Beruflich Dokumente
Kultur Dokumente
Mitsunobu
Claire M. Filloux
Department of Chemistry, Colorado State University, Fort Collins, CO 80523
cfilloux@gmail.com
ABSTRACT
OH
R1
OH
X OH
R2
O
H2O
R1
R1
R2
X
R2
H2O
Despite overt simplicity, alcohol inversion remains a significant synthetic challenge. Classical solutions such as the
Mitsunobu reaction rely on the use of stoichiometric reagents that complicate purification and engender
stoichiometric wastes. Efforts to improve efficiency of inversion within and outside the Mitsunobu manifold have
been advanced. This review examines the contributions and limitations of these strategies, and it identifies progress
that
has
been
made
toward
the
development
of
a
catalytic
inversion
protocol.
(1) (a) Overman, L. E.; Paone, D. V. J. Am. Chem. Soc. 2001, 123,
9465. (b) Heintzelman, G. R.; Fang, W.; Keen, S. P.; Wallace, G. A.;
Weinreb, S. M. J. Am. Chem. Soc. 2002, 124, 3939.
(2) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
935.
OH
R1 1 R2
O
R3
2
OH
(a)
O
R3
5 R
1
R2
(b)
3+4
2
R3
O
O
Ph3P
H
N N
EtO2C 6 CO2Et
OH
1
R1 R2
Ph3P
O
R3 7 O
PPh3
R1 1 R2
R3
9 R
1
O
R2
Retention Product
R1 8 R2
O
O
2 R3
OH
O PPh3
10
H
H
N N
EtO2C 11 CO2Et
EtO2C
CO2Et
N N
H 11 H
O
R3
5 R
1
O
R2
Inversion Product
(5) For a review, see: Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
(6) Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P.
Teterahedron Lett. 1999, 40, 4497.
OH
R1 1 R2
3
N N
CO2Et
EtO2C
(10 mol %)
PPh3 4
(2 equiv)
2
OH
THF, 23 C
R3
PhI(OAc)2 12
(2 equiv)
PhI + AcOH
(2 equiv)
O
R3
5 R
1
O
R2
OH
R1
13
R3
R2
Me
i) n-BuLi
PPh2
ii) Ph2PCl
O
THF
iii) solvent R
R3
1
R
removal
14 2
Me
15
O
ROH
CH2Cl2
OSO2R3
Me
H
OH
R1
Me
R3
R2
18 O
R
inversion
product
Me
Me
+
O
P
Ph2
17
R1
16
O
RO
R1
O
PPh2
R3
R2
R2
19
O
!+
R3N H O 20
!PhMe, 50-110 C
O
R4
O 21
R1
R2
OH
29
1
R
R2
Cl
R1
O
10 + HCl
31 +
P
Ph
Ph
R2
Ph
Ph
Cl
Ph
Cl
Cl
24
R1
OH
-HCl
R2
CH2Cl2 or
CH3CN
Cl
Ph 22
Ph 23
79% recovery
SOCl2
Ph
R1
27
Ph
R1
(COCl)2 32 (1 equiv)
(O)PPH3 10 (10 mol %)
OH
Cl
R1
29
R2
Cl
R2
R1
O
Ph 25
Ph
Cl
O +
Ph 28
R2
31
R1
CHCl3
Cl
R2
Ph 26
O
10
P
Ph
Ph
Ph
Ph
Ph
P
Ph
O HCl
34
R1 R2 Cl
29
R1
Cl
R1
OH
R2
Cl
30 Cl P
Ph
Ph
Ph
31
R2
O
Cl
32 O
Cl
O 33
O
Cl P
O
Ph
Ph
Ph
Cl
C=O
O C O