Y. Noguchi et al. / Tetrahedron Letters 42 (2001) 5253–5256
5255
Me
Me
O-
Me
O
OH
Pd (0)
Pd+
CO2Et
CO2Et
CO2Et
NH
Z
N
Z
NH
Z
3
4
A
Pd(0)
Me
OH
Me
O-
Pd+
CO2Et
N
Z
CO2Et
NH
Z
3'
B
Figure 1. Mechanism of the Pd-catalyzed cyclization.
Me
Me
Me
OH
OH
OH
CHO
O3, MeOH, -78
+
then Me2S, 0
CO2Et
CHO
9 (82%)
N
Z
N
Z
N
Z
3 (90 : 10 mixture)
9' (9%)
Me
OH
Me
NaClO4, NaH2PO4
2-methyl-2-butene
tBuOH - H2O
OH
H2(1atm), Pd-C
9
MeOH, r.t., 24h
quant
26
CO2H
N
α
[
]
D = -40.2 (c 0.42, H2O)
D = -41 (c 0.4, H2O)
CO2H
N
H
r.t., 1.5h
88%
18
Z
[α
]
10
lit:
2
Scheme 4. Synthesis of (2S,3R)-3-hydroxy-3-methylproline (2).
ture of the present synthesis is that the stereochemistry
at C-2 and C-3 was controlled by Pd-catalyzed cycliza-
tion of alkenyloxirane without a base. Preparation of
other segments and the coupling toward the total syn-
thesis of polyoxypeptin are now in progress.
1), and was unambiguously confirmed by successful
correlation to 2. The isomeric 3% might be derived from
p-allyl palladium B formed by an intermolecular SN2-
type attack of Pd(0) to p-allyl palladium A. The forma-
tion of 3% is also possible by the direct epoxide opening
by 5-endo mode. However, this seems unlikely because
no reaction occurred without Pd(PPh3)4 in refluxing
THF.
References
Transformation of 3 into (2S,3R)-3-hydroxy-3-methyl-
proline (2) is summarized in Scheme 4. Cleavage of the
double bond using O3 oxidation gave the desired alde-
hyde 9 in 82% yield. The C2-epimer 9%, which was
derived from 3%, was separated from 9 by silica gel
column chromatography (9% yield). The aldehyde 9
was then oxidized with NaClO2, and finally deprotec-
tion of the benzyloxycarbonyl group with H2–Pd/C
completed the first synthesis of 2.8 Spectral data as well
as the optical rotation value of the synthetic 2 were in
good accordance with those of the natural (2S,3R)-3-
hydroxy-3-methylproline reported by Umezawa’s
group.1b
1. (a) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.;
Kondo, S.; Naganawa, H.; Kinoshita, N.; Hashizume, H.;
Hamada, M.; Takeuchi, T.; Ohba, S. Tetrahedron Lett.
1998, 39, 1389–1392; (b) Umezawa, K.; Nakazawa, K.;
Ikeda, Y.; Naganawa, H.; Kondo, S. J. Org. Chem. 1999,
64, 3034–3038.
2. (a) Noguchi, Y.; Yamada, T.; Uchiro, H.; Kobayashi, S.
Tetrahedron Lett. 2000, 41, 7493–7497; (b) Noguchi, Y.;
Yamada, T.; Uchiro, H.; Kobayashi, S. Tetrahedron Lett.
2000, 41, 7499–7502; (c) Recently, synthesis of the acyl
side-chain segment of polyoxypeptin was reported: Lorca,
M.; Kurosu, M. Tetrahedron Lett. 2001, 42, 2431–2434.
3. (a) Similar Pd-catalyzed intramolecular N-allylation of
carbamate, see: Takao, K.; Nigawara, Y.; Nishino, E.;
Takagi, I.; Maeda, K.; Tadano, K.; Ogawa, S. Tetrahedron
In conclusion we were able to achieve the first synthesis
of (2S,3R)-3-hydroxy-3-methylproline 2. The key fea-