Biomimetic Total Syntheses of (−)‐Leucoridines A and C through the Dimerization of (−)‐Dihydrovalparicine

Concise biomimetic syntheses of the Strychnos‐Strychnos‐type bis‐indole alkaloids (?)‐leucoridine A ( 1 ) and C ( 2 ) were accomplished through the biomimetic dimerization of (?)‐dihydrovalparicine ( 3 ). En route to 3 , the known alkaloids (+)‐geissoschizoline ( 8 ) and (?)‐dehydrogeissoschizoline ( 10 ) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza‐Michael/spirocyclization sequence over the alternate hetero‐Diels–Alder cycloaddition reaction.     

Catalytic Asymmetric Total Synthesis of (−)‐Galanthamine and (−)‐Lycoramine

The catalytic asymmetric total syntheses of (?)‐galanthamine ( 1 ) and (?)‐lycoramine ( 2 ) have been achieved by using a conceptually new strategy featuring two metal‐catalyzed reactions as the key steps. A new method for the construction of 3,4‐fused benzofurans has been developed through a palladium‐catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2 . To achieve the asymmetric synthesis of 1 and 2 , a Sc^III/N,N′‐dioxide complex was used to catalyze the enantioselective conjugate addition of 3‐alkyl‐substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.     

TiCl3-Mediated Synthesis of 2,3,3-Trisubstituted Indolenines: Total Synthesis of (+)-1,2-Dehydroaspidospermidine, (+)-Condyfoline,and (−)-Tubifoline

2,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃-mediated reductive cyclization of tetrasubstituted alkenes bearing a 2-nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)-1,2-dehydroaspidospermidine featuring a late-stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π-electron-5-atom electrocyclization and a 1,2-alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)-condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2-alkyl shift. The exclusive formation of (+)-condyfoline indicates that the 1,2-alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro-Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)-condyfoline to (−)-tubifoline by way of a retro-Mannich/1,3-prototropy/transannular cyclization cascade are also documented.     

An Enantioselective Total Synthesis of (−)‐Isoschizogamine

A concise enantioselective total synthesis of (?)‐isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N‐Alkylation of an enantio‐enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one‐pot process leading to the formation of one C? C bond and three C? N bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Organocatalytic,Asymmetric Total Synthesis of (−)‐Haliclonin A

The first total synthesis of the alkaloid (?)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI₂‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.     

Total Synthesis of (−)‐Nakadomarin A

A highly efficient 12‐step synthesis of the marine alkaloid (?)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (?)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.     

Total Synthesis of (−)‐Norzoanthamine

No bones about it : (?)‐Norzoanthamine, a promising candidate for an anti‐osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H₂O gave the DEFG ring, while the cyclization precursor was prepared by installing the remaining bisaminal unit after oxidative cleavage of the cyclopentanol moiety.

     

Total Synthesis of (−)‐Daphenylline

Total synthesis of (?)‐daphenylline, a hexacyclic Daphniphyllum alkaloid, was achieved. Construction of the tricyclic DEF ring system was initiated by asymmetric Negishi coupling followed by an intramolecular Friedel–Crafts reaction. Installation of a side chain onto the tricyclic core was carried out through Sonogashira coupling, stereocontrolled Claisen rearrangement by taking advantage of the characteristic conformation of the tricyclic DEF core, and the stereoselective alkylation of a lactone. After the introduction of a glycine unit, the ABC ring system was stereoselectively constructed through intramolecular cycloaddition of the cyclic azomethine ylide.     

Total Syntheses of (−)‐Huperzine Q and (+)‐Lycopladines B and C

Utilizing a late‐stage enamine bromofunctionalization strategy, the twelve‐step total synthesis of (?)‐huperzine Q was accomplished. Furthermore, the first total syntheses of (+)‐lycopladines B and C are described. An unprecedented X‐ray crystal structure of an unusual epoxyamine intermediate is also reported, and the synthetic application of this intermediate in natural product synthesis is demonstrated.     

Total Synthesis of (−)‐ and (+)‐Decarbamoyloxysaxitoxin and (+)‐Saxitoxin

Playing the sax : The enantioselective total syntheses of (?)‐ and (+)‐decarbamoyloxysaxitoxin (doSTX) and (+)‐saxitoxin (STX) are reported. A new methodology was developed for the synthesis of STXs, featuring discriminative reduction of the nitro group and N? O bond in nitroisoxazolidine.

     

Enantioselective Total Synthesis of (−)‐Terengganensine A

A seven‐step enantioselective total synthesis of (?)‐terengganensine A, a complex heptacyclic monoterpene indole alkaloid, was accomplished. Key steps included: a) Noyori's catalytic enantioselective transfer hydrogenation of the iminium salt to set up the absolute configuration at the C21 position; b) a highly diastereoselective C7 benzoyloxylation with dibenzoyl peroxide under mild conditions; and c) an integrated one‐pot oxidative cleavage of cyclopentene/triple cyclization/hydrolysis sequence for the construction of the dioxa azaadamantane motif with complete control of four newly generated stereocenters.     

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin,and (−)‐Pavidolide B: A Divergent Approach

A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (?)‐3‐oxochatancin, and (?)‐pavidolide B, has been developed, and it also led to the structural revision of (?)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.