A Synthesis of Calothrixin B

Abstract

A new short and efficient synthesis of calothrixin B is ­reported. The key reaction is a hetero-Diels-Alder reaction between 3-bromo-9H-carbazole-1,4-dione and a ‘push-pull’ 2-aza-1,3-diene.

calothrixin B - hetero-Diels-Alder reaction - 2-aza-1,3-diene - natural product

References

1 Rickards RW. Rothschild JM. Willis AC. De Chazal NM. Kirk J. Kirk K. Saliba KJ. Smith GD. Tetrahedron  1999,  55:  13513 

2a Doan NT. Rickards RW. Rothschild JM. Smith GD. J. Appl. Phycol.  2000,  12:  409 

2b Doan NT. Stewart PR. Smith GD. FEMS Microbiol. Lett.  2001,  196:  135 

Previous syntheses of calothrixins A and B:

3a Kelly TR. Zhao Y. Cavero M. Torneiro M. Org. Lett.  2000,  2:  3735 

3b Bernardo PH. Chai CLL. Elix JA. Tetrahedron Lett.  2002,  43:  2939 

3c Bernardo PH. Chai CLL. J. Org. Chem.  2003,  68:  8906 

4 Collet SC. Rémi JF. Cariou C. Laïb S. Guingant AY. Wu NQ. Dujardin G. Tetrahedron Lett.  2004,  45:  4911 

5 Heinzman SW. Grunwell JR. Tetrahedron Lett.  1980,  21:  4305 

6

The position of the bromine atom on the phenyl ring has not yet been established with certainty.

7 Poumaroux A. Bouaziz Z. Domard M. Fillion H. Heterocycles  1997,  43:  585 

8

9-Benzyl-3-bromo-9 H -carbazole-1,4-dione (2): red needles; mp 208 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.84 (s, 2 H, CH₂N), 7.14 (d, 2 H, J = 7.6 Hz, H-Ar), 7.17 (s, 1 H, CH=), 7.26-7.29 (m, 3 H, H-Ar), 7.37-7.46 (m, 3 H, H-Ar), 8.31 (d, 1 H, J = 7.6 Hz, H-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 48.4, 111.8, 116.4, 123.4, 124.4, 125.3, 126.9 (2 C), 127.7, 128.1, 129.0 (2 C), 133.3, 136.0, 137.4, 139.3, 140.4, 175.2, 178.2. FT-IR (KBr): 3036, 1663, 1646, 1583, 1518 cm^-1. MS (EI, 70 eV): m/z (%) = 367 (11) [M⁺ , ⁸¹Br], 365 (11) [M⁺ , ⁷⁹Br], 91 (100). HRMS (EI): m/z calcd for C₁₉H₁₂NO₂ ⁷⁹Br: 365.0051. Found: 365.006 [M⁺ ].

9

At this stage, the regioselectivity of the cycloaddition could not be determined by inspection of NMR data. The structure of adduct 4 was tentatively assigned on the basis of the usual bromine directing effect⁴ and confirmed later by the obtention of calothrixin B.
Experimental Procedure for the Synthesis of 12-Benzyl-2,3,4,7,12,13-hexahydro-1 H -indolo[3,2- j ]phen-anthridine-1,7,13-trione (4):
To a solution of diene 3 (0.60 mmol) in dry MeCN (4 mL), a solution of 9-benzyl-3-bromo-9H-carbazole-1,4-dione 2 (0.55 mmol) in dry MeCN (4 mL) was added at r.t. with stirring. After 48 h at 40 °C, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (CH₂Cl₂-EtOAc = 95:5) to give the cycloadduct 4 as an orange powder (80% yield); mp 118 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.27 (quint, 2 H, J = 6.6 Hz, CH₂), 2.93 (t, 2 H, J = 6.6 Hz, CH₂), 3.18 (t, 2 H, J = 6.6 Hz, CH₂), 5.89 (s, 2 H, CH₂N), 7.20-7.32 (m, 5 H, H-Ar), 7.40-7.47 (m, 3 H, H-Ar), 8.43 (d, 1 H, J = 7.8 Hz, H-Ar), 9.41 (s, 1 H, CH=N). ¹³C NMR (75 MHz, CDCl₃): δ = 21.4, 33.1, 39.2, 48.6, 111.7, 118.4, 123.6, 123.9, 125.1, 126.8, 127.0 (2 C), 128.0, 128.1, 128.2, 128.9 (2 C), 135.6, 136.0, 140.0, 140.7, 150.3, 168.2, 177.5, 179.3, 198.3. FT-IR (KBr): 3041, 2958, 1702, 1666, 1569, 1509, 743 cm^-1. MS (EI, 70 eV): m/z (%) = 406 (100) [M⁺ ], 378 (21), 315 (6), 287 (2), 91 (93). HRMS (EI): m/z calcd for C₂₆H₁₈N₂O₃: 406.1317. Found: 406.133 [M⁺ ].

10

Compound 4 was formed along with the product arising from the addition of dimethylamine to 2 (13%).

11a Hirota K. Isobe Y. Maki Y. J. Chem. Soc., Perkin Trans. 1  1989,  2513 

11b Cacchi S. Ciattini PG. Morera E. Ortar G. Tetrahedron Lett.  1986,  27:  5541 

12 Murakami Y. Watanabe T. Kobayashi A. Yokoyama Y. Synthesis  1984,  738