Efficient synthesis of cryptophycin-52 and novel para-alkoxymethyl unit A analogues.
Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multi-drug-resistant tumour cells. Cryptophycins are composed of four building blocks (units A-D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para-alkoxymethyl analogues from which cryptophycin-52 and three analogous cryptophycins were prepared. Macrocyclisation of the seco-depsipeptides was based on ring-closing metathesis.
Eissler
Stefan
S
Bielefeld University, Department of Chemistry, Organic and Bioorganic Chemistry, Universitätsstrasse 25, 33615 Bielefeld, Germany.
Bogner
Tobias
T
Nahrwold
Markus
M
Sewald
Norbert
N
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; C114033:cryptophycin 52