acid (3) or that of its derivatives to R,β-unsaturated
ketones,6,7 which have recently been under active inves-
tigation,8 are extremely promising. However, there has
been only one report of asymmetric catalysis for the addi-
tion of the aryl group into 2,9,10 and the catalysis using 5%
Rh/chiral bis-sulfoxide required the use of Ar4BNa instead
of 3 and a long reaction time of 24 h to give a moderate
yield of 1. One of the reasons for this insufficient result is
due to the less reactive substrate of 2 in the Rh-catalyzed
catalysis. Recently, we reported a high-performance Rh
catalyst bearing (6,60-dimethoxybiphenyl-2,20-diyl)bis[bis-
(3,4,5-trifluorophenyl)phosphine] (MeO-F12-BIPHEP,
4) for the asymmetric 1,4-addition of 3.11 The reaction
of 3 with an R,β-unsaturated ketone in the presence
of Rh/(R)-4 showed a high turnover frequency of up to
53000 h-1 in the model reaction11b or gave optically pure
4-phenylchroman-2-one in high yield.11c In particular, in
the latter case, the fact that the Rh/(R)-4 catalyst was
highly effective for the less reactive coumarin substrate,
which is a structural isomer of 2, raised our hopes for the
success of the reaction of 2. Therefore, we attempted the
efficient synthesis of chiral flavanones by using the Rh/4
catalyst.
Typically, the Rh-catalyzed asymmetric 1,4-additions
have been performed using Rh-Cl species as precatalysts,
which are converted to Rh-OH species as an active species
by treatment with base such as KOH in situ.12 However,
flavanone 1 undergoes ring-opening under strongly basic
conditions.13 Therefore, we used a [RhOH(cod)]2 complex
as a catalyst precursor to avoid basic conditions. Although
the use of [RhOH(cod)]2 with chiral ligands for the asym-
metric 1,4-addition often decreases the enantioselectivity
of the products because of the high catalytic activity
of [RhOH(cod)]2 itself,14 the reaction of 2a with 2 equiv
of phenylboronic acid (3a) in the presence of 1.5%
[RhOH(cod)]2 complex (3% Rh) in toluene/H2O at 20 °C
for 1 h gave no product (see Table 1, entry 1).15 The
addition of 1 equiv of (S)-4 for Rh largely accelerated the
catalysis to yield 60% of (S)-flavanone (1aa) with 99% ee
(entry 2). In this case, no remaining 3a was observed at the
end of the reaction. When 3.5 equiv of 3a was used, a 95%
yield of (S)-1aa was obtained (entry 3). The catalyst
loading could be decreased to 0.5% Rh to yield 93% of
(S)-1aa with 99% ee within just 1 h (entry 4). The effec-
tiveness of the ligand (S)-4 was obvious because the
reaction using 3% Rh/(S)-MeO-F28-BIPHEP11a or Rh/
(S)-BINAP gave no product under the same conditions
(entry 5 or 6).
Table 1. Asymmetric 1,4-Addition of 3a to 2a
entry
L*
Rh (%) 3a (equiv) 1aaa (%) eeb (%)
1
2
3
4
5
6
none
(S)-4
(S)-4
(S)-4
3
2.0
2.0
3.5
3.5
2.0
2.0
0
60
95
93
0
3
99
99
99
3
0.5
3
(S)-MeO-F28-BIPHEP
(S)-BINAP
3
0
a Isolated yield. b The enantiomeric excess was determined by chiral
HPLC analyses (see the Supporting Information).
In the case of the reaction using Rh/(S)-4(entries 3 and 4),
3% of the byproduct 2,4-diphenyl-4-chromanol (5aaa),16
which was the 1,2- and 1,4-adduct,17 was obtained as a
single diastereomer. Because no 5aaa was observed in the
reaction at a 60% conversion (entry 2), the 1,2-addition of
the phenyl group proceeded after 1,4-addition. Each phe-
nyl group of 5aaa was the anti relationship, which was
determined by NOE (NOESY) experiment and DFT
calculations (see the Supporting Information). Because
the stereochemistry of the byproduct 5aaa was identical
to that of the product of the 1,2-addition of 3a to (S)-1aa in
the presence of 3% Rh/(R)-4 (eq 1), the absolute config-
uration of the product was (2S,4R).
(9) Chen, J.; Chen, J.-M.; Lang, F.; Zhang, X.-Y.; Cun, L.-F.; Zhu,
J.; Deng, J.-G.; Liao, J. J. Am. Chem. Soc. 2010, 132, 4552.
(10) Hoveyda reported Cu-catalyzed asymmetric addition of an alkyl
group to 2: Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2005, 44, 5306.
(11) (a) Korenaga, T.; Osaki, K.; Maenishi, R.; Sakai, T. Org. Lett.
2009, 11, 2325. (b) Korenaga, T.; Maenishi, R.; Hayashi, K.; Sakai, T.
Adv. Synth. Catal. 2010, 352, 3247. (c) Korenaga, T.; Maenishi, R.;
Osaki, K.; Sakai, T. Heterocycles 2010, 80, 157.
(12) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
Next, we applied 4-tolylboronic acid (3b) to the asym-
metric 1,4-addition of 2a (Table 2). In this case, the
formation of the byproduct 5abb severely disturbed the
synthesis of (S)-1ab. The reaction of 2a with 3.5 equiv of 3b
in the presence of 0.5% [RhOH(cod)]2 complex (1% Rh)
(13) Cisak, A.; Mielczarek, C. J. Chem. Soc., Perkin Trans. 2 1992,
1603.
(14) Lukin, K.; Zhang, Q.; Leanna, M. R. J. Org. Chem. 2009, 74,
929.
(15) When the catalysis was perfomed at 50 °C for 6 h, (()-1aa was
obtained in 7% yield.
(16) The absolute configuration had been unclear in the past report:
Elkaschef, M. A. F.; Nosseir, M. H.; Mohamed, H.-E.-D. M. J. Chem.
Soc. 1965, 494.
(17) (a) Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.;
Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363. (b) Iuliano,
A.; Facchetti, S.; Funaioli, T. Chem. Commun 2009, 457.
Org. Lett., Vol. 13, No. 8, 2011
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