An endocyclic trans-amide linkage within the macrocyclic antitumor agent cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated "click"-cyclization. Compared to cryptophycin-52, in vitro cytotoxicity of "clicktophycin-52" against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced.
[reaction: see text] Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality, while all further stereogenic centers are introduced under substrate control. The key step of the first route is a vinylogous Mukaiyama aldol addition, which introduces the alpha,beta-unsaturated ester moiety with defined configuration at the delta-carbon atom. Likewise, allylation with allyltributylstannane diastereoselectively gives the homoallylic alcohol that can be converted by a metathesis reaction to a unit A precursor.
The cryptophycins are a family of cyclic depsipeptides with four retrosynthetic units A to D which correspond to the respective amino acids and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres by introducing two of them in a catalytic asymmetric dihydroxylation, followed by substrate-controlled diastereoselective reactions. The diol also serves as the epoxide precursor. This approach provides selective access to stereoisomers of unit A (enantiomers, epimers) for structure-activity relationship studies. The unit A derivatives were incorporated into cryptophycin-1, cryptophycin-52 and a novel epimer of cryptophycin-52.
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.
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