The Total Synthesis of Vitamin · PDF fileThe Total Synthesis of Vitamin B12 ... work-up step...
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The Total Synthesis of Vitamin B12
Nathan S. Werner
Denmark Group Meeting
September 28th, 2010
The most advanced synthetic intermediate as of 1968
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Biology of Vitamin B12•Vitamin B12, common name cobalamin, is a water soluble molecule produced by bacteria and algae•It is involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation•Vitamin B12 deficiency can potentially cause sever and irreversible damage to the nervous system
Brown, K. L. Chem. Rev. 2005, 2075–2149
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The Pigments of Life
Vitamin B12
corrin, 1973
Hemeporphin, 1929
Chlorophyll Achlorin, 1960
Woodward, R.B. Pure Appl. Chem. 1973, 145–177Fischer, H. et al. Justus Liebigs Ann. Chem. 1929, 468R. B. Woodward et al. J. Am. Chem. Soc. 1960, 3800
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X-Ray Crystal Structure
Hodgkin, D. C.; et al. Nature 1956, 1032–1033
X-Ray Crystal Structure Solved 1956
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Structural Analysis
•Cobalt complex•15-membered macrocycle•4 heterocyclic rings•9 stereogenic centers•6 contiguous stereogenic centers•4 quaternary carbon atoms•6 amide side chains•1 carboxylic acid side chain•Direct linkage between A-D rings
Bernhauer, K.; et al. Helv. Chim. Acta 1960, 704–712Mulzer, J. Eur. J. Org. Chem. 2005, 30–45
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Retrosynthetic Analysis
Bernhauer, K.; et al. Helv. Chim. Acta 1960, 704–712
Woodward, R.B. Pure Appl. Chem. 1968, 519–520Woodward, R.B. Pure Appl. Chem. 1971, 283–304Woodward, R.B. Pure Appl. Chem. 1973, 145–177
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b-Corrnorsterone Retrosynthetic Analysis
Woodward, R.B. Pure Appl. Chem. 1968, 519–520
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Woodward’s Western Fragment Synthesis
Woodward, R.B. Pure Appl. Chem. 1968, 519–520
The (-)-enantiomer was used to test synthetic routes
“our experience has been such that this is just about the only kind of model study which we regard as wholly reliable” –R. B. Woodward
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Preparation of Pentacyclenone
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Preparation of Beckmann Precursor
wrong epimer
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Preparation of b-Corrnorsterone
Corrnorsterone•corr for corrin•norsterone for norsteroid•cornerstone (Slurvian)
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Equilibration of Corrnorsterones
Brominatedent-b-corrnorsterone
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First Generation A-D Ring Synthesis
CONH2
CONH2
CONH2
COOH
1. O3
2. CH2N2
1. NaBH4
2. Ms2OLiBr
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The Solution to Side-Chain Differentiation
UV
Complete C–O bond cleavage
observedCF3CO2H
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Preparation of A-D Ring Cyanobromide
Oxidation at sulfur is
observed with other thiols
Thioester vs Ester•Similar reactivity O-bases•Less reactive to acid hydrolysis•More reactive to N-nucleophiles
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Thiodextrolin Retrosynthetic Analysis
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Eschenmoser Synthesis of B-Ring
Arndt-Eistert Homologation
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Preparation of the C-Ring
Rings B and C can be prepared from a common intermediate
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Group Question
?
?
Please provide a mechanism for the formation of 52 and 55.
Zn, MeOH
work-up step
work-up step
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Vinylogous Amidine
The condensation of enamines with iminoesters
was successfully used in simple model systems, but
failed with complex intermediates
Eschenmoser, A. Pure Appl. Chem. 1969, 1–23Eschenmoser, A. Pure Appl. Chem. 1963, 297–316
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Eschenmoser Sulfide Contraction
Eschenmoser, A. Pure Appl. Chem. 1969, 1–23
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Preparation of Thiodextrolin
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East Meets West
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Secocorrin to Corrin
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Outline of the Utopian Synthesis
Eschenmoser, A.; et al. Science 1977, 1410–1420
1. Produce all four rings from a common racemic starting material
2. Secocorrin → corrin metal-templated ring closure
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Retrosynthetic Analysis
Eschenmoser, A.; et al. Science 1977, 1410–1420
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Synthesis of the A-Ring
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Synthesis of the D-Ring
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Attachment of D-Ring
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Attachment of A-Ring
The cadium complex is helically labile
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Woodwood & Hoffman’s Prediction
Eschenmoser, A.; et al. Science 1977, 1410–1420
Eschenmoser, A. Pure Appl. Chem. 1969, 1–23Woodward, R. B. Angew. Chem. Int. Ed. 1969, 781–853
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Secocorrin → Corrin
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Remaining Challenges
Eschenmoser, A.; et al. Science 1977, 1410–1420
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Selective Methylation
Me+
Me+
Me+
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Application of Selective Methylation
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End-Game
78:28epi/nat
70–80%
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Eschenmoser’s Amide Solution
Eschenmoser, A.; et al. Science 1977, 1410–1420 Woodward, R.B. Pure Appl. Chem. 1973, 145–177
“a diabolically clever scheme” –R. B. Woodward
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Conclusions
For additional analysis and references:Nicolaou, K.C.; Sorensen, E. J. Vitamin B12. Classics in Total Synthesis, VCH: New York, 2003; 100–136For additional references on the chemistry of corrins:Eschenmoser, A. Pure Appl. Chem. 1963, 297–316Eschenmoser, A. Angew. Chem. Int. Ed. 1988, 5–39
•The asymmetric total synthesis of Vitamin B12 stands as one of the most significant achievements in organic chemistry.
•Produced chemical understanding in the form of:•Synthetic Strategy & Methods•Physical Organic Chemistry
•The Woodward-Hoffman Rules•Corrin Chemistry•Diastereoselective Synthesis
•Remains unrivaled even after almost 40 years