Synthesis of orthogonally protected cyclic homooligomers from sugar amino acids

Article abstract of DOI:10.1021/jo0502899

Two new families of orthogonally protected cyclic homooligomers with two to four sugar units were synthesized from pyranoid sugar amino acids. Cyclic oligomers composed of amide-linked sugar amino acids (1-3) were prepared by cyclization of linear oligome

Full text of DOI:10.1021/jo0502899

Synthesis of Orthogonally Protected Cyclic Homooligomers from
Sugar Amino Acids
Mickae¨l Me´nand,† Jean-Claude Blais,† Louis Hamon,‡ Jean-Marc Vale´ry,† and Juan Xie*,§
Synthe`se, Structure et Fonction des Mole´cules Bioactives, CNRS UMR 7613, Universite´ Pierre et Marie
Curie, 4 Place Jussieu, F-75005 Paris, France, Laboratoire de Synthe`se Asyme´trique, CNRS UMR 7611,
Universite´ Pierre et Marie Curie, 4 Place Jussieu, F-75005 Paris, France, and Laboratoire de
Photophysique et Photochimie Supramole´culaires et Macromole´culaires, CNRS UMR 8531,
Ecole Normale Supe´rieure de Cachan, 61 Avenue du Pt Wilson, F-94235 Cachan, France
joanne.xie@ppsm.ens-cachan.fr
Received February 15, 2005
Two new families of orthogonally protected cyclic homooligomers with two to four sugar units were
synthesized from pyranoid sugar amino acids. Cyclic oligomers composed of amide-linked sugar
amino acids (1-3) were prepared by cyclization of linear oligomers of the novel orthogonally
protected pyranoid sugar amino acid 12 using a solution-phase coupling method. These orthogonally
protected cyclic molecules can be selectively or fully deprotected, affording the macrocycles ready
to further functionalization. The straightforward reduction of the amide bonds in the cyclic oligomers
1-3 gave the corresponding amine-linked macrocycles 4-6. This kind of amine-linked carbohydrate-
based cyclic oligomer has never been reported before. These flexible molecular receptors could be
studied as molecular hosts for molecular, cationic, and anionic recognition. Conformational analysis
by molecular modeling (AM1) showed that all of the deprotected cyclic trimers and tetramers
4
preferred a C1 chair conformation with oxygen atoms of the sugar ring located on the interior of
the cavity and the secondary hydroxyl groups outward. In the amide-linked macrocycles, all of the
amide bonds are in s-trans conformation. The estimated size of the internal cavity is about 4.5 Å
for the cyclic trimer and 6.9 Å for the cyclic tetramer. The amine-linked macrocycles displayed
similar conformational behavior with a slight decrease in internal cavity.
Introduction
molecular receptors, cyclodextrines, cyclic oligomers com-
posed of R(1f4) linked D-glucopyranose units, have been
most extensively studied as a result of their ability to
include a variety of guest molecules in their hydrophobic
cavities.1 Development of analogues of cyclodextrines
with a modified cavity would be of particular interest as
potential specific host molecules.2
As part of our ongoing project on sugar amino acids
based molecular design, we are interested in synthesizing
analogues of cyclodextrines from sugar amino acids. An
obvious advantage of this approach is that the amino and
the carboxylic acid functionalities in the sugar amino
acids can be linked via amide bonds following well-
Host-guest recognition is implicated in a variety of
physical, chemical, and biological processes. Progress
toward the artificial recognition of ions and molecules
may lead to the development of new chemical sensors
design, purification, enantiomeric resolution, enzymatic
mimics, or drug delivery systems. Various hosts such as
cyclodextrines, crown ethers, cyclophanes, and calix-
arenes have been developed and widely studied in mo-
lecular or ionic recognition and inclusion. Among these
* To whom correspondence should be addressed. Tel: 33-1-47-40-
53-39. Fax: 33- 1-47-40-24-54.
† CNRS UMR 7613, Universite´ Pierre et Marie Curie.
‡ CNRS UMR 7611, Universite´ Pierre et Marie Curie.
§ Ecole Normale Supe´rieure de Cachan.
(1) (a) Szejtli, J. Chem. Rev. 1998, 98, 1743-1753. (b) Hedges, A.
R. Chem. Rev. 1998, 98, 2035-2044.
10.1021/jo0502899 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/26/2005
J. Org. Chem. 2005, 70, 4423-4430
4423

Me´nand et al.
SCHEME 1a
SCHEME 2a
a Reagents and conditions: (i) (1) BCl3, CH2Cl2, -78 °C, (2)
Ac2O, pyridine, 100%; (ii) (1) MeONa, MeOH, (2) NaH, MOMCl,
DMF, 97%; (iii) KMnO4, AcOH, aliquat 336, H2O, CH2Cl2, 69%;
(iv) (1) KMnO4, AcOH, aliquat 336, H2O, CH2Cl2, (2) NaHCO3,
MeI, DMF, 49%; (v) PPh3, H2O, THF, 98.5%.
a Reagents and conditions: (i) DEPC, Et3N, DMF, 83%; (ii)
LiOH, H2O/MeOH/THF, 93%; (iii) (1) H2, Pd/C, MeOH, (2) DEPC,
Et3N, DMF, 60%; (iv) H2, Pd/C, Pd black, AcOH, MeOH/EtOAc,
99% for 15, 74% for 17; (v) AcCl, MeOH, 98%.
established peptide chemistry. Furthermore, a reduction
of amide into amine would lead to a novel series of more
flexible cyclic derivatives. Kessler and co-workers have
first reported the synthesis of cyclic oligomers of pyranoid
sugar amino acids as host molecules that could form
inclusion complexes with p-nitrophenol and benzoic acid.3
Cyclic oligomers of sugar amino acids bearing pyranoid
â-anomer of sugar amino acids4 or furanoid R- and
â-anomers of sugar amino acids4b,5 have been reported.
Functionalization of these artificial receptors would be
of interest for supramolecular chemistry. As selective
modification of hydroxyl groups is still a challenge,
orthogonally protected cyclic molecules are preferred for
further development. Herein we report the synthesis of
novel orthogonally protected cyclic oligomers of pyranoid
R-anomer of sugar amino acid (compounds 1-3), their
selective deprotection, and their transformation into
amine-linked cyclic molecules (compounds 4-6). Confor-
mational analysis by molecular modeling (AM1) was
performed on fully deprotected cyclic trimers and tet-
ramers.
(2) (a) Gattuso, G.; Nepogodiev, S. A.; Stoddart, J. F. Chem. Rev.
1998, 98, 1919-1958. (b) Bu¨rli, R.; Vasella, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1852-1853. (c) Chong, P. Y.; Petillo, P. A. Org. Lett.
2000, 2, 1093-1096. (d) Fan, L.; Hindsgaul, O. Org. Lett. 2002, 4,
4503-4506. (e) Benito, J. M.; Jime´nez B.; Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J. M. Angew. Chem., Int. Ed. 2002, 41, 3674-3676. (f)
Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004, 126,
1638-1639. (g) Velasco-Torrijos, T.; Murphy, P. V. Tetrahedron:
Asymmetry 2005, 16, 261-272.
Results and Discussions
(3) Locardi, E.; Sto¨ckle, M.; Gruner, S.; Kessler, H. J. Am. Chem.
Soc. 2001, 123, 8189-8196.
Synthesis of Cyclic Oligomers 1-3. The synthesis
was started by preparing orthogonally protected sugar
amino acids (Scheme 1). We have recently discovered a
new regioselective debenzylation reaction of C-glycosides
by boron trichloride.6 Treatment of R-C-allyl glucoside 7
with BCl3 followed by acetylation gave quantitatively the
diacetate 8.6 Zemple´n desacetylation and methoxymethy-
lation of 8 furnished 9 in 97% yield. Oxidation of the
alkene function with KMnO4 led to carboxylic acid 10,
which was transformed into methyl ester 11. Reduction
of the azido function in 11 afforded amino ester 12 in
47% overall yield.
(4) (a) Sto¨ckle, M.; Voll. G.; Gu¨nther, R.; Lohof, E.; Locardi, E.;
Gruner, S.; Kessler, H. Org. Lett. 2002, 4, 2501-2504. (b) van Well,
R. M.; Marinelli, L.; Erkelens, K.; van der Marel, G. A.; Lavecchia, A.;
Overkleeft, H. S.; van Boom, J. H.; Kessler, H.; Overhand, M. Eur. J.
Org. Chem. 2003, 2303-2313. (c) Billing, J. F.; Nilsson, U. J.
Tetrahedron 2005, 61, 863-874. (d) Billing, J. F.; Nilsson, U. J.
Tetrahedron Lett. 2005, 46, 991-993.
(5) (a) van Well, R. M.; Overkleeft, H. S.; Overhand, M.; Vang
Carstenen, E.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett.
2000, 41, 9331-9335. (b) Gruner, S. A. W.; Truffault, V.; Voll, G.;
Locardi, E.; Sto¨ckle, M.; Kessler, H. Chem. Eur. J. 2002, 8, 4366-
4376. (c) van Well, R. M.; Marinelli, L.; Altona, C.; Erkelens, K.; Siegal,
G.; van Raaij, M.; Llamas-Saiz, A. L.; Kessler, H.; Novellino, E.;
Lavecchia, A.; van Boom, J. H.; Overhand, M. J. Am. Chem. Soc. 2003,
125, 10822-10829. (d) Chakraborty, T. K.; Srinivasu, P.; Bikshapathy,
E.; Nagaraj, R.; Vairamani, M.; Kiran Kumar, S.; Kunwar, A. C. J.
Org. Chem. 2003, 68, 6257-6263. (e) Bornaghi, L. F.; Wilkinson, B.
L.; Kiefel, M. J.; Poulsen, S.-A. Tetrahedron Lett. 2004, 45, 9281-9284.
(6) Xie, J.; Me´nand, M.; Vale´ry, J.-M. Carbohydr. Res. 2005, 340,
481-487.
4424 J. Org. Chem., Vol. 70, No. 11, 2005

Cyclic Homooligomers from Sugar Amino Acids
SCHEME 3a
SCHEME 4a
a Reagents and conditions: (i) DEPC, Et3N, DMF, 100%; (ii) (1)
LiOH, H2O/MeOH/THF, (2) H2, Pd/C, MeOH, (3) DEPC, Et3N,
DMF, 62%; (iii) H2, Pd/C, Pd black, MeOH/EtOAc, 59%.
a Reagents and conditions: (i) PPh3, H2O, THF, 82%; (ii) DEPC,
Et3N, DMF, 53%; (iii) (1) LiOH, H2O/MeOH/THF, (2) H2, Pd/C,
MeOH, (3) DEPC, Et3N, DMF, 35%.
Subsequent saponification/reduction/coupling transformed
19 into the desired compound 2 in 35% yield (Scheme 3).
Similarly, coupling of 14 with 18 produced quantitatively
the linear tetramer 20, which was converted into 3 in
62% yield (Scheme 4). Debenzylation of 20 afforded the
partially deprotected cyclic compound 21 in 59% yield.
Synthesis of Cyclic Oligomers 4-6. These amine-
linked macrocycles can be obtained by reduction of the
amide bonds in compounds 1-3. Reduction of compound
1 with BH3‚THF10 (15 equiv/amide bond) gave the desired
product 4 in 91% yield (Scheme 5). However, treatment
of compounds 2 and 3 with BH3‚THF led to partial
deprotection of the MOM groups. So we decided to remove
all of the methoxymethyl substituants with AcCl/MeOH,
which led to the partially deprotected cyclic compounds
5 and 6. To the best of our knowledge, these amine-linked
cyclic molecules have never been reported before. Re-
placement of the amide function by amine could make
the macrocycle more flexible. Recently, a flexible cyclo-
phane receptor with significantly improved host-guest
recognition compared to that of the rigid parent host has
been reported.11 It would be of interest to study the host-
guest basic attractive force with the more flexible cyclic
compounds 4-6 and to compare their recognition proper-
ties with their parent compounds. Moreover, replacement
The coupling of amino ester 12 with azido acid 10 was
carried out with diethyl phosphoryl cyanide (DEPC)7/
Et3N to give dimer 13 (Scheme 2). For final end-to-end
cyclization, it was better to first convert ester 13 into acid
14 before the reduction of the azido function. It is to be
noted that catalytic hydrogenation with Pd/C reduced
selectively the azido function without debenzylation.
Cyclic dimer 1 was obtained in 60% yield for the last two
steps after cyclization using DEPC/Et3N.
At this stage, we decided to deprotect selectively or
totally compound 1. The 3-O-benzyl group seemed to be
particularly resistant under the usual debenzylation
conditions. However, complete debenzylation could be
achieved by Pd black-catalyzed hydrogenolysis in the
presence of AcOH in a mixture of MeOH/EtOAc,8 which
led to 15 in 99% yield. Alternatively, treatment of 1 with
AcCl/MeOH9 gave cyclodimer 16 in 98% yield. Further
debenzylation afforded the fully deprotected cyclic com-
pound 17 in 74% yield.
Schemes 3 and 4 show the synthesis of cyclic trimer 2
and tetramer 3. Reduction of azide 13 under Staudinger
condition furnished amine 18 in 82% yield. Condensation
of 18 with azido acid 10 gave the linear trimer 19 (53%).
(7) Hayashi, K.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1992, 33,
5075-5076.
(10) Liang, X.; Petersen, B. O.; Duus, J. Ø.; Bols, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 2764-2773.
(11) Sarri, P.; Venturi, F.; Cuda, F.; Roelens, S. J. Org. Chem. 2004,
69, 3654-3661.
(8) Lecourt, T.; Herault, A.; Pearce, A. J.; Sollogoub, M.; Sinay¨, P.
Chem. Eur. J. 2004, 10, 2960-2971.
(9) Bu¨rli, R.; Vasella, A. Helv. Chim. Acta 1997, 80, 2215-2237.
J. Org. Chem, Vol. 70, No. 11, 2005 4425

Me´nand et al.
FIGURE 1. Energy-minimized structures of 2b (top left), 3b (bottom left), 5b (top right), and 6b (bottom right).
of the amide bond by amine in the macrocycles could
allow recognition for both cationic and anionic guests.
Conformational Analysis. The 1H and 13C NMR
spectra of all cyclic compounds displayed symmetric
structure, since only one set of signals from their sugar
unit is observed. However, because of the extensive
overlapping of signals, the 3JH,H coupling constants could
FIGURE 2. Rotamer conformation for the C2-C1′ bond (a)
and the C6′-C5′ bond (b) of 2b and 3b.
not be determined for either amide- or amine-linked cyclic
oligomers. For amide-linked cyclic compounds, no sig-
nificant chemical shifts of the amide protons were
observed upon cyclization, with δNH ranges from 6.83 to
7.09 ppm in compounds 1-3, 15, and 21, suggesting that
N-H is not involved in intramolecular H-bonding. The
geminal protons at C2 have, however, well-resolved
chemical shifts. The geminal C2H resonating at lower
field (arbitrarily assigned as H2b) displayed a large
coupling constant with H1′ (J1′,2 ) 11.7 Hz for cyclic dimer
1 and tetramer 3, 9.6 Hz for cyclic trimer 2). This
indicates that compounds 1-3 adopt a similar conforma-
tion with H2b in an anti relationship relative to H1′. To
find the most probable structures, conformational analy-
sis was performed on corresponding fully deprotected
cyclic trimers 2b, 5b and tetramers 3b, 6b by molecular
modeling techniques (AM1 calculations in the GAMESS12
suite of programs) (Figure 1).
oxygen atoms in the sugar ring are located on the interior
and the secondary hydroxyl groups are oriented outward.
No significant shape modification is observed between
amide- and amine-linked macrocycles (2b vs 5b, and 3b
vs 6b). In amide-linked macrocycles, the s-trans orienta-
tion represents the most stable conformation, with all of
the carbonyls pointing to the one side of the ring and the
N-H bonds in the opposite direction, which practically
ruled out the formation of intramolecular H-bonding
between the amide proton and adjacent carbonyl group.
This point is supported by the observed relative high field
amide proton chemical shifts (δNH ) 6.83-7.09 ppm). The
minimized structures also reveal that the C2-C1′ bond
adopts the ap conformation in 2b and 3b (Figure 2), with
(12) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J., J.; Koseki, S.; Matsunaya, N.; Nguyen, K.
A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput.
Chem. 1993, 14, 1347-1363.
In all cyclic compounds, the obtained energy-minimized
structures displayed a 4C1 chair conformation. The
4426 J. Org. Chem., Vol. 70, No. 11, 2005

Cyclic Homooligomers from Sugar Amino Acids
SCHEME 5a
fully deprotected, offering possibilities for further func-
tionalization. These macrocycles can be used as host
molecules in both organic and aqueous environment.
Furthermore, we have realized the direct conversion of
the amide-linked macrocycles into amine-linked ones,
which represent the first example of this type of carbo-
hydrate-derived host molecules. Conformational analysis
by molecular modeling (AM1) showed that all of the
deprotected cyclic trimers and tetramers displayed a 4C1
chair conformation with oxygen atoms of the sugar ring
located on the interior of the cavity and the secondary
hydroxyl groups outward. This would provide a hydro-
phobic internal cavity as in the case of cyclodextrines.
These information will be useful for further recognition
studies of these novel cyclic compounds.
Experimental Section
Conformational Analysis by Molecular Modeling. A
coarse drawing of the structure leads to a geometry that is
first improved using molecular mechanics technics (MM2)
implemented in ChemBats3D 5.0, and the resulting structure
is then optimized by the semiempirical Hamiltonian AM1 in
the GAMESS12 suite of programs. These programs were run
on RS/6000 System Regatta Power4 machines. To perform the
optimization, no symmetry constraint was imposed, allowing
the whole (3N-6) degrees of freedom. The minimum in energy
was obtained by minimizing the gradient norm using the
default (BFGS) algorithm. A search for other possible confor-
mations (for example in the amide link) leads to worse
energies, so the proposed conformations appear the best ones,
and the structures obtained show serendipitous symmetry.
Reduction of Azido Function (General Method A). To
a solution of azido-sugar (1 equiv) in freshly distilled THF (0.1
M) under an argon atmosphere were added water (11.1 equiv)
and triphenylphosphine (1.1 equiv), and the mixture was
stirred at room temperature for 24 h. Then, an additionnal
amount of PPh3 (0.11 equiv) was added, and the solution was
stirred for another 24 h. The solvent was removed, and the
residue was purified over silica gel (EtOAc, then 9:1 CH2Cl2/
MeOH) to afford the corresponding amino-sugar.
Reduction of Azido Function (General Method B). A
stirred solution of azido-sugar and Pd/C (10% w/w) in methanol
was hydrogenated under H2 atmosphere overnight. The mix-
ture was filtered over a Celite pad, washed with MeOH, and
evaporated to give the corresponding amino-sugar.
Amide Formation (General Method C). DEPC (1.5
equiv) and Et3N (3 equiv) were successively added, at 0 °C
under an argon atmosphere, to a stirred solution of amine (1
equiv) and acid (1 equiv) in DMF (73 mM). The solution was
allowed to warm to room temperature and stirred for 1-3 days.
Then, the mixture was partitioned in EtOAc/H2O (1:1), the
organic layer was washed with brine, and the aqueous layers
were combined and extracted with EtOAc (2×). The organic
layers were combined, dried (MgSO4), evaporated, and purified
over silica gel to give the corresponding amide.
a Reagents and conditions: (i) BH3‚THF, THF, reflux, 91%; (ii)
(1) BH3‚THF, THF, reflux, (2) AcCl, MeOH; 42% for 5; 68% for 6.
H2(pro-S) in an anti conformation in relation to H1′ and
H2(pro-R) pointing into the interior of the cavity. Con-
sequently, the diastereotopic proton resonating at lower
field (H2b, J1′,2b ) 9.7-11.7 Hz) can be assigned as a H2-
(pro-S). Otherwise, the C6′-C5′ bond prefers a positive
synclinal orientation (+sc), which makes the amide
protons slightly pointing into the ring, in parallel to H5′.
These last two points are different from the conforma-
tional behavior of the reported â-anomer of 2b, where
the most populated rotamer for both C2-C1′ and C6′-
C5′ adopts the -sc conformation.4b However, these two
anomeric cyclic trimers displayed a similar tripod bowl-
shaped structure. The estimated size of the internal
cavity is about 4.5 Å for 2b and 6.9 Å for 3b (by the
calculated average distance between two opposite closest
protons (H2pro-R)). So the cavity of cyclic tetramer 3b
is intermediate to that of R- and â-cyclodextrines (5.7 and
7.8 Å, respectively).
In amine-linked macrocycles 5b and 6b, the C6′-C5′
bond prefers also a positive synclinal orientation (+sc),
which makes the amine protons slightly pointing into the
ring as their amide analogues. The calculated average
distance between two opposite closest protons is about
4.2 Å for 5b and 6.7 Å for 6b.
Saponification (General Method D). LiOH‚H2O (1.5
equiv) was added to a solution of methyl ester (1 equiv) in a
mixture of THF/MeOH/H2O (1:1:1; 0.33 M). The solution was
stirred for 1-2 days at room temperature and then acidified
to pH 4 with HCl (10%). The mixture was extracted with
EtOAc, and the organic layer was washed with water and
brine, dried (MgSO4), and evaporated to give the corresponding
acid.
Oligomer Cyclization (General Method E). Cyclization
was realized in dilute DMF (2.2 mM) following the general
method C.
Debenzylation (General Method F). Pd/C and Pd black
(1:1, 10% w/w) were added to a solution of benzylated cyclic
oligomer in a mixture of MeOH/EtOAc (1:1). The resulting
Conclusions
We have accomplished the synthesis of three orthogo-
nally protected cyclic oligomers of pyranoid R-anomer of
sugar amino acids that constitute a new class of molec-
ular scaffolds. These molecules have been selectively and
J. Org. Chem, Vol. 70, No. 11, 2005 4427

Me´nand et al.
suspension was stirred under H2 atmosphere (1 atm) for 1-4
days. The mixture is filtered over a Celite pad, washed with
MeOH, and evaporated to give the corresponding debenzylated
cyclic oligomer.
Deprotection of the MOM Group (General Method G).
A solution of HCl (0.3 M) in MeOH was prepared by addition
of AcCl (213 µL, 3 mmol) to distilled MeOH (10 mL). To this
solution was added methoxymethylated oligomer (1 equiv HCl/
MOM), and the solution was heated at 50 °C overnight. After
evaporation, the mixture was diluted in EtOH and evaporated
to give the corresponding deprotected oligomer.
atmosphere. After 24 h of stirring, an additional amount of
methyl iodide (1.75 mL, 28.20 mmol) was added, and the
mixture was stirred for 48 h. The solvent was removed, and
the resulting residue was partitioned (EtOAc/H2O,1:1, 200 mL)
and extracted with EtOAc (2 × 50 mL). The combined extracts
were washed with brine, dried (MgSO4), evaporated, and
purified over silica gel (1:5 then 1:4 EtOAc/cyclohexane) to give
11 (3.01 g, 6.86 mmol, 49%) as a colorless oil: Rf 0.55 (2:3
1
EtOAc/cyclohexane), [R]D +46.6 (c 2, CH2Cl2); H NMR (250
MHz, CDCl3) δ 2.59 (d, J ) 7.4 Hz, 2H), 3.17 (s, 3H), 3.19 (s,
3H), 3.22-3.30 (m, 2H), 3.33 (t, J ) 8.5 Hz, 1H), 3.45 (t, J )
8.5 Hz, 1H), 3.56 (s, 3H), 3.57-3.67 (m, 1H), 3.65 (t, J ) 8.5
Hz, 1H), 4.39-4.47 (m, 1H), 4.43 (d, J ) 6.5 Hz, 1H), 4.47 (d,
J ) 6.8 Hz, 1H), 4.54 (d, J ) 11.7 Hz, 1H), 4.58 (d, J ) 6.8 Hz,
1H), 4.65 (d, J ) 11.7 Hz, 1H), 4.66 (d, J ) 6.5 Hz, 1H), 7.05-
7.24 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 32.6, 51.4, 52.0,
56.0, 56.3, 71.6, 72.2, 75.0, 76.5, 80.5, 97.2, 98.1, 127.7, 127.8,
128.4, 138.1, 171.4. Anal. Calcd for C20H29N3O8 (439.46): C,
54.66; H, 6.65; N, 9.56. Found: C, 54.82; H, 6.78; N, 9.26.
3-(6′-Azido-3′-O-benzyl-6′-deoxy-2′,4′-di-O-methoxy-
methyl-r-D-glucopyranosyl)-prop-1-ene (9). MeONa in
MeOH (1 M, 50 mL) was added to a solution of 86 (11.64 g,
28.21 mmol) in MeOH (250 mL), and the mixture was stirred
overnight. After acidification with HCl (10%) to pH 4, the
solvent was removed, the residue was partitioned (EtOAc/H2O,
1:1, 400 mL) and extracted (EtOAc, 2 × 100 mL), and the
combined organic layers were washed with brine, dried
(MgSO4), and evaporated. The resulting oil was diluted in DMF
(40 mL) and added dropwise to a cold (0 °C) suspension of
washed NaH (3.95 g, 98.70 mmol, 60% in oil) in DMF (90 mL)
under an argon atmosphere. The mixture was stirred for 1 h
and warmed to room temperature. Then, the methoxymethyl
chloride (7.50 mL, 98.70 mmol) was added dropwise, and the
solution was stirred at room temperature overnight. After
addition of methanol (20 mL), the solvent was evaporated, and
the resulting residue was partitioned (EtOAc/H2O, 1:1, 400
mL) and extracted with EtOAc (2 × 100 mL). The combined
extracts were washed with brine, dried (MgSO4), and evapo-
rated to give 9 (11.12 g, 97%) as a slightly yellow oil: Rf 0.43
(1:4 EtOAc/cyclohexane); [R]D +55.1 (c 2, CH2Cl2); 1H NMR
(250 MHz, CDCl3) δ 2.36-2.61 (m, 2H), 3.35 (s, 3H), 3.36 (s,
3H), 3.37-3.54 (m, 3H), 3.62-3.73 (m, 2H), 3.77 (dd, J ) 5.5,
8.9 Hz, 1H), 4.07-4.19 (m, 1H), 4.61 (d, J ) 6.5 Hz, 1H), 4.65
(d, J ) 6.8 Hz, 1H), 4.71 (d, J ) 11.1 Hz, 1H), 4.77 (d, J ) 6.8
Hz, 1H), 4.83 (d, J ) 11.1 Hz, 1H), 4.84 (d, J ) 6.5 Hz, 1H),
Methyl 2-(6′-Amino-3′-O-benzyl-6′-deoxy-2′,4′-di-O-meth-
oxymethyl-r-D-glucopyranosyl)-ethanoate (12). Com-
pound 11 (2.33 g, 5.31 mmol) was reduced using general
method A to give amine 12 (2.16 g, 98.5%) as a slightly yellow
1
oil: Rf 0.19 (9:1 CH2Cl2/MeOH), [R]D +68.0 (c 1, CH2Cl2); H
NMR (250 MHz, CDCl3) δ 1.79 (s, 2H), 2.68 (dd, J ) 15.2, 4.8
Hz, 1H), 2.78 (dd, J ) 15.2, 9.7 Hz, 1H), 2.89 (dd, J ) 15.0,
4.6 Hz, 1H), 2.95 (dd, J ) 15.0, 4.6 Hz, 1H), 3.35 (s, 6H), 3.45
(t, J ) 8.0 Hz, 1H), 3.55 (td, J ) 4.6, 8.0 Hz, 1H), 3.61 (t, J )
8.0 Hz, 1H), 3.70 (s, 3H), 3.75 (dd, J ) 8.0, 5.4 Hz, 1H), 4.54
(ddd, J ) 4.8, 9.7, 5.4 Hz, 1H), 4.57 (d, J ) 6.5 Hz, 1H), 4.62
(d, J ) 6.8 Hz, 1H), 4.69 (d, J ) 11.1 Hz, 1H), 4.73 (d, J ) 6.8
Hz, 1H), 4.79 (d, J ) 11.1 Hz, 1H), 4.86 (d, J ) 6.5 Hz, 1H),
7.23-7.39 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 32.8, 42.6,
52.0, 56.1, 56.3, 70.9, 73.7, 74.9, 75.9, 76.8, 80.6, 97.2, 98.0,
127.8, 128.5, 138.2, 171.9. Anal. Calcd for C20H31NO8 (413.46):
C, 58.10; H, 7.56; N, 3.39. Found: C, 57.89; H, 7.76; N, 3.28.
Synthesis of Azido Ester 13. Amine 12 (2.02 g, 4.88 mmol)
and acid 10 (2.07 g, 4.88 mmol) were coupled using general
method C and purified over silica gel (6:4 EtOAc/cyclohexane)
to give 13 (3.31 g, 83%) as a white solid: Rf 0.44 (6:4 EtOAc/
5.08-5.24 (m, 2H), 5.76-5.97 (m, 1H), 7.27-7.42 (m, 5H); 13
C
NMR (62.9 MHz, CDCl3) δ 30.4, 51.7, 56.0, 56.4, 71.3, 74.1,
75.1, 77.1, 77.9, 81.1, 97.5, 98.3, 117.3, 127.8, 128.5, 134.4,
138.3. Anal. Calcd for C20H29N3O6 (407.46): C, 58.95; H, 7.17;
N, 10.31. Found: C, 58.64; H, 7.28; N, 10.19.
1
cyclohexane), mp 114 °C, [R]D +62.9 (c 1, CH2Cl2); H NMR
(250 MHz, CDCl3) δ 2.57 (dd, J ) 16.3, 3.1 Hz, 1H), 2.56-
2.75 (m, 2H), 2.85 (dd, J ) 16.3, 10.5 Hz, 1H), 3.31 (s, 3H),
3.32 (s, 3H), 3.34 (s, 3H), 3.35 (s, 3H), 3.37-3.68 (m, 8H), 3.70
(s, 3H), 3.73-3.90 (m, 4H), 4.46 (ddd, J ) 10.5, 3.1, 3.1 Hz,
1H), 4.53-4.84 (m, 13H), 6.80-6.93 (m, 1H), 7.21-7.40 (m,
10H); 13C NMR (62.9 MHz, CDCl3) δ 33.7, 34.2, 38.7, 51.4, 52.0,
56.1, 56.2, 67.8, 71.3, 72.1, 73.0, 73.6, 75.2, 76.0, 76.4, 77.4,
80.0, 73.9, 74.7, 96.9, 97.1, 97.9, 127.8, 128.0, 128.4, 128.5,
137.7, 138.1, 170.1, 172.5. MS (MALDI) m/z 843.7 [M + Na]+.
(6′-Azido-3′-O-benzyl-6′-deoxy-2′,4′-di-O-methoxymethyl-
r-D-glucopyranosyl)-ethanoic Acid (10). Acetic acid (8 mL,
140.10 mmol) and aliquat 336 (490 mg) were added to a
solution of 9 (3 g, 7.37 mmol) in a mixture of CH2Cl2/H2O (1:
1; 75 mL). The reaction mixture was cooled to 0 °C, KMnO4
(4.314 g; 27.27 mmol) was added in two portions, and the
solution was allowed to warm to room temperature and stirred
for 24 h. After dilution in CH2Cl2 (100 mL), the excess of
KMnO4 was reduced with Na2SO3 (4.8 g). The aqueous layer
was extracted, and the combined organic layers were washed
with brine, dried (MgSO4), and evaporated. The resulting
residue was purified over silica gel (1:3 EtOAc/cyclohexane,
then 95:5 CH2Cl2/MeOH) to give 10 (2.16 g, 69%) as a colorless
Synthesis of Azido Acid 14. Ester 13 (1.63 g, 1.98 mmol)
was saponified using general method D to give acid 14 (1.49
g, 93%) as a white solid: Rf 0.47 (4:1 EtOAc/cyclohexane), mp
102 °C, [R]D +65.8 (c 1, CH2Cl2); 1H NMR (250 MHz, CDCl3) δ
2.48-2.75 (m, 2H), 2.61 (dd, J ) 15.5, 3.5 Hz, 1H), 2.84 (dd, J
) 15.5, 11.0 Hz, 1H), 3.29-3.91 (m, 12H), 3.33 (s, 3H), 3.34
(s, 3H), 3.35 (s, 3H), 3.37 (s, 3H), 3.43-3.84 (m, 14H), 6.78-
6.88 (m, 1H), 7.21-7.40 (m, 10H); 13C NMR (62.9 MHz, CDCl3)
δ 33.3, 34.2, 39.5, 51.3, 56.1, 56.2, 56.3, 56.4, 69.3, 71.5, 71.8,
72.3, 74.4, 74.7, 74.9, 75.9, 76.1, 77.0, 78.7, 79.8, 97.1, 97.19,
97.24, 97.8, 127.9, 128.6, 137.9, 138.1, 170.5, 174.2. MS
(MALDI): m/z 829.3 [M + Na]+.
1
oil: Rf 0.65 (9:1 CH2Cl2/MeOH), [R]D +60.1 (c 2, CH2Cl2); H
NMR (250 MHz, CDCl3) δ 2.78 (dd, J ) 15.5, 8.5 Hz, 1H), 2.84
(dd, J ) 15.5, 5.7 Hz, 1H), 3.37 (s, 3H), 3.39 (s, 3H), 3.42-
3.55 (m, 2H), 3.56 (t, J ) 8.2 Hz, 1H), 3.66 (t, J ) 8.2 Hz, 1H),
3.76-3.90 (m, 2H), 4.64 (d, J ) 6.5 Hz, 1H), 4.67 (d, J ) 6.8
Hz, 1H), 4.74 (d, J ) 11.3 Hz, 1H), 4.78 (d, J ) 6.8 Hz, 1H),
4.85 (d, J ) 11.3 Hz, 1H), 4.87 (d, J ) 6.5 Hz, 1H), 7.22-7.41
(m, 5H), 10.2 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 31.7, 51.2,
55.9, 56.2, 71.4, 72.1, 74.9, 76.3, 76.4, 80.4, 97.1, 98.0, 127.7,
128.4, 138.0, 176.2. Anal. Calcd for C19H27N3O8 (425.43): C,
53.64; H, 6.40; N, 9.88. Found: C, 53.88; H, 6.21; N, 9.67.
Synthesis of Cyclic Dimer 1. Compound 14 (706 mg,
0.876 mmol) was reduced using general method B, cyclized
using general method E, and purified over silica gel (1:1
EtOAc/CH2Cl2 then 9:1 CH2Cl2/MeOH) to give 1 (400 mg, 60%)
as a white solid: Rf 0.63 (9:1 CH2Cl2/MeOH), mp 266 °C, [R]D
Methyl (6′-Azido-3′-O-benzyl-6′-deoxy-2′,4′-di-O-meth-
oxymethyl-r-D-glucopyranosyl)-ethanoate (11). Com-
pound 9 (5.74 g, 14.099 mmol) was oxidized as described
previously to afford crude 10 (6.20 g). NaHCO3 (4.74 g, 56.40
mmol) and methyl iodide (3.51 mL, 56.40 mmol) were added
to the solution of 10 in DMF (22 mL) under an argon
1
+84.7 (c 1, CH2Cl2); H NMR (250 MHz, CDCl3) δ 2.62 (dd, J
) 17.3, 2.5 Hz, 2H), 2.76 (dd, J ) 17.3, 11.7 Hz, 2H), 2.99-
3.15 (m, 2H), 3.28-3.38 (m, 2H), 3.33 (s, 6H), 3.41 (s, 6H),
3.53-3.65 (m, 4H), 3.72 (dd, J ) 5.6, 8.9 Hz, 2H), 4.11-4.26
(m, 2H), 4.43 (ddd, J ) 2.5, 11.7, 5.6 Hz, 2H), 4.59 (d, J ) 6.8
4428 J. Org. Chem., Vol. 70, No. 11, 2005

Cyclic Homooligomers from Sugar Amino Acids
Hz, 2H), 4.60 (d, J ) 6.5 Hz, 2H), 4.68 (d, J ) 11.4 Hz, 2H),
4.74 (d, J ) 6.5 Hz, 2H), 4.78 (d, J ) 11.4 Hz, 2H), 4.87 (d, J
) 6.8 Hz, 2H), 6.83-6.95 (m, 2H), 7.22-7.40 (m, 10H); 13C
NMR (62.9 MHz, CDCl3) δ 32.3, 40.4, 56.2, 56.6, 71.3, 72.2,
75.3, 77.2, 77.3, 80.0, 97.7, 98.2, 127.9, 128.6, 138.1, 170.2. MS
(MALDI): m/z 785.6 [M + Na]+.
Synthesis of Cyclic Dimer 15. Compound 1 (50 mg, 0.066
mmol) was debenzylated with Pd/C and Pd black (1:1, 20%
w/w) in a MeOH/EtOAc/AcOH (1:1:0.4, 2.4 mL) mixture
according to general method F and purified over silica gel (95:5
CH2Cl2/MeOH) to give 15 (38 mg, 99%) as a white solid: Rf
0.25 (9:1 CH2Cl2/MeOH), mp 211 °C, [R]D +77.6 (c 1, CH2Cl2);
1H NMR (250 MHz, CDCl3) δ 2.57-2.80 (m, 4H), 2.91-3.05
(m, 2H), 3.14 (dd, J ) 8.3, 9.5 Hz, 2H), 3.39 (s, 6H), 3.45 (s,
6H), 4.48-4.76 (m, 6H), 4.10-4.23 (m, 2H), 4.40-4.51 (m, 2H),
4.672 (d, J ) 6.8 Hz, 2H), 4.674 (d, J ) 6.8 Hz, 2H), 4.79 (d,
J ) 6.8 Hz, 2H), 4.87 (d, J ) 6.8 Hz, 2H), 6.90-7.00 (m, 2H);
13C NMR (62.9 MHz, CDCl3) δ 31.7, 40.7, 56.0, 56.3, 70.2, 71.6,
72.1, 77.7, 81.4, 97.7, 98.0, 171.0. MS (MALDI): m/z 605.2 [M
+ Na]+.
EtOAc/CH2Cl2 then 9:1 CH2Cl2/MeOH) to give 2 (72 mg, 35%)
as a white solid: Rf 0.45 (9:1 CH2Cl2/MeOH), mp 226 °C, [R]D
1
+63.8 (c 1, CH2Cl2); H NMR (250 MHz, CDCl3) δ 2.57 (dd, J
) 15.4, 4.3 Hz, 3H), 2.68 (dd, J ) 15.4, 9.6 Hz, 3H), 3.32 (s,
9H), 3.35 (s, 9H), 3.36-3.49 (m, 6H), 3.64 (t, J ) 6.3 Hz, 3H),
3.70 (dd, J ) 4.0, 6.3 Hz, 3H), 3.78-3.88 (m, 6H), 4.47 (ddd, J
) 4.0, 4.3, 9.6 Hz, 3H), 4.58 (d, J ) 6.8 Hz, 3H), 4.63 (d, J )
11.4 Hz, 3H), 4.68 (d, J ) 6.8 Hz, 3H), 4.72 (d, J ) 6.5 Hz,
3H), 4.73 (d, J ) 11.4 Hz, 3H), 4.75 (d, J ) 6.5 Hz, 3H), 6.99-
7.09 (m, 3H), 7.21-7.40 (m, 15H); 13C NMR (62.9 MHz, CDCl3)
δ 35.1, 39.2, 56.0, 56.2, 69.2, 72.4, 74.1, 74.8, 75.7, 78.5, 97.2,
97.3, 127.90, 127.94, 128.5, 137.9, 170.8. MS(MALDI): m/z
1166.9 [M + Na]+.
Synthesis of Tetramer 20. Compound 18 (383 mg, 0.467
mmol) and compound 14 (395 mg, 0.490 mmol) were coupled
using general method C and purified over silica gel (9:1 CH2-
Cl2/MeOH) to give 20 (739 mg, 100%) as a white solid: Rf 0.11
(9:1 CH2Cl2/MeOH), mp 171 °C, [R]D +56.9 (c 1.35, CH2Cl2);
1H NMR (250 MHz, CDCl3) δ 2.32-2.94 (m, 8H), 3.21-3.92
(m, 52 H), 4.33-4.85 (m, 27H), 6.74-6.91 (m, 1H), 7.13-7.42
(m, 22H); 13C NMR (62.9 MHz, CDCl3) δ 32.1, 33.4, 33.8, 35.0,
38.69, 38.72, 38.8, 40.1, 51.3, 51.9, 55.90, 55.92, 55.93, 56.03,
56.04, 56.08, 56.11, 56.19, 59.61, 67.99, 71.09, 71.45, 71.83,
72.07, 72.55, 72.61, 72.65, 72.66, 73.60, 73.72, 73.87, 76.09,
76.12, 76.29, 76.41, 77.24, 79.83, 80.66, 96.57, 96.67, 96.70,
96.85, 96.88, 97.01, 97.55, 97.82, 97.99, 127.61, 127.69, 127.71,
127.78, 127.79, 127.87, 127.97, 128.37, 128.42, 128.46, 128.47,
128.51, 137.60, 137.66, 137.85, 137.91, 138.27, 170.23, 170.62,
170.93, 172.47. MS (MALDI): m/z 1606.1 [M + Na]+.
Synthesis of Cyclic Dimer 16. Compound 1 (50 mg, 0.066
mmol) was deprotected using general method G to give 16 (38
mg, 98%) as a pale yellow solid: Rf 0.64 (1:1 acetone/MeOH),
1
mp 131 °C (decomp), [R]D +73.5 (c 1, MeOH); H NMR (250
MHz, CD3OD) δ 2.54 (dd, J ) 15.6, 2.7 Hz, 2H), 2.72 (dd, J )
15.6, 12.2 Hz, 2H), 3.24-3.38 (m, 4H), 3.44 (t, J ) 8.5 Hz,
2H), 3.55-3.73 (m, 4H), 3.76 (dd, J ) 5.7, 8.7 Hz, 2H), 4.34
(ddd, J ) 2.7, 12.2, 5.7 Hz, 2H), 4.85 (s, 4H), 7.21-7.37 (m,
6H), 7.38-7.47 (m, 4H); 13C NMR (62.9 MHz, CD3OD) δ 33.2,
42.1, 71.8, 73.5, 73.7, 74.2, 75.8, 82.7, 128.5, 129.1, 129.2, 140.3,
173.4. MS (MALDI): m/z 609.3 [M + Na]+.
Synthesis of Cyclic Tetramer 3. Compound 20 (364 mg,
0.230 mmol) was saponified (method F), reduced (method B),
then cyclized (method E), and purified over silica gel (1:1
EtOAc/CH2Cl2 then 9:1 CH2Cl2/MeOH) to give 3 (218 mg, 62%)
as a white solid: Rf 0.13 (95:5 CH2Cl2/MeOH), mp 183 °C, [R]D
Synthesis of Cyclic Dimer 17. Compound 16 (20 mg,
0.034 mmol) was deprotected using general method F and
purified by precipitation in a MeOH/acetone mixture and
centrifugation (2×), giving 17 (10 mg, 74%) as a pale yellow
solid: Rf 0.35 (1:1 acetone/MeOH), mp 192 °C, [R]D +57.3 (c
1
+57.0 (c 1, CH2Cl2); H NMR (250 MHz, CDCl3) δ 2.51 (dd, J
) 15.4, 1.8 Hz, 4H), 2.79 (dd, J ) 15.4, 11.7 Hz, 4H), 3.14-
3.32 (m, 4H), 3.33 (s, 12H), 3.34 (s, 12H), 3.36-3.44 (m, 4H),
3.64 (t, J ) 7.1 Hz, 4H), 3.75 (dd, J ) 4.6, 7.1 Hz, 4H), 3.79-
3.92 (m, 4H), 3.93-4.09 (m, 4H), 4.50-4.85 (m, 28H), 6.87-
7.03 (m, 4H), 7.19-7.40 (m, 20H); 13C NMR (62.9 MHz, CDCl3)
δ 33.9, 40.3, 56.1, 56.3, 69.9, 71.3, 74.2, 76.0, 76.4, 79.0, 97.0,
97.3, 127.7, 127.8, 128.5, 138.1, 170.9. MS (MALDI): m/z
1547.9 [M + Na]+.
1
0.7, MeOH); H NMR (250 MHz, D2O) δ 2.54 (dd, J ) 15.5,
3.1 Hz, 2H), 2.72 (dd, J ) 15.5, 12.4 Hz, 2H), 3.19 (t, J ) 9.1
Hz, 2H), 3.36-3.64 (m, 8H), 3.72 (dd, J ) 6.1, 10.2 Hz, 2H),
4.36 (ddd, J ) 3.1, 12.4, 6.1 Hz, 2H); 13C NMR (62.9 MHz,
D2O) δ 32.3, 41.4, 70.8, 70.6, 72.9, 73.3, 73.7, 174.2. MS
(MALDI): m/z 429.1 [M + Na]+.
Synthesis of Amino Ester 18. Azido ester 13 (1.28 g, 1.56
mmol) was reduced using general method A to give 18 (1.02
g, 82%) as a white solid: Rf 0.33 (9:1 CH2Cl2/MeOH), mp 200
°C, [R]D +68.0 (c 1, CH2Cl2); 1H NMR (250 MHz, CDCl3) δ 1.86
(s, 2H), 2.55 (dd, J ) 15.4, 3.4 Hz, 1H), 2.60 (dd, J ) 16.1, 3.7
Hz, 1H), 2.69 (dd, J ) 15.4, 10.6 Hz, 1H), 2.82 (dd, J ) 16.1,
10.3 Hz, 1H), 2.85-3.01 (m, 2H), 3.33 (s, 3H), 3.34 (s, 3H),
3.35 (s, 3H), 3.36 (s, 3H), 3.39-3.49 (m, 3H), 3.71 (s, 3H), 3.56-
3.80 (m, 7H), 4.42-4.57 (m, 2H), 3.55-3.86 (m, 12H), 6.91-
7.04 (m, 1H), 7.27-7.37 (m, 10H); 13C NMR (62.9 MHz, CDCl3)
δ 33.7, 34.3, 39.0, 42.4, 52.1, 56.2, 56.3, 68.4, 70.6, 74.1, 74.7,
72.9, 73.6, 74.0, 75.5, 75.7, 76.6, 77.8, 80.1, 97.0, 97.7, 127.9,
128.0, 128.6, 137.8, 138.2, 170.7, 172.5. MS (MALDI): m/z
795.6 [M + H]+, 817.6 [M + Na]+.
Synthesis of Trimer 19. Compound 18 (642 mg, 0.809
mmol) and compound 10 (344 mg, 0.809 mmol) were coupled
using general method C and purified over silica gel (8:2 EtOAc/
cyclohexane) to give 19 (514 mg, 53%) as a white solid: Rf 0.35
(8:2 EtOAc/cyclohexane), mp 131 °C, [R]D +57.8 (c 1, CH2Cl2);
1H NMR (250 MHz, CDCl3) δ 2.40-2.95 (m, 6H), 3.13-3.97
(m, 40 H), 4.35-4.91 (m, 20H), 6.75-6.89 (m, 1H, NH), 7.09-
7.39 (m, 16H); 13C NMR (62.9 MHz, CDCl3) δ 33.6, 34.0, 35.3,
38.6, 38.8, 51.4, 52.0, 56.0, 56.1, 56.2, 56.3, 67.8, 67.9, 71.5,
71.9, 72.8, 72.9, 73.4, 73.7, 73.8, 74.0, 74.8, 75.2, 76.1, 76.4,
77.3, 80.6, 96.7, 96.9, 97.0, 97.9, 127.67, 127.71, 127.80, 127.83,
127.9, 128.0, 128.4, 128.5, 137.7, 137.8, 138.3, 170.2, 170.8,
172.5. MS (MALDI): m/z 1224.8 [M + Na]+.
Synthesis of Cyclic Tetramer 21. Compound 3 (20 mg,
0.013 mmol) was debenzylated using the general method F
and purified over silica gel (95:5 CH2Cl2/MeOH) to give 21 (9
mg, 59%) as a white solid: Rf 0.31 (9:1 CH2Cl2/MeOH), mp
120 °C, [R]D +51.2 (c 0.6, CH2Cl2); 1H NMR (250 MHz, CDCl3)
δ 2.52 (dd, J ) 15.3, 2.9 Hz, 4H), 2.67 (dd, J ) 15.3, 12.2 Hz,
4H), 2.89-3.04 (m, 4H), 3.19 (t, J ) 8.9 Hz, 4H), 3.42 (s, 12H),
3.46 (s, 12H), 3.65 (dd, J ) 5.8, 8.9 Hz, 4H), 3.69-3.81 (m,
4H), 3.83 (t, J ) 8.9 Hz, 4H), 3.91-4.04 (m, 4H), 4.42-4.56
(m, 4H), 4.68 (d, J ) 6.8 Hz, 4H), 4.71 (d, J ) 6.8 Hz, 4H),
4.80 (d, J ) 6.8 Hz, 4H), 4.83 (d, J ) 6.8 Hz, 4H), 6.93-7.06
(m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 32.4, 41.6, 56.0, 56.3,
69.8, 71.3, 72.1, 78.0, 81.9, 97.4, 98.2, 170.9. MS (MALDI): m/z
1187.6 [M + Na]+.
Synthesis of Cyclic Dimer 4. BH3‚THF (1.5 M in THF,
1.05 mL, 1.572 mmol) was added to a solution of compound 1
(40 mg, 0.0525 mmol) in distilled THF (4 mL), and the mixture
was heated at 66 °C overnight. A few drops of EtOH were
added after cooling the solution, then the solvent was removed,
and the residue diluted in EtOH (4 mL) and refluxed for 48 h.
After evaporation, the residue was partitioned in a CH2Cl2/
NaOH (1 M in H2O) mixture. The aqueous layer was extracted
with CH2Cl2 (2×), and the combined organic layers were dried
(MgSO4) and evaporated to give 4 (35 mg, 91%) as a colorless
oil: Rf 0.26 (95:5:1 CH2Cl2/MeOH/Et3N), [R]D +60.1 (c 0.1, CH2-
1
Cl2); H NMR (250 MHz, CDCl3) δ 1.77-1.84 (m, 2H), 2.01-
Synthesis of Cyclic Trimer 2. Compound 19 (216 mg,
0.180 mmol) was saponified (method F), reduced (method B),
then cyclized (method E), and purified over silica gel (1:1
2.27 (m, 2H), 2.56-5.82 (m, 4H), 2.98-3.19 (m, 4H), 3.25 (t, J
) 8.2 Hz, 2H), 3.32 (s, 6H), 3.35 (s, 6H), 3.58-3.73 (m, 4H),
3.84-4.02 (m, 2H), 4.07-4.22 (m, 2H), 4.58 (d, J ) 6.8 Hz,
J. Org. Chem, Vol. 70, No. 11, 2005 4429

Me´nand et al.
2H), 4.61 (d, J ) 6.8 Hz, 2H), 4.68 (d, J ) 11.1 Hz, 2H), 4.74
(d, J ) 6.5 Hz, 2H), 4.78 (d, J ) 11.1 Hz, 2H), 4.83 (d, J ) 6.5
Hz, 2H), 7.21-7.40 (m, 10H); 13C NMR (62.9 MHz, CDCl3) δ
23.9, 48.6, 51.6, 55.9, 56.4, 70.1, 75.2, 75.5, 78.1 (2 × C), 80.9,
97.4, 98.0, 127.8, 128.5, 138.3. MS (MALDI): m/z 735.2 [M +
H]+, 757.2 [M + Na]+.
Synthesis of Cyclic Tetramer 6. Compound 3 (20 mg,
0.013 mmol) in distilled THF (2 mL) was reduced with BH3‚
THF (1.5 M in THF, 525 µL, 0.787 mmol) as described
previously. Subsequent deprotection with AcCl/MeOH (method
G) afforded 6 (10 mg, 68%) as a white solid: Rf 0.07 (8:2 CH2-
Cl2/MeOH), mp 157 °C, [R]D +39.0 (c 0.6, MeOH); 1H NMR
(250 MHz, CD3OD) δ 2.00-2.46 (m, 8H), 3.14-3.39 (m, 12H),
3.45 (t, J ) 8.5 Hz, 4H), 3.47-3.59 (m, 4H), 3.67 (t, J ) 8.5
Hz, 4H), 3.79 (dd, J ) 5.1, 8.5 Hz, 4H), 3.98-4.10 (m, 4H),
4.10-4.24 (m, 4H), 4.80-4.89 (m, 8H), 7.32-7.51 (m, 20H);
13C NMR (62.9 MHz, CD3OD) δ 22.9, 46.2, 50.2, 69.7, 70.8,
72.4, 74.0, 76.0, 81.1, 129.4, 129.5, 129.7, 138.4. MS (MAL-
DI): m/z 1117.6 [M + H]+, 1139.5 [M + Na]+.
Synthesis of Cyclic Trimer 5. Compound 2 (23 mg, 0.02
mmol) in distilled THF (1.5 mL) was treated with BH3‚THF
(1.5 M in THF, 670 µL, 1.01 mmol) as described previously.
Subsequent deprotection with AcCl/MeOH (method G) and
purification over silica gel (8:2 CH2Cl2/MeOH) afforded 5 (7
mg, 42%) as a slightly yellow solid: Rf 0.30 (8:2 CH2Cl2/MeOH),
mp 163 °C, [R]D +42.7 (c 0.7, MeOH); 1H NMR (250 MHz, CD3-
OD) δ 2.06-2.30 (m, 6H), 3.05-3.42 (m, 12H), 3.46 (t, J ) 6.8
Hz, 3H), 3.57 (t, J ) 6.8 Hz, 3H), 3.76 (dd, J ) 4.3, 6.8 Hz,
Supporting Information Available: General methods
and 1H and 13C NMR spectra of all the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
3H), 3.99-4.23 (m, 6H), 4.81 (s, 6H), 7.21-7.48 (m, 15H); 13
C
NMR (62.9 MHz, CD3OD) δ 24.7, 46.9, 49.6, 71.1, 72.1, 72.8,
73.3, 75.1, 81.2, 128.7, 129.1, 129.3, 139.9. MS (MALDI): m/z
838.3 [M + H]+, 860.3 [M + Na]+.
JO0502899
4430 J. Org. Chem., Vol. 70, No. 11, 2005