3-Azidotetrahydrofuran-2-carboxylates: Monomers for five-ring templated β-amino acid foldamers?

Article abstract of DOI:10.1016/S0957-4166(99)00205-0

Four diastereomeric methyl 3-azidotetrahydrofuran-2-carboxylates were prepared from diacetone glucose as precursors for the synthesis of β-amino acid oligomers with secondary structure.

Full text of DOI:10.1016/S0957-4166(99)00205-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1855–1859
3-Azidotetrahydrofuran-2-carboxylates: monomers for five-ring
templated β-amino acid foldamers?
Mark P. Watterson,a Lea Pickering,a Martin D. Smith,a Sarah J. Hudson,a Paul R. Marsh,a
Jacqueline E. Mordaunt,c David J. Watkin,b Christopher J. Newman b and George W. J. Fleet a,∗
aDyson Perrins Laboratory, Oxford Centre for Molecular Sciences, South Parks Road, Oxford, OX1 3QY, UK
bChemical Crystallography Department, Oxford University, Parks Road, Oxford, OX1 3PD, UK
cGlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Received 29 April 1999; accepted 20 May 1999
Abstract
Four diastereomeric methyl 3-azidotetrahydrofuran-2-carboxylates were prepared from diacetone glucose as
precursors for the synthesis of β-amino acid oligomers with secondary structure. © 1999 Elsevier Science Ltd. All
rights reserved.
Conformationally constrained amino acids provide access to short sequences of peptide mimetics with
secondary structure and thus may generate new opportunities for the design of antagonists and agonists
of specific protein–protein interactions.1 Oligomers of β-amino acids are more prone than those derived
from α-amino acids to possess conformational rigidity.2 There has recently been much interest in the
synthesis of monomers — and the structures of oligomers — containing a β-amino acid moiety.3 For
example, Gellman has shown that oligomers containing only six β-amino acid residues — some of which
were a trans-2-aminocyclohexane carboxylic acid — can form stable helices in aqueous solutions.4 Other
structural units which have β-amino acid equivalents in rigid ring templates are likely to induce secondary
structure in relatively short sequences.5
Oligomers derived from different diastereomers of 5-azidomethyl carboxylates 1 form both β-turns6
and α-helices;7 one diastereomer of 1 was shown by Chakraborty to be an isostere for Gly-Gly
in enkephalins, producing materials with much the same biological activity as that of the natural
products.8 The synthesis of 1 depends on the efficient acid and base catalysed conversions of 2-
O-trifluoromethanesulfonates (triflates) of γ- and δ-lactones to highly substituted tetrahydrofuran-2-
carboxylates (THFC) 3 (Scheme 1).9 Esterification of 3 at C-5 to afford sulfonates 2 and subsequent
reaction with sodium azide allows a general approach to 1. Radical bromination of 3, followed by
treatment of the resulting α-bromoester with sodium azide, permits the generation of α-azidoesters
4 which also provides the opportunity to generate peptidomimetics with secondary structure.10 One
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00205-0

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M. P. Watterson et al. / Tetrahedron: Asymmetry 10 (1999) 1855–1859
strategy for the synthesis of the diastereomeric β-azidoesters 8 is the activation of the C-3 hydroxyl
group in 3 to give 9; although the 3-sulfonylesters 9 were readily formed — and in some cases could
be isolated — all attempts to induce substitution of the leaving group with an azide ion resulted in
elimination reactions; in fact sodium azide in DMF was among the most efficient bases to induce
elimination to the corresponding α,β-unsaturated esters.11 Accordingly, a different approach to the
synthesis of the azidoesters 8 is required in which the azide is introduced into the sugar prior to the
formation of the THF ring.
Scheme 1. (i) Aq. CF3COOH; (ii) Br2, BaCO3, H2O; then Me2CO, CSA; (iii) Tf2O, pyridine, CH2Cl2; then HCl, MeOH
This paper reports the synthesis of four diastereomeric β-azidoTHFC esters 8 from the four diastereo-
meric diacetone azides 5, all of which were prepared from diacetone glucose 21 (Scheme 2). In the case
of each diastereomer of 5, hydrolysis gave the corresponding free 3-azidohexose 6. Oxidation of each
of the diastereomers of 6 with bromine water gave mixtures of lactones and open chain acids, but direct
protection of these mixtures allowed the isolation of the protected azidolactones 7. Esterification of the
remaining free hydroxyl group in 7 with triflic anhydride, followed by reaction with hydrogen chloride
in methanol, formed the target β-azidoesters 8; this transformation involved removal of the acetonide
protecting group, methanolysis of the lactone to give the open chain methyl ester, and attack by the
free C-5 OH group at the C-2 triflate to give SN2 ring closure with inversion at C-2 producing the β-
azidoTHFC 8.
Thus, oxidation of diacetone glucose 21 with PCC in dichloromethane in the presence of molecular
sieve gave the ketone 15 which with acetic anhydride in pyridine afforded the enol acetate 10 (Scheme 2).
Hydrogenation of the enol acetate in the presence of palladium black in ethyl acetate, followed by ester
exchange, gave the gulo-alcohol 11, epimeric with 21 at both C-3 and C-4, as previously described.12
Triflation of the free hydroxyl group in 11, followed by azide displacement, gave the azide 1213 in 96%
yield. Removal of the protecting groups in 12 by aqueous trifluoroacetic acid, followed by oxidation of
the free sugar with bromine and treatment of the residue of the reaction with acetone in the presence
of camphorsulfonic acid, afforded the galactono-azide 13,14 oil, [α]D −68.2 (c, 1.00 in CHCl3), in an
25
overall yield of 75%. Further reaction of the lactone 13 with triflic anhydride in dichloromethane in the
presence of pyridine, followed by treatment with hydrogen chloride in methanol, gave the azidotalonate
1415 in 75% yield. Reduction of the ketone 11 with sodium borohydride gave the allo-alcohol 16 which
was converted into the azide 17 in 95% yield, as previously described.16 Hydrolysis of 17, followed by
23
oxidation and acetonation, afforded the glucono-azide 18, oil, [α]D +71.1 (c, 1.11 in chloroform), in
an overall yield of 79%. Triflation of 18 with subsequent acidic methanolysis gave the azidomannonate
19,17 epimeric at C-4 with 14, in 73% yield. The structure of 19 was unequivocally established by X-ray
crystallographic analysis18 of the silyl ether 20.19
For the synthesis of the two other diastereomeric azidoTHFC esters 25 and 30, diacetone glucose 21
was converted to the triflate 22; treatment of 22 with sodium azide in DMF20 gave a 1:1 mixture of
the vinyl ether 26 and the allo-azide 23 in a combined yield of 90%. Elaboration of 23 by hydrolysis,

M. P. Watterson et al. / Tetrahedron: Asymmetry 10 (1999) 1855–1859
1857
Scheme 2. (i) PCC, CH2Cl2, molecular sieve; (ii) pyridine, Ac2O; (iii) Pd black, H2, EtOAc; then K2CO3 in MeOH; (iv) Tf2O,
pyridine, CH2Cl2; (v) NaN3, DMF; (vi) aq. CF3COOH; then Br2, BaCO3, H2O; then Me2CO,CSA; (vii) Tf2O, pyridine, CH2Cl2;
then HCl, MeOH; (viii) 9-BBN in THF; then H2O2, NaOH; (ix) TBDMSCl, imidazole, DMF
25
oxidation and acetonation afforded the allono-azide 24, m.p. 176–177°C, [α]D +110.5 (c, 1.08 in
acetone), in 75% yield; triflation of 24 followed by acidic methanolysis gave the azidoaltronate 2521
in 66% yield. The structure of 25 was confirmed by X-ray crystallographic analysis.18 Hydroboration of
the alkene 26 with 9-borabicyclononane [9-BBN] in THF followed by oxidation with alkaline hydrogen
peroxide gave the galacto-alcohol 27 in 86% yield, significantly higher than that obtained with borane
in THF.22 Triflation of 27 followed by reaction with sodium azide in DMF gave the previously unknown
25
gulo-azide 28, m.p. 86–87°C, [α]D +146.5 (c, 1.05 in CHCl3), in 94% yield [together with a small
amount of the elimination product 26]. The contrast in the ratio of elimination to substitution in this case
in comparison to the reaction of the gluco-triflate 22 is noteworthy. The diacetonide 28 was elaborated
24
to give the gulono-lactone 29, m.p. 166–167°C, [α]D +120.4 (c, 1.21 in acetone) [in 58% yield] and
further to the azidoidonate 3023 [in 80% yield].
In summary, this paper validates a general approach to 3-azidoTHFC esters from 3-azidolactones.
Studies on the synthesis and structures of oligomers derived from the two cis- 25 and 30 and the two
trans- 14 and 19 β-amino acid monomers are currently in progress.
Acknowledgements
Support from BBSRC and EPSRC is acknowledged.

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M. P. Watterson et al. / Tetrahedron: Asymmetry 10 (1999) 1855–1859
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12. Legler, G.; Pohl, S. Carbohydr. Res. 1986, 155, 119.
13. Lowary, T. L.; Hindsgaul, O. Carbohydr. Res. 1994, 251, 33.
14. Satisfactory spectroscopic and microanalytical or HRMS data was obtained for all new compounds reported.
15. Data for azidotalonate 14: colourless oil; [α]D25 +72.8 (c, 0.25 in CHCl3); νmax (film) 3369 (OH), 2114 (N3), 1742 (C_O)
cm−1; δH (CDCl3, 400 MHz) 3.83 (3H, s, CO2CH3), 3.92 (1H, dd, J6 ,5 4.1, J6 ,6 12.3, H-60), 3.97 (1H, dd, J6,5 4.6, J6 ,6
12.3, H-6), 4.09 (1H, dd, J3,2 7.3, J3,4 4.7, H-3), 4.22 (1H, app-q, J 4.3, H-5), 4.52 (1H, app-t, J 4.4, H-4), 4.57 (1H, d, J2,3
7.3, H-2); δC (CDCl3, 50.3 MHz) 52.8 (q, CO2CH3), 61.0 (t, C-6), 66.2, 73.3, 78.0, 81.3 (4×d, C-2, C-3, C-4, C-5), 171
(s, C-1).
0
0
0
16. Austin, G. N.; Baird, P. D.; Fleet, G. W. J.; Peach, J. M.; Smith, P. W.; Watkin, D. J. Tetrahedron 1987, 43, 3095.
24
17. Data for azidomannonate 19: yellow oil; [α]D +75.3 (c, 1.01 in methanol); νmax (film) 3400 (OH), 2113 (N3), 1744
(C_O) cm−1; δH (d4-methanol, 400 MHz) 3.63 (1H, dd, J6 ,5 4.7, J6 ,6 12.2, H-60), 3.75 (1H, dd, J6,5 3.5, J6,6 12.2, H-6),
3.81 (3H, s, CO2CH3), 3.92–3.96 (1H, m, H-5), 4.07 (1H, app-t, J 5.8, H-4), 4.15 (1H, app-t, J 5.6, H-3), 4.30 (1H, d, J2,3
5.6, H-2); δC (CDCl3, 50.3 MHz) 52.9 (q, CO2CH3), 61.3 (t, C-6), 69.9, 75.4, 79.2, 84.4 (4×d, C-2, C-3, C-4, C-5), 171.3
(s, C-1).
0
0
0
18. The X-ray crystal structures of 20 and 25 will be reported in a full paper.
24
19. Data for the silyl ether 20: m.p. 73–75°C (ethyl acetate); [α]D +39.7 (c, 1.00 in chloroform); νmax (film) 3463 (OH),
2105 (N3), 1742 (C_O) cm−1; δH (CDCl3, 400 MHz) 0.09 (6H, s, Si(CH3)2), 0.91 (9H, s, SiC(CH3)3), 2.55 (1H, s, br,
OH), 3.72 (1H, dd, J6 ,5 6.3, J6 ,6 10.6, H-60), 3.83 (3H, s, CO2CH3), 3.86 (1H, dd, J6,5 4.2, J6,6 10.6, H-6), 4.03 (1H,
app-dt, J 4.2, J 6.3, H-5), 4.15 (1H, app-t, J 5.6, H-3), 4.22 (1H, app-t, J 5.6, H-4), 4.39 (1H, d, J2,3 5.6, H-2); δC (CDCl3,
50.3 MHz) −5.7 (q, Si(CH3)2), 18.1 (s, SiC(CH3)3), 25.7 (q, SiC(CH3)3), 52.7 (q, CO2CH3), 62.8 (t, C-6), 69.9, 76.9, 79.6,
84.3 (4×d, C-2, C-3, C-4, C-5), 171.6 (s, C-1).
0
0
0
20. Daley, L.; Monneret, C.; Gautier, C.; Roger, P. Tetrahedron Lett. 1992, 33, 3749.

M. P. Watterson et al. / Tetrahedron: Asymmetry 10 (1999) 1855–1859
1859
25
21. Data for azidoaltronate 25: m.p. 94–95°C (toluene/ethyl acetate); [α]D +95.2 (c, 0.88 in CHCl3); νmax (KBr disc) 3489,
3370 (OH), 2121 (N3), 1757 (C_O) cm−1; δH (CD3OD, 400 MHz) 3.58 (1H, dd, J6 ,5 3.7, J6 ,6 12.4, H-60), 3.78 (3H, s,
0
0
0
CO2CH3), 3.81 (1H, dd, J6,5 2.4, J6,6 12.4, H-6), 3.90 (1H, app-dt, J 3.0, J5,4 8.6, H-5), 4.36 (1H, app-t, J 4.8, H-3), 4.44
(1H, dd, J4,3 5.1, J4,5 8.6, H-4), 4.70 (1H, d, J2,3 4.6, H-2); δC (CD3OD, 50.3 MHz) 52.7 (q, CO2CH3), 61.8 (t, C-6), 67.0,
73.2, 79.1, 83.7 (4×d, C-2, C-3, C-4, C-5), 171.6 (s, C-1).
22. Paulsen, H.; Behre, H. Carbohydr. Res. 1966, 2, 80.
24
23. Data for azidoidonate 30: oil; [α]D +50.9 (c, 1.05 in CHCl3); νmax (film) 3369 (OH), 2116 (N3), 1749 (C_O) cm−1; δH
(CD3OD, 400 MHz) 3.72 (1H, dd, J6 ,5 5.8, J6 ,6 11.6, H-60), 3.77 (1H, dd, J6,5 5.4, J6,6 11.6, H-6), 3.78 (3H, s, CO2CH3),
4.15 (1H, app-dt, J 5.5, J5,4 3.7, H-5), 4.30–4.32 (2H, m, H-3, H-4), 4.84 (1H, d, J2,3 4.8, H-2); δC (CD3OD, 50.3 MHz)
52.6 (q, CO2CH3), 61.1 (t, C-6), 70.9, 76.1, 79.6, 83.4 (4×d, C-2, C-3, C-4, C-5), 171.9 (s, C-1).
0
0
0