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.
�hal-00085197�

HAL Id: hal-00085197

https://hal.archives-ouvertes.fr/hal-00085197
Submitted on 12 Jul 2006

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F3C i-Pr
PCy3 Mes N N Mes Mes N N Mes Mes N N Mes
F3C Cl Ph
N Ru Cl Ph Cl Cl Ph
O i-Pr Cl Ru Ru N Ru
Mo PCy3 Cl Cl
O Cl N
Ph PCy3 O Br
F3C
F3C Br
[Mo] [Ru]-I [Ru]-II [Ru]-IV [Ru]-VI

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OAc [Ru]-II OAc

O CH2Cl2 O CHO
Br reflux Br
CHO
OTIPS OTIPS
1 89% 2

OH
O O
OH

MeO OH
O Furaquinocin B

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3 equiv 3 equiv
OH CHO OH 2 steps OAc OAc CHO OAc OAc
PMBO PMBO CHO PMBO PMBO CHO
[Ru]-IV, 25°C [Ru]-IV, 25°C
3 CH2Cl2, 36 h 4 5 CH2Cl2, 12 h 6
79% 63%
2 steps

Ph 3 equiv
O Ph OAc OAc OAc COOEt OAc OAc OAc
Ti
PMBO COOEt PMBO
O O 1 [Ru]-IV, 25°C
14 8 7
(S,S)-9 CH2Cl2, 24 h
Ph Ph O C1-C14 fragment of amphidinol 3 61%

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Fragment A
CM
O
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O O HN Cl
O O

O N O OMe
CM O H
10
Cryptophycin 1

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OH OH
2 equiv C13H27
O O C13H27
NBn [Ru]-VI, CH2Cl2 NBn
O 11 reflux, 1.5 h, 59% O 12

OPMB 5 equiv OPMB

C13H27
TBDPSO TBDPSO C13H27
13 NHFmoc [Ru]-II, 82% 14 NHFmoc
E only
OH 10 equiv OH
C13H27
HO [Ru]-II, benzene HO C13H27
15 NHBoc 55°C, 62% 16 NHBoc
E only
OH
D-erythro-Sphingosine R = H
HO C13H27 D-erythro-Ceramide R = C(O)C H
15 31
NHR

O O OH
Me3N P
O O C13H27
HN C13H27

Sphingomyelin O

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O O
H
N 4:1 CH2Cl2/ R
O NH
O O [Ru]-II, 40°C, 38 h
17
O O
R H
N
O NH
O O
R = H 76% E/Z = 9:1
R = Me 28%
Precursors of bengamides

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H H AcO H H H H
OBn OAc OBn OBn
A B
O OBn [Ru]-I, CH2Cl2 5
O OBn 5
O OBn
H H reflux, 33 h AcO H H AcO H H
18 H OBn OAc
H
OBn OAc
H
OBn
[Ru]-I CH2Cl2, 20°C, < 30 min, 95% 19 8% 20 19%

H H [Ru] H H
OBn AcO [Ru] OBn
OAc
18
O OBn O OBn
H H AcO H H
OBn H OBn
22 OAc 21

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SS
H
O H OTBDPS
O O
Me O 23
H H
3 equiv PivO [Ru]-II, CH2Cl2, reflux
12 h, 60%

SS
H
O H OTBDPS
PivO O O
Me O
H H 24

H
O H OH
O Me
HO O
Me O HO
H H O
O
H
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NH O
Me
Azaspiracid-1 O
O
Me H Me

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MOMO

O
OTIPS OAc
O COOEt
25 26
[Ru]-II, CH2Cl2, reflux 85%
OMOM

O
OAc
O
E/Z = 11:1 27 OTIPS COOEt

OH

O O

(+)-Amphidinolide W

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[Ru]-I, CH2Cl2 [Ru]-I, CH2Cl2

BzO BzO TBSO
reflux, 64% OBz reflux, 82%
28 29 E/Z = 11.3:1 30
H
O N O
O TBSO
O N OR
Me N E/Z > 5:1
H 31 R = Bz
FR-900848 32 R = H
HO OH

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O O

OMe [Ru]-II, 2 h OMe

Me Me
H H
Me O Me O
88%
33 Core of garsubellin A

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 4.2 equiv O
OH HOOC
O
[Ru]-IV, CH2Cl2;
H2, Pd/C
34 OBn 56% 35
OH
OH

MeO

(-)-Centrolobine

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RO O
1) [Ru]-IV, toluene, 80°C
(CH2)7COOMe
NHCbz 2) TBAF 78% (2 steps)
36a R = H 37
36b R = TMS
O
1) H2, Pd/C
HO HO
(CH2)7COOMe
2) KOH, MeOH
N (CH2)7COOH 100% NHCbz 38
H (2 steps)
(+)-Carpamic acid

Hept O O
[Ru]-IV, CH2Cl2, 40°C
HN 2 72 h, 69%
COOBn
39 40

H2, Pd/C O O
Hept N Hept
73% 2
NHCOOBn 41
Xenovenine

O O
[Ru]-IV, CH2Cl2, 40°C
Hex NHCOOBn 2 O
72 h, 69%
42 43

O O
H2, Pd/C
Hex N 2 O
MeOH, HCl
88% Hex NHCOOBn 44
Indolizidine 209D

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MOMO OH 1) 20 equiv MOMO OH

C6H13
Ph Ph C9H19
[Ru]-II
OH 45 OH 46
CH2Cl2, 8 h
reflux, 84%
1) MsCl, Et3N
2) H2, Pd/C 48% 2) MeNH , DMF
2
73%
HO MOMO
6 N HCl, THF
Ph Ph
N C9H19 81% N C9H19
Me 47 Me
(+)-Preussin

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 OMe OMe
MeO MeO
H H RCM/H2

N HN

MeO MeO
(-)-Antofine

OMe OAc
MeO
49
R or
NHCbz OAc
AcO
50
48a R = Me
MeO 48b R = H
[Ru]-II CH2Cl2, reflux, 24 h
OMe
MeO

OAc

NHCbz
51 38% with 49 E/Z = 4:1
MeO 82% with 50 E/Z = 8:1

1) H2, Pd/C, 95%

2) 5 N NaOH, 90%
3) DIAD, PPh3, 68%

OMe OMe
MeO MeO
HCHO H
HCl
HN 67% N
52
MeO MeO
(-)-Cryptopleurine

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BnO OBoc
OAc
t-BuOOC O Ph
t-BuOOC O
COOt-Bu Me
53 OH 54
(1.2 equiv)
1) [Ru]-II, benzene, 70°C, 8 h 67%
2) H2, Pd/BaSO4 87%

BnO OBoc
OAc
t-BuOOC O Ph
t-BuOOC O
COOt-Bu Me
OH 55

Ph O OH
OAc
Me
HOOC O Ph
Zaragozic acid C HOOC O
COOH Me
OH

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H H
O O
SiMe3 SiMe3
Me O Me O
[Ru]-II
H CH2Cl2, 40°C H
Bn Bn
Me 96% Me
56
N O N O

57 O O E/Z = 1:1 O O 58

98% H2, Pd/C

OH
H H
Me O
SiMe3
Me O O Me O
H H
O O Bn
Me
N O
Me
(+)-Amphidinolide T1 59 O O

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O O

O H O H
[Ru]-II, toluene
H H
allyltritylamine R
N H O O DIPEA N
H 85% H
60 61

[Ru]-IV, TsOH, CH2Cl2

81%
reflux, ethylene
O O

O H O H
H H2, Pd/C H
R
N H O O 97% N
H H
62

(-)-Tuberostemonine

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CH3(CH2)9 (CH2)3OPiv
O O
63 OMOM OH OAc 4 equiv 64
98% 1) [Ru]-II, CH2Cl2
97% 2) H2, Pd/C

CH3(CH2)9 (CH2)3OPiv
O O
OMOM OH OAc 65
Me
OH
O
CH3(CH2)9
O O 7
OH OH OH O

Squamostatin C

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3 equiv Me
Me Me Me
OTBS Me Me
Me O Me O Me O
O O 67 O OTBS LiOH O OTBS
OAc OAc OH
[Ru]-II, CH2Cl2, 64% O 79% O
Br 66 Br 68 E only Br 69
70% cat. PPTS
OH OH
Me H Me Me
O OH OH Me OH
1) H2NNH2 Me
Me Me Me O Me
O Ti(Oi-Pr)4 O H2O2, 70% O OTBS
O O O
H H H H H O
58% 2) TBAF
Br Br 71 Br 70
ABC tristetrahydropyran 90%
of thyrsiferol and venustatriol

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72
[Ru]-I, CH2Cl2, 23°C

O
73
50%, 2 steps KOOCN=NCOOK, AcOH

O
74

HO OH
O O O O O
H Me H Me H H Me H Me H
75

HO OH
O O O O O
H Me H Me H H Me H Me H
Glabrescol

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O O Br O
O
BO Br
O2 N
(E)-78
O OMe [Ru]-II, CH2Cl2 O OMe Pd(PPh3)4, TlOEt O OMe 30%
O reflux O Br O
76 (RO)2B 77 O2N
98% (Z)-78
E/Z = 1:1.2
42%
95% Me2Zn, Pd(t-Bu3P)2

O O

1) Zn, NH4Cl, 98%

O O OMe O OMe
2) AcCl, Pyridine, 80%
N O O2N O
H N-Acetylaureothamine Aureothin

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OH OTBDPS [Ru]-IV O OH OR
CH2Cl2, reflux
MeO
79 MeOOC 80
3 equiv
89% PhCHO, t-BuOK
H OAc
Ph
OH
H H Me O O O OR
O H MeO
H O 81
Cochleamycin A

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4 equiv O
O O
Me3Si
TIPSO O
[Ru]-II OTBDPS
OTBDPS CH2Cl2 TIPSO
82
reflux SiMe3
80% 83 E/Z = 3:1
TiCl4 90%
HO O
TBDPSO O
H H
O
OH
HO H
H TIPSO
84 dr > 19:1
(+)-Brefeldin A

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OAc 4 equiv OAc SiMe3

Me3Si
NBoc NBoc
Ar N [Ru]-II, CH2Cl2 Ar N
reflux
O 85 51% O 86
OAc OAc
BF3.OEt2 95%

OMe OH
H Cbz Boc
N N
N Ar N
MeO
OBn O O 87
OTIPS OAc
(-)-Lemonomycin core

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OH O
Me3Si
Ar NCOOCH3 Ar NCOOCH3
[Ru]-II, CH2Cl2
O 3 reflux O 3 SiMe3
88 74% 89
Ar = 2,4,6-triisopropylphenyl HCOOH 77%

NH NCOOCH3
COCH3

O
(+)-Anatoxin-a
Ar 90

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CM OBn 5 equiv OBn

9
RCM 9
91 O [Ru]-II, CH2Cl2 92 O
reflux, 8 h, 65% O
O
H2, Pd/C 82%
O
OH OH
O
9 9
OH O O
Rollicosin O (-)-Muricatacin O

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MeO OMe

MeO OMe MeO OMe

93 94
[Ru]-I, CH2Cl2, 20°C, 75 h 61%
[Ru]-II, benzene, 40°C, 27 h 58% E,E only
[Mo], benzene, 20°C, 2 h 72%
1) H2, Pd/C 84%
2) BBr3 (2 steps)

HO OH

HO OH

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

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Me
7 7 COOMe

WCl6, Me4Sn
68%
PhCl, 80°C, 18 h

Me COOMe LiAlH4 Me
7 10 7 28 OH
80%
95 Z/E = 1:3.6 Triacontanol-1

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1) [Ru]-II, O O OBn OBn

OBn 1.5 equiv 97 O OBn O OBn
NPht benzene, 60°C NPht Me 99 NPht

Me 96 2) H2SO4, CH3CN 98 Me [Ru]-II, benzene 100 Me

68%, 60°C
63% (2 steps) H O OH H Me
Me N H
O N H O
O H H Me O HO
H

Me
Me
Me
Me
OH Bistramide A
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102 E/Z = 1:1.5

Me
4 equiv O
Me OTBDPS
O
OTBDPS [Ru]-I
Me
benzene
101 O
20°C OTBDPS

103 E/Z = 1:1.5

then [Ru]-II, reflux; 23%

Me TBAF
O H O O Me
O OH
AcO
(+)-Mycoepoxydiene 104

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Me O Me
H Me
[Ru]-II
ethylene
benzene O O
105 O 106
50°C, 10 h;
80°C, 10 h O
74% (+)-Astericanolide

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 OTBS
[Ru]-I, CH2Cl2 OTBS
reflux, 57 h N
107 N Boc 98% Boc 108
2 steps

OMe
O O
OMe OMe
N 110 N
Boc 111 E only [Ru]-IV, CH2Cl2 Boc 109
OMe
reflux, 6 h
85%
[Ru]-IV, 110, CH2Cl2
reflux, 12 h, 48%
H
O
N

OH

112 N Boc MeO (-)-Lasubine II

OMe

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Me Me
[Ru]-IV, CH2Cl2
22°C, 30 min, 84%
Me Me
113 114

one-pot 2 equiv [Ru]-IV

< 20% O CH2Cl2
Me 22°C, 24 h
Me 74%
Me
H
Me

Me Me
Erogorgiaene
115

Me Me O Me

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 OBn H O OBn H O
[Ru]-I, ethylene 4 steps N COOEt N
Me H Me H
MeOOC N CH2Cl2, 20°C MeOOC N [Ru]-IV,CH2Cl2
24 h, 76% N 20°C, 17 h N
Cbz Cbz COOEt
116 117 118 O 60% 119 O

OH H O
Me Me Me
H H H Me N H
[Ru]-II 1) LDA, MeI, 90% O
O O O
O 70% O 2) [Ru]-II, O , 66% Me O N
COOEt
H H H O
3 equiv Me
120 121 (-)-Dihydroxanthatin (+)-Anthramycin

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