ALKYNE METATHESIS - Max-Planck-Institut für Kohlenforschung · ALKYNE METATHESIS CATALYSTS cheap...

45
ALKYNE METATHESIS BACKGROUND AND CATALYST DEVELOPMENT

Transcript of ALKYNE METATHESIS - Max-Planck-Institut für Kohlenforschung · ALKYNE METATHESIS CATALYSTS cheap...

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ALKYNE METATHESIS

BACKGROUND AND CATALYST DEVELOPMENT

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ALKYNE METATHESIS

F. Pennella et al., Chem. Commun. 1968, 1548

(supported tungsten oxide, 200-450°C)

A. Mortreux et al., Chem. Commun. 1974, 786

(Mo(CO)6 + phenol, > 130°C)

mechanism: T. J. Katz et al., JACS 1975, 97, 1592

first example of alkyne metathesis using defined

alkylidyne complexes, e. g. (tBuO)3WCCMe3:

R. R. Schrock et al., JACS 1981, 103, 3932

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ALKYNE METATHESIS CATALYSTS

cheap

air stable

user friendly

harsh

slow

limited compatibility

expensive

laborious

(highly) sensitive (O2, H2O, N2)

short lifetimes

(highly) active: W > Mo

excellent compatibility: Mo > W

broad scope

MORTREUX SYSTEMS

SCHROCK ALKYLIDYNES

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ALKYNE METATHESIS

140 °C

1,2-dichlorobenzene

Mo(CO)6 cat. + phenol (30%)

+ 2-butyne

MeO OMe2 MeO

2

equilibrium reached in < 5 min at ambient temperature!

(tBuO)3W cat.

+

R. R. Schrock et al., J. Am. Chem. Soc. 1981, 103, 3932; Organometallics 1984, 3, 1563.

original report: A. Mortreux et al., Chem. Commun. 1974, 786

optimizations: M. Mori et al., Chem. Lett. 1995, 627; U. H. W. Bunz et al., Tetrahedron Lett 1999, 40, 2481;

D. Villemin et al., Tetrahedron Lett. 2001, 42, 3701; K. Grela et al., Tetrahedron Lett. 2002, 4, 3747; R.

Chauvin et al., New J. Chem. 2003, 27, 1412;

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RING CLOSING ALKYNE METATHESIS (RCAM)

A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 110, 1758

Lindlar Birch

(tBuO)3W R

Schrock-type alkylidyne

Review on alkyne metathesis: A. Fürstner, P. W. Davies, Chem. Commun. 2005, 2307

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TOTAL SYNTHESIS OF TURRIANES

OMe

OR

OR

OROMe

OR

OR

ORRu

PCy3

PCy3

Cl

Cl

Ph

cat.

84%

E : Z = 6.9 : 1

but the natural product is (Z)-configured !

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A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.

turrianes are efficient DNA-cleaving agents under oxidative conditions;

for the total synthesis and biological evaluation see:

OMe

OR

OR

OR

76%

F3CC6H4OH

Mo(CO)6 cat.

OMe

OR

OR

OROMe

OR

OR

OR

Lindlar

96%

R = PMB

R = H

BF3, EtSH

54%

or:

(tBuO)3W CCMe3 cat.

61%

TOTAL SYNTHESIS OF TURRIANES

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NN

N

Mo

C. C. Cummins et al., Chem. Commun. 1998, 1777

designed for the stoichiometric cleavage of N2

toluene, 80°COO

O OOO

O O

80%

NN

N

C

Mo

H

CH2Cl2

cat.

A. F. with C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999, 121, 9453;

Chem. Eur. J. 2001, 7, 5299

ALTERNATIVE

CATALYST

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FURTHER DEVELOPMENT

W. Zhang, S. Kraft, J. S. Moore, Chem. Commun. 2003, 832; idem, J. Am. Chem. Soc. 2004, 126, 392;

See also: C. C. Cummins et al., Organometallics 2003, 22, 3351.

NN

N

Cl

MoN

NN

C

Mo

H

NN

N

Mo

CH2Cl2+

NN

N

Cl

MoN

NN

C

Mo

R

+

R-CHCl2

Mg

ArAr

OOO

C

Mo

Ar

R

ArOH

A. Fürstner et al.,

J. Am. Chem. Soc.

1999, 121, 9453

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THE NEXT GENERATION OF ALKYNE METATHESIS CATALYSTS

0

10

20

30

40

50

0 10 20 30 40 50 60time [min]

yield [%]

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0

20

40

60

80

100

0 10 20 30 40 50 60time [min]

yield [%]

in the presence of molecular sieves 5Å

much improved rate AND conversion !

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air stable for weeksindefinitely air stable

superbly active & selective

STABLE, CHEAP, SCALEABLE VERSIONS

inactiveinactive

A. F. with J. Heppekausen, R. Stade, R. Goddard, J. Am. Chem. Soc. 2010, 132, 11045

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SCOPE

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ALKYNE METATHESIS

APPLICATIONS

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AMPHIDINOLIDE V

O

OH H

O

OH

Amphidinolide V

Isolation: J.-I. Kobayashi et al., Tetrahedron Lett. 2000, 41, 713

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TOTAL SYNTHESIS OF AMPHIDINOLIDE V

A. F. with O. Larionov, S. Flügge

Angew. Chem. Int. Ed. 2007, 46, 5545;

Chem. Eur. J. 2009, 15, 4011

30 mol%

80°C

With: A. F. with J. Heppekausen, R. Stade, R. Goddard,

J. Am. Chem. Soc.. 2010, 132, 11045

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MARINE OXYLIPINS

M. Kurada et al., Chem. Lett. 1989, 267; W. H. Gerwick et al., J. Nat. Prod. 1994, 57, 171;

K. Kosuaka et al., J. Nat. Prod. 2003, 66, 1318

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A. Fürstner et al. Chem. Eur. J. 2001, 7, 4811

now commercially available from Umicore and Evonik

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PROTECTING GROUP FREE TOTAL SYNTHESIS OF ECKLONIALACTONE A

A. F. with V. Hickmann, M. Alcarazo, J. Am. Chem. Soc. 2010, 132, 11042

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LACTIMIDOMYCIN: ANALYSIS

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TOTAL SYNTHESIS OF LACTIMIDOMYCIN

A. F. with K. Micoine, J. Am. Chem. Soc. 2010, 132, 14064

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A. F. with M. Bindl, L. Jean, Angew. Chem. Int. Ed. 2007, 46, 9275; Chem. Eur. J. 2009, 15, 12310

A. F. with L. Turet, Angew. Chem. Int. Ed. 2005, 44, 3462; Chem. Eur. J. 2007, 13, 115 and 135

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A. F. with K. Radkowski, Chem. Commun. 2002, 2182; Tetrahedron 2004, 60, 7315

for the trans-hydrosilylation, see: B. M. Trost et al. J. Am. Chem. Soc. 2002, 124, 7922

A. F. with M. Bonnekessel, J. T. Blank, K. Radkowski, G. Seidel, F. Lacombe, B. Gabor, R. Mynott,

Chem. Eur. J. 2007, 13, 8762

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A. F. with A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org. Chem. 2003, 68, 1521.

Nysin-loop isostere: A. F. with R. M. J. Liskamp et al., Org Lett. 2005, 7, 2961

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EPOTHILONES VIA RCAM

A. Fürstner, Ch. Mathes, K. Grela Chem. Commun. 2001, 1057; Chem. Eur. J. 2001, 7, 5299

O

OR

ORO

S

N

O

O

OR

ORO

S

N

O

O

OH

O

OHO

S

N

O

O

OR

ORO O

S

N

OH

S

N

O

OO O

R = TBS

[Mo] cat.

80%

Lindlar, H2

CH2Cl2

R = TBS

R = H

aq. HF

Epothilone C

OO

literature: 70%

Epothilone A79% over both steps

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SOPHOROSE LIPID LACTONE

RORO

OROO

OO

O

RORO

OR

O

OO

O

RORO

OR

RO

ORO

OR

O

O

OO

O

RORO

OR

RO

ORO

OR

O

O

R = PMB

R = H

Mo[N(tBu)(Ar)]3 (10 mol%)

toluene/CH2Cl2

78%

Lindlar / H2

quant.DDQ

93%

A. Fürstner, K. Radkowski, J. Grabowski, C. Wirtz, R. Mynott J. Org. Chem. 2000, 65, 8758

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A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.

turrianes are efficient DNA-cleaving agents under oxidative conditions;

for the total synthesis and biological evaluation see:

OMe

OR

OR

OR

76%

F3CC6H4OH

Mo(CO)6 cat.

OMe

OR

OR

OROMe

OR

OR

OR

Lindlar

96%

R = PMB

R = H

BF3, EtSH

54%

or:

(tBuO)3W CCMe3 cat.

61%

TOTAL SYNTHESIS OF TURRIANES

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TOTAL SYNTHESIS OF PGE2-LACTONE

O

O

HO

O

O

TBSO

Bu3Sn OTES

1. BuLi

2. Me2Zn

3.

OTES

MO

TBSO

IOR

O

TBSO

R = TES

R = H

HOAc, aq. THF

80% over both steps

O

O

TBSO

O

5-heptynoic acid

DCC, DMAP cat.

94%

O

O

TBSO

O

[(tBu)(Ar)N]3Mo cat.

CH2Cl2 / toluene

70%

ee > 99% ee = 98%

1. H2, Lindlar, 86%

2. HF, MeCN, 88%

A. Fürstner, K. Grela, Angew. Chem. Int. Ed. Engl. 2000, 39, 1234.

A. Fürstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 2000, 122, 11799.

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ALKYNE CROSS METATHESIS

A. Fürstner, C. Mathes Org. Lett. 2001, 3, 221.

PGE2

COOH

OHHO

O

51%

COOMe

O

TBSO OTES[Mo] cat., CH2Cl2, toluene, 80°C

OMe

MeO O

O

OTES

O

TBSO

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DEHYDROHOMOANCEPSENOLIDE

A. Fürstner, Th. Dierkes Org. Lett. 2000, 2, 2463.

96%

Lindlar

75%

cat.

(tBuO)3W

70%

[Ru] cat.

70%

1

3. ester 1

I2.

1. CuCN (1 eq.)

ZnX = ZnI

X = I

O

O

O

O

X X

O

OO

O O

OO

O

71%

DEAD, PPh3OHBrHO

O

+BrO

O

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isolated from various marine organisms by Kashman (1980), Scheuer (1985), Crews (1987), Jefford (1996), Hoye (2002)

potent actin microfilament disrupting agents, cf. I. Spector et al., Science 1983, 219, 493.

total syntheses: A. B. Smith et al., J. Am. Chem. Soc. 1992, 114, 2995; J. D. White et al., J. Org. Chem. 1992, 57, 5292

O

O

O

HN

S

OHH

O

O

O

O

HN

S

OHH

O

OH

O

O

OH

HN

S

H

O

OMe

O

O

O

HN

S

H

O

Latrunculin A Latrunculin B

Latrunculin C Latrunculin D

Latrunculia magnifica

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LATRUNCULIN B: RETROSYNTHETIC ANALYSIS

O

O

O

HN

S

OH

H

O

Latrunculin B

RCAM/Lindlar Fe-catalyzed cross coupling

aldol

Fe-catalyzed cross coupling

OR

O

S

RN

O

O

O

OH

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TOTAL SYNTHESIS OF LATRUNCULIN B

O

OR

OEt

OO

OEt

OOTfMgBr

Fe(acac)3 cat.

97%

R = Et

R = H

NaOH, MeOH

92%

Ph-N(Tf)2

KHMDS

61%

for a comprehensive study on Fe-catalyzed cross coupling reactions of enol triflates see:

B. Scheiper, M. Bonnekessel, H. Krause, A. Fürstner, J. Org. Chem. 2004, 69, 3943

for a short review see: A. Fürstner, R. Martin Chem. Lett. 2005, 34, 624

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TOTAL SYNTHESIS OF LATRUNCULIN B

in the absence of Fe cat.: < 30% yield

using Cu(I) in catalytic or stoichiometric amounts instead of Fe cat. leads to decomposition

O2S1

C2

O2'

N3

C30

C5

C2'

C4

C2"

C31

C32

C36

C33

C35

C34

O37

C38

S

RN

O

O

H2N

O OEt

SH S

PMBN

O OH

O

S

PMBN

O Cl

O

MeMgBr

Fe(acac)3 cat.

Cl

NMe23 steps

ee = 87%

ee = 99%recryst.

80%

for a short review on Fe-catalyzed cross coupling, see: A. Fürstner, R. Martin. Chem. Lett. 2005, 34, 624

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OTBS

O

S

PMBN

O

O

TiCl4, iPrNEt2

73%

TBSO O

PMBNS

O

OH

dr = 2:1

1. HCl

2. CSA, MeOH

64%

O

PMBN

S

OH

O

OMeH

dr = 7:1

O

PMBN

S

O

O

OMeH

O1. Tf2O, pyridine

2. NaO

O

58%

citronellene

TOTAL SYNTHESIS OF LATRUNCULIN B

O2

S1

C2

C3'

C4'

N3

O4'

C30

C5

C5'

C4

C2'

C31

C32

O2'

O1'

C6'

C36

C33

C7'

C2"

C34

C12'

C35

C11'C8'

O37

C10'

C9'

C38

C9"

X-ray of minor isomer

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TOTAL SYNTHESIS OF LATRUNCULIN B

C9"

C7'

C9'

C5'

C10'C11'

C8'

C12'

C2"

C4'

O4'

O1'

C16'

C13'

C3'

C15'

O16'

C14'

C14"

C30

C2'

O2

N3

C36

O2'

C31

C2

C4

C6'

C35

C32

S1

C5

C34

C33

C38

O37

O

PMBN

S

O

O

OMeH

O[Mo] cat.

CH2Cl2/toluene

70%O

PMBN

S

O

O

OMeH

O

O

O

O

HN

S

OHH

O

Latrunculin B

1. Lindlar, quant.

2. CAN, 78%

A. Fürstner, D. De Souza, L. Parra-Rapado, J. Jensen,

Angew. Chem. Int. Ed. 2003, 42, 5358

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O

RN

S

OH

O

OMeH

O

TeocN

S

O

O

OMeH

O [Mo]

toluene/CH2Cl2

70%

O

O

O

HN

S

OHH

O

Latrunculin A

O

O

O

TeocN

S

OMeH

O

ENYNE-YNE METATHESIS: LATRUNCULIN A

L. Turet, A. Fürstner,

Angew. Chem. Int. Ed. 2005, 44, 3462;

Chem. Eur. J., 2007, 13, 115

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O

RN

S

OH

O

OMeH

RN

S

O

H

O

OTBS

O

OTBS

O

HH

RN

S

O

H

O

RN

O

O

H

O

RN

O

O

H

O

O

RN

S

OH

O

OMeH

O

RN

O

OH

O

OMeH

O

RN

S

OH

O

OMeH

HH

O

RN

O

OH

O

OMeH

HH

O

RN

O

OH

O

OMeH

HH

O

OH

O

OH

O

OH

O

OH

O

OH

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DIVERTED TOTAL SYNTHESIS

O

O

OH

HN

SO

H

O

O

O

OH

HN

OO

H

O

O

O

HN

S

O

OHH

O

H

O

O

HN

S

O

OHH

O

O

O

HN

S

O

OHH

O

H

HH

O

O

HN

O

O

OHH

O

O

O

HN

O

O

OHH

O

HH

O

O

HN

O

O

OHH

O

HH

H

O

O

NH

S

O

OHH

O

H

H

O

OO

HN

S

OHH

O

O

O

OH

O

N

S

O

HO

HH

H

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O

O

O

HN

S

OHH

O LAT-B

O

O

O

HN

S

H

OHH

O

H

H

A. Fürstner, D. Kirk, M. Fenster, C. Aissa, D. De Souza, O. Müller, PNAS 2005, 102, 8103

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QM/MM CALCULATIONS

Latrunculin A / Actin Complex

refined and corrected picture of H-bonding network

importance of hydrophopic interactions

“Lat 32” / Actin Complex

different but equally strong hydrogen bond network

hydrophobic interactions optimized

A. F. with D. Kirk, M. D. B. Fenster, C. Aissa, D. De

Souza, C. Nevado, T. Tuttle, W. Thiel, Chem. Eur. J.

2007, 13, 135

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(E)-ALKENES FROM ALKYNES

Lindlar

method other

than Birch ?

Page 45: ALKYNE METATHESIS - Max-Planck-Institut für Kohlenforschung · ALKYNE METATHESIS CATALYSTS cheap air stable user friendly harsh slow limited compatibility expensive laborious (highly)

(E)-ALKENES FROM ALKYNES

N

Ts

Si(OEt)3

N

Ts

[Cp*Ru(MeCN)3]PF6 cat.

(EtO)3SiH

80%

E : Z > 97 : 3

N

Ts

AgF

THF / MeOH

85%

E : Z > 97 : 3

A. Fürstner, K. Radkowski, Chem. Commun. 2002, 2182; idem, Tetrahedron 2004, 60, 7315

see also: B. M. Trost, Z. T. Ball and T. Jöge J. Am. Chem. Soc., 2002, 124, 7922