Hetaryleneaminopolyols and hetarylenecarbopeptoids: A new type of glyco- and peptidomimetics. Syntheses and studies on solution conformation and dynamics

Article abstract of DOI:10.1021/jo026631o

Ready access to a new class of oligomers has been demonstrated by the synthesis of hetaryleneaminopolyols and hetarylenecarbopeptoids using 3-hydroxymethyl-5-(4-amino-4-deoxy-D-arabinotetritol1-yl)-2-methylfuran and 5-(4-amino-4-deoxy-D-arabinotetritol-1-yl)-2-methyl-3-furoic acid as novel scaffolds. The conformational behavior of peptidomimetics 22, 23, 25, 26, and 36 have been analyzed by NMR spectroscopy and extensive molecular dynamics simulations. MD simulations using the GB/SA continuum solvent model for water and the MM3* force field provide a population distribution of conformers which satisfactorily agrees with the experimental NMR data for the torsional degrees of freedom of the molecule.

Full text of DOI:10.1021/jo026631o

Heta r ylen ea m in op olyols a n d Heta r ylen eca r bop ep toid s: a New
Typ e of Glyco- a n d P ep tid om im etics. Syn th eses a n d Stu d ies on
Solu tion Con for m a tion a n d Dyn a m ics
Antonio J . Moreno-Vargas,† J esu´s J ime´nez-Barbero,‡ and Inmaculada Robina*,†
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Apartado 553,
E-41071 Sevilla, Spain, and Instituto de Qu´ımica Orga´nica, CSIC, J uan de la Cierva 3,
Madrid 28006, Spain
robina@us.es
Received October 30, 2002
Ready access to a new class of oligomers has been demonstrated by the synthesis of hetarylene-
aminopolyols and hetarylenecarbopeptoids using 3-hydroxymethyl-5-(4-amino-4-deoxy-D-arabinotetritol-
1-yl)-2-methylfuran and 5-(4-amino-4-deoxy-D-arabinotetritol-1-yl)-2-methyl-3-furoic acid as novel
scaffolds. The conformational behavior of peptidomimetics 22, 23, 25, 26, and 36 have been analyzed
by NMR spectroscopy and extensive molecular dynamics simulations. MD simulations using the
GB/SA continuum solvent model for water and the MM3* force field provide a population distribution
of conformers which satisfactorily agrees with the experimental NMR data for the torsional degrees
of freedom of the molecule.
In tr od u ction
cal processes and because of the limitations of natural
bioactive peptides. Potentially useful peptidomimetics
should resist in vivo hydrolysis and present some con-
formational bias3 having been already developed a num-
ber of peptide-based drugs.4 For the synthesis of oligopep-
tides, a variety of structurally constrained molecular
scaffolds have been used.5 For instance, Gellman and co-
workers6 have prepared peptides from rigidified cyclic
amino acids. Glycosamino acids, which are hybrid struc-
tures of carbohydrates and amino acids, are good scaf-
folds to generate glyco- and peptidomimetics because of
the rigidity of the furan or pyran moiety.7 These com-
pounds may be inserted in appropriate sites of small
peptides originating the specific three-dimensional struc-
tures required for binding to their receptors2,8 or can be
connected furnishing peptide-bond linked carbohydrates9
In recent years, the mimickry of the structure and
biological function of biopolymers have attracted much
attention, and a large variety of biomimetics with oligo-
meric structures have been prepared.1 A number of
scaffolds that mimick the fundamental building blocks
used in nature are threaded together in specific se-
quences using iterative synthetic procedures giving ac-
cess to natural-like or unnatural oligomeric structures
with multifunctional groups anchored on a lineal, two-
dimensional, or three-dimensional backbone.2 Peptides
and proteins have been extensively targeted in biomi-
metics design1-3 due to their fundamental role in biologi-
† Universidad de Sevilla.
‡ CSIC.
* Corresponding author.
(1) (a) Kirshenbaum, K.; Zuckermann, R. N.; Dill, H. A. Curr. Opin.
Struct. Biol. 1999, 9, 530-535. (b) Barron, A. E.; Zuckermann, R. N.
Curr. Opin. Chem. Biol. 1999, 3, 681-687.
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Pharmacol. Toxicol. 2002, 90, 285-296. (b) Dragovich, P. S.; Prins, T.
J .; Zhou, R.; Brown, E. L.; Maldonado, F. C.; Furhman, S. A.; Zalman,
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10.1021/jo026631o CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
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J . Org. Chem. 2003, 68, 4138-4150

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
SCHEME 1. Syn th esis of Bu ild in gs Block s,
Electr op h ilesa
F IGURE 1.
(carbopeptoids). Some of them exhibit interesting biologi-
cal properties, such as HIV replication inhibition.10
Aminoglycoside antibiotic mimetics, made from N-acetyl-
neuraminic acid, have been reported.11 In addition, Fleet
and co-workers12 have made extensive use of carbohydrate-
derived tetrahydrofuran systems for the synthesis of
peptidomimetics that adopt interesting secondary struc-
tures. On their side, Kunwar and co-workers13 have
prepared peptidomimetics containing furanoid sugar
amino acids and sugar dicarboxylic acids. In a similar
way, scaffolds based on pyrrolidine systems14 have been
used as a means to introduce some rigidity in peptido-
mimetics.
Searching for new molecules that can be assembled
with themselves and/or other amino acids using well-
established combinatorial techniques, we propose a new
scaffold, Aij (Figure 1), which contains a polyol fragment
(i) the length and chirality of which are given by the
aldose used to make it, and a 5-alkylfuran moiety, the
alkyl group (j) of which can be varied on changing the
acyl acetate employed in the condensation together with
the starting aldose.15 We now describe the synthesis of
one member of the sub-library Aij (i, n ) 3, configura-
tion: D-arabino) and demonstrate that it can be combined
to generate oligomers by applying either solution- or
solid-phase procedures. The polyhydroxy and alkylfuran
moieties make these compounds attractive, as complex
biochemical processes involve molecular recognition based
on polar (e.g., hydrogen bonds) and hydrophobic interac-
tions.16 We have also studied the solution conformation
a
Reagents and conditions: (a) NaH/BnBr, DMF, 77%; (b)
TBDMSCl/imidazole, DMF, 70°, 90%; (c) LiAlH4, THF, 87%; (d)
Ts(Ms)Cl (2 equiv)/py (2 equiv), Cl2CH2, 80% conversion; (e)
Ts(Ms)Cl (2 equiv)/py (exc) 47% conversion; (f) CCl4, Ph3P, reflux,
MS 4A, 100% conversion; (g) (1) NH3, DMF, rt, (2) Ac2O/py (i +
ii), 43%; (h) BuNH2, DMF, rt, 84%; (i) NaN3, DMF, rt, 90%.
and dynamics of these oligomers (compounds 22, 23, 25,
26, and 36) using NMR techniques and molecular dy-
namics calculations.17,18 The combination of both tech-
niques give us a first picture of the conformation19 of
these new systems in water, methanol, and DMSO.
Resu lts a n d Discu ssion s
Syn th eses of Heta r ylen ea m in op olyols. These com-
pounds, formed by enantiomerically pure polyols with
heterocyclic spacers joined by amine-type linkages, have
been designed as an attempt to have them acting as
amino-oligosaccharide mimetics.
They are prepared by nucleophilic displacement be-
tween electrophile and nucleophile buildings blocks.
Scheme 1 discloses the preparation of several electro-
philic reactants. Starting from compound 1, which is
readily available from D-glucose and ethyl acetoacetate,15
O-protection with benzyl and TBS groups followed by
reduction with LiAlH4 gave 3a 20 and 3b , respectively.
(8) (a) Moitessier, N.; Dufour, S.; Chre´tien, F.; Thiery, J . P.; Maigret,
B.; Chapleur, Y. Bioorg. Med. Chem. 2001, 9, 511-523. (b) Hanessian,
S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubel, W. D. Tetrahedron
1997, 53, 12789-12854. (c) Giannis, A.; Kolter, T. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1244-1267. (d) Hirschamann, R.; Nicolaou, K. C.;
Pietranico, S.; Leahy, E. M.; Salvino, J .; Arison, B.; Cichy, M. A.;
Spoors, P. G.; Shakespeare, W. C.; Sprengler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale,
W.; Freidinger, R. M.; Cascier, M. R.; Strader, C. D. J . Am. Chem.
Soc. 1993, 115, 12550-12568.
(9) Nicolaou, K. C.; Flo¨rke, H.; Egan, M. G.; Barth, T.; Estevez, V.
A. Tetrahedron Lett. 1995, 36 1775-1779.
(10) Yoshimoto, S.; Ichikawa, M.; Hildreth, J . E. K.; Ichikawa, Y.
Tetrahedron Lett. 1996, 37, 2549-2552.
(11) (a) Park, W. K. C.; Auer, M.; J aksche, H.; Wong, C.-H. J . Am.
Chem. Soc. 1996, 118, 10150-10155. (b) Ramamoorthy, P. S.; Gervay,
J . J . Org. Chem. 1997, 62, 7801-7805.
(16) (a) Silverman, D. N.; Lindskog, S. Acc. Chem. Res. 1988, 21,
30-36; Greener, B.; Rose, J . Chem. Commun. 1999, 2361-2362. (b)
Lehn, J . M. Supramolecular Chemistry-Concepts and Perspectives;
VCH: Weinheim 1995.
(17) Rutherford, T. J .; Spackman, D. G.; Simpson, P. J .; Homans,
S. W. Glycobiology 1994, 4, 49-57. (b) Poveda, A.; Asensio, J . L.;.
Martin-Pastor, M.; J ime´nez-Barbero, J . J . Chem. Soc., Chem. Commun.
1996, 421-422. (c) Harris, R. Kiddle, G. R., Field, R. A., Milton, M.
A., Ernst, B.; Magnani, J . L.; Homans, S. W. J . Am. Chem. Soc. 1999,
121, 2546-2551.
(18) (a) Meyer, B. Top. Curr. Chem. 1990, 154, 141-208. (b) Imberty,
A. Curr. Opin. Struct. Biol. 1997, 7, 617-623. (c) Peters, T.; Pinto, B.
M. Curr. Opin. Struct. Biol. 1996, 6, 710-720.
(12) (a) Hungerford, N. L.; Claridge, T. D. W.; Watterson, M. P.;
Aplin, R. T.; Moreno, A.; Fleet, G. W. J . J . Chem. Soc., Perkin Trans
1 2000, 3666-3679. (b) Hungerford, N. L.; Fleet, G. W. J . J . Chem.
Soc., Perkin Trans. 1 2000, 3680-3685. (c) Smith, M. D.; Fleet, G. W.
J . J . Peptide Sci. 1999, 5, 425-441 and references therein.
(13) (a) Chakraborty, T. K.; J ayaprakash, S.; Srinivasu, P.; Madhav-
endra, S. S.; Ravi Sankar, A.; Kunwar, A. C. Tetrahedron 2002, 58,
2853-2859. (b) Chakraborty, T. K.; Ghosh, S.; J ayaprakash, S.;
Sharma, J . A. R. P.; Ravikanth, V.; Diwan, P. V.; Nagaraj, R.; Kunwar,
A. C. J . Org. Chem. 2000, 65, 6441-6457.
(14) (a) Chakraborty, T. K.; Srinivasu, P.; Kiran Kumar, S.; Kunwar,
A. C. J . Org. Chem. 2002, 67, 2093-2100. (b) Crespo, L.; Sanclimens,
G.; Royo, M.; Giralt, E.; Albericio, F. Eur. J . Org. Chem. 2002, 1756-
1762.
(15) Garc´ıa Gonza´lez, F.; Go´mez Sa´nchez, A. Adv. Carbohydr. Chem.
1965, 20, 303-355.
(19) (a) Imberty, A.; Hardman, K. D.; Carver, J . P.; Perez, S.
Glycobiology 1991, 1, 631-642. (b) Espinosa, J . F.; Can˜ada, F. J .;
Asensio, J . L.; Mart´ın-Pastor, M.; Dietrich, H.; Mart´ın-Lomas, M.;.
Schmidt, R. R.; J ime´nez-Barbero, J . J . Am. Chem. Soc. 1996, 118,
10862-10871. (c) Dowd, M. K., Reilly, O. J .; French, A. D. Biopolymers
1994, 34, 625-638.
J . Org. Chem, Vol. 68, No. 11, 2003 4139

Moreno-Vargas et al.
TABLE 1. Rea ctivity of th e Nu cleop h ilic Su bstitu tion
w ith 4a , 5a , 6a
SCHEME 3. Heta r ylen e Am in op olyol Cou p lin g
Rea ction sa
compoundsa
reagents and conditions
4a
5a
6a
b
N.R.
N. R.
N.R.
7
c
N.R.
N.R.
8
43%
8
d
N.R.
9
<10%
9
84%
9
e
65%
70%
90%
a
Obtained compound, %,yield; N.R. ) no reaction. b BuOH,NaH,
DMF, 100 °C. c (1) NH3, DMF, rt, (2) Ac2O/py. BuNH2, DMF, 75
d
°C. e NaN3, DMF, 90 °C.
SCHEME 2. Syn th esis of Bu ild in gs Block s,
Nu cleop h ilesa
a
Reagents and conditions: (a) (i) Na2CO3, DMF, 80 °C, 1.5 h,
(ii) Ac2O/py; (b) (i) Na2CO3, DMF, 80 °C, 18 h, (ii) Ac2O/py; (c)
TBAF (1 M)/THF; (d) Ac2O/py.
SCHEME 4. Heta r ylen e Ca r bop ep toid Bu ild in gs
Block sa
a
Reagents and conditions: (a) TsCl/py, -15 °C, 57%; (b) N3Na/
DMF 100°, 65%; (c) BnBr, NaH, DMF, 85%; (d) TBDMSCl/
imidazole, DMF, 70 °C, 86%; (e) H2/Pd-C (10%), EtOH (85%); (f)
LiAlH4/THF, 87%.
Reaction of 3a with an equimolar amount of TsCl or MsCl
and pyridine gave compounds 4a that were unstable and
were used without purification in the next steps. When
the reaction took place with py as solvent, the pyridinium
salt 5a was obtained. Reaction of 3a and 3b with an
excess of MsCl/DMF or with CCl4/Ph3P at reflux gave 6a
and 6b with 100% of conversion, respectively. To evaluate
the electrophile efficiency of compounds 4a , 5a , and 6a ,
they were made to react with several nucleophilic re-
agents. The results are summarized in Table 1. They
indicate that the higher reactivity is observed with the
chloro derivative 6.
The preparation of the nucleophile building blocks is
depicted in Scheme 2. Azido ester 11 is obtained by SN2
displacement of tosylate 10.21 Subsequent O-protection
(OBn, OTBS) gave compounds 12a and 12b in 85% and
86% yield, respectively. Reduction of 12a with LiAlH4
gave amino alcohol 13a in 87% yield. Reduction of 12b
with H2/Pd/C gave 13b in 85% yield.
a
Reagents and conditions: (a) NaOH 1 M, EtOH, 60 °C, 3 h,
(ii) IR-120 (H+), MeOH, (i + ii) 80-90%); (b) Ac2O/py, 100%; (c)
H2, Pd/C, EtOH, 98%; (d) (i) NaOH 1 M, EtOH, 60 °C, 3 h, (ii)
HCl 1 M, (i + ii), 80%; (e) (i) TMSCl/py, 1 h, (ii) FmocCl, 1 h, (iii)
H2O, 2h, (i + ii + iii) 95%.
supported the proposed structure of 14a . Furthermore,
its H NMR spectrum indicates the existence of equilibria
1
between various conformers. Hydrogenolysis of 14a led
to a complex mixture of compounds resulting from
hydrogenolysis of benzyl ethers and from the furan
moiety and the partial debenzylation of benzyl ethers.
Other debenzylation procedures led to the formation of
undesired products.20 Hetarylene aminopolyol 15 was
then successfully obtained applying a coupling reaction
(18 h) between 6b and 13b with subsequent deprotetion
with TBAF in THF. The dimeric product 15 was char-
acterized as its peracetate, the latter being isolated in
an overall yield of 32% (based on 3b).
The coupling reaction (Scheme 3) between 6a (crude
product) and 13a in the presence of Na2CO3 was com-
pleted in 1 h, and the dimeric compound 14a was isolated
after conventional acetylation in an overall yield (based
on 3a ) of 45%. The 13C NMR and HRFABMS data
Syn th eses of Heta r ylen e Ca r bop ep toid s. Scheme
4 outlines the synthesis of the corresponding building
blocks that starts from ester 1 and azidoester 11. Hy-
drolysis of esters 1 and 11 provided carboxylic acids 17a 15
(20) Moreno-Vargas, A. J .; Ferna´ndez-Bolan˜os, J . G.; Fuentes, J .;
Robina, I. Tetrahedron: Asymmetry, 2001, 12, 3257-3266.
(21) Moreno-Vargas, A. J .; Robina, I.; Demange, R.; Vogel, P. Helv.
Chim. Acta, in press.
4140 J . Org. Chem., Vol. 68, No. 11, 2003

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
SCHEME 5. Hea d Elon ga tion a
SCHEME 6. Ta il Elon ga tion a
a
Reagents and conditions: (a) (1) 2 equiv of Ph3P, 2 equiv of
a
PyS-SPy, DMF, 2 equiv of of 18, 12 h, (2) Ac2O, py, 12 h (54% for
two steps); (b) (1) 2 equiv of Ph3P, 2 equiv of PyS-SPy, DCM/
DMF (3:1), 1 equiv of 19, 6 h, (2) (74% for two steps); (c) (1) NaOH
1 M, EtOH, 10 h, 60 °C, (2) IR-120 (H+), MeOH, (3) Ac2O, py (89%
for three steps); (d) step b (60% for two steps); (e) NaOMe, MeOH
(quant).
Reagents and conditions: (a) PyBOP, DIPEA, DMF, 1 equiv
of 19, 45 min (62%); (b) H2, Pd/C, EtOH, 30 min (95%); (c) (1) step
a, (2) Ac2O, pyridine, 12 h (60% for two steps); (d) NaOMe, MeOH
(quant).
As we wanted to test whether the solid-phase tech-
niques could be used in the preparation of oligomeric
systems incorporating our scaffold Aij, we envisaged the
synthesis of the pseudotetrapeptide 38 according to the
following method (Scheme 7). We chose to use the Fmoc
strategy and the HMBA-AM resin in which the linker is
the 4-hydroxymethylbenzoic acid.25 The coupling reac-
tions were accomplished without protection of the polyol
moiety of the Fmoc-amino acid 21. The commercially
available Fmoc-glycine was attached to the OH resin
using 2,6-dichlorobenzoyl chloride and pyridine.26 This
offers a double advantage: to favor the anchoring to the
HO-resin by avoiding competitive reactions with the free
OH groups of 21 on one hand and to facilitate the final
cleavage of the oligomer from the resin on the other hand.
Subsequent treatment with piperidine gave the solid-
supported amine 31. The Fmoc-amino acid 21 was then
coupled by treatment with PyBOP and DIPEA in DMF,
affording the immobilized dimer 32 after further treat-
ment with piperidine. The process was repeated two,
three, and four times to obtain the polymer-bound
compounds 33, 34, and 35 that were removed from the
solid support on treatment with 1 M NaOH and THF as
cosolvent to assist swelling of the resin.
Finally, it is worth noting that to increase the efficiency
of the coupling reactions the Fmoc-amino acid 21 as well
as PyBOP and DIPEA have to be used in excess.
Fortunately, the excess of activated Fmoc-amino acid 39
(see Scheme 7) can be recovered by extraction from the
resin by washing with DMF. Compound 39 is a stable
compound that can be purified by chromatography (see
the Experimental Section).
The amino acids 36-38 showed high water solubility
and can be obtained in good overall yields This method
open ways to libraries of oligomers that can expected to
have high bioavailability.
and 19, respectively. The analogue 17b was obtained
from 17a after acetylation. Hydrogenation of 11 rendered
aminoester 18. Reduction of the azide 19 delivered amino
acid 20 which was N-protected as the Fmoc derivative
21.
The polyol moiety had to be protected as a polysilyl
ether in order to avoid formation of carbonates (a
regioselective direct reaction gives complex mixtures and
a low yield for 21). Koole’s procedure22 (TMSCl/py, then
FmocCl, then, H2O) led to 21 in 95% overall yield.
Considering the nature of our scaffold, we define the
alkylfuran moiety as the head and the polyolic chain as
the tail of the systems. The strategy of head elongation
(Scheme 5) is based on the condensation of acid 17a with
the aminoester 18 under Mukaiyama conditions.23 After
acetylation, this gave the dimeric derivative 22. The
latter was treated with methanolic NaOMe to give ester
23. Compound 22 was hydrolyzed into acid 24 and
coupled again with the aminoester 18 to give the trimer
25. When using a mixture of Cl2CH2/DMF, the protected
peracetate 17b, and 18, the yield was increased.
For the tail elongation (Scheme 6), the coupling of
unprotected 18 and 19 was carried out in DMF with
PyBOP (benzotriazolyloxytrispyrrolidinophosphonium
hexafluorophosphate) and DIPEA24 (N,N-diisopropyl-
ethylamine) as activating reagents. After 45 min of
reaction and subsequent acetylation, the dimeric product
27 was isolated in 70% yield. Methanolysis and reduction
of the azido group gave 28. Subsequent coupling reaction
with azidocarboxylic acid 19 gave the corresponding
trimeric product that was purified as the peracetated 29
isolated in 60% yield.
(22) Koole, L. H.; Moody, H. M.; Broeders, N. L. H. L.; Quaedflieg,
P. J . L. M.; Kuijpers, W. H. A.; van Genderen, M. H. P.; Coenen, A. J .
J . M.; van der Wal, S.; Buck, H. M. J . Org. Chem. 1989, 54, 1657-
1664.
(23) Mukaiyama. T. In Challenges in Synthetic Organic Chemistry;
Rowlinson, J . S., Ed.; Clarendon Press: Oxford, 1994.
(24) J . Coste, D. Le-Nguyen and B. Castro Tetrahedron Lett. 1990,
31, 205-208.
(25) Atherton, E.; Sheppard, R. C. In Solid Phase Peptide Synthesis.
A Practical Approach; Rickwood, D. R., J ones, B. D., Eds.; IRL Press:
Oxford, 1989.
(26) Sieber, P. Tetrahedron Lett. 1987, 28, 6147-6150.
J . Org. Chem, Vol. 68, No. 11, 2003 4141

Moreno-Vargas et al.
SCHEME 7. Solid -P h a se Syn th esis: F m oc Str a tegya
a
Reagents and conditions: (i) 2,6-dichlorobenzoyl chloride, py, DMF, Fmoc-Gly-OH; (ii) 20% PIP/DMF; (iii) PyBOP, DIPEA, DMF, 1
equiv of 21; (iv) 1 M, NaOH, THF; (v) 1 M AcOH (60% overall).
TABLE 2. 1H Ch em ica l Sh ifts (δ, p p m ) of 22, 23, 25, 26,
a n d 36
SCHEME 8. Sch em a tic View of th e Acetyla ted a n d
Dea cyla ted Tr im er s Sh ow in g th e Atom ic a n d
proton/unit
22a
23b
25a
26b
36c
Mon om er Nu m ber in g
4, 4′/a
b
4.11, 4.24 3.96, 4.11 4.11, 4.24 3.97, 4.11 2.77, 2.95
3.16, 4.00 3.81, 4.01 3.16, 4.00 3.76,4.02 3.41, 3.41
c
d
3.14, 3.99
3.78, 4.01 3.31, 3.45
3.54, 3.54
3/a
b
c
2/a
b
c
1/a
b
c
5.15
5.03
5.02
5.58
5.46
5.45
6.01
6.06
6.05
4.05
4.18
5.15
5.03
4.05
4.18
4.19
4.10
4.18
4.18
5.23
5.22
5.22
6.96
6.96
6.98
2.85
2.82
2.81
3.66
3.64
3.60
3.54
3.52
3.53
4.75
4.71
4.65
6.62
6.65
6.58
2.52
2.52
2.52
4.08
4.15
5.59
5.46
5.23
5.22
6.01
6.06
furan H-5/a 6.41
b
c
CH3-6/a
b
c
6.92
6.97
6.41
6.61
6.60
6.61
2.55
2.54
2.54
2.82
2.81
2.56
2.56
NH/a
b
c
d
6.14
6.09
6.14
7.67
7.62
7.25
Con for m a tion a l An a lysis. NMR Stu d ies. Since
NMR parameters are averaged on time and on many
molecules, the information that is possible to deduce from
these experiments corresponds to the time-averaged
conformation of the oligomers in solution. 1H NMR
spectra of the oligomers 22, 23, 25, 26, and 36 were
completely assigned by a combination of homonuclear
COSY and TOCSY techniques. A schematic view of the
acetylated and deacetylated trimers showing the atomic
and monomer numbering is outlined in Scheme 8. The
corresponding 1H NMR chemical shifts are listed in Table
2, and a comparison of the 1D of 22, 23, 25, and 26 is
given in the figures found in the Supporting Information.
The couplings for the C1′-C4′ lateral chains are
defined by ω2, ω3, and ω4 torsion angles (Figure 2). The
corresponding values (Table 3) were constant in all
CDCl3. D2O. c DMSO-d6.
a
b
molecules, independent of the position of the monomer
in the chain and of the solvent. The couplings were in
the range J 1′,2′ 1.5-3.0 Hz and J 2′,3′ 8.0-8.5 Hz, J 3′,4′ 3.0-
4.0 Hz, and J 3,4′′ 5.0-6.0 Hz. Clearly, there is a very
predominant gauche-like relationship between H-1′ and
H-2′ and an anti-type orientation between H-2′ and H-3′.
The ω4 torsion is flexible, as deduced for the two averaged
J
3′,4′ coupling constant values between 3 and 6 Hz. In fact,
according to the well-known relationship between cou-
plings and torsion angles,27 these values indicate the
existence of one or two major conformations around the
4142 J . Org. Chem., Vol. 68, No. 11, 2003

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
F IGURE 3. Perspective of the global minimum of the mono-
mer as deduced by MM3* calculations.
data from the NOESY and ROESY experiments were in
also in agreement with the J data, and the complete set
of observed data indicated the existence of conformational
equilibria in all cases.
F IGURE 2. Schematic view of the monomer showing the
Con for m a tion a l An a lysis. Molecu la r Dyn a m ics
Stu d ies. (a ) Th e Mon om er : Sta r tin g Con for m a tion s
a n d Con for m a tion a l Distr ibu tion s. As a first step to
determine the overall three-dimensional structure of the
molecules, molecular mechanics and dynamics calcula-
tions were performed on the monomer building block
(Figure 3). After MM2* minimization of the starting
geometries, information on the conformational space
accessible was obtained through molecular dynamics
simulations.29 In particular, the MD simulations were
performed using several output geometries of the molec-
ular mechanics calculations as starting structures (see
above). Thus, different ωi torsions were considered. A
summary of the MM2* results is given in Table S1
(Supporting Information).
Two clusters of values are observed for ω2: In the first
cluster, this torsion angle adopts a value around -60°.
In the second cluster, the angle changes to 180°, provid-
ing a smaller relative steric energy value. Regarding ω3,
the computed dihedral angle values are close to 180°.
Major equilibria are predicted around ω5 and ω6, inde-
pendent of the starting structure. Therefore, although the
presence of other conformers cannot be discarded and it
is, indeed, fairly possible that several geometries are
simultaneously taking place, a representative view of the
global minimum is shown in the Figure 3.
(b) Tow a r d a Mod el of Oligom er ic F r a gm en ts.
Once the repeating units had been analyzed, three units
were built from the global minima, extensively mini-
mized, and then combined to generate models of 22, 23,
25, 26, and 36. These geometries were minimized, and
the two lowest energy minima obtained in this manner
were then submitted to MD simulations. The initial
conformations of the lateral chains were selected to agree
with the experimental data (see above).
From the MD (Figure 4 and 5), it can be observed that
a major syn relationship between the five-membered ring
and the lateral chain is adopted, with values around
-120°. In all cases, the torsional oscillations were more
pronounced around ω1, ω5, and ω6. With respect to the
relevant torsion angles
TABLE 3. Vicin a l P r oton /P r oton Cou p lin g Con sta n ts
for 22, 23, 25, 26, a n d 36 (Hz)a
H-pair/unit
22
23
25
26
36
1-2/a
1-2/b
1-2/c
1-2/d
2-3/a
2-3/b
2-3/c
3-4
4.5
3.5
4.0
3.5
3.5
4.5
4.0
3.5
3.5
3.5
3.0
2.5
1.5
8.0
8.5
8.5
3.0
5.5
3.5
5.5
3.5
5.5
9.2
9.2
9.2
9.2
9.2
9.2
9.2
3.3
6.0
3.5
6.6
3.5
6.6
8.5
8.5
8.5
3.0
5.5
3.0
5.0
3.5
5.5
3.3
6.0
3.5
6.6
3.3
6.0
3.5
6.6
3-4′/a
3-4
3-4′/b
3-4
3-4′/c
a
Couplings involving amide protons were in all cases between
5.5 and 6.0 Hz.
ω2 (anti and/or g-) and ω3 (anti) linkages, and the
existence of a conformational equilibrium for ω4 (anti, g-
> g+).
Then, the NOESY/ROESY experiments performed with
different mixing times were used to qualitatively esti-
mate proton/proton interresidue distances.28 For all the
molecules, all NOESY cross-peaks were positive at 500
MHz as expected for a fast tumbling molecule. NOEs
were assigned as strong (s), medium (m), and weak (w)
and then quantitated. The NOEs can be grouped into
different groups: The first group defines the presence of
conformational equilibria around the carbonyl-furan
linkages. Indeed, NOEs between the NH protons (25, 26,
and 36) and both the methyl groups and H-4 attached to
their adjacent furane rings may be appreciated in CDCl3
and DMSO-d6 solvents. Additionally, in all solvents, the
H-4 at the furan rings give NOEs to their attached H-3,
H-2, and H-5. Taking into account the simultaneous
existence of all these NOEs, the existence of conforma-
tional equilibrium around ω1 and ω6 is granted, as also
deduced from the coupling information. No remote NOEs
between different subunits were observable. Thus, the
(29) (a) Homans, S. W. Biochemistry 1990, 29, 9110-9118. (b)
Mukhopadhyay, C.; Miller, K. E.; Bush, C. A. Biopolymers 1994, 34,
21. (c) Rutherford, T. J .; Partridge, J .; Weller, C. T.; Homans, S. W.
Biochemistry 1993, 32, 12715-12724. (d) Siebert, H. C.; Reuter, G.;
Schauer, R.; von der Lieth, C. W.; Dabrowski, J . Biochemistry 1992,
31, 6962-6971. (e) Engelsen, S. B.; Herve du Penhoat, C.; Perez, S. J .
Phys. Chem. 1995, 99, 13334-13351.
(27) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783-2793.
(28) Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York, 1989.
J . Org. Chem, Vol. 68, No. 11, 2003 4143

Moreno-Vargas et al.
F IGURE 4. Different perspectives of the global minimum of compound 36 as deduced by MM3* calculations.
F IGURE 5. Superimposition of 3 × 100 structures obtained by MD simulations of 36 with the MM3* force field. Structures from
three different time periods are superimposed.
rest of ωi torsions, although, according to the simulations,
a variety of possibilities could occur, the most stable one
by far corresponds to ω2 g-, ω3 anti, ω4 anti (Table S2,
Supporting Information).
perimental data when a homogeneous distribution of
lateral chains are considered.
Exp er im en ta l Section
Gen er a l Meth od s. Dried solvents and reagents were
freshly distilled under N2 prior to use: THF from sodium and
benzophenone, CH2Cl2, DMF from BaO, and i-Pr2NEt from
CaH2. TLC was performed on silica gel HF254 (Merck), with
detection by UV light and charring with H2SO4. Silica gel 60
(Merck, 230 mesh) was used for preparative chromatography.
Optical rotations were measured in a 0.1 dm tube at 25 °C in
a spectropolarimeter. 1H NMR and 13C NMR spectra were
recorded on solutions in CDCl3, DMSO-d6, CD3OD and D2O,
J values are given in Hz and δ in ppm. Assignments were
confirmed by homonuclear 2D COSY and heteronuclear 2D
correlated (HETCOR) experiments. The HRFABMS spectra
were obtained with 3-nitrobenzyl alcohol or thioglycerol as
matrix and NaI as salt.
Con clu sion
We have prepared a new class of peptidomimetics that
can be obtained in combinatorial fashion potentially. The
subunits are readily available with high structural
diversity with respect to functionality and stereochem-
istry. The water solubility and stability of the new
oligomers may lead to new bioactive compounds. Some
of the new oligomers have been submitted to conforma-
tional studies. From the experimental and computational
results, it seems that there is an important amount of
conformational freedom for the torsion angles of these
molecules, which do not depend on the solvent and on
the size. Unrestrained MM and MD simulations provide
a picture that agrees satisfactorily with the NMR ex-
3-Eth oxyca r bon yl-2-m eth yl-5-(1′,2′,3′,4′-tetr a -O-ter t-bu -
tyld im eth ylsilyl-D-a r a bin o-tetr itol-1-yl)fu r a n (2b). To a
solution of 115 (200 mg, 0.73 mmol) in dry DMF (2.5 mL) were
added tert-butyldimethylsilyl chloride (1.31 g, 8.76 mmol) and
4144 J . Org. Chem., Vol. 68, No. 11, 2003

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
imidazole (1.2 g, 17.5 mmol), and the mixture was heated at
60 °C for 10 h. Then, the solution was concentrated, and the
residue was diluted with dichloromethane and washed with
water and brine. The organic layer was dried (Na2SO4) and
concentrated. The residue was purified by column chromatog-
raphy (ether/petroleum ether, 1:10 f 1:5) to give 2b as a
colorless oil (460 mg, 0.63 mmol, 87%): [R]D +3 (c 1.5, CH2-
CDCl3) δ 7.43-7.21 (m, Ph), 6.63 (s, H-4), 4.62, 4.33 (2d, 2J H,H
2
) 11.8, CH2Ph), 4.60, 4.55 (2d, J H,H ) 11.1, CH2Ph), 4.56 (d,
2
J 1′,2′ ) 5.1, H-1′), 4.49, 4.34 (2d, J H,H ) 11.3, CH2Ph), 4.31 (q,
3J H,H ) 7.1, CH2CH3), 3.97 (t, J 2′,3′ ) 5.3, H-2′), 3.65 (m, H-3′),
3.42 (d, J 3,4 ) 4.4, H-4a, H-4b), 2.54 (s, CH3), 1.37 (t, CH2CH3);
13C NMR (75.4 MHz, CDCl3) δ 163.8 (COOEt), 159.2, 149.3
(C-2, C-5), 137.9, 137.9, 137.5 (3 C-1 of Ph), 128.3-127.6 (15
C of Ph), 114.2 (C-3), 110.1 (C-4), 80.1 (C-2′), 78.2 (C-3′), 74.9,
74.3 (C-1′, CH2Ph), 72.0, 71.1 (2 CH2Ph), 60.1 (CH2CH3), 50.6
(C-4′), 14.3 (CH2CH3), 13.8 (CH3); FABMS m/z 592 [100, (M +
Na)+]. Anal. Calcd for C33H35O6N3: C, 69.57; H, 6.19; N, 7.34.
Found: C, 69.71; H, 6.14; N, 7.64.
1
Cl2); H NMR (300 MHz, CDCl3) δ 6.42 (s, H-4), 4.66 (d, J 1′,2′
3
) 6.6, H-1′), 4.26 (q, J H,H ) 7.1, CH2CH3), 3.91 (d, H-2′), 3.72
(dd, J 3′,4′a ) 6.8, J 3′,4′b ) 4.5, H-3′), 3.21 (dd, J 4′a,4′b ) 10.3, H-4′a),
3.12 (dd, H-4′b), 2.53 (s, CH3), 1.33 (t, CH2CH3), 0.91-0.84 (m,
CH3 de tert-butyl), 0.11-0.05 (m, CH3 of TBS); 13C NMR (75.4
MHz, CDCl3) δ 164.1 (COOEt), 157.8, 152.7 (C-2, C-5), 113.9
(C-3), 108.3 (C-4), 79.6 (C-2′), 74.7 (C-3′), 70.3 (C-1′), 64.7 (C-
4′), 59.9 (CH2CH3), 26.0-25.9 (12 C, (CH3)3C), 18.3-18.0 (4
C, (CH3)3C), 14.2 (CH2CH3), 13.6 (CH3), from -4.4 to -5.7 (8
C, t-Bu(CH3)2Si). Anal. Calcd for C36H74O7Si4: C, 59.12; H,
10.20. Found: C, 59.05; H, 10.02.
5-(4′-Azido-1′,2′,3′-tr i-O-ter t-bu tyldim eth ylsilyl-4′-deoxy-
D-a r a bin o-t et r it ol-1′-yl)-3-et h oxyca r b on yl-2-m et h ylfu -
r a n (12b). To a solution of 11 (155 mg, 0.52 mmol) in dry DMF
(2.5 mL) were added tert-butyldimethylsilyl chloride (0.71 g,
4.7 mmol) and imidazole (0.64 g, 9.36 mmol). The mixture was
stirred at 70 °C for 10 h, and then the solvent was evaporated.
The residue was diluted with dichloromethane and washed
with water and brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (petroleum
ether f ether/petroleum ether 1:10) to give 12b as a colorless
oil (287 mg, 0.45 mmol, 86%): [R]D -9 (c 1, CH2Cl2); 1H NMR
3-Hyd r oxym eth yl-2-m eth yl-5-(1′,2′,3′,4′-tetr a -O-ter t-bu -
tyld im eth ylsilyl-D-a r a bin o-tetr itol-1′-yl)fu r a n (3b). To a
suspension of LiAlH4 (41 mg, 1.08 mmol) in dry THF (1 mL)
was added a solution of 2b (393 mg, 0.54 mmol) in dry THF
(2 mL) under N2. The reaction mixture was stirred for 15 min
and then diluted with ether (10 mL). A saturated aqueous
solution of Na2SO4 (10 mL) was added, and the resulting
precipitate was filtered off and washed with ethanol. The
filtrate was concentrated to give 3b as a colorless oil (320 mg,
0.47 mmol, 87%): [R]D -10 (c 1, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 6.13 (s, H-4), 4.65 (d, J 1′,2′ ) 6.7, H-1′), 4.41 (d, J CH,OH
) 5.6, CH2OH), 3.91 (d, H-2′), 3.71 (dd, J 3′,4′a ) J 3′,4′b ) 5.4,
H-3′), 3.21 (d, H-4′a, H-4′b), 2.24 (s, CH3), 1.16 (t, CH2OH),
0.91-0.85 (m, CH3 of tert-butyl), 0.11-0.06 (m, CH3 of TBS);
13C NMR (75.4 MHz, CDCl3) δ 152.7, 147.8 (C-2, C-5), 119.5
(C-3), 108.8 (C-4), 79.8 (C-2′), 74.7 (C-3′), 70.5 (C-1′), 64.7 (C-
4′), 56.7 (CH2OH), 26.0-25.9 (12 C, (CH3)3C), 18.4-18.1 (4 C,
(CH3)3C), 11.5 (CH3), -4.4 to -5.6 (8 C, t-Bu(CH3)2Si). Anal.
Calcd for C34H72O6Si4: C, 59.24; H, 10.53. Found: C, 59.29;
H, 10.78.
5-(4′-Azid o-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-3-eth oxy-
ca r bon yl-2-m eth ylfu r a n (11). To a stirred solution of 1021
(254 mg, 0.59 mmol) in DMF (2.5 mL) was added sodium azide
(82 mg, 1.18 mmol). The mixture was heated at 110 °C for 3
h. Then, the solvent was evaporated and the residue parti-
tioned between AcOEt and water. The organic layer was dried
(Na2SO4) and concentrated. The resulting residue was purified
by column chromatography (ether/petroleum ether, 1:3 f 1:1)
to give 11 as a white solid (115 mg, 0.38 mmol, 65%) that
crystallized from ether/petroleum ether: mp ) 85-87 °C; [R]D
+7 (c 0.9, CH3OH); IR νmax 3357, 2928, 2109, 1720, 1672, 1394,
1236, 1093 cm-1; 1H NMR (300 MHz, CD3OD) δ 6.57 (s, H-4),
4.86 (under MeOH, H-1′), 4.26 (q, 3J H,H ) 7.1, CH2CH3), 3.82
(m, H-3′), 3.69 (dd, J 1′,2′ ) 2.3 J 2′,3′ ) 8.4, H-2′), 3.51 (dd, J 3′,4′a
) 2.8, J 4′a,4′b ) 12.8, H-4′a), 3.38 (dd, J 3′,4′b ) 6.4, H-4′b), 2.53
(s, CH3), 1.32 (t, CH2CH3); 13C NMR (75.4 MHz, CDCl3) δ 165.7
(COOEt), 159.6, 155.5 (C-2, C-5), 115.1 (C-3), 108.5 (C-4), 74.3
(C-2′), 71.6 (C-3′), 67.6 (C-1′), 61.3 (CH2CH3), 55.5 (C-4′), 14.7
(CH2CH3), 13.8 (CH3); FABMS m/z 322 [100, (M + Na)+]. Anal.
Calcd. for C12H17N3O6: C, 48.16; H, 5.73; N, 14.04. Found: C,
48.15; H, 5.43; N, 14.25.
(300 MHz, CDCl3) δ 6.43 (s, H-4), 4.53 (d, J 1′,2′ ) 5.2, H-1′),
3
4.28 (q, J H,H ) 7.1, CH2CH3), 3.99 (dd, J 3′,4′a ) 8.4, J 3′,4′b
)
2.3, H-3′), 3.91 (d, H-2′), 2.96 (dd, J 4′a,4′b ) 13.0, H-4′a), 3.12
(dd, H-4′b), 2.56 (s, 3 H, CH3), 1.35 (t, CH2CH3), 0.91-0.88
(m, (CH3)3), 0.12 to -0.05 (m, CH3Si); 13C NMR (75.4 MHz,
CDCl3) δ 163.9 (COOEt), 158.1, 151.1 (C-2, C-5), 114.0 (C-3),
108.7 (C-4), 79.7 (C-2′), 72.0 (C-3′), 70.6 (C-1′), 60.0 (CH2CH3),
54.4 (C-4′), 25.7-25.6 (9 C, (CH3)3C), 18.1-17.8 (3 C, (CH3)3C),
14.1 (CH2CH3), 13.6 (CH3), -4.5 to -5.2 (6 C, t-Bu(CH3)2Si).
Anal. Calcd. for C30H59O6Si3N3: C, 56.12; H, 9.26; N, 6.54.
Found: C, 56.62; H, 9.02; N, 6.71.
5-(4′-Am in o-1′,2′,3′-tr i-O-ben zyl-4′-deoxy-D-a r a bin o-tetr i-
tol-1′-yl)-3-h ydr oxym eth yl-2-m eth ylfu r an (13a). To a stirred
suspension of LiAlH4 (43 mg, 1.06 mmol) in dry THF (1.5 mL)
was added a solution of 12a (156 mg, 0.27 mmol) in dry THF
(3 mL) under N2. The mixture was stirred at rt for 15 min
and diluted with ether (25 mL). Saturated aqueous solution
of Na2SO4 (25 mL) in water was added. The precipitate was
filtered off and washed with ether. The filtered solution was
concentrated and the residue diluted with dichloromethane
and washed with water, dried (Na2SO4) and concentrated to
give 13a as a colorless oil. (118 mg, 0.23 mmol, 87%). [R]D -36
(c 1, CH2Cl2); IR νmax 3370, 2920, 2864, 1578, 1454, 1101, 1063,
739 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.37-7.21 (m, Ph),
2
6.31 (s, H-4), 4.76, 4.70 (2d, J H,H ) 11.4, CH2Ph), 4.61, 4.40
2
(2d, J H,H ) 11.8, CH2Ph), 4.51 (d, J 1′,2′ ) 6.5, H-1′), 4.45, 4.36
2
(2d, J H,H ) 11.6, CH2Ph), 4.41 (s, CH2OH), 4.12 (dd, J 2′,3′
4.1, H-2′), 3.28 (m, H-3′), 2.87 (dd, 1 H, J 4a,4b ) 13.5, J 3,4a
)
)
6.7, H-4a), 2.70 (dd, 1 H, J 3,4b ) 3.4, H-4b), 2.28 (s, 3 H, CH3);
13C NMR (75.4 MHz, CDCl3) δ 149.2, 149.1 (C-2, C-5), 138.5,
138.2, 137.9 (3 C-1 of Ph), 128.2-126.8 (15 C of Ph), 119.7
(C-3), 110.8 (C-4), 80.4 (C-3′), 80.1 (C-2′), 75.6 (C-1′), 74.7, 71.3,
70.9 (3 CH2Ph), 56.2 (CH2OH), 41.4 (C-4′), 11.6 (CH3); CIMS
m/z 502 [100, (M + H)+]; HRCIMS m/z found 502.2589, calcd
for C31H35NO5 + H 502.2593. Anal. Calcd for C31H35NO5: C,
74.28; H, 7.00; N, 2.79. Found: C, 74.86; H, 6.47; N, 2.40.
5-(4′-Azido-1′,2′,3′-tr i-O-ben zyl-4′-deoxy-D-a r a bin o-tetr i-
tol-1′-yl)-3-eth oxyca r bon yl-2-m eth ylfu r a n (12a ). To a so-
lution of 11 (1 g, 3.34 mmol) and sodium hydride (721 mg, 30.1
mmol) in dry DMF (5 mL) cooled at 0 °C was added benzyl
bromide (3.6 mL, 30.1 mmol). The reaction mixture was stirred
at rt for 2 h and then quenched with triethylamine and
methanol. The mixture was concentrated and the residue
dissolved in dichloromethane and washed with water and
brine. The organic layer was dried over Na2SO4 and the solvent
evaporated. The resulting residue was purified by column
chromatography (ether/petroleum ether, 1:3 f 1:1) to give 12a
as a colorless oil (1.61 g, 2.84 mmol, 85%): [R]D -21 (c 2.8,
5-(4′-Am in o-1′,2′,3′-tr i-O-ter t-bu tyldim eth ylsilyl-4′-deoxy-
D-a r a bin o-t et r it ol-1′-yl)-3-et h oxyca r b on yl-2-m et h ylfu -
r a n (13b). A solution of 12b (89 mg, 0.14 mmol) in methanol
(8 mL) was hydrogenated with Pd-C (10%)(10 mg) at 1 atm
for 12 h. The catalyst was filtered off and the solvent
concentrated to give pure 13b as a colorless oil (80 mg, 0.13
mmol, 93%): [R]D -6 (c 1, CH2Cl2); 1H NMR (300 MHz, CDCl3)
3
δ 6.43 (s, H-4), 4.56 (d, J 1′,2′ ) 5.7, H-1′), 4.25 (q, J H,H ) 7.1,
CH2CH3), 3.93 (d, H-2′), 3.75 (dd, J 3′,4′a ) 6.7, J 3′,4′b ) 3.5, H-3′),
2.53 (s, CH3), 2.38 (dd, J 4′a,4′b ) 13.9, H-4′a), 2.11 (dd, H-4′b),
1.34 (t, CH2CH3), 0.91-0.84 (m, (CH3)3), 0.11- -0.05 (m, CH3-
Si); 13C NMR (75.4 MHz, CDCl3) δ 163.9 (COOEt), 157.9, 151.9
(C-2, C-5), 114.0 (C-3), 108.3 (C-4), 80.1 (C-2′), 74.5 (C-3′), 70.6
1
CH2Cl2); IR νmax 2928, 2109, 1720 cm-1; H NMR (300 MHz,
J . Org. Chem, Vol. 68, No. 11, 2003 4145

Moreno-Vargas et al.
(C-1′), 59.9 (CH2CH3), 43.9 (C-4′), 25.8-25.7 (9 C, (CH3)3C),
18.1-17.9 (3 C, (CH3)3C), 14.1 (CH2CH3), 13.6 (CH3), -4.1 to
-5.1 (6 C, t-Bu(CH3)2Si). Anal. Calcd for C30H61NO6Si3: C,
58.48; H, 9.98; N, 2.27. Found: C, 58.21; H, 9.80; N, 2.23.
in THF (5 mL) at 0 °C was added a solution of TBAF in THF
(1 M, 1.54 mL, 1.54 mmol). The mixture was stirred for 2.5 h
and then the solvent evaporated. Column chromatography
(dichloromethane/methanol, 20:1 f 10:1) gave the unprotected
compound as a white solid. 15 (49 mg, 0.093 mmol, 85%): [R]D
-11 (c 1, CH3OH); FABMS m/z 552 [100, (M + Na)+];
HRFABMS m/z found 552.2065, calcd for C24H35NO12 + Na
552.2057.
5-[4′-[N-Acetyl-N-[2-m eth yl-5-(1′,2′,3′,4′-tetr a -O-ben zyl-
D-a r a bin o-tetr itol-1′-yl)fu r a n -3-ylm eth yl]a m in o]-1′,2′,3′-
tr i-O-ben zyl-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl]-3-a cetoxy-
m eth yl-2-m eth ylfu r a n (14a ). To a solution of 3a (300.9 mg,
0.51 mmol) in dry CCl4 (6.4 mL) containing molecular sieves
(4 Å) was added triphenylphosphine (273 mg, 1.02 mmol) in
CCl4 (5 mL) under N2 atmosphere. The mixture was heated
at reflux for 8 h. The solution was concentrated to give
3-chloromethyl-2-methyl-5-(1′,2′,3′,4′-tetra-O-benzyl-D-arabino-
tetritol-1′-yl)furan (6a ) which was used without further puri-
fication in the next step. To a solution of 13a (286 mg, 0.57
mmol) and Na2CO3 (60 mg, 0.57 mmol) in dry DMF (2 mL)
with molecular sieves (4 Å) was added a solution of 6a in dry
DMF (3 mL) under N2 atmosphere. The reaction mixture was
stirred at 70 °C for 1.5 h and then filtered. The filtrate was
evaporated and the residue acetylated conventionally. Column
chromatography (dichloromethane/acetone f dichloromethane,-
10:1) gave 14a as a colorless oil (248 mg, 0.21 mmol, 42%, three
steps): [R]D -19 (c 1.7, CH2Cl2); 13C NMR (125.7 MHz, CDCl3,
mixture of two conformers) δ 170.9, 170.9, 170.7, 169.9
(CONR1R2, CH3COOR), 151.2, 150.8, 150.3, 149.6, 149.3, 149.1,
149.1 148.5 (2 C-2, 2 C-5), 138.9-137.4 (7 C-1 of Ph), 128.3-
127.2 (35 C of Ph), 116.3, 115.8, 115.5, 115.3 (2 C-3), 112.4,
111.6, 111.0, 109.5 (2 C-4), 81.2, 80.9, 80.9 (C-2′a, C-2′b), 78.3,
78.2, 78.1, 76.5 (C-3′a, C-3′b), 75.7, 75.7, 75.5, 75.2, 74.9, 74.8,
74.7, 74.6 (C-1′a, C-1′b, 2 CH2Ph), 73.2, 73.1, 71.9, 71.8, 71.6,
71.2, 71.0, 70.9 (5 CH2Ph), 69.5, 69.4 (C-4′a), 57.9, 57.5 (CH2-
OAc), 47.1, 45.5 (C-4′b), 45.1, 39.6 (CH2RNAc), 21.5, 21.4, 20.9,
20.8 (CH3COOR, CH3CONR1R2), 11.6, 11.6, 11.4, 11.4 (2 CH3);
FABMS m/z 1182 [100, (M + Na)+]; HRFABMS m/z calcd for
Conventional acetylation of 15 with acetic anhydride and
pyridine gave 16 (mixture of two conformers) as an oil in 100%
yield. Major conformer: 1H NMR (500 MHz, CDCl3) δ 6.65 (s,
H-4b), 6.20 (s, H-4a), 5.99-5.97 (m, H-1′a), 5.95 (d, J 1′b,2′b
)
5.7, H-1′b), 5.54-5.51 (m, H-2′a), 5.48 (t, J 2′b,3′b ) 5.6, H-2′b),
5.26-5.20 (m, H-3′b), 5.16-5.12 (m, H-3′a), 4.56, 3.86 (2d, 2J H,H
) 15.0, CH2NAcR), 4.28-4.14 (m, RCOOCH2CH3, H-4′a),
4.09-4.03 (m, H-4′′a), 3.45-3.40 (m, H-4′b), 3.15 (dd, J 4′′b,3′b
) 2.9, J 4′′b,4′b ) 15.4, H-4′′b), 2.55 (s, CH3b), 2.26 (s, 3 H, CH3a),
2.08-2.01 (m, 7 CH3CO), 1.33-1.30 (m, 6 H, COOCH2CH3);
13C NMR (125.7 MHz, CDCl3) δ 170.7-169.2 (7 CO of Ac,
CONRR′), 163.2 (COOEt), 159.8, 150.5 (C-2b, C-5b), 146.7,
146.2 (C-2a, C-5a), 115.8 (C-3a), 114.5 (C-3b), 111.7 (C-4a),
111.0 (C-4b), 71.3 (C-2′b), 70.2 (C-2′a), 68.6 (C-3′a), 67.1 (C-
3′b), 65.8 (C-1′a), 65.4 (C-1′b), 61.5 (C-4′a), 60.3 (COOCH2CH3),
46.4 (C-4′b), 38.4 (CH2NAcR), 21.4 (CH3CONRR′), 20.7-20.4
(7 CH3CO), 14.2 (COOCH2CH3), 13.7 (CH3b), 11.4 (CH3a).
Minor conformer: 1H NMR (500 MHz, CDCl3) δ 6.62 (s, H-4b),
6.11 (s, H-4a), 6.04 (d, J 1′b,2′b ) 5.1, H-1′b), 5.99-5.97 (m, 2 H,
H-1′a), 5.54-5.51 (m, H-2′a), 5.48 (t, J 2′b,3′b ) 5.6, H-2′b), 5.26-
5.20 (m, H-3′b), 5.16-5.12 (m, H-3′a), 4.28-4.14 (m, RCOOCH2-
CH3, H-4′a, CH2NAcR), 4.09-4.03 (m, H-4′′a), 3.53 (dd, J 4′b,3′b
) 8.6, J 4′′b,4′b ) 14.5, H-4′b), 3.45-3.40 (m, H-4′′b), 2.53 (s,
CH3b), 2.22 (s, 3 H, CH3a), 2.08-2.01 (m, 7 CH3CO), 1.33-
1.30 (m, COOCH2CH3); 13C NMR (125.7 MHz, CDCl3) δ 170.7-
169.2 (7 CO of Ac, CONRR′), 163.4 (COOEt), 159.6, 149.2 (C-
2b, C-5b), 147.4, 146.5 (C-2a, C-5a), 115.6 (C-3a), 114.3 (C-
3b), 110.6 (C-4a), 109.7 (C-4b), 71.3 (C-2′b), 70.0 (C-2′a), 69.3
(C-3′b), 68.5 (C-3′a), 65.8 (C-1′a, C-1′b), 61.5 (C-4′a), 60.1
(COOCH2CH3), 44.4 (C-4′b), 43.8 (CH2NAcR), 21.5 (CH3-
CONRR′), 20.7-20.4 (7 CH3CO), 14.2 (COOCH2CH3), 13.7
(CH3b), 11.5 (CH3a).
C
73H77NO12 + Na 1182.5376, found 1182.5376.
5-[4′-[N-Acetyl-N-[2-m eth yl-5-(1′,2′,3′,4′-tetr a -O-ter t-bu -
tyldim eth ylsilyl-D-a r a bin o-tetr itol-1′-yl)fu r an -3-ylm eth yl]-
a m in o]-1′,2′,3′-t r i-O-ter t-b u t yld im et h ylsilyl-4′-d eoxy-D-
a r a bin o-t et r it ol-1′-yl]-3-et h oxyca r b on yl-2-m et h ylfu r a n
(14b). To a solution of 3b (422 mg, 0.58 mmol) in dry CCl4 (5
mL) containing molecular sieves (4 Å) was added triphen-
ylphosphine (321 mg, 1.2 mmol) in CCl4 (2 mL) under N2
atmosphere. The mixture was heated at reflux for 8 h, and
then the solution was concentrated to give 3-chloromethyl-2-
methyl-5-(1′,2′,3′,4′-tetra-O-tert-butyldimethylsilyl-D-arabino-
tetritol-1′-yl)furan (6b) which was used without further puri-
fication in the next step. A solution of compound 6b in dry
DMF (4 mL) was added under N2 atmosphere to a solution of
13b (535 mg, 0.87 mmol) and Na2CO3 (97 mg, 0.87 mmol) in
dry DMF (4 mL) containing molecular sieves 4 Å. The reaction
mixture was stirred at 90 °C for 8 h and then filtered. The
filtrate was evaporated and the residue acetylated convention-
ally. Column chromatography (ether/petroleum ether, 1:30 f
1:8) gave 14b as a colorless oil (290 mg, 0.22 mmol, 38%, three
steps): [R]D -9 (c 1.6, CH2Cl2); 13C NMR (125.7 MHz, CDCl3,
mixture of two conformers) δ 170.7, 170.9 (CONR1R2), 164.1,
163.5 (COOEt), 158.2 (C-2b), 153.1, 152.6 (C-2a), 152.2, 152.1
(C-5b), 147.4, 146.3 (C-5a), 116.4, 116.0 (C-3a), 114.3, 114.0
(C-3b), 109.6 (C-4a), 109.2, 108.0 (C-4b), 80.1, 79.9, 79.8, 79.5
(C-2′a, C-2′b), 74.9, 74.8 (C-3′b), 71.5-70.0 (C-1′a, C-1′b, C-3′a),
64.6 (C-4′a), 60.2, 59.9 (CH2CH3), 48.9, 48.4 (C-4′b), 46.6 (CH2-
NR1R2), 26.2-25.2 ((CH3)3C), 22.1, 21.5 (CH3CONR1R2), 18.5-
17.9 ((CH3)3C), 14.2 (CH2CH3), 13.6 (CH3b), 11.7, 11.6 (CH3a);
Anal. Calcd for C66H133NO12Si7: C, 59.63; H, 10.08; N, 1.05.
Found: C, 59.88; H, 10.09; N, 1.06.
2-Meth yl-5-(1′,2′,3′,4′-tetr a -O-a cetyl-D-a r a bin o-tetr itol-
1′-yl)-3-fu r oic Acid (17b). A solution of 1 (3 g, 10.9 mmol) in
EtOH-NaOH 1M (2:1, 60 mL) was heated at 60 °C for 8 h
and then neutralized with Amberlite IR-120 (H+). The solution
was filtered and evaporated, and the residue was acetylated
conventionally. Column chromatography (dichloromethane/
methanol, 80:1 f 30:1) afforded 17b as a colorless oil (4.06 g,
9.8 mmol, 90%): [R]D -33 (c 1.6, CH2Cl2); IR νmax 3500-2800
(COOH), 1760 (CO), 1696 (CO), 1379, 1228, 1053 cm-1
;
1H
NMR (300 MHz, CDCl3) δ 6.63 (s, 1 H, H-4), 6.03 (d, J 1′,2′
)
4.4, H-1′), 5.58 (dd, J 2′,3′ ) 7.6, H-2′), 5.17 (m, H-3′), 4.24 (dd,
J 3′,4′a ) 3.1, J 4′a,4′b ) 12.4, H-4′a), 4.12 (dd, J 3′,4′b ) 5.3, H-4′b),
2.57 (s, CH3), 2.09, 2.08, 2.06 y 2.05 (4s, 4 CH3CO); 13C NMR
(75.4 MHz, CDCl3) δ 170.4, 169.6, 169.5, 169.2 (4 CH3CO),
168.5 (COOH), 161.2, 147.0 (C-2, C-5), 113.6 (C-3), 110.5 (C-
4), 69.6 (C-2′), 68.4 (C-3′), 65.7 (C-1′), 61.5 (C-4′), 20.6, 20.5 (2
CH3CO), 13.8 (CH3); FABMS m/z 437 [100, (M + Na)+]. Anal.
Calcd for C18H22O11: C, 52.17; H, 5.35; O, 42.47. Found: C,
52.07; H, 5.36.
5-(4′-Am in o-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-3-eth oxy-
ca r bon yl-2-m eth ylfu r a n (18). A solution of benzyl derivative
11 (500 mg, 1.67 mmol) in anhydrous ethanol (15 mL) was
hydrogenated with Pd-C (10%) (50 mg) at 1 atm for 20 min.
The catalyst was removed by filtration, and the solvent was
concentrated giving as a white solid 18 (445 mg, 1.63 mmol,
98% yield): [R]D -17 (c 1, CH3OH); mp 118-120 °C; 1H NMR
(300 MHz, CD3OD) δ 6.57 (s, H-4), 4.8 (bs, 1 H, H-1′), 4.26 (c,
3J H,H ) 7.1, CH2CH3), 3.68-3.58 (m, H-2′,H-3′), 2.93 (dd, J 3′,4′a
) 3.3, J 4′a,4′b ) 13.2, H-4′a), 2.71 (dd, J 3′,4′b ) 6.8, H-4′b), 2.53
(s, CH3), 1.32 (t, CH2CH3); 13C NMR (75.4 MHz, CDCl3) δ 165.7
(COOEt), 159.6, 155.4 (C-2, C-5), 115.2 (C-3), 108.5 (C-4), 75.4,
72.5 (C-2′, C-3′), 67.9 (C-1′), 61.3 (CH2CH3), 45.3 (C-4′), 14.7
5-[4′-[N-Acetyl-N-[(5-D-a r a bin o-tetr itol-1′-yl)-2-m eth yl]-
fu r a n -3-ylm eth yl]a m in o]-4′-d eoxy-D-a r a bin o-tetr itol-1′-
yl]-3-eth oxyca r bon yl-2-m eth ylfu r a n (15) a n d 5-[4′-[N-
Acetyl-N-[1′,2′,3′,4′-tetr a -O-a cetyl(5-D-a r a bin o-tetr itol-1′-
yl)-2-m eth yl]fu r an -3-ylm eth yl]am in o]-1′,2′,3′-tr i-O-acetyl-
4′-d e oxy-D-a r a bin o-t e t r it ol-1′-yl]-3-e t h oxyca r b on yl-2-
m eth ylfu r a n (16). To a solution of 14b (147 mg, 0.11 mmol)
4146 J . Org. Chem., Vol. 68, No. 11, 2003

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
(CH2CH3), 13.8 (CH3); FABMS m/z 274 [100, (M + H)+]. Anal.
Calcd for C12H19 N O6: C, 52.74; H, 7.01; N, 5.13. Found: C,
52.41; H, 6.75; N, 5.03.
To a stirred solution of 18 (180 mg, 0.66 mmol) and Ph3P (346
mg, 1.32 mmol) in dry DMF (1.5 mL) was added a solution of
17b (272 mg, 0.65 mmol) and 2,2′-dithiodipyridine (292 mg,
1.32 mmol) in dichloromethane (2.5 mL) under N2. After 6 h
at rt, the solution was concentrated and the resulting residue
was acetylated conventionally. Column chromatography (ether/
petroleum ether, 1:1 f 4:1 gave 22 as a white solid (393 mg,
0.49 mmol, 74%): [R]D -15 (c 2.8, CH2Cl2); 1H NMR (500 MHz,
5-(4′-Azid o-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-2-m eth yl-
3-fu r oic Acid (19). To a solution of 11 (0.41 g, 1.36 mmol) in
EtOH (10 mL) was added NaOH (1 M) (5 mL). The reaction
mixture was heated at 60 °C during 2 h, cooled to rt, and
neutralized with Amberlite IR-120 (H+). After filtration and
evaporation, column chromatography of the residue (dichlo-
romethane/methanol 20:1 f 10:1) gave 19 as a pale yellow
solid (332 mg, 1.22 mmol, 90%): [R]D +8 (c 0.6, CH3OH); IR
νmax 3500-2260 (OH, COOH), 2106 (N3), 1686 (CO), 1588,
1408, 1103 cm-1; 1H NMR (300 MHz, CD3OD) δ 6.57 (s, H-4),
4.87 (m, H-1′), 3.83 (ddd, J 2′,3′ ) 8.4, J 3′,4′b ) 6.4, J 3′,4′a ) 2.8,
H-3′), 3.70 (dd, J 1′,2′ ) 2.4, H-2′), 3.51 (dd, J 4′a,4′b ) 12.8, H-4′a),
3.38 (dd, H-4′b), 2.53 (s, CH3); 13C NMR (75.4 MHz, CD3OD) δ
167.6 (COOH), 159.6, 155.3 (C-2, C-5), 115.5 (C-3), 108.8 (C-
4), 74.3 (C-2′), 71.6 (C-3′), 67.6 (C-1′), 55.5 (C-4′), 13.7 (CH3);
FABMS m/z 294 [33, (M + Na)+], m/z 316 [28, (M - H +
2Na)+]. Anal. Calcd for C10H13N3O6: C, 44.28; H, 4.83; N, 15.49.
Found: C, 43.80; H, 5.09; N, 15.37.
3
CDCl3) Tables 1 and 2, and δ 4.24 (q, J H,H ) 7.1, CH2CH3),
2.13-2.02 (m, 7 Ac), 1.30 (t, CH2CH3); 13C NMR (125.7 MHz,
CDCl3) δ 170.5-169.3 (7 COCH3), 163.4, 163.2 (CONHR,
COOEt), 159.4, 157.6 (2 C-2), 146.7, 146.4 (2 C-5), 116.1, 114.3
(2 C-3), 110.5, 108.4 (2 C-4), 70.5 (C-2′b), 69.8 (C-2′a), 69.2 (C-
3′b), 68.5 (C-3′a), 65.7 (C-1′a), 65.6 (C-1′b), 61.4 (C-4′a), 60.2
(CH2CH3), 38.1 (C-4′b), 20.7-20.5 (7 COCH3), 14.2 (CH2CH3),
13.7, 13.4 (2 CH3); FABMS m/z 818 [100, (M + Na)+]. Anal.
Calcd for C36H45NO19: C, 54.34; H, 5.70; N, 1.76. Found: C,
54.61; H, 5.89; N, 1.94.
3-Eth oxyca r bon yl-2-m eth yl-5-[4′-d eoxy-4′-[2-m eth yl-5-
(D-a r a bin o-tetr itol-1′-yl)-3-fu r a m id e]-D-a r a bin o-tetr itol-
1′-yl]fu r a n (23). To a solution of 22 (100 mg, 0.12 mmol) in
dry methanol (4 mL) was added NaOMe/MeOH (1 M) until
pH ) 12. The reaction mixture was allowed to stand a rt for
2 h and then neutralized with Amberlite IR-120 (H+). Filtra-
tion and evaporation gave pure 23 as a white solid (53 mg,
0.116 mmol, 98%): 1H NMR Table 1; FABMS m/z 524 [70, (M
+ Na)+]; 13C NMR (75.4 MHz, CD3OD) δ 167.4 (CONHR,
COOEt), 159.6, 157.1 (2 C-2), 155.4, 155.2 (2 C-5), 117.0, 115.0
(2 C-3), 108.6, 107.0 (2 C-4), 75.1, 74.3 (2 C-2′), 72.7 (C-3′a),
71.4 (C-3′b), 68.0, 67.8 (2 C-1′), 64.8 (C-4′a), 61.3 (CH2CH3),
43.9 (C-4′b), 14.6 (CH2CH3), 13.8, 13.6 (2 CH3); HRFABMS m/z
found 524.1744, calcd for C22H31NO12 + Na 524.1741.
5-(4′-Am in o-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-2-m eth yl-
3-fu r oic Acid (H-Th a bf-OH)30 (20). A solution of 19 (272 mg,
1 mmol) in abs EtOH (12 mL), was hydrogenated at 1 atm
and rt over Pd-C (10%) (55 mg) for 1 h. The reaction mixture
was filtered and evaporated giving pure 20 as an amorphous
white solid (222 mg, 0.9 mmol, 90%): [R]D -6 (c 0.5, H2O); IR
ν
max 3397, 2917 (NH, OH, COOH), 1636 (CO), 1522, 1435, 1098,
812 cm-1; 1H NMR (300 MHz, D2O) δ 6.50 (s, H-4), 4.87 (under
H2O, H-1′), 3.92 (dd, J 1′,2′ ) 4.8, J 2′,3′ ) 6.3, H-2′), 3.85 (m, H-3′),
3.26 (dd, J 3′,4′a ) 3.2, J 4′a,4′b ) 13.2, H-4′a), 3.00 (dd, J 3′,4′b
)
9.2, H-4′b), 2.45 (s, CH3); 13C NMR (75.4 MHz, D2O) δ 172.9
(COOH), 156.7, 150.2 (C-2, C-5), 118.9 (C-3), 109.4 (C-4), 74.3
(C-2′), 67.4 (C-3′), 66.6 (C-1′), 41.6 (C-4′), 12.8 (CH3). Anal.
Calcd for C10H15NO6: C, 48.98; H, 6.17; N, 5.71. Found: C,
48.72; H, 6.24; N, 5.98.
2-Meth yl-5-[1′,2′,3′-tr i-O-a cetyl-4′-d eoxy-4′-[2-m eth yl-5-
(1′,2′,3′,4′-t et r a -O-a cet yl-D-a r a bin o-t et r it ol-1′-yl)-3-fu r a -
m id e]-D-a r a bin o-tetr itol-1′-yl]-3-fu r oic Acid (24). To a
solution of 22 (244 mg, 0.36 mmol) in EtOH (6 mL) was added
NaOH (1 M) (3 mL). The reaction mixture was heated at 60
°C for 10 h, cooled to rt, and neutralized with Amberlite IR-
120 (H+). The solvent was evaporated and the residue acetyl-
ated conventionally. Column chromatography (dichloromethane/
methanol (50:1 f 20:1) afforded 24 as a white solid (230 mg,
0.33 mmol, 89%): [R]D -17 (c 1.8, CH2Cl2); IR νmax 3600-2875
5-[4′-Deoxy-4-(flu or en ylm eth oxyca r bon yl)a m in o-D-a r -
a bin o-tetr itol-1′-yl]-2-m eth yl-3-fu r oic Acid F m oc-Th a bf-
OH (21). To a stirred mixture of 20 (803 mg, 3.26 mmol) in
dry pyridine (25 mL) at 0 °C was dropped trimethylsilyl
chloride (4.2 mL, 32.6 mmol), and the reaction mixture was
stirred for 45 min at rt. Then the reaction mixture was cooled
to 0 °C, 9-fluorenylmethoxycarbonyl chloride (1.09 g, 4.23
mmol) was added, and the mixture was stirred for 1.5 h at rt.
Water (2.5 mL) was added, and the reaction mixture stirred
for 1 h at rt and then evaporated. Column chromatography
(dichloromethane/methanol, 15:1 f 8:1) afforded pure 21 as
an amorphous white solid (1.39 g, 3 mmol, 92%): [R]D 0 (c 1,
CH3OH), [R]405 -8 (c 1, CH3OH), [R]435 -4 (c 1, CH3OH), [R]546
-2 (c 1, CH3OH), [R]577 0 (c 1, CH3OH); IR νmax 3600-2200
(OH, COOH), 1705 (CO), 1663 (CO) 1537, 1262, 735 cm-1; 1H
NMR (300 MHz, CD3OD, 45 °C) δ 7.77-7.61 (m, H-aromat.
Fmoc), 7.39-7.25 (m, H-aromat. Fmoc), 6.57 (s, H-4), 4.84
(broad d, J 1′,2′ ) 2.5, H-1′), 4.36 (d, 3J H,H ) 6.8, CH2 of Fmoc),
4.20 (t, CH of Fmoc), 3.78-3.65 (m, H-2′, H-3′), 3.49 (dd, J 3′,4′a
) 3.1, J 4′a,4′b ) 13.9, H-4′a), 3.23 (dd, J 3′,4′b ) 6.5, H-4′b), 2.50
(s, CH3); 13C NMR (75.4 MHz, CD3OD, 45 °C, δ ppm) δ 167.8
(COOH), 159.5, 155.0 (C-2, C-5), 145.4, 142.6 (4 C, C-aromat.
of Fmoc), 128.7, 128.1, 126.1, 120.9 (8 C, C-aromat. of Fmoc),
115.8 (C-3), 109.1 (C-4), 75.1, 71.7 (C-2, C-3), 68.0 (C-1′, CH2
of Fmoc), 48.7 (CH de Fmoc), 45.1 (C-4′), 13.7 (CH3); FABMS
m/z 490 [100, (M + Na)+], m/z 512 [55, (M + 2Na - H)+];
HRFABMS m/z obsd 490.1485, calcd for C25H25NO8 + Na
490.1478. Anal. Calcd for C25H25NO8: C, 62.23; H, 5.39; N,
3.00. Found: C, 61.84; H, 5.77; N, 2.83.
(COOH), 1760 (CO), 1379, 1228, 1053 cm-1 1H NMR (300
;
MHz, CDCl3) δ 6.61, 6.45 (s each, 2 H-4), 6.24 (t a, NH), 6.06
(d, J 1′b,2′b ) 3.5, H-1′b), 5.99 (d, J 1′a,2′a ) 4.8, H-1′a), 5.58 (dd,
J 2′a,3′a ) 7.3, H-2′a), 5.44 (dd, J 2′b,3′b ) 8.5, H-2′b), 5.17-5.12
(m, H-3′a), 5.05-4.99 (m, H-3′b), 4.23 (dd, J 3′a,4′a ) 3.0, J 4′a,4′′a
) 12.4, H-4′a), 4.09 (dd, J 3′a,4′′a ) 4.1, H-4′′a), 3.98 (ddd, J 3′b,4′b
,
J NH,4′b ) 2.7, 7.0, J 4′b,4′′b ) 14.9, H-4′b), 3.15 (dt, J 3′b,4′′b ) J NH,4′′b
) 4.9, H-4′′b), 2.56, 2.53 (s, 2 CH3), 2.14-2.03 (m, 7 Ac); 13C
NMR (75.4 MHz, CDCl3) δ 170.5-169.3 (7 COCH3), 167.9
(COOH), 163.2 (CONHR), 160.9, 157.6 (2 C-2), 147.1, 146.4 (2
C-5), 116.0, 113.7 (2 C-3), 110.4, 108.5 (2 C-4), 70.4 (C-2′b),
69.8 (C-2′a), 69.2 (C-3′b), 68.5 (C-3′a), 65.7 (C-1′a), 65.6 (C-
1′b), 61.4 (C-4′a), 38.1 (C-4′b), 20.7-20.5 (7 C, 7 COCH3), 13.8,
13.4 (2 CH3); FABMS m/z 790 [100, (M + Na)+]. Anal. Calcd
for C34H41NO19: C, 53.19; H, 5.38; N, 1.83. Found: C, 52.69;
H, 5.59; N, 1.94.
2-Meth yl-5-(1′,2′,3′,4′-tetr a -O-a cetyl-D-a r a bin o-tetr itol-
1′-yl)-3-fu r a m id e-(Nf4′)-2-m eth yl-5-(1′,2′,3′-tr i-O-a cetyl-
4′-d eoxy-D-a r a bin o-t et r it ol-1′-yl)-3-fu r a m id e-(Nf4′)-3-
eth oxyca r bon yl-2-m eth yl-5-(1′,2′,3′-tr i-O-a cetyl-4-d eoxy-
D-a r a bin o-tetr itol-1′-yl)fu r a n (25). To a stirred solution of
18 (180 mg, 0.66 mmol) and Ph3P (91 mg, 0.35 mmol) in dry
DMF (0.75 mL) was added a solution of 24 (134 mg, 0.17 mmol)
and 2,2′-dithiodipyridine (77 mg, 0.35 mmol) in dichlo-
romethane (2.5 mL) under N2. After 7 h at rt, the solution was
concentrated and the resulting residue was acetylated con-
ventionally. Column chromatography (ether/acetone, 100:1 f
25:1) gave 25 as a white solid (120 mg, 0.10 mmol, 60%): [R]D
3-E t h oxyca r b on yl-2-m et h yl-5-[1′,2′,3′-t r i-O-a cet yl-4′-
d eoxy-4′-[2-m eth yl-5-(1′,2′,3′,4′-tetr a -O-a cetyl-D-a r a bin o-
tetr itol-1′-yl)-3-fu r am ide]-D-a r a bin otetr itol-1′-yl]fu r an (22).
(30) To simplify the nomenclature of this compound and further
derivatives, we introduce an alternative nomenclature based on petides
where Thabf stands for trihydroxyaminobutylfuran.
1
-10 (c 2.0, CH2Cl2); H NMR (500 MHz, CDCl3) Table 1 and
3
δ 4.23 (q, J H,H ) 7.1, CH2CH3), 2.13-2.01 (m, 10 Ac), 1.30 (t,
J . Org. Chem, Vol. 68, No. 11, 2003 4147

Moreno-Vargas et al.
CH2CH3); 13C NMR (125.7 MHz, CDCl3) δ 170.3-169.2 (10
COCH3), 163.3, 163.2, 163.1 (2 CONHR, COOEt), 159.4, 157.4,
157.3 (3 C-2), 146.7, 146.6, 146.5 (3 C-5), 116.2, 116.1, 114.3
(3 C-3), 110.4, 108.5, 108.4 (3 C-4), 70.6, 70.5, 69.9 (3 C-2′),
69.5, 69.4, 68.6 (3 C-3′), 65.8-65.7 (3 C-1′), 61.4 (C-4′a), 60.1
(CH2CH3), 38.2, 38.1 (C-4′b, C-4′c), 20.6-20.4 (10 COCH3), 14.1
(CH2CH3), 13.6, 13.3 (3 CH3); FABMS m/z 1171 [100, (M +
Na)+]. Anal. Calcd for C52H64N2O27: C, 54.35; H, 5.61; N, 2.44.
Found: C, 53.89; H, 5.65; N, 2.84.
2-Meth yl-5-(1′,2′,3′-tr i-O-a cetyl-4′-a zid o-4′-d eoxy-D-a r a -
bin o-tetr itol-1′-yl)-3-fu r a m id e-(Nf4′)-2-m eth yl-5-(1′,2′,3′-
tr i-O-a cetyl-4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-3-fu r a m id e-
(Nf4′)-3-eth oxyca r bon yl-2-m eth yl-5-(1′,2′,3′-tr i-O-a cetyl-
4-d eoxy-D-a r a bin o-tetr itol-1′-yl)fu r a n (29). To a stirred
solution of 28 (28 mg, 0.056 mmol) and 19 (15 mg, 0.056 mmol)
in dry DMF (1.5 mL) were added PyBOP (29 mg, 0.056 mmol)
and diisopropiletilamine (20 µL, 0.112 mmol). The reaction
mixture was stirred for 1 h, concentrated, and conventionally
acetylated. Column chromatography (ether f ether/acetone
10:1) gave 29 (38 mg, 0.034 mmol, 61%) as a white solid: [R]D
-9 (c 1.0, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.60 (s, H-4),
6.45 (s, 2 H-4), 6.27, 6.20 (t a each, 2 NH), 6.06, 6.04 (d each,
2 H, J 1′b,2′b, J 1′c,2′c ) 3.8, 4.1, H-1′b, H-1′c), 5.97 (d, 1 H, J 1′a,2′a
) 5.3, H-1′a), 5.59 (dd, J 2′a,3′a ) 6.8, H-2′a), 5.48-5.42 (m, H-2′b,
H-2′c), 5.13-5.01 (m, H-3′a), 5.05-4.97 (m, H-3′b, H-3′c), 4.26
(q, 3J H,H ) 7.1, CH2CH3), 4.02-3.98 (m, H-4′b, H-4′c), 3.44 (dd,
J 3′a,4′a ) 3.6, J 4′a,4′′a ) 13.4, H-4′a), 3.32 (dd, J 3′a,4′′a ) 6.2, H-4′′a),
3.17-3.11 (m, H-4′′b, H-4′′c), 2.55, 2.54 (s each, 3 CH3), 2.18-
2.05 (m, 9 Ac), 1.30 (, CH2CH3); 13C NMR (75.4 MHz, CDCl3)
δ 170.5-169.2 (9 COCH3), 163.3, 163.2, 163.1 (2 CONHR,
COOEt), 159.4, 157.6, 157.4 (3 C-2), 146.7, 146.5, 146.3 (3 C-5),
116.1, 114.3 (3 C-3), 110.4, 108.5 (3 C-4), 70.5, 70.4, 70.3 (3
C-2′) 69.4, 69.3, 69.2 (3 C-3′), 65.6-65.5 (3 C-1′), 60.1 (CH2-
CH3), 50.1 (C-4′a), 38.1, 38.0 (C-4′b, C-4′c), 20.7-20.5 (9
COCH3), 14.1 (CH2CH3), 13.6, 13.3 (3 CH3); FABMS m/z 1154
[100, (M + Na)+]. Anal. Calcd for C50H61N5O25: C, 53.05; H,
5.43; N, 6.19. Found: C, 52.95; H, 5.38; N, 6.50.
2-Meth yl-5-(D-a r a bin o-tetr itol-1′-yl)-3-fu r am ide-(Nf4′)-
2-m eth yl-5-(4′-d eoxy-D-a r a bin o-tetr itol-1′-yl)-3-fu r a m id e-
(Nf4′)-3-eth oxyca r bon yl-2-m eth yl-5-(4-d eoxy-D-a r a bin o-
tetr itol-1′-yl)fu r a n (26). Conventional methanolysis of 25 (60
mg, 0.05 mmol) as described above for the preparation of 101
afforded 26 as a white solid (35 mg, 0.049 mmol, 97%): [R]D
1
-2 (c 0.7, CH3OH); H NMR Table 1; 13C NMR (125.7 MHz,
CDCl) δ 167.4 (2 CONHR), 165.8 (COOEt), 159.6, 157.1, 157.0,
155.4, 155.2, 155.1 (3 C-2, 3 C-5), 117.3 (C-3a, C-3b), 115.2
(C-3c), 108.6 (C-4c), 107.1, 106.9 (C-4a, C-4b), 75.3, 75.2 (C-
2′b, C-2′c), 74.4 (C-2′a) 72.8 (C-3′a), 71.5 (C-3′b, C-3′c), 68.1,
68.0, 67.8 (3 C-1′), 64.8 (C-4′a), 61.3 (CH2CH3), 44.0, 43.9 (C-
4′b, C-4′c), 14.6 (CH2CH3), 13.8, 13.6 (3 CH3); FABMS m/z 751
[35, (M + Na)+]; HRFABMS m/z found 751.2530, calcd for
C
32H44N2O17 + Na 751.2538.
3-E t h oxyca r b on yl-2-m et h yl-5-[1′,2′,3′-t r i-O-a cet yl-4′-
d eoxy-4′-[2-m et h yl-5-(1′,2′,3′,3′-t r i-O-a cet yl-4′-a zid o-4′-
d eoxy-D-a r a bin o-t et r it ol-1′-yl)-3-fu r a m id e]-D-a r a bin o-
tetr itol-1′-yl]fu r a n (27). To a stirred solution of 18 (36 mg,
0.13 mmol) and 19 (36 mg, 0.13 mmol) in dry DMF (2 mL)
were added PyBOP (69 mg, 0.132 mmol) and diisopropilethyl-
amine (46 µL, 0.26 mmol). The reaction mixture was stirred
for 1 h, evaporated to dryness, and acetylated conventionally.
Column chromatography (ether/petroleum ether 1:3 f 3:1)
gave 27 as a white solid (64 mg, 0.08 mmol, 62%): [R]D -7 (c
0.6, CH2Cl2); IR νmax 2943, 2104 (N3), 1751 (CO), 1373, 1217,
2-[5-(4′-Am in o-4′-deoxy-D-a r a bin o-tetr itol-1′-yl)-2-m eth -
yl-3-fu r a m id e-(Nf4′)-5-(D-a r a bin otetr itol-1′-yl)-2-m eth yl-
3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-t et r it ol-1′-yl)-2-m et h yl-
3-fu r a m id e]a cetic Acid (36).
2-[5-(4′-Am in o-4′-deoxy-D-a r a bin o-tetr itol-1′-yl)-2-m eth -
yl-3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-tetr itol-1′-yl)-2-m eth -
yl-3-fu r am ide-(Nf4′)-5-(D-a r a bin o-tetr itol-1′-yl)-2-m eth yl-
3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-t et r it ol-1′-yl)-2-m et h yl-
3-fu r a m id e]a cetic Acid (37).
1
1047 cm-1; H NMR (300 MHz, CDCl3) δ 6.61, 6.45 (s each, 2
H-4), 6.17 (dd a, J NH,4′b ) 6.9, J NH,4′′b ) 5.1, NH), 6.06 (d, J 1′b,2′b
) 3.6, H-1′b), 5.98 (d, J 1′a,2′a ) 5.2, H-1′a), 5.59 (dd, J 2′a,3′a
)
2′-[5-(4′-Am in o-4′-deoxy-D-a r a bin o-tetr itol-1′-yl)-2-m eth -
yl-3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-tetr itol-1′-yl)-2-m eth -
yl-3-fu r am ide-(Nf4′)-5-(D-a r a bin o-tetr itol-1′-yl)-2-m eth yl-
3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-t et r it ol-1′-yl)-2-m et h yl-
3-fu r a m id e-(Nf4′)-5-(D-a r a bin o-t et r it ol-1′-yl)-2-m et h yl-
3-fu r a m id e]a cetic Acid (38).
6.8, H-2′a), 5.44 (dd, J 2′b,3′b ) 8.6, H-2′b), 5.12 (m, H-3′a), 5.01
(m, H-3′b), 4.26 (q, 2 H, 3J H,H ) 7.1, CH2CH3), 4.02 (ddd, J 4′b,4′′b
) 15.1, J 4′b,3′b ) 3.1, H-4′b), 3.44 (dd, J 3′a,4′a ) 3.6, J 4′a,4′′a
13.4, H-4′a), 3.32 (dd, J 3′a,4′′a ) 6.2, H-4′′a), 3.14 (dt, J 4′′b,3′b
)
)
5.0, H-4′′b), 2.56, 2.55 (s each, 2 CH3), 2.17-2.05 (m, 6 Ac),
1.32 (t, CH2CH3); 13C NMR (75.4 MHz, CDCl3) δ 170.1-169.2
(6 COCH3), 163.3, 163.0 (CONHR, COOEt), 159.5, 157.6 (2
C-2), 146.7, 146.2 (2 C-5), 116.4, 114.3 (2 C-3), 110.4, 108.5 (2
C-4), 70.4, 70.3 (2 C-2′), 69.4, 69.1 (2 C-3′), 65.6, 65.5 (2 C-1′),
60.1 (CH2CH3), 50.1 (C-4′a), 38.0 (C-4′b), 20.7-20.5 (6 C, 6
COCH3), 14.1 (CH2CH3), 13.6, 13.4 (2 CH3); FABMS m/z 801
[100, (M + Na)+]. Anal. Calcd for C34H42N4O17: C, 52.44; H,
5.44; N, 7.20. Found: C, 52.40; H, 5.62; N, 7.15.
5-[4′-[5-(4′-Am in o-4′-d eoxy-D-a r a bin o-t et r it ol-1′-yl)-2-
m et h yl-3-fu r a m id e]-4′-d eoxy-D-a r a bin o-t et r it ol-1′-yl]-3-
eth oxyca r bon yl-2-m eth ylfu r a n (28). Conventional metha-
nolysis of 27 (75 mg, 0.096 mmol), as described above for the
preparation of 23, afforded after evaporation a residue that
was dissolved in absolute EtOH (5 mL) and hydrogenated at
1 atm over Pd-C (10%) (10 mg). After 30 min, the reaction
mixture was filtered and evaporated giving pure 28 as a
colorless oil (40 mg, 0.08 mmol, 84%): [R]D -6 (c 0.8, CH3-
OH); 1H NMR (300 MHz, CD3OD) δ 6.68, 6.58 (s each, 2 H-4),
4.9 (m, H-1′a, H-1′b), 4.26 (q, 3J H,H ) 7.1, CH2CH3), 3.83-
3.78 (m, H-3′b), 3.68-3.62 (m, H-2′a, H-2′b, H-3′a, H-4′b), 3.47
(dd, J 3′b,4′′b ) 6.5, J 4′b,4′′b ) 14.0, H-4′′b), 2.96 (dd, J 3′a,4′a ) 3.1,
J 4′a,4′′a ) 12.9, H-4′a), 2.74 (dd, J 3′a,4′′a ) 6.2, H-4′′a), 2.53, 2.52
(s, 6 H, 2 CH3), 1.32 (t, CH2CH3); 13C NMR (75.4 MHz, CD3-
OD) δ 167.4 (CONHR), 165.7 (COOEt), 159.6, 157.1 (2 C-2),
155.4, 155.1 (2 C-5), 117.3, 115.1 (2 C-3), 108.5, 107.0 (2 C-4),
75.6, 75.1 (2 C-2′), 72.0 (C-3′a), 71.4 (C-3′b), 68.8, 67.7 (2 C-1′),
61.3 (CH2CH3), 45.0 (C-4′a), 43.9 (C-4′b), 14.6 (CH2CH3), 13.8,
13.6 (2 CH3); FABMS m/z 523 [95, (M + Na)+]; HRFABMS
m/z obsd 523.1912, calcd for C22H32N2O11 + Na 523.1903.
Ester ifica tion of HMBA-AM Resin . A mixture of HMBA-
AM resin (100 mg, substitution ) 1.16 mmol/g) and Fmoc-
glycine (103 mg, 0.35 mmol) in dry DMF (1.5 mL) was agitated
for 15 min, and then a mixture of pyridine (44µL, 0.55 mmol)
and 2,6-dichlorobenzoyl chloride (50 µL, 0.35 mmol) was added
and agitated for 12 h. The reaction mixture was filtered and
the resin washed with DMF (5 × 3 mL) and DCM (3 × 3 mL).
The resin was dried under vacuum giving 132 mg of a solid
residue (100% sustitution). The residue was treated with
piperidine in DMF (20%) (1 mL) and stirred for 10 min. The
resin was collected by filtration, washed with DMF (3 × 2 mL)
and DCM (4 × 2 mL), and dried under vacuum to afford the
Fmoc-glycine bound resin 32 (106.6 mg).
Su ccessive Cou p lin g of 5-[4-Deoxy-4-(F lu or en ylm eth -
oxyca r bon yl)a m in o-D-a r a bin o-tetr itol-1-yl]-2-m eth yl-3-
fu r oic Acid Un its (21) to H-Gly-OResin (31). To 31 (106.6
mg, 0.116 mmol) in a filtrating reaction tube was added a
solution of 21(108 mg, 0.23 mmol), PyBOP (120 mg, 0.23
mmol), and DIPEA (40 µL, 0.23 mmol) in dry DMF (2.5 mL).
The reaction mixture was agitated for 1 h. The resin was
collected by filtration, washed with DMF (4 × 3 mL) and DCM
(4 × 3 mL), and dried. The same treatment was repited twice
until constant weight of the amino acid bound resin (158.6 mg,
94% sustitution). Treatment with piperidine as described
above, washing of the resin and drying under vacuum gave
32 (132.4 mg, 100%).
Subsequent treatment as described above gave the resin
bound amino acids 32-34 (92-100% sustitution).
4148 J . Org. Chem., Vol. 68, No. 11, 2003

Hetaryleneaminopolyols and Hetarylenecarbopeptoids
Clea va ge fr om th e Resin . To the resin-bound products
32-34 was added a solution of NaOH (1 M)-THF (1:1) (2 mL
/100 mg) at 0 °C, and the mixture was stirred for 15 min and
filtered. The resin was washed with water (3 × 3 mL) and the
filtrate neutralized to pH 6-7 with aqueous acetic acid (10%)
(2 mL) and evaporated to dryness. Column chromatography
(biogel P-2) eluting with MeOH-water (1:1) gave 36, 37, or
38 (98-100%), respectively.
implemented in MACROMODEL 4.5.32 A schematic view is
given in Figure 2. Starting geometries were selected according
to the NMR data (J couplings, see below) as follows: ω2 was
set as 180° and -60° (anti), ω3 was set as 180° (anti), (see
below), although both angles were let free during the mini-
mizations and the molecular dynamics simulations. The three
possible staggered orientations of ω1, ω4, ω5, and ω6 torsions
were then combined to give the 81 initial conformations of the
monosaccharide. The torsion angles for all angles ωi are
dubbed as g+, g-, or anti, denoting angles in the proximity of
+60, -60, or 180°.
Molecu la r Mech a n ics Ca lcu la tion s. Oligomers 22, 23,
25, 26, and 36 were built from the minimized structures of
the monomers. The amide linkages were built in their usual
trans conformations. Calculations for a dielectric constant ꢀ
) 80 and for the continuum GB/SA solvent model33 (MM2*)
were performed in order to search different ways to satisfac-
torily reproduce the conformational behavior of these deriva-
tives in solution.34 First, the 81 starting structures were
minimized with 5000 conjugate gradient iterations or until the
rms derivative was smaller than 0.05 kcal mol-1 Å-1. These
calculations were carried out with all the initial geometries.
From the individual minimizations, the probability distribu-
tions for the chain orientations were calculated.
Molecu la r Dyn a m ics Sim u la tion s. The two lowest en-
ergy minima of the minimizations of the starting geometries
of 1-5 were used as input for molecular dynamics (MD)
simulations at 300 K, and their results were analyzed. Average
torsions and proton-proton distances were calculated for the
10 MD simulations.
Separate calculations were performed with the GB/SA
(Generalized Born solvent-accessible surface area) solvent
model for water and for a bulk dielectric constant of 80. For
all molecules, the simulations were carried out with a time
step of 1 fs. The equilibration period was 100 ps. Structures
were saved every 1 ps. The total simulation time was 1.0 ns
for every run.35
NMR Sp ectr oscop y. NMR experiments were recorded on
a 500 spectrometer, using approximate 5 mM solutions at
different temperatures (between 299 and 320 K). The spectra
were recorded in CDCl3 (22, 25), D2O (23, 26), and DMSO-d6
(36). Chemical shifts are reported in ppm, using external DSS
or TMS (0 ppm) as reference. The double quantum filtered
COSY35 spectrum was performed using 256 increments of 1K
real points to digitize a spectral width of 2000 Hz. Sixteen
scans were used with a relaxation delay of 1 s. The 2D TOCSY
experiment was performed using a data matrix of 256 incre-
ments of 1K real points to digitize a spectral width of 2000
Hz. Four scans were used per increment with a relaxation
delay of 2 s. MLEV 17 was used for the 100 ms isotropic mixing
time. 2D-T-ROESY36 experiments were performed using four
different mixing times, namely 150, 300, 450, and 600 ms, with
256 increments of 2K real points. Good linearity was observed
in the cross-peak built up. Estimated errors in the NOE
intensities are smaller than 20%. 1D-NOESY experiments
Tetr a m er 36: [R]D +13 (c 1.0, H2O); 1H NMR (500 MHz,
DMSO-d6) Table 1 and δ 3.80-3.95 (m, CH2COOH); 13C NMR
(125.7 MHz, D2O) δ 178.0 (COOH), 168.0, 168.0, 167.4 (3
CONHR), 157.9-157.8 (3 C-2), 152.9 (3 C-5), 116.8 (3 C-3),
108.0, 108.0, 107.8 (3 C-4), 75.2 (3 C-2), 70.8, 70.7 (C-3′b,c),
68.7 (C-3′a), 67.8, 67.8, 67.6 (3 C-1′), 44.4 (C-2′d), 43.2-42.8
(C-4′a,b,c), 14.0 (3 CH3); MALDI-TOF MS m/z 756 [100, (M +
H)+], 778 [70, (M + Na)+], 800 [40, (M - H + 2Na)+].
1
P en ta m er 37: [R]D +13 (c 0.5, H2O); H NMR (300 MHz,
D2O) δ 6.60, 6.59, 6.58, 6.58 (s each, 4 H-4), 4.86-4.83 (m, 4
H-1′), 3.92-3.80 (m, 4 H-2′, 4 H-3′, H-2′e, H-2′′e), 3.80-3.95
(m, CH2COOH),0.67-3.62 (m, H-4′b,c,d), 3.43-3.36 (m,
H-4′′b,c,d), 3.32 (dd, J 3a,4a ) 3.1, H-4′a), 3.04 (dd, J 3′a,4′′a ) 8.6,
J 4′a,4′′a ) 13.0, H-4′′a), 2.45, 2.43, 2.43, 2.42 (s each, 4 CH3);
13C NMR (75.5 MHz, D2O) δ 178.6 (COOH), 169.2 (3 CONHR),
168.3 (CONHR), 159.1-159.0 (4 C-2), 154.1 (4 C-5), 118.0-
117.9 (4 C-3), 109.1-109.0 (4 C-4), 76.3 (4 C-2′), 71.8 (C-3′b,c,d),
69.5 (C-3′a), 68.9-68.7 (4 C-1′), 45.5 (C-2′e), 44.3-43.9 (C-
4′a,b,c,d), 15.1 (4 CH3); ESIMS m/z 984.2 [90, (M + H)+].
Hexa m er 38: [R]D +12 (c 0.4, H2O); 1H NMR (500 MHz,
D2O) δ 6.59, 6.58, 6.57, 6.57, 6.56 (s each, 5 H-4), 4.85 (m, J 1′a,2′a
) 3.5, H-1′a), 4.85-4.82 (m, 4 H-1′b,c,d,e), 3.80-3.95 (m, CH2-
COOH), 3.90-3.77 (m, 5 H-2′, 5 H-3′, H-2′f, H-2′′f), 3.65-3.59
(m, H-4′b,c,d,e), 3.39-3.34 (m, H-4′′b,c,d,e), 3.31 (dd, J 3′a,4′a
)
3.2, J 4′a,4′′a ) 13.6, H-4′a), 3.03 (dd, J 3′a,4′′a ) 8.7, H-4′′a), 2.44,
2.43, 2.42, 2.41, 2.40 (s each, 5 CH3); 13C NMR (125.7 MHz,
D2O) δ 175.1 (COOH), 165.1 (CONHR), 165.0 (3 CONHR),
164.4 (CONHR), 155.0-154.8 (5 C-2), 150.0-149.9 (5 C-5),
113.9-113.8 (5 C-3), 105.0-104.8 (5 C-4), 72.2-72.1 (5 C-2′),
67.8 (C-3′b,c,d,e), 65.6 (C-3′a), 64.8-64.6 (5 C-1′), 41.5 (C-2′f),
44.3-43.9 (C-4′a,b,c,d,e), 11.0 (5 CH3); ESIMS m/z 1211.5 [100,
(M + H)+].
3-Ben zot r ia zoloxica r b on yl-5-[4-d eoxy-4-N-(9-flu or e-
n ylm et h oxyca r b on yl)a m in o-D-a r a bin o-t et r it ol-1-yl]-2-
m eth ylfu r a n o´ F m oc-Th a bf-OBt (39). The excess of acti-
vated amino acid, PyBOP and DIPEA, were extracted from
the resin after each coupling by washing with DMF. After
concentration to dryness, the residue was diluted with Cl2CH2,
washed with HCl (1 M) and water, dried (Na2SO4), and
evaporated. Column chromatography of the residue (ether/
petroleum ether,1:2 f 3:1) gave 39 as a white amorphous
solid: [R]D -7 (c 1, CH3OH); IR νmax 3579-2230 (OH), 1788
(COBOHt), 1692 (CO), 1576, 1101, 963 cm-1 1H NMR (300
;
MHz, CD3OD, 45 °C) δ 8.05-7.27 (m, 12 H, H-arom of Fmoc
and BOHt), 6.87 (s, 1 H, H-4), 4.97 (d, J 1′,2′ ) 2.2, H-1′), 4.36
(d, 3J H,H ) 7.2, CH2 of Fmoc), 4.21 (t, CH of Fmoc), 3.77-3.72
(m, H-2′, H-3′), 3.54 (dd, J 3′,4′a ) 3.2, J 4′a,4′b ) 14.1, H-4′a), 3.30
(dd, J 3′,4′b ) 6.6, H-4′b), 2.63 (s, CH3); 13C NMR (75.4 MHz,
CD3OD, 45 °C) δ 164.4 (COOBOHt), 161.1 (CO of Fmoc), 159.5,
157.3 (C-2, C-5), 145.3, 142.6 (4 C, C-arom of Fmoc), 128.8,
128.1, 126.2, 120.9 (8 C, C-arom of Fmoc), 144.5, 130.3, 126.5,
120.7, 109.9 (6 C, C arom of Fmoc), 109.5 (C-3), 107.7 (C-4),
74.9 (C-2′), 71.3 (C-3′), 68.0, 67.8 (C-1′, CH2 of Fmoc), 49.9-
48.2 (CH of Fmoc), 45.1 (C-4′), 14.1 (CH3); FABMS m/z 607
[70, (M + Na)+]; HRFABMS m/z obsd 607.1808, calcd for
(32) Mohamadi, F.; Richards, N. G. I.; Guida, W. C.; Liskamp, R.;.
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Singh, J . L. Asensio, M. D. Dalda, A. Ferna´ndez-Mayoralas, J . J ime´nez-
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Espinosa, J . F.; Asensio, J . L.; Bruix, M.; J ime´nez-Barbero, J . An.
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(35) For a relevant survey of the application of molecular mechanics
and dynamics simulations to carbohydrate molecules, see: French, A.
D., Brady, J . D., Eds. Computer Modelling of Carbohydrate Molecules;
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C
31H28N4O8 + Na 607.1805.
Molecu la r Mech a n ics a n d Dyn a m ics Ca lcu la tion s.
Sta r tin g Str u ctu r es. Molecular mechanics and dynamics
calculations were performed using the MM2* force field31 as
(31) Allinger, N. L.; Yuh, Y. H.; Lii, J . H. J . Am. Chem. Soc. 1989,
111, 8551-8556. The MM3* force field implemented in MACRO-
MODEL differs of the regular MM3 force field in the treatment of the
electrostatic term since it uses charge-charge instead of dipole-dipole
interactions.
(36) Hwang, T. L.; Shaka, A. J . J . Am. Chem. Soc. 1992, 114, 3157-
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J . Org. Chem, Vol. 68, No. 11, 2003 4149

Moreno-Vargas et al.
using the double pulse field gradient spin-echo technique37
were also acquired with the same mixing times.
A.J .M.-V. This work is part of the European COST
Program, working groups D13/0001/98 and D25/0001/
02.
Ack n ow led gm en t. We thank Professor Pierre Vogel
(Institute of Molecular and Biological Chemistry, EPFL,
Lausanne) for helpful discussions, the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica of Spain (Grant
Nos. PB 97-0730, PB96-0833, and BQU-2001-3779) for
financial support, the J unta de Andalucı´a (nos. 134 and
142), and the University of Seville for a fellowship to
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 6-9. 1H and 13C of 14a , 15, 16, 21, 23, 26, 28, and
37-39. Comparison of 1H NMR of 22, 23, 25, 26, and 36.
TOCSY spectrum of 36 and T-RO. ESY spectra 25 and 22.
Summary of the MM2* results of the monomer (Table S1) and
average torsion angles for the MD-based structures of 22, 23,
25, 26 and 36 (Table S2). This material is available free of
charge via the Internet at http://pubs.acs.org.
(37) Stott, K.; Stonehouse, J .; Keeler, J .; Hwang T.-L.; Shaka, A. J .
J . Am. Chem. Soc. 1995, 117, 4199-4203.
J O026631O
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