First Atropo-Divergent Total Synthesis of the Antimalarial Korupensamines A and B by the “Lactone Method”

Abstract

The stereoselective total synthesis of the antimalarial korupensamines A (1a) and B (1b) by application of the "lactone method" is described. Key steps of this first atropo-selective access to 5,8'-coupled naphthylisoquinoline alkaloids were the regioselective intramolecular coupling of ester 8 to give the configurationally labile lactone-bridged biaryl 9 and its atropisomer-selective cleavage with a variety of chiral and achiral H-nucleophiles, yielding the configurationally stable P-diol 10a or, optionally, the M-product 10b. From the axially chiral phenylisoquinolines thus obtained atropo-diastereodivergently, the authentic natural naphthylisoquinolines with the respective axial configurations, korupensamines A (1a) and B (1b), were obtained by completion of the second naphthalene ring, starting from the previous "bridgehead" C1 unit.

Atropselektive Synthese axial‐chiraler Biaryle

“…(M)-137 genutzt. [164,165] Die Hauptvorteile der [(Aren) Cr 3 ]-Komplexen, die für die Synthese der stereochemisch homogenen Biaryle benötigt werden. [166] Weiterhin sinken die ansonsten exzellenten Kupplungsausbeuten und Diastereoselektivitäten mit steigender sterischer Hinderung an den Kupplungsstellen, was beispielsweise die atropselektive Synthese von vierfach ortho-substituierten Biarylen sehr einschränkt.…”

Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products

“…a broad variety of such sometimes complicated natural biaryls have been synthesized regio-and stereoselectively by the 'lactone technique'. korupensamines A (387a) and B (387b) (933,934). The biaryl coupling is not done directly, i.e.…”

First Atroposelective Total Synthesis of Enantiomerically Pure Ancistrocladidine and Ancistrotectorine

“…The intriguing structural properties of the naphthylisoquinoline alkaloids, along with their pronounced biological activities, make them rewarding, but also challenging, target molecules. 5,1′‐, 7,1′‐, 5,8′‐, and N ,8′‐coupled representatives have already been synthesized in an atropisomerically pure form, whereas this has not yet been achieved for 7,3′‐coupled representatives, such as ancistrocladidine ( 1 ) or ancistrotectorine ( 2 , Figure ), which occur in various Ancistrocladus species …”

“…With its substitution pattern next to the axis, a C 1 unit at C2′, and an oxygen functionality at C8 (and at C6), the structures of molecules 1 and 2 should be suitable for a directed synthetic construction that is based on the “lactone concept” . This strategy has been the key approach in the directed synthesis of a broad variety of axially chiral natural products, which includes 5,1′‐, 7,1′‐, and 5,8′‐coupled naphthylisoquinoline alkaloids . Herein, we report the first atroposelective preparation of natural alkaloids 1 and 2 from simple starting materials by applying the “lactone concept”.…”