Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

Article abstract of DOI:10.1021/acs.joc.8b02759

The synthesis of vinyl sulfones and (α,β-unsaturated) nitriles from carboxylic acids was realized through oxidative decarboxylation with 1,4-dicyanoanthracene as an organic photoredox catalyst. Various types of C-radicals are generated and used to construct three different classes of potential covalent protease inhibitors. The procedure is functional group tolerant and applicable to natural products and druglike scaffolds. It may serve for the rapid construction of screening candidates as demonstrated by a three-step synthesis of the known protease inhibitor K11777.

Full text of DOI:10.1021/acs.joc.8b02759

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Featured Article
Photoredox-Alkenylation of Carboxylic Acids and
Peptides: Synthesis of Covalent Enzyme Inhibitors
Lisa Marie Kammer, Benjamin Lipp, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02759 • Publication Date (Web): 20 Dec 2018
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Photoredox-Alkenylation of Carboxylic Acids and
Peptides: Synthesis of Covalent Enzyme Inhibitors
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Lisa Marie Kammer, Benjamin Lipp, and Till Opatz*
Address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128
Mainz, Germany
Email: opatz@uni-mainz.de
Table of Contents/ Abtract Graphic
CN
HS
SO2Ph
H2N
HO
O
CN
OH
CN
CN
PhO2S
PhO2S
SO2Ph
CN
=
alkyl,
peptide,
steroid
X
one method – three warheads
The synthesis of vinyl sulfones and (α,β-unsaturated) nitriles from carboxylic acids was realized
through oxidative decarboxylation with 1,4-dicyanoanthracene as an organic photoredox
catalyst. Various types of C-radicals are generated and used to construct three different classes
of potential covalent protease inhibitors. The procedure is functional group tolerant and
applicable to natural products and drug-like scaffolds. It may serve for the rapid construction
of screening candidates as demonstrated by a three-step synthesis of the known protease
inhibitor K11777.
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Introduction
An important goal of method development in organic synthesis is to provide selective
transformations with high functional group tolerance. Ideally, new protocols operate under mild
conditions on polyfunctional substrates and permit their derivatization at late synthetic stages.
The chemistry of carbon-centered radicals is currently witnessing a renaissance since it fulfils
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several of these criteria. Here, we present a method which allows the conversion of carboxylic
acids (including peptides) into Michael acceptors of the vinyl sulfone and acrylonitrile type in
a single step.
Vinyl sulfones and their derivatives are valuable intermediates in organic synthesis and versatile
building blocks in medicinal chemistry.2-4 Due to their vinylogous acceptor reactivity, they
readily participate in conjugate additions and cycloadditions.2, 5 In medicinal chemistry, these
so called "warheads" are well known to form covalent bonds with types of cysteine proteases.6-7
Furthermore, vinyl sulfones are key structures in several other bioactive molecules possessing
anticancer and anti-trypanosomal activity.8-9 Traditionally, such substrates have been prepared
through oxidation and β-elimination, Horner-type olefinations or Pd-catalyzed cross
couplings.10-15 However, these methods often suffer from harsh reaction conditions and the use
of strong oxidants or expensive metal catalysts.
Recently, solutions have been reported to overcome these drawbacks.16-21 Most of these
methods rely on free radical strategies and photoredox catalysis may be used to provide radical
species under exceptionally mild reaction conditions.22-23 Based on our interest in bioactive
molecules and decarboxylative transformations of amino acids and peptides,23-26 we sought for
radical vinylsulfonylations of these ubiquitous radical precursors and of carboxylic acids in
general. Although late-stage functionalizations and decarboxylative cross-coupling reactions of
peptides have been in the focus of recent scientific interst,27-30 only very few methods for their
radical vinylsulfonylation could be found in the literature (Scheme 1). In 2016, the groups of
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Deng, Xiang, and Cai reported decarboxylative sulfonylations of cinnamic acids with sulfonyl
radicals derived from either manganese-mediated oxidation of sodium sulfinates or photoredox-
catalyzed oxidative cleavage of sulfonyl hydrazines.16, 21 Since the carboxylic acids are used as
electrophilic radical acceptors, the scope is of course limited to α,β-unsaturated derivatives
preventing the application of these methods to the modification of proteinogenic amino acids
and peptides. For this purpose, the carboxylic acids would have to be the radical precursors. A
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suitable radical acceptor could in this case be (E)-1,2-bis(phenylsulfonyl)ethylene (2), which
furnishes vinyl sulfones upon elimination of stabilized phenyl sulfonyl radicals.31-34 To the best
of our knowledge, this strategy has so far only been applied to the vinylsulfonylation of
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thiohydroxamate esters by Kim et al. in 2004 (Scheme 1b). Decarboxylation is initiated by V-
0 (1,1′-azobis(cyanocyclohexane)) at 110 °C. α-Amino acids and peptides have however not
4
been used as substrates. We thus sought to develop a photoredox-catalyzed protocol for a
related decarboxylative vinylsulfonylation, allowing for the facile and fast construction of
peptidomimetics with an electrophilic warhead which could function as inhibitor of those
enzymes that recognize the parent peptide chain (Scheme 1b). Along the same lines, the use of
(E)-3-phenylsulfonylprop-2-enenitrile (3) as radical trap would lead to acrylonitriles which are
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also found in covalent cysteine proteases inhibitors. Such a one-step procedure could be of
synthetic utility, given that the C-terminal incorporation of a vinyl sulfone warhead into
peptidomimetics is usually achieved in multi-step synthesis. The electrophilic warhead is either
introduced through reduction of the carboxy functionality to the corresponding aldehyde
followed by a Horner-type-olefination with (phenylsulfonyl)methylphosphonate or through the
C-terminal alkyne (again prepared through the aldehyde stage) via alkyne hydrothiolation and
subsequent oxidation.35-37
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Scheme 1. Free-radical strategies for the synthesis of vinyl sulfones.
(a) Decarboxylative sulfonylations using cinnamic acids as radical acceptors
Deng and Xiang et al. 2016[21]
SO2Na
O
S
R1
Mn(OAc)2, DMSO,
air, 110 °C
O
+
R2
CO2H
R2
22 examples,
up to 86% yield
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R1
Cai et al. 2016[16]
O
eosin Y (1 mol%), KI,
Cs CO , O (1 atm),
DMF/H2O, blue LEDs, rt
R1
S
NHNH2
2
3
2
SO2R1
O
R2
+
CO2H
R2
33 examples,
up to 92% yield
(b) Decarboxylative sulfonylations using carboxylic acids and derivatives
as radical source
Kim et al. 2004[19]
CN
N
Decarboxylation of
thiohydroxamate esters
N
CN
V-40 initiator
V-40, Ph-Cl,
O
Me
N
SMe
110 °C
R3
R3
PhO2S
O
+
2
SO Ph
2
SO Ph
8
examples,
S
2
up to 75% yield
This work:
CN
Direct decarboxylation through redox-
mediated singlet state photoredox
catalysis
DCA CN
PhO2S
DCA, biphenyl, K2CO3, R3
MeCN, blue LEDs, rt
SO2Ph
CN
2
SO Ph
O
R3
+
2
or
or
OH
30 examples,
up to 87% yield
R3
PhO2S
CN
3
To achieve the decarboxylative radical generation, 9,10-dicyanoanthracene (DCA) was used as
organic photocatalyst and biphenyl (BP) as a redox mediator. The developed reaction is devoid
of any expensive or toxic reagent and allows for the decarboxylative incorporation of three
different types of warheads under visible light irradiation. It may thus be of value in the search
for new cysteine protease inhibitors and covalent inhibitors of other target enzymes.
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Results and Discussion
Extensive optimization studies were carried out using N-Boc-L-phenylalanine (1a) as model
substrate to produce vinyl sulfone 4a (Supporting Information, Tables S1–S6). Since oxidative
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decarboxylations are quite challenging (e.g. for N(n-Bu) -salt of phenyl-acetic acid:
4


38
E (RCO /RCO ) = +1.27 V vs. SCE) , various strongly oxidizing photocatalysts were
1
/2
2
2
screened (Table S1). The inexpensive organic photocatalyst 1,4-dicyanonaphthalene (DCN,
1


39
E ( [DCN] /DCN ) = +2.42 V vs. SCE, 50 mol-%) provided 4a in 48% yield. This figure
1
/2
could be further increased to 63% when using a threefold excess of the radical precursor,
equimolar amounts K CO and acetonitrile as solvent ([2] = 20 mM, Tables S2–S5). However,
2
3
the excitation of DCN requires high-energy UV-B irradiation which may induce side reactions
1


39
in sensitive substrates. Thus, DCA [E ( [DCA] /DCA ) = +1.99 V vs. SCE] was tested as
1/2
a visible-light absorbing alternative. At the same time, we reasoned that the developed reaction
could benefit from the addition of BP as redox mediator.40-41 Indeed, the use of only 1 mol-%
of DCA in the presence of one equivalent of BP resulted in a 70% yield of 4a under irradiation
with blue light (Table S6). Like most redox mediators, BP is used in stoichiometric amounts
(vide infra) but can easily be recovered via column chromatography in yields ranging from 88–
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9% (Supporting Information, Section IV). Under these optimized conditions, scope and
limitations of the decarboxylative coupling were evaluated (Schemes 2–4).
A variety of natural and unnatural α-amino acids with both acid and base sensitive protective
groups (Cbz, Boc, Fmoc) afforded the desired vinyl sulfones (Scheme 2, 4a–4m) in good yields,
while only the tosyl group seemed less suitable (4e). Due to the mild reaction conditions,
aspartic acid with an ester-protected side chain is well tolerated (4j). The same holds true for
unprotected hydroxy functionalities (4h, 4i and 4k).
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Scheme 2. Scope of the decarboxylative vinyl-sulfonylation.
CN
biphenyl (1.0 equiv.)
O
CN
K CO (3.0 equiv.), MeCN,
2
3
R1
PhO2S
R1
(1 mol%)
rt, blue LEDs, 24 h
SO2Ph

SO2Ph
OH
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1
(3.0 equiv.)
2 (1.0 equiv.)
17 examples, up to 87% yield
4
Cbz
Fmoc
Ts
N
H
SO2Ph
N
H
SO2Ph
N
H
SO2Ph
R
N
H
SO2Ph
4a R= Boc (77%)
b R= Cbz (77%, 75%b)
4c (57%)
4d (73%)
4e (35%)
4
OH
OH
Boc
HO
Fmoc
Fmoc
Fmoc
tBuO
N
H
SO Ph
N
2
SO Ph
N
H
SO2Ph
2
N
SO2Ph
SO2Ph
H
H
4f (65%)
4g (62%)
4h (36%)
4i (54%, 71:29 dr)
Br
BocN
SO2Ph
N
O
N
BocHN
Boc
BocHN
4l (60%)
SO2Ph
BocHN
SO2Ph
4j (70%)
4k (67%, 52:48 dr)
4m (87%)
without -nitrogen
limitations
SO2Ph
SO2Ph
SO2Ph
4n (37%)
SO2Ph
Ph
4s (traces)c
r (traces)c
4
SO2Ph
O
4o (30%)
N
PhO2S
PhO2S
PhO2S
N
4t (n.d.)d
4u (traces)c
CO2Bn
N
Boc
p (10%)
BocHN
4
(S)-4q (17%)
a
Unless stated otherwise, the reactions were performed according to the general procedure.
b
All yields are those of isolated products. The reaction was performed on a 5 mmol scale of
c
d
the limiting reagent 2. detected via HPLC-MS. n.d. = not detected. judged by HPLC-MS.
Aryl bromides are also well tolerated (4m), so that further functionalization through classical
cross-coupling reactions may be used to access more complex target structures. Next, we sought
to extend the scope to precursors of simple alkyl radicals lacking the electron-donating and
radical-stabilizing α-nitrogen atom. As expected, the less stable and less nucleophilic simple
aliphatic radicals did not undergo the intended vinyl-sulfonylation as efficiently as their α-
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amino counterparts. Nevertheless, primary and secondary carboxylic acids furnished the
desired products (4n–4q) in appreciable yields considering the difficulty of such
transformations. This opens up the possibility to functionalize acidic side chains such as present
in aspartic acid (4q). It is also noteworthy that the reaction can easily be performed on a
multigram scale (4.5 g of compound 1a used in a single batch) with no reduction of yield.
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The vinyl sulfone-products are stable under the reaction conditions and substitution of the
second phenyl-sulfonyl group has never been observed. This may be explained by the resulting
vinyl sulfones possessing the largest LUMO-coefficient in -position to the electron-
withdrawing group, which is therefore the preferred site for the attack of nucleophilic C-
centered radicals.42-45 The resulting radical adducts are not able to eliminate a phenyl-sulfonyl
radical and would rather undergo one-electron reduction with subsequent protonation to
4
5
generate the saturated Giese-type products. Given that the starting alkene bears two electron-
withdrawing groups, it should be considerably more reactive towards nucleophilic alkyl
radicals than the produced vinyl sulfones, which also display a higher steric hindrance.
The reported reaction displays some limitations: sterically hindered tertiary radicals are not
suitable reactions partners (4r) while the highly unstable aryl radicals (4u) likely do not form
(Scheme 2). Presumably due to the reversibility of their addition to olefins, highly stabilized
benzylic or allylic radicals are also not amenable to the reported C–C-coupling (4s and 4t).
To further extend the scope of the electrophilic warheads which can be incorporated into
carboxylic acids, (E)-3-phenylsulfonylprop-2-enenitrile (3) was used as radical acceptor
(Scheme 3). Gratifyingly, the corresponding acrylic nitriles (5a–5f) could be obtained in
moderate to high yields (33–70%). Lastly, these acrylic nitriles were further modified to
generate saturated nitriles, a third type of covalent inhibitors. The nitrile function is known to
undergo reversible covalent binding to proteolytic enzymes through the formation of
hemiacetals, thiohemiacetals, imidates or thioimidates with activated serine and cysteine side
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chains. Nitriles 6a and 6b could be obtained in excellent yields by post-functionalization of
the previously prepared acrylic nitriles 5c and 5e.
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Scheme 3. Scope of acrylonitrile-incorporation and hydrogenation towards saturated nitriles.
CN
O
R1
CN (1 mol%)
OH
biphenyl (1.0 equiv.)
1 (3.0 equiv.)
K2CO3 (3.0 equiv.), MeCN,

rt, blue LEDs, 24 h
R1
CN
PhO2S
CN
(1.0 equiv.)
5
examples, 33–70%
5
3
CN
CO2Me
Ph
CbzHN
CN
BocHN
CN
HO
BocHN
CO2Bn
5
a (41%)
5b
(S)-5d (33%)
(53%)
HO
CN
Pd/C, H2
CN
N
N
Boc
c (70%, 52:48 dr)
Boc
5
6a (quant.)
BocN
BocN
N
Pd/C, H2
N
BocHN
e (39%)
CN
BocHN
6b (90%)
CN
5
a
Unless stated otherwise, the reactions were performed according to the general procedure.
All yields are those of isolated products.
Encouraged by the broad scope of the developed reaction, we turned our attention to the late-
stage functionalization of more complex biomolecules to access drug-like scaffolds. Both
peptides (Scheme 4, 4v, 4w, 4y and 5f) and steroids (4x) afforded the desired vinyl sulfones or
acrylic nitriles in good yields. Protection of the hydroxy groups in steroids such as cholic acid
is not required. These examples showcase how the method could be used to rapidly construct a
broad variety of vinyl sulfones and (acrylic) nitriles as lead structures for screening purposes
and initial biological evaluation. To further exemplify the applicability to medicinal chemistry,
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we sought to prepare the potent cysteine protease inhibitor K11777.4, 35, 46 The designed
synthesis provided compound 7 in only three steps and 27% overall yield (diastereomeric
mixture) from Fmoc-L-phenylalanine (see the Supporting Information for more detail). All of
these late-stage functionalization reactions could be accomplished using equimolar mixtures of
the reactants with small reduction in yield (Scheme 4).
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0
1
2
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0
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2
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2
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3
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1
2
3
4
5
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8
9
0
Scheme 4. Functionalization of peptides and steroids.
CN
biphenyl (1.0 equiv.)
CN
O
K CO (1.0–3.0 equiv.), MeCN,
2
3
R1
R1
PhO2S
R2
4: R2 = SO Ph
R2
(1 mol%)
rt, blue LEDs, 24–70 h

OH
2
1
(1.0–3.0 equiv.)
2 or 3 (1.0 equiv.)
: R2 = CN
5
peptides & steroids
SO2Ph
Ph
HO
H
H
H
H
N
SO2Ph
HO
N
SO2Ph
N
CN
CbzHN
H
FmocHN
FmocHN
O
O
O
H
H
one step from
cholic acid
4x (30%)
b
OH
5f (59%, 50%b,
4
v (79%, 69%b,
2:48 dr)
4w (57%, 52% , Ph
54:46 dr)c
H
5
64:36 dr)
3-step synthesis of K11777
i.) 1H-benzotriazole, SOCl2,
THF, -45 °C
then
ii.) L-homophenylalanine, NEt3,
MeCN/H2O/DMSO 6:3:1,
2
SO Ph
H
0
°C  rt
2
PhO S
N
FmocHN
CO2H
FmocHN
51%
O
CO2H
1
y
DCA, biphenyl, K2CO3,
MeCN/H2O 9:1,
c
79% , 6:4 dr
65% after HPLC, 56%b,c
(
)
blue LEDs, rt, 24 h
Ph
O
O
N
H
4 3,
i.) [Bmim][BF ], NEt rt
N
SO2Ph
then
ii.) NEt3, abs. THF, 0 °C  rt
Cl
CH3
N
H
N
H3C
O
H
H
N
7
Ph
N
N
FmocHN
6
0:40 dr
Cl
O
(S)-(S)-7= K11777
cysteine protease inhibitor
81%, 6:4 dr
4y
SO2Ph
a
Unless stated otherwise, the reactions were performed according to the general procedure.
All yields are those of isolated products. 1.00 equiv. of acid and base was used. c
b
d
MeCN/H O (9:1) as solvent. After preparative HPLC.
2
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A mechanistic proposal for the designed vinylsulfonylation is depicted in Scheme 5 and most
probably also applies to the analogous synthesis of acrylic nitriles. Upon excitation (λmax
=
*
422 nm, see Figure S2), DCA is converted to its first excited singlet state (S ), which has a
1
4
7
*
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
lifetime of approximately 15 ns in nitrogen-saturated acetonitrile. As a rule of thumb, the S -
1
lifetime only needs to be longer than 1 ns for productive single-electron transfer (SET) to occur
and DCA displays extremely inefficient intersystem crossing (φISC  0.01 in acetonitrile).1, 48
*
Thus, the described reaction is most likely mediated by the S -state of DCA. The latter is
1
1

 
39
known to be strongly oxidizing (E ( [DCA] /DCA ) = +1.99 V vs. SCE) and can easily
1
/2


accept an electron from the carboxylate (for Boc-Pro-OCs: E (RCO /RCO ) = +0.95 V vs.
1
/2
2
2
SCE).49
Scheme 5. Proposed reaction mechanism.
O 1
2
SO2Ph

CO2
R
V
O
9
.
PhO2S
0
redox

R
mediation
1´
BP
V
5
direct
decarboxylation
CO2
9
BP 
.
1
1[DCA]


R
SO2Ph

0.9 V

1.99 V
O
PhO2S
R
2´
O
1
DCA 
h
R
SO2Ph
1
SO2Ph
0.91 V
3
0.50 V
DCA

CN
CN
SO2Ph
lifetime:  15 ns
s-range
Indeed, fluorescence quenching studies (Figure 1) prove that excited DCA is quenched
efficiently by the carboxylate while it is not quenched by alkene 2. As mentioned previously,
the designed reaction benefitted significantly from the addition of BP as redox mediator


(Supporting Information, Table S6). According to the oxidation potential of BP (E (BP /BP)
1
/2
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=
+1.95 V vs. SCE) , reductive quenching of DCA by this hydrocarbon is thermodynamically
1
feasible and the fluorescence of the catalyst is quenched efficiently by BP (Figure 1). The


radical cation BP may then induce oxidative decarboxylation of the carboxylate resulting in
nucleophilic alkyl radicals, which were trapped by TEMPO providing further evidence for the
proposed mechanism (Supporting Information, Scheme S4). The radicals 1’ are readily trapped
by the electron-deficient alkene 2.32 In contrast to the usual conjugate addition , this is not
followed by one-electron reduction of intermediate 2´, but by the elimination of a stabilized
1
1
1
1
1
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1
1
1
1
2
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2
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0
1
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9
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0
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9
0
45
phenylsulfonyl radical.51-54 These radicals are then easily reduced (E (PhO S /PhO S ) =


1
/2
2
2
5
1

55
+0.50 V vs. SCE) by the radical anion of DCA (E (DCA/DCA ) = –0.91 V vs. SCE) ,
1
/2
thereby completing the catalytic cycle.
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Figure 1. Flourescence quenching studies and Stern-Volmer plots.
0
1
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-6
Fluorescence quenching of DCA (1 × 10 M in MeCN) by biphenyl (BP, top left), Boc-Phe-
OCs (Carboxylate, top right), and (E)-1,2-bis(phenylsulfonyl)ethene (Alkene 2, bottom left)
upon excitation at 422 nm. Stern-Volmer plots derived from these data at 432 nm emission.
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Control experiments (Supporting Information, Table S7) revealed that the addition of BP results
in much shorter reaction times (complete conversion after 24 h compared to 72 h) as well as a
higher overall yield (70% compared to 59%), potentially by suppressing side reactions. There
are mainly two reasons for the positive effect of BP: (1) Oxidative decarboxylation occurs from
the carboxylate rather than from the protonated carboxylic acid (for phenylacetic acid:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
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1
2
3
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5
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9
0


38
E (RCO /RCO H = +2.51 V vs. SCE)
and therefore, photoredox-catalyzed
1/2
2
2
decarboxylative couplings are usually performed in the presence of a base. As the potassium
carboxylates are poorly soluble in acetonitrile, the concentration of these species in the reaction
solution is presumably low. Given the relatively short lifetime of DCA´s S
*-state and the low
1
quencher concentration, the quantum yield of such a reaction will most probably be poor.
In contrast to the carboxylates, BP is perfectly soluble in the reaction medium, thereby
increasing the likelihood of the excited catalyst encountering a suitable reaction partner within
its lifetime. The radical cation of BP has a much longer lifetime (for a related DCA/BP system


in argon-saturated acetonitrile, the half-life of BP was reported to be 2 µs as judged by
5
6
*-state, which is favorable for the consecutive
transient absorption spectra ) than DCA´s S
1
oxidative decarboxylation.40
The original quencher can be outcompeted by using
4
0
stoichiometric amounts of the redox mediator. (2) Electron transfer from the excited catalyst
to its quencher results in a close radical (ion) pair. These odd-electron species may then either
diffuse apart and undergo further transformations or they may immediately back-exchange the
electron and reform the ground state species. This event is referred to as back electron transfer
(BET) and the main reason for the low quantum yields of most photoredox-catalyzed
transformations.39 Assuming that BET is operating in the Marcus-inverted region where



increased exergonicity results in a lower rate constant, BET from BP to DCA should be
slower than from the oxidized carboxylate.57-58 A more detailed mechanistic discussion is
included in the SI (Supporting Information, chapter IV).
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Conclusion
In summary, an efficient visible light-induced decarboxylative synthesis of vinyl sulfones or
acrylic) nitriles from structurally diverse carboxylic acids, including peptides and steroids, is
(
0
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reported. The developed method is operationally simple, transition-metal free, and can be
performed on a multigram scale. It should be of value for the fast construction of potential
cysteine protease inhibitors or other biologically active compounds for screening purposes. The
method will likely allow the introduction of further substituents into the warheads and thus is
ideally suited for the synthesis of reactive electrophiles at a late synthetic stage.
Experimental Section
General:
Unless stated otherwise, all solvents and reagents were obtained from commercial suppliers and
used
without
prior
purification.
9,10-Dicyanoanthracene,
trans-1,2-
bis(phenylsulfonyl)ethylene biphenyl were purchased from commercial suppliers and used
without further purification. trans-3-Phenylsulfonylprop-2-enenitrile was synthesized
5
9
according to a literature procedure. Solvents for irradiations were degassed in an ultrasonic
bath by argon sparging for 20 min. Reactions requiring anhydrous conditions were performed
in dried glassware under an atmosphere of argon. Chromatographic purification of products
was performed as flash column chromatography on silica gel (35–70 µm, Acros Organics)
according to the procedure by Still or with a computerized automatic purification system with
60
gradient elution capability and an integrated diode array detector. Thin-layer chromatography
(TLC) was carried out on silica plates (TLC Silica 60 F254, Merck). Visualization of the
compounds was accomplished by projecting UV-light onto the developed plates and by
potassium permanganate or ninhydrin stain. Analytical HPLC was performed on a system with
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a binary pump and a diode array detector. An ACE C18 PFP column (150 x 4.6 mm, 3 µm,
4
0 °C, flow: 1 mL/min) was used. Preparative HPLC was carried out using acetonitrile and
water as eluents on an ACE 5 C18 PFP column (150 x 30 mm) with a flow rate of 37.5 mL/min.
NMR spectra were recorded on high resolution spectrometers equipped with 5 mm probe heads
using standard pulse sequences. Chemical shifts are referenced to residual solvent signals
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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5
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0
1
2
3
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5
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8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
13
(
CDCl : 7.26 ppm and 77.16 ppm, DMSO-d : 2.50 ppm and 39.52 ppm for H-NMR and C-
3
6
NMR respectively) and reported in parts per million (ppm) relative to tetramethylsilane (TMS).
Multiplicities of NMR signals are abbreviated as follows: br = broad, s = singlet, d = doublet, t
=
triplet, q = quartet, m = multiplet and combinations thereof, app = apparent. Infrared (IR-)
spectra were recorded on an FTIR-spectrometer equipped with a diamond ATR unit and are
–1
reported in terms of frequency of absorption 휈 [cm ]. UV-Vis spectra and fluorescence spectra
were recorded on commercial instruments using 10 mm quartz cuvettes. For the fluorescence
spectra, a cuvette with a septum-screw cap was used. The cuvette was flushed with argon before
the sample was injected, followed by argon sparging for 30 seconds. Electrospray ionization
(ESI) mass spectra were recorded on a commercial LCMS-system with a binary pump and
integrated diode array detector coupled to an ion trap mass spectrometer or on a Q-TOF mass
spectrometer. High resolution mass spectra were recorded on the same Q-TOF instrument using
a multiplexing source and a suitable external calibrant. Melting points were determined in open
capillary tubes using a thermoelectric melting point meter. Optical rotations were determined
using at the wavelength of the sodium D-line (λ = 589 nm). 푎temp-values are reported at a certain
D
temperature (temp) and all concentrations are given in g/100 mL.
Synthesis of vinyl sulfones
General Procedure for irradiations on a preparative scale:
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2
2
2
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A 25 mL round-bottom flask equipped with a magnetic stir bar and a septum was charged with
the carboxylic acid (1, 0.9 mmol, 3.00 equiv.), (E)-1,2-bis(phenylsulfonyl)ethylene (2,
0.3 mmol, 1.00 equiv.), potassium carbonate (124.2 mg, 0.9 mmol, 3.00 equiv.), as well as
0
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9
,10-dicyanoanthracene (1.36 mg, 3 µmol, 1 mol%) and biphenyl (46.6 mg, 0.3 mmol, 1.00
equiv.). The flask was flushed with argon, followed by the addition of degassed acetonitrile
16 mL, see section I). After argon sparging for 1 min the solution was irradiated for 24 h with
(
a 34 W Kessil A150W Deep Ocean Blue LED (distance bulb–sample approximately 5 cm). The
reaction mixture was diluted with DCM (20 mL) and extracted with saturated, aqueous
NaHCO solution (2 x 15 mL) and brine (1 x 15 mL). The organic layer was dried over MgSO
3
4
and concentrated in vacuo. Flash column chromatography afforded the desired products.
tert-Butyl[(3E)1-phenyl-4-(phenylsulfonyl)but-3-en-2-yl]carbamate (4a). This compound
was prepared according to the general procedure using Boc-L-phenylalanine (1a, 239 mg,
c
0
.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc 6:1) afforded the
2
c
1
title compound (89.0 mg, 231 µmol, 77%) as a colorless oil. R : 0.22 ( Hex/EtOAc 5:1), H-
f
NMR, COSY (600 MHz, CDCl ): δ/ppm = 7.81 (d, J = 7.7 Hz, 2H, H -2, H -6), 7.66–7.58
3
Ar
Ar
(
m, 1H, H -4), 7.52 (app t, J = 7.7 Hz, 2H, H -3, H -5), 7.28–7.25 (m, 2H, H -3’, H -5’),
Ar Ar Ar Ar Ar
7
.24–7.21 (m, 1H, H -4’), 7.15–7.07 (m, 2H, H -2’, H -6’), 6.94 (dd, J = 15.1, 4.9 Hz, 1H,
Ar Ar Ar
H-3), 6.31 (dd, J = 15.1, 1.7 Hz, 1H, H-4), 4.67 (s, 1H, H-2), 4.49 (d, J = 8.5 Hz, 1H, NH), 2.91
1
3
(
d, J = 6.8 Hz, 2H, H-1), 1.35 (s, 9H, CH ), C-NMR, HSQC, HMBC (151 MHz, CDCl ):
3
3
δ/ppm = 154.8 (C=O), 145.9 (C-3), 140.1 (SO C ), 135.7 (C ’ ), 133.6 (C -4), 130.9 (C-4),
2
q
Ar q
Ar
1
29.5 (C -2’, C -6’), 129.4 (C -3, C -5), 128.8 (C -3’, C -5’), 127.8 (C -2, C -6), 127.3
Ar Ar Ar Ar Ar Ar Ar Ar
–
1
(C -4’), 80.4 (C ), 52.0 (C-2), 40.6 (C-1), 28.3 (CH ), IR: 휈 [cm ] = 3334, 3062, 1733, 1584,
Ar
q
3
+
1
447, 1245, 1145, 1079, 788, 695, ESI-MS: m/z = 410.2 (100%, [M+Na] , calc. 439.2). The
analytical data are consistent with those reported in the literature.61
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Benzyl[(1E)-4-phenyl-1-(phenylsulfonyl)prop-1-en-2-yl]carbamate (4b). This compound
was prepared according to the general procedure using Cbz-L-phenylalanine (1b, a) 134 mg,
0.9 mmol, b) 4.5 g, 15 mmol, 3.00 equiv.) and trans-1,2-bis(phenylsulfonyl)ethylen (a) 93 mg,
c
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
4
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5
5
5
5
5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
4
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7
8
9
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2
3
4
5
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7
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9
0
0
.3 mmol, b) 1.5 g, 5 mmol, 1.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc,
2
gradient from 0% to 45% EtOAc in 10 min, product elutes at 40% EtOAc) afforded the title
c
1
compound (98.0 mg, 231 µmol, 77%) as a colorless oil. R : 0.35 ( Hex/EtOAc 3:1), H-NMR,
f
COSY (300 MHz, CDCl ): δ/ppm = 7.82–7.79 (m, 2H, H -2, H -6), 7.65–7.60 (m, 1H, H -
3
Ar
Ar
Ar
4
), 7.55–7.50 (m, 2H, H -3, H -5), 7.34–7.31 (m, 3H, H -2’’, H -4’’, H -6’’), 7.27–7.23
Ar Ar Ar Ar Ar
(
m, 5H, H -3’, H -4’, H -5’, H -3’’, H -5’’), 7.10–7.07 (m, 2H, H -2’, H -6’), 6.95 (dd,
Ar Ar Ar Ar Ar Ar Ar
J = 15.1, 4.7 Hz, 1H, H-2), 6.32 (dd, J = 15.1, 1.6 Hz, 1H, H-1), 5.03 (s, 2H, CH O), 4.83–4.75
2
13
(
m, 2H, NH, H-3), 2.92 (d, J = 6.4 Hz, 2H, H-4), C-NMR, HSQC, HMBC (75 MHz, CDCl ):
3
δ/ppm = 155.4 (C=O), 145.4 (C-2), 140.1 (SO C ), 136.1 (C ’’ ), 135.4 (C ’ ), 133.6 (C -4),
2
q
Ar
q
Ar q
Ar
1
5
5
6
31.1 (C-1), 129.5 (C -2, C -6, C -2’’, C -6’’), 129.4 (C -2’, C -6’), 128.9 (C -3’, C -
Ar Ar Ar Ar Ar Ar Ar Ar
’), 128.7 (C -4’’), 128.4 (C -3’’, C -5’’), 127.8 (C -2, C -6), 127.4 (C -4’), 67.2 (CH O),
Ar
Ar
Ar
Ar
Ar
Ar
2
–
1
2.4 (C-3), 40.5 (C-4), IR: 휈 [cm ] = 3334, 3062, 3031, 1703, 1497, 1245, 1145, 1085, 749,
+
98, ESI-MS: m/z = 439.4 (100%, [M+NH ] , calc. 439.5). The analytical data are consistent
4
with those reported in the literature.62
Benzyl[(1E)-4-phenyl-1-(phenylsulfonyl)but-3-en-2-yl]carbamate (4c). This compound
was prepared according to the general procedure using Cbz-L-alanine (1c, 100 mg, 0.90 mmol,
c
3
.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc, gradient from 0% to 45%
2
EtOAc in 10 min, product elutes at 40% EtOAc) afforded the title compound (59.0 mg,
c
1
1
71 µmol, 57%) as a colorless oil. R : 0.12 ( Hex/EtOAc 8:1), H-NMR, COSY (300 MHz,
f
CDCl ): δ/ppm = 7.94–7.90 (m, 3H, H -2, H -6, H -3’), 7.68–7.61 (m, 2H, H -4, H -5’),
3
Ar
Ar
Ar
Ar
Ar
7
1
8
.58–7.53 (m, 2H, H -3, H -5), 7.39–7.34 (m, 3H, H -2’’, H -4’’, H -6’’), 6.95 (dd, J =
Ar Ar Ar Ar Ar
5.1, 4.6 Hz, 1H, H-2), 6.44 (dd, J = 15.1, 1.7 Hz, 1H, H-1), 5.09 (s, 2H, CH O), 4.83 (d, J =
2
1
3
.3 Hz, 1H, NH), 4.55 (brs, 1H, H-3), 1.33 (d, J = 7.0 Hz, 3H, CH ), C-NMR, HSQC, HMBC
3
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4
4
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5
5
5
5
5
6
(
75 MHz, CDCl ): δ/ppm = 155.4 (C=O), 145.0 (C-2), 140.5 (SO C ), 135.1 (C ’ ), 133.6 (C -
3
2
q
Ar q
Ar
4
), 130.2 (C-1), 129.5 (C -3, C -5), 128.7 (C -2’, C -6’), 128.6 (C -3’, C -5’), 128.3 (C -
Ar Ar Ar Ar Ar Ar Ar
–
1
4’), 127.8 (C -2, C -6), 67.2 (CH O), 47.3 (C-3), 20.2 (CH ), IR: 휈 [cm ] = 3350, 3035, 1716,
Ar
Ar
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
584, 1308, 1145, 1050, 780, 750, 598, ESI-MS: m/z = 363.3 (100%, [M+NH ] , calc. 363.5),
4
+
+
ESI-HRMS: m/z: [M+Na] calc. for [C H NNaO S] : 368.0927, found: 368.0921.
1
8
19
4
9
H-Fluoren-9-ylmethyl[(1E)-4-methyl-1-(phenylsulfonyl)pent-1-en-3yl]carbamate (4d).
This compound was prepared according to the general procedure using Fmoc-L-valine (1d,
c
305 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc, gradient
2
from 0% to 45% EtOAc in 10 min, product elutes at 30% EtOAc) afforded the title compound
c
1
(139 mg, 220 µmol, 73%) as a colorless oil. R : 0.35 ( Hex/EtOAc 3:1), H-NMR, COSY (300
f
MHz, CDCl ): δ/ppm = 7.86 (d, J = 7.7 Hz, 2H, H -2,H -6), 7.75 (d, J = 7.5 Hz, 2H, H ’),
3
Ar
Ar
Ar
7
.61–7.58 (m, 5H, H -3, H -5, H ’), 7.41–7.37 (m, 2H, H ’), 7.32–7.28 (m, 2H, H ’), 6.93
Ar Ar Ar Ar Ar
(dd, J = 15.1, 5.1 Hz, 1H, H-2), 6.39 (dd, J = 15.1, 1.8 Hz, 1H, H-1), 4.84 (d, J = 9.2 Hz, 1H,
NH), 4.48–4.40 (m, 2H, CH O), 4.30–4.28 (m, 1H, H-3), 4.15 (t, J = 6.7 Hz, 1H, H-CH O),
2
2
1
3
1
.93–1.87 (m, 1H, H-4), 0.93–0.88 (m, 6H, (CH ) ), C-NMR, HSQC, HMBC (75 MHz,
3 2
CDCl ): δ/ppm = 155.8 (C=O), 145.3 (C-2), 143.8 (C ’ ), 141.4 (C ’ ), 140.2 (SO C ), 135.1
3
Ar q
Ar q
2
q
(C ’ ), 133.6 (C -4), 131.4 (C-1), 129.4 (C -3, C -5), 127.9 (C -2, C -6), 127.7 (C ’H),
Ar q Ar Ar Ar Ar Ar Ar
127.2 (C ’H), 124.9 (C ’H), 120.1 (C ’H), 66.8 (CH O), 56.9 (C-4), 32.4 (C-5), 19.0 (CH ),
Ar
Ar
Ar
2
3
–1
1
8.1 (CH ), IR: 휈 [cm ] = 3351, 3046, 2962, 1704, 1524, 1465, 1307, 1232, 1145, 757, ESI-
3
+
+
MS: m/z = 479.3 (100%, [M+NH ] , calc. 479.4), ESI-HRMS: m/z: [M+Na] calc. for
4
+
[C H NNaO S] : 484.1553, found: 484.1546.
2
7
27
4
4-Methyl-N-[(1E)-5-methyl-1-(phenylsulfonyl)hex-1-en-3-yl]benzenesulfonamide
(4e).
This compound was prepared according to the general procedure using p-tosyl-L-leucine (1e,
c
2
57 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc, gradient
2
from 0% to 100% EtOAc in 10 min, product elutes at 40% EtOAc) afforded the title compound
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c
1
(
43.0 mg, 105 µmol, 35%) as a colorless oil. R : 0.17 ( Hex/EtOAc 5:1), H-NMR, COSY (300
f
MHz, CDCl ): δ/ppm = 7.80–7.76 (m, 2H, H -2, H -6), 7.66–7.60 (m, 3H, H -4, H ’-2,
3
Ar
Ar
Ar
Ar
H ’-6), 7.56–7.50 (m, 2H, H -3, H -5), 7.20–7.17 (m, 2H, H ’-3, H ’-5), 6.73 (dd, J = 15.0,
Ar
Ar
Ar
Ar
Ar
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
.6 Hz, 1H, H-2), 6.31 (dd, J = 15.0, 1.4 Hz, 1H, H-1), 4.90 (d, J = 7.8 Hz, 1H, NH), 4.01 (tddd,
J = 7.8, 6.9, 5.6, 1.4 Hz, 1H, H-3), 2.38 (s, 3H, Ar-CH ), 1.62–1.53 (m, 1H, H-5), 1.35–1.30
3
1
3
(
m, 2H, H-4), 0.81 (d, J = 6.6 Hz, 3H, CH ), 0.73 (d, J = 6.6 Hz, 3H, CH ), C-NMR, HSQC,
3
3
HMBC (75 MHz, CDCl ): δ/ppm = 145.66 (C-2),144.0 (C ’ -4), 140.0 (SO C ), 137.4
3
Ar q
2
q
(
SO C’ ), 133.6 (C -4), 131.1 (C-1), 129.9 (C ’-3, C ’-5), 129.4 (C -3, C -5), 127.9 (C -
2 q Ar Ar Ar Ar Ar Ar
2
, C -6), 127.0 (C ’-2, C ’-6), 52.5 (C-3), 44.1 (C-4), 24.4 (C-5), 22.7 (CH ), 21.8 (CH ),
Ar Ar Ar 3 3
–
1
21.7 (Ar-CH ), IR: 휈 [cm ] = 3287, 2961, 2901, 1597, 1318, 1146, 1082, 815, 749, 667, ESI-
3
+
+
MS: m/z = 425.2 (100%, [M+NH ] , calc. 425.6), ESI-HRMS: m/z: [M+Na] calc. for
4
+
[C H NNaO S ] : 430.1117, found: 430.1117.
2
0
25
4 2
9
H-Fluoren-9-ylmethyl[(1E)-5-methyl-1-(phenylsulfonyl)hex-1-en-3-yl]carbamate (4f).
This compound was prepared according to the general procedure using Fmoc-L-leucine (1f,
c
3
18 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc, gradient
2
from 0% to 100% EtOAc in 10 min, product elutes at 25% EtOAc) afforded the title compound
c
1
(
93.0 mg, 195 µmol, 65%) as a yellow oil. R : 0.32 ( Hex/EtOAc 3:1), H-NMR, COSY (300
f
MHz, CDCl ): δ/ppm = 7.88 (d, J = 7.8 Hz, 2H, H -2,H -6), 7.78 (d, J = 7.5 Hz, 2H, H ’),
3
Ar
Ar
Ar
7
6
.59–7.50 (m, 5H, H -3, H -4, H -5, H ’), 7.44–7.38 (m, 2H, H ’), 7.32–7.28 (m, 2H, H ’),
Ar Ar Ar Ar Ar Ar
.92 (dd, J = 15.0, 4.9 Hz, 1H, H-2), 6.41 (dd, J = 15.0, 1.4 Hz, 1H, H-1), 4.79 (d, J = 8.8 Hz,
1H, NH), 4.50–4.39 (m, 3H, H-3, CH O), 4.17 (t, J = 6.7 Hz, 1H, H-CH O), 1.64–1.58 (m, 1H,
2
2
13
H-5), 1.43 (pseudot, J = 7.3 Hz, 2H, H-4), 0.93 (d, J = 6.7 Hz, 6H, (CH ) ), C-NMR, HSQC,
3
2
HMBC (75 MHz, CDCl ): δ/ppm = 155.6 (C=O), 146.8 (C-2), 143.8 (C ’ ), 141.4 (C ’ ),
3
Ar q
Ar q
1
40.2 (SO C ), 133.6 (C -4), 130.2 (C-1), 129.4 (C -3, C -5), 127.8 (C ’H) 127.7 (C -2,
2 q Ar Ar Ar Ar Ar
C -6), 127.2 (C ’H), 125.0 (C ’H), 120.1 (C ’H), 66.7 (CH O), 49.9 (C-3), 47.3 (CH), 43.4
Ar
Ar
Ar
Ar
2
–
1
(
CH ), 24.8 (CH(CH ) ), 22.9 (CH ), 21.9 (CH ), IR: 휈 [cm ] = 3349, 3065, 2957, 2870, 1714,
2
3 2
3
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+
1
523, 1286, 1145 757, 736, ESI-MS: m/z = 493.4 (100%, [M+NH ] , calc. 493.5), ESI-HRMS:
4
+
+
m/z: [M+Na] calc. for [C H NNaO S] : 498.1710, found: 498.1710.
2
8
29
4
tert-Butyl[(1E)-4-dimethyl-1(phenylslfonyl)pent-1-en-3-yl]carbamate (4g). This compound
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was prepared according to the general procedure using N-Boc-L-tert-leucine (1g, 208 mg,
c
0
.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc 5:1) afforded the
2
c
1
title compound (66.0 mg, 185 µmol, 62%) as a colorless oil. R : 0.24 ( Hex/EtOAc 8:1), H-
f
NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.87–7.84 (m, 2H, H -2,H -6), 7.60–7.57 (m, 1H,
3
Ar
Ar
H -4), 7.54–7.49 (m, 2H, H -3, H -5), 6.99 (dd, J = 15.0, 5.7 Hz, 1H, H-2), 6.43 (dd, J =
Ar
Ar
Ar
1
5.0, 1.6 Hz, 1H, H-1), 4.61 (d, J = 9.9 Hz, 1H, NH), 4.21 (dd, J = 9.9, 5.7 Hz, 1H, H-3), 1.36
1
3
(
s, 9H, OC(CH ) ), 0.93 (s, 9H, (CH ) ), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm
3 3 3 3 3
= 155.3 (C=O), 144.4 (C-2), 140.4 (SO C ), 133.5 (C -4), 131.7 (C-1), 129.4 (C -3, C -5),
2
q
Ar
Ar
Ar
–1
1
27.7 (C -2, C -6), 80.1 (C ), 59.7 (C-3), 28.3 (CH ) 26.4 (CH ), IR: 휈 [cm ] = 2967, 1697,
Ar
Ar
q
3
3
+
1
447, 1145, 1055, 908, 842, 727, 686, 572, ESI-MS: m/z = 376.4 (100%, [M+Na] , calc. 376.5),
+
+
ESI-HRMS: m/z: [M+Na] calc. for [C H NNaO S] : 376.1553, found: 376.1547.
18 27
4
9
H-Fluoren-9-ylmethyl[(1E,4R)-4-hydroxy-1-(phenylsulfonyl)but-1-en-3-yl]carbamate
(
4h). This compound was prepared according to the general procedure using Fmoc-L-serine
c
(
1h, 513 mg, 0.9 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc 1:1)
2
c
afforded the title compound (50.0 mg, 108 µmol, 33%) as a yellow oil. R : 0.20 ( Hex/EtOAc
f
1
1:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.88 (d, J = 7.4 Hz, 2H, H -2, H -6), 7.75
3
Ar
Ar
(
dd, J = 7.6, 1.0 Hz, 2H, H ’), 7.58–7.53 (m, 5H, H -3, H -4, H -5, H ’), 7.40–7.36 (m, 2H,
Ar Ar Ar Ar Ar
H ’), 7.30–7.27 (m, 2H, H ’), 6.99 (dd, J = 15.1, 4.6 Hz, 1H, H-2), 6.50 (dd, J = 15.2, 1.3 Hz,
Ar
Ar
1H, H-1), 5.45 (d, J = 8.6 Hz, 1H, NH), 4.53–4.50 (m, 1H, H-3), 4.43 (brs, 1H, OH), 4.40 (d, J
13
=
7.0 Hz, 2H, OCH ), 4.14 (t, J = 7.0 Hz, 1H, H-CH O), 3.76 (brs, 2H, H-4), C-NMR, HSQC,
2
2
HMBC (75 MHz, CDCl ): δ/ppm = 156.0 (C=O), 143.8 (C-2), 143.7 (C ’ ), 141.4 (C ’ ),
3
Ar q
Ar q
1
39.9 (SO C ), 133.8 (C -4), 132.2 (C-1), 129.6 (C -3, C -5), 127.9 (C -2, C -6), 127.8
2 q Ar Ar Ar Ar Ar
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(
C ’H), 127.2 (C ’H), 125.1 (C ’H), 120.2 (C ’H), 67.1 (CH O), 63.8 (C-4), 53.3 (C-3),
Ar
Ar
Ar
Ar
2
–
1
4
7.3 (CH), IR: 휈 [cm ] = 3359, 3063, 2946, 1709, 1632, 1522, 1306, 1146, 1084, 758, ESI-
+
+
MS: m/z = 474.2 (100%, [M+Na] , calc. 474.2), ESI-HRMS: m/z: [M+Na] calc. for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[C H NNaO S] : 472.1189, found: 472.1197.
2
5
23
5
9
H-Fluoren-9-ylmethyl[(1E,4R)-4-hydroxy-1-(phenylsulfonyl)pent-1-en-3-yl]carbamate
(4i). This compound was prepared according to the general procedure using Fmoc-L-threonine
c
(1i, 307 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc,
2
gradient from 0% to 100% EtOAc in 10 min, product elutes at 40% EtOAc) afforded the title
compound as a diastereomeric mixture (dr = 71:29 determined by analytical HPLC, 75.0 mg,
c
1
1
62 µmol, 54%) as a yellow oil. R : 0.29 ( Hex/EtOAc 1:1), H-NMR, COSY (400 MHz,
f
CDCl ): for both diastereomers A) and B) δ/ppm = 7.87 (d, J = 7.7 Hz, 4H, A) H -2,H -6, B)
3
Ar
Ar
H -2, H -6), 7.79 (d, J = 7.7 Hz, 2H, A) H ’), 7.75 (d, J = 7.7 Hz, 2H, B) H ’), 7.60–7.51
Ar
Ar
Ar
Ar
(m, 8H, A) H -3, H -4, H -5, H ’, B) H -3, H -4, H -5, H ’), 7.42–7.34 (m, 4H, A) H ’,
Ar Ar Ar Ar Ar Ar Ar Ar Ar
B) H ’), 7.29–7.24 (m, 4H, A) H ’, B) H ’), 7.07 (dd, J = 15.2, 4.5 Hz, 1H, A) H-2), 7.00
Ar
Ar
Ar
(dd, J = 15.1, 4.5 Hz, 1H, B) H-2), 6.54 (dd, J = 15.2, 1.3 Hz, 1H, A) H-1), 6.49 (dd, J = 15.1,
1
.3 Hz, 1H, B) H-1), 5.52 (d, J = 8.9 Hz, 1H, A) NH), 5.43 (d, J = 9.0 Hz, 1H, B) NH), 4.46–
.36 (m, 4H, A) CH O, H-3, B) CH O, H-3), 4.25 (t, J = 6.8 Hz, 1H, A) H-CH O), 4.15 (t, J =
4
2
2
2
6.8 Hz, 1H, B) H-CH O), 4.04 (brs, 2H, A) H* B) H*), 2.42 (brs, 1H, B) OH), 2.35 (brs, 1H,
2
13
A) OH), 1.21 (s, 3H, B) CH ), 1.19 (s, 3H, A) CH ), C-NMR, HSQC, HMBC (100.1 MHz,
3
3
CDCl ): δ/ppm = 156.4/156.0 (C=O), 144.9 (C-2), 143.8/143.6 (C ’ ), 141.5/141.4 (C ’ ),
3
Ar q
Ar q
140.2/139.9 (SO C ), 134.1/133.8 (C -4), 131.9 (C-1), 129.5 (C -3, C -5), 128.4 (C ’H),
2
q
Ar
Ar
Ar
Ar
1
28.1 (C ’H), 127.9/127.8 (C -2, C -6), 127.3/127.2 (C ’H), 125.1 (C ’H), 120.2/120.1
Ar Ar Ar Ar Ar
(C ’H), 68.8/68.5 (C*H), 67.1/67.0 (CH O), 56.9/55.0 (C-3), 47.3 (CHCH O), 21.6 (CH ),
Ar 2 2 3
–
1
25
2
0.6 (CH ), IR: 휈 [cm ] = 3359, 3063, 2974, 2930, 1707, 1522, 1378, 1146, 1106, 758, [α] D:
3
+
+
6.8 (c = 1.0 g/100 mL, CHCl ), ESI-MS: m/z = 481.3 (100%, [M+NH ] , calc. 481.3), ESI-
3
4
+
+
HRMS: m/z: [M+Na] calc. for [C H NNaO S] : 486.1346, found: 486.1347.
2
6
25
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tert-Butyl(4E)-3[(tert-butoxycarbonyl)amino]-5-(phenylsulfonyl)pent-4-enoate (4j). This
compound was prepared according to the general procedure using N-Boc-L-aspartic-acid-4-
tbutyl ester (1j, 260 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO2,
cHex/EtOAc 5:1) afforded the title compound (86.0 mg, 208 µmol, 70%) as a yellow oil. Rf:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
1
0
.12 ( Hex/EtOAc 8:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.88–7.85 (m, 2H, H -
3 Ar
2
, H -6), 7.64–7.60 (m, 1H, H -4), 7.55–7.50 (m, 2H, H -3, H -5), 6.93 (dd, J = 15.1, 4.6 Hz,
Ar
Ar
Ar
Ar
1H, H-4), 6.46 (dd, J = 15.1, 1.8 Hz, 1H, H-5), 5.37 (d, J = 9.2 Hz, 1H, NH), 4.68 (brs, 1H,
13
H-3), 2.65–2.52 (m, 2H, CH ) 1.40 (s, 18H, (CH ) ), C-NMR, HSQC, HMBC (75 MHz,
2
3 3
CDCl ): δ/ppm = 169.7 (C=O), 154.8 (C=O), 145.3 (C-4), 140.2 (SO C ), 133.6 (C -4), 131.2
3
2
q
Ar
(C-5), 129.4 (C -3, C-5), 127.8 (C -2, C -6), 82.3 (C ), 80.4 (C ), 47.9 (C-3), 39.3 (CH ),
Ar
Ar
Ar
Ar
q
q
2
–1
2
7
8.4 ((CH ) ), 28.1 ((CH ) ), IR: 휈 [cm ] = 3367, 3041, 3978, 2930, 1714, 1321, 1146, 842,
3
3
3 3
+
+
82, 574, ESI-MS: m/z = 434.2 (100%, [M+Na] , calc. 434.5), ESI-HRMS: m/z: [M+Na] calc.
+
for [C H NNaO S] : 434.1608, found: 434.1606.
2
0
29
6
tert-Butyl(4R)-4-hydroxy-2[(E)-2-(phenylsulfonyl)ethenyl]pyrrolidine-1-carboxylat (4k).
This compound was prepared according to the general procedure using trans-4-hydroxy-L-
proline (1k, 194 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO2,
cHex/EtOAc, gradient from 0% to 100% EtOAc in 10 min, product elutes at 50% EtOAc)
afforded the title compound as a diastereomeric mixture (dr = 52:48 determined by analytical
c
1
HPLC, 71.0 mg, 200 µmol, 67%) as a colorless oil. R : 0.20 ( Hex/EtOAc 3:1), H-NMR,
f
COSY (300 MHz, CDCl ): δ/ppm = 7.91–7.88 (m, 2H, H -2,H -6), 7.63–7.52 (m, 3H, H -3,
3
Ar
Ar
Ar
H -4, H -5), 6.84 (dd, J = 15.0, 5.1 Hz, 1H, H-1’), 6.31 (d, J = 15.0 Hz, 1H, H-2’), 4.44–4.36
Ar
Ar
(
m, 1H, H-2), 3.41 (brs, 3H, H-5), 2.18–2.10 (m, 1H, H-3 ), 1.89–1.77 (m, 2H, H-3 , H-4, OH),
A B
1
3
1
1
1
.18 (s, 0H, (CH ) ), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 154.1 (C=O),
3 3 3
46.7/146.2 (C-1’), 140.2 (SO C ), 133.6 (C -4), 130.4/130.0 (C-2’), 129.4 (C -3, C-5),
2
q
Ar
Ar
Ar
27.8/127.4 (C -2, C -6), 80.0 (C ), 57.3/57.1 (C-2), 46.5 (C-5), 31.5/30.7 (C-3), /28.428.2
Ar
Ar
q
–
1
(
CH ), 23.8/23.0 (C-4), IR: 휈 [cm ] = 2975, 2932, 2879, 1689, 1390, 1282, 1145, 105, 729,
3
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31, [α]25D: +3.9 (c = 1.0 g/100 mL, CHCl ), ESI-MS: m/z = 354.3 (100%, [M+H] , calc.
+
6
3
+
+
3
54.5), ESI-HRMS: m/z: [M+Na] calc. for [C H NNaO S] : 376.1189, found: 376.1188.
1
7
23
5
tert-Butyl[(3E)-2-[(tert-butoxycarbonyl)amino]-4-(phenylsulfonyl)but-3-en-1-yl]-1H-
imidazole-1-carboxylate (4l). This compound was prepared according to the general procedure
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
using N,N’-di-Boc-L-histidine (1l, 320 mg, 0.90 mmol, 3.00 equiv.). Flash column
c
chromatography (SiO , Hex/EtOAc 3:1) afforded the title compound (86.0 mg, 180 µmol,
2
c
1
6
0%) as a yellow oil. R : 0.32 ( Hex/EtOAc 1:1), H-NMR, COSY (400 MHz, CDCl ): δ/ppm
f 3
= 7.92 (d, J = 1.3 Hz, 1H, H ’-3), 7.77 (app d, J = 7.7 Hz, 2H, H -2, H -6), 7.59–7.55 (m,
Ar
Ar
Ar
1
H, H -4), 7.47 (pseudo t, J = 7.7 Hz, 2H, H -3, H -5), 7.12 (d, J = 1.3 Hz, 1H, H ’-5), 6.86
Ar Ar Ar Ar
(
dd, J = 15.0, 4.9 Hz, 1H, H-3), 6.36 (dd, J = 15.0, 1.7 Hz, 1H, H-4), 5.90 (d, J = 8.4 Hz, 1H,
NH), 4.86 (brs, 1H, H-2), 2.94–2.78 (m, 2H, H-1), 1.60 (s, 9H, (CH ) ), 1.36 (s, 9H, (CH ) ),
3
3
3 3
13
C-NMR, HSQC, HMBC (100.1 MHz, CDCl ): δ/ppm = 155.1 (C=O), 146.8 (C=O), 146.2
3
(
C-3), 140.4 (SO C ), 138.5 (C ’ ), 137.0 (C ’-3), 133.4 (C -4), 130.8 (C-4), 129.2 (C -3,
2 q Ar q Ar Ar Ar
C -5), 127.6 (C -2, C -6), 114.9 (C ’-5), 85.9 (C ), 79.9 (C ), 50.6 (C-2), 31.8 (CH ), 28.3
Ar
Ar
Ar
Ar
q
q
2
–
1
(
CH ), 28.0 (CH ), IR: 휈 [cm ] = 2975, 2930, 1708, 1324, 1149, 1081, 908, 730, 686, 570, ESI-
3
3
+
+
MS: m/z = 378.2 (100%, [M-Boc+H] , calc. 378.5), ESI-HRMS: m/z: [M+H] calc. for
+
[
C H N O S] : 378.1482, found: 378.1478.
18 24
3
4
9
H-Fluoren-9-ylmethyl[(3E)-1-(4-bromphenyl)-4-(phenylsulfonyl)but-e-3n-2-
yl]carbamate (4m). This compound was prepared according to the general procedure using
Fmoc-L-4-bromo-phenylalanine (1m, 420 mg, 0.90 mmol, 3.00 equiv.). Flash column
c
chromatography (SiO , Hex/EtOAc, gradient from 0% to 100% EtOAc in 10 min, product
2
elutes at 30% EtOAc) afforded the title compound (154 mg, 262 µmol, 87%) as a colorless
c
1
solid. R : 0.16 ( Hex/EtOAc 5:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.81–7.77 (m,
f
3
4
7
H, H -2,H -6, H ’), 7.64–7.60 (m, 1H, H -4), 7.54–7.50 (m, 4H, H -3, H -5, H ’), 7.42–
Ar Ar Ar Ar Ar Ar Ar
.30 (m, 6H, H ’, H ’’), 6.97–6.90 (m, 3H, H ’’, H-3), 6.27 (d, J = 15.1 Hz, 1H, H-4), 4.78–
Ar
Ar
Ar
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6
4
.68 (m, 2H, NH, H-2), 4.47–4.43 (m, 2H, CH ), 4.12 (t, J = 6.3 Hz, 1H, H-CH O), 2.85 (d,
2
2
1
3
J = 6.3 Hz, 2H, H-1), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 155.4 (C=O),
3
144.7 (C-3), 143.7 (C ’ ), 141.5 (C ’ ), 140.0 (SO C ), 133.8 (C -4), 132.0 (C ’’H), 131.1
Ar q
Ar q
2
q
Ar
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
(
C-4, C ’’H), 129.4 (C -3, C -5), 128.0 (C ’H), 127.9 (C ’H), 127.8 (C -2, C -6), 125.0
Ar Ar Ar Ar Ar Ar Ar
C ’H), 124.9 (C ’’ -1), 121.3 (C ’’ -4), 120.2 (C ’H), 66.8 (CH O), 52.2 (C-2), 47.3
Ar
Ar
q
Ar
q
Ar
2
–
1
CHCH O), 39.9 (C-1), IR: 휈 [cm ] = 2987, 2901, 1718, 1248, 1146, 1067, 871, 755, 652, 590,
2
8
0
+
Mp.: 158.9–161.4 °C, ESI-MS: m/z = 612.1 (100%, [MBr +Na] , calc. 612.1), 610.1 (95%,
78
+
+
79
+
[MBr +Na] , calc. 610.1), ESI-HRMS: m/z: [M+Na] calc. for [C H BrNaNO S] :
31 26 4
8
1
+
6
11.0692, found: 611.0694, calc. for [C H BrNaNO S] : 613.0671, found: 613.0675.
31 26 4
(1E)-Hex-1-en-1-yl phenylsulfone (4n). This compound was prepared according to the general
procedure using pentanoic acid (1n, 92.0 mg, 0.90 mmol, 3.00 equiv.). Flash column
c
chromatography (SiO , Hex/EtOAc 5:1) afforded the title compound (25.0 mg, 110 µmol,
2
c
1
3
7%) as a yellow oil. R : 0.34 ( Hex/EtOAc 8:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm
f 3
=
7.92–7.88 (m, 2H, H -2,H -6), 7.61–7.53 (m, 5H, H -3, H -4, H -5), 7.02 (dt, J = 15.0,
Ar Ar Ar Ar Ar
6
1
.8 Hz, 1H, H-2), 6.33 (dt, J = 15.0, 1.6 Hz, 1H, H-1), 2.26 (qd, J = 6.8, 1.6 Hz, 2H, H-3), 1.49–
1
3
.44 (m, 3H, H-4, H-5), 1.42–1.33 (m, 3H, H-5, H-6), 0.91 (t, J = 7.2 Hz, 3H, CH ), C-NMR,
3
HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 147.5 (C-2), 140.9 (SO C ), 133.3 (C -4), 130.4
3
2
q
Ar
(C-1), 129.4 (C -3, C -5), 127.7 (C -2, C -6), 31.3 (C-3), 29.8 (C-4, C-5), 22.3 (C-6), 13.9
Ar
Ar
Ar
Ar
–1
(CH ), IR: 휈 [cm ] = 2957, 2929, 2871, 1625, 1317, 1306, 1145, 1085, 688, 593, ESI-MS: m/z:
3
+
=
225.2 (100%, [M+H] , calc. 225.3). The analytical data are consistent with those reported in
the literature.63
4[(E)-2-(Phenylsulfonyl)ethenyl)]tetrahydro-2H-pyran (4o). This compound was prepared
according to the general procedure using tetrahydro-2H-pyran-4-carboxilic acid (1o, 117 mg,
c
0
.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc, gradient from 0%
2
to 100% EtOAc in 10 min, product elutes at 90% EtOAc) afforded the title compound (23.0 mg,
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9
c
1
8
9.6 µmol, 30%) as a colorless oil. R : 0.30 ( Hex/EtOAc 2:1), H-NMR, COSY (300 MHz,
f
CDCl ): δ/ppm = 7.89–7.86 (m, 2H, H -2,H -6), 7.66–7.54 (m, 3H, H -3, H -4, H -5), 6.95
3
Ar
Ar
Ar
Ar
Ar
(dd, J = 15.2, 6.2 Hz, 1H, H-1’), 6.29 (dd, J = 15.2, 1.5 Hz, 1H, H-2’), 4.00–3.95 (m, 2H,
CH O), 3.43–3.40 (m, 2H, CH O), 2.49–2.40 (m, 1H, H-4), 1.71–1.65 (m, 2H, CHCH ), 1.57–
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
1
3
1
1
.48 (m, 2H, CHCH ), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 149.5 (C-1’),
2 3
40.6 (SO C ), 133.5 (C -4), 129.5 (C-2’), 129.4 (C -3, C -5), 127.8 (C -2, C -6), 67.3
2
q
Ar
Ar
Ar
Ar
Ar
–
1
(CH O), 37.3 (CH), 31.1 (CH ), IR: 휈 [cm ] = 2936, 2846, 1620, 1446, 1317, 1146, 1122,
2
2
+
013, 835, 625, ESI-MS: m/z = 253.2 (100%, [M+H] , calc. 253.3), ESI-HRMS: m/z: [M+Na]+
1
+
calc. for [C H NaO S] : 275.0712, found: 275.0708.
1
3
16
3
tert-Butyl 4[(E)-2-(phenylsulfonyl)ethenyl]-piperidine-1-carboxylate (4p). This compound
was prepared according to the general procedure using N-Boc-piperidine-4-carboxylic acid (1p,
c
2
06 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO , Hex/EtOAc 5:1)
2
c
afforded the title compound (10.0 mg, 29.0 µmol, 10%) as a colorless oil. R : 0.57 ( Hex/EtOAc
f
1
1
:1), H-NMR, COSY (400 MHz, CDCl ): δ/ppm = 7.88–7.85 (m, 2H, H -2,H -6), 7.64–7.60
3
Ar
Ar
(
m, 1H, H -4), 7.56–7.52 (m, 2H, H -3, H -5), 6.94 (dd, J = 15.2, 6.3 Hz, 1H, H-1’), 6.29
Ar Ar Ar
(
dd, J = 15.2, 1.5 Hz, 1H, H-2’), 4.19–4.14 (m, 2H, H), 2.73 (t, J = 11.7 Hz, 2H, H-2, H-6),
1
3
2
.38–2.30 (m, 1H, H-4), 1.75–1.70 (m, 2H, H), 1.44 (s, 9H, CH ), 1.34–1.30 (m, 2H, H), C-
3
NMR, HSQC, HMBC (100.1 MHz, CDCl ): δ/ppm = 154.7 (C=O), 149.4 (C-1’), 140.6
3
(
SO C ), 133.5 (C -4), 129.7 (C-2’), 129.5 (C -3, C -5), 127.8 (C -2, C -6), 79.9 (C ), 43.1
2 q Ar Ar Ar Ar Ar q
–
1
(
CH ), 38.3 (CH), 30.4 (CH ), 29.8 (CH ), 28.6 (CH ), IR: 휈 [cm ] = 2975, 2930, 2373, 2345,
2
2
2
3
+
1700, 1560, 1147, 703, 686, 590, ESI-MS: m/z = 374.2 (100%, [M+Na] , calc. 374.5), ESI-
+
+
HRMS: m/z: [M+Na] calc. for [C H NNaO S] : 374.1397, found: 374.1401.
1
8
25
4
Benzyl-(S,E)-2-[(tert-butoxycarbonyl)amino]-5-(phenylsulfonyl)pent-4-enoate (4q). This
compound was prepared according to the general procedure using N-Boc-L-aspartic-acid-1-
benzylester (1q, 291 mg, 0.90 mmol, 3.00 equiv.). Flash column chromatography (SiO2,
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cHex/EtOAc 5:1) afforded the title compound (23.0 mg, 51.4 µmol, 14%) as a colorless oil. Rf:
c
1
0
.26 ( Hex/EtOAc 3:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.86–7.83 (m, 2H, H -
3 Ar
2, H -6), 7.61–7.59 (m, 1H, H -4), 7.54–7.50 (m, 2H, H -3, H -5), 7.37–7.33 (m, 3H, H -
Ar
Ar
Ar
Ar
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
’, H -4’, H -5’), 7.30–7.27 (m, 2H, H -2’, H -6’), 6.87 (dt, J = 14.9, 7.3 Hz, 1H, H-4), 6.34
Ar Ar Ar Ar
(
dt, J = 14.9, 1.4 Hz, 1H, H-5), 5.17 (d, J = 7.8 Hz, 1H, NH), 5.10 (s, 2H, OCH ), 4.49 (q, J =
2
6
.4 Hz, 1H, H-3), 2.79 (app. dt, J = 7.1, 6.4 Hz, 1H, H-2 ), 2.62 (app.dt, J = 14.6, 6.4 Hz, 1H,
A
1
3
H-2 ), 1.41 (s, 9H, (CH ) ), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 170.8
B
3 3
3
(
C=O), 155.0 (C=O), 140.6 (C-4), 140.2 (SO C ), 134.8 (C ’ ), 133.7 (C-5), 133.5 (C -4),
2 q Ar q Ar
1
29.3 (C -3, C -5), 128.7 (C -3’, C -4’, C -5’), 128.5 (C -2’, C -6’), 127.8 (C -2, C -
Ar Ar Ar Ar Ar Ar Ar Ar Ar
–
1
6), 80.5 (C ), 67.6 (OCH ), 52.3 (C-3), 34.4 (CH ), 28.2 ((CH ) ), IR: 휈 [cm ] = 3372, 2977,
q
2
2
3 3
2
931, 1741, 1514, 1391, 1319, 1147, 822, 688, [α]25D:+17.5 (c = 1.0 g/100 mL, CHCl ), ESI-
3
+
+
MS: m/z = 468.2 (100%, [M+Na] , calc. 468.5), ESI-HRMS: m/z: [M+Na] calc. for
+
[C H NNaO S] : 468.1451, found: 468.1452.
2
3
27
6
9
1
H-Fluoren-9-ylmethyl[(2S)-1{[(1E)-4-methyl-1-(phenylsulfonyl)pent-1-en-3-yl]amino}-
-oxopropan-2-yl]-carbamate (4v). This compound was prepared according to the general
procedure using Fmoc-L-alanine-L-valine (1v, 370 mg, 0.90 mmol, 3.00 equiv.). Flash column
c
chromatography (SiO , Hex/EtOAc, gradient from 0% to 100% EtOAc in 15 min, product
2
elutes at 45% EtOAc) afforded the title compound as a diastereomeric mixture (dr = 51:48
c
determined by analytical HPLC, 126 mg, 236 µmol, 79%) as a yellow oil. R : 0.40 ( Hex/EtOAc
f
1
1
:1), H-NMR, COSY (300 MHz, CDCl ): δ/ppm = 7.86–7.75 (m, 5H, H -2, H -6, H ’),
3
Ar
Ar
Ar
7.59–7.54 (m, 2H, H -4, H ’), 7.52–7.50 (m, 2H, H -3, H -5), 7.43–7.37 (m, 4H, H ’), 6.92
Ar
Ar
Ar
Ar
Ar
(ddd, J = 15.1, 5.0, 3.2 Hz, 1H, H-2), 6.54–6.43 (m, 1H, H-1), 5.39 (d, J = 7.5 Hz, 1H, NH),
5
.29 (d, J = 7.5 Hz, 1H, NH), 4.57–4.50 (m, 1H, H-3), 4.41–4.33 (m, 2H, CH O), 4.22–4.19
2
(
m, 2H, H-CH O, H*), 1.92–1.85 (m, 1H, H-4), 1.34 (pseudo t, J = 8.1 Hz, 3H, CH ), 0.90–
2
3
1
3
0
.87 (m, 6H, CH(CH ) ), C-NMR, HSQC, HMBC (75 MHz, CDCl ): δ/ppm = 172.2/172.1
3 2 3
(
C=O), 156.5 (C=O), 145.0 (C-2), 143.8 (C ’ ), 143.7 (C ’ ), 141.4 (C ’ ), 140.2 (SO C ),
Ar q Ar q Ar q 2 q
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8
9
1
33.7/133.6 (C -4), 131.5/131.4 (C-1), 129.4/129.4 (C -3, C -5), 128.0 (C ’H), 127.7/127.6
Ar
Ar
Ar
Ar
(C -2, C -6), 127.3 (C ’H), 125.2 (C ’H), 120.2 (C ’H), 67.4 (CH O), 54.8/54.7 (C-3), 50.1
Ar Ar Ar Ar Ar 2
–
1
(C*), 47.1 (CH-CH O), 32.3 (C-4), 19.1/19.0 (CH ), 18.1 (CH ), IR: 휈 [cm ] = 3326, 3278,
2
3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
964, 1701, 1629, 1523, 1246, 1146, 1052, 784, [α]25D: +9.6 (c = 1.0 g/100 mL, CHCl ), ESI-
3
2
+
+
MS: m/z = 533.5 (100%, [M+H] , calc. 533.7), ESI-HRMS: m/z: [M+Na] calc. for
+
[C H N NaO S] : 555.1924, found: 555.1930.
30 32
2
5
(S)-2-((S)-2-(((Benzyloxy)carbonyl)amino)-3-phenylpropanamido)-4-phenylbutanoic
acid (1w). This compound was prepared according to a modified procedure by Katritzky and
co-workers.64 A flame-dried Schlenk flask was charged with 1H-benzotriazole (2.38 g,
2
0.0 mmol, 4.00 equiv.) in dry THF (30 mL). Upon addition of thionyl chloride (363 µL,
595 mg, 5.00 mmol, 1.00 equiv.) at ambient temperature, the reaction mixture was stirred for
0 min and subsequently cooled to –45 °C. An ice cold solution of ((benzyloxy)carbonyl)-L-
2
phenylalanine (Cbz-L-Phe-OH 1b, 1.50 g, 5.00 mmol, 1.00 equiv.) in dry THF (20 mL) was
added dropwise, followed by stirring for 4 h at –45 °C. Precipitate which had formed during
the reaction was removed by suction filtration and the filtrate was concentrated under reduced
pressure. The resulting residue was dissolved in ethyl acetate (100 mL) and washed with a
saturated aqueous solution of sodium carbonate (3 × 50 mL) and brine (3 × 50 mL). The organic
layer was dried over sodium sulfate and the solvent was removed in vacuo. The resulting crude
benzyl (S)-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamate (1.60 g,
4
.00 mmol, 80%) was added to a solution of L-homophenylalanine (717 mg, 4.00 mmol,
1.00 equiv.) and triethylamine (666 µL, 486 mg, 4.80 mmol, 1.20 equiv.) in acetonitrile (140
mL) as well as water (60 mL) at 0 °C. The reaction mixture was stirred at the same temperature
for 2 h and subsequently quenched by the addition of hydrochloric acid (4 M, 20 mL). Most
acetonitrile (115 mL) was removed under reduced pressure and the residue was extracted with
ethyl acetate (3 × 200 mL). The combined organic extracts were washed with hydrochloric acid
(4 M, 3 × 150 mL) and brine (3 × 150 mL), dried over sodium sulfate and the solvent was
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1
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1
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2
2
2
2
2
2
2
2
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3
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4
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5
6
c
removed in vacuo. Flash column chromatography (SiO , Hex/EtOAc, gradient from 0% to
2
1
00% EtOAc in 10 min, product elutes at 35% EtOAc) afforded the title compound (1.42 g,
c
3.08 mmol, 77%, 62% from 1b) as colorless solid. R = 0.14 (SiO , Hex/EtOAc/HOAc
f
2
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
0:10:1), H-NMR, COSY (400 MHz, DMSO-d ): δ/ppm = 12.68 (br s, 1H, CO H), 8.38 (d, J
6 2
=
7.8 Hz, 1H, NHCOCH), 7.54 (d, J = 8.7 Hz, 1H, NHCO CH ), 7.35–7.13 (m, 15H, 15 × H ),
2 2 Ar
5
.00–4.91 (m, 2H, CO CH ), 4.39–4.31 (m, 1H, (CO)CHCH ), 4.22–4.14 (m, 1H, CHCO H),
2 2 2 2
3.03 (dd, J = 13.8, 3.5 Hz, 1H, (CO)CHCH H ), 2.76 (dd, J = 13.8, 11.0 Hz, 1H,
a
b
(
CO)CHCH H ), 2.71–2.57 (m, 2H, CHCH CH ), 2.09–1.98 (m, 1H, CHCH H CH ), 1.98–
a b 2 2 a b 2
1
3
1
.85 (m, 1H, CHCH H CH ), C-NMR, HSQC, HMBC (100.6 MHz, DMSO-d ): δ/ppm =
a b 2 6
173.5 (CO H), 171.8 (NHCOCH), 155.9 (NHCOCH ), 141.0 (C -1), 138.2 (C -1´´), 137.0
2
2
Ar
Ar
(
C -1´), 129.2 (2C, C -2´´, C -6´´), 2 × 128.4 (2 × 2C, C -2, C -6, 2 × CH), 128.3 (2C, 2 ×
Ar Ar Ar Ar Ar
CH), 128.1 (2C, 2 × CH), 127.7 (CH), 127.5 (2C, C -2´, C -6´), 126.3 (CH), 126.0 (CH), 65.2
Ar
Ar
(
CO CH ), 56.0 ((CO)CHCH ), 51.3 (CHCO H), 37.3 ((CO)CHCH ), 32.8 (CHCH CH ), 31.3
2 2 2 2 2 2 2
2
9
(
CHCH CH ), 푎 = –17.5° (c = 1.0 g/100 mL, MeOH), Mp.: 157.9–158.3 °C, IR (ATR):
2
2
D
–
1
휈 [cm ] = 3307, 3029, 2926, 2858, 1702, 1661, 1537, 1456, 1220, 773, ESI-MS (pos.): m/z =

+

461.3 (100%, [M+H] ), ESI-HRMS (pos.): m/z: [M+H] calc. for [C H N O ] : 461.2071,
2
7
29
2
5
found: 461.2070. Although this compound is known, no analytical data could be found in the
literature.
Benzyl
((2S)-1-oxo-3-phenyl-1-(((E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-
yl)amino)propan-2-yl)carbamate (4w). This compound was prepared according to the
general procedure using (S)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-4-
phenylbutanoic acid (1w, 967 mg, 2.10 mmol, 3.00 equiv.) and a 9:1-mixture of acetonitrile
c
(
36 mL) and water (4 mL) as solvent. Flash column chromatography (SiO , Hex/EtOAc 3:1)
2
afforded the title compound (228 mg, 401 µmol, 57%, pale yellow solid) as a diastereomeric
1
mixture (dr = 54:46, A:B, determined by H-NMR spectroscopy based on the integrals of
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CHCH=CH). When performing the reaction using 1.00 equiv. of peptide 1w (40.0 mg,
8
6.9 µmol) under otherwise identical conditions, the title compound (25.8 mg, 45.4 µmol, 52%)
c
1
was also obtained as pale yellow solid (identical dr). R = 0.11 (SiO , Hex/EtOAc 3:1), H-
f
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR, COSY (400 MHz, CDCl ): δ/ppm = 7.87–7.82 (m, 2H, H -2´´´, H -6´´´), 7.63–7.45
3
Ar
Ar
(
m, 3H, H -3´´´, H -4´´´, H -5´´´), 7.34–7.08 (m, 13H, H -2, H -3, H -4, H -5, H -6,
Ar Ar Ar Ar Ar Ar Ar Ar
H -2´, H -3´, H -4´, H -5´, H -6´, H -3´´, H -4´´, H -5´´), 7.06–7.00 (m, 2H, H -2´´,
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
H -6´´), 6.88–6.76 (m, 1H, CHCH=CH), 6.49 (d, J = 14.7 Hz, 1H diastereomer A,
Ar
CHCH=CH), 6.38–6.21 (m, 1H, NH(CO)CH), 6.08–6.03 (m, 1H diastereomer B, CHCH=CH),
5
.41 (dd, J = 14.7, 7.7 Hz, 1H, NHCO CH ), 5.07–4.91 (m, 2H, OCH ), 4.68–4.58 (m, 1H,
2 2 2
NHCHCH CH ), 4.37 (pseudo-q, J = 7.5 Hz, 1H, (CO)CHCH ), 3.10–2.96 (m, 2H,
2
2
2
(
CO)CHCH ), 2.62–2.45 (m, 1H, NHCHCH CH H ), 2.38 (t, J = 7.8 Hz, 1H,
2 2 a b
NHCHCH CH H ), 1.92–1.59 (m, 2H, NHCHCH CH ), 13C-NMR, HSQC, HMBC
2
a
b
2
2
(
(
(
100.6 MHz, CDCl ): δ/ppm = 170.8/170.7 (CHCONH), 156.1 (OCONH), 145.6/145.5
3
CHCH=CH), 2 × 140.4 (C -1´´), 140.1 (C -1´´´), 136.1 (C -1´), 136.0 (C -1), 2 × 133.6
Ar
Ar
Ar
Ar
C -4´´´), 130.8/130.5 (CHCH=CH), 129.4 (2C, C -3´´´, C -5´´´), 2 × 129.3 (2 × 1C, 2 ×
Ar
Ar
Ar
CH), 2 × 128.9 (2 × 1C, 2 × CH), 2 × 128.7/128.6 (5 × 1C, 5 × CH), 2 × 128.4 (C -2´´, C -
Ar
Ar
6´´), 128.1 (2C, 2 × CH), 127.7 (2C, C -2´´´, C -6´´´), 127.4/127.3 (CH), 2 × 126.4 (C -4´´),
Ar
Ar
Ar
6
7.3 (OCH ), 56.7/56.6 ((CO)CHCH ), 2 × 49.3 (NHCHCH CH ), 38.4/38.2 ((CO)CHCH ), 2
2 2 2 2 2
2
9
×
35.5 (NHCHCH CH ), 31.9/31.7 (NHCHCH CH ), 푎 = –3.4° (c = 1.0 g/100 mL, CHCl ),
D
2
2
2
2
3
–
1
Mp.: 155.1–155.8 °C, IR (ATR): 휈 [cm ] = 3305, 3062, 3030, 2927, 1661, 1528, 1307, 1145,

+
1
085, 749, ESI-MS (pos.): m/z = 583.3 (100%, [M+H] ), ESI-HRMS (pos.): m/z: [M+Na] calc.

for [C H N O SNa] : 605.2081, found: 605.2079. Although this compound is known, no
3
4
34
2
5
analytical data could be found in the literature.
Vinyl sulfone derived from cholic acid (4x). This compound was prepared according to the
general procedure using cholic acid (1y, 368 mg, 0.90 mmol, 3.00 equiv.). Flash column
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