Synthesis of a C3-symmetric macrocycle with alternating sugar amino acid and tyrosine residues

Article abstract of DOI:10.1016/j.tetlet.2004.12.038

A C₃-symmetric macrocycle with alternating sugar amino acid and tyrosine residues was synthesized in seven steps from tyrosine tert-butyl ester and a sugar amino acid precursor derived from D-glucosamine. An Fmoc-protected D-glucosamine derivative was oxidized at C-6 to give the sugar amino acid, which was immediately coupled to tyrosine tert-butyl ester to produce an orthogonally protected building block. This building block was subsequently elongated to the trimer via the dimer, and finally cyclized to give the C₃-symmetric macrocycle.

Full text of DOI:10.1016/j.tetlet.2004.12.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 991–993
Synthesis of a C3-symmetric macrocycle with alternating
sugar amino acid and tyrosine residues
Johan F. Billing and Ulf J. Nilsson*
Organic and Bioorganic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
Received 11 October 2004; revised 1 December 2004; accepted 8 December 2004
Available online 22 December 2004
Abstract—A C3-symmetric macrocycle with alternating sugar amino acid and tyrosine residues was synthesized in seven steps from
tyrosine tert-butyl ester and a sugar amino acid precursor derived from D-glucosamine. An Fmoc-protected D-glucosamine deriva-
tive was oxidized at C-6 to give the sugar amino acid, which was immediately coupled to tyrosine tert-butyl ester to produce an
orthogonally protected building block. This building block was subsequently elongated to the trimer via the dimer, and finally cycl-
ized to give the C3-symmetric macrocycle.
Ó 2004 Elsevier Ltd. All rights reserved.
Cyclic sugar amino acid/amino acid hybrids have in
recent years attracted interest as peptidomimetics1–7
and have also been proposed as potential artificial recep-
tors.8–10 The sugar amino acids have mainly been used
to induce turns, but in the present work a sugar amino
acid that has previously been shown to induce an ex-
tended conformation1 has been used in an attempt to
obtain a rigid macrocycle that can form a central cavity
without collapsing. Such molecules have the potential to
forma binding site for guest molecules in the center and
thus act as artificial receptors. We here present the syn-
thesis of a C3-symmetric macrocycle with alternating
sugar amino acid and tyrosine residues. To the best of
our knowledge, this is the first example of a C3-symmet-
ric macrocycle with alternating sugar amino acid and
a-amino acid residues, although examples with b- or
e-amino acids have been prepared by others.9,11
OH
O
Tyr OtBu
O
O
BzO
BzO
i
BzO
BzO
OMe
NHFmoc
OMe
53%
NHR
2 R=Fmoc
3 R=H
ii
91%
1
Scheme 1. Synthesis of the building blocks for the macrocycle.
Reaction conditions: (i) (a) CrO3/H2SO4(aq)/acetone, (b) H–Tyr–
OtBu/EDCÆHCl/HOBt/N-methylmorpholine/THF, 16 h; (ii) TBAF/n-
C8H17SH/THF, sonication, 5 min.
With the necessary building blocks in hand, we turned
to the synthesis of the macrocycle (Scheme 2). In the first
attempt, building block 2 was treated with 33% trifluo-
roacetic acid in CH2Cl2 with Et3SiH as a scavenger13
to cleave the tert-butyl ester and the crude product
was directly coupled to building block 3 using N-(3-di-
methylaminopropyl)-N0-ethyl carbodiimide hydrochloride
(EDCÆHCl) and 1-hydroxybenzotriazole (HOBt) in an
attempt to produce 4. This yielded 27% of the desired
material 4 along with 19% of epimerized product.
Clearly, coupling conditions with lower epimerization
were needed and we turned to diisopropylcarbodiimide
(DIC) and HOBt in the absence of a base,14 which
gave 58% of 4 and only 6% of the undesired epimer after
separation by flash chromatography.
The first building block for the macrocycle was synthe-
sized by oxidizing sugar amino acid precursor 110 using
Jonesꢀ reagent and then directly coupling the crude
sugar amino acid to tyrosine tert-butyl ester, which
afforded 2 in 53% yield over two steps (Scheme 1). Sugar
amino acid/amino acid hybrid 2 was deprotected using
tetrabutylammonium fluoride (TBAF) and 1-octaneth-
iol in THF12 to give the second building block 3.
The tert-butyl ester of compound 4 was cleaved with
TFA/CH2Cl2/Et3SiH and the crude product was cou-
pled to building block 3 to afford 5 in 68% yield. No epi-
merization was observed in this coupling. The Fmoc
Keywords: Sugar amino acids; Cyclic peptides; C3 symmetry;
Macrocycles.
*
Corresponding author. Tel.: +46 46 2228218; fax: +46 46 2228209;
e-mail: ulf.nilsson@bioorganic.lth.se
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.038

992
J. F. Billing, U. J. Nilsson / Tetrahedron Letters 46 (2005) 991–993
HO
OR
O
RO
O
Tyr OtBu
O
O
BzO
BzO
H
N
O
NH
Tyr OtBu
O
OMe
O
BzO
BzO
NH
OH
MeO
O
Tyr
OMe
O
HN
MeO
i
i
iii
O
NH
NH
BzO
2
OMe
BzO
Tyr
O
58%
68%
27%
O
O
O
RO
NH
O
OMe
BzO
RO
Tyr
OMe
NHFmoc
BzO
O
BzO
BzO
HN
OR
OR
O
N
OMe
NHR
O
H
4
O
5 R=Fmoc
6 R=H
ii
iv
16%
7 R=Bz
8 R=H
98%
HO
Scheme 2. Synthesis of the C3-symmetric macrocycle 8. Reaction conditions: (i) (a) TFA/Et3SiH/CH2Cl2, 4 h, (b) 3/DIC/HOBt/THF, 16 h; (ii) DBU/
N-(2-mercaptoethyl)aminomethyl polystyrene, 6 h; (iii) (a) TFA/Et3SiH/CH2Cl2, 4 h, (b) HAPyU/DIPEA/THF, 3 h; (iv) NaOMe/MeOH (2 mM),
5 days.
group of 5 was cleaved using DBU with a solid-phase
thiol as a scavenger15 to give 6 in excellent yield.
After cleavage of the tert-butyl ester in compound 6, the
crude linear material was cyclized using 1-(1-pyrrolidin-
yl-1H-1,2,3-triazolo[4,5-b]pyridinylmethylene)pyrrolidi-
16
niumhexafluorophosphate-3-oxide (HAPyU),
and
N,N-diisopropylethylamine (DIPEA) in THF under di-
lute conditions to give 7 in 27% yield. Deprotection of
7 using 10 mM NaOMe in MeOH gave a number of
products and only 11% of the desired compound 8 was
obtained after purification by HPLC. The main product
of the reaction was instead a compound that had a mass
that was 18 lower than expected (HRMS 1061.3606, cal-
culated for 8 + Na 1079.3709) and exhibited an NMR
spectrum indicative of a nonsymmetrical compound
with an unexpected signal in the olefinic region at
ꢀ6 ppm. This evidence led us to conclude that elimina-
tion of water or benzoic acid had taken place during
the reaction. Deprotection at lower base concentration
(2 mM) reduced the elimination somewhat and im-
proved the yield to 16%. Deprotection in MeOH using
Figure 1. Representative calculated minimum conformation of 8.
Sidechains and methoxy groups omitted for clarity.
20
˚
either Et3N, MeNH2 or 4 A molecular sieves was also
attempted, but these conditions gave even more side
reactions.
residues in only five steps fromthe building blocks.
The synthetic strategy is flexible in the sense that it will
allow structural diversification by varying the amino
acid building blocks to give symmetrical as well as non-
symmetrical macrocycles possessing up to three different
amino acids, with potential to function as host mole-
cules in an aqueous environment.
3
The JHH coupling constants in the sugar amino acid
residues decrease from8–10 Hz to 7–8 Hz upon cycliza-
tion of 6 to 7, which indicates that the 4C1 conformation
no longer is the only major conformation of the sugar
amino acids. This prompted us to carry out a computa-
tional study on the conformation of 8 using Monte-
Carlo conformational searches in MacroModel 8.5
(MMFFs force field with water as solvent, 20,000 steps,
all backbone torsions were selected for randomvaria-
tion). The calculated low-energy conformers all had only
one of the three sugar amino acid residues in the chair
conformation, the other two were either in the boat or
skew conformations (Fig. 1). Thus it appears that the
macrocyclic ring is rather strained, which may be a rea-
son for the difficulties experienced in the deprotection of
the macrocycle.
Acknowledgments
We thank the Swedish Research Council, the Swedish
Strategic Research Foundation, and the program ꢁGly-
coconjugates in Biological Systemsꢀ sponsored by the
Swedish Strategic Research Foundation for financial
support.
Supplementary data
In conclusion, we have prepared a C3-symmetric macro-
cycle with alternating sugar amino acid and tyrosine
Experimental procedures and physical data for com-
pounds 2–8. Supplementary data associated with this

J. F. Billing, U. J. Nilsson / Tetrahedron Letters 46 (2005) 991–993
993
10. Billing, J. F.; Nilsson, U. J. Tetrahedron 2004, 61, 863–
874.
11. Mayes, B. A.; Cowley, A. R.; Ansell, C. W. G.; Fleet, G.
W. J. Tetrahedron Lett. 2004, 45, 163–166.
article can be found, in the online version, at
doi:10.1016/j.tetlet.2004.12.038.
12. Ueki, M.; Nishigaki, N.; Aoki, H.; Tsurusaki, T.; Katoh,
T. Chem. Lett. 1993, 721–724.
References and notes
13. Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T.
Tetrahedron Lett. 1992, 37, 5441–5444.
14. Quibell, M.; Packman, L. C.; Johnson, T. J. Chem. Soc.,
Perkin Trans. 1 1996, 1219–1225.
1. Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann,
M.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156–
10167.
2. Lohof, E.; Planker, E.; Mang, C.; Burkhart, F.; Dechants-
reiter, M. A.; Haubner, R.; Wester, H.-J.; Schwaiger, M.;
Ho¨lzemann, G.; Goodman, S. L.; Kessler, H. Angew.
Chem., Int. Ed. 2000, 39, 2761–2763.
15. Sheppeck, J. E., II; Kar, H.; Hong, H. Tetrahedron Lett.
2000, 41, 5329–5333.
16. The HATU and HBTU coupling reagents were long
believed to be uroniumsalts, but have been shown to be
guanidiniumsalts when prepared using the conventional
methods.17 This is likely to be true for HAPyU as well.
´
3. Gruner, S. A. W.; Keri, G.; Schwab, R.; Venetianer, A.;
Kessler, H. Org. Lett. 2001, 3, 3723–3725.
4. Sto¨ckle, M.; Voll, G.; Gunther, R.; Lohof, E.; Locardi, E.;
¨
HAPyU was prepared from1-hydroxy-7-azabenzotriazole
17
potassiumsalt (KOAt)
and commercially available
Sibylle, G.; Kessler, H. Org. Lett. 2002, 4, 2501–2504.
5. van Well, R. M.; Overkleeft, H. S.; van der Marel, G. A.;
Bruss, D.; Thibault, G.; de Groot, P. G.; van Boom, J. H.;
Overhand, M. Bioorg. Med. Chem. Lett. 2003, 13, 331–
334.
6. Grotenbreg, G. M.; Timmer, M. S. M.; Llamas-Saiz, A.
L.; Verdoes, M.; van der Marel, G. A.; van Raaij, M. J.;
Overkleeft, H. S.; Overhand, M. J. Am. Chem. Soc. 2004,
126, 3444–3446.
7. Raunkjær, M.; El Oualid, F.; van der Marel, G. A.;
Overkleeft, H. S.; Overhand, M. Org. Lett. 2004, 6, 3167–
3170.
8. van Well, R. M.; Overkleeft, H. S.; Overhand, M.; Vang
Carstenen, E.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 2000, 41, 9331–9335.
chloro-N,N,N0,N0-bis(tetramethylene)-formamidinium hexa-
fluorophosphate using Knorrꢀs method for the preparation
of similar coupling reagents.18,19
17. Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.;
Zhang, C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay,
C.; Mu¨gge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.;
Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 442–445.
18. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927–1930.
19. Bienert, M.; Henklein, P.; Beyermann, M.; Carpino, L. A.
In Houben-Weyl Methods of Organic Chemistry 4th ed.,
Vol. E22a, Goodman, M., Felix, A., Moroder, L.,
Toniolo, C., Eds.; Georg Thieme: Stuttgart, 2002; Chap.
3.8, p. 562.
20. Kartha, K. P. R.; Mukhopadhyay, B.; Field, R. A.
Carbohydr. Res. 2004, 339, 729–732.
9. Gruner, S. A. W.; Truffault, V.; Voll, G.; Locardi, E.;
Sto¨ckle, M.; Kessler, H. Chem. Eur. J. 2002, 8, 4366–4376.