Tandem Radical Cyclisation and Translocation Approaches to Biologically Important Mitomycin Ring Systems

Gillian M.  Allan; Andrew F.  Parsons; Jean-François  Pons

doi:10.1055/s-2002-33522

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Synlett 2002(9): 1431-1434
DOI: 10.1055/s-2002-33522

LETTER

Tandem Radical Cyclisation and Translocation Approaches to Biologically Important Mitomycin Ring Systems

Gillian M. Allan, Andrew F. Parsons*, Jean-François Pons
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
Fax: +44(1904)432516; e-Mail: afp2@york.ac.uk;

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Publication History

Received 17 June 2002
Publication Date:
17 September 2002 (online)

Abstract
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Abstract

New free-radical cyclisation and translocation approaches to the tricyclic mitomycin ring system have been developed. These convergent approaches involve either a tandem 5-endo/5-exo radical cyclisation or alternatively, a 1,6-hydrogen-atom transfer followed by 5-exo cyclisation sequence.

Key words

cyclisations - mitomycin - radical reactions - tandem reactions - tin

References

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7

All new compounds exhibited satisfactory spectral and analytical (high-resolution mass) data.

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Tricycle 12: ¹H NMR (270 MHz, CDCl₃): δ = 7.80 (1 H, d, J = 8 Hz, H-1 aromatic), 7.53-6.97 (8 H, m, aromatic), 4.26 (2 H, q, J = 7 Hz, CO₂CH ₂), 3.78 (1 H, dd, J = 11 and 4.5 Hz, CHCH ₂CO₂), 2.75 (1 H, dd, J = 17.5 and 11 Hz, CHCO₂), 2.62-2.15 (5 H, m, CHCO₂, NCOCH ₂ and NCOCH₂CH ₂) and 1.32 (3 H, t, J = 7 Hz, CO₂CH₂CH ₃). MS (CI, NH₃): m/z (%) = 336 (100) [M + H⁺]. Found (CI, NH₃): 336.1598 [M + H⁺]. C₂₁H₂₁NO₃ requires for [M + H⁺], 336.1600. Tricycle 13: ¹H NMR (270 MHz, CDCl₃): δ = 9.02 (1 H, d, J = 8.2 Hz, H-1 aromatic), 7.46-6.99 (8 H, m, aromatic), 4.36-4.26 (2 H, m, CO₂CH ₂), 3.03 (1 H, dd, J = 13.3 and 4.1 Hz, CHCHCO₂), 2.89-2.30 (6 H, m, CHCHCO₂, NCOCH ₂ and NCOCH₂CH ₂) and 1.36 (3 H, t, J = 7 Hz, CO₂CH₂CH ₃). MS (CI, NH₃): m/z (%) = 336 (100) [M + H⁺]. Found (CI, NH₃): [M + H⁺] 336.1599. C₂₁H₂₁NO₃ requires for [M + H⁺] 336.1600.

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5,5,6-Tricycle 21. Diastereoisomer 1: ¹H NMR (500 MHz, CDCl₃): δ = 7.63 (1 H, d, J = 7.8 Hz, H-1 aromatic), 7.27-7.18 (2 H, m, aromatic), 7.05-7.01 (1 H, m, aromatic), 4.81-4.75 (1 H, m, NCH), 4.17 (2 H, q, J = 7.1 Hz, CO₂CH ₂), 3.74-3.69 (1 H, m, CHCH₂CO₂), 2.90-2.82 (1 H, m, NCOCH), 2.63-2.57 (2 H, m, CHCO₂ and NCOCH), 2.43 (1 H, dd, J = 16.8 and 5.7 Hz, CHCO₂), 2.19-2.14 (1 H, m, NCOCH₂CH), 2.00-1.91 (1 H, m, NCOCH₂CH) and 1.26
(3 H, t, J = 7 Hz, CO₂CH₂CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 171.6, 170.7 (NCO and CO₂), 138.0, 137.0 (2 × C=CH aromatic), 128.4, 125.2, 124.3, 114.5 (4 × C=CH aromatic), 65.0 (NCH), 60.9 (CO₂ CH₂), 38.3 (CHCH₂CO₂), 36.4, 36.2 (CHCH₂CO₂ and NCOCH₂), 23.3 (CH₂ CH₂CH₂), 14.2 (CO₂CH₂ CH₃). MS (CI, NH₃): m/z (%) = 260 (100) [M + H⁺]. Found (CI, NH₃): [M + H⁺] 260.1290. C₁₅H₁₇NO₃ requires for [M + H⁺] 260.1287. Diastereoisomer 2: ¹H NMR (500 MHz, CDCl₃): δ = 7.61 (1 H, d, J = 7.8 Hz, H-1 aromatic), 7.41-7.04 (3 H, m, aromatic), 4.34-4.30 (1 H, m, NCH), 4.25-4.16 (2 H, m, CO₂CH₂), 3.60-3.55 (1 H, m, CHCH₂CO₂), 3.03 (1 H, dd, J = 16.4 and 4.4 Hz, CHCO₂), 2.86-2.78 (1 H, m, NCOCH), 2.61-2.51 (3 H, m, CHCO₂, NCOCH and NCOCH₂CH), 2.15-2.06 (1 H, m, NCOCH₂CH) and 1.30 (3 H, t, J = 7 Hz, CO₂CH₂CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 171.6 (NCO and CO₂), 139.1, 136.3, 128.4, 124.4, 123.9, 115.0 (C=CH aromatic), 69.8 (NCH), 60.9 (CO₂ CH₂), 44.8 (CHCH₂CO₂), 37.8, 36.1 (CHCH₂CO₂ and NCOCH₂), 29.2 (CH₂ CH₂CH₂), 14.4 (CO₂CH₂ CH₃). MS (CI, NH₃): m/z (%) = 260 (100) [M + H⁺]. Found (CI, NH₃): [M + H⁺] 260.1288. C₁₅H₁₇NO₃ requires for [M + H⁺] 260.1287. 5,6,6-Tricycle 22. ¹H NMR (270 MHz, CDCl₃): δ = 8.70 (1 H, d, J = 9.1 Hz, H-1 aromatic), 7.27-7.04 (3 H, m, aromatic), 4.26 (2 H, q, J = 7.2 Hz, CO₂CH ₂), 4.07-3.97 (1 H, m, NCH), 3.14-3.09 (2 H, m, CHCHCO₂ and CH₂CHCO₂), 2.74-2.33 (4 H, m, NCOCH ₂, CHCHCO₂ and NCOCH₂CH), 1.93-1.77 (1 H, m, NCOCH₂CH) and 1.32 (3 H, t, J = 7.2 Hz, CO₂CH₂CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 173.6, 172.6 (NCO and CO₂), 136.0, 128.9, 127.4, 124.0, 123.9, 119.1 (C=CH aromatic), 61.2 (CO₂ CH₂), 58.9 (NCH), 45.4 (CHCO₂), 31.9, 31.5 (NCOCH₂ and CH₂CHCO₂), 24.0 (CH₂ CH₂CH₂), 14.3 (CH₂ CH₃). Found (CI, NH₃): [M + H⁺] 260.1285. C₁₅H₁₇NO₃ requires for [M + H⁺] 260.1287.

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The low yield (30%) for the N-acylation/cyclisation reactions (to form the pyrrolidinone ring) was due to the formation of an alkyne in 55% yield, which resulted from dehydrobromination of vinyl bromide 24 by ethoxide.