Baran Group Meeting
July 2003
The Legacy of Biotin
Biosynthesis/ Early Synthesis
Ryan Shenvi
O
HN
(+)-biotin
NH
Wolf, Harris
First synthesis of (±)-biotin, 1943
CO2H
S
BzHN
-Biotin (or Vitamin H) is the active cofactor of pyruvate carboxylase;
responsible for anaplerotic conversion of pyruvate to oxaloacetate;
rejuvinates the Krebs Cycle
O
1. CH3OH
O
-Important additive to poultry and swine food stocks
O
O
2. SOCl2
3. H2, Pd/C
MeO
O
BzHN
O
O
S
Pipiridine; HOAc
H
S
(CH2)3CO2CH3
-Contained in human diet, but not essential;
biosynthetically available from colonic bacteria
NH2OH,
Py.
-For a comprehensive review, see: De Clerq, P. Chem. Rev. 1997, 6, 1755.
-For the most recent synthesis, see: Seki, M., et al, Chem. Eur. J. 2004, 10, 6102.
BzHN
S
Biosynthetic Pathway
SCoA
+
O
(CH2)4CO2H
Pimelyl CoA
H2N
Me
Me
HN
H2N
NH
Me
S
(CH2)4CO2H
(+)-Biotin
Me
S
(CH2)4CO2H
dethiobiotin
N OH
S
(CH2)3CO2CH3
O
O
NH2
Na2CO3,
C(O)Cl2
(CH2)4CO2H
HN
HN
NH
O
NH
HN
+
S
(CH2)4CO2H
(±)-biotin
O
NH
Zn,
HOAc, H2O
(CH2)4CO2H
S
HN
BzHN
NHAc
Ba(OH)2,
140 °C
NH2
H2N
O
BzHN
(CH2)4CO2CH3
7-oxo-8-amino
pelargonic acid
L-Alanine
Pd/C, H2
(CH2)3CO2CH3
O
CO2H
NHAc
NH
+
S
(CH2)4CO2H
(±)-allobiotin
NH2
(CH2)4CO2H
7,8-diamino
pelargonic acid
Harris, J. A.; Wolf, D. E.; Mozingo, R.; Folkers, K. Science 1943, 97, 447.
S
(CH2)4CO2H
(±)-epibiotin
Baran Group Meeting
July 2003
O
OH
HO
2. BnNH2
O
H
1. Br2
Bn N
NHBn
1. C(O)Cl2,
KOH
OH
HO
BnHN
1.
2(S
Bn
N
H
MeO2C
O
E
Bn N
N
Bn
Zn, HOAc
HO
O
S
Bn N
N
Bn
Bn
N
HN
AcO
O
O
Ph
H
1. ClMg(CH2)3OCH3
O
O
H2O, D
87%
OH
Bn
H2, Pd/C
Bn N
N
HN
Bn
H
H HH
OCH3
S
N
S
O
N
HN
Ph
S
COCl
Cl
N
ONa
NH
EtO
Bn N
S
COCl
H
Cl
O
Bn
HN
NH
HBr, H2O
OEt
AcO
2. HBr (aq.)
(+)-biotin
Goldberg, M. W., Sternbach, L. H. US Pat. 2,489,238, Nov. 22, 1949
X
S
CO2Me
Cl
NaBH4,
DMF, 80 °C
68%
O
N
Ph
MeOH
O
O
O
1.
CO2H
H
O
2. Silver
d-Camphorsulfonate
S
Ph
NH
H
O
1. HBr
HN
S
O
2. ClCO2Me, THF,
Na2CO3, 0 °C
65%
NH
O
HN
N
H
OCH3
S
O
H
NH
O
1. Zn, AcOH,
H2O, 70 °C
O
CO2H
Ph
O
N
S
SOCl2, Et2O
68%
2. HOAc
Bn N
H
N
O
Ph
2. BnNH(OH)•HCl,
CH2Cl2
68%
O
H
H H
HO
S
MeO2C N
Ph
Ba(OH)2,
dioxane,
N
S
2. KSH, EtOH
O
S
Bn N
1. H2S, HCl
H
PhCH3, D
63%
O
O
O
S
E = CO2Me
Zn,
Ac2O,
HOAc
O
1. DIBAL, PhCH3
H
-78 °C
NH
2. Zn, AcOH, air
(Z:E = 9:1)
59%
O
O
Cl ,
Pyr., CH2Cl2, 0 °C
NH2
2. Ac2O
O
H
O
O
H
Ryan Shenvi
Hoffmann-La Roche
Synthesis of (+)-biotin, 1982
Goldberg, Sternbach
First synthesis of (+)-biotin, 1946
O
The Legacy of Biotin
Early-Recent Syntheses
HN
N
Ph
85%
S
CO2H
(+)-biotin
Baggiolini, E. G., et al., J. Am. Chem. Soc., 1982, 104, 6460.
S
H
CO2Me
Baran Group Meeting
July 2003
The Legacy of Biotin
Related Methods and Studies
O
Ryan Shenvi
O
Bn N
N
Bn
CH3COSK, DMF, 150 °C
N
>90%
O
O
Bn N
Bn
R
N
O
S
O
MeO
Ph
Py•HBr3
MeO2C
MeOH
S
MeO2C
Br
H
N
S
Ph
R
Ph
Br
MeO2CHN
Br
N
S
H2O
– PhCHO
R
R
S
Gerecke, M., et al, Helv. Chim. Acta 1970, 53, 991.
Confalone, P. N., et al., J. Am. Chem. Soc., 1975, 97, 5935.
Li
O Al H
O
OEt
O
Bn N
O
N
O
Bn
O
Bn N
(R)-BiNAL-H,
O
Bn
BnN
-78 ° C Æ rt, THF
76%
O
N
O
O
N3
D
BnN
O
N N
N
R
O
S
90% ee (95% ee
after recrystalization)
S
BnN
O
N
N-
BnN
N2
R
S
O
BnN
R
R
S
S
H
R
De Clercq, P. J., et al. J. Org. Chem. 1994, 35, 2615.
Matsuki., et al, Tetrahedron Lett. 1993, 34, 1167.
OH
OO2N
O
BnN
HO2C
NBn
CO2H
2. LiAlH4
96%
BnN
NBn
NBn
BnN
1. MsCl, Et3N
2. Na2S, EtOH
OH (86% over 4 steps)
HO
(±)-biotin
MeLi,
HMPA, THF;
O
3 Steps: 43%
S
N
I(CH2)4CO2tBu,
OtBu -30 °C, 80%
O
Marquet, A., et al. Tetrahedron Lett. 1975, 827
Marquet, A., et al. J. Am. Chem. Soc. 1978, 100, 1558.
MeO2CHN
H
S
H
S
S
PPA
22%
NaIO4,
H2O
+
S
S
O
H
O
CN
MeO2CHN
H
H
S
S
OH2
N
CO2Me
N H
HN
H2N
H
S
MeO2CHN
O
9 : 1
MeO2CHN
NBn
BnN
OH2
N
H
O
NBn
BnN
S
N
O
S
O
O
NBn
N+
80%
100%
BnN
PhNCO
O
O
1. MeOH,
BF3•Et2O
NH
H2N
O
H
S
S
O
O
H
N
(CH2)4CN
"Abnormal" Beckman
with Aziridination
"Abnormal" Beckman
with epimerization
Confalone, P. N., et al. J. Am. Chem. Soc. 1978, 100, 6292.
S