Synthesis of oligomers of tetrahydrofuran amino acids: Furanose carbopeptoids

Article abstract of DOI:10.1039/a805364b

An acid catalysed ring rearrangement of a triflate derivative of D-mannono-γ-lactone 6 is the key step in the synthesis of the C-glycosyl sugar amino acid derivatives 3 and 4, examples of carbohydrate amino acid building blocks with specific conformational preferences suitable for incorporation into combinatorial amide libraries; homo-oligomerisation via solution phase coupling procedures affords furanose carbopeptoids 1 which adopt novel solution state secondary structures.

Full text of DOI:10.1039/a805364b

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Synthesis of oligomers of tetrahydrofuran amino acids: furanose carbopeptoids
Martin D. Smith,a Daniel D. Long,a Daniel G. Marquess,b,c Timothy D. W. Claridge and George W. J. Fleet*a†
a Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, UK OX1 3QY
b Glaxo Wellcome Ltd., Gunnels Wood Road, Stevenage, Herts, UK SG1 2NY
c Advanced Medicine Inc., 270 Littlefield Avenue, Suite B, South San Francisco, CA 94080, USA
An acid catalysed ring rearrangement of a triflate derivative
of -mannono-g-lactone 6 is the key step in the synthesis of
C-5 hydroxy group, no C-glycopyranosides were isolated; ring
closures to C-glycopyranoses by nucleophilic displacement at
C-2 of a sugar are rare.12
D
the C-glycosyl sugar amino acid derivatives 3 and 4,
examples of carbohydrate amino acid building blocks with
specific conformational preferences suitable for incorpora-
tion into combinatorial amide libraries; homo-oligomerisa-
tion via solution phase coupling procedures affords furanose
carbopeptoids 1 which adopt novel solution state secondary
structures.
The strategy adopted for the synthesis of carbopeptoids 1
utilises well-established peptide bond forming methodology.
For the synthesis of sugar amino acid building blocks 3 and 4,
it is necessary to introduce nitrogen at C-6. Selective esterifica-
tion of 2 with toluene-p-sulfonyl chloride in pyridine (to give
the 6-O-tosyl derivative 8) and subsequent displacement of the
sulfonate ester with NaN3 in DMF at 90 °C gave the azide 9 in
72% yield over two steps.13 Hydrolysis of the methyl ester with
aq. NaOH and purification by ion exchange chromatography
afforded the carboxylic acid 3 in quantitative yield. Catalytic
hydrogenation of the methyl ester 9 gave the bicyclic lactam 10
via a non-isolable amine; a more hindered ester is required to
enable isolation of the required 6-amino component 4. Accord-
ingly, transesterification of the methyl ester 9 with K2CO3 in
PriOH gave the isopropyl derivative 11 in 79% yield.14
Hydrogenation of the azide 11 in the presence of Pd-C in PriOH
afforded the amine 4 as the major product together with an
unidentified and inseparable minor component; the highly polar
amine 4, characterised as its triacetate 12, (90% yield from
11),was used without purification in all further reactions.
Coupling of 4 and 3 was then performed using 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) in
DMF in the presence of 1-hydroxybenzotriazole (HOBt). This
reaction allowed the isolation of the dimeric compound 13 in
74% yield (from the azide 11) as an easily handled solid
(Scheme 2). No protection of the secondary hydroxy groups is
necessary during the coupling procedure. Iteration of the
coupling procedure gave ready access to the tetramer 1 (n = 2)
and the hexamer 1 (n = 4). The dimer 13 was treated with aq.
NaOH and purified by ion exchange chromatography to afford
Carbohydrate amino acids are attractive building blocks for the
routine incorporation of carbohydrate moieties into combinato-
rial libraries by standard peptide coupling techniques.1 The
conformational influence of the sugar backbone on peptide
chains has been exploited in the rational design of non-peptide
peptidomimetics.2 Homo-oligomeric sugar amino acids (‘car-
bopeptoids’3) based upon a pyranose template have been
prepared by solution4 and solid5 phase approaches, though to
date there are no furanose6 analogues. Here we describe the
synthesis of a C-glycofuranosyl sugar amino acid analogue and
its oligomerisation to materials which adopt a well-defined
secondary structure.
RO
OR
RO
OR
RO
OR
H
N
H
N
N3
R'O
O
O
O
O
O
O
n
1
HO
OH
HO
OH
OH
R1
MeO2C
R2O2C
O
O
2
3
4
R1 = N3, R2 = H
R1 = NH2, R2 = Pri
2-O-Triflates (trifluoromethanesulfonates) of g- and
d-lactones in basic7 or acidic8 MeOH give good to excellent
yields of highly substituted tetrahydrofurancarboxylates. Such a
procedure has recently been utilised for the synthesis of
C-glycosides of glucofuranose,9 which have provided scaffolds
for the generation of glucofuranose libraries. For the synthesis
of the C-arabinosyl derivative 2, the triflate 6 is required; in
order to effect esterification at C-2, it is necessary to protect the
OH
RO
HO
OH
ii
TfO
MeO2C
O
O
O
O
CH2OH
HO
7
5
6
R = H
R = Tf
i
primary hydroxy group at C-6 in
kinetic monoacetonide 5, easily accessible in 74% yield from
the diacetonide of
-mannose.10 Treatment of the diol 5 with
D-mannonolactone as its
R2O
OR2
HO
OH
vii
D
R1
R
PriO2C
MeO2C
O
O
Tf2O in CH2Cl2 in the presence of pyridine caused highly
regioselective esterification of the hydroxy group at C-2 to give
the stable triflate 6, which may be isolated in 85% yield; 6 has
previously been described but in a significantly poorer yield.11
Treatment of the crude triflate 6 with HCl in MeOH gave the
required ester 2 in 84% yield from 5, providing multigram
11 R1 = N3, R2 = H
R1 = NH2, R2 = H
12 R1 = NHAc, R2 = Ac
2
8
9
R = OH
R = OTs
R = N3
viii
ix
iii
iv
6
vi
v
O
HO
OH
quantities of 2 in an overall yield of 62% from -mannose. The
D
O
HO
key transformation of 6 to 2 by treatment with acidic MeOH
involves hydrolysis of the side chain acetonide, methanolysis of
the lactone, followed by intramolecular SN2-like closure of the
resulting open chain hydroxy triflate 7 with inversion of
configuration at C-2 (Scheme 1). Although it is possible that
intermediates such as 7 could undergo alternative closure to a
tetrahydropyran, resulting from attack by the C-6 rather than the
N3
NH
HO2C
O
OH
10
3
Scheme 1 Reagents and conditions: i, Tf2O, Py, CH2Cl2; ii, 1% HCl in
MeOH; iii, TsCl, Py; iv, NaN3, DMF; v, 0.5
M aq. NaOH, dioxane, ion
exchange; vi, H2, Pd, EtOH; vii, K2CO3, PriOH; viii, H2, Pd, PriOH; ix,
Ac2O, Py
Chem. Commun., 1998
2039

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HO
OH
Notes and References
N3
i
† E-mail: george.fleet@chem.ox.ac.uk
HO2C
O
HO
OH
HO
OH
3
1 J. P. McDevitt and P. T. Lansbury, J. Am. Chem. Soc., 1996, 118, 3818;
P.S. Ramamoorthy and J. Gervay, J. Org. Chem., 1997, 62, 7801; M. J.
Sofia, R. Hunter, T. Y. Chan, A. Vaughan, R. Dulina, H. Wang and D.
Gange, J. Org. Chem., 1998, 63, 2802.
2 E. G. von Roedern, E. Lohof, G. Hessler, M. Hoffmann and H. Kessler,
J. Am Chem. Soc., 1996, 118, 10 156.
H
R2
+
N
R1O2C
O
O
HO
OH
O
13 R1 = Pri, R2 = N3
14 R1 = H, R2 = N3
15 R1 = Pri, R2 = NH2
ii
NH2
iii
PrO2iC
O
3 K. C. Nicolaou, H. Florke, M. G. Egan, T. Barth and V. A. Estevez,
Tetrahedron Lett., 1995, 36, 1775.
4
iv
4 J. Gervay, T. M. Flaherty and C. Nguyen, Tetrahedron Lett., 1997, 38,
1493 and references cited therein.
R3O
OR3
R3O
OR3
R3O
OR3
5 C. Muller, E. Kitas and H. P. Wessel, J. Chem. Soc. Chem. Commun.,
1995, 2425; B. Drouillat, B. Kellam, G. Dekany, M. S. Starr and I. Toth,
Bioorg. Med. Chem. Lett., 1997, 7, 2247.
6 L. Poitout, Y. le Merrer and J.-C. Depazay, Tetrahedron Lett., 1995, 36,
6887.
7 S. S. Choi, P. M. Myerscough, A. J. Fairbanks, B. M. Skead, C. J. F.
Bichard, S. J. Mantell, J. C. Son, G. W. J. Fleet, J. Saunders and D.
Brown, J. Chem. Soc., Chem. Commun., 1992, 1605.
8 J. R. Wheatley, C. J. F. Bichard, S. J. Mantell, J. C. Son, D. J. Hughes,
G. W. J. Fleet and D. Brown, J. Chem. Soc., Chem. Commun., 1993,
1065.
9 C. J. F. Bichard, T. W. Brandstetter, J. C. Estevez, G. W. J. Fleet, D. J.
Hughes and J. R. Wheatley, J. Chem. Soc., Perkin Trans. 1, 1996,
2151.
10 O. T. Schmidt, Methods Carbohydr. Chem., 1963, 2, 319; A. R.
Beacham, I. Bruce, S. Choi, O. Doherty, A. J. Fairbanks, G. W. J. Fleet,
B. M. Skead, J. M. Peach, J. Saunders and D. J. Watkin, Tetrahedron:
Asymmetry, 1991, 2, 883; S. Morgenlie, Acta Chem. Scand., 1972, 26,
2518; D. Horton and J. S. Jewel, Carbohydr. Res., 1966, 2, 251;
J. A. J. M. Vekemans, J. Boerekamp, E. F. Godefroi and G. J. F. Chit-
tenden, Recl. Trav. Chim. Pays-Bas, 1985, 104, 266.
H
H
N
N
R2
R1O2C
O
O
O
O
2O
16
17
18
R
R
R
1 = Pri, R2 = N3, R3 = Ac
1 = Me, R2 = N3, R3= H
1 = Pri, R2 = NH2, R3 = Ac
v
iii
iv
OAc
AcO
OAc
AcO
O
AcO
O
OAc
H
H
N3
N
N
PriO2C
O
O
O
4
19
Scheme 2 Reagents and conditions: i, EDCI, HOBt, Pri2NEt, DMF; ii, 0.5
M
aq. NaOH, dioxane, then Amberlite IR-120 (H+); iii, H2, Pd, PriOH; iv, 14
(1 equiv.), EDCI, HOBt, Pri2NEt, DMF, then Ac2O, Py; v, NaOMe, MeOH,
then Amberlite IR-120 (H+)
the free acid 14 in quantitative yield. Additionally the
N-terminal azide in 13 was reduced with H2 in the presence of
Pd-C to afford the amine 15. Coupling of the dimeric building
blocks 14 and 15 was performed using EDCI in DMF in the
presence of HOBt. The reaction mixture was treated with Ac2O
in pyridine to facilitate isolation of the tetramer 1615 (55% from
13) from which the acetate groups can be removed with NaOMe
in MeOH to afford the deprotected carbopeptoid 17 in
quantitative yield. Hydrogenation of the tetramer 16 in the
presence of Pd gave the N-terminal amine 18 which was
coupled crude to the dimeric acid 14 using EDCI in DMF in the
presence of HOBt. Treatment of the reaction mixture with Ac2O
in pyridine gave the hexamer 19 in 68% yield from the tetramer
16.
11 I. Kalwinsh, K-H. Metten, and R. Brückner, Heterocycles, 1995, 409,
939.
12 J. C. Estevez, A. J. Fairbanks, K. Y. Hsia, P. Ward and G. W. J. Fleet,
Tetrahedron Lett., 1994, 35, 3361.
13 Selected data for 2: dH(500 MHz, CD3CN) 3.58 (1H, d, J 3.7, OH-4),
3.64–3.74 (3H, m, H-6, H-6A, OH-6), 3.70 (3H, s, CO2Me), 3.88 (1H, q,
J 3.2, H-5), 4.03–4.05 (1H, m, H-4), 4.12 (1H, ddd, J 4.3, 1.9, 8.4, H-3),
4.33 (1H, d, J 8.4, OH-3), 4.59 (1H, d, J 4.3, H-2).
14 Selected data for 11: dH(500 MHz, CD3OD) 1.27 (6H, t, J 6.2, Me2CH),
3.38 (1H, dd, J 4.7, 12.7, H-6A), 3.62, (1H, dd, J 7.5, 12.7, H-6A),
3.91–3.94 (1H, m, H-5), 3.95 (1H, dd, J 2.8, 5.7, H-4), 4.26 (1H, dd, J
2.8, 5.1, H-3), 4.61 (1H, d, J 5.1, H-2), 5.07 (1H, septet, J 6.2,
Me2CH).
15 Selected data for 16 (500 MHz, CDCl3, 298 K):
The ease with which highly functionalised tetrahydrofurans,
such as 4, can be synthesised is likely to offer opportunities for
the production of a range of carbohydrate amino acid building
blocks with specific conformational preferences suitable for
incorporation into combinatorial amide libraries. The diversity
of possible structures afforded by a carbohydrate template in
terms of backbone stereochemistries and protecting group
manipulations allows formation of hydrophobic or hydro-
philic—and thus water soluble—derivatives. Efficient unpro-
tected oligomerisation to give compounds with well-defined
secondary structure emphasizes the versatility of the sugar
amino acid building block and alludes to the possibility of a
more rational design tailored to specific applications. The
following paper provides evidence for conformational prefer-
ences of the hexamer 19 and the tetramer 16; NMR and
molecular dynamics indicate that both adopt a well-defined
secondary structure based around a repeating b-turn mimic
stabilised by intramolecular hydrogen bonds.16
Ring A
Ring B
Ring C
Ring D
dC(C1)
dH(C2)
dC(C2)
dH(C3)
dC(C3)
dH(C4)
dC(C4)
dH(C5)
dC(C5)
dH(C6)
167.81
4.669
81.02
5.646
76.08
4.904
78.40
4.153
85.00
3.708/
3.461
51.43
—
168.11
4.692
81.74
5.559
75.57
4.837
78.06
4.027
85.18
4.027/
3.224
41.28
6.910
167.68
4.708
81.38
5.495
76.01
5.003
77.68
4.123
85.00
3.861/
3.228
41.28
8.025
167.15
4.687
78.93
5.475
76.66
5.250
77.57
4.055
83.19
3.781/
3.481
40.48
8.191
dC(C6)
dH(NH)
Carbopeptoids are identified alphabetically from the N- to the C-terminus;
protons on each ring are numbered according to IUPAC recommendations
on carbohydrate nomenclature.
16 M. D. Smith, T. D. W. Claridge, G. E. Tranter, M. S. P. Sansom and
G. W. J. Fleet, Chem. Commun., 1998, 2041.
The support of the EPSRC and GlaxoWellcome in the form
of a CASE studentship (to D. D. L.) is gratefully acknowl-
edged.
Received in Liverpool, UK, 10th July 1998; 8/05364B
2040
Chem. Commun., 1998