S(N)/S(N)' competition: selective access to new 10-fluoro artemisinins.
In this paper, we report a simple route to accede to a new family of C-10 fluorinated derivatives of artemisinin 7. We demonstrated that nucleophilic substitution of the allylic bromide 6 with alcohols can occur at carbon 10 (compounds 7) under solvolytic conditions (S(N)'/S(N) ratio, 87:13). Furthermore, using the particular properties of hexafluoroisopropanol (HFIP), we are able to increase the selectivity of the substitution. Primary alcohols are completely selective for allylic substitution. With amines as nucleophiles, selectivity of substitution is dependent on their nucleophilicity, but attack at carbon 16 was always favored. However, the S(N)'/S(N) ratio could be slightly increased by adding HFIP, which is able to modulate their nucleophilicity through hydrogen bonding. In preliminary in vitro assessments, these new compounds, 7, exhibited a satisfying activity against malaria.
Chollet
Constance
C
Laboratoire Réactivité des molécules fluorées, BioCIS, UMR CNRS 8076, Faculté de pharmacie Paris XI, 5 rue J.B. Clément, 92296 Chatenay-Malabry, France.
Crousse
Benoit
B
Ourévitch
Michèle
M
Bonnet-Delpon
Danièle
D
D000588:Amines / Q000737:chemistry; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry*
D000588:Amines; D037621:Artemisinins; D012717:Sesquiterpenes; D005461:Fluorine; C031327:artemisinin