Direct 3-Acylation of Indolizines by Carboxylic Acids for the Practical Synthesis of Red Light-Releasable Caged Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.1c01244

To enhance the practicality of photouncaging system using 3-acyl-2-methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed using condensation reagents, generally used for peptide coupling. This method allowed for caging a broad range of carboxylic acids with indolizines. The method enabled a facile synthesis of water-soluble caged bioactive carboxylic acids having an intramolecular photosensitizer. The efficient release of carboxylic acids from the synthesized caged compounds upon red light irradiation was confirmed in neutral buffered solutions.

Full text of DOI:10.1021/acs.joc.1c01244

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Direct 3‑Acylation of Indolizines by Carboxylic Acids for the Practical
Synthesis of Red Light-Releasable Caged Carboxylic Acids
Kenji Watanabe,* Nodoka Terao, Takashi Niwa, and Takamitsu Hosoya*
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ABSTRACT: To enhance the practicality of photouncaging system using 3-acyl-2-
methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed
using condensation reagents, generally used for peptide coupling. This method allowed
for caging a broad range of carboxylic acids with indolizines. The method enabled a
facile synthesis of water-soluble caged bioactive carboxylic acids having an intra-
molecular photosensitizer. The efficient release of carboxylic acids from the synthesized
caged compounds upon red light irradiation was confirmed in neutral buffered solutions.
Scheme 1. Photoinduced Release of a Carboxylic Acid from
3-Acyl-2-methoxyindolizine
INTRODUCTION
■
Carboxylic acids are omnipresent in various bioactive
molecules such as amino acids, lipids, natural products, and
pharmaceuticals.1 Generally, their bioactivities are triggered by
the interaction of the carboxy group with the binding site of
target molecules. The development of efficient protection/
deprotection sequences for carboxylic acids is important for
realizing the on-demand inactivation/activation of their
biofunctions for practical use in prodrugs, drug delivery, and
molecular biology tools. In particular, photoinduced uncaging
systems have been often employed because they can release
bioactive carboxylic acids at a desired position and at a specific
time point simply upon activation by light irradiation.2 For this
purpose, compounds responsive to long-wavelength light are
preferable for biological experiments, mainly due to the high
tissue permeability of this type of light.3 Although various
ultraviolet- or visible light-responsive precursors have been
developed, only a few precursors that efficiently release
bioactive carboxylic acids upon irradiation of long-wavelength
light have been reported so far.4 In this context, we recently
developed novel indolizine compounds that serve as light-
activable precursors for the release of carboxylic acids.5 Our
study revealed that irradiation of 3-acyl-2-methoxyindolizines
with a red light-emitting diode (LED; λ = 660 nm) in the
presence of a catalytic amount of photosensitizer such as
methylene blue triggered the photooxidation of the indolizine
moiety,6 resulting in the release of the corresponding
carboxylic acid from the C3 position of the indolizine scaffold
(Scheme 1).
the corresponding carboxylic acids generally requires strong
acidic conditions,9 which results in low functional group
tolerance. To apply the indolizine-based photoreleasing system
for bioactive carboxylic acids, which typically have complex
structures with various functional groups, mild conditions are
required for the acylation step. To establish a practical
synthetic method for diverse 3-acyl-2-methoxyindolizines, we
focused on direct acylation of 2-methoxyindolizine (1).
Although direct electrophilic C-acylation using carboxylic
acids as acyl donors has been described in the literature,
such a transformation requires the use of a strong Lewis/
Brønsted acid and/or high temperature (180−250 °C) to
generate an acylium equivalent that is typically essential for C-
acylation,10 thereby limiting the scope of the employable
carboxylic acids. The carbon at the 3 position of 1 is expected
to exhibit significant nucleophilicity owing to the presence of
the nitrogen atom and 2-methoxy group because C3-acylation
using acyl chlorides does not require an activator such as a
Lewis acid.5 This unique reactivity inspired us to explore
methods for the moderate electrophilic activation of carboxylic
Despite having several advantages compared with the related
methods, such as the applicability of the long-wavelength light
and a significantly high reaction rate, this system presents a
drawback regarding the limited availability of 3-acyl-2-
methoxyindolizines.7 The acylation at the C3 position of
indolizines is generally achieved by treatment with acyl
chlorides.8 However, the preparation of acyl chlorides from
Received: May 28, 2021
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A

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acids, such as their treatment with condensation reagents
generally applied for N-acylation, to introduce an acyl group at
the 3 position of 1 under neutral and mild conditions.
afford the corresponding acylated products 12−14 in high
yields. The C3-acylation using carboxylic acids having a
relatively sterically hindering methyl group uneventfully gave
the corresponding acylated products (15 and 16).
RESULTS AND DISCUSSION
We also investigated the scope of indolizines for the C3-
benzoylation. Indolizine having a sterically hindering methyl
group at the 5 position was efficiently benzoylated to afford 17
in high yield. Similarly, indolizines bearing a substituent at
other positions, such as 1-methyl and 6-progargyloxy
derivatives, participated in the reaction to afford 18 and 19
in high yields, respectively. Notably, the terminal alkyne group
remained intact when the 2-methoxy-6-(propargyloxy)-
indolizine was used in the reaction affording 19. Furthermore,
2-phenyl and 2-methylindolizines were successfully acylated by
extending the reaction time and elevating the reaction
temperature to afford 20 and 21 in moderate yields.
■
Synthesis of 3-Acylindolizines. We selected 3-phenyl-
propanoic acid, as a model substrate to investigate the
acylation of 1 using various condensation reagents, additives,
and solvents (Table 1 and Table S1 for all of the screening
Table 1. C3-Acylation of 2-Methoxyindolizines (1) by
a b
,
Carboxylic Acids
The excellent tolerance of the acylation to various functional
groups prompted us to examine the acylation using functional
carboxylic acids comprising various functionalities. We found
that the reactions of various bioactive compounds and a
polyethylene glycol (PEG) derivative containing a carboxylic
acid proceeded uneventfully to give the corresponding
indolizine adducts with N-Boc-phenylalanine (22), N-
benzoylglycylglycine (23), cholic acid (24), indomethacin
(25), and PEG (26) derivatives. For carboxylic acids that were
insoluble in dichloromethane, N,N-dimethylformamide
(DMF) was used as the solvent that provided the products
with comparable efficiency (23 and 24). Particularly, the
preparation of 22, which could not be achieved by the
conventional method via the formation of the acid chloride
owing to the instability of the Boc group under acidic
conditions, demonstrates the synthetic utility of our method
(Figure S2). Furthermore, we confirmed that racemization at
the α position of 22 did not occur during the acylation (>99%
ee). Thus, this reaction was found to be convenient to
introduce a variety of bioactive compounds having chiral
centers into indolizines. To demonstrate the scalability, we
performed the reaction using 2.0 mmol of indomethacin, which
afforded 0.95 g of 25 (97% yield).
To gain insight into the mechanistic aspects of the reaction,
we performed the following experiments. The treatment of 1
with EDC·HCl in the absence of a carboxylic acid afforded
indolizine adduct I in almost quantitative yield (Scheme 3A).
The subsequent addition of benzoic acid and DMAP to the
solution containing I did not provide acylated product 3,
suggesting that EDC·HCl first reacts with the carboxylic acid
to produce an activated ester, similar to conventional
condensation reactions.12 The ester could smoothly react
with DMAP to afford urea II and acylpyridinium species III,
which is a plausible intermediate for the acylation (Scheme
3B).13
a
b
1H NMR yields. Isolated yields in the parentheses.
results). We found that the combination of 1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl; 1.1
equiv) and a catalytic amount of 4-dimethylaminopyridine
(DMAP; 0.2 equiv) in the presence of N,N-diisopropylethyl-
amine (i-Pr2NEt; 1.5 equiv) in dichloromethane (CH2Cl2)
gave the desired product 2 in nearly quantitative yield (Table
1, entry 1). The addition of DMAP was critical for the effective
transformation, although other nucleophilic organocatalysts,
such as HOBt, HOAt, and oxyma, instead of DMAP, were also
operational (entries 2−5). A similar trend was observed for the
acylation using benzoic acid (3). Eventually, we found that the
reaction proceeded in excellent yields under neutral conditions
in the absence of i-Pr2NEt (entry 6).
Next, we investigated the substrate scope of the acylation
reaction (Scheme 2). Under the optimized conditions, the
reactions proceeded efficiently with 4-substituted benzoic acids
having various electron-withdrawing and -donating groups
(Schemes 2, 4−10); however, the substrates with electron-
donating groups required longer reaction time (20 h) to afford
the acylated products in high yields (5 and 6). In contrast, the
reaction of 4-(hydroxymethyl)benzoic acid under the same
conditions gave a poor yield of 11. This was because indolizine
1 was less reactive for the acylation than the primary alcohol,
and the formation of the corresponding ester was predominant,
as demonstrated by a competition experiment (Figure S1).
After reexamining the reaction conditions, acylated product 11
was obtained in 77% yield by employing 4-(4,6-dimethoxy-
1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-
MM)11 as a condensation reagent in methanol for 20 h
(Table S2). α,β-Unsaturated carboxylic acids and isonicotinic
acid containing a pyridinyl group participated in the reaction to
The electrophilic addition of III to the 3 position of 1 with
the concomitant regeneration of DMAP and deprotonation
provides the acylated products, while urea II captures the
liberated proton and keeps the reaction media neutral. The
generation of the corresponding acylium cation, a well-known
intermediate in the Friedel−Crafts C-acylation reaction, is not
likely, as typical electron-rich arenes, such as 1,3,5-trimethox-
ybenzene, did not react under the optimized conditions.
Scope of Photoreactions. Next, we evaluated the
reactivity of the synthesized 3-acylindolizines toward photo-
oxidation. The reactions were conducted by irradiating a
solution of the substrates in methanol-d4, water-d2, or an
B
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a
Scheme 2. Scope of the C3-Acylation of Indolizines
a
b
c
d
e
Isolated yields. 20 h. In methanol with DMT-MM. In DMF. 40 °C, 48 h.
aqueous acetonitrile solution (CH3CN/H2O = 4/1) in the
presence of methylene blue (1 mol %) with a 660 nm red LED
up to 1 min, which afforded the carboxylic acids in excellent
yields (Scheme 4). Carboxylic acid 28 having a thioether group
susceptible to oxidation14 was also released in 85% yield after
photoirradiation for 30 s. The release of 4-azidobenzoic acid
(29), isonicotinic acid (30), and α,β-unsaturated carboxylic
acid 31 proceeded in nearly quantitative yields without
affecting the azido, pyridinyl, and alkene functionalities. Next,
we prepared amine 33 from Boc-deprotection of 26 (Scheme
5). Efficient release of amine 32 from 33 was confirmed in
neutral sodium phosphate water-d2 buffer (pD 7.0) in the
absence of any organic co-solvents (Scheme 4).
The release of 2-methyl-3-phenylpropionic acid (34), 2-
methylbenzoic acid (35), and (E)-2-methyl-3-phenylacrylic
acid (36) proceeded in nearly quantitative yields. The apparent
C
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Scheme 3. (A) Control Experiments and (B) Plausible Mechanism of the C3-Acylation Reaction
rate constant for the release of 2-methylbenzoic acid from 15
(kobs = 0.0720 s−1) was relatively slower than that of benzoic
acid (kobs = 0.138 s−1, released from 3), but reached >95%
yield within 1 min (Figures S3 and S4). In addition, the release
of N-Boc-phenylalanine (37) took place without the loss of
enantiopurity (>99% ee). The presence of substitutions at 1-,
6-, and sterically hindering 5 positions of indolizines did not
affect the photoreaction efficiency (17−19). N-Benzoylglycyl-
glycine (38), indomethacin (39), and cholic acid (40) were
also released in excellent yields. Extension of the irradiation
time to 2 min allowed to increase the substrate concentration
and the reaction scale, as indomethacin (39) was successfully
isolated in excellent yield. Because amino15 and amide16
groups are generally unstable to photooxidation, our method
that can leave these functionalities intact is an effective system,
demonstrating the broad applicability for releasing various
molecules with a wide range of functional groups. Moreover,
the release of carboxylic acid proceeded almost quantitatively
even under hypoxic conditions (1% O2), indicating the high
photoreactivity of the present system (Figure S5).
yields (Scheme 6A). Next, alkynes 41 and 42 were connected
with ZnPPIX having two azido-PEG linkers (43) derived from
PPIX, via copper-catalyzed Huisgen cyclization to afford 44
and 45, respectively, in high yields (Scheme 6B). As expected,
these acylindolizines dissolved well in pH 7.4 sodium
phosphate buffer containing 5 v/v% dimethylsulfoxide
(DMSO), and red light irradiation of the solutions for 5 min
afforded pseudolaric acid B and Suc−Ala−Pro−Ala−pNA
from 44 and 45 in 77 and 74% yields, respectively (Scheme
6C).
The releasing efficiencies of these compounds did not
decrease significantly even in the presence of human serum
albumin despite the high serum protein binding rate of
ZnPPIX (Kd = 1 μM).20 These results demonstrate that the all-
in-one design, involving an indolizine core, a releasing
carboxylic acid, and a photosensitizer, provides a platform for
the use of the indolizine photouncaging system for biological
applications.
There is still scope for the improvement of the indolizine
system to realize biological applications. For instance, the
indolizine core exhibits low water solubility, which compelled
us to use an excess amount of organic solvents for the
photoreactions in our previous research.5 Moreover, the use of
a photosensitizer is essential. A simultaneous addition of
indolizines and the photosensitizer may decrease their
concentrations in cells or at target tissues due to their
diffusion, thereby reducing the efficiency of the photoreaction.
To address these issues, we designed and synthesized
acylindolizines having zinc protoporphyrin IX (ZnPPIX),17
an intramolecular red light-absorbing dye, connected by water-
soluble poly(ethylene glycol) (PEG) linkers. We selected two
carboxylic acids as model compounds, i.e., pseudolaric acid
B,18 a bioactive natural product with potent microtubule-
destabilizing activity,19 and a tripeptide, Suc−Ala−Pro−Ala−
pNA (Scheme 6).
CONCLUSIONS
■
In conclusion, we have developed a synthetic method for
obtaining 3-acyl-2-methoxyindolizines from various carboxylic
acids mediated by condensation reagents under neutral and
mild conditions with wide functional group tolerance. This
method enables the caging of a broad range of bioactive
carboxylic compounds bearing various functional groups with
indolizines. We have demonstrated the efficient photouncaging
of the carboxylic acids from the corresponding 3-acyl-2-
methoxyindolizines without any side reactions, such as
oxidation of an amino and amide group or decomposition of
an azido group. Moreover, we have designed and synthesized
water-soluble photoreactive precursors conjugated with a
photosensitizer through PEG linkers, which efficiently release
bioactive carboxylic acids upon red LED irradiation in a
neutral aqueous buffered solution in the presence of human
serum albumin. Further studies including biological applica-
tions of this photouncaging system will be reported in due
course.
Acylation of an indolizine bearing an alkyne moiety with
these densely functionalized carboxylic acids proceeded
efficiently using our newly developed acylation conditions,
and the caged compounds 41 and 42 were obtained in high
D
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a
Scheme 4. Scope of the Photoreaction
a
b
c
d
1H NMR yields, unless otherwise noted. 30 s irradiation. In CH3CN/H2O (4/1), HPLC yields. In sodium phosphate, D2O (pD 7.0, 20 mM).
e
5 mM, 2 min irradiation, isolated yield.
and shading from light unless otherwise indicated. The definition for
room temperature (rt) is 23−27 °C. An IKA RCT basic hot plate
stirrer equipped with aluminum blocks was used for heating.
Analytical thin-layer chromatography (TLC) was performed on
precoated (0.25 mm) silica-gel plates (Merck, Merck Silica Gel 60
F254). Column chromatography was conducted on a YAMAZEN
Automated Flash Chromatography System that consists of AI-580 and
Parallel Frac FR-360 or a Biotage ISO-PSV Isolera Prime with a silica-
gel-packed column (Universal Premium Silica Gel 30 μm or Biotage
Scheme 5. Synthesis of Amine 33
̈
Sfar Silica HC D High Capacity Duo 20 μm). Freeze drying was
conducted with an EYELA FDS-2000. Melting points (mp) were
measured with an OptiMelt automated melting point apparatus
1
(Stanford Research Systems, Inc.) and were uncorrected. H NMR
(400 MHz) and 13C{1H} NMR (100 MHz) spectra were obtained
from measurements at room temperature on a JEOL ECS400
spectrometer. Chloroform-d1 (CDCl3) containing 0.05% tetramethyl-
silane (TMS) (99.8%D, Cambridge Isotope Laboratories, Inc.),
methanol-d4 (99.8%D, Merck, Inc.), and dimethylsulfoxide-d6
(DMSO-d6, 99.9%D, Cambridge Isotope Laboratories, Inc.) were
used as a solvent for NMR measurements. Chemical shifts (δ) for 1H
NMR are given in parts per million (ppm) downfield from the signal
of residual CHCl3 (δ 7.26 ppm) and dimethylsulfoxide (δ 2.50 ppm)
EXPERIMENTAL SECTION
General Information. All reactions for the synthesis of
photoreactive substrates were performed under argon atmosphere
■
E
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with the absorption band given in cm−1. High performance liquid
chromatography was performed on Shimadzu HPLC Systems that
consists of LC-20AB (liquid chromatograph), DGU-20A3 (degasser),
SPD-M20A (diode array detector), SIL-20A (autosampler), CTO-
20AC (column oven), and CBM-20A (communication bus) or LC-
20AR (liquid chromatograph), DGU-20A5R (degasser), SPD-M20A
(diode array detector), FRC-40 (fraction collector), and CBM-20A
(communications bus) units. Recycle gel permeation chromatography
(GPC) was performed on a YMC LC-Forte/R multiple preparative
HPLC system. High-resolution mass spectra (HRMS) were measured
on a Thermo Fisher Scientific Exactive Plus Orbitrap mass
spectrometer.
Scheme 6. (A) Synthesis of Pseudolaric Acid B and Suc−
Ala−Pro−Ala−pNA-Caged Indolizines, (B) Connection to
Photosensitizer, and (C) Evaluation of Photoreleasing
Efficiency in Aqueous Buffered Solutions
Synthesis of Substrates. 2-Methoxyindolizine (1),5 2-methoxy-
6-(prop-2-yn-1-yloxy)indolizine,5 2-phenylindolizine,21 2-methylindo-
lizine,22 1-(2-ethoxy-2-oxoethyl)-2-ethylpyridin-1-ium bromide,23 and
1-(2-ethoxy-2-oxoethyl)-2,6-dimethylpyridin-1-ium bromide23 were
synthesized according to the literature.
2-Methoxy-5-methylindolizine. 1-(2-Ethoxy-2-oxoethyl)-2,6-di-
methylpyridin-1-ium bromide (1.10 g, 4.01 mmol, 1 equiv), DMF
(20 mL), and i-PrOH (20 mL) were added into a 100 mL round-
bottom flask. The flask was filled with argon and set into an ice water
bath. Cesium hydroxide monohydrate (1.34 g, 7.98 mmol, 2.0 equiv)
was added to the solution in one portion. The resulting mixture was
stirred at room temperature for 30 min. The flask was set into an ice
water bath, and dimethyl sulfate (505 mg, 4.00 mmol, 1.0 equiv) was
added dropwise to the mixture over 5 min. The mixture was further
stirred at room temperature for 2 h. The mixture was then poured
into a solution of n-hexane (120 mL) and ethyl acetate (EtOAc, 60
mL). The resulting mixture was washed with brine (120 mL × 3).
The organic layer was dried with Na2SO4 and evaporated. The residue
was purified by silica-gel column chromatography (n-hexane/EtOAc =
1/0 to 85/15) to afford the product. Yield: 389 mg (2.41 mmol,
1
60.1%). Red oil; TLC Rf = 0.47 (n-hexane/EtOAc = 6:1); H NMR
(CDCl3): δ 7.18 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.69
(dd, J = 8.8, 6.8 Hz, 1H), 6.33 (d, J = 6.8 Hz, 1H), 6.15 (d, J = 1.6 Hz,
1H), 3.88 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (CDCl3): δ 153.3,
132.6, 132.0, 117.9, 115.4, 108.8, 93.6, 86.5, 57.9, 19.0; IR (ZnSe,
cm−1) 710, 766, 1036, 1159, 1321, 1416, 1537, 1551, 2932; HRMS
(ESI) m/z: [M + H]+ calcd for C10H12NO+ 162.0913; found
162.0913.
2-Methoxy-1-methylindolizine. 1-(2-Ethoxy-2-oxoethyl)-2-ethyl-
pyridin-1-ium bromide (1.92 g, 7.00 mmol, 1 equiv), DMF (35
mL), and i-PrOH (35 mL) were added into a 200 mL round-bottom
flask. The flask was filled with argon and set into an ice water bath.
Cesium hydroxide monohydrate (2.35 g, 14.0 mmol, 2.0 equiv) was
added to the solution in one portion. The resulting mixture was
stirred at room temperature for 30 min. The flask was set into an ice
water bath, and dimethyl sulfate (883 mg, 7.00 mmol, 1.0 equiv) was
added dropwise to the mixture over 5 min. The mixture was further
stirred at room temperature for 2 h. The mixture was then poured
into a solution of n-hexane (220 mL) and EtOAc (110 mL). The
resulting mixture was washed with brine (300 mL × 3). The organic
layer was dried with Na2SO4 and evaporated. The residue was purified
by silica-gel column chromatography (n-hexane/EtOAc = 1/0 to 92/
8) to afford the product. Yield: 244 mg (1.51 mmol, 21.6%); Pale
yellow solid (mp 58.1−59.4 °C); TLC Rf = 0.56 (n-hexane/EtOAc =
1
4:1); H NMR (CDCl3): δ 7.76−7.74 (m, 1H), 7.15 (d, J = 8.8 Hz,
1H), 6.90 (s, 1H), 6.62−6.58 (m, 1H), 6.34−6.30 (m, 1H), 3.84 (s,
3H), 2.20 (s, 3H); 13C{1H} NMR (CDCl3): δ 151.5, 129.1, 125.2,
116.3, 116.0, 108.4, 95.3, 94.6, 58.0, 6.8; IR (ZnSe, cm−1) 733, 1016,
1067, 1211, 1294, 1350, 1535, 2909; HRMS (ESI) m/z: [M + H]+
calcd for C10H12NO+ 162.0913; found 162.0912.
a
b
c
Isolated yields. DMAP (1 equiv). HPLC yields.
General Procedure for the Synthesis of 3-Acylindolizines
(Schemes 2 and 6A). To a solution (CH2Cl2 or DMF, 2.0 mL) of
carboxylic acid (0.400 mmol, 1 equiv), 2-methoxyindolizine (1, 88.3
mg, 0.600 mmol, 1.5 equiv), and DMAP (9.8 mg, 80 μmol, 20 mol %)
in a 4 mL vial were added EDC·HCl (84.3 mg, 0.440 mmol, 1.1
equiv) and a magnetic stir bar. The vial was filled with argon, and the
solution was stirred at 30 °C (or 40 °C) for the indicated time. The
reaction mixture was poured into EtOAc (15 mL) and brine (15 mL)
as internal standards with coupling constants (J) in hertz (Hz).
Chemical shifts (δ) for 13C{1H} NMR are given in parts per million
(ppm) downfield from the signal of residual CDCl3 (δ 77.2 ppm) and
dimethylsulfoxide-d6 (δ 39.5 ppm) as internal standards. The
abbreviations s, d, t, q, and m signify singlet, doublet, triplet, quartet,
and multiplet, respectively. IR spectra were measured by attenuated
total reflection method on a Shimadzu IRPrestige-21 spectrometer
F
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and extracted with EtOAc (15 mL × 3). The combined organic layer
was dried with Na2SO4 and evaporated. The residue was purified by
silica-gel column chromatography (n-hexane/EtOAc) to afford the
product.
1063, 1285, 1419, 1445, 1452, 1499, 1514, 1585, 1603, 2033, 2118;
HRMS (ESI) m/z: [M + H]+ calcd for C16H13N4O2+ 293.1033; found
293.1030.
(4-Chlorophenyl)(2-methoxyindolizin-3-yl)methanone (8). Pre-
pared from 4-chlorobenzoic acid (62.6 mg, 0.400 mmol) in CH2Cl2 at
30 °C for 4 h. Yield: 107 mg (0.374 mmol, 93.7%); Pale yellow solid
1-(2-Methoxyindolizin-3-yl)-3-phenylpropan-1-one (2). Prepared
with 3-phenylpropionic (60.1 mg, 0.400 mmol) acid in CH2Cl2 at 30
°C for 4 h. Yield: 109 mg (0.390 mmol, 97.5%); Pale yellow solid (mp
1
(mp 120.1−121.0 °C); TLC Rf = 0.52 (n-hexane/EtOAc = 2:1); H
1
94.0−96.0 °C); TLC Rf = 0.44 (n-hexane/EtOAc = 4:1); H NMR
NMR (CDCl3): δ 9.83 (d, J = 6.4 Hz, 1H), 7.63−7.60 (AA′BB′, 2H),
7.39−7.36 (m, 3H), 7.21−7.17 (m, 1H), 6.87−6.83 (m, 1H), 6.00 (s,
1H), 3.72 (s, 3H); 13C{1H} NMR (CDCl3): δ 182.4, 158.5, 139.7,
138.3, 136.5, 130.3, 128.8, 127.9, 125.7, 117.1, 113.0, 111.5, 85.6,
57.7; IR (ZnSe, cm−1) 760, 826, 1069, 1344, 1416, 1445, 1502, 1585;
(CDCl3): δ 9.98 (d, J = 7.6 Hz, 1H), 7.35−7.28 (m, 5H), 7.23−7.17
(m, 1H), 7.15−7.10 (m, 1H), 6.81−6.77 (m, 1H), 6.01 (s, 1H), 3.97
(s, 3H), 3.25−3.21 (m, 2H), 3.07−3.03 (m, 2H); 13C{1H} NMR
(CDCl3): δ 187.9, 158.8, 142.4, 137.0, 128.8, 128.6, 128.4, 125.8,
124.8, 116.8, 112.6, 111.4, 85.1, 57.9, 42.7, 31.5; IR (ZnSe, cm−1)
768, 1082, 1414, 1460, 1503, 1597, 2926; HRMS (ESI) m/z: [M +
+
HRMS (ESI) m/z: [M + H]+ calcd for C16H13ClNO2 286.0629;
found 286.0627.
+
H]+ calcd for C18H18NO2 280.1332; found 280.1332.
(4-Bromophenyl)(2-methoxyindolizin-3-yl)methanone (9). Pre-
pared from 4-bromobenzoic acid (80.4 mg, 0.400 mmol) in CH2Cl2 at
30 °C for 4 h. Yield: 128 mg (0.388 mmol, 96.9%); Pale yellow solid
2-Methoxyindolizin-3-yl Phenyl Ketone (3). Prepared from
benzoic acid (48.8 mg, 0.400 mmol) in CH2Cl2 at 30 °C for 4 h.
Yield: 97.1 mg (0.386 mmol, 96.7%); Pale yellow solid (mp 60.0−
61.0 °C); TLC Rf = 0.44 (n-hexane/EtOAc = 4:1); 1H NMR
(CDCl3): δ 9.85 (d, J = 8.0 Hz, 1H), 7.69−7.66 (m, 2H), 7.49−7.36
(m, 4H), 7.19−7.15 (m, 1H), 6.86−6.82 (m, 1H), 6.01 (s, 1H), 3.70
(s, 3H); 13C{1H} NMR (CDCl3): δ 183.9, 158.4, 141.3, 138.0, 130.4,
128.7, 127.6, 125.3, 117.0, 112.7, 111.6, 85.4, 57.6; IR (ZnSe, cm−1)
696, 743, 1053, 1342, 1418, 1503, 1557; HRMS (ESI) m/z: [M +
1
(mp 126.3−127.5 °C); TLC Rf = 0.52 (n-hexane/EtOAc = 2:1); H
NMR (CDCl3): δ 9.83 (d, J = 6.8 Hz, 1H), 7.58−7.51 (m, 4H), 7.38
(d, J = 8.8 Hz, 1H), 7.21−7.17 (m, 1H), 6.87−6.83 (m, 1H), 6.00 (s,
1H), 3.72 (s, 3H); 13C{1H} NMR (CDCl3): δ 182.4, 158.5, 140.2,
138.3, 130.8, 130.5, 128.8, 125.8, 124.9, 117.1, 113.0, 111.4, 85.6,
57.7; IR (ZnSe, cm−1) 756, 823, 959, 1057, 1206, 1256, 1346, 1416,
1445, 1504, 1584; HRMS (ESI) m/z: [M + H]+ calcd for
+
H]+ calcd for C16H14NO2 252.1019; found 252.1019.
+
C16H13BrNO2 330.0124; found 330.0121.
(2-Methoxyindolizin-3-yl)(p-tolyl)methanone (4). Prepared from
4-methylbenzoic acid (54.5 mg, 0.400 mmol) in CH2Cl2 at 30 °C for
4 h. Yield: 98.7 mg (0.372 mmol, 92.9%); Pale yellow solid (mp
127.3−128.6 °C); TLC Rf = 0.50 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 9.81 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.36
(d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.16−7.12 (m, 1H),
6.83−6.79 (m, 1H), 6.01 (s, 1H), 3.73 (s, 3H), 2.42 (s, 3H); 13C{1H}
NMR (CDCl3): δ 183.9, 158.1, 140.9, 138.4, 137.8, 129.1, 128.7,
128.3, 125.1, 117.1, 112.6, 111.7, 85.5, 57.7, 21.8; IR (ZnSe, cm−1)
754, 768, 1063, 1310, 1339, 1418, 1441, 1503, 1557, 1585; HRMS
4-(2-Methoxyindolizine-3-carbonyl)benzonitrile (10). Prepared
from 4-cyanobenzoic acid (58.9 mg, 0.400 mmol) in CH2Cl2 at 30
°C for 4 h. Yield: 102 mg (0.369 mmol, 92.2%); Pale yellow solid (mp
189.8−190.8 °C); TLC Rf = 0.39 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 9.88 (d, J = 7.2 Hz, 1H), 7.78−7.63 (m, 4H), 7.40 (d, J =
8.4 Hz, 1H), 7.25−7.23 (m, 1H), 6.92−6.88 (m, 1H), 5.99 (s, 1H),
3.69 (s, 3H); 13C{1H} NMR (CDCl3): δ 181.2, 158.9, 145.6, 138.9,
131.6, 129.1, 129.0, 126.5, 119.0, 117.2, 113.4, 111.3, 85.8, 57.8; IR
(ZnSe, cm−1) 704, 760, 832, 959, 1059, 1231, 1252, 1342, 1418,
1445, 1504, 1580, 2224; HRMS (ESI) m/z: [M + H]+ calcd for
+
(ESI) m/z: [M + H]+ calcd for C17H16NO2 266.1176; found
+
C17H13N2O2 277.0972; found 277.0970.
266.1176.
(4-(Hydroxymethyl)phenyl)(2-methoxyindolizin-3-yl)methanone
(11). To a solution (CH3OH, 2.0 mL) of 4-(hydroxymethyl)benzoic
acid (60.9 mg, 0.400 mmol, 1 equiv), 2-methoxyindolizine (1, 88.3
mg, 0.600 mmol, 1.5 equiv) in a 4 mL vial were added 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DMT-
MM, 122 mg, 0.441 mmol, 1.1 equiv) and a magnetic stir bar. The
vial was filled with argon, and the resulting solution was stirred at 30
°C for 20 h. The reaction mixture was poured into EtOAc (15 mL)
and brine (15 mL) and extracted with EtOAc (15 mL × 3). The
combined organic layer was dried with Na2SO4 and evaporated. The
residue was purified by silica-gel column chromatography (n-hexane/
EtOAc = 1/0 to 1/4) to afford the product. Yield: 86.1 mg (0.306
mmol, 76.5%); Pale yellow solid (mp 117.4−119.2 °C); TLC Rf =
0.44 (n-hexane/EtOAc = 1:2); 1H NMR (CDCl3): δ 9.84 (d, J = 8.0
Hz, 1H), 7.70−7.67 (m, 2H), 7.41−7.36 (m, 3H), 7.19−7.15 (m,
1H), 6.86−6.81 (m, 1H), 6.01 (s, 1H), 4.77 (s, 2H), 3.71 (s, 3H);
13C{1H} NMR (CDCl3): δ 183.6, 158.4, 143.3, 140.7, 138.1, 129.2,
(2-Methoxyindolizin-3-yl)(4-methoxyphenyl)methanone (5).
Prepared from 4-methoxylbenzoic acid (60.9 mg, 0.400 mmol) in
CH2Cl2 at 30 °C for 20 h. Yield: 95.9 mg (85.2%); Pale yellow solid
1
(mp 150.0−151.0 °C); TLC Rf = 0.41 (n-hexane/EtOAc = 2:1); H
NMR (CDCl3): δ 9.74 (d, J = 7.2 Hz, 1H), 7.73−7.70 (AA′BB′, 2H),
7.36 (d, J = 8.8 Hz, 1H), 7.15−7.10 (m, 1H), 6.93−6.91 (AA′BB′,
2H), 6.82−6.78 (m, 1H), 6.02 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H);
13C{1H} NMR (CDCl3): δ 183.2, 161.9, 157.8, 137.6, 133.7, 131.2,
128.6, 124.8, 117.1, 112.9, 112.5, 111.7, 85.4, 57.8, 55.5; IR (ZnSe,
cm−1) 762, 833, 1022, 1063, 1157, 1233, 1258, 1344, 1422, 1454,
+
1518, 1584; HRMS (ESI) m/z: [M + H]+ calcd for C17H16NO3
282.1125; found 282.1124.
(2-Methoxyindolizin-3-yl)(4-(methylthio)phenyl)methanone (6).
Prepared from 4-(methylthio)benzoic acid (60.9 mg, 0.400 mmol) in
CH2Cl2 at 30 °C for 20 h. Yield: 103 mg (0.346 mmol, 86.6%); Pale
yellow solid (mp 107.4−109.0 °C); TLC Rf = 0.56 (n-hexane/EtOAc
1
= 2:1); H NMR (CDCl3): δ 9.79 (d, J = 7.6 Hz, 1H), 7.66−7.62
128.8, 126.0, 125.5, 117.1, 112.8, 111.7, 85.6, 65.4, 57.7; IR (ZnSe,
cm−1) 758, 953, 1053, 1231, 1346, 1416, 1505, 1545, 1578, 3383;
HRMS (ESI) m/z: [M + H]+ calcd for C17H16NO3+ 282.1125; found
282.1121.
(AA′BB′, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.27−7.24 (m, 2H), 7.18−
7.13 (m, 1H), 6.84−6.80 (m, 1H), 6.01 (s, 1H), 3.74 (s, 3H), 2.54 (s,
3H); 13C{1H} NMR (CDCl3): δ 183.1, 158.1, 140.0, 137.9, 137.7,
129.6, 128.7, 125.3, 124.8, 117.1, 112.7, 111.6, 85.5, 57.8, 15.4; IR
(ZnSe, cm−1) 756, 824, 851, 895, 955, 1063, 1088, 1234, 1312, 1420,
1445, 1582; HRMS (ESI) m/z: [M + H]+ calcd for C17H16NO2S+
298.0896; found 298.0895.
(E)-1-(2-Methoxyindolizin-3-yl)-2-methyl-3-phenylprop-2-en-1-
one (12). Prepared from (E)-2-methyl-3-phenyl-2-propenoic acid
(64.9 mg, 0.400 mmol) in CH2Cl2 at 30 °C for 20 h. Yield: 92.5 mg
(0.317 mmol, 79.3%); Colorless solid (mp 75.1−76.4 °C); TLC Rf =
0.57 (n-hexane/EtOAc = 2:1); 1H NMR (CDCl3): δ 9.75 (d, J = 7.6
Hz, 1H), 7.43−7.34 (m, 5H), 7.30−7.26 (m, 1H), 7.15−7.11 (m,
1H), 6.88 (d, J = 1.6 Hz, 1H), 6.82−6.78 (m, 1H), 6.01 (s, 1H), 3.87
(s, 3H), 2.21 (d, J = 1.2 Hz, 3H); 13C{1H} NMR (CDCl3): δ 187.2,
158.5, 138.6, 137.7, 137.5, 132.9, 129.4, 128.8, 128.4, 127.3, 125.0,
117.0, 112.6, 110.9, 85.5, 58.0, 15.3; IR (ZnSe, cm−1) 768, 1024,
1063, 1252, 1412, 1452, 1555; HRMS (ESI) m/z: [M + H]+ calcd for
(4-Azidophenyl)(2-methoxyindolizin-3-yl)methanone (7). Pre-
pared from 4-azidobenzoic acid (65.3 mg, 0.400 mmol) in CH2Cl2
at 30 °C for 4 h. Yield: 105 mg (0.359 mmol, 89.7%); Brown solid
1
(mp 120.2−121.8 °C); TLC Rf = 0.49 (n-hexane/EtOAc = 2:1); H
NMR (CDCl3): δ 9.80 (d, J = 7.2 Hz, 1H), 7.72−7.69 (AA′BB′, 2H),
7.38 (d, J = 8.8 Hz, 1H), 7.20−7.15 (m, 1H), 7.08−7.05 (AA′BB′,
2H), 6.86−6.82 (m, 1H), 6.01 (s, 1H), 3.76 (s, 3H); 13C{1H} NMR
(CDCl3): δ 182.5, 158.2, 142.3, 138.1, 137.9, 130.9, 128.8, 125.5,
118.2, 117.2, 112.9, 111.6, 85.6, 57.8; IR (ZnSe, cm−1) 752, 895, 955,
+
C19H18NO2 292.1332; found 292.1330.
G
https://doi.org/10.1021/acs.joc.1c01244
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1-(2-Methoxyindolizin-3-yl)-3-methylbut-2-en-1-one (13). Pre-
pared from 3-methylbut-2-enoic acid (40.0 mg, 0.400 mmol) in
CH2Cl2 at 30 °C for 20 h. Yield: 65.1 mg (0.283 mmol, 71.1%);
Colorless solid (mp 62.7−63.7 °C); TLC Rf = 0.43 (n-hexane/EtOAc
= 4:1); 1H NMR (CDCl3): δ 10.08 (dd, J = 7.6, 0.8 Hz, 1H), 7.35−
7.32 (m, 1H), 7.14−7.08 (m, 1H), 6.96−7.08 (m, 1H), 6.96−6.95
(m, 1H), 6.79−6.74 (m, 1H), 6.02 (s, 1H), 2.26 (d, J = 1.6 Hz, 3H),
1.98 (d, J = 0.8 Hz, 3H); 13C{1H} NMR (CDCl3): δ 180.5, 157.9,
151.2, 137.0, 128.8, 124.72, 124.65, 116.9, 112.7, 112.4, 85.4, 58.1,
28.2, 21.1; IR (ZnSe, cm−1) 756, 1020, 1096, 1248, 1306, 1346, 1418,
1450, 1501, 1641, 2901, 2934s; HRMS (ESI) m/z: [M + H]+ calcd
1393, 1443, 1552, 1568, 1587, 2928; HRMS (ESI) m/z: [M + H]+
calcd for C17H16NO2 266.1176; found 266.1176.
+
(2-Methoxy-6-(prop-2-yn-1-yloxy)indolizin-3-yl)(phenyl)-
methanone (19). Prepared from benzoic acid (24.4 mg, 0.200 mmol)
and 2-methoxy-6-(prop-2-yn-1-yloxy)indolizine (60.4 mg, 0.300
mmol) in CH2Cl2 (1.0 mL) at 30 °C for 4 h. Yield: 57.6 mg
(0.189 mmol, 94.4%); Pale yellow solid (mp 135.8−137.1 °C); TLC
Rf = 0.47 (n-hexane/EtOAc = 2:1); 1H NMR (CDCl3): δ 9.80 (d, J =
2.4 Hz, 1H), 7.69−7.67 (m, 2H), 7.48−7.39 (m, 3H), 7.30 (d, J = 9.6
Hz, 1H), 7.04 (dd, J = 9.6, 2.0 Hz, 1H), 5.97 (s, 1H), 4.75 (d, J = 2.4
Hz, 2H), 3.68 (s, 3H), 2.60 (t, J = 2.4 Hz, 1H); 13C{1H} NMR
(CDCl3): δ 184.1, 157.9, 147.6, 141.2, 134.6, 130.6, 128.9, 127.6,
120.0, 117.3, 113.7, 112.6, 85.4, 78.0, 76.5, 57.7, 57.4; IR (ZnSe,
cm−1) 654, 720, 810, 989, 1026, 1055, 1200, 1240, 1271, 1354, 1410,
1452, 1504, 1555; HRMS (ESI) m/z: [M + H]+ calcd for
+
for C14H16NO2 230.1176; found 230.1172.
(2-Methoxyindolizin-3-yl)(pyridin-4-yl)methanone (14). Prepared
from isonicotinic acid (75.3 mg, 0.400 mmol) in CH2Cl2 at 30 °C for
20 h. Yield: 75.3 mg (0.298 mmol, 74.7%); Colorless solid (mp
1
+
205.2−206.3 °C); TLC Rf = 0.55 (EtOAc); H NMR (CDCl3): δ
C19H16NO3 306.1125; found 306.1123.
Phenyl(2-phenylindolizin-3-yl)methanone (20). Prepared from
benzoic acid (48.8 mg, 0.400 mmol) and 2-phenylindolizine (116 mg,
0.600 mmol) in CH2Cl2 at 40 °C for 48 h. Yield: 43.5 mg (0.146
mmol, 36.6%); Pale yellow solid (mp 135.1−136.6 °C); TLC Rf =
0.45 (n-hexane/EtOAc = 4:1); 1H NMR (CDCl3): δ 9.80 (dd, J = 7.2,
0.8, Hz, 1H), 7.57−7.54 (m, 1H), 7.43−7.40 (m, 2H), 7.20−7.12 (m,
2H), 7.10−7.06 (m, 2H), 7.03−6.99 (m, 5H), 6.92−6.88 (m, 1H),
6.59 (s, 1H); 13C{1H} NMR (CDCl3): δ 186.9, 140.3, 139.9, 137.7,
136.1, 130.8, 130.3, 129.8, 128.4, 127.7, 127.5, 126.8, 124.3, 120.2,
118.5, 113.7, 104.3; IR (ZnSe, cm−1) 692, 745, 752, 812, 883, 1015,
1136, 1341, 1404, 1570, 1585, 2853, 2922; HRMS (ESI) m/z: [M +
H]+ calcd for C21H16NO+ 298.1226; found 298.1224.
9.91 (d, J = 7.2 Hz, 1H), 8.70−8.68 (m, 2H), 7.46−7.44 (m, 2H),
7.40 (d, J = 9.2 Hz, 1H), 7.27−7.23 (m, 1H), 6.92−6.88 (m, 1H),
5.99 (s, 1H), 3.68 (s, 3H); 13C{1H} NMR (CDCl3): δ 181.0, 159.2,
149.6, 148.8, 139.1, 129.1, 126.6, 122.4, 117.2, 113.4, 111.2, 85.8,
57.7; IR (ZnSe, cm−1) 667, 760, 1053, 1233, 1344, 1422, 1462, 1504,
+
1539, 1564; HRMS (ESI) m/z: [M + H]+ calcd for C15H13N2O2
253.0972; found 253.0969.
(2-Methoxyindolizin-3-yl)(o-tolyl)methanone (15). Prepared from
2-methylbenzoic acid (54.5 mg, 0.400 mmol) in CH2Cl2 at 30 °C for
4 h. Yield: 92.2 mg (0.348 mmol, 86.8%); Colorless solid (mp 117.1−
118.9 °C); TLC Rf = 0.49 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 10.05 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.30−
7.25 (m, 2H), 7.23−7.18 (m, 3H), 6.89−6.85 (m, 1H), 5.95 (s, 1H),
3.60 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (CDCl3): δ 184.7, 159.3,
142.2, 138.3, 134.9, 130.0, 129.1, 128.6, 127.2, 125.8, 125.2, 117.0,
113.0, 112.1, 85.6, 57.9, 19.4; IR (ZnSe, cm−1) 743, 770, 897, 959,
1059, 1196, 1250, 1344, 1416, 1445, 1504, 1568; HRMS (ESI) m/z:
(2-Methylindolizin-3-yl)(phenyl)methanone (21). Prepared from
benzoic acid (48.8 mg, 0.400 mmol) and 2-methylindolizine (78.7
mg, 0.600 mmol) in CH2Cl2 at 40 °C for 48 h. Yield: 43.0 mg (0.183
mmol, 45.7%); Pale yellow solid (mp 62.2−63.1 °C); TLC Rf = 0.50
1
(n-hexane/EtOAc = 4:1); H NMR (CDCl3): δ 9.74 (d, J = 6.8 Hz,
+
[M + H]+ calcd for C17H16NO2 266.1176; found 266.1174.
1H), 7.61−7.58 (m, 2H), 7.53−7.41 (m, 4H), 7.14−7.10 (m, 1H),
6.84−6.80 (m, 1H), 6.32 (s, 1H), 1.90 (s, 3H); 13C{1H} NMR
(CDCl3): δ 186.4, 142.3, 138.4, 135.7, 130.7, 128.8, 128.6, 128.3,
124.5, 121.7, 117.7, 113.1, 105.4, 15.8; IR (ZnSe, cm−1) 704, 743,
841, 962, 1020, 1134, 1229, 1337, 1408, 1585, 3051; HRMS (ESI)
m/z: [M + H]+ calcd for C16H14NO+ 236.1070; found 236.1068.
tert-Butyl (S)-(1-(2-methoxyindolizin-3-yl)-1-oxo-3-phenylpro-
pan-2-yl)carbamate (22). Prepared from (tert-butoxycarbonyl)-L-
phenylalanine (106 mg, 0.400 mmol) in CH2Cl2 at 30 °C for 20 h.
Yield: 152 mg (0.385 mmol, 96.4%, 99.2% ee); Colorless solid (mp
1-(2-Methoxyindolizin-3-yl)-2-methyl-3-phenylpropan-1-one
(16). Prepared from 2-methyl-3-phenylpropanoic acid (65.7 mg, 0.400
mmol) in CH2Cl2 at 30 °C for 20 h. Yield: 108 mg (0.368 mmol,
1
92.0%); Colorless oil; TLC Rf = 0.60 (n-hexane/EtOAc = 4:1); H
NMR (CDCl3): δ 10.02 (d, J = 7.6 Hz, 1H), 7.35−7.33 (m, 1H),
7.29−7.24 (m, 4H), 7.21−7.11 (m, 2H), 6.81−6.77 (m, 1H), 6.02 (s,
1H), 4.00 (s, 3H), 3.97−3.88 (m, 1H), 3.19 (dd, J = 13.6, 6.0 Hz,
1H), 2.62 (dd, J = 13.6, 8.8 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H);
13C{1H} NMR (CDCl3): δ 192.4, 158.5, 141.2, 137.2, 129.4, 129.0,
128.3, 125.9, 125.0, 116.9, 112.7, 111.2, 85.4, 58.0, 43.6, 40.2, 16.7; IR
(ZnSe, cm−1) 698, 760, 970, 1074, 1248, 1368, 1418, 1503, 1597,
2932; HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO2+ 294.1489;
found 294.1487.
1
43.9−44.6 °C); TLC Rf = 0.60 (n-hexane/EtOAc = 2:1); H NMR
(CDCl3): δ 9.87 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.24−
7.14 (m, 6H), 6.83 (t, J = 7.2 Hz, 1H), 6.03 (s, 1H), 5.64−5.52 (m,
2H), 4.03 (s, 3H), 3.26−3.21 (m, 1H), 2.85−2.79 (m, 1H), 1.37 (s,
9H); 13C{1H} NMR (CDCl3): δ 185.4, 158.9, 155.5, 138.3, 137.7,
129.8, 129.0, 128.2, 126.5, 125.8, 117.1, 113.0, 110.0, 85.6, 79.2, 58.3,
56.9, 40.6, 28.5; IR (ZnSe, cm−1) 698, 764, 1020, 1076, 1167, 1248,
1420, 1504, 1593, 1705; HRMS (ESI) m/z: [M + H]+ calcd for
(2-Methoxy-5-methylindolizin-3-yl)(phenyl)methanone (17).
Prepared from benzoic acid (48.8 mg, 0.400 mmol) and 2-methoxy-
5-methylindolizine (96.7 mg, 0.600 mmol) in CH2Cl2 at 30 °C for 20
h. Yield: 79.5 mg, (0.300 mmol, 75.0%); Pale yellow solid (mp
108.1−109.2 °C); TLC Rf = 0.53 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 7.97−7.94 (m, 2H), 7.55−7.51 (m, 1H), 7.47−7.43 (m,
2H), 7.32 (d, J = 9.2 Hz, 1H), 7.15 (dd, J = 9.2, 6.8 Hz, 1H), 6.70 (d,
J = 6.8 Hz, 1H), 6.09 (s, 1H), 3.69 (s, 3H), 2.43 (s, 3H); 13C{1H}
NMR (CDCl3): δ 182.5, 158.5, 140.4, 139.6, 139.3, 131.7, 130.5,
127.9, 124.7, 114.8, 114.4, 112.9, 85.4, 57.8, 23.3; IR (ZnSe, cm−1)
710, 862, 1045, 1229, 1329, 1422, 1499, 1514, 1595, 2959; HRMS
+
C23H27N2O4 395.1965; found 395.1962. Optical rotation [α]2D3 +7.6
(c 1.00, CHCl3).
tert-Butyl (1-(2-methoxyindolizin-3-yl)-1-oxo-3-phenylpropan-2-
yl)carbamate (rac-22). Prepared from a 1:1 mixture of (tert-
butoxycarbonyl)-L-phenylalanine and (tert-butoxycarbonyl)-D-phe-
nylalanine (53.1 mg, 0.200 mmol) in CH2Cl2 (1.0 mL) at 30 °C
for 20 h. Yield: 76.1 mg (0.193 mmol, 96.4%); Colorless solid (110
°C, decomposed); TLC Rf = 0.60 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 9.87 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.23−
7.14 (m, 6H), 6.82 (t, J = 6.8 Hz, 1H), 6.02 (s, 1H), 5.64−5.52 (m,
2H), 4.03 (s, 3H), 3.25−3.21 (m, 1H), 2.85−2.80 (m, 1H), 1.37 (s,
9H); 13C{1H} NMR (CDCl3): δ 185.4, 158.9, 155.5, 138.3, 137.7,
129.8, 129.0, 128.2, 126.5, 125.8, 117.1, 113.0, 110.0, 85.6, 79.2, 58.3,
56.9, 40.6, 28.5; IR (ZnSe, cm−1) 698, 1020, 1076, 1167, 1248, 1440,
1504, 1593, 1705; HRMS (ESI) m/z: [M + H]+ calcd for
+
(ESI) m/z: [M + H]+ calcd for C17H16NO2 266.1176; found
266.1175.
(2-Methoxy-1-methylindolizin-3-yl)(phenyl)methanone (18).
Prepared from benzoic acid (48.8 mg, 0.400 mmol) and 2-methoxy-
1-methylindolizine (96.7 mg, 0.600 mmol) in CH2Cl2 at 30 °C for 20
h. Yield: 90.4 mg (0.341 mmol, 85.3%); Pale yellow solid (mp 111.9−
113.2 °C); TLC Rf = 0.52 (n-hexane/EtOAc = 2:1); 1H NMR
(CDCl3): δ 9.82 (d, J = 6.8 Hz, 1H), 7.74−7.71 (m, 2H), 7.52−7.39
(m, 4H), 7.19−7.15 (m, 1H), 6.88−6.84 (m, 1H), 3.33 (s, 3H), 2.23
(s, 3H); 13C{1H} NMR (CDCl3): δ 184.1, 155.5, 141.0, 136.4, 130.7,
128.8, 128.7, 127.8, 124.3, 116.1, 113.3, 101.7, 62.4, 7.3; IR (ZnSe,
cm−1) 696, 750, 758, 867, 912, 1001, 1016, 1051, 1234, 1306, 1377,
+
C23H27N2O4 395.1965; found 395.1962.
N-(2-((2-(2-Methoxyindolizin-3-yl)-2-oxoethyl)amino)-2-
oxoethyl)benzamide (23). Prepared from N-benzoylglycylglycine
(94.5 mg, 0.400 mmol) in DMF at 30 °C for 20 h. Yield: 115 mg
H
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(0.315 mmol, 78.7%); Pale yellow solid (204 °C, decomposed); TLC
Rf = 0.48 (EtOAc only); 1H NMR (DMSO-d6): δ 9.73 (d, J = 6.8 Hz,
1H), 8.83 (t, J = 6.0 Hz, 1H), 8.06 (t, J = 5.6 Hz, 1H),7.92−7.90 (m,
2H), 7.60−7.47 (m, 4H), 7.31−7.26 (m, 1H), 6.98−6.94 (m, 1H),
6.34 (s, 1H), 4.40 (d, J = 5.2 Hz, 2H), 3.99−3.98 (m, 5H); 13C{1H}
NMR (DMSO-d6): δ 181.6, 169.2, 166.5, 158.5, 137.0, 134.0, 131.3,
128.3, 127.3, 125.4, 117.4, 113.1, 109.1, 86.0, 58.4, 46.5, 42.7; IR
(ZnSe, cm−1) 675, 696, 764, 1076, 1231, 1312, 1416, 1470, 1537,
1578, 1641, 1690, 3312; HRMS (ESI) m/z: [M + H]+ calcd for
yloxy)indolizine (22.6 mg, 113 mmol), and DMAP (9.2 mg, 75
mmol) in CH2Cl2 at 30 °C for 20 h. Yield: 36.5 mg (61.9 μmol,
82.6%); Pale yellow solid (110 °C, decomposed); TLC Rf = 0.43 (n-
hexane/EtOAc = 1:2); 1H NMR (CDCl3): δ 9.63 (d, J = 2.4 Hz, 1H),
7.30−7.28 (m, 1H), 7.24−7.21 (m, 1H), 7.01−6.98 (m, 1H), 6.62−
6.55 (m, 1H), 6.45 (d, J = 12.4 Hz, 1H), 5.96 (s, 1H), 5.66 (d, J =
14.8 Hz, 1H), 4.71 (d, J = 2.8 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H),
3.27 (d, J = 6.0 Hz, 1H), 3.11−3.06 (m, 1H), 2.93−2.88 (m, 1H),
2.80−2.74 (m, 1H), 2.64−2.59 (m, 2H), 2.19−2.11 (m, 4H), 2.08 (d,
J = 0.8 Hz, 3H), 1.90−1.72 (m, 5H), 1.61 (s, 3H); 13C{1H} NMR
(CDCl3): δ 186.4, 173.3, 169.6, 168.3, 157.6, 147.4, 142.0, 140.0,
139.4, 134.6, 134.2, 131.7, 122.7, 119.6, 117.3, 113.6, 111.9, 90.4,
85.3, 84.1, 78.0, 76.5, 57.9, 57.4, 55.4, 52.2, 49.8, 33.5, 30.9, 28.8,
28.0, 24.4, 22.0, 20.4, 14.4; IR (ZnSe, cm−1) 665, 748, 1028, 1206,
1236, 1449, 1504, 1552, 1730, 2949; HRMS (ESI) m/z: [M + H]+
+
C20H20N3O4 366.1448; found 366.1444.
(R)-1-(2-Methoxyindolizin-3-yl)-4-((3S,5R,7S,8S,9R,10S,12R,13S,-
14R,16R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthren-16-yl)pentan-1-one (24). Prepared from
cholic acid (163 mg, 0.399 mmol) in DMF at 30 °C for 20 h. Yield:
202 mg (0.376 mmol, 94.2%). White solid (mp 204.2−205.6 °C);
1
+
TLC Rf = 0.44 (EtOAc); H NMR (CDCl3): δ 9.95 (d, J = 8.0 Hz,
calcd for C35H38NO9 616.2541; found 616.2539; Optical rotation
[α]2D3 −6.1 (c 0.50, CHCl3).
1H), 7.34−7.31 (m, 1H), 7.13−7.09 (m, 1H), 6.78−6.75 (m, 1H),
6.01 (s, 1H), 4.01 (s, 1H), 3.98 (s, 3H), 3.84 (d, J = 2.4 Hz, 1H),
3.47−3.42 (m, 1H), 3.01−2.93 (m, 1H), 2.83−2.76 (m, 1H), 2.50 (s,
1H), 2.28−1.23 (m, 22H), 1.16−1.06 (m, 4H), 1.01−0.93 (m, 1H),
0.88 (s, 3H), 0.70 (s, 3H); 13C{1H} NMR (CDCl3): δ 190.2, 158.7,
137.0, 128.8, 124.8, 116.8, 112.5, 111.6, 85.2, 73.3, 72.1, 68.6, 58.0,
47.6, 46.7, 42.0, 41.7, 39.83, 39.75, 38.3, 36.1, 35.5, 34.9, 34.8, 32.0,
30.7, 28.3, 27.7, 26.7, 23.4, 22.7, 17.9, 12.8; IR (ZnSe, cm−1) 746,
1078, 1249, 1312, 1420, 1462, 1581, 2864, 2934, 3363; HRMS (ESI)
(S)-1-((4-(2-Methoxy-6-(prop-2-yn-1-yloxy)indolizin-3-yl)-4-oxo-
butanoyl)-L-alanyl)-N-((S)-1-((4-nitrophenyl)amino)-1-oxopropan-
2-yl)pyrrolidine-2-carboxamide (42). Prepared from succinyl-L-
alanyl-L-prolyl-L-alanine p-nitroanilide (Suc-Ala-Pro-Ala-pNA, 47.7
mg, 99.9 μmol) and 2-methoxy-6-(prop-2-yn-1-yloxy)indolizine
(60.5 mg, 0.150 mmol) in CH2Cl2 (0.5 mmol) at 30 °C for 20 h.
Yield: 60.5 mg (66.0 μmol, 91.7%); Pale yellow solid (115 °C,
1
decomposed); TLC Rf = 0.56 (CHCl3/CH3OH = 8:1); H NMR
+
m/z: [M + H]+ calcd for C33H48NO5 538.3527; found 538.3525.
(CDCl3): δ 9.75 (d, J = 2.4 Hz, 1H), 9.26 (s, 1H), 8.16−8.12 (m,
2H), 8.00−7.95 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 9.6
Hz, 1H), 7.06−7.03 (m, 1H), 6.82 (d, J = 4.0 Hz, 1H), 5.98 (s, 1H),
4.68 (d, J = 2.0 Hz, 2H), 4.53−4.45 (m, 3H), 3.95 (s, 3H), 3.90−3.84
(m, 1H), 3.77−3.71 (m, 1H), 3.40−3.32 (m, 1H), 3.21−3.11 (m,
1H), 2.77−2.60 (m, 2H), 2.58 (t, J = 2.4 Hz, 1H), 2.31−2.21 (m,
1H), 2.01−1.94 (m, 3H), 1.50 (d, J = 7.6 Hz, 3H), 1.29 (d, J = 7.2
Hz, 3H); 13C{1H} NMR (CDCl3): δ 186.5, 174.1, 173.1, 171.7,
171.6, 158.9, 147.4, 144.8, 143.3, 134.2, 124.9, 124.7, 119.7, 119.4,
117.4, 114.3, 112.1, 85.4, 62.2, 58.1, 57.5, 51.7, 50.0, 47.6, 35.5, 30.1,
28.5, 25.9, 16.7, 16.5; IR (ZnSe, cm−1) 629, 750, 1254, 1331, 1454,
Optical rotation [α]2D3 +7.8 (c 1.00, CHCl3).
2-(1-(4-Chlorobenzoyl)-6-methoxy-2-methyl-1H-indol-3-yl)-1-(2-
methoxyindolizin-3-yl)ethan-1-one (25). To a solution (CH2Cl2, 10
mL) of indomethacin (716 mg, 2.00 mmol, 1 equiv), 2-
methoxyindolizine (1, 442 mg, 3.00 mmol, 1.5 equiv), and DMAP
(48.9 mg, 0.400 mmol, 20 mol %) in a 50 mL round-bottom flask
were added EDC·HCl (422 mg, 2.20 mmol, 1.1 equiv) and a
magnetic stir bar. The flask was filled with argon, and the solution was
stirred at 30 °C for 20 h. The reaction mixture was poured into
EtOAc (100 mL) and washed with brine (60 mL × 2). The organic
layer was dried with Na2SO4 and evaporated. The residue was purified
by silica-gel column chromatography (n-hexane/EtOAc = 1/0 to 1/1)
to afford the product. Yield: 948 mg (1.95 mmol, 97.3%); Pale yellow
solid (mp 151.0−151.9 °C); TLC Rf = 0.41 (n-hexane/EtOAc = 2:1);
1H NMR (CDCl3): δ 9.93 (d, J = 7.2 Hz, 1H), 7.71−7.68 (AA′BB′,
+
1504, 1595; HRMS (ESI) m/z: [M + H]+ calcd for C33H37N6O9
661.2617; found 661.2613; Optical rotation [α]2D3 +4.7 (c 0.40,
CHCl3).
Procedure for Synthesis of Amine 33 (Scheme 5). 1-Amino-
15-(2-methoxyindolizin-3-yl)-3,6,9,12-tetraoxapentadecan-15-one
(33). To a solution of tert-butyl (15-(2-methoxyindolizin-3-yl)-15-
oxo-3,6,9,12-tetraoxapentadecyl)carbamate (26, 98.0 mg, 0.200
mmol, 1 equiv) in CH2Cl2 (3.0 mL) was added trifluoroacetic acid
(0.60 mL) and a magnetic stir bar on an ice water bath. The vial was
filled with argon, and the resulting solution was stirred on an ice water
bath for 1 h. The solution was evaporated, and the residue was
dissolved in CH2Cl2 (15 mL) and washed with a Na2CO3 saturated
aqueous solution (15 mL x 3). The organic layer was dried with
Na2SO4 and evaporated to afford the product. Yield: 76.1 mg (0.193
mmol, 96.5%); Pale yellow oil; 1H NMR (CDCl3): δ 9.94 (d, J = 6.4
Hz, 1H), 7.36−7.34 (m, 1H), 7.16−7.12 (m, 1H), 6.81−6.77 (m,
1H), 6.02 (s, 1H), 3.99 (s, 3H), 3.93 (t, J = 6.8 Hz, 2H), 3.69−3.61
(m, 12H), 3.54 (t, J = 5.6 Hz, 2H), 3.26 (t, J = 6.8 Hz, 2H), 2.90 (t, J
= 6.8 Hz, 2H); 13C{1H} NMR (CDCl3): δ 186.1, 159.1, 137.2, 128.8,
125.1, 116.9, 112.7, 111.7, 85.3, 73.1, 70.70, 70.66, 70.5, 70.4, 67.5,
58.0, 41.9, 40.9; IR (ZnSe, cm−1) 764, 1020, 1084, 1248, 1308, 1422,
1462, 1503, 1597, 1694, 2864; HRMS (ESI) m/z: [M + H]+ calcd for
2H), 7.48−7.45 (AA′BB′, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.18−7.14
(m, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.79−
6.76 (m, 1H), 6.63 (dd, J = 9.2, 2.8 Hz, 1H), 6.10 (s, 1H), 4.32 (s,
2H), 4.09 (s, 3H), 3.78 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR
(CDCl3): δ 184.8, 168.5, 158.9, 156.1, 139.0, 137.5, 136.1, 134.5,
132.0, 131.3, 131.1, 129.2, 129.0, 125.4, 117.0, 115.3, 115.1, 112.9,
111.3, 111.3, 102.0, 85.4, 58.2, 55.8, 35.7, 13.9; IR (ZnSe, cm−1) 754,
851, 1015, 1067, 1080, 1223, 1310, 1352, 1418, 1454, 1599, 1672,
+
2926; HRMS (ESI) m/z: [M + H]+ calcd for C28H24ClN2O4
487.1419; found 487.1417.
tert-Butyl (15-(2-methoxyindolizin-3-yl)-15-oxo-3,6,9,12-
tetraoxapentadecyl)carbamate (26). Prepared from 2,2-dimethyl-
4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oic acid (146 mg, 0.400
mmol) in CH2Cl2 at 30 °C for 20 h. Yield: 189 mg (0.382 mmol,
95.6%); Colorless oil; TLC Rf = 0.44 (EtOAc only); 1H NMR
(CDCl3): δ 9.93 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 7.15−
7.11 (m, 1H), 6.80−6.76 (m, 1H), 6.01 (s, 1H), 5.08 (s, 1H), 3.98 (s,
3H), 3.93 (t, J = 6.8 Hz, 2H), 3.71−3.58 (m, 12H), 3.53 (t, J = 4.8
Hz, 2H), 3.33−3.29 (m, 2H), 3.26 (t, J = 6.8 Hz, 2H), 1.44 (s, 9H);
13C{1H} NMR (CDCl3): δ 186.1, 159.0, 156.2, 137.2, 128.8, 125.1,
+
C20H31N2O6 395.2177; found 395.2177.
Procedures for Synthesis Indolizines Connected with an
Intramolecular Photosensitizer (Scheme 6B). Diazido 46. To a
solution of PPIX (281 mg, 0.499 mmol, 1 equiv), 17-azido-
3,6,9,12,15-pentaoxaheptadecan-1-amine (383 mg, 1.25 mmol, 2.5
equiv), and DMAP (61.1 mg, 0.500 mmol, 1.0 equiv) in DMF (10
mL) in a 20 mL vial were added EDC·HCl (211 mg, 1.10 mmol, 2.2
equiv) and a magnetic stir bar. The vial was filled with argon, and the
solution was stirred at 30 °C for 20 h. The solution was poured into a
mixture of CH2Cl2 (50 mL) and washed with saturated NH4Cl
aqueous solution (50 mL × 3). The organic layer was dried with
Na2SO4 and evaporated. The residue was purified by silica-gel column
116.9, 112.7, 111.7, 85.2, 79.3, 70.74, 70.4, 67.5, 58.0, 40.9, 40.5, 28.6;
IR (ZnSe, cm−1) 762, 1020, 1686, 1248, 1422, 1503, 1599, 1709,
+
2868; HRMS (ESI) m/z: [M + Na]+ calcd for C25H38N2NaO8
517.2520; found 517.2520.
Methyl (3S,4R,4aR,9aS)-4a-acetoxy-3-((1E,3E)-5-(2-methoxy-6-
(prop-2-yn-1-yloxy)indolizin-3-yl)-4-methyl-5-oxopenta-1,3-dien-
1-yl)-3-methyl-1-oxo-3,4,4a,5,6,9-hexahydro-1H-4,9a-
ethanocyclohepta[c]pyran-7-carboxylate (41). Prepared from pseu-
dolaric acid B (32.4 mg, 74.9 μmol), 2-methoxy-6-(prop-2-yn-1-
I
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chromatography (CHCl3/CH3OH) to afford the product. Yield: 386
mg (0.339 mmol, 67.8%). Purple oil; TLC Rf = 0.56 (CHCl3/
CH3OH = 8:1); 1H NMR (CDCl3): δ 9.99 (s, 1H), 9.95 (s, 2H), 9.81
(s, 1H), 8.25−8.16 (m, 2H), 7.03−6.95 (m, 2H), 6.37−6.31 (m, 2H),
6.20−6.16 (m, 2H), 4.35−4.32 (m, 4H), 3.63 (s, 6H), 3.55 (s, 3H),
3.53 (s, 3H), 3.35−3.26 (m, 20H), 3.19−3.09 (m, 12H), 3.05 (t, J =
7.6 Hz, 4H), 2.83−2.78 (m, 6H), 2.74 (t, J = 5.2 Hz, 2H), 2.23−2.10
(m, 8H), −4.33 (s, 2H); 13C{1H} NMR (CDCl3): δ 173.1, 136.3,
130.4, 120.9, 97.7, 97.2, 97.1, 96.9, 70.48, 70.46, 70.41, 70.3, 70.1,
69.9, 69.84, 69.81, 69.5, 69.4, 69.31, 69.26, 69.2, 69.1, 50.6, 39.8, 39.2,
23.2, 12.9, 12.8, 11.8, 11.7; IR (ZnSe, cm−1) 677, 737, 851, 1103,
1275, 1639, 2100, 2864, 3308; HRMS (ESI) m/z: [M + H]+ calcd for
(7.94 mg, 40.0 μmol, 2.0 equiv) in water (200 μL) were combined.
The resulting solution was combined with solutions alkyne 42 (39.6
mg, 59.9 μmol, 3.0 equiv) in CH3OH (1.4 mL) and diazido 43 (24.1
mg, 20.1 μmol, 1 equiv) in CHCl3 (0.6 mL) in a 4 mL vial. The
resulting solution was stirred at 30 °C for 4 h under argon
atmosphere. The solution was then passed through a 0.21 μm syringe
filter and purified by HPLC (COSMOSIL C18-MS-II, 10 × 250 mm;
H2O/acetonitrile, 95/5 to 5/95, 30 min, 5 mL/min). The eluent was
freeze-dried to afford the product. Yield: 45.5 mg (18.0 μmol, 89.8%).
Purple solid (121 °C, decomposed); TLC Rf = 0.55 (CHCl3/CH3OH
1
= 8:1); H NMR (CDCl3): δ 10.14 (s, 1H), 10.01 (s, 1H), 9.98 (s,
1H), 9.87 (s, 1H), 9.11 (s, 2H), 9.03 (s, 2H), 8.36−8.26 (m, 2H),
8.02 (d, J = 9.2 Hz, 4H), 7.81 (d, J = 9.2 Hz, 4H), 7.43−7.30 (m,
4H), 7.04−7.00 (m, 2H), 6.93 (d, J = 10.4 Hz, 2H), 6.88 (t, J = 6.0
Hz, 2H), 6.60−6.56 (m, 2H), 6.35−6.29 (m, 2H), 6.14−6.08 (m,
2H), 5.75 (d, J = 3.2 Hz, 2H), 4.33−4.18 (m, 10H), 3.96−3.88 (m,
3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.76−3.73 (m, 5H), 3.69 (s, 3H),
3.65 (s, 3H), 4.47−3.45 (m, 8H), 3.38−3.34 (s, 2H), 3.26−3.20 (m,
4H), 3.10−2.60 (m, 48H), 2.28−2.18 (m, 4H), 2.03−2.01 (m, 2H),
1.80−1.68 (m, 6H), 1.28 (s, 3H), 1.26 (s, 3H), 1.16 (s, 3H), 1.14 (s,
3H); HRMS (ESI) m/z: [M + Na]+ calcd for C124H152N24NaO30Zn+
2544.0290; found 2544.0281; 13C{1H} NMR could not be
characterized due to concentration-dependent self-aggregation of
zinc porphyrin;24 Optical rotation could not be characterized due to
absorbance and emission of zinc porphyrin at 589 nm; HPLC Rt 23.9
min (COSMOSIL C18-MS-II, 4.6 × 100 mm; H2O/acetonitrile = 90/
10 to 0/100, 30 min, 1.0 mL/min). Note that compound 45 is
sensitive to daylight. The experiments were performed in the dark.
Procedures for Photoreactions. The photoreaction setup and
+
C58H82N12NaO12 1161.6067; found 1161.6071.
Diazido Photosensitizing Unit 43. To a stirring solution of diazido
46 (114 mg, 0.100 mmol, 1 equiv) in CHCl3 (10 mL) in a 20 mL vial
was added a solution zinc(II) acetate (64.2 mg, 0.350 mmol, 3.5
equiv) in CH3OH (5 mL) at 60 °C. The heating was continued for 16
h under argon atmosphere. After the reaction, the resulting solution
was washed with brine (15 mL × 3). The organic layer was dried with
Na2SO4 and evaporated. The residue was purified by silica-gel column
chromatography (CHCl3/CH3OH = 1/0 to 10/1) to afford the
product. Yield: 118 mg (98.1 μmol, 98.2%). Purple oil; TLC Rf = 0.55
(CHCl3/CH3OH = 8:1); 1H NMR (CDCl3): δ 9.46 (s, 2H), 9.22 (s,
1H), 9.17 (s, 1H), 8.21−8.06 (m, 2H), 6.77−6.72 (m, 2H), 6.33−
6.24 (m, 2H), 6.18−6.12 (m, 2H), 4.21−4.13 (m, 4H), 3.54 (s, 3H),
3.50 (s, 3H), 3.43 (s, 3H), 3.35 (s, 3H), 3.18−2.98 (m, 24H), 2.86−
2.77 (m, 12H), 2.69−2.61 (m, 4H), 2.54−2.50 (m, 4H), 2.17−2.05
(m, 8H); 13C{1H} NMR (CDCl3): δ 173.2, 146.9, 146.7, 146.0,
145.5, 139.3, 139.1, 136.5, 136.4, 136.2, 136.0, 130.84, 130.77, 119.5,
97.7, 97.1, 96.8, 70.3, 70.2, 70.1, 69.8, 69.6, 69.5, 69.2, 69.0, 50.3,
39.8, 39.1, 23.1, 13.0, 12.9, 11.7, 11.6; IR (ZnSe, cm−1) 708, 851, 934,
1103, 1553, 1638, 2100, 2864, 3289; HRMS (ESI) m/z: [M + H]+
calcd for C58H81N12O12Zn+ 1201.5383; found 1201.5375.
1
the method for determination of reaction yields using H NMR and
HPLC measurements are according to our previous report.5 The
photoreactions were performed in a 4 mL glass vial (GL Sciences)
placed in PhotoRedOx Box (EvoluChem) equipped with a Kessil
H160 Tuna Flora LED lamp (40 W, maximum irradiation of a red
channel) as a light source without use of a filter, unless otherwise
noted. The distance from the light source to the irradiation vessel was
ca. 10 cm.
Pseudolaric Acid B Caged 44. A solution of copper(II) sulfate
pentahydrate (6.49 mg, 26.0 μmol, 2.0 equiv) in water (260 μL), a
solution of TBTA (27.6 mg, 52.0 μmol, 4.0 equiv) in DMSO (900
μL), and a solution of sodium L-ascorbate (5.2 mg, 26 μmol, 2.0
equiv) in water (140 μL) were combined. The resulting solution was
combined with solutions of alkyne 41 (39.6 mg, 59.9 μmol, 3.0 equiv)
in CH3OH (900 μL) and diazido 43 (15.6 mg, 13.0 μmol, 1 equiv) in
CHCl3 (0.4 mL) in a 4 mL vial. The resulting solution was stirred at
30 °C for 4 h under argon atmosphere. The solution was then diluted
with EtOAc (15 mL), and the resulting mixture was washed with
brine (10 mL × 3). The organic layer was dried with Na2SO4 and
evaporated. The residue was purified by silica-gel column chromatog-
raphy (CHCl3/CH3OH = 1/0 to 9/1). The product was further
purified by GPC (YMC-GPC T2000, 21.2 × 600 mm, CHCl3) to
afford the product. Yield: 26.1 mg (10.7 μmol, 82.7%). Purple solid
Procedure A. Photoinduced release of compounds 17, 18, 19, 27,
28, 29, 30, 31, 34, 35, 36, and 40 was performed according to
procedure A. To a solution of a substrate (2.0 mM) and t-BuOH (2.0
mM) in methanol-d4 (700 μL) in a 4 mL vial were added a solution of
methylene blue in methanol-d4 (2.0 mM, 7.0 μL, 1.0 mol %) and a
magnetic stir bar under air. The solution was vigorously stirred by a
magnetic stirrer at room temperature and photoirradiated for 30−60
s. After the irradiation, the solution was transferred to an NMR tube,
1
and H NMR measurement was performed. The reaction yields (%)
were determined by comparison of the integral values of the peaks
corresponding to the carboxylic acids and that of t-BuOH as an
internal standard.
1
(110 °C, decomposed); TLC Rf = 0.55 (CHCl3/CH3OH = 8:1); H
NMR (CDCl3): δ 10.17 (s, 1H), 10.05 (s, 1H), 10.02 (s, 1H), 9.96 (s,
1H), 9.14 (s, 1H), 8.38−8.30 (m, 2H), 7.23−7.21 (m, 1H), 7.13 (s,
1H), 7.11 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 6.0 Hz, 1H), 6.64−6.52
(m, 4H), 6.33 (d, J = 16.8 Hz, 4H), 6.10 (d, J = 11.2 Hz, 2H), 5.85 (s,
2H), 5.66 (d, J = 14.8 Hz, 2H), 4.37−4.33 (m, 4H), 4.04 (d, J = 8.4
Hz, 3H), 3.81 (s, 5H), 3.73 (s, 8H), 3.70−3.69 (m, 8H), 3.65−3.57
(m, 3H), 3.54 (d, J = 5.2 Hz, 5H), 3.25−2.36 (m, 57H), 2.17−1.72
(m, 24H), 1.60 (s, 10H), 1.25 (s, 2H); IR (ZnSe, cm−1) 642, 1231,
1416, 1447, 1516, 1714, 1730; HRMS (ESI) m/z: [M + Na]+ calcd
for C128H154N14NaO30Zn+ 2454.0139; found 2454.0132; 13C{1H}
NMR could not be characterized due to concentration-dependent
self-aggregation of zinc porphyrin;24 Optical rotation could not be
characterized due to absorbance and emission of zinc porphyrin at
589 nm; HPLC Rt 24.5 min (COSMOSIL C18-MS-II, 4.6 × 100 mm;
H2O/acetonitrile = 90/10 to 0/100, 30 min, 1.0 mL/min). Note that
compound 44 is sensitive to daylight. The experiments were
performed in the dark.
Procedure B. Photoinduced release of compounds 32 was
performed according to procedure B. To a solution of a substrate
(2.0 mM), t-BuOH (2.0 mM), Na2HPO4/NaH2PO4 (20 mM) in
D2O (700 μL, pD 7.0) in a 4 mL vial were added a solution of
methylene blue in D2O (2.0 mM, 7.0 μL, 1.0 mol %) and a magnetic
stir bar under air. The solution was vigorously stirred by a magnetic
stirrer at room temperature and photoirradiated for 60 s. After the
1
irradiation, the solution was transferred to an NMR tube, and H
NMR measurement was performed. The reaction yield (%) was
determined by comparison of the integral values of the peaks
corresponding to 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid
and that of t-BuOH as an internal standard.
Procedure C. Photoinduced release of compounds 37 and 38 were
performed according to procedure C. To a solution of a substrate in
acetonitrile (2.5 mM, 400 μL) in a 4 mL vial were added ultrapure
water (100 μL), an aqueous solution of methylene blue (1.0 mM, 10
μL, 1.0 mol %), and a magnetic stir bar under air. The solution was
vigorously stirred by a magnetic stirrer at room temperature and
photoirradiated for 60 s. After the photoirradiation, a solution of 1-
naphthol in acetonitrile (4.0 mM, 250 μL) was added, and a portion
of the resulting solution was subjected to HPLC analysis. The
Succinyl-L-alanyl-L-prolyl-L-alanine p-nitroanilide Caged 45. A
solution of copper(II) sulfate pentahydrate (9.99 mg, 40.0 μmol, 2.0
equiv) in water (400 μL), a solution of TBTA (42.5 mg, 80.1 μmol,
4.0 equiv) in DMSO (1.4 mL), and a solution of sodium L-ascorbate
J
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Article
reaction yields (%) were determined by comparison of the peak area
of the carboxylic acids and that of 1-naphthol as a standard. The peak
areas of the products were calibrated against that of 1-naphthol
(R2>0.99). The conditions for HPLC analysis are as below: Column:
L-column3 C18, 5 μm, 4.6 × 100 mm (Chemical Evaluation and
Research Institution); Mobile phase: A = acetonitrile, B = aqueous
H3PO4 (40 mM); Gradient method: A/B = 5/95 to 95/5 (0−30
min); Flow rate: 0.50 mL/min.
Procedure D. Photoinduced release of compounds 39 was
performed according to procedure D. To an acetonitrile solution
(32 mL) of 25 (97.4 mg, 0.200 mmol, 1 equiv) in a 100 mL round-
bottom flask were added ultrapure water (7.0 mL), an aqueous
solution of methylene blue (1.0 mL, 2.0 mM, 1.0 mol %), and a
magnetic stir bar under air. The solution was vigorously stirred by a
magnetic stirrer at room temperature and photoirradiated for 120 s.
The distance from the light source to the flask was ca. 1 cm. After the
photoirradiation, the solvent was evaporated, and the residue was
dried under vacuum. The residue was purified by silica-gel column
chromatography (CHCl3/CH3OH/HCO2H = 99/0/1 to 80/19/1)
to afford indomethacin (39) for 70.4 mg (0.197 mmol, 98.4%) yield.
1H NMR (CDCl3): δ 7.65 (AA′BB′, 2H), 7.47 (AA′BB′, 2H), 6.94
(d, J = 2.0 Hz, 1H), 6.85 (d, J = 9.2Hz, 1H), 6.67 (dd, J = 9.2, 2.0 Hz,
1H), 3.82 (s, 3H), 3.68 (s, 2H), 2.38 (s, 3H); 13C{1H} NMR
(CDCl3): δ 176.0, 168.5, 156.2, 139.6, 136.4, 134.0, 131.4, 131.0,
130.7, 129.3, 115.2, 112.1, 111.9, 101.4, 55.9, 30.1, 13.5. The spectral
data was consistent with the literature.25
Procedure E. Photoreactions of compounds 44 and 45 were
performed according to procedure C. To a pH 7.4 sodium phosphate-
buffered solution (0.1 M, 475 μL) containing serum albumin (0−2.0
mg/mL) in a 4 mL vial was added a DMSO solution of a substrate
(0.40 mM, 25 μL) and a magnetic stir bar under air. The solution was
vigorously stirred by a magnetic stirrer at room temperature and
photoirradiated for 300 s. After the photoirradiation, a solution of
phenol in DMSO (4.0 mM, 5.0 μL) was added, and a portion of the
resulting solution was subjected to HPLC analysis. The reaction yields
(%) were determined by comparison of the peak area of the
carboxylic acids and that of phenol as a standard. The peak areas of
the carboxylic acids were calibrated against that of phenol (R2>0.99).
Photoirradiation of compound 44 (20 μM) produced pseudolaric acid
B for 30.8 μM (77.1% yield) and 29.0 μM (72.6% yield) in the
absence and presence of serum albumin (30 μM), respectively.
Irradiation of compound 45 (20 μM) produced Suc-Ala-Pro-Ala-pNA
for 29.2 μM (73.8% yield) and 25.6 μM (64.0% yield) in the absence
and presence of serum albumin (30 μM), respectively. The conditions
for HPLC analysis are as below: Column: COSMOSIL MS-II C18, 5
μm, 4.6 × 100 mm (Nacalai Tesque); Mobile phase: A = acetonitrile,
B = aqueous H3PO4 (40 mM); Gradient method: A/B = 10/90 to
60/40 (0−30 min, for 44), A/B = 10/90 to 90/10 (0−30 min, for
45); Flow rate: 1.0 mL/min. Note that compounds 44 and 45 are
sensitive to daylight. The experiments were performed in the dark.
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Chiyoda-ku, Tokyo 101-
0062, Japan; orcid.org/0000-0002-7270-351X;
Email: thosoya.cb@tmd.ac.jp
Authors
Nodoka Terao − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan
Takashi Niwa − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; orcid.org/0000-0002-6209-5362
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01244
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Japan Agency for Medical
Research and Development (AMED) under Grant Nos.
JP20am0401021 (Science and Technology Platform Program
for Advanced Biological Medicine) and JP20am0101098
(Platform Project for Supporting Drug Discovery and Life
Science Research, BINDS); JSPS KAKENHI Grant No.
JP19K05707 (C; K.W.); the Cooperative Research Project of
Research Center for Biomedical Engineering; the Pioneering
Project “Chemical Probe” and the Incentive Projects from
RIKEN.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01244.
■
sı
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AUTHOR INFORMATION
Corresponding Authors
■
Kenji Watanabe − Laboratory for Chemical Biology, RIKEN
Center for Biosystems Dynamics Research (BDR), Kobe 650-
0047, Japan; orcid.org/0000-0001-6249-8666;
Email: kenji.watanabe.vs@riken.jp
Takamitsu Hosoya − Laboratory for Chemical Biology,
RIKEN Center for Biosystems Dynamics Research (BDR),
Kobe 650-0047, Japan; Laboratory of Chemical Bioscience,
(3) (a) Bardhan, A.; Deiters, A. Development of photolabile
protecting groups and their application to the optochemical control of
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