Construction of the Pentacyclic Core and Formal Total Synthesis of (rac)‐Renieramycin T

Abstract

A formal total synthesis of the antitumor marine natural product (rac)‐renieramycin T, which possesses a characteristic ecteinascidin‐type A ring in the renieramycin–saframycin core skeleton, was elaborated. The key steps in the synthesis of (rac)‐renieramycin T are a modified Pictet–Spengler cyclization of dialkylated oxomalonate derivatives and decarboxylation via a monocarboxylic acid derivative followed by stereocontrolled protonation of the enol intermediate. A key intermediate in our previous synthesis of renieramycin T was used, and the formal synthesis was accomplished in 21 steps from a known piperazine‐2,5‐dione derivative.

1. Introduction

Many 1,2,3,4‐tetrahydroisoquinolines exhibit various bioactivities, such as antitumor, antibacterial, antiviral, anticoagulant, anti‐inflammatory, anti‐Alzheimer, and anticonvulsant activities.1 Among them, members of the saframycin, renieramycin, and ecteinascidin families have captured intense attention due to their interesting biological activities and intriguing structures (Figure 1). Particularly, novel marine‐derived ecteinascidin 7432 (2, Trabectedin, Yondelis) has superior antitumor activity and was approved by the European Commission in 20073 and the US Food and Drug Administration (FDA) in 20154 for the treatment of soft‐tissue sarcomas.

Figure 1.

Structures of 1,2,3,4‐tetrahydroisoquinoline natural products.

A large number of renieramycin marine natural products5 have been discovered in sponges of genera Reniera,6 Xestospongia,7 Haliclona,8 Cribrochalina,9 and Neopetrosia 10 in miniscule amounts. In our continuing chemical studies on renieramycins,11 we found that the transformation of an unstable aminal group in a natural product, such as renieramycin E (1 a), into an aminonitrile group by pretreatment with KCN prior to extraction and isolation furnished many kinds of stable renieramycin derivatives, such as renieramycin M (1 b).12 We also elucidated the chemical structure of renieramycin T (1 c), which was isolated from the blue sponge Xestospongia sp. in Thailand11c and the Philippines.11b Renieramycin T (1 c) possesses a highly substituted phenol in the terminal A ring and a condensed 1,3‐dioxole ring, which are exactly the same as those in ecteinascidins. As the chemical structure of 1 c is the first example of a hybrid pentacyclic core, we are very interested in the biosynthetic pathway and the biological activity of 1 c and its derivatives. To date, two total syntheses of (−)‐1 c by us and Chen's group have been reported.13 However, we focused on an alternative route for supplying a large amount of 1 c to promote research of structure–activity relationships. Herein, we report a formal total synthesis of 1 c, which includes the Pictet–Spengler reaction of a primary amine with an oxomalonic acid ester followed by decarboxylation and stereocontrolled protonation at C1 of the enol intermediate from the less‐hindered face.14

2. Results and Discussion

We embarked on an alternative total synthesis of 1 c on the basis of our previous synthetic studies on saframycin antitumor antibiotics (Scheme 1).15 Condensation of highly functionalized benzaldehyde 4 16 with known piperazine‐2,5‐dione derivative 5 15b afforded Z isomer 6 in 79 % yield. Chemoselective reduction of the carbonyl group activated by an isopropyloxycarbonyl group in 6, followed by treatment with trifluoroacetic acid (TFA) gave cyclized product 7 (78 %, two steps). Removal of the isopropoxycarbonyl group in 7 with TFA and H₂SO₄ gave a secondary amine that was treated with a NaBH₃CN–aqueous formaldehyde system to provide tertiary amine 8 in 68 % overall yield. Hydrogenation (2.8 MPa) of the exo olefin in 8 on 20 % Pd(OH)₂ in EtOH at 80 °C along with hydrogen attack from the less‐hindered α face gave 9 as a single isomer in 77 % yield. At that point, we thought it would be important to distinguish the two phenolic OH groups in both terminal rings, because regioselective oxidation was required to prepare p‐quinone in the E ring phenol at a later stage. Thus, the phenolic OH group of the E ring of 9 was protected with an allyl group, and the tosyl group in the A ring was removed with KOH/H₂O to increase its reactivity for the Pictet–Spengler cyclization to give 10 in 80 % over two steps.

Scheme 1.

Preparation of tricyclic lactam 10. Reagents and conditions: a) tBuOK, tBuOH, CH₂Cl₂, 0 °C, 1 h, 79 %; b) 1) Li(tBuO)₃AlH, THF, 25 ^oC, 6 h; 2) TFA, CH₂Cl₂, 25 ^oC, 3 h, 78 % (two steps); c) 1) H₂SO₄, TFA, anisole, 25 °C, 7.5 h; 2) NaBH₃CN, 37 % aq HCHO, MeOH, AcOH, 25 °C, 2 h, 68 % (two steps); d) H₂ (2.8 MPa), 20 % Pd(OH)₂/C, EtOH, 80 °C, 27 h, 77 %; e) 1) allyl bromide, K₂CO₃, acetone, reflux, 5.5 h; 2) aq KOH, EtOH, reflux, 3 h, 80 % (two steps). Ts=tosyl, Ac=acetyl, MOM=methoxymethyl.

With precursor 10 in hand, we focused on the construction of a pentacyclic core by using the Pictet–Spengler cyclization (Scheme 2). Partial reduction of the lactam carbonyl group in 10, followed by the introduction of a cyanide group gave aminonitrile 11. We had hoped that the aminonitrile would be more reactive than lactam 10 in the Pictet–Spengler cyclization. However, it was revealed that the Pictet–Spengler cyclization of 11 with even commonly used simple aldehydes,15c for example, the reaction of 11 with benzoyloxyacetaldehyde, did not proceed at all.17 Furthermore, substrate decomposition was observed if harsher reaction conditions were used. It was clarified that the aminonitrile moiety of 11 was relatively unstable under acidic or high‐temperature conditions. Therefore, we abandoned this route at this stage.

Scheme 2.

Cyclization attempt by using the Pictet–Spengler reaction of aminonitrile 11. Reagents and conditions. a) Cp₂ZrHCl, THF, −20 to 0 °C, 1 h; aq KCN, 25 °C, 4 h, 96 %. Cp=η⁵‐cyclopentadienyl.

This problem was solved by applying our protocol to the total synthesis of saframycin A (3, Scheme 3).18 Primary amine I did not have a relatively unstable aminonitrile group, and so steric repulsion would be reduced. Thus, it would be easy to construct desired pentacyclic core IV by using a three‐step sequence through compound II, which includes the Pictet–Spengler cyclization with oxomalonic acid ester to install a diester unit, decarboxylation, and stereoselective protonation from the convex face of these “V”‐shaped bis‐1,2,3,4‐tetrahydroisoquinoline natural products.

Scheme 3.

Recently established strategy for construction of the B ring of bis‐tetrahydroisoquinoline natural products, represented by saframycin A (3).

Activation of the lactam carbonyl group in 10 with di‐tert‐butyl dicarbonate (Boc₂O) gave 13 in 72 % yield according to a protocol independently outlined by Fukuyama and Stoltz19 (Scheme 4). Reductive cleavage of the lactam ring in 13 with NaBH₄ in EtOH, followed by treatment with TFA in CH₂Cl₂ gave primary amine 14 (73 %, two steps). Pictet–Spengler cyclization of 14 with allyl ethyl oxomalonate hydrate20 furnished diester 15 as an inseparable diastereomeric mixture (1:1) in 80 % yield. Then, the phenolic OH group in 15 was protected by a benzyl (Bn) group (83 %), and Swern oxidation of 16 followed by treatment with KCN afforded pentacyclic core 17 (56 %, two steps). Removal of the allyl group in 17 with Pd(PPh₃)₄ and dimedone, followed by decarboxylation exclusively gave ester 18 as a single diastereomer in 72 % yield.21, 22 The stereochemistry of 18 was determined by nuclear Overhauser enhancement (NOE) experiments, which indicated that 18 had a syn relationship between the C1 and C3 diaxial protons.

Scheme 4.

Construction of the B ring. Reagents and conditions. a) Boc₂O, 4‐(dimethylamino)pyridine (DMAP), MeCN, reflux, 57.5 h, 72 %; b) 1) NaBH₄, EtOH, 25 °C, 3 h; 2) TFA, CH₂Cl₂, 25 °C, 1.5 h, 73 % (two steps); c) 1‐allyl 3‐ethyl 2,2‐dihydroxymalonate, TFA, AcOH, 25 °C, 6 h, 80 %; d) BnBr, K₂CO₃, acetone, 25 °C, 8 h, 83 %; e) 1) Swern oxidation; 2) aq KCN, AcOH, THF, 25 °C, 2 h, 56 % (two steps); f) 1) Pd(PPh₃)₄, dimedone, THF, 25 °C, 1 h; 2) CHCl₃, reflux, 2 h, 72 % (two steps).

Finally, reduction of ester 18 (71 %), followed by oxidative demethylation of 19 into quinone ring afforded 20 (51 %) (Scheme 5). This is the key intermediate in our total synthesis;13a its ¹H NMR, ¹³C NMR, and IR spectroscopy data; MS data; and TLC behavior were identical to those of an authentic sample upon comparison Thus, we accomplished a formal synthesis of (rac)‐renieramycin T (1 c).

Scheme 5.

Formal synthesis of (rac)‐renieramycin T (1 c). Reagents and conditions. a) LiBH₄, MeOH, THF, 25 °C, 3 h, 71 %; b) aq ceric ammonium nitrate (CAN), THF, 0 °C, 20 min, 51 %.

3. Conclusions

We accomplished a formal synthesis of (rac)‐renieramycin T (1 c). Whereas the aromatic ring having a 1,3‐dioxole ring suppressed reactivity during the Pictet–Spengler cyclization, reductive cleavage of the lactam ring in 13 afforded primary amine 14. Then, treatment of 14 with allyl ethyl oxomalonate in the Pictet–Spengler reaction, followed by decarboxylation and stereoselective protonation of the resulting enol intermediate from the less‐hindered face produced the desired bis‐1,2,3,4‐tetrahydroisoquinoline intermediate.

Ways of utilizing this strategy for the synthesis of ecteinascidins along with fennebricin B23 are under investigation in our laboratory.

Experimental Section

General Methods

All reactions involving air‐ and moisture‐sensitive reagents were performed in oven‐dried glassware and by using standard syringe‐septum cap techniques. All reactions were monitored by thin‐layer chromatography (silica gel GF₂₅₄) examined under UV light (λ=254 nm). Flash column chromatography was performed on Merck Silica Gel (230–400 mesh) with the solvent indicated. IR spectra were obtained with a Shimadzu Prestige‐21/IR Affinity‐1 Fourier Transform Infrared (FTIR) spectrometer. ¹H NMR and ¹³C NMR spectroscopic data were recorded with a JEOL ECS‐400 spectrometer at 400 MHz for ¹H and 100 MHz for ¹³C and with a JEOL AL‐400 spectrometer at 400 MHz for ¹H and 100 MHz for ¹³C. NMR spectra were measured in CDCl₃, and the chemical shifts were recorded in δ _H values relative to (CH₃)₄Si as the internal standard. Low‐ and high‐resolution mass (HRMS) mass spectra were recorded with a JMS‐700 instrument with a direct inlet system operating at 70 eV.

Syntheses

(Z)‐Isopropyl 2‐[4,5‐dimethoxy‐2‐(methoxymethoxy)‐3‐methylbenzyl]‐5‐{[7‐methyl‐6‐(tosyloxy)benzo[d][1,3]dioxol‐5‐yl]methylene}‐3,6‐dioxopiperazine‐1‐carboxylate (6)

A solution of tBuOK in tBuOH (1 m, 30 mL, 30 mmol) was added dropwise to a stirred solution of aldehyde 4 (8.36 g, 25 mmol) and acetate 5 (11.66 g, 25 mmol) in CH₂Cl₂ (100 mL) at 0 °C over 1 h, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with saturated aqueous NH₄Cl solution (200 mL) and extracted with CH₂Cl₂ (3×250 mL). The combined extract was washed with brine (200 mL), dried, and concentrated in vacuo to give a residue (18.26 g), which was subjected to flash column chromatography on SiO₂ (500 g) with hexane/EtOAc (3:2) to afford 6 (14.62 g, 79 %) as a colorless amorphous powder; R _f=0.35 (hexane/EtOAc 1:1); ¹H NMR (400 MHz, CDCl₃): δ=7.62 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 7.24 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 7.10 (br s, 1 H, NH), 6.41 (s, 1 H, 4“‐H), 6.34 (s, 1 H, 6′‐H), 6.15 (s, 1 H, 5a‐H), 6.07 (d, J=1.2 Hz, 1 H, 2”‐H), 6.05 (d, J=1.2 Hz, 1 H, 2“‐H), 5.17 (sept, J=5.7 Hz, 1 H, CH(CH₃)₂), 5.03 (t, J=4.9 Hz, 1 H, 2‐H), 4.88 (d, J=5.9 Hz, 1 H, OCH ₂OCH₃), 4.82 (d, J=5.9 Hz, 1 H, OCH ₂OCH₃), 3.73 (s, 3 H, 5′‐OCH₃), 3.58 (s, 3 H, OCH₂OCH ₃), 3.53 (s, 3 H, 4′‐OCH₃), 3.30 (d, J=4.9 Hz, 2 H, 2a‐H₂), 2.34 (s, 3 H, C₆H₄CH ₃), 2.27 (s, 3 H, 7”‐CH₃), 2.00 (s, 3 H, 3′‐CH₃), 1.43 (d, J=5.7 Hz, 3 H, CH(CH ₃)₂), 1.41 ppm (d, J=5.7 Hz, 3 H, CH(CH ₃)₂); ¹³C NMR (100 MHz, CDCl₃): δ=164.9 (C‐3), 157.4 (C‐6), 152.2 (CO₂), 149.5 (C‐2′ or 5′), 149.3 (C‐2′ or 5′), 148.1 (C‐4′ or 7“a), 148.0 (C‐4′ or 7”a), 145.6 (C‐3“a), 145.4 (C ₆H₄CH₃), 141.8 (C‐6”), 132.3 (C ₆H₄CH₃), 130.1 (C ₆H₄CH₃), 128.7 (C ₆H₄CH₃), 125.9 (C‐3′), 124.7 (C‐5), 122.3 (C‐1′), 119.7 (C‐5“), 117.1 (C‐7”), 113.9 (C‐5a), 112.9 (C‐6′), 104.6 (C‐4“), 102.3 (C‐2”), 100.0 (CH₂OCH₃), 72.0 (CH(CH₃)₂), 60.1 (4′‐OCH₃), 59.9 (C‐2), 57.6 (CH₂OCH₃), 55.8 (5′‐OCH₃), 33.8 (C‐2a), 21.8 (CH(CH₃)₂), 21.8 (CH(CH₃)₂), 21.5 (C₆H₄ CH₃), 10.9 (7“‐CH₃), 10.4 ppm (3′‐CH₃); FTIR (KBr): $\tilde{\nu }$ =1773, 1694, 1479, 1420, 1375, 1281, 1233, 1196, 1173, 1103, 1080, 1061, 1022, 972, 806 cm⁻¹; MS (EI): m/z (%): 741 (40), 740 (100) [M]⁺, 569 (33), 568 (31), 499 (31), 467 (55), 319 (21), 287 (59), 230 (27), 225 (43), 220 (23), 219 (46), 191 (23), 190 (22), 181 (73); HRMS (EI): m/z: calcd for C₃₆H₄₀O₁₃N₂S: 740.2251 [M]⁺; found: 740.2250.

(Z)‐Isopropyl (1R*,5S*)‐7‐hydroxy‐9,10‐dimethoxy‐8‐methyl‐2‐ {[7‐methyl‐6‐(tosyloxy)‐benzo[d][1,3]dioxol‐5‐yl]methylene}‐ 4‐oxo‐1,2,3,4,5,6‐hexahydro‐1,5‐iminobenzo[d]azocine‐11‐ carboxylate (7)

Li(tBuO)₃AlH (6.36 g, 25 mmol) was added to a stirred solution of 6 (3.70 g, 5 mmol) in THF (170 mL) at 0 °C over 40 min, and the mixture was stirred at 25 °C for 6 h. The mixture was diluted by adding a saturated aqueous Rochelle salt solution (100 mL) and was then extracted with CHCl₃ (3×300 mL). The combined extract was washed with brine (300 mL), dried, and concentrated in vacuo to give a residue, which was used in the next step without further purification. TFA (22.5 mL) was added to a stirred solution of the above product (3.71 g) in CH₂Cl₂ (45 mL), and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo, and the residue was diluted with H₂O (200 mL). Then, the mixture was brought to pH 9 with concd. NH₄OH (25 mL) and was extracted with CH₂Cl₂ (3×300 mL). The combined extract was washed with brine (300 mL), dried, and concentrated in vacuo to give a residue (3.75 g), which was subjected to column chromatography on SiO₂ (100 g) with CHCl₃/EtOAc (4:1) to afford tricyclic lactam 7 (2.64 g, 78 %, two steps) as a pale‐yellow amorphous powder. As it was a mixture of rotational isomers, the ¹H NMR and ¹³C NMR spectra are both extremely complex at 25 °C in CDCl₃; R _f=0.23 (CHCl₃/EtOAc 4:1); ¹H NMR (400 MHz, [D₆]DMSO, 100 °C): δ=8.67 (s, 1 H, OH or NH), 7.99 (s, 1 H, OH or NH), 7.74 (d, J=8.0 Hz, 2 H, C₆ H ₄CH₃), 7.44 (d, J=8.0 Hz, 2 H, C₆ H ₄CH₃), 6.57 (s, 1 H, 4′‐H), 6.02 (s, 2 H, 2′‐H₂), 5.72 (s, 1 H, 1‐H), 5.65 (s, 1 H, 2a‐H), 4.89 (sept, J=5.3 Hz, 1 H, CH(CH₃)₂), 4.81 (dd, J=5.2, 2.3 Hz, 1 H, 5‐H), 3.77 (s, 3 H, 10‐OCH₃), 3.72 (s, 3 H, 9‐OCH₃), 2.92 (d, J=2.3 Hz, 1 H, 6‐Hα), 2.91 (d, J=5.2 Hz, 1 H, 6‐Hβ), 2.44 (s, 3 H, C₆H₄CH ₃), 2.07 (s, 3 H, 8‐CH₃), 1.99 (s, 3 H, 7′‐CH₃), 1.25 (d, J=5.3 Hz, 3 H, CH(CH ₃)₂), 1.24 ppm (d, J=5.3 Hz, 3 H, CH(CH ₃)₂); ¹³C NMR (100 MHz, [D₆]DMSO, 100 °C): δ=167.6 (C‐1), 152.5 (CO₂), 149.1 (C‐7 or 9), 148.3 (C‐7 or 9), 145.4 (C‐7′a), 145.1 (C ₆H₄CH₃), 144.6 (C‐3′a), 142.5 (C‐10a), 139.6 (C‐6′), 133.9 (C‐2 or 5′ or 7′), 132.4 (C ₆H₄CH₃), 129.4 (C ₆H₄CH₃), 127.5 (C ₆H₄CH₃), 124.0 (C‐8 or 6a or 10a), 121.7 (C‐2 or 5′ or 7′), 118.5 (C‐8 or 6a or 10a), 114.8 (C‐8 or 6a or 10a), 114.0 (C‐2 or 5′ or 7′), 106.0 (C‐4′), 101.3 (C‐2′), 101.2 (C‐2a), 68.8 (CH(CH₃)₂), 59.5 (10‐OCH₃), 59.2 (9‐OCH₃), 51.6 (C‐5), 48.8 (C‐1), 26.0 (C‐6), 21.2 (CH(CH₃)₂), 21.2 (CH(CH₃)₂), 20.6 (C₆H₄ CH₃), 9.8 (7′‐CH₃), 8.7 ppm (8‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3379, 1684, 1476, 1458, 1420, 1373, 1352, 1298, 1275, 1248, 1217, 1192, 1180, 1167, 1109, 1078, 1024, 1001, 816, 808 cm⁻¹; MS (EI): m/z (%): 680 (13) [M]⁺, 526 (41), 525 (100), 440 (23), 439 (92), 221 (13), 220 (54), 205 (11); HRMS (EI): m/z: calcd for C₃₄H₃₆O₁₁N₂S: 680.2040 [M]⁺; found: 680.2039.

(Z)‐{(1R*,5S*)‐1,2,3,4,5,6‐Hexahydro‐2‐[7‐hydroxy‐9,10‐di‐ methoxy‐8,11‐dimethyl‐4‐oxo‐3,4,5,6‐tetrahydro‐1,5‐imino‐ benzo‐[d]azocin‐2(1H)‐ylidene]methyl}‐4‐methylbenzo‐[d][1,3]‐ dioxol‐5‐yl 4‐methylbenzenesulfonate (8)

Anisole (1.1 mL, 10 mmol) and concd. H₂SO₄ (2.4 mL) were successively added to a stirred solution of 7 (1.36 g, 2 mmol) in TFA (47.6 mL) at 0 °C, and the mixture was stirred at 25 °C for 7.5 h. After the mixture was diluted with H₂O (800 mL) at 0 °C, it was made alkaline with concd. NH₄OH (75 mL) and was then extracted with CHCl₃ (2×700 mL) and, finally, CHCl₃/MeOH (9:1, 2×700 mL). The combined extract was dried and concentrated in vacuo to give a residue, which was used in the next step without further purification. An analytical sample of the secondary amine was obtained as a yellow amorphous powder by column chromatography with EtOAc/MeOH (19:1); R _f=0.39 (EtOAc/MeOH 19:1); ¹H NMR (400 MHz, CDCl₃): δ=7.77 (d, J=8.3 Hz, 2 H, C₆ H ₄CH₃), 7.33 (d, J=8.3 Hz, 2 H, C₆ H ₄CH₃), 7.22 (br s, 1 H, NH), 6.42 (s, 1 H, 4′‐H), 5.97 (d, J=1.1 Hz, 1 H, 2′‐H), 5.96 (d, J=1.1 Hz, 1 H, 2′‐H), 5.71 (s, 1 H, 2a‐H), 4.77 (s, 1 H, 1‐H), 3.98 (br s, 1 H, 5‐H), 3.85 (s, 3 H, 10‐OCH₃), 3.78 (s, 3 H, 9‐OCH₃), 3.01–2.92 (overlapped, 2 H, 6‐H₂), 2.46 (s, 3 H, C₆H₄CH ₃), 2.14 (s, 3 H, 8‐CH₃), 1.94 ppm (s, 3 H, 7′‐CH₃); ¹³C NMR (100 MHz, CDCl₃): δ=171.4 (C‐4), 149.7 (C‐9), 148.0 (C‐7), 146.4 (C‐7′a), 145.6 (C‐5′), 145.4 (C‐3′), 143.8 (C‐10), 140.8 (C‐6′), 136.9 (C‐2), 134.1 (C ₆H₄CH₃), 129.7 (C ₆H₄CH₃), 128.2 (C ₆H₄CH₃), 125.6 (C‐6a or 10a), 121.9 (C ₆H₄CH₃), 117.7 (C‐8), 115.5 (C‐7′), 114.6 (C‐6a or 10a), 106.1 (C‐4′), 101.9 (C‐2′), 101.3 (C‐2a), 60.2 (10‐CH₃), 60.1 (9‐OCH₃), 52.4 (C‐5), 48.8 (C‐1), 27.0 (C‐6), 21.7 (C₆H₄ CH₃), 10.5 (7′‐CH₃), 8.8 ppm (8‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3305, 1670, 1476, 1460, 1418, 1350, 1219, 1192, 1179, 1076 cm⁻¹; MS (EI): m/z (%): 594 (8) [M]⁺, 440 (31), 439 (100), 221 (13), 220 (50); HRMS (EI): m/z: calcd for C₃₀H₃₀O₉N₂S: 594.1672 [M]⁺; found: 594.1669.

A 37 % aqueous solution of formaldehyde (8 mL), NaBH₃CN (1.51 g, 24 mmol), and AcOH (26.3 mL) were successively added to a stirred solution of the above product (1.00 g) in MeOH (100 mL) at 0 °C, and the mixture was then stirred at 25 °C for 2 h. The mixture was diluted with H₂O (200 mL), it was made alkaline with concentrated NH₄OH (40 mL) and extracted with CHCl₃ (3×300 mL). The combined extract was washed with brine (200 mL), dried, and concentrated in vacuo to give a residue (2.92 g), which was subjected to column chromatography on SiO₂ (60 g) with hexane/EtOAc (13:7) to afford 8 (833.8 mg, 68 %, two steps) as a colorless amorphous powder; R _f=0.23 (hexane/EtOAc 9:1); ¹H NMR (400 MHz, CDCl₃): δ=7.73 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 7.30 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 6.44 (s, 1 H, 4′‐H), 5.96 (s, 2 H, 2′‐H₂), 5.78 (s, 1 H, 2a‐H), 4.83 (br s, 1 H, NH), 4.53 (s, 1 H, 1‐H), 3.85 (s, 3 H, 10‐OCH₃), 3.78 (s, 3 H, 9‐OCH₃), 3.64 (d, J=7.2 Hz, 1 H, 5‐H), 3.07 (dd, J=17.0, 7.2 Hz, 1 H, 6‐Hα), 2.93 (d, J=17.0 Hz, 1 H, 6‐Hβ), 2.56 (s, 3 H, NCH₃), 2.46 (s, 3 H, C₆H₄CH ₃), 2.15 (s, 3 H, 8‐CH₃), 1.92 ppm (s, 3 H, 7′‐CH₃); ¹³C NMR (100 MHz, CDCl₃): δ=169.9 (C‐4), 149.8 (C‐9), 147.7 (C‐7), 146.4 (C‐7′a), 145.6 (C‐3′a or C ₆H₄CH₃), 145.4 (C‐3′a or C ₆H₄CH₃), 143.9 (C‐10), 140.6 (C‐6′), 134.6 (C‐2 or 6a), 133.7 (C ₆H₄CH₃), 129.8 (C ₆H₄CH₃), 128.3 (C ₆H₄CH₃), 126.0 (C‐10a), 122.3 (C‐5′), 117.1 (C‐8), 115.8 (C‐7′), 113.9 (C‐2 or 6a), 106.2 (C‐4′), 103.9 (C‐2a), 101.9 (C‐2′), 60.3 (10‐OCH₃), 60.2 (9‐OCH₃), 59.1 (C‐5), 55.5 (C‐1), 41.5 (NCH₃), 26.7 (C‐6), 21.7 (C₆H₄ CH₃), 10.4 (7′‐CH₃), 8.7 ppm (8‐CH₃); FTIR (KBr): $\tilde{\nu }$ =1476, 1460, 1418, 1371, 1352, 1215, 1192, 1179, 1165, 1115, 1078, 1063 cm⁻¹; MS (EI): m/z (%): 608 (7) [M]⁺, 454 (28), 453 (100), 235 (14), 234 (47); HRMS (EI): m/z: calcd for C₃₁H₃₂O₉N₂S: 608.1829 [M]⁺; found: 608.1829.

{(1R*,2S*,5S*)‐[7‐Hydroxy‐9,10‐dimethoxy‐8,11‐dimethyl‐4‐ oxo‐1,2,3,4,5,6‐hexahydro‐1,5‐iminobenzo[d]azocin‐2‐yl]‐ methyl}‐4‐methylbenzo[d][1,3]dioxol‐5‐yl 4‐methylbenzene‐ sulfonate (9)

A suspension of 8 (608.7 mg, 1 mmol) in EtOH (25 mL) was hydrogenated over 20 % Pd(OH)₂ on carbon (280.9 mg) at 80 °C for 27 h under a hydrogen atmosphere (2.8 MPa). The catalyst was removed by filtration, and the residue trapped by the filter paper was washed with CHCl₃ and MeOH. The combined filtrate was concentrated in vacuo to give a residue, which was subjected to column chromatography on SiO₂ (15 g) with EtOAc/MeOH (9:1) to afford 9 (472.3 mg, 77 %) as a colorless amorphous powder; R _f=0.23 (EtOAc/MeOH 19:1); ¹H NMR (400 MHz, CDCl₃): δ=7.66 (d, J=8.0 Hz, 2 H, C₆ H ₄CH₃), 7.33 (d, J=8.0 Hz, 2 H, C₆ H ₄CH₃), 6.49 (s, 1 H, 4′‐H), 5.97 (d, J=1.5 Hz, 1 H, 2′‐H), 5.96 (d, J=1.5 Hz, 1 H, 2′‐H), 4.21–4.14 (overlapped, 2 H, 1‐H & 2‐H), 3.83 (s, 3 H, 10‐OCH₃), 3.82 (s, 3 H, 9‐OCH₃), 3.59 (d, J=7.2 Hz, 1 H, 5‐H), 3.48 (dd, J=14.6, 2.4 Hz, 1 H, 2a‐Hα), 2.96 (dd, J=17.2, 7.2 Hz, 1 H, 6‐Hα), 2.78 (d, J=17.2 Hz, 1 H, 6‐Hβ), 2.47 (s, 3 H, C₆H₄CH ₃), 2.45 (s, 3 H, NCH₃), 2.24–2.15 (overlapped, 1 H, 2a‐Hβ), 2.19 (s, 3 H, 8‐CH₃), 1.95 ppm (s, 3 H, 7′‐CH₃); ¹³C NMR (100 MHz, CDCl₃): δ=172.2 (C‐4), 149.8 (C‐9), 147.9 (C‐7), 146.1 (C‐7′a), 145.7 (C‐3′a), 145.3 (C ₆H₄CH₃), 144.8 (C‐10), 141.2 (C‐6′), 133.7 (C ₆H₄CH₃), 129.9 (C ₆H₄CH₃), 127.9 (C ₆H₄CH₃), 124.6 (C‐5′), 121.8 (C‐6a or 10a), 117.5 (C‐8), 115.4 (C‐7′), 114.6 (C‐6a or 10a), 107.5 (C‐4′), 101.8 (C‐2′), 60.5 (9‐OCH₃), 60.2 (10‐OCH₃), 58.1 (C‐5), 55.9 (C‐2), 54.4 (C‐1), 40.1 (NCH₃), 33.3 (C‐2a), 23.1 (C‐6), 21.8 (C₆H₄ CH₃), 10.6 (7′‐CH₃), 8.9 ppm (8‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3364, 2936, 1736, 1661, 1476, 1456, 1418, 1344, 1194, 1180, 1076, 1055 cm⁻¹; MS (EI): m/z (%): 610 (9) [M]⁺, 456 (10), 455 (19), 235 (28), 234 (100); HRMS (EI): m/z: calcd for C₃₁H₃₄O₉N₂S: 610.1985 [M]⁺; found: 610.1987.

(1R*,2S*,5S*)‐7‐(Allyloxy)‐2‐[(6‐hydroxy‐7‐methylbenzo[d]‐ [1,3]dioxol‐5‐yl)methyl]‐9,10‐dimethoxy‐8,11‐dimethyl‐ 2,3,5,6‐tetrahydro‐1,5‐iminobenzo[d]azocin‐4(1H)‐one (10)

A solution of 9 (1.36 g, 2.23 mmol) in acetone (110 mL) was stirred in the presence of K₂CO₃ (1.55 g, 11.14 mmol) at 0 °C, allyl bromide (385 μL, 4.45 mmol) was added over 10 min, and the mixture was heated at reflux for 5.5 h. The mixture was filtered, and the combined filtrate was concentrated in vacuo to give a residue, which was used in the next step without further purification. An analytical sample was obtained as a colorless amorphous powder by column chromatography with EtOAc to EtOAc/MeOH (19:1); R _f=0.21 (CHCl₃/MeOH 97:3); ¹H NMR (400 MHz, CDCl₃): δ=7.65 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 7.34 (d, J=8.5 Hz, 2 H, C₆ H ₄CH₃), 6.50 (s, 1 H, 4′‐H), 6.09 (ddt, J=17.2, 10.7, 5.4 Hz, 1 H, OCH₂CH=CH₂), 5.96 (d, J=1.2 Hz, 1 H, 2′‐H), 5.95 (d, J=1.2 Hz, 1 H, 2′‐H), 5.45 (dq, J=17.2, 1.5 Hz, 1 H, OCH₂CH=CH ₂), 5.27 (dq, J=10.7, 1.5 Hz, 1 H, OCH₂CH=CH ₂), 5.20 (s, 1 H, NH), 4.33 (ddt, J=12.7, 5.4, 1.5 Hz, 1 H, OCH ₂CH=CH₂), 4.28 (ddt, J=12.7, 5.4, 1.5 Hz, 1 H, OCH ₂CH=CH₂), 4.20–4.15 (overlapped, 2 H, 1‐H and 2‐H), 3.87 (s, 3 H, 10‐OCH₃), 3.82 (s, 3 H, 9‐OCH₃), 3.54 (d, J=7.1 Hz, 1 H, 5‐H), 3.45 (dd, J=14.4, 1.7 Hz, 1 H, 2a‐Hα), 3.07 (dd, J=18.0, 7.1 Hz, 1 H, 6‐Hα), 2.95 (d, J=18.0 Hz, 1 H, 6‐Hβ), 2.47 (s, 6 H, C₆H₄CH ₃ & NCH₃), 2.22 (s, 3 H, 8‐CH₃), 2.25–2.18 (overlapped, 1 H, 2a‐Hβ), 1.94 ppm (s, 3 H, 7′‐CH₃); ¹³C NMR (100 MHz, CDCl₃): δ=172.1 (C‐4), 151.2 (C‐7), 149.8 (C‐9), 147.4 (C‐10), 146.1 (C‐3′a or 7′a), 145.6 (C‐3′a or 7′a), 145.4 (C ₆H₄CH₃), 141.1 (C‐6′), 133.8 (OCH₂ CH=CH₂), 133.6 (C ₆H₄CH₃), 129.9 (C ₆H₄CH₃), 127.8 (C ₆H₄CH₃), 125.0 (C‐8), 124.6 (C‐5′), 122.4 (C‐6a or 10a), 122.3 (C‐6a or 10a), 117.1 (OCH₂CH=CH₂), 115.3 (C‐7′), 107.5 (C‐4′), 101.8 (C‐2′), 72.9 (OCH₂CH=CH₂), 60.2 (9‐OCH₃), 60.1 (10‐OCH₃), 58.2 (C‐5), 55.5 (C‐2), 54.4 (C‐1), 40.3 (NCH₃), 33.3 (C‐2a), 24.2 (C‐6), 21.7 (C₆H₄ CH₃), 10.6 (7′‐CH₃), 9.7 ppm (8‐CH₃); FTIR (KBr): $\tilde{\nu }$ =1674, 1476, 1450, 1414, 1358, 1339, 1192, 1180, 1113, 1076 cm⁻¹; MS (EI): m/z (%): 650 (18) [M]⁺, 610 (14), 609 (38), 496 (22), 495 (38), 275 (29), 274 (100), 235 (12), 234 (39), 233 (17), 219 (11), 218 (36); HRMS (EI): m/z: calcd for C₃₄H₃₈O₉N₂S: 650.2298 [M]⁺; found: 650.2294.

A solution of KOH (7.35 g, 0.111 mmol) in H₂O (33 mL) was added dropwise to a stirred solution of the above product (1.54 g) in EtOH (33 mL) at 25 °C, and the mixture was heated at reflux for 3 h. The mixture was diluted with H₂O (130 mL), neutralized with 6 m aq HCl solution, and extracted with CHCl₃ (3×200 mL). The combined extract was washed with brine (200 mL), dried, and concentrated in vacuo to give a residue (1.10 g), which was subjected to column chromatography on SiO₂ (30 g) with CHCl₃/MeOH (97:3) to afford 10 (889.1 mg, 80 %, two steps) as a brown amorphous powder; R _f=0.24 (CHCl₃/MeOH 97:3); ¹H NMR (400 MHz, CDCl₃): δ=6.39 (s, 1 H, 4′‐H), 6.06 (ddt, J=17.6, 10.6, 5.5 Hz, 1 H, OCH₂CH=CH₂), 5.91 (br s, 1 H, NH), 5.87 (d, J=1.4 Hz, 1 H, 2′‐H), 5.85 (d, J=1.4 Hz, 1 H, 2′‐H), 5.41 (br dd, J=17.6, 1.4 Hz, 1 H, OCH₂CH=CH ₂), 5.24 (br dd, J=10.7, 1.4 Hz, 1 H, OCH₂CH=CH ₂), 4.30 (ddt, J=12.5, 5.5, 1.4 Hz, 1 H, OCH ₂CH=CH₂), 4.27 (ddt, J=12.5, 5.5, 1.4 Hz, 1 H, OCH ₂CH=CH₂), 4.21–4.18 (overlapped, 2 H, 1‐H & 2‐H), 3.83 (s, 3 H, 10‐OCH₃), 3.80 (s, 3 H, 9‐OCH₃), 3.55 (d, J=7.2 Hz, 1 H, 5‐H), 3.20 (d, J=14.5 Hz, 1 H, 2a‐Hα), 3.06 (dd, J=17.5, 7.2 Hz, 1 H, 6‐Hα), 2.95 (d, J=17.5 Hz, 1 H, 6‐Hβ), 2.48 (s, 3 H, NCH₃), 2.21 (s, 3 H, 8‐CH₃), 2.10 (s, 3 H, 7′‐CH₃), 2.02 ppm (dd, J=14.5, 10.4 Hz, 1 H, 2a‐Hβ); ¹³C NMR (100 MHz, CDCl₃): δ=172.3 (C‐4), 151.3 (C‐7), 149.8 (C‐9), 147.3 (C‐10 or 6′), 147.1 (C‐10 or 6′), 145.5 (C‐7′a), 140.8 (C‐3′a), 133.7 (OCH₂ CH=CH₂), 125.0 (C‐8), 122.5 (C‐6a or 10a), 122.4 (C‐6a or 10a), 117.3 (OCH₂CH=CH₂), 115.6 (C‐5′), 107.8 (C‐7′), 107.5 (C‐4′), 100.8 (C‐2′), 73.0 (OCH₂CH=CH₂), 60.2 (10‐OCH₃), 60.1 (9‐OCH₃), 58.0 (C‐5), 56.0 (C‐2), 54.4 (C‐1), 40.3 (NCH₃), 32.4 (C‐2a), 24.2 (C‐6), 9.7 (8‐CH₃), 9.0 ppm (7′‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3370, 2936, 1655, 1476, 1456, 1412, 1339, 1252, 1238, 1184, 1111, 1092, 1076, 1057 cm⁻¹; MS (EI): m/z (%): 497 (29), 496 (100) [M]⁺, 456 (18), 455 (48), 275 (28), 274 (89), 260 (14), 234 (39), 233 (24), 219 (13), 218 (47); HRMS (EI): m/z: calcd for C₂₇H₃₂N₂O₇: 496.2210 [M]⁺; found: 496.2211.

(1R*,2S*,4R*,5S*)‐7‐(Allyloxy)‐2‐[(6‐hydroxy‐7‐methylbenzo[d]‐ [1,3]dioxol‐5‐yl)methyl]‐9,10‐dimethoxy‐8,11‐dimethyl‐1,2,3,‐ 4,5,6‐hexahydro‐1,5‐iminobenzo[d]azocine‐4‐carbo‐nitrile (11)

A suspension of Cp₂ZrHCl (31.9 mg, 0.12 mmol) in THF (0.5 mL) was added to a stirred solution of 10 (19.9 mg, 0.04 mmol) in THF (1 mL) at −20 °C, and the mixture was warmed to 0 °C over 1 h. A solution of KCN (20.8 mg, 0.32 mmol) in H₂O (640 μL) was added to the above solution, and the mixture was stirred at 25 °C for 4 h. The mixture was diluted with saturated aqueous NaHCO₃ solution (10 mL) and extracted with CHCl₃ (3×15 mL). The combined extract was washed with brine (10 mL), dried, and concentrated in vacuo to give a residue (21.5 mg), which was subjected to column chromatography on SiO₂ (6 g) with CHCl₃ to give 11 (19.4 mg, 96 %) as a brown amorphous powder; R _f=0.40 (hexane/CHCl₃ 1:4); ¹H NMR (400 MHz, CDCl₃): δ=6.43 (s, 1 H, 4′‐H), 6.09 (ddt, J=17.3, 10.6, 5.4 Hz, 1 H, OCH₂CH=CH₂), 5.86 (d, J=1.4 Hz, 1 H, 2′‐H), 5.85 (d, J=1.4 Hz, 1 H, 2′‐H), 5.44 (dq, J=17.3, 1.5 Hz, 1 H, OCH₂CH=CH ₂), 5.28 (dq, J=10.6, 1.5 Hz, 1 H, OCH₂CH=CH ₂), 4.34 (ddt, J=12.7, 5.4, 1.5 Hz, 1 H, OCH ₂CH=CH₂), 4.29 (ddt, J=12.7, 5.4, 1.5 Hz, 1 H, OCH ₂CH=CH₂), 4.08 (d, J=2.7 Hz, 1 H, 1‐H), 3.97 (d, J=1.5 Hz, 1 H, 4‐H), 3.82 (s, 3 H, 10‐OCH₃), 3.80 (s, 3 H, 9‐OCH₃), 3.64 (dt, J=10.2, 2.7 Hz, 1 H, 2‐H), 3.28 (dd, J=7.8, 1.5 Hz, 1 H, 5‐H), 3.03 (dd, J=18.7, 7.8 Hz, 1 H, 6‐Hα), 2.91 (dd, J=14.9, 2.7 Hz, 1 H, 2a‐Hα), 2.45 (d, J=18.7 Hz, 1 H, 6‐Hβ), 2.32 (s, 3 H, NCH₃), 2.21 (s, 3 H, 8‐CH₃), 2.08 (s, 3 H, 7′‐CH₃), 2.02 ppm (dd, J=14.9, 10.2 Hz, 1 H, 2a‐Hβ); ¹³C NMR (100 MHz, CDCl₃): δ=150.6 (C‐7), 150.0 (C‐9), 148.2 (C‐6′), 147.6 (C‐10), 145.4 (C‐7′a), 140.2 (C‐3′a), 133.7 (OCH₂ CH=CH₂), 124.5 (C‐8), 123.0 (C‐6a), 122.0 (C‐10a), 119.0 (CN), 117.3 (OCH₂CH=CH₂), 115.8 (C‐5′), 108.8 (C‐7′), 107.2 (C‐4′), 100.7 (C‐2′), 72.9 (OCH₂CH=CH₂), 60.4 (10‐OCH₃), 60.2 (9‐OCH₃), 57.7 (C‐2), 56.6 (C‐1), 53.9 (C‐5), 53.5 (C‐4), 42.0 (NCH₃), 34.2 (C‐2a), 21.3 (C‐6), 9.7 (8‐CH₃), 9.1 ppm (7′‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3447, 2936, 2361, 1458, 1412, 1250, 1111, 1092, 1074, 1055, 1042, 1020 cm⁻¹; MS (FAB): m/z (%): 508 [M+H]⁺; HRMS (FAB): m/z: calcd for C₂₈H₃₄N₃O₆: 508.2448 [M]⁺; found: 508.2452.

(1R*,2S*,5S*)‐tert‐Butyl 7‐(allyloxy)‐2‐{(6′‐[(tert‐butoxy‐ carbonyl)oxy‐7′‐methylbenzo‐[d][1,3]dioxol‐5‐yl]methyl}‐ 9,10‐dimethoxy‐8,11‐dimethyl‐4‐oxo‐1,2,5,6‐tetrahydro‐1,5‐ iminobenzo[d]azocine‐3(4H)‐carboxylate (13)

A mixture of 10 (568.5 mg, 1.14 mmol) and DMAP (279.4 mg, 2.29 mmol, 2 equiv) in MeCN (11.5 mL) was cooled at 0 °C; then, Boc₂O (5.3 mL, 22.90 mmol, 20 equiv.) was added to the mixture, which was heated at reflux for 17.5 h. As the starting material still remained, as indicated by TLC monitoring, DMAP (279.4 mg, 2.29 mmol, 2 equiv.) was added to the mixture at 25 °C, and the reaction mixture was heated under reflux for an additional 40 h. The mixture was diluted with H₂O (30 mL) and extracted with CHCl₃ (3×50 mL). The combined extract was washed with brine (50 mL), dried, and concentrated in vacuo to give a residue, which was subjected to column chromatography on SiO₂ (15 g) with hexane/EtOAc (11:9) to afford 13 (570.9 mg, 72 %) as a brown amorphous powder; R _f=0.30 (hexane/EtOAc 11:9); ¹H NMR (400 MHz, CDCl₃): δ=6.55 (s, 1 H, 4′‐H), 6.07 (ddt, J=17.3, 10.6, 5.4 Hz, 1 H, CH₂CH=CH₂), 5.90 (s, 2 H, 2′‐H₂), 5.42 (dq, J=17.3, 1.5 Hz, 1 H, CH₂CH=CH ₂), 5.26 (dq, J=10.6, 1.5 Hz, 1 H, CH₂CH=CH ₂), 4.99 (q, J=6.2 Hz, 1 H, 2‐H), 4.39 (dd, J=6.2, 1.5 Hz, 1 H, 1‐H), 4.32 (ddt, J=12.4, 5.4, 1.5 Hz, 1 H, CH ₂CH=CH₂), 4.26 (ddt, J=12.4, 5.4, 1.5 Hz, 1 H, CH ₂CH=CH₂), 3.77 (dd, J=7.7, 1.5 Hz, 1 H, 5‐H), 3.72 (s, 3 H, 9‐OCH₃), 3.61 (s, 3 H, 10‐OCH₃), 3.07 (dd, J=18.5, 7.7 Hz, 1 H, 6H‐α), 2.96 (dd, J=18.5, 1.5 Hz, 1 H, 6‐Hβ), 2.91 (dd, J=15.6, 6.2 Hz, 1 H, 2a‐Hα), 2.46 (s, 3 H, NCH₃), 2.18 (s, 3 H, 8‐CH₃), 2.05 (s, 3 H, 7′‐CH₃), 1.99 (dd, J=15.6, 6.2 Hz, 1 H, 2a‐Hβ), 1.49 (s, 9 H, C(CH ₃)₃), 1.31 ppm (s, 9 H, C(CH ₃)₃); ¹³C NMR (100 MHz, CDCl₃): δ=173.2 (C‐4), 151.6 (CO₂), 151.5 (CO₂), 151.1 (C‐7), 149.8 (C‐9), 147.6 (C‐10), 144.7 (C‐7′a), 144.3 (C‐3′a), 142.6 (C‐6′), 133.7 (CH₂ CH=CH₂), 125.1 (C‐8), 124.0 (C‐5′), 122.9 (C‐10a), 121.8 (C‐6a), 117.3 (CH₂CH=CH₂), 112.9 (C‐7′), 105.7 (C‐4′), 101.2 (C‐2′), 83.5 (C(CH₃)₃), 82.9 (C(CH₃)₃), 73.1 (CH₂CH=CH₂), 60.1 (10‐OCH₃), 59.8 (9‐OCH₃), 59.8 (C‐5), 57.8 (C‐2), 54.0 (C‐1), 40.0 (NCH₃), 32.3 (C‐2a), 27.6 (C(CH₃)₃), 27.5 (C(CH₃)₃), 22.7 (C‐6), 9.6 (8‐CH₃), 9.4 ppm (7′‐CH₃); FTIR (KBr): $\tilde{\nu }$ =1757, 1732, 1697, 1477, 1456, 1412, 1395, 1369, 1341, 1275, 1256, 1152, 1099, 1063 cm⁻¹; MS (EI): m/z (%): 696 (4) [M]⁺, 596 (13), 555 (13), 497 (14), 496 (47), 455 (24), 275 (31), 274 (100), 271 (14), 260 (11), 234 (32), 233 (22), 232 (12), 219 (11), 218 (38), 57 (14); HRMS (EI): m/z: calcd C₃₇H₄₈N₂O₁₁: 696.3258 [M]⁺; found: 696.3256.

1. ‐(2′S*)‐(1“R,3”S)‐[(5“‐Allyloxy‐3”‐hydroxymethyl‐7“, 8”‐di‐ methoxy‐2“,6”‐dimethyl‐1“,2”,3“,4”‐tetrahydroisoquinolin‐ 1“‐yl)‐2′‐aminoethyl]‐4‐methylbenzo[d][1,3]dioxol‐5‐ol (14)

NaBH₄ (892.4 g, 23.59 mmol) was added to a stirred solution of 13 (821.8 mg, 1.179 mmol) in EtOH (12 mL) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was diluted with saturated aqueous NH₄Cl (10 mL) and H₂O (40 mL) at 0 °C and extracted with CHCl₃ (3×50 mL). The combined extract was washed with brine (30 mL), dried, and concentrated in vacuo to give a residue, which was used in the next step without further purification. An analytical sample of the protected compound (857.3 mg) was obtained as a colorless amorphous powder by column chromatography with hexane/EtOAc (13:7); R _f=0.21 (hexane/EtOAc 7:3); ¹H NMR (400 MHz, CDCl₃): δ=6.60 (s, 1 H, 4“‐H), 6.05 (ddt, J=17.1, 10.8, 5.6 Hz, 1 H, CH₂CH=CH₂), 5.90 (d, J=1.4 Hz, 1 H, 2”‐H), 5.88 (d, J=1.4 Hz, 1 H, 2“‐H), 5.38 (dd, J=17.1, 1.4 Hz, 1 H, CH₂CH=CH ₂), 5.22 (dd, J=10.8, 1.4 Hz, 1 H, CH₂CH=CH ₂), 4.49 (br d, J=9.5 Hz, 1 H, 1‐H), 4.27 (dd, J=12.5, 5.6 Hz, 1 H, CH ₂CH=CH₂), 4.12 (dd, J=12.5, 5.6 Hz, 1 H, CH ₂CH=CH₂), 3.88–3.76 (overlapped, 1 H, 2‐H), 3.86 (s, 3 H, 8′‐OCH₃), 3.83 (s, 3 H, 7′‐OCH₃), 3.77 (d, J=9.5 Hz, 1 H, 1′‐H), 3.48 (dd, J=11.3, 3.3 Hz, 1 H, 2‐H), 3.13 (br d, J=13.1 Hz, 1 H, 3′a‐H), 2.88 (dd, J=15.5, 4.8 Hz, 1 H, 4′‐H), 2.75 (dd, J=15.5, 12.6 Hz, 1 H, 4′‐H), 2.50 (s, 3 H, NCH₃), 2.38 (m, 1 H, 3′‐ and 3′a‐H), 2.17 (s, 3 H; 6′‐CH₃), 2.06 (s, 3 H, 7”‐CH₃), 1.57 (s, 9 H, C(CH ₃)₃), 1.14 ppm (s, 9 H, C(CH ₃)₃); ¹³C NMR (100 MHz, CDCl₃): δ=155.0 (CO), 151.9 (CO), 150.0 (C‐5′), 149.0 (C‐7′), 146.5 (C‐8′), 145.0 (C‐7“a), 144.6 (C‐3”a), 142.4 (C‐6“), 133.9 (CH₂ CH=CH₂), 126.7 (C‐4′a or 8′a), 125.9 (C‐4′a or 8′a), 124.0 (C‐6′ or 5”), 123.8 (C‐6′ or 5“), 117.4 (CH₂CH=CH₂), 112.9 (C‐7”), 106.8 (C‐4“), 101.2 (C‐2”), 83.5 (C(CH₃)₃), 78.3 (C(CH₃)₃), 74.1 (CH₂CH=CH₂), 64.4 (C‐2), 63.7 (C‐1′), 63.1 (C‐3′), 60.5 (8′‐OCH₃), 60.1 (7′‐OCH₃), 55.6 (C‐1), 46.6 (NCH₃), 32.6 (C‐3′a), 28.1 (C(CH₃)₃), 27.6 (C(CH₃)₃), 24.4 (C‐4′), 9.50 (6′‐CH₃), 9.45 ppm (7“‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3422, 2978, 2930, 1751, 1715, 1516, 1477, 1458, 1369, 1281, 1258, 1153, 1101, 1063 cm⁻¹; MS (FAB): m/z (%): 701 [M+H]⁺; HRMS (FAB): m/z: calcd for C₃₇H₅₃N₂O₁₁: 701.3649 [M]⁺; found: 701.3646.

TFA (18 mL) was added to a stirred solution of the crude product in CH₂Cl₂ (36 mL) at 0 °C, and the mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with H₂O (40 mL) at 0 °C, made alkaline with concentrated NH₄OH (30 mL), and extracted with CHCl₃ (3×80 mL). The combined extract was washed with brine (60 mL), dried, and concentrated in vacuo to give a residue (568.6 mg), which was subjected to column chromatography on SiO₂ (15 g) with CHCl₃/MeOH (97:3) to afford 14 (433.2 mg, 73 %, two steps) as a brown amorphous powder; R _f=0.19 (CHCl₃/MeOH 97:3); ¹H NMR (400 MHz, CDCl₃): δ=6.44 (s, 1 H, 7‐H), 6.05 (ddt, J=17.0, 10.4, 5.6 Hz, 1 H, CH₂CH=CH₂), 5.87 (d, J=1.4 Hz, 1 H, 2‐H), 5.82 (d, J=1.4 Hz, 1 H, 2‐H), 5.37 (dq, J=17.0, 1.4 Hz, 1 H, CH₂CH=CH ₂), 5.25 (dq, J=10.4, 1.4 Hz, 1 H, CH₂CH=CH ₂), 4.25 (ddt, J=11.1, 5.6, 1.4 Hz, 1 H, CH ₂CH=CH₂), 4.19 (ddt, J=11.1, 5.6, 1.4 Hz, 1 H, CH ₂CH=CH₂), 3.84 (s, 3 H, 8“‐OCH₃), 3.80 (s, 3 H, 7”‐OCH₃), 3.79 (dd, J=10.5, 4.0 Hz, 1 H, 3“a‐H), 3.67 (d, J=9.4 Hz, 1 H, 1”‐H), 3.46 (dd, J=10.5, 2.6 Hz, 1 H, 3′a‐H), 3.14 (d, J=13.6 Hz, 1 H, 1′‐H), 2.95 (d, J=11.0 Hz, 1 H, 4“‐H), 2.75 (dd, J=13.6, 9.4 Hz, 1 H, 1′‐H), 2.69 (t, J=9.4 Hz, 1 H, 2′‐H), 2.51 (s, 3 H, NCH₃), 2.42–2.32 (overlapped, 2 H, 3”‐ & 4“‐H), 2.21 (s, 3 H, 6”‐CH₃), 2.11 ppm (s, 3 H, 4‐CH₃); ¹³C NMR (100 MHz, CDCl₃): δ=150.6 (C‐5 or 5“), 150.4 (C‐5 or 5”), 149.7 (C‐7“), 146.9 (C‐8”), 145.4 (C‐3a), 139.3 (C‐7a), 133.5 (CH₂ CH=CH₂), 126.7 (C‐8“a), 124.8 (C‐4”a or 6“), 124.6 (C‐4”a or 6“), 117.7 (CH₂CH=CH₂), 117.6 (C‐6), 109.3 (C‐4), 107.0 (C‐7), 100.5 (C‐2), 74.5 (CH₂CH=CH₂), 65.0 (C‐1”), 63.9 (C‐3“a), 63.0 (C‐3”), 60.7 (8“‐OCH₃), 60.1 (7”‐OCH₃), 59.1 (C‐2′), 46.6 (NCH₃), 38.2 (C‐1′), 24.3 (C‐4“), 9.7 (6”‐CH₃), 9.3 ppm (4‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3441, 3370, 2938, 2866, 1470, 1414, 1248, 1115, 1094, 1057, 934 cm⁻¹; MS (EI): m/z (%): 500 (1) [M]⁺, 307 (18), 306 (100), 234 (15), 218 (10); HRMS (EI): m/z: calcd C₂₇H₃₆N₂O₇: 500.2523 [M]⁺; found: 500.2520.

(6aS*,7R*,13S*,14R*,16R*)‐Ethyl 5‐(benzyloxy)‐14‐cyano‐11‐ hydroxy‐8,9‐dimethoxy‐4,10,17‐trimethyl‐6a,7,12,13,14,16‐ hexahydro‐6H‐7,13‐iminobenzo[4,5]azocino‐[1,2‐b]‐[1,3]‐ dioxolo[4,5‐h]isoquinoline‐16‐carboxylate (18)

14→15: A solution of 1‐allyl 3‐ethyl 2,2‐dihydroxymalonate20 (238.2 mg, 1.167 mmol) in TFA (6 mL) was added to a stirred solution of 14 (116.8 mg, 0.233 mmol) in AcOH (1.5 mL), and the mixture was stirred at 25 °C for 6 h. The mixture was diluted with H₂O (60 mL) at 0 °C, made alkaline with concentrated NH₄OH (11 mL), and extracted with CHCl₃ (3×80 mL). The combined extract was washed with brine (40 mL), dried, and concentrated in vacuo to give a residue (358.9 mg), which was subjected to column chromatography on SiO₂ (10 g) with hexane/EtOAc (2:3) to afford an inseparable 1:1 diastereomer mixture of 15 (124.9 mg, 80 %) as a yellow amorphous powder.

15→16: BnBr (533 μL, 4.40 mmol) was added to a stirred solution of 15 (147.1 mg, 0.22 mmol) in the presence of K₂CO₃ (763.9 mg, 5.50 mmol) in acetone (55 mL), and the mixture was stirred at 25 °C for 8 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was subjected to column chromatography on SiO₂ (6 g) with hexane/EtOAc (1:1) to afford an inseparable 1:1 diastereomer mixture of 16 (137.2 mg, 83 %) as a yellow amorphous powder.

16→17: (COCl)₂ (25 μL, 0.3 mmol) was added to a stirred solution of DMSO (43 μL, 0.6 mmol) in CH₂Cl₂ (1 mL) at −78 °C, and the mixture was stirred at −78 °C for 15 min. A solution of 16 (45.5 mg, 60 μmol) in CH₂Cl₂ (1 mL) was added to the above solution at −78 °C over 10 min, and the mixture was stirred at −78 °C for 4 h. Et₃N (167 μL, 1.2 mmol) was then added to the mixture at −78 °C over 5 min, and stirring was continued at −78 °C for 30 min. After the mixture was warmed to 25 °C over a period of 3 h and stirred for 2 h, it was diluted with saturated aqueous NaHCO₃ solution (5 mL) at 0 °C and extracted with CHCl₃ (3×10 mL). The combined extract was washed with brine (10 mL), dried, and concentrated in vacuo to give a residue that was used in the next step without purification. A solution of KCN (31.9 mg, 0.48 mmol) in H₂O (960 μL) was added to a stirred solution of the crude product (63.4 mg) in THF (1 mL) in the presence of AcOH (381 μL, 6.6 mmol) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with saturated aqueous NaHCO₃ (5 mL) at 0 °C and extracted with CHCl₃ (3×10 mL). The combined extract was washed with brine (10 mL), dried, and concentrated in vacuo to give a residue (41.5 mg), which was subjected to column chromatography on SiO₂ (6 g) with hexane/EtOAc (3:1) to afford an inseparable 1:1 diastereomer mixture of 17 (25.8 mg, 56 %, two steps) as a colorless amorphous powder.

17→18: A solution of Pd(PPh₃)₄ (16.4 mg, 13.8 μmol) in THF (1.0 mL) was added to a stirred solution of 17 (35.2 mg, 46 μmol) and dimedone (32.6 mg, 0.23 mmol) in THF (2.0 mL) under an argon atmosphere, and the mixture was stirred at 25 °C for 1 h. After the mixture was concentrated in vacuo, the resulting residue was dissolved in CHCl₃ (2.5 mL) and heated at reflux for 2 h. The mixture was concentrated in vacuo to give a residue, which was subjected to column chromatography on SiO₂ (6 g) with CHCl₃/EtOAc (4:1) to afford 18 (21.2 mg, 72 %, two steps) as a pale‐yellow amorphous powder; R _f=0.20 (CHCl₃/EtOAc 4:1); ¹H NMR (400 MHz, CDCl₃): δ=7.56 (m, 2 H, C₆H₅), 7.46 (m, 2 H, C₆H₅), 7.40 (m, 1 H, C₆H₅), 5.94 (d, J=1.4 Hz, 1 H, 2‐H), 5.89 (d, J=1.4 Hz, 1 H, 2‐H), 4.70 (d, J=10.4 Hz, 1 H, PhCH₂), 4.58 (d, J=10.4 Hz, 1 H, PhCH₂), 4.47 (s, 1 H, 16‐H), 4.39 (br s, 1 H, OH), 4.27 (d, J=2.5 Hz, 1 H, 14‐H), 4.07 (dq, J=10.9, 7.1 Hz, 1 H, CH ₂CH₃), 4.04 (br d, J=2.6 Hz, 1 H, 7‐H), 3.95 (dq, J=10.9, 7.1 Hz, 1 H, CH ₂CH₃), 3.77 (s, 3 H, 8‐OCH₃), 3.72 (s, 3 H, 9‐OCH₃), 3.43 (br d, J=8.1 Hz, 1 H, 13‐H), 3.30 (dd, J=15.4, 2.6 Hz, 1 H, 6H‐α), 3.20 (dt, J=11.7, 2.6 Hz, 1 H, 6a‐H), 2.91 (dd, J=17.6, 8.1 Hz, 1 H, 12‐Hα), 2.33 (d, J=17.6 Hz, 1 H, 12‐Hβ), 2.32 (s, 3 H, NCH₃), 2.17 (s, 3 H, 4‐CH₃), 2.13 (s, 3 H, 10‐CH₃), 2.02 (dd, J=15.4, 11.7 Hz, 1 H, 6‐Hβ), 1.04 ppm (t, J=7.1 Hz, 3 H, CH₂CH ₃); ¹³C NMR (100 MHz, CDCl₃): δ=170.5 (CO), 149.0 (C‐9), 148.2 (C‐5), 146.5 (C‐11), 144.9 (C‐8), 144.4 (C‐3a), 140.0 (C‐16b), 137.1 (C₆H₅), 128.6 (C₆H₅), 128.5 (C₆H₅), 128.3 (C₆H₅), 123.0 (C‐7a), 121.1 (C‐5a or 16a), 117.6 (CN), 116.1 (C‐11a), 115.6 (C‐10), 113.1 (C‐4), 109.9 (C‐5a or 16a), 101.4 (C‐2), 75.3 (PhCH₂), 61.3 (CH₂CH₃), 61.1 (C‐14), 60.3 (C‐16, 8 & 9‐OCH₃), 56.8 (C‐6a & 7), 54.9 (C‐13), 41.8 (NCH₃), 26.3 (C‐6), 21.0 (C‐12), 13.7 (CH₂ CH₃), 9.4 (4‐CH₃), 8.6 ppm (10‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3437, 2934, 2228, 1728, 1456, 1431, 1416, 1344, 1254, 1109, 1092, 1074, 1028 cm⁻¹; MS (EI): m/z (%): 641 (7) [M]⁺, 543 (14), 541 (17), 523 (19), 451 (23), 450 (18), 274 (40), 235 (33), 234 (100); HRMS (EI): m/z: calcd for C₃₆H₃₉N₃O₈: 641.2737 [M]⁺; found: 641.2735.

(6aS*,7R*,13S*,14R*,16R*)‐5‐(Benzyloxy)‐11‐hydroxy‐16‐ (hydroxymethyl)‐8,9‐dimethoxy‐4,10,17‐trimethyl‐6a,7,12,‐ 13,14,16‐hexahydro‐6H‐7,13‐iminobenzo[4,5]azocino‐[1,2‐b]‐ [1,3]‐dioxolo[4,5‐h]isoquinoline‐14‐carbonitrile (19)

LiBH₄ (6.4 mg, 0.281 mmol) was added to a stirred solution of 18 (18.0 mg, 28.1 μmol) in THF (1 mL) and MeOH (11 μL, 0.281 mmol), and the mixture was stirred at 25 °C for 3 h. After the mixture was diluted with brine (5 mL) slowly at 0 °C, it was extracted with CHCl₃ (2×10 mL) and then CHCl₃/MeOH (19:1, 2×10 mL). The combined extract was dried and concentrated in vacuo to give a residue (19.6 mg), which was subjected to column chromatography on SiO₂ (6 g) with CHCl₃/EtOAc (3:2) to afford 19 (11.9 mg, 71 %) as a colorless amorphous powder; R _f=0.24 (hexane/EtOAc 2:3); ¹H NMR (400 MHz, CDCl₃): δ=7.56 (m, 2 H, C₆H₅), 7.46 (m, 2 H, C₆H₅), 7.40 (m, 1 H, C₆H₅), 5.95 (d, J=1.4 Hz, 1 H, 2‐H), 5.89 (d, J=1.4 Hz, 1 H, 2‐H), 4.67 (d, J=10.4 Hz, 1 H, PhCH₂), 4.58 (br s, 1 H, OH), 4.55 (d, J=10.4 Hz, 1 H, PhCH₂), 4.08 (d, J=2.3 Hz, 1 H, 14‐H), 4.07 (d, J=2.5 Hz, 1 H, 7‐H), 4.01 (t, J=3.3 Hz, 1 H, 16‐H), 3.77 (s, 3 H, 8‐OCH₃), 3.70 (s, 3 H, 9‐OCH₃), 3.68 (br d, J=11.3 Hz, 1 H, CH ₂OH), 3.50 (dd, J=11.3, 3.3 Hz, 1 H, CH ₂OH), 3.47 (br d, J=9.0 Hz, 1 H, 13‐H), 3.31 (dt, J=12.8, 2.5 Hz, 1 H, 6a‐H), 3.31 (dd, J=16.0, 2.5 Hz, 1 H, 6H‐α), 2.99 (dd, J=18.1, 9.0 Hz, 1 H, 12‐Hα), 2.40 (d, J=18.1 Hz, 1 H, 12‐Hβ), 2.36 (s, 3 H, NCH₃), 2.16 (s, 3 H, 4‐CH₃), 2.14 (s, 3 H, 10‐CH₃), 1.93 ppm (dd, J=16.0, 12.8 Hz, 1 H, 6‐Hβ); ¹³C NMR (100 MHz, CDCl₃): δ=149.3 (C‐9), 148.2 (C‐5), 146.7 (C‐11), 145.0 (C‐8), 144.5 (C‐3a), 139.1 (C‐16b), 137.1 (C₆H₅), 128.6 (C₆H₅), 128.4 (C₆H₅), 128.3 (C₆H₅), 123.2 (C‐7a), 121.1 (C‐5a), 117.7 (CN), 116.0 (C‐10), 115.6 (C‐11a), 113.4 (C‐16a), 112.5 (C‐4), 101.2 (C‐2), 75.1 (PhCH₂), 63.4 (CH₂OH), 60.3 (8 & 9‐OCH₃), 60.0 (C‐14), 58.1 (C‐16), 56.9 (C‐7), 56.5 (C‐6a), 54.9 (C‐13), 41.8 (NCH₃), 26.3 (C‐6), 21.3 (C‐12), 9.3 (4‐CH₃), 8.7 ppm (10‐CH₃); FTIR (KBr): $\tilde{\nu }$ =3447, 2934, 2228, 1456, 1431, 1418, 1344, 1109, 1092, 1074 cm⁻¹; MS (EI): m/z (%): 599 (1) [M]⁺, 572 (17), 544 (17), 543 (47), 338 (41), 264 (18), 248 (10), 236 (18), 235 (28), 234 (100), 218 (10), 91 (10); HRMS (EI): m/z: calcd for C₃₄H₃₇N₃O₇: 599.2632 [M]⁺; found: 599.2629.

(6aS*,7R*,13S*,14R*,16R*)‐5‐(Benzyloxy)‐16‐(hydroxymethyl)‐ 9‐methoxy‐4,10,17‐trimethyl‐8,11‐dioxo‐6a,7,8,11,12,13,14,16‐ octahydro‐6H‐7,13‐iminobenzo[4,5]azocino[1,2‐b][1,3]‐ dioxolo[4,5‐h]isoquinoline‐14‐carbonitrile (20)

A solution of CAN (21.6 mg, 37.5 μmol) in H₂O (700 μL) was added to a stirred solution of 19 (9.00 mg, 15 μmol) in THF (2.1 mL) at 0 °C, and the mixture was stirred at 0 °C for 20 min. The mixture was diluted with H₂O (5 mL) and then extracted with EtOAc (3×10 mL). The combined extract was washed with brine (5 mL), dried, and concentrated in vacuo to give a residue (9.8 mg), which was subjected to column chromatography on SiO₂ (6 g) with hexane/EtOAc (1:1) to afford 20 (4.43 mg, 51 %) as a yellow gummy solid. Compound 20 was identical with an authentic sample13a on direct comparison of the characterization data (¹H NMR, ¹³C NMR, IR, MS) and TLC behavior; R _f=0.20 (hexane/EtOAc 3:2); ¹H NMR (400 MHz, CDCl₃): δ=7.50–7.36 (m, 5 H, C₆H₅), 5.98 (d, J=1.4 Hz, 1 H, 2‐H), 5.90 (d, J=1.4 Hz, 1 H, 2‐H), 4.66 (d, J=10.6 Hz, 1 H, PhCH₂), 4.60 (d, J=10.6 Hz, 1 H, PhCH₂), 4.15 (d, J=2.5 Hz, 1 H, 14‐H), 4.04 (t, J=4.3 Hz, 1 H, 16‐H), 4.01 (br d, J=2.7 Hz, 1 H, 7‐H), 3.94 (s, 3 H, 9‐OCH₃), 3.71 (br d, J=10.8 Hz, 1 H, CH ₂OH), 3.51(m, 1 H, CH ₂OH), 3.39 (br d, J=7.6 Hz, 1 H, 13‐H), 3.18 (dt, J=12.1, 2.7 Hz, 1 H, 6a‐H), 3.04 (dd, J=15.1, 2.7 Hz, 1 H, 6H‐α), 2.82 (dd, J=20.8, 7.6 Hz, 1 H, 12‐Hα), 2.30 (s, 3 H, NCH₃), 2.29 (d, J=20.8 Hz, 1 H, 12‐Hβ), 2.16 (s, 3 H, 4‐CH₃), 1.95 (s, 3 H, 10‐CH₃), 1.66 ppm (dd, J=15.1, 12.1 Hz, 1 H, 6‐Hβ); ¹³C NMR (100 MHz, CDCl₃): δ=186.5 (C‐11), 182.5 (C‐8), 155.3 (C‐9), 148.2 (C‐5), 144.9 (C‐3a), 141.3 (C‐11a), 139.2 (C‐16b), 136.7 (C₆H₅), 136.2 (C‐7a), 128.6 (C₆H₅), 128.6 (C‐10), 128.5 (C₆H₅), 128.3 (C₆H₅), 120.6 (C‐5a), 117.4 (CN), 112.6 (C‐4 & 16a), 101.3 (C‐2), 75.5 (PhCH₂), 65.2 (CH₂OH), 60.9 (9‐OCH₃), 59.8 (C‐14), 58.5 (C‐16), 56.0 (C‐6a), 54.8 (C‐7 or 13), 54.7 (C‐7 or 13), 41.5 (NCH₃), 27.7 (C‐6), 21.5 (C‐12), 9.4 (4‐CH₃), 8.7 ppm (10‐CH₃); FTIR (KBr): $\tilde{\nu }$ =2936, 1653, 1614, 1456, 1429, 1306, 1105, 1092 cm⁻¹; MS (FAB): m/z (%): 583 [M+H]⁺; HRMS (FAB): m/z: calcd for C₃₃H₃₃N₃O₇: 583.2319 [M]⁺; found: 584.2391.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

S. Kimura, N. Saito, ChemistryOpen 2018, 7, 764.