Total Synthesis of (−)‐Himeradine A

(?)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2,4,6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (?)‐Himeradine A was prepared in 17 steps in the longest linear sequence.     

Enantioselective Total Synthesis of (−)‐Deoxoapodine

The first enantioselective total synthesis of (−)‐deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum‐catalyzed enantioselective ring‐closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5‐quaternary stereocenter. After C21‐oxygenation, the pentacyclic core was accessed by electrophilic C19‐amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6‐etherification reaction proved highly effective to secure the F‐ring and the fourth contiguous stereocenter of (−)‐deoxoapodine with complete stereochemical control.     

Enantioselective Total Synthesis of (+)‐Flavisiamine F via Late‐Stage Visible‐Light‐Induced Photochemical Cyclization

The structural features Kopsia alkaloids, in particular multiple all‐carbon quaternary stereocenters in a caged and strained polycyclic skeleton, poses particular challenges for enantioselective total synthesis. Herein, we reported the first total synthesis of (+)‐flavisiamine F. The synthetic approach involved a room‐temperature Overman rearrangement for introducing the chiral amine at C21, a TMS‐promoted ketal Claisen rearrangement for constructing the all‐carbon quaternary stereocenter at C20, and a late‐stage visible‐light‐induced photochemical cyclization for establishing the all‐carbon quaternary stereocenter at C7.     

A Local‐Desymmetrization‐Based Divergent Synthesis of Quinine and Quinidine

Herein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a “local‐desymmetrization” approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.     

Asymmetric Total Synthesis of (+)‐Neooxazolomycin Using a Chirality‐Transfer Strategy

The total synthesis of (+)‐neooxazolomycin was achieved from the amino‐acid d ‐serine. The efficiency of this approach is derived from the use of principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of a serine derivative to build the densely functionalized lactam framework and to install three contiguous stereocenters. The key intermediate was readily elaborated to the target natural product.     

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.     

Asymmetric Total Syntheses of the Akuammiline Alkaloids (−)‐Strictamine and (−)‐Rhazinoline

Strictamine and rhazinoline are representative methanoquinolizidine‐containing akuammiline alkaloids that possess different stereochemistry at the C16 position. A unified approach to the enantioselective total syntheses of these two molecules is described. The key steps in this synthesis include a photocatalytic intra/intermolecular type II radical cascade reaction, a Tsuji–Trost allylation, a palladium‐ or nickel‐mediated cyclization, and a late‐stage intramolecular N‐alkylation reaction.     

Total Synthesis of (−)‐Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction

Stereoselective total syntheses of (−)‐histrionicotoxin and (−)‐histrionicotoxin 235A are described. The 1‐azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation–cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (−)‐histrionicotoxin 235A through a one‐pot partial‐reduction–allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3‐amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (−)‐histrionicotoxin.     

Total Synthesis of Dictyodendrins by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles

In total and formal syntheses of dictyodendrins B, C, E, and F, the key step involved the direct construction of the pyrrolo[2,3‐c ]carbazole core by the gold‐catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki–Miyaura coupling), C2 (addition to an aldehyde), N3 (alkylation), and C5 positions (Ullman coupling) provided divergent access to dictyodendrins.     

Visible‐Light Photoredox Catalysis Enables the Biomimetic Synthesis of Nyingchinoids A,B, and D,and Rasumatranin D

The total synthesis of nyingchinoids A and B has been achieved through successive rearrangements of a 1,2‐dioxane intermediate that was assembled using a visible‐light photoredox‐catalysed aerobic [2+2+2] cycloaddition. Nyingchinoid D was synthesised with a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, we proposed a structure revision of the related natural product rasumatranin D, which was confirmed through total synthesis. Under photoredox conditions, we observed the conversion of a cyclobutane into a 1,2‐dioxane through retro‐[2+2] cycloaddition followed by aerobic [2+2+2] cycloaddition.     

Die Woodward‐Doering‐/Rabe‐Kindler‐Totalsynthese von Chinin: ein Mythos?

1918 beschrieben Paul Rabe und Karl Kindler die dreistufige Umwandlung von d‐Chinotoxin in Chinin. Robert B. Woodward und William von Eggers Doering veröffentlichten 1944 die Totalsynthese von Homomerochinen und d‐Chinotoxin aus 7‐Hydroxyisochinolin. Auf der Grundlage der Umsetzungen von Rabe und Kindler beanspruchten Woodward und Doering im Titel zweier Arbeiten von 1944 und 1945 die “Total Synthesis of Quinine”. In den Jahren 2000 und 2001 stempelte Gilbert Stork Woodwards und Doerings Anspruch aber als ungültig, weil sie in Cambridge nur Homomerochinen und d‐Chinotoxin, nicht aber synthetisches Chinin hergestellt hatten. Tatsächlich haben Rabe und Kindler die experimentellen Einzelheiten ihrer Umwandlung von d‐Chinotoxin in Chinin nie veröffentlicht. Dieser Aufsatz stellt die Ergebnisse einer detaillierten Untersuchung der Synthesechemie von Cinchona‐Alkaloiden vor und gibt anhand von bisher unveröffentlichtem Material sowie zahlreichen Interviews einen Einblick in das Leben der Hauptpersonen dieser fast 100 Jahre währenden Geschichte.