The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular “Inside‐Out” Approach

Abstract

Bisquinolizidine alkaloids are characterized by a chiral bispidine core (3,7-diazabicyclo[3.3.1]nonane) to which combinations of an α,N-fused 2-pyridone, an endo- or exo-α,N-annulated piperidin(on)e, and an exo-allyl substituent are attached. We developed a modular "inside-out" approach that permits access to most members of this class. Its applicability was proven in the asymmetric synthesis of 21 natural bisquinolizidine alkaloids, among them more than ten first enantioselective total syntheses. Key steps are the first successful preparation of both enantiomers of C -symmetric 2,6-dioxobispidine by desymmetrization of a 2,4,6,8-tetraoxo precursor, the construction of the α,N-fused 2-pyridone by using an enamine-bromoacrylic acid strategy, and the installation of endo- or, optionally, exo-annulated piperidin(on)es.

The Hydroxylated, Tetracyclic Bisquinolizidine Alkaloids Baptifoline and Epibaptifoline: Enantioselective Synthesis and Unambiguous Assignment of their Configuration at C‐13

“…The synthesis of epibaptifoline ( B ) and baptifoline ( A ) started with 11‐allylcytisine ( 12 , Scheme ), prepared according to Scheme , . Following Bohlmann's original procedure, the tricyclic alkaloid 12 was simply treated with aqueous formaldehyde in a phosphate buffer (pH = 5), which delivered synthetic epibaptifoline ( B ) in high 86 % yield as a single diastereomer ( dr > 98:2, structure 5b , assignment see below).…”

“…Epibaptifoline (B, Structure 5b): According to a literature procedure, a solution of 11‐allylcytisine ( 12 , 110 mg, 478 µmol) and formaldehyde (37 % aq. ; 680 µL, 8.37 mmol) in phosphate buffer (0.1 m , 12 mL, pH = 5) was stirred for 19 h at 45 °C.…”

“…We recently developed a modular “inside‐out” route to bisquinolizidine alkaloids that permits enantioselective access to a variety of members of this class (> 20 synthesized, Scheme ) , . Desymmetrization of achiral tetraoxobispidine ( 9 ) provided the N ‐Boc activated bispidine lactam 10 or, optionally, ent ‐ 10 in 99 % ee .…”

Die enantioselektive Totalsynthese von Bischinolizidin‐Alkaloiden: Ein modularer “Inside‐Out”‐Zugang

“…[11] Fürd ie Desymmetrisierung muss eines der beiden enantiotopen Paare der Carbonylgruppen desoxygeniert werden. [13] Reduktive Abspaltung der chiralen Auxiliare unter Birch-Bedingungen und Aktivierung der Amidgruppen als N-Boc-Imide lieferte das chirale Schlüsselintermediat 8 in 30-34 %A usbeute und ! Das Diamid 12 wurde nahezu vollständig regio-und stereoselektiv erhalten (dr > 99:1) [12] und seine absolute Konfiguration anhand der Rçntgenkristallstruktur bestimmt.…”

“…Das Diamid 12 wurde nahezu vollständig regio-und stereoselektiv erhalten (dr > 99:1) [12] und seine absolute Konfiguration anhand der Rçntgenkristallstruktur bestimmt. [13] Reduktive Abspaltung der chiralen Auxiliare unter Birch-Bedingungen und Aktivierung der Amidgruppen als N-Boc-Imide lieferte das chirale Schlüsselintermediat 8 in 30-34 %A usbeute und ! 99 % ee über fünf Stufen ausgehend von 9.D as Enantiomer ent-8 wurde analog mit (R)-10 synthetisiert.…”