(+/-) n - Faculté de Chimie

Reactivity of acetylenic-ω-ketoesters in presence of
TBAF and TBAF / Molecular Sieves. Toward the
synthesis of steroids displaying cardiotonic or
antihypertensive properties.
Marie-Paule Ballet, Philippe Geoffroy et Michel Miesch.
Université de Strasbourg – Institut de Chimie – Laboratoire de Chimie Organique Synthétique
UMR 7177 – 1, Rue Blaise Pascal BP296/R8 67008 Strasbourg
e-mail: [email protected], [email protected], [email protected]
Previous results
C) Extension of the TBAF and TBAF / MS
enantiomerically pure acetylenic-ω-ketoesters
The carbanionic cascade reaction induced by TBAF afforded bicyclic allenoates with
total diastereoselectivity for the ring junction.
reactions
to
Total chemoselctive reactions were observed leading either to enantiomerically pure
allenoates (TBAF) or to enantiomerically pure oxetanes (TBAF + MS).
H
O
m
OH
m
n
C
CO2Et
EtO2C
Cis
Cis
Trans
Goal
Synthesis and reactivity of acetylenic-ω-ketoesters derived from 2-methylcycloalkane1,3-diones in order to obtain the C-D unit of steroids bearing a 14ß-hydroxy group.
O
O
CO2Et
n = 1, m = 1 : 63%
n = 1, m = 2 : 88%
n = 2, m = 1 : 80%
n = 2, m = 2 : 89%
Cis
Cis
Cis
Trans/Cis
n
C
n = 1, m = 2 : quant. Cis
n = 2, m = 2 : quant. Trans
D) Reactivity of the oxetanes : formation of
polyfunctionalized fused ring systems
O
O
O
HBF4 (1 éq.)
1) O3, DMS, -78°C
m
n
n
O
O
n
2) MeONa, 25°C, 1h
EtOH, 25°C, 15h
O
OH
OH
MeO
n = 1, 2
m = 1, 2
O
O
CO2Et
CO2Et
(+/-)
Results
(+/-)
n = 1 : 61% for 2 steps
n = 2 : 55% for 2 steps
A) Formation of allenoates
The treatment of the acetylenic-ω-ketoesters derived from 2-methylcycloalkane-1,3diones with TBAF delivered efficiently bicyclic allenoates.
n = 1 : 80%
n = 2 : 56%
E) Reactivity of the allenoates : formation of 1,3 dienes
OAc
OAc
O
O
PPh3, Phénol
O
TBAF 1 M
n
n
(+/-)
CO2Et
O
5,6 and 6,6
O
O
OH
O
n
n
m
THF, 25°C, 2h
O
CO2Et
O
n
CO2Et
n = 1, m = 2 : 50%
n = 2, m = 1 : 59%
n = 2, m = 2 : 70%
O
m
THF, 25°C, 30 min
OH
C
TBAF 1 M
MS
CO2Et
TBAF 1 M
m
THF, 25°C, 30 min
n
O
n
TBAF 1M
O
+
Toluène, 110°C, 4h30
THF, 25°C, 2h
OH
OH
n
m
OAc
O
C
OH
m
C
(+/-)
CO2Et
CO2Et
n = 1, m = 1 : 69%
n = 1, m = 2 : 70% *
n = 2, m = 1 : 60%
n = 2, m = 2 : 70%
* Acetate group.
CO2Et
(+/-)
EtO2C
(+/-)
(+/-) O
46%
34%
Perspectives : synthesis of 14ß-hydroxy steroids through a Diels
Alder reaction
Cis
Cis
Cis
Trans/Cis : 1/1
OAc
OAc
C
B) Formation of oxetanes
+
In the presense ot TBAF and Molecular Sieves 4 Å (MS), a complete chemoselective
reaction affording quantitatively oxetanes was observed.
C
D
R
R
D
A
B
OH
OH
A
CO2Et
CO2Et
O
O
O
n
O
TBAF 1 M
MS
THF, 25°C, 30 min
O
O
m
O
O
O
n
O
H
EtO2C
H
H
(+/-)
CO2Et
H
n = 1, m = 2 : quant.
n = 2, m = 2 : quant.
Cis
Trans
Gly
H
OH
O
H
Digitoxin (cardiotonic activity)
OH
HO
H
Rostafuroxin
(antihypertensive activity)