β-Sugar aminoxy peptides as rigid secondary structural scaffolds

Article abstract of DOI:10.1021/jo801810z

(Chemical Equation Presented) Short homo-oligomers of a new building block, cis-β^2,3-furanoid sugar aminoxy acid, are designed, characterized, and found to exhibit rigid ribbon-like secondary structures composed of 5/7 bifurcated intramolecular hydrogen bonds.

Full text of DOI:10.1021/jo801810z

SCHEME 1. Schematic Representation of ꢀ-Aminoxy
Compounds and Corresponding Dihedral Angles
ꢀ-Sugar Aminoxy Peptides As Rigid Secondary
Structural Scaffolds
Srivari Chandrasekhar,*,† Chennamaneni Lohitha Rao,†
Marepally Srinivasa Reddy,† Ganti Dattatreya Sharma,‡
Marelli Udaya Kiran,‡ Police Naresh,‡
Gunturu Krishna Chaitanya,§ Kotamarthi Bhanuprakash,§ and
Bharatam Jagadeesh*,‡
Organic DiVision-I, Center for Nuclear Magnetic Resonance,
and Inorganic Chemistry DiVision, Indian Institute of
Chemical Technology, Hyderabad, India 500 007
logues. Their studies have shown that di- and tripeptides of both
linear ꢀ-aminoxy acids7a (Scheme 1) and trans-ꢀ2,3-cycloalkane
constrained aminoxy acids7b (aminoxy analogues of Gellman’s
classic trans-ꢀ2,3-ACPC and trans-ꢀ2,3-ACHC1,2d) preferentially
adopt rigid N-O turns or helical folds stabilized by nine-
membered inter-residue NHi-COi-2 hydrogen bonding (9-hb).
These findings are consistent with Hoffman’s theoretical predic-
tions8 that 9-helical and 14-helical folds are most favorable in
the homo-oligomers of γ-amino acids. On the other hand, it is
evident from earlier reports that the choice of cis over trans
geometry around the CR-Cꢀ bond of ꢀ2,3-amino acids results
in a conformational switch in the backbone folding, by forming
strand structures in oligomers of cis-ꢀ2,3-aminocyclopentane
carboxylic acid (cis-ꢀ2,3-ACPC)2e and a right-handed 14-helix
in oligomers of cis-ꢀ2,3-cyclic furanoid sugar amino acid
(cis-ꢀ-FSAA),4c,d in contrast to the left-handed 12-helix9a and
12/10-helix9b exhibited by trans-ꢀ2,3-ACPC and ꢀ-FSAA oli-
gomers, respectively. In light of the above theoretical and
experimental findings, it is interesting to investigate the folding
propensities of cis-ꢀ2,3-cyclic aminoxy peptides in general.
Furthermore, although the ꢀ-aminoxy acids reported so far are
either aliphatic type or cycloalkane constrained, their analogues
with carbohydrate rings on the backbone have not been explored.
As sugar amino acids10 have been recognized as versatile
structure building blocks, herein we report short oligopeptides
based on a new class of building block, cis-ꢀ2,3-furanoid sugar
aminoxy acid (cis-FSAOA) (Scheme 1), which exhibit ribbon-
like secondary structures that are unprecedented in ꢀ-aminoxy
peptides. The present work focuses on the residue-based
conformational control in deriving diverse secondary structural
scaffolds.
sriVaric@iict.res.in; bj@iict.res.in
ReceiVed August 21, 2008
Short homo-oligomers of a new building block, cis-ꢀ2,3-
furanoid sugar aminoxy acid, are designed, characterized,
and found to exhibit rigid ribbon-like secondary structures
composed of 5/7 bifurcated intramolecular hydrogen bonds.
ꢀ-Peptidic oligomers have emerged as highly versatile
structural scaffolds in recent years, as they exhibit well-defined
secondary structures, “foldamers”,1 such as helices, strands, and
turns,2 which bring about the appropriate spatial arrangements
of the functional groups for biological applications.3 Design and
synthesis of conformationally restricted ꢀ-peptide building
blocks4 for deriving specific foldamers is topical in peptidomi-
metics.5 By substituting oxygen atom in place of the Cγ atom
of γ-amino acid, Yang and co-workers have designed novel rigid
turn-inducing building blocks, ꢀ-aminoxy acids,6 which are
considered as extended ꢀ-amino acids or γ-amino acid ana-
(4) (a) Barchi, J. J., Jr; Huang, X.; Appella, D. H.; Christianson, L. A.; Durell,
S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 2711. (b) Martinek, T. A.;
Fulop, F. Eur. J. Biochem. 2003, 270, 3657. (c) Chandrasekhar, S.; Reddy, M. S.;
Jagadeesh, B.; Prabhakar, A.; Rao, M. H. V. R.; Jagannadh, B. J. Am. Chem.
Soc. 2004, 126, 13586. (d) Chandrasekhar, S.; Reddy, M. S.; Babu, B. N.;
Jagadeesh, B.; Prabhakar, A.; Jagannadh, B. J. Am. Chem. Soc. 2005, 127, 9664.
(e) Jagadeesh, B.; Prabhakar, A.; Sarma, G. D.; Chandrasekhar, S.; Chan-
drashekar, G.; Reddy, M. S.; Jagannadh, B. Chem. Commun. 2007, 371. (f)
Chandrasekhar, S.; Babu, B. N.; Prabhakar, A.; Sudhakar, A.; Reddy, M. S.;
Kiran, M. U.; Jagadeesh, B. Chem. Commun. 2006, 1548.
(5) (a) Horne, W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. J. Am. Chem.
Soc. 2007, 129, 4178. (b) Freire, F.; Fisk, J. D.; Peoples, A. J.; Ivancic, M.;
Guzie, I. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 7839.
(6) Li, X.; Yang, D. Chem. Commun. 2006, 3367.
(7) (a) Yang, D.; Zhang, Y. H.; Zhu, N. Y. J. Am. Chem. Soc. 2002, 124,
9966. (b) Yang, D.; Zhang, D. W.; Hao, Y.; Wu, Y. D.; Luo, S. W.; Zhu, N. Y.
Angew. Chem., Int. Ed. 2004, 43, 6719.
(8) Baldauf, C.; Gunther, R.; Hoffman, H. J. HelV. Chim. Acta 2003, 86,
2573.
(9) (a) Horne, W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. J. Am. Chem.
Soc. 2007, 129, 4178. (b) Gruner, S. A. W.; Truffault, V.; Georg, V.; Locardi,
E.; Stockle, M.; Kessler, H. Chem. Eur. J. 2002, 8, 4365.
† Organic Divison-I.
‡ Center for Nuclear Magnetic Resonance.
§ Inorganic Chemistry Division.
(1) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang,
X.; Barchi, J. J.; Gellman, S. H. Nature 1997, 381.
(2) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Seebach, D.; Beck,
A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111. (c) Martinek, T. A.;
Mandity, I. M.; Fulop, L.; Toth, G. K.; Vass, E.; Hollosi, M.; Forro, E.; Fulop,
F. J. Am. Chem. Soc. 2006, 128, 13539. (d) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219. (e) Martinek, T. A.; Toth, G. K.;
Vass, E.; Hollosi, M.; Fulop, F. Angew. Chem., Int. Ed. 2002, 41, 1718.
(3) (a) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem.
Biol. 2007, 3, 252. (b) Raguse, T. L.; Porter, E. A.; Weisblum, B.; Gellman,
S. H. J. Am. Chem. Soc. 2002, 124, 12774. (c) Leplae, P. R.; Fisk, J. D.; Porter,
E. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 6820. (d)
Price, J. L.; Home, W. S.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 6376.
(e) Home, W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. J. Am. Chem. Soc.
2007, 129, 4178.
10.1021/jo801810z CCC: $40.75
Published on Web 11/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9443–9446 9443

SCHEME 2. Schematic Representation of Compounds
1-10a
FIGURE 1. DFT calculated minimum conformers for 8 (a) and 6 (b).
to constrained geometry of the gauche-configured cis-FSAOA
with rigid NOCꢀCR (∼108°), resulting in the positioning of
furan-Oi, NHi+1, and COi+1 groups in the same plane. In trimer
(Phth)-7, one of the two minimum energy conformers has
exhibited an additional 12-membered hydrogen bonding (12-
hb), which was not realized in NMR studies.
a Compounds 1, 2, 3, 5, 6, and 7 are protected at the N-terminus by
phthalimide (phth), whereas compounds 8, 9, and 10 are protected by
pivoloyl (piv).
NMR studies of 4-8 were carried out in CDCl3 solvent at
303 and 279 K. The complete resonance assignments were
accomplished by using a combination of 1D and 2D gDQF-
COSY, TOCSY, and ROESY data (Supporting Information).
The 1H NMR spectra of all the compounds have shown a clear
dispersion of amide-NH (δNH ∼6.7 ppm) and aminoxy-NHs
(δNH ) 9.5-9.7 ppm) resonances. Solvent titration studies
(Supporting Information) for these compounds (with sequential
addition of aliquots of DMSO up to 10% v/v) showed chemical-
shift changes (∆δNH) of ∼0.15 and 1.1-1.45 ppm for amide-
NH and aminoxy-NHs, respectively. These findings suggest that
the amide-NH is not solvent-accessible and participates in a
strong intra molecular hydrogen bonding, whereas the aminoxy-
NHs are involved only in a weak hydrogen bonding. The
Monomer acid 3 was synthesized from the known O-
phthalimido sugar derivative 1.11 Compounds 4-10, which were
derived from 3, were synthesized by using EDCI and HOBt
reagents (Scheme 2). Whereas 4 was synthesized to look for
specific hydrogen bonding, 5-10 were explored for the folding
behavior of the backbone. Detailed structural studies have been
carried out by using NMR, ab initio DFT calculations, FT-IR,
and restrained MD simulation techniques (Supporting Informa-
tion).
To explore the folding propensities and hydrogen bond modes
in cis-ꢀ2,3-FSAOA homo-oligomers, we have carried out DFT
calculations for the compounds 6-8 (Supporting Information).
All geometries have been fully optimized using Gaussian 0312
software, and the minima were confirmed by harmonic fre-
quency calculations. Initially, the potential energy surface was
scanned for minima with various starting structures and for
different possible hydrogen bonding modes at the B3LYP/6-
31G(d,p) level. The lowest two minima obtained for each
molecule were further refined at the higher B3LYP/6-311++G(d,
p) level. The relative energies were calculated, and unscaled
ZPVE correction at the 6-31G (d,p) level has been applied. The
resultant minimum energy structures of monomer (Piv)-8, dimer
(Phth)-6, and trimer (Phth)-7 have predominantly exhibited
gauche conformation around HCR-CꢀH (∼40°) and a second-
ary folding with aminoxy-NH groups involved in a bifurcated
three-center hydrogen bonding (Figure 1): seven-membered
intra-residue (NHi-CdOi) hydrogen bonding (7-hb) and five-
membered inter-residue (NHi-furan-Oi-1) hydrogen bonding
(5-hb). This preferential three-center 5/7-hb backbone folding
over the nine-membered (9-hb) helical turns7b may be attributed
3
measured JCRH-CꢀH coupling constant for all of the FSAOA
residues is <4 Hz (∼ -40°), which suggests a highly restricted
gauche conformation around the CR-Cꢀ bond and that the
backbone folding is uniform along its length.4d
Explicit ROESY analysis of 6-8 could yield the preferred
local backbone conformation and the possible hydrogen bonding
modes it can favor. For the monomer (Piv)-8 and dimer (Phth)-
6, the presence of characteristic intra-residue NOEs, NHi-CꢀHi
(medium), NHi-CRHi (weak), and NHi-CγHi (weak), and inter-
residue NOEs, NHi-CδHi-1 (medium), NHi-CRHi-1 (medium),
and NHi-CꢀHi-1 (weak) (Figure 2), rules out helical turns or
random coil2e and can be assigned to a predominantly strand
or ribbon-like secondary structure.4f,13
This spatial arrangement implicates the aminoxy-NHs to
participate in a three-center bifurcated hydrogen bonding
composed of intra-residue (NHi-CdOi) 7-hb and inter-residue
(NHi-furan-Oi-1) 5-hb, while the terminal NHa can only be
involved in two-center 5-hb, which is consistent with the DFT
calculations. The NMR (ROESY) studies of ꢀ-peptidic strands
stabilized by intramolecular bifurcated 7-hb γ-peptidic ribbons13
and of 5/6-hb rings14 also support our analysis. The inter-residue
(10) (a) Well, R. M. V.; Marinelli, L.; Altona, C.; Erkelens, K.; Siegal, G.;
Raaij, M. V.; Saiz, A. L. L.; Kessler, H.; Novellino, E.; Lavecchia, A.; Boom,
J. H. V.; Overhand, M. J. Am. Chem. Soc. 2003, 125, 10822. (b) Chakraborty,
T. K.; Prakash, S. J.; Diwan, P. V.; Nagaraj, R.; Jampani, S. R. B.; Kunwar,
A. C. J. Am. Chem. Soc. 1998, 120, 12962. (c) Chakraborty, T. K.; Srinivasu,
P.; Tapadar, S.; Mohan, B. K. J. Chem. Sci. 2004, 116, 187. (d) Smith, M. D.;
Long, D. D.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G. W. J. Chem.
Commun. 1998, 2039. (e) Risseeuw, M. D. P.; Overhand, M.; Fleet, G. W. J.;
Simone, M. I. Tetrahedron: Asymmetry 2007, 18, 2001.
(11) Tronchet, J. M. J.; Zosimo-Landolfo, G.; Galland-Barrera, G.; Dolatshahi,
N. Carbohydr. Res. 1990, 204, 145.
(12) Frisch, M. J. et al. Gaussian 03; Gaussian, Inc.: Wallingford, CT, 2004.
For complete citation, see Supporting Information.
(13) Kothari, A.; Qureshi, M. K. N.; Beck, E. M.; Smith, M. D. Chem.
Commun. 2007, 2814.
(14) Motorina, I. A.; Huel, C.; Quiniou, E.; Mispelter, J.; Adjadj, E.; Grierson,
D. S. J. Am. Chem. Soc. 2001, 123, 8.
(15) (a) Yang, J.; Gellman, S. H. J. Am. Chem. Soc. 1998, 120, 9090. (b)
Yang, J.; Christianson, L. A.; Gellman, S. H. Org. Lett. 1999, 1, 11.
(16) (a) Baker, E. N.; Hubbard, R. E. Prog. Biophys. Mol. Biol. 1984, 44,
97. (b) Allain, F. H. T.; Varani, G. J. Mol. Biol. 1995, 250, 333. (c) Aggarwal,
A. K.; Rodgers, D. W.; Drottar, M.; Ptashne, M.; Harrison, S. C. Science 1988,
242, 899. (d) Nelson, H. C. M.; Finch, J. T.; Luisi, B. F.; Klug, A. Nature 1987,
330, 221.
9444 J. Org. Chem. Vol. 73, No. 23, 2008

FIGURE 2. Schematic representation of ROEs (blue) and hydrogen bonding (dashed lines) in monomer (Piv)-8 (a), dimer (Phth)-6 (b), and trimer
(Phth)-7 (c) that characterize 5/7 hydrogen-bonded ribbons. For the sake of clarity, only the long-range CδHi-2-CꢀHi and CδHi-2-CRHi are shown
for 7.
5°), three-center NHO (112 ( 5° and 124 ( 5° for 5- hb and
7-hb, respectively), and two-center 5-hb NHO (104 ( 3°) for
terminal NHa are in agreement with our DFT studies. These
nonlinear NHO values are characteristic of bifurcated hydro-
gen bonding between adjacent residues15 and match well with
those observed in 5/6-hb strands.14
However, normally, three-center hydrogen bonds and non-
linear NHO are not optimal for strong hydrogen bonding.
Nevertheless, it is noteworthy that the conformational stability
is not necessarily related to the stability of hydrogen bonding.
It is reasonable to speculate that the resultant 5-hb and the
consecutive 5/7-hbs in these peptides are due to the manifesta-
tion of the rigid conformation19 of the cis-FSAOA motif and
FIGURE 3. Superposition of 15 lower energy structures obtained in
that the strong 5-hb of terminal NHa over the weak 5/7-hb of
aminoxy-NHs is due to the energetic superiority of an isolated
5-hb interaction, relative to 5-hb as part of a three-center
hydrogen bonding.15 Our preliminary molecular mechanics
calculations on a simulated tetramer also showed an increased
population of ribbon conformation (Supporting Information).
The striking feature revealed from these findings is that despite
the presence of 14-helix nucleating motif, furanoid sugar ring
as a backbone constraint, the cis-ꢀ2,3-FSAOA oligomers do not
support the formation of either 9- or 14-helical folds, which
otherwise are favorable for γ-amino acid oligomers,8 but rather
preferentially adopt ribbon-like structures. These findings may
shed more light on understanding the mechanism scope for
generating diverse secondary scaffolds.
The FT-IR spectra showed resolved N-H stretching bands
for amide-NH and aminoxy-NHs and suggested their participa-
tion in hydrogen bonding (Supporting Information). The dimer
(Phth)-6 and trimer (Phth)-7 exhibited predominantly two
distinct peaks (3318 and 3224 cm-1) and (3321 and 3235 cm-1),
respectively, whose relative intensities are in accordance with
the population of possible hydrogen bonding groups in the
compounds. The bands at 3318 and 3321 cm-1 correspond to
the hydrogen-bonded amide-NH, whereas the bands at 3224 and
3235 cm-1 can be attributed to the hydrogen-bonded aminoxy-
NHs7b,20 for 6 and 7, respectively. The assignments have been
supported by the observed single band at ∼3325 for the control
samples, monomer imine-4 and monomer (Phth)-5 (which do
not have aminoxy groups), that predominantly correspond to
the hydrogen-bonded amide-NH. Weak signatures of non-
hydrogen-bonded amide-NH and aminoxy-NHs are also noticed
around ∼3450 and ∼3390 cm-1, respectively. The increase in
MD calculations for dimer 6 (a) and trimer 7 (b).
two-atom 5-hb as a part of a three-center bifurcated hydrogen
bond is not uncommon in peptidomimetics,15 biopolymers,16
and natural products17 and also has been found to be crucial in
stabilizing the side chain of taxol.18 The formation of 5-hb in
the present compounds has been further confirmed by analyzing
the monomeric reference 4, which showed NOE pattern and
DMSO titration (∆δNHa ∼0.15 ppm) very similar to that
observed for NHa of 5-8 (Supporting Information). The ROESY
data of trimer (Phth)-7 has also exhibited unambiguous and
similar periodic ROEs as in 6 and 8, which supported the
propagation of 5/7-hb ribbon-like backbone in this higher
oligomer. Furthermore, the observed long-range ROEs (weak)
CδHi-2-CꢀHi and CδHi-2-CRHi suggest that the backbone is
not fully stretched4f (Figure 2c). The NMR spectra of dimer
(Piv)-9 and trimer (Piv)-10 also showed signatures of secondary
folding (Supporting Information). However, a detailed structural
elucidation has been hampered due to the presence of rotamers,
which is not the case with 4-8.
The minimum energy structures derived from ROE-restrained
MD calculations for 5-8 by following simulated annealing
protocol (Insight-II) (Supporting Information) are found to be
in good agreement with those discussed above. Superposition
of these structures (Figure 3) showed good convergence,
suggesting a predominantly single backbone conformation
composed of bifurcated 5/7-hb rings. The measured values of
5/7-hb distances (∼2.3 Å), NOCꢀCR (112 ( 10°), θ (40 (
(17) (a) Baur, W. H. Acta Crystallogr. 1965, 19, 909. (b) Taylor, R.; Kennard,
O.; Versichel, W. J. Am. Chem. Soc. 1982, 104, 244. (c) Jeffrey, G. A.; Mitra,
J. J. Am. Chem. Soc. 1982, 104, 5546. (d) Reutzel, S. M.; Etter, M. C. J. Phys.
Org. Chem. 1992, 5, 44.
(18) (a) Miller, R. W.; Powell, R. G.; Smith, C. R.; Arnold, Jr. E.; Clardy,
J. J. Org. Chem. 1981, 46, 1469. (b) Mastropaolo, D.; Camerman, A.; Luo, Y.;
Brayer, G. D; Camerman, N. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6920. (c)
Gao, Q.; Chen, S. H. Tetrahedron Lett. 1996, 37, 3425. (d) Gao, Q.; Parker,
W. L. Tetrahedron 1996, 52, 2291.
(19) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008.
(20) (a) Yang, D.; Zhang, Y. H.; Li, B.; Zhang, D. W.; Chan, J. C. Y.; Zhu,
N. Y.; Luo, S. W.; Wu, Y. D. J. Am. Chem. Soc. 2004, 126, 6956. (b) Chen, F.;
Song, K. S.; Wu, Y. D.; Yang, D. J. Am. Chem. Soc. 2008, 130, 743. (c) Chen,
F.; Zhu, N. Y.; Yang, D. J. Am. Chem. Soc. 2004, 126, 15980.
J. Org. Chem. Vol. 73, No. 23, 2008 9445

was stirred for overnight at room temperature, solvent was removed
under reduced pressure, and the mixture was washed with brine
(10 mL) and extracted with EtOAc (4 × 60 mL). The combined
organic solution was dried (Na2SO4) and concentrated in vacuo.
This treatment afforded the intermediate acid 3, which was dissolved
in dry CH2Cl2/DMF (1:1, 40 mL), to which were added sequentially
HOBt (1.88 g, 13.7 mmol) and EDCI (2.63 g, 13.7 mmol) at 0 °C
under N2 atmosphere. After 10 min, isobutyl amine (1.1 mL, 11
mmol) was added to the reaction mixture. The reaction mixture
was allowed to warm room temperature and stirred further for 12 h
under N2 atmosphere. It was diluted with CHCl3 and washed with
5% aqueous NaHCO3 solution (15 mL), water (15 mL), and brine
(15 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. Silica gel column chromatography
(EtOAc/hexanes, 30:70) of the residue gave 5 (2.46 g, 69% yield)
as a white solid, mp 230.5-234.8 °C; [R]D ) -37.0 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.88-7.74 (m, 4H), 6.62 (t, J )
5.8 Hz, 1H), 6.21 (d, J ) 3.6 Hz, 1H), 5.10 (d, J ) 3.6 Hz, 1H),
4.90 (d, J ) 3.6 Hz, 1H), 4.85 (d, J ) 3.6 Hz, 1H), 3.24 (qn, J )
6.5 Hz, 1H), 3.10 (qn, J ) 6.5 Hz, 1H), 1.87-1.76 (m, 1H), 1.52
(s, 3H), 1.34 (s, 3H), 0.92 (s, 3H), 0.91 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 165.2, 163.2, 134.7, 128.7, 123.7, 113.1, 105.3,
88.7, 81.5, 79.5, 46.4, 28.3, 26.8, 26.3, 20.0. ESI (MS): m/z 427
[M + Na]+, ESI-HRMS calcd for C20H24N2O7Na [M + Na]+
427.1481, found 427.1465.
the population of the hydrogen-bonded aminoxy-NHs in dimer
(Phth)-6 is reflected in the intensity of its band at 3235 cm-1
.
However, the relatively higher values (by ∼10 cm-1) of
aminoxy-NH bands compared to those in other ꢀ-aminoxy
peptides may be due to the weaker bifurcated hydrogen bonding,
which is consistent with the NMR data.
In summary, we have reported the synthesis and characteriza-
tion of a new class of ꢀ-aminoxy acid motif, cis-ꢀ2,3-FSAOA
and its short oligomers. The DFT, NMR, and MD studies
highlight that the combination of geometry around ꢀ2,3 positions
on the sugar ring constrained backbone and rigid N-O
conformation exerts significant control of the folding preferences
in the compounds studied. The results showed that the peptidic
backbone accesses unusual ribbon-like secondary structure
favoring 5/7 bifurcated intramolecular hydrogen-bonded rings,
in contrast to the 9-helical turns in trans-cyclo alkane con-
strained ꢀ-aminoxy acid oligomers. These findings offer scope
for generating diverse rigid scaffolds with residue based
conformational control of the folding propensities.
Experimental Section
(3aR,5S,6R,6aR)-6-(1,3-dioxoisoindolin-2-yloxy)-N-isobutyl-2,2-
dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole-5-carboxamide (5). To
a stirred solution of compound 2 (3.2 g, 8.76 mmol) in 80% aqueous
THF (35 mL) was added NaIO4 (3.75 g, 17.5 mmol) in three
portions at 0 °C. After 6 h, the reaction mixture was filtered and
washed with EtOAc (50 mL). The filtrate was concentrated, taken
in ether, washed with water (15 mL) and brine (15 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. This protocol
afforded the intermediate aldehyde, which was dissolved in CH3CN
(18 mL), and to this were added a solution of NaClO2 (1.3 g, 14.4
mmol) in 10 mL of water, NaH2PO4 (1.72 g, 14.4 mmol) in 7 mL
of water, and 30% H2O2 (4.35 mL, 38.4 mmol) at 0 °C. The mixture
Acknowledgment. C.L.R., G.D.S., M.U.K., P.N., and G.K.S.
thank CSIR-New Delhi for the award of research fellowships.
Supporting Information Available: Experimental proce-
dures, copies of 1H and 13C NMR spectra, NMR details, solvent
titration plots, and MD studies. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO801810Z
9446 J. Org. Chem. Vol. 73, No. 23, 2008