Helical secondary structures in 2:1 and 1:2 α/γ-peptide foldamers

Article abstract of DOI:10.1016/j.tet.2012.01.079

Oligomers containing both α- and γ-amino acid residues in a 1:1 alternating pattern have recently been shown by several research groups to adopt helical secondary structures. We have begun to explore the folding behavior of oligomers with different α-resi

Full text of DOI:10.1016/j.tet.2012.01.079

Tetrahedron 68 (2012) 4413e4417
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Helical secondary structures in 2:1 and 1:2
a
/g
-peptide foldamers
,
Li Guo a, Weicheng Zhang b, Ilia A. Guzei b, Lara C. Spencer b, Samuel H. Gellman b
*
a The Dow Chemical Company, 1712 Building, Office 21-5, Midland, MI 48674, USA
b Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Oligomers containing both a- and g-amino acid residues in a 1:1 alternating pattern have recently been
Received 28 October 2011
Received in revised form 19 January 2012
Accepted 27 January 2012
Available online 3 February 2012
shown by several research groups to adopt helical secondary structures. We have begun to explore the
folding behavior of oligomers with different -residue/ -residue backbone patterns. Previously we re-
ported that the -amino acids bearing a cyclohexyl constraint at the CbeCg bond and a variable side chain
at Ca strongly promote a helical conformation containing 12-atom C]O(i)/HeN(iþ3) hydrogen bonds
for 1:1 backbones. Here we report synthesis and crystallographic analysis of 2:1 and 1:2 -peptides
a
g
g
a
:g
a/g
Keywords:
a/g-Peptide
Foldamer
that adopt C]O(i)/HeN(iþ3) hydrogen-bonded helical conformations.
Ó 2012 Elsevier Ltd. All rights reserved.
Helical secondary structure
12-Helix
1. Introduction
a 1:1
a/
g
backbone pattern.7f,8a,9 Computational surveys by Hof-
mann et al. of helical conformations available to the unsubstituted
-peptide backbone have identified a number of possible helical
secondary structures.9c The helix containing 12-atom-ring C]
O(i)/HeN(iþ3) H-bonds, which may be designated the -pep-
tide ‘12-helix’, is predicted to have gauche conformations about the
CaeCb ( ) and CbeCg ) backbone bonds of each -residue. Recent
work suggests that oligomers constructed from - and flexible
amino acid subunits can display a variety of discrete folding pat-
terns.9b,f In contrast, we found that conformationally restricted
The ability of biopolymers (proteins and nucleic acids) to adopt
a wide variety of specific conformations is essential for many of the
complex functions carried out by these macromolecules. The re-
lationship between molecular shape and function has led many
researchers to explore unnatural oligomers (foldamers) for the
ability to adopt specific conformations,1,2 which can ultimately
provide a basis for activities, such as catalysis, self-assembly, and
selective recognition of biopolymers.3,4 New backbones potentially
offer distinct ways to arrange side chains in space, which can widen
the range of functions available to foldamers; therefore, efforts to
discover new foldamers are underway in many laboratories.
a/g
a/g
z
(q
g
a
g-
g-
residues I, bearing a cyclohexyl constraint at the CbeCg bond and
a variable side chain at Ca (Fig.1), strongly promote formation of the
a/g
-peptide 12-helix.9g
Oligomers constructed from
tides’) or from combinations of
peptides’) are among most widely studied foldamers.1,2,5,6
acid residues can be endowed with stronger intrinsic folding pro-
pensities than those of residues by use of cyclic constraints to
limit backbone torsional mobility. Analogous benefits should result
from the use of constrained -amino acid residues in foldamers, but
only a few types of ring-containing
-amino acids are known.7,8
Peptides containing acyclic subunits, such as
4-amino acid resi-
2,3,4-residues have been shown by
b
-amino acid residues (‘
- and -amino acid residues (‘
-Amino
b-pep-
a/b-
a
b
2. Results and discussion
b
Here we explore foldamers with backbone patterns other than
a
1:1 alternation of
either 2:1 or 1:2
a
g
- and
g-residues; the new oligomers contain
a:
backbone patterns. Fig. 1 shows four new a/g-
g
peptides (1e4) for which crystal structures have been obtained. The
structure set includes two -peptides with the 2:1 backbone
pattern (1 and 2), which contain four and seven residues, re-
spectively, and two -peptides with the 1:2 backbone pattern (3
and 4), containing three and six residues, respectively. Most of the
-residues are derived from (R,R,R)- residue I, and the -residues
are derived from -alanine III; however, oligomer 4 contains the
(S,S,S)- residue II and -alanine. Crystals of -peptides 1, 2, and 4
g
g-
a/g
g
dues,
g g
2,4-residues, and
a/g
Hanessian et al.7a and Seebach et al.7b to favor a helical confor-
mation defined by 14-atom C]O(i)/HeN(iþ3) hydrogen bonds
(designated the ‘14-helix’). Recently several research groups have
g
g
a
D
explored the folding behavior of short
a/g-peptides containing
g
L
a/g
were grown by slow evaporation of dichloroethane/heptane solu-
tions. Crystals of 3 were grown by slow evaporation of a methanol/
dichloromethane solution.
* Corresponding author. Tel.: þ1 608 262 3303; fax: þ1 608 265 4534; e-mail
address: gellman@chem.wisc.edu (S.H. Gellman).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.079

4414
L. Guo et al. / Tetrahedron 68 (2012) 4413e4417
Fig. 3. Crystal structures of 2 (left), 4 (right): (top) views perpendicular to helical axes;
(bottom) views along the helical axes.
The crystal structure of a/g-peptide 2 contains two molecules in
Fig. 1. Structures of a/g-peptides 1e4 (arrows indicate hydrogen bonds in the crystal
the asymmetric unit (1:1 ratio); the two conformations are very
similar to one another. Each independent molecule forms all four
possible 12-membered-ring hydrogen bonds, and a 10-atom-ring
hydrogen bond forms across the central Ala-Ala segment. It is in-
structures).
2.1. Crystal structures of 2:1 and 1:2 a/g-peptides
Thecrystalstructuresfor1e4areshowninFigs. 2and3. Eachofthe
two 2:1 -peptides (1 and 2) displays a fully helical conformation in
teresting to compare this 12-helix with an ideal 310-helix among
a-
a/g
peptides. Fig. 4 shows a superimposition of the 12-helical confor-
the solid state, with the maximum number of the C]O(i)/HeN(iþ3)
hydrogen bonds (12-atom hydrogen-bonded rings) formed in each
case. This internal hydrogen-bonding pattern is comparable to that of
ꢀ
mation of
a
/g
-peptide 2 and an idealized 310-helix (RMSD¼1 A),
which demonstrates the similarity of the foldamer helix to a natural
prototype.
the 310-helix observed for some peptides composed exclusively of
a-
amino acids. The structure of 1:2 -peptide trimer 3 reveal a 12-
a/g
atom hydrogen-bonded ring and a 14-atom hydrogen-bonded ring;
in the latter ring the donor is the C-terminal carboxylic acid group.
Heptamer 4, containing
adopts a right-handed helix in the crystalline state as expected given
that the other three -peptides are built from residues with R con-
a- and g-residues with S configurations,
a/g
figurations and form left-handed helices. In 4, all four possible C]
O(i)/HeN(iþ3) hydrogen bondsare formed. Three of thesehydrogen
bondsform12-atom rings, whilethefourthhydrogenbond,acrossthe
central geg segment, forms a 14-atom ring. The resulting data set al-
lows us to establish archetypal structural parameters for the i,iþ3
hydrogen-bonded helical secondary structures formed by 2:1 and 1:2
a/g-peptides and to compare these parameters with those of the
a-
peptide helices (310), and the 1:1 -peptide helix.
a/g
Fig. 4. Superposition of backbone atoms of an ideal 310-helix (magenta) with
a/g-peptide 2 (molecule A, cyan) backbone.
2.2. Backbone torsion angle analysis
Table 1 compares backbone torsion angles for the
a- and
g-
residues observed in crystal structures of the four
a/g-peptides
described here. Two sets of torsion angles are provided for 2, be-
cause the crystal structure contains two independent molecules. In
addition, backbone torsion angles are given for a previously
reported 1:1
the (R,R,R)-
a/g
-peptide crystal structure;9g this example contains
g
residue I and
D
-alanine (as do 1e3). All (S,S,S)-
g
resi-
dues II display gþ,gþ local conformations about the CaeCb
(z) and
CbeCg
(q) bonds, and
j
and
4
torsion angle near ꢀ120ꢁ, with
Fig. 2. Crystal structures of 1 (left) and 3 (right); views approximately perpendicular to
the helical axes.
a somewhat wider distribution for the latter torsion angle. The

L. Guo et al. / Tetrahedron 68 (2012) 4413e4417
4415
Table 1
Table 2
Backbone torsion angles (deg) for
a
/g-Peptides 1e4
Average parameters for C]O(i)/HeN(iþ3) hydrogen-bonded helices
Peptides
2:1 -Tetramer 1
-Residue I)
Residues
f
q
z
j
Backbone
Helix type
Res/turn n
Rise/turn
p (A)
Rise/res
d (A)
Radius
r (A)
ꢀ
ꢀ
ꢀ
a
/g
a
a
g
a
73.0
130.2
65.1
27.0
117.4
27.3
(
g
ꢀ56.3
ꢀ54.8
1:1
2:1
1:2
a
a
a
/
/
/
g-Peptide
g-Peptide
g-Peptide
12-Helix
d
3.0
3.0
2.5
3.2
6.1
5.7
5.3
5.8
2.0
1.9
2.0
1.8
2.5
2.3
2.5
2.0
142.9
170.1
d
a
-Peptide
310-Helix
2:1
-Residue I)
Molecule A
a
/g-Heptamer
a
g
a
a
g
a
a
69.6
133.1
63.4
35.9
119.8
29.6
(
g
ꢀ48.8
ꢀ56.3
ꢀ60.5
ꢀ62.8
68.7
21.3
ꢀ
number of residues per turn (3.0 vs 3.2), rise per turn (5.7 A vs
148.2
115.8
130.2
117.5
ꢀ8.9
ꢀ
ꢀ
ꢀ
5.8 A), and rise per residue (1.9 A vs 1.8 A). In addition, the radii are
ꢀ
similar (2.3 vs 2.0 A) for these two helices.
ꢀ23.5
2:1
-Residue I)
Molecule B
a
/
g
-Heptamer 2
a
g
a
a
g
a
a
75.2
134.4
62.5
27.9
117.3
30.9
3. Conclusions
(
g
ꢀ56.5
ꢀ55.8
ꢀ51.9
ꢀ63.3
65.0
26.8
The set of crystal structures reported here provides atomic
resolution structural characterization of two new foldameric sec-
ondary structures, the C]O(i)/HeN(iþ3) H-bonded helices
formed by backbones that contain either a 2:1 or a 1:2 repeating
148.7
123.2
124.5
113.7
ꢀ6.7
ꢀ29.2
1:2
a
/g-Trimer 3
a
g
g
65.7
155.4
149.7
30.1
115.3
140.5
pattern of a- and g-amino acid residues. The structural parameters
(
g-Residue I)
ꢀ58.3
ꢀ52.4
ꢀ62.2
ꢀ46.8
deduced from multiple sets of crystallographic data for each
backbone family show that these new folding patterns are com-
parable to C]O(i)/HeN(iþ3) hydrogen-bonded helices formed by
1:2
a
/g-Hexamer 4
a
g
g
a
g
g
ꢀ74.0
ꢀ139.1
ꢀ143.8
ꢀ54.1
ꢀ19.2
ꢀ131.1
ꢀ110.6
ꢀ35.2
(S,S,S) (
g-Residue II)
56.2
57.9
58.0
53.7
pure
a-residue oligomers (the 310-helix), and by oligomers con-
taining a 1:1
a/g repeat (the 12-helix). This information should be
ꢀ145.8
ꢀ111.4
56.5
55.6
61.7
60.3
ꢀ115.5
ꢀ144.0
useful to any researcher who seeks to use these foldamer scaffolds
for function-based design.
1:1
a
/g
-Hexamer9g
a
g
a
g
a
g
75.5
134.3
56.3
134.7
67.2
22.8
109.4
41.1
109.8
45.9
(
g-Residue I)
ꢀ57.7
ꢀ56.7
ꢀ55.4
ꢀ50.5
ꢀ55.7
ꢀ51.3
4. Experimental section
4.1. General procedures for
a/g-peptide synthesis
162.1
116.0
The -peptides reported here were prepared via conventional
solution-phase methods. As in conventional peptide synthesis, or-
thogonal amino and carboxyl protecting groups are required for
a/g
Computational study
By Hofmann9c
a
g
a
g
a
g
72.3
123.4
69.8
123.3
69.6
28.8
124.9
29.1
122.6
30.6
ꢀ52.6
ꢀ52.1
ꢀ53.8
ꢀ62.3
ꢀ62.7
ꢀ64.0
synthesis involving
g-residues. The tert-butyloxycarbonyl group
(Boc) was used for N-terminal protection, and C-termini were
protected as benzyl esters (OBn). Deprotection at the N-terminus
was performed using 4 N HCl in dioxane, and hydrogenation was
122.8
129.8
used to remove the C-terminal benzyl esters.
rivatives were purchased from SigmaeAldrich, NovaBiochem, and
Chem-Impex International. Protected forms of -amino acids I and
a-Amino acid de-
(R,R,R)-
CaeCb
those of (S,S,S)-
predictions for a C]O(i)/HeN(iþ3) hydrogen-bonded helical
conformation of 1:1
-peptides from Hofmann et al.9e The
residue -Ala
torsion angles in our crystal structures (near 30ꢁ for
or the opposite for -Ala) are similar to those observed for a ca-
g
residues I display gꢀ,gꢀ local conformations about the
) and CbeCg ) bonds, with torsion angles opposite to
residues II. These values are consistent with the
(z
(q
g
g
II were prepare according to previously reported procedures.9g For
peptide coupling, EDCI (1.2 equiv)þHOBt (1.2 equiv)þDIEA
(1.2 equiv) or EDCI (1.5 equiv)þDMAP (1.1 equiv) were used. After
the coupling reaction was complete, the mixture was diluted with
excess EtOAc, and the organic solution was washed with 10%
aqueous NaHSO4, saturated aqueous NaHCO3, and then brine. The
organic layer was dried over Na2SO4, filtered, and concentrated to
a/
g
a-
j
D
L
nonical 310-helix, which shares the C]O(i)/HeN(iþ3) hydrogen-
bonding pattern.
give
a crude product, which was purified by silica gel
2.3. Helical parameter analysis
chromatography.
Average parameters for the C]O(i)/HeN(iþ3) hydrogen-
4.1.1. Boc-(
HCl$NH2-
CDCl3)
D
)Ala-
g
(I)-OBn. Boc-(
D
)-Ala-OH
was
coupled
to
bonded helices formed by 2:1 and 1:2
a
/g-peptides were derived
g
(I)-OBn to give the desired dipeptide. 1H NMR (300 MHz,
d 7.37e7.29 (m, 5H), 6.66 (br, 1H), 4.99, 5.20 (AB,
from the structural data as described previously10 and are pre-
sented in Table 2. Each helical parameter was calculated from a set
JAB¼12.3 Hz, 2H), 4.99 (br, 1H), 4.14 (m, 1H), 4.07 (p, J¼7.2 Hz, 1H),
2.28 (ddd, J¼4.2, 9.9, 9.9 Hz, 1H), 1.89e1.62 (m, 6H), 1.52 (m, 2H)
1.44 (s, 9H), 1.27 (m, 1H), 1.23 (m, 1H), 1.24 (d, J¼7.1 Hz, 3H), 1.07 (m,
of four consecutive
were excluded from these calculations. For C
used as an imaginary -carbon. Table 2 includes for comparison
parameters for two other helices that contain C]O(i)/HeN(iþ3)
hydrogen bonds: the 1:1 -peptide 12-helix and the -peptide
a-carbons. Nonhelical residues at C-termini
b
of -residues was
g
a
1H), 0.83 (t, J¼7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 175.55,
171.91, 156.13, 136.37, 128.60, 128.22, 80.26, 77.68, 77.26, 76.83,
66.50, 50.12, 49.63, 46.77, 41.52, 31.11, 28.52, 25.70, 24.82, 23.29,
20.63, 17.40, 11.65; HRMS m/z (ESI): calcd for: C25H38N2O5Na
[MþNa]þ 469.2673, found 469.2672.
a/
g
a
310-helix. The parameters for all four helices are quite similar. De-
tailed comparison of the two independent helices observed in the
crystal of the 2:1
a
/g-peptide heptamer 2 and the
a
-peptide 310
-
The dipeptide was dissolved in methanol (10 mL), and the flask
was flushed with N2. To the flask was added 10% Pd/C (0.05 g), and
helix reveals further similarities: both helices have a comparable

4416
L. Guo et al. / Tetrahedron 68 (2012) 4413e4417
the flask was attached to a Parr apparatus and shaken for 6e7 h
under 10 psi H2. The reaction mixture was filtered through a pad of
g(I)-g(I)-OBn. The tripeptide was dissolved in methanol (10 mL),
and the flask was flushed with N2. To the flask was added 10% Pd/C
(0.05 g), and the flask was attached to a Parr apparatus and shaken
for 6e7 h under 10 psi H2. The reaction mixture was filtered
through a pad of Celite and concentrated to give the desired
Celite and concentrated to give a white solid (Boc-(
D)Ala-g(I)eOH).
The crude product was carried on without purification.
4.1.2. Boc-(
to HCl$NH2-(
to give the tripeptide Boc-(
(300 MHz, CDCl3) 7.65 (br, 1H), 7.39e7.29 (m, 5H), 6.71 (d,
D
)Ala-
)Ala-OBn by the general procedure described above
)Ala- (I)-(
)Ala-OBn. 1H NMR
g
(I)-(
D
)Ala-OBn. Boc-(
D
)Ala-
g
(I)eOH was coupled
product 3 (Boc-(D)Ala-g(I)-g(I)eOH). After chromatographic puri-
fication, an X-ray quality crystal was grown by slow evaporation of
a methanol/dichloromethane solution.
D
D
g
D
d
J¼9.0 Hz, 1H), 5.19 (AB, JAB¼12.6 Hz, 2H), 4.89 (br, 1H), 4.57 (p,
J¼7.1 Hz, 1H), 4.25 (m, 1H), 4.14 (p, J¼6.9 Hz 1H), 1.88 (ddd, J¼4.2,
10.4, 10.4 Hz, 1H), 1.82e1.62 (m, 5H), 1.58e1.22 (m, 22H) 0.82 (t,
4.1.6. Boc-(
(II)-OBn (4). (
synthesize -peptide 4, via the fragment approach described
above. Trimer Boc-( )Ala-(S,S,S) (II)-(S,S,S) (II)-OBn (1 equiv) was
treated with 4.0 M HCl in dioxane (w10 equiv). The mixture was
stirred for 30 min and then concentrated under a nitrogen gas
stream to give the HCl salt form of the amine, which was coupled
L
)Ala-(S,S,S)
g
(II)-(S,S,S)
g
(II)-(
L)Ala-(S,S,S)g(II)-(S,S,S)
g
L
)-Alanine and (S,S,S)-
g-amino acid II were used to
a/g
J¼7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
175.20, 173.20, 172.51,
L
g
g
156.12, 136.09, 128.68, 128.26, 80.77, 66.93, 51.10, 50.12, 48.75,
47.01, 42.85, 30.89, 28.53, 25.88, 24.39, 22.44, 20.53, 18.12, 17.77,
14.32, 12.21; HRMS m/z (ESI): calcd for: C28H43N3O6Na [MþNa]þ
540.3045, found 540.3035.
with Boc-(L)Ala-(S,S,S)g(II)-(S,S,S)g(II)eOH by the general coupling
The tripeptide was dissolved in methanol, and the flask was
flushed with N2. To the flask was added 10% Pd/C, and the flask was
attached to a Parr apparatus and shaken for 6e7 h under 10 psi H2.
The reaction mixture was filtered through a pad of Celite and
method to give the desired product 4. After chromatographic pu-
rification, an X-ray quality crystal was grown by slow evaporation
of a dichloroethane/heptane solution. 1H NMR (300 MHz, CDCl3)
d
7.79 (d, J¼10.0 Hz, 1H), 7.74(d, J¼9.2 Hz, 1H), 7.62 (br, 1H),
concentrated to give a white solid (Boc-(
D)Ala-
g(I)-(
D
)AlaeOH). The
7.46e7.44 (m, 2H), 7.34e7.25 (m, 3H), 6.59 (d, J¼10.0 Hz, 1H), 6.53
(d, J¼9.1 Hz, 1H), 5.26, 5.06 (AB, J¼12.5 Hz, 2H), 4.87 (d, J¼10.0 Hz,
1H), 4.43 (m, 1H), 4.25 (m, 1H), 4.12 (m, 1H), 4.03 (m, 2H), 3.91 (m,
1H), 2.91 (m, 1H), 2.17 (ddd, J¼3.8, 10.5, 10.5 Hz, 1H), 2.0e1.19 (m,
61H), 0.91e0.79 (m, 12H); HRMS m/z (ESI): calcd for: C58H94N6O9Na
[MþNa]þ 1041.6975, found 1041.6941.
crude product was carried on without purification.
4.1.3. Boc-(
AlaeOH) coupled to HCl$NH2-(
method to give the tetrapeptide Boc-(
D
)Ala-
g
(I)-(
D
)Ala-(
D
)Ala-OBn
)Ala-OBn by the general coupling
)Ala- (I)-( )Ala-( )Ala-OBn
(1). (Boc-(D)Ala-g(I)-(D)
D
D
g
D
D
(1). After chromatographic purification, an X-ray quality crystal was
grown by slow evaporation of a dichloroethane/heptane solution.
Acknowledgements
1H NMR (300 MHz, CDCl3)
d
7.78 (d, J¼7.3 Hz, 1H), 7.37e7.29 (m,
5H), 6.95 (d, J¼6.8 Hz, 1H), 6.60 (d, J¼9.6 Hz, 1H), 5.14 (AB,
JAB¼12.4 Hz, 2H), 4.89 (d, J¼6.8 Hz, 1H), 4.65 (p, J¼7.4 Hz, 1H), 4.46
(p, J¼7.1 Hz, 1H), 4.14 (m, J¼6.9 Hz 1H), 4.20 (m, 1H), 1.84 (m, 2H),
1.76 (m, 2H), 1.64 (m, 1H), 1.56e1.18 (m, 25H), 0.82 (t, J¼7.2 Hz, 3H);
This research was supported by NSF (CHE-0848847). NMR spec-
trometers were purchased with partial support from NIH and NSF.
Supplementary data
13C NMR (75 MHz, CDCl3)
d 175.29, 172.86, 172.57, 156.30, 136.17,
128.68, 128.17, 81.20, 66.76, 51.96, 50.55, 50.16, 48.42, 46.86, 42.31,
31.06, 28.54, 25.74, 24.43, 22.97, 20.57, 18.15, 17.98, 17.84, 11.86;
HRMS m/z (ESI): calcd for: C31H48N4O7Na [MþNa]þ 611.3416, found
611.3391.
Copies of 1H and 13C spectra for 1e4. Supplementary data re-
lated to this article can be found online at doi:10.1016/
j.tet.2012.01.079.
References and notes
4.1.4. Boc-(
D
)Ala-
g
(I)-(
D
)Ala-(
D
)Ala-
g
(I)-(D)Ala-(D)Ala-OBn
(2). Tetramer 1 (1 equiv) was treated with 4.0 M HCl in dioxane
(w10 equiv). The mixture was stirred for 30 min and then con-
centrated under a nitrogen gas stream to give the HCl salt form of
1. (a) Guichard, G.; Huc, I. Chem. Commun. 2011, 5933; (b) Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173; (c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity
2004, 1, 1111; (d) Foldamers: Structure, Properties and Applications; Hecht, S.,
Huc, I., Eds.; Wiley-VCH Weinheim: Germany, 2007; (e) Goodman, C. M.; Choi,
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the amine, which was coupled with Boc-(
D
)Ala-g(I)-(D)Ala-OH by
the general coupling method to give the desired product 2. After
chromatographic purification, an X-ray quality crystal was grown
by slow evaporation of a dichloroethane/heptane solution. 1H NMR
2. (a) Barron, A. E.; Zuckermann, R. N. Curr. Opin. Chem. Biol. 1999, 3, 681; (b)
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Lamour, K.; Decossas, M.; Fournel, S.; Heurtault, B.; Godet, J.; Mely, Y.; Jamart-
Gregoire, B.; Averlant-Petit, M.-C.; Briand, J.-P.; Duportail, G.; Monteil, H.;
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Liu, D. H.; Kim, H.; Scott, R. W.; Winkler, J. D.; DeGrado, W. F. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 6968; (e) Bautista, A. D.; Stephens, O. M.; Wang, L. G.; Domaoal,
R. A.; Anderson, K. S.; Schepartz, A. Bioorg. Med. Chem. Lett. 2009, 19, 3736; (f)
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47, 1808; (g) For earlier examples, see Ref. 1d.
(300 MHz, CDCl3)
d
8.39 (d, J¼3.9 Hz, 1H), 7.89 (d, J¼7.5 Hz, 1H), 7.47
(d, J¼6.1 Hz, 1H), 7.39e7.28 (m, 5H), 7.17 (d, J¼8.2 Hz, 1H), 7.01 (br,
1H), 6.64 (d, J¼12.7 Hz, 1H), 5.18, 5.13 (AB, J¼13.0 Hz, 2H), 5.10 (d,
J¼2.7 Hz, 1H), 4.63 (p, J¼7.4 Hz, 1H), 4.41 (p, J¼6.6 Hz, 1H), 4.11 (m,
J¼6.9 Hz, 3H), 3.97 (m, 2H), 2.31 (ddd, J¼3.5, 10.4, 10.4 Hz),
1.92e1.76 (m, 6H), 1.73e1.59 (m, 7H), 1.55e1.14 (m, 34H), 0.81 (m,
6H); 13C NMR (75.4 MHz, CDCl3)
d 177.30, 177.04, 175.18, 174.01,
172.36, 172.27, 156.34, 137.41, 128.87, 128.36, 127.60, 81.50, 66.03,
52.70, 52.45, 50.41, 49.82, 49.20, 47.59, 47.44, 47.27, 47.03, 46.33,
41.96, 41.33, 39.36, 33.12, 32.69, 32.09, 31.17, 30.68, 28.55, 26.53,
26.46, 26.37, 26.07, 25.58, 24.36, 23.95, 23.68, 23.39, 23.25, 23.14,
22.86, 20.53, 20.36, 20.15, 18.03, 17.93, 12.45, 11.48, 10.85, 10.36;
HRMS m/z (ESI): calcd for: C47H75N7O10Na [MþNa]þ 920.5468,
found 920.5466.
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4.1.5. Boc-(
pled to HCl$NH2-
(1.1 equiv) as coupling reagents to give the tripeptide Boc-(
D
)Ala-
g
(I)-
(I)-OBn by using EDCI (1.5 equiv) and DMAP
)Ala-
g(I)eOH (3). Boc-(D)Ala-g(I)eOH was cou-
g
D

L. Guo et al. / Tetrahedron 68 (2012) 4413e4417
4417
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