B. J. Postnikova, E. V. Anslyn / Tetrahedron Letters 45 (2004) 501–504
503
Acknowledgements
1) 6 - 8, solvent
[2.2.1] cryptand (1.5 eq)
2) R-X (5 eq), solvent, -76 ºC
O
Alkylation
Product
Host 3b, 3c, 3e
This work has been supported by the National Institutes
of Health.
(1.1 eq)
O
O
O
O
O
References and Notes
6
7
8
1. Caine, D. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
Chapter 11.
Scheme 2. Alkylation studies.
2. Caine, D. In Carbon–Carbon Bond Formation; Augustine,
R. L., Ed.; Marcel Dekker: New York, 1979; Vol. 1,
Chapter 2.
3. (a) Mulzer, J. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Spring-
er: Berlin, 1999; Vol. I, pp 66–74; (b) Arya, P.; Qin, H.
Tetrahedron 2000, 917–947; (c) Evans, D. A. In Asymmet-
ric Synthesis; Morrison, J. D., Ed.; Academic: New York,
1984; Vol. 3, pp 1–110.
4. (a) Yamoshita, T.; Matsui, M.; Watanabe, H.; Nakamura,
N. Bull. Chem. Soc. Jpn. 1982, 55, 961–962; (b) Aoki, K.;
Tomioka, K.; Noguchi, H.; Koga, K. Tetrahedron 1997,
53, 13641–13656; (c) Ando, A.; Shioiri, T. J. Chem. Soc.,
Chem. Commun. 1987, 656.
Table 1. Alkylation of enolates 6–8 with benzyl bromide in the pres-
ence of hosts 3b, 3c and 3e
Host
Enolate Time
(h)
Solvent
T (ꢁC) Yield
(%)
Eea
None
None
None
3c
6
7
8
7
7
7
7
6
8
8
6
THF
THF
THF
THF
)78
)65
)78
)78
54
80
76
36
57
44
40
54
62
0
0
12
8
0
20
10
<3
42
<3
4
3b
3e
8
Toluene )78
Toluene )50
THF
THF
THF
7
3e
3e
8
)65
)78
)78
5. Kelly-Rowley, A. M.; Lynch, V. M.; Anslyn, E. V. J. Am.
Chem. Soc. 1995, 117, 3438–3447.
10
12
3e
6. Snowden, T. S.; Bisson, A. P.; Anslyn, E. V. J. Am. Chem.
Soc. 1999, 121, 6324–6325.
a Ee was determined by chiral HPLC.
7. (a) Iverson, D. J.; Hunter, G.; Blount, J. F.; Damewood, J.
R., Jr.; Mislow, K. J. Am. Chem. Soc. 1981, 103, 6073–
6083; (b) Kilway, K. V.; Siegel, J. S. J. Am. Chem. Soc.
1992, 114, 255–261.
8. Hanes, R. E., Jr.; Lavigne, J. J.; Anslyn, E. V.; Kilway, K.
V.; Siegel, J. Org. Syn. 2003, in preparation.
9. Carpino, L. A.; Cohen, B. J.; Stephens, K. E., Jr.; Sadat-
Aalee, S. Y.; Tien, J.; Langridge, D. L. J. Org. Chem.
1986, 51, 3732–3734.
in any enantiomeric enrichment of the alkylation prod-
uct. This suggests that the organization of the coordi-
nating ligands on one face of the hexasubstituted
benzene scaffold in 3 is responsible for forming a binding
cavity for enolate recognition, thereby directing enolate
alkylation enantioselectively.
10. Bernasconi, C. F.; Kanavarioti, A. J. Am. Chem. Soc.
1986, 108, 7744–7751.
In summary, we have shown that a hydrogen-bonding
chiral receptor can act as a template for directing eno-
late alkylation.13 In our case, a moderate enantiomeric
enrichment of the product was obtained. Further studies
must focus on improving the enantioselectivity of the
reaction and broadening the scope of this concept to
other reactions. However, the principle has been dem-
onstrated, and it suggests that other hydrogen-bonding
molecular receptors can be used in enolate reactions,
hopefully significantly improving on the initial studies
described herein.
11. Tsukube, H.; Furuta, H.; Odani, A.; Takeda, Y.; Kudo,
Y.; Inoue, Y.; Liu, Y.; Sakamoto, H.; Kimura, K. In
Comprehensive Supramolecular Chemistry; Davies, J. E.
D., Ripmeester, J. A., Eds.; Pergamon: Oxford, 1996; Vol.
8, Chapter 10.
12. Typical experimental procedure: In a drybox under
nitrogen, enolate 12 (30 mg, 0.20 mmol) was added to
[2.2.1] cryptand (100 mg, 272 mmol). Receptor 7b (180 mg,
0.20 mmol) in THF (20 mL) was added under Ar atmo-
sphere followed by THF (20 mL). The solution was stirred
for 30 min and cooled to )78 ꢁC. Benzyl bromide
(0.16 mL,1.35 mmol) in THF (10 mL) was added and the
solution stirred for 8 h. The reaction was quenched with
water (1 mL) and the THF was removed in vacuo. The
residue was dissolved in methylene chloride and washed
with water (30 mL · 1), saturated aqueous NaHCO3
(30 mL · 1) and brine, and dried with MgSO4. After
filtration, the filtrate was concentrated in vacuo to give a
yellow oil. This crude product was purified by flash
chromatography (hexanes/ethyl acetate (90/10)) to give the
desired product.
O
O
H
N
O
N
O
O
H
N
O
O
O
N
H
NH2
O
Enantiomeric excess of the product was determined by
HPLC under the following conditions: Chiralcel AD
(hexane/2-propanol ¼ 30/1, 1.0 mL/min, 260 nm).
13. For other enantioselective tripodal directed reactions see:
(a) Kim, S.-G.; Ahn, K. H. Tetrahedron Lett. 2001, 42,
CH2Cl2, Et3N
9 (67%)
Scheme 3.