Asymmetric Retro- and Transfer-Aldol Reactions
COMMUNICATION
erally difficult to make by the asymmetric aldol reaction,
were indeed quite good substrates for retro-aldol reactions.
In all these cases, the resolution reactions proceeded
smoothly affording the optically pure aldol adducts in excel-
lent ee (95–99% ee) with 40–48% yield (Table 1, entries 1–
5). The reactions worked well with racemic aldol adducts
derived from less electron-donating aromatic aldehydes,
such as p-tert-butylbenzaldehye and trans-cinnamaldehyde,
with s factors over 20 (Table 1, entries 6 and 7). In all these
cases, good anti diastereoselectivities were maintained for
the isolated products. Notably, the resolution could be
equally applied to syn-aldol products derived from electron-
donating aldehydes, such as 2i, and in this case the optically
pure product was recovered in 33% yield, 99:1 syn/anti and
98% ee (Table 1, entry 8). The aldol product derived from
acetone was also applicable in the current protocol with an
s factor of 24 (Table 1, entry 9).
As expected, the retro reaction of aldol products, either
anti or syn adducts, derived from activated aromatic alde-
hydes showed very sluggish reaction rates, but high s factors
were still maintained in these cases (Table 1, entries 10 and
11). The generally high s factors in these resolutions suggest
that high enantioselectivity would be achieved if the equilib-
rium could be displaced in favor of the retro-aldol reactions.
Bearing in mind that the same primary amine catalyst could
promote both the aldol and retro-aldol reactions, it is thus
conceived that the consumption of the in situ generated al-
dehyde by an aldol reaction catalyzed by the same catalyst
(e.g., 1b/TfOH, Scheme 3) would drive the equilibrium of
the retro-aldol reaction to achieve optimal resolution
(Scheme 3). The net outcome would be a transfer-aldol pro-
cess between a racemic aldol product and an active aldol
donor (e.g., acetone, Scheme 3). In principle, such a trans-
fer-aldol reaction would lead to two aldol products A and B
with opposite chiral induction by taking advantage of both
the retro-aldol and aldol catalytic properties of 1b/TfOH.
Our subsequent experiments proved that the hypothetical
transfer-aldol reaction was indeed possible in the presence
of an excess of active aldol donors, such as acetone. When
conducted in neat acetone, the resolution reaction of race-
mic 2a in the presence of 1b/TfOH (20 mol%) proceeded
smoothly and the expected two enantioenriched aldol ad-
ducts were isolated in approximately theoretical yield with
good enantioselectivity (98 and 78% ee for 2a and 3b, re-
spectively, Table 2, entry 1). To the best of our knowledge,
this represents the first asymmetric transfer-aldol reaction
that generates two optically pure aldol adducts with oppo-
site configurations.[10]
Table 2. Asymmetric transfer-aldol reaction.[a]
A
B
Entry
R
Yield
[%][b]
anti/syn[b]
ee
Yield
[%][b]
ee
[%][c]
[%][c]
1
2
3
4
4-NO2
2-NO2
H
2a/50
2k/48
2l/50
98:2
98:2
97:3
98:2
99:1
98:2
98:2
98:2
98:2
98:2
89:11
98
98
97
99
98
98
98
98
91
98
94
3b/50
3c/50
3d/36
3e/24
3e/11
3 f/42
3g/49
3h/47
3i/30
3j/40
3b/50
78
83
84
90
80
86
80
70
84
81
11
2b/48
2b/46
2m/40
2n/44
2o/45
2p/45
2q/42
2j/46
4-MeO
5[d]
6
2-Cl
4-Cl
2,4-Cl2
4-Ph
1-naphthyl
4-NO2
7
8
9
10
11[e]
[a] Unless otherwise specified, all reactions were carried out with racemic
anti-aldol products at 0.25m in acetone with catalyst (20 mol%) at 258C
for 36 h. [b] Yield of the isolated product based on the racemic substrate.
[c] Determined by HPLC on a chiral phase. [d] 4.25 mmol scale (0.5m) in
the presence of catalyst (10 mol%). [e] The reaction was carried out with
the syn-aldol adduct at 508C, the starting syn/anti ratio was 99:1.
The scope of the asymmetric transfer-aldol reaction was
explored next. As shown in Table 2, racemic aldol adducts
derived from either electron-withdrawing or electron-donat-
ing aromatic aldehydes can be applied in the present trans-
fer-aldol protocol. The reactions normally reached equilibri-
um in 36 h, affording two enantioenriched aldol adducts in
high (recovery) yields with good to excellent enantioselec-
tivities (Table 2, entries 1–10). Importantly, the transfer-
aldol reaction also enabled the kinetic resolution of syn-
aldol adducts of cyclic ketones, such as rac-2j (Table 2,
entry 11). The desired enantioenriched syn-aldol product
(S,S)-2j was isolated in 46% yield and 94% ee. High tem-
perature was applied in this case to facilitate the reaction
with, unfortunately, a sacrifice of the enantioselectivity of
the aldol adduct 3b (11% ee, Table 2, entry 11). A decrease
of the syn diastereoselectivity from 99:1 to 89:11 was ob-
served in this case. A large scale (4.25 mmol) transfer reac-
tion has also been examined in the presence of 1b/TfOH
(10 mol%) (Table 2, entry 5), which gave consistently excel-
lent resolution, illustrating the synthetic applicability of this
reaction.
Based on the microscopic principle, an enamine catalytic
cycle and the same transition state (TS-II and TS-III for anti
and syn products, respectively) as that in the aldol reaction
may be proposed for the retro, as well as for the transfer-
Scheme 3. Primary amine catalyzed transfer-aldol reaction.
Chem. Eur. J. 2010, 16, 4457 – 4461
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4459