Synthesis and structural characterization of homochiral homo-oligomers of parent cis- and trans-furanoid-β-amino acids

Article abstract of DOI:10.1002/chem.201101855

The synthesis of homochiral homo-oligomers of cis- and trans-3- aminotetrahydrofuran-2-carboxylic acids (parent cis- and trans-furanoid-β- amino acids, referred to as "cis-/trans-FAA") has been carried out to understand their secondary structures and their dependence on the ring heteroatom. The oligomers of two diastereomers have been shown to have a distinct left-handed helicity. The cis-FAA homo-oligomers show a 14-helix structure, in contrast to the homo-oligomers of cis-ACPC, which adopt a sheet like structure. The trans-FAA homo-oligomers were found to adopt a 12-helix structure, the same trend found in trans-ACPC homo-oligomers. With the help of ab initio calculations, the structural features of cis-ACPC and cis-FAA hexamers were compared. We believe that the more compact packing of the cis-FAA hexapeptide should be due to a more favorable interaction between the ring and the backbone amide hydrogen. It's the heteroatom that counts: trans-Furanoid-β-amino acid (FAA) homo-oligomers adopt a 12-helix structure similar to that of trans-ACPC (2-aminocyclopentane carboxylic acid) oligomers. However, cis-FAA oligomers seem to adopt 14-helix solution structures, which is in contrast to cis-ACPC oligomers, for which a sheetlike structure has been observed. Calculations reveal that this preference in cis-FAAs is due to a more favorable contact between the backbone and the ring (see scheme). Copyright

Full text of DOI:10.1002/chem.201101855

DOI: 10.1002/chem.201101855
Synthesis and Structural Characterization of Homochiral Homo-oligomers of
Parent cis- and trans-Furanoid-b-Amino Acids
Sunil K. Pandey,[a] Ganesh F. Jogdand,[b] Jo¼o C. A. Oliveira,[c] Ricardo A. Mata,*[c]
Pattuparambil R. Rajamohanan,[b] and Chepuri V. Ramana*[a]
Abstract: The synthesis of homochiral
homo-oligomers of cis- and trans-3-
aminotetrahydrofuran-2-carboxylic
acids (parent cis- and trans-furanoid-b-
amino acids, referred to as “cis-/trans-
FAA”) has been carried out to under-
stand their secondary structures and
their dependence on the ring hetero-
homo-oligomers show a 14-helix struc-
ture, in contrast to the homo-oligomers
of cis-ACPC, which adopt a sheet like
structure. The trans-FAA homo-oligo-
mers were found to adopt a 12-helix
structure, the same trend found in
trans-ACPC homo-oligomers. With the
help of ab initio calculations, the struc-
tural features of cis-ACPC and cis-
FAA hexamers were compared. We be-
lieve that the more compact packing of
the cis-FAA hexapeptide should be
due to a more favorable interaction be-
tween the ring and the backbone
amide hydrogen.
Keywords: ab initio calculations ·
amino acids · density functional cal-
culations · secondary structures ·
peptides
ACHTUNGTRENNUNGatom. The oligomers of two diastereo-
mers have been shown to have a dis-
tinct left-handed helicity. The cis-FAA
Introduction
the homo-oligomers derived from the cis-2-aminocyclopen-
tane carboxylic acid (cis-ACPC) form a sheet-like struc-
ture.[5d] Interestingly, the homo-oligomers of the cis-fura-
noid-b-amino acid 3 adopt a stable 14-membered helix
(Scheme 1),[7a] unlike the sheet structure formed by cis-
ACPC homo-oligomers.[5d] This difference has been attribut-
ed to the rigid conformation of the furanose ring in 3 be-
cause of the 1,2-acetonide group. The synthesis of the corre-
sponding trans-b-aminofuranose acid 4 has been reported,[7i]
however no information about the corresponding homo-olig-
In recent years, several approaches have been put forward
to address the mimicking of the secondary structures of the
peptides on the one hand and the in vitro stability of syn-
thetic peptides for medicinal applications on the other.[1]
The groups of Seebach and Gellman have introduced b-pep-
tides as expeditious tools in this context.[2] The homo- and
heterooligomeric b-peptides have been shown to adopt di-
verse secondary structures (helices, sheets, and turns) and
form interesting molecular architectures by self assembly.[3]
The homo-oligomers derived from the conformationally
ꢀ
constrained (through ring annulations at the Ca Cb bond) b-
amino acids have been the subject of extensive structural in-
vestigations.[4–7] The nature of the secondary structure of
their homo-oligomers seems to depend mainly upon 1) the
relative stereochemistry of the amine and acid groups,
2) ring atoms, and 3) the ring size. For example, the homo-
oligomers constructed by the trans-2-aminocyclopentane car-
boxylic acid (trans-ACPC) form a stable 12-helix,[5c] whereas
[a] Dr. S. K. Pandey, Dr. C. V. Ramana
Division of Organic Chemistry
[b] G. F. Jogdand, Dr. P. R. Rajamohanan
Central NMR Facility, National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411-008 (India)
Fax : (+91)20-25902629
[c] J. C. A. Oliveira, Prof. Dr. R. A. Mata
Institute for Physical Chemistry
Tammannstrasse 6, 37077 Gçttingen (Germany)
Fax : (+49)551-39-3144
E-mail: rmata@gwdg.de
Scheme 1. Five-membered-ring constrained b-amino acids and the secon-
dary structures reported for the corresponding homo-oligomers and the
simple cis-/trans-furanoid-b-amino acids.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101855.
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Chem. Eur. J. 2011, 17, 12946 – 12954

FULL PAPER
Scheme 2. Synthesis of cis-/trans-b-FAA monomers 8/8-Me, and 9/9-Me.
omers has been documented. Very recently, Cosstick and
co-workers have documented the synthesis of the oligomers
of nucleic acid derived furanoid-b-amino acid 5 and showed
that they adopt an unusual 8-membered helix,[7d] which has
partly been attributed to the b4-carbon substituent. Interest-
ingly, for the same tetramer, Chandrasekharꢁs group had re-
ported a 12-helix solution structure.[7e]
From the structures of the furanoid-b-amino acids report-
ed, it is clear that each b-FAA has its own unique structural
elements. What is presently blocking a systematic analysis of
the b-FAAs and the prediction of their secondary structures
is the absence of a basis of comparison, such as the parent
furanoid-b-amino acids 6 and 7 proposed herein. The struc-
tural analysis of the homo-oligomers of 6 and 7 has the po-
tential to provide considerable insight into the influence of
the ring heteroatom along with setting a basis for compari-
son between the homo-oligomers of FAAs. In this report,
we document the synthesis of the homo-oligomers of 6 and
7 and reveal their secondary structures in solution. With the
help of ab initio calculations, we reason that the homo-oligo-
mers of cis-FAAs favor a 14-helix structure over a sheet-like
structure (reported for the cis-ACP oligomers) due to a
more favorable contact between the backbone and the ring.
shown in Scheme 2, in CH2Cl2 the regioselectivity towards
the opening at C(3) was high and 13/14 were obtained in a
7:1 ratio. The free hydroxyl group of 13 was converted to
the corresponding mesylate and subjected to the nucleophil-
ic displacement with azide to obtain the azidoacetal 15 in
70% yield. The acetal group in 15 was deprotected by em-
ploying 50% TFA at 08C to room temperature and the re-
sultant crude aldehyde was oxidized to acid 8 by treating
with sodium chlorite and sodium dihydrogen phosphate in
tBuOH and water in the presence of 2-methyl-2-butene as a
scavenger. Treatment of acid
8 with diazomethane in
CH2Cl2/ether at 08C gave the methyl ester 8-Me. To prepare
the trans-FAA, the free C(3)-OH of 13 was oxidized under
Swern conditions and the resulting ketone was reduced with
sodium borohydride in MeOH to procure 16. Compound 16
was transformed to the corresponding acid 9 and ester 9-Me
by following a similar reaction sequence as used in the syn-
thesis of 8/8-Me from 15.
The synthesis of corresponding homo-oligomers was ach-
ieved in two steps (Scheme 3). In the first step, the reduc-
tion of the azide group was carried out by employing Raney
nickel in EtOH under a hydrogen atmosphere at room tem-
perature to obtain the corresponding amine, which was cou-
pled immediately with the acid by using 1-ethyl-3-(3-di-
AHCTUNGTREGmNNNU ethylaminopropyl)carbodiimide (EDCI) and hydroxyben-
Results and Discussion
zotriazole (HOBt), diisopropylethylamine (DIPEA) in
CH2Cl2 at room temperature to afford the homo-oligomers
in 35–73% yield. In case of the trans-b-FAA oligomers, we
could only prepare the hexamer. The synthesis of the octa-
mer was hampered by the poor solubility of the coupling
partners.
For a preliminary understanding of the secondary struc-
tures across the series 18–21, their CD data were recorded
in methanol and trifluoroethanol at 200 mmol concentra-
The synthesis of the monomeric building blocks began with
acid-mediated ring transposition from the known ditosylate
10 to procure the dimethylacetal 11 in quantitative yields.
The treatment of dimethylacetal with potassium carbonate
in methanol provided the oxirane 12.[8] The regiochemistry
of the opening of epoxide 12 with diisobutylaluminum hy-
dride (DIBAL-H) was found to be solvent dependent. As
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C. V. Ramana, R. A. Mata et al.
Scheme 3. Reagents and conditions: a) Raney Ni, H2, RT, EtOH, 2 h; b) NaOH (aq), dioxane, RT, 1 h; c) EDCI, HOBt, DIEA, CH2Cl2, 24–40 h, RT.
tions. As shown in Figure 1i)a), the CD spectra of cis-dimer
18 did not show any significant ellipticity. The CD spectrum
of cis-tetramer 19 displays a shallow minimum at about
219 nm and a maximum at about 193 nm. The hexamer 20
and the octamer 21 have a CD pattern similar to that of 19,
except that both the minimum and maximum are slightly
redshifted (220 and 195 nm) and more intense for 21. The
pattern observed for cis-FAA oligomers indicates a left-
handed 14-helix (slightly redshifted) and is in agreement
with the data reported for the cis-FAA 3 oligomers. The CD
spectrum of 20 in trifluoroethanol (Figure 1i)b)) shows the
two minima at about 221 and 214 nm, a maximum at about
193 nm, and zero crossing at about 211 nm. In the CD spec-
trum of 21 in trifluoroethanol, the minimum at about
214 nm, maximum at about 193 nm, and zero crossing at
about 211 nm revealed that 21 adopted a robust 14-helix
structure.
The CD spectra of trans-dimer 22, trans-tetramer 23 and
trans-hexamer 24 in methanol showed maxima at 198 nm,
zero crossing at 207 nm, and minima at 222 nm (Fig-
ure 1ii)a)). This CD pattern suggests a left-handed 12-helix
and is similar to the trans-ACPC 2 homo-oligomers and also
cyclic-pyrrolidine-based trans-b-amino acid homo-oligomers.
The CD spectra of trans-FAA (22–24) showed a similar pat-
tern in trifluroethanol as in methanol.
The 2D NMR of the homo-oligomers was recorded in
CDCl3 (except for 24 for which [D6]DMSO was used). For
all the oligomers, the amide protons are well-resolved and
displayed a downfield shift (d=6.8–8.5 ppm) that suggested
ꢀ
their involvement in hydrogen bonding. The N H chemical
shifts are concentration independent, which indicates that
this downfield shift is due to internal structure rather than
molecular aggregation. Further, the solvent titration studies
(by adding the [D6]DMSO up to 33% v/v, see Figures SI1–
SI9 of the Supporting Information) and variable-tempera-
ture experiments (from 0–508C by 58C intervals (see Fig-
Figure 1. The CD spectral graph of i) cis-b-FAA oligomers a) in MeOH
b) in TFE and ii) trans-b-FAA oligomer a) in MeOH b) in TFE.
AHCTUNGTREGuNNNU res SI1–SI9 of the Supporting Information) support the in-
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Homooligomers of Parent cis- and trans-Furanoid-b-Amino Acids
FULL PAPER
tramolecular hydrogen bonding present in these oligomers.
ACPC hexamers were used as starting estimates for the cis-
FAA structures by introducing an O atom in each building
block in place of a CH2 fragment. This was followed by opti-
mization at the same level of theory. We adopted this proce-
dure to maximize the conformational similarity between the
two different hexapeptides, which allows for a comparison
on a relatively equal footing, while avoiding an extensive
minima search. This would be prohibitive due to the system
size, even if semiempirical methods were to be used. Alter-
natively, one could opt for the use of molecular mechanics
(MM). Although recent efforts have been made in obtaining
reliable MM parameters for the description of b-peptides,
such as in the case of ACPC,[11] there is no consistent set
available for both molecules considered in this study. In a
final set of calculations, density-fitted local second order
Møller–Plesset theory (DF-LMP2)[12a] single points were car-
ried out on each structure, including solvent effects through
the COSMO model.[13] Two dielectric constant values were
used for each conformer, e=26.14 (trifluoroethanol) and e=
80.10 (water). The basis set used was the Dunning cc-pVTZ
basis,[12b] with diffuse functions added to the non-hydrogen
atoms.[14] This basis will be hereafter referred to as aug’-cc-
pVTZ. In the local calculations, Pipek–Mezey orbitals[15]
were used in combination with the NPA domain selection
criteria,[16] with TNPA=0.03. The implementation details of
DF-LMP2 in combination with the COSMO model will be
published elsewhere.[17] All calculations were carried out
with a development version of the software package Molpro
2010.2.[18]
1
In the H NMR spectrum of the tetramer 19, the observed
3J
N
cates an antiperiplanar arrangement of NH and CbH protons
and f=138ꢁ28 (C(O)-N-Cb-Ca, see Table SI1, Supporting
Information for complete details). NOESY data of 19 (Fig-
ure SI10 in the Supporting Information) reveal some inter-
residue medium to long range NOE signals between
CaH(i)!NH(i+1), NH(i+2)!CaH(i+3) and NH(i+2)!MeO2C).
In the case of the hexapeptide 20, several inter-residue
NOEs NH(i+1)!CbH(i+3)
,
NH(i+2)!CbH(i+4)
,
NH(i+3)
!
CbH(i+5) were observed that confirmed a 14-helix (Figure 2).
Figure 2. Observed NOEs for cis-FAA oligomer 20.
Due to the overlapping CbH protons, the NOEs between
CbH and CaH could not be assigned. The observed long
range NOEs between NH(i+1)!CbH(i+3), NH(i+2)!CbH(i+4)
,
NH(i+2)!CaH(i+4), NH(i+3)!CbH(i+5), NH(i+3)!CaH(i+5), and
NH(i+4)!CbH(i+6), supported the 14-helix structure proposed
from the CD data of octamer 21 (Figure SI11 in the Sup-
porting Information).
Both the b-sheet and the 14-helix structures for the cis-
ACPC and cis-b-FAA hexamers were optimized in the gas
phase, and by using a continuum description of trifluoro-
The presence of a 12-helix structure in a solution of trans-
b-FAA oligomer 23 was confirmed with the help of the ob-
served inter-residue NOEs (Figure SI12 in the Supporting
Information) Due to the overlapping of two of the five
ACHTUNGTRENeNUGN thanol and water. In Figure 3 we present a superposition of
the optimized cis-FAA geometries. The allylic hydrogen
atoms were removed for a better visualization.
We will start by discussing the optimized 14-helix struc-
tures. A comparison of the cis-ACPC and the cis-FAA struc-
tures shows that the differences are relatively subtle. A first
observation would be that the cis-ACPC hexapeptide shows
a hydrogen bond between the methyl ester cap carbonyl
group and the i-3 residue, which is absent in the cis-FAA
case. This is due to the fact that the ester group in the cis-
ACPC oligomer presents an eclipsed conformation, instead
of a gauche conformation as is observed in the cis-FAA oli-
gomer. It is relatively difficult to judge whether this is an
effect directly linked to the substitution in the ring or an ar-
tifact from our optimization approach. One would need a
more complete study of the conformational landscape, using
more than a single structure for each conformer. We would
also like to note that such changes in the terminal ends can
easily happen due to the conformational flexibility in these
regions, but should have a rather small effect in the relative
conformational energies. Comparing the remaining hydro-
gen bond distances and angles, we see only small changes
(hydrogen bonds vary by about 0.05 ꢂ, well within the mean
square root deviation). In conclusion, there are no structural
features that would support the idea of enhanced hydrogen
1
amide protons in the H NMR spectra of 24, interpretation
of some of the observed long-range NOEs is complicated.
The important inter-residue NOEs observed in the NOESY
of the trans-hexamer 24 which supported a left-handed 12-
helix are given in Figure SI.13 (in the Supporting Informa-
tion). The dihedral angles (f)=1358 and (q)=52ꢁ28 calcu-
3
3
lated from the observed JACTHNUTRGENNUG(NH-CbH)>7.6 Hz and JHCATUNGTREN(NGUN CaH-
CbH)<5.0 Hz are in support of the 12-helix structure. We
now turn to the theoretical results
Computational results: The model structures for the ACPC
hexamers, both cis and trans isomers, were built on the basis
of previous structural studies. The same caps were used as in
the experiment, namely an azide group and a methyl ester.
A set of geometries was obtained by varying the dihedral
angles of the backbone. To generate suitable starting struc-
tures, preliminary optimizations with varying dihedral angles
were carried out with the RM1 semiempirical method, as
implemented in the MOPAC quantum chemistry program
package.[9] The structures thus obtained were then optimized
at the B3LYP/6-31G* level of theory.[10] The minima of cis-
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C. V. Ramana, R. A. Mata et al.
in turn, f=ꢀ145.868, q=38.708, and y=ꢀ114.068. The y
dihedral angles are usually taken as the determining param-
eters for the backbone structure.[19] We observe that the cis-
FAA 14-helix presents a smaller y. This is in agreement
with the SASA ratio, which supports the idea of tighter
packing in the cis-FAA hexapeptide.
The b-sheet structures are kept almost unchanged from
one case to the other. Aside from a distortion in the rings,
the angles are perfectly comparable. This is mostly expected,
since an unstrained conformation should only weakly
depend on substitutions in the ring.
The relative energies for the cis-ACPC and cis-FAA hexa-
peptides are displayed in Table 1. The values are given as
the energy difference E
G
ACHTUNGERTN(NUNG b-sheet), so that posi-
Table 1. Relative energy differences (in kcalmolꢀ1) between the b-sheet
and 14-helix conformers computed at the DF-LMP2/aug’-cc-pVTZ level
of theory (E
(14-helix)ꢀE
ACHTUNGTREN(NUNG b-sheet)). The structures were optimized with
B3LYP/6-31G*. The COSMO model was used to approximate solvent ef-
fects for both single point and optimization runs. The DFT energies are
given in parenthesis, for comparison.
cis-ACPC
cis-FAA
gas phase
trifluoroethanol
water
6.0 (17.1)
3.3 (12.8)
3.4 (12.3)
ꢀ16.7 (ꢀ4.3)
ꢀ7.7 (1.4)
ꢀ8.6 (2.3)
tive values indicate a larger stabilizing force for the b-sheet,
whereas negative values indicate that the 14-helix conforma-
tion is more stable. In this case, we also look at the results
obtained from including an approximate solvent description.
In the case of trifluoroethanol and water, the COSMO
model was used both in the optimization step as well as in
the DF-LMP2 calculation. In agreement with previous ex-
perimental[5d] and theoretical studies,[3b] the cis-ACPC hexa-
peptide has a preference for the b-sheet conformation. The
DF-LMP2 energy differences between the latter and the 14-
helix range between 3.8 kcalmolꢀ1 in water and 6.0 kcal
molꢀ1 in the gas phase. However, in the case of cis-FAA, the
ordering is inverted. In the gas phase, as well as in the two
solvents considered, the 14-helix conformer is more stable.
The relative energies are almost unchanged in going from
trifluoroethanol to water. Although we do not take into ac-
count the explicit structure of the solvent around the oligo-
peptide, this is already an indication that the energetic or-
dering should only be marginally affected by the solvent in
use. The largest difference is in the cis-FAA case, on going
from the gas phase to trifluoroethanol (9 kcalmolꢀ1).
Comparing now the cis-FAA to the cis-ACPC, the differ-
ences in the relative energies are quite pronounced. In total,
there is a shift of 10–23 kcalmolꢀ1. Although the hydrogen-
bonding network is one of the main structural features in
the 14-helix, changes in these bonds could not explain such
a difference. Each bond should contribute only 2–5 kcal
molꢀ1, and since we do not observe significant changes in
distances/angles, it would be difficult to sum their contribu-
tions to such a large value. A destabilization of the b-sheet
Figure 3. Superimposed optimized structures for the cis-FAA b-sheet
(left) and cis-FAA 14-helix (right) under different solvent descriptions.
The structures are color coded distinguishing gas phase (blue) from tri-
fluoroethanol (red), and water (gray).
bonding in the cis-FAA case. However, there is a visible dif-
ference in the tightness of the loop. Comparing the distances
between the backbone amide hydrogen and the ring oxygen
(cis-FAA) or carbon (cis-ACPC) the distances in the former
case are found to be much shorter. In the 14-helix cis-FAA
the hydrogen is 2.1–2.2 ꢂ away from the oxygen. In the cis-
ACPC the distance between the ring carbon and the hydro-
gen is 2.5–2.6 ꢂ. The reasons behind this difference are
straightforward. By replacing a CH2 group with an oxygen
atom, one reduces steric effects and also introduces a favor-
able electrostatic interaction between the latter and the
amide hydrogen. We have also calculated the solvent-acces-
sible surface area (SASA) for the 14-helix structures. This
shows that the cis-FAA 14-helix exhibits an accessible area
6% smaller than cis-ACPC. This would mean that the
former structure is more compact. This is in line with our
observation above. The loop in the cis-FAA can be made
much tighter as a repulsive interaction between the back-
bone and the ring has been removed. A closer look into the
backbone average dihedral angles for the 14-helix geome-
tries reveals that the cis-ACPC hexapeptide can be charac-
terized by the following angles: f=ꢀ138.668, q=46.108, and
y=ꢀ124.068. The cis-FAA hexapeptide average angles are,
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Homooligomers of Parent cis- and trans-Furanoid-b-Amino Acids
FULL PAPER
1
12 (50 g, 78% in two steps). H NMR (200 MHz, CDCl3): d=4.28 (d, J=
4.5 Hz, 1H), 4.08 (d, J=4.5 Hz, 1H), 3.97 (d, J=10.3 Hz, 1H), 3.83 (d,
J=10.3 Hz, 1H), 3.82 (d, J=3.0, 0.8 Hz, 1H), 3.78 (dd, J=3.0, 0.8 Hz,
1H), 3.46 (s, 3H), 3.44 ppm (s, 3H); 13C NMR (50 MHz, CDCl3 +CCl4):
d=54.8 (q), 55.8 (q), 56.0 (d), 56.3 (d), 67.5 (t), 77.4 (d), 104.6 ppm (d);
MS (ESI): m/z (%): 183.1 (100) [M+ +Na]; elemental analysis calcd (%)
for C7H12O4: C 51.49, H 7.55; found: C 51.73, H 7.53.
is also unlikely. There are no unfavorable contacts linked to
the ring oxygen. We argue that this effect can only be ex-
plained by a reduced strain in the 14-helix, as discussed
above in connection to the SASA values.
The B3LYP/6-31G* relative energies have also been in-
cluded in Table 1. At this lower level of theory, the 14-helix
is strongly disfavored, with the cis-FAA hexapeptide even
becoming less stable than the b-sheet conformation in both
solvents. The reason behind the discrepancy between DF-
LMP2 and B3LYP is easy to understand. The DFT method
is unable to correctly describe dispersion interactions, which
are of utmost importance to the stability of the helix. Al-
though the method is relatively suitable for obtaining quali-
tative structures of b-oligopeptides, one should be cautious
about comparing the energetics of such systems at the DFT
level. This is particularly true when comparing packed to ex-
tended conformers.
Reduction of 3,4-epoxy-5-(R-trans)-dimethoxymethyltetrahydrofuran
(12): At 08C, diisobutylaluminium hydride (250 mL, 2.5m solution in tol-
uene, 625 mmol) was added to a solution of 12 (50 g, 212.5 mmol) in dry
CH2Cl2 (800 mL) and the reaction mixture was stirred until compound 12
was consumed. The reaction mixture was cooled to ꢀ108C and quenched
by adding MeOH (30 mL) and saturated sodium potassium tartrate. The
resulting suspension was filtered, dried (Na2SO4) and concentrated. The
crude product was subjected to chromatographic purification (25% ethyl
acetate in petroleum ether) to yield 13 (37.5 g, 74%) and the regioisomer
14 (4.6 g, 9%) as colorless oils.
(2R,3R)-2-(Dimethoxymethyl)tetrahydrofuran-3-ol (13): [a]2D5 =ꢀ28.8
(c=2.0 in MeOH). 1H NMR (200 MHz, CDCl3): d=4.27 (dt, J=5.5,
2.5 Hz, 1H), 4.15 (d, J=5.7 Hz, 1H), 3.87 (dd, J=8.2, 5.7 Hz, 2H), 3.67
(dd, J=5.7, 3.5 Hz, 1H), 3.37 (s, 3H), 3.35 (s, 3H), 2.03 (ddd, J=12.8,
8.1, 6.9 Hz, 1H), 1.81 ppm (dddd, J=12.8, 9.4, 5.7, 3.7 Hz, 1H). MS
(ESI): m/z (%): 131 (100) [M+ꢀOCH3]; elemental analysis calcd (%) for
C7H14O4: C 51.84, H 8.70; found: C 51.69, H 8.61.
Conclusion
(3S,5R)-5-(Dimethoxymethyl)tetrahydrofuran-3-ol (14): [a]2D5 =ꢀ1.9 (c=
1.5, MeOH); 1H NMR (200 MHz, CDCl3): d=4.42 (ddd, J=5.8, 3.8,
1.8 Hz, 1H), 4.17 (d, J=6.7 Hz, 1H), 3.86 (dd, J=6.7, 3.8 Hz, 2H), 3.70
(dd, J=9.6, 3.9 Hz, 1H), 3.36 (s, 6H), 1.94–1.86 ppm (m, 2H); 13C NMR
(50 MHz, CDCl3 +CCl4): d=36.3 (t), 53.9 (q), 55.0 (q), 71.6 (d), 75.5 (t),
77.1 (d), 105.6 ppm (d); MS (ESI): m/z (%): 185.07 (100) [M+ +Na]; ele-
mental analysis calcd (%) for C7H14O4: C 51.84, H 8.70; found: C 51.73,
H 8.54.
To summarize, the homo-oligomers of two diastereomeric
FAAs have shown distinct left-handed helicity in which the
cis-FAA oligomers were showing 14-helix structures, which
is in contrast to the cis-ACPC, which adopt a sheet-like
structure. We observe that trans-FAA adopted a 12-helix
structure, like the trans-ACPC oligomers. The similar secon-
dary structures observed for the oligomers of cis-FAAs 6
and 3 reveal that a rigid conformation in the monomer may
not be sufficient premise for the noticed 14-helical confor-
mation, instead of sheet-like structure, of cis-ACPC homo-
oligomers. By comparing the structural features of cis-
ACPC and cis-FAA hexamers, we observe no marked
change in the hydrogen bond strength, but the overall con-
formation of the cis-FAA is seen to be more compact, favor-
ing close dispersion contacts. This is evidenced in comparing
DFT with DF-LMP2 results, in which the former lack the
description of van der Waals forces. The more compact
packing of the cis-FAA hexapeptide should be due to a
more favorable interaction between the ring and the back-
bone fold, primarily in the amide hydrogen pointing towards
the ring. The replacement of CH2 with oxygen removes
steric repulsion and introduces an electrostatic interaction
which allows for a tighter fold.
AHCTUNGTERG(NNUN 2R,3S)-3-Azido-2-(dimethoxymethyl)tetrahydrofuran (15): A solution of
13 (5.0 g, 38.83 mmol) and Et3N (9.8 mL, 69.37 mol) in CH2Cl2 (50 mL)
was treated with mesyl chloride (3.0 mL, 37.61 mol) at 08C and stirred
for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and
quenched with cold water and then washed with water and brine. The or-
ganic extract was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to obtain the intermediate mesylate (6.96 g, 94%) as a
liquid. A portion of the mesylate was purified by column chromatogra-
phy for the analytical data. Otherwise the crude mesylate was directly
subjected to azidation reaction. 1H NMR (200 MHz, CDCl3): d=5.18–
5.10 (m, 1H), 4.23 (dd, J=4.2, 1.0 Hz, 1H), 4.05–3.96 (m, 2H), 3.86 (ddd,
J=8.3, 7.8, 1.3 Hz, 1H), 3.42 (s, 3H), 3.40 (s, 3H), 2.99 (s, 3H), 2.22–
2.12 ppm (m, 2H); 13C NMR (50 MHz, CDCl3 +CCl4): d=33.8 (t), 37.6
(q) 54.6 (q), 56.3 (q), 67.2 (t), 82.0 (d), 83.6 (d), 103.8 ppm (d); MS (ESI):
m/z (%): 263.1 (100) [M+ +Na].
The mesylate (6.9 g, 28.27 mmol) was dissolved in dry DMSO (180 mL)
and sodium azide (5.6 g, 86.15 mmol) was added. The contents were
stirred at 1008C for 12 h. The reaction mixture was diluted with EtOAc
(450 mL), washed with water (3ꢃ80 mL). The organic extract was
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by silica gel column chromatog-
raphy (10!20% EtOAc in petroleum ether) to obtain 15 (4.03 g, 75%)
as a colorless oil. [a]D25 = +46.8 (c=1, CHCl3); 1H NMR (200 MHz,
CDCl3): d=4.47 (d, J=7.5 Hz, 1H), 4.10 (ddd, J=5.6, 3.9, 1.7 Hz, 1H),
4.04–3.92 (m, 1H), 3.88 (dd, J=8.6, 4.2 Hz, 1H), 3.76 (dd, J=7.5, 3.9 Hz,
1H), 3.44 (s, 3H), 3.43 (s, 3H), 2.29–2.00 ppm (m, 2H); 13C NMR
(50 MHz, CDCl3 +CCl4): d=32.4 (t), 53.5 (q), 55.0 (q), 62.7 (d), 66.7 (t),
80.7 (d), 103.2 ppm (d); IR (CHCl3): n˜ =3352, 2939, 2888, 2833, 2514,
2105, 1634, 1445, 1401, 1333, 1274, 1192, 1144, 1083, 1018, 977, 959, 931,
873, 757, 666 cmꢀ1; MS (ESI): m/z (%): 210.1 (100) [M+ +Na], 226.0 (65)
[M+ +K], 188.2 (45) [M+ +1]; elemental analysis calcd (%) for
C7H13N3O3: C 44.91, H 7.00, N 22.45; found: C 44.83, H 6.89, N 22.39.
Experimental Section
3,4-Epoxy-5-(R-trans)-dimethoxymethyltetrahydrofuran (12): A solution
of ditosyl compound 10 (200 g, 400 mmol) was dissolved in MeOH
(1.6 L) and treated with a catalytic amount of p-toluene sulfonic acid
(6.4 g, 10.0 mmol) and heated to reflux for 24 h. After completion, the re-
action mixture was cooled to 08C and added the potassium carbonate
(138.4 g, 1.0 mol) and stirred at RT for 2 h. The reaction mixture was fil-
tered (Celite), neutralized (1n HCl) and concentrated under reduced
pressure. The crude product was extracted with EtOAc and the ethyl ace-
tate layer was washed with brine, dried (Na2SO4), and concentrated. The
crude product was purified by silica gel column chromatography to give
AHCTUNGTERG(NNUN 2R,3S)-3-Azidotetrahydrofuran-2-carboxylic acid (8): A suspension of
azido-acetal 15 (15 g, 80.13 mmol) in trifluoroacetic acid (50%, 150 mL)
was stirred at RT for 12 h. The reaction mixture was cooled to 08C
CH2Cl2 (200 mL) and then neutralized with sodium bicarbonate and ex-
Chem. Eur. J. 2011, 17, 12946 – 12954
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12951

C. V. Ramana, R. A. Mata et al.
tracted with CH2Cl2 (3ꢃ200 mL). The combined organic layer was
washed with brine, dried (Na2SO4), and concentrated under reduced pres-
sure. The resulting crude aldehyde was used directly for the next step
without any further purification.
A solution of the above crude mesylate in DMSO (100 mL) was treated
with sodium azide (6.0 g, 92.5 mmol) and the contents were stirred at
1008C for 5 h. The reaction mixtures were cooled to RT and diluted with
EtOAc (500 mL), washed with water (3ꢃ100 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (10!20% EtOAc in petroleum ether)
to obtain 17 (12.12 g, 48%, from 13) as a colorless oil. [a]2D5 =ꢀ18.2 (c=
1.0, CHCl3); 1H NMR (200 MHz, CDCl3): d=4.25 (d, J=4.9 Hz, 1H),
4.10 (dd, J=7.5, 3.8 Hz, 1H), 4.01–3.92 (m, 1H), 3.88 (ddd, J=11.2, 8.4,
7.5 Hz, 2H), 3.43 (s, 3H), 3.42 (s, 3H), 2.15 (ddd, J=15.9, 13.1, 7.5 Hz,
1H), 1.89 ppm (dddd, J=13.1, 11.1, 4.5, 4.0 Hz, 1H); 13C NMR (50 MHz,
CDCl3 +CCl4): d=32.5 (t), 54.4 (q), 56.0 (q), 61.9 (d), 67.5 (t), 83.4 (d),
104.3 ppm (d); IR (CHCl3): n˜ =3400, 3083, 3015, 2937, 2866, 2835, 2110,
1588, 1494, 1462, 1443, 1408, 1306, 1226, 1186, 1129, 986, 930, 843, 814,
756, 666 cmꢀ1; MS (ESI): m/z (%): 210.1 (100) [M+ +Na], 226.0 (39)
[M+ +K], 188.2 (19) [M+ +1]; elemental analysis calcd (%) for
C7H13N3O3: C 44.91, H 7.00, N 22.45; found: C 44.83, H 7.12, N 22.17.
NaH2PO4·2H2O (2.24 g, 16.03 mmol dissolved in 15 mL water, pH 7) was
added to a cooled solution of the above aldehyde and 2-methyl-2-butene
(84.3 g, 1.20 mol) in tBuOH and H2O (2:1, 75 mL). Sodium chlorite
(80%, 27.18 g, 240.4 mmol) was added slowly and the resulting mixture
was stirred at RT for 10 h. After the reaction was completed, solid
NaHCO3 was added. The reaction mixture was extracted with CH2Cl2
(2ꢃ100 mL) and the CH2Cl2 layer was discarded. The aqueous layer was
neutralized with concd HCl and extracted with CH2Cl2 (3ꢃ200 mL). The
combined organic layer was dried (Na2SO4) and concentrated. The crude
product was purified by column chromatography (silica gel 20!90%
EtOAc in petroleum ether) to procure acid 8 (12.6 g, 73% over 2 steps)
as a colorless oil. [a]2D5 = +70.5 (c=1.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d=8.69 (sbr, 1H), 4.54 (d, J=5.1 Hz, 1H), 4.38 (ddd, J=7.7,
5.2, 2.6 Hz, 1H), 4.42–3.99 (m, 2H), 2.33–2.11 ppm (m, 2H); 13C NMR
(50 MHz, CDCl3 +CCl4): d=31.1 (t), 62.8 (d), 67.6 (t), 78.0 (d),
172.4 ppm (s); IR (CHCl3): n˜ =2960, 2560, 2115, 1746, 1483, 1330, 1272,
1113, 1085, 1026, 967, 937, 871, 789, 759, 698, 665 cmꢀ1; MS (ESI): m/z
(%): 180.1 (100) [M+ +Na], 196.3 (53) [M+ +K], 158.1 (32) [M+ +1]; el-
emental analysis calcd (%) for C5H7N3O3: C 38.22, H 4.49, N 26.74;
found: C 38.31, H 4.41, N 26.58.
AHCTUNGERTG(NNUN 2R,3R)-3-Azidotetrahydrofuran-2-carboxylic acid (9): Compound 9 was
prepared by using the procedure used for the preparation of compound
8. [a]2D5 =ꢀ91.8 (c=1.0, CHCl3); 1H NMR (200 MHz, CDCl3): d=8.99
(sbr, 1H), 4.42 (d, J=2.8 Hz, 1H), 4.38 (dt, J=6.1, 3.1 Hz, 1H), 4.20–
3.98 (m, 2H), 2.31–2.14 (m, 1H), 2.10–2.95 ppm (m, 1H); 13C NMR
(50 MHz, CDCl3 +CCl4): d=31.6 (t), 64.4 (d), 68.4 (t), 81.5 (d),
174.9 ppm (s); IR (CHCl3): n˜ =3020, 2400, 2107, 1602, 1519, 1475, 1432,
1217, 1094, 929, 771, 666 cmꢀ1; MS (ESI): m/z (%): 180.1 (100) [M+
+
ACHTUNGTRENNUNG(2R,3S)-Methyl 3-azidotetrahydrofuran-2-carboxylate (8-Me): At 08C, a
Na]; elemental analysis calcd (%) for C5H7N3O3: C 38.22, H 4.49, N
26.74; found: C 38.31, H 4.41, N 26.47.
solution of acid 8 (6.0 g, 38.2 mmol) in CH2Cl2 (50 mL) and was treated
with a solution of diazomethane in ether (300 mL) until the color of the
diazomethane persisted. The solution was kept standing for 2 h and treat-
ed with few drops of acetic acid to quench the residual diazomethane.
The solvent was removed and the residue was purified by silica gel
column chromatography (silica gel 15!25% EtOAc in petroleum ether)
to afford 8-Me (6.27 g, 96%) as colorless syrup. [a]2D5 = +10.4 (c=1.0,
CHCl3); 1H NMR (200 MHz, CDCl3): d=4.49 (d, J=5.3 Hz, 1H), 4.38
(ddd, J=8.2, 5.3, 2.8 Hz, 1H), 4.13 (dt, J=9.6, 7.2 Hz, 1H), 3.97 (ddd,
J=12.7, 8.2, 4.5 Hz, 1H), 3.79 (s, 3H), 2.34–2.10 ppm (m, 2H); 13C NMR
(50 MHz, CDCl3 +CCl4): d=31.5 (t), 51.5 (q), 62.6 (d), 67.1 (t), 79.8 (d),
168.8 (s); IR (CHCl3): n˜ =3359, 2956, 2894, 2560, 2112, 1760, 1439, 1326,
1268, 1113, 1033, 1013, 924, 869, 795, 745 cmꢀ1; MS (ESI): m/z (%): 194.1
(100) [M+ +Na], 233.0 (35) [M+ +K]; elemental analysis calcd (%) for
C6H9N3O3: C 42.10, H 5.30, N 24.55; found: C 42.19, H 5.37, N 24.49.
AHCTUNGERTG(NNUN 2R,3R)-Methyl 3-azidotetrahydrofuran-2-carboxylate (9-Me): The
esterification of acid 9 (6 g, 38.2 mmol) with diazomethane following the
procedure used in the preparation of 8-Me, gave 9-Me (6 g, 92%) as col-
orless oil. [a]2D5 = +34.5 (c=1.5, CHCl3); 1H NMR (200 MHz, CDCl3):
d=4.38 (d, J=3.0 Hz, 1H), 4.26 (dd, J=6.5, 3.2 Hz, 1H), 4.13 (dd, J=
8.5, 4.3 Hz, 1H), 4.04–3.96 (m, 1H), 3.77 (s, 3H), 2.28–2.17 (m, 1H),
2.08–1.94 ppm (m, 1H); 13C NMR (50 MHz, CDCl3 +CCl4): d=31.5 (t),
52.5 (q), 64.3 (t), 68.1 (d), 81.7 (d), 170.9 ppm (s); IR (CHCl3): n˜ =3020,
2974, 2874, 2842, 2112, 1753, 1655, 1598, 1504, 1479, 1463, 1415, 1342,
1215, 1134, 1113, 1028, 928, 889, 866, 756, 668 cmꢀ1; MS (ESI): m/z (%):
194.1 (100) [M+ +Na], 233.0 (31) [M+ +K]; elemental analysis calcd (%)
for C6H9N3O3: C 42.10, H 5.30, N 24.55; found: C 42.31, H 5.18, N 24.57.
Synthesis of cis-dipeptide (18): A solution of azido ester 8-Me (1 g,
5.84 mmol) in EtOH (20 mL) was stirred under an atmosphere of hydro-
gen in the presence of Raney nickel (0.5 g,) for 1 h. After the completion
of reaction as indicated by TLC, the reaction mixture was filtered
through celite and the solvent removed under reduced pressure to obtain
crude amine.
ACHTUNGTRENNUNG(2R,3R)-3-Azidotetrahydrofuran-2-carboxylic acid (17): In a flame-dried,
two necked, round-bottom flask (1 L) was dissolved oxalyl chloride
(32 mL, 372 mmol) under N2 atmosphere in dry CH2Cl2 (600 mL). After
the solution was cooled to ꢀ788C, dry DMSO (35.0 mL, 492 mmol) was
added dropwise with stirring for 15 min. To this, a solution of alcohol 13
(20 g, 121.2 mmol) in dry CH2Cl2 (150 mL) was added dropwise and
stirred for 30 min at the same temperature and treated with Et3N
(103.2 mL, 185 mmol) and stirred for an additional 30 min at ꢀ788C. The
reaction mixture was partitioned between CH2Cl2 and water, the organic
phase was separated, and the aqueous phase was extracted with CH2Cl2.
Combined organic phases were washed with brine, dried (Na2SO4), and
concentrated. Purification of the crude product by column chromatogra-
phy (15% ethyl acetate in petroleum ether) afforded ketone as a color-
less oil which was used for next step without any purification.
A solution of acid 8 (1.0 g, 6.4 mmol), 1-hydroxybenzotriazole (950 mg,
7.0 mmol), and diisopropylethylamine (2.54 mL, 14.6 mmol) in dry
CH2Cl2 (20 mL) was treated with EDCI·HCl (1-(3-dimethylaminoprop-
yl)-3-ethylcarbodiimide hydrochloride) (1.1 g, 7.0 mmol) and stirred for
30 min. After that a solution of crude amine in CH2Cl2 (7 mL) was added
and reaction mixture was stirred for 24 h at RT. The reaction mixture
was diluted with CH2Cl2 (150 mL) and washed with brine. The organic
phase was dried (Na2SO4) and concentrated. The crude product was puri-
fied over a silica gel column chromatography (50!60% ethyl acetate in
petroleum ether) to obtain the dimer 18 (1.2 g, 73%) as a thick syrup.
[a]2D5 =ꢀ24.2 (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=6.99 (d,
J=8.6 Hz, 1H), 4.89 (ddd, J=10.6, 6.2, 4.9 Hz, 1H), 4.47 (d, J=5.9 Hz,
1H), 4.43 (dt, J=4.9, 1.3 Hz, 1H), 4.33 (d, J=4.5 Hz, 1H), 4.15 (dt, J=
8.3, 6.9 Hz, 1H), 3.99–3.90 (m, 3H), 3.74 (s, 3H), 2.32 (ddt, J=13.6, 8.3,
6.9 Hz, 1H), 2.17 (ddt, J=13.6, 9.2, 5.2 Hz, 1H), 2.07 (dddd, J=10.3, 5.2,
4.1, 1.3 Hz, 1H), 1.96 ppm (dddd, J=13.6, 10.3, 5.9, 4.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=32.7 (t), 32.9 (t), 50.7 (d), 51.9 (d), 62.9
(q), 67.3 (t), 67.7 (t), 78.9 (d), 81.8 (d), 167.9 (s), 170.1 ppm (s); IR
(CHCl3): n˜ =3338, 2956, 2107, 1745, 1667, 1532, 1440, 1266, 1098,
At ꢀ158C, a solution of the crude ketone in methanol (500 mL) was
treated with NaBH4 (13.04 g, 370.0 mmol) in portions with a 10 min inter-
val. After completing the additions, stirring was continued for another
1 h at 08C. The contents were concentrated and dissolved in ethyl acetate
(500 mL). The ethyl acetate solution was washed with water and brine,
then dried (Na2SO4) and concentrated to get syrup like compound 16,
which was used directly for the next step.
At 08C,
a solution of the crude alcohol 16 and Et3N (51.6 mL,
370.0 mmol) in CH2Cl2 (400 mL) was treated with mesyl chloride
(10.48 mL, 135.6 mmol) and stirred for 3 h at RT. The reaction mixture
was diluted with CH2Cl2 (150 mL) and washed with cold water and brine.
The organic layer was dried (Na2SO4) and concentrated under reduced
pressure to afford crude mesylated compound. The crude product was di-
vided into four parts and used directly for the next step.
728 cmꢀ1; MS (ESI): m/z (%): 307.2 (100) [M+ +Na], 323.1(32) [M+
+
K], 285.2 (29) [M+ +1], 301 (15) [M+ +H2Oꢀ1]; elemental analysis
calcd (%) for C11H16N4O5: C 46.48, H 5.67, N 19.71; found: C 46.39, H
5.58, N 19.63.
12952
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12946 – 12954

Homooligomers of Parent cis- and trans-Furanoid-b-Amino Acids
FULL PAPER
Synthesis of cis-tetrapeptide (19): To a solution of dimer 18 (500 mg,
1.76 mmol) in EtOH (15 mL) was added Raney nickel (400 mg,) and
stirred under an atmosphere of hydrogen for 1 h. The reaction mixture
was filtered through Celite and concentrated under reduced pressure.
41%) as amorphous solid (purification by column chromatography 10!
15% methanol in CH2Cl2). Rf =0.25 (MeOH/CH2Cl2 1:9); [a]2D5 =ꢀ144–
1
155 (c=0.1, CHCl3); H NMR (400 MHz, CDCl3): d=8.28 (d, J=8.5 Hz,
1H), 8.22 (d, J=9.8 Hz, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.03 (d, J=9.7 Hz,
1H), 7.89 (d, J=9.9 Hz, 1H), 7.10 (d, J=9.7 Hz, 1H), 6.83 (d, J=8.6 Hz,
1H), 5.13–5.01 (m, 5H), 4.94–4.81 (m, 3H), 4.57 (d, J=7.4 Hz, 1H), 4.46
(sbr, 2H), 4.44 (d, J=7.8 Hz, 1H), 4.39 (d, J=9.2 Hz, 1H), 4.35 (d, J=
9.5 Hz, 1H), 4.25 (dbr, J=8.6, 3H), 4.19–4.09 (m, 7H), 4.07 (t, J=
7.7 Hz, 1H), 3.96 (ddd, J=12.9, 7.3, 1.4 Hz, 3H), 3.85 (dd, J=6.7, 1.4 Hz,
1H), 3.81 (s, 3H), 3.73–3.65 (m, 4H), 2.38–2.33 (m, 2H), 2.29–2.22 (m,
3H), 2.19–2.12 (m, 5H), 2.10–2.05 (9 m, 5H), 1.96–1.92 ppm (m, 1H);
13C NMR (100 MHz , CDCl3): d=30.0 (t), 30.2 (t), 30.6 (t), 30.9 (t), 30.9
(t), 31.1 (d), 32.0 (t), 32.5 (t), 50.4 (d), 50.6 (d), 50.8 (d), 51.0 (d), 51.1 (d,
2C), 51.3 (d), 52.5 (d), 63.0 (d), 67.4 (t), 67.5 (t), 67.6 (t), 67.7 (t, 2C),
67.8 (t), 77.2 (d), 77.7 (d, 2C), 77.8 (d), 79.1 (d), 81.4 (d), 168.9 (s), 169.6
(s), 170.2 (s), 170.5 (s), 170.6 (s), 170.8 (s), 171.1 (s), 171.3 ppm (s); IR
(CHCl3): n˜ =3324, 2925, 2854, 2112, 1725, 1717, 1661, 1656, 1653, 1649,
1523, 1459, 1082, 987, 728 cmꢀ1; MS (ESI): m/z (%): 985.7 (7) [M+ +Na],
963.7 (5) [M+ +H], 549.4 (100) [M+ꢀ413], 492 (63) [M+ꢀ470]; elemen-
tal analysis calcd (%) for C41H58N10O17: C 51.14, H 6.07, N 14.55; found:
C 51.23, H 6.11, N 14.49.
To a stirred solution of dimer 18 (500 mg, 1.76 mmol) in dioxane/water
9:1 (14 mL), aqueous sodium hydroxide (3.0 mL, 2m) was added at 08C
and the reaction mixture was stirred for 1 h at RT. The reaction mixture
was neutralized with 2n HCl and concentrated under reduced pressure.
The crude residue was extracted with CH2Cl2 (3ꢃ50 mL). The combined
organic layer was dried (Na2SO4) and the solvent was removed under re-
duced pressure to procure the dimer acid.
At 08C
a solution of crude cis-dimer acid, 1-hydroxybenzotriazole
(285 mg, 2.11 mmol) and diisopropylethylamine (0.8 mL, 4.40 mmol) in
dry CH2Cl2 (15 mL) was treated with 1-(3-Dimethylaminopropyl)-3-eth-
ylcarbodiimide hydrochloride (330 mg, 2.11 mmol) and stirred for 30 min.
To this, a solution of crude amine in CH2Cl2 (5 mL) was introduced and
the contents stirred at RT for 35 h. The reaction mixture was diluted with
dichloromethane (100 mL) and washed with H2O (20 mL, 3 times). The
organic phase was dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by the silica gel column chromatography (1!
3% methanol in CH2Cl2) to obtain the tetramer 19 (560 mg, 62%) as col-
orless amorphous solid. [a]2D5 =ꢀ52.3 (c=1.0, CHCl3); IR (CHCl3):
1H NMR (400 MHz, CDCl3): d=8.06 (d, J=7.5 Hz, 1H), 7.72 (d, J=
8.2 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.85–4.73 (m, 3H), 4.49 (d, J=
6.0 Hz, 1H), 4.43 (dt, J=6.0, 4.5, 1.8 Hz, 1H), 4.37 (d, J=4.5 Hz, 1H),
4.35 (d, J=7.3 Hz, 1H), 4.27 (d, J=8.2 Hz, 1H), 4.21 (dd, J=8.2, 4.5 Hz,
1H), 4.17 (dd, J=8.2, 6.2 Hz, 1H), 4.09 (ddd, J=10.8, 8.5, 2.3 Hz, 1H),
4.06 (dd, J=9.1, 6.7 Hz, 1H), 3.98 (dd, J=8.5, 3.5 Hz, 1H), 3.96–3.90 (m,
3H), 3.86 (d, J=10.2, 8.9, 6.2 Hz, 1H), 3.75 (s, 3H), 2.47–2.29 (m, 1H),
2.23–2.15 (m, 1H), 2.13–2.07 (m, 1H), 1.96–1.90 (m, 1H), 1.86–1.79 (m,
1H), 1.67–1.57 ppm (m, 1H); 13C NMR (100 MHz , CDCl3): d=30.9 (t),
31.8 (t), 32.1 (t), 32.6 (t), 50.4 (d), 51.1 (d), 51.2 (d), 52.3 (d), 63.0 (d),
67.2 (t), 67.6 (t), 67.7 (t), 67.8 (t), 75.8 (d), 77.2 (d), 78.9 (d), 81.9 (d),
168.6 (s), 170.4 (s), 170.5 ppm (s, 2C); n˜ =3383, 2925, 2113, 1729, 1668,
1520, 1451, 1271, 1219, 1085, 1027, 1007, 759, 728 cmꢀ1; MS (ESI): m/z
(%): 533.5 (100) [M+ +Na], 549.5 (31) [M+ +K], 511.5 (63) [M+ +1]; el-
emental analysis calcd (%) for C21H30N6O9: C 49.41, H 5.92, N 16.46;
found: C 49.39, H 5.97, N 16.39.
Synthesis of trans-dipeptide (22): The same sequence of procedures as
for the preparation of cis-FAA dimer 18 were used with the acid 9
(808 mg, 5.14 mmol) and monomer–amine (prepared by the hydrogenoly-
sis of the azide 9-Me using Raney nickel, 800 mg, 4.67 mmol) to afford
trans-FAA dimer 22 (915 mg, 69%) as colorless syrup. [a]2D5 =ꢀ141.4 (c=
2.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=6.88 (d, J=6.9 Hz, 1H),
4.63 (ddd, J=11.2, 7.5, 3.8 Hz, 1H), 4.39 (dt, J=2.9, 5.9 Hz, 1H), 4.33 (d,
J=3.4 Hz, 1H), 4.30 (d, J=2.8 Hz, 1H), 4.20–4.11 (m, 1H), 4.09–3.98 (m,
3H), 3.77 (s, 3H), 2.40–2.31 (m, 1H), 2.11–1.98 (m, 2H), 1.91–1.83 (m,
1H). 13C NMR (100 MHz, CDCl3): d=31.3 (t), 31.8 (t), 52.1 (d), 53.3 (d),
64.0 (q), 67.6 (t), 67.9 (t), 81.2 (d), 82.8 (d), 169.7 (s), 171.1 ppm (s); IR
(CHCl3): n˜ =3341, 2955, 2890, 2107, 1746, 1667, 1532, 1439, 1267, 1212,
1098, 924, 729 cmꢀ1
;
MS (ESI): m/z (%): 307.2 (100) [M+ +Na],
323.1(31) [M+ +K], 285.2 (30) [M+ +1], 301 (14) [M+ +H2Oꢀ1]; ele-
mental analysis calcd (%) for C11H16N4O5: C 46.48, H 5.67, N 19.71;
found: C 46.53, H 5.61, N 19.67.
Synthesis of trans-tetrapeptide (23): The procedures used in the prepara-
tion of cis-FAA tetramer 19 were followed. Coupling of the dimer acid
(prepared by alkaline hydrolysis of 22, 400 mg, 1.41 mmol) and dimer
amine (prepared by the hydrogenolysis of the azide 22 using Raney
nickel, 400 mg, 1.41 mmol) using the standard coupling protocol gave the
trans-FAA tetramer 23 (365 mg, 53%) as colorless amorphous solid.
[a]2D5 =ꢀ101.3 (c=2.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.40 (d,
J=6.5 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.06 (d, J=5.8 Hz, 1H), 4.60–
4.53 (m, 1H), 4.39–4.30 (m, 3H), 4.29–4.25 (m, 1H), 4.24–4.22 (m, 1H),
4.16 (dd, J=7.1, 5.0 Hz, 2H), 4.08 (dd, J=7.9, 2.0 Hz, 1H), 4.02–3.96 (m,
6H), 3.69 (s, 3H), 2.29–2.20 (m, 3H), 2.08–1.99 (m, 1H), 1.96–1.81 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=31.5 (t), 32.0 (t), 32.2 (t), 32.2
(t), 52.3 (d), 53.4 (d), 54.5 (d), 54.6 (d), 64.2 (d), 67.9 (t, 2C), 68.0 (t), 68.1
(t), 81.5 (d), 82.1 (d), 82.2 (d), 83.0 (d), 170.3 (s), 170.8 (s), 170.9 (s),
171.4 ppm (s); IR (CHCl3): n˜ =3301, 2955, 2890, 2106, 1744, 1667, 1524,
Synthesis of cis-hexapeptide (20): The procedure used for the synthesis
of tetrapeptide 19 was followed to prepare the hexapeptide 20. The
amine partner was made by the reduction of the azide group of cis-tetra-
mer 19 (100 mg, 0.193 mmol) and the acid partner obtained from ester
hydrolysis of cis-dimer 18 (60 mg, 0.21 mmol). The resulting crude prod-
uct after the coupling reaction was purified by column chromatography
(5!10% methanol in CH2Cl2) to afford the cis-hexamer 20 (82 mg,
57%) as colorless amorphous solid. [a]2D5 =ꢀ65.3 (c=0.5, CHCl3);
1H NMR (400 MHz, CDCl3): d=8.20 (d, J=8.4 Hz, 1H), 8.10 (d, J=
9.5 Hz, 1H), 7.87 (d, J=9.7 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 6.86 (d, J=
8.6 Hz, 1H), 5.08–4.98 (m, 3H), 4.94–4.81 (m, 2H), 4.56 (d, J=7.3 Hz,
1H), 4.48–4.41 (m, 3H), 4.38 (d, J=8.9 Hz, 1H), 4.34 (d, J=9.3 Hz, 1H),
4.27 (d, J=9.0 Hz, 1H), 4.22 (dd, J=8.6, 4.4 Hz, 1H), 4.18–4.05 (m, 5H),
3.99–3.93 (m, 2H), 3.88–3.81 (m, 2H), 3.80 (s, 3H), 3.78–3.71 (m, 2H),
2.39–2.31 (m, 1H), 2.29–2.22 (m, 2H), 2.18–2.01 (m, 7H), 1.99–1.92 ppm
(m, 2H); 13C NMR (100 MHz , CDCl3): d=30.6 (t), 30.9 (t), 30.9 (t), 31.3
(t), 32.0 (t), 32.5 (t), 50.4 (d), 50.7 (d), 50.8 (d), 51.0 (d), 51.2 (d), 52.5
(d), 63.0 (d), 67.4 (t), 67.5 (t), 67.6 (t), 67.7 (t), 67.7 (t), 67.7 (t), 77.0
(d),77.2 (d), 77.4 (d), 77.7 (d, 2C), 79.0 (d), 81.5 (d), 168.8 (s), 169.6 (s),
170.3 (s), 170.4 (s), 170.7 (s), 171.1 ppm (s); IR (CHCl3): n˜ =3324, 2925,
1267, 1218, 1086, 759, 729 cmꢀ1; MS (ESI): m/z (%): 533.0 (100) [M+
+
Na], 549.0 (33) [M+ +K], 511.0 (30) [M+ +1], 301 (13) [M+ +H2Oꢀ1];
elemental analysis calcd (%) for C21H30N6O9: C 49.41, H 5.92, N 16.46;
found: C 49.39, H 5.99, N 16.51.
Synthesis of trans-hexapeptide (24): The same sequence of procedures, as
used in the preparation of cis-FAA hexamer 20, was followed. The dimer
acid (prepared by alkaline hydrolysis of 22, 70 mg, 0.245 mmol) and tetra-
mer amine (prepared by the hydrogenolysis of the azide 23 using Raney
nickel, 100 mg, 0.195 mmol) gave trans-FAA hexamer 24 (53 mg, 35%)
as a colorless amorphous solid. [a]2D5 =ꢀ79.4 (c=0.5, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.53–7.49 (m, 3H), 7.30 (d, J=7.5 Hz, 1H), 7.05
(d, J=6.6 Hz, 1H), 4.64 (ddd, J=11.0, 7.5, 4.0 Hz, 1H), 4.49–4.40 (m,
4H), 4.39–4.35 (m, 1H), 4.33 (d, J=3.3 Hz, 1H), 4.17–4.13 (m, 1H), 4.29
(d, J=2.8 Hz, 1H), 4.24–4.18 (m, 4H), 4.10–4.01 (m, 11H), 3.75 (s, 3H),
2.38–2.28 (m, 5H), 2.03–1.88 ppm (m, 7H); 13C NMR (100 MHz, CDCl3):
d=31.9 (t), 32.1 (t), 32.2 (t, 2C), 32.3 (t, 2C), 52.4 (d), 53.5 (d), 54.5 (d),
2846, 2113, 1728, 1665, 1660, 1651, 1520, 1274, 1083, 991, 758, 729 cmꢀ1
;
MS (ESI): m/z (%): 759.5 (100 [M+ +Na], 775.4 (7) [M+ +K], 301.2
(100) [M+-435]); elemental analysis calcd (%) for C31H44N8O13: C 50.54,
H 6.02, N 15.21; found: C 50.59, H 5.99, N 15.27.
Synthesis of cis-octapeptide (21): The preparation of octamer 21 was car-
ried out as described for the preparation of cis-tetramer 19. Both the cou-
pling partners were obtained from the cis-tetramer 19. The amine partner
made by the reduction of the azide group of tetramer 19 (60 mg,
0.117 mmol) and acid partner obtained from ester hydrolysis of tetramer
19 (60 mg, 0.117 mmol) and coupled to obtain the octamer 21 (46 mg,
Chem. Eur. J. 2011, 17, 12946 – 12954
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12953

C. V. Ramana, R. A. Mata et al.
54.6 (d), 54.7 (d, 3C), 64.3 (d), 68.0 (t, 2C), 68.1 (t, 2C), 68.2 (t), 81.6 (d),
82.2 (d), 82.3 (d), 82.4 (d), 83.1 (d, 2C), 170.5 (s), 171.0 (s), 171.2 (s),
171.3 (s, 2C), 171.5 ppm (s); IR (CHCl3): n˜ =3301, 2955, 2106, 1744, 1672,
1667, 1656, 1648, 1528, 1521, 1269, 1085, 729 cmꢀ1; MS (ESI): m/z (%):
759.5 (22) [M+ +Na], 775.4 (11) [M+ +K], 633.5 (77) [M+ꢀ203], 533.
(100) [M+ꢀ203]; elemental analysis calcd (%) for C31H44N8O13: C 50.54,
H 6.02, N 15.21; found: C 50.63, H 6.09, N 15.18.
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Acknowledgements
We thank NCL-IGIB Joint Research Initiative Program (CSIR-NWP-
0013) for funding. S.K.P. and G.F.J. thank CSIR, New Delhi for the finan-
cial assistance in the form of a research fellowship.
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Received: June 16, 2011
Published online: October 20, 2011
12954
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12946 – 12954