Backbone modification of β-hairpin-forming tetrapeptides in asymmetric acyl transfer reactions

Article abstract of DOI:10.1021/jo200403g

Synthetic oligopeptides as mimics of enzymes have been increasingly exploited as catalysts for asymmetric reactions, but highly effective oligopeptide catalysts with relatively low molecular weight are still in great demand. In this paper, we showed the conformational engineering of the β-hairpin-forming tetrapeptide 4 which was first reported by Miller's group as the catalyst for the asymmetric acyl transfer reaction of trans-2-(N-acetylamino)cyclohexan-1-ol (k_rel = 28). Through our backbone modification strategy, thioamide and sulfonamide as the isosteres of amide were introduced in the β-hairpin secondary structure. The thioxo peptides also adopt β-hairpin conformations as the oxopeptide supported by the combined use of NMR, IR, and X-ray techniques. Thioxo tetrapeptide 14 formed a more constrained β-hairpin conformation and therefore delivered much higher enantioselectivity (k_rel = 109) in the same reaction. Moreover, the examination of the conformational changes of tetrapeptide 8 upon the protonation of the N^π-methylhistidine moiety provided evidence to explain the variation of its catalytic efficiency in the asymmetric acyl-transfer reaction.

Full text of DOI:10.1021/jo200403g

FEATURED ARTICLE
pubs.acs.org/joc
Backbone Modification of β-Hairpin-Forming Tetrapeptides
in Asymmetric Acyl Transfer Reactions
Peng Chen and Jin Qu*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
S Supporting Information
b
ABSTRACT: Synthetic oligopeptides as mimics of enzymes
have been increasingly exploited as catalysts for asymmetric
reactions, but highly effective oligopeptide catalysts with rela-
tively low molecular weight are still in great demand. In this
paper, we showed the conformational engineering of the β-
hairpin-forming tetrapeptide 4 which was first reported by
Miller’s group as the catalyst for the asymmetric acyl transfer
reaction of trans-2-(N-acetylamino)cyclohexan-1-ol (krel = 28).
Through our backbone modification strategy, thioamide and
sulfonamide as the isosteres of amide were introduced in the β-hairpin secondary structure. The thioxo peptides also adopt β-hairpin
conformations as the oxopeptide supported by the combined use of NMR, IR, and X-ray techniques. Thioxo tetrapeptide 14 formed
a more constrained β-hairpin conformation and therefore delivered much higher enantioselectivity (krel = 109) in the same reaction.
Moreover, the examination of the conformational changes of tetrapeptide 8 upon the protonation of the Nπ-methylhistidine moiety
provided evidence to explain the variation of its catalytic efficiency in the asymmetric acyl-transfer reaction.
Chart 1. Early Examples of Highly Enantioselective Oligo-
peptide Catalysts
’ INTRODUCTION
Enzymes as the most powerful catalysts in nature exhibit
extremely high specificity in the selection and the transformation
of their substrates. Chemists have longed to imitate the active site of
enzymes with synthetic oligopeptides which are much less compli-
cated than enzymes. In recent years, more and more oligopeptide
catalysts were successfully applied to various types of asymmetric
syntheses.1,2 The conformational rigidity is important for a chiral-
inducing agent, and this is also true for oligopeptide catalysts. In this
context, cyclic oligopeptides with reduced freedom of rotation
present special rigidity. A typical example is the cyclic dipeptide
catalyst 1 (Chart 1), documented by Inoue et al. in 1981, which can
catalyze the asymmetric hydrocyanation of benzaldehyde with
90% ee.3 Linear oligopeptides are much more flexible than cyclic
oligopeptides, and a longer sequence is often needed to form a well-
defined secondary conformation. It was reported that for poly-L-
alanine 2, the catalyst of the JuliꢀaꢀColonna epoxidation, only
oligomers longer than 10-mer can form the stable R-helix structure
crucial for the excellent asymmetric induction.4
The most applied tool for confining the conformation of a linear
oligopeptide catalyst is the alternation of the R-amino acid side
chains. In the side-chain modification strategy, R-amino acids with
unnatural side chains are also utilized to lock an oligopeptide into
the desired conformation.5,2h Compared to side-chain alternation,
backbone modification provides more room in controlling the
secondary structure of oligopeptides. Building blocks which have
been found to have special folding characteristics such as β- or γ-
amino acids (referred to as foldamers) can be incorporated in the
peptide chain or even used to build the entire oligopeptide
catalyst.6,2e Also, the amide moiety in the backbone of oligopeptides
can be replaced with its isosteres (Chart 2). As far as we know, this
backbone modification strategy using amide isosteres was majorly
employed to generate more protease-stable oligopeptides or oligo-
peptides with better bioactivities7 but seldom utilized in the
development of oligopeptide catalysts.8
A thioamide (Ψ[CSNH])9 in which the oxygen of the amide is
replaced by a sulfur atom is perhaps the closest structural mimic of
amide (Chart 3, top). A thioamide NH is more acidic and therefore
can form a much stronger hydrogen bond than an amide NH.10 The
larger radius of sulfur and the larger charge transfer from nitrogen to
sulfur make thioamide have a higher barrier of the rotation about the
CꢀN bond.11 Thioamide replacement has been investigated in
peptide design to determine whether it is a neutral, conformationally
rigidifying, or conformationally destabilizing amide isostere. Com-
putational studies predict that the conformational freedom of the
residues preceding and following a thioamide is more restricted
compared to an amide bond.12 Miwa et al. inserted a thioamide
linkage in peptides adopting R-helix or β-hairpin conformations and
Received: February 22, 2011
Published: March 15, 2011
r
2011 American Chemical Society
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|

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FEATURED ARTICLE
Chart 2. Commonly Employed Isosteres of Amide
Scheme 1. β-Hairpin-Forming Tetrapeptides Designed for
Asymmetric Acyl-Transfer Reactions
Chart 3. Backbone Modification through Thioamide
Replacement
epoxidation,21,8b asymmetric aldol reaction,2b and atropisomer-selec-
tive aromatic bromination reaction,2g etc. Shortly after tetrapeptide 4
was reported, the same group showed that octapeptide 5 with a more
rigid β-hairpin conformation by forming four interstrand hydrogen
bonds gave a much higher enantioselectivity (krel = 51) in the same
reaction.18d In 2004, Toniolo and co-workers showed that the side-
chain modification of tetrapeptide 4 by replacing the Aib residue with
a (R-Me)Val could afford slightly improved enantioselectivity
(krel = 33) than tetrapeptide 4.5d Alternatively, we envision that the
improvement of the conformational rigidity of tetrapeptide 4 might
be achieved by backbone modification rather than elongating the
peptide sequence or the side-chain variation. Herein, we report on the
backbone modification of tetrapeptide 4 through thioamide re-
placement in its β-hairpin structure. The conformation of the resulted
thioxo peptides were investigated by combined NMR, IR, and X-ray
analysis. One of these tetrapeptides with thioamide and sulfonamide
replacement formed a more constrained β-hairpin conformation and
therefore delivered much higher enantioselectivity (krel = 109) in the
asymmetric acyl transfer reaction of 3.
found that the thioxo peptides folded into conformations identical
to the native peptides and even with increased thermal stability of an
R-helix.13 The reports from Seebach14 and Helbing15 also indicated
that thioxo peptides adopted similar conformations as the corre-
sponding oxopeptides together with some unknown conformers.
But a more recent report from Kiefhaber’s group demonstrated that
introducing a thioamide linkage in an alanine-based R-helix caused
strong destabilizing effect.16 Our previous study found that the
thioamide replacement in 1-methylhistidine methyl ester, a catalyst
developed for asymmetric acylation reactions, strengthened the
hydrogen bond between the catalyst and the substrate, but it also
rotated the bond of the CRꢀCβ of that amino acid derivative.17
Starting from 1998, Miller’s research group designed a series of
oligopeptides as the catalysts for asymmetric acyl transfer reactions
and their work for the first time showed that short acyclic oligopep-
tides can serve as efficient asymmetric catalysts.18,5e Tetrapeptide 4
(Scheme 1) adopts a β-hairpin conformation induced by a D-Pro-Aib
motif and it also bears a Nπ-methylhistidine at the N-terminus as a
nucleophilic catalyst. It afforded remarkable enantioselectivity
(krel = 28) in the kinetic resolution of trans-2-(N-acetylamino)-
cyclohexan-1-ol 3 (Scheme 1). Moreover, the D-Pro-Aib β-turn motif
discovered in this study was afterward proved to be a versatile scaffold
for attaining high enantioselectivities in many other reactions such
as desymmetrized phosphorylation,19 desymmetrized sulfonyla-
tion,2c asymmetric conjugate addition of azide,20,5c asymmetric
’ RESULTS AND DISCUSSION
Design and Synthesis of the Tetrapeptides. The mechan-
istic studies carried on the tetrapeptide 4 catalyzed asymmetric
acyl-transfer reactions indicated that the substrate was first
bound to the catalyst through an intermolecular hydrogen bond
formed between the Aib amide NH and the acetamido carbonyl
oxygen in the substrate and then the N-methylimidazole trans-
ferred acyl group to the alcohol embedded in a chiral auxiliary
environment.8a We expected that the introduction of thioamide
could possibly bring some degree of restriction rather than
distortion of the β-hairpin conformation of tetrapeptide 4. To
test our hypothesis, we have designed modifications of tetrapep-
tide 4 at three amide sites (Chart 3, bottom). The incorporation
of a thioamide at the protecting group of the N-terminus Nπ-
methylhistidine at the i position is expected to strengthen the
second interstrand hydrogen bond of the β-hairpin structure.
The insertion of a thioamide at the i þ 1 position of the β-hairpin,
the binding site of the catalyst, can reinforce the intermolecular
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FEATURED ARTICLE
Scheme 2. Synthesis of Tetrapeptides 7ꢀ11
Figure 1. (a) Amide region of the FTIR absorption spectra of tetra-
peptides 4 and 7ꢀ11 (2 mM in CH2Cl2). (b) X-ray crystal structure of
tripeptide 8e.
following the method developed by Heimgartner et al.24 The Fmoc-
protected D-Pro was first transformed to its thioacid 8a with H2S.
Compound 8a was treated with 2,2-N-trimethyl-N-phenyl-2H-azirin-
3-amine to afford the thioamide 8b in 70% yield. After the ZnCl2/HCl-
catalyzed isomerization, 8c was obtained with a yield of 87% without
any epimerization and was then further converted into 8d under acidic
condition with nearly quantitative yield. Treatment of 8d with H2N-
Phe-OMe gave thioxo tripeptide 8e, andfinally the deprotected 8e was
coupled with Boc-(π-Me)-His-OH to give tetrapeptide 8. The thio
modification of the protecting group of the (π-Me)-histidine at the i
position of the β-hairpin structure was not successful because the
connection between Piv-CSNH-(π-Me)-His-OMe and Fmoc-D-Pro-
Aib-Phe-OMe segments failed to gave the desired peptide coupling
product. Alternatively, we noticed that a sulfonamide NH is also more
acidic and has been previously applied in the modification of amino
acid derived organocatalysts.25 Therefore, catalysts 9ꢀ11 were con-
structed by introducing mesyl (Ms), nosyl (Ns), or tosyl (Ts) at the i
position of the β-hairpin structure, respectively.
Conformational Analysis of Tetrapeptides 7ꢀ11. Tetrapep-
tides 7ꢀ11 were first subjected to conformational studies to deter-
mine their secondary structures. In the 1H NMR titration
experiments in which DMSO-d6 was gradually added into the CDCl3
solution (2 mM) of tetrapeptides 7ꢀ11, the (π-Me)-His NHs and
the Phe NHs constantly exhibited relatively small downfield shifts
while the Aib NHs shifted downfield significantly.26 This result
implies that in each tetrapeptide, the (π-Me)-His NH and the Phe
NH are intramolecularly hydrogen-bonded while the Aib NH is free
amide NH. This pattern is same with tetrapeptide 4and indicated that
tetrapeptides 7ꢀ11 also have the β-hairpin structure as the oxo-
tetrapeptide. Subsequently, we examined the amide region in the FT-
IR absorption spectra of tetrapeptide 4 and tetrapeptides 7ꢀ11
hydrogen bond with the substrate. The incorporation of a
thioamide linkage at the i þ 2 position of the β-hairpin is likely
to make the first interstrand hydrogen bond stronger.
Among several methods developed to convert an oxygen atom to a
sulfur atom in a molecule, Lawesson’s reagent is the most frequently
used one due to its facile procedure and racemization-free nature.22
The reactivities of oxygen containing functional groups toward Law-
esson’s reagent is alcohol > amide > ketone > ester. We initially tried to
synthesis the thioxo peptides by treating tetrapeptide 4 with an
excessive amount of Lawesson’s reagent.23 But the direct thionation
of tetrapeptide 4 led to a mixture of isomers and pure thionated
tetrapeptides could not be obtained by column purification. Thus the
thio-modified tetrapeptides were separately synthesized by fragment
coupling of the thio-modified dipeptides (Scheme 2). Treatment of
Boc-Aib-Phe-OMe 7c with Lawesson’s reagent in toluene for 5 h gave
Boc-Aib-CSNH-Phe-OMe 7d in 60% yield, which was then coupled
with Boc-(π-Me)-His-D-Pro-OH 7b to complete the synthesis of
tetrapeptide 7 with a thioamide modification at the i þ 2 position of
the β-hairpin structure. But the same strategy did not work in the
synthesis of tetrapeptide 8 with a thioamide modification at the i þ 1
position of the β-hairpin structure. Because of the steric hindrance of
2-aminobutyric acid (Aib), the efficiency of the thionation of Boc-D-
Pro-Aib-OMe using Lawesson’s reagent was very low (in a control
experiment, Lawesson’s reagent worked well in the thionation reaction
of Boc-D-Pro-Gly-OMe). Therefore, tetrapeptide 8 was synthesized
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FEATURED ARTICLE
(Figure 1a). For tetrapeptide 4, the absorption at 3426 cmꢀ1 is
caused by the regular stretching of the free Aib NH, and the
intramolecular hydrogen-bonded (π-Me)-His NH and Phe NH
Table 1. Asymmetric Acylation of 3 by Tetrapeptides 7ꢀ11a
both appear at a lower wavenumber of 3355 cm .
ꢀ1 18b For tetrapep-
tide 7, the band of the Aib NH at 3424 cmꢀ1 is similar to the Aib NH
of tetrapeptide 4. The band of Phe thioamide NH at 3287 cmꢀ1
corresponds to a typical thioamide NH absorption in a 1r4t C10to β-
turn of a 10-membered ring hydrogen bond.27 The absorption of the
(π-Me)-His NH at 3356 cmꢀ1 is parallel with that of tetrapeptide 4,
implying that the second interstrand hydrogen bond in tetrapeptide 7
is not affected when a more acidic thioamide NH serves as the
hydrogen bond donor in the first interstrand hydrogen bond. For
tetrapeptide 8, there is only one broad peak appeared at 3367 cmꢀ1
which is assigned to be the overlap of the absorptions of the free Aib
thioamide NH and the intramolecular hydrogen-bonded (π-Me)-
His NH and Phe NH. Because of the overlap of these peaks, it is
impossible to judge if the two interstrand hydrogen bonds are
strengthened after the thioamide modification at the i þ 1 position
of the β-hairpin structure. The crystal structure of tripeptide 8e
(Figure 1b) which is the synthetic precursor of tetrapeptide 8 clearly
displays the type II0 β-turn conformation (the dihedral angles for
tripeptide 8e are φiþ1 =þ58.6°,ψiþ1 =ꢀ133.2°, φiþ2 =þ57.7°, and
ψiþ2 = þ32.8°). The thioamide plane is almost perpendicular to the
plane of the β-turn. The length of the hydrogen bond between the
(π-Me)-His CdO and the Phe amide NH is 2.21 Å, and the angle of
153.9°. For tetrapeptides 9ꢀ11, the free Aib NHs fall in the region
around 3423ꢀ3427 cmꢀ1. The (π-Me)-His sulfonamide NHs
exhibit different levels of shifts to lower wavenumbers than free
sulfonamide NHs (normally appearing at 3389 cmꢀ1), indicating that
the (π-Me)-His sulfonamide NHs are all hydrogen-bonded.28 The
hydrogen-bonded Phe NHs falling in the region of 3339ꢀ3350 cmꢀ1
shift to lower wavenumbers compared with tetrapeptide 4. This shift
implies that the first interstrand hydrogen bond of the β-hairpin
structure is strengthened in tetrapeptides 9and 11 when a more acidic
sulfonamide NH serves as the hydrogen bond donor in the second
interstrand hydrogen bond.
Kinetic Resolution Using Tetrapeptides 7ꢀ11. The catalytic
efficiencies of tetrapeptides 7ꢀ11 were tested in the kinetic
resolution reaction of trans-2-(N-acetylamino)cyclohexan-1-ol 3
(Table 1). To make sure that results from our laboratory are
comparable with those reported by Miller’s group, the kinetic
resolution reaction of 3 was first run with tetrapeptide 4 prepared
in our laboratory. The reaction reached 50% conversion in 65 min
and the same selective factor (krel = 28) was obtained, which was in
good agreement with Miller’s report.18b,d Our initial attempts found
that both thioxo tetrapeptides 7 and 8 showed lower enantioselec-
tivities than tetrapeptide 4 in the kinetic resolution reactions of 3.
The selective factor for tetrapeptide 7 was 19 and tetrapeptide 8 also
afforded a lower selective factor (krel = 20) at a considerably lowered
rate with the half-reaction time up to 12 h. Among tetrapeptides
9ꢀ11, we anticipated that tetrapeptide 10 would give the highest
selective factor since it bears the most acidic sulfonamide NH.
However, tetrapeptide 9 and 10 gave similar stereoselectivities as
tetrapeptide 4, but tetrapeptide 11 with Ts protected (π-Me)-
histidine afforded a better result (krel = 40). To our surprise, when
the reactions were conducted with 1 equiv of DIEA, the selective
factor of tetrapeptide 8 was significantly enhanced to 63 and the
reaction time for reaching 50% conversion of 3 was reduced to 45
min. Other modified tetrapeptides gave slightly higher selective
factors in the presence of 1 equiv. of DIEA compared with the
reaction condition without base. Several other bases were also tested
in the kinetic resolution using tetrapeptide 8. TEA in the reaction
c
cat. time1/2(min)
base
none
ee% (SM)b ee % (prod)b convc (%) krel
7
8
120
720
90
78.8
79.5
81.3
82.7
84.7
82.8
90.2
82.1
83.8
85.4
92.8
89.0
84.2
83.9
77.6
78.6
82.1
84.0
87.4
80.1
90.6
82.8
84.9
88.3
89.7
89.7
82.3
79.4
50.4
50.3
49.8
49.6
49.2
50.8
49.9
49.8
49.7
49.2
50.8
49.8
50.6
51.4
19
20
25
30
40
23
63
27
32
44
63
55
27
23
none
9
none
10
11
7
150
120
100
45
none
none
DIEA
DIEA
DIEA
DIEA
DIEA
TEA
8
9
90
10
11
8
130
120
40
8
50
PMP
8
20
DABCO
pyridine
8
540
a Conditions: alcohol (0.032 mmol), catalyst (2.5 mol %), base (0.032
mmol), and Ac2O (25 μL) in toluene (3.2 mL) were stirred at 25 °C.
b Determined by GC analysis. c Calculated according to the method
established by Kagan.29
afforded a same selective factor as DIEA. More hindered trialk-
ylamine PMP (1,2,2,6,6-pentamethylpiperidine) gave a slightly
lower selective factor (krel = 55) and a slower reaction rate. DABCO
accelerated the reaction but reduced the enantioselectivity of the
reaction (krel = 27), which might be due to the increased back-
ground reaction catalyzed by DABCO. Weak bases such as pyridine
furnished a krel value of 23 with a much slower reaction rate.
Conformational Change of Tetrapeptide 8 Induced by
Histidine Protonation. We proceeded to interpret the reason for
the lower enantioselectivity when no base was present in the kinetic
resolution reaction catalyzed by tetrapeptide 8. In Toniolo’s paper,
1
they mentioned that the H NMR spectrum of tetrapeptide 4
prepared in their laboratory was different from the one reported
by Miller’s laboratory, and this problem could be fixed by treating
tetrapeptide 4 with 3 equiv of TEA. They concluded that such a
difference in the 1H NMR spectrum came from the protonation of
the imidazole moiety in tetrapeptide 4 that they initially synthesized.
We thought the less active tetrapeptide 8 we initially applied in the
kinetic resolution reaction might also suffer from the same problem.
Tetrapeptide 8 (spectrum A in Figure 2a) was hence treated with 3
equiv of TEA followed by evaporation, and the resulted tetrapeptide
1
8 was analyzed by H NMR. Compared with spectrum A of the
untreated tetrapeptide 8, the chemical shifts of most of the protons
changed in spectrum B (Figure 2a). The hydrogen (ΔδH
=
0.87 ppm) and the methyl (Δδmethyl = 0.17) on the Nπ-methylimi-
dazole ring significantly shifted upfield. The upfield shift was in
agreement with the deprotonation process of a protonated histidine
imidazole reported in the literature.30 When a trace amount of solid
KHSO4 was added to the above NMR tube containing tetrapeptide
8,31 the signals of the protons (spectrum C) shifted toward the form
in spectrum A, although the two spectra were not exactly the same.
When a small amount of DIEA was further added to neutralize
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The Journal of Organic Chemistry
FEATURED ARTICLE
(Δδ = 0.39 ppm), the proline CR-H (Δδ = 0.21 ppm), and
Cδ-H (Δδ = 0.20 ppm) exhibited different extents of shift. This
indicated that the conformation of tetrapeptide 8 has changed to
some degree upon the protonation of the N-methylimidazole ring.
The Aib thioamide NH (Δδ = 0.80 ppm) downfield-shifted
considerably. But the Aib thioamide NHs in tripeptide 8e did not
shift downfield upon the addition of solid KHSO4, suggesting that
the downfield shift of the Aib thioamide NH in tetrapeptide 8 was
not caused by the formation of an intermolecꢀular hydrogen bond
between the Aib thioamide NH and HSO4 anion. DMSO-d6
titration experiments showed that the Aib thioamide NH, the
(π-Me)-His NH, and the Phe NH are all intramolecularly hydro-
gen-bonded in the protonated form of tetrapeptide 8.32 ROESY
spectra of tetrapeptides 8 at both forms were recorded, and the
observed NOE differences are summarized in Figure 2c. The NOE
between the CR-H of proline and the Aib thioamide NH was strong
in the free-base form of tetrapeptide 8, which was in agreement with
a typical type II0 β-turn conformation. Nevertheless, this signal was
somewhat weaker in the protonated form of tetrapeptide 8. The two
strands of the β-hairpin structure were closer in the protonated form
of tetrapeptide 8, supported by the medium NOE between the Boc
group and the methyl ester. The 1r3t C7to γ-turn is often observed
in thioxo peptides (γ-turns are less frequently observed in normal
oligopeptides) because the thioamide NH is a good hydrogen bond
donor and has a strong preference to form a hydrogen bond.33 We
thus proposed the (π-Me)-His carbonyl was involved in a three-
center (bifurcated) hydrogen bond34 with the Aib thioamide NH
and the Phe amide NH and tetrapeptide 8 at the protonated form
adopted a β-turn conformation associated with a seven-membered
1r3t C7to γ-turn. This may explain the observation that the acyl-
transfer reaction was extremely slow when using the partially
protonated tetrapeptide 8. That was because that the Aib thioamide
NH formed an intramolecular hydrogen bond in the protonated
from and was not available for anchoring the substrate. The two
conformations of tetrapeptide 8 were in a fast equilibrium in the
solution which was represented by spectrum A in Figure 2a. Due to
the distortion of the β-hairpin conformation, the observed enantios-
electivity of the partially protonated tetrapeptide 8 was relatively
low. The phenomenon of the protonation of the N-methylimidazole
in tetrapeptide 4 has been documented by Toniolo’s group, but the
catalytic efficiency of the protonated tetrapeptide 4 was not men-
tioned in their report.5d We found that the acyl transfer reaction with
the protonated tetrapeptide 4 (by treatment of tetrapeptide 4 with
solid KHSO4) reached 50% conversion within 70 min, which was
equally fast compared with tetrapeptide 4 in the free-base form, but
gave a lowered selective factor of 17. This might suggest that in the
protonated form of tetrapeptide 4, the Aib NH is still a free amide
NH and is capable of binding substrates. However, the β-hairpin
conformation of tetrapeptide 4 may also be distorted and conse-
quently gave a lower selective factor. It is still not clear to us why
the conformations of these simple tetrapeptides change upon the
protonation of the N-methylimidazole in histidine residue. The
histidine protonation-induced conformational change is widely
observed in pH-sensitive proteins. The activity of these proteins is
thereby regulated by the protonation state of one or more histidine
residues.35
Figure 2. (a) 1H NMR spectra of tetrapeptide 8 at different forms. (b)
Time dependent 1H NMR spectra of the protonation process of
tetrapeptide 8. (c) Conformations of tetrapeptide 8 at the free-base
form and the protonated form.
KHSO4, the 1H NMR signal (spectrum D) shifted back to be the
same with spectrum B. This experiment showed that the N-
methylimidazole moiety of tetrapeptide 8 we initially applied in
the kinetic resolution reaction was partially protonated. The N-
methylimidazole moiety can reversely bind proton, and the two
conformations of the fully protonated form (spectrum C) and the
free-base form (spectrum B and D) interconvert too quickly to be
resolved by the NMR time scale (spectrum A).
The conformational transition of tetrapeptide 8 from the free-
base form to the protonated form could be tracked by recording
an 1H NMR spectrum every 6 min ca. 0.5 h after the addition of
solid KHSO4 (Figure 2b). The proton signal of tetrapeptide 8
became broadened at first and then sharpened, a typical process
of the conformational change in oligopeptides. It was also
interesting to note that trace amount of H2O in the CDCl3
solution of the tetrapeptide 8 was necessary for the protonation
of the N-methylimidazole moiety. If the CDCl3 solution was
thoroughly dried by 4 Å molecular sieves, tetrapeptide 8 did not
undergo the conformation change upon the addition of solid
KHSO4, suggesting that a solid acid could not protonate tetra-
peptide 8 directly.
Tetrapeptides with Two Backbone Modifications. The Ts
modification at the protecting group of the (π-Me)-histidine residue
(tetrapeptide 11) strengthens the second interstrand hydrogen bond
in the β-hairpin structure and also improves the stereoselectivity of
the acyl transfer reaction. The thio modification at the i þ 1 position
of the β-hairpin structure (tetrapeptide 8) made the hydrogen bond
From the comparison of the 1H NMR spectra of tetrapeptide 8 at
the free-base form and the fully protonated form (spectra B and C,
respectively), the Aib thioamide NH (Δδ = 0.80 ppm), the Phe
amide NH (Δδ = 0.08 ppm), the (π-Me)-His amide NH
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FEATURED ARTICLE
Table 2. Kinetic Resolution of 3 Catalyzed by Tetrapeptides 12ꢀ14a
c
cat.
time1/2 (min)
DIEA (equiv)
ee (%) (starting material)b
ee (%) (prod)b
convc (%)
krel
47
12
13
14
14
14
14
75
75
40
40
60
55
1
88.9
92.5
92.8
92.6
94.4
92.4
88.1
87.2
93.9
94.0
91.4
91.6
50.2
51.5
49.7
49.6
50.8
50.2
1
49
108
109
80
1
0.2
0.1
none
76
a Conditions: alcohol (0.032 mmol), catalyst (2.5 mol %), DIEA, and Ac2O (25 μL) in toluene (3.2 mL) were stirred at 25 °C. b Determined by GC
analysis. c Calculated according to the method established by Kagan.29
Scheme 3. Synthesis of Tetrapeptides 12ꢀ14
between the catalyst and the substrate more favorable although at this
stage we do not know if the thioamide modification could make the
β-hairpinstructuremoreconstrained. It would be interesting to apply
Figure 3. FT-IR absorption spectra for tetrapeptides 12ꢀ14.
modifications simultaneous at both i and i þ 1 position of the β-
hairpin structure to generate even more effective tetrapeptide
catalysts. Thus tetrapeptides 12ꢀ14 with two modifications were
rigid β-hairpin structure. Tetrapeptides 10 and 14 bear the most
synthesized starting from 8e (Scheme 3).
acidic nosyl sulfonamide NH as the hydrogen bond donors and
thus are capable of forming very strong interstrand hydrogen
bonds, but they did not give the highest stereoselectivities in the
asymmetric acyl transfer reactions. This observation was in
agreement with Miller et al.’s conclusion that a very tight β-
hairpin conformation does not necessarily lead to a higher
stereoselectivity. They found that adding a covalent linkage
between the two strands of the β-hairpin structure of octapeptide
5 resulted in a decreased stereoselectivity.18d This maybe in
accord with the findings that a modicum of flexibility is necessary
for the function of enzyme.
Finally, we examined the substrate scope of the asymmetric
acyl-transfer reaction using tetrapeptide 14 (Table 3). Tetrapep-
tide 14 showed higher stereoselectivities for six- and seven-
membered-ring trans cyclic acetamide-functionalized alcohols
(entry 1 and 2, Table 3) than tetrapeptide 4 which gave krel
values of 28 and 17, respectively.18d For substrate 16 with a
double bond in the cyclohexane ring (entry 3), the value of krel
was also high (krel = 77). However, the enantioselectivity for
substrate 17 with a five-membered ring was low (entry 3), just
like tetrapeptide 4 (krel = 6).18d Substrate 18 with an eight-
membered ring also afforded reasonably high enantioselectivity
(krel = 34) which had not been tested with tetrapeptide 4. But
substrate 19 with a double bond in the cyclooctane ring showed a
diminished krel value of 4 (entry 6) under the same conditions.
For the acyclic substrates 20 and 21, both the activities and the
Tetrapeptides 12ꢀ14 were subsequently evaluated in the kinetic
resolution reaction of 3 (Table 2). Tetrapeptides 12ꢀ14 all afforded
better stereoselectivities than tetrapeptides 9ꢀ11. To our delight,
tetrapeptide 14 achieved a high selective factor of 108, and the time
for reaching 50% conversion was only 40 min. Considering that
tetrapeptide catalysts might also be sensitive to tiny amount of acid in
the reaction system and this might significantly affect the stereo-
selectivity of the catalyst, the acyl-transfer reactions were conducted in
the presence of 1 equiv of DIEA. The kinetic resolution reaction
under no base conditions provided a substantially lower selective
factor (krel = 76). The addition of 0.2 equiv of DIEA gave the same
result as that with 1 equiv of DIEA.
The conformations of tetrapeptides 12ꢀ14 were investigated
by FT-IR analysis. The non-hydrogen-bonded Aib thioamide
NHs appears at about 3370 cmꢀ1 (Figure 3). The absorptions of
sulfonamide NHs in the range of 3248ꢀ3273 cmꢀ1 are the same
as those of tetrapeptides 9ꢀ11. The absorption of the Phe NHs
shift to lower wavenumbers after the thio modification (Δv =
12ꢀ19 cmꢀ1), implying more tight first interstrand hydrogen
bonds in tetrapeptides 12ꢀ14. This suggested that the thio
modification at the i þ 1 position of the β-hairpin structure could
make the β-hairpin conformation more constrained. It should
still be noted that the thio modification does not always bring
beneficial effects since the thio modification at the i þ 2 position
of the β-hairpin structure in tetrapeptide 7 did not lead to a more
2999
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The Journal of Organic Chemistry
FEATURED ARTICLE
Table 3. Kinetic Resolutions with Tetrapeptide 14a
oligopeptide catalysts. Moreover, the conformational change of
thioxo tetrapeptide 8 upon the protonation of its Nπ-methylhis-
tidine was examined. The distorted β-hairpin conformation with
altered intramolecular hydrogen bond pattern caused the ob-
served decreased activity and enantioselectivity in the acyl-
transfer reaction. These studies provided useful information to
understand the special characteristics of oligopeptide catalyst
which resemble some features of enzymes, the changeable and
regulable conformation of the catalyst.
’ EXPERIMENTAL SECTION
General Procedure for Peptide Coupling. Boc-L-(π-Me)-
His-D-Pro-OMe (7a). To a solution of Boc-(π-Me)-L-His-OH (135
mg, 0.5 mmol) in DMF (10 mL) were added HOBt (88 mg, 0.65 mmol)
and HATU (247 mg, 0.65 mmol). The mixture was stirred at 0 °C for 10
min, and then H2N-D-Pro-OMe HCl (108 mg, 0.65 mmol) and DIEA
3
(165 μL, 1 mmol) were added. The solution was stirred at 0 °C for 1 h
and overnight at room temperature. After removal of DMF under
reduced pressure, the residue was diluted with CH2Cl2 and washed
with 5% NaHCO3, water, and brine, respectively. Dried over Na2SO4
and concentrated, the crude product was purified by chromatography on
silica gel (eluent: 0ꢀ5% MeOH/CH2Cl2) to give 7a in 65% yield:
colorless oil; TLC Rf = 0.55 (8% MeOH/CH2Cl2); [R]20D þ35.7 (c 1.0,
1
CH2Cl2); IR (CH2Cl2) νmax 3427, 1746, 1710, 1650, 1422 cmꢀ1; H
NMR (400 MHz CDCl3) (trans/cis = 0.8:0.2) δ 7.85 (s, 0.2H), 7.77 (s,
0.8H), 6.95 (s, 0.2H), 6.93 (s, 0.8H), 5.48 (d, J = 8.3 Hz, 0.8H), 5.35 (d,
J = 9.2 Hz, 0.2H), 4.87 (t, J = 5.3 Hz, 0.2H), 4.63 (m, 0.8H), 4.47 (m,
0.2H), 4.41 (dd, J = 3.8, 8.4 Hz, 0.8H), 3.75ꢀ3.65 (overlapping s and m,
7H), 3.20ꢀ3.05 (m, 2H), 3.00ꢀ2.89 (m, 1H), 2.30ꢀ2.13 (m, 1H),
2.09ꢀ1.82 (m, 3H), 1.42 (s, 7.4H), 1.38 (s, 1.6H); 13C NMR (100 MHz
CDCl3) δ 172.3, 169.0, 155.0, 137.1, 128.1, 124.6, 80.1, 59.1, 52.2, 51.5,
46.9, 32.0, 28.9, 28.2, 27.1, 24.5; HRMS (ESI) for C18H28N4O5 calcd for
[M þ H]þ m/z 381.2132, found 381.2135.
a Conditions: alcohol (0.032 mmol), tetrapeptide 14 (2.5 mol %), DIEA
(20 mol %), and Ac2O (25 μL) in toluene (3.2 mL) were stirred at 25 °C.
b Determined by GC analysis. c The enantiomers of the starting material
can not be separated by chiral GC column; the conversion of the
reaction was determined by achiral GC column. d The reaction was in a
4 ꢁ scale. e Determined by HPLC analysis. f The reaction was run under
ꢀ60 °C.
Boc-Aib-CSNH-L-Phe-OMe (7d). To a solution of Boc-Aib-L-
Phe-OMe (200 mg, 0.55 mmol) in toluene (10 mL) was added
Lawesson’s reagent (133 mg, 0.33 mmol). The mixture was stirred at
120 °C for 5 h. Then the reaction mixture was concentrated in vacuo and
directly purified by chromatography on silica gel (eluent: 15% EtOAc/
petroleum ether) to give the product as a yellow oil (125 mg, 60%): TLC
Rf = 0.4 (20% EtOAc/petroleum ether); [R]20D þ80.7 (c 1.0, CH2Cl2);
IR (CH2Cl2) νmax 3428, 3346, 1731, 1505, 808 cmꢀ1; 1H NMR (400
MHz CDCl3) δ 8.73 (s, 1H), 7.31ꢀ7.21 (m, 3H), 7.16ꢀ7.06 (m, 2H),
5.34 (m, 1H), 5.06 (s, 1H), 3.72 (s, 3H), 3.44ꢀ3.34 (m, 1H), 3.28ꢀ3.18
(m, 1H), 1.64 (s, 3H), 1.57 (s, 3H), 1.41 (s, 3H); 13C NMR (100 MHz
CDCl3) δ 207.3, 171.2, 154.3, 135.6, 129.2, 128.5, 127.1, 80.4, 62.0, 58.7,
52.3, 36.1, 28.8, 28.2; HRMS (ESI) for C19H28N2O4S calcd for [M þ
Na]þ m/z 403.1662, found 403.1655.
enantioselectivities of tetrapeptide 14 declined. The reaction of
1-phenylethanol 22 (entry 9), which has no hydrogen-bonding
site, was extremely slow. However, this substrate can be resolved
(krel = 20) by an octapeptide which was identified through a
fluorescence-based activity assay by Miller’s group.18f This
suggests that a longer oligopeptide with a more complicated
conformation is needed to recognize unfunctionalized alcohols.
Boc-(π-Me)-L-His-D-Pro-Aib-CSNH-L-Phe-OMe (7). Com-
pound 7 was synthesized by general peptide coupling between
Boc-(π-Me)-L-His-D-Pro-OH (deprotection of 7a with LiOH) and
’ CONCLUSION
Much work is still needed toward designing an oligopeptide
catalyst which can precisely fold into the three-dimensional
conformation appropriate for a specific asymmetric transforma-
tion based on the knowledge we obtained from enzyme catalysis.
The combinatorial screening technique is still the prominent
method in the discovery of new oligopeptide catalysts. Never-
theless, conformational engineering of a known oligopeptide
catalyst provides powerful tools in generating more effective
catalysts. We found that tetrapeptide 14 generated by thioamide
and sulfonamide replacement of tetrapeptide 4 adopted a more
constrained β-hairpin conformation and thereby afforded much
higher stereoselectivity in asymmetric acyl-transfer reactions. We
believe the approaches we showed here, the backbone modifica-
tion using amide isosteres, can be extended to other types of
H2N-Aib-CSNH-L-Phe-OMe TFA (deprotection of 7d with TFA):
3
colorless oil, yield 72%; TLC Rf = 0.5 (8% MeOH/CH2Cl2); [R]25
D
þ24.5 (c 1.0, CH2Cl2); IR (CH2Cl2) νmax 3356, 1742, 1703, 1638,
1502 cmꢀ1; 1H NMR (400 MHz CDCl3) δ 8.74 (d, J = 7.1 Hz, 1H), 7.42
(s, 1H), 7.30ꢀ7.18 (m, 5H), 6.83 (s, 1H), 6.77 (s, 1H), 5.83 (d, J = 7.1
Hz, 1H), 5.49 (dd, J = 7.6, 14.4 Hz, 1H), 4.55 (dd, J = 8.9, 14.7 Hz, 1H),
4.22 (dd, J = 3.5, 7.3 Hz, 1H), 3.73 (s, 1H), 3.66 (overlapping m and s,
4H), 3.41ꢀ3.23 (m, 2H), 3.16ꢀ3.02 (m, 2H), 2.95ꢀ2.85 (m, 1H),
2.16ꢀ1.77 (m, 4H), 1.70 (s, 3H), 1.42 (overlapping s and s, 12H); 13C
NMR (100 MHz CDCl3) δ 207.4, 171.8, 170.5, 169.6, 155.4, 137.1,
136.0, 129.2, 128.4, 128.1, 126.9, 125.7, 80.1, 62.9, 61.1, 58.9, 52.4, 52.0,
47.4, 36.6, 31.9, 29.7, 28.4, 28.2, 27.5, 26.6, 24.9; HRMS (ESI) for
C31H44N6O6S calcd for [M þ H]þ m/z 629.3116, found 629.3115.
3000
dx.doi.org/10.1021/jo200403g |J. Org. Chem. 2011, 76, 2994–3004

The Journal of Organic Chemistry
FEATURED ARTICLE
Fmoc-D-Pro-1,3-thiazol-5(4H)-one (8d). Compound 8d was
synthesized according to the previous literature24g from D-Pro-OH:
yellow oil; TLC Rf = 0.6 (50% EtOAc/petroleum ether); [R]20D þ72.5
(c 1.0, CH2Cl2); 1H NMR (400 MHz CDCl3, two isomers) δ 7.82ꢀ7.70
(m, 2H), 7.68ꢀ7.51 (m, 2H), 7.45ꢀ7.26 (m, 4H), 4.75 (m, 1H),
4.59ꢀ4.44 (m, 1H), 4.42ꢀ4.31 (m, 1H), 4.30ꢀ4.23 (m, 0.5H),
4.19ꢀ4.11 (m, 0.5H), 3.55 (m, 2H), 2.41ꢀ2.11 (m, 2H), 2.09ꢀ1.90
(m, 2H), 1.43 (s, 1.5H), 1.39 (s, 1.5H), 1.33 (s, 1.5H), 1.32 (s, 1.5H);
13C NMR (100 MHz CDCl3, two isomers) δ 211.1, 210.8, 168.1, 167.8,
154.9, 154.7, 143.9, 143.67, 143.4, 141.3, 141.2, 127.7, 127.0, 125.2,
125.1, 124.9, 124.8, 119.9, 83.7, 67.6, 67.4, 61.2, 60.8, 47.4, 47.2, 46.8,
32.3, 31.0, 29.6, 24.5, 24.3, 23.3; HRMS (ESI) for C24H24N2O3S calcd
for [M þ H]þ m/z 421.1580, found 421.1572.
HRMS (ESI) for C9H15N3O4S calcd for [M þ H]þ m/z 262.0856, found
262.0863.
Nosyl-(π-Me)-L-His-OMe (10a): yield 77%; light yellow solid; mp
100ꢀ102 °C (from CH2Cl2); TLC Rf = 0.55 (8% MeOH/CH2Cl2);
[R]25 þ3.2 (c 1.0, CH2Cl2); IR (CH2Cl2) νmax 3332, 3054,
D
1748 cmꢀ1; 1H NMR (400 MHz CDCl3) δ 8.27 (d, J = 8.7 Hz, 2H),
8.04 (d, J = 8.7 Hz, 2H), 7.29 (s, 1H), 6.46 (s, 1H), 4.37 (t, J = 4.8 Hz,
1H), 3.64 (s, 3H), 3.58 (s, 3H), 3.30ꢀ3.03 (m, 2H); 13C NMR (100
MHz CDCl3) δ 170.2, 149.5, 146.8, 137.4, 128.0, 127.2, 126.1, 123.8,
55.81, 52.1, 31.7, 27.5; HRMS (ESI) for C14H16N4O6S calcd for [M þ
H]þ m/z 369.0863, found 369.0858.
Tosyl-(π-Me)-L-His-OMe (11a): yield 80%; white solid; mp
176ꢀ178 °C (from CH2Cl2); TLC Rf = 0.55 (8% MeOH/CH2Cl2);
Fmoc-D-Pro-CSNH-Aib-L-Phe-OMe (8e). To a solution of 8d
(421 mg, 1 mmol) in CH3CN (10 mL) were added DIEA (330 μL, 2
[R]25 þ11.7 (c 1.0, CH2Cl2); IR (CH2Cl2) νmax 3326, 2963,
D
1745 cmꢀ1; 1H NMR (400 MHz CDCl3) δ 7.68 (d, J = 7.8 Hz, 2H),
7.32 (s, 1H), 7.27 (d, J = 7.7 Hz, 2H), 6.83 (broad s 1H), 6.65 (s, 1H),
4.16 (t, J = 5.0 Hz, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 3.17ꢀ3.07 (m, 2H),
2.41 (s, 3H); 13C NMR (100 MHz CDCl3) δ 170.6, 143.5, 138.3, 136.7,
129.6, 128.1, 127.0, 125.9, 55.6, 52.6, 31.7, 27.7, 21.5; HRMS (ESI) for
C15H19N3O4S: Calcd for [M þ H]þ m/z 338.1169, found 338.1164.
Synthesis of Catalysts 9ꢀ11. Compounds 9ꢀ11 were synthe-
sized by general peptide coupling between the corresponding NR-
sulfonyl-(π-Me)-L-His-OH (deprotection of 9aꢀ11a with LiOH) and
H2N-D-Pro-Aib-L-Phe-OMe.
mmol), HOBt (276 mg, 2 mmol), and H2N-L-Phe-OMe HCl (238 mg,
3
1.1 mmol). The solution was stirred for 5 days at rt, diluted with CH2Cl2,
and washed with 5% NaHCO3, 5% KHSO4, and brine, respectively.
Dried over Na2SO4 and concentrated, the crude product was purified by
chromatography on silica gel (eluent: 35% EtOAc/petroleum ether) to
give pure product as a white solid (234 mg, 40%): mp 149ꢀ151 °C
(from EtOAcꢀpetroleum ether); TLC Rf = 0.4 (50% EtOAc/petroleum
ether); IR (CH2Cl2) νmax 3428, 3350, 3263, 1743, 1678, 1509,
1413 cmꢀ1; [R]15 þ49.9 (c 1.0, CH2Cl2); 1H NMR (400 MHz
D
CDCl3) (trans/cis =0.8:0.2) δ 8.48 (broad s, 1H), 7.76 (d, J = 7.1 Hz,
1H), 7.60 (d, J = 7.1 Hz, 1H), 7.44ꢀ7.26 (m, 4H), 7.23ꢀ7.04 (m, 5H),
6.90 (s, 0.8H), 6.25 (s, 0.2H), 4.79 (m, 1H), 4.58ꢀ4.29 (m, 3H), 4.23
(broad s, 1H), 3.76ꢀ3.44 (m, 5H), 3.22ꢀ3.00 (m, 2H), 2.43ꢀ2.05 (m,
3H), 1.93ꢀ1.81 (m, 1H), 1.67 (s, 3H), 1.54 (s, 3H); 13C NMR (100
MHz CDCl3) δ 202.3, 172.3, 171.6, 156.2, 143.6, 141.1, 136.2, 129.2,
128.2, 127.7, 127.0, 126.7, 125.0, 119.9, 68.4, 67.8, 60.3, 53.4, 51.9, 47.0,
37.5, 32.2, 25.4, 24.3, 23.5; HRMS (ESI) for C34H37N3O5S calcd for
[M þ Na]þ m/z 622.2346, found 622.2346.
Mesyl-(π-Me)-L-His-D-Pro-Aib-L-Phe-OMe (9): yield 70%;
white foam; TLC Rf = 0.4 (8% MeOH/CH2Cl2); [R]25D þ 47.0 (c 1.0,
CH2Cl2); IR(CH2Cl2) νmax 3339, 1738, 1678, 1641, 1504 cmꢀ1; 1H NMR
(400 MHz CDCl3) δ 7.42 (overlapping s and s, 2H), 7.30ꢀ7.17 (m, 5H),
6.87 (s, 1H), 6.56 (s, 1H), 6.27 (d, J = 5.1 Hz, 1H), 4.88 (dd, J = 7.9, 14.5
Hz, 1H), 4.40 (broad s, 1H), 4.17 (t, J = 5.6 Hz, 1H), 3.78ꢀ3.72 (m, 1H),
3.71 (s, 3H), 3.64 (s, 3H), 3.22ꢀ3.01 (m, 5H), 2.98 (s, 3H), 2.10ꢀ1.98 (m,
3H), 1.84ꢀ1.72 (m, 1H), 1.47 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz
CDCl3) δ 174.0, 173.3, 170.6, 170.0, 138.1, 136.4, 129.2, 128.3, 127.5,
126.7, 126.6, 61.3, 57.4, 54.0, 53.3, 52.3, 47.5, 41.1, 38.1, 31.6, 28.8, 27.9,
26.5, 24.9, 24.4; HRMS (ESI) for C27H38N6O7S: Calcd for [M þ H]þ m/z
591.2596, found 591.2588.
Boc-(π-Me)-L-His-D-Pro-CSNH-Aib-L-Phe-OMe (8). Compound
8 was synthesized by general peptide coupling between Boc-(π-Me)-L-His-
OH and H2N-D-Pro-CSNH-Aib-L-Phe-OMe (deprotection of 8e with
excess Et2NH): yield 68%; white foam; TLC Rf = 0.5 (8% MeOH/
CH2Cl2); [R]25D ꢀ55.9 (c 1.0, CH2Cl2); IR (CH2Cl2) νmax 3367, 1636,
1508, 1099 cmꢀ1; 1H NMR (600 MHz CDCl3) δ 8.03 (s, 1H), 7.38 (s,
1H), 7.26ꢀ7.17 (m, 5H), 7.09 (d, J = 8.2 Hz, 1H), 6.84 (s, 1H), 6.67
(d, J= 7.0 Hz, 1H), 4.89 (dd, J= 8.1, 14.9 Hz, 1H), 4.60 (dd, J= 7.7, 13.9 Hz,
1H), 4.48 (dd, J = 5.9, 7.9 Hz, 1H), 3.74ꢀ3.67 (overlapping m and s, 4H),
3.65 (s, 3H), 3.38ꢀ3.31 (m, 1H), 3.19ꢀ3.05 (m, 3H), 2.95ꢀ2.89 (m, 1H),
2.32ꢀ2.23 (m, 1H), 2.22ꢀ2.07 (m, 2H), 1.84ꢀ1.75 (m, 1H), 1.68 (s, 3H),
1.42 (overlapping s and s, 12H); 13C NMR (100 MHz CDCl3) δ 203.9,
172.9, 172.4, 168.7, 155.5, 136.3, 135.0, 131.1, 129.2, 128.4, 126.8, 119.0,
80.2, 68.8, 60.7, 53.1, 52.2, 51.4, 48.2, 37.5, 33.3, 32.1, 28.1, 26.8, 25.6, 24.8,
22.5; HRMS (ESI) for C31H44N6O6S calcd for [M þ H]þ m/z 629.3116,
found 629.3115.
Nosyl-(π-Me)-L-His-D-Pro-Aib-L-Phe-OMe (10): yield 87%;
white foam; TLC Rf = 0.5 (10% MeOH/CH2Cl2); [R]25 þ 13.7 (c
D
1
1.0, CH2Cl2); IR (CH2Cl2) νmax 3350, 1733, 1641, 1533 cmꢀ1; H
NMR (400 MHz CDCl3) δ 8.36 (d, J = 8.7 Hz, 2H), 8.10 (d, J = 8.7 Hz,
2H), 7.51 (d, J = 8.7 Hz, 1H), 7.45 (s, 1H), 7.26ꢀ7.13 (m, 5H), 6.90 (s,
1H), 6.79 (s, 1H), 4.94ꢀ4.84 (m, 1H), 4.21ꢀ4.09 (overlapping m, 2H),
3.68 (s, 3H), 3.63 (s, 3H), 3.30ꢀ3.15 (m, 2H), 3.13ꢀ2.94 (m, 3H),
2.88ꢀ2.78 (m, 1H), 2.03ꢀ1.76 (m, 3H), 1.68ꢀ1.57 (m, 1H), 1.53 (s,
3H), 1.23 (s, 3H); 13C NMR (100 MHz CDCl3) δ 174.0, 173.8, 170.3,
168.6, 149.9, 146.1, 137.9, 136.4, 129.2, 128.3, 128.2, 127.2, 126.8, 126.6,
124.6, 61.2, 57.3, 54.2, 53.2, 52.6, 47.4, 38.2, 31.6, 28.6, 28.3, 27.2, 24.8,
23.8; HRMS (ESI) for C32H39N7O9S calcd for [M þ H]þ m/z
698.2603, found 698.2612.
General Procedure for the Synthesis of Nr-Sulfonyl-(π-Me)-
L-His-OMe. Mesyl-(π-Me)-L-His-OMe (9a). To a suspension of
H2N-(π-Me)-L-His-OMe (183 mg, 1 mmol) in CH2Cl2 (10 mL) at
0 °C were added TEA (576 μL, 4 mmol) and the corresponding sulfonyl
chloride (1.1 mmol in 5 mL of CH2Cl2) dropwisely. The solution was
stirred at 0 °C for 30 min and at room temperature overnight. The reaction
mixture was diluted with CH2Cl2, washed by 5% NaHCO3, water, and
brine, respectively, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by chromatography on silica gel (eluent: 0ꢀ5%
MeOH/CH2Cl2) to give the pure product: yield 61%; white solid; mp
Tosyl-(π-Me)-L-His-D-Pro-Aib-L-Phe-OMe (11): yield 77%;
white foam; TLC Rf = 0.5 (8% MeOH/CH2Cl2); [R]25 þ9.3 (c 1.0,
D
CH2Cl2); IR(CH2Cl2) νmax 3339, 1734, 1674, 1637, 1506 cmꢀ1; 1H NMR
(400 MHz CDCl3) δ 7.76 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H),
7.33ꢀ7.15 (m, 8H), 6.78ꢀ6.62 (overlapping s, s, d, 3H), 4.91 (dd, J = 7.9,
14.7 Hz, 1H), 4.20ꢀ4.15 (m, 1H), 4.06 (broad s, 1H), 3.67 (s, 3H), 3.51 (s,
1H), 3.40ꢀ3.32 (m, 1H), 3.23ꢀ3.03 (m, 3H), 2.94ꢀ2.85 (m, 2H), 2.43 (s,
3H), 2.15ꢀ1.86 (m, 3H), 1.78ꢀ1.65 (m, 1H), 1.49 (s, 3H), 1.35 (s, 3H);
13C NMR (100 MHz CDCl3) δ 173.9, 173.4, 170.2(2 Cs), 144.0, 138.1,
136.6, 136.5, 129.8, 129.3, 128.3, 127.9, 127.2, 126.7, 126.5, 61.5, 57.4, 54.0,
53.3, 52.3, 47.2, 31.3, 28.5, 27.3, 26.2, 24.9, 24.7, 21.5; HRMS (ESI) for
C33H42N6O7S calcd for [M þ H]þ m/z 667.2908, found 667.2914.
Synthesis of Tetrapeptides 12ꢀ14. Compound 12ꢀ14 was
synthesized by general peptide coupling between corresponding NR-
sulfonyl-(π-Me)-L-His-OH and H2N-D-Pro-CSNH-Aib-L-Phe- OMe.
136ꢀ137 °C (from CH2Cl2); TLCRf =0.5 (8%MeOH/CH2Cl2); [R]25
D
þ3.5 (c1.0, CH2Cl2);IR(CH2Cl2) νmax 3340, 2962, 1745 cmꢀ1; 1H NMR
(400 MHz CDCl3) δ 7.34 (s, 1H), 6.67 (s, 1H), 4.43 (t, J = 5.5 Hz, 1H),
3.83 (s, 3H), 3.61 (s, 3H), 3.26ꢀ3.04 (m, 2H), 2.90 (s, 3H); 13C NMR
(100 MHz CDCl3) δ 171.3, 137.9, 127.3, 126.4, 55.8, 52.8, 41.3, 31.7, 27.6;
3001
dx.doi.org/10.1021/jo200403g |J. Org. Chem. 2011, 76, 2994–3004

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FEATURED ARTICLE
Mesyl-(π-Me)-L-His-D-Pro-CSNH-Aib-L-Phe-OMe (12): yield
57%; white foam; TLC Rf = 0.4 (8% MeOH/CH2Cl2); [R]20D þ19.3 (c
1.0, CH2Cl2); IR (CH2Cl2) νmax 3327, 1738, 1678, 1641 1503 cmꢀ1; 1H
NMR (400 MHz CDCl3) δ 8.35 (s, 1H), 7.52 (s, 1H), 7.27ꢀ7.17 (m,
6H), 6.91 (s, 1H), 6.32 (broad s, 1H), 4.86 (m, 1H), 4.59 (t, J = 6.3 Hz,
1H), 4.40 (dd, J = 5.0, 9.2 Hz, 1H), 3.79ꢀ3.72 (m, 1H), 3.70 (s, 3H),
3.69 (s, 3H), 3.25ꢀ3.11 (m, 3H), 3.10ꢀ3.03 (m, 2H), 3.02 (s, 3H),
2.23ꢀ2.08 (m, 3H), 1.80ꢀ1.71 (m, 1H), 1.68 (s, 3H), 1.37 (s, 3H); 13C
NMR (100 MHz CDCl3) δ 203.6, 173.2, 172.3, 169.4, 137.7, 136.5,
129.3, 128.4, 127.2, 126.8, 126.5, 68.5, 61.0, 54.2, 53.2, 52.4, 48.2, 41.4,
38.1, 32.0, 28.5, 27.4, 24.8, 22.6; HRMS (ESI) for C27H38N6O6S2 calcd
for [M þ Na]þ m/z 629.2187, found 629.2180.
Characterization of the Acylation Products. trans-2-Aceta-
midocyclohexyl acetate (3-Ac):18a. TLC Rf = 0.5 (80% EtOAc/petro-
leum ether); 1H NMR (400 MHz CDCl3) δ 5.74 (d, J = 6.8 Hz, 1H),
4.65 (dt, J = 4.5, 10.6 Hz, 1H), 3.87 (m, 1H), 2.05 (overlapping m and s,
4H), 1.93 (overlapping m and s, 4H), 1.83ꢀ1.64 (m, 2H), 1.55ꢀ1.11
(m, 2H); 13C NMR (100 MHz CDCl3) δ 171.9, 169.6, 74.6, 52.8, 32.0,
31.0, 24.1, 24.0, 23.4, 21.1; GC analysis: Beta DEX 120 column (30 m ꢁ
0.25 mm ꢁ 0.25 μm film thickness), flow rate 20 cm/s, temperature
155 °C, tR = 35.4 min (1S, 2S, minor), 36.3 min (1R, 2R, major). The
absolute configuration of 3-Ac was determined by the same GC
stereoselective results compared with those of Miller’s catalyst. GC
analysis for starting material: Gamma DEX 225 column (30 m ꢁ 0.25
mm ꢁ0.25 μm film thickness), flow rate 20 cm/s, temperature 180 °C,
tR = 17.4 min (1R, 2R, minor), 17.7 min (1S, 2S, major).
Nosyl-(π-Me)-L-His-D-Pro-CSNH-Aib-L-Phe-OMe (13): yield
75%; white foam; TLC Rf = 0.5 (8% MeOH/CH2Cl2); [R]20D ꢀ5.5 (c
1.0, CH2Cl2); IR (CH2Cl2) νmax 3331, 1736, 1676, 1639, 1533 cmꢀ1
;
trans-2-Acetamidocycloheptyl acetate (15-Ac):18a TLC Rf = 0.45
(80% EtOAc/petroleum ether); 1H NMR (400 MHz CDCl3) δ 5.78 (d,
J = 6.1 Hz, 1H), 4.81 (m, 1H), 4.02 (dq, J = 3.5, 8.8 Hz, 1H), 2.04 (s,
3H), 1.92 (s, 3H), 1.90ꢀ1.45 (m, 10H); 13C NMR (100 MHz CDCl3) δ
171.5, 169.3, 77.4, 55.1, 31.4, 31.3, 27.6, 24.0, 23.4, 22.5, 21.2; GC
analysis: β DEX 120 column, flow rate 20 cm/s, temperature 135 °C for
80 min, 1 deg/min to 150 °C, keep 30 min, 2 deg/min to 220 °C, keep
10 min, tR = 122.2 min (1S, 2S, minor), 124.1 min (1R, 2R, major). The
absolute configuration of 15-Ac was determined by the same GC
stereoselective results compared with those of Miller’s catalyst. GC
analysis for starting material: Gamma DEX 225 column, flow rate
20 cm/s, temperature 180 °C, tR = 24.5 min (1R, 2R, minor), 25.2
min (1S, 2S, major).
1H NMR (400 MHz CDCl3) δ 8.72 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H),
8.19 (d, J = 8.8 Hz, 2H), 7.41 (s, 1H), 7.39 (s, 1H), 7.25ꢀ7.16 (m, 5H),
6.74 (s, 1H), 4.91 (td, J = 5.9, 9.2 Hz, 1H), 4.50 (t, J = 6.9 Hz, 1H), 4.10
(dd, J = 4.1, 10.6 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.38ꢀ3.28 (m,
1H), 3.23ꢀ2.95 (m, 4H), 2.84ꢀ2.76 (m, 1H), 2.08ꢀ1.93 (m, 3H), 1.72
(s, 3H), 1.59ꢀ1.49 (m, 1H), 1.26 (s, 3H); 13C NMR (100 MHz CDCl3)
δ 204.2, 173.8, 172.5, 167.8, 149.9, 146.3, 138.1, 136.5, 129.2, 128.32,
128.26, 127.0, 126.9, 126.7, 124.4, 67.2, 61.0, 54.3, 53.0, 52.6, 48.0, 38.1,
31.7, 29.6, 29.1, 28.5, 24.8, 21.7; HRMS (ESI) for C32H39N7O8S2 calcd
for [M þ Na]þ m/z 736.2194, found 736.2198.
Tosyl-(π-Me)-L-His-D-Pro-CSNH-Aib-L-Phe-OMe (14): yield
79%; white foam; TLC Rf = 0.5 (8% MeOH/CH2Cl2); [R]20D ꢀ9.6 (c
1.0, CH2Cl2); IR (CH2Cl2) νmax 3325, 1737, 1639, 1502 cmꢀ1; 1H NMR
(400 MHz CDCl3) δ 9.14 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.44 (s, 1H),
7.34ꢀ7.12 (m, 8H), 6.73 (s, 1H), 4.87 (dd, J= 8.2, 15.1 Hz, 1H), 4.64 (t, J=
5.8 Hz, 1H), 4.06 (dd, J = 4.0, 9.8 Hz, 1H), 3.66 (s, 3H), 3.60 (s, 3H),
3.27ꢀ3.00 (m, 5H), 2.90ꢀ2.81 (m, 1H), 2.42 (s, 3H), 2.10ꢀ1.94 (m, 3H),
1.70 (s, 3H), 1.63ꢀ1.52 (m, 1H), 1.37 (s, 3H); 13C NMR (100 MHz
CDCl3) δ 203.6, 173.2, 172.4, 168.9, 143.6, 137. 8, 137.1, 136.6, 129.8,
129.3, 128.2, 127.14, 127.1, 126.8, 126.6, 67.8, 60.9, 54.0, 53.1, 52.4, 47.7,
38.0, 31.7, 31.6, 27.9, 27.4, 24. 6, 22.7, 21.5; HRMS (ESI) for
C33H42N6O6S2 calcd for [M þ Na]þ m/z 705.2499, found 705.2497.
Boc-(π-Me)-L-His-D-Pro-Aib-L-Phe-OMe (4). Compound 4 was
synthesized according to the previous literature:5d,18b white foam; Rf = 0.4
trans-6-Acetamidocyclohex-3-enyl acetate (16-Ac):18a TLC Rf =
1
0.45 (80% EtOAc/petroleum ether); H NMR (400 MHz CDCl3) δ
5.77 (d, J = 6.7 Hz, 1H), 5.60 (m, 2H), 4.98 (dd, J = 9.1, 15.1 Hz, 1H),
4.22 (m, 1H), 2.65ꢀ2.24 (m, 3H), 2.07 (s, 3H), 1.95 (overlapping m
and s, 4H); 13C NMR (100 MHz CDCl3) δ 171.8, 169.8, 124.6, 123.9,
70.8, 48.7, 31.5, 30.5, 23.4, 21.1; GC analysis: γ DEX 225 column, flow
rate 20 cm/s, temperature 160 °C, tR = 28.6 min (1S, 2S, minor), 29.5
min (1R, 2R, major). The absolute configuration of 16-Ac was deter-
mined by the same GC stereoselective results compared with those of
Miller’s catalyst. GC analysis for conversion: Rtx-5 column (30 m ꢁ
0.25 mm ꢁ0.25 μm film thickness), flow rate 30 cm/s, temperature
220 °C, tR = 3.2 min (starting material), 3.5 min (product), response
factor = (mol starting material)(area product)/(mol product)(area
starting material) = 1.296.
1
(5% MeOH/CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.40 (s, 1H),
7.31ꢀ7.17 (m, 6H), 6.82 (s, 1H), 6.44 (s, 1H), 6.00 (d, J = 6.7 Hz, 1H), 4.88
(m, 1H), 4.56 (m, 1H), 4.16 (m, 1H), 3.70 (s, 3H), 3.65 (overlapping m and
s, 4H), 3.21ꢀ3.06 (m, 4H), 2.94ꢀ2.87 (m, 1H), 2.15ꢀ2.03 (m, 2H),
2.00ꢀ1.91 (m, 1H), 1.84ꢀ1.76 (m, 1H), 1.50 (s, 3H), 1.41 (s, 9H), 1.29 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 174.0, 172.3, 170.7, 170.4, 155.2,
138.0, 136.5, 129.3, 128.2, 127.9, 126.9, 126.7, 80.1, 61.0, 57.3, 54.0, 52.1, 52.0,
trans-2-Acetamidocyclopentyl acetate (17-Ac):18d TLC Rf = 0.45
(80% EtOAc/petroleum ether); 1H NMR (400 MHz CDCl3) δ 6.00 (s,
1H), 4.97 (q, J = 6.3 Hz, 1H), 4.14 (quintet, J = 7.4 Hz, 1H), 2.30ꢀ2.18
(m, 1H), 2.05 (overlapping m and s, 4H), 1.96 (s, 3H), 1.83ꢀ1.62 (m,
3H), 1.48ꢀ1.35 (m, 1H); 13C NMR (100 MHz CDCl3) δ 170.8, 170.1,
79.1, 55.5, 30.0, 29.7, 22.7, 20.8, 20.7; GC analysis: γ DEX 225 column,
flow rate 25 cm/s, temperature 140 °C for 40 min, 1 deg/min to 220 °C,
tR = 45.5 min (1R, 2R, major), 49.3 min (1S, 2S, minor). The absolute
configuration of 17-Ac was determined by the same GC stereoselective
results compared with those of Miller’s catalyst. GC analysis for starting
material: γ DEX 225 column, flow rate 25 cm/s, temperature 160 °C, tR
= 28.6 min (1S, 2S, major), 29.7 min (1R, 2R, minor).
47.2, 38.0, 31.4, 28.2, 28.1, 27.0, 26.1, 24.8, 24.7; [R]25 ꢀ27.6 (c 1.0,
D
MeOH); IR (CH2Cl2) νmax 3426, 3355, 1699, 1636, 1506, 1449 cmꢀ1
.
General Procedure for the Kinetic Resolution of Racemic
Alcohols. A stock solution of substrate was prepared by dissolving
alcohols (0.16 mmol) in 16 mL of toluene (freshly distilled from Na). To
an oven-dried reaction vessel was added 50 μL of catalyst solution (0.08
mmol catalyst in 5 mL of CH2Cl2, 0.0008 mmol) followed removal of
CH2Cl2 by reduced pressure, and then 3.2 mL of the substrate solution
was added. The mixture was stirred at 25 °C in a thermostatic bath for 25
min, then the base (0.0064 mmol) and 25 μL of acetic anhydride was
introduced. During the reaction. Aliquots of 50 μL were removed per 5
min, quenched with 50 μL of methanol, and directly tested by chiral GC
analysis. For substrate 18 and 20, the reaction was conducted at 4 times
scales, and quenched with 10 mL of methanol at the half conversion
time. Then the solution was concentrated in vacuo, and purified by
chromatography on silica gel to give products and recovered starting
material for chiral GC or HPLC analysis. The krel value and conversion
were calculated by the method of Kagan.29
trans-2-Acetamidocyclooctyl acetate (18-Ac): TLC Rf = 0.5 (80%
1
EtOAc/petroleum ether); [R]20 þ4.2 (c 1.0, EtOH) for 88.6% ee; H
D
NMR (400 MHz CDCl3) δ 5.72 (d, J = 4.8 Hz, 1H), 4.90ꢀ4.99 (m, 1H),
4.44ꢀ4.11 (m, 1H), 2.04 (s, 1H), 1.92 (s, 1H), 1.88ꢀ1.40 (m, 12H); 13C
NMR (100 MHz CDCl3) δ 171.8, 169.4, 76.2, 53.1, 30.6, 29.5, 25.7, 25.6,
24.8, 24.1, 23.4, 21.3; HRMS (ESI) for C12H21NO3 calcd for [M þ Na]þ
m/z 250.1414, found 250.1412. HPLC analysis: Chiralcel AD-H column,
hexane/2-propanol = 90:10, flow rate 0.6 mL/min 210 nm, tR = 9.2 min
(1R, 2R, major), 11.1 min (1S, 2S, minor). The absolute configuration was
determinded by comparing optical rotation value with reported 2-amino-
cyclooctanol after removal of the acyl protection group, [R]20 ꢀ13.2
D
3002
dx.doi.org/10.1021/jo200403g |J. Org. Chem. 2011, 76, 2994–3004

The Journal of Organic Chemistry
FEATURED ARTICLE
(c 1.0, EtOH) (lit.36 [R]D þ19 (c 0.765, EtOH) for (1S, 2S) configuration)
HPLC analysis for starting material: Chiralcel AD-H column, hexane/2-
propanol = 90:10, flow rate 0.6 mL/min 210 nm, tR = 10.7 min (1R, 2R,
minor), 13.4 min (1S, 2S, major).
Project (B06005), and the 863 Project of the Ministry of Science and
Technology of China (2006AA020502). We thank Prof. Chi Zhang
at Nankai University for helpful discussions.
trans-(Z)-8-Acetamidocyclooct-4-enyl acetate (19-Ac): TLC Rf =
1
0.45 (80% EtOAc/petroleum ether); H NMR (400 MHz CDCl3) δ
’ REFERENCES
5.86ꢀ5.59 (m, 3H), 4.84 (dt, J = 2.9, 8.4 Hz, 1H), 4.34ꢀ4.19 (m, 1H),
2.49ꢀ2.30 (m, 2H), 2.28ꢀ2.15 (m, 2H), 2.05 (s, 3H), 1.99ꢀ1.82
(overlapping m and s, 6H), 1.74ꢀ1.62 (m, 1H); 13C NMR (100 MHz
CDCl3) δ 171.5, 169.0, 129.5, 128.8, 75.1, 51.1, 31.5, 31.1, 23.3, 23.0,
22.7, 21.0; HRMS (ESI) for C12H19NO3 calcd for [M þ Na]þ m/z
248.1257, found 248.1260. GC analysis: γ DEX 225 column, flow rate
22 cm/s, temperature 170 °C for 40 min, 1 deg/min to 200 °C, keep 20
min. tR = 38.5 min (1S, 2S, minor), 39.5 min (1R, 2R, major). The
absolute configuration was determined by compared the stereoselective
results with 18-Ac after hydrogenation. GC analysis for starting material:
β DEX 120 column, flow rate 20 cm/s, temperature 100 °C for 30 min,
1 deg/min to 120 °C, keep 40 min, tR = 75.6 min (1R, 2R, minor), 76.4
min (1S, 2S, major).
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threo-2-Acetamido-1,2-diphenylethyl acetate (20-Ac):37 TLC Rf =
0.6 (80% EtOAc/petroleum ether); [R]20D ꢀ7.2 (c 1.0, EtOH) for 25.3%
1
ee; H NMR (400 MHz CDCl3) δ 7.24ꢀ7.09 (m, 10H), 6.37 (d, J =
8.9 Hz, 1H), 6.07 (d, J = 7.4 Hz, 1H), 5.43 (dd, J = 7.4, 8.9 Hz, 1H), 2.09 (s,
3H), 1.96(s, 3H); 13C NMR (100 MHz CDCl3) δ 170.6, 169.3, 138.3,
136.8, 128.4, 128.3, 128.2, 127.7, 127.2, 127.0, 77.5, 57.7, 23.2, 21.0; HPLC
analysis: Chiralcel AD-H column, hexane/2-propanol = 85:15, flow rate
0.6 mL/min 220 nm, tR = 13.5 min (major), 18.0 min (minor). HPLC
analysis for starting material: Chiralcel AD-H column, hexane/2-propanol =
85:15, flow rate 0.6 mL/min 220 nm, tR = 23.1 min (minor), 26.5 min
(major). The absolute configuration was not determined.
2-Acetamido-1-phenylethyl acetate (21-Ac):38 TLC Rf = 0.45 (80%
EtOAc/petroleum ether); 1H NMR (400 MHz CDCl3) δ 7.45ꢀ7.30 (m,
5H), 5.84 (dd, J = 4.3, 8.2 Hz, 1H), 5.79 (broad s, 1H), 3.73ꢀ3.53 (m, 2H),
2.11 (s, 3H), 1.96 (s, 3H); 13C NMR (100 MHz CDCl3) δ 170.4, 170.1,
137.6, 128.6, 128.4, 126.4, 74.5, 44.4, 23.2, 21.1; GC analysis: γ DEX 225
column, flow rate 20 cm/s, temperature 180 °C for 40 min, 1 deg/min to
220 °C, tR = 34.6 min (major), 35.7 min (minor). GC analysis for starting
material: the same conditions as the product, tR = 46.1 min (minor), 47.4
min (major). The absolute configuration was not determined.
1-Phenylethyl acetate (22-Ac):39 TLC Rf = 0.5 (5% EtOAc/
petroleum ether); 1H NMR (400 MHz CDCl3) δ 7.41ꢀ7.24 (m,
5H), 5.88 (q, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H);
13C NMR (100 MHz CDCl3) δ 170.2, 141.6, 128.4, 127.8, 126.0, 72.2,
22.1, 21.3.
’ ASSOCIATED CONTENT
Supporting Information. Details of the 1H NMR titra-
S
b
tion experiment, the ROESY spectra of tetrapeptide 8 in two
1
forms, H NMR, 13C NMR, and HRMS spectra of catalysts
7ꢀ14, and products in Table 3, HPLC and GC data, X-ray
structural analysis data of 8e (CIF). This material are available
free of charge via the Internet at http://pubs.acs.org.
(7) (a) Pauletti, G. M.; Gangwar, S.; Siahaan, T. J.; Aubꢀe, J.;
Borchardt, R. T. Adv. Drug Delivery Rev. 1997, 27, 235. (b) Hruby,
V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945. (c) Ahn, J.-M.; Boyle,
N. A.; Macdonald, M. T.; Janda, K. D. Mini-Rev. Med. Chem. 2002, 2, 463.
(d) Gentilucci, L.; Tolomelli, A.; Squassabia, F. Curr. Med. Chem. 2006,
13, 2449. (e) Vagner, J.; Qu, H.-C.; Hruby, V. J. Curr. Opi. Chem. Bio.
2008, 12, 292.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: qujin@nankai.edu.cn.
(8) For examples, see: (a) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J.
Angew. Chem., Int. Ed. 2001, 40, 2824. (b) Jakobsche, C. E.; Peris, G.;
Miller, S. J. Angew. Chem., Int. Ed. 2008, 47, 6707.
(9) For this nomenclature, see the recommendations of the IU-
PACꢀIUB Joint Commission on Biochemical Nomenclature.
’ ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (20402007, 20772065, and 21072098),
Program for New Century Excellent Talents in University, the 111
3003
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The Journal of Organic Chemistry
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