Classic Synthesis Progesterone cEM852S-2004 Ghayoor Abbas Choana January 31, 2004
Classic Synthesis Progesterone CEM 852 S-2004 Ghayoor Abbas Chotana January 31,2004
Progesterone CH3 C-CH CH3 H C-CH3 CH3 H CH3 HH H esW..Johnson(1971) e Six contiguous stereogenic centers. Class of molecules: Steroids e Steroids are important biomolecules because of their powerful biological activity C D 6 g Subject of attempts of chemical modification total synthesis in hopes of uncovering routes to new molecules of greater and different bioactivities e. g to control human fertility
Progesterone ?W. S. Johnson (1971). ? Six contiguous stereogenic centers. Class of molecules : Steroids. ?Steroids are important biomolecules because of their powerful biological activity. ? Subject of attempts of chemical modification & total synthesis in hopes of uncovering routes to new molecules of greater and different bioactivities e.g to control human fertility. O H CH3 H CH3 C O CH3 H H H CH3 CH3 H C O O CH3 H A B 1 C D 2 3 4 5 6 7 8 9 10 11 12 13 17 16 15 14
Synthetic Methodolog e Synthesis of fused cyclohexanoid framework g Robinson annulation- Setpwise cyclization, One ring at a time base/H2O O g Acid catalyzed cyclization of 1, 5 dienes A
Synthetic Methodology 1 ? Synthesis of fused cyclohexanoid framework ? Robinson annulation – Setpwise cyclization, One ring at a time. O + C O base/H2O O ? Acid catalyzed cyclization of 1,5 dienes. H -H
Synthetic Methodology 2 es special cases of acid catalyzed cyclization of 1, 5 dienes eCase 1-Butenylcyclohexhene OAC HOAC and H H x Concerted trans addition e Case 2-What if initiating cation is not proton but a carbocation? &s Stork-Eschenmoser Hypothesis H Polyunsaturated molecules with trans olefinic linkages should exhibit an inherent preference for cyclizing in a stereospecific fashion to give a polycyclic molecule with trans, anti, trans ring fusion stereochemistry &s Corollary-cis double bond will give cis-fused ring system s Stork. G. et. AL. J Am. Chem. Soc. 1955. 77. 5068-5077
Synthetic Methodology 2 ? Special cases of acid catalyzed cyclization of 1,5 dienes. ?Case 1- Butenylcyclohexhene ?Case 2- What if initiating cation is not proton but a carbocation? ? Concerted trans addition. ? Stork-Eschenmoser Hypothesis Polyunsaturated molecules with trans olefinic linkages should exhibit an inherent preference for cyclizing in a stereospecific fashion to give a polycyclic molecule with trans,anti,trans ring fusion stereochemistry. ? Corollary- cis double bond will give cis-fused ring system. ? Stork. G., et. Al.; J.Am.Chem.Soc.1955, 77, 5068-5077. R R H R OAc HOAc -H R R H R R H and H H H H R R H
Synthetic Methodology 3 &s p-Cationic Cyclization: a Biomimetic approach, complex polycyclic array in a single step Squalene oxide H H HO Dammaradienol H HO e Stereospecific es At one full swoop Four carbocyclic rings at the expense of single oxirane ring, and six contiguous stereogenic centers are created! e Triple bond participate in cyclization to form five membered ring
Synthetic Methodology 3 ? p-Cationic Cyclization: a Biomimetic approach, complex polycyclic array in a single step. ? Stereospecific. ? At one full swoop, Four carbocyclic rings at the expense of single oxirane ring, and six contiguous stereogenic centers are created ! ? Triple bond participate in cyclization to form five membered ring. H O Squalene oxide HO H H H HO H Dammaradienol H