Rapid Assembly of the 1-Azabicyclo[3.1.0]hexane Skeleton of Ficellomycin

Abstract

The 1-azabicyclo[3.1.0]hexane core of ficellomycin can be assembled in a concise manner by way of a double cyclisation reaction involving in situ generation of an NH aziridine and further intramolecular conjugate addition onto a dehydroamino ester.

antibiotics - aziridines - 1,2-azido alcohols - conjugate addition reactions - polymer supported triphenylphosphine

References

1 Argoudelis AD. Reusser F. Whaley HA. Baczynskyj L. Mizsak SA. Wnuk RJ. J. Antibiot.  1976,  29:  1001 

2 Reusser F. Biochemistry  1977,  16:  3406 

3 Kuo M.-S. Yurek DA. Mizsak SA. J. Antibiot.  1989,  42:  357 

4 For a review, see Hodgkinson TJ. Shipman M. Tetrahedron  2001,  57:  4467 

5 Zhao Z. PhD Thesis   University of California; Los Angeles: 1993. 

For some alternative approaches to 1-azabicyclo[3.1.0]-hexanes, see:

6a Buyle R. Chem. Ind. (London)  1966,  195 

6b Laurent DA. Chimia  1976,  30:  274 

6c Hudlicky T. Frazier JO. Seoane G. Tiedje M. Seoane A. Kwart LD. Beal CJ. J. Am. Chem. Soc.  1986,  108:  3755 

6d Mulzer J. Becker R. Brunner E. J. Am. Chem. Soc.  1989,  111:  7500 

6e Sasaki M. Yudin AK. J. Am. Chem. Soc.  2003,  125:  14242 

Intramolecular conjugate additions involving aziridine nucleophiles are known. For example, see:

7a Moran EJ. Tellew JE. Zhao Z. Armstrong RW. J. Org. Chem.  1993,  58:  7848 

7b Coleman RS. Li J. Navarro A. Angew. Chem. Int. Ed.  2001,  40:  1736 

7c

ref. 5.

8

Prepared by oxidation of of 4-penten-1-ol (PCC, CH₂Cl₂, 3 h, r.t.), which was used directly in the olefination reaction without purification.

9 Hiebl J. Kollmann H. Rovenszky F. Winkler K. J. Org. Chem.  1999,  64:  1947 

10

Selected Spectroscopic Data. Compound 6a/b: IR (neat): ν_max = 3334, 2951, 1713, 1498 cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 7.22-7.15 (2 H, m, ArH), 7.11-7.00 (3 H, m, ArH), 5.87 (0.75 H, d, J = 8.5 Hz, NH), 5.73 (0.25 H, d, J = 8.0 Hz, NH), 5.14-4.98 (2 H, m, CH₂Ph), 4.48 (0.25 H, dd, J = 8.5, 3.8 Hz, H-2), 4.40-4.33 (0.75 H, m, H-2), 3.41 (0.25 H, dd, J = 8.5, 3.5 Hz, H-3), 3.33 (0.75 H, s, CH₃O), 3.29 (2.25 H, s, CH₃O), 2.95 (0.75 H, t, J = 7.5 Hz, H-3), 2.02-1.98 (0.75 H, m, H-6), 1.91-1.85 (0.25 H, m, H-6), 1.61-1.43 (3 H, m, 2 × H-5, H-4), 1.31 (0.75 H, d, J = 5.2 Hz, H-7 _exo ), 1.29 (0.25 H, d, J = 5.5 Hz, H-7 _exo ), 1.18-0.88 (1 H, m, H-4), 0.56 (0.75 H, d, J = 3.3 Hz, H-7 _endo ), 0.53 (0.25 H, d, J = 3.5 Hz, H-7 _endo ). ¹³C NMR (100 MHz, C₆D₆): δ = 172.0 (CH₃OCO), 171.4 (CH₃OCO), 157.0 (NHCOO), 156.2 (NHCOO), 137.2 (ArC), 128.5-128.4 (ArCH), 67.1 (CH₂), 67.0 (CH₂), 66.9 (C-3), 66.0 (C-3), 59.9 (C-2), 58.1 (C-2), 51.9 (CH₃O), 51.7 (CH₃O), 41.0 (C-6), 40.0 (C-6), 28.2 (C-7), 28.0 (C-7), 26.1 (C-5), 25.0 (C-5), 24.3 (C-4), 22.6 (C-4). MS (ES⁺): m/z = 305 [MH⁺], 261, 91. HRMS (ES⁺): m/z calcd for C₁₆H₂₁N₂O₄: 305.1496; found: 305.1493 [MH⁺]. Compound 7a: IR (neat): ν_max = 3319, 3172, 2947, 1712, 1527, 1435 cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 7.22-7.18 (2 H, m, ArH), 7.11-7.01 (3 H, m, ArH), 5.99 (1 H, d, J = 9.0 Hz, NH), 5.09 (1 H, d, J = 12.3 Hz, CHHPh), 5.01 (1 H, d, J = 12.3 Hz, CHHPh), 4.54 (1 H, t, J = 8.4 Hz, H-2), 3.33 (3 H, s, CH₃O), 3.21-3.14 (1 H, m, H-3), 2.07-2.02 (1 H, m, H-6), 1.59-1.52 (1 H, m, H-5), 1.43-1.33 (1 H, m, H-5′), 1.26 (1 H, d, J = 4.8 Hz, H-7 _exo ), 1.20-1.05 (2 H, m, H-4), 0.99 (1 H, d, J = 2.0 Hz, H-7 _endo ). ¹³C NMR (100 MHz, C₆D₆): δ = 172.2 (CH₃OCO), 156.2 (NHCOO), 137.2 (ArC), 128.4-128.3 (ArCH), 67.0 (CH₂Ph), 65.4 (C-3), 56.8 (C-2), 51.7 (CH₃O), 38.7 (C-6), 26.0 (C-5), 23.1 (C-7), 22.2 (C-4). MS (ES⁺): m/z = 305 [MH⁺], 91. HRMS (ES⁺): m/z calcd for C₁₆H₂₁N₂O₄: 305.1496; found: 305.1492 [MH⁺]. Anal. Calcd for C₁₆H₂₀NO₄: C, 63.14; H, 6.62; N, 9.20%. Found: C, 63.10; H, 6.65; N, 8.80%. Compound 7b: IR (neat): ν_max = 3368, 3181, 2948, 1710, 1499 cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 7.22-7.16 (3 H, m, ArH and NH), 7.11-6.99 (3 H, m, ArH), 5.08 (1 H, d, J = 12.0 Hz, CHHPh), 5.03 (1 H, d, J = 12.0 Hz, CHHPh), 4.33 (1 H, dd, J = 8.8, 6.6 Hz, H-2), 3.38-3.29 (4 H, m, CH₃O and H-3), 2.15-2.09 (1 H, m, H-6), 1.51 (1 H, dd, J = 13.0, 8.0 Hz, H-5), 1.44-1.34 (1 H, m, H-5′), 1.22 (1 H, d, J = 5.0 Hz, H-7 _exo ), 1.18-1.09 (1 H, m, H-4), 1.05-0.96 (1 H, m, H-4′), 0.93 (1 H, m, H-7 _endo ). ¹³C NMR (100 MHz, C₆D₆): δ = 172.0 (CH₃OCO), 156.6 (NHCOO), 137.3 (ArC), 128.5-128.2 (ArCH), 70.0 (CH₂Ph), 63.7 (C-3), 57.7 (C-2), 51.8 (CH₃O), 38.8 (C-6), 26.2 (C-5), 22.8 (C-7), 22.5 (C-4). MS (ES⁺): m/z = 305 [MH⁺], 261, 91. HRMS (ES⁺): m/z calcd for C₁₆H₂₁N₂O₄: 305.1496; found: 305.1496 [MH⁺].