Thiol-Ene click reactions - Versatile tools for the modification of unsaturated amino acids and peptides

Article abstract of DOI:10.1002/ejoc.201300672

Terminal γ,δ-unsaturated amino acids, easily available by Claisen rearrangement or palladium-catalysed allylic alkylation, are excellent substrates for radical thiol additions. These click reactions allow the introduction of highly functionalized side-chains into a given amino acid or peptide. This protocol is suitable for the modification of all kinds of terminal alkenes, such as allyl protecting groups. Terminal γ,δ-unsaturated amino acids and peptides, easily available by Claisen rearrangement or palladium-catalysed allylic alkylation, are excellent substrates for radical thiol additions. These click reactions allow the introduction of highly functionalized side-chains into a given amino acid or peptide. This protocol is also suitable for the modification of allyl protecting groups. Copyright

Full text of DOI:10.1002/ejoc.201300672

FULL PAPER
DOI: 10.1002/ejoc.201300672
Thiol-Ene Click Reactions – Versatile Tools for the Modification of
Unsaturated Amino Acids and Peptides
Lisa Karmann[a] and Uli Kazmaier*[a]
Dedicated to Professor Wolfgang Steglich on the occasion of his 80th birthday
Keywords: Amino acids / Peptides / Click chemistry / Allylation / Thiols
Terminal γ,δ-unsaturated amino acids, easily available by
Claisen rearrangement or palladium-catalysed allylic alkyl-
ation, are excellent substrates for radical thiol additions.
These click reactions allow the introduction of highly func-
tionalized side-chains into a given amino acid or peptide.
This protocol is suitable for the modification of all kinds of
terminal alkenes, such as allyl protecting groups.
double bonds, as long as they are not too sterically hin-
dered.[8,9]Therefore, in general, the best results are obtained
with terminal alkenes. These reactions also work well with
alkynes to produce 1,2-dithiolated alkanes.[13] The radical
thiol addition proceeds under completely neutral conditions
and allows the regioselective modification of, for example,
unsaturated carbohydrates[14] and amino acids.[15] With the
latter class of compounds, in some cases, a partial racemiza-
tion of the chiral α-centre is observed, as a result of an
internal radical hydrogen shift.[16]
Introduction
Since the introduction of “click chemistry” by Sharpless
in 2001,[1] click reactions have become extremely popular in
many fields of advanced chemistry.[2] Besides polymer and
materials synthesis,[3] also the life sciences benefit enor-
mously from such reactions.[4] Typical characteristics of
click reactions are their generally high yields (almost no
side-reactions), their high regio- and stereoselectivities, their
high tolerance of oxygen and water, and their orthogonality
towards a wide range of other important functional groups.
Many of the reactions can even be carried out in aqueous
systems, and this makes them highly suitable for the modifi-
cation of biomolecules.[4] Although some of the popular
click reactions are “relatively old”, new and very mild ver-
sions have been developed in recent years, and this has
made them applicable to sensitive systems. Probably the
best example of this is the copper-free azide–alkyne cyclo-
addition,[2b,5] based on the [3+2]-cycloadditions[6] reported
by Huisgen in the early 1960’s.[7] The omission of the toxic
copper allows these click reactions to be carried out in liv-
ing cells.[8] Another popular and extremely mild click reac-
tion is the addition of thiols to alkenes (and alkynes),[9]
known as thiol-ene click chemistry.[10] These reactions also
give almost quantitative yields in many cases, and they find
widespread application in polymer chemistry[11] and chemi-
cal biology.[12] Although the nucleophilic thiol addition is
restricted to electron-poor alkenes, the radical version
works well with both electron-poor and electron-rich
Results and Discussion
Our group is involved in the development of methods for
the synthesis of unnatural amino acids, especially unsatu-
rated ones.[17] γ,δ-Unsaturated amino acids can easily be
obtained either by chelate Claisen rearrangement[18] or by
transition-metal-catalysed allylic alkylation.[19] Besides Pd
catalysts, complexes of Rh[20] and Ru[21] can be used in the
allylic alkylations. The two protocols, the Claisen rearrange-
ment and the allylic alkylation, complement each other
nicely, and give access to both stereoisomers (if β-substi-
tuted amino acids are formed) in a highly stereoselective
fashion.[22] If stannylated substrates are used, the metallated
amino acid formed can be subjected to subsequent cross-
coupling reactions to generate libraries of structurally re-
lated amino acids and peptides.[23] To increase the potential
of γ,δ-unsaturated amino acids even more, we became inter-
ested in their thiol-ene click reactions. Depending on the
thiol used, the new substituent could be used to introduce
specific properties (polarity, water solubility, etc.) or labels
(fluorescence, photoaffinity, biotin, etc.) into a given amino
acid or peptide. Therefore, we started to investigate the
thiol-ene click reaction of protected allyl-glycine 1 with a
wide range of thiols (Table 1).
[a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
E-mail: u.kazmaier@mx.uni-saarland.de
http://www.uni-saarland.de/lehrstuhl/kazmaier.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300672.
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Table 1. Thiol-ene click reactions of protected allyl-glycine 1.
ities can be introduced, e.g., by the addition of N-protected
cysteamine derivatives (Table 1, entry 7). The almost quan-
titative addition of thioacetic acid (Table 1, entry 8) is espe-
cially interesting, because saponification of the thioester
gives rise to higher homologues of cysteine. In principle,
such thiolated amino acids could be subjected to further
thiol-ene click reactions, as illustrated by the addition of
protected cysteine (Table 1, entry 9). The diamino acids
formed are suitable candidates for the synthesis of cross-
linked or cyclic peptides.[25] The introduction of a trime-
thoxysilane side-chain (Table 1, entry 10) should allow the
immobilization of amino acids and peptides on solid sup-
ports.[26]
To test the scope and limitations of this protocol, we next
investigated the addition of thiols to substituted allyl-
glycine derivatives (Scheme 1). Starting from cinnamyl
alcohol, β-phenylated amino acid 3 could easily be obtained
by a chelated Claisen rearrangement,[27] while δ-phenylated
derivative 4 was obtained by allylic alkylation.[20]
[a] Yield of pure compound 2. [b] Contaminated with the corre-
sponding cystine derivative (2%). [c] Contaminated with thiol
(9%). Boc = tert-butoxycarbonyl.
Initial experiments were carried out in CH2Cl2 using
stoichiometric amounts of tBuSH as the thiol component.
Irradiation using an ultravitalux lamp provided the product
in 44% yield after irradiation for 3 h. The reaction could
be optimized by using a threefold excess of the thiol and
prolonging the irradiation time to 6 h. Ethanol was found
to be the solvent of choice. Under these conditions, a yield
of 73% could be obtained with tBuSH (Table 1, entry 1).
To obtain comparable results, the conditions were kept con-
stant for the addition reactions of further thiols. The rela-
tively moderate yield obtained with tBuSH can probably
be explained as being due to the reversibility of the thiol
addition,[24] which led to a mixture of the starting material
and the addition product. An even more dramatic effect
was observed in the addition reaction of thiophenol. Here,
a product yield of only 12% could be obtained, probably
because of the relative stability of the thiophenol radical
and an unfavourable equilibrium. But these problems can
be overcome completely if sterically less demanding ali-
phatic thiols are used. With linear primary thiols, an almost
quantitative yield of the addition product was obtained
(Table 1, entries 2 and 3). Such nonpolar substituents can
be used to decrease the polarity of amino acids and pept-
ides. On the other hand, the polarity can be significantly
increased by the addition of hydroxylated or carboxylated
thiols (Table 1, entries 4–6). These substituents should in-
crease the water solubility of a given peptide. In addition,
the introduction of a free carboxylic acid directly into an
amino acid (Table 1, entry 6) would allow it to be coupled
Scheme 1. Thiol-ene click reactions of substituted allyl-glycines.
TFA = trifluoroacetyl.
Branched amino acid 3, with a terminal double bond,
reacted nicely, and gave results comparable to those ob-
tained with unsubstituted allyl-glycine 1. However, no reac-
tion was observed with linear amino acid 4, with an internal
double bond. Even though a well-stabilized benzyl radical
can be formed from compound 4, probably for steric
reasons the thiol-ene click reaction proceeds selectively at
terminal double bonds.
Bearing in mind that Broxterman et al. observed a slight
decrease of the enantiomeric purity of the amino acids in
comparable studies,[16] we also investigated the addition of a
thiol to enantiomerically enriched allyl-glycine (Scheme 2),
easily accessible by asymmetric Claisen rearrangement.[28]
And indeed, a slight drop in the ee was observed following
the addition of mercaptopropanoate, confirming the pre-
viously reported results. This effect might be explained as
being due to a competitive 1,3-hydrogen shift of the radical
intermediate.[16]
Scheme 2. Thiol-ene click reaction of enantiomerically enriched
directly with other amino acids or labels. Amine functional- allyl-glycine 1.
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To test whether this is an issue of allyl-glycine in particu- strates are used. Only with unsubstituted allyl acetates and
lar, or whether it might be generally found in thiol-ene click carbonates are significantly worse selectivities obtained
reactions of amino acids and peptides, we also synthesized (Scheme 3).
some allylated dipeptides and subjected them to thiol ad-
To tackle this issue, we decided to evaluate the allylation
dition reactions. Allylated dipeptides can easily be obtained reaction with a substituted allylic substrate that could later
by Pd-catalysed allylic alkylation in a highly stereoselective be cleaved to reveal a terminal double bond. The synthesis
fashion.[29] Diastereomeric product ratios of Ն90:10 are and application of a suitable substrate is shown in
generally obtained, especially if substituted allylic sub- Scheme 4. Starting from commercially available glycerol
allyl ether, oxidative cleavage, using NaIO4 immobilized on
silica,[30] gave rise to the corresponding aldehyde, which was
directly (without further purification) subjected to a vinyl
Grignard addition. The allylic alcohol obtained was con-
verted into the corresponding allyl carbonate (i.e., 8), the
substrate for the desired allylic alkylation reaction. And in-
deed, with this substituted allylic substrate, the diastereo-
selectivity in the allylation step could be increased to
Ͼ90%. (The term “% ds” describes the percentage of the
major diastereomer formed.) Unfortunately, the reactivity
of this allylic substrate seemed to be lower than that of
other substrates such as the methallyl carbonate used pre-
viously. A lower yield was obtained, even when the dipept-
ide was used in slight excess, and therefore the product (i.e.,
9) was contaminated with the peptide starting material,
which could not be removed by flash chromatography. Nev-
ertheless, impure allylated peptide 9 was subjected to ring-
closing metathesis, which resulted in the cleavage of the all-
ylic substituent and the formation of the allyl-glycine sub-
unit (i.e., 6).
With allylated peptides 6 and 7 in hand, we subjected
them to the thiol-ene click reactions (Table 2). The yields
Scheme 3. Synthesis of allylated peptides 6 and 7. LHMDS = lith-
ium hexamethyldisilazide.
Scheme 4. Synthesis of allylated peptide 6.
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obtained were slightly worse than those obtained in the re-
To demonstrate the broad scope of this reaction, another
actions of the amino acid, but they were still in the prepara- tetrapeptide with an O-allyl group instead of a C-allyl unit
tively useful range. Interestingly, no epimerization of the was prepared by standard methods and subjected to the
stereogenic centres was observed in these cases.
thiol addition reaction conditions (Table 4). Also with this
tetrapeptide (i.e., 14), excellent yields were obtained under
the same conditions (Table 4, entries 1–3).
Table 2. Addition of thiols to allylated dipeptides 6 and 7.
Table 4. Thiol-ene click reactions of O-allylated tyrosine peptide
14.
1
[a] Determined by H NMR spectroscopy. [b] 1:1 (R/S) mixture in
the side-chain.
To further examine the substrate scope, we also subjected
some tetrapeptides such as 12 to the thiol-ene click reac-
tions. Due to the high polarity of the tetrapeptide, the ex-
periments were carried out in a 2:1 mixture of ethanol and
THF (Table 3). Based on the results of the irradiations with
the dipeptides, the excess of the thiol was increased to
6 equiv. Under these conditions, the yields of compounds
13a–c were in the same range as those obtained with the
dipeptides (i.e., of 10 and 11) (Table 3, entries 1–3).
[a] Contaminated with the corresponding thiol (6%). [b] Contami-
nated with starting material 14 (6%).
Table 3. Addition of thiols to tetrapeptide 12 containing an allyl-
glycine subunit.
Conclusions
In conclusion, we have shown that the thiol-ene click re-
action can be used to introduce a wide range of side chains
(polar, nonpolar, or functionalized) into unsaturated amino
acids and peptides. Further applications of this protocol are
currently under investigation.
Experimental Section
General Remarks: All air- and moisture-sensitive reactions were
carried out in dried glassware under a nitrogen atmosphere. THF
was distilled from sodium benzophenone. LHMDS solutions were
prepared from freshly distilled HMDS (hexamethyldisilazane) and
commercially available n-butyllithium solution (1.6 m in hexane) in
THF before use. In the thiol-ene click reactions, an ultravitalux
lamp (280–740 nm; 300 W) served as light source. The radiations
were carried out in quartz tubes under a nitrogen atmosphere. The
products were purified by flash chromatography on silica gel col-
umns (40–63 μm). Mixtures of hexanes and ethyl acetate or dichlo-
romethane and methanol were generally used as eluents. 1H and
13C NMR spectra were recorded in CDCl3 or D4[methanol] (1H:
400 and 500 MHz, 13C: 100 and 125 MHz). Chemical shifts are
reported in ppm (δ), and tetramethylsilane or CHCl3 were used as
internal standards. Mass spectra were recorded on a quadrupole
[a] Contaminated with the corresponding thiol (5%).
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Thiol-Ene Click Reactions
spectrometer using the CI technique. In case of compounds con-
taining non-removable impurities, the yield was calculated accord-
ing to the H NMR spectrum.
HRMS (CI): calcd. for C13H26NO5S [M + H]+ 308.1526; found
308.1540.
1
Methyl 2-(tert-Butoxycarbonylamino)-5-(2,3-dihydroxypropylthio)-
pentanoate (2e): Following GP, thioglycerin (361 mg, 3.00 mmol,
90% in water) and 1 (230 mg, 1.00 mmol) were subjected to the
thiol-ene click reaction in ethanol. After evaporation and purifica-
tion (silica, dichloromethane/methanol, 9:1), compound 2e
(328 mg, 972 μmol, 97%) was isolated as a colourless oil. 1H NMR
(CDCl3, 400 MHz): δ = 1.44 (s, 9 H), 1.58–1.78 (m, 3 H), 1.91 (m,
1 H), 2.22 (br. s, 1 H), 2.51–2.72 (m, 4 H), 2.92 (br. s, 1 H), 3.56
(m, 1 H), 3.74 (s, 3 H), 3.79 (m, 2 H), 4.31 (m, 1 H), 5.10 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.3, 28.3,
31.6, 31.9, 35.6, 52.4, 52.8, 65.3, 70.0, 80.1, 155.4, 173.0 ppm.
C14H27NO6S (337.43): calcd. C 49.83, H 8.07, N 4.15; found C
50.07, H 7.84, N 3.94. HRMS (CI): calcd. for C14H28NO6S [M +
H]+ 338.1632; found 338.1637.
General Procedure for the Thiol-Ene Click Reactions (GP): A solu-
tion of the ene component (1.0 equiv.) and the thiol (3.0–6.0 equiv.)
in a suitable solvent (EtOH, MeOH, or EtOH/THF; 0.17–0.33 m)
was irradiated until no further consumption of the starting material
was observed (TLC). During irradiation, the internal temperature
rose to 70 °C. After cooling to room temperature, the solvent was
evaporated under reduced pressure, and the residue was purified by
flash chromatography.
Methyl 2-(tert-Butoxycarbonylamino)-5-(tert-butylthio)pentanoate
(2a): According to GP, tert-butylthiol (151 mg, 1.67 mmol) and 1[31]
(128 mg, 556 μmol) were subjected to the thiol-ene click reaction
in ethanol. After evaporation of the solvent and purification (silica,
hexanes/ethyl acetate, 98:2), compound 2a (130 mg, 407 μmol,
73%) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):
δ = 1.31 (s, 9 H), 1.44 (s, 9 H), 1.54–1.78 (m, 3 H), 1.92 (m, 1 H),
2.54 (m, 2 H), 3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 6.8 Hz, 1
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.7, 27.8, 28.3, 31.0,
32.2, 42.0, 52.3, 53.1, 79.9, 155.3, 173.2 ppm. HRMS (CI): calcd.
for C15H30NO4S [M + H]+ 320.1890; found 320.1893.
2-[4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopentylthio]prop-
anoic Acid (2f): According to GP, thiolactic acid (318 mg,
3.00 mmol) and 1 (229 mg, 1.00 mmol) were subjected to the thiol-
ene click reaction in ethanol. After evaporation of the solvent and
purification (silica, hexanes/ethyl acetate/acetic acid 70:29:1), com-
pound 2f (265 mg, 0.79 mmol, 79%) was isolated as a colourless
oil. 1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 9 H), 1.44 (d, J =
6.9 Hz, 3 H), 1.56–1.80 (m, 3 H), 1.90 (m, 1 H), 2.68 (m, 2 H), 3.39
(q, J = 7.1 Hz, 1 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.12 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 16.9, 25.0,
28.3, 30.8, 31.7, 40.8, 52.4, 53.0, 80.2, 155.5, 173.2, 177.6 ppm.
C14H25NO6S (335.42): calcd. C 50.13, H 7.51, N 4.18; found C
50.17, H 7.08, N 3.67. HRMS (CI): calcd. for C14H26NO6S [M +
H]+ 336.1476; found 336.1473.
Methyl 2-(tert-Butoxycarbonylamino)-5-(butylthio)pentanoate (2b):
Following GP, n-butylthiol (145 mg, 1.61 mmol) and 1 (123 mg,
537 μmol) were subjected to the thiol-ene click reaction in ethanol.
After evaporation and purification (silica, hexanes/ethyl acetate,
85:15), compound 2b (171 mg, 535 μmol, 99%) was isolated as a
pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ = 0.91 (t, J =
7.3 Hz, 3 H), 1.40 (m, 2 H), 1.44 (s, 9 H), 1.55 (m, 2 H), 1.60–1.77
(m, 3 H), 1.92 (m, 1 H), 2.49 (t, J = 7.4 Hz, 2 H), 2.52 (m, 2 H),
3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 7.1 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 13.7, 22.0, 25.4, 28.3, 31.5, 31.7,
31.8, 31.9, 52.3, 53.1, 79.9, 155.3, 173.2 ppm. C15H29NO4S
(319.46): C 56.40, H 9.15, N 4.38; found C 57.11, H 9.32, N 4.71.
HRMS (CI): calcd. for C15H30NO4S [M + H]+ 320.1890; found
320.1896.
Methyl
5-(2-Acetamidoethylthio)-2-(tert-butoxycarbonylamino)-
pentanoate (2g): Following GP, N-acetylcysteamine (221 mg,
1.85 mmol; 98%, contaminated with 2% of the corresponding di-
sulfide) and 1 (134 mg, 585 μmol) were subjected to the thiol-ene
click reaction in ethanol. After evaporation of the solvent and puri-
fication (silica, ethyl acetate), compound 2g (195 mg, 561 μmol,
96%) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):
δ = 1.45 (s, 9 H), 1.57–1.77 (m, 3 H), 1.92 (m, 1 H), 2.00 (s, 3 H),
2.55 (m, 2 H), 2.65 (t, J = 6.4 Hz, 2 H), 3.43 (td, J = 6.1 Hz, 2 H),
3.75 (s, 3 H), 4.32 (m, 1 H), 5.06 (d, J = 6.5 Hz, 1 H), 5.93 (br. s,
1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.3, 25.3, 28.3, 31.0,
31.8, 31.9, 38.4, 52.4, 64.6, 80.0, 155.2, 167.6, 170.1 ppm. HRMS
(CI): calcd. for C15H29N2O5S [M + H]+ 349.1787; found 349.1783.
Methyl
2-(tert-Butoxycarbonylamino)-5-(dodecylthio)pentanoate
(2c): According to GP, dodecanthiol (607 mg, 3.00 mmol) and 1
(229 mg, 1.00 mmol) were subjected to the thiol-ene click reaction
in ethanol. After evaporation of the solvent and purification (silica,
hexanes/ethyl acetate, 9:1), compound 2c (406 mg, 0.94 mmol,
94%) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):
δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (s, 16 H), 1.36 (m, 2 H), 1.44 (s,
9 H), 1.52–1.76 (m, 5 H), 1.91 (m, 1 H), 2.48 (m, 2 H), 2.52 (m, 2
Methyl 5-(Acetylthio)-2-(tert-butoxycarbonylamino)pentanoate (2h):
According to GP, thioacetic acid (228 mg, 3.00 mmol) and 1
(229 mg, 1.00 mmol) were subjected to the thiol-ene click reaction
in ethanol. After evaporation of the solvent and purification (silica,
hexanes/ethyl acetate, 8:2), compound 2h (303 mg, 992 μmol, 99%)
H), 3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 7.2 Hz, 1 H) ppm. 13
C
NMR (CDCl3, 100 MHz): δ = 14.1, 22.7, 25.4, 28.3, 28.9, 29.3,
29.3, 29.5, 29.6, 29.6, 29.6, 29.6, 31.5, 31.9, 31.9, 32.1, 52.3, 53.1,
79.9, 155.3, 173.1 ppm. C23H45NO4S (431.67): calcd. C 63.99, H
10.51, N 3.24; found C 63.93, H 10.09, N 2.96. HRMS (CI): calcd.
for C23H46NO4S [M + H]+ 432.3142; found 432.3161.
1
was isolated as a colourless oil. H NMR (CDCl3, 400 MHz): δ =
1.44 (s, 9 H), 1.58–1.72 (m, 3 H), 1.87 (m, 1 H), 2.32 (s, 3 H), 2.88
(t, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.01 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.5, 28.3,
28.5, 30.6, 31.8, 52.3, 53.0, 80.0, 155.3, 173.0, 195.6 ppm.
C13H23NO5S (305.39): calcd. C 51.13, H 7.59, N 4.59; found C
50.84, H 7.18, N 4.13. HRMS (CI): calcd. for C13H24NO5S [M +
H]+ 306.1370; found 306.1393.
Methyl 2-(tert-Butoxycarbonylamino)-5-(2-hydroxyethylthio)pent-
anoate (2d): According to GP, 2-mercaptoethanol (116 mg,
1.48 mmol) and 1 (113 mg, 493 μmol) were subjected to the thiol-
ene click reaction in ethanol. After evaporation of the solvent and
purification (silica, hexane/ethyl acetate, 1:1), compound 2d
(138 mg, 449 μmol, 91%) was isolated as a colourless oil. 1H NMR
(6R)-Dimethyl 2,2,16,16-Tetramethyl-4,14-dioxo-3,15-dioxa-8-thia-
(CDCl3, 400 MHz): δ = 1.44 (s, 9 H), 1.57–1.77 (m, 3 H), 1.92 (m, 5,13-diazaheptadecane-6,12-dicarboxylate (2i): According to GP,
1 H), 2.20 (t, J = 5.9 Hz, 1 H), 2.56 (m, 2 H), 2.71 (t, J = 5.9 Hz, starting from (R)-methyl 2-(tert-butoxycarbonylamino)-3-mercap-
2 H), 3.72 (td, J = 5.8 Hz, 2 H), 3.75 (s, 3 H), 4.32 (m, 1 H), 5.04 topropanoate (468 mg, 1.99 mmol) and 1 (140 mg, 611 μmol) in
(d, J = 7.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.4, ethanol, after evaporation and purification (silica, hexanes/ethyl
28.3, 30.9, 31.9, 35.2, 52.4, 52.8, 60.3, 80.0, 155.3, 173.1 ppm.
acetate, 8:2), compound 2i (263 mg, 566 μmol, 93%) was obtained,
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L. Karmann, U. Kazmaier
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contaminated with the corresponding disulfide of the protected cys-
teine (7.97 mg, 17.0 μmol), as a colourless oil. 1H NMR (CDCl3,
400 MHz): δ = 1.44 (s, 9 H), 1.45 (s, 9 H), 1.59–1.75 (m, 3 H), 1.89
(m, 1 H), 2.55 (m, 2 H), 2.94 (m, 2 H), 3.74 (s, 3 H), 3.76 (s, 3 H),
1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 9 H), 2.34 (m, 1 H), 2.40
(m, 1 H), 3.03 (dd, J = 13.6, 8.6 Hz, 1 H), 3.17 (dd, J = 13.6,
5.5 Hz, 1 H), 4.44 (ddd, J = 7.5, 5.5, 5.5 Hz, 1 H), 4.65 (ddd, J =
7.9, 7.9, 5.6 Hz, 1 H), 4.97 (ddt, J = 17.0, 1.5, 1.5 Hz, 1 H), 5.04
4.30 (m, 1 H), 4.52 (m, 1 H), 5.05 (br. s, 1 H), 5.33 (br. s, 1 H) (dd, J = 10.3, 1.4 Hz, 1 H), 5.41 (ddt, J = 17.3, 10.2, 7.2 Hz, 1
ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.3, 28.3, 28.3, 31.8, 32.2,
34.6, 52.3, 52.5, 53.0, 53.3, 80.0, 80.2, 155.1, 155.3, 171.1,
171.5 ppm. HRMS (CI): calcd. for C20H37N2O8S [M + H]+
465.2265; found 465.2258.
H), 5.96 (br. s, 1 H), 7.20–7.35 (m, 6 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 27.9, 36.4, 38.7, 52.2, 54.8, 82.7, 115.6 (J = 288 Hz),
119.2, 127.4, 128.8, 129.3, 131.7, 135.3, 156.6 (J = 38.0 Hz), 168.7,
169.9 ppm. Selected data for the minor diastereomer: 1H NMR
(CDCl3, 400 MHz): δ = 1.46 (s, 9 H), 2.50 (m, 2 H), 3.08 (dd, J =
13.8, 7.8 Hz, 1 H), 4.41 (ddd, J = 7.2, 5.6, 5.6 Hz, 1 H), 5.56 (ddt,
J = 17.3, 10.2, 7.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 36.4, 52.3, 119.5, 128.8, 129.3 ppm.
Methyl 3,3-Dimethoxy-15,15-dimethyl-13-oxo-2,14-dioxa-7-thia-12-
aza-3-silahexadecane-11-carboxylate (2k): Following GP, 3-(trime-
thoxysilyl)propane-1-thiol (589 mg, 3.00 mmol) and 1 (230 mg,
1.00 mmol) were subjected to the thiol-ene click reaction in dry
methanol. After evaporation, compound 2k (424 mg, 995 μmol,
99%) was isolated, contaminated with the corresponding thiol
(53 mg, 270 μmol, 9%). 1H NMR (CDCl3, 400 MHz): δ = 0.75 (m,
2 H), 1.44 (s, 9 H), 1.61–1.97 (m, 6 H), 2.46–2.57 (m, 4 H), 3.57 (s,
9 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.03 (d, J = 7.7 Hz, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 8.5, 22.9, 25.4, 28.2, 31.3, 31.8,
34.9, 50.5, 52.2, 53.0, 79.9, 155.3, 173.1 ppm. HRMS (CI): calcd.
for C17H36NO7SSi [M + H]+ 426.1971; found 426.1969.
1-(Allyloxy)but-3-en-2-yl Acetate (8): 1-(Allyloxy)but-3-en-2-ol
(990 mg, 7.72 mmol) was dissolved in dichloromethane (0.5 m), and
dry pyridine (918 mg, 11.6 mmol, 0.93 mL) was added. The mix-
ture was cooled to 0 °C, and then ethyl chloroformate (1.00 g,
9.26 mmol, 0.88 mL) was slowly added dropwise. The ice-bath was
removed, and the mixture was stirred overnight at room tempera-
ture. The resulting solution was diluted with dichloromethane and
then washed with CuSO4 (1 m aq.) until the excess pyridine was
removed. The organic phase was dried with Na2SO4, and the sol-
vent was evaporated under reduced pressure. The crude product
was purified by flash chromatography (silica, hexanes/ethyl acetate,
(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-ethoxy-3-oxopropyl-
thio)pentanoate (2l): According to GP, ethyl-3-thiopropionate
(199 mg, 1.48 mmol) and (S)-1 (114 mg, 495 μmol, 86% ee) were
subjected to the thiol-ene click reaction in ethanol. After evapora-
tion of the solvent and purification (silica, hexane/ethyl acetate,
8:2), compound (S)-2l (160 mg, 440 μmol, 89%) was isolated as a
1
9:1) to give 8 (1.39 g, 6.94 mmol, 90%) as a colourless liquid. H
NMR (CDCl3, 400 MHz): δ = 1.31 (t, J = 7.1 Hz, 3 H), 3.54 (dd,
J = 9.8, 3.5 Hz, 1 H), 3.58 (dd, J = 9.7, 5.7 Hz, 1 H), 4.00 (ddt, J
= 13.0, 5.6, 1.5 Hz, 1 H), 4.05 (ddt, J = 12.9, 5.6, 1.5 Hz, 1 H),
4.20 (q, J = 7.1 Hz, 2 H), 5.18 (ddt, J = 10.4, 1.3, 1.3 Hz, 1 H),
5.24–5.30 (m, 3 H), 5.39 (ddd, J = 17.2, 1.2, 1.2 Hz, 1 H), 5.84
(ddd, J = 17.4, 10.4, 6.4 Hz, 1 H), 5.88 (ddt, J = 17.3, 10.5, 5.6 Hz,
1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.2, 64.0, 71.2, 72.2,
77.1, 117.3, 118.6, 132.9, 134.4, 154.5 ppm. C10H16O4 (200.23):
calcd. C 59.98, H 8.05; found C 59.96, H 7.55. HRMS (CI): calcd.
for C10H17O4 [M + H]+ 201.1122; found 201.1116.
pale yellow oil. [α]2D0 = –11.2 (c = 1.0, CHCl3; 81% ee). H NMR
1
(CDCl3, 400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H),
1.56–1.77 (m, 3 H), 1.91 (m, 1 H), 2.56 (m, 2 H), 2.58 (t, J = 7.2 Hz,
2 H), 2.77 (t, J = 7.2 Hz, 2 H), 3.74 (s, 3 H), 4.16 (q, J = 7.1 Hz,
2 H), 4.31 (m, 1 H), 5.03 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 14.2, 25.3, 26.9, 28.3, 31.6, 31.8, 34.9, 52.3,
53.0, 60.7, 80.0, 155.3, 171.9, 173.1 ppm. GC (Chirasil-l-Val): T0
= 80 °C [10 min], 1 °C/min to 180 °C [100 min], (S)-2l: tR
=
(R,E)-tert-Butyl 6-(Allyloxy)-2-[(S)-3-phenyl-2-(2,2,2-trifluoroacet-
amido)propanamido]hex-4-enoate (9): n-Butyllithium (1.6 m
1.64 mL, 2.63 mmol) was added dropwise to a solution of HMDS
(460 mg, 2.85 mmol, 4.22 mL) in THF (0.6 m) at –78 °C. The mix-
ture was stirred for 5 min, then it was allowed to warm up to room
153.93 min, (R)-2l: tR = 154.80 min. C16H29NO6S (363.47): calcd.
C 52.87, H 8.04, N 3.85; found C 52.85, H 8.04, N 4.34. HRMS
(CI): calcd. for C16H30NO6S [M + H]+ 364.1788; found 364.1772.
(2S,3S)-Methyl
5-(Acetylthio)-2-(tert-butoxycarbonylamino)-3-
phenylpentanoate (5): According to GP, thioacetic acid (356 mg,
4.68 mmol) and 3[27] (310 mg, 1.02 mmol) were subjected to the
thiol-ene click reaction in ethanol. After evaporation of the solvent
and purification (silica, hexanes/ethyl acetate, 95:5), compound 5
(362 mg, 0.95 mmol, 95%) was isolated as a pale yellow solid, m.p.
61–65 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.39 (s, 9 H), 2.00 (m,
1 H), 2.08 (m, 1 H), 2.28 (s, 3 H), 2.65 (ddd, J = 13.7, 7.9, 7.9 Hz,
1 H), 2.83 (ddd, J = 13.9, 8.5, 5.7 Hz, 1 H), 3.29 (dt, J = 9.8,
5.2 Hz, 1 H), 3.65 (s, 3 H), 4.60 (dd, J = 9.4, 4.7 Hz, 1 H), 4.82 (d,
J = 9.3 Hz, 1 H), 7.10–7.32 (m, 5 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 27.0, 28.2, 30.5, 31.3, 47.0, 52.1, 57.3, 79.9, 127.6,
128.2, 128.7, 137.8, 155.5, 171.8, 195.4 ppm. HRMS (CI): calcd.
for C19H28NO5S [M + H]+ 382.1677; found 382.1670.
temperature.
A solution of dipeptide TFA-(S)-Phe-Gly-OtBu
(281 mg, 0.75 mmol) and dried zinc chloride (113 mg, 0.83 mmol)
in THF (0.15 m) was prepared and then cooled to –78 °C. The
freshly prepared LHMDS solution was also cooled to –78 °C, and
then the dipeptide/ZnCl2 solution was slowly added. A solution of
allylpalladium chloride dimer (3.7 mg, 10.1 μmol), PPh3 (10.5 mg,
40.0 μmol), and ethyl carbonate 8 (105 mg, 0.52 mmol) was pre-
pared in THF (1.5 mL). The catalyst/substrate solution was stirred
for 5 min, and then it was added slowly to the chelated enolate at
–78 °C. The dry ice was removed from the cooling bath, and the
mixture was allowed to warm to room temperature overnight. The
solution was diluted with diethyl ether, and then HCl (1 m aq.)
was added. After separation of the phases, the aqueous phase was
(R)-tert-Butyl 2-[(S)-3-Phenyl-2-(2,2,2-trifluoroacetamido)propan- extracted three times with diethyl ether, and the combined organic
amido]pent-4-enoate (6): Compound 9 (197 mg, 0.41 mmol) con-
taminated with dipeptide TFA-Phe-Gly-OtBu (80 mg, 0.21 mmol)
was dissolved in dichloromethane (0.1 m), and Grubbs catalyst I
(8.4 mg, 10.3 μmol) was added. The mixture was stirred at room
temperature overnight. The solvent was evaporated, and the residue
was purified (silica, hexanes/ethyl acetate, 9:1 to 8:2) to give com-
extracts were dried with Na2SO4. The solvent was removed in
vacuo, and the residue was purified by flash chromatography (silica
gel, hexanes/ethyl acetate, 8:2) to give a mixture of 9 (210 mg,
1
0.43 mmol, 83%; 91% ds, determined by H NMR spectroscopy)
and the original dipeptide (87 mg, 0.23 mmol). Data for the major
diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.42 (s, 9 H), 2.33
(m, 1 H), 2.41 (m, 1 H), 3.03 (dd, J = 13.6, 8.6 Hz, 1 H), 3.16 (dd,
J = 13.6, 5.6 Hz, 1 H), 3.86 (d, J = 5.8 Hz, 2 H), 3.94 (dt, J = 5.6,
1.4 Hz, 2 H), 4.44 (ddd, J = 7.5, 5.5, 5.5 Hz, 1 H), 4.65 (ddd, J =
1
pound 6[29] (157 mg, 0.38 mmol, 92%; 91% ds, determined by H
NMR spectroscopy) as a colourless solid, m.p. 80–83 °C. [α]20
=
–7.9 (c = 1.0, CHCl3, 91% ds). Data for the major diastereomer:
7106
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7101–7109

Thiol-Ene Click Reactions
8.0, 8.0, 5.8 Hz, 1 H), 5.18 (ddt, J = 10.4, 1.4, 1.4 Hz, 1 H), 5.23– 252 μmol) were subjected to the thiol-ene click reaction in ethanol
5.33 (m, 2 H), 5.52 (dtt, J = 15.4, 5.9, 1.2 Hz, 1 H), 5.89 (ddt, J = (0.75 mL). After evaporation of the solvent and purification (silica,
17.2, 10.5, 5.6 Hz, 1 H), 5.99 (br. s, 1 H), 7.19–7.36 (m, 6 H) ppm.
hexanes/ethyl acetate, 1:1), compound 11a (89.3 mg, 176 μmol,
13C NMR (CDCl3, 100 MHz): δ = 28.0, 35.0, 38.8, 52.3, 54.8, 70.0,
70%) was isolated as a colourless oil. [α]20 = +8.7 (c = 1.0, CHCl3;
1
71.2, 82.8, 115.6 (J = 288 Hz), 117.0, 126.5, 127.5, 128.9, 129.3, 90% ds, determined by H NMR spectroscopy, 1:1 mixture in the
1
131.2, 134.6, 135.3, 156.7 (J = 37.8 Hz), 168.4, 169.8 ppm. Selected
side-chain). Data for the major diastereomers: H NMR (CDCl3,
1
data for the minor diastereomer: H NMR (CDCl3, 400 MHz): δ
400 MHz): δ = 0.97 (d, J = 6.3 Hz, 1.5 H), 0.99 (d, J = 6.7 Hz, 1.5
= 1.43 (s, 9 H), 2.53 (m, 2 H), 4.41 (m, 1 H), 5.76 (m, 1 H) ppm. H), 1.43 (s, 4.5 H), 1.43 (s, 4.5 H), 1.55–1.73 (m, 2 H), 2.34–2.51
13C NMR (CDCl3, 100 MHz): δ = 27.9, 117.0, 126.4, 128.8, 129.3, (m, 2 H), 2.59 (m, 1 H), 2.68 (t, J = 5.9 Hz, 2 H), 2.89 (br. s, 0.5
131.2, 134.4 ppm. HRMS (CI): calcd. for C24H31N2O5F3 [M]+
484.2180; found 484.2139.
H), 2.99 (m, 1 H), 3.16 (dd, J = 13.2, 5.7 Hz, 0.5 H), 3.19 (dd, J =
13.4, 5.7 Hz, 0.5 H), 3.73 (m, 2 H), 3.92 (br. s, 0.5 H), 4.37 (ddd,
J = 8.2, 8.2, 4.9 Hz, 0.5 H), 4.39 (ddd, J = 8.0, 8.0, 5.8 Hz, 0.5 H),
4.68 (ddd, J = 8.2, 8.2, 5.7 Hz, 1 H), 6.12 (d, J = 8.0 Hz, 0.5 H),
6.17 (d, J = 8.0 Hz, 0.5 H), 7.15–7.35 (m, 6 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 19.2, 19.7, 27.9, 27.9, 30.0, 30.1, 35.5, 35.6,
38.1, 38.3, 38.5, 38.5, 38.9, 39.1, 51.2, 51.3, 54.8, 54.8, 60.7, 60.8,
82.5, 82.8, 115.6 (J = 288 Hz), 115.6 (J = 288 Hz), 127.4, 127.4,
128.8, 128.8, 129.2, 129.3, 135.3, 135.4, 156.8 (J = 37.8 Hz), 156.8
(J = 37.8 Hz), 168.9, 169.1, 170.8, 171.1 ppm. Selected data for the
(R)-tert-Butyl 5-(2-Hydroxyethylthio)-2-[(S)-3-phenyl-2-(2,2,2-tri-
fluoroacetamido)propanamido]pentanoate (10a): According to GP,
2-mercaptoethanol (48.8 mg, 624 μmol) and 6 (85.7 mg, 208 μmol)
were subjected to the thiol-ene click reaction in ethanol (1.5 mL).
After evaporation of the solvent and purification (silica, hexanes/
ethyl acetate, 6:4), compound 10a (70.4 mg, 143 μmol, 69%; 91%
ds, determined by 1H NMR spectroscopy) was isolated as a colour-
less solid, m.p. 74–79 °C. [α]20 = +2.1 (c = 1.0, CHCl3, 91% ds).
1
minor diastereomer: H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 4.5
1
Data for the major diastereomer: H NMR (CDCl3, 400 MHz): δ
H), 1.47 (s, 4.5 H), 1.01 (d, J = 6.4 Hz, 1.5 H), 1.03 (d, J = 6.5 Hz,
1.5 H) ppm. HRMS (CI): calcd. for C23H34F3N2O5S [M + H]+
507.2130; found 507.2156.
= 1.36 (m, 2 H), 1.43 (s, 9 H), 1.66 (m, 2 H), 2.26 (br. s, 1 H, OH),
2.44 (dt, J = 12.8, 6.1 Hz, 1 H), 2.50 (dt, J = 10.4, 5.9 Hz, 1 H),
2.70 (t, J = 5.9 Hz, 2 H), 3.03 (dd, J = 13.6, 8.9 Hz, 1 H), 3.19 (dd,
J = 13.5, 5.4 Hz, 1 H), 3.73 (m, 2 H), 4.37 (m, 1 H), 4.67 (ddd, J
= 8.5, 5.8, 5.8 Hz, 1 H), 6.08 (br. s, 1 H), 7.19–7.36 (m, 6 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 24.9, 27.9, 31.1, 31.3, 35.2, 38.6,
52.4, 54.8, 60.5, 82.8, 115.6 (J = 288 Hz), 127.5, 128.9, 129.2, 135.3,
156.7 (J = 37.9 Hz), 168.7, 170.5 ppm. Selected data for the minor
diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 9 H), 2.67
(t, J = 5.9 Hz, 2 H), 3.11 (dd, J = 14.6, 6.2 Hz, 1 H), 6.21 (br. s, 1
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 27.9, 60.4 ppm.
C22H31F3N2O5S (492.55): calcd. C 53.65, H 6.34, N 5.69; found C
54.10, H 6.43, N 5.19. HRMS (CI): calcd. for C22H32F3N2O5S [M
+ H]+ 493.1979; found 493.1995.
(2R)-tert-Butyl
5-(3-Ethoxy-3-oxopropylthio)-4-methyl-2-[(S)-3-
phenyl-2-(2,2,2-trifluoroacetamido)propanamido]pentanoate (11b):
According to GP, ethyl-3-thiopropionate (201 mg, 1.50 mmol) and
7
[29] (214 mg, 0.50 mmol) were subjected to the thiol-ene click reac-
tion in ethanol (1.5 mL). After evaporation of the solvent and puri-
fication (silica, hexanes/ethyl acetate, 8:2), compound 11b (229 mg,
0.41 mmol, 82%) was isolated as a pale yellow oil. [α]20 = +11.8 (c
1
= 1.0, CHCl3; 90% ds, determined by H NMR spectroscopy, 1:1
mixture in the side-chain). Data for the major diastereomers: 1H
NMR (CDCl3, 400 MHz): δ = 0.95 (d, J = 6.4 Hz, 1.5 H), 0.99 (d,
J = 6.6 Hz, 1.5 H), 1.27 (t, J = 7.1 Hz, 1.5 H), 1.29 (t, J = 7.2 Hz,
1.5 H), 1.35 (m, 0.5 H), 1.42 (s, 4.5 H), 1.43 (s, 4.5 H), 1.55–1.72
(m, 2 H), 1.81 (ddd, J = 13.7, 10.9, 3.4 Hz, 0.5 H), 2.27 (dd, J =
13.3, 8.2 Hz, 0.5 H), 2.36 (dd, J = 12.8, 7.2 Hz, 0.5 H), 2.46 (dd, J
= 13.3, 5.5 Hz, 0.5 H), 2.52–2.80 (m, 4.5 H), 3.02 (dd, J = 13.6,
8.7 Hz, 0.5 H), 3.07 (dd, J = 13.6, 8.7 Hz, 0.5 H), 3.16 (dd, J =
13.6, 5.7 Hz, 0.5 H), 3.21 (dd, J = 13.7, 5.7 Hz, 0.5 H), 4.16 (q, J
= 7.1 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 1 H), 4.31 (ddd, J = 10.8, 7.8,
4.0 Hz, 0.5 H), 4.39 (ddd, J = 7.8, 7.8, 6.5 Hz, 0.5 H), 4.67 (ddd, J
= 8.0, 8.0, 5.9 Hz, 0.5 H), 4.75 (ddd, J = 8.0, 8.0, 5.7 Hz, 0.5 H),
5.92 (d, J = 7.9 Hz, 0.5 H), 6.46 (d, J = 7.6 Hz, 0.5 H), 7.19–7.36
(m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1, 14.1, 19.0,
19.3, 27.1, 27.5, 27.8, 27.8, 29.3, 29.9, 34.5, 34.9, 37.6, 38.4, 38.5,
38.8, 38.9, 39.5, 51.0, 51.2, 54.6, 54.7, 60.6, 60.9, 82.1, 82.5, 115.6
(J = 287 Hz), 115.6 (J = 287 Hz) 127.2, 127.3, 128.6, 128.7, 129.2,
129.2, 135.4, 135.5, 156.6 (J = 37.7 Hz), 156.7 (J = 37.8 Hz), 168.8,
169.4, 170.8, 171.0, 171.9, 172.3 ppm. Selected data for the minor
diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 4.5 H),
1.48 (s, 4.5 H), 4.47 (m, 0.5 H), 6.21 (d, J = 8.2 Hz, 0.5 H, NH),
6.61 (d, J = 8.3 Hz, 0.5 H) ppm. C26H37F3N2O6S (562.64): calcd.
C 55.60, H 6.46, N 4.99; found C 55.10, H 6.38, N 4.60. HRMS
(CI): calcd. for C22H30N2O6F3S [M – tBu + 2H]+ 507.1771; found
507.1789.
(R)-tert-Butyl
5-(3-Ethoxy-3-oxopropylthio)-2-[(S)-3-phenyl-2-
(2,2,2-trifluoroacetamido)propanamido]pentanoate (10b): According
to GP, ethyl-3-thiopropionate (201 mg, 1.50 mmol) and 6 (207 mg,
0.50 mmol) were subjected to the thiol-ene click reaction in ethanol
(1.5 mL). After evaporation of the solvent and purification (silica,
hexanes/ethyl acetate, 7:3), compound 10b (244 mg, 0.44 mmol,
1
88%; 91% ds, determined by H NMR spectroscopy) was isolated
as a colourless solid, m.p. 61–65 °C. [α]20 = +3.7 (c = 1.0, CHCl3,
91% ds). Data for the major diastereomer: 1H NMR (CDCl3,
400 MHz): δ = 1.27 (t, J = 7.2 Hz, 3 H), 1.35 (m, 2 H), 1.43 (s, 9
H), 1.65 (m, 2 H), 2.42 (dt, J = 12.9, 7.3 Hz, 1 H), 2.51 (dt, J =
12.5, 6.8 Hz, 1 H), 2. 58 (m, 2 H), 2.75 (m, 2 H), 3.02 (dd, J =
13.6, 8.9 Hz, 1 H), 3.20 (dd, J = 13.6, 5.4 Hz, 1 H), 4.17 (q, J =
7.2 Hz, 2 H), 4.35 (ddd, J = 7.2, 7.2, 5.4 Hz, 1 H), 4.67 (ddd, J =
8.2, 8.2, 5.5 Hz, 1 H), 6.01 (d, J = 7.1 Hz, 1 H), 7.19–7.36 (m, 6
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1, 24.7, 26.9, 27.9,
31.2, 31.5, 34.8, 38.7, 52.5, 54.8, 60.7, 82.6, 115.6 (J = 288 Hz),
127.4, 128.8, 129.2, 135.5, 156.6 (J = 37.7 Hz), 168.7, 170.5,
172.0 ppm. Selected data for the minor diastereomer: 1H NMR
(CDCl3, 400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.47 (s, 9 H),
4.16 (q, J = 7.2 Hz, 2 H), 6.22 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 14.2, 27.9, 34.5, 60.8, 82.8, 135.4 ppm.
C25H35F3N2O6S (548.62): calcd. C 54.73, H 6.43, N 5.11; found C
54.97, H 6.32, N 4.76. HRMS (CI): calcd. for C25H36F3N2O6S [M
+ H]+ 549.2241; found 549.2239.
Boc-L-Ala-(rac)-2-amino-5-(2-hydroxyethylthio)pentanoic-acid-L-
Phe-GlyOMe (13a): According to GP, 2-mercaptoethanol (234 mg,
3.00 mmol) and 12 (252 mg, 0.50 mmol) were subjected to the
thiol-ene click reaction in a mixture of ethanol (2 mL) and THF
(1 mL). After evaporation of the solvent, purification (silica,
CH2Cl2/MeOH, 98:2, 95:5), and lyophilization (acetonitrile/water),
13a (277 mg, 475 μmol, 95%; 1:1 mixture of diastereomers) was
(2R)-tert-Butyl 5-(2-Hydroxyethylthio)-4-methyl-2-[(S)-3-phenyl-2-
(2,2,2-trifluoroacetamido)propanamido]pentanoate (11a): According
to GP, 2-mercaptoethanol (59.0 mg, 756 μmol) and 7[29] (108 mg,
Eur. J. Org. Chem. 2013, 7101–7109
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7107

L. Karmann, U. Kazmaier
FULL PAPER
isolated as a colourless solid, contaminated with the corresponding
thiol (11 mg, 0.14 mmol), m.p. 136–139 °C. 1H NMR (CDCl3,
500 MHz): δ = 1.25 (d, J = 6.9 Hz, 1.5 H), 1.32 (d, J = 7.1 Hz, 1.5
H), 1.37–1.55 (m, 2 H), 1.42 (s, 4.5 H), 1.42 (s, 4.5 H), 1.56–1.86
(m, 2 H), 2.40–2.55 (m, 3 H), 2.63 (t, J = 6.1 Hz, 1 H), 2.65 (t, J
= 6.0 Hz, 1 H), 2.97 (dd, J = 14.3, 8.9 Hz, 0.5 H), 3.00 (dd, J =
14.6, 7.6 Hz, 0.5 H), 3.17 (dd, J = 14.0, 6.2 Hz, 0.5 H), 3.23 (dd, J
= 14.1, 5.6 Hz, 0.5 H), 3.69 (m, 2 H), 3.70 (s, 1.5 H), 3.71 (s, 1.5
H), 3.89–4.06 (m, 2 H), 4.23 (m, 0.5 H), 4.30 (m, 0.5 H), 4.41 (m,
0.5 H), 4.50 (m, 0.5 H), 4.84 (m, 1 H), 5.43 (m, 0.5 H) 5.48 (m, 0.5
H), 7.17–7.48 (m, 8 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
18.6, 18.7, 24.8, 25.1, 28.3, 28.3, 30.8, 31.1, 31.2, 31.4, 34.7, 34.9,
37.8, 38.1, 41.1, 41.3, 50.0, 50.1, 52.2, 52.3, 52.5, 52.9, 54.1, 54.3,
60.8, 61.0, 80.2, 80.2, 126.8, 126.8, 128.5, 128.6, 129.2, 129.3, 136.5,
136.7, 155.6, 155.8, 169.9, 170.3, 171.4, 171.4, 171.5, 171.7, 173.3,
173.3 ppm. HRMS (CI): calcd. for C27H42N4O8S [M]+ 582.2717;
found 582.2718.
196.4 ppm. C27H40N4O8S (580.69): calcd. C 55.85, H 6.94, N 9.65;
found C 55.21, H 6.82, N 9.37. HRMS (CI): calcd. for
C27H41N4O8S [M + H]+ 581.2640; found 581.2670.
Boc-
propanoic-acid-Gly-
L
-2-Amino-3-{4-[3-(2-hydroxyethylthio)propoxy]phenyl}-
-Phe-Gly (15a): According to GP, 2-mercapto-
L
ethanol (234 mg, 3.00 mmol) and 14 (298 mg, 0.50 mmol) were sub-
jected to the thiol-ene click reaction in a mixture of ethanol (2 mL)
and THF (1 mL). After evaporation of the solvent, purification
(silica, CH2Cl2/MeOH, 98:2, 95:5), and lyophilisation (acetonitrile/
water), compound 15a (325 mg, 0.48 mmol, 96%) was isolated as a
colourless solid, contaminated with the corresponding thiol (14 mg,
0.18 mmol), m.p. 109–112 °C. 1H NMR ([D4]methanol, 500 MHz):
δ = 1.37 (s, 9 H), 2.01 (tt, J = 6.9, 6.1 Hz, 2 H), 2.66 (t, J = 6.8 Hz,
2 H), 2.71 (t, J = 7.2 Hz, 2 H), 2.77 (dd, J = 13.9, 9.1 Hz, 1 H),
2.93 (dd, J = 13.8, 9.5 Hz, 1 H), 3.03 (dd, J = 13.9, 5.6 Hz, 1 H),
3.22 (dd, J = 14.0, 5.2 Hz, 1 H), 3.63 (m, 1 H), 3.68 (t, J = 6.8 Hz,
2 H), 3.71 (s, 3 H), 3.90 (m, 3 H), 4.04 (t, J = 6.1 Hz, 2 H), 4.21
(dd, J = 9.1, 5.6 Hz, 1 H), 4.66 (dd, J = 9.1, 5.2 Hz, 1 H), 6.83 (d,
J = 8.6 Hz, 2 H), 7.12 (d, J = 8.6 Hz, 2 H), 7.17–7.21 (m, 1 H),
7.22–7.28 (m, 4 H) ppm. 13C NMR ([D4]methanol, 125 MHz): δ =
28.8, 29.5, 30.7, 35.3, 38.2, 38.7, 42.0, 42.2, 52.7, 56.0, 57.9, 62.5,
67.4, 80.8, 115.6, 127.8, 129.5, 130.4, 130.6, 131.4, 138.5, 157.8,
159.3, 171.4, 171.5, 173.9, 175.1 ppm. HRMS (CI): calcd. for
C28H39N4O7S [M + H]+ 575.2534; found 575.2547.
Boc-
acid-
L
-Ala-(rac)-2-amino-5-(3-ethoxy-3-oxopropylthio)pentanoic-
-Phe-GlyOMe (13b): According to GP, ethyl-3-thiopropion-
L
ate (402 mg, 3.00 mmol) and 12 (252 mg, 0.50 mmol) were sub-
jected to the thiol-ene click reaction in a mixture of ethanol (2 mL)
and THF (1 mL). After evaporation of the solvent, purification
(silica, CH2Cl2/MeOH, 98:2, 95:5), and lyophilization (acetonitrile/
water), 13b (298 mg, 0.47 mmol, 94 %; 1:1 mixture of dia-
stereomers) was isolated as a colourless solid, m.p. 123–127 °C.
1
[α]20 = –27.7 (c = 1.0, CHCl3). H NMR (CDCl3, 500 MHz): δ =
Boc-L-2-Amino-3-{4-[3-(3-ethoxy-3-oxopropylthio)propoxy]phenyl}-
propanoic-acid-Gly-L-Phe-Gly (15b): According to GP, ethyl-3-thio-
1.25 (t, J = 7.1 Hz, 3 H), 1.27 (d, J = 7.1 Hz, 1.5 H), 1.31 (d, J =
7.1 Hz, 1.5 H), 1.41 (s, 4.5 H), 1.42 (s, 4.5 H), 1.35–1.51 (m, 2 H),
1.52–1.83 (m, 2 H), 2.37 (m, 2 H), 2.55 (t, J = 7.3 Hz, 1 H), 2.56
(t, J = 7.3 Hz, 1 H), 2.71 (t, J = 7.2 Hz, 1 H), 2.71 (t, J = 7.5 Hz,
1 H), 2.98 (dd, J = 13.9, 8.7 Hz, 0.5 H), 3.01 (dd, J = 13.7, 8.4 Hz,
0.5 H), 3.23 (dd, J = 14.1, 5.6 Hz, 1 H), 3.10 (s, 1.5 H), 3.71 (s, 1.5
H), 3.89–4.08 (m, 2 H), 4.14 (q, J = 7.2 Hz, 1 H), 4.14 (q, J =
7.1 Hz, 1 H), 4.22 (m, 1 H), 4.35 (m, 1 H), 4.82 (m, 1 H), 5.31 (d,
J = 6.7 Hz, 0.5 H), 5.44 (d, J = 7.4 Hz, 0.5 H), 7.11–7.32 (m, 8 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.2, 14.2, 18.1, 18.6, 24.8,
24.9, 26.8, 26.8, 28.3, 28.3, 30.8, 30.8, 31.5, 31.5, 34.7, 34.8, 37.7,
37.7, 41.1, 41.1, 50.0, 50.3, 52.2, 52.3, 52.7, 53.3, 53.8, 54.2, 60.7,
60.7, 80.0, 80.3, 126.7, 126.9, 128.4, 128.5, 129.1, 129.2, 136.6,
136.7, 155.6, 155.8, 169.9, 170.2, 171.2, 171.2, 171.3, 171.5, 172.0,
172.1, 173.3, 173.5 ppm. C30H46N4O9S (638.77): calcd. C 56.41, H
7.26, N 8.77; found C 56.09, H 7.18, N 8.60. HRMS (CI): calcd.
for C30H46N4O9S [M]+ 638.2980; found 638.2997.
propionate (403 mg, 3.00 mmol) and 14 (298 mg, 0.50 mmol) were
subjected to the thiol-ene click reaction in a mixture of ethanol
(2 mL) and THF (1 mL). After evaporation of the solvent, purifica-
tion (silica, CH2Cl2/MeOH, 98:2, 95:5) and lyophilisation (acetoni-
trile/water), compound 15b (355 mg, 0.49 mmol, 98%) was isolated
as a colourless solid, m.p. 96–102 °C. [α]20 = +0.9 (c = 1.0, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.37
(s, 9 H), 2.02 (m, 2 H), 2.59 (t, J = 7.4 Hz, 2 H) 2.69 (t, J = 7.2 Hz,
2 H), 2.78 (t, J = 7.4 Hz, 2 H), 2.90 (m, 1 H), 2.98–3.04 (m, 2 H),
3.17 (dd, J = 5.6, 13.7 Hz, 1 H), 3.69 (s, 3 H), 3.74 (m, 1 H), 3.87–
4.03 (m, 5 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.36 (m, 1 H), 4.77 (m, 1
H), 5.26 (m, 1 H), 6.79 (d, J = 8.5 Hz, 2 H), 7.01–7.27 (m, 10 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.2, 27.0, 28.2, 28.6, 29.2,
34.8, 37.3, 37.8, 41.4, 43.2, 52.3, 54.3, 55.9, 60.7, 66.1, 80.3, 114.6,
126.9, 128.5, 128.5, 129.2, 130.3, 136.5, 155.7, 157.8, 168.9, 170.1,
171.1, 171.9, 172.5 ppm. C36H50N4O10S (730.87): calcd. C 59.16, H
6.90, N 7.67; found C 59.10, H 6.87, N 7.66. HRMS (CI): calcd.
for C36H51N4O10S [M + H]+ 731.3320; found 731.3338.
Boc-L-Ala-(rac)-5-(acetylthio)-2-aminopentanoic-acid-L-Phe-Gly-
OMe (13c): According to GP, thioacetic acid (228 mg, 3.00 mmol)
and 12 (252 mg, 0.50 mmol) were subjected to the thiol-ene click
reaction in a mixture of ethanol (2 mL) and THF (1 mL). After
evaporation of the solvent, purification (silica, CH2Cl2/MeOH,
98:2, 95:5), and lyophilisation (acetonitrile/water), 13c (287 mg,
0.49 mmol, 98%; 1:1 mixture of diastereomers) was isolated as a
colourless solid, m.p. 151–159 °C. [α]20 = –30.5 (c = 1.0, CHCl3).
Boc-
Gly-
L
-3-{4-[3-(Acetylthio)propoxy]phenyl}-2-aminopropanoic-acid-
L-Phe-Gly (15c): According to GP, thioacetic acid (228 mg,
3.00 mmol) and 14 (298 mg, 0.50 mmol) were subjected to the
thiol-ene click reaction in a mixture of ethanol (2 mL) and THF
(1 mL). After evaporation of the solvent, purification (silica,
CH2Cl2/MeOH, 98:2, 95:5) and lyophilisation (acetonitrile/water),
1H NMR (CDCl3, 500 MHz): δ = 1.25 (d, J = 7.1 Hz, 1.5 H), 1.29 compound 15c (318 mg, 0.47 mmol, 94%) was isolated as a colour-
(d, J = 7.1 Hz, 1.5 H), 1.32–1.53 (m, 2 H), 1.39 (s, 4.5 H), 1.40 (s,
4.5 H), 1.55–1.76 (m, 2 H), 2.27 (s, 3 H), 2.68–2.88 (m, 2 H), 2.95
(dd, J = 14.3, 8.9 Hz, 0.5 H), 2.98 (dd, J = 14.3, 8.4 Hz, 0.5 H),
3.17 (m, 0.5 H), 3.22 (dd, J = 14.2, 5.6 Hz, 0.5 H), 3.68 (s, 3 H),
3.96 (m, 2 H), 4.23 (m, 1 H), 4.37 (m, 0.5 H), 4.45 (m, 0.5 H), 4.81
less solid, contaminated with 14 (18 mg, 0.03 mmol), m.p. 88–
92 °C. H NMR (CDCl3, 500 MHz): δ = 1.35 (s, 9 H), 2.00 (m, 2
H), 2.30 (s, 3 H), 2.87 (m, 1 H), 2.96–3.01 (m, 4 H), 3.15 (dd, J =
13.8, 6.1 Hz, 1 H), 3.67 (s, 3 H), 3.73 (m, 1 H), 3.85–4.00 (m, 5 H),
4.35 (m, 1 H), 4.76 (ddd, J = 9.4, 6.1, 6.1 Hz, 1 H), 5.26 (d, J =
1
(m, 1 H), 5.26 (d, J = 7.0 Hz, 0.5 H), 5.43 (d, J = 7.5 Hz, 0.5 H), 8.8 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 2 H), 7.03–7.08 (m, 4 H), 7.15–
7.13–7.30 (m, 8 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 18.4, 7.25 (m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 25.8, 28.3,
18.7, 25.2, 25.5, 28.2, 28.3, 28.3, 28.4, 30.6, 30.6, 30.9, 31.0, 37.8,
37.9, 41.1, 41.1, 50.0, 50.2, 52.2, 52.3, 52.5, 52.8, 54.0, 54.1, 80.0,
80.2, 126.8, 126.9, 128.4, 128.5, 129.2, 129.2, 136.7, 136.7, 155.6,
155.6, 169.9, 170.2, 171.2, 171.2, 171.3, 171.4, 173.0, 173.3, 195.9,
29.2, 30.6, 37.4, 37.9, 41.1, 43.2, 52.3, 54.3 55.9, 66.1, 80.3, 114.6,
126.9, 128.5, 128.5, 129.2, 130.3, 136.5, 155.7, 157.8, 168.9, 170.1,
171.2, 172.5, 195.8 ppm. HRMS (CI): calcd. for C33H45N4O9S [M
+ H]+ 673.2902; found 673.2908.
7108
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7101–7109

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Acknowledgments
Financial support from the Deutsche Forschungsgemeinschaft
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Received: May 7, 2013
Published Online: September 13, 2013
Eur. J. Org. Chem. 2013, 7101–7109
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7109