Asymmetric total syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated from Lycopodium serratum

Two new Phlegmarine-type alkaloids, lycoposerramines-V and -W, were isolated from Lycopodium serratum, and their structures including the absolute configuration were established by asymmetric total synthesis involving such key steps as Johnson-Claisen rearrangement, asymmetric allylation, and ring-closing metathesis (RCM)- or SmI(2)-mediated stereoselective piperidine ring construction.     

The Lycopodium alkaloids

Lycopodium alkaloids are quinolizine, or pyridine and alpha-pyridone type alkaloids. Some Lycopodium alkaloids are potent inhibitors of acetylcholinesterase (AChE). Huperzine A (HupA) is reported to increase efficiency for learning and memory in animals, and it shows promise in the treatment of Alzheimer's disease (AD). 201 Lycopodium alkaloids from 54 species of Lycopodium (sensu lato) have been reported so far. This review is intended to to cover the chemical, pharmacological and clinical research on Lycopodium alkaloids reported in the literature from the spring of 1993 to August 2004. Structures of 81 new Lycopodium alkaloids are presented, classified and analyzed. The structural characters and biogenetic relationships of the four major Lycopodium alkaloid groups (lycopodine, lycodine, fawcettimine and miscellaneous) are discussed. Bioactivities of Lycopodium alkaloids, especially HupA, are summarized. In particular, the effect of HupA and other cholinesterase inhibitors (anti-AD drugs) on acetylcholine esterase (AChE) activity in the rat cortex and butylcholine esterase activity are compared. Structure-activity relationships and structure modifications of HupA and its analogs are described. Information on clinical trials with HupA and its derivative ZT-1 is presented. The state of HupA availability and recent advances in in vitro propagation of HupA producing plants are outlined. Finally, hypotheses about Lycopodium alkaloid biosynthetic pathways are discussed.     

First asymmetric total syntheses of cernuane-type Lycopodium alkaloids, cernuine, and cermizine D

The first total syntheses of two cernuane-type Lycopodium alkaloids, (-)-cernuine and (+)-cermizine D, were accomplished starting from (+)-citronellal. The syntheses involved organocatalytic alpha-amination to afford oxazolidinone, which is used for diastereoselective allylation, and asymmetric transfer aminoallylation followed by stereoselective construction of an aminal moiety as key steps.     

Application of the Helquist annulation in Lycopodium alkaloid synthesis: unified total syntheses of (-)-8-deoxyserratinine, (+)-fawcettimine, and (+)-lycoflexine

A unified strategy for total synthesis of the Lycopodium alkaloids (-)-8-deoxyserratinine (7), (+)-fawcettimine (1), and (+)-lycoflexine (4) is detailed. The key features include a highly efficient Helquist annulation to assemble the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, providing access to the common tricyclic skeleton, asymmetric Shi epoxidation, delivering the desired β-epoxide stereospecifically to furnish (-)-8-deoxyserratinine (7), SmI(2) reduction of dihydroxylation derivative 35 to enable formation of (+)-fawcettimine (1), and a rapid biomimetic transformation of (+)-fawcettimine (1) into (+)-lycoflexine (4) via an intramolecular Mannich cyclization.     

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 strategy for the synthesis of the "miscellaneous" lycopodium alkaloids: total synthesis of (+/-)-lyconadin A

Total synthesis of the Lycopodium alkaloid lyconadin A was achieved in 18 steps starting from a readily available vinylogous ester and bromopicoline. The key step in the total synthesis is a proximity-driven oxidative C-N bond-forming reaction that yields the lyconadin pentacycle from a tetracyclic precursor. The key tetracycle, which has been prepared for the first time, is a versatile intermediate that may be utilized for the total synthesis of a variety of Lycopodium alkaloids. Critical to the success of this plan was the efficient preparation of a pyridine-annulated cycloheptadiene tricycle that promises to be a general strategy to access a variety of seven-membered ring containing natural products.     

Synthesis and reactivity of pelletierine-derived building blocks and pelletierine analogs

Lycopodium alkaloids are unique (and often impressive in terms of structures) polycyclic alkaloids that attract great interest from a biological point of view and that also provide ideal targets for total synthesis. Propylpiperidine units closely related to pelletierine are involved in the biosynthesis of these alkaloids. Therefore, stable pelletierine-like compounds, especially a (R)-phenylglycinol-based oxazolopiperidine analog, were prepared and their reactivity investigated. The compounds described in this work expand the tool-box of small building blocks in the piperidine series and pelletierine analogs and could be suitable for the synthesis of Lycopodium alkaloids following biosynthetically inspired strategies.     

Palladium-catalyzed asymmetric allylic substitution of 2-arylcyclohexenol derivatives: asymmetric total syntheses of (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine

Much interest has been shown in Amaryllidaceae alkaloids as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from members of the Amaryllidaceae family; most of them can be classified into eight skeletally homogeneous groups. We have succeeded in the first asymmetric total syntheses of the crinane-type alkaloids (+)-crinamine (1), (-)-haemanthidine (2), and (+)-pretazettine (3). The starting cyclohexenylamine 14 was obtained from allyl phosphonate 11c by palladium-catalyzed asymmetric amination in 82% yield and with 74% ee. The product was recrystallized from MeOH. Interestingly, (-)-14 with 99% ee was obtained from the mother liquor (74% recovery). Intramolecular carbonyl-ene reaction of (-)-10 proceeds in a highly stereoselective manner to give hexahydroindole derivative 9 as the sole product. In the Lewis-acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product, 20, was isolated in high yield. From 9, (+)-crinamine was synthesized. Thus, the asymmetric total synthesis of (+)-crinamine was achieved in 10 steps from 11c, and the overall yield is 19%. The total synthesis of (-)-haemanthidine was also achieved from 9 by a short sequence of steps.     

Indolizidine and quinolizidine alkaloids

This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids. Included in the review are the hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from animal sources, including ants, amphibians and beetles; indolizidine alkaloids from the genera Polygonatum, Prosopis and Elaeocarpus; indolizidine and phenanthroindolizidine alkaloids; alkylquinolizidine alkaloids, including myrtine, epimyrtine, plumerinine and Lycopodium metabolites; Lythraceae and Nuphar alkaloids; lupine alkaloids; and alkaloids from marine sources. 150 references are cited.     

Indolizidine and quinolizidine alkaloids

This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids from microbial, plant and animal sources. Included in the review are the hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from animal sources, including ants, amphibians and beetles; ipalbidine, phenanthroindolizidines and related alkaloids; Lycopodium alkaloids; lupine alkaloids; and alkaloids from bacterial and marine sources. The literature from July 2002 to June 2003 is reviewed, and 174 references are cited.     

Direct methoxypyridine functionalization approach to magellanine-type Lycopodium alkaloids

A concise enantioselective approach to the tetracyclic core of the magellanine-type Lycopodium alkaloids is reported. Key to this approach is the use of the Hajos-Parrish reaction to set a challenging quaternary stereocenter, thereby guiding the stereoselectivity for the remainder of the synthesis, as well as the use of a palladium-mediated direct pyridine functionalization reaction to forge the tetracyclic core.     

A New Approach to the Asymmetric Synthesis of 3-Methylpyrrolidine Alkaloids

3-Methylpyrrolidine alkaloids 1-5,isolated from the poison gland of several species of ants Leptothoracini (Myrmicinae), have been found to be pheromones and chemical weapons of them^[1,2].Since these alkaloids are only available at nanogram scale, the development of asymmetric synthesis is of importance, in particular for evaluating their bioactivities.     

Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction.

A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Sch?llkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Sch?llkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.     

Regiospecific,enantiospecific total synthesis of the alkoxy-substituted indole bases, 16-epi-N(a)-methylgardneral, 11-methoxyaffinisine,and 11-methoxymacroline as well as the indole alkaloids alstophylline and macralstonine

A regiospecific, enantiospecific approach to the synthesis of ring-A-substituted indole alkaloids was developed via a doubly convergent strategy. The asymmetric Pictet-Spengler reaction and enolate-driven palladium cross-coupling processes were both executed in stereospecific fashion and served as the stereochemical basis of this approach. The synthesis of 16-epi-N(a)-methylgardneral (15), 11-methoxyaffinisine (16), and 11-methoxymacroline (22) has been accomplished in high yield and in enantiospecific fashion. Moreover, the key C-19 ketosarpagine system (borane adducts) 19a,b employed for the construction of 11-methoxymacroline (22) was also transformed into alstophylline 25, which resulted in completion of the total synthesis of the bisindole macralstonine (1). [reaction: see text]     

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.     

IMDA/retro-Mannich approach to cis-perhydroquinoline Lycopodium alkaloids: asymmetric synthesis of (+)-luciduline

[formula: see text] The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished. Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich ring opening, and a novel cationic reductive cyclization reaction.     

Stereoselective syntheses of lycopodium alkaloids, (±)-fawcettimine and (±)-8-deoxyserratinine

Lycopodium alkaloids, (±)-fawcettimine (1) and (±)-8-deoxyserratinine (3) were stereoselectively synthesized through the stereoselective Diels-Alder reaction and the regioselective aldol condensation reaction of the dialdehyde (8).     

Malycorins A--C, New lycopodium alkaloids from Lycopodium phlegmaria

A novel C(19)N-type Lycopodium alkaloid, malycorin A (1) consisting of a serratinane skeleton with 2-propanol unit has been isolated from the club moss Lycopodium phlegmaria, together with two new C(16)N-type alkaloids, malycorins B (2) and C (3), and the structures and relative stereochemistry were elucidated on the basis of spectroscopic data.     

The enantiospecific,stereospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-majvinine, (+)-10-methoxyaffinisine,and (+)-N(a)-methylsarpagine,as well as the total synthesis of the alstonia bisindole alkaloid macralstonidine

The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-N(a)-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been accomplished. This approach employed the Sch?llkopf chiral auxiliary for the stereospecific construction of the desired d-(+)-tryptophan unit required for the asymmetric Pictet-Spengler reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd(0) coupling process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline (2) and N(a)-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other alkaloids for it is stereospecific and either enantiomer can be prepared with ease.     

Total syntheses of Lycopodium alkaloids (+)-fawcettimine, (+)-fawcettidine, and (-)-8-deoxyserratinine

A shared story: Three fawcettimine- and serratinine-type Lycopodium alkaloids are prepared from a common tetracyclic spirodiketone intermediate in concise total syntheses. The intermediate was constructed by a remarkable biosynthesis-inspired transannular N-C bond formation to the spiro-configured carbon center and a hydroxy-directed pinacol coupling promoted by SmI(2).