Anatoxin synthesis

From aryl halide 110 From alcohol 156 Protection 100, 101, 144 Amino acid from hydroxy acid 40 Amphidinolide synthesis 50,94 Anatoxin synthesis 82 Aromatic ring construction 171,191 Aromatic ring substitution 10,18,19,21, 48, 54, 65,69, 104, 108, 110, 111, 120, 122,138, 149, 164, 171, 174, 175, 190,205... 

Cells of C. reinhardtii were exposed to cell-free filtrates from A. flos-aquae, pure microcystin-LR or anatoxin-a, or combinations of the toxins. Both the position of the cells and the chlorophyll-a concentration of the cultures were observed for 12 days. Exposure to crude extracts as well as to combinations of the toxins significantly decreased chlorophyll levels in the cultures. Furthermore, these compounds were all capable of paralyzing the algae and thus promoted the settlement of C. reinhardtii cells. One intriguing aspect of this dynamic interaction is the separate finding that C. reinhardtii may actually induce toxin synthesis in A. flos-aquae (Kearns and Hunter 2000), essentially signaling its own demise. 

Shono and coworkers have used a pair of amide oxidation reactions to synthesize the naturally occurring alkaloid Anatoxin A [77]. As illustrated in Scheme 41, the synthesis used the first anodic amide oxidation to functionalize... 

Scheme 41 A double N-a-methoxylation for the synthesis of the a.a -disubstituted proline Anatoxin.

Total synthesis of anatoxin-a was achieved by Martin and Mori through the same strategy (Scheme 38). 

The key step is the construction of a bicyclo[4.2.1] system. To this end, pyrrolidine derivative 95 having fif-substituents is synthesized from (+)-pyroglutamic acid and subjected to enyne metathesis using Ig to result in formation of 96 in 84% yield. From 96, synthesis of (+)-anatoxin-a is straightforward and successfully achieved. 

The Pd-catalyzed intramolecular aminocarbonyiation has also been applied to the formal total synthesis of Anatoxin-A 219, an acetylcholine mimic (Equation (16)). Thus, the reaction of 5-(methoxycarbonylamino)-cyclooctene 216a in the presence of a catalytic amount of PdCl2 and cupric chloride (CUCI2) (3 equiv.) in methanol under ambient pressure of CO gave the desired azabicyclo[4.2.1]nonane 217 as the predominant product. The regioselectivity of this reaction is highly dependent on the nature of the A -substituent. Thus, the... 

Reproduced from Oh, C.-Y. Kim, K.-S. Ham, W.-H. A fonnal total synthesis of (+)-anatoxin-A by an intramolecular Pd-catalyzed aminocarbonylation reaction. Tetrahedron Lett. 1998, 39, 2133-2136, with pennission from Elsevier. 

Alkyne Metathesis in Synthesis Syntheses of (+)-Ferrugine and Anatoxin-a... 

An enantiospecific synthesis of the potent anti-Alzheimer s agent (-t-)-ferruginine 1 and two enantiospecific syntheses of the potent anti-Alzheimer s agent anatoxin-a 2 were submitted essentially simultaneously earlier this year. In each case, the starting material used was the inexpensive pyroglutamic acid 3, and in each case the synthesis depended on Ru-catalyzed alkyne-alkene metathesis. 

An elegant synthesis of the neurotoxic alkaloid anatoxin has exploited the electrocyclic opening of the dibromobicyclo[5.1.0]octane followed by transannular cyclization (Scheme 13).238 Similarly, the thermal electrocyclic opening of the dichlorocyclopropane followed by intramolecular trapping of the developing allylic cation by a suitably positioned amine has been used in a homoaporphine synthesis.238... 

Scheme 39 Synthesis of anatoxin-a precursor 118 via MeLi mediated [3-lactam ring opening...

The unique structure of anatoxin-a, and its potential as a pharmacological tool, has inspired many different chemical syntheses of anatoxin-a and analogs. The earliest synthesis, in 1977, used (—)-cocaine as starting material [23]. Subsequently, there... 

The total synthesis of homoanatoxin-a, as an analog of anatoxin-a, was also accomplished in 1992 [33]. It is a potent nicotinic agonist active at the postsynaptic nicotinic ACh receptor channel complex [54]. Although not as potent as anatoxin-a, homoanatoxin-a has provided valuable insight for SAR studies of anatoxin-a and its homologs. 

One of the most popular methods for creating the anatoxin-a skeleton is by transannular cyclization of a suitably substituted cyclooctene. This approach was used in the first synthesis of racemic anatoxin-a (Campbell et al. 1979). They carried out two different methodologies in order to reach the 9-azabicyclo[4.2.1]nonane structure (Scheme 7.3). The 1,5-cyclooctadiene (10) starting compound was transformed into the methyl amine 11 which was treated with hypobromous acid to produce the desired bicycle 12 as a mixture of diastereoisomers in 29% overall yield, with some amount of the azabicyclo[3.2.1] analogue (Bastable etal. 1972). 

The conversion of amino ketone 14 into A -methyl anatoxin (4) was accomplished through the intermediate enonitrile 19 (DTncanand Seyden-Peime 1975 Wroble and Watt 1976). A -Demetlyla-tion was achieved before with diethyl azodicarboxylate (Campbell et al. 1979) thus, this completed the synthesis of racemic anatoxin-a. 

Subsequently, alternative methods were developed by Stjernlbf and co-workers for introducing the acyl moiety and different sidechains in the ketone intermediate 14 (Lindgren et al. 1987 Stjemlof et al. 1989 Ferguson et al. 1995), which was achieved using the Campbell synthesis (Campbell et al. 1979). The resolution of 14 was performed by traditional diastereomeric crystallisation of its (+)- and ( )-dibenzoyltartaric acid salts from ethanol (Stjemlof et al. 1989). This allowed the syntheses of both ( )- and (+)-anatoxin-a in 96% ee, respectively, as they could prove later in a different conversion of 14 into anatoxin-a (Ferguson et al. 1995). 

Intramolecular aminocarboi lation (Chiou et al. 2005) was used in the synthesis of anatoxin-a by the Ham group. The key step involved an intramolecular palladium catalyzed aminocarboi lation reaction to reach the bicyclic ring skeleton characteristic of anatoxin-a (Oh et al. 1998) (Scheme 7.6). 

Continuing with palladium chemistiy, Trost proposed a new asymmetric synthesis of anatoxin-a (Trost and Oslob, 1999) and the crucial step was the introduction of chirality by a catalytic process involving an intramolecular asymmetric allylic alkylation (Trost 2004) of the intermediate ( )-29 affording (+)-31 (Scheme 7.7). This step was catalyzed by palladium in presence of a chiral phosphine ligand. 

Simpkins and co-workers were the first to use an asymmetric catalytic process in (-)-anatoxin-a synthesis (Newcombe and Simpkins, 1995) instead of resorting to the chiral pool strategy. Their total synthesis of (-)-anatoxin-a relied on an enantioselective enolisation reaction of a readily available ( )-3-tropinone (33), by a chiral lithium amide base (34) (Bunn et al. 1993a, 1993b) and subsequent cyclopropanation/ring expansion reaction giving the ketone 37 (Scheme 7.8). 

Synthesis of Anatoxin-a via Intramolecular Cyclization of Iminium Ions... 

Speckamp and Hiemstra (1985) proposed a similar approach to anatoxin-a synthesis by applying their previous work on A -acyliminium chemistry. The use of a carbomethoxy group on the nitrogen, inside an alkyl group, would enhance the electrophilicity of the iminium ion owing to the electron-attracting... 

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