Enantioselektive Steroidsynthese durch organokatalytische Radikalpolycyclisierung
Final Report Abstract
Steroids and terpenes are important classes of naturally occurring molecules that have a wide range of biological activities. Numerous congeners are known to show activity profiles in the context of cancer and HIV, as well as anti-inflammatory implications have been reported. The common structural motif of these natural products is their polycyclic all-carbon skeleton bearing mulliple defined stereocenters. Due to their inherent utility, it is therefore not surprising that synthetic organic chemistry has devised stereocontrolled approaches toward generating such ring systems. However, efficient approaches to enantioselectively construct steroidal or terpenoidal ring systems following the blueprints of nature using cationic polyene cyclization methodology has been limited to substrate-controlled approaches or required stoichiometric amounts of a chiral catalyst or reagent. In order to meet these challenges, we devised and developed a novel concept for non-biomimetic catalytic polyene cyclization. Important features of this novel process are: (1) An imidazolidinone catalyst generates a sacrificial amount of a chiral enamine which is oxidized by a simple copper(ll) complex to give enamine radical cation intermediate; (2) the latter species participates in a sequence of 6-endo radical cyclizations onto trisubstituted alkenes in a highly enantio- and diastereoselective fashion under the influence of the catalyst geometry; (3) a second single electron transfer step to the metal oxidant followed by proton loss terminates the cyclization sequence; (4) this sequence is (a) catalytic in organocatalyst (30 mol%), (b) stoichimetric in the metal oxidant (2.5 equiv of Cu(OTf)2), (c) allows for the first time to achieve modest catalyst turnover (turnover number = 2-3), (d) proceeds readily at room temperature to give (e) highly enantio- and diastereoenriched polycycles (85-93% ee, single diastereomers) via the generation of up to six new rings (= 6 carbon-carbon bonds, 11 contiguous stereocenters of which 5 are all-carbon quaternary). It is expected that these results bode well for future applications in the context of natural products from terpenoid or steroidal origin.
Publications
- "Enantioselective Polyene Cyclization via Organo-SOMO Catalysis", Journal of the American Chemical Society 20W, 132 (published online March 24, 2010)
S. Rendler, D. W. C. MacMillan
(See online at https://doi.org/10.1021/ja100185p)
