Synthesis of Cyanocobalamin

Structure of Cyanocobalamin

C63H89CoN14O14P

Principal investigatorRobert B. Woodward
Publication year1973
Synthesis typeFormal
Number of steps 72 (7 parts)
References
Part 1 of 7
intermediate structure + intermediate structure
H3PO4
80 °C, , 82%
intermediate structure + intermediate structure
SnCl4
PhH
RT, , 73%
"The enantiomers were resolved with (+)- and (-)-phenylethylamine."
intermediate structure
CrO3, H2SO4
Acetone
RT, , 75%
intermediate structure
SOCl2
77 °C
intermediate structure
CH2N2
Et2O, Dioxane
RT
intermediate structure
Ag2O
MeOH
65 °C, , 69% (3 steps)
intermediate structure
NH3
MeOH
RT, , 55%
intermediate structure
P2S5
THF
RT, , 85%
intermediate structure
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
Part 3 of 7
intermediate structure + intermediate structure
Bz2O, HCl
CH2Cl2
RT
intermediate structure
P(OEt)3
Xylene(s)
125 °C, , 85% (2 steps)
intermediate structure
P2S5, 4-Methylpyridine
Xylene(s)
130 °C, , 84%
intermediate structure
Part 4 of 7
intermediate structure
MeMgI, Propargyl bromide
intermediate structure
HgO, BF3.OEt2
MeOH
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
Part 5 of 7
intermediate structure
"No experimental details were reported for this whole part."
intermediate structure
intermediate structure 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
Part 6 of 7
intermediate structure + intermediate structure
intermediate structure
KOt-Bu
t-BuOH
intermediate structure
(CH2OH)2, TsOH
PhH
intermediate structure
Et3O+ BF4-
intermediate structure
MeOH
intermediate structure
PhMe
Reflux
intermediate structure
Li, NH3
THF, 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
O3, HIO4
MeOH
intermediate structure
CH2N2
Et2O
intermediate structure
Pyrrolidinium acetate
MeOH
intermediate structure
MsCl, Et3N
intermediate structure
O3, HIO4
EtOAc, H2O
intermediate structure
CH2N2
Et2O
intermediate structure
Polystyrenesulfonic acid
MeOH
170 °C
"Also isolated was the C3-epimer which was equilibrated to the desired product."
intermediate structure
PhSH, HCl
MeOH
intermediate structure
O3
intermediate structure
NH3
intermediate structure
NaBH4
intermediate structure
Ms2O
intermediate structure
LiBr
DMF
intermediate structure
Part 7 of 7
intermediate structure + intermediate structure
KOt-Bu
100%
intermediate structure
P(CH2CH2CN)3
CF3CO2H, MeNO2
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
CF3CO2H, CH2Cl2
intermediate structure
CoCl2
THF
intermediate structure
NaCN
intermediate structure
I2
AcOH
intermediate structure
BnOCH2Cl
Sulfolane
75-80 °C
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
Remaining...
(1 step)
"See: Helv. Chim. Acta 1960 , 43, 704."
intermediate structure