Variable and stereoselective synthesis of azasugar analogues by a ruthenium-catalyzed ring rearrangement

Article abstract of DOI:10.1021/ol000188r

(Matrix presented) A novel ruthenium-catalyzed ring opening/ring closing tandem metathesis reaction with a catalytic transfer of stereocenters from a ring to an olefinic chain is described. This ring rearrangement serves as the key step in the stereoselec

Full text of DOI:10.1021/ol000188r

ORGANIC
LETTERS
2000
Vol. 2, No. 25
3971-3974
Variable and Stereoselective Synthesis
of Azasugar Analogues by a
Ruthenium-Catalyzed Ring
Rearrangement
Ulrike Voigtmann and Siegfried Blechert*
Institut fu¨r Organische Chemie, Technische UniVersita¨t Berlin,
Strasse des 17. Juni 135, 10623 Berlin, Germany
blechert@chem.tu-berlin.de
Received July 17, 2000
ABSTRACT
A novel ruthenium-catalyzed ring opening/ring closing tandem metathesis reaction with a catalytic transfer of stereocenters from a ring to an
olefinic chain is described. This ring rearrangement serves as the key step in the stereoselective synthesis of the new azasugar analogues
1 and 2.
During the past few years, ring closing metathesis (RCM)
has become a useful method in the synthesis of numerous
carbo- and heterocycles,1 mainly utilizing Grubbs’ ruthenium
catalyst [Ru].2 This method has also been increasingly
applied as a key step in the synthesis of important natural
products.3 The ruthenium-catalyzed ring opening metathesis
(ROM) has only rarely been used, with the principal
exception of polymerizations (ROMP),4 for the conversion
of strained cyclic olefins into monomeric products. For
example, ROM has successfully been combined with a highly
selective cross metathesis (CM) using an acyclic olefin to
avoid polymerization.5 A combination of ROM and RCM
by using suitably substituted cyclic olefins is possible as well.
Strained cyclic olefins bearing an alkene side chain rearrange
due to the loss of ring strain.6 Such ring rearrangement
reactions can also be combined with a final CM step.6a The
ROM of relatively unstrained cyclic olefins such as cyclo-
pentene and cyclohexene derivatives proceeds with reactants
bearing two olefinic substituents in combination with a
double RCM.7 The driving force of these tandem reactions
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Schuster, M.; Blechert, S. Angew. Chem. 1997, 109, 2124; Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2036. (c) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (d) Schmalz, H. G. Angew. Chem. 1995, 107, 1981;
Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (e) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 37.
(2) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs R. H. Angew. Chem.
1995, 107, 2179; Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(3) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.
Angew. Chem. 1997, 109, 170; Angew. Chem., Int. Ed. Engl. 1997, 36,
166. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653.
(c) Fu¨rstner, A.; Mu¨ller, T. J. Org. Chem. 1998, 63, 424. (d) Ziegler, F. E.;
Wang, Y. J. Org. Chem. 1998, 63, 426.
(5) (a) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S. Angew. Chem.
1997, 109, 257; Angew. Chem., Int. Ed. Engl. 1997, 36, 257. (b) Schneider,
M. F.; Blechert, S. Angew. Chem. 1996, 108, 479; Angew. Chem., Int. Ed.
Engl. 1996, 35, 410. (c) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J.
Am. Chem. Soc. 1995, 117, 9610. (d) La, D. S.; Ford, J. G.; Sattely, S. E.;
Bonitatebus, P. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 11603.
(4) (a) Grubbs, R. H. J. Macromol. Sci. Chem. 1994, A31 (11),1829. (b)
Schrock, R. R. Pure Appl. Chem. 1994, 66, 1447.
(6) (a) Stragies, R.; Blechert, S. Synlett 1998, 169. (b) Adams, J. A.;
Ford, J. G.; Stamatos, P. J.; Hoveyda, A. H. J. Org. Chem. 1999, 64, 9690.
10.1021/ol000188r CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/11/2000

is the entropy gain in the formation of a volatile olefin, which
is usually ethylene.
remarkable attention due to their ability to inhibit glycohy-
drolases resulting in potential antibacterial, antiviral, anti-
metastatic, or antidiabetes activity.10,11 Most of these active
compounds are naturally occurring alkaloids, isolated from
plants and microorganisms, and have been targets of many
total syntheses.10,12 However, unnatural analogues are inter-
esting targets as well and may be useful in obtaining a better
understanding of mechanisms of action and may aid in the
design of even more potent inhibitors.
Herein we would like to report a ruthenium-catalyzed ring
rearrangement of chiral cyclopentene derivatives of type I
and the application of this concept to the synthesis of new
indolizidine and quinolizidine azasugar analogues.
As depicted in Scheme 1, we assume that the most
accessible terminal double bond reacts initially with the
To the best of our knowledge, indolizidines and quino-
lizidines with the substitution patterns of 1 or 2, respectively,
are unknown and were therefore chosen for our synthesis.
Our efforts were focused on the creation of a flexible and
stereocontrolled access to these classes of compounds by
applying the methodology presented above.
Scheme 1
Both heterocycles can be obtained by diastereoselective
dihydroxylation and appropriate cyclization from the key
intermediate 3, which can be derived from the (1R,3S)-(+)-
cis-4-cyclopentene-1,3-diol 1-acetate 4 via the described ring
rearrangement (Scheme 2). The synthetic route to the
Scheme 2
catalyst to form the ruthenium-carbene complex II. The
intramolecular formation of a metallacyclobutane with the
endocyclic double bond in II followed by [2 + 2]-cyclo-
reversion forms carbene complex III. This process is faster
than the reaction of I with II, which would lead to
dimerization products, and these were not observed.
The catalytic cycle is completed by the reaction of III
with another molecule of I by methylene transfer yielding
product IV and re-forming the ruthenium carbene complex
II. In principle, dimerization would be possible too but was
not observed in the presence of ethylene. Since all steps in
this tandem process are reversible, the yield of IV strongly
depends on the different thermodynamic stabilities of
substrate I and product IV.8
This concept of ring rearrangement opens flexible access
toward heterocycles of defined configuration originating from
readily available enantiomerically pure carbocycles. In this
rearrangement reaction a catalytic transfer of stereocenters
from a cyclic core into a side chain takes place.
Heterocyclic structures such as piperidines, indolizidines,
or quinolizidines form the skeleton of many pharmaceuticals
and natural products.9 Polyhydroxylated indolizidine alka-
loids and their ring-expanded analogues have attracted
enantiomerically pure polyhydroxylated indolizidines and
quinolizidines 1 and 2 should allow for variation of the
configuration of the stereocenters by small modifications of
the synthetic pathway.
Compound 4 is readily prepared in high enantiomeric
purity (>99% ee) by enzymatic hydrolysis of the meso-
diacetate.13 Several enantiomerically pure metathesis precur-
(10) Iminosugars as Glucosidaseinhibitors; Stu¨tz, A. E., Ed.; Wiley-
VCH: Weinheim, 1998.
(11) (a) Schaller, C.; Vogel, P. Synlett 1999, 1219. (b) Pearson, W. H.;
Hembre, E. J. J. Org. Chem. 1996, 61, 5537. (c) Carretero, J. C.; Arrayas,
R. G.; De Garcia, I. S. Tetrahedron Lett. 1997, 38, 8537. (d) Herzegh, P.;
Kovacs, I.; Szilagyi, L.; Sztaricskai, F.; Bericibar, A.; Riche, C.; Chiaroni,
A.; Olesker, A.; Lukacs, G. Tetrahedron 1995, 51, 2969. (e) Rassu, G.;
Casiraghi, G.; Pinna, L.; Spanu, P.; Ulgheri, F.; Cornia, M.; Zanardi, F.
Tetrahedron 1993, 49, 6627. (f) Gradnig, G.; Berger, A.; Grassberger, V.;
Stu¨tz, A. E. Tetrahedron Lett. 1991, 32, 4889.
(12) (a) Trost, B. M.; Patterson, D. E. Chem. Eur. J. 1999, 11, 3279. (b)
Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547.
(13) (a) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876. (b)
Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287.
(7) (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 6634. (b) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org.
Chem. 1998, 63, 8626.
(8) (a) Adams, J. A.; Ford, J. G.; Stamatos P. J.; Hoveyda, A. H. J. Org.
Chem. 1999, 64, 9690. (b) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 1488. (c) Harrity, J. P. A.;
Visser, M. S.; Cefalo, D. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120,
2343.
(9) (a) Elbein, A. D.; Molyneux, R. J. in Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1987.
3972
Org. Lett., Vol. 2, No. 25, 2000

sors of type I can be synthesized from 4. The cis-
cyclopentene derivative 5a was obtained by Pd0-catalyzed
allylation of N-nosylbutenylamine with 4 (Scheme 3).14
Scheme 4a
Scheme 3a
a Reagents and conditions: (a) Pd(OAc)2, PPh3, N-nosylbute-
nylamine, DMF, rt to 40 °C (80%); (b) TBDMSCl, imidazole,
DMF, rt (98%); (c) 1 mol % [Ru], CH2Cl2, rt (95%).
Investigations in our group have shown that introduction
of the bulky TBDMS-protecting group, to give 5b, has a
favorable effect on the equilibrium of the ring rearrangement.
a Reagents and conditions: (a) (i) K2CO3, PhSH, DMF, 45 °C,
(ii) CbzCl, rt (82%); (b) OsO4, 2.5 equiv of NMO, acetone/H2O
1/1, 0 °C to rt (50% de); (c) (i) 4-MTrCl, Et3N, CH2Cl2, rt, (ii)
(MeO)2CMe2, PPTS, rt (90% over three steps); (d) NaIO4, HCOOH/
Et2O 1/1, 0 °C to rt (60%); (e) Pd/C, H2, methanol, rt (93%); (f)
AcOH, rf (50%) (MTrCl, 4-methoxytrityl chloride; NMO, N-
methylmorpholine N-oxide).
1
Whereas a 1:2-mixture (as judged by H NMR) of starting
material and rearranged product was obtained from 5a, the
rearrangement of 5b with only 1 mol % of [Ru] in CH2Cl2
resulted in the formation of a single product, 3, as determined
by NMR spectroscopy after approximately 24 h. We suppose
that a bulky protecting group causes differences in the relative
thermodynamic stabilities of substrate and product. Accord-
ing to Hoveyda,8a ethylene (an amount of approximately the
solvent volume) was added via syringe to the solution to
accelerate the rearrangement reaction and to avoid the
formation of dimerization byproducts.
After filtration through silica, the unsaturated piperidine
3, which serves as the key intermediate in the synthesis of
both heterocycles 1 and 2, was obtained in a virtually
quantitative yield.
The indolizidine azasugar 1 was prepared as shown in
Scheme 4. Deprotection of 3 followed by Cbz protection in
one pot yielded 6.
In the next step, both double bonds in 6 were dihydroxy-
lated by employing a catalytic amount of OsO4 and 2.5 equiv
of NMO to yield 7.15 As expected, the endocyclic double
bond was exclusively attacked from the R-side, whereas the
stereoselection at the side chain was rather low, resulting in
the formation of two diastereomers. However, the configu-
ration of the acyclic, secondary hydroxyl group was not
important in the synthesis. To differentiate between the
endocyclic and acyclic diol, in the subsequent synthesis steps,
the primary alcohol in 7 was selectively protected with the
sterically demanding 4-methoxytrityl group by employing
1.5 equiv of 4-methoxytrityl chloride, which was carefully
added over a period of 48 h.16 The remaining endocyclic
diol was then ketalized17 in dimethoxypropane over 78 h to
give the orthogonally protected piperidine derivative 8, which
was isolated in 90% yield over three steps.
The 4-methoxytrityl protecting group of 8 was selectively
removed under mild acidic conditions.18 Without workup,
the resulting free exocyclic diol was successfully cleaved
by addition of sodium periodate to give aldehyde 9 (60%
yield over two steps), which was considered an optimal
precursor for the closure of the second ring. Reductive
amination with Pd/C and H2 under atmospheric pressure
yielded indolizidine 10. Complete deprotection in refluxing
concentrated acetic acid gave the novel compound (2S,7S,8R,-
8aR)-octahydroindolizine-2,7,8-triol 1 in an overall yield of
13% over 11 steps.
A small variation of the synthetic route described above,
starting with key intermediate 3, also allows for the short
and stereoselective synthesis of polyhydroxylated quinoli-
zidines. First, 3 was deprotected to give alcohol 11 (Scheme
5) to serve as chelating compound in the next step.
Dihydroxylation of the terminal double bond in 11 with
(16) (a) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B.
J.; McGaarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc.
1983, 105, 1988. (b) Gaffney, P. R. J.; Changsheng, L.; Vaman Rao, M.;
Reese, C. B.; Ward, J. G. J. Chem. Soc., Perkin Trans. 1 1991, 1355. (c)
Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1992, 114, 5859.
(17) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290.
(14) (a) Heck, R. F. Palladium Reagents and Catalysts; Academic
Press: London, 1985. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV.
1996, 96, 395. (c) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New
York, 1995. (d) Gibson, S. E. Transition Metals in Organic Synthesis;
Oxford University Press: Oxford, 1997.
(15) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(b) Shoberu, K. A.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1992,
2419.
(18) Bessodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett. 1986,
27, 579.
Org. Lett., Vol. 2, No. 25, 2000
3973

from the dihydroxylation reaction was easily carried out by
column chromatography. The double bond in 14 enables
several possibilities for further functionalizations. Cis-
dihydroxylation with OsO4 and NMO yielded (1R,2S,7R,8S,-
9aR)-octahydroquinolizidine-1,2,7,8-tetrol 2 as a single
Scheme 5a
1
diastereomer (determined by H NMR) in an overall yield
of 13% (eight steps).
In summary, we present a highly efficient ring opening/
ring closing tandem metathesis process and the application
of this method to the syntheses of the new azasugar analogues
1 and 2. Starting from readily available enantiomerically pure
substrates, the intramolecular ring rearrangement concept
opens up flexible access toward substituted heterocycles with
defined stereochemistry transferring chirality from a me-
tathesis precursor into its products. Applications of this
approach to other members of the indolizidine or quinolizi-
dine family of alkaloids by simple modification of the routes
described above can be foreseen. Several studies on this
subject are currently being performed in our group.
a Reagents and conditions: (a) TBAF, THF, rt (96%); (b) OsO4,
1 equiv of NMO, acetone/H2O 1/1 0 °C to rt (60%) 70% de; (c)
K2CO3, PhSH, DMF, 40 °C (90%); (d) PPh3, DEAD, pyridine, 0
°C (53%); (e) OsO4, 1.5 equiv of NMO, acetone/H2O 1/1 0 °C to
rt (81%) > 95% de (DEAD, diethyl azadicarboxylate).
catalytic amounts of OsO4 and 1 equiv of NMO resulted in
chemoselective formation of the triol 12, which was isolated
in 60% yield with a diastereomeric ratio of 85:15. Complete
separation of the diastereomers was difficult at this stage
and was therefore performed after the cyclization step where
the configuration of the hydroxyl groups at C8 and C9 of
the major diastereomer were also assigned to the structure
given for quinolizidine 14 by NOED measurement.
Acknowledgment. A NaFo¨G scholarship (Berlin) for
U.V. is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 1-3 and 5-17
(1H NMR, 13C NMR, IR, HRMS; EA for 3, 5, 6, 9, 13, 14).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound 12 was deprotected and subjected to several
cyclization conditions. The best results were achieved by a
Mitsunobu reaction19 in pyridine at 0 °C to give 14 in 53%
yield. At this stage, the separation of diastereomers resulting
OL000188R
(19) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Chen, Y.; Vogel, P. J.
Org. Chem. 1994, 59, 2487.
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Org. Lett., Vol. 2, No. 25, 2000