New ventures in the chemistry of avermectins.
An overview is given on recent work towards new avermectin derivatives of extremely high insecticidal and acaricidal activity. These compounds were prepared from commercially available abamectin (avermectin B1) 1. For the synthesis, many novel entries have been opened up, making use of modern synthetic methods and applying them, for the first time, to the chemistry of avermectins. Several types of avermectin derivatives can be regarded as key innovations in the field. These are, in particular, 4''-deoxy-4''-(S)-amino avermectins 3, 4'-O-alkoxyalkyl avermectin monosaccharides 5, 4''-deoxy-4''-C-substituted 4''-amino avermectins 6 and 2''-substituted avermectins 7. 4''-Deoxy-4''-(S)-amino avermectins 3 were obtained by the consecutive application of the Staudinger and Aza-Wittig reaction. 4'-O-Alkoxyalkyl avermectin monosaccharides 5 were prepared by alkoxyalkylation of 5-O-protected avermectin monosaccharide. For the synthesis of 4''-deoxy-4''-C-substituted 4''-amino avermectins 6, several methods were used to construct the fully substituted 4''-carbon centre, such as a modified Strecker synthesis, the addition of organometallics to a 4''-sulfinimine and a modified Ugi approach. In order to prepare 2''-substituted avermectins 7, 5-O-protected avermectin monosaccharide was coupled with carbohydrate building blocks. An alternative synthesis involved the hitherto unknown enol ether chemistry of 4''-oxo-avermectin and the conjugate addition of a cuprate to an avermectin 2'',3''-en-4''-one. In addition, a number of other highly potent derivatives were synthesised. Examples are 4''-O-amino avermectins 8, as well as products arising from intramolecular rhodium catalysed amidations and carbene insertions. A radical cyclisation led to an intriguing rearrangement of the avermectin skeleton. Many of the new avermectins surpassed the activity of abamectin 1 against insects and mites.
Pitterna
Thomas
T
Syngenta Crop Protection Münchwilen AG, Crop Protection Research, Chemistry, Schaffhauserstr. 101, CH-4332 Stein, Switzerland. thomas.pitterna@syngenta.com
Cassayre
Jérôme
J
Hüter
Ottmar Franz
OF
Jung
Pierre M J
PM
Maienfisch
Peter
P
Kessabi
Fiona Murphy
FM
Quaranta
Laura
L
Tobler
Hans
H
D018556:Crops, Agricultural / Q000254:growth & development; D004187:Disaccharides / Q000737:chemistry; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004187:Disaccharides; D007306:Insecticides; C048324:abamectin; D007559:Ivermectin; C019264:avermectin; C443359:emamectin