Synthesis of a constrained polyfunctional bicyclic iminocyclitol scaffold from l-sorbose via a tandem sequence including stereoselective intramolecular Huisgen cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2009.05.060

The synthesis of a functionalized (azido, amino, and hydroxy) 8-oxa-3-azabicyclo[3.2.1]octane framework and its conversion into a protected sugar amino acid and a tricyclic framework is described. The sequence includes a one-pot Huisgen 1,3-dipolar cycloaddition, with decomposition to an aziridine and subsequent ring opening by azide. The stereoselectivity observed in the Huisgen cycloaddition reaction is attributed to minimization of allylic strain.

Full text of DOI:10.1016/j.tetlet.2009.05.060

Tetrahedron Letters 50 (2009) 4427–4429
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a constrained polyfunctional bicyclic iminocyclitol scaffold from
L-sorbose via a tandem sequence including stereoselective intramolecular
Huisgen cycloaddition
Ciaran O’Reilly a, Colin O’Brien a, Paul V. Murphy a,b,
*
a UCD School of Chemistry and Chemical Biology and Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
b School of Chemistry, National University of Ireland, Galway, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a functionalized (azido, amino, and hydroxy) 8-oxa-3-azabicyclo[3.2.1]octane frame-
work and its conversion into a protected sugar amino acid and a tricyclic framework is described. The
sequence includes a one-pot Huisgen 1,3-dipolar cycloaddition, with decomposition to an aziridine
and subsequent ring opening by azide. The stereoselectivity observed in the Huisgen cycloaddition reac-
tion is attributed to minimization of allylic strain.
Received 13 April 2009
Revised 28 April 2009
Accepted 15 May 2009
Available online 23 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
This Letter is dedicated to Professor R. N.
Butler on the occasion of his 65th birthday
A variety of scaffolds have been investigated in medicinal chem-
istry, including monosaccharides and related compounds.1 The use
of carbohydrate scaffolds in bioactive compound generation has
been a success in part because the inherent pyran or furan frame-
work contains multiple sites (alcohol, amine, and carboxylic acid)
to which pharmacophoric groups can be attached. Polyhydroxylat-
ed piperidines, also known as iminosugars or iminocyclitols, are
analogues of monosaccharides. The use of iminosugars as scaf-
folds2 for bioorganic and medicinal chemistry offers the possibility,
not available to pyranosides, of incorporating a charged hydrogen
bond donor through protonation of the ring nitrogen atom. In addi-
tion, pharmacophoric groups can be grafted to the nitrogen atom.
Iminocyclitols have been of significant interest as glycosidase
inhibitors3 prompting the development of a range of syntheses of
these and their related compounds. Herein we describe the synthe-
N
N
H
H
N
O
Huisgen
reaction
O
H
N
N
N
O
O
O
N
O
O
N
O
N
H
HO
HO
O
3
HO
1
2
Nu
H
O
N
O
O
O
O
Nu
- N2
Nu
O
O
O
N
HN
HO
4
HO
5
O
HO
Scheme 1. Synthesis of functionalized scaffold 5 from L-sorbose.
sis of a polyfunctionalized bicyclic iminocyclitol from
The product contains azide, amino, and hydroxy groups that would
facilitate its exploitation in medicinal chemistry.
Recently the intramolecular 1,3-dipolar cycloaddition reac-
tions4 of azides and alkenes (Huisgen reaction)5 were used in a se-
quence of reactions for the synthesis of 1-deoxynojirimycin (DNJ)
and close structural analogues from a sugar lactone percursor.6
As an extension, it was envisaged that the azide–alkene cycloaddi-
tion of substrate 1, obtained from readily available L-sorbose,
would provide access to the protected polyfunctional bicyclic scaf-
fold 5.
As in the DNJ synthesis it was anticipated that an intermediate
(Scheme 1) of the type 2 would be favored as it would minimize
L
-sorbose.
allylic strain and provide a single triazoline stereoisomer 3. The
intermediate triazoline would be expected to lose nitrogen, possi-
bly giving the aziridine 47 which on reaction with a nucleophile
would give the polyfunctional bicyclic compound 5.
The synthesis of 9 (Scheme 2) began from 7, which was avail-
able from L
-sorbose 6 (furanose form) as described previously.8
The regioselective ring opening of the more labile isopropylidene
group was carried out by treatment of 7 with 60% acetic acid at
60 °C for 2 h giving the diol 8 in good yield. With this diol in hand,
the exchange of the primary alcohol with an azide and subsequent
Huisgen reaction9 were next investigated. Diol 8 was thus treated
with thionyl chloride and pyridine in dichloromethane at 0 °C for
2 h giving a cyclic sulfite. This intermediate was treated with ex-
cess sodium azide in DMF at 110 °C. The crystalline bicyclic prod-
uct 9 was isolated in 40% yield; other by-products were not
obtained. The formation of 9 is explained by the cascade sequence
* Corresponding author. Fax: +353 91 525700.
E-mail address: paul.v.murphy@nuigalway.ie (P.V. Murphy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.060

4428
C. O’Reilly et al. / Tetrahedron Letters 50 (2009) 4427–4429
one-pot sequence included azide incorporation, Huisgen cycload-
OH
OH
O
O
O
dition, triazoline decomposition, aziridine formation, and its
subsequent reaction with azide. The 8-oxa-3-azabicyclo[3.2.1-
]octanes are of medicinal interest. For example, achiral 8-oxa-3-
azabicyclo[3.2.1]octane12,13 has analgesic and anti-inflammatory
effects in vivo14 and analogues have been prepared.15 The pro-
tected amino acid 10 could have application in peptidomimetic
development.16 Sorbose derivative 9 can be considered a conform-
ationally constrained morpholine derivative17 and is structurally
related to bicyclic alkaloids with nortropane skeletons, which have
been found to have biological activity as glycosidase inhibitors.18
Lactam 12 contains a tricyclic framework.19 A recent analysis of
scaffolds investigated in organic chemistry showed that a small
number of frameworks are found in a large number of all known
compounds.20 The approach described herein using readily avail-
able carbohydrate precursors has potential to be applied to gener-
ating new functional frameworks for organic chemistry.
Ref. 8
46%
O
HO
O
O
OH
HO
7
6
1. SOCl2, py.
O
O
60% AcOH, 79%
HO
2. NaN3, DMF,
heat, 40% two
steps
O
HO
8
N3
N3
H
H
N
N
HCl, MeOH
60%
O
O
OH
O
O
HO
HO
OH
9
10
Scheme 2.
Acknowledgments
described in Scheme 1, where, under the reaction conditions, it was
not possible to observe the triazoline or aziridine intermediates.10
Efforts to improve the yield of 9 from the one-pot reaction were
not successful. The X-ray crystal structure of 9 (Fig. 1) confirmed
the structure of the bicyclic compound and the configuration of
the newly generated stereocenter. Removal of the isopropylidene
from 9 was effected using 0.2 M HCl in MeOH to give polyhydroxy-
lated compound 10.
The authors are grateful to the UCD NMR and MS services and to
Dr. Helge Mueller-Bunz for the X-ray crystal structure determina-
tion. The research was supported by Science Foundation Ireland
(PI/IN1/B966, 03/IBN/B352) and the Higher Education Authority’s
Programme for Research in Third Level Institutions.
Treatment of 9 with ethyl bromoacetate in THF along with a
catalytic amount of tetrabutylammonium iodide gave 11 (61%),
which can be considered to be a protected sugar amino acid.11 Cat-
alytic hydrogenation of 11 caused reduction of the azide to the
amine which led to spontaneous lactam formation; subsequent re-
moval of the acetonide from the intermediate gave tricyclic deriv-
ative 12 in 58% yield over two steps (Scheme 3).
Supplementary data
Supplementary (general experimental methods, experimental
procedures, analytical data, 1H and 13C NMR spectra, crystallo-
graphic information file for 9) data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.05.060.
In summary, iminocyclitols with an ether bridge have been pre-
References and notes
pared in a concise and stereoselective manner from L-sorbose. The
1. For recent reviews on carbohydrates as scaffolds, see: (a) Murphy, P. V.;
Velasco-Torrijos, T. In Glycoscience—Chemistry and Chemical Biology; Fraser-
Reid, B., Tatsuta, K., Thiem, J., Eds., 2nd ed.; Springer: Berlin, Heidelberg, 2008; p
997; (b) Velter, I.; La Ferla, B.; Nicotra, F. J. Carbohydr. Chem. 2006, 25, 97–138;
(c) Meutermans, W.; Le, G. T.; Becker, B. Chem. Med. Chem. 2006, 1, 1164–1194.
2. (a) Le Merrer, Y.; Poitout, L.; Depezay, J. C.; Dosbaa, I.; Geoffroy, S.; Foglietti, M.
J. Bioorg. Med. Chem. 1997, 5, 519–533; (b) Gouin, S.; Murphy, P. V. J. Org. Chem.
2005, 70, 8527–8532; (c) Chagnault, V.; Lalot, J.; Murphy, P. V. Chem. Med.
Chem. 2008, 3, 1071–1076; (d) Chery, F.; Cronin, L.; O’Brien, J.; Murphy, P. V.
Tetrahedron 2004, 60, 6597–6608; (e) Chery, F.; Murphy, P. V. Tetrahedron Lett.
2004, 45, 2067–2069; (f) Danieli, E.; Lalot, J.; Murphy, P. V. Tetrahedron 2007,
63, 6827–6834.
3. (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 135–162; (b) Winchester, B.;
Fleet, G. W. J. Glycobiology 1992, 2, 199; (c) D’Alonzo, D.; Guaragna, A.;
Palumbo, G. Curr. Med. Chem. 2009, 16, 473–505; (d) Cox, T. M.; Platt, F. M.;
Aerts, J. M. F. G. In Iminosugars; Compain, P., Martin, O. R., Eds.; John Wiley &
Sons Ltd: Chichester, UK, 2007; pp 295–326; (e) Greimel, P.; Spreitz, J.; Stutz, A.
E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513–523.
N1
N2
C5
N3
N4
C6
O1
C3
C4
O3
C7
C8
C1
C10
C9
O4
O2
C2
Figure 1. ORTEP representation of the X-ray crystal structure of 9. The atomic
4. For reviews on intramolecular 1,3-dipolar cycloaddition in targeted synthesis,
see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–12275; (b) Padwa, A. In
1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Vol. 2; Wiley-Interscience:
New York, 1984; p 316.
5. Huisgen, R. J. Org. Chem. 1968, 33, 2291–2297.
6. Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777–3780.
displacement parameters are at the 50% level. CCDC 731460.
N3
O
EtO2C
H
N
N3
O
Br
CO2Et
N
O
TBAI, Et3N, THF
O
7. Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem.
2007, 72, 4886–4891.
8. (a) Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3413–3416; (b) Izquierdo Cubero,
I.; Lopez-Espinosa, M. T. P.; Kari, N. Carbohydr. Res. 1994, 261, 231–242.
reflux, 6 h
63%
O
HO
HO
O
9. For
a review on applications of organic azides including alkene–azide
O
9
11
cycloadditions, see: Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240.
NH
N
1. Pd-C, H2
EtOAc, 83%
10. Herein is described a tandem azide substitution–cycloaddition reaction. For
examples of tandem alkene formation–cycloaddition sequences using sugar
derivatives, see: (a) Herdeis, C.; Schiffer, T. Tetrahedron 1999, 55, 1043–1056;
(b) Attia, M. I.; Timmermann, M.; Högger, P.; Herdeis, C. Eur. J. Org. Chem. 2007,
3669–3675.
O
2.HCl-MeOH
70%
OH
11. For reviews on sugar amino acids, see: (a) Gruner, S. A. W.; Locardi, E.; Lohof,
E.; Kessler, H. Chem. Rev. 2002, 102, 491–514; (b) Schweizer, F. Angew. Chem.,
Int. Ed. 2002, 41, 231–253.
HO
OH
12
12. Neth, H.; Wiggins, L. F. J. Chem. Soc. 1948, 155–158.
Scheme 3.

C. O’Reilly et al. / Tetrahedron Letters 50 (2009) 4427–4429
4429
13. Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov, D. V.; Plaisier, J. R.;
Van der Marel, G. A.; Overkleeft, H. S.; Van Boom, J. H. Tetrahedron: Asymmetry
2005, 16, 177–185.
14. Cope, A. C.; Baxter, W. N. J. Am. Chem. Soc. 1955, 77, 393–396.
15. (a) Kilonda, A.; Dequeker, E.; Compernolle, F.; Delbeke, P.; Toppet, S.; Babady,
B.; Hoornaert, G. J. Tetrahedron 1995, 51, 849–858; (b) Poitout, L.; Le Merrer, Y.;
Depezay, J. C. Tetrahedron Lett. 1996, 37, 1613–1616.
16. (a) Hirschmann, R. Angew. Chem., Int. Ed. 1991, 30, 1278–1301; (b) Nicolaou, K.
C.; Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.; Freidinger, R. M.;
Hirschmann, R. In Peptides: Chemical Structure and Biology; Marshall, G. R., Ed.;
Escom: Leiden, 1990; pp 881–884; (c) Hirschmann, R.; Nicolaou, K. C.;
Pietranico, S.; Salvino, J.; Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A.
B., III; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.;
Maechler, L. J. Am. Chem. Soc. 1992, 114, 9217–9218.
18. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2005, 12, 1239–1287; (b) Asaano, N.; Kato, A.; Miyauchi, M.; Kizu, H.;
Tamimori, T.; Matsui, K.; Nash, R. J.; Molyneux, R. J. Eur. J. Biochem. 1997,
248, 296–303.
19. The generation of polyfunctional scaffolds from a monosaccharide is a means
of further increasing the diversity of scaffolds, see: (a) Holt, D. J.; Barker, W. D.;
Jenkins, P. R.; Panda, J.; Ghosh, S. J. Org. Chem. 2000, 65, 482–493; (b) Cervi, G.;
Peri, F.; Gennari, C.; Battistini, C.; Nicotra, F. Bioorg. Med. Chem. 2006, 14, 3349–
3367; (c) Timmer, M. S. M.; Verdoes, M.; Sliedregt, L.; van der Marel, G. A.; van
Boom, J. H.; Overkleeft, H. S. J. Org. Chem. 2003, 68, 9406–9411; (d) Reddy, B. G.;
Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44, 2001–2004; (e) Laventine, D. M.;
Jenkins, P. R.; Cullis, P. M. Tetrahedron Lett. 2005, 46, 2295–2298; (f) Abrous, L.;
Jokiel, P. A.; Friedrich, S. R.; Hynes, J.; Smith, A. B.; Hirschmann, R. J. Org. Chem.
2004, 69, 280–302.
17. Morpholine based scaffolds have recently been of interest, see: Sladojevich, F.;
Trabocchi, A.; Guarna, A. Org. Biomol. Chem. 2008, 6, 3328–3336.
20. Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F., III; Schenck, R. J.;
Trippe, A. J. J. Org. Chem. 2008, 73, 4443–4451.