LETTER
Simple Synthesis of (2S, 3R, 4R)-3,4-Dihydroxyproline
615
This methodology has been applied to the synthesis of The ambiguity about the intermediacy of 16 or 17 was re-
trans 3,4-dihydroxyproline 15. The compound 15, a con- solved by isolating the intermediate 5b in 50% yield.5 The
stituent amino acid of virotoxin in Amanita virosa mush- isolation of 5b indicates that 16 is probably not a major in-
rooms,6 exhibits an important role in biological systems termediate. Additionally, if 16 were formed it would like-
including glycosidase inhibition.7 A number of routes to ly exist as the hydroiodide salt and be unreactive towards
15 based on carbohydrates8 and noncarbohydrates9 have cyclization. The most likely mechanism for the formation
been reported. Most suffer from the lack of selectivity or of 15 from 11 is simple activation of the mesylate by io-
low overall yield. We started from the diisopropylidene dine which promotes intramolecular amination to give in-
mannonate 11, which was easily synthesized from D-glu- termediate 5b. The iodine increases the positive character
cono-d-lactone.10 The terminal isopropylidene group in 11 of the nitrogen of 5b and then the iodide attacks the ben-
was selectively cleaved by treatment with Dowex 50W- zylic position of the Pf group to give the desired natural
8X resin (H+-form) in 90% methanol to give diol 12. The product 15.
diol 12 was oxidized in presence of NaIO4: Sodium boro-
In conclusion, we found that iodine was an efficient re-
hydride reduction of the resulting aldehyde led to the for-
agent for deprotection of the Pf group of tertiary amines,
mation of alcohol 13 in quantitative yield. After
and for the one-pot cyclization of multiprotected com-
mesylation of alcohol 13, mesylate 14 was refluxed with
pounds such as 14. It should be attractive to expand one-
60% (w/w) iodine in methanol for 3 h. To the reaction
pot of cyclization and deprotection of Pf group toward
mixture was added Dowex 50W-8X which was then re-
polyhydroxylated aza sugars. We have also developed the
fluxed for an additional 2 h to hydrolyze the remaining
simplest route for the preparation of enantiomerically
pure (2S, 3R, 4R)-3,4-dihydroxyproline 15 in above 60%
overall yield from diisopropylidene mannonate 11.
methyl ester completely. The Dowex 50W-8X was fil-
tered and washed with methanol, then eluted with a 3N
NH3 solution to afford compound 1511 in 85% yield
(Scheme 2).
Acknowledgement
This work was supported by a grant from High-Technology De-
O
O
HO
O
O
O
velopment Project for Agriculture, Forestry and Fisheries. We also
thank the financial support of the Korea Research Foundation (No.
1998-015-D00175).
a
O
HO
90%
OCH3
OCH3
O
NHPf
O
NHPf
11
12
References and Notes
87%
O
b
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd Ed., John Wiley: 1991, 309–405, New York.
(2) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109,
236; Bergmeier, S. C.; Cobas, A. A.; Rapoport, H. J. Org.
Chem. 1993, 58, 2369; Park, K. H.; Rapoport, H. J. Org.
Chem. 1994, 59, 394.
(3) Cristie, B. D.; Rapoport, H. J. Org. Chem. 1985, 50, 1239;
Feldman, P. L.; Rapoport, H. J. Org. Chem. 1986, 51, 3882.
(4) Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R.
Tetrahedron Lett. 1986, 27, 3827.; Vaino, A. R.; Szarek, W.
A. Chem. Commun. 1996, 2351.
O
HO
OH
d
RO
OCH3
Pf :
85%
OH
O
NHPf
N
H
15
13: R = H
14: R = Ms
O
c
97%
Scheme 2. Conditions: a) Dowex 50W-8X, MeOH, 25 °C, 20 h;
b) NaIO4, EtOH, 2 h and NaBH4, 10min, 25 °C;. c) MsCl, Et3N,
THF, 25 °C; d) 60% (w/w) I2, MeOH, reflux, 4 h, and Dowex
50W-8X, MeOH, reflux, 3 h
(5) The remarkable difference may be due to the following
plausible reaction mechanism.
This step could also be achieved in one-pot with simulta-
neous deprotection of both the acetonide group and Pf
group followed by intramolecular amination. During the
one-pot ring closure giving 3,4-dihydroxyproline 15, it
was ambiguous whether iodine-promoted cyclization of
compound 15 occurs through either of the intermediates
16 or 17 (Scheme 3).
(6) Buku, A.; Faulstich, H.; Wieland, T.; Dabrowski, J. Proc.
Natl. Acad. Sci. U. S. A. 1980, 77, 2370.
(7) Rule, C. J.; Wurzburg, B. A.; Ganem, B. Tetrahedron Lett.
1985, 26, 5379; Winchester, B.; Fleet, G. W. J. Glycobiology
1992, 2, 199; Karl, J.-U.; Wieland, T. Liebigs Ann. Chem.
1981, 1445.
HO
OH
OH
O
(8) Karl, J.-U.; Wieland, T. Liebigs Ann. Chem. 1981, 1445;
Fleet, G. W. J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1,
119.
(9) Pohlit, A. M.; Correia, C. R. D. Hetereocycles 1997, 45, 2321;
Bols, M.; Lunt, I. Acta Chem. Scand. 1992, 46, 298; Arakawa,
Y.; Yoshifuji, S. Chem. Pharm. Bull. 1991, 39, 2219.
HO
I2
OCH3
OCH3
14
15
N
NHR
Pf-I
MsO
I
I
O
Pf
5b
16 : R = H
17 : R = Pf
Scheme 3
Synlett 1999, No. 5, 614–616 ISSN 0936-5214 © Thieme Stuttgart · New York