reaction of 2i, with two different alkyl groups (cyclohexyl and
Me), gave product 4i with moderate enantioselectivity
(Table 2, entry 9). The absolute configuration of the product
4e was determined as S by comparison with reported
compounds.[15] For unreported compounds 4, the absolute
configuration was tentatively assigned by analogy.
Yield [%][b]
e.r.
À
Si H
Entry
1
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1d
1c
1c
(EtO)3SiH
(EtO)2MeSiH
(MeO)3SiH
PhMe2SiH
Ph2SiH2
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
52
87
90
13
57
99
97
91
83.5 :16.5
77.5 :22.5
86.5 :13.5
72.5 :27.5
81.5 :18.5
85.5 :14.5
87:13
75.5 :24.5
88.5 :11.5
–
9[c]
10[d]
82
To further broaden the utility of this protocol, we focused
on cyclohexadienones 5 incorporating a spirocarbocyclic
backbone (Scheme 1). Spiro-containing chiral compounds
are unique motifs found in natural compounds isolated from
a wide range of biological sources.[16] Cyclohexadienone 5a
was converted into the corresponding product 6a in 89%
yield with e.r. 96.5 :3.5. Reactions of 5b–g, with electron-
donating or -withdrawing substituents at various positions of
the aromatic ring of the tetrahydronaphthalene core gave the
desired products 6b–g with uniformly high e.r. values in the
range of 92 :8 to 96.5 :3.5. Since spirocarbocycles containing
heteroatoms are ubiquitous structures in nature, we also
employed the spiro-fused heterocyclic compounds 5h–n.[16]
The enantioselective conjugate hydrosilylation proceeded
smoothly to furnish the desired products 6h–n in good
yields and with good enantioselectivity. Finally, we deter-
mined that the ring size of 5 had a significant impact on the
enantioselectivity. For example, the reaction of 5o containing
a five-membered ring provided the product 6o with slightly
lower enantioselectivity (e.r. 89 :11). In contrast, a dramatic
decrease in enantioselectivity was observed for the reaction of
5p, with a seven-membered ring (e.r. 61.5 :38.5).
no reaction
[a] Reaction conditions: 2a (0.1 mmol), hydrosilane (0.115 mmol),
1 (2 mol%), toluene (1 mL), 508C, 1 h. [b] Yield of the isolated product.
[c] The reaction was carried out at 408C. [d] The reaction was carried out
at room temperature.
performed at a lower temperature of 408C gave 4a with the
highest enantiomeric ratio (e.r. 88.5 :11.5; Table 1, entry 9),
whereas a reaction attempted at room temperature did not
proceed at all (entry 10). The absolute configuration of 4a
was determined as S by comparison with reported com-
pounds.[15]
Next, we examined the generality of the reaction of 4-aryl
4-methylcyclohexadienone substrates 2 (Table 2). Since we
À
initially hypothesized that the Rh H species would approach
from the less-hindered prochiral face of 2a to avoid the large
phenyl ring, we carried out the reaction with 4-aryl 4-
methylcyclohexadienones 2b–g bearing various substituents
on the phenyl ring to increase steric bulkiness. The introduc-
tion of meta or ortho substituents tended to slightly diminish
the enantioselectivity, contrary to expectations (Table 2,
entries 2–4). To examine the electronic effect of the substitu-
ents, we conducted the reaction with compounds 2e and 2 f
(Table 2, entries 5 and 6). The introduction of an electron-
donating group improved the enantioselectivity of the
To enhance the synthetic utility of the present protocols,
we examined the derivatization of product 6a (Scheme 2A).
a-Iodination of 6a by the procedure described by Johnson
et al.[17] gave a-iodocyclohexenone 7, which could be a versa-
tile building block. For example, the Suzuki–Miyaura cross-
coupling of 7 furnished the corresponding product 8 in 85%
yield and without loss of enantiomeric purity.
Table 2: Reaction of 4-alkyl 4-aryl cyclohexadienones 2.[a]
Since the present transformation proceeds through the
generation of 2-silyloxy dienes, such as 3a, we next performed
an enantioselective desymmetrizing conjugate hydroslylation
and Rubottom oxidation[18] sequence (Scheme 2B). The
Entry
R
R’
Yield [%][b]
e.r.
corresponding a-hydroxycyclohexenone
9 was obtained,
1
2
3
4
5
6
7
8
9
Ph
p-tolyl
Me (2a)
Me (2b)
Me (2c)
Me (2d)
Me (2e)
Me (2 f)
Me (2g)
Et (2h)
82 (4a)
95 (4b)
95 (4c)
99 (4d)
92 (4e)
92 (4 f)
53 (4g)
99 (4h)
89 (4i)
88.5 :11.5
88.5 :11.5
85.5 :14.5
85 :15
90.5 :9.5
82.5 :17.5
88 :12
albeit with low diastereoselectivity. Oxidative cleavage of 9
by treatment with Pb(OAc)4 in methanol provided the
functionalized compound 10 with a,b-unsaturated-ester and
aldehyde moieties in 80% yield with e.r. 95 :5.[18]
To determine which hydrogen atom of the products was
transferred from the hydrosilane, we investigated the reaction
of 2a with Ph2SiD2 (Scheme 3). In this deuterium-incorpo-
ration experiment, deuterium was selectively introduced at
the b-carbon atom of [D]4a in a cis orientation to the methyl
group.[19]
m-tolyl
o-tolyl
p-MeOC6H4
p-F3CC6H4
2-Np
Ph
cyclohexyl
68.5 :31.5
84 :16
Me (2i)
[a] Reaction conditions: 2 (0.1 mmol), trimethoxysilane (0.115 mmol),
1c (2 mol%), toluene (1 mL), 408C, 1 h. [b] Yield of the isolated product.
Np=naphthyl.
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Scheme 2. Derivatization of chiral spirocyclic compounds. Reagents
and conditions: a) I2 (3 equiv), DMAP (10 mol%), CCl4/pyridine (1:1),
508C, 24 h; b) PhB(OH)2 (2 equiv), 10% Pd/C, K3PO4; c) [Rh(Phebox-
sBu)] (1c; 2 mol%), (MeO)3SiH (1.15 equiv), toluene (0.1m), 408C,
1 h, then mCPBA (1.5 equiv), NaHCO3, toluene/H2O, 08C, 1.5 h;
d) Pb(OAc)4 (2 equiv), MeOH/benzene (1:1), 08C, 10 min. DMAP=
4-dimethylaminopyridine, mCPBA=m-chloroperbenzoic acid.
are illustrated in Figure 1.[14] Cyclohexadienone 2a coordi-
nates to a vacant site of the Rh complex, which would have
the hydride in the equatorial position.[14c] The Rh H species
À
attacks the Re face of the unsaturated bond owing to steric
repulsion between the bulky sec-butyl group and 2a, as shown
in intermediates I-1A and I-2A, thus leading to the required
group selectivity. At the same time, the steric environment of
the two substituents (Ph and Me) at the g-position of 2a can
be differentiated owing to the steric repulsion of the bulky
sec-butyl group of 1c and the trimethoxysilyl substituent on
Scheme 1. Reaction of spirocyclic cyclohexadienones 5. [a] Catalyst
loading: 6 mol%.
In terms of the stereochemical nature of the transforma-
tion, the olefinic groups of 2a are enantiotopic, whereas the
two faces of each olefin are diastereotopic. Therefore, both
group and face selection must be controlled for high
enantioselectivity. On the basis of the deuterium-incorpora-
tion experiment, plausible models for asymmetric induction
Figure 1. Plausible models of asymmetric induction and an optimized
structure of I-1B.
Scheme 3. Deuterium-incorporation experiment.
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À
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Acknowledgements
This research was supported by Grants-in-Aid for Scientific
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Keywords: asymmetric synthesis · desymmetrization ·
hydrosilylation · quaternary centers · rhodium
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Received: February 17, 2016
Published online: April 21, 2016
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