A highly chemoselective Mukaiyama aldol reaction of saturated aldehyde over unsaturated aldehyde with enol tris(2,6-diphenylbenzyl)silyl ether

Article abstract of DOI:10.1016/S0040-4039(02)00036-9

An exceedingly high chemoselective Mukaiyama aldol reaction of saturated aldehydes in the presence of unsaturated aldehydes (benzaldehyde and α,β-enals) has been realized for the first time by using the structurally unique enol tris(2,6-diphenylbenzyl)sil

Full text of DOI:10.1016/S0040-4039(02)00036-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1469–1472
A highly chemoselective Mukaiyama aldol reaction of saturated
aldehyde over unsaturated aldehyde with enol
tris(2,6-diphenylbenzyl)silyl ether
Seiji Shirakawa and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Received 2 November 2001; revised 17 December 2001; accepted 21 December 2001
Abstract—An exceedingly high chemoselective Mukaiyama aldol reaction of saturated aldehydes in the presence of unsaturated
aldehydes (benzaldehyde and a,b-enals) has been realized for the first time by using the structurally unique enol tris(2,6-diphenyl-
benzyl)silyl ether under the influence of BF3·OEt2 as a Lewis acid. Among unsaturated aldehydes, benzaldehyde is found to be
more reactive than a,b-enals. The structural uniqueness of the enol tris(2,6-diphenylbenzyl)silyl ether can be visualized by X-ray
1
crystallography as well as H and 13C NMR spectroscopy. © 2002 Elsevier Science Ltd. All rights reserved.
Bu3SnClO4 or
Bu2Sn(OTf)2
Due to powerful yet highly selective carbonꢀcarbon
bond formations, the Mukaiyama aldol reaction has
Un-R2
X
found numerous applications in selective organic syn-
thesis,1 and a number of related modifications have
been elaborated for this purpose. Among these, the
chemoselective functionalization between two different
carbonyl acceptors is a synthetically useful operation
and is closely related to the chemistry of molecular
recognition. Recently, the chemoselective aldol reaction
of a,b-enals with ketene silyl acetals has been achieved
under the influence of organotin Lewis acids in compe-
tition with saturated aldehydes.2 Surprisingly, however,
despite several other reports on the preferential attack
of certain nucleophiles to a,b-unsaturated carbonyl
substrates over the corresponding saturated car-
bonyls,3,4 the reverse selectivity, i.e. the chemoselective
aldol reaction of saturated aldehydes (R1-CHO) in the
presence of unsaturated aldehydes (Un-R2-CHO), has
never been developed to a useful level due to the lack of
appropriate reagents (Scheme 1). Indeed, attempted
Lewis acid-promoted aldol reaction between saturated
and unsaturated aldehydes with a series of enol silyl
ethers resulted in a total lack of chemoselectivity, as
shown in Scheme 2. During the course of our recent
investigations on the chemistry of the functionalized,
bowl-shaped tris(2,6-diphenylbenzyl)metal moiety,5–8
[ref 2]
OH
2
O
X
C
OSiR3
R1-CHO
Un-R2-CHO
H2C
+
R1
X
OH
O
?
3
Scheme 1.
we studied the chemoselective Mukaiyama aldol reac-
tion with the structurally unique enol tris(2,6-diphenyl-
benzyl)silyl ether 1a (hereafter, enol TDS ether;
TDS=tris(2,6-diphenylbenzyl)silyl). Here we wish to
report the hitherto unknown, unusual discriminative
ability of enol TDS ether 1a in the Mukaiyama aldol
reaction between saturated and unsaturated aldehydes
under the influence of BF3·OEt2 as a Lewis acid, giving
an aldol product 3 almost exclusively over aldol 2
(Schemes 1 and 2).
The ordinary Lewis acid-promoted aldol reaction
between heptanal and trans-2-heptenal (1.1 equiv. each)
with
enol
trimethylsilyl
ether
of
acetone
(CH2ꢁC(Me)OSiMe3) in the presence of BF3·OEt2 (2.2
equiv.) gave rise to a mixture of two different aldols 4
and 5 in a ratio of 1:1.6. Switching the silyl moiety of
Keywords: chemoselectivity; Mukaiyama aldol reaction; aldehyde;
silicon.
* Corresponding author. Tel./fax: +00 81 75 753 4041; e-mail:
maruoka@kuchem.kyoto-u.ac.jp
CH2ꢁC(Me)OSiR3
from
trimethylsilyl
to
t-
butyldimethylsilyl (t-BuMe2Si) and triisopropylsilyl (i-
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00036-9

1470
S. Shirakawa, K. Maruoka / Tetrahedron Letters 43 (2002) 1469–1472
Scheme 2.
Pr3Si) resulted in a slight increase in chemoselectivity
[4/5=2.7:1 and 3.2:1, respectively]. In marked contrast,
however, the corresponding enol TDS ether 1a showed
virtually complete discriminative ability (4/5=>99:<1),
leaving unsaturated aldehyde intact. Such a discrimina-
tion pattern is totally opposite to those in chemoselec-
tivity reported previously [4/5=1:23 with catalytic
Bu2Sn(OTf)2 and 1b].2,3 Other examples including vari-
ous combinations of saturated and unsaturated alde-
hydes are listed in Table 1. Several characteristic
features of the present chemoselective aldol reaction
follow. (1) In general, unsaturated aldehydes such as
benzaldehyde and a,b-enals are highly reluctant toward
the Lewis acid-promoted aldol reaction with enol TDS
ether 1a in the presence of saturated aldehyde under
ordinary aldol conditions. Such unreactivity can be
observed even in combination with sterically more hin-
dered aldehyde (entry 7 versus 6 and 17 versus 16). (2)
In contrast, enol TDS ether 1a showed none of the
chemoselectivity in the combination of the two satu-
rated aldehydes (entries 8 and 9 versus 6 and 7). (3)
Among unsaturated aldehydes, benzaldehyde is found
to be more reactive than a,b-enal (entry 21). (4) Dis-
crimination between saturated and even homoconju-
gated a-phenylated aldehyde appears feasible (entries
22 and 23). (5) The amount of BF3·OEt2 as a Lewis
Table 1. Chemoselective aldol reaction between two different aldehydes with enol silyl ethersa
Entry
Enol silyl ether
Two different aldehydes
% Yieldb (ratio)c
1
2
3
4
5
6
7
8
1b
1c
1d
1a
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
Hexyl-CHO+Bu-CHꢁCHCHO
89 (1:1.6)
22 (2.7:1)
43 (3.2:1)
73 (\99:B1)d
81 (71:1)d,e
96 (1.2:1)
79 (\99:B1)d
79 (1:1.2)
57 (1:1.5)
80 (1:1.4)
75 (45:1)d
69 (1:1.8)
63 (40:1)d
83 (1:2.5)
85 (23:1)
c-Hexyl-CHO+Bu-CHꢁCHCHO
c-Hexyl-CHO+Hexyl-CHO
Hexyl-CHO+PhCHO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph(CH2)2CHO+PhCHO
c-Hexyl-CHO+PhCHO
Ph2CHCHO+PhCHꢁCHCHO
Ph(CH2)2CHO+PhCHꢁCHCHO
PhCHO+PhCHꢁCHCHO
Ph(CH2)2CHO+PhCH(Me)CHO
61 (1:1)
63 (\99:B1)d
82 (4.1:1)
84 (\99:B1)d
90 (5.4:1)
75 (34:1)d
82 (2.4:1)
64 (21:1)
a Unless otherwise specified, the aldol reaction was carried out with enol silyl ether 1 (1 equiv.) and two different aldehydes (1.1 equiv. each)
(R1-CHO and Un-R2-CHO) in the presence of BF3·OEt2 (2.2 equiv.) in CH2Cl2 at −78°C for 0.5–1.5 h.
b Isolated yield of 3 (X=Me) and 2 (X=Me).
c The ratio of two aldol products 3 (X=Me) and 2 (X=Me) was determined by 1H NMR analysis.
d Determined by capillary GLC analysis after conversion to diols by treatment of two aldol products with MeLi (3 equiv.) in THF.
e Use of catalytic BF3·OEt2 (30 mol%).

S. Shirakawa, K. Maruoka / Tetrahedron Letters 43 (2002) 1469–1472
1471
acid can be reduced to catalytic (ꢀ30 mol%) without
affecting the chemoselectivity (entry 5). (6) A similar
tendency was also observed with other Lewis acids such
as TiCl4, SnCl4, and Me2AlCl.9
The structural uniqueness of the enol TDS ether 1a can
be visualized by X-ray crystallography as well as NMR
spectroscopy. As shown in Fig. 1, the X-ray structure
of 1a indicated a well-oriented p,p interaction between
one nearby phenyl and the isopropenyl group;10 this is
also supported by the upfield shift of isopropenyloxy
A similar high chemoselectivity was also observable in
the aldol reaction between heptanal and trans-2-hepte-
nal (1.1 equiv. each) with enol TDS ether of 2-butanone
in the presence of BF3·OEt2 (2.2 equiv.).
1
moiety by H and 13C NMR spectral study of the enol
TDS ether 1a in CDCl3, where the upfield shift of
isopropenyl protons in 1a compared to other silyl ana-
Ph
Si(CH2
Ph
H2C
)
3
C O
H3CH2C
CHO
OH
O
+
+
BF3•OEt2
CH2Cl2
CHO
OH
42% yield (>99:<1)
O
–78 °C, 1 h
CHO
CHO
CH2=C(Me)OSiR3, 1
CH2Cl2, –78 °C
OMe
+
NC
MeO
OH
O
O
OH
O
O
O
+
+
7'
7
6
NC
MeO
MeO
enol silyl ether Lewis acid (equiv)
yield
63%
45%
84%
ratio of 6:(7+7') [7:7']
BF3•OEt2 (2.2)
BF3•OEt2 (2.2)
1 : 1 ( 1.7:1 )
1b
1a
1b
>99 : <1
Bu2Sn(OTf)2 (0.3)
<1 : >99 ( 1:1.5 )
Another interesting feature includes the chemoselective
aldol reaction of p-substituted benzaldehydes on the
electronic effect of p-substituents of these benzalde-
hydes. While catalytic Bu2Sn(OTf)2 (30 mol%) gives
p-anisaldehyde-derived aldol 7 and its dimerization
product 7% preferentially, our silylating agent 1a reacted
reluctantly to furnish p-cyanobenzaldehyde-derived
aldol 6 exclusively.
logues such as trimethylsilyl, t-butyldimethylsilyl, and
triisopropylsilyl derivatives was clearly observed.
Although the origin of the observed chemoselectivity
using the enol TDS ether 1a is unclear at present, the
electronic stabilization of the isopropenyloxy moiety
with one nearby phenyl group of tris(2,6-diphenylben-
zyl)silyl group via the p,p interaction (Fig. 1) seems to
be essential to achieve the high discriminative ability in
the Mukaiyama aldol reaction. Further clarification of
such unusual chemoselectivity using 1a is currently
underway, and will be reported in due course.
a
H2C
C O SiR3
b
H3C
1
c
1H & 13C NMR Data
1a
H(a)
H(c)
δ 0.92
δ 1.78
δ 1.76
C(a)
δ 90.17 δ 152.38 δ 22.66
δ 22.84
δ 91.16 δ 155.83
C(b)
C(c)
δ 2.34, 2.58
δ 4.05, 4.06
δ 4.03
1b (R = Me)
1c (R3 = ButMe2)
1d (R = Pri)
δ 156.12 δ 22.78
δ 156.26 δ 22.82
δ 91.20
δ 90.45
δ 4.01, 4.05
δ 1.81
Acknowledgements
Figure 1. ORTEP diagram of the enol tris(2,6-diphenylben-
zyl)silyl ether 1a.
This work was supported by a Grant-in-Aid for Scien-
tific Research (No. 13853003) from the Ministry of

1472
S. Shirakawa, K. Maruoka / Tetrahedron Letters 43 (2002) 1469–1472
Education, Culture, Sports, Science and Technology,
Japan.
Chem., Int. Ed. Engl. 1997, 36, 2223; (d) Goto, K.; Holler,
M.; Okazaki, R. J. Am. Chem. Soc. 1997, 119, 1460.
7. Molecule capsules: (a) Meissner, R. S.; Rebek, J., Jr.;
Mendoza, J. Science 1995, 270, 1485; (b) Kang, J.; Rebek,
J., Jr. Nature 1997, 385, 50; (c) Kang, J.; Hilmersson, G.;
Santamaria, J.; Rebek, J., Jr. J. Am. Chem. Soc. 1998, 120,
3650; (d) Kang, J.; Santamaria, J.; Hilmersson, G.; Rebek,
J., Jr. J. Am. Chem. Soc. 1998, 120, 7389.
8. Concave reagents: (a) Luning, U.; Muller, M.; Gelbert, M.;
Peters, K.; von Schnering, H. G.; Keller, M. Chem. Ber.
1994, 127, 2297; (b) Hagen, M.; Luning, U. Chem. Ber./
Recueil 1997, 130, 231; (c) Ross, H.; Luning, U. Tetra-
hedron Lett. 1997, 38, 4539; (d) Lofflwe, F.; Hagen, M.;
Luning, U. Synlett 1999, 1826.
9. Attempted aldol reaction of a 1:1 mixture of heptanal and
benzaldehyde with 1a or 1b in the presence of TiCl4, SnCl4
or Me2AlCl gave the following results: 52% (1.1:1) with
1b/TiCl4; 41% (19:1) with 1a/TiCl4; 48% (1:1.1) with
1b/SnCl4; 64% (>99:<1) with 1a/SnCl4; 47% (4.5:1) with
1b/Me2AlCl; 47% (>99:<1) with 1a/Me2AlCl. (i-
PrO)2TiCl2 was found to be unreactive for effecting the
chemoselective aldol reaction with 1a.
References
1. Reviews of aldol reactions: (a) Mukaiyama, T. Org. React.
1982, 28, 203; (b) Carreira, E. M. Comprehensive Asymmet-
ric Catalysis; Springer-Verlag: Berlin, 1999; Vol. 3, p. 997.
2. Chen, J.; Otera, J. Synlett 1997, 29.
3. (a) Hanyuda, K.; Hirai, K.; Nakai, T. Synlett 1997, 31; (b)
Marko, I. E.; Leung, C. W. J. Am. Chem. Soc. 1994, 116,
371; (c) Mori, A.; Ohno, H.; Inoue, S. Chem. Lett. 1992,
631; (d) Mikami, K.; Terada, M.; Nakai, T. J. Org. Chem.
1991, 56, 5456; (e) Reetz, M. T. Organotitanium Reagents
in Organic Synthesis; Springer-Verlag: Berlin, 1986; Chap-
ter 3.
4. Chemoselective aldol reaction of less hindered saturated
aldehydes: (a) Maruoka, K.; Saito, S.; Yamamoto, H.
Synlett 1994, 439; (b) Marx, A.; Yamamoto, H. Angew.
Chem., Int. Ed. 2000, 39, 178.
5. Chemistry of bowl-shaped tris(2,6-diphenylbenzyl)metal
moiety: (a) Iwasaki, A.; Kondo, Y.; Maruoka, K. J. Am.
Chem. Soc. 2000, 122, 10238; (b) Sasaki, K.; Kondo, Y.;
Maruoka, K. Angew. Chem., Int. Ed. 2001, 40, 411.
6. Reaction bowls: (a) Goto, K.; Tokitoh, N.; Okazaki, R.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1124; (b) Sasaki, T.;
Goto, K.; Tokitoh, N.; Okazaki, R. J. Org. Chem. 1996,
61, 2924; (c) Sasaki, T.; Goto, K.; Okazaki, R. Angew.
10. The single-crystal of enol TDS ether 1a was obtained by
recrystallization from benzene/hexane solvents. Crystal
structure data for 1a: C60H50OSi·C6H6, Mw=893.25, tri-
clinic, space group P-1, a=13.0354, b=13.9145, c=
3
31.9467 A, V=5101.9 A , Z=4, Dcalcd=1.163 g cm−1
R1=0.055.
,
,
,