Total Synthesis of (-)-Anominine
Ben Roembke
Department of Chemistry and Biochemistry
University of Maryland, College Park
Ben Bradshaw and Josep Bonjoch


University of Barcelona
School of Pharmacy
Department of Pharmacology and
Therapeutic Chemistry
Much of their recent work has been with
terpenoids but more generally they work on
synthesis of a variety of natural products
What is Anominine?
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Anominine is a diterpenoid stored in the
sclerotia of the Aspergillus flavus fungus
What are all these words you say?
Terpenoids are a large class of natural
products that are assemblies of the 5 carbon
unit isoprene


A diterpenoid contains 4 isoprene units (e.g. 20
carbons)
“Sclerotia are reproductive bodies produced
by certain fungi as a mechanism for survival
and propagation of the species.”
Gloer, J. Acc. Chem. Res. 1995, 28, 343-350.
Sclerotia
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Scelrotia are much more rugid than
other parts of the fungus thus they can
survive in extreme conditions.
Under favorable conditions sclerotia
will germinate to produce mycelia
(finger like protrusions that absorb
nutrients), fruiting bodies
(mushrooms, etc.) and spores
Gloer, J. Acc. Chem. Res. 1995, 28, 343-350.
Sclerotia

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In other words sclerotia is an important
vestibule to store excess chemical
energy to regrow fungus later on down
the road.
Sclerotia must also contain secondary
metabolites to ward off potential
predators
Gloer, J. Acc. Chem. Res. 1995, 28, 343-350.
Anominine

Exhibits an activity against the crop
pest Helicoverpa zea

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Cited as the most important insect pest in
terms of economic losses in the United
States
Such a compound could be useful as
an insecticide if able to be produced
Gloer, J. Acc. Chem. Res. 1995, 28, 343-350.
Robinson Annulation
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
Starts with a Michael addition
No stereochemistry at this point
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Robinson Annulation

Catalyst contains two elements of chirality


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Axial chirality (hindered rotation)
Chiral center (L-Proline)
Chiral catalyst results in an asymmetric catalysis
N-Ts-(Sa)-binam-LProline
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Robinson Annulation

Covalent catalysis
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Robinson Annulation

Newly formed alkene can act as a
nucleophile to close the ring
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Wieland-Miescher Ketone

Gives correct enatiomer in 94% ee and
96% yield
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Dialkyl Cuprate

Reaction of the Wieland-Miescher ketone
with a dialkyl cuprate yielded the correct
enantiomer of the second quaternary
carbon in 94%ee
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Diasterioselective Reduction of Ketone
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Hydride attacks from less sterically
hindered side creating this alcohol
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Grieco Elimination

Treatment of alcohol with aryl
selenocyanate and tributyl phosphine
creates alkyl aryl selenide.
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Greico, P. J. Org. Chem. 1976, 41, 1484-1486.
Oxidation of the Selenide
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mCPBA (meta chloro perbezoic acid) is used to
oxidize the selenide
This makes a chiral center at the selenium.
Only one of the enatiomers will react to form the
alcohol due to hindered rotation
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Considerations
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This reaction did not work in dry solvent. Why?
Oxidation by mCPBA is not a stereoselective process but
only one of the two chiral selenoxides will react
Water was introduced into the system establishing this
equilibrium:
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Epimerization at Selenium
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Selenoxide reacts with the endocyclic
alkene to form the fourth cis-stereo center
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Coupling of Indole to Product
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A Lewis acid had to be used to activate
the double bond for nucleophilic attack
KF in ethanol was added which cleaved
the acetate
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Oxidation of Alchol with TPAP
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TPAP (tetra-n-propylammonium perruthenate):
Oxidizes carbon one electron at a time
Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, 5966-5967
Wittig Reaction
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The Wittig reaction reduces the two
carbonyls in the compound
Selective Olefin Cross-Metathesis
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Alkene gains two methyl groups through
this process
(-)-Anominine
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The TES group is
cleaved by TBAF
(tetra-nbutylammonium
fluoride) to give the
final product
Acknowledgements
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
Sonja
Dr. Davis