Angewandte
Chemie
Table 4: Scope of the intramolecular cyclopropanation reaction under optimal conditions.
excellent result represents the first
enantioselective organocatalytic
intramolecular cyclopropantion
reaction. The use of NaI as an
additive gave a similar yield and
enantiomeric excess. Moreover,
with amine 6 as catalyst, the oppo-
site cyclopropane enantiomer was
obtained with an excellent ee value
(94%), thus demonstrating the
potential efficacy of this organo-
catalytic process (see Table 3).
Entry
1[a]
Substrate
Time
18
Product
Yield%
1a
1b
1c
1d
1e
1 f
2a
2b
2c
2d
2e
2 f
91
2[a]
3[b]
4[b]
5[b]
6[b]
2
95
90
82
65
42
In summary, we have devel-
oped an organocatalytic intramo-
lecular cyclopropanation reaction
for the formation of synthetically
versatile [n.1.0]bicycloalkanes as
single diastereoisomers. This pow-
erful catalytic process effects the
controlled formation of three ster-
eocenters, two carbon–carbon
bonds, and two rings in a single
transformation. The reaction is
enantioselective with a catalytic
amount of chiral amine and can
form either enantiomer. We are
currently exploring the scope of
the catalytic enantioselective proc-
ess and applications towards the
synthesis of complexmolecules.
7
2
9
18
7[b]
1g
11
9
2g
72
50
Received: February 12, 2004 [Z54007]
Published Online: April 28, 2004
8[b]
1h
1i
2h
2i
Keywords: cyclization ·
.
cyclopropanation ·
diastereoselectivity ·
enantioselectivity · homogeneous
catalysis
9a[b]
9b[b]
9
9
48
65[c]
[1] K. C. Nicolaou, S. A. Snyder,
Angew. Chem. 2002, 114, 1742;
Angew. Chem. Int. Ed. 2002, 41,
1668, and references therein.
10[b]
1j
38
2j
81
[2] a) L. Yet, Chem. Rev. 2000, 100,
2963; b) A. Fürstner, Angew.
Chem. 2000, 112, 3140; Angew.
Chem. Int. Ed. 2000, 39, 3012.
[a] DCE at 608C. [b] MeCN at 808C. [c] 1 equiv of DABCO.
[3] a) Z. Hajos, D. R. Parrish, J. Org.
Chem. 1974, 39, 1615; b) U. Eder,
G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492; Angew.
Chem. Int. Ed. Engl. 1971, 10, 496; c) P. I. Dalko, L. Moisan,
Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001, 40,
3726.
DABCO was selected as the catalyst because of structural
similarity to the cinchona alkaloids, thus making it a racemic
model for an enantioselective reaction. On replacement of
DABCO with 20 mol% of 5, cyclopropane 2a was produced
in 67% yield with an enantiomeric excess (ee) of 64%, after a
5 day reaction (Table 4).[11] However, we proposed that the
addition of NaBr would accelerate the reaction by facilitating
formation of the quaternary ammonium salt. Therefore, the
addition of 0.4 equivalents of NaBr led to a 61% yield of 2a
with an ee value of 94%. To the best of our knowledge this
[4] a) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 2458; b) D. B. Ramachary, N. S. Chowdari, C. F. Barbas III,
Angew. Chem. 2003, 115, 4365; Angew. Chem. Int. Ed. 2003, 42,
4233; c) J.-C. Wang, S.-S. Ng, M. J. Krische, J. Am. Chem. Soc.
2003, 125, 3682; d) L.-C. Wang, A. L. Luis, K. Agapiou, H.-Y.
Jang, M. J. Krische, J. Am. Chem. Soc. 2002, 124, 2402; e) S. A.
Frank, D. J. Mergott, W. A. Roush, J. Am. Chem. Soc. 2002, 124,
Angew. Chem. Int. Ed. 2004, 43, 2681 –2684
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