The first example of linear peptides containing a N-trifluoroethylated backbone amide linkage and the surprising solution dynamics observed by 19F NMR

Article abstract of DOI:10.1016/j.jfluchem.2007.04.005

The α-amino group of (l)phenylalanine methyl ester was trifluoroethylated using (2,2,2-trifluoroethyl)phenyliodonium N,N-bis(trifluoromethylsulfonyl)imide. A dipeptide Gly(l)Phe containing a trifluoroethylated peptide bond was synthesized by removing the α-amino proton of N^α-trifluoroethyl (l)phenylalanine methyl ester followed by coupling with N^α-phthaloyl glycine acid fluoride. The dipeptide was further coupled with (l)leucine methyl ester under conventional carboxyl activation conditions to provide two diastereomers of the tripeptide Gly(d,l)Phe(l)Leu. The solution dynamic behavior of the tripeptide was investigated as a function of solvents, by NOESY and variable temperature (VT) ¹⁹F NMR experiments.

Full text of DOI:10.1016/j.jfluchem.2007.04.005

Journal of Fluorine Chemistry 128 (2007) 832–838
www.elsevier.com/locate/fluor
The first example of linear peptides containing a N-trifluoroethylated
backbone amide linkage and the surprising solution
19
dynamics observed by F NMR
*
Changqing Lu, Darryl D. DesMarteau
Department of Chemistry, Clemson University, Clemson, SC 29634, USA
Received 19 February 2007; received in revised form 2 April 2007; accepted 4 April 2007
Available online 8 April 2007
Abstract
The a-amino group of (L)phenylalanine methyl ester was trifluoroethylated using (2,2,2-trifluoroethyl)phenyliodonium N,N-bis(trifluoro-
a
methylsulfonyl)imide. A dipeptide Gly(L)Phe containing a trifluoroethylated peptide bond was synthesized by removing the a-amino proton of N -
a
trifluoroethyl (L)phenylalanine methyl ester followed by coupling with N -phthaloyl glycine acid fluoride. The dipeptide was further coupled with
(
L)leucine methyl ester under conventional carboxyl activation conditions to provide two diastereomers of the tripeptide Gly(D,L)Phe(L)Leu. The
1
9
solution dynamic behavior of the tripeptide was investigated as a function of solvents, by NOESY and variable temperature (VT) F NMR
experiments.
#
2007 Elsevier B.V. All rights reserved.
1
9
F
Keywords: (2,2,2-Trifluoroethyl)phenyliodonium N,N-bis(trifluoromethylsulfonyl)imide; Trifluoroethylation; Peptide bonds; Solution dynamic behavior;
NMR; Conformational study
1
. Introduction
potential of the fluoroalkyl groups to both affect and act as a
probe of the solution dynamics of small peptides.
Selective trifluoroethylation of bioactive compounds has
been investigated since the early 1960s [1–5]. However, the
progress in this research area is much slower compared to
selective fluorination of bioactive compounds, such as amino
acids and peptides [6,7]. In the past decade, we have focused on
the synthesis and applications of the novel trifluoroethylating
agent CF CH I(C H )N(SO CF ) . The chemo selectivity of
2
. Results and discussion
Converting a secondary amide bond to a trifluoroethylated
tertiary counterpart can be carried out by two potential
synthetic routes: pre-trifluoroethylation and post-trifluoroethy-
lation. In the early 1970s, Steinman et al. [2] prepared 1-
trifluoroethyl-5-phenyl-1,4-benzodiazepin-2-one (II in Scheme
3
2
6
5
2
3 2
this agent was demonstrated by trifluoroethylation of the
functionalities of a-amino acids [8–10]. The CF CH – group
3
2
1
) in low yields by first removing proton from 1 position of
was introduced at the N-terminus of leucine and methionine
enkephalins to improve the lipophilicity of these brain peptides.
The nucleophilicity of the trifluoroethylated N-terminus was
shown in intramolecular cyclization reactions [11]. Herein we
report our results on the incorporation of the CF CH – group
parent compound (I) and then reacting with trifluoroethyl
iodide. This reaction could not be substantially improved by
altering the reaction conditions or by the use of trifluoroethyl
benzenesulfonate or trifluoroethyl trichloromethanesulfonate
3
2
(triclate) as the alkylating agents.
The possibility of introducing the trifluoroethyl group at an
into peptide bonds of model linear peptides, which leads to
unanticipated conformational behavior in solution as observed
1
9
by F NMR. The fluorine labeled peptides illustrate the
earlier stage in the synthesis of (II) was then investigated.
Based on Dickey’s research [12], trifluoroethylation of anilines
with 2-chloro-1,1,1-trifluoroethane by autoclave reactions, and
Hansen’s work [13], trifluoroethylation of diethylamine with
trifluoroethyl trifluoromethanesulfonate (triflate), Steinman
*
Corresponding author. Tel.: +1 864 656 1251; fax: +1 864 656 2545.
E-mail address: fluorin@clemson.edu (D.D. DesMarteau).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.04.005

C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
833
nitrogen of amino acids in the conventional linear peptide
coupling reactions was caused by both steric and electronic
effects of the CF CH – group [9,10]. However, a trifluor-
3
2
oethylated a-amino group could form an amide bond in an
intramolecular cyclization reaction leading to cyclic dipeptide
formation [11]. We reasoned that deprotonating the a-amino
group would lead to reactivity.
Trifluoroethylating agent (2,2,2-trifluoroethyl)phenyliodo-
nium triflate was initially synthesized by Umemoto and Gotoh
[15] and used to trifluoroethylate different nucleophiles during
Scheme 1.
1980s [16]. In 1994, the same trifluoroethylating agent was
prepared using the modified method by Resnati and used for N-
trifluoroethylation of amino alcohols under dry conditions [17].
In this research, novel trifluoroethylating agent (2,2,2-
trifluoroethyl)phenyliodonium N,N-bis(trifluoromethylsulfo-
nyl)imide was synthesized [8] and used for N-trifluoroethyla-
tion of a-amino acids.
et al. [2] prepared and used triclate to obtain the secondary N-
trifluoroethylated anilines and aminobenzophenones. These
were then coupled directly with bromoacetyl bromide and
phthalimidoacetyl chloride to form desired tertiary amide
functionalities.
In the late 1990s, Claremon et al. [14a] and Selnick et al.
14b] used excess trifluoroethyl iodide with 5-phenyl-1,4-
The reaction of (L)phenylalanine methyl ester with
CF CH I(C H )N(SO CF ) in two phase solvents CH Cl /
[
3
2
6
5
2
3 2
2
2
a
H O resulted in N -trifluoroethyl (L)phenylalanine methyl ester
benzodiazepin-2-one (I, X = H, Y = H) in the presence of
Cs CO in DMF at 50 8C to obtain 1-trifluoroethyl-5-phenyl-
2
1 (Scheme 2), which was then deprotonated at the a-amino
position to provide ionic intermediate 2.
2
3
1,4-benzodiazepin-2-one (II, X = H, Y = H) in 60–68% yields.
To obtain a trifluoroethylated peptide bond, we tried the
reaction of both N-phthaloyl and C-methyl ester protected Gly-
a
Glycine was protected with phthalic anhydride to form N -
phthaloyl glycine 3 (Scheme 3), which was converted to acid
TM
(L)Phe dipeptide under the same reaction conditions, but the
reaction failed.
fluoride 4 using Deoxo-Fluor
.
Coupling between ionic intermediate 2 and acid fluoride 4
formed the desired peptide bond (Scheme 4). After basic
hydrolysis and acidification, dipeptide 5 was obtained.
Dipeptide 5 was further coupled with (L)leucine methyl ester
under conventional carboxyl activation conditions to give
tripeptide 6 (Scheme 5).
We then turned our attention to introducing CF CH – group
3
2
to the a-amino nitrogen of amino acids at an earlier stage
followed by a coupling reaction with an amino acid fluoride, but
failed in the coupling step. Our earlier research showed that the
lack of nucleophilicity of the trifluoroethylated a-amino
Scheme 2.
Scheme 3.
Scheme 4.

834
C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
Scheme 5.
Fig. 1. Crystal structures of tripeptide 6.
31 3 6 3
Fig. 2. HRMS of tripeptide 6, formula (M + H) C28H N O F , calc 562.2165, found 562.2155.
Tripeptide 6 was characterized by crystal structure analysis
Fig. 1) and HRMS (Fig. 2).
From the crystal structures of tripeptide 6, it was clear that
belonged to another diastereomer, and full racemization at a-
carbon of (L)phenylalanine occurred at the carboxyl activation
step during the coupling reaction with (L)leucine methyl ester.
Presumably, full racemization at the a-carbon was facilitated
by the attachment of the electron withdrawing CF CH – group
(
the tripeptide was obtained in diastereomeric forms. Both
secondary peptide bond and trifluoroethylated tertiary peptide
bond of each diastereomer assumed the sterically favored Z
conformation about the C(=O)–N bond in the solid state.
Initially, when tripeptide 6 was subjected to NMR
characterization, four well resolved triplets were observed in
3
2
to the adjacent nitrogen, although the effect of N-methylation of
peptides on the base-catalyzed epimerization at the adjacent Ca
position was also observed [18,19].
1
9
The F NMR spectra of tripeptide 6 revealed that in solution
each diastereomer existed in two different conformations. The
equilibrium between two corresponding conformers was
affected by the polarity of solvents.
1
9
F NMR spectra shown in Fig. 3. In different deuterated
solvents, the relative intensities of four triplets changed
dramatically. However, it was found that the ratio of
(
and was always 1. Therefore, it was inferred that triplets A and
A + A )/(B + B ) was constant in different NMR solvents
The exchange between two conformations for each
9
1
2
1
2
1
diastereomer of tripeptide 6 was further verified by a 2D
1
F
NOESY experiment shown in Fig. 4. A 2D H NOESY
1
A belonged to one diastereomer of tripeptide 6, B and B
2
2
1

C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
835
19
3 6
Fig. 3. F NMR spectra of diastereomeric tripeptide 6 in CD CN (top) and DMSO-d (bottom) (188.31 MHz, 21 8C).
experiment was also carried out (Fig. 5, zoomed in NH proton
region), in which each pair of negative cross peaks (in dotted
line) represented the conformational exchange.
The dynamic behavior of tripeptide 6 was further
1
investigated by variable temperature F NMR experiments
9
from 25 8C up to 128 8C in DMSO-d (Fig. 6).
6
In N-monosubstituted amides shown in Scheme 6(a), both
1
rotamers could always be detected in formamides (R = H)
At ca. 88 8C, the resonances of the trifluoroethyl groups of
the two conformers from each diastereomer of tripeptide 6
coalesced. This suggested the rotation around the trifluor-
oethylated tertiary peptide bond (Z and E exchange) shown in
Scheme 6(b). At the higher temperatures, the signals from two
diastereomers of tripeptide 6 gradually merged and sharpened
indicating that the inversion at the trifluoroethylated a-amino
nitrogen became faster on the NMR time scale.
1
20]; whereas in higher amides (R = Alkyl) only the form Z, in
[
which the R and R were trans to each other, was found in most
1
2
1
cases [20–22]. Therefore the exchange peaks in 2D H NOESY
spectrum (Fig. 5, NH proton region) reflected the rotation (Z
and E exchange) about the trifluoroethylated tertiary amide
bond shown in Scheme 6(b) instead of the secondary amide
bond to which the NH proton belonged. This was further
verified by the consistency of the integration ratios of the four
In summary, the trifluoroethyl group has been introduced
into peptide bonds by deprotonating trifluoroethylated a-amino
group followed by the coupling reaction with acid fluoride. The
introduction of CF CH – group facilitates peptide bond
1
9
triplets in F NMR spectra (Figs. 3 and 4) and that of the four
1
doublets in the H NMR spectrum (Fig. 5, NH proton region)
3
2
obtained in the same solvent DMSO-d6 at the same
temperature.
In unsymmetrically N,N-disubstituted amides, LaPlanche
rotation and results in different conformations. The solution
dynamic behavior of the corresponding linear peptides can be
1
investigated using a variety of F NMR techniques.
9
2
and Rogers [23] found that the bulkier substituent (R ) on
1
nitrogen was trans to the acetyl methyl group (R ) of
acetamides, in the preferred isomer. N-Alkylation of a linear
3. Experimental
2
1
peptide increased the proportion of cis (R cis to R ) peptide
present [19,24]. This is even more evident in our case,
presumably because the CF CH – group is an electron
Trifluoroethylating agent CF CH I(Ph)N(SO CF ) was
3
2
2
3 2
synthesized [8]. Other reagents and solvents were obtained
from commercial suppliers and used without further purifica-
tion. NMR spectra were obtained on Bruker AC-200, Bruker
Avance 300, JEOL ECX-300, and JEOL Eclipse+ 500
3
2
withdrawing group which decreases the double bond character
of the amide bond and makes its rotation easier.
2
Scheme 6. Z and E exchange: (a) about secondary amide bond and (b) about trifluoroethylated tertiary amide bond (R > –CH
2
CF
3
).

836
C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
19
6
Fig. 4. 2D F NOESY spectrum of diastereomeric tripeptide 6 in DMSO-d (282.78 MHz, 21 8C).
spectrometers. Chemical shifts are given in ppm relative to
m), 3.19–3.40 (1H, m), 3.53–3.72 (1H, m), 3.61 (3H, s), 7.16–
7.34 (5H, m).
1
9
1
CFCl for F, and relative to deuterated solvents used for H
3
1
and C NMR. Melting points are uncorrected.
3
3
.2. Deprotonated ionic intermediate 2
a
.1. N -Trifluoroethyl (L)phenylalanine methyl ester 1
3
a
N -Trifluoroethyl (L)phenylalanine methyl ester 1 (0.784 g,
(L)Phenylalanine methyl ester hydrochloride (2.157 g,
0.00 mmol) was suspended in CH Cl (70 mL). Water
3.00 mmol) and NaH (95%, 0.106 g, 4.20 mmol) were
dissolved/suspended in dry THF (15 mL). The reaction mixture
was refluxed under N protection for 24 h. The conversion of
1
2
2
(
stirred for 30 min. The clear organic layer was separated.
70 mL) and Na CO (7.0 g) were added. The mixture was
2
3
2
a
N -trifluoroethyl (L)phenylalanine methyl ester to the corre-
a
sponding N -deprotonated anionic intermediate 2 was 93.6%
NaHCO (1.008 g, 12.00 mmol), water (70 mL) and trifluor-
3
1
based on F NMR.
9
oethylating
1.00 mmol) were added with stirring at room temperature.
After 3 h, the CH Cl layer was again separated and washed
agent CF CH I(Ph)N(SO CF )
(6.237 g,
3
2
2
3 2
1
9
1
Intermediate 2:
F NMR (188.31 MHz, (CD ) CO):
3 2
À71.24 (3F, t, J = 8.66 Hz).
a
3.3. N -Phthaloyl glycine 3
2
2
with 3 Â 100 mL of water. The organic solvent was evaporated.
The obtained residue was subjected to column chromatography
using 10–30% acetone in hexanes to give 2.523 g (9.658 mmol,
9
6.6%) of compound 1.
Compound 1: colorless oil.
Glycine (1.137 g, 15.00 mmol) and phthalic anhydride
(2.244 g, 15.00 mmol) were grinded together thoroughly. The
mixture was heated at 150–160 8C for 30 min under N2
1
9
F NMR (188.31 MHz,
1
CD CN): À71.76 (3F, t, J = 9.75 Hz).
H
200.13 MHz, CD CN): 2.91–2.94 (2H, m), 2.96–3.19 (1H,
NMR
3
(
protection. The crude product was crystallized from CH OH/
3
3

C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
837
a
H O yielding 2.911 g (14.18 mmol, 94.6%) of N -phthaloyl
glycine 3.
2
1
Compound 3: white solid; mp 193–196 8C. H NMR
(
200.13 MHz, CD CN): 4.35 (2H, s), 7.75–7.87 (4H, mc).
3
a
.4. N -Phthaloyl glycine acid fluoride 4
3
a
N -Phthaloyl glycine 3 (0.615 g, 3.00 mmol) was suspended
in dry CH Cl (15 mL) under N protection. The suspension
2
2
2
was cooled in an ice bath with stirring. [Bis(2-methoxyethy-
TM
l)amino]sulfur
3
trifluoride
(Deoxo-Fluor
,
0.68 mL,
.6 mmol) was added dropwise through a syringe. The reaction
was continued at 0 8C for 1 h and at room temperature for 2.5 h.
Ice cooled water (20 mL) was added. The mixture was stirred
vigorously for 10 min. The organic layer was separated and
dried with anhydrous Na SO . The solvent was evaporated, and
2
4
the obtained residue was dried under vacuum at 40 8C for 1 h.
The conversion of N -phthaloyl glycine 3 to N -phthaloyl
a
a
1
glycine acid fluoride 4 was 92.4% based on H NMR.
1
19
Compound 4: colorless semi-crystalline solid. F NMR
Fig. 5. 2D H NOESY spectrum of 6 in DMSO-d
00.13 MHz, 21 8C).
6
(NH proton region,
1
188.31 MHz, CD CN): 32.99 (1F, t, J = 3.77 Hz). H NMR
3
(
3
19
6
Fig. 6. Variable temperature F NMR spectra of tripeptide 6 in DMSO-d (282.38 MHz).

838
C. Lu, D.D. DesMarteau / Journal of Fluorine Chemistry 128 (2007) 832–838
2
H = 0.96 A); full-matrix least-squares on F refinement;
˚
(
200.13 MHz, CD CN): 4.65–4.68 (2H, d, J = 3.76 Hz), 7.79–
3
2
R = 8.15%/R (F ) = 18.64%. CCDC 609,457.
7
.92 (4H, mc).
w
3
.5. Dipeptide 5
Acknowledgments
Intermediate 2 (1.87 mmol, 10.0 mL of reaction solution
from 3.2) was added dropwise into 5 mL of dry THF containing
Financial support of this research by the National Science
Foundation is gratefully acknowledged. HRMS data were
obtained in the Mass Spectrometry Laboratory, School of
Chemical Sciences, University of Illinois. Crystallographic
data were supplied by Dr. Don VanDerveer. The authors thank
Dr. Alex Kitaygorodskiy for assistance with NMR measure-
ments.
a
2
.77 mmol of N -phthaloyl glycine acid fluoride 4 with stirring
at 60 8C. The reaction mixture was refluxed for 16 h. Aqueous
M NaOH solution (15 mL) was added and the mixture was
2
stirred for 10 h at room temperature. The reaction mixture was
cooled in an ice bath and acidified with conc. HCl to pH 4.5.
After evaporating solvents, the obtained residue was suspended
in 15 mL of CH Cl and washed with 15 mL of H O twice. The
2
2
2
References
organic layer was separated and the solvent was evaporated.
The obtained residue was subjected to column chromatography
with 5–20% MeOH in CHCl3 as eluent to yield 0.487 g
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[
2] M. Steinman, J.G. Topliss, R. Alekel, Y.-S. Wong, E.E. York, J. Med.
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(
1.12 mmol, 59.9%) dipeptide 5.
[
3] (a) E.H. Banitt, W.E. Coyne, J.R. Schmid, A. Mendel, J. Med. Chem. 18
1
Compound 5: white solid. F NMR (188.31 MHz, CD CN,
9
3
(
(
1975) 1130–1134;
1
for major isomer): À69.94 (3F, t, J = 9.15 Hz). H NMR
b) E.H. Banitt, W.R. Bronn, W.E. Coyne, J.R. Schmid, J. Med. Chem. 20
(
500.16 MHz, CD CN, for major isomer): 3.10–3.23 (2H, m),
3
(1977) 821–826.
[
4] J.R. Wetterau, R.E. Gregg, T.W. Harrity, C. Arbeeny, M. Cap, F. Connolly,
C.-H. Chu, R.J. George, D.A. Gordon, H. Jamil, K.G. Jolibois, L.K.
Kunselman, S.-J. Lan, T.J. Maccagnan, B. Ricci, M. Yan, D. Young, Y.
Chen, O.M. Fryszman, J.V.H. Logan, C.L. Musial, M.A. Poss, J.A. Robl,
L.M. Simpkins, W.A. Slusarchyk, R. Sulsky, P. Taunk, D.R. Magnin, J.A.
Tino, R.M. Lawrence Jr., J.K. Dickson, S.A. Biller, Science 282 (1998)
3
J = 5.05 Hz, J = 5.05 Hz), 4.30–4.60 (2H, mc), 7.22–7.41 (5H,
.23–3.32 (1H, m), 3.91–4.01 (1H, mc), 4.08–4.14 (1H, dd,
1
m), 7.82–7.93 (4H, mc). C NMR (125.77 MHz, CD CN, for
3
3
major isomer): 34.1, 39.4, 39.7, 49.7 (q, J = 34.2 Hz), 64.7,
1
1
23.4, 125.6 (q, J = 290.2 Hz), 128.8, 129.1, 129.5, 132.1,
34.5, 137.8, 167.2, 167.8, 169.9.
7
51–754.
[
5] J.A. Robl, R. Sulsky, C.-Q. Sun, L.M. Simpkins, T. Wang Jr., J.K. Dickson,
Y. Chen, D.R. Magnin, P. Taunk, W.A. Slusarchyk, S.A. Biller, S.-J. Lan,
F. Connolly, L.K. Kunselman, T. Sabrah, H. Jamil, D. Gordon, T.W.
Harrity, J.R. Wetterau, J. Med. Chem. 44 (2001) 851–856.
3
.6. Tripeptide 6
Dipeptide 5 (0.362 g, 0.830 mmol), (L)leucine methyl ester
0.185 g, 1.00 mmol), HOBt (0.160 g, 1.16 mmol) and
[6] N.C. Yoder, K. Kumar, Chem. Soc. Rev. 31 (2002) 335–341.
[
[
[
7] X.-L. Qiu, W.-D. Meng, F.-L. Qing, Tetrahedron 60 (2004) 6711–
745.
8] D.D. DesMarteau, V. Montanari, J. Chem. Soc., Chem. Commun. 20
1998) 2241–2242.
9] D.D. DesMarteau, V. Montanari, Chem. Lett. 29 (2000) 1052–1053.
(
6
EDACÁHCl (0.227 g, 1.16 mmol) were suspended in 15 mL
of CH Cl . The reaction mixture was stirred and cooled at 0 8C.
2
2
(
DIPEA (0.42 mL, 1.9 mmol) was added in one portion through
a syringe. The reaction was continued at 0 8C for 2 h and at
room temperature for 14 h.
[10] D.D. DesMarteau, V. Montanari, J. Fluorine Chem. 109 (2001) 19–23.
[
[
11] D.D. DesMarteau, C. Lu, Tetrahedron Lett. 47 (2006) 561–564.
12] J.B. Dickey, E.B. Towne, M.S. Bloom, G.J. Taylor, H.M. Hill, R.A.
Corbitt, M.A. McCall, W.H. Moore, Ind. Eng. Chem. 46 (1954) 2213–
The reaction mixture was washed with 20 mL of 0.5 M HCl,
2
0 mL of 0.1 M NaHCO , and 3 Â 20 mL of H O, respectively.
3
2
2
220.
The organic layer was separated, and the solvent was
evaporated. The obtained crude product was subjected to
column chromatography twice using 1–5% MeOH in CHCl3
and 20–30% acetone in hexanes, respectively, yielding 0.437 g
[
13] R.L. Hansen, J. Org. Chem. 30 (1965) 4322–4324.
[14] (a) D.A. Claremon, N. Liverton, H.G. Selnick. US Pat. 5,658,901 (1997).
b) H.G. Selnick, N.J. Liverton, J.J. Baidwin, J.J.J.W. Butcher, D.A.
(
Claremon, J.M. Elliott, R.M. Freidinger, S.A. King, B.E. Libby, C.J.
McIntyre, D.A. Pribush, D.C. Remy, G.R. Smith, A.J. Tebben, N.K.
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Slaughter, K. Vyas, J. Med. Chem. 40 (1997) 3865–3868.
(
0.780 mmol, 93.4%) of tripeptide 6.
Compound 6: white solid; mp 147–149 8C. HRMS (ESI) for
+
M + H) : C H N O F ; calc: 562.2165; found: 562.2155.
(
[15] T. Umemoto, Y. Gotoh, J. Fluorine Chem. 28 (1985) 235–239.
2
8 31 3 6 3
[
[
[
16] T. Umemoto, Y. Gotoh, J. Fluorine Chem. 31 (1986) 231–236.
17] V. Montanari, G. Resnati, Tetrahedron Lett. 35 (1994) 8015–8018.
18] (a) J.R. McDermott, N.L. Benoiton, Can. J. Chem. 51 (1973) 2562–2570;
Crystallographic data of tripeptide 6: formula,
C H N O F ; M = 561.21; monoclinic; C ; T = 253(2) K;
2
8
30
3
6
3
2
˚
À3
a = 24.800(5),
b = 8.0711(16),
3
c = 29.210(6) A,
b =
(
b) J.R. McDermott, N.L. Benoiton, Chem. Biol. Pept., Proc. Am. Pept.
Symp., 3rd (1972) 369.
[19] P. Gund, D.F. Veber, J. Am. Chem. Soc. 101 (1979) 1885–1887.
˚
1
m = 0.107 mm ; empirical absorption correction (0.9696–
06.60(3)8; V = 5603.2(19) A ; D = 1.331 g cm ; Z = 8;
calc
À1
[
[
[
[
20] L.A. LaPlanche, M.T. Rogers, J. Am. Chem. Soc. 86 (1964) 337–341.
21] H. Kessler, Angew. Chem. Int. Ed. 9 (1970) 219–235.
0
.9926); Mo Ka radiation with graphite monochromator,
˚
l = 0.71073 A; Rigaku AFC-8S diffractometer; 22,997 mea-
sured reflections (Rint = 13.58%); 9892 reflections used with
I > 2s(I); 2umax = 50.108; 724 parameters; non-H atoms refined
anisotropically; H atoms fixed in calculated positions (C–
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