Synthesis of (±)- and (-)-botryodiplodin using stereoselective radical cyclizations of acyclic esters and acetals

TETRAHEDRON:

ASYMMETRY

Pergamon

Tetrahedron: Asymmetry 14 (2003) 3005–3018

Synthesis of ( )- and (−)-botryodiplodin using stereoselective

radical cyclizations of acyclic esters and acetals

Robert Nouguier,^a,* Ste´phane Gastaldi,^aDidier Stien,^aMiche`le Bertrand,^aFe´lix Villar,^b

Olivier Andrey^band Philippe Renaud^b,*^,†

^aLaboratoire de Chimie Mole´culaire Organique, UMR 6517, Boite 562, Faculte´ des Sciences St Je´roˆme,

Universite´ d’Aix-Marseille III, Av. Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France

^bUniversite´ de Fribourg, De´partement de Chimie, Pe´rolles, CH-1700 Fribourg, Switzerland

Received 30 May 2003; accepted 19 June 2003

Abstract—Three different routes for the stereoselective synthesis of botryodiplodin have been investigated. The intramolecular

allylation of acetals proved to be unsatisfactory due to unstable intermediates and poor stereocontrol. Zard intramolecular radical

allylation of a 2-iodopropionate derivative allows the development of an expeditious synthesis of racemic botryodiplodin. The

relative conﬁguration within the ﬁnal product was corrected by a deprotonation–reprotonation step. The cyclization of allenyl

bromoacetals was investigated next and proved to be satisfactory for the synthesis of racemic and enantiomerically pure

botryodiplodin. Good stereocontrol was achieved by cyclizing a gem-dibromide followed by the stereoselective reduction of the

thus formed cyclic monobromide.

1. Introduction

2. Results and discussion

(−)-Botryodiplodin (−)-1 is a simple lactol natural

product which has been isolated from Botryodiplodia

theobromae,^1,2Penicillium roqueforti,³Penicillium

stipitatum^4,5and other fungi.⁶This mycotoxin exhibits

antibiotic and antileukemic activity.^1,4,7,8Its relative

and absolute conﬁguration has been established by

total synthesis.^9–19However, despite a strong interest

for its preparation, only two syntheses of enantiomeri-

cally pure botryodiplodin have been reported.^13,15,16

Both approaches use chiral building blocks derived

2.1. Approach 1. Allylic sulfones: cyclization of acetal

derivatives

Due to the ready fragmentation of b-sulfonylated alkyl

radicals, allyl sulfones have become very popular radi-

cal allylating reagents.^22–32Previously we have reported

a formal synthesis of kainic acids based on the radical

rearrangement of an allylic sulfone.³³This intramolecu-

lar allylation allows the construction of the basic skele-

ton of kainic acid, a 2,3,4-trisubstituted pyrrolidine

bearing an isopropylidene in position 4, in a one step

process (Scheme 1).

from natural products (D-ribose and methylenomycin

A). Herein we report our efforts toward the stereoselec-

tive synthesis of ( )-botryodiplodin using radical

cyclizations.^20,21The absolute conﬁguration of a key

acetal intermediate is controlled by a chiral auxiliary,

allowing the preparation of naturally occurring (−)-

botryodiplodin.

Since the isopropylidene group can readily be trans-

formed into an acetyl group via ozonolysis, we thought

that the same methodology could be applied for the

synthesis of ( )-botryodiplodin 1 (Scheme 2).

Sulfone 2 was prepared in two steps starting from 3,

which is easily available from acetoxychlorination of

isoprene (Scheme 3).^34,35The reaction of 3 with acrolein

diethylacetal led to 4 which was then oxidized with

meta-chloroperbenzoic acid.

* Corresponding authors. Tel.: +33-4-91288232; fax: +33-4-9167-0944

(R.N.); Tel.: +41-31-631-4359; fax: +41-31-631-3426 (P.R.); e-mail:

robert.nouguier@univ.u-3mrs.fr; philippe.renaud@ioc.unibe.ch

^†Present address: Universita¨t Bern, Departement fu¨r Chemie und

Biochemie, Freiestrasse 3, CH-3000 Bern 9, Switzerland.

doi:10.1016/j.tetasy.2003.06.004

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R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

mation of para-toluenesulﬁnic acid, the formation of 6

could not be avoided, even when the rearrangement

was performed in the presence of pyridine.

Though 6 might be converted readily into 5, we thought

we could avoid the elimination of EtOH by rearranging

sulﬁde 4 in the presence of a catalytic amount of

para-thiocresol (Scheme 5). However, the resulting

products 7 formed in a 10:20:25:45 ratio were too

unstable to be isolated by chromatography on silica gel.

The direct reduction of the crude mixture with Bu₃SnH

failed to give 7%. Therefore, the cyclization products 7

were converted by oxidation with meta-chloroperben-

zoic acid into a 25:39:17:19 mixture of the four dias-

teromers of 5. GC analysis of the crude product showed

that 6 was not present and that a new cyclized product,

presumably (r-2,t-3,c-4)-5, was produced. No attempt

to isolate a pure sample of this fourth isomer was

made.

Scheme 1.

The rearrangement of 2 was performed in reﬂuxing

benzene in the presence of a catalytic amount of

TolSO₂SePh (20 mol%) and AIBN as the initiator. This

led to 5 (mixture of 3 diastereomers) and the elimina-

tion product 6 in a 70:30 ratio (Scheme 4). The relative

conﬁgurations within the three diastereomers of 5 was

unambiguously assigned from NOESY experiments

after isolation of pure samples by semi-preparative

HPLC.

The diastereoselectivity of these 5-exo ring closures is

low compared to the related cyclizations of 1,2-disubsti-

tuted 3-oxa- and 3-aza-5-hexenyl radicals. These two

systems afford ﬁve-membered heterocycles with sub-

stituents at C(2) and C(3) in a trans arrangement (see

Scheme 1 for such an example).^33,36The stereoselect-

ivity can be rationalized by the inﬂuence of an ano-

meric effect that favors transition states bearing a pseudo-

axial ethoxy group. The major isomer (r-2,c-3,c-4)-5

Due to the instability of the acetal moiety in the

reaction media, which becomes acidic through the for-

Scheme 2.

Scheme 3.

Scheme 4.

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

3007

Scheme 5.

would originate from the transition structure A (Fig. 1).

Based on our recent study of the Ueno–Stork reaction,

the low stereoselectivity is not surprising.^37,38Indeed,

large alkyl groups at C(4), such as a 2,2-disubtituted

ethenyl substituents, give only moderate cis stereoselec-

tivity relative to the alkoxy group at C(2). Moreover,

the stereogenic center at C(3) is not controlled when

simple alkyl substituents are present.

Even when the reaction was carried out by slow addi-

tion of tributyltin hydride at 80°C using a syringe

pump, the reduction product 11 was the major product.

In order to modify the Z/E conformational equilibrium

of the ester moiety by complexation of the carbonyl

with a Lewis acid, we performed the reduction of 9 in

the presence of 1 equiv. of Bu₃SnCl.^41,42Under these

conditions, lactone 10, formed as a 57:43 mixture of

trans and cis isomers, became the major product. How-

ever, the non-cyclized product 11 was still isolated in

23% yield (Scheme 6).

The iodine atom transfer methodology was shown to be

one of the best procedures to suppress the direct reduc-

tion competing with lactone ring closure.^39,40,43In our

case, this procedure could only be applied if the sulfo-

nyl radical ejected during the b-fragmentation step

would produce, through a-scission, an alkyl radical that

is able to react with the starting material via atom

transfer. Zard allylation protocol involving allyl ethyl

sulfones was ideally suited to that purpose.^28–30

Figure 1.

2.2. Approach 2. Allylic sulfones: Intramolecular allyla-

tion of 2-bromopropionate derivatives

Both the low selectivity and the instability of the

acetals, led us to investigate a closely related pathway

involving a-alkoxycarbonyl radicals. For such systems,

it is well established that the 5-exo ring closure is a slow

process due to the preferred unfavourable Z conforma-

tion of esters.^39,40This is well demonstrated by the

cyclization of bromide 9, which was prepared according

to Scheme 6.

Iodide 14 was prepared according to Scheme 7 and was

irradiated with a sun lamp in the presence of a catalytic

amount of hexabutylditin. The cyclization became

efﬁcient at 80°C and lactone 10 was isolated in 63%

yield as a trans/cis 60:40 mixture of isomers.

The relative conﬁguration of the major isomer was

incorrect to prepare botryodiplodin 1. Therefore, it was

Scheme 6.

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R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

Scheme 7.

Scheme 8.

necessary to invert the conﬁguration at C(3) by depro-

tonation and kinetic reprotonation of the enolate with

camphorsulfonic acid (CSA) according to Scheme 8.

After separation by HPLC (the trans isomer could be

recycled), the cis isomer was transformed into ( )-

botryodiplodin ( )-1 according to literature proce-

dure.¹⁹The lactol ( )-1 was obtained as a mixture of

epimers, its structure was unambiguously assigned after

achieved at position 4 when the formed tetrahydrofuran

is not substituted at position 3. This observation opens

a possibility for controlling the absolute stereochem-

istry by using a chiral auxiliary approach. A facile

preparation of enantiomerically pure 4-vinyl-g-butyro-

lactone from an enantiomerically and diastereomeri-

cally pure allenyl acetal has been achieved to

demonstrate the feasibility of this process (Scheme

9).^37,51The choice of the allenyl radical trap was dic-

tated by the necessity to have a small (or linear) sub-

stituent to achieve high level of cis stereocontrol relative

to the alkoxy group at C(2).

1

acetylation and comparison of H and ¹³C NMR spec-

tra of acetate ( )-16 with literature data of the acetate

derived from natural botryodiplodin.^3,9,14

This 2-bromopropionate cyclization strategy described

here is suitable for the preparation of racemic botryo-

dipodin. However, it cannot be easily extended to enan-

tiomerically enriched botryodiplodin.

This reaction opens a very straightforward approach

for the synthesis of botryodiplodin depicted in Scheme

10. The key reactions being the radical cyclization of an

allenyl acetal leading to a 4-vinylsubstituted tetra-

hydrofuran and a Wacker oxidation to convert the

vinyl moiety into an acetyl group. By using a chiral

auxiliary, this method is expected to deliver optically

active botryodiplodin.

2.3. Approach 3. Cyclization of bromoacetals

We have recently reported a detailed study of the

stereochemistry of the radical cyclization of haloacetals

(Ueno–Stork reaction^44–49).^37,38The stereochemical out-

come of such reactions can be efﬁciently controlled by

the stereogenic acetal center.⁵⁰For instance, we have

shown that an excellent level of stereocontrol can be

Based on our stereochemical model for the Ueno–Stork

reaction, the stereoselective preparation of 3,4-disubsti-

tuted tetrahydrofurans was expected to be problematic:

Scheme 9.

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3009

Scheme 10.

the C(4) center should be nicely controlled by the acetal

center (model B). However, the C(3) center should not

be easy to control because of the opposing effects of the

two vicinal substituents. Indeed, according to the classi-

cal Beckwith–Schiesser–Houk model,^52,53the alkoxy

group should favor the trans product (model C) and the

C(4) substituent should favor the cis product (model

C%). This expected low stereochemical control is sup-

ported by previous cyclizations of systems bearing alkyl

substituents at position 3.³⁷This was further conﬁrmed

with 17, a non-volatile model system for the synthesis

of botryodiplodin. Treatment of 17 under standard

cyclization conditions (Bu₃SnH, Et₃B, O₂at −78°C)

gave 18 in good yield but as mixture of three isomers

(Scheme 11).

imide (Scheme 12). Radical cyclization with 1 equiv. of

tin hydride furnished the intermediate bromotretrahy-

drofuran 21 (mixture of two isomers). Without isola-

tion of bromide 21, a second equiv. of tin hydride was

added to the reaction mixture and the desired reduced

acetal (r-2,c-3,c-4)-22 was isolated as a 2:1 mixture

with (r-2,t-3,c-4)-22.

A better stereocontrol was

obtained when a bulkier reducing agent such as

tris(trimethylsilyl)silane^54,55was used for the second

reduction step. In this way, the desired product (r-2,c-

3,c-4)-22 was obtained in 62% yield in a one-pot proce-

dure starting from 20. Traces of organotin derivatives

were removed by treatment of the reaction mixture with

an aqueous NaOH solution.⁵⁶Careful analysis of the

crude product revealed that (r-2,t-3,c-4)-22 was also

present (c-3/t-3 4:1) together with 2% of non-identiﬁed

isomers. The preferential formation of (r-2,c-3,c-4)-22

is easily explained by reduction of the cyclic radical

from the less hindered face anti to the two vicinal

substituents (model D).⁵⁷

The synthesis of racemic botryodiplodin ( )-1 was

achieved by hydrolysis of the acetal 22 (10% HCl)

followed by Wacker oxidation (PdCl₂/Cu(OAc)₂/O₂)⁵⁸

of the lactol 23 (Scheme 13). Under these mild condi-

tions, the unstable botryodiplodin was obtained as a

mixture of anomers. Physical and spectral data are in

accordance with literature data.^3,14For further charac-

terization, the lactol was transformed to the known

( )-botryodiplodin acetate 16.^3,9

Scheme 11.

In order to solve this stereoselectivity problem, the

gem-dibromide 20 was prepared from enol ether 19 and

2,3-butadien-1-ol by treatment with N-bromosuccin-

The preparation of enantiomerically pure (−)-botryo-

diplodin (−)-1 was examined next (Scheme 14). For this

purpose, we decided to start with easily available

Scheme 12.

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R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

Scheme 13.

Scheme 14.

(1R,2S)-2-phenylcyclohexanol as a chiral auxiliary.⁵⁹

Allylation of the alcohol gave the allyl ether 24 in

quantitative yield. The double bond was isomerized

under basic conditions to afford the cis-1-propenyl

ether 25. Bromination of the double bond followed by

elimination reaction gave the b-bromopropenyl ether 26

in 60% yield. Treatment of 26 with NBS in the presence

of 2,3-butadien-1-ol led to the gem-dibromoacetal 27 in

42% yield as a 70:30 mixture of diastereoisomers which

were separated by ﬂash chromatography. Cyclization of

the major isomer (R)-27 was carried out in one pot by

adding ﬁrst 1.2 equiv. of Bu₃SnH followed by 1.2 equiv.

of (Me₃Si)₃SiH to give the reduced cyclic acetal 28

in 73% yield and good diastereoselectivity (3R/

3S 90:10) (Scheme 14). Separation of the diastereo-

mers by ﬂash chromatography gave the pure

(2R,3R,4S)-24.

(>99% ee) was determined by GC analysis on a chiral

column.

3. Conclusions

In conclusion, we have examined several different

routes for the stereoselective synthesis of botryo-

diplodin. Zard intramolecular radical allylation of a

2-iodopropionate derivative allows to synthesize

racemic botryodiplodin. However, the relative conﬁgu-

ration of the ﬁnal product has to be corrected by a

deprotonation–reprotonation

step.

The

due to the instability of the intermediates under our

reaction conditions and poor stereocontrol. Finally, the

cyclization of allenyl bromoacetals proved to be satis-

factory for the synthesis of racemic botryodiplodin. A

good stereocontrol was achieved by cyclizing a gem-

dibromide followed by the stereoselective reduction of

the formed cyclic monobromide. The use of (1R,2S)-2-

phenylcyclohexanol as chiral auxiliary allows enan-

tiomerically pure (−)-botryodiplodin to be prepared.

These results demonstrate that the gem-dibromoacetal

method is suitable for asymmetric synthesis of polysub-

stituted g-lactones, a motive frequently encountered in

biologically active natural products.

The synthesis of (−)-botryodiplodin was achieved by

hydrolysis of the cyclic acetal (2R,3R,4S)-28 to opti-

cally active 23. At this stage, the chiral auxiliary

(1R,2S)-2-phenylcyclohexanol was recovered in 61%

yield. Finally, Wacker oxidation of the resulting

lactol 23 led to (−)-botryodiplodin (−)-1 as a mixture

of anomers in 41% yield. The enantiomeric purity

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

3011

4. Experimental

min, and the mixture was stirred for 3 h. The mixture

was basiﬁed with 30% NH₄OH and extracted with

CH₂Cl₂. The organic layer was successively washed

with diluted NH₄OH, brine, dried over Na₂SO₄, con-

centrated, and puriﬁed by FC (pentane/EtOAc 90:10 to

4.1. General

THF was freshly distilled from K under N₂; CH₂Cl₂

from CaH₂under N₂. Et₃B soln (1 M) in hexane was

freshly prepared from commercially available Et₃B

(95%, Aldrich). Other reagents were obtained from

commercial sources and used as received. Flash column

chromatography (FC) and ﬁltration: Baker silica gel

(0.063–0.200 mm); AcOEt, Et₂O and hexane as eluents.

Thin-layer chromatography (TLC): Merck silica gel 60

F₂₅₄analytical plates; detection either with UV or by

spraying with a soln of vanilin and subsequent heating.

Semi-preparative high-pressure liquid chromatography

(HPLC): Waters 610 ﬁtted with two columns in series

1

80:20) to give 2 (90 mg, 68%). H NMR (200 MHz,

CDCl₃): 7.72 (d, 2H, J=8.3 Hz, 2 arom. H), 7.37 (d,

2H, J=8.3 Hz, 2 arom. H), 5.78 (ddd, 1H, J=15.1,

10.3, 4.6 Hz, CHꢀCH₂), 5.4–5.2 (m, 3H, 3 vinyl. H),

4.80 (d, 1H, J=4.6 Hz, OCH(OEt)CHꢀCH₂), 4.1–3.9

(m, 2H, OCH₂CHꢀ), 3.74 (s, 2H, CH₂SO₂), 3.6–3.3 (m,

2H, OCH₂CH₃), 2.44 (s, 3H, CH₃Ar), 1.81 (s, 3H,

CH₃Cꢀ), 1.20 (t, 3H, J=6.8 Hz, CH₃CH₂O). ¹³C NMR

(50 MHz, CDCl₃): 144.6 (s), 135.4 (s), 134.9 (d), 132.0

(d), 129.6 (d), 128.4 (d), 127.1 (s), 118.4 (t), 100.7 (d),

65.9 (t), 61.2 (t), 60.9 (t), 21.6 (q), 17.2 (q), 15.1 (q).

Anal. calcd for C₁₇H₂₄O₄S: C, 62.94; H, 7.46. Found:

C, 62.91; H, 7.36.

(25×100 mm) Prep Nova-Pak^®HR silica 6 mm 60 A.

,

Gas chromatography (GC): Shimadzu GC-14A ﬁtted

with a capillary column J&W (DB-1, 30 m, ¥ 0.32 mm,

N₂1 bar). FT-IR: Mattson Unicam 5000. NMR:

Varian Gemini 200 (¹H=200 MHz, ¹³C=50.3 MHz),

Bruker AM 360 (¹H=360 MHz), Bruker avance DRX

500 (¹H=500.13 MHz, ¹³C=125.8 MHz); chemical

shift in ppm relative to tetramethylsilane (=0 ppm) or

4.2.3. Cyclization of 2: 2-Ethoxy-4-isopropenyl-3-(tolu-

ene-4-sulfonylmethyl)tetrahydrofuran

5 and 3-isopro-

penyl-4-(toluene-4-sulfonylmethyl)-2,3-dihydrofuran 6. A

solution of 2 (90 mg, 0.28 mmol) in degassed benzene

(10 mL) was stirred at reﬂux for 10 h. Every 1 h,

TolSO₂SePh and AIBN were added by portions (total

amount: 19 mg (0.06 mmol) and 3 mg (0.02 mmol),

respectively). The solution was concentrated and the

oily residue was puriﬁed by semi-preparative HPLC on

silica gel (trimethylpentane/AcOEt 95:5, 30 mL/min) to

give by order of elution: (r-2,c-3,t-4)-5 (17 mg), 6 (11

mg), (r-2,c-3,c-4)-5 (20 mg), (r-2,t-3,t-4)-+5 (18 mg),

global yield 75%.

1

CHCl₃(=7.26 ppm) for H and CDCl₃(=77.0 ppm)

for ¹³C. MS: Vacuum Generators Micromass VG 70/

70E and DS 11-250; CI (CH₄), EI (70 eV); m/z (%).

High resolution mass spectra (HRMS) were recorded

on a FTICR mass spectrometer Bruker 4.7 BioApex II.

Elementary analysis: Ilse Beetz, Microanalytisches Lab-

oratorium, D-8640 Kronach (Germany).

4.2. Approach 1

1

(r-2,c-3,t-4)-5. H NMR (400 MHz, CDCl₃): 7.80 (d,

4.2.1. 1-[(E)-4-(1-Ethoxyallyloxy)-2-methylbut-2-enylsul-

fanyl]-4-methylbenzene 4. A solution of 3 (1.0 g, 5.8

mmol), acrolein diethylacetal (3.15 g, 24.2 mmol) and

PPTS (376 mg, 1.5 mmol) in CH₂Cl₂(20 mL) was

heated at reﬂux for 2 h. Meanwhile CH₂Cl₂was dis-

tilled to remove EtOH, and fresh CH₂Cl₂was gradually

added to maintain the volume of the solution constant.

After the solution was cooled to room temperature, 1 g

of NaHCO₃was added. The resulting slurry was con-

centrated and puriﬁed by FC (pentane/EtOAc 100:0 to

2H, J=8.2 Hz, 2 arom. H), 7.35 (d, 2H, J=8.2 Hz, 2

arom. H), 4.88 (d, 1H, J=4.5 Hz, OCH(OEt)CH), 4.82

(br s, 1H, ꢀCH₂), 4.73 (s, 1H, ꢀCH₂), 3.95 (pseudo t,

1H, J=8.6 Hz, OCHHCH), 3.62 (dq, 1H, J=9.6, 7.2

Hz, OCHHCH₃), 3.58 (pseudo t, 1H, J=8.4 Hz, OCH-

HCH), 3.57 (dd, 1H, J=14.3, 11.0 Hz, CHHTs), 3.19

(dq, 1H, J=9.6, 7.2 Hz, OCHHCH₃), 3.0 (dd, 1H,

J=14.3, 1.8 Hz, CHHTs), 2.73 (pseudo dt, 1H, J=

11.0, 8.6 Hz, CHCH₂O), 2.43 (s, 3H, CH₃Ar), 2.40

(superimposed tdd, 1H, J=11.0, 4.5, 1.8 Hz,

CHCH₂Ts), 1.51 (s, 3H, CH₃CꢀCH₂), 1.1 (t, 3H, J=7.2

Hz, CH₃CH₂O). ¹³C NMR (50 MHz, CDCl₃): 144.7 (s),

141.3 (s), 136.6 (s), 129.8 (d), 128.1 (d), 114.5 (t), 102.2

(d), 69.2 (t), 63.2 (t), 54.0 (t), 49.3 (d), 41.5 (d), 21.6 (q),

18.4 (q), 15.2 (q).

1

93:7) to give 4 (800 mg, 57%). H NMR (200 MHz,

CDCl₃): 7.25 (d, 2H, J=8.6 Hz, 2 arom. H), 7.06 (d,

2H, J=8.6 Hz, 2 arom. H), 5.80 (ddd, 1H, J=15.4,

10.5, 4.9 Hz, CHꢀCH₂), 5.4–5.2 (m, 3H, 3 vinyl. H),

4.75 (d, 1H, J=4.9 Hz, OCH(OEt)CHꢀCH₂), 4.02 (d,

2H, J=6.9 Hz, OCH₂CHꢀ), 3.6–3.3 (m, 4H,

OCH₂CH₃+CH₂STol), 2.30 (s, 3H, CH₃Ar), 1.75 (s,

3H, CH₃Cꢀ), 1.19 (t, 3H, J=7.1 Hz, CH₃CH₂O). ¹³C

NMR (50 MHz, CDCl₃): 136.4 (s), 135.2 (d), 134.9 (s),

132.1 (d), 131.1 (d), 129.3 (d), 124.6 (d), 118.2 (t), 100.4

(d), 61.4 (t), 60.8 (t), 44.4 (t), 20.9 (q), 15.4 (q), 15.1 (q).

Anal. calcd for C₁₇H₂₄O₂S: C, 69.82; H, 8.27. Found:

C, 69.78; H, 8.21.

1

(r-2,c-3,c-4)-5. H NMR (400 MHz, CDCl₃): 7.77 (d,

2H, J=8.1 Hz, 2 arom. H), 7.32 (d, 2H, J=8.1 Hz, 2

arom. H), 4.88 (s, 1H, ꢀCH₂), 4.78 (d, 1H, J=5.1 Hz,

OCH(OEt)CH), 4.76 (s, 1H, ꢀCH₂), 3.94 (pseudo t, 1H,

J=8.7 Hz, OCHHCH), 3.74 (dd, 1H, J=8.9, 6.6 Hz,

OCHHCH), 3.59 (dq, 1H, J=9.4, 7.1 Hz, OCHHCH₃),

3.45 (dd, 1H, J=14.5, 10.0 Hz, CHHTs), 3.12 (dq, 1H,

J=9.4, 7.2 Hz, OCHHCH₃), 3.05 (dd, 1H, J=14.5, 2.8

Hz, CHHTs), 3.02 (superimposed ddd, 1H, J=11.0,

8.7, 6.6 Hz, CHCH₂O), 2.75 (dddd, 1H, J=11.0, 10.0,

5.1, 2.8 Hz, CHCH₂Ts), 2.40 (s, 3H, CH₃Ar), 1.66 (s,

3H, CH₃CꢀCH₂), 1.06 (t, 3H, J=7.1 Hz, CH₃CH₂O).

13C (50 MHz, CDCl₃): 144.6 (s), 142.7 (s), 136.7 (s),

4.2.2. 1-[(E)-4-(1-Ethoxyallyloxy)-2-methylbut-2-ene-1-

sulfonyl]-4-methylbenzene 2. A slurry of 4 (120 mg, 0.41

mmol) and NaHCO₃(154 mg, 1.85 mmol) in CH₂Cl₂(4

mL) was cooled in an ice bath. Wet 70% m-CPBA (222

mg, 1 mmol) was slowly added to the slurry over 20

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R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

129.8 (d), 128.1 (d), 116.8 (t), 102.0 (d), 69.0 (t), 62.8 (t),

53.1 (t), 47.3 (d), 40.7 (d), 21.6 (q), 20.6 (q), 15.0 (q).

1H, J=6.4 Hz, ꢀCHCH₂OH), 4.08 (d, 2H, J=6.4 Hz,

ꢀCHCH₂OH), 3.72 (s, 2H, CH₂SO₂), 2.43 (s, 3H,

CH₃Ar), 2.33 (s broad, 1H, OH), 1.78 (s, 3H, CH₃Cꢀ).

13C (50 MHz, CDCl₃): 144.8 (s), 135.5 (s), 134.7 (s),

129.6 (d), 128.3 (d), 126.0 (d), 65.9 (t), 58.9 (t), 21.6 (q),

17.1 (q).

1

(r-2,t-3,t-4)-5. H NMR (400 MHz, CDCl₃): 7.80 (d,

2H, J=8.0 Hz, 2 arom. H), 7.35 (d, 2H, J=8.0 Hz, 2

arom. H), 4.92 (s, 1H, OCH(OEt)CH), 4.49 (s, 1H,

ꢀCH₂), 4.55 (s, 1H, ꢀCH₂), 3.95 (pseudo t, 1H, J=8.0

Hz, OCHHCH), 3.72 (pseudo t, 1H, J=9.0 Hz, OCH-

HCH), 3.62 (dq, 1H, J=9.6, 7.1 Hz, OCHHCH₃), 3.35

(dq, 1H, J=9.6, 7.1 Hz, OCHHCH₃), 3.21 (pseudo q,

1H, J=8.0 Hz, OCH₂CH), 2.92–2.79 (ABX pattern,

4.3.2. 2-Bromopropionic acid (E)-3-methyl-4-(toluene-4-

sulfonyl)but-2-enyl ester 9. To a solution of 8 (440 mg,

1.83 mmol) and Et₃N (0.56 mL) in CH₂Cl₂(15 mL),

cooled at −40°C, 2-bromopropionyl bromide (412 mg,

1.9 mmol) was added. The solution was stirred for 2 h

at −20°C, warmed to 0°C, and acidiﬁed with 1N HCl.

The organic layer was washed successively with 1N

HCl, saturated NaHCO₃and brine, dried over Na₂SO₄,

concentrated, and puriﬁed by FC (pentane/EtOAc

2H,

J_AB=14.6 Hz, J_AX=10.6 Hz, J_BX=2.4 Hz,

CH₂Ts), 2.65 (ddd, 1H, J=10.6, 7.2, 2.4 Hz,

CHCH₂Ts), 2.40 (s, 3H, CH₃Ar), 1.55 (s, 3H, CH₃Cꢀ),

1.15 (t, 3H, J=7.1 Hz, CH₃CH₂O). 13C (100 MHz,

CDCl₃): 145.0 (s), 141.0 (s), 136.5 (s), 130.18 (d), 128.5

(d), 113.4 (t), 106.6 (d), 68.3 (t), 63.3 (t), 53.6 (t), 46.4

(d), 42.2 (d), 23.2 (q), 21.8 (q), 15.3 (q).

1

80:20 to 70:30) to give 9 (450 mg, 66%). H NMR (200

MHz, CDCl₃): 7.75 (d, 2H, J=8.3 Hz, 2 arom. H), 7.35

( d, 2H, J=8.3 Hz, 2 arom. H), 5.28 (br t, 1H, J=6.8

Hz, ꢀCHCH₂O), 4.60 (m, 2H, CH₂O), 4.33 (q, 1H,

J=6.9 Hz, CHBrCH₃), 3.75 (s, 2H, CH₂Ts), 2.45 (s,

3H, CH₃Ar), 1.85 (br s, 3H, CH₃Cꢀ), 1.79 (d, J=6.0

Hz, 3H, CH₃CHBr). 13C (50 MHz, CDCl₃): 169.5 (s),

144.5 (s), 135.0 (s), 130.1 (s), 129.5 (d), 128.2 (d), 127.9

(d), 65.4 (t), 61.6 (t), 39.6 (d), 21.4 (q), 21.3 (q), 17.2 (q).

Anal. calcd for C₁₅H₁₉O₄SBr: C, 48.01; H, 5.10. Found:

C, 47.83; H, 4.92.

1

6. H NMR (200 MHz, CDCl₃): 7.75 (d, 2H, J=8.3

Hz, 2 arom. H), 7.35 (d, 2H, J=8.3 Hz, 2 arom. H), 6.2

(s, 1H, OCHꢀ), 4.82 (br s, 1H, ꢀCHH), 4.72 (br s, 1H,

ꢀCHH), 4.41 (dd, 1H, ꢀCH, J=10.5, 9.3 Hz, OCH-

HCH), 4.19 (dd, 1H, J=10.5, 5.9 Hz, OCHHCH), 3.78

(br d, 1H, J=14.4 Hz, CHHTs), 3.72 (br d, 1H,

J=14.4 Hz, CHHTs), 3.60 (superimposed m, 1H,

CHCH₂O), 2.45 (s, 3H, CH₃Ar), 1.60 (br s, 3H,

CH₃CꢀCH₂). ¹³C NMR (50 MHz, CDCl₃): 148.3 (d),

144.6 (s), 142.9 (s), 135.5 (s), 129.6 (d), 128.4 (d), 113.8

(t), 104.1 (s), 74.8 (t), 52.8 (t), 51.0 (d), 21.5 (q), 18.1

(q).

4.3.3. Cyclization of 9: 4-Isopropenyl-3-methyldihydro-

furan-2-one 10 and propionic acid (E)-3-methyl-4-(tolu-

ene-4-sulfonyl)but-2-enyl ester 11. A solution of 9 (150

mg, 0.4 mmol) and Bu₃SnCl (0.180 mL, 0.4 mmol) in

degassed benzene (9 mL) was heated at reﬂux for 12 h

while a solution of Bu₃SnH (0.14 mL, 1.3 equiv.) and

AIBN (7 mg, 0.1 equiv.) in benzene (1 mL) was added

over a period of 11 h. After cooling the solution was

concentrated, the residue was dissolved in t-BuOH (4

ml) and heated at reﬂux with NaBH₃CN (34 mg, 0.54

mmol) for 1 h. The reaction mixture was concentrated

and the residue dissolved in CH₂Cl₂was washed with

H₂O, dried over Na₂SO₄, concentrated, analyzed by

GPC, and puriﬁed by chromatography on silica gel

(pentane/EtOAc 100:0 to 70:30) to give 10 (25 mg, 45%)

as a 40:60 mixture of cis/trans isomers (cf. part 4.3.7.

for the separation and for spectral data of each isomer),

and 11 (28 mg, 23%).

4.2.4. Cyclization of 4: 2-Ethoxy-4-isopropenyl-3-(tolu-

ene-4-sulfonylmethyl)tetrahydrofuran 5. To a solution of

4 (200 mg, 0.68 mmol) in reﬂuxing degassed benzene

(14 mL) was added over 5 h with a syringe pump a

solution of thiocresol (17 mg, 0.14 mmol) and AIBN

(23 mg, 0.14 mmol) in benzene (1 mL). After the end of

the addition, the mixture was reﬂuxed for 1 h and then

concentrated. CH₂Cl₂(6 mL) was added to the residue

followed by m-CPBA (293 mg, 1.7 mmol) and

NaHCO₃(571 mg, 6.8 mmol) at 0°C. Once the oxida-

tion completed (TLC monitoring), the crude reaction

was washed with H₂O and dried over Na₂SO₄. After

concentration, the crude product was puriﬁed by ﬁltra-

tion through a short pad of silica gel yielding a mixture

of the four diastereoisomers of 5 (106 mg, 0.33 mmol,

49%) in a 15:39:17:19 ratio.

1

11: H NMR (200 MHz, CDCl₃): 7.55 (d, 2H, J=8.3

Hz, 2 arom. H), 7.35 (d, 2H, J=8.3 Hz, 2 arom. H),

5.25 (t, 1H, J=6.8 Hz, ꢀCHCH₂O), 4.55 (d, 2H, J=6.8

Hz, CH₂O), 3.75 (s, 2H, CH₂Ts), 2.45 (s, 3H, CH₃Ar),

2.30 (q, 2H, J=7.0 Hz, CH₂CH₃), 1.80 (s, 3H, CH₃Cꢀ),

1.10 (t, 3H, J=7.0 Hz, CH₂CH₃).

4.3. Approach 2

4.3.1. (E)-3-Methyl-4-(toluene-4-sulfonyl)but-2-en-1-ol 8.

A slurry of 4-chloro-3-methylbut-2-en-1-ol (400 mg,

2.46 mmol), sodium p-toluenesulﬁnate (1.93 g, 5.4

mmol) and TBAB (200 mg) in a mixture of acetone (4

mL), benzene (4 mL) and H₂O (5 mL) was stirred at

60°C for 15 h. The mixture was cooled, diluted with

water (10 mL) and extracted with Et₂O (3×10 mL). The

combined organic layers were dried over Na₂SO₄, con-

centrated and the residue was puriﬁed by FC (pentane/

4.3.4. (E)-4-Ethylsulfanylbut-2-en-1-ol 12. To a solution

4-chloro-3-methylbut-2-en-1-ol acetate (3.0 g, 18.4

mmol) in THF (30 mL) was slowly added a solution of

EtSNa (2.10 g, 36.8 mmol) in EtOH (30 mL). After the

solution was stirred for 4 h, the reaction mixture was

concentrated, and dissolved in Et₂O. The organic layer

was washed with water, and the aqueous layer was

extracted with Et₂O (3×30 mL). The combined organic

layers were dried over Na₂SO₄, concentrated and

1

EtOAc 80:20 to 60:40) to give 8 (240 mg, 41%). H

NMR (200 MHz, CDCl₃): 7.74 (d, 2H, J=8.3 Hz, 2

arom. H), 7.25 (d, 2H, J=8.3 Hz, 2 arom. H), 5.25 (t,

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

3013

puriﬁed by chromatography on silica gel (pentane/

EtOAc 97:3 to 90:10) to give 12 (1.5 mg, 56%). ¹H

NMR (200 MHz, CDCl₃): 5.40 (t, 1H, J=6.6 Hz,

ꢀCHCH₂O), 4.05 (d, 2H, J=6.6 Hz, CH₂O), 3.0 (s, 2H,

CH₂S), 2.75 (br s, 1H, OH), 2.30 (q, 2H, J=7.6 Hz,

CH₃CH₂S), 1.65 (s, 3H, CH₃Cꢀ), 1.10 (t, 3H, J=7.6

Hz, CH₃CH₂S). ¹³C NMR (50 MHz, CDCl₃): 134.2 (s),

126.2 (d), 58.7 (t), 40.3 (t), 24.6 (t), 14.9 (q), 14.2 (q).

still contained cyclization products, was dissolved in

EtOH and 50% aqueous NaOH was added. The solu-

tion was heated at reﬂux for 1 h, cooled and concen-

trated. The residue was dissolved in H₂O and extracted

with Et₂O (3×10 mL) to remove the tin derivatives. The

aqueous layer was acidiﬁed with 1N HCl and extracted

with Et₂O (5×10 mL). The combined organic extracts

were dried over Na₂SO₄, concentrated, and puriﬁed by

FC (pentane/EtOAc 100:0 to 95:5) to give an additional

crop of 10 as a cis/trans 20:80 mixture (very volatile;

global yield: 1.29 g, 63%). Pure samples of both

stereoisomers of 10 were obtained by semi-preparative

HPLC on silica gel (trimethylpentane/EtOAc 96:4, 20

mL/min).

4.3.5. 2-Bromopropionic acid (E)-4-ethanesulfonyl-3-

methylbut-2-enyl ester 13. To a solution of 12 (500 mg,

3.44 mmol) in CH₂Cl₂(3 mL) was added pyridine (306

ml, 3.8 mmol). The solution was cooled in an ice bath,

treated with 2-bromopropionyl bromide (817 mg, 3.8

mmol) and stirred for 1 h. The reaction mixture was

diluted with CH₂Cl₂(20 mL) and washed twice with

H₂O. The organic layer was dried over Na₂SO₄and

concentrated. The residue was dissolved in MeOH (10

mL) and cooled at 0°C. A cooled solution of Oxone^®

(6.26 g, 3 equiv.) in H₂O (15 mL) was added. The

reaction mixture was stirred for 2 h and CHCl₃(30 mL)

was added. After extraction with CHCl₃(3×15 mL), the

combined organic layers were dried over Na₂SO₄and

concentrated. The residue was puriﬁed by FC (pentane/

EtOAc 80:20 to 70:30) to give 13 (660 mg, 62%; the

yield was improved up to 78% when starting from 3.3 g

of 12). ¹H NMR (200 MHz, CDCl₃): 5.60 (t, 1H, J=6.8

Hz, ꢀCHCH₂O), 4.70 (m, 2H, CH₂O), 4.35 (q, 1H,

J=6.8 Hz, CHBrCH₃), 3.65 (s, 2H, CH₂SO₂), 2.95 (q,

2H, J=7.5 Hz, CH₃CH₂SO₂), 1.85 (s, 3H, CH₃Cꢀ),

1.72 (d, 3H, J=6.8 Hz, CHBrCH₃), 1.27 (t, 3H, J=7.5

Hz, CH₃CH₂SO₂). ¹³C NMR (50 MHz, CDCl₃): 169.4

(s), 130.5 (s), 127.3 (d), 61.4 (t), 60.9 (t), 45.4 (t), 39.7

(d), 21.1 (q), 16.8 (q), 6.0 (q). Anal. calcd for

C₁₀H₁₇O₄SBr: C, 38.35; H, 5.47. Found: C, 38.25; H,

5.43.

1

trans-10: H NMR (200 MHz, CDCl₃): 4.91 (br s, 1H,

CH₂ꢀC), 4.85 (s, 1H, CH₂ꢀC), 4.33 (dd, 1H, J=9.0, 8.1

Hz, CHHO), 3.90 (dd, 1H, J=10.3. 9.0 Hz, CHHO),

2.75 (pseudo td, 1H, J=10.7, 8.1 Hz, CHCH₂O), 2.50

(dq, 1H, J=11.2, 7.0 Hz, CHCH₃), 1.70 (s, 3H,

CH₃Cꢀ), 1.20 (d, J=7.0 Hz, 3H, CH₃CH). (50 MHz,

CDCl₃): 179.1 (s), 140.5 (s), 113.8 (t), 69.4 (t), 51.1 (d),

38.0 (d), 19.6 (q), 13.6 (q).

1

cis-10: H NMR (200 MHz, CDCl₃): 4.80 (br s, 1H,

CH₂ꢀC), 4.65 (s, 1H, CH₂ꢀC), 4.24 (dd, 1H, J=9.5, 6.1

Hz, CHHO), 4.12 (dd, 1H, J=9.5, 3.9 Hz, CHHO),

3.05 (ddd, 1H, J=8.1, 6.1, 3.9 Hz, CHCH₂O), 2.64 (dq,

1H, J=8.1, 7.3 Hz, CHCH₃), 1.55 (br s. 3H, CH₃Cꢀ),

0.98 (d, J=7.3 Hz, 3H, CH₃CH). ¹³C NMR (50 MHz,

CDCl₃): 179.2 (s), 141.4 (s), 113.8 (t), 69.6 (t), 46.2 (d),

36.9 (d), 20.6 (q), 9.9 (q).

10 (mixture of diastereomers): Anal. calcd for C₈H₁₂O₂:

C. 68.55; H, 8.63. Found: C, 68.52; H, 8.60.

4.3.8. Isomerization of 10. To a solution of LDA (1.646

g of i-Pr₂NH and 11.8 mL of 1.25 M n-BuLi in hexane)

in THF (50 mL) cooled at −20°C was added a cis/trans

40:60 mixture of 10 (1.14 g, 8.1 mmol). The solution

was stirred at −20°C for 20 min and then warmed up to

0°C. This solution was added to a solution of camphor-

sulfonic acid (CSA, 5.66 g, 3 equiv.) in CH₂Cl₂(50 mL)

at −100°C. The reaction mixture was stirred and

warmed from −100°C to room temperature, and then

saturated NaHCO₃(10 mL) was added with vigorous

stirring. After extraction with CH₂Cl₂, the combined

organic layers were washed with brine, dried over

Na₂SO₄, and concentrated. The crude residue was a

4.3.6. 2-Iodopropionic acid (E)-4-ethanesulfonyl-3-

methylbut-2-enyl ester 14. To a solution of 13 (157 mg,

0.5 mmol) in acetone (0.5 mL) was added NaI (105 mg,

0.7 mmol). The solution was stirred in the dark for 1 h,

Et₂O (2 mL) was added, and the slurry was ﬁltered

through a pad of silica gel, the pad was washed with

Et₂O. The ﬁltrate was concentrated at low temperature

in the dark to give 14 (180 mg, quantitative) pure

enough to be used in the following step without further

1

puriﬁcation. H NMR (200 MHz, CDCl₃): 5.63 (t, 1H,

J=6.8 Hz, ꢀCHCH₂O), 4.66 (m, 2H, CH₂O), 4.40 (q,

1H, J=7.1 Hz, CHICH₃), 3.60 (s, 2H, CH₂SO₂), 2.95

(q, 2H, J=7.6 Hz, CH₃CH₂SO₂), 1.95 (s, 3H, CH₃Cꢀ),

1.85 (d, 3H, J=7.1 Hz, CHICH₃), 1.33 (t, 3H, J=7.6

Hz, CH₃CH₂SO₂). ¹³C NMR (50 MHz, CDCl₃): 171.7

(s), 130.9 (s), 127.8 (d), 61.7 (×2 t), 45.8 (t), 23.2 (q),

17.4 (q), 12.7 (d), 6.5 (q).

1

cis/trans 82:18 mixture of isomers, as determined by H

NMR (based on the signals of vinylic protons at 4.85

and 4.65 ppm, trans-10 and cis-10, respectively), GC

and HPLC (iso-octane/EtOAc 96:4, 2 mL/min, reten-

tion time 3.9 and 6.1 min for trans-10 and cis-10,

respectively). It was puriﬁed as previously decribed to

give 10 (1.0 g, 88%). The mixture was separated by

semi-preparative chromatography on silica gel

(trimethylpentane/EtOAc 96:4, 20 mL/min) which pro-

vided pure cis-10 (0.75 g).

4.3.7. Cyclization of 14: 4-Isopropenyl-3-methyldihydro-

furan-2-one 10. A solution of 14 (5.3 g 14.71 mmol) and

hexabutylditin (2.2 mL, 4.41 mmol) in degassed ben-

zene (74 mL) was irradiated for 5 h with a 300 W sun

lamp, while heating at reﬂux. The benzene was slowly

evaporated and the residue was bulb to bulb distilled

(150°C, 20 mbar). The cyclized product 10 was

obtained as a cis/trans 40:60 mixture. The residue, that

4.3.9. Acetic acid 4-acetyl-3-methyltetrahydrofuran-2-yl

ester 16. A solution of cis-10 (70 mg, 0.5 mmol) in

CH₂Cl₂(6 mL) was cooled at −78°C. DIBALH (1 M in

3014

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

hexane, 1.25 mL, 1.25 mmol) was added and the mix-

ture was stirred for 15 min. The reaction mixture was

treated with MeOH (0.5 mL) and a solution of

Rochelle salt (15 mL, 12.5 equiv.) and saturated NH₄Cl

(15 mL) were added. The mixture was extracted with

CH₂Cl₂, the organic extracts were dried over Na₂SO₄,

concentrated, and puriﬁed by FC (pentane/EtOAc 95:5

to 70:30) to give 15 (60 mg, 85%) as a single epimer at

4.4.2. 3-Benzyl-2-methoxy-4-vinyltetrahydrofuran 18. To

a soln of 17 (1.0 g, 3.4 mmol) and Bu₃SnH (1.2 g, 4.1

mmol) in toluene (84 mL) was added a 1 M soln of

Et₃B in hexane (4.7 mL, 4.7 mmol) at −78°C followed

by air (3 mL). The soln was kept at −78°C for 3 h. A

1 M NaOH soln (45 mL) was added and the hetero-

geneous mixture was stirred for 2 h at rt. The organic

layer was washed with H₂O, dried (MgSO₄) and con-

centrated under reduced pressure. The crude product

was puriﬁed by FC (hexane/Et₂O 40:1) to afford the

cyclic acetal 18 (0.61 g, 82%) as a 52:11:37 mixture of

three diastereoisomers.

1

C2. H NMR (200 MHz, CDCl₃): 5.18 (s, 1H, H2),

4.89 (pseudo sext, 1H, J=1.2 Hz, ꢀCH₂), 4.60 (br s,

1H, ꢀCH₂), 4.12 (pseudo t, 1H, J=7.9 Hz, CHHO),

3.96 (pseudo t, 1H, J=8.9 Hz, CHHO), 3.15 (pseudo q,

1H, J=7.9 Hz, CHCH₂O), 2.31 (pseudo quint, 1H,

J=7.3 Hz, CHCH₃), 1.75 ( br s, 3H, CH₃Cꢀ), 0.80 (d,

3H, J=7.1 Hz, CH₃CH), (OH not observed). ¹³C NMR

(50 MHz, CDCl₃): 141.9 (s), 111.4 (t), 104.5 (d), 68.9

(t), 46.2 (d), 42.2 (d), 23.3 (q), 11.4 (q). Anal. calcd for

C₈H₁₄O₂: C. 67.57; H, 9.92. Found: C, 67.55; H, 9.91.

IR (KBr): 3078, 3028, 2912, 2831, 1494, 1454, 1041

cm⁻¹. ¹H NMR (360 MHz, CDCl₃). Major diastereoiso-

mer: 7.30–7.15 (m, 5 Arom. H), 6.04 (dt, 1H, J=10.1,

17.1 Hz, CHꢀCH₂), 4.97–4.90 (m, 2H, CHꢀCH₂), 4.66

(d, 1H, J=4.3 Hz, MeOCHCHBn), 4.12 (dd, 1H,

J=7.6, 8.5 Hz, OCHHCHꢀCH₂), 3.74 (dd, 1H, J=3.4,

8.5 Hz, OCHHCHꢀCH₂), 3.34 (s, 3H, OCH₃), 2.89–

2.39 (m, 4H). Second diastereoisomer: 5.69 (ddd, 1H,

J=8.5, 9.5, 17.4 Hz, CHꢀCH₂), 4.73 (d, 1H, J=2.8 Hz,

MeOCHCHBn), 4.00 (t, 1H, J=8.5 Hz, OCH-

HCHꢀCH₂), 3.66 (t, 1H, J=8.9 Hz, OCHHCHꢀCH₂).

CI-MS (CH₄) m/z (%): 219 (M⁺+1, 7), 187 (100), 169

(67), 157 (86), 129 (23), 117 (29), 91 (66). Anal Calcd.

for C₁₄H₁₈O₂(218.30): C, 77.03; H, 8.31. Found: C,

77.07; H, 8.31.

The ozonolyzis of 15 was conducted according to litera-

1

ture.¹⁹The H spectrum of botryodiplodin 1 in CDCl₃

resulted from an equilibrium between the different iso-

meric forms. Acetylation according to literature proce-

dure produced the known acetate 16.^{14 1}H NMR data

were very similar to those described in the literature.^2,9

1

Only one epimer at C(2) was detected. H NMR (200

MHz, CDCl₃): 5.95 (s, 1H, OCHO), 4.35 (pseudo t, 1H,

J=8.5 Hz, CHHO), 4.1 (pseudo t, 1H, J=9.0 Hz,

CHHO), 3.7–3.5 (m, 1H, CHCH₂O), 2.69 (pseudo

quint, 1H, J=8.0 Hz, CHCH₃), 2.22 (s, 3H, CH₃CꢀO),

2.07 (s, 3H, CH₃CꢀO), 0.9 (d, 3H, J=7.3 Hz, CH₃CH).

4.4.3.

4-(2,2-Dibromo-1-ethoxypropoxy)-1,2-butadiene

20. To a soln of (Z/E)-b-bromopropenyl ethyl ether 19

(1.65 g, 10 mmol) and 2,3-butadien-1-ol (0.70 g, 10

mmol) in CH₂Cl₂(15 mL) cooled at −20°C was added

NBS (1.78 g, 10 mmol) in portions. The mixture was

stirred at the same temperature for 2 h. Then hexane

was added to precipitate the succinimide. After ﬁltra-

tion, the organic phase was washed succesively with

KOH (5%), H₂O and NaCl. Dried with MgSO₄and the

solvent removed under reduced pressure. Puriﬁcation

by FC (hexane/Et₂O 20:1) gave the dibromoacetal 20

(1.75 g, 56%) as a colorless oil.

4.4. Approach 3

4.4.1.

1-[2-Bromo-3-(2,3-butadienyloxy)-3-methoxy-

propyl]benzene 17. To a soln of 1-methoxy-3-phenyl-

propene (1.23 g, 8.3 mmol) and 2,3-butadien-1-ol (0.58

g, 8.3 mmol) in CH₂Cl₂was added at −30°C NBS (1.48

g, 8.3 mmol) in portions. The mixture was stirred at

−20°C for 3 h, diluted with hexane, ﬁltered and washed

successively with KOH (5%), H₂O and sat. NaCl. The

organic phase was dried and concentrated under

reduced pressure to give the bromoacetal 17 (1.5 g,

61%) as a yellow oil.

IR (KBr): 2980, 2930, 2881, 1955, 1442, 1373, 1105,

1

1068, 910, 871 cm⁻¹. H NMR (360 MHz, CDCl₃): 5.31

Mixture of diastereoisomers. IR (KBr): 3030, 2933,

(q, 1H, J=7 Hz, OCH₂CHꢀCꢀCH₂), 4.83 (td, 2H,

J=2.1, 6.4 Hz, OCH₂CHꢀCꢀCH₂), 4.64 (s, 1H,

OCHCBr₂Me), 4.40–4.37 (m, 2H, OCH₂CHꢀCꢀCH₂),

3.95–3.80 (m, 2H, OCH₂CH₃), 2.42 (s, 3H, CBr₂CH₃),

1.29 (t, 3H, J=7.2 Hz, OCH₂CH₃). ¹³C NMR (50

MHz, CDCl₃): 209.6 (s), 105.9 (d), 87.2 (d), 76.1 (t),

67.9 (t), 67.5 (t), 67.3 (s), 34.0 (q), 15.2 (q). CI-MS

(CH₄) m/z (%): 247 (53), 245 (100), 243 (56), 183 (11),

181 (12), 153 (23), 101 (95), 99 (21).

1

2835, 1955, 1604, 1454, 1354, 1120, 1060, 850 cm⁻¹. H

NMR (360 MHz, CDCl₃): 7.35–7.21 (m, 5 arom. H),

5.33–5.24 (m, 1H, CHꢀCꢀCH₂), 4.84–4.81 (m, 2H,

CHꢀCꢀCH₂), 4.57 (d, 1H, J=4.6 Hz, MeOCHCHBr, 1

diast.), 4.54 (d, 1H, J=5.2 Hz, MeOCHCHBr, 2

diast.),

4.20–4.14

(m,

3H,

OCH₂CHꢀC,

MeOCHCHBr), 3.49 (s, 3H, CH₃O, 1 diast.), 3.47 (s,

3H, CH₃O, 2 diast.), 3.41 (dd, 1H, J=3.4, 14.7 Hz,

CHBrCHHPh), 3.02 (dd, 1H, J=10.1, 14.7 Hz,

CHBrCHHPh). ¹³C NMR (50 MHz, CDCl₃).

Diastereoisomer 1: 209.5 (s), 138.1 (s), 129.3 (d), 128.3

(d), 126.7 (d), 104.1 (d), 87.4 (d), 76.1 (t), 66.0 (t), 56.0

(d), 55.4 (q), 38.9 (t). Diastereoisomer 2: 103.6 (d), 87.3

(d), 66.2 (t), 39.4 (t). CI-MS (CH₄) m/z (%): 229

(M⁺[Br⁸¹]−69, 39), 227 (M⁺[Br⁷⁹]−69, 38), 197 (76), 195

(79), 151 (49), 149 (57), 147 (54), 133 (86), 119 (39), 91

(100), 85 (27), 61 (31). Anal. Calcd. for C₁₄H₁₇O₂Br

(297.19): C, 56.58; H, 5.77. Found: C, 56.52; H, 5.72.

4.4.4.

(r-2,c-3,c-4)-2-Ethoxy-3-methyl-4-vinyltetra-

hydrofuran 22. A soln of 20 (1.43 g, 4.56 mmol) and

Bu₃SnH (1.57 g, 5.4 mmol) in toluene (100 mL) was

cooled at −78°C and a 1 M soln of Et₃B in hexane (6.4

mL, 6.4 mmol) was added followed by air (4.0 mL).

The resulting soln was kept at −78°C for 3 h. Then

(TMS)₃SiH (1.34 g, 5.4 mmol) was added followed by

air (4 mL). The resulting soln was kept at −78°C for 3

h. A 1 M NaOH soln (60 mL) was added and the

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

3015

heterogeneous mixture was stirred for 2 h at rt. The

organic layer was washed with H₂O, dried over MgSO₄

and evaporated under reduced pressure. The crude

product was puriﬁed by FC (pentane/Et₂O 60:1) to

afford (r-2,c-3,c-4)-22 (0.44 g, 62%) as a colorless oil.

1H, J=7.3 Hz, H3), 2.51–2.40 (m, 1H, H3%), 2.29 (s,

3H, CH₃CO), 2.20 (s, 3H, CH%₃CO), 1.06 (d, 3H, J=7.3

Hz, CHCH₃), 0.86 (d, 3H, J=7.0 Hz, CHCH%). ¹³C

NMR (50 MHz, CDCl₃): 206.4 (s), 104.1 (d), 100³.3 (d%),

69.8 (t%), 66.4 (t), 53.0 (d), 52.8 (d%), 42.5 (d), 41.2 (d%),

32.3 (q%), 30.3 (q), 12.3 (q), 9.5 (q%). CI-MS (CH₄) m/z

(%): 145 (M⁺+1, 6), 127 (M⁺+1−H₂O, 100), 97 (5), 83

(17). HRMS (ESI) for C₇H₁₂O₃Na: calculated

167.06786; found 167.06780.

IR (KBr): 3076, 2976, 2881, 1639, 1428, 1078, 1043, 912

cm⁻¹. ¹H NMR (500 MHz, CDCl₃): 5.96 (dt, 1H,

J=10.1, 17.1 Hz, CHꢀCH₂), 4.98–4.92 (m, 2H,

CHꢀCH₂), 4.91 (d, 1H, J=4.7 Hz, OCHCHMe), 4.06

(t, 1H, J=7.6 Hz, OCHHCHCHꢀCH₂), 3.77–3.68 (m,

2H, OCHHCHCHꢀCH₂, OCHHCH₃), 3.41 (dq, 1H,

J=7.1, 9.8 Hz, OCHHCH₃), 2.77 (ddd, 1H, J=4.3,

9.3, 7.0 Hz, CHCHꢀCH₂), 2.38–2.10 (m, 1H, CHCH₃),

1.18 (t, 3H, J=7.1 Hz, OCH₂CH₃), 0.91 (d, 3H, J=7.2

Hz, CHCH₃). ¹³C NMR (50 MHz, CDCl₃): 139.6 (d),

115.4 (t), 104.9 (d), 72.1 (t), 62.7 (t), 46.1 (d), 41.2 (d),

15.3 (q), 9.7 (q). CI-MS (CH₄): 157 (M⁺+1, 17, 155 (30),

139 (30), 127 (35), 126 (42), 111 (100), 87 (13). HRMS

(CI-isobutane) calculated for C₉H₁₇O₂([M⁺+1]):

157.12230. Found: 157.12239.

4.4.7. (1R,2S)-2-Phenylcyclohexyl 2-propenyl ether 24.

A round-bottomed ﬂask was charged with NaH (300

mg, 12.5 mmol). After removing the mineral oil by

washing with pentane (3×5 mL) it was suspended in

THF (28 mL). A soln of (1R,2S)-phenylcyclohexanol

(2.0 g, 11.4 mmol) in THF (10 mL) was added at 0°C.

The grey mixture was stirred at rt until hydrogen

evolution was ﬁnished (ca. 30 min). Allyl bromide (1.52

g, 12.54 mmol) was added at rt and the mixture was

heated at reﬂux for 3 h. Finally, aq. NH₄Cl was added

slowly to the reaction mixture to neutralize the base.

After extraction with Et₂O, the organic phase was

washed with NaCl, dried and the solvent evaporated

under reduced pressure to afford 24 as a yellow oil

(2.35 g, 95%).

4.4.5. 3-Methyl-4-vinyltetrahydro-2-furanol 23. A soln of

(r-2,c-3,c-4)-22 (163 mg, 1.04 mmol) in THF (2 mL)

and 10% HCl (1 mL) was kept at rt for 30 min. After

extraction with Et₂O, the organic phases were washed

with sat. NaHCO₃and H₂O, dried over MgSO₄and

concentrated under reduced pressure. The crude

product was puriﬁed by FC (pentane/Et₂O 1:1) to

afford 23 (81 mg, 61%) as a mixture of two anomers.

¹H NMR (360 MHz, CDCl₃): 7.31–7.16 (m, 5 arom.

H), 5.57 (ddt, 1H, J=5.5, 9.5, 18.0 Hz, CHꢀCH₂),

4.97–4.95 (m, 1H, CHꢀCHH), 4.94–4.91 (m, 1H,

CHꢀCHH), 3.78 (ddt, 1H, J=1.2, 5.5, 13.0 Hz, OCH-

HCHꢀCH₂), 3.58 (ddt, 1H, J=1.5, 5.5, 12.8 Hz, OCH-

HCHꢀCH₂), 3.34 (dt, 1H, J=4.6, 10.4 Hz,

OCHCHPh), 2.54 (ddd, 1H, J=3.7, 10.1, 13.7 Hz,

OCHCHPh), 2.21–2.13 (m, 1H), 1.90–1.82 (m, 2H),

1.76–1.70 (m, 1H), 1.58–1.46 (m, 1H), 1.40–1.35 (m,

3H). ¹³C NMR (50 MHz, CDCl₃): 144.8 (s), 135.5 (d),

128.0 (d), 127.8 (d), 126.0 (d), 115.9 (t), 81.6 (d), 70.2

(t), 51.3 (d), 33.9 (t), 32.6 (t), 26.1 (t), 25.1 (t).

¹H NMR (360 MHz, CDCl₃): Major diasteroisomer:

5.75 (ddd, 1H, J=8.5, 10.7, 16.8 Hz, CHꢀCH₂), 5.17–

5.09 (m, 2H, CHꢀCH₂), 5.10 (d, 1H, J=0.9 Hz,

HOCHCHMe), 4.14 (t, 1H, J=8.2 Hz, OCH-

HCHCHꢀCH₂), 3.75 (t, 1H, J=8.2 Hz, OCH-

HCHCHꢀCH₂), 3.15–3.04 (m, 1H, CHCHꢀCH₂),

2.73–2.68 (m, 1H, OH), 2.29–2.00 (m, 1H, CHCH₃),

0.94 (d, 3H, J=7.3 Hz, CHCH₃). Minor diasteroiso-

mer: 5.96 (ddd, 1H, J=9.2, 10.4, 16.8 Hz, CHꢀCH₂),

5.34 (t, 1H, J=4.6 Hz, HOCHCHMe), 5.06–5.00 (m,

2H, CHꢀCH₂), 4.04 (dd, 1H, J=7.0, 8.6 Hz, OCH-

HCHCHꢀCH₂), 3.90 (dd, 1H, J=4.0, 8.5 Hz, OCH-

HCHCHꢀCH₂), 2.86–2.78 (m, 1H, CHCHꢀCH₂),

2.73–2.68 (m, 1H, OH), 2.59–2.53 (m, 1H, CHCH₃),

0.99 (d, 3H, CHCH₃).

4.4.8. (1R,2S)-2-Phenylcyclohexyl (Z)-1-propenyl ether

25. A soln of 24 (5.68 g, 26.3 mmol) was added to a

soln of t-BuOK (1.02 g, 9.1 mmol) in dry DMSO (10

mL) at rt. The black reaction mixture was heated at

40°C for 5 days. The reaction was neutralized by addi-

tion of a saturated aq. soln of NaCl. After extraction

with Et₂O, the organic phase was washed with H₂O,

dried over MgSO₄and the solvent evaporated to fur-

nish the 25 (4.98 g, 88%) as a yellow oil.

4.4.6. ( )-Botryodiplodin ( )-1. A suspension of lactol

(40 mg, 0.31 mmol), PdCl₂(6 mg, 0.031 mmol) and

Cu(OAc)₂·2H₂O (133 mg, 0.61 mmol) in N,N-dimethyl-

acetamide/H₂O (7:1) (0.6 mL) was placed under oxygen

and stirred at rt for 4 days. The mixture was diluted

with Et₂O, ﬁltered through Celite employing Et₂O to

wash the ﬁlter cake, poured into water (3 mL) and

extracted with Et₂O. The organic phases were dryed

and evaporated under reduced pressure. The crude

product was puriﬁed by FC (pentane/Et₂O 1:1) to

furnish ( )-botryodiplodin 1 (27 mg, 38%).

IR (KBr): 3030, 2931, 2858, 1666, 1448, 1259, 1089

1

cm⁻¹. H NMR (360 MHz, CDCl₃): 7.31–7.14 (m, 5

arom. H), 5.73 (dq, 1H, J=1.8, 6.1 Hz, OCHꢀCH),

4.12 (quint, 1H, J=6.7 Hz, OCHꢀCH), 3.58 (dt, 1H,

J=4.0, 10.1 Hz, OCHCHPh), 2.64 (ddd, 1H, J=3.7,

10.1, 13.7 Hz, OCHCHPh), 2.43–2.38 (m, 1H), 2.22–

2.12 (m, 2H), 1.94–1.83 (m, 2H), 1.78–1.72 (m, 1H),

1.62–1.33 (m, 2H), 1.33 (dd, 3H, J=1.5, 6.7 Hz,

CHꢀCHCH₃). ¹³C NMR (50 MHz, CDCl₃): 144.5 (d),

144.0 (s), 128.2 (d), 127.8 (d), 126.1 (d), 100.7 (d), 83.8

(d), 50.5 (d), 33.6 (t), 32.9 (t), 25. 9(t), 25.0 (t), 9.1 (q).

CI-MS (CH₄) m/z (%): 217 (M⁺+1, 19), 216 (M+. 33),

160 (30), 159 (100), 157 (17), 91 (32).

¹H NMR (360 MHz, CDCl₃): 5.18 (s, 1H,

HOCHCHMe), 4.28 (t, 1H, J=8.9 Hz, H5), 4.09–3.99

(m, H5 and H5%), 3.67 (q, 1H, J=7.0 Hz, H5%), 3.42 (dt,

1H, J=2.8, 7.6 Hz, H4), 2.91 (bs, 1H, OH), 2.61 (quint,

3016

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

4.4.9. 2-Bromo-1-propenyl (1R,2S)-2-phenylcyclohexyl

ether 26. Bromine (2.96 g, 18.52 mmol) was added

dropwise to a soln of 25 (4.0 g, 18.5 mmol) in CH₂Cl₂

(10 mL) cooled at −20°C until the orange color remain.

Then, solid Na₂S₂O₃was added. The resulting mixture

was ﬁltered and dried. After evaporation, the dibro-

moether was isolated as a red dark oil (5.86 g, 15.6

mmol) that was directly slowly added to a reﬂuxing

soln of N,N-diethylaniline (3.25 g, 21.8 mmol) in ben-

zene (10 mL). After 45 min heating under reﬂux, the

black mixture was cooled down to rt and diluted with

Et₂O. A soln of HCl 2N (4 mL) was added and the

aqueous phase was extracted several times with Et₂O.

Finally the organic phases were washed with H₂O. The

crude product was puriﬁed by FC (hexane/Et₂O 40:1)

over silica gel previously treated with Et₃N (2.5%). The

bromopropenyl ether 26 was isolated (2.76 g, 60%) as a

mixture of isomers. IR (KBr): 3028, 2933, 2858, 1678,

CHꢀCꢀCH₂), 4.79 (dt, 2H, J=2.1, 6.4 Hz,

CHꢀCꢀCH₂), 4.74 (s, 1H, OCHCBr₂Me), 3.90 (dt, 2H,

J=2.1, 7.0 Hz, OCH₂CHꢀCꢀCH₂), 3.82 (dt, 1H, J=

4.3, 10.4 Hz, OCHCHPh), 2.65 (dt, 1H, J=3.9, 10.4

Hz, OCHCHPh), 2.31–2.26 (m, 1H), 2.16 (s, 3H, CH₃),

1.96–1.91 (m, 2H), 1.79–1.76 (m, 1H), 1.63–1.56 (m,

2H), 1.41–1.32 (m, 2H). ¹³C NMR (50 MHz, CDCl₃):

209.2 (s), 143.9 (s), 128.1 (d), 127.9 (d), 126.1 (d), 102.4

(d), 87.8 (d), 78.7 (d), 75.9 (t), 68.0 (t), 67.9 (s), 50.4 (d),

33.6 (q), 33.5 (t), 31.3 (t), 25.8 (t), 24.8 (t).

Mixture of diasteroisomers: IR (KBr): 3028, 2931,

2856, 1955, 1448, 1105, 1066, 848 cm⁻¹. FAB-MS: 375

(M⁺−69, 20), 296 (60), 294 (63), 231 (35), 211 (68), 159

(100), 129 (95).

4.4.11. (2R,3R,4S)-3-Methyl-2-{[(1R,2S)-2-phenylcyclo-

hexyl]oxy}-4-vinyl tetrahydrofuran 28. A soln of (R)-27

(0.42 g, 1 mmol) and Bu₃SnH (0.35 g, 1.2 mmol) in

toluene (25 mL) was cooled at −78°C and a 1 M soln of

Et₃B in hexane (1.4 mL. 1.4 mmol) was added followed

by air (1.0 mL). The resulting soln was kept at −78°C

for 3 h, then (TMS)₃SiH (0.30 g, 1.2 mmol) was added

followed by air (1 mL). The reaction mixture was kept

at −78°C for 3 h and a 1 M NaOH soln (15 mL) was

added and the heterogeneus mixture was stirred for 2 h

at rt. The organic layer was washed with H₂O, dried

over MgSO₄and concentrated under reduced pressure.

The crude product (90% ds) was puriﬁed by FC (pen-

tane/Et₂O 40:1) to afford the (2R,3R,4S)-28 (0.21 g,

73%) as a colorless oil. [h]²_D⁵=+8.2 (c 1, CH₂Cl₂). IR

(KBr): 3030, 2955, 2928, 2856, 1521, 1365, 1244, 1074,

1

1448, 1186, 1024 cm⁻¹. H NMR (360 MHz, CDCl₃):

7.30–7.15 (m, 5 arom. H), 5.89 (q, 1H, J=1.2 Hz,

OCHꢀCHBrMe), 3.68 (dt, 1H, J=4.6, 10.4 Hz,

OCHCHPh), 2.69 (ddd, 1H, J=3.7, 10.1, 13.7 Hz,

OCHCHPh), 2.26–2.10 (m, 1H), 1.93–1.85 (m, 2H),

1.86 (d, 3H, J=1.5, CH₃), 1.79–1.73 (m, 1H), 1.61–1.58

(m, 2H), 1.42–1.30 (m, 2H). ¹³C NMR (50 MHz,

CDCl₃): 143.2 (s), 141.5 (d), 128.1 (d), 127.9 (d), 126.4

(d), 97.5 (s), 85.2 (d), 50.3 (d), 33.1 (t), 33.0 (t), 25.6 (t),

24.9 (t), 22.2 (q). EI-MS m/z (%): 296 (M⁺+1, 21), 294

(20), 159 (86), 158 (36), 1290 (30), 117 (67), 115 (74), 92

(59), 91 (100).

4.4.10. 2,3-Butadienyl (1R)-2,2-dibromo-1-{[(1R,2S)-2-

phenyl cyclohexyl]oxy}prop-1-yl ether (R)-27. To a soln

of 26 (1.47 g, 5.0 mmol) and 2,3-butadien-1-ol (0.35 g,

5.0 mmol) in CH₂Cl₂(5 mL) cooled at −20°C was

added in portions NBS (0.89 g, 5.0 mmol). The result-

ing mixture was stirred at the same temperature for 2 h.

Hexane was added to precipitate succinimide. After

ﬁltration, the ﬁltrate was washed successively with

KOH (5%), H₂O and NaCl, dried over MgSO₄and the

solvent was removed under reduced pressure. Puriﬁca-

tion by FC (hexane/Et₂O 40:1) furnished 27 as 7:3

mixture of diasteroisomers. The two diasteroisomers

were separated by FC (hexane/Et₂O 85:1) and (R)-27

(0.94 g, 42%) was isolated.

1

1035 cm⁻¹. H NMR (360 MHz, CDCl₃): 7.28–7.13 (m,

5 arom. H), 5.87 (dt, 1H, J=10.1, 17.1 Hz, CHꢀCH₂),

4.90 (dd, 1H, J=2.1, 10.1 Hz, CHꢀCHH), 4.84 (ddd,

1H, J=0.6, 2.1, 17.1 Hz, CHꢀCHH), 4.30 (d, 1H,

J=4.6 Hz, OCHCHMe), 3.96 (dd, 1H, J=7.6 Hz,

OCHHCHCHꢀCH₂), 3.63 (dd, 1H, J=4.3, 8.5 Hz,

OCHHCHCHꢀCH₂), 3.51 (dt, 1H, J=4.3, 10.1 Hz,

OCHCHPh), 2.59 (dq, 1H, J=4.3, 9.5, 17.4 Hz,

CHCHꢀCH₂), 2.48 (ddd, 1H, J=3.7, 10.1, 13.4 Hz,

OCHCHPh), 2.19–2.12 (m, 1H), 1.89–1.68 (m, 4H),

1.62–1.23 (m, 4H), 0.44 (d, 3H, J=7.3 Hz, CHCH₃).

¹³C NMR (50 MHz, CDCl₃): 144.7 (s), 140.0 (d), 128.1

(d), 127.9 (d), 125.9 (d), 115.0 (t), 106.0 (d), 81.3 (d),

71.9 (t), 51.6 (d), 45.9 (d), 41.3 (d), 35.0 (t), 33.3 (t),

25.9 (t), 25.2 (t), 9.4 (q). CI-MS (CH₄) m/z (%): 288

(M⁺+1, 11), 287 (50), 217 (20), 159 (100), 111 (86), 91

(19). Anal. Calcd. for C₁₉H₂₆O₂(288.42): C, 79.68; H,

9.15. Found: C, 79.20; H, 9.41.

1

(R)-27 (major isomer): [h]²_D⁵=−2.3 (c 1, CH₂Cl₂). H

NMR (360 MHz, CDCl₃): 7.30–7.16 (m, 5 arom. H),

5.35 (quint, 1H, J=6.7 Hz, OCH₂CHꢀCꢀCH₂), 4.87–

4.84 (m, 2H, OCH₂CHꢀCꢀCH₂), 4.36 (ddt, 1H, J=1.8,

7.0, 11.3 Hz, OCHHCHꢀCꢀCH₂), 4.29 (ddt, 1H, J=

1.5, 7.3, 11.6 Hz, OCHHCHꢀCꢀCH₂), 4.16 (s, 1H,

OCHCBr₂Me), 3.77 (dt, 1H, J=4.3, 10.1 Hz,

OCHCHPh), 2.63 (ddd, 1H, J=3.7, 10.1, 13.7 Hz,

OCHCHPh), 2.29–2.22 (m, 1H), 1.93–1.86 (m, 1H),

1.86 (s, 3H, CH₃), 1.78–1.72 (m, 1H), 1.62–1.30 (m,

5H). ¹³C NMR (50 MHz, CDCl₃): 209.4 (d), 144.1 (s),

128.2 (d), 126.5 (d), 106.0 (d), 87.7 (d), 82.1 (d), 76.1 (t),

69.5 (t), 68.1 (s), 51.1 (d), 34.3 (q), 34.1 (t), 33.8 (t), 25.7

(t), 25.1 (t).

4.4.12.

(3R,4S)-3-Methyl-4-vinyltetrahydrofuran-2-ol

(3R,4S)-23. A soln of (2R,3R,4S)-28 (80 mg, 0.28

mmol) in THF (1.3 mL) and 10% HCl (1 mL) was kept

at rt for 30 min. After extraction with Et₂O, the organic

phases were washed with sat. NaHCO₃and H₂O, dried

over MgSO₄and concentrated under reduced pressure.

The crude product was puriﬁed by FC (pentane/Et₂O

1:1) to afford (3R,4S)-23 (20 mg, 56%) and (1R,2S)-

phenylcyclohexanol (30 mg, 61%). Spectral data identi-

cal with racemic compound (vide supra).

1

(S)-27 (minor isomer): H NMR (360 MHz, CDCl₃):

7.29–7.23 (m, 5 arom. H), 5.11 (quint, 1H, J=7.0 Hz,

R. Nouguier et al. / Tetrahedron: Asymmetry 14 (2003) 3005–3018

3017

4.4.13. (−)-Botryodiplodin (−)-1. A suspension of lactol

(15 mg, 0.12 mmol), PdCl₂(2 mg, 0.012 mmol) and

Cu(OAc)₂·2H₂O (52 mg, 0.24 mmol) in N,N-dimethyl-

acetamide/H₂O 7:1 (0.3 mL) was placed under oxygen

and stirred at rt for 4 days. The mixture was diluted

with Et₂O, ﬁltered through Celite with Et₂O to wash

the ﬁlter cake, poured into water (1.5 mL) and

extracted with Et₂O. The organic phases were dried and

concentrated under reduced pressure. The crude

product was puriﬁed by FC (pentane/Et₂O 1:1) to

furnish (−)-botryodiplodin (7 mg, 41%). The optical

purity (>98% ee) was determined by GC (b-cyclodex-

trin, 35% diacetoxy, 120°C): (−)-1: t_R=10.09 min, (+)-1:

t_R=10.40 min. Spectral data identical with literature

data.²[h]_D²⁵=−68 (c 0.35, MeOH) {lit.:⁶[h]²_D⁵=−70 (c

0.124, MeOH)}.

19. Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J. W.;

Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M.

J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunning-

ham, P. S.; Berliner, M. A. J. Org. Chem. 1997, 62, 1976.

20. For a preliminary communication of this work, see:

Nouguier, R.; Gastaldi, S.; Stien, D.; Bertrand, M.;

Renaud, P. Tetrahedron Lett. 1999, 40, 3371.

21. For a preliminary communication of this work, see:

Villar, F.; Andrey, O.; Renaud, P. Tetrahedron Lett.

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Article Doi

Synthesis of (±)- and (-)-botryodiplodin using stereoselective radical cyclizations of acyclic esters and acetals

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