Synthesis of Cyanocobalamin

Structure of Cyanocobalamin

C63H89CoN14O14P

Principal investigatorRobert B. Woodward
Publication year1973
Synthesis typeFormal
Number of steps 72 (7 parts)
References
Pure Appl. Chem. 1973, 33, 45. Pure Appl. Chem. 1971, 25, 283. Pure Appl. Chem. 1968, 17, 519. Science 1977, 196, 1410.
Part 1 of 7
intermediate structure + intermediate structure
H3PO4
80 °C, 82%
See the Claisen-Schmidt Condensation
intermediate structure + intermediate structure
SnCl4
PhH
RT, 73%
See the Diels-Alder Reaction
"The enantiomers were resolved with (+)- and (-)-phenylethylamine."
intermediate structure
CrO3, H2SO4
Acetone
RT, 75%
intermediate structure
SOCl2
77 °C
intermediate structure
CH2N2
Dioxane , Et2O
RT
intermediate structure
Ag2O
MeOH
65 °C, 69% (3 steps)
See the Wolff Rearrangement
intermediate structure
NH3
MeOH
RT, 55%
intermediate structure
P2S5
THF
RT, 85%
intermediate structure
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Part 2 of 7
intermediate structure
CH2N2, NaOMe
Et2O, MeOH
92%
intermediate structure
H2S
CF3CO2H
RT, 78%
intermediate structure
(Ph3P)3RhCl
PhMe
110 °C, 30%
intermediate structure
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Part 3 of 7
intermediate structure + intermediate structure
HCl, Bz2O
CH2Cl2
RT
intermediate structure
P(OEt)3
Xylene(s)
125 °C, 85% (2 steps)
See the Eschenmoser Sulfide Contraction
intermediate structure
P2S5, 4-Methylpyridine
Xylene(s)
130 °C, 84%
intermediate structure
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Part 4 of 7
intermediate structure
MeMgI, Propargyl bromide
intermediate structure
BF3.OEt2, HgO
MeOH
See the Mannich Reaction
See the Kucherov Reaction
intermediate structure + intermediate structure
""the diastereomeric ureas resulting from the combination of the racemic tricyclic ketone with optically active alpha-phenylethylisocyanate are very readily separable""
intermediate structure
""and are readily re-converted to the parent active tricyclic ketones when pyrolyzed""
intermediate structure
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Part 5 of 7
intermediate structure
"No experimental details were reported for this whole part."
intermediate structure
intermediate structure
See the Hofmann Rearrangement
intermediate structure
intermediate structure
intermediate structure
intermediate structure
LiAlH4
intermediate structure
CrO3
intermediate structure + intermediate structure
See the Wittig Reaction
intermediate structure
intermediate structure
intermediate structure
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Part 6 of 7
intermediate structure + intermediate structure
intermediate structure
KOt-Bu
t-BuOH
See the Michael Addition
intermediate structure
(CH2OH)2, TsOH
PhH
intermediate structure
Et3O+ BF4-
intermediate structure
MeOH
intermediate structure
PhMe
Reflux
intermediate structure
Li, NH3
THF
See the Birch Reduction
intermediate structure
90%
""When subjected to acid treatment under carefully controlled condition""
intermediate structure
""further treated with acid""
intermediate structure
NH2OH
intermediate structure
NaNO2
AcOH
intermediate structure
HIO4, O3
MeOH
intermediate structure
CH2N2
Et2O
intermediate structure
Pyrrolidinium acetate
MeOH
See the Aldol Condensation
intermediate structure
MsCl, Et3N
intermediate structure
HIO4, O3
EtOAc, H2O
intermediate structure
CH2N2
Et2O
intermediate structure
Polystyrenesulfonic acid
MeOH
170 °C
See the Beckmann Rearrangement
"Also isolated was the C3-epimer which was equilibrated to the desired product."
intermediate structure
HCl, PhSH
MeOH
intermediate structure
O3
intermediate structure
NH3
intermediate structure
NaBH4
intermediate structure
Ms2O
intermediate structure
LiBr
DMF
See the Finkelstein Reaction
intermediate structure
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Part 7 of 7
intermediate structure + intermediate structure
KOt-Bu
100%
intermediate structure
P(CH2CH2CN)3
MeNO2, CF3CO2H
See the Eschenmoser Sulfide Contraction
intermediate structure
P2S5, 4-Methylpyridine
PhMe
intermediate structure
Me2NH
intermediate structure
ZnCl2
intermediate structure
I2
MeOH
intermediate structure
""it was a relatively easy matter to remove the zinc by treatment with acid""
intermediate structure
Ph3P
CH2Cl2, CF3CO2H
See the Eschenmoser Sulfide Contraction
intermediate structure
CoCl2
THF
intermediate structure
NaCN
intermediate structure
I2
AcOH
intermediate structure
BnOCH2Cl
Sulfolane
75-80 °C
See the Blanc Halomethylation
intermediate structure
PhSH
intermediate structure
Ni (Raney)
intermediate structure
CH2N2
Et2O
intermediate structure
H2SO4
H2O
60 min
"Also isolated was the C13-epimer in an unfavorable 28:72 ratio."
intermediate structure
N2O4, NaOAc
CCl4
0 °C, 60 min, 70-80%
intermediate structure
NH3, NH4Cl
Ethylene Glycol
75 °C, 10 h, 100%
intermediate structure
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Remaining...
(1 step)
"See: Helv. Chim. Acta 1960 , 43, 704."
intermediate structure