Formal Asymmetric Synthesis of a 7-Methoxyaziridinomitosene

Joseph P. Michael; Charles B. de Koning; Theophilus T. Mudzunga; Riaan L. Petersen

doi:10.1055/s-2006-951532

LETTER

Formal Asymmetric Synthesis of a 7-Methoxyaziridinomitosene

Joseph P. Michael*, Charles B. de Koning, Theophilus T. Mudzunga, Riaan L. Petersen
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, PO Wits 2050, South Africa
Fax: +27(11)7176749; e-Mail: jmichael@chem.wits.ac.za;

Abstract

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Abstract

The conversion of (-)-2,3-O-isopropylidene-d-erythronolactone (14) and 2-benzyloxy-6-bromo-4-methoxy-3-methylaniline (18) into {(1R,2R)-(-)-1-azido-2,3,5,8-tetrahydro-7-methoxy-6-methyl-2-methanesulfonyloxy-5,8-dioxo-1H-pyrrolo-[1,2-a]indol-9-yl}methyl phenyl carbonate (39) has been accomplished in 17 steps by way of the enaminone 26. Key steps included the preparation of 26 by a Reformatsky reaction on a thiolactam precursor 25, and intramolecular Heck reaction of 26 to form the indole ring. The preparation of 39 constitutes a formal synthesis of the fully functionalised 7-methoxyaziridinomitosene 12, only the second such synthesis to have been accomplished.

Key words

antitumour agents - asymmetric synthesis - aziridines - enaminones - Heck reaction

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References

References and Notes

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Synthesis of (-)-Ethyl (2 E)-{(3aR,6aS)-5-[2-(Benzyloxy)-6-bromo-4-methoxy-3-methyphenyl]dihydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyrrol-6 (5H )-ylidene}acetate (26) : To a solution of ethyl bromoacetate (6.70 mL, 60.4 mmol, 5 equiv) in THF (250 mL) was added activated zinc powder (11.9 g, 181.9 mmol, 15 equiv) at r.t. After 5 min of stirring, iodine (2.15 g, 8.47 mmol, 0.7 equiv) was added in one portion, resulting in spontaneous reflux of the reaction mixture for a period of 5-10 min. The resulting greyish suspension was allowed to cool to r.t. over 1 h and then subjected to sonication for 1 h at 45 °C under an atmosphere of nitrogen. The mixture was allowed to cool to r.t. over 30 min, after which thiolactam 25 (rotameric mixture, 5.79 g, 12.1 mmol, 1 equiv) was added in one portion. The mixture was subsequently heated at reflux for 48 h, and then cooled to r.t. A further portion of organozinc reagent, prepared on the same scale as described above, was added, after which the mixture was heated again under reflux for 72 h. The reaction mixture was allowed to cool to r.t., and an ice-water mixture (200 mL) was added, which resulted in precipitation of inorganic solids. The organic material was extracted into Et₂O, which was dried (MgSO₄) and evaporated to yield a crude orange oil. Purification by column chromatography on silica gel using EtOAc-hexane (3:17, then 2:8) as eluent gave an inseparable mixture of vinylogous urethane rotamers 26 (5.62 g, 87%, 4:5 mixture of N-Ar rotamers by NMR spectroscopy; vide infra) as a viscous yellow oil-foam; R _f 0.41 (EtOAc-hexane 3:7); [α]_D ²³ -67.5 (c = 0.46, CHCl₃). IR (CHCl₃): 2981 (w), 1697 (s, C=O), 1476 (m), 1233 (w), 1134 (s), 735 (s) cm^-1. HRMS (EI): m/z [M⁺] calcd for C₂₆H₃₀NO₆ ⁷⁹Br: 531.1257; found: 531.1266.
Minor Rotamer: ¹H NMR (300 MHz, CDCl₃): δ = 7.26-7.44 (m, 5 H, CH₂ Ph), 6.92 (s, 1 H, 5-H), 5.65 (d, J = 6.3 Hz, 1 H, 3a-H), 4.86 (d, J = 11.4 Hz, 1 H, OCH _aH_bPh), 4.67 (d, J = 11.4 Hz, 1 H, OCH_a H _bPh), 4.56 (td, J ≈ 2.0, 6.2 Hz, 1 H, 6a-H), 4.38 (s, 1 H, =CHCO₂Et), 4.13 (q, J = 7.0 Hz, 2 H, OCH ₂CH₃), 3.82 (s, 3 H, ArOCH ₃), 3.77 (dd, J = 6.3, 10.8 Hz, 1 H, NCH _aH_b), 3.50 (dd, J = 1.8, 10.8 Hz, 1 H, NCH_a H _b), 2.12 (s, 3 H, ArCH ₃), 1.41, 1.56 (2 × s, 6 H, 2 × CH₃), 1.22 (t, J = 7.0 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 167.78 (C=O), 160.73 (C-4), 158.63, 156.40, 136.86, 128.57, 128.21, 127.97, 124.84, 121.45, 120.76 (arom C), 112.28 (O₂ CMe₂), 111.12 (arom C), 84.46 (=CHCO₂Et), 80.29 (C-3a), 75.93 (OCH₂Ph), 75.01 (C-6a), 58.79 (OCH₂CH₃), 57.61 (C-6), 55.96 (ArOCH₃), 27.15, 25.33 (2 × CH₃), 14.42 (OCH₂ CH₃), 9.59 (ArCH₃). Major Rotamer: ¹H NMR (300 MHz, CDCl₃): δ = 7.26-7.44 (m, 5 H, CH₂ Ph), 6.90 (s, 1 H, arom H), 5.93 (d, J = 6.6 Hz, 1 H, H-3a), 5.07 (d, J = 11.1 Hz, 1 H, OCH _aH_bPh), 4.94 (td, J = 2.4, 6.3 Hz, 1 H, H-6a), 4.71 (d, J = 11.1 Hz, 1 H, OCH_a H _bPh), 4.43 (s, 1 H, =CHCO₂Et), 4.13 (q, J = 7.0 Hz, 2 H, OCH ₂CH₃), 3.83-3.89 (m, 2 H, NCH₂), 3.84 (s, 3 H, ArOCH ₃), 1.99 (s, 3 H, ArCH ₃), 1.36, 1.44 (2 × s, 6 H, 2 × CH₃), 1.22 (t, J = 7.0 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 167.97 (C=O), 160.56 (C-4), 158.61, 156.21, 136.74, 128.31, 127.97, 127.48, 124.80, 121.47, 120.12 (arom C), 112.21 (O₂ CMe₂), 111.12 (arom C), 85.04 (=CHCO₂Et), 80.03 (C-3a), 76.00 (OCH₂Ph), 75.19 (C-6a), 58.82 (OCH₂CH₃), 57.68 (C-6), 55.93 (ArOCH₃), 24.85, 26.75 (2 × CH₃), 14.40 (OCH₂ CH₃), 9.45 (ArCH₃).

<A NAME="RD26706ST-21">21</A> Tietze LF. Petersen S. Eur. J. Org. Chem. 2000, 11: 1827

Synthesis of (-)-Ethyl (3a R,10bS)-6-Benzyloxy-8-methoxy-2,2,7-trimethyl-3a,10b-dihydro-4H-[1,3]dioxolo-[4′,5′:3,4]pyrrolo[1,2-a ]indole-10-carboxylate (27) : A solution of the vinylogous urethane 26 (N-Ar rotameric mixture, 5.62 g, 10.6 mmol, 1.0 equiv) in a mixture of DMF (70 mL), MeCN (70 mL) and H₂O (15 mL) was thoroughly degassed with nitrogen for 10 min. Palladium(II) acetate (710 mg, 3.16 mmol, 0.3 equiv), P(o-tolyl)₃ (5.15 g, 16.9 mmol, 1.6 equiv) and Et₃N (14.7 mL, 105 mmol, 10 equiv) were added in succession and the resulting orange mixture was heated at reflux for 4 h. The dark brown reaction mixture was cooled to r.t., diluted with H₂O (200 mL) and stirred vigorously for 1 h. The mixture was extracted with CH₂Cl₂, which was then dried (MgSO₄) and evaporated to afford a dark brown oil. Purification by column chromatography on silica gel with EtOAc-hexane (1:9 then 2:8) as eluent gave the pyrrolo[1,2-a]indole 27 (3.92 g, 82%) as a pale yellow solid. Recrystallisation from EtOAc-hexane yielded a colourless crystalline solid; mp 90-91 °C; R _f 0.49 (EtOAc-hexane, 3:7); [α]_D ²³ -85.5 (c = 0.57, abs. EtOH). IR (CHCl₃): 2982 (w), 1697 (s, C=O), 1570 (m), 1454 (m), 1433 (m), 1275 (s), 1206 (m), 1129 (s), 747 (w) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.33-7.41 (m, 6 H, 9-H, CH₂ Ph), 5.77 (s, J = 6.2 Hz, 1 H, 10b-H), 5.22 (br t, J ≈ 5.8 Hz, 1 H, 3a-H), 4.96 (d, J = 11.4 Hz, 1 H, OCH _aH_bPh), 4.90 (d, J = 11.4 Hz, 1 H, OCH_a H _bPh), 4.40 (q, J = 7.1 Hz, 2 H, OCH ₂CH₃), 4.15-4.27 (m, 2 H, NCH₂), 3.91 (s, 3 H, ArOCH ₃), 2.27 (s, 3 H, ArCH ₃), 1.26, 1.44 (2 × s, 6 H, 2 × CH₃), 1.42 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 164.82 (C=O), 155.28 (C-10), 146.45, 143.40, 136.70, 130.16, 128.65, 128.28, 127.74, 121.57, 115.68 (arom C), 112.61 (O₂ CMe₂), 101.73 (C-10a), 98.09 (C-9), 81.60 (C-3a), 76.92 (OCH₂Ph), 76.41 (C-10b), 59.53 (OCH₂CH₃), 55.82 (ArOCH₃), 53.30 (C-4), 26.97, 25.59 (2 ¥ CH₃), 14.48 (OCH₂ CH₃), 9.61 (ArCH₃). HRMS (EI): m/z calcd for C₂₆H₂₉NO₆: 451.1995; found: 451.2006. Anal. Calcd for C₂₆H₂₉NO₆·0.5H₂O: C, 67.81; H, 6.57; N, 3.04. Found: C, 67.99; H, 6.56; N, 3.19.

<A NAME="RD26706ST-23">23</A> Wiegerinck PHG. Flucks L. Hammink JB. Mulders SJE. de Groot FMH. van Rozendaal HLM. Scheeren HW. J. Org. Chem. 1996, 61: 7092

{(1 R,2R)-(-)-1-Azido-2,3,5,8-tetrahydro-7-methoxy-6-methyl-2-methanesulfonyloxy-5,8-dioxo-1H-pyrrolo[1,2-a ]indol-9-yl}methyl Phenyl Carbonate (39) : R _f 0.13 (EtOAc-hexane, 3:7); [α]_D ²³ -121.6 (c = 1.02, CHCl₃). IR (CHCl₃): 3018 (m), 2939 (m), 2108 (s, N₃), 1761 (s, ester C=O), 1647 (s, quinone C=O), 1507 (m), 1365 (s), 1319 (s), 1246 (br s), 1210 (s), 1176 (s), 1106 (s), 960 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.18-7.41 (m, 5 H, arom H), 5.56 (d, J = 13.4 Hz, 1 H, CH _aH_bOCO₂Ph), 5.50 (d, J = 13.4 Hz, 1 H, CH_a H _bOCO₂Ph), 5.47 (br dd, J ≈ 2.4, 4.2 Hz, 1 H, H-2), 5.28 (d, J = 1.2 Hz, 1 H, H-1), 4.50-4.64 (m, 2 H, NCH₂), 4.06 (s, 3 H, OCH₃), 3.07 (s, 3 H, OSO₂CH₃), 1.97 (s, 3 H, ArCH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 178.79, 178.63 (2 × quinone C=O), 157.46 (C-10), 153.47 (carbonate C=O), 150.99 (arom C), 135.95 (C-7), 129.50, 128.15, 127.51, 126.19, 124.22, 120.97 (3 × arom C, C-4, C-6, C-9), 114.53 (C-10), 84.25 (C-2), 61.99, 61.78 (C-1, CH₂OCO₂Ph), 61.29 (quinone OCH₃), 51.71 (C-3), 38.71 (OSO₂CH₃), 8.49 (quinone CH₃). LRMS (FAB): m/z = 517 [MH⁺].