Angewandte
Chemie
Table 2: Enantioselective direct vinylogous aldol reaction of dibromofur-
anone (2b) with 3a catalyzed by (R)-1h.[a]
exhibited a marked influence not only on the enantio- and
diastereoselectivity of the reaction but also on the catalytic
activities (Table 1, entries 1–8). The introduction of a bulky
benzhydryl substituent (1b) onto the guanidine nitrogen
afforded an increase in the catalytic activities and enantiose-
lectivities in comparison with those obtained with the steri-
cally less-hindered methyl-substituted catalyst (1a; Table 1,
entry 1 versus 2). Introduction of the sterically demanding
tert-butyl substituents onto the phenyl rings lowered the
enantioselectivity (Table 1, entry 3). Therefore, we focused
our attention on the modification of benzhydryl substituents
(Table 1, entries 4–8). The electron-withdrawing trifluoro-
methyl-substituted catalyst (1e) exhibited a low catalytic
activity (Table 1, entry 5). In contrast, the enantiomeric
excess was improved when the methyl-substituted catalyst
(1d) was used (Table 1, entry 4). When the benzhydryl moiety
was further modified by the introduction of electron-donating
methoxy substituents, the enantiomeric excess of syn-4aa was
found to increase in accordance with the number of methoxy
groups introduced (Table 1, entries 6–8). Although the pre-
cise mechanism for this marked dependence of diastereo- and
enantioselectivities on the G substituent is not yet clear,
trimethoxy-substituted catalyst (1h) exhibited the best per-
formance with respect to catalytic activity and enantioselec-
tivity, albeit with moderate diastereoselectivity (Table 1,
entry 8). As expected, the enantiomeric excess and diaste-
reomeric ratio were improved by lowering the reaction
temperature to À408C (Table 1, entry 9).
Entry
Solvent
Yield[b]
[%]
d.r.[c]
(syn/anti)
ee [%][d]
syn
anti
1
2
3
4
5
6
7
8
THF
82
59
30
17
13
52
65
77
85:15
83:17
81:19
82:18
88:12
92:8
99
99
97
97
99
99
99
98
78
90
62
66
76
89
84
84
DME[e]
tBuOMe
CPME[f]
EtOAc
Acetone
acetone/THF (4:1)
acetone/THF (1:1)
90:10
90:10
[a] All reactions were carried out using 0.005 mmol of (R)-1h (5 mol%),
0.10 mmol of 2b, and 0.12 mmol of 3a (1.2 equiv) in 0.5 mL of solvent at
À408C for 5 h unless otherwise noted. [b] Yield of isolated product.
[c] Determined by 1H NMR analysis. [d] Determined by HPLC analysis on
a chiral stationary phase (for details, see the Supporting Information).
[e] 1,2-Dimethoxyethane. [f] Cyclopentyl methyl ether.
Table 3: Enantioselective direct vinylogous aldol reaction of 2b with
various aldehydes (3) catalyzed by (R)-1h.[a]
Entry
3, R
4
Yield[b]
[%]
d.r.[c]
(syn/anti)
ee [%][d]
syn
anti
1[e]
2
3b, 2-MeC6H4
3c, 2-BrC6H4
3d, 4-MeC6H4
3e, 4-MeOC6H4
3 f, 4-BrC6H4
3g, 1-naphthyl
3h, 2-furyl
4bb
4bc
4bd
4be
4bf
82
91
95
58
87
74
79
91:9
97
96
99
97
96
96
97
60
58
80
80
79
74
88
Although syn-4aa was obtained in almost optically pure
form (Table 1, entry 9), the diastereoselectivity remained
moderate. Therefore, we turned our attention to the dibro-
minated analogue of 2a, 3,4-dibromofuran-2(5H)-one (2b).[8]
To our delight, the diastereoselectivity was slightly improved
(Table 2, entry 1), presumably owing to the additional steric
demands of the bromine substituents. We further explored
different solvents to increase the diastereoselectivities whilst
maintaining a high level of enantioselectivity. However, other
ethereal solvents such as acyclic ethers and DME (dimethoxy-
ethane) compromised the diastereoselectivity and signifi-
cantly retarded the reaction (Table 2, entries 2–4). Interest-
ingly, the use of oxygenated organic solvents that have a
carbonyl functionality, namely ethyl acetate and acetone,
enhanced the diastereoselectivity, albeit at the expense of
product yield (Table 2, entries 5 and 6). Of the solvents tested,
acetone exhibited the highest diastereoselectivity whilst
equally high enantioselectivity was also achieved. Therefore,
we considered a mixed-solvent system composed of acetone
and THF to improve the conversion to the aldol product
(4ba) whilst retaining high stereoselectivities (Table 2,
entries 7 and 8). As expected, under the acetone/THF
mixed-solvent system, the chemical yield of 4ba could be
improved with higher diastereoselectivity than that obtained
using only THF as the solvent (Table 2, entry 8 versus 1).
With a promising catalyst and optimal reaction conditions
in hand, we next investigated the substrate scope of the
reaction using dibromofuranone 2b (Table 3).[11] Guanidine
1h functions as an efficient catalyst, and the corresponding
products (4) were obtained in good yield with the exception of
the products arising from aldehydes that had an electron-
88:12
86:14
87:13
87:13
94:6
3[e,f]
4[e,f]
5
6
7
4bg
4bh
85:15
[a] All reactions were carried out using 0.01 mmol of (R)-1h (5 mol%),
0.20 mmol of 2b, and 0.24 mmol of 3 (1.2 equiv) in 1.0 mL of 1:1 mixture
of acetone and THF at À408C for 5 h unless otherwise noted. [b] Yield of
isolated product. [c] Determined by 1H NMR analysis. [d] Determined by
chiral stationary phases HPLC analysis (for details, see the Supporting
Information). [e] THF was employed as the only solvent. [f] 0.02 mmol of
(R)-1h (10 mol%) for 12 h.
donating methyl or methoxy substituent (3b,d,e). The low
reactivity of 3d and 3e was circumvented by increasing the
catalyst loading, prolonging the reaction time, and using THF
as the solvent (Table 3, entries 3 and 4). In the reaction of
substituted benzaldehydes, excellent enantioselectivities and
high diastereoselectivities were observed for the major syn
isomers, irrespective of the electronic properties and the steric
demand of the aromatic rings (Table 3, entries 1–6). The
heteroaromatic, 2-furyl, aldehyde was also a good reaction
partner, affording the product in relatively high diastereose-
lectivity with excellent enantioselectivity for the major syn
isomer (Table 3, entry 7).
Next, we investigated the reaction of an a-monobromi-
nated furanone, 3-bromofuran-2(5H)-one (2c),[12] using cata-
lyst 1h [Eq. (2)].[13] The reaction of 2c provided syn-4ca as the
major product in equally high enantioselectivity. However,
b,g-unsaturated product 4ca’[8] was also obtained as a single
Angew. Chem. Int. Ed. 2010, 49, 1858 –1861
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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