The laulimalide family: Total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue

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DOI: 10.1002/chem.200802605

The Laulimalide Family: Total Synthesis and Biological Evaluation of

Neolaulimalide, Isolaulimalide, Laulimalide and a Nonnatural Analogue

Andreas Gollner,*^[a]Karl-Heinz Altmann,^[b]Jꢀrg Gertsch,^[b]and Johann Mulzer*^[a]

Abstract: We herein describe in full

detail the first total synthesis of the an-

titumor agents neolaulimalide and iso-

laulimalide as well as a highly efficient

route to laulimalide. A Kulinkovich re-

action followed by a cyclopropyl–allyl

rearrangement is used to install the

exo-methylene group. The C₂–C₁₆alde-

hyde fragment is coupled with the C₁₇–

C₂₈sulfone fragments by a highly (E)-

selective Julia–Lythgoe–Kocienski ole-

fination to deliver the key intermedi-

ates of all three syntheses. Various con-

ditions for the Yamaguchi macrolacto-

nization are applied to close the indi-

vidual macrocycles. Finally a carefully

elaborated endgame was developed to

solve the problem of acyl migration in

the case of neolaulimalide. All com-

pounds were tested against several cell

lines. The cytotoxicity of neolaulima-

lide could be confirmed for the first

time since its original isolation and it

could be shown that it induces tubulin

polymerization as efficiently as lauli-

malide.

Keywords: acyl migration

· anti-

tumor agents · natural products ·

olefination · total synthesis

Introduction

nolides (D–I) each varying with respect to the oxidation

state and/or substitution pattern of the C₂₀sidechain.^[1e]

Laulimalide (1) and neolaulimalide (2) inhibit the prolif-

eration of several tumor cell lines with IC₅₀values in the

low nanomolar range (1: KB IC₅₀=15 nm, MDA-MB-435

IC₅₀=6–7 nm;^[1b,2]2: P-388 IC₅₀=50 nm, A-549=10 nm, HT-

29 IC₅₀=25 nm, MEL 28 IC₅₀=25 nm^[1c,d]) whereas isolauli-

malide (3) and fijianolides D-I show reduced activity (3:

HT-29 IC₅₀=20–97 mm, MDA-MB-435 IC₅₀=20 mm).^[1d,e,2]In

1999 the group of Mooberry discovered that 1 stabilizes mi-

crotubules similar to paclitaxel.^[2]Later this was confirmed

The laulimalides (Scheme 1), also known as fijianolides, are

a family of polyketide natural products obtained from vari-

ous marine sources.^[1]The 20-membered macrolide laulima-

lide (fijianolide B, 1) and its isomer isolaulimalide (fijiano-

lide A, 3) have been isolated almost contemporaneously by

two groups from the marine sponges Cacospongia mycofi-

jiensis,^[1a]respectively Hyatella sp. and a nudibranch preda-

tor, Chromodoris lochi^[1b]back in 1988. A third isomer

named neolaulimalide (2) was isolated along with 1, 3 and

other cytotoxic compounds from the sponge Fasciospongia

rimosa in 1996.^[1c,d]Reisolation from Cacospongia mycofi-

jiensis unearthed, in addition to 1 and 3, six additional fijia-

[a] Dipl.-Ing. A. Gollner, Prof. Dr. J. Mulzer

University of Vienna, Institute of Organic Chemistry

Wꢀhringerstrasse 38, 1090 Vienna (Austria)

Fax : (+43)1-4277-52189

Homepage: http://www.univie.ac.at/rg_mulzer/

E-mail: andreas.gollner@univie.ac.at

johann.mulzer@univie.ac.at

[b] Prof. Dr. K.-H. Altmann, Dr. J. Gertsch

ETH Zꢁrich, Institut f. Pharmazeut. Wissenschaften

HCI H 405, Wolfgang-Pauli-Strasse 10

8093 Zꢁrich (Switzerland)

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.200802605.

Scheme 1. The laulimalides (CSA=camphorsulfonic acid).

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by different groups along with the result that 1 binds to tu-

bulin in a similar fashion as paclitaxel does, however, the

binding site is different.^[3]Laulimalide is synergistic with

other anticancer agents and is also very potent against cell

lines showing multidrug-resistance (MDR).^[3]According to a

first in vivo study 1 does not generate significant tumor-

growth inhibition within the limit of acceptable toxicity,^[4a]

whereas a second evaluation by a different group reports

significant inhibition of growth in HCT-116 tumors.^[4b]

Due to its epoxide function 1 is an intrinsically unstable

compound. On exposure to acid, it rearranges to 3 within

two hours via an acid-catalyzed S_N2-type attack of the C₂₀-

hydroxyl group on the C₁₇position of the epoxide

(Scheme 1).^[1b]Compound 2 shows an appreciably reduced

lability towards acid.^[1c,d]First it undergoes ring contraction

to 1, which then isomerizes to 3 as expected. After two days,

the rearrangement is complete.

Owing to its potential as an anticancer lead, the total syn-

thesis of 1 and the preparation of analogues thereof is a hot

topic for over a decade now.^[5,6]However, since acid lability

has been identified as a major drawback in developing 1 as

an anticancer drug,^[6a]2 should be considered as a promising

alternative lead compound. To our surprise the equally

active isomer 2 has been completely ignored since its discov-

ery. Moreover, 2 has been isolated only once and so we de-

cided to develop a first total synthesis for a re-evaluation of

the promising biological properties.^[7]

route to 1 as well, which should be suited for the acquisition

of larger quantities of material.

Results and Discussion

Strategic consideration: Our retrosynthesis (Scheme 2) was

focused on the development of a common key intermediate

that could be used for the preparation of all three laulima-

lides.

It was obvious that we have to install the labile epoxide

and 2,3-(Z)-enoate functions of 1 and 2 at the end of the

synthesis, after generating the macrocycle. For the synthesis

of 3 we envisaged the formation of the characteristic tetra-

hydrofuran moiety via an epoxide opening prior to macro-

cyclization. These considerations guided us to the common

key intermediate 4 which should be adapted to the different

tasks by a proper choice of the protecting groups. For opti-

ꢀ

mal convergency the C₁₆C₁₇double bond in 4 was discon-

nected to deliver aldehyde 5 and sulfone 6 suitable for a

Julia-Lythgoe-Kocienski olefination.^[5a–c,8]

Preparation of the fragments—The aldehyde fragment 5:

For the preparation of the C₂–C₁₆fragment 5, which was

used in all three syntheses, we envisioned two routes

(Scheme 2). In the first approach (Scheme 3) the C₁₁stereo-

center was generated by alkylating the sodium enolate of 11

with 2,3-dibromo-1-propene to obtain 12 in 70% yield. Re-

ductive removal of the auxiliary led to alcohol 13^[9]which

was subjected to a C-1 elongation by standard tosylation

and S_N2 displacement with sodium cyanide. Nitrile 14 was

reduced to the volatile aldehyde 8. Allylation with (ꢀ)-Ipc–

allylborane gave the homoallylic alcohol 16 in 85% yield

and a 14:1 d.r.^[10]The dihydropyran 7 was generated by

We see a potential for 3 as an alternative perfectly stable

lead compound as well. Hence we aimed for a flexible first

total synthesis of 3 which should open the space for the

preparation of biological active analogues.^[7]Finally, we real-

ized that the material for the in vivo testing of 1 is still

partly obtained from marine sources and not by total syn-

thesis.^[4b]This stimulated us to develop a late generation

Scheme 2. Retrosynthesis of 1, 2 and 3 (PG=protecting group, HWE=Horner–Wadsworth–Emmons olefination, PMB=para-methyloxybenzyl, PT=1-

phenyl-1H-tetrazole, RCAM=ring-closing alkyne metathesis, RCM=ring-closing metathesis, SAE=Sharpless asymmetric epoxidation, TBS=tert-butyl-

dimethylsilyl).

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ether and oxidation with 2-iodoxybenzoic acid (IBX) to the

aldehyde delivered fragment 5 in 21% yield over 14 linear

steps.

The sulfone fragments 6a–e (Scheme 4): The syntheses of

sulfones 6a, 6b and 6c started with the removal of the TES-

ether from the known intermediate 31a^[5h]with HF·pyridine

Scheme 3. Synthesis of aldehyde 5, first generation approach. a)

NaHMDS, THF, ꢀ78 to ꢀ308C (70%); b) LiBH₄, H₂O, Et₂O, 0 8C

(93%); c) TsCl, DMAP, pyridine, RT (97%); d) NaCN, DMSO, 858C

(99%); e) DIBALH, CH₂Cl₂, ꢀ788C to RT (80%); f) (ꢀ)-Ipc-allylbor-

ane, pentane, Et₂O, ꢀ1008C (86%); g) (EtO)₂CHCH=CH₂, PPTS, tolu-

ene, 408C; h) [Cl₂ACHTUNGTRENNUNG(PCy₃)₂Ru=CHPh], CH₂Cl₂, reflux (80% over two

steps) (DIBALH=diisobutylaluminium hydride, DMAP=N,N-dimethyl-

aminopyridine, DMSO=dimethylsulfoxide, Ipc=isopinocampheyl,

NaHMDS=sodium bis(trimethylsilyl)amide, PPTS=pyridinium toluene-

4-sulfonate, THF=tetrahydrofuran, Ts=p-toluenesulfonyl).

forming the mixed allylic acetal and subsequent ring-closing

metathesis (RCM).^[11]However, several attempts to open

epoxide 17 with differnt cuprate species generated from

vinyl bromide 7 failed in our hands.

Since our first route to aldehyde 5 had misfired we fo-

cused on the development of a second, more robust and reli-

able approach. Thus we decided to start with commercially

available diol 19 which can be obtained from very cheap

natural (S)-malic acid in two steps and provides us with the

correct configuration at C₁₅.^[12]The TBS-protected diol 20

was used in a Kulinkovich reaction^[13]to generate cyclopro-

panol 21 which was used without further purification in the

next step. Mesylation of 21 and treatment of the crude prod-

uct with MgBr₂·OEt₂in refluxing CH₂Cl₂resulted in a rapid

cyclopropyl–allyl rearrangement furnishing allylbromide 10

in 73% yield over three steps.^[13]This sequence could be car-

ried out without problems on a 30 gram scale. Alkylation of

N-propionyloxazolidinone 23 with 10 proceeded in good

yields. The auxiliary was removed by reduction with LiBH₄

and gave alcohol 25. At this stage we used a Mitsunobu re-

action for C-1 elongation to the cyanide alternative to tosy-

lation and S_N2 displacement with sodium cyanide.^[14]Reduc-

tion of nitrile 26 with DIBALH led to aldehyde 27 and sub-

sequent Brown allylation^[10]gave us alcohol 9 in very good

yield and a high d.r. of 16:1. The formation of the dihydro-

pyran unit could be streamlined as well. After generation of

the mixed allylic acetal we were able to perform RCM^[11]

and the subsequent installation of the C₂–C₃sidechain, by

addition of vinyloxytrimethylsilane and montmorilonite

K10, in one pot. The resulting aldehyde 28 was converted

into the terminal alkyne with the Bestmann-Ohira reagent

in 75% yield.^[15]Selective deprotection of the primary TBS

Scheme 4. Synthesis of aldehyde 5, second-generation approach. a)

TBSCl, Im, CH₂Cl₂, RT (99%); b) TiACTHNUGTRNEUNG(OiPr)₄, EtMgBr, 108C, Et₂O; c)

MsCl, NEt₃, 08C; d) MgBr₂·Et₂O, CH₂Cl₂, reflux (73% over three steps);

e) NaHMDS, THF, ꢀ78 to ꢀ308C, (77%, 79% conversion); f) LiBH₄,

H₂O, Et₂O, 0 8C (97%); g) PPh₃, DIAD, acetone cyanohydrin, THF, RT

(94%); h) DIBALH, CH₂Cl₂, ꢀ788C to RT (92%); i) (ꢀ)-Ipc-allylbor-

ane, pentane, Et₂O, ꢀ1008C (95%); j) (EtO)₂CHCH=CH₂, PPTS, tolu-

ene, 408C; k) [Cl₂ACHTUNRGTNEGN(U PCy₃)₂Ru=CHPh], CH₂Cl₂, reflux, then montmorilon-

ite K10, vinyloxytrimethylsilane, RT (70% over two steps); l) K₂CO₃, di-

methyl-1-diazo-2-oxopropylphosphonate, MeOH, RT (75%); m) NH₄F,

EtOH, RT (93%, 71% conversion); n) IBX, MeCN, reflux (98%) (Bn=

benzyl, DIAD=diisopropyl azodicarboxylate, Im=imidazole, IBX=2-

iodoxybenzoic acid, Ms=methanesulfonyl).

to give the primary alcohol, which was immediately trans-

formed into sulfide 32a (90% over two steps) by a Mitsuno-

bu reaction with 1-phenyl-1H-tetrazol-5-thiol (PT-SH).

Luche^[16]reduction of 32a at low temperatures delivered the

syn-product 33a in almost quantitative yield and good dia-

stereoselectivity (d.r. 17:1). The newly generated OH group

at C₂₀was protected as TBS-, TES- and MOM-ethers 34a–c

which were oxidized to the sulfones 6a, 6b and 6c. This

worked well for 6a and 6c. In the case of the very labile al-

lylic OTES ether in 6b we had to use buffered heptamolyb-

date^[17]and carefully monitor the reaction progress to avoid

desilylation and subsequent epoxidation of the allylic alco-

hol.

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For the synthesis of 6d we started from 31b and trans-

formed it to sulfide 32b as described above for 32a

Scheme 5. The Luche reduction of 32b gave even better dia-

stereoselectivity (d.r. > 20:1) and excellent yields. The re-

sulting alcohol 33b was oxidized to the sulfone, the TBDPS-

ether was removed with 70% HF·pyridine and the obtained

vicinal diol was capped with TES groups to furnish 6d.

The sulfonyl ketone 6e was obtained by oxidizing sulfide

32a.

Scheme 6. Synthesis of the Gallagher Intermediate 4a. a) KHMDS, THF,

ꢀ788C (87%) (KHMDS=potassium bis(trimethylsilyl)amide).

Alkyne-metathesis approach to 1: After having achieved a

formal access to 1 we envisioned the development of a more

effective endgame and considered RCAM (ring-closing

alkyne metathesis) as a promising alternative method for

closing the macrocycle (Scheme 7), since this method has

been successful on several occasions.^[18]We therefore methy-

lated the terminal alkyne of 29 and cleaved the primary

TBS-ether with NH₄F. Oxidation of alcohol 38 with IBX de-

livered aldehyde 39 which was used in a Julia–Lythgoe–Ko-

cienski olefination with sulfone 6c to deliver intermediate

40 in 74% yield. After oxidative cleavage of the PMB group

with DDQ the resulting alcohol 41 was esterified with 2-bu-

tynoic acid and DIC to furnish the required RCAM precur-

sor 42. To our disappointment treatment of 42 with the com-

mercially available Schrock alkyne metathesis catalyst 43^[19]

Scheme 5. Synthesis of the sulfone fragments 6a–e. a) 7% HF·pyridine,

THF, RT (98% both cases); b) PPh₃, PTSH, DEAD, THF, 08C to RT

(92% both cases); c) NaBH₄, CeCl₃·7H₂O, MeOH, ꢀ788C (33b),

ꢀ1008C (33a) (33b: 97%, d.r. > 20:1; 33a: 98%, d.r. 17:1); d) TBSOTf,

2,6-lutidine, CH₂Cl₂, ꢀ208C to RT (93%); e) TESOTf, 2,6-lutidine,

CH₂Cl₂, ꢀ308C to RT (97%); f) MOMCl, NEtiPr₂, CH₂Cl₂, RT (98%);

g) H₂O₂, (NH₄)₆Mo₇O₂₄, EtOH, RT (73%); h) H₂O₂, (NH₄)₆Mo₇O₂₄,

EtOH, pH 7 buffer, RT (61%) i) H₂O₂, (NH₄)₆Mo₇O₂₄, EtOH, RT

(76%); j) H₂O₂, (NH₄)₆Mo₇O₂₄, EtOH, RT (70%); k) 70% HF·pyridine,

THF, 08C to RT (94%); l) TESOTf, 2,6-lutidine, CH₂Cl₂, ꢀ208C to RT

(97%); m) H₂O₂, (NH₄)₆Mo₇O₂₄, EtOH, RT (73%) (DEAD=diethyl

azodicarboxylate, MOM=methyloxymethyl, OTf=trifluoromethanesul-

fonate, TBDPS=tert-butyldiphenylsilyl, TES=triethylsilyl).

Total synthesis of laulimalide (1)—The Gallagher intermedi-

ate: After the successful coupling of aldehyde 5 with sulfone

6a via a completely (E)-selective Julia–Lythgoe–Kocienski

olefination^[8]we obtained intermediate 4a in excellent yield

(Scheme 6). This compound had been used as a 1:1 mixture

of diastereomers at C₁₅in a gram scale synthesis of 1 by Gal-

lagher et al that provided material for an in vivo study.^[5k]

We can now provide a shorter, higher yielding and stereose-

lective route to 4a.

Scheme 7. Alkyne metathesis approach to 1: a) nBuLi, MeI, THF, ꢀ788C

(85%); b) NH₄F, EtOH, RT (89%, 65% conversion); c) IBX, MeCN,

reflux (98%) d) KHMDS, THF, ꢀ788C (74%); e) DDQ, phosphate

buffer pH 7, CH₂Cl₂, RT (89%) f) DIC, 2-butynoic acid, DMAP, CH₂Cl₂,

08C to RT (70%); g) Schrock catalyst 43, PhH (DIC=N,N’-diisopropyl-

carbodiimide).

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under several conditions^[20]did not produce the desired

product. We mainly isolated unconverted 43 along with un-

identified decomposition products. The ester function next

to a triple bond in 43 might be a reason for our failure since

Fꢁrstner reported a related case earlier.^[21]

Macrolactonization approach to 1: We next aspired an effec-

tive macrolactonization approach (Scheme 8). Julia–Lyth-

goe–Kocienski olefination of 5 and sulfone 6d again gave us

fragment 4b in excellent yield and (E)-selectivity. Then, we

were able to generate seco acid 44 in just one operation as

C-1 elongation with nBuLi and carbon dioxide followed by

selective deprotection of the TES groups with 7% HF·pyri-

dine could be performed in the same pot. Yamaguchi mac-

rolactonization under Yonemitsu conditions^[22]delivered the

20-membered ring 45 exclusively in good yields. The macro-

cycle was desilylated to 46 and Lindlar-reduction of the

triple bond led to desoxylaulimalide (47). Finally, Sharpless

asymmetric epoxidation (SAE) furnished 1 in 75% yield.^[4c]

All analytical data of 1 were in full accord with the ones re-

ported.^[1]

Scheme 9. First total synthesis of 2. a) KHMDS, THF, ꢀ788C (76%), b)

nBuLi, CO₂then 7% HF·pyridine, THF, ꢀ788C to RT (85%); c) 2,4,6-

Cl₃C₆H₃C(O)Cl, NEt₃, DMAP, PhH, RT (35% + 4% dimer); d) 35%

HF·pyridine, THF, 08C to RT (87%); e) DDQ, phosphate buffer pH 7,

CH₂Cl₂, RT (90%); f) Lindlar cat., quinoline, EtOAc/cyclohexene

(98%); g) DDQ, phosphate buffer pH 7, CH₂Cl₂, ultrasound, 32–428C

(96%); h) Ti

(73%).

N

would provide us 2 as well. In fact desilylation of the TBS

ether proceeded smoothly with 35% HF·pyridine and deliv-

ered 50 in 87% yield. However, on attempting to remove

the remaining OPMB protecting group, we realized how

strong the driving force was to restore the more favorable

20-membered lactone. Thus on treatment of 22 with an

excess of DDQ in CH₂Cl₂/phosphate buffer pH 7 the desired

oxidative cleavage of the PMB ether was ensued by a rapid

acyl migration and macrolactone 47 was isolated as the sole

product. Model studies indicated that the ring strain which

disfavors the larger macrolide would be much reduced in

the (Z)-enoate. Due to this considerations we generated the

labile (Z)-enoate prior to the crucial deprotection by Lind-

lar reduction to 51. After intensive experimentation we

were delighted to see that ultrasound treatment of 51 with

DDQ under strictly neutral conditions during reaction and

workup gave desoxyneolaulimalide (52) in excellent yield.

During our deprotection studies we found that the notori-

ously acid labile macrocycle is even more sensitive to base

promoted trans-acylation. To avoid this complication in the

final step of our synthesis we had to develop a modified

non-basic work up for the SAE reaction. Therefore, after

successful epoxidation we were able to obtain 2 in 73%

yield. All analytical data perfectly matched those in the lit-

erature.^[1c]

Scheme 8. Synthesis of 1. a) KHMDS, THF, ꢀ788C (80%); b) nBuLi,

CO₂then 7% HF·pyridine, THF, ꢀ788C to RT (87%); c) 2,4,6-

Cl₃C₆H₃C(O)Cl, NEt₃, DMAP, benzene, RT (75%); d) 35% HF·pyridine,

THF, 08C to RT (95%); e) H₂, Lindlar cat., quinoline, EtOAc/cyclohex-

ene, RT (85%); f) TiACHTUNGTRENNUNG(OiPr)₄, (+)-DIPT, tBuOOH, 4 ꢃ MS, CH₂Cl₂,

ꢀ208C (75%) (DIPT=diisopropyl tartrate, MS=molecular sieves).

Total synthesis of neolaulimalide (2): For the synthesis of 2

the macrolactonization had to generate the obviously unfa-

vored 21-membered macrocycle, an objective which had to

be enforced by appropriate protective group manipulations.

Hence we coupled aldehyde 5 with sulfone 6b to 4c

(Scheme 9) and obtained seco acid 48 in one pot by C-1

elongation and subsequent desilylation in good yield. Our

first Yamaguchi macrolactonization attempts again under

Yonemitsu conditions delivered unacceptable 1:1 mixtures

of the desired macrocycle 49 and its dimer in moderate com-

bined yield. A change to classical Yamaguchi conditions^[22,23]

and higher dilution reduced dimer formation to 4% and

yielded 49 in 35%. With the 21-membered macrocycle in

hands we expected that the simple endgame we used for 1

Total synthesis of isolaulimalide (3): To generate the THF

ring we envisioned an efficient reduction/epoxide opening

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J. Mulzer, A. Gollner et al.

sequence to convert 54 into 59 (Scheme 10). Therefore we

had to perform a Julia olefination with unsaturated sulfone

6e and 5. Since difficulties were expected, we started our in-

vestigations with a model system. Treatment of 6e and an

excess of cycohexanecarbaldehyde under Barbier conditions

with KHMDS lead to enone 53 in 69% yield. To our disap-

pointment the analogous reaction of aldehyde 5 with 6e

never gave yields higher than 24%, when we used both

components in stoichiometric amounts. At this point we had

to reconsider our synthesis and change the strategy. Never-

theless we obtained the valuable information that even an

unsaturated ketone such as 6e can be applied in Julia olefi-

nations though with limited success.

Scheme 10. First approach to 3. a) KHMDS, THF, ꢀ788C (70%); b)

KHMDS, THF, ꢀ788C (24%).

Scheme 11. First total synthesis of 3. a) KHMDS, THF, ꢀ788C (86%); b)

70% HF·pyridine, THF, 08C to RT (95%); c) TiACTHNUTRGENUG(N OiPr)₄, (+)-DIPT,

tBuOOH, 4 ꢃ MS, CH₂Cl₂, ꢀ208C (73%); d) several acidic conditions

(e.g. HCl, EtOH; TMSBr, DCM); e) BF₃·Et₂O, PhSH, THF, ꢀ208C to

08C (70%); f) TBSOTf, 2,6-lutidine, CH₂Cl₂, ꢀ208C to RT (87%); g)

DDQ, phosphate buffer pH 7, CH₂Cl₂(90%); h) nBuLi, CO₂, THF,

ꢀ788C (86%); i) 2,4,6-Cl₃C₆H₃C(O)Cl, NEt₃, DMAP, benzene, RT; j)

70% HF·pyridine, THF, 08C to RT (32% over two steps); k) H₂, Lindlar

cat., quinoline, EtOAc/cyclohexene (97%); l) cat. CSA, CDCl₃(90%).

Our next approach started with the formation of inter-

mediate 4e from sulfone 6c and 5 in excellent yield

(Scheme 11). Desilylation of the TBS-ether with HF·pyri-

dine led to allylic alcohol 56. Its SAE delivered 57 as a

modified cyclisation precursor. First attempts to deprotect

the OMOM ether and subsequent opening of the epoxide

with various acids or Lewis acids did not deliver the desired

tetrahydrofuran. Instead, along with unidentified decompo-

sition products, epoxide 58 was isolated as the product of an

acid-catalyzed Payne rearrangement. After extensive experi-

mentation we found that when we removed the OMOM

protecting group with BF₃·OEt₂and PhSH at ꢀ20 to 08C,

intramolecular opening of the epoxide occurred to give tet-

rahydrofuran 59 in 70% yield. TBS protection of the result-

ing vicinal diol led to compound 60, whose PMB deprotec-

tion and C-1 elongation delivered seco-acid 61. We suspect-

ed that macrolactonization would not be facile, due to the

transannular strain exerted by the rigid tetrahydrofuran

ring. Therefore we were pleased to isolate, from a Yamagu-

chi macrolactonization, the desired macrolactone in 38%

yield, along with 9% of the dimer. This mixture was difficult

to separate; however, after removal of the TBS-protecting

groups monomer 63 could be easily isolated by chromatog-

raphy. Reduction of the triple bond to the (Z)-enoate finally

gave 3 which was identical with the sample we obtained

from 1 by treatment with a catalytic amount of acid

(Scheme 11, Figure 1). All analytical data of 3 matched

those reported in literature.^[1a,b]

Synthesis of an C-20 O ester analogue (67): During our syn-

thesis of 1 we observed that ester 64 was generated when

we used an excess of 2,4,6-trichlorobenzoyl chloride in the

macrolactonization of seco-acid 44 (Scheme 12). We con-

verted this intermediate to the laulimalide analogue 67 by

subsequent desilylation, Lindlar reduction and SAE. This se-

quence might be used for the generation of a library of C-20

OH ester analogues by simply adding the corresponding

acid chlorides to the reaction mixture after macrolactoniza-

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Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

Figure 1. Conversion of laulimalide (1) to isolaulimalide (3) by treatment with a catalytic amount of TFA in CDCl₃, followed by ¹H NMR (600 MHz).

Table 1. Inhibition of proliferation.^[a]

cell line

MCF-7

PC-3M

HCT-116

compound

IC₅₀[nm]

laulimalide (1)

neolaulimalide (2)

isolaulimalide (3)

67

11.6ꢁ0.5

13.2ꢁ0.6

4900ꢁ200

>10000

5.9ꢁ0.3

8.4ꢁ0.7

4400ꢁ300

>10000

6.4ꢁ1.5

7.8ꢁ0.8

4.5ꢁ0.6

4800ꢁ300

>10000

2.8ꢁ0.4

epothilone A

2.9ꢁ0.3

[a] Cells were treated with varying concentrations of the compounds for

72 h. The values represent the means of three experiments ꢁSD.

showed the same activity as reported in the original isola-

tion publication^[1c]and is as active 1. As expected 3 showed

only marginal cytotoxicity. The unnatural analogue 67 was

almost inactive. The EC₅₀values for tubulin polymerization

(Table 2) showed that neolaulimalide (2) induces tubulin

polymerization as potent as 1 and epothilone A and is there-

fore a potent member of the MSAA family.

Scheme 12. Synthesis of analogue 67. a) 2,4,6-Cl₃C₆H₃C(O)Cl (3 equiv),

NEt₃, DMAP, benzene, RT (72%); b) 35% HF·pyridine, THF, 08C to

RT (86%); c) H₂, Lindlar cat., quinoline, EtOAc/cyclohexene, RT

Table 2. Potency for tubulin polymerization of all compounds.^[a]

compound

EC₅₀values (ab-tubulin polymerization)

(70%); d) Ti

(71%).

(OiPr)₄, (+)-DIPT, tBuOOH, 4 ꢃ MS, CH₂Cl₂, ꢀ208C

laulimalide (1)

neolaulimalide (2)

isolaulimalide (3)

67

4.0ꢁ0.5 mm

3.9ꢁ0.4 mm

> 10 mm

epothilone A

4.4ꢁ0.3 mm

tion. This should enable the synthesis of unnatural ana-

logues like 67 without adding steps to the synthesis.

[a] The EC₅₀(half maximal effective concentration) values represent the

means of three experimentsꢁSD.

Biological activities: All synthetic laulimalides (1–3) were

tested for their effects on the proliferation of three tumor

cell lines (Table 1), along with the standard epothilone A. 2

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5985

J. Mulzer, A. Gollner et al.

2H), 1.68 (dd, J=14.6, 5.3 Hz, 1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.79–0.68

(m, 2H), 0.52–0.46 (m, 1H), 0.43–0.37 (m, 1H), 0.11 (s, 3H), 0.10 (s, 3H),

0.08 (s, 3H), 0.07 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=73.6

(CH), 67.1 (CH₂), 54.0 (C_q), 42.2 (CH₂), 26.0 (3ꢄCH₃), 25.9 (3ꢄCH₃),

18.4 (C_q), 18.1 (C_q), 13.6 (CH₂), 12.6 (CH₂), ꢀ4.3 (CH₃), ꢀ4.7 (CH₃),

ꢀ5.2 (CH₃), ꢀ5.3 ppm (CH₃); IR (film): n˜ =3443, 2956, 2930, 2886, 2858,

1463, 1257, 1119, 837, 778 cm^ꢀ1; HRMS(EI): m/z: calcd for C₁₈H₄₀O₃Si₂:

360.2516, found: 360.2523.

Conclusion

We described a fully stereoselective and flexible approach

to the laulimalide family including the first total synthesis of

neolaulimalide (2) in 21 steps along the longest linear se-

quence in 3% overall yield. As the compound is now avail-

able again for the first time, the biological re-evaluation of 2

was possible and we could prove the promising cytotoxic

properties.^[1c,d]The more acid stable 2 is as active as 1 and

polymerizes tubulin in the same concentration range. Sec-

ondly, isolaulimalide (3) was synthesized for the first time.

This approach which proceeded in 2% yield and 24 linear

steps enables the preparation of a range of analogues not

accessible from 1 by modifications of the fully stable late

stage intermediates 59/60. Finally we made further improve-

ments towards the preparation of larger amounts of laulima-

lide (1) and are now able to present a robust synthesis that

starts from cheap materials and produces the compound in

7% yield over 20 linear steps.

(S)-2-(tert-Butyldimethylsilyloxy)-3-(1-(methylsulfonyloxy)cyclopropyl)-

propyl methanesulfonate (22): To a stirred solution of crude 21 (18.8 g)

in absolute Et₂O (80 mL) at 08C was added Et₃N (1.99 g, 197.1 mol).

Methanesulfonyl chloride (11.28 g, 98.5 mmol) was added dropwise over

a period of 30 min and the reaction was stirred for another 45 min at the

same temperature. The reaction was quenched by adding water (80 mL)

and the aqueous layer was extracted three times with Et₂O. The organic

phase was dried over magnesium sulfate, filtered and the solvent was re-

moved under vacuum. Crude mesylate 22 (21.4 g) was obtained as a

yellow, viscous oil and was used in the next step without further purifica-

tion. An analytical sample was obtained by column chromatography

(silica gel, hexane/EtOAc 15:1) as a clear, colorless oil. [a]²_D⁰= ꢀ5.0 (c=

1

1.10 in CH₂Cl₂); H NMR (400 MHz, CDCl₃): d=4.07–4.00 (m, 1H), 3.63

(dd, J=10.1, 4.3 Hz, 1H), 3.50 (dd, J=10, 6.0 Hz, 1H), 2.99 (s, 3H), 2.42

(dd, J=15.2, 4.0 Hz, 1H), 1.67–1.60 (m, 1H), 1.34–1.25 (m, 1H), 1.24–

1.15 (m, 1H), 0.93–0.79 (m, 19H), 0.78–0.71 (m, 1H), 0.09 (s, 6H),

0.05 ppm (s, 6H); ¹³C NMR (100 MHz, CDCl₃): d=70.7 (CH), 67.2

(CH₂), 64.4 (C_q), 40.5 (CH₂), 40.1 CH₃), 26.1 (3ꢄCH₃), 26.0 (3x CH₃),

18.5 (C_q), 18.1 (C_q), 12.7 (CH₂), 11.4 (CH₂), ꢀ4.3 (CH₃), ꢀ4.5 (CH₃),

ꢀ5.2 ppm (2ꢄCH₃); IR (film): n˜ =2930, 2857, 1472, 1361, 1256, 1165, 836,

776, 668 cm^ꢀ1; HRMS(EI): m/z: calcd for C₁₉H₄₂O₅SSi₂: 438.2291, found:

438.2281.

Experimental Section

All reactions were carried out in oven-dried glassware under an argon at-

mosphere, unless otherwise stated. Anhydrous toluene and Et₂O were

distilled from sodium/benzophenone under argon. Anhydrous CH₂Cl₂

was distilled from CaH₂under argon or reduced pressure, respectively.

Anhydrous THF (tetrahydrofurane) was purchased from Acros (99.85%,

water < 50 ppm). All other solvents were HPLC grade. Reactions were

magnetically stirred and monitored by thin-layer chromatography (TLC)

with E. Merck silica gel 60-F254 plates. Flash column chromatography

was performed with Merck silica gel (0.04–0.063 mm, 240–400 mesh)

under pressure. Yields refer to chromatographically and spectroscopically

pure compounds, unless otherwise stated. NMR spectra were recorded

on either Bruker Avance DRX 400 or DRX 600 MHz spectrometer.

Unless otherwise stated, all NMR spectra were measured in CDCl₃solu-

tions and referenced to the residual CHCl₃signal (¹H, d=7.26 ppm; ¹³C,

d=77.16 ppm). All ¹H and ¹³C shifts are given in ppm (s=singlet; d=

doublet; t=triplet; q=quadruplet; m=multiplet; br=broad signal). As-

signments of proton resonances were confirmed, when possible, by corre-

lated spectroscopy. Optical rotations were measured on a P 341 Perkin-

Elmer polarimeter. Mass spectra were measured on a Micro mass, trio

200 Fisions Instruments. High resolution mass spectra (HRMS) were per-

formed with a Finnigan MAT 8230 with a resolution of 10000. The Sup-

porting Information of this paper includes experimental details for com-

pounds 7, 8, 14–16; 37–42; 6e, 53–54, 64–67 and NMR spectra of all new

compounds.

Allylbromide 10: To a stirred solution of crude mesylate 22 (21.4 g) in

CH₂Cl₂(200 mL) was MgBr₂·Et₂O (40.7 g, 157.6 mmol). The reaction

mixture was refluxed for 3 h, then cooled to 08C and quenched with H₂O

(150 mL). The aqueous layer was extracted three times with EtOAc. The

combined organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The obtained yellow oil was pu-

rified by column chromatography (silica gel, hexane/EtOAc 15:1), yield-

ing 10 as clear, colorless oil (17.5 g, 41.3 mmol, 73% over three steps).

[a]²_D⁰= +0.9 (c=1.50 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=5.25

(brs, 1H), 5.02 (brs, 1H), 4.07 (d, J=9.9 Hz, 1H), 4.01 (d, J=9.7 Hz,

1H), 3.86–3.78 (m, 1H), 3.52 (dd, J=10.0, 5.1 Hz, 1H), 3.41 (dd, J=10.0,

6.7 Hz, 1H), 2.57 (dd, J=14.1, 4.7 Hz, 1H), 2.28 (dd, J=14.1, 6.7 Hz,

1H), 0.90–0.87 (m, 18H), 0.07–0.04 ppm (m, 12H); ¹³C NMR (100 MHz,

CDCl₃): d=142.8 (C_q), 118.2 (CH₂), 72.3 (CH), 66.8 (CH₂), 38.2 (CH₂),

37.8 (CH₂), 26.1 (3ꢄCH₃), 26.0 (3ꢄCH₃), 18.5 (C_q), 18.2 (C_q), ꢀ4.3

(CH₃), ꢀ4.5 (CH₃), ꢀ5.2 ppm (2ꢄCH₃); IR (film): n˜ =2956, 2930, 2858,

1472, 1256, 1117, 1083, 836, 811, 776 cm^ꢀ1; HRMS(EI): m/z: calcd for

C₁₈H₃₉O₂BrSi₂: 422.1672, found: 422.1656.

(R)-4-Benzyl-3-((2S,6S)-6,7-bis(tert-butyldimethylsilyloxy)-2-methyl-4-

methyleneheptanoyl)oxazolidin-2-one (24): To a stirred solution of Evans

N-propionyloxazolidinone 23 (9.07 g, 38.9 mmol) in THF (150 mL) was

added NaHMDS (44.74 mL, 44.74 mmol,1m solution in THF) at ꢀ788C

in 30 min. The solution was stirred for 15 min at the same temperature

before allylbromide 10 (8.21 g, 19.45 mmol) was added. The reaction was

allowed to reach ꢀ308C and stirred for 8 h at this temperature. The reac-

tion was warmed to 08C and quenched by adding aq. sat. NH₄Cl

(150 mL). The aqueous layer was extracted three times with EtOAc. The

combined organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The residue was purified by

column chromatography (silica gel, hexane/EtOAc 20:1 ! 6:1), yielding

24 as clear, colorless oil (6.82 g, 11.85 mmol, 61%) and unconsumed 10

(1.73 g, 4.085 mmol, 21%). [a]²_D⁰=25.1 (c=1.15 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=7.25–7.26 (m, 3H), 7.23–7.19 (m, 2H), 4.88 (brs,

1H), 4.86 (brs, 1H), 4.71–4.64 (m, 1H), 4.20–4.12 (m, 2H), 4.03 (dt, J=

14.1, 7.0 Hz, 1H), 3.86–3.79 (m, 1H), 3.52 (dd, J=10.1, 5.3 Hz, 1H), 3.46

(dd, J=10.0, 5.7 Hz, 1H), 3.29 (dd, J=13.3, 3.4 Hz, 1H), 2.67 (dd, J=

13.4, 9.9 Hz, 1H), 2.58 (dd, J=14.4, 7.6 Hz, 1H), 2.34 (dd, J=13.9,

4.8 Hz, 1H), 2.20–2.11 (m, 2H), 1.18 (d, J=6.8 Hz, 3H), 0.89 (brs, 9H),

(S)-1-(2,3-Bis(tert-butyldimethylsilyloxy)propyl)cyclopropanol (21): To a

stirred solution of TBS-protected diol 20 (21.20 g, 56.3 mmol) in THF

(170 mL) at 108C was added TiACHTUNTRGNEUNG(OiPr)₄(4.80 g, 61.7 mmol). A solution of

EtMgBr (56.3 mL, 3m in Et₂O, 168.9 mmol) was added dropwise over the

period of 4 h. After the addition the black solution was stirred for anoth-

er 1 h at the same temperature. The solvent was removed under vacuum

and the oily, black residue was diluted with CH₂Cl₂(250 mL) and cooled

to 08C. The solution was quenched with aq. sat. NH₄Cl solution (35 mL).

The resulting mixture was filtered and the precipitate was washed with

CH₂Cl₂(5ꢄ60 mL). The filtrate was washed with aq. sat. NaHCO₃solu-

tion, the organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. Crude cyclopropanol 21 (18.9 g)

was obtained as a yellow, viscous oil and was used in the next step with-

out further purification. An analytical sample was obtained by column

chromatography (silica gel, hexane/EtOAc 20:1) as a clear, colorless oil.

[a]²_D⁰= +13.7 (c=1.15, in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=

4.02–3.95 (m, 1H), 3.70–3.61 (m, 2H), 2.00 (ddd, J=14.7, 5.6, 1.0 Hz,

5986

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Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

0.88 (brs, 9H), 0.06 (brs, 3H), 0.05 (brs, 3H), 0.04 ppm (brs, 3H);

¹³C NMR (100 MHz, CDCl₃): d=177.1 (C_q), 153.2 (C_q), 143.9 (C_q), 135.6

(C_q), 129.6 (2ꢄCH), 129.0 (2ꢄCH), 127.4 (CH), 114.3 (CH₂), 72.3 (CH),

67.3 (CH₂), 66.1 (CH₂), 55.6 (CH), 41.1 (CH₂), 40.4 (CH₂), 38.2 (CH₂),

35.9 (CH), 26.2 (3ꢄCH₃), 26.1 (3ꢄCH₃), 18.5 (C_q), 18.3 (C_q), 17.4 (CH₃),

ꢀ4.1 (CH₃), ꢀ4.5 (CH₃), ꢀ5.2 ppm (CH₃); IR (film): n˜ =2955, 2929, 2857,

9H), 0.03 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=202.7 (C_q),

144.4 (C_q), 114.7 (CH₂), 72.5 (CH), 67.2 (CH₂), 50.9 (CH₂), 44.4 (CH₂),

40.6 (CH₂), 26.5 (CH), 26.1 (3ꢄCH₃), 26.0 (3ꢄCH₃), 20.1 (CH₃), 18.5

(C_q), 18.3 (C_q), ꢀ4.2 (CH₃), ꢀ4.5 (CH₃), ꢀ5.1 (CH₃), ꢀ5.2 ppm (CH₃);

IR (film): n˜ =2956, 2930, 2858, 1729, 1472, 1361, 1256, 1119, 1006, 836,

776 cm^ꢀ1

414.2988.

; HRMS(EI): m/z: calcd for C₂₂H₄₆O₃Si₂: 414.2985, found:.

1784, 1386, 1251, 1103, 835, 776 cm^ꢀ1

C₃₁H₅₃NO₅Si₂: 575.3462, found: 575.3457.

; HRMS(EI): m/z: calcd for

(4S,6S,10S)-10,11-Bis(tert-butyldimethylsilyloxy)-6-methyl-8-methylene-

undec-1-en-4-ol (9): Aldehyde 27 (2.40 g, 5.786 mmol) was dissolved in

Et₂O (70 mL) and cooled to ꢀ1008C. A solution of (ꢀ)-Ipc-allylborane

(10.49 mL, 8.390 mmol, 0.8m solution in pentane) was added precooled

(ꢀ788C) via a cannula in 20 min. The reaction was stirred at ꢀ1008C for

2 h and quenched by adding MeOH (4 mL). The reaction was warmed to

RT and the solvent was removed under vacuum. The residue was taken

up in H₂O/THF 1:1 (120 mL), NaBO₃·4H₂O (2.23 g, 14.465 mmol) was

added and the mixture was stirred overnight. The solution was diluted

with brine (100 mL) and extracted three times with EtOAc. The com-

bined organic phase was dried over magnesium sulfate, filtered and the

solvent was removed under vacuum. The obtained oil was purified by

column chromatography (silica gel, hexane/EtOAc 40:1), yielding 9 as

colorless oil (2.43 g, 5.509 mmol, 95%, d.r. 16:1 determined by HPLC).

[a]²_D⁰=+9.5 (c=1.05 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=5.89–

5.77 (m, 1H), 5.17–5.13 (m, 1H), 5.13–5.10 (m, 1H), 4.82 (brs, 1H), 4.78

(brs, 1H), 3.81–3.71 (m, 2H), 3.51 (dd, J=10.0, 5.6 Hz, 1H), 3.43 (dd, J=

9.9, 5.8 Hz, 1H), 2.32–2.23 (m, 2H), 2.20–2.11 (m, 1H), 2.08–1.99 (m,

2H), 1.92–1.84 (m, 2H), 1.54–1.46 (m, 1H), 1.44 (d, J=4.2 Hz, 1H, OH),

1.27–1.11 (m, 1H), 0.90–0.88 (m, 12H), 0.87 (brs, 9H), 0.05–0.04 ppm (m,

12H); ¹³C NMR (100 MHz, CDCl₃): d=144.9 (C_q), 135.0 (CH), 118.2

(CH₂), 113.9 (CH₂), 72.3 (CH), 68.6 (CH), 67.4 (CH₂), 45.1 (CH₂), 44.4

(CH₂), 43.0 (CH₂), 40.9 (CH₂), 27.5 (CH), 26.2 (3ꢄCH₃), 26.1 (3ꢄCH₃),

19.4 (CH₃), 18.5 (C_q), 18.3 (C_q), ꢀ4.1 (CH₃), ꢀ4.5 (CH₃), ꢀ5.1 (CH₃),

ꢀ5.2 ppm (CH₃); IR (film): n˜ =3368, 2929, 2858, 1643, 1472, 1361, 1256,

ACHTUNGTRENNUNG(2S,6S)-6,7-Bis(tert-butyldimethylsilyloxy)-2-methyl-4-methyleneheptan-

1-ol (25): Compound 24 (6.80 g, 11.81 mmol) was dissolved in Et₂O

(150 mL), H₂O (215 mL) was added and the mixture was cooled to 08C.

LiBH₄(334 mg, 15.35 mmol) was added portionwise over 30 min and the

reaction was stirred for another 5 h at the same temperature. The reac-

tion was quenched by adding 0.1n aq. NaOH (150 mL). The aqueous

layer was extracted three times with EtOAc. The combined organic

phase was dried over magnesium sulfate, filtered and the solvent was re-

moved under vacuum. The obtained oil was purified by column chroma-

tography (silica gel, hexane/EtOAc 7:1), yielding 25 as viscous, colorless

oil (4.62 g, 11.47 mmol, 97%). [a]²_D⁰=ꢀ1.2 (c=1.05 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=4.84 (brs, 1H), 4.82 (brs, 1H), 3.81–3.74 (m, 1H),

3.55–3.49 (m, 2H), 2.48–3.40 (m, 2H), 2.32 (dd, J=13.8, 4.9 Hz, 1H),

2.22–2.12 (m, 1H), 2.07 (dd, J=13.9, 7.1 Hz, 1H), 1.90–1.80 (m, 1H),

1.33 (t, J=5.7 Hz, 1H, OH), 0.92–0.86 (m, 21H), 0.06–0.03 ppm (m,

12H); ¹³C NMR (100 MHz, CDCl₃): d=145.0 (C_q), 114.0 (CH₂), 72.4

(CH), 68.5 (CH₂), 67.3 (CH₂), 40.9 (CH₂), 40.8 (CH₂), 34.0 (CH), 26.1

(3ꢄCH₃), 26.0 (3ꢄCH₃), 18.5 (C_q), 18.3 (C_q), 16.8 (CH₃), ꢀ4.2 (CH₃),

ꢀ4.5 (CH₃), ꢀ5.1 (CH₃), ꢀ5.2 ppm (CH₃); IR (film): n˜ =2930, 2859, 1739,

1683, 1652, 1538, 1471, 1464, 1257, 1121, 834, 671 cm^ꢀ1; HRMS(EI): m/z:

calcd for C₂₁H₄₆O₃Si₂: 402.2985, found: 402.2974.

ACHTUNGTRENNUNG(3S,7S)-7,8-Bis(tert-butyldimethylsilyloxy)-3-methyl-5-methyleneoctane-

nitrile (26): Alcohol 25 (300 mg, 0.746 mmol) was dissolved in Et₂O

(10 mL) and cooled to 08C. PPh₃(401 mg, 1.490 mmol) and DIAD

(301 mg, 1.490 mmol) were added followed by acetone cyanohydrin

(137 mL, 128 mg, 1.490 mmol). The yellow reaction mixture was stirred at

08C for 1 h and allowed to warm to RT overnight. The reaction mixture

was flashed through a short pad of silica gel and the solvent was removed

under vacuum. The crude product was purified by column chromatogra-

phy (silica gel, hexane/EtOAc 20:1), yielding 26 as slightly yellow oil

(288 mg, 0.699 mmol, 94%). [a]²_D⁰= +3.2 (c=1.45 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=4.90 (brs, 1H), 4.85 (brs, 1H), 3.79–3.72 (m, 1H),

3.52 (dd, J=10.0, 5.2 Hz, 1H), 3.41 (dd, J=10.0, 6.4 Hz, 1H), 2.38–2.27

(m, 2H), 2.21 (dd, J=16.8, 6.7 Hz, 1H), 2.14–1.99 (m, 4H), 1.08 (d, J=

6.3 Hz, 3H), 0.89 (brs, 9H), 0.87 (brs, 9H), 0.06–0.04 (m, 9H), 0.04 ppm

(brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=143.6 (C_q), 118.8 (C_q), 115.1

(CH₂), 72.5 (CH), 67.0 (CH₂), 43.5 (CH₂), 40.4 (CH₂), 28.7 (CH), 26.1

(3ꢄCH₃), 26.0 (3ꢄCH₃), 24.2 (CH₂), 19.6 (CH₃), 18.5 (C_q), 18.3 (C_q),

ꢀ4.2 (CH₃), ꢀ4.6 (CH₃), ꢀ5.2 ppm (2ꢄCH₃); IR (film): n˜ =2956, 2930,

2858, 1733, 1557, 1505, 1472, 1464, 1257, 1115, 835, 777 cm^ꢀ1; HRMS(EI):

m/z: calcd for C₂₂H₄₅NO₂Si₂: 411.2989, found: 411.2986.

1117, 991, 836, 776 cm^ꢀ1

456.3455, found: 456.3451.

; HRMS(EI): m/z: calcd for C₂₅H₅₂O₃Si₂:

2-((2R,6R)-6-((2S,6S)-6,7-Bis(tert-butyldimethylsilyloxy)-2-methyl-4-

methyleneheptyl)-5,6-dihydro-2H-pyran-2-yl)acetaldehyde (28): Acrolein

diethyl acetal (6 mL) and a catalytic amount of PPTS were added to ho-

moallylalcohol 9 (2.41 g, 5.275 mmol) in toluene (75 mL). The mixture

was rotated on a rotary evaporator at 80 mbar and 408C to remove the li-

berated EtOH. The volume of the reaction was kept constant by adding

toluene occasionally. After 90 min the reaction was concentrated to

about 5 mL and purified by column chromatography (silica gel, hexane/

EtOAc 50:1 + 1% Et₃N). The obtained mixed acetal was used immedi-

ately for the next step. Grubbs’ catalyst 1st gen. (224 mg, 0.264 mmol)

was added in one portion to the mixed acetal dissolved in degased

CH₂Cl₂(300 mL) at 408C and the reaction was refluxed overnight. The

reaction was cooled to RT and air was bubbled through the reaction for

10 min. The solvent was reduced to 20 mL and vinyloxytrimethylsilane

(3.07 g, 26.375 mmol) and montmorillonite K10 (2.5 g) were added. After

sirring for 10 min the reaction was filtered through a short pad of silica

gel and concentrated in vacuum. The obtained brown oil was purified by

column chromatography (silica gel, hexane/EtOAc 20:1), yielding 28 as

colorless oil (1.89 g, 3.699 mmol, 70%, over two steps). [a]²_D⁰=ꢀ32.0 (c=

1.12 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=9.82–9.79 (m, 1H),

5.90–5.85 (m, 1H), 5.72–5.76 (m, 1H), 4.82 (brs, 1H), 4.80–4.71 (m, 2H),

3.80–3.71 (m, 2H), 3.49 (dd, J=10.0, 5.6 Hz, 1H), 3.44 (dd, J=10.0,

5.6 Hz, 1H), 2.73 (ddd, J=16.2, 8.9, 3.0 Hz, 1H), 2.53 (ddd, J=16.2, 4.8,

1.8 Hz, 1H), 2.25 (dd, J=13.8, 5.6 Hz, 1H), 3.09–1.81 (m, 6H), 1.69–1.60

(m, 1H), 1.15–1.06 (m, 1H), 0.90–0.83 (m, 21H), 0.05 (brs, 3H), 0.04–

0.03 ppm (m, 9H); ¹³C NMR (100 MHz, CDCl₃): d=201.1 (CH), 144.9

(C_q), 128.0 (CH), 125.8 (CH), 113.8 (CH₂), 72.4 (CH), 68.0 (CH), 67.5

(CH₂), 65.7 (CH₂), 48.1 (CH₂), 45.1 (CH₂), 42.4, (CH₂), 41.0 (CH₂), 31.1

(CH₂), 26.9 (CH), 26.2 (3ꢄCH₃), 26.1 (3ꢄCH₃), 19.4 (CH₃), 18.5 (C_q),

18.3 (C_q), ꢀ4.2 (CH₃), ꢀ4.5 (CH₃), ꢀ5.1 (CH₃), ꢀ5.2 ppm (CH₃); IR

(film): n˜ =2928, 1730, 1472, 1361, 1256, 1097, 835, 775 cm^ꢀ1; HRMS(EI):

m/z: calcd for C₂₈H₅₄O₄Si₂: 510.3561, found:. 510.3556.

ACHTUNGTRENNUNG(3S,7S)-7,8-Bis(tert-butyldimethylsilyloxy)-3-methyl-5-methyleneoctanal

(27): Cyanide 26 (2.63 g, 6.387 mmol) was dissolved in CH₂Cl₂(65 mL)

and cooled to ꢀ788C. DIBAL (6.39 mL, 9.581 mmol, 1.5m in toluene)

was added drop wise over 15 min and the reaction was stirred for 45 min

at the same temperature before it was allowed to warm to RT. The reac-

tion was stirred for 5 h at RT and then cooled again to ꢀ788C. EtOAc

(2 mL) was added and the reaction was allowed to warm to 08C before it

was poured into a flask containing sat. aq. KNa-tartrate (200 mL) and

EtOAc (200 mL). The cloudy mixture was stirred vigorous for 6 h. The

aqueous layer was extracted three times with EtOAc. The combined or-

ganic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The obtained oil was purified by column

chromatography (silica gel, hexane/EtOAc 10:1), yielding 27 as colorless

oil 2.43 g (5.856 mmol, 92%). [a]²_D⁰=ꢀ6.8 (c=1.05 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=9.75 (t, J=2.0 Hz, 1H), 4.87 (brs, 1H), 4.80 (brs,

1H), 3.80–3.73 (m, 1H), 3.52 (dd, J=10.0, 5.4 Hz, 1H), 3.42 (dd, J=10.0,

6.2 Hz, 1H), 2.47–2.40 (m, 1H), 2.31 (ddd, J=14.0, 4.9, 0.8 Hz, 1H),

2.27–2.16 (m, 2H), 2.09–2.01 (m, 2H), 1.98 (dd, J=13.9, 7.1 Hz, 1H),

0.95 (d, J=6.3 Hz, 3H), 0.89 (brs, 9H), 0.87 (brs, 9H), 0.05–0.04 (m,

TBS-ether 29: To a solution of aldehyde 28 (1.87 g, 3.660 mmol) in

MeOH (10 mL) was added K₂CO₃(1.01 g, 7.320 mmol) and Bestman–

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5987

J. Mulzer, A. Gollner et al.

Ohira reagent (879 mg, 4.575 mmol). After stirring for 4 h at RT the reac-

tion was quenched by adding sat. aq. NaHCO₃solution (10 mL), diluted

with H₂O (10 mL) and extracted four times with CH₂Cl₂. The combined

organic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The residue was purified by column chro-

matography (silica gel, hexane/EtOAc 30:1), yielding 29 as colorless oil

(1.39 g, 2.737 mmol, 75%). [a]²_D⁰=ꢀ49.5 (c=1.00 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=5.93–5.82 (m, 2H), 4.81 (brs, 1H), 4.78 (brs, 1H),

4.36–4.28 (m, 1H), 3.85–3.73 (m, 2H), 3.54–3.40 (m, 2H), 2.55–2.39 (m,

2H), 2.32–2.23 (m, 1H), 2.10–1.83 (m, 7H), 1.68–1.57 (m, 1H), 1.16–1.07

(m, 1H), 0.90–0.80 (m, 21H), 0.06–0.03 ppm (m, 12H); ¹³C NMR

(100 MHz, CDCl₃): d=145.0 (C_q), 128.1 (CH), 125.7 (CH), 113.8 (CH₂),

81.2 (C_q), 72.4 (CH), 70.9 (CH), 70.2 (CH), 67.5 (CH₂), 66.1 (CH), 45.1

(CH₂), 42.6 (CH₂), 41.0 (CH₂), 31.3 (CH₂), 27.0 (CH), 26.2 (3ꢄCH₃), 26.1

(3ꢄCH₃), 24.7 (CH₂), 19.4 (CH₃), 18.5 (C_q), 18.3 (C_q), ꢀ4.1 (CH₃), ꢀ4.5

(CH₃), ꢀ5.1 (CH₃), ꢀ5.2 ppm (CH₃); IR (film): n˜ =3314, 2954, 2928,

1642, 1472, 1255, 1093, 835, 776, 708 cm^ꢀ1; HRMS(EI): m/z: calcd for

C₂₉H₅₄O₃Si₂: 506.3611, found: 506.3604.

extracted four times with EtOAc. The combined organic phase was dried

over magnesium sulfate, filtered and the solvent was removed under

vacuum. The obtained oil was purified by column chromatography (silica

gel, hexane/EtOAc 1:1 + 1% Et₃N), yielding the labile alcohol as color-

less, viscous oil (2.76 g, 7.98 mmol, 98%) which was immediately used for

the next step. A solution of OTES deprotected 31a (2.71 g, 7.823 mmol)

in THF (35 mL) was cooled to 08C and added PPh₃(3.08 g,

11.734 mmol), 1-phenyl-1H-tetrazol-5-thiol (2.09 g, 11.734 mmol) and

DEAD (2.45 g, 14.081 mmol). The reaction was stirred at 08C for 1 h and

4 h at RT. The reaction was quenched by adding sat. aq. NaHCO₃solu-

tion (60 mL) and extracted four times with EtOAc. The combined organ-

ic phase was dried over magnesium sulfate, filtered and the solvent was

removed under vacuum. The obtained oil was purified by column chro-

matography (silica gel, hexane/EtOAc 3:1), yielding sulfide 32a as color-

less oil (3.66 g, 7.224 mmol, 92%). [a]²_D⁰=ꢀ97.5 (c=1.10 in CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=7.58–7.51 (m, 5H), 7.28–7.22 (m, 2H),

7.03 (dd, J=15.7, 4.0 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 6.74 (dd, J=15.8,

1.8 Hz, 1H), 5.45 (brs, 1H), 4.56 (d, J=11.4 Hz, 1H), 4.32 (d, J=

11.3 Hz, 1H), 4.28–4.15 (m, 3H), 4.10 (dd, J=8.7, 4.4 Hz, 1H), 3.79 (s,

3H), 3.54–3.40 (m, 2H), 2.30–2.12 (m, 2H), 2.11–1.93 (m, 2H), 1.72 ppm

(brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=200.5 (C_q), 159.7 (C_q), 154.1

(C_q), 147.7 (CH), 133.8 (C_q), 131.2 (C_q), 130.2 (CH), 130.1 (2ꢄCH), 129.9

(2ꢄCH), 129.3 (C_q), 123.9 (2ꢄCH), 122.8 (CH), 119.9 (CH), 114.1 (2ꢄ

CH), 81.6 (CH), 72.7 (CH), 72.7 (CH₂), 65.9 (CH₂), 55.5 (CH), 35.1

(CH₂), 31.7 (CH₂), 29.5 (CH₂), 23.0 ppm (CH₃); IR (film): n˜ =3469, 2930,

2150, 1692, 1612, 1384, 1302, 1247, 1090, 761, 516 cm^ꢀ1; HRMS(EI): m/z:

calcd for C₂₇H₃₀O₄N₄SNa: 529.1885, found: 529.1878.

ACHTUNGTRENNUNG(2S,6S)-2-(tert-Butyldimethylsilyloxy)-6-methyl-4-methylene-7-((2R,6R)-

6-(prop-2-ynyl)-3,6-dihydro-2H-pyran-2-yl)heptan-1-ol (30): To a stirred

solution of compound 29 (1.38 g, 2.72 mmol) in MeOH (10 mL) was

added NH₄F (4 g) and stirred at RT for 32 h. To the reaction was added

H₂O (50 mL) and it was extracted four times with CH₂Cl₂. The combined

organic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The obtained oil was purified by column

chromatography (silica gel, hexane/EtOAc 20:1 ! 10:1), yielding 30 as

colorless oil (699 mg, 1.78 mmol, 65%, 95% based on recovered starting

material) along with recovered 29 (408 mg, 0.80 mmol). [a]²_D⁰=ꢀ57.0 (c=

1.00, CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃): d=5.92–5.88 (m, 1H), 5.86–

5.83 (m, 1H), 4.82 (brs, 1H), 4.80 (brs, 1H), 4.35–4.30 (m, 1H), 3.90–

3.84 (m, 1H), 3.83–3.78 (m, 1H), 3.60–3.55 (m, 1H), 3.47–3.42 (m, 1H),

2.51 (ddd, J=16.4, 6.9, 2.7 Hz, 1H), 2.43 (ddd, J=16.6, 7.1, 2.6 Hz, 1H),

2.25–2.18 (m, 2H), 2.01 (t, J=2.8 Hz, 1H), 2.00–1.95 (m, 3H), 1.95–1.87

(m, 3H), 1.65–1.59 (m, 1H), 1.08 (ddd, J=14.0, 9.4 3.0 Hz, 1H), 0.91–

0.89 (m, 12H), 0.10 (brs, 3H), 0.09 ppm (brs, 3H); ¹³C NMR (125 MHz,

CDCl₃): d=144.4 (C_q), 128.1 (CH), 125.8 (CH), 114.1 (CH₂), 81.2 (C_q),

71.6 (CH), 71.0 (CH), 70.2 (CH), 66.2 (CH₂), 65.9 (CH), 45.1 (CH₂), 42.3

(CH₂), 40.6 (CH₂), 31.3 (CH₂), 27.0 (CH), 26.0 (3ꢄCH₃), 24.6 (CH₂), 19.6

(CH₃), 18.3 (C_q), ꢀ4.1 (CH₃), ꢀ4.5 ppm (CH₃); IR (film): n˜ =3452, 3312,

AHCTUNGTERG(NNUN 3S,4S,E)-4-(4-Methoxybenzyloxy)-1-((S)-4-methyl-3,6-dihydro-2H-pyran-

2-yl)-6-(1-phenyl-1H-tetrazol-5-ylthio)hex-1-en-3-ol (33a): Compound

32a (3.61 g, 7.097 mmol) was dissolved in MeOH (35 mL) and cooled to

ꢀ1008C. CeCl₃·7H₂O (4.49 g, 12.066 mmol) was added and stirred for

10 min. Following NaBH₄(398 mg, 10.646 mmol) was added in three por-

tions and stirred for 90 min at the same temperature. The reaction was

quenched by adding EtOAc (2 mL) and warmed to RT. H₂O (60 mL)

was added and extracted four times with EtOAc. The combined organic

phase was washed with brine, dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The obtained oil was purified by

column chromatography (silica gel, hexane/EtOAc 1:1), yielding alcohol

33a as colorless oil (3.53 g, 6.940 mmol, 98%). [a]²_D⁰=ꢀ59.4 (c=1.20 in

1

CH₂Cl₂); H NMR (400 MHz, CDCl₃): d=7.58–7.54 (m, 5H), 7.27 (d, J=

2928, 1256, 1092, 837, 777, 611 cm^ꢀ1

C₂₃H₄₀O₃Si₂: 392.2747, found: 392.2751.

; HRMS(EI): m/z: calcd for

7.6 Hz, 2H), 6.86 (d, J=7.8 Hz, 2H), 5.89 (dd, J=15.7, 4.9 Hz, 1H), 5.80

(ddd, J=15.7, 5.8, 1.0 Hz, 1H), 5.41 (brs, 1H), 4.62- 4.55 (m, 2H), 4.21–

4.15 (m, 3H), 4.07–4.01 (m, 1H), 3.79 (s, 3H), 3.58–3.52 (m, 1H), 3.49–

3.40 (m, 2H), 2.39 (d, J=4.8 Hz, 1H, OH), 2.21–2.11 (m, 1H), 2.10–2.00

(m, 2H), 1.95–1.87 (m, 1H), 1.70 ppm (brs, 3H);¹³C NMR (100 MHz,

CDCl₃): d=159.6 (C_q), 154.4 (C_q), 133.8 (C_q), 133.5 (CH), 131.5 (C_q),

130.2 (CH), 130.1 (C_q), 130.0 (4ꢄCH), 129.8 (CH), 124.0 (2ꢄCH), 119.8

(CH), 114.1 (2ꢄCH), 80.2 (CH), 73.7 (CH), 73.4 (CH), 72.9 (CH₂), 65.8

(CH₂), 55.4 (CH₃), 35.8 (CH₂), 30.5 (CH₂), 29.6 (CH₂), 23.1 ppm (CH₃);

ACHTUNGTRENNUNG

a

solution of alcohol 30 (550 mg, 1.40 mmol) in MeCN was added IBX

(784 mg, 2.80 mmol) in one portion. The reaction was refluxed for

20 min, cooled to RT and filtered over celite. The solvent was removed

under vacuum and the obtained oil was purified by column chromatogra-

phy (silica gel, hexane/EtOAc 10:1), yielding 5 as colorless oil (535 mg,

1.37 mmol, 98%). [a]²_D⁰=ꢀ72.4 (c=1.00 in CH₂Cl₂); ¹H NMR (400 MHz,

CDCl₃): d=9.59 (d, J=1.8 Hz, 1H), 5.93–5.89 (m, 1H), 5.86–5.81 (m,

1H), 4.87 (brs, 1H), 4.86 (brs, 1H), 4.36–4.30 (m, 1H), 4.09 (ddd, J=7.6,

5.3, 1.8 Hz, 1H), 3.84–3.76 (m, 1H), 2.51 (ddd, J=16.5, 7.0, 2.7 Hz, 1H),

2.42 (ddd, J=16.4, 7.0, 2.7 Hz, 1H), 2.38 (dd, J=14.1, 4.9 Hz, 1H), 2.29

(dd, J=14.2, 7.5 Hz, 1H), 2.06–2.00 (m, 1H), 2.02 (t, J=2.7 Hz, 1H),

2.00–1.85 (m, 4H), 1.61 (ddd, J=13.8, 9.9, 3.4 Hz, 1H), 1.11 (ddd, J=

13.9, 9.1, 3.1 Hz, 1H), 0.90 (brs, 9H), 0.89 (d, J=6.2 Hz, 3H), 0.07 (brs,

3H), 0.05 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=203.5 (CH),

142.7 (C_q), 128.1 (CH), 125.8 (CH), 115.2 (CH₂), 81.2 (C_q), 76.7 (CH),

71.2 (CH), 70.2 (CH), 66.2 (CH), 44.9 (CH₂), 42.6 (CH₂), 39.0 (CH₂), 31.3

(CH₂), 26.9 (CH), 25.9 (3ꢄCH₃), 24.6 (CH₂), 19.3 (CH₃), 18.3 (C_q), ꢀ4.5

(CH₃), ꢀ4.7 ppm (CH₃); IR (film): n˜ =3314, 2929, 1737, 1092, 839, 778,

IR (film): n˜ =3430, 2359, 1612, 1513, 1384, 1247, 1174, 1032, 762 cm^ꢀ1

HRMS(EI): m/z: calcd for C₂₇H₃₂O₄N₄S: 508.2144, found: 508.2158.

;

Sulfide 34a: To a stirred solution of 33a (85 g, 0.136 mmol) in CH₂Cl₂

(2 mL) at ꢀ308C was added 2,6-lutidine (25.5 mg, 0.238 mmol) and drop-

wise TESOTf (54 mg, 0.204 mmol). The reaction was stirred at the same

temperature for 20 min, then allowed to warm to RT and stirred for an-

other 3 h. The reaction was quenched with aq. sat. NaHCO₃(5 mL) and

extracted four times with CH₂Cl₂. The combined organic phase was dried

over magnesium sulfate, filtered and the solvent was removed under

vacuum. The obtained viscous oil was purified by column chromatogra-

phy (silica gel, hexane/EtOAc 10:1), yielding sulfide 34a as colorless, vis-

cous oil (83 mg, 0.127 mmol, 93%). [a]²_D⁰=ꢀ50.8 (c=1.50, CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=7.56–7.53 (m, 5H), 7.25 (d, J=8.6 Hz,

2H), 6.84 (d, J=8.6 Hz, 2H), 5.82 (dd, J=15.7, 3.8 Hz, 1H), 5.76 (dd, J=

15.7, 4.5 Hz, 1H), 5.40 (brs, 1H), 4.64 (d, J=11.4 Hz, 1H), 4.47 (d, J=

11.4 Hz, 1H), 4.38 (t, J=4.3 Hz, 1H), 4.16 (brs, 2H), 4.07–4.01 (m, 1H),

3.78 (s, 3H), 3.54–3.46 (m, 2H), 3.39–3.32 (m, 1H), 2.14–1.99 (m, 2H),

1.89 (brd, J=17.7 Hz, 1H), 1.85–1.73 (m, 1H), 1.70 (brs, 3H), 0.85 (brs,

9H), 0.02 (brs, 3H), 0.01 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃):

d=159.5 (C_q), 154.5 (C_q), 134.0 (C_q), 132.2 (CH), 131.6 (C_q), 130.5 (C_q),

611 cm^ꢀ1

390.2586.

(S,E)-4-(4-Methoxybenzyloxy)-1-((S)-4-methyl-3,6-dihydro-2H-pyran-2-

; HRMS(EI): m/z: calcd for C₂₃H₃₈O₃Si: 390.2590, found:

ACHTUNGTRENNUNG

yl)-6-(1-phenyl-1H-tetrazol-5-ylthio)hex-1-en-3-one (32a): To a solution

of compound 31a (3.77 g, 8.184 mmol) in THF (35 mL) was added 7%

HF/pyridine (13 mL) over a period of 5 min at RT. The reaction was

stirred 30 min and quenched with sat. aq. NaHCO₃solution (90 mL) and

5988

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

130.1 (CH), 129.9 (2ꢄCH), 129.8 (2ꢄCH), 129.5 (CH), 123.9 (2ꢄCH),

119.9 (CH), 114.0 (2ꢄCH), 80.0 (CH), 73.6 (CH), 72.4 (CH), 72.2 (CH₂),

65.7 (CH₂), 55.4 (CH₃), 35.9 (CH₂), 30.5 (CH₂), 29.0 (CH₂), 25.9 (3ꢄ

CH₃), 23.1 (CH₃), 18.3 (C_q), ꢀ4.4 (CH₃), ꢀ4.8 ppm (CH₃); IR (film): n˜ =

3400, 2930, 2856, 1718, 1611, 1512, 1500, 1249, 1073, 976, 837, 778,

694 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₃H₄₆O₄N₄SSiNa: 645.2907, found:

645.2912.

4.39–4.36 (m, 1H), 4.17 (brs, 2H), 4.07–4.02 (m, 1H), 3.81 (s, 3H), 3.80–

3.73 (m, 1H), 3.69–3.59 (m, 1H), 3.53 (ddd, J=9.0, 4.4, 4.3 Hz, 1H), 2.19

(ddd, J=19.3, 9.7, 4.6 Hz, 1H), 2.08–1.86 (m, 3H), 1.70 (brs, 3H), 0.88

(brs, 9H), 0.03 ppm (brs, 6H); ¹³C NMR (100 MHz, CDCl₃): d=159.7

(C_q), 153.6 (C_q), 133.3 (C_q), 132.7 (CH), 131.5 (CH), 130.1 (2ꢄC_q), 129.9

(2ꢄCH), 129.8 (2ꢄCH), 128.7 (CH), 125.3 (2ꢄCH), 119.9 (CH), 114.2

(2ꢄCH), 79.3 (CH), 73.4 (CH), 72.4 (CH₂), 72.4 (CH), 65.7 (CH₂), 55.5

(CH₃), 53.3 (CH₂), 35.9 (CH₂), 26.0 (3ꢄCH₃), 23.1 (CH₃), 22.6 (CH₂),

18.3 (C_q), ꢀ4.4 (CH₃), ꢀ4.8 ppm (CH₃); IR (film): n˜ =2954, 2856, 1611,

1513, 1498, 1342, 1249, 1150, 1101, 836, 762 cm^ꢀ1; HRMS(EI): m/z: calcd

for C₃₃H₄₆O₆N₄SSiNa: 677.2805, found: 677.2803.

Sulfide 34b: To a stirred solution of 33a (1.21 g, 2.379 mmol) in CH₂Cl₂

(20 mL) at ꢀ308C was added 2,6-lutidine (446 mg, 4.163 mmol) and drop-

wise TESOTf (943 mg, 3.569 mmol). The reaction was stirred at the same

temperature for 20 min, then allowed to warm to RT and stirred for an-

other 2 h. The reaction was cooled to ꢀ308C again and Et₃N (1 mL) was

added. The reaction was quenched with aq. sat. NaHCO₃(20 mL),

warmed to RT and extracted four times with CH₂Cl₂. The combined or-

ganic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The obtained viscous oil was purified by

column chromatography (silica gel, hexane/EtOAc 10:1 + 1% Et₃N),

yielding sulfide 34b as colorless, viscous oil (1.38 g, 2.215 mmol, 93%).

[a]²_D⁰=ꢀ69.4 (c=1.00, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.57–

7.52 (m, 5H), 7.25 (d, J=8.9 Hz, 2H), 6.84 (d, J=8.9 Hz, 2H), 5.81–5.78

(m, 2H), 5.41 (brs, 1H), 4.64 (d, J=11.4 Hz, 1H), 4.47 (d, J=11.4 Hz,

1H), 4.38–4.35 (m, 1H), 4.19–4.14 (m, 2H), 4.06–4.00 (m, 1H), 3.78 (s,

3H), 3.54–3.46 (m, 2H), 3.40–3.31 (m, 1H), 2.13–1.98 (m, 2H), 1.89 (brd,

J=17.0 Hz, 1H), 1.85–1.73 (m, 1H), 1.70 (brs, 3H), 0.91 (t, J=7.9 Hz,

9H), 0.56 ppm (q, J=7.9 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): d=

159.5 (C_q), 154.6 (C_q), 134.0 (C_q), 132.3 (CH), 131.6 (C_q), 130.6 (C_q),

130.1 (CH), 129.9 (2ꢄCH), 129.8 (2ꢄCH), 129.5 (CH), 123.9 (2ꢄCH),

119.9 (CH), 114.0 (2ꢄCH), 80.1 (CH), 73.6 (CH), 72.5 (CH), 72.5 (CH₂),

65.7 (CH₂), 55.4 (CH₃), 35.9 (CH₂), 30.5 (CH₂), 29.2 (CH₂), 23.1 (CH₃),

7.0 (3ꢄCH₃), 5.0 ppm (3ꢄCH₂); IR (film): n˜ =2954, 1611, 1512, 1500,

1456, 1382, 1246, 1173, 1014, 974, 744; HRMS(EI): m/z: calcd for

C₃₃H₄₆O₄N₄SSiNa: 645.2907, found: 645.2916.

Sulfone 6b: Ammonium molybdate (1.1 g, 0.98 mmol) was added to

H₂O₂(30% aqueous solution, 2.4 mL) and phosphate buffer (0.5m,

1.2 mL) at 08C and stirred for 15 min. The yellow solution was added

dropwise to a solution of 34b (950 mg, 1.525 mmol) in EtOH (20 mL) at

08C and stirred for 30 min before it was allowed to reach RT. After stir-

ring for another 4 h the reaction was diluted with aq. sat. NaHCO₃

(35 mL) and extracted four times with CH₂Cl₂. The combined organic

phase was dried over magnesium sulfate, filtered and the solvent was re-

moved under vacuum. The obtained oil was purified by column chroma-

tography (silica gel, hexane/EtOAc 4:1), yielding sulfone 6b as viscous

oil (612 mg, 0.935 mmol, 61%). [a]²_D⁰=ꢀ27.5 (c=1.10 in CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=7.61–7.55 (m, 5H), 7.25 (d, J=8.6 Hz,

2H), 6.89 (d, J=8.6 Hz, 2H), 5.84–5.76 (m, 2H), 5.41 (brs, 1H), 4.62 (d,

J=11.4 Hz, 1H), 4.48 (d, J=11.4 Hz, 1H), 4.39–4.35 (m, 1H), 4.19–4.14

(m, 2H), 4.08–4.02 (m, 1H), 3.81 (s, 3H), 3.80–3.73 (m, 1H), 3.68–3.59

(m, 1H), 3.54–3.49 (m, 1H), 2.24–2.13 (m, 1H), 2.08–1.98 (m, 2H), 1.98–

1.86 (m, 2H), 1.70 (brs, 3H), 0.91 (t, J=7.9 Hz, 9H), 0.56 (q, J=7.9 Hz,

6H); ¹³C NMR (100 MHz, CDCl₃): d=159.7 (C_q), 153.6 (C_q), 133.2 (C_q),

132.8 (CH), 131.6 (CH), 130.1 (2ꢄC_q), 129.9 (2ꢄCH), 129.8 (2ꢄCH),

128.8 (CH), 125.3 (2ꢄCH), 119.9 (CH), 114.1 (2ꢄCH), 79.4 (CH), 73.4

(CH), 72.6 (CH), 72.5 (CH₂), 65.7 (CH₂), 55.5 (CH₃), 53.3 (CH₂), 35.8

(CH₂), 23.1 (CH₃), 22.6 (CH₂), 7.0 (3ꢄCH₃), 5.0 (3ꢄCH₃); IR (film): n˜ =

Sulfide 34c: To a solution of 33a (2.12 g, 4.168 mmol) in CH₂Cl₂(20 mL)

at 08C was added EtNiPr₂(5.39 g, 41.680 mmol) and subsequent drop-

wise MOMCl (1.68 g, 20.840 mmol). The reaction was allowed to reach

RT and was stirred for 24 h. The reaction was quenched by adding sat.

aq. NH₄Cl solution (20 mL) and extracted four times with Et₂O. The

combined organic phase was washed with brine, dried over magnesium

sulfate, filtered and the solvent was removed under vacuum. The ob-

tained colorless oil was purified by column chromatography (silica gel,

hexane/EtOAc 3:1), yielding sulfide 34c as colorless oil (2.26 g,

4.089 mmol, 98%). [a]_D²⁰=ꢀ62.1 (c=1.00, CH₂Cl₂); ¹H NMR (400 MHz,

CDCl₃): d=7.57–7.52 (m, 5H), 7.25 (d, J=8.6 Hz, 2H), 6.83 (d, J=

8.6 Hz, 2H), 5.83 (ddd, J=15.7, 5.4, 0.8 Hz, 1H), 5.67 (ddd, J=15.7, 6.8,

1.3 Hz, 1H), 5.41 (brs, 1H), 4.71–4.67 (m, 2H), 4.57 (d, J=6.8 Hz, 1H),

4.50 (d, J=11.2 Hz, 1H), 4.26–4.21 (m, 1H), 4.19–4.14 (m, 2H), 4.07–4.00

(m, 1H), 3.77 (s, 3H), 3.65–3.59 (m, 1H), 3.51–3.43 (m, 1H), 3.34 (s, 3H),

2.13–2.05 (m, 1H), 2.04–1.99 (m, 1H), 1.97–1.85 (m, 2H), 1.69 ppm (brs,

3H); ¹³C NMR (100 MHz, CDCl₃): d=159.5 (C_q), 154.5 (C_q), 133.9 (C_q),

131.5 (C_q), 130.4 (CH), 130.0 (2ꢄCH), 129.9 (2ꢄCH), 126.9 (CH), 123.9

(2ꢄCH), 119.8 (CH), 114.0 (2ꢄCH), 94.6 (CH₂), 78.8 (CH), 77.4 (CH),

73.4 (CH), 72.8 (CH₂), 65.8 (CH₂), 55.8 (CH₃), 55.4 (CH₃), 35.9 (CH₂),

30.3 (CH₂), 30.2 (CH₂), 23.0 ppm (CH₃); IR (film): n˜ =2931, 1612, 1513,

1500, 1384, 1247, 1032, 821, 762, 694 cm^ꢀ1; HRMS(EI): m/z: calcd for

C₂₉H₃₆O₅N₄SNa: 575.2304, found: 575.2321.

2954, 2875, 1611, 1513, 1498, 1342, 1248, 1150, 1100, 821, 743 cm^ꢀ1

;

HRMS(EI): m/z: calcd for C₃₃H₄₆O₆N₄SSiNa: 677.2805, found: 677.2814.

Sulfone 6c: Ammonium molybdate (1.1 g, 0.87 mmol) was added to

H₂O₂(30% aqueous solution, 4.4 mL) at 08C and stirred for 15 min. The

yellow solution was added dropwise to

a solution of 34c (2.21 g,

4.000 mmol) in EtOH (40 mL) at 08C and stirred for 45 min before it

was allowed to reach RT. After stirring for another 3.5 h the reaction was

diluted with H₂O (50 mL) and extracted four times with CH₂Cl₂. The

combined organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The obtained oil was purified by

column chromatography (silica gel, hexane/EtOAc 4:1), yielding sulfone

6c as white crystals (1.77 g, 3.027 mmol, 76%). M.p. 85–868C; [a]_D²⁰

=

ꢀ34.1 (c=1.10 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.68–7.55

(m, 5H), 7.26 (d, J=8.2 Hz, 2H), 6.88 (d, J=6.8 Hz, 2H), 5.85 (dd, J=

15.8, 5.3 Hz, 1H), 5.68 (dd, J=15.8, 6.7 Hz, 1H), 5.41 (brs, 1H), 4.68 (d,

J=6.8 Hz, 1H), 4.67 (d, J=11.4 Hz, 1H), 4.57 (d, J=6.8 Hz, 1H), 4.50

(d, J=11.4 Hz, 1H), 4.25 (t, J=5.9 Hz, 1H), 4.19–4.15 (m, 2H), 4.08–4.01

(m, 1H), 3.84–3.75 (m, 1H), 3.81 (s, 3H), 3.67–3.59 (m, 2H), 3.36 (s, 3H),

2.26–2.16 (m, 1H), 2.09–1.98 (m, 2H), 1.90 (brd, J=16.7 Hz, 1H),

1.70 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=159.6 (C_q), 153.6

(C_q), 135.6 (CH), 133.2 (C_q), 131.6 (CH), 131.5 (C_q), 130.0 (2ꢄCH), 129.9

(C_q), 129.8 (2ꢄCH), 126.1 (CH), 125.3 (2ꢄCH), 119.8 (CH), 114.1 (2ꢄ

CH), 94.6 (CH₂), 77.8 (CH), 77.0 (CH), 73.3 (CH), 72.7 (CH₂), 65.7

(CH₂), 55.9 (CH₃), 55.4 (CH₃), 53.0 (CH₂), 35.8 (CH₂), 23.5 (CH₂),

23.0 ppm (CH₃); IR (film): n˜ =2913, 2358, 1613, 1513, 1341, 1248, 1151,

1101, 1033, 764, 689 cm^ꢀ1; HRMS(EI): m/z: calcd for C₂₉H₃₆O₇N₄SNa:

607.2202, found: 607.2217.

Sulfone 6a: Ammonium molybdate (59 mg) was added to H₂O₂(30%

aqueous solution, 0.33 mL) at 08C and stirred for 15 min. The yellow so-

lution was added dropwise to a solution of 34a (130 mg, 0.209 mmol) in

EtOH (4 mL) at 08C and stirred for 30 min before it was allowed to

reach RT. After stirring for another 3.5 h the reaction was diluted with

aq. sat. NaHCO₃(10 mL) and extracted four times with CH₂Cl₂. The

combined organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The obtained oil was purified by

column chromatography (silica gel, hexane/EtOAc 4:1), yielding sulfone

6a as viscous oil (100 mg, 0.153 mmol, 73%). [a]²_D⁰=ꢀ61.9 (c=1.10 in

CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.68–7.64 (m, 2H), 7.62–7.56-

AHCTUNGTERG(NNUN S,E)-4-(tert-Butyldiphenylsilyloxy)-1-((S)-4-methyl-3,6-dihydro-2H-

pyran-2-yl)-6-(1-phenyl-1H-tetrazol-5-ylthio)hex-1-en-3-one (32b): To a

solution of compound 31b (3.98 g, 6.874 mmol) in THF (30 mL) was

added 7% HF·pyridine (12 mL) over a period of 5 min at RT. The reac-

tion was stirred 30 min, quenched with sat. aq. NaHCO₃solution (80 mL)

and extracted four times with EtOAc. The combined organic phase was

dried over magnesium sulfate, filtered and the solvent was removed

under vacuum. The obtained oil was purified by column chromatography

ACHTUNGTRENNUNG

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5989

J. Mulzer, A. Gollner et al.

(silica gel, hexane/EtOAc 3:1 + 1% Et₃N), yielding labile alcohol as col-

orless, viscous oil (3.14 g, 6.757 mmol, 98%) which was immediately used

for the next step. A solution of alcohol OTES deprotected 31b (3.12 g,

6.714 mmol) in THF (30 mL) was cooled to 08C and added PPh₃(2.29 g,

8.728 mmol), 1-phenyl-1H-tetrazol-5-thiol (1.79 g, 10.044 mmol) and

DEAD (1.75 g, 10.048 mmol). The reaction was stirred at 08C for 1 h and

3 h at RT. The reaction was quenched by adding sat. aq. NaHCO₃solu-

tion (50 mL) and extracted three times with EtOAc. The combined or-

ganic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The obtained oil was purified by column

chromatography (silica gel, hexane/EtOAc 7:1), yielding sulfide 32b as

colorless, viscous oil (3.85 g, 6.154 mmol, 92%). [a]²_D⁰=ꢀ40.9 (c=1.40 in

CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.67–7.56 (m, 4H), 7.56–7.47

(m, 5H), 7.41–7.28 (m, 6H), 6.87 (dd, J=15.7, 3.8 Hz, 1H), 6.76 (dd, J=

15.8, 1.5 Hz, 1H), 5.43 (brs, 1H), 4.40 (t, J=6.0 Hz, 1H), 4.22–4.11 (m,

3H), 3.38–3.22 (m, 2H), 2.29–2.19 (m, 1H), 2.18–2.09 (m, 1H), 2.02–1.87

(m, 2H), 1.72 (brs, 3H), 1.11 ppm (s, 9H); ¹³C NMR (100 MHz, CDCl₃):

d=199.8 (C_q), 154.0 (C_q), 147.2 (CH), 136.1 (2ꢄCH), 136.0 (2ꢄCH),

133.8 (C_q), 133.1 (C_q), 132.7 (C_q), 131.2 (C_q), 130.1 (3ꢄCH), 129.9 (2ꢄ

CH), 127.9 (2ꢄCH), 127.8 (2ꢄCH), 123.8 (2ꢄCH), 122.9 (CH), 119.9

(CH), 77.0 (CH), 72.5 (CH), 65.8 (CH₂), 35.0 (CH₂), 34.2 (CH₂), 28.7

(CH₂), 27.1 (3ꢄCH₃), 23.0 (CH₃), 19.5 ppm (C_q); IR (film): n˜ =2931,

52.8 (CH₂), 35.6 (CH₂), 27.3 (3ꢄCH₃), 25.9 (CH₂), 23.1 (CH₃), 19.6 ppm

(C_q); IR (film): n˜ =2930, 1701, 1685, 1560, 1497, 1426, 1341, 1104, 702,

508 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₅H₄₂O₅N₄SSiNa: 681.2543, found:

681.2552.

AHCTUNGTRENNUNG

a

flask) of compound 35 (2.46 g, 3.734 mmol) in THF (15 mL) was added

HF·pyridine (70%, 15 mL) at 08C dropwise over 15 min. The reaction

was stirred at the same temperature for 30 min before it was allowed to

warm to RT and stir for another 10 h. The reaction was diluted with

CH₂Cl₂(100 mL), cooled to 08C and quenched carefully with sat. aq.

NaHCO₃(200 mL). The phases were separated and the aqueous phase

extracted four times with CH₂Cl₂. The combined organic phase was dried

over magnesium sulfate, filtered and the solvent was removed under

vacuum. The residue was purified by column chromatography (silica gel,

hexane/EtOAc 1:1 ! EtOAc), yielding diol 34 as colorless oil (1.48 g,

3.520 mmol, 94%). [a]_D²⁰=ꢀ66.5 (c=1.2 in CH₂Cl₂); ¹H NMR (400 MHz,

CDCl₃): d=7.71–7.66 (m, 2H), 7.64–7.57 (m, 3H), 5.90 (dd, J=15.8,

4.9 Hz, 1H), 5.76 (ddd, J=15.7, 6.5, 1.1 Hz, 1H), 5.41 (brs, 1H), 4.20–

4.14 (m, 2H), 4.06–3.94 (m, 3H), 3.90–3.80 (m, 1H), 3.08–2.42 (brs, 2H,

OH), 2.24–2.14 (m, 1H), 2.13–2.06 (m, 1H), 2.05–2.00 (m, 1H), 1.91

(brd, J=16.7 Hz, 1H), 1.70 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

d=153.6 (C_q), 134.8 (CH), 133.1 (C_q), 131.6 (CH), 131.5 (C_q), 129.8 (2ꢄ

CH), 129.1 (CH), 125.3 (2ꢄCH), 119.7 (CH), 75.3 (CH), 73.0 (CH), 72.1

(CH), 65.9 (CH₂), 53.3 (CH₂), 35.7 (CH₂), 26.1 (CH₂), 23.1 ppm (CH₃);

1630, 1500, 1427, 1111, 762, 703 cm^ꢀ1

C₃₅H₄₀O₃N₄SSiNa: 647.2488, found: 647.2502.

ACHTUNGTRENNUNG((3S,4S,E)-4-(tert-Butyldiphenylsilyloxy)-1-((S)-4-methyl-3,6-dihydro-2H-

; HRMS(EI): m/z: calcd for

IR (film): n˜ =3401, 2133, 1634, 1498, 1341, 1154, 976, 764, 689 cm^ꢀ1

HRMS(EI): m/z: calcd for C₁₉H₂₄O₅N₄SNa: 443.1365, found: 443.1358.

;

pyran-2-yl)-6-(1-phenyl-1H-tetrazol-5-ylthio)hex-1-en-3-ol (33b): Com-

pound 32b (3.48 g, 5.569 mmol) was dissolved in MeOH (30 mL) and

cooled to ꢀ788C. CeCl₃·7H₂O (2.72 g, 7.239 mmol) was added and stirred

for 10 min. Following NaBH₄(270 mg, 7.223 mmol) was added in three

portions and stirred for 30 min at the same temperature. The reaction

was quenched by adding sat. aq. NH₄Cl (50 mL) solution, warmed to RT

and extracted four times with EtOAc. The combined organic phase was

washed with brine, dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The obtained oil was purified by column

chromatography (silica gel, hexane/EtOAc 2:1), yielding alcohol 33b as

colorless, viscous oil (3.39 g, 5.401 mmol, 97%). [a]²_D⁰=ꢀ23.3 (c=1.05 in

CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.69–7.63 (m, 4H), 7.56–7.46

(m, 5H), 7.42–7.31 (m, 6H), 5.87 (dd, J=15.8, 4.8 Hz, 1H), 5.80 (dd, J=

15.9, 4.8 Hz, 1H), 5.41 (brs, 1H), 4.22–4.14 (m, 3H), 4.02–3.96 (m, 1H),

3.86 (dd, J=10.5, 5.3 Hz, 1H), 3.33–3.17 (m, 2H), 2.34 (d, J=6.1 Hz, 1H,

OH), 2.10–1.97 (m, 2H), 1.70 (brs, 3H), 1.07 ppm (brs, 9H); ¹³C NMR

(100 MHz, CDCl₃): d=154.2 (C_q), 136.1 (4ꢄCH), 133.8 (C_q), 133.4 (C_q),

133.3 (C_q), 133.1 (CH), 131.6 (C_q), 130.1 (4ꢄCH), 129.9 (2ꢄCH), 128.0

(2ꢄCH), 127.0 (2ꢄCH), 123.9 (2ꢄCH), 119.8 (CH), 75.0 (CH), 74.0

(CH), 73.4 (CH), 65.7 (CH₂), 35.8 (CH₂), 32.8 (CH₂), 29.4 (CH₂), 27.2

(3ꢄCH₃), 23.1 (CH₃), 19.7 ppm (C_q); IR (film): n˜ =3286, 2931, 1500,

1427, 1110, 741, 704 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₅H₄₂O₃N₄SSiNa:

649.2645, found: 649.2648.

Sulfone 6d: To a stirred solution of diol 36 (1.45 g, 3.448 mmol) in

CH₂Cl₂(30 mL) at ꢀ208C was added 2,6-lutidine (1.035 g, 9.656 mmol)

and dropwise TESOTf (1.869 g, 7.586 mmol). The reaction was allowed

to reach RT and was stirred for 1 h. Et₃N (2 mL) was added, cooled to

ꢀ58C and quenched with sat. aq. NaHCO₃(50 mL). The phases were

separated and the aqueous phase extracted three times with CH₂Cl₂. The

combined organic phase was dried over magnesium sulfate, filtered and

the solvent was removed under vacuum. The obtained oil was purified by

column chromatography (silica gel, hexane/EtOAc 10:1 + 1% NEt₃),

yielding sulfone 6d as colorless, viscous oil (2.17 g, 3.345 mmol, 97%).

[a]²_D⁰=ꢀ50.3 (c=0.9 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.70–

7.67 (m, 2H), 7.63–7.56 (m, 3H), 5.88–5.78 (m, 2H), 5.41 (brs, 1H), 4.27–

4.34 (m, 1H), 4.19–4.15 (m, 2H), 4.10–4.04 (m, 1H), 3.87–3.74 (m, 3H),

2.23–2.12 (m, 1H), 2.10–1.99 (m, 1H), 1.98–1.89 (m, 2H), 1.70 (brs, 3H),

1.00–0.89 (m, 18H), 0.67–0.55 ppm (m, 12H); ¹³C NMR (100 MHz,

CDCl₃): d=153.6 (C_q), 133.3 (C_q), 132.4 (CH), 131.6 (C_q), 131.5 (C_q),

129.8 (2ꢄCH), 128.6 (CH), 125.3 (2ꢄCH), 119.9 (CH), 74.6 (CH), 73.5

(2ꢄCH), 65.7 (CH₂), 53.4 (CH₂), 35.8 (CH₂), 24.4 (CH₂), 23.1 (CH₃), 7.0

(6ꢄCH₃), 5.1 (3ꢄCH₂), 5.0 ppm (3ꢄCH₂); IR (film): n˜ =3568, 2956,

2877, 1498, 1345, 1107, 975, 743, 688 cm^ꢀ1; HRMS(EI): m/z: calcd for

C₂₉H₄₇O₅N₄SSi₂(=M - CH₂CH₃): 619.2806, found: 619.2802.

ACHTUNGTRENNUNG(3S,4S,E)-4-(tert-Butyldiphenylsilyloxy)-1-((S)-4-methyl-3,6-dihydro-2H-

Total synthesis of laulimalide (1)

pyran-2-yl)-6-(1-phenyl-1H-tetrazol-5-ylsulfonyl)hex-1-en-3-ol (35): Am-

monium molybdate (2.1 g, 1.70 mmol) was added to H₂O₂(30% aqueous

solution, 10 mL) at 08C and stirred for 15 min. The yellow solution was

added dropwise to a solution of 33b (3.38 g, 5.392 mmol) in EtOH

(55 mL) at 08C and stirred for 45 min before it was allowed to reach RT.

After stirring for another 3 h the reaction was diluted with H₂O (80 mL)

and extracted four times with CH₂Cl₂. The combined organic phase was

dried over magnesium sulfate, filtered and the solvent was removed

under vacuum. The obtained oil was purified by column chromatography

(silica gel, hexane/EtOAc 3:1), yielding sulfone 35 as colorless, viscous

oil (2.47 g, 3.750 mmol, 70%). [a]²_D⁰=ꢀ27.1 (c=1.05 in CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=7.72–7.54 (m, 9H), 7.48–7.35 (m, 6H),

5.86 (dd, J=15.9, 5.1 Hz, 1H), 5.78 (dd, J=15.9, 5.3 Hz, 1H), 5.41 (brs,

1H), 4.19–4.14 (m, 3H), 4.03–3.96 (m, 1H), 3.88 (dd, J=10.2, 5.1 Hz,

1H), 3.79–3.69 (m, 1H), 3.62–3.53 (m, 1H), 2.20–2.07 (m, 1H), 2.07–1.96

(m, 3H), 1.87 (brd, J=16.9 Hz, 1H), 1.70 (brs, 3H), 1.09 ppm (brs, 9H);

¹³C NMR (100 MHz, CDCl₃): d=153.4 (C_q), 136.1 (2ꢄCH), 136.0 (2ꢄ

CH), 133.6 (CH), 133.2 (C_q), 133.0 (C_q), 132.9 (C_q), 132.5 (C_q), 131.5

(C_q), 130.4 (CH), 130.3 (CH), 129.8 (2ꢄCH), 129.2 (CH), 128.1 (4ꢄCH),

125.3 (2ꢄCH), 119.8 (CH), 74.3 (CH), 74.1 (CH), 73.2 (CH), 65.7 (CH₂),

TBS ether 4a: To a stirred solution of 6a (28 mg, 0.043 mmol) in THF

(1 mL) at ꢀ788C was added KHMDS (74 mL, 0.049 mmol, 0.5m in tolu-

ene) dropwise over 4 min. The yellow solution was allowed to stir for

3 min before 5 (15 mg, 0.039 mmol, in 0.5 mL THF) was added dropwise

over 5 min. After stirring for another 90 min at the same temperature the

reaction was quenched by adding H₂O (4 mL) and warmed to RT. The

phases were separated and the aqueous phase was extracted four times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The obtained

oil was purified by column chromatography (silica gel, hexane/EtOAc

15:1), yielding compound 4a as viscous oil (28 mg, 0.034 mmol, 87%).

[a]²_D⁰=ꢀ67.8 (c=0.73 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.26

(d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.92–5.87 (m, 1H), 5.87–5.78

(m, 2H),5.75 (dd, J=15.8, 4.9 Hz, 1H), 5.63 (dt, J=15.5, 6.8 Hz, 1H),

5.47 (dd, J=15.5, 6.6 Hz, 1H), 5.41 (brs, 1H), 4.78 (brs, 1H), 4.77 (brs,

1H), 4.52 (brs, 2H), 4.34–4.25 (m, 2H), 4.20–4.14 (m, 3H), 4.06–4.00 (m,

1H), 3.83–3.77 (m, 4H), 3.32 (ddd, J=8.6, 5.3, 3.0 Hz, 1H), 2.50 (ddd,

J=16.4, 6.6, 2.8 Hz, 1H), 2.42 (ddd, J=16.4, 7.3, 2.8 Hz, 1H), 2.33–2.19

(m, 2H), 2.11 (dd, J=13.9, 6.3 Hz, 1H), 2.08–1.85 (m, 9H), 1.70 (brs,

5990

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

3H), 1.63 (ddd, J=13.9, 9.9, 3.3 Hz, 1H), 1.09 (ddd, J=13.9, 9.2, 3.1 Hz,

1H), 0.90–0.86 (m, 21H), 0.03 (brs, 3H), 0.01 (brs, 6H), 0.00 ppm (brs,

3H); ¹³C NMR (150 MHz, CDCl₃): d=159.3 (C_q), 144.8 (C_q), 135.2 (CH),

131.6 (C_q), 131.6 (CH), 131.2 (C_q), 130.4 (CH), 129.5 (2ꢄCH), 128.1

(CH), 127.5 (CH), 125.7 (CH), 119.9 (CH), 113.9 (CH₂), 113.9 (2ꢄCH),

82.9 (CH), 82.0 (C_q), 73.8 (CH), 72.9 (CH), 72.6 (CH), 72.6 (CH₂), 70.9

(CH), 70.2 (CH), 66.0 (CH), 65.7 (CH₂), 55.4 (CH₃), 45.3 (CH₂), 45.1

(CH₂), 42.5 (CH₂), 35.8 (CH₂), 32.9 (CH₂), 31.3 (CH₂), 26.9 (CH), 26.1

(3ꢄCH₃), 26.0 (3ꢄCH₃), 24.6 (CH₂), 23.1 (CH₃), 19.5 (CH₃), 18.4 (C_q),

18.3 (C_q), ꢀ4.0 (CH₃), ꢀ4.3 (CH₃), ꢀ4.5 (CH₃), ꢀ4.7 ppm (CH₃); IR

(film): n˜ =3310, 2929, 1617, 1513, 1250, 1090, 836, 776 cm^ꢀ1; HRMS(EI):

m/z: calcd for C₄₉H₇₈O₆Si₂Na: 841.5235, found: 841.5233.

(C_q), ꢀ4.0 (CH₃), ꢀ4.6 ppm (CH₃); IR (film): n˜ =3307, 2928, 2236, 1582,

1363, 1254, 1074, 972, 836, 777, 708 cm^ꢀ1; HRMS(EI): m/z: calcd for

C₃₆H₅₆O₇SiNa: 651.3693, found: 651.3702.

Macrolactone 45: To

a stirred solution of seco acid 44 (57 mg,

0.0906 mmol) in benzene (2 mL) at RT was added Et₃N (25.2 mL,

0.1812 mmol) and dropwise 2,4,6-trichlorobenzoyl chloride (14.2 mL,

0.0997 mmol). The solution was stirred for 4 h before it was diluted with

benzene (100 mL). DMAP (110.6 mg, 0.9057 mmol) in benzene (20 mL)

was added over 6 h via a syringe pump. After additional 6 h, aq. sat.

NaHCO₃(70 mL) was added and the mixture was stirred for 20 min. The

phases were separated and the aqueous layer was extracted three times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 3:1),

yielding compound macrolactone 45 as viscous oil (41.3 mg, 0.0676 mmol,

75%). [a]²_D⁰=ꢀ39.2 (c=0.65 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃):

d=5.94–5.85 (m, 2H), 5.75 (ddd, J=15.6, 5.8, 1.3 Hz, 1H), 5.64–5.57 (m,

2H), 5.42 (brs, 1H), 5.00 (dd, J=13.1, 6.9 Hz, 1H), 4.78 (brs, 1H), 4.76

(brs, 1H), 4.42 (d, J=10.9 Hz, 1H), 4.24–4.15 (m, 4H), 4.05 (ddd, J=9.7,

4.7, 4.7 Hz, 1H), 3.74–3.65 (m, 1H), 2.71 (dd, J=17.5, 11.5 Hz, 1H), 2.39

(dd, J=17.5, 2.6 Hz, 1H), 2.32 (t, J=6.8 Hz, 1H), 2.12–2.02 (m, 4H),

1.98–1.91 (m, 4H), 1.89–1.82 (m, 1H), 1.70 (brs, 3H), 1.62–1.54 (m, 1H),

1.08 (ddd, J=14.0, 9.9, 1.7 Hz, 1H), 0.86–0.83 (m, 12H), ꢀ0.01 (brs, 3H),

ꢀ0.03 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=153.4 (C_q), 145.1

(C_q), 138.6 (CH), 134.2 (CH), 131.5 (C_q), 128.7.0 (CH), 127.7 (CH), 127.1

(CH), 123.3 (CH), 119.9 (CH), 114.4 (CH₂), 87.6 (C_q), 77.8 (CH), 73.7

(CH), 73.4 (C_q), 73.3 (CH), 71.6 (CH), 71.2 (CH), 65.8 (CH), 65.7 (CH₂),

45.8 (CH₂), 43.9 (CH₂), 43.1 (CH₂), 35.8 (CH₂), 32.8 (CH₂), 31.5 (CH₂),

26.6 (CH), 26.0 (3ꢄCH₃), 24.2 (CH₂), 23.1 (CH₃), 19.2 (CH₃), 18.4 (C_q),

ꢀ4.0 (CH₃), ꢀ4.7 ppm (CH₃); IR (film): n˜ =3392, 2235, 1638, 1246, 1070,

833, 775, 704 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₆H₅₄O₆SiNa: 633.3587,

found: 633.3595.

TBS-ether 4b: To a stirred solution of 6d (289 mg, 0.445 mmol) in THF

(5 mL) at ꢀ788C was added KHMDS (1.024 mL, 0.512 mmol, 0.5m in

toluene) dropwise over 4 min. The yellow solution was allowed to stir for

3 min before 5 (174 mg, 0.445 mmol, in 1 mL THF) was added dropwise

over 5 min. After stirring for another 90 min at the same temperature the

reaction was quenched by adding H₂O (5 mL) and warmed to RT. The

phases were separated and the aqueous phase was extracted four times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The obtained

oil was purified by column chromatography (silica gel, hexane/EtOAc

30:1), yielding compound 4d as viscous oil (289 mg, 0.355 mmol, 80%).

[a]²_D⁰=ꢀ76.8 (c=0.94 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=5.93–

5.80 (m, 2H), 5.83 (dd, J=15.9, 4.3 Hz, 1H), 5.77 (dd, J=15.9, 5.2 Hz,

1H), 5.47–5.38 (m, 1H), 5.41 (brs, 1H), 4.78 (brs, 1H), 4.77 (brs, 1H),

4.35–4.29 (m, 1H), 4.05 (ddd, J=9.3, 4.6, 4.6 Hz, 1H), 3.85–3.77 (m, 1H),

3.59 (ddd, J=8.5, 4.2, 4.2 Hz, 1H), 2.51 (ddd, J=16.4, 6.7, 2.6 Hz, 1H),

2.43 (ddd, J=16.3, 7.0, 2.6 Hz, 1H), 2.33–2.25 (m, 1H), 2.23 (dd, J=13.8,

7.7 Hz, 1H), 2.14–2.03 (m, 2H), 2.01 (t, J=2.7 Hz, 1H), 1.99–1.86 (m,

7H), 1.71 (brs, 3H), 1.63 (ddd, J=13.6, 10.0, 3.5 Hz, 1H), 1.09 (ddd, J=

13.6, 9.1, 3.5 Hz, 1H), 0.99–0.92 (m, 18H), 0.90–0.85 (m, 12H), 0.64–0.59

(m, 12H), 0.03 (s, 3H), 0.01 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃):

d=144.8 (C_q), 135.1 (CH), 131.7 (C_q), 131.3 (CH), 130.3 (CH), 128.1

(CH), 127.7 (CH), 125.7 (CH), 119.9 (CH), 113.8 (CH₂), 81.2 (C_q), 76.2

(CH), 74.8 (CH), 73.9 (CH), 72.7 (CH), 71.0 (CH), 70.2 (CH), 66.0 (CH),

65.7 (CH₂), 45.3 (CH₂), 45.0 (CH₂), 42.5 (CH₂), 35.9 (CH₂), 34.9 (CH₂),

31.3 (CH₂), 27.0 (CH), 26.1 (3ꢄCH₃), 24.6 (CH₂), 23.1 (CH₃), 19.5 (CH₃),

18.4 (C_q), 7.2 (4ꢄCH₃), 7.1 (2ꢄCH₃), 5.3 (4ꢄCH₂), 5.1 (2ꢄCH₂), ꢀ4.0

(CH₃), ꢀ4.5 ppm (CH₃); IR (film): n˜ =3314, 2955, 2122, 1644, 1460, 1361,

1093, 1005, 973, 836, 756 cm^ꢀ1; HRMS(EI): m/z: calcd for C₄₇H₈₄O₅Si₃Na:

835.5524, found: 835.5531.

Diol 46: To a stirred solution (PVC flask) of compound 45 (40 mg,

0.655 mmol) in THF (2 mL) at 08C was added HF·pyridine (70%,

550 mL) dropwise in 10 min. After stirring at 08C for another 10 min the

reaction was allowed to reach RT and stirred for 40 min. The mixture

was diluted with CH₂Cl₂(10 mL), cooled to 08C and quenched by slow

addition of aq. sat. NaHCO₃(35 mL). The phases were separated and the

aqueous layer was extracted four times with CH₂Cl₂. The combined or-

ganic phase was dried over magnesium sulfate, filtered and the solvent

was removed under vacuum. The residue was purified by column chro-

matography (silica gel, hexane/EtOAc 1:1), yielding compound 46 as vis-

cous oil (31 mg, 0.0624 mmol, 95%). [a]²_D⁰=ꢀ34.3 (c=0.75 in CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=5.94–5.87 (m, 2H), 5.75 (ddd, J=15.7,

6.1, 1.3 Hz, 1H), 5.69–5.65 (m, 2H), 5.64–5.58 (m, 1H), 5.42 (brs, 1H),

5.03 (dd, J=13.4, 6.7 Hz, 1H), 4.89 (brs, 2H), 4.43 (brd, J=11.5 Hz,

1H), 4.29 (brd, J=10.5 Hz, 1H), 4.24–4.15 (m, 3H), 4.05 (ddd, J=9.8,

4.6, 4.4 Hz, 1H), 3.66 (dt, J=9.3, 3.4 Hz, 1H), 2.70 (dd, J=17.4, 11.1 Hz,

1H), 2.41–2.27 (m, 4H), 2.15 (dd, J=13.1, 6.1 Hz, 1H), 2.10–1.87 (m,

8H), 1.70 (brs, 3H), 1.61–1.59 (m, 1H), 1.08 (ddd, J=13.8, 10.3, 1.3 Hz,

1H), 0.85 ppm (d, J=6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

153.4 (C_q), 145.1 (C_q), 137.1 (CH), 134.3 (CH), 131.4 (C_q), 128.0 (CH),

127.7 (CH), 127.1 (CH), 124.9 (CH), 119.9 (CH), 114.4 (CH₂), 87.7 (C_q),

76.8 (CH), 73.6 (CH), 73.3 (C_q), 73.2 (CH), 71.4 (CH), 69.2 (CH), 65.8

(CH₂), 65.6 (CH), 45.7 (CH₂), 42.8 (2ꢄCH₂), 35.7 (CH₂), 33.0 (CH₂), 31.4

(CH₂), 26.3 (CH), 24.1 (CH₂), 23.1 (CH₃), 19.2 ppm (CH₃); IR (film): n˜ =

3401, 2923, 2235, 1708, 1435, 1245, 1067, 971 cm^ꢀ1; HRMS(EI): m/z:

calcd for C₃₀H₄₀O₆Na: 519.2723, found: 519.2735.

Seco-acid 44: To

a stirred solution of compound 4d (168 mg,

0.2064 mmol) in THF (3 mL) at ꢀ788C was added nBuLi (0.206 mL,

0.3304 mmol) dropwise over a period of 5 min. The bright yellow solution

was stirred for 5 min and then CO₂(g) was bubbled through the reaction

for 10 min. Now HF·pyridine (7%, 3 mL) was added dropwise over

5 min to the colorless reaction mixture. The reaction was allowed to

warm to RT and stirred for another 90 min. The reaction was quenched

by slow addition of aq. sat. NaHCO₃(10 mL) and diluted with CH₂Cl₂

(15 mL). The pH of the aqueous phase was set to pH 3 by addition of

HCl (1n in H₂O), the phases were separated and the aqueous phase was

extracted four times with CH₂Cl₂. The combined organic phase was dried

over magnesium sulfate, filtered and the solvent was removed under

vacuum. The obtained oil was purified by column chromatography (silica

gel, CH₂Cl₂/MeOH 5:1), yielding seco acid 44 as viscous oil (113 mg,

0.1797 mmol, 87%). [a]²_D⁰=ꢀ46.7 (c=1.15 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=5.88–5.79 (m, 3H), 5.76 (dd, J=15.7, 6.3 Hz, 1H),

5.63–5.50 (m, 2H), 5.39 (brs, 1H), 4.77 (brs, 1H), 4.75 (brs, 1H), 4.38–

4.29 (m, 1H), 4.25–4.17 (m, 2H), 4.17–4.11 (m, 2H), 4.08–3.96 (m, 2H),

3.81–3.71 (m, 1H), 3.64–3.55 (m, 1H), 2.57 (dd, J=16.4, 7.1 Hz, 1H),

2.52–2.43 (m, 1H), 2.39–2.27 (m, 1H), 2.23–1.75 (m, 9H), 1.69 (brs, 3H),

1.64–1.55 (m, 1H), 1.15–1.05 (m, 1H), 0.86–0.82 (m, 12H), 0.00 (brs,

3H), ꢀ0.01 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃): d=160.5 (C_q),

144.8 (C_q), 137.6 (CH), 133.9 (CH), 131.6 (C_q), 130.0 (CH), 128.3 (CH),

125.5 (CH), 125.0 (CH), 119.8 (CH), 114.1 (CH₂), 94.8 (C_q), 79.5 (C_q),

74.3 (CH), 73.5 (CH), 73.3 (CH), 72.1 (CH), 70.5 (CH), 65.9 (CH), 65.7

(CH₂), 45.2 (CH₂), 44.7 (CH₂), 42.6 (CH₂), 36.1 (CH₂), 35.7 (CH₂), 31.2

(CH₂), 27.2 (CH), 26.8 (3ꢄCH₃), 24.8 (CH₂), 23.1 (CH₃), 19.6 (CH₃), 18.4

Desoxylaulimalide (47): To a stirred solution of compound 46 (21 mg,

0.0423 mmol) in a 1:1 mixture of EtOAc and cyclohexene (2 mL) at RT

was added quinoline (17.5 mg). H₂(balloon) was bubbled through the re-

action and Lindlar catalyst (16.5 mg) was added. After 2 h the reaction

was filtered through a short pad of celite, to remove the catalyst and the

solvent was removed under vacuum. The residue was purified by column

chromatography (silica gel, hexane/EtOAc 1:1), yielding desoxylaulimal-

die 47 as colorless oil (18 mg, 0.0361 mmol, 85%), that was identical in

every aspect with the compound derived from prior laulimalide synthe-

ses.^[5]

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5991

J. Mulzer, A. Gollner et al.

Laulimalide (1): To a stirred suspension of powdered molecular sieves

4 ꢃ (300 mg) in CH₂Cl₂(3.5 mL) at ꢀ20 C, was added (+)-diisopropyl

24.6 (CH₂), 23.1 (CH₃), 19.4 (CH₃), 18.4 (C_q), 7.1 (3ꢄCH₃), 5.0 (3ꢄCH₂),

ꢀ4.0 (CH₃), ꢀ4.6 ppm (CH₃); IR (film): n˜ =3312, 2929, 1612, 1513, 1302,

tartrate (57 mL, 0.0287 mmol, 0.5m in CH₂Cl₂) and Ti

G

1248, 1091, 1039, 1006, 836, 776 cm^ꢀ1

; HRMS(EI): m/z: calcd for

0.02429 mmol, 0.5m in CH₂Cl₂). The mixture was stirred for 30 min at the

same temperature before tert-butyl hydroperoxide (44 mL, 0.0485, 1.1m in

CH₂Cl₂, dried over molecular sieves 4 ꢃ) was added dropwise. The mix-

ture was stirred for another 30 min before a solution of 47 (11 mg,

0.022 mmol, in 0.4 mL CH₂Cl₂) was added dropwise. The reaction was

stirred for 3.5 h at ꢀ208C before it was quenched by addition of aq

NaOH (3 mL, 1m in brine). After stirring for 10 min the mixture was di-

luted with CH₂Cl₂and brine, the phases were separated and the aqueous

layer was extracted four times with CH₂Cl₂. The combined organic phase

was dried over magnesium sulfate, filtered and the solvent was removed

under vacuum. The residue was purified by column chromatography

(silica gel, hexane/EtOAc 1:1), yielding laulimalide (1) as white solid

(8.5 mg, 0.0165 mmol, 75%), that was identical in every aspect with the

compound derived from prior laulimalide syntheses and the reported

data of the natural compound.^[1,5][a]_D²⁰=ꢀ198.4 (c=0.25 in CH₂Cl₂);

¹H NMR (600 MHz, CDCl₃): d=6.45 (ddd, J=11.4, 10.0, 3.7 Hz, 1H),

5.91 (ddd, J=11.5, 2.5,1.3 Hz, 1H), 5.87 (ddd, J=15.7, 5.4, 1.2 Hz, 1H),

5.85–5.82 (m, 1H), 5.75 (ddd, J=15.7, 5.7, 1.2 Hz, 1H), 5.71–5.67 (m,

1H), 5.42 (brs, 1H), 5.15 (ddd, J=11.2, 5.3, 1.6 Hz, 1H), 4.86 (brs, 1H),

4.85 (brs, 1H), 4.33–4.28 (m, 1H), 4.22 (brq, J=5.3, 1H), 4.19–4.16 (m,

2H), 4.10–4.06 (m, 1H), 4.05–4.01 (m, 1H), 3.78–3.69 (m, 2H), 3.06 (ddd,

J=9.2, 3.5, 2.4 Hz, 1H), 2.90 (brt, J=2.5 Hz, 1H), 2.39–2.35 (m, 2H),

2.22 (d of m, J=16.7 Hz, 1H), 2.12 (brd, J=15.7 Hz, 1H), 2.06–2.00 (m,

2H), 1.99 (dd, J=15.7, 8.7 Hz, 1H), 1.95–1.85 (m, 4H), 1.78 (dd, J=13.1,

10.0 Hz, 1H), 1.74–1.70 (m, 1H), 1.69 (brs, 3H), 1.50 (ddd, J=14.4, 11.1,

9.3 Hz, 1H), 1.45 (dt, J=14.9, 7.6 Hz, 1H), 1.32 (ddd, J=14.4, 4.7,

3.5 Hz, 1H), 0.83 ppm (d, J=6.5 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃):

d=166.1 (C_q), 150.4 (CH), 145.0 (C_q), 134.0 (CH), 131.4 (C_q), 128.8

(CH), 128.6 (CH), 125.3 (CH), 120.6 (CH), 119.8 (CH), 112.6 (CH₂), 73.6

(CH), 73.3 (CH), 73.2 (CH), 72.4 (CH), 68.0 (CH), 66.7 (CH), 65.8

(CH₂), 60.8 (CH), 52.2 (CH), 45.7 (CH₂), 43.5 (CH₂), 37.2 (CH₂), 35.7

(CH₂), 33.9 (CH₂), 33.5 (CH₂), 31.8 (CH₂), 29.7 (CH₃), 23.1 (CH),

20.9 ppm (CH₃); IR (film): n˜ =3424, 3073, 3030, 2847, 1720, 1642, 1424,

1214, 1170, 895 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₀H₄₂O₇Na: 537.2828,

found: 537.2833.

C₄₉H₇₈O₆Si₂Na: 841.5235, found: 841.5241.

Seco-acid 48: To stirred solution of compound 4c (165 mg,

a

0.2013 mmol) in THF (3 mL) at ꢀ788C was added nBuLi (0.214 mL,

0.342 mmol, 1.6m in hexane) dropwise over a period of 5 min. The bright

yellow solution was stirred for 5 min and then CO₂(g) was bubbled

through the reaction for 10 min. Now HF·pyridine (7%, 2.8 mL) was

added dropwise over 5 min to the colorless reaction mixture and it was

allowed to warm to RT and stirred for another 90 min. The reaction was

quenched by slow addition of aq. sat. NaHCO₃(10 mL) and diluted with

CH₂Cl₂(15 mL). The pH of the aqueous phase was set to pH 3 by addi-

tion of HCl (1n), the phases were separated and the aqueous phase was

extracted four times with CH₂Cl₂. The combined organic phase was dried

over magnesium sulfate, filtered and the solvent was removed under

vacuum. The obtained oil was purified by column chromatography (silica

gel, CH₂Cl₂/MeOH 6:1), yielding seco acid 48 as viscous oil (136 mg,

0.182 mmol, 85%). [a]_D²⁰=ꢀ25.2 (c=1.10 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=7.26 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H),

5.95–5.87 (m, 1H), 5.72 (dd, J=15.3, 6.3 Hz, 1H), 5.84 (dd, J=15.3,

5.4 Hz, 1H), 5.72–5.65 (m, 1H), 5.60–5.52 (m, 2H), 5.41 (brs, 1H), 4.80

(brs, 1H), 4.78 (brs, 1H), 5.63 (d, J=11.3 Hz, 1H), 4.46 (d, J=11.3 Hz,

1H), 4.39 (brs, 1H), 4.23–4.16 (m, 3H), 4.11 (t, J=6.2 Hz, 1H), 4.05

(ddd, J=9.6, 4.8, 4.6 Hz, 1H), 3.80 (s, 3H), 3.80–3.74 (m, 1H), 3.40 (dd,

J=11.1, 5.6 Hz, 1H), 2.64 (dd, J=17.2, 9.0 Hz, 1H), 2.47 (dd, J=17.3,

4.3 Hz, 1H), 2.44–2.37 (m, 1H), 2.33–2.24 (m, 1H), 2.17 (d, J=6.3 Hz,

2H), 2.12–1.79 (m, 7H), 1.70 (brs, 3H), 1.62 (ddd, J=12.9, 10.0, 3.0 Hz,

1H), 1.05 (t, J=12.2 Hz, 1H), 0.88–0.85 (m, 12H), 0.02 (s, 3H), 0.00 ppm

(s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=159.6 (C_q), 154.9 (C_q), 144.6

(2ꢄC_q), 137.7 (CH), 133.1 (CH), 131.6 (C_q), 130.6 (CH), 129.9 (2ꢄCH),

127.6 (CH), 126.7 (CH), 124.0 (CH), 119.5 (CH), 114.4 (CH₂), 114.0 (2ꢄ

CH), 86.7 (C_q), 81.3 (CH), 74.5 (C_q), 73.9 (CH), 72.8 (CH), 72.1 (CH₂),

71.8 (CH), 70.7 (CH), 66.0 (CH), 65.6 (CH₂), 55.4 (CH₃), 45.4 (CH₂), 44.3

(CH₂), 43.2 (CH₂), 35.8 (CH₂), 32.8 (CH₂), 31.4 (CH₂), 26.8 (CH), 26.1

(3ꢄCH₃), 24.5 (CH₂), 23.1 (CH₃), 19.4 (CH₃), 18.4 (C_q), ꢀ4.0 (CH₃),

ꢀ4.6 ppm (CH₃); IR (film): n˜ =3450, 2928, 2238, 1708, 1513, 1382, 1249,

1174, 1091, 835, 777, 610 cm^ꢀ1; HRMS(EI): m/z: calcd for C₄₄H₆₄O₈SiNa:

771.4268, found: 771.4284.

Total synthesis of neolaulimalide (2)

TBS-ether 4c: To a stirred solution of 6b (202 mg, 0.313 mmol) in THF

(4 mL) at ꢀ788C was added KHMDS (0.688 mL, 0.344 mmol, 0.5m in

toluene) dropwise over 4 min. The yellow solution was allowed to stir for

3 min before 5 (122 mg, 0.313 mmol, in 0.7 mL THF) was added dropwise

over 5 min. After stirring for another 90 min at the same temperature the

reaction was quenched by adding H₂O (4 mL) and warmed to RT. The

phases were separated and the aqueous phase was extracted four times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The obtained

oil was purified by column chromatography (silica gel, hexane/EtOAc

Macrolactone 49: To a stirred solution of seco acid 48 (35 mg,

0.0467 mmol) in benzene (1 mL) at RT was added Et₃N (13.0 mL,

0.0934 mmol) and dropwise 2,4,6-trichlorobenzoyl chloride (14.4 mL,

0.0794 mmol). The solution was stirred for 4 h before it was diluted with

benzene (20 mL) and added over 6 h via a syringe pump into a stirred so-

lution of DMAP (57 mg, 0.4673 mmol) in benzene (200 mL). After addi-

tional 6 h the mixture was concentrated to about 20 mL, aq. sat.

NaHCO₃(30 mL) was added and the mixture was stirred for 20 min. The

phases were separated and the aqueous layer was extracted four times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 10:1

! 8:1), yielding compound 49 as viscous oil (12 mg, 0.0164 mmol, 35%)

and the dimer of 49 (3 mg, 0.0021 mmol, 4%). [a]²_D⁰=ꢀ22.4 (c=0.78 in

CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃): d=7.26 (d, J=8.7 Hz, 2H), 6.87

(d, J=8.7 Hz, 2H), 5.95–5.81 (m, 1H), 5.84–5.82 (m, 2H), 5.63–5.60 (m,

1H), 5.52–5.50 (m, 1H), 5.43–5.40 (m, 3H), 4.76 (brs, 2H), 4.56 (d, J=

11.7 Hz, 1H), 4.53 (d, J=11.7 Hz, 1H), 4.46–4.42 (m, 1H), 4.22–4.16 (m,

3H), 4.04 (ddd, J=10.5, 3.6, 3.6 Hz, 1H), 3.80 (s, 3H), 3.76–3.72 (m, 1H),

3.13 (ddd, J=7.0, 7.0, 2.8 Hz, 1H), 2.61 (dd, J=17.4, 10.0 Hz, 1H), 2.48

(dd, J=17.4, 2.5 Hz, 1H), 2.36–2.30 (m, 2H), 2.22 (dd, J=13.9, 7.9 Hz,

1H), 2.14 (dd, J=13.9, 5.4 Hz, 1H), 2.10 (dd, J=13.6, 5.4 Hz, 1H), 2.08–

2.04 (m, 1H), 1.98–1.87 (m, 4H), 1.74 (dd, J=13.6, 10.0 Hz, 1H), 1.70

(brs, 3H), 1.62 (ddd, J=13.9, 9.8, 3.9 Hz, 1H), 1.13 (ddd, J=13.9, 9.7,

2.8 Hz, 1H), 0.86 (m, 9H), 0.83 (d, J=6.6 Hz, 3H), 0.01 (brs, 3H),

0.00 ppm (brs, 3H); ¹³C NMR (150 MHz, CDCl₃): d=159.4 (C_q), 153.1

(C_q), 144.5 (C_q), 136.9 (CH), 134.5 (CH), 131.5 (C_q), 130.3 (C_q), 129.7 (2ꢄ

CH), 127.7 (CH), 127.0 (CH), 124.7 (CH), 124.5 (CH), 119.9 (CH), 113.9

(2ꢄCH₂), 88.1 (C_q), 77.9 (CH), 77.5 (CH), 73.5 (C_q), 73.4 (CH), 71.8

(CH), 71.4 (CH), 71.2 (CH), 66.0 (CH), 65.8 (CH₂), 55.4 (CH₃), 45.0

15:1

+ 1% Et₃N), yielding compound 4c as viscous oil (195 mg,

0.238 mmol, 76%). [a]_D²⁰=ꢀ79.3 (c=1.2 in CH₂Cl₂); ¹H NMR (600 MHz,

CDCl₃): d=7.26 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.91–5.85

(dt, J=2.5, 1.1 Hz, 1H), 5.84–5.82 (m, 1H), 5.81 (ddd, J=15.4, 4.6,

1.1 Hz, 1H), 5.76 (ddd, J=15.5, 5.3, 1.1 Hz, 1H), 5.65–5.58 (m, 1H), 5.47

(dd, J=15.5, 6.4 Hz, 1H), 5.41 (brs, 1H), 4.79 (brs, 1H), 4.77 (brs, 1H),

4.53 (brs, 2H), 4.34–4.30 (m, 1H), 4.26 (t, J=4.9 Hz, 1H), 4.19–4.15 (m,

3H), 4.03 (ddd, J=10.0, 4.7, 4.3 Hz, 1H), 3.82–3.72 (m, 1H), 3.80 (s, 3H),

3.31 (ddd, J=8.6, 5.2, 3.3 Hz, 1H), 2.50 (ddd, J=16.5, 6.7, 2.7 Hz, 1H),

2.43 (ddd, J=16.5, 7.2, 2.7 Hz, 1H), 2.29 (ddd, J=14.7, 7.2, 3.0 Hz, 1H),

2.23 (dd, J=13.8, 6.6 Hz, 1H), 2.11 (dd, J=13.8, 6.6 Hz, 1H), 2.06–1.85

(m, 8H), 1.70 (s, 3H), 1.63 (ddd, J=13.9, 9.9, 3.4 Hz, 1H), 1.09 (ddd, J=

14.0, 9.5, 3.4 Hz, 1H), 0.92 (t, J=7.9 Hz, 9H), 0.89 (d, J=6.4 Hz, 3H),

0.87 (s, 9H), 0.58–0.53 (m, 6H), 0.03 (brs, 3H), 0.01 ppm (s, 3H);

¹³C NMR (150 MHz, CDCl₃): d=159.3 (C_q), 144.7 (C_q), 135.2 (CH), 131.6

(C_q), 131.6 (CH), 131.1 (C_q), 130.4 (CH), 129.5 (2ꢄCH), 128.1 (CH),

127.4 (CH), 125.7 (CH), 119.9 (CH), 113.9 (CH₂), 113.8 (2ꢄCH), 82.9

(CH), 82.0 (C_q), 73.7 (CH), 73.0 (CH), 72.6 (CH₂), 71.5 (CH), 70.9 (CH),

70.2 (CH), 66.0 (CH), 65.7 (CH₂), 55.4 (CH₃), 45.3 (CH₂), 45.1 (CH₂),

42.5 (CH₂), 35.8 (CH₂), 32.9 (CH₂), 31.3 (CH₂), 26.9 (CH), 26.1 (3ꢄCH₃),

5992

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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

(CH₂), 44.0 (CH₂), 43.4 (CH₂), 35.8 (CH₂), 34.4 (CH₂), 31.3 (CH₂), 27.1

(CH), 26.0 (3ꢄCH₃), 24.4 (CH₂), 23.1 (CH₃), 19.0 (CH₃), 18.4 (C_q), ꢀ4.0

(CH₃), ꢀ4.6 ppm (CH₃); IR (film): n˜ =2926, 2854, 2234, 1709, 1513, 1460,

1247, 1070, 969, 835, 776 cm^ꢀ1; HRMS(EI): m/z: calcd for C₄₄H₆₂O₇SiNa:

753.4162, found: 753.4149.

phases were separated and the aqueous layer was extracted four times

with CH₂Cl₂. The combined organic layer was washed four times with

H₂O and dried over magnesium sulfate, filtered and the solvent was re-

moved under vacuum. The residue was purified by column chromatogra-

phy (silica gel, hexane/EtOAc 2:1 to 1:1), yielding 52 as white solid

(5.0 mg, 0.01003 mmol, 96%). [a]²_D⁰=12.9 (c=0.21 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=6.45 (ddd, J=11.4, 9.2, 7.5 Hz, 1H), 5.95 (d, J=

11.4 Hz, 1H), 5.88 (dd, J=15.8, 4.4 Hz, 1H), 5.85–5.77 (m, 2H), 5.74–

5.60 (m, 2H), 5.52 (dd, J=15.5, 5.6 Hz, 1H), 5.42 (brs, 1H), 5.25 (dd, J=

5.2, 3.5 Hz, 1H), 4.89 (brs, 1H), 4.86 (brs, 1H), 4.26–4.15 (m, 4H), 4.06

(ddd, J=10.2, 4.0, 4.0 Hz, 1H), 3.98–3.90 (m, 1H), 3.89–3.81 (m, 1H),

3.15–3.07 (m, 1H), 2.53 (ddd, J=12.6, 8.5, 8.4 Hz, 1H), 2.48–2.39 (m,

1H), 2.28–2.11 (m, 4H), 2.11–1.99 (m, 1H), 1.92 (brd, J=16.9 Hz, 1H),

1.86–1.67 (m, 5H), 1.69 (brs, 3H), 1.04–0.95 (m, 1H), 0.88 ppm (d, J=

6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=165.3 (C_q), 144.8 (C_q),

136.6 (CH), 135.0 (CH), 131.5 (C_q), 129.1 (CH), 126.0 (CH), 125.0 (CH),

124.2 (CH), 121.6 (CH), 119.8 (CH), 114.6 (CH₂), 75.4 (CH), 73.2 (CH),

72.1 (CH), 70.8 (CH), 70.3 (CH), 67.9 (CH), 65.8 (CH₂), 45.0 (CH₂), 43.5

(CH₂), 41.3 (CH₂), 37.1 (CH₂), 35.8 (CH₂), 35.5 (CH₂), 30.4 (CH₂), 27.1

(CH), 23.1 (CH₃), 19.5 ppm (CH₃); IR (film): n˜ =3401, 2920, 2851, 1716,

Alcohol 50: To a stirred solution (PVC flask) of macrolactone 49 (10 mg,

0.0137 mmol) in THF (0.75 mL) at 08C was added HF·pyridine (35%,

500 mL) dropwise in 5 min. After stirring at 08C for another 10 min the

reaction was allowed to reach RT and stirred for 5 h. The mixture was di-

luted with CH₂Cl₂(4 mL), cooled to 08C and quenched by slow addition

of aq. sat. NaHCO₃(7 mL). The phases were separated and the aqueous

layer was extracted four times with CH₂Cl₂. The combined organic phase

was dried over magnesium sulfate, filtered and the solvent was removed

under vacuum. The residue was purified by column chromatography

(silica gel, hexane/EtOAc 2:1), yielding compound 50 as colorless oil

(7.3 mg, 0.0119 mmol, 87%). [a]²_D⁰=ꢀ38.0 (c=0.38 in CH₂Cl₂); ¹H NMR

(600 MHz, CDCl₃); d=7.26 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),

5.94–5.90 (m, 1H), 5.87–5.80 (m, 2H), 5.62–5.55 (m, 3H), 5.51 (dd, J=

15.5, 6.5 Hz, 1H), 5.43 (brs, 1H), 4.88 (brs, 2H), 4.57 (d, J=11.7 Hz,

1H), 4.54 (d, J=11.7 Hz, 1H), 4.45 (brd, J=9.9 Hz, 1H), 4.25 (ddd, J=

9.8, 6.4, 3.4 Hz, 1H), 4.20–4.17 (m, 2H), 4.06–4.01 (m, 1H), 3.80 (s, 3H),

3.69–3.64 (m, 1H), 3.58 (ddd, J=6.8, 5.3, 2.8 Hz, 1H), 2.58 (dd, J=17.3,

10.1 Hz, 1H), 2.47 (dd, J=17.3, 2.3 Hz, 1H), 2.43–2.36 (m, 2H), 2.34 (dd,

J=13.9, 3.7 Hz, 1H), 2.22–2.16 (m, 2H), 2.11–2.04 (m, 1H), 2.02–1.89 (m,

4H), 1.88–1.83 (m, 2H), 1.70 (brs, 3H), 1.66 (ddd, J=14.0, 10.5, 2.6 Hz,

1H), 1.10 (ddd, J=14.0, 10.3, 1.6 Hz, 1H), 0.86 ppm (d, J=6.5 Hz, 3H);

¹³C NMR (150 MHz, CDCl₃): d=159.5 (C_q), 153.2 (C_q), 144.5 (C_q), 135.5

(CH), 134.2 (CH), 131.5 (C_q), 130.2 (C_q), 129.7 (2ꢄCH), 127.7 (CH),

127.0 (CH), 125.9 (CH), 124.5 (CH), 119.9 (CH), 114.0 (2ꢄCH₂), 88.5

(C_q), 77.2 (CH), 77.8 (CH), 73.4 (CH), 73.2 (C_q), 71.6 (CH), 71.3 (CH),

69.3 (CH), 66.0 (CH), 65.8 (CH₂), 55.4 (CH₃), 45.7 (CH₂), 43.6 (CH₂),

43.0 (CH₂), 35.8 (CH₂), 34.8 (CH₂), 31.4 (CH₂), 26.8 (CH), 24.3 (CH₂),

23.1 (CH₃), 19.1 ppm (CH₃); IR (film): n˜ =2925, 2234, 1707, 1513, 1248,

1070 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₈H₄₈O₇Na: 639.3298, found:

639.3315.

1260, 1079, 799, 473, 446, 405 cm^ꢀ1

C₃₀H₄₂O₆Na: 521.2879, found: 521.2882.

; HRMS(EI): m/z: calcd for

Neolaulimalide (3): To a stirred suspension of powdered molecular sieves

4 ꢃ (160 mg) in CH₂Cl₂(1.7 mL) at ꢀ208C, was added (+)-diisopropyl

tartrate (25.6 mL, 0.0128 mmol, 0.5m in CH₂Cl₂) and TiACHTUNTRGNE(UNG OiPr)₄(21.4 mL

0.0107 mmol, 0.5m in CH₂Cl₂). The mixture was stirred at the same tem-

perature for 10 min before tert-butyl hydroperoxide (27.3 mL, 0.0150,

0.55m in CH₂Cl₂, dried over molecular sieves 4 ꢃ) was added dropwise.

The mixture was stirred for another 30 min before a solution of 52

(4.4 mg, 0.00882 mmol, in 0.3 mL CH₂Cl₂) was added dropwise. The reac-

tion was stirred for 2.5 h at ꢀ208C before it was quenched by addition of

aq. sat. NH₄Cl (2 mL) and warmed to RT. After stirring for 4 min the

mixture was diluted with Et₂O and sat. aq. KNa-tartrate and stirred for

45 min, the phases were separated and the aqueous layer was extracted

four times with Et₂O. The combined organic phase was dried over mag-

nesium sulfate, filtered and the solvent was removed under vacuum. The

residue was purified by column chromatography (silica gel, hexane/

EtOAc 2:1 ! 1:2), yielding neolaulimalide (1) as white solid (3.3 mg,

0.00641 mmol, 73%), that was identical in every aspect with the reported

data of the natural compound. [a]²_D⁰=ꢀ53.3 (c=0.30 in CH₂Cl₂);

¹H NMR (600 MHz, CDCl₃): d=6.35 (ddd, J=11.7, 8.1, 8.1 Hz, 1H), 5.91

(ddd, J=15.7, 4.9, 0.9 Hz, 1H), 5.90 (d, J=11.7 Hz, 1H), 5.86–5.83 (m,

1H), 5.83 (ddd, J=15.9, 6.8, 1.5 Hz, 1H), 5.73–5.70 (m, 1H), 5.42 (brs,

1H), 5.32 (dd, J=6.8, 4.9 Hz, 1H), 4.95 (brs, 1H), 4.90 (brs, 1H), 4.29–

4.25 (m, 1H), 4.18 (brs, 2H), 4.10–4.07 (m, 1H), 4.07–4.03 (m, 1H), 3.96–

3.91 (m, 1H), 3.83–3.80 (m, 1H), 3.19 (dt, J=6.4, 2.5 Hz, 1H), 3.02 (t, J=

2.5 Hz, 1H), 2.95–2.89 (m, 1H), 2.89–2.83 (m, 1H), 2.76 (d, J=6.4 Hz,

1H, OH), 2.37 (dd, J=14.5, 6.4 Hz, 1H), 2.18 (dd, J=14.5, 6.8 Hz, 1H),

2.11–2.08 (m, 1H), 2.06–2.00 (m, 3H, 1ꢄOH), 1.99–1.97 (m, 1H), 196–

1.93 (m, 1H), 1.92–1.89 (m, 1H), 1.89–1.85 (m, 1H), 1.80–1.74 (m, 1H),

1.69 (brs, 3H), 1.68–1.64 (m, 1H), 1.63–1.60 (m, 1H), 1.10 (ddd, J=13.9,

8.6, 4.8 Hz, 1H), 0.90 ppm (d, J=6.4 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃): d=165.6 (C_q), 144.8 (CH), 143.8 (C_q), 136.0 (CH), 131.5 (C_q),

128.6 (CH), 125.2 (CH), 124.8 (CH), 122.5 (CH), 119.7 (CH), 114.1

(CH₂), 77.1 (CH), 73.0 (CH), 72.3 (CH), 70.6 (CH), 67.4 (CH), 66.5

(CH), 65.8 (CH₂), 60.8 (CH), 52.4 (CH), 46.4 (CH₂), 41.9 (CH₂), 38.6

(CH₂), 35.7 (CH₂), 35.4 (CH₂), 35.3 (CH₂), 31.0 (CH₂), 27.0 (CH), 23.0

(CH₃), 20.1 ppm (CH₃); IR (film): n˜ =3437, 2919, 2850, 1715, 1640, 1607,

1168, 855, 407 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₀H₄₂O₆Na: 537.2828,

found: 537.2831.

Enone 51: To a stirred solution of compound 50 (8.1 mg, 0.01314 mmol)

in a 1:1 mixture of EtOAc and cyclohexene (3 mL) at RT was added

quinoline (18 mL). H₂(balloon) was bubbled through the reaction and

Lindlar catalyst (15 mg) was added. After 1 h the reaction was filtered

through

a short pad of celite and the solvent was removed under

vacuum. The residue was purified by column chromatography (silica gel,

hexane/EtOAc 5:1 to 1:1), yielding 51 as colorless oil (8.0 mg,

0.01293 mmol, 89%). [a]²_D⁰=38.6 (c=0.70 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=7.26 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H),

6.43 (ddd, J=11.5, 9.4, 7.2 Hz, 1H), 5.95 (d, J=11.5 Hz, 1H), 5.88 (dd,

J=15.9, 5.3 Hz, 1H), 5.85–5.77 (m, 2H), 5.69 (dd, J=10.4, 2.0 Hz, 1H),

5.61–5.51 (m, 1H), 5.46 (dd, J=15.5, 5.7 Hz, 1H), 5.44–5.38 (m, 2H),

4.87 (brs, 1H), 4.85 (brs, 1H), 4.57 (d, J=11.6 Hz, 1H), 4.52 (d, J=

11.6 Hz, 1H), 4.25–4.12 (m, 4H), 4.06–4.01 (m, 1H), 3.99–3.92 (m, 1H),

3.80 (s, 3H), 3.64 (ddd, J=8.6, 5.4, 3.2 Hz, 1H), 3.22 (ddd, J=13.5, 9.1,

4.1 Hz, 1H), 2.47–2.26 (m, 5H), 2.34–2.26 (m, 2H), 2.12–2.00 (m, 2H),

1.89 (brd, J=16.6 Hz, 1H), 1.81–1.71 (m, 4H), 1.70 (brs, 3H), 0.99 (ddd,

J=13.8, 8.4, 3.6 Hz, 1H), 0.86 ppm (d, J=6.3 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=165.4 (C_q), 159.4 (C_q), 147.3 (C_q), 145.0 (C_q),

135.8 (CH), 133.2 (CH), 131.5 (C_q), 130.2 (C_q), 129.7 (2ꢄCH), 129.3

(CH), 126.4 (CH), 125.9 (CH), 124.1 (CH), 121.4 (CH), 119.9 (CH),

114.7 (CH₂), 113.9 (2ꢄCH), 78.4 (CH), 73.9 (CH), 73.5 (CH), 71.9 (CH₂),

70.2 (CH), 70.1 (CH), 67.8 (CH), 65.8 (CH₂), 55.4 (CH₃), 45.2 (CH₂), 43.0

(CH₂), 40.7 (CH₂), 35.8 (CH₂), 35.2 (CH₂), 34.2 (CH₂), 30.3 (CH₂), 27.0

(CH), 23.1 (CH₃), 19.4 ppm (CH₃); IR (film): n˜ =3469, 2917, 1714, 1513,

1247, 1168, 1033, 819, 447, 419 cm^ꢀ1

C₃₈H₅₀O₇Na: 641.3454, found: 641.3450.

;

HRMS(EI): m/z: calcd for

Total synthesis of isolaulimalide (3)

TBS-ether 4e: To a stirred solution of 6c (253 mg, 0.4327 mmol) in THF

(8 mL) at ꢀ788C was added KHMDS (0.952 mL, 0.4760 mmol, 0.5m in

toluene) dropwise over 5 min. The yellow solution was allowed to stir for

3 min before 5 (144 mg, 0.369 mmol, in 1.0 mL THF) was added dropwise

over 5 min. After stirring for another 90 min at the same temperature the

reaction was quenched by adding H₂O (7 mL) and warmed to RT. The

phases were separated and the aqueous phase was extracted four times

Desoxyneolaulimalide (52): To a solution of 51 (6.5 mg, 0.0105 mmol) in

a biphasic 1:1 mixture of CH₂Cl₂/aq. (pH 7) buffer (6 mL) was added

DDQ (4 mg) in one portion. The flask was closed with a septum and

placed into an ultrasound bath at 358C. After 1 h additional DDQ (4 mg)

was added and the same after 2.5 h. The reaction was diluted with H₂O

(10 mL) and CH₂Cl₂(5 mL) after a total reaction time of 3.5 h. The

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

5993

J. Mulzer, A. Gollner et al.

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The obtained

oil was purified by column chromatography (silica gel, hexane/EtOAc

4:1), yielding compound 4e as viscous oil (273 mg, 0.3164 mmol, 86%).

[a]²_D⁰=ꢀ49.6 (c=0.72 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.26

(d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 5.92–5.81 (m, 2H), 5.79 (dd,

J=15.7, 5.3 Hz, 1H), 5.68 (dd, J=15.7, 6.7 Hz, 1H), 5.64–5.56 (m, 1H),

5.51 (dd, J=15.4, 6.0 Hz, 1H), 5.42 (brs, 1H), 4.79 (brs, 1H), 4.77 (brs,

1H), 4.68 (d, J=6.6 Hz, 1H), 4.58 (d, J=6.6 Hz, 1H), 4.55 (s, 2H), 4.35–

4.28 (m, 1H), 4.22–4.11 (m, 4H), 4.06–3.99 (m, 1H), 3.85–3.77 (m, 1H),

3.79 (s, 3H), 3.46–3.40 (m, 1H), 3.35 (s, 3H), 2.50 (ddd, J=16.4, 6.8,

2.5 Hz, 1H), 2.42 (ddd, J=16.4, 7.0, 2.6 Hz, 1H), 2.38–2.29 (m, 1H),

2.27–2.16 (m, 2H), 2.27–2.16 (m, 9H), 1.70 (brs, 3H), 1.62 (ddd, J=13.5,

10.1, 3.2 Hz, 1H), 1.09 (ddd, J=13.6, 9.5, 3.2 Hz, 1H), 0.92–0.84 (m,

12H), 0.03 (brs, 3H), 0.01 ppm (brs, 3H); ¹³C NMR (100 MHz, CDCl₃):

d=159.4 (C_q), 144.7 (C_q), 135.9 (CH), 134.5 (CH), 131.5 (C_q), 131.0 (C_q),

129.6 (2ꢄCH), 128.1 (CH), 127.8 (CH), 126.4 (CH), 125.7 (CH), 119.9

(CH), 113.9 (CH₂), 113.8 (2ꢄCH), 94.6 (CH₂), 81.5 (C_q), 81.4 (CH), 77.4

(CH), 73.5 (CH), 72.7 (CH₂), 72.5 (CH), 70.9 (CH), 70.3 (CH), 66.5

(CH), 65.7 (CH₂), 55.8 (CH₃), 55.4 (CH₃), 45.3 (CH₂), 45.0 (CH₂), 42.5

(CH₂), 35.9 (CH₂), 33.7 (CH₂), 31.3 (CH₂), 27.0 (CH), 26.1 (3ꢄCH₃), 24.6

(CH₂), 23.1 (CH₃), 19.5 (CH₃), 18.4 (C_q), ꢀ4.0 (CH₃), ꢀ4.6 ppm (CH₃);

73%). [a]²_D⁰=ꢀ82.5 (c=1.18 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃):

d=7.29 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.92–5.86 (m, 1H),

5.85–5.77 (m, 2H), 5.67 (dd, J=15.9, 6.8 Hz, 1H), 5.41 (brs, 1H), 4.90

(brs, 1H), 4.88 (brs, 1H), 4.71–4.66 (m, 2H), 4.62–4.56 (m, 2H), 4.35–

4.29 (m, 1H), 4.24–4.19 (m, 1H), 4.17 (brs, 2H), 4.03 (ddd, J=9.8, 4.7,

4.5 Hz, 1H), 3.82–3.76 (m, 1H), 3.79 (s, 3H), 3.71 (ddd, J=9.3, 5.1,

3.7 Hz, 1H), 3.36 (s, 3H), 3.17–3.12 (m, 1H), 2.79 (dd, J=4.0, 2.3 Hz,

1H), 2.51 (ddd, J=16.5, 7.1, 2.7 Hz, 1H), 2.42 (ddd, J=16.5, 6.8, 2.7 Hz,

1H), 2.30 (dd, J=14.3, 3.9 Hz, 1H), 2.17 (dd, J=14.4, 9.1 Hz, 1H), 2.11–

2.00 (m, 3H), 1.99–1.83 (m, 6H), 1.83–1.77 (m, 1H), 1.70 (brs, 3H), 1.65–

1.59 (m, 3H), 1.13 (ddd, J=13.8, 9.5, 3.2 Hz, 1H), 0.89 ppm (d, J=

6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): d=159.5 (C_q), 144.2 (C_q),

134.9 (CH), 131.5 (C_q), 130.7 (C_q), 129.8 (2ꢄCH), 128.1 (CH), 127.1

(CH), 125.8 (CH), 119.9 (CH), 114.5 (CH₂), 113.8 (2ꢄCH), 94.6 (CH₂),

81.3 (C_q), 78.5 (CH), 77.4 (CH), 73.5 (CH), 73.2 (CH₂), 71.1 (CH), 70.3

(CH), 67.5 (CH), 66.1 (CH), 65.7 (CH₂), 61.5 (CH), 55.8 (CH₃), 55.4

(CH₃), 53.4 (CH), 44.6 (CH₂), 42.7 (CH₂), 40.5 (CH₂), 35.9 (CH₂), 33.7

(CH₂), 31.3 (CH₂), 27.1 (CH), 24.6 (CH₂), 23.1 (CH₃), 19.4 ppm (CH₃);

IR (film): n˜ =2927, 1653, 1617, 1513, 1248, 1093, 1035, 668 cm^ꢀ1

HRMS(EI): m/z: calcd for C₃₉H₅₄O₈Na: 673.3716, found: 673.3728.

;

Diol 59: To a stirred solution of epoxide 57 (83 mg, 0.1275 mmol) in THF

(2 mL) at ꢀ208C was added thiophenol (114 mL, 1.02 mmol) and drop-

wise BF₃·Et₂O (61.4 mL, 0.4845 mmol). The mixture was stirred at the

same temperature for 6 h and then allowed to warm to RT and stirred for

another 3 h. Et₃N (1.4 mL) was added, the reaction, quenched with aq.

sat. NaHCO₃(10 mL) and diluted with CH₂Cl₂(12 mL). The phases were

separated and the aqueous layer was extracted four times with CH₂Cl₂.

The combined organic phase was dried over magnesium sulfate, filtered

and the solvent was removed under vacuum. The residue was purified by

column chromatography (silica gel, hexane/EtOAc 4:1 ! 1:1), yielding

diol 59 as colorless oil (54 mg, 0.0890 mmol, 70%). [a]²_D⁰=ꢀ51.4 (c=1.05

in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=7.25 (d, J=8.7 Hz, 2H),

6.86 (d, J=8.7 Hz, 2H), 5.96 (ddd, J=15.7, 7.3, 1.0 Hz, 1H), 5.92–5.86

(m, 1H), 5.85–5.78 (m, 2H), 5.42 (brs, 1H), 4.92 (brs, 1H), 4.91 (brs,

1H), 4.52 (d, J=11.7 Hz, 1H), 4.44 (d, J=11.7 Hz, 1H), 4.43–4.39 (m,

2H), 4.36–4.29 (m, 1H), 4.19 (brs, 2H), 4.10–4.03 (m, 2H), 3.82–3.73 (m,

3H), 3.80 (s, 3H), 2.56–2.46 (m, 2H), 2.42 (ddd, J=16.5, 6.9, 2.6 Hz, 1H),

2.31–2.25 (m, 2H), 2.22 (ddd, J=13.1, 6.3, 1.8 Hz, 1H), 2.17–2.02 (m,

4H), 1.98–1.84 (m, 5H), 1.70 (brs, 3H), 1.67–1.59 (m, 2H), 1.16 (ddd, J=

13.8, 9.0, 3.2 Hz, 1H), 0.89 ppm (d, J=6.3 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃): d=159.3 (C_q), 145.0 (C_q), 134.1 (CH), 131.6 (C_q), 130.6 (C_q),

129.2 (2ꢄCH), 128.0 (CH), 127.9 (CH), 125.8 (CH), 119.9 (CH), 114.8

(CH₂), 113.9 (2ꢄCH), 83.1 (CH), 81.3 (C_q), 80.8 (CH), 78.7 (CH), 75.1

(CH), 73.8 (CH), 71.4 (CH₂), 71.1 (CH), 70.3 (CH), 69.8 (CH), 66.2

(CH), 65.7 (CH₂), 55.4 (CH₃), 44.3 (CH₂), 42.6 (CH₂), 39.9 (CH₂), 35.9

(CH₂), 33.4 (CH₂), 31.3 (CH₂), 27.2 (CH), 24.6 (CH₂), 23.1 (CH₃),

19.4 ppm (CH₃); IR (film): n˜ =3436, 2913, 1613, 1513, 1248, 1174, 1037,

IR (film): n˜ =3855, 2927, 1700, 1653, 1513, 1249, 1038, 835, 668 cm^ꢀ1

HRMS(EI): m/z: calcd for C₄₅H₆₈O₇Na: 771.4632, found: 771.4626.

;

Alcohol 56: To a stirred solution (PVC flask) of compound 4e (235 mg,

0.3137 mmol) in THF (3.5 mL) at 08C was added HF·pyridine (70%,

1.0 mL) dropwise in 10 min. After stirring at 08C for another 10 min the

reaction was allowed to reach RT and stirred for 2 h. The mixture was di-

luted with CH₂Cl₂(50 mL), cooled to 08C and quenched by slow addition

of aq. sat. NaHCO₃(100 mL). The phases were separated and the aque-

ous layer was extracted four times with CH₂Cl₂. The combined organic

phase was dried over magnesium sulfate, filtered and the solvent was re-

moved under vacuum. The residue was purified by column chromatogra-

phy (silica gel, hexane/EtOAc 2:1), yielding alcohol 56 as viscous oil

1

(189 mg, 0.2977 mmol, 95%). [a]²_D⁰=ꢀ69.0 (c=1.40 in CH₂Cl₂); H NMR

(400 MHz, CDCl₃): d=7.27 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H),

5.92–5.87 (m, 1H), 5.86–5.76 (m, 3H), 5.74–5.64 (m, 2H), 5.59–5.48 (m,

1H), 5.42 (brs, 1H), 4.89 (brs, 1H), 4.88 (brs, 1H), 4.69 (dd, J=13.2,

6.2 Hz, 1H), 4.61–4.52 (m, 3H), 4.35–4.29 (m, 1H), 4.22–4.13 (m, 4H),

4.03 (ddd, J=9.7, 4.7, 4.7 Hz, 1H), 3.85–3.76 (m, 1H), 3.79 (s, 3H), 3.47

(ddd, J=7.5, 5.0, 5.0 Hz, 1H), 3.37 (s, 3H), 2.51 (ddd, J=16.5, 7.0,

2.6 Hz, 1H), 2.42 (ddd, J=16.5, 6.8, 2.6 Hz, 1H), 2.37–2.31 (m, 1H),

2.29–2.12 (m, 3H), 2.12–2.02 (m, 2H), 2.02 (t, J=2.7 Hz, 1H), 2.01–1.79

(m, 5H), 1.70 (brs, 3H), 1.63 (ddd, J=14.0, 9.9, 3.4 Hz, 1H), 1.14 (ddd,

J=14.0, 9.6, 3.2 Hz, 1H), 0.89 ppm (d, J=6.3 Hz, 3H); NMR (100 MHz,

CDCl₃): d=159.3 (C_q), 144.8 (C_q), 135.0 (CH), 134.7 (CH), 131.5 (C_q),

131.0 (C_q), 129.8 (2ꢄCH), 128.1 (CH), 127.9 (CH), 127.7 (CH), 125.8

(CH), 119.9 (CH), 114.5 (CH₂), 113.8 (2ꢄCH), 94.5 (CH₂), 81.2 (C_q), 80.9

(CH), 77.7 (CH), 73.5 (CH), 72.8 (CH₂), 71.1 (CH), 70.2 (CH), 70.0

(CH), 66.1 (CH), 65.7 (CH₂), 55.8 (CH₃), 55.4 (CH₃), 44.6 (CH₂), 44.3

(CH₂), 42.7 (CH₂), 35.9 (CH₂), 33.9 (CH₂), 31.3 (CH₂), 27.0 (CH), 24.6

(CH₂), 23.1 (CH₃), 19.5 ppm (CH₃); IR (film): n˜ =3468, 2912, 1612, 1513,

1247, 1091, 1034, 707 cm^ꢀ1; HRMS(EI): m/z: calcd for C₃₉H₅₄O₇Na:

657.3767, found: 657.3777.

706 cm^ꢀ1

629.3446.

; HRMS(EI): m/z: calcd for C₃₇H₅₀O₇Na: 629.3454, found:

TBS-ether 60: To a stirred solution of diol 59 (52 mg, 0.0857 mmol) in

CH₂Cl₂(2 mL) at ꢀ208C was added 2,6-lutidine (55 mg, 0.510 mmol) and

dropwise TBSOTf (114 mg, 0.431 mmol). The reaction was allowed to

reach RT after addition and was stirred for 8 h. The mixture was cooled

to 08C, diluted with CH₂Cl₂(70 mL) and quenched with sat. aq. NaHCO₃

(10 mL). The phases were separated and the aqueous phase extracted

three times with CH₂Cl₂. The combined organic phase was dried over

magnesium sulfate, filtered and the solvent was removed under vacuum.

The obtained oil was purified by column chromatography (silica gel,

hexane/EtOAc 10:1 ! 5:1), yielding compound 60 as colorless, viscous

oil (62 mg, 0.0742 mmol, 87%). [a]²_D⁰=ꢀ82.3 (c=0.65 in CH₂Cl₂);

¹H NMR (400 MHz, CDCl₃): d=7.26 (d, J=8.7 Hz, 2H), 6.85 (d, J=

8.7 Hz, 2H), 5.94 (ddd, J=15.6, 7.3, 0.9 Hz, 1H), 5.91–5.86 (m, 1H),

5.85–5.81 (m, 1H), 5.78 (dd, J=15.6, 6.0 Hz, 1H), 5.42 (brs, 1H), 4.84

(brs, 1H), 4.80 (brs, 1H), 4.50 (d, J=11.6 Hz, 1H), 4.43 (d, J=11.6 Hz,

1H), 4.34–4.27 (m, 3H), 4.19 (brs, 2H), 4.09–4.03 (m, 1H), 4.03–3.98 (m,

1H), 3.90–3.86 (m, 1H), 3.85–3.82 (m, 1H), 3.82–3.77 (m, 2H), 3.80 (s,

3H), 2.49 (ddd, J=16.4, 6.7, 2.7 Hz, 1H), 2.42 (ddd, J=16.4, 7.2, 2.7 Hz,

1H), 2.20 (dd, J=14.3, 6.9 Hz, 1H), 2.16–2.05 (m, 4H), 2.00 (t, J=

2.7 Hz, 1H), 1.98–1.85 (m, 6H), 1.70 (brs, 3H), 1.68–1.59 (m, 1H), 1.13–

Epoxide 57: To a stirred suspension of powdered molecular sieves 4 ꢃ

(1.4 g) in CH₂Cl₂(4.5 mL) at ꢀ208C, was added (+)-diisopropyl tartrate

(708 mL, 0.354 mmol, 0.5m in CH₂Cl₂) and TiACTHNUTRGEN(UNG OiPr)₄(590 mL 0.295 mmol,

0.5m in CH₂Cl₂). The mixture was stirred for 30 min at the same temper-

ature before tert-butyl hydroperoxide (749 mL, 0.412, 0.55m in CH₂Cl₂,

dried over molecular sieves 4 ꢃ) was added dropwise. The mixture was

stirred for another 30 min before a solution of 56 (155 mg, 0.244 mmol, in

1.2 mL CH₂Cl₂) was added dropwise. The reaction was stirred for 3.5 h at

ꢀ208C before it was quenched by addition of aq NaOH (4 mL, 1m in

brine). After stirring for 10 min the mixture was diluted with CH₂Cl₂and

brine, the phases were separated and the aqueous layer was extracted

four times with CH₂Cl₂. The combined organic phase was dried over

magnesium sulfate, filtered and the solvent was removed under vacuum.

The residue was purified by column chromatography (silica gel, hexane/

EtOAc 3:1), yielding epoxide 57 as colorless oil (115 mg, 0.177 mmol,

5994

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

1.02 (m, 1H), 0.94–0.82 (m, 21H), 0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H),

0.03 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=159.2 (C_q), 144.7

(C_q), 133.4 (CH), 131.8 (C_q), 130.9 (C_q), 129.2 (2ꢄCH), 128.8 (CH), 128.1

(CH), 125.7 (CH), 119.9 (CH), 114.4 (CH₂), 113.9 (2ꢄCH), 83.9 (CH),

81.4 (CH), 81.2 (C_q), 78.0 (CH), 77.3 (CH), 74.3 (CH), 74.0 (CH₂), 71.3

(CH), 70.8 (CH), 70.2 (CH), 65.9 (CH), 65.8 (CH₂), 55.4 (CH₃), 44.9

(CH₂), 42.3 (CH₂), 40.6 (CH₂), 35.9 (CH₂), 33.8 (CH₂), 31.2 (CH₂), 27.1

(CH), 26.2 (6ꢄCH₃), 24.6 (CH₂), 23.1 (CH₃), 19.6 (CH₃), 18.4 (C_q), 18.3

(C_q), ꢀ3.8 (CH₃), ꢀ3.9 (CH₃), ꢀ4.5 ppm (2ꢄCH₃); IR (film): n˜ =2928,

0.0312 mmol). The solution was stirred for 4 h before it was diluted with

benzene (10 mL) and added over 6 h via a syringe pump into a stirred so-

lution of DMAP (24.2 mg, 0.1982 mmol) in benzene (130 mL). After ad-

ditional 6 h the mixture was concentrated to about 20 mL, aq. sat.

NaHCO₃(15 mL) was added and the mixture was stirred for 20 min. The

phases were separated and the aqueous layer was extracted four times

with EtOAc. The combined organic phase was dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 10:1

! 7:1), yielding a 4:1 mixture of 62 and its dimer as viscous oil (8.4 mg)

that was used without further separation in the next step. To a stirred so-

lution (PVC flask) of the 4:1 mixture of compound 62 and the dimer

(7 mg) in THF (1 mL) at 08C was added HF·pyridine (70%, 400 mL)

dropwise in 5 min. After stirring at 08C for another 10 min the reaction

was allowed to reach RT and stirred for 5 h. The mixture was diluted

with CH₂Cl₂(5 mL), cooled to 08C and quenched by slow addition of aq.

sat. NaHCO₃(8 mL). The phases were separated and the aqueous layer

was extracted five times with CH₂Cl₂. The combined organic phase was

dried over magnesium sulfate, filtered and the solvent was removed

under vacuum. The residue was purified by column chromatography

(silica gel, hexane/EtOAc 2:1 ! 1:2), yielding diol 63 as colorless oil

(3.2 mg, 0.00619 mmol, 32% over two steps). [a]²_D⁰=26.2 (c=0.13 in

CH₂Cl₂); ¹H NMR (600 MHz, CDCl₃): d=5.93–5.89 (m, 1H), 5.86–5.84

(m, 2H), 5.63–5.60 (m, 1H), 5.43–5.41 (m, 2H), 4.92 (brs, 2H), 4.55 (dd,

J=6.2, 4.9 Hz, 1H), 4.43 (brd, J=10.6 Hz, 1H), 4.29 (ddd, J=11.7, 3.8,

1.5 Hz, 1H), 4.20 (brs, 1H), 4.20–4.16 (m, 2H), 3.78–3.73 (m, 1H), 2.72

(dd, J=18.0, 11.1 Hz, 1H), 2.41 (dd, J=18.0, 2.3 Hz, 1H), 2.34 (d, J=

2.6 Hz, 1H), 2.22 (ddd, J=13.6, 11.7, 3.4 Hz, 1H), 2.17–2.08 (m, 3H),

2.05 (dd, J=13.6, 4.2 Hz, 1H), 2.03–1.98 (m, 1H), 1.98–1.92 (m, 3H),

1.86 (dd, J=13.6, 11.0 Hz, 1H), 1.70 (brs, 3H), 1.60 (ddd, J=14.0, 10.6,

3.0 Hz, 1H), 1.15 (ddd, J=14.0, 11.1, 2.6 Hz, 1H), 0.80 ppm (d, J=

6.4 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): d=153.1 (C_q), 144.2 (C_q),

135.8 (CH), 131.5 (C_q), 127.6 (CH), 126.6 (CH), 126.0 (CH), 119.8 (CH),

113.9 (CH₂), 87.7 (C_q), 80.9 (CH), 78.7 (CH), 78.3 (CH), 73.8 (C_q), 73.6

(CH), 71.8 (CH), 71.1 (CH), 69.7 (CH), 65.7 (CH₂), 64.4 (CH), 46.2

(CH₂), 44.4 (CH₂), 35.8 (CH₂), 35.4 (CH₂), 34.6 (CH₂), 31.6 (CH₂), 25.8

(CH), 24.2 (CH₂), 23.1 (CH₃), 17.3 ppm (CH₃); IR (film): n˜ =2924, 2853,

1514, 1249, 1091, 835, 776 cm^ꢀ1

C₄₉H₇₈O₇Si₂Na: 857.5184, found: 857.5195.

Alcohol 60a: To stirred solution of compound 60 (52 mg,

;

HRMS(EI): m/z: calcd for

a

0.06225 mmol) in a biphasic 1:1 mixture of CH₂Cl₂/aq. (pH 7) buffer

(4 mL) was added DDQ (55 mg, 0.2573 mmol) portion wise at RT. The

reaction was stirred overnight and diluted with aq. sat. NaHCO₃(15 mL)

and CH₂Cl₂(10 mL). The phases were separated and the aqueous layer

was extracted with four times with CH₂Cl₂. The combined organic layer

was washed two times with aq. sat. NaHCO₃, dried over magnesium sul-

fate, filtered and the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 10:1

! 4:1), yielding 60a as viscous oil (41 mg, 0.05733 mmol, 90%). [a]_D²⁰

=

ꢀ43.7 (c=1.23 in CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=5.93–5.86

(m, 2H), 5.85–5.79 (m, 2H), 5.42 (brs, 1H), 4.84 (brs, 1H), 4.80 (brs,

1H), 4.37–4.29 (m, 3H), 4.27–4.23 (m, 1H), 4.18 (brs, 2H), 4.09–4.03 (m,

1H), 3.95–3.91 (m, 1H), 3.84 (brd, J=4.1 Hz, 1H), 3.82–3.77 (m, 1H),

2.50 (ddd, J=16.4, 6.8, 2.8 Hz, 1H), 2.42 (ddd, J=16.4, 7.2, 2.8 Hz, 1H),

2.24 (dd, J=14.4, 6.6 Hz, 1H), 2.21–2.02 (m, 4H), 2.01 (t, J=2.6 Hz,

1H), 2.00–1.83 (m, 6H), 1.70 (brs, 3H), 1.68–1.59 (m, 1H), 1.10 (ddd, J=

13.7, 9.6, 3.1 Hz, 1H), 0.93–0.85 (m, 21H), 0.10 (s, 3H), 0.05 (s, 6H),

0.03 ppm (s, 3H); ¹³C NMR (100 MHz, CDCl₃): d=144.8 (C_q), 134.5

(CH), 131.6 (C_q), 128.1 (CH), 127.3 (CH), 125.8 (CH), 119.8 (CH), 114.4

(CH₂), 82.6 (CH), 81.2 (C_q), 78.0 (CH), 77.8 (CH), 74.7 (CH), 74.1 (CH),

73.7(CH), 70.9 (CH), 70.2 (CH), 66.0 (CH), 65.8 (CH₂), 44.9 (CH₂), 42.5

(CH₂), 40.1 (CH₂), 37.5 (CH₂), 35.9 (CH₂), 31.3 (CH₂), 27.0 (CH), 26.2

(6ꢄCH₃), 24.6 (CH₂), 23.1 (CH₃), 19.4 (CH₃), 18.4 (C_q), 18.3 (C_q), ꢀ3.7

(CH₃), ꢀ4.0 (CH₃), ꢀ4.5 (CH₃), ꢀ4.6 ppm (CH₃); IR (film): n˜ =3313,

2929, 2856, 1407, 1254, 1123, 836, 777, 636 cm^ꢀ1; HRMS(EI): m/z: calcd

for C₄₁H₇₀O₆Si₂Na: 737.4609, found: 737.4625.

2236, 1713, 1459, 1247, 1071, 672 cm^ꢀ1

C₃₀H₄₀O₇Na: 535.2672, found: 535.2682.

; HRMS(EI): m/z: calcd for

Seco-acid 61: To

a stirred solution of compound 60a (35 mg,

Isolaulimalide (3): To a stirred solution of diol 63 (3.1 mg, 0.00602 mmol)

in EtOAc/cyclohexene 1:1 (1 mL) at RT was added quinoline (3.6 mL). H₂

(balloon) was bubbled through the reaction and Lindlar catalyst (3 mg)

was added. After 2 h the reaction was filtered through a short pad of

celite, subsequently the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 2:1 to

1:2). Yielding isolaulimalide (3) as white solid (3.0 mg, 0.00583 mmol,

97%), that was identical in every aspect with the reported data of the

natural compound. [a]²_D⁰=ꢀ17.9 (c=0.28 in CH₂Cl₂); ¹H NMR

(600 MHz, CDCl₃): d=6.19 (ddd, J=11.7, 10.6, 6.8 Hz, 1H), 5.90 (ddd,

J=15.7, 5.8, 1.4 Hz, 1H), 5.88–5.84 (m, 2H), 5.76–5.72 (m, 1H), 5.70

(ddd, J=15.7, 5.9, 1.4 Hz, 1H), 5.56 (t, J=4.0 Hz, 1H), 5.37 (brs, 1H),

4.89 (brs, 1H), 4.88 (brs, 1H), 4.63–4.60 (m, 1H), 4.36 (ddd, J=10.9, 4.8,

4.8 Hz, 1H), 4.32–4.27 (m, 1H), 4.15–4.11 (m, 3H), 4.06 (brd, J=9.4 Hz,

1H), 4.00–3.96 (m, 1H), 3.66–3.61 (m, 1H), 3.18 (dddd, J=12.0, 10.5, 5.3,

1.5 Hz, 1H), 2.51 (dddd, J=12.1, 9.7, 6.9, 0.8 Hz, 1H), 2.36 (ddd, J=13.7,

10.9, 4.4 Hz, 1H), 2.30–2.24 (m, 1H), 2.21 (dd, J=13.5, 5.2 Hz, 1H),

2.23–2.17 (m, 2H), 2.12–2.08 (m, 1H), 2.02–1.92 (m, 4H), 1.87–1.81 (m,

2H), 1.67 (brs, 3H), 1.51 (ddd, J=14.0, 9.2, 2.2 Hz, 1H), 1.13 (ddd, J=

14.0, 9.4, 2.6 Hz, 1H), 0.86 ppm (d, J=6.4 Hz, 3H); ¹³C NMR (150 MHz,

CDCl₃): d=165.5 (C_q), 145.0 (C_q), 143.2 (CH), 134.1 (CH), 131.5 (C_q),

128.3 (CH), 125.9 (CH), 125.7 (CH), 123.1 (CH), 119.9 (CH), 113.8

(CH₂), 81.6 (CH), 78.2 (CH), 76.8 (CH), 74.6 (CH), 73.5 (CH), 73.0

(CH), 70.6 (CH), 66.9 (CH), 65.6 (CH₂), 45.7 (CH₂), 43.0 (CH₂), 36.0

(CH₂), 35.7 (CH₂), 35.5 (CH₂), 34.7 (CH₂), 31.9 (CH₂), 27.5 (CH), 23.1

0.0489 mmol) in THF (1.5 mL) at ꢀ788C was added nBuLi (0.122 mL,

0.195 mmol, 1.6m in hexane) dropwise over a period of 5 min. The bright

yellow solution was stirred for 5 min and then CO₂(g) was bubbled

through the reaction for 15 min. The reaction was warmed to RT,

quenched by addition of aq. sat. NH₄Cl (7 mL) and diluted with CH₂Cl₂

(10 mL), the phases were separated and the aqueous phase was extracted

four times with CH₂Cl₂. The combined organic phase was dried over

magnesium sulfate, filtered and the solvent was removed under vacuum.

The obtained oil was purified by column chromatography (silica gel,

CH₂Cl₂/MeOH 6:1), yielding compound 61 as viscous oil (32 mg,

0.0421 mmol, 86%). [a]²_D⁰=ꢀ37.8 (c=0.88 in CH₂Cl₂); ¹H NMR

(400 MHz, CDCl₃): d=5.93–5.82 (m, 4H), 5.40 (brs, 1H), 4.84 (brs, 1H),

4.80 (brs, 1H), 4.37–4.27 (m, 4H), 4.20 (brs, 2H), 4.11–4.05 (m, 1H),

3.96–3.90 (m, 1H), 3.82 (brd, J=3.9 Hz, 1H), 3.87–3.70 (m, 1H), 2.57

(dd, J=16.3, 5.8 Hz, 1H), 2.48 (dd, J=16.3, 7.9 Hz, 1H), 2.24–1.94 (m,

8H), 1.94–1.79 (m, 4H), 1.69 (brs, 3H), 1.67–1.08 (m, 1H), 1.16–1.08 (m,

1H), 0.91–0.86 (m, 21H), 0.11 (s, 3H), 0.05 (s, 6H), 0.02 ppm (s, 3H);

¹³C NMR (100 MHz, CDCl₃): d=160.1 (C_q), 144.7 (C_q), 134.1 (CH), 131.5

(C_q), 128.2 (2ꢄCH), 125.8 (CH), 119.7 (CH), 114.4 (CH₂), 88.6 (C_q), 82.8

(CH), 78.3 (CH), 78.1 (CH), 74.8 (CH), 74.0 (CH), 73.1 (C_q), 73.7(CH),

70.4 (CH), 66.4 (CH), 65.8 (CH₂), 45.2 (CH₂), 42.5 (CH₂), 37.5 (CH₂),

37.5 (CH₂), 31.6 (CH₂), 29.9 (CH₂), 27.2 (CH), 26.3 (6ꢄCH₃), 24.9 (CH₂),

23.1 (CH₃), 19.6 (CH₃), 18.4 (C_q), 18.3 (C_q), ꢀ3.7 (CH₃), ꢀ3.9 (CH₃),

ꢀ4.5 (CH₃), ꢀ4.6 ppm (CH₃); IR (film): n˜ =2929, 2857, 1580, 1388, 1254,

1046, 835, 777 cm^ꢀ1; HRMS(EI): m/z: calcd for C₄₂H₇₀O₈Si₂Na: 781.4507,

found: 781.4519.

(CH₃), 19.9 ppm (CH₃); IR (film): n˜ =3425, 2917, 1713, 1644, 1033 cm^ꢀ1

HRMS(EI): m/z: calcd for C₃₀H₄₂O₇: 514.2931, found: 514.2922.

;

Macrolactone 63: To

0.0198 mmol) in benzene (1 mL) at RT was added Et₃N (8.2 mL,

0.0812 mmol) and dropwise 2,4,6-trichlorobenzoyl chloride (7.6 mL,

a stirred solution of seco acid 61 (15.0 mg,

Cytotoxicity assay (Table 1): The MCF-7 (breast cancer), HCT116 (colon

carcinoma) and PC-3m (prostate cancer) cell lines originate from the

American Type Culture (ATCC) and were obtained as a generous gift

Chem. Eur. J. 2009, 15, 5979 – 5997

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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5995

J. Mulzer, A. Gollner et al.

from Markus Wartmann, Novartis AG, Switzerland. Cells were seeded at

1.5ꢄ10³per well into 96-well microtiter plates and incubated overnight.

Compounds were added in serial dilutions on day 1. Subsequently, the

plates were incubated for 72 h and then fixed with 3.3% v/v glutaralde-

hyde, washed with water and stained with 0.05% methylene blue. After

washing, the dye was eluted with 3% v/v HCl and the optical density

measured at 665 nm with a GeniosPro photometer (Tecan, Switzerland).

IC₅₀values were determined by the GraphPad Prim software (San Diego,

USA) using the formula (OD_treatedꢀOD_start)/(OD_controlꢀOD_start)ꢄ100. IC₅₀

is defined as the drug concentration which leads to 50% of cells per well

as compared to control cultures (100%) at the end of the incubation

period. Experiments were performed three times on different days.

[4] a) J. Liu, M. J. Towle, H. Cheng, P. Saxton, C. Reardon, J. Wu, E. A.

Murphy, G. Kuznetsov, C. W. Johannes, M. R. Tremblay, H. Zhao,

M. Pesant, F. G. Fang, M. W. Vermeulen, B. M. Gallagher, Jr., B. A.

Littlefield, Anticancer Res. 2007, 27, 1509–1518; b) T. A. Johnson,

K. Tenney, R. H. Cichewicz, B. I. Morinaka, K. N. White, T. Amaga-

ta, B. Subramanian, J. Media, S. L. Mooberry, F. A. Valeriote, P.

Crews, J. Med. Chem. 2007 , 50 , 379 5 –3 803.

[5] Total synthesis of 1: a) A. K. Ghosh, Y. Wang, J. Am. Chem. Soc.

2000 , 122 , 1102 7 –1 1028; b) A. K. Ghosh, Y. Wang, J. T. Kim, J. Org.

Chem. 2001 , 66 , 897 3 –8 982; c) J. Mulzer, E. ꢆhler Angew. Chem.

2001, 113, 3961–3964; Angew. Chem. Int. Ed. 2001 , 40, 384 2 –3 846;

Angew. Chem. Int. Ed. 2001, 40, 3842–3846; d) I. Paterson, C.

De Savi, M. Tudge, Org. Lett. 2001 , 3 , 314 9 –3 152; e) J. Mulzer, V. S.

Enev, H. Kaehlig, J. Am. Chem. Soc. 2001, 123, 10764–10765;

f) P. A. Wender, S. G. Hegde, R. D. Hubbard, L. Zhang, J. Am.

Chem. Soc. 2002 , 124 , 495 6 –4 957; g) D. R. Williams, M. Liang, R. J.

Mullins, R. E. Stites, Tetrahedron Lett. 2002 , 43 , 484 1 –4 844; h) J.

Mulzer, A. Ahmed, E. K. Hoegenauer, V. S. Enev, M. Hanbauer, H.

Kaehlig, E. ꢆhler, J. Org. Chem. 2003, 68, 3026–3042; i) M. T. Crim-

mins, M. G. Stanton, S. P. Allen, J. Am. Chem. Soc. 2002 , 124 , 595 8 –

5959; j) S. G. Nelson, W. S. Cheung, A. J. Kassick, M. A. Hilfiker, J.

Am. Chem. Soc. 2003, 125, 13654–13655; k) B. M. Gallagher, Jr.,

F. G. Fang, C. W. Johannes, M. Pesant, M. R. Tremblay, H. Zhao, K.

Akasaka, X. Y. Li, J. Liu, B. A. Littlefield, Bioorg. Med. Chem. Lett.

2004, 14, 575–579; l) J. Uenishi, M. Ohmi, Angew. Chem. 2005 , 117 ,

281 6 –2 820; Angew. Chem. Int. Ed. 2005 , 44 , 275 6 –2 760. For a

review, see: m) J. Mulzer, E. ꢆhler, Chem. Rev. 2003, 80, 3753–

3786.

[6] Synthesis of analogues of 1: a) P. A. Wender, S. G. Hegde, R. D.

Hubbard, L. Zhang, S. L. Mooberry, Org. Lett. 2003 , 5 , 350 7 –3 509;

b) I. Paterson, H. Bergmann, D. Menche, A. Berkessel, Org. Lett.

2004 , 6 , 129 3 –1 295; c) S. L. Mooberry, D. A. Randall-Hlubek, R. M.

Leal, S. G. Hegde, R. D. Hubbard, L. Zhang, P. A. Wender, Proc.

Natl. Acad. Sci. USA 2004 , 101 , 880 3 –8 804; d) B. M. Gallagher Jr.,

H. Zhao, M. Pesant, F. G. Fang, Tetrahedron Lett. 2005 , 46 , 92 3 –

926; e) I. Paterson, D. Menche, A. E. Hakansson, A. Longstaff, D.

Wong, I. Barasoain, R. M. Buey, J. F. Diaz, Bioorg. Med. Chem.

Lett. 2005 , 15 , 224 3 –2 247; f) P. A. Wender, M. K. Hilinski, N. G. Sol-

dermann, S. L. Mooberry, Org. Lett. 2006 , 8 , 150 7 –1 510; g) P. A.

Wender, M. K. Hilinski, P. R. Skaanderup, N. G. Soldermann, S. L.

Mooberry, Org. Lett. 2006 , 8 , 410 5 –4 108; h) C. Faveau, M. Mondon,

J. P. Gesson, T. Mahnke, S. Gebhardt, U. Koert, Tetrahedron Lett.

2006 , 47 , 830 5 –8 308.

Tubulin polymerization assay (Table 2): Pure ab-tubulin (> 95%) was

isolated from fresh pig brain according to the method of Castoldi and

Popov with slight modifications as previously reported.^[24,25]For the tubu-

lin polymerization assays freshly thawed solutions of ab-tubulin in

BRB80 buffer (80 mm PIPES, 1 mm MgCl₂, 1 mm EGTA adjusted to pH

6.8 with KOH) were centrifuged at 5000 g for 5 min at 58C. This solution

was incubated with additional BRB80 and test compounds, as 2 mm

DMSO solutions, were then added on ice. Experiments were carried out

in a 96-well quartz plate in 100 mL volumes at a concentration of 30 mm

tubulin and 30 mm test compound. The polymerization was monitored by

following the increase in absorption at 340 nm in a temperature-con-

trolled TECAN GeniosPro spectrophotometer at RT (actual measuring

temperature was 24–278C). The concentration of DMSO used in the

polymerization experiments was found to be highly critical; concentra-

tions >2% DMSO induced considerable microtubule formation even in

the absence of test compounds. All experiments, along with both negative

(untreated ab-tubulin) and vehicle (DMSO) controls, were carried out in

triplicate. The maximal polymerization for each compound was deter-

mined using the GraphPad Prim software (San Diego, USA) and the

EC₅₀(half maximal effective concentration) values were calculated from

the concentration-effect curve. Experiments were performed with at least

two different ab-tubulin batches.

Acknowledgements

We gratefully acknowledge financial support from The Austrian Science

Fund (FWF project L202-N19). We thank Dr. H. Kꢀhlig, Dr. L. Brecker

and S. Felsinger, Universitꢀt Wien, for NMR spectra, M. Zinke and S.

Schneider, Universitꢀt Wien, for HPLC analysis and M. Wartmann, No-

vartis AG, Switzerland, for donation of the cell lines for the cytotoxicity

assays.

[7] A. Gollner, J. Mulzer, Org. Lett. 2008 , 10 , 470 1 –4 704.

[8] a) P. R. Blakemore, W. J. Cole, P. J. Kocienski, P. J. Morley, Synlett

1998 , 2 6 –2 8; For a review, see: b) P. R. Blakemore, J. Chem. Soc.

Perkin Trans. 1 2002 , 256 3 –2 585.

[9] D. A. Evans, S. L. Bender, J. Morris, J. Am. Chem. Soc. 1988 , 110 ,

250 6 –2 526.

[10] H. C. Brown, P. K. Jadhav, K. S. Bhat, T. Perumal, J. Org. Chem.

1986, 51, 432–439.

[1] a) E. Quinoa, Y. Kakou, P. Crews, J. Org. Chem. 1988 , 53 , 364 2 –

3644; b) D. G. Corley, R. Herb, R. E. Moore, P. J. Scheuer, V. J.

Paul, J. Org. Chem. 1988 , 53 , 364 4 –3 646; c) T. Higa, J.-i. Tanaka, G.

Bernardinelli, C. W. Jefford, Chem. Lett. 1996, 255–256; d) T. Higa,

J.-i. Tanaka, D. Garcia Gravalos, WO 9710242, 1997; e) T. A. John-

son, K. Tenney, R. H. Cichewicz, B. I. Morinaka, K. N. White, T.

Amagata, B. Subramanian, J. Media, S. L. Mooberry, F. A. Valeriote,

P. Crews, J. Med. Chem. 2007 , 50 , 379 5 –3 803.

[11] For reviews, see: a) R. H. Grubbs, S. Chang, Tetrahedron 1998 , 54 ,

441 3 –4 450; b) S. K. Armstrong, J. Chem. Soc. Perkin Trans. 1 1998,

371–388; c) A. Fꢁrstner, Angew. Chem. 2000 , 112 , 314 0 –3 172;

Angew. Chem. Int. Ed. 2000 , 39 , 301 2 –3 043; d) R. H. Grubbs, T. M.

Trinka, Acc. Chem. Res. 2001, 34, 18–29.

[12] S. Saito, T. Ishikawa, A. Kurada, K. Koga, T. Moriwake, Tetrahedron

1992 , 48 , 406 7 –4 086.

[2] a) S. L. Mooberry, G. Tien, A. H. Hernandez, A. Plubrukarn, B. S.

Davidson, Cancer Res. 1999, 59, 653–660; b) review: B. M. Galla-

gher, Jr., Curr. Med. Chem. 2007, 14, 2959–2967.

[13] a) O. G. Kulinkovich, Y. Y. Kozyrkov, A. V. Bekish, E. A. Matiush-

enkov, I. L. Lysenko, Synthesis 2005 , 171 3 –1 717; For reviews, see:

b) O. G. Kulinkovich, A. de Meijere, Chem. Rev. 2000 , 100 , 278 9 –

2834; c) O. G. Kulinkovich, Chem. Rev. 2003 , 103 , 259 7 –2 632.

[14] a) B. Wilk, Synth. Commun. 1993 , 23 , 2481; b) T. Tsunoda, K.

Uemoto, C. Nagino, M. Kawamura, H. Kaku, S. Ito, Tetrahedron

Lett. 1999 , 40 , 7355.

[15] a) S. Ohira, Synth. Commun. 1989 , 19 , 56 1 –5 64; b) H. J. Bestmann,

S. Mꢁller, B. Liepold, G. J. Roth, Synlett 1996, 521–522; c) G. J.

Roth, B. Liepold, S. G. Mꢁller, H. J. Bestmann, Synthesis 2004 , 5 9 –

62.

[3] a) D. E. Pryor, A. OꢅBrate, G. Bilcer, J. F. Diaz, Y. F. Wang, Y.

Wang, M. Kabaki, M. K. Jung, J. M. Andreu, A. K. Ghosh, P. Gian-

nakakou, E. Hamel, Biochemistry 2002 , 41 , 910 9 –9 115; b) T. N. Gai-

tanos, R. M. Buey, F. J. Diaz, P. T. Northcote, P. Teesdale-Spittle,

J. M. Andreu, J. H. Miller, Cancer Res. 2004 , 64 , 506 3 –5 067; c) E.

Hamel, B. W. Day, J. H. Miller, K. M. Jung, P. T. Northcote, A. K.

Ghosh, P. D. Curran, M. Cushman, K. C. Nicolaou, I. Paterson, E. J.

Sorensen, Mol. Pharmacol. 2006 , 70 , 155 5 –1 564; d) E. J. Gapud, R.

Bai, A. K. Ghosh, E. Hamel, Pharmacology 2004, 66, 113–121.

5996

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 5979 – 5997

The Laulimalide Family

FULL PAPER

[16] J. L. Luche, J. Am. Chem. Soc. 1978 , 100 , 222 6 –2 227.

[17] S. H. Kang, S. Y. Kang, H.-w. Choi, C. M. Kim, H.-S. Jun, J.-H.

Youn, Synthesis 2004 , 110 2 –1 114.

[18] For reviews, see: a) A. Fꢁrstner, P. W. Davies, Chem. Commun.

2005 , 230 7 –2 320; b) W. Zhang, J. S. Moore, Adv. Synth. Catal. 2007,

93–120.

[22] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.

Chem. Soc. Jpn. 1979 , 52 , 198 9 –1 993; b) H. Tone, T. Nishi, Y.

Oikawa, M. Hikota, O. Yonemitsu, Tetrahedron Lett. 1987 , 28 ,

456 9 –4 572.

[23] For a review, see: A. Parenty, X. Moreau, J.-M. Campagne, Chem.

Rev. 2006, 83, 911–939.

[19] J. H. Wengrovius, J. Sancho, R. R. Schrock, J. Am. Chem. Soc. 1981 ,

103 , 393 2 –3 934. For a review, see: R. R. Schrock, Chem. Rev. 2002,

79, 145–179.

[24] M. Castoldi, A. V. Popov, Protein Expression Purif. 2003 , 32 , 8 3 –8 8.

[25] J. Gertsch, S. Meier, M. Mꢁller, K.-H. Altmann, ChemBioChem

2009 , 10 , 16 6 –1 75.

[20] We tried different solvents (PhH, PhMe) combined with variation of

the temperature (RT to reflux) for RCAM.

[21] A. Fꢁrstner, O. Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999 ,

121 , 1110 8 –1 1113.

Received: December 11, 2008

Published online: April 28, 2009

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Article Doi

The laulimalide family: Total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue

DOI: 10.1002/chem.200802605

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