New polyhydroxylated pyrrolidines derived from enantiopure 3,6-dihydro-2H-1,2-oxazines

Article abstract of DOI:10.1021/ol0260573

(Matrix Presented) Diastereoselective hydroborations of enantiopure 3,6-dihydro-2H-1,2-oxazines led to dihydroxy-substituted 1,2-oxazines. Samarium diiodide-induced N-O bond cleavage generated 1,4-amino alcohols which were recyclized to polyhydroxylated pyrrolidines which are potential glycosidase inhibitors.

Full text of DOI:10.1021/ol0260573

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2353-2355
New Polyhydroxylated Pyrrolidines
Derived from Enantiopure
3,6-Dihydro-2H-1,2-oxazines
Robert Pulz, Ahmed Al-Harrasi, and Hans-Ulrich Reissig*
Institut fu¨r Chemie - Organische Chemie, Freie UniVersita¨t Berlin, Takustrasse 3,
D-14195 Berlin, Germany
Hans.Reissig@Chemie.FU-Berlin.de
Received April 22, 2002
ABSTRACT
Diastereoselective hydroborations of enantiopure 3,6-dihydro-2H-1,2-oxazines led to dihydroxy-substituted 1,2-oxazines. Samarium diiodide-
induced N−O bond cleavage generated 1,4-amino alcohols which were recyclized to polyhydroxylated pyrrolidines which are potential glycosidase
inhibitors.
We recently reported1 a new entry to enantiopure 3,6-
dihydro-2H-1,2-oxazines by addition of lithiated methoxy-
allene 2a to (R)-glyceraldehyde-derived nitrone 12 and
subsequent cyclization of the primary allene adducts. In THF,
1,2-oxazine 3a was formed with excellent syn-selectivity
whereas precomplexation of 1 with Et2AlCl in Et2O afforded
3a with high anti-preference. Thus, both diastereomers of
3a were obtained in enantiopure form. Lithiated benzyloxy-
allene 2b and 2-(trimethylsilyl)ethoxyallene 2c furnished the
corresponding syn-1,2-oxazines 3b,c in good yield and
diastereoselectivity (Scheme 1).
stereodivergent synthesis of 3-methoxypyrrolidines4 and of
enantiopure furan and pyran derivatives5 starting from 3a
and 3c. Oxygenation of the enol ether double bond of 3
should lead to protected azasugar derivatives (Scheme 2).
Scheme 2
1,2-Oxazines are known to be valuable intermediates in
synthetic organic chemistry.3 We earlier accomplished the
Scheme 1
Cleavage of the N-O bond should afford amino sugars,
while recyclization should give imino sugar derivatives,
which are known to be strong glycosidase inhibitors.6 Here-
in we present the diastereoselective hydroboration of
10.1021/ol0260573 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/08/2002

1,2-oxazines 3 and subsequent syntheses of polyhydroxylated
pyrrolidine derivatives.
Scheme 4a
Treatment of syn-3a with borane-THF complex7 and
subsequent oxidation of the boron species led to 5-hydroxy-
substituted 1,2-oxazine 4a as a single diastereomer which
was isolated in good yield after chromatography (Scheme
3). The relative configuration of the newly generated
Scheme 3a
a Reagents and conditions: (a) TIPSOTf, Et3N, CH2Cl2, rt, 1 d;
(b) NaH, BnBr, DMF, rt, overnight.
6 and 9 in moderate yield while benzylation of 4a and 4b
led to 7 and 8 in excellent yield (Scheme 4).
Attempts to cleave the N-O bond by known methods such
11
as catalytic hydrogenation,9 Zn/acetic acid,10 or Mo(CO)6
a Reagents and conditions: (a) BH3‚THF, THF, -30 °C to rt, 3
h rt then NaOH, H2O2, -10 °C to rt, overnight rt.
did not yield satisfactory results with our substrates. Sa-
marium diiodide is also well-known to affect N-O reductive
cleavage reactions.12 Reaction of 4c with SmI2 afforded
amino alcohol 10 in excellent yield and high purity. No
further purification was required. Similar results were
obtained with 1,2-oxazine derivatives 6-9 leading to the
expected amino alcohols 11-14 in 91% to quantitative yield
(Scheme 5).
stereocenter was proven by NOESY experiments. As ex-
pected the addition of BH3 to the enol ether double bond
proceeds to the sterically less hindered side of the 1,2-oxazine
ring. Reaction of 3b provided 4b as single diastereomer under
the same conditions in good yield. A similar result could be
obtained by reaction of 3c with BH3 which furnished 1,2-
oxazine 4c. Interestingly, treatment of anti-3a with borane
under standard conditions afforded the expected product 5a
only in moderate yield.8
Scheme 5
To avoid problems during subsequent cyclization of the
N-O bond cleaved products, we protected the free hydroxy
groups. Thus, treatment of 4a and 5a with TIPSOTf under
standard reaction conditions furnished protected 1,2-oxazines
(1) Schade, W.; Reissig, H.-U. Synlett 1999, 632-634.
(2) Synthesis: Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.;
Merino, P.; Tejero, T. Synth. Commun. 1994, 24, 2537-2550.
(3) Recent reviews: (a) Streith, J.; Defoin, A. Synlett 1996, 189-200.
(b) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137-165. (c)
Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317-1348.
(4) Pulz, R.; Watanabe, T.; Schade, W.; Reissig, H.-U. Synlett 2000,
983-986.
(5) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Synlett 2002, 817-819.
(6) (a) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T. Angew.
Chem. 1995, 107, 453-474 and 569-593; Angew. Chem., Int. Ed. Engl.
1995, 34, 412-432 and 521-546. (b) Iminosugars as Glycosidase
Inhibitors; Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, 1999. (c) Heightman,
T. D.; Vasella, A. T. Angew. Chem. 1999, 111, 794-815; Angew. Chem.,
Int. Ed. 1999, 38, 750-770. (d) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645-1680. (e)
Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV. 2002, 102,
515-553.
a 3 h.
The synthesis of polyhydroxylated pyrrolidine derivatives
was achieved in a one-pot procedure by treatment of amino
(7) Achab, S.; Das, B. C. J. Chem. Soc., Perkin Trans. 1 1991, 727-
732.
(8) After protection of the crude product and subsequent chromatography
two side products with cleaved N-O bond were isolated in 41% yield.
Similar results were obtained with anti-3b and anti-3c.
(9) See ref 4 and references therein.
(10) Denis, J.-N.; Tchertchian, S.; Tomassini, A.; Vallee, Y. Tetrahedron
Lett. 1997, 38, 5503-5506.
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Org. Lett., Vol. 4, No. 14, 2002

Scheme 6
Scheme 7a
a Reagents and conditions: (a) p-TsOH, MeOH, rt, 2 d; (b) H2,
Pd/C, HCl/MeOH, MeOH, rt, 22 h.
alcohols 11, 12, and 14 with 1.1-1.5 equiv of mesyl chloride
and triethylamine (Scheme 6). After column chromatography,
cyclization products 16-18 were isolated in moderate to very
good yields. One equivalent of mesyl chloride was not
sufficient to perform the cyclization of 10. However, use of
2 equiv furnished the O-mesylated pyrrolidine 15 in moderate
yield, which should allow introduction of other groups at
C-4 by nucleophilic substitution.
Cleavage of the dioxolane group was achieved by treat-
ment with p-toluenesulfonic acid. Thus, reaction of 17 led
to compound 19 in almost quantitative yield, and 18 was
deprotected under the same reaction conditions yielding 21
(Scheme 7). Catalytic hydrogenation of 19 with palladium
on charcoal in the presence of HCl led to O3-methylated 1,4-
dideoxy-1,4-imino-D-iditol hydrochloride 20 in high yield
and purity.
suitable tool for further synthetic operations. All compounds
were prepared from (R)-glyceraldehyde-derived nitrone 1 and
alkoxyallenes 2 in few straightforward steps which can be
carried out in gram scale. This again demonstrates the
versatility and practicability of alkoxyallenes as C3 building
blocks for stereoselective syntheses of heterocycles.13
Acknowledgment. The authors thank the Deutsche For-
schungsgemeinschaft, Fonds der Chemischen Industrie, and
Schering AG for financial support of this project. We thank
Sultan Qaboos University (Oman) for financial support of
master studies of A. A.-H. at Freie Universita¨t Berlin and
H. Go¨ksel and A. Karasch for experimental assistance.
Supporting Information Available: Detailed description
of experimental procedures and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, we have shown a new route to enantiopure
imino sugar derivatives. The diol side chain provides a
OL0260573
(11) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni,
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