we envisaged the enantioselective synthesis of bicyclo[3.n.1]-
alkanones (n ) 3 or 2) 213 from σ-symmetric keto-aldehydes
1 via enolexo mode9f of intramolecular aldolization with
amino acid catalysis (Scheme 1).
Scheme 2. Preparation of the Substrates
Scheme 1. Issues in the Selectivity of the Aldolization of 1
(>99% ee) by single recrystallization (diisopropyl ether/
hexane). The absolute stereochemistry of (-)-endo-2 was
unequivocally established to be 1S,5R,8R by connecting to
the known compound (R)-615 via a retro-Dieckmann reaction
of 5 as shown in Scheme 3.14
Our hope of using 2 as building blocks and the mechanistic
interest in the issue of selectivity prompted us to investigate
the feasibility of the process. We report herein an organo-
catalytic entry to chiral bicyclo[3.n.1]alkanones (n ) 3 or
2) and the discovery of several interesting factors that
markedly enhance the efficiency of aldolization.
The σ-symmetric keto-aldehydes 1a and 1b were prepared
from ethyl 4-hydroxycinnamate and 1,4-cyclohexanedione
monoethylene acetal, respectively, as shown in Scheme 2.14
To scout the inherent reactivity toward aldolization, 1a
and 1b were subjected to typical conditions employing K2-
Scheme 3. Determination of Absolute Stereochemistry of
(-)-2
12
CO3 or pyrrolidine as the catalyst. In both cases, bicyclo-
[3.n.1]-type products 2 were produced as the mixtures of
endo-/exo-diastereomers, and bicyclo[2.2.m]-type products
3 were not detected (entries 1-4). It was, therefore,
interesting to find that L-proline catalyzed the highly dias-
tereoselective aldolization of 1b to furnish endo-2b in 52%
yield with 94% de, although ee was 10% (entry 5). To our
satisfaction, the L-proline-catalyzed aldolization of 1a to
furnish (-)-endo-8-hydroxy-bicyclo[3.3.1]nonan-2-one (endo-
2a) in 60% yield with an excellent de of 98% and a high ee
of 78% under the standard conditions (25 mol % catalyst,
DMSO, rt, 72 h, entry 6), which was easily optically purified
Since the preliminary experiments revealed that L-proline
cannot be used to examine various reaction conditions
because of its inherent low solubility in conventional organic
solvents, we designed a series of proline derivatives 7-1114
with the hope of conferring a lipophilic property onto the
proline motif, thereby securing the basis for the evolution
of the catalytic activity.16 It was found that both 7 and 8
showed improved solubilities17 in MeCN and enhanced
catalytic potencies to convert 1a to a bicyclo[3.3.1]-type
product with opposite enantiopreferences and different enan-
tiocontrolling proficiencies. Thus, although 7 gave diastereo-
and enantioselectivities almost comparable with those of
(10) For selected references on intermolecular aldolization, see: (a) Notz,
W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) List, B.; Pojarliev, P.;
Castello, C. Org. Lett. 2001, 3, 573. (c) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (d) Northup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (e) Chowdari,
N. S.; Ramachary, D. B.; Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett.
2002, 43, 9591. (f) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
Co´rdova, A. Angew. Chem., Int. Ed. 2004, 43, 2-4. (g) Northup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2004, 43, 2152 (h) Chan, V.; Kim, J. G.; Jimeno, C.; Carroll, P. J.; Walsh,
P. J. Org. Lett. 2004, 6, 2051. (i) Thayumanavan, R.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2004, 6, 3541. (j) Northup, A. B.; MacMillan, D. W.
C. Science 2004, 305, 1752. (k) Ward, D. E.; Jheengut, V.; Akinnusi, O.
T. Org. Lett. 2005, 7, 1181. (l) Suri, J. T.; Ramachary, D. B.; Barbas, C.
F., III. Org. Lett. 2005, 7, 1383.
(11) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.
(12) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (b)
Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-
Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5263. (c) Cobb, A. J. A.;
Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (d) Mase, N.; Tanaka, F.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420.
(13) A highly enantioselective synthesis of (+)-endo-2 by yeast-mediated
asymmetric reduction of bicyclo[3.3.1]nonan-2,8-dione has been reported.
Mori, K.; Takayama, S.; Kido, M. Bioorg. Med. Chem. 1994, 2, 395.
(14) See Supporting Information.
(15) Elliot, M. L.; Urban, F. J. Border. J. Org. Chem. 1985, 50, 1752.
(16) (a) Hoang, L.; Bahmanya, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16. (b) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong,
P. H.-E.; Houk, N. K. Acc. Chem. Res. 2004, 37, 558. (c) Bahmanyar, S.;
Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273. (d) Bahmanyar, S.; Houk,
K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.
(17) For discussions on solubility and reactivity of organocatalysts, see:
(a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S.
L. Org. Biomol. Chem. 2005, 3, 84. (b) Darbre, T.; Machuqueiro, M. Chem.
Commun. 2003, 1090.
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