The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3-dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate.
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.
Charakteristischf ürB ischinolizidin-Alkaloidei st ein chirales .1]nonan), an das Kombinationen aus einem a,N-anellierten 2-Pyridon, endo-oder exo-a,N-anellierten Piperidin(on)en und einem exo-Allylsubstituenten angebrachts ind. Wire ntwickelten eine modulare "Inside-Out"-Strategie,die einen Zugang zu den meisten Vertretern dieser Naturstoffklasse erlaubt. Ihr Anwendungspotential wurde anhand der asymmetrischen Synthese von 21 Bischinolizidin-Naturstoffen demonstriert, darunter mehr als zehne nantioselektive Erstsynthesen. Schlüsselschritte sind die erste erfolgreicheH erstellung beider Enantiomere von C 2 -symmetrischem 2,6-Dioxobispidin durch Desymmetrisierung einer 2,4,6,8-Tetraoxo-Vorstufe,d er Aufbau des a,N-anellierten 2-Pyridons über eine Enamin-Bromacrylsäure-Strategie und die Einführung von endo-oder, wahlweise,exo-anellierten Piperidin(on)en. 2018W iley-VCH Verlag GmbH &C o. KGaA, Weinheim Angew.C hem. 2018, 130,2 456 -2460Schema 1. Retrosynthese der Bischinolizidin-Naturstoffe. Nur eines der beiden enantiomeren Bispidin-Kerngerüste ist abgebildet.Schema 2. Synthese des chiralen Schlüsselintermediats 8 und die Rçntgenkristallstrukturenvon 11 und 12.[13] DEAD = Diethylazodiacarboxylat, ADDP = 1,1'-(Azodicarbonyl)dipiperidin, TFA = Trifluoressigsäure, Boc = tert-Butoxycarbonyl.Schema 3. Anellierungvon 8 zum tricyclischen Schlüsselintermediat 7. Piv = Pivaloyl.Schema 4. Tricyclische Bischinolizidin-Naturstoffe 18-23 aus 7.
The epimeric bisquinolizidines baptifoline and epibaptifoline are C‐13 hydroxylated derivatives of the well‐known lupine alkaloid anagyrine. We synthesized both compounds from 11‐allylcytisine and determined their uncertain configuration at the C‐13 stereocenter by NMR, chemical transformation, and X‐ray. The alcohol function was found to be in endo (α) position in baptifoline (configuration: 7R, 9R, 11R, 13R) and in exo (β) position in epibaptifoline (configuration: 7R, 9R, 11R, 13S).
21 natürliche Bischinolizidin‐Alkaloide wurden nach einem modularen “Inside‐out”‐Ansatz hergestellt, den M. Breuning et al. in ihrer Zuschrift auf S. 2456 vorstellen. Unter den Beispielen sind mehr als zehn erste enantioselektive Totalsynthesen. Entscheidend waren die erfolgreiche Herstellung beider Enantiomere von C2‐symmetrischem 2,6‐Dioxobispidin durch Desymmetrisierung und die sukzessive α,N‐Anellierung eines 2‐Pyridons und endo‐ oder exo‐kondensierter Piperidine an den chiralen Kernbaustein.
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