Efficient Synthesis of Cryptophycin‐52 and Novel para‐Alkoxymethyl Unit A Analogues

Abstract

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.

Total synthesis and biological evaluation of fluorinated cryptophycins

“…The cyclic orthoester resulting from this transformation was directly subjected to reaction with acetyl bromide to form a bromohydrin formate. This was then treated with a potassium carbonate/ethylene glycol/dimethoxyethane-emulsion to bring about cleavage of the formyl ester accompanied by epoxide formation as previously described by us [19]. The trifluoromethyl substituted cryptohycin-52 analogue 22 was obtained in a yield of 39% over the final four steps.…”

“…Unit A para -alkoxymethyl derivatives of cryptophycin-52 have been synthesized and were shown to retain cytotoxicity even against MDR tumor cell lines [19]. The introduction of a fluorine substituent in the same position also provides a cytotoxic analogue, albeit with decreased biological activity by a factor of 5 [8].…”

“…In the frame of our on-going SAR studies on cryptophycins [19,23–30], we envisaged the synthesis of analogues of cryptophycin-52 with a para -trifluoromethyl substituent at the unit A aryl ring. In addition, we targeted the replacement of the unit B by a D-pentafluorophenylalanine residue.…”

Chemical Constituents of Aerial Parts and Roots of <i>Pycnanthemum flexuosum</i>

“…The NMR data of cis-4-hydroxy-5-phenyl-tetrahydrofuran-2-one were not inconsistent with those of 4, 27) suggesting that 4 had a (4R,5S) or (4S,5R) configuration. The (4S,5R)-configuration of 4 was deduced from the optical rotation data ([α] D 20 −51.1°), which was different from that of the synthesized (4R,5S)-isomer.…”

The Chelation-controlled Mukaiyama Aldol Reaction of Chiral α- and β-Alkoxy Aldehydes

“…36 Efficient syntheses of cryptophycin-52 and novel analogs of the p-alkoxymethyl unit A were reported by Sewald et al in which chelation-controlled Mukaiyama aldol reactions as well as allyl stannane additions play key roles. 37 An example is the MgBr 2 -mediated vinylogous Mukaiyama aldol addition of enol silane 65 to aldehyde 64 leading to a single diastereomer 66 (Scheme 15).…”