Total Synthesis of Grossularines1 and 2

1
Total Synthesis of Grossularines-1 and -2

• J. Org. Chem., 1995, 60, 5899-5904

Ricardo Barata 13309 - LQA
2
Grossularines-1 and -2
Isolated in 1989 from Dendroa grossularia
First naturally occuring pyrido2,3-bindoles
Structures determined by spectroscopic evidence
and X-Ray analysis (though only for
Grossularine-2)
Chalenging due to their unique tetracyclic
structure.
3
Retrosynthesis
Grossularine 1 R1 NMe2 R2 H R3
3-indolyl Grossularine 2 R1 NMe2 R2 H R3
p-hydroxyphenyl
4
Retrosynthesis
Next we considered that the tetracyclic
pyrido2,3-bindole 3 would be obtained by a
thermal electrocyclic reaction of
3-imidazolindole-2-isocyanate 4 (...)
5
Retrosynthesis
6
Synthesis
h83
h82
7
Synthesis
h87
h88
8
Synthesis
h94
9
Synthesis
1 método
2 métodos
10
Synthesis
18
(Method A)

• (19a) 93
• h (19b) 77

h19
11
Synthesis

• (19a) 37
• h (19b) 63

• (19a) 61
• h (19b) 51

12
Mechanism - Arylstannane
13
Mechanism Stille Coupling
Stille Coupling
14
Mechanism Isocyanate Formation
Wittig-type mechanism
-N2
15
Mechanism - Cyclization
16
Conclusions
This approach provides an effective route to the
imidazo4,54,4pyrido2,3-bindole ring
First total synthesis of Grossularine-1 (h28,
from iodoindole 6)
Improvement of total synthesis of Grossularine-2
(h33, from iodoindole 6).
17
Bibliography
T. Choshi et al, J. Org. Chem, 1995, 60, 5899-5904
Clayden, Greeves, Warren and Wothers, Organic
Chemistry, 1st edition, Oxford University Press,
2001
Carruthers and Coldham, Modern Methods of Organic
Synthesis, 4th edition, Cambridge University
Press, 2004