Fawcettimine‐Type Lycopodium Alkaloids as a Driving Force for Discoveries in Organic Synthesis

Ever since the pioneering synthetic work reported by both Inubushi and Heathcock back in 1980s, the fawcettimine‐type Lycopodium alkaloids have continuously served as a driving force for discoveries in organic synthesis. In this personal account, we summarized our recent synthetic efforts towards the total synthesis of fawcettimine‐type Lycopodium alkaloids, along with a brief summary of relevant syntheses reported by others. Our discussions focus mainly on the key reactions applied during the synthesis of fawcettimine‐type Lycopodium alkaloids.     

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

A new approach for synthesis of fawcettimine‐type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels–Alder reaction followed by redox‐controlled elaboration. Eventually, (?)‐8‐deoxyserratinine, (+)‐fawcettimine, (?)‐lycopoclavamine‐A, (?)‐serratine, (?)‐lycopoclavamine‐B and (?)‐serratanidine were successfully accessed.     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

Synthetic Efforts toward the Lycopodium Alkaloids Inspires a Hydrogen Iodide Mediated Method for the Hydroamination and Hydroetherification of Olefins

Progress toward the total syntheses of a diverse set of fawcettimine‐type Lycopodium alkaloids via a “Heathcock‐type” 6–5–9 tricycle is disclosed. This route features an intermolecular Diels–Alder cycloaddition to rapidly furnish the 6–5‐fused bicycle and a highly chemoselective directed hydrogenation to build the azonane fragment. While conducting these synthetic studies, trimethylsilyl iodide was found to effect a hydroamination reaction to furnish the tetracyclic core of serratine and related natural products. This observation has been expanded into a general method for the room temperature hydroamination of unactivated olefins with tosylamides utilizing catalytic “anhydrous” HI (generated in situ from trimethylsilyl iodide and water). The presence of the iodide anion is critical to the success of this Brønsted acid catalyzed protocol, possibly due to its function as a weakly coordinating anion. These conditions also effect the analogous hydroetherification reaction of alcohols with unactivated olefins.     

Two Novel Lycopodium Alkaloids from Huperzia serrata

Huperzine Q ( 1 ) and N‐oxyhuperzine Q ( 2 ), two novel irregular fawcettimine‐type Lycopodium alkaloids were isolated from the CHCl₃ fraction of the basic material of the whole plant of the Chinese medicinal herb Huperzia serrata. Their structures were determined as 13‐epi‐13β,16‐epoxydihydrofawcettimine ( 1 ) and N‐oxy‐13‐epi‐13β,16‐epoxydihydrofawcettimine ( 2 ) by means of spectroscopic studies and X‐ray crystallographic analysis.     

Global detection and semi‐quantification of Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus by a non‐targeted multiple reaction monitoring approach

Methods based on triple quadrupole tandem mass spectrometry have been widely used and reported as highly selective and sensitive methods for quantifying substances of herbal medicines. However, most of them were limited to targeted components, due to the difficulties to optimize the multiple reaction monitoring transitions without authentic standards. This study proposed a novel strategy for non‐targeted optimization of multiple reaction monitoring method based on the diagnostic ion guided family classifications, tandem mass spectrometry database establishment, and transitions and collision energy screening. Applying this strategy, 59 Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus have been classified, and 51 of these Fritillaria alkaloids were successfully detected by the optimal multiple reaction monitoring method. For semi‐quantification, the easy‐to‐obtain Fritillaria alkaloids of each type, such as verticinone for cevanine type and peimisine for jervine type, were used as the reference standards to calibrate the other Fritillaria alkaloids in the same type. The method was demonstrated a good linearity (R² > 0.998) with satisfactory accuracy and precision, and the lower limits of quantification of verticinone and peimisine were estimated to be 0.076 and 0.216 pg, respectively. In addition, the results suggested that the proposed strategy might obtained high quality metabolomics data in discrimination of Fritillaria unibracteata and Fritillaria ussuriensis.     

Total Synthesis of (+)‐trans‐Trikentrin A

Several syntheses have already been reported for cis‐trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans‐1,3‐dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans‐trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)‐mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity.     

Total Syntheses of Lycoposerramine‐V and 5‐epi‐Lycoposerramine‐V

Enantioselective total syntheses of lycopodium alkaloids lycoposerramine‐V and 5‐epi‐lycoposerramine‐V have been accomplished. Features of the newly established total synthesis include: 1) introduction of the first chiral center with a scalable desymmetrization reaction of an meso‐anhydride; 2) chemoselective functionalization of a bis‐Weinreb‐amide with Grignard addition; and 3) construction of the multifunctionalized cyclohexanone with a stereoselective intramolecular Michael addition.     

Rapid screening and identification of lycodine‐type alkaloids in Lycopodiaceae and Huperziaceae plants by ultra‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry

Lycodine‐type alkaloids have gained significant interest owing to their unique skeletal characteristics and acetylcholinesterase activity. This study established a rapid and reliable method using ultra‐performance liquid chromatography coupled with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐ESI‐Q/TOF‐MS/MS) for comprehensive characterization of lycodine‐type alkaloids for the first time. The lycodine‐type alkaloids were detected successfully from Lycopodiastrum casuarinoides, Huperzia serrata and Phlegmarirus carinatus in seven plants of the Lycopodiaceae and Huperziaceae families, based on the established characteristic MS fragmentation of five known alkaloids. Furthermore, a total of 13 lycodine‐type alkaloids were identified, of which three pairs of isomers were structurally characterized and differentiated. This study further improves mass analysis of lycodine‐type alkaloids and demonstrates the superiority of UPLC with a high‐resolution mass spectrometer for the rapid and sensitive structural elucidation of other trace active compounds. Copyright © 2016 John Wiley & Sons, Ltd.     

Michael addition-based cyclization strategy in the total synthesis of Lycopodium alkaloids

Lycopodium alkaloids, a unique family of biologically important natural products isolated and characterized from various species of Lycopodium (sensu lato), have attracted extensive attention from chemists and pharmacists in the past three decades. Michael addition-based cyclization has been successfully employed as an elegant and efficient ring-construction protocol of constructing key cyclohexanone intermediates in the total synthesis of Lycopodium alkaloids. This mini-review chooses and summarizes several representative total syntheses of various Lycopodium alkaloids in which intramolecular Michael addition severed as the key methodology.     

Total Synthesis of (−)‐Vindorosine

Outlined herein is a novel and scalable synthesis of (−)‐vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone‐derived lithium dienolates with indolyl N ‐tert‐butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza‐Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)‐vindorosine and related alkaloids.     

Enantioselective,Protecting‐Group‐Free Total Synthesis of Sarpagine Alkaloids—A Generalized Approach

A generalized synthetic access to sarpagine alkaloids through a joint synthetic sequence has been accomplished. Its applicability is showcased by the enantioselective total syntheses of vellosimine ( 1 ), N‐methylvellosimine ( 3 ), and 10‐methoxyvellosimine ( 8 ). The synthetic sequence is concise (eight steps) from known compound 13 , and requires no protecting groups. The indole heterocycle was introduced in the last step. This strategy allows access to sarpagine alkaloids through a shared synthetic route leading to precursor 10 , which we term “privileged intermediate”. Starting from this intermediate, all sarpagine alkaloids can be synthesized using phenylhydrazines with different substitution patterns ( 15 – 17 ). Our approach brings about the advantage, that synthesis optimization only needs to be performed once for many natural products. The key features of the synthesis are a [5+2]‐cycloaddition and a ring enlargement.     

Ten new fawcettimine-related alkaloids from three species of Lycopodium

Ten new fawcettimine-related alkaloids, i.e., lycopoclavamines, lycoposquarrosamine-A, and other hydroxylated fawcettimine derivatives, were isolated from three species of Lycopodium (Lycopodium clavatum, Lycopodium serratum, and Lycopodium squarrosum). The structures of the new alkaloids were elucidated by spectroscopic methods and chemical correlation.     

Unified total syntheses of fawcettimine class alkaloids: fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B

The total syntheses of the lycopodium alkaloids fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring.     

Structural characterization and identification of C19‐ and C20‐diterpenoid alkaloids in roots of Aconitum carmichaeli by rapid‐resolution liquid chromatography coupled with time‐of‐flight mass spectrometry

Aconite alkaloids from the roots of Aconitum carmichaeli (Fuzi, in Chinese) have been investigated by rapid‐resolution liquid chromatography coupled with time‐of‐flight mass spectrometry (TOFMS) in positive mode. With dynamic adjustment of the key role as fragmentor voltage in TOFMS, an efficient transmission of the ions was achieved to obtain the best sensitivity for providing the molecular formula for each analyte, and abundant fragment ions for structural information. Fifteen authentic standards isolated from Fuzi with various structures were first characterized by TOFMS, including diester‐diterpenoid alkaloids (DDAs), monoester‐diterpenoid alkaloids (MDAs), alkylol amine‐diterpenoid alkaloids (ADAs), veatchine‐type alkaloids and atisine‐type alkaloids. Fragmentation rules and key diagnostic fragment ions have been summarized, and possible pathways of fragmentation have been proposed. By accurate mass measurements within 5 ppm error for each ion, 30 C₁₉‐diterpenoid alkaloids including 10 DDAs, 3 MDAs, 9 ADAs and 8 other type alkaloids, and 8 C₂₀‐diterpenoid alkaloids including 4 veatchine‐type alkaloids and 4 atisine‐type alkaloids could be identified in a methanolic extract of Fuzi. Some isomers of aconite alkaloids were also differentiated. Based on the differences between their fragmentation pathways and special fragment ions, each type of aconite alkaloids was differentiated. Copyright © 2009 John Wiley & Sons, Ltd.     

Lycopodine‐Type Lycopodium Alkaloids from Huperzia serrata

Eleven Lycopodium alkaloids with a lycopodine‐type skeleton were isolated from the basic material of the whole plant of Huperzia serrata (Thunb .) Trev. (Huperziaceae). Among them, 12‐epilycodoline N‐oxide (=(12α,15R)‐12‐hydroxy‐15‐methyllycopodan‐5‐one N‐oxide; 1 ), 7‐hydroxylycopodine (=(15S)‐7‐hydroxy‐15‐methyllycopodan‐5‐one; 2 ), and 4,6α‐dihydroxylycopodine (=(6α,15R)‐4,6‐dihydroxy‐15‐methyllycopodan‐5‐one; 3 ) are new compounds. Their structures were identified spectroscopically, especially by means of 1D‐ and 2D‐NMR.     

The profiling and identification of chemical components,prototypes and metabolites of Run‐zao‐zhi‐yang capsule in rat plasma,urine and bile by an UPLC‐Q‐TOF/MSE‐based high‐throughput strategy

Run‐zao‐zhi‐yang (RZZY) capsule, a traditional Chinese medicine formula, is popularly used for the treatment of dermatitis and eczema. However, few studies have been carried out on RZZY and its metabolites. In this study, we developed a three‐step strategy to rapidly characterize the chemical constituents and metabolites of RZZY using ultra‐high‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry. A total of 41 chemical components were characterized from RZZY. Among these, there are 11 flavonoids, six alkaloids, six stilbene glycosides, five anthraquinones and 13 other compounds. In addition, 18 prototypes and 35 metabolites were detected in rat plasma, urine and bile. This study offers an applicable approach for high‐throughput profiling and identification of chemical components and metabolites derived from traditional Chinese medicine formula in vivo, and also provides essential data for exploring bioactive ingredients and action mechanisms of RZZY.     

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis,Dendrobate, and Spruce Alkaloids

A method for the stereoselective synthesis of 2,6‐disubstituted piperidines has been developed that is based on the use of an intramolecular iridium‐catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2‐vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru‐catalyzed cross‐metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)‐prosopinine, (+)‐prosophylline, (+)‐prosopine, and of the dendrobate alkaloid (+)‐241D and its C6 epimer are described.     

Total Syntheses of Hyperforin and Papuaforins A–C,and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane‐2,4,9‐trione frameworks have inspired synthetic organic chemists over the last decade. The concise total syntheses of four natural products PPAPs; hyperforin and papuaforins A–C, and the formal synthesis of nemorosone are reported. Key to the realization of this strategy is the short and scalable synthesis of densely substituted PPAP scaffolds through a gold(I)‐catalyzed 6‐endo‐dig carbocyclization of cyclic enol ethers for late‐stage functionalization.     

Total Syntheses of Hyperforin and Papuaforins A–C,and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane‐2,4,9‐trione frameworks have inspired synthetic organic chemists over the last decade. The concise total syntheses of four natural products PPAPs; hyperforin and papuaforins A–C, and the formal synthesis of nemorosone are reported. Key to the realization of this strategy is the short and scalable synthesis of densely substituted PPAP scaffolds through a gold(I)‐catalyzed 6‐endo‐dig carbocyclization of cyclic enol ethers for late‐stage functionalization.