Total synthesis of terpenoids isolated from caulerpale algae and their inhibition of tubulin assembly

1

66

FEATURE ARTICLE

Total Synthesis of Terpenoids Isolated from Caulerpale Algae and Their

Inhibition of Tubulin Assembly

a

a,b

b

c

b

S

L

ynthesis of Ter

a

penoids Iso

u

lated fromC

r

aulerpa

e

le

A

lgae nt Commeiras, Julien Bourdron, Soazig Douillard, Pascale Barbier, Nicolas Vanthuyne, Vincent Peyrot,*

a

Jean-Luc Parrain*

a

UMR-CNRS 6178 SymBio, équipe Synthèse par voie Organométallique, Université Paul Cézanne, Aix-Marseille III, France

Fax +33(4)91288861; E-mail: jl.parrain@univ.u-3mrs.fr

b

c

FRE-CNRS 2737, Interaction entre Systèmes Protéiques dans la Cellule Tumorale, Faculté de Pharmacie, Aix-Marseille II, France

Fax +33(4)91835505; E-mail: vincent.peyrot@pharmacie.univ-mrs.fr

UMR 6180 ‘Chirotechnologies: Catalyse et Biocatalyse’, Laboratoire de Stéréochimie Dynamique et Chiralité, Université Paul Cézanne,

Aix-Marseille III, France

Received 28 September 2005

AcO

Abstract: Total synthesis of four analogue terpenoids isolated from

Caulerpa taxifolia was achieved in good yield with a total control

of each double bond. Biological tests to compare the activities of in

vitro tubulin polymerisation between the natural caulerpenyne and

the synthetic caulerpenyne and its derivatives were also performed.

OAc

O

AcO

Caulerpenyne (1)

Taxifolial A (2)

Key words: total synthesis, caulerpenyne, dihydrorhipocephalin,

furocaulerpin, terpenoids, microtubule polymerisation

AcO

O

OAc

Introduction

AcO

Dihydrorhipocephalin (3)

Furocaulerpin (4)

Marine algae of the order Caulerpales are known for their

chemical defence against predators by producing second-

ary metabolites. The majority of these compounds are ses-

quiterpenoids and diterpenoids, often acyclic. The

terminal 1,4-diacetoxybutadiene moiety is a functional

group common to most of these metabolites and uniquely

found in this group of marine algae. To date, more than

thirty toxins with this moiety have been isolated from the

Udoteaceae and Caulerpaceae families such as cauler-

AcO

OAc

AcO

Crispatenine

Flexiline

penyne, flexiline, dihydrorhipocephalin and crispatenine

Figure 1 Some of the toxins isolated from Udoteaceae and Cauler-

paceae algae

1

(Figure 1).

The 1,4-diacetoxybutadiene moiety represents an acetyl-

ated bis-enol form of the 1,4-dialdehyde constellation, to

which a high degree of biological activity is generally at-

tributed. Indeed, some metabolites containing this moiety

have been implicated in chemical defence against grazing

fishes and invertebrates in herbivore-rich tropical waters

and this has, for example, been proposed to explain the

proliferation from Italy to Spain of Caulerpa taxifolia, a

tropical green seaweed accidentally introduced in the

Mediterranean sea. From Caulerpa taxifolia were isolated₂

nine mono- and sesquiterpenes such as caulerpenyne

CYN is well known for its important biological activity: it

displays antineoplastic and antibacterial properties. It in-

3

hibits the first division of sea urchin eggs without affect-

4

ing fertilization and induces a transient cytoplasmic

5

acidification followed by an efflux of protons. In addi-

2

+

tion, CYN alters ATP-dependent Ca storage in intracel-

lular organelles, protein phosphorylation, and DNA

4

synthesis. Moreover, Fischel et al. showed that CYN in-

6

hibited growth in eight human cancer cell lines. Their

study showed that in the presence of CYN, cells exhibited

an early and marked shift into S phase followed by a

(

CYN, 1) which represents the main secondary metabolite

of this algae.

blockage in the G /M phase. Recently, we have demon-

2

strated that natural CYN induced an inhibition of neuro-

blastoma SK-N-SH cell line with an inhibitory

concentration of 8±1 mM after 24 hours of incubation. No

blockage in G /M phase but an increase in cell death was

2

observed. By immunofluorescence of the tubulin cyto-

skeleton, we observed a modification of the microtubule

network in presence of natural CYN. Moreover, natural

CYN inhibits the tubulin polymerisation in vitro with an

SYNTHESIS 2006, No. 1, pp 0166–0181

Advanced online publication: 16.12.2005

DOI: 10.1055/s-2005-921760; Art ID: Z18505SS

0

6

.

0

1

.2

0

6

©

Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE

Biographical Sketches

Synthesis of Terpenoids Isolated from Caulerpale Algae

167

Laurent Commeiras, born from Caulerpale algae under Lecturer at the University of

in 1975 in Marseille the supervision of Dr. Jean- Marseille. His research in-

(

France), received his Ph.D. Luc Parrain. After postdoc- terests include the total syn-

in 2002 from the Université toral research in the labora- thesis of natural and

Paul Cézanne of Marseille tory of Professor Sir Jack E. biological compounds.

working on the total synthe- Baldwin at the University of

sis of terpenoids isolated Oxford (UK), he became

Julien Bourdron was born and at the Université Paul ing on the synthesis and bio-

in Saint-Gaudens (France) Cézanne of Marseille. He is logical

evaluation

of

in 1981. He has studied now in the third year of his Caulerpenyne and deriva-

chemistry at the chemical Ph.D. under the supervision tives.

engineering

school

of of Drs. Jean-Luc Parrain

Marseille (ENSSPICAM) and Vincent Peyrot, work-

Soazig Douillard was born two years studying actin dy- search working on the

in 1973. She is postgraduat- namics and cell migration at microtubule cytoskeleton at

ed in Biotechnology from the University of Bristol the Faculty of Pharmacy of

the University of Com- (England). She is now in- Marseille.

piègne (France). She spent volved in biophysics re-

Pascale Barbier was born ing on the interaction of new research interests are the in-

in Toulon (France) in 1968. analogues of colchicine teraction mechanism of syn-

She received her Ph.D. in with tubulin. She is now lec- thetic or natural drugs with

biochemistry in 1996 from turer at the Faculty of Phar- tubulin, an essential constit-

University of Paris XI work- macy of Marseille. Her uent of the cytoskeleton.

Nicolas Vanthuyne was ceived his Ph.D. under the by chiral HPLC. His re-

born in Lille (France) in supervision of Professor search interests include

1

977. He studied chemistry Christian Roussel in 2004, chiral recognition mecha-

at the chemical engineering working on synthesis and nisms, dynamic stere-

school of Marseille and at evaluation of chiral selec- ochemistry and synthesis of

the Université Paul Cézanne tors. He is currently working heterocyclic atropisomers.

of Marseille, where he re- on separation of enantiomers

Vincent Peyrot was born in Pharmacology in 1986 from of Pharmacy of Marseille in

Gap (France) in 1957. Doc- University of Marseille. He 1998 and his research inter-

tor in pharmacy since 1980, was promoted to Professor ests are in biophysical

he received his Ph.D. in in biophysics at the Faculty ligand-receptor interactions.

Jean-Luc Parrain ob- of Oxford, he joined the His research interests in-

tained, in 1990, his Ph.D. in CNRS as chargé de recher- clude new catalytic reac-

Chemistry at the University che at the laboratory of Or- tions toward new synthetic

of Nantes (France) under the ganic Synthesis of the methods, development of

supervision of Professor University of Nantes. In new organotin and silicon

Jean-Paul Quintard. After 1995, he moved to the Uni- reagents and total synthesis

post-doctoral studies in the versity of Marseille and then of natural compounds.

laboratory of Professor was appointed a CNRS di-

Steve Davies at University rector of research in 2001.

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

68

L. Commeiras et al.

FEATURE ARTICLE

inhibitory concentration of 21±2 mM. By electronic mi- Synthesis of Caulerpenyne (1) and Dihydrorhipoceph-

croscopy, we concluded that CYN induced aggregation of alin (3)

tubulin which may be responsible for the microtubule in-

hibition.

Our planned synthesis of 1 and 3 (Scheme 1) called for the

initial preparation of common functionalized fragments

7

In order to study the structure-activity relationship con-

cerning the pharmacophore requirements, to prove the

significant role of the diacetoxybutadiene moiety in bio-

logical effects of such terpenoids and to evaluate the role

of the chiral centre, the terminal alkyl chain and stereo-

chemistry of diacetoxybutadiene moiety, we have under-

taken the first total racemic synthesis of CYN (1) and the

first total synthesis of three other natural analogues of

CYN: taxifolial A (2), dihydrorhipocephalin (3) and furo-

caulerpin (4).

I and II (X = halogen for CYN and X = alkyl for 3). The

main structural features of CYN (1) are a diacetoxybuta-

diene moiety, a secondary acetate stereocentre, and a di-

enyne function in which the trisubstituted central double

bond presents an E configuration. Our strategy for synthe-

sizing caulerpenyne (1) is based on the synthesis of one of

its metabolites taxifolial A (2). Aldehyde 2 was construct-

ed by coupling of three fragments I, II and III.

Synthesis of fragment I (Scheme 2) began with a palladi-

9

um complex catalyzed hydrostannation reaction of but-2-

This article is a full account of the synthesis of CYN (1)

yndiol to give E-alkenyltin reagent 5 in which the more

accessible alcohol function was selectively protected as

tert-butyldimethylsilyl ether in 64% yield over two

and three other, naturally occurring analogous terpenoids

8

2

, 3 and 4 completed by the biological evaluations/com-

10

parisons on the in vitro inhibition of the polymerisation of

microtubules for each of enantiomeric and diastereomeric

forms of all synthetic metabolites.

steps. Synthesis of the fragment III (Scheme 2) was per-

formed via the Corey alkynylation reaction.¹¹Commer-

cially available 3,3-dimethylacrolein was reacted with the

reagent prepared from carbon tetrabromide, zinc and

triphenylphosphine to give gem-dibromodiene 7. Treat-

ment of 7 with butyllithium (2 equiv) followed by addi-

tion of trimethyltin chloride afforded the corresponding

alkynyl stannane 8 in 88% yield over two steps. If we

want to realize a Negishi coupling the alkynyllithium can

be trapped by zinc dibromide to afford the nonisolable

alkynylzinc 9.

Results and Discussion

In this part, we describe the synthesis of CYN (1) and the

other natural secondary metabolites [taxifolial A (2), di-

hydrorhipocephalin (3) and furocaulerpin (4)] in racemic

and enantio-enriched forms.

With fragments I and III in hand, we next focussed our at-

tention towards the synthesis of fragment II which was

found more difficult than the two others. The main prob-

Cross-coupling

AcO

OAc

O

AcO

caulerpenyne (1)

Nucleophilic addition

taxifolial A (2)

OH

M

O

Li

OP

X

O

HO

III

II

I

AcO

OAc

O

AcO

dihydrorhipocephalin (3)

Nucleophilic addition

Scheme 1 Retrosynthetic analysis of the synthesis of caulerpenyne and others

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

169

Synthesis of fragment I

OH

a

b

OH

HO

OH

SnBu3

OTBS

SnBu3

99%

65%

5

6

Synthesis of fragment III

Br

c

d

O

Br

quant.

8

8%

SnMe3

7

8

e

ZnBr

9

Scheme 2 Synthesis of fragments I and III. Reagents and conditions: a) Bu SnH, PdCl (PPh ) ; b) TBDMSCl, imidazole; c) CBr , PPh , Zn,

3

2

3 2

4

3

r.t.; d) (i) BuLi, –78 °C, (ii) Me SnCl, –78 °C to r.t.; e) (i) BuLi, –78 °C, (ii) ZnBr

3

2

lem is to prepare a functionalised homoallylic aldehyde To explain the large amount of unreacted starting material

controlling the regio- and stereoselectivity of the double 11, we propose that the intermediate iodo–titanium com-

bond. The synthesis began with the formation of the alle- plex B can undergo a b-elimination process to form 11

nylaluminum reagent, from propargyl bromide promoted (Scheme 3).

by a catalytic amount of mercuric chloride, which reacts

To avoid this problem, we chose to invert the order of the

at low temperature with triethyl orthoformate to give the

addition of electrophiles (Scheme 4): the proton source

1

2

corresponding 1,1-diethoxybut-3-yne (10). Then, the

methylation reaction of 10 was performed with 1) lithium

amide in ammonia and 2) methyl iodide to afford 11 in

was added first followed by the iodine. Using acetic acid

as first electrophile, the reaction furnished a 73:27 regio-

isomeric mixture of 12 and 12¢. With this encouraging

result, we tried several proton sources at different temper-

atures. The best result was obtained when the reaction was

conducted at –70 °C with isopropanol affording a 90:10

mixture of 12 and 12¢ (Table 1).

1

3

6

5% yield. The next step is the construction of the vinyl

iodide with an E configuration. First of all, we turned our

attention to the hydrozirconation-iododemetallation reac-

1

4

tions using the Schwartz’s reagent. Unfortunately, after

several experiments, these conditions did not furnish the

expected alkenyl iodide. Similar results were observed

with the carboalumination-iododemetallation reaction de-

scribed by Miller using a chloroalkyne instead of methyl-

OEt 1) Proton source

OEt

I

+

Ti

OEt

2) I₂

OEt

I

1

5

(O-i-Pr)2

alkyne 11 as starting material. Another method to create

functionalised double bond is to use Kulinkovich’s

A

12

12'

1

6

17

reagent well studied by Sato. Our first intention was to

Scheme 4 Decomposition of alkyne–titanium complex with proton

sources (Table 1)

generate the alkyne-titanium complex, then add, at first,

iodine then NH Cl as electrophiles sources to obtain the

4

desired alkenyl iodide 12. In this case, we observed 1) a

low rate of conversion with 70% recovery of starting ma-

terial, 2) the formation of two alkenyl iodide regioisomers

Unfortunately, even though this reaction gave interesting

results, these two regioisomers could not be separated by

chromatography on silica gel, which is not acceptable for

the final stages of the synthesis. So, we turned our atten-

1

2 and 12¢ (20%) in 1:1 ratio, and 3) 10% of alkene 13

produced from the hydrolysis of complex A (Scheme 3).

1) Ti(O-i-Pr)4

1

) LiNH2

Et O

1) I , –78 °C

2

OEt

2

OEt

2

) MeI

2

) i-PrMgCl (2 equiv) Ti

OEt

2) NH4Cl

I

+

OEt

11

(

O-i-Pr)2

I

OEt

1

0

A

1

2, 10%

12', 10%

13, 10%

I2

ref. 12

OEt

I(i-PrO)2Ti

B

Br

I

Scheme 3 Synthesis of 12 via alkyne–titanium complex

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

70

L. Commeiras et al.

FEATURE ARTICLE

H O,²²LiBF /H O ), but none gave satisfactory results.

23

Table 1 Effect of Different Electrophiles on the Yield of Vinyl Io-

dide 12

2

4

2

In all the case, the desired aldehyde 16 was obtained as a

mixture with the aldehyde that results from the isomerisa-

tion of the central double bond (more than 30%) and other

undetermined aldehydic products. Such a compound be-

ing very sensitive in the following reaction condition

prompted us to invert the coupling steps by first coupling

the central fragment II with the fragment I. But once

again, the obtaining of the corresponding aldehyde (17)

was a problem. Even using neutral conditions, such as 5 to

H⁺

T (°C)

Time (h)

12 (%)

73

12¢ (%)

27

CH CO H

–50/–60

1

2

1

3

2

–100

70

30

CF CO H

–50/–60

77

23

3

2

i-PrOH

89

11

1

0% of FeCl or 5 equivalents of water in refluxing ace-

–70

90

10

3

tone, the reaction well furnished the corresponding alde-

hyde 17. However, the aldehyde was unstable on silica

gel, and the presence of other impurities made the purifi-

cation of the crude aldehyde difficult, and it was not pure

t-BuOH

–50/–60

77

23

tion towards the preparation of alkenyltin reagents, easily enough to be used at the end of the synthesis.

made by hydrostannation or stannylcupration reactions,

and easier to separate than iodide analogues. The palladi-

um-catalysed hydrostannation reaction furnished in 68%

yield the corresponding alkenyltin reagent 14 and 14¢ as a

The hydrolysis of the ketal function revealing as a real

problem, we chose to introduce the aldehyde via an alco-

hol. So we revised the synthesis of the central fragment

and started from 2,3-dihydrofuran (Scheme 6). The Wad-

man–Kocienski rearrangement, as already described by

Pancrazi et al., afforded 19 with complete regio- and ste-

1

:1 mixture of two regioisomers. To increase the regiose-

lectivity of the reaction, we realized a stannylcupration re-

1

8

action. Using three equivalents of Lipshutz’s reagent, at

78 °C, a 8:2 mixture of 14/14¢ was obtained in 90%

yield. A similar reaction conducted in methanol and at

10 °C furnished, in 78% yield, a separated 88:12 mixture

24

reoselectivity. The configuration of the double bond was

–

established on the basis of the H–Sn coupling constant

3

(

J_S_n_,_H= 70 Hz) which is consistent with an E-alkenyl-

–

stannane. The alkenylstannane 19 was also prepared from

but-3-yn-1-ol using the following sequence. The lithium

acetylide derived from but-1-ynol was alkylated with

in favour of 14. The attribution of the configuration of the

double bond was based on the H–Sn coupling constant

3

(

^JSn,H = 65 Hz) which is consistent with an E-vinylstan-

13

methyl iodide to give pentynol 18 in 56% yield. The ste-

1

9

nane. Iododestannylation reaction with iodine in diethyl

ether afforded in 99% the corresponding alkenyl iodide 12

with retention of configuration (Scheme 5).

reo- and regioselective stannylcupration using Lipshutz

reagent in the presence of methanol cleanly furnished vi-

nyltin reagent 19 in 78% yield. Iododestannylation reac-

The assembly of the three fragments began with the tion with iodine in diethyl ether afforded quantitatively

Negishi cross-coupling between the alkynylzinc reagent 9 the corresponding iodopentenol 20 which was then oxi-

2

0

25

and the vinyl iodide 12 (Scheme 5). This reaction, catal- dized with Dess–Martin periodinane providing the cen-

ysed by 5% of PdCl (MeCN) , furnished in 80% yield the tral segment 17. The sensitive iodo aldehyde was found to

2

desired compound 15. To realise the second assembly, the be sufficiently pure to be used without purification (41%

acetal function must be deprotected to an aldehyde. We over four steps).

used several conditions (formic acid, acetic acid, FeCl /

2

1

3

OEt

a

OEt

14' (20%)

+

Bu3Sn

9

0%

OEt

3

Bu Sn

11

1

4 (80%)

99 %

b

c

O

OEt

I

8

0%

17

1

2

15

O

1

6

Scheme 5 Synthesis of 12 via iododestannylation reaction. Reagents and conditions: a) Bu (Bu)SnCuLi·LiCN (3 equiv), –78 °C; b) I , Et O;

3

2

c) 9, PdCl (PPh ) , THF, r.t.

2

3 3

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

171

sium acetate (3 equiv) only iso-caulerpenyne was

obtained in 88% yield.²⁹

O

ref. 24

OH

To explain the configuration of the diacetoxybutadiene

moiety of iso-caulerpenyne obtained, we propose that the

dienol having the Z,Z configuration is kinetically formed

from taxifolial A in its s-cis conformation (Scheme 8).

a

b

OH

5

6%

X

18

1

9, X = SnBu3 (78%)

c

20, X = I (97%)

H

AcO

O

OH

OAc

Z

Ac2O

Z

d

O

9

8%

I

OAc

17

Scheme 8 Formation of kinetically favoured Z,Z configuration in 1

Scheme 6 New synthesis of fragment II. Reagents and conditions:

a) (i) LiNH /NH , (ii) MeI; b) Bu (Bu)SnCuLi·LiCN, MeOH, –40 °C;

2

3

c) I , 0 °C to r.t.; d) Dess–Martin reagent

In order to find optimal conditions to generate (Z,E)-di-

acetoxybutadiene, we decided to prepare a model com-

pound that would be able to lead to the above mentioned

moiety. Hence, we planned to prepare a simplified ana-

logue of taxifolial A using a similar procedure

2

The coupling of the different fragments 6, 8 and 17 and

the construction of carbon skeleton of the caulerpenyne is

described in Scheme 7. The coupling reaction between the

second segment 17 and the carbanion generated by tin–

(

Scheme 9). Enal 28 was obtained in 56% yield over 4

30

9

steps from 6.

lithium exchange reaction on the first segment 6 gave

diol 21 in fair yield (56%). At this stage, the two hydroxyl

groups of 21 were protected as acetate using acetic anhy-

dride and a catalytic amount of DMAP in pyridine to give

bis-acetate 22 (96%). The carbon skeleton 23 of cauler-

penyne was achieved in a high yield through a Stille cross-

coupling between the vinyl iodide 22 and the fragment III

AcO

RO

c

a

6

OH

OTBS

OR

AcO

2

5, R = H

27

b

(

8) using 5 mol% of bis-acetonitrile palladium chloride in

2

6, R = OAc

2

0b,26

DMF.

At this stage, it should be noted that no isom-

AcO

erisation product resulting from a palladium insertion re-

action into the allylic acetate moiety was observed

proving that the carbon–iodine insertion of palladium is

largely favoured over the allylic acetate insertion.

OAc

3

0

AcO

d

AcO

2

Ac O

OAc

+

O

conditions

OAc

2

7

Desilylation of 23 by the HF/pyridine complex provided

OAc

2

8

primary alcohol 24, which was oxidized by Dess–Martin

periodinane, affording (±)-taxifolial A [(±)-2] in 96%

yield. Subsequent transformation of 2 into caulerpenyne

OAc

2

8

2

9

31

OAc

Scheme 9 Synthesis of a model compound. Reagents and condi-

tions: a) (i) BuLi (2.2 equiv), –78 to –35 °C, (ii) propanal, –78 °C; b)

Ac O, DMAP, pyridine, r.t.; c) HF/pyridine, r.t.; d) Dess–Martin re-

(

1) failed: upon attempted trapping the dienyl enol of tax-

ifolial A using acetic anhydride in the presence of potas-

2

agent

RO

AcO

c

a

6

I

OTBS

OR

AcO

21, R = H (56%)

23, R = TBS (99%)

b

d

22, R = OAc (96%)

24, R = H (76%)

AcO

OAc

e

f

O

96%

8

8%

OAc

AcO

(

±)-taxifolial A ꢀ(±)-2]

iso-(±)-caulerpenyne ꢀiso-(±)-1]

Scheme 7 Synthesis of (±)-taxifolial A (2) and iso-(±)-caulerpenyne (iso-1). Reagents and conditions: a) (i) BuLi (2.2 equiv), –78 to –35 °C,

(

ii) 17, –78 °C; b) Ac O, DMAP, pyridine; c) 8, PdCl (MeCN) , DMF; d) HF/pyridine, r.t.; e) Dess–Martin reagent; f) KOAc, Ac O, benzene,

2

8

0 °C

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

72

L. Commeiras et al.

FEATURE ARTICLE

1

Firstly, we tested acetate salts other than potassium ace- those reported in the literature (500 MHz H NMR CDCl

3

13

tate (Table 2). The reactions were performed with 1.5 and C D and 125 MHz C NMR CDCl ). Moreover, the

6

3

equivalents of M(OAc) , 3 equivalents of acetic anhydride mixture (±)-1 and iso-(±)-1 was purified by semi-prepara-

n

1

at 80 °C and followed by H NMR spectroscopy. CuOAc, tive chiral HPLC to give (+)-1, (–)-1, iso-(+)-1 and iso-

Cu(OAc) , Mg(OAc) , and Pb(OAc) did not give the ex- (–)-1 in enantiomerically pure forms.

2

pected diacetoxybutadienyl derivatives and led to a com-

plex mixture of several unidentified products, among

them numerous aldehydes. LiOAc, CsOAc and Zn(OAc)₂

afforded cleanly a mixture of isomers 29, 30 and 31. As a

slight trend, if the cation exhibits some Lewis acidity, the

E/Z-isomer was obtained in each case. Nevertheless, the

desired isomer 29 was always obtained as the minor iso-

mer.

(±)-caulerpenyne ꢀ(±)-1] (40%)

AcO

a

c

OAc

b

AcO

Et3N, DMAP

Ac2O, 80 °C

(±)-2

+

AcO

9

6%

a'

OAc

Tertiary amines were also used. Et N as base/solvent, 3

3

c'

equivalents of Ac O with 5% of DMAP at 80 °C gave bet-

2

b'

ter results than those observed in the use of M(OAc) . Re-

AcO

n

actions, checked by GC, were rapid and afforded cleanly

a 24:75:<1 mixture of E,Z/Z,Z/E,E isomers. The same re-

action performed with 1 or 3 equivalents of DMAP gave

the best results with a ratio of 45:55 of E,Z/Z,Z isomers

iso-(±)-caulerpenyne ꢀiso-(±)-1] (60%)

Scheme 10 Synthesis of (±)-caulerpenyne (1)

with no evidence of 31 being formed. Other amines such On top of the biological activity of the diacetoxybutadiene

as pyridine or Hunig’s base led to a larger amount of iso- moiety, we wanted to know if the terminal unsaturated

mer 31. It should be noted that treatment of enal 28 with alkyl chain of CYN has a role. So, we investigated the

LiHMDS, NaHMDS or KHMDS at –78 °C in THF fol- synthesis of dihydrorhipocephalin (3), a sesquiterpene

lowed by quenching with Ac O did not furnish the desired isolated from Penicillus capitatus and Udotea cyathiform-

2

dienes.

is and which represents 10% of the chloroform extracts in

both species.³¹Dihydrorhipocephalin (3) exhibits the

same structure as CYN (1) except the internal triple bond

which is replaced by a single bond. Our synthesis plan for

dihydrorhipocephalin (3) was based on that used for 1 and

called for the initial preparation of two fragments I and II

in which fragment I was the same as that used in the syn-

thesis of CYN (1). Homogeranial (fragment II) can be ob-

tained from the corresponding homogeraniol 32.

Finally, we applied the following conditions – 3 equiva-

lents of Ac O, 1 equivalent of DMAP, Et N at 80 °C – to

taxifolial A (2) that yielded a 96% mixture of 40:60 of (±)-

caulerpenyne [(±)-1] with the E,Z configuration of the di-

acetoxybutadiene moiety and iso-(±)-caulerpenyne [iso-

2

3

(

±)-1] with the Z,Z configuration (Scheme 10). Their ste-

1

reochemistry was established by the H NMR spectrum

J_b_,_c= 12.7 Hz characteristic of H-H E-coupling constant

(

and J_b_¢_,_c_¢= 7.3 Hz characteristic of H-H Z-coupling con- Compound 32 was synthesized in two steps using Kocien-

1

32

stant) and a H NMR NOESY experiment (presence of ski’s procedure where the key step is the stereo- and re-

cross peak between H and H and presence of low rela- gioselective construction of the central trisubstituted

a

b

tionship between H and H ). Moreover, the data of the double bond through a Wenkert reaction. Homogeranial

synthetic (±)-caulerpenyne [(±)-1] are in agreement with 33 was then obtained by Dess–Martin periodinane oxida-

a¢

b¢

Table 2 Tested Reaction Conditions for the Preparation of Diacetoxybutadiene 29

Conditions

29 (%)

30 (%)

31 (%)

Conditions

29 (%)

24

30 (%)

75

31 (%)

<1

LiOAc, C H , 80 °C

27

–

73

–

Et N, DMAP (5 mol%), 80 °C

6

3

CuOAc, C H , 80 °C

–

Et N, DMAP (1 equiv), 80 °C

45

54

<2

6

3

Cu(OAc) , C H , 80 °C

–

Et N, DMAP (3 equiv), 80 °C

45

55

trace

<2

2

6

3

Mg(OAc) , C H , 80 °C

–

Et N, DMAP (5 mol%), r.t.

29

69

2

6

3

Pb(OAc) , C H , 80 °C

–

Et N, DMAP (1 equiv), 80 °C

20

78

<2

2

6

3

CsOAc, C H , 80 °C

10

45

11

90

41

88

–

Pyridine, DMAP (5 mol%), r.t.

Pyridine, DMAP (5 mol%), 80 °C

38

47

15

6

Zn(OAc) , C H , 80 °C

14

–

20

72

8

2

6

Et N, 80 °C

i-Pr NEt, DMAP (1 equiv), r.t. to 80 °C

51

32

17

3

2

i-Pr NEt, DMAP (1 equiv), 80 °C

37

56

7

2

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

173

tion of the primary hydroxyl group of homogeraniol 32 in the synthesis of CYN (1). For this analogue, we opted for

quantitative yield. The coupling of the two fragments 6 an enantioselective synthesis where the control of the

and 26 was achieved via the cross-coupling reaction be- chiral centre would be achieved through an enzymatic res-

tween 33 and the carbanion generated by tin–lithium ex- olution (Scheme 12).

change reaction on 6 which gave diol 34 in fair yield

(

47%). At this stage, the two hydroxyl groups were pro-

Stannylcupration,

iododestannylation

tected as acetates and desilylation of 35 by the HF/pyri-

dine complex provided 36. The primary hydroxyl group

was oxidized by Dess–Martin periodinane furnishing in

quantitative yield the aldehyde 37. A mixture of 3 equiv-

alents of Ac O, 1 equivalent of DMAP, Et N at 80 °C af-

Stille coupling

O

SnMe3

+

I

OAc

AcO

furocaulerpin (–)-4

2

3

forded, in 80% yield, a mixture of 45:55 of (±)-

dihydrorhipocephalin [(±)-3] with E,Z configuration of

diacetoxybutadiene moiety and (±)-iso-dihydrorhipo-

cephalin [iso-(±)-3] with Z,Z configuration (Scheme 11).

The configuration of the diacetoxybutadiene moiety was

confirmed by H NMR and H NMR NOESY experi-

ments. The mixture (±)-3 and iso-(±)-3 was purified by

semi-preparative chiral HPLC to give iso-(+)-3, iso-(–)-3,

O

OH

Scheme 12 Retrosynthetic scheme

1

The synthesis of the first fragment (Scheme 13) began

with condensation of allenylmagnesium bromide to 3-

furaldehyde furnishing the crude alcohol 38 in 99%

yield. The next step was methylation of 38. First the hy-

droxyl function was protected as tetrahydropyranyl ether

using dihydropyran in the presence of small amount of

PPTS. Then the methylation of protected 38 was per-

formed with 1) LiNH /NH and 2) MeI to afford 40 in

(

+)-3 and (–)-3 in enantiomeric pure form.

34

Enantioselective Synthesis of Furocaulerpin

2

3

Finally, the last natural compound, analogue of 1, was fu-

rocaulerpin (4), extracted and identified from Caulerpa

9

4

9% yield over three steps. After acetic acid hydrolysis of

0 (84%), we turned our attention to the enzymatic reso-

3

prolifera by De Napoli et al. in 1981. Compared to 1,

this secondary metabolite presents a furan ring instead of

a diacetoxybutadiene moiety. Our synthesis plan of furo-

caulerpin (4) was also based on that used for CYN and

called for the initial preparation of two fragments. Thus,

construction of 4 involved a Stille reaction between the re-

sidual vinyl iodide function of a first fragment and an

alkynylstannane 8 (second fragment) already prepared for

lution of alcohol 41. To this end, we examined the trans-

esterification of 41 with vinyl acetate and various lipases

under standard conditions. Best results in conversion rate

and in enantiomeric excess were obtained with

Pseudomonas fluorescens (see Table 3). In a study of en-

zymatic resolution of secondary alcohols by the lipases

from Pseudomonas sp. Burgess has proposed a simple ac-

Synthesis of homogeranial (33)

ref. 32

a

OH

O

3

32

Synthesis of (±)-dihydrorhipocephalin ꢀ(±)-3]

AcO

c

AcO

HO

b

d

6

8

6%

OH

4

7%

OTBS

9

0%

OTBS

OAc

AcO

OH

36

34

35

AcO

OAc

e

f

80%

+

OAc

O

quant.

OAc

37

iso-(±)-Dihydrorhipocephalin ꢀiso-(±)-3] 45%

(

±)-Dihydrorhipocephalin ꢀ(±)-3] 55%

Scheme 11 Synthesis of (±)-dihydrorhipocephalin [(±)-3]. Reagents and conditions: a) Dess–Martin reagent, 0 °C to r.t.; b) (i) BuLi (2.2

equiv), –78 to –35 °C, (ii) 33, –78 °C; c) Ac O, DMAP, pyridine; d) HF/pyridine, r.t.; e) Dess–Martin reagent; f) Et N, Ac O, DMAP, 80 °C

2

3

2

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

74

L. Commeiras et al.

FEATURE ARTICLE

tive site model for predicting the enantioselectivity.³⁵^,³⁶Table 3 Results in Conversion Rate and in Enantiomeric Excess

This model predicts that alcohols resolved most efficient-

Lipase

Time (h)

120

72

Conv (%)

ee (%)

ly have one small and one relatively large group attached

to the hydroxymethine functionality. According to this

model, we assume that only R-isomer of 41 was trans-

formed into acetate 42. After 26 hours at room tempera-

ture, the active enzyme was recovered for re-use after

filtration. Separation by chromatography on silica gel af-

forded a 57% yield of the alcohol (–)-41 (65% ee) and a

Candida antartica

Candida cylindracea

Mucor miehei

Aspergillus niger

Ps. cepacia

42

12

<5

6

88

–

96

–

72

–

2

4

3

7% yield of the acetate (+)-42 {[a]_D+41.4 (c = 1,

12

46

45

<5

91

94

–

CHCl ), 92% ee}. The remaining alcohol (–)-41 was re-

subjected to the same conditions of enzymatic transester- Ps. fluorescens

3

8

ification using the recovered enzyme. The progress of the

reaction was monitored by chiral phase analytical GC un-

Rhizopus arrhizus

72

til one enantiomer of the starting material was completely Rhizopus niveus

72

–

2

4

consumed. After 100 h, (–)-41 {[a]_D–32.8, (c = 1,

Hog pancreas

96

–

CHCl )} was obtained in 40% overall yield and 99% ee.

3

Starting from (–)-41 and (+)-42, the first fragment was

prepared via the stannylcupration of the triple bond fol-

lowed by iododestannylation. The stannylcupration reac-

tion of (+)-42 using the stannyl cuprate

In contrast, clean access of (–)-43 from (–)-41 was found

to depend on temperature and the presence of methanol. In

each case and independently of the number of equivalent

of the Lipshutz reagent, the stannylcupration in presence

or not of methanol was incomplete (10% of conversion

without MeOH at –78 °C, 70% with MeOH at –40 °C and

Bu Sn(Bu)CuLi·LiCN (Lipshutz reagent) at –78 °C gave

3

unexpected products. A 4:6 mixture of alcohol (+)-41 and

vinylstannane (+)-43 was obtained using three equiva-

lents of Lipshutz reagent whereas six equivalents fur-

nished a 2:8 mixture of the same products. After

7

6% at –10 °C). After purification, pure vinylstannane

2

4

2

4

(–)-43 {([a]

D

–11.7 (c = 1, CHCl )} was obtained in 43%

3

purification, pure vinylstannane (+)-43 {[a]_D+10 (c = 1,

yield. Iododestannylation of (+)-43 and (–)-43 with iodine

CHCl )} was obtained in 58% yield with a surprising total

3

in diethyl ether yielded respectively 99% and 96% of the

regio- and stereoselectivity (E configuration). It should be

noted that in each attempt we conducted, the acetate func-

tion was removed. The formation of alcohol (+)-41 could

be explained by the addition of a butyl moiety of the al-

kenylcuprate intermediate to the ester carbonyl group

followed by a retrostannylcupration giving the corre-

sponding alcohol.

24

corresponding vinyl iodides (+)-44 {[a] +12.3 (c = 1,

D

24

CHCl )} and (–)-44 {[a] –13.0 (c = 1, CHCl )}. The

3

D

3

hydroxyl group of (+)-44 and (–)-44 was protected as

acetate using acetic anhydride and a catalytic amount of

DMAP in pyridine providing respectively (+)-45 in 93%

24

yield {[a]_D+25 (c = 1, CHCl ), 92% ee} and (–)-45 in

3

O

b

c

e

a

+

99 %

O

OH

OTHP

OR

OH

OAc

38

39

4

0, R = OTHP

(–)-41 (57%)

5% ee

(+)-42 (37%)

d

(99% over 3 steps)

6

92% ee

4

1, R = H (84%)

f

O

j

i

g

I

X

g, h, i, j

50%

90%

87%

OH

OAc

–)-furocaulerpin ꢀ(–)-4]

OAc

–)-45

OH

(

–)-43, X = SnBu3 (43%)

(–)-41 (40%

from rac-4)

(

h

(–)-44, X = I (96%)

9

9% ee

O

OAc

+)-furocaulerpin ꢀ(+)-4]

(

Scheme 13 Synthesis of furocaulerpin. Reagents and conditions: a) allenylmagnesium bromide, –78 to 0 °C; b) DHP, PPTS, CH Cl ; c) (i)

2

LiNH /NH , (ii) MeI; d) AcOH–H O–THF, 45 °C; e) vinyl acetate, hexane, Ps. fluorescens, 26 h; f) vinyl acetate, hexane, Ps. fluorescens, 100

2

3

2

h; g) Bu Sn(Bu)CuLi·LiCN (4 equiv), MeOH, –10 °C; h) I , Et O, 0 °C to r.t.; i) Ac O, DMAP, pyridine; j) 8, PdCl (MeCN) , DMF

3

2

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

175

2

4

8

7% yield {[a]_D–26.6 (c = 1 CHCl ), ee >99%}. The investigated for (–)-caulerpenyne and its analogues iso-

3

last step of the synthesis is the coupling reaction between (+)-1, iso-(–)-1, (±)-2, iso-(+)-3, iso-(–)-3, (+)-3, (–)-3,

alkenyl iodide (+)-4 and (–)-45 with stannylenyne 8 using (+)-4 and (–)-4 and are summarized in Table 4.

5

mol% of bis-acetonitrile palladium chloride, giving non-

Both (+)- and (–)-dihydrorhipocephalin (3), as well as iso-

+)-dihydrorhipocephalin [iso-(+)-3], have a half inhibito-

2

4

natural (+)-furocaulerpin [(+)-4] {[a]_D+13.8 (c = 1,

CHCl )} in 94% yield and (–)-furocaulerpin [(–)-4]

(

3

4

ry concentration IC₅₀around 50 mM. So, replacement of

2

(

[a] –14.6, c = 1, CHCl )} in 90% yield. The data of

1

D

3

the internal triple bond by a CH –CH linkage leads to a

2

this synthetic (–)-furocaulerpin [(–)-4] (500 MHz H

non significant decrease of the activity on tubulin poly-

merisation. Curiously, in the case of iso-(–)-dihydrorhipo-

cephalin [iso-(–)-3], the activities of the two enantiomers

were largely different as iso-(+)-dihydrorhipocephalin

1

3

NMR CDCl , 50 MHz C NMR CDCl and GC/MS) are

in agreement with those reported in the literature.

3

[

iso-(+)-3] is three times more powerful than iso-(–)-dihy-

Biological Testing

drorhipocephaline [iso-(–)-3]).

Hence, the presence of the internal triple bond, the config-

uration of the chiral centre and the configuration of the di-

acetoxybutadiene moiety do not appreciably influence the

activity on tubulin polymerisation compared to CYN.

The effect of each enantiomer of caulerpenyne (1), iso-

caulerpenyne (iso-1) and analogues (±)-2, iso-(+)-3, iso-

(

–)-3, (+)-3, (–)-3, (+)-4, (–)-4, on the in vitro polymerisa-

tion of pure tubulin was investigated by turbidimetry. As

7

for the natural product, tubulin (15 mM) was incubated However, racemic taxifolial A (±)-2 is inactive at a con-

for 35 min at 37 °C without (control) or with various con- centration below 200 mM and (+)- and (–)-furocaulerpin

2

+

centrations of CYN or analogues in Mg -free polymeri- (4) have a half inhibitory concentration IC of about 100–

5

0

sation buffer. After 35 min, 10 mM MgCl was added to 200 mM. These results confirm that biological activities of

2

the samples (Figure 2) to induce the formation of micro- CYN could be attributed to the diacetoxybutadiene moi-

tubules. In the control experiment, turbidity increased ety as has been predicted biologists.

with time resulting in a typical sigmoid curve with a lag

time, a drastic increase in the turbidity and a plateau value

corresponding to the amount of microtubules formed Conclusion

(

Figure 2, upper trace). With increasing concentrations of

+)-caulerpenyne [(+)-1], the rate of assembly as well as We have accomplished the first total synthesis of several

the final amount of microtubules were decreased and the metabolites isolated from algae order caulerpales. The ac-

turbidity generated by the self-assembly of 15 mM tubulin tivity on tubulin polymerisation of such terpenoids is

was reduced to half the control value at a concentration of mainly due to the presence of the diacetoxybutadiene moi-

1

4 ± 2 mM (inset Figure 2). After 35 min of polymerisa- ety. The configuration of the chiral centre, the configura-

tion process, the samples were cooled to 10 °C and all the tion of the diacetoxybutadiene moiety and the unsaturated

samples totally depolymerised. Similar experiments were terminal chain were not significant. Investigations to

Table 4 Half-Inhibitory Concentrations of CYN and Analogues on

Pure Tubulin Polymerisation

Metabolites

IC₅₀(mM)

21 ± 2

natural (+)-caulerpenyne

(

–)-caulerpenyne

+)-caulerpenyne

+)-furocaulerpin

–)-furocaulerpin

±)-taxifolial A

14 ± 2

34 ± 3

101 ± 16

171 ± 27

>200

iso-(+)-caulerpenyne³⁷

iso-(–)-caulerpenyne³⁷

31 ± 3

54 ± 9

(

+)-dihydrorhipocephalin³⁷

–)-dihydrorhipocephalin³⁷

52 ± 8

57 ± 15

40 ± 9

iso-(+)-dihydrorhipocephalin³⁷

iso-(–)-dihydrorhipocephalin³⁷

123 ± 14

Figure 2 Inhibition of tubulin polymerisation by (+)-caulerpenyne

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

76

L. Commeiras et al.

FEATURE ARTICLE

specify the interaction with the tubulin system are ongo- After stirring for 15 min, THF was evaporated under vacuum. The

crude product was then purified by flash chromatography (PE–

ing and should help to provide new details concerning the

mechanism of action of this interesting class of terpenes.

Et O, 6:4 to 2:8) to give 5; yield: 11.3 g (99%).

2

1

H NMR (300 MHz, CDCl ): d = 0.84–0.93 (m, 15 H, 3 × CH ,

3

× CH ), 1.23–1.35 (m, 6 H, 3 × CH ), 1.43–1.53 (m, 6 H,

2

All reactions sensitive to oxygen and moisture were carried out in

oven-dried glassware under a slight positive pressure of argon un-

3

× CH ), 1.64 (br t, J = 5.6 Hz, 1 H, OH), 1.73 (br t, J = 5.2

2

H,H

3

Hz, 1 H, OH), 4.18 (br t, J = 5.4 Hz, 2 H, CH ), 4.36 (br d,

H,H

2

3

1

13

less otherwise noted. H NMR and C NMR spectra were deter-

mined on Bruker AC200, AC300, AM400 or AC500 spectrometers.

3

J_H_,_H= 3.7 Hz, J

= 37 Hz, 2 H, CH ), 5.77 (br t, J = 5.4 Hz,

Sn,H

2 H,H

J_S_n_,_H= 67 Hz, 1 H, CH).

1

Chemical shifts for H NMR were reported in parts per million

(

ppm) downfield from tetramethylsilane as the internal standard and

(

E)-4-tert-Butyldimethylsilyloxy-2-tributylstannylbut-2-en-1-ol

6)

1

3

coupling constants are in Hertz (Hz). Chemical shifts for C NMR

were reported in ppm relative to the central line of a triplet at 77.1

ppm for CDCl . IR spectra were recorded on a Perkin-Elmer 1600

10

To a solution of 5 (3.8 g, 10 mmol) in DMF (100 mL) at 0 °C was

added imidazole (0.68 g, 10 mmol) and tert-butyldimethylsilyl

chloride (1.5 g, 10 mmol). The solution was stirred at 0 °C for 6 h,

then crushed ice (2.5 g) was added. The solution was diluted with

Et O (200 mL), washed with sat. aq NH Cl solution, dried (MgSO )

and evaporated. The crude product was then purified by flash chro-

matography (PE–Et O, 10:0 to 9:1) to give 6; yield: 3.19 g (65%).

3

Fourier Transform Infrared spectrophotometer and are reported in

–1

wave numbers (cm ). Mass spectra (MS) were obtained on a

Hewlett Packard apparatus (engine 5989A) at 70 eV in the GC/MS

mode. Enantiomeric excess (ee) was determined by the ratio of the

peak areas obtained by GC separation using a chiral phase (WCOT

Fused Silica 25 m × 0.25 mm Coating CP CHIRASIL-DEX CB

DF = 0.25). High resolution mass spectra were measured on a Wa-

ters 2790-Micromass LCT electrospray ionisation mass spectrome-

ter and on a VG autospec chemical ionisation mass spectrometer.

Analytical TLC was performed on Merck precoated analytical

plates, 0.25 mm thick, silica gel 60 F254. Flash column chromatog-

raphy was performed on Merck Kieselgel 60 (230–400 mesh). Re-

agents and solvents were commercial grades and were used as

supplied. CH Cl , benzene, and toluene were distilled from CaH

2

4

2

1

H NMR (300 MHz, CDCl ): d = 0.06 (s, 6 H, 2 × CH ), 0.84–0.92

3

(

m, 15 H, 3 × CH , 3 × CH ), 0.88 (s, 9 H, 3 × CH ), 1.23–1.53 (m,

3

2

3

1

2 H, 6 × CH ), 1.80 (br t, J = 5.5 Hz, 1 H, OH), 4.20 (br d,

2

H,H

3

4

2

J

= 5.4 Hz, J

= 15 Hz, 2 H, CH ), 4.32 (br d, J = 5.5 Hz,

H,H

Sn,H 2 H,H

3

^JSn,H = 37 Hz, 2 H, CH ), 5.68 (br t, J = 5.4 Hz, J

= 69 Hz,

2

H,H

Sn,H

1

H, CH).

1

,1-Dibromo-4-methylpent-1,3-diene (7)¹¹^b

2

CBr (24.87 g, 75 mmol), Ph P (19.67 g, 75 mmol) and Zn dust (4.9

and stored over molecular sieves 4 Å. THF and Et O were distilled

4

3

2

g, 75 mmol) were placed in a dry 500-mL round-bottomed flask un-

der N . The flask was cooled to 0 °C and CH Cl (300 mL) was add-

ed to the mixture of the solids, giving a green suspension. The

reaction mixture was allowed to warm to r.t. and was then stirred for

from sodium benzophenone prior to use. DMF and hexanes were

purchased anhydrous and stored over molecular sieves 4Å under ar-

gon. PE refers to the fraction boiling in the range 30–40 °C.

2

The analytical chiral HPLC experiments were performed on a unit

composed of a Merck D-7000 system manager, Merck-Lachrom L-

7

UV-detector, and on-line Jasco CD-1595 circular dichroism. Hex-

ane and propan-2-ol, HPLC grade, were degassed and filtered on a

0

2

4 h, after which time it was pink in colour. 3-Methylbut-2-enal

(2.89 mL, 30 mmol) was then added via syringe and the mixture

100 pump, Merck-Lachrom L-7360 oven, Merck-Lachrom L-7400

stirred for a further 2 h. The now purple suspension was transferred

to a large conical flask, pentane (400 mL) was added and the result-

ant solution was filtered. The residue was dissolved in CH Cl

2

.45 mm membrane before use. The column used is Whelk-O1 (S,S)

250 × 4.6 mm) from Regis (Morton Grove, USA). The sign given

(200 mL) and then more pentane (500 mL) was added. This was

(

also filtered and the combined filtrates were concentrated to a co-

lourless oil. This was triturated with pentane (20 mL) and filtered

through a short pad of silica to remove Ph PO. After removal of sol-

vents in vacuum, gem-dibromodiene 7 was obtained as colourless

oil; yield: 7.20 g (quant).

by the on-line circular dichroism is the sign of the product in the sol-

vent used for the chromatographic separation. The four analyses

were performed at 25 °C, with hexane–propan-2-ol (95:5) as mobile

phase and 1 mL/min as flow-rate, with UV and CD at 220 nm.

Semi-preparative separations were performed on an unit composed

of Merck D-7000 system manager, Merck-Hitachi L-6000 pump,

Rheodyne valve with a 500 mL loop and a Merck-Hitachi L-4000

UV-detector. For dihydrorhipocephalin and iso-dihydrorhipoceph-

alin, Whelk-O1 (S,S) (250 × 4.6 mm) was used with hexane–pro-

pan-2-ol (95:5) as mobile phase, 1 mL/min as flow-rate and UV at

3

1

H NMR (400 MHz, CDCl ): d = 1.74 (s, 3 H, CH ), 1.78 (s, 3 H,

3

CH ), 5.83 (m, J = 10.6 Hz, 1 H, CH), 7.07 (d, J = 10.6 Hz,

3

H,H

1

H, CH).

1

-Trimethylstannyl-4-methylpent-3-en-1-yne (8)

To a solution of 7 (1 g, 4.2 mmol) in THF (15 mL) under N at

2

20 nm. For caulerpenyne, Chiralpak AD (250 × 10 mm), an amy-

2

–

78 °C, was added dropwise BuLi (2.5 M, 3.5 mL, 8.8 mmol). The

lose tris(3,5-dimethylphenylcarbamate) chiral stationary phase

available from Chiral Technology Europa (Illkirch, France) was

used with hexane–propan-2-ol (98:2) as mobile phase, 4.5 mL/min

as flow-rate and UV at 220 nm. For iso-caulerpenyne, Chiralcel OD

clear yellow solution was stirred at –78 °C for 1.5 h and then

Me SnCl (710 mg, 3.57 mmol) was added. After warming to r.t., the

mixture was quenched with H O and the aqueous phase was extract-

ed with Et O. The combined organic layers were washed with H O,

dried (MgSO ), filtered and concentrated under vacuum to give 8;

yield: 763 mg (88%).

3

2

(

250 × 10 mm), a cellulose tris(3,5-dimethylphenylcarbamate)

chiral stationary phase available from Chiral Technology Europa

Illkirch, France) was used with hexane–propan-2-ol (95:5) as mo-

2

4

(

1

2

bile phase, 4.5 mL/min as flow-rate and UV at 220 nm.

H NMR (400 MHz, CDCl ): d = 0.25 (s, J

= 59 Hz, 9 H,

3

Sn,H

3

× CH ), 1.74 (s, 3 H, CH ), 1.87 (s, 3 H, CH ), 5.25 (s, 1 H, CH).

Compounds 4, 38–45 were prepared according reference 8e.

3

1

3

1

C NMR (50 MHz, CDCl ): d = –7.7 ( J

= 404 Hz, CH ), 21.1

3

Sn,C

(

E)-2-Tributylstannylbut-2-ene-1,4-diol (5)⁹

(CH ), 24.7 (CH ), 94.8 (C), 105.7 (CH), 107.3 (C), 149.1 (C).

3 3

To a THF solution (15 mL) of but-2-yn-1,4-diol (2.58 g, 30 mmol)

and PdCl (PPh ) (420 mg, 2 mol%) was added dropwise a THF so-

1

19

Sn NMR (149.21 MHz, CDCl ): d = –67.73.

3

2

3 2

+

·

MS (EI, 70 eV): m/z (%), organotin fragments = 244 (M , 18), 229

(100), 199 (32), 120 (10).

lution (20 mL) of Bu SnH (9.68 mL, 36 mmol) over a period of 1 h.

3

The originally light yellow solution abruptly turned orange-brown.

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

177

3

4

-Methylpent-3-en-1-yn-1-zinc Bromide (9)

(m, 4 H, 2 × CH ), 4.46 (t, J = 5.7 Hz, 1 H, CH), 6.15 (br t,

2

H,H

3

To a solution of 7 (0.72 g, 3 mmol) in THF (10 mL) under N at

J

= 7.4 Hz, 1 H, CH).

H,H

2

–

78 °C, was added dropwise BuLi (2.5 M, 2.5 mL, 6.3 mmol). The

clear yellow solution was stirred at –78 °C for 1.5 h and then ZnBr₂

740 mg, 3.3 mmol) was added. The resulting solution was warmed

13

C NMR (50 MHz, CDCl ): d = 15.3 (2 × CH ), 27.9 (CH ), 35.3

3

(

CH ), 61.7 (2 × CH ), 95.7 (C), 101.5 (CH), 135.6 (CH).

2

(

+

HRMS: m/z calcd for C H IO [M + H] : 285.0352; found:

to r.t. and the corresponding alkynylzinc was used as such for the

next step.

9

18

2

85.0352.

_,₁_D_i_e_t_h_o_x_y_p_e_n_t_-₃_-_y_n_e₍₁₁₎₃8

To a solution of Li (7.6 g, 0.11 mol), Fe(NO ) (15 mg) and NH

150 mL), was added 1,1-diethoxybut-3-yne (10; 14.2 g, 0.1 mol) at

40 °C. The mixture was stirred at –40 °C for 2 h then MeI (6.3 mL,

.1 mol) was added. After 48 h, the reaction was quenched with sat.

(6E)-9,9-Diethoxy-2,6-dimethylnona-2,6-dien-4-yne (15)

To a solution of 9 (2.11 mmol) prepared as described above, was

added dropwise (E)-2-iodo-5,5-diethoxypent-2-ene (12; 0.2 g, 0.7

1

3

(

–

0

mmol) in THF (1.6 mL). Then, PdCl (MeCN) (15 mg, 0.058

2

mmol) was added and the resulting mixture was stirred for 16 h at

r.t. The reaction was quenched with sat. aq NH Cl solution and the

aq NH Cl solution and the aqueous layer was extracted with Et O.

4

2

aqueous layer was extracted with Et O. The organic layers were

The organic layers were washed with brine, dried (MgSO ) and con-

centrated under vacuum. The residue was purified by distillation

bp 113 °C/50 Torr) to give 1,1-diethoxypent-3-yne 11; yield: 10.2

g (65%).

2

4

washed with brine, dried (MgSO ) and concentrated under vacuum.

4

The crude product was purified by column chromatography on sili-

(

ca gel (PE–Et O, 10:0 to 95:5) to give 15; yield: 132 mg (80%).

2

–

1

3

IR (film): 2177, 1667, 1120, 1060, 733 cm .

H NMR (200 MHz, CDCl ): d = 1.2 (t, J = 7 Hz, 6 H, 2 × CH ),

3

H,H

3

5

1

.76 (t, J = 2.6 Hz, 3 H, CH ), 2.45 (dq, J = 5.5, 2.6 Hz, 2 H,

1

H,H

3

H,H

3

H NMR (400 MHz, CDCl ): d = 1.18 (t, J = 7 Hz, 6 H, 2 × CH ),

3

H,H

3

CH ), 3.44–3.73 (m, 4 H, 2 × CH ), 4.58 (t, J = 5.5 Hz, 1 H,

2

H,H

1.79 (br s, 3 H, CH ), 1.81 (br s, 3 H, CH ), 1.87 (br s, 3 H, CH ),

2

3

CH).

3

.42 (t, J = 6.6 Hz, 2 H, CH ), 3.44–3.66 (m, 4 H, 2 × CH ), 4.48

H,H

2

3

(

t, J = 5.8 Hz, 1 H, CH), 5.34 (br s, 1 H, CH), 5.78 (br t,

H,H

(

E)-2-Tributylstannyl-5,5-diethoxypent-2-ene (14)

CuCN (0.86 g, 9.6 mmol) was suspended in freshly distilled THF

24 mL), cooled at –78 °C and treated with BuLi in hexane (2.5 M,

.7 mL, 19.2 mmol). The mixture was allowed to react until a ho-

3

J_H_,_H= 7.3 Hz, 1 H, CH).

1

3

C NMR (50 MHz, CDCl ): d = 15.3 (2 × CH ), 17.8 (CH ), 20.9

3

(

7

(

1

CH ), 24.8 (CH ), 33.6 (CH ), 61.4 (2 × CH ), 84.7 (C), 94.5 (C),

02.1 (CH), 105.4 (CH), 120.4 (C), 130.8 (CH), 147.7 (C).

3

2

mogenous solution was obtained. Then, at –78 °C, Bu SnH (5.16

3

+

mL, 19.2 mmol) was added dropwise via a syringe. Stirring was

continued and, over ca. 15 min, the solution turned yellow and H₂

gas was liberated. 1,1-Diethoxypent-3-yne (11; 0.5 g, 3.2 mmol)

was added. The reaction was followed by TLC (3 h) and quenched

HRMS: m/z calcd for C15

H

25

O

2

[M + H] : 237.1855; found:

237.1851.

Pent-3-yn-1-ol (18)¹³

with sat. aq NH Cl solution. The mixture was filtered and the aque-

To a solution of Li (0.367 g, 0.0528 mol), Fe(NO

) (15 mg) and

3 3

4

ous layer was extracted with Et O. The organic layers were washed

NH (200 mL) was added but-3-yn-1-ol (0.926 g, 13.2 mmol) at

3

2

with brine, dried (MgSO ) and concentrated under vacuum. The

crude product was purified by column chromatography on silica gel

–40 °C. The mixture was stirred at –40 °C for 2 h, then MeI (4.11

mL, 66 mmol) was added. After 12 h, the reaction was quenched

4

(

PE–Et O, 98:2) to afford a separable mixture (8.2) of two regioiso-

with sat. aq NH

with EtOAc. The organic layers were dried (MgSO

trated under vacuum. The residue was purified by flash chromatog-

4

Cl solution and the aqueous layer was extracted

2

mers 14 and 14¢; yield: 1.30 g (90%).

4

) and concen-

1

4

raphy (PE–Et

mg (56%).

2

O, 6:4 to 4:6) to give pent-3-yn-1-ol (18); yield: 610

–

1

IR (film): 1613, 1120, 1061, 861 cm .

1

_I_R₍_f_i_l_m₎_:₃₃₄₀_,₁₀₄₆_c_m–1_.

1

H NMR (200 MHz, CDCl ): d = 0.65–1.00 (m, 15 H, 3 × CH ,

3

× CH ), 1.18 (t, J = 7.2 Hz, 6 H, 2 × CH ), 1.18–1.60 (m, 12

5

2

H,H

3

H NMR (400 MHz, CDCl ): d = 1.82 (t, J = 2.6 Hz, 3 H, CH₃),

3

H,H

H, 6 × CH ), 1.82 (br s, 3 H, CH ), 2.45 (t, J = 6.3 Hz, 2 H,

CH ), 3.41–3.72 (m, 2 H, CH ), 4.50 (t, J = 6 Hz, 1 H, CH), 5.52

(

1

3

2

3

H,H

1

.90 (br t, J = 6.1 Hz, 1 H, OH), 2.42 (tq, J = 6.1, 2.6 Hz, 2

H,H H,H

3

2

H,H

3

H, CH ), 3.69 (q, J = 6.1 Hz, 2 H, CH₂).

2

H,H

3

br t, J = 6.7 Hz, J

= 65 Hz, 1 H, CH).

H,H

Sn,H

1

3

C NMR (50 MHz, CDCl ): d = 3.1 (CH ), 22.7 (CH ), 61.0 (CH ),

3

2

3

1

C NMR (50 MHz, CDCl ): d = 9.2 ( J

= 322 Hz, 3 × CH ),

3

Sn,C

2

7

5.6 (C), 77.1 (C).

1

3

6

3.8 (3 × CH ), 15.4 (2 × CH ), 19.4 (CH ), 27.5 ( J

= 55 Hz,

Sn,C

3

+

·

2

3

MS (EI, 70 eV): m/z (%) = 84 (M , 16), 55 (13), 54 (100), 53 (40),

52 (10), 51 (18), 50 (15), 43 (10), 41 (11), 39 (59).

× CH ), 29.2 ( J

= 19 Hz, 3 × CH ), 32.9 ( J

= 54 Hz, CH₂),

2

Sn,C

2

Sn,C

2

1.2 (2 × CH ), 102.7 (CH), 134.8 ( J

= 32 Hz, CH), 140.6 (C).

2

Sn,C

+

HRMS: m/z calcd for C H O Sn [M + H] : 449.2442; found:

4

_E₎_-₄_-_T_r_i_b_u_t_y_l_s_t_a_n_n_y_l_p_e_n_t_-₃_-_e_n_-₁_-_o_l₍₁₉₎24a

2

1

45

2

(

49.2446.

CuCN (0.639 g, 7.13 mmol) was suspended in freshly distilled THF

20 mL), cooled at –78 °C and treated with BuLi in hexane (2.5 M,

.7 mL, 14.3 mmol). The mixture was allowed to react until a ho-

(

5

(

E)-2-Iodo-5,5-diethoxypent-2-ene (12)

To a solution of 14 (0.2 g, 0.54 mmol) in anhyd Et O (2 mL), was

2

mogenous solution was obtained. Then, at –78 °C, Bu SnH (3.84

3

added dropwise I (0.136 g, 0.45 mmol) in anhyd Et O (2 mL) at

0

KF solution (1 mL) and acetone (1 mL). After stirring for 2 h, the

solution was filtered through a pad of Celite and the aqueous layer

was extracted with Et O. The organic layers were washed with sat.

aq Na S O solution, dried (MgSO ) and concentrated under vacu-

um. The crude product was purified by chromatography (PE–Et O,

1

2

mL, 14.3 mmol) was added dropwise via a syringe. Stirring was

continued and, over ca. 10 min, the solution turned yellow and H₂

gas was liberated. MeOH (10.59 mL, 0.26 mol) was then added, and

the mixture was allowed to warm to –40 °C and pent-3-yn-1-ol (18;

°C. The mixture was stirred 2 h at r.t. and quenched with 1 M aq

2

0

.2 g, 2.38 mmol) was added. The reaction was followed by TLC

2

3

4

and quenched with sat. aq NH Cl solution. The mixture was filtered

and aqueous layer was extracted with EtOAc. The organic layers

were washed with brine, dried (MgSO ) and concentrated under

vacuum. The crude product (93:7 ratio of regioisomers) was puri-

4

2

0:0 to 98:2) to give 12; yield: 127 mg (quant).

4

–

1

IR (film): 1645, 1130, 1070, 930 cm .

1

H NMR (200 MHz, CDCl ): d = 1.19 (t, 3_J_H_,_H= 7 Hz, 6 H,

fied by column chromatography on silica gel (PE–Et

2

O, 8:2) to give

3

1

9; yield: 700 mg (78%).

2

× CH ), 2.30–2.37 (m, 2 H, CH ), 2.37 (br s, 3 H, CH ), 3.40–3.71

3

2

3

Synthesis 2006, No. 1, 166–181 © Thieme Stuttgart · New York

1

78

L. Commeiras et al.

FEATURE ARTICLE

1

H NMR (300 MHz, CDCl ): d = 0.84–0.89 (m, 15 H, 3 × CH ,

2-[2-(tert-Butyldimethylsilyloxy)ethylidene]-1,3-diacetoxy-6-

iodohept-5-ene (22)

3

× CH ), 1.24–1.49 (m, 13 H, 6 × CH , OH), 1.85 (br s, J

= 44

2

Sn,H

3

Hz, 3 H, CH ), 2.41 (br q, J = 6.1 Hz, 2 H, CH ), 3.64 (br q,

A solution of diol 21 (0.190 g, 0.46 mmol), Ac O (0.173 mL, 1.84

3

H,H

2

3

J_H_,_H= 6.2 Hz, 2 H, CH ), 5.50 (br t, J = 7 Hz, J

= 70 Hz, 1

mmol) and DMAP (4.6 mg) in pyridine (5 mL) was stirred over-

2

H,H

Sn,H

H, CH).

night. The mixture was quenched with sat. aq NaHCO solution.

3

The aqueous layer was extracted with Et O and the organic layers

2

(

E)-4-Iodopent-3-en-1-ol (20)²⁴^a

were washed with sat. aq CuSO solution and H O, dried (MgSO )

4

2

4

To a solution of 19 (0.355 g, 0.95 mmol) in anhyd Et O (4 mL), was

and concentrated under vacuum to give 22; yield: 217 mg (96%).

2

added dropwise I (0.29 g, 1.14 mmol) in anhyd Et O (4 mL) at

_I_R₍_f_i_l_m₎_:₁₇₄₂_,₁₆₃₈_,₁₄₃₀_,₁₀₂₇_,₈₃₇_,₇₇₈_c_m–1_.

2

0

°C. The mixture was stirred for 2 h at r.t. and quenched with 1 M

1

H NMR (300 MHz, CDCl ): d = 0.05 (s, 6 H, 2 × CH ), 0.88 (s, 9

aq KF solution (2 mL) and acetone (2 mL). After stirring for 2 h, the

solution was filtered through a pad of Celite and the aqueous layer

was extracted with EtOAc. The organic layers were washed with

sat. aq Na S O solution, dried (MgSO ) and concentrated under

3

H, 3 × CH ), 2.03 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.35–2.48 (m, 2

H, CH ), 2.36 (s, 3 H, CH ), 4.29 (d, J = 5.8 Hz, 2 H, CH ), 4.60

(

3

2

3

H,H

2

3

s, 2 H, CH ), 5.22 (t, J = 6.4 Hz, 1 H, CH), 5.82 (t, J = 5.8

2

H,H

3

H,H

2

3

4

Hz, 1 H, CH), 6.06 (br t, J(H,H) = 6.8 Hz, 1 H, CH).

vacuum. The crude product was purified by chromatography (PE–

Et O, 9:1 to 0:10) to give 20; yield: 193 mg (97%).

13

2

C NMR (75 MHz, CDCl ): d = –5.2 (2 × CH ), 18.3 (C), 20.9

3

1

3

(CH ), 21.1 (CH ), 25.9 (3 × CH ), 27.8 (CH ), 34.5 (CH ), 59.46

(CH ), 59.50 (CH ), 73.9 (CH), 96.4 (C), 132.1 (C), 134.7 (CH),

H NMR (400 MHz, CDCl ): d = 1.40 (br t, J = 5.7 Hz, 1 H),

3

2

3

H,H

3

2

.29 (m, 2 H, CH ), 2.39 (br s, 3 H, CH ), 3.64 (br q, J = 6.2 Hz,

H, CH ), 6.17 (br t, J = 7.5 Hz, 1 H, CH).

2 2

2

3

H,H

3

135.3 (CH), 169.8 (C), 170.5 (C).

MS (PCI, CH , 70 eV): m/z (%) = 437 (M⁺– CH COO, 15), 379

2

H,H

·

4

3

(

E)-4-Iodopent-3-en-1-al (17)

(

16), 378 (21), 377 (100), 249 (17), 245 (47), 159 (21), 135 (25), 89

To a stirred solution of 20 (0.1 g, 0.47 mmol) in CH Cl (12 mL) at

2

(24), 61 (26).

0

°C was added Dess–Martin periodinane (0.26 g, 0.61 mmol). The

+

HRMS: m/z calcd for C H IO Si [M + H] : 497.1220; found:

1

9

34

5

reaction mixture was stirred under N at r.t. and followed by TLC.

2

4

97.1215.

After disappearance of the starting material, the mixture was poured

into a separating funnel containing sat aq Na S O /NaHCO solu-

2

3

2

6

-[2-(tert-Butyldimethylsilyloxy)ethylidene]-1,3-diacetoxy-

,10-dimethylundecadi-5,9-en-7-yne (23)

tion (26 mL, 1:1) and shaken vigorously for 5 min. The aqueous lay-

er was extracted with Et O and the organic layers were washed with

2

In a dry 10-mL Schlenk tube, a solution of 22 (0.1 g, 0.2 mmol) in

sat. aq NaHCO solution, dried (MgSO ) and concentrated under

3

4

DMF (2 mL) was added to PdCl (MeCN) (2.6 mg, 0.01 mmol).

2

vacuum to give crude 17; yield: 97 mg (98%).

The solution was degassed and 1-trimethylstannyl-4-methylpent-3-

en-1-yne (8; 0.073 g, 0.3 mmol) was added and the reaction mixture

immediately became black. The solution was stirred at r.t. and after

1

H NMR (400 MHz, CDCl ): d = 2.37 (s, 3 H, CH ), 3.15 (d,

3

J

= 7 Hz, 2 H, CH ), 6.33 (t, J = 7 Hz, 1 H, CH), 9.60 (s, 1

H,H

2 H,H

H, CH).

disappearance of diacetate 22, H O was added and the aqueous lay-

2

1

3

er was extracted with Et O. The combined organic layers were

C NMR (75 MHz, CDCl ): d = 28.1 (CH ), 44.9 (CH ), 98.2 (C),

2

3

2

washed with H O, dried (MgSO ) and concentrated under vacuum.

1

29.6 (CH), 197.2 (CH).

2

4

Chromatography (PE–Et O, 8:2) furnished 23; yield: 90 mg (99%).

2

1

-[2-(tert-Butyldimethylsilyloxy)ethylidene]-6-iodohept-5-ene-

,3-diol (21)

1

H NMR (400 MHz, CDCl ): d = 0.03 (s, 6 H, 2 × CH ), 0.86 (s, 9

3

H, 3 × CH ), 1.78 (s, 3 H, CH ), 1.79 (s, 3 H, CH ), 1.85 (s, 3 H,

CH ), 2.01 (s, 3 H, CH ), 2.03 (s, 3 H, CH ), 2.38–2.53 (m, 2 H,

3

To a solution of 6 (1.66 g, 3.37 mmol) in THF (55 mL) at –78 °C

was added dropwise BuLi (2.5 M, 3 mL, 7.41 mmol). The reaction

mixture was warmed to –35 °C for 2 h and then cooled to –78 °C,

then (E)-4-iodopent-3-en-1-al (17; 0.85 g, 4.04 mmol) was added

dropwise. The solution was kept at –78 °C for 1 h and quenched

with sat. aq NH Cl solution. The aqueous layer was extracted with

EtOAc. The organic layers were washed with sat. aq NH Cl solu-

tion, dried (MgSO ) and concentrated under vacuum. The crude

product was then purified by flash chromatography (PE–Et O, 3:7)

3

CH ), 4.28 (d, J = 5.8 Hz, 2 H, CH ), 4.60 (s, 2 H, CH ), 5.22 (t,

2

H,H

2

3

J_H_,_H= 6.7 Hz, 1 H, CH), 5.31 (br s, 1 H, CH), 5.66 (br t, J = 7.4

H,H

3

Hz, 1 H, CH), 5.82 (t, J = 5.8 Hz, 1 H, CH).

1

H,H

3

C NMR (100 MHz, CDCl ): d = –5.1 (2 × CH ), 17.8 (CH ), 18.3

3

4

(

C), 20.9 (CH ), 21.0 (CH ), 21.2 (CH ), 24.9 (CH ), 25.9

3 3 3 3

4

3 × CH ), 32.8 (CH ), 59.58 (CH ), 59.64 (CH ), 74.7 (CH), 85.2

3

2

4

C), 94.2 (C), 105.3 (CH), 121.2 (C), 130.7 (CH), 132.4 (C), 134.6

CH), 148.1 (C), 170.0 (C), 170.7 (C).

2

to afford 21; yield: 778 mg (56%).

+·

–

1

MS (EI, 70 eV): m/z (%) = 448 (M , 1), 197 (23), 155 (10), 133

32), 105 (21), 61 (24), 83 (10), 77 (16), 75 (84), 73 (76), 57 (11),

IR (film): 3400, 1606, 1033, 837 cm .

(

1

H NMR (300 MHz, CDCl ): d = 0.08 (s, 6 H, 2 × CH ), 0.89 (s, 9

3

55 (11), 43 (100), 41 (27).

3

H, 3 × CH ), 2.14 (br d, J = 4.1 Hz, 1 H, OH), 2.30–2.46 (m, 2

H, CH ), 2.38 (s, 3 H, CH ), 2.60 (br t, J = 6 Hz, 1 H, OH), 4.15–

3

H,H

+

3

HRMS: m/z calcd for C25H O Si [M + H] : 449.2723; found:

41 5

449.2724.

2

3

H,H

3

4

.22 (m, 3 H, CH , CH), 4.27 (d, J = 6 Hz, 2 H, CH ), 5.71 (t,

2 H,H 2

3

J_H_,_H= 6 Hz, 1 H, CH), 6.16 (br t, J = 6.8 Hz, 1 H, CH).

H,H

4

-Acetoxy-3-acetoxymethyl-7,11-dimethyldodecatri-2,6,10-en-

1

3

C NMR (75 MHz, CDCl ): d = –5.2 (2 × CH ), 18.3 (C), 25.9

3

8-yn-1-ol (24)

(

3 × CH ), 27.9 (CH ), 36.9 (CH ), 58.1 (CH ), 59.5 (CH ), 74.6

CH), 95.8 (C), 129.1 (CH), 136.8 (CH), 141.4 (C).

3

2

To a solution of 23 (150 mg, 0.334 mmol) in THF (5 mL) was

quickly added an excess of HF/pyridine (0.153 mL). The reaction

was monitored by TLC. After disappearance of the starting materi-

al, the mixture was concentrated under vacuum. The crude product

(

1

4

+

·

MS (EI, 70 eV): m/z (%) = 379 (M – H O – Me, 20), 378 (14), 377

2

(

63), 337 (27), 267 (18), 263 (47), 251 (13), 249 (12), 245 (23), 211

11), 181 (14), 161 (13), 153 (48), 137 (17), 136 (64), 135 (100),

95:5 ratio of isomers) was then purified by flash chromatography

PE–EtOAc, 6:4) to give 24; yield: 85 mg (76%).

1

7

34 (12), 133 (61), 123 (34), 115 (35), 109 (13), 108 (16), 107 (51),

05 (23), 99 (33), 95 (19), 93 (52), 91 (14), 89 (35), 83 (21), 75 (42),

3 (30), 71 (43).

H NMR (400 MHz, CDCl ): d = 1.79 (br s, 3 H, CH ), 1.80 (d,

3

J

= 1.2 Hz, 3 H, CH ), 1.87 (br s, 3 H, CH ), 2.03 (s, 3 H, CH ),

H,H

3

+

2.04 (s, 3 H, CH ), 2.40–2.55 (m, 2 H, CH ), 4.26 (d, J = 6.8 Hz,

2

HRMS: m/z calcd for C H IO Si [M + H] : 413.1009; found:

4

3

2

H,H

2

1

5

30

3

2

H, CH ), 4.64 (d, J = 12.4 Hz, 1 H, CH ), 4.72 (d, J = 12.4

13.1007.

2

H,H

2

H,H

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

179

3

Hz, 1 H, CH ), 5.22 (t, J = 6.7 Hz, 1 H, CH), 5.33 (br s, 1 H,

(C), 119.0 (C), 134.3 (CH), 135.0 (CH), 137.0 (CH), 137.7 (CH),

167.2 (C), 167.3 (C), 167.4 (C), 167.9 (C), 170.2 (2 × C).

2

H,H

3

CH), 5.66 (tq, J_H_,_H= 7.4, 1.2 Hz, 1 H, CH), 5.94 (t, J = 6.8 Hz,

H,H

1

H).

1

3

Iso-caulerpenyne [iso-(±)-1]

C NMR (75 MHz, CDCl ): d = 17.8 (CH ), 20.9 (CH ), 21.0

3 3 3 2 2 2

3

A solution of taxifolial A [(±)-2; 44 mg, 0.132 mmol], KOAc (19.5

(

7

1

CH ), 21.1 (CH ), 24.8 (CH ), 32.8 (CH ), 58.3 (CH ), 59.5 (CH ),

4.5 (CH), 85.2 (C), 94.0 (C), 105.2 (CH), 121.2 (C), 130.1 (CH),

33.0 (C), 134.3 (CH), 148.2 (C), 170.1 (C), 171.0 (C).

mg, 0.198 mmol), Ac O (0.037 mL, 0.396 mmol) in benzene (3 mL)

2

was heated at reflux. After disappearance of the starting material,

the mixture was concentrated under vacuum. The crude product was

then purified by flash chromatography (hexane–Et O, 8:2) to give

+

HRMS: m/z calcd for C H O [M + H] : 335.1859; found:

3

1

9

27

5

2

35.1862.

iso-caulerpenyne [iso-(±)-1]; yield: 43 mg (88%).

¹H NMR (500 MHz, CDCl

CH ), 1.86 (s, 3 H, CH ), 2.02 (s, 3 H, CH ), 2.19 (s, 6 H, 2 × CH ),

): d = 1.79 (s, 3 H, CH ), 1.80 (s, 3 H,

3

_T_a_x_i_f_o_l_i_a_l_A_[₍_±₎_-₂_]₃9

3

To a stirred solution of alcohol 24 (46 mg, 0.14 mmol) in CH Cl₂

2

.36 (dt, J = 14.5, 7.3 Hz, 1 H, CH ), 2.54 (dt, J = 14.5, 7.3

H,H 2 H,H

(3.5 mL) at 0 °C was added Dess–Martin periodinane (88 mg, 0.2

3

Hz, 1 H, CH ), 5.18 (d, J = 7.3 Hz, 1 H, CH), 5.32 (s, 1 H, CH),

2

H,H

mmol). The reaction mixture was stirred under argon at r.t. and

monitored by TLC. After disappearance of the starting material, the

mixture was poured into a separating funnel containing sat. aq

Na S O /NaHCO solution (9 mL, 1:1) and shaken vigorously for 5

3

5

.66 (br t, J = 7.3 Hz, 1 H, CH), 5.86 (t, J = 7.3 Hz, 1 H,

CH), 7.22 (d, J = 7.3 Hz, 1 H, CH), 7.81 (s, 1 H, CH).

H,H

3

H,H

1

3

C NMR (125 MHz, CDCl ): d = 17.8 (CH ), 20.85 (CH ), 20.89

3 3 3 3 2

2

3

min. The aqueous layer was extracted with Et O. The combined or-

(CH ), 21.0 (CH ), 21.2 (CH ), 24.9 (CH ), 32.4 (CH ), 68.7 (CH),

2

ganic layers were washed with sat. aq NaHCO solution, dried

85.2 (C), 94.2 (C), 103.6 (CH), 105.3 (CH), 116.9 (C), 121.5 (C),

129.9 (CH), 135.2 (CH), 137.6 (CH), 148.2 (C), 167.2 (C), 167.4

(C), 170.0 (C).

3

(

[

1

MgSO ) and concentrated under vacuum to give crude taxifolial A

(±)-2]; yield: 52 mg (96%).

4

H NMR (500 MHz, C D ): d = 1.47 (s, 3 H, CH ), 1.50 (s, 3 H,

6

3

_C_a_u_l_e_r_p_e_n_y_n_e_[₍_±₎_-₁_]2

CH ), 1.58 (s, 3 H, CH ), 1.74 (s, 3 H, CH ), 1.82 (s, 3 H, CH ), 2.21

3

2

In a Schlenk tube, under N

0.15 mmol], DMAP (18.4 mg, 0.15 mmol), Ac

mmol) and Et N (4 mL). The mixture was warmed to 80 °C and the

2

, was placed taxifolial A [(±)-2; 50 mg,

(

m, 2 H, CH ), 4.59 (d, J = 13.8 Hz, 1 H, CH ), 4.76 (d,

2 H,H 2

2

3

2

O (42 mL, 0.45

J_H_,_H= 13.8 Hz, 1 H, CH ), 5.28 (t, J = 6.3 Hz, 1 H, CH), 5.43

2

H,H

3

(

s, 1 H, CH ), 5.83 (t, J = 7.4 Hz, 1 H, CH), 6.03 (d, J = 7.1

3 H,H H,H

3

reaction was monitored by GC. After disappearance of the starting

material, the mixture was concentrated under vacuum and purified

by chromatography on silica gel (pentane–EtOAc, 8:2) to give a

40:60 mixture of caulerpenyne [(±)-1] and iso-caulerpenyne [iso-

(±)-1]; yield: 54 mg (96%).

Hz, 1 H, CH), 9.86 (d, J = 7.1 Hz, 1 H, CH).

H,H

1

H NMR (200 MHz, CDCl ): d = 1.80 (s, 3 H, CH ), 1.81 (s, 3 H,

3

CH ), 1.87 (s, 3 H, CH ), 2.07 (s, 3 H, CH ), 2.10 (s, 3 H, CH ), 2.53

3

2

(

m, 2 H, CH ), 5.00 (d, J = 13.8 Hz, 1 H, CH ), 5.10 (d,

2 H,H 2

2

J_H_,_H= 13.8 Hz, 1 H, CH ), 5.32 (m, 1 H, CH), 5.33 (s, 1 H, CH),

2

3

Caulerpenyne [(±)-1]

5

.67 (br t, J = 7.5 Hz, 1 H, CH), 6.12 (d, J = 7.3 Hz, 1 H,

H,H

3

H,H

1

CH), 10.09 (d, J = 7.3 Hz, 1 H, CH).

H NMR (500 MHz, CDCl ): d = 1.79 (s, 3 H, CH ), 1.81 (s, 3 H,

H,H

3

1

3

CH

3

), 1.86 (s, 3 H, CH

3

), 2.05 (s, 3 H, CH

3

), 2.13 (s, 3 H, CH ), 2.17

3

C NMR (75 MHz, C D ): d = 17.9 (CH ), 20.1 (CH ), 20.2 (CH ),

6

3

2

(

s, 3 H, CH ), 2.45 (dt, J = 14.7, 7.5 Hz, 1 H, CH ), 2.63 (dt,

3

H,H

2

1.0 (CH ), 24.6 (CH ), 32.8 (CH ), 59.1 (CH ), 73.0 (CH), 86.4

3 3 2 2

2

J_H_,_H= 14.7, 7.5 Hz, 1 H, CH ), 5.33 (s, 1 H, CH), 5.67 (br t,

2

(

C), 94.6 (C), 106.2 (CH), 122.5 (C), 129.0 (CH), 129.7 (CH), 147.9

C), 154.0 (C), 169.2 (C), 169.6 (C), 189.5 (CH).

3

J

= 7.5 Hz, 1 H, CH), 5.80 (d, J = 12.6 Hz, 1 H, CH), 5.85

H,H

3

(

t, ³J = 7.5 Hz, 1 H, CH), 7.23 (s, 1 H), 7.62 (d, J = 12.6, 1 H,

H,H H,H

CH).

(

1

1Z,3E) and (1Z,3Z)-1,4-Diacetoxy-2-(1-acetoxyprop-1-yl)but-

,3-diene (29 and 30)

1

3

C NMR (75 MHz, CDCl ): d = 17.8 (CH ), 20.7 (2 × CH ), 21.0

3 3 3 2

3

In a Schlenk tube, under N , was placed 28 (15 mg, 0.065 mmol),

(CH ), 21.2 (CH ), 24.9 (CH ), 32.1 (CH ), 68.9 (CH), 85.3 (C),

2

DMAP (8 mg, 0.065 mmol), Ac O (18.5 mL, 0.2 mmol) and Et N

94.1 (C), 105.3 (CH), 109.3 (CH), 118.7 (C), 121.6 (C), 129.9 (CH),

134.3 (CH), 137.0 (CH), 148.2 (C), 167.1 (C), 167.9 (C) et 170.0

(C).

2

3

(

0.5 mL). The mixture was warmed to 80 °C and the reaction was

monitored by GC. After disappearance of the starting material, the

mixture was concentrated under vacuum and purified by chroma-

tography on silica gel (pentane–EtOAc, 8:2) to give a 45:65 mixture

Homogeranial (33)

2

9 and 30; yield: 14.3 mg (85%).

To a stirred solution of homogeraniol (32; 0.4 g, 2.38 mmol) in

1

3

CH Cl (60 mL) at 0 °C was added Dess–Martin periodinane (2.00

2 2

H NMR (300 MHz, C D ): d = 0.79 (t, J = 7 Hz, 3 H, CH₃),

6

H,H

3

g, 4.75 mmol). The reaction mixture was stirred under argon at r.t.

and monitored by TLC. After disappearance of the starting material,

the mixture was poured into a separating funnel containing sat. aq

0

3

2

.83 (t, J = 7 Hz, 3 H, CH ), 1.53 (s, 3 H, CH ), 1.58 (s, 9 H,

H,H 3 3

× CH ), 1.67 (s, 3 H, CH ), 1.71 (s, 3 H, CH ), 1.45–1.92 (m, 4 H,

3

× CH ); characteristic signals of 29: 5.76 (d, J = 12.7 Hz, 1 H,

2

H,H

3

Na

5 min. The aqueous layer was extracted with Et

organic layers were washed with sat. aq NaHCO

(MgSO ) and concentrated under vacuum to give crude homogera-

2

S

2

O

3

/NaHCO

3

solution (200 mL, 1:1) and shaken vigorously for

O. The combined

solution, dried

CH), 6.07 (t, J = 7.5 Hz, 1 H, CH), 7.36 (s, 1 H, CH), 7.92 (d,

H,H

3

2

J_H_,_H= 12.7 Hz, 1 H, CH); characteristic signals of 30: 5.11 (d,

J_H_,_H= 7.2 Hz, 1 H, CH), 6.14 (t, J = 7.3 Hz, 1 H, CH), 7.35 (d,

J_H_,_H= 7.2 Hz, 1 H, CH), 8.22 (s, 1 H).

3

H,H

4

nial 33; yield: 396 mg (quant).

1

3

H NMR (300 MHz, CDCl ): d = 0.84 (t, J = 7.5 Hz, 6 H,

3

H,H

1

H NMR (200 MHz, CDCl ): d = 1.58 (s, 3 H, CH ), 1.62 (s, 3 H,

3

2

3

2

7

× CH ), 1.48–1.89 (m, 4 H, 2 × CH ), 2.01 (s, 3 H, CH ), 2.03 (s,

3

2

3

CH ), 1.66 (s, 3 H, CH ), 2.06 (m, 4 H, 2 × CH ), 3.11 (br d,

3

2

H, CH ), 2.11 (s, 3 H, CH ), 2.16 (s, 3 H, CH ), 2.18 (s, 6 H,

3

J

= 7.2 Hz, 2 H, CH ), 5.00–5.13 (m, 1 H, CH), 5.29 (br t,

H,H = 7.2 Hz, 1 H, CH), 9.60 (t, JH,H = 2.1 Hz, 1 H, CH).

H,H

2

× CH ), 5.73–5.80 (m, 3 H, 3 × CH); characteristic signals of 29:

3

.22 (s, 1 H, CH), 7.57 (d, J = 12.7 Hz, 1 H, CH); characteristic

H,H

3

13

signals of 30: 5.15 (d, J(H,H) = 7.2 Hz, 1 H, CH), 7.20 (d,

C NMR (50 MHz, C D ): d = 16.4 (CH ), 17.7 (CH ), 25.8 (CH ),

6

3

J_H_,_H= 7.2 Hz, 1 H, CH), 7.82 (s, 1 H, CH).

26.9 (CH ), 39.9 (CH ), 43.4 (CH ), 113.9 (CH), 124.5 (CH), 131.5

2 2 2

1

3

(C), 140.5 (C), 198.0 (CH).

C NMR (75 MHz, CDCl ): d = 9.5 (CH ), 9.8 (CH ), 20.71 (CH ),

3

+

2

0.74 (CH ), 21.1 (CH ), 20.8 (2 × CH ), 21.2 (CH ), 25.9 (CH ),

6.1 (CH ), 70.8 (CH), 71.0 (CH), 103.8 (CH), 109.4 (CH), 117.1

HRMS: m/z calcd for C H O [M + H] : 167.1436; found:

3

2

11 19

167.1432.

2

1

80

L. Commeiras et al.

FEATURE ARTICLE

3

(

2E,6E)-1-(tert-Butyldimethylsilyloxy)-3-hydroxymethyl-7,11-

³J = 6.8 Hz, 2 H, CH ), 4.62 (d, J = 12.5 Hz, 1 H, CH ), 4.72

H,H

3

2

H,H

2

dimethyldodeca-2,6,10-triene (34)

(d, J = 12.5 Hz, 1 H, CH ), 5.01–5.06 (m, 2 H, 2 × CH), 5.21 (t,

J_H_,_H= 6.7 Hz, 1 H, CH), 5.93 (t, J = 6.8 Hz, 1 H, CH).

H,H

2

3

To a solution of 6 (0.935 g, 1.91 mmol) in THF (30 mL) at –78 °C

was added dropwise BuLi (2.5 M, 1.68 mL, 4.19 mmol). The reac-

tion mixture was warmed to –35 °C for 2 h and then cooled to

13

C NMR (50 MHz, CDCl ): d = 16.2 (CH ), 17.6 (CH ), 20.9

3

(

5

(

CH ), 21.1 (CH ), 25.6 (CH ), 26.5 (CH ), 32.3 (CH ), 39.7 (CH ),

3 3 3 2 2 2

–

78 °C, then homogeranial 33 (0.380 g, 2.28 mmol) was added

8.3 (CH ), 59.6 (CH ), 75.3 (CH), 118.6 (CH), 124.0 (CH), 131.5

2 2

C), 132.6 (CH), 134.6 (C), 138.4 (C), 170.2 (C), 171.0 (C).

dropwise. The solution was kept at –78 °C for 1 h and quenched

with sat. aq NH Cl solution. The aqueous layer was extracted with

EtOAc. The combined organic layers were dried (MgSO ) and con-

centrated under vacuum. The crude product was then purified by

4

+

HRMS: m/z calcd for C H O [M + H] : 339.2172; found:

19 31

5

4

3

39.2172.

flash chromatography (PE–Et O, 4:6) to afford 34; yield: 320 mg

2

(

2

2E,6E)-4-Acetoxy-3-acetoxymethyl-7,11-dimethyldodeca-

,6,10-trienal (37)

To a stirred solution of 36 (60 mg, 0.18 mmol) in CH Cl (5 mL) at

(

47%).

1

H NMR (200 MHz, CDCl ): d = 0.04 (s, 6 H, 2 × CH ), 0.86 (s, 9

3

2

H, 3 × CH ), 1.55 (s, 3 H, CH ), 1.58 (s, 3 H, CH ), 1.63 (s, 3 H,

3

0

°C was added Dess–Martin periodinane (150 mg, 0.35 mmol).

CH ), 1.92–2.10 (m, 4 H, 2 × CH ), 2.17–2.43 (m, 2 H, CH ), 2.75

3

2

The reaction mixture was stirred under argon at r.t. and monitored

by TLC. After disappearance of the starting material, the mixture

was poured into a separating funnel containing sat. aq Na S O /

NaHCO solution (15 mL, 1:1) and shaken vigorously for 5 min.

The aqueous layer was extracted with Et O. The combined organic

layers were washed with sat. aq NaHCO solution, dried (MgSO )

and concentrated under vacuum to give crude aldehyde 37; yield: 59

3

(

br s, 1 H, OH), 3.15 (br s, 1 H, OH), 4.11 (br t, J = 7 Hz, 1 H,

H,H

3

CH), 4.16 (br s, 2 H, CH ), 4.25 (br d, J = 6.1 Hz, 2 H, CH₂),

4

2

H,H

3

2

3

.99–5.11 (m, 2 H, 2 × CH), 5.63 (t, J = 6.1 Hz, 1 H, CH).

H,H

3

1

3

C NMR (50 MHz, CDCl ): d = –5.2 (2 × CH ), 16.3 (CH ), 17.7

3

2

(

CH ), 18.3 (C), 25.7 (CH ), 25.9 (3 × CH ), 26.6 (CH ), 34.7

3

2

3

4

CH ), 39.8 (CH ), 58.4 (CH ), 59.5 (CH ), 75.7 (CH), 119.7 (CH),

2

1

24.1 (CH), 128.8 (CH), 131.6 (C), 138.8 (C), 141.8 (C).

mg (quant).

+

1

HRMS: m/z calcd for C H O Si [M + H] : 369.2825; found:

H NMR (300 MHz, CDCl ): d = 1.55 (s, 3 H, CH ), 1.57 (s, 3 H,

2

1

41

3

69.2824.

CH ), 1.63 (s, 3 H, CH ), 1.93–2.07 (m, 4 H, 2 × CH ), 2.03 (s, 3 H,

3

2

CH ), 2.07 (s, 3 H, CH ), 2.38–2.43 (m, 2 H, CH ), 4.94 (d,

3

2

(

2E,6E)-1-(tert-Butyldimethylsilyloxy)-4-acetoxy-3-acetoxy-

methyl-7,11-dimethyldodeca-2,6,10-trienes (35)

J_H_,_H= 13.9 Hz, 1 H, CH ), 4.96–5.07 (m, 2 H, 2 × CH), 5.10 (d,

2

3

J

= 13.9 Hz, 1 H, CH ), 5.29 (t, J = 6.1 Hz, 1 H, CH), 6.07

H,H

3

2

H,H

3

A solution of 34 (0.217 g, 0.59 mmol), Ac O (0.221 mL, 2.35

(d, J = 7.5 Hz, 1 H, CH), 10.06 (d, J = 7.5 Hz, 1 H, CH).

2

H,H

mmol) and DMAP (3.6 mg, 0.03 mmol) in pyridine (4.5 mL) was

stirred until the disappearance of the starting material. Then the

13

C NMR (75 MHz, CDCl ): d = 16.3 (CH ), 17.7 (CH ), 20.8

3 3 3 2 2 2

3

(

CH ), 20.9 (CH ), 25.7 (CH ), 26.5 (CH ), 32.2 (CH ), 39.7 (CH ),

mixture was quenched with sat. aq NaHCO solution. The aqueous

3

5

9.3 (CH ), 73.8 (CH), 117.5 (CH), 123.9 (CH), 128.9 (CH), 131.7

2

layer was extracted with Et O and the combined organic layers were

2

(

C), 139.6 (C), 154.7 (C), 169.9 (C), 170.2 (C), 190.4 (CH).

washed with sat. aq CuSO solution and H O, dried (MgSO ) and

4

2

4

+

HRMS: m/z calcd for C H O [M + H] : 337.2015; found:

concentrated under vacuum. The crude product was purified by

19 29

5

3

37.2019.

flash chromatography (PE–Et O, 8:2) to give 35; yield: 230 mg

2

(

86%).

(

±)-Dihydrorhipocephalin [(±)-3] and iso-(±)-Dihydrorhipo-

31

1

H NMR (200 MHz, CDCl ): d = 0.03 (s, 6 H, 2 × CH ), 0.86 (s, 9

3

cephalin [iso-(±)-3)]

In a Schlenk tube, under N , were placed 37 (23 mg, 0.068 mmol),

H, 3 × CH ), 1.56 (s, 3 H, CH ), 1.58 (s, 3 H, CH ), 1.64 (s, 3 H,

CH ), 1.99 (s, 3 H, CH ), 2.01 (s, 3 H, CH ), 1.89–2.10 (m, 4 H,

3

2

3

DMAP (8.3 mg, 0.068 mmol), Ac O (19 mL, 0.2 mmol) and Et N

3

2

3

2

× CH ), 2.22–2.47 (m, 2 H, CH ), 4.28 (d, J = 5.8 Hz, 2 H,

2

H,H

(1.5 mL). The mixture was warmed to 80 °C and the reaction was

CH ), 4.59 (s, 2 H, CH ), 4.96–5.06 (m, 2 H, 2 × CH), 5.21 (t,

2

followed by GC. After disappearance of the starting material, the

mixture was concentrated under vacuum and purified by flash chro-

matography (pentane–EtOAc, 8:2) to give a 45:55 mixture of (±)-

dihydrorhipocephalin [(±)-3] and iso-(±)-dihydrorhipocephalin

[iso-(±)-3]; yield: 20 mg (80%).

3

1

3

J

= 6.8 Hz, 1 H, CH), 5.80 (t, J = 5.8 Hz, 1 H, CH).

H,H

3

C NMR (50 MHz, CDCl ): d = –5.1 (2 × CH ), 16.3 (CH ), 17.7

3 3 3 3

3

(

CH ), 18.3 (C), 20.9 (CH ), 21.2 (CH ), 25.7 (CH ), 25.9

3 × CH ), 26.7 (CH ), 32.3 (CH , 39.8 (CH ), 59.6 (CH ), 59.7

3

2

2)

2

CH ), 75.5 (CH), 118.8 (CH), 124.1 (CH), 131.5 (C), 132.7 (C),

1

2

H NMR (500 MHz, CDCl ), (±)-dihydrorhipocephalin [(±)-3]:

3

1

34.3 (CH), 138.4 (C), 170.1 (C), 170.7 (C).

d = 1.57 (s, 3 H, CH ), 1.59 (s, 3 H, CH ), 1.65 (s, 3 H, CH ), 1.93–

3

+·

MS (EI, 70 eV): m/z (%) = 332 (M – 2 × CH COOH, 11), 263(14),

2

1

2.05 (m, 4 H, 2 × CH ), 2.03 (s, 3 H, CH ), 2.13 (s, 3 H, CH ), 2.16

3

2

3

13 (11), 201 (34), 159 (20), 157 (11), 145 (21), 131 (15), 119 (13),

17 (84), 105 (12), 93 (12), 91 (13), 81 (11), 77 (12), 75 (100), 69

28), 45 (16), 41 (26).

(s, 3 H, CH ), 2.37 (dt, J = 14.3, 7.3 Hz, 1 H, CH ), 2.52 (dt,

3 H,H 2

J

= 14.3, 7.3 Hz, 1 H, CH ), 5.02–5.05 (m, 2 H, 2 × CH), 5.80 (d,

3

H,H

2

3

(

J_H_,_H= 12.7 Hz, 1 H, CH), 5.83 (t, J = 7.3 Hz, 1 H, CH), 7.20 (s,

H,H

3

+

1 H, CH), 7.61 (d, JH,H = 12.7 Hz, 1 H, CH).

HRMS: m/z calcd for C H O Si [M + H] : 453.3036; found:

4

2

5

45

5

1

53.3039.

H NMR (500 MHz, CDCl ), iso-(±)-dihydrorhipocephalin [iso-

3

(

±)-3]: d = 1.57 (s, 3 H, CH ), 1.59 (s, 3 H, CH ), 1.65 (s, 3 H, CH ),

3 3 3

(

2E,6E)-4-Acetoxy-3-acetoxymethyl-7,11-dimethyldodeca-

,6,10-trien-1-ol (36)

1.93–2.05 (m, 4 H, 2 × CH ), 2.01 (s, 3 H, CH ) 2.18 (s, 6 H,

2

3

2

2 × CH ), 2.26 (dt, J = 14.3, 7.3 Hz, 1 H, CH ), 2.44 (dt,

3

H,H

2

To a solution of 35 (224 mg, 0.5 mmol) in THF (7 mL) was quickly

added an excess of HF/pyridine (0.455 mL). The reaction was mon-

itored by TLC. After the disappearance of the starting material, the

mixture was concentrated under vacuum. The crude product (95:5

J

= 14.3, 7.3 Hz, CH ), 5.02–5.05 (m, 2 H, 2 × CH), 5.20 (d,

H,H

2

3

J_H_,_H= 7.3 Hz, 1 H, CH), 5.85 (t, J = 7.3 Hz, 1 H, CH), 7.21 (d,

J_H_,_H= 7.3 Hz, 1 H, CH), 7.80 (s, 1 H, CH).

H,H

3

13

C NMR (125 MHz, CDCl ), (±)-dihydrorhipocephalin [(±)-3] and

3

ratio of isomers) was purified by flash chromatography (PE–Et O,

5

2

iso-(±)-dihydrorhipocephalin [iso-(±)-3]: d = 16.3 (CH ), 16.4

(

21.1 (CH ), et 21.2 (CH ), 25.7 (2 × CH ), 26.7 (2 × CH ), 31.6

(CH ), 31.9 (CH ), 39.79 (CH ), 39.82 (CH ), 69.4 (CH), 69.5 (CH),

3

:5 to 0:10) to give 36; yield: 130 mg (90%).

CH ), 17.7 (2 × CH ), 20.8 (2 × CH ), 20.85 (CH ), 20.88 (CH ),

3

1

H NMR (300 MHz, CDCl ): d = 1.58 (s, 3 H, CH ), 1.59 (s, 3 H,

3

2

CH ), 1.66 (s, 3 H, CH ), 1.93–2.04 (m, 5 H, 2 × CH , OH), 2.02 (s,

3

2

2 2 2 2

H, CH ), 2.04 (s, 3 H, CH ), 2.29–2.45 (m, 2 H, CH ), 4.25 (br t,

104.0 (CH), 109.5 (CH), 117.3 (C), 118.06 (CH), 118.11 (CH),

3

2

FEATURE ARTICLE

Synthesis of Terpenoids Isolated from Caulerpale Algae

181

1

19.2 (C), 124.0 (2C, CH), 131.60 (C), 131.61 (C), 134.0 (CH),

34.9 (CH), 137.0 (CH), 137.5 (CH), 138.8 (C), 138.9 (C), 167.2

(15) Miller, J. A. J. Org. Chem. 1989, 54, 1000.

(16) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;

(

C), 167.3 (C), 167.5 (C), 167.9 (C), 170.1 (2 × C).

Prityskaya, T. S. Zh. Org. Khim. 1989, 25, 2244; J. Org.

Chem. USSR (Engl. Transl.); 1990, 26, 2027.

(17) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36,

3203.

Biology

Lamb brain pure tubulin was purified from brain soluble extract by

(

NH ) SO fractionation and ion exchange chromatography. Then,

(18) (a) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter,

D. C. Tetrahedron Lett. 1989, 30, 2065. (b) Beaudet, I.;

Parrain, J.-L.; Quintard, J.-P. Tetrahedron Lett. 1991, 32,

6333. (c) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi,

A.; Prunet, J. J. Org. Chem. 1997, 62, 7768.

(19) Baekelmans, P.; Gielen, M.; Malfroid, P.; Nasielski, J. Bull.

Soc. Chim. Belg. 1968, 77, 85.

(20) (a) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc.,

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Res. 1982, 15, 340.

4

2

4

0

pure tubulin was stored in liquid N and prepared for use. Tubulin

concentration was determined spectrometrically at 275 nm in 6 M

2

–

1

–1

guanidine hydrochloride (E₂₇₅nm = 1.09 L·g ·cm ) or in 0.5%

sodium dodecyl sulfate in neutral aqueous buffer (E nm = 1.07

L·g ·cm ). The buffer solution used to polymerize pure tubulin

consisted of 20 mM sodium phosphate buffer, 1 mM EGTA, 3.4 M

glycerol, and 0.1 mM GTP, pH 6.95. After 35 min of incubation at

2

75

–

1

–1

3

7 °C with CYN analogues or DMSO (control), the polymerisation

reaction was started by addition of 10 mM MgCl . To determine the

2

inhibitory effect, we calculated the difference between the polymer-

isation plateau value and the depolymerisation plateau value and ex-

pressed it in percent of inhibition relative to the control.

(21) Barbot, F.; Miginiac, P. Synthesis 1983, 651.

(22) Michaud, S.; Viala, J. Tetrahedron 1999, 55, 3019.

(23) Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. Tetrahedron

Lett. 1981, 22, 4603.

(

24) (a) Fargeas, V.; Le Ménez, P.; Berque, I.; Ardisson, J.;

Pancrazi, A. Tetrahedron 1996, 52, 6613. (b) Kocienski, P.;

Wadman, S. J. Am. Chem. Soc. 1989, 111, 2363.

25) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.

26) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.

Acknowledgment

L.C. thanks CNRS and MESR, and J.B. thanks Région PACA and

DIPTA for providing financial support.

(

b) Thibonnet, J.; Abarbri, M.; Duchêne, A.; Parrain, J.-L.

Synlett 1999, 141. (c) Fargeas, V.; Le Ménez, P.; Berque, I.;

Ardisson, J.; Pancrazi, A. Tetrahedron 1996, 52, 6613.

(27) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J.

Org. Chem. 1979, 44, 4011.

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Article Doi

Total synthesis of terpenoids isolated from caulerpale algae and their inhibition of tubulin assembly

DOI: 10.1055/s-2005-921760

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Article abstract of DOI:10.1055/s-2005-921760

Full text of DOI:10.1055/s-2005-921760

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