(+/-) n - Faculté de Chimie
Transcription
(+/-) 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)