Prostaglandin Nomenclature

HO Letter refers to cyclopentane structure CO2H Me

O O O HO OH e.g. Rα Rα Rα PGF2α

Rω Rω Rω A B C OH O OH PGF: Four contiguous stereocenters

Rα Rα Rα PGE: Labile β-hydroxyketone

O Rω HO Rω HO Rω

D E Fα

OH

Rα Rα

HO Rω O Rω

Fβ J Prostaglandin Nomenclature

HO Letter refers to cyclopentane structure CO2H Me

O O O HO OH e.g. Rα Rα Rα PGF2α

Rω Rω Rω A B C OH O OH G, H, I?

Rα Rα Rα

O Rω HO Rω HO Rω CO2H D E Fα O OH

Rα Rα HO HO Rω O Rω OH

PGI2: Prostacyclin Fβ J Prostaglandin Nomenclature

HO

Number refers to degree of CO2H unsaturation on side-chains. Me

HO OH

e.g. PGF2α

CO2H Rα = CO H 1: 2 Me Me Rω = dihomo-γ-linolenic acid OH

CO H Rα = CO H 2 2: 2 Me Me Rω = arachidonic acid OH

R = CO2H α CO2H 3: Rω = Me Me eicosapentaenoic acid OH Biosynthesis 4

Prostaglandin Biosynthesis

Tyr O H H H

O O Cyclooxygenase O O

CO2H CO2H CO2H

O O

O O O O O O O O O HO O Tyr-OH Peroxidase O HO

PGG2 CO2H CO2H CO2H CO2H PGH2

Cyclooxygenase and Peroxidase functionality exist in the same enzyme

PGH2: Key biosynthetic intermediate to Prostaglandins, related compounds

Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304. Biosynthesis 5

Prostaglandin Biosynthesis

R

HO HO R R R O α α 5 > pH > 8 α

Rω Rω Rω HO O O Rω HO PGF2α PGD2 PGJ2 PGI2

O O CO H 2 Rα R α O O R OH ω O Rω HO TxA2 PGH2 PGE2

5 > pH > 8

OH O O O R R R Rα α α α

HO O Rω Rω Rω Rω TxB2 PGB2 PGC2 PGA2

Das, S. et al. Chem. Rev. 2007, 107, 3286–3337. Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; p 66. Corey's Prostaglandin Syntheses "It was in 1969 when Corey disclosed his elegant and versatile bicycloheptane prostaglandin synthetic strategy. Over the course of the ensuing two and half decades, Corey's original strategy has evolved in a manner that closely parallels the development of the science of organic synthesis..."

- K.C. Nicolaou & E. J. Sorensen

More generally: Prostaglandin research embodies the intertwined nature of target oriented synthesis & methodology development

Original Bicycloheptane Retrosynthesis: Iodolactonization Wittig reaction HO OH O O

CO2H O O HO Me

HO OH O OMe OMe PGF HWE reaction 2α AcO AcO HO Corey Lactone

Diels-Alder

MeO MeO OMe Cl CN

O O O

Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675–5677. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; pp 65–81. Corey's Original Bicycloheptane Route

Cl CN OMe MeO MeO NaH, THF KOH mCPBA Cu(BF ) , 0 °C Cl MeOCH2Cl 4 2 H2O/DMSO NaHCO3 THF, -55 °C CH2Cl2 (> 90% yield) CN (80% yield) O mixture of (> 95% yield) diastereomers

O MeO HO O O O O NaOH KI3 1. Ac2O, pyr I O H2O, 0 °C NaHCO3 2. Bu3SnH OMe H2O, 0 °C AIBN, PhH OMe HO OMe AcO O (90% yield) HO (80% yield) (99% yield) Corey Lactone

O O O C5H12 O (MeO) OP 1. BBr3, CH2Cl2 2 O O 0 °C (> 90%) O Zn(BH4)2 NaH, DME, 25 °C DME 2. CrO3•2pyr C H C H CH2Cl2, 0 °C O 5 12 5 12 AcO (70% yield, 2 steps) (97% yield) AcO O AcO 1:1 d.r. OH MnO2 (recycle undesired epimer)

Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675–5677. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; pp 65–81. Corey's Original Bicycloheptane Route - 1969

O O OH - CO2 O O O Ph P 1. K2CO3, MeOH DIBAL-H 3 3

2. DHP, TsOH, PhMe, -60 °C C H C H C H 5 12 CH2Cl2 5 12 5 12

AcO OH THPO OTHP THPO OTHP

HO

AcOH, H2O, 37 °C CO2H (> 90% yield) HO HO OH CO2H PGF2 1. H2Cr2O7, PhH/H2O α C5H12 2. AcOH, H2O, 37 °C (70% yield, 2 steps) O THPO OTHP CO2H

HO OH

PGE2 O

O • Limitations: Diels-Alder gives racemic product, non selective enone reduction OMe

• Corey Lactone applied in the synthesis of a variety of PG AcO derivatives in a search for pharmaceuticals Corey Lactone

Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675–5677. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996; pp 65–81. Chiral Auxilliary Modification - 1975

O OBn O BnO BnO Ph AlCl3 LDA OH CH2Cl2, -55 °C then O2, P(OEt)3 THF Me (89% yield) O OR O OR (90% yield) 97:3 d.r. 2:1 exo:endo

BnO 1. LAH (95% yield) • Menthol derivative could be recycled after LAH reduction

2. NaIO4, t-BuOH O • Phenyl substitution gives remarkably higher e.e. than ordinary (97% yield) menthol

Phenyl group blocks Diels Alder @ Si face of olefin

Me O "The first highly enantioselective version of the π lewis acid/base Diels–Alder reaction" O interaction AlCl 3 Oh, and a novel enolate oxidation method as well.

Farmer, R. F.; Hamer, J. J. Org. Chem. 1966, 31, 2418–2419. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908–6909. Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. Development of Catalytic Enantioselective Diels Alder Reactions: 1979–1989 Prevailing strategy:

O O R* achiral catalyst * R* O O

First catalytic enantioselective Diels-Alder Reaction: Koga, 1979

O Cl2Al O (12 mol%) CHO H PhMe/Hexane -78 °C 57% ee (56% yield) Two point substrate binding: Chapuis, 1987 Ph

O O OTMS Lewis Acid (1 equiv) NH N O OTMS S CH2Cl2, -78 °C TiCl O EtAlCl O N 4 2 2 Ph O O 99% yield 75% yield 98% ee 98% ee

Reviews: (a) Oppolzer, W. Angew. Chem. Int. Ed. Engl. 1984, 23, 876–889. (b) Kagan, H.B.; Riant, O. Chem. Rev. 1992, 92, 1007–1019. Hashimodo, S.; Komeshima, N.; Koga, K. J. Chem. Soc., Chem. Commun. 1979, 437. Chapuis, C.; Jurczak, J. Helv. Chim. Acta. 1987, 70, 436–440. Catalytic Enantioselective Diels–Alder - 1989–1991

Ph Ph

OBn NR2 BnO O O F3CO2SN NSO2CF3 Al BnO (10 mol%) N O O Me Ph H O CH2Cl2, -78 °C O N Al O (93% yield, > 95% ee) Ph Me

Catalytic variant of Chapuis system applied to bicycloheptane synthesis BnO

O

HN O H Br N OBn O TsN O H B BnO Br (5 mol%) H O H BnO O H O CHO CH2Cl2, -78 °C B H N Br (83% yield, 92% ee) Ts

Attractive interaction between acrylate & tryptophan proposed: With non aromatic side-chains, opposite enantiomeric series observed

For a review on Enantioselective D-A developed by Corey, see: Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650-1667. Corey, E. J. et al. J. Am. Chem. Soc. 1989, 111, 5493–5495. Corey, E. J.; Imai, N.; Pikul, S. Tetrahedron Lett. 1991, 32, 7517–7520. Corey, E. J.; Loh, T. P. J. Am. Chem. Soc. 1991, 113, 8966-8967 Catalytic Enantioselective Diels–Alder: Extensions OMe O Me Yamamoto, 1988 Me O Catalyst (10 mol%) SIPh3 H PhMe, -20 °C O Ph TMSO O then TFA, CH2Cl2 Me Al-Me Me O (84% yield) 95% ee 10:1 cis:trans SiPh3

O O Evans, 1993 Catalyst (10 mol%) O N O O CH Cl , -78 °C, 18 h O 2 2 O N O N (86% yield) N Cu t-Bu t-Bu 98% ee TfO OTf 98:2 endo:exo

O MacMillan, 2000 Catalyst (20 mol%) H O

MeOH/H2O, 23 °C CHO NMe 94% ee (82% yield) Bn N 14:1 endo:exo H • HCl

O Corey, 2002–2003 O Catalyst (20 mol%) H Et H Ph Et neat, -20 °C, 88 h Ph

(87% yield) N O NTf2 80% ee H B Yamamoto, H. et al. J. Am. Chem. Soc. 1988, 110, 310–312. o-tol Evans, D. A.; Miller, S. J.; Lectka, T. 1993, 115, 6460–6461. Ahrendt, K. A.; Borths, C. J.; Macmillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388–6390. Catalytic Enantioselective Diels–Alder: Extensions O O O H Me OH OH Catalyst O Me toluene TIPSO TIPSO -78 °C, 2.5 h H H H O Me O (95% yield; O 90% ee) cortisone (Merck/Sarett, 1952) H Ph Ph

N O O O O B Tf2N H H H ent-Catalyst o-tol

toluene O Catalyst MeO OMe -78 °C, 2.5 h Me H O O H (95% yield) N

(–)-dendrobine (Kende/Bentley, 1974)

HO H H H OMe H O O OH H H O H H Me H O OH Me O O H O (+)-hirsutene silphinene nicandrenone core (+)-myrocin C (–)-coriolin (Mehta, 1986) (Mehta, 1986) (Stoltz/Corey, 2000) (Chu-Moyer / Danishefsky, 1992)

Review on cationic oxazaborolidines: Corey, E. J. Angew. Chem. int. Ed. 2009, 48, 2100–2117. Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808–3809. Hu, Q. Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708–13713. Strategies toward C(15) stereoselectivity - 1971–1987

O O

O O H O Borohydride Me B HMPA Li PB = C5H11 THF/Et2O/pentane C5H12 -120 °C Me Ph PBO O PBO OH

82:18 α : β Borohydride 92:8 with carbamate analogue • Derived from (±)-limonene

O O

O O DIBAL•BHT (10 equiv)

PhMe, -78 → -20 °C C5H11 C5H12

OH O OH OH

95% yield, 92:8 d.r.

O O

O O 3 equiv BINAL-H Match/Mismatch O H Effect Observed w/ THF, -100 → -78 °C Al Li (R) enantiomer C5H11 C5H12 O OEt OR O OR OH

R = THP, > 99:1 (S)-BINAL-H R = Ac, > 99:1

Corey, E. J. et al. J. Am. Chem. Soc. 1971, 93, 1491–1492. Corey, E. J.; Becker, K. B.; Varma, R. K. J. Am. Chem. Soc. 1972, 94, 8616–8618. Yamamoto, H. et al. J. Org. Chem. 1979, 44, 1363–1364. Noyori, R.; Tomino, I.; Nishizawa, M. J. Am. Chem. Soc. 1979, 101, 5843–5844. CBS Reduction & C(15) stereoselectivity - 1987

O O

O O Ph BH3•THF (0.6 equiv) H Ph

(R)-Me-CBS (10 mol%) O C5H12 N C5H11 THF, 23 °C, 2 min B Me PBO PBO O OH (R)-Me-CBS 9:1 α : β

CBS Catalyst has found widespread use in organic synthesis

TMS OTBS TMS OTBS O (S)-p-t-BuPh-CBS H O O catecholborane H OH O CH2Cl2, -40 °C OH (92%, 95% ee) OH O NIC-1 & NIC-1 Lactone

OH O OH RN (S)-H-CBS H OH O catecholborane PhMe MeO I MeN (93% yield, 96% ee) OBn (–)-morphine

Review: Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1987–2012. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. Corey E. J. et al. J. Am. Chem. Soc. 1987, 109, 7925–7926 Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029 Stoltz, B. M.; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2002, 122, 9044–9045 Alternative Routes to Prostaglandins

Corey Route: O Wittig reaction 6 HO O 7 8 6 5 CO2H 8 14 12 Me 12 8 steps OMe 8 steps OMe 13 13 HO OH (Original Route) HO (Original Route) 13 HWE reaction

Conjugate Addition:

Conjugate Addition O HO HO [M] CO2H 7 8 CO2H CO2H 12 Me Me 13 HO [M] Me HO OH O OH Conjugate Addition OH

Three Component Coupling: Enolate Alkylation or HO Conjugate Addition X CO2H 7 [M] CO2H O 8 HO CO2H 12 Me 13 HO OH HO O [M] Me Enolate Alkylation X Me or OH Conjugate Addition OH Approaches by Conjugate Addition - Sih, 1972

O HO Br CO2Et 6 6 CO2Et H O , NaOCl 6 CO2Et 6 CO2Et Li 2 2 THF, r.t.

(100% yield) HO O 1:4 mixture recycled by oxidation/reduction (1:2)

O O O O Li C5H11 6 CO2Et DHP 6 CO2Et 6 CO2H 6 CO2H 1. OEE + H CuI•Bu3P C5H11 C5H11 HO THPO HO HO 2. AcOH/H2O/THF HO HO 3. bakers yeast PGE1 (28%, 3 steps; 1:1 d.r.)

O

O C5H11 O resolution with C5H11 O C H (S)-α-phenylethylamine 10% NaOH 5 11 O O O 60 °C OH (±) then 1% NaOH, 25 °C HO2C HO2C

C5H11 1. DIBAL (3 equiv) I C5H11 OEt I C5H11 Li(s) Li C5H11

H+ OH 2. I2 OH OEE OEE

Sih, C. J. et al. J. Chem. Soc., Chem. Commun. 1972, 240–241. Sih, C. J. et al. J. Am. Chem. Soc. 1972, 94, 3643–3644. Fried, J. et al. Ann. N.Y. Acad. Sci. 1971, 180, 64. Synthetic Improvements - Propargyl Alcohol

(S)-MeO-BINAL-H C5H11 C5H11 THF, -100 → 78 °C Noyori, 1984 O OH (87% yield) 84% ee

Candida antarctica C5H11 lipase B C5H11 NaCN, MeOH C5H11 Johnson, 1993 OH , 25 ° C OAc (83% yield OH OAc after conv. to > 98% ee (40% yield) TBS ether)

TIPS catecholborane (1.2 equiv) TIPS

C5H11 C5H11 (S)-CH2TMS-CBS (5 mol%) Parker/Corey, 1996 CH2Cl2, -78 °C O 97% ee OH (98% yield)

i-Pr TMS Ts TMS Catalyst (0.5 mol%) Ph N C H Ru C5H11 5 11 Noyori, 1996 i-PrOH, 28 °C Ph N 97% ee H O OH (99% yield) Catalyst

OH N-methylephedrine (2.1 equiv) K CO (1 equiv) H C5H11 HO 2 3 C5H11 C5H11 Zn(OTf) (2.0 equiv), 23 °C 18-crown-6 (20-40 mol%) O 2 OBz then BzCl OBz 98% ee (91% yield) (78% yield) Carreira, 2000 Noyori, R. et al. J. Am. Chem. Soc. 1984, 106, 6717–6725. Johnson, C. R. Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014–11015. CBS application: (a) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214–3217. (b) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118, 10938–10939. Noyori, R. et al. J. Am. Chem Soc. 1997, 119, 8738–8739. Stoichiometric: Carreira, E. M. et al. Org. Lett. 2000, 2, 4233–4236. Catalytic Enantioselective: Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688. Synthetic Improvements - Cyclopentenone

HO immobilized AcO 1. TBSCl, imidazole, DMF O O Candida antarctica 2. NaCN, MeOH I Lipase B 3. PDC, CH2Cl2 I2 (1.8 equiv)

(97% yield) pyridine/CCl4 (3:2) , 50°C, 72 h HO OAc HO TBSO (93% yield) TBSO (48% yield) (–), > 99% ee (+ 43% diacetate)

O O BBN-(CH2)6CO2Me CO2Me 6 CO2Me PdCl2(dppf) Ph3As, Cs2CO3 DMF/THF/H2O, 25 °C TBSO HO OH PGE1 (70–80% yield) HO

CH3CO3H AcOH (1 equiv) Ac2O (1.1 equiv)

Na CO Pd(Ph P) (0.2 mol%) imidazole (1.1 equiv) 2 3 O 3 4 THF, 0 °C DCM, 0 °C → r.t. (62% yield) AcO (72–76% yield) (96–98% yield)

AcO Electric HO Eel Acetyl cholinesterase

(86–87% yield) H OHC H AcO AcO H O 96% ee

Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287–7290. H Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014–11015. Deardorff, D. R.; Myles, D. C. Org. Synth., Coll. Vol. VIII 1993, 13–17. Variecolin Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth., Coll Vol. IX 1998, 487–497 Krout, M. R. Stoltz Group Research Seminar. June 11, 2007. Three Component Coupling: Challenges to Overcome

Electrophile must be compatible with nascent enolate

O Li C5H11 O [M]

OR X no reaction

Cu C5H11 X = Br or I

RO

R = –OC(CH3)2OMe

TMSO O

3 TMS-Cl Li, NH3 CO2Me

C5H11 C5H11 Br 3 CO2Me RO RO

Enolate Isomerization & β-elimination must be avoided

O [Cu] C5H11 O O

OR then C5H11 C5H11 TBSO TBSO I , HMPA RO RO

Patterson, J. W.; Fried, J. H. J. Org. Chem. 1979, 39, 2506–2509 Davis, R.; Untch, K. G. J. Org. Chem. 1979, 44, 3755–3759 Noyori, R.; Suzuki, M. Angew. Chem. Int. Ed. Engl. 1984, 23, 847–876. Stork PGF2α Synthesis via 3 component coupling - 1975

AcO O I C5H11 OH Ph O 1) KOH, MeOH OBOM

AcOH, Cu(OAc)2 2) Jones Oxidation t-BuLi, then FeSO4, H2O O O CuI•PBu3, then (48% yield, 3 steps) formaldehyde Ph Ph (50-60% yield)

O O OH 1. I 1) MsCl, pyr 4 OEE C5H11 C5H11 2) Hunig's Base t-BuLi, then O OBOM O OBOM CuI•PBu3 (80% yield) 2. AcOH, H2O Ph Ph 3. Jones Oxidation 1.3:1 d.r. at C(11) (78% yield)

O HO H 1) Li(s-Bu) BH CO2H 3 CO2H Me C5H11 2) Na, NH3(l) H O OBOM HO OH Ph PGF2α

Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 4745–4746. Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 6260–6261. Stockdill, J. Stoltz Group Literature Seminar, January 29, 2007. Noyori 3-Component Synthesis: 1982–1984

O I C5H11 O O OH OHC CO2Me [M] (1 equiv) OTBS 7 CO2Me C H C H t-BuLi (2 equiv) 5 11 BF3•OEt (1 equiv) 5 11 CuI (1 equiv) Et2O, -78 °C, 30 min TBSO TBSO TBSO Bu3P (2.6 equiv) OTBS OTBS THF, -78 °C, 1 h (83% yield) 1:1 epimers at C(7)

S O O Ph Cl , DMAP 1. 1. H2, 5% Pd/BaSO4 (71% yield) CO2Me quinoline CO2Me C H C H 2. Bu3SnH, t-BuO–Ot-Bu 5 11 PhH / cyclohexane, 87% yield 5 11 Δ TBSO HO (98% yield) OTBS 2. HF/pyr, 98% yield OH

PGE2 Methyl Ester

Requires a two-step deoxygenation:

A method for direct alkylation would be preferable for maximum efficiency

Limited Electrophile Choice - Alter enolate?

Review: Noyori, R.; Suzuki, M. Angew. Chem. Int. Ed. Engl. 1984, 23, 847–876. Suzuki, M.; Noyori, R. et al. Tetrahedron Lett. 1982, 23, 4057–4060. Suzuki, M.; Kawagishi, T.; Noyori, R. Tetrahedron Lett. 1982, 23, 5563–5566. Noyori 3-Component Synthesis: 1982–1989

O I C5H11 O O HMPA (11 equiv, 30 min) [M] Ph SnCl (1 equiv, 10 min) OTBS 3 CO2Me t-BuLi (2 equiv) C5H11 C5H11 I CO2Me CuI (1 equiv) TBSO TBSO (5 equiv) TBSO Bu3P (2.6 equiv) OTBS OTBS THF, -78 °C, 1 h -30 to -20 °C, 17 h alkyl: 20% yield Transmetallation to tin enolate was the solution! allyl: 78% yield Limits enolate isomerization, allows warmer temperatures propargyl: 82% yield

O I C5H11 O O I CO2Me [M] (5 equiv) OTBS CO2Me n-BuLi (1 equiv) C5H11 HMPA (10 equiv) C5H11 Me Zn (1 equiv) -78 to -40 °C, 24 h TBSO 2 TBSO TBSO THF, -78 °C, 1 h OTBS OTBS (71% yield)

Tin/Phosphine free conditions disclosed in 1989 CO2Me O HO

CO2Me DIBAL-H CO2Me 1. Hg(CF3COO)2

C5H11 C5H11 O 2. NaBH4 TBSO OTBS TBSO OTBS

C5H11 PGE1 & PGE2 PGF2α & PGF1α TBSO OTBS Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 107, 3348–3349. Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989, 54, 1785–1787. PGI2 Tin enolates: a) Tardella, P. A. Tetrahedron Lett. 1969, 14, 1117–1120. b) Nishiyama, H.; Sakuta, K.; Itoh, L. Tetrahedron Lett. 1984, 25, 223–226. c) ibid. pp 2487–2488 Review on Multicomponent Couplings: Tourée, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486. Catalytic Asymmetric α-alkylation of Sn-enolates to form 4° stereocenters: Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62–63. Recent Applications

Recent Applications: (–)-incarvillateine & (±)-Garsubellin A

Bu3Sn O O O H PdCl(MeCN)2 OTBS Et3N, HCO2H NTs Ts O n-BuLi, Me2Zn N MeCN, r.t. THF, -78 °C I H TBSO then MeI, HMPA TBSO OTBS (72% yield) (77% yield) OMe MeN H Me OH O MeO O Me H NMe Me H O HO O O H Me H Me O HO Me H NMe (+)-incarvine C OMe

(+)-incarvillateine C

O O OH O O H O O NaOAc CH3MgBr O O O CuI (22 mol%) 200 °C O O then OHC Me (96% yield) O MOMO Me MOMO (61% yield)

O O O O Hoveyda-Grubbs II (20 mol%) O O O HO O (92% yield) O MOMO

(±)-Garsubellin A Review on Multicomponent Reactions in Synthesis: Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486. Kibayashi, C. et al. J. Am. Chem. Soc. 2004, 126, 16553–16558. Shibasaki, M. et al. J. Am. Chem. Soc. 2005, 127, 14200–14201. Feringa Catalytic Enantioselective 3 Component Coupling - 2001

Ph Ph Me Ph Ph O Ph P N O Zn Me CO2Me O 2 Ph (6 mol%) O H O O CO2Me Zn(BH4)2 Cu(OTf)2 (3 mol%) H PhMe, -40 °C, 18h Et2O, -30 °C, 3h H O O SiMe Ph O (38% yield, two steps) 2 OH SiMe2Ph ~5:1 d.r. (C13) Ph Ph Ph Ph

1. TBAF (3 equiv) O H O H Pd(CH3CN)2Cl2 (5 mol%) O CO2Me O CO2Me methylpropionate THF, 3h DMSO, 80 °C, 20 min (63% yield) Ac O, DMAP, pyr, 20 min HO H 2. 2 AcO H OH SiMe2Ph OAc (71% yield, two steps) 94% ee

Ph Ph Ph Ph

O H O H O H O CO2Me K2CO3 O CO2Me CAN (cat.) CO2Me

MeOH, 18h buffer (pH=8) 60 °C, 2 h AcO H (90% yield) HO H HO H OAc OH (45% yield) OH

PGE1 Methyl Ester Vinylic Zn reagents were not compatible with 3CC

Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841–5842. Full Paper: Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244–7254. Allylic Transposition: Grieco, P. A. et al. J. Am. Chem. Soc. 1980, 102, 7587–7588. Summary

Synthetic testing ground for new methods:

O O

O O BH3•THF (0.6 equiv) Corey–Bakshi-Shibata (R)-Me-CBS (10 mol%) C H Catalytic Enantioselective Reduction of Ketones C5H11 THF, 23 °C, 2 min 5 12 PBO PBO O OH 9:1 α : β

O O O I I2 (1.8 equiv) BBN-(CH2)6CO2Me 6 CO2Me

Direct α-iodination of enones pyridine/CCl4 (3:2) PdCl2(dppf) TBSO TBSO Ph3As, Cs2CO3 TBSO (93% yield) DMF/THF/H2O, 25 °C

(70–80% yield)

Inspiration for new synthetic methods:

Ph Ph

OBn BnO O O F3CO2SN NSO2CF3 Al (10 mol%) N O O Me Catalytic Enantioselective Diels–Alder Reaction CH Cl , -78 °C O N 2 2 O (93% yield, > 95% ee)

I O I C5H11 O O CO2Me [M] (5 equiv) Tandem conjugate OTBS CO2Me addition/aldol reaction n-BuLi (1 equiv) C5H11 HMPA (10 equiv) C5H11 -78 to -40 °C, 24 h TBSO Me2Zn (1 equiv) TBSO TBSO THF, -78 °C, 1 h OTBS OTBS (71% yield) Useful References

Bindra, J. S. and Bindra, R., Prostaglandin Synthesis; Academic Press: New York, 1977.

Historical Background, Incl. Degradation Studies, Detailed breakdown of synthetic strategies through 1977

Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533–1564 Das, S.; Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286–3337

Reviews of new synthetic approaches to prostaglandins & analogues.

Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996

Detailed descriptions of Corey's bicycloheptane route & Stork's enantiospecific routes

Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304.

Overview of Mechanism of PG synthesis, including some isotopic studies, and later biochemical work.

Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876–889. Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007–1019. Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. Corey, E. J. Angew. Chem. Int. Ed. 2009, 48, 2100–2117.

Various enantioselective Diels-Alder reviews

Noyori, R.; Suzuki, M. Angew. Chem. Int. Ed. Engl. 1984, 23, 847–876.

Account of 3 component coupling development (does not include most recent advances, i.e. tin and tin free alkylations)

Caton, M. P. L. Tetrahedron 1979, 35, 2705–2742. Noyori, R.; Suzuki, M. Angew. Chem. Int. Ed. Engl. 1984, 23, 847–876.

Describe new synthetic methodologies which arose as a result of prostaglandin research Extra slides! Prostaglandin Biosynthesis

dihomo-γ-linolenic acid PGE1 homogenized O H 14CO H 14 sheep vesicular 2 CO2 14 glands MgBr CO2H Me Me Me H HO OH

• Characterized by TLC, observation of radioactivity on product band • First demonstration of biosynthesis of PGs from polyunsaturated fatty acids

O H * CO2H CO2H Cyclooxygenase-1 3H H * 3H labelled substrate mixed with 14C Me Me labelled substrate, then incubated H with enzyme HO H OH 3-fold 3H enrichment after 3 75% conversion 0.05% retention of H label

O H * CO2H CO2H H 3H * • pro-(S) hydrogen is selectively removed Me Me • KIE consistent with H abstraction preceeding reaction with oxygen H HO 3H OH No 3H enrichment in partially converted material 89% retention of 3H label

Review on fatty acid oxygenation: Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304. Labelling studies: Van Dorp, D. A. et al. Nature 1964, 203, 839–841. Hamberg, M.; Samuelsson, B. J. Biol. Chem. 1967, 242, 5336–5343. Prostaglandin Biosynthesis

HO H MeO H 18 16 CO Et CO H O2 + O2 2 2 6 CO2Et Me vesicular gland Me CO2Et H H HO OH MeO then NaBH4 EtOH, 0 °C

• Reduction of ketone to prevent O label exchange • Conversion to diethyl ester in order to distinguish losses in MS

18 16 18 16 Me O H Me O H Me O H Me O H

6 CO2Et 6 CO2Et 6 CO2Et 6 CO2Et

CO2Et CO2Et CO2Et CO2Et H H H H Me18O Me16O Me16O Me18O observed not observed

• Both oxygen atoms on cyclopentane are derived from the same oxygen molecule

HO H O H CO2H CO2H CO2H pig lung tissue Me Me Me H H HO OH HO OH

PGF2α PGE2

• Labelled PGE2 is not converted to PGF2α under reaction conditions: Derived from common intermediate

Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304. Hamberg, M.; Samuelsson, B. J. Biol. Chem. 1967, 242, 5329–5335. Prostaglandin Biosynthesis

H H 14 sheep vesicular CO2H glands O CO2H O CO2H O Me O Me Me 30 seconds H H OH O OH

PGH2 PGG2 • Short reaction time allows for isolation of endoperoxide intermediates • Stable for weeks in anhydrous Et2O or Acetone at -20 °C. Decomposes rapidly in presence of H2O or EtOH

Structural confirmation:

HO H

CO2H Me SnCl SnCl2 2 H HO OH

H HO H H O CO H Pb(OAc) O CO H 2 CO2H 4 2 O Me Me O Me then PPh H H 3 H OH HO O O OH PGH2 PGG2 buffer O H buffer O H CO2H SnCl 2 CO H Me 2 Me H HO OH H HO O OH

Rouzer, C. A.; Marnett, L. J. Chem. Rev. 2003, 103, 2239–2304. Hamberg, M.; Svensson, J.; Wakabaya, T.; Samuelsson, B. P. Natl. Acad. Sci. USA 1974, 71, 345-349. HO

Stork Enantiospecific Route From Glucose – 1978 CO2H Me

HO OH

PGF2α

OH OH 1. NaBH , H O OH H 4 2 H NaBH4 O HCN pH 3–3.5 O O O OH MeOH, 10 °C HO HO HO O OH OH 2. Acetone, O Ac2O, pyr OH cat. H2SO4 CHCl3, -7 °C α-D-glucose HO OH O O (68% yield overall)

NMe2 Me Me Me MeO OMe Me OH O O O O

O H NMe2 OAc Ac2O O O O Δ O OH Δ O O O O O Me OAc (40% yield) Me OAc Me Me Me Me Me Me

Me Me O OH CuSO4, MeOH, H2O 1. "base" O reflux O O O O 2. MeO2CCl, acetone, H SO pyr., 0 °C O 2 4 O O Me O OMe 25 °C Me Me Me O (54% yield, 4 steps)

Stork, G. et al. J. Am. Chem. Soc. 1978, 100, 8272–8273. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1966: pp 144–151. HO

Stork Enantiospecific Route From Glucose – 1978 CO2H Me

HO OH

PGF2α

MeO2C OH MeO OMe Me Me OMe O O Me O O O O O O O CH3CH2CO2H O O O O Me OMe H Me Me O (80% yield) Me O

O MeO2C 1. n-Bu2CuLi (10 equiv) O + 1. NaOMe Et2O, -40°C ethyl vinyl ether, H C5H11 O OTs 2. p-TsCl, pyr. 2. H2SO4(aq), LHMDS, THF, -78°C O OEE THF, 25 °C HO OH 3. ethyl vinyl ether Me then + H Me Br 4 OTBDPS (35% yield, 5 steps) THF/HMPA, -40→ -20 °C

(71% yield)

O OH OTBDPS 1. DIBAL OTBDPS 2. HCN, EtOH NC O 3. 50% AcOH, THF, 35 °C 4. p-TsCl, pyr. TsO EEO OEE OH OH (37% yield)

Stork, G. et al. J. Am. Chem. Soc. 1978, 100, 8272–8273. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1966: pp 144–151. HO

Stork Enantiospecific Route From Glucose – 1978 CO2H Me

HO OH

PGF2α

CN OEE EEO OTBDPS OTBDPS 1. F-, THF NC KHMDS 2. CrO3•2pyr PhH, reflux TsO 3. AgNO3, H2O, EtOH, KOH OEE OEE EEO OEE (72% yield) (83% overall yield)

CN CN EEO HO AcOH CO2H CO2H L-Selectride THF, 40 °C THF, -78 °C

EEO OEE HO OH (73% yield, two steps)

HO

CO2H

Stork's synthesis demonstrates synthetic utility of new technologies: HO OH • Umpolung acyl anion chemistry PGF 2α • Johnson–Claisen rearrangement

Stork, G. et al. J. Am. Chem. Soc. 1978, 100, 8272–8273. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1966: pp 144–151. Acyl Anion alkylation via cyanohydrin: Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286–5287 Overview of acyl anion equivalents: http://www.chem.wisc.edu/areas/reich/chem547/5-orgmet%7B06%7D.htm Vinyl Cyclopropane Rearrangement Route - Wulff, 1990

+ I O- NBu4 OAc (OC) Cr (OC) Cr t-BuLi (2 equiv) 5 AcBr (1 equiv) 5 C H 5 11 Et2O, -78 → 0 °C, 2h DCM, -40 °C, 1 h PMBO then Cr(CO)6 (1.4 equiv) C H C H then TBAF 5 11 5 11 PMBO PMBO

filtered

OTBS TBSO OAc AcO (10 equiv) n-BuLi (2 equiv)

-40 °C, 42h Bu2O, 190 °C, 2h C5H11 HMPA C5H11 (38% yield) (85% yield) TBSO OPMB Ph3SnCl PMBO then

I CO2Me

O O DDQ (1.5 equiv) CO2Me CO2Me C H C H 5 11 CH2Cl2/H2O, 10 °C, 1h, 80% yield 5 11

TBSO OPMB HF/pyr, MeCN, 0 → 25 °C, 15 h HO OH 86% yield

PGE2 Methyl ester & C15 epimer

First natural product synthesis employing a Fischer Carbene as a key intermediate

Murray, C. K.; Yang, D. C.; Wulff, W. D. J. Am. Chem. Soc. 1990, 112, 5660–5662.