Synthesis and structural study of novel dimethylcyclobutyl β-peptides

Article abstract of DOI:10.1016/j.tet.2009.05.039

The synthesis of some representative compounds of a new class of cyclobutane-containing β-peptides starting from (-)-verbenone as a chiral precursor is presented. In these products, the cyclobutane moiety is not a part of the peptide backbone but a bulky

Full text of DOI:10.1016/j.tet.2009.05.039

Tetrahedron 65 (2009) 5669–5675
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and structural study of novel dimethylcyclobutyl
b-peptides
a
a
a
b
c
´
´
´
Elisabeth Torres , Carles Acosta-Silva , Federico Rua , Angel Alvarez-Larena , Teodor Parella ,
Vicenç Branchadell a , Rosa M. Ortun˜o
,
a,
*
*
a
´
`
Departament de Quımica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
b Servei de Difraccio´ de Raigs X, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
c Servei de RMN, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some representative compounds of a new class of cyclobutane-containing b-peptides
Received 31 March 2009
Received in revised form 11 May 2009
Accepted 18 May 2009
starting from (ꢀ)-verbenone as a chiral precursor is presented. In these products, the cyclobutane moiety is
not a part of the peptide backbone but a bulky substituent at the
b
3-position. These compounds have been
carefully characterized and studied on the basis of the combined use of several experimental techniques
together with molecular modeling by means of theoretical calculations. In the solid state, the non-cyclic
Available online 23 May 2009
b
-peptides adopt a hairpin-like molecular folding ruled by intermolecular hydrogen bonds in the crystal
Keywords:
packing.
b
-Peptides
Ó 2009 Elsevier Ltd. All rights reserved.
Crystal structure
Hydrogen bonds
Cyclobutanes
1. Introduction
As the first step to understand this variety of structural features,
the synthesis and investigation of small peptides is highly useful.
Designed peptides offer enormous possibilities for the prepa-
ration of materials with determined properties because they are
chiral compounds that usually adopt well defined secondary and,
in some cases, tertiary and quaternary structures.1 Among them,
Several studies have been reported on the behavior of b-peptides in
solution,2,3 but data related to their structure in the solid state are
scarce. However, the knowledge of the crystal structure of peptides
is very important regarding their incorporation in chiral materials.
We decided, therefore, to investigate the crystal structures of small
b
-peptides have revealed to be valuable elements in molecular
architecture. Their propensity to give sheets, helices or strands, as
cyclobutane-containing b-peptides.
the main foldings, has been established.2 They present the ad-
Previously, we had prepared two main types of cyclobutane b-
vantage with respect to
a
-peptides that the number of residues
peptides8 corresponding to structures 1–4 in Chart 1. Products 19 and
usually needed to form foldamers is lower than that required in
210 are constituted by oligopeptides derived from (1R,2S)-2-amino-
a
-oligomers.
cyclobutane-1-carboxylic acid, and b-alanine units that, in the case of
The control of chirality in the monomers combined with the use
tetrapeptide 2, are joined in alternation. On the contrary, di-
astereomeric dipeptides 3 and 4 result from the direct coupling of two
cyclobutane residues with the same or opposite chirality, re-
spectively.11 Tetrapeptide 2 presents a 14-helix type folding by for-
mation of an intramolecular hydrogen bond as shown in Chart 1.
Although this compound is a solid, unfortunately crystals were not
good enough for X-ray structural study. Dipeptides 1, 3, and 4 pre-
sented intramolecular hydrogen bonds in solution giving cis-fused
[4.2.0]octane structural units, in the same way that a recently described
tetrapeptide constituted by four cyclobutane-containing residues.5 In
a clear contrast, these peptides in the solid state are intermolecularly
hydrogen bonded yielding infinite antiparallel chains. The crystal
packing determines a hairpin-like folding for these molecules.
of carbocycles or other rigid rings, such as oxetanes, incorporated in
the peptide backbone3 has allowed to prepare
b-peptides with in-
teresting structural features that include the formation of nano sized
fibrils and micelles.4,5 The obtained results have permitted a better
understanding of the combined influence of chirality and confor-
mational flexibility on the molecular and supramolecular arrange-
ment of these compounds. The acquired knowledge has been useful
in the preparation of several materials such as nucleic acid mimics6
and nanotubes.7
* Corresponding authors. Tel.: þ34 935 812 175; fax: þ34 935 812 920 (V.B.); Tel.:
þ34 935 811 602; fax: þ34 935 811 265 (R.M.O).
In a recent publication,12 we reported on the efficient and
stereoselective addition of N-benzyl hydroxylamine to chiral alke-
noates affording N-benzyl isoxazolidinones as single stereoisomers.
E-mail addresses: vicenc.branchadell@uab.es (V. Branchadell), rosa.ortuno@
uab.es (R.M. Ortun˜o).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.039

5670
E. Torres et al. / Tetrahedron 65 (2009) 5669–5675
CO2Me
are suitably protected for their selective incorporation into oligo-
mers. Furthermore, methylation of 8 led to the totally protected
amino acid 9.
Then we prepared dipeptides 10–12 (Scheme 2). Presumably,
compound 10 must display greater flexibility than the monomer 9,
the dipeptide 11 is intended to be conformationally restricted and
cyclic dimer 12 must be highly rigid.
O
MeO2C
O
N
H
O
HN
N
N
N
H
O
H
H
NH
O
O
OBn
OBn
2
1
H
CO2Me
13
N
15
10
O
H
H
OMe
OMe
HCl·H2NCH2CH2CO2Me, TEA
EDAC, HOBt, DMF
rt, 72 h
9
O
O
8
O
H
O
H
NHBoc
8
N
O
N
O
10
50%
H
H
CO2Me
N
N
H
H
15
13
N
O
O
OBn
OBn
O
10
O
O
H
9
EDAC, HOBt, DMF
H
3
O
4
7 + 8
O
12
rt, 96 h
H
Chart 1. Representative features of cyclobutane
b-peptides.
O
NHBoc
8
60%
11
These compounds yield, upon hydrogenation, the corresponding
b
-amino acids in good yields.
O
1
HN
8
In this work, we have designed and synthesized some b-peptides
H
H
10
containing a dimethylcyclobutyl unit at the b
3-position, which is not
EDAC, HOBt, DMF
9'
4
6
O
O
9
rt, 10 days
incorporated in the peptide backbone. It is a bulk substituent that
could afford rigidity to these cyclobutane-containing molecules.
These newcompounds havebeensynthesizedfromisoxazolidinones,
prepared, in turn, from (ꢀ)-verbenone as a chiral precursor providing
the dimethylcyclobutyl motif. We have also been successful in syn-
O
NH
10'
H
H
5
36%
O
12
Scheme 2. Synthesis of b-peptides 10–12.
thesizing the first cyclic cyclobutane-containing
compare it with the open-chain products.
b-peptide in order to
The synthesis of the
(Scheme 2). Acid 8 was coupled with
b
-peptides was carried out as follows
-Ala–OMe by treatment with
These
b-dipeptides have been characterized and studied by
means of NMR and IR spectroscopies,13 circular dichroism (CD), X-
ray structural analysis, and theoretical calculations. Determination
of the molecular conformation and the crystal packing in the solid
state has been also accomplished.
b
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC) as dehy-
drating agent and 1 equiv of 1-hydroxybenzotriazole (HOBt) as
a catalyst in anhydrous DMF solution at room temperature for 72 h.
Dipeptide 10 was thus obtained in 50% yield after purification by
column chromatography. In turn, bis(dimethylcyclobutyl) di-
peptide 11 was prepared in 60% yield by coupling of acid 8 with
amine 7 under similar conditions as before but for 4 days. The
synthesis of cyclic 12 was accomplished in 36% yield by self-cou-
pling of two molecules of free amino acid 6. Longer reaction time
(ca. 10 days) was required in this case to achieve the cyclization.
These new products are solid and were fully characterized. Cir-
cular dichroism (CD) in MeOH for dipeptide 10 showed a band at
208 nmwhile a positive Cotton effect, with bands at 205 and 225 nm,
was observed for dipeptides 11 and 12 (see Supplementary data). IR
spectra of the solids 10 and 12 displayed only one band centered at
3300 cmꢀ1. This band arises from the intermolecularly bonded
2. Results and discussion
Selectively protected
corporated into the different
b
-amino acids were synthesized to be in-
-peptides. For this purpose, we
b
employed as a starting material the isoxazolidone 5 prepared from
(ꢀ)-verbenone as previously described.12 One-pot hydrogenolysis
of the N–O and the N-benzyl bonds, in the presence of palladium
hydroxide as a catalyst, gave free amino acid 6. Interestingly, this
compound could be chemoselectively methylated by reaction with
diazomethane to provide amino ester 7 (Scheme 1).
Alternatively, catalytic hydrogenation of 5 in the presence of
(Boc)2O afforded tert-butyl carbamate 8. Both compounds 7 and 8
O
H
H
CO2Me
NH2
O
O
H
CO2H
O
4 atm H2, Pd(OH)2/C
96% EtOH
CH2N2
85%
O
O
O
O
N
Bn
NH2
H
H
H
95%
6
5
7
H
CO2H
O
O
H
H
CO2Me
NHBoc
4 atm H2, Pd(OH)2/C
(Boc)2O, 96% EtOH
CH2N2
53% (two steps)
O
O
NHBoc
H
8
9
Scheme 1. Synthesis of conveniently protected
b-amino acids.

E. Torres et al. / Tetrahedron 65 (2009) 5669–5675
5671
Table 1
amide and carbamate protons as can be established from X-ray
studies (see below). Otherwise, IR spectra of dipeptides 10 and 12 at
different concentrations in chloroform solution showed well defined
bands at 3450 cmꢀ1 and a shoulder at 3300 cmꢀ1. At 5 mM concen-
tration, the existence of intermolecular aggregates can be excluded
as shown by 1H NMR. Then, the weak band at lower frequency can be
attributed to intramolecularly bonded NH protons. The carbonyl re-
gion could not be investigated due to the signal overlap.
Relative energiesa obtained at B3LYP/6-31G(d) level of theory in the gas phase and in
chloroform solution for conformers of dipeptides 10 and 11
Conformer
E (gas phase)
E (chloroform)b
10
11
I
II
III
0.0
0.7
2.4
0.0 (0.0)
0.8 (0.7)
2.5 (2.2)
I
II
III
0.0
1.3
2.9
0.0
2.0
4.0
Complete 1H and 13C NMR chemical shift assignments for all
dipeptides 10–12 were performed. In addition, we have considered
the use of NOE data to account for the conformational bias in so-
lution of the non-cyclic compounds 11 and 12, as similarly reported
by related peptides.5,10,11 Theoretical calculations were also carried
out to model the most stable conformations for 10 and 11.
a
Relative to the most stable conformer. In kcal molꢀ1
In parentheses, values obtained for geometries optimized in solution.
.
b
For dipeptide 10, the most stable conformer, 10-I, presents two
For both compounds, a conformational search afforded three
representative structures, which were optimized at the B3LYP/6-
31G(d) level of calculation. The geometries of the conformers of 10
were optimized both in the gas phase and in chloroform solution
but only slight changes were observed for the two media. There-
fore, geometries for 11 were optimized only in the gas phase. Fig-
ure 1 shows the structures of the conformers of 10 and Table 1
presents the relative energies of the most stable conformers of both
dipeptides. The conformers of 11 are similar to those obtained for
10 and their structures can be found as Supplementary data.
hydrogen bonds. The strongest one, between NH8 and O12, was
already present in 9 while the second one takes place between
NH13 and O17. These hydrogen bonds lead two six-membered
rings. The other two conformers present only one hydrogen bond.
For 10-II it involves NH8 and the carbonyl of the methyl ester group,
leading to the formation of a 10-membered ring. Finally, in 10-III
we can observe an eight-membered ring due to the hydrogen bond
between NH13 and O7.
The computed energy difference in chloroform solution be-
tween 10-I and 10-II is only 0.8 kcal molꢀ1, while 10-III lies
2.5 kcal molꢀ1 above 10-I (see Table 1). This result is in good
agreement with the results of Baquero et al. for other b
-peptides.14
In this case, the combined C10 and C6/C6 conformers made up
about two-thirds of the population. Moreover, the predominance of
C6/C6 confomers has been also predicted by theoretical calcula-
tions on some open-chain models.3e
Regarding dipeptide 11, the energy differences between the
most stable three conformers (4.0 kcal molꢀ1) increase with respect
to dipeptide 10 (2.5 kcal molꢀ1). This result reflects a larger degree
of conformational rigidity in 11 due to the presence of the second
cyclobutane ring.
OMe
2.35 Å
15
O
13
H
13
N
11
11
12
O
O
H
H
12
8
O
9
8
N
2.11 Å
H
7
6
6
7
OtBu
O
10-I
10
1
3
2
8
9
12
O
12
11
9’
O
13
13
O
4
5
NH
H
7
11
10’
6
8
9
H
6
15
ButO
8
N
7
6
H
O
OMe
O
7
2.05 Å
10-II
Twist
10
O
12
1
2
3
OMe
9
O
13
15
O
12
11
N
H
11
8
2.03 Å
9’
H
O
4
13
6
O
H
HN
8
7
9
7
6
5
8
OtBu
7
10’
6
10-III
Chair
Figure 1. DFT calculated structures for the most stable conformers of dipeptide 10 in
chloroform solution.
Figure 2. DFT calculated structures for the twist and chair conformers of dipeptide 12.

5672
E. Torres et al. / Tetrahedron 65 (2009) 5669–5675
Figure 3. Molecular conformations of dipeptides 10 and 11 (from left to right) in the solid state.
The 2D NOESY spectrum of 11 was recorded in both CDCl3 and
with (E,E)-1,5-cyclooctadiene.16 Figure 2 shows the optimized
structures of the most stable twist and chair conformers. The twist
conformer is more stable than the chair one by 2.0 kcal molꢀ1 in
chloroform. In the twist conformer both NH protons are trans with
respect to CH4 and CH8, respectively. On the other hand, in the
chair structure NH1 is trans with respect to CH8, but NH5 is cis with
respect to CH4. In the 1H NMR spectrum of 12 both NH/CH coupling
constants present the same value (10.8 Hz). This result is in good
agreement with a twist conformation for the macrocycle.
benzene-d6 solutions to disclose the chemical shifts and NOE
contacts for all relevant protons (see Supplementary data). The
most significant NOEs conclude that the same geometry is retained
in both different solvents. The high diastereotopicity and the line-
shape broadening shown with temperature increasing for the
methylene protons H10a,b (
for the presence of some fluxional process in solution.
d
¼2.11 and 2.43 in CDCl3) also accounts
Conformational analysis of cyclic dimer 12 was also performed
by 1H NMR and theoretical calculations. The high rigidity of this
cyclic C2-symmetric molecule can be realized by the noticeable
As mentioned above, all three
b-peptides are solids. For di-
peptide 12, although TEM analysis revealed the existence of micro-
crystals, the obtained crystals were not suitable for X-ray studies
(see Supplementary data). A detailed study on 10 and 11 was car-
ried out allowing us the determination of the molecular confor-
mation in the solid state and the main features of the crystal
packing for each dipeptide.
diastereotopicity shown by the
a-carbonyl methylene protons,
which appear at
d
¼2.33 and 2.89, respectively, in the 1H NMR
spectrum in CDCl3, while the NH proton resonates at 6.48 ppm,
which is well resolved as a large doublet. The 2D NOESY pointed out
that protons H4/H8 are close to the methylene protons H3/H7 but
NOE between NH and other any proton was not observed (see
Scheme 2 for atom numeration). As mentioned above, the CD
spectrum also accounts for the conformational restriction showing
a strong Cotton effect. This spectrum is closely related to those of
conformationally constrained 2,2-dimethylcyclobutane substituted
Crystal structure of compound 10 has been determined from
single crystal X-ray diffraction data. Suitable crystals were obtained
from dichloromethane–pentane solution. In the case of compound
11, to obtain adequate single crystals was more difficult. Finally, its
crystallization from methanol afforded middling quality single
crystals whose structure proved to be a monohydrate of 11.
These two peptides, as well as the previously described bis
a
-dipeptides prepared in our laboratory and recently described.15
The macrocycle of dipeptide 12 may present two different
conformations, which may be named as chair and twist by analogy
(cyclobutane) b
-dipeptides,11 adopt hairpin-like foldings in the
Figure 4. Intermolecular hydrogen bonds forming infinite chains in the crystal structure of dipeptides 10 and 11 (from left to right).

E. Torres et al. / Tetrahedron 65 (2009) 5669–5675
5673
Table 2
4. Experimental section
4.1. Computational details
Geometries of the intermolecular hydrogen bonds forming infinite chains in the
crystal structures of dipeptides 10 and 11a
Dipeptide 10
N13/O12(s)b
H13/O12(s)b
N13–H13/O12(s)c
s: x,ꢀyþ3/2,zꢀ1/2
s: x,ꢀyþ3/2,zꢀ1/2
The Monte Carlo conformational search18 was done using the
MMFF force field19 implemented in the Macromodel 7.0 program.20
The solvent effect has been included using the GB/SA method21
using chloroform as solvent. Within a range of 5 kcal molꢀ1 the
number of conformers was 70 for 9, 510 for peptide 10, and 424 for
peptide 11. For peptide 12 both a twist and chair conformation of
the macrocycle were considered. The number of conformers within
a range of 5 kcal molꢀ1 was 26 and 47, respectively. Geometries of
the most representative structures were optimized using the B3LYP
density functional method22 with the 6-31G(d) basis set.23 Har-
monic vibrational frequencies were calculated in order to verify
that these structures correspond to energy minima (all frequencies
are real). These calculations were carried out using the Gaussian-03
program.24 Single point calculations in chloroform using the con-
tinuum model25 implemented in the Jaguar 5.5 program26 were
also done for the structures optimized in the gas phase. The ge-
ometries of 9 and of the conformers of 10 were also optimized
including the effect of the solvent.
2.831(5)
1.83
164
N8/O7(s)b
2.861(4)
H8/O7(s)b
1.84
N8–H8/O7(s)c
169
Dipeptide 11
N13/O7(s)b
2.956(5)
H13/O7(s)b
2.06
N13–H13/O7(s)c
144
s: ꢀx,yꢀ1/2,ꢀzþ1/2
s: ꢀx,yꢀ1/2,ꢀzþ1/2
s: ꢀx,yþ1/2,ꢀzþ1/2
N8/Ow(s)b
2.991(6)
H8/Ow(s)b
1.99
N8–H8/Ow(s)c
164
Ow/O17(s)b
2.956(7)
Hw1/O17(s)b
2.04
Ow–Hw1/O17(s)c
164
Ow/O12b
2.832(6)
Hw2/O12b
2.01
Ow–Hw2/O12c
146
a
s is the symmetry code of the neighbor molecule; w denotes that the atom
belongs to a water molecule. N–H (1.03 Å), Ow–H (0.94 Å), and the rest of param-
eters involving hydrogens have been normalized.
b
In angstroms.
In degrees.
c
solid state (Fig. 3). These conformations are ruled by intermolecular
hydrogen bonds in the crystal packing. In this way, crystal structure
of 10 contains infinite parallel chains of molecules linked by hy-
drogen bonds involving amide groups (Fig. 4, left). Each amide
group adopts a trans disposition and acts both as donor (N–H) and
as acceptor group (C]O). So, each molecule is linked to its neighbor
in the chain by two NH/O]C hydrogen bonds (Table 2).
4.2. Crystal structure analysis
CCDC-681292 (10) and CCDC-681293 (11$H2O) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
In the hydrate of 11, the crystal structure also contains infinite
parallel chains of molecules linked by hydrogen bonds with the
water molecules inserted in them in such a way that two neighbor
molecules in the chain, M1 and M2, are bonded by a (M1)NH/
O]C(M2) hydrogen bond and the water molecule is bonded to M1
by (M1)NH/Ow and OwH/O]C–OMe(M1) bonds, and to M2 by
OwH/O]CNH(M2) bonds (Fig. 4, right). The parameters listed in
Table 2 illustrate these features.
4.3. NMR spectroscopy
NMR Data were collected on Bruker 250 MHz, 360 MHz, and
500 MHz spectrometers. All products were structurally character-
ized using 1D and 2D 1H/13C NMR methods. Variable-temperature
experiments were also recorded when necessary. See text and
Supplementary data for more experimental details.
Although the number of crystal structures described for
peptides is limited (about 30), the molecular and supramolecular
arrangements described herein seems to be frequent in short b3
substituted
-peptides.17 In these cases, H-bonds point in the same
direction along the chain axis and, therefore, chains are polar. This
arrangement, i.e., folded conformers with no intramolecular H-
bonds and linked by intermolecular NH/O]C hydrogen bonds
b-
4.4. Synthesis and purification of amino acids and peptides
4.4.1. (3S,10S,30R)-3-tert-Butoxycarbonylamino-3-[20,20-dimethyl-
-
30-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]propanoic acid, 8
b
A
mixture of oxazolidinone 512 (850 mg, 2.5 mmol), 20%
Pd(OH)2–C (214 mg), and (BOC)2O (700 mg, 3.2 mmol) in 96% EtOH
(72 mL) was hydrogenated at room temperature under 4 atm of
pressure. The reaction mixture was filtered through Celite, and the
solvent was removed at reduced pressure to afford compound 8
(870 mg, 99% yield), which was pure enough to be used in the next
steps without additional purification. For characterization pur-
poses, a portion was chromatographed on Baker silica gel (1:6
into an infinite chain, has also been found in constrained
b-peptides
where C –C
a
b
are included in a cyclobutyl ring.11 In these com-
pounds, however, the two H-bonds of every conformer point in
opposite directions and, as a result, chains are not polar.
3. Conclusion
hexane–EtOAc as eluent) to afford a colorless oil. [
CH2Cl2); IR: 3424, 2981, 1718, 1709 cmꢀ1 1H NMR (360 MHz,
CDCl3):
a
]
þ6.1 (c 2.5,
D
;
In summary, we have synthesized and studied three new
dimethylcyclobutyl
Among them, we describe the first cyclic cyclobutane-containing
d
¼1.13 (s, 6H), 1.23 (s, 3H), 1.42 (s, 9H), 1.66–2.10 (complex
b
-dipeptides with different types of structures.
absorption, 4H), 2.26–2.66 (complex absorption, 2H), 3.74–4.07 (m,
b
-
4H), 5.04 (d, J¼10.8 Hz), 8.66 (br s, 1H); 13C NMR (90 MHz, CDCl3):
peptide. The possibility to easily transform the side-chain of the
d
¼15.9, 21.6, 23.3, 27.93, 3.26, 40.6, 44.4, 47.8, 48.6, 62.9, 64.8, 78.6,
cyclobutane ring in various functional groups8a gives access to
108.9, 140.6, 176.1; HRMS (ESI) calcd for MþNa: 380.2044, found:
a great diversity of substituted-cyclobutyl chiral
b
-peptides. The
380.2044.
structural analysis of 10 and 11 has been achieved by experimental
techniques in conjunction with molecular modeling. Although
theoretical calculations predict intramolecularly hydrogen bonded
conformations in solution, dipeptides 10 and 11 do not display
a well defined preferential bias. The most rigid compound 12
preferentially adopts a twist conformation. In the solid state, di-
peptides 10 and 11 adopt a hairpin-like conformation ruled by the
intermolecular hydrogen bonds in the crystal packing.
4.4.2. Methyl (3S,10S,30R)-3-tert-butoxycarbonylamino-3-[20,20-
dimethyl-30-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]propanoate, 9
A solution of diazomethane (600 mg, 14.3 mmol) in CH2Cl2
(40 mL) was distilled onto a stirred solution of crude acid 8 (1 g,
2.8 mmol) in CH2Cl2 (10 mL). After stirring at room temperature for
1 h, excess diazomethane was destroyed by adding methanol and
solvents were removed. The residue was chromatographed on

5674
E. Torres et al. / Tetrahedron 65 (2009) 5669–5675
Baker silica gel (3:2 hexane–EtOAc as eluent) to afford product 9 as
(d, J¼10.45 Hz, 1H), 6.26 (d, J¼10.5 Hz, 1H); 13C NMR (125 MHz,
solid (480 mg, 53% yield for the two steps). Crystals, mp 93–95 ꢁC
CDCl3):
d
¼16.8, 22.7, 23.7, 28.3, 31.5, 38.0, 40.5, 44.5, 46.7, 49.0, 51.7,
(from ether–pentane); [
a
]
þ22.6 (c 0.7, CH2Cl2); IR 3432, 2978,
63.7, 65.5; elemental analysis calcd for C32H54N2O9: C 62.93, H 8.91,
N 4.59; found: C 62.22, H 8.84, N 4.45.
D
1721, 1701, 1500 cmꢀ1; 1H NMR (250 MHz, CDCl3):
d
¼1.08 (complex
absorption, 3H), 1.11 (complex absorption, 3H), 1.21 (s, 3H), 1.41 (s,
9H), 1.68–1.91 (complex absorption, 3H), 2.02 (dd, J¼7.5 Hz,
J0¼11.4 Hz, 1H), 2.29 (dd, J¼5.6 Hz, J0¼15.7 Hz, 1H), 2.55 (dd,
J¼3.7 Hz, J0¼15.7 Hz, 1H), 3.65 (s, 3H), 3.78–3.98 (m, 5H), 4.96 (d,
4.5.3. Dipeptide 12
Yield 36%. Crystals, mp 260–263 ꢁC; [
a
]
D ꢀ10.14 (c 0.69, CH2Cl2);
IR: 3337, 2968, 1656, 1461 cmꢀ1; 360-MHz 1H NMR (CDCl3)
d
1.13–
J¼10 Hz); 13C NMR (62.5 MHz, CDCl3):
d¼16.5, 22.2, 23.5, 28.1, 31.0,
1.23 (complex absorption, 18H), 1.57 (dd, J¼9.72 Hz, J0¼20.52 Hz,
2H), 1.80–1.87 (m, 2H), 1.97–2.05 (m, 2H), 2.13 (dd, J¼7.5 Hz,
J0¼11.3 Hz, 2H), 2.33 (dd, J¼10.8 Hz, J0¼15.7 Hz, 2H), 2.89 (dd,
J¼6 Hz, J0¼14.6 Hz, 2H), 3.66 (m, 1H), 3.78–4.01 (m, 8H), 6.18 (d,
38.2, 40.3, 44.9, 48.2, 48.7, 51.3, 63.4, 65.2, 78.7, 109.5, 155.3, 171.9;
elemental analysis calcd for C19H33NO6: C 61.43, H 8.95, N 3.77;
found: C 61.47, H 9.01, N, 3.72.
J¼15.12 Hz, 1H); 90-MHz 13C NMR (CDCl3)
d 16.8, 22.9, 23.5, 31.1,
4.4.3. Methyl (3S,10S,30R)-3-amino-3-[20,20-dimethyl-30-(2-methyl-
1,3-dioxolan-2-yl)cyclobutyl]propanoate, 7
Following the same protocol described above for the prepara-
tion of ester 9, amino ester 7 was quantitatively obtained from
amino acid 611 as yellow oil that decomposed under the usual
40.1, 42.9, 47.8, 48.4, 50.6, 63.3, 65.1, 109.2, 171.9. Anal. Calcd for
C32H54N2O9: C, 65.25; H, 8.84; N, 5.85. Found: C, 64.98; H, 8.99; N,
5.22; HRMS (ESI) calcd for MþNa: 501.2935; found 501.2942.
Acknowledgements
chromatographic conditions. [
a
]
ꢀ10.8 (c 2.5, CH2Cl2); IR: 3379,
D
2955,1733 cmꢀ1; 1H NMR (360 MHz, CDCl3):
d
¼1.09–1.27 (complex
´
Financial support from Ministerio de Educacion y Ciencia (MEC)
absorption, 9H), 1.56–2.48 (complex absorption, 4H), 3.11 (m, 1H),
(CTQ2006-01080, CTQ2007-61704/BQU) and Generalitat de Cata-
lunya (GC) (2005SGR-103) is gratefully acknowledged. We thank
NMR and X-ray Services of the UAB for the use of their facilities. E.T.
and C.A.-S. acknowledge to GC and MEC, respectively, for pre-
doctoral fellowships.
3.72 (s, 3H), 3.81–4.02 (complex absorption, 4H); 13C NMR
(90 MHz, CDCl3):
d
¼16.5, 22.6, 23.4, 31.4, 40.2, 48.7, 49.3, 51.5, 63.6,
65.5, 109.3, 172.9; HRMS (ESI) calcd for MþNa: 294.1676; found:
294.1671.
4.5. General procedure for peptide coupling
Supplementary data
1H and 13C NMR spectra for new products 7–11; NMR studies for
compounds 9–11; CD spectra of 9–12; TEM images of 12; computed
structures of amino acid 9 and conformers of dipeptides 10–12.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.05.039.
A standard reaction is described as follows for the synthesis of
b-Ala–OMe hydrochloride (320 mg, 2.3 mmol), DEC (1 g,
10.
5.2 mmol), dry Et3N (1 mL), and HOBt (162 mg, 1.2 mmol) were
successively added to a solution of crude 8 (620 mg, 1.7 mmol) in
dry DMF (65 mL). The mixture was stirred at room temperature
under nitrogen atmosphere for 72 h. Then EtOAc (50 mL) was
added and the resultant solution was washed with saturated
aqueous NaHCO3 (3ꢂ45 mL). The organic layers were dried over
MgSO4 and solvents were removed at reduced pressure. The resi-
due was chromatographed through Baker silica gel (EtOAc as elu-
ent) to afford peptide 10 (310 mg, 50%). Following the same
procedure, peptide 11 was obtained in 60% (ca. 96 h). For peptide
12, different portions of DEC (5.7 g, 30 mmol), dry Et3N (4.2 mL)
and HOBt (2 g, 15 mmol) were successively added to a solution of
crude 6 (850 mg, 3.3 mmol) in dry DMF (200 mL). After 10 days,
peptide 12 was obtained in 36% yield.
References and notes
1. For a definition of secondary and tertiary structures in peptides, see, for instance:
(a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; For recent reports on helix bundle
quaternary structures of
b and a/b peptides, respectively, see: (b) Daniels, D. S.;
Petersson, E. J.; Qiu, J. X.; Schepartz, A. J. Am. Chem. Soc. 2007,129,1532; (c) Horne,
W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 4178.
2. See, for instance: Gelman, M. A.; Gellman, S. H. In Enantioselective Synthesis of
b-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; John Wiley and Sons:
New Jersey, NJ, 2005; pp 527–585.
3. For some representative references, see: (a) Appella, D. H.; Christianson, L. A.;
Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071; (b)
Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am.
Chem. Soc. 1999, 121, 6206; (c) Appella, D. H.; Christianson, L. A.; Klein, D. A.;
Richards, M. R.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 7574; (d)
Barchi, J. J., Jr.; Huang, X.; Appella, D. H.; Christianson, L. A.; Durrell, S. L.;
Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 2711; (e) Mo¨hle, K.; Gu¨nther, R.;
Thormann, M.; Sewald, N.; Hofmann, H.-J. Biopolymers 1999, 50, 167; (f) Mar-
tinek, T. A.; To´th, G.; Vass, E.; Hollo´ si, M.; Fu¨lo¨p, F. Angew. Chem., Int. Ed. 2002,
41, 1718; (g) Schmitt, M. A.; Choi, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem.
Soc. 2006, 128, 4538; (h) Fu¨lo¨p, F.; Martinek, T. A.; To´th, G. K. Chem. Soc. Rev.
2006, 35, 323; (i) Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus, D.;
Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet, G. W. Tetrahedron Lett.
2001, 42, 4251.
4.5.1. Dipeptide 10
Yield 50%. Crystals, mp 130–132 ꢁC (from CH2Cl2–pentane); [
a]
D
þ57.1 (c 0.31, CH2Cl2); IR: 3305, 2953, 1737, 1685, 1650, 1536 cmꢀ1
;
1H NMR (250 MHz, CDCl3):
d
¼1.07–1.08 (complex absorption, 6H),
1.2 (s, 3H), 1.4 (s, 9H), 1.63–2.03 (complex absorption, 4H), 2.14 (dd,
J¼5.3 Hz, J0¼14.5 Hz, 1H), 2.41 (dd, J¼2.6 Hz, J0¼14.5 Hz, 1H), 2.51 (t,
J¼6 Hz, 2H), 3.46 (m, 2H), 3.66 (s, 3H), 3.73–3.96 (complex ab-
sorption, 5H), 5.21 (d, J¼6.5 Hz, 1H), 6.45 (m, 1H); 13C NMR
´
´
´
¨ ¨
4. (a) Hetenyi, A.; Mandity, I. M.; Martinek, T. A.; Toth, G. K.; Fulop, F. J. Am. Chem.
Soc. 2005, 127, 547; (b) Martinek, T. A.; Ma´ndity, I. M.; Fu¨ lo¨p, L.; To´th, G. K.; Vass,
E.; Hollo´si, M.; Forro´, E.; Fu¨ lo¨p, F. J. Am. Chem. Soc. 2006, 128, 13539; (c) Mar-
(62.5 MHz, CDCl3):
d¼16.5, 22.2, 23., 28.0, 31.3, 33.5, 34.9, 40.2, 40.2,
45.2, 48.5, 48.7, 51.4, 63.4, 65.3, 79.2, 109.9, 156.1, 170.7, 172.6; ele-
mental analysis calcd for C22H38N2O7: C 59.71, H 8.65, N 6.33;
found: C 59.69, H 8.83, N 6.29.
´
¨ ¨
´
´
´
´
¨ ¨
tinek, T. A.; Hetenyi, A.; Fulop, L.; Mandity, I. M.; Toth, G. K.; Dekany, I.; Fulop, F.
Angew. Chem., Int. Ed. 2006, 45, 2396.
´
´
´
˜
5. Rua, F.; Boussert, S.; Parella, T.; Dıez-Perez, I.; Branchadell, V.; Giralt, E.; Ortuno,
R. M. Org. Lett. 2007, 9, 3643.
4.5.2. Dipeptide 11
6. Bru¨ckner, A. M.; Chakraborty, P.; Gellman, S. H.; Diederichsen, U. Angew. Chem.,
Int. Ed. 2003, 42, 4395.
7. Fora recent work, see: Hirata, T.; Fujimura, F.;Kimura, S. Chem. Commun. 2007,1023.
8. For reviews on conformationally constrained amino acids and peptides in-
cluding cyclobutane derivatives, see: (a) Ortun˜o, R. M.; Moglioni, A. G.; Mol-
trasio, G. Y. Curr. Org. Chem. 2005, 9, 237; (b) Ortun˜o, R. M. In Enantioselective
Yield 60%. Crystals, mp 80–83 ꢁC (from EtOH); [
a
]
D þ91.0 (c 0.72,
CH2Cl2); IR: 3314, 2950, 1693, 1658, 1493 cmꢀ1; 1H NMR (500 MHz,
CDCl3):
d
¼1.09–1.11 (complex absorption, 12H), 1.21 (s, 6H), 1.41 (s,
9H), 1.62–2.02 (complex absorption, 8H), 2.11 (dd, J¼4.35 Hz,
J0¼15.75 Hz, 1H), 2.34 (dd, J¼5.25 Hz, J0¼15.75 Hz, 1H), 2.43 (dd,
J¼3.45 Hz, J0¼14.85 Hz, 1H), 2.52 (dd, J¼3.5 Hz, J0¼16.15 Hz, 1H),
3.66 (s, 3H), 3.75–3.98 (complex absorption, 9H), 4.24 (m, 1H), 5.30
Synthesis of
b-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; John
Wiley and Sons: New Jersey, NJ, 2005; pp 117–137.
´
´
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9. Martın-Vila, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.; Branchadell, V.;
Minguillo´n, C.; Giralt, E.; Ortun˜o, R. M. Tetrahedron: Asymmetry 2000, 11, 3569.

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