Asymmetric, regioselective direct aldol coupling of enones and aldehydes with chiral rhodium(bis-oxazolinylphenyl) catalysts

Article abstract of DOI:10.1002/chem.200901329

A study was conducted to demonstrate asymmetric and regioselective direct aldol coupling of enones and aldehydes with chiral rhodium(bis-oxazolinphenyl) catalysts. It was demonstrated that the [Rh(Phebox) complex acted as a Lewis acid and a Bronsted base

Full text of DOI:10.1002/chem.200901329

COMMUNICATION
DOI: 10.1002/chem.200901329
Asymmetric, Regioselective Direct Aldol Coupling of Enones and Aldehydes
with Chiral Rhodium(bis-oxazolinylphenyl) Catalysts
Masato Mizuno, Hiroko Inoue, Tatsuo Naito, Li Zhou, and Hisao Nishiyama*[a]
The asymmetric direct aldol coupling reactions of ketones
as enolate sources have been extensively developed by the
use of chiral organocatalysts via in situ generated enamine
species to provide optically active b-hydroxyketones effi-
ciently.[1] However, among the candidate ketone substrates,
acyclic and cyclic enones as enolate sources have rarely
been applied because of problems of instability, as well as
the ability for enones to act as reactive acceptors in conju-
gate additions, the possibility of retro-aldol equilibrium, or
b-hydroxy elimination from the aldol products. It is clearly
of importance that the vinylogous unsaturated aldol prod-
ucts derived from enones possess high potential to serve as
useful components for organic synthesis. In 2005, Trost et al.
first disclosed a potent catalyst based on a dinuclear Zn
complex for the asymmetric direct aldol coupling of substi-
tuted aliphatic aldehydes with methyl vinyl ketone (MVK)
as an enolate source with up to 98% enantiomeric excess
(ee) (Scheme 1).[2] Nevertheless, there is still a challenge in
terms of the scope of the substrate ketones. On the other
hand, in terms of similar vinylogous aldol couplings, versa-
tile methods that use silyl-protected dienolates have been
successfully developed to give multifunctional unsaturated
compounds.[3] In addition, the regioselective direct aldol
coupling of enones is thought to be a promising approach to
the synthesis of the corresponding unsaturated aldol prod-
ucts.
sioned the possibility of regioselective formation of dieno-
À
late A (Scheme 2) by activation of Ca’ H, which leads ex-
clusively to the formation of the unsaturated aldol product
Scheme 1. Dinuclear zinc catalyst for asymmetric direct aldol coupling of
MVK reported by Trost et al.
We have demonstrated that rhodium(bis-oxazolinylphen-
yl) ([Rh
ric direct aldol reactions of cyclohexanone and aldehydes.
We hypothesized that the [Rh(Phebox)] complex acts as a
ACHTUNGTRENNUNG(Phebox)]) acetate complexes catalyze the asymmet-
AHCTUNGTRENNUNG
Lewis acid and a Brønsted base to form a rhodium–enolate
species (Scheme 2).[4,5] On the basis of our findings, we envi-
[a] M. Mizuno, H. Inoue, T. Naito, Dr. L. Zhou, Prof. H. Nishiyama
Department of Applied Chemistry, Graduate School of Engineering
Nagoya University, Chikusa, Nagoya, 464-8603 (Japan)
Fax : (+81)52-789-3209
E-mail: hnishi@apchem.nagoya-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901329.
Scheme 2. [Rh
formation of dienolates.
ACHTUNGTREN(NUGN Phebox)] complexes, aldol reaction, and regioselective
Chem. Eur. J. 2009, 15, 8985 – 8988
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8985

C as opposed to the formation of dienolate B by the activa-
retro-aldol reaction by the recovery of 4a in 74% yield with
a slight decrease in the diastereomeric ratio (Scheme 3,
method A). Hence, we attempted to trap the aldol product
À
tion of Cg H.
In an initial trial, we selected cyclohex-2-eneone (2) as
the enolate source and the electron-deficient aldehyde 4-ni-
trobenzaldehyde (3) as the coupling partner. The coupling
was performed in the presence of 1a (5 mol%) in toluene at
608C for 72 h (Table 1).[6] The coupling product was ob-
Table 1. Asymmetric, regioselective direct aldol coupling of 2 and 3 cata-
lyzed by [RhACHTUNGTRENNUNG
(Phebox)] complexes.[a]
Additive
Solvent Product Yield Ratio
ee [%] ee [%]
[%]
anti/syn anti
syn
Scheme 3. Retro-aldol reaction and acetylation of 4a under different re-
action conditions.
1
2
–
toluene 4a
toluene 4a
toluene 4a
toluene 4a
toluene 4a
26
34
73
63
58
21
41
48
80
74
74
72
29
59
78:22
93:7
91:9
95:5
87:13
91:9
93:7
64:36
97:3
96:4
95:5
92:8
82:16
93:7
72
91
86
92
90
82
77
58
93
93
92
93
73
63
16
16
25
35
37
À22
13
5
–
–
–
–
AgOTf
3[b] AgOTf
4[c]
5
6
AgOTf
HOTf
AgOTf
AgOTf
AgOAc
in situ by acetylation with acetic anhydride. Addition of
acetic anhydride (3 equiv relative to 3), under the conditions
detailed in entry 2, produced the corresponding acetylated
product 4b in 80% yield with the highest anti selectivity
thus far of 97% and with 93% ee for the anti diastereomer
(Table 1, entry 9). Increased reaction time, addition of five
equivalents of acetic anhydride, or five equivalents of the
enone 2 did not increase the yield (Table 1, entries 10–12).
In place of the isopropyl catalyst 1a, the benzyl (1b) and
phenyl (1c) derivatives did not give better results (Table 1,
entries 13 and 14).
Next, we examined the acetylation of the aldol product
4a under the coupling conditions at 608C (Scheme 3,
method B). However, only 10% of the acetylated product
4b was obtained. This fact evidently shows that most of the
acetylation in the reaction media occurs on the in situ
formed rhodium–aldolate species.
THF
4a
7
tBuOH 4a
toluene 4a
8
9[d] AgOTf/Ac2O toluene 4b
10[e] AgOTf/Ac2O toluene 4b
11[f] AgOTf/Ac2O toluene 4b
12[g] AgOTf/Ac2O toluene 4b
13[h] AgOTf/Ac2O toluene 4b
14[i] AgOTf/Ac2O toluene 4b
6
9
[a] 1a (5 mol%, 0.025 mmol), additive (AgOTf, HOTf, or AgOAc,
0.025 mmol), 2 (5.0 mmol), 3 (0.50 mmol), solvent (0.5 mL), 608C, 72 h.
[b] 808C, 72 h. [c] Rh cat. (10 mol%), AgOTf (10 mol%), scale:
0.25 mmol of 3. [d] Ac2O (1.5 mmol). [e] Ac2O (1.5 mmol), 608C, 192 h.
[f] Ac2O (2.5 mmol). [g] 2 (2.5 mmol). [h] 1b (5 mol%), Ac2O
(1.5 mmol). [i] 1c (5 mol%), Ac2O (2.5 mmol).
served in 26% yield with a moderate anti selectivity of 78%
and a good ee value of 72% (Table 1, entry 1). Addition of
AgOTf (OTf=trifluoromethanesulfonate) enhanced the cat-
alytic reactivity to slightly increase the yield to 34% with
93% anti selectivity and 91% ee for the anti product
(Table 1, entry 2). The yield was increased to 73% by con-
ducting the reaction at a higher temperature (808C), howev-
er, the stereoselectivity decreased a little (Table 1, entry 3).
A catalyst loading of 10 mol% increased the ee value to
92% (Table 1, entry 4). Interestingly, the addition of TfOH
in place of AgOTf worked similarly well (Table 1, entry 5).
Although THF and tBuOH were used as solvents, the cou-
pling reactions resulted in lower yields (Table 1, entries 6
and 7). Carrying out the reaction in the presence of extra
acetate ion by the addition of AgOAc was not effective
(Table 1, entry 8). The yields remained moderate, approxi-
mately 60–70%, therefore, it was strongly presumed that
the retro-aldol reaction was in equilibrium. Therefore, we
examined the treatment of 4a in the presence of the catalyst
1a and AgOTf at 608C for 48 h and indeed observed the
Under the standard conditions (Table 1, entries 2 and 9),
the direct coupling of 2 and cyclopent-2-enone with some ar-
omatic aldehydes containing electron-withdrawing aromatic
substituents were examined (Scheme 4). In the presence of
acetic anhydride, the product yields of 5b, 6b, 7b, and 8b
were improved, to between 55 and 66%, relative to those
without acetic anhydride. The highest enantioselectivities of
93 and 94% were obtained for 5b and 6b, respectively, and
were accompanied with high anti selectivity up to 97%. The
reaction of benzaldehyde and 2-naphthaldehyde, aldehydes
without an electron-withdrawing group, resulted in approxi-
mately 30% yields of 9b and 10b with good stereoselectiv-
ity. The reaction with 3-methylcyclohex-2-enone gave a mix-
ture of b-hydroxy and acetoxy products. Therefore, the
crude products were treated with acetic anhydride and pyri-
dine to give 11b in 40% yield with 89% anti selectivity and
85% ee. The use of cyclopent-2-enone as an enolate source
increased the yields to approximately 50–70%. However, to
our surprise, the acetylation did not proceed smoothly in the
8986
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8985 – 8988

Asymmetric Aldol Coupling of Enones and Aldehydes
COMMUNICATION
Scheme 6. Proposed transition-state model for the coupling reaction.
In summary, we have developed a new asymmetric, regio-
selective direct aldol coupling reaction using chiral rho-
dium(bis-oxazolinylphenyl) catalysts. Although the yields
are still moderate, this is an important synthetic approach to
access challenging aldol products and the corresponding ace-
tylated products. We think that the development of transi-
tion-metal catalysts that can act as Lewis acid and Brønsted
base catalysts is progressing, and as such, we are exploring
the reaction further.
Scheme 4. Asymmetric, regioselective direct aldol coupling of 2 and cy-
clopent-2-enone with various aldehydes catalyzed by 1c.
presence of acetic anhydride. It is thought that the corre-
sponding intermediate rhodium–aldolate derived from cy-
clopent-2-enone could not be efficiently captured by acetic
anhydride to release the product.
The absolute configuration 6S,1’R of product 4a was un-
ambiguously confirmed by hydrogenation with Pd-C/hydro-
gen to give the b-hydroxyketone 4c, the absolute configura-
tion of which, 2S,1’R, was already determined (Scheme 5).
Experimental Section
Typical procedure for the direct aldol coupling of 2 and 3 with acetic an-
hydride (Table 1, entry 9): The rhodium complex 1a (13.5 mg,
0.025 mmol, 5.0 mol% relative to aldehyde 3), compound 3 (75.6 mg,
0.50 mmol), and silver trifluoromethanesulfonate (6.4 mg, 0.025 mmol)
were placed in a flask. Under an argon atmosphere, toluene (0.5 mL),
compound 2 (481 mg, 5.0 mmol, 10 equiv relative to aldehyde 3) and
acetic anhydride (153 mg, 1.5 mmol, 3 equiv relative to aldehyde) were
added. The mixture was stirred at 608C for 72 h. The reaction was moni-
tored by TLC; Rf =0.24 (ethyl acetate/hexane=1:2). The reaction mix-
ture was directly introduced onto a silica-gel column and eluted with
ethyl acetate/hexane (1:5) to give the desired acetate product 4b as a
pale yellow oil (80%, 115 mg, 0.40 mmol). The diastereomeric ratio
(97:3) was determined by 1H NMR spectroscopy. 1H NMR (300 MHz,
CDCl3): anti: d=1.48 (m, 1H), 2.08 (m, 1H), 2.14 (s, 3H), 2.40 (m, 2H),
3.00 (m, 1H), 5.95 (d, J=10.2 Hz, 1H; CH=C), 6.50 (d, J=5.2 Hz, 1H;
CHOAc), 6.93 (m, 1H), 7.54 (d, J=7.8 Hz, 2H), 8.16 ppm (d, J=7.8 Hz,
2H); syn: 6.08 (m, 1H; CH=C), 6.53 ppm (d, J=3.6 Hz, 1H; CHOAc);
13C NMR (75 MHz, CDCl3): anti: d=21.4, 24.2, 25.6, 51.6, 72.8, 123.4,
128.0, 129.6, 145.0, 147.4, 149.8, 169.4, 196.6 ppm; IR (neat), n=3487,
1742, 1676, 1518, 1345 cmÀ1; HRMS (FAB): m/z: calcd for C15H16NO5:
290.1028 [M+H]; found: 290.1030; the ee was determined by HPLC:
Daicel Chiralpak AD-H; hexane/2-propanol (90:10, 1.0 mLminÀ1); reten-
tion times: 22.5 (anti, major), 25.2 (anti, minor), 36.8 (syn, major),
60.4 min (syn, minor); 93% ee for the anti product.
Scheme 5. Determination of the absolute configuration of 4a.
On the basis of the absolute configuration, the transition-
state model was proposed as follows: attack from the Re
face of the intermediate dienolate (Scheme 6, i) to the Re
face of the aldehyde forms the rhodium aldolate (Scheme 6,
ii), which then releases the aldol or acetylation product. We
think that in the case of cyclopent-2-enone, which does not
result in formation of the acetylated product, the release of
the aldol product may be very quick and is therefore not
acetylated. We also examined linear enones, such as MVK
and benzalacetone, but we obtained very low yields.
Acknowledgements
This work was partly supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Technology
Chem. Eur. J. 2009, 15, 8985 – 8988
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8987

H. Nishiyama et al.
of Japan (Concerto Catalysts, 460:18065011), the Japan Society for the
Promotion of Science (18350049).
[3] For reviews on catalytic enantioselective, vinylogous aldol reactions,
see: a) S. E. Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew.
Chem. 2005, 117, 4760–4777; Angew. Chem. Int. Ed. 2005, 44, 4682–
4698; b) M. Kalesse in Natural Product Synthesis II, Targets, Methods,
Concepts, Top. Curr. Chem. (Ed.: J. Mulzer), Springer, Berlin, 2005,
pp. 43–76; c) G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi, Synlett
1999, 1333–1350; d) G. Casiraghi, F. Zanardi, G. Appendino, G.
Rassu, Chem. Rev. 2000, 100, 1929–1972.
Keywords: aldol reaction
dienolates · enones · rhodium
·
asymmetric catalysis
·
[4] H. Inoue, M. Kikuchi, J. Ito, H. Nishiyama, Tetrahedron 2008, 64,
493–499.
[1] For reviews on asymmetric organocatalytic direct aldol reactions via
enamines, see: a) A. Berkessel, H. Grçger in Asymmetric Organoca-
talysis, Wiley-VCH, Weinheim, 2005, Chapter 6, pp. 140–179; b) B.
List in Modern Aldol Reactions, Vol. 1, (Ed.: R. Mahrwald), Wiley-
VCH, Weinheim, 2004, pp. 161–200; c) B. List, Acc. Chem. Res. 2004,
37, 548–557; d) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem. Res.
2004, 37, 580–591; e) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List,
Chem. Rev. 2007, 107, 5471–5569; f) G. Guillena, C. Nꢁjera, D. J.
Ramꢂn, Tetrahedron: Asymmetry 2007, 18, 2249–2293; g) A. Dondo-
ni, A. Massi, Angew. Chem. 2008, 120, 4716–4739; Angew. Chem. Int.
Ed. 2008, 47, 4638–4660.
[5] For examples of regioselective dienolate formation, see: a) J. S.
Panek, O. A. Bula, Tetrahedron Lett. 1988, 29, 1661–1664; b) M. Ma-
jewski, D. M. Gleave, Tetrahedron Lett. 1989, 30, 5681–5684; c) M.
Zaidlewicz, W. Sokꢂl, A. Wojtczak, P. Neumann, M. Nissinen, Tetra-
hedron Lett. 2002, 43, 3525–3528; d) F. A. Silva, V. Gouverneur, Tet-
rahedron Lett. 2005, 46, 8705–8709; e) B. Bazꢁn-Tejeda, G. Bluet, G.
Broustal, J.-M. Campagne, Chem. Eur. J. 2006, 12, 8358–8366; f) S. B.
Han, M. J. Krische, Org. Lett. 2006, 8, 5657–5660; g) B. M. Trost,
R. N. Bream, J. Xu, Angew. Chem. 2006, 118, 3181–3184; Angew.
Chem. Int. Ed. 2006, 45, 3109–3112.
[2] a) B. M. Trost, S. Shin, J. A. Sclafani, J. Am. Chem. Soc. 2005, 127,
8602–8603; for acetone as an enolate source, see: b) B. M. Trost,
E. R. Silcoff, H. Ito, Org. Lett. 2001, 3, 2497–2500; for a vinylogous
direct aldol reaction with an aluminum reagent, see: c) H. Takikawa,
K. Ishihara, S. Saito, H. Yamamoto, Synlett 2004, 732–734; for vinylo-
gous Michael reactions, see: d) J. Christoffers, Synlett 2001, 0723–
0732.
[6] For the synthesis of [RhACTHUNGTERNNU(G Phebox)] acetate complexes, see: a) Y. Ka-
nazawa, Y. Tsuchiya, K. Kobayashi, T. Shiomi, J. Ito, M. Kikuchi, Y.
Yamamoto, H. Nishiyama, Chem. Eur. J. 2006, 12, 63–71; b) J. Ito, T.
Shiomi, H. Nishiyama, Adv. Synth. Catal. 2006, 348, 1235–1240.
Received: May 19, 2009
Published online: July 31, 2009
8988
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8985 – 8988