1.Cryptophycin-39 Unit A Precursor Synthesis by a Tandem Shi Epoxidation and Lactonization Reaction of trans-Styryl Acetic Acid
Benedikt Sammet, Hanna Radzey, Beate Neumann, Hans-Georg Stammler, Norbert Sewald
Unit A of cryptophycins is a delta-hydroxy acid with two or four stereogenic centers. The first synthesis of the unit A building block of cryptophycin-39 is based on a catalytic asymmetric Shi epoxidation of trans-styryl acetic acid followed by an in situ lactonization. The scope of this reaction has been investigated with respect to various beta,gamma-unsaturated carboxylic acids as substrates for the asymmetric synthesis of 4-hydroxy-5-phenyl-tetrahydrofuran-2-ones under Shi conditions.
2.Synthetic routes towards cryptophycin unit A diastereomers
Eissler, Stefan; Neumann, Beate; Stammler, Hans-Georg; Sewald, Norbert
Unit A of cryptophycin 1 is a delta-hydroxy acid with four stereogenic centres. Our unit A synthesis introduces the first two stereogenic centres by a catalytic, asymmetric dihydroxylation, whereas the remaining two stereogenic centres are established by diastereoselective reactions. In this letter, we focus on the diastereoselectivity of these reactions and discuss the accessibility of cryptophycin unit A diastereomers.
3.The Synthesis of Cryptophycins
Stefan Eissler, Arvydas Stoncius, Markus Nahrwold, Norbert Sewald
Nature provides a huge reservoir of highly diverse chemical compounds with interesting biological properties. Secondary metabolites continue to represent promising candidates for therapeutic applications and drugs are very often based on natural products. Frequently, the total synthesis of such compounds is a real challenge, and this also drives the development of new synthetic methodology. This review article focuses on the biochemistry and chemistry of cryptophycins, a class of 16-membered macrocyclic depsipeptides. The first representative was isolated more than 15 years ago from cyanobacteria. With respect to structure, the class can be subdivided into two structural categories, containing either an epoxide or an alkene moiety. The bioactivity of cryptophycins is based on their ability to interact with tubulin. They display considerable tumour-selective cytotoxicity both against multidrug-resistant tumour cell lines and solid tumours implanted in mice. Consequently, cryptophycin derivatives are considered as potential antitumour drugs. Despite the fact that the cryptophycins were discovered only recently, several different synthetic approaches have already been published. In addition to information on the synthesis of the subunits A-D, strategies for both their assembly and the macrocyclisation are compiled in this review.