under similar conditions in the previous report.1 It seems
that the intramolecular addition is much faster here than the
dehydroxymethylation. The initial reaction with KOH (1.0
equiv) as base showed moderate selectivity (about 5:1) for
the desired trans diastereomer of 7.
Scheme 1a
The optimal conditions for 7 trans in the cyclization step
were then explored. The effects of the amount of base, the
concentration of 6, and the type of base on the diastereo-
selectivity of the conjugate addition were examined, and the
results are shown in Tables 1 and 2. First, the effect of the
Table 1. Effect of Amount of KOH and Concentration of
Substrate 6 on Diastereoselectivity
KOH
concn of 6
ratio
(7 tr a n s:7 cis)a
yield
(%)
entry
(equiv)
(M)
1
2
3
4
5
6
0.1
0.5
1.0
1.0
1.0
1.0
0.33
0.33
0.10
0.33
0.44
1.00
2.5:1
5.6:1
3.8:1
8.0:1
9.6:1
10.4:1
82
95
88
85
86
57
a Reagents and conditions: (i) cat. CSA, (CH2O)n, PhH, reflux
(80%) and then NaBH4, MeOH, 0 °C (85%); (ii) Ph3PdCHCO2Me,
PhH, reflux (95%); (iii) K2CO3, MeOH, rt (85%); (iv) 6 N HCl,
reflux; (v) ion-exchange resin column and then recrystallization
(41%).
a The ratio was determined by GC.
attracted a lot of interest because of its potential use in the
treatment of hypertension and congestive heart failure.
Considerable efforts have been devoted to the asymmetric
synthesis of statine and its analogues.3,6-8 However, there
has been no successful synthetic study for (-)-statine with
conjugate addition of the hydroxyl group, although this
method looks conceptually simple and has been utilized with
carbohydrates.9
A diastereomeric mixture of the L-leucinal derivative 5
was prepared from commercially available N-Boc-L-leucine
in 68% overall yield in two steps (Scheme 1).1 However,
the NaBH4 reduction10 of 4 was employed in the present
study to give higher yield (85%) of 5 because the reduction
with DIBALH resulted in lower yield (75%). The Wittig
olefination of 5 with the stabilized ylide afforded the desired
(E)-γ-amino-R,â-conjugated ester 6 with the N-hydroxy-
methyl group in excellent yield and selectivity. No (Z)-alkene
was detectable, and the N-hydroxymethyl group was stable
under the reaction conditions. We were gratified that an
intramolecular conjugate addition of the hydroxyl group of
6 was successful to give the expected cyclized product,
oxazolidine 7. The N-hydroxymethyl group was removed
amount of KOH was examined under constant concentration
of 6 (0.33 M in MeOH). The results in Table 1 (entries 1, 2,
Table 2. Effect of Type of Base on Diastereoselectivity
reaction
time (h)
ratio
(7 tr a n s:7 cis)b
yield
(%)
entry
basea
Et3N
1
2
3
4
5
6
20
1
60
1
0.5
0.5
1.7:1
4.3:1
2.1:1
10.7:1
10.5:1
10.4:1
88
87
83
85
54
57
DBU
NaHCO3
K2CO3
NaOH
KOH
a One equivalent of base was used with 1.0 M of 6. b The ratio was
determined by GC.
and 4) indicate that increase of the amount of KOH gives
better selectivity. The conjugate addition with KOH was
usually complete within 30 min at room temperature. Next,
the effect of concentration of 6 was investigated (entries
3-6). In all cases, 1 equiv of KOH was used. Increase of
the reaction concentration produces better selectivities.
However, the yield of the ester product is low at higher
concentration (entry 6) because the ester is partially hydro-
lyzed to give the corresponding carboxylic acid as a
byproduct.
To alleviate the problem of partial hydrolysis at higher
concentration, we have conducted the conjugate addition with
several weaker bases at 1.0 M concentration of 6 in MeOH
(Table 2). The best diastereoselectivity was attained with K2-
CO3, and the yield was satisfactory, too (entry 4). Although
NaOH gave selectivity comparable to that of KOH, the same
(6) (a) Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995, 60, 6248.
(b) D’Aniello, F.; Mann, A.; Matii, D.; Taddei, M. J. Org. Chem. 1994,
59, 3762 and references therein.
(7) (a) Kessler, H.; Schudok, M. Synthesis 1990, 457. (b) Kazmaier, U.;
Krebs, A. Tetrahedron Lett. 1999, 40, 479.
(8) (a) Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans. 1
1987, 1177. (b) Ma, D.; Ma, J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry
1996, 7, 2365.
(9) For the unsuccessful effort on the intramolecular conjugate addition,
see: Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1987, 28, 3987. For the
intramolecular conjugate addition of a hydroxyl group with carbohydrates,
see: (a) Lichtenthaler, F. W.; Klinger, F. D.; Jarglis, P. Carbohyd. Res.
1984, 132, C1-C4. (b) Buchanan, J. G.; Edgar, A. R.; Hewitt, B. D. J.
Chem. Soc., Perkin Trans. 1 1987, 2371.
(10) (a) Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.; Arison, B. H. J.
Org. Chem. 1983, 48, 77. (b) Reddy, G. V.; Rao, G. V.; Iyengar, D. S.
Tetrahedron Lett. 1999, 40, 2653.
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Org. Lett., Vol. 4, No. 7, 2002