《有机合成设计导论》课程教学资源（案例）合成实例1 Classic Synthesis

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

Synthetic Methodology 4 Wittig reaction &s Stabilized phosphorus ylides give trans olefins es Non- stabilized phosphorus ylides give cis olefins &s How to get trans olefins from nonstabilized phosphorus ylides? e Schlosser modifcation of wittig reaction RR (HSCB)3P-CH-Rx R-CH=O (HSC6l3P-CH-CHIx LiCh 675 OLI OLI OLi H R (H5C6)3P 563 x KotBu H R H R LI R R Li R H erythro threo 8 Johnson W. s: et al J Am. chem. Soc. 1978.100 4274

Synthetic Methodology 4 ?Wittig reaction. ?Stabilized phosphorus ylides give trans olefins ?Non- Stabilized phosphorus ylides give cis olefins ? How to get trans olefins from nonstabilized phosphorus ylides? ? Schlosser modifcation of wittig reaction. (H5C6 )3P-CH-R Li X (H5C6 )3P-CH-CH X R` OLi R LiC6H5 (H5C6)3P Li OLi H R` R X (H5C6 )3P R OLi H R` Li X R`-CH=O erythro threo KOtBu R` R H H ? Johnson W. S; et. Al., J.Am.Chem.Soc.1978,100,4274

Synthetic Methodology 4 e Claisen rearrangment H2C=CHCH20CH=CH2- H2C" CH_ HC CH H2CCH HC、C H2 HC CH HC/CH2 allyl vinyl ether CH2 pentenal s trans-Trisubstituted olefinic Bonds via johnson ortho-ester modification of Claisen Rearangment R R R CH3C(oEt)3+ HO R2 EtO O R< F10O R2/ Eto EtO O R2 ss Johnson W.s. et. Al. J. Am. chem. Soc. 1970.92.741-743

Synthetic Methodology 4 H2C=CHCH2OCH=CH2 HC HC C H CH CH O H2C HC C H2 CH2 CH O allyl vinyl ether 4-pentenal H2C HC CH2 CH2 CH O ? trans-Trisubstituted Olefinic Bonds via Johnson ortho-ester modification of Claisen Rearangment. ? Claisen Rearangment. CH3C(OEt)3 + HO R 2 R 1 O R 2 R 1 EtO EtO O R2 R1 EtO O R 2 R 1 EtO ? Johnson W. S. et. Al.; J. Am. Chem. Soc.1970,92,741-743

Retrosynthetic Analysis 1 CH3 c-CH3 CH3 C-CH CH3 C-CH3 H H CHa CH3H H H HH Cationic -? Intramolecular Cyclization aldolldehydration CH3 intramolecular aldol/dehydration 6 00 o WiTtig reaction 10

Retrosynthetic Analysis 1 O CH3 H CH3 C O CH3 H H CH3 CH3 Intramolecular aldol/dehydration O CH3 H CH3 C O CH3 H H CH3 H CH3 C O CH3 H H O H H H O OH O O Cationic-? Cyclization Intramolecular aldol/dehydration O O O O Wittig reaction O O O O O PPh3 + 1 2 3 5 4 6 7 8 9 10

Retrosynthetic Analysis 2 12 PP Br Br Alkylate 14 Johnson orthoester claisen rearrangment Eto o EtoO Carbonyl addition CHO Brig 19 18

Retrosynthetic Analysis 2 O O O O PPh3 9 O O O O Br 11 O Br Alkylation O Br Br + 12 13 14 O 10 15 EtO O Johnson orthoester claisen rearangment EtO O 16 HO 17 BrMg 18 CHO 19 + Carbonyl addition

Total Synthesis 1 &s Synthesis of aldehyde 10 CH3C(OEt CHO Brig C2HCO2H(0.3%) 19 18 138C (55% for two steps oEt Eto -EtoH EtO E00 1LiAH4Eto,0°C 16 3, 3] Johnson- Eto o 2.CrO3. 2Pyr, CH2 Cl2, 23C O Claisen 10

Total Synthesis 1 ? Synthesis of aldehyde 10. O 10 15 EtO O HO 17 BrMg 18 CHO 19 + HO OEt OEt .. CH3C(OEt)3 , C2H5CO2H(0.3%), 138 oC (55% for two steps) O EtO EtO EtO O -EtOH 1.LiAlH4 ,EtO,0 oC 2.CrO3 .2Pyr.,CH2Cl2 ,23 oC Johnson￾Claisen 16 [3,3]