Synthesis and structural analysis of cyclic oligomers consisting of furanoid and pyranoid ε-sugar amino acids

Article abstract of DOI:10.1002/ejoc.200300031

Cyclic oligomers composed of amide-linked furanoid (i.e., 1, 3) and pyranoid (i.e., 2, 4) ε-sugar amino acids (SAAs) were prepared by a cyclization/cleavage approach with use of the oxime resin. These cyclic homooligomers were constructed by use of the known N-Boc protected furanoid ε-SAA 11 and the novel pyranoid hydroxymethylene homologue 22. Conformational analysis of cyclic trimer 1 by an unrestrained simulated annealing technique showed that the furanoid rings of the residues I flip between a twist (north, P = 0°) and an envelope (south, P = 167°) conformation. Furthermore, the side chains connecting the carbonyl functionality (i.e. C2) proved to be rigid, while the other side chains (C7) are conformationally flexible. Similar conformational behaviour is observed for the side chains of the pyranoid ε-SAA II residues in trimer 2, but the pyranoid ring chair conformation remains stable during the calculation. These conformational details may have important implications in the future design of SAA-based artificial receptors or peptidomimetics. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300031

FULL PAPER
Synthesis and Structural Analysis of Cyclic Oligomers Consisting of Furanoid
and Pyranoid ε-Sugar Amino Acids
Renate M. van Well,[a] Luciana Marinelli,[b] Kees Erkelens,[a] Gijsbert A. van der Marel,[a]
Antonio Lavecchia,[c] Herman S. Overkleeft,[a] Jacques H. van Boom,[a] Horst Kessler,[b] and
Mark Overhand*[a]
Keywords: Amino acids / Conformational analysis / Cyclization / Molecular dynamics
Cyclic oligomers composed of amide-linked furanoid (i.e., 1,
3) and pyranoid (i.e., 2, 4) ε-sugar amino acids (SAAs) were
side chains connecting the carbonyl functionality (i.e. C2)
proved to be rigid, while the other side chains (C7) are con-
prepared by a cyclization/cleavage approach with use of the formationally flexible. Similar conformational behaviour is
oxime resin. These cyclic homooligomers were constructed
by use of the known N-Boc protected furanoid ε-SAA 11 and
observed for the side chains of the pyranoid ε-SAA II resi-
dues in trimer 2, but the pyranoid ring chair conformation
the novel pyranoid hydroxymethylene homologue 22. Con- remains stable during the calculation. These conformational
formational analysis of cyclic trimer 1 by an unrestrained si- details may have important implications in the future design
mulated annealing technique showed that the furanoid rings of SAA-based artificial receptors or peptidomimetics.
of the residues I flip between a twist (north, P = 0°) and an
envelope (south, P = 167°) conformation. Furthermore, the
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
quences on a tritylchloropolystyrene resin by a Fmoc-based
peptide synthesis technique, followed by cleavage from the
resin and cyclization under high-dilution conditions.
Naturally occurring cyclic structures provide an impetus
for the design and synthesis of molecular receptors.[1] One
type of cyclic oligomers found in nature are the cyclodex-
trins. These cyclic oligomers, composed of carbohydrate
units, have been used in the areas of drug delivery, asym-
metric synthesis, and chromatography, and also as enzyme
mimetics.[2] Novel host molecules with differently shaped
internal cavities have been obtained by replacement of the
natural glycosidic bonds connecting the individual carbo-
hydrate derivatives by other types of linkages. Vasella and
co-workers reported the development of cyclic oligomers
composed of acetylene-linked carbohydrate residues, which
were shown to accommodate a nucleoside.[3] In addition, a
first example of oligomers containing amide bonds instead
of glycosidic linkages was disclosed recently.[4,5] These latter
compounds, containing pyranoid δ-sugar amino acids
(SAAs),[6] were prepared by the assembly of the linear se-
As part of a program directed towards the synthesis and
conformational analysis of SAA-containing oligomers, we
present here the utility of a cyclization/cleavage strategy for
the solid-phase synthesis of the novel cyclic SAA oligomers
1؊4 (Figure 1). The cyclic trimers (1, 2) and tetramers (3, 4)
contain the known 3,6-anhydro-amino-2,7-dideoxy--allo-
[a]
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden
University,
P.O. Box 9502, 2300 RA Leiden, The Netherlands
Fax: (Internat.) ϩ31-71-5274307
E-mail: Overhand@chem.leidenuniv.nl
[b]
Institut für Organische Chemie und Biochemie, Technische
Universität München,
Lichtenbergstrasse 4, 85747 Garching, Germany
[c]
Dipartimento di Chimica Farmaceutica
Universita di Napoli ‘‘Federico II’’,
Via D. Montesano 49, 80131 Napoli, Italy
e Tossicologica,
Figure 1. Cyclic homooligomers composed of furanoid ε-SAAs or
pyranoid ε-SAAs
Eur. J. Org. Chem. 2003, 2303Ϫ2313
DOI: 10.1002/ejoc.200300031
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2303

M. Overhand et al.
FULL PAPER
heptulosonic acid (furanoid ε-SAA I)[7,8] residue and the desired, suitably protected furanoid ε-SAA 11 in 73% yield
new 3,7-anhydro-8-amino-2,8-dideoxy--gulo--glycero-oc- over the last three steps.
tulonic acid (pyranoid ε-SAA II) residue. As furanoid and
The synthesis of pyranoid ε-SAA 22 (Scheme 2) com-
pyranoid carbohydrates[9] are known to adopt different mences with condensation of the known[12] peracetylated C-
conformations, we investigated the conformational behav- glycoside 12 with methanol to furnish ester 13 in 83% yield.
´
iour of the trimers 1 and 2 by unrestrained simulated an- Subjection of 13 to Zemplen deacetylation conditions, fol-
nealing calculations[10] in conjunction with NMR analysis.
Results
lowed by protection of the primary hydroxy group as the
trityl ether, gave compound 15 in 85% yield over the two
steps. Treatment of 15 with sodium hydride and benzyl bro-
mide and subsequent removal of the trityl function with
pTsOH furnished compound 17 in 88% yield. The free pri-
mary alcohol was now transformed into the azide as de-
scribed above in the synthesis of the furanoid SAA (i.e., 17
to 19) in 77% yield. The azide 19 was then converted into
the Boc-protected amine 20 by means of a modified Staud-
inger reaction, with trimethylphosphane and 2-(tert-butoxy-
carbonyl)oxyimino-2-phenylacetonitrile (Boc-ON), in an
excellent yield of 95%.[13] Palladium-catalysed hydrogen-
ation of 20 and saponification of the intermediate methyl
ester 21 yielded the desired pyranoid ε-SAA 22 in 20%
overall yield based on 12.
Synthesis of SAA Building Blocks 11 and 22
The synthesis of the Boc-protected furanoid SAA 11[7]
started with the Wittig olefination of 2,3-O-isopropylidene-
protected ribose 5 with methyl (triphenylphosphoranylid-
ene)acetate to afford the methyl ester 6 in 81% yield
(Scheme 1).[11] Treatment of 6 with methanesulfonyl chlo-
ride in pyridine, followed by substitution of the intermedi-
ate mesylate with sodium azide, furnished the fully pro-
tected SAA 8 in a yield of 87%. Palladium-catalysed hydro-
genation of compound 8 in the presence of hydrochloric
acid resulted in the reduction of the azide functionality with
concomitant cleavage of the isopropylidene protective
group to give the amine 9 as its HCl salt. Finally, treatment
of 9 with Boc2O under SchottenϪBaumann conditions and
Solid-Support Synthesis of Cyclic SAA Oligomers 1؊4
Previous work from our laboratory[7] demonstrated the
subsequent saponification of the methyl ester yielded the use of a cyclization/cleavage strategy for the synthesis of
Scheme 1. Reagents and reaction conditions: (i) a) methyl (triphenylphosphoranylidene)acetate, CH3CN, ∆; b) NaOMe (0.1 equiv.),
MeOH (81%); (ii) MsCl, pyridine (93%); (iii) NaN3, DMF, 75 °C, 1 h (94%); (iv) H2, Pd/C, HCl/EtOH; (v) Boc2O, NaHCO3, Na2CO3,
H2O/dioxane (82%); (vi) NaOH, H2O/dioxane (89%)
Scheme 2. Reagents and reaction conditions: (i) MeOH, DIC, DMAP, DCM, 16 h (83%); (ii) NaOMe, MeOH (quant.); (iii) TrCl,
pyridine (85%); (iv) BnBr, NaH, DMF (88%); (v) pTsOH, DCM/MeOH (9:1); (vi) MsCl, pyridine (quant.); vii) NaN3, DMF, 75 °C, 2 h
(77%); (viii) Me3P, Boc-ON (95%); (ix) H2/Pd-C, EtOH/EtOAc (1:1); (x) NaOH, dioxane (70%).
2304
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2303Ϫ2313

Cyclic Oligomers Consisting of Furanoid and Pyranoid ε-Sugar Amino Acids
FULL PAPER
Scheme 3. Reagents and reaction conditions: (i) a) SAA 11 or 22 (5 equiv.), BOP (5 equiv.), DIPEA (6.5 equiv.), NMP/DCM (1:1, v/v),
2 h, 2 ϫ ; b) 25% TFA, 1% TiPS, DCM; (ii) a) SAA 11 or 22 (5 equiv.), BOP (5 equiv.), DIPEA (6.5 equiv.), NMP/DCM (1:1, v/v),
45 min, 2 ϫ ; b) 25% TFA, 1% TiPS, DCM; (iii) DIPEA (2 equiv.), AcOH (2 equiv.), DMF, 36 h
related artificial receptor molecules based on a combination preted with the utmost care. A three-dimensional model
of furanoid SAAs and naturally occurring amino acids.[14] was used in order to correlate the ROE-derived distances.
The solid-phase synthesis of the cyclic oligomers 1؊4 by
the same strategy is presented in Scheme 3. In the case of Cyclic Trimer 1
cyclic trimer 1, for instance, Kaiser’s p-nitrobenzophenone
The signals of three of the four protons of the furanoid
rings in compound 1 overlap in the 1D spectrum (see Fig-
oxime resin[15] 23 was loaded with SAA building block 11
under the agency of benzotriazol-1-yloxytris(dimethylamin-
ure 2), making it impossible to calculate the conformations
of the furan rings on the basis of the coupling constants.[17]
The signals belonging to the protons of the two methylene
side chains (i.e., H7a, H7b, H2a and H2b) have well re-
solved chemical shifts; however, diastereotopic assign-
ment[18] of the individual protons was not possible at this
point. The geminal proton at C2 resonating at higher field
(arbitrarily assigned as H2b) displayed a large coupling
constant with H3 (J2b,3 ϭ 9.3 Hz). This observation implies
a rotamer population with one of the H2 protons in an anti
relationship relative to H3.[19] The protons attached to C7
have small coupling constants with H6 (J7a,6 ϭ 2.9 and
J7b,6 ϭ 5.5 Hz), giving no direct insight in the rotamer
populations.
o)phosphonium hexafluorophosphate (BOP) and diisopro-
pylethylamine (DIPEA).[16] The condensation step was per-
formed twice in order to ensure optimal loading. The im-
mobilised SAA 24 was treated with 25% TFA in DCM to
remove the Boc group and subsequently condensed with the
second SAA building block 11 (BOP/DIPEA).
By repetition of the deprotection/coupling/deprotection
steps the linear immobilised precursor trimer 26 was ob-
tained. Cyclization was accomplished by treatment of the
resin with a 1:1 mixture of DIPEA and acetic acid for 36 h,
furnishing the cyclic trimer 1 in 20% yield after RP-HPLC.
Elongation of the immobilised linear trimer 26 to the corre-
sponding tetramer 27, followed by the described cyclisation/
cleavage procedure, provided compound 3 with comparable
efficiency. The immobilised linear precursors 28؊29 were
prepared from 25 in a similar fashion, following a sequen-
tial elongation using the corresponding pyranoid SAA
building block 22. Subsequent acid-catalysed cyclization
gave compounds 2 and 4 in 5Ϫ10% yields after purification.
The ROESY spectrum of 1 showed medium cross-peaks
between the amide proton and both neighbouring methyl-
Conformational Analysis
NMR spectroscopy (in 10% D2O in H2O as solvent) in
combination with molecular dynamics calculations was
used to determine the three-dimensional structures of the
cyclic oligomers 1 and 2. On the NMR timescale, both com-
pounds were shown to have Cn symmetry, such that only
one set of signals for the SAA building blocks is observed.
Because the observed ROEs can be caused by intra- and/or
Figure 2. Part of the 1H spectrum of the cyclic furanoid SAA
trimer 1 (for the numbering see Figure 1) recorded at 600 MHz in
interresidual interactions the ROESY data should be inter- 10% D2O in H2O
Eur. J. Org. Chem. 2003, 2303Ϫ2313
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2305

M. Overhand et al.
FULL PAPER
ene protons H7a and H7b. A strong cross-peak was ob-
served between the amide proton and H2b, while H2a and
H3 gave weak ROEs. The H2/HN cross-peaks most prob-
ably arise from the interaction between two sequential resi-
dues, indicating the energetically favourable trans confor-
mation of the amide bonds. Because of our inability to as-
sign the ROESY spectrum further it was decided not to use
distance restraints for the molecular dynamics simulations.
Instead, simulated annealing calculations[20] were carried
out in order to search the entire conformational space ac-
cessible in solution for compound 1, the outcome of which
was correlated with the obtained NMR spectroscopic data
in a later stage. To this end, one hundred and fifty low-
energy conformers were obtained by gradual heating of a
randomly build structure, starting from 300 and increasing
to 800 K, and subsequent cooling down to 300 K. Each re-
sulting structure was then minimised by use of steepest de-
scent followed by conjugate gradient algorithms.
Analysis of the conformations of the furanoid rings in
the 150 structures revealed that only two conformations oc-
cur. In one conformation, the five-membered rings adopt a
twist conformation with C5 endo and C4 in the exo position
(adopted nucleic acid nomenclature).[21] According to the
concept of pseudorotation,[17] this is a north conformation
[pseudorotational phase angle (P) ϭ 0°]. The other confor-
mation found for the furan ring is an envelope with C4
endo, corresponding to a south conformation (P ϭ 167°).
The occurrence of these two conformations during the
simulation is illustrated by plotting the dihedral angle
C3ϪC4ϪC5ϪC6 as a function of the frame number (Fig-
ure 3).
Figure 4. Newman projections of: a) the possible conformations
around C6ϪC7, and b) the conformation around C2ϪC3 in 1; the
large coupling constant found for H2b in the NMR experiments
corresponds to this anti relationship and H2b can therefore be as-
signed as H2S.[18]
The resulting simulated structures were evaluated on the
basis of their NMR spectroscopic data. All the confor-
mations that did not have a trans amide bond and an anti
relationship between H3 and one of the neighbouring pro-
tons H2, as indicated by the observed large coupling con-
stant, were omitted. The geometries of the side chains at
C6ϪC7 of the SAA residues in the selected structures were
found to be either Ϫsynclinal (Ϫsc)[22] or ϩsc (see Figure 4,
a). There seems to be a small preference for the ϩsc confor-
mation around C6ϪC7, which is corroborated by the differ-
ence in coupling constants for the two geminal protons at
C7 (J ϭ 2.9 and J ϭ 5.5 Hz). The C2ϪC3 bond only adopts
[17]
a Ϫsc conformation in which H2S
has a trans relation-
ship with H3 (Figure 4, b). The two sugar puckers, in com-
bination with the geometries of the side chains, result in
four different SAA conformations. These four different
SAA conformations are represented in Figure 5, and a low-
energy conformer of the cyclic trimer 1 is depicted in Fig-
ure 6.
Cyclic Trimer 2
In the 1D NMR spectrum of trimer 2 (Figure 7), all the
ring protons displayed large coupling constants (J ϭ 9 Hz),
indicating a chair conformation of the pyranose rings with
4
equatorial hydroxy groups (corresponding to the C1 con-
formation of glucose).[23] Again, diastereotopic assignment
of the methylene protons at C2 and C8 proved impossible.
A large coupling constant (J2b,3 ϭ 9.7 Hz) was observed for
one of the geminal protons attached to C2 (H2b), implying
an anti relationship with H3. Because of the extensive over-
lapping with other signals, the coupling constants for the
methylene protons at C8 could not be determined. Strong
ROEs were observed between the amide proton and the
neighbouring methylene protons (H8a and H8b), as well as
between the amide proton and H2b. Furthermore, medium
Figure 3. Graph of C3ϪC4ϪC5ϪC6 dihedral angle of one SAA
residue during molecular simulations. A positive angle (35°) de-
notes the north conformation, and a negative angle (Ϫ35°) the
south conformation.
Figure 5. The four different monomer conformations resulting from simulated annealing calculations: a) 4E and ϩsc; b) 4E and Ϫsc;
5
5
c) T and ϩsc; d) T and Ϫsc conformations for the furan ring and C6ϪC7 rotamer, respectively
4
4
2306
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2303Ϫ2313

Cyclic Oligomers Consisting of Furanoid and Pyranoid ε-Sugar Amino Acids
FULL PAPER
Figure 6. Stereoplot of
a
low-energy conformer of
1
resulting from simulated annealing calculations with SAA1: 54T
5
4
and Ϫsc; SAA2: T and ϩsc; SAA3: E and ϩsc
4
energy structure from the simulated annealing calculations
is displayed in Figure 9.
1
Figure 7. Part of the H NMR spectrum of 2 (for the numbering
Figure 8. a) Rotamer conformation for C2ϪC3 bonds; b) most
populated rotamer for C7ϪC8 of the pyranoid SAA in 2; the signal
of the methylene proton resonating at higher field (H2b), with a
coupling constant J2b,3 of 9.7 Hz, could therefore be assigned as
H2S
see Figure 1) recorded in 10% D2O in H2O
ROEs were observed between the amide proton and H2a
and H6.
As the strong H2b/HN and medium H2a/HN ROEs are
judged to be sequential, the amide bonds of compound 2
have to be trans (as in 1).
Discussion
In this paper we present the synthesis of a new series of
The same simulated annealing technique as used for the cyclic SAA-containing molecules composed of furanoid ε-
furanoid SAA trimer was performed on the pyranoid-con- (i.e., 1, 3) and pyranoid ε-SAAs (i.e., 2, 4). The latter com-
taining trimer 2. The chair conformations of the six-mem- pounds were prepared on oxime resin by a cyclization/cleav-
bered rings remain stable during the simulations. Further- age strategy, thus avoiding the difficulties associated with
more, as also observed for the C2ϪC3 side chain of the cyclization in solution. Because of the apparent Cn sym-
furanoid SAA, H2S adopts an anti conformation in relation metry of the trimers 1 and 2 in their NMR spectra, an unre-
to H3 (i.e. Ϫsc, Figure 8). All three possible staggered con- strained simulated annealing technique was used to search
formations around C7ϪC8 were found in the simulated the entire conformational space in order to compare their
structures. However, the Ϫsc rotamer, with both methylene conformational behaviour. Analysis of the cyclic trimer 1
protons in a gauche position relative to H7, is the most revealed that the five-membered rings of the SAA residues
populated (see Figure 8). This conformation has the amide flip between twist (north, P ϭ 0°) and envelope (south, P ϭ
proton positioned above the sugar ring, explaining the ob- 167°) conformations. As the pyranoid rings adopt chair
served HN/H6 ROE cross-peak. An example of one low- conformations stabilised by the equatorial positions of all
Eur. J. Org. Chem. 2003, 2303Ϫ2313
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2307

M. Overhand et al.
FULL PAPER
Figure 9. Stereoplot of a low-energy conformation of 2 with all C7ϪC8 rotamers as Ϫsc
Figure 10. Side and top view of Connolly surface area plots of compounds 1 (a) and 2 (b)
the hydroxy groups, the trimer 2, composed of pyranoid the carbonyl side-chain methylene groups (i.e., C2) of the
SAAs, is less flexible than its furanoid counterpart. The SAAs in both compounds 1 and 2 are restrained, as this
methylene functionalities attached to the amine groups of region exclusively adopts the Ϫsc conformation. In both
the SAA residues in the two trimers 1 and 2 are flexible, cyclic trimers the oxygen atoms in the sugar ring are located
with varying rotamer conformations around the C6ϪC7 on the interior and the secondary hydroxy groups are ori-
bond in 1 and C7ϪC8 bond in 2, respectively. Surprisingly, ented outwards.
2308
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2303Ϫ2313

Cyclic Oligomers Consisting of Furanoid and Pyranoid ε-Sugar Amino Acids
FULL PAPER
ation (EM) and molecular dynamics (MD) calculations were car-
ried out with the DISCOVER program by use of the CVFF force
field[25] and a dielectric constant of 80. After EM using steepest
descent and conjugate gradient, the system was heated gradually,
starting from 300 K and increasing to 800 K, and subsequently co-
oled to 300 K with 5 ps steps at every temperature, each by direct
scaling of velocities. All the structures originating from the MD
simulations were minimised, again by use of steepest descent and
conjugate gradient algorithms. During the MD calculations no re-
straints were taken into account. The resulting structures were fi-
The possibility of cavity formation by the cyclic trimers
is illustrated in the surface area plots of symmetrical con-
formers of 1 and 2 (Figure 10). It can clearly be seen that
the structure of the furanoid SAA trimer is compact and
does not contain a water-accessible cavity. On the other
hand, the pyranoid SAA trimer does posses a small cavity.
Both the furanoid SAA trimer and the pyranoid one have
flat structures. The findings described in this paper provide
important conformational data relating to the behaviour of
furanoid and pyranoid ε-SAAs in small cyclic structures. nally evaluated on the basis of the NOEs and 3J coupling constants.
By similar synthetic strategies, larger cyclic oligomers as
Methyl 3,6-Anhydro-2-deoxy-4,5-O-isopropylidene-D-allo-heptulon-
well as structures containing more restrained SAA units
should be constructed in the near future, as potential novel
artificial host molecules.
ate (6): Compound 5 (29 g, 154 mmol) was coevaporated with tolu-
ene (3 ϫ 50 mL) and dissolved in acetonitrile (500 mL), and methyl
(triphenylphosphoranylidene)acetate (56.5 g, 169 mmol) was ad-
ded. The reaction mixture was heated under reflux for 2 h and con-
centrated, and the residue was dissolved in MeOH (300 mL). So-
dium methoxide (0.83 g, 15.4 mmol) was added, and the reaction
mixture was stirred for 10 min. The reaction mixture was neutral-
ised with Dowex-Hϩ, the ion-exchange resin was removed by fil-
tration, and the filtrate was concentrated. The residue was purified
by silica gel column chromatography (eluent: EtOAc/light petro-
leum, 2:8 Ǟ 8:2, v/v) to give compound 6 in 81% yield (30.6 g) as
a colourless syrup. The spectroscopic data were in full agreement
with those reported in the literature.[13]
Experimental Section
General Procedures and Materials: Mass spectra were recorded with
PE/SCIEX API 165 with electronspray interface. Column chroma-
tography was performed on Fluka 60 silica gel (0.04Ϫ0.063 mm).
TLC analysis was conducted on ‘‘DC Plastikfolien’’ (Merck 60 F254
silica gel) with detection by UV absorption (254 nm) where appli-
cable and by spraying with 20% H2SO4 in ethanol, a ninhydrin
solution or ammonium molybdate (25 g/L) and ceric ammonium
sulfate (10 g/L), followed by charring at ഠ 150 °C. Reactions were
run at ambient temperature, unless stated otherwise. Reactions re-
quiring anhydrous conditions were stirred under argon or nitrogen.
Acetone (Acros, p.a.), DCE (Biosolve, HPLC-grade), DMF (Baker,
p.a.), toluene (Biosolve, p.a.), 1,4-dioxane (Baker, p.a.), pyridine
(Baker, p.a.) and DCM (Baker, p.a.) were stored over molecular
Methyl
3,6-Anhydro-2-deoxy-4,5-O-isopropylidene-7-O-mesyl-D-
allo-heptulonate (7): Compound 6 (14.76 g, 60 mmol) was coevapo-
rated with pyridine (3 ϫ 50 mL) and dissolved in pyridine
(300 mL). Methanesulfonyl chloride (5.6 mL, 72 mmol) was added,
and the reaction mixture was stirred for 16 h. The solvent was re-
moved under reduced pressure and the residue was dissolved in
EtOAc (300 mL). The organic phase was washed with H2O
(150 mL), aq. NaHCO3 (3 ϫ 150 mL) and brine (100 mL), dried
(MgSO4) and concentrated. The crude product was applied to a
silica gel column and eluted with EtOAc/light petroleum (3:7 Ǟ
7:3, v/v) to afford compound 7 in 93% (18.2 g) as a colourless oil.
1H NMR (CDCl3): δ ϭ 4.65 (dd, H5, J4,5 ϭ 6.6, J5,6 ϭ 4.4 Hz, 1
H), 4.55 (dd, J3,4 ϭ 3.7, J4,5 ϭ 6.6 Hz 1 H, H4), 4.35 (m, 3 H, H3,
H7a, H7b), 4.18 (m, 1 H, H6), 3.71 (s, 3 H, OMe), 3.05 (s, 3 H,
Ms), 2.73 (dd, J2a,3 ϭ 5.1 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2a), 2.60
(dd, J2b,3 ϭ 6.9 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2b), 1.55 (s, 3 H, CH3
isoprop), 1.35 (s, 3 H, CH3 isoprop) ppm. 13C NMR (CDCl3): δ ϭ
170.3 (C1), 114.5 (Cq isoprop), 83.7, 81.6, 80.8 (C3, C4, C5, C6),
68.9 (C7), 51.5 (CH3 OMe), 37.7 (C2), 37.1 (CH3 Ms), 27.0 (CH3
isoprop), 25.1 (CH3 isoprop) ppm. ES-MS: m/z ϭ 324.9[M ϩ H]ϩ,
346.9 [M ϩ Na]ϩ, 363 [M ϩ K]ϩ.
˚
sieves (4 A). Acetonitrile (Biosolve, p.a.) and MeOH (Biosolve, p.a.)
˚
were stored over molecular sieves (3 A). Triethylamine (Acros) was
boiled under reflux for 3 h with CaH2, distilled and stored over
KOH. Methyl (triphenylphosphoranylidene)acetate (Aldrich), 2,2-
dimethyl-1,3-dioxan-4,6-dione (Acros), Boc-ON (Janssen chimica),
oxime resin (Nova Biochem), BOP (Senn chemicals) and DIPEA
(Biosolve) were used as received. Solid-phase chemistry was per-
formed in DCM (Biosolve, peptide synthesis grade) and NMP (Bi-
osolve, peptide synthesis grade). Preparative RP HPLC was per-
formed on an Altima C18 reversed-phase column-TFA 10.00 mmd
installed on BioCad ‘‘Vision’’ workstation (Perseptive Biosystems).
The products were eluted at 5 mL/min with CH3CN/H2O contain-
ing 0.1% TFA; detection was performed at 214 nm.
NMR Measurements: 1H and 13C NMR spectra were recorded with
Jeol JNM-FX-200 (200/50.1 MHz), Bruker WM 300 (300/
75.1 MHz) or Bruker DMX 600 (600/150 MHz) spectrometers.
Chemical shifts are given in ppm (δ) relative to tetramethylsilane
as internal standard. All 13C spectra given are proton-decoupled.
All spectra of the cyclic SAA homooligomers were recorded in
H2O/D2O (9:1, v/v) at 278 K with a Bruker DMX 600 or a Bruker
DMX 500 spectrometer equipped with a pulsed field gradient ac-
cessory. Standard DQF-COSY (512c ϫ 2084c) spectra were re-
corded with use of presaturation for solvent suppression. NOESY
and ROESY spectra (400c ϫ 2048c, τmix ϭ 180 ms) were recorded
with use of the Watergate solvent suppression.[24] All spectra were
recorded in phase-sensitive mode, by using either the TPPI or
States-TPPI for quadrature detection in the indirect dimension.
Homonuclear coupling constants were determined from the corre-
Methyl
3,6-Anhydro-7-azido-2,7-dideoxy-4,5-O-isopropylidene-D-
allo-heptulonate (8): Compound 7 (18.2 g, 56 mmol) was coevapo-
rated with toluene (3 ϫ 50 mL) and dissolved in DMF (200 mL).
Sodium azide (9.1 g, 140 mmol) was added and the resulting mix-
ture was stirred at 75 °C for 1.5 h. The reaction mixture was al-
lowed to cool down to room temperature, after which it was diluted
with H2O (100 mL). Extraction with EtOAc (3 ϫ 200 mL) and sub-
sequent drying (MgSO4) of the combined organic phases gave com-
pound 8, after purification by column chromatography (eluent:
EtOAc/light petroleum, 2:8 Ǟ 7:3, v/v), in a yield of 94% (14.3 g)
as a colourless syrup. 1H NMR (CDCl3): δ ϭ 4.51 (m, 2 H, H5,
H6), 4.32 (dd, 1 H, H4), 4.14 (m, 1 H, H3), 3.71 (s, 3 H, OMe),
3.55 (dd, 1 H, H7a, J7a,6 ϭ 3.7 Hz, J7a,7b ϭ 13.1 Hz), 3.34 (dd, 1
H, H7b, J7b,6 ϭ 5.1 Hz, J7a,7b ϭ 13.2 Hz), 2.75 (dd, 1 H, H2a,
J2a,3 ϭ 5.1 Hz, J2a,2b ϭ 15.3 Hz), 2.64 (dd, 1 H, H2b, J2b,3 ϭ 6.9
Hz, J2a,2b ϭ 15.3 Hz)., 1.55 (s, 3 H, CH3 isoprop), 1.35 (s, 3 H,
1
sponding H spectra.
Computer Simulations: The structure calculations were performed
with a Silicon Graphics Origin R10000 computer. Energy minimis-
Eur. J. Org. Chem. 2003, 2303Ϫ2313
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2309

M. Overhand et al.
CH3 isoprop) ppm. 13C NMR (CDCl3): δ ϭ 170.5 (C1), 114.7 (Cq NMR (CDCl3): δ ϭ 170.1, 169.8, 169.3, 169.1 [C1, 4 ϫ C(O) Ac],
FULL PAPER
isoprop), 83.9, 82.8, 81.8, 80.6 (C3, C4, C5, C6), 51.9 (C7), 51.6
(CH3 OMe), 37.8 (C2), 27.2 (CH3 isoprop), 25.2 (CH3 isoprop)
ppm. ES-MS: m/z ϭ 293.9 [M ϩ Na]ϩ.
75.4, 74.1, 73.7, 71.1, 68.0 (C3, C4, C5, C6, C7), 61.7 (C8), 51.5
(OMe), 36.6 (C2), 20.2 (4 ϫ CH3 Ac) ppm.
Methyl 3,7-Anhydro-2-deoxy-8-O-trityl-d-gulo-D-glycero-octulonate
Methyl 3,6-Anhydro-7-[(tert-butoxycarbonyl)amino]-2,7-dideoxy-
allo-heptulonate (10): Compound 8 (12.85 g, 50 mmol) was dis-
D
-
(15): Compound 13 (12.5 g, 30.9 mmol) was coevaporated with
toluene (3 ϫ 50 mL) and dissolved in MeOH (200 mL). NaOMe
solved in ethanol (200 mL) containing HCl (3 , 20 mL). After (0.17 g, 3.1 mmol) was added, and the resulting mixture was stirred
degassing of the solution, Pd/C (1.4 g) was added and the solution
was degassed again. The reaction mixture was stirred for 18 h un-
der H2, after which only baseline material was visible by TLC. The
solution was filtered through Glass Fibre (GF/2A, Whatman) and
the filtrate was concentrated under reduced pressure. Crude 9 was
dissolved in H2O (100 mL), and Na2CO3 (10.6 g, 100 mmol) and
NaHCO3 (16.8 g, 200 mmol) were added. After the reaction mix-
ture had been cooled to 0 °C, a solution of Boc2O (11.99 g,
55 mmol, 1.1 equiv.) in dioxane (100 mL) was added. After stirring
for 18 h the solution was acidified with HCl (1 ⁾ and extracted
with EtOAc (3 ϫ 150 mL). The combined organic phases were
dried (MgSO4) and concentrated. The residue was purified by col-
umn chromatography (eluent: EtOAc/light petroleum, 2:8 Ǟ 8:2,
for 2 h. The reaction mixture was neutralised with Dowex-Hϩ, the
ion-exchange resin was removed by filtration, and the filtrate was
concentrated. The residue was coevaporated with pyridine (3 ϫ
50 mL) and dissolved in pyridine (150 mL). TrCl (10.3 g,
37.1 mmol) was added and the reaction mixture was stirred for
16 h. After concentration of the solution, the residue was taken up
in EtOAc (150 mL), washed with H2O(100 mL), aq. NaHCO3 (3
ϫ 100 mL) and brine (100 mL), dried (MgSO4) and concentrated.
Crude 15 was purified by column chromatography (eluent: EtOAc/
light petroleum, 1:9 Ǟ 1:1) to give a yield of 85% (12.55 g) of a
colourless oil. 1H NMR (CDCl3): δ ϭ 7.44Ϫ7.12 (m, 15 H, Tr),
4.88 (br. s, 1 H, OH), 4.43 (br. s, 1 H, OH), 3.88 (br. s, 1 H, OH),
3.65 (m, 1 H, H3), 3.58 (s, 3 H, OMe), 3.37, 3.20 (2 ϫ m, 6 H, H4,
v/v) to give compound 10 in a yield of 82% (12.9 g), over the two H5, H6, H7, 2 ϫ H8), 2.79 (dd, J2a,3 ϭ 2.9 Hz, J2a,2b ϭ 15.0 Hz,
steps, as a slightly yellow syrup. 1H NMR (CDCl3): δ ϭ 4.87 (t,
1 H, H2a), 2.45 (dd, J2b,3 ϭ 8.8 Hz, J2a,2b ϭ 15.3 Hz, 1 H, H2b)
J ϭ 6.2 Hz, 1 H, HN), 4.12 (m, 1 H, H6), 3.95Ϫ3.82 (m, 3 H, H3, ppm. 13C NMR (CDCl3): δ ϭ 172.1 (C1), 143.8 (Cq Tr), 128.4,
H4, H5), 3.73 (s, 3 H, OMe), 3.35 (dd, J ϭ 4.4 Hz, J ϭ 5.8 Hz, 2 127.5, 126.7 (CHarom Tr), 86.2 (Cq Tr), 78.3, 75.9, 73.2, 70.8 (C3,
H, H7a, H7b), 2.72 (dd, J2a,3 ϭ 5.1 Hz, J2a,2b ϭ 15.3 Hz, 1 H,
H2a), 2.63 (dd, J2b,3 ϭ 6.6 Hz, J2a,2b ϭ 15.7 Hz, 1 H, H2b), 1.45
(s, 9 H, tert-Bu Boc) ppm. 13C NMR (CDCl3): δ ϭ ϭ 171.4 (C1),
156.2 [C(O) Boc), 82.3, 79.0, 73.9, 71.5 (C3, C4, C5, C6), 51.5 (CH3
OMe), 41.8 (C7), 39.2 (C2), 27.2 (3 ϫ CH3 Boc) ppm. ES-MS: m/
z ϭ 306 [M ϩ H]ϩ, 328.2 [M ϩ Na]ϩ, 633.5 [2M ϩ Na]ϩ
C4, C5, C6, C7), 60.1 (C8), 51.6 (OMe), 37.6 (C2) ppm.
Methyl 3,7-Anhydro-4,5,6-tri-O-benzyl-2-deoxy-8-O-trityl-D-gulo-
D-glycero-octulonate (16): After coevaporation of compound 15
(8.61 g, 18 mmol) with toluene (3 ϫ 30 mL), DMF (100 mL), BnBr
(7.7 mL, 64.8 mmol) and NaH (2.38 g, 59.4 mmol) were added and
the resulting mixture was stirred for 16 h. MeOH (10 mL) was ad-
ded to quench the excess of NaH, and the solution was concen-
trated. The residue was dissolved in EtOAc (150 mL), washed with
H2O(100 mL), aq. NaHCO3 (3 ϫ 100 mL) and brine (100 mL),
3,6-Anhydro-7-[(tert-butoxycarbonyl)amino]-2,7-dideoxy-D-allo-
heptulonic Acid (11): NaOH (1 , 10 mL) was added to a mixture
of compound 9 (2.57 g, 8.4 mmol) in dioxane (20 mL). After stir-
ring for 2.5 h, the reaction mixture was acidified to pH 2 with HCl dried (MgSO4) and applied to a silica gel column. Compound 16
(1 ) and extracted with EtOAc (6 ϫ 60 mL). The combined or-
ganic phases were dried (MgSO4) and concentrated. The residue
was applied to a silica gel column and eluted with EtOAc/MeOH
(1:0 Ǟ 9:1, v/v) containing 1% AcOH to give compound 11 in 89%
was obtained as an amorphous white solid in 88% (11.84 g) by
elution with EtOAc/light petroleum (0:1 Ǟ 3:7, v/v). 1H NMR
(CDCl3): δ ϭ 7.51Ϫ7.16 (m, 30 H, Tr, 3 ϫ Bn), 4.89 (m, 3 H, CH2
Bn), 4.69 (2 ϫ d, J ϭ 4.8 Hz, J ϭ 11.0 Hz, 2 H, CH2 Bn), 4.37 (d,
yield (2.25 g) as an amorphous white solid. 1H NMR (MeOD): δ ϭ J ϭ 10.2 Hz),1 H, CH2 Bn, 3.85Ϫ3.39 (m, 6 H, H3, H4, H5, H6,
4.94 (s, 1 H, HN), 4.12 (m, 1 H, H6), 3.86Ϫ3.73 (m, 3 H, H3, H4, H7, H8a), 3.65 (s, 3 H, OMe), 3.16 (dd, J7,8b ϭ 3.7 Hz, J8a,8b
ϭ
H5), 3.25 (dd, J6,7a ϭ 2.9 Hz, 1 H, H7a), 3.17(dd, J6,7b ϭ 4.0 Hz, 10.2 Hz, 1 H, H8b), 2.86 (dd, J2a,3 ϭ 3.7 Hz, J2a,2b ϭ 14.6 Hz, 1
1 H, H7b), 2.65 (dd, J2a,3 ϭ 4.4 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2a),
2.45 (dd, J2b,3 ϭ 8.2 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2b), 1.44 (s, 9 H,
tert-Bu Boc) ppm. 13C NMR (MeOD): δ ϭ 174.8 (C1), 158.3 [C(O)
H, H2a), 2.58 (dd, J2b,3 ϭ 8.0 Hz, J2a,2b ϭ 14.6 Hz, 1 H, H2a) ppm.
13C NMR (CDCl3): δ ϭ 171.2 (C1), 143.8 (Cq Tr), 138.2Ϫ137.6 (3
ϫ Cq Bn), 128.6Ϫ126.7 (CHarom Tr, Bn), 86.0 (Cq Tr), 86.9, 81.1,
Boc), 84.1, 80.3, 75.5, 73.2 (C3, C4, C5, C6), 43.4 (C7), 37.7 (C2), 78.5, 78.3, 75.7 (C3, C4, C5, C6, C7), 75.6Ϫ74.9 (3 ϫ CH2 Bn),
27.9 (3 ϫ CH3 Boc) ppm. ES-MS: m/z ϭ 313.9[M ϩ Na]ϩ, 605.4
[2M ϩ Na]ϩ, 896.5 [3M ϩ Na]ϩ.
62.2 (C8), 51.6 (OMe), 37.5 (C2) ppm.
Methyl 3,7-Anhydro-4,5,6-tri-O-benzyl-2-deoxy-D-gulo-D-glycero-
Methyl 4,5,6,8-Tetra-O-acetyl-3,7-anhydro-2-deoxy-
D
-glycero-
D
-
octulonate (17): Compound 16 (11.84 g, 15.9 mmol) was treated
gulo-octulonate (13): Compound 12[13] (14.43 g, 37 mmol) was co- with a mixture of 3% pTsOH in DCM/MeOH (1:1, v/v, 100 mL).
evaporated with DCE (3 ϫ 50 mL) and dissolved in DCM
(200 mL). MeOH (2.23 mL, 55 mmol), DIC (6.29 mL, 40.7 mmol)
and DMAP (0.45 g, 3.7 mmol) were added, and the reaction mix-
When TLC analysis revealed complete conversion (ഠ 3 h) into a
lower running product, the reaction mixture was neutralised with
aq. NaHCO3 and concentrated. The residue was taken up in EtOAc
ture was stirred at room temperature. After 3 the reaction mixture (150 mL), washed with H2O (100 mL), aq. NaHCO3 (3 ϫ 100 mL)
was filtered through a short pad of Hyflo and concentrated. Purifi- and brine (100 mL) and dried (MgSO4). Purification by column
cation by column chromatography (eluent: EtOAc/light petroleum, chromatography (eluent: EtOAc/light petroleum, 0:1 Ǟ 4:6, v/v)
1
0:1 Ǟ 1:1, v/v) afforded compound 13 in 83% (12.5 g) as a colour-
less syrup. H NMR (CDCl3): δ ϭ 5.20 (t, J ϭ 9.5 Hz, 1 H, H6),
afforded 17 in quantitative yield (7.90 g) as a colourless syrup. H
NMR (CDCl3): δ ϭ 7.31 (m, 15 H, Harom 3 ϫ Bn), 4.92 (m, 4 H,
1
5.07 (t, J ϭ 9.5 Hz, 1 H, H5), 4.93 (t, J ϭ 9.5 Hz, 1 H, H4), 4.25 CH2 Bn), 4.64 (2 ϫ d, J ϭ 8.4 Hz, J ϭ 11.0 Hz, 2 H, CH2 Bn),
(dd, J7,8a ϭ 5.1 Hz, J8a,8b ϭ 12.4 Hz, 1 H, H8a), 4.06 (dd, J7,8b
2.2 Hz, J8a,8b ϭ 12.4 Hz, 1 H, H8b), 3.99Ϫ3.90 (m, 1 H, H7),
ϭ
3.85Ϫ3.39 (m, 7 H, H3, H4, H5, H6, H7, 2 ϫ H8), 3.63 (s, 3 H,
OMe), 2.74 (dd, J2a,3 ϭ 3.7 Hz, J2a,2b ϭ 15.7 Hz, 1 H, H2a), 2.40
3.74Ϫ3.65 (m, 1 H, H3), 3.70 (s, 3 H, OMe), 2.53 (m, 2 H, 2 ϫ (dd, J2b,3 ϭ 8.4 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2b) ppm. 13C NMR
H2), 2.07, 2.05, 2.03, 2.00 (4 ϫ s, 12 H, 4 ϫ CH3 Ac) ppm. 13C (CDCl3): δ ϭ 171.3 (C1), 138.3Ϫ137.9 (3 ϫ Cq Bn), 128.4Ϫ127.7
2310
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2303Ϫ2313

Cyclic Oligomers Consisting of Furanoid and Pyranoid ε-Sugar Amino Acids
(CHarom Bn), 86.9, 81.2, 79.2, 78.1, 75.6 (C3, C4, C5, C6, C7), 79.6, 78.1 (C3, C4, C5, C6, C7), 75.6, 75.5 (3 ϫ CH2 Bn), 52.1
FULL PAPER
75.5Ϫ75.0 (3 ϫ CH2 Bn), 61.7 (C8), 51.7 (OMe), 37.3 (C2) ppm. (OMe), 41.5 (C8), 37.8 (C2), 28.8 (tert-Bu Boc) ppm.
ES-MS: m/z ϭ 507.2 [M ϩ H]ϩ, 329.2 [M ϩ Na]ϩ.
Methyl 3,7-Anhydro-8-[(tert-butoxycarbonyl)amino]-2,8-dideoxy-D-
gulo-D-glycero-octulonate (21): A solution of compound 20
Methyl 3,7-Anhydro-4,5,6-tri-O-benzyl-2-deoxy-8-O-mesyl -
D-gulo-
(0.215 g, 0.36 mmol) in EtOAc (3 mL) was degassed and Pd/C
(20 mg) was added, and the solution was degassed for a second
time. The reaction mixture was stirred under H2 for 16 h. Filtering
of the solution through Glass Fibre (GF/2A, Whatman) and con-
centration of the filtrate afforded the crude product, which was
applied to a silica gel column. Elution with EtOAc/light petroleum
(3:7 Ǟ 1:0, v/v) afforded 21 in quantitative yield (0.12 g) as a pale
D
-glycero-octulonate (18): Compound 17 (2.5 g, 5 mmol) was co-
evaporated with pyridine (20 mL) and then redissolved in pyridine
(30 mL), and MsCl (0.46 mL, 6 mmol) was added. The reaction
mixture was stirred for 16 h, after which TLC analysis showed the
reaction to be complete. After concentration of the solution, the
residue was dissolved in EtOAc (50 mL) and washed with H2O
(25 mL), aq. NaHCO3 (3 ϫ 25 mL) and brine (25 mL). Drying
over MgSO4 and purification by column chromatography (eluent:
EtOAc/light petroleum, 0:1 Ǟ 4:6, v/v) afforded 18 in quantitative
1
green syrup. H NMR (CDCl3): δ ϭ 5.17 (br. s, 1 H, HN), 3.68 (s,
3 H, OMe), 3.53Ϫ3.26 (m, 7 H, H3, H4, H5, H6, H7, 2 ϫ H8),
2.88 (bd, J2a,2b ϭ 15.3 Hz, 1 H, H2a), 2.44 (dd, J2b,3 ϭ 9.5 Hz,
J2a,2b ϭ 13.5 Hz, 1 H, H2b), 1.42 (s, 9 H, tert-Bu Boc) ppm. 13C
NMR (CDCl3): δ ϭ 171.9 (C1), 156.5 [C(O) Boc), 79.3 (Cq Boc),
77.9, 77.2, 75.7, 73.1, 71.1 (C3, C4, C5, C6, C7), 51.4 (OMe), 41.2
(C8), 37.0 (C2), 27.9 (tert-Bu Boc) ppm. ES-MS: m/z ϭ 358.2.2 [M
ϩ Na]ϩ, 693.4 [2M ϩ Na]ϩ.
1
yield (2.94 g) as colourless oil. H NMR (CDCl3): δ ϭ 7.31 (m, 15
H, Harom 3 ϫ Bn), 4.90 (m, 4 H, CH2 Bn), 4.63 (dd, 2 H, 2 ϫ CH2
Bn), 3.82Ϫ3.51 (2 m, 6 H, H3, H4, H5, H6, H7, H8a), 3.63 (s, 3
H, OMe), 3.35 (t, J ϭ 9.5 Hz, 1 H, H8b), 2.97 (s, 3 H, Ms), 2.74
(dd, J2a,3 ϭ 3.7 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2a), 2.38 (dd, J2b,3
ϭ
8.4 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2b) ppm. 13C NMR (CDCl3): δ ϭ
170.9 (C1), 137.9, 137.5, 137.3 (3 ϫ Cq Bn), 128.4Ϫ127.7 (CHarom
Bn), 86.6, 80.6, 77.3, 76.5, 75.7 (C3, C4, C5, C6, C7), 75.4Ϫ74.9
(3 ϫ CH2 Bn), 68.6 (C8), 51.6 (OMe), 37.3 (Ms), 37.0 (C2) ppm.
3,7-Anhydro-8-[(tert-butoxycarbonyl)amino]-2,8-dideoxy-D-gulo-D-
glycero-octulonic Acid (22): A mixture of compound 21 (0.12 g,
0.36 mmol) and aq. NaOH (0.4 mL of a 1  solution) in dioxane
(1 mL) was stirred for 4 h. The solution was acidified to pH 2 with
HCl (1 ⁾ and extracted thoroughly with EtOAc (6 ϫ 5 mL). The
combined organic phases were dried (MgSO4), concentrated and
purified by column chromatography (eluent: MeOH/EtOAc, 0:1 Ǟ
1:9, v/v, containing 0.5% AcOH). Compound 22 was obtained in a
70% yield (0.081 g) as an amorphous white solid. 1H NMR
(MeOD): δ ϭ 3.60 (dt, J ϭ 2.6 Hz, J ϭ 9.5 Hz, 1 H, H3),
3.51Ϫ3.04 (6 H, H4, H5, H6, H7, 2 ϫ H8), 2.84 (dd, J2a,3 ϭ 2.6
Hz, J2a,2b ϭ 15.7 Hz, 1 H, H2a), 2.34 (dd, J2b,3 ϭ 9.1 Hz, J2a.2b
15.7 Hz, 1 H, H2b), 1.43 (s, 9 H, tert-Bu Boc) ppm. 13C NMR
(MeOD): δ ϭ 175.6 (C1), 158.2 [C(O) Boc), 80.1 (Cq Boc), 79.4,
78.3, 77.1, 74.2, 72.1 (C3, C4, C5, C6, C7), 42.4 (C8), 38.7 (C2),
29.3 (tert-Bu Boc) ppm. ES-MS: m/z ϭ 322.2 [M ϩ H]ϩ, 344.2 [M
ϩ Na]ϩ, 643.7 [2M ϩ H]ϩ, 665.3 [2M ϩ Na]ϩ.
Methyl 3,7-Anhydro-8-azido-4,5,6-tri-O-benzyl-2,8-dideoxy-
D-gulo-
D-glycero-octulonate (19): Traces of water were removed from com-
pound 18 (2.94 g, 5 mmol) by coevaporation with toluene (3 ϫ
20 mL). DMF (25 mL) and NaN3 (0.72 g, 11 mmol) were added,
and the resulting mixture was stirred for 1.5 h at 75 °C. The solu-
tion was diluted with H2O (20 mL) and extracted with EtOAc (3
ϫ 40 mL) and the combined organic phases were dried (MgSO4).
The crude product azide was purified by column chromatography
(eluent: EtOAc/light petroleum, 0:1 Ǟ 1:1, v/v) to give product 19
in a yield of 77% (2.05 g) as a colourless syrup. 1H NMR (CDCl3):
δ ϭ 7.32 (m, 15 H, Harom 3 ϫ Bn), 4.91 (m, 4 H, CH2 Bn), 4.62
(dd, J ϭ 9.5 Hz, J ϭ 10.6 Hz, 2 H, CH2 Bn) 3.84Ϫ3.33 (2 ϫ m, 6
H, H3, H4, H5, H6, H7, H8a), 3.63 (s, 3 H, OMe), 3.24 (dd, J7,8b ϭ
4.4 Hz, J8a,8b ϭ 12.8 Hz, 1 H, H8b), 2.74 (dd, J2a,3 ϭ 3.7 Hz,
J
2a,2b ϭ 15.4 Hz, 1 H, H2a), 2.42 (dd, J2b,3 ϭ 8.4 Hz, J2a,2b ϭ 15.4
General Procedure for the Synthesis of Cyclic SAA Molecules: The
assembly of the cyclic molecules was performed on an ABI 433A
(Applied Biosystems, division of PerkinϪElmer) peptide syn-
thesiser by use of a Boc strategy. The synthesis was performed on
Kaiser oxime resin (0.53 mmol/g) on a 50 µmol scale. Stock solu-
tions of BOP (0.5 ), and DIPEA (0.65 ) in NMP were prepared.
The building blocks were dissolved in 1:1 mixtures of NMP and
DCM at concentrations of 0.25 . For the Boc cleavage reactions,
a solution of 25% TFA in DCM containing 1% TIPS was prepared.
Hz, 1 H, H2b) ppm. 13C NMR (CDCl3): δ ϭ 170.8 (C1), 137.9,
137.6, 137.5 (3 ϫ Cq Bn), 128.2Ϫ127.4 (CHarom Bn), 86.6, 80.8,
78.6, 78.3, 75.5 (C3, C4, C5, C6, C7), 75.2Ϫ74.8 (3 ϫ CH2 Bn),
51.6 (OMe), 50.8 (C8), 37.0 (C2) ppm.
Methyl
amino]-2,8-dideoxy-
3,7-Anhydro-4,5,6-tri-O-benzyl-8-[(tert-butoxycarbonyl)-
-gulo- -glycero-octulonate (20): Compound 19
D
D
(2.05 g, 3.9 mmol) was coevaporated with toluene (10 mL) and re-
dissolved in toluene (20 mL). Me3P (4.1 mL of a 1  solution in
toluene) was added and the reaction mixture was stirred for 1 h.
The solution was cooled (Ϫ20 °C) and Boc-ON (2.24 g, 3.7 mmol),
dissolved in toluene (2.5 mL), was added slowly. The reaction mix-
ture was allowed to warm to room temperature and stirring was
continued for 5 h. The reaction mixture was concentrated and re-
dissolved in EtOAc (25 mL), washed with H2O, aq (15 mL).
NaHCO3 (3 ϫ 15 mL) and brine (15 mL) and dried (MgSO4). Puri-
fication by column chromatography (eluent: EtOAc/light petro-
The resin was placed in the reaction vessel and was swollen in
DCM (5 ϫ 2.5 mL) and NMP (5 ϫ 2.5 mL). The stock solutions
of BOP (0.5 mL, 5 equiv.) and DIPEA (0.5 mL, 6.5 equiv.) were
added to the building block solution (1 mL, 5 equiv.), and the re-
sulting mixture was added to the resin. The reaction vessel was
shaken for 2 h, after which it was drained. Without rinsing of the
resin, a second coupling reaction was performed under the same
conditions. The resin was washed with NMP (5 ϫ 2.5 mL) and
DCM (5 ϫ 2.5 mL). The Boc group was removed by several 5 min
treatments of the resin with the TFA solution (5 ϫ 2 mL). The
resin was washed with DCM and NMP (5 ϫ 2.5 mL each). Success-
ive SAA building blocks were coupled as described above, with
reaction times of 45 min. Each coupling was followed by the same
washing and Boc removal procedure.
leum, 0:1 Ǟ 4:6, v/v) afforded compound 20 in 95% yield (2.24 g)
as a colourless oil. H NMR (CDCl3): δ ϭ 7.32 (s, 15 H, Harom
1
3
ϫ Bn), 4.97Ϫ4.79 (m, 4 H, CH2 Bn), 4.66 (d, J ϭ 5.9 Hz, 1 H,
CH2 Bn), 4.60 (d, J ϭ 6.6 Hz, 1 H, CH2 Bn), 3.76Ϫ3.27 (2 ϫ m,
7 H, H3, H4, H5, H6, H7, 2 ϫ H8), 3.64 (s, 3 H, OMe), 2.73 (dd,
J2a,3 ϭ 3.7 Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2a), 2.37 (dd, J2b,3 ϭ 8.8
Hz, J2a,2b ϭ 15.4 Hz, 1 H, H2b), 1.44 (s, 9 H, tert-Bu Boc) ppm.
13C NMR (CDCl3): δ ϭ 171.6 (C1), 156.1 [C(O) Boc), 138.7Ϫ138.3
For the cyclization reaction, AcOH (0.1 , 1 mL, 2 equiv.) and
(3 ϫ Cq Bn), 128.9, 128.3, 128.1 (15 ϫ CHarom Bn), 87.3, 81.6, DIPEA (0.1 , 1 mL, 2 equiv.) in DMF (2 mL) were added and
Eur. J. Org. Chem. 2003, 2303Ϫ2313
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2311

M. Overhand et al.
FULL PAPER
the reaction vessel was shaken for 36 h. The filtrate was collected,
the resin was rinsed with DMF (3 ϫ 2 mL), and the combined
DMF fractions were concentrated.
Cyclic Pyranoid SAA Trimer 2: 1H NMR, COSY, ROESY(10%
D2O/H2O, 600 MHz): δ ϭ 7.88 (t, J8a,N ϭ J8b,N 5.1 Hz, 3 H, 3 ϫ
HN), 3.68 (dt, J2a,3 ϭ 2.9 Hz, J2b,3 ϭ J3,4 ϭ 9.2 Hz, 3 H, 3 ϫ H3),
3.58 (m, 3 H, 3 ϫ H8a), 3.51 (m, 3 H, 3 ϫ H5), 3.49 (m, 3 H, 3 ϫ
H8b), 3.45 (m, 3 H, 3 ϫ H7), 3.28 (t, J5,6 ϭ J6,7 ϭ 9.3 Hz, 3 H, 3
ϫ H6), 3.25 (t, J3,4 ϭ J4,5 ϭ 9.3 Hz, 3 H, 3 ϫ H4), 2.83 (dd, J2a,3 ϭ
2.5 Hz, J2a,2b ϭ 14.7 Hz, 3 H, 3 ϫ H2a), 2.46 (dd, J2b,3 ϭ 9.1 Hz,
J2a,2b ϭ 14.7 Hz, 3 H, 3 ϫ H2b) ppm. LCMS: Rt ϭ 10.48 (ACN/
H2O, 0 Ǟ 25%), m/z ϭ 610.5 [M ϩ H]ϩ. HRMS: calcd. for
C24H39N3O15 [M ϩ H] 610.2460; found 610.2568.
The crude cyclic molecules were analysed by LCMS and purified
by RP-HPLC with H2O/CH3CN as eluent. The pure fractions were
lyophilised and analysed by LCMS and NMR spectroscopy.
Cyclic Furanoid SAA Trimer 1: 1H NMR, COSY, NOESY, ROESY
(10% D2O/H2O, 600 MHz): δ ϭ 8.41 (s, 3 H, 3 ϫ HN), 4.12 (m, 3
H, 3 ϫ H3), 3.97Ϫ3.89 (m, 9 H, 3 ϫ H4, 3 ϫ H5, 3 ϫ H6), 3.46
(dd, J6,7a ϭ 2.9 Hz, J7a,7b ϭ 14.7 Hz, 3 H, 3 ϫ H7a), 3.37 (dd,
Cyclic Pyranoid SAA Tetramer 4: 1H NMR, COSY(10% D2O/H2O,
600 MHz): δ ϭ 7.89 (t, J8a,N ϭ J8b,N 5.3 Hz, 4 H, 4 ϫ HN), 3.64
(d, J8a,8b ϭ 14.6 Hz, 4 H, 4 ϫ H8a), 3.60 (dt, J2a,3 ϭ 1.5 Hz, J2b,3 ϭ
J3,4 ϭ 9.5 Hz, 4 H, 4 ϫ H3), 3.42 (t, J4,5 ϭ J5,6 ϭ 9.0 Hz, 4 H, 4
ϫ H5), 3.35 (t, J6,7 ϭ J7,8b ϭ 8.3 Hz, 4 H, 4 ϫ H7), 3.21 (m, 4 H,
4 ϫ H8b), 3.17 (t, J5,6 ϭ J6,7 ϭ 9.5 Hz, 4 H, 4 ϫ H6), 3.15 (t,
J3,4 ϭ J4,5 ϭ 9.4 Hz, 4 H, 4 ϫ H4), 2.77 (dd, J2a,2b ϭ 14.9 Hz, 4
H, 4 ϫ H2a), 2.39 (dd, J2b,3 ϭ 9.8 Hz, J2a,2b ϭ 15.3 Hz, 4 H, 4 ϫ
H2b). LCMS: Rt ϭ 18.74 (ACN/H2O, 0Ǟ25%), m/z ϭ 813.4 [M
ϩ H]ϩ. HRMS: calcd. for C32H52N4O20 [M ϩ H] 813.3253;
found 813.3482.
J6,7b ϭ 5.5 Hz, J7a,7b ϭ 14.7 Hz, 3 H, 3 ϫ H7b), 2.62 (dd, J2a,3
ϭ
3.7 Hz, J2a,2b ϭ 14.4 Hz, 3 H, 3 ϫ H2a), 2.41 (dd, J2b,3 ϭ 9.3 Hz,
J2a,2b ϭ 14.5 Hz, 3 H, 3 ϫ H2b) ppm. LCMS: Rt ϭ 7.35 (ACN/
H2O, 0 Ǟ 25% ), m/z ϭ 520.4 [M ϩ H]ϩ. HRMS: calcd. for
C21H33N3O12 [M ϩ H] 520.2143; found 520.2254.
1
Cyclic Furanoid SAA Tetramer 3: H NMR, COSY, NOESY (10%
D2O/H2O, 600 MHz): δ ϭ 7.81 (s, 4 H, 4 ϫ HN), 4.15 (t, J3,4
ϭ
J4,5 ϭ 5.6 Hz, 4 H, 4 ϫ H4), 4.04 (dt, J2a,3 ϭ 4.0 Hz, J2b,3 ϭ 6.4
Hz J3,4 ϭ 5.6 Hz, 4 H, 4 ϫ H3), 3.96 (t, J4,5 ϭ J5,6 ϭ 5.9 Hz, 4 H,
4 ϫ H5), 3.89 (dt, J5,6 ϭ 6.1, J6,7a ϭ 6.2 Hz, J6,7b ϭ 3.3 Hz, 4 H,
4 ϫ H6), 3.53 (dt, J ϭ 6.9 Hz, J ϭ 14.3 Hz, 4 H, 4 ϫ H7a), 3.34
(dt, J ϭ 3.3 Hz, J ϭ 14.4 Hz, 4 H, 4 ϫ H7b), 2.67 (dd, J2a,3 ϭ 3.8
Hz, J2a,2b ϭ 15.1 Hz, 4 H, 4 ϫ H2a), 2.57 (dd, J2b,3 ϭ 6.7 Hz,
J2a,2b ϭ 15.1 Hz, 4 H, 4 ϫ H2b) ppm. LCMS: Rt ϭ 6.93 (ACN/
H2O, 0 Ǟ 25% ), m/z ϭ 693.4 [M ϩ H]ϩ. HRMS: calcd. for
C28H44N4O16 [M ϩ H] 693.2831; found 693.2369.
[1]
J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle, Com-
prehensive Suprmolecular Chemistry, Elsevier, Oxford, 1996,
vol. 1Ϫ11.
[2]
G. Wenz, Angew. Chem. Int. Ed. Engl. 1994, 33, 803Ϫ822. R.
Breslow, S. D. Dong, Chem. Rev. 1998, 98, 1997Ϫ2011.
[3]
R. Bürli, A. Vasella, Angew. Chem. Int. Ed. Engl. 1997, 36,
Table 1. List of cross-peaks observed in a ROESY spectrum of 1
in 10% D2O in H2O with a mixing time of 180 ms
1852Ϫ1853.
[4]
E. Locardi, M. Stöckle, S. Gruner, H. Kessler, J. Am. Chem.
Soc. 2001, 123, 8189Ϫ8196.
Several groups have reported the synthesis of linear SAA oligo-
Atom 1
Atom 2
Intensity[a]
[5]
mers: C. Müller, E. Kitas, H. P. Wessel, Chem. Commun. 1995,
23, 2425Ϫ2426.Y. Suhara, J. E. K. Hildreth, Y. Ichikawa, Tetra-
hedron Lett. 1996, 37, 1575Ϫ1578. C. M. Timmers, J. J. Turner,
C. M. Ward, G. A. van der Marel, M. L. C. E. Kouwijzer, P.
D. J. Grootenhuis, J. H. van Boom, Chem. Eur. J. 1997, 3,
920Ϫ929. L. Szabo, B. L. Smith, K. D. McReynolds, A. L.
Parrill, E. R. Morris, J. Gervay, J. Org. Chem. 1998, 63,
1074Ϫ1078. M. D. Smith, D. D. Long, A. Martin, D. G. Mar-
quess, T. D. W. Claridge, G. W. J. Fleet, Chem. Commun. 1998,
2039Ϫ2040. M. D. Smith, D. D. Long, A. Martin, D. G. Mar-
quess, T. D. W. Claridge, G. W. J. Fleet, Tetrahedron Lett. 1999,
40, 2191Ϫ2194.D. E. A. Brittain, M. P. Watterson, T. D. W.
Claridge, M. D. Smith, G. W. J. Fleet, J. Chem. Soc., Perkin
Trans. 1 2000, 3655Ϫ3665. Y. Suhara, Y. Yamaguchi, B. Col-
lins, R. Schnaar, M. Yanagishita, J. E. K. Hildreth, I. Shimada,
Y. Ichikawa, Bioorg. Med. Chem. 2002, 10, 1999Ϫ2013. T. K.
Chakraborty, S. Jayapraksah, P. Srinivasu, S. S. Madhavendra,
R. Ravi Sankar, A. C. Kunwar, Tetrahedron 2002, 58,
2853Ϫ2859.
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:H2a
SAAi:H2b
SAAi:H2a
SAAi:H7a
SAAiϪ1:H2a
SAAiϪ1:H2b
SAAi:H7a
SAAi:H7b
SAAiϪ1:H3
SAAi:H3
m
w
w
w
w
s
s
s
s
SAAi:H3
SAAi:H2b
SAAi:H7b
[a] The intensities of the cross-peaks are given as weak (w), medium
(m) or strong (s).
Table 2. List of cross-peaks observed in a ROESY spectrum of 2
in 10% D2O in H2O with a mixing time of 180 ms
Atom 1
Atom 2
Intensity[a]
[6]
For reviews on SAAs: E. Lohof, F. Burkhart, M. A. Born,
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:HN
SAAi:H2a
SAAi:H2b
SAAi:H2a
SAAi:H2b
SAAi:H2a
SAAi:H7a
SAAiϪ1:H2a
SAAiϪ1:H2b
SAAi:H8a
SAAi:H8b
SAAiϪ1:H6
SAAi:H3
m
w
m
m
w
s
m
m
m
s
E. Planker, H. Kessler, Advances in Amino Acid Mimetics and
Peptidomimetics, A. Abell, JAI Press Inc.: Stanford, Connet-
icut, 1999, vol. 2, p. 263Ϫ292. S. W. Gruner, E. Locardi, E.
Lohof, H. Kessler, Chem. Rev. 2002, 102, 491Ϫ514. F.
Schweizer, Angew. Chem. Int. Ed. 2002, 41, 230Ϫ253. T. K.
Chakraborty, S. Ghosh, S. Jayaprakash, Curr. Med. Chem.
2002, 9, 421Ϫ435.
R. M. van Well, H. S. Overkleeft, M. Overhand, E. Vang Carst-
enen, G. A. van derMarel, J. H. van Boom, Tetrahedron Lett.
2000, 41, 9331Ϫ9335.
J. P. McDevitt, P. T. Lansbury, Jr., J. Am. Chem. Soc. 1996,
118, 3818Ϫ3828.
J. F. Stoddart, Stereochemistry of Carbohydrates, John Wiley &
Sons, New York, 1971.
SAAi:H3
SAAi:H4
[7]
SAAi:H4
SAAi:H2b
SAAi:H7b
[8]
s
[a]
[9]
The intensities of the cross-peaks are given in weak (w) medium
(m) or strong (s).
2312
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2303Ϫ2313

Cyclic Oligomers Consisting of Furanoid and Pyranoid ε-Sugar Amino Acids
FULL PAPER
[10]
[11]
[17]
J. E. H. Koehler, W. Saenger, W. F. van Gunsteren, J. Mol. Biol.
1988, 203, 241Ϫ250.
C. Altona, M. Sudaralingam, J. Am. Chem. Soc. 1972, 94,
8205Ϫ8212. F. A. A. M. de Leeuw, C. Altona, J. Comp. Chem.
1983, 4, 428Ϫ437.
K. R. Hanson, J. Am. Chem. Soc. 1966, 88, 2731Ϫ2742. H.
Hirschmann, K. R. Hanson, J. Org. Chem. 1971, 36,
3293Ϫ3306.
M. Karplus, J. Am. Chem. Soc. 1963, 85, 2870Ϫ2871.
S. Kirkpatrick, C. D. Gelatt, Jr., M. P. Vecchi, Science 1983,
220, 671Ϫ680.
NMR of proteins and nucleic acids, K. Wüthrich, John Wiley &
Sons, 1986, chapter 11, p. 207.
W. Klyne, V. Prelog, Experientia 1960, 16, 521Ϫ523.
S. J. Angyal, Angew. Chem. Int. Ed. Engl. 1969, 8, 157Ϫ226. R.
J. Ferrier, P. M. Collins, Monosaccharide Chemistry, Penguin
Books, London, 1972, chapter 2.
M. Piotto, V. Saudek, J. Sklenar, Biom. NMR 1992, 2,
661Ϫ665.
H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T.
Christensen, S. K. Byram, J. Am. Chem. Soc. 1975, 97,
4602Ϫ4613.
[18]
[12]
[13]
[14]
´
F. Z. Mata, M. B. Martinez, J. A. G. Perez, Carbohydr. Res.
[19]
[20]
1992, 225, 159Ϫ161.
´
X. Ariza, F. Urpı, C. Viladomat, J. Vilarrasa, Tetrahedron Lett.
1998, 39, 9101Ϫ1902.
[21]
Other syntheses of SAA/AA hybrid molecules: M. Stöckle, G.
Voll, R. Günther, E. Locardi, S. Gruner, H. Kessler, Org. Lett.
2002, 4, 2501Ϫ2504. S. A. W. Gruner, V. Truffault, G. Voll, E.
Locardi, M. Stöckle, H. Kessler, Chem. Eur. J. 2002, 8,
4365Ϫ4375.
[22]
[23]
[15]
[16]
G. Ösapay, J. W. Taylor, J. Am. Chem. Soc. 1990, 112,
6046Ϫ6051. N. Nishino, M. Xu, H. Mihara, T. Fujimoto, Y.
Ueno, H. Kumagai, Tetrahedron Lett. 1992, 33, 1479Ϫ1482.
R. M. van Well, H. S. Overkleeft, G. A. van der Marel, D.
Bruss, G. Thibault, P. G. de Groot, J. H. van Boom, M. Over-
hand, Biorg. Med. Chem. Lett. 2003, 13, 331Ϫ334.
[24]
[25]
A. F. Hagler, S. Lifson, P. Dauber, J. Am. Chem. Soc. 1979,
101, 5122Ϫ5130.
Received January 22, 2003
Eur. J. Org. Chem. 2003, 2303Ϫ2313
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2313