Paper
Organic & Biomolecular Chemistry
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
Org. Biomol. Chem.
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