Cyclic homooligomers of furanoid sugar amino acids

Article abstract of DOI:10.1021/jo034586u

Cyclic homooligomers of mannose-derived furanoid sugar amino acid 1 [H-Maa(Bn₂)-OH] were synthesized by using BOP reagent in the presence of DIPEA under dilute conditions that converted the sugar amino acid monomer directly into its cyclic homooligomers 3a and 4a. The glucose-based sugar amino acid 2 [H-Gaa(Bn₂)-OH] under the same reaction conditions gave a bicyclic lactam 5a as the major product. Cyclic homooligomers of 2 were prepared by cyclizing their linear precursors 6 and 7 leading to the formation of cyclic peptides 8a and 9a, respectively. Conformational analysis by NMR and constrained MD studies revealed that all the cyclic products, 3, 4, 8, and 9, had symmetrical structures. The deprotected cyclic trimer of Maa 3b displayed a conformation in which all the C=O and the N-H bonds of the molecule point in opposite directions. In the deprotected cyclic tetramer of Maa 4b, the COs and NHs were in the plane of the ring with the former pointing to outside and the latter inside the ring. The structure of the cyclic Gaa dimer 8b displayed an unusual six-membered intramolecular hydrogen bond between NH_i → C3-O_i-1 and a syn orientation between the C2-H and CO. In this molecule, the C2-hydrogens and the COs can be seen on one side of the ring while the NHs point to the other side. Addition of the bicyclic lactam 5b resulted in the influx of Na⁺ ions across the lipid bilayer leading to the dissipation of valinomycin-mediated K⁺ diffusion potential.

Full text of DOI:10.1021/jo034586u

Cyclic Hom ooligom er s of F u r a n oid Su ga r Am in o Acid s
T. K. Chakraborty,*,† P. Srinivasu,† E. Bikshapathy,‡ R. Nagaraj,‡ M. Vairamani,†
S. Kiran Kumar,† and A. C. Kunwar*,†
Indian Institute of Chemical Technology and Centre for Cellular and Molecular Biology,
Hyderabad-500 007, India
chakraborty@iict.ap.nic.in
Received May 6, 2003
Cyclic homooligomers of mannose-derived furanoid sugar amino acid 1 [H-Maa(Bn2)-OH] were
synthesized by using BOP reagent in the presence of DIPEA under dilute conditions that converted
the sugar amino acid monomer directly into its cyclic homooligomers 3a and 4a . The glucose-based
sugar amino acid 2 [H-Gaa(Bn2)-OH] under the same reaction conditions gave a bicyclic lactam 5a
as the major product. Cyclic homooligomers of 2 were prepared by cyclizing their linear precursors
6 and 7 leading to the formation of cyclic peptides 8a and 9a , respectively. Conformational analysis
by NMR and constrained MD studies revealed that all the cyclic products, 3, 4, 8, and 9, had
symmetrical structures. The deprotected cyclic trimer of Maa 3b displayed a conformation in which
all the CdO and the N-H bonds of the molecule point in opposite directions. In the deprotected
cyclic tetramer of Maa 4b, the COs and NHs were in the plane of the ring with the former pointing
to outside and the latter inside the ring. The structure of the cyclic Gaa dimer 8b displayed an
unusual six-membered intramolecular hydrogen bond between NHi f C3-Oi-1 and a syn orientation
between the C2-H and CO. In this molecule, the C2-hydrogens and the COs can be seen on one
side of the ring while the NHs point to the other side. Addition of the bicyclic lactam 5b resulted
in the influx of Na+ ions across the lipid bilayer leading to the dissipation of valinomycin-mediated
K+ diffusion potential.
In tr od u ction
used method to constrain their conformational degrees
of freedom and induce desirable structural biases es-
sential for their biological activities, such as tubular
structures for transporting ions or molecules across
membranes.3 It was envisaged that the cyclic homooli-
gomers of sugar amino acids with structurally rigid
molecular scaffolds could be moulded to build predisposed
cavities of precise dimensions providing attractive tools
to study diverse molecular recognition processes.4 Herein
we describe the synthesis and conformational studies of
the cyclic homooligomers of mannose-derived furanoid
sugar amino acid 1 and its glucose-based congener 2.
Sugar amino acids have emerged as versatile templates
that have been used extensively in recent years as
conformationally constrained scaffolds in many peptido-
mimetic studies and as an important class of synthetic
monomers leading to many de novo oligomeric libraries.1
As part of our ongoing project on sugar amino acid based
molecular designs, we were interested in synthesizing
cyclic homooligomers2 of furanoid sugar amino acids.
Cyclization of linear peptides or covalent bridging of their
constituent amino acids at appropriate places is a widely
† Indian Institute of Chemical Technology.
(3) For leading references on cyclic peptide based tubular structures
and ion channels see: (a) Sa´nchez-Quesada, J .; Isler, M. P.; Ghadiri,
M. R. J . Am. Chem. Soc. 2002, 124, 10004. (b) Semetey, V.; Didierjean,
C.; Briand, J .-P.; Aubry, A.; Guichard, G. Angew. Chem., Int. Ed. 2002,
41, 1895. (c) Gauthier, D.; Baillargeon, P.; Drouin, M.; Dory, Y. L.
Angew. Chem., Int. Ed. 2001, 40, 4635. (d) Ishida, H.; Qi, Z.; Sokabe,
M.; Donowaki, K.; Inoue, Y. J . Org. Chem. 2001, 66, 2978. (e) Bong,
D. T.; Clark, T. D.; Granja, J . R.; Ghadiri, M. R. Angew. Chem., Int.
Ed. 2001, 40, 988. (f) Gademann, K.; Seebach, D. Helv. Chim. Acta
2001, 84, 2924 and the references therein. (g) Ranganathan, D.;
Lakshmi, C.; Karle, I. J . Am. Chem. Soc. 1999, 121, 6103. (h)
Eisenberg, B. Acc. Chem. Res. 1998, 31, 117. (i) Voyer, N. Top. Curr.
Chem. 1996, 184, 1-37. (j) Gokel, G. W.; Murillo, O. Acc. Chem. Res.
1996, 29, 425. (k) Ghadiri, M. R.; Granja, J . R.; Buehler, L. K. Nature
1994, 369, 301.
(4) For some recent works see: (a) Kubik, S.; Goddard, R. Eur. J .
Org. Chem. 2001, 311. (b) Choi, K.; Hamilton, A. D. J . Am. Chem. Soc.
2001, 123, 2456. (c) Cho, C. Y.; Youngquist, R. S.; Paikoff, S. J .;
Beresini, M. H.; Hebert, A. R.; Berleau, L. T.; Liu, C. W.; Wemmer, D.
E.; Keough, T.; Schultz, P. G. J . Am. Chem. Soc. 1998, 120, 7706. (d)
Ranganathan, D.; Haridas, V.; Karle, I. L. J . Am. Chem. Soc. 1998,
120, 2695. (e) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248 and
the references therein.
‡ Centre for Cellular and Molecular Biology.
(1) For recent reviews see: (a) Gruner, S. A. W.; Locardi, E.; Lohof,
E.; Kessler, H. Chem. Rev. 2002, 102, 491. (b) Chakraborty, T. K.;
Ghosh, S.; J ayaprakash, S. Curr. Med. Chem. 2002, 9, 421. (c)
Chakraborty, T. K.; J ayaprakash, S. ;Ghosh, S. Comb. Chem. High
Throughput Screening 2002, 5, 373. (d) Schweizer, F. Angew. Chem.,
Int. Ed. 2002, 41, 230. (e) Peri, F.; Cipolla, L.; Forni, E.; La Ferla, B.;
Nicotra, F. Chemtracts Org. Chem. 2001, 14, 481.
(2) For some important earlier works on cyclic oligomers and
homooligomers of sugar amino acids and related compounds see: (a)
Sto¨ckle, M.; Voll, G.; Gu¨nther, R.; Lohof, E.; Locardi, E.; Gruner, S.;
Kessler, H. Org. Lett. 2002, 4, 2501. (b) Campbell, J . E.; Englund, E.
E.; Burke, S. D. Org. Lett. 2002, 4, 2273. (c) Gruner, S. A. W.; Truffault,
V.; Voll, G.; Locardi, E.; Sto¨ckle, M.; Kessler, H. Chem. Eur. J . 2002,
8, 4365. (d) Locardi, E.; Sto¨ckle, M.; Gruner, S.; Kessler, H. J . Am.
Chem. Soc. 2001, 123, 8189. (e) Gruner, S. A. W.; Ke´ri, G.; Schwab,
R.; Venetainer, A.; Kessler, H. Org. Lett. 2001, 3, 3723. (f) Well, R. M.
van; Overkleeft, H. S.; Overhand, M.; Carstenen, E. V.; Narel, G. A.
van der; Boom, J . H. van Tetrahedron Lett. 2000, 41, 9331. (g) Lohof,
E.; Planker, E.; Mang, C.; Burkhart, F.; Dechantsreiter, M. A.;
Haubner, R.; Wester, H.-J .; Schwaiger, M.; Ho¨lzemann, G.; Goodman,
S. L.; Kessler, H. Angew. Chem., Int. Ed. 2000, 39, 2761.
10.1021/jo034586u CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003
J . Org. Chem. 2003, 68, 6257-6263
6257

Chakraborty et al.
SCHEME 1a
SCHEME 2 a
a
Reagents and conditions: (i) BOP reagent, DIPEA, DMF, 0
°C, 7 h; (ii) H2, Pd(OH)2-C, MeOH, rt, 24 h.
product during the synthesis of Boc-Gaa(Bn2)-OH6,7 and
a debenzylated version of the same by Fleet, who also
reported the synthesis of similar bicyclic lactams from
different furanoid sugar amino acids.8 Formation of other
products from 2, especially the expected cyclic oligomers
or any linear oligomer, although not isolated, was neg-
ligible as revealed by the hplc analysis of the crude
reaction mixture after aqueous workup.
The requisite cyclic homooligomers, however, could be
synthesized from their linear precursors (Scheme 2). The
linear dimer 6 and tetramer 7 of H-Gaa(Bn2)-OH were
prepared by conventional solution phase peptide synthe-
sis methods, using 1-ethyl-3-(3-(dimethylamino)propyl)-
carbodiimide hydrochloride (EDCI) and 1-hydroxyben-
zotriazole (HOBt) as coupling agents and dry CH2Cl2 as
solvent. While the tert-butoxycarbonyl (Boc) group was
used for N-protection, the C-terminal was protected as a
methyl ester (OMe). Deprotection of the former was done
in TFA-CH2Cl2 and saponification of the later was
performed with LiOH in THF-MeOH-H2O. Reactions
of 6 and 7 with BOP reagent in the presence of DIPEA
under the conditions described above furnished the
cyclized products 8a in 56% yield and 9a in 52% yield,
respectively, as the major products.
a
Reagents and conditions: (i) BOP reagent, DIPEA, DMF, 0
°C, 7 h; (ii) H2, Pd(OH)2-C, MeOH, rt, 24 h.
Resu lts a n d Discu ssion s
Syn t h esis of t h e Cyclic H om ooligom er s. The
method that we planned to use for the synthesis of these
cyclic peptides is based on a reaction (Scheme 1) used
earlier by us and others,5 which was expected to convert
the sugar amino acid monomers directly into their cyclic
homooligomers, thus avoiding lengthy stepwise assem-
bling of linear precursors, the process conventionally
followed for synthesizing similar cyclic homooligomers.2
Accordingly, the TFA-salt of H-Maa(Bn2)-OH 1,6 dis-
solved in DMF (10-2 M), was treated with benzotriazol-
1-yloxytris(dimethylamino)phosphonium hexafluorophos-
phate (BOP reagent) at 0 °C, followed by the slow
addition of N,N-diisopropylethylamine (DIPEA). After
aqueous workup and chromatographic purification, the
Bn-protected cyclic products 3a and 4a were isolated in
31% and 12% yields, respectively. Mass spectrometric
analysis revealed that 3a was the cyclic trimer of
H-Maa(Bn2)-OH and 4a was its tetrameric homologue.
Although not isolated, formation of other cyclic and/or
linear oligomers in small quantities is not ruled out.
Finally, the Bn-protections of all the products were
removed by Pd-catalyzed hydrogenation to furnish the
corresponding debenzylated compounds 3b-5b, 8b, and
9b in quantitative yields.
Mass spectrometric analysis was used to characterize
all the products. It is interesting to note here that the
ESI9 mass spectra of some of these products showed not
only the expected [M + H]+ peaks, but also signals of
dimeric [2M + H]+ or even higher order aggregates that
were found to be concentration dependent. In such cases,
the molecular weights were confirmed by matching the
peak shapes to calculated isotopic distribution patterns.
Con for m ation al An alysis: NMR Stu dies. The NMR
Next, it was decided to carry out the cyclohomooligo-
merization of the gluconic congener 2. To our surprise,
compound 2, when subjected to the same oligomerizartion
reaction under identical conditions as described above,
furnished an intramolecularly cyclized bicyclic lactam 5a
as the major product in 75% yield. The N-Boc derivative
of compound 5a was isolated earlier by us as a side
1
spectra (both H and 13C) of the protected as well as the
deprotected cyclic products displayed symmetric struc-
tures with only one set of resonances from their constitu-
(7) Chakraborty, T. K.; J ayaprakash, S.; Diwan, P. V.; Nagaraj, R.;
J ampani, S. R. B.; Kunwar, A. C. J . Am. Chem. Soc. 1998, 120, 12962.
(8) (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. (b) Long, D. D.; Stetz, R. J . E.; Nash, R. J .; Marquess, D. G.;
Lloyd, J . D.; Winters, A. L.; Asano, N.; Fleet, G. W. J . J . Chem. Soc.,
Perkin Trans. 1 1999, 901. (c) Smith, M. D.; Long, D. D.; Marquess,
D. G.; Claridge, T. D. W.; Fleet, G. W. J . Chem. Commun. 1998, 2039.
(9) (a) Bruins, A. P.; Covey, T. R.; Henion, J . D. Anal. Chem. 1987,
59, 2642. (b) Iribane, J . V.; Thomson, B. A. J . Chem. Phys. 1976, 64,
2287.
(5) (a) Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002, 43,
6335. (b) Chakraborty, T. K.; Tapadar, S.; Kumar, S. K. Tetrahedron
Lett. 2002, 43, 1317. (c) Somogyi, L.; Haberhauer, G. H.; Rebek, J ., J r.
Tetrahedron 2001, 57, 1699. (d) Singh, Y.; Sokolenko, N.; Kelso, M. J .;
Gahan, L. R.; Abbenante, G.; Fairlie, D. P. J . Am. Chem. Soc. 2001,
123, 333. (e) Blake, A. R.; Hannam, J . S.; J olliffe, K. A.; Pattenden, G.
Synlett 2000, 1515.
(6) Chakraborty, T. K.; Ghosh, S.; J ayaprakash, S.; Sarma, J . A. R.
P.; Ravikanth, V.; Diwan, P. V.; Nagaraj, R.; Kunwar, A. C. J . Org.
Chem. 2000, 65, 6441.
6258 J . Org. Chem., Vol. 68, No. 16, 2003

Cyclic Homooligomers of Furanoid Sugar Amino Acids
TABLE 1. 1H Ch em ica l Sh ifts (δ in p p m ) a n d Cou p lin g Con sta n ts (J in Hz) of Cyclic P ep tid es 3b, 4b, 8b, a n d 9b
protons
3b
4b
8b
9b
NH
8.36 (dd) (1.8, 7.5)
4.07 (d) (4.3)
4.09 (ddd) (4.3, 4.5, 5.2)
5.56 (d) (5.2)
3.53 (dd) (4.5, 5.4)
5.40 (d) (5.4)
3.53 (t) (6.5)
7.62 (dd) (5.2, 5.9)
4.11 (d) (3.2)
4.10 (ddd) (3.2, 3.9, 4.0)
5.50 (d) (4.0)
3.67 (ddd) (3.4, 3.9, 4.2)
5.24 (d) (4.2)
3.97 (dt) (3.4, 9.4)
3.33 (ddd) (3.4, 5.9, 13.8)
3.24 (ddd) (5.2, 9.4, 13.8)
8.11 (dd) (3.4, 8.0)
4.31 (d) (7.9)
4.15 (t) (7.9)
5.72 (s) (-)
3.56 (ddd) (5.0, 7.9, 7.5)
5.39 (d) (5.0)
3.78 (dd) (4.1, 7.5)
3.68 (dd) (8.0, 14.3)
3.17 (ddd) (3.4, 4.1, 14.3)
8.09 (t) (6.6)
4.31 (d) (3.9)
4.01 (ddd) (1.4, 3.9, 4.6)
5.28 (d) (4.6)
3.87 (ddd) (1.4, 1.6, 4.3)
5.30 (d) (4.3)
C2-H
C3-H
C3-OH
C4-H
C4-OH
C5-H
C6-H
C6-H′
3.82 (m) (-)
3.73 (dd) (7.5, 13.7)
2.89 (ddd) (1.8, 6.5, 13.7)
3.57 (m) (-)
3.25 (m) (-)
F IGURE 2. Schematic representation of the three possible
rotamers about the C5-C6 bond: negative synclinal (-sc),
antiperiplanar (ap), and positive synclinal (+sc).
F IGURE 1. Schematic representation of the long-range rOes
used as constraints in the MD studies of the deprotected cyclic
trimer 3b (A) and tetramer 4b (B) of Maa and cyclic dimer 8b
of Gaa (C).
The long-range distance restraints derived from the
ROESY cross-peaks of 3b in DMSO-d6 (A in Figure 1)
were used in the MD calculations. The MD studies were
carried out by using the Simulated Annealing protocol
for 50 cycles, each of 6 ps period with a total duration of
300 ps, and 25 structures were collected at regular
intervals after every two cycles. The structures were
subsequently energy minimized and superimposed align-
ing their backbones. Out of the 25 structures sampled
during the 300-ps MD simulations, 5 structures that
deviated considerably from the rest of them during
backbone alignment were not included in the ensemble
of the superimposed structures displayed in Figure 3.
These structures clearly reveal that C2-H and CO are
placed on one side of the ring while the NHs point to the
other side.
ent sugar residues in all the solvents they were studied.
The NMR spectra of 3b, 4b, 8b, and 9b in DMSO-d6 were
well-resolved and most of the spectral parameters could
be obtained easily and are reported in the Table 1. While
the assignments were carried out with the help of total
correlation spectroscopy (TOCSY), rotating frame nuclear
Overhauser effect spectroscopy (ROESY) experiments
provided the information on the proximity of protons, the
details of which are provided in the Experimental Sec-
tion. Variable-temperature studies were carried out to
measure the temperature coefficients (∆δ/∆T) of the
amide proton chemical shifts that were used to determine
their involvements in intramolecular hydrogen bonds.
The cross-peak intensities in the ROESY spectra, shown
schematically in Figure 1, were used for obtaining the
restraints in the simulated molecular dynamics (MD)
calculations, the detailed protocol of which is included
in the Experimental Section.
Con for m a tion a l An a lysis of 4b. Mannose based
sugar amino acid cyclic tetramer 4b is a 24-membered
macrocyclic peptide. The vicinal coupling constants of the
3
3
amide proton, J NH-H6 ) 5.9 Hz and J NH-H6′ ) 5.2 Hz,
are consistent with the value of |120°| for dihedral angles
H-N-C6-H(pro-S) and H-N-C6-H(pro-R) about the
Con for m a tion a l An a lysis of 3b. The mannose based
sugar amino acid containing cyclic trimer 3b is an 18-
membered macrocyclic peptide. The vicinal coupling
3
N-C6 bond.10 The coupling constants J H6(pro-R)-H5 ) 9.4
3
Hz and J H6(pro-S)-H5 ) 3.4 Hz, as well as the observation
3
constants for the amide proton, J NH-H6(pro-S) ) 7.5 Hz
of strong rOe between NHiTC5-Hi, are consistent with
the positive synclinal orientation (+sc) about the C5-
C6 bond. This leads to the amide protons pointing into
the ring and the carbonyls pointing to the outside, and
unlike in other molecules, the C2-H and CO take an
intermediate orientation about the C2-CO bond, which
is neither a syn nor an anti orientation, as revealed by
the structures, shown in Figure 4, sampled during the
restrained MD calculations based on the ROESY cross-
peaks found for 4b in DMSO-d6 (B in Figure 1). Here
also, out of the 25 structures sampled during the 300-ps
MD simulations, 5 structures that deviated considerably
from the rest of them during backbone alignment were
not included in the ensemble displayed in Figure 4. The
backbone and the average pairwise heavy-atom RMSD
are 1.03 ( 0.49 and 1.62 ( 0.34 Å, respectively, deter-
mined by analyzing the structures with the MOLMOL
program.
3
and J NH-H6(pro-R) ) 1.8 Hz, imply the presence of a
predominant single rotamer about the N-C6 bond.10 The
3
other vicinal couplings of J H6(pro-S)-H5 ≈ 0 Hz and
3J H6(pro-R)-H5 ) 6.5 Hz, as well as the appearance of rOe
between NHiTC5-Hi, NHiTC3-Hi-1, and C4-OHiTC6-
Hi(pro-R) indicate about 30° deviation from the negative
synclinal (-sc) rotamer about the C5-C6 bond (Figure
2). The rOe between NHiTC3-Hi-1, the negative syncli-
nal rotamer about the C5-C6, and a single rotamer
about N-C6 are in agreement with the syn orientation
of the C2-H and CO that practically ruled out the
formation of intramolecular hydrogen bonding of the
amide proton. This is further supported by the large
magnitude of the temperature coefficient of the amide
proton chemical shift (∆δ/∆T).
(10) Demarco, A.; Ilinas, M.; Wuthrich, K. Biopolymers 1978, 17,
617.
J . Org. Chem, Vol. 68, No. 16, 2003 6259

Chakraborty et al.
F IGURE 3. Superimposition of the energy-minimized structures sampled during the MD simulations of 3b.
F IGURE 4. Superimposition of the energy-minimized structures sampled during the MD simulations of 4b.
F IGURE 5. Superimposition of the energy-minimized structures sampled during the MD simulations of 8b.
Con for m a tion a l An a lysis of 8b. In the Gaa cyclic
which shows the superimposed display of the structures
dimer 8b, the vicinal coupling constants, 3J NH-H6(pro-R)
)
sampled during the MD studies, using the long-range
constraints derived from the rOe cross-peaks (C in Figure
1). In these structures, the C2-hydrogens and the COs
can be seen on one side of the ring while the NHs point
3
8.0 and J NH-H6(pro-S) ) 3.4 Hz, imply that the dihedral
angle æ (CO-N-C6-C5) is about |90°|. The other vicinal
3
3
couplings of J H6(pro-R)-H5 ≈ 0 Hz and J H6(pro-S)-H5 ) 4.1
Hz indicate the indisputable evidence for the deviation
of ca. 30° from synclinal (-sc) orientation about the C5-
C6 bond (Figure 2). Moderate magnitude of the temper-
ature coefficient for the Gaa amide proton (∆δ/∆T ) -3.0
ppb/deg K in DMSO-d6) in the variable-temperature
experiments hints at its involvement in intramolecular
hydrogen bonding. The observation of rOe cross-peaks
3
to the other side. The J coupling constants between the
3
protons of the sugar ring have the values of J H2-H3
)
3
3
7.9 Hz, J H3-H4 ) 7.9 Hz, and J H4-H5 ) 7.5 Hz that are
in agreement with 4T sugar puckering (where 3 and 4
3
refer to C3 and C4, respectively).11
In the cyclic Gaa tetramer 9b, due to exchange
broadening of the resonances, we were unable to obtain
any structural information.
between NHiTC4-Hi, NHiTC2-Hi-1, NHiTC3-Hi-1
,
C2-HiTC5-Hi and the negative synclinal rotation about
C5-C6, coupled with the intramolecular hydrogen bond-
ing of NH indicate the presence of an unusual six-
membered hydrogen bond between NHifC3-Oi-1. This
unusual six-membered hydrogen bonding and the rOe
between NHiTC4-Hi are in agreement with the syn
orientation of C2-H and CO, as revealed in Figure 5
Ion F lu x Stu d y. The abilities of the Bn-deprotected
products 3b, 4b, 5b, 8b, and 9b to transport ions across
model membranes (large unilamellar vesicles from palm-
itoyl-oleoyl phosphatidylcholine12) were assessed by moni-
(11) Haasnoot, C. A. G.; Leeuw, F. A. A. M. de; Leeuw, H. P. M. de;
Altona, C. Biopolymers 1981, 20, 1211.
6260 J . Org. Chem., Vol. 68, No. 16, 2003

Cyclic Homooligomers of Furanoid Sugar Amino Acids
applicable in the cyclohomooligomerization of other
(C2,C5)-trans furanoid sugar amino acids. Detailed NMR
studies in DMSO-d6 and subsequent constrained MD
simulations reveal that in the cyclic trimer of Maa 3b,
the C2-H and CO are placed on one side of the ring while
the NHs point to the other side, with both CO and NH
being perpendicular to the ring. In the cyclic tetramer of
Maa 4b, the amide protons point into the ring while the
carbonyls are positioned outside. The structure of the
cyclic Gaa dimer 8b is characterized by an unusual six-
membered intramolecular hydrogen bond between NHif
C3-Oi-1 and a syn orientation between C2-H and CO.
This study will be useful in creating de novo cyclic
peptides based on other furanoid sugar amino acids. The
well-defined structures of these macrocyclic peptides will
be useful in carrying out investigations on many interest-
ing molecular recognition processes.
Exp er im en ta l Section
Syn th esis of 3a a n d 4a . To a solution of Boc-Maa(Bn2)-
OMe6 (1.0 g, 2.1 mmol) in THF-MeOH-H2O (3:1:1, 10 mL)
at 0 °C was added LiOH‚H2O (265 mg, 6.3 mmol) with stirring
from 0 °C to room temperature for 4 h. The reaction mixture
was then acidified to pH 2 with 1 N HCl. It was diluted with
EtOAc, washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo to obtain the acid. The acid was
dissolved in CH2Cl2 (7 mL) and to this solution was added
trifluoroacetic acid (3 mL) with stirring from 0 °C to room
temperature for 2 h. The reaction mixture was then concen-
trated in vacuo to give TFA.H-Maa(Bn2)-OH.
F IGURE 6. The profile shows that the addition of valinomycin
at point Vm sets in diffusion potential as it triggers the
transportation of K+ ions, from inside to outside, across the
model membrane of large unilamellar vesicles of palmitoyl-
oleoyl phosphatidylcholine, which is reflected by a sharp fall
in the fluorescence monitored by the fluorescent dye method.
Addition of 5b at point C in the profile resulted in the influx
of Na+ ions from the suspension medium back into the vesicles
leading to the dissipation of the aforesaid diffusion potential
as indicated by the increase in the fluorescence again.
To a solution of the above-prepared TFA-salt of Maa(Bn2) 1
(429 mg, 0.91 mmol) in amine-free dry DMF (91 mL, 10-2 M)
was added BOP reagent (604 mg, 1.36 mmol) at 0 °C and the
reaction mixture was stirred for 15 min. This was followed by
the slow addition of DIPEA (1.12 mL, 6.37 mmol) to the
reaction mixture and stirring was continued at 0 °C for 7 h.
Evaporation of the DMF under reduced pressure gave a
residue that was dissolved in EtOAc, washed with saturated
aqueous NH4Cl, saturated aqueous NaHCO3, and brine, dried
(Na2SO4), and concentrated in vacuo. The crude was purified
by column chromatography (SiO2, 60-65% EtOAc in petroleum
ether eluant) to afford 3a (96 mg, 31%) and 4a (37 mg, 12%)
as solids. Data for 3a : Rf )0.5 (silica gel, 60% EtOAc in
toring the collapse of valinomycin-mediated K+ diffusion
potential on adding these substrates with use of the
fluorescent dye method.13 Addition of the deprotected
bicyclic lactam 5b resulted in the dissipation of the
diffusion potential created by valinomycin (Figure 6) in
a concentration-dependent manner indicating that the
molecule is able to cause the influx of Na+ ions across
the lipid bilayer. The lipid-molecule ratio indicates that
it is less effective than valinomycin in causing flux of Na+
ions across the lipid bilayer. Hence, it is unlikely that a
carrier mechanism involving complexation between Na+
and 5b is operative. It is possible that self-assembling
structures are formed that can conduct ions across the
bilayer.4 The cyclic homoologomers of Maa 3b, 4b, and
the Gaa-based compounds 8b and 9b did not show any
significant ion influx.
Con clu sion . Cyclic homooligomers of furanoid sugar
amino acids constitute a new class of novel molecular
scaffolds that display interesting 3-D structures. It is
noteworthy that in case of mannose-derived sugar amino
acid Maa 1, having a trans relationship between C2-H
and C5-H, the monomeric unit could be transformed
directly into its cyclic homooligomers in a single-step
process, an interesting finding that is expected to be
petroleum ether); [R]20 38.1 (c 0.975, CHCl3); mp 88-90 °C;
D
IR (KBr) νmax 3396, 2909, 2847, 1670, 1513, 1098, 1066, 682
cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.40-7.20 (m, 10 H, ArH),
6.72 (dd, J ) 7.4, 3.0 Hz, 1 H, NH), 4.76 (d, J ) 11.8 Hz, 1 H,
PhCH2O), 4.60 (d, J ) 11.8 Hz, 1 H, PhCH2O), 4.51 (d, J )
11.5 Hz, 1 H, PhCH2O), 4.48 (t, J ) 3.2 Hz, 1 H, C3-H), 4.47
(d, J ) 3.2 Hz, 1 H, C2-H), 4.43 (d, J ) 11.5 Hz, 1 H, PhCH2O),
3.85 (dt, J ) 7.0, 2.7 Hz, 1 H, C5-H), 3.83 (t, J ) 3.3 Hz, 1 H,
C4-H), 3.76 (ddd, J ) 13.8, 7.4, 2.6 Hz, 1 H, C6-H), 3.23 (ddd,
J ) 13.8, 9.6, 3.0 Hz, 1 H, C6-H′); 13C NMR (CDCl3, 75 MHz)
δ 170.1, 137.4, 136.9, 128.4, 128.2, 128.0, 127.94, 85.6, 85.2,
82.9, 81.4, 72.2, 72.1, 42.0; MS (LSIMS) m/z (%) 1018 (74) [M
+ H]+, 1040 (30) [M + Na]+.
Data for 4a : Rf 0.4 (silica gel, 60% EtOAc in petroleum
ether); [R]20D 40.5 (c 0.80, CHCl3); mp 75-77 °C; IR (KBr) νmax
1
3396, 2917, 2862, 1662, 1521, 1090, 823, 674 cm-1; H NMR
(CDCl3, 500 MHz) δ 7.40-7.13 (m, 10 H, ArH), 6.82 (dd, J )
6.5, 5.4 Hz, 1 H, NH), 4.71 (d, J ) 11.9 Hz, 1 H, PhCH2O),
4.60 (d, J ) 11.9 Hz, 1 H, PhCH2O), 4.56 (d, J ) 2.1 Hz, 1 H,
C2-H), 4.45 (t, J ) 2.1 Hz, 1 H, C3-H), 4.39 (d, J ) 11.2 Hz, 1
H, PhCH2O), 4.28 (d, J ) 11.2 Hz, 1 H, PhCH2O), 3.97 (dt, J
) 9.1, 3.4 Hz, 1 H, C5-H), 3.78 (dd, J ) 3.4, 1.9 Hz, 1 H, C4-
H), 3.50 (ddd, J ) 13.7, 9.4, 5.2 Hz, 1 H, C6-H), 3.38 (ddd, J
) 13.7, 6.7, 3.8 Hz, 1 H, C6-H′); 13C NMR (CDCl3, 75 MHz) δ
170.2, 137.3, 137.2, 128.5, 128.4, 128.0, 127.9, 127.8, 84.6, 84.5,
84.1, 83.4, 77.2, 71.9, 71.6, 41.0; MS (ESI) m/z (%) 702 (12)
[1/2M + Na]+, 1381 (<1) [M + Na]+.
(12) MacDonald, R. C.; MacDonald, R. I.; Menco, B. Ph. M.;
Takeshita, K.; Subbarao, N. K.; Hu, L.-R. Biochim. Biophys. Acta 1991,
1061, 297.
(13) Sims, P. J .; Waggoner, A. S.; Wang, C. H.; Hoffman, J . F.
Biochemistry 1974, 13, 3315.
J . Org. Chem, Vol. 68, No. 16, 2003 6261

Chakraborty et al.
Syn th esis of 3b. To a solution of 3a (71 mg, 0.07 mmol) in
MeOH (2 mL) was added Pd(OH)2 on C (20%, 50 mg) and the
mixture was hydrogenated under atmospheric pressure with
use of a H2 balloon for 24 h. The reaction mixture was then
filtered through a short pad of Celite, and the filter cake was
washed with MeOH. The filtrate and the washings were
combined and concentrated in vacuo to get a quantitative yield
of 3b (30 mg). Data for 3b: Rf 0.43 (silica gel, nBuOH:AcOH:
being stirred for 12 h at room temperature, the reaction
mixture was diluted with EtOAc, washed with saturated
NH4Cl solution, saturated NaHCO3 solution, water, and
brine, dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2, 45-50%
EtOAc in petroleum ether eluant) afforded the protected linear
dimer Boc-[(Gaa(Bn2)]2-OMe (1.26 g, 74%). Data for
Boc-[(Ga a (Bn 2)]2-OMe: Rf 0.4 (silica gel, 40% EtOAc in
H2O ) 4:2:2); [R]20 97.6 (c 0.59, H2O); IR (KBr) νmax 3396,
petroleum ether); [R]20 25.1 (c 1.2, CHCl3); mp 38-40 °C; IR
D
D
2854, 1639, 1529, 1035, 823 cm-1
;
1H NMR (DMSO-d6, 500
(neat) νmax 3356, 2901, 1686, 1654, 1529, 1190, 729 cm-1; H
1
MHz) see Table 1; 13C NMR (DMSO-d6, 75 MHz) δ 170.8, 82.8,
NMR (CDCl3, 500 MHz) δ 7.75 (t, J ) 5.2 Hz, 1 H, Gaa(2)-
NH), 7.35-7.18 (m, 20 H, ArH), 5.73 (t, J ) 5.5 Hz, 1 H,
Gaa(1)NH), 4.78 (d, J ) 6.3 Hz, 1 H, Gaa(2)C2-H), 4.61 (d, J
) 3.7 Hz, 1 H, Gaa(1)C2-H), 4.56-4.36 (m, 8 H, PhCH2O), 4.32
(dd, J ) 6.3, 3.3 Hz, 1 H, Gaa(2)C3-H), 4.27 (d, J ) 3.7 Hz, 1
H, Gaa(1)C3-H), 4.18 (dt, J ) 5.9, 4.3 Hz, 1 H, Gaa(2)C5-H),
4.14 (dt, J ) 7.6, 2.6 Hz, 1 H, Gaa(1)C5-H), 3.98 (dd, J ) 4.3,
3.3 Hz, 1 H, Gaa(2)C4-H), 3.77 (s, 3 H, OCH3), 3.74 (d, J ) 2.6
Hz, 1 H, Gaa(1)C4-H), 3.70 (ddd, J ) 14.2, 5.2, 4.3 Hz, 1 H,
Gaa(2)C6-H), 3.62 (dt, J ) 14.2, 5.8 Hz, 1 H, Gaa(2)C6-H′),
3.46 (ddd, J ) 14.3, 6.3, 3.0 Hz, 1 H, Gaa(1)C6-H), 3.38 (ddd,
J ) 14.3, 7.5, 6.0 Hz, 1 H, Gaa(1)C6-H′), 1.39 (s, 9 H, Boc);
13C NMR (CDCl3, 75 MHz) δ 171.1, 168.7, 156.2, 137.6, 137.4,
137.3, 137.0, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5,
126.8, 84.5, 83.7, 83.6, 82.5, 82.3, 82.2, 81.6, 79.0, 77.2, 72.6,
72.4, 72.1, 71.7, 52.2, 43.0, 39.8, 28.3; MS (LSIMS) m/z (%)
81.6, 80.2, 80.0, 41.8; MS (ESI) m/z (%) 500 (10) [M + Na]+.
Syn th esis of 4b. Compound 4b was synthesized from 4a
in quantitative yield following the same procedure described
above for the synthesis of 3b. Data for 4b: Rf 0.31 (silica gel,
nBuOH:AcOH:H2O ) 4:2:2); [R]20 46.5 (c 0.41, MeOH); IR
D
(KBr) νmax 3396, 2894, 1639, 1529, 1066 cm-1
;
1H NMR
(DMSO-d6, 500 MHz) see Table 1; 13C NMR (DMSO-d6, 75
MHz) δ 170.6, 84.1, 83.9, 79.9, 78.8, 41.5; MS (ESI) m/z (%)
660 (40) [M + Na]+.
Syn th esis of 5a . Compound 5a was synthesized from 2 in
75% yield, following the same procedure described above for
the cyclooligomerization of 1 with the same reagents in
identical molar equivalents and under identical reaction
conditions. Data for 5a : Rf 0.4 (silica gel, 60% EtOAc in
petroleum ether); [R]20 -28.6 (c 0.76, CHCl3); IR (neat) νmax
D
711 (30) [M+
+ H - C5H8O2], 811 (6) [M + H]+; HRMS (ESI)
3254, 2870, 2807, 1678, 1262, 1074, 800 cm-1; 1H NMR (CDCl3,
500 MHz) δ 7.39-7.29 (m, 10 H, ArH), 5.65 (br s, 1 H, NH),
4.79 (d, J ) 11.1 Hz, 1 H, PhCH2O), 4.70 (d, J ) 6.4 Hz, 1 H,
C2-H), 4.53 (d, J ) 11.7 Hz, 1 H, PhCH2O), 4.48 (d, J ) 11.1
Hz, 1 H, PhCH2O), 4.48 (d, J ) 11.7 Hz, 1 H, PhCH2O), 4.36
(d, J ) 4.7 Hz, 1 H, C5-H), 4.34 (dd, J ) 6.4, 3.0 Hz, 1 H,
C3-H), 4.05 (d, J ) 3.0 Hz, 1 H, C4-H), 3.70 (dd, J ) 11.6, 4.7
Hz, 1 H, C6-H), 3.17 (dd, J ) 11.6, 2.6 Hz, 1 H, C6-H′); 13C
NMR (CDCl3, 75 MHz) δ 168.6, 137.3, 137.1, 128.5, 128.45,
128.39, 128.05, 127.98, 127.9, 87.5, 78.6, 77.3, 72.9, 71.7, 45.5;
MS (ESI) m/z (%) 679.8 (100) [2M + H]+, 340.3 (50) [M + H]+;
HRMS (LSIMS) calcd for C20H22NO4 [M + H]+ 340.1549, found
340.1558.
calcd for C46H55N2O11 [M + H]+ 811.3850, found 811.3806.
To a solution of Boc-[Gaa(Bn2)]2-OMe (250 mg, 0.30 mmol)
in THF-MeOH-H2O (3:1:1, 2.5 mL) at 0 °C was added LiOH‚
H2O (38 mg, 0.93 mmol) with stirring from 0 °C to room
temperature for 4 h. The reaction mixture was then acidified
to pH 2 with 1 N HCl. It was diluted with EtOAc, washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo to
obtain the acid that was dissolved in CH2Cl2 (7 mL). To this
solution was added trifluoroacetic acid (3 mL) with stirring
from 0 °C to room temperature for 2 h. The reaction mixture
was then concentrated to give the TFA-salt of 6 that was used
directly in the synthesis of 8a .
Syn th esis of 5b. Compound 5b was synthesized from 5a
in quantitative yield, following the same procedure described
above for the synthesis of 3b. Data for 5b: Rf 0.5 (silica gel,
Syn th esis of H-[(Ga a (Bn 2)]4-OH (7). To a solution of Boc-
[Gaa(Bn2)]2-OMe (502 mg, 0.62 mmol) in THF-MeOH-H2O
(3:1:1, 5 mL) at 0 °C was added LiOH:H2O (78 mg, 1.86 mmol)
with stirring from 0 °C to room temperature for 4 h. The
reaction mixture was then acidified to pH 2 with 1 N HCl and
then diluted with EtOAc, washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to obtain the acid.
In another round-bottom flask a solution of Boc-[Gaa(Bn2)]2-
OMe (502 mg, 0.62 mmol) in CH2Cl2 (5 mL) was added. To
this was added trifluoroacetic acid (2 mL) with stirring from
0 °C to room temperature for 2 h. The reaction mixture was
then concentrated to give TFA.H-[Gaa(Bn2)]2-OMe.
nBuOH:AcOH:H2O ) 4:2:2); [R]20 -35.7 (c 0.54, MeOH); IR
D
(KBr) νmax 3490, 3278, 2909, 1678, 1425, 1098, 1027 cm-1; 1H
NMR (DMSO-d6, 500 MHz) δ 7.34 (dd, J ) 2.6, 1.0 Hz, 1 H,
NH), 5.41 (d, J ) 4.0 Hz, 1 H, C3-OH), 5.32 (d, J ) 4.7 Hz, 1
H, C4-OH), 4.09 (ddd, J ) 7.0, 4.0, 2.4 Hz, 1 H, C3-H), 4.08
(d, J ) 7.0 Hz, 1 H, C2-H), 4.04 (d, J ) 5.0 Hz, 1 H, C5-H),
3.88 (dd, J ) 4.7, 2.4 Hz, 1 H, C4-H), 3.38 (ddd, J ) 11.9, 5.0,
1.0 Hz, 1 H, C6-H), 3.04 (dd, J ) 11.9, 2.6 Hz, 1 H, C6-H′); 13
C
NMR (DMSO-d6, 75 MHz) δ 168.4, 83.0, 81.9, 80.2, 80.1, 44.8;
MS (ESI) m/z (%) 341 (15) [2M + Na]+, 182 (38) [M + Na]+;
HRMS (LSIMS) calcd for C6H9NO4 [M]+ 159.0531, found
159.0527.
The above-prepared crude acid was dissolved in CH2Cl2
(4 mL) and cooled to 0 °C. Then it was sequentially treated
with HOBt‚H2O (92 mg, 0.68 mmol) and EDCI (130 mg, 0.68
mmol). After 10 min, TFA.H-[Gaa(Bn2)]2-OMe prepared above
and dissolved in CH2Cl2 (4 mL) was added to the reaction
mixture followed by the addition of DIPEA (0.21 mL, 1.23
mmol). After being stirred for 12 h at room temperature, the
reaction mixture was diluted with EtOAc, washed with
saturated NH4Cl solution, saturated NaHCO3 solution, water,
and brine, dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2, 50-60% EtOAc
in petroleum ether eluant) afforded the protected linear
tetramer Boc-[Gaa(Bn2)]4-OMe (563 mg, 61%). Data for
Boc-[Ga a (Bn 2)]4-OMe: Rf 0.3 (silica gel, 50% EtOAc in
Syn th esis of H-[(Ga a (Bn 2)]2-OH (6). To a solution of Boc-
Gaa(Bn2)-OMe6 (1.0 g, 2.1 mmol) in THF-MeOH-H2O (3:1:
1, 10 mL) at 0 °C was added LiOH‚H2O (265 mg, 6.3 mmol)
with stirring from 0 °C to room temperature for 4 h. The
reaction mixture was then acidified to pH 2 with 1 N HCl and
then diluted with EtOAc, washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to obtain the acid.
In another round-bottom flask a solution of Boc-Gaa(Bn2)-
OMe (1.0 g, 2.1 mmol) in CH2Cl2 (7 mL) was added. To this
solution was added trifluoroacetic acid (3 mL) with stirring
from 0 °C to room temperature for 2 h. The reaction mixture
was then concentrated in vacuo to give TFA.H-Gaa(Bn2)-OMe.
The above-prepared crude acid was dissolved in CH2Cl2 (6
mL) and cooled to 0 °C. Then it was sequentially treated with
HOBt‚H2O (315 mg, 2.3 mmol) and EDCI (447 mg, 2.3 mmol).
After 10 min, TFA.H-Gaa(Bn2)-OMe prepared above and
dissolved in CH2Cl2 (6 mL) was added to the reaction mixture
followed by the addition of DIPEA (0.75 mL, 4.2 mmol). After
petroleum ether); [R]20 38.0 (c 0.25, CHCl3); mp 65-68 °C;
D
IR (neat) νmax 3278, 2901, 1662, 1537, 1098, 1058, 721 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 8.30 (t, J ) 5.6 Hz, 1 H, Gaa-
(4)NH), 8.21 (t, J ) 5.9 Hz, 1 H, Gaa(3)NH), 7.71 (t, J ) 5.7
Hz, 1 H, Gaa(2)NH), 7.38-7.10 (m, 40 H, aromatic protons),
5.08 (t, J ) 5.8 Hz, 1 H, Gaa(1)NH), 4.68-4.15 (m, 16 H, OCH2-
Ph), 4.67 (d, 1 H, Gaa(4)C2-H), 4.67 (d, 1H, Gaa(3)C2-H), 4.59
6262 J . Org. Chem., Vol. 68, No. 16, 2003

Cyclic Homooligomers of Furanoid Sugar Amino Acids
(d, 1 H, Gaa(1)C2-H), 4.56 (d, 1 H, Gaa(2)C2-H), 4.28 (m, 1 H,
Gaa(3)C3-H), 4.24 (m, 1 H, Gaa(2)C3-H), 4.21 (m, 1 H, Gaa-
(1)C3-H), 4.18 (m, 1 H, Gaa(4)C3-H), 4.16 (m, 1 H, Gaa(4)C5-
H), 4.14 (m, 1 H, Gaa(3)C5-H), 4.14 (m, 1 H, Gaa(2)C5-H), 3.99
(m, 1 H, Gaa(1)C5-H), 3.92 (m, 1 H, Gaa(2)C4-H), 3.88 (m, 1
H, Gaa(3)C4-H), 3.86 (m, 1 H, Gaa(4)C4-H), 3.75 (m, 1 H, Gaa-
(2)C6-H), 3.70 (m, 1 H, Gaa(4)C6-H), 3.70 (m, 1 H, Gaa(3)C6-
H), 3.65 (s, 3 H, OCH3), 3.64 (m, 1 H, Gaa(4)C6-H′), 3.63 (m,
1 H, Gaa(3)C6-H′), 3.59 (m, 1 H, Gaa(1)C4-H), 3.57 (m, 1 H,
Gaa(1)C6-H), 3.17 (m, 1 H, Gaa(2)C6H′), 3.14 (m, 1 H, Gaa-
(1)C6H′), 1.40 (s, 9 H, Boc); 13C NMR (CDCl3, 75 MHz) δ 169.8,
169.7, 169.5, 169.4, 156.6, 137.7, 137.62, 137.57, 137.4, 137.3,
137.1, 128.44, 128.36, 128.33, 127.89, 127.85, 127.81, 127.76,
127.71, 127.66, 127.6, 127.52, 127.48, 127.43, 85.4, 85.1, 84.6,
84.0, 83.8, 83.6, 83.4, 83.3, 82.7, 82.6, 82.5, 82.1, 81.9, 81.8,
80.1, 79.4, 73.1, 72.9, 72.8, 71.8, 71.6, 71.5, 71.4, 71.3, 51.9,
43.0, 41.8, 40.9, 28.3; MS (LSIMS) m/z (%) 1390 (10) [M+ + H
- C5H8O2].
To a solution of Boc-[Gaa(Bn2)]4-OMe (447 mg, 0.3 mmol)
in THF-MeOH-H2O (3:1:1, 5 mL) at 0 °C was added LiOH‚
H2O (38 mg, 0.9 mmol) with stirring from 0 °C to room
temperature for 4 h. The reaction mixture was then acidified
to pH 2 with 1 N HCl and diluted with EtOAc, washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo to
obtain the acid that was dissolved in CH2Cl2 (3.5 mL). To this
solution was added trifluoroacetic acid (1.5 mL) with stirring
from 0 °C to room temperature for 2 h. The reaction mixture
was then concentrated to give the TFA-salt of 7 that was used
directly in the synthesis of 9a .
Syn th esis of 8b. Compound 8b was synthesized from 8a
in quantitative yield, following the same procedure described
above for the synthesis of 3b. Data for 8b: Rf 0.45 (silica gel,
nBuOH:AcOH:H2O ) 4:2:2); [R]20 -70.8 (c 0.36, MeOH); IR
D
(KBr) νmax 3444, 3300, 2928, 1647, 1546, 1419, 1166, 1126,
1064 cm-1 1H NMR (DMSO-d6, 500 MHz) see Table 1; 13C
;
NMR (DMSO-d6, 75 MHz) δ 171.7, 81.4, 76.3, 75.9, 75.1, 37.4;
MS (ESI) m/z (%) 659.21 (40) [2M + Na]+, 643.24 (38) [2M +
Li]+, 341.07 (100) [M + Na]+, 325.11 (76) [M + Li]+; HRMS
(ESI) calcd for C12H19N2O8 [M + H]+ 319.1141, found 319.1135.
Syn th esis of 9a . Compound 9a was synthesized from 7 in
52% yield, following the same procedure described above for
the cyclooligomerization of 1 with the same reagents in
identical molar equivalents and under identical reaction
conditions. Data for 9a : Rf 0.2 (silica gel, 60% EtOAc in
petroleum ether); [R]20 82.5 (c 0.21, CHCl3); mp 58-60 °C;
D
IR (KBr) νmax 3404, 3060, 3032, 2924, 1668, 1536, 1455, 1097,
739, 698 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.35-7.23 (m, 10
H, ArH), 7.01 (dd, J ) 7.2, 5.0 Hz, 1 H, NH), 4.58 (d, J ) 3.9
Hz, 1 H, C2-H), 4.54 (d, J ) 12.1 Hz, 1 H, PhCH2O), 4.48 (d,
J ) 12.1 Hz, 1 H, PhCH2O), 4.39 (s, 2 H, PhCH2O), 4.25 (dd,
J ) 3.9, 1.1 Hz, 1 H, C3-H), 4.11 (ddd, J ) 8.4, 3.6, 2.2 Hz, 1
H, C5-H), 3.92 (ddd, J ) 14.4, 7.2, 2.2 Hz, 1 H, C6-H), 3.70
(dd, J ) 3.6, 1.1 Hz, 1H, C4-H), 3.20 (ddd, J ) 14.4, 8.4, 5.0
Hz, 1 H, C6-H′); 13C NMR (CDCl3, 75 MHz) δ 168.5, 137.5,
137.2, 128.5, 128.4, 127.9, 127.8, 127.6, 84.5, 84.2, 82.8, 82.3,
72.8, 71.8, 42.1; MS (ESI) m/z (%) 1359 (100) [M + H]+.
Syn th esis of 9b. Compound 9b was synthesized from 9a
in quantitative yield, following the same procedure described
above for the synthesis of 3b. Data for 9b: Rf 0.3 (silica gel,
Syn th esis of 8a . Compound 8a was synthesized from 6 in
56% yield, following the same procedure described above for
the cyclooligomerization of 1 with the same reagents in
identical molar equivalents and under identical reaction
conditions. Data for 8a : Rf 0.3 (silica gel, 60% EtOAc in
nBuOH:AcOH:H2O ) 4:2:2); [R]20 25.5 (c 0.18, MeOH); IR
D
(neat) νmax 3424, 2921, 1636, 1399, 1097 cm-1
;
1H NMR
(DMSO-d6, 500 MHz) see Table 1; 13C NMR (DMSO-d6, 75
MHz) δ 169.2, 85.5, 82.1, 78.0, 77.5, 41.1; MS (ESI) m/z (%)
659.2 (70) [M + Na]+, 643.2 (100) [M + Li]+.
petroleum ether); [R]20 -15.5 (c 0.91, CHCl3); IR (KBr) νmax
D
2924, 1670, 1538, 1218, 1086, 769 cm-1; 1H NMR (CDCl3, 500
MHz) δ 7.49 (dd, J ) 6.7, 5.4 Hz, 1 H, NH), 7 33-7.16 (m, 10
H, ArH), 4.72 (d, J ) 6.6 Hz, 1 H, C2-H), 4.57 (d, J ) 11.9 Hz,
1H, PhCH2O), 4.53 (d, J ) 11.9 Hz, 1 H, PhCH2O), 4.43 (dd,
J ) 6.6, 4.3 Hz, 1 H, C3-H), 4.39 (d, J ) 11.7 Hz, 1 H,
PhCH2O), 4.27 (d, J ) 11.7 Hz, 1 H, PhCH2O), 4.25 (dd, J )
5.4, 4.3 Hz, 1 H, C5-H), 3.93 (t, J ) 4.3 Hz, 1 H, C4-H), 3.77
(dt, J ) 14.4, 5.4 Hz, 1 H, C6-H), 3.59 (dd, J ) 14.4, 6.7 Hz, 1
H, C6-H′); 13C NMR (CDCl3, 75 MHz) δ 169.7, 137.6, 136.5,
128.7, 128.6, 128.4, 127.8, 127.4, 84.6, 82.3, 82.0, 81.0, 73.3,
72.2, 40.2; MS (ESI) m/z (%) 1359 (2) [2M + H]+, 680 (94) [M
+ H]+; HRMS (ESI) calcd for C40H43N2O8 [M + H]+ 679.3019,
found 679.3046.
Ack n ow led gm en t. We thank CSIR and UGC New
Delhi for research fellowships (S.K.K. and P.S., respec-
tively) and DST, New Delhi for financial support.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures, NMR spectroscopy, molecular dynamics and
1
ion flux studies; H and 13C NMR spectra of all the products;
ROESY spectra of 3b, 4b, and 8b. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O034586U
J . Org. Chem, Vol. 68, No. 16, 2003 6263