プロスタグランジンの工業的製造

O 1 HO 8 O 5 16 HO O 11 CF3 OH 16-[3-(Trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2 isopropyl ester Travoprost glaucoma 2009 12 1 O TBDMSO O O H OMe AcO H TBDMSO O 2 prostagrandins PG

20 1 CO2H 8 10 20 12 O prostanoic acid HO CO2H HO PGE2 OH CO2H HO PGF2 OH 3 PG 1930 Kurzrok Lieb 1934 von Euler 1935 prostate gland Ulf von Euler The Nobel Prize in Physiology or Medicine 1970

for the discoveries concerning the humoral transmitters in the nerve terminals and the mechanism for their storage, release and inactivation (19051983) 4 PG 1957 Bergstrm PGE1 PGF1 mg PGE E PGF F 1962 6 PG Bergstrm 30 PG 46 O HO CO2H CO2H PGF1 HO PGE1 OH HO O OH HO CO2H CO2H HO OH PGE2 HO HO OH CO2H O

CO2H HO HO PGF2 OH PGE3 PGF3 OH Sune K. Bergstrm (19162004) The Nobel Prize in Physiology or Medicine 1982 for the discoveries concerning prostaglandins and related biologically active substances 5 O CO2H CO2H HO HO OH CO2H PGE1 HO OH -- DHL 20:3 6 PGF1 O CO2H CO2H HO CO2H HO OH PGE2

HO OH PGF2 AA 20:4 6 O CO2H CO2H HO CO2H HO OH PGE3 HO OH PGF3 EPA 20:5 3 6 A2 (phospholipase A2) O O N O P O O + H O O R O OH O

cyclooxygenase CO2H O O AA R = C12C20 L-(R) - CO2H O CO2H PGH2 OH O O PGI2 CO2H HO HO OH HO HO PGE2 HO OH OH CO2H CO2H PGF2

TXA2 O OH PGD2 7 cyclooxygenase Cyclooxygenase (COX) [PGH synthase (PGHS)] O CO2H arachidonic acid AA 20:4 6 O COX-1 (PGHS-1) COX-2 (PGHS-2) OAc OH H2N S N PGH2 O O CO2H N CF3 CO2H MeO

CO2H N O Cl CO2H COX-1 COX-2 IL-1 TNF 8 CO2H 1 CO2H H H H 13 H 385 Tyr O CO2H H C13 pro-S COX Tyr-385 9 - NO N O

N O O - N N 385 Tyr O N O O N Fe(IV) N CO2H HO2C N O peroxinitrite ion Fe(II) N O2 His N - long range electron transfer CO2H HO2C HO

385 Tyr 10 C-11 O O CO2H 8 9 13 H 11 9 O O O2 CO2H 11 H CO2H O H C8C9 O H 12 11 C8 C12C13 9

O O H CO2H 11 8 14 H H CO2H O 15 O 12 H O2 CO2H H O O H O H O O 8 H CO2H O H

14 15 C15 O O 12 PGG2 PGH2 Tyr CO2H H 385 O H O H O O H O CO2H 15 O O CO2H O O PGG2 OOH PGH2 OH N N Fe(II) N

N O Fe(IV) N N N His N 13 PGH2 PG CO2H TXA COX O PGE CO2H O O OH TXA2 CO2H O PGI OH O PGH2 CO2H O PGI2 CO2H PGD

HO OH HO PGE2 OH HO HO CO2H CO2H PGF2 HO OH O OH PGD2 14 Vane Samuelson John R. Vane (19272004) 1971 COX 1976 PGI2 10 37 C Bengt I. Samuelsson (1934) 1975 TXA2 30 37 C 1980 Corey AA 5- The Nobel Prize in Physiology or Medicine 1982 for their discoveries concerning prostaglandins and related biologically active substances 15

16-[3-(Trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF2 O HO 8 6 1 15 OH PGF2 20 11 HO OH O O HO HO O R CF3 OH R=H fluprostenol R = CHMe2 travoprost 16 Corey PGF2 retrosynthesis HO 1 8 15

11 13 CHO 20 HO OH Wittig Wadsworth-Emmons O O Corey CHO CO2H 5 HO HO Wittig 9 OH 6 CO2H 7 OH 11 AcO 13

HO OH 17 Corey O O O - O + I OR trans HO O O I OR OR HO HO O HO O RO - OH + HO

O I OR OH O HO OR 18 Corey Baeyer-Villiger Diels-Alder O RO RO OH OH O Baeyer-Villiger O RO RO X Y H X H O OR Y H

H C Diels-Alder [4 + 2] O [2 + 2] [4 + 2] 19 Diels-Alder H NaH H - H [4 + 2] THF -55 C Cl OMe (slightly excess) OMe -55 C Cu(BF4)2 OMe OMe H 1,5- Cl CN (5 equiv) H H MeO 0 C (> 90%) Cl

CN bp 9699 C/0.7 mmHg 20 - KOH (2.5 equiv) MeO Cl CN anti MeO H2O, DMSO (80%) O bp 6466 C/0.1 mmHg MeO MeO Cl O Cl - - O H N H MeO C N N H MeO MeO Cl -

HO C N HN O O 21 Baeyer-Villiger Cl O MeO mCPBA 1.25 equiv MeO O OH NaHCO3, CH2Cl2 (> 95%) O O O H O O Cl Ar O B-V Ar = MeO O O O

O Ar O H 3 > 2 > benzyl > phenyl > 1 > methyl HO Ar 22 - MeO O 1. NaOH (2.5 equiv), H2O, 0 C O 2. CO2 (> 90%) MeO OH O O- 9 MeO CO2H OH 8 12 HO CO2H OMe 13 D-A B-V 3 23

CO2H Me CO2H MeHN H (R) HO H (S) Ph HO C6H6 (1:1) - + CO2 MeH2N Ph HO (+)-(1S,2R)-ephedrine OH OMe OMe One recryst from C6H6 CO2 - + MeH2N OH fully resolved salt OMe (34%) Ph OMe

OH OH 24 Me ()-acid MeHN H (R) HO H (S) CO2H OMe HO Ph (-)-(1R,2S)-ephedrine (+)-(1S,2R)-ephedrine PGA1 Me (S) H NHMe (R) H OH (+)-acid HO (+)-Cotton CO2H Ph O HO2C 1) CH2N2 MeO (-)-acid OH 2) MnO2

MeO2C (-)-Cotton 238 nm (-14000) MeO O 25 HO - O KI, I2 NaHCO3 HO OMe O - O I + H2O 05 C 20 h HO + O I HO OMe O OMe (+)-acid O I2

5 3.3.0 cis - trans O I (97%) HO OMe mp 99.9100 C 26 O O O O O (Ac2O) O ,-azoisobutyronitrile (AIBN) O I N N CN CN I HO N OMe AcO 25 C, 15 min (n-Bu)3SnH C6H6 25 C

OMe O O O + N - O O OMe AcO 2 99% 27 N N N C N N N C C N heat + C N ,-azoisobutyronitrile (AIBN) R N C X H Sn

X Sn Sn H R R H 28 1 O O BBr3 (5.5 equiv) O CH2Cl2 > 90% OMe AcO Corey O OH AcO O Br O Me B O O O B Br Br O CrO32Py CH2Cl2 0 C Collins O

Br Br O Me Br Me O AcO H 29 Wadsworth-Emmons O O O 6 MeO MeO 9 8 11 AcO P O 12 O MeO NaH 25 C, 1 h (DME) H C11 AcO OMe

C13 2 70% O O (E)- 14 AcO 13 15 O 30 (E)- O MeO MeO Na O P H + R1 R H Na MeO O P Ktrans > kcis O H O 1

R1 O P NaO OMe O P OMe R1 2 R O MeO R1 R2 O R2 kcis OMe O P OMe Na O OMe NaO R1 R2 R O P O R1 Na MeO MeO R2 R2

H O O 2 O NaH ktrans O O MeO P OMe ONa MeO R1 R2 O 31 C15 1,2- O O NaBH4 + ZnCl2 OMe MeO (DME) 6 8 Zn(BH4)2 (excess) 15 11 20 C, 0.5 h 13 AcO O

(>97%) SiO2 chromatog (prep TLC/Et2O) MnO2, CH2Cl2 or 15R (1:1) 15S O Cl O O CN O O Cl CN O (DDQ) dioxane 50 C AcO OH AcO OH 32 (15S)- EtO2C CO2Et - MeLi (2 equiv) +

I Ph3P Ph3P OH OH O Li + THP O O - O O O O O O - THPO THPO B O O O H H O O H low yield

O O THPO O H OH Ph3P OR PGF3 33 C11 C15 THP O O O 6 9 O 11 O K2CO3 (1.0 equiv) MeOH 25 C, 15 min 15 12 O HO OH OH O O

O (DHP) (10 equiv) 2 THP O S OH H2O (TsOH) (0.01 equiv) O O O O O THP (tetrahydropyranyl) CH2Cl2, 25 C, 15 min 34 THP 3,4-dihydro-2H-pyran (DHP) R 1 OH H + + R1 O H O H O + O R1

O R1 O H + + O O H O : S OH H2O (PTS) O O S O R1 - + HN + O H + O (PPTS) O 35 lactone lactol O O (DIBAL-H) (2.0 equiv) Al

THP H THP O O O PhMe -60 C, 30 min O i-Bu i-Bu Al H i-Bu O O H O Al i-Bu OH O O THPO OTHP 36 Wittig HO O OH O - Ph Ph P Ph O Na

+ O THPO O Me THPO (DMSO) OTHP (Z)- THP 3 80% S Me HO CO2H THPO PGF2 OTHP PGE2 37 Wittig H2 O Na + H H CH2 S Me - Na + O

CH2 O DMSO Ph Ph Br O + H Na CH2SOMe Ph3P H - + - + O Na + CH2SOMe NaBr + 2 DMSO P Ph - H2C S Me - - S Me - +

CO2 Na CH2SOMe Ph3P - + CO2 Na 38 lactol Wittig O- OH - + (CH2)3 CO2 Na R2 = O O R1 R1 THPO R2 Ph3P + Ph3P H THPO R2 H H - O HO O O

R1 R1 THPO R1 = THPO C5H11 - O R2 OTHP R1 R2 Ph3P H THPO 39 ylide Z - O R R 3 2 O - R2 R3 H + H R O H

H PPh3 3 R + 2 R O 3 Ph PPh3 P+ Ph Ph - PPh3 - PPh3 R2 R H R2 H O Ph - P R2 R3 3 +

Ph R3 R2 H O PPh3 R2 R3 Ph R 2 - + O PPh3 R3 R2 40 PGF2 HO AcOH/H2O (2:1), 47 C, 4 h CO2H THPO THF OTHP HO CO2H R H O H

O HO + OH (82%) O R + O H OH2 + HO O H H + HO O 41 PGE2 HO CrO3-H2SO4 H2O, MeCOMe Jones -10 C, 30 min CO2H THPO OTHP O CO2H THPO OTHP O CO2H

HO OH AcOH/H2O (2:1) [70% (two steps)] PGE2 C11 42 Fluprostenol Wittig O O O O BzO O Bz = OH HO HO O CF3 OH Horner-Emmons Corey - Wittig - Horner-Emmons 43 Corey O O HO O CHO OBz O O

HO CF3 OH 15-(S) 15-(R) O CF3 O BCl 15 O OBz O H (-)-DIP-ChlorideTM 2 (-)-B-chlorodiisopinocamphenylborane 44 Roberts Newton O O HO O HO CF3 OH Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. CF3 O K +

- O O PPh3 TBDMS = H Si TBDMSO I H O OTBDMS Tricyclo[3.2.0.02,7]heptanone 45 Tricyclo[3.2.0.02,7]heptanone O H H O - H H Br TBDMSO TBDMS = O RO

Si R = TBDMS R=H Cl O C Cl [2+2] O H H H Cl Cl H Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 46 [2 + 2] Cl Cl + Cl Cl Et3N (1.0 equiv) O H n-hexane rt, 15 h Cl (2.0 equiv) bp 4950 C /0.3 mm O H

(85%) Cl N Cl H Cl O C O Cl Cl Grieco, P. A. J. Org. Chem. 1972, 37, 2364. 47 Cl O O Cl H Zn (6.0 equiv) H H AcOH 70 C, 40 min H bp 60 C /15 mm (95%) O O R1 Zn R2 H

3 R Cl O O H O R1 R1 - R3 R2 R3 R2 Grieco, P. A. J. Org. Chem. 1972, 37, 2364. 48 bicyclo[3.2.0]hept-2-en-6-one O 6 H H H 1 O H H H 2 O SO2 (4.5 equiv) H2O (1.1 equiv) CH2Cl2 (14 w/w) < 25 C 05 C

H O H 3 H2N Ph (+)-(R)--methylbenzylamine (MBA) (1.0 equiv) OH - + SO3 H3N H H SO3 OH Ph H H + H3N Ph 43.3% (75% ee) 49 - (+)-(R)-MBA H H O Ph S O O H H

(+)-(R)-MBA O H H2N H O S O OH O - + H3N OH + SO3 H3N Ph H H Ph 50 SO3 OH + SO3 H3N H H OH Ph H H + H3N Ph (75% ee)

i-PrOH 2.7 w/w 67 C 2.5 w/w 67 5 C 2.5 w/w 67 5 C 5 C 25.7% 89% ee 05 C 23.2% 97% ee 05 C 22.7% 99% ee OH + SO3 H3N H Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. H Ph 22.7% (99% ee) 51 (-)-(1R,5R)-Bicyclo[3.2.0]hept-2-en-6-one OH + SO3 H3N H H Na2CO3 (3.3 equiv) Ph H2O CH2Cl2 99% ee O H2N Na2SO3 + + Ph H H Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 52

O Br O O N H O N (0.5 equiv) H H Br H Br MeCOMe, H2O 1520 C HO 62% O + Br Br N Br N O H H H2O H H

O O Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 53 2 O O H Si Cl 1.4 equiv H Br N 2.0 equiv O DMF HO H Si Cl H Br HN H N H N Si 38% R O Si N N HCl R O Si HN N HCl Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138.

54 3 tricyclo[3.2.0.02,7]heptane-6-one O K H + - KOt-Bu (1.3 equiv) O H Br O H H PhMe O -10 -20 C 1 h O Si Br Si O H Si H - O K + PhMe Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 55

(E)- CF3 I CF3 O O OTBDMS OTBDMS CF3 Si TBDMS = Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. O O CF3 CF3 O MgBr H O O O OH 56 (3- ) CF3 EtO

CF3 Br (1.0 equiv) EtO EtO O K2CO3 (1.2 equiv) HO (NMP) O EtO N (84%) 140150 C, 8 h CF3 2 M H2SO4 (2.8 equiv) THF reflux, 45 h CF3 + H O O HO [90% (3:1)] Wiped film distillation (oil jacket: 150 C; cold finger: 0 C; vacuum: 8 mmHg) O EtO Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 57

wiped film distillation 58 ()-4-(3- )-1 -3 MgBr (1.2 equiv) THF (0.5 M) < 20 C CF3 CF3 + H HO O O (3:1) O EtO 20 C, 2.5 h CF3 O OH Wiped film distillation oil jacket: 150 C cold finger: 5 C vacuum: 0.4 mmHg (78% from bromoacetaldehyde diethyl acetal) Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 59 bioresolution CF3 CF3 O

O OH OH (R) (R)- (S)- CF3 (S) (R)- CF3 O O O O OH Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 60 (R)- CF3 O (1.3 equiv) O Chirazyme L-9 (Rhizomucor) Heptane 22 C, 45 h O OH () CF3 CF3 O + (1:1)

O O (R) (> 98% ee) O OH (S) (> 90% ee) Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 61 (S)- CF3 CF3 MeSO2Cl (1.4 equiv) Et3N (2.6 equiv) CH2Cl2 < 2 C, 0.5 h O OH (S) (> 90% ee) + O O S O O (S) + CF3 CF3 (S):(R) (1:1) O O O O O (R)

(> 98% ee) O (R) Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 62 (R)- CF3 OH (1.4 equiv) O O (S) (> 90% ee) S O CF3 O O + (S):(R) (1:1) CF3 Et3N (1.3 equiv) 110120 C 2h O O O (R) (90% ee) CF3 O O O

OH O (R) (> 98% ee) (< 5%) Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 63 CF3 CF3 N SO3 DMF O OH O (< 5%) O O S O + O - + HN CF3 1) sat aq NaHCO3 2) 10% aq KHSO4 3) sat aq NaHCO3 O O O

(R) (90% ee) (R)- 90% ee 96% Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 64 (R)- CF3 CF3 Chirazyme L-2 (Candida antarctica) O O O (R) + (95%) Phosphate buffer pH 6.97.1 (4 M NaOH) 30 C 90% conv (3 h) O OH 84% (> 99% ee) + (R):(S) (95:5) CF3 810% (90% ee) O O O O (S) CF3 (5%) L-9 L-2

O O Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 65 CF3 CF3 Si Cl (1.0 equiv) O N O OH (R) DMF rt, 15 h + O NH (1.3 equiv) Si (R) + CF3 (S) (S) O O CF3 O O O O Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 66

(S)- CF3 O K2CO3 (0.13 equiv) MeOH rt, 3 h O (R) CF3 O (R) O Si + Si + CF3 CF3 (S) O (S) O O OH O Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 67 (S)- CF3 O

O (0.25 equiv) O O (R) O O O Si Et3N (0.3 equiv) CH2Cl2 rt, 2 h + CF3 Si (R) + CF3 CF3 (S) O O O OH Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. O O (S) HO 68

(S)- (R)- CF3 CF3 (S) (R) O O O O O 10% aq Na2CO3 O Si HO heptane 0.3 w/w heptane CF3 (> 99%ee) O O Si 58% Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 69 hydrozirconation Cp MgCl Zr Cl Cl Cp2Zr PhMe

20 28 C Cp Cl Zr 50 C,1 h Cl H Schwartz CF3 CF3 Cp2ZrHCl (1.2 equiv) O O Si PhMe 5060 C 5h H Cp2(Cl)Zr O O Si Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. 70 (E)- Zr I CF3 CF3 H H Cp2(Cl)Zr O O Si I2 (3.3 M in THF, 1.5 equiv)

-40 C rt (1 h) I O O Si 1.7 w/w heptane Lennon, I. C.; et al. Adv. Synth. Catal. 2002, 344, 50. Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 71 11 O CF3 H H Tricyclo[3.2.0.02,7]heptanone I O TBDMSO OTBDMS O OTBDMS CF3 Baeyer-Villiger O O OTBDMS O HO HO

[O] O OH CF3 Wittig Ph3P - O K + O Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 72 OTBDMS F3 C O I OTBDMS (0.71 M in Et2O) O Li Li (1.7 M in pentane) -79 -60 C 1.5 h (1.9 equiv) CF3 H R R I I H +

Li Li Li + LiI Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 73 OTBDMS n-BuLi (1.0 equiv) (2.5 M in hexanes) S THF, -30 C -20 C, 20 min O S Li CF3 -20 C, 15 min CuCN (1.0 equiv) THF (9.5 v/w) Cu(CN)Li S -10 C 20 min Et2O/pentane O -70 C 2030min (dark-brown soln) OTBDMS F3C Li Cu(CN)Li2

-70 C 30min S Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 74 OTBDMS O Cu(CN)Li2 S Et2O/pentane/THF 2 w/w EtOAc/heptane (2% 10%) -70 C, 1 h CF3 -70 C, 20 min O H H CF3 1.1 M in PhMe-THF (6:1) (64%) O TBDMSO TBDMS = Si Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. OTBDMS O OTBDMS 75 11 OTBDMS O O CF3

O O OH (1.8 equiv) AcOH AcONa (3.3 equiv) rt, 5 h OTBDMS B-V OTBDMS OTBDMS O O O CF3 O CF3 O O OTBDMS (1:3) OTBDMS Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 76 2- [3.2.1] -3- OTBDMS OTBDMS O CF3 O O O CF3 O

O OTBDMS OTBDMS (1:3) MeCN, rt, 2 h O 1 M aq NaOH (0.48 equiv) MTBE TBDMSO OH HO2C O OTBDMS CF3 heptane -70 C 20% CH2Cl2/heptane 47 % mp 7778 C Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 77 OTBDMS CF3 O DIBAL-H O O Al H OTBDMS PhMe 78 C, 3 h i-Bu2AlH (DIBAL-H) (1.5 M in PhMe, 1.5 equiv) OTBDMS

O R H Al O HO CF3 O O OTBDMS OTBDMS Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 78 Wittig OTBDMS - + Br Ph3P HO THF < 10 C Ph3P O t-BuOK (1 M in THF) (2.0 equiv) (CH2)3CO2 K CF3 O (CH2)3CO2H THF OTBDMS (3.0 equiv)

+ < 2 C 3045 min 1.5 h CO2H R1O 0 C rt trans 3% trans 5% 9 R2O 12 O OTBDMS CF3 R1 = TBDMS, R2 = H R1 = H, R2 = TBDMS 9 12 Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 79 Wittig R1 R1 O HO - OTBDMS R1 R2 Ph3P R2 +

Ph3P H O O H OTBDMS H R1 - HO O O O OTBDMS R R1 1 O O Si R2 OTBDMS -O O 2 R Si R2 Ph3P H 80 O N OH R1O

N (2.1 equiv) DBU (1,8-diazabicyclo[6.4.0]undec-7-ene) O R2 O I CF3 MeCOMe, rt, 20 h OTBDMS O 8 w/w AcOEt/heptane (1:6) O R1O O R2 O (2.1 equiv) OTBDMS CF3 R1 = TBDMS, R2 = H R1 = H, R2 = TBDMS (95%) Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. 81 Travoprost O R1 = TBDMS, R2 = H R1 = H, R2 = TBDMS O R1O 2 M aq HCl R2O

O CF3 i-PrOH, rt, 2 h AcOEt OTBDMS Biotage 75 AcOEt O HO O HO Lennon, I. C.; et al. Org. Process Res. Dev. 2002, 6, 138. O OH CF3 (70%) 82 Corey Newton-Roberts Corey 6 9 O 8 11 O OMe 11 13 BzO CF3 O

7 9 6 O O 8 15 OH 12 13 [O] 13 BzO O O Newton-Roberts TBDMSO 9 8 9 O 7 8 9 H 6 CF3 TBDMSO 15 H 11

7 O 6 O 6 O O OTBDMS [O] 83 1 O O O 6 7 9 11 BzO HO 9 O 12 13 H 11 8 12 HO TBDMSO

O 7 8 9 12 15 H CF3 O 7 O OH H 6 8 9 11 12 15 Corey * Newton-Roberts

* Wittig 84 3 O CuI, Ph3P Ph3SnO Ph3SnCl 10 HMPA TBDMSO Li TBDMSO OTBDMS OTBDMS C10 HO TBDMSO LiB[CH(Me)CH2Me]3H (L-Selectride) I MeO2C O TBDMSO CO2Me OTBDMS 85 2 O O TBDMSO

6 9 8 9 7 HO H 12 11 12 BzO O H 13 H 7 O 6 9 11 O 3 8 9 CO2R1 8 R2 12

HO TBDMSO OH 11 12 8 9 11 12 15 Corey Newton-Roberts * *

* 9 86 Corey Noyori Elias James Corey (1928) The Nobel Prize in Chemistry 1990 for his development of the theory and methodology of organic synthesis Ryoji Noyori (1938) The Nobel Prize in Chemistry 2001 for his work on chirally catalysed hydrogenation reactions Ar P O H Li + Al O OEt Ar RuX2L2 P Ar Ar 87 O TBDMSO O O H OMe

AcO H TBDMSO O 88 1 1. 10 2007 2. 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, 2006; pp 573587. 3. 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, 6, 138145. 4. Grieco, P. A. Cyclopentenones. An Efficient Synthesis of cis-Jasmone. J. Org. Chem. 1972, 37, 23632364. 5. Grudzinski, Z.; Roberts, S. M. Electrophilic Bromination of Bicyclo[3.2.0]hept2-en-6-ones. J. Chem. Soc. Perkin I 1975, 17671773. 6. Lee, T. V.; Roberts, S. M.; Dimsdale, M. J.; Newton, R. F.; Rajney, D. K.; Webb, C. F. Total Synthesis of Prostaglandin-F2 through Homoconjugate Addition of an Organocuprate Reagent to a Tricyclo[3.2.0.02,7]heptanone. J. Chem. Soc. Perkin I 1978, 11761178. 7. Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague, R.; Parratt, J. S. An Enantioconvergent Synthesis of (R)-4-Aryloxy1-butyne-3-ols for Prostanoid Side Chains. Adv. Synth. Catal. 2002, 344, 5056. 89 2 8. Swanson, D. R.; Nguyen, T.; Noda, Y.; Negishi, E. A Convenient Procedure for Hydrozirconation of Alkynes with i-BuZrCp2Cl Generated in Situ by Treatment of Cp2ZrCl2 with t-BuMgCl. J. Org. Chem. 1991, 56, 2590 2591. 9.

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, 1995; pp 57 66. 10. 1981 11. 15 2006 12. 2006 13. 2004 14. 2 PGE1 1999, 57, 422 428. 90 3 15. McMurry, J. E.; Begley, T. P. The Organic Chemistry of Biological Pathways; Roberts & Co. Publishers: Greenwood Village, 2005. 16. Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. Stereo-Controlled Synthesis of Prostaglandins F2 and E2 (dl). J. Am. Chem. Soc. 1969, 91, 5675. 17. Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinshenker, N. M.; Total Synthesis of Prostaglandins F2 and E2 as the Naturally Occurring Forms. J. Am. Chem. Soc. 1970, 92, 397. 91

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    In your groups identify as many strengths and weaknesses of the constitution as you can think of.Think about the key features and concepts you have learnt about; pros and consThink about praise or criticism of the UK political system you...
  • DigiTrol+ Panel Kubota Mechanical Diesel Engines Pressure Transducer

    DigiTrol+ Panel Kubota Mechanical Diesel Engines Pressure Transducer

    MSG Pressure Gauge (Metric/English Selectable) Displays pressure (PSI/BAR) Low Pump Water Pressure Shutdown (shut down at 15 psi, 10 second start up delay Panel Materials Anodized aluminum plate (.09" thickness both panels) Panel Color (Gray metallic background with black lettering)...
  • LWW PPT Slide Template Master

    LWW PPT Slide Template Master

    Nursing theory is not related to actual nursing practice because it only provides a basis for research. Answer False Rationale: Nursing theory provides the basis for research on how nurses can be more effective, guides practice, and helps nurses recognize...
  • Romeo and Juliet Cast of Characters - Denton ISD

    Romeo and Juliet Cast of Characters - Denton ISD

    Sampson, Gregory, Potpan - servants to Capulet. Romeo Montague. The House of Montague. Lord Montague - Romeo's father. Lady Montague- Romeo's mother. ... Escalus - Prince of Verona. Paris - young nobleman and kinsman to the prince. Page - servant...
  • Research To Practice

    Research To Practice

    Current Controversies, Recent Developments and Emerging Strategies in the Management of Prostate Cancer — A Clinical Investigator Think Tank September 7, 2012 75-year-old with PSA-only disease PowerPoint Presentation A 55-year-old underwent radical prostatectomy 5 years ago recurrence salvage radiation PSA...
  • Master Slide - Leeds School of Business

    Master Slide - Leeds School of Business

    Step 1: Establish the Facts Gather all relevant facts Irrelevant facts may become relevant later Constantly be aware that new facts may be needed as the research progresses Significant Facts Client's tax entity Client's personal (family) situation Client's marginal tax...