Synthesis of four novel natural product inspired scaffolds for drug discovery.
Inspired by the novel spiro structures of a number of bioactive natural products such as the histrionicotoxins, a series of novel spiro scaffolds have been designed and robust syntheses developed. The scaffolds are ready-to-use building blocks and can be easily prepared on a 5-20 g scale. They contain two amino groups (one Boc-protected) and have been designed for ease of conversion to a lead generation library, using either amide formation or reductive amination procedures. The synthesis of the 1,9-diazaspiro[5.5]undecane and 3,7-diazaspiro[5.6]dodecane ring systems was achieved using RCM as the key step. A simple workup procedure is reported for the removal of highly colored ruthenium residues. The synthesis of the 1,8-diazaspiro[4.5]decane scaffold has been achieved using a bromine-mediated 5-endo cyclization of the corresponding 4-aminobutene intermediate under acidic conditions. This is the first example of this type of cyclization to be reported. A novel mechanism involving a bromine transfer reaction from an initially formed bromonium ion to a neighboring nitrogen atom is suggested as the reason for the failure of this type of reaction under "normal" bromination conditions. An unusual rearrangement of a 1-acyl-1,9-diazaspiro[5.5]undecane to the corresponding 9-acyl-1,9-diazaspiro[5.5]undecane is reported.
Jenkins
Ian D
ID
Eskitis Institute, Griffith University, Brisbane, QLD, 4111, Australia. i.jenkins@griffith.edu.au
Lacrampe
Fabienne
F
Ripper
Justin
J
Alcaraz
Lilian
L
Le
Phuc Van
PV
Nikolakopoulos
George
G
de Almeida Leone
Priscila
P
White
Rodney H
RH
Quinn
Ronald J
RJ
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis*; D003500:Cyclization; D015195:Drug Design; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry*
D000588:Amines; D001688:Biological Products; D013141:Spiro Compounds