Novel Synthesis of Bromoindolenine with Spiro-β-lactam in Chartelline

Abstract

Model compounds containing an indolenine β-lactam moiety in chartelline were synthesized by nucleophilic substitution at the nitrogen atom of O-sulfonylated hydroxamic acid prepared from 2-methylindole-3-acetic acid.

chartelline - indole - β-lactam - cyclization - marine natural product

References

1a Chevolot L. Chevolot A.-M. Gajhede M. Lasen C. Anthoni U. Christophersen C. J. Am. Chem. Soc.  1985,  107:  4542 

1b Anthoni U. Chevolot L. Lasen C. Nielsen PH. Christophersen C. J. Org. Chem.  1987,  52:  4709 

For other synthetic studies from other laboratory, see:

2a Lin X. Weinreb SM. Tetrahedron Lett.  2001,  42:  2631 

2b

Sun, C.; Lin, X.; Weinreb, S. M. Presented at the 19th International Congress of Heterocyclic Chemistry, Colorado, USA, August 2003; Abstracts p. 324.

3 Nishikawa T. Kajii S. Isobe M. Chem. Lett.  2004,  33:  440 

4

The oxindole-β-lactam 4 (R = Bn, MOM) was synthesized in an analogous way to those described in ref. [3] ; however, the yields were poor.

5 Somei M. Heterocycles  1999,  50:  1157 

For examples, see:

6a Nakatsuka S. Tanino H. Kishi Y. J. Am. Chem. Soc.  1975,  97:  5008 

6b Nakatsuka S. Tanino H. Kishi Y. J. Am. Chem. Soc.  1975,  97:  5010 

6c Baldwin JE. Au A. Christie M. Haber SB. Hesson D. J. Am. Chem. Soc.  1975,  97:  5957 

7 Scott AI. Yoo SE. Chung S.-K. Lacadie JA. Tetrahedron Lett.  1976,  17:  1137 

8 Hone ND. Payne LJ. Tetrahedron Lett.  2000,  41:  6149 

9 Singh SB. Tomassini JE. J. Org. Chem.  2001,  66:  5504 

10 Bittner S. Knobler Y. Frankel M. Tetrahedron Lett.  1965,  6:  95 

11

Spectral Data for 14a: Mp 144-148 °C. IR (KBr): 3367, 2914, 1773, 1715, 1534, 1349, 1193 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.29 (3 H, s, -CH ₃ ), 3.35 (3 H, s, -N-CH ₃ ), 3.64 (2 H, s, -CH ₂ -), 7.03 (1 H, br t, J = 7.5 Hz, indole), 7.11 (1 H, td, J = 7.5 Hz, indole), 7.21 (1 H, br d, J = 7.5 Hz, indole), 7.25 (1 H, br d, J = 7.5 Hz, indole), 7.84 (1 H, br s, NH of indole), 8.09 (2 H, br d, J = 9.0 Hz, phenyl), 8.21 (2 H, d, J = 9.0 Hz, phenyl). ¹³C NMR (100 MHz, CDCl₃): δ = 11.8, 29.5, 39.5, 103.0, 110.4, 117.6, 119.7, 121.6, 124.1, 127.4, 128.1, 129.0, 130.7, 132.9, 135.0, 139.3, 151.2, 174.7. HRMS (FAB): m/z calcd for C₁₈H₁₈N₃O₆S₁ [M + H]: 404.0916. Found: 404.0933.

12

Data for 15a: IR (KBr): 3423, 2956, 1763, 1589, 1459, 1377 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.35 (3 H, s, -CH ₃ ), 2.57 (3 H, s, -N-CH ₃ ), 3.26 (1 H, d, J = 15.0 Hz, -CH _A H_B-), 3.32 (1 H, d, J = 15.0 Hz, -CH_A H _B -), 7.27 (1 H, br t, J = 7.5 Hz, indole), 7.38 (1 H, d, J = 7.5 Hz, indole), 7.42 (1 H, td, J = 7.5 Hz, indole), 7.54 (1 H, d, J = 7.5 Hz, indole). ¹³C NMR (100 MHz, CDCl₃): δ = 15.0, 26.7, 46.1, 69.1, 120.9, 122.2, 126.3, 130.4, 133.5, 154.2, 165.8, 180.4. HRMS (FAB): m/z calcd for C₁₂H₁₃N₂O₁ [M + H]: 201.1028. Found: 201.1000.

13

In contrast to the report by Weinreb (2-vinyl substituent instead of 2-methyl substituent) (ref. [2a] ), products 15a and 15b were stable enough to purify on silica gel chromatography.

14

N-Methylamide 16a was separated as its Boc derivative from the mixture of 15a and 16a with Boc₂O and DMAP. The structure of 16a was determined by the following spectroscopic data. IR (KBr): 3296, 2976, 2933, 1732, 1653, 1541, 1459, 1358, 1324, 1137 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.70 (9 H, s, -Boc), 2.55 (3 H, s, -CH ₃ ), 2.71 (3 H, d, J = 5.0 Hz, -NH-CH ₃ ), 3.65 (2 H, s, -CH ₂ -), 5.50 (1 H, br s, -NH-Me), 7.22-7.32 (2 H, m, indole), 7.41 (1 H, br d, J = 7 Hz, indole), 8.12 (1 H, br d, J = 8.0 Hz, indole). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 26.4, 28.3, 32.0, 84.2, 111.6, 115.6, 117.8, 123.0, 124.1, 129.3, 135.7, 135.8, 150.5, 170.9. HRMS (FAB): m/z calcd for C₁₇H₂₃N₂O₃ [M + H]: 303.1709. Found: 303.1672.

15 Piper JR. Stevens FJ. J. Heterocycl. Chem.  1966,  95 

16

Data for 15b: IR (KBr): 3312, 2928, 1762, 1586, 1456, 1377 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.34 (3 H, s, -CH ₃ ), 2.55 (3 H, s, -N-CH ₃ ), 3.23 (1 H, d, J = 15.0 Hz, -CH _A H_B-), 3.30 (1 H, d, J = 15.0 Hz, -CH_A H _B -), 7.24 (1 H, d, J = 8.0 Hz, indole), 7.41 (1 H, dd, J = 8.0, 1.5 Hz, indole), 7.67 (1 H, d, J = 1.5 Hz, indole). ¹³C NMR (100 MHz, CDCl₃): δ = 15.0, 26.8, 46.1, 69.0, 123.2, 124.0, 124.4, 129.1, 132.5, 155.5, 165.3, 182.2. Anal. Calcd for C₁₂H₁₁BrN₂O: C, 51.63; H, 3.97; N, 10.04. Found: C, 51.64; H, 4.05; N, 10.01.

17 Quite recently, a synthesis of indolenine-3 spiro compounds through intramolecular S_N2-type reaction at the oxime nitrogen was reported, see: Tanaka K. Mori Y. Narasaka K. Chem. Lett.  2004,  33:  26