A new scaffold for the stereoselective synthesis of α-O-linked glycopeptide mimetics

Article abstract of DOI:10.1021/jo049441h

α-O-Linked glycohomoglutamates are obtained as diastereomerically pure compounds by chemo-, regio-, and stereoselective cycloadditions between glycals and aspartic acid derivatives. The latter constitute orthogonally functionalized scaffolds for glycopept

Full text of DOI:10.1021/jo049441h

SCHEME 1. Syn th esis of â-Ketoester s 2 a n d
Glycoh om oglu ta m a tes 5
A New Sca ffold for th e Ster eoselective
Syn th esis of r-O-Lin k ed Glycop ep tid e
Mim etics
Francesca Venturi, Chiara Venturi, Francesca Liguori,
Martina Cacciarini, Monica Montalbano, and
Cristina Nativi*
Dipartimento di Chimica Organica “Ugo Schiff”,
Universita` di Firenze, via della Lastruccia,
13 I-50019 Sesto Fiorentino (FI), Italy
cristina.nativi@unifi.it
Received April 5, 2004
Abstr a ct: R-O-Linked glycohomoglutamates are obtained
as diastereomerically pure compounds by chemo-, regio-, and
stereoselective cycloadditions between glycals and aspartic
acid derivatives. The latter constitute orthogonally func-
tionalized scaffolds for glycopeptide mimetics.
The remarkable structural complexity of glycoproteins,
which arises from the different combination of amino
acids and carbohydrates, is an ideal tool for coding cell’s
information.1 As a matter of fact, in eukaryotic organisms
most proteins are glycosylated and the consequences are
evident in many physiological events such as cell-cell
adhesion, cell growth, or cell-virus interaction.2 The
study of cell surface glycopeptides has recently been
focused on glycopeptide mimetics3 because the synthesis
of native glycoproteins still remains an ambitious, time-
consuming target. Thus, novel chemical approaches have
been developed to introduce non-native linkages into
large biomolecules to render complex glycopeptidic struc-
tures more easily available. In this context, although
most of the glycoproteins present the peptide motif
â-linked at the anomeric carbon of the terminal monosac-
charide unit, the importance of naturally occurring R-O-
glycopeptides such as mucins4 or R-N-glycopeptides such
as nephritogenoside5 has stimulated many researchers
to develop new selective methods for achieving R-O-
glycosidation of amino acids.6,7 We wish to describe here
an easy and totally stereoselective method for the prepa-
ration of O-glycoamino acids that retain the R stereo-
chemistry of native sugar-peptide linkage8 and that can
be used as multifunctional scaffolds for glycopeptide
mimetics.
In the present approach, O-glycohomoglutamates are
obtained as diastereomerically pure R-isomers from gly-
cals and aspartic esters. The issue of linking a carbohy-
drate domain to an amino acid under strict stereochem-
ical control has been solved by the cycloaddition of
appropriately protected glycals to δ-amino-R-thio-â-ke-
toesters9 derived from N-BOC-aspartic acid benzyl ester
(1) which occurs with complete chemo-, regio- and ste-
reoselectivity. (Scheme 1)
The transformation of 1 into â-ketoesters 2 using
Meldrum’s acid10,11 represents a valuable tool for the
preparation of a variety of suitable phthalimidosulfenyl
derivatives 3, by reaction with phthalimidosulfenyl chlo-
ride (PhtNSCl). Highly reactive 4, generated from 3 by
base treatment, was trapped “in situ” by glycals to give
R-O-glycohomoglutamates 5 as diastereomerically pure
isomers,12 in good yields (Table 1).
Selective transformation of multifunctional O-gly-
coamino acids 5 afforded new glycopeptide mimetics. For
example, the tert-butoxycarbonyl group (BOC) on 5a was
(6) (a) Li, B.; Franck, R. W.; Capozzi, G.; Menichetti, S.; Nativi, C.
Org. Lett. 1999, 1, 111. (b) Li, B.; Franck, R. W. Bioorg. Med. Chem.
Lett. 1999, 9, 2629.
(7) (a) Nakahara, Y.; Nakahara, Y.; Ogawa, T. Carbohydr. Res. 1996,
292, 71. (b) Paulsen, H.; Schleyer, A.; Mathieux, N.; Meldal, M.; Bock,
K. J . Chem. Soc., Perkin Trans. 1 1997, 281. (c) Debailleul, V.; Laine,
A.; Huet, G.; Mathon, P.; d’Hooghe, M. C.; Aubert, J . P.; Porchet, N. J .
Biol. Chem. 1998, 273, 881. (d) Live, D. H.; Williams, L. J .; Kuduk, S.
D.; Schwartz, J . B.; Glunz, P. W.; Chen, X.-T.; Sames, D.; Kumar, R.
A.; Danishefsky, S. J . Proc. Nat. Acad. Sci. U.S.A. 1999, 96, 3489. (e)
Davis, B. G. Chem. Rev. 2002, 102, 579.
(8) For the synthesis of 2-deoxyglycopeptide, see: (a) Laupichler,
L.; Sowa, C. E.; Thiem, J . Biorg. Med. Chem. 1994, 2, 1281. (b) Reddy,
B. G.; Madhusudanam, K. P.; Vankar, Y. D. J . Org. Chem. 2004, 69,
2630.
(9) Rodriguez, E. C.; Winans, K. A.; King, D. S.; Bertozzi, C. R. J .
Am. Chem. Soc. 1997, 119, 9905.
(10) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org. Chem. 1978, 43,
2087.
(11) Boccardo, G.; Capozzi, G.; Giuntini, M.; Menichetti, S.; Nativi,
C. Tetrahedron 1997, 53, 17383.
* To whom correspondence should be addressed. Tel: +39-055-
4573540. Fax: +39-055-4573570.
(1) Hang, H. C.; Bertozzi, C. R. Acc. Chem. Res. 2001, 34, 727.
(2) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Lee, Y. C.; Lee, R. T.
Acc. Chem. Res. 1995, 28, 321.
(3) (a) Dwek, R. A. Chem. Rev. 1996, 96, 683. (b) Sears, P.; Wong,
C. H.; Angew. Chem., Int. Ed. 1999, 38, 836. (c) Marcaurelle, L. A.;
Bertozzi, C. R. Chem. Eur. J . 1999, 5, 1384. (d) Herzner, H.; Reipen,
T.; Shultz, M.; Kunz, H. Chem. Rev. 2000, 100, 4495. (e) Dondoni, A.;
Marra, A. Chem. Rev. 2000, 100, 4395. (f) Kro¨ger, L.; Henkensmeier,
D.; Scha¨fer, A.; Thiem, J . Bioorg. Med. Chem. Lett. 2004, 14, 73.
(4) (a) Schwarz, J . B.; Kuduk, S. D.; Chen, X.-T.; Sames, D.; Glunz,
P. W.; Danishefsky, S. J . J . Am. Chem. Soc. 1999, 121, 2662. (b) Coltart,
D. M.; Royyuru, A. K.; Williams, L. J .; Glunz, P. W.; Sames, D.; Kuduk,
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10.1021/jo049441h CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004
J . Org. Chem. 2004, 69, 6153-6155
6153

SCHEME 3. Syn th esis of Glu cod ip ep tid e 14a
TABLE 1. â-Ketoester s 4a -e a n d Syn th esis of
Cycloa d d u cts 5a -f
a
Key: (a) TBAF, THF, rt, 4 h, 65%; (b) H-L-Tyr(tBu)-O-
tBu‚HCl, HOBt, EDCI, DIPEA, DMF, 1.5 h, 84%.
SCHEME 4. Syn th esis of Diben zyl Der iva tive 16
a n d Disa cch a r id e 18a
a
b
Isolated. Cycloadduct 5d is not stable: if it is stored at rt
for few hours retrocycloaddition is observed.
removed and the crude amino derivative 9 was reacted
with N-benzyloxycarbonyl-L-Phe (Cbz-L-Phe-OH) and
with N-fluorenyl-(N-tert-butoxycarbonyl)-L-Trp [Fmoc-L-
Trp(BOC)-OH] under standard conditions13 to give the
desired R-O-glycodipeptides 10 and 11, respectively
(Scheme 2).
a
Key: (a) TMSOTf, Ac2O, -40 °C, 1.5 h, 77%; (b) MeONa,
SCHEME 2. Syn th esis of r-O-Glu cod ip ep tid es 10
a n d 11
MeOH, CH2Cl2, rt, 86%; (c) TMSOTf, CH2Cl2-Et2O, -5 °C to rt
(65%).
12 was obtained as major or single product through a
more common deprotection procedure using trifluoroace-
tic or hydrochloric acid15 (see Scheme 2).
The selective deprotection of the R,â-unsaturated ester
was initially attempted on cycloadduct 5a . Alkaline
treatment (NaOH, dioxane, rt or 60 °C) of the latter
afforded the desired carboxylic acid 13, though with
unsatisfactory yields (10-30%). Treatment under differ-
ent conditions [K2CO3, MeOH, rt (83%); DBU, LiBr, Me3-
SiCH2CH2OH THF, rt (15%)] gave mainly transesterifi-
cation of the benzyl ester. More efficiently, cycloadduct
5e was transformed into the corresponding monoester 13
by treatment with tetrabutylammonium fluoride (TBAF)
in THF (65%) or CsF in DMF (65%) at room temperature.
Reaction of 13 with O-tert-butyl-L-Tyr-tert-butyl ester
(12) (a) Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marzabadi,
C.; Menichetti, S.; Nativi, C.; Tabarez, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 805. (b) Bartolozzi, A.; Li, B.; Franck, R. W. Bioorg. Med.
Chem. 2003, 11, 3021. (c) For a review article regarding the hetero
Diels-Alder approach to O-glycosides, see: Menichetti, S.; Nativi, C.
The Hetero Diels-Alder Approach to Oxathiins. In Targets in Hetero-
cyclic Systems; Attanasi, O. A., Spinelli, D., Eds.; SCI: Rome, 2003;
Vol. 7, pp 108-139.
(13) (a) Ko¨nig, W.; Geiger, R.; Chem. Ber. 1970, 103, 788. (b)
Sheehan, J . C.; Ledis, S. L. J . Am. Chem. Soc. 1973, 95, 875.
(14) Kaiser, E.; Picart, F.; Kubiak, T.; Tam, J . P.; Merriefield, R. B.
J . Org. Chem. 1993, 58, 5167.
a
Key: (a) Me3SiCl (4 M)-PhOH (4 M) CH2Cl2; (b) N-Cbz-L-
Phe, HOBt, EDCl, DIPEA, DMF, rt, 62% (two steps); (c) N-Fmoc-
(N-BOC)-L-Trp, HOBt, EDCI, DIPEA, DMF, rt, 66% (two steps).
Removal of the BOC group was successfully achieved
by the treatment of 5a with solutions of Me3SiCl (4 M in
CH2Cl2) and PhOH (4 M in CH2Cl2);14 instead, compound
(15) (a) Stahl, G. L.; Walter, R.; Smith, C. W. J . Org. Chem. 1978,
43, 2285. (b) Lundt, B. F.; J ohansen, N. L.; Vølund, A.; Markussen, J .
Int. Pept. Protein Res. 1978, 12, 258.
6154 J . Org. Chem., Vol. 69, No. 18, 2004

SCHEME 5. Syn th esis of
gave the non-natural R-O-glycodipeptide 14 (84%) as
diastereomerically pure compound (Scheme 3).
r-O-Glu coh om oglu ta m a te Der iva tives 25 a n d 26a
Cycloadduct 5a was converted into the monoacetyl
glycoside 15 by trimethylsilyltriflate and acetic anhydride
at low temperature;16 the latter was deacetylated to give
the dibenzyl derivative 16 (Scheme 4). The complete
removal of benzyl groups on the carbohydrate moiety
through standard methods (H2-Pd/C or Pd(OH)2/C in
THF, MeOH, or EtOAc) was instead unsuccessful, con-
sistently leading to recovery of unaltered starting mate-
rial. Compound 16 exposed to a trichloroacetimidate
donor 17 gave the expected disaccharide 18 in good yield
(64%) (Scheme 4), thus proving the effective use of the
new scaffold we propose for the assembly of oligosaccha-
ride chains.
R-O-Glucohomoglutamates with two unprotected car-
boxylic acids and a fully unprotected glyco moiety were
prepared by cycloaddition of the disilyl glucal 7 to 4e.
The O-glycoside 19 (Scheme 5), obtained as the pure
R-isomer, was subsequently transformed into the corre-
sponding amides 20 and 21 by reacting the crude
aminoderivative 22 with biphenyl-4-yl- and naphthalene-
2-ylacetyl chlorides, respectively. Treatment of 20 and
21 with CsF in DMF at room temperature allowed the
simultaneous removal of the triisopropyl silyl group at
C-3 and the deprotection of the trimethylethyl ester to
afford monoesters 23 (65%) and 24 (65%). Hydrogenation
of 23 and 24 gave the dicarboxylic acids 25 and 26 in
quantitative yield (Scheme 5).
In conclusion, a highly efficient approach for the
synthesis of R-O-linked glycohomoglutamates scaffolds
5 has been described. These scaffolds, characterized by
two differentiated carboxyls, a protected R-amino func-
tion, and a selectively functionalized monosaccharidic
unit, were successfully employed to give an array of
diastereomerically pure building blocks for R-O-glyco-
peptide mimetics.
a
Key: (a) PhtNSCl, Py, CHCl3, 60 °C, 30 h, 40%; (b) Me3SiCl
(4 M)-PhOH (4 M), CH2Cl2, conv > 90%; (c) ArCH2COCl, Et3N,
rt, 1 h, 20 (50%), 21 (43%); (d) CsF, DMF, rt, 12 h, 23 (65%), 24
(65%); (e) H2-Pd(OH)2/C, MeOH, rt, 20 h, 25 (>90%), 26 (>90%).
Scientifica e Tecnologica, Rome, and by the University
of Florence. Financial support by Ente Cassa di Ris-
parmio di Firenze for acquisition of a 400 NMR spec-
trometer is gratefully acknowledged.
Ack n ow led gm en t. We are grateful to Mr. Maurizio
Passaponti for elemental analysis. This research was
carried out within the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni”, supported by the Ministero della Ricerca
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for compounds 2a -e, 5a -c,e,f,
9, 10-16, 18-21, and 23-26. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) (a) Angibeaud, P.; Utille, J . P. Synthesis 1991, 737. (b) Alzeer,
J .; Vasella, A. Helv. Chim. Acta 1995, 78, 177.
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