A gram-scale batch and flow total synthesis of perhydrohistrionicotoxin.
The total synthesis of the spiropiperidine alkaloid (-)-perhydrohistrionicotoxin (perhydro-HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)-(-)-6-Pentyltetrahydro-pyran-2-one 8 underwent nucleophilic ring opening to afford the alcohol 10, which was elaborated to the nitrone 13. Protection of the nitrone as the 1,3-adduct of styrene and side-chain extension to the unsaturated nitrile afforded a precursor 17, which underwent dipolar cycloreversion and 1,3-dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro-HTX 2. The principal steps to the spirocycle 18 have successfully been transferred into flow mode by using different types of microreactors and in a telescoped fashion, allowing for a more rapid access to the histrionicotoxins and their analogues by continuous processing.
Brasholz
Malte
M
CSIRO Molecular and Health Technologies, Bayview Avenue, Clayton, VIC 3168, Australia.
Macdonald
James M
JM
Saubern
Simon
S
Ryan
John H
JH
Holmes
Andrew B
AB
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000664:Amphibian Venoms / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D000470:Alkaloids; D000664:Amphibian Venoms; D007555:Isoxazoles; C004792:perhydrohistrionicotoxin; C007948:histrionicotoxin