A short and efficient route to (±)-anatoxin-a

Abstract

A new route to Anatoxin-a 1 is reported which involves a tandem methyllithium mediated ring opening/intramolecular cyclisation as a key step to provide the required 2-acetyl-9-azabicyclo 14.2.1 I nonane ring structure in one synthetic operation.Certain strains of Anabaena flos aqua, a freshwater blue-green algae, produce an alkaloidal neurotoxin that has proved fatal to livestock, waterfowl and fish.' This toxin was identified by Xray crystallography2 and spectroscopy3 as a secondary amine containing the 9-azabicyclo[4.2. llnonane ring structure and was named anatoxin-a 1 or 'Very Fast Death Factor' (VFDF).4 The LD50 intraperitoneal (IP) mouse for purified toxin is 200 pg kg-1 body mass, with a survival time of 4-7 min.5 Anatoxina mimics the neurotransmitter acetylcholine and acts as a potent agonist for the nicotinic acetylcholine receptor (nAChR).6 Such powerful biological activity coupled with its unique ring structure has led to numerous racemic7 and chiralg syntheses of this molecule over the last twenty years. Construction of the aforementioned ring system and introduction of the methyl ketone at the correct oxidation level have proved to be the major challenges in this regard. We wish to report a short and efficient route to anatoxin-a which allows access to a variety of analogues.The key step in our approach involves a tandem methyllithium induced 13-lactam ring opening-intramolecular cyclisation, to afford the desired ring structure, complete with methyl ketone in one synthetic operation. Transformation of the resultant alcohol 5 to Boc-dihydroanatoxin-a 7 was easily achieved and the synthesis was completed using methods developed by Rapoport and coworkers.sh,d The advantage of our route stems from the accessibility of multigram quantities of the relatively simple precursors and an early entry into the 2-acetyl-9-azabicyclo [4.2.1] nonane ring system. The 13-lactam 2 was prepared by careful addition of chlorosulfonyl isocyanate to 1,5-~yclooctadiene in dichloromethane (DCM) containing anhydrous sodium carbonate at 0 "C and hydrolysis of the chlorosulfonyl P-lactam intermediate. Removal of the polymeric side products by work up and flash silica chromatography afforded the (3-lactam 2 as a white solid in 48% yield. Alkylation to provide the benzyl protected (3-lactam 3 could be achieved in 60% yield by treatment of 2 with sodium hydride (1,l equiv.) in THF followed by addition of benzyl bromide in the presence of a catalytic amount of 18-crown-6 ether. In our hands the alkylation of 2 under phase transfer conditions proved to be the most efficient method, affording 3 as a white solid in excellent yield (95%). Treatment of the benzyl protected P-lactam 3 with MCPBA in DCM provided the racemic epoxide 4 in 84% yield, as a white solid. X-ray crystallography9 confirmed the relative anti-relationship of the (3-lactam to the epoxide, and was attributed to the reaction of the peroxyacid with the least hindered face of the double bond. This relationship provides the correct geometry necessary for the key nitrogen...

PdII‐Mediated Oxidative Amination for Access to a 9‐Azabicyclo[4.2.1]nonane Compound Library and Anatoxin‐a

“…We were also compelled to apply the oxidative amination conditions to the synthesis of anatoxin‐a ( 1 ). Parsons' 2000 synthesis[12a] utilised a selenium‐mediated ring closure of the N ‐Boc methyl ketone 18 to construct the 9‐azabicyclo[4.2.1]nonane framework (Scheme ). The intermediate selenide was not isolated but instead treated with H 2 O 2 , promoting oxidation and elimination to yield the key aza‐bridged bicycle 19 in 55% over two steps.…”

“…Interestingly, despite the report that PdCl 2 , Pd(OAc) 2 and RhCl 3 were unsuccessful at bringing about the heterocyclisation of 18 , we were delighted to observe that utilisation of our optimised oxidative amination conditions allowed the isolation of 19 in a much improved 86% yield. This was achieved in a single synthetic operation and constitutes a useful refinement to the seminal work of Parsons[12a] and Rapoport. [7b]…”

“…An aminocarbonylation strategy was reported by Ham in 1998, however this heterocyclisation was observed not to be regioselective. A series of reports by Parsons saw the development of a selenium‐mediated ring closure, however this approach requires stoichiometric quantities of toxic phenylselenyl chloride. Ho reported a catalytic palladium mediated cyclisation of a corresponding trans ‐derivative, although yields were hampered by the formation of an undesired tricyclic side‐product.…”

Copper(I)‐Catalyzed Synthesis of Chlorinated Tetrahydropyridazin‐3‐ones and 1,2‐Diazepan‐3‐ones from N‐Allyl‐N′‐trichloroacetylhydrazines

“…The allylated‐alkylated products 12 , thus obtained were treated with trifluoroacetic acid in DCM at room temperature (23–25 °C) for 1 h to furnish the deprotected trisubstituted hydrazines 13 . Trichloroacetylation23 of 13 with trichloroacetyl chloride in diethyl ether in the presence of triethylamine at 23–25 °C afforded the cyclization precursors 8 in high yields.…”

Chapter 6. Heterocyclic compounds

“…It appears that in 90 years or so since its discovery'2 the Darzens reaction has only now been attempted with a phenyl ester.I3 Interestingly the chloro ester (23) with a suitable lithium amide base and a ketone gives via (24), not an oxirane, but lactone (25) (Scheme Scheme 12 Reagents: i, (Ph,P),Pd, Bu3N, CO 9). Corresponding bromo esters (26) and ketones are converted into di-, tri-or tetra-substituted /?-lactones (27) using indium powder or electrochemically using a sacrificial indium anode14 (Scheme 10). Yields are variable, but usually good.…”