Intermolecular antiselective and enantioselective reductive coupling of enones and aromatic aldehydes with chiral rh(phebox) catalysts

Article abstract of DOI:10.1021/ol802939u

The intermolecular reductive coupling reaction of cyclopent-2-enone and aromatic aldehydes was realized by chiral rhodium-(bisoxazolinyl)phenyl catalysts, Rh(Phebox-Ph)(OAc)₂(H₂O), with diphenymethylsilane as a hydride donor to give

Full text of DOI:10.1021/ol802939u

ORGANIC
LETTERS
2009
Vol. 11, No. 4
1011-1014
Intermolecular Antiselective and
Enantioselective Reductive Coupling of
Enones and Aromatic Aldehydes with
Chiral Rh(Phebox) Catalysts
Takushi Shiomi, Takahiro Adachi, Jun-ichi Ito, and Hisao Nishiyama*
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya UniVersity, Chikusa, Nagoya 464-8603, Japan
hnishi@apchem.nagoya-u.ac.jp
Received December 22, 2008
ABSTRACT
The intermolecular reductive coupling reaction of cyclopent-2-enone and aromatic aldehydes was realized by chiral rhodium-(bisoxazolinyl)phenyl
catalysts, Rh(Phebox-Ph)(OAc)2(H2O), with diphenymethylsilane as a hydride donor to give the corresponding ꢀ-hydroxyketones in high anti-
selectivity (up to 96%) with high enantioselectivity (up to 93%).
Catalytic reductive coupling reactions enabled on conjugate
reduction of R,ꢀ-unsaturated carbonyl compounds followed
by aldol-type coupling reaction toward aldehydes or ketones
as acceptors have been recognized as a versatile synthetic
method of ꢀ-hydroxycarbonyl compounds.1 In 1990, Matsuda
et al. first reported Rh4(CO)12/phosphine-catalyzed direct
coupling of R,ꢀ-unsaturated linear and cyclic ketones toward
hexanal or benzaldehyde in the presence of diethylmethyl-
silane as a hydride donor to give the corresponding aldol
products in the range of moderate to high yields with
moderate syn-selectivity of 10-66%.2 Recently, several
intermolecular direct couplings of enones toward aldehydes
using copper,3 indium,4 and rhodium catalysts5 have been
reported to show synthetic versatility with high syn stereo-
selectivity. Krische et al. reported the coupling reaction
between vinyl ketones and aldehydes under hydrogenation
condition with [Rh(COD)2]OTf/(2-furyl)3P catalyst to attain
high diastereoselectivity up to 99:1 of syn:anti, and extended
the reaction to synthesis of R,ꢀ,γ-stereotriads with optically
active R-amino aldehydes.6-8 In terms of enantioselective
reductive coupling, Krische et al. reported intermolecular
hydrogenative aldol coupling of vinyl ketones catalyzed by
[Rh(COD)2]OTf/phosphonite to find high diastereoselectivity
to 50:1 and enantioselectivity of 96%.9 As for the intra-
(3) (a) Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.; Schafani,
J. A.; Vivian, R. W.; Keith, J. M. Tetrahedron 2000, 56, 2779. For anti
selective: (b) Welle, A.; D´ıez-Gonza´lez, S.; Tinant, B.; Nolan, S. P.; Riant,
O. Org. Lett. 2006, 8, 6059.
(1) (a) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653. (b)
Chiu, P. Synthesis 2004, 2210. (c) Nishiyama, H.; Shiomi, T. Metal
Catalyzed Reductive C-C Bond Formation. In Topics in Current Chemistry;
Krische, M. J., Ed.; Springer-Verlag: Berlin/Heidelberg, Germany, 2007;
Vol. 279, p 105. (d) Iida, H.; Krische, M. J. Metal Catalyzed Reductive
C-C Bond Formation. In Topics in Current Chemistry; Krische, M. J., Ed.;
Springer-Verlag: Berlin/Heidelberg, Germany, 2007; Vol. 279, p 77. (e)
Han, S. B.; Hassan, A.; Krische, M. J. Synthesis 2008, 2669.
(4) (a) Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2004, 43, 711. (b) Miura, K.; Yamada, Y.; Tomita, M.;
Hosomi, A. Synlett 2004, 1985.
(5) (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 15156. (b) Willis, M. C.; Woodward, R. L. J. Am. Chem.
Soc. 2005, 127, 18012.
(6) (a) Jung, C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8,
(2) Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331.
519. (b) Jung, C.-K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051.
10.1021/ol802939u CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society

molecular coupling, Lipshutz succeeded with enantioselective
coupling of enone-ketone substrates with copper-hydride
species combined with chiral bis-phosphines.10 In this trend,
the enantioselective intermolecular reductive coupling is still
an important class of carbon-carbon coupling reactions to
obtain the corresponding aldol products directly from enone
substrates. We have, therefore, challenged the subject using
our catalytic system.
methylsilane, unfortunately, resulted in lower yields, respec-
tively (entries 10 and 11).
Table 1. Enantioselective Reductive Coupling of
Cyclopent-2-enone and 2-Naphthaldehyde with Rh(Phebox-R)
Catalysts and Ph2MeSiHa
So far, we have demonstrated enantioselective reductive
coupling of R,ꢀ-unsaturated esters with aldehydes or ketones
as acceptors catalyzed by chiral rhodium(bisoxazolinyl-
phenyl) complexes, Rh(Phebox), to show high potential for
anti-selectivity and high enantioselectivity.11,12 We have
therefore intended to execute the coupling with enones and
aldehydes catalyzed by Rh(Phebox-R) and hydrosilanes.
yield
(%)
dr
anti:syn
ee (%)
anti/syn
entry
cat.
solvent
THF
THF
THF
THF
THF
C6H5CH3
C6H5CH3
CH3COCH3
CH3CO2C2H5
THF
1
2
3
4
5
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
72
71
83
71
76
79
95
85
77
63
44
93:7
86:14
89:11
88:12
94:6
96:4
93:7
93:7
94:6
93:7
92:8
68/-19
72/25
82/-58
84/-27
86/60
86/65
85/69
87/72
85/67
81/60
84/62
6
We selected cyclopent-2-enone (2) and 2-naphthaldehyde
(3) as coupling partners to give ꢀ-hydroxyketone 4 with
Rh(Phebox) acetates 1a-e and diphenylmethylsilane as a
hydride donor (Table 1, entries 1-5). The mixture of 2 and
3 (1:1 mol ratio) was treated in THF at 50 °C in the presence
of 1 mol % of the catalyst and 1.2 equiv of the hydrosilane.
After hydrolysis, the corresponding ꢀ-hydroxyketone 4 was
obtained in 71-83% yields with high anti-selectivity up to
94%. Use of Rh(Phebox-Ph) 1e resulted in 86% ee (entry
5). In place of THF, toluene was employed to show a slight
increase of diastereoselectivity (entry 6). The excess of
aldehyde 3 apparently enabled an increase in the product
yield (entry 7). Surprisingly, acetone was tolerated as a
solvent to provide a high yield of 85% with similar
diastereoselectivity and 87% ee (entry 8). Ethyl acetate also
could be used as a solvent (entry 9). In place of diphenyl-
methylsilane, use of phenyldimethylsilane and diethoxy-
7b
8
9
10c
11d
THF
a 2 (1.0 mmol), 3 (1.0 mmol), cat. 1 (0.01 mmol), Ph2MeSiH (1.2 mmol),
solvent (1.0 mL). b 3 (1.5 mmol), Ph2MeSiH (1.7 mmol), yield based on 2.
The isolated yield was corrected by 1H NMR, because the product included
naphthalen-2-ylmethanol. c PhMe2SiH (1.2 mmol) was used. d (EtO)2MeSiH
(1.2 mmol) was used.
Next, several aromatic aldehydes 5a-i were subjected to
the reductive coupling with cyclopent-2-enone (2) under the
optimized condition with the catalyst 1e (1.0 mol%) and
Ph2MeSiH (1.7 equiv) similar to entry 7 of Table 1 to give
the aldol products in 49-90% yields (Table 2). 1-Naphthal-
dehyde (5a) gave rise to an increase of ee up to 90% for
anti-diastereomer compared to that of 2-naphthaldehyde (3)
(entry 1). The aldehydes bearing electron-withdrawing groups
kept ee values in the 90-93% range (entries 3-5). It is
noteworthy that the acetyl group survived during the reduc-
tion and the aldol reaction to give 62% yield with 90% ee
for anti. The 4-methoxy group decreased ee to 65% (entry
6), whereas teh 3-methoxy substituent improved the yield
and the stereoselectivities (entry 8). On the other hand,
3-acetylbenzaldehyde resulted in a lower yield (entry 7).
In place of cyclopent-2-enone, several cyclic enones 7, 9,
and 11 (Scheme 1) were subjected to the coupling with
1-naphthaldehyde (5a) selected as an acceptor under the
similar condition to entry 1 of Table 2. 4,4-Dimethylcyclo-
pentenone 7 gave almost complete anti-selectivity with 87%
ee, while 2-cyclohexenone (9) drastically decreased the yield
to 31%. The conjugate reduction of 2-cylcohexenone pre-
dominately proceeded to form cyclopentanone. It was
(7) For other metal-catalyzed reductive coupling reactions of enones see
the following: [Cu and tinhydride]: (a) Ooi, T.; Doda, K.; Sakai, D.;
Maruoka, K. Tetrahedon Lett. 1999, 40, 2133[Pt]: (b) Lee, H.; Jang, M.-
S.; Hong, J.-T.; Jang, H.-Y. Tetrahedron Lett. 2008, 49, 5785[L-Selectride]:
(c) Ghosh, A. K.; Kass, J.; Anderson, D. D.; Xu, X.; Marian, C. Org. Lett.
2008, 10, 4811. [Ru]: (d) Fukuyama, T.; Doi, T.; Minamino, S.; Omura,
S.; Ryu, I. Angew. Chem., Int. Ed. 2007, 46, 5559.
(8) For organo-Lewis base-catalyzed reductive aldol coupling of enones
with trichlorosilane as reducing agent, see: Sugiura, M.; Sato, N.; Kotani,
S.; Nakajima, M. Chem. Commun. 2008, 4309.
(9) Bee, C.; Han, S.-B.; Hassan, A.; Iida, H.; Krische, H.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 2746.
(10) Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J. Am. Chem. Soc. 2008,
130, 14378.
(11) (a) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am.
Chem. Soc. 2005, 127, 6972. (b) Ito, J.; Shiomi, T.; Nishiyama, H. AdV.
Synth. Catal. 2006, 348, 1234. (c) Shiomi, T.; Ito, J.; Yamamoto, Y.;
Nishiyama, H. Eur. J. Org. Chem. 2006, 5594. (d) Shiomi, T.; Nishiyama,
H. Org. Lett. 2007, 9, 1651. (e) Hashimoto, T.; Shiomi, T.; Ito, J.;
Nishiyama, H. Tetrahedron 2007, 63, 12883
(12) For the preparation method for Rh(Phebox) acetates, see: Kanazawa,
Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Ito, J.; Kikuchi, M.;
.
Yamamoto, Y.; Nishiyama, H. Chem. Eur. J. 2006, 12, 63
.
1012
Org. Lett., Vol. 11, No. 4, 2009

Thus, we have demonstrated enantioselective reductive
coupling with several enones and aromatic aldehydes.13 We
observed high anti-selectivity for most of the cases and high
enantioselectivity of anti-products over 90% ee for some
cases. However, the yields drastically chagned depending
on the enones.
Table 2. Enantioselective Reductive Coupling of
Cyclopent-2-enone and Aromatic Aldehydes 5 with
Rh(Phebox-Ph) Catalysts and Ph2MeSiHa
The absolute configuration of the anti-products 6b-anti and
6e-anti was confirmed by comparison with those reported
in the literature.14 Both anti-products were found to have
2S,1′R, and for 6b-syn, 2S,1′S. On the basis of anti-selectivity
and the absolute configuration, a cyclic transition state was
postulated as illustrated in Figure 1. The Re-face of the
enolate carbon atom may attack the Re-face of the aldehyde
carbon atom to form 2S,1′R stereochemistry via cyclic
transition state on the rhodium active site. One of a little
bulky phenyl substituent on the oxazoline rings could
appropriately control enolate formation derived from cyclo-
pent-2-enone to give high stereoselectivities rather than those
with the isopropyl or sec-butyl group of other catalysts.
yield of
6 (%)
dr
ee (%)
entry
aldehyde
anti:syn anti/syn
1
2
3
4
5a 1-NaphCHO
5b C6H5CHO
5c 4-CH3COC6H4CHO
5d 4-CF3C6H4CHO
5e 4-NO2C6H4CHO
4-MeOC6H4CHO
5g 3-CH3COC6H4CHO
5h 3-CH3OC6H4CHO
90
80
62
70
68
72
49
81
68
94:6
95:5
90/85
85/64
90/73
91/84
93/85
65/24
82/78
87/69
68/75
85:15
79:21
70:30
88:12
79:21
93:7
5
6b
7c
8
5f
9
5i
2-CH3OC6H4CHO
94:6
a 2 (1.0 mmol), 5 (1.5 mmol), cat. 1e (0.01 mmol), Ph2MeSiH (1.7
mmol), toluene (1.0 mL). b 2 h. c At 80 °C.
assumed that the intermediate enolate could not smoothly
be captured by the aldehyde. On the other hand, a chro-
menone derivative 11 with excellent anti-selectivity of 94%
gave a moderate yield with 60% and 70% ee. However,
methyl vinyl ketone (13) as a linear enone resulted in a low
yield with 57% ee of anti.
Figure 1. Hypothetical transition state giving anti-stereoselectivity
and 2S,1′R absolute configurtion.
To confirm the coupling reaction mechanism, after the
conjugate reduction of the enone 2 under the condition
Scheme 1. Enantioselective Reductive Coupling of Several
Enones and 1-Naphtaldehyde (5a) with Rh(Phebox-Ph) Catalyst
and Ph2MeSiH
(13) The reaction of cyclopent-2-one with PhCH2CH2CHO as an
acceptor resulted in formation of a trace of the corresponding aldol at 80
°C under the same condition of Table 2.
(14) For 6b: (a) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem.
2000, 65, 9125. For 6e: (b) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128,
734.
(15) Typical procedure: Table 1, entry 7: Rh(Phebox-Ph)(OAc)2(H2O)
(1e) (6.1 mg, 0.01 mmol) was placed in a 10 mL flask. Under an argon
atmosphere, cyclopent-2-enone (2) (82.2 mg, 1.0 mmol), 2-naphtaldehyde
(3) (235 mg, 1.50 mmol), and toluene (1.0 mL) were added. Methyldi-
phenylsilane (337 mg, 1.7 mmol) was slowly added at 50 °C by syringe,
and the mixture was stirred for 1 h. The reaction was monitored by TLC
examination; Rf ca. 0.6 for the silyl ether of the aldol product (eluent: EtOAc/
hexane ) 1:3). To the mixture was added EtOH (1 mL) and aq HCl (1
mL, 4 N) at 0 °C, and the mixture was stirred at room temperature for 2 h;
TLC, Rf ca. 0.6 for the aldol product 4 (eluent: EtOAc/hexane ) 1:1). The
mixture was treated with aq NaHCO3 (ca. 10 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic layer was washed with saturated brine
(5 mL) and then dried over MgSO4. After concentration, the residue was
purified by silica gel column chromatography with EtOAc/hexane as eluent
to give the aldol product 4 in 95% yield (0.95 mmol, 229 mg, corrected by
1H NMR because of contamination of naphthalen-2-ylmethanol) as a white
yellowish oil. 1H NMR: for anti, δ 1.52-1.79 (m, 3H), 1.95 (m, 1H), 2.30
(m, 1H), 2.41-2.64 (m, 2H), 4.69 (s, 1H, OH), 4.88 (d, J ) 9.3 Hz, 1H,
CHOH), 7.45-7.52 (m, 3H), 7.78-7.86 (m, 4H); for syn, δ 5.47 (m, 1H,
CHOH) ppm. 13C NMR δ 20.8, 27.3, 39.0, 55.5, 75.5, 124.2, 125.6, 125.9,
126.1, 127.6 (×2), 128.0, 128.3, 133.1, 138.7, 222.7 ppm. IR (neat) ν 3460
(broad, OsH), 1717 (CdO) cm-1. EI-HRMS [M+] m/z, found 240.1153,
calcd (C16H16O2) 240.1150. Chromatography DAICEL CHIRALCEL OD-
H; eluent hexane/2-propanol (90:10) (1.0 mL/min); retention time 27.8 min
(syn, minor), 33.7 min (syn, major), 44.5 min (anti, minor), 48.3 min (anti,
major).
Org. Lett., Vol. 11, No. 4, 2009
1013

described for entry 7 of Table 1, the aldehyde 3 was added
to the mixture. However, the coupling product 4 was not
formed. Therefore, it is assumed that the intermediate
rhodium enolate directly attacks the enone to form rhodium
aldolate, which releases the coupling product.15
for the Promotion of Science (18350049). T.S. acknowledges
the Research Fellowship of the Japan Society for the
Promotion of Science (DC1).
Supporting Information Available: Examples of the
reactions and spectroscopic data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(Concerto Catalysts, 460:18065011) and the Japan Society
OL802939U
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Org. Lett., Vol. 11, No. 4, 2009