In Situ Switching of Site-Selectivity with Light in the Acetylation of Sugars with Azopeptide Catalysts

Article abstract of DOI:10.1021/acs.joc.9b01913

We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected sugars using light as external stimulus and oligopeptide catalysts equipped with an azobenzene moiety. The isomerizable azobenzene-peptide backbone defines the size and shape of the catalytic pocket, while the π-methyl-l-histidine (Pmh) moiety transfers the electrophile. Photoisomerization of the E- to the Z-azobenzene catalyst (monitored via NMR) with an LED (λ = 365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety, so that the light-induced change in the catalyst shape alters site-selectivity. As a proof of principle, we employed (4,6-O-benzylidene)methyl-α-d-pyranosides, which provide a change in regioselectivity from 2:1 (E) to 1:5 (Z) for the monoacetylated products at room temperature. The validity of this new catalyst-design concept is further demonstrated with the regioselective acetylation of the natural product quercetin. In situ irradiation NMR spectroscopy was used to quantify photostationary states under continuous irradiation with UV light.

Full text of DOI:10.1021/acs.joc.9b01913

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Article
In situ Switching of Site-Selectivity with Light in the
Acetylation of Sugars with Azo-Peptide Catalysts
Dominik Niedek, Frederik R. Erb, Christopher Topp, Alexander Seitz, Raffael C. Wende,
Andre K. Eckhardt, Jonas Kind, Dominik Herold, Christina M. Thiele, and Peter R. Schreiner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01913 • Publication Date (Web): 25 Nov 2019
Downloaded from pubs.acs.org on November 27, 2019
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In situ Switching of Site-Selectivity with Light in the Acetylation of
Sugars with Azo-Peptide Catalysts
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Dominik Niedek,a Frederik R. Erb,a Christopher Topp,a Alexander Seitz,a Raffael C. Wende,a
André K. Eckhardt,a Jonas Kind,b Dominik Herold,b Christina M. Thiele,b and Peter R. Schreiner*a
aInstitute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen (Germany).
bClemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt,
Alarich-Weiss-Str. 16, 64287 Darmstadt (Germany).
KEYWORDS Azobenzene • Catalysis • Catalyst-control • Peptides • Photoswitches • Regioselectivity
ABSTRACT: We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected
sugars based on light as external stimulus using oligopeptide catalysts equipped with an azobenzene moiety. The isomerizable
azobenzene-peptide backbone defines the size and shape of the catalytic pocket while the -methyl-L-histidine (Pmh) moiety
transfers the electrophile. Photoisomerization of the E- to the Z-azobenzene catalyst (monitored via NMR) with an LED ( =
365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety so that the light-induced
change in catalyst shape alters site-selectivity. As a proof-of-principle we employed (4,6-O-benzylidene)methyl--D-
pyranosides, which provide a change in regioselectivity from 2:1 (E) to 1:5 (Z) for the monoacetylated products at room
temperature. The validity of this new catalyst-design concept is further demonstrated with the regioselective acetylation of
the natural product quercetin. In situ irradiation NMR spectroscopy was used to quantify photostationary states under
continuous irradiation with UV light.
Previous work
Introduction
The control of chemoselectivity, defined as “the preferential
reaction of a chemical reagent with one of two or more
different functional groups“1 is one of the current goals in
synthetic organic chemistry that presents a challenge for
catalyst development. This is even more apparent for site-
This work
selectivity that strives to “differentiate reactivity among the
same kind of functional groups that have different chemical
environments“,2 which can only be achieved with highly
specific catalysts that allow the differentiation of even small
differences in binding energies and substrate
configurations. One of the biggest challenges is that for the
functionalization of each similarly reactive position
typically a specific catalyst has to be used. A single catalyst
Z-catalyst
E-catalyst
enabling the differentiation of comparably reactive
positions would be a major step forward, especially if
Fig. 1. Three different modes of (photo)switchable catalysts
selectivity could be controlled externally (Fig. 1).3
with external stimuli: 1) Switching activity on and off,4-
6,7a,7b,8a,9a
2) triggering catalyst stereoselectivity,12 and 3) site-
The use of light as external stimulus is of particular interest
due to its spatiotemporal controllability.4 There are already
several examples of photoswitchable catalysts5 used in
reactions based on azobenzenes,6 dithienylethenes or
diarylethenes,7 spiropyranes,8 stilbenes9 or donor–acceptor
Stenhouse adducts.10 Notwithstanding these notable
examples, Dorel and Feringa state that “Photoswitchable
catalysis is a young but rapidly evolving field that offers great
potential for non-invasive dynamic control of both activity
and selectivity in catalysis“.11
selective catalysis by light.
The majority of these catalysts display on / off modes,
implying that one of the catalyst’s photoisomers is more
active but not more selective (Fig. 1.1). A more challenging
approach is in situ switching and controlling
stereoselectivity by light (Fig. 1.2). Important steps in this
direction were taken by the Feringa group demonstrating
that a single sterically crowded molecular motor type
photocatalyst can enrich both enantiomers in Michael
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additions by stepwise unidirectional rotation.12
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Results and discussion
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8
Subsequently, several other examples based on this system
We envisaged that similarly sized peptidic moieties flanking
the azobenzene core would lead to drastically different
structures of the catalyst depending on the configuration of
the azobenzene bridge. Our orientational computations
(Scheme 1C) support this assumption: E-6 is elongated with
the Pmh catalytic moiety being prominently displayed
toward one side of the azobenzene unit, thereby offering a
well-defined binding site. Catalyst Z-6 on the other hand is
a folded structure with the Pmh moiety enclosed inside the
fold. Apart from shape and steric demand, however,
hydrogen bonding, polar, and dispersion interactions17 with
the substrate are also expected to be very different for the
two catalyst isomers. After a conformational analysis using
molecular mechanics we optimized the energetically
preferred E- and Z-conformers at the DLPNO-
CCSD(T)/def2-tzvpp//B3LYP-D3(BJ)/6-311G(d,p) level of
theory. Our resulting thermochemistry data (Tables S3 and
S4) as well as NMR investigations (Fig. S16) indicate that the
Z-catalyst is only populated in very small quantities
ensuring that E-6 is the major isomer present at room
temperature in the dark (Scheme 1C).
have been reported.13
We envisioned that photoswitchable catalysts would be also
good candidates for achieving site-selectivity (Fig. 1.3).
Herein we present a variety of new catalysts based on
oligopeptides containing a photoswitchable azobenzene
group in the peptide backbone that induces significant
conformational changes. The E→Z photoisomerization of
the azo unit changes the catalyst’s selectivity but not
9
activity.
Even
though
peptides
containing
a
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photoswitchable unit have already been described in a
variety of examples for spatiotemporal control of biological
functions,14 to the best of our knowledge, they have not been
utilized as in situ photoswitchable organocatalysts for site-
selective transformations before. We combine the
azobenzene moiety with an acetylation catalyst containing
-methyl-L-histidine (Pmh) (Scheme 1B) as catalytically
active site.15 As model system the site-selective acylation of
(4,6-O-benzylidene)methyl--D-pyranosides was chosen to
test the applicability of this novel concept. While already a
broad variety of catalysts has been designed for site-
selective reactions of carbohydrates and polyols,16 our
catalytic system is the first that enables the external
photochemical control of such reactions.
Scheme 1. Selection of carbohydrates and catalyst design: A) (4,6-O-benzylidene)methyl--D-pyranoside substrates, B) design of
photoswitchable acylation catalysts, and C) E→Z photoisomerization of catalyst 6, the corresponding van-der-Waals surfaces and
relative energies at the B3LYP-D3(BJ)/6-311G(d,p) (DLPNO-CCSD(T)/def2-tzvpp//B3LYP-D3(BJ)/6-311G(d,p)) levels of theory.
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For the application in catalysis it is essential to obtain
of the thermal Z→E isomerization rates by means of an
Arrhenius approach gives Ea = 24.0 kcal mol–1. These results
are in good agreement with the computed values Ea,calc
22.1 kcal mol–1 (B3LYP-D3(BJ)/6-311G(d,p)) and 28.7 kcal
mol–1
(DLPNO-CCSD(T)/def2-tzvpp//B3LYP-D3(BJ)/6-
1
2
3
4
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6
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8
information on the photochromic properties such as the
time scales of the E→Z and Z→E photoisomerization, the
molar fractions of E- and Z-isomers in the photostationary
states during constant irradiation with the respective
wavelengths, and thermal Z→E isomerization rates in
different solvents of the catalyst (6 was chosen as an
example). As all catalysts are of the amidoazobenzene type,
shorter half-lives and bathochromic shifts are expected in
the UV/Vis absorption spectra of the E- and Z-isomers for
the prominent →* transitions as compared to the parent
azobenzene. These bathochromic shifts are indeed
observed (for spectra see Supplementary Information, SI,
Fig. S1-S4).18
=
311G(d,p))
Next, we probed whether the photochemical Z→E
isomerization can also be achieved. Excitation of the n→*
transitions with blue light (λ
= 448 nm) induces
photochemical Z→E isomerization within seconds. In both
toluene-d8 and DMF-d7, continuous irradiation led to a
second photostationary state with ca. 20% of the Z-isomer
(Fig. S24). Hence, pulsed irradiation with blue light can be
used to enhance the thermal Z→E isomerization thus
ensuring that not only the E→Z but also the Z→E conversion
is accessible within time scales convenient for synthesis.
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To determine switching efficiency, thermal half-lives, and
molar ratios of the photoisomers in the photostationary
states, in situ irradiation NMR spectroscopy was used.19
We chose (4,6-O-benzylidene)methyl--D-pyranosides 1–
3a (Scheme 1A) that are widely used in regioselective
acetylations (with individual catalysts) to benchmark the
performance of catalysts 4–7 (Scheme 1B).16a Yields and
selectivities can readily be determined by 1H NMR
spectroscopy (see SI, Fig. S29–S34). For the acetylation of
1–3a typical conditions for peptide catalyzed acylations of
polyols were used.15 The reaction was carried out either in
the dark or under continuous irradiation at 365 nm (Tables
1; S11-13).
NMR spectra of
6 in toluene-d8 show a significant
dependence of chemical shifts and line widths on
temperature (see SI, Fig. S9). This could indicate that
aggregation plays a role in solution at mM and µM
concentration at low temperatures,17b which in fact was
observed and measured in UV/Vis absorbance experiments
of less concentrated solutions of 6 (see SI, Fig. S5 and S6). A
more detailed NMR-spectroscopic investigation is out of the
scope of the current work. Irradiation of the NMR sample
with UV light at 300 K leads to a photostationary state
within minutes with ca. 90% of Z-6 present irrespective of
concentration (see SI, Fig. S10 and S13). To exclude effects
caused by aggregation and lower solubility of 6 in toluene-
d8, the NMR experiments were repeated in DMF-d7, in which
temperature as well as concentration dependence of the
chemical shifts were not observed. Depending on the
concentration of 6, continuous irradiation with UV light led
to photostationary states with 94% Z-isomer on the minute
or hour time scale (Fig. 2). Thermal Z→E isomerization
rates were examined at T = 0–50 °C. The observed half-lives
vary from 48 d at 0 °C to 1 h at 50 °C, in line with the
computations (days to minutes at the same T). Examination
For the photoreactions a simple tailor-made device was
assembled (see SI, Fig. S7). While C2-symmetric catalyst 4
shows virtually no change in site-selectivity for the
acetylation of (4,6-O-benzylidene)methyl--D-pyranosides
(1-3a) in the dark or under irradiation, there are noticeable
selectivity differences for catalysts 5-7 (see also SI,
additional
results),
especially
for
(4,6-O-
benzylidene)methyl--D-mannopyranoside (3a) (a cis-diol)
where site-selectivity can be switched through irradiation.
While the E-catalysts favor acetylation of the axial 2-
position, the Z-catalysts activate the equatorial, sterically
less hindered 3-hydroxy group (Tables 1, S13, and Fig. 3).
Fig. 2. Kinetic profiles of the E→Z photoisomerization of catalyst 6 under continuous irradiation (λ = 365 nm) Left: stacked plot of
1H NMR spectra in DMF-d7 (1.3 mM) at 0 °C for the amide protons NH19 (located between the azo- and Pmh moieties) and NH35
(located at the Boc protecting group). Right: relative concentration profiles of the E- and Z-isomers with respect to the amide proton
NH19.
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Note that E-6 generates preferentially 2-acetylated product In view of the half-life of catalyst Z-6 determined via NMR at
1
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4
5
6
7
8
14a that is not available via NMI, while Z-6 (at 0 °C) yields
3-acetylated product 15a in higher yields and in much
better selectivities compared to NMI (Fig. 3). The higher
activity of the catalysts with this substrate also leads to a
larger amount of diacetylated product 16a possibly due to
the cis configuration and the resulting intramolecular
hydrogen bond network16a of the diol. Decreasing the
amount of diacetylated product by reducing the catalyst
loading, the equivalents of Ac2O or lowering of the
concentration was not successful. While the selectivity for
3-acetylation using Z-6 can be further increased from 5:1 up
to 20:1 by lowering the reaction temperature (Table 1,
entry 7) the activity of E-6 is drastically reduced at 0 °C also
resulting in lower selectivities for 2-acetylation (Table 1,
entry 3). In case of constant irradiation with λ = 448 nm at
0 °C 2-acetylation is disfavored (Table 1, entry 5). The
reason for this is that under these conditions 20% of Z-6 is
present (caused by the photostationary state at 448 nm,
vide supra), which shows the same activity at lower
temperatures in contrast to E-6 that is less active. One
possible explanation for this phenomenon is the lower
solubility of E-6 at low temperatures, which could be shown
experimentally by using UV-Vis spectroscopy (see SI, Fig. S5
and S6).
0 °C in toluene-d8 in the absence of Ac2O and pyranosides
(see SI, Fig. S14), it would be expected that switching from
E→Z before the reaction starts should be as effective as
continuous irradiation. Nevertheless, we observed that
irradiation of 6 for 10 min with λ = 365 nm at 0 °C before
adding Ac2O is not as effective as compared to the reaction
under constant irradiation (Table 1, entry 8). This indicates
that the half-life of Z-6 is significantly influenced by the
reaction mixture. Irradiation of 6 for 10 min with λ = 448
nm also resulted in slightly lower selectivity compared to
the thermally equilibrated reaction in the dark (Table 1,
entries 2 and 4), in accord with NMR data (20% Z-isomer of
6 under irradiation with blue light).
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The performance of catalyst 6 in terms of conversion, yield
and selectivity is always as good as or even better than
those of NMI (Tables 1 and S11-13). Note that the
corresponding conversions obtained with our catalysts are
always in the same range as with NMI or even higher. There
is no background reaction at the chosen conditions with 1-
3a in the absence catalyst. These results are in line with our
working hypothesis that the light-induced E/Z catalyst
isomerization controls the shape of the catalytic pocket
resulting in
a significant change of the chemical
environment around the Pmh moiety.
Table 1. Acetylation of (4,6-O-benzylidene)methyl--D-mannopyranoside (3a).
Catalyst
NMI
14a / %
15a / %
35
16a / %
4
Conversion / %
1
2
5
32
10
32
11
7
44
62
21
66
34
61
74
66
68
77
6
16
14
3
3
6[b]
8
4
6 (448 nm)[a]
6 (448 nm)[b]
6 (365 nm)
6 (365 nm)[b]
6 (365 nm)[a, b]
7
18
16
8
5
15
6
32
22
24
18
20
27
7
2
48
8
6
42
9
30
4
18
10
7 (365 nm)[b]
46
Yields determined via 1H NMR (see SI, Fig. S31). [a] 10 min irradiation before addition of Ac2O; reaction in the dark. [b] Reaction at 0 °C. NMI = N-
methylimidazole.
We also employed naphthylidene, methylidene, and
acetonide protected methyl--D-mannopyranosides (3b-d)
to examine size and orientation effects (Table 2). The
reaction under constant irradiation was always done at 0 °C
based on the results obtained for 3a (Table 1, entry 7).
Substituents at R1 show some size-dependent selectivity
(Table 2, entries 1–4 and 7/8): it increases with substituent
size to a limit before it drops again (H < Nap << Ph). In
contrast, R2 substituents bigger than hydrogen decrease the
selectivity drastically but increase reactivity, thereby
emphasizing the high sensitivity of the catalytic system to
even small changes (Table 2, entries 5 and 6).
Regardless of the protecting group (3a-d) E-6 generally
favors 2-acetylation (Table 2, entries 1, 3, 5 and 7) while Z-
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6 highly favors 3-acetylation (Table 2, entries 2, 4, 6 and 8). Accordingly, the orientation of the substrate relative to the
1
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3
4
5
6
7
8
This experimental observation points to the fact that the
selectivities are not exclusively a result of the steric demand
of the 4,6-O-protecting group but are controlled by
substrate-catalyst binding,20 indicating that the different
catalyst isomers are engaged in rather different transition
states. The computed transition structures for 3a and 6 (Fig.
4; Tables S5 and S6) lead to the conclusion that two
completely different transition structure geometries are
obtained for the different catalyst isomers. For the E-6
photoisomer the substrate is placed “inside” the pocket E2-
6ǂ, as initially assumed. In marked contrast, for ball-shape
Z-6 the substrate interacts with the “outside” catalyst
surface Z3-6ǂ.
Pmh moiety is completely different, thereby altering the
nucleophilic attack of the substrate. The very different
computed transition structures (E2-6ǂ and Z3-6ǂ) for the
acetylation process support our idea that the intrinsic
selectivity of a catalytic system can be overcome by using
light as external stimulus (Fig. 4). The transition states (E3-
6ǂ and Z2-6ǂ) for the experimentally disfavored products
computed at B3LYP-D3(BJ)/cc-pVTZ//B3LYP-D3(BJ)/6-
31G(d) provide further evidence the experimentally
observed selectivities (see SI, Tables S5 and S6). For both
catalyst isomers the computations are qualitatively in good
agreement with the experimental data: while E-6 favors 2-
acetylation (2:1, ∆E = 2.3 kcal mol–1), Z-6 favors 3-
acetylation (5:1, ∆E = 6.0 kcal mol–1).
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To demonstrate the potential of our new catalytic system
we employed the flavonoid quercetin 17, which displays
five hydroxy groups. To avoid a very fast background
reaction the most reactive 4’-OH and the 3’-OH were
protected as diphenylmethylene ketal.21 Based on the
reactivity order of the remaining three hydroxy groups in
quercetin (7 > 3 >> 5) products 18–20 are expected.21
Despite the rigid sp2-system, we obtained a switch of the
ratio of the monoacetylated products 18 and 19 upon
photoisomerization: E-6 preferably acetylates the 3-OH
group, while Z-6 prefers the sterically less hindered 7-OH
group (Table 3).
Fig.
3.
Product
ratios
obtained
for
(4,6-O-
Benzylidene)methyl--D-mannopyranoside (3a). The total
conversions are given in bold on top.
Table 2. Acetylation of (4,6-O-protected)methyl--D-mannopyranosides 3a-d.
Substrate
14a-d / %
15a-d / %
16a-d / %
Conversion / %
1
2
3
4
5
6
7
8
3a
3a (365 nm)[a]
3b
32
2
16
48
8
14
24
18
11
9
62
74
16
1
42
3b (365 nm)[a]
3c
13
32
53
11
32
25
34
24
26
3
75
3c (365 nm)[a]
3d
14
7
91
44[b]
54[b]
3d (365 nm)[a]
19
Yields determined via 1H NMR (see SI, Fig. S31-34). [a] Reaction at 0 °C. [b] Yield not determined exactly due to some decomposition of the methylidene
protecting group.
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Conclusions
1
2
We demonstrate the light-controlled change in site-
selectivity in peptide-catalyzed acetylation reactions of
(4,6-O-benzylidene)methyl--D-pyranosides and 2-(2,2-
diphenyl-1,3-benzodioxol-5-yl)-3,5,7-trihydroxy-4H-1-
benzopyran-4-one 17 (DPQ). To the best of our knowledge,
this is the first example where the intrinsic site-selectivity
of a catalyzed esterification reaction could be overcome,
and the product distribution can be switched using light as
external stimulus. With our proof-of-principle studies we
exemplify the potential of peptide catalysts equipped with a
photoswitchable unit such as an azobenzene moiety that
enables the external control of site-selectivity. Even though
the selectivities and yields currently are moderate, our new
catalyst design concept provides a promising base for future
investigations.
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The possibility to use a single catalyst for addressing
different sites in a chosen substrate externally triggered by
light further enhances the application scope of
photoswitchable catalysts. Instead of using different
catalysts and reaction conditions that have to be optimized
for specifically targeting a particular substrate site, one can
use a single catalyst where the conformation is switched by
light under otherwise identical reaction conditions. This
makes the catalyst system more economically friendly and
results in higher atom economy.22
As there are many other catalytic moieties, e.g., proline,
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), ureas or
thioureas and thiazolium salts for controlling site-, regio-
and/or chemoselective transformations with light that can
readily be attached to the photoswitchable backbone, the
applicability of such externally light-controlled, selective
transformations appears to be broad. Furthermore, the new
catalyst design concept is reasonably simple and robust and
relies on a common building block strategy that is readily
adaptable to a multitude of catalyzed reactions.
Fig. 4. Computed acetylation transition state structures:
Acetylation
of
(4,6-O-benzylidene)methyl--D-
mannopyranoside (3a) at B3LYP-D3(BJ)/6-31G(d); E2-6ǂ
transition state for the 2-acetylation resulting from E-6 and 3a
(top) and Z3-6ǂ transition state for the 3-acetylation resulting
from Z-6 and 3a (bottom).
Experimental Section
General Information. All chemicals were purchased from
commercial suppliers and were used without further
purification. Solvents for column chromatography,
extractions and filtrations were distilled prior to use. Dry
Table 3. Acetylation of 2-(2,2-diphenyl-1,3-benzodioxol-5-yl)-
3,5,7-trihydroxy-4H-1-benzopyran-4-one (diphenylquercitin,
DPQ) (17).
solvents were purchased from Acros Organics (AcroSealTM
)
and stored under Ar and over activated molecular sieves (3
Å or 4 Å). Column chromatography was carried out using
silica gel 60 M (Macherey–Nagel; 0.040–0.063 mm, 230–
400 mesh ASTM). TLC was performed using precoated
plastic sheets Polygram ® SIL G/UV 254 (Macherey–Nagel;
0.2 mm silica gel layer with fluorescent indicator). For
visualization, UV light (λ = 254 nm) or staining solutions
(KMnO4: 2.5
g KMnO4, 8.3 g K2CO3, 250 mL H2O;
phosphomolybdic acid: 9.86 g in 250 mL ethanol) were
utilized. All NMR spectra for characterization were
recorded on Bruker AV 400/AV 400HD or AV 600
spectrometers. Chemical shifts (δ) are reported in parts per
million (ppm) using either tetramethylsilane (TMS) or the
corresponding residual solvent signal as internal standard.
For all azopeptides only the signals of the E-photoisomers
are given for better transparency. In some cases, integration
was difficult due to overlap of E/Z-photoisomers especially
in the aromatic region. IR spectra were measured with a
Bruker IFS25 spectrometer. HRMS were recorded with a
Catalyst
None
18
21
15
25
19
5
20
1
Conversion / %
27
68
73
6
24
20
29
28
6 (365 nm)
Yields determined via 1H NMR (see SI, Fig. S35).
6
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The Journal of Organic Chemistry
Bruker MicroTOF. UV/Vis data were recorded either on and degassed toluene. Acetic acid was added, the mixture
1
2
3
4
Jasco V670 (Jasco, measuring range: 190 – 850 nm, max.
resolution: 0.1 nm) or HP8453 (Agilent, diode array
spectrometer, measuring range: 190 – 1100 nm).
heated to 60 °C and stirred for 24-48 h under Ar. After
cooling to r.t. the solvent was removed under reduced
pressure and the crude product was purified via column
chromatography. The azo compound was obtained as bright
orange/red solid.
General procedures. Procedure 1: Amide bond formation
(peptide coupling) Amine building block, carboxylic acid
5
6
7
8
9
building
block,
1-Ethyl-3-(3-
Procedure 6: Boc--methyl-L-histidine (Boc-Pmh) coupling
Amine building block (hydrochloride), Boc-Pmh, EDC·HCl
and HOBt were dissolved in DCM. TEA was added via
syringe and the resulting mixture stirred at r.t. for 48 h. The
mixture was diluted with EtOAc and washed three times
with saturated aqueous NaHCO3 solution and once with
brine. The organic layer was dried over MgSO4, filtered and
the solvent was removed under reduced pressure. The
product was obtained after column chromatography as a
bright orange/red solid.
dimethylaminopropyl)carbodiimide (EDC·HCl) and 1-
hydroxybenzotriazole (HOBt) were dissolved in
dichloromethane (DCM). Triethylamine (TEA) was added
via syringe and the resulting mixture was stirred at room
temperature (r.t.) for 24 h. The mixture was diluted with
ethyl acetate (EtOAc) and washed three times each with 0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
M
citric acid, saturated aqueous sodium bicarbonate
solution (NaHCO3) and once with brine. The organic layer
was dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The product is a solid (if necessary,
a column chromatography was performed).
Procedure 7: The substrate and DMAP were dissolved in
DCM. Acetic anhydride (Ac2O) was added and the resulting
mixture stirred at r.t. for 24 h, while reaction progress was
monitored via TLC. The solvent was removed under
reduced pressure. The three desired products were
obtained each after column chromatography as a colorless
solid or oil.
Procedure 2: Boc-deprotection The Boc-protected amine
was dissolved in 4.0 M HCl in 1,4-dioxane. The resulting
mixture was stirred in a sealed flask at r.t. for 1 h. Residual
HCl was removed using an argon stream and the solvent
was removed under reduced pressure. The product was
obtained as a solid and used without further purification.
General procedure for the catalyzed reactions The catalyzed
reactions were carried out on a 0.1 mmol scale in dry
toluene (0.01 M). Therefore, the starting material and 2
mol% catalyst were dissolved in 10 mL of solvent in a
disposable screw glass that was sealed using a standard NS
14.5 septum. The vessel was placed in a homemade
photoreactor (see SI, Fig. S7). After equilibration (24 h for
the reactions in the dark and 1 h under irradiation) acetic
anhydride was added through the septum. The resulting
mixture was stirred for 18 h at the given temperature.
Temperature control was carried out using a Huber
Ministat 230 cryostat. Afterwards some drops of methanol
were added to quench the remaining anhydride. All
volatiles were removed under reduced pressure and the
residue was dissolved in a deuterated solvent and directly
transferred to an NMR tube. The selectivities and yields
were determined via 1H NMR.
Procedure 3: Hydrogenation The nitro compound was
dissolved either in methanol or EtOAc, palladium on
activated carbon (10%) was added and the mixture was
stirred at r.t. for 24 h under H2-atmosphere. The reaction
mixture was filtered through a pad of celite® and the
solvent was removed under reduced pressure. The product
was obtained as a colorless solid and used without further
purification.
Procedure 4a: Oxidation using meta-chloroperoxybenzoic
acid (mCPBA) Aniline derivative was dissolved in freshly
distilled tetrahydrofuran (THF) and mCPBA added in one
portion. The mixture was stirred at r.t. and monitored via
TLC. After completion of the oxidation to desired nitroso
compound the solvent was removed under reduced
pressure, the residue was dissolved in EtOAc and washed
with saturated aqueous bicarbonate solution and brine. The
organic layer was dried over MgSO4 and the solvent was
removed under reduced pressure. The crude product was
purified via column chromatography. The green fractions
were collected to obtain the nitroso compound as slightly
green solid. The nitroso compound was directly used for
Baeyer-Mills coupling.
Example reaction: 28.2 mg (0.100 mmol, 1.00 equiv.) (4,6-
O-benzylidene)methyl--D-mannopyranoside (3a) and
1.62 mg (0.00201 mmol, 0.0201 equiv.) catalyst 6 were
dissolved in 9.5 mL dry toluene. After equilibration, 10.2 mg
(9.44 µL, 0.100 mmol, 1.00 equiv.) acetic anhydride was
dissolved in 0.50 mL dry toluene and added to the
substrate-catalyst solution under exclusion of ambient light.
The resulting mixture was stirred for 18 h. The remaining
acetic anhydride was quenched by the addition of some
drops of methanol. All volatiles were removed under
reduced pressure and the resulting solid was directly
dissolved in 0.6 mL deuterated methanol and used for NMR
analysis without further purification.
Procedure 4b: Oxidation using potassium peroxymonosulfate
(Oxone®) Aniline derivative was dissolved in DCM and
oxone® dissolved in demineralized water was added. The
resulting biphasic mixture was vigorously stirred at r.t. and
the reaction monitored via TLC. After completion the
organic phase was separated, and the aqueous phase was
extracted twice with DCM. The combined organic layers
were dried over MgSO4 and the solvent was removed under
reduced pressure. The crude product was purified via
column chromatography. The green fractions were
collected to obtain the nitroso compound as slightly green
solid. The nitroso compound was directly used for Baeyer-
Mills coupling.
(4,6-O-naphtylidene)methyl--D-mannopyranoside (3b) 4.12
g Methyl--D-mannopyranoside (21.2 mmol, 1.00 equiv.)
were suspended in 32 mL CH3CN/DMF (1:1), 5.00 g 2-
naphthaldehyde (32.0 mmol, 1.51 equiv.) and 0.100 g
pTsOH (0.581 mmol, 0.0274 equiv.) were added. The
resulting mixture was stirred at r.t. for 48 h. The suspension
was poured into water (30 mL) containing 0.250 g of
bicarbonate. The aqueous phase was extracted three times
Procedure 5: Azo-coupling (Baeyer-Mills coupling)23 Nitroso-
and aniline derivatives (1:1) were dissolved under Ar in dry
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using 25 mL CH2Cl2. The combined extracts were dried over
Page 8 of 16
NMR (100 MHz, CDCl3):  = 171.2, 137.1, 129.2, 128.4, 126.3,
101.7, 100.2, 78.8, 72.4, 72.0, 69.0, 62.9, 55.7, 21.2 ppm.26
1
2
3
4
5
6
7
8
Na2SO4 and all volatiles were removed by lyophilization.
The obtained crude product was further purified via column
chromatography. Yield: 0.850 g (2.56 mmol, 12%) 3b
colorless solid. Rf = 0.31 (1:2 n-hexane:EtOAc). HRMS (ESI-
TOF): m/z = [M+Na]+ Calcd. for C18H20O6Na 355.1152;
Found 355.1153. IR (ATR): ν/cm–1 3198, 2902, 1129, 1109,
2,3-O-Diacetyl-(4,6-O-benzylidene)methyl-α-D-
glucopyranoside (10) Procedure 7: 28.2 g (1.00 mmol, 1.00
equiv.) (4,6-O-benzylidene)methyl-α-D-glucopyranoside,
12.2 g (0.100 mmol, 0.100 equiv.) DMAP, 13.8 g (128 L,
1.35 mmol, 1.35 equiv.) Ac2O. Yield: 44.0 g (0.120 mmol,
12%) 10 colorless solid. Rf = 0.63 (1:1 n-hexane:EtOAc). 1H
NMR (400 MHz, CDCl3):  = 7.49 – 7.41 (m, 2H), 7.40 – 7.31
(m, 3H), 5.58 (t, J = 9.7 Hz, 1H), 5.51 (s, 1H), 4.96 – 4.88 (m,
2H), 4.30 (dd, J = 10.3, 4.8 Hz, 1H), 3.93 (td, J = 9.9, 4.8 Hz,
1H), 3.77 (t, J = 10.3 Hz, 1H), 3.65 (t, J = 9.6 Hz, 1H), 3.41 (s,
3H), 2.09 (s, 3H), 2.05 (s, 3H) ppm. 13C {1H} NMR (100 MHz,
CDCl3):  = 170.6, 169.9, 137.1, 129.2, 128.4, 126.3, 101.7,
97.8, 79.4, 71.7, 69.1, 69.0, 62.5, 55.5, 21.0, 20.9 ppm.27
1
1092, 1069, 1030, 989, 856, 805, 749. H NMR (400 MHz,
MeOH-d4):  = 8.01 – 7.98 (m, 1 H, ar), 7.91 – 7.80 (m, 3 H,
ar), 7.62 (dd, J = 8.6, 1.7 Hz, 1 H, ar), 7.53 – 7.45 (m, 2 H, ar),
5.77 (s, 1 H, CH), 4.69 (d, J = 1.5 Hz, 1 H, CH), 4.25 (dd, J =
10.0, 4.8 Hz, 1 H, CH), 4.04 – 3.82 (m, 4 H, CH, CH2), 3.76
(ddd, J = 10.3, 8.8, 4.7 Hz, 1 H, CH), 3.41 (s, 3 H, CH3) ppm.
13C {1H} NMR (100 MHz, MeOH-d4):  = 136.7, 135.1, 134.3,
129.3, 128.7, 128.7, 127.4, 127.2, 126.8, 125.2, 103.8, 103.4,
80.3, 72.6, 70.0, 69.6, 65.1, 55.4 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4,6-O-acetonide)methyl--D-mannopyranoside (3c) Yield:
182 mg (0.777 mmol, 8%) 3c colorless oil. Rf = 0.23 (1:2 n-
hexane:EtOAc). 1H NMR (400 MHz, MeOH-d4):  = 4.88 (s, 1
H, CH), 4.13 – 4.08 (m, 1 H, CH), 4.00 (t, J = 6.2 Hz, 1 H, CH),
3.83 (dd, J = 11.9, 2.2 Hz, 1 H, CH), 3.65 (dd, J = 11.9, 5.5 Hz,
1 H, CH), 3.56 – 3.44 (m, 2 H, CH2), 3.40 (s, 3 H, CH3), 1.48 (s,
3 H, CH3), 1.33 (s, 3 H, CH3) ppm. 13C NMR {1H} (100 MHz,
MeOH-d4):  = 110.4, 99.4, 80.2, 77.1, 71.8, 70.2, 62.6, 55.2,
28.4, 26.5 ppm. Was synthesized according to the
literature.24
(4,6-O-methylidene)methyl--D-mannopyranoside
(3d)
Yield: 587 mg (2.85 mmol, 29%) 3d colorless solid. Rf = 0.47
1
(acetone:Et2O 2:7). H NMR (400 MHz, MeOH-d4):  = 5.00
(d, J = 6.2 Hz, 1 H, CH2), 4.66 (d, J = 6.2 Hz, 1 H, CH2), 4.62 (d,
J = 1.5 Hz, 1 H, CH), 4.05 (dd, J = 9.5, 3.7 Hz, 1 H, CH), 3.87 –
3.76 (m, 2 H, CH, CH2), 3.67 – 3.48 (m, 3 H, CH, CH2), 3.36 (s,
3 H, CH3) ppm. 13C {1H} NMR (100 MHz, MeOH-d4):  = 103.7,
95.1, 80.1, 72.6, 69.6, 69.5, 65.3, 55.3 ppm. Was synthesized
according to the literature.25
2-O-Acetyl-(4,6-O-benzylidene)methyl-α-D-glucopyranoside
(8) Procedure 7: 282 mg (1.00 mmol, 1.00 equiv.) (4,6-
O-benzylidene)methyl-α-D-glucopyranoside,
12.2
mg
(0.100 mmol, 0.100 equiv.) DMAP, 13.8 mg (128 L, 1.35
mmol, 1.35 equiv.) Ac2O. Yield: 62.0 mg (0.191 mmol, 19%)
1
8 colorless solid. Rf = 0.42 (1:1 n-hexane:EtOAc). H NMR
(400 MHz, CDCl3):  = 7.53 – 7.48 (m, 2H), 7.43 – 7.34 (m,
3H), 5.55 (s, 1H), 4.96 (d, J = 3.7 Hz, 1H), 4.81 (dd, J = 9.7, 3.8
Hz, 1H), 4.30 (dd, J = 9.9, 4.5 Hz, 1H), 4.18 (t, J = 9.5 Hz, 1H),
3.85 (td, J = 9.6, 4.5 Hz, 1H), 3.76 (t, J = 10.2 Hz, 1H), 3.56 (t,
J = 9.3 Hz, 1H), 3.41 (s, 3H), 2.46 (bs, 1H), 2.16 (s, 3H) ppm.
13C {1H} NMR (100 MHz, CDCl3):  = 170.8, 137.1, 129.5,
128.5, 126.4, 102.2, 97.7, 81.5, 73.7, 69.0, 68.8, 62.1, 55.6,
21.1 ppm.26
3-O-Acetyl-(4,6-O-benzylidene)methyl-α-D-glucopyranoside
(9) Procedure 7: 28.2 mg (1.00 mmol, 1.00 equiv.) (4,6-
O-benzylidene)methyl-α-D-glucopyranoside,
12.2
mg
(0.100 mmol, 0.100 equiv.) DMAP, 13.8 mg (128 L, 1.35
mmol, 1.35 equiv.) Ac2O. Yield: 184 mg (0.567 mmol, 57%)
1
9 colorless solid. Rf = 0.26 (1:1 n-hexane:EtOAc). H NMR
(400 MHz, CDCl3):  = 7.48 – 7.42 (m, 2H), 7.39 – 7.33 (m,
3H), 5.49 (s, 1H), 5.32 (t, J = 9.7 Hz, 1H), 4.81 (d, J = 3.8 Hz,
1H), 4.30 (dd, J = 10.2, 4.7 Hz, 1H), 3.87 (td, J = 9.8, 4.7 Hz,
1H), 3.75 (t, J = 10.3 Hz, 1H), 3.66 (dd, J = 9.5, 3.8 Hz, 1H),
3.58 (t, J = 9.6 Hz, 1H), 3.47 (s, 3H), 2.12 (s, 3H) ppm. 13C {1H}
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Yield: 33.0 mg (0.0881 mmol, 17%) 15b colorless solid. Rf =
0.69 (1:2 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
(0.100 mmol, 0.100 equiv.) DMAP, 11.3 mg (105 L, 1.11
1
2
3
4
5
6
7
8
=
mmol, 1.11 equiv.) Ac2O. Yield: 48.0 mg (0.148 mmol, 15%)
14a colorless solid. Rf = 0.45 (2:1 n-hexane:EtOAc). 1H NMR
(400 MHz, MeOH-d4):  = 7.53 – 7.46 (m, 2H), 7.38 – 7.31 (m,
3H), 5.64 (s, 1H), 5.10 (dd, J = 3.7, 1.5 Hz, 1H), 4.67 (d, J = 1.6
Hz, 1H), 4.22 (dd, J = 9.7, 4.4 Hz, 1H), 4.12 – 4.06 (m, 1H),
3.91 (dd, J = 10.0, 9.0 Hz, 1H), 3.86 – 3.80 (m, 1H), 3.79 –
3.72 (m, 1H), 3.40 (s, 3H), 2.13 (s, 3H) ppm. 13C {1H} NMR
(100 MHz, MeOH-d4):  = 172.0, 139.2, 129.9, 129.3, 129.0,
127.8, 127.5, 103.3, 100.9, 80.2, 74.0, 69.7, 67.9, 65.0, 55.5,
20.8 ppm.30
[M+Na]+ Calcd. for C20H22O7Na 397.1258; Found 397.1256.
IR (ATR): ν/cm-1 3470, 2912, 1735, 1370, 1234, 1127, 1091,
1058, 1031, 975, 734, 480. 1H NMR (400 MHz, MeOH-d4): 
= 7.92 – 7.88 (m, 1H), 7.86 – 7.79 (m, 3H), 7.54 (dd, J = 8.5,
1.7 Hz, 1H), 7.48 – 7.43 (m, 2H), 5.72 (s, 1H), 5.19 (dd, J =
10.3, 3.3 Hz, 1H), 4.71 (d, J = 1.7 Hz, 1H), 4.33 – 4.18 (m, 2H),
4.10 (dd, J = 3.4, 1.6 Hz, 1H), 3.95 – 3.85 (m, 2H), 3.39 (s, 3H),
2.06 (s, 3H) ppm. 13C {1H} NMR (100 MHz, MeOH-d4):  =
172.2, 136.3, 135.0, 134.2, 129.3, 128.9, 128.7, 127.5, 127.2,
126.8, 125.0, 103.5, 103.4, 77.4, 72.4, 70.1, 69.8, 65.3, 55.4,
20.9 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
34
35
36
37
38
39
40
41
42
43
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53
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55
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60
3-O-Acetyl-(4,6-O-benzylidene)methyl-α-D-mannopyranoside
(15a) Procedure 7: 28.2 mg (1.00 mmol, 1.00 equiv.) (4,6-
O-benzylidene)methyl-α-D-mannopyranoside, 12.2 mg
(0.100 mmol, 0.100 equiv.) DMAP, 11.3 mg (105 L, 1.11
mmol, 1.11 equiv.) Ac2O. Yield: 225 mg (0.694 mmol, 69%)
15a colorless solid. Rf = 0.29 (2:1 n-hexane:EtOAc). 1H NMR
(400 MHz, MeOH-d4):  = 7.47 – 7.39 (m, 2H), 7.39 – 7.30 (m,
3H), 5.59 (s, 1H), 5.13 (dd, J = 10.3, 3.4 Hz, 1H), 4.69 (d, J =
1.6 Hz, 1H), 4.28 – 4.17 (m, 1H), 4.17 – 4.08 (m, 1H), 4.06
(dd, J = 3.7, 1.9 Hz, 1H), 3.90 – 3.77 (m, 2H), 3.41 (s, 3H), 2.07
(s, 3H) ppm. 13C {1H} NMR (100 MHz, MeOH-d4):  = 172.3,
139.0, 130.0, 129.1, 127.5, 103.6, 103.3, 77.3, 72.4, 70.1,
69.8, 65.3, 55.4, 20.9, 20.9 ppm.31
2,3-O-Diacetyl-(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside (16b) Procedure 7: 169 mg (0.509 mmol,
1.00
equiv.)
(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside, 6.22 mg (0.0509 mmol, 0.100 equiv.)
DMAP, 65.9 mg (61.0 L, 0.646 mmol, 1.27 equiv.) Ac2O.
Yield: 44.0 mg (0.106 mmol, 21%) 16b colorless solid. Rf =
0.79 (1:2 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
=
[M+Na]+ Calcd. for C22H24O8Na 439.1309; Found 439.1307.
IR (ATR): ν/cm–1 2935, 1746, 1370, 1237, 1217, 1128, 1073,
1030, 972, 736, 479. 1H NMR (400 MHz, MeOH-d4):  = 7.92
(s, 1H), 7.89 – 7.82 (m, 3H), 7.56 (dd, J = 8.5, 1.7 Hz, 1H), 7.51
– 7.46 (m, 2H), 5.80 (s, 1H), 5.34 – 5.28 (m, 2H), 4.74 (d, J =
1.3 Hz, 1H), 4.34 – 4.27 (m, 1H), 4.20 – 4.13 (m, 1H), 3.98 –
2,3-O-Diacetyl-(4,6-O-benzylidene)methyl-α-D-
mannopyranoside (16a) Procedure 7: 28.2 mg (1.00 mmol,
3.90 (m, 2H), 3.45 (s, 3H), 2.15 (s, 3H), 1.97 (s, 3H) ppm. 13
C
1.00
equiv.)
(4,6-O-benzylidene)methyl-α-D-
{1H} NMR (100 MHz, MeOH-d4):  = 171.9, 171.6, 136.2,
135.2, 134.3, 129.3, 128.9, 128.7, 127.5, 127.3, 126.9, 125.0,
103.4, 101.0, 77.4, 71.1, 70.1, 69.7, 65.2, 55.6, 20.7, 20.6
ppm.
mannopyranoside, 12.2 mg (0.100 mmol, 0.100 equiv.)
DMAP, 11.3 mg (105 L, 1.11 mmol, 1.11 equiv.) Ac2O. Yield:
44.0 mg (0.120 mmol, 12%) 16a colorless solid. Rf = 0.59
(2:1 n-hexane:EtOAc). 1H NMR (400 MHz, MeOH-d4):  =
7.48 – 7.40 (m, 2H), 7.37 – 7.30 (m, 3H), 5.63 (s, 1H), 5.31 –
5.25 (m, 2H), 4.72 (d, J = 1.3 Hz, 1H), 4.31 – 4.20 (m, 1H),
4.15 – 4.08 (m, 1H), 3.94 – 3.82 (m, 2H), 3.43 (s, 3H), 2.14 (s,
3H), 1.97 (s, 3H) ppm. 13C {1H} NMR (100 MHz, MeOH-d4): 
= 171.8, 171.6, 138.9, 130.1, 129.1, 127.5, 103.3, 101.0, 77.3,
71.1, 70.0, 69.7, 65.2, 55.6, 20.9, 20.6, 20.6 ppm.32
2-O-Acetyl-(4,6-O-acetonide)methyl-α-D-mannopyranoside
(14c) Procedure 7: 101 mg (0.431 mmol, 1.00 equiv.) (4,6-
O-acetonide)methyl-α-D-mannopyranoside,
5.00
mg
(0.0409 mmol, 0.095 equiv.) DMAP, 57.2 mg (53.0 L, 0.560
mmol, 1.30 equiv.) Ac2O. Yield: 54.0 mg (0.195 mmol, 45%)
14c colorless liquid. Rf = 0.43 (1:1 n-hexane:EtOAc). HRMS
(ESI-TOF): m/z = [M+Na]+ Calcd. for C12H20O7Na 299.1101;
Found 299.1103. IR (ATR): ν/cm–1 3482, 2912, 1733, 1374,
1240, 1224, 1137, 1091, 1034, 975, 859. 1H NMR (400 MHz,
MeOH-d4):  = 4.97 – 4.90 (m, 2H), 4.21 – 4.14 (m, 2H), 3.67
– 3.56 (m, 2H), 3.52 (dd, J = 12.1, 6.3 Hz, 1H), 3.41 (s, 3H),
2.08 (s, 3H), 1.49 (s, 3H), 1.32 (s, 3H) ppm. 13C {1H} NMR
(150 MHz, MeOH-d4):  = 171.9, 110.9, 99.3, 77.3, 77.2, 71.5,
69.9, 62.3, 55.3, 28.0, 26.6, 20.8 ppm.
2-O-Acetyl-(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside (14b) Procedure 7: 169 mg (0.509 mmol,
1.00
equiv.)
(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside, 6.22 mg (0.0509 mmol, 0.100 equiv.)
DMAP, 65.9 mg (61.0 L, 0.646 mmol, 1.27 equiv.) Ac2O.
Yield: 110 mg (0.294 mmol, 58%) 14b colorless solid. Rf =
0.50 (1:2 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
=
[M+Na]+ Calcd. for C20H22O7Na 397.1258; Found 397.1255.
IR (ATR): ν/cm-1 3460, 2912, 1744, 1374, 1232, 1128, 1096,
1071, 1030, 972, 734, 477. 1H NMR (400 MHz, MeOH-d4): 
= 7.99 (s, 1H), 7.89 – 7.82 (m, 3H), 7.62 (dd, J = 8.5, 1.7 Hz,
1H), 7.52 – 7.46 (m, 2H), 5.80 (s, 1H), 5.13 (dd, J = 3.7, 1.6
Hz, 1H), 4.69 (d, J = 1.5 Hz, 1H), 4.28 (dd, J = 9.8, 4.5 Hz, 1H),
4.13 (dd, J = 10.0, 3.7 Hz, 1H), 3.98 (dd, J = 10.1, 9.0 Hz, 1H),
3.92 – 3.85 (m, 1H), 3.84 – 3.77 (m, 1H), 3.41 (s, 3H), 2.15 (s,
3H) ppm. 13C {1H} NMR (100 MHz, MeOH-d4):  = 172.0,
136.5, 135.1, 134.3, 129.3, 128.8, 128.7, 127.5, 127.2, 126.8,
125.2, 103.4, 100.9, 80.3, 74.0, 69.8, 68.0, 65.1, 55.5, 20.8
ppm.
3-O-Acetyl-(4,6-O-acetonide)methyl-α-D-mannopyranoside
(15c) Procedure 7: 101 mg (0.431 mmol, 1.00 equiv.) (4,6-
O-acetonide)methyl-α-D-mannopyranoside,
5.00
mg
(0.0409 mmol, 0.095 equiv.) DMAP, 57.2 mg (53.0 L, 0.560
mmol, 1.30 equiv.) Ac2O. Yield: 19.0 mg (0.0688 mmol,
16%) 15c colorless liquid. Rf = 0.33 (1:1 n-hexane:EtOAc).
HRMS (ESI-TOF): m/z = [M+Na]+ Calcd. for C12H20O7Na
299.1101; Found 299.1103. IR (ATR): ν/cm–1 3462, 2938,
1740, 1370, 1240, 1219, 1141, 1083, 1051, 1017, 970, 857.
1H NMR (400 MHz, MeOH-d4):  = 4.88 – 4.85 (m, 1H), 4.38
(dt, J = 11.9, 2.1 Hz, 1H), 4.17 (ddd, J = 11.8, 6.6, 2.0 Hz, 1H),
4.12 (dd, J = 5.7, 2.0 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.70 – 3.63
(m, 1H), 3.54 – 3.47 (m, 1H), 3.39 (s, 3H), 2.07 (s, 3H), 1.49
(s, 3H), 1.34 (s, 3H) ppm. 13C {1H} NMR (100 MHz, MeOH-
d4):  = 172.7, 110.5, 99.4, 80.0, 77.0, 70.2, 69.2, 64.8, 55.2,
28.4, 26.5, 20.7 ppm.
3-O-Acetyl-(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside (15b) Procedure 7: 169 mg (0.509 mmol,
1.00
equiv.)
(4,6-O-naphtylidene)methyl-α-D-
mannopyranoside, 6.22 mg (0.0509 mmol, 0.100 equiv.)
DMAP, 65.9 mg (61.0 L, 0.646 mmol, 1.27 equiv.) Ac2O.
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2,3-O-Diacetyl-(4,6-O-acetonide)methyl-α-D-
mannopyranoside (16c) Procedure 7: 101 mg (0.431 mmol,
1.00 equiv.) (4,6-O-acetonide)methyl-α-D-
J = 10.1 Hz, 1H), 3.41 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H) ppm.
13C {1H} NMR (100 MHz, CDCl3):  = 171.7, 171.5, 100.9,
1
2
95.0, 77.3, 71.1, 69.9, 69.3, 65.3, 55.6, 20.6, 20.6 ppm.
mannopyranoside, 5.00 mg (0.0409 mmol, 0.095 equiv.)
DMAP, 57.2 mg (53.0 L, 0.560 mmol, 1.30 equiv.) Ac2O.
Yield: 22.0 mg (0.0691 mmol, 16%) 16c colorless liquid. Rf
= 0.70 (1:1 n-hexane:EtOAc). HRMS (ESI-TOF): m/z =
[M+Na]+ Calcd. for C14H22O8Na 341.1207; Found 341.1208.
IR (ATR): ν/cm–1 2988, 1741, 1370, 1217, 1137, 1088, 1040,
3
4
5
6
7
8
9
2-(2,2-diphenyl-1,3-benzodioxol-5-yl)-3,5,7-trihydroxy-4H-1-
benzopyran-4-one (17) Yield: 0.930 g (1.99 mmol, 66%) 17
pale yellow solid. Rf = 0.35 (2:1 n-hexane:EtOAc). H NMR
1
(400 MHz, DMSO-d6):  = 12.38 (s, 1H), 10.83 (s, 1H), 9.64
(s, 1H), 7.85 – 7.78 (m, 2H), 7.60 – 7.54 (m, 4H), 7.49 – 7.42
(m, 6H), 7.22 (dd, J = 8.2, 0.6 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H),
6.20 (d, J = 2.1 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6):
 = 176.0, 164.1, 160.7, 156.2, 147.6, 146.7, 145.6, 139.4,
136.4, 129.5, 128.6, 125.8, 125.2, 123.0, 117.1, 108.8, 107.8,
103.1, 98.3, 93.6 ppm. Was synthesized according to the
literature.21
1
975, 856, 737, 519. H NMR (400 MHz, MeOH-d4):  = 5.00
(dd, J = 10.4, 7.3 Hz, 1H), 4.93 (s, 1H), 4.26 – 4.15 (m, 3H),
4.05 (dd, J = 12.2, 2.5 Hz, 1H), 3.83 (dddd, J = 10.4, 5.6, 2.6,
0.7 Hz, 1H), 3.40 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 1.50 (s,
3H), 1.33 (d, J = 0.7 Hz, 3H) ppm. 13C {1H} NMR (150 MHz,
CDCl3):  = 172.4, 171.7, 111.0, 99.5, 77.2, 77.1, 70.9, 67.3,
63.6, 55.4, 28.0, 26.6, 20.8, 20.7 ppm.
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16
17
18
19
20
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23
24
25
26
27
28
29
30
31
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59
60
7-Acetyl-2-(2,2-diphenyl-1,3-benzodioxol-5-yl)-3,5-
dihydroxy-4H-1-benzopyran-4-one (18) Procedure 7: 330 mg
(0.707 mmol, 1.00 equiv.) 2-(2,2-diphenyl-1,3-benzodioxol-
5-yl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one 17, 8.64 mg
(0.0707 mmol, 0.100 equiv.) DMAP, 94.0 mg (87.0 L, 0.921
mmol, 1.30 equiv.) Ac2O. Yield: 10.0 mg (0.0197 mmol, 3%)
18 colorless solid. Rf = 0.56 (CH2Cl2). HRMS (ESI-TOF): m/z
2-O-Acetyl-(4,6-O-methylidene)methyl-α-D-
mannopyranoside (14d) Procedure 7: 128 mg (0.621 mmol,
1.00
equiv.)
(4,6-O-methylidene)methyl-α-D-
mannopyranoside, 7.60 mg (0.0622 mmol, 0.100 equiv.)
DMAP, 82.1 mg (76.0 L, 0.805 mmol, 1.30 equiv.) Ac2O.
Yield: 30.0 mg (0.121 mmol, 19%) 14d colorless solid. Rf =
=
[M+Na]+ Calcd. for C30H20O8Na 531.1050; Found
0.24 (1:1 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
=
531.1048. IR (ATR): ν/cm–1 3335, 1772, 1606, 1486, 1180,
[M+Na]+ Calcd. for C10H16O7Na 271.0788; Found 271.0789.
IR (ATR): ν/cm–1 3466, 2913, 1737, 1369, 1234, 1165, 1130,
1057, 1030, 1004, 960, 921, 889. 1H NMR (400 MHz, MeOH-
d4):  = 5.07 – 5.03 (m, 1H), 4.97 (d, J = 6.3 Hz, 1H), 4.65 (d,
J = 6.3 Hz, 1H), 4.63 (dd, J = 5.8, 1.6 Hz, 1H), 4.09 – 4.06 (m,
1H), 4.01 (dd, J = 3.4, 1.7 Hz, 1H), 3.87 – 3.81 (m, 1H), 3.74 –
3.67 (m, 1H), 3.60 – 3.52 (m, 2H), 3.39 (s, 3H), 2.08 (s, 3H)
ppm. 13C {1H} NMR (100 MHz, MeOH-d4):  = 172.2, 103.5,
95.0, 77.3, 72.3, 70.2, 69.5, 65.4, 55.4, 20.9 ppm.
1
1130, 1017, 823, 697. H NMR (400 MHz, DMSO-d6):  =
12.44 (s, 1H), 9.97 (s, 1H), 7.89 – 7.85 (m, 2H), 7.59 – 7.55
(m, 4H), 7.50 – 7.43 (m, 6H), 7.27 – 7.22 (m, 1H), 7.06 (d, J =
2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 2.30 (s, 3H). 13C {1H} NMR
(100 MHz, DMSO-d6):  = 176.6, 168.5, 160.0, 155.5, 154.9,
148.0, 147.0, 146.7, 139.3, 137.2, 129.5, 128.6, 125.8, 124.9,
123.5, 117.2, 108.9, 108.0, 107.4, 104.1, 101.4, 54.9, 20.9
ppm.
3-Acetyl-2-(2,2-diphenyl-1,3-benzodioxol-5-yl)-5,7-
3-O-Acetyl-(4,6-O-methylidene)methyl-α-D-
mannopyranoside (15d) Procedure 7: 128 mg (0.621 mmol,
dihydroxy-4H-1-benzopyran-4-one (19) Procedure 7: 0.330 g
(0.707 mmol, 1.00 equiv.) 2-(2,2-diphenyl-1,3-benzodioxol-
5-yl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one 17, 8.64 mg
(0.0707 mmol, 0.100 equiv.) DMAP, 94.0 mg (87.0 L, 0.921
mmol, 1.30 equiv.) Ac2O. Yield: 27.0 mg (0.0531 mmol, 8%)
19 colorless solid. Rf = 0.59 (CH2Cl2). HRMS (ESI-TOF): m/z
1.00
equiv.)
(4,6-O-methylidene)methyl-α-D-
mannopyranoside, 7.60 mg (0.0622 mmol, 0.100 equiv.)
DMAP, 82.1 mg (76.0 L, 0.805 mmol, 1.30 equiv.) Ac2O.
Yield: 3.00 mg (0.0121 mmol, 2%) 15d colorless solid. Rf =
0.08 (1:1 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
=
=
[M+Na]+ Calcd. for C30H20O8Na 531.1050; Found
[M+Na]+ Calcd. for C10H16O7Na 271.0788; Found 271.0789.
531.1048. IR (ATR): ν/cm–1 3335, 1772, 1644, 1606, 1487,
1369, 1243, 1180, 1130, 1017, 823, 697. 1H NMR (400 MHz,
DMSO-d6):  = 12.10 (s, 1H), 11.07 (s, 1H), 7.61 – 7.53 (m,
5H), 7.52 – 7.43 (m, 7H), 7.25 (d, J = 8.3 Hz, 1H), 6.52 (d, J =
2.1 Hz, 1H), 6.26 (d, J = 2.1 Hz, 1H), 2.32 (s, 3H) ppm. 13C {1H}
NMR (100 MHz, DMSO-d6):  = 174.9, 168.0, 164.8, 161.0,
156.7, 155.2, 149.0, 147.0, 139.1, 130.3, 129.7, 128.7, 125.8,
124.0, 123.0, 117.6, 109.3, 108.2, 103.6, 99.2, 94.4, 20.2
ppm.
IR (ATR): ν/cm–1 3467, 2939, 1737, 1443, 1369, 1230, 1164,
1
1082, 1041, 1021, 942. H NMR (400 MHz, MeOH-d4):  =
5.13 (d, J = 0.8 Hz, 1H), 4.97 – 4.95 (m, 1H), 4.93 – 4.92 (m,
1H), 4.39 (dd, J = 11.9, 2.3 Hz, 1H), 4.17 (dd, J = 11.8, 6.4 Hz,
1H), 4.11 – 4.07 (m, 1H), 3.86 (dd, J = 5.6, 0.8 Hz, 1H), 3.70
(dddd, J = 10.4, 6.4, 2.3, 0.6 Hz, 1H), 3.44 (dd, J = 10.4, 7.4 Hz,
1H), 3.39 (s, 3H), 2.06 (s, 3H) ppm. 13C {1H} NMR (100 MHz,
CDCl3):  = 172.7, 99.4, 95.6, 79.3, 77.6, 69.1, 67.9, 64.8, 55.2,
20.7 ppm.
3,7-Diacetyl-2-(2,2-diphenyl-1,3-benzodioxol-5-yl)-5-
2,3-O-Diacetyl-(4,6-O-methylidene)methyl-α-D-
mannopyranoside (16d) Procedure 7: 128 mg (0.621 mmol,
hydroxy-4H-1-benzopyran-4-one (20) Procedure 7: 0.330 g
(0.707 mmol, 1.00 equiv.) 2-(2,2-diphenyl-1,3-benzodioxol-
5-yl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one 17, 8.64 mg
(0.0707 mmol, 0.100 equiv.) DMAP, 94.0 mg (87.0 L, 0.920
mmol, 1.30 equiv.) Ac2O. Yield: 23.0 mg (0.0418 mmol, 6%)
20 colorless solid. Rf = 0.32 (CH2Cl2). HRMS (ESI-TOF): m/z
= [M+H]+ Calcd. for C32H23O8 551.1337; Found 551.1337. IR
(ATR): ν/cm–1 1776, 1652, 1607, 1486, 1449, 1176, 1135,
1017, 697. 1H NMR (400 MHz, DMSO-d6):  = 12.11 (s, 1H),
7.62 (d, J = 1.8 Hz, 1H), 7.59 – 7.53 (m, 5H), 7.52 – 7.42 (m,
6H), 7.27 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.73 (d,
J = 2.0 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 3H) ppm. 13C {1H} NMR
1.00
equiv.)
(4,6-O-methylidene)methyl-α-D-
mannopyranoside, 7.60 mg (0.0622 mmol, 0.100 equiv.)
DMAP, 82.1 mg (76.0 L, 0.805 mmol, 1.30 equiv.) Ac2O.
Yield: 30.0 mg (0.103 mmol, 17%) 16d colorless solid. Rf =
0.51 (1:1 n-hexane:EtOAc). HRMS (ESI-TOF): m/z
=
[M+Na]+ Calcd. for C12H18O8Na 313.0894; Found 313.0896.
IR (ATR): ν/cm–1 2927, 1728, 1455, 1370, 1222, 1159, 1114,
1
1081, 1065, 1030, 964, 949, 862, 620. H NMR (400 MHz,
MeOH-d4):  = 5.24 (dd, J = 3.6, 1.6 Hz, 1H), 5.22 – 5.17 (m,
1H), 5.00 – 4.95 (m, 2H), 4.69 (d, J = 6.3 Hz, 1H), 4.67 (d, J =
1.6 Hz, 1H), 4.14 – 4.07 (m, 1H), 3.79 – 3.76 (m, 1H), 3.57 (t,
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The Journal of Organic Chemistry
(d, J = 7.2 Hz, 3 H, CH3) ppm. 13C {1H} NMR (100 MHz, CDCl3):
(100 MHz, DMSO-d6):  = 175.5, 168.4, 167.8, 160.3, 156.3,
1
2
3
156.2, 155.5, 149.3, 147.1, 139.0, 130.9, 129.7, 128.7, 125.8,
124.4, 122.7, 117.7, 109.4, 108.4, 107.9, 105.5, 102.0, 20.9,
20.2 ppm.
 = 170.6 (C=O), 156.0 (C=O), 143.4, 129.3, 122.0, 115.6,
80.6, 50.7, 28.5, 18.0 ppm.
Carbamic acid-N-[(1S)-2-[(4-aminophenyl)amino]-2-oxo-1-
4
5
6
7
8
9
L-Phenylalanine-N-(4-nitrobenzoyl)-methyl
ester
(21)
(cyclohexylmethyl)ethyl]-1,1-dimethylethyl
ester
(25)
Procedure 1: 5.12 g (30.6 mmol, 1.00 equiv.) p-Nitrobenzoic
acid, 8.40 g (43.8 mmol, 1.43 equiv.) EDC·HCl, 5.30 g (39.2
mmol, 1.28 equiv.) HOBt, 7.11 g (32.9 mmol, 1.08 equiv.) L-
Phe-OMe·HCl, and 3.43 g (4.72 mL, 33.9 mmol, 1.11 equiv.)
TEA in 175 mL CH2Cl2.Yield: 9.13 g (27.8 mmol, 91%) 21
colorless solid. 1H NMR (400 MHz, CDCl3):  = 8.30–8.25 (m,
2 H, ar), 7.89–7.84 (m, 2 H, ar), 7.34–7.24 (m, 3 H, ar), 7.14–
7.09 (m, 2 H, ar), 6.62 (d, J = 7.5 Hz, 1 H, NH), 5.12–5.05 (m,
1 H, CH), 3.80 (s, 3 H, CH3), 3.32 (dd, J = 13.9, 5.8 Hz, 1 H,
CH2), 3.24 (dd, J = 13.9, 5.4 Hz, 1 H, CH2) ppm. 13C {1H} NMR
(100 MHz, CDCl3):  = 171.9 (C=O), 164.9 (C=O), 149.9,
139.5, 135.6, 129.4, 128.9, 128.4, 127.6, 124.0, 53.8, 52.8,
37.8 ppm.33
Procedure 1 (not washed with citric acid): 2.16 g (20.0 mmol,
1.00 equiv.) p-Phenylenediamine, 4.22 g (22.0 mmol, 1.10
equiv.) EDC·HCl, 3.37 g (22.0 mmol, 1.10 equiv.) HOBt, 9.05
g (20.0 mmol, 1.00 equiv.) Boc-L-Cha-OH, and 2.23 g (3.05
mL, 22.0 mmol, 1.10 equiv.) TEA in 200 mL CH2Cl2. Yield:
3.13 g (8.66 mmol, 43%) 25 colorless solid. Rf = 0.38
(CH2Cl2:MeOH 20:1). HRMS (ESI-TOF): m/z = [M+Na]+
Calcd. for C20H31N3O3Na 384.2258; Found 384.2261. IR
(ATR): ν/cm–1 3285, 2921, 2850, 1656, 1606, 1513, 1429,
1365, 1281, 1247, 1162, 1023, 828, 520. 1H NMR (400 MHz,
CDCl3):  = 8.77 (s, 1 H, NH), 7.21 (d, J = 8.2 Hz, 2 H, ar), 6.50
(s, 2 H, ar), 5.49 (d, J = 8.3 Hz, 1 H, NH), 4.39 (s, 1 H, CH), 3.53
(s, 2 H, NH2), 1.88 – 1.50 (m, 7 H, CH, CH2), 1.40 (s, 9 H, CH3),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.29 – 1.05 (m, 4 H, CH2), 1.02 – 0.81 (m, 2 H, CH2) ppm. 13
C
L-Phenylalanine-N-(4-aminobenzoyl)-methyl ester (22)
Procedure 3: 1.64 g (5.00 mmol, 1.00 equiv.) 21, 0.540 g
(0.507 mmol, 0.101 equiv.) Pd/C (10%) in 50 mL MeOH.
Yield: 1.41 g (4.73 mmol, 95%) 22 colorless solid. HRMS
{1H} NMR (100 MHz, CDCl3):  = 171.2 (C=O), 156.4 (C=O),
143.1, 129.6, 121.9, 115.4, 80.1, 53.2, 40.2, 34.2, 33.8, 32.7,
28.4, 26.6, 26.4, 26.2 ppm.
(ESI-TOF): m/z
=
[M+Na]+ Calcd. for C17H18N2O3Na
4,4'-Azobenzenedicarboxylic acid (26) Yield: 2.96 g (11.0
mmol, 74%) 26 pale orange solid. 1H NMR (400 MHz,
DMSO-d6):  = 13.15 (bs, 2 H, COOH), 8.38 – 8.30 (m, 4 H, ar),
8.22 – 8.14 (m, 4 H, ar) ppm. 13C {1H} NMR (100 MHz, DMSO-
d6):  = 166.6, 154.1, 133.4, 130.6, 122.8 ppm. Was
synthesized according to the literature.34
321.1210; Found 321.1211. IR (ATR): ν/cm–1 3338, 1742,
1627, 1602, 1503, 1294, 1273, 1216, 1184, 1169, 982, 832,
772, 699. 1H NMR (400 MHz, CDCl3):  = 7.58–7.53 (m, 2 H,
ar), 7.31–7.21 (m, 3 H, ar), 7.15–7.10 (m, 2 H, ar), 6.65–6.60
(m, 2 H, ar), 6.43 (d, J = 7.2 Hz, 1 H, NH), 5.10–5.04 (m, 1 H,
CH), 3.99 (bs, 2 H, NH2), 3.74 (s, 3 H, CH3), 3,26 (dd, J = 13,8,
5,8 Hz, 1 H, CH2), 3,20 (dd, J = 13,8, 5,4 Hz, 1 H, CH2) ppm.
13C {1H} NMR (100 MHz, CDCl3):  = 172.5 (C=O), 166.6
(C=O), 150.0, 136.2, 129.5, 129.0, 128.7, 127.2, 123.4, 114.2,
53.5, 52.5, 38.1 ppm.
Methyl
methyl-3H-imidazol-4-
(2S)-2-{p-[(E)-p-{[(1S)-1-methoxycarbonyl-2-(3-
yl)ethylamino]carbonyl}phenylazo]benzoylamino}-3-(3-
methyl-3H-imidazol-4-yl)propionate (4) Procedure 1: 270
mg (1.00 mmol, 1.00 equiv.) 26, 436 mg (2.27 mmol, 2.27
equiv.) EDC·HCl, 339 mg (2.21 mmol, 2.21 equiv.) HOBt, 452
mg (2.47 mmol, 2.47 equiv.) H-L-Pmh-OMe, and 223 mg
(307 L, 2.20 mmol, 2.20 equiv.) TEA in 25 mL acetonitrile.
Yield: 74.0 mg (0.123 mmol, 12%) 4 red solid. HRMS (ESI-
TOF): m/z = [M+H]+ Calcd. for C30H33N8O6 601.2518; Found
601.2520. IR (ATR): ν/cm–1 1737, 1642, 1536, 1508, 1499,
L-Phenylalanine-N-(4-nitrosobenzoyl)-methyl ester (23)
Procedure 4a: 0.581 g (1.95 mmol, 1.00 equiv.) 22, 1.13 g
(6.55 mmol, 3.36 equiv.) mCPBA in 40 mL THF. Yield: 0.372
g (1.19 mmol, 61%) 23 pale green solid. Rf = 0.61 (n-
hexane:EtOAc 1:1). HRMS (ESI-TOF): m/z = [M+Na]+ Calcd.
for C17H16N2O4Na 335.1002; Found 335.1005. 1H NMR (400
MHz, CDCl3):  = 8.00 – 7.87 (m, 4H), 7.36 – 7.22 (m, 3H),
7.19 – 7.07 (m, 2H), 6.63 (d, J = 7.5 Hz, 1H), 5.10 (dt, J = 7.6,
5.6 Hz, 1H), 3.80 (s, 3H), 3.33 (dd, J = 13.9, 5.7 Hz, 1H), 3.25
(dd, J = 13.9, 5.4 Hz, 1H) ppm. 13C {1H} NMR (100 MHz,
CDCl3):  = 171.9 (C=O), 165.5, 164.6, 139.3, 135.7, 129.4,
128.9, 128.6, 127.6, 121.0, 53.9, 52.8, 37.9 ppm. Note: The
product was directly used for the subsequent step due to air
sensitivity.
1
1330, 1284, 1217, 1170, 1106, 1010, 863, 774, 661. H NMR
(400 MHz, CDCl3):  = 7.92 (bs, 8 H, ar), 7.40 – 7.36 (m, 2 H,
ar), 7.27 (d, J = 5.1, 2 H, ar), 6.85 – 6.82 (m, 2 H, NH), 5.04
(dt, J = 7.3, 5.9 Hz, 2 H, CH), 3.81 (s, 6 H, CH3), 3.58 (s, 6 H,
CH3), 3.26 (dd, J = 15.5, 5.9 Hz, 2 H, CH2), 3.19 (dd, J = 15.5,
5.9 Hz, 2 H, CH2) ppm. 13C {1H} NMR (100 MHz, CDCl3):  =
171.7, 166.4, 154.4, 138.7, 135.8, 128.3, 126.6, 123.4, 60.5,
53.0, 52.4, 31.6, 26.5 ppm. UV/Vis: (E) →*, λmax = 320 nm;
n→*, λmax = 440 nm; (Z) n→*, λmax = 440 nm.
Carbamic acid-N-[(1S)-2-[(4-aminophenyl)amino]-2-oxo-1-
(methyl)ethyl]-1,1-dimethylethyl ester (24) Procedure 1 (not
washed with citric acid): 3.24 g (30.0 mmol, 1.00 equiv.) p-
Phenylenediamine, 8.40 g (43.8 mmol, 1.46 equiv.) EDC·HCl,
5.29 g (39.2 mmol, 1.3 equiv.) HOBt, 6.45 g (34.1 mmol, 1.14
equiv.) Boc-L-Ala-OH, and 3.50 g (4.82 mL, 34.6 mmol, 1.15
equiv.) TEA in 175 mL CH2Cl2. Yield: 1.12 g (4.01 mmol,
13%) 24 colorless solid. Rf = 0.41 (CH2Cl2:MeOH 7:1). HRMS
Methyl
(2S)-2-(p-{(E)-p-[(2S)-2-(tert-
butoxycarbonylamino)propionylamino]phenylazo}benzoyla
mino)-3-phenylpropionate (27) Procedure 5: 83.0 mg (0.266
mmol, 1.00 equiv.) 23, 169 mg (0.605 mmol, 2.27 equiv.) 24,
and 145 mg (138 L, 2.42 mmol, 9.10 equiv.) AcOH in 10 mL
PhMe. Yield: 109 mg (0.190 mmol, 72%) 27 orange solid. Rf
= 0.30 (n-hexane:EtOAc 1:1). HRMS (ESI-TOF): m/z =
[M+Na]+ Calcd. for C31H35N5O6Na 596.2479; Found
596.2477. IR (ATR): ν/cm–1 1743, 1668, 1642, 1597, 1520,
1449, 1366, 1246, 1156, 858, 699. 1H NMR (400 MHz,
CDCl3):  = 9.19 (s, 1H), 7.77 – 7.61 (m, 6H), 7.55 (d, J = 8.5
Hz, 2H), 7.28 – 7.15 (m, 3H), 7.14 – 7.09 (m, 2H), 6.96 (d, J =
7.5 Hz, 1H), 5.34 (d, J = 7.3 Hz, 1H), 5.02 (dt, J = 7.6, 6.0 Hz,
(ESI-TOF): m/z
=
[M+Na]+ Calcd. for C14H21N3O3Na
302.1475; Found 302.1473. IR (ATR): ν/cm–1 3322, 1688,
1667, 1512, 1313, 1244, 1167, 1070, 1048, 836, 670. 1H
NMR (400 MHz, CDCl3):  = 8.11 (bs, 1 H, NH), 7.29–7.22 (m,
2 H, ar), 6.65–6.59 (m, 2 H, ar), 5.19–5.00 (m, 1 H, NH), 4.37–
4.20 (m, 1 H, CH), 3.59 (bs, 2 H, NH2), 1.45 (s, 9 H, CH3), 1.42
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1H), 4.39 (s, 1H), 3.70 (s, 3H), 3.26 (dd, J = 13.8, 5.8 Hz, 1H), 5.4 Hz, 1 H, CH2), 3.01 (dd, J = 15.5, 7.6 Hz, 1 H, CH2), 1.92 –
1
2
3
4
5
6
7
8
3.18 (dd, J = 13.9, 6.4 Hz, 1H), 1.39 (s, 9H), 1.38 (s, 3H) ppm.
13C {1H} NMR (100 MHz, CDCl3):  = 172.3 (C=O), 171.8
(C=O), 166.8 (C=O), 156.5 (C=O), 154.5, 148.8, 141.3, 136.2,
135.3, 129.4, 128.8, 128.1, 127.3, 124.3, 122.8, 119.8, 81.0,
54.0, 52.6, 51.1, 37.9, 28.5, 17.7 ppm.
1.82 (m, 1 H, CH2), 1.77 – 1.54 (m, 6 H, CH, CH2), 1.43 (s, 9 H,
CH3), 1.38 – 1.06 (m, 4 H, CH2), 1.02 – 0.83 (m, 2 H, CH2) ppm.
13C {1H} NMR (100 MHz, CDCl3):  = 172.2 (C=O), 171.4
(C=O), 170.4 (C=O), 166.5 (C=O), 154.6 (C=O), 149.0, 141.4,
138.7, 136.0, 135.4, 129.5, 128.8, 128.3, 128.1, 127.4, 126.8,
124.3, 122.9, 120.2, 81.4, 53.9, 52.6, 52.4, 39.2, 38.0, 34.3,
33.7, 32.7, 31.6, 28.4, 26.4, 26.2, 26.1 ppm. UV/Vis: (E)
Methyl
(2S)-2-{p-[(E)-p-{(2S)-2-[(2S)-3-(3-methyl-3H-
imidazol-4-yl)-2-(tert-
→*, λmax = 368 nm; n→*, λmax = 449 nm; (Z) n→*, λmax
=
butoxycarbonylamino)propionylamino]propionylamino}phe
nylazo]benzoylamino}-3-phenylpropionate (5) Procedure 2:
61.0 mg (0.106 mmol, 1.00 equiv.) 27 in 2 mL 4.0 M HCl in
1,4-dioxane. Yield: 57.0 mg (0.106 mmol, >99%) 28 orange
solid. Procedure 6: 57.0 mg (0.106 mmol, 1.00 equiv.) 28,
34.0 mg (0.126 mmol, 1.19 equiv.) Boc-L-Pmh-OH, 30.0 mg
(0.156 mmol, 1.47 equiv.) EDC·HCl, 20.0 mg (0.131 mmol,
1.24 equiv.) HOBt, and 13.0 mg (18.0 µL, 0.128 mmol, 1.21
equiv.) TEA in 9 mL CH2Cl2. Yield: 43.0 mg (0.0593 mmol,
56%) 5 orange solid. Rf = 0.53 (CH2Cl2:MeOH 7:1). HRMS
449 nm.
9
Benzyl
(2S)-2-{p-[(E)-p-{(2S)-2-[(2S)-3-(3-methyl-3H-
10
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12
13
14
15
16
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23
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27
28
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60
imidazol-4-yl)-2-(tert-
butoxycarbonylamino)propionylamino]-3-
cyclohexylpropionylamino}phenylazo]benzoylamino}-3-
phenylpropionate (7) Procedure 1: 0.949 g (4.00 mmol, 1.00
equiv.) Boc-4-Abz-OH, 1.17 g (4.00 mmol, 1.00 equiv.) L-
Phe-OBn·HCl, 0.844 g (4.40 mmol, 1.10 equiv.) EDC·HCl,
0.674 g (4.40 mmol, 1.10 equiv.) HOBt, and 0.445 g (610 L,
4.40 mmol, 1.10 equiv.) TEA in 25 mL CH2Cl2. Yield: 1.78 g
(ESI-TOF): m/z
=
[M+Na]+ Calcd. for C38H44N8O7Na
747.3225; Found 747.3208. IR (ATR): ν/cm–1 1650, 1596,
1503, 1447, 1366, 1247, 1153, 859, 699. 1H NMR (400 MHz,
CDCl3):  = 9.18 (s, 1 H, NH), 7.96 – 7.71 (m, 8 H, ar), 7.52 (s,
1 H, NH), 7.34 – 7.27 (m, 3 H, ar), 7.21 – 7.10 (m, 3 H, ar),
6.91 (s, 1 H, ar), 6.70 (d, J = 7.6 Hz, 1 H, NH), 5.34 (d, J = 6.2
Hz, 1 H, NH), 5.11 (q, J = 6.1 Hz, 1 H, CH), 4.63 (t, J = 7.1 Hz,
1 H, CH), 4.38 (q, J = 6.5 Hz, 1 H), 3.78 (s, 3 H, CH3), 3.61 (s,
3 H, CH3), 3.32 (dd, J = 13.7, 5.8 Hz, 1 H, CH2), 3.25 (dd, J =
13.8, 5.5 Hz, 1 H, CH2), 3.16 (dd, J = 15.8, 5.5 Hz, 1 H, CH2),
3.05 (dd, J = 15.6, 7.4 Hz, 1 H, CH2), 1.47 (d, J = 7.1 Hz, 3 H,
CH3), 1.43 (s, 9 H, CH3) ppm. 13C {1H} NMR (100 MHz, CDCl3):
 = 172.2 (C=O), 171.2 (C=O), 170.4 (C=O), 166.4 (C=O),
154.7 (C=O), 149.0, 141.4, 136.0, 135.4, 129.5, 128.8, 128.2,
127.4, 124.4, 123.0, 120.2, 81.5, 77.2, 53.8, 52.6, 50.3, 38.1,
31.9, 28.4, 17.7 ppm. UV/Vis: (E) →*, λmax = 365 nm;
n→*, λmax = 450 nm; (Z) n→*, λmax = 450 nm.
(3.74 mmol, 94%) 31 colorless solid. Rf
= 0.72
(CH2Cl2:MeOH 20:1). Procedure 2: 1.78 g (3.74 mmol, 1.00
equiv.) 31 in 15 mL 4.0 M HCl in 1,4-dioxane. Yield: 1.54 g
(3.74 mmol, >99%) 32 colorless solid. 1.54 g (3.74 mmol,
1.00 equiv.) 32 were dissolved in 20 mL CH2Cl2 and 1.14 g
(1.56 mL, 11.2 mmol, 3.00 equiv.) TEA was added. The
resulting mixture was stirred at r.t. for 60 min. The organic
layer was washed with sat. aq. NaHCO3 and brine, dried over
MgSO4 and the solvent was removed under reduced
pressure. Yield: 1.28 g (3.43 mmol, 91%) 33 colorless solid.
Rf = 0.51 (CH2Cl2:MeOH 20:1). Procedure 4b: 1.28 g (3.43
mmol, 1.00 equiv.) 33 in 14 mL CH2Cl2, 4.80 g (15.6 mmol,
4.55 equiv.) Oxone® in 34 mL H2O (dest.). Yield: 0.413 g
(1.06 mmol, 31%) 34 pale brown solid. Rf
= 0.82
(CH2Cl2:MeOH 20:1). Procedure 5: 413 mg (1.06 mmol, 1.00
equiv.) 34, 383 mg (1.06 mmol, 1.00 equiv.) 25, and 255 mg
(243 L, 4.25 mmol, 4.01 equiv.) AcOH in 25 mL PhMe.
Yield: 268 mg (0.366 mmol, 35%) 35 red solid. Rf = 0.60
(CH2Cl2:MeOH 20:1). Procedure 2: 268 mg (0.366 mmol,
1.00 equiv.) 35 in 10 mL 4.0 M HCl in 1,4-dioxane. Yield: 248
mg (0.366 mmol, >99%) 36 deep red solid. Procedure 6: 248
mg (0.366 mmol, 1.00 equiv.) 36, 102 mg (0.379 mmol, 1.04
equiv.) Boc-L-Pmh-OH, 108 mg (0.563 mmol, 1.54 equiv.)
EDC·HCl, 87.0 mg (0.568 mmol, 1.55 equiv.) HOBt and 60.0
mg (82.6 µL, 0.593 mmol, 1.62 equiv.) TEA in 10 mL CH2Cl2.
Yield: 146 mg (0.165 mmol, 45%) 7 yellow solid. Rf = 0.74
(CH2Cl2:MeOH 20:1). HRMS (ESI-TOF): m/z = [M+H]+ Calcd.
for C50H59N8O7 883.4501; Found 883.4503. IR (ATR): ν/cm-
Methyl
(2S)-2-{p-[(E)-p-{(2S)-2-[(2S)-3-(3-methyl-3H-
imidazol-4-yl)-2-(tert-
butoxycarbonylamino)propionylamino]-3-
cyclohexylpropionylamino}phenylazo]benzoylamino}-3-
phenylpropionate (6) Procedure 5: 365 mg (1.01 mmol, 1.00
equiv.) 25, 372 mg (1.19 mmol, 1.18 equiv.) 23, and 240 mg
(0.229 mL, 4.00 mmol, 3.96 equiv.) AcOH in 35 mL PhMe.
Yield: 410 mg (0.625 mmol, 62%) 29 orange solid. Rf = 0.50
(n-hexane:EtOAc 1:1). Procedure 2: 410 mg (0.625 mmol,
1.00 equiv.) 29 in 3 mL 4.0 M HCl in 1,4-dioxane. Yield: 368
mg (0.625 mmol, >99%) 30 orange solid. Procedure 6: 368
mg (0.625 mmol, 1.00 equiv.) 30, 192 mg (0.713 mmol, 1.14
equiv.) Boc-Pmh, 181 mg (0.944 mmol, 1.51 equiv.)
EDC·HCl, 112 mg (0.731 mmol, 1.17 equiv.) HOBt, and 71.0
mg (98.0 µL, 0.702 mmol, 1.12 equiv.) TEA in 4 mL CH2Cl2.
Yield: 352 mg (0.436 mmol, 70%) 6 orange solid. Rf = 0.16
(CH2Cl2:MeOH 20:1). HRMS (ESI-TOF): m/z = [M+Na]+
Calcd. for C44H54N8O7Na 829.4008; Found 829.3991. IR
(ATR): ν/cm–1 2923, 1650, 1596, 1500, 1447, 1245, 1145,
1
3289, 2923, 2855, 1651, 1596, 1498, 1444, 1246, 1147,
857, 697, 545. 1H NMR (600 MHz, acetone-d6):  = 9.67 (s, 1
H, NH), 8.15 (d, J = 8.0 Hz, 1 H, ar), 8.02 – 7.99 (m, 2 H, ar),
7.93 (s, 3 H, ar), 7.92 – 7.90 (m, 2 H, ar), 7.71 (d, J = 8.8 Hz, 1
H, NH), 7.38 – 7.17 (m, 12 H, ar), 6.79 (s, 1 H, NH), 6.75 (s, 1
H, NH), 5.19 (d, J = 1.5 Hz, 2 H, CH2), 5.10 – 4.96 (m, 1 H, CH),
4.69 – 4.64 (m, 1 H, CH), 3.62 (s, 3 H, CH3), 3.77 – 3.67 (m, 3
H, CH, CH2), 3.32 (dd, J = 13.9, 5.7 Hz, 1 H, CH2), 3.21 (dd, J =
13.9, 9.1 Hz, 1 H, CH2), 3.18 – 3.11 (m, 2 H, CH2), 1.87 – 1.56
(m, 5 H, CH, CH2), 1.40 (s, 9 H, CH3), 1.31 – 1.13 (m, 4 H, CH2),
1.04 – 0.85 (m, 2 H, CH2) ppm. 13C {1H} NMR (150 MHz,
acetone-d6):  = 172.3 (C=O), 172.2 (C=O), 172.0 (C=O),
166.9 (C=O), 155.1 (C=O), 149.3, 143.3, 138.9, 138.3, 137.0,
136.8, 130.1, 129.3, 129.2, 128.9, 128.7, 128.3, 128.0, 127.5,
124.8, 123.2, 120.6, 120.4, 79.9, 71.8, 69.4, 67.2, 64.9, 55.5,
1
856, 699. H NMR (400 MHz, CDCl3):  = 9.26 (s, 1 H, NH),
7.90 – 7.78 (m, 6 H, ar), 7.78 – 7.72 (m, 2 H, ar), 7.41 – 7.39
(m, 1 H, ar), 7.33 – 7.24 (m, 3 H, ar), 7.18 – 7.14 (m, 2 H, ar),
7.00 (s, 1 H, NH), 6.88 (s, 1 H, ar), 6.79 (d, J = 7.5 Hz, 1 H, NH),
5.34 (d, J = 6.5 Hz, 1 H, NH), 5.10 (dt, J = 7.7, 5.8 Hz, 1 H, CH),
4.68 – 4.61 (m, 1 H, CH), 4.38 (q, J = 6.6 Hz, 1 H, CH), 3.78 (s,
3 H, CH3), 3.56 (s, 3 H, CH3), 3.32 (dd, J = 13.9, 5.8 Hz, 1 H,
CH2), 3.24 (dd, J = 13.8, 5.7 Hz, 1 H, CH2), 3.14 (dd, J = 15.4,
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The Journal of Organic Chemistry
Photocontrol of catalytic activity of capped cyclodextrin. J.
55.0, 54.2, 52.8, 43.9, 38.0, 34.7, 34.5, 32.9, 31.4, 30.3, 28.6,
28.5, 27.2, 26.9, 26.7 ppm. UV/Vis: (E) →*, λmax = 367 nm;
n→*, λmax = 450 nm; (Z) n→*, λmax = 450 nm.
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ASSOCIATED CONTENT
Supporting Information. In situ irradiation NMR
spectroscopy, computational details, spectroscopic data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*prs@uni-giessen.de
ACKNOWLEDGMENT
manipulation of catalyst performance via the
This work was financially supported by the Adolf Messer
Foundation and the DFG (TH1115/9-1, TH1115/12-1, CRC
1194, and SCHR 597/28-2, SPP1807 “Dispersion”). A.K.E.
thanks the Fonds der Chemischen Industrie for a scholarship.
photocontrolled aggregation/dissociation state of the
catalyst. Chem. Commun. 2013, 49, 4628-4630; (m)
Lawrence, R. L.; Scola, B.; Li, Y.; Lim, C.-K.; Liu, Y.; Prasad, P.
N.; Swihart, M. T.; Knecht, M. R. Remote Optically
Controlled Modulation of Catalytic Properties of
Nanoparticles through Reconfiguration of the
Inorganic/Organic Interface. ACS Nano 2016, 10, 9470-9477;
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Nanozyme Mediated by a Light-Sensitive Cofactor. J. Am.
Chem. Soc. 2017, 139, 1794-1797; (p) Szewczyk, M.;
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Swinging Molecule Confined on the Surface of a Colloidal
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of Stereoselectivity in Catalysis Using a Copper
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Eisenreich, F.; Jurissek, C.; Dallmann, A.; Gurke, J.; Hecht, S.
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