Formal synthesis of (-)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester-a flow photochemistry approach

Article abstract of DOI:10.1039/c5ob01844g

We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and l-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin.

Full text of DOI:10.1039/c5ob01844g

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Formal synthesis of (−)-podophyllotoxin through
the photocyclization of an axially chiral
3,4-bisbenzylidene succinate amide ester – a flow
photochemistry approach†
Cite this: DOI: 10.1039/c5ob01844g
Kamil Lisiecki,a Krzysztof K. Krawczyk,a Piotr Roszkowski,a Jan K. Maurinb,c and
Zbigniew Czarnocki*a
We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin
and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-
bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl
succinate and L-prolinol. The photocyclization was found to be more efficient when irradiation was per-
formed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to
perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with
the Schwartz’s reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be
easily reduced to the corresponding alcohol, completing the formal synthesis of (−)-podophyllotoxin.
Received 3rd September 2015,
Accepted 23rd October 2015
DOI: 10.1039/c5ob01844g
www.rsc.org/obc
Introduction
Lignans, a large family of secondary metabolites consisting of
dimerized phenylpropanoid units, are widely distributed in
the plant kingdom.1–5 Among them, aryltetralin lignans are
one of the most extensively studied groups of natural products
due to their antiviral, antibacterial and antineoplastic pro-
perties.6 Particularly valuable in the chemotherapy of cancer is
podophyllotoxin 1 (Fig. 1) which served as a lead structure for
the development of its semisynthetic derivatives etoposide 2
and teniposide 3, both of which are currently in clinical use.7
Interestingly, the diverse biological activity of podophyllotoxin
derivatives is a result of not one, but at least two different,
unrelated molecular mechanisms.8–11 The fact that similar
compounds exhibit such potent, yet fundamentally distinct
activities prompted extensive screening for new leads. Such are
desirable, since the therapeutic potential of podophyllotoxin
and its derivatives is often hindered by problems of drug
resistance,12 hydrophobicity and low selectivity.13 Although
many bioactive compounds were derived from natural lignans,
Fig. 1 Structure of podophyllotoxin (with numbering and ring lettering
systems), etoposide and teniposide.
podophyllotoxin finds limited use as a direct synthetic precur-
sor to more valuable analogues because of its sensitivity to
extensive chemical modification. Therefore, there has been
intense interest in the development of general synthetic
schemes for related compounds over the last few decades.14,15
Very recently, three interesting contributions to the enantio-
selective synthesis of podophyllotoxin have been disclosed.
Ishikawa16 completed the formal synthesis of (−)-1 from
(2S,3R)-3-arylaziridine-2-carboxylate 3,3-diarylpropanoate as a
common intermediate. On the other hand, Maimone and
Ting17 presented a short total synthesis of podophyllotoxin
using a Pd-catalyzed C(sp3)–H arylation reaction. Finally, Nishi
and co-workers18 reported on organocatalyzed enantioselective
cyclopropanation and Lewis acid-mediated ring expansion
leading to chiral podophyllic aldehydes, highly valuable inter-
mediates which can be easily modified enabling diverse ana-
logue preparation.
aFaculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland.
E-mail: czarnoz@chem.uw.edu.pl
bNational Medicines Institute, Chełmska 30/34, Warsaw 00-725, Poland
cInstitute of Atomic Energy, Otwock-Świerk 05-400, Poland
†Electronic supplementary information (ESI) available: NMR, UV spectra, photo
of the system for “in-flow” photoreactions and crystallographic data. CCDC
1415848. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ob01844g
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In this paper, we explore the relatively less studied strategy
to synthesize cyclolignans through the photocyclization of 3,4-
bisbenzylidenesuccinic acid amide esters. Although this kind
Results and discussion
Synthesis of 3,4-bisbenzylidenesuccinate cyclic amide ester 10
of photocyclization was excessively studied for photochromic The methylenedioxy substituent forming ring A of podophyllo-
compounds belonging to the fulgide family (fulgides, fulg- toxin and 3,4,5-trimethoxyphenyl ring E are regarded as the
imides, and fulgenates),19,20 there are only a few examples “optimal” substituents responsible for the potent activity of
where it was employed in the synthesis of cyclolignans.21–23 In podophyllotoxin derivatives. Our synthesis starts thus from the
2004 Charlton et al. used (−)-ephedrine as a chiral auxiliary to construction of a non-symmetric bisbenzylidenesuccinic acid
obtain a cyclic 3,4-bisbenzylidenesuccinic amide ester, which derivative by means of a double Stobbe condensation. We have
upon photocyclization resulted in enantiomerically pure previously24 found that the cyclization of 3,4-bisbenzylidene-
(1S,2R)-trans-dihydronaphthalene (Scheme 1A).23 Although 1,2- succinates occurred exclusively on the aryl ring adjacent to the
cis-dihydronaphthalene would have been the more desired amide moiety (Scheme 1B), which allowed us to rationally
product, it has been shown that a bidentate chiral auxiliary design our synthetic scheme. We take advantage of the excel-
could impose a single configuration of the pseudoenantio- lent regioselectivity of the Stobbe condensation,28 during
meric 2,3-bisbenzylidenesuccinate by asymmetrically “pinning” which only one ester moiety (opposite to the introduced benzyl-
the carboxylate moieties.
idene group) is hydrolyzed. Diethyl succinate was thus first
In a previous report,24 we demonstrated that when L-proli- reacted with piperonal in the presence of t-BuOK in toluene,
nol is used instead of (−)-ephedrine, a (1R,2R)-cis-dihydro- leading to α,β-unsaturated ester 4 which was hydrolyzed to
naphthalene is obtained as the major photocyclization diacid 5 in a one-pot procedure. Fischer esterification of the
product, which has the same stereochemical features at C-1 crude product with MeOH gave the corresponding diester 6 in
and C-2 as podophyllotoxin (Scheme 1B). These results encour- 66% yield after two steps. The dimethyl ester can be purified
aged us to adapt this strategy for the synthesis of podophyllo- on a short column or by distillation under reduced pressure,
toxin and its close analogues.
which is beneficial in the case of large scale preparations. The
In order to study further transformations of 1,2-cis-dihydro- second condensation with 3,4,5-trimethoxybenzaldehyde pro-
naphthalenes, the key photoreaction in our synthetic ceeded in 76% yield to give E,E-bisbenzylidenesuccinic acid
scheme should be performed on a multigram scale. To monomethyl ester 7 (Scheme 2).
meet this practical requirement we have decided to employ
The chiral auxiliary was introduced using a one-pot protocol
flow chemistry, which is known to be readily scalable.25 leading to amide-ester 8, which was subsequently hydrolyzed
Perhaps especially in the case of photochemical prep- using K2CO3 in methanol/water to give the corresponding acid
arations, flow chemistry is an attractive alternative to batch 9. The whole reaction sequence gives succinamic acid 9 in a
synthesis, as it allows to overcome difficulties arising from nearly quantitative overall yield (Scheme 3). The closing of the
the logarithmic decrease of light transmission through the 8-membered ring via macrolactonization of 9 was optimized in
reactive medium.26 Precise tuning of only one parameter, a series of experiments, summarized in Table 1.
i.e. the flow rate, enables the residence time to be adjusted
We found that both the coupling with (benzotriazol-1-yloxy)-
to avoid over-irradiation, which could lead to the formation tris(dimethylamino)phosphonium hexafluorophosphate (BOP)
of side products and photopolymers.27
and Steglich esterification29 are possible alternatives for the
macrolactonization of 9. While the reaction with BOP was pre-
ferred for small scale preparations due to the simpler workup,
the DCC/DMAP protocol is a more cost efficient alternative for
large scale preparations, and it also gave a slightly higher
yield. As expected, high dilution conditions, achieved by slow
addition of the substrate were beneficial since the undesired
intermolecular reaction was suppressed.
Scheme 1 The use of chiral auxiliaries in cyclolignan synthesis – (A)
(−)-ephedrine,23 (B) L-prolinol.24
Scheme 2 Double Stobbe condensation leading to bisbenzylidene-
succinic acid methyl monoester 7.
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forming intermediate 11 into product 12 is not likely to occur
under the applied reaction conditions. In order to achieve the
formal [1–5]-H shift we decided to use a protic solvent. Solvent
protonation at C-2 was previously described as an alternative
mechanism to a concerted [1,5]-sigmatropic hydrogen shift.19
Indeed, we succeeded to obtain the desired product 12 when
irradiation was performed in methanol. Further experiments
confirmed that the use of an acidic additive (0.01 mM TFA)
further accelerated the reaction, and helped to avoid excessive
photolytic degradation, as proposed previously by Charlton.22
We also found that the relatively strong absorption of dihydro-
naphthalene lignans in the UV region (Fig. S1 in the ESI†),
may result in an inner filter effect leading to photodegradation
upon prolonged irradiation. Indeed, the batch synthesis could
be completed significantly faster when the substrate was ir-
radiated at high dilution, which also led to an increased yield
of 12, probably by minimizing photodegradation. Although we
managed to obtain product 12 with 32% yield (Scheme 4B),
the high dilution conditions made the batch synthesis ineffi-
cient, due to the time consuming work up.
Scheme 3 The synthesis of cyclic amide-ester 10.
Table 1 Optimization of the macrolactonization reaction
Isolated
yield
Entry Conditions
We therefore decided to use a simple home-made apparatus
for continuous flow irradiation (Scheme 5; Fig. S2†). The
apparatus consists of a quartz tube, which is multiply folded
to form a rectangular reactor. The reactor was placed in front
of the window of the mercury lamp. The diagonal of the lamp
window was ca. 18 cm and the total length of the quartz tube
within the reactor was ca. 3 m. A solution of 10 in MeOH con-
taining 0.01 mM of TFA was pumped through the reactor,
which was placed ca. 3 cm away from the UV light source. To
precisely regulate the flow, we used a HPLC pump, but a
simple peristaltic pump is a possible alternative. To avoid over-
heating of the irradiated solution of the sample, we cooled the
tube with a stream of air during irradiation (the temperature at
the surface of the reactor was ca. 30 °C). The use of a quartz
tube allowed us to use relatively high flow velocities: a 0.4 mM
solution of 10 in methanol containing 0.01 mM TFA could be
1
2
3
4
5
6
7
8
BOP, DCM, 5 °C, 25 mM of 9
BOP, DCM, 25 °C, 25 mM of 9
60%
64%
54%
25%
23%
64%
46%
BOP, THF, 25 to 60 °C, 25 mM of 9
BOP, toluene, 25 to 80 °C, 25 mM of 9
DCC, HOBT, DCM, 25 °C, 100 mM of 9
DCC, DMAP, DCM, −40 °C, 100 mM of 9
DCC, DMAP, DCM, 25 °C, 100 mM of 9
DCC, DMAP, DCM, 25 °C, addition with syringe 74%
pump
Photocyclization of 10
Having product 10 in hand, we could start optimizing the con-
ditions for photocyclization. The batch experiments were
carried out using a quartz cuvette, which was irradiated for 1 h
using a medium pressure mercury lamp (λmax ≈ 365 nm,
Fig. S3 in the ESI†). At first, we tried the same conditions for
irradiation as previously reported (1 mM solution irradiated in
chloroform).24 Under these conditions, however, only trace
amounts of the desired product 12 were obtained, even after
prolonged irradiation. Interestingly, upon irradiation, the reac-
tion mixture quickly turned deep orange, indicating the for-
mation of intermediate 11 (Scheme 4A). The low yield of the
reaction suggests that the sigmatropic hydrogen shift trans-
Scheme 5 Block diagram showing components of the system for
photoreactions “in flow”. A – substrate tank; B – HPLC pump; C –
quartz reactor; D – UV source; E – cooler, and F – product tank.
Scheme 4 Irradiation of 10 leading to cyclolignan structure.
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irradiated at a flow rate of 0.7 mL min−1. These conditions
allowed us to obtain compound 12 with an isolated yield of
61%. The continuous flow process is easily scalable and the
excessive solvent can be quantitatively recycled.
The resulting product 12 proved to be unstable – upon pro-
longed exposure to air, aromatization of the C ring occurs.
We found that the strained 8-membered ring can be easily
opened by methanolysis, which proceeds with a very good
yield (94%) to give stable product 13. Since the conditions for
methanolysis are essentially the same as for irradiation, we
found that photocyclization and transesterification can be
carried out during direct acidic work-up, which was more prac-
tical (Scheme 6).
Fig. 2 ORTEP diagram of compound 14. The non-H atoms are shown
as 30% probability ellipsoids.
We were not able to grow a crystal of neither 12 nor 13. To
determine the configuration of 12 at C-1 and C-2, we therefore
performed 2D NMR experiments (HSQC, HMBC, and ROESY).
From the HSQC and HMBC spectra it can be concluded
that the proton at C-1 appeared as a doublet of doublets at
4.42 ppm, whereas the proton at C-2 as a doublet at 3.88 ppm.
In the ROESY spectrum an interaction between these protons
was observed, indicating that the relative configuration at C-1
and C-2 must be cis. In order to obtain crystals suitable for
ation at C-1 and C-2 turned out to be the same as in 1 (1R, 2R)
(Fig. 2).
Removal of the chiral auxiliary
X-ray analysis to unequivocally determine the regio- and stereo- Our initial attempt was to remove the chiral auxiliary by acid
selectivity of the photocyclization, we decided to derivatize the catalyzed hydrolysis, since basic hydrolysis is known to result
stable ester 13 (Scheme 7). A monocrystal suitable for X-ray in epimerization at C-2. Although similar amides could be
diffraction analysis could be grown by slow evaporation of a hydrolyzed at 85 °C in 5 M HCl/glyme,30 amide ester 13 was
methanol solution of 14. As expected, the absolute configur- converted into an untreatable mixture of decomposition
products.
Procter et al. have recently reported a mild method for the
reduction of tertiary amides to alcohols using the SmI2/amine/
H2O reducing system.31 It was expected that SmI2 would in the
first place lead to the reduction of the double bond and we
hoped that the excess of reducing complex would be capable
of amide cleavage. Although the latter proved not true, we were
able to successfully reduce the double bond, yielding product
15 with 56% yield. Interestingly, only one diastereomer of 15
3
was obtained. The coupling constant of J = 16.8 Hz indicates
the trans configuration of the substituents at C-3 and C-2
atoms. The use of SmI2/amine/H2O system could thus be a
competitive method for the reduction of aryldihydronaphtha-
lenes to aryltetralines (Scheme 8). Interestingly, our attempts
to hydrogenate 13 over Pd or Pt proved unsuccessful
(a complex mixture of products was obtained).
Scheme 6 Synthesis of stable derivative 13 from compound 10
through the unstable intermediate and in the direct acidic work-up
procedure.
As both acid hydrolysis and the reduction of the amide to
the alcohol have failed, we decided to use the Schwartz’s
reagent (Cp2Zr(H)Cl), which is known to reduce tertiary
amides to the corresponding aldehydes.32,33 The advantage of
this reaction is its compatibility with many functional groups,
including esters and double bonds. Very recently Snieckus34
has reported that in situ generation of the Schwartz’s reagent
overcomes the disadvantage of this reagent related to contami-
nation with the unreacted reducing agent (which may react
with the substrate and the intermediates) and over-reduced
Cp2ZrH2. Considering this, we decided to compare the reaction
of 13 with commercially available Schwartz’s reagent with the
in situ generated complex (Scheme 9).
Scheme 7 Synthesis of 14.
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Scheme 10 Reduction of aldehyde 16 using NaBH4.
Conclusions
We have completed the formal synthesis of (−)-1 by preparing
compound 17 from piperonal in 9 steps with 13% overall yield,
using L-prolinol as the source of chirality. The crucial step of
the synthesis, a photocyclization, was optimized to be per-
formed in continuous flow, which showed clear advantages
over batch photochemical synthesis. In comparison to pre-
vious total syntheses of podophyllotoxin our approach employs
exclusively cheap and easily available substrates, and avoids
the use of sophisticated organocatalysts or heavy metal cata-
lysts. It can be assumed that our synthetic strategy allows
various substitution patterns on rings B, C and E (e.g. the
introduction of an additional substituent at C-1),24 thus pro-
viding access to cyclolignan analogs which are inaccessible
from natural plant sources.
Scheme 8 Reactions of 13 with hydrogen, HCl and SmI2/Et3N/H2O
reducing system.
Scheme 9 Reduction of 13 to aldehyde using commercially available
Schwartz’s reagent and the in situ generated reagent.
Experimental section
General experimental methods
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 atmos-
phere 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, 3 Å. Methanol was dried
with KOH powder for 24 h, distilled and was stored over acti-
vated molecular sieves, 3 Å. Dichloromethane (DCM) was dried
by storing it over activated molecular sieves, 3 Å, for at least
3 days. TLC analysis was performed on Merck TLC plates
(silica gel 60 F254 on glass plates). 1H-NMR and 13C-NMR
spectra were recorded with a Bruker AVANCE 500/300 spectro-
meter. Chemical shifts were reported in ppm from tetramethyl-
silane with the solvent resonance as the internal standard in
CDCl3 solution. High-resolution mass (ESI-TOF MS) spectra
were recorded on a Micromass LCT spectrometer.
E-(3,4-Methylenedioxybenzylidene)butanedioic acid (5). To
an oven dried 500 mL three-necked round-bottom flask,
equipped with a large stirring bar and flushed with argon,
30.0 g (6.67 eq., 0.26 mol) of t-BuOK was inserted and sus-
pended in 150 mL of dry toluene. To the vigorously stirred sus-
pension, a solution of 18.0 g (1.33 eq., 0.12 mol) of piperonal
and 15.7 g (1 eq., 0.09 mol) of diethyl succinate in 200 mL of
We discovered that the reduction of amide 13 to aldehyde
16 is more efficient with commercially available Schwartz’s
reagent (67% yield). The low yield of the reaction with the
in situ generated complex may be caused by the formation of a
coordinated Al(O-tBu)3-Schwartz’s reagent species, which pro-
vides additional steric hindrance in the reduction process.34
It is noteworthy that aldehyde 16 shows potent cytotoxicity
and its benzimidazole derivatives, obtained by condensation
with o-phenyldiamines, were proven to be inhibitors of tubulin
polymerization.35 To complete the formal synthesis of 1, alde-
hyde 16 must be reduced to alcohol (+)-17 which is a chiral
intermediate in the Thompson synthesis of rac-1.36,37 Simple
reduction with NaBH4 proved successful, leaving the methyl
ester moiety intact. As expected, no epimerization at C-2 was
observed35 (Scheme 10) and the desired product was obtained
with 90% yield.
By synthesizing compound (+)-17 we have also completed
the formal synthesis37 of (1R, 2R)-podophyllic aldehyde, a cyto-
toxic C-2 epimer of 16, which exhibits high selectivity towards
human colon carcinoma and is a starting material in the syn-
thesis of cytotoxic, C-9 oxidized podophyllotoxin derivatives.38
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dry toluene was added dropwise. The color of the suspension M.p. 72.8–73.7 °C. 1H NMR (CDCl3 with 0.03% v/v TMS,
changed immediately from white to yellow, and later to brown. 500 MHz): δ 7.79 (s, 1H), 6.87–6.84 (m, 2H), 6.82 (dd, J = 7.6,
After complete addition, the suspension was stirred for 0.9 Hz, 1H), 5.98 (s, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 3.54 (s, 2H).
another 1.5 h. The reaction mixture was then transferred into a 13C NMR (CDCl3, 125 MHz): δ 171.6, 167.9, 148.3, 147.9, 141.9,
1 L round-bottom flask and the solvent was removed on a 128.8, 124.4, 124.0, 109.1, 108.6, 101.4, 52.2, 52.2, 33.5. HRMS
rotary evaporator. The reaction flask was washed with 200 mL (ESI-TOF) m/z: calcd for C14H14O6Na [M + Na]+, 301.0688;
of water and a minimal amount (ca. 40 mL) of ethanol and the found, 301.0694
liquids were added to the solid residue in the 1 L flask. The
2E-(3,4-Methylenedioxybenzylidene)-3E-(3,4,5-trimethoxy-
obtained dark solution was placed in a rotary evaporator in a benzylidene)butanedioic acid monomethyl ester (7). To an
water bath at 60 °C and rotated without vacuum for 1 h to oven dried 250 mL three-necked round-bottom flask, equipped
completely hydrolyze the remaining ethyl esters. After the indi- with a stirring bar and flushed with argon, 2.22 g (1.1 eq.,
cated time, vacuum was applied carefully to evaporate ethanol 19.77 mmol) of t-BuOK was inserted, and was suspended in
and ca. 40 mL of water. The dark aqueous solution was cooled 65 mL of dry toluene. To the vigorously stirred suspension, a
to room temperature and transferred to a separatory funnel. solution of 3.53 g (1 eq., 17.97 mmol) of 3,4,5-trimethoxybenz-
The flask was washed with a total of ca. 40 mL of water and aldehyde and 5.0 g (1 eq., 17.97 mmol) of ester 6 in 50 mL of
100 mL of AcOEt. The mixture was extracted with small por- dry toluene was added dropwise. The color of the suspension
tions of AcOEt until the extracts were completely colorless. All changed immediately from white to yellow, and later to brown.
extracts were discarded, and the aqueous layer was acidified to After complete addition, the suspension was stirred for
ca. pH 2 with small portions of concentrated HCl. The precipi- another 1.5 h. The reaction mixture was then poured into ice
tating diacid was extracted with small portions (ca. 25 mL) of and the reaction flask was washed with ice-cold distilled water,
AcOEt until the obtained extracts were colorless (typically 6–10 to which was then added the cooled residue and was trans-
times). The aqueous layer was discarded and the combined ferred into a separatory funnel. The mixture was extracted
organic layers were washed once with distilled water, once with three times with small portions of AcOEt. All these extracts
brine and then dried over anhydrous sodium sulphate. After were discarded, and the aqueous layer was acidified to ca. pH
filtration and solvent removal a dense yellow gum was formed. 2 with small portions of concentrated HCl. The precipitating
The product was used for the next reaction without further acid was extracted with small portions of AcOEt until the
purification. HRMS (ESI-TOF) m/z: calcd for C12H10O6Na obtained extracts were colorless. The aqueous layer was dis-
[M + Na]+, 273.0375; found, 273.0367.
carded and the combined organic extracts were washed once
Dimethyl 2E-(3,4-methylenedioxybenzylidene)butanedioate with distilled water, once with brine and then dried over an-
(6). In a round bottom flask of 250 mL, equipped with a stir- hydrous sodium sulphate. After filtration and solvent removal,
ring bar and under an argon atmosphere, 18.2 g (1 eq., the resulting oil was purified on a short silica gel column,
72.8 mmol) of crude diacid 5 and 150 mL of dry MeOH were using MeOH in CHCl3 (gradient, from 0% to 1%) as an eluent.
added. The vigorously stirred suspension was cooled in a The product was dissolved in 100 mL of diethyl ether and was
water-ice bath, and 30 mL of AcCl was added dropwise. After precipitated from n-hexane. The precipitated solid was filtered
addition of a few mL of AcCl the solid had dissolved comple- and dried in a desiccator to give 6.04 g (13.66 mmol, 76%) of a
tely, and the solution changed its color from yellowish to white crystalline solid. M.p. 154.3–156.1 °C. 1H NMR (CDCl3
orange. The ice bath was replaced with an oil bath, and the with 0.03% v/v TMS, 500 MHz): δ 7.91 (s, 1H), 7.85 (s, 1H), 7.05
flask was equipped with a reflux condenser protected from (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.3, 1.8 Hz, 1H), 6.78 (s, 2H),
moisture. The temperature of the oil bath was set to 80 °C. The 6.75 (d, J = 8.0 Hz, 1H), 5.96 (d, J = 1.4 Hz, 1H), 5.95 (d, J =
reaction mixture was refluxed for 12 h, and was then trans- 1.4 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.73 (s, 6H). 13C NMR
ferred into a 500 mL round bottom flask. Most of the solvent (CDCl3, 125 MHz): δ 172.2, 167.2, 153.0, 149.6, 148.2, 144.1,
was removed on a rotary evaporator and the residue was cooled 142.9, 139.6, 129.6, 128.4, 126.8, 124.9, 123.8, 108.8, 108.6,
in an ice-water bath. The reaction flask was washed with 107.3, 101.6, 60.9, 55.9, 52.6. HRMS (ESI) m/z: calcd for
100 mL of ice-cold distilled water, which was then added to C23H22O9Na [M + Na]+, 465.1161; found, 465.1180.
the cooled residue, shaken until all the solids had dissolved
Monomethyl (S)-(+)-2-pyrrolidinemethanol-2E-(3,4-methyl-
and was transferred into a separatory funnel. The flasks were enedioxybenzylidene)-3E-(3,4,5-trimethoxybenzylidene)butan-
washed with 2 more portions (50 mL each) of ice-cold water. ediate amide ester (8). Warning: Oxalyl chloride is corrosive
The mixed liquids were extracted four times with small por- and forms toxic vapors. Special attention should be given
tions of AcOEt, and the combined organic layers were washed when working with this reagent. In a Schlenk tube of 50 mL,
once with distilled water, once with brine and then dried over equipped with a stirring bar, 500 mg (1.0 eq., 1.13 mmol) of
anhydrous magnesium sulphate. After filtration and solvent monoester 7 was added and placed under an argon atmos-
removal, the resulting oil was purified on a silica gel column, phere. The substrate was dissolved in 20 mL of dry DCM and
using AcOEt in n-hexane (gradient, from 0% to 12%) as an cooled in a water-ice bath with vigorous stirring. To the cooled
eluent. The product was crystallized from the mixture of solution, 195 µL (2.0 eq., 2.26 mmol) of oxalyl chloride was
n-hexane and 2-propanol (10 : 1 v/v) and 13.33 g (0.048 mol, added in one portion. The reaction was allowed to reach room
66% over 2 steps) of a yellowish crystalline solid was obtained. temperature and the mixture was stirred for 2 h. After this, the
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solvent was removed on a rotary evaporator, which was vented 152.8, 147.7, 146.6, 140.9, 130.3, 130.2, 128.4, 127.0, 124.3,
with argon. The oily residue was dissolved in 10 mL of dry 119.6, 117.6, 109.1, 107.3, 106.9, 106.7, 101.3, 61.5, 61.1, 60.9,
DCM and added dropwise, under argon, to a stirred solution 56.1, 56.0, 55.7, 25.2, 22.6. HRMS (ESI-TOF) m/z: calcd for
of L-prolinol (120 mg, 1.05 eq., 1.19 mmol) and triethylamine C27H28NO9 [M − H]−, 510.1764; found, 510.1780.
(0.47 mL, 340 mg, 3.00 eq., 3.4 mmol) in 5 mL of dry DCM.
2E-(3,4-Methylenedioxybenzylidene)-3E-(3,4,5-trimethoxybenzyl-
The resulting solution was allowed to be stirred for 1 h and the idene)butanediate (S)-(+)-2-pyrrolidinemethanol cyclic amide
solvent was evaporated. The residue was dissolved in 20 mL of ester (10). To a solution of 6.05 g (29.4 mmol, 1.5 equiv.) of
AcOEt and washed with 10 mL of water, and back-extracted DCC and 2.65 g (21.6 mmol, 1.1 equiv.) of DMAP in 80 mL of
with 10 mL of AcOEt. The combined organic layers were dry DCM, a solution of 10.0 g (19.6 mmol) of 9 in 40 mL
washed with 10 mL of 10% citric acid solution, 10 mL of a 5% of DCM was added dropwise using a syringe pump. The
solution of NaHCO3 and 10 mL of brine. The organic layer was addition was completed during approx. 4 h and the reaction
dried with anhydrous sodium sulphate and filtered. After mixture was allowed to be stirred for 1 h. After this, the result-
removal of the solvent on a rotary evaporator, 593 mg ing suspension was filtered at atmospheric pressure and the
(1.12 mmol, 99%) of an amorphous solid was obtained. The filtrate was concentrated under vacuum. The residue was dis-
1
product had a purity of at least 97% according to the H NMR solved in AcOEt and filtered. The resulting filtrate was washed
spectrum and could be used for the next step without further twice with 0.5 N HCl and twice with saturated aqueous
purification. Trace impurities however, can be removed on a NaHCO3. The organic layer was dried over anhydrous MgSO4
silica gel column, using MeOH in CHCl3 (gradient, from 0% to and concentrated under vacuum. The resulting oil was purified
2%) as an eluent. [α]2D5 = +423.5 (c 1.0, CHCl3); 1H NMR (CDCl3 by column chromatography (isocratic elution, CHCl3). The
with 0.03% v/v TMS, 500 MHz): δ 7.72 (s, 1H), 6.95–6.46 (m, product was precipitated from n-hexane to give 7.16
g
6H), 5.92 (s, 2H), 4.15 (br s, 2H), 3.83 (s, 3H), 3.80 (br s, 9H), (14.5 mmol, 74%) of a yellowish crystalline solid. M.p.
1
3.68 (s, 3H), 3.27 (br s, 1H), 2.02 (s, 1H), 1.80 (br d, 2H), 1.44 103.8–104.2 °C. [α]2D5 = +949.4 (c 1.0, CHCl3); H NMR (CDCl3
(br s, 1H). 13C NMR (CDCl3, 125 MHz): δ 167.3, 166.8, 153.0, with 0.03% v/v TMS, 500 MHz): δ 7.54 (s, 1H), 7.47 (s, 1H), 7.11
147.9, 147.6, 143.8, 130.4, 130.3, 129.7, 126.9, 126.5, 123.9, (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.5, 1.5 Hz, 1H), 7.03 (s, 2H),
123.8, 108.3, 108.2, 106.7, 101.3, 61.7, 61.3, 60.9, 56.1, 52.4, 6.76 (d, J = 8.1 Hz, 1H), 5.95 (d, J = 1.4 Hz, 1H), 5.93 (d, J =
31.6, 25.3, 22.6. HRMS (ESI-TOF) m/z: calcd for C28H31NO9Na 1.4 Hz, 1H), 4.62 (dd, J = 13.9, 4.9 Hz, 1H), 4.31 (d, J = 13.8 Hz,
[M + Na]+, 548.1896; found, 548.1879.
(S)-(+)-2-Pyrrolidinemethanol-2E-(3,4-methylenedioxybenzyl- 3.58–3.40 (m, 2H), 2.29 (dt, J = 12.1, 5.3 Hz, 1H), 1.91 (dt, J =
idene)-3E-(3,4,5-trimethoxybenzylidene)butanedioic
acid 11.6, 5.8 Hz, 1H), 1.78–1.51 (m, 2H). 13C NMR (CDCl3,
1H), 4.05 (dq, J = 11.5, 5.9 Hz, 1H), 3.88 (s, 6H), 3.85 (s, 3H),
amide (9). In a 50 mL round bottom flask, 1.24 g (1 eq., 125 MHz): δ 168.13, 167.15, 153.14, 149.16, 148.14, 145.60,
2.36 mmol) of amide ester 8 was dissolved in 15 mL of MeOH. 140.94, 140.26, 128.65, 128.08, 126.57, 126.06, 124.37, 109.16,
The solution was stirred magnetically, and a solution of 1.63 g 108.56, 108.38, 101.51, 73.45, 60.85, 59.63, 56.34, 48.10, 34.54,
(5 eq., 11.8 mmol) of K2CO3 in 20 mL of water was added drop- 22.46. HRMS (ESI-TOF) m/z: calcd for C27H27NO8Na [M + Na]+,
wise, which resulted in the formation of a yellowish suspen- 516.1635; found, 516.1648.
sion. After complete addition, the dropping funnel was
2E-(3,4-Methylenedioxybenzylidene)-3E-(3,4,5-trimethoxybenzyl-
replaced with a reflux condenser and the flask was kept in an idene)butanediate (S)-(+)-2-pyrrolidinemethanol cyclic amide
oil bath at 80 °C for 3 h. During this time, the suspension ester (10). 6.3 g (12.3 mmol) of acid 9 was dissolved in 500 mL
turned into a clear orange solution. After complete reaction, of DCM and the resulting yellow solution was stirred vigor-
the solution was cooled and MeOH was removed on a rotary ously at room temperature. 8.17 g (18.5 mmol, 1.5 equiv.) of
evaporator. The aqueous solution was transferred into a BOP was added in a single portion, followed by the addition of
separatory funnel. The aqueous layer was extracted twice with 5.15 mL of triethylamine (3.74 g, 37 mmol, 3 equiv.). After
AcOEt, and the extracts were discarded. The aqueous layer was 1.5 h of stirring at room temperature the reaction mixture was
acidified by slow addition of 15 mL of 10% citric acid during concentrated under vacuum and the resulting residue was dis-
which the product precipitated as an oil. The product was solved in DCM. This solution was extracted thrice with 10% aq.
extracted 5 times with 10 mL of AcOEt, and the combined citric acid, thrice with 5% aq NaHCO3 and once with distilled
organic fractions were washed with brine and dried with anhy- water. The organic layer was dried over anhydrous MgSO4 and
drous sodium sulphate. After filtration and removal of the concentrated under vacuum. The resulting oil was purified on a
solvent, 1.20 g (2.34 mmol, 99%) of acid 9 were obtained in short column, under the same conditions as described above,
the form of a yellowish, amorphous solid. The product con- to give 3.88 g (7.87 mmol, 64%) of compound 10.
tains only trace impurities and can be used in the next step
(1R,2R)-1-(3,4,5-Trimethoxyphenyl)-6,7-methylenedioxy-1,2-
(S)-(+)-2-pyrrolidine-
without further purification. [α]2D5 = +151.7 (c 1.0, CHCl3); dihydronaphthalene-2,3-dicarboxylate
1H NMR (CDCl3 with 0.03% v/v TMS, 300 MHz): δ 7.81–7.54 methanol cyclic amide ester (12). In a 50 mL quartz cuvette,
(m, 2H), 7.18–6.84 (m, 2H), 6.79 (d, J = 11.0 Hz, 1H), 6.75–6.59 25 mg (0.051 mmol) of compound 10 was dissolved in 50 mL
(m, 2H), 5.89 (s, 2H), 4.85 (br s, 1H), 3.98 (br d, 1H), 3.87–3.75 of MeOH. The solution was flushed with dry argon for
(m, 3H), 3.69 (dd, J = 10.9, 2.9 Hz), 3.34 (s, 3H), 3.16 (br s, 1H), 10 minutes, and 38 µL (final concentration 0.01 M) of TFA was
2.22–1.54 (m, 4H). 13C NMR (CDCl3, 125 MHz): δ 166.3, 165.9, added. The reaction mixture was irradiated for 1 h, using a
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medium pressure mercury lamp. During irradiation, the solu- vacuum, along with traces of HCl. The resulting oil was puri-
tion was vigorously flushed with dry argon, which guaranteed fied on a silica gel column, using EtOAc in DCM (gradient,
constant mixing of the solution. The color of the reaction from 0% to 45%) as an eluent. The product was precipitated
mixture changed within the first 20 s of irradiation from color- from n-hexane to give 136 mg (0.258 mmol, 94%) of a white,
less to yellow. During irradiation the solution turned strongly UV-fluorescent amorphous solid. M.p. 102.5–104.2 °C. [α]D25
=
blue-fluorescent. After 1 h of irradiation, the TLC analysis −47.2 (c 1.0, CHCl3); 1H NMR (CDCl3 with 0.03% v/v TMS,
showed complete disappearance of the starting material. The 500 MHz): δ 6.69 (s, 1H, C-5), 6.66 (d, J = 2.4 Hz, 1H, C-4), 6.58
solution was transferred into a round bottom flask and the (s, 1H, C-8), 6.32 (s, 2H, C-2′, C-6′), 5.96 (d, J = 1.4 Hz, 1H, –O–
solvent was removed under vacuum. The resulting yellow oil CH2–O–), 5.95 (d, J = 1.4 Hz, 1H, –O–CH2–O–), 4.62 (s, 1H,
was purified on a silica gel column under dry argon, using –OH), 4.42 (d, J = 8.3 Hz, 1H, C-1), 4.38 (dd, J = 8.4, 2.4 Hz, 1H,
degassed AcOEt in degassed DCM (gradient, from 0% to 40%) C-2), 4.20 (dtd, J = 9.7, 7.6, 2.4 Hz, 1H, C-2″), 3.86–3.80 (br m,
as an eluent. 8 mg (0.016 mmol, 32%) of product 12 was 1H, C-5″), 3.78 (s, 3H, –OCH3), 3.78 (m, 1H, C-1″), 3.73 (s, 6H,
obtained in the form of a white, UV-fluorescent gum. [α]D25
=
2× –OCH3), 3.61 (m, 1H, C-1″), 3.49 (s, 3H, C-13), 3.56–3.43 (m,
+720.7 (c 1.0, CHCl3); 1H NMR (CDCl3 with 0.03% v/v TMS, 1H, C-5″), 2.15–2.05 (m, 1H, C-3″), 1.90–1.76 (m, 1H, C-4″),
500 MHz): δ 6.72 (br s, 2H, C-2′, C-6′), 6.63 (s, 1H, C-5), 6.57 (d, 1.74–1.49 (m, 2H, C-3″, C-4″). 13C NMR (CDCl3, 125 MHz):
J = 1 Hz, 1H, C-8), 6.50 (s, 1H, C-4), 5.92 (d, J = 1.4 Hz, 1H, –O– δ 172.7 (C-11), 171.6 (C-12), 152.9 (C-3′, C-5′), 148.5 (C-7), 147.0
CH2–O–), 5.90 (d, J = 1.4 Hz, 1H, –O–CH2–O–), 4.42 (dd, J = 6.5, (C-6), 137.3 (C-1′), 135.2 (C-3), 130.5 (C-4′), 129.6 (C-9), 129.5
1.0 Hz, 1H, C-1), 4.31 (dd, J = 11.1, 4.5 Hz, 1H, C-1″), 4.15–4.04 (C-4), 125.0 (C-10), 109.3 (C-8), 107.8 (C-5), 105.9 (C-2′, C-6′),
(m, 1H, C-2″), 3.88 (d, J = 6.5 Hz, 1H, C-2), 3.85 (s, 3H, –OCH3), 101.4 (–O–CH2–O–), 67.3 (C-1″), 61.0 (C-2″), 60.8 (–OCH3), 56.0
3.80 (s, 6H, 2× –OCH3), 3.61 (dd, J = 8.8, 5.3 Hz, 2H, C-5″), 3.23 (–OCH3), 51.8 (C-13), 50.7 (C-5″), 49.1 (C-2), 46.7 (C-1), 28.5
(t, J = 11.2 Hz, 1H, C-1″), 2.17–1.90 (m, 3H, C-3″, C-4″), (C-3″), 24.8 (C-4″). HRMS (ESI-TOF) m/z: calcd for
1.69–1.59 (m, 1H, C-3″). 13C NMR (CDCl3, 125 MHz): δ 171.1 C28H31NO9Na [M + Na]+, 548.1896; found, 548.1914.
(C-12), 169.5 (C-11), 153.2 (C-3′, C-5′), 148.3 (C-7), 146.1 (C-6),
Monomethyl (S)-(+)-2-pyrrolidinemethanol-(1R,2R)-1-(3,4,5-
137.2 (C-1′), 134.6 (C-3), 131.0 (C-4′), 130.5 (C-9), 129.2 (C-4), trimethoxyphenyl)-6,7-methylenedioxy-1,2-dihydronaphthalene-
124.8 (C-10), 108.2 (C-5), 108.1 (C-8), 107.3 (C-2′, C-6′), 101.2 2,3-dicarboxylate amide ester (13) – acidic work-up. The con-
(–O–CH2–O–), 65.0 (C-1″), 60.8 (–OCH3), 56.5 (C-2″), 56.0 tinuous flow irradiation was carried out as described above.
(–OCH3), 51.3 (C-2), 46.9 (C-1), 45.1 (C-5″), 26.9 (C-3″), 22.3 After the whole solution passed through the microreactor,
(C-4″). HRMS (ESI-TOF) m/z: calcd for C27H27NO8Na [M + Na]+, most of the solvent was removed under vacuum, to leave a
516.1635; found, 516.1627.
(1R,2R)-1-(3,4,5-Trimethoxyphenyl)-6,7-methylenedioxy-1,2- 100 mL round bottom flask and supplemented with
dihydronaphthalene-2,3-dicarboxylate (S)-(+)-2-pyrrolidine- dry methanol saturated with HCl to a final volume of 30 mL.
volume of ca. 20 mL. This solution was transferred into a
methanol cyclic amide ester (12). In a 1 L flat bottom flask, The flask was placed on an oil bath, and stirred for 1 h at
200 mg (1 eq., 0.405 mmol) of compound 10 was dissolved in 40 °C. The solvent was subsequently removed on a rotary evap-
1.0 L of degassed MeOH and 740 µL of TFA (final concen- orator and the residue was dissolved in a small amount of
tration 0.01 M) was added. The solution was pumped through dry toluene, which was also evaporated under vacuum,
a multiply folded quartz tube, which was irradiated from the along with traces of HCl. The resulting oil was purified on a
side with a medium pressure mercury lamp. To achieve a silica gel column as described above, to give 125 mg
constant pumping speed, a HPLC pump was employed, and (0.238 mmol, 59%) of a white, UV fluorescent amorphous
the flow rate was set to 0.7 mL min−1. To avoid overheating of solid.
the solution inside the quartz tube of the flow reactor, the
Monomethyl (S)-pyrrolidin-2-ylmethyl 3-bromobenzoate-
solution was cooled with a stream of air. The irradiated solu- (1R,2R)-1-(3,4,5-trimethoxyphenyl)-6,7-methylenedioxy-1,2-di-
tion was collected in a 2 L round bottom flask. After all the hydronaphthalene-2,3-dicarboxylate amide ester (14). To a
mixture had passed through the flow-reactor, the solvent was stirred solution of 47 mg (0.089 mmol) of 13 in DCM, 12.4 µL
removed under vacuum. The resulting yellow oil was (1 equiv.) of TEA and 12.3 µL (1.05 equiv.) of 3-bromobenzoyl
purified as described above and 122 mg (0.247 mmol, 61%) of chloride were added at room temperature. After 2 h of stirring,
the product was obtained in the form of a white, UV-fluo- the reaction mixture was poured into an ice-water mixture. The
rescent gum.
organic phase was washed once with 10% citric acid and twice
Monomethyl (S)-(+)-2-pyrrolidinemethanol-(1R,2R)-1-(3,4,5- with water. After purification by column chromatography
trimethoxyphenyl)-6,7-methylenedioxy-1,2-dihydronaphthalene- (SiO2, EtOAc : DCM 15 : 85) 44 mg (0.062 mmol, 70%) of the
2,3-dicarboxylate amide ester (13). In a round bottom flask of product was obtained. Crystals suitable for X-ray analysis were
50 mL, equipped with a stirring bar and under an argon grown by slow evaporation of the methanol solution. M.p.
atmosphere, 135 mg (1 eq., 0.274 mmol) of compound 12 was 181.0–182.5 °C. [α]2D5 = −46.0 (c 1.0, CHCl3); 1H NMR (CDCl3
dissolved in 20 mL of dry MeOH saturated with HCl. The solu- with 0.03% v/v TMS, 500 MHz): δ 8.18 (s, 1H), 7.99 (d, J = 7.8
tion was stirred for 45 min at 40 °C. The solvent was removed Hz, 1H), 7.71 (dd, J = 8.1, 2.0 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H),
on a rotary evaporator. The residue was dissolved in a small 6.67 (s, 1H), 6.63–6.58 (m, 1H), 6.57 (s, 1H), 6.32 (s, 2H), 5.96
portion of dry toluene, which was also evaporated in a (d, J = 1.4 Hz, 1H), 5.94 (d, J = 1.3 Hz, 1H), 4.53 (br s, 1H), 4.47
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(br s, 2H), 4.41 (s, 2H), 3.78 (s, 4H), 3.73 (s, 6H), 3.55 (br s, extracts were washed with brine, dried over anhydrous MgSO4
1H), 3.49 (s, 3H), 2.19–2.06 (m, 1H), 2.00–1.84 (m, 2H), and concentrated in vacuo. The residue was purified using
1.84–1.72 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 172.2 (not flash column chromatography (silica gel, EtOAc/hexane, gradi-
observed), 171.7, 165.1, 152.9, 148.5, 147.0, 137.4, 136.0, 135.4, ent from 0% to 20% of EtOAc) to yield 14 mg (0.032 mmol,
132.6, 132.1, 130.6, 130.1, 129.9, 128.3, 125.2, 122.5, 109.3, 20%) of product 16 as a yellowish gum. The analytical data for
108.0 (not observed), 105.9, 101.4, 67.8 (not observed), 61.1 product 16 were identical to those reported in the literature.35
(not observed), 60.8, 56.1, 51.8, 50.7 (not observed), 49.1, 46.8, [α]2D5 = +156.5 (c 1.0, CHCl3); 1H NMR (CDCl3 with 0.03% v/v
28.9 (not observed), 24.9 (not observed). HRMS (ESI-TOF) m/z: TMS, 500 MHz): δ 9.60 (s, 1H), 7.36 (s, 1H), 6.89 (s, 1H), 6.62
calcd for
C35H34BrNO10Na [M +
Na]+, 730.1264; found, (s, 1H), 6.46 (s, 2H), 6.01 (d, J = 1.4 Hz, 1H), 5.99 (d, J = 1.4 Hz,
730.1279. The detailed structural parameters have been de- 1H), 4.41 (d, J = 7.9, 1H), 3.98 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H),
posited with the Cambridge Crystallographic Data Centre 3.81 (s, 6H), 3.40 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 191.0,
under the number CCDC 1415848.
171.4, 153.3, 150.4, 147.1, 146.8, 137.4, 134.6, 134.3, 134.1,
Monomethyl (S)-(+)-2-pyrrolidinemethanol-(1R,2R)-1-(3,4,5- 125.6, 109.6, 109.2, 106.4, 101.7, 60.9, 56.1, 51.7, 48.3, 44.1.
trimethoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydronaphthal- HRMS (ESI-TOF) m/z: calcd for C23H22O8Na [M + Na]+,
ene-2,3-dicarboxylate amide ester (15). 62 mg (1 eq., 449.1212; found, 449.1232.
0.118 mmol) of product 13 and a stirring bar were placed in a
Monomethyl
3-formyl-(1R,2R)-1-(3,4,5-trimethoxyphenyl)-
15 mL Schlenk tube under an argon atmosphere. Dry THF 6,7-methylenedioxy-1,2-dihydronaphthalene-2-carboxylate ester
(1.2 mL) was added, and the solution was stirred vigorously. (16). Compound 13 (150 mg, 0.285 mmol) was dissolved in
Samarium iodide solution (8,3 mL, 7 eq., 0.83 mmol) was 8 mL of anhydrous THF under argon. This solution is then
added in a single portion, followed by the addition of 1035 µL added to 2 eq. of Schwartz’s reagent at room temperature
of triethylamine (751 mg, 63 eq., 7.43 mmol) and 134 µL of under argon. After 10 min of stirring, the Schwartz’s reagent
water (63 eq., 7.43 mmol). Immediately after the addition of was dissolved completely, marking the completion of the reac-
water, the color of the reaction mixture changed from dark tion. The mixture was quenched by addition of 5 mL of H2O. A
brown to white. TLC analysis showed complete disappearance solution of 0.5 N HCl was used to adjust the pH to ca. 6 and
of the starting material. The reaction mixture was stirred for the product was extracted 3 times with small portions of
1 more h at room temperature and the suspension was then EtOAc. The combined organic extracts were washed with brine,
poured into 20 mL of 2.0 M hydrochloric acid. The product dried over anhydrous MgSO4 and concentrated in vacuo. The
was extracted with chloroform three times, and the combined residue was purified as described above to yield 82 mg
organic fractions were washed with brine and dried over anhy- (0.192 mmol, 67%) of product 16.
drous sodium sulphate. After filtration and removal of the
Monomethyl 3-(hydroxymethyl)-(1R,2R)-1-(3,4,5-trimethoxy-
solvent, the resulting oil was purified on a short column (silica phenyl)-6,7-methylenedioxy-1,2-dihydronaphthalene-2-carboxy-
gel, CHCl3 : MeOH 100 : 1). The product (35 mg, 0.066 mmol, late ester (17). 58 mg (0.136 mmol, 1 equiv.) of product 16 and
56%) is a yellowish gum which foams upon solvent removal. a stirring bar were placed in a 25 mL round bottom flask. A
[α]2D5 = −41.0 (c 1.0, CHCl3); 1H NMR (CDCl3 with 0.03% v/v volume of 3 mL of MeOH was added, and the solution was
TMS, 300 MHz): δ 6.62 (s, 1H), 6.41 (s, 2H), 6.38 (s, 1H), 5.87 stirred vigorously at 0 °C. Sodium borohydride (7.5 mg, 1.46
(d, J = 1.4 Hz, 1H), 5.86 (d, J = 1.4 Hz, 1H), 4.39 (br s, 1H), eq., 0.198 mmol) was added in a single portion. The color of
4.29–4.13 (m, 2H), 3.83 (s, 3H), 3.78 (s, 7H), 3.74–3.63 (m, 2H), the solution changed from orange to yellow. The reaction was
3.63–3.46 (m, 2H), 3.41 (s, 3H), 3.24 (m, 2H), 2.74 (dd, J = 16.8, allowed to reach room temperature and the mixture was stirred
4.8 Hz, 1H), 2.17–1.81 (m, 3H), 1.77–1.60 (m, 1H). 13C NMR for 30 min. After this, the reaction mixture was quenched by
(CDCl3, 75 MHz): δ 174.1, 173.3, 153.1, 146.2, 145.9, 137.1, addition of saturated aqueous NH4Cl solution (ca. 15 mL) and
129.1, 128.7, 127.2, 108.7, 108.3, 106.8, 100.8, 66.4, 61.2, 60.9, diluted with EtOAc (ca. 50 mL). The organic layer was separ-
56.2, 51.3, 49.6, 48.2, 48.0, 42.8, 29.7, 28.2, 24.7. HRMS ated, dried over anhydrous Na2SO4 and concentrated under
(ESI-TOF) m/z: calcd for C28H33NO9Na [M + Na]+, 550.2053; vacuum. The resulting oil was purified by column chromato-
found, 550.2075.
graphy (EtOAc/hexane, gradient from 0% to 20% EtOAc) to
Monomethyl
3-formyl-(1R,2R)-1-(3,4,5-trimethoxyphenyl)- yield 52.5 mg (0.123 mmol, 90%) of product 17 as a white
6,7-methylenedioxy-1,2-dihydronaphthalene-2-carboxylate ester gum. 1H NMR signals for product 17 were identical to those
(16). The reaction was performed according to a literature pro- reported in the literature.37 [α]D25 = +112.9 (c 1.0, CHCl3); 1H
tocol.31 To a solution of 85 mg (0.16 mmol) of 13 in anhydrous NMR (CDCl3 with 0.03% v/v TMS, 500 MHz): δ 6.65 (s, 1H),
THF was slowly added a 1 M THF solution of LiAlH(O-tBu)3 6.53 (s, 1H), 6.52 (s, 1H), 6.49 (s, 2H), 5.90 (d, J = 1.5 Hz, 1H),
(2.4 equiv.). The reaction was carried out at room temperature 5.90 (d, J = 1.6 Hz, 1H), 4.34 (d, J = 7.3, 1H), 4.24 (s, 2H), 3.83
and under an argon atmosphere. The solution was stirred at (s, 3H), 3.79 (s, 6H), 3.68 (d, J = 7.0, 1H), 3.51 (s, 3H), 2.31 (br
room temperature for 5 min. A 0.24 M THF solution of s, 1H). 13C NMR (CDCl3, 125 MHz): δ 172.5, 153.1, 147.1,
Cp2ZrCl2 (1.4 equiv.) was added rapidly. After stirring for 146.3, 137.2, 135.5, 133.7, 130.1, 127.0, 126.8, 108.4, 107.5,
2 min, the reaction mixture was quenched by H2O. Hydro- 106.1, 101.0, 65.3, 60.8, 56.1, 51.7, 48.9, 48.7. HRMS (ESI-TOF)
chloric acid (0.5 M) was added to reach a pH of ca. 6 and the m/z: calcd for C23H24O8Na [M + Na]+, 451.1369; found,
solution was extracted with EtOAc. The combined organic 451.1347.
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20 R. J. Hart and H. G. Heller, J. Chem. Soc., Perkin Trans. 1,
Acknowledgements
1972, 1321.
Financial support from the polish National Science Centre in 21 H. G. Heller and P. J. Strydom, J. Chem. Soc., Chem.
the form of grant NCN-2012/07/B/ST5/02476 is acknowledged. Commun., 1976, 50.
The work was also supported by the grant 120000-501/ 22 P. K. Datta, C. Yau, T. S. Hooper, B. L. Yvon and
86-DSM-110200. We are obliged to our collegue prof. J. L. Charlton, J. Org. Chem., 2001, 66, 8606.
Dr Wojciech Gadomski from the Faculty of Chemistry, Univer- 23 T. Assoumatine, P. K. Datta, T. S. Hooper, B. L. Yvon and
sity of Warsaw, for measuring the emission spectrum of the
UV-lamp and invaluable discussions.
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