Carbohydrates in asymmetric synthesis: enantioselective allylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.05.109

An enantioselective metal-mediated addition of allylic bromides to carbonyl compounds was achieved in the presence of the inexpensive and easily accessible carbohydrates saccharose and β-cyclodextrin. The desired products were obtained in moderate to exce

Full text of DOI:10.1016/j.tetlet.2008.05.109

Tetrahedron Letters 49 (2008) 4956–4957
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbohydrates in asymmetric synthesis: enantioselective allylation of aldehydes
a,*
a
a
a
a
Helmoz R. Appelt , Jane B. Limberger , Minéia Weber , Oscar E. D. Rodrigues , Julieta S. Oliveira ,
b
c,
*
Diogo S. Lüdtke , Antonio L. Braga
Centro Universitário Franciscano, Rua dos Andradas, 1614—Centro, 97010-032 Santa Maria, RS, Brazil
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil
Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective metal-mediated addition of allylic bromides to carbonyl compounds was achieved in
the presence of the inexpensive and easily accessible carbohydrates saccharose and b-cyclodextrin. The
desired products were obtained in moderate to excellent yields and with up to 93% enantiomeric excess.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 April 2008
Accepted 23 May 2008
Available online 29 May 2008
The synthesis of enantiomerically enriched homoallylic alcohols
is an important goal in organic synthesis. This is mainly because
homoallylic alcohols are versatile intermediates that can be con-
OH
HO
O
O
O
OH HO
OH
1
O
verted to a wide variety of synthetically useful compounds. In this
OH
OH
HO
HO
O
context, the enantioselective allylation of aldehydes plays a major
role in the field, and many different systems have been developed
O
OH
HO
HO
O
O
OH
2
HO
OH
O
OH
to achieve this goal. For example, chiral Lewis acids based on
O
HO
O
OH
OH
3
4
5
6
7
metals such as Ti, In, B, Cr, and Rh have proven to afford homo-
allylic alcohols in high ee’s.
O
OH
OH
HO
1 saccharose
OH
OH
On the other hand, carbohydrates and their derivatives have
recently emerged as an important tool for stereoselective synthesis
and as a chiral pool for the design of chiral ligands. Carbohydrates
O
OH
O OH
O
OHO
HO
O
OH
are particularly useful in this context, mainly due to their availabil-
ity, several stereocenters, and weak coordination sites.8,9 However,
2 β-cyclodextrin
despite all these new advances, the application of simple carbo-
hydrates in stereoselective synthesis is still scarcely studied.
Herein, we wish to disclose our results in the enantioselective
allylation of aldehydes, using simple, inexpensive, and readily
available carbohydrates, for example, saccharose 1 and b-cyclodex-
trin 2 as chiral promoters for the enantioselective addition of in
situ generated allylmetal reagents to aldehydes (Fig. 1).
Figure 1. Structures of saccharose and b-cyclodextrin.
of the product had increased to 55%, although the yield was still
low (entry 6). Next, we sought to examine the influence of the
metal in the reaction outcome; and indium and tin were used in
the enantioselective allylation, in the presence of 1.2 equiv of
saccharose. When indium was used, quite disappointing results
were achieved, since the homoallylic alcohol was obtained in low
yield and negligible enantiomeric excess (entry 8). On the other
hand, tin has proved to be much more efficient, furnishing product
in 71% ee when the reaction was carried out at room temperature
and in 81% ee when the temperature was reduced to 0 °C (entries
–10).
Furthermore, b-cyclodextrin 2 was also examined as the chiral
promoter for the allylation of benzaldehyde (entries 11–16). Quan-
tities of 0.5 and 1.0 equiv of 2 were used in the presence of zinc,
indium, or tin as the metal. Again, indium furnished disappointing
result with very low conversion and ee. When tin was used as the
metal, the product was obtained in high yields, but with almost no
enantioselectivity. Gratifyingly, when zinc was employed, better
Our survey has started by choosing benzaldehyde as the alde-
hyde of choice for optimization studies.10 A number of reaction
conditions were examined, and the results are depicted in Table
1. When the reaction was carried out in the presence of different
amounts of saccharose 1 as the chiral promoter and zinc powder
as the metal, at room temperature, only moderate results were
achieved for the desired homoallylic alcohol, even when 1 was
used in up to 2 equiv (entries 1–4). Lowering the reaction temper-
ature to 0 °C showed some improvement in the ee of 4. For exam-
ple, when the reaction was carried out using 1.2 equiv of 1, the ee
4
9
*
Corresponding authors. Tel.: +55 55 32201200; fax: +55 55 3220 1226 (H.R.A);
tel.: +55 55 3220 8761; fax: +55 55 3220 8998 (A.L.B).
E-mail addresses: helmoz@gmail.com, helmoz@unifra.br (H. R. Appelt), albraga@
quimica.ufsm.br (A. L. Braga).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.109

H. R. Appelt et al. / Tetrahedron Letters 49 (2008) 4956–4957
4957
Table 1
Table 2
Allylation of benzaldehyde in the presence of carbohydrate 1 or 2
Enantioselective allylation of substituted benzaldehydes
O
OH
O
OH
Metal,
H
chiral promoter 1 or 2
H
Conditions
Br
Br
THF, 1 h
R
R
3
a
4a
3
4
Entry
Promoter (equiv)
Metal
Temperature (°C)
Yielda (%)
eeb (%)
Entry
Conditiona
Metal
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1 (0.5)
1 (1.0)
1 (1.2)
1 (2.0)
1 (1.0)
1 (1.2)
1 (2.0)
1 (1.2)
1 (1.2)
1 (1.2)
2 (0.5)
2 (1.0)
2 (0.5)
2 (1.0)
2 (0.5)
2 (0.5)
Zn
Zn
Zn
Zn
Zn
Zn
Zn
In
Sn
Sn
Zn
Zn
Zn
Zn
Sn
In
rt
rt
rt
rt
0
15
14
23
18
28
26
17
14
19
25
17
56
36
36
84
8
11
14
21
28
41
55
42
3
71
81
62
70
90
23
5
1
2
3
4
5
6
7
8
9
A
A
A
B
B
B
C
C
C
Zn
Zn
Zn
Sn
Sn
Sn
Zn
Zn
Zn
OMe
Me
Cl
OMe
Me
Cl
OMe
Me
Cl
60
70
88
67
61
81
91
67
75
87
75
85
16
66
68
93
72
63
0
0
rt
rt
0
rt
rt
0
0
0
0
1
1
1
1
1
1
1
Absolute configurations R were determined by comparison with the Ref. 11.
a
Condition A: saccharose (1.2 equiv), Zn (1 equiv); condition B: saccharose
(
1.2 equiv), Sn (1 equiv); condition C: b-cyclodextrin (1 equiv), Zn (1 equiv).
b
Yields determined by GC.
Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD
c
column.
11
Absolute configuration R was determined by comparison with the Ref. 11.
a
Yields determined by GC.
Enantiomeric excesses were determined by chiral HPLC on a Chiralcel OD
b
sive, and readily available carbohydrates. The reaction proceeds
in short reaction times, under simple operational conditions; and
the homoallylic alcohols are obtained in useful levels of enantio-
meric excess.
column.
results were achieved and an ee of 90% of 4 was obtained in the
presence of 1 equiv of 2, at 0 °C (entry 13).
Worth to mention is that no special conditions such as inert
atmosphere or dried solvents are required for the allylation reac-
tion, since all reactions were carried out in an open vessel, using
ACS grade THF. The only special care that must be taken in consid-
eration is regarding the reaction time, since a decrease in the ee
was observed when the reaction was maintained for 4 h, in an
attempt to increase the yield of product 4.
Acknowledgments
We are grateful to the following Brazilian Agencies for support:
FAPESP (2007/02382-8) and CNPq for a sustainable environment
for partial support of our research.
After all the experimentation described in Table 1, we decided
to extend the study to a broader range of substituted aromatic
aldehydes and we choose to evaluate those conditions that
furnished the best results for the allylation of benzaldehyde, which
are using 1 (1.2 equiv) as the chiral promoter and either zinc (con-
dition A) or tin (condition B) as the metal, and using 2 (1.0 equiv)
and zinc as the metal (condition C).
Thus, the reaction was first performed using saccharose as the
agent responsible for the chiral induction, under conditions A
and B (Table 2). With condition A, using zinc as the metal, high
levels of enantioselection were achieved with p-anisaldehyde and
p-chlorobenzaldehyde, although the yield for the former was only
moderate, while for the latter very good conversion was observed
References and notes
1.
(a) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem., Int. Ed 2002, 41, 3701; (b)
Hornberger, K. R.; Hamblet, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122,
1
2894; (c) Felpin, F. X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192; (d) Yamamoto,
Y. Acc. Chem. Res. 1987, 20, 243; (e) de Fátima, A.; Pilli, R. A. Tetrahedron Lett.
003, 44, 8721.
2
2. For reviews, see: (a) Denmark, S. E.; Fu, J.-P. Chem. Rev. 2003, 103, 2763; (b) de
Fátima, A.; Robello, L. G.; Pilli, R. A. Química Nova 2006, 29, 1009.
3
4
.
.
Kii, S.; Maruoka, K. Tetrahedron Lett. 2001, 42, 1935.
(a) Lu, J.; Ji, S.-J.; Teo, Y. C.; Loh, T. P. Org. Lett. 2005, 7, 159; (b) Teo, Y. C.; Tan, K.-
T.; Loh, T. P. Chem. Commun. 2005, 1318; (c) Haddad, T. D.; Hirayama, L. C.;
Taynton, P.; Singaram, B. Tetrahedron Lett. 2008, 49, 508.
5.
6.
7.
Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910.
Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248.
Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391.
(
entries 1 and 3). Reaction with p-tolualdehyde resulted in some-
8. (a) Diéguez, M.; Pàmies, O.; Ruiz, A.; Díaz, Y.; Castillón, S.; Claver, C. Coord.
Chem. Rev. 2004, 248, 2165; (b) Diéguez, M.; Pàmies, O.; Claver, C. Chem. Rev.
what lower ee of the corresponding product (entry 2). By changing
to conditions B, that used tin as the metal, only moderate yields
and enantioselectivity were observed for all aldehydes tested
2004, 104, 3189.
9.
(a) Diéguez, M.; Claver, C.; Pàmies, O. Eur. J. Org. Chem. 2007, 4621; (b) Boysen,
M. M. K. Chem. Eur. J. 2007, 13, 8648–8659.
1
0. Typical experimental procedure: To a 25 mL round-bottomed flask were added
saccharose (0.1–5.0 mmol), zinc powder (1.2 mmol), allyl bromide (1.2 mmol),
benzaldehyde (1.0 mmol), and the solvent (6 mL). The mixture was stirred
vigorously for 1 h at room temperature, and quenched with 4 mL of a dilute
HCl solution. The aqueous layer was extracted with hexane (10 mL Â 3). The
combined organic extracts were washed with brine, dried over anhydrous
sodium sulfate, and concentrated under vacuum to afford the homoallylic
alcohol.
(
entries 4–6). On the other hand, the employment of condition C,
with b-cyclodextrin 2 as the chiral agent and zinc as metal, a very
high ee of 93% was achieved by reaction with p-anisaldehyde, in
9
achieved with p-chloro- and p-tolualdehyde (72% and 63%, respec-
tively; entries 8 and 9).
1% yield (entry 7). Lower levels of enantioselectivity were
In conclusion, we have described the enantioselective allylation
of substituted benzaldehydes in the presence of simple, inexpen-
11. Denmark, S. E.; Coe, D. M.; Pratt, N. P.; Griedel, B. D. J. Org. Chem. 1994, 59,
161.
6