Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes: Incorporation of polyhydroxylated carbocyclic β-amino acids into peptides

Article abstract of DOI:10.1021/ol034127f

(Matrix presented) A promising new strategy for the transformation of nitrohexofuranoses into cyclopentylamines, based on intramolecular cyclization followed by controlled opening of the resulting 2-oxabicyclo[2.2.1]heptane derivatives, allowed the first

Full text of DOI:10.1021/ol034127f

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1423-1425
Stereocontrolled Transformation of
Nitrohexofuranoses into
Cyclopentylamines via
2-Oxabicyclo[2.2.1]heptanes:
Incorporation of Polyhydroxylated
Carbocyclic â-Amino Acids into
Peptides
Raquel G. Soengas, Juan C. Este´vez, and Ramo´n J. Este´vez*
Departamento de Qu´ımica Orga´nica, UniVersidade de Santiago,
15782 Santiago de Compostela, Spain
qorjec@usc.es
Received January 23, 2003
ABSTRACT
A promising new strategy for the transformation of nitrohexofuranoses into cyclopentylamines, based on intramolecular cyclization followed
by controlled opening of the resulting 2-oxabicyclo[2.2.1]heptane derivatives, allowed the first total synthesis of a carbocyclic â-amino acid
and its incorporation into peptides. This strategy also afforded a new route to cyclopentylamines with well-known glycosidase inhibition
properties.
The biological functions and pharmacological limitations of
natural peptides have in recent years prompted intense work
on the preparation of analogues with pharmacological
advantages.1 Particularly interesting are oligomers of â-amino
acids, which have pharmacologically interesting properties
associated with their resistance to enzymatic degradation and
which tend to be more rigid than R-peptides.2 Accordingly,
there has recently been much interest in the enantioselective
synthesis of â-amino acids,3,4 including water-soluble hy-
droxylated5 or aminated6 derivatives of sugar â-amino acids
(a class of carbopeptoids7). Major contributions to this field
by Kessler, Fleet, and others have resulted in the preparation
of a plethora of oxetose, furanose, and pyranose amino acids
and in their assembly as peptides that adopt interesting
secondary structures.8
(1) For reviews, see: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 717.
(b) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr. Opin. Struct.
Biol. 1999, 9, 530. (c) Stigers, K. D.; Soth, M. J.; Nowick, J. S. Curr.
Opin. Chem. Biol. 1999, 3, 714. (d) Andrews, M. J. L.; Tabor, A. B.
Tetrahedron 1999, 55, 11711. (e) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. ReV. 2001, 101, 3131.
(2) For a recent review on â-peptides which includes references to work
by the Seebach and the Gellman groups, the most active in this field, see:
Cheng, R. P.; Gellman, S. H.; DeGrado, W. Chem. ReV. 2001, 101, 3219.
(3) For a recent book, see: Enantioselective Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
10.1021/ol034127f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/29/2003

The conversion of sugars into carbocycles is another area
that has attracted considerable attention,9 and the pharma-
cological promise of carbasugars10 has prompted the devel-
opment of several approaches to the synthesis of optically
pure carbasugars from sugars and other chiral sources.11 In
fact, particular attention has been paid to amino carbasugars
such as 17, a mannosidase inhibitor, and other inhibitors of
glycosidases,12 due to their potential for the treatment of
diseases involving carbohydrate metabolism or glycoprotein-
mediated processes13 (diabetes, cancer, viral infections, etc.).
Similar work on polyhydroxylated cycloalkyl amino acids
has been much less abundant: as far as we know, the
preparation of this kind of compounds from sugars has been
limited to the preparation of a polyhydroxylated cyclohexane
R-amino acid and two polyhydroxylated cyclopentane R-ami-
no acids,14 and neither total nor partial synthesis of similar
â-amino acids has been reported.
trated by the easy transformation of glucofuranose derivative
1 into a tripeptide containing a polyhydroxylated cyclopen-
tane â-amino acid via the corresponding lactone (Scheme
1).
Scheme 1. Synthesis of Peptides Containing Alicyclic
â-Amino Acids
This paper reports preliminary results on the synthesis of
polyhydroxylated alicyclic â-amino acids from sugars, ilus-
(4) For reviews on the synthesis of â-amino acids, see: (a) Cole, D. C.
Tetrahedron 1994, 50, 9517. (b) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181.
(c) Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629. Recent articles
in this field include: (d) Martin Vila, M.; Minguillon, C.; Ortuno, R. M.
Tetrahedron: Asymmetry 1998, 9, 4291. (e) Gademann, K.; Jaun, B.;
Seebach, D.; Perozzo, R.; Scapozza, L.; Folkers, G. HelV. Chim. Acta 1999,
82, 1. (f) Abele, S.; Guichard, G.; Seebach, D. HelV. Chim. Acta 1998, 81,
2141. (g) Chung, Y. J.; Christianson, L. A.; Stanger, H. E.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1998, 120, 10555. (h) Applequist, J.;
Bode, K. A.; Apella, D. H.; Christianson, L. A.; Gellman, S. H. J. Am.
Chem. Soc. 1998, 120, 4891. (i) Daura, X.; Gademann, K.; Jaun, B.;
Seebach, D.; vanGunsteren, W. F.; Mark, A. E. Angew. Chem., Int. Ed.
1999, 38, 236.
(5) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206.
(6) Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J. Org.
Chem. 2000, 65, 4766.
(7) Nicolaou, K. C.; Flo¨rke, H.; Egan, M. G.; Barth, T.; Estevez, V. A.
Tetrahedron Lett. 1995, 36, 1775.
(8) For a recent review on sugar amino acids, see: Gruner, S. A. W.;
Locardi, E.; Lohof, E.; Kessler, H. Chem. ReV. 2002, 102, 491.
(9) For reviews on the preparation of carbocycles from carbohydrates,
see: (a) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779. (b) Fraser-
Reid, B.; Tsang, R. In Strategies and Tactics in Organic Synthesis;
Academic Press: New York, 1989; Vol. 2, Chapter 4.
(10) Suami, T.; Ogawa, S. AdV. Carbohydr. Chem. Biochem. 1990, 48,
21.
Reaction of the easily prepared nitroglucofuranose deriva-
tive 115 with trifluroacetic acid and water, followed by
anomeric oxidation16 of the resulting hydroxy lactol 2 with
bromine and barium carbonate, afforded the lactone 3 as a
yellow oil (58% yield from 1). Reaction of 3 with triflic
anhydride in pyridine furnished the corresponding triflate 4,
which when treated with TBAF in THF readily underwent
intramolecular displacement of the triflate group by the
carbanion R to the nitro group, affording the bicyclic
(11) (a) Ogawa, S. In Studies in Natural Products Chemistry; Rahman,
A.-U.; Ed.; Elsevier Science: New York, 1993; Vol. 13, p 187. (b) Suami,
T. Pure Appl. Chem. 1987, 59, 1509. (c) Hudlicky, T.; Entwistle, D. A.;
Pitzer, K. K.; Thorpe, A. J. Chem. ReV. 1996, 96, 1195. (d) Arjona, O.;
Plumet, J. Recent Res. DeV. Org. Chem. 1999, 3, 265.
(12) For two recent reviews on inhibitors of glicosidases, see: (a) Asano,
N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645. (b) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M.
Chem. ReV. 2002, 102, 515. Recent selected articles in this field: (c) Uchida,
C.; Ogawa, S. Recent Res. DeV. Pure Appl. Chem. 1999, 3, 161. (d) Leroy,
E.; Reymond, J.-L. Org. Lett. 1999, 1, 775. (e) Boss, O.; Leroy, E.; Blaser,
A.; Reymond, J.-L. Org. Lett. 2000, 2, 151. (f) Kleban, M.; Hilgers, P.;
Greul, J. N.; Kugler, R. D.; Li, Jing; P., Sylviane; V., Pierre; Jager, V.
ChemBioChem 2001, 2, 365. (g) Greul, J. N.; Kleban, M.; Schneider, B.;
Picasso, S.; Jager, V. ChemBioChem 2001, 2, 368.
(13) Recent reviews: (a) Hughes, A. B.; Rudge, A. J. J. Nat. Prod. 1994,
57, 135. (b) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 5. (c) Ganem,
B. Acc. Chem. Res. 1996, 29, 340. (d) Bols, M. Acc. Chem. Res. 1998, 31,
1. (e) Heighten, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. Engl. 1999,
38, 750. (f) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 1999, 38,
2300. (g) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV. 1999,
99, 779.
(14) (a) Fairbanks, A. J.; Hui, A.; Skead, B. M.; de Q. Lilley, P. M.;
Lamont, B.; Storer, R.; Saunders: J.; Watkin, D. J.; Fleet, G. W. J.
Tetrahedron Lett. 1994, 35, 8891. (b) Hui, A.; Fairbanks, A. J.; Nash, R.
J.; de Q. Lilley, P. M.; Storer, R.; Watkin, D. J.; Fleet, G. W. J. Tetrahedron
Lett. 1994, 35, 8895.
â-nitrolactone 5, in 41% yield from 3 ([R]20 -35 (c 0.85
D
in chloroform)). Subsequent selective reduction of the nitro
group of 5 by catalytic hydrogenation with Raney nickel
yielded the desired amino derivative 6. As the lactone of a
polyhydroxylated cyclopentane â-amino acid, we aimed to
(15) Compound 1 was easily prepared by ozonolysis of the corresponding
azide, which was obtained from D-glucose, as per: Fleet, G. W. J.; Carpenter,
N. M.; Petursson, S.; Ramsden, N. G. Tetrahedron Lett. 1990, 31, 409-
412.
(16) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
45, 327.
1424
Org. Lett., Vol. 5, No. 9, 2003

Scheme 2. Synthesis of Polyhydroxylated Cyclopentylamine
17
Figure 1. Molecular structure of compound 13 in the solid state.
nickel gave amine 14, which was directly treated with benzyl
chloroformate and sodium bicarbonate to obtain bicycle 15
in 70% yield from 13 ([R]20D -32.2 (c 1.2 in chloroform)).
Subsequent hydrolysis of acetal 15 with trifluoroacetic acid
was followed by the immediate reduction with NaBH4 of
the implicit carbonyl group of the resulting bicyclic hemi-
acetal 16 ([R]20D +103.64 (c 2.2 in methanol)). The resulting
cyclopentanoid was directly transformed into amino carba-
sugar hydrochoride 17 by removal of the benzyl and Z
protecting groups by hydrogenation using Pd/C as the catalyst
and subsequent addition of hydrochloric acid (50% overall
yield from 15).
use this compound as the basis for the construction of
peptides containing this â-amino acid.
In summary, we have developed a promising new strategy
for the transformation of nitrosugars into carbasugars which
allowed us to carry out the first total synthesis of a
polyfunctionalized cyclopentane â-amino acid with total
stereochemical control and incorporate it into a peptide. This
intramolecular R-alkylation of nitrosugars also provided a
convenient new route to the powerful glycosidase inhibitor
17, selective oxidation of which at its primary alcohol should
constitute an alternative path to polyhydroxylated cyclopen-
tane â-amino acids.
We are currently applying this strategy systematically to
other sugars studying the preparation and properties of homo-
and heteropeptides derived from the resulting cycloalkane
â-amino acids.
Freshly isolated 6 was subjected to peptide coupling with
ethyl chloroformate, triethylamine and benzyloxycarbonyl-
glycine, giving the expected dipeptide 7. Treatment of 7 with
hydrazine in methanol gave hydrazide 8, and this unstable
gum was directly reacted with tert-butyl nitrite and HCl. The
resulting acyl azide 9 in turn directly reacted with methoxy-
carbonylglycine and triethylamine giving tripeptide 10 (65%
yield from 7, [R]20 -3.2 (c 1.05 in methanol)).
D
A slight modification of the above route to alicyclic
â-amino acids allowed us to obtain the cyclopentylamine
17. Reaction of R-hydroxy furanoside 2 with acetyl chloride
in methanol provided 11 in 90% yield as a 1:1 epimeric
mixture, and the C2 hydroxy group of this compound was
converted into an OTf leaving group as before by reaction
with triflic anhydride in pyridine (Scheme 2). Treatment of
the resulting mixture of compounds 12 with TBAF afforded
Acknowledgment. We thank the Spanish Ministry of
Science and Technology for financial support and for a FPI
grant to Raquel G. Soengas and Prof. George W. J. Fleet
for useful suggestions and discussions.
the bicycle 13 in 46% yield from 11 ([R]20 -47.2 (c 1 in
D
chloroform)). The sterereochemisty of 13, firmly established
by X-ray crystallography (Figure 1),17 suggests it must have
been formed by an intramolecular cyclization of the â isomer
of compound 12. Catalytic hydrogenation of 13 using Raney
Supporting Information Available: Experimental pro-
cedures for all compounds and spectroscopic data for
compounds 1, 3, 5-7, 10, 11, 13, 15, and 17. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Crystallographic data for the structure of compound 13 have been
deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC-205610. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, U.K. (fax (+44)1223-336-033; e-mail deposit@ccdc.cam.ac.uk).
OL034127F
Org. Lett., Vol. 5, No. 9, 2003
1425