Unusual visible-light photolytic cleavage of tertiary amides during the synthesis of cyclolignans related to podophyllotoxin

Article abstract of DOI:10.1016/j.tet.2017.09.021

During the attempted photochemical cyclization of 2,3-bisbenzylidene-γ-hydroxybutyric acid cyclic amide ester, it was observed that a γ-butyrolactone ring was formed, which was concurrent with the release of the amine fragment from the amide. The process occurs with high yield giving rise to the formation of β-apopicropodophyllin and its regioisomer. Additional experiments confirmed the photochemical nature of this transformation, and that it is independent from the photocyclization of the benzylidene groups – a typical reactivity for the members of the fulgide family. In contrast to the latter UV-driven cyclization, the photochemical cleavage of the amide was proven to proceed under irradiation with visible light.

Full text of DOI:10.1016/j.tet.2017.09.021

Accepted Manuscript
Unusual visible-light photolytic cleavage of tertiary amides during the synthesis of
cyclolignans related to podophyllotoxin
Kamil Lisiecki, Krzysztof K. Krawczyk, Piotr Roszkowski, Jan K. Maurin, Armand
Budzianowski, Zbigniew Czarnocki
PII:
S0040-4020(17)30943-2
10.1016/j.tet.2017.09.021
TET 28972
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 February 2017
Revised Date: 25 August 2017
Accepted Date: 13 September 2017
Please cite this article as: Lisiecki K, Krawczyk KK, Roszkowski P, Maurin JK, Budzianowski A,
Czarnocki Z, Unusual visible-light photolytic cleavage of tertiary amides during the synthesis of
cyclolignans related to podophyllotoxin, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.021.
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Unusual visible-light photolytic cleavage of tertiary
amides during the synthesis of cyclolignans related
to podophyllotoxin
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Kamil Lisiecki, Krzysztof K. Krawczyk, Piotr Roszkowski, Jan K. Maurin, Armand Budzianowski, Zbigniew
Czarnocki
Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland.

1
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Tetrahedron
journal homepage: www.elsevier.com
Unusual visible-light photolytic cleavage of tertiary amides during the synthesis of
cyclolignans related to podophyllotoxin
Kamil Lisieckia, Krzysztof K. Krawczyka, Piotr Roszkowskia, , Jan K. Maurinb,c, Armand Budzianowskic,
Zbigniew Czarnockia
a Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland
b National Medicines Institute, Chełmska 30/34, Warsaw 00-725, Poland
c National Centre for Nuclear Research, Sołtana 7, Otwock 05-400, Poland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
During the attempted photochemical cyclization of 2,3-bisbenzylidene-γ-hydroxybutyric acid
cyclic amide ester, it was observed that a γ-butyrolactone ring was formed, which was
concurrent with the release of the amine fragment from the amide. The process occurs with high
yield giving rise to the formation of β-apopicropodophyllin and its regioisomer. Additional
experiments confirmed the photochemical nature of this transformation, and that it is
independent from the photocyclization of the benzylidene groups – a typical reactivity for the
members of the fulgide family. In contrast to the latter UV-driven cyclization, the photochemical
cleavage of the amide was proven to proceed under irradiation with visible light.
Available online
Keywords:
Lignan
Podophyllotoxin
Photochemistry
Visible-light photolysis
Amide cleavage
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Podophyllotoxin is sensitive to extensive chemical
manipulation and thus finds limited use as a synthetic precursor.
Therefore, there is interest in the development of general, fully
synthetic protocols towards cyclolignans.14-16 The routes based on
the photocyclization of bisbenzylidene succinate derivatives,
although long known, have been relatively little studied. Heller
and co-workers first discovered the photochemical
rearrangements of fulgimides and fulgides.17,18 That reactivity
was soon to be employed in the synthesis of lignans from E,E-
dibenzylidenesuccinates.19,20 In 2004 Charlton and co-workers
presented the asymmetric synthesis of (+)-lyoniresinol dimethyl
ether based on photocyclization, using (-)-ephedrine as a chiral
auxiliary.21 It has been shown that a bidentate chiral auxiliary
could impose a single configuration of the pseudoenantiomeric
2,3-bisbenzylidenesuccinate by covalently binding the
carboxylate moieties in an asymmetric fashion. Charlton obtained
(1S,2R)-trans-dihydronaphthalene, but in 2011 our group
Lignans, a large family of natural products, have attracted
considerable interest due to their antiviral, antibacterial and
antineoplastic properties.1 Podophyllotoxin 1 (Fig. 1), the
bioactive component of Podophyllum peltatum and Podophyllum
hexandrum,2 is the best-known antitumor lignan. Semisynthetic
derivatives of podophyllotoxin etoposide 2 and teniposide 3 are
currently in clinical use.3 However, low water solubility, low
selectivity4 and drug resistance5 have limited their therapeutic
potential. Moreover, the continuously increasing demand for
aryltetralin lignans has almost exhausted natural sources.6
Consequently, lignans have been the subject of numerous
synthetic studies which are compiled in several reviews.7-13
demonstrated that the use of
L-prolinol as a chiral auxiliary
instead of (-)-ephedrine resulted in the formation of (1R,2R)-cis-
dihydronaphthalene,22 which has the same configuration at C-1
and C-2 as in podophyllotoxin. Based on this discovery, a formal
synthesis of (-)-podophyllotoxin was later completed,23 with the
use of a continuous flow irradiation process.
In this report we describe our efforts in the use of the natural
amino acid
L-proline as a chiral auxiliary in the attempted
Fig. 1. Structures of podophyllotoxin, etoposide and teniposide.
stereoselective synthesis of dihydronaphthalene lignans (Fig. 2).
———
Corresponding author. Tel. : + 48 22 55 26 276; e-mail: roszkowski@chem.uw.edu.pl

2
Tetrahedron
Heller’s mechanism24 of the photocyclization of fulgides
In order to introduce the chiral auxiliary, the Steglich
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involves excitation of the carbonyl group which results in
electron deficiency at the benzylic carbon atom. In fulgide-type
derivatives in which two carbonyl groups are conjugated with the
benzylic moieties, the photocyclization can take place non-
selectively at both sites of the molecule. Our idea was to
synthesize a molecule with only one carbonyl group conjugated
with the benzylic moiety that would promote a regiospecific
esterification26 with Boc-protected
L-proline was used. The
desired product 8 was obtained in 89% yield and was then treated
with trifluoroacetic acid (TFA) to remove the protecting group.
The analytical data confirmed the cyclic structure 9 (Scheme 3).
cyclization. Therefore, L-proline appeared a good candidate for
the chiral auxiliary. Importantly, the lactone ring D found in 1-3
was expected to be easily formed upon the removal of the
auxiliary.
Scheme 3. Steglich esterification of 7 Boc-protected
catalyzed cyclization of 8.
L-proline and acid-
A plausible mechanism for the cyclization of 8 is proposed in
Scheme 4.
Fig. 2. Comparison of previous22 and current studies.
2. Results and discussion
The E,E-bisbenzylidenesuccinic acid monomethyl ester 6 was
prepared by a two-step Stobbe condensation reaction using
piperonal and 3,4,5-trimethoxybenzaldehyde, as previously
reported (Scheme 1). 23
Scheme 4. The proposed mechanism for the cyclization of 8 catalyzed by
TFA.
Scheme 1. Synthesis of E,E-bisbenzylidenesuccinic acid monomethyl ester 6.
Since the acidity of hydrohalogenic acids can be dramatically
different in organic solvents compared to water, we expected
that TFA in DCM could efficiently protonate the carbonyl group
in the ester moiety. Indeed, when methanolic HCl was used
instead of TFA, the desired product 10 was obtained in 67% yield
(Scheme 5).
27
A chemoselective reduction of the carboxylic moiety was
carried out using the borane-dimethyl sulfide complex (BMS)
giving 2,3-bisbenzylidene-γ-hydroxybutyric acid methyl ester 7
in very good yield (Scheme 2). A similar reaction was reported
previously by Charlton.25
Scheme 5. Deprotection of Boc group with HCl.
Scheme 2. Chemoselective reduction of the carboxylic group with BMS.

3
Having the deprotected product 10 in hand, we started the
optimization of the macrolactamization. Although secondary
amines can react with esters to give amides, none of the screened
reaction conditions were successful (ESI, Table S1). Instead of
the desired product 11, only lactone 12 was detected (Scheme 6).
To avoid the use of acidic conditions, necessary for Boc
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cleavage, we decided to use the fluorenylmethyloxycarbonyl
(Fmoc) protecting group which can be removed under basic
conditions. The reaction between alcohol 7 and Fmoc-protected
L
-proline under Steglich conditions led us to the desired product
15 with 83% yield. We expected that the basic conditions
necessary for Fmoc removal (piperidine/DCM), and the presence
of the free secondary amino group would allow a spontaneous
reaction. Unfortunately, lactamization didn’t occur and we
isolated only product 10. Attempts to hydrolyze the methyl ester
group and remove the Fmoc group without cleaving the
L-proline
fragment failed (hydroxy acid 16 was obtained) (Scheme 9).
Scheme 6. Attempted macrocyclization of 10.
In order to accomplish the macrocyclization through a
coupling agent mediated lactamization, the methyl ester in 10 had
to be hydrolyzed to obtain 13. This approach failed, even when
mild hydrolytic conditions were used (LiOH, THF/H2O, RT).
Also in this case the only isolated product was lactone 12
(Scheme 7).
Scheme 9. Synthesis of 16 and its reactions under basic conditions.
Considering these results we decided to introduce the chiral
auxiliary by establishing the amide bond first. As expected, the
direct coupling between 16 and L-proline methyl ester 19 using
coupling reagents (BOP/TEA, DCC/DMAP, DCC/HOBT), failed
(ESI, Table S3) - the intramolecular reaction leading to lactone
12 was always preferred. The hydroxyl group was thus protected
in 7 with TBDMS-Cl in quantitative yield. For the next step a
selective hydrolysis of the methyl ester group was required. After
careful optimization, including the type and the number of
equivalents of the base, the solvent and temperature (ESI, Table
S4), we were able to selectively hydrolyze the methyl ester in
79% yield. Installing the chiral auxiliary by the coupling between
Scheme 7. Attempted hydrolysis of the methyl ester group in 10.
We therefore decided to hydrolyze the methyl ester group in
compound 8 before removing the Boc protecting group. Reaction
with LiOH in THF/H2O at room temperature for 24 h gave
carboxylic acid 14 with almost quantitative yield. Unfortunately,
we could not remove the Boc group to obtain compound 13
(Scheme 8) (ESI, Table S2). The reactions led either to product
12 or to decomposition. Only in the case when H3PO4 was used
in DCM at 25 °C did we observe the formation of traces of the
desired product by 1H NMR.
carboxylic acid 18 and L-proline methyl ester 19 gave the desired
product 20 in 61% yield. The BOP reagent was used for the
coupling. Fortunately, the removal of the TBDMS group and
hydrolysis of the methyl ester occurred simultaneously when
K2CO3/MeOH/H2O was used. The closure of the 8-membered
lactone was performed using BOP/TEA as a coupling reagent,
similarly as previously reported.23 We obtained compound 11 in
50% yield (Scheme 10).
Product 11 was very unstable: it was not possible to purify it
either on silica gel or alumina. Therefore, a product containing
1
approximately 28% of impurities (based on H-NMR) was used
for the further reactions.
We applied the same irradiation conditions as previously
reported.23 Upon irradiation of 11 in methanol and in
continuous-flow conditions (flow rate 0.7 mL/min; λmax = 365
nm) the β-apopicropodophyllin 22 and its isomer 23 were
obtained in a ratio 2.8/7.2 of (Scheme 11).
After separating the isomers on silica gel we did not observe any
optical activity of the products. The X-ray analysis confirmed
that they were racemates (Fig. 3).
Scheme 8. Hydrolysis of methyl ester group in 8 and attempts to remove Boc
protecting group in 14.

4
Tetrahedron
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O
O
O
O
Si
Cl
OH
O Si
1. NaOH
2-propanol
2. H+
79%
MeO
MeO
MeO
MeO
imidazole
DMF
97%
OMe
OMe
O
O
MeO
MeO
17
7
O
O
O
OMe
O
N
H
O Si
N
O
O Si
OH
19
MeO
MeO
MeO
MeO
BOP, TEA,
DCM
Scheme 12. Irradiation of 11 in toluene under continuous-flow conditions.
Products 22 and 23 were previously described by Heller and
MeO
61%
O
O
MeO
O
OMe
18
20
Strydom, who obtained them by irradiating lactone 12 at λmax
=
O
366 nm in benzene.19 The formation of racemates in our
experiment indicates that upon irradiation, the amide bond in 11
is cleaved and the lactone is formed before the cyclization occurs.
This is a very unexpected observation since in the case of a very
similar compound,23 the amide bond cleavage was very difficult.
To confirm that the amide-bond cleavage is a photochemical
process, we performed an experiment on samples of stable
hydroxy acid 21 in THF. One of the samples was heated in the
dark while the other was exposed to sunlight at room
temperature. In the heated sample, no changes were observed
after 24 h, but after irradiation with sunlight, lactone 12 was
formed in 65% yield (Scheme 13).
O
O
K2CO3
BOP, TEA
O
OH
N
O
N
O
MeOH/H2O MeO
DCM
50%
93%
MeO
MeO
MeO
O
O
MeO
O
21
OH
MeO
11
(unstable on silica gel and alumina)
Scheme 10. Synthetic pathway leading to compound 11 with the use of the
TBDMS protecting group.
Scheme 13. Reactions of 21 under thermal and photochemical conditions.
Scheme 11. Irradiation of 11 in methanol under continuous-flow conditions
These experiments indicate that the amide bond cleavage is a
purely photochemical process. Additionally, it was shown that
the cleavage is a separate photochemical process, occurring upon
excitation with a different wavelength, than the photochemical
cyclization of bisbenzylidenesuccinates. Visible light does not
induce the photocyclization of lignans.28 According to the UV-
Vis spectrum (ESI, Fig. S3) the wavelength of light that is
required to promote this transformation is in the range of 390 –
470 nm.
In order to study the photochemical release of amine (
proline) 1H NMR spectra were taken, immediately after the
irradiation of 21, after addition of a small portion of -proline to
L-
L
the reaction mixture, and after extraction of the reaction mixture
with with HClaq. The spectra confirmed that during the irradiation
the free amine is released (ESI, Fig. S2).
To test the generality of this process, we synthesized amide 24
by coupling 14 with diethylamine. After irradiation of 24 in
toluene and under continuous-flow conditions we obtained
products 22 and 23 accompanied by the free amine (Scheme 14)
(Fig. 5).
22 (A)
23 (B)
Fig. 3. ORTEP diagrams of compounds 22 and 23. A) The conformation of
22. Non-H atoms are shown as 30% probability ellipsoids. The solvent
molecule was omitted for clarity (ESI, Fig. S4); B) The conformation of 23.
Non-H atoms are shown as 30% probability ellipsoids. Only one orientation
of every disordered part of the molecule is shown and the water molecule is
omitted for the clarity.
Since methanol is a protic solvent which can protonate the
substrate leading to racemization, we switched to aprotic toluene.
Surprisingly, the same products were obtained, also in the form
of racemates, although the ratio between these two products was
now inversed to 7.2/2.8 (Scheme 12) (ESI, Fig. S1).
Scheme 14. Synthesis of 24 and its irradiation in toluene under continuous-
flow conditions.

5
This experiment indicated that such photochemical
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deprotection can also occur for other tertiary amides with the
same framework, establishing a unique, mild photochemical
cleavage of the amide protecting group.
In order to check how the structure and substitution pattern
influence the cleavage of amides, we decided to synthetize
hydroxyamides and amidoesters with symmetrically substituted
benzylidene groups. Firstly, a series of trimethoxy substituted
compounds were synthesized as shown in Scheme 15.
The reaction of diethyl succinate with two equivalents of
trimethoxybenzaldehyde and NaH as a base leads to fulgenic acid
25. Dehydration with acetyl chloride and then opening of the 5-
membered ring gave amidoacid 27 which can be quantitatively
converted into ester 28. The ester group was then reduced under
different conditions. With LiBH4, the double bond was also
reduced leading to compound 29. The reduction of only the ester
group was achieved with DIBAL-H as a reducting agent and BF3
as a Lewis acid. The resulting compound 31 was esterified to
amidoester 32. Additionally, borane-dimethylsulfide was used to
simultaneusly reduce the carboxyl group to the hydroxy group
and the amide group to the amine group in compound 27, giving
product 30.
Fig. 5. Selected regions of 1H NMR spectra (in CDCl3) after irradiation of 24
in toluene: A - reaction mixture immediately after irradiation (before
extraction); B - reaction mixture after irradiation (before extraction) + small
amount of NHEt2; C - reaction mixture after irradiation (before extraction) +
large amount of NHEt2; D - reaction mixture after extraction with HClaq.
Hydroxyamides 29, 30, 31 and amidoester 32 were then
irradiated under different conditions: in THF using sunlight, in
MeOH using UV light (365 nm) and in toluene using UV light
(365 nm). The results of these experiments are summarized in
Table 1.
Table 1. The results of irradiation of compound 29 – 32 under different
conditions.
Product
Substrate
sunlight/THF
UV/MeOH
UV/toluene
29
30
31
-
-
-
-
-
-
-
-
-
32
-
It can be concluded, that in the case of trimethoxy substituted
benzylidene groups the conjugated system as well as the presence
of an ester and amide group is essential for the photoactivity of
the compound. However, in this case we did not observe the
photocleavage of the amide bond. Only cyclization leading to
cyclolignan 33 took place.
Considering these results we synthesized compounds 42 and
44 with monomethoxy substituents and 43 and 45 with no
substituent on aromatic rings to confirm that the change of
substituents inhibits the photocleavage of the amide bond. The
synthetic pathway was analogous to the synthesis of trimethoxy
derivatives (Scheme 16).
Compounds 42 – 45 were then irradiated under the same
conditions as in the case of the trimethoxy substituted
compounds (sunlight/THF; UV/MeOH; UV/toluene). None of
these compounds were photoactive – the conversion of substrate
was less than 5%.
Results from the experiments with symmetrically substituted
hydroxyamides and amidoesters indicate that the presence of
both the trimethoxy and methylenedioxy groups is essential for
the cleavage of the amide bond. Moreover, the conjugated system
of double bonds as well as high electronic density on the
aromatic rings are essential for the cyclization of these
compounds.
Scheme 15. The synthesis of hydroxyamides 29, 30, 31 and amidoester 32.

6
Tetrahedron
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Scheme 16. The synthetic pathway leading to hydroxyamides 42, 43 and amidoesters 44, 45.
Possible mechanisms for the photolysis are presented in Scheme 17.
.
Scheme 17. Possible mechanisms of photolysis of tertiary amides with bisbenzylidenesuccinyl platform: A – mechanism involves 1,4-HAT; B – mechanism
involves 1,5-HAT; C – mechanism involves 1,6-HAT.
The proposed mechanism starts with the cleavage of the ester
group. After excitation of the carbonyl group, the ester bond
dissociates to produce an alkoxy radical. Then hydrogen atom
abstraction from the solvent takes place and the hydroxyamide is
formed. The next step is the excitation of the second carbonyl
group. At this stage three different mechanisms are possible
(Scheme 15 A, B, C).
experiments. Mechanism B involves 1,5-hydrogen atom transfer
and cyclobutanone derivative production. This product was also
not observed. In mechanism C 1,6-hydrogen atom transfer takes
place leading to the lactol derivative. But in this case nucleophilic
attack of the nitrogen lone pair on the –OH proton and in
consequence formation of lactone with amine release is possible.
We propose that mechanism C is the most feasible.
Mechanism A assumes 1,4-hydrogen atom transfer leading to
a lactol derivative. This product was not observed during our

7
3. Conclusions
5 mL of DCM and washed twice with 5 mL of 0.5 M HCl, and
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twice with 5 mL of saturated aqueous NaHCO3. The organic
layer was dried over anhydrous MgSO4 and concentrated under
vacuum to give 234 mg of yellow oil (3.74 mmol, 89%) that
required no further purification. Rf (5% CHCl3/MeOH) 0.69.
We present a rare example of a reaction, in which the amide bond
is photolytically cleaved with visible light. Thus, a possible use
of the bisbenzylidenesuccinyl platform as an amine protecting
group was demonstrated. We believe that this reaction may be
useful in the preparation of cyclolignans with two different
benzylidenic substituents. Although the synthesis of the target
molecules was not accomplished, the obtained (±)-β-
apopicropodophyllin and its isomer, as well as the novel aryl-
naphthalene lignan 9 have potential anticancer activity.29,30
25
1
[α]D = –52.4 (c 1.0, CHCl3). H NMR (CDCl3, 300 MHz): δ
7.72 (s, 1H), 7.01–6.55 (m, 6H), 5.89 (d, J = 3.1 Hz, 2H), 4.89–
4.71 (m, 2H), 4.26–4.08 (m, 1H) 3.83 (s, 3H), 3.76 (s, 3H), 3.74
(s, 6H), 3.50–3.22 (m, 2H), 2.12–1.90 (m, 1H), 1.84–1.55 (m,
3H), 1.44 (s, 4H), 1.37 (s, 5H). 13C NMR (CDCl3, 75 MHz): δ
172.6, 167.1, 153.6, 153.0, 147.8, 147.5, 142.3, 139.6, 130.1,
129.9, 129.6, 129.0, 126.7, 123.3, 108.3, 107.7, 107.4, 101.2,
79.9, 60.9, 59.2, 58.8, 56.0, 52.5, 46.5, 30.5, 28.3, 24.3. HRMS
(ESI) m/z: calcd for C33H39NO11Na [M+Na]+, 648.2415; found,
648.2419.
4. Experimental section
All chemicals were purchased from Sigma-Aldrich and used
as received. Piperonal, 3,4,5-trimethoxybenzaldehyde and t-
BuOK were flushed with dry argon and kept under an inert
atmosphere after every use. Toluene was dried by boiling for ca.
2 h with pieces of Na metal and subsequent distillation, and was
stored over activated molecular sieves (3Å). Methanol was dried
with KOH powder for 24 h, distilled and was stored over
activated molecular sieves (3Å). Dichloromethane (DCM) was
dried by storing it over activated molecular sieves (3Å), for at
least 3 days. TLC analysis was performed on Merck TLC plates
Methyl
4-(benzo[d][1,3]dioxol-5-yl)-5,6,7-trimethoxy-3-
methyl-2-naphthoate (9). 50 mg (0.08 mmol) of compound 8
was dissolved in 0.5 mL of DCM. The resulting solution was
stirred and cooled in an water-ice bath and 0.5 mL of TFA was
added in three portions. The color of the solution changed from
yellow to red. The cooling bath was removed and the solution
was allowed to reach room temperature (Warning: during the
reaction gases are released, do not close the reaction vessel
hermetically). After 1 h of stirring the solution was concentrated
under vacuum and the residue was dissolved in 5 mL of AcOEt
and washed thrice with 3 mL of saturated aqueous NaHCO3 and
twice with 3 mL of brine. The organic layer was dried over
anhydrous MgSO4 and concentrated under vacuum. 26 mg (0.063
mmol, 80%) of product 9 was obtained in the form of an opaque
(silica gel 60 F254, aluminium sheets). H NMR and 13C NMR
spectra were recorded on
1
a Bruker AVANCE 500/300
spectrometer. Chemical shifts were reported in ppm from
tetramethylsilane, with the solvent resonance as the internal
standard in CDCl3, CD3OD or DMSO-d6 solution. High-
resolution mass (ESI-TOF MS) spectra were run on the
Micromass LCT spectrometer. Compounds 4, 5 and 6 were
synthesized as previously reported.23
1
white, UV-fluorescent gum. Rf (30% AcOEt/DCM) 0.75. H
NMR (CDCl3, 300 MHz): δ 8.19 (s, 1H), 7.00 (s, 1H), 6.86 (d, J
= 7.8 Hz, 1H), 6.70 (d, J = 1.5 Hz, 1H), 6.61 (dd, J = 7.8, 1.8 Hz,
1H), 6.02 (d, J = 1.5 Hz, 1H), 6.01 (d, J = 1.5 Hz, 1H), 3.97 (s,
3H), 3.94 (s, 3H), 3.87 (s, 3H), 3.33 (s, 3H), 2.23 (s, 3H). 13C
NMR (CDCl3, 75 MHz): δ 169.0, 152.6, 149.3, 146.9, 145.7,
144.3, 137.1, 136.9, 132.1, 129.5, 129.1, 128.9, 125.2, 121.6,
109.6, 107.5, 103.6, 100.8, 60.9, 60.8, 55.8, 52.1, 18.3. HRMS
(ESI) m/z: calcd for C23H22O7Na [M+Na]+, 433.1258; found,
433.1271.
(2E,3E)-methyl
4-(benzo[d][1,3]dioxol-5-yl)-3-
(hydroxymethyl)-2-(3,4,5-trimethoxybenzylidene)but-3-
enoate (7). To a solution of 1.0 g (2.3 mmol) of 6 in anhydrous
THF (25 mL) was slowly added a 2.14 mL (22.6 mmol, 10 eq) of
borane-dimethyl sulfide complex (BMS) solution. The reaction
was carried out at room temperature and under argon atmosphere.
After stirring for 3.5 h, the reaction mixture was quenched with
ethanol (50 mL). The solvent was evaporated and a second
aliquot of ethanol (30 mL) was added and evaporated. This
procedure was repeated twice more. The residue was dissolved in
CHCl3 (60 mL) and washed with 5% NaHCO3 (3x30 mL), dried
over anhydrous MgSO4, filtered and concentrated under vacuum
to give a yellow oil that required no further purification (0.822 g,
1.92 mmol, 85%). Rf (5% CHCl3/MeOH) 0.56. 1H NMR (CDCl3,
500 MHz): δ 7.71 (s, 1H), 6.91 (s, 2H), 6.90 (d, J = 1.5 Hz, 1H),
6.83 (dd, J = 8.5, 1.5 Hz, 1H), 6.78 (s, 1H), 6.70 (d, J = 8.0 Hz,
1H), 5.91 (s, 2H), 4.26 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.76 (s,
3H), 3.75 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ 167.8, 153.0,
147.7, 147.0, 141.4, 139.4, 134.2, 130.4, 129.6, 129.2, 128.0,
122.8, 108.2, 107.6, 107.1, 101.0, 66.6, 60.8, 55.9, 52.5. HRMS
(ESI) m/z: calcd for C23H24O8Na [M+Na]+, 451.1363; found,
451.1373.
(R)-2-((2E,3E)-2-(benzo[d][1,3]dioxol-5-ylmethylene)-3-
(methoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)but-3-enyl) 1-
tert-butyl pyrrolidine-1,2-dicarboxylate (8). To a stirred
solution of 180 mg (0.42 mmol) of 7 in 1.5 mL of DCM at room
temperature was added 181 mg (0.84 mmol, 2 eq) of Boc-
protected proline and 5 mg (0.04 mmol, 0.1 eq) of DMAP. The
resulting solution was cooled in a water-ice bath and 95 mg (0.46
mmol, 1.1 eq) of DCC was added in one portion. After 5 min of
stirring at 0 °C the cooling bath was removed and the solution
was allowed to reach room temperature. After 3 h TLC analysis
showed complete conversion of the substrate. The resulting
suspension was filtrated at atmospheric pressure and the filtrate
was concentrated under vacuum. The residue was dissolved in
(R)-((2E,3E)-2-(benzo[d][1,3]dioxol-5-ylmethylene)-3-
(methoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)but-3-enyl)
pyrrolidine-2-carboxylate (10). Method 1: In a round bottom
flask of 50 mL, equipped with a stirring bar and under an argon
atmosphere, 80 mg (0.13 mmol) of compound 8 was dissolved in
12 mL of dry MeOH saturated with HCl. Resulting solution was
stirred at room temperature for 3 hours (Warning: during the
reaction gases are released, do not close the reaction vessel
hermetically). After this time a white solid precipitated. The
resulting suspension was concentrated under vacuum and the
residue was washed thrice with 5 mL of saturated aqueous
NaHCO3 and twice with 5 mL of brine. The organic layer was
dried over anhydrous MgSO4 and concentrated under vacuum.
The resulting oil was purified on a silica gel column, using
AcOEt in hexane (gradient from 0% to 90%). After evaporation
of the solvent 45 mg (0.086 mmol, 67%) of product 10 was
obtained as a yellow oil. Method 2: 100 mg (0.134 mmol) of
compound 15 was dissolved in 2 mL of piperidine/DCM mixture
(3:7 v/v) and stirred at room temperature for 30 min. The reaction
mixture was evaporated to dryness, 5 mL of DCM was added and
again evaporated to dryness. The crude product was purified on a
silica gel column, using AcOEt/hexane as an eluent (gradient
from 0% to 90% of AcOEt). After evaporation of the solvent,
42 mg (0.08 mmol, 60%) of product 10 was obtained as a yellow
25
oil. Rf (3% CHCl3/MeOH) 0.10. [α]D = –29.2 (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz): δ 7.73 (s, 1H), 6.88 (s, 3H), 6.82
(dd, J = 7.8, 1.2 Hz, 1H), 6.76 (s, 1H), 6.69 (d, J = 8.1 Hz, 1H),

8
Tetrahedron
ACCEPTED MANUSCRIPT
5.90 (s, 2H), 4.86 (d, J = 13.8 Hz, 1H), 4.81 (d, J = 13.8 Hz,
1.1 eq) of DCC was added in one portion. The cooling bath was
1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.74 (s, 6H), 3.61–3.48 (br m,
1H), 2.88 (br d, 2H), 2.33 (br s, 1H), 1.93 (br m, 1H), 1.77–1.51
(br m, 3H). 13C NMR (CDCl3, 75 MHz): δ 174.9, 167.1, 152.9,
147.8, 147.5, 142.2, 139.5, 132.9, 129.7, 129.5, 128.9, 126.7,
123.3, 108.3, 107.6, 107.3, 101.1, 68.7, 60.8, 59.6, 55.9, 52.5,
46.7, 29.6, 25.2. HRMS (ESI) m/z: calcd for C28H31NO9Na
[M+Na]+, 548.1891; found, 548.1885.
(3E,4E)-4-(benzo[d][1,3]dioxol-5-ylmethylene)-3-(3,4,5-
trimethoxybenzylidene)dihydrofuran-2(3H)-one (12). M.p.
182.1–183.4 °C. Rf (5% CHCl3/MeOH) 0.80. H NMR (CDCl3,
300 MHz): δ 7.59 (s, 1H), 6.52 (s, 1H), 6.49–6.39 (m, 2H), 6.22
(s, 2H), 6.07 (d, J = 1.2 Hz, 1H), 5.76 (s, 2H), 5.01 (s, 2x1H),
3.76 (s, 3H), 3.63 (s, 6H). 13C NMR (CDCl3, 75 MHz): δ 172.6,
151.8, 147.7, 146.3, 139.8, 137.1, 130.9, 130.4, 127.4, 125.6,
122.8, 120.8, 107.7, 106.8, 106.5, 101.1, 71.2, 60.8, 55.6. HRMS
(ESI) m/z: calcd for C22H20O7Na [M+Na]+, 419.1101; found,
419.1095.
removed and the solution was allowed to reach room
temperature. After a few minutes of stirring, a white solid
precipitated. After 3 hours the suspension was filtered at
atmospheric pressure and the filtrate was concentrated under
vacuum. The residue was dissolved in 10 mL of DCM, washed
twice with 5 mL of 0.5 N HCl, twice with 5 mL of saturated
aqueous NaHCO3, dried over anhydrous MgSO4, filtered and
evaporated to dryness. The resulting oil was purified on a silica
gel column, using MeOH in DCM (gradient from 0% to 0.7%) to
obtain 144 mg (0.193 mmol, 83%) of product 15 in the form of a
1
25
yellow oil. Rf (2% CHCl3/MeOH) 0.71. [α]D = –39.8 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.75 (d, J = 6.6 Hz, 2H),
7.70 (s, 1H), 7.57 (dt, J = 15.7, 7.8 Hz, 2H), 7.44–7.19 (m, 4H),
6.94–6.65 (m, 5H), 6.65 (d, J = 8.1 Hz, 1H), 5.88 (s, 2H), 5.01–
4.64 (m, 2H), 4.48–4.10 (m, 4H), 3.83 (s, 3H), 3.73 (m, 9H),
3.61–3.39 (m, 2H), 2.19–1.98 (m, 1H), 1.97–1.69 (m, 3H). 13C
NMR (CDCl3, 75 MHz): δ 172.2, 167.3, 154.8, 153.0, 147.7,
147.3, 144.1, 143.9, 141.3, 139.6, 139.6, 132.6, 129.5, 128.9,
127.7, 127.0, 125.1, 125.1, 124.9, 119.9, 108.3, 107.8, 107.4,
101.1, 68.8, 68.3, 67.5, 60.9, 56.0, 52.5, 47.2, 46.4, 29.5, 24.3.
HRMS (ESI) m/z: calcd for C43H41NO11Na [M+Na]+, 770.2572;
found, 770.2594.
(2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-(((R)-1-(tert-
butoxycarbonyl)pyrrolidine-2-carbonyloxy)methyl)-2-(3,4,5-
trimethoxybenzylidene)but-3-enoic acid (14). 95 mg (0.15
mmol) of ester 8 was placed in a round bottom flask, dissolved in
3 mL of THF and stirred at room temperature. A suspension of
50 mg (2.1 mmol, 13.7 eq) of LiOH in 3 mL of distillated water
was added in one portion. The resulting orange suspension was
stirred at room temperature for 24 h. After this time the reaction
mixture was acidified with 6 M HCl to pH ≈ 2, 6 mL of brine
was added and the mixture was transferred into a separatory
funnel. After extraction with AcOEt (3 x 6 mL) the organic
layers were combined, dried over anhydrous MgSO4 and
concentrated under vacuum. The product 14 (89 mg, 1.5 mmol,
96%) was obtained as a white solid. M.p. 131–132.4 °C. Rf (5%
CHCl3/MeOH) 0.14. [α]D = –44.0 (c 1.0, CHCl3). H NMR
(CDCl3, 300 MHz): δ 7.79 (s, 1H), 6.93 (s, 2H), 6.91 (d, J = 1.5
Hz, 1H), 6.84 (dd, J = 8.1, 1.5 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J =
8.1 Hz, 1H), 5.90 (s, 2H), 4.46–4.16 (m, 3H), 3.85 (s, 3H), 3.75
(s, 6H), 3.68–3.21 (br m, 2H), 2.27 (br s, 1H), 2.17–1.74 (m, 3H),
1.48 (s, 5H), 1.40 (s, 4H). 13C NMR (CDCl3, 75 MHz): δ 178.6,
175.8, 171.8, 153.0, 147.8, 147.1, 143.1, 139.8, 133.8, 130.3,
130.0, 129.4, 127.5, 122.9, 108.3, 107.8, 107.4, 101.0, 81.1, 66.7,
60.9, 59.0, 56.0, 46.3, 30.8, 28.2, 23.6. HRMS (ESI) m/z: calcd
for C32H36NO11 [M-H]–, 610.2294; found, 610.2305.
(2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-(((R)-pyrrolidine-2-
carbonyloxy)methyl)-2-(3,4,5-trimethoxybenzylidene)but-3-
enoic acid (13). In a 5 mL vial 100 mg (0.163 mmol) of
compound 14 was dissolved in 1.0 mL of DCM. The resulting
solution was stirred at room temperature and 28 ꢀL (0.49 mmol,
3 eq) of 15 M H3PO4 was added in one portion. After stirring
overnight the solvent was evaporated and the residue was
dissolved in 5 mL of CHCl3 resulting in the precipitation of a
white solid. The resulting suspension was filtered under vacuum
to give 2 mg (3.3 ꢀmol, 2%) of product 15 as a white solid. Rf
(2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-2-
(3,4,5-trimethoxybenzylidene)but-3-enoic acid (16). M.p.
161.0–163.2 °C. Rf (5% CHCl3/MeOH) 0.05. 1H NMR (CD3OD,
300 MHz): δ 7.71 (s, 1H), 7.00 (s, 2H), 6.87 (d, J = 1.7 Hz, 1H),
6.85–6.79 (m, 1H), 6.77 (s, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.85 (s,
2H), 4.25 (d, J = 14.9 Hz, 1H), 4.10 (d, J = 14.9 Hz, 1H), 3.75 (s,
3H), 3.73 (s, 6H). 13C NMR (CD3OD, 75 MHz): 170.4, 154.3,
149.1, 148.2, 142.4, 140.4, 136.9, 132.4, 131.6, 130.4, 128.4,
123.8, 109.0, 108.6, 108.3, 102.3, 65.9, 61.1, 56.6. HRMS (ESI)
m/z: calcd for C22H21O8 [M-H]–, 413.1242; found, 413.1222.
(2E,3E)-methyl
butyldimethylsilyloxy)methyl)-2-(3,4,5-
trimethoxybenzylidene)but-3-enoate (17). To a stirred solution
of 1.47 g (3.43 mmol) of alcohol 7 in 5 mL of dry DMF,
imidazole (0.584 g, 8.58 mmol, 2.5 eq) was added in one portion
at room temperature. The resulting solution was cooled in an
25
1
4-(benzo[d][1,3]dioxol-5-yl)-3-((tert-
˚
water-ice bath to 0 C and 0.621 g (1.2 eq) of TBDMS-Cl was
added. The reaction mixture was stirred at 0 °C for 15 min and
then for 4 h at room temperature. Diethyl ether (3 mL) and ethyl
acetate (3 mL) were added. The white imidazolium chloride
precipitated and was filtered off. The filtrate was transferred to a
separatory funnel, washed with water (3x5 mL), with brine (1x5
mL), dried over anhydrous MgSO4, filtered and concentrated
under vacuum to give a yellow oil (1.8 g, 3.3 mmol, 97%) that
1
required no further purification. Rf (2% CHCl3/MeOH) 0.83. H
NMR (CDCl3, 300 MHz): δ 7.67 (s, 1H), 6.94 (s, 2H), 6.86 (s,
1H), 6.83–6.75 (m, 2H), 6.68 (d, J = 8.1 Hz, 1H), 5.88 (s, 2H),
4.35–4.03 (m, 2H), 3.84 (s, 3H), 3.76 (s, 6H), 3.73 (s, 3H), 0.90
(s, 9H), 0.03 (s, 6H). 13C NMR (CDCl3, 75 MHz): δ 167.5,
153.0, 147.7, 146.7, 141.6, 139.4, 134.6, 131.0, 129.9, 128.1,
126.8, 122.5, 108.2, 107.8, 107.2, 100.9, 65.4, 60.9, 56.0, 52.3,
25.9, 18.3, -5.5. HRMS (ESI) m/z: calcd for C29H38O8SiNa
[M+Na]+, 565.2228; found, 565.2250.
1
(10% CHCl3/MeOH) 0.27. H NMR (DMSO-d6, 300 MHz): δ
7.59 (s, 1H), 7.08 (s, 2H), 6.87 (s, 1H), 6.82 (s, 1H), 6.81 (s, 1H),
6.72 (s, 1H), 5.95 (d, J = 1 Hz, 1H), 5.94 (d, J = 1 Hz, 1H), 4.10
(dd, J = 15.6, 1.8 Hz, 1H), 4.05–3.97 (m, 1H), 3.88 (d, J = 15.6,
1H), 3.68 (s, 6H), 3.65 (s, 3H), 3.30 – 2.99 (m, 2H), 2.25-2.07
(m, 1H), 1.97 – 1.71 (m, 3H).
(2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-((tert-
butyldimethylsilyloxy)methyl)-2-(3,4,5-
(R)-1-(9H-fluoren-9-yl)methyl
(benzo[d][1,3]dioxol-5-ylmethylene)-3-(methoxycarbonyl)-4-
(3,4,5-trimethoxyphenyl)but-3-enyl) pyrrolidine-1,2-
dicarboxylate (15). To a stirred solution of 100 mg (0.233
mmol) of hydoxyester 7 in 2 mL of DCM, Fmoc-protected
proline (158 mg, 0.466 mmol, 2 eq) and DMAP (3 mg, 0.02
mmol, 0.1 eq) were added. The resulting yellow solution was
cooled in an water-ice bath to 0 °C and 53 mg (0.26 mmol,
2-((2E,3E)-2-
trimethoxybenzylidene)but-3-enoic acid (18). In a round
bottom flask equipped with a stirring bar 50 mg (0.092 mmol) of
ester 17 was dissolved in 1.0 mL of 2-propanol at room
temperature. To the vigorously stirring solution, 183 ꢀL of 1M
NaOH (0.184 mmol, 2 eq) was added in one portion and the
resulting solution was heated to 60 °C. After 24 hours the
reaction mixture was cooled down to 0 °C and acidified with 1M
HCl to pH ≈ 3. Ethyl acetate was added (1 mL) and the solution
L-

9
was transferred to a separatory funnel. After shaking the mixture
vigorously, 1 mL of brine was added and the organic layer was
collected and dried over anhydrous MgSO4. After filtration and
solvent removal, the resulting oil was purified on a silica gel
column, using MeOH in CHCl3 (gradient, from 0% to 1.5%) as
an eluent. A yellow oil was obtained (38.5 mg, 0.073 mmol,
79%). Rf (5% CHCl3/MeOH) 0.14. 1H NMR (CDCl3, 300 MHz):
δ 7.76 (s, 1H), 6.97 (s, 2H), 6.90 (d, J = 1.5 Hz, 1H), 6.86–6.80
(m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 5.89 (s, 2H), 4.32 (d, J = 14.4
Hz, 1H), 4.14 (d, J = 14.4 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 6H),
0.89 (s, 9H), 0.04 (d, J = 9.0 Hz, 6H). 13C NMR (CDCl3, 75
MHz): δ 171.8, 153.0, 147.7, 146.9, 143.2, 139.7, 133.8, 130.7,
129.5, 127.9, 127.6, 122.8, 108.3, 107.8, 107.5, 101.0, 65.9, 60.9,
56.0, 25.8, 18.3, -5.5. HRMS (ESI) m/z: calcd for C28H35O8Si
[M-H]–, 527.2107; found, 527.2087.
15 mL of MeOH at room temperature. To the vigorously stirred
ACCEPTED MANUSCRIPT
solution, 540 mg (3.91 mmol, 5 eq) of K2CO3 in 15 mL of
distillated water was added dropwise. The flask was equipped
with a reflux condenser and heated in an oil bath (90 °C) for 7 h.
The solution became yellow and clear. The methanol was
removed under reduced pressure and the resulting water solution
was transferred to a separatory funnel and washed twice with
10 mL of AcOEt. The aqueous layer was acidified with 1M HCl
to pH ≈ 2 and extracted three times with 10 mL of AcOEt. The
organic layer was dried over anhydrous MgSO4. After filtration
and solvent removal 370 mg (0.723 mmol, 93%) of compound 21
25
was obtained as yellow oil. Rf (10% CHCl3/MeOH) 0.05. [α]D
=
1
+53.6 (c 1.0, CHCl3). H NMR (CDCl3, 300 MHz): δ 6.98–6.61
(m, 7H), 5.89 (s, 2H), 4.49 (t, J = 6.6 Hz, 1H), 4.26 (s, 2H), 3.85
(s, 3H), 3.76 (s, 6H), 3.74–3.57 (m, 2H), 2.25–2.04 (m, 2H),
2.05–1.63 (m, 2H). 13C NMR (CDCl3, 75 MHz): δ 174.7, 170.7,
153.0, 151.8, 147.4, 147.0, 138.7, 136.1, 131.9, 131.3, 130.6,
130.0, 122.3, 108.1, 107.9, 106.3, 101.0, 66.7, 60.9, 59.7, 56.0,
50.3, 28.8, 25.2. HRMS (ESI) m/z: calcd for C27H28NO9 [M-H]–,
510.1770; found, 510.1745.
(S)-methyl pyrrolidine-2-carboxylate (19).31,32 A mixture of
6.0 g (52 mmol) of L-proline and 150 mL of MeOH was cooled
down to 0 °C in an water-ice bath and 5.7 mL (78 mmol, 1.5 eq)
of SOCl2 was added dropwise. The ice bath was replaced with an
oil bath, and the flask was equipped with a reflux condenser
protected from moist with a CaCl2 tube. The temperature of the
oil bath was set to 90 °C. The reaction mixture was refluxed for
2 h and then cooled down to room temperature. The solvent was
evaporated and 8.6 g of orange oil was obtained. This oil was
dissolved in 500 mL of MeOH and to this mixture activated zinc
dust (5.0 g) was added in one portion. The mixture was stirred for
3 h at room temperature and then was filtered and concentrated in
vacuo. The amino ester was obtained as a yellow oil (6.06 g, 47
mmol, 90%). Rf (10% CHCl3/MeOH) 0.14. [α]D25 = –51.8 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ 6.21 (s, 1H), 4.36 (dd, J
= 8.7, 5.4 Hz, 1H), 3.80 (s, 3H), 3.36 (t, J = 6.9 Hz, 2H), 2.45–
2.21 (m, 1H), 2.10–1.78 (m, 3H). 13C NMR (DMSO-d6, 75
MHz): δ 172.4, 59.0, 52.3, 46.4, 28.8, 24.2. HRMS (ESI) m/z:
calcd for C6H12NO2 [M+H]+, 130.0863; found, 130.0869.
(S,4E,5E)-4-(benzo[d][1,3]dioxol-5-ylmethylene)-5-(3,4,5-
trimethoxybenzylidene)hexahydro-1H-pyrrolo[2,1-
c][1,4]oxazocine-1,6(3H)-dione (11). To a solution of 85 mg
(0.17 mmol) of hydroxy acid 21 in 10 mL of dry DCM, 110 mg
(0.25 mmol, 1.5 eq) of BOP and 57.8 ꢀL (0.415 mmol, 2.5 eq) of
TEA were added at 0 °C. After 5 min of stirring, the water-ice
bath was removed and the solution was allowed to reach room
temperature overnight. The reaction mixture was transferred to a
separatory funnel and washed thrice with 5 mL of 10% aqueous
citric acid, thrice with 5 mL of 5% aqueous NaHCO3 and once
with 5 mL of water. The organic layer was dried over anhydrous
MgSO4. After filtration and concentration, the resulting oil was
purified on a silica gel column, using AcOEt in hexane (gradient
from 0% to 40%). Product 11 (41 mg, 0.083 mmol, 50%) was
25
(S)-methyl 1-((2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-((tert-
butyldimethylsilyloxy)methyl)-2-(3,4,5-
trimethoxybenzylidene)but-3-enoyl)pyrrolidine-2-carboxylate
(20). 1.5 g (2.8 mmol) of acid 18 was dissolved in 20 mL of
DCM in a round bottom flask equipped with a stirring bar. Then,
obtained as a yellow oil. Rf (40% AcOEt/hexane) 0.20. [α]D
=
+91.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.54 (d, J =
11.1 Hz, 1H), 7.18–6.96 (m, 2H), 6.79–6.75 (m, 1H), 6.74 (s,
2H), 6.63 (d, J = 9.1 Hz, 1H), 5.99–5.87 (m, 2H), 5.14–4.81 (m,
3H), 3.82 (s, 3H), 3.71 (s, 6H), 3.64–3.42 (m, 1H), 2.67–2.45 (m,
1H), 2.44–2.20 (m, 1H), 2.20– 1.91 (m, 2H), 1.88–1.54 (m, 1H).
13C NMR (CDCl3, 75 MHz): δ 171.0, 166.1, 153.1, 148.3, 148.3,
140.7, 139.2, 131.8, 130.3, 129.8, 129.4, 128.6, 124.0, 108.6,
108.3, 106.4, 101.4, 71.6, 60.9, 56.3, 56.0, 48.4, 31.6, 23.1.
HRMS (ESI) m/z: calcd for C27H27NO8Na [M+Na]+, 516.1629;
found, 516.1651.
a solution of 1.1 g (8.4 mmol, 3 eq) of L-proline methyl ester 19
and 35 mg (0.28 mmol, 0.1 eq) of DMAP in 10 mL of DCM was
added in one portion at room temperature. To the vigorously
stirring solution, 0.703 g (3.36 mmol, 1.2 eq) of DCC was added
at 0 °C. The resulting solution was stirred at room temperature
for 3 h. The resulting suspension was filtered at atmospheric
pressure and the filtrate was concentrated in vacuo. The residue
was dissolved in 15 mL of DCM, washed twice with 10 mL of
0.5 M HCl, twice with 10 mL of saturated aqueous NaHCO3, and
dried over anhydrous MgSO4. After filtration and concentration
the resulting oil was purified on a silica gel column, using AcOEt
in hexane (gradient from 0% to 25%). 1.1 g (1.7 mmol, 61%) of
product 20 was obtained as a yellow oil. Rf (50% AcOEt/hexane)
0.38. [α]D25 = +55.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz):
δ 6.84 (s, 2H), 6.81–6.69 (m, 4H), 6.65 (d, J = 8.0 Hz, 1H), 5.87
(s, 2H), 4.48 (dd, J = 8.4, 5.2 Hz, 1H), 4.27 (q, J = 14.3 Hz, 2H),
3.82 (s, 3H), 3.76 (s, 6H), 3.72 (s, 3H), 3.68–3.56 (m, 2H), 2.32–
2.11 (m, 1H), 2.06–1.63 (m, 3H), 0.89 (s, 9H), 0.03 (d, J = 2.5
Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ 172.9, 169.0, 152.9,
147.3, 146.5, 138.4, 136.7, 136.0, 132.6, 131.4, 130.7, 127.5,
122.2, 108.2, 107.9, 106.2, 100.8, 65.9, 60.8, 59.3, 56.0, 52.1,
49.4, 29.1, 25.9, 25.4, 18.3, -5.5. HRMS (ESI) m/z: calcd for
C34H45NO9SiNa [M+Na]+, 662.2756; found, 662.2788.
Irradiation of 11. In a 1 L flat bottom flask, 200 mg (0.405
mmol) of compound 11 was dissolved in 1.0 L of degassed
solvent (methanol or toluene). The solution was pumped through
a multiply folded quartz tube,23 which was irradiated from the
side with a medium pressure mercury lamp (λmax = 365 nm). To
achieve a constant pumping speed, a HPLC pump was employed,
and the flow rate was set to 0.7 mL/min. To avoid overheating of
the solution inside the quartz tubing of the flow reactor, the
solution was cooled with a stream of air. The irradiated solution
was collected in a 2 L round bottom flask. After all the mixture
had passed through the flow-reactor, the solvent was removed
under vacuum. The resulting yellow oil was on a silica gel
column, using AcOEt in hexane (gradient from 0% to 30%).
When methanol was used as a solvent, product 22 was obtained
with 18% yield (29 mg, 0.073 mmol), and product 23 with 46%
yield (74 mg, 0.19 mmol). When toluene was used, product 22
was obtained with 46% yield (74 mg, 0.19 mmol) and product 23
with 18% yield (29 mg, 0.073 mmol). Crystals suitable for X-ray
analysis were grown by slow evaporation of the AcOEt solution
(22 – plates, 23 – needles). (±)-β-Apopicropodophyllin (22). Rf
(S)-1-((2E,3E)-4-(benzo[d][1,3]dioxol-5-yl)-3-
(hydroxymethyl)-2-(3,4,5-trimethoxybenzylidene)but-3-
enoyl)pyrrolidine-2-carboxylic acid (21). In a round bottom
flask 500 mg (0.781 mmol) of compound 20 was dissolved in
1
(60% AcOEt/hexane) = 0.37. M.p. = 214.2–215.3 °C. H NMR

10
Tetrahedron
ACCEPTED MANUSCRIPT
(CDCl3, 300 MHz): δ 6.72 (s, 1H), 6.63 (s, 1H), 6.37 (s, 2H),
General procedure for dehydration with acetyl chloride:
5.95 (d, J = 1.5 Hz, 1H), 5.94 (d, J = 1.5 Hz, 1H), 4.96– 4.74 (m,
3H), 3.86 (dd, J = 22.5, 4.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 6H),
3.65 (dd, J = 22.3, 3.9 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ
172.2, 157.3, 153.2, 147.2, 147.0, 138.3, 137.0, 129.6, 128.1,
123.7, 109.5, 107.7, 105.6, 101.3, 71.0, 60.8, 56.2, 42.8, 29.2. 1H,
13C signals and melting point for compound 22 were identical to
those reported in the literature.33,34 HRMS (ESI) m/z: calcd for
C22H20O7Na [M+Na]+, 419.1101; found, 419.1121. The detailed
structural parameters have been deposited with the Cambridge
Crystallographic Data Centre under the number CCDC 1531474.
10-(3,4,5-trimethoxyphenyl)-9,10-dihydro-6H-
[2]benzofuro[5,6-g][1,3]benzodioxol-9-one (23). Rf (60%
AcOEt/hexane) = 0.43. M.p. = 200.0–201.5 °C. 1H NMR
(CDCl3, 300 MHz): δ 6.79 (s, 2H), 6.53–6.38 (m, 2H), 5.90 (s,
2H), 5.04 (s, 1H), 4.89 (d, J = 17.1 Hz, 1H), 4.79 (dd, J = 17.0,
2.0 Hz, 1H), 3.87 (dd, J = 21.9, 3.3 Hz, 1H), 3.78 (s, 3H), 3.76 (s,
6H), 3.66 (dd, J = 21.9, 2.8 Hz, 1H). 13C NMR (CDCl3, 75
MHz): δ 172.2, 158.3, 153.1, 146.3, 145.8, 137.0, 136.5, 127.9,
125.2, 121.2, 119.1, 107.7, 105.2, 101.4, 71.1, 60.7, 56.1, 37.5,
28.5. HRMS (ESI) m/z: calcd for C22H20O7Na [M+Na]+,
419.1101; found, 419.1121. The detailed structural parameters
have been deposited with the Cambridge Crystallographic Data
Centre under the number CCDC 1531472.
(R)-2-((2E,3E)-2-(benzo[d][1,3]dioxol-5-ylmethylene)-3-
(diethylcarbamoyl)-4-(3,4,5-trimethoxyphenyl)but-3-enyl) 1-
tert-butyl pyrrolidine-1,2-dicarboxylate (24). In a 5 mL vial,
100 mg (0.163 mmol) of acid 14 and 2 mg (0.02 mmol, 0.1 eq) of
DMAP were dissolved in 3 mL of DCM. The resulting solution
was stirred at room temperature and 18.6 ꢀL (0.179 mmol,
1.1 eq) of diethylamine and 37 mg (0.18 mmol, 1.1 eq) of DCC
were added. After stirring overnight, the suspension was filtered
at atmospheric pressure and the filtrate was concentrated under
vacuum. The residue was dissolved in 5 mL of DCM, washed
twice with 5 mL of 0.5 M HCl, twice with 5 mL of saturated
aqueous NaHCO3 and dried over anhydrous MgSO4. The
resulting oil was purified on a silica gel column, using MeOH in
CHCl3 (gradient from 0% to 5%). Product 24 (61 mg, 0.092
To a 250 mL three-necked round bottom flask, equipped with a
reflux condenser protected from moisture, thermometer and
flushed with argon, 1 g (25 mmol, 4.89 equiv.) of NaH (60%
dispersion in mineral oil) was inserted and suspended in 5 mL of
dry DMF. To the vigorously stirred suspension, a solution of
2.44 equiv. of benzaldehyde and 0.85 mL (5.11 mmol) of diethyl
succinate in 25 mL of dry DMF was added dropwise. After
complete addition, the mixture was stirred for 5 h in 105 °C.
After this time the reaction mixture was cooled to 80 °C and
15 mL of 0.2 M (30 mmol) aqueous solution of KOH was added.
Resulting mixture was refluxed for 1 h and then cooled to room
temperature. 30 mL of distilled water was added and the mixture
was transferred into a separatory funnel and extracted with ethyl
acetate (5x20 mL). The combined organic layers were washed
once with 50 mL of distilled water, once with 50 mL of brine and
then dried over anhydrous magnesium sulphate. After filtration
and solvent removal a dense yellow gum was formed. This crude
product was dissolved in 8 mL of dry DCM and the flask was
flushed with argon. 1.6 mL of acetyl chloride was added
dropwise at room temperature and the resulting mixture was
refluxed for 6 h. Volatile components were evaporated under
reduced pressure. Resulting orange solid was purified on a short
silica gel column, using 20% of AcOEt in DCM as an eluent.
(3E,4E)-3,4-bis(3,4,5-trimethoxybenzylidene)dihydrofuran-
2,5-dione (26). 815 mg (1.79 mmol, 35%) of product 26 was
obtained in the form of orange solid. M. p. = 202.9–204.9 °C. Rf
(AcOEt) 0.76. 1H NMR (CDCl3, 300 MHz): δ 7.78 (s, 2H), 6.24
(s, 4H), 3.77 (s, 6H), 3.61 (s, 12H). 13C NMR (CDCl3, 75 MHz):
δ 166.0, 152.1, 141.6, 139.0, 129.1, 118.6, 108.4, 61.3, 55.8.
HRMS (ESI) m/z: calcd for C24H24O9Na [M+Na]+, 479.1313;
found, 479.1309.
(3E,4E)-3,4-bis(4-methoxybenzylidene)dihydrofuran-2,5-
dione (36). 602 mg (1.79 mmol, 35%) of product 36 was
obtained in the form of orange solid. M. p. = 158.0–160.0 °C. Rf
(AcOEt) 0.76. 1H NMR (CDCl3, 300 MHz): δ 7.84 (s, 2H), 6.71
(d, J = 8.1 Hz, 4H), 6.40 (d, J = 9.0 Hz, 4H), 3.72 (s, 6H). 13C
NMR (CDCl3, 75 MHz): δ 166.7, 162.4, 137.9, 132.3, 126.8,
117.5, 112.4, 55.3. HRMS (ESI) m/z: calcd for C20H16O5Na
[M+Na]+, 359.0890; found, 359.0908.
mmol, 56%) was obtained, as
a yellow oil. Rf (10%
25
1
CHCl3/MeOH) 0.75. [α]D = –41.0 (c 1.0, CHCl3). H NMR
(CDCl3, 300 MHz): δ 7.81 (s, 1H), 6.92 (s, 3H), 6.87–6.74 (m,
2H), 6.74–6.65 (m, 1H), 5.90 (d, J = 3.2 Hz, 2H), 5.01–4.69 (m,
2H), 4.33–4.01 (m, 1H), 3.95–3.63 (m, 13H), 3.50–3.23 (m, 2H),
2.11–1.90 (m, 1H), 1.84–1.53 (m, 3H), 1.44 (s, 4H), 1.37 (s, 5H),
1.36–1.16 (≈t, 6H). 13C NMR (CDCl3, 75 MHz): δ 172.8, 170.9,
153.8, 153.0, 147.9, 147.4, 143.7, 140.0, 130.0, 129.7, 129.3,
128.6, 123.5, 123.4, 108.4, 107.8, 107.6, 101.2, 80.0, 60.9, 59.3,
56.1, 49.5, 46.2, 38.7, 29.7, 28.3, 23.6, 14.1. HRMS (ESI) m/z:
calcd for C36H46N2O10Na [M+Na]+, 689.3045; found, 689.3021.
Study of the photochemical cleavage the amide in 21 and
24 by 1H NMR. In a 1 L flat bottom flask, 200 mg of compound
21 (0.39 mmol) or 24 (0.30 mmol) was dissolved in 1.0 L of
degassed toluene. The solution was irradiated in flow, in the
same fashion as described in the preparation of 22 and 23. The
irradiated solution was collected in a 2 L round bottom flask.
After all the mixture had passed through the flow-reactor, the
solvent was removed under vacuum. The resulting yellow oil was
(3E,4E)-3,4-dibenzylidenedihydrofuran-2,5-dione
(37).
495 mg (1.79 mmol, 35%) of product 37 was obtained in the
form of yellow solid. M. p. = 198.3–200.3 °C. Rf (AcOEt) 0.78.
1H NMR (CDCl3, 300 MHz): δ 7.93 (s, 2H), 7.16 (m, 2H), 6.85
(m, 8H). 13C NMR (CDCl3, 75 MHz): δ 166.0, 139.6, 133.9,
130.8, 130.0, 127.2, 119.4. HRMS (ESI) m/z: calcd for
C18H12O3Na [M+Na]+, 299.0679; found, 299.0672.
General procedure for aminolysis: In a round bottom flask,
0.88 mmol of cyclic anhydride was dissolved in 1.5 mL of dry
DCM. The flask was flushed with argon and the solution of
135 ꢀL (0.97 mmol, 1.1 equiv.) of trimethylamine in 1 mL of dry
DCM was added. Resulting solution changed its color from
yellow to dark green. After 3 h volatile components were
evaporated on a rotary evaporator. The residue was dissolved in
5 mL of AcOEt and washed once with 3 mL of 10% aqueous
solution of citric acid, one with 3 mL of brine and then dried over
anhydrous magnesium sulphate. After filtration and solvent
removal a yellow oil was formed and purified by column
chromatography using 3% MeOH in CHCl3.
1
dissolved in 2.0 mL of CDCl3 and its H NMR spectrum was
recorded. Then, a portion of amine (L-proline in the case of 21
and diethylamine in the case of 24) was added to the sample in
the NMR tube and the H NMR spectrum was recorded again.
(2E,3E)-3-(diethylcarbamoyl)-2-(3,4,5-
trimethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)but-3-
enoic acid (27). 441 mg (0.83 mmol, 95%) of compound 27 in
1
Finally, 5.0 mL of DCM was added to the sample, and it was
extracted thrice with 5 mL of 1 M HCl, dried over anhydrous
MgSO4 and concentrated in vacuo. The resulting oil was
1
the form of yellow oil. Rf (AcOEt) 0.15. H NMR (CDCl3, 300
MHz): δ 7.69 (s, 1H), 6.69 (s, 2H), 6.67 (s, 1H), 6.59 (s, 1H),
3.81 (s, 3H), 3.78 (s, 9H), 3.65 (s, 6H), 3.36 (br d, 4H), 0.99 (br
d, 6H). 13C NMR (CDCl3, 75 MHz): δ 171.7, 170.0, 153.1,
1
dissolved again in 2.0 mL of CDCl3 in order to record the H
NMR spectrum.

11
152.8, 141.8, 138.9, 138.7, 136.4, 130.2, 129.8, 129.7, 128.2,
106.5, 106.3, 60.8, 60.8, 56.1, 55.9, 43.4, 13.5. HRMS (ESI) m/z:
calcd for C28H34NO9 [M-H]–, 528.2239; found, 528.2223.
(E)-N,N-diethyl-4-hydroxy-3-(3,4,5-trimethoxybenzyl)-
ACCEPTED MANUSCRIPT
2-(3,4,5-trimethoxybenzylidene)butanamide (29). In a round
bottom flask 50 mg (0.09 mmol) of compound 28 was dissolved
in 1 mL of diethyl ether and 0.5 mL of THF. The flask was
flushed with argon and 3 mg (0.1 mmol, 1.5 eq) of LiBH4 was
added in one portion. Resulting mixture was stirred at room
temperature for 2 h. The reaction was quenched by addition of
5 mL of brine. After 30 min of stirring the reaction mixture was
transferred into a separatory funnel. The layers were separated
and aqueous layer was extracted thrice with 2 mL of ethyl
acetate. Organic layers were combined and dried over anhydrous
magnesium sulphate. After filtration and solvent removal a
yellow oil was formed and purified by column chromatography
(hexane/ethyl acetate, gradient from 0% to 55% of AcOEt), to
give 20 mg (0.039 mmol, 43%) of compound 28 in the form of
yellowish oil. Rf (50% AcOEt/hexane, developed twice) 0.16. 1H
NMR (CDCl3, 300 MHz): δ 6.55 (s, 1H), 6.51 (s, 2H), 6.28 (s,
2H), 4.68 (s, 1H), 3.85 (s, 3H), 3.85 (s, 6H), 3.79 (s, 3H), 3.72 (s,
6H), 3.85-3.72 (2H, under –OMe signals), 3.54 (m, 2H), 3.36 (m,
2H), 3.07 (m, 1H), 2.72 (m, 2H), 1.23 (t, J = 6.9 Hz, 3H), 1.15 (t,
J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 171.9, 153.2,
153.1, 138.3, 137.8, 136.4, 135.0, 131.6, 131.0, 106.0, 105.7,,
65.5, 60.9, 56.2, 43.4, 42.0, 39.1, 35.6, 14.0, 12.6. HRMS (ESI)
m/z: calcd for C28H39NO8Na [M+Na]+, 540.2568; found,
540.2557.
(2E,3E)-3-(diethylcarbamoyl)-2-(4-methoxybenzylidene)-4-(4-
methoxyphenyl)but-3-enoic acid (38). 340 mg (0.83 mmol,
95%) of compound 38 in the form of yellow oil. Rf (AcOEt)
1
0.22. H NMR (CDCl3, 300 MHz): δ 7.75 (s, 1H), 7.27-7.18 (m,
6H), 6.73 (s, 1H), 3.40 (br d, 4H), 1.02 (br s, 6H). 13C NMR
(CDCl3, 75 MHz): δ 172.0, 170.9, 160.5, 160.0, 142.8, 136.0,
132.3, 131.2, 130.7, 127.3, 127.2, 126.9, 114.0, 113.6, 55.2, 42.4,
13.1. HRMS (ESI) m/z: calcd for C24H26NO5 [M-H]–, 408.1816;
found, 408.1808.
(2E,3E)-2-benzylidene-3-(diethylcarbamoyl)-4-phenylbut-3-
enoic acid (39). 280 mg (0.80 mmol, 91%) of compound 39 in
1
the form of yellowish oil. Rf (AcOEt) 0.26. H NMR (CDCl3,
300 MHz): δ 7.78 (s, 1H), 7.33 (m, 4H), 6.75 (m, 5H), 3.73 (s,
6H), 3.44 (br s, 4H), 1.02 (br s, 6H). 13C NMR (CDCl3, 75
MHz): δ 171.6, 170.4, 143.2, 139.6, 136.3, 134.8, 134.5, 130.0,
129.5, 129.0, 128.9, 128.8, 128.5, 128.1, 39.6, 13.7. HRMS (ESI)
m/z: calcd for C22H22NO3 [M-H]–, 348.1605; found, 348.1617.
General procedure for O-alkylation of carboxylic group:
0.35 mmol of acid was dissolved in 2 mL of DMSO and 8 mL of
acetone in round bottom flask. The flask was flushed with argon
and 242 mg (1.75 mmol, 5.0 equiv.) of K2CO3 and 140.7 ꢀL
(1.75 mmol, 5.0 equiv.) of ethyl iodide was added at room
temperature. The flask was equipped with a reflux condenser
protected from moisture and placed in oil bath. The temperature
was set to 65 °C. After 1 h the mixture was cooled to room
temperature and acetone was removed on a rotary evaporator.
20 mL od distilled water was added to resulting residue and it
was extracted twice with 10 mL of ethyl acetate. The combined
organic layers were washed once with 10 mL of brine and then
dried over anhydrous magnesium sulphate. After filtration and
solvent removal, amorphous solid was obtained.
(2E,3E)-3-((diethylamino)methyl)-2-(3,4,5-
trimethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)but-3-en-
1-ol (30). To a solution of 50 mg (0.094 mmol) of 27 in
anhydrous THF (2 mL) was slowly added a 90 ꢀL (0.94 mmol,
10 eq) of borane-dimethyl sulfide complex (BMS) solution. The
reaction was carried out at room temperature and under argon
atmosphere. After stirring for 1.5 h, the reaction mixture was
quenched with ethanol (10 mL). After 30 min of stirring the
solvents were evaporated. The residue was dissolved in 5 mL of
AcOEt and washed once with 5 mL of 5% NaHCO3, dried over
anhydrous MgSO4, filtered and concentrated under vacuum,
resulting 30 (15 mg, 0.03 mmol, 31%). Rf (50% AcOEt/hexane,
(2E,3E)-ethyl 3-(diethylcarbamoyl)-2-(3,4,5-
trimethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)but-3-
enoate (28). 190 mg (0.34 mmol, 98%) of an amorphous solid.
1
1
Rf (AcOEt) 0.59. H NMR (CDCl3, 300 MHz): δ 7.69 (s, 1H),
developed twice) 0.41. H NMR (CDCl3, 300 MHz): δ 6.84 (s,
6.90 (s, 1H), 6.83 (s, 2H), 6.42 (s, 2H), 4.13 (q, J = 7.2 Hz, 2H),
3.81 (s, 3H), 3.79 (s, 9H), 3.73 (s, 6H), 3.39 (br s, 4H), 1.14 (t, J
= 7.2 Hz, 3H), 1.03 (br s, 6H). 13C NMR (CDCl3, 75 MHz): δ
170.2, 167.0, 152.8, 152.7, 143.8, 139.1, 138.0, 136.7, 131.7,
131.4, 130.0, 127.7, 107.0, 105.8, 61.2, 60.8, 60.8, 56.1, 55.9,
42.7, 14.1, 13.4. HRMS (ESI) m/z: calcd for C30H39NO9Na
[M+Na]+, 580.2517; found, 580.2538.
2H), 6.83 (s, 1H), 6.81 (s, 1H), 6.74 (s, 2H), 4.43 (d, J = 14.7 Hz,
1H), 4.26 (d, J = 14.7 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.81 (s,
6H), 3.78 (s, 6H), 3.56 (d, J = 13.2 Hz, 1H), 3.39 (d, J = 13.2 Hz,
1H), 2.82 (m, 4H), 1.16 (q, J = 7.2 Hz, 6H). 13C NMR (CDCl3,
75 MHz): δ 153.2, 140.5, 138.8, 138.2, 137.7, 137.6, 132.3,
131.5, 131.1, 127.5, 105.5, 105.4, 65.2, 64.3, 61.0, 56.1, 56.1,
53.4, 9.1, 9.0. HRMS (ESI) m/z: calcd for C28H39NO7H [M+H]+,
502.2799; found, 502.2821.
(2E,3E)-ethyl 3-(diethylcarbamoyl)-2-(4-
methoxybenzylidene)-4-(4-methoxyphenyl)but-3-enoate (40).
149 mg (0.34 mmol, 98%) of an amorphous solid. Rf (AcOEt)
0.60. 1H NMR (CDCl3, 300 MHz): δ 7.75 (s, 1H), 7.54 (m, 2H),
6.83 (s, 2H), 6.90 (s, 1H), 6.73 (m, 4H), 4.11 (q, J = 6.9 Hz, 2H),
3.75 (s, 3H), 3.73 (s, 3H), 3.41 (br s, 4H), 1.14 (t, J = 6.9 Hz,
3H), 1.04 (br s, 6H). 13C NMR (CDCl3, 75 MHz): δ 170.8, 167.3,
160.6, 159.4, 143.6, 135.7, 131.7, 130.1, 129.5, 128.5, 127.3,
125.6, 113.6, 113.5, 60.9, 55.2, 40.8, 14.1, 13.3. HRMS (ESI)
m/z: calcd for C26H31NO5Na [M+Na]+, 460.2094; found,
460.2113.
General procedure for ester reduction using DIBAL-H:
0.18 mmol of ester was dissolved in 2 mL of DCM. Resulting
solution was cooled to –78 °C in 2-propanol/dry ice cooling bath
and 22.3 ꢀL (0.18 mmol, 1.0 equiv.) of BF3OEt2 was added.
After 15 min of stirring 0.54 mL (0.54 mmol, 3 equiv.) of
DIBAL-H was added in one portion and the resulting solution
was stirred in –78 °C for 3 h. The reaction was quenched by
addition of 160 ꢀL of acetic acid, 160 ꢀL of distilled water and 4
mL of diethyl ether. Cooling bath was removed and when the
mixture reached room temperature anhydrous MgSO4 was added.
After 30 min of stirring, drying agent was filtered out and the
filtrate was evaporated to dryness. The residue was purified by
column chromatography (hexane/ethyl acetate, gradient from 0%
to 40% of AcOEt).
(2E,3E)-ethyl 2-benzylidene-3-(diethylcarbamoyl)-4-
phenylbut-3-enoate (41). 128 mg (0.34 mmol, 97%) of an
amorphous solid. Rf (AcOEt) 0.67. 1H NMR (CDCl3, 300 MHz):
δ 7.76 (s, 1H), 7.49-7.43 (m, 2H), 7.20-7.09 (m, 8H), 6.85 (s,
1H), 4.14 (q, J = 7.2 Hz, 2H), 3.45 (br s, 4H), 1.17 (t, J = 7.2 Hz,
3H), 1.07 (br s, 6H). 13C NMR (CDCl3, 75 MHz): δ 170.5, 167.0,
144.3, 135.8, 135.7, 134.7, 131.3, 129.3, 129.0, 128.4, 128.1,
128.1, 127.9, 127.9, 61.1, 43.2, 14.1, 12.4. HRMS (ESI) m/z:
calcd for C24H27NO3Na [M+Na]+, 400.1883; found, 400.1874.
(2E,3E)-N,N-diethyl-3-(hydroxymethyl)-2-(3,4,5-
trimethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)but-3-
enamide (31). 56 mg (0.11 mmol, 61%) of compound 31 in the
1
form of yellow oil. Rf (AcOEt) 0.65. H NMR (CDCl3, 300
MHz): δ 6.84 (s, 2H), 6.76 (s, 1H), 6.56 (s, 2H), 6.54 (s, 1H),
4.71 (s, 1H), 4.34 (s, 2H), 3.86 (s, 3H), 3.79 (s, 6H), 3.79 (s, 3H),

12
Tetrahedron
3.67 (s, 6H), 3.28 (s, 4H), 0.99 (s, 6H). 13C NMR (CDCl3, 75
135.3, 133.7, 133.4, 132.4, 131.8, 129.0, 128.5, 128.3, 128.2,
ACCEPTED MANUSCRIPT
MHz): δ 171.5, 153.2, 152.9, 138.7, 138.1, 137.6, 133.1, 132.3,
132.2, 131.1, 130.3, 106.3, 105.4, 67.1, 61.0, 60.8, 56.1, 56.0,
43.1, 14.1. HRMS (ESI) m/z: calcd for C28H37NO8Na [M+Na]+,
538.2411; found, 538.2435.
128.1, 127.9, 127.4, 67.8, 39.5, 21.0, 14.1. HRMS (ESI) m/z:
calcd for C24H27NO3Na [M+Na]+, 400.1883; found, 400.1897.
(3-(diethylcarbamoyl)-5,6,7-trimethoxy-4-(3,4,5-
trimethoxyphenyl)-3,4-dihydronaphthalen-2-yl)methyl
acetate (33). In a 1 L flat bottom flask, 75 mg (0.13 mmol) of
compound 32 was dissolved in 375 mL of degassed solvent
(methanol or toluene). The solution was pumped through a
multiply folded quartz tube,23 which was irradiated from the side
with a medium pressure mercury lamp (λmax = 365 nm). To
achieve a constant pumping speed, a HPLC pump was employed,
and the flow rate was set to 0.7 mL/min. To avoid overheating of
the solution inside the quartz tubing of the flow reactor, the
solution was cooled with a stream of air. The irradiated solution
was collected in a 2 L round bottom flask. After all the mixture
had passed through the flow-reactor, the solvent was removed
under vacuum. The resulting yellow oil was on a silica gel
column, using AcOEt in hexane (gradient from 0% to 35%).
When methanol was used as a solvent, product 33 was obtained
with 38% yield (28.5 mg, 0.051 mmol), and when toluene was
used, product 33 was obtained with 35% yield (26 mg,
0.047 mmol) as a white oil. Rf (50% AcOEt/hexane, developed
thrice) 0.33. 1H NMR (CDCl3, 300 MHz): δ 7.61 (s, 1H), 6.98 (s,
1H), 6.54 (s, 1H), 6.49 (s, 1H), 4.99 (d, J = 13.2 Hz, 1H), 4.83 (d,
J = 13.2 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.89-3.88 (1H, under
-OCH3 signal ), 3.88 (s, 3H), 3.84-3.82 (1H, under -OCH3
signal), 3.84 (s, 3H), 3.82 (s, 3H), 3.41-3.34 (m, 2H), 3.37 (s,
3H), 3.24-3.16 (m, 2H), 1.98 (s, 3H), 1.16 (t, J = 6.9 Hz, 6H). 13C
NMR (CDCl3, 75 MHz): δ 170.1, 169.9, 153.9, 152.1, 150.2,
143.2, 139.8, 136.6, 135.4, 131.1, 126.3, 124.0, 106.5, 102.8,
62.2, 61.1, 60.8, 60.8, 56.2, 56.1, 55.9, 43.1, 41.0, 38.8, 20.9,
12.7. HRMS (ESI) m/z: calcd for C30H39NO9Na [M+Na]+,
580.2517; found, 580.2546.
(2E,3E)-N,N-diethyl-3-(hydroxymethyl)-2-(4-
methoxybenzylidene)-4-(4-methoxyphenyl)but-3-enamide
(42). 43 mg (0.11 mmol, 60%) in the form of yellow oil. Rf
(AcOEt) 0.66. 1H NMR (CDCl3, 300 MHz): δ 7.52 (~t, 1H), 7.49
(~t, 1H), 7.23 (~t, 1H), 7.21 (~t, 1H), 6.86 (~t, 1H), 6.83 (~t, 1H),
6.78-6.72 (m, 3H), 6.59 (s, 1H), 5.11 (br s, 1H), 4.24 (s, 2H),
3.80 (s, 3H), 3.74 (s, 3H), 3.29 (q, J = 6.9 Hz, 4H), 0.98 (t, J =
6.9 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ 172.0, 160.0, 159.0,
136.9, 133.0, 131.5, 130.6, 129.4, 127.5, 114.2, 113.6, 67.2, 55.3,
55.3, 43.6, 13.9. HRMS (ESI) m/z: calcd for C24H29NO4Na
[M+Na]+, 418.1989; found, 418.1985.
(2E,3E)-2-benzylidene-N,N-diethyl-3-(hydroxymethyl)-4-
phenylbut-3-enamide (43). 20 mg (0.6 mmol, 33%) in the form
1
of white oil. Rf (AcOEt) 0.67. H NMR (CDCl3, 300 MHz): δ
7.56 (m, 2H), 7.38-7.27 (m, 5H), 7.25-7.19 (m, 3H), 6.84 (s, 1H),
6.63 (s, 1H), 4.96 (br s, 1H), 4.27 (s, 2H), 3.24 (br d, 4H), 0.98
(t, J = 6.9 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ 171.6, 138.5,
137.0, 134.9, 133.2, 132.6, 132.1, 129.0, 128.8, 128.7, 128.2,
128.1, 127.5, 67.1, 43.0, 13.9. HRMS (ESI) m/z: calcd for
C22H25NO2Na [M+Na]+, 358.1778; found, 358.1795.
General procedure for esterification: In a round bottom
flask, 0.43 mmol of vinyl alcohol was dissolved in10 mL of dry
DCM and the flask was flushed with argon. 52 ꢀL (0.65 mmol,
1.5 equiv.) of pyridine was added at room temperature and the
solution was cooled in an water-ice bath. Acetic anhydride (81.1
ꢀL, 0.86 mmol, 2 equiv.) was then added and the ice bath was
removed. The resulting mixture was stirred at room temperature
for 4 h. After this time 10 mL of DCM was added and the
mixture was transferred to a separatory funnel and washed once
with 10 mL of distilled water, once with 10 mL of brine and
dried over anhydrous MgSO4. After filtration and solvent
removal resulting crude product was purified by column using
CHCl3 as a eluent.
Acknowledgements
Financial support from the National Science Centre in the form
of grant NCN-2012/07/B/ST5/02476 is kindly acknowledged.
The work was also supported by the grant 120000-501/86-DSM-
112700.
(2E,3E)-3-(diethylcarbamoyl)-2-(3,4,5-
trimethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)but-3-enyl
acetate (32). 150 mg (0.269 mmol, 63%) of compound 32 in the
form of yellow oil. Rf (AcOEt) 0.50. H NMR (CDCl3, 300
MHz): δ 6.67 (s, 3H), 6.55 (s, 2H), 6.47 (s, 1H), 4.81 (s, 2H),
3.81 (s, 3H), 3.77 (s, 3H), 3.75 (s, 6H), 3.70 (s, 6H), 3.44 (q, J =
6.6 Hz, 4H), 2.04 (s, 3H), 1.13 (t, J = 6.6 Hz, 6H). 13C NMR
(CDCl3, 75 MHz): δ 170.5, 170.3, 152.9, 152.7, 138.1, 137.5,
134.0, 133.5, 132.3, 131.6, 131.1, 130.7, 105.8, 105.7, 67.9, 60.9,
60.8, 56.1, 56.0, 39.1, 21.0, 13.4. HRMS (ESI) m/z: calcd for
C30H39NO9Na [M+Na]+, 580.2517; found, 580.2544.
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