title: Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20s proteasome inhibitor, clasto-lactacystin beta-lactone.
abstract: A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Donohoe
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
authors.forename: Leena
authors.initials: L
authors.lastname: Sisangia
authors.forename: Karl W
authors.initials: KW
authors.lastname: Ace
authors.forename: Paul M
authors.initials: PM
authors.lastname: Guyo
authors.forename: Andrew
authors.initials: A
authors.lastname: Cowley
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
mesh_terms: D000641:Ammonia / Q000737:chemistry; D004583:Electrons; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C098869:clasto-lactacystin beta-lactone; D000641:Ammonia