title: Bispidine : Faszinierende Naturstoffe und effiziente Liganden
Creators: name: Goller, Jessica
Publisher: name: University of Bayreuth
Year: 2019
Subjects: subject: Bispidine
subject: Bischinolizidin-Alkaloide
subject: Organische Synthese
subject: Naturstoffsynthese
subject: Enantioselektive Totalsynthese
subject: Alkaloide
subject: Naturstoffe
subject: Bispidin-Liganden
subject: asymmetrische Katalyse
subject: bispidines
subject: bisquinolizidine alkaloids
subject: organic synthesis
subject: natural product synthesis
subject: enantioselective synthesis
subject: alkaloids
subject: natural products
subject: bispidine ligands
subject: asymmetric catalysis
subject: 500
subject: 540

description: Bisquinolizidine alkaloids are a fascinating natural product class of secondary metabolites with about 50 members. The most prominent ones are (−)-sparteine (9), which can be isolated from scotch broom and serves as the ligand of choice in several asymmetric reactions, but also has antiarrhythmic and oxytocic properties, and cytisine (13), which is a partial agonist of the nicotinic acetylcholine receptor and pharmaceutically marketed for smoking cessation. Common structural element of all bisquinolizidine natural products is a 3,7-diazabicyclo[3.3.1]-nonane skeleton, which builds the chiral core and appears in nature in both enantiomeric forms (7S/9S and 7R/9R series). Combinations of an α,N-fused pyridone, endo- or exo-α,N-annulated piperidin(on)es, and an exo-allyl substituent can be attached to it. To date, several elegant, enantioselective total syntheses are described, but these are all based on an “outside-in” strategy. The periphery, in which the natural products are differing, is constructed first and the common bispidine core is closed in a later stage. This usually limits the applicability of the approach to particular target molecules. A flexible route, as required for the efficient total synthesis of bisquinolizidine natural products and for the synthesis of new bispidine ligands, is still missing. Main goal of this work was the development of a modular, enantioselective “inside-out”-strategy for the synthesis of tri- and tetracyclic bisquinolizidine alkaloids. The achiral tetraoxobispidine 7 was desymmetrized in the first key step, which delivered the dioxobispidine 6 or, optionally, its enatiomer ent-6 in 34% yield and &gt;99% ee over five steps. The installation of the α,N-fused pyridone 123, which exclusively occurs in the 7R/9R-series, was the second key step and achieved, after selective modification of only one of the two imide groups, via an enamine-bromoacrylic acid strategy. Six steps were needed for that, giving the pyridone 123 in an overall yield of 35% and &gt;99% ee. The enantiomeric pyridone was hydrogenated to provide the key intermediate 122 of the 7S/9S-series. By choice of the reaction sequence endo-substituents were attached via addition and subsequent reduc¬tion, while exo-substituents were installed via reduction and following addition. In conclusion, a modular and broadly applicable route to bisquinolizidine alkaloids was developed. The versatility was proven in the asymmetric synthesis of 21 natural products, inclu¬ding the first enantioselective total syntheses of angustifoline (14), α-isosparteine (15), ther¬mospsine (16), anagyrine (17), (+)- and (−)-lupanine (23 and ent-23), tetrahydrorhombifoline (37), 11-allylcytisine (125), 11-oxocytisine (133), tinctorine (135), isolupanine (140), and N-methylangustifoline (142). The second project was the synthesis of baptifoline (19) and epibaptifoline (epi-19) and the unambiguous elucidation of their configuration at C13. The configuration suggested by CAS/scifinder is based on a 50-year-old assignment, which was done on basis of IR spectroscopy, by using the wavenumber of the OH vibration. In other literature, however, the opposite configuration is given. To unambiguously determine the correct stereochemistry, epi-bapti¬foline (epi-19) was synthesized from allylcytisine (125) in 86% yield (&gt;98:2 dr) and converted via an oxidation/reduction-sequence into baptifoline (19, 50% yield, dr &gt;98:2). By hydration to ent,epi-18, the enantiomer of 13β-hydroxylupanine (epi-18), NMR spectroscopic studies, and X-ray analysis, the configuration at C13 bearing the alcohol function was unequivocally determined: it is equatorial in epibaptifoline (epi-19) and axial in baptifoline (19). A side project dealt with the modular, stereoselective synthesis of new bispidine ligands derived from key intermediate 124, which was synthesized in five steps and 48% yield. Endo-substituents were introduced via addition followed by reduction. By doing so, the three new ligands 11a,b and 12 as well as the known (−)-sparteine surrogate (10) were synthesized. Under optimized conditions, ligand 11b delivered the β-nitroalcohols 154 in enantioselective, Cu-catalyzed Henry reactions with 2-4 mol% catalyst in 80-99% yield and 96-99% ee (ten examples). Enantioselective and diastereoselective Henry reactions of 152 with nitroethane or nitropropane were done on six examples, giving 51-99% yield, 96-99% ee, and up to 86:14 d.r. Thus, diamine 11b is the most efficient bispidine derived ligand for this reaction.