Formal Ring-Opening/Cross-Coupling Reactions of 2-Pyrones: Iron-Catalysed Entry into Stereodefined Dienyl Carboxylates

Dr. Chan-Liang Sun Pr. Alois Fürstner Iron

Litterature Meeting

Maxime DauphinaisNovember 13th, 2013

Pr. Alois Fürstner

• 2009 - 2012 Managing Director of the Max-Planck-Institut für Kohlenforschung• 1998 - Director at the MPIfK and professor at the Technical University of Dortmund• 1993 – 1998 Group leader MPIfK and lecturer at the University of Dortmund

• 1992 Habilitation in organic chemistry at the Technical University of Graz, Austria• 1990 – 1991 Post-doctoral fellow at the University of Geneva, Switzerland (Oppolzer)• 1987 – 1990 PhD at the Technical University of Graz, Austria (Weidmann)

•1962 Birth in Austria

Pr. Alois Fürstner

24 major awards

• Arthur C. Cope Scholar Award• Mukaiyama Award• Prelog Medal

Member of boards of 15 journals

• Angewandte Chemie• Organic Syntheses• Journal of Organic Chemistry

Author of over 300 publications

« Organometallic Chemistry »

• Alkyne Metathesis

• Alkene Metathesis

• π-Acid Catalysis

Fürstner Group

O

TBSO O

C5H11O

O

TBSO O

C5H11O

P N

Ph

Ph

O

OAu

ClAr

Ar

ArAr

MeO

MeO

Ph

E

E

E

E

H

H PhAgBF4

commercial

• Novel Concepts for Catalysis

• Total Synthesis

• Iron catalysisOTf

O O

MeMgBr

Fe(acac)3 cat.

Ru

PhPCy3

PCy3

Cl

Cl

2-Pyrones Reactivity with Nucleophiles

1,2 – addition : Hard organometallics

Dreux, Tet. Lett. 1984, 1551.Christl, Eur. JOC 2006, 531.

O O

R-MgX

O O

RR-MgX

Y R

O OH

RY Y

1,2 – addition : L.A. Hydrides

O O

DIBAL-H

O OH

R

RR

R

2-Pyrones Reactivity with Nucleophiles

1,4 – addition : Organocuprates

O O

CuBr-SMe2 (5 mol %)

(R,S)-Rev-Josiphos

t-BuOMe, -72 oC

O

OMgBr

hex

OMe

Ohex

H

OMeOH (5 eq.)

-72 oC to rt 66% yield94:6 er

hex-MgX

Feringa, Org. Lett. 2013, 286.

2-Pyrones Reactivity with Nucleophiles

1,6 – addition : Cyanide and other heteroatom nucleophiles

O

O

KCN

DMF

NC

CO2H

O O

Fe(acac)3 5 mol %

Et2O / toluene, -78 oC

RMgBrR

OH

O

1,6 – addition : Grignards with Fe cat

1,6 – addition : Non-L.A. Hydrides

Vogel, Chemistry & Industry 1962, 1829.Vogel, Chemistry & Industry 1962, 268.

O

O

NaBH4

THF CO2H

Initial Foray in Fe-Catalysed Couplings

Kharasch, JACS 1942, 2972.

“Although (Table I) no one of the metallic halides (2 to 5 mole per cent.) has any effect on the ratio of the 1,2 and 1,4 addition of methylmagnesium bromide to chalcone, yet they profoundly influence the nature of the products formed in the reaction.”

Ph Ph

O

Ph Ph

OH

Ph Ph

O

Me

MeMeMgBr

Ph

O

Ph

Ph Ph

O

no additiveCoCl2CuCl2FeCl2

0000

5906966

082721

< 20 oC

Urabe’s Work on Acyclic Substrates

Urabe, Tet. Lett. 2004, 603.

R1

R2

COY

R3

i) ArMgBr (1.8 equiv)

FeCl2 (0.1 equiv)

THF, -30 oC, 3h

ii) E+

R1

R2

COY

R3

E

Ar

Previous Fe Work with 2-Pyrones

O O

Fe(acac)3 5 mol %OTf

O O

R

THF / NMP, 5 min, 0 oC

R = MeMgBr 44%R = BuMgCl 37%

RMgX

Initial « Discovery »

O O

Fe(acac)3 5 mol %

HO OEt2O, -78 oC

8%11%

RMgX

O O

R = MeMgCl 79%R = C14H19MgCl 74%

OTf RR

Maulide, JOC 2010, 7962.

Optimisation

Exclusive cis isomer requires complete absence of THF

Accessing the Trans Isomer and Scope

• Most cis isomers > 20 : 1 (-30 oC)• Trans isomers 8-10 :1 (r.t.)

• Compatible with • primary alkyl iodides• esters• α-cyclopropanes

• Complete conversion in 20-40 min

• Methyl only?

Limitations

• No example of secondary R-MgX

• Only E isomer accessible (>10:1)

• Works best with 3 equiv. of R-MgX

• For cis isomer, no THF solution

O O

Fe(acac)3 5 mol %

Et2O / toluene, -78 oC

84%, >10:182%, >10:1

RMgX

R = Me(CH2)5 R = Ph(CH2)3

R

OH

O

O O

Fe cat.

OH

O

MgX

R R

R R

?

Mechanism – Acyclic System

Urabe, Tet. Lett. 2004, 603.

• expected 1,6-addition product with trans alkene

• no reaction with cis alkene

• 2-pyrone forces cis alkene

Mechanism – pyrones

Fürstner, ACIE 2006, 440.DePuy, JACS 1977, 4070.

Standard redox cycle unlikely

OO

O

O O

O

Substrates that could not be engaged

Sequential Couplings : Back to the Beginning

O O

Fe(acac)3 5 mol %

Et2O / toluene, -30 oC

68%, >20:1 Z84%, >20:1 Z73%, >20:1 Z

MeMgBr

R = iPr R = iBuR = (CH2)3Ph

RMe

OH

OR

O O

Fe(acac)3 5 mol %

THF / NMP, -78 oC

RMgBrOTf

78%74%60%

R = iPr R = iBuR = (CH2)3Ph

Synthesis of Fragment of Pateamine AO

O OTBSOTBSO

COOH

Fe(acac)3 5 mol %

Et2O / toluene, -60 oC

MeMgBr

80%, >10:1 Z Me2N

O

S

N

O O

OH2N

pateamine A

Total Synthesis of Granulatamide B

Cytotoxic tryptamine derivative from Eunicella granulate

4-step synthesis from cheap commercial materials

57% overall yield

COOEt

hept Cl

O

AlCl3

CH2Cl2, reflux heptCOOEt

O

MeMgBrFe(acac)3 (5 mol%)Et2O / toluene, -30 oC80%

H2SO4,

HOAc, 40 oC

87%, 2 stepsO Ohept

hept

COOH

tryptamine, HOBt, EDC-HCl, Et3N

CH2Cl2 / DMF82%

NH

HNO

hept

Granulatamide B

Conclusion

• 1,6-addition of Grignards to 2-pyrones complements 1,2 and 1,4-addition precedents

• Cis and trans isomers can be obtained almost exclusively by tweaking conditions

• Possible to alkylate sequentially two different positions of 2-pyrone with Grignard reagents

• One partial synthesis and one total synthesis accomplished using this methodology

O O

Fe(acac)3 5 mol %

Et2O / toluene, -78 oC

RMgBrR

OH

O

Questions?