The stereochemistry would have to be created with each

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Vitamin B12By Jason Merriman

• Closing the gap between structural determination
  and synthesis.

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Vitamin B12 Structure
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Vitamin B12

• The structure was fully elucidated 1956 by
  Dorothy Crowfoot-Hodgkin (same person who helped
  Watson and Crick)
• Families of marcocyclic compounds.
• Through the combine efforts of RB Woodward and A
  Eschenmoser it took 12 years.
• The rich detail of stereochemistry (10
  stereocenters)
• Bernhauer et al converted Cobyric acid to Vitamin
  B12.

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Retrosynthesis
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Retrosynthesis

• Molecule was divided into four quadrants.
• The stereochemistry would have to be created with
  each quadrant.
• Woodward would take the A-D rings and Eschenmoser
  would take the B-C rings.

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Woodward part of the Retrosynthesis
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Retrosynthesis

• Eschenmoser part of the ring system
• Only has four stereocenters.

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Final steps in Retrosynthesis
All rings could be created from one compound
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Total Synthesis of Vitamin B12
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Woodward Synthesis
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Woodward Synthesis
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Woodward Synthesis
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Major product formed presented a major hurdle
How was Woodward going to overcome this?
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Pure Genius
All this for a little H.
This product is highly favored and in high yields
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Woodward Synthesis
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Woodward Synthesis
Methanesulfonic anhydride

• The final product had the correct stereochemistry
  and was ready for final assembly.

The choice of Ms2O was not arbitrary.
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Eschenmoser synthesis
Diels-Alder is stereo- specific
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Eschenmoser synthesis
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Eschenmoser synthesis
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Eschenmoser synthesis
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Final Eschenmoser synthesis
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Eschenmoser sulfide contraction
Desired bond formation
Alkylative Mechanism
Eschenmoser developed two methods for ring
bonding
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Eschenmoser sulfide contraction
Both methods involve sulfide contractions
Second method for ring contraction
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Final steps for Corrin ring system
Eschenmosers ring contraction developed for this
step
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Final steps for Corrin ring system
Target for main synthesis
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Biological system of Vitamin B12
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Final thoughts

• Simplicity
• Elegance
• Creative solutions to very complex problems
• Whenever in the synthesis of complex organic
  molecules one is confronted with a situation
  where the success of an intermolecular synthetic
  process is thwarted by any type of kinetically
  controlled lack of reactivity, one should look
  out for opportunities of altering the structural
  stage in such a way that the critical synthetic
  step can proceed intramolecularly rather than
  intermolecularly A Eschnemoser.