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1 prostagrandins PG 5 [3(Trifluoromethyl)phenoxy],,,20tetranor isopropyl ester PG ! " prostanoic acid 30 urzrok Lieb 34 von Euler 35 prostate gland Travoprost glaucoma The Nobel Prize in Physiology or Medicine 0 for the discoveries concerning the humoral transmitters in the nerve terminals and the mechanism for their storage, release and inactivation Ulf von Euler (05 3) PG cyclooxygenase 5 Bergström PGE PGF! mg PGE EPGF F 2 PG Bergström 30 PG 4 PGE PGF! PGE PGF! # DHL20:3 " AA20:4 " A 2 (phospholipase A 2 ) AA cyclooxygenase L R = C 2 C 20 TXA 2 PGI 2 Cyclooxygenase (COX) [PGH synthase (PGHS)] COX (PGHS) arachidonic acid! COX2 AA20:4 " (PGHS2)!! PGE 3 PGF 3! Sune. Bergström ( 2004) The Nobel Prize in Physiology or Medicine 2 for the discoveries concerning prostaglandins and related biologically active substances PGE 3 PGF 3! EPA20:5 "3 PGD 2 COX COX2 IL TNF! 5 C C C2 C3 NO O 2 3 peroxinitrite ion Tyr O 2 O 2 C3 pros COX Tyr35 35 Tyr long range electron transfer 35 Tyr 2 C C 5 C PGG 2 PG Vane Samuelson [3(Trifluoromethyl)phenoxy],,,20tetranor PGG 2 5 Tyr 35 3 COX PGE TXA PGI PGD TXA 2 PGI 2 PGD 2 4 John R. Vane (2 2004) COX PGI C Bengt I. Samuelsson (34 ) 5 TXA C 0 Corey AA 5 The Nobel Prize in Physiology or Medicine 2 for their discoveries concerning prostaglandins and related biologically active substances R = H fluprostenol R = CHMe 2 travoprost

2 Corey retrosynthesis 3 5 Wittig 5 20 Wittig WadsworthEmmons Corey 3 Corey trans! Corey BaeyerVilliger DielsAlder [2 2] [4 2] BaeyerVilliger DielsAlder [4 2] NaH THF 55 C (slightly excess),5 DielsAlder 55 C [4 2] Cu(BF 4 ) 2 0 C (5 equiv) (> 0%) bp C/0. mmhg 20! BaeyerVilliger $ OH (2.5 equiv) H 2 O, DMSO (0%) Cl anti bp 4 C/0. mmhg NaHCO 3, (> 5%) Ar = mcpba.25 equiv BV. NaOH (2.5 equiv), H 2 O, 0 C 2. CO 2 (> 0%) 2 3 (:) One recryst from C H C H ()(S,2R)ephedrine HO 3 > 2 > benzyl > phenyl > > methyl DA BV 3 fully resolved salt (34%) (±)acid ()(R,2S)ephedrine ()(S,2R)ephedrine ()Cotton ) CH 2 N 2 2) MnO 2 ()acid PGA ()acid ()Cotton 23 nm (% 4000 ) ()acid I, I 2 NaHCO 3 H 2 O 0 5 C 20 h I cis trans (%) mp. 00 C (Ac 2 O) 25 C, 5 min!,! azoisobutyronitrile (AIBN) (nbu) 3 SnH C H 25 C 2 %!,! azoisobutyronitrile (AIBN) heat R WadsworthEmmons " (E) C 5,2 BBr 3 (5.5 equiv) > 0% Corey CrO 3 2Py 0 C Collins 2 C AcO & (E) NaH 25 C, h 4 (DME) C 3 2 0% NaH trans > k cis k trans 3 MnO 2, or 5 Zn(BH 4 ) 2 (excess) 20 C, 0.5 h 5R (:) NaBH 4 ZnCl 2 (>%) (DME) SiO 2 chromatog (prep TLC/Et 2 O) 5S k cis 3 (DDQ) dioxane 50 C 32

3 33 (5S) " C C 5 lactonelactol I MeLi (2 equiv) Li CO 3 (.0 equiv) MeOH 25 C, 5 min H 3,4dihydro2Hpyran (DHP) H (DIBALH) (2.0 equiv) 0 C, 30 min & B PGF 3! low yield (DHP) (0 equiv) H 2 O (TsOH) (0.0 equiv), 25 C, 5 min 2 (tetrahydropyranyl) : H 2 O (PTS) (PPTS) H Wittig! Wittig lactol Wittig ylidez Na DMSO H 2 Na R 2 = Na (Z) 3 0% (DMSO) Na Br CH 2 SOMe Na NaBr 2 DMSO CH 2 SOMe CH 2 SOMe Na Na R = Fluprostenol Corey AcOH/H 2 O (2:), 4 C, 4 h THF CrO 3 H 2 SO 4 H 2 O, MeCOMe Jones 0 C, 30 min Wittig! 5! 5 H OH 2 H (2%) [0% (two steps)] AcOH/H 2 O (2:) C & Bz = HornerEmmons Corey! Wittig " HornerEmmons 5 ()DIPChloride TM 2 ()Bchlorodiisopinocamphenylborane Roberts Newton Tricyclo[ , ]heptanone [2 2]! Org. Process Res. Dev. 2002,, 3. R = TBDMS R = H (2.0 equiv) Et 3 N (.0 equiv) nhexane rt, 5 h bp 4 50 C /0.3 mm (5%) Zn (.0 equiv) AcOH 0 C, 40 min bp 0 C /5 mm (5%) [22] Zn Tricyclo[ , ]heptanone 45 Org. Process Res. Dev. 2002,, 3. 4 Grieco, P. A. J. Org. Chem. 2, 3, Grieco, P. A. J. Org. Chem. 2, 3,

4 4 bicyclo[3.2.0]hept2enone! ()!MBA ()(R,5R)Bicyclo[3.2.0]hept2enone Na 2 CO 3 (3.3 equiv) 2 SO 2 (4.5 equiv) H 2 O (. equiv) (4 w/w) < 25 C! 0 5 C 3 ()!methylbenzylamine (!MBA) (.0 equiv) ()!MBA (5% ee) iproh 2. w/w C! 5 C 25.% % ee 2.5 w/w ± 5 C! 0 5 C 23.2% % ee 2.5 w/w ± 5 C! 0 5 C 22.% % ee % ee Na 2 SO 3 H 2 O 43.3% (5% ee) Org. Process Res. Dev. 2002,, % (% ee) Org. Process Res. Dev. 2002,, tricyclo[ , ]heptaneone " (E) (0.5 equiv).4 equiv OtBu (.3 equiv) MeCOMe, H 2 O 5 20 C 2% 2.0 equiv DMF 3% HCl 0 20 C h Adv. Synth. Catal. 2002, 344, 50. H 2 O Org. Process Res. Dev. 2002,, Org. Process Res. Dev. 2002,, 3. HCl 54 Org. Process Res. Dev. 2002,, (3) wiped film distillation (±)4(3)3 bioresolution (.0 equiv) (.2 equiv) THF (0.5 M) 2 M H 2 SO 4 (2. equiv) THF reflux, 4 5 h 2 CO 3 (.2 equiv) C, h (NMP) [0% (3:)] Wiped film distillation (oil jacket: 50 C; cold finger: 0 C; vacuum: mmhg) (4%) < 20 C 20 C, 2.5 h (3:) Wiped film distillation oil jacket: 50 C cold finger: 5 C vacuum: 0.4 mmhg (% from bromoacetaldehyde diethyl acetal) Adv. Synth. Catal. 2002, 344, Adv. Synth. Catal. 2002, 344, Adv. Synth. Catal. 2002, 344, (±) (> % ee) (.3 equiv) Chirazyme L (Rhizomucor) Heptane 22 C, 45 h (:) (> 0% ee) Et 3 N (2. equiv) CH (> 0% ee) 2 Cl 2 < 2 C, 0.5 h (> % ee) MeSO 2 Cl (.4 equiv) : (:) (> 0% ee) : (:) (.4 equiv) Et 3 N (.3 equiv) 0 20 C 2 h (> % ee) (0% ee) (< 5%) (< 5%) (0% ee) SO 3 DMF ) sat aq NaHCO 3 2) 0% aq HSO 4 3) sat aq NaHCO 3 0% ee % Adv. Synth. Catal. 2002, 344, 50. Adv. Synth. Catal. 2002, 344, Adv. Synth. Catal. 2002, 344, Adv. Synth. Catal. 2002, 344, 50. 4

5 5 Chirazyme L2 (Candida antarctica) (.0 equiv) 2 CO 3 (0.3 equiv) (0.25 equiv) (5%) : (5:5) Phosphate buffer ph.. (4 M NaOH) 30 C 0% conv (3 h) 0% (0% ee) 4% (> % ee) (.3 equiv) DMF rt, 5 h MeOH rt, 3 h Et 3 N (0.3 equiv) rt, 2 h (5%) L L2 Adv. Synth. Catal. 2002, 344, 50. Adv. Synth. Catal. 2002, 344, 50. Adv. Synth. Catal. 2002, 344, 50. Adv. Synth. Catal. 2002, 344, 50. hydrozirconation (E)Zr " I Cp Tricyclo[ , ]heptanone 0% aq Na 2 CO 3 20! 2 C 50 C, h Cp Schwartz BaeyerVilliger [O] heptane (> %ee) 0.3 w/w heptane 5% Adv. Synth. Catal. 2002, 344, 50. Cp 2 ZrHCl (.2 equiv) 50 0 C 5 h Adv. Synth. Catal. 2002, 344, I 2 (3.3 M in THF,.5 equiv) 40 C " rt ( h). w/w heptane Adv. Synth. Catal. 2002, 344, 50. Org. Process Res. Dev. 2002,, 3. Wittig Org. Process Res. Dev. 2002,, 3. 2 " (0. M in Et 2 O) (. M in pentane) (. equiv) " 0 C.5 h nbuli (.0 equiv) (2.5 M in hexanes) CuCN (.0 equiv) THF (.5 v/w) THF, 30 C 20 C, 20 min 20 C, 5 min 0 C 20 min (darkbrown soln) Et 2 O/pentane 0 C 20 30min. M in THF (:) Et 2 O/pentane/THF 0 C, h 0 C, 20 min 2 w/w EtOAc/heptane (2% " 0%) BV (. equiv) AcOH AcONa (3.3 equiv) rt, 5 h LiI 0 C 30min (4%) (:3) Org. Process Res. Dev. 2002,, 3. 3 Org. Process Res. Dev. 2002,, 3. 4 Org. Process Res. Dev. 2002,, 3. 5 Org. Process Res. Dev. 2002,, 3. 2[3.2.] 3 Wittig! Wittig Br DIBALH THF tbuo ( M in THF) < 0 C (2.0 equiv) THF MeCN, rt, 2 h (:3) M aq NaOH (0.4 equiv) Org. Process Res. Dev. 2002,, 3. MTBE heptane 0 C 20% /heptane 4 % mp C ibu 2 AlH (DIBALH) (.5 M in,.5 equiv) C, 3 h Org. Process Res. Dev. 2002,, 3. 2 (3.0 equiv) Org. Process Res. Dev. 2002,, 3. < 2 C min.5 h R = TBDMS, R 2 = H R = H, R 2 = TBDMS 0 C trans 3% rt trans 5% 2 0

6 Travoprost Corey NewtonRoberts (5%) (2. equiv) DBU (,diazabicyclo[.4.0]undecene) (2. equiv) MeCOMe, rt, 20 h w/w AcOEt/heptane (:) R = TBDMS, R 2 = H R = H, R 2 = TBDMS Org. Process Res. Dev. 2002,, 3. Biotage 5 AcOEt (0%) R = TBDMS, R 2 = H R = H, R 2 = TBDMS 2 M aq HCl AcOEt Org. Process Res. Dev. 2002,, 3. iproh, rt, 2 h 2 Corey 3 [O] NewtonRoberts 2 3 " " [O] Corey!!! * " NewtonRoberts!!!!! * Wittig Corey Noyori CuI, Ph 3 P Ph 3 SnCl HMPA C 0 LiB[CH(Me)CH 2 Me] 3 H (LSelectride) Corey!!! " NewtonRoberts!!!!! * *!! Elias James Corey(2 ) The Nobel Prize in Chemistry 0 for his development of the theory and methodology of organic synthesis Ryoji Noyori (3 ) The Nobel Prize in Chemistry 200 for his work on chirally catalysed hydrogenation reactions Li *! Fox, M.; Jackson, M.; Lennon, I. C.; McCague, R. Commercial Synthesis of the Antiglaucoma Prostanoid Travoprost. In Handbook of Chiral Chemicals, 2nd. Ed.; Ager, D. J, Ed.; CRC Press: Boca Raton, 200; pp Boulton, L. T.; Brick, D.; Fox, M. E. Jackson, M.; Lennon, I. C.; McCague, R.; Parkin, N.; Rhodes, D.; Ruecroft, G. Synthesis of the Potent Antiglaucoma Agent, Travoprost. Org. Process Res. Dev. 2002,, Grieco, P. A. Cyclopentenones. An Efficient Synthesis of cisjasmone. J. Org. Chem. 2, 3, Grudzinski, Z.; Roberts, S. M. Electrophilic Bromination of Bicyclo[3.2.0]hept 2enones. J. Chem. Soc. Perkin I 5, 3.. Lee, T. V.; Roberts, S. M.; Dimsdale, M. J.; Newton, R. F.; Rajney, D..; Webb, C. F. Total Synthesis of ProstaglandinF 2! through Homoconjugate Addition of an Organocuprate Reagent to a Tricyclo[ , ]heptanone. J. Chem. Soc. Perkin I,.. Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.; Parratt, J. S. An Enantioconvergent Synthesis of 4Aryloxybutyne3ols for Prostanoid Side Chains. Adv. Synth. Catal. 2002, 344, Swanson, D. R.; Nguyen, T.; Noda, Y.; Negishi, E. A Convenient Procedure for Hydrozirconation of Alkynes with ibuzrcp 2 Cl Generated in Situ by Treatment of Cp 2 ZrCl 2 with tbumgcl. J. Org. Chem., 5, Lee, S.; Robinson, G. Development of a manufacturing route for cloprostenol sodium. Process Development: Fine chemicals from grams to kilograms; Oxford Chemistry Primers 30; Oxford University Press: Oxford, 5; pp PGE, 5, McMurry, J. E.; Begley, T. P. The Organic Chemistry of Biological Pathways; Roberts & Co. Publishers: Greenwood Village, Corey, E. J.; Weinshenker, N. M.; Schaaf, T..; Huber, W. StereoControlled Synthesis of Prostaglandins F 2! and E 2 (dl). J. Am. Chem. Soc.,, 55.. Corey, E. J.; Schaaf, T..; Huber, W.; oelliker, U.; Weinshenker, N. M.; Total Synthesis of Prostaglandins F 2! and E 2 as the Naturally Occurring Forms. J. Am. Chem. Soc. 0, 2, 3.

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