Partial reduction of pyrroles: application to natural product synthesis.
The partial reduction of N-Boc pyrroles has been explored giving stereoselective routes to disubstituted pyrrolines in good yields and with excellent diastereoselectivities. A novel methodology has been developed to carry out reductive aldol reactions on 2-substituted N-Boc pyrroles; use of aldehydes under reductive aldol conditions gave the anti aldol product in good selectivity. This chemistry was used as the key transformation in a synthesis of omuralide, which was achieved in 13 steps and 14% overall yield. We also report a methodology for selectively forming either cis or trans 2,5-disubstituted pyrrolines via a partial reduction of an electron-deficient N-Boc pyrrole. The trans pyrroline formed using this route was utilized in the syntheses of the polyhydroxylated pyrrolizidine natural products hyacinthacine A1 and 1-epiaustraline. Further investigation has led to the development of routes to enantiopure substituted pyrroline compounds. This has been achieved via a chiral protonation approach using easily accessible chiral acids, such as ephedrine and oxazolidinones, to quench enolates formed during the partial reduction process. Alternatively, enzymatic desymmetrization of symmetrical diol compounds formed from the partial reduction products of substituted pyrroles is also reported. This leads to formation of both enantiomers of 2,2- and 2,5-disubstituted N-Boc pyrrolines in excellent ee and yields.
Donohoe
Timothy J
TJ
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom. timothy.donohoe@chem.ox.ac.uk
Thomas
Rhian E
RE
D001688:Biological Products / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011522:Protons; D011758:Pyrroles / Q000737:chemistry*; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis; D013237:Stereoisomerism
D001688:Biological Products; D007783:Lactones; D011522:Protons; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; C508850:hyacinthacine A1; C117645:omuralide