formal asymmetric synthesis of echinopine a and bccc.chem.pitt.edu/wipf/current...

Filip Petronijevic Current Literature Presentation February, 26th 2011.

Formal Asymmetric Synthesis of Echinopine A and B

Peixoto, P. A.; Severin, R.; Tseng, C.-C.; Chen, D. Y. –K. Angew. Chem. Int. Ed. 2011, Early view.

Filip Petronijevic @ Wipf Group Page 1 of 14 2/28/2011

Echinopines A and B: Sesquiterpenoids Possessing an Unprecedented Skeleton

(a) Dong, M.; Cong, B.; Yu, -H.S.; Sauriol F.; Huo, C. –H.; Shi, Q. –W.; Gu, Y. –C.; Zamir, L.O.; Kiyota, H. Org. Lett. 2008, 10, 701. (b) http://www.metafro.be/prelude/view_plant?pi=05205.

Echinops spinosus!

H

O

OR

R = H, Echinopinoic acid = Echinopine AR = CH3, Echinopine B

1

23

45

6

78

910

11 12

1314

15

H

H

H4

13

O

RO

12

35

6

7

8

910

1112

14

15

• unique 3,5,5,7-framework!

• structure elucidated by spectroscopic analysis!

• 7-membered ring adopts a (flat) chair form!

Filip Petronijevic @ Wipf Group Page 2 of 14 2/28/2011

Part 1: How Does Nature Make Echinopines A and B?

(a) A. A. Newman, Chemistry of Terpens and Terpenoids, Academic Press, London and New York, 1970. (b) Rohdich, F.; Kis, K.; Bacher, A.; Eisenreich, W. Curr. Opin. Chem. Biol. 2001, 5, 535. (c) Kraker, J.; Franssen, M.C.; Dalm, M. C.; Groot, A.; Bouwmeester, H.J. Plant Physiol. 2001, 125, 1930. (d) drew, D. P.; Krichau, N.; Reichwald, K.; Simonsen, H. T. Phytochem Rev 2009, 8, 581.

O

-O

O

SCoA

O

SCoA

O

Thiolase

Ac-CoA CoASH

Acetoacetyl-CoA

Ac-CoA

Acetyl-CoA

O

SCoA

HO CH3CoASH

HMG-CoA Synthase

Hydroxymethylglutaryl-CoA(HMG-CoA)

2 NADPH + 2 H+

2 NADP+, CoASH

OH

HO CH3O

-O

3R-Mevalonate

HMG-CoA Reductase

Mevalonate kinasePhosphomevalonate kinase

2 ATP2 ADP

O

HO CH3O

-O P O P O-O-

O- O-

O-

5-Pyrophosphomevalonate

O P O P O-O-

O- O-

O-

ATP

ADP + Pi + CO2

Pyrophosphomevalonatedecarboxylase

Isopentenyl pyrophosphate(IPP, C5 - unit)

O P O P O-O-

O- O-

O-

Dimethylallyl pyrophosphate(DMAPP, C5 - unit)

Isopentenyl pyrophosphateisomerase (2 IPP + DMAPP)

2 PPi

OPP

Farnesyl pyrophosphate(FPP)

Germacrene A

H

Sesquiterpenesynthase

12-GermacratrienolOH

O2, NADPH + H+ NADP+, H2O

Germacrene A hydroxylase

CO2H

Germacratrienoic acid

2 NADPH + 2 H+

2 NADP+

Germacratrienoldehydrogenase

Farnesyldiphosphate

synthase

Filip Petronijevic @ Wipf Group Page 3 of 14 2/28/2011

Part 2: How Does Nature Make Echinopines A and B?

(a) A. A. Newman, Chemistry of Terpens and Terpenoids, Academic Press, London and New York, 1970. (b) Rohdich, F.; Kis, K.; Bacher, A.; Eisenreich, W. Curr. Opin. Chem. Biol. 2001, 5, 535. (c) Kraker, J.; Franssen, M.C.; Dalm, M. C.; Groot, A.; Bouwmeester, H.J. Plant Physiol. 2001, 125, 1930. (d) drew, D. P.; Krichau, N.; Reichwald, K.; Simonsen, H. T. Phytochem Rev 2009, 8, 581.

CO2H

Germacratrienoic acid

CO2HOH OO

Costunolide

O2, NADPH + H+ NADP+, H2OH2O

4,5-epoxidation

OO

O

Parthenolide

H3C OH OO

Guaianolide

unknown pathway

HO2C

Guaia-trien-oic acid

HO2C

OHhydration

H+

CO2H

7 7

1111

1313

C7 (11 13)rearrangement +

H

7 134

15

O

OH

elimination

H+

C13-C15cyclization

7

134

15 CO2H

+

H

B:-

7

134

15 CO2R

C13-C4cyclization

R = H, Echinopinoic acid = Echinopine AR = CH3, Echinopine B

To be investigated …!

Known natural products!

Filip Petronijevic @ Wipf Group Page 4 of 14 2/28/2011

Previous Work in the Field of Echinopines’ Synthesis

Filip Petronijevic @ Wipf Group Page 5 of 14 2/28/2011

The Magauer-Tiefenbacher Sytnhesis of (+)-Echinopine A and B

H

O

OR

R = H, Echinopinoic acid = Echinopine AR = CH3, Echinopine B

H

OR

DMDO epoxydationLAH regioselective epoxide openingIBX oxidationWittig reaction

Triflate formation (Comin's reagent)Musco-Santi's chain extension Furukawa-Simmons-Smith cyclopropanation

MeO O SiCH3

CH3CH3

OTf

Pd(PPh3)4LiOAcTHF, reflux

OMeO

Musco-Santi's protocol

H

OR

H

OR

RCM (Grubbs II)

OH

H

Diastereoselective allylation

R = H (RCM: 84%) or Me (no RCM)

HH O

OOH

H

Myers' [3,3]-rearrangement

HO

ON

H

HN

HArO2S

HH O

O

ArSO2NHNH2

PPh3, DEADTHF, -40 °C to rtH

H O

O

O

(a) Magauer, T.; Mulzer, J.; Teifenbacher, K. Org. Lett. 2009, 11, 5306. (b) for Furukawa’s conditions, see: Furukawa, J.; Kawabata N,; Nishimura, J. Tetrahedron Lett. 1966, 7, 3353. ; Simmons, H.E. , Jr.; Smith, R.D. J. Am. Chem, Soc. 1958, 80, 5323. (c) for Musco-Santi’s conditions, see: Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J. Org. Chem. 1991, 56, 261. (d) for Myer’s rearrangement, see: Myers, A.G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841.

Filip Petronijevic @ Wipf Group Page 6 of 14 2/28/2011

The Nicolaou-Chen Synthesis of Echinopines A and B

H

O

OR

R = H, Echinopinoic acid = Echinopine AR = CH3, Echinopine B

SmI2-assisted pinacol couplingTebbe reagent

OTBSO

HO

H

OO

SmIII

HO

HO

H

O

OTBS

1. DMP 2. Ac2O

O

O

RO

Sm •I

I

SmI2

thenH+

H

TBSOO

SmI2

TBSOOTBS

Rh-catalyzedcyclopropanation

O

MeO2C

TBSO

N2

TBSOO

N2CO2Me

H

H

TBSO CHO

O

SmI2, HMPA

(a) Nicolaou, K.C.; Ding, H.; Richard, J.-A.; Chen, D.Y.-K. J. Am. Chem. Soc. 2010, 132, 3815. (b) for samarium diiodide reaction, see: Edmonds, D. J.; Johnston, D.; Procter, D.J. Chem. Rev. 2004, 104, 3371. ; Molander, G.A.; Harris, C.R. Chem. Rev. 1996, 96, 307.

Filip Petronijevic @ Wipf Group Page 7 of 14 2/28/2011

Chen’s Formal Aymmetric Synthesis of Echinopine A and B: Retrosynthesis

H

O

OR

R = H, Echinopinoic acid = Echinopine AR = CH3, Echinopine B

1

23

45

6

78

910

11 12

1314

15

Magauer-TiefenbacherSynthesis

H

O

DMDO epoxydationLAH regioselective epoxide openingIBX oxidationWittig reaction

Triflate formation (Comin's reagent)Musco-Santi's chain extension Furukawa-Simmons-Smith cyclopropanation

1

2

3

45

6

78

9

1013

OTBSH

CO2CH3

H

12

34

58

910

137

6

IntramolecularDiels-AlderReaction

Pd-catalyzedcycloisomerisation

MeO2C

TBSOH 10

9

8

7

13

56

2

3

4

7 134

15

O

OH

C13-C15cyclization 7

134

15 CO2H

+

H

B:-

7

134

15 CO2R

C13-C4cyclization

Note similarstructures

biosynthesis

synthesis

Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view

Filip Petronijevic @ Wipf Group Page 8 of 14 2/28/2011

Chen’s Synthesis of Echinopines: Construction of the Acyclic Cycloisomerisation/DA Cascade precursor

MeO2C

TBSOH 10

5

62

3

4

1

13

OTBSH

n-BuLi, THF, -78 to -15 °Cthen CuI (1.1 equiv.), -15 °C, 1 h

then CHO

then TMSI, -78 °C to rt

OTBS

CHOLindlar catalyst

quinolineH2 (1 atm)

toluene, rt, 5 h99%

48%

OTBSOHC10

13

Ph3PCH3+I-

n-BuLi, THF, -78 °C

then TMSCH2I (1.2 equiv.)rt, 10 h

Ph3P-CH2

Ph3P=CH2

I

TMSPh3P TMS

I-

n-BuLi, THF0 °C, 1 hthen

OHCTMS

-78 °C to rt, 2 hTMS

TMS

12

3

4

1 2

345

6

56

Cuprate conjugate addition

Wittig reaction

(a) Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view; (b) Imamura, K.-I.; Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 5339.

Filip Petronijevic @ Wipf Group Page 9 of 14 2/28/2011

MeO2C

TBSOH 10

5

62

3

4

1

13

OTBS

10

13

TMSTMS

1

2

34

5

6

TiCl4

CH2Cl2-78 °C, 1 h

75%

O

H

TiCl3Cl

OTBS

10

13

TMSTMS

1

2

34

5

6

HO

H

+

Cl-

H

H

HSiMe3

TMS

OTBS

TiCl3

Cl-

Coupling Red and Blue: Sakurai reaction

OTBS

10

13

TMS

1

2

34

5

6

HOH

O

H

OTBS

10

13TMS

1

2

34

5

6

HOH

H

OTBS

10

13

TMS

1

2

34

5

6

HOH

H

syn-diastereomer

dr ca. 3:1

Chen’s Synthesis of Echinopines: Construction of the Acyclic Cycloisomerisation/DA Cascade precursor

(a) Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view; (b) For Hosomi-Sakurai reaction, see: Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941. ; Fleming, I. Org. React. 1989, 37, 57.

Filip Petronijevic @ Wipf Group Page 10 of 14 2/28/2011

Cascade Cyclization/Intramolecular Diels-Alder Reaction

OTBS

TMS

HOH

H 1. Et3N, TBSOTf, CH2Cl2, 92% 2. p-TsOH, CH2Cl2/MeOH, 95%

3. K2CO3, MeOH, 98%4. DMP, NaHCO3, CH2Cl2

OHC

TBSOH

H

H3CO2C

TBSOH

H1. Pinnick oxidation, 95%

2. MeI, KHCO3, 99%

Pd(OAc)2, PPh3, toluene, 80 °C, 2 hthen160 °C, 6 h, 75%

H

H3CO2C

OTBS

H

OTBSH

CO2CH3

H

1

4

510

137

6

1

4

5

6

7

13

1

4

5 6

7

13

TBSOH

H1

4

5

6

MeO2C

PdLxII

TBSOH

H1

4

5 6

MeO2C

PdLx

TBSOHH

1

4

56

MeO2C

PdLxIV

H

TBSOHH

1

4

56

MeO2C

PdLxIV

H

cis-stereochemistry!

(a) Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view; (b) For Pd-Catalyzed Cycloisomerizations, see: Michelet, V.; Toullec, P.Y.; Genet, J. –P. Angew. Chem. Int. Ed. 2008, 47, 4268.

Filip Petronijevic @ Wipf Group Page 11 of 14 2/28/2011

Finishing the Formal Synthesis of Echinopines OTBS

H

CO2CH3

H

1

4

510

137

6

OTBSH

H

1. Dibal-H, -78 °C

2. PtO2, H2, EtOAc

quantitative OHH

H

OTBSH

H4

51

10

H

H

CO2CH3

H HPtO2

1. MsCl, Et3N, CH2Cl2 then NaI, acetone, 60 °C, 86%

2. DBU, THF, rt, 76%3. OsO4, NMO then Pb(OAc)4, CH2Cl2, 0 °C, 91%

OTBSH

OHH

H

1. LDA, THF, PhSeBr, -78 °C then H2O2, CH2Cl2, 51%2. NaOH, H2O2, MeOH, 85%

Montmorillionite K10 benzene, 80 °C

OTBSH

OH

H

OH

4

13

OTBSH

OH

H4

13

OHC

OTBSH

OH

H4

13

H

NaOH

Et2O71%

p-TsOH

MeOH83%

OHH

OH

H4

13

H

(+ 23% TBS-deprotected alcohol)

Martin's sulfuraneEt3N, CH2Cl2

60%

H

OH

H4

13

H

H

O

retro-Aldolreaction

Stereoselective reduction

Ring contractionand C-extrusion

diastereomers separatedat this stage

H

O

OR

DMDO epoxydationLAH regioselective epoxide openingIBX oxidationWittig reaction

Triflate formation (Comin's reagent)Musco-Santi's chain extension Furukawa-Simmons-Smith cyclopropanation

Echinopines

(a) Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view; (b) for rearrangement – ring contraction See: Elings, J.; Lempers, H.; Sheldon, R. Eur. J. Org. Chem. 2000, 1905.

Filip Petronijevic @ Wipf Group Page 12 of 14 2/28/2011

Echinopine A and B: An Asymmetric Approach by Aldol Chemistry

S NH

S

Bn

TMSCOOH

DCC, CH2Cl2

S N

S

Bn

O

TMS56%

TiCl4 (1 equiv.), CH2Cl2

iPr2NEt, -78 to -30 °C81%

S N

S

Bn

O

TMS

OTBSOH

OTBSO

H

imidazoleDMAPMeOH87%

O

TMS

OTBSOH

MeO

OHC

TBSOH

H

• optically active form• single diastereomer

Asymmetric Aldol Reaction

desired stereochemistry

asymmetriccycloisomerization

precursor

Peixoto, P.A.; Severin, R.; Tseng, C. –C., Chen, D.Y.-K. Angew. Chem. Int. Ed. 2011, Early view

Filip Petronijevic @ Wipf Group Page 13 of 14 2/28/2011

Conclusions

• Asymmetric formal synthesis of (+)-Echinopine A and B has been accomplished through! cycloisomerization/intramolecular Diels-Alder reaction !

OTBSH

CO2CH3H

12

34

58

910

137

6

IntramolecularDiels-AlderReaction

Pd-catalyzedcycloisomerisation

MeO2C

TBSOH 10

9

8

7

13

56

2

3

4

H1

2

34

5

8

910

13 7

6

H3CO2C

OTBSPd-catalyzed

cycloisomerisationIntramolecularDiels-AlderReaction

• 5,5-system made by contraction of 5,6-system!

Montmorillionite K10 benzene, 80 °C

OTBSH

OH

H

OH

4

13

OTBSH

OH

H4

13

OHC

OTBSH

OH

H4

13

H

NaOH

Et2O71%

retro-Aldolreaction

Ring contractionand C-extrusion

• Asymmetric version through Aldol Chemistry has been demonstrated!

Filip Petronijevic @ Wipf Group Page 14 of 14 2/28/2011