Prostaglandin Nomenclature

HO
Letter refers to cyclopentane structure
CO2H
Me

O O O
HO OH
Rα Rα Rα e.g. 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
Rα Rα Rα e.g. 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

Fβ J PGI2: Prostacyclin
 Prostaglandin Nomenclature
HO

Number refers to degree of CO2H

unsaturation on side-chains. Me

HO OH
e.g. PGF2α

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

Rα = CO2H
CO2H
2: Me Me
Rω =
arachidonic acid
OH

Rα = CO2H CO2H
3:
Rω = Me Me
eicosapentaenoic acid
OH
 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.
 Prostaglandin Biosynthesis
R

HO HO
Rα Rα Rα
O 5 > pH > 8

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

O
O CO2H Rα
Rα
O
O
Rω
O Rω OH
HO
TxA2
PGH2 PGE2

5 > pH > 8

OH
O O O
Rα Rα Rα Rα

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 OH O O
HO
CO2H O O HO
Me

HO OH O OMe OMe
HWE reaction
PGF2α
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 MeO MeO
OMe
NaH, THF KOH mCPBA

MeOCH2Cl Cu(BF4)2, 0 °C Cl H2O/DMSO NaHCO3

THF, -55 °C CH2Cl2
(> 90% yield) CN O
(80% yield)
mixture of (> 95% yield)
diastereomers

MeO O O
HO
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
1. BBr3, CH2Cl2 O (MeO)2OP
O O
0 °C (> 90%) O Zn(BH4)2

2. CrO3•2pyr NaH, DME, 25 °C DME

CH2Cl2, 0 °C O C5H12 C5H12
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

O O CO2-
O Ph3P
1. K2CO3, MeOH DIBAL-H 3

2. DHP, TsOH, PhMe, -60 °C

C5H12 CH2Cl2 C5H12 C5H12

AcO OH THPO OTHP THPO OTHP

HO

AcOH, H2O, 37 °C CO2H

(> 90% yield)
HO
HO OH
CO2H PGF2α
1. H2Cr2O7, PhH/H2O
C5H12 2. AcOH, H2O, 37 °C
(70% yield, 2 steps) O
THPO OTHP
CO2H

HO OH
PGE2
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 BnO BnO
O
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

AlCl3
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 TiCl4 O2 EtAlCl2
O N
Ph
O 99% yield 75% yield
O
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
F3CO2SN NSO2CF3
NR2 BnO
O O
Al BnO
(10 mol%) O
N
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

HN O H
Br N
OBn
O TsN O H
Br B BnO
H (5 mol%)
H BnO O
O O CHO
CH2Cl2, -78 °C H 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
O
Me
(84% yield) 95% ee
10:1 cis:trans SiPh3

O O Evans, 1993
Catalyst (10 mol%)
O N O
O O
CH2Cl2, -78 °C, 18 h
O N
O N
(86% yield) N
Cu
98% ee t-Bu t-Bu
TfO OTf
98:2 endo:exo

O MacMillan, 2000
Catalyst (20 mol%)
H O
MeOH/H2O, 23 °C CHO NMe

(82% yield) 94% ee Bn

14:1 endo:exo N
H • HCl

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

(87% yield) N O NTf2

80% ee B
H
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
O OH
Catalyst
Me
TIPSO toluene
-78 °C, 2.5 h TIPSO
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 o-tol
ent-Catalyst

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

(–)-dendrobine
(Kende/Bentley, 1974)

H HO H OMe
H O
H
O
OH
H
H O H H Me
H O OH Me
O O H
O
(+)-hirsutene (–)-coriolin silphinene nicandrenone core
(+)-myrocin C (Mehta, 1986) (Stoltz/Corey, 2000)
(Mehta, 1986)
(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 Li Al
C5H11 C5H12 O (R) enantiomer
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

C5H11 THF, 23 °C, 2 min C5H12 N
B
Me
PBO PBO OH
O
(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
O CH2Cl2, -40 °C OH 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 [M] CO2H
O HO HO
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 [M] Me O X Me
Enolate Alkylation
or
OH Conjugate Addition OH
 Approaches by Conjugate Addition - Sih, 1972
O HO
Br CO2Et
6 6 CO2Et H2O2, NaOCl 6 CO2Et 6 CO2Et
Li
THF, r.t.

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

O O Li C5H11 O O

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
C5H11 O resolution with C5H11 O
C5H11 (S)-α-phenylethylamine 10% NaOH
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

2. I2 H+
OH 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 TBS ether)
(40% yield)

TIPS catecholborane (1.2 equiv) TIPS

C5H11 (S)-CH2TMS-CBS (5 mol%) C5H11 Parker/Corey, 1996
CH2Cl2, -78 °C
O 97% ee OH
(98% yield)
i-Pr
TMS Ph Ts
TMS Catalyst (0.5 mol%) N
C5H11 Ru
C5H11
N
Noyori, 1996
i-PrOH, 28 °C Ph H
97% ee OH
O
(99% yield) Catalyst

OH H C5H11 N-methylephedrine (2.1 equiv) K2CO3 (1 equiv) C5H11

HO
C5H11
Zn(OTf)2 (2.0 equiv), 23 °C 18-crown-6 (20-40 mol%)
O then BzCl OBz
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)

OAc
, 50°C, 72 h
HO 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)

Na2CO3 Pd(Ph3P)4 (0.2 mol%) imidazole (1.1 equiv)

O
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

TMS-Cl Li, NH3 3 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) MsCl, pyr 1. I 4 OEE
C5H11 C5H11
2) Hunig's Base t-BuLi, then
O OBOM O CuI•PBu3
OBOM
(80% yield) 2. AcOH, H2O
Ph Ph 3. Jones Oxidation
1.3:1 d.r. at C(11) (78% yield)

O HO H
CO2H 1) Li(s-Bu)3BH CO2H
C5H11 2) Na, NH3(l) Me
H
O HO OH
OBOM
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
OTBS [M] (1 equiv) 7 CO2Me

t-BuLi (2 equiv) C5H11 BF3•OEt (1 equiv) C5H11

CuI (1 equiv) Et2O, -78 °C, 30 min
TBSO TBSO OTBS TBSO OTBS
Bu3P (2.6 equiv)
THF, -78 °C, 1 h (83% yield)
1:1 epimers at C(7)

S
O O
1. Ph Cl , DMAP 1. H2, 5% Pd/BaSO4
(71% yield) CO2Me quinoline CO2Me
2. Bu3SnH, t-BuO–Ot-Bu C5H11 PhH / cyclohexane, 87% yield C5H11
Δ
(98% yield) TBSO OTBS HO OH
2. HF/pyr, 98% yield

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]
OTBS Ph3SnCl (1 equiv, 10 min) CO2Me

t-BuLi (2 equiv) C5H11 C5H11

I CO2Me
CuI (1 equiv) (5 equiv)
TBSO TBSO OTBS TBSO OTBS
Bu3P (2.6 equiv)
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

Me2Zn (1 equiv) -78 to -40 °C, 24 h
TBSO TBSO OTBS TBSO OTBS
THF, -78 °C, 1 h
(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: (–)-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
(+)-incarvine C H NMe
OMe

(+)-incarvillateine C

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

O O O O
Hoveyda-Grubbs II (20 mol%) HO O O
O
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 Ph
Ph O
Me Ph
P N
Zn O
Me
CO2Me
O 2 Ph
(6 mol%) OH
O O CO2Me Zn(BH4)2
Cu(OTf)2 (3 mol%)
H PhMe, -40 °C, 18h Et2O, -30 °C, 3h

O O H (38% yield, two steps)

O SiMe2Ph OH SiMe2Ph

~5:1 d.r. (C13)

Ph Ph
Ph Ph

OH 1. TBAF (3 equiv) OH Pd(CH3CN)2Cl2 (5 mol%)

O CO2Me O CO2Me
methylpropionate THF, 3h
DMSO, 80 °C, 20 min
(63% yield)
H 2. Ac2O, DMAP, pyr, 20 min H
HO OH SiMe2Ph AcO OAc
(71% yield, two steps)
94% ee

Ph Ph
Ph Ph

OH OH 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
C5H11
(R)-Me-CBS (10 mol%)
THF, 23 °C, 2 min C5H12 Catalytic Enantioselective Reduction of Ketones
PBO PBO OH
O
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 Me O Catalytic Enantioselective Diels–Alder Reaction
CH2Cl2, -78 °C O N
O
(93% yield, > 95% ee)

I C5H11 I
O O CO2Me O
[M] (5 equiv)
Tandem conjugate OTBS CO2Me
addition/aldol reaction n-BuLi (1 equiv) C5H11 HMPA (10 equiv) C5H11
Me2Zn (1 equiv) -78 to -40 °C, 24 h
TBSO TBSO OTBS TBSO OTBS
THF, -78 °C, 1 h
(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
14CO sheep vesicular 2H
2
14CO
glands
MgBr 2H 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
3H
CO2H Cyclooxygenase-1 3H
H * labelled substrate mixed with 14C
Me Me labelled substrate, then incubated
H with enzyme
HO H OH
3-fold 3H
enrichment after
75% conversion 0.05% retention of 3H label

O H
* CO2H
3H
CO2H
H * • 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
18O 16O CO2Et
CO2H 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

Me18O H Me16O H Me18O H Me16O 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
14CO sheep vesicular
2H
glands O CO2H O CO2H

30 seconds O Me O Me
Me
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
SnCl2 Me SnCl2
H
HO OH

H HO H H
O CO2H CO2H Pb(OAc)4 O CO2H
O Me Me O Me
H then PPh3 H
H
OH HO O O
OH
PGH2
PGG2
buffer O H buffer
O H
CO2H SnCl2
CO2H
Me
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.
 Stork Enantiospecific Route From Glucose – 1978
HO

CO2H
Me

HO OH

PGF2α

OH
OH 1. NaBH4, H2O OH NaBH4
H H
O HCN O pH 3–3.5 O MeOH, 10 °C
HO O OH
HO O
HO
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 Δ O
O OH Δ O
OAc O O O O OAc
Me (40% yield) Me
Me Me
Me Me Me Me

Me
Me
O CuSO4, MeOH, H2O OH
1. "base" O reflux
O O O O
2. MeO2CCl, acetone, H2SO4
pyr., 0 °C O 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.
 Stork Enantiospecific Route From Glucose – 1978
HO

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)
1. NaOMe Et2O, -40°C O 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.
 Stork Enantiospecific Route From Glucose – 1978
HO

CO2H
Me

HO OH

PGF2α

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

CN CN
EEO HO
CO2H AcOH 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
PGF2α
• 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)5Cr (OC)5Cr
t-BuLi (2 equiv) AcBr (1 equiv)
C5H11 Et2O, -78 → 0 °C, 2h DCM, -40 °C, 1 h
PMBO then Cr(CO)6 (1.4 equiv) C5H11 C5H11
then TBAF
PMBO PMBO

filtered

OTBS TBSO OAc AcO

(10 equiv)
n-BuLi (2 equiv)
-40 °C, 42h Bu2O, 190 °C, 2h C5H11
HMPA
C5H11 Ph3SnCl
(38% yield) (85% yield) TBSO OPMB
PMBO then
I CO2Me

O O

CO2Me DDQ (1.5 equiv) CO2Me

C5H11 CH2Cl2/H2O, 10 °C, 1h, 80% yield C5H11

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.