Catalytic asymmetric hydroxymethylation of silicon enolates using an aqueous solution of formaldehyde with a chiral scandium complex

Article abstract of DOI:10.1021/ja047896i

Catalytic asymmetric hydroxymethylation of silicon enolates has been achieved. In this reaction, an aqueous solution of formaldehyde can be used to realize an easy and safe procedure, and high enantioselectivities have been obtained. This is the first exa

Full text of DOI:10.1021/ja047896i

Published on Web 09/11/2004
Catalytic Asymmetric Hydroxymethylation of Silicon Enolates Using an
Aqueous Solution of Formaldehyde with a Chiral Scandium Complex
Shunpei Ishikawa, Tomoaki Hamada, Kei Manabe, and Sh uj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku Tokyo 113-0033, Japan
Received April 12, 2004; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 1. Optimization of Reaction Conditionsa
Formaldehyde is one of the most important C1 electrophiles in
organic synthesis. Although hydroxymethylation of enolates with
formaldehyde provides an efficient method to introduce a C1
functional group at the R-position of carbonyl groups, there have
been few successful examples of catalytic asymmetric hydroxym-
ethylation that satisfy synthetic utility in terms of both yield and
1
selectivity for a wide range of substrates. To achieve such reactions,
2
Lewis acid-catalyzed hydroxymethylation of silicon enolates is
promising. The reactions proceed regioselectively, and excellent
3
substrate generality and synthetic efficiency can be expected. As
yieldb (%)
eec (%)
entry
solvent
X
Y
time (h)
for the source of formaldehyde, use of a commercial aqueous
solution of formaldehyde is the most convenient, because tedious
and harmful procedures to generate formaldehyde monomer from
formaldehyde oligomers such as paraformaldehyde and trioxane
1
2
3
4
5
6
7
8
9
H2O/EtOH ) 1/9
20 24
20 24
20 24
20 24
20 24
20 24
1.5
1
2
11
2
6
15
15
67
21
24
24
32
14
35
53
78
81
86
87
5
87
81
62
80
73
83
84
80
66
90
90
86
H2O/MeOH ) 1/9
H O/PrOH ) 1/9
2
i
H2O/ PrOH ) 1/9
H2O/THF ) 1/9
H2O/DME ) 1/9
4
can be avoided. Although we have previously reported the use of
an aqueous solution of formaldehyde for hydroxymethylation of
H2O/1,4-dioxane ) 1/9 20 24
5
silicon enolates, it is still difficult to realize catalytic asymmetric
H O/CH CN ) 1/9
20 24
20 24
20 24
10 12
2
3
versions of this reaction. Quite recently, the catalytic asymmetric
hydroxymethylation of silicon enolates in aqueous solvents was
H2O
1
1
1
0
1
2
H2O/DME ) 1/9
H2O/DME ) 1/9
H2O/DME ) 1/9
82
80
67
6
7
first achieved by our group and Yamamoto et al. However, in
both cases, the enantioselectivities were moderate, and there still
remained several issues to be resolved. To achieve a higher level
of yields and selectivity in this reaction, development of a new
catalytic system is required. We report here that a novel chiral
scandium complex has realized highly enantioselective, catalytic
hydroxymethylation of silicon enolates with a formaldehyde aque-
ous solution.
5
6
a
Reaction was performed at 0 °C (entries 1-9) or -20 °C (entries 10-
1
(
2). The amounts of formaldehyde were 10 equiv (entries 1-10) or 5 equiv
entries 11 and 12). The reaction was performed in 0.18 M (entries 1-10)
b
or 0.36 M (entries 11 and 12) concentrations. Isolated yield after silica gel
c
chromatography. Ee was determined by chiral HPLC analysis.
First, we screened various chiral ligands in scandium triflate (Sc-
(
OTf)
mercial aqueous solution (35%) of formaldehyde, because Sc(OTf)
is one of the strongest Lewis acids that can be used for aldol
3
)-catalyzed asymmetric hydroxymethylation using a com-
3
8
9
reactions in aqueous solvents. It was found that 1 was an effective
ligand and afforded high selectivity in the reaction of silicon enolate
2
in H
selectivity, we investigated the reaction conditions further (Table
). When alcoholic cosolvents were used, lower yields were
obtained because rapid hydrolysis of the silicon enolate occurred
entries 2-4). On the other hand, water-soluble aprotic cosolvents
2
O/EtOH (Table 1, entry 1). To increase the yield and
1
Figure 1. [1‚ScBr2‚H2O]+ moiety in the X-ray structure of [1‚ScBr2‚H2O]‚
Br‚H2O. Hydrogen atoms are omitted for clarity.
(
such as THF, 1,2-dimethoxyethane (DME), 1,4-dioxane, and
acetonitrile afforded high yields (entries 5-8). When water without
organic cosolvents was used, the reaction proceeded sluggishly
were constructed with high selectivities (entries 6-11 and 13-
15). Unfortunately, in the cases where rapid hydrolysis of silicon
enolates occurred, the reactions resulted in low yields (entries 12,
16). In some cases, addition of 2,6-di-tert-butylpyridine slightly
improved the yield (entry 3).1
(entry 9). Under higher concentration and at lower temperature in
0,11
2
H O/DME, the reaction proceeded in high yield with high selectivity
even using 10 mol % of the catalyst (entry 11). Five mol % of the
catalyst also worked well (entry 12).
To obtain some information on the chiral Sc complex, X-ray
crystal structural analysis was performed. Single crystals that were
Under the optimized conditions as shown in Table 1, entry 11,
we next examined other substrates and were delighted to find that
various substrates could be successfully employed (Table 2). Silicon
enolates having an ethyl or a siloxy group on the R-position of the
carbonyl groups gave the products with high selectivity (entries 2
and 3). Moreover, it is noted that asymmetric quaternary carbons
3
suitable for X-ray analysis were obtained from a 1-ScBr complex
1
2
(Figure 1). The complex adopts a pentagonal bipyramidal
structure13 in which the hydroxy groups of 1 coordinate to Sc in
a tetradentate manner. Formation of this type of structure may be
a key for obtaining high enantioselectivity. In addition, on consider-
ing the absolute configurations of some of the hydroxymethylated
3+
12236
9
J. AM. CHEM. SOC. 2004, 126, 12236-12237
10.1021/ja047896i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Hydroxymethylation of Silicon
Acknowledgment. This work was partially supported by
CREST, SORST, and ERATO, Japan Science and Technology
Agency (JST), and a Grant-in-Aid for Scientific Research from
Japan Society of the Promotion of Science. The authors thank Dr.
Motoo Shiro (Rigaku Corporation) for his assistance in obtaining
the X-ray structure. T.H. thanks the JSPS fellowship for Japanese
Junior Scientists.
Enolatesa
Supporting Information Available: Experimental procedures,
spectral data, and crystallographic data (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(
(
(
1) Catalytic asymmetric hydroxymethylation without using silicon enolates:
a) Fujii, M.; Sato, Y.; Aida, T.; Yoshihara, M. Chem. Express 1992, 7,
09. (b) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71.
(
3
(c) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983.
2) For a review on silicon enolates, see: Kobayashi, S.; Manabe, K.; Ishitani,
H.; Matsuo, J. In Science of Synthesis, Houben-Weyl Methods of Molecular
Transformation; Bellus, D., Ley, S. V., Noyori, R., Regitz, M., Schaumann,
E., Shinkai, I., Thomas, E, J., Trost, B. M., Eds.; Georg Thieme Verlag:
Stuttgart, 2002; Vol. 4, p 317.
3) For reviews on asymmetric aldol reactions, see: (a) Machajewski, T. D.;
Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. (b) Carreira, E. M.
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pflatz, A.,
Yamamoto, H., Eds.; Springer; Heidelberg, 1999; Vol. 3, p 998. (c) Nelson,
S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(
4) Trioxane was used as a formaldehyde surrogate: Mukaiyama, T.; Banno,
K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
(
5) (a) Kobayashi, S. Chem. Lett. 1991, 2187. For hydroxymethylation of a
silicon enolate in aqueous media without any catalysts, see: (b) Lubineau,
A.; Meyer, E. Tetrahedron 1988, 44, 6065.
(
(
(
(
6) Manabe, K.; Ishikawa, S.; Hamada, T.; Kobayashi, S. Tetrahedron 2003,
59, 10439.
7) Ozawa, N.; Wadamoto, M.; Ishihara, K.; Yamamoto, H. Synlett 2003,
219.
2
8) (a) Kobayashi, S. Eur. J. Org. Chem. 1999, 15. (b) Kobayashi, S.; Sugiura,
M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV. 2002, 102, 2227.
9) (a) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990,
2
9, 205. (b) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber.
1
992, 125, 1169.
(
10) 2,6-Di-tert-butylpyridine was used as an additive for Lewis acid-catalyzed
aldol reactions. For example: (a) Murata, S.; Suzuki, M.; Noyori, R.
Tetrahedron 1988, 44, 4275. (b) Hamada, T.; Manabe, K.; Ishikawa, S.;
Nagayama, S.; Shiro, M.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
2989.
(
11) It is also noteworthy that water is essential in this reaction. To see the
effects of water in this catalytic system, we performed an asymmetric
aldol reaction of benzaldehyde where anhydrous conditions were easy to
a
b
2
access. While the reaction of benzaldehyde with 2 in H O/DME (1:9) at
Reaction was performed in 0.36 M concentration. Isolated yield after
c
-20 °C for 21 h proceeded smoothly with good yield (76%) and modest
selectivity (syn/anti ) 78/22, 59% ee (syn)) using 10 mol % of the chiral
Sc catalyst, the reaction in DME without water did not proceed at all
silica gel chromatography. Ee was determined by chiral HPLC analysis.
Absolute configuration is shown in parentheses. 2,6-Di-tert-butylpyridine
100 mol %) was added. T ) -30 °C. T ) -40 °C. Ee was determined
by chiral HPLC analysis of its benzoate. Reaction was performed in H2O/
CH3CN.
d
e
f
g
(
(
-20 °C, 24 h). This result indicates that water plays an important role
h
for the catalytic activity in this system. For effects of water in rare earth
metal triflate-catalyzed aldol reactions, see: Kobayashi, S.; Hachiya, I.
J. Org. Chem. 1994, 59, 3590. Also see: ref 10b.
3
+
(
12) We performed the hydroxymethylation of 2 using 20 mol % Sc source
and 24 mol % 1 in H O/1,4-dioxane at 0 °C. As a result, Sc(OTf) and
ScBr afforded almost the same results (Sc(OTf) : 15 h, 86% yield, 84%
ee; ScBr : 22 h, 75% yield, 83% ee).
13) Pentagonal bipyramidal structures have also been reported for Sc(OTf)
products6,14 shown in Tables 1 and 2, it is clear that formaldehyde
tends to react with the same face of the silicon enolates in no relation
to the substituents at the R-position.
2
3
3
3
3
(
3
-
In conclusion, we have achieved successful catalytic asymmetric
hydroxymethylation of silicon enolates using a 1-Sc(OTf) com-
3
complexes with chiral ligands: (a) Evans, D. A.; Sweeney, Z. K.; Rovis,
T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095. (b) Evans, D. A.;
Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc.
2003, 125, 10780.
plex as the catalyst. In this reaction, a commercial aqueous solution
of formaldehyde can be used, and as a result, this process can be
conducted very easily and safely. This new catalytic system will
provide not only a useful method to synthesize optically active
R-hydroxymethylated carbonyl compounds but also a guide to
various kinds of catalytic asymmetric C-C bond-forming reactions
in aqueous media.15
(
14) (a) Baliri, P. L.; Catelani, G.; Giori, R.; Mastrorilli, E. Enantiomer 1998,
3
, 357. (b) Miyaoka, H.; Kajiwara, Y.; Hara, M.; Suma, A.; Yamada, Y.
Tetrahedron: Asymmetry 1999, 10, 3189.
(
15) For reviews on catalytic asymmetric carbon-carbon bond-forming reac-
tions in aqueous media, see: (a) Sinou, D. AdV. Synth. Catal. 2002, 344,
221. (b) Lindstr o¨ m, U. M. Chem. ReV. 2002, 102, 2751. (c) Manabe, K.;
Kobayashi, S. Chem. Eur. J. 2002, 8, 4094.
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