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1Synthesis of Natural Products Containing Medium-sizeCarbocycles by Ring-closing Alkene MetathesisNicolas Blanchard and Jacques Eustache

1.1Introduction

This chapter deals with the synthesis of naturally occurring molecules (or relatedmodels) and focuses on the construction of medium-size carbocycles by ring-closingmetathesis (RCM). We have arbitrarily chosen to organize this chapter by increasingring size. Strategic aspects and potential problems are discussed.

1.2Formation of Five-membered Carbocycles by RCM

Strategic positioning of the double bonds of a 1,6-diene prior to RCM can be effi-ciently accomplished via [3,3]-sigmatropic rearrangements. Only selected examplesare discussed below, based on originality and efficiency criteria. Catalytic asymmet-ric Claisen rearrangement was reported by Hiersemann et al. in the enantioselectivesynthesis of the C10–C18 segment of ecklonialactone B (1), a C18-oxylipin iso-lated from the brown algae Ecklonia stolonifera and Egregia menziessi [1]. The[3,3]-sigmatropic rearrangement of 2 using catalyst 3 led to the acyclic α-keto ester4 that can be reduced and cyclized to the corresponding disubstituted cyclopen-tene 5 using [Ru]-II. Further functional group transformations led to the desiredC10–C18 fragment 6 of the natural product (Scheme 1.1).

A [3,3]-sigmatropic rearrangement/RCM sequence [2] was also used as a key stepin the total synthesis of a bioactive spirobenzofuran 7 isolated from the myceliumcultures of Acremonium sp. HKI 0230 [3]. The two consecutive quaternary centersembedded in the 1,6-diene 9 are worthy of note in the context of cyclopenteneformation by RCM, and the five-membered ring compound 10 was obtained inhigh yield (97%) using catalyst [Ru]-I. The same type of strategy was applied forthe efficient construction of the two vicinal quaternary carbon atoms present in theherbertanes sesquiterpenes (Scheme 1.2) [4].

Besides the Ireland–Claisen [3,3]-sigmatropic rearrangement/RCM sequence,some examples of Johnson–Claisen/RCM were reported by Ghosh and Maity [5].

Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts. Edited by Janine Cossy,Stellios Arseniyadis, and Christophe MeyerCopyright 2010 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32440-8

2 1 Synthesis of Natural Products Containing Medium-size Carbocycles

OEt

O

OH

H

( )7

(−)-Ecklonialactone B (1)

H

H

OBnO

CO2Me

O

BnO

CO2MeN

CuN

OO

H2O OH2t-But-Bu

2+

2 SbF6−

3 (7.5 mol%)

CF3CH2OH, CH2Cl2rt, 3d92% 4

(dr > 95 : 5, ee = 92%)

1. K-selectride(dr > 95 : 5)

2. [Ru]-II (1 mol%)

75% (2 steps)

OH

CO2Me

OBn OH

H

OBnOH

Et

Steps

2

5 6

1

10

1316

Cl(CH2)2Cl

Scheme 1.1

O

O

OHHO

Spirobenzofuran fromAcremonium sp. HKI0230 (7)

ArO

O

1. LDATMSCl·Et3N

2. Reflux thenHCl

3. CH2N2

Ar CO2Me

[Ru]-I(5 mol%)

CH2Cl2, rt97%

Ar CO2Me

Steps

1098

Ar = 2,5-Dimethoxy-4-methylphenyl

Scheme 1.2

OH

HO

SequosempervirinA (11)

OO

OH

CH3C(OEt)3propionic acid

Xylenes, 140 °C66%

OO

CO2Et

StepsOO

PMB

HO

[Ru]-I(4 mol%)

CH2Cl2, rt81%

OO

HO

PMB

Steps

12 13 14 15

Scheme 1.3

In the first total synthesis of sequosempervirin A (11), a norlignan isolated fromSequoia sempervirens, the γ , δ-unsaturated carbonyl derivative 13 was prepared from12 by Johnson–Claisen rearrangement. Further steps led to 14, the precursor of thekey RCM reaction catalyzed by [Ru]-I, which established the desired spiro structureof compound 15 (Scheme 1.3).

An analogous Johnson–Claisen rearrangement/RCM sequence was used byGhosh et al. in the synthesis of the carbocyclic core of the nucleoside (−)-BCA(16), a potential inhibitor of HIV reverse transcriptase (Scheme 1.4) [6]. The chiralcyclopentene 20 was obtained in excellent yield through a [Ru]-I-mediated RCMof 1,6-diene 19. Further epoxidation and functional group transformations led to(−)-BCA core structure 23.

1.2 Formation of Five-membered Carbocycles by RCM 3

N

N

NH2

N

N

HO

HO

Bis(hydroxymethyl)cyclopentenyl adenine, (−)-BCA (16)

CH3C(OEt)3propionic acid

140 °C, 6 h68%

OO

CO2Et

StepsO

O

EtO2C

H [Ru]-I

C6H6, 60 °C, 20 h96%

NH2

HO

HO

BnOH

BnO

BnOH

BnO

Om-CPBA

85%

Steps

18(dr = 1 : 1)

19(dr = 3 : 1)

OO

EtO2C

H

20 21 22 23

Steps

OO

17OH

Scheme 1.4

p-Tol

Laurokamurene B (24)

OH

[Ru]-II(15 mol%)

CH2Cl2

HO

OH

Steps

O

O

1. LDA

2. HCl3. CH2N2

MeO2CSteps

25 26 27

28 29

MoistSiO2

Scheme 1.5

Another [3,3]-sigmatropic rearrangement/RCM sequence was developed bySrikrishna and coworkers in the first total synthesis of the aromatic sesquiter-pene (±)-laurokamurene B (24) (Scheme 1.5) [7]. RCM of 27 led to cyclopentenol28 bearing a labile hydroxyl moiety, both benzylic and allylic. The latter compoundwas found to be unstable and when treated with silica gel delivered the rearrangedalcohol 29 in a one-pot operation.

Derivatives of nitiol (30), a novel complex sesterterpenoid that acts as a modulatorof IL-2 gene expression, were prepared using RCM of vinyl ketone 33 as a key step(Scheme 1.6) [8]. Worthy of note is the use of catalyst [Ru]-XIII [9] as [Ru]-II wasfound to increase intermolecular cross-metathesis at the expense of the desired


OOPMB

O

( )4 LDA

TMSCl, Et3N

HO

O

OPMB( )

2

O

OPMB( )2

O

OPMB( )2

Steps[Ru]-XIII(5 mol%)

CH2Cl2, 40 °C81%

OSO2CF3

OPMB( )2

1. LiHB(s-Bu)3

2. PhNTf2

OTBS

SnBu3

CO2Me

Cat. Pd(PPh3)4CuCl, LiCl

OTBS

CO2Me

( )3

OPMB

HOH

Nitiol (30)

HOH

OH

1,22-Dihydroxynitianes

31 32 33

34 35

36

37

Scheme 1.6

RCM. Conjugate reduction of enone 34 using l-selectride followed by trapping ofthe resulting enolate with PhNTf2 delivered enol triflate 35. The latter was thensubmitted to a Stille cross-coupling reaction with vinyl stannane 36 leading to theadvanced intermediate 37 in the synthesis of 1,22-dihydroxynitianes.

In the total synthesis of (−)-allosamizoline (38), the carbocyclic fragment ofthe chitinase inhibitor allosamidin, Donohoe and Rosa reported the efficientelaboration of the cyclopentenyl moiety via the RCM of a 1,6-diene (Scheme 1.7)[10]. Wittig olefination of aldehyde 39, readily obtained from d-glucosamine, provedtroublesome when basic phosphorus ylide 40 was used and the 1,6-diene 42 wasisolated in 18% yield. Since the terminal substituents of the alkenes are nottransferred into the cyclized products during RCM reactions, the reactivity ofacrylate 43 was evaluated as the latter was obtained in high yield (91%) using theless basic ylide 41. RCM proceeds equally well, delivering cyclopentene 44 in 88%yield.

Formation of cyclopentenes through the RCM of 1,6-dienes can prove itselfdifficult in very crowded environment. During synthetic efforts toward the tetra-cyclic skeleton of the sesquiterpenoid tashironin (47), Mehta and Maity reportedthe efficient RCM of 50 using [Ru]-I that led to 51 in 86% yield [11]. However,the RCM of 52 having a methyl substituent in allylic position led to 53 in consid-erably lower yield (25%) even in the presence of the more active [Ru]-II catalyst(Scheme 1.8).

A rapid elaboration of the ABC core structure of the tetranortriterpene dumsin(54) was reported by Srikrishna et al. starting from the readily available (R)-carvone[12]. Two independent efficient RCM reactions, catalyzed by [Ru]-I, were used as


OMOM

MOMO NHCO2MeRMOMO

MOMONHCO2Me

[Ru]-II(10 mol%)

Toluene90 °C

42: R = H (18%)43: R = CO2Me (91%)

OMOMOMOMO

NHCO2Me

OMOM

MOMO NH

46

O

NMe21. NIS

2. AllylSnBu3

Ph3P=CHR40: R = H41: R = CO2Me

Toluene, 90 °C

Steps

OMOMMOMO

N

O NMe2

(−)-Allosamizoline (38)

Steps

45

39 4480% (from 48)88% (from 49)

OHHO

N

O NMe2

HO

AIBN

Scheme 1.7

O

MeO O

O

MeO O

[Ru]-I(10 mol%)

C6H6reflux86%

O

MeOO

O

MeO O[Ru]-II (20 mol%)

C6H6, reflux 25%

O

RO O

O

BzO O

OH

OHO

Tashironin (47) Tetracylic corestructure

OHMeO

OH

PhI(OCOCF3)2

THF, rt40%

O

MeO O [4+2]

Toluenereflux76%

48 49 50 51

52 53

Scheme 1.8

OO

HO

AcO

H

AcO

HO

O

O

i BuO

A

A′B

CD

Dumsin (54) Dumsin ABC tricycle

O O [Ru]-I(5 mol%)

CH2Cl299%

O

1. AllylZnBr

2. PCCO

Li, liq NH3

Allyl bromideTHF/t-BuOH

OO

[Ru]-I(5 mol%)

CH2Cl2100%

Steps

(R)-Carvone

H

H

O

RCM RCM

A

B

C

55 56 57

58 59

Scheme 1.9

key steps to create the spiro cyclopentene in compound 56 and the trans-fused BCrings in compound 59 (Scheme 1.9).

In challenging cases, simple transformations of the allylic substituents maypromote a productive RCM of 1,6-dienes to the corresponding cyclopentenes asshown by Eustache et al. in the stereoselective synthesis of spiroepoxide 61, a


O

OMe

i-Bu i-Bu

O

OMe

[Ru]-II(15 mol%)

Toluene70 °C30%

OH

OMe

i-Bu

NaBH4, CeCl3·7H2OMeOH, 0 °C

i-Bu

HO

OMe

[Ru]-II(15 mol%)

CH2Cl240 °C

Dess–MartinperiodinaneCH2Cl2, 20 °C55% (3 steps)

OMOM

i-Bu i-Bu

OMOM

[Ru]-II(15 mol%)

CH2Cl240 °C42%

HOPMPO

HOPMPO

OH

i-Bu i-Bu

OH

[Ru]-II(5 mol%)

CH2Cl240 °C80%

HOPMPO

HO

PMPO

BF3·SMe2CH2Cl2, −78 °C

O

OOMe

O

O

CO2H

Fumagillin (60)

OMe

O

Spiroepoxide analog (61)

62 63

64 65

66 67

68 69

Scheme 1.10

potential methionine aminopeptidase-2 inhibitor related to the natural productfumagillin (60) (Scheme 1.10) [13]. Actually, the RCM of vinyl ketone 62 wasfound to be sluggish using catalyst [Ru]-II (toluene, 70 ◦C) yielding only 30% of thecyclopentenone 63. The enhanced reactivity of the corresponding allylic alcohol 64allowed a significant yield increase (55%, over three steps from 62). However, thepresence of a potential coordination site for the catalyst could also be detrimentalto the efficiency of the RCM. Thus, RCM of the Methoxymethyl (MOM) ether 66gave cyclopentene 67 in moderate yield (42%), whereas the corresponding freealcohol 68 cyclized to 69 in 80% yield with a threefold decrease in catalyst loading(Scheme 1.10).

Cyclopentenes bearing a trisubstituted double bond could be efficiently preparedvia the RCM of the corresponding 1,6-diene. Catalyst [Ru]-II is well suited forthis transformation since [Ru]-I usually leads to inferior yields. The prochiraltrisubstituted olefin could then be further reduced or oxidized, thus creating a newtertiary or quaternary stereogenic center.

Trauner et al. used RCM as a key step to elaborate the cyclopentyl core of(−)-guanacastepene E (70) and (−)-heptemerone B (71) (Scheme 1.11) [14]. Thecyclization precursor was prepared via an asymmetric ene reaction of glyoxylate 72.Further transformations led to 1,6-diene 74 that could be cyclized to cyclopentenone75 in 86% yield using [Ru]-II (5 mol%). Conjugate addition of the organocuprate76 then established the C11 quaternary stereocenter. The central seven-memberedring was then closed with an electrochemical oxidation.

Fomannosin (79) is a sesquiterpene metabolite isolated from the wood-destroyingBasidiomycetes fungus Fomes annonsus (Fr.) Karst. Its inherent instability and verycongested structure have elicited a great deal of interest from the synthetic


OO

OAcRO

R = H: (−)-Guanacastepene E (70)R = Ac: Heptemerone B (71)

H

R*O

O

O

SnCl4, −78 °C

Steps

O

OBn

O

OBn

[Ru]-II (5 mol%)

Toluene, reflux86%

O

PO

Cu(CN)(2-Th)Li2

BF3·OEt2THF, −40 °C O

O

OBn

1. KHMDS2. TBSOTf

3. Anodicoxidation

Steps

PO11

72 73(dr = 10 : 1)

74 75

76: P = TBDPS

77

OO

OBnPO

H

78

R*O

O

OH

R = (1S,2R )-2-Phenylcyclohexyl

Scheme 1.11

PMBO OTBS

OP

PMBO OTBS

OP

O

OH

O

O

O

OPMB

OMePOCp2ZrBu2

OP

PMBO OH

Steps

PMBO OH

O SEt

O O

1. IBX, DMSO

2. Pd/C, Et3SiHsilica gel

Steps

THF

O

OH

OPMBO OH

(+)-Fomannosin (79)

Steps

80: P = TBDPS 81

(dr = 2.4 : 1)

82 83

84 85

[Ru]-II(5 mol%)

C6H6reflux91%

Scheme 1.12

community. Paquette et al. reported a straightforward strategy for the elaboration

of both antipodes of fomannosin. Compound 80 (prepared from α-d-glucose)

underwent a zirconium-promoted ring contraction providing the four-membered

ring 81. The challenging RCM of 82 catalyzed by [Ru]-II was used as a key step, and

led to cyclopentene derivative 83 featuring a trisubstituted double bond adjacent to


OBn

OMe

OMe

OH

OBn

OMe

OMe

HO[Ru]-II

CH2Cl2reflux, 20 h

88%

OH

O

O

HO2C

(+)-Puraquinonic acid (86)

OMe

OMe

OBr

EtO

OEtBr2,

OMe

OMe

OEtO

Bu3SnH

AIBN85%

Br

OHC

OH

91%

Steps

OBn OBn

87 88 89

90 91

Steps

Scheme 1.13

BnO

BnO

OH

OH

BnO

[Ru]-II (10 mol%)

Toluene, 60 °C,24 h 24%

BnO

BnO

OHBnO

OH

BnO

BnO

OAc

OAc

BnO

BnO

BnO

OAcBnO

OAc

HO

HO

OHHO

O ORHO

HO

OHHO

OH

Galactofuranosides (92) Carbagalactofuranose (93)

94 95

96 97

[Ru]-II (8 mol%)

Toluene, 60 °C,24 h 89%

Scheme 1.14

a quaternary stereocenter (Scheme 1.12) [15]. The lactone ring was then elaboratedby an intramolecular Knoevenagel reaction.

RCM was used as a key step in the total synthesis of (+)-puraquinonic acid(86), a fungal metabolite that induces differentiation in HL-60 cells [16]. Startingfrom aromatic aldehyde 87, the RCM precursor 88 was prepared in a few steps.Following RCM leading to 89 (88%), the newly formed trisubstituted alkene wasinvolved in a radical cyclization. Bromo acetal 90 was treated with Bu3SnH andAIBN thus triggering a stereoselective 5-exo trig cyclization reaction. Further stepsled to the natural product 86 (Scheme 1.13).

Carbahexofuranoses and carbapentofuranoses syntheses have been intensivelyinvestigated and RCM reaction emerged as one of the most practical and effi-cient methods to this effect. Among the numerous syntheses of such derivatives,


the synthesis of 4α-carba-β-d-galactofuranose 93 is worthy of note [17]. A dra-matic protecting group effect was observed during the RCM of 94 and 96.Whereas free allylic alcohols are known to enhance reactivity, RCM of 94leads to the five-membered ring 95 in poor yield (24%). Under the same con-ditions, the diacetate 96 undergoes an efficient RCM providing 97 in 89% yield(Scheme 1.14).

Two simultaneous RCM have been used in efforts toward the core structure ofthe elisabethin diterpenoids [18]. Trisallylcarveol (99), accessible from (R)-carvone,can be transformed in a single step under mild conditions albeit with a moderateyield into the tricyclic compound 100 possessing the core structure of the desiredtarget molecule (Scheme 1.15).

Tetrasubstituted double bonds embedded in a five-membered ring can also beefficiently prepared via RCM. In the total synthesis of (±)-spirotenuipesines A (101)

OHO

Steps

OH

[Ru]-I(5 mol%)

CH2Cl2reflux, 24 h

40%

HO

O

MeOH

H

Elisabethin A (98)(R )-Carvone 99 100

Scheme 1.15

O

O

HO

HO

O

Spirotenuipesine B(102)

O

HO

HO

O

Spirotenuipesine A(101)

TBSO

OH

[Ru]-II(5 mol%)

C6H6reflux82%

HO

OTBSO

N2 O

AcO

O

O

H

MeS(S)CO

O

O

H

OO OH

I

Steps

Steps

Steps

Bu3SnHAIBN

Toluene

1. KOHMeOH

2. HCl3. I2, KI

NaHCO3

O

O

H

Cu(II) cat

OAc

103 104 105

106 107 108

109

O

O

H

Scheme 1.16


and B (102), Danishefsky et al. simplified the preparation of a key intermediate,compound 104, from nine steps [19] to three steps when an RCM strategy wasadopted (Scheme 1.16) [20]. The resulting tetrasubstituted double bond in 104was then submitted to an intramolecular diazoester cyclopropanation reaction.Radical opening of the resulting strained cyclopropyl group in 107 deliveredbicyclic lactone 108, which was converted to 109 by iodolactonization. The lattercompound could be further transformed to (±)-spirotenuipesines A (101) andB (102).

Another example of elaboration of tetrasubstituted double bonds by RCM wasdisclosed by Kotora et al. in a formal total synthesis of estrone (Scheme 1.17).Starting from 110, two zirconium-mediated cyclizations enabled the preparationof compound 112 whose RCM catalyzed by [Ru]-II (20 mol%) (toluene, 90 ◦C)provided estrone precursor 113 in 82% yield [21].

MeO

H [Ru]-II(20 mol%)

Toluene, 90 °C82% MeO

H

MeO

H F 1. Cp2ZrBu2

2. Methallyl chlorideCuCl (10 mol%)MeO

1. Cp2ZrBu2

2. CuCl(10 mol%)F

Cl

MeO

110 111

113112

StepsEstrone

Scheme 1.17

O

O

OMeOH

OMeOPMB

O

OMeOPMB

O

O N

O O

Bn

XN*

O

OH

OPMB

Fumagillol (114)

55%

Steps

1. LDA

PhSe

OPMB

2.

[Ru]-I,Ti(Oi-Pr)4 Steps

3. Bu4NIO4

115 116

117 118

12

345

678

1′2′ 3′

4′5′

XN*

O

H

CH2Cl2, 55 °C

53%

Scheme 1.18

1.3 Formation of Six-membered Carbocycles by RCM 11

1.3Formation of Six-membered Carbocycles by RCM

Among the recently reported synthetic approaches to angiogenesis inhibitors suchas ovalicin, fumagillin, and synthetic analogs, several use RCM to construct thesix-membered ring characteristic of this family of molecules [22–24]. In the firstmetathesis-based synthesis of fumagillol (114) (Scheme 1.18) [22a], the nonfunc-tionalized C7–C8 bond was established through an RCM/hydrogenation sequence.In agreement with Furstner’s observations, adding Ti(Oi-Pr)4 was required for theRCM of 117 to proceed with catalyst [Ru]-I [25]. The resulting advanced intermediate118 was easily converted to fumagillol. The approach was used for the preparationof fumagillin analogs 121–123, (Scheme 1.19) [22b] Using the more active [Ru]-IIeliminated the need for Ti(Oi-Pr)4 in the RCM of 119 to 120.

The second approach to fumagillol (114) relies on a Claisen/RCM sequence(Scheme 1.20) [23c]. Starting from 1,2;5,6-di-O-isopropylidene d-mannitol (124),the ester 125 was prepared and subjected to a glycolate-Claisen rearrangementleading to 126 (77%). RCM of 126 afforded cyclohexene 127 in high yield (94%),which was converted to an advanced intermediate previously used by Sorensenet al. in their synthesis of fumagillol [26].

OMe

OPMB

O

OMe

OPMB

O O

O

OMe

OCinn

119 120

O

OMe

OCinn

O

OMeOCinn

HO

121

122 123

O

OMe

Cinn =

[Ru]-II (10 mol%)

Toluene, 70 °C78%

Scheme 1.19

TBDPSOO

OO

OO

OH

OH

O O

124 125

Steps

O

OPMB

1. KHMDS2. TMSCl

O

O

COOHPMBO

TBDPSO

O

O

COOHPMBO

Steps

77%

126

127

Fumagillol[Ru]-I (10 mol%)

CH2Cl2, 40 °C94%

Scheme 1.20


O

O

OMeO

OMeOH

Li

Ovalicin (128)

Steps

129

OH

OO

O

O O

OH OO

TBDPSO

OMeOH

OO

TBDPSO

OMeOH

OO

TBDPSO

OMeOH

OO

TBDPSO

130

133131

132 OO

OMeOTES

1.

2. TBAF

+

[Ru]-II (2 mol%)

Toluene, 80 °C84%

[Ru]-II (1 mol%)

Toluene, 80 °C94%

Steps

Steps 134

1343. TPAP, NMO4. VO(acac)2, t -BuOOH

Scheme 1.21

OH

H

OMe

OH

OH

H

OMe

OH

rac-Ottelione A (135)

O OHC

Ar

OHC

Ar ArHO

Ar

H

H

HO

137 138 139

140

Steps

Li

CuI, Bu3P

56%

MgBr

Steps

62%

OHC

Ar

138

ArHO Ar

H

H

HO

Steps

MgBr

62%

141 142 143

Ar = OMe

OTBDMS

rac-Ottelione B (136)

[Ru]-II (5 mol%)

CH2Cl2, rt85%

[Ru]-II (5 mol%)

CH2Cl2, rt86%

Scheme 1.22

In contrast to the two previous syntheses, the six-membered ring was constructedfirst in Takahashi’s et al. synthesis of ovalicin (128) (Scheme 1.21) [24]. Thus,2,3;5,6-di-O-isopropylidene-d-mannose (129) was converted to the diastereomericRCM substrates 130 and 131, which smoothly cyclized to compounds 132 and 133in the presence of [Ru]-II catalyst.

Clive et al. designed a synthesis of both otteliones A (135) and B (136),featuring an efficient cuprate conjugate addition/Grignard reaction/RCM sequence


O

HN

OHO

HO

COOHO

Platencin (144)145

COOMe

COOH

CH2OAc

CH2OAc

CH2OAcCH2OAc

OH

Steps

OH

146 147 148 149

150

[Ru]-II (5 mol%)

CH2Cl2, 40 °C95%

Bu3SnHAIBN Steps

Steps

Scheme 1.23

(Scheme 1.22) [27]. Starting from cyclopentenone, the cyclopentene carboxalde-hyde 137 was prepared. Conjugate addition of the organocopper derived from2-butadienyllithium generated 138 and subsequent treatment with vinylmagne-sium bromide afforded the RCM substrate 139. This compound was cyclized usingcatalyst [Ru]-II to furnish intermediate 140, which was converted to rac-ottelione Ain two steps. Using the same sequence, the epimeric trans-aldehyde 141 (obtainedby equilibration of 138) afforded rac-ottelione B via 142 and 143. An asymmetricversion of these syntheses was also developed.

Very recently, two RCM-based but conceptually different formal syntheses ofplatencin 144 were disclosed [28, 29]. In both cases, the target was intermediate145 that has been previously converted to platencin by Nicolaou et al. [30a] andRawal et al. [30c].

In Lee’s et al. synthesis [28], the bicyclo[2.2.2]octane moiety was assembledthrough a radical cyclization/skeletal rearrangement [31]. Standard chemical ma-nipulation then led to triene 149 whose RCM ([Ru]-II) afforded cyclohexenol 150in 95% yield (Scheme 1.23).

Mulzer’s et al. approach implies a nonobvious construction of the strainedbicyclo[2.2.2]octane skeleton by RCM (Scheme 1.24) [29]. Starting from(−)-perillaldehyde (151), the decaline 152 was prepared. Wittig reaction affordedtriene 153, which was submitted to RCM conditions ([Ru]-II, CH2Cl2, reflux).RCM completion required more than 24 hours and 8 mol% of catalyst but the yieldof 154 was excellent (90%) and no side-products were reported. Compound 154bwas then converted to intermediate 145 in two steps (Scheme 1.24).

Polyprenylated acylphloroglucinols, such as garsubellin A (155) and hyperforinA (156), are bioactive molecules characterized by a polycyclic bridged system [32].In 2005, Shibasaki et al. described a RCM-based total synthesis of (±)-garsubellinA (Scheme 1.25) [33].

The α,β-unsaturated ketone 157 was converted to cyclohexanone 158 and aClaisen rearrangement/RCM sequence was used to construct the characteristicbicyclo[3.3.1]nonane skeleton.1) Thus, enol ether 159 cleanly rearranged at hightemperature to diene 160.2) Treatment of 160 by [Ru]-III [(20 mol%), toluene, reflux,

1) The Claisen/RCM sequence has been usedrepeatedly for constructing various ring sys-tems.

2) Ethylene carbonate was added to the reac-tion mixture to compensate for carbonatehydrolysis in 183.


O

145

CHO

NMe2

OTBDMSCHO

H

O

H

O

H

O

151

[Ru]-II (8 mol%)

68%

Ph3P CH2

80%

1. NBS

152 153

154

CH2Cl2, reflux90%

2. CrCl2

Scheme 1.24

OO

O

HO

Garsubellin A (155)

O

OEt O OTIPS

OMOM

O OTIPS

OMOM

OO

O

O OTIPS

OMOM

OO

O

O OTIPS

OO

O

O OOO

HO

I

OMOM

157 158 159

160 161

162

200 °C

96%

Steps Steps

Steps

1 step

[Ru]-III (20 mol%)

Toluene, reflux92%

Scheme 1.25

48 hours] led to intermediate 161 in excellent yield [34]. Finally, 161 was convertedto 162 and then to (±)-garsubellin A (155). As shown in Scheme 1.26, the methodcould not be extended to hyperforin (156) as RCM of 163 led to 164 possessing aseven-membered ring (Scheme 1.26).

Eight to ten-membered-rings, which are common in natural products [35], canbe prepared by heterolytic fragmentation of bicyclic systems [36]. The latter can beformed by several methods among which RCM is one of the most efficient.


MOMO

OMeO

O

MOMO

OMeO O

163 164

OO

HO

Hyperforin A (156)

[Ru]-III

Scheme 1.26

O

OTBDMS

( )n

1. Vinyl (or allyl)lithium

2. Allylbromide

HO

O

( )n

OH

O

( )n

165 166a : n = 0 166b : n = 1

167a : n = 0 (95%)167b : n = 1 (87%)

O

COOMe

168a : n = 0 (84%)168b : n = 1 (78%)

3. TBAF

[Ru]-I (7 mol%)

CH2Cl2, 20 °C

Pb(OAc)4

MeOH

Scheme 1.27

Mascarenas et al. reported an RCM/ring fragmentation strategy to eight-and nine-membered carbocycles (Scheme 1.27) [37]. Starting from 1,2-cyclohexanedione, the dienes 166a and 166b were obtained. When submitted toRCM conditions ([Ru]-I, 20 ◦C), only the diastereomers having the two unsaturatedside chains in a syn relationship reacted. The resulting bridged compounds 167aand 167b were cleaved by lead tetraacetate to afford ketoesters 168a and 168b. Bycontrast, direct construction of the eight-membered ring 170 by RCM of 169 wasunsuccessful (Scheme 1.28) [37a].

A related RCM/fragmentation protocol was used for preparing germacranolidesthat may exist as E,E-, E,Z-, or Z,Z-10-membered rings (Figure 1.1) [38].

Starting from (R)-carvone, the trienes 171 and 172 were prepared and RCMprovided decalines 173 and 174, respectively (Scheme 1.29). Selective conversion ofthe secondary alcohols in 173 and 174 to the corresponding mesylates and Whartonfragmentation [39] led to (Z,Z)- and (E,Z)-germacratrienes 177 and 178. The moresubstituted germacrenes 179–182 were also prepared using this strategy [38].

A similar strategy was reported for a synthesis of (±)-periplanone C(183) (Scheme 1.30) [40]. The triene 185 was prepared in a few steps from3-isopropylanisole and smoothly cyclized using [Ru]-I (3 mol%) to the trans-decaline

OH

TBDMSO

[Ru]-I or [Ru]-II

OH

TBDMSO

170169

Scheme 1.28


O OO

HO

HO

COOMe

OO

CHO

O

O

O

Figure 1.1 Various types of germacranolides.

171

OHHO

HO

OH

173

HO

OMs

O

NaH

79%

175 177

Steps

172

OHHO

HO

OH

174

HO

OMs

NaH

67%

176 178

O

O O O O

179 180 181 182

[Ru]-I (5 mol%)

C6H6, 80 °C94%

[Ru]-I (10 mol%)

C6H6, 80 °C78%

Steps

Scheme 1.29

O

(±)-Periplanone C (183)

OMe OCOOMe

HO

MeOOC

HO

186

OMs

O

184 185

187

KOH

74%

Steps Steps [Ru]-I (3 mol%)

CH2Cl2, rt81%

Steps

Scheme 1.30

186 (81%). Mono-O-mesylation and treatment with KOH afforded cyclodecanone

187, which was converted to (±)-periplanone C (183) in a few steps. Interestingly,

using the same conditions, epi-185 did not cyclize. This was attributed to the favor-

able preorganization of 185, favoring RCM, whereas the more stable conformation

of epi-185 places the two olefins away from each other (Scheme 1.31) [41].


MeOOC

HO

MeOOC

epi-185

No RCMOHCOOMe

HO

MeOOC

H

H OH

MeOOC

H OH

185 186

[Ru]-I

[Ru]-I

Scheme 1.31

O

OAc OH

TMSO TMSO

OH

MsClEt3N

O

75%

190 191 188

Steps

R'O

RO

O

HBzO

HO

189

AB

C

D

[Ru]-I (30 mol%)

C6H6, reflux90% OAcO

OH

Scheme 1.32

OH

TMSO

192

TMSO

OH

193 194

O

OH

TMSO

195

TMSO

OH

196 197

Steps

Steps

[Ru]-I (30 mol%)

C6H6, reflux93%

[Ru]-I (30 mol%)

C6H6, reflux83%

Scheme 1.33

Access to anti-Bredt alkenes is possible using an RCM/fragmentation sequence[42]. The strategy has been used for preparing the bicyclic ketone 188 havinga structure similar to the AB rings of taxanes 189. RCM of 190 catalyzed by[Ru]-I afforded 191 (90%) and subsequent fragmentation provided ketone 188(Scheme 1.32). Application to the construction of other bridged ring systems hasbeen examined. RCM of 192 delivered 193 in high yield (93%) and the cyclizationof 195 to afford the strained cycloalkene 196 (83%) is noteworthy (Scheme 1.33).

In 2006, Robichaud and Tremblay reported the first RCM-based formal synthesisof (+)-compactin (198) [43]. The functionalized cyclohexene 199 (ring A) wasprepared and submitted to RCM conditions to construct the six-membered B


OHOH

TMSH

OHTMS H

OHO

H

OO

HO O

OHH

OH

Compactin (198)201199 200

A B

[Ru]-II (20 mol%)

CH2Cl2, reflux85%

Scheme 1.34

O

OH

I

OH

OH

OH

OH

OH

OBz

O

O

BzO

OBz

O

OTBDMS

BzO

OBz

OMe

O

BzO

StepsLDA

TBDMSCl

60%OBz

MeOOCOBz

(−)-Perrotinene (202)

203 205 206

207 208

Bu3Sn

OH

Cat. Pd(0)

(S)

1. Ireland–

2. MeOH,DCC Steps

204

[Ru]-II (5 mol%)

CH2Cl2, reflux91%

Claisen

Scheme 1.35

ring, thus completing the elaboration of the fully functionalized decaline system200. Removal of the trimethylsilyl (TMS) group was difficult, and provided thetarget compound 201 in 31% yield, whose transformation to compactin had beenpreviously described (Scheme 1.34).

The first synthesis of (−)-perrotinene 202 was reported in 2008 [44]. The strategyis again characterized by an Ireland–Claisen rearrangement/RCM key sequence(Scheme 1.35). Alcohol 205 was prepared by Stille coupling between the aryliodide 203 and the enantiomerically pure vinyl stannane 204. The ensuing, highlystereoselective, Ireland–Claisen rearrangement of the silyl ketene acetal derivedfrom 206 allows a complete chirality transfer and the control of the configuration ofthe two stereogenic centers in 207. RCM of the latter substrate proceeded smoothlyand gave cyclohexene 208 in high yield (91%).

Recently, Li et al. described a synthesis of (−)-10α- and (−)-10β-hydroxy-4-muurolen-3-one (209) [45]. Starting from (R)-carvone, compound 210 was preparedin a few steps and its RCM proceeded smoothly using catalyst [Ru]-II to affordintermediate 211 in quantitative yield (Scheme 1.36).

Vannusal A (212) is a complex triterpene characterized by a pentacyclic bridgedcore. Nicolaou et al. have devised a synthetic approach to compound 216 possessingthe core structure of vannusal A (Scheme 1.37) [46]. A Mn(III)-induced radical


OH

H

OH

(−)-10a-hydroxy-4-muurolen-3-one (209)

O

(R )-Carvone

StepsO

HO

H

HHO

Steps

210 211

[Ru]-II (5 mol%)

CH2Cl2, reflux100%H

Scheme 1.36

OAc

H

H

OH

OH

OHC

OH

Vannusal A (212)

OMeH

OH H

OAcOAc

H

OMeOOC

OMe

OMeHOAc

Mn(OAc)3Cu(OAc)2

COOMe

OMeHOAc

OTES

H

Steps

216

AB

C

D

E

213 214 215

76%

1. [Ru]-II (33 mol%)CH2Cl2, 50 °C

84%

2. PPTS, MeOH91%

Scheme 1.37

HO

Br

ClAB

(+)-Elatol (217)

O

O

O

i-BuO

O

ClO

O

i-BuOCl

O

i-BuO

Cl

218 220 (ee = 87%)

82%

Steps

Steps

O

Cl

(+)-Laurencenone B (222)

Steps

219, Pd(0)

221

N

OP

t-BuCF3

F3C CF3

[Ru]-X (5 mol%)

219

C6H6, 60 °C97%

Scheme 1.38

cyclization of the β-ketoester 213 was used to prepare the bridged tricyclic systemABC 214. This compound was converted in a few steps to the RCM substrate 215whose cyclization proceeded cleanly and in good yield (84%) using catalyst [Ru]-II(33 mol%).

In 2008, Stoltz et al. reported the first synthesis of elatol 217 (Scheme 1.38) [47].Starting from dimedone, the mixed carbonate 218 was prepared. Decarboxylativeoxygen-to-carbon migration was effected using a Pd(0) complex based on the chiral


Durhamycine aglycone

OH

HO

OH

OH

O

OMeH

OHOHOHO

O

OMeH

OHBOMO

OO

OTCE

OMeO

O

Durhamycine aglycone model (227)

OTCE

OMeO

Ollpc2B

O

BOMOBOMO

+

O O CCl3

OH

OMeO

O

BOMO

H

1. Et3B, O2, Bu3SnH2. [Ru]-II (15 mol%)

Ti(Oi-Pr)4 (15 mol%)CH2Cl2, 40°C

3. Zn, AcOH, Et3N

O

34% (3 steps)

223 224 225 TCE =

226

S

MeS

Scheme 1.39

O OH

OH

OH

HO OBn

OBn

BnO

MeOOC

OBn

OBn

BnO

MeOOC

OH

OH

HO

O

HO

D-Xylose 228 229 (+)-Cyclophellitol (230)

Steps Steps[Ru]-I (15 mol%)

CH2Cl2, 25 °C92%

Scheme 1.40

phosphine 219 [48] to afford the optically enriched ketone 220 (ee = 87%) in goodyield (82%). The challenging RCM of 220, leading to a tetrasubstituted doublebond, proceeded exceedingly well using catalyst [Ru]-X [49]. The RCM product 221was then converted to (+)-laurencenone (222) then (+)-elatol (217) in a few steps.

Roush et al. have reported the synthesis of a durhamycin aglycon model(Scheme 1.39) [50]. Allylation of aldehyde 223 with the allylic borane 224 pro-vided 225 after the formation of a xanthate. Deoxygenation gave the requisite RCMprecursor whose cyclization proceeded reasonably well provided that Ti(Oi-Pr)4

was used as an additive. As suggested by model studies, this additive may avoidthe coordination of the ruthenium carbene by either the aryl ether (OBOM) or theneighboring ethers (OMe, OTCE).

The mild conditions of the olefin metathesis reaction make it an ideal methodfor the preparation of cyclitols and carbasugars [51, 52]. In general, the synthesesstart from readily available carbohydrate derivatives that are converted to dienesand then submitted to RCM conditions. The resulting functionalized cyclohexenesare then converted to the target molecules in a few straightforward steps [53b].According to this principle, the syntheses of (+)-cyclophellitol (230) (Scheme 1.40)[54], valienamine (233) (Scheme 1.41) [53, 55], valiolamine (236) (Scheme 1.42)[56], conduritol derivatives 238–240 (Scheme 1.43) [57], phosphatidyl inositol [58],and analogs (243) (Scheme 1.44) [59] have been reported.

Noncarbohydrate starting materials may also be used for preparing carbasugars.For example, Roush’s et al. asymmetric allylation of chiral aldehyde 244 gave diene245. Subsequent RCM catalyzed by [Ru]-II and dihydroxylation allowed access to


O OH

OBn

OBn

BnO

2,3,4,6-Tetra-O-benzyl-D-glucopyranose

231 232 (+)-Valienamine (233)

Steps Steps

BnO

OBn

OBn

BnO

BnO

HO

OBn

OBn

BnO

BnO OH

OH

OH

HO

HONH2[Ru]-I (14 mol%)

CH2Cl2, rt58%

Scheme 1.41

2,3,4-Tri-O-benzyl-D-arabinofuranose

234 235 (+)-Valiolamine (236)

Steps

OBn

BnO

BnO

OTMSO OH

OBn

BnO

BnOOBn

OBnOBn

TMSO

OH

HO

HO

OH

OH

NH2Steps RCM

92% (with [Mo]-I)42% (with [Ru]-I)

Scheme 1.42

OH OH

OHOH

HO

Glucitol 237 Tetra-O-benzylconduritol F (238)

Steps

OH

OBnOBn

BnO

BnO

OBnOBn

BnO

BnO

Tetra-O-benzylconduritol E (239)

OBnOBn

BnO

BnO

Tetra-O-benzylconduritol A (240)

OBnOBn

BnO

BnO

Mannitol Galactitol

RCM

32% (with [Ru]-I)89% (with [Ru]-II)92% (with [Mo]-I)

Steps Steps

Scheme 1.43

O OMe

OHOH

HO

Methyl a-D-glucopyranoside

Steps

OHOH

OBnOBn

BnO 83%

OH

OBnOBn

BnO

O

OHOH

HO

OHHO

PO

O OH

OC16H33

OH

Phosphatidylinositol analog (243)

Steps

241 242

[Ru]-I

Scheme 1.44


CHO

OBn

OBn

OBn

OBn OH

SiMe2Ph

87%

SiMe2Ph

OBn

OH

OBn

OsO4

SiMe2Ph

OBn

OH

OBn

HO

HO

OHOH

HO

HOOH

OH

OHHO

OH

OH

OH

OH

HO

HO

244 245 246 247

(+)-Conduritol F (248) D-(+)-chiro- inositol (250)(+)-Conduritol B (249)

BdIpc2PhMe2Si[Ru]-II

SiMe2Ph

OBn

OH

OBn

HO

HO

247

or or

Scheme 1.45

NH

O

O

O

HO OH

OH

OH

O

HO OHOH

OH

D-Xylose

StepsBnO OBn

OBn

COOMe

Ar2CuMgBr

BnO OBnOBn

COOMeAr

BnO OBn

OBn

Ar

BnO OBn

OBn

Ar90–95%

95–97%

OH

StepsAr = Ph, p-anisyl

Pancratistatin (251) 252

253 254 255

[Ru]-I

Scheme 1.46

the pivotal intermediate 247. This compound was converted to conduritols F (248)and B (249) by stereospecific syn (basic conditions) or anti (acidic conditions) Peter-son elimination, respectively, and debenzylation. Alternatively, Tamao–Flemingoxidation and debenzylation provided d-(+)-chiro-inositol (250) (Scheme 1.45) [60].

Pancratistatin (251), an important anticancer product, is structurally relatedto carbasugars. In 2004, Kornienko and Nadein reported a synthesis of 1-aryl-1-deoxyconduritols that were used as synthetic intermediates to prepare a seriesof simplified pancratistatin analogs. Compound 252, prepared from d-xylose,underwent conjugate addition of magnesium diarylcuprates to afford 253. Furthersteps led to 254 whose RCM catalyzed by [Ru]-I provided aryl deoxyconduritols 255(Scheme 1.46) [61, 62].

1.4Formation of Seven-membered Carbocycles by RCM

RCM of 1,8-dienes constitutes an efficient access to cycloheptenes since di-, tri-,and tetrasubstituted olefins could be elaborated in good yields with catalyst loadingas low as 1 mol%. In this context, the highly demanding field of natural productsynthesis constitutes an efficient test for the development of more active and

1.4 Formation of Seven-membered Carbocycles by RCM 23

OMeOMe

N

OHOMe

OH

O

ONO

O

OMeA

B

CD

E F

N

O

ONO

O

OH

Methyllicaconitine (256)

N

EtO2COH

N

EtO2COH

[Ru]-I(10 mol%) Steps

257 258 259

CH2Cl2, rt,24 h 97%

Scheme 1.47

functional group tolerant catalysts as shown by Stoltz in the (−)-cyanthiwigin Fsynthesis. The following section, by no mean exhaustive, covers the more recentapplications in RCM of 1,8-dienes applied to the synthesis of biologically relevanttargets. When possible, comparison between various catalysts and experimentalconditions is also discussed.

Challenging RCM was reported during the synthesis of the ABE tricyclic analogs259 of the alkaloid methyllicaconitine (256), a competitive antagonist of nico-tine acetylcholine receptors [63]. The B ring system was synthesized via a [Ru]-Icatalyzed RCM of the 1,8-diene 257 possessing two contiguous quaternary stere-ogenic centers. Compound 258 having the characteristic trans AB ring fusion ofmethyllicaconitine was obtained in excellent yield (97%) (Scheme 1.47).

A key step in the total synthesis of (±)-frondosin B (260) reported by Mehta andLikhite is RCM of 1,8-diene 262 using [Ru]-I (C6H6, reflux) [64]. The correspondingbicyclic 6,7-fused ring system 263 was obtained in good yield (80%). Cyclization of264 mediated by boron trifluoride led to the corresponding benzofuran 265, andsubsequent acid-catalyzed isomerization of the trisubstituted olefin then provided(±)-frondosin B (260) (Scheme 1.48).

In synthetic studies toward rameswaralide (266), a promising anti-inflammatoryagent, the cycloheptenone tricyclic core 269 was efficiently prepared through RCMof the acyclic ω-alkenyl acrylate 268 under very mild conditions using [Ru]-II(10 mol%) (CH2Cl2, rt) in high yield (90%) (Scheme 1.49) [65].

A related ω-alkenyl acrylate RCM was used in the first total synthesis of(+)-sundiversifolide (270) reported by Shishido et al. [66]. An excellent yield ofchiral cycloheptenone 273 was obtained from 272 using catalyst [Ru]-II. Enone 273was then chemoselectively reduced to the corresponding allylic alcohol 274, thussetting the stage for an Eschenmoser–Claisen rearrangement. Further iodolac-tonization/radical reduction led to bicyclic lactone 275, a late intermediate in thesynthesis of the natural product (Scheme 1.50).


A

B

CDO

HO

O

MeO

OMe

H OTBS

OH

MeO

OMe

H OTBS

OH

MeO

OMe

H OHO

OH

BF3·OEt2

CH2Cl2, 0 °C

H O

HO

TsOH

C6H6

[Ru]-I

C6H6, reflux80%

Steps

(±)-Frondosin B (260)

Steps

261 263

264 265

262

Scheme 1.48

OOTES

O

O

H

H

O

O

O

H

OH

CO2Me

H H

OH

A

B

CDO

OTES

O

O

H

H

OOTES

OTES

O

H

H

267

Rameswaralide (266)

Steps[Ru]-II

(10 mol%)

CH2Cl2, rt90%

268 269

Scheme 1.49

OO

HOH

H

(+)-Sundiversifolide (270)

N O

O

Bn

OOH

TBSO

O

Steps [Ru]-II (5 mol%)

CH2Cl2, reflux95%

TBSO

O

TBSO

OH1. Me2NC(OMe)2Me

toluene

2. I2, THF, H2O3. Bu3SnH, AIBN

OOTBSO

H

H

Steps

Red-Al

Et2O

271 272 273

274 275

Scheme 1.50

Trisubstituted olefins embedded in seven-membered carbocycles are also syn-thesized in high yields from the corresponding 1,8-dienes. In their elegant totalsynthesis of (−)-cyanthiwigin F (276), Stoltz and Enquist used for the first timecatalyst [Ru]-X [49] possessing an increased activity for the generation of trisub-stituted olefins. A double Pd-catalyzed decarboxylative allylic alkylation of 277 in


O

H

(−)-Cyanthiwigin F (276)

O

O

O

O

O

O

Ph2P N

O

t-Bu

Pd(dmdba)2Et2O, 25 °C

78% O

O

278(dr = 4.4 : 1, ee = 99%)

O

Steps

[Ru]-X (10 mol%)C6H6, 60 °C

OB

O

O

O t-BuSHAIBN

C6H6, 80 °C57%

O

H

OSteps

A B

C

277 279

280 281

dmdba = Bis(3,5-dimethoxybenzylidene)acetone

then NaBO351%

Scheme 1.51

OEtTESO

H

H OMOM

PO

OEtTESO

H

H OMOM

PO

[Ru]-II(5 mol%)

CH2Cl288%

O

O O

OHept

H OAc

O

O

OH

OH

OPr

O

Thapsigargin (282)

AD-mix a

96%O

TESOH

H OMOM

PO OHSteps

Cl

THPOH

O

NaOMe

MeOH0 °C

H

THPO

CO2MeH

Steps

283 284 285: P = TBDPS

286 287

Scheme 1.52

the presence of a chiral ligand gave 278, which was converted to tetraene 279[67]. RCM of 279 followed by a one-pot cross-metathesis with vinylpinacolboronateled after oxidation to the bicyclic aldehyde 280 possessing the BC ring system ofthe natural product. Radical cyclization of the latter compound (t-BuSH, AIBN)established the desired ABC tricyclic motif 281 that could be further transformedto (−)-cyanthiwigin F (276) (Scheme 1.51).

The guaianolide class of natural products is characterized by a tricyclic 5,7,5-ringsystem [68]. Among these promising sesquiterpene lactones were identified thethapsigargins (such as 282, Scheme 1.52), potent inhibitors of sarco/endoplasmicreticulum ATPases (SERCAs). Recently, Ley reported a successful strategy to accessthese complex natural products based on the construction of the seven-memberedring by RCM. Compound 283, prepared from (S)-carvone, underwent Favorskiiring contraction and 284 was converted to enol ether 285. RCM of 285, usingcatalyst [Ru]-II (5 mol%) allows the formation of the bicyclic enol ether 286 in


excellent yield (88%) [69, 70]. The latter was then efficiently converted into thecorresponding α-hydroxyketone 287 via asymmetric dihydroxylation. The samekey step was used in the total synthesis of closely related guaianolides, trilobolide,nortrilobolide and thapsivillosin F [71].

Ingenol (288) is a diterpenoid possessing a fascinating bicyclo[4.4.1]undecaneskeleton, with a highly strained intrabridgehead topology. RCM-based strate-gies for the construction of the B ring of ingenol were reported by Wood [72]and Kigoshi [73]. In Wood’s total synthesis, compound 289 (synthesized from3-carene) underwent Diels–Alder cycloaddition with cyclopentadiene to afford290 (Scheme 1.53). Ring-opening metathesis (ROM) with ethylene gave 291,which was further elaborated to the RCM precursors 292 and 293. Only 45% of

Cyclopentadiene

BF3·OEt259% OO

StepsO

H

HR

O98%

292: R = H293: R = CH2OPMB

[Ru]-I (80 mol%)for 292

[Ru]-III (25 mol%)for 293

294: R = H (45% from 292)295: R = CH2OPMB (76% from 293)

O

R

H

Steps

O

O

O

O

289 290 291

O

OH

H

HOHOHO

A B

C

D

Ingenol (288)

[Ru]-I (2 mol%)H2C CH2

Scheme 1.53

Et3CONa

Et3COH/xylenereflux, 53% O

O

H

HO

Cl

Steps

[Ru]-II (25 mol%)

Toluene, reflux87%

O

H

H

SeO2

Dioxane

296 297 298

299 Winkler's intermediate (300)

O

H

HCHO

Scheme 1.54


the desired cycloheptenone 294 was obtained from 287 using [Ru]-I (80 mol%),whereas an excellent 87% yield of 295 was obtained from 293 with [Ru]-III(25 mol%).

Kigoshi’s formal synthesis (Scheme 1.54) relies on the efficient spirocyclizationreaction of ketone 296 also prepared from 3-carene. The AC ring system was thenfurther elaborated into 1,8-diene 298 that could be cyclized to 299 in 87% yield using[Ru]-II (25 mol%). A dramatic temperature and solvent effect was observed as noreaction took place in dichloromethane. Allylic oxidation then delivered aldehyde300, an intermediate in Winkler’s total synthesis of ingenol [74].

A rare example of formation of cycloheptadiene from 1,3,8-triene was reportedby Hiemstra et al. in the enantioselective synthesis of the tetracyclic left-handsubstructure 301 of solanoeclepin A (302) (Scheme 1.55) [75]. Starting fromcompound 303, a [4+2]-cycloaddition was used to elaborate the oxabicyclic motif.Nolan’s catalyst [Ru]-VI (15 mol%) was used to cyclize the 1,3,8-triene 305 to thedesired cycloheptadiene 306 in quantitative yield. It is worth mentioning that[Ru]-I was quite inefficient in this case even if a stoichiometric quantity was used.

A concise asymmetric total synthesis of (+)-cyanthiwigin U (307) was reportedby Phillips and Pfeiffer relying on the clever use of tandem metathesis of bi-cyclo[2.2.2]octenes (Scheme 1.56) [76]. The two-directional tandem ROM–RCMof compound 308, using catalyst [Ru]-II under an atmosphere of ethylene,simultaneously generated the cyclopentenone and the cycloheptenone rings of

HO2C

H

OO

HO

O

O

OH

NOH

O

Ph

O

O N

O

Ph

HO

1. n-BuMgCl−60 °C

2. Toluenereflux

OAc

OOSteps

TBDPS

OAc

O

O

TBDPS

[Ru]-VI(15 mol%)

Toluene, reflux99%

OH

O

O

OMeO

Steps

301 Solanoeclepin A (302)

303 304 305

306

Scheme 1.55

Cyanthiwigin U (307)

H

O

OHO

OToluene>43%

H

O

OSteps

309308

[Ru]-II(20 mol%)

H2C CH2

Scheme 1.56


309 with great efficiency. This synthetic strategy was later extended to the synthesisof cyanthiwigin W and Z [77].

An RCM was reported by Wicha et al. in a synthetic approach to the diterpenesguanacastepene A (310) and heptemerone G (311) (Scheme 1.57) [78]. The1,8-diene 312 possessing a 1,1-disubstituted olefin was cyclized efficiently to 313in high yield (96%) using catalyst [Ru]-II. Further functional group transformationincluding epoxidation and Dauben oxidation [79] led to the AB core structure 314of the targeted diterpenes.

This very efficient RCM should not mask the fact that trisubstituted double bondsof terpenoids, imposed by the biosynthesis pathway from isoprene units, could bechallenging to prepare through the RCM of 1,8-dienes as subtle differences in themetathesis precursor can have a dramatic impact on the reaction rate and yields [80].

For example, [Ru]-I could efficiently catalyze the RCM of the substituted 1,8-diene315 to the corresponding trisubstituted cycloheptene 316 as demonstrated by Toriet al. in the total synthesis of two sphenolobane-type diterpenes (Z,E)- and (E,E)-320isolated from the liverwort Anastrophyllum aurium (Scheme 1.58) [81].

However, during a synthesis of (−)-tormesol (321), a diterpene isolated fromHalimium viscosum, the cyclization of the related nonenolizable β-ketoester 322proved sluggish as only 50% conversion was observed using catalyst [Ru]-I incombination with Ti(Oi-Pr)4 (1 equiv.). The more active [Ru]-II overcame thislimitation and allowed the synthesis of cycloheptene 323 in excellent yield with a low

O OHCOR2

i-Pr

R1

R1 = OAc, R2 = H : Guanacastepene A (310)R1 = H, R2 = Ac : Heptemerone G (311)

AB

C

OOPiv

O

H

OPiv

[Ru]-II

CH2Cl2, reflux96%

O

i-Pr

O

HO

Steps

313 314312

Scheme 1.57

(Z,E )- and (E,E )-320Sphenolobane-type diterpenoids

TESOCO2Et [Ru]-I

(10 mol%)

CH2Cl2, 40 °C94%

TESOCO2Et

H

Steps

H

CNSteps

O

O

MgBr1.

2. PCC O

H CHO

319

Steps

318

317316315

O

H

OH

Scheme 1.58


catalyst loading (1 mol%) [82]. Compound 323 was then converted to (−)-tormesolthrough intermediates 324 and 325 (Scheme 1.59) [81, 82].

A very challenging RCM was reported by Reiser et al. during the enantiose-lective synthesis of arglabin (326), a promising antitumor agent isolated fromArtemisia glabella [83]. Condensation of cyclopropanecarbaldehyde 327 with allylicsilane 328 led, after treatment under basic conditions, to adduct 329, which wasfurther elaborated to 330. The tetrasubstituted double bond embedded into theseven-membered ring of 331 was efficiently prepared via the RCM of compound330. Worthy of note is that an inert gas sparging of the reaction combined withcatalyst [Ru]-II (15 mol%) had to be used to ensure complete conversion. Epox-idation from the α-face of the seven-membered ring proved troublesome sincethe more stable β-epoxide was obtained using dimethyldioxirane or peracids. Ahydroxyl-directed vanadium-catalyzed epoxidation of the homoallylic alcohol 331overcame the intrinsic bias of the system, leading to the desired epoxide 332 ingood yield and selectivity (Scheme 1.60).

HO

H

(−)-Tormesol (321)

OCO2Et

[Ru]-I (30 mol%)Ti(Oi-Pr)4 (100 mol%)40 °C, 50% conv.

or[Ru]-II (1 mol%), 45 °C88–95%

OCO2Et O

CN

Steps

HO

Li

Et2O, −78 °C

Steps

322 323 324

325

Scheme 1.59

OO

OH

H

H

(+)-Arglabin (326)

CHO

OO H

H

H

OPMB

OHC

O

CO2Et

TMS

OPMB

OCO2Me BF3·OEt2, −78 °C

then

Ba(OH)2·8H2O0 °C62%

OO H

H

H

AcO

OPMB

Steps

OO H

H

H

AcO

OH

1. [Ru]-II (15 mol%)TBHP

V(O)(acac)2(2 mol%)

78% OO H

H

H

AcO

OH

O

Steps

327 328 329 330

331 332(a /b = 90 : 10)

2. DDQ (90%)

+

toluene, 95 °Csparging with Ar(70%)

Scheme 1.60


1.5Formation of Eight-membered Carbocycles by RCM

Cyclooctanoids are among the most difficult carbocycles to elaborate from acyclicprecursors due to severe developing ring strain and restricted bond rotation inthe precyclization conformer [84]. In the mid 1990s, RCM of 1,9-dienes emergedas a powerful strategy for the synthesis of carbocyclic eight-membered ring [85].Steric and conformational effects were found to have a dramatic impact on the rateand efficiency of cyclization reactions. High catalyst loading (up to 50 mol%), longreaction times, and elevated temperatures were usually reported. Up to 2006, anexcellent review compiles the recent advances in the synthesis of challenging di-[86] and trisubstituted [87] double bonds embedded in cyclooctenyl rings [88].

The dicyclo[a,b]cyclooctane ring systems found in ophiobolin M (333) andfusicoccin A (334) terpenes have stimulated a great deal of interest. The groups ofWilliams [89] and Wicha [90] reported two different RCM approaches aiming at therapid elaboration of the eight-membered B ring system. The first approach reliedon a [Ru]-I catalyzed RCM of triene 335 leading to cyclooctene 336 in moderate yield(Scheme 1.61) [89]. Worthy of note is the fact that [Ru]-II proved inferior as a catalystleading to lower conversion and partial isomerization of the terminal olefin(s).

The second approach [90] reports the synthesis of the AB ring system ofserpendione (337) via RCM reaction of 338 (Equation 1, Scheme 1.62) that contains

O[Ru]-I (6 mol%)

CH2Cl2, 45 °C45%

O

O

O

HOH

HH

Ophiobolin M (333)

335 336

OAc

RO

H

OMe

HO

OH

Fusicoccin A (334)(R = Carbohydrate)

( )3

Scheme 1.61

O

HH

Serpendione (337)

O

MeO

O

COOMe

H

O

COOMe

H

O

[Ru]-II (3 mol%)

CH2Cl2, reflux95%

COOMe

H

O

[Ru]-II(3 mol%)

CH2Cl2reflux95%

COOMe

H+

O

341 (34%)

COOMe

H

O

342 (49%)

338 339

340

(1)

(2)

Scheme 1.62

1.5 Formation of Eight-membered Carbocycles by RCM 31

OO O

AcO

H

Me

(±)-Mycoepoxydiene (343)

O

Me

OTBDPS [Ru]-I (20 mol%)

C6H6, reflux83%

O

Me

OTBDPS

Steps

O HMe

OOH

V(O)(acac)2TBHP

OO OH

O

HMe

Steps

344 345

346 347

76%

Scheme 1.63

both a geminal disubstituted and a monosubstituted olefin. The [Ru]-II catalyzedtransformation was extremely efficient and delivered compound 339 possessingthe AB ring system in 95% yield. When exposed to [Ru]-II, the epimeric compound340 could be transformed to the desired cyclooctene 341, albeit in low yield(34%). Isomerization of the allylic double bond prior to cyclization accounts forthe major cycloheptene product 342 (49%) (Equation 2, Scheme 1.62), thus onceagain stressing the importance of subtle steric and conformational effects in theformation of medium rings by RCM. By contrast, the use of [Ru]-I led only todimerization.

Imposing a conformational constraint that favors cyclization is a useful strategyfor the RCM of 1,9-dienes. In the total synthesis of (±)-mycoepoxydiene (343),Tadano et al. reported the RCM of the diallylated tetrahydrofuran 344 using catalyst[Ru]-I under diluted conditions to prevent oligomerization [91]. A good yield of thedesired oxygen-bridged cyclooctene 345 was obtained (83%). A dramatic solventdependence was noted as CH2Cl2 induced only decomposition of the starting diene344. Compound 345 was converted to (±)-mycoepoxydiene 343 in several stepsincluding oxidation of furylcarbinol 346 to dihydropyranone 347 (Scheme 1.63).

Vinigrol (348) is a metabolite of the fungal strain Virgaria nigra that possessesa fascinating tricyclo[4.4.4.04a,8a]tetradecane skeleton [92]. Its biological activity,including antihypertensive, platelet aggregation-inhibiting, and tumor necrosisfactor antagonist properties, has fueled a considerable synthetic interest. Thegroups of Barriault [93] and Paquette [94] investigated two different approachesinvolving disconnections of the carbocyclic eight-membered ring through RCMat the C9–C10 or C10–C11 positions, respectively. Unfortunately, these twostrategies met with failure. As observed in previous studies, [Ru]-I was not activeenough to promote the RCM of 1,9-dienes 349, 350, and 351, and [Ru]-II led todouble bond migration (Scheme 1.64).

In order to increase conformational flexibility in the cyclization precursor,Paquette et al. considered the relocation of the double bond from the �3,4 to the�2,3 site to project axially the two C1 and C5 substituents. As shown by MM3calculations on model systems, the closer proximity of these two substituents inthe �2,3 isomer could allow a more RCM. Diene 352 was then prepared and


HO

HO HO

H

9

10

11

Vinigrol (348)

H

O

O

H

OO H

H

9

109

10

[Ru]-I or[Ru]-II

X

10

11

O

R1

R2

350: R1, R2 = OCH2CH2O351: R1 = OTBDPS, R2 = H

H

10

11O

R1

R2

X

349

[Ru]-I or[Ru]-II

Scheme 1.64

OH1 2

34

5 1 234 5

13 5

HH OH

HH

H

OH1

3 5

H

OH OH

OH

H

HO OH

H

H

HH

2OTBDPS

1

3 5

AcO AcO

AcO AcO

H

10

11

OP

X

∆3,4 isomer ∆2,3 isomer

352

[Ru]-II

Scheme 1.65

subjected to catalyst [Ru]-II but unfortunately, only starting material was recovered(Scheme 1.65).

Prunet et al. have extensively investigated the possibility of synthesizing the Bring system of Taxol (353) via the RCM of 1,9-diene 355 (Scheme 1.66) [95].When a diastereomeric mixture of the latter compound and epi-355 was subjectedto catalyst [Ru]-I, only compound 355 cyclized to cyclooctene 356 (possessing theC9–C10 unsaturation) albeit slowly, emphasizing once again that RCM is highlydependent upon the conformational and steric effects in the cyclization precursor(Equation 1, Scheme 1.66). Recently, the formation of the C10–C11 unsaturationby RCM was reported and proved more efficient in terms of protecting groupcompatibility and catalyst efficiency (Equation 2, Scheme 1.66). Unprotected diol357 led to the desired cyclooctene ring 358 in an impressive quantitative yield,thus suggesting that the BC ring system of taxol may be synthesized accordingto this strategy. These recent results are in stark contrast to the previous C9–C10

1.6 Formation of Nine-membered Carbocycles by RCM 33

O OH

OOAc

HHO

R2O

O

OBz

R1 = Bz, R2 = Ac: Taxol (paclitaxel) (353)R1 = Boc, R2 = H: Taxotere (docetaxel) (354)

AB

D

910

O O

O

Bu

[Ru]-I(10 mol%)

C6H6, reflux, 8 d

910

O O

O

Bu+ +

910

O O

O

Bu O O

O

Bu

355

21 2121 21

356 (34%)epi -355 epi -355 (46%)

OR1HN

PhOH

OH OHBu

[Ru]-II(5 mol%)CH2Cl2

OHBu OH

357 358

Reflux100%

(1)

(2)

C

Scheme 1.66

RCM strategy that was thwarted by conformational constraints imposing a cycliccarbonate protecting group of the C1–C2 diol motif.

1.6Formation of Nine-membered Carbocycles by RCM

The failed metathesis-based synthesis of pestalotiopsin A 359, compared to thesuccessful synthesis of cornexistins, reported by Paquette et al. [96] and Clark et al.[97] illustrates well the uncertainty linked to RCM toward 8 to 10-membered rings.RCM of several substrates 360–362 was evaluated (Figure 1.2). For 360 and 361,regardless of the catalyst used ([Ru]-I, II, III, VII, and XI), the starting diene waseither recovered (when the reaction was performed below 80 ◦C) or decomposed(in refluxing toluene). The MOM ether 362 was isomerized to 363.

OHO

H

AcO

OHOMe

H

OO

H H

O

OHOMe

OO

H H OHOMe

OO

OO

H H OMOMOMe

OO

OO

H H OMOMOMe

OO

Pestalotiopsin A (359) 360 361 362 363

Figure 1.2 Pestalotiopsin a synthesis:unteactive RCM substrates.


OHOHO

OH5

OO O

Hydroxycornexistin (364)O O

OO

O

OO

O

OO

O

+

H H

365 366

367 (dr = 1 : 1) 368 369

RCM

[Ru]-I, CH2Cl2reflux (70%)

or [Ru]-II, toluene80 °C (61%)

368/369 = 2 : 3

Scheme 1.67

In 2003, Clark et al. reported a novel strategy for the preparation of cornexistins.

In model studies, attempts to form intermediate 364, featuring a trisubstituted

olefin, by the RCM of 365 were unsuccessful regardless of the catalyst used ([Ru]-Ior [Ru]-II). In contrast, the cyclization of 367 (a racemic mixture of two diastere-

omers) led to the isomeric mixtures 368 and 369 in good yield. In subsequent

studies, the RCM reaction was examined more closely and shown to be signif-

icantly stereoselective (368/369 = 2 : 3) [98].3) Compound 368 was converted to

(±)-5-epi-hydroxycornexistin in a few additional steps (Scheme 1.67).

1.7Formation of 10-membered Carbocycles by RCM

In 2001 and 2002, Koskinen et al. reported what appeared to be the first examples of

10-membered ring carbocycle syntheses via RCM [99]. As can be seen in Table 1.1,

the reaction proved difficult to perform and yields remained moderate even under

optimized conditions. Using alcohol 370a (syn/anti = 2 : 1), a single cyclized product

(371a) was obtained in low yield and some starting material was recovered. With

the silyl ether 370b as substrate, the reaction was cleaner, affording a mixture of

three diastereomers in fair yield. Addition of Ti(Oi-Pr)4 was slightly beneficial. The

roughly 2 : 1 trans/cis ratio of the major RCM products 371b and 372b compares

well with the corresponding 2 : 1 syn/anti ratio of the substrate 370b [99a]. When

3) [Ru]-I catalyst was used for this transforma-tion (18 hours, CH2Cl2, reflux, 77%). [Ru]-II

did not bring any significant improvement(personal communication from Dr Clark).

1.7 Formation of 10-membered Carbocycles by RCM 35

OO

HO

O

O

O

Diversifolin (374)

OHO

O

TBDMSO

OHO

O

OTBDMS

OHO

O

TBDMSO

+

OHO

O

TBDMSO

375dr = 1 : 1

377 (35%)(R )-376 (31%)(S )-376 (40%)

Toluenereflux

Toluenereflux

(R )-376 (27%)(S )-376 (trace)

[Ru]-II(10 mol%)

BQ (20 mol%)[Ru]-II

(10 mol%)

Scheme 1.68

Table 1.1 Cyclization of alcohol 370a and TBDMS ether 370b.

O OR

i-Pr

O OR

i-Pr

O OR

i-Pr

O OR

i-Pr+ +

370a : R = H370b : R = TBDMS

371a371b

372a372b

373a373b

[Ru]-I

CH2Cl2reflux, 48 h

(syn/anti : 2 : 1)

Substrate Substrate recovery (%) Products

370a 25 371a (11%) – –370b 6 371b (16%) 372b (35%) 373b (11%)370b + Ti(Oi-Pr)4 (20 mol%) 0 371b (21%) 372b (47%) 373b (8%)

the more active [Ru]-II catalyst was used, only the syn-370b precursor cyclized toafford a mixture of 371b and 373b in a 1 : 6 ratio. The anti-370b isomer was notrecovered and was probably converted to polymeric material [99b].

A synthetic study toward diversifolin (374) was published in 2007 by Kobayashiet al. (Scheme 1.68) [100]. First, a long sequence (17 steps) led to the key RCMsubstrate 375, obtained as a mixture of epimers. RCM was difficult and requiredsignificant optimization. While using [Ru]-I no reaction was observed, whereas[Ru]-II in 1,2-dichloroethane (DCE) led to the formation of 377 in low yield (15%) inwhich one of the terminal olefin had shifted. When toluene was used as the solvent,


O

O

OO

O

OH

H

O

O

H

O

Me OMe

OTf

O

O

H

O

Me OMe

O

O

O

O

H

O

Me OMe

O

O

O

OKN(SiMe3)2 +

O

O

H

O

Me OMe

O

O

(+)-Eremantholide A (378)

379 380 381

384

HCl

81%

O

O

H

O

Me OMe

O

O

+O

O

H

O

Me OMe

O

O383 (32%)382 (28%)

54% 82%

2. MsCl, base

1. HCHO

[Ru]-III383

380/381 = 1 : 1

LiN(SiMe3)2

Scheme 1.69

OO

O

O

O

ent-Clavilactone B (385)

OHCO

OSiPh2t-Bu

OMe

OMe

F

1. BuLi

2. ClMgMeO

OMe

O

OSiPh2t-Bu387386 388

65%

OH

Steps

389

OO

O

OMe

OMe

OO

O

O

O

CAN

390

3.

[Ru]-II (40 mol%)slow addition

Tetrafluoro-1,4-benzoquinone (80 mol%)toluene, 80 °C

65%

Scheme 1.70

377 was obtained in 35% yield along with (3R)-376 (27%), and some startingmaterial was recovered. Only (3R)-375 cyclizes rapidly and no (3S)-376 was formed.RCM of (3S)-375 is more difficult allowing the competing olefin isomerizationto prevail. This may be avoided by adding 1,4-benzoquinone (BQ), whose roleis probably to prevent the accumulation of ruthenium hydrides (decompositionproducts of [Ru]-II) that are thought to be responsible for olefin migration [101].

In Hale’s and Li’s synthesis of (+)-eremantholide A (378) (Scheme 1.69), theRCM step takes place almost at the end of the synthesis and involves a fairly

1.7 Formation of 10-membered Carbocycles by RCM 37

hindered substrate. Epimers 382 and 383 were prepared by alkylation of triflate379 followed by hydroxymethylation and subsequent dehydration. Using [Ru]-IIIas catalyst, the reaction works well. Remarkably, only epimer 383 reacted, affordingthe desired bicyclic system 384 in 54% yield and (+)-eremantholide A, while theother diastereomer 382 cross-metathesized [102].

In Barrett’s synthesis of ent-clavilactone B 385 (Scheme 1.70), the benzyneintermediate generated from 386 was allowed to react with methallylmagnesiumchloride and epoxy-aldehyde 387, leading to compound 388, which was convertedto the RCM precursor 389. As expected, RCM proved to be difficult and had tobe performed under special conditions: the catalyst [Ru]-II (40 mol%) was slowlyadded, along with tetrafluoro-1,4-BQ (to prevent olefin isomerization), and theformed ethylene was removed during the reaction. Under these conditions, theRCM product 390 was obtained in a satisfactory yield (65%) and converted toent-clavilactone B [103].

During the period 2001–2006, Gennari et al. published a series of accountsdescribing the synthesis, via RCM, of simplified eleuthesides as potential anticanceragents [104–106]. In particular, these authors recently reported a novel formalsynthesis of eleutherobin 391 (Scheme 1.71) [105, 106].

Starting from (R)-(−)-carvone, the half-protected dialdehyde 392 was prepared.Diastereoselective reagent-controlled oxyallyltitanations (with TADDOL as

O

OMeH

O

O

N NH

O

O

OAcOH

OHEleutherobin (391)

O

OMeH

H

OPiv

397

OHOPMP

H

MOMOH

OPivOH

CHO

H

H

PMPOs-BuLi

[(S,S )-TADDOLCpTiCl]

OPMP

H

MOMOH

Steps

CHO

OPMP

H

MOMOH

OMe

OMe

OMe

OMe

1.

2. MOMCl, Et3N

2. PivCl, DMAP, i -Pr2NEt

OPMP

H

MOMOH

OPivOH

HH

392 393 394

395 396

Steps

PMPOs-BuLi

[(R,R )-TADDOLCpTiCl]

1.[Ru]-II

(30 mol%)slow

addition

Toluenereflux64%

Scheme 1.71


the chiral ligand) of both aldehydic functions led to the RCM precursor395, which was cyclized using [Ru]-II catalyst to afford the 10-memberedcarbocycle 396. The latter was converted to the advanced intermediate397 that had previously been converted to eleutherobine. Forcing RCMconditions were necessary ([Ru]-II [30 mol%], slow addition, toluene, reflux),and surprisingly, only the (E)-cycloalkene 396 was obtained [25, 106, 107].Using simplified models of 395, Gennari et al. have shown by a variety ofmethods (molecular mechanics, DFT) that the trans-four-membered ruthenacycleintermediates 398 leading to (E)-cyclodecenes are significantly more stablethan the corresponding cis-ruthenacycles 399, leading to (Z)-cyclodecenes(Scheme 1.72). RCM of diastereomer 400 was more difficult than that of 395,affording the ring-cyclized product 401 in low yield alongside with regioisomer402 resulting from a metathetic ring rearrangement (RCM–ROM–RCMcascade).

Excentricine 403 belongs to a rare class of isoquinoline alkaloids featuring abridged, bicyclic ether moiety. A possible approach to this class of compounds wasillustrated by the synthesis of the simplified model compound 408 (Scheme 1.73)[108]. The strategy relies on a Bischler–Napieralski isoquinoline synthesis and anRCM as key reactions. The site of the RCM reaction was chosen so as to avoidthe formation of inactive ruthenium complexes (likely to be observed for γ ,δ- orδ,ε-unsaturated amides or esters). RCM of diene 406 proceeded smoothly usingcatalyst [Ru]-II to afford the desired 10-membered ring 407 in good yield (68%).However, the last deprotection step was unsatisfactory and proceeded only in lowyield. The solution to this problem was provided by simply inverting the reactionsequence. Thus, a facile RCM in the presence of [Ru]-I afforded the 14-memberedmacrocyclic lactam 409. After hydrogenation of the olefin, a Bischler–Napieralskireaction led to the 2,3-dihydroisoquinoline 410 that was reduced to 408.

OPMP

H

MOMOH

OPivOPMP

OPMP

H

MOMOH

OPivOPMP

HH

400 401 (27%)

+ MOMO

PMPO

H

H

OPMP

OPiv

402 (15%)

OPh

H

OMeH

OPivOPh

HH RuLn

More stable than

OPh

H

OMeH

OPivOPh

RuLn

H

H

398 (+34.1 kJ) 399 (+47.3 kJ)

Intermediates (relative energy)

[Ru]-II

Scheme 1.72

1.8 Conclusion 39

NAc N

Ac

HN O

MeO

MeON

MeO

MeO

NH

MeO

MeO

O

HH

OH

H

NH

MeO

MeO

CHO

MeO

OH

Steps POCl3

Steps

Excentricine (403)

408

Vanillin 404 405

406 407

MeO

MeO

MeO

MeO

95%

404NH

409

MeO

MeOO

N

MeO

MeO

[Ru]-II

CH2Cl2reflux68%

Steps[Ru]-I

CH2Cl2rt

88%

410

Steps

H2, Pd/C408

Scheme 1.73

1.8Conclusion

In the last decade, the alkene/alkyne metathesis reaction has become a major

synthetic tool for the preparation of complex organic molecules and, not surpris-

ingly, RCM has proved to be particularly useful for the synthesis of medium-size

(5–10-membered) rings. For ring sizes of five to seven, the reaction works well but

for larger (8–10-membered) rings, the metathesis is less predictable and its outcome

depends on still imperfectly understood factors. Remarkable sequences, in partic-

ular [3,3]-sigmatropic rearrangement/RCM or RCM/fragmentation combinations,

have been classically used as synthetic strategies.


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