Unique Synthetic Utility of BF3*OEt2 in the Highly Diastereoselective Reduction of Hydroxy Carbonyl and Dicarbonyl Substrates

Article abstract of DOI:10.1021/ol000056y

. A new aspect of commonly used BF3*OEt2 has been illuminated by successfully demonstrating the unique but highly stereoselective reactions of hydroxy carbonyl and dicarbonyl substrates. For example, treatment of γ-hydroxy ketone 1c with BF2*OEt2/Bu3SnH in CH2Cl2 at -78 to -40 deg C afforded the corresponding 1,4-diol 2c with virtually complete diastereoselection, while use of TiCl4 as a Lewis acid under similar reaction conditions caused a total lack of diol yield and selectivity (17%; 2c/3c = 1.2:1), accompanied by a significant formation of 2,3-disubstituted tetrahydrofuran 4 (44%).

Full text of DOI:10.1021/ol000056y

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2015-2017
Unique Synthetic Utility of BF3‚OEt2 in
the Highly Diastereoselective Reduction
of Hydroxy Carbonyl and Dicarbonyl
Substrates
Takashi Ooi, Daisuke Uraguchi, Junko Morikawa, and Keiji Maruoka*
Departments of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan, and Graduate School of Science,
Hokkaido UniVersity, Sapporo 060-0810, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received March 14, 2000
ABSTRACT
A new aspect of commonly used BF3‚OEt2 has been illuminated by successfully demonstrating the unique but highly stereoselective reactions
of hydroxy carbonyl and dicarbonyl substrates. For example, treatment of γ-hydroxy ketone 1c with BF3‚OEt2/Bu3SnH in CH Cl2 at −78 to −40
2
°C afforded the corresponding 1,4-diol 2c with virtually complete diastereoselection, while use of TiCl4 as a Lewis acid under similar reaction
conditions caused a total lack of diol yield and selectivity (17%; 2c/3c ) 1.2:1), accompanied by a significant formation of 2,3-disubstituted
tetrahydrofuran 4 (44%).
Undoubtedly, stereochemical control in acyclic and cyclic
systems (1,n asymmetric induction) has been of great and
continuous interest for synthetic organic chemists.1 Lewis
acid catalyzed regio- and/or stereoselective addition of
organosilicon and organotin compounds to carbonyl sub-
strates has certainly played an essential role, and a number
of simple but highly sophisticated methodologies have been
developed particularly for the stereocontrolled syntheses of
â-hydroxycarbonyl compounds and 1,3-polyols.2 Boron
trifluoride etherate (BF3‚OEt2), which is apparently one of
the most familiar and thoroughly investigated Lewis acids,3-7
has been utilized as a reliable carbonyl activator in this field
as exemplified by erythro-selective addition of allyltrialkyl-
stannane to aldehydes.8 However, the full synthetic potential
of BF3‚OEt2 in organic synthesis has yet to be realized
especially in terms of functional group compatibility and
(2) Reviews: (a) Denmark, S. E.; Willson, T. M. In SelectiVities in Lewis
Acid Promoted Reactions; Schinzer, D., Ed.; Kluwer Academic Publish-
ers: 1989; p 247. (b) Fleming, I. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p
563. (c) Gennari, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 629. (d) Santelli,
M.; Pons, J.-M. Lewis Acids and SelectiVity in Organic Synthesis; CRC
Press: Boca Raton, 1995.
(3) Reviews: (a) Bednarski, M. D.; Lyssikatos, J. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, p 661. (b) Yamaguchi, M. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 1, p 325.
(1) (a) Bartlett, P. A. Tetrahedron 1980, 36, 3. (b) Morrison, J. D.;
Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall: Englewood
Cliffs, NJ, 1971. (c) Eliel, E. L. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic Press: New York, 1983; Vol. 2A, p 125. (d) Oishi, T.;
Nakata, T. Synthesis 1990, 635.
(4) (a) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.;
Maruyama, K. J. Org. Chem. 1982, 47, 119. (b) Wada, M.; Sakurai, Y.;
Akiba, K. Tetrahedron Lett. 1984, 25, 1079.
10.1021/ol000056y CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

stereoselectivity. Here we wish to report the unique synthetic
utility of BF3‚OEt2 in stereoselective reactions of hydroxy
carbonyl and dicarbonyl substrates, clearly demonstrating its
advantage over ordinary transition-metal Lewis acids.9
With information on the commercial availability of several
BF3‚ROH’s in hand, we first examined the stereoselectivity
in the reduction of a series of hydroxy ketones with BF3‚
OEt2 (Scheme 1), since direct use of free hydroxy groups
propiophenone 1a with BF3‚OEt2 (1.2 equiv) in toluene at
-78 °C and subsequent addition of Bu3SnH (1.2 equiv)
resulted in clean formation of the corresponding diols 2a
and 3a in 80% yield with high syn selectivity (syn/anti )
13:1; entry 1), while the selectivity was dramatically lowered
when TiX4 (X ) Cl, F) was used as the chelating Lewis
acid, regardless of the reaction temperature (entries 2-5).10
Using SnCl4, the reduction did not proceed and most of the
starting R-hydroxy ketone was recovered (entry 6). In the
case of â-hydroxy ketone 1b, high levels of diastereoselec-
tivities were uniformly observed with BF3‚OEt2, TiX4 (X )
Cl, F), and SnCl4 (entries 7-10). Moreover, even γ-hydroxy
ketone 1c on reaction with BF3‚OEt2/Bu3SnH gave rise to
the corresponding 1,4-diol 2c with virtually complete dia-
stereoselection (entry 11). In sharp contrast, however, use
of TiCl4 as a Lewis acid under similar reaction conditions
caused a total lack of selectivity, and 2,3-disubstituted
tetrahydrofuran 4 was obtained as a major product via facile
hemiacetal formation [A] and subsequent reduction under
the reaction conditions (entry 12). Such hemiacetal formation
took precedence over the desired reduction with TiF4 and
SnCl4 (entries 13 and 14).11
Scheme 1
The distinct advantage of BF3‚OEt2 over ordinary transi-
tion-metal Lewis acids is further illustrated by the stereo-
selective reactions of substituted γ-keto aldehydes 5a,b and
8 as shown in Table 2. Here again, BF3‚OEt2 works well
without a protection-deprotection sequence is quite conve-
nient for functional transformation. Selected data are sum-
marized in Table 1. Thus, initial treatment of R-hydroxy-
Table 2. Diastereoselective Reduction of Substituted γ-Keto
Aldehydes 5a,b and 8a
Table 1. Diastereoselective Reduction of Hydroxy Ketones
1a-ca
keto
syn/anti ratiob
syn/anti ratiob,c
entry aldehyde
reagents
condition
(% yield)c
entry ketone
reagents
condition
(% yield)d
1
2
3
4
5
5a
BF3‚OEt2/Bu3SnH -78, 6; -40, 4.5
12:1 (99)
-78, 4; -40, 2.5 >20:<1 (52)d
1
2
1a
BF3‚OEt2/Bu3SnH -78, 2
13:1 (80)
- (trace)e
1:1.6 (75)
TiCl4/Bu3SnH
TiCl4/Et3SiH
TiCl4/PhMe2SiH
TiF4/Bu3SnH
SnCl4/Et3SiH
-78, 1
-78, 1, 25, 8
-78, 0.5, -40, 12 1:1.3 (75)
-78, 0.1; 25, 20f 1:1.8 (87)
-78, 0.1; 25, 20
TiCl4/Et3SiH
-78, 6, 0, 4.5
3.6:1 (23)e
10:1 (40)d,f
10:1 (94)g
3
5b
8
BF3‚OEt2/Bu3SnH -78, 4; -40, 6
BF3‚OEt2/Bu3SnH -78, 3; -40, 0.5
4
5
a Unless otherwise specified, the reaction was carried out in CH2Cl2 with
1.05 equiv of Lewis acid and 2.1 equiv of Bu3SnH under the indicated
conditions. b syn/anti ratio was determined by 300 MHz 1H NMR analysis.
c Isolated yield. d Use of toluene as solvent. e Starting γ-keto aldehyde was
recovered with concomitant formation of the partially reduced hydroxy
ketone. f The syn configuration was confirmed by correlation to the authentic
sample prepared from 4-phenyl-3-buten-1-ol by OsO4-catalyzed dihydroxyl-
ation (Xu, D.; Park, C. Y.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
2495). g The stereochemical assignment was made by comparison of the
signals of hydroxy bearing carbons in the 13C NMR spectrum (Breitmaier,
E.; Voelter, W. Carbon-13 NMR Spectroscopy; VCH: Weinheim, 1987).
6
- (trace)
>20:<1 (98)
19:1 (84)
7
1b
1c
BF3‚OEt2/Bu3SnH -78, 0.5
8
TiCl4/Et3SiH
TiF4/Bu3SnH
SnCl4/Et3SiH
-78, 1, -20, 2
-78, 0.1; 25, 4f
-78, 6
9
>20:<1 (87)
14:1 (<8)
>20:<1 (74)
10
11
12
13
14
BF3‚OEt2/Bu3SnH -78, 12; -40, 1
TiCl4/Et3SiH
TiF4/Bu3SnH
SnCl4/Et3SiH
-78, 9; -40, 0.5 1.2:1 (17) [44]g
-78, 0.1; 25, 12f - (trace) [49]g
-78, 6; -40, 2
- (trace) [86]g
a The reaction was carried out in toluene or CH2Cl2 with 1.2 equiv of
each reagent under the indicated conditions. b syn/anti ratio was determined
by 300 MHz H NMR analysis. c The relative configuration of the major
1
not only to obtain the desired alcohols with high stereo-
selectivity but also to suppress the otherwise favorable
hemiacetalization leading to cyclic ethers such as 4.
isomer was determined as follows: Correlation to the authentic sample
independently synthesized from trans-â-methylstylene according to the
Sharpless protocol (Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
1
10515) (entries 1-6). Evaluation of J values in the H NMR analysis of
the corresponding acetonide derived with catalytic PPTS and dimethoxy-
propane in CH2Cl2 (entries 7-10). Comparison with the known (1R,2S)-
2-methyl-1-phenyl-1,4-butanediol (Matsumoto, K.; Aoki, Y.; Oshima, K.;
Utimoto, K.; Rahman, N. A. Tetrahedron 1993, 49, 8487) (entries 11-
14). d Isolated yield. e Bu3SnH was consumed instantaneously to give
probably Bu3SnCl and the reduction did not proceed further even after
warming to room temperature. f Higher reaction temperature was necessary
because of the insolubility of TiF4 in both CH2Cl2 and toluene. g Yield of
2,3-disubstituted furan 4 as a side product is given in brackets.
(5) (a) Suzuki, M.; Yanagisawa, A.; Noyori, R. Tetrahedron Lett. 1982,
23, 3595. (b) Pelter, A.; Al-Bayati, R. Tetrahedron Lett. 1982, 23, 5229.
(c) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron Lett. 1983, 24,
5121. (d) Volkmann, R. A.; Davis, J. T.; Meltz, C. N. J. Am. Chem. Soc.
1983, 105, 5946. (e) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem.
Soc. 1984, 106, 3693.
(6) (a) Denmark, S. E.; Henke, B. R.; Weber, E. J. Am. Chem. Soc. 1987,
109, 2512. (b) Denmark, S. E.; Wilson, T.; Willson, T. M. J. Am. Chem.
Soc. 1988, 110, 984.
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Org. Lett., Vol. 2, No. 14, 2000

Scheme 2
Since hydroxy ketones 10 and 1112 can be reduced to 12
and 6b, respectively, by the BF3‚OEt2/Bu3SnH system with
high diastereoselectivity, either syn- or anti-stereoisomeric
triols of type 6b or 7b can be synthesized from the single
starting material, dihydroxy ketone 9, by appropriately
protecting the hydroxy functionalities (Scheme 2). This
picture demonstrates that the present BF3‚OEt2-mediated
method certainly offers a new stereoselective approach for
the construction of polyhydroxy backbones.
bonyl and dicarbonyl substrates, which provides 1,n-diols
(n ) 2-4) with almost complete diastereoselection. Aside
from the clear synthetic utility of the present system, the
origin of selectivity is unclear and is under current investiga-
tion.
In conclusion, we observed characteristic features of
BF3‚OEt2 in the stereocontrolled reduction of hydroxycar-
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (No. 706:
Dynamic Control of Stereochemistry) from the Ministry of
Education, Science, Sports and Culture, Japan. D.U. is
grateful to the Japan Society for the Promotion of Science
for a Research Fellowship for Young Scientists.
(7) For complexation with carbonyl substrates, see: (a) Reetz, M. T.;
Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729. (b) Shambayati,
S.; Crowe, W. E.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 1990, 29,
256.
(8) Yamamoto, Y.; Yatagai, H.; Naruta, Y.; Maruyama, K. J. Am. Chem.
Soc. 1980, 102, 7109. See also ref 2.
(9) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(10) PhMe2SiH exhibited higher reactivity than Et3SiH and allowed the
reduction to be performed at lower temperature. However, the diastereo-
selectivity was not improved.
(11) Reduction of hemiacetal of 1c leading to 2,3-disubstituted tetrahy-
drofuran of type 4 has been reported, see, for example: Kraus, G. A.;
Molina, M. T.; Walling, J. A. J. Org. Chem. 1987, 52, 1273.
(12) Hydroxy ketone 11 was found to be in equilibrium with its
hemiacetal in solution. Treatment of 11 with Ac2O, pyridine and catalytic
DMAP in CH2Cl2 afforded the corresponding keto acetate (80% yield) which
was completely characterized spectroscopically. See Supporting Information.
Supporting Information Available: Representative ex-
perimental procedure as well as spectroscopic characteriza-
tion of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL000056Y
Org. Lett., Vol. 2, No. 14, 2000
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