Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products

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Submitted on 12 Jul 2006

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Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products

Joëlle Prunet

To cite this version:

Joëlle Prunet. Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products. Current Topics in Medicinal Chemistry, Bentham Science Publishers, 2005, 5, pp.1559.

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6 3 equiv

[Ru]-IV, 25°C CH₂Cl₂, 36 h

79% 2 steps

7 3 equiv

(S,S)-9 8

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[Ru]-IV, 25°C CH₂Cl₂, 12 h

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[Ru]-IV, 25°C CH₂Cl₂, 24 h

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[Ru]-VI, CH₂Cl₂ reflux, 1.5 h, 59%

2 equiv

12

[Ru]-II, 82%

[Ru]-II, benzene 55°C, 62%

10 equiv

13 14

15 16

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E/Z = 9:1 R = H 76%

R = Me 28%

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OBn OBn

H H

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OBn AcO OBn

OAc

H H

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OBn AcO OBn

OAc

H H

H H

H OBn [Ru]

O

OBn AcO OBn

OAc

H H

H H

H OBn

5 5

8% 19%

[Ru]-I, CH₂Cl₂ reflux, 33 h CH₂Cl₂, 20°C, < 30 min, 95%

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H Me H

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O Me H O O Me NH

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[Ru]-II, CH₂Cl₂, reflux 12 h, 60%

Azaspiracid-1

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OMOM

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O OH [Ru]-II, CH₂Cl₂, reflux 85%

25 26

27

(+)-Amphidinolide W E/Z = 11:1

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[Ru]-I, CH₂Cl₂ reflux, 64%

28 29 E/Z = 11.3:1 30

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E/Z > 5:1

[Ru]-I, CH₂Cl₂ reflux, 82%

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OMe Me

Me H

O

O

OMe Me

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O Core of garsubellin A [Ru]-II, 2 h

33 88%

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[Ru]-IV, CH₂Cl₂; H₂, Pd/C

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(-)-Centrolobine

34 35

4.2 equiv

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Hex NHCOOBn O

O O Hept N

N H HO

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N Hex

HN COOBn Hept

NHCbz RO

1) [Ru]-IV, toluene, 80°C 2) TBAF 78% (2 steps) 36a R = H

36b R = TMS

1) H₂, Pd/C 2) KOH, MeOH

(+)-Carpamic acid

100%

(2 steps) 37

38

[Ru]-IV, CH₂Cl₂, 40°C 72 h, 69%

40 39

2

41 2 H₂, Pd/C

Xenovenine

73%

[Ru]-IV, CH₂Cl₂, 40°C 72 h, 69%

43 42

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H₂, Pd/C

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88% 44

MeOH, HCl 2

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1) 20 equiv [Ru]-II CH₂Cl₂, 8 h reflux, 84%

2) H₂, Pd/C 73%

1) MsCl, Et₃N 2) MeNH₂, DMF 48%

(+)-Preussin

6 N HCl, THF 81%

45 46

47

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OMe MeO

MeO

N H

OMe MeO

MeO

HN OMe MeO

MeO

NHCbz R

OMe MeO

MeO

NHCbz

OAc [Ru]-II

HCHO HCl

OMe MeO

MeO

HN H

OAc

OMe MeO

MeO

N H AcO OAc

or

48a R = Me 48b R = H

49

50 CH₂Cl₂, reflux, 24 h

51

1) H₂, Pd/C, 95%

2) 5 N NaOH, 90%

3) DIAD, PPh₃, 68%

38% with 49 E/Z = 4:1 82% with 50 E/Z = 8:1

52

(-)-Cryptopleurine 67%

(-)-Antofine

RCM/H₂

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O O BnO OBoc

OH t-BuOOC t-BuOOC

COOt-Bu

Ph OAc

Me

O O BnO OBoc

OH t-BuOOC t-BuOOC

COOt-Bu

Ph OAc

Me

O O

O OH

OH HOOC HOOC

COOH

Ph OAc

Me Ph

O

Me

(1.2 equiv) 1) [Ru]-II, benzene, 70°C, 8 h

2) H₂, Pd/BaSO₄

67%

87%

Zaragozic acid C

53 54

55

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H Me

O O H

H Me

SiMe₃ O

O H

H Me

SiMe₃

N O Me

O O Bn

O O H

H Me

SiMe₃

N O Me

O O Bn [Ru]-II

N O Me

O O Bn

(+)-Amphidinolide T1

CH₂Cl₂, 40°C 96%

H₂, Pd/C 98%

56

57 58

59 E/Z = 1:1

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R O

H

H [Ru]-II, toluene H

allyltritylamine DIPEA

N O

R O

H

H H [Ru]-IV, TsOH, CH₂Cl₂ reflux, ethylene 81%

85%

N O

O O

O H

H H

H H₂, Pd/C 97%

60 61

62

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O OAc

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O OAc

(CH₂)₃OPiv

O OH OH CH₃(CH₂)₉

O OH

OH O

O Me 1) [Ru]-II, CH₂Cl₂

2) H₂, Pd/C

4 equiv 98%

97%

7

Squamostatin C

63 64

65

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Ti(Oi-Pr)₄ O Br

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O Me OH

H H O Br

OAc

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Me

OTBS Me O

2) TBAF 1) H₂NNH₂

LiOH O

Br

OH

Me O

Me

OTBS Me O

O Br

O

Me OTBS

Me O Me

OH

H [Ru]-II, CH₂Cl₂, 64%

66

67 3 equiv

68 69

79%

E only

70 cat. PPTS 70%

71

H₂O₂, 70%

ABC tristetrahydropyran 90%

of thyrsiferol and venustatriol 58%

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O

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O O O O OH

H Me H Me H H Me H Me H

O HO

O O O O OH

H Me H Me H H Me H Me H [Ru]-I, CH₂Cl₂, 23°C

KOOCN=NCOOK, AcOH

Glabrescol 72

73

74

75 50%, 2 steps

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OMe O₂N O

O₂N Br Br

(RO)₂B O

O O

OMe

O O

OMe N O

H O

B O O

O O

OMe

O 76 77

[Ru]-II, CH₂Cl₂ reflux

98% E/Z = 1:1.2

Pd(PPh₃)₄, TlOEt

(E)-78

(Z)-78 42%

30%

Me₂Zn, Pd(t-Bu₃P)₂ 95%

Aureothin N-Acetylaureothamine

1) Zn, NH₄Cl, 98%

2) AcCl, Pyridine, 80%

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[Ru]-IV CH₂Cl₂, reflux

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PhCHO, t-BuOK 89%

81 Cochleamycin A

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TiCl₄ O

OTBDPS O

TIPSO

SiMe₃ 90%

82

E/Z = 3:1 83

4 equiv [Ru]-II CH₂Cl₂ reflux

80%

(+)-Brefeldin A 84 dr > 19:1

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Ar OAc

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Cbz OMe

MeO OBn

OH H

BF₃.OEt₂ N

NBoc

O OAc

Ar OAc

SiMe₃

N N

O Ar

OAc Boc 95%

4 equiv

[Ru]-II, CH₂Cl₂ reflux

85 51% 86

87 (-)-Lemonomycin core

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HCOOH NCOOCH₃ O

O Ar

SiMe₃ 77%

3 3

88 89

[Ru]-II, CH₂Cl₂ reflux

74%

Ar = 2,4,6-triisopropylphenyl

(+)-Anatoxin-a

90

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O O OH

O O

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O O

CM OBn

O O

RCM ⁹

9

(-)-Muricatacin 9

Rollicosin

H₂, Pd/C 82%

9 5 equiv

[Ru]-II, CH₂Cl₂ reflux, 8 h, 65%

91 92

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MeO OMe MeO OMe

OMe MeO

HO OH

OH HO

R

R

E,E only [Ru]-I, CH₂Cl₂, 20°C, 75 h

[Ru]-II, benzene, 40°C, 27 h [Mo], benzene, 20°C, 2 h

61%

58%

72%

93 94

1) H₂, Pd/C 2) BBr₃

84%

(2 steps)

(-)-Cyclindrocyclophane F R = H (-)-Cyclindrocyclophane A R = OH

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COOMe

Me LiAlH₄ Me

OH 7 7

WCl₆, Me₄Sn

PhCl, 80°C, 18 h 68%

7 10 7 80% ²⁸

Triacontanol-1 Z/E = 1:3.6

95

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NPht Me

OBn

O O

96 98

NPht Me

OBn O

N H

H N O

Me OH

O O O

Me Me

H H O H

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H

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Me

OH

OBn Me

OBn 99

100

NPht Me

OBn O

1) [Ru]-II,

2) H₂SO₄, CH₃CN 63% (2 steps)

[Ru]-II, benzene 68%, 60°C benzene, 60°C

1.5 equiv 97

Bistramide A

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AcO

O Me

OTBDPS

O Me

OTBDPS

Me O OH 4 equiv

[Ru]-I benzene 101 20°C

102 E/Z = 1:1.5

103 E/Z = 1:1.5 then [Ru]-II, reflux;

TBAF 23%

104 (+)-Mycoepoxydiene

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O H Me

[Ru]-II

Me

O

Me

O O

O 105

(+)-Astericanolide ethylene

benzene 50°C, 10 h;

80°C, 10 h 74%

106

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N Boc

O N

Boc

OTBS

OMe OMe

MeO OMe

N OH H N

Boc

OMe OMe O

OTBS

N Boc

O

N Boc

[Ru]-I, CH₂Cl₂ reflux, 57 h

107 108

111 E only 109

2 steps

[Ru]-IV, CH₂Cl₂ reflux, 6 h 98%

85%

112

110

[Ru]-IV, 110, CH₂Cl₂ reflux, 12 h, 48%

(-)-Lasubine II

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Me

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Me

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Me

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Me

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Me [Ru]-IV, CH₂Cl₂

22°C, 30 min, 84%

2 equiv [Ru]-IV CH₂Cl₂ 22°C, 24 h 74%

Erogorgiaene

113 114

115

< 20%

one-pot

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N Cbz MeOOC

O Me

H

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[Ru]-II

O Me

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H O N Cbz MeOOC

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H

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H

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O

COOEt Me

OBn

N H N

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H

COOEt

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N H N

O O

H

COOEt 4 steps

[Ru]-I, ethylene CH₂Cl₂, 20°C 24 h, 76%

116 117 118

[Ru]-IV,CH₂Cl₂ 20°C, 17 h

60% 119

(+)-Anthramycin 70%

120 121 (-)-Dihydroxanthatin

1) LDA, MeI, 90%

2) [Ru]-II, 3 equiv

, 66%

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