The synthesis and characterization of a pentafluorosulfanylated peptide

Article abstract of DOI:10.1002/ejoc.201200327

The design and synthesis of pentafluorosulfanyl-containing heptad amino acid sequence was described. The three-dimensional conformation of the peptide was investigated by using CYANA (combined assignment and dynamics algorithm for NMR applications) and th

Full text of DOI:10.1002/ejoc.201200327

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Date: 05-06-12 18:01:05
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FULL PAPER
DOI: 10.1002/ejoc.201200327
The Synthesis and Characterization of a Pentafluorosulfanylated Peptide
Dong Sung Lim,[a] Jin-Hong Lin,[a] and John T. Welch*[a]
Dedicated to Professor George A. Olah on the occasion of his 85th birthday
Keywords: Amino acids / Peptides / Fluorinated substituents / Conformation analysis / Helical structures
The design and synthesis of pentafluorosulfanyl-containing
heptad amino acid sequence was described. The three-di-
mensional conformation of the peptide was investigated by
using CYANA (combined assignment and dynamics algo-
rithm for NMR applications) and the integrated autoassign-
ment. This study shows that the one of the diastereomers as-
sumed a very tight coiled conformation in [D6]DMSO where
both pentafluorosulfanyl groups assumed a synclinal rela-
tionship. The propensity of the protected heptapeptide to
form such a tight coil and of the pentafluorosulfanyl groups
to align so uniformly is suggestive of the utility of penta-
fluorosulfanylated amino acids in promoting conformational
control.
fluorine interactions.[5a,6] It has also been shown that elec-
trostatic effects involving side chain interactions with a
peptide core may diminish the energetic accessibility of
some conformations.[7]
Introduction
The pentafluorosulfanyl (SF5) group has attracted sig-
nificant attention as a fluorine-containing substituent.[1] To
date, the utility of this totally novel functional group has
been largely restricted to applications as an aromatic sub-
stituent.[2] Combined with the unique octahedral geometry
around sulfur, the steric and electronic effects of pentafluo-
rosulfanylation can profoundly modify the properties of
molecules into which the substituent has been introduced.[3]
The effects of SF5 group in peptide chemistry remain un-
known because of the paucity of available SF5-containing
amino acids and the lack of methods for the direct intro-
duction of a SF5 moiety to a peptide. To illustrate the sta-
bility of the SF5 group in common synthetic transforma-
tions and to assess the influence of the substituent on pept-
ide conformations, a heptapeptide containing an SF5-sub-
stituted amino acid has been prepared.
Extensive fluorination is known to dramatically influence
both the reactivity and conformation of amino acids.[4]
Most commonly analogs of leucine and valine have been
prepared that contain one or two trifluoromethyl replace-
ments for the methyl parts of the terminal isopropyl groups,
or alternatively, three to six omega fluorines were intro-
duced. The effect of fluorination has long been thought to
increase the lipophobicity of the side chain.[5] However, the
hydrophobic properties of the trifluoromethyl group may
have a greater effect than lipophobicity or specific fluorine–
These influences have been widely employed in the design
of peptides that assume an α-helical conformation. The
consequent coiled-coil interactions have been used to study
the effect of fluorination on protein-protein interactions. As
the core of the coiled-coil should be occupied by hydro-
phobic amino acids,[8] fluorination of the side chains of
those core residues have been shown to confer a general
increase in the thermodynamic stability of the coiled-
coil.[6a,6b,7b,9] While incorporation of fluorinated analogues
of leucine, isoleucine or valine at the core of coiled-coil hep-
tad repeat led to enhanced thermal stability, there are excep-
tions. It has been found that some fluorinated amino acids
exhibit a reduced propensity to form an α-helix in compari-
son with hydrocarbon analogues.[10] Neither the effect of
the pentafluorosulfanyl group on an amino acid or the in-
fluence of this substituent on the conformation of peptides
has previously been disclosed.
Results and Discussion
A simple SF5-containing heptapeptide was prepared
based on design principles established for de novo synthesis
of novel coiled-coil structures.[8,11] An SF5-containing
amino acid derived from allyl glycine (SF5-substituted nor-
valine derivative, SF5NVa) was introduced at the first and
fifth position of a heptapeptide sequence (SF5NVa-Glu-Ser-
Lys-SF5NVa-Lys-Glu or SF5NV-E-S-K-SF5NV-K-E) (Fig-
ure 1). Conceptually, SF5NVa introduces a pentafluoro-
sulfanyl group that could yield a hydrophobic interaction in
[a] Department of Chemistry, University at Albany, SUNY,
1400 Washington Ave., Albany, NY 12222
Fax: +518-442-3462
E-mail: jwelch@albany.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200327.
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D. S. Lim, J.-H. Lin, J. T. Welch
FULL PAPER
the folded state. We assumed that an appropriately designed
heptad sequence might tend to assume a coiled conforma-
tion with the SF5-bearing side chains on one side of the
coil.
Scheme 1. Synthesis of SF5-containing amino acid SF5NVa. a) 1.
LDA, 2. allylbromide, –78 °C to 0 °C, 4 h, 95%; b) citric acid
(15%), THF, room temp., 11 h, 70%; c) (Boc)2O, DCM, room
temp., 3 h, 82%; d) SF5Br (1.3 equiv., 0.5 m–1 m in CCl3F), Et3B,
0 °C, 10 min, 85%; e) DBU, benzene, room temp., 30 min, 96%; f)
NaOH (1 n in H2O), EtOH, 0 °C to room temp., 13 h, 98%.
Figure 1. The SF5-containing heptapeptide (SF5NVa-Glu-Ser-Lys-
SF5NVa-Lys-Glu or SF5NV-E-S-K-SF5NV-K-E) and a coiled rep-
resentation showing the pentafluorosulfanyl groups in close prox-
imity.
The preparation of the heptad was divided into three
steps: (i) the synthesis of (2RS)-SF5NVa; (ii) the syntheses
of the N-terminal fragment [(2RS)-SF5NVa-Glu-Ser-Lys]
and the C-terminal fragment [(2RS)-SF5NVa-Lys-Glu]; and
(iii) the coupling of these two fragments to give the peptide.
To prepare Boc-protected SF5NVa (7) (Scheme 1), com-
mercially available 1 was transformed to protected amino
acid 2 by first deprotonation with LDA and alkylation with
allyl bromide.
Deprotection with citric acid (15%) gave amine 3 which
was protected with Boc anhydride. The SF5 group was in-
troduced by Et3B-promoted addition of SF5Br (0.5 m–1 m
in CCl3F) to the double bond in 85% yield. Dehydrobromi-
nation using DBU yielded compound 6 quantitatively. Sa-
ponification of 6 with NaOH in ethanol provided 7 in good
yield.
The dipeptide 10 required for the C-terminal fragment
(SF5NVa-Lys-Glu), was synthesized in 77% yield using
peptide coupling with EDC in CH2Cl2. Boc deprotection of
10 with trifluoroacetic acid in dichloromethane[12] formed
the TFA salt 11. After drying in vacuo, the resulting TFA
salt was used without further purification. Synthesis of the
C-terminal fragment 12 (SF5NVa-Lys-Glu) was completed
in 80% yield using EDC in dichloromethane for coupling.
The SF5 amino acid 7 required the addition of a small
amount of DMF as a co-solvent to improve solubility in
reactions with 11 (Scheme 2).
Scheme 2. The synthesis of C-terminal fragment. a) Et3N, HOBt,
EDC·HCl, DCM, 0 °C to room temp., 16 h, 77%; b) TFA, DCM,
0 °C to room temp.; c) 7, Et3N, HOBt, EDC·HCl, DCM, DMF,
0 °C to room temp., 16 h, 80%.
Scheme 3. The protection of carboxylic acid group. a) allyl brom-
ide, DIPEA, MeCN, 96%; b) 20% piperidine, DCM, 0 °C to room
temp., 94%.
The synthesis of the N-terminal fragment (SF5NVa-Glu-
Ser-Lys) began with Fmoc-Boc-protected lysine 13. The
carboxylic acid residue was protected with an allyl group to
yield 14 (96%). The deprotection of Fmoc group was car-
The coupling reaction[14] of deprotected lysine 15 and
ried out using 20% piperidine in dichloromethane to yield protected serine 16 was successfully effected in good yield
a colorless liquid (94%) (Scheme 3).[13]
(90%) to form dipeptide 17 (Scheme 4).
2
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Synthesis and Characterization of a Pentafluorosulfanylated Peptide
formed in 88% crude yield (Scheme 6). The final deprotec-
tion of the heptad was carried out with TFA, but the purifi-
cation of the desired product was not successful (Scheme 6).
Scheme 4. The coupling reaction of 15 and 16. a) 15, NMM, HOBt,
EDC·HCl, THF, 0 °C to room temp./15 h, 90%.
Fmoc deprotection of dipeptide 17 was effected with
20% piperidine in dichloromethane at 0 °C, yielding depro-
tected dipeptide 18 in 76%. The dipeptide and Fmoc-pro-
tected glutamic acid were coupled over 12 h, to give the
tripeptide 19 (Glu-Ser-Lys) in 81% yield. The Fmoc pro-
tecting group of tripeptide 19 was removed in 92% yield.
Then, coupling of deprotected tripeptide and Boc-protected
pentafluorosulfanyl amino acid 7 was conducted over 4 h
to form the N-terminal fragment 21 (SF5NVa-Glu-Ser-Lys)
(Scheme 5).
Scheme 6. The coupling reaction of N-terminal fragment with C-
terminal fragment. a) TFA, DCM, 0 °C to room temp.; b) 22,
NMM, HOBt, EDC·HCl, THF, 0 °C to room temp., 4 h, 88%
(crude); c) TFA.
The protected heptad 24 (Figure 2) was characterized by
1H-NMR spectroscopy. The three-dimensional structure of
the protected heptad was investigated using CYANA (com-
bined assignment and dynamics algorithm for NMR appli-
cations, see: http://www.las.jp/products/cyana/eg/index.
html) and the integrated autoassignment module
CANDID.[16] CARA (computer-aided resonance assign-
ment, see: http://www.nmr.ch) was used to generate
CYANA data input from NOESY NMR spectroscopic
data.
Scheme 5. The synthesis of N-terminal fragment. a) 20% piper-
idine, DCM, 0 °C to room temp., 76%; b) HO2CCH(NHFmoc)-
CH2CH2CO2tBu, NMM, HOBt, EDC·HCl, THF, 0 °C to room
temp., 12 h, 81%; c) 20% piperidine, DCM, 0 °C to room temp.,
92%; d) 7, NMM, HOBt, EDC·HCl, THF, 0 °C to room temp.,
4 h, 93%; e) N-ethylaniline, (Ph3P)4Pd, THF, room temp., 91%.
Prior to coupling N-terminal fragment 22 and C-ter-
minal fragment 12, the allyl group protection of 21 was re-
moved using N-ethylaniline and tetrakis(triphenylphos-
phane)palladium(0) in THF at room temperature in 91%
yield (Scheme 5).[13,15]
Figure 2. Proton numbering for NMR spectra analyses.
The Boc group was removed from tripeptide 12 to enable
One-dimensional 1H, 19FNMR, and two-dimensional
the peptide coupling as well. The protected heptad 24 was COSY, NOESY, and TOCSY spectra of the heptad were
prepared from 22 and TFA tripeptide salt 23, under the acquired in [D6]DMSO for the initial NOE (nuclear Over-
usual conditions for 4 h. The protected heptad 24 was hauser effect) cross-peak assignments and unambiguous as-
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D. S. Lim, J.-H. Lin, J. T. Welch
FULL PAPER
signments of the individual resonances. NOE peaks were though the three structures were not fit precisely to an α-
used in the structure calculations. An expansion of the helix. Heptad B had a stretched right-handed helix struc-
amide group region of the NOESY spectrum is shown in ture. Heptad D [L1-E2 (7b)-S3-K4(16b)-L5-K6-E7] was the
Figure 3. Glu (E2) and Lys (K4) were assigned to a pair of best fit for an α-helix in comparison with literature values
NH cross-peaks by analysis of the NOESY and TOCSY (Figure 4).
NMR spectroscopic data of diastereomeric mixture 24 (Fig-
ure 2). In the amide region of the NOESY ([D6]DMSO),
the two sets of NH NOEs labelled E2 (resonances 7a and
b, Figure 2) and K4 (resonances 16a and b, Figure 2) are
shown. Since SF5NVa was prepared as a racemate, the four
possible diastereomeric combinations of the heptad, such
as (7a, 16a), (7a, 16b), (7b, 16a), and (7b, 16b), necessarily
were examined. For the structure fitting, it was necessary
to substitute the two SF5NVa residues by leucine (L1, L5)
and to remove the protecting groups to accommodate the
limitations of the software.
Figure 3. Expansion of the amide resonance region in the NOESY
of 24.
Four possible diastereomeric heptad structures were gen-
erated using CYANA and the integrated autoassignment
module CANDID. The chemical shift identification toler-
ance was set to 0.020 ppm in both proton dimensions. Ini-
tial NOE cross-peaks were manually assigned in the NMR
view of CARA. A total number of 100 structures were gen-
erated per CANDID round with 10,000 torsion angle dy-
The four lowest energy conformers obtained from the NOE-con-
Figure 4. NMR-derived structures of heptads (A, B, C, and D).
namics (TAD) steps in the CYANA annealing protocol.
The final number of both manual and CANDID assigned
NOE cross-peaks used in structural determination was 154.
The 20 lowest-energy structures in the final CANDID
round were retained as an ensemble representation of the
family of generated structures. A single structure, the most
stable among the best 20 structures in each case, was chosen
to represent the heptad.
strained simulated annealing. These structures are shown from up
and both sides. The N-terminal end is at the top and the carbonyl
oxygens point down. For clarity, all side chains and hydrogens are
omitted. A seven-stranded ribbon (yellow) has been added to trace
the helical backbone. The SF5NVa residues have been substituted
by leucine to accommodate software limitations.
The peptide backbone of a helix can be stabilized by in-
tramolecular hydrogen bond between the N–H group of an
The lowest-energy structures of heptad A [L1-E2(7a)-S3- amino acid and the C=O group of an amino acid four resi-
K4(16a)-L5-K6-E7], B [L1-E2(7a)-S3-K4(16b)-L5-K6-E7], dues earlier. The α-helix conformations therefore yield a
C [L1-E2(7b)-S3-K4(16a)-L5-K6-E7], and D [L1-E2(7b)- consecutive series of strong to medium NOEs between adja-
S3-K4(16b)-L5-K6-E7] are shown in Figure 4. Heptads A, cent amide protons, NN(i, i + 1), between amide and α-pro-
C, and D show the right-handed helix conformation al- tons in the same residue, αN(i, i), and between β-protons
4
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Synthesis and Characterization of a Pentafluorosulfanylated Peptide
and amide protons in adjacent residues, βN(i, i + 1), me-
dium to weak for the relation between αN(i, i + 1),
αN(i, i + 2), αN(i, i + 3), αβ(i, i + 3), and weak interactions
for the NN(i, i + 2) and αN(i, i + 4) (see part A of Fig-
ure 5).[17]
Figure 6. NMR-derived structure of modified heptad D in which
leucines (L1, L5) were replaced with SF5NVa (SF5NV1, SF5NV5).
These structures are shown from bottom and side. The N-terminal
end is in the foreground and at the bottom, respectively. For clarity,
the side chains with the exception of SF5NVa are omitted.
conformation. Apparently the less polar environment miti-
gated the intramolecular propensity of the SF5 groups to
associate in polar DMSO. These findings suggest that in-
corporation of selectively introduced SF5NVa residues
would be predicted to influence both the quaternary and
tertiary structure of longer peptides, especially when those
peptides were in a highly polar aqueous environment.
Conclusions
1
Figure 5. A. Notation for H–1H distances in polypeptide chains;
B. NOE relationships for 24 detected in [D6]DMSO.
A pentafluorosulfanylated aliphatic amino acid, (E)-
(RS)-2-(tert-butoxycarbonylamino)-5-(pentafluorosulf-
anyl)pent-4-enoic acid (7), SF5NVa, was prepared via the
addition of pentafluorosulfanyl bromide to a protected allyl
glycine intermediate.
In an analysis of heptad D (Figure 5, B) when compared
1
with the literature values for H–1H distances [dαN(i, i + 4)
= 4.2 Å, dαN(i, i + 3) = 3.4 Å, dαβ(i, i + 3) = 2.5–4.4 Å], both
1
the H–1H distances dαN(i, i + 4) (4.53 Å) in heptad D and
1
1
The heptad amino acid sequence [Boc-(2RS)-SF5NVa-
Glu(tBu)-Ser(tBu)-Lys(Boc)-(2RS)-SF5NVa-Lys(Cbz)-Glu-
(Et)-OEt] was prepared via conventional synthetic manipu-
lations. The SF5 group showed good stability towards gene-
ral organic transformations, polypeptide protection and de-
protection reactions and peptide coupling conditions.
Characterization of the peptide conformation by NMR
spectroscopy is reported in this work. The three-dimen-
sional conformation of the protected heptad, designed to
form an α-helix, was reported using CYANA and the inte-
grated autoassignment module CANDID. Figure 4 shows
possible NMR-derived structures of heptads (A, B, C, and
D). As anticipated with the heptad, Figure 6 reveals a heli-
cal structure close to an ideal α-helix in dimensions. This
investigation reveals that an SF5 group can be introduced
into a polypeptide and have a potent effect on overall poly-
peptide structure.
the H–1H distances dαN(i, i + 3) (4.73 Å) are longer. H–
1H distances dαβ(i, i + 3) were not found in this model struc-
ture. Overall, the information obtained from the sequential
NOE connectivities suggested that the structure for hep-
tad D is closer to an α-helix than a 310 helix (i + 3 Ǟ i hy-
drogen bonding) or π-helix (i + 5 Ǟ i hydrogen bonding).[18]
The dαN (i, i + 4) connectivity observed would be expected
only for an α-helical conformation. With only a heptad, the
putative assignments cannot assure a complete α-helix but
are rather indicative only of a more tightly coiled conforma-
tion. Based upon spectroscopic data, the heptad D struc-
ture has a slightly larger diameter helix when compared to
an α-helix. For the final structure representation of original
heptad
(SF5NVa-Glu-Ser-Lys-SF5NVa-Lys-Glu),
the
NMR-derived structure of modified heptad D, in which
leucines (L1, L5) are replaced with SF5NVa (SF5NV1,
SF5NV5), is shown in Figure 6.
In contrast with the above analysis in [D6]DMSO, where
one diastereomer of the protected synthetic heptad (Fig-
ure 6) was found to form a coil with the SF5NVa groups
extending away from the peptide backbone in a synclinal
orientation, in CDCl3, profound changes in NOE relation-
Experimental Section
General: Thin-layer chromatography was performed with silica gel
F254 (Merck) as the adsorbent on 0.2 mm thick, plastic-backed
ships was strongly suggestive of 24 assuming a less ordered plates. The chromatograms were visualized under UV (254 nm) or
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D. S. Lim, J.-H. Lin, J. T. Welch
FULL PAPER
by staining with a KMnO4 aqueous solution followed by heating.
Column chromatography was performed using silica gel 60 (70–
230 mesh, Merck). MALDI-TOF mass spectra was measured on a
Bruker Ultraflex III MALDI/TOF/TOF.
(10 mL) was added DBU (0.51 g, 3.33 mmol) and then stirred for
30 min at room temperature. The reaction mixture was quenched
with water and then extracted with dichloromethane. The com-
bined organic layers were dried with MgSO4, filtered and then con-
centrated. The crude product was purified by flash chromatography
to afford 0.99 g of a colorless liquid (96% yield). 1H NMR
(400 MHz, CDCl3): δ = 6.49–6.35 (m, 2 H), 5.23 (d, J = 6.9 Hz, 1
H), 4.45–4.38 (m, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 2.73–2.63 (m, 1
1
NMR Experiments: H, 13C and 19F-NMR spectra were recorded
on a Varian Gemini-300 MHz NMR spectrometer at 300, 75.43
and 282.20 MHz respectively or a Bruker Avance-400 MHz NMR
spectrometer at 400, 100 and 376 MHz, respectively. The chemical
shifts of 1H and 13C-NMR are reported relative to the residual
signal of CDCl3. 19F-NMR spectra are reported relative to the res-
onance assigned to CFCl3. For the COSY, TOCSY and NOESY
2048ϫ128, 8192ϫ480 and 2048ϫ480 data points were collected,
respectively. The number of transients collected for each experiment
was 16 for COSY and 48 for TOCSY and NOESY. The spectral
width was 14, 8 and 12 ppm, respectively. The relaxation delay for
the COSY was 1.48 and 1 s for both TOCSY and NOESY. The
NOESY mixing time was 250 ms.
H), 2.55–2.45 (m, 1 H), 1.40 (s, 9 H), 1.24 (t, J = 7.1 Hz, 3 H)
2
ppm. 19F NMR (282 MHz, CDCl3): δ = 82.6 (quintet, JSF-SF4
=
150.4 Hz, 1 F, axial SF), 62.0 (d, J = 148.7 Hz, 4 F, equatorial SF)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 155.0, 142.9 (t, J =
19.8 Hz), 133.6 (t, J = 7.0 Hz), 80.3, 61.9, 52.2, 34.1, 28.2, 14.0
ppm. C12H20F5NO4S (369.34): calcd. C 39.02, H 5.46; found C
39.28, H 5.62.
(RS)-2-(tert-Butoxycarbonylamino)-5-pentafluorosulfanylhex-4-enoic
Acid [Boc-(2RS)-SF5NVa] (7): To
a solution of 6 (0.30 g,
Ethyl 2-(Diphenylmethyleneamino)pent-4-enoate (2): To a solution
of N,N-diisopropylamine (2.2 mL, 16 mmol) in THF (30 mL) was
added nBuLi (6.3 mL, 16 mmol) slowly at 0 °C. The mixture was
0.81 mmol) in ethanol was added 1 n NaOH solution (0.97 mL)
and then stirred for 13 h at room temperature. The reaction mixture
was washed with dichloromethane and then the solution acidified
stirred for 30 min after addition was complete. Ethyl 2-(diphenyl- (pH 3) with 1 n HCl. The acidic solution was extracted with dichlo-
methyleneamino)acetate (4.0 g, 15 mmol) was added to the reaction
mixture at –78 °C. The mixture was stirred for 1 h after addition
was complete, and then added allyl bromide (1.9 g, 16 mmol). After
stirring for an additional hour, the temperature of the reaction mix-
ture was allowed to slowly increase to 0 °C. The reaction mixture
was quenched with water and then extracted with ethyl acetate. The
organic layer was separated and the aqueous layer washed with
ethyl acetate. The combined organic layers were dried with MgSO4
and then concentrated. The product was obtained in 95% crude
yield (4.4 g).
romethane in three portions. The combined organic layers were
dried with MgSO4, filtered and then concentrated. The crude prod-
uct was purified by flash chromatography to afford 0.27 g of a col-
1
orless liquid (98% yield). H NMR (400 MHz, CDCl3): δ = 10.45
(br. s, 1 H), 6.54–6.38 (m, 2 H), 5.19 (br. s, 1 H), 4.58–4.54 (m, 1
H), 2.84–2.67 (m, 1 H), 2.59–2.49 (m, 1 H), 1.43 (s, 9 H) ppm. 19F
2
NMR (282 MHz, CDCl3): δ = 82.3 (quintet, JSF-SF4 = 150.3 Hz,
1 F, axial SF), 61.9 (d, J = 149.2 Hz, 4 F, equatorial SF) ppm.
13CNMR (100 MHz, CDCl3): δ = 175.1, 155.2, 143.3 (t, J =
19.7 Hz), 133.2 (t, J = 7.4 Hz), 80.9, 52.1, 33.7, 28.2 ppm.
C10H16F5NO4S (341.29): calcd. C 35.16, H 4.73; found C 35.23, H
4.80.
Ethyl (RS)-2-Aminopent-4-enoate (3): A 15% solution of citric acid
(40 mL) was added to the monoalkylated Schiff base 2 (2.2 g,
7.2 mmol) in THF (40 mL) at room temperature and then was al-
lowed to stir for 11 h. Acid-base work up with 10% HCl, satd.
NaHCO3 solution and dichloromethane gave the crude product in
70% yield (0.77 g). The purity of the product was sufficient to pro-
ceed to the next step without further purification.
Boc-Lys(Cbz)-Glu(Et)-OEt (10): The hydrochloride of Glu(Et)-OEt
(9) (0.50 g, 2.1 mmol) was dissolved in CH2Cl2 (5 mL) and cooled
to 0 °C. This solution was treated with Et3N (1.16 g, 11.5 mmol),
1-hydroxybenzotriazole (HOBt) (0.34 g, 2.51 mmol), a solution of
the Boc-Lys(Cbz) (8) (0.80 g, 2.1 mmol) in CH2Cl2 (10 mL), and
Ethyl (RS)-2-(tert-Butoxycarbonylamino)pent-4-enoate (4): To a 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide
hydrochloride
solution of the amine compound 3 (2.2 g, 15 mmol) in dichloro-
methane (30 mL) was added Et3N (4.66 g, 46.0 mmol) and di-tert-
(EDC·HCl) (0.48 g, 2.5 mmol). The mixture was warmed to room
temperature, and stirring was continued for 16 h with exclusion of
butyl dicarbonate (4.04 g, 18.5 mmol) at room temp. which was light. Subsequent dilution with CHCl3 was followed by thorough
then allowed to stir for 3 h. The reaction mixture was quenched
with water and then extracted with dichloromethane. The com-
bined organic layers were dried with MgSO4, filtered and concen-
trated. The crude product was purified by flash chromatography to
afford 3.07 g of a colorless liquid (82% yield).
washing with 1 m HCl solution in three portions, satd. aq.
NaHCO3 in two portions and brine solution. The organic phase
was dried with MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
1
to afford 0.91 g of a white solid (77% yield). H NMR (400 MHz,
CDCl3): δ = 7.25–7.08 (m, 6 H), 5.50 (s, 2 H), 4.94 (s, 2 H), 4.47–
4.38 (m, 1 H), 4.09–3.87 (m, 5 H), 3.03 (br. s, 2 H), 2.32–2.16 (m,
2 H), 2.10–1.98 (m, 1 H), 1.90–1.75 (m, 1 H), 1.72–1.59 (m, 1 H),
1.56–1.44 (m, 1 H), 1.43–1.32 (m, 2 H), 1.29 (m, 10 H), 1.08 (t, J
= 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3,
172.1, 171.2, 156.3, 155.3, 136.4, 128.0, 127.6, 127.5, 79.2, 66.0,
61.1, 60.2, 53.8, 53.2, 51.2, 40.0, 31.6, 29.8, 28.9, 27.9, 27.1, 26.6,
21.9, 13.7, 13.6 ppm.
Ethyl (2RS,4RS)-4-Bromo-2-(tert-butoxycarbonylamino)-5-(penta-
fluorosulfanyl)hexanoate (5): To 7.8 mL of an 0.55 m solution of
pentafluorosulfanyl bromide (0.89 g, 4.3 mmol) in CCl3F was
added an 1 m solution of triethylborane in hexane (0.33 mL,
0.33 mmol) followed by the slow addition of Boc-protected amino
acid 4 (0.80 g, 3.3 mmol) at 0 °C. The reaction mixture was stirred
for 10 min at 0 °C. The reaction mixture was quenched with satd.
NaHCO3 solution and then extracted with dichloromethane. The
combined organic layers were dried with MgSO4, filtered and con-
centrated. The crude product was purified by flash chromatography
to afford the diastereoisomer mixture of colorless liquid (1.26 g,
85% yield). The diastereoisomeric mixture was used without fur-
ther purification.
TFA·Lys(Cbz)-Glu(Et)-OEt (11): Boc-protected amino acid 10
(0.45 g, 0.79 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to
0 °C. An equal volume of TFA was added, and the mixture was
warmed to room temp., and stirring continued for 1.5 h. Concen-
tration under reduced pressure, co-evaporation with CH2Cl2, and
drying of the residue under high vacuum yielded the crude TFA
salt, which was used without further purification.
Ethyl (RS)-2-(tert-Butoxycarbonylamino)-5-(pentafluorosulfanyl)-
hex-4-enoate (6): To a solution of 5 (1.25 g, 2.78 mmol) in benzene
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Pages: 10
Synthesis and Characterization of a Pentafluorosulfanylated Peptide
Boc-(2RS)-SF5NVa-Lys(Cbz)-Glu(Et)-OEt (12): Crude dipeptide
11 (0.044 g, 0.79 mmol) was dissolved in CH2Cl2 (3 mL) and cooled
to 0 °C. This solution was treated with Et3N (0.44 g, 4.4 mmol),
HOBt (0.14 g, 1.0 mmol), a solution of the Boc-(2RS)-SF5NVa-OH
(7) (0.27 g, 0.79 mmol) in CH2Cl2 (5 mL), and DMF (1.5 mL) and
EDC·HCl (0.20 g, 1.0 mmol). The mixture was warmed to room
temp., and stirring was continued for 16 h with exclusion of light.
Subsequent dilution with CHCl3 was followed by thorough wash-
ing with 1 m HCl solution in three portions, satd. aq. NaHCO3 in
two portions and brine solution. The organic phase was dried with
MgSO4, filtered and then concentrated under reduced pressure.
The crude product was purified by flash chromatography to afford
0.50 g of a mixture of diastereomers as a white solid (80% yield).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.25 (m, 5 H), 7.05–6.87
(m, 2 H), 6.53–6.34 (m, 2 H), 5.39–5.26 (m, 1 H), 5.19–4.98 (m, 3
H), 4.54–4.46 (m, 1 H), 4.46–4.37 (m, 1 H), 4.37–4.25 (m, 1 H),
4.18–4.02 (m, 4 H), 3.21–3.07 (m, 2 H), 2.77–2.62 (m, 1 H), 2.51–
2.24 (m, 3 H), 2.21–2.08 (m, 1 H), 2.03–1.91 (m, 1 H), 1.90–1.75
(m, 2 H), 1.72–1.59 (m, 1 H), 1.57–1.44 (m, 2 H), 1.40 (m, 10 H),
1.25–1.17 (m, 6 H) ppm. 19F NMR (282 MHz, CDCl3): δ = 82.7
= 8, 4 Hz, 2 H), 3.37 (t, J = 8 Hz, 1 H), 3.07 (dt, J = 7, 2 Hz, 2
H), 1.92–1.82 (m, 2 H), 1.75–1.65 (m, 2 H), 1.53–1.44 (m, 2 H),
1.41 (s, 9 H), 1.21 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 171.5, 170.2, 155.9, 143.9, 143.7, 141.3, 131.5, 127.7, 127.0, 125.1,
119.9, 119.0, 79.1, 77.2, 74.3, 67.1, 65.9, 61.7, 54.2, 52.2, 47.1, 32.1,
29.5, 28.4, 27.3, 22.4 ppm.
Ser(tBu)-Lys(Boc)-O-Allyl (18): To Fmoc-Ser(tBu)-Lys(Boc)-O-
Allyl (17) (0.45 g, 0.69 mmol) was added 20% piperidine in CH2Cl2
(4 mL) at 0 °C. After 30 min stirring at room temp., toluene
(10 mL) was added and volatiles were removed under vacuum. The
residue was purified by flash chromatography to afford 0.23 g of a
1
pale yellow liquid (76% yield). H NMR (400 MHz, CDCl3): δ =
7.83 (br. s, 2 H), 5.78 (m, 1 H), 5.21 (d, J = 16.8 Hz, 1 H), 5.12 (d,
J = 10.4 Hz, 1 H), 4.74 (t, J = 6 Hz, 1 H), 4.50 (d, J = 8.6 Hz, 2
H), 4.46 (dd, J = 8.0, 2.8 Hz, 1 H), 3.44–3.37 (m, 1 H), 2.86 (m, 1
H), 1.87 (br. s, 2 H), 1.80–1.70 (m, 2 H), 1.63–1.52 (m, 2 H), 1.30
(s, 9 H), 1.06 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.9, 171.7, 155.7, 131.4, 118.5, 78.6, 73.1, 65.5, 63.6, 54.9, 51.5,
40.0, 32.0, 29.2, 28.2, 27.2, 22.2 ppm.
2
Fmoc-Glu(tBu)-Ser(tBu)-Lys(Boc)-O-Allyl (19): The Ser(tBu)-Lys-
(Boc)-O-Allyl (18) (0.19 g, 0.43 mmol) was dissolved in THF
(7 mL) and cooled to 0 °C. This solution was treated successively
with the Fmoc-Glu(tBu)-OH (0.17 g, 0.41 mmol), HOBt (0.12 g,
0.86 mmol), EDC·HCl (0.17 g, 0.86 mmol), N-methylmorpholine
(0.13 g, 1.3 mmol). The mixture was warmed to room temp., and
stirring was continued for 3 h. The reaction mixture was concen-
trated under reduced pressure. The residue was purified by flash
chromatography to afford 0.29 g of a colorless liquid (81% yield).
1H NMR (400 MHz, CDCl3): δ = 7.80–7.21 (m, J = 8 Hz), 7.03 (d,
J = 6 Hz, 1 H), 5.87 (m, 1 H), 5.30 (dq, J = 17.3, 1.32 Hz, 1 H),
5.22 (dq, J = 10.4, 6.2 Hz, 1 H), 4.59 (d, J = 6 Hz, 1 H), 4.56 (m,
1 H), 4.44 (m, 1 H), 4.40–4.28 (m, 2 H), 4.25–4.16 (m, 1 H), 3.81
(dd, J = 8.1, 4.0 Hz 1 H), 3.38 (t, J = 7.6 Hz 1 H), 3.00 (t, J =
6.9 Hz 2 H), 2.54–2.30 (m, 2 H), 2.18–2.08 (m, 2 H), 2.02–1.90 (m,
2 H), 1.89–1.77 (m, 2 H), 1.72–1.60 (m, 2 H), 1.44 (s, 9 H), 1.41 (s,
9 H), 1.17 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1,
171.5, 171.2, 169.9, 156.3, 156.0, 143.8, 141.3, 131.6, 127.7, 127.1,
125.1, 120.0, 118.9, 81.2, 79.2, 77.2, 74.2, 67.3, 65.8, 61.1, 54.8,
53.2, 53.1, 52.2, 47.1, 40.4, 32.0, 29.4, 28.4, 28.1, 27.4, 22.4 ppm.
(quintet, 1 F, JSF-SF4 = 149.7 Hz, axial SF), 62.0 (d, J = 149.3 Hz,
4 F, equatorial SF) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.8,
172.8, 171.3, 171.2, 171.1, 170.81, 170.77, 170.1, 170.0, 156.5,
156.4, 155.1, 142.9 (m, J = 19.7 Hz), 142.7 (m, J = 19.8 Hz), 136.3,
136.2, 133.7 (m, J = 7.4 Hz), 128.2, 127.7, 80.3, 66.4, 66.3, 61.4,
60.61, 60.56, 52.6, 51.7, 39.8, 33.3, 31.4, 30.04, 29.99, 28.8, 27.9,
26.4, 21.7, 21.4, 13.7 ppm.
Fmoc-Lys(Boc)-O-Allyl (14): To a solution of acetonitrile (10 mL)
and allyl bromide (12 mL) was added Fmoc-Lys(Boc)-OH (13)
(2.3 g, 5.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.8 mL,
10 mmol) and then stirred for 4 h at 40 °C. The reaction mixture
was concentrated to half volume. Subsequent dilution with ethyl
acetate was followed by a thorough washing with 1 m HCl solution
in three portions, aq. NaHCO3 (half saturated) in two portions
and then brine solution. The organic phase was dried with MgSO4,
filtered and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography to afford 2.44 g of a pale
yellow solid (96% yield).
Lys(Boc)-O-Allyl (15): To Fmoc-Lys(Boc)-O-Allyl (14) (2.19 g,
4.31 mmol) was added 20% piperidine in CH2Cl2 (10.4 mL) at
0 °C. After 30 min stirring at room temperature, toluene (10 mL)
was added and volatiles were removed under vacuum. The residue
was purified by flash chromatography to afford 1.16 g of a colorless
liquid (94% yield). 1H NMR (400 MHz, CDCl3): δ = 5.87 (m, 1
H), 5.27 (ddt, J = 17.14, 1.46, 1.3 Hz, 1 H), 5.20 (ddt, J = 10.43,
1.8, 1.2 Hz, 1 H), 4.56 (ddd, J = 5.85, 1.4, 1.7 Hz, 2 H) 3.42 (m, 2
H), 3.08 (m, 2 H), 1.84 (m, 2 H), 1.72 (m, 2 H), 1.57 (m, 2 H), 1.4
(m, 2 H),1.38 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
175.4, 155.9, 131.9, 118.6, 78.9, 65.4, 54.3, 40.2, 34.3, 29.7, 28.3,
22.8 ppm.
Glu(tBu)-Ser(tBu)-Lys(Boc)-O-Allyl (20): To Fmoc-Glu(tBu)-
Ser(tBu)-Lys(Boc)-O-Allyl (19) (0.32 g, 0.38 mmol) was added 20%
piperidine in CH2Cl2 (4 mL) at 0 °C. After 30 min stirring at room
temperature, toluene (10 mL) was added and volatiles were re-
moved under vacuum. The residue was purified by flash
chromatography to afford 0.22 g of a colorless liquid (92% yield).
1H NMR (400 MHz, CDCl3): δ = 7.8 (d, 1 H), 7.30 (d, 1 H), 5.78
(m, 1 H), 5.21 (dd, J = 17, 1.32 Hz, 1 H), 5.14 (dt, J = 10.4 Hz,
1.21 1 H), 4.71 (t, 1 H), 4.51 (d, 2 H), 4.47 (m, 2 H), 4.34 (m, 2
H), 3.65 (dd, 1 H), 3.47–3.26 (m, 2 H), 2.96 (q, 2 H), 2.32–2.21 (m,
2 H), 2.04–1.94 (m, 1 H),1.93–1.67 (m, 2 H), 1.67–1.55 (m, 2 H),
1.32 (s, 9 H), 1.31 (s, 9 H), 1.10 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 174.39, 172.46, 171.48, 170.08, 155.78, 131.37, 118.67,
80.29, 78.70, 73.88, 65.60, 61.15, 54.42, 52.57, 52.00, 39.97, 31.75,
31.63, 29.94, 29.24, 28.21, 27.85, 27.17, 22.21 ppm.
Fmoc-Ser(tBu)-Lys(Boc)-O-Allyl (17): The Lys(Boc)-O-Allyl (15)
(0.36 g, 1.3 mmol) was dissolved in THF (13 mL) and cooled to
0 °C. This solution was treated with the Fmoc-Ser(tBu)-OH 16
(0.46 g, 1.2 mmol), HOBt (1-hydroxybenzotriazole) (0.20 g,
1.5 mmol), EDC·HCl (0.29 g, 1.5 mmol), N-methylmorpholine
(0.25 g, 2.5 mmol). The mixture was warmed to room temp., and
stirring was continued for 15 h. The reaction mixture was concen-
trated under reduced pressure. The residue was purified by flash
chromatography to afford 0.74 g of a colorless liquid (90% yield).
1H NMR (400 MHz, CDCl3): δ = 7.76–7.27 (m, 8 H), 5.88 (m, 1
H), 5.31 (d, J = 16.5 Hz, 1 H), 5.24 (d, J = 10.9 Hz, 1 H), 4.60 (m
Boc-(2RS)-SF5NVa-Glu(tBu)-Ser(tBu)-Lys(Boc)-O-Allyl (21): The
Glu(tBu)-Ser(tBu)-Lys(Boc)-O-Allyl (20) (0.21 g, 0.34 mmol) was
dissolved in THF (6 mL) and cooled to 0 °C. This solution was
treated with the Boc-(2RS)-SF5NVa-OH (7) (0.12 g, 0.34 mmol),
HOBt (0.055 g, 0.41 mmol), EDC·HCl (0.079 g, 0.41 mmol), N-
methylmorpholine (0.069 g, 0.68 mmol). The mixture was warmed
to room temp., and stirring was continued for 4 h. The reaction
1 H), 4.38 (d, J = 8 Hz, 2 H), 4.21 (t, J = 7 Hz, 1 H), 3.81 (dd, J mixture was concentrated under reduced pressure. The residue was
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20327
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Pages: 10
D. S. Lim, J.-H. Lin, J. T. Welch
FULL PAPER
purified by flash chromatography to afford 0.30 g of a mixture of
diastereomers as
HRMS (MALDI-TOF): calcd. for [M + Na]+ C65H103F10N9-
a
colorless liquid (93% yield). 1H NMR NaO19S2: 1590.6550, found 1590.6553.
(400 MHz, CDCl3): δ = 6.49–6.31 (m, 1 H), 5.85–5.73 (m, 1 H),
5.22 (dq, J = 16.9, 1.37 Hz, 1 H), 5.14 (dq, J = 10.32, 1.03 Hz, 1
H), 4.51 (d, J = 5.6 Hz, 2 H), 4.47–4.37 (m, 1 H), 4.35–4.26 (m, 1
H), 4.22–4.15 (m, 1 H), 3.63–3.55 (m, 1 H), 3.46–3.39 (m, 1 H),
3.36 (br. s, 2 H), 3.26 (p, J = 1.56 Hz, 1 H), 3.02–2.91 (m, 2 H),
2.64–2.54 (m, 1 H), 2.42–2.30 (m, 1 H), 2.24 (t, J = 7.23 Hz,2 H),
2.03–1.91 (m, 1 H), 1.98–1.69 (m, 2 H), 1.66–1.54 (m, 1 H), 1.34
(s, 9 H), 1.33 (s, 9 H), 1.32 (s, 9 H), 1.09 (s, 9 H) ppm. 19F NMR
(282 MHz, CDCl3): δ = 82.72 (q, 2JSF-SF4 = 150 Hz, 1 F, axial SF),
82.65 (q, 2JSF-SF4 = 149.7 Hz, 1 F, axial SF), 61.76 (d, J = 149.4 Hz,
4 F, equatorial SF), 61.78 (d, J = 148.1 Hz, 4 F, equatorial SF)
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.8, 171.50, 171.48,
170.9, 170.0, 156.3, 155.5, 142.7, 142.7, 134.08, 134.07, 131.4,
118.7, 81.1, 81.0, 80.3, 79.2, 77.2, 74.0, 74.0, 65.7, 61.0, 52.7, 52.6,
52.0, 49.5, 49.3, 49.1, 48.9, 48.7, 48.5, 48.3, 33.6, 31.7, 31.6, 31.39,
31.35, 29.5, 29.1, 28.2, 28.0, 27.76, 27.75, 27.1, 27.0, 22.3 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra are available
for key intermediates and TOCSY and NOESY data for the final
product.
Acknowledgments
We are very grateful for the helpful comments and suggestions of
our colleague Prof. Alex Shekhtman. We further acknowledge the
support of the Donors of the American Chemical Society Petro-
leum Research Fund (46219-AC4) and the National Science Foun-
dation (NSF) (CHE0957544) for partial support of this work.
[1] a) M. Salwiczek, S. Samsonov, T. Vagt, E. Nyakatura, E.
Fleige, J. Numata, H. Colfen, M. T. Pisabarro, B. Koksch,
Chem. Eur. J. 2009, 15, 7628–7636; b) D. Lentz, K. Seppelt, in:
Chemistry of Hypervalent Compounds (Ed.: K.-y. Akiba),
Wiley-VCH, New York, 1999, pp. 295–325; c) R. W. Winter,
R. A. Dodean, G. L. Gard, ACS Symp., Ser. 2005, 911, 87–
118; d) G. L. Gard, Chim. Oggi 2009, 27, 10–13.
Boc-(2RS)-SF5NVa-Glu(tBu)-Ser(tBu)-Lys(Boc)-OH (22): To
a
solution of Boc-(2RS)-SF5NVa-Glu(tBu)-Ser(tBu)-Lys(Boc)-O-
Allyl (21) (0.176 g, 0.188 mmol) in THF (6 mL) at room temp.
was added tetrakis(triphenylphosphane)palladium(0) (0.044 g,
0.038 mmol) and N-ethylaniline (0.228 g, 1.88 mmol). After stirring
for 32 min at room temp., dilution with ethyl acetate was followed
by a thorough washing with aq. saturated NH4Cl solution. The
water layer was extracted with ethyl acetate in three portions. The
combined organic layer was dried with MgSO4, filtered and then
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography to afford 0.154 g of a white solid
(91% yield).
[2] J. T. Welch, in: Fluorine in Pharmaceutical and Medicinal Chem-
istry: From Biophysical Aspects to Clinical Applications, vol. 5
(Eds.: V. Gouverneur, K. Mueller), Imperial College Press Co.,
2012, pp. 171–204.
[3] P. Kirsch, G.-V. Röschenthaler, ACS Symp., Ser. 2007, 949,
221–243.
[4] M. Salwiczek, E. Nyakatura, U. I. M. Gerling, S. Ye, B.
Koksch, Chem. Soc. Rev. 2012, 41, 2135–2171.
[5] a) A. Niemz, D. A. Tirrell, J. Am. Chem. Soc. 2001, 123, 7407–
7413; b) B. Bilgicer, X. Xing, K. Kumar, J. Am. Chem. Soc.
2001, 123, 11815–11816; c) B. Bilgicer, K. Kumar, Tetrahedron
2002, 58, 4105–4112.
[6] a) H.-Y. Lee, K.-H. Lee, H. M. Al-Hashimi, E. N. G. Marsh,
J. Am. Chem. Soc. 2006, 128, 337–343; b) K.-H. Lee, H.-Y. Lee,
M. M. Slutsky, J. T. Anderson, E. N. G. Marsh, Biochemistry
2004, 43, 16277–16284; c) T. Arai, T. Imachi, T. Kato, H. I.
Ogawa, T. Fujimoto, N. Nishino, Bull. Chem. Soc. Jpn. 1996,
69, 1383–1389; d) M. Salwiczek, B. Koksch, ChemBioChem
2009, 10, 2867–2870; e) T. Arai, T. Imachi, T. Kato, N. Nishino,
Bull. Chem. Soc. Jpn. 2000, 73, 439–445.
[7] a) S. S. Pendley, Y. B. Yu, T. E. Cheatham III, Proteins Struct.,
Funct., Bioinf. Proteins 2009, 74, 612–629; b) C. Jäckel, M. Sal-
wiczek, B. Koksch, Angew. Chem. 2006, 118, 4305; Angew.
Chem. Int. Ed. 2006, 45, 4198–4203; c) C. Jaeckel, W. Seufert,
S. Thust, B. Koksch, ChemBioChem 2004, 5, 717–720.
[8] J. M. Mason, K. M. Arndt, ChemBioChem 2004, 5, 170–176.
[9] a) Y. Tang, G. Ghirlanda, W. A. Petka, T. Nakajima, W. F. De-
Grado, D. A. Tirrell, Angew. Chem. 2001, 113, 1542; Angew.
Chem. Int. Ed. 2001, 40, 1494–1496; b) S. Son, I. C. Tanrikulu,
D. A. Tirrell, ChemBioChem 2006, 7, 1251–1257; c) B. C. Buer,
R. de la Salud-Bea, H. M. Al Hashimi, E. N. G. Marsh, Bio-
chemistry 2009, 48, 10810–10817; d) J. K. Montclare, S. Son,
G. A. Clark, K. Kumar, D. A. Tirrell, ChemBioChem 2009, 10,
84–86; e) B. Bilgicer, A. Fichera, K. Kumar, J. Am. Chem. Soc.
2001, 123, 4393–4399; f) Y. Tang, D. A. Tirrell, J. Am. Chem.
Soc. 2001, 123, 11089–11090.
(2RS)-SF5NVa-Lys(Cbz)-Glu(Et)-OEt (23): Boc-(2RS)-SF5NVa-
Lys(Cbz)-Glu(Et)-OEt (12) (0.085 mg, 0.095 mmol) was dissolved
in CH2Cl2 (0.5 mL) and cooled to 0 °C. An equal volume of TFA
was added, and the mixture was warmed to room temp., and stir-
ring continued for 1.5 h. Concentration under reduced pressure, co-
evaporation with CH2Cl2, and drying of the residue under high
vacuum yielded the crude TFA salt, which was used without further
purification.
Boc-(2RS)-SF5NVa-Glu(tBu)-Ser(tBu)-Lys(Boc)-(2RS)-SF5NVa-
Lys(Cbz)-Glu(Et)-OEt (24): The (2RS)-SF5NVa-Lys(Cbz)-Glu(Et)-
OEt (23) (0.040 g, 0.05 mmol) was dissolved in THF (3 mL)
and cooled to 0 °C. This solution was treated with the Boc-
(2RS)-SF5NVa-Glu(tBu)-Ser(tBu)-Lys(Boc)-OH (22) (0.046 g,
0.051 mmol), HOBt (1-hydroxybenzotriazole) (0.009 g, 0.06 mmol),
EDC·HCl (0.012 g, 0.062 mmol), N-methylmorpholine (0.026 g,
0.26 mmol). The mixture was warmed to room temp., and stirring
was continued for 6.5 h. Subsequent dilution with CHCl3 was fol-
lowed by a thorough washing with 1 m HCl solution in three por-
tions, satd. aq. NaHCO3 in two portions and brine solution. The
organic phase was dried with MgSO4, filtered and then concen-
trated under reduced pressure. The product was obtained in 88%
1
crude yield (0.070 g). H NMR (400 MHz, CDCl3): δ = 8.25 (m, 1
H), 8.18 (d, J = 7 Hz, 1 H), 8.03–7.93 (m, 3 H), 7.79 (d, J = 6.6 Hz,
1 H), 7.37–7.26 (m, 5 H), 7.12 (t, J = 5.6 Hz, 1 H), 7.05–6.95 (m,
1 H), 6.91–6.75 (m, 2 H), 6.60 (d, J = 6.1 Hz, 1 H), 6.62–6.50 (m,
2 H), 5.0 (s, 2 H), 4.51–4.42 (m, 1 H), 4.37–4.29 (m, 2 H), 4.29–
4.21 (m, 3 H), 4.21–4.13 (m, 1 H), 4.11 (m, 2 H), 3.54–3.44 (m, 2
H), 3.02–2.99 (m, 2 H), 2.92–2.84 (m, 2 H), 2.66–2.55 (m, 2 H),
2.48–2.39 (m, 2 H), 2.34 (t, J = 7.5 Hz, 2 H), 2.21 (t, J = 7.5 Hz,
2 H), 2.06–1.82 (m, 2 H), 1.87–1.71 (m, 2 H), 1.7–1.58 (m, 2 H),
1.58–1.46 (m, 2 H), 1.45–1.22 (m, 4 H), 1.40–1.37 (s, 9 H), 1.37 (s,
9 H), 1.13–1.07 (apparent s, 9 H), 1.18 (t, J = 7.0 Hz, 3 H) ppm.
[10] H.-P. Chiu, Y. Suzuki, D. Gullickson, R. Ahmad, B. Kokona,
R. Fairman, R. P. Cheng, J. Am. Chem. Soc. 2006, 128, 15556–
15557.
[11] a) M. Salwiczek, T. Vagt, B. Koksch, in: Fluorine in Medicinal
Chemistry and Chemical Biology (Ed.: I. Ojima), Blackwell
Publishing, 2009, pp. 391–409; b) B. Apostolovic, M. Danial,
H.-A. Klok, Chem. Soc. Rev. 2010, 39, 3541–3575; c) H. Rob-
son Marsden, A. Kros, Angew. Chem. 2010, 122, 3050; Angew.
Chem. Int. Ed. 2010, 49, 2988–3005; d) A. L. Boyle, D. N.
8
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Job/Unit: O20327
/KAP1
Date: 05-06-12 18:01:05
Pages: 10
Synthesis and Characterization of a Pentafluorosulfanylated Peptide
Woolfson, Chem. Soc. Rev. 2011, 40, 4295–4306; e) N. R. Zac-
cai, B. Chi, A. R. Thomson, A. L. Boyle, G. J. Bartlett, M. Bru-
ning, N. Linden, R. B. Sessions, P. J. Booth, R. L. Brady, D. N.
Woolfson, Nat. Chem. Biol. 2011, 7, 935–941.
D. Seebach, T. Sifferlen, D. J. Bierbaum, M. Rueping, B. Jaun,
B. Schweizer, J. Schaefer, A. K. Mehta, R. D. O’Connor, B. H.
Meier, M. Ernst, A. Glättli, Helv. Chim. Acta 2002, 85, 2877–
2917.
[16] a) P. Güntert, in: Methods in Molecular Biology, vol. 278, 2004,
pp. 353–378; b) P. Guntert, Prog. Nucl. Mag. Res. Sp. 2003, 43,
105–125; c) P. Güntert, in: BioNMR in Drug Research, Wiley-
VCH, 2003, pp. 39–66; d) C. Mumenthaler, P. Güntert, W.
Braun, K. Wüthrich, J. Biomol. NMR 1997, 10, 351–362; e) P.
Guntert, in: Protein NMR Spectroscopy: Practical Techniques
and Applications, John Wiley & Sons, 2011, pp. 159–192; f) T.
Ikeya, J.-G. Jee, Y. Shigemitsu, J. Hamatsu, M. Mishima, Y.
Ito, M. Kainosho, P. Güntert, J. Biomol. NMR 2011, 50, 137–
146.
[12]
[13]
R. Hamzavi, F. Dolle, B. Tavitian, O. Dahl, P. E. Nielsen, Bio-
conjugate Chem. 2003, 14, 941–954.
[17] a) K. Wüthrich, in: NMR of Proteins and Nucleic Acids, 1986;
b) D. G. Reid, in: Methods in Molecular Biology, vol. 60, 1997.
[18] N. Sewald, H.-D. Jakubke, in: Peptides: Chemistry and Biology,
Wiley-VCH, 2002.
[14] a) Z. Chen, J. Deng, T. Ye, Arkivoc 2003, vii, 268–285; b) H.
Tamiaki, T. Obata, Y. Azefu, K. Toma, Bull. Chem. Soc. Jpn.
2001, 74, 733–738.
[15] S. K. George, T. Schwientek, B. Holm, C. A. Reis, H. Clausen,
J. Kihlberg, J. Am. Chem. Soc. 2001, 123, 11117–11125.
Received: March 15, 2012
Published Online: ᭿
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Job/Unit: O20327
/KAP1
Date: 05-06-12 18:01:05
Pages: 10
D. S. Lim, J.-H. Lin, J. T. Welch
FULL PAPER
Conformational Control of Peptides
D. S. Lim, J.-H. Lin,
J. T. Welch* .................................... 1–10
The Synthesis and Characterization of a
Pentafluorosulfanylated Peptide
Keywords: Amino acids
/ Peptides /
Fluorinated substituents / Conformation
analysis / Helical structures
The design and synthesis of pentafluoro-
sulfanyl-containing heptad amino acid se-
quence was described. The investigation of
the peptide conformation shows that the
one of the diastereomers assumed a very
tight coiled conformation in [D6]DMSO
where both pentafluorosulfanyl groups as-
sumed a synclinal relationship. The pro-
pensity of the protected heptapeptide to
form such a tight coil and of the penta-
fluorosulfanyl groups to align so uniformly
is suggestive of the utility of pentafluoro-
sulfanylated amino acids in promoting con-
formational control.
10
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