Facile synthesis of fused furanosyl β-amino acids from protected sugar lactones: Incorporation into a peptide chain

Article abstract of DOI:10.1016/S0957-4166(02)00473-1

The synthesis of fused furanosyl β-amino esters from protected sugar lactones is described, using the combination of a Wittig type reaction and 1,4-addition of benzylamine on the resulting glycosylidenes. This sequence of reactions afford either N-glycosy

Full text of DOI:10.1016/S0957-4166(02)00473-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1707–1711
Facile synthesis of fused furanosyl b-amino acids from protected
sugar lactones: incorporation into a peptide chain
Claude Taillefumier,a Younes Lakhrissi,a Mohammed Lakhrissib and Yves Chapleura,*
aGroupe SUCRES, UMR 7565 CNRS, Universite´ Henri Poincare´, Nancy I, BP 239, F-54506 Nancy-Vandoeuvre, France
bLaboratoire de Synthe`se Organique, Faculte´ des Sciences, Universite´ Ibn Tofail, Kenitra, Morocco
Received 4 June 2002; revised 30 July 2002; accepted 12 August 2002
Abstract—The synthesis of fused furanosyl b-amino esters from protected sugar lactones is described, using the combination of
a Wittig type reaction and 1,4-addition of benzylamine on the resulting glycosylidenes. This sequence of reactions afford either
N-glycosyl-3-ulosonic acid esters, which are the b-analogues of anomeric sugar a-amino esters, or open-chain sugar b-enamino
esters, when a retro-Michael reaction takes place after addition of benzylamine. Incorporation of the fused furanosyl b-amino
ester 2a into a peptide chain is also described. © 2002 Elsevier Science Ltd. All rights reserved.
Sugar amino acids (SAAs), which have been defined as
chemical structures bearing both an amino and a car-
boxylate group on a regular carbohydrate framework
are of current interest for organic chemists because they
form part of a large number of natural products. They
occur in nature as subunits of oligosaccharides (neu-
raminic acids) or in the cell wall of bacteria (muraminic
acid).1 Recently special efforts have been devoted to the
elaboration of non natural sugar amino acids because
of the extraordinary diversity offered by sugars as
highly hydroxylated chiral templates.2 These sugar
amino acids can be incorporated into a regular peptide
backbone, where they may function as dipeptide con-
formational surrogates.3 For instance pyranoid3f and
furanoid sugar amino acids have been incorporated
into Leu-enkephalin in the Gly-Gly position as a dipep-
tide isostere.4 SAAs can also be considered as monomer
units in oligomerisation studies,5 Such homooligomers,
the so-called carbopeptoides6 have shown great ability
to fold in a specific manner in very short sequences.7
Finally, SAAs can be regarded as a new class of
scaffold for the construction of peptidomimetics.8
b-Amino acids have been recognised as a very impor-
tant class of compounds. They are found as fragments
of many natural products12 and are also valuable syn-
thetic intermediates for the construction of more com-
plex molecules, in the preparation of b-lactam
antibiotics13a and in b-peptide synthesis.13b Recently,
Hindsgaul et al. have published a paper dealing with
the synthesis of a,a-disubstituted pyran diamides bear-
ing a sugar b-amino acid core.14 This has prompted us
to publish our preliminary results concerning the syn-
thesis and chemical manipulation of a series of glycosyl
b-amino acids having the general structure B (Fig. 1),
where the amino group is directly linked to the
anomeric centre while the carboxylate is spaced from
that carbon by a methylene group. Such structures can
be regarded as b,b-disubstituted b-amino acids.
The synthesis of such structures requires a two carbon
chain elongation of the sugar skeleton. This transfor-
mation was performed from protected aldonolactones
using the Wittig type methodology developed in our
group several years ago.15 exo-Glycals like 1, obtained
this way, proved interesting intermediates in the synthe-
sis of sugar derivatives.16–18 They were found to be
A special situation occurs when both the amino and
carboxylate groups are carried by the anomeric centre
of a sugar (Fig. 1, structure A). Our group and others
have described the synthesis9 and chemical manipula-
tion of such fused glycosyl a-amino acids.10,11
* Corresponding author. Tel.: +33 383 68 47 73; fax: +33 383 68 47
80; e-mail: yves.chapleur@meseb.uhp-nancy.fr
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00473-1

1708
C. Taillefumier et al. / Tetrahedron: Asymmetry 13 (2002) 1707–1711
Thus, we turned to benzylamine20 as a source of nitro-
gen and found that the reaction of 1a in neat benzyl-
amine at room temperature proceeds cleanly and with
high conversion for the both E and Z isomers (Scheme
1 and Table 1: entries 1 and 2). It should be noted that
despite the N,O-acetal character of the anomeric centre,
only one isomer was isolated which formally results
from the approach of benzylamine to the less crowded
face of the sugar, i.e. anti to the fused acetonide. No
equilibration of 2a to the other anomer was observed at
any stage of the reaction or during purification and this
compound proved very stable even after storing for
prolonged time. The configuration of the anomeric
centre was first established by the observation of a
strong NOE between N3H and C4H (ulosonic acids
numbering, Scheme 1) and was confirmed by X-ray
crystallographic analysis of compound 2a.21 We further
investigated the reaction of benzylamine with other
glycosylidenes, the results, which are shown in Table 1,
deserve comment: Compounds 1e (Z) and 1b (Z- and
E-mixture) gave good yields of the corresponding
anomeric b-amino esters (82 and 73%, respectively). It
is interesting to note that for the substrates 1a, 1b and
1e all of the substituents are directed toward the same
face of the sugar which allow an effective approach of
the reagent. For all of these starting compounds only
one configuration was obtained for the anomeric cen-
tre, the configuration in which the benzylamino group
is trans to the 4,5-dioxolane moiety. The two last
suitable precursors for the synthesis of N-glycosyl b-
amino esters 2 by 1,4-addition of a nitrogen source19
(Fig. 2).
For this purpose a series of diverse furano- and pyrano-
glycosylidenes (Fig. 3 and Fig. 4) were prepared. We
first attempted to react the gulo compound 1a with
sodium azide in DMF but this reaction failed to give
the expected b-azido ester.
Figure 2.
furanoglycosylidenes studied 1c (
D
-ribo) and 1d (D-allo)
were converted to the Michael adducts 2c and 2d in 57
and 50% yields, respectively (78% based on recovered
material). However, these two compounds were con-
taminated by trace amounts of the corresponding
enamino esters 3c and 3d. The reactivity of pyranogly-
cosylidenes towards benzylamine addition was next
examined.
On treatment with BnNH2 for 14 days the D-glycero-D-
Figure 3. Structures of furanoglycosylidenes 1a–e (left) and
compounds obtained upon addition of benzylamines 2a–e and
3c,d.
gulo compound 1f afforded exclusively the enamino
ester 3f arising from a retro-Michael process in 71%
yield. The manno derivative 1g was also reacted with
BnNH2 to give the enamino ester 3g as the main
product, the latter being accompanied by the Michael
1
adduct 2g in a 5/1 ratio as shown by H NMR. Both
compounds 3f and 3g were fully characterised as their
acetate22 (4f and 4g, respectively). Compounds 1h and
1i having the gluco configuration remained unchanged
even after prolonged reaction times. This lack of reac-
tivity could arise from the bulky protecting groups
present in these two molecules or maybe from the
absence of a fused 2,3-isopropylidene acetal (sugar lac-
Figure 4. Structures of pyranoglycosylidenes 1f–i and com-
pounds obtained upon addition of benzylamine.
Scheme 1. Michael addition of benzylamine on compound 1a
and NOE measurements in 2a.

C. Taillefumier et al. / Tetrahedron: Asymmetry 13 (2002) 1707–1711
Table 1. 1,4-Addition of benzylamine on glycosylidenes of type 1a–i
1709
Entry
1a–k
Time (h)
Product(s) ratio
Yield (%)a
NH/4,5-dioxolane relationshipc
1
2
3
4
5
6
7
8
9
1a (Z)
1a (E)
1b (Z+E)
1c (Z)
1d (Z)
1e (Z)
1f (Z)
1g (Z)
1h (Z)
1i (Z)
48
48
48
48
70
48
14 days
44
96
2a
2a
2b
89
91
73
trans
trans
trans
trans
trans
trans
2c/3c (traces)
2d/3d (traces)
2e
57
50, 78b
82
3f
71, 98b
2g/3g: 1/5
Starting material
Starting material
73
0
0
Not determined
10
96
a Isolated yields after chromatography.
b Yields based on recovered material.
1
c The anomeric configuration was ascertained on the base of NOE measurements and by comparison of H NMR data of compound 2a of known
configuration.
tone numbering). The fused acetonide ring, which is
present in all the other substrates, make these starting
materials quite rigid and could explain the enhanced
reactivity of these substrates as Michael acceptors.
MeOH and water. The coupling reaction of the result-
ing acid with Ala-NHMe using PyBop and TEA in
DMF afforded the target tripeptide 7 as a glassy solid
in 78% overall yield (two steps).
Another aim of this work was to demonstrate that
fused anomeric b-amino esters previously synthesised
could be incorporated into a peptide chain (Scheme 2).
Compound 2a was chosen as a model for this study.
Catalytic hydrogenation of this compound afforded the
free amine 5 which was isolated as an inseparable
mixture of anomers. Coupling of this mixture with
benzyloxycarbonylglycine (Z-GlyOH) using PyBOP as
coupling reagent and TEA in DMF furnished the
desired dipeptide 6 in 84% overall yield (two steps).
Interestingly only one isomer was isolated. The
anomeric configuration was unambiguously determined
by the observation of a strong NOE between the
anomeric NH and the two protons H-4 and H-6 (ulo-
sonic acids numbering). This is only consistent with a
trans relationship between the anomeric nitrogen and
the 4,5-dioxolane ring.11
In conclusion, the 1,4-addition of benzylamine has been
performed on a series of glycosylidenes. It would
appear that the expected Michael adducts 2 are either
exclusively obtained or at least as the major compounds
when the reaction is conducted with furanoglycosylide-
nes. In the case of pyrano compounds the open-chain
enamino esters were the sole or the major compounds.
The latter arises from 1,4-addition of benzylamine fol-
lowed by a retro-Michael process, leading to the open-
ing of the sugar. These b-enamino esters can be
regarded as synthetic precursors of highly oxygenated
b,b-disubstituted b-amino acids.23 Compound 2a24 was
used as a model to show that despite the N,O-acetal
character of compounds of type 2 they can be manipu-
lated as standard amino acids. With this aim in mind,
the tripeptide 725 was elaborated from 2a in 65% overall
yield (four steps). The scope and limitation of the
incorporation of compounds 2 into peptide chains is
currently under study in our laboratory.
Extension from the C-terminus was next envisaged.
Hydrolysis of the ester was performed with K2CO3 in
References
1. Lindberg, B. Adv. Carbohydr. Chem. Biochem. 1990, 48,
279–318.
2. (a) Lohof, E.; Burkhart, F.; Born, M. A.; Planker, E.;
Kessler, H. Adv. Amino Acid Mimet. Peptidomimet. 1999,
2, 263–292; (b) Schweizer, F. Angew. Chem., Int. Ed.
2002, 41, 230–253.
3. (a) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetra-
hedron Lett. 1995, 36, 6887–6890; (b) Overkleeft, H. S.;
Verhelst, S. H. L.; Pieterman, E.; Meeuwenoord, N. J.;
Overhand, M.; Cohen, L. H.; van der Marel, G. A.; van
Boom, J. H. Tetrahedron Lett. 1999, 40, 4103–4106; (c)
Smith, A. B., III; Sasho, S.; Barwis, B. A.; Sprengeler, P.;
Barbosa, J.; Hirschmann, R.; Cooperman, B. S. Bioorg.
Med. Chem. Lett. 1998, 8, 3133–3136; (d) Aguilera, B.;
Siegal, G.; Overkleeft, H. S.; Meeuwenoord, N. J.;
Rutjes, F. P. J. T.; van Hest, J. C. M.; Schoemaker, H.
Scheme 2. Reagents and conditions: (a) H2 1 atm, Pd/C 10%,
EtOAc; (b) Z-GlyOH (1.1 equiv.), PyBOP (1.1 equiv.), Et3N
(1.1 equiv.), DMF, rt, 14 h.; 84% (two steps); (c) K2CO3 (1.1
equiv.), MeOH/H2O: 10/1, rt, 48 h; (d) Ala-NHMe·HCl (1.1
equiv.), PyBOP (1.1 equiv.), Et3N (2.2 equiv.), DMF, rt, 14 h;
78% (two steps).

1710
C. Taillefumier et al. / Tetrahedron: Asymmetry 13 (2002) 1707–1711
E.; van der Marel, G. A.; van Boom, J. H.; Overhand, M.
D. Eur. J. Org. Chem. 2000, 1–15 and references cited
therein; (d) See also: Enantioselective Synthesis of i-
Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York,
1997.
Eur. J. Org. Chem. 2001, 1541–1547; (e) Lohof, E.;
Planker, E.; Mang, C.; Burkhart, F.; Dechantsreiter, M.
A.; Haubner, R.; Wester, H. J.; Schwaiger, M.; Holze-
mann, G.; Goodman, S. L.; Kessler, H. Angew. Chem.,
Int. Ed. 2000, 39, 2761–2764; (f) von Roedern, E. G.;
Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler, H. J. Am.
Chem. Soc. 1996, 118, 10156–10167.
14. Schweizer, F.; Lohse, A.; Otter, A.; Hindsgaul, O. Synlett
2001, 1434–1436.
15. Lakhrissi, M.; Chapleur, Y. Angew. Chem., Int. Ed. Engl.
1996, 35, 750–752.
4. (a) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S.;
Sarna, J. A. R. P.; Ravikanth, V.; Diwan, P. V.; Nagaraj,
R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441–6457;
(b) Chakraborty, T. K.; Jayaprakash, S.; Diwan, P. V.;
Nagaraj, R.; Jampani, S. R. B.; Kunwar, A. C. J. Am.
Chem. Soc. 1998, 120, 12962–12963.
16. (a) Lakhrissi, Y.; Taillefumier, C.; Lakhrissi, M.; Chap-
leur, Y. Tetrahedron: Asymmetry 2000, 11, 417–421; See
also: (b) Molina, A.; Czernecki, S.; Xie, J. Tetrahedron
Lett. 1998, 39, 7507–7510; (c) Xie, J.; Molina, A.; Czer-
necki, S. J. Carbohydr. Chem. 1999, 18, 481–498.
17. Lakhrissi, M.; Taillefumier, C.; Chaouch, A.; Didierjean,
C.; Aubry, A.; Chapleur, Y. Tetrahedron Lett. 1998, 39,
6457–6460.
5. Suhara, Y.; Hildreth, J. E. K.; Ichikawa, Y. Tetrahedron
Lett. 1996, 37, 1575–1578.
6. Nicolaou, K. C.; Florke, H.; Egan, M. G.; Barth, T.;
Estevez, V. A. Tetrahedron Lett. 1995, 36, 1775–1778.
7. Smith, M. D.; Fleet, G. W. J. J. Peptide Sci. 1999, 5,
425–441.
8. (a) von Roedern, E. G.; Kessler, H. Angew. Chem., Int.
Ed. Engl. 1994, 33, 670–671; (b) Sofia, M. J.; Hunter, R.;
Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang, H.; Gange,
D. J. Org. Chem. 1998, 63, 2802–2803.
18. Taillefumier, C.; Lakhrissi, M.; Chapleur, Y. Synlett
1999, 697–700.
19. (a) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51,
2820–2822; (b) D’Angelo, J.; Maddaluno, J. J. Am.
Chem. Soc. 1986, 108, 8112–8114; (c) Amoroso, R.;
Cardillo, G.; Sabatino, P.; Tomasini, C.; Trere, A. J. Org.
Chem. 1993, 58, 5615–5619.
20. While our work was in progress a similar approach was
published: Sharma, G. V. M.; Reddy, V. G.; Chander, A.
S.; Reddy, K. R. Tetrahedron: Asymmetry 2002, 13, 21–
24.
21. Crystallographic data have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication number CCDC 185237. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2, 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
22. Structural assignment of CꢀC double bond geometry is
based on NMR studies: Bartoli, G.; Cimarelli, C.; Dal-
pozzo, R.; Palmieri, G. Tetrahedron 1995, 51, 8613–8622.
23. (a) Cimarelli, C.; Palmieri, G.; Bartoli, G. Tetrahdron:
Asymmetry 1994, 5, 1455–1458; (b) Cimarelli, C.;
Palmieri, G.; Volpini, E. Synth. Commun. 2001, 31, 2943–
2953.
9. (a) Dondoni, A.; Scherrmann, M.-C.; Marra, A.;
Dele´pine, J.-L. J. Org. Chem. 1994, 59, 7517–7520; (b)
Somsak, L.; Sos, E.; Gyorgydeak, Z.; Praly, J.-P.;
Descotes, G. Tetrahedron 1996, 52, 9121–9136; (c)
Lakhrissi, M.; Chapleur, Y. Tetrahedron Lett. 1998, 39,
4659–4662; (d) Gyollai, V.; Somsak, L.; Szilagyi, L. Tet-
rahedron Lett. 1999, 40, 3969–3972; (e) Smith, M. D.;
Long, D. D.; Martin, A.; Campbell, N.; Bleriot, Y.;
Fleet, G. W. J. Synlett 1999, 1151–1153; (f) Dondoni, A.;
Marra, A. Chem. Rev. 2000, 100, 4395–4421.
10. (a) Burton, J. W.; Son, J. C.; Fairbanks, A. J.; Choi, S.
S.; Taylor, H.; Watkin, D. J.; Winchester, B. G.; Fleet,
G. W. J. Tetrahedron Lett. 1993, 34, 6119–6122; (b)
Estevez, J. C.; Ardron, H.; Wormald, M. R.; Brown, D.;
Fleet, G. W. J. Tetrahedron Lett. 1994, 35, 8889–8890; (c)
Estevez, J. C.; Smith, M. D.; Lane, A. L.; Crook, S.;
Watkin, D. J.; Besra, G. S.; Brennan, P. J.; Nash, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 1996, 7, 387–390;
(d) Estevez, J. C.; Smith, M. D.; Wormald, M. R.; Besra,
G. S.; Brennan, P. J.; Nash, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 1996, 7, 391–394; (e) Estevez, J.
C.; Burton, J. W.; Estevez, R. J.; Ardron, H.; Wormald,
M. R.; Dwek, R. A.; Brown, D.; Fleet, G. W. J. Tetra-
hedron: Asymmetry 1998, 9, 2137–2154; (f) Gasch, C.;
Salameh, B. A. B.; Pradera, M. A.; Fuentes, J. Tetra-
hedron Lett. 2001, 42, 8615–8617.
24. Analytical data for compound 2a: mp 123°C; [h]2D6=−9.6
(c 0.9, CHCl3); wmax (KBr) 3357 (NH), 1730 (CꢀO); 1H
NMR (CDCl3, 250 MHz): l 1.27 (s, 3H, CH3), 1.40 (s,
3H, CH3), 1.45 (br s, 6H, 2×CH3), 2.10–2.23 (m, 1H,
NH), 2.94 (d, 1H, Jgem 17.5 Hz, H-2), 3.14 (d, 1H, Jgem
17.5 Hz, H%-2), 3.65–3.88 (m, 6H, H-8, CO2CH3 and
CH2Ph), 4.06 (dd, 1H, J5,6 4.4, J6,7 8.0 Hz, H-6), 4.21 (dd,
1H, Jgem 8.0, J7,8% 6.5 Hz, H%-8), 4.40 (m, 1H, H-7), 4.45
(d, 1H, J4,5 5.8 Hz, H-4), 4.72 (dd, 1H, J5,6 4.4, J4,5 5.8
Hz, H-5), 7.20–7.38 (m, 5H, Ph); 13C NMR (CDCl3, 62.9
MHz): l 171.5 (CꢀO), 140.3 (Cipso), 128.4–126.8 (5C, Ar),
112.7 (acetal), 109.6 (acetal), 95.1 (C-3), 85.9, 81.0, 80.9,
75.5 (4C, C-4, C-5, C-6, C-7), 66.1 (C-8), 51.5 (CO2CH3),
45.1 (CH2Ph), 34.8 (C-2), 26.8 (CH3), 26.0 (CH3), 25.3
(CH3), 24.8 (CH3). Anal. calcd for C22H31NO7 (421.48):
C, 62.69; H, 7.41; N, 3.32. Found: C, 62.73; H, 7.37; N,
3.36%.
11. For the first synthesis of tri- and tetrapeptides incorporat-
ing an a-amino acid at the anomeric position of a sugar,
see: Estevez, J. C.; Estevez, R. J.; Ardron, H.; Wormald,
M. R.; Brown, D.; Fleet, G. W. J. Tetrahedron Lett.
1994, 35, 8885–8888.
12. See for example: (a) Chemistry and Biochemistry of Amino
Acids, Peptides and Proteins; Spatola, A. F.; Weinstein,
B., Eds.; Dekka: New York, 1983; (b) Chemistry and
Biochemistry of Amino Acids; Drey, C. N. C.; Barrett, G.
C., Eds.; Chapman and Hall: London, 1985.
25. Analytical data for compound 7: mp 92–95°C (decompo-
sition); [h]2D6=+18.4 (c 0.9, CHCl3); 1H NMR (CDCl3,
400 MHz): l 8.12 (s, 1H, NH), 7.28–7.41 (m, 5H, Ar),
6.73 (d, 1H, J 7.5 Hz, NHAla), 6.57 (pseudo q, 1H,
NHMe), 5.71 (pseudo t, 1H, NHGly), 5.20 (d, 1H, J4,5 5.7
Hz, H-4), 5.07–5.18 (m, 2H, CH2Ph), 4.98 (pseudo t, 1H,
13. (a) Juraristi, E.; Quimtama, D.; Escalante, J. Aldrichimica
Acta 1994, 27, 3–11; (b) Seebach, D.; Matthews, J. L.
Chem. Commun. 1997, 2015–2022; (c) Abele, S.; Seebach,

C. Taillefumier et al. / Tetrahedron: Asymmetry 13 (2002) 1707–1711
1711
169.6 (3×CꢀO), 156.4 (NHCOOCH2), 136.1 (Cipso),
128.0–128.4 (5C, Ar), 109.7 (acetal), 112.9 (acetal), 92.7
(C-3), 84.7 (C-4), 84.5 (C-6 or C-7), 81.7 (C-5), 76.1 (C-6
or C-7), 67.1 (CH2Ph), 65.9 (C-8), 49.3 (CaAla), 44.6
(CaGly), 41.3 (C-2), 26.6, 26.3, 25.8, 25.4, 24.1 (5C, 4×
CH3 and NHCH3), 17.9 (CH3 Ala).
H-5), 4.42 (m, 1H, HaAla), 4.16–4.31 (m, 3H, H-6, H-7
and H-8), 3.83–3.91 (m, 2H, 2×HaGly), 3.70 (t, 1H,
J
gem=J7,8% 7.5 Hz, H%-8), 2.77–2.90 (m, 5H, 2×H-2 and
NHCH3), 1.50 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.36 (d,
3H, J 7.2 Hz, CH3 Ala), 1.32 (s, 3H, CH3), 1.27 (s, 3H,
CH3); 13C NMR (CDCl3, 100.6 MHz): l 172.6, 169.8,