130288-24-3

Basic information

• Product Name: Duocarmycin SA
• Synonyms: Duocarmycin SA;Cyclopropacpyrrolo3,2-eindole-6-carboxylic acid, 1,2,4,5,8,8a-hexahydro-4-oxo-2-(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl-, methyl ester, (7bR)-;Antibiotic DC 113;Cyclopropa[c]pyrrolo[3,2-e]indole-6-carboxylicacid,1,2,4,5,8,8a-hexahydro-4-oxo-2-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-,methyl ester, (7bR,8aS)-
• CAS NO: 130288-24-3
• Molecular Formula: C₂₅H₂₃N₃O₇
• Molecular Weight: 477.471
• Mol File: 130288-24-3.mol
• Article Data: 11

Chemical Properties

• Boiling Point: 787.7°Cat760mmHg
• Flash Point: 430.2°C
• Appearance: /
• Density: 1.53g/cm³
• Vapor Pressure: 8.82E-25mmHg at 25°C
• Refractive Index: 1.711
• PKA: 13.12±0.20(Predicted)
• CAS DataBase Reference: Duocarmycin SA(CAS DataBase Reference)
• NIST Chemistry Reference: Duocarmycin SA(130288-24-3)
• EPA Substance Registry System: Duocarmycin SA(130288-24-3)

Safety Data

• Hazardous Substances Data: 130288-24-3(Hazardous Substances Data)

Usage

Uses

Duocarmycin SA is an antitumor antibiotic.

InChI:InChI=1/C25H23N3O7/c1-32-17-6-11-5-14(26-19(11)22(34-3)21(17)33-2)23(30)28-10-12-9-25(12)13-7-15(24(31)35-4)27-20(13)16(29)8-18(25)28/h5-8,12,26-27H,9-10H2,1-4H3/t12-,25-/m1/s1

Synthetic route

methyl (S)-4-hydroxy-8-(hydroxymethyl)-6-(5,6,7-trimethoxy-1Hindole-2-carbonyl)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-2-carboxylate → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With tributylphosphine; azodicarbonyl dimorpholide In tetrahydrofuran for 2h; Inert atmosphere; enantioselective reaction;	94%
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran for 0.333333h; Inert atmosphere;

(8S)-4-hydroxy-8-methanesulfonyloxymethyl-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-3,6,7,8-tetrahydro-3,6-diaza-as-indacene-2-carboxylic acid methyl ester → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With caesium carbonate In acetonitrile at 23℃; for 1h;	92%

duocarmycin (144667-38-9) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 3h; Ambient temperature;	91%
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 0.5h;	87%
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 30h;
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 25℃; for 1h;

methyl (S)-4-[(5,6,7-trimethoxyindol-2yl)carbonyl]-2,6-dihydroxy-1,2,3,4-tetrahydropyrrolo[3,2-f]quinoline-8-carboxylate (919535-11-8) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 25℃; for 0.5h; Mitsunobu reaction;	62%

(R)-8-Chloromethyl-4-hydroxy-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-3,6,7,8-tetrahydro-pyrrolo[3,2-e]indole-2-carboxylic acid methyl ester → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 30h;

C13H12N2O3 + 1-(5,6,7-trimethoxyindole-2-carbonyl)imidazole (157425-68-8) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With sodium hydride 1.) DMF, THF, 2.) DMF, THF, 0 deg C; Yield given. Multistep reaction;

(+)-(7bR,8aS)-methyl 4-oxo-1,2,4,5,8,8a-hexahydrocyclopropapyrrolo<3,2-e>indole-6-carboxylate (150992-82-8) + 1-(5,6,7-trimethoxyindole-2-carbonyl)imidazole (157425-68-8) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With sodium hydride 1.) DMF-THF, 2.) 0 deg C; Yield given. Multistep reaction;
With sodium hydride 1.) THF, DMF, 0 deg C, 20 min, 2.) THF, DMF, 0 deg C, 4 h; Yield given. Multistep reaction;

methyl (7bS)-(-)-1,2,4,5,8,8a-hexahydro-4-oxocyclopropapyrrolo<3,2-e>indole-6-carboxylate (151062-83-8) + 1-(5,6,7-trimethoxyindole-2-carbonyl)imidazole (157425-68-8) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
With sodium hydride 1.) THF, DMF, 0 deg C, 20 min, 2.) THF, DMF, 0 deg C, 4 h; Yield given. Multistep reaction;

3-(benzyloxy)-5-nitrobenzaldehyde (881422-32-8) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 12 steps 1.1: 78 percent / NaOMe / methanol; tetrahydrofuran / 17 h / -25 °C 2.1: 68 percent / xylene / 7 h / 140 °C 3.1: 98 percent / DMAP / tetrahydrofuran / 1 h / 25 °C 4.1: 98 percent / Zn; NH4Cl / acetone; H2O / 0.5 h / 25 °C 5.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 6.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 7.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 8.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 8.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 9.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 10.1: HCl / ethyl acetate / 3 h / 25 °C 11.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 12.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl 2-azido-3-(3-benzyloxy-5-nitrophenyl)acrylate → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 11 steps 1.1: 68 percent / xylene / 7 h / 140 °C 2.1: 98 percent / DMAP / tetrahydrofuran / 1 h / 25 °C 3.1: 98 percent / Zn; NH4Cl / acetone; H2O / 0.5 h / 25 °C 4.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 5.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 6.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 7.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 7.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 8.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 9.1: HCl / ethyl acetate / 3 h / 25 °C 10.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 11.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

4,8-dihydroxy-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinoline-2-carboxylic acid methyl ester → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions	Yield
Multi-step reaction with 2 steps 1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 2: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl (S)-4,7-di-tert-butoxycarbonyl-2,6-dihydroxy-1,2,3,4-tetrahydropyrrolo[3,2-f]quinoline-8-carboxylate (919535-09-4) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions	Yield
Multi-step reaction with 3 steps 1: HCl / ethyl acetate / 3 h / 25 °C 2: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 3: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

1-(1,1-dimethylethyl)-2-methyl 5-[[(1,1-dimethylethoxy)-carbonyl]amino]-4-iodo-7-(phenylmethoxy)indole-1,2-dicarboxylate (919535-06-1) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 2.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 2.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 3.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 4.1: HCl / ethyl acetate / 3 h / 25 °C 5.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 6.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl (S)-4,7-di-tert-butoxycarbonyl-6-benzyloxy-2-hydroxy-1,2,3,4-tetrahydropyrrolo[3,2-f]quinoline-8-carboxylate (919535-08-3) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions	Yield
Multi-step reaction with 4 steps 1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 2: HCl / ethyl acetate / 3 h / 25 °C 3: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 4: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl (R)-7-benzyloxy-1-(tert-butoxycarbonyl)-5-(tert-butoxycarbonyl-(oxiran-2-ylmethyl)amino)-4-iodoindole-2-carboxylate (919535-07-2) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions	Yield
Multi-step reaction with 5 steps 1.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 1.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 2.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 3.1: HCl / ethyl acetate / 3 h / 25 °C 4.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 5.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

3,5-dinitrobenzaldehyde (14193-18-1) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 13 steps 1.1: syn-benzaldehyde oxime; K2CO3 / dimethylformamide / 1.25 h / 90 °C 1.2: 86 percent / dimethylformamide / 2 h / 25 °C 2.1: 78 percent / NaOMe / methanol; tetrahydrofuran / 17 h / -25 °C 3.1: 68 percent / xylene / 7 h / 140 °C 4.1: 98 percent / DMAP / tetrahydrofuran / 1 h / 25 °C 5.1: 98 percent / Zn; NH4Cl / acetone; H2O / 0.5 h / 25 °C 6.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 7.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 8.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 9.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 9.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 10.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 11.1: HCl / ethyl acetate / 3 h / 25 °C 12.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 13.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl 7-(benzyloxy)-5-nitro-1H-indole-2-carboxylate (539856-42-3) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 10 steps 1.1: 98 percent / DMAP / tetrahydrofuran / 1 h / 25 °C 2.1: 98 percent / Zn; NH4Cl / acetone; H2O / 0.5 h / 25 °C 3.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 4.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 5.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 6.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 6.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 7.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 8.1: HCl / ethyl acetate / 3 h / 25 °C 9.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 10.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

1-(1,1-dimethylethyl)-2-methyl-5-nitro-6-(phenylmethoxy)-indole-1,2-dicarboxylate (539856-49-0) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 9 steps 1.1: 98 percent / Zn; NH4Cl / acetone; H2O / 0.5 h / 25 °C 2.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 3.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 4.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 5.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 5.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 6.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 7.1: HCl / ethyl acetate / 3 h / 25 °C 8.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 9.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl 5-amino-7-(benzyloxy)-1-(tert-butoxycarbonyl)indole-2-carboxylate (539856-43-4) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 227 mg / tetrahydrofuran / 10 h / 25 °C 2.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 3.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 4.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 4.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 5.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 6.1: HCl / ethyl acetate / 3 h / 25 °C 7.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 8.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

methyl 7-(benzyloxy)-1-(tert-butoxycarbonyl)-5-[(tert-butoxycarbonyl)amino]indole-2-carboxylate (539856-50-3) → (+)-duocarmycin SA (130288-24-3) + calf thymus DNA

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 91 percent / N-iodosuccinimide; AcOH / toluene / 8 h / 25 °C 2.1: 96 percent / NaH / dimethylformamide / 2 h / 0 °C 3.1: i-PrMgBr / tetrahydrofuran / 1 h / -40 °C 3.2: 69 percent / CuI; Bu3P / tetrahydrofuran / 1.5 h / -78 - -40 °C 4.1: 82 percent / H2 / Pd/C / methanol; tetrahydrofuran / 0.5 h / 25 °C 5.1: HCl / ethyl acetate / 3 h / 25 °C 6.1: 3.7 mg / EDCI / dimethylformamide / 2 h / 0 °C 7.1: 62 percent / Bu3P; ADDP / tetrahydrofuran / 0.5 h / 25 °C View Scheme

p-nitrophenyl methanesulfonate (20455-07-6) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 26 steps 1.1: 100 percent / H2 / Ra-Ni / ethyl acetate; ethanol / 24 h / 23 °C / 72400.7 Torr 2.1: 94.5 g / Br2 / methanol; CH2Cl2 / 0.5 h / 0 - 23 °C 3.1: aq. NaNO2; H2SO4 / acetonitrile / 0 °C 3.2: 96 percent / aq. KI / acetonitrile / 0.75 h 4.1: 100 percent / KOH / CH2Cl2; methanol / 0.08 h / 23 °C 5.1: 88 percent / K2CO3 / dimethylformamide / 1 h / 23 °C 6.1: n-BuLi / toluene; hexane / -78 °C 6.2: 4.18 g / toluene 7.1: aq. acetic acid / 3 h / 100 °C 8.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 9.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 10.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 11.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 12.1: K2CO3 / dimethylformamide / 1 h / 23 °C 13.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 14.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 15.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 16.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 16.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 17.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 18.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 19.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 20.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 21.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 22.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 23.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 24.1: 88 percent / pyridine / 0.17 h / 23 °C 25.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 26.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

methanesulfonic acid 4-aminophenyl ester (24690-19-5) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 25 steps 1.1: 94.5 g / Br2 / methanol; CH2Cl2 / 0.5 h / 0 - 23 °C 2.1: aq. NaNO2; H2SO4 / acetonitrile / 0 °C 2.2: 96 percent / aq. KI / acetonitrile / 0.75 h 3.1: 100 percent / KOH / CH2Cl2; methanol / 0.08 h / 23 °C 4.1: 88 percent / K2CO3 / dimethylformamide / 1 h / 23 °C 5.1: n-BuLi / toluene; hexane / -78 °C 5.2: 4.18 g / toluene 6.1: aq. acetic acid / 3 h / 100 °C 7.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 8.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 9.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 10.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 11.1: K2CO3 / dimethylformamide / 1 h / 23 °C 12.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 13.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 14.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 15.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 15.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 16.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 17.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 18.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 19.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 20.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 21.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 22.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 23.1: 88 percent / pyridine / 0.17 h / 23 °C 24.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 25.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

2-bromo-3,4,5-tri-methoxybenzaldehyde (35274-53-4) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
Multi-step reaction with 10 steps 1: 97 percent / 1,1,3,3-tetramethylguanidine / CH2Cl2 / 48 h / 23 °C 2: 98 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 3: 99 percent / H2 / Pd/C / ethyl acetate; ethanol / 3 h / 23 °C 4: 89 percent / aq. KOH / methanol / 1 h / Heating 5: SOCl2; DMF / toluene / 0.33 h / 70 °C 6: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 7: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 8: 88 percent / pyridine / 0.17 h / 23 °C 9: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 10: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme
Multi-step reaction with 9 steps 1.1: potassium acetate / tetrahydrofuran / 2 h / 60 °C / Inert atmosphere 2.1: triethylamine / methanol / 0.5 h / 60 °C 3.1: 1,10-Phenanthroline; potassium carbonate; copper(l) iodide / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 4.1: water; tetrahydrofuran / 3 h / 60 °C / Inert atmosphere 5.1: oxalyl dichloride / N,N-dimethyl-formamide; tetrahydrofuran / 1 h / Inert atmosphere 5.2: Reflux 6.1: 2,6-dimethylpyridine / dichloromethane / 0.5 h / 2.2 °C / Inert atmosphere 7.1: 10 wt% Pd(OH)2 on carbon; hydrogen; ammonium formate / methanol / 1 h / 35 - 50 °C / Inert atmosphere 8.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 35 °C / Inert atmosphere 9.1: tributylphosphine; azodicarbonyl dimorpholide / tetrahydrofuran / 2 h / Inert atmosphere View Scheme

5,6,7-trimethoxy-1H-indole-2-carboxylic acid (128781-07-7) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: SOCl2; DMF / toluene / 0.33 h / 70 °C 2: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 3: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 4: 88 percent / pyridine / 0.17 h / 23 °C 5: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 6: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme
Multi-step reaction with 2 steps 1: EDCI, NaHCO3 / dimethylformamide / 15 h / 25 °C 2: 87 percent / NaH / tetrahydrofuran; dimethylformamide / 0.5 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; tetrahydrofuran / 1 h / Inert atmosphere 1.2: Reflux 2.1: 2,6-dimethylpyridine / dichloromethane / 0.5 h / 2.2 °C / Inert atmosphere 3.1: 10 wt% Pd(OH)2 on carbon; hydrogen; ammonium formate / methanol / 1 h / 35 - 50 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 35 °C / Inert atmosphere 5.1: tributylphosphine; azodicarbonyl dimorpholide / tetrahydrofuran / 2 h / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 0.5 h 2.1: 2,6-dimethylpyridine / dichloromethane / 0.5 h 3.1: zinc; acetic acid / acetonitrile / 72 h 4.1: magnesium sulfate / dichloromethane / 23 h 4.2: 4 h / 50 °C 5.1: 20% palladium hydroxide-activated charcoal; ammonium formate; methanol / water / 50 °C / Inert atmosphere 5.2: 3 h / 35 °C / Inert atmosphere 6.1: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 0.33 h / Inert atmosphere View Scheme

5,6,7-trimethoxy-1H-indole-2-carboxylic acid methyl ester (118292-37-8) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: 89 percent / aq. KOH / methanol / 1 h / Heating 2: SOCl2; DMF / toluene / 0.33 h / 70 °C 3: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 4: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 5: 88 percent / pyridine / 0.17 h / 23 °C 6: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 7: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

3,4,5-trimethoxy-benzaldehyde (86-81-7) → (+)-duocarmycin SA (130288-24-3)

Conditions	Yield
Multi-step reaction with 11 steps 1: 87 percent / Br2; AcOH / CH2Cl2 / 0.5 h / 0 °C 2: 97 percent / 1,1,3,3-tetramethylguanidine / CH2Cl2 / 48 h / 23 °C 3: 98 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 4: 99 percent / H2 / Pd/C / ethyl acetate; ethanol / 3 h / 23 °C 5: 89 percent / aq. KOH / methanol / 1 h / Heating 6: SOCl2; DMF / toluene / 0.33 h / 70 °C 7: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 8: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 9: 88 percent / pyridine / 0.17 h / 23 °C 10: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 11: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme
Multi-step reaction with 10 steps 1.1: N-Bromosuccinimide / acetonitrile / 1 h / 50 °C / Inert atmosphere 2.1: potassium acetate / tetrahydrofuran / 2 h / 60 °C / Inert atmosphere 3.1: triethylamine / methanol / 0.5 h / 60 °C 4.1: 1,10-Phenanthroline; potassium carbonate; copper(l) iodide / N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere 5.1: water; tetrahydrofuran / 3 h / 60 °C / Inert atmosphere 6.1: oxalyl dichloride / N,N-dimethyl-formamide; tetrahydrofuran / 1 h / Inert atmosphere 6.2: Reflux 7.1: 2,6-dimethylpyridine / dichloromethane / 0.5 h / 2.2 °C / Inert atmosphere 8.1: 10 wt% Pd(OH)2 on carbon; hydrogen; ammonium formate / methanol / 1 h / 35 - 50 °C / Inert atmosphere 9.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 35 °C / Inert atmosphere 10.1: tributylphosphine; azodicarbonyl dimorpholide / tetrahydrofuran / 2 h / Inert atmosphere View Scheme

3,5-dibromo-4-iodophenyjl (556038-75-6) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 22 steps 1.1: 88 percent / K2CO3 / dimethylformamide / 1 h / 23 °C 2.1: n-BuLi / toluene; hexane / -78 °C 2.2: 4.18 g / toluene 3.1: aq. acetic acid / 3 h / 100 °C 4.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 5.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 6.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 7.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 8.1: K2CO3 / dimethylformamide / 1 h / 23 °C 9.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 10.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 11.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 12.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 12.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 13.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 14.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 15.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 16.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 17.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 18.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 19.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 20.1: 88 percent / pyridine / 0.17 h / 23 °C 21.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 22.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

methanesulfonic acid 4-amino-3,5-dibromophenyl ester (556038-73-4) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 24 steps 1.1: aq. NaNO2; H2SO4 / acetonitrile / 0 °C 1.2: 96 percent / aq. KI / acetonitrile / 0.75 h 2.1: 100 percent / KOH / CH2Cl2; methanol / 0.08 h / 23 °C 3.1: 88 percent / K2CO3 / dimethylformamide / 1 h / 23 °C 4.1: n-BuLi / toluene; hexane / -78 °C 4.2: 4.18 g / toluene 5.1: aq. acetic acid / 3 h / 100 °C 6.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 7.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 8.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 9.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 10.1: K2CO3 / dimethylformamide / 1 h / 23 °C 11.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 12.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 13.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 14.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 14.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 15.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 16.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 17.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 18.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 19.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 20.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 21.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 22.1: 88 percent / pyridine / 0.17 h / 23 °C 23.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 24.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

methanesulfonic acid 3,5-dibromo-4-iodophenyl ester (556038-74-5) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 23 steps 1.1: 100 percent / KOH / CH2Cl2; methanol / 0.08 h / 23 °C 2.1: 88 percent / K2CO3 / dimethylformamide / 1 h / 23 °C 3.1: n-BuLi / toluene; hexane / -78 °C 3.2: 4.18 g / toluene 4.1: aq. acetic acid / 3 h / 100 °C 5.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 6.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 7.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 8.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 9.1: K2CO3 / dimethylformamide / 1 h / 23 °C 10.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 11.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 12.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 13.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 13.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 14.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 15.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 16.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 17.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 18.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 19.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 20.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 21.1: 88 percent / pyridine / 0.17 h / 23 °C 22.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 23.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

3,5-dibromo-4-iodophenol benzyl ether (556038-43-8) → (+)-duocarmycin SA (130288-24-3)

Conditions

Yield

Multi-step reaction with 21 steps 1.1: n-BuLi / toluene; hexane / -78 °C 1.2: 4.18 g / toluene 2.1: aq. acetic acid / 3 h / 100 °C 3.1: H5IO6 / tetrahydrofuran / 0.08 h / 0 °C 4.1: 2.76 percent / NaBH4 / methanol / 0.08 h / -78 °C 5.1: aq. HCl; Fe; FeCl2 / ethanol / 2 h / Heating 6.1: 3.42 percent / aq. NaHCO3 / CH2Cl2 / 0.08 h / 23 °C 7.1: K2CO3 / dimethylformamide / 1 h / 23 °C 8.1: 1.91 g / PhSH / dimethylformamide / 1 h / 23 °C 9.1: 67 percent / CuI; CsOAc / dimethylsulfoxide / 24 h / 23 °C 10.1: 100 percent / imidazole / dimethylformamide / 0.17 h / 23 °C 11.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 11.2: 97 percent / I2 / tetrahydrofuran; hexane / 0.33 h / -78 °C 12.1: 72 percent / PdCl2; P(o-tolyl)3; Et3N / acetonitrile / 4 h / 90 °C / Heating 13.1: 82 percent / NBS / dimethylformamide / 0.08 h / 23 °C 14.1: 100 percent / CuI; CsOAc / dimethylsulfoxide / 0.17 h / 23 °C 15.1: 77 percent / NaHCO3 / acetonitrile / 0.33 h / 70 °C 16.1: 58 percent / Zn; aq. KH2PO4 / tetrahydrofuran / 1 h / 23 °C 17.1: 83 percent / pyridine; CH2Cl2 / 0.17 h / 0 °C 18.1: 85 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.5 h / 23 °C 19.1: 88 percent / pyridine / 0.17 h / 23 °C 20.1: 81 percent / H2 / Pd/C / ethanol; ethyl acetate / 0.17 h / 23 °C 21.1: 92 percent / Cs2CO3 / acetonitrile / 1 h / 23 °C View Scheme

(+)-duocarmycin SA (130288-24-3) → (+)-(7bR,8aS)-methyl 4-oxo-1,2,4,5,8,8a-hexahydrocyclopropapyrrolo<3,2-e>indole-6-carboxylate (150992-82-8)

Conditions	Yield
With sodium methylate In methanol; acetonitrile for 1h; Ambient temperature;	99%

(+)-duocarmycin SA (130288-24-3) → duocarmycin (144667-38-9)

Conditions	Yield
With hydrogenchloride In ethyl acetate at 0℃; for 0.25h;	96%

(+)-duocarmycin SA (130288-24-3) + calf thymus DNA → (+)-duocarmycin SA-adenine adduct

Conditions	Yield
With potassium phosphate buffer In N,N-dimethyl-formamide at 37℃; for 24h;	81%
With sodium phosphate buffer 1.) 25 deg C, 24 h, 2.) 100 deg C, 25 min; Yield given. Multistep reaction;

(+)-duocarmycin SA (130288-24-3) → (S)-8-Chloromethyl-4-oxo-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-3,4,6,7,8,8a-hexahydro-pyrrolo[3,2-e]indole-2-carboxylic acid methyl ester

Conditions	Yield
With hydrogenchloride In acetonitrile for 1h; Ambient temperature;

(+)-duocarmycin SA (130288-24-3) → (S)-8-Bromomethyl-4-oxo-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-3,4,6,7,8,8a-hexahydro-pyrrolo[3,2-e]indole-2-carboxylic acid methyl ester

Conditions	Yield
With hydrogen bromide In acetonitrile for 1h; Ambient temperature;

(+)-duocarmycin SA (130288-24-3) + calf thymus DNA → (-)-duocarmycin SA-adenine adduct

Conditions	Yield
With sodium phosphate buffer 1.) 25 deg C, 3 d, 2.) 100 deg C, 30 min; Yield given. Multistep reaction;

Upstream product

• 144667-38-9 duocarmycin 
• 152785-82-5 (R)-8-Chloromethyl-4-hydroxy-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-3,6,7,8-tetrahydro-pyrrolo[3,2-e]indole-2-carboxylic acid methyl ester 
• 157425-68-8 1-(5,6,7-trimethoxyindole-2-carbonyl)imidazole 
• 150992-82-8 (+)-(7bR,8aS)-methyl 4-oxo-1,2,4,5,8,8a-hexahydrocyclopropapyrrolo<3,2-e>indole-6-carboxylate 
• 151062-83-8 methyl (7bS)-(-)-1,2,4,5,8,8a-hexahydro-4-oxocyclopropapyrrolo<3,2-e>indole-6-carboxylate 
• 919535-11-8 methyl (S)-4-[(5,6,7-trimethoxyindol-2yl)carbonyl]-2,6-dihydroxy-1,2,3,4-tetrahydropyrrolo[3,2-f]quinoline-8-carboxylate 
• 14193-18-1 3,5-dinitrobenzaldehyde 
• 881422-32-8 3-(benzyloxy)-5-nitrobenzaldehyde 

Downstream Products

• 144667-38-9 duocarmycin 
• 152718-06-4 4'-methoxy cinnamoyl duocarmycin SA 

Relevant articles and documents

ENANTIOSELECTIVE SYNTHESIS OF PYRROLOINDOLE COMPOUNDS

Compounds according to formula (I) or (II), wherein R1, R2, and R3 are as defined in the specification, are versatile intermediates for the synthesis of DNA minor groove binder- alkylators having a cyclopropapyrroloindole (CPI) or seco-CPI alkylating subunit.

Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity

A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration.

Total synthesis of the duocarmycins

The total synthesis of (+)-duocarmycin A and SA through a common indoline intermediate is described. The key reactions include selective lithiation of a 2,6-dibromoiodobenzene derivative and diastereoselective addition to a chiral nitroalkene, copper-mediated aryl amination, and addition of aryllithium to azlactones. Copyright