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Synthesis 2012; 44(17): 2743-2753
DOI: 10.1055/s-0032-1316579
paper
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies toward Ecteinascidin 743 (Trabectedin)

Takahiro Imai
,
Hiyoku Nakata
,
Satoshi Yokoshima
,
Tohru Fukuyama*
Further Information

Publication History

Received: 01 May 2012

Accepted after revision: 31 May 2012

Publication Date:
06 July 2012 (online)

 
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Abstract

An alternative synthetic route to an intermediate in the synthesis of ecteinascidin 743 has been established by using a Pictet–Spengler reaction and a Friedel–Crafts type reaction.


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Key words

alkaloids - anticancer drugs - Pictet–Spengler reaction - Friedel–Crafts reaction - total synthesis

Tetrahydroisoquinoline alkaloids show a broad range of biological properties, including antitumor and antimicrobial activities.[ 2 ] Ecteinascidin 743 (Et 743, 1; Figure [1], also known as trabectedin or Yondelis®), isolated from the Caribbean tunicate Ecteinascidia turbinate,[ 3 ] has been shown to display highly potent cytotoxicity against a variety of tumor cell lines at very low concentrations. Because of the unique mechanism of action against the tumor cell lines,[ 4 ] Et 743 was considered as a potential anticancer drug. Extensive clinical trials resulted in the approval of Et 743 in 2007 for the treatment of advanced soft tissue sarcoma and, in 2009, for relapsed platinum-sensitive ovarian cancer in combination with liposomal doxorubicin. Et 743 is currently in clinical trials for the treatment of breast, lung, pancreas, and prostate cancers.[ 5 ]

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Figure 1 Structure of ecteinascidin 743 (1; trabectedin)

The structural complexity and the limited availability of Et 743 from nature have made it a very attractive synthetic target. The first total synthesis of Et 743 was accomplished in 1996 by Corey and co-workers.[ 6 ] Since then, total­ syntheses have been reported from our own laboratories[ 7 ] and also by Zhu and co-workers.[ 8 ] Three formal total syntheses were reported by Williams,[ 9 ] Danishefsky,[ 10 ] and Takemoto[ 11 ] along with synthetic approaches by several other research groups.[ 12 ] Despite considerable effort toward the total synthesis of Et 743, its clinical supply relies solely on a long semisynthetic route from cyanosafracin B, produced by bacterial fermentation.[ 13 ] A practical and scalable synthesis of Et 743 is therefore eagerly sought.

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Scheme 1

Our previous synthesis of Et 743, featuring the Ugi four-component condensation reaction, allowed easy access to the diketopiperazine through an intramolecular Heck reaction for the construction of the bicyclo [3.3.1] skeleton. Phenol-aldehyde cyclization was employed to construct the B ring, followed by the acid-induced ten-membered sulfide formation (Scheme [1]).[ 7b ] Herein, we disclose another synthetic approach to the key intermediate 7 via a Pictet–Spengler reaction and a Friedel–Crafts type reaction of an iminolactone.

In our previous total synthesis, amine 2 was prepared by the addition of phenol 10 to iminolactone 11 (Scheme [2]). Transformation of the resulting adduct 12 into amine 2, however, required a rather tedious cleavage of the chiral auxiliary, which was clearly problematic from a synthetic perspective. As illustrated in Scheme [3], we envisioned that the intermediate 7 could be constructed by incorporating the chiral auxiliary moiety in a synthetic intermediate itself. In a retrosynthetic sense, cleavage of the oxazolidine ring in 7 and manipulation of the diols at C4 and C22 would lead to lactone 14. The addition of an aryl group to iminolactone 15 would occur from the less hindered face, giving the desired trans product. The iminolactone 15 could be derived from aminoalcohol 16, which, in turn, could be prepared via a Pictet–Spengler reaction between aldehyde 17 and amine 18.

Our synthesis commenced with the preparation of the amine unit 18 (Scheme [4]). After benzylation of the known aldehyde 19,[ 14 ] a Horner–Wadsworth–Emmons reaction of 20 was conducted with phosphonate 21 [ 15 ] using N,N,N′,N′-tetramethylguanidine as a base to give dehydrophenylalanine 22 stereoselectively. Asymmetric hydrogenation of 22 through the use of {Rh[(cod)-(S,S)-Et-DuPHOS]OTf}[ 16 ] under a hydrogen atmosphere (500 psi) at 50 °C proceeded uneventfully to give aminoester 23 in 85% yield with 95% enantiomeric excess. After switching the Boc group to a Cbz group,[ 17 ] the methyl ester was converted into Weinreb amide 24 via a two-step sequence involving basic hydrolysis followed by condensation of the resulting carboxylic acid with N,O-dimethylhydroxylamine. Reduction of 24 with diisobutylaluminum hydride (DIBAL-H) gave an aldehyde, which was protected as its dimethyl acetal. Subsequent hydrogenolysis of the Cbz and benzyl groups afforded 18.

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Scheme 2

The aldehyde unit was prepared in the following manner (Scheme [5]). A p-nosyl group was introduced to the amino group of l-serine methyl ester (25). After formation of the acetonide, the methyl ester moiety was reduced with DIBAL-H to afford 27 in good yield.[ 18 ]

With the amine unit 18 and the aldehyde unit 27 in hand, we next attempted the crucial Pictet–Spengler reaction (Scheme [6]). After extensive optimization, we found that the reaction proceeded in dichloromethane by mixing 18 and 27 in the presence of formic acid and sodium sulfate at ambient temperature, thereby providing the desired tetrahydroisoquinoline 28 as a single diastereomer. The regio­- and stereoselectivity of the reaction was secured by a NOESY experiment as shown in Scheme [6], which showed that the reaction proceeded with complete cis-selectivity. Selective benzylation of the phenol in 28 and protection of the secondary amine moiety as its 2-chloroethyl carbamate furnished 29. Treatment of 29 with 2-mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) caused concomitant cleavage of the p-nosyl group and the acetonide to give 1,2-aminoalcohol 30 in 84% yield.

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Scheme 3

We next focused on introducing the A ring unit via a Friedel­–Crafts type arylation of an iminolactone (Scheme [7]).[ 19 ] Aminoalcohol 30 was treated with phenyl bromoacetate (31) according to Harwood’s procedure[ 20 ] to furnish morpholinone 32, which was oxidized with N-bromosuccinimide (NBS) to give iminolactone 33 in good yield. Addition of phenol 34 to 33 proceeded smoothly in the presence of a large excess of trifluoroacetic acid (TFA) at 0 °C, yielding 35 as a single product. The reaction occurred from the less hindered face of the iminolactone to produce the desired isomer. The product 35 was then converted into the intermediate of our previous synthetic route. Thus, conversion of the phenol into the corresponding triflate, followed by methanolysis, afforded a hydroxyester, which was protected with a TBS group to give 36 in good yield. The ester moiety in 36 was reduced to give alcohol 37.[ 21 ] Upon treatment with BF3·OEt2, 37 underwent cleavage of the dimethyl acetal moiety, which induced formation of a bicyclo [3.3.1] skeleton and an oxazolidine ring to furnish 38 in 73% yield. This result confirmed that the crucial Pictet–Spengler reaction proceeded with cis-selectivity. At this stage,[ 22 ] a Pd-catalyzed cross coupling between 38 and MeZnCl[ 23 ] was performed to give 39 in 76% yield. Finally, the protective group on the secondary amine was converted into a 2,2,2-trichloroethoxycarbonyl (Troc) group in three steps to afford the desired synthetic intermediate 7, the spectral data of which were consistent with those reported previously.

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Scheme 4 Reagents and conditions: (a) BnBr, K2CO3, acetone, r.t., 90%; (b) phosphonate 21, N,N,N′,N′-tetramethylguanidine, r.t., 89%; (c) H2 (500 psi), {Rh[(cod)-(S,S)-Et-DuPHOS]OTf} (1.5 mol%), EtOAc, 50 °C, 85%; (d) AcCl, MeOH, 0 °C to r.t.; (e) CbzCl, Et3N, CH2Cl2, 0 °C to r.t., 75% (2 steps); (f) LiOH, H2O, 0 °C to r.t.; (g) MeNHOMe·HCl, EDCI·HCl, HOBt, Et3N, 0 °C to r.t., 80% (2 steps); (h) DIBAL-H, –78 °C; (i) HC(OMe)3, TsOH, MeOH, r.t.; (j) 10% Pd/C, MeOH, 62% (3 steps).
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Scheme 5 Reagents and conditions: (a) p-NsCl, Et3N, CH2Cl2, 0 °C to r.t., 92%; (b) 2,2-dimethoxypropane, TsOH, benzene, reflux, 98%; (c) DIBAL-H, –78 °C, toluene, quant.
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Scheme 6 Reagents and conditions: (a) HCO2H, Na2SO4, CH2Cl2, 83%; (b) BnBr, K2CO3, acetone, 99%; (c) 2-chloroethyl chloroformate, pyridine, CH2Cl2, 0 °C to r.t., 90%; (d) 2-mercaptoethanol, DBU, MeCN, 0 °C to r.t., 84%.
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Scheme 7 Reagents and conditions: (a) phenyl bromoacetate (31), i-Pr2NEt, MeCN, 0 °C to r.t., 90%; (b) NBS, Et3N, CH2Cl2, 0 °C to r.t., 89%; (c) phenol 34, TFA, CH2Cl2, 0 °C, 81%; (d) Tf2O, pyridine, CH2Cl2, 0 °C, 80%; (e) Et3N, MeOH; (f) TBSCl, imidazole, DMF, 0 °C to r.t., 90% (2 steps); (g) NaBH4, LiCl, THF–EtOH, 89%; (h) BF3·OEt2, CH2Cl2, 0 °C, 73%; (i) MeZnCl, [PdCl2(dppf)], THF, reflux, 76%; (j) NaI, DMF, 110 °C, 96%; (k) Zn, AcOH, THF, r.t.; (l) TrocCl, pyridine, CH2Cl2, 44% (2 steps).

In summary, an alternative synthetic route to the late-stage intermediate in our previous synthesis of ecteinascidin 743 has been developed. The approach features a Pictet–Spengler reaction and a Friedel–Crafts type reaction as key steps. Further investigations to establish a truly practical synthesis of ecteinascidin 743 are underway in our laboratories.

All non-aqueous reactions were carried out in oven-dried glass tubes under a slightly positive pressure of argon unless otherwise noted. Dehydrated CH2Cl2, toluene, THF, Et2O, MeCN, DMF, MeOH, and EtOH were purchased from Kanto Chemical Co., Inc. and stored over 3 Å or 4 Å molecular sieves. Pyridine, Et3N and N,N-diisopropylethylamine (DIPEA) were dried over KOH. All other reagents were commercially available and used without further purification. Preparative flash chromatography was performed using Silica Gel 60 (spherical, 40–100 μm) purchased from Kanto Chemical Co., Inc. 1H and 13C NMR spectra were recorded with JEOL LA-MHz and ECS-400 spectrometers. IR spectra were recorded with a JASCO FT/IR-5300 Fourier Transform Infrared Spectrophotometer. Mass spectra (MS) were obtained with an Agilent 6530 Q-TOF/MS (HRMS), Shimazu QP2010 (GC-MS) instrument. Optical rotations were measured with a JASCO DIP-370 instrument. Melting points were measured with an Ishii melting points apparatus.


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(S)-Methyl 2,2-Dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidine-4-carboxylate (26)

To a mixture of l-serine methyl ester (25; 15.3 g, 98.3 mmol) and Et3N (34.3 mL, 246 mmol, 2.50 equiv) in CH2Cl2 (300 mL) was added p-nitrobenzenesulfonyl chloride (24.0 g, 108 mmol, 1.10 equiv) portionwise at 0 °C. The reaction mixture was allowed to warm to r.t. and stirred for 16.5 h. The mixture was diluted with EtOAc (300 mL) and poured into ice-cooled sat. aq NaHCO3 (100 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL), and the combined organic phase was sequentially washed with brine (50 mL), 1 M aq HCl (50 mL), brine (50 mL), sat. aq NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was washed with ice-cooled EtOAc (5 mL) to afford a p-nitrobenzenesulfonamide.

Yield: 27.4 g (90.0 mmol, 92%); white solid; mp 160–162 °C (dec.); [α]D 25 –2.5 (c 0.59, MeOH).

IR (neat film): 2361, 2341, 1743, 1606, 1529, 1440, 1350, 1311, 1222, 1167, 1126, 1093, 854, 769, 738 cm–1.

1H NMR (400 MHz, CD3OD): δ = 8.36 (d, J = 8.7 Hz, 2 H), 8.07 (d, J = 8.7 Hz, 2 H), 4.08 (dd, J = 5.0 Hz, 1 H), 3.77 (dd, J = 11.0, 5.0 Hz, 1 H), 3.68 (dd, J = 11.0, 5.0 Hz, 1 H), 3.48 (s, 3 H).

13C NMR (100 MHz, CD3OD): δ = 171.2, 151.1, 147.9, 129.3, 124.9, 63.9, 59.5, 52.6.

HRMS (ESI): m/z [M – H]+ calcd for C10H11N2O7S: 303.0287; found: 303.0295.

To a solution of the above p-nitrobenzenesulfonamide (1.11 g, 3.65 mmol) in benzene (15 mL) were added 2,2-dimethoxypropane (2.3 mL, 19 mmol, 5.0 equiv) and p-TsOH·H2O (36 mg, 0.19 mmol, 5.0 mol%). The reaction mixture was heated to reflux for 2.5 h. After cooling, the mixture was diluted with EtOAc (15 mL), and quenched with sat. aq NaHCO3 (15 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc­–n-hexane, 33%) to afford 26.

Yield: 1.23 g (3.57 mmol, 98%); orange solid; mp 75–77 °C; [α]D 25 –51 (c 0.56, CHCl3).

IR (neat film): 2361, 2341, 1755, 1531, 1352, 1309, 1259, 1205, 1165, 1101, 1035, 856, 771, 738 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 9.0 Hz, 2 H), 8.09 (d, J = 9.0 Hz, 2 H), 4.52 (dd, J = 6.8, 2.7 Hz, 1 H), 4.21 (dd, J = 9.6, 6.8 Hz, 1 H), 4.12 (dd, J = 9.6, 2.7 Hz, 1 H), 3.64 (s, 3 H), 1.70 (s, 3 H), 1.62 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 169.9, 149.8, 146.1, 128.7, 123.9, 99.3, 67.2, 60.2, 52.8, 27.3, 26.1.

HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O7S: 345.0756; found: 345.0760.


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(S)-2,2-Dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidine-4-carbaldehyde (27)

To a stirred solution of 26 (1.23 g, 3.57 mmol) in toluene (40 mL) was added DIBAL-H (0.99 M in toluene, 5.5 mL, 5.5 mmol, 1.5 equiv) dropwise over 55 min at –78 °C under argon. After stirring at –78 °C for 35 min, MeOH (4 mL) and 30% aq Rochelle’s salt (10 mL) were added to the mixture. The mixture was then diluted with EtOAc (10 mL), and stirred at r.t. for 1 h. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 33%) to afford 27.

Yield: 1.16 g (3.69 mmol, quant); orange solid; mp 77–78 °C; [α]D 22 –85 (c 0.21, CHCl3).

IR (neat film): 3107, 2989, 2939, 2866, 2363, 1736, 1606, 1531, 1479, 1402, 1352, 1311, 1228, 1209, 1165, 1099, 1035, 1010, 920, 856, 831, 738, 686 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.59 (d, J = 2.7 Hz, 1 H), 8.39 (ddd, J = 8.5, 2.4, 2.4 Hz, 2 H), 8.06 (ddd, J = 8.5, 2.4, 2.4 Hz, 2 H), 4.13–4.18 (m, 2 H), 4.05–4.09 (m, 1 H), 1.74 (s, 3 H), 1.55 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 197.2, 150.0, 145.5, 128.6, 124.3, 99.3, 65.6, 64.4, 28.5, 25.1.

GC-MS (SCI): m/z = 315 [M + H]+.


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3-(Benzyloxy)-4-methoxy-5-methylbenzaldehyde (20)

To a solution of 19 (3.24 g, 19.5 mmol) in acetone (50 mL) were added benzyl bromide (12 mL, 100 mmol, 5.0 equiv) and K2CO3 (13.5 g, 97.7 mmol, 5.00 equiv) at r.t., and the mixture was stirred at r.t. for 2 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 10→30%) to afford 20.

Yield: 4.51 g (17.6 mmol, 90%); colorless oil.

IR (neat film): 2935, 2829, 2735, 2361, 2341, 1689, 1583, 1489, 1437, 1381, 1329, 1294, 1234, 1138, 1086, 1003, 854, 736, 696, 669 cm–1.

1H NMR (400 MHz, CDCl3): δ = 9.83 (s, 1 H), 7.32–7.47 (m, 7 H), 5.15 (s, 2 H), 3.92 (s, 3 H), 2.33 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 191.0, 153.0, 151.9, 136.2, 132.4, 131.7, 128.4, 127.9, 127.2, 127.1, 110.4, 70.7, 60.4, 16.1.

HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1178; found: 257.1176.


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(Z)-Methyl 3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]acrylate (22)

To a mixture of 20 (4.51 g, 17.6 mmol) and phosphonate 21 (8.0 g, 27 mmol, 1.5 equiv) in CH2Cl2 (100 mL) was added N,N,N′,N′-tetramethylguanidine (3.3 mL, 26 mmol, 1.5 equiv) at r.t., and the mixture was stirred at r.t. for 2 d. The reaction mixture was quenched with 15% aq citric acid (30 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc­–n-hexane, 10→30%) to afford 22.

Yield: 6.69 g (15.6 mmol, 89%); yellow solid; mp 95–97 °C.

IR (neat film): 3315, 3065, 2978, 2949, 2361, 2339, 1718, 1639, 1579, 1494, 1454, 1435, 1367, 1334, 1292, 1251, 1159, 1132, 1089, 1051, 1028, 1006, 912, 844, 773, 736, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.30–7.46 (m, 4 H), 7.18 (br, 1 H), 7.09 and 7.10 (s, 1 H), 6.99 and 7.00 (s, 1 H), 6.11 (br, 1 H), 5.08 (s, 2 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 2.25 (s, 3 H), 1.42 (br, 9 H).

13C NMR (100 MHz, CDCl3): δ = 165.9, 152.7, 151.2, 148.6, 136.6, 131.8, 130.7, 129.1, 128.4, 127.8, 127.1, 125.5, 123.2, 113.1, 80.8, 70.6, 60.2, 52.5, 28.2, 16.1.

HRMS (ESI): m/z [M + Na]+ calcd for C24H29NO6Na: 450.1893; found: 450.1890.


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(S)-Methyl 3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (23)

A degassed solution of 22 (13.7 g, 31.9 mmol) and {Rh[(cod)-(S,S)-Et-DuPHOS]OTf} (346 mg, 0.479 mmol, 1.50 mol%) in EtOAc (130 mL) was placed in a high-pressure Parr reactor, which was sealed under hydrogen (500 psi). After stirring at 50 °C for 3 d, the solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (EtOAc–CH2Cl2, 5%) to afford 23. The enantiomeric excess of the product was determined after conversion of the Boc group into a Cbz group.

Yield: 12.5 g (29.1 mmol, 91%); pale-yellow foam; [α]D 25 27 (c 0.31, CHCl3).

IR (neat film): 3362, 2976, 2930, 2361, 2341, 1745, 1714, 1589, 1498, 1437, 1390, 1365, 1284, 1230, 1167, 1076, 1012, 844, 738, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.30–7.45 (m, 5 H), 6.57 and 6.57 (s, 1 H), 6.54 (s, 1 H), 5.06 (s, 2 H), 4.95 and 5.04 (d, J = 7.3 Hz, 1 H), 4.51–4.56 (m, 1 H), 3.81 and 3.82 (s, 3 H), 3.67 (s, 3 H), 2.91–3.02 (m, 2 H), 2.23 and 2.24 (s, 3 H), 1.43 (br, 9 H).

13C NMR (100 MHz, CDCl3): δ = 172.1, 154.8, 151.4, 146.6, 136.9, 131.8, 131.1, 128.4, 127.7, 127.1, 124.0, 112.8, 79.9, 70.7, 60.2, 54.4, 52.2, 38.0, 28.4, 16.0.

HRMS (ESI): m/z [M + Na]+ calcd for C24H31NO6Na: 452.2049; found: 452.2058.


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(S)-Benzyl {3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (24)

To a solution of 23 (12.5 g, 29.1 mmol) in a mixture of MeOH (25 mL) and CH2Cl2 (12 mL) at 0 °C, was added a solution of ice-cooled HCl in MeOH [prepared by mixing AcCl (21.0 mL, 295 mmol, 10.0 equiv) with MeOH (29 mL) at 0 °C], and the mixture was allowed to warm to r.t. After stirring for 1.5 h, the reaction mixture was concentrated under reduced pressure. To a solution of the crude product in CH2Cl2 (25 mL) were added CbzCl (8.3 mL, 58 mmol, 2.0 equiv) and a solution of Et3N (12.2 mL, 87.9 mmol, 3.00 equiv) in CH2Cl2 (10 mL) at 0 °C, and the mixture was allowed to warm to r.t. and stirred for 1 h. To the mixture was added Et3N (5.0 mL, 36 mmol, 1.2 equiv) and the mixture was stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (35 mL), and quenched with sat. aq NaHCO3 (30 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc­–n-hexane, 30%) to afford a Cbz-protected amino ester.

Yield: 10.1 g (21.8 mmol, 75% over 2 steps); colorless oil; [α]D 25 34.2 (c 1.82, CHCl3); 95% ee {determined by HPLC (DAICEL-CHIRALCEL-OD-H; hexane–i-PrOH, 90:10; flow rate 1.0 mL/min) tR = 23.3 (S), 28.5 (R) min}.

IR (neat film): 3342, 3032, 2951, 2361, 2339, 1722, 1589, 1498, 1439, 1377, 1346, 1282, 1215, 1149, 1060, 1010, 910, 842, 738, 696, 667 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.24–7.41 (m, 10 H), 6.54 (s, 1 H), 6.51 (s, 1 H), 5.05–5.20 (m, 3 H), 5.01 (s, 2 H), 4.60 (dd, J = 13.9, 5.9 Hz, 1 H), 3.80 (s, 3 H), 3.66 (s, 3 H), 2.97–3.00 (m, 2 H), 2.21 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.7, 155.4, 151.4, 146.7, 136.8, 136.0, 131.9, 130.7, 128.3, 128.0, 127.9, 127.6, 127.0, 126.7, 123.9, 112.7, 70.6, 66.9, 60.1, 54.8, 52.2, 37.9, 16.0.

HRMS (ESI): m/z [M + H]+ calcd for C27H30NO6: 464.2073; found: 464.2076.

To a solution of the above Cbz-protected amino ester (10.1 g, 21.8 mmol) in a mixture of MeOH (50 mL), H2O (12.5 mL), and THF (12.5 mL) was added LiOH (1.90 g, 45.3 mmol, 2.00 equiv) at 0 °C. The mixture was allowed to warm to r.t. and stirred for 55 min. The reaction mixture was diluted with toluene (100 mL) and concentrated under reduced pressure. To the residue was added 10% aq citric acid (30 mL), and the resulting suspension was extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give a carboxylic acid. To a mixture of the crude carboxylic acid and N,O-dimethylhydroxylamine hydrochloride (3.20 g, 32.8 mmol, 1.50 equiv) in CH2Cl2 (100 mL) were added WSCD·HCl (5.80 g, 32.6 mmol, 1.50 equiv), HOBt (5.00 g, 32.7 mmol, 1.50 equiv) and Et3N (9.2 mL, 66 mmol, 3.0 equiv) at 0 °C. The mixture was allowed to warm to r.t. and stirred for 24 h. The reaction mixture was diluted with EtOAc (100 mL), and washed with brine. The aqueous phase was extracted three times with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 40%) to afford 24.

Yield: 8.60 g (17.5 mmol, 80% over 2 steps); colorless oil; [α]D 25 9.9 (c 1.5, CHCl3).

IR (neat film): 3304, 3063, 3034, 2937, 2827, 2363, 2249, 1720, 1658, 1589, 1529, 1496, 1454, 1388, 1323, 1282, 1253, 1232, 1180, 1149, 1089, 1053, 1028, 1010, 910, 846, 773, 736, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.23–7.42 (m, 10 H), 6.59 (s, 1 H), 6.56 (s, 1 H), 5.40 (br, 1 H), 5.02–5.11 (m, 4 H), 4.94 (br, 1 H), 3.79 (s, 3 H), 3.62 (s, 3 H), 3.13 and 3.39 (s, 3 H), 2.94 (br, 1 H), 2.80 (br, 1 H), 2.21 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.9, 155.9, 151.6, 146.8, 137.2, 136.3, 132.0, 131.6, 128.6, 128.2, 128.0, 127.9, 127.3, 124.2, 113.1, 70.7, 66.9, 61.6, 60.3, 52.0, 38.3, 32.1, 16.0.

HRMS (ESI): m/z [M + H]+ calcd for C28H33N2O6: 493.2339; found: 493.2328.


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(S)-5-(2-Amino-3,3-dimethoxypropyl)-2-methoxy-3-methylphenol (18)

To a stirred solution of 24 (8.60 g, 17.5 mmol) in toluene (120 mL) was added DIBAL-H (0.99 M in toluene, 27.0 mL, 26.7 mmol, 1.50 equiv) dropwise over 1 h at –78 °C under argon. To the mixture was added additional DIBAL-H (0.99 M in toluene, 6.0 mL, 5.9 mmol, 0.3 equiv) dropwise over 15 min at –78 °C. After stirring at –78 °C for an additional 15 min, MeOH (25 mL) and 30% aq Rochelle’s salt (60 mL) were added to the mixture. The mixture was then diluted with EtOAc (30 mL), and stirred at r.t. for 1 h. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with sat. aq NaCl (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was filtered through a pad of silica gel and concentrated under reduced pressure, then used without further purification.

To a mixture of the crude product and trimethyl orthoformate (75.0 mL, 685 mmol, 39.1 equiv) in MeOH (220 mL) was added TsOH·H2O (332 mg, 1.75 mmol, 10.0 mol%), and the resulting mixture was stirred at r.t. for 1.5 h. To the reaction mixture was added NaH (100 mg, 2.50 mmol, 0.14 equiv) and the mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH–CHCl3, 1%) to afford a dimethyl acetal.

Yield: 9.60 g; white solid; mp 100–101 °C; [α]D 25 –25 (c 0.81, CHCl3).

IR (neat film): 3317, 3065, 3036, 2932, 2829, 2361, 1689, 1589, 1548, 1498, 1442, 1385, 1340, 1286, 1265, 1230, 1186, 1149, 1130, 1072, 1008, 964, 912, 852, 773, 734, 696 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.27–7.44 (m, 10 H), 6.65 (s, 1 H), 6.61 (s, 1 H), 4.93–5.11 (m, 5 H), 4.13 (d, J = 3.2 Hz, 1 H), 3.99–4.06 (m, 1 H), 3.81 (s, 3 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 2.79 (dd, J = 13.9, 6.3 Hz, 1 H), 2.70 (dd, J = 13.9, 7.6 Hz, 1 H), 2.23 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 155.8, 151.3, 146.1, 137.0, 136.3, 132.9, 131.7, 128.3, 127.8, 127.7, 127.6, 127.0, 123.9, 112.7, 104.4, 70.5, 66.6, 60.2, 55.7, 55.7, 53.4, 35.9, 16.0.

HRMS (ESI): m/z [M + Na]+ calcd for C28H33NO6Na: 502.2206; found: 502.2208.

A mixture of the above dimethyl acetal (9.60 g, 37.5 mmol) and 10% Pd/C [10.0 g, AD-type (wet), 50% water; purchased from Kawaken Fine Chemicals Co.] in MeOH (120 mL) was stirred under 1 atm of hydrogen at r.t. for 2 d. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH–CHCl3, 10%) to afford 18.

Yield: 3.37 g (13.2 mmol, 62% over 3 steps); yellow oil; [α]D 21 –23 (c 0.99, CHCl3).

IR (neat film): 3360, 3292, 2935, 2833, 1589, 1494, 1446, 1315, 1278, 1232, 1190, 1140, 1066, 1008, 970, 842 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.64 (d, J = 1.9 Hz, 1 H), 6.53 (d, J = 1.9 Hz, 1 H), 4.14 (d, J = 5.8 Hz, 1 H), 3.77 (s, 3 H), 3.45 (s, 3 H), 3.44 (s, 3 H), 3.10 (ddd, J = 9.5, 3.9, 1.7 Hz, 1 H), 2.85 (dd, J = 13.4, 3.9 Hz, 1 H), 2.39 (dd, J = 13.4, 9.5 Hz, 1 H), 2.25 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 148.9, 144.0, 134.5, 130.8, 122.8, 114.2, 107.2, 60.3, 55.2, 55.0, 54.0, 37.7, 16.0.

HRMS (ESI): m/z [M + H]+ calcd for C13H22NO4: 256.1549; found: 256.1547.


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(1R,3S)-3-(Dimethoxymethyl)-1-{(R)-2,2-dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidin-4-yl}-7-methoxy-6-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (28)

To a mixture of dried Na2SO4 (10.1 g), amine 18 (1.02 g, 4.00 mmol) and aldehyde 27 (1.39 g, 4.42 mmol, 1.10 equiv) in CH2Cl2 (30 mL) at 0 °C, was added HCO2H (0.76 mL, 20.1 mmol, 5.00 equiv), and the reaction mixture was allowed to warm to r.t. and stirred for 24 h. The reaction mixture was diluted with EtOAc (30 mL), and quenched with sat. aq NaHCO3 (30 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc­ (3 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was dissolved in a minimum amount of EtOAc, and hexane was added to induce precipitation. The precipitates were collected by filtration to afford 28.

Yield: 1.83 g (3.32 mmol, 83%); yellow solid; mp 96–98 °C; [α]D 23 –105 (c 0.63, CHCl3).

IR (neat film): 3458, 3107, 2988, 2941, 2893, 2835, 1668, 1606, 1581, 1531, 1500, 1458, 1417, 1350, 1309, 1290, 1232, 1203, 1165, 1147, 1084, 1064, 1032, 999, 958, 910, 856, 831, 736, 688 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.39 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 8.23 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 6.48 (s, 1 H), 6.02 (s, 1 H), 4.93 (br, 1 H), 4.72 (ddd, J = 7.3, 6.1, 2.9 Hz, 1 H), 4.26 (d, J = 7.3 Hz, 1 H), 3.85 (dd, J = 8.5, 6.1 Hz, 1 H), 3.77 (s, 3 H), 3.53 (dd, J = 8.5, 7.3 Hz, 1 H), 3.44 (s, 3 H), 3.41 (s, 3 H), 2.95–3.00 (m, 1 H), 2.66 (dd, J = 15.1, 2.2 Hz, 1 H), 2.51 (dd, J = 15.1, 10.9 Hz, 1 H), 2.40 (br, 1 H), 2.25 (s, 3 H), 1.75 (s, 3 H), 1.53 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 149.6, 145.6, 145.1, 143.1, 132.5, 128.9, 128.5, 123.9, 122.7, 118.6, 107.0, 99.3, 65.4, 60.9, 60.4, 54.0, 53.7, 52.7, 52.6, 32.4, 28.4, 25.4, 15.8.

HRMS (ESI): m/z [M + H]+ calcd for C25H34N3O9S: 552.2016; found: 552.2015.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-1-{(R)-2,2-dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidin-4-yl}-7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (29)

To a solution of 28 (2.01 g, 3.65 mmol) in acetone (40 mL) at 0 °C, were added benzyl bromide (0.53 mL, 4.46 mmol, 1.20 equiv) and K2CO3 (606 mg, 4.38 mmol, 1.20 equiv), and the reaction mixture was allowed to warm to r.t. and stirred for 24 h. To the mixture were added benzyl bromide (3.80 mL, 31.9 mmol, 8.60 equiv) and K2CO3 (4.50 g, 32.6 mmol, 8.90 equiv) at 0 °C, and the reaction mixture was allowed to warm to r.t. and stirred for an additional 17.5 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 0→20%) to afford a benzyl ether.

Yield: 2.32 g (3.62 mmol, 99%); pale-yellow foam; [α]D 23 –115 (c 0.57, CHCl3).

IR (neat film): 3364, 3105, 2988, 2937, 2891, 2835, 2363, 1606, 1531, 1483, 1452, 1413, 1350, 1313, 1232, 1201, 1167, 1149, 1084, 1064, 1030, 1001, 964, 910, 856, 833, 738, 688 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.83 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 7.76 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 7.59–7.61 (m, 2 H), 7.36–7.44 (m, 3 H), 5.18 (d, J = 10.4 Hz, 1 H), 5.08 (br, 1 H), 4.92 (d, J = 10.4 Hz, 1 H), 4.61 (ddd, J = 6.8, 6.8, 3.1,Hz, 1 H), 4.26 (d, J = 7.1 Hz, 1 H), 3.87 (s, 3 H), 3.72 (dd, J = 8.7, 6.8 Hz, 1 H), 3.47 (s, 3 H), 3.43 (s, 3 H), 3.40 (dd, J = 8.7, 6.8 Hz, 1 H), 3.00–3.05 (m, 1 H), 2.71 (dd, J = 15.3, 2.6 Hz, 1 H), 2.53 (dd, J = 15.3, 10.9 Hz, 1 H), 2.39 (br, 1 H), 2.26 (s, 3 H), 1.69 (s, 3 H), 1.37 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 149.6, 149.2, 148.9, 146.0, 137.0, 132.1, 131.0, 128.8, 128.6, 128.5, 128.4, 126.8, 126.2, 123.7, 107.2, 98.7, 75.7, 65.2, 62.4, 60.8, 54.0, 54.0, 53.2, 52.6, 32.6, 28.2, 25.4, 15.8.

HRMS (ESI): m/z [M + H]+ calcd for C32H40N3O9S: 642.2485; found: 642.2485.

To a solution of the above benzyl ether (49.3 mg, 0.0768 mmol) in CH2Cl2 (1.0 mL) at 0 °C were added pyridine (0.07 mL, 0.9 mmol, 10 equiv), and 2-chloroethyl chloroformate (0.08 mL, 0.8 mmol, 10 equiv), and the mixture was allowed to warm to r.t. and stirred for 1 h. The reaction mixture was diluted with EtOAc (5 mL), and quenched with sat. aq NaHCO3 (5 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with sat. aq NaCl (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH–CH2Cl2, 1%) to afford 29.

Yield: 51.7 mg (0.0691 mmol, 90%); pale-yellow foam; [α]D 23 –32.7 (c 1.03, CHCl3).

IR (neat film): 3624, 2935, 2361, 2341, 1697, 1604, 1531, 1462, 1404, 1354, 1307, 1238, 1167, 1066, 912, 854, 733 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.3 Hz, 2 H), 7.86 (d, J = 8.3 Hz, 2 H), 7.56–7.62 (m, 2 H), 7.32–7.41 (m, 3 H), 6.76 (s, 1 H), 5.86–5.97 (m, 1 H), 5.14–5.22 (m, 1 H), 4.80–4.82 (m, 2 H), 4.56–4.59 (m, 2 H), 4.24 (br, 1 H), 4.08 (br, 2 H), 3.89–3.92 (m, 3 H), 3.64–3.70 (m, 2 H), 3.62 (s, 3 H), 3.52 (s, 3 H), 3.10–3.16 (m, 1 H), 2.95 (br, 1 H), 2.27 (s, 3 H), 1.61 (s, 3 H), 1.43 (br, 1 H), 1.23 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.0, 155.3, 149.8, 149.4, 148.6, 147.7, 137.2, 136.8, 131.6, 130.5, 129.5, 128.6, 128.3, 128.1, 127.8, 124.9, 123.7, 105.7, 104.7, 99.2, 75.9, 75.6, 66.6, 65.7, 61.3, 60.5, 57.5, 57.4, 55.5, 54.9, 52.1, 42.7, 41.9, 29.4, 29.0, 24.9, 24.8, 16.0.

HRMS (ESI): m/z [M – H]+ calcd for C35H41ClN3O11S: 746.2150; found: 746.2156.


#

(1R,3S)-2-Chloroethyl 1-[(R)-1-Amino-2-hydroxyethyl]-8-(benzyloxy)-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (30)

To a solution of 29 (805 mg, 1.08 mmol) in MeCN (20 mL) at 0 °C were added 2-mercaptoethanol (0.12 mL, 1.71 mmol, 1.50 equiv) and DBU (0.25 mL, 1.7 mmol, 1.5 equiv), and the mixture was allowed to warm to r.t. and stirred for 2 h. The reaction mixture was diluted with EtOAc (20 mL), and quenched with sat. aq NaHCO3 (10 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The organic phase was sequentially washed with sat. aq NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (MeOH–CHCl3, 5%) to afford 30.

Yield: 471 mg (0.901 mmol, 83%); pale-yellow foam; [α]D 23 13 (c 0.27, CHCl3).

IR (neat film): 2937, 2361, 2341, 1693, 1454, 1408, 1352, 1313, 1238, 1116, 1068, 999, 906, 808 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.50–7.54 (m, 2 H), 7.31–7.42 (m, 3 H), 6.82 (s, 1 H), 5.46 and 5.56 (d, J = 10.7 Hz, 1 H), 5.14 and 5.24 (d, J = 10.7 Hz, 1 H), 4.80–4.87 (m, 2 H), 4.36–4.41 and 4.53–4.58 (m, 1 H), 4.16–4.19 and 4.23–4.29 (m, 1 H), 3.92–3.99 (m, 1 H), 3.81 and 3.84 (s, 3 H), 3.59–3.79 (m, 4 H), 3.57 (s, 3 H), 3.51 and 3.53 (s, 3 H), 3.10 (dd, J = 15.3, 12.2 Hz, 1 H), 2.98–3.00 (m, 1 H), 2.80–2.89 (m, 1 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.5, 149.4, 147.8, 136.7, 131.5, 131.5, 130.0, 128.2, 127.8, 127.7, 127.5, 127.1, 125.4, 125.2, 105.2, 104.5, 74.7, 65.7, 65.3, 63.7, 63.4, 60.1, 57.4, 57.2, 55.7, 54.9, 54.8, 54.6, 53.2, 42.4, 41.9, 24.3, 24.0, 15.7.

HRMS (ESI): m/z [M + H]+ calcd for C26H36ClN2O7: 523.2211; found: 523.2217.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-7-methoxy-6-methyl-1-[(R)-6-oxomorpholin-3-yl]-3,4-dihydro­isoquinoline-2(1H)-carboxylate (32)

To a solution of 30 (606 mg, 1.16 mmol) in MeCN (12 mL) was added a solution of phenyl bromoacetate (31; 277 mg, 1.29 mmol, 1.10 equiv) and DIPEA (0.23 mL, 1.3 mmol, 1.1 equiv) in MeCN (12 mL) dropwise over 30 min at 0 °C. The mixture was allowed to warm to r.t. and stirred for 23 h. The solution was concentrated under reduced pressure and the residue was purified by column chromatography (neutral silica gel; EtOAc–hexane, 40%) to afford 32.

Yield: 589 g (1.05 mmol, 91%); pale-yellow foam; [α]D 25 –17.3 (c 1.18, CHCl3).

IR (neat film): 3348, 2939, 2837, 2363, 1743, 1697, 1585, 1485, 1454, 1406, 1356, 1309, 1236, 1211, 1138, 1113, 1070, 1033, 999, 912, 812, 754, 702 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.32–7.54 (m, 5 H), 6.82 (s, 1 H), 5.54 and 5.66 (d, J = 10.5 Hz, 1 H), 5.10 and 5.19 (d, J = 10.5 Hz, 1 H), 4.90 and 4.96 (d, J = 10.1 Hz, 1 H), 4.81 and 4.85 (br, 1 H), 4.55 and 4.58 (d, J = 3.6 Hz, 1 H), 4.15–4.53 (m, 3 H), 3.98 (ddd, J = 12.4, 6.9, 2.3 Hz, 1 H), 3.81 and 3.84 (s, 3 H), 3.52–3.77 (m, 3 H), 3.56 (s, 3 H), 3.52 and 3.54 (s, 3 H), 3.38–3.46 (m, 2 H), 3.07–3.16 (m, 1 H), 2.84–2.92 (m, 1 H), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 169.0, 156.2, 155.4, 149.7, 149.5, 148.3, 137.6, 137.2, 132.6, 132.4, 130.3, 130.2, 128.7, 128.4, 128.2, 127.6, 127.1, 126.4, 125.9, 125.8, 105.6, 104.5, 75.3, 74.8, 73.4, 72.6, 65.9, 65.6, 60.3, 57.6, 57.4, 55.6, 55.1, 53.4, 51.7, 51.4, 47.0, 42.6, 42.l, 24.4, 24.2, 15.9.

HRMS (ESI): m/z [M + H]+ calcd for C28H36ClN2O8: 563.2160; found: 563.2144.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-7-methoxy-6-methyl-1-[(R)-6-oxo-3,6-dihydro-2H-1,4-oxazin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (33)

To a solution of 32 (566 mg, 1.01 mmol) in CH2Cl2 (12 mL) were added Et3N (1.40 mL, 10.0 mmol, 10.0 equiv) and NBS (198 mg, 1.11 mmol, 1.10 equiv) at 0 °C. After stirring for 30 min, the reaction mixture was diluted with EtOAc (12 mL), and quenched with sat. aq NaHCO3 (10 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with sat. aq NaCl (5 mL) , dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (neutral silica gel; EtOAc–hexane, 50%) to afford 33.

Yield: 500 mg (0.891 mmol, 88%); pale-yellow foam; [α]D 24 –51 (c 0.54, CHCl3).

IR (neat film): 2939, 2837, 2361, 2341, 1747, 1699, 1630, 1587, 1547, 1485, 1460, 1406, 1354, 1313, 1273, 1236, 1219, 1138, 1114, 1072, 1035, 999, 906, 868, 812, 771, 733, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.60 and 7.65 (br, 1 H), 7.29–7.45 (m, 5 H), 6.84 (s, 1 H), 5.66 and 5.78 (d, J = 11.0 Hz, 1 H), 5.11 (s, 1 H), 5.03 and 5.13 (d, J = 11.0 Hz, 1 H), 4.84 and 4.89 (br, 1 H), 4.57–4.60 (m, 1 H), 4.13–4.53 (m, 5 H), 4.04–4.09 (m, 1 H), 3.79 and 3.80 (s, 3 H), 3.58 (s, 3 H), 3.57–3.73 (m, 1 H), 3.53 and 3.55 (s, 3 H), 3.16 and 3.19 (d, J = 12.4 Hz, 1 H), 2.91–2.99 (m, 1 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 156.1, 155.3, 154.6, 152.6, 152.4, 149.7, 149.5, 148.6, 148.3, 138.2, 137.9, 132.6, 132.5, 129.8, 128.5, 127.8, 127.8, 127.0, 126.5, 125.5, 125.4, 74.3, 74.0, 68.9, 68.5, 65.9, 65.5, 60.1, 58.6, 58.4, 57.7, 57.6, 57.3, 57.2, 55.5, 55.0, 51.2, 50.8, 42.6, 42.1, 24.4, 24.1, 16.0.

HRMS (ESI): m/z [M + Na]+ calcd for C28H33ClN2O8Na: 583.1823; found: 583.1831.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-{(3R,5R)-5-[6-(benzyl­oxy)-7-hydroxybenzo[d][1,3]dioxol-4-yl]-6-oxomorpholin-3-yl}-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (35)

To a solution of 33 (483 mg, 0.861 mmol) and phenol 34 (315 mg, 1.29 mmol, 1.50 equiv) in CH2Cl2 (10 mL) was added TFA (1.28 mL, 17.4 mmol, 20.0 equiv) dropwise. After stirring for 25 min, the mixture was diluted with EtOAc (10 mL), and poured into sat. aq NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL) , dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–hexane, 50%) to afford 35.

Yield: 564 mg (0.700 mmol, 81%); colorless foam; [α]D 23 –7.2 (c 0.84, CHCl3).

IR (neat film): 3630, 3331, 2939, 2361, 2253, 1743, 1697, 1498, 1458, 1406, 1356, 1309, 1234, 1207, 1113, 1070, 1035, 999, 947, 912, 814, 733, 700.

1H NMR (400 MHz, CDCl3): δ = 7.52 and 7.59 (d, J = 7.1 Hz, 2 H), 7.32–7.41 (m, 8 H), 6.80 and 6.84 (s, 1 H), 5.70–6.02 (m, 3 H), 5.66 (br, 1 H), 5.41 (br, 1 H), 4.91–5.19 (m, 3 H), 4.84 (m, 1 H), 4.70 (s, 2 H), 4.42–4.66 (m, 3 H), 4.23–4.28 (m, 1 H), 3.97–4.02 (m, 1 H), 3.78 and 3.79 (s, 3 H), 3.57 (s, 3 H), 3.49 and 3.52 (s, 3 H), 3.49–3.75 (m, 3 H), 2.96–3.05 (m, 1 H), 2.81–2.90 (m, 1 H), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 168.8, 168.7, 155.7, 155.0, 149.4, 149.2, 148.1, 141.9, 141.8, 140.5, 137.0, 136.7, 135.7, 133.6, 132.0, 131.8, 130.4, 130.0, 128.6, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 127.7, 126.2, 125.6, 125.5, 110.1, 110.0, 105.2, 104.8, 104.6, 101.5, 75.5, 75.1, 71.9, 70.5, 70.3, 65.6, 65.4, 60.1, 60.0, 57.4, 56.9, 56.8, 55.3, 55.0, 54.9, 54.8, 51.3, 51.1, 50.8, 50.4, 42.5, 41.9, 24.2, 24.0, 15.7.

HRMS (ESI): m/z [M + H]+ calcd for C42H46ClN2O12: 805.2739; found: 805.2743.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-{(4R,6R)-4-[6-(benzyl­oxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-4-yl]-9,9,10,10-tetramethyl-3-oxo-2,8-dioxa-5-aza-9-silaundecan-6-yl}-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (36)

To a solution of 35 (537 mg, 0.667 mmol) in CH2Cl2 (10 mL) at 0 °C were added pyridine (0.08 mL, 1.0 mmol, 1.5 equiv) and Tf2O (0.17 mL, 1.0 mmol, 1.5 equiv). After stirring for 0.5 h, the reaction mixture was diluted with EtOAc (10 mL), and quenched with sat. aq NaHCO3 (10 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–hexane, 40%) to afford the corresponding triflate.

Yield: 503 mg (0.537 mmol, 81%); colorless foam; [α]D 23 –13 (c 0.64, CHCl3).

IR (neat film): 3319, 2939, 2837, 2363, 1743, 1699, 1498, 1460, 1425, 1408, 1377, 1358, 1309, 1288, 1211, 1138, 1087, 1001, 956, 912, 831, 734, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.52 and 7.58 (d, J = 7.1 Hz, 2 H), 7.33–7.43 (m, 8 H), 6.82 (s, 1 H), 5.85–6.08 (m, 3 H), 5.78 and 5.79 (br, 1 H), 4.85–5.18 (m, 4 H), 4.72 (s, 2 H), 4.45–4.69 (m, 3 H), 4.27–4.30 (m, 1 H), 3.99–4.04 (m, 1 H), 3.76 and 3.78 (s, 3 H), 3.68–3.74 (m, 2 H), 3.58 (s, 3 H), 3.50 and 3.52 (s, 3 H), 3.50–3.61 (m, 2 H), 2.97–3.06 (m, 1 H), 2.84–2.92 (m, 1 H), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 168.2, 168.0, 156.0, 155.2, 149.6, 149.4, 148.3, 146.2, 146.1, 140.6, 140.2, 137.0, 136.7, 135.3, 132.4, 132.2, 132.1, 130.2, 128.9, 128.6, 128.3, 128.2, 128.1, 128.0, 127.3, 126.9, 126.2, 125.9, 125.8, 124.0, 123.0, 122.5, 119.8, 119.0, 118.8, 116.6, 105.5, 105.4, 104.2, 103.0, 75.8, 75.5, 71.7, 70.4, 70.3, 60.2, 57.6, 57.0, 56.9, 55.5, 55.0, 54.8, 54.7, 51.7, 51.5, 50.9, 50.5, 42.7, 42.2, 24.4, 24.2, 15.9.

HRMS (ESI): m/z [M + H]+ calcd for C43H45ClF3N2O14S: 937.2232; found: 937.2235.

To a solution of the above triflate (179 mg, 0.191 mmol) in MeOH (8 mL) was added Et3N (0.06 mL, 0.4 mmol, 2 equiv) at r.t., and the reaction was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in DMF (8 mL) at 0 °C were added TBSCl (44.0 mg, 0.29 mmol, 1.5 equiv) and imidazole (19.5 mg, 0.286 mmol, 1.50 equiv), and the mixture was allowed to warm to r.t. and stirred for 1 h. TBSCl (22.0 mg, 0.146 mmol, 0.80 equiv) and imidazole (10.0 mg, 0.147 mmol, 0.80 equiv) were added at r.t. and the mixture was stirred for an additional 1 h. The reaction mixture was diluted with EtOAc (15 mL), and washed with brine (15 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL) and the combined organic phase was washed with 20% aq NaCl (3 × 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 20%) to afford 36.

Yield: 187 mg (0.173 mmol, 91% over 2 steps); colorless foam; [α]D 23 –16 (c 0.42, CHCl3).

IR (neat film): 2953, 2932, 2856, 2363, 2341, 1741, 1699, 1643, 1496, 1458, 1427, 1406, 1358, 1311, 1271, 1249, 1213, 1138, 1078, 1005, 956, 902, 835, 773, 736, 696 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.51–7.52 (m, 2 H), 7.29–7.38 (m, 8 H), 6.80 (s, 1 H), 6.42 (s, 1 H), 5.95 (s, 1 H), 5.86 and 5.86 (s, 1 H), 5.60 and 5.75 (d, J = 10.5 Hz, 1 H), 5.11–5.20 (m, 1 H), 5.02 and 5.05 (s, 1 H), 4.84–4.86 (m, 2 H), 4.68 and 4.76 (br, 1 H), 4.18–4.23 (m, 2 H), 3.94–3.98 (m, 1 H), 3.39–3.79 (m, 6 H), 3.76 (s, 3 H), 3.53 (s, 3 H), 3.42 (s, 3 H), 3.14–3.21 (m, 2 H), 2.78–2.82 (m, 1 H), 2.26 (s, 3 H), 0.84 (s, 9 H), 0.01 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 171.2, 155.6, 149.3, 148.0, 146.1, 140.7, 139.3, 137.9, 135.3, 132.4, 131.1, 130.5, 128.0, 127.9, 127.7, 127.2, 126.8, 124.9, 124.6, 121.9, 119.7, 119.0, 118.9, 116.5, 105.9, 104.8, 103.9, 102.5, 73.9, 71.4, 65.1, 65.0, 60.0, 57.4, 57.1, 56.9, 56.7, 55.3, 51.8, 51.3, 41.7, 25.8, 24.0, 18.3, 15.8, –5.4.

HRMS (ESI): m/z [M + H]+ calcd for C50H63ClF3N2O15SSi: 1083.3359; found: 1083.3356.


#

(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-[(R)-1-({(R)-1-[6-(benzyloxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-4-yl]-2-hydroxyethyl}amino)-2-{(tert-butyldimethylsilyl)oxy}ethyl]-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (37)

To a mixture of 36 (245 mg, 0.226 mmol) and LiCl (96.0 mg, 2.26 mmol, 10.0 equiv) in THF (3.75 mL) were added NaBH4 (86.0 mg, 2.27 mmol, 10.0 equiv) and EtOH (7.5 mL) at 0 °C, and the mixture was allowed to warm to r.t. and stirred for 2 d. The reaction mixture was diluted with EtOAc (10 mL), and quenched with 1 M aq HCl (10 mL) at 0 °C, and the mixture was neutralized with sat. aq NaHCO3 (10 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 30%) to afford 37.

Yield: 217 mg (0.206 mmol, 91%); colorless foam; [α]D 23 9.7 (c 0.42, CHCl3).

IR (neat film): 3476, 2932, 2858, 2361, 2341, 1699, 1647, 1498, 1456, 1425, 1406, 1358, 1311, 1286, 1249, 1211, 1138, 1078, 1003, 951, 835, 773, 736, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.52–7.57 (m, 2 H), 7.28–7.38 (m, 8 H), 6.84 (s, 1 H), 6.29 and 6.32 (br, 1 H), 5.83–5.91 (m, 2 H), 5.09–5.78 (m, 1 H), 4.70–4.95 (m, 4 H), 4.02–4.48 (m, 2 H), 3.83 (br, 3 H), 3.56 (s, 3 H), 3.06–3.77 (m, 12 H), 2.85–2.87 (m, 1 H), 2.28 (s, 3 H), 0.81 (s, 9 H), –0.01 (s, 3 H), –0.08 (br, 3 H).

13C NMR (100 MHz, CDCl3): δ = 149.7, 148.2, 146.3, 140.1, 139.5, 137.9, 137.7, 135.4, 131.2, 129.7, 129.2, 128.5, 128.2, 128.0, 127.6, 127.4, 126.9, 125.6, 121.9, 119.9, 116.7, 106.2, 105.0, 104.4, 104.2, 102.5, 71.7, 65.4, 63.5, 62.0, 61.0, 60.3, 58.8, 57.9, 57.7, 57.4, 57.2, 57.0, 56.0, 55.5, 51.6, 51.3, 42.8, 41.7, 25.9, 24.3, 18.5, 16.0, –5.4, –5.7.

HRMS (ESI): m/z [M + H]+ calcd for C49H63ClF3N2O14SSi: 1055.3410; found: 1055.3413.


#

(3R,5R,6R,12S,12aS)-2-chloroethyl 7-(benzyloxy)-3-[6-(benzyl­oxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-4-yl]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-8-methoxy-9-methyl-3,5,6,11,12,12a-hexahydro-2H-6,12-epiminobenzo[e]oxazolo[3,2-a]azocine-13-carboxylate (38)

To a solution of 37 (124 mg, 0.117 mmol) in CH2Cl2 (4 mL) was added a solution of BF3·OEt2 (0.075 mL, 0.59 mmol, 5.0 equiv) in CH2Cl2 (1 mL) at 0 °C, and the reaction was stirred for 1 h. To the reaction mixture was added a solution of BF3·OEt2 (0.075 mL, 0.52 mmol, 5.0 equiv) in CH2Cl2 (1 mL) at 0 °C, and the mixture was stirred for an additional 55 min. The reaction mixture was diluted with EtOAc (10 mL), and quenched with sat. aq NaHCO3 (10 mL) at 0 °C. The organic layer was separated at r.t., and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 25%) to afford 38.

Yield: 85.2 mg (0.0859 mmol, 73%); white foam; [α]D 23 –31 (c 0.43, CHCl3).

IR (neat film): 2953, 2930, 2887, 2856, 2361, 2341, 1707, 1635, 1489, 1452, 1427, 1344, 1325, 1286, 1251, 1215, 1138, 1093, 1020, 906, 835, 773, 736, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.1 Hz, 1 H), 7.53 (d, J = 6.6 Hz, 1 H), 7.26–7.44 (m, 8 H), 6.75 and 6.77 (s, 1 H), 6.55 (s, 1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.87 and 5.88 (d, J = 1.2 Hz, 1 H), 5.46 and 5.48 (d, J = 2.2 Hz, 1 H), 5.37 and 5.41 (dd, J = 8.1, 4.2 Hz, 1 H), 5.20 and 5.25 (d, J = 10.5 Hz, 1 H), 4.73–4.91 (m, 4 H), 4.22–4.45 (m, 4 H), 4.11 (dd, J = 7.3, 1.0 Hz, 1 H), 3.86 and 3.87 (s, 3 H), 3.60–3.71 (m, 3 H), 3.18–3.26 (m, 2 H), 3.08 and 3.11 (d, J = 8.3 Hz, 1 H), 2.69 (d, J = 17.3 Hz, 1 H), 2.21 and 2.21 (s, 3 H), 0.63 and 0.65 (s, 9 H), –0.28 and –0.25 (s, 3 H), –0.36 and –0.33 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 154.0, 153.4, 149.2, 149.0, 147.7, 147.5, 145.3, 139.4, 139.4, 137.0, 136.9, 135.4, 131.2, 131.0, 129.8, 129.5, 128.2, 128.1, 127.8, 127.8, 127.7, 127.1, 125.2, 125.1, 124.8, 124.4, 123.6, 121.2, 119.7, 116.5, 103.1, 103.1, 102.5, 92.1, 75.3, 75.1, 71.0, 68.1, 68.0, 66.8, 66.7, 65.3, 64.9, 60.1, 60.0, 59.8, 59.6, 47.9, 47.4, 47.1, 46.1, 42.1, 41.8, 30.5, 30.2, 25.4, 17.8, 17.7, 15.7, –5.9, –5.9, –6.0.

HRMS (ESI): m/z [M + H]+ calcd for C47H55ClF3N2O12SSi: 991.2886; found: 991.2887.


#

(3R,5R,6R,12S,12aS)-2-Chloroethyl 7-(benzyloxy)-3-[6-(benzyl­oxy)-7-methylbenzo[d][1,3]dioxol-4-yl]-5-{[(tert-butyldi­methylsilyl)oxy]methyl}-8-methoxy-9-methyl-3,5,6,11,12,12a-hexahydro-2H-6,12-epiminobenzo[e]oxazolo[3,2-a]azocine-13-carboxylate (39)

To a degassed solution of 38 (76.7 mg, 0.0774 mmol) in THF (3 mL) at 0 °C was added MeZnCl (2.0 M in THF, 0.15 mL, 0.30 mmol, 3.0 equiv), and the mixture was allowed to warm to r.t. To the mixture was added [PdCl2(dppf)] (6.3 mg, 0.0086 mmol, 10 mol%), and the resulting mixture was heated to reflux. After stirring for 1 h, [PdCl2(dppf)] (6.0 mg, 0.0082 mmol, 10 mol%) and MeZnCl (2.0 M in THF, 0.60 mL, 1.2 mmol, 12 equiv) were added to the mixture and heating was continued for an additional 2.5 h. The reaction mixture was diluted with EtOAc (5 mL) and quenched with sat. aq NaHCO3 (5 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 25%) to afford 39.

Yield: 50.3 mg (0.0587 mmol, 76%); colorless foam; [α]D 23 –34.3 (c 1.57, CHCl3).

IR (neat film): 3065, 3032, 2953, 2930, 2885, 2856, 2361, 2251, 1950, 1707, 1610, 1581, 1485, 1427, 1379, 1342, 1325, 1284, 1257, 1224, 1195, 1114, 1072, 1020, 939, 908, 839, 775, 734, 698, 667 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 6.8 Hz, 1 H), 7.54 (d, J = 7.1 Hz, 1 H), 7.29–7.48 (m, 8 H), 6.73 and 6.75 (s, 1 H), 6.40 and 6.41 (s, 1 H), 5.85 and 5.86 (s, 1 H), 5.77 and 5.77 (s, 1 H), 5.48 and 5.50 (d, J = 1.7 Hz, 1 H), 5.35 and 5.41 (dd, J = 7.3, 3.4 Hz, 1 H), 5.18 and 5.23 (d, J = 10.7 Hz, 1 H), 4.70–4.90 (m, 4 H), 4.22–4.45 (m, 5 H), 3.85 and 3.87 (s, 3 H), 3.61–3.75 (m, 3 H), 3.14–3.25 (m, 3 H), 2.69 (d, J = 17.3 Hz, 1 H), 2.21 (s, 3 H), 2.08 (s, 3 H), 0.67 and 0.69 (s, 9 H), –0.24 and –0.27 (s, 3 H), –0.29 and –0.32 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 154.0, 153.4, 151.4, 149.1, 148.9, 147.7, 147.4, 146.1, 137.8, 137.0, 130.9, 130.8, 130.1, 129.8, 128.2, 128.2, 128.0, 127.9, 127.7, 127.4, 127.1, 126.9, 125.2, 125.1, 125.0, 124.5, 120.5, 107.6, 101.7, 101.6, 100.4, 92.0, 91.9, 75.3, 75.1, 70.2, 68.1, 67.9, 66.6, 66.5, 65.2, 64.9, 60.2, 60.1, 60.1, 60.0, 59.8, 59.7, 48.1, 47.5, 47.1, 46.2, 42.1, 41.8, 30.5, 30.2, 25.5, 17.8, 17.8, 15.7, 8.7, –5.8, –5.8, –5.9, –5.9.

HRMS (ESI): m/z [M + H]+ calcd for C47H58ClN2O9Si: 857.3600; found: 857.3588.


#

(3R,5R,6R,12S,12aS)-2,2,2-Trichloroethyl 7-(Benzyloxy)-3-[6-(benzyloxy)-7-methylbenzo[d][1,3]dioxol-4-yl]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-8-methoxy-9-methyl-3,5,6,11,12,12a-hexahydro-2H-6,12-epiminobenzo[e]oxazolo[3,2-a]azocine-13-carboxylate (7)

To a solution of 39 (8.7 mg, 0.010 mmol) in DMF (1 mL) was added NaI (30.0 mg, 0.200 mmol, 20.0 equiv) at r.t., and the resulting mixture was heated at 110 °C with stirring for 18 h. The reaction mixture was diluted with EtOAc (5 mL) at r.t., and quenched with H2O (5 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with 20% aqueous NaCl (3 × 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–n-hexane, 25%) to afford the iodide.

Yield: 9.1 mg (0.0096 mmol, 96%); colorless oil; [α]D 23 –32 (c 0.46, CHCl3).

IR (neat film): 2951, 2928, 2883, 2856, 1707, 1608, 1548, 1485, 1425, 1379, 1342, 1323, 1284, 1259, 1222, 1195, 1111, 1068, 1012, 939, 906, 839, 773, 734, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 6.8 Hz, 1 H), 7.53 (d, J = 6.9 Hz, 1 H), 7.30–7.44 (m, 8 H), 6.73 and 6.74 (s, 1 H), 6.39 and 6.40 (s, 1 H), 5.85 and 5.86 (s, 1 H), 5.76 and 5.77 (s, 1 H), 5.46 and 5.48 (br, 1 H), 5.35 and 5.41 (dd, J = 7.4, 3.2 Hz, 1 H), 5.18 and 5.26 (d, J = 11.0 Hz, 1 H), 4.70–4.89 (m, 4 H), 4.22–4.44 (m, 5 H), 3.84 and 3.86 (s, 3 H), 3.69–3.74 (m, 1 H), 3.32 and 3.33 (d, J = 6.8 Hz, 1 H), 3.13–3.27 (m, 4 H), 2.67 (d, J = 17.4 Hz, 1 H), 2.20 (s, 3 H), 2.08 (s, 3 H), 0.67 and 0.70 (s, 9 H), –0.21 and –0.27 (s, 3 H), –0.27 and –0.32 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 154.3, 153.7, 151.9, 149.5, 149.3, 148.2, 148.0, 146.5, 138.3, 137.6, 137.5, 137.4, 131.4, 131.2, 130.5, 130.2, 128.7, 128.6, 128.5, 128.2, 128.1, 127.8, 127.3, 125.6, 125.4, 124.9, 120.9, 107.9, 102.0, 101.9, 100.8, 92.3, 75.6, 75.4, 70.5, 68.4, 68.2, 66.9, 66.7, 65.8, 65.5, 60.4, 60.4, 60.2, 60.0, 60.0, 48.3, 47.7, 47.3, 46.4, 30.8, 30.4, 25.7, 25.7, 18.0, 17.9, 15.8, 8.8, 1.7, –5.7, –5.8.

HRMS (ESI): m/z [M + H]+ calcd for C47H58IN2O9Si: 949.2956; found: 949.2964.

To a solution of the above iodide (9.1 mg, 0.00959 mmol) in THF (1.0 mL) at r.t. were added an excess of zinc powder, and acetic acid (0.03 mL). After stirring for 1 h, additional acetic acid (0.03 mL) and excess zinc powder were added to the mixture, which was stirred for another 1 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue in CH2Cl2 (1.0 mL) at 0 °C were added pyridine (0.5 mL, large excess) and 2,2,2-trichloroethyl chloroformate (0.25 mL, large excess). After stirring for 1 h, the reaction mixture was diluted with EtOAc (5 mL), and quenched with sat. aq NaHCO3 (5 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc–hexane, 30%) to afford 7.

Yield: 3.9 mg (0.0042 mmol, 44% over 2 steps); colorless oil; [α]D 23 –32 (c 0.16, CHCl3).

IR (neat film): 3726, 3626, 3586, 2928, 2883, 2854, 2361, 2341, 1720, 1485, 1427, 1377, 1342, 1323, 1282, 1259, 1222, 1195, 1116, 1072, 1022, 939, 906, 839, 775, 667 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 6.8 Hz, 1 H), 7.26–7.49 (m, 8 H), 6.77 and 6.73 (s, 1 H), 6.41 and 6.40 (s, 1 H), 5.86 (s, 1 H), 5.77 (s, 1 H), 5.57 and 5.51 (s, 1 H), 5.41 (br, 1 H), 5.21 (dd, J = 10.4, 10.4 Hz, 1 H), 4.93 (dd, J = 7.2, 6.0 Hz, 1 H), 4.69–5.02 (m, 5 H), 4.20–4.35 (m, 3 H), 3.87 and 3.83 (s, 3 H), 3.74 (m, 1 H), 3.14–3.35 (m, 3 H), 2.73 (dd, J = 17.6, 6.0 Hz, 1 H), 2.21 (s, 3 H), 2.09 (s, 3 H), 0.71 and 0.69 (s, 9 H), –0.21 and –0.26 (s, 3 H), –0.27 and –0.31 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 153.1, 153.5, 151.8, 149.5, 149.4, 148.1, 147.6, 146.5, 138.2, 137.4, 137.3, 131.4, 131.2, 130.2, 129.9, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.7, 127.2, 127.2, 125.5, 125.0, 124.4, 120.7, 120.6, 107.9, 101.9, 101.7, 100.7, 100.6, 95.4, 62.1, 62.1, 75.5, 75.2, 75.0, 74.8, 70.3, 68.9, 68.3, 68.1, 66.7, 66.6, 60.5, 60.3, 60.2, 60.1, 60.0, 59.9, 48.5, 48.1, 47.5, 46.7, 30.7, 30.5, 25.6, 17.8, 15.7, 15.7, 8.7, –5.9, –5.9, –6.0, –6.0.

HRMS (ESI): m/z [M + H]+ calcd for C47H56Cl3N2O9Si: 927.2791; found: 927.2787.


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Acknowledgment

This work was financially supported by Grants-in-Aid for Scientific Research (20002004, 22590002) from the Japan Society for the Promotion of Science (JSPS), the Research Foundation for Pharmaceutical Sciences, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Uehara Memorial Foundation.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Zoom Image
Figure 1 Structure of ecteinascidin 743 (1; trabectedin)
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Scheme 1
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Scheme 2
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Scheme 3
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Scheme 4 Reagents and conditions: (a) BnBr, K2CO3, acetone, r.t., 90%; (b) phosphonate 21, N,N,N′,N′-tetramethylguanidine, r.t., 89%; (c) H2 (500 psi), {Rh[(cod)-(S,S)-Et-DuPHOS]OTf} (1.5 mol%), EtOAc, 50 °C, 85%; (d) AcCl, MeOH, 0 °C to r.t.; (e) CbzCl, Et3N, CH2Cl2, 0 °C to r.t., 75% (2 steps); (f) LiOH, H2O, 0 °C to r.t.; (g) MeNHOMe·HCl, EDCI·HCl, HOBt, Et3N, 0 °C to r.t., 80% (2 steps); (h) DIBAL-H, –78 °C; (i) HC(OMe)3, TsOH, MeOH, r.t.; (j) 10% Pd/C, MeOH, 62% (3 steps).
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Scheme 5 Reagents and conditions: (a) p-NsCl, Et3N, CH2Cl2, 0 °C to r.t., 92%; (b) 2,2-dimethoxypropane, TsOH, benzene, reflux, 98%; (c) DIBAL-H, –78 °C, toluene, quant.
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Scheme 6 Reagents and conditions: (a) HCO2H, Na2SO4, CH2Cl2, 83%; (b) BnBr, K2CO3, acetone, 99%; (c) 2-chloroethyl chloroformate, pyridine, CH2Cl2, 0 °C to r.t., 90%; (d) 2-mercaptoethanol, DBU, MeCN, 0 °C to r.t., 84%.
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Scheme 7 Reagents and conditions: (a) phenyl bromoacetate (31), i-Pr2NEt, MeCN, 0 °C to r.t., 90%; (b) NBS, Et3N, CH2Cl2, 0 °C to r.t., 89%; (c) phenol 34, TFA, CH2Cl2, 0 °C, 81%; (d) Tf2O, pyridine, CH2Cl2, 0 °C, 80%; (e) Et3N, MeOH; (f) TBSCl, imidazole, DMF, 0 °C to r.t., 90% (2 steps); (g) NaBH4, LiCl, THF–EtOH, 89%; (h) BF3·OEt2, CH2Cl2, 0 °C, 73%; (i) MeZnCl, [PdCl2(dppf)], THF, reflux, 76%; (j) NaI, DMF, 110 °C, 96%; (k) Zn, AcOH, THF, r.t.; (l) TrocCl, pyridine, CH2Cl2, 44% (2 steps).