Classic Synthesis Progesterone CEM 852 S-2004 Ghayoor Abbas Chotana January 31,2004 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. HO CH3 H CH3 C O CH3 HH HCH 3 CH3 H C O O CH3 H A B C D1 2 3 4 5 6 7 8 910 11 12 13 17 16 1514 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 ?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 RR H and H H HH R R H 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 HDammaradienol 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 X(H5C6)3P-CH-CH R` OLi R LiC 6H5 (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 H2C=CHCH2OCH=CH2 HC HC C H CH CHO H2C HC C H2 CH2 CHO allyl vinyl ether 4-pentenal H2C HC CH 2 CH2 CHO ?trans-Trisubstituted Olefinic Bonds via Johnson ortho-ester modification of Claisen Rearangment. ?Claisen Rearangment. CH3C(OEt)3 + HO R2 R1 O R2 R1 EtO EtO O R2 R1 EtO O R2 R1 EtO ?Johnson W. S. et. Al.; J. Am. Chem. Soc.1970,92,741-743. Retrosynthetic Analysis 1 O CH3 H CH3 C O CH3 HH CH3 CH3 Intramolecular aldol/dehydration O CH3 H CH3 C O CH3 HH CH3 H CH3 C O CH3 HH O H H H OHO O O Cationic-? Cyclization Intramolecular aldol/dehydration O O OO Wittig reaction O O OO O PPh3 + 1 2 3 45 6 7 8 9 10 Retrosynthetic Analysis 2 O O OO PPh 3 9 O O OO Br 11 O Br Alkylation O Br Br + 12 13 14 O 10 15 OEtO Johnson orthoester claisen rearangment OEtO 16 HO 17 BrMg 18 CHO 19 + Carbonyl addition Total Synthesis 1 ?Synthesis of aldehyde 10. O 10 15 OEtO HO 17 BrMg 18 CHO 19 + HO OEt OEt .. CH3C(OEt)3, C2H5CO2H(0.3%), 138oC (55% for two steps) O EtO EtO OEtO -EtOH 1.LiAlH4,EtO,0oC 2.CrO3.2Pyr.,CH2Cl2,23oCJohnson- Claisen 16 [3,3] Total Synthesis 2 ?Synthesis of Ylide. O O OO Br 11 O Br O Br Br 12 13 14 1. n-BuLi, THF, -30 -20 oC 2. 23 oC-20 (2.9 equiv.) (75%) HO(CH2)2OH(3.2 equiv.), p-TsOH (0.026 equiv.), hydroquinone (trace), PhH, reflux[-H2O] (71%) NaI (1.4 equiv.), PhH, 80 oC(94%) O O OO I 201O O OO PPh 3 21 I Ph3P(1.4 equiv.), PhH, 80 oC (94%) Total Synthesis 3 O O OO PPh3 9O O OO PPh 3 21 I THF, PhLi (1 equiv.) Ether OH O O O O O OO O 56 7 8 10 1. 2. PhLi(1 equiv.); then excess MeOH, -30 oC KOtBu 8 9 ( 8,9 trans:Cis/ 97:3)? 0.1N HCl in H2O/ MeOH (3:10),40oC EtOH/2% NaOH in H2O,reflux (40% from 10) MeLi,Et2O (99%) Total Synthesis 4 O CH3 H CH3 C O CH3 HH CH3 CH3 O CH3 H CH3 C O CH3 HH CH3 H CH3 C O CH3 HH O HH H OH Cationic-? Cyclization 12 3 45 CH3 H CH3 HH 22 O O O O O O Cl(CH2)2Cl, TFA, 0oC K2CO3,H2O/MeOH (72% from 5) O3,MeOH/CH2Cl2, -70oC; then Zn,AcOH H2O,-15 23oC H2O/5%KOH(5:2), 23oC (51%) ( )-1:( )-progesteron Synthetic Methodology 5 H3C OO CH3 O O H2O/H O OH OH O O O HH ?A source of one five dicarbonyl compound ?A source of One four dicarbonyl compound