A concise sultone route to highly oxygenated 1,10-seco-eudesmanolides - enantioselective total synthesis of the antileukemic sesquiterpene lactones (-)-eriolanin and (-)-eriolangin

FULL PAPER

DOI: 10.1002/ejoc.200500739

A Concise Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides –

Enantioselective Total Synthesis of the Antileukemic Sesquiterpene Lactones

(–)-Eriolanin and (–)-Eriolangin

Jörn Merten,^[a]André Hennig,^[a]Pia Schwab,^[a][‡]Roland Fröhlich,^[b][‡]Sergey V. Tokalov,^[c]

Herwig O. Gutzeit,^[c]and Peter Metz*^[a]

Dedicated to Professor Günter Domschke on the occasion of his 75th birthday

Keywords: Antitumor agents / Domino reactions / Sulfur heterocycles / Terpenoids / Total synthesis

Using a sultone as the key intermediate, the first enantiose- generate the common basic structure and two additional

lective total synthesis of the antileukemic 1,10-seco-eudes-

manolides (–)-eriolanin (1) and (–)-eriolangin (2) was

achieved, which also established the hitherto unknown abso-

lute configuration of these sesquiterpene lactones. Starting

from 2-bromo-1-(2-furyl)ethanone, 24 steps were required to

steps in each case for completion of the natural products. The

effect of 1 and 2 on the cell cycle of human leukemia (HL-

60) cells was investigated by flow cytometry.

Germany, 2006)

Introduction

Eriolanin (1) and eriolangin (2) isolated from the plant

Eriophyllum lanatum^[1]are highly oxygenated members of

the 1,10-seco-eudesmanolide family of sesquiterpene lac-

tones, which also includes the britannilactones 3a–c^[2,3]and

ivangulin (4)^[4](Figure 1). For lactones 1–3, interesting bio-

activities have been reported. Thus, 1 and 2 inhibit the in

vitro growth of the human KB tumor cell line and addition-

ally display a significant antileukemic activity in vivo in

mice.^[1]Likewise, compounds 3 have been shown to be cyto-

toxic in cancer cells.^[5]Moreover, 3b inhibits inducible nitric

oxide synthase,^[6]and 3c effects cell cycle arrest at the

G₂+M phase as well as polymerization of microtubules.^[5b]

The constitution and relative configuration of the 1,10-

seco-eudesmanolides 1 and 2 was elucidated by NMR tech-

niques and X-ray analysis^[1]and confirmed by several syn-

theses of racemic 1^[7,8]and one of racemic 2,^[7]whereas the

[a] Institut für Organische Chemie, Technische Universität

Dresden,

Bergstr. 66, 01069 Dresden, Germany

Fax: +49-351-463-33162

E-mail: peter.metz@chemie.tu-dresden.de

[b] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-

versität Münster,

Figure 1. Representatives of the 1,10-seco-eudesmanolides.

Corrensstr. 40, 48149 Münster, Germany

Fax: +49-251-833-9772

absolute configuration of these compounds was unknown

prior to our work. Herein we give a full account of our

sultone approach^[9]culminating in the first enantioselective

total synthesis^[10]of (–)-eriolanin (1) and (–)-eriolangin (2)

that also opens a synthetic access toward the less highly

E-mail: frohlic@nwz.uni-muenster.de

[c] Institut für Zoologie, Technische Universität Dresden,

Zellescher Weg 19, 01069 Dresden, Germany

Fax: +49-351-463-37093

E-mail: Herwig.Gutzeit@mailbox.tu-dresden.de

[‡] X-ray diffraction analysis

1144

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

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oxygenated, cytotoxic britannilactone (3a) and its deriva- ran 11^[13](Scheme 2). To this end, we subjected the α-bromo

tives 3b,c. Furthermore, we disclose our investigations on ketone 8^[14]to a catalytic enantioselective transfer hydro-

the effects of 1 and 2 on the cell cycle of human leukemia genation under conditions modified from those reported for

(HL-60) cells by flow cytometry.

α-chloro ketone derivatives.^[15]The resulting bromohydrin 9

was obtained in excellent optical purity (Ͼ99% ee accord-

ing to capillary GC) and delivered the highly sensitive epox-

ide 10 after mild basic treatment. As already reported for

the racemic series,^[16]ring opening of 10 with methylmagne-

sium bromide or methylcyanocuprate took place with good

(MeMgBr: 10:1) to complete [MeCu(CN)Li] regioselectivity

at the sterically more hindered position to give a primary

alcohol. The stereochemical course, however, was strongly

dependent on the nature of the methyl nucleophile. While

the reaction proceeded with extensive racemization (Ͻ20%

ee according to capillary GC) in case of methylmagnesium

bromide, complete inversion of configuration to give 11 was

observed for the less Lewis acidic cyanocuprate. Subsequent

treatment of 11 with β-chloroethanesulfonic acid chlo-

ride^[17]and triethylamine triggered a domino process con-

sisting of dehydrohalogenation, esterification, and intra-

molecular Diels–Alder reaction to afford a mixture of the

exo sultones 7a and 7b. Following thermal equilibration,^[11]

the required diastereomer 7a was isolated in excellent yield

by recrystallization.

Results and Discussion

Synthetic Plan

According to our synthetic plan, both target molecules 1

and 2 would be derived from the common alcohol precur-

sor 5 and thus, their syntheses would differ only in the

penultimate esterification step (Scheme 1). Further retro-

synthetic disconnection of 5 leads to the highly function-

alized methylenecyclohexene 6 revealing three major tasks:

A) elongation of the side chain by a C₂unit, B) generation

of the enediol fragment with correct configuration at C6

(eudesmane numbering) from a semicyclic 1,3-diene sub-

unit, and C) construction of the γ-lactone moiety by elabo-

ration of the latent 1,4-diol already present in 6. The key

intermediate 6 was envisioned to be accessible from the sul-

tone 7a, the racemic mixture of which already enabled a

short and highly diastereoselective synthesis of the 1,10-

seco-eudesmanolide ivangulin 4,^[11]through a one-pot elimi-

nation/alkoxide-directed 1,6-addition/desulfurization with

simultaneous methylenation.^[12]

Scheme 2. Preparation of sultone 7a: a) 0.2 mol-%

[Cp*RhCl((R,R)-tsdpen)], HCO₂H, Et₃N, EtOAc, 0 °C, Ͼ99% ee;

b) K₂CO₃, MeCN, room temp.; c) MeCu(CN)Li, Et₂O, –78 °C to

room temp., 50% (3 steps), Ͼ98.5% ee; d) β-chloroethanesulfonic

acid chloride, Et₃N, CH₂Cl₂, room temp.; e) cat. BHT, EtOAc,

120 °C, microwaves, 80% 7a (2 steps).

Synthesis of the Cyclohexene Core

The one-pot sequential transformation^[12]of the sultone

7a to the methylenecyclohexene 6 was initiated by depro-

tonation of 7a using one equivalent of methyllithium to

bring about cleavage of the oxo bridge by β-elimination

with formation of the intermediate 12 (Scheme 3). This elec-

tron-deficient 1,3-diene underwent a completely regio- and

diastereoselective alkoxide-directed 1,6-addition upon treat-

ment with the lithiosilane 18 prepared by reductive lithi-

ation of the thio ether 17,^[18]which in turn was derived from

the vinylsilane 16^[19]through radical addition^[20]of thio-

Scheme 1. Retrosynthetic analysis for eriolanin (1) and eriolangin

(2).

Synthesis of Enantiopure Sultone 7a

Initially, we focused on the development of a multi-gram- phenol. The resulting allyllithium species 13 was then re-

scale synthesis of the enantiomerically pure hydroxyalkylfu- gioselectively alkylated using (iodomethyl)magnesium chlo-

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Scheme 3. Sequential one-pot transformation of the sultone 7a to the methylenecyclohexene 6: a) (i) MeLi, THF, –78 °C, (ii) 18, –78 °C

to –20 °C, (iii) ICH₂MgCl, THF, –78 °C to room temp., 61%; b) PhMgBr, THF, reflux, 83%; c) PhSH, AIBN, 100 °C, 87%; d) LiDBB,

THF, –78 °C.

ride^[21]to furnish the β-metallosultone 14, which upon tion in solution similar to the crystal structure of the corre-

warming to room temperature collapsed by β-elimination sponding diol 6 (Figure 2), this selectivity is readily under-

with rupture of the δ-sultone to give the methylenecyclohex- stood. Due to minimization of A^1,3strain, the hydrogen

ene 6 in good yield. In a single synthetic operation, the atom at C4 points toward the exo methylene unit, which

prefunctions for a γ-lactone were unfolded, an activation forces the hydroxymethyl group up to deliver the epoxid-

for 1,4-dioxygenation was created by virtue of the 1,3-diene, ation reagent from the top face. The relative configuration

and the primary hydroxy group was liberated for side-chain of the epoxide 21 was clearly revealed by a 2D NOESY

elongation. At this stage, both the relative and absolute investigation (strong NOEs between C6-H and C7-H and

configuration of compound 6 were determined by X-ray between C6-H and C15-H₃). Whereas efforts to generate an

diffraction analysis using anomalous scattering (Fig- enediol fragment through S_N2Ј ring opening of the vinyl

ure 2).^[22,23]

Figure 2. Crystal structure of the methylenecyclohexene 6.^[22,23]

1,4-Difunctionalization, Part I

Our first attempts to eventually 1,4-dioxygenate the 1,3-

diene moiety of 6 are depicted in Scheme 4. Conversion of 6

to the bis(silyl) ether 19 followed by chemoselective mono-

deprotection furnished the primary alcohol 20. The array

of functional groups present in 20 appeared to provide an

ideal basis for a chemoselective hydroxy-directed epoxid-

ation^[24]of the more electron-rich endocyclic double bond

trans to the substituents on the six-membered ring. Unfor-

Scheme 4. 1,4-Difunctionalization of the 1,3-diene subunit, part I:

a) TBSCl, imidazole, DMAP, DMF, room temp., 99%; b) TBAF,

THF, 0 °C, 81% 20 + 17% 6; c) mCPBA, NaHCO₃, CH₂Cl₂, H₂O,

0 °C; d) TBSCl, imidazole, DMAP, CH₂Cl₂, 0 °C; e) 23, THF,

tunately, the undesired diastereomer 21 was always the

major product. Using m-chloroperbenzoic acid,^[25]com-

pound 21 was obtained as a single regio- and stereoisomer

in quantitative yield. If the alcohol 20 adopts a conforma- Et₂O, –20 °C to 0 °C, 50% (3 steps).

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

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epoxide with oxygen nucleophiles met with failure in our this stage, we opted for generation of the enediol prior to

hands,^[7]this mode of attack was accomplished in the reac- setting up the γ-lactone.

tion of the silyl ether 22 with the silicon nucleophile 23 as

a latent hydroxy anion equivalent.^[26]However, experiments

1,4-Difunctionalization, Part II

to amend the configuration at C6 of the resulting allylsilane

24 by Mitsunobu inversion^[27]failed and additionally re-

vealed an extreme sensitivity of 24 toward acid-triggered

elimination with reformation of the 1,3-diene 19. Because

of this instability and the chemoselectivity problems that

might be encountered after Tamao–Fleming oxidation of

both carbon–silicon bonds in 24,^[28]we decided to elongate

the side chain before taking care of the enediol.

An intramolecular protocol was eventually decisive for

the efficient generation of the enediol fragment of the target

molecules (Scheme 6). Encouraged by reports of Rousseau

on the facile iodolactonization of ω-heptenoic acids to give

ε-lactones,^[35]we envisioned an access to the enediol subunit

through such a cyclofunctionalization of the dienylcarbox-

ylic acid 33 and subsequent iodine–acyloxy exchange. To

this end, the methyl ester 28 was saponified, and the re-

sulting acid 33 was treated with bis(s-collidine)iodine()

hexafluorophosphate^[35]in toluene as the solvent of choice,

whereupon the unstable iodolactone 34 along with small

amounts of the regioisomer 35 were formed. Addition of

Side-Chain Elongation and Construction of the γ-Lactone

Moiety

For side-chain elongation, we applied a strategy similar silver acetate and dimethylformamide^[36]to this reaction

to the one used in our synthesis of ivangulin (4) mixture selectively converted 34 to the formyloxy ε-lactone

(Scheme 5).^[11]After conversion^[29]of the alcohol 20 to the 36 in a one-pot procedure, whereas the minor isomer 35

iodide 25, the required C₂unit was attached by alkylation proved to be completely unreactive under these conditions

with dimethyl malonate. Since 25 was prone to undergo de- and could be reductively^[37]eliminated to return 33 in a

hydrohalogenation, utilization of proazaphosphatrane 26^[30]separate operation. Apparently, the intermediate allylcar-

was essential for efficient conversion to 27. Mild demeth- benium ion generated from the allylic iodide 34 is trapped

oxycarbonylation^[11,31]of 27 followed by reduction and pro- by the solvent dimethylformamide as the nucleophile to give

tection afforded the MOM ether 30. For construction of an iminium ion, which is converted into the formate 36 dur-

the γ-lactone moiety, we took full advantage of the Tamao– ing aqueous workup. In line with this rationale, exchange

Fleming oxidation,^[28,32]which smoothly delivered the diol of dimethylformamide against acetonitrile^[36]did not allow

31. Addition of molecular sieves (4 Å) in the first step conversion of 34. Replacement of the formylation of 34 by

caused a significant increase in yield, presumably due to reductive deiodination^[38,39]should allow a straightforward

enhancing the reactivity of tetrabutylammonium fluoride. access to britannilactone (3a) and its derivatives 3b,c. The

Subsequent chemoselective oxidative ring closure of 31 to relative configuration of 36 was elucidated by 2D NOESY

give the lactone 32 proved to be unexpectedly difficult, and investigations at the stage of iodolactone 34 isolated on an

only ultrasound-accelerated^[33]TPAP oxidation^[34]led to an analytical scale prior to addition of silver acetate and di-

acceptable yield of 32. Unfortunately, attempted 1,4-dioxy- methylformamide in the racemic series (strong NOEs be-

genation of the 1,3-diene subunit of 32 by epoxidation fol- tween C6-H and C7-H and between C6-H and C15-H₃).

lowed by S_N2Ј ring opening led to complex mixtures of re- Likewise, the relative configuration of the iodolactone 35

gio- and diastereoisomers. Due to the lack of selectivity at was determined by 2D NOESY experiments (strong NOEs

Scheme 5. Side-chain elongation and synthesis of the lactone 32: a) I₂, Ph₃P, imidazole, THF, MeCN, –20 °C to room temp., 84%; b) 26,

dimethyl malonate, MeCN, room temp., 91%; c) PhSH, K₂CO₃, DMF, 90 °C, 89%; d) LiAlH₄, Et₂O, 0 °C, 100%; e) MOMCl,

Et(iPr)₂N, CH₂Cl₂, 0 °C to room temp., 99%; f) (i) TBAF, MS (4 Å), THF, reflux, (ii) KF, H₂O₂, NaHCO₃, THF, MeOH, reflux, 87%;

g) 10 mol-% TPAP, NMO, MS (4 Å), MeCN, 15 °C to 20 °C, ultrasound, 65%.

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between C14-H_aand C7-H and between C14-H_aand C8- 38. While this reaction sequence effected a rapid construc-

H). Reduction of the diester 36 with lithium aluminum hy- tion of the enediol moiety, the undesired configuration at

dride at 0 °C smoothly gave a hydroxy lactol after aqueous C6 set up in the iodolactonization event had to be corrected

workup. Because increasing the reaction temperature in or- subsequently.

der to achieve complete reduction of 36 caused desilylation

of the secondary alcohol, the hydroxy lactol was further

reduced with lithium borohydride to afford the triol 37 in

Completion of the Bicyclic Framework

excellent overall yield. Chemoselective tritylation of the two

Because experiments toward Mitsunobu inversion at C6

primary alcohols in 37 cleanly afforded the bis(trityl) ether

in 38 were not successful, presumably due to steric reasons,

we tried to assemble the sterically less demanding γ-lactone

subunit prior to inversion. Deprotection of 38 gave the diol

39, which was subsequently transformed to the triol 40 by a

modified Tamao–Fleming oxidation (Scheme 7). However,

TEMPO oxidation of 40 utilizing N-chlorosuccinimide as

the cooxidant under biphasic conditions^[40]afforded exclu-

sively the undesired γ-lactone 41. Finally, correction of the

configuration at C6 was cleanly achieved by an oxidation/

reduction strategy. Dess–Martin oxidation^[41]of 38 to give

the enone 42 followed by desilylation under mild condi-

tions^[42]in order to avoid base- or acid-promoted degrada-

tion led to the β-hydroxy ketone 43. Hydroxy-directed^[24]

reduction of 43 with the sodium aluminum dihydride Red-

Al furnished the desired 6α allyl alcohol 44 with excellent

diastereoselectivity (dr = 24:1). Exposure of this compound

to the modified Tamao–Fleming oxidation conditions fur-

nished the triol 45 featuring the completely oxygenated skel-

eton of the target molecules with correct configuration at

all stereogenic centers. To our delight, chemoselective oxi-

dation^[43]of the triol 45 efficiently provided the requisite

hydroxy γ-lactone 46.

Scheme 6. 1,4-Difunctionalization, part II: a) KOH, MeOH, H₂O,

reflux, 100%; b) (i) I(col)₂PF₆, PhMe, 0 °C, (ii) AgOAc, DMF,

Final Steps Toward the Target Molecules

PhMe, 0 °C to room temp., 67% 36 + 15% 35; c) zinc dust, HOAc,

The final stage of our route to 1 and 2 was initiated by

H₂O, THF, 0 °C to room temp., 86%; d) LiAlH₄, Et₂O, –10 °C to

protection of the secondary hydroxy group in 46 followed

by a one-step α-methylenation of the silyl ether 47 using

0 °C; e) LiBH₄, Et₂O, 0 °C to room temp., 91% (2 steps); f) TrCl,

DMAP, pyridine, CH₂Cl₂, room temp., 90%.

Scheme 7. Synthesis of lactone 41 and completion of the bicyclic framework 46: a) TBAF, HOAc, THF, room temp., 97%; b) (i) TBAF,

MS (4 Å), THF, 100 °C, sealed tube, (ii) KF, H₂O₂, NaHCO₃, THF, MeOH, 100 °C, sealed tube, 88%; c) cat. TEMPO, NCS, TBACl,

K₂CO₃, NaHCO₃, CH₂Cl₂, H₂O, room temp., 84%; d) Dess–Martin periodinane, pyridine, CH₂Cl₂, room temp., 99%; e) TBAF, HOAc,

THF, room temp., 96%; f) Red-Al, CH₂Cl₂, PhMe, –20 °C to room temp., 90%; g) (i) TBAF, MS (4 Å), THF, reflux, (ii) KF, H₂O₂,

NaHCO₃, THF, MeOH, reflux, 99%; h) cat. TEMPO, bis(acetoxy)iodobenzene, CH₂Cl₂, room temp., 75%.

1148

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

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sodium hydride and paraformaldehyde (Scheme 8).^[44]After tical to the natural product by comparison of spectral^[7]and

desilylation, the lactone 5a, the common alcohol precursor optical rotation data.^[1]Thus, our synthesis of 1 and 2 also

to both target esters 1 and 2, was isolated in good overall clarifies the previously unknown absolute configuration of

yield. Preparation^[7]of the methacrylate 48 as well as detri- these sesquiterpene lactones, because the absolute configu-

tylation to give 1 proceeded uneventfully and delivered (–)- ration of the hydroxyalkylfuran 11 was unambiguously es-

eriolanin, which proved to be identical to the natural prod- tablished.^[13]In addition, X-ray diffraction analyses of 6

uct by comparison of spectral^[7]and optical rotation data.^[1](Figure 2) and our synthetic product 1 (Figure 3)^[10]pro-

Using a modified Yamaguchi esterification,^[45]the lactone vided further independent prove of the absolute configura-

5a could be smoothly transformed to angelate 49 without tion by anomalous X-ray scattering.

Z/E isomerization.^[7]Deblocking to give compound 2 deliv-

ered (–)-eriolangin, which likewise turned out to be iden-

Biological Investigations

We examined the effect of (–)-eriolanin (1), (–)-eriolangin

(2) and, as a reference, the compound taxol on the cell cycle

of human leukemia (HL-60) cells in vitro. This cell line was

chosen because it is well characterized and gives a rather

uniform response to distinct apoptotic stimuli.^[46–48]

Apoptosis can conveniently be quantified by flow cyto-

metry. The criteria used (sub-G₁DNA content) was shown

previously to reflect the apoptotic process as determined

with other genetic or biochemical methods.^[49,50]After

staining with propidium iodide (PI), the fractions of cells

in different phases of the cell cycle (G₀₊₁, S and G₂+M

phases) were quantified and populations of proliferating,

arrested and apoptotic cells distinguished (Figure 4). In

control cultures the fraction of apoptotic cells is low and

was determined to be 4 2% (Table 1).

Cell cultures were incubated in parallel with different

concentrations of the test compounds for 1, 2, and 4 days.

After 1 day of incubation, the reference compound taxol

produced, as expected, a cell cycle arrest at the G₂+M

stage^[51]at all concentrations tested (66 3% for 0.01 µ,

83 5% for 0.1 µ and 94 4 for 1.0 µ, p Ͻ 0.05). When

the cells were exposed for 2 or 4 days to 0.1 µ taxol, the

cells remained blocked (Figure 4, Table 1). At lower concen-

trations (0.01 µ), a large fraction of cells was released from

Scheme 8. Final steps of the synthesis of (–)-eriolanin (1) and (–)-

eriolangin (2): a) TMSCl, imidazole, CH₂Cl₂, room temp., 96%; b)

NaH, paraformaldehyde, THF, 100 °C, sealed tube; c) TBAF, THF,

0 °C, 61% (2 steps); d) methacrylic acid anhydride, Et₃N, DMAP,

THF, 0 °C to room temp., 85%; e) (i) angelic acid, 2,4,6-trichloro-

benzoyl chloride, Et₃N, PhMe, room temp., (ii) 5a, 100 °C, 60%; f)

cat. pTsOH, MeOH, room temp., 97% 1 from 48, 85% 2 from 49.

the block and became apoptotic thus producing a “tail” of

decreasing DNA content in two-dimensional plots (Fig-

ure 4). We have no evidence that the blocked cells reenter

the cell cycle during 4 days of culture and hence, all cells

in this tail were classified as apoptotic (Table 1). When the

substances (–)-eriolanin (1) or (–)-eriolangin (2) were tested

at low concentrations (0.1–10.0 µ), no significant effect

with reference to the control cultures was noticed (p Ͼ 0.05,

data not shown). At 30 µ concentration both compounds

produced a strong G₂+M block similar to taxol (Figure 4).

Already after 1 day culture a large fraction of cells was in

this phase (26 3% for 1 and 33 3% for 2, for both values

p Ͻ 0.05). However, a small fraction of cells escaped the

block and remained cycling. This effect was stronger for 1,

and after exposure for 4 days a prominent population of

cells was in the third or fourth round of cell division similar

to untreated control cultures (Figure 4). At intermediate

concentrations (20 µ), when the G₂+M block was incom-

plete and some cells continued cycling, the largest fraction

of apoptotic cells was observed (Table 1). At higher concen-

trations, the cell cycle block was more complete and fewer

cells could enter the apoptotic pathway.

Figure 3. Crystal structure of synthetic (–)-eriolanin (1).^[10,23]

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Figure 4. Effect of (–)-eriolanin (1), (–)-eriolangin (2), and taxol on cell proliferation: Asynchronously proliferating HL-60 cells were

stained with carboxyfluorescein diacetate succinimidyl ester (CFSE; area defined as division 0) and after 1 h treated with 1 and 2 (30 µmol/

L). An additional control culture was exposed to taxol in concentrations, which lead to cell cycle arrest at the G₂+M phase (0.01 and

0.1 µmol/L). After 1, 2, and 4 days, the cells were fixed, stained with propidium iodide (PI) and characterized by single-parameter (A:

PI) or by two-parameter analysis (B and C: PI/CFSE). Cycling cells of different cell generations (labeled 1–4) and arrested cells (delayed

at the position of the division 0) can be distinguished on the basis of their CFSE content. Furthermore, the presence of apoptotic cells

(hypodiploid, left of the dashed line in A–C) and the cell cycle phases can be quantified in the respective cell generations.

Table 1. Effect of (–)-eriolanin (1), (–)-eriolangin (2), and taxol on cell proliferation.

Test

substance Concentration Apoptotic cells Cycling cells

2 days after exposure^[a]

4 days after exposure^[a]

Arrested cells

[%]

Apoptotic cells

[%]

Cycling cells

[%]

Arrested cells

[%]

[µmol/L]

[%]

control

taxol

–

4

55

8

2

90

n.q.

84

80

50

24

11

86

70

26

16

5

6

3

4

80

8

2

94

n.q.

85

82

60

45

10

80

73

36

11

10

4

2

0.01

0.1

5

10

20

30

60

5

10

20

30

60

2

4

3

45

92

8

10

30

64

78

8

20

60

72

5

3

4

20

92

5

4

5

1

2

8

5

4

5

10

16

20

15

17

20

12

15

4

2

5

4

5

4

5

4

5

3

10

20

12

11

6

10

14

12

4

3

4

3

4

2

20

40

73

3

5

6

3

4

2

4

5

4

3

7

47

77

75

4

3

[a] The data show the effect of the test substances on the proliferation of HL-60 cells after exposure for 2 and 4 days (average standard

deviation of 4 independent experiments). Statistically significant differences (p Ͻ 0.05) to control cultures are printed in bold; n.q. = not

quantified (see text for explanation).

Conclusion

tone strategy applied, a rapid access to the key methylenecy-

clohexene 6 was achieved and thus, our route to 1 and 2

In conclusion, the first enantioselective total synthesis of requires only 26 steps from the α-bromo ketone 8. Average

the bioactive 1,10-seco-eudesmanolides (–)-eriolanin (1) yields of 87% for 1 and 86% for 2 highlight the efficacy of

and (–)-eriolangin (2) has been developed. Due to the sul- our approach as well as a novel one-pot iodolactonization–

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

FULL PAPER

and the pellet was resuspended in PBS (1.5 mL) at room tempera-

ture. After centrifugation, the cell pellet was resuspended in DNA

staining solution (1 mL) containing propidium iodide (PI; 50 µg/

mL; Sigma, Germany) and RNase (0.2 mg/mL; Sigma, Germany)

and incubated for at least 45 min at room temperature in the dark.

The same number of cells (5·10⁵) per sample was analyzed by flow

cytometry (CyFlow, Partec, Germany). The excitation wavelength

was 473 nm, and green (520 nm for CFSE) and red fluorescence

(Ͼ590 nm for PI) were recorded. For each variable (exposure con-

ditions, culture periods etc.) a minimum of 4 samples was quanti-

fied. The fraction of cells present in different cell generations, their

representation in the respective cell cycle phases, and percentage

of apoptotic cells were calculated using CyFlow software (Partec,

Germany).

formylation and a high-yielding modified Tamao–Fleming

oxidation. Using flow cytometry, both 1 and 2 were shown

to cause a strong G₂+M block in human leukemia (HL-60)

cells similar to taxol at 30 µ concentration. The selective

manipulation of the diverse hydroxy groups on the 1,10-

seco-eudesmanolide framework possible with our approach

offers great flexibility with respect to the assembly of syn-

thetic analogs. Along these lines, an enantioselective synthe-

sis of britannilactone (3a) and its derivatives 3b,c from

iodolactone 34 is currently under investigation.

Experimental Section

Bromohydrin 9. 1. Preparation of the [Cp*RhCl((R,R)-tsdpen)] Solu-

tion: (Pentamethylcyclopentadienyl)rhodium chloride dimer

(68.5 mg, 0.1 mol-%) and (1R,2R)-(–)-N-(p-tolylsulfonyl)-1,2-di-

phenylethylenediamine (82.3 mg, 0.2 mol-%) were stirred in a solu-

tion (1.5 mL) of Et₃N and HCO₂H [HCO₂H (4.45 mL, 118 mmol)

and Et₃N (14.45 mL, 148 mmol)] at room temperature for 45 min.

General Remarks: All reactions requiring exclusion of moisture

were run under argon using flame-dried glassware. Solvents were

dried by distillation from Na/K and benzophenone (THF), Na (tol-

uene), CaH₂(Et₂O, MeCN), or by passing through activated alu-

mina (CH₂Cl₂). All commercially available compounds were used

as received unless otherwise stated. Flash chromatography: Merck

silica gel 60 (40–63 µm). Thin layer chromatography: Merck silica

gel 60 F₂₅₄plates. Melting points: Kleinfeld Labortechnik Electro-

thermal IA 9100 apparatus. Chiral capillary GC: Shimadzu 9A GC

coupled with a Shimadzu C-R3A integrator and a Hydrodex^®-β-

6-TBDM column (25 m length, 0.25 mm i.d.). Optical rotation:

Perkin–Elmer 341 polarimeter, solvent: CHCl₃. ¹H and ¹³C NMR:

Bruker DRX-500 (¹H: 500 MHz, ¹³C: 126 MHz, calibrated to the

residual resonance of the solvent). FT-IR: Nicolet 205 and Nicolet

Avatar 360 spectrometer. Mass spectra: Hewlett–Packard 5890 GC

coupled with a Hewlett–Packard 5972 detector and Agilent 6890N

GC coupled with an Agilent 5973N detector (GC/MS); Bruker Es-

quire-LC (direct injection as a methanolic NH₄OAc solution,

CID). Exact mass: Finnigan MAT 95 (EI, 70 eV). Elemental analy-

sis: Carlo–Erba Instruments EA 1108 and Hekatech EA 3000. X-

ray: Bruker Kappa CCD diffractometer.

2. Transfer Hydrogenation: To a solution of the bromo ketone 8

(21.43 g, 114 mmol) in EtOAc (220 mL) was added the solution

of [Cp*RhCl((R,R)-tsdpen)] diluted with EtOAc (10 mL) at 0 °C

followed by addition of the remaining Et₃N/HCO₂H solution (de-

scribed above) within 60 min. The resultant solution was stirred

at 0 °C for 4 h, quenched with aqueous NaHCO₃(300 mL, 5%),

extracted with EtOAc (3×100 mL), washed with brine (100 mL),

and dried with MgSO₄. MgSO₄was separated by filtration through

a pad of silica gel followed by removal of the solvent and distil-

lation of the crude mixture in the dark, which gave 9 (15.2 g, ap-

prox. 70%) along with small amounts of inseparable impurities as

an extremely light-sensitive, colorless liquid. Attempts at further

purification by chromatography led to the decomposition of 9. R_f

= 0.44 (pentane/Et₂O, 2:1). b.p. 50–52 °C (2×10^–2mbar). Ͼ99% ee

1

(chiral GC, 110 °C, isothermal). H NMR (CDCl₃): δ = 2.54 (d, J

= 5.5 Hz, 1 H), 3.72 (dd, J = 6.8, 10.5 Hz, 1 H), 3.74 (dd, J = 4.8,

10.5 Hz, 1 H), 4.96 Hz (ddd, J = 5.5, 6.8, 4.8 Hz, 1 H), 6.38 (2 d,

2×J = 1.3 Hz, 2 H), 7.44 (dd, J = 1.3, 1.3 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃): δ = 36.66 (t), 67.74 (d), 107.46 (d), 110.42 (d), 142.53 (d),

152.78 (s) ppm.

Cell Culture and Analysis of Cell Cycle Effects by Flow Cytometry:

Acute myeloid leukemia cells (HL-60, DSMZ, Germany) were

maintained in RPMI 1640 medium with 10% heat-inactivated foe-

tal calf serum (Gibco, France). Cells were grown at 37 °C in humid-

ified 5% CO₂and maintained at a density of 2·10⁵–1·10⁶cells/mL.

Cell cultures (0.5·10⁶cells/mL, 10 mL per flask) were exposed for

1, 2, and 4 days to different concentrations of (–)-eriolanin (1) and

(–)-eriolangin (2) ranging from 0.1 µ to 60.0 µ. For comparison,

paclitaxel (“taxol”, from Taxus brevifolia, Sigma, Germany) was

used at concentrations of 0.01 µ, 0.1 µ, and 1.0 µ. The stock

solutions of the compounds were prepared in DMSO, and the final

concentration of DMSO in all cell cultures was adjusted to 0.1%.

The cells were characterized by flow cytometry using two criteria:

the DNA content by staining with propidium iodide (PI; Fluka,

Germany) and the fluorescence of the dye carboxyfluorescein di-

acetate succinimidyl ester (CFSE; Molecular Probes, Eugene, OR,

USA), which reacts with cellular proteins and allows to analyze the

dynamics of cell proliferation due to the decreasing fluorescent sig-

nal in successive cell generations. The technique has been applied

to HL-60 cells before.^[46]Briefly, HL-60 cells were stained with

10 µ CFSE in phosphate-buffered saline (PBS) for 10 min at

37 °C. The cells were washed with PBS, and culture medium was

added. After different incubation times (see results), cells were re-

moved from the culture, washed with PBS and centrifuged at 100 g

for 10 min. The cell pellet was resuspended in PBS (100 µL), fixed

in 70% (vol/vol) ethanol by adding cold (–20 °C) ethanol (1 mL)

and stored overnight at –20 °C. The cells were spun down again,

(R)-2-Oxiranylfuran (10): To a solution of the slightly impure bro-

mohydrin 9 (15.2 g) in MeCN (160 mL) was added K₂CO₃(22.0 g,

160 mmol). The mixture was vigorously stirred at room tempera-

ture for 14 h in the dark followed by filtration of the solid. The

solvent was evaporated at 30 °C to afford 10 (7.22 g, approx. 80%)

as an extremely light-, moisture-, and acid-sensitive red liquid in

approx. 90% purity (¹H NMR integration). For spectral data see

ref.^[52]

.

(S)-2-(Furan-2-yl)propan-1-ol (11): To a suspension of CuCN

(10.50 g, 117 mmol) in Et₂O (120 mL) was added MeLi (73 mL,

117 mmol, 1.6  in Et₂O) at –78 °C within 15 min. The mixture

was warmed to 0 °C and stirred until it turned to a black solution,

which was cooled again to –78 °C, and a solution of the crude

epoxide 10 (7.22 g, approx. 80%) in Et₂O (80 mL) was added over

30 min. The mixture was allowed to reach ambient temperature

overnight, carefully quenched with an aqueous buffer (300 mL,

satd. NH₄Cl/NH₃25%, 1:1) at 0 °C and extracted with Et₂O

(3×150 mL). The combined extracts were washed with brine

(100 mL), dried with MgSO₄, and after filtration and removal of

the solvent, the residue was purified by distillation to afford 11

(7.22 g, 50% from 8) as a colorless liquid. Ͼ98.5% ee (chiral GC,

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1151

P. Metz et al.

FULL PAPER

70 °C, isothermal). [α]²_D⁰= +20.6 (c = 0.99); ref.^[13][α]²_D⁵= +6.5 (c

3050, 2959, 1592, 1428, 1404, 1250, 1113, 1008, 953, 836, 818, 776,

731, 701 cm^–1. GC/MS: m/z (%) = 162 (25), 147 (100), 148 (15),

135 (26), 121 (56), 120 (4), 105 (23), 104 (21), 77 (20). C₁₀H₁₄Si

(162.30): calcd. C 74.00, H 8.69; found C 73.71, H 8.38.

= 1.00 in CHCl₃). For further data see ref.^[13]

.

Sultone 7a: To a solution of the alcohol 11 (13.4 g, 106.3 mmol)

and Et₃N (58.8 mL, 425 mmol) in CH₂Cl₂(1000 mL) was added

dropwise β-chloroethanesulfonic acid chloride (19.0 g, 117 mmol)

diluted with CH₂Cl₂(200 mL) at room temperature. The resultant

solution was stirred for 16 h at ambient temperature and heated

under reflux for 2 h. The reaction was quenched with H₂O

Dimethyl(phenyl)(2-phenylsulfanylethyl)silane (17): A mixture of the

vinylsilane 16 (13.0 g, 80.0 mmol), thiophenol (13.2 g, 132.2 mmol)

and a catalytic amount of AIBN was stirred at 100 °C for 24 h.

At room temperature the solution was diluted with Et₂O (30 mL),

(300 mL), extracted with CH₂Cl₂(3×100 mL), washed with brine extracted with aqueous KOH (45 mL, 2 ), washed with brine

(150 mL), dried with MgSO₄, and filtered through a pad of silica

gel. After evaporation of the solvent, the residue was dissolved in

a small amount of EtOAc, and 7a along with the diastereomer 7b

(21.5 g, 94%, dr = 1.4:1) were crystallized by addition of pentane.

To a solution of 7a and 7b (5.75 g, 26.6 mmol) in EtOAc (300 mL)

was added a small amount of BHT, and the solution was heated in

a sealed tube by microwaves to 120 °C (5 min Ǟ 120 °C, 120 °C for

30 min, 15 min Ǟ 20 °C). After removal of the solvent, the crude

product was suspended in Et₂O/pentane (300 mL, 1:1), stirred over-

night and filtered to afford 7a along with the diastereomer 7b

(5.70 g, 99%, dr = 6:1). Pure 7a was finally obtained by recrystalli-

zation from EtOAc. For collection of the analytical data, a sample

of both isomers was chromatographically separated (pentane/Et₂O/

(25 mL), and dried with MgSO₄. After filtration and evaporation

of the solvent, the crude product was purified by distillation to give

17 (19.0 g, 87%) as colorless crystals. B.p. 134 °C (4·10^–2mbar).

M.p. 36 °C. R_f= 0.13 (pentane/CH₂Cl₂, 9:1). ¹H NMR (CDCl₃): δ

= 0.20 (s, 6 H), 1.02–1.08 (m, 2 H), 2.79–2.84 (m, 2 H), 7.00–7.07

(m, 1 H), 7.13 (m, 4 H), 7.24–7.27 (m, 3 H), 7.36–7.39 (m, 2 H)

ppm. ¹³C NMR (CDCl₃): δ = –3.15 (q, 2 C), 16.11 (t), 29.28 (t),

125.66 (d), 127.89 (d, 2 C), 128.79 (d, 2 C), 128.95 (d, 2 C), 129.17

(d), 133.56 (d, 2 C), 136.89 (s), 138.00 (s) ppm. IR (neat): ν =

˜

3052, 3020, 2954, 1584, 1480, 1439, 1426, 1263, 1250, 836, 818,

736, 700 cm^–1. GC/MS: m/z (%) = 272 (20), 244 (62), 229 (22), 137

(69), 136 (80), 135 (100), 109 (34), 105 (30), 91 (17). C₁₆H₂₀SSi

(272.48): calcd. C 70.53, H 7.40; found C 70.63, H 7.44.

EtOAc, 2:1:2). 7a: R_f= 0.47 (pentane/Et₂O/EtOAc, 2:1:2). [α]³_D⁰

=

Methylenecyclohexene 6. (A) Preparation of the Lithium Alkoxide

12: To a –78 °C cold solution of the sultone 7a (7.12 g, 33.0 mmol)

in THF (170 mL) was added MeLi (20.6 mL, 33.0 mmol, 1.6  in

Et₂O) within 20 min, and the solution was further stirred at the

same temperature for 20 min to give a solution of 12. (B) Prepara-

tion of the Lithiated Silane 18: To oxide-free lithium chips (750 mg,

108 mmol) in THF (250 mL) was added 4,4Ј-di-tert-butylbiphenyl

(DBB) (21.9 g, 82 mmol) at 0 °C, and stirring was maintained for

12 h. The turquoise solution of LiDBB was cooled to –78 °C, silane

17 (9.43 g, 34.7 mmol) in THF (125 mL) was added within 30 min,

and the solution was stirred at the same temperature for additional

1

–15.5 (c = 1.00). M.p. 143 °C. H NMR (CDCl₃): δ = 1.04 (d, J =

7.1 Hz, 3 H), 1.83 (dd, J = 7.9, 12.3 Hz, 1 H), 2.54 (ddd, J = 3.5,

4.6, 12.3 Hz, 1 H), 3.16 (m, 1 H), 3.16 (dd, J = 3.5, 7.9 Hz, 1 H),

4.31 (dd, J = 5.2, 11.8 Hz, 1 H), 4.50 (dd, J = 11.8, 11.9 Hz, 1 H),

5.23 (dd, J = 1.6, 4.6 Hz, 1 H), 6.23 (d, J = 5.6 Hz, 1 H), 6.58 (dd,

J = 1.6, 5.6 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ = 10.93 (q), 29.70

(t), 31.68 (d), 57.47 (d), 73.04 (t), 78.62 (d), 91.06 (s), 135.02 (d),

140.34 (d) ppm. IR (KBr): ν = 3040, 2922, 1330, 1308, 1235, 1148,

˜

1105, 948, 881, 764, 715, 694 cm^–1. GC/MS: m/z (%) = 216 (1), 108

(100), 95 (99), 91 (9), 81 (19), 79 (10), 67 (17), 41 (17). C₉H₁₂O₄S

(216.25): calcd. C 49.99, H 5.59; found C 50.04, H 5.66. 7b: R_f=

0.42 (pentane/Et₂O/EtOAc, 2:1:2). [α]²_D⁵= +43.8 (c = 0.99). M.p.

107 °C. ¹H NMR (CDCl₃): δ = 1.46 (d, J = 7.2 Hz, 3 H), 1.74 (dd,

J = 7.9, 12.3 Hz, 1 H), 2.41 (m, 1 H), 2.60 (ddd, J = 3.3, 4.7,

12.3 Hz, 1 H), 3.26 (dd, J = 3.3, 7.9 Hz, 1 H), 4.23 (dd, J = 1.4,

11.7 Hz, 1 H), 4.98 (dd, J = 2.3, 11.7 Hz, 1 H), 5.21 (dd, J = 1.8,

4.7 Hz, 1 H), 6.05 (d, J = 5.7 Hz, 1 H), 6.63 (dd, J = 1.8, 5.7 Hz,

1 H) ppm. ¹³C NMR (CDCl₃): δ = 14.38 (q), 29.48 (t), 30.77 (d),

55.99 (d), 73.99 (t), 78.60 (d), 91.90 (s), 132.72 (d), 141.07 (d) ppm.

20 min. (C) (Iodomethyl)magnesium Chloride:

A solution of

iPrMgCl (100 mL, 200 mmol, 2  in THF) was diluted with THF

(330 mL) and cooled to –90 °C. Under vigorous mechanical stirring

CH₂I₂(53.4 g, 200 mmol) was added over 2 h, and the resulting

grey suspension was stirred for another 2 h at –90 °C. (D) 1,6-

Addition Reaction to Give 13: The –78 °C cold solution of 12 [de-

scribed in paragraph (A)] was cannulated into the solution of 18

[described in paragraph (B)] at –78 °C within 20 min. The resulting

brown solution was then stirred for 30 min at –78 °C, for 30 min

at –20 °C and recooled to –78 °C to give 13. (E) Methylenation with

Simultaneous Desulfurization to Give 6: The –78 °C cold solution

of 13 [described in paragraph (D)] was cannulated into the suspen-

sion of (iodomethyl)magnesium chloride [described in paragraph

(C)] at –90 °C within 30 min. The resulting grey suspension was

warmed to ambient temperature overnight. Aqueous NaHCO₃

(200 mL, 2%) was added carefully at 0 °C, and the separated aque-

ous layer was neutralized with HCl (6 ). The organic layer was

washed with the neutralized aqueous layer, which was then ex-

tracted with Et₂O (3×200 mL). The combined extracts were

washed successively with satd. aqueous Na₂S₂O₃(100 mL) and

brine (100 mL), dried with MgSO₄, and filtered. After evaporation

of the solvent, the residue was filtered through a pad of silica gel

(pentane) in order to remove DBB. Subsequent rinsing with EtOAc

furnished the crude product, which was then purified by flash

chromatography (Et₂O/CH₂Cl₂, 1:1 + 0.5% Et₃N) to afford 6

(6.64 g, 61%) as a white solid. R_f= 0.35 (Et₂O/CH₂Cl₂, 1:1). M.p.

IR (KBr): ν = 3040, 2922, 1330, 1308, 1235, 1148, 1105, 1067, 1034,

˜

948, 881, 764, 715, 694 cm^–1. GC/MS: identical to 7a. C₉H₁₂O₄S

(216.25): calcd. C 49.99, H 5.59; found C 50.12, H 5.63.

Dimethyl(phenyl)vinylsilane (16): For the preparation of the Grig-

nard reagent a mixture of Mg chips (6.12 g, 252 mmol) in THF

(26 mL) was treated with neat bromobenzene (1.3 mL, 12.4 mmol).

After initiation of the reaction, bromobenzene (25.1 mL,

238.5 mmol) in THF (70 mL) was slowly added, and the mixture

was heated under reflux for 8 h. To the resulting solution was added

dropwise chlorodimethylvinylsilane (15) (26.4 mL, 192 mmol) di-

luted with THF (70 mL) followed by heating under reflux for 6 h

and quenching with ice water. The organic layer was separated, the

aqueous layer extracted with Et₂O (100 mL), and the combined

organic layers were dried with MgSO₄. After filtration and evapo-

ration of the solvent, the crude product was purified by distillation

to give 16 (25.75 g, 83%) as a colorless liquid. B.p. 67 °C (18 mbar).

¹H NMR (CDCl₃): δ = 0.20 (s, 6 H), 5.60 (dd, J = 3.9, 20.1 Hz, 1

H), 5.92 (dd, J = 3.9, 14.6 Hz, 1 H), 6.14 (dd, J = 14.6, 20.1 Hz, 1

H), 7.19–7.22 (m, 3 H), 7.37–7.39 (m, 2 H) ppm. ¹³C NMR

1

66–68 °C. [α]²_D⁶= +49.5 (c = 0.99). H NMR (CDCl₃): δ = 0.27 (s,

3 H), 0.28 (s, 3 H), 0.78 (ddd, J = 4.4, 12.8, 14.0 Hz, 1 H), 0.92

(CDCl₃): δ = –2.92 (q, 2 C), 127.79 (d, 2 C), 128.99 (d), 132.78 (t), (ddd, J = 4.6, 12.9, 14.0 Hz, 1 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.36

133.84 (d, 2 C), 138.03 (d), 138.44 (s) ppm. IR (neat): ν = 3069, –1.43 (m, 1 H), 1.50–1.60 (m, 1 H), 2.19–2.22 (m, 1 H), 2.48 (ddd,

˜

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

FULL PAPER

J = 2.1, 4.5, 14.8 Hz, 1 H), 2.60 (dd, J = 4.6, 14.8 Hz, 1 H), 2.81

(ddq, J = 6.0, 6.0, 6.6 Hz, 1 H), 3.54 (dd, J = 6.0, 10.6 Hz, 1 H),

(d), 128.82 (d), 133.51 (d, 2 C), 136.63 (s), 139.23 (s), 140.86 (s)

ppm. IR (neat): ν = 3100–3650 cm^–1(broad), 2929, 2893, 2857,

˜

3.59 (dd, J = 6.0, 10.6 Hz, 1 H), 4.02–4.06 (m, 1 H), 4.91 (broad s, 1472, 1463, 1428, 1250, 1114, 1093, 880, 836, 774, 700 cm^–1. GC/

1 H), 5.16 (broad s, 1 H), 5.35 (broad s, 1 H), 7.25–7.36 (m, 3 H), MS: m/z (%) = 444 (2), 387 (3), 209 (25), 149 (12), 135 (100), 124

7.50–7.52 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = –3.19 (q), –3.07

(42), 73 (28). C₂₆H₄₄O₂Si₂(444.80): calcd. C 70.21, H 9.97; found

(q), 12.95 (t), 16.96 (q), 25.59 (t), 36.04 (d), 40.54 (t), 44.75 (d), C 69.83, H 9.88.

66.50 (d), 67.00 (t), 111.55 (t), 127.12 (d), 127.78 (d, 2 C), 128.89

Epoxide 21: Racemic 20 was used. To a vigorously stirred biphasic

(d), 133.55 (d, 2 C), 137.70 (s), 139.21 (s), 139.36 (s) ppm. IR (neat):

solution of alcohol rac-20 (511 mg, 1.15 mmol) in CH₂Cl₂(10 mL)

and aqueous satd. NaHCO₃(20 mL) was added a solution of

mCPBA (258 mg, 1.50 mmol, 100%) in CH₂Cl₂(10 mL) at 0 °C

within 4 h. After stirring at 0 °C for additional 60 min, the solution

was diluted with H₂O (5 mL), and the aqueous layer was extracted

with CH₂Cl₂(3×20 mL). The combined organic layers were dried

with MgSO₄and filtered through a pad of silica gel (CH₂Cl₂).

Evaporation of the solvent gave 21 (563 mg, Ͼ100%) as an ex-

tremely sensitive colorless liquid in high purity [approx. 90% (¹H

NMR integration)], which was used without further purification.

ν = 3350, 3068, 3018, 2955, 2928, 2877, 1451, 1421, 1343, 1259,

˜

1141, 958, 837, 817, 731, 701 cm^–1. GC/MS: m/z (%) = 331 (3), 315

(4), 281 (12), 279 (12), 234 (55), 145 (24), 135 (100), 121 (11), 105

(12), 91 (7). C₂₀H₃₀O₂Si (330.54): calcd. C 72.67, H 9.15; found C

72.27, H 8.76.

Bis(silyl) Ether 19: To a solution of the diol 6 (2.64 g, 8.0 mmol) in

dry DMF (50 mL) was successively added imidazole (2.73 g,

40.0 mmol), DMAP (1.96 g, 16.0 mmol), and TBSCl (3.57 g,

24.0 mmol), and the solution was stirred for 18 h at room tempera-

ture. The slightly yellowish suspension was diluted with pentane

(50 mL) and poured into aqueous NaHCO₃(100 mL, 5%). The

aqueous layer was extracted with pentane (3×50 mL), and the

combined extracts were washed with brine (30 mL), dried with

MgSO₄, and filtered. After evaporation of the solvent, the crude

product was purified by filtering through a pad of silica gel (pen-

tane/Et₂O, 10:1) to give 19 (4.42 g, 99%) as a colorless viscous li-

1

R_f= 0.30 (pentane/Et₂O, 7:3 + 2% Et₃N). H NMR (C₆D₆): δ =

0.07 (s, 3 H), 0.08 (s, 3 H), 0.39 (s, 3 H), 0.42 (s, 3 H), 0.82 (d, J =

6.6 Hz, 3 H), 0.85 (ddd, J = 4.4, 12.6, 13.8 Hz, 1 H), 1.20 (ddd, J

= 4.4, 12.6, 12.8 Hz, 1 H), 1.02 (s, 9 H), 1.84–1.90 (m, 1 H), 1.91–

1.97 (m, 1 H), 2.01 (dd, J = 3.2, 13.2 Hz, 1 H), 2.01–2.08 (m, 1 H),

2.62–2.68 (m, 2 H), 3.39 (d, J = 4.4 Hz, 1 H), 3.43 (dd, J = 5.0,

11.4 Hz, 1 H), 3.47 (dd, J = 8.2, 11.4 Hz, 1 H), 3.78 (ddd, J = 3.2,

6.3, 10.9 Hz, 1 H), 5.14 (s, 1 H), 5.24 (s, 1 H), 7.29–7.36 (m, 3 H),

7.62–7.65 (m, 2 H) ppm. ¹³C NMR (C₆D₆): δ = –4.88 (q), –4.55

(q), –3.25 (q), –2.86 (q), 13.65 (t), 14.34 (q), 18.25 (s), 19.11 (t),

25.96 (q, 3 C), 35.11 (d), 38.13 (t), 42.74 (d), 58.63 (d), 64.14 (t),

64.59 (s), 70.86 (d), 114.89 (t), 128.14 (d, 2 C), 129.16 (d, C), 133.93

quid. R_f= 0.84 (pentane/Et₂O, 10:1). [α]²_D⁷= +61.5 (c = 0.98). H

1

NMR (CDCl₃): δ = –0.01 (s, 3 H), 0.02 (s, 3 H), 0.03 (s, 3 H), 0.03

(s, 3 H), 0.26 (s, 3 H), 0.27 (s, 3 H), 0.72–0.90 (m, 2 H), 0.82 (s, 9

H), 0.89 (s, 9 H), 1.11 (d, J = 6.7 Hz, 3 H), 1.20–1.27 (m, 1 H),

1.64–1.70 (m, 1 H), 2.11–2.14 (m, 1 H), 2.32 (ddd, J = 1.5, 1.5,

14.5 Hz, 1 H), 2.59 (dd, J = 8.0, 14.5 Hz, 1 H), 2.71 (ddq, J = 6.7,

6.7, 8.7 Hz, 1 H), 3.21 (dd, J = 8.7, 9.6 Hz, 1 H), 3.59 (dd, J = 6.7,

9.6 Hz, 1 H), 3.95–3.90 (m, 1 H), 4.74 (broad s, 1 H), 5.04 (broad

s, 1 H), 5.49 (d, J = 3.5 Hz, 1 H), 7.33–7.37 (m, 3 H), 7.49–7.53

(m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = –5.43 (q), –5.31 (q), –4.80

(q), –5.27 (q), –3.20 (q), –3.08 (q), 13.37 (t), 16.80 (q), 18.05 (s),

18.33 (s), 24.61 (t), 25.78 (q, 3 C), 25.91 (q, 3 C), 36.24 (d), 39.70

(t), 45.46 (d), 68.57 (t), 68.59 (d), 108.56 (t), 127.76 (d, 2 C), 128.19

(d), 128.77 (d), 133.54 (d, 2 C), 137.70 (s), 139.48 (s), 141.68 (s)

(d, 2 C), 139.40 (s), 143.87 (s) ppm. IR (neat): ν = 3430 cm^–1

˜

(broad), 2954, 2929, 2885, 2856, 1463, 1250, 1098, 1044, 899, 868,

833, 815, 772, 728, 699 cm^–1.

Bis(silyl) Ether 22: To a solution of the alcohol 21 (60 mg, approx.

130 µmol) in CH₂Cl₂(1.5 mL) was successively added at 0 °C imi-

dazole (44 mg, 650 µmol), DMAP (5 mg, 40 µmol) and TBSCl

(39 mg, 260 µmol), and stirring was maintained for 2 h. The solu-

tion was treated with Et₃N (100 µL) and rapidly filtered through a

pad of silica gel (pentane/Et₂O, 40:1 + 2% Et₃N). Evaporation of

the solvent gave 22 (67 mg, approx. 94%) in high purity as an ex-

tremely sensitive colorless oil, which was used without further puri-

fication. R_f= 0.66 (pentane/Et₂O, 40:1). ¹H NMR (C₆D₆): δ =

–0.01 (s, 3 H), 0.01 (s, 3 H), 0.04 (s, 3 H), 0.05 (s, 3 H), 0.31 (s, 3

H), 0.33 (s, 3 H), 0.94 (s, 9 H), 0.98 (s, 9 H), 0.90–1.00 (m, 1 H),

1.12 (d, J = 6.9 Hz, 3 H), 1.20–1.33 (m, 1 H), 1.72–2.07 (m, 4 H),

2.37 (q, J = 6.9 Hz, 1 H), 2.70 (dd, J = 12.3, 12.3 Hz, 1 H), 3.45

(d, J = 4.3 Hz, 1 H), 3.56 (dd, J = 6.6, 9.8 Hz, 1 H), 3.76–3.84 (m,

2 H), 5.07 (s, 1 H), 5.19 (s, 1 H), 7.18–7.28 (m, 3 H), 7.51–7.58 (m,

2 H) ppm. ¹³C NMR (C₆D₆): δ = –4.90 (q), –4.85 (q), –4.34 (q),

–4.09 (q), –2.74 (q), –2.34 (q), 14.24 (t), 14.81 (q), 18.77 (s), 18.93

(s), 19.44 (t), 26.48 (q, 3 C), 26.62 (q, 3 C), 37.55 (d), 39.06 (t),

43.54 (d), 61.23 (d), 63.92 (s), 65.07 (t), 71.93 (d), 114.47 (t), 128.36

(d, 2 C), 129.59 (d), 134.74 (d, 2 C), 139.60 (s), 145.27 (s) ppm.

ppm. IR (neat): ν = 2955, 2893, 2857, 1460, 1252, 1113, 1091, 836,

˜

813, 775 cm^–1. GC/MS: m/z (%) = 558 (0.1), 501 (1), 263 (5), 209

(34), 147 (12), 135 (100), 73 (38), 43 (17). C₃₂H₅₈O₂Si₃(559.06):

calcd. C 68.75, H 10.46; found C 68.73, H 10.22.

Alcohol 20: To an ice-cold solution of the bis(silyl) ether 19

(12.40 g, 22.3 mmol) in THF (180 mL) was added TBAF (36 mL,

36 mmol, 1  in THF) over 8 h. The solution was maintained at

this temperature for additional 30 h and then quenched with aque-

ous Na₂CO₃(200 mL, 5%). The aqueous layer was extracted with

Et₂O (3×200 mL), and the combined extracts were washed with

brine (100 mL), dried with MgSO₄, and filtered. After evaporation

of the solvent, the crude mixture was chromatographically purified

(pentane/Et₂O, 4:1 Ǟ CH₂Cl₂/Et₂O, 1:1) to give 20 (8.00 g, 81%)

as a colorless viscous liquid and 6 (1.30 g, 17%). R_f= 0.38 (pen-

tane/Et₂O, 4:1). [α]²_D⁴= +77.1 (c = 0.99). ¹H NMR (CDCl₃): δ =

–0.03 (s, 3 H), 0.00 (s, 3 H), 0.24 (s, 3 H), 0.26 (s, 3 H), 0.76–0.87 Silane 24: To oxide-free lithium chips (70 mg, 10 mmol) in THF

(m, 2 H), 0.78 (s, 9 H), 1.07 (d, J = 6.9 Hz, 3 H), 1.22–1.33 (m, 1

H), 1.51–1.65 (m, 1 H), 2.10–2.14 (m, 1 H), 2.36 (ddd, J = 2.2, 2.2,

(4 mL) was added dropwise with stirring at –10 °C chlorodimethyl-

phenylsilane (340 mg, 2.0 mmol). The mixture was stirred at the

14.9 Hz, 1 H), 2.49 (dd, J = 6.0, 14.9 Hz, 1 H), 2.66–2.75 (m, 1 H), same temperature for another 24 h to give a red solution of lithiodi-

3.45 (dd, J = 5.4, 10.5 Hz, 1 H), 3.51 (dd, J = 5.3, 10.5 Hz, 1 H),

3.96–4.01 (m, 1 H), 4.77 (broad s, 1 H), 5.05 (broad s, 1 H), 5.45

(broad s, 1 H), 7.30–7.34 (m, 3 H), 7.45–7.50 (m, 2 H) ppm.¹³C

NMR (CDCl₃): δ = –4.90 (q), –4.19 (q), –3.07 (q), –2.97 (q), 13.36

(t), 16.40 (q), 17.99 (s), 25.54 (t), 25.73 (q, 3 C), 35.48 (d), 40.12

methylphenylsilane (approx. 0.5 ). To a suspension of CuI (26 mg,

137 µmol) in Et₂O (0.7 mL) was added a solution of lithiodimethyl-

phenylsilane (600 µL, approx. 300 µmol, 0.5  in THF, preparation

described above) at –20 °C within 5 min. The mixture was placed

in an ice bath and additionally stirred for 15 min. The resulting

(t), 45.60 (d), 66.68 (t), 68.06 (d), 109.68 (t), 127.73 (d, 2 C), 128.49 purple solution of the silylcuprate 23 was cooled to –20 °C, and

Eur. J. Org. Chem. 2006, 1144–1161

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1153

P. Metz et al.

FULL PAPER

vinyl epoxide 22 (50 mg, 91 µmol) diluted in Et₂O (500 µL) was

added dropwise. Stirring was maintained at the same temperature

for 2.5 h, followed by addition of lithiodimethylphenylsilane

(450 µL, approx. 225 µmol). The mixture was stirred for 1 h at 0 °C

and quenched with aqueous NaHCO₃(5 mL, 5%). The aqueous

layer was extracted with Et₂O (3×5 mL), and the combined ex-

tracts were dried with MgSO₄and filtered. Removal of the solvent

and subsequent purification by flash chromatography (pentane/

(10 mL), and heated under reflux for 2 h. For precipitation and

isolation of 26×HI, the resulting clear solution was concentrated at

40 °C (100 mbar) and filtered. After evaporation of the remaining

solvent and purification by flash chromatography (pentane/Et₂O,

9:1 + 0.5% Et₃N), 27 (2.52 g, 91%) was isolated as a colorless vis-

cous liquid. R_f= 0.37 (pentane/Et₂O, 9:1). [α]²_D³= +77.5 (c = 1.00).

¹H NMR (CDCl₃): δ = –0.01 (s, 3 H), 0.02 (s, 3 H), 0.25 (s, 3 H),

0.26 (s, 3 H), 0.74 (ddd, J = 4.6, 13.8, 14.2 Hz, 1 H), 0.82 (s, 9 H),

Et₂O, 30:1) afforded 24 (34 mg, 50% from 20) as an acid sensitive 0.90 (ddd, J = 4.4, 14.2, 18.1 Hz, 1 H), 1.07 (d, J = 6.9 Hz, 3 H),

colorless liquid. R_f= 0.31 (pentane/Et₂O, 30:1). ¹H NMR (CDCl₃):

δ = –0.04 (s, 3 H), –0.02 (s, 3 H), 0.01 (s, 3 H), 0.02 (s, 3 H), 0.27

(s, 3 H), 0.28 (s, 3 H), 0.29 (s, 3 H), 0.29 (s, 3 H), 0.68–0.84 (m, 2

1.27 (dddd, J = 4.6, 8.5, 12.9, 18.1 Hz, 1 H), 1.64–1.72 (m, 1 H),

1.97 (ddd, J = 6.9, 8.6, 14.8 Hz, 1 H), 2.05 (ddd, J = 6.0, 8.5,

14.8 Hz, 1 H), 2.10–2.15 (m, 1 H), 2.31 (ddd, J = 1.5, 1.5, 14.4 Hz,

H), 0.81 (s, 9 H), 0.88 (s, 9 H), 0.96 (d, J = 6.9 Hz, 3 H), 1.16–1.21 1 H), 2.47 (dd, J = 7.8, 14.4 Hz, 1 H), 2.57–2.61 (m, 1 H), 3.41

(m, 1 H), 1.46–1.54 (m, 1 H), 1.53 (d, J = 13.9 Hz, 1 H), 1.65–1.76 (dd, J = 8.6, 6.0 Hz, 1 H), 3.67 (s, 3 H), 3.68 (s, 3 H), 3.94–3.98

(m, 1 H), 2.00 (dd, J = 1.6, J = 14.7 Hz, 1 H), 2.04 (d, J = 13.9, 1

(m, 1 H), 4.72 (s, 1 H), 4.96 (s, 1 H), 5.54 (d, J = 3.3 Hz, 1 H),

H), 2.06 (dd, J = 3.7, 14.7 Hz, 1 H), 2.69 (tq, J = 6.9, 6.9 Hz, 1 7.32–7.36 (m, 3 H), 7.48–7.53 (m, 2 H) ppm. ¹³C NMR (CDCl₃):

H), 3.18 (d, J = 10.8 Hz, 1 H), 3.60 (d, J = 6.9 Hz, 2 H), 3.95 (dd, δ = –4.91 (q), –4.23 (q), –3.23 (q), –3.14 (q), 13.31 (t), 18.02 (s),

J = 3.6, 10.8 Hz, 1 H), 3.97–3.99 (m, 1 H), 7.30–7.35 (m, 6 H), 20.95 (q), 24.71 (t), 25.76 (q, 3 C), 30.88 (d), 35.90 (t), 39.76 (t),

7.46–7.53 (m, 4 H) ppm. ¹³C NMR (CDCl₃): δ = –5.21 (q, 2 C), 45.33 (d), 49.56 (d), 52.27 (q), 52.35 (q), 68.67 (d), 108.89 (t), 127.57

–5.05 (q), –4.67 (q), –3.22 (q), –3.14 (q), –2.26 (q), –2.18 (q), 13.07

(t), 14.90 (q), 23.30 (t), 23.38 (t), 17.75 (s), 18.35 (s), 25.68 (q, 3 C),

26.02 (q, 3 C), 38.60 (d), 42.81 (t), 46.03 (d), 66.21 (d), 67.93 (t),

(d), 127.57 (d, 2 C), 128.77 (d), 133.53 (d, 2 C), 139.43 (s, 2 C),

141.35 (s), 170.19 (s), 170.26 (s) ppm. IR (neat): ν = 2953, 2925,

˜

1753, 1736, 1435, 1248, 1152, 1113, 1091, 884, 811, 771, 729,

70.01 (d), 126.80 (s), 127.71 (d, 2 C), 127.75 (d, 2 C), 128.78 (d), 699 cm^–1. GC/MS: m/z (%) = 558 (0.3), 527 (0.5), 501 (24), 469 (5),

128.98 (d), 132.81 (s), 133.46 (d, 2 C), 133.59 (d, 2 C), 139.24 (s),

395 (2), 317 (3), 279 (17), 229 (5), 209 (19), 135 (100), 113 (12).

C₃₁H₅₀O₅Si₂(558.90): calcd. C 66.62, H 9.02; found C 66.71 H

139.46 (s) ppm. IR (neat): ν = 3530 cm^–1(broad), 2953, 2929, 2886,

˜

2858, 1469, 1426, 1361, 1250, 1112, 1068, 1030, 922, 829, 773, 728, 9.16.

697 cm^–1. MS (CID, –25 V): m/z (%) = 769 (100). C₄₀H₇₀O₃Si₄

(711.32): calcd. C 67.54, H 9.92; found C 67.73, H 10.11.

Methyl Ester 28: To a solution of the malonate 27 (7.37 g,

13.2 mmol) in DMF (130 mL) were added thiophenol (2.94 g,

26.4 mmol) and K₂CO₃(1.82 g, 13.2 mmol) at 90 °C. The resulting

suspension was stirred at the same temperature for 100 min, diluted

with aqueous NaHCO₃(250 mL, 5%) at room temperature, and

extracted with pentane (3×200 mL). The combined extracts were

washed successively with aqueous NaOH (50 mL, 2 ), H₂O

(50 mL), brine (50 mL), dried and filtered. The residue was purified

by flash chromatography (pentane/CH₂Cl₂, 7:3 + 0.5% Et₃N) to

afford 28 (5.89 g, 89%) as a colorless liquid. R_f= 0.23 (pentane/

CH₂Cl₂, 7:3). [α]²_D²= +96.7 (c = 1.00). ¹H NMR (CDCl₃): δ =

–0.02 (s, 3 H), –0.01 (s, 3 H), 0.25 (s, 3 H), 0.26 (s, 3 H), 0.74–0.80

(m, 2 H), 0.81 (s, 9 H), 1.05 (d, J = 6.9 Hz, 3 H), 1.20–1.29 (m, 1

Iodide 25: To a solution of alcohol 20 (8.00 g, 18.00 mmol) in a

mixture of THF (250 mL) and MeCN (100 mL) were added imida-

zole (7.85 g, 125 mmol) and Ph₃P (15.09 g, 57.6 mmol). The mix-

ture was cooled to –20 °C, I₂(14.52 g, 57.6 mmol) was added, and

the resulting solution was stirred in the dark for 1 h at –20 °C and

for 4 h at room temperature. The reaction was quenched with aque-

ous NaHCO₃(200 mL, 5%) and extracted with pentane

(3×200 mL). The combined extracts were successively washed with

aqueous satd. Na₂S₂O₃(50 mL) and brine (200 mL) and dried with

MgSO₄. After filtration and evaporation of the solvent, the crude

mixture was purified by filtering through a pad of silica gel (pen-

tane + 1% Et₃N) to furnish 25 (8.37 g, 84%) essentially pure as a H), 1.63–1.80 (m, 3 H), 2.09–2.15 (m, 1 H), 2.17–2.29 (m, 2 H),

light sensitive colorless liquid. R_f= 0.29 (pentane). [α]²_D⁵= +108.8

(c = 1.01). H NMR (CDCl₃): δ = 0.00 (s, 3 H), 0.03 (s, 3 H), 0.26

(s, 3 H), 0.27 (s, 3 H), 0.74 (ddd, J = 4.4, 13.8, 13.8 Hz, 1 H), 0.83

(s, 9 H), 0.90 (ddd, J = 4.3, 13.8, 13.8 Hz, 1 H), 1.21 (d, J = 6.7 Hz,

3 H), 1.22–1.33 (m, 1 H), 1.67–1.77 (m, 1 H), 2.11–2.16 (m, 1 H),

2.31 (ddd, J = 1.5, 1.5, 14.5 Hz, 1 H), 2.47 (dd, J = 7.9, 14.5 Hz,

1 H), 2.59 (ddq, J = 6.8, 6.8, 6.9 Hz, 1 H), 3.62 (s, 3 H), 3.94–3.98

(m, 1 H), 4.73 (s, 1 H), 4.99 (s, 1 H), 5.49 (d, J = 3.3 Hz, 1 H),

7.31–7.35 (m, 3 H), 7.48–7.52 (m, 2 H) ppm.¹³C NMR (CDCl₃): δ

= –4.89 (q), –4.22 (q), –3.27 (q), –3.09 (q), 13.33 (t), 18.02 (s), 20.44

1

2.31 (ddd, J = 1.5, 1.5, 14.4 Hz, 1 H), 2.49 (dd, J = 8.5, 14.4 Hz, (q), 24.77 (t), 25.76 (q, 3 C), 31.70 (t, 2 C), 32.24 (d), 39.78 (t),

1 H), 2.68–2.75 (m, 1 H), 3.08 (dd, J = 8.1, 9.5 Hz, 1 H), 3.35 (dd,

J = 4.0, 9.5 Hz, 1 H), 3.94–3.97 (m, 1 H), 4.79 (broad s, 1 H), 4.94

(broad s, 1 H), 5.58 (d, J = 3.9 Hz, 1 H), 7.33–7.35 (m, 3 H), 7.49–

45.32 (d), 51.32 (q), 68.64 (d), 108.78 (t), 127.23 (d), 127.70 (d, 2

C), 128.76 (d), 133.52 (d, 2 C), 139.41 (s), 139.67 (s), 141.58 (s),

174.53 (s) ppm. IR (neat): ν = 2954, 2929, 2888, 2857, 1741, 1435,

˜

7.53 (m,

2 δ =

H) ppm. ¹³C NMR (CDCl₃): –4.84 (q), 1250, 1169, 1113, 1093, 1065, 876, 837, 814, 774, 729, 700 cm^–1.

–4.29 (q), –3.22 (q), –3.01 (q), 13.36 (t), 16.02 (t), 18.04 (s), 19.71

GC/MS: m/z (%) = 500 (0.3), 485 (0.2), 469 (0.3), 443 (19), 385 (1),

(q), 24.33 (t), 25.79 (q, 3 C), 35.76 (d), 39.38 (t), 45.40 (d), 68.64

351 (6), 305 (3), 221 (19), 209 (23), 135 (100), 119 (7). C₂₉H₄₈O₃Si₂

(d), 108.83 (t), 127.71 (d, 2 C), 128.79 (d), 128.88 (d), 133.56 (d, 2 (500.86): calcd. C 69.54, H 9.66; found C 69.88, H 9.57.

C), 138.04 (s), 139.38 (s), 141.11 (s) ppm. IR (neat): ν = 2955, 2928,

˜

Alcohol 29: Racemic 28 was used. A solution of methyl ester rac-

28 (2.13 g, 4.25 mmol) in Et₂O (40 mL) was treated with LiAlH₄

(242 mg, 6.37 mmol) at 0 °C, and stirring was maintained for

90 min. The resulting suspension was diluted with Et₂O (100 mL),

quenched with aqueous NaHCO₃(130 mL, 5%), stirred at 0 °C for

30 min and at room temperature for 30 min. The inorganic salts

were separated by filtration and carefully rinsed with Et₂O, and the

aqueous layer was extracted with Et₂O (3×100 mL). The combined

extracts were washed brine (50 mL), dried, filtered and the solvents

2893, 2857, 1250, 1113, 1093, 883, 858, 836, 813, 774, 729,

700 cm^–1. GC/MS: m/z (%) = 501 (2), 413 (1), 385 (2), 291 (2), 263

(6), 209 (35), 147 (12), 136 (13), 135 (100), 73 (35). C₂₆H₄₃IOSi₂

(554.69): calcd. C 56.30, H 7.81; found C 56.10, H 7.79.

Malonate 27: To a solution of the proazaphosphatrane 26 (1.74 g,

8.0 mmol) in MeCN was added dimethyl malonate (1.32 g,

10.0 mmol) diluted with MeCN (15 mL). The solution was stirred

at room temperature for 15 min, then treated with iodide 25 (2.77 g,

5.0 mmol), diluted with a mixture of toluene (10 mL) and MeCN evaporated. The crude product was purified by flash chromatog-

1154 Eur. J. Org. Chem. 2006, 1144–1161

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

FULL PAPER

raphy (pentane/Et₂O, 4:1 + 0.5% Et₃N) to afford 29 (57 mg, 100%)

as a colorless liquid. R_f= 0.34 (pentane/Et₂O, 4:1). ¹H NMR

(CDCl₃): δ = 0.00 (s, 3 H), 0.03 (s, 3 H), 0.26 (s, 3 H), 0.27 (s, 3

H), 0.75 (ddd, J = 4.8, 12.9, 14.2 Hz, 1 H), 0.80–0.87 (m, 1 H),

δ = 20.67 (q), 27.63 (t), 32.90 (t), 33.13 (d), 34.03 (t), 39.69 (d),

39.95 (t), 55.10 (q), 60.59 (t), 67.45 (d), 67.97 (t), 96.30 (t), 110.98

(t), 125.57 (d), 139.45 (s), 141.26 (s) ppm. IR (neat): ν = 3380 cm^–1

˜

(broad), 2937, 2879, 1455, 1453, 1443, 1148, 1111, 1042, 919, 880,

0.82 (s, 9 H), 1.06 (d, J = 6.9 Hz, 3 H), 1.20–1.28 (m, 1 H), 1.38– 866 cm^–1. GC/MS: m/z (%) = 283 (0.5), 267 (1), 235 (4), 204 (16),

1.43 (m, 1 H), 1.46–1.54 (m, 3 H), 1.69 (ddt, J = 5.1, 13.2, 5.1 Hz,

1 H), 2.01–2.16 (m, 1 H), 2.32 (ddd, J = 1.5, 1.5, 14.4 Hz, 1 H),

191 (9), 185 (22), 175 (24), 159 (30), 147 (31), 131 (33), 119 (50),

105 (56), 91 (59), 79 (30), 45 (100). C₁₆H₂₈O₄(284.39): calcd. C

2.47 (dd, J = 8.0, 14.4 Hz, 1 H), 2.52–2.56 (m, 1 H), 3.58 (t, J = 67.57, H 9.92; found C 67.27, H 10.05.

6.0 Hz, 2 H), 3.95–3.99 (m, 1 H), 4.74 (s, 1 H), 5.00 (s, 1 H), 5.51

Lactone 32: A solution of the diol 31 (98 mg, 345 µmol) in MeCN

(d, J = 3.5 Hz, 1 H), 7.32–7.35 (m, 3 H), 7.49–7.52 (m, 2 H) ppm.

¹³C NMR (CDCl₃): δ = –4.84 (q), –4.25 (q), –3.27 (q), –3.04 (q),

13.38 (t), 18.05 (s), 20.73 (q), 24.66 (t), 25.78 (q, 3 C), 30.50 (t),

32.68 (d), 32.84 (t), 39.74 (t), 45.29 (d), 63.23 (t), 68.83 (d), 108.49

(t), 126.91 (d), 127.70 (d, 2 C), 128.77 (d), 133.59 (d, 2 C), 139.49

(2 mL) was treated with NMO (412 mg, 3.52 mmol) in an ultra-

sound bath at 15–20 °C for 10 min followed by addition of TPAP

(14.5 mg, 35 µmol). After sonication at the same temperature for

additional 50 min, the green mixture was filtered through a pad of

silica gel (EtOAc). The solvent was removed, and the crude product

was purified by flash chromatography (CH₂Cl₂/Et₂O, 19:1 + 0.5%

Et₃N) to afford 32 (63 mg, 65%) as a colorless viscous liquid. R_f=

0.26 (CH₂Cl₂/Et₂O, 19:1). ¹H NMR (CDCl₃): δ = 1.05 (d, J =

6.8 Hz, 3 H), 1.37–1.44 (m, 1 H), 1.48–1.58 (m, 3 H), 2.30 (dd, J

= 4.0, 17.2 Hz, 1 H), 2.53 (ddq, J = 6.7, 6.7, 6.7 Hz, 1 H), 2.57

(dddd, J = 1.6, 1.6, 3.3, 14.7 Hz, 1 H), 2.73 (dd, J = 5.7, 14.7 Hz,

1 H), 2.79 (dd, J = 8.8, 17.2 Hz, 1 H), 3.14 (ddd, J = 3.9, 9.1,

9.1 Hz, 1 H), 3.33 (s, 3 H), 3.47 (dd, J = 6.1, 8.6 Hz, 2 H), 4.58 (s,

2 H), 4.74 (ddd, J = 3.5, 5.7, 5.7 Hz, 1 H), 4.98 (s, 1 H), 5.19 (s, 1

H), 5.31 (d, J = 3.2 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ = 20.51

(q), 27.70 (t), 32.90 (t), 33.86 (d), 35.57 (d), 35.64 (t), 36.16 (t),

55.11 (q), 67.80 (t), 77.62 (d), 96.37 (t), 112.80 (t), 121.45 (d),

(s), 140.42 (s), 141.81 (s) ppm. IR (neat): ν = 3380 cm^–1(broad),

˜

2954, 2929, 2893, 2857, 2360, 2333, 1462, 1428, 1250, 1113, 1095,

1065, 837, 814, 774, 729, 700 cm^–1. GC/MS: m/z (%) = 472 (0.1),

415 (0.2), 323 (2), 251 (3), 245 (3), 209 (13), 187 (4), 136 (14), 135

(100), 119 (8), 75 (22). C₂₈H₄₈O₂Si₂(472.85): calcd. C 71.12, H

10.23; found C 71.27, H 10.43.

MOM Ether 30: To a solution of the alcohol 29 (2.00 g, 4.24 mmol)

in CH₂Cl₂(50 mL) was added DIPEA (2.1 mL, 12.72 mmol) and

MOMCl (840 µL, 10.62 mmol) at 0 °C. The resulting solution was

allowed to reach room temperature overnight. The mixture was fil-

tered through a pad of silica gel to afford essentially pure 30

(2.16 g, 99%) as a colorless viscous liquid. R_f= 0.42 (pentane/Et₂O,

1

19:1). H NMR (CDCl₃): δ = –0.04 (s, 3 H), 0.00 (s, 3 H), 0.22 (s,

136.73 (s), 143.73 (s), 176.05 (s) ppm. IR (neat): ν = 2934, 2871,

˜

3 H), 0.23 (s, 3 H), 0.67–0.90 (m, 2 H), 0.79 (s, 9 H), 1.03 (d, J =

6.8 Hz, 3 H), 1.15–1.28 (m, 1 H), 1.35–1.42 (m, 1 H), 1.44–1.56 (m,

3 H), 1.61–1.73 (m, 1 H), 2.07–2.14 (m, 1 H), 2.28 (dd, J = 3.0,

14.4 Hz, 1 H), 2.45 (dd, J = 8.0, 14.4 Hz, 1 H), 2.52–2.55 (m, 1 H),

3.31 (s, 3 H), 3.44 (t, J = 6.0 Hz, 2 H), 3.93 (ddd, J = 3.0, 4.5,

8.0 Hz, 1 H), 4.56 (s, 2 H), 4.70 (s, 1 H), 4.97 (s, 1 H), 5.49 (d, J =

3.7 Hz, 1 H), 7.29–7.32 (m, 3 H), 7.46–7.49 (m, 2 H) ppm. ¹³C

NMR (CDCl₃): δ = –4.83 (q), –4.24 (q), –3.22 (q), –3.07 (q), 13.36

(t), 18.05 (s), 20.66 (q), 24.61 (t), 25.80 (q, 3 C), 27.47 (t), 32.80

(d), 33.42 (t), 39.70 (t), 45.31 (d), 55.05 (q), 68.10 (t), 68.89 (d),

96.37 (t), 108.47 (t), 126.92 (d), 127.71 (d, 2 C), 128.76 (d), 133.54

1766, 1459, 1429, 1186, 1156, 1105, 1071, 1035, 995, 944, 915, 885,

866 cm^–1. GC/MS: m/z (%) = 281 (0.1), 249 (3), 218 (11), 217 (16),

205 (7), 189 (28), 179 (23), 175 (13), 171 (31), 159 (28), 157 (18),

133 (27), 119 (30), 105 (40), 91 (44), 45 (100). C₁₆H₂₄O₄(280.36):

calcd. C 68.54, H 8.63; found: C 68.55, H 8.66.

Carboxylic Acid 33: To a solution of the methyl ester 28 (5.89 g,

11.78 mmol) in MeOH (60 mL) and H₂O (30 mL) was added KOH

(6.60 g, 118 mmol), and the resulting suspension was heated under

reflux for 90 min. The clear solution was concentrated at 40 °C

(100 mbar), diluted with EtOAc (200 mL), and carefully neutral-

ized with aqueous HCl (2 ). The aqueous layer was extracted with

EtOAc (2×200 mL), and the combined extracts were successively

washed with aqueous satd. NH₄Cl (50 mL) and brine (50 mL). Af-

ter drying over MgSO₄, filtration and removal of the solvent, the

crude product was rinsed through a pad of silica gel (Et₂O) to

afford essentially pure 33 (5.73 g, 100%) as a colorless liquid. R_f=

0.61 (pentane/Et₂O, 1:1). [α]²_D¹= +98.2 (c = 1.01). ¹H NMR

(CDCl₃): δ = –0.01 (s, 3 H), 0.02 (s, 3 H), 0.25 (s, 3 H), 0.26 (s, 3

H), 0.72–0.87 (m, 2 H), 0.81 (s, 9 H), 1.08 (d, J = 6.7 Hz, 3 H),

1.21–1.30 (m, 1 H), 1.64–1.83 (m, 3 H), 2.10–2.16 (m, 1 H), 2.21–

2.36 (m, 3 H), 2.49 (dd, J = 7.7, 14.5 Hz, 1 H), 2.61 (ddq, J = 6.7,

6.7, 6.7 Hz, 1 H), 3.94–3.99 (m, 1 H), 4.74 (s, 1 H), 5.00 (s, 1 H),

5.50 (d, J = 3.5 Hz, 1 H), 7.31–7.35 (m, 3 H), 7.47–7.52 (m, 2 H)

ppm. ¹³C NMR (CDCl₃): δ = –4.94 (q), –4.27 (q), –3.34 (q), –3.16

(q), 13.32 (t), 17.97 (s), 20.40 (q), 24.72 (t), 25.71 (q, 3 C), 31.35

(t), 31.48 (t), 32.19 (d), 39.74 (t), 45.28 (d), 68.58 (d), 108.81 (t),

127.29 (d), 127.65 (d, 2 C), 128.71 (d), 133.47 (d, 2 C), 139.35 (s),

(d, 2 C), 139.48 (s), 140.52 (s), 141.86 (s) ppm. IR (neat): ν = 2952,

˜

2935, 2929, 2895, 2883, 2858, 1471, 1428, 1250, 1113, 1098, 1045,

919, 874, 837, 814, 774, 700 cm^–1. GC/MS: m/z (%) = 516 (2), 485

(0.3), 459 (1), 385 (0.6), 353 (1), 209 (13), 159 (6), 135 (100), 136

(14), 75 (18). C₃₀H₅₂O₃Si₂(516.90): calcd. C 69.71, H 10.14; found

C 69.73, H 10.24.

Diol 31: To activated molecular sieves (4 Å, 4.00 g) was added a

solution of the silane 30 (2.10 g, 4.07 mmol) in a fresh charge of

TBAF (24.4 mL, approx. 24.4 mmol, 1  in THF), and the re-

sulting dark grey suspension was heated under reflux for 3.5 h. KF

(842 mg, 14.51 mmol), NaHCO₃(354 mg, 4.1 mmol), MeOH

(30 mL), and H₂O₂(8.2 mL, 30% in H₂O) were added sequentially,

and the mixture was heated under reflux for an additional 1 h. The

resulting white suspension was poured at room temperature into

aqueous diluted NaHCO₃(250 mL) and extracted with EtOAc

(4×150 mL). The combined extracts were washed with brine

(50 mL), dried, filtered and the solvents evaporated. The residue

was purified by flash chromatography (EtOAc + 0.5% Et₃N) to

give 31 (1.00 g, 87%) as a colorless viscous liquid. R_f= 0.24

139.49 (s), 141.48 (s), 179.55 (s) ppm. IR (neat): ν = 3050 cm^–1

˜

(broad), 2954, 2929, 2857, 1708, 1426, 1250, 1111, 1093, 876, 836,

774, 700 cm^–1. MS (CID, –25 V): m/z (%) = 567 (40), 485 (100).

C₂₈H₄₆O₃Si₂(486.83): calcd. C 69.08, H 9.52; found C 69.20, H

9.57.

1

(EtOAc). H NMR (CDCl₃): δ = 1.04 (d, J = 6.9 Hz, 3 H), 1.37–

1.45 (m, 1 H), 1.49–1.60 (m, 3 H), 1.64–1.69 (m, 1 H), 1.78–1.85

(m, 1 H), 2.48–2.60 (m, 4 H), 3.33 (s, 3 H), 3.48 (dt, J = 1.0, 5.1 Hz,

2 H), 3.71 (ddd, J = 4.6, 7.3, 10.9 Hz, 1 H), 3.76 (ddd, J = 4.7, 6.7,

Preparation of the Formyloxy ε-Lactone 36: To a solution of car-

10.9 Hz, 1 H), 4.01 (ddd, J = 3.2, 3.2, 6.1 Hz, 1 H), 4.58 (s, 2 H), boxylic acid 33 (49 mg, 100 µmol) in toluene (1.5 mL) was added

4.89 (s, 1 H), 5.12 (s, 1 H), 5.33 (s, 1 H) ppm. ¹³C NMR (CDCl₃): bis(sym-collidine)iodine() hexafluorophosphate (69 mg, 135 µmol)

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1155

P. Metz et al.

FULL PAPER

at 0 °C. After stirring at this temperature for 14 h in the dark, DMF

(1.5 mL) and AgOAc (25 mg, 150 µmol) were added to the mixture.

The resulting suspension was stirred at 0 °C for 2 h and an ad-

ditional 1 h at room temperature. The solids were removed, the

filtrate was poured into aqueous NaHCO₃(5 mL, 5%), and the

aqueous layer was extracted with Et₂O (3×5 mL). The combined

extracts were washed successively with aqueous satd. Na₂S₂O₃

(5 mL), H₂O (5 mL) and brine (5 mL), dried with MgSO₄and fil-

tered. After evaporation of the solvent, the crude mixture was puri-

fied by flash chromatography (pentane/Et₂O, 3:2) to give 36

(20). C₂₈H₄₅IO₃Si₂(612.73): calcd. C 54.89, H 7.40; found C 55.22,

H 7.63.

Recycling of 35: To a solution of the iodolactone 35 (533 mg,

869 µmol) in THF (17 mL) were added zinc dust (554 mg,

8.53 mmol), HOAc (120 µL, 2.1 mmol), and H₂O (120 µL) at 0 °C.

The mixture was stirred for 30 min at this temperature and at room

temperature overnight. After complete conversion, the solids were

removed, the filtrate was poured into aqueous satd. NH₄Cl, and the

aqueous layer was extracted with Et₂O (3×25 mL). The combined

extracts were washed with aqueous satd. Na₂S₂O₃(10 mL), dried

with MgSO₄and filtered. After evaporation of the solvent, the

crude mixture was purified by flash chromatography (pentane/

Et₂O, 3:2) to afford 33 (365 mg, 86%) as a colorless viscous liquid.

(35.5 mg, 67%) and 35 (8 mg, 15%) as extremely light sensitive

25

colorless liquids. 36: R_f= 0.34 (pentane/Et₂O, 3:2). [α] = +52.4

D

(c = 1.00). ¹H NMR (CDCl₃): δ = –0.01 (s, 3 H), 0.00 (s, 3 H), 0.28

(s, 3 H), 0.29 (s, 3 H), 0.67 (ddd, J = 4.7, 12.9, 13.9 Hz 1 H), 0.76

(ddd, J = 4.7, 12.9, 13.9 Hz, 1 H), 0.84 (s, 9 H), 1.08 (d, J = 7.3 Hz,

3 H), 1.31–1.36 (m, 1 H), 1.53–1.65 (m, 1 H), 1.68–1.80 (m, 2 H),

1.84–1.92 (m, 1 H), 2.25 (dd, J = 4.2, 18.4 Hz, 1 H), 2.34 (dd, J =

1.6, 18.4 Hz, 1 H), 2.43 (ddd, J = 1.3, 8.2, 15.0 Hz, 1 H), 2.84 (ddd,

J = 1.3, 12.0, 15.0 Hz, 1 H), 3.19–3.26 (m, 1 H), 4.03 (dd, J = 1.6,

1.6 Hz, 1 H), 4.63 (d, J = 12.1 Hz, 1 H), 4.74 (d, J = 4.1 Hz, 1 H),

4.77 (d, J = 12.1 Hz, 1 H), 7.33–7.36 (m, 3 H), 7.49–7.53 (m, 2 H),

8.06 (s, 1 H) ppm. ¹³C NMR (CDCl₃): δ = –4.85 (q), –4.49 (q),

–3.27 (q), –3.14 (q), 13.07 (t), 17.96 (q), 17.96 (s), 22.93 (t), 25.60

(q, 3 C), 28.57 (t), 30.06 (t), 32.26 (d), 38.58 (t), 45.90 (d), 62.79

(t), 65.37 (d), 69.73 (d), 127.79 (d, 2 C), 128.33 (s), 128.88 (d),

133.56 (d, 2 C), 136.65 (s), 139.22 (s), 160.74 (d), 174.30 (s) ppm.

Triol 37: LiAlH₄(547 mg, 14.48 mmol) was added within 30 min

to a solution of the lactone 36 (3.82 g, 7.21 mmol) in Et₂O

(350 mL) at –10 °C. The resulting mixture was stirred at –10 °C for

30 min and was then warmed to 0 °C within 3 h. If any remaining

36 was detectable, additional LiAlH₄(137 mg, 3.62 mmol) was

added and the reaction time was extended for 1 h. The reaction

was quenched with H₂O (4 mL) and heated under reflux for

15 min. The white solid was separated by filtering through a pad

of silica gel (Et₂O), and the filtrate was concentrated to dryness to

give a mixture of reduced derivatives of 36, which was then dis-

solved in Et₂O (80 mL), placed in an ice bath and treated with

LiBH₄(536 mg, 24.36 mmol). The solution was stirred at 0 °C for

10 min, warmed to room temperature and stirred for additional

2 h. The resulting suspension was diluted with Et₂O (30 mL), suc-

cessively treated with acetone (2 mL) and aqueous NaHCO₃

(30 mL, 5%) and stirred until gas evolution has ceased. The aque-

ous layer was extracted with EtOAc (2×100 mL), and the com-

bined extracts were washed with brine (50 mL), dried and filtered.

After removal of the solvent, the crude product was purified by

flash chromatography (Et₂O) to afford 37 (2.93 g, 91%) as a color-

IR (neat): ν = 2953, 2926, 2856, 1722, 1426, 1250, 1149, 1113, 1089,

˜

1025, 832, 809, 771, 729, 699 cm^–1. MS (CID, –10 V): m/z (%) =

588 (100). C₂₉H₄₆O₅Si₂(530.84): calcd. C 65.61, H 8.73; found C

65.71, H 8.94. 35: R_f= 0.60 (pentane/Et₂O, 3:2). [α]²_D¹= +92.8 (c

1

= 1.00) ppm. H NMR (CDCl₃): δ = 0.05 (s, 3 H), 0.09 (s, 3 H),

0.26 (s, 3 H), 0.27 (s, 3 H), 0.69 (ddd, J = 4.5, 13.2, 13.2 Hz, 1 H),

0.81–0.96 (m, 1 H), 0.84 (s, 9 H), 1.15 (d, J = 6.8 Hz, 3 H), 1.14–

1.25 (m, 2 H), 1.79–1.85 (m, 1 H), 1.95 (ddd, J = 13.5, 9.3, 1.2 Hz,

1 H), 2.01–2.10 (m, 2 H), 2.31 (ddd, J = 13.0, 5.0, 1.8 Hz, 1 H),

2.35 (dd, J = 13.5, 4.0 Hz, 1 H), 2.47–2.55 (m, 2 H), 3.22 (d, J =

11.0 Hz, 1 H), 3.45 (dd, J = 11.0, 1.2 Hz, 1 H), 3.95 (ddd, J = 4.0,

9.3, 9.3 Hz, 1 H), 5.67 (d, J = 3.9 Hz, 1 H), 7.32–7.35 (m, 3 H),

7.47–7.49 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = –4.90 (q), –4.14

(q), –3.51 (q), –3.07 (q), 13.42 (t), 15.57 (t), 18.03 (s), 18.20 (q),

23.91 (t), 25.81 (q, 3 C), 30.67 (d), 32.68 (t), 34.17 (t), 40.56 (t),

45.58 (d), 67.20 (d), 81.53 (s), 126.81 (d), 127.79 (d, 2 C), 128.96

(d), 138.41 (d, 2 C), 138.87 (s), 139.09 (s), 171.92 (s) ppm. IR (neat):

less viscous liquid. R_f= 0.34 (Et₂O). [α]²_D⁵= +11.4 (c = 0.96). H

1

NMR (CDCl₃): δ = 0.01 (s, 3 H), 0.06 (s, 3 H), 0.29 (s, 6 H), 0.67

(ddd, J = 4.4, 13.9, 13.9 Hz, 1 H), 0.81–0.88 (m, 1 H), 0.82 (s, 9

H), 1.04 (d, J = 6.9 Hz, 3 H), 1.26–1.30 (m, 1 H), 1.44–1.52 (m, 1

H), 1.53–1.60 (m, 3 H), 1.72–1.83 (m, 2 H), 2.30 (dd, J = 4.0,

18.0 Hz, 1 H), 2.43 (dd, J = 1.3, 18.0 Hz, 1 H), 2.78–2.83 (m, 1 H),

3.60 (dt, J = 10.4, 6.0 Hz, 1 H), 3.63 (dt, J = 10.4, 6.0 Hz, 1 H),

3.88 (d, J = 10.2 Hz, 1 H), 4.08 (dd, J = 4.1, 10.2 Hz 1 H), 4.09

(d, J = 12.0 Hz, 1 H), 4.16–4.18 (m, 1 H), 4.20 (d, J = 12.0 Hz, 1

H), 7.33–7.36 (m, 3 H), 7.51–7.54 (m, 2 H) ppm. ¹³C NMR

(CDCl₃): δ = –5.15 (q), –4.62 (q), –3.24 (q), –3.21 (q), 12.90 (t),

17.72 (s), 20.58 (q), 23.19 (t), 25.60 (q, 3 C), 31.09 (t), 32.12 (t),

34.98 (d), 38.18 (t), 45.57 (d), 62.34 (t), 62.82 (t), 66.84 (d), 70.07

(d), 127.73 (d, 2 C), 128.19 (s), 128.28 (d), 133.57 (d, 2 C), 139.25

ν = 2952, 2931, 1728, 1452, 1246, 1207, 1149, 1112, 1095, 1015,

˜

834, 815, 772, 696, 674 cm^–1. MS (CID, –25 V): m/z (%) = 671

(100). C₂₈H₄₅IO₃Si₂(612.73): calcd. C 54.89, H 7.40; found C

54.97, H 7.22. rac-34 from rac-33: R_f= 0.50 (pentane/Et₂O, 3:2).

¹H NMR (C₆D₆): δ = 0.20 (s, 3 H), 0.22 (s, 3 H), 0.50 (s, 6 H),

0.77–0.88 (m, 2 H), 0.79 (d, J = 7.1 Hz, 3 H), 1.05–1.10 (m, 1 H),

1.10–1.16 (m, 1 H), 1.19 (s, 9 H), 1.55 (ddd, J = 5.1, 12.5, 12.7 Hz,

1 H), 1.69 (dddd, J = 5.0, 6.3, 12.8, 18.6 Hz, 1 H), 2.03–2.12 (m, 1

H), 2.24 (dd, J = 1.6, 17.8 Hz, 1 H), 2.25–2.32 (m, 1 H), 2.33 (dd,

J = 4.7, 17.8 Hz, 1 H), 2.47 (ddd, J = 1.1, 12.5, 13.9 Hz, 1 H), 2.67

(ddq, J = 4.9, 5.1, 7.1 Hz 1 H), 3.47 (d, J = 9.5 Hz, 1 H), 3.53 (d,

J = 9.5 Hz, 1 H), 3.82 (m, 1 H), 4.52 (d, J = 4.2 Hz, 1 H), 7.31–

7.35 (m, 1 H), 7.37–7.42 (m, 2 H), 7.68–7.71 (m, 2 H) ppm. ¹³C

NMR (C₆D₆): δ = –4.72 (q), –3.95 (q), –3.12 (q), –2.92 (q), 6.35

(t), 13.17 (t), 16.91 (q), 18.43 (s), 23.59 (t), 26.13 (q, 3 C), 28.20 (t),

29.84 (t), 32.48 (d), 38.95 (t), 46.00 (d), 66.30 (d), 69.13 (d), 128.29

(d, 2 C), 129.37 (d), 131.30 (s), 133.96 (d, 2 C), 135.29 (s), 139.19

(s), 140.61 (s) ppm. IR (neat): ν = 3383 cm^–1(broad), 2953, 2929,

˜

2858, 1467, 1426, 1250, 1113, 1056, 1004, 829, 774, 729, 698 cm^–1.

MS (CID, –25 V): m/z (%) = 565 (100). C₂₈H₅₀O₄Si₂(506.87):

calcd. C 66.35, H 9.94; found C 66.45, H 10.04.

Bis(trityl) Ether 38: Triol 37 (3.13 g, 6.20 mmol) was dissolved in

CH₂Cl₂(300 mL), and pyridine (975 µL, 124 mmol), DMAP

(908 mg, 7.44 mmol), and trityl chloride (4.89 g, 17.56 mmol) were

added. The resulting mixture was stirred at room temperature for

40 h. The solvent was evaporated, and the residue was filtered

through a pad of silica gel (pentane/Et₂O, 9:1). Final purification

was achieved by flash chromatography (pentane/Et₂O, 9:1 + 0.5%

Et₃N) to give 38 (5.51 g, 90%) as a cured foam. R_f= 0.37 (pentane/

Et₂O, 9:1). [α]²_D¹= –4.1 (c = 1.00). H NMR (CDCl₃): δ = 0.00 (s,

1

(s), 172.68 (s) ppm. IR (neat): ν = 2953, 2926, 2856, 1726, 1447,

˜

1362, 1247, 1149, 1111, 1084, 1023, 960, 916, 832, 810, 771, 728,

698, 674 cm^–1. MS (CID, 25 V): m/z (%) = 613 (100), 630 (20), 635

3 H), 0.03 (s, 3 H), 0.29 (s, 6 H), 0.75 (ddd, J = 4.4, 13.9, 13.9 Hz,

1 H), 0.82 (ddd, J = 4.7, 13.9, 13.9 Hz, 1 H), 0.79 (s, 9 H), 0.87 (d,

1156

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Eur. J. Org. Chem. 2006, 1144–1161

Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

FULL PAPER

J = 6.9 Hz, 3 H), 1.20–1.24 (m, 1 H), 1.24–1.27 (m, 1 H), 1.38–

1.48 (m, 3 H), 1.49–1.58 (m, 1 H), 1.70–1.79 (m, 1 H), 2.29–2.33 (m,

1 H), 2.36 (dd, J = 4.0, 18.1 Hz, 1 H), 2.47 (dd, J = 1.3, 18.1 Hz, 1

1.89–1.96 (m, 1 H), 2.04–2.12 (m, 1 H), 2.34 (ddq, J = 7.0, 7.0,

7.0 Hz, 1 H), 2.52 (d, J = 18.5 Hz, 1 H), 2.66 (dd, J = 4.4, 18.5 Hz,

1 H), 2.89 (t, J = 6.5 Hz, 2 H), 3.51 (d, J = 10.5 Hz, 1 H), 3.75 (d,

H), 2.82–2.91 (m, 2 H), 3.47 (d, J = 10.8 Hz, 1 H), 3.56 (d, J = J = 10.5 Hz, 1 H), 3.81–3.90 (m, 2 H), 4.13 (broad s, 2 H), 7.18–

10.7 Hz, 1 H), 3.65 (d, J = 10.7 Hz, 1 H), 3.96 (dd, J = 3.5, 10.8 Hz,

1 H), 4.15 (broad s, 1 H), 7.16–7.27 (m, 18 H), 7.32–7.35 (m, 3 H),

7.36–7.40 (m, 6 H), 7.41–7.45 (m, 6 H), 7.50–7.54 (m, 2 H) ppm.

¹³C NMR (CDCl₃): δ = –5.13 (q), –4.58 (q), –3.23 (q), –3.18 (q),

12.93 (t), 17.73 (s), 19.58 (q), 23.19 (t), 25.65 (q, 3 C), 29.01 (t),

7.22 (m, 6 H), 7.22–7.28 (m, 12 H), 7.36–7.39 (m, 6 H), 7.40–7.44

(m, 6 H) ppm. ¹³C NMR (CDCl₃): δ = 19.65 (q), 28.84 (t), 31.51

(t), 32.49 (t), 35.38 (d), 38.51 (t), 39.97 (d), 60.89 (t), 63.29 (t), 64.00

(t), 67.21 (d), 68.85 (d), 86.36 (s), 86.50 (s), 126.76 (d, 3 C), 126.93

(d, 3 C), 127.63 (d, 6 C), 127.84 (d, 6 C), 127.73 (s) 128.64 (d, 6

32.84 (t), 35.57 (d), 38.17 (t), 45.63 (d), 63.24 (t), 64.04 (t), 67.33 C), 128.67 (d, 6 C), 139.13 (s), 144.06 (s, 3 C), 144.40 (s, 3 C) ppm.

(d), 69.97 (d), 86.08 (s), 86.44 (s), 125.88 (s), 126.67 (d, 3 C), 126.88

(d, 3 C), 127.59 (d, 6 C) 127.70 (d, 8 C), 128.67 (d, 6 C), 128.71

(d, 6 C), 128.77 (d), 133.59 (d, 2 C), 139.41 (s), 140.41 (s), 144.15

IR (neat): ν = 3330 cm^–1(broad), 3057, 2927, 2863, 1447, 1372,

˜

1220, 1155, 1055, 1032, 986, 899, 763, 746, 700 cm^–1. MS (CID/

50 V): m/z (%) = 797 (9), 781 (100). C₅₂H₅₄O₅(758.98): calcd. C

82.29, H 7.17; found C 82.24, H 7.22.

(s, 3 C), 144.57 (s, 3 C) ppm. IR (neat): ν = 3510 cm^–1(broad),

˜

3058, 2952, 2929, 2858, 1558, 1489, 1447, 1251, 1112, 1059, 1031,

987, 831, 771, 745, 698 cm^–1. MS (CID/75 V): m/z (%) = 1014 (100).

C₆₆H₇₈O₄Si₂(991.49): calcd. C 79.95, H 7.93; found C 79.43, H

8.23.

Lactone 41: Triol 40 (65 mg, 86 µmol), TEMPO (4 mg, 26 µmol),

and TBACl (4 mg, 9 µmol) in a biphasic mixture of CH₂Cl₂

(1.5 mL) and an aqueous solution of NaHCO₃(0.5 ) and K₂CO₃

(0.05 ) were vigorously stirred at room temperature. NCS (63 mg,

474 µmol) was added, and stirring was maintained for 3 h. The

resulting mixture was diluted with H₂O (1 mL) and extracted with

CH₂Cl₂(4×3 mL). The combined extracts were washed with brine

(5 mL), dried with MgSO₄, filtered and the solvents evaporated.

The residue was purified by flash chromatography (Et₂O) to give

41 (54.5 mg, 84%) as a cured white foam. R_f= 0.30 (Et₂O). [α]²_D²

Diol 39: To a solution of the silyl ether 38 (50 mg, 50 µmol) in THF

(1.5 mL) was added a mixture of TBAF (250 µL, approx. 250 µmol,

1  in THF) and HOAc (5 µL, 88 µmol). The solution was stirred

at room temperature for 3 h, diluted with Et₂O (2 mL), and

quenched with aqueous NaHCO₃(0.5 mL, 5%). The aqueous layer

was extracted with Et₂O (3×2 mL), and the combined extracts

were dried, filtered and the solvents evaporated. The residue was

purified by flash chromatography (pentane/Et₂O, 7:3) to afford 39

(43 mg, 97%) as a cured white foam. R_f= 0.66 (pentane/Et₂O, 1:1).

1

= +0.3 (c = 0.91). H NMR (CDCl₃): δ = 0.94 (d, J = 7.0 Hz, 3

H), 1.15–1.21 (m, 1 H), 1.23–1.32 (m, 2 H), 1.39–1.46 (m, 2 H),

2.34 (ddq, J = 7.0, 7.0, 7.0 Hz, 1 H), 2.51 (dd, J = 4.3, 17.8 Hz, 1

H), 2.55–2.71 (m, 4 H), 2.85–2.92 (m, 2 H), 3.56 (d, J = 10.8 Hz,

1 H), 3.80 (d, J = 10.8 Hz, 1 H), 3.98–4.03 (m, 1 H), 4.90 (d, J =

5.6 Hz, 1 H), 7.17–7.28 (m, 18 H), 7.30–7.37 (m, 6 H), 7.37–7.42

1

[α]²_D²= +3.8 (c = 1.01). H NMR (CDCl₃): δ = 0.30 (s, 6 H), 0.84

(ddd, J = 5.5, 5.5, 11.0 Hz, 2 H), 0.87 (d, J = 6.9 Hz, 3 H), 1.17–

1.26 (m, 1 H), 1.32–1.45 (m, 4 H), 1.63–1.70 (m, 1 H), 1.72–1.79

(m, 1 H), 2.31–2.35 (m, 1 H), 2.41 (d, J = 5.0 Hz, 1 H), 2.48 (dd, (m, 6 H) ppm. ¹³C NMR (CDCl₃): δ = 18.07 (q), 28.78 (t), 31.85

J = 1.0, 18.6 Hz, 1 H), 2.57 (dd, J = 4.4, 18.6 Hz, 1 H), 2.86 (d, J

= 8.1 Hz, 1 H), 2.89 (t, J = 6.5 Hz, 2 H), 3.50 (d, J = 10.4 Hz, 1

H), 3.72 (d, J = 10.5 Hz, 1 H), 4.08 (dd, J = 2.9, 7.8 Hz, 1 H),

4.14–4.17 (m, 1 H), 7.17–7.28 (m, 18 H), 7.33–7.36 (m, 3 H), 7.36–

7.39 (m, 6 H), 7.41–7.44 (m, 6 H), 7.52–7.55 (m, 2 H) ppm. ¹³C

(t), 32.99 (t), 34.60 (t), 35.04 (d), 39.02 (d), 63.08 (t), 63.78 (t), 66.08

(d), 76.49 (d), 86.28 (s), 86.83 (s), 126.80 (d, 3 C), 127.14 (d, 3 C),

127.68 (d, 6 C), 127.86 (d, 6 C), 128.64 (d, 6 C), 128.67 (d, 6 C),

131.20 (s), 134.78 (s), 143.73 (s, 3 C), 144.39 (s, 3 C), 176.40 (s)

ppm. IR (neat): ν = 3450 cm^–1(broad), 3058, 2927, 2857, 1773,

˜

NMR (CDCl₃): δ = –3.16 (q), –3.12 (q), 12.88 (t), 19.77 (q), 22.70 1490, 1447, 1183, 1155, 1056, 1032, 984, 900, 763, 746, 699 cm^–1.

(t), 28.68 (t), 32.43 (t), 35.40 (d), 38.91 (t), 45.26 (d), 63.32 (t), 64.01

(t), 66.96 (d), 68.45 (d), 86.39 (s), 86.49 (s), 126.78 (d, 3 C), 126.93

(d, 3 C), 127.53 (s), 127.65 (d, 6 C), 127.74 (d, 6 C), 127.77 (d, 2

C), 128.66 (d, 6 C), 128.69 (d, 6 C), 128.85 (d), 133.59 (d, 2 C),

139.39 (s), 139.55 (s), 144.10 (s, 3 C), 144.41 (s, 3 C) ppm. IR (neat):

MS (CID/100 V): m/z (%) = 777 (100). C₅₂H₅₀O₅(754.95): calcd.

C 82.73, H 6.68; found C 82.85, H 6.58.

Cyclohexenone 42: Bis(trityl) ether 38 (990 mg, 1.00 mmol) was dis-

solved in CH₂Cl₂(60 mL), and pyridine (600 µL, 6.00 mmol) and

Dess–Martin periodinane (850 mg, 2.00 mmol) were added. The re-

sulting solution was stirred in the dark at room temperature for

3.5 h. The reaction mixture was directly subjected to flash

chromatography (pentane/Et₂O, 9:1) to give 42 (980 mg, 99%) as a

cured white foam. R_f= 0.37 (pentane/Et₂O, 9:1). [α]²_D⁵= –3.3 (c =

ν = 3360 cm^–1(broad), 3058, 3024, 2931, 1489, 1448, 1247, 1218,

˜

1113, 1054, 1029, 987, 834, 763, 745, 699 cm^–1. MS (CID/75 V):

m/z (%) = 899 (100). C₆₀H₆₄O₄Si (877.23): calcd. C 82.15, H 7.35;

found C 81.78, H 7.32.

1

Triol 40: To activated molecular sieves (4 Å, 90 mg) was added a

solution of silane 39 (50 mg, 57 µmol) in a fresh charge of TBAF

(1.0 mL, approx. 1.0 mmol, 1  in THF), and the mixture was

heated in a sealed tube at 100 °C for 14 h. To the resulting grey

suspension were sequentially added KF (12 mg, 208 µmol),

1.00). H NMR (CDCl₃): δ = –0.03 (s, 3 H), 0.00 (s, 3 H), 0.26 (s,

3 H), 0.27 (s, 3 H), 0.63 (ddd, J = 4.2, 14.1, 14.1 Hz, 1 H), 0.71–

0.79 (m, 1 H), 0.75 (s, 9 H), 0.94 (d, J = 6.0 Hz, 3 H), 1.26–1.37

(m, 3 H), 1.48–1.58 (m, 2 H), 1.76–1.85 (m, 1 H), 2.16 (ddd, J = 2.8,

7.3, 7.3 Hz, 1 H), 2.34–2.46 (m, 1 H), 2.65 (dd, J = 4.7, 18.7 Hz, 1

NaHCO₃(10 mg, 120 µmol), MeOH (0.5 mL), and H₂O₂(0.2 mL, H), 2.70 (dd, J = 3.8, 18.7 Hz, 1 H), 2.84 (t, J = 6.4 Hz, 2 H), 3.70

30% in H₂O) at room temperature. The mixture was then heated

at 90 °C for 90 min and cooled to room temperature. The molecular

sieves were separated by filtration and sequentially washed with

EtOAc (3 mL) and H₂O (3 mL). The filtrate was neutralized with

aqueous satd. NH₄Cl, and the aqueous layer was extracted with

EtOAc (3×5 mL). The combined extracts were washed with brine

(5 mL), dried with MgSO₄, filtered and the solvents evaporated.

The residue was purified by flash chromatography (EtOAc) to give

40 (37 mg, 88%) as a cured white foam. R_f= 0.53 (EtOAc). [α]²_D²

(d, J = 12.3 Hz, 1 H), 3.85 (d, J = 12.3 Hz, 1 H), 4.26–4.30 (m, 1

H), 7.18–7.33 (m, 21 H), 7.37–7.41 (m, 6 H), 7.37–7.41 (m, 6 H),

7.48–7.51 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = –4.92 (q), –4.42

(q), –3.22 (q), –3.16 (q), 13.08 (t), 17.87 (s), 18.93 (t), 19.20 (q),

25.62 (q, 3 C), 28.88 (t), 31.44 (t), 32.76 (d), 36.85 (t), 56.85 (d),

63.38 (t), 63.81 (t), 68.25 (d), 86.15 (s), 86.97 (s), 126.71 (d, 3 C),

127.15 (d, 3 C), 127.60 (d, 6 C), 127.71 (d, 2 C), 127.88 (d, 6 C),

128.61 (d, 6 C), 128.67 (d, 6 C), 128.78 (d), 133.54 (d, 2 C), 138.30

(s), 139.30 (s), 143.64 (s, 3 C), 144.47 (s, 3 C), 147.91 (s), 200.23 (s)

1

= +5.0 (c = 1.00). H NMR (CDCl₃): δ = 0.89 (d, J = 7.0 Hz, 3

H), 1.18–1.28 (m, 1 H), 1.34–1.46 (m, 3 H), 1.69–1.75 (m, 1 H),

ppm. IR (neat): ν = 3059, 3021, 2947, 2856, 1671, 1447, 1250, 1111,

˜

1067, 1032, 987, 834, 771, 745, 699 cm^–1. MS (CID/50 V): m/z (%)

Eur. J. Org. Chem. 2006, 1144–1161

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1157

P. Metz et al.

FULL PAPER

= 1027 (30), 1011 (5), 243 (100). C₆₆H₇₆O₄Si₂(989.48): calcd. C

80.11, H 7.74; found C 80.17, H 7.78.

(8 mL), and H₂O₂(3.4 mL, 30% in H₂O) were added sequentially

at room temperature, and the mixture was then heated under reflux

for 1 h. The resulting white suspension was cooled to room tem-

perature, the molecular sieves were separated by filtration and

washed sequentially with EtOAc (20 mL) and H₂O (20 mL). The

filtrate was neutralized with aqueous satd. NH₄Cl, and the aqueous

layer was extracted with EtOAc (3×30 mL). The combined extracts

were washed with brine (20 mL), dried, filtered and the solvents

evaporated. The residue was purified by flash chromatography

(EtOAc) to give 45 (722 mg, 99%) as a cured white foam. R_f= 0.29

Alcohol 43: To a solution of the silyl ether 42 (980 mg, 0.99 mmol)

in THF (30 mL) was added a mixture of TBAF (4.8 mL, 4.8 mmol,

1  in THF) and HOAc (90 µL, 1.55 mmol). The solution was

stirred at room temperature for 26 h and then poured into aqueous

NaHCO₃(20 mL, 5%). The aqueous layer was extracted with Et₂O

(3×20 mL), and the combined extracts were washed with brine

(20 mL), dried, filtered and the solvents evaporated. The residue

was purified by flash chromatography (pentane/Et₂O, 3:2 + 0.1%

Et₃N) to afford 43 (830 mg, 96%) as a cured white foam. R_f= 0.28

(pentane/Et₂O, 3:2). [α]²_D⁵= –2.5 (c = 1.01). ¹H NMR (CDCl₃): δ

= 0.27 (s, 6 H), 0.69 (ddd, J = 4.6, 13.6, 14.3 Hz, 1 H), 0.71 (ddd,

J = 4.7, 12.9, 13.6 Hz, 1 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.23–1.54

(m, 5 H), 1.85–1.93 (m, 1 H), 2.26 (ddd, J = 2.8, 7.3, 7.3 Hz, 1 H),

2.36–2.44 (m, 1 H), 2.70 (dd, J = 4.3, 18.8 Hz, 1 H), 2.80–2.86 (m,

3 H), 3.71 (d, J = 12.2 Hz, 1 H), 3.91 (d, J = 12.2 Hz, 1 H), 4.31–

4.33 (m, 1 H), 7.17–7.33 (m, 18 H), 7.30–7.33 (m, 3 H) 7.36–7.39

(m, 6 H), 7.40–7.43 (m, 6 H), 7.48–7.50 (m, 2 H) ppm. ¹³C NMR

(CDCl₃): δ = –3.24 (q), –3.16 (q), 12.80 (t), 18.98 (q + t, 2 C), 28.91

(t), 31.43 (t), approx. 32.5 (d, signal detectable only via HSQC and

COSY), 36.36 (t), 55.71 (d), 63.49 (t), 63.82 (t), 67.62 (d), 86.21 (s),

89.09 (s), 126.74 (d, 3 C), 127.20 (d, 3 C), 127.63 (d, 6 C), 127.77

(d, 2 C), 127.91 (d, 6 C), 128.59 (d, 6 C), 128.64 (d, 6 C), 128.88

(d), 133.53 (d, 2 C), 138.67 (s), 139.12 (s), 143.59 (s, 3 C), 144.43

1

(EtOAc). [α]²_D²= –23.7 (c = 1.00). H NMR (CDCl₃): δ = 0.96 (d,

J = 7.0 Hz, 3 H), 1.20–1.31 (m, 5 H), 1.56–1.65 (m, 1 H), 2.06 (ddt,

J = 3.5, 4.0, 8.0 Hz, 1 H), 2.22 (dd, J = 9.6, 17.7 Hz, 1 H), 2.23–

2.28 (m, 1 H), 2.70 (dd, J = 5.8, 17.7 Hz, 1 H), 2.90 (t, J = 6.3 Hz,

2 H), 3.52 (d, J = 10.6 Hz, 1 H), 3.59–3.64 (m, 1 H), 3.67 (d, J =

10.6 Hz, 1 H), 3.70–3.74 (m, 1 H), 4.05 (d, J = 3.5 Hz, 1 H), 4.32

(ddd, J = 4.0, 5.8, 9.6 Hz, 1 H), 7.17–7.22 (m, 6 H), 7.23–7.28 (m,

12 H), 7.35–7.39 (m, 6 H), 7.41–7.44 (m, 6 H) ppm. ¹³C NMR

(CDCl₃): δ = 20.47 (q), 28.49 (t), 29.73 (t), 32.19 (t), 34.16 (t), 34.31

(d), 45.95 (d), 62.07 (t), 62.74 (t), 63.63 (t), 65.66 (d), 69.66 (d),

86.29 (s), 86.66 (s), 126.85 (d, 3 C), 126.98 (d, 3 C), 127.68 (d, 6

C), 127.78 (d, 6 C), 128.62 (d, 6 C), 128.67 (d, 6 C), 131.77 (s),

136.98 (s), 143.98 (s, 3 C), 144.34 (s, 3 C) ppm. IR (neat): ν =

˜

3320 cm^–1(broad), 3057, 2926, 2863, 1448, 1378, 1220, 1182, 1055,

1030, 1001, 899, 762, 745, 696 cm^–1. MS (CID/100 V): m/z (%) =

797 (32), 781 (100). C₅₂H₅₄O₅(758.98): calcd. C 82.29, H 7.17;

found C 82.34, H 7.15.

(s, 3 C), 147.90 (s), 199.83 (s) ppm. IR (neat): ν = 3450 cm^–1

˜

(broad), 3058, 3026, 2929, 2868, 1666, 1447, 1247, 1112, 1065, 984,

834, 764, 745, 699 cm^–1. MS (CID/–10 V): m/z (%) = 931 (100).

C₆₀H₆₂O₄Si (875.22): calcd. C 82.34, H 7.14; found C 82.41, H

7.29.

Lactone 46: To a solution of the triol 45 (457 mg, 603 µmol) in

CH₂Cl₂(7 mL) were added TEMPO (18 mg, 115 µmol) and bis-

(acetoxy)iodobenzene (388 mg, 1.20 mmol) at room temperature.

After stirring for 3 h in the dark, the same amount of oxidant and

cooxidant were added, and stirring was maintained for 6 h. The

resulting orange solution was directly subjected to flash chromatog-

raphy (Et₂O) to afford 46 (341 mg, 75%) as a cured white foam. R_f

= 0.31 (Et₂O). [α]²_D⁴= –11.0 (c = 1.04). ¹H NMR (CDCl₃): δ = 1.00

(d, J = 6.8 Hz, 3 H), 1.05–1.12 (m, 1 H), 1.21–1.33 (m, 3 H), 1.57

(s, 1 H), 2.03 (dd, J = 5.3, 18.6 Hz, 1 H), 2.30–2.34 (m, 1 H), 2.66–

2.78 (m, 3 H), 2.88–2.94 (m, 2 H), 2.96–3.03 (m, 1 H), 3.77 (d, J

= 11.0 Hz, 1 H), 3.80 (d, J = 11.0 Hz, 1 H), 4.10 (broad s, 1 H),

5.03 (ddd, J = 2.4, 4.0, 8.0 Hz, 1 H), 7.18–7.23 (m, 6 H), 7.25–7.30

(m, 12 H), 7.37–7.42 (m, 12 H) ppm. ¹³C NMR (CDCl₃): δ = 19.18

(q), 28.08 (t), 30.90 (t), 30.59 (t), 32.39 (t), 33.60 (d), 39.44 (d),

62.99 (t), 63.09 (t), 66.72 (d), 77.97 (d), 86.32 (s), 86.78 (s), 126.82

(d, 3 C), 127.04 (d, 3 C), 127.69 (d, 6 C), 127.82 (d, 6 C), 128.59

(d, 6 C), 128.65 (d, 6 C), 132.51 (s), 139.70 (s), 143.98 (s, 3 C),

Diol 44: To a solution of enone 43 (1.20 g, 1.37 mmol) in CH₂Cl₂

(140 mL) was added Red-Al (1.6 mL, approx. 5.5 mmol, 3.5  in

toluene) at –20 °C within 1 h. The mixture was allowed to reach

room temperature overnight. After quenching with aqueous satd.

NH₄Cl, the mixture was stirred until gas evolution ceased and dried

with MgSO₄. The mixture was filtered, the solvent was removed,

and the crude mixture was purified by flash chromatography (Et₂O)

to give 44 (1.08 g, 90%) and 39 (43 mg, 4%) as cured white foams.

1

44: R_f= 0.39 (Et₂O). [α]²_D²= –21.9 (c = 1.01). H NMR (CDCl₃):

δ = 0.15 (s, 3 H), 0.20 (s, 3 H), 0.71–0.75 (m, 2 H), 0.93 (d, J =

7.0 Hz, 3 H), 0.96–1.04 (m, 1 H), 1.10–1.29 (m, 3 H), 1.19 (d, J =

6.3 Hz, 1 H), 1.37–1.41 (m, 1 H), 1.56–1.62 (m, 1 H), 1.70 (ddt, J

= 3.8, 8.0, 8.0 Hz, 1 H), 2.13 (dd, J = 9.2, 17.6 Hz, 1 H), 2.22–2.26

(m, 1 H), 2.53 (dd, J = 5.7, 17.6 Hz, 1 H), 2.84–2.93 (m, 2 H), 3.53

(d, J = 10.5 Hz, 1 H), 3.58 (d, J = 10.5 Hz, 1 H), 4.11 (dd, J = 3.8,

6.3 Hz, 1 H), 4.25 (ddd, J = 5.7, 8.0, 9.2 Hz, 1 H), 7.18–7.29 (m,

21 H), 7.38–7.45 (m, 14 H) ppm. ¹³C NMR (CDCl₃): δ = –3.33

(q), –3.03 (q), 13.60 (t), 17.99 (t), 20.39 (q), 28.54 (t), 32.10 (t),

34.25 (t), 34.53 (d), 50.08 (d), 62.81 (t), 63.80 (t), 65.74 (d), 69.34

(d), 86.29 (s), 86.52 (s), 126.82 (d, 3 C), 126.95 (d, 3 C), 127.67 (d,

6 C), 127.75 (d, 6 C), 127.72 (d, 2 C), 128.62 (d, 6 C), 128.65 (d, 6

C), 128.84 (d), 131.14 (s), 133.46 (d, 2 C), 137.73 (s), 139.14 (s),

144.25 (s, 3 C), 175.92 (s) ppm. IR (neat): ν = 3480 cm^–1(broad),

˜

3054, 2926, 2851, 1762, 1715, 1489, 1448, 1183, 1150, 1054, 1026,

899, 760, 746, 696 cm^–1. MS (CID/50 V): m/z (%) = 793 (93), 777

(100). C₅₂H₅₀O₅(754.95): calcd. [M⁺] 754.3658; found [M⁺]

754.3667.

Silyl Ether 47: To a solution of alcohol 46 (184 mg, 244 µmol) in

CH₂Cl₂(7 mL) were added imidazole (83 mg, 1.22 mmol) and

TMSCl (61 µL, 488 µmol) at room temperature. The solution was

stirred for 30 min and then filtered rapidly through a pad of silica

gel (Et₂O). After evaporation of the filtrate, essentially pure 47

(193 mg, 96%) was obtained as a cured white foam. R_f= 0.42 (pen-

tane/Et₂O, 3:2). [α]²_D⁴= –26.4 (c = 1.00). ¹H NMR (CDCl₃): δ =

0.14 (s, 9 H), 0.92 (d, J = 6.9 Hz, 3 H), 1.05–1.15 (m, 1 H), 1.19–

1.37 (m, 3 H), 2.07 (dd, J = 6.6, 18.4 Hz, 1 H), 2.30–2.34 (m, 1 H),

2.61 (dd, J = 11.2, 18.4 Hz, 1 H), 2.66 (dd, J = 2.1, 16.1 Hz, 1 H),

2.77 (dd, J = 4.8, 16.1 Hz, 1 H), 2.85–2.95 (m, 3 H), 3.51 (d, J =

10.6 Hz, 1 H), 3.62 (d, J = 10.6 Hz, 1 H), 4.15 (d, J = 2.4 Hz, 1

143.99 (s, 3 C), 144.35 (s, 3 C) ppm. IR (neat): ν = 3450 cm^–1

˜

(broad), 3057, 2924, 2868, 1489, 1448, 1427, 1247, 1220, 1113,

1056, 1031, 987, 812, 761, 744, 696 cm^–1. MS (CID/25 V): m/z (%)

= 894 (100). C₆₀H₆₄O₄Si (877.23): calcd. C 82.15, H 7.35; found C

81.78, H 7.32.

Triol 45: To activated molecular sieves (4 Å, 1.50 g) was added a

solution of the silane 44 (841 mg, 0.96 mmol) in a fresh charge of

TBAF (10.0 mL, approx. 10.0 mmol, 1  in THF), and the re-

sulting dark grey suspension was heated under reflux for 4 h. KF

(195 mg, 3.37 mmol), NaHCO₃(186 mg, 2.21 mmol), MeOH H), 5.00 (ddd, J = 2.1, 4.8, 7.4 Hz, 1 H), 7.16–7.30 (m, 18 H), 7.37–

1158

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Eur. J. Org. Chem. 2006, 1144–1161

Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

7.43 (m, 12 H) ppm. ¹³C NMR (CDCl₃): δ = 0.68 (q, 3 C), 19.00 (t), 31.16 (t), 33.57 (d), 42.43 (d), 62.85 (t), 62.89 (t), 69.33 (d),

FULL PAPER

(q), 28.27 (t), 30.86 (t), 31.00 (t), 32.05 (t), 33.91 (d), 40.40 (d),

62.76 (t), 63.23 (t), 67.05 (d), 78.06 (d), 86.31 (s), 86.58 (s), 126.83

(d, 3 C), 126.92 (d, 3 C), 127.69 (d, 6 C), 127.76 (d, 6 C), 128.65

(d, 6 C), 128.67 (d, 6 C), 131.02 (s), 139.51 (s), 144.04 (s, 3 C),

75.63 (d), 86.13 (s), 86.81 (s), 125.09 (t), 126.20 (t), 126.78 (d, 3 C),

127.04 (d, 3 C), 127.69 (d, 6 C), 127.84 (d, 6 C), 128.57 (d, 6 C),

128.66 (d, 6 C), 134.40 (s), 135.71 (s), 135.83 (s), 136.18 (s), 143.93

(s, 3 C), 144.30 (s, 3 C), 167.05 (s), 169.33 (s) ppm. IR (neat): ν =

˜

144.30 (s, 3 C), 176.10 (s) ppm. IR (neat): ν = 3058, 2953, 2864,

3057, 2927, 2866, 1765, 1710, 1490, 1448, 1274, 1150, 1065, 1031,

1003, 978, 943, 899, 745, 704, 697 cm^–1. MS (CID/50 V): m/z (%)

= 873 (61), 857 (100). C₅₇H₅₄O₆(835.04): calcd. C 81.99, H 6.52;

found C 81.78, H, 6.68.

˜

1772, 1490, 1448, 1356, 1250, 1183, 1154, 1056, 1030, 899, 878,

838, 745, 696 cm^–1. MS (CID/10 V): m/z (%) = 849 (100), 845 (20).

C₅₅H₅₈O₅Si (827.13): calcd. C 79.86, H 7.07; found C 79.89, H

7.12.

(–)-Eriolanin (1): A solution of bis(trityl) ether 48 (24.5 mg,

29.3 µmol) in MeOH (1.5 mL) containing pTsOH×H₂O (1.1 mg,

5.9 µmol) was stirred at room temperature for 17 h and then diluted

with EtOAc (3 mL). The solvent was evaporated without a heating

source, and the residue was purified by flash chromatography

(EtOAc) to give (–)-1 (10.0 mg, 97%) as colorless crystals. R_f=

0.34 (EtOAc); m.p. 133–134 °C; ref.^[1]126.5–128 °C. [α]²_D⁵= –88.6

α-Methylene-γ-lactone 5a: To a solution of the lactone 47 (60 mg,

72 µmol) in THF (3 mL) in a sealed tube was added dry paraform-

aldehyde (66 mg, 2.2 mmol) and NaH (10.4 mg, 432 µmol). The

colorless mixture was stirred for 15–120 min at 100 °C. A change

in color of the mixture to yellowish brown within this time period

indicates termination of the reaction, and the heating source was

removed immediately. The resulting solution was cooled to room

temperature, diluted with Et₂O (4 mL) and filtered rapidly through

a pad of silica gel. After evaporation of the solvent, the crude mix-

ture was dissolved in THF (6 mL) and placed in an ice bath. TBAF

(95 µL, approx. 95 µmol, 1  in THF) was added, and the solution

was stirred at this temperature for 20 min. The reaction was

quenched with aqueous satd. NH₄Cl (2 mL), and the aqueous layer

was extracted with Et₂O (3×3 mL). The combined extracts were

washed with brine (2 mL), dried with MgSO₄, filtered and the sol-

vents evaporated. The residue was purified by flash chromatog-

raphy (pentane/Et₂O, 1:9) to give 5a (33.5 mg, 61% from 47) as a

cured white foam. R_f= 0.34 (pentane/Et₂O, 1:9). [α]²_D⁴= +34.7 (c

1

(c = 0.97); ref.^[1][α]²_D⁵= –93 (CHCl₃). H NMR (CDCl₃): δ = 0.88

(d, J = 6.9 Hz, 3 H), 1.02–1.12 (m, 2 H), 1.21–1.34 (m, 2 H), 1.92

(s, 3 H), 2.62 (dd, J = 3.3, 16.1 Hz, 1 H), 2.28 (tq, J = 3.5, 6.9 Hz,

1 H), 2.94 (dd, J = 2.3, 16.1 Hz, 1 H), 3.43 (dt, J = 12.1, 6.2 Hz, 1

H), 3.52–3.56 (m, 1 H), 3.53 (dt, J = 12.1, 6.0 Hz, 1 H), 4.18 (d, J

= 12.6 Hz, 1 H), 4.24 (d, J = 12.6 Hz, 1 H), 5.03 (ddd, J = 2.3, 3.3,

7.5 Hz, 1 H), 5.26 (d, J = 1.6 Hz, 1 H), 5.58 (t, J = 1.6 Hz, 1 H),

6.01 (d, J = 2.3 Hz, 1 H), 6.04 (s, 1 H), 6.39 (d, J = 2.6 Hz, 1 H)

ppm. ¹³C NMR (CDCl₃): δ = 18.19 (q), 18.83 (q), 29.78 (t), 30.88

(t), 30.91 (t), 33.06 (d), 43.12 (d), 61.43 (t), 62.63 (t), 69.49 (d),

75.53 (d), 126.03 (t), 126.35 (t), 135.45 (s), 136.02 (s), 136.07 (s),

136.32 (s), 167.05 (s), 170.45 (s) ppm. IR (neat): ν = 3360 cm^–1

˜

1

= 1.00). H NMR (CDCl₃): δ = 0.80–0.88 (m, 1 H), 0.92–1.02 (m,

(broad), 2935, 2877, 2850, 1751, 1710, 1658, 1634, 1410, 1316,

1270, 1156, 1137, 1053, 1026, 1007, 976, 901, 818, 745, 665 cm^–1.

MS (CID/10 V): m/z (%) = 391 (34), 368 (100), 351 (8).

1 H), 0.99 (d, J = 6.7 Hz, 3 H), 1.04–1.12 (m, 1 H), 1.26–1.34 (m,

1 H), 2.21–2.29 (m, 1 H), 2.69–2.75 (m, 1 H), 2.71 (dd, J = 4.3,

16.1 Hz, 1 H), 2.84 (dd, J = 2.3, 16.1 Hz, 1 H), 2.85–2.90 (m, 1 H),

3.42 (d, J = 11.1 Hz, 1 H), 3.47–3.50 (m, 1 H), 3.82 (d, J = 11.1 Hz,

1 H), 4.11 (s, 1 H), 5.00–5.03 (m, 1 H), 5.55 (s, 1 H), 6.04 (d, J =

2.1 Hz, 1 H), 7.16–7.30 (m, 18 H), 7.39–7.42 (m, 12 H) ppm. ¹³C

NMR (CDCl₃): δ = 19.37 (q), 27.84 (t), 30.57 (t), 31.31 (t), 33.33

(d), 44.68 (d), 62.79 (t), 63.16 (t), 68.33 (d), 75.64 (d), 86.13 (s),

86.82 (s), 123.98 (t), 126.78 (d, 3 C), 127.04 (d, 3 C), 127.65 (d, 6

C), 127.83 (d, 6 C), 128.61 (d, 6 C), 128.66 (d, 6 C), 132.01 (s),

136.48 (s), 140.11 (s), 144.00 (s, 3 C), 144.30 (s, 3 C), 169.66 (s)

Methacrylate 49: To a solution of angelic acid (20 mg, 200 µmol)

in toluene (100 µL) were added 2,4,6-trichlorobenzoyl chloride

(48.8 mg, 200 µmol) and Et₃N (27.8 µL, 200 µmol). After stirring

for 3.5 h at room temperature, alcohol 5a (14.0 mg, 18.3 µmol) was

added, and the solution was stirred at 100 °C for 8 h. The mixture

was cooled to room temperature, diluted with Et₂O (2 mL), and

filtered. The solvent was removed, and the residue was purified by

flash chromatography (pentane/Et₂O, 7:5) to afford 49 (9.3 mg,

60%) as a cured white foam. R_f= 0.41 (pentane/Et₂O, 7:5). [α]²_D⁵

ppm. IR (neat): ν = 3510 cm^–1(broad), 3056, 2958, 2929, 2861,

˜

1

1760, 1490, 1448, 1275, 1183, 1062, 1030, 1002, 899, 746, 704 cm^–1.

MS (CID/75 V): m/z (%) = 789 (100), 805 (20). C₅₃H₅₀O₅(766.96):

calcd. C 83.00, H 6.57; found C 83.33, H 6.69.

= –27.8 (c = 1.00). H NMR (CDCl₃): δ = 0.85 (d, J = 6.7 Hz, 3

H), 0.88–0.97 (m, 1 H), 1.00–1.12 (m, 2 H), 1.30–1.38 (m, 1 H),

1.89 (dd, J = 1.2, 1.2 Hz, 3 H), 2.04 (dd, J = 1.4, 7.3 Hz, 3 H),

2.25–2.33 (m, 1 H), 2.72 (dt, J = 8.6, 7.0 Hz, 1 H), 2.77 (dd, J =

3.7, 16.4 Hz, 1 H), 2.86 (dt, J = 8.6, 5.8 Hz, 1 H), 2.90 (dd, J =

1.9, 16.4 Hz, 1 H), 3.36 (d, J = 10.7 Hz, 1 H), 3.55 (dddd, J = 1.7,

2.2, 2.7, 7.8 Hz, 1 H), 3.80 (d, J = 10.7 Hz, 1 H), 4.99 (ddd, J =

1.9, 3.7, 7.8 Hz, 1 H), 5.34 (d, J = 1.7 Hz, 1 H), 5.83 (d, J = 2.2 Hz,

1 H), 6.13 (d, J = 2.7 Hz, 1 H), 6.15 (dq, J = 1.2, 7.3 Hz, 1 H),

7.18–7.23 (m, 6 H), 7.24–7.29 (m, 12 H), 7.35–7.37 (m, 6 H) 7.38–

7.42 (m, 6 H) ppm. ¹³C NMR (CDCl₃): δ = 15.82 (q), 18.85 (q),

20.61 (q), 27.87 (t), 30.89 (t), 31.15 (t), 33.67 (d), 42.53 (d), 62.84

(t), 63.01 (t), 68.55 (d), 74.08 (d), 86.14 (s), 86.73 (s), 125.11 (t),

126.78 (d, 3 C), 127.04 (d, 3 C), 127.55 (s), 127.67 (d, 6 C), 127.84

(d, 6 C), 128.55 (d, 6 C), 128.67 (d, 6 C), 134.22 (s), 135.84 (s),

136.01 (s), 139.15 (d), 143.95 (s, 3 C), 144.31 (s, 3 C), 167.56 (s),

Acrylate 48: To an ice-cold solution of the alcohol 5a (30 mg,

39 µmol) in THF (0.5 mL) were added successively Et₃N (80 µL,

590 µmol), DMAP (2.3 mg, 18.8 µmol), and methacrylic anhydride

(11.6 µL, 78.4 µmol). The mixture was stirred at 0 °C for 1 h and

at room temperature for additional 2 h. MeOH (25 µL) was added,

and stirring was maintained for 10 min. After evaporation of the

volatile compounds, the crude mixture was purified by flash

chromatography (pentane/Et₂O, 1:1) to give 48 (27.7 mg, 85%) as

a cured white foam. R_f= 0.43 (pentane/Et₂O, 1:1). [α]²_D⁶= –30.9 (c

= 0.91). ¹H NMR (CDCl₃): δ = 0.81 (d, J = 6.9 Hz, 3 H), 0.88–

0.97 (m, 1 H), 1.02–1.14 (m, 2 H), 1.28–1.38 (m, 1 H), 1.96 (s, 3

H), 2.24–2.32 (m, 1 H), 2.71 (dd, J = 3.8, 16.2 Hz, 1 H), 2.71–2.75

(m, 1 H), 2.88 (dt, J = 8.8, 5.8 Hz, 1 H), 2.96 (dd, J = 1.9, 16.2 Hz,

1 H), 3.46 (d, J = 11.0 Hz, 1 H), 3.55 (dddd, J = 1.9, 2.2, 2.8,

7.6 Hz, 1 H), 3.79 (d, J = 11.0 Hz, 1 H), 4.99 (ddd, J = 1.9, 3.8,

7.6 Hz, 1 H), 5.29 (d, J = 1.9 Hz, 1 H), 5.62 (s, 1 H), 5.83 (d, J =

2.2 Hz, 1 H), 6.09 (s, 1 H), 6.15 (d, J = 2.8 Hz, 1 H), 7.18–7.24 (m,

169.39 (s) ppm. IR (neat): ν = 3062, 2927, 2859, 1764, 1707, 1490,

˜

1448, 1273, 1226, 1147, 1133, 1031, 978, 945, 899, 745, 704,

696 cm^–1. MS (CID/10 V): m/z (%) = 866 (100). C₅₈H₅₆O₆(849.06):

calcd. C 82.05, H 6.65; found C 82.12, H 6.51.

6 H), 7.25–7.30 (m, 12 H), 7.36–7.39 (m, 6 H), 7.41–7.44 (m, 6 H) (–)-Eriolangin (2): A solution of the bis(trityl) ether 49 (21.0 mg,

ppm. ¹³C NMR (CDCl₃): δ = 18.19 (q), 18.69 (q), 27.89 (t), 30.56

24.7 µmol) in MeOH (2 mL) containing pTsOH×H₂O (1.5 mg,

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1159

P. Metz et al.

FULL PAPER

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8.3 µmol) was stirred at room temperature for 24 h and then diluted

with EtOAc (3 mL). The mixture was filtered through a pad of

silica gel, evaporated and purified by chromatography (EtOAc) to

give (–)-2 (7.6 mg, 85%) as colorless crystals. R_f= 0.37 (EtOAc);

m.p. 95–97 °C; ref.^[1]94–96 °C. [α]²_D⁴= –87.5 (c = 1.05); ref.^[1][α]²_D⁵

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[22] Crystal dimensions 0.90×0.33×0.31 mm³, monoclinic, space

group P2₁(No. 4), a = 13.892(2), b = 8.9400(1), c =

16.561(2) Å, α = γ = 90°, β = 103.120(1)°, V = 2003.1(4) Å³,

ρ_calcd.= 1.096 g/cm³, λ = 0.71073 Å, ω/2θ-scans, T = 198(2) K,

33326 reflections collected, 6048 independent (R_int= 0.228),

completeness to theta (24.40°) = 96.9%, µ = 0.125 mm^–1, em-

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refined parameters, hydrogen atoms calculated and refined as

riding atoms, R = 0.038, wR²= 0.049, max./min. largest differ-

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–0.03(8). Programs used: Collect, Dirax/Isq, SHELXS-97,

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1

= –91 (CHCl₃). H NMR (CDCl₃): δ = 0.91 (d, J = 6.9 Hz, 3 H),

1.01–1.16 (m, 2 H), 1.23–1.36 (m, 2 H), 1.84 (dd, J = 1.5, 1.5 Hz,

3 H), 1.97 (dd, J = 1.5, 7.2 Hz, 3 H), 2.64 (dd, J = 3.2, 16.1 Hz, 1

H), 2.74–2.78 (m, 1 H), 2.93 (dd, J = 2.5, 16.1 Hz, 1 H), 3.43 (dt,

J = 12.1, 6.3 Hz, 1 H), 3.53 (dt, J = 12.1, 6.1 Hz, 1 H), 3.55 (dddd,

J = 1.7, 2.2, 2.5, 7.5 Hz, 1 H), 4.16 (d, J = 12.5 Hz, 1 H), 4.24 (d,

J = 12.5 Hz, 1 H), 5.05 (ddd, J = 2.5, 3.2, 7.5 Hz, 1 H), 5.31 (d, J

= 1.7 Hz, 1 H), 6.05 (d, J = 2.2 Hz, 1 H), 6.11 (qq, J = 1.5, 7.2 Hz,

1 H), 6.39 (d, J = 2.5 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ = 15.76

(q), 18.95 (q), 20.50 (q), 29.91 (t), 30.92 (t, 2 C), 33.16 (d), 43.27

(d), 61.51 (t), 62.68 (t), 68.69 (d), 75.56 (d), 126.00 (t), 127.39 (s),

135.71 (s), 136.09 (s), 136.15 (s), 139.23 (d), 167.49 (s), 170.44 (s)

ppm. IR (neat): ν = 3250 cm^–1(broad), 2956, 2913, 2870, 2849,

˜

1752, 1696, 1461, 1409, 1388, 1269, 1251, 1228, 1134, 1065, 1051,

1026, 1014, 994, 976, 933, 902, 820, 741 cm^–1. MS (CID/10 V):

m/z (%) = 382 (100).

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft

and the Fonds der Chemischen Industrie.

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Sultone Route to Highly Oxygenated 1,10-seco-Eudesmanolides

FULL PAPER

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Received: September 28, 2005

Published Online: December 20, 2005

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1161

Article Doi

A concise sultone route to highly oxygenated 1,10-seco-eudesmanolides - enantioselective total synthesis of the antileukemic sesquiterpene lactones (-)-eriolanin and (-)-eriolangin

DOI: 10.1002/ejoc.200500739

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Full text of DOI:10.1002/ejoc.200500739

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