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Total Synthesis of Azadirachtin: 22 Years to Harvest
Nathan Werner
Denmark Group Meeting
December 11th, 2007
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Total Synthesis
Sanderson, K. Nature 2007, 630‐631.
Natural‐product synthesis:•originated in the 1820’s when Friedrick Wöhlersynthesized urea•has generated serendipitous discoveries such as the first synthetic dye, mauveine, by William Perkin in 1856 while attempting to synthesize quinine
Has modern natural‐products synthesis outgrown it’s
usefulness?
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Isolation of Azadirachtin
goree.rice.edu/?q=taxonomy/term/7
•Azadirachta indica (Neem Tree) is native to tropical and subtropical areas of India•First isolated from the ethanolic exctract of Neem seeds in 1968 by Morgan and coworkers
www.turfarm.com/Trees.aspx
Morgan, E. D; et al. Chem. Commun. 1968, 23‐24.
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Biological Activity
Morgan, E. D; et al. Chem. Commun. 1968, 23‐24.Schmutterer, H. The Neem Tree, VCH, Weinheim, 1995.
www.le.ac.uk/neurosciences/matheson.html
•Initial biological studies by Morgan and coworkers found Azadiractin to completely inhibit feeding by the desert locust Schistocerca gregaria at 1 ng / cm2
•Further studies have revealed that azadirachtin exhibits potent anitfeedant and growth‐disruptant properties against a broad spectrum of insects yet low mammalian toxicity (LD50(rat) > 5 g / kg).
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Structural Assignment
First complete structure of
Azadirachtin by Nakanishi in 1975 using
extensive NMR
Revised structure by Kraus in 1985 which proposed a C13‐C14
epoxide
Nakanishi, K.; et al. J. Am. Chem. Soc. 1975, 1975‐1977.Kraus, W. et al. Tetrahedron Lett. 1985, 6435‐6438.
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Structural Features
16 stereogenic centers
7 tetrasubstituted carbon atomsEnol ether
Hemi‐acetal
Tetrasubstituted epoxide
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Retrosynthetic Question
?
Please take a few minutes to come up with a general retrosynthetic analysis.
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Synthetic Endeavors
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.Nicolaou, K. C.; et al. Angew. Chem. Int. Ed. 2005, 3443‐3447.
Murai, A.; et al. Org. Lett. 2002, 2877‐2880.Watanabe, H.; et al. Angew. Chem. Int. Ed. 2007, 1512‐1516.
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Ley’s Original Retrosynthetic Analysis
Decalin Fragment Pyran Fragment
Coupling Reaction
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Beginning – The Decalin Fragment
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762.
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Synthesis of IMDA Precursor
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762.
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Intramolecular Diels‐Alder Reaction
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762.
4 possible diastereomers; please make a general
prediction of the product ratio by transition state structure analysis of this simplified
model
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IMDA Answer
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2763‐2777.
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Synthesis of Decalin Fragment
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762.
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Formation of the Hemi‐Acetal
Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762.
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Synthesis of Decalin Fragment
Ley, S. V.; et al. Pure Appl. Chem.2005, 1115‐1130.
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Coupling of Fragments
Ley, S. V.; et al. Pure Appl. Chem. 2005, 1115‐1130.
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Ley’s Revised Retrosynthetic Analysis
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Ley’s Revised Retrosynthetic Analysis
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Beginning ‐ Pyran Fragment
Madsen, R.; et al. J. Chem. Soc. Perkin Trans. 1 2001, 543‐551.Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Formation of the Furan Ring
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Synthesis of Pyran Fragment
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Coupling of Fragments and Key Intramolecular Claisen
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Radical Cyclization
Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.
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Epoxidation / End‐Game
Azadirachtin Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7629‐7632.Ley, S. V.; et al. Angew. Chem. Int. Ed. 2007, 7633‐7635.
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Summary of Synthesis
Intramolecular Diels‐Alder reaction
IntramolecularClaisen rearrangement
Intramolecularradical cyclization
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Summary and Comments
Jauch, J.; et al. Angew. Chem. Int. Ed. 2007, ASAP.
•0.00015% Overall Yield•71 Synthetic Steps •48 Step longest linear sequence•More than 35 co‐workers•Interesting Chemical Reactions:•Intramolecular (IM) Diels‐Alder reaction•IM Claisen rearrangement•IM radical cyclization
Was new synthetic technology reaped over the course of the 22
year synthesis?
Do elegant syntheses have aesthetic and monetary value?
www.scripps.edu/chem/baran/html/home.html