Synthesis of the Steroidal Natural Product Ouabainand Aglycone Ouabagenin

OHHO

O OO O

and Aglycone Ouabagenin

HOOH

HO

HO

H

OH

OH

HOOH

HO

HO

H

OHOH

OHOHO

OH

OOH

Ouabain Ouabagenin

Matt HaleyFebruary 20 2008February 20, 2008

Background

HOOHHO

H

O O

HOOHHO

O O

HO

OH

OHOHO

HO

HO

HO

H

OH

OH

‐isolated from the African ouabio tree

OH

Ouabain Ouabagenin

isolated from the African ouabio tree  (Acokanthera ouabio) in 1888 by Arnaud‐cardiac glycoside elicits effect by binding to myocardial Na+, K+‐ATPase (responsible for regulating intracellularNa , K ATPase (responsible for regulating intracellularNa+ transport‐used in Africa to make poison arrows‐unique steroid structure:q

‐sugar at the 3β position‐β butenolide ring at C17Acokanthera oblongifolia

Synthetic Efforts to Date

‐completed total synthesis of ouabain and ouabagenin reported by Deslongchamps in 2008

‐completed tetracyclic core reported by Overman in 1998

t di t d AB bi li f t t d b J i 2003‐studies towards AB bicyclic fragment reported by Jung in 2003

Deslongchamps’ Retrosynthetic AnalysisO

OR''

PGO

R''

OOPG

E

OPG

OOPGPGO

Haldol

Michael addition

R3Si

E

OO

O

OO

HR3Si

H

E

CO2R'O

HR3Si

H

OH

H

+

Wittig

ROMichael addition

R''PGOPGO

OOR'''

O

O

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

Synthesis of Cyclic Enone

O

( S )

O

LiAl(t B O) H

OH

(Me2PhSi)Et2ZnLi

96%PhMe2Si

(±)

LiAl(t-BuO)3H

THF, -60 °C, 16h99% >14:1

PhMe2Si(±)

Amino Lipase PS powder

i-Pr2O, 60 °C, 23 h

OH

PhMe2Si

O 1) i. KHii. HCO2Et

2) PhSeCl, pyr

O O

2 , , PhMe2Si

OR

48% PDC

93%

PhMe2Si

O

3) H2O2, CH2Cl274% 3 steps

PhMe2Si

PhMe2Si

50%

R = AcMeO-

PhMe2Si

R = HMeO99%

Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 811Trudeau, S.; Deslongshamps, P. J. Org. Chem. 2004, 69, 832

Synthesis of Cyclic Enone

O 1. NaBH4, 94% CN O 1. NaBH4, 96%

O

O2. TsCl, pyr, 93%3. NaCN, DMSO, 85%

O

CN 1. (CH2OH)2, pTSA, 95%2. DIBAL-H, 91%

O

O

O 2. 1 M HCl, acetone, 95%3. TBDPSCl, imid, DMF, 99%

AcOAcOOTBDPS Pb(OAc)4

88%+

OTBDPSOTBDPS 1. NaIO4, RuCl3, 80%2. EtSH, DCC, DMAP, 81%

O OO

88%1 : 8.3

OTBDPS 1 Et3SiH Pd(OAc)2AcO

OTBDPS

AcO

OOEtS

1. Et3SiH, Pd(OAc)2,acetone, sieves

2. HPh3P

EtO

OO

OO

O O3. 80% AcOH (aq)

68% 3 steps

O

Yang, Z.; Shannon, D.; Truong, V‐L.; Deslongshamps, P. Org. Lett. 2002, 4, 4693

Synthesis of Ouabagenin

AcOOTBDPS

O

O O1. Cs2CO3, 85%

OTBDPS

+

O

O OAc1. Li(Et3CO)3AlH, 89%2. PMBOC(NH)CCl3, La(OTf)3, 83%

OH

OO

PhMe2Si2. [Pd(PPh3)4],morpholine, 92%

+OO

HPhMe2Si

H

OTBDPS

OOAcPMBO

KHMDS, 83%

OTBDPS

OOAcPMBO

H1. K2CO3, THF, MeOH, 98%2. NaBH4, 97%

OO

HPhMe2Si O

HPhMe2Si

OH

H H

OTBDPSOHPMBO OTBDPS

OO

PMP

O

HO

HPhMe2Si

H

OH

H

DDQ, 84%

O

O

HPhMe2Si

H

OH

H

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

Synthesis of Ouabagenin

O S

PMPPMP

OTBDPS

O

OO

HPhMe Si

O

H

OH

1. TBSOTf, NEt3, 90%2. DDQ, 2,6-di-tert -butyl-4-methylpyridine, 100%

OTBDPS

OO

H

O

H

OHOPhMe2SiOPhMe2SiH

1. NaBH4, 96%2 mCPBA NaHCO3 85%

OTBDPS

OOO

PMP

1. MsCl, pyr, 98%OTBDPS

OOHHO

PMP

O

2. mCPBA, NaHCO3, 85% O

HPhMe2Si

H

OHOH

O

2. i. LiBH4, DME, rt, 24 hii. reflux 8 hiii. silica

58%

O

HPhMe2Si

H

OH

OH

PMP

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

Synthesis of Ouabagenin

OTBDPS

OOHHO

HPMP

O

1. Ac2O, pyr, DMAP, 90%2 TBAF 88%

OH

OOHAcO

HPMP

O

Hg(OAc)2, AcOH:AcOOH (1:1), 93%

HPhMe2Si

OH

OH

2. TBAF, 88%

HPhMe2Si

OH

OH

g( )2, ( ),

OH

OOH

H

AcO

H

OH

PMP

O

HHO

OH

OH

dTamao oxidation:

Hg(OAc)2

R RM

R RRhydrolysis

Si

PhHgOAc

R 1

Me

MeSi R 1

Me

O MeO

Si R 1

Me

Me OO O

R 1OSi

O

O

Me

MeR 1

R

HO

hydrolysis

O OH

O

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272Jones, G. R. Tetrahedron, 1996, 52, 7599

Synthesis of Ouabagenin

OH

OOHAcO

HPMP

O1. TBDPSCl, imid, 75%2. Ac2O, pyr, DMAP, 65%

OTBDPS

OOAcAcO

HPMP

O

HHO

OH

OH

HAcO

OH

OH

OTBDPS

OOAcAcO

HPMP

O

1. TBAF, 90%2 DMP 75%

O

OOAcAcO

HPMP

O[(PPh3)3RhCl], PPh3,iPrOH, TMSCHN2, 67% O

OAcAcO

HPMP

O

HAcO

H

OH

OH

2. DMP, 75%

HAcO

H

OH

OH

iPrOH, TMSCHN2, 67%

HAcO

H

OH

OH

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

Rhodium Catalyzed Methylenation

NN

Rh(I)TMS H

NN

i-PrOH

TMS H

ClRh(PPh3)3

PPh

N2

TMS H

NN

Rh(I)

H

i-PrO-

PPh

TMS H

PPh3

H

i-PrO-

PPh3

PPh3i PrOTMS+

HHi-PrOTMS+

Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320

B

Synthesis of Ouabagenin

OOAcAcO

HPMP

O

1. OsO4, NMO, 95:5, 82%2 nBu SnO benzene reflux

OOAcAcO

HPMP

OOSn

O

nBunBu

NBS CHClH

AcOOH

OH

2. nBu2SnO, benzene, reflux

HHO

H

OH

OH

NBS, CHCl3

73% 2 steps

OOAcAcO

HPMP

OOH

O

Ph3PCCO, TEA, 68%O

OAcAcOPMP

O

O O

0.5 N Na2CO3, MeOH, 85%H

HOOH

OH

O

HHO

H

OH

OH

PMP 2 3, ,

HOOHHO

O O

HO

HHO

H

OH

OHouabageninouabagenin

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 127241 steps

Synthesis of Ouabain

OHOHO

OH

OHBzCl, pyr, DMAP, 82%

OBzOBzO

OBz

OBz1. AcBr, MeOH2. Ag2CO3, acetone, 58% 2 steps OBzO

BzOOBz

OHK2CO3, Cl3CCN

68%

OBzO

O Cl3

NH

O OO O

BzOOBz

O O

+

TMSOTf, 4 Å M.S.

90% OOAc

H

O

H

OH

O

1. 2 N HCl, MeOH, 92%2. 0.5 N Na2CO3, MeOH 88% HO

OH

HO

HO

H

OH

OOAc

H

O

H

OH

O O HO

OH

OHOBzO

BzOOBz

OOH

OHOHO

OHouabain47 steps

OHHO

O OO O

HHO

OH

OH

HOOH

HHO

HO

H

OH

OH

conc. HCl, acetone, 80%O

OH

H

O

H

OH

1. Ac2O, pyr, DMF, DMAP, 78%2. 0.5 N Na2CO3, MeOH, 70%

OHHOOH

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

C13 of Synthetic Sample of Ouabain

Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem. Int. Ed. 2008, 47, 1272

Overman Synthetic Efforts

Intramolecular Heck Approach:

R RORLnPd

RO

OR

R

OR

R

RO

OR

OR

RO

OR

X

OR

OR

Overman, L. E.; et al. J. Org. Chem. 1996, 61, 6760

Overman Synthetic Efforts

O 1. NaBH4 OTMS

1. Et2NLi, HMPA2.

OI

OH

O

2. Me2NNH23. TMS-imidazole

85% NNMe2

3. AcOH, THF, H2O, NaOAc90%

O O

O

OO

1 MsCl pyr O

CN

1. NaBH4, CeCl3•7H2O, MeOH2. VO(acac)2, t-BuO2H

CN

1. MsCl, pyr2. KCN, 18-C-6, DMSO

O

O

O

( )2, 23. TPAP, NMO

68%

O

O

O

O80%

i. SmI2ii. TMS-imidazole; H2O TMSO

CN

OHO

CN

OHTBAF

2

O

O

OH80%

O

O

OH

Rucker, P. V; Overman, L. E. Tetrahedron Let. 1998, 39, 4643

Overman Synthetic Efforts

CN

O

CNCN

KHMDS, PhN(Tf)2TfO

O

O

OH Pd(dppb), KOAc, DMA

90%80%OH

O

OO

O

O

OH

CN

(CF CO) O AcOH

CN

AcO1. SeO2, 1,4-dioxane, 80 °C2 DMP 72% (2 steps)

CN

AcO

OTMS

O

O

(CF3CO)2O, AcOH

70% OTMS

OH

cO 2. DMP, 72% (2 steps)

OTMS

OHO

OHHO

O O

HOOH

HHO

HO

H

OH

OHOH

OuabageninRucker, P. V; Overman, L. E. Tetrahedron Let. 1998, 39, 4643Rucker, P. V; Overman, L. E. Heterocycles 2000, 52, 1297

Jung Synthetic Efforts

Robinson Annulation Approach:

+ EtO

O

RORO

Robinson Annulation Approach:

OMe+ EtO

ORO

HO

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

Jung Synthetic EffortsFirst Attempt:

Me2PhSi

O

O

MeO2C

+Na, MeOH

41%, d.r. 6:1O

Co2MePhMe2Si Hg(TFA)2, AcOH,

TFA, AcOOH

79%

Co2MeOH 1. TBSCl, imid. 85%

2. NaBH4, CeCl3,MeOH, 98%

Co2MeTBSO

mCPBACo2Me

TBSOPCC

O

MeOH, 98%

HO HOO

96%

CO2MeTBSO

OO

Al foil, HgCl2, THFH2O, EtOH, NaHCO3

56% (2 steps)

CO2MeTBSO

OOH

(iBu)3AlCO2Me

TBSO

HOOH

95%

OH

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

Jung Synthetic EffortsMore Successful Approach:

EtO

O

KOtBu, EtOHCO2Et 1. TSBOTf

NE

small scale:OH

OMe+

EtO

O

KOtBu, EtOH

refluxO

NEt3

2. DIBAL51% 3 steps

O

(HOCH2)2, TsOH i. LiAlHii. H2SO437% 3 steps

CO2Et

Olarge scale:

O

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

Jung Synthetic Efforts

O

OHH2O2, NaOH, MeOH

O

OH

O

SeO2

O

OH

O

H2O2, NaHCO3

33% 3 steps O

OH

O

O

OH

Al foil, HgCl2

O

OH

OH

OH1. LiEt3BH

2. HC(OEt)3,MeOH;0 5% HCl

OO

O

H

OH

Ac2O, pyr

92% OO

O

H

OAc

0.5% HCl42% 3 steps

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

Jung Synthetic Efforts

2 C l l i

OH

MM2 Calculations:

OO

HO

-79.86 kcal/mol

O

OH

desired

3.77 kcal/mol

OO

O

H

-83.63kcal/molobservedobserved

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

Jung Synthetic Efforts

OH

changing step sequence:

O

OH

O

O1. Al foil, HgCl22. HC(OEt)3, PPTS

OO

OHi. NaBH4ii. Ac2O, pyr

25% 3 stepsO

O

O

H

OAc

O

use of boron chelate:1. Al foil, HgCl2

H

O

OH

O

O2. LiEt3BH3. HC(OEt)3, MeOH;

0.5% HCl

34% 3 stepsO

O

O

H

OH

OO

HO

OH

+ Ac2O, pyr

89%O

O

AcO

OH

O O

1.1 : 1

Al foil, HgCl2 ii. HC(OEt)3, MeOH;0.5% HCl

HOOH

H

HO

H

OHO

O

O

B

OH

O

OH

OH

OHi. LiEt3BH

Jung, M. E; Piizzi, G. Org. Let. 2003, 5, 137

HOOH

Ouabagenin

OH