A convergent asymmetric synthesis of γ-butenolides

Article abstract of DOI:10.1016/S0040-4020(01)00078-3

The addition of aldehydes to the new enantiomerically pure lithiated sulfoxide-orthoester 13 yielded γ-butenolides of high enantiomeric purities after elimination of phenylsulfinic acid. The cyclocondensation with ketones was less stereoselective. This new asymmetric synthesis of γ-butenolides has been applied to a convergent preparation of the antifungal antibiotic (+)-cerulenin.

Full text of DOI:10.1016/S0040-4020(01)00078-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2597±2608
A convergent asymmetric synthesis of g-butenolides
a
Marc Renard and Leon A. Ghosez
a,b,p
Â
a
Á Â
Laboratoire de Chimie Organique de Synthese, Universite Catholique de Louvain, Unite CHOM, place L. Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Institut Europeen de Chimie et Biologie (IECB), ENSCP, Avenue Pey-Berland 16, BP 108, 33607 Pessac Cedex, France
b
Â
Au Professeur H. B. Kagan, avec toute mon admiration
Received 16 August 2000; accepted 6 November 2000
AbstractÐThe addition of aldehydes to the new enantiomerically pure lithiated sulfoxide-orthoester 13 yielded g-butenolides of high
enantiomeric purities after elimination of phenylsul®nic acid. The cyclocondensation with ketones was less stereoselective. This new
asymmetric synthesis of g-butenolides has been applied to a convergent preparation of the antifungal antibiotic (1)-cerulenin. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
products of the chiral pool,2 or by asymmetric syntheses
using microbial3 or chiral reagents.4
g-Lactones and butenolides (g-substituted-2(5H)-fura-
nones) form an important class of compounds which appear
as substructures in many natural products and also constitute
pivotal building blocks for the synthesis of a wide range of
biologically active compounds. Consequently, the develop-
ment of ef®cient routes towards enantiomerically pure
butenolides has received considerable attention. They
have been obtained by resolution,1 by transformation of
Recently, a convergent and general method of synthesis of
g-lactones and butenolides has been reported from our
laboratory.5 It involved the cyclocondensation of aldehydes
or ketones with a C3 reagent 1 acting as a 1,3 dipole equiva-
lent (Scheme 1). The wide scope of the method prompted us
to study an asymmetric version of the sequence.6 We now
report the full details of these studies and their application to
Scheme 1.
Keywords: sulfoxides; asymmetric synthesis; cyclocondensation; g-butenolides; cerulenin.
Corresponding author. Tel.: 132-10-4742782; fax: 132-10-472788; e-mail: ghosez@chim.ucl.ac.be; leon.ghosez@iecb-polytechnique.u-bordeaux.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00078-3

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M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
Scheme 2. Conditions: (a) PhSH, Et3N in MeOH, rt; (b) HClg in EtOH (sat.), rt; (c) (^)-9 in CH2Cl2. 9:
Scheme 3.
an enantioselective synthesis of the antifungal antibiotic
(1)-cerulenin.
The sul®de-orthoester 12 was readily prepared in three
steps from simple starting materials (Scheme 4). It was
cleanly converted into the corresponding racemic sulfoxide
13 by reaction with rac-oxaziridine 14 under strictly
anhydrous conditions. There was no contamination by the
corresponding ester. The moisture-sensitive orthoester-
sulfoxide 13 could be kept for several weeks at rt under
dry atmosphere.
2. Synthesis of the C3 reagent
Arylsulfoxide-stabilised carbanions have been shown to add
to aldehydes with high stereoselectivities7 with the excep-
tion of the dianion derived from g-phenylsul®nylpropionic
acid.8 We felt that the replacement of the carboxyl group by
an orthoester would generate a monoanion adding to
prochiral carbonyl compounds with higher facial selectivity.
The corresponding C3 reagent 7 could not be prepared by
the obvious method consisting of the reaction of menthyl
tolylsul®nate with a Grignard reagent (Anderson's method9)
because the orthoesters were unstable under these con-
ditions.
Resolution of rac-13 was readily effected by preparative
hplc followed by recrystallisation of the enantiomers in
ethyl acetate. Both enantiomers were obtained in good
yields and high enantiomeric purities ($99.9%). The abso-
lute con®guration of the (2)-enantiomer 13 was shown to be
(S) by an X-ray diffraction analysis.12
The need for a resolution by hplc led us to examine an
alternative route for the synthesis of individual enantiomers
of 13. We considered the asymmetric oxidation of
sul®des to sulfoxides which has already been widely
explored with many different oxidants.13 However, we
found that very few of these reagents have general
application and even fewer would be compatible with
the presence of the sensitive orthoester function. In
earlier experiments, we had selected Kagan's modi®ca-
tion of the Sharpless epoxidation system.13a However,
the bulky triisopropylphenyl-substituted sul®de group
of 12 could not be oxidised by Kagan's reagent even
after 48 h at rt. The inertness of 12 towards oxidants
was further con®rmed by the slow rate of its reaction
with Davis' camphorsulfonyloxaziridine reagents 15a
and b14 (Scheme 5). The reactions had to be conducted
at rt for c.a. 2±3 days with the more reactive 15a and
for c.a. 5 days with 15b. We used 15b in most cases
because it was easier to prepare. With (1)-15b, yields
of pure (S)-13 were reproducibly 50±55% with an ee of
97%. This method represents a convenient asymmetric
synthesis of both enantiomers (S)- and (R)-13 in high
enantiomeric purity.
A conventional sequence of reaction gave the sul®de-
orthoester 6 which was oxidised to the corresponding sulf-
oxide with (^)-oxaziridine 910 (Scheme 2). The correspond-
ing sulfoxide was obtained in good yields, but was always
contaminated by ^10% of the corresponding ester 8. All
attempts to purify 7 led to increasing amount of ester 8
accompanied by unidenti®ed products. The intrinsic
instability of 7 probably resulted from an anchimeric assis-
tance of the ionisation of the orthoester by sulfoxide
(Scheme 3).
We then selected the bicyclic orthoester described by Corey
et al. for its greater stability and its easy preparation from
the corresponding carboxylic acid.11 A bulky aryl sub-
stituent was selected (a) to hinder the sulfoxide group
which would be less prone to assist the ionisation of the
orthoester, (b) to enhance the facial selectivity in both
the asymmetric oxidation of the sul®de precursor and
the addition of the sulfoxide-stabilised anion to a carbonyl
group.

M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
2599
Scheme 4. Conditions: (a) LiAlH4, Et2O, D then methylacrylate (3 equiv.), Et3N 5% in MeOH followed by LiOH in aqueous THF; (b) N,N-carbonyldi-
imidazole (1.07 equiv.) in CH2Cl2 then 3-methyl-3-oxetanemethanol (1.2 equiv.); (c) BF3´OEt2 (0.25 equiv.), CH2Cl2; (d) 14, CH2Cl2; (e) preparative hplc on
Chiralpak-AD column, elution with dry n-hexane/i-propanol (9:1), recrystallisation in dry AcOEt. 14:
Scheme 5.
3. Asymmetric synthesis of g-butenolides
one pot, three-step sequence using enantiomerically pure
(S)-13 as C3 component. Table 1 shows that: (a) yields
were good. As a matter of fact the total yield is higher
with sulfoxide reagent 13 than with the corresponding sul-
fone reagent 1.5 Thus, even for the production of racemic
g-butenolide, we recommend the racemic sulfoxide reagent
13 instead of the phenylsulfone 1; (b) enantiomeric excesses
vary. They were high with aliphatic and aromatic aldehydes.
trans-Crotonaldehyde gave a much lower ee, but this was
the result of partial racemisation under the reaction con-
ditions. As expected, facial selectivity was much lower
with ketones.
Treatment of enantiomerically pure (S)-13 C3-reagent with
LDA gave the corresponding sulfoxide-stabilised carbanion
(Scheme 6). At 2788C over a period of 6 h, it quantitatively
added to both aldehydes and ketones. At 2408C, the
reaction was not complete, probably as a result of a less
favourable equilibrium or/and a competitive enolisation of
the carbonyl compound under these strongly basic con-
ditions. The crude adducts were directly re¯uxed in THF
containing aqueous 2 M H2SO4. With the aldehyde adducts
16 (R2ˆH), both cyclisation and elimination of phenyl-
sulfenic acid were complete after 12 h. With the ketone
adducts 16 (R1, R2±H), the elimination step was slower:
additional re¯ux of the worked-up mixture in toluene was
needed.
The absolute con®guration of the known butenolides 16a,8
b,15 c3a and g8 were assigned by comparison of their optical
rotations with those reported earlier. Absolute con®gu-
rations of 16d±f were assigned by analogy.
A representative series of carbonyl compounds was then
converted into the corresponding g-butenolides by this
The absolute con®guration of all butenolides 16a±f (major

2600
M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
Scheme 6.
isomer) can be explained or (and) predicted on the basis of a
six-membered ring transition state with a lithium cation
coordinated to the oxygen atom of the carbonyl and sul®nyl
groups (Figs. 1 and 2).9a,16 There are four possible transition
states for the addition of the lithium carbanion derived
from (S)-13 to a prochiral carbonyl compound. Both
transition states B and C should be disregarded, since
they involve an approach of the carbonyl compound on
the face containing the very bulky aryl substituent of the
sulfur atom.
Table 1. Asymmetric synthesis of g-butenolides 16
Entry
g-Butenolide 16
Yield (%)
79
eea (%)
[a]20D (CHCl3)
1
93
90
85
89
53
29
32
1271.2 (c 1.02) (R)
2
3
4
5
6
78
79
82
70
95
65
1109.5 (c 1.02) (S)
171.1 (c 1.48) (S)
1127.7 (c 1.01) (S)
155.0 (c 0.60) (S)
14.6 (c 1.42) (S)
167.9 (c 1.22) (R)
7
a
Measured by chiral GC with racemic mixture of butenolide as reference.

M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
2601
Figure 1.
Figure 2.
Examination of the most probable chair conformation of
transition states, A and D, easily explain the observed facial
selectivities. A has all large groups equatorial whereas, in D,
the largest substituent of the aldehyde is axial. Thus A
should be of lower energy than D. This explains the good
facial selectivity with aldehydes (RS much smaller than RL)
and the poor selectivity with ketones (RS not very different
from RL).
fatty acid biosynthesis in a variety of yeast cells.18 It was
also found to be inhibitory for various bacteria, fungi and
yeasts.19 In protic conditions, the molecule can cyclise to a
mixture of diastereomeric g-lactams 18 (Scheme 7). The
actual active tautomer of 17 is still unknown.
As a result of its interesting biological activity and its
peculiar structural features, this natural product has
attracted much interest in the community of synthetic
chemists.20 Still, only six syntheses lead to the optically
active natural compound.21 Several are rather long and
linear. The best yields were obtained by the convergent
routes developed by Yoda et al.21c (19.5%, 7 steps) and
Townsend et al.21e (26%, 10 steps).
4. Application to the total asymmetric synthesis of
(1)-cerulenin
(1)-Cerulenin 17 is an antifungal antibiotic which was
®rst isolated from the culture ®ltered of Cephalosporium
caerulens.17 This natural product is a powerful inhibitor of
Our retrosynthetic Scheme 8 involved butenolide (R)-24 as

2602
M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
Scheme 7.
Scheme 8.
key intermediate. This compound has already been
converted into (1)-cerulenin.20b It should be easily prepared
by the one-pot asymmetric synthesis of butenolides
described above, starting from the (R) enantiomer of the
C3 reagent.
butenolide synthesis. This synthetic route compares well
with that of Townsend et al. in terms of yields (^42%)
and selectivity ($93% of E,E isomer).
The aldehyde 23 was then reacted with the enantiomerically
pure C3-reagent (R)-13 as described above (Scheme 10).
The butenolide (R)-24 was obtained in 75% yield and
84.5% ee (chiral hplc). It was converted in three steps into
(1)-cerulenin: stereoselective oxidation to the epoxylactone
25 was effected following the procedure described by
Hegedus et al.,21d aminolysis of 25 as described before,
and oxidation of the resulting alcohol 26 to (1)-cerulenin
was performed as described by Townsend et al.21e The
natural product was obtained as a mixture of three
tautomers. Intermediates 25 and 26 were obtained with
eeù84±85% showing that all transformations had occurred
The aldehyde compound is (4E,7E)-nonadienal 23 which
had been prepared earlier by Townsend et al.21e Having
experienced some problems in scaling up the described
synthesis, we devised another route shown in Scheme 9.
The protected pentynol 20 was coupled with trans-crotyl
bromide to yield 82% of 21 (E/Zˆ19:1). Reduction of the
triple bond by lithium in liquid ammonia followed by
methanolysis gave (4E,7E)-nonadienal 22 (isomeric
purity$93%). Swern oxidation gave aldehyde 23, which
was not stable and was therefore, immediately used in the
Scheme 9. Conditions: (a) 2,3-dihydropyrane, PTSA, CH2Cl2, D; (b) n-BuLi, CuBr´DMS, THF, 2788C then trans-crotyl bromide, 2788C ! rt, 8 h; (c) Li,
NH3, t-BuOH, (NH4)2SO4, 2788C then MeOH, PPTS, 408C; (d) DMSO, oxalyl chloride, Et3N in CH2Cl2, 2788C.

M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
2603
Scheme 10. Conditions: (a) LDA, THF, 2788C1(R)-13, add 23, 6 h, 2788C, then H2SO4, D, 12 h; (b) NaClO, Et2O±DMF, 08C; (c) NH3 in MeOH, 08C;
Ê
(d) TPAPcat, NMO, CH2Cl2, MS 4 A, rt, 1 h.
without epimerisation. It is therefore reasonable to assume
that the ees of each of the tautomer of (1)-cerulenin is also
in the range 84±85%.
Merck) or with gel 40 (230±400 mm, Merck). THF, Et2O
were dried on Na/benzophenone and distilled; CH2Cl2,
1,2-dichloroethane, AcOEt, n-hexane, petroleum ether,
i-Pr2NH were dried on CaH2 then distilled, EtOH was
dried on magnesium ethoxide and distilled. Aldehydes and
ketones were distilled before use.
This nine-step asymmetric synthesis of (1)-cerulenin is
rather short and practical although, it gives lower yield
(9%, 10 steps) than Yoda's and Townsend's previous syn-
theses. However, its highly convergent character makes it
uniquely suited for the synthesis of analogs of (1)-cerulenin
for agrochemical and pharmacological studies.
5.1.1. 3-(Phenylsulfenyl)propanenitrile 5. 5.8 mL
(88 mmol) of acrylonitrile was added dropwise to a solution
containing 10 mL of thiophenol (97 mmol) and 0.6 mL of
Et3N (4 mmol) in 180 mL of methanol. The reaction
mixture was stirred overnight then concentrated under
reduced pressure. The oily residue was puri®ed by bulb-
to-bulb distillation (1208C, 1023 mmHg) to give pure sul®de
5. Experimental
5.1. General
1
5. Yield: 13.65 g (95%). H NMR: 2.58 (t, 2H, Jˆ7.5 Hz),
3.12 (t, 2H, Jˆ7.5 Hz), 7.26±7.45 (m, 5H). 13C NMR: 17.9,
29.8, 117.8, 127.3, 129.1, 131, 133. IR (CH2Cl2): 3050,
2929, 2240, 1590. Mass (EI1Q1MS): 163, 123, 109, 77, 54.
1H and 13C NMR spectra were recorded with a Varian
Gemini-200, VXR-200, Gemini-300 or Brucker AM-500;
CDCl3 was used as solvent and tetramethylsilane as internal
reference, dH values are in ppm. IR spectra were registered
on a BIO-RAD TFS 135 FT-IR spectrometer. All absorption
values are expressed in wavenumbers (cm21). Mass spectra
were recorded with a Finnigan MAT-TSQ 700 apparatus.
[a]D values were obtained on a Perkin±Elmer 241 MC
polarimeter. Melting points are uncorrected. Enantiomeric
excesses were measured on hplc with a Millipore Waters
600 Controller, UV Millipore Waters 486 as detector and
®tted with Diacel Chiralpak-AD, -AS, OD-H analytical
column. A Carlo Erba Fractovap GC apparatus was used
®tted with a polymethoxysiloxane RSL-150 column (achiral
phase) or Chrompack CP-Chirasil-Dex-Cb (Chiral phase).
Resolution on preparative hplc were run on an apparatus
developed by Dr E. Cavoy (UCB-Pharma, Belgium) and
®tted with a Diacel Chiralpak-AD column (Lˆ25 cm,
fˆ5 cm). TLC were run on silicagel 60F254; column
chromatography was performed with gel 60 (60±200 mm,
5.1.2. 1,1-Diethoxy-3-(phenylsulfenyl)propyl ethyl ether
6. Step A. A cooled solution (2358C) of 10 g (61.26 mmol)
of nitrile 5 and 5.35 mL of dry ethanol in 50 mL of
methylene chloride was saturated with anhydrous gaseous
hydrogen chloride. The solution was kept at 58C for 20 h
then concentrated in vacuo. The residue was washed with
dry ether and the solvent was removed under reduced
pressure. The iminoester salt was obtained in quantitative
1
yield and used without puri®cation. H NMR: 1.44 (t, 3H,
Jˆ7.1 Hz), 3.06 (t, 2H, Jˆ7.0 Hz), 3.30 (t, 2H, Jˆ7.0 Hz),
4.56 (q, 6H, Jˆ7.1 Hz), 7.2±7.5 (m, 5H), 11.5 (sbroad, 1H),
12.4 (sbroad, 1H). 13C NMR: 13.5, 30.0, 33.5, 71.0, 127.3,
129.2, 131, 134, 177, I.R.: 3300, 2400, 1655, 1590, 1090.
Step B. A solution of the iminoester salt (17 g, 59.8 mmol)
in 55 mL of anhydrous methylene chloride and 33 mL of
ethanol was kept at rt for 60 h. The precipitate was ®ltered

2604
M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
and solvents were removed in vacuo. The residual oil was
treated with dry ether and insoluble materials were ®ltered
off. The oily residue was puri®ed by ¯ash chromatography
using silicagel (petroleum ether/diethyl ether, 20:80),
which had been treated with an eluent containing 5% of
Et3N or by bulb-to-bulb distillation (bp 1508C, 0.5 mmHg).
149.7, 153.1, 172.3. IR (neat): 3043, 2962, 2929, 2869,
1745, 1169. Mass (EI1Q1MS): 203, 189, 322. HRMS
(EI): calcd for C19H30O2S: 322.1966; found: 322.1974.
5.1.7. 3-[(2,4,6-Triisopropylphenyl)sulfenyl]propionic
acid 10. A biphasic mixture of methyl ester 28 (207 g,
609 mmol), LiOH (137 g, 1.830 mol), THF (2.6 L) and
water (1.8 L) was stirred at rt for 7 h. After acidi®cation
by addition of 6N HCl (pH 1) and extraction by CH2Cl2,
the combined organic phases were concentrated under
reduced pressure. The crude acid was puri®ed by recrystal-
lisation in hot n-hexane to give needles (mp: 122±1248C).
1
Yield: 13.6 g (80%). H NMR: 1.19 (t, 9H, Jˆ7.1 Hz),
2.1±2.18 (m, 2H), 3.11±3.19 (m, 2H), 3.7 (q, 6H, Jˆ
7.1 Hz), 7.5±8.0 (m, 5H). 13C NMR: 14.8, 27.4, 32, 56.9,
113.9, 125.8, 128.5, 129.1, 136.1. I.R. (CH2Cl2): 3060,
2990, 2950, 2895, 1590, 1480, 1170. Mass (EI1Q1MS):
239, 147, 123, 109, 137, 284. Anal. calcd for C15H24O3S: C
63.34%, H 8.50%, S 11.27%; found: C 63.21%, H 8.58%,
S 10.70%.
1
Yield: 159.7 g (85%). H NMR: 1.23 (d, 12H, Jˆ6.8 Hz),
1.25 (d, 6H, Jˆ6.9 Hz), 2.59 (t, 2H, Jˆ7.3 Hz), 2.87 (hept,
1H, Jˆ6.9 Hz), 2.87 (t, 2H, Jˆ7.3 Hz), 3.89 (hept, 2H, Jˆ
6.9 Hz), 7.00 (s, 2H), 10.2 (sbroad, 1H). 13C NMR: 23.8, 24.4,
31.5, 31.9, 34.1, 34.2, 121.9, 127.3, 149.8, 153.2, 178.3. IR
(KBr,): 3044, 2964, 2656, 1701. Mass (CI1Q1MS): 309,
267, 249, 203. Anal. calcd for C18H28O2S: C 70.08%, H
9.15%, S 10.39%; found: C 70.20%, H 9.13%, S 10.17%.
5.1.3. Phenyl 3,3,3-triethoxypropyl sulfoxide 7. To a
solution of sul®de 6 (500 mg, 1.75 mmol) in anhydrous
methylene chloride (5 mL) was added dropwise 560 mg of
oxaziridine 9 (1.75 mmol) in CH2Cl2 (3 mL). After 2 min,
the solvent was removed in vacuo and the resulting solid
was triturated in dry ether. The suspension was ®ltered off
and the solvent was removed under reduced pressure to
yield crude sulfoxide 7 which could not be separated from
5.1.8. (3-Methyl-3-oxethanyl)methyl 3-[(2,4,6-triisopro-
pylphenyl)sulfenyl]propionate 11. A solution of 50 g of
acid 10 (0.163 mol) in 210 mL of anhydrous methylene
chloride was added dropwise to a suspension of N,N0-
carbonyldiimidazole (28.3 g, 0.175 mol) in methylene
chloride (210 mL). After 30 min, 3-methyl-3-oxetane-
methanol (20 mL, 0.2 mol) was added. After 36 h at rt, the
mixture was concentrated in vacuo and the crude product
was puri®ed by ¯ash chromatography (petroleum ether/
AcOEt, 4:1) on silicagel, pretreated with a mixture of
petroleum ether/ethyl acetate (4:1) containing 5% of Et3N.
Yield: 60.8 g (95%) (colourless oil). 1H NMR: 1.23 (d, 12H,
Jˆ6.9 Hz), 1.25 (d, 6H, Jˆ6.9 Hz), 1.34 (s, 3H), 2.60 (t, 2H,
Jˆ7 Hz), 2.88 (t, 2H, Jˆ7.3 Hz), 2.77±2.98 (m, 1H), 3.88
(hept, 2H, Jˆ6.8 Hz), 4.19 (s, 2H), 4.44 (AB, 4H, Jˆ
26.2 Hz), 7.01 (sbroad, 2H). 13C NMR: 21.1, 23.8, 24.4,
31.4, 32.5, 34.2, 34.3, 39.1, 68.8, 79.4, 121.8, 127.6,
149.7, 153.0, 171.8. IR (neat): 3047, 2960, 2930, 2869,
1741, 1167, 1017, 985. Mass (EI1Q1MS): 43, 85, 203,
235. HRMS (EI): calcd for C23H36O3S: 392.2385; found:
392.2379.
1
ester 8. Yield: 493 mg (95%). H NMR (crude): 1.12±1.25
(m, 9H), 1.89 (ddd, 1H, Jˆ14.7, 11.3, 5 Hz), 2.22 (ddd, 1H,
Jˆ14.6, 11.2, 4.9 Hz), 2.72 (ddd, 1H, Jˆ13.5, 11.2, 4.9 Hz),
2.98 (ddd, 1H, Jˆ13.6, 11.3, 4.9 ), 3.34±3.53 (m, 6H),
7.48±7.64 (m, 5H). 13C NMR (crude): 14.8, 32.1, 38.9,
57.1, 114.1, 124.1, 129.4, 130.9, 141.2. IR (neat): 3062,
2991, 1590, 1170, 1050.
5.1.4. Ethyl 3-phenylsul®nylpropionate 8.22 1H NMR:
1.25 (t, 3H, Jˆ7.1 Hz), 2.50±2.60 (m, 1H), 2.85±2.97 (m,
2H), 3.17±3.28 (m, 1H), 4.12 (q, 2H, Jˆ7.1 Hz), 7.5±7.7
(m, 5H). 13C NMR: 13.9, 25.9, 50.8, 60.8, 123.8, 129, 130.9,
142.6, 170.9. IR (CH2Cl2): 3060, 2990, 2950, 2920, 1740,
1590, 1490, 1450, 1050.
5.1.5. 2,4,6-Triisopropylbenzenethiol 27.23 To a suspen-
sion of LiAlH4 (115.5 g, 2.89 mol) in anhydrous ether
(2 L) was added slowly a solution of 2,4,6-triisopropyl-
benzensulfonyl chloride (300 g, 0.96 mol) in ether (2 L).
The reaction mixture was re¯uxed for 4 h, cooled to 08C
and neutralised by careful addition of aqueous 2N HCl.
Extraction with diethyl ether gave the crude thiol in quanti-
tative yield (227 g). It could be further puri®ed by bulb-to-
bulb distillation (1108C, 1.3£1023 Bar) or used without any
puri®cation. 1H NMR: 1.24 (d, 6H, Jˆ6.9 Hz), 1.26 (d, 12H,
Jˆ7.0 Hz), 2.87 (hept, 1H, Jˆ6.9 Hz), 3.07 (s, 1H), 3.51
(hept, 1H, Jˆ7.0 Hz), 7.01 (s, 2H). 13C NMR: 23.3, 24.1,
31.8, 34.2, 121.3, 124.0, 147.1, 148.2. Mass (EI1Q1MS):
221, 236, 193, 203.
5.1.9. 2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)ethyl
2,4,6-triisopropylphenyl sul®de 12. 5.84 mL (46.5 mmol)
of BF3´OEt2 was added dropwise to a solution of ester 11
(73 g, 186 mmol) in dry methylene chloride (186 mL) at
08C. The solution was stirred at 08C for 2 h. Addition of
130 mL of dry Et3N in ether gave a precipitate, which was
®ltered off. The solvent was removed under reduced
pressure and the crude orthoester was puri®ed by ¯ash
chromatography (AcOEt/n-hexane, 1:1) using silicagel,
which had been treated with an eluent containing 5% of
1
5.1.6. Methyl 3-[(2,4,6-triisopropylphenyl)sulfenyl]pro-
pionate 28. A solution of thiol 27 (100 g, 423 mmol) and
methyl acrylate (76 mL, 846 mmol) in methanol (428 mL)
containing 3 mL of Et3N was stirred overnight. Evaporation
of the solvent gave quantitatively the methyl ester (136.5 g),
Et3N. Yield: 62 g (85%). Mp: 148±1508C. H NMR: 0.77
(s, 3H), 1.22 (d, 12H, Jˆ6.9 Hz), 1.24 (d, 6H, Jˆ6.9 Hz),
1.89±1.94 (m, 2H), 2.68±2.74 (m, 2H), 2.86 (hept, 2H,
Jˆ6.9 Hz), 3.84 (s, 6H), 3.92 (hept, 2H, Jˆ7.3 Hz), 6.98
(s, 2H). 13C NMR: 14.5, 23.9, 24.5, 31.3, 31.4, 31.4, 34.2,
36.9, 72.6, 108.3, 128.3, 128.3, 149.2, 153.1. IR (KBr):
3045, 2958, 2877, 1054. Mass (CI1Q1MS): 393.3,
249.2, 234.2, 157.1. Anal. calcd for C23H36O3S: C
70.36%, H 9.24%, S 8.17%. Found: C 70.45%, H 9.37%,
S 8.54%.
1
which could be used without any puri®cation. H NMR:
1.23 (d, 12H, Jˆ6.9 Hz), 1.25 (d, 6H, Jˆ6.9 Hz), 2.55 (t,
2H, Jˆ7.6 Hz), 2.87 (t, 2H, Jˆ7.6 Hz), 2.81±2.94 (m, 1H),
3.65 (s, 3H), 3.89 (hept, 2H, Jˆ6.9 Hz), 7.01 (s, 2H). 13C
NMR: 23.9, 24.4, 31.4, 32.3, 34.2, 34.2, 51.6, 121.8, 127.4,

M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
2605
5.1.10. 2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)ethyl
2,4,6-triisopropylphenyl sulfoxide 13. Racemic serie. To a
solution of sul®de 12 (10 g, 25.47 mmol) in anhydrous
methylene chloride (20 mL) was added 6.65 g (25.47
mmol) of (^)-trans-3-phenyl-2-phenylsulfonyloxaziridine
1424 in 20 mL of CH2Cl2. After 1 h, the solvent was
removed under reduced pressure and the crude mixture
was puri®ed by recrystallisation in hot anhydrous AcOEt
(30 mL) to yield pure sulfoxide as colourless crystals
(mp:145±1488C). Yield: 8.3 g (80%).
which were puri®ed by chromatography on silicagel.
Enantiomeric purities were determined by GC analysis
on a 25 m£0.25 mm (ID) CHROMPACK CP-CHIRASIL-
DEX-CB column.
5.2.1. (5R)-5-Phenyl-2(5H)-furanone 16a.8 Colourless oil.
Yield: 155 mg (79%). ee: 93%. [a]20 ˆ1271.2 (c 1.02,
D
1
CHCl3) {Lit.8 [a]20 ˆ1304 (c 1.0, CHCl3)}. H NMR:
D
6.02 (dd, 1H, Jˆ2.1, 1.9 Hz), 6.22 (dd, 1H, Jˆ5.6,
2.1 Hz), 7.25±7.29 (m, 2H), 7.37±7.41 (m, 3H), 7.54 (dd,
1H, Jˆ5.6, 1.9 Hz). 13C NMR: 84.3, 120.9, 126.5, 129,
129.3, 134.3, 155.8, 173.1. IR (CH2Cl2): 3057, 1760,
1160, 1090, 1080, 855, 815.
Resolution on chiral hplc. 40 mL of a solution of 5 g
(25.47 mmol) sulfoxide (^)-13 in 1 L of an anhydrous
mixture of i-PrOH/n-hexane (10:90) was injected every
12 min on a hplc apparatus ®tted with a Chiralpak-AD
column (Lˆ25 cm, fˆ5 cm). The column was eluted
with a dry mixture of i-PrOH/n-hexane (10:90). Each
enantiomer was collected, the solvents were removed in
vacuo and the enantiomers were recrystallised from anhy-
drous ethyl acetate. S enantiomer: yield 1.6 g (32%).
5.2.2. (5S)-5-Isopropyl-2(5H)-furanone 16b.15 Colourless
oil. Yield: 120 mg (78%). ee: 90%. [a]20 ˆ1109.51 (c
D
1.02, CHCl3), [a]20 ˆ1111.5 (c 1.56, dioxane) {Lit.15
D
1
[a]20 ˆ1121 (c 2, dioxane)}. H NMR: 1.00 (d, 6H, Jˆ
D
6.9 Hz), 1.95±2.11 (m, 1H), 4.84±4.88 (m, 1H), 6.17 (dd,
1H, Jˆ5.7, 2 Hz), 7.46 (dd, 1H, Jˆ5.7, 2 Hz). 13C NMR:
17.6, 17.9, 31.6, 87.9, 122.2, 154.8, 170.5. IR (CH2Cl2):
2998, 1760, 1160, 1090, 1080, 855, 815.
.99.9% ee. [a]20 ˆ2168.8 (c 1.48, THF). R enantiomer:
D
yield 1.5 g (30%). .99.9% ee. [a]20 ˆ1167.3 (c 1.4,
D
THF).
5.2.3. (5S)-5-Pentyl-2(5H)-furanone 16c.3a Colourless oil.
Asymmetric oxidation. In a 25 mL round bottomed ¯ask
were introduced 1 g (2.547 mmol) of sul®de 12, 0.783 g
(2.547 mmol) of (1)-N-(phenylsulfonyl)camphoroxaziri-
dine 15a14 and 3 mL of dry methylene chloride. The solu-
tion was stirred for 6 days. Removal of the solvent under
high vacuum left a residue which was recrystallised from
anhydrous AcOEt to give pure sulfoxide as white solid (mp
145±1488C) in 55% yield (0.572 g). 97% ee (S enantiomer),
Yield: 149 mg (79%). ee: 79%. [a]20 ˆ171.1 (c 1.48,
D
1
CHCl3) {Lit.3a (R) [a]20 ˆ285.55 (c 1.35, CHCl3)}. H
D
NMR:, 0.82±0.88 (m, 3H), 1.19±1.43 (m, 6H), 1.6±1.76
(m, H), 4.97±5.05 (m, 1H), 6.07 (dd, 1H, Jˆ5.7, 2 Hz),
7.44 (dd, 1H, Jˆ5.7, 2 Hz). 13C NMR: 13.8, 22.3, 24.5,
31.3, 33, 83.4, 121.4, 156.4, 173.1. IR (CH2Cl2): 2935,
1755, 1163, 1032, 820.
[a]20 ˆ2163.5 (c 1.48, THF). 1H NMR: 0.78 (s, 3H), 1.23
5.2.4. (5S)-5-Cyclohexyl-2(5H)-furanone 16d.25 White
solid. Mp 45±488C. Yield: 167 mg (82%). ee: 89%.
D
(d, 6H, Jˆ6.2 Hz), 1.24 (d, 6H, Jˆ6.7 Hz), 1.24 (d, 6H,
Jˆ6.8 Hz), 2.00 (ddd,, 1H, Jˆ6, 10.3, 14 Hz), 2.17 (ddd,,
1H, Jˆ5.2, 10.4, 14.1 Hz), 2.87 (hept, 1H, Jˆ6.8 Hz), 3.03
(ddd, 1H, Jˆ6.1, 10.4, 13.1 Hz), 3.45 (ddd, 1H, Jˆ5.2, 10.4,
13.1 Hz), 3.85±4.09 (m, 2H), 3.86 (s, 6H), 7.05 (sbroad, 2H).
13C NMR: 14.3, 23.6, 24.2, 24.4, 27.9, 30.3, 31.4, 34.2, 48.9,
72.7, 108.4, 123, 134.3, 150, 152. IR (cm21): 3048, 2959,
2879, 1598, 1460, 1398, 1047, 934, 887, 730. MS (CI-
Q1MS): 157, 209, 203, 234, 252, 393, 409, 437. Anal.
calcd for C23H36O4S: C 67.61%, H 8.88%, S 7.85%;
found: C 67.39%, H 9.00%, S 8.10%.
1
[a]20 ˆ1127.7 (c 1.01, CHCl3). H NMR: 1.1±1.3 (m,
D
5H), 1.7±1.8 (m, 6H), 4.8±4.9 (m, 1H), 6.1 (dd, 1H, Jˆ
5.7, 2 Hz), 7.5, 6.1 (dd, 1H, Jˆ5.7, 2 Hz). 13C NMR: 25.6,
25.7, 25.9, 28.0, 28.4, 41.1, 87.4, 121.7, 155.4, 173.1. IR
(CH2Cl2): 2940, 2860, 1752.
5.2.5. (5S)-5-[(E)-1-Propenyl]-2(5H)-furanone 16e.25
Colourless oil. Yield: 106 mg (70%). ee: 53%. [a]20
ˆ
D
1
155.04 (c 0.60, CHCl3). H NMR: 1.76 (dd, 3H, Jˆ6.6,
1.6 Hz), 5.35 (ddq, 1H, Jˆ14.8, 7.9, 1.6 Hz), 5.38±5.43
(m, 1H), 5.93 (dq, 1H, Jˆ14.8, 6.6 Hz), 6.12 (dd, 1H, Jˆ
5.7, 1.9 Hz), 7.37 (dd, 1H, Jˆ5.7, 1.9 ). 13C NMR: 17.7,
83.8, 121.4, 124.6, 132.7, 155.2, 172.8. IR (CHCl3): 2950,
1755, 1290, 1075, 1020, 970, 820.
5.2. General procedure for the preparation of g-buten-
olides 19
A solution of the sulfoxide (S)-13 (0.5 g, 1.224 mmol) in
THF was added dropwise to a solution of LDA (1.1 equiv.)
in THF at 2788C. The mixture was stirred for 1 h. The
carbonyl compound (1.2 equiv.) was then added dropwise
and the reaction mixture was stirred for 6 h at 2788C. The
mixture was quenched by 6 mL of H2SO4 (2 M) at 2788C.
The resulting mixture was then re¯uxed overnight. Extrac-
tion with methylene chloride gave a crude product, which
was puri®ed by chromatography on silica gel to yield pure
butenolides 16 when starting from aldehydes. With ketones,
the product consisted of a mixture of butenolide and the
corresponding phenylsul®nyl lactones. It was diluted in
10 mL of toluene and re¯uxed for 6 h. Addition of water,
extraction with methylene chloride and concentration of
the combined organic phases yielded crude butenolides,
5.2.6.
(5S)-5-Methyl-5-butyl-2(5H)-furanone
16f.26
Colourless oil. Yield: 179 mg (95%). ee: 29%. [a]20
ˆ
D
1
14.57 (c 1.42, CHCl3). H NMR: 0.89 (t, 3H, Jˆ7.0 Hz),
1.16±1.39 (m, 4H), 1.47 (s, 3H), 1.70±1.78 (m, 2H), 6.01 (d,
1H, Jˆ5.7 Hz), 7.39 (d, 1H, Jˆ5.7 Hz). 13C NMR: 13.7,
22.6, 23.8, 25.7, 37.9, 89.0, 120.3, 160.6, 172.7. IR
(CH2Cl2): 2935, 1753, 1163, 1032, 816.
5.2.7. (5R)-5-Methyl-5-phenyl-2(5H)-furanone 16g.8
Colourless oil. Yield: 139 mg (65%). ee: 32%. [a]20
ˆ
D
167.97 (c 1.22, CHCl3) {Lit.8 [a]20 ˆ1276 (c 3.7,
D
1
CHCl3)}. H NMR: 1.83 (s, 3H), 6.06 (d, 1H, Jˆ5.6 Hz),
7.3±7.45 (m, 5H), 7.64 (d, 1H, Jˆ5.6 Hz). 13C NMR: 26.3,
88.9, 119.4, 124.8, 128.3, 130.8, 149.8, 160.3, 173.2. IR

2606
M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
(CH2Cl2): 3012, 2993, 2987, 1760, 1600, 1450, 1235, 1120,
1080.
methylene chloride. After 5 min, a solution of alcohol 22
(1.5 g, 10.69 mmol) in methylene chloride (22.5 mL) was
added dropwise at 2788C and the stirring was maintained
for 15 min before adding 11.9 mL of Et3N. Care should be
taken not to raise the temperature above 2608C during
addition of the successive reagents. Then, the mixture was
brought up to rt. Addition of 30 mL of 1N HCl solution
followed by extraction with methylene chloride gave the
crude aldehyde 23 which was ¯ash chromatographed
(AcOEt/n-hexane, 5:95). Pure (4E,7E)-4,7-nonadienal was
obtained as a colourless oil. Yield: 1.25 g (84.5%). Bp 858C
5.2.8. 4-Pentynyl tetrahydro-2H-pyran-2yl ether 20.20b
6.38 mL (69.19 mmol) of dihydropyran was added dropwise
to a solution of 4-pentyn-1-ol (5 mL, 57.66 mmol) and
p-toluenesulfonic acid (10 mg, 0.06 mmol) in anhydrous
methylene chloride (150 mL) at 08C. The mixture was
then stirred for 3 h at 08C. Removal of the solvent in
vacuo gave the crude ether 20 which was puri®ed by distil-
lation (46±498C, 0.1 mmHg). Yield: 7.52 g (84%) as a
1
1
colourless oil. H NMR: 1.48±1.90 (m, 6H), 1.96 (t, 1H,
(4.5 mmHg). H NMR: 1.66 (d, 3H, Jˆ4.7 Hz), 2.31±2.38
Jˆ2.6 Hz), 3.44±3.55 (m, 2H), 3.79±3.90 (m, 2H), 4.61
(t, 1H, Jˆ3.3 Hz). 13C NMR: 15.3, 19.4, 25.4, 28.6, 30.6,
62.1, 65.7, 68.3, 83.9, 98.7. IR (neat): 3295, 2944, 2873,
2118.
(m, 2H), 2.48±2.53 (m, 2H), 2.65±2.59 (m, 2H), 5.34±5.53
(m, 4H), 9.77 (s, 1H). 13C NMR: 17.9, 25.1, 35.5, 43.4,
125.7, 128.3, 129.3, 130.7, 201.2. IR (CH2Cl2): 2959,
2718, 1727, 969.
5.2.9. (E)-7-Nonen-4-ynyl tetrahydro-2H-pyran-2-yl ether
21.27 7.77 mL of a solution of 2.25 M n-BuLi in hexanes
(17.49 mmol) was added dropwise to a stirred solution of
the pyranyl ether 20 (2.675 g, 15.9 mmol) and CuBr´DMS
(0.650 g, 3.16 mmol) in 80 mL of THF at 2788C. After
1.5 h, freshly distilled crotyl bromide (2.31 mL, 19.08
mmol) was added dropwise. The temperature was slowly
raised to rt and the mixture was stirred overnight. An
aqueous solution of ammonium chloride was added and
the aqueous phase was extracted with diethyl ether. The
collected organic phases were dried over MgSO4, ®ltered
off and concentrated in vacuo. The oily residue was puri®ed
by ¯ash chromatography on silicagel (AcOEt/n-hexane,
10:90) to give pure 21 as a colourless oil. Yield: 2.68 g
5.2.12. (5R)-5-[(3E,6E)-3,6-Octadienyl]-2(5H)-furanone
24.20e A procedure similar to the one described above
for the preparation of butenolides 16 was used for the syn-
thesis of (5R)-5-[(3E,6E)-3,6-octadienyl]-2(5H)-furanone
24 starting from 1 g (2.45 mmol) of sulfoxide (R)-13 and
0.372 g (2.69 mmol) of (4E,7E)-nonadienal. Yield: 353 mg
1
(75%). ee: 84.5%. [a]20 ˆ253.08 (c 0.83, CHCl3). H
D
NMR: 1.66 (m, 3H), 1.69±1.88 (m, 2H), 2.19 (m, 2H),
2.66±2.68 (m, 2H), 5.03±5.06 (m, 1H), 5.35±5.55 (m,
4H), 6.11 (dd, 1H, Jˆ5.7, 2 Hz), 7.47 (dd, Jˆ5.7, 2 Hz).
13C NMR: 17.8, 28.0, 33.0, 35.5, 82.7, 121.5, 126.7, 128.4,
129.2, 130.8, 156.2, 173.1. IR (CH2Cl2): 2970, 2890, 1755.
5.2.13. (1R,4R,5S)-4-[(3E,6E)-3,6-Octadienyl]-3,6-dioxa-
bicyclo[3.1.0]hexan-2-one 25.21e A 13% aqueous solution
of NaClO (0.65 mL, 1.37 mmol) was added dropwise at 08C
into a solution of butenolide 24 (140 mg, 0.69 mmol) in
28 mL of a mixture of ether/DMF (1:1). The mixture was
stirred for 1 h at 08C; then, the reaction was quenched by
addition of 5 mL of 10% Na2S2O3 solution. The aqueous
phase was extracted three times with ether and the collected
organic phases concentrated in vacuo. The oily residue was
¯ash chromatographed (hexane/ether, 5:1) to yield a colour-
1
(80.5%). H NMR: 1.47±1.86 (m, 6H), 1.68 (dd, 3H, Jˆ2,
3 Hz), 2.26±2.35 (m, 2H), 2.84±2.87 (m, 2H), 3.42±3.55
(m, 2H), 3.77±3.93 (m, 2H), 4.62 (t, 1H, Jˆ3 Hz), 5.29±
5.73 (m, 2H). 13C NMR: 15.7, 17.6, 19.5, 21.9, 25.5, 29.2,
30.7, 62.1, 66.1, 98.8, 105.3, 105.5, 125.9, 126.3. IR (neat):
2944, 2873, 2212.
5.2.10. (4E,7E)-4,7-Nonadienyl-1-ol 22.20e Step A. 95 mg
of lithium wire (13.66 mmol) was added smoothly to a
solution of acetylene 21 (1 g, 4.50 mmol), t-butanol
(1.06 mL, 14.36 mmol) and ammonium sulphate (1.261 g,
10.25 mmol) in liquid NH3. Stirring was maintained for
30 min then 1.35 g of ammonium chloride was added.
Ammonia was slowly evaporated at rt. Addition of water,
extraction with diethyl ether and concentration in vacuo
gave a colourless oil (29), which was directly used in the
next step.
less oil. Yield: 65 mg (45%). ee: 85.9%. [a]20 ˆ146.0 (c
D
1
0.5, CHCl3) {Lit.21e [a]20 ˆ156.7 (c 0.025, CHCl3)}. H
D
NMR: 1.66 (d, 3H, Jˆ4.5 Hz), 1.72±1.79 (m, 2H), 2.10±
2.29 (m, 2H), 2.66±2.70 (m, 2H), 3.77 (d, 1H, Jˆ2.6 Hz),
3.98 (d, 1H, Jˆ2.6 Hz), 4.57±4.62 (m, 1H), 5.33±5.56 (m,
4H). 13C NMR: 17.8, 27.2, 31.8, 35.5, 49.8, 57.9, 79.1,
125.8, 128.0, 129.1, 131.0, 170.2. IR (neat): 2980, 1789,
1191, 967, 855.
Step B. A solution of the crude ole®n 29 (3.5 g, 15.6 mmol)
and PPTS (0.4 g, 1.56 mmol) in MeOH (140 mL) was
heated at 408C for 4 h. The solvent was removed in vacuo
and the oily residue was ¯ash chromatographed (AcOEt/
n-hexane, 10:90) to give pure alcohol 22 as a colourless
5.2.14. (2R,3R)-3-[(1R,4E,7E)-1-Hydroxy-4,7-nonadienyl]-
2-oxiranecarboxamide 26.21e 75 mL of a 25% aqueous
ammonia solution (0.48 mmol) was added dropwise into a
solution of epoxylactone 25 (50 mg, 0.24 mmol) in 1 mL of
methanol at 08C. After stirring 3 h, the reaction was stopped
by addition of 2 mL of 0.5N HCl solution. The aqueous
phase was extracted three times with methylene chloride
and the combined organic phases were concentrated in
vacuo. The solid residue was ¯ash chromatographed
(AcOEt/hexane, 1:1) to give amide 26 as a white solid.
1
oil. Yield: 1.57 g (72%). H NMR: 1.62±1.67 (m, 3H),
2.06±2.14 (m, 2H), 2.67±2.75 (m, 2H), 3.66 (t, 2H, Jˆ
6.6 Hz), 5.40±5.47 (m, 4H). 13C NMR: 17.8, 28.9, 32.5,
35.6, 62.6, 125.5, 129.4, 129.7, 130.1.
5.2.11. (4E,7E)-4,7-Nonadienal 23.21e A solution of DMSO
(3.04 mL, 42.78 mmol) in 22.5 mL of anhydrous methylene
chloride was added dropwise at 2788C into a solution of
oxalyl chloride (1.86 mL, 21.39 mmol) in 37.5 mL of
Yield: 50 mg (92%) (Lit.21e 90%). ee: 84.5%. [a]20
ˆ
D
155.5 (c 0.72, CHCl3) {Lit.21e [a]20 ˆ167.4 (c 0.24,
D
CHCl3)}. 1H NMR: 1.65±1.67 (m, 3H), 1.70±1.78 (m,
2H), 2.07±2.30 (m, 2H), 2.65±2.68 (m, 2H), 3.12 (dd, 1H,

M. Renard, L. A. Ghosez / Tetrahedron 57 (2001) 2597±2608
2607
Alonso, D.; Font, J. Tetrahedron Lett. 1986, 27, 1079±1080.
(e) Sanchez-Sancho, F.; Valverde, S.; HerradoÄn, B.
Tetrahedron: Asymmetry 1996, 7, 3209±3246.
Jˆ4.6, 8.2 Hz), 3.45±3.54 (m, 1H), 3.53 (d, 1H, Jˆ4.6 Hz),
6.33±6.57 (m, 4H), 6.33 (sbroad, 1H), 6.57 (sbroad, 1H). 13C
NMR: 17.8, 27.8, 34.6, 35.5, 54.3, 60.1, 68.1, 125.5, 128.1,
128.6, 129.7, 170.5. IR: 3386, 1678, 1595, 1426, 1119,
1072.
3. (a) Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem. 1995,
60, 5628±5633. (b) Takahata, H.; Uchida, Y.; Momose, T.
Tetrahedron Lett. 1994, 35, 4123±4124. (c) Tsuboi, S.;
Sakamoto, J.; Yamashita, H.; Sakai, T.; Utaka, M. J. Org.
Chem. 1998, 63, 1102±1108. (d) Tanikaga, R.; Hosoya, K.;
Kaji, A. Synthesis 1987, 389±390.
5.2.15. (1)-Cerulenin 17.21e 8 mg (22 mmol) of TPAP was
added at once to a solution of alcohol 26 (50 mg,
0.23 mmol), NMO (95 mg, 0.68 mmol) in anhydrous
Ê
methylene chloride on 4 A molecular sieves. The reaction
4. (a) Hannessian, S.; Hodges, P. J.; Murray, P. J.; Sahoo, S. P.
J. Chem. Soc., Chem. Commun. 1986, 754±755. (b) White,
J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991±4998. (c) Makabe, H.; Tanaka, A.; Oritani, T.
mixture was stirred for 1 h then diluted with anhydrous ether
and ®ltered through a short column of Celitew. The organic
phase was washed with water and the aqueous phase was
extracted with methylene chloride. The crude product was
puri®ed on silicagel (AcOEt/hexane, 2:3) to give a white
solid corresponding to tautomers of cerulenin. Yield: 39 mg
Â
Tetrahedron Lett. 1997, 38, 4247±4250. (d) Solladie, G.;
Â
Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem. 1986,
51, 1912±1914. (e) Grieco;, P. A.; Burke, S. P. J. Org.
Chem. 1975, 40, 542±543. (f) Sharpless, K. B.; Lauer, R. F.;
Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137±6139.
(g) Rodriguez, C. M.; Martin, T.; Ramirez, M. A.; Martin,
V. S. J. Org. Chem. 1994, 59, 4461±4472. (h) Makabe, H.;
Tanaka, A.; Oritani, T. Tetrahedron Lett. 1997, 38, 4247±
4250. (i) Midland, M. M.; Tramontano, A. Tetrahedron Lett.
1980, 21, 3549±3552. (j) Midland, M. M.; McDowell, D. C.;
Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102,
867±869. (k) Sato, F.; Okamoto, S.; Ito, T. Tetrahedron Lett.
1990, 31, 6399±6402. (l) Takano, S.; Morimoto, M.;
Ogasawara, K. Synthesis 1984, 834±835. (m) Miller, M.;
Hegedus, L. S. J. Org. Chem. 1993, 58, 6779±6785.
(n) Chen, M.-Y.; Fang, J.-M. J. Org. Chem. 1992, 57,
2937±2941. (o) Datta, A.; Schmidt, R. R. Synlett 1992,
429±430.
(75%) (Lit.21e 80%). ee: 85%. [a]20 ˆ157.2 (c 0.2, MeOH)
D
{Lit.21e [a]20 ˆ162.0 (c 0.15, MeOH)}. Linear isomer: 1H
D
NMR: 1.64±1.67 (m, 3H), 2.18±2.36 (m, 2H), 2.62±2.71
(m, 4H), 3.73 (d, 1H, Jˆ5.3 Hz), 3.87 (d, 1H, Jˆ5.3 Hz),
5.37±5.59 (m, 4H), 6.33 (sbroad, 1H), 6.57 (sbroad, 1H). 13C
NMR: 17.9 (C1), 25.9, 29.7, 35.4, 40.8, 55.3, 125.8, 127.7,
1
129.2, 130.7, 167.2, 202. Cyclic isomers: H NMR: 1.64±
1.67 (m, 6H), 1.76±2.05 (m, 4H), 2.18±2.36 (m, 4H), 2.62±
2.71 (m, 4H), 3.59 (d, 1H, Jˆ2.5 Hz), 3.61 (d, 1H,
Jˆ2.5 Hz), 3.65 (sbroad, 1H), 3.82 (d, 1H, Jˆ2.5 Hz), 3.83
(d, 1H, Jˆ2.5 Hz), 5.37±5.59 (m, 8H), 6.33 (sbroad, 1H).
5.2.16. Registry numbers. 3055-87-6, 53075-94-8, 22693-
41-0, 70404-21-6, 90366-21-5, 98878-30-9, 98878-24-1,
101836-41-3, 118917-42-3, 60112-29-0, 104923-70-8,
137449-38-8, 137449-41-3, 67596-41-2, 52264-9-34435-
19-2, 62992-46-5, 79532-17-5, 62964-98-1, 62499-92-7,
64807-39-2, 72301-01-0, 72301-02-1, 17397-89-6.
5. Carretero, J. C.; Lombaert, S. D.; Ghosez, L. Tetrahedron Lett.
1987, 28, 2135±2138.
6. Renard, M.; Ghosez, L. Tetrahedron Lett. 1999, 40, 6237±
6240.
7. (a) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961±998.
(b) Carreno, M. C. Chem. Rev. 1995, 95, 1717±1760.
Acknowledgements
Â
(c) Solladie, G. Synthesis 1981, 185±196.
This work was generously supported by the `Fonds pour la
8. Albinati, A.; Bravo, P.; Ganazzoli, F.; Resnati, G.; Viani, F.
J. Chem. Soc., Perkin Trans. 1 1986, 1405±1415.
9. Andersen, K. K. Tetrahedron Lett. 1962, 93±95.
Á
Formation a la Recherche dans l'Industrie et dans l'Agri-
culture' (fellowship to M. Renard), the `Ministere de l'Edu-
Á
Â
cation et de la Recherche, Communaute francËaise de
Belgique' (action concertee, convention 96/01-197) and
10. Davis, F. A.; Lamendola, J. J.; Nadir, U.; Kluger, E. W.;
Sedergran, T. C.; Panunto, T. W.; Billmers, R.; Jenkins, J.;
Turchi, I. J.; Watson, W. H.; Chen, J. S.; Kimura, M. J. Am.
Chem. Soc. 1980, 102, 2000±2005.
Â
Â
the `Universite catholique de Louvain'. We thank Professor
E. de Hoffmann for the mass spectra and Dr R. Touillaux for
his ef®cient help in NMR spectroscopy. The assistance of Dr
E. Cavoy (UCB-Pharma, Belgium) in hplc separation is
gratefully acknowledged.
11. Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571±5574.
12. We thank Dr B. Tinant and J.P. Declercq for the X-ray
diffraction analysis. Details will be published shortly in Z.
Kristallogr.ÐNew Cryst. Struct.
13. (a) Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987,
43, 5135±5144. (b) Palombi, L.; Bonadies, F.; Pazienza, A.;
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Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org.
Chem. 1993, 58, 4529±4533. (d) Superchi, S.; Rosini, C.
Tetrahedron: Asymmetry 1997, 8, 349±352. (e) Yamanoi,
Y.; Imamoto, T. J. Org. Chem. 1997, 62, 8560±8564.
(f) Palucki, M.; Hanson, P.; Jacobsen, E. N. Tetrahedron
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