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G. Manickam et al.
LETTER
(8) (a) Hamashima, Y.; Sawada, D.; Kanai, M. Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 2641-2642. (b) Hamashima, Y.;
Sawada, D.; Nogami, H.; Kanai, M. Shibasaki, M
Tetrahedron 2001, 57, 805-814.
(9) Kanai, M.; Hamashima, Y.; Shibasaki, M. Tetrahedron Lett.
2000, 41, 2405-2409.
(10) Gacek, M.; Undheim, K. Tetrahedron 1974, 30, 4233-4237.
(11) Relative configurations of 11, 17, 13 and 19 were determined,
comparing the spectroscopic data with the reported ones after
hydrolysis: Kobayashi, Y.; Takemoto, Y.; Kamijo, T.;
Harada, H.; Ito, Y.; Terashima, S. Tetrahedron 1992, 48,
1853-1868.
(12) Relative configurations of 12 and 18 were determined,
comparing the spectroscopic data with the reported ones. See
ref 6d.
In summary, this work has demonstrated that the bifunc-
tional catalyst 6 promotes cyanosilylation of chiral -ami-
no aldehydes in excellent yields and with high
diastereoselectivities. Both anti and syn isomers for the
synthesis of HIV protease inhibitor and bestatin are ob-
tained selectively, dependent on the type of protecting
group at the nitrogen. The high yields, high selectivity and
the easy operation20 are the main advantages of this new
methodology. Furthermore, tendencies of the reactivity
and diastereoselectivity of the three protected amino alde-
hydes are well explained from the dual activation mecha-
nism of the bifunctional catalyst.
(13) (a) Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205.
(b) Anh, N. T. Top. Stereochem. 1980, 88, 145.
(14) Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181-
186.
(15) The initial reaction rate of 10 was 1.2 times faster than 16,
when 9 mol% of 6 was used. Considering that 10 gave a
slightly higher diastereoselectivity than 16, the combination
of 6 and 10 appeared to be the matched pair.
Acknowledgement
Financial support was provided by CREST, The Japan Science and
Technology Corporation (JST), and RFTF of Japan Society for the
Promotion of Science.
References and Notes
(16) Using 9 mol% of Et2AlCl, only 35% yield of 13 was obtained
after 48 h with lower diastereomeric ratio (13a:13s) of 78:22.
(17) The silylated ligand of catalyst 7 gradually appeared on TLC,
indicating partial decomposition of the catalyst under the
reaction conditions. However, even a trace amount of the
silylated ligand of 6 was not observed. The reason why
catalyst 6 is more stable than 7 is currently under
investigation.
(18) The matched transition state as 28 in the combination of 6 and
16 might have some contribution, although the relative
position of the aldehyde and the activated TMSCN seems not
optimum.
(1) Umezawa, H.; Ishizuka, M.; Aoyagi, T.; Takeuchi, T. J.
Antibiot. 1976, 29, 857. Ino, K.; Goto, S.; Nomura, S.; Isobe,
K.-I.; Nawa, A.; Okamoto, T.; Tomoda, Y. Anticancer Res.
1995, 15, 2081.
(2) For selected examples of the synthesis of bestatin or its
component, see: (a) Nemoto, H.; Ma, R.; Suzuki, I.; Shibuya,
M. Org. Lett. 2000, 2, 4245-4247. (b) Wasserman, H. H.; Xia,
M.; Petersen, A. K.; Jorgensen, M. R.; Curtis, E. A.
Tetrahedron Lett. 1999, 40, 6163-6166. (c) Bergmeier, S. C.;
Stanchina, D. M. J. Org. Chem. 1999, 64, 2852-2859.
(d) Matsuda, F.; Matsumoto, T.; Ohsaki, M.; Ito, Y.;
Terashima, S. Bull. Chem. Soc. Jpn. 1992, 65, 360-365. (e)
Matsuda, F.; Matsumoto, T.; Ohsaki, M.; Ito, Y.; Terashima,
S. Chem. Lett. 1990, 723-724.
(3) Mimoto, T.; Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.;
Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251-2253.
(4) Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao,
B. G.; Tung, R. D.; Navia, M. A. J. Am. Chem. Soc. 1995, 117,
1181-1182.
OtBu
NC
H
Me
3Si
NH
Ph
O
O
O
Ph
Ph
P
Al
Cl
O
H
O
O
28
(5) For selected examples of the synthesis of HIV protease
inhibitors or their component, see: (a) Corey, E. J.; Zhang, F.-
Y. Angew. Chem. Int. Ed. 1999, 38, 1931-1934. (b) Fässler,
A.; Bold, G.; Steiner, H. Tetrahedron Lett. 1998, 39, 4925-
4928. (c) Shibata, N.; Itoh, E.; Terashima, S. Chem. Pharm.
Bull. 1998, 46, 733-735. (d) Shibata, N. Katoh, S.; Terashima,
S. Tetrahedron Lett. 1997, 38, 619-620. (e) Sasai, H.; Kim,
W.-S.; Suzuki, T.; Shibasaki, M.; Mitsuda, M.; Hasegawa, J.;
Ohashi, T. Tetrahedron Lett. 1994, 35, 6123-6126.
(6) For other examples than ref 2 and 3, see: (a) Reetz, M. T.;
Drewes, M. W.; Harms, K.; Reif, W. Tetrahedron Lett. 1988,
29, 3295-3298. (b) Reetz, M. T. Angew. Chem. Int. Ed. Engl.
1991, 30, 1531-1546. (c) Gu, J.-H.; Okamoto, M.; Terada, M.;
Mikami, K.; Nakai, T. Chem Lett. 1992, 1169-1172.
(d) Ipaktschi, J.; Heydari, A. Chem. Ber. 1993, 126, 1905-
1912.
(19) Representative procedures: To a solution of the ligand (66 mg,
0.2 mmol) in CH2Cl2 (3.5 mL), Et2AlCl in hexane solution
(0.93 M, 0.2 mmol) was added at ambient temperature. After
30 min, a solution of aldehyde 14 (5 g, 20 mmol) in CH2Cl2
(50 mL) and TMSCN (3.2 mL, 24 mmol in 3.2 mL of CH2Cl2)
were added dropwise at 78 C. The reaction was completed
in 15 h in this scale. Adding H2O and usual workup gave a
crude mixture of 17 and the ligand. The mixture was treated
with 6 N HCl at 60 C for 48 h, and then the solution was
washed by in CH2Cl2. The aqueous layer was evaporated, and
recrystallization of the residue from MeOH/Et2O gave 3.2 g of
pure 29 (75% yield).
(20) The chiral ligand of 6 could be obtained in 5 steps from the
commercially available D-glucal: 1) hydrogenation (Pd/C, H2,
MeOH), 2) methanolysis (NaOMe, MeOH, then amberlyst
H+), 3) selective tosylation (TsCl, py), 4) introduction of
diphenylphosphino group (Ph2PK, THF), 5) oxidation (H2O2,
MeOH.
(7) For example, in ref 6a, a stoichiometric amount of BF3•OEt2
or ZnBr2 was used as a promotor and only anti isomer was
obtained with high selectivity (95:5). In ref 6c, 5 mol% of
Eu(fod)3 was used, however, the diastereomeric ratio was not
high (82:18).
Article Identifier:
1437-2096,E;2001,0,05,0617,0620,ftx,en;Y04701ST.pdf
Synlett 2001, No. 5, 617–620 ISSN 0936-5214 © Thieme Stuttgart · New York