1-Aminoxymethylcyclopropanecarboxylic acid as building block of β N-O turn and helix: Synthesis and conformational analysis in solution and in the solid state

Article abstract of DOI:10.1016/j.tet.2010.10.037

Cyclopropane side-chained β^2,2-aminoxy oligopeptides were synthesized and conformationally studied. β N-O turn in solution and β N-O helix in the solid state was characterized by ¹H NMR, 2D NOESY and FT-IR as well as X-ray crystallography studies. Almost no changes has been observed with the disturbance at α carbon bond angle compared with dimethyl substituted one. This study provided the opportunity to design the bioactive peptidomimetics in a more elaborate way.

Full text of DOI:10.1016/j.tet.2010.10.037

Tetrahedron 66 (2010) 9733e9737
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1-Aminoxymethylcyclopropanecarboxylic acid as building block of
b NeO turn
and helix: synthesis and conformational analysis in solution and in the solid state
y
y
*
Xiao-Wei Chang , Qing-Chuan Han , Zhi-Gang Jiao, Lin-Hong Weng, Dan-Wei Zhang
Department of Chemistry, Fudan University, 220 Handan road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
b
2,2-aminoxy oligopeptides were synthesized and conformationally studied.
Article history:
Received 5 May 2010
Received in revised form 6 October 2010
Accepted 15 October 2010
Available online 9 November 2010
Cyclopropane side-chained
b
NeO turn in solution and
FT-IR as well as X-ray crystallography studies. Almost no changes has been observed with the disturbance
at carbon bond angle compared with dimethyl substituted one. This study provided the opportunity to
b
NeO helix in the solid state was characterized by 1H NMR, 2D NOESY and
a
design the bioactive peptidomimetics in a more elaborate way.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b
b
2,2-aminoxy acid
NeO turn
Cyclopropane side chain
Secondary structure
1. Introduction
(a)
(b)
H
N
H
N
H
N
H
N
H
N
H
N
Research of synthetic foldamers (peptidomimetics) has been
attracted most attention not only on discovering predictable and
well-defined secondary structures, but also on the harnessing of
latent bioactivities in enzyme mimic as well as drug design and
development.1 Constrained cyclopropane ring has been served as
such a useful segment in the peptidomimetic design. On the one
hand, cyclopropane-containing peptides, natural or synthetic, have
been found to exhibit various bioactivities, for example, to be in-
volved in the process of the biosynthesis of ethylene, being in-
hibitor of the carboxypeptidase, being the hepatitis C virus NS3
protease, and so on.1d,2ꢀ5 On the other hand, introducing the cy-
clopropane ring to the backbone has been employed to give the
extra rigidity to the conformation or create different secondary
structures.6,7 For example, in the oligomers composed of 1-(ami-
O
O
O
O
O
O
8-membered H-bonded ring
2,2-peptides and intramolecular hydrogen bond form.
Fig. 1. Achiral
b
Aminoxy peptides are kinds of backbone-modified peptidomi-
metics with inserting of one oxygen atom between the nitrogen
atom and one of the backbone carbon atom.1e,9,10 Well-defined
secondary structures, for example, NeO turns, NeO helices, reverse
turn, etc. have been found to exhibit by short
peptide sequences.
a-,
b
-,
g
b
-aminoxy
-aminoxy
b
3-Aminoxy peptides, a subclass of
peptides, possess a strong nine-membered ring intramolecular hy-
drogen bond, i.e.,
b NeO turn, (Fig. 2a) between adjacent residues,
nomethyl)-cyclopropylcarboxylic acid (hAcc, a kind of b
2,2-amino
(a)
acid), eight-membered ring intramolecular hydrogen bond was
formed (Fig.1a), while no intramolecular hydrogen bond is found in
the oligomers derived from 3-amino-2,2-dimethylpropanoic acid
(Fig. 1b).7 And this eight-membered ring intramolecular hydrogen
bond secondary structure hasn’t been found in the known chiral b-
peptides.1c,8
(b)
* Corresponding author. Tel.: þ86 21 6564 3576; fax: þ86 21 6564 1740; e-mail
b-Aminoxy acid and b NeO turn; (b) Dimethyl side-chained b
2,2-aminoxy
address: zhangdw@fudan.edu.cn (D.-W. Zhang).
Fig. 2. (a)
oligomers I and II.
y
Chang, X.-W. and Han, Q.-C. contributed equally to this work.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.037

9734
X.-W. Chang et al. / Tetrahedron 66 (2010) 9733e9737
but the molecular conformation is side chain dependent.10a For the
dimethyl substituted
2,2-aminoxy acid (Fig. 2b), both monomer I
and dipeptide II involve NeO turn, which is coincident with one
form of NeO turns existing in
3-aminoxy peptide.10b And achiral
dipeptide II can form helix structure consisting of two consecutive
homochiral NeO turns in the solid state. Recently, wereported that
the chirality of the achiral NeO turn adopted by 1-(aminoxy)
cyclopropanecarboxylic acid unit (OAcc) in the building block of
chiral -aminoxy acid/achiral cyclopropane -aminoxy acid can be
induced by the previous chiral
-aminoxyacid unit.10d However, this
kind of induction is much weaker in chiral -aminoxy acid/achiral 2-
Conventional protection/deprotection, and coupling reaction were
then employed to build up the amide bonds in monomer 1.14 Due to
the low yield in the key cyclopropanation process and the diffi-
culties in separating compound 6 from 7, several other methods,
such as photolysis13b and Pd(OAc)2 catalyzed route15 were tried but
failed to improve the yield of compound 6.
b
b
b
b
b
a
Then we changed the synthetic protocol to prepare dipeptide 2
startingfromdiethylmalonateasshowninScheme 3. Thecyclopropyl
group was introduced via substitution by 1,2-dibromo ethane. Af-
terwards, compound 8 underwent hydrolysis followed by reduction
to afford the key intermediate 10, for introduction of aminoxy group
a
a
a
a
aminoxyacetic acid (OGly) unit. On further developing constrained
cyclopropane ring incorporated bioactive peptidomimetics, we are
interested in the structure and properties of cyclopropane ring
in next step. b
2,2-Aminoxy dipeptide 2 (Piv-hOAcc-hOAcc-NH-c-Hex)
was finally obtained in good yield through conventional protection/
deprotection and coupling reactions.
substituted b
2,2-aminoxy peptide, which has much flexible back-
bone with one carbon prolonged than that of OAcc unit. Here we
reported the synthesis and conformational studies of monomer 1
and dipeptide 2 (Fig. 3) derived from 1-aminoxymethyl-cyclo-
propanecarboxylic acid (hOAcc).
2.2. Conformational studies
2.2.1. Conformation in solution.
2.2.1.1. 1H NMR dilution and titration studies of monomer 1 and di-
peptide 2. The conformations of monomer 1 and dipeptide 2 in
solution were studied by 1H NMR spectroscopy at first. The in-
tramolecularly hydrogen-bonded amide proton is solvent in-
accessible and its chemical shift will not show significant change on
dilution by CDCl3 or titration by DMSO-d6. While the chemical shift
of the solvent accessible proton will move downfield dramatically
in these two experiments. As shown in Fig. 4, the amide NHb proton
of monomer 1 showed little changes when its solution in CDCl3
were diluted from 200 to 1.56 mM (Fig. 4a), or when DMSO-d6 was
added gradually to its 5 mM solution in CDCl3 (Fig. 4b).16
O
O
Ha
N
Ha
N
Hc
N
O
O
N
O
N
Hb
Hb
O
O
O
1
2
Piv-hOAcc-hOAcc-NH-c-Hex
2,2-aminoxy monomer 1 and di-
Piv-hOAcc-NH-i-Bu
Fig. 3. Structures of cyclopropane side-chained
peptide 2.
b
2. Results and discussion
But the chemical shift of the aminoxy amide NHa of 1 changed
dramatically upon dilution in CDCl3 or by DMSO-d6 addition.17
Table 1 summarized the chemical shifts of all the amide protons
of 1 and 2 at 2 mM in CDCl3 at room temperature. The chemical
shifts of C-terminal regular amide NH protons of 1 (dHb 8.63 ppm)
and 2 (dHc 8.42 ppm) were more downfield than the regular amide
NHs (ca. 6.5 ppm).17 And the chemical shift of aminoxy amide NHb
2.1. Synthesis of 1-aminoxymethylcyclopropanecarboxylic
acid monomer 1 and dipeptide 2
Cyclopropane side-chained
b
2,2-Aminoxy monomer 1 (Piv-
hOAcc-NH-i-Bu) was synthesized as shown in Scheme 1. In-
termediate methyl 2-(hydroxymethyl)acrylate (3) was obtained
through BayliseHillman reaction from 37% formalin and methyl
proton of dipeptide 2 (
d
12.05 ppm) was also more downfield than
O
PhthNOH
DIAD, PPh3
O
O
O
O
DABCO • 6H2O
+
HO
O
O
N
O
O
H
H
O
THF, 0°C, 1h;
then r.t., 12h
1,4-dioxane/H2O
(3.1:1), r.t., 2d
O
3 (38%)
4 (15%)
1. CH2N2, Et2O; then
toluene reflux, 5h
O
O
1. LiOH, THF/MeOH/
H2O (3:1:1), 0°C, 6h
H
N
O
H
N
O
N
H
2. NH2NH2 • H2O,
MeOH, r.t., 1h
3. PivCl, CH2Cl2/H2O
r.t., 12h
2. i-BuNH2, HOAt, EDCI
CH2Cl2, 12h
O
O
5 (9%)
1 (56%)
Scheme 1. Synthesis of cyclopropane substituted
D¼diisopropyl azodicarboxylate; PivCl¼pivaloyl chloride; HOAt¼1-hydroxyazabenzotriazole; EDCI¼1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methyl hydrochloride.
b
2,2-aminoxy monomer 1. Abbreviations: DABCO¼1,4-diazabicyclo[2.2.2]octane; PhthNOH¼N-hydroxyphthalimide; DIA-
acrylate.11 Then, Mitsunobu reaction transformed hydroxyl group
to aminoxy group to introduce the NeO segment.12 The key step
was cyclopropanation of the ethylene group using diazomethane
under reflux in toluene, but the cyclopropane compound 6 and
byproduct 7 was obtained as an unseparated mixture (Scheme 2).13
the non-hydrogen-bonded aminoxy amide NH (ca. 8.5 ppm). But
the chemical shifts of N-terminal aminoxy amide NHa protons of 1
(d 8.46 ppm) and 2 (d 8.57 ppm) were in the region of non-hy-
drogen-bonded aminoxy amide NHs. This result indicated that NHb
and NHc protons are intramolecular hydrogen-bonded to form
O
O
O
O
O
O
1. CH2N2,
Et2O
+
N
O
O
O
N
O
O
N
O
O
O
2. toluene
reflux 5h
O
Z/E
4
6
7
81%
Scheme 2. Cyclopropanation of compound 4 with diazomethane.

X.-W. Chang et al. / Tetrahedron 66 (2010) 9733e9737
9735
Scheme 3. Synthesis of cyclopropane substituted b
2,2-aminoxy dipeptide 2.
(a)
(b)
Fig. 4. 1H NMR dilution study and DMSO-d6 addition study of monomer 1. (a) Amide proton chemical shift as a function of logarithm of concentration (in CDCl3 at room tem-
perature); (b) Amide proton chemical shift as a function of the amount of DMSO-d6 added in a 5 mM solution (0.5 mL in CDCl3 at room temperature).
Table 1
compound 1 and 2 could be assigned accordingly. The band at 3419
and 3411 cmꢀ1 could be assigned to the non-hydrogen-bonded
aminoxy amide NeH stretches, 3317 and 3288 cmꢀ1 to the hy-
drogen-bonded amide NeH stretches. The absorption at 3213 cmꢀ1
for compound 2 could be attributed to the hydrogen-bonded ami-
noxy NeH stretch. The FT-IR results were coincident with that of 1H
NMR experiments. The results suggested that one nine-membered
ring intramolecular hydrogen bond was formed in monomer 1 and
two for dipeptide 2 in aprotic solvent.
1H NMR chemical shifts (
d
ppm) of amide protons of 1 and 2 at 2 mM in CDCl3
a
Compound
NHa
NHb
NHc
1
2
8.46 (s)
8.57 (s)
8.63 (br)
12.05 (s)
8.42 (d)
a
The chemical shifts underlined are those of the C-terminal regular amide NH
protons, others are those of aminoxy amide NH protons.
b
NeO turns, while the NHa protons are not intramolecular hy-
drogen-bonded, namely, solvent accessible. Compared to those of
2,2-aminoxy peptide I and II,10b the chemical shifts of hydrogen-
b
2.2.1.3. 2D NOESY studies. More information of the conforma-
tion in solution of compound 1 and 2 was obtained from 2D Nuclear
Overhauser Effect Spectroscopy experiment (NOESY) recorded in
CDCl3.19 Monomer 1 showed strong nuclear Overhauser effects
bonded amide NHs of 1 and 2 were all more downfield with the
differences in a range of 0.31e0.78 ppm, correspondingly. But little
differences (0.06 and 0.02 ppm) existed between the chemical
shifts of the N-terminal non-hydrogen-bonded NH protons of cy-
clopropane and dimethyl substituted one, separately. This differ-
ence could be attributed to the substituent effect. Cyclopropane
(NOEs) between NHb and Hb (
b proton), but medium NOEs between
NHa and Hb (Fig. 6). Dipeptide 2 exhibited strong NOEs between the
pairs of NHb/H1b proton of unit 1, N-terminal), and NHc/H2b
(b (b
proton of unit 2, C-terminal), but medium NOEs between NHa/H1b,
andNHb/H2b. Thatis tosay, the amide protonNHi has strongNOEwith
substituted
b
2,2-aminoxy peptides can form more strong intra-
molecular hydrogen bond than dimethyl substituted one.
the
proton CbHi in the same residue. And two residues of dipeptide 2
possess same conformation. This kind of NOE pattern of compound 1
and 2 matched well with that of dimethyl substituted
2,2-aminoxy
peptides, which supported the view that similar conformation of
nine-membered ring intramolecular hydrogen bond ( NeO turn) is
formed of compound 1 and 2 in solution. And the absence of NOE
b proton CbHiꢀ1 in adjacent residue, but medium NOE with the
2.2.1.2. FT-IR spectra studies. Fig. 5 presented the FT-IR spectra
of compound 1 and 2 in the NeH stretch region. The spectra were
recorded in CH2Cl2 at low concentration (2 mM) at which in-
termolecular hydrogen bond is seldom to occur. Following the
principle for distinguishing the hydrogen-bonded and non-hydro-
gen-bonded NeH stretching frequencies,18 the FT-IR signals of
b
b
b

9736
X.-W. Chang et al. / Tetrahedron 66 (2010) 9733e9737
0.05
0.04
0.03
0.02
0.01
0.00
-0.032
(a)
(b)
3317 cm
1
2
-0.034
3288 cm
3213 cm
3411 cm
-0.036
-0.038
-0.040
-0.042
3419 cm
3500
3450
3400
3350
3300
3250
3500 3450 3400 3350 3300 3250 3200 3150 3100
Wavenumber (cm−1)
wavenumber (cm−1)
Fig. 5. NeH stretch region FT-IR data for (a) monomer 1 and (b) dipeptide 2 at 2 mM in CH2Cl2 at room temperature after subtraction of the spectrum of pure CH2Cl2.
Table 2
Dihedral angles of cyclopropane substituted
b
2,2-aminoxy peptides 1 and 2
Fig. 6. The NOEs review of compound 1 and 2 according to their 2D NOESY spectra
Compound Unit 1 (N-terminal)
ɸ1 q1 41
Unit 2 (C-terminal)
(5 mM in CDCl3 at 25 ꢁC).
j1
ɸ2
q2
42
j2
1
2
87.4ꢁ ꢀ169.2ꢁ 64.8ꢁ ꢀ1.0ꢁ
92.7ꢁ ꢀ167.3ꢁ 67.0ꢁ
6.4ꢁ 90.6ꢁ ꢀ172.1ꢁ 78.8ꢁ ꢀ17.4ꢁ
between the protons on C-terminus and on N-terminus of dipeptide
2 implied that it adopts an extended structure.
II10b are comparable, except slightly differences of
f and j. The
2.2.2. Conformation in the solid state: X-ray diffraction ana-
lysis.
b
b
2,2-Aminoxy acid monomer 1 and dipeptide 2 adopted
bond angles of :C¼OCaCb in 1 and 2 (ca. 120ꢁ) attributed to cy-
clopropane substituent are larger than that of dimethyl
substituted I and II (ca. 109ꢁ of regular sp3 hybrid carbon bond
angle). This disturbance of backbone geometry did not change the
conformations of the compound 1 and 2 in solid state, but little
NeO turn structure in solution as determined by 1H NMR, 2D
NOESY and FT-IR spectroscopic methods. Such high coincidence in
the structure between compound 1 (2) and its dimethyl counter-
part I (II) was also observed in the solid state as revealed by X-ray
structural analysis.20
As shown in Fig. 7, the crystal of monomer 1 shows a strong
nine-membered ring intramolecular hydrogen bond with the
changes of dihedral angle
and NeO helix structure were possessed by compound 1 and 2,
respectively.
f and j of the backbone. b NeO turn
b
Fig. 7. X-ray structures of b
2,2-aminoxy (a) monomer 1 and (b) dipeptide 2.
ꢁ
ꢀ
NH/O distance of 2.12 A and the :NHO angle of 163.8 . There is
also a six-membered ring intramolecular hydrogen bond formed
between amide NHb and aminoxy oxygen atom (NH/O distance of
3. Conclusions
The monomer 1 and dipeptide 2 derived from hOAcc were
synthesized and their conformations were characterized by 1H
NMR, 2D NOESY and IR spectrometries as well as X-ray crystal-
lography. It turns out that in solution or in the solid state both of
ꢁ
ꢀ
2.39 A and the :NHO angle of 121.3 ), as that in monomer I, to
further stabilize the NeO turn conformation. The dihedral angles
ɸ, q, 4 and j of the backbone of 1 were listed in Table 2 and found
b
close to those of monomer I.10b
them adopted
counterparts I and II. This study provided us deep comprehension
of the structural characteristic of -aminoxy peptide and also lends
b NeO turn in the same pattern as their dimethyl
Dipeptide 2 adopted a helix structure stabilized by two con-
secutive homochiral
b
NeO turns, i.e.,
b
NeO helix, in the solid
b
state, which is also in accordance with the helix form of dipeptide
II. The dihedral angles the backbone of dipeptide 2 (Table 2) and
us the opportunity to design the bioactive peptidomimetics in
a more elaborate way.

X.-W. Chang et al. / Tetrahedron 66 (2010) 9733e9737
9737
4. Experimental section
Supplementary data
4.1. N-Isobutyl 1-((1-(N-pivaloylamidoxy))methyl)
cyclopropanformamide (Piv-hOAcc-NH-i-Bu, 1)
Synthetic schemes and characterization data of 1, 2 and their
synthetic intermediates; copies of 2D NOESY spectra of 1 and 2;
crystallographic data of 1 and 2. Supplementary data related to this
article can be found online at doi:10.1016/j.tet.2010.10.037. These
data include MOL files and InChiKeys of the most important
compounds described in this article.
To a mixture solvent of compound 5 (83 mg, 0.36 mmol) in THF
(6 mL), MeOH (2 mL) and H2O (2 mL) was added lithium hydroxide
(45.8 mg 1.09 mmol) at 0 ꢁC. After stirring for 6 h at 0 ꢁC, the re-
action mixture was added 15 mL of EtOAc and acidified with 1 N
HCl to pH¼1. After extracted with EtOAc and washed with brine,
the organic layer was dried over anhydrous MgSO4 and concen-
trated. The resulting acid was azeotroped with toluene three times
and directly used for the next step reaction.
References and notes
1. For selected reviews: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173e180; (b)
Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57, 7431e7448; (c) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. Chem. Rev. 2001, 101, 3219e3232; (d) Brackmann,
F.; de Meijere, A. Chem. Rev. 2007, 107, 4493e4537; (e) Li, X.; Wu, Y.-D.; Yang, D.
Acc. Chem. Res. 2008, 41, 1428e1438; (f) Seebach, D.; Gardiner, J. Acc. Chem. Res.
2008, 41, 1366e1375; (g) Tsantrizos, Y. S. Acc. Chem. Res. 2008, 41, 1252e1263.
2. Pirrung, M. C. Acc. Chem. Res. 1999, 32, 711e718.
Freshly distilled CH2Cl2 (12 mL) was added to the flask of dried
free acid under nitrogen atmosphere, followed by the addition of
HOAt (75 mg, 0.55 mmol), iso-butyl amine (0.07 mL, 0.7 mmol) and
finally EDCI (0.21 g, 0.72 mmol). After stirring overnight, the re-
action mixture was diluted with CH2Cl2. The organic layer was
washed with 5% NaHCO3, 0.1 N H2SO4 and brine, then dried over
anhydrous MgSO4 and concentrated. The residue was purified by
flash column chromatography (with 2:1 hexane/EtOAc as eluent) to
afford compound 1 (59 mg, 56%) as a white solid. TLC Rf 0.18 (2:1
hexane/EtOAc); mp 168ꢀ169 ꢁC; IR (KBr) 3419, 3317, 2963, 1637,
3. Salaun, J. Top. Curr. Chem. 2000, 207, 1e67.
4. Zhao, H. Drug Discovery Today 2007, 12, 149e155.
5. (a) Ner, S. K.; Suckling, C. J.; Bell, A. R.; Wrigglesworthbt, R. J. Chem. Soc., Chem.
Commun. 1987, 480e482; (b) MacInnes, I.; Schorstein, D.; Suckling, C. J.;
Wrigglesworth, R. J. Chem. Soc., Perkin Trans. 1 1983, 2771e2776; (c) Breck-
enridge, R. J.; Suckling, C. J. Tetrahedron 1986, 42, 5665e5677; (d) Rancourt, J.;
Cameron, D. R.; Gorys, V.; Lamarre, D.; Poirier, M.; Thibeault, D.; Llinas-Brunet,
M. J. Med. Chem. 2004, 47, 2511e2522.
6. For example employing cyclopropane ring constraint in
a-peptides, see: (a)
1634 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 8.66 (s, br, 1H), 8.48 (s, 1H),
Burgess, K.; Li, W.; Lim, D.; Moye-Sherman, D. Biopolymers 1997, 42, 439e453;
(b) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc. 1994, 116, 799e800; (c)
Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc. 1995, 117, 54e65; (d)
Burgess, K.; Ho, K.-K.; Pal, B. J. Am. Chem. Soc. 1995, 117, 3808e3819; (e) Burgess,
K.; Ke, C.-Y. J. Org. Chem. 1996, 61, 8627e8631.
3.92 (s, 2H), 3.16 (dd, J¼5.5, 6.9 Hz, 2H),1.91e1.94 (m,1H),1.32e1.34
(m, 2H), 1.22 (s, 9H), 0.93 (d, J¼6.9 Hz, 6H), 0.68e0.70 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 177.5, 172.4, 77.4, 47.7, 37.8, 28.4, 27.2, 22.8,
20.5, 13.6, 13.3; LRMS (EI, 20 eV) m/z 271 (Mþþ1, 12), 227 (20), 198
(59), 154 (100); HRMS (EI) for C14H26N2O3 (Mþ): calcd 270.1943,
found 270.1944.
€
7. (a) Seebach, D.; Abele, S.; Sifferlen, T.; Hanggi, M.; Gruner, S.; Seiler, P. Helv.
Chim. Acta 1998, 81, 2218e2243; (b) Abele, S.; Seiler, P.; Seebach, D. Helv. Chim.
Acta 1999, 82, 1559e1571; (c) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1e15.
8. (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiver. 2004, 1, 1111e1239;
(b) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206e243.
9. Li, X.; Yang, D. Chem. Commun. 2006, 32, 3367e3379 and references cited therein.
10. (a) Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W.; Chan, J. C.-Y.; Zhu, N.-Y.; Luo, S.-W.;
Wu, Y.-D. J. Am. Chem. Soc. 2004, 126, 6956e6966; (b) Yang, D.; Zhang, Y.-H.; Zhu,
N.-Y. J. Am. Chem. Soc. 2002, 124, 9966e9967; (c) Yang, D.; Zhang, D.-W.; Hao, Y.;
Wu, Y.-D.; Luo, S.-W.; Zhu, N.-Y. Angew. Chem., Int. Ed. 2004, 43, 6719e6722; (d)
Yang, D.;Chang, X.-W.;Zhang, D.-W.; Jiang, Z.-F.;Song, K.-S.; Zhang, Y.-H.;Zhu, N.-
Y.; Weng, L.-H.; Chen, M.-Q. J. Org. Chem. 2010, 75, 4796e4805.
11. (a) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049e3052; (b) Yu, C. Z.; Liu, B.;
Hu, L. Q. J. Org. Chem. 2001, 66, 5413e5418; (c) Huang, H.; Liu, X. C.; Qiu, M.;
Zheng, Z.; Deng, J. Org. Lett. 2006, 8, 3359e3364.
4.2. Piv-hOAcc-hOAcc-NH-c-Hex (2)
Following the stoichiometric ratio and procedure for the syn-
thesis of compound 13, compound 2 (34 mg, 28%) was obtained as
a white solid from cyclohexanamine (0.1 ml, 0.9 mmol) and com-
pound 13 (107 mg, 0.3 mmol). Mp 241ꢀ244 ꢁC; IR (CH2Cl2) 3411,
3288, 3213 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 12.09 (s, 1H), 8.69 (s,
12. Mitsunobu, O. Synthesis 1981, 1e28.
1H), 8.46 (d, J¼6.9 Hz, 1H), 3.96 (s, 2H), 3.85 (s, 2H), 3.70e3.80 (m,
13. (a) Rodriguez, A.; Pina, I.; Acosta, L.; Ramirz, C.; Soto, J. J. Org. Chem. 2001, 66,
648e658; (b) Fuchikami, T.; Shibata, Y.; Suzuki, Y. Tetrahedron Lett. 1986, 27,
3173e3176.
1H), 1.86e1.92 (m, 2H), 1.68e1.78 (m, 2H), 1.23 (s, 9H), 1.17e1.41 (m,
10H), 0.72e0.78 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 178.2, 171.5,
14. (a) Yang, D.; Li, B.; Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. Org. Chem. 2001, 66,
7303e7312; (b) Shin, I.; Lee, M. R.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem.
2000, 65, 7667e7675.
170.6, 79.1, 78.9, 49.0, 37.7, 32.7, 27.1, 25.6, 25.4, 22.8, 21.5, 13.6,13.3;
LRMS (EI, 20 eV) m/z 410 (Mþþ1, 9), 353 (2), 212 (10), 180 (100);
HRMS (EI) for C21H35N3O5 (Mþ): calcd 409.2577, found 409.2579.
ꢁ
ꢁ
~
15. (a) Rodrõguez-Garcõa,C.;Oliva,A.;Ortuno,R.;Branchadell, V.J. Am.Chem.Soc.2001,
123, 6157e6163; (b) Roble, J.; Cimarusti, M.; Simpkins, L.; Brown, B.; Ryono, D.; Bird,
J.; Asaad, M.; Schaeffer, T.; Trippodo, N. J. Med. Chem. 1996, 39, 494e502; (c)
Christoffers, J.; Kauf, T.; Werner, T.; Rossle, M. Eur. J. Org. Chem. 2006, 2601e2608.
16. 1H NMR dilution and titration experiments were not carried out for dipeptide 2,
due to its poor solubility in CDCl3 at low concentration.
Acknowledgements
17. Liang, G. B.; Rito, C. J.; Gellman, S. H. J. Am. Chem. Soc. 1992, 114, 4440e4442.
18. Yang, D.; Ng, F.-F.; Li, Z.-J.; Wu, Y.-D.; Chan, K. W. K.; Wang, D.-P. J. Am. Chem.
Soc. 1996, 118, 9794e9795.
Financial support by the National Natural Science Foundation
of China (Project No. 20202001), and Fok Ying Tung Education
Foundation (Project No. 94023) are gratefully acknowledged.
D.-W.Z. thanks Fudan University for the conferment of the Century
Star Award.
19. For details, please see the Supplementary data.
20. CCDC 795383 and 795384 contains 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.