Enantioselective sulfoxide-directed preparation of 1,2-diols from oxalic compounds: Formal synthesis of the 10-membered lactone core of ascidiatrienolides and didemnilactones

Article abstract of DOI:10.1016/j.tetasy.2005.01.050

The synthesis of diene 17, which is available in both possible absolute configurations is described. This diene constitutes the key intermediate of a previous synthesis of the 10-membered lactone core of the marine natural products ascidiatrienolides and

Full text of DOI:10.1016/j.tetasy.2005.01.050

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1503–1511
Enantioselective sulfoxide-directed preparation of 1,2-diols from
oxalic compounds: formal synthesis of the 10-membered
lactone core of ascidiatrienolides and didemnilactones
à
*
´
Irene Izzo, Robin Crumbie, Guy Solladie and Gilles Hanquet
´ ´ ´ ´
Laboratoire de Stereochimie associe au CNRS, ECPM, Universite Louis Pasteur, 25 rue Becquerel, 67087 Strasbourg, France
Received 18 January 2005; accepted 31 January 2005
Available online 16 March 2005
Abstract—The synthesis of diene 17, which is available in both possible absolute configurations is described. This diene constitutes
the key intermediate of a previous synthesis of the 10-membered lactone core of the marine natural products ascidiatrienolides and
didemnilactones. This intermediate is available via two successive highly diastereoselective sulfoxide-directed reductions of oxalic
diamide 18.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1.Introduction
family are also 10-membered lactones. Ascidiatrieno-
lides and didemnilactones are fatty acid metabolites ex-
tracted from the marine ascidian Didemnum candidum or
isolated from the colonial tunicate Didemnum moseleyi
and exhibit strong in vitro inhibitory activity towards
A few years ago, we described a straightforward access
to enantiomerically pure monoprotected 1,2-diols by
two successive diastereoselective sulfoxide-directed
reductions of oxalate derivatives (Scheme 1).1 As a syn-
thetic application, we planned to prepare the common
10-membered lactone core of ascidiatrienolide A 12
and didemnilactones 2–4 (Fig. 1).3 As we were able to
prepare both anti- or syn-configured diols, our strategy
should also be efficient for the synthesis of the epimers
at C-8 (ascidiatrienolide numbering), ascidiatrienolides
B 5 and C 6.2c
2
the enzyme phospholipase A2 and weak binding affini-
ties to leukotriene B4 receptors, respectively.3 Metabo-
lites 1–4 have already been subject of total synthesis2,3
or formal total synthesis in the past, starting from natu-
ral sources.4
Herein, we report our synthetic investigations to obtain
the common lactone core segment of 1–4 and of the epi-
mers at the 9 position of 5 and 6 starting from oxalic
derivatives.
The ascidiatrienolides were originally assigned as nine-
membered lactone structures until Holmes and co-work-
ers2a established unambiguously that ascidiatrienolide A
possessed a 10-membered lactone structure, and pre-
sumably the other members of the ascidiatrienolide
We first embarked upon synthetic studies to prepare the
(9R,10S) lactone 7 from diethyl oxalate 8 and (S)-
methyl-p-tolylsulfoxide 9 (Scheme 2).1c Protection and
HO
O
pTol
S
O
*
OH
*
*
R
R1=OEt or N(Me)OMe
R1
OP
H
O
Scheme 1.
*
Corresponding author. Tel.: +33 3 90242746; fax: +33 3 90242742; e-mail: ghanquet@chimie.u-strasbg.fr
On leave from the University of Salerno, Italy.
à On leave from the University of Western Sydney Macarthur, Australia.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.050

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I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
OH
(R)
OH
(R)
(S)
(S)
O
O
O
O
Ascidiatrienolide A 1
Didemnilactone A 2
OH
OH
(R)
(S)
(R)
(S)
O
O
O
O
Didemnilactone B 3
Didemnilactone C 4
O
(R)
O
O
(R)
(R)
OH
O
(R)
Ascidiatrienolide C 6
OH
Ascidiatrienolide B 5
Figure 1.
OH
:
O
OtBu
OH
(R)
(R)
(S)
(S)
pTol
pTol
:
(S)
S
OEt
OR1
S
:
O
EtO
1-4
5-6
+
(R)
O
O
O
OTBS
O
10
9
8
O
7
OH
:
O
(R)
(R)
pTol
:
(R)
OEt
OR1
S
EtO
+
O
O
O
8
9
7
O
Scheme 2.
reduction of the key intermediate 10 into the corre-
sponding aldehyde, followed by Wittig reaction with
the ylide of (4-carboxybutyl)triphenyl phosphonium
bromide5 provided an excellent precursor of the (R,S)-
lactone 7.
protection of the hydroxyl group, b-silyloxysulfoxide 13
was transformed into the b-silyloxy-c-ketosulfoxide 14
by condensation of the lithium tert-butylacetate enolate.
Dibal-H reduction of the latter gave a high de (>95%) in
favour of the desired anti-diol8 10 but a low yield (55%).
The use of Yb(OTf)3 in order to increase the yield1 pro-
vided no conversion in this case.
2.Results and discussion
The next step was the protection of the c-hydroxy
group, which proved very difficult. No protection was
observed under mild basic conditions (BnBr/Ag2O;
Diethyl oxalate 8 was transformed into the correspond-
ing b-ketosulfoxide 11. This condensation occurred with
excellent conversion using 0.5 equiv of methyl-p-tolyl-
sulfoxide in the presence of 0.75 equiv of LDA6 but
needed attention during purification.7
TBDPSCl/imidazole or MEMCl/HunigÕs base) while
¨
stronger conditions (NaH; DBU) resulted in decomposi-
tion of the starting material. We therefore attempted to
prepare triol 16 using a Pummerer/LAH or NaBH4
reduction sequence. Unfortunately, this resulted in only
19% yield of the required triol 16.
b-Ketosulfoxide 11 was then stereoselectively reduced to
b-hydroxysulfoxide 12 using Dibal-H (Scheme 3). After

I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
1505
O
O
O
(S)
S
pTol
:
(S)
S
pTol
:
pTol
:
(S)
S
LDA, THF
-78°C
OEt
+
Dibal-H, 1.5 eq
EtO
EtO
EtO
O
THF, -78°C
67%, 2 steps
O
O
12
O
O
OH
8
9
11
TBDMSCl
DMF
92%
Imidazole
OtBu
O
OH
(R)
O
OtBu
(S)
O
pTol
:
(S)
pTol
:
(S)
Dibal-H, 1.5 eq
pTol
:
(R)
S
OtBu
O
S
(R)
S
O
EtO
THF, -78°C
55%
O
OTBS
LICA, 3eq, THF
94%
O
O
OTBS
OTBS
10
14
13
OMe
1) Ac2O
AcONa
PPTS
OMe
19%
2) NaBH4
OtBu
OH
(S)
OtBu
(R)
O
(S)
pTol
:
(R)
OH
O
S
(R)
O
OTBS
O
O
16
15
Scheme 3.
During this time, Furstner and Schlede4 described a
7 (R1 = H,
the corresponding b-hydroxysulfoxide 20 in high de
(>95%). The (S)-absolute configuration of the secondary
carbinol has previously been established by the solid-
state molecular structure of a structurally close deriva-
tive.1b Protection of the resulting secondary alcohol in
21 as a TBDMS ether followed by addition of the al-
lyl-magnesium bromide afforded b-silyloxy-c-ketosulf-
oxide 22 in good overall yields. As chromatography of
the latter gave a mixture of the desired product with
the corresponding a,b-unsaturated ketone, even when
treated silica gel (NEt3 5%) was used, the crude product
was used in the next step without purification. Highly
diastereoselective Dibal-H/ZnI2 reduction of the crude
product afforded, after purification, the required syn12
c-hydroxy-b-silyloxysulfoxide 23 in 70% yield for two
steps. We next turned our attention to the removal of
the chiral auxiliary. We first tried to perform a Pum-
merer reaction on free alcohol 23. We selected two dif-
ferent procedures. The first one used trifluoroacetic
anhydride, 2,4,6-collidine in acetonitrile, followed by
NaBH4 reduction.13 Unfortunately, the best result was
only 30% yield of expected product 26 (Scheme 6).
¨
concise racemic synthesis of lactone
R2 = TBDPS) starting from glyceraldehyde and using
a metathesis olefination as the key step. He showed that
a better Z/E ratio was obtained from the syn-configured-
diene 17, using the Ôsecond generationÕ Grubbs type
catalyst bearing an N-heterocyclic carbene ligand.
Subsequent epimerization at C-9 using Mitsunobu con-
ditions9 installed the required anti-configuration of lac-
tone 7 (Scheme 4).
As our methodology depicted a straightforward access
to 1,2-diols in all possible absolute configurations, we
decided to prepare the syn-configured (9R,10R)-diene
17 starting from oxalic diamide10 18 and (R)-methylsulf-
oxide 9 (Scheme 5).
The lithium anion of (R)-methyl-p-tolylsulfoxide 9 was
added to diamide 18. Quenching of the reaction needed
a strong acid and carefully demetalled silica gel11 for
purification to obtain good yields. The resulting b-keto-
sulfoxide 19 was subjected to Dibal-H reduction to give
OMe
OMe
OR2
:
OR1
O
:
O
O
:
O
glyceraldehyde
O
RCM
Z/E=2.8/1
O
O
O
(rac)-7
O
O
17
Scheme 4.

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I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
O
9
pTol
(R)
S
OMe O
N
Me
O
O
(R)
1.3 eq
pTol
pTol
:
(R)
S
Dibal-H, 1.6 eq
(S)
S
:
N
N
LICA
70%
N
THF, -78°C
80% de>95%
O
O
MeO
O
OH
MeO
O
OMe
(R)-19
(R,S)-20
18
TBDMSCl
DBU
95%
O
CH2Cl2
OH
(S)
(R)
O
pTol
MgBr
(R)
pTol
(R)
(S)
pTol
S
(S)
Dibal-H, ZnI2
:
(R)
S
:
S
N
:
O
OTBS
O
THF, -78°C
70%, 2 steps
OTBS
THF, 0°C
O
MeO
OTBS
(R,S,R)-23
(R,S)-22
(R,S)-21
Scheme 5.
PMB
O
OH
(R)
OH
OTBS
26
OH
(S)
1) p-MeOC6H4CH(OMe)2
p-TsOH, DMF
(R)
1) (CF3CO)2O, CH3CN
2,4,6-collidine
pTol
:
O
S
(R)
(R)
66% from 24
O
2) NaBH4
30%
OTBS
OTBS
27
(R,S,R)-23
LiBH4
1) (CH3CO)2O
CH3COONa
OAc
(S)
OAc OAc
pTol
+
pTol
(S)
S
S
(R)
(R)
OTBS
OTBS
(S,R)-25
64%
(S,R)-24
Scheme 6.
The second method used classical conditions (Ac2O,
AcONa, 135 ꢁC, 30h) and gave a mixture of two
acetates, namely the desired 24 (64% yield) and the
corresponding sulfide 25 (in variable proportions).
Reduction of the acetate 24 was successful using
LiBH414 in ether as hydride transfer reagent. These con-
ditions of reduction gave the most reproducible results
as NaBH4 or LiAlH4 gave lower yields or resulted in
the cleavage or migration of the TBS group. Crude diol
26 was protected without previous purification using p-
anisaldehyde dimethyl acetal to afford the acetal 27.15
Unfortunately, we detected partial epimerization at the
homoallylic hydroxylic centre, which had probably oc-
curred during the precedent reductive step (Scheme 6)
in variable amounts from one attempt to another (0–
25%).
ether 29 gave the thioacetal 30 in 82% yield while the
subsequent reduction using LiBH4 resulted in the pri-
mary alcohol 31 in 89% isolated yield (Scheme 7). Selec-
tive cleavage of the MEM–ether using catechol boron
bromide17 in dichloromethane followed by acetalization
of the crude diol15 afforded acetal 27 in 62% yield. Final-
ly, treatment with TBAF and esterification of the alco-
hol 28 with 5-hexenoic acid delivered the diene 17
(24% overall yield from 23), which was identical
([a]D) = À37 (c 0.2, CHCl3) to the racemic key interme-
diate prepared by Furstner.
¨
3.Conclusion
In summary, this study witnesses the efficiency of
sequential Dibal-H sulfoxide-directed reduction of oxa-
lic derivatives to prepare enantiomerically pure 1,2-
monosilylated diols. Contrary to the use of natural
sources, this methodology opens the door to the prepa-
ration of the 10-membered lactone core in both absolute
configurations. The total syntheses of acsidiatrienolides
B and C are currently under investigation in our
laboratory.
As we were unable to control this epimerization, we
tried to repeat this sequence starting from the protected
sulfoxide 23. Not surprisingly, we encountered difficul-
ties associated with the protection step, as already ob-
served with the anti-diol 10. Finally we found that the
use of KH/MEMCl16 in THF at À78 ꢁC to room tem-
perature gave the most reproducible and acceptable re-
sult (77%). Pummerer reaction of the resulting MEM–

I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
1507
OMEM
(S)
OAc
S
(CH3CO)2O
OMEM
OH
(S)
(R)
(R)
MEMCl, KH
DME
pTol
pTol
:
CH3COONa
pTol
(S)
(R)
S
S
(R)
(R)
OTBS
82%
77%
O
O
OTBS
OTBS
(S,R)-30
(R,S,R)-23
(R,S,R)-29
PMB
PMB
O
O
OMEM
(R)
O
O
(R)
1) TBAF
BBr
1)
O
quant.
LiBH4
89%
O
(R)
OH
(S,R)-30
(R)
(R)
2) 5-hexenoic acid
DIC, DMAP
(R)
OTBS
2) p-MeOC6H4CH(OMe)2
p-TsOH, DMF
OTBS
O
(R,R)-31
(S,R,R)-27
O
(S,R,R)-17
40% from 31
Scheme 7.
4.Experimental
4.1. General remarks
indicator paper) with 5% H2SO4, and the product ex-
tracted into ether (4 · 100 mL). The organic layers were
washed with brine, dried over magnesium sulfate and
the solvent removed. Unreacted diethyl oxalate was re-
moved by chromatography on a short column com-
posed of two layers; the lower, deactivated silica gel,
and the upper, Celite, in equal volume. The column
was eluted rapidly, first with hexane, then 50% hexane
in ether and finally with ether. The product thus ob-
tained was a yellow oil (5.5 g), which was used without
further purification. 1H NMR (300 MHz, CDCl3): d
7.43 ((AB)2 system, 4H, JAB = 8 Hz, Dm = 40Hz), 4.15
(q, 2H J = 7 Hz), 4.1 (2H, AB system, JAB = 12 Hz),
2.46 (s, 3H), 1.32 (t, 3H, J = 7 Hz).
All reactions were carried out under dry argon. Stan-
dard syringe and cannula techniques were employed
for transfer of dry solvents and air- or moisture-sensitive
reagents. Tetrahydrofuran (THF) was distilled under
argon from sodium/benzophenone, dichloromethane from
phosphorus pentoxide, diisopropylamine from KOH.
n-Butyllithium was purchased as a 1.6 M solution in
hexane. Starting materials not mentioned below were
commercially available. Enantiopure menthyl-p-tolyl-
sulfinates 3 and methyl-p-tolylsulfoxides 4 in both con-
figurations were prepared according to the previously
described methods.18 Di-N-methoxy-N-methylamide of
oxalic acid was prepared from oxalyl chloride according
to the literature.10 Reactions were monitored by thin
layer chromatography on silica gel plates (Merck
60F254) and stained by the use of p-anisaldehyde. Merck
silica gel 60H was used for column chromatography and
demetallated following a known procedure11 when re-
quired. NMR spectra were obtained at 200 MHz (1H)
or 50MHz ( 13C) and 300 MHz (1H) or 75 MHz (13C)
on Bruker AC 200 and AC 300 instruments, with deu-
terochloroform as solvent. Chemical shifts (d) are given
in ppm relative to tetramethylsilane (d = 0ppm) or to
residual protons in the solvent as internal standard. IR
spectra were recorded with a Perkin–Elmer Spectrum
One, and absorption bands are given in cmÀ1. The
Microanalyses Service of the Strasbourg Faculty of
Chemistry performed microanalyses.
4.3. Ethyl (2R,SS)-2-hydroxy-3-(p-tolylsulfinyl)propio-
nate 12
Crude sulfinyl ketone 11 (5.4 g, 22 mmol) was dissolved
in THF (200 mL) and cooled to À78 ꢁC with stirring.
Dibal-H (23.3 mL, 1 M in toluene, 1.1 equiv) was then
added dropwise over 2.5 h. After a further 15 min, the
reaction was quenched by the addition of methanol
(10mL) and then a saturated ammonium chloride solu-
tion (100 mL), and allowed to warm to 0 ꢁC. The pH
was then cautiously adjusted to 3–4 with 5% H2SO4.
The THF was removed under vacuum at room temper-
ature and the residue extracted with ether (8 · 100 mL).
The aqueous layer was tested before each extraction,
and 5% H2SO4 added cautiously as required to keep
the pH between 3 and 4.19 The organic extracts were
then washed with brine (50mL), dried over MgSO 4
and concentrated to afford a yellow oil, which was puri-
fied by flash chromatography on demetallated silica gel
to give 4.6 g, 67% from 8. A sample was recrystallized
from ether to afford white prisms. [a]D = À170( c 0.2,
EtOH). Mp = 86 ꢁC. 1H NMR (300 MHz, CDCl3): d
7.51 ((AB)2 system, 4H, JAB = 8 Hz, Dm = 40Hz), 4.73
(dd, X of an ABX system, 1H), 4.22 (q, 2H J = 7 Hz),
3.9 (br s, 1H), 3.08 (AB fragment of an ABX system,
4.2. Ethyl (SS)-2-oxo-3-(p-tolylsulfinyl)propionate 11
n-Butyllithium (28 mL of a 1.45 M solution in hexane,
40mmol, 1.5 equiv) was added dropwise to a stirred
solution of diisopropylamine (5.4 mL, 39 mmol,
1.45 equiv) in THF (150mL) at À78 ꢁC. After 15 min,
(S)-methyl-p-tolylsulfoxide 9 (4.2 g, 27 mmol, 1 equiv)
in THF (20mL) was added dropwise and the solution
stirred over 1.5 h. Diethyl oxalate 8 (8.3 g, 55.3 mmol,
2 equiv) in THF (10mL) was then added as a single ali-
quot and the reaction mixture stirred for a further 2 h,
then quenched with saturated ammonium chloride solu-
tion (50mL). The pH was adjusted to 3–4 (universal
2H,
JAX = 3 Hz,
JBX = 9.8 Hz,
JAB = 13.1 Hz,
Dm = 55 Hz), 2.43 (s, 3H), 1.28 (t, 3H, J = 7 Hz). 13C
NMR (75 MHz, CDCl3): d 172.4, 141.9, 139.8, 130.1,
124, 85.9, 62.2, 61.1, 21.4, 14.1. Anal. Calcd for
C11H16O4S (244): C, 54.08; H, 6.60. Found: C, 53.97;
H, 6.38.

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I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
4.4. Ethyl (2R,SS)-2-tert-butyl-dimethylsilyloxy-3-
(p-tolylsulfinyl)propionate 13
argon. Dibal-H (5.3 mL, 1 M in toluene, 1.5 equiv) was
then added dropwise over 2 h. After a further 30min,
the reaction was quenched by the addition of methanol
(10mL) and THF removed under vacuum. The residue
was dissolved in ethyl acetate (50mL) and stirred with
a saturated solution of disodium tartrate until a good
separation of phases occurred. The aqueous layer was ex-
tracted with ethyl acetate (3 · 50mL) and the organic ex-
tracts were washed with brine (50mL), dried over
MgSO4 and concentrated to afford a pale-yellow solid,
which was purified by flash chromatography on silica
gel to give 0.85 g, 55% of pure 10 as white solid.
[a]D = À142 (c 0.1, EtOH). 1H NMR (200 MHz, CDCl3):
d 7.39 ((AB)2 system, 4H, JAB = 8 Hz, Dm = 40Hz), 4.18
(m, 1H), 4.09 (m, 1H), 2.88 (2H, non-interpretable AB
part of ABX system), 2.8 (br, 1H), 2.41 (s, 3H), 2.32
(d, 2H, J = 6.4 Hz), 1.44 (s, 9H), 0.96 (s, 9H), 0.18 and
0.25 (2s, 6H). 13C NMR (50MHz, CDCl 3): d 171,
141.5, 131, 123.8, 81.5, 71.4, 69.6, 62.5, 37.9, 28.1, 26,
18.3, À4.1, À4.6. Anal. Calcd for C22H40O5SSi (444):
C, 59.42; H, 9.07. Found: C, 59.37; H, 9.01.
Alcohol 12 (2.2 g, 9 mmol) was dissolved in DMF
(100 mL). Imidazole (1.3 g, 18 mmol, 2 equiv) was then
added and the stirred mixture cooled to 0 ꢁC. tert-Butyl-
dimethylsilyl chloride (2.1 g, 13.5 mmol, 1.5 equiv) was
added and the mixture allowed to stir overnight at room
temperature. Saturated ammonium chloride solution
(100 mL) and ether (100 mL) were added at 0 ꢁC and
the biphasic mixture stirred for 30min. The organic
layer was removed and the aqueous phase further ex-
tracted with ether (2 · 100 mL). The organic extracts
were washed with saturated ammonium chloride solu-
tion (2 · 100 mL), then with brine and dried over
MgSO4 and the solvent removed. Chromatography on
silica gel (40% ether/60% hexane) gave the product as
a colourless oil (3 g, 92%). [a]D = À152 (c 0.3, EtOH).
1H NMR (300 MHz, CDCl3): d 7.47 ((AB)2 system,
4H, JAB = 8 Hz, Dm = 40Hz), 4.76 (dd, X of an ABX
system, 1H), 4.15 (q, 2H, J = 7.5 Hz), 2.94 (AB of an
ABX
system,
2H,
JAX = 2 Hz,
JBX = 10Hz,
JAB = 14 Hz, Dm = 45 Hz), 2.41 (s, 3H), 1.24 (t, 3H,
J = 7.5 Hz), 0.92 (s, 9H), 0.1 and 0.2 (2s, 6H). 13C
NMR (75 MHz, CDCl3): d 171.7, 141.5, 140.8, 130,
123.7, 67, 63.9, 61.5, 25.7, 21.4, 18.4, 4.1. Anal. Calcd
for C17H30O4SSi (358.6): C, 56.94; H, 8.43. Found: C,
57.07; H, 8.58.
4.7. tert-Butyl (3R,4R,SS)-3,4-(diisopropylidene ketal)-
5-(p-tolylsulfinyl)pentanoate 15
Monosilylated diol 10 (0.5 g, 1.2 mmol) was dissolved at
À40 ꢁC in THF (20mL) with TBAF (1.5 mL, 1 M in
THF, 1.1 equiv) and the mixture stirred until disappear-
ance of the starting material (TLC). The crude mixture
was concentrated under vacuum and the residue dis-
solved in acetone (5 mL). Dimethoxypropane (2 mL)
and PPTS (10mg) were added and the mixture stirred
overnight. Acetone was removed on vacuum and the
residue poured into dichloromethane (20mL). The mix-
ture was washed with a 5% sodium bicarbonate solution
(20mL), then, dried over MgSO 4 and concentrated to
afford a pale-yellow solid, which was purified by flash
chromatography on silica gel to give 0.35 g, 70% of pure
4.5. tert-Butyl (4R,SS)-3-oxo-4-tert-butyl-dimethylsilyl-
oxy-5-(p-tolylsulfinyl)pentanoate 14
n-Butyllithium (14 mL of a 1.45 M solution in hexane,
20mmol, 3 equiv) was added dropwise to a stirred solu-
tion of dicyclohexylamine (4 mL, 20mmol, 3 equiv) in
THF (50mL) at À78 ꢁC. After 15 min, tert-butylacetate
(2.3 g, 20mmol, 3 equiv) in THF (20mL) was added
dropwise and the solution stirred 1.5 h. Silyloxy-sulfox-
ide 13 (2.4 g, 6.5 mmol) in THF (10mL) was then added
via cannula and the reaction mixture stirred until it
reached room temperature, at which point it was
quenched with saturated ammonium chloride solution
(50mL). The THF was removed under vacuum at room
temperature and the residue extracted with ethyl acetate
(3 · 100 mL). The organic extracts were then washed
with brine (50mL), dried over MgSO 4 and concentrated
to afford a pale-yellow oil, which was purified by flash
chromatography on silica gel to give 3 g, 94% of pure
14. [a]D = À158 (c 0.1, EtOH). 1H NMR (300 MHz,
1
15 as a white crystals. H NMR (200 MHz, CDCl3): d
7.44 ((AB)2 system, 4H, JAB = 8 Hz, Dm = 40Hz), 4.74
(m, 1H), 4.61 (m, 1H), 2.43 (s, 3H), from 2.25 to 2.87
(2 AB parts of 2 ABX systems, 4H), 1.51 (s, 3H), 1.42
(s, 3H), 1.38 (s, 9H). 13C NMR (50MHz, CDCl 3): d
169.3, 141.5, 130.2, 123.9, 109.3, 81.5, 74, 71.6, 60.3,
36.7, 28.3, 28.07, 25.7, 21.5.
4.8. (RS)-N-Methyl-N-methoxy-2-oxo-3-(p-tolylsulfinyl)-
propionamide 19
CDCl3):
d
7.42 ((AB)2 system, 4H, JAB = 8 Hz,
To a solution of cyclohexyl-isopropylamine (2.2 mL,
13.6 mmol) in dry THF (20mL), cooled to À78 ꢁC, a
solution of n-BuLi (9.1 mL, 1.6 M in hexane) was added.
The solution was stirred for 30min at À78 ꢁC and (R)-
methyl-p-tolylsulfoxide (1.7 g, 11.0mmol), dissolved in
dry THF (20mL) added. The solution was stirred for
1 h at À78 ꢁC then warmed to À40 ꢁC and Weinreb
amide 18 (1.5 g, 8.52 mmol), dissolved in THF (20mL,
the dissolution is slow), was added. The solution was stir-
red overnight. A solution of H2SO4 (ꢀ30mL, 10%) was
added until pH 3–4 and the mixture extracted three times
with ethyl acetate (10mL · 3) and one time with CH2Cl2
(10mL). The combined organic layers were washed with
brine, dried over MgSO4 and evaporated under reduced
Dm = 40Hz), 4.71 (dd, X of an ABX system, 1H), 3.5
(2H, AB system, JAB = 14 Hz), 2.9 (AB of an ABX sys-
tem, 2H, JAX = 2 Hz, JBX = 9 Hz, JAB = 13 Hz,
Dm = 40Hz), 2.41 (s, 3H), 1.45 (s, 9H), 1.06 (s, 9H),
0.19 and 0.26 (2s, 6H). 13C NMR (75 MHz, CDCl3): d
203.5, 175.7, 166, 141.7, 130.1, 123.8, 82.2, 73.2, 45.8,
27.9, 25.7, 18.1, À4.7, À5.
4.6. tert-Butyl (3R,4R,SS)-3-hydroxy-4-tert-butyl-di-
methylsilyloxy-5-(p-tolylsulfinyl)pentanoate 10
b-Silyloxy-sulfoxide 14 (1.5 g, 3.5 mmol) in solution in
THF (50mL) was cooled to À78 ꢁC and stirred under

I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
1509
pressure. The crude product was purified by flash chro-
matography (the product has to be purified immediately)
on silica gel affording a yellow oil (1.6 g, 70%). Column:
d = 4 cm, h = 14 cm silica gel demetalled, 1 cm silica gel
normal; solvent: Et2O (ꢀ500 mL), Et2O–AcOEt
(ꢀ400 mL, 4:1), Et2O–AcOEt (ꢀ200 mL, 1:1). Rf: (hex-
ane–ethyl acetate 3:2) 0.37. 1H NMR (200 MHz,
CDCl3): d 7.44 ((AB)2 system, 4H, JAB = 8.2 Hz,
Dm = 40Hz), 4.12 (2H, AB system, J = 14 Hz), 3.70(s,
3H), 3.20(s, 3H), 2.41 (s, 3H). 13C NMR (50MHz,
CDCl3): d 190.2, 165.1, 142.1, 139.5, 129.8, 123.9, 65.7,
62.2, 31.8, 21.2.
(75 MHz, CDCl3): d 174.2, 141.6, 141.1, 130, 123.7,
65.5, 61.9, 61.2, 32.9, 25.8, 21.3, 19.1, 14. Anal. Calcd
for C18H31NO4SSi (386): C, 56.07; H, 8.1. Found: C,
55.97; H, 8.18.
4.11. (2S,RS)-1-(p-Tolylsulfinyl)-2-tert-butyl-
dimethylsilyloxy-5-ene-3-hexanone 22
To a solution of 21 (1.20g, 3.12 mmol) in dry THF
(25 mL), cooled to À20 ꢁC, allyl-magnesium bromide
(6.2 mL, 1 M ether, 2 equiv) was added and the mixture
stirred for 1 h. Saturated aqueous solution of NH4Cl
(15 mL) was added and the mixture extracted three
times with CH2Cl2 (30mL · 3). The organic layer was
washed with brine, dried over MgSO4 and concentrated
in vacuum. The crude residue (1.3 g) was filtered on sil-
ica gel (1 cm) and used in the next step without further
purification. Chromatography should be avoided. Rf:
(hexane–ethyl acetate 3:2) 0.6. 1H NMR (200 MHz,
CDCl3): d 7.42 ((AB)2 system, 4H, JAB = 8.2 Hz,
Dm = 40Hz), 5.6 (m, 1H), 4.95 (m, 2H), 4.76 (dd, 2H),
2.72–3.01(2 AB fragment of 2 ABX systems, 4H), 2.42
(s, 3H), 0.97 (s, 9H), 0.23 and 0.34 (2s, 6H).
4.9. (2S,RS)-N-Methyl-N-methoxy-2-hydroxy-3-
(p-tolylsulfinyl)-propionamide 20
To a solution of 19 (1.22 g, 4.53 mmol) in dry THF
(25 mL), cooled to À78 ꢁC under argon, Dibal-H
(7.2 mL, 1 M in toluene, 7.2 mmol, 1.6 equiv) was added
dropwise for 10min. The solution was stirred for 20min
at the same temperature and MeOH (4 mL) added. The
solution was concentrated in vacuum, dissolved in ethyl
acetate (30mL) and a saturated solution of sodium and
potassium tartrate (15 mL) added. The mixture was stir-
red vigorously until two phases were visible (ꢀ3 h).
Then the mixture was extracted two times with ethyl
acetate (10mL · 3) and one time with CH2Cl2
(10mL). The combined organic layers, were dried over
MgSO4 and evaporated under reduced pressure. The
crude mixture was purified by flash chromatography
(ether–methanol: 1–5% gradient) and the resulting white
solid recrystallized in ether/hexane/ethyl acetate. Rf:
(ethyl acetate–methanol 96:4) 0.21. Mp = 126 ꢁC.
[a]D = +232 (c 0.5, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.41 ((AB)2 system, 4H, JAB = 8.2 Hz,
Dm = 41 Hz), 4.97 (dd, X of an ABX system, 1H), 3.78
(d, 1H, J = 7 Hz), 3.70(s, 3H), 3.20(s, 3H), 2.95 (AB
fragment of an ABX system, 2H, JAX = 1.4 Hz,
JBX = 10.4 Hz, JAB = 13 Hz, Dm = 50Hz), 2.41 (s, 3H).
13C NMR (75 MHz, CDCl3): d 174, 141.7, 140.9,
130.1, 124, 64.1, 62.6, 61.8, 32.7, 21.5. Anal. Calcd for
C12H17NO4S (271): C, 53.12; H, 6.32. Found: C,
53.07; H, 6.38.
4.12. (3R,2S,RS)-1-(p-Tolylsulfinyl)-2-tert-butyl-
dimethylsilyloxy-3-hydroxy-5-hexene 23
ZnI2 (1.09 g, 3.4 mol) was warmed under reduced pres-
sure. Then a solution of the a,b unsaturated ketone 22
(1.24 g, 3.09 mmol) in dry THF (25 mL) was added
and the mixture stirred for 1 h at room temperature.
The solution was cooled to À78 ꢁC and Dibal-H
(4.6 mL, 1 M in hexane, 4.6 mmol) added dropwise.
After 20min, MeOH (4 mL) was added. The solution
was concentrated in vacuum, dissolved in ethyl acetate
(30mL) and a saturated solution of sodium and potas-
sium tartrate (15 mL) added. The mixture was stirred
vigorously until two phases were visible (ꢀ2 h). Then
the mixture was extracted with ethyl acetate
(10mL · 3) and one time with CH2Cl2 (10mL). The
combined organic layers were dried over MgSO4 and
evaporated under reduced pressure. The crude was puri-
fied by flash chromatography on silica gel (hexane–ethyl
acetate 4:1 to hexane–ethyl acetate 3:2) affording a col-
ourless oil (0.802 g, 70%, two steps).
4.10. (2S,RS)-N-Methyl-N-methoxy-2-tert-butyl-
dimethylsilyloxy-3-(p-tolylsulfinyl)-propionamide 21
1
[a]D = +181 (c 0.1, acetone). H NMR (CDCl3): d 7.52
To a solution of 20 (1.00 g, 3.69 mmol) in dry CH2Cl2
(25 mL), DBU (0.82 mL, 5.5 mmol) and TBDMSCl
(0.945 g, 6.27 mmol) were added. The mixture was stir-
red for 2 h then CH2Cl2 (15 mL) and a saturated aque-
ous solution of NH4Cl (15 mL) added. The resulting
mixture was extracted three times with CH2Cl2
(30mL · 3). The organic layer was washed with brine,
dried over MgSO4 and concentrated in vacuum. The
crude was purified by flash chromatography (hexane–
ether 1:1 to ether) affording a colourless oil (1.20, 84%).
((AB)2 system, 4H, JAB = 8.2 Hz, Dm = 40Hz), 5.75 (m,
1H), 5.14 (m, 2H), 4.25 (dt, 1H, J = 10.6, 1.7 Hz), 3.55
(m, 1H), 2.9 (AB fragment of an ABX system, 2H,
JAX = 1.7 Hz, JBX = 10.6 Hz, JAB = 13.1 Hz, Dm =
40Hz), 2.41 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H), 0.96
(s, 9H), 0.26 (s, 3H), 0.16 (s, 3H). 13C NMR (CDCl3):
d 141.5, 141.1, 134.8, 130.1, 129.9, 117.8, 73.6, 69.2,
63.1, 37.3, 26.0, 21.5, 18.3, À4.2.
4.13. (3R,2S)-1-(p-Tolylsulfenyl)-1-(acetoxy)-2-tert-
butyl-dimethylsilyloxy-3-acetoxy-5-hexene 24
Rf: (hexane–ethyl acetate 3:2) 0.25. [a]D = +201 (c 0.5,
acetone). 1H NMR (300 MHz, CDCl3): d 7.4 ((AB)2 sys-
tem, 4H, JAB = 8 Hz, Dm = 42 Hz), 5.15 (dd, X of an
ABX system, 1H), 3.70(s, 3H), 3.14 (s, 3H) 2.94 (m,
2H), 2.39 (s, 3H), 0.98 (s, 9H), 0.19 (s, 6H). 13C NMR
To a solution of 23 (200 mg, 0.56 mmol) in glacial Ac2O
(10mL) was added AcONa (700mg, 8 mmol) under
argon. The mixture was refluxed for 36 h at 125–135 ꢁC.
Toluene was added many times and evaporated to

1510
I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
eliminate Ac2O. The crude was dissolved in diethyl ether
and filtered on a short plug of Celite. The Et2O was evap-
orated in vacuum and the crude purified by flash chroma-
tography on silica gel (hexane–ether 8:2–65:35) to afford
a colourless oil 24 (143 mg, 64%). Sulfide 25 (10–30%)
was isolated as the secondary product during the various
was refluxed overnight at 120–130 ꢁC. Toluene was
added many times and evaporated to eliminate Ac2O.
The crude was dissolved in diethyl ether and filtered
on a short plug of Celite. Et2O was evaporated in vac-
uum and the crude purified by flash chromatography
on silica gel (hexane–ether 8:2–65:35) affording a color-
less oil (74 mg, 82%).
1
attempts. H NMR (200 MHz, CDCl3): d 7.36 (d, 2H,
J = 8.0Hz, C 6H4, I dia), 7.32 (d, 2H, J = 8.0Hz, C 6H4,
II dia), 7.11 (d, 4H, J = 8.0Hz, C 6H4, I and II dia), 6.4
(d, 1H, J = 3 Hz, I dia), 6.12 (d, 1H, J = 7 Hz, II dia),
5.80(m, 2H, I and II dia), 5.3 (m, 2H, I and II dia),
5.02 (m, 4H, I and II dia), 4.88 (dd, 1H, J = 7 and
3 Hz, I dia), 3.86 (dd, 1H, J = 7 and 1 Hz, II dia), 2.31
(s, 6H), 2.05 (s, 3H), 2.01 (s, 6H), 1.99 (s, 3H, II dia),
2.43–1.99 (m, 4H), 0.87 (s, 9H, s, I dia), 0.85 (s, 9H, II
dia), 0.07, 0.06, 0.05 (s, 12H, I and II dia). 13C NMR
(CDCl3): d 169.7, 169.5, 168.5, 138.4, 137.8, 134.5,
134.2, 132.6, 129.5, 129, 127.7, 117.7, 117.4, 97.1, 96.3,
82.3, 81.0, 72.8, 72.3, 38.2, 37.6, 25.8, 21.1, 18.2, À4.1,
1
Rf (two diastereoisomers, half point): 0.52. H NMR
(300 MHz, CDCl3): d 7.38 (d, 2H, J = 8.0Hz, C 6H4, I
dia), 7.33 (d, 2H, J = 8.0Hz, C 6H4, II dia), 7.09 (d,
4H, J = 8.0Hz, I and II dia), 6.34 (d, 1H, J = 4.2 Hz, I
dia), 6.32 (d, 1H, J = 2.7 Hz, II dia), 5.80(m, 2H, I
and II dia), 5.02 (m, 4H, I and II dia), 4.85 (d, 4H,
J = 7.0Hz superimposed of I and II dia), 3.98–3.52
(m, 12H, I and II dia), 3.37 (s, 3H, I dia), 3.36 (s, 3H,
II dia), 2.31 (s, 9H), 2.01 (s, 3H, I dia), 1.99 (s, 3H, II
dia), 2.43–1.99 (m, 4H), 0.88 (s, 9H, I dia), 0.86 (s,
9H, II dia), 0.07, 0.06, 0.05 (s, 12H, I and II dia). 13C
NMR (75 MHz, CDCl3): d 169.3, 169.1, 138.6, 138.0,
134.7, 134.4, 132.8, 129.7, 129.2, 127.9, 117.7, 117.4,
97.1, 96.5, 82.3, 81.0, 80.5, 80.1, 72.8, 72.3, 71.6, 67.8,
67.4, 58.9, 38.2, 37.6, 25.8, 21.1, 17.9, À4.4, À4.7.
1
À4.5. H NMR (200 MHz, CDCl3) of sulfide 25: d 7.29
(d, 2H, J = 7 Hz), 7.12 (d, 2H, J = 7 Hz), 5.72 (m, 1H),
5.05 (m, 3H), 3.85 (m, 1H), 3.02 (AB of an ABX system,
2H, JAX = 3 Hz, JBX = 7 Hz, JAB = 13 Hz, Dm = 45 Hz),
2.2–3 (m, 2H), 2.02 (s, 3H), 0.88 (s, 9H), 0.1 (2s, 6H).
13C NMR (50MHz, CDCl 3) of sulfide 25: d 168.5,
136.2, 127.4, 129.9, 124.6, 117.6, 75.2, 72.5, 36.8, 33.3,
25.7, 20.9, 18.6, À0.4, À0.43.
4.16. (3R,2R)-1-Hydroxy-2-tert-butyl-dimethylsilyloxy-
3-methoxyethoxymethyloxy-5-hexene 31
To a solution of 30 (0.248 g, 0.496 mmol) in dry Et2O
(12 mL), LiBH4 (43 mg, 1.99 mmol) was added. The
solution was stirred at room temperature for 3 h. The
solution was cooled to 0 ꢁC, diluted with Et2O (10mL)
and HCl (1 M, 10mL) added slowly. The aqueous phase
was extracted twice with CH2Cl2 (20mL) and once with
AcOEt (20mL). The organic layer was washed with
brine, dried over MgSO4 and concentrated in vacuum.
The crude was purified by flash chromatography (hex-
ane–ethyl acetate 4:1–3:2) affording a white amorphous
crystals (118 mg, 71%). Rf: (hexane–ethyl acetate 3:2)
4.14. (3R,2S,RS)-1-(p-Tolylsulfinyl)-2-tert-butyl-dimeth-
ylsilyloxy-3-methoxyethoxymethyloxy-5-hexene 29
To a suspension of KH (9.5 mg, 0.316 mmol) in dry
THF (1 mL) cooled to À78 ꢁC was added dropwise a
solution of alcohol 23 (58 mg, 0.158 mmol) in dry
THF (1.5 mL). The suspension was stirred for 30min
at À78 ꢁC and MEMCl (36 lL, 0.316 mmol) added.
The solution was stirred at À78 ꢁC for 15 min and at
rt for 1 h 30min. Saturated aqueous NH 4Cl (5 mL)
was added and the mixture extracted twice times with
AcOEt (10mL · 2) and once with CH2Cl2 (10mL).
The combined organic layers were washed with brine,
dried over MgSO4 and evaporated under reduced pres-
sure. The crude was purified by flash chromatography
on silica gel (hexane–ether 1:1 to ether) to afford a col-
ourless oil (53 mg, 77%). Rf: (hexane–ethyl acetate 3:2)
0.4. 1H NMR (300 MHz, CDCl3): d 7.41 ((AB)2 system,
4H, JAB = 8.2 Hz, Dm = 40Hz), 5.75 (m, 1H), 4.99 (m,
2H), 4.91 (d, 1H, J = 7.0Hz), 4.89 (d, 1H, J = 7.0Hz),
4.13 (m, 1H), 3.97 (m, 1H), 3.78 (m, 2H), 3.58 (m,
2H), 3.39 (s, 3H), 2.87 (AB fragment of an ABX system,
2H, JAX = 1.7 Hz, JBX = 10.6 Hz, JAB = 13.1 Hz,
Dm = 45 Hz), 2.40(s, 3H), 1.98 (m, 2H), 0.85 (s, 9H),
0.08 (s, 3H), 0.03 (s, 3H). 13C NMR (CDCl3): d 142.0,
141.4, 135.6, 130.0, 123.9, 117.1, 96.4, 75.2, 72.2, 71.8,
67.6, 59.3, 59.1, 36.1, 25.9, 21.4, 18.0, À4.33, À4.51.
1
0.4; H NMR (200 MHz, CDCl3): d 5.77 (m, 1H), 5.02
(br d, 1H), 5.01 (br d, 1H), 4.81 (d, 1H, J = 7.0Hz),
4.71 (d, 1H, J = 7.0Hz,), 3.86–3.46 (m, 6H), 3.35 (s,
3H), 2.34 (m, 1H), 2.10 (m, 1H), 0.85 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H). 13C NMR (50MHz, CDCl 3): d
135.0, 117.0, 96.5, 84.0, 72.6, 71.5, 67.3, 62.2, 58.8,
37.2, 25.7, 17.9, À4.6, À4.7. [a]D = +36 (c 2.2, CHCl3).
References
´
1. (a) Hanquet, G.; Solladie, G.; Rolland, C. Tetrahedron
Lett. 1997, 38, 5847–5850; (b) Hanquet, G.; Solladie, G.;
´
Rolland, C. Tetrahedron Lett. 1999, 40, 177–180; (c)
´
Hanquet, G.; Solladie, G.; Izzo, I.; Crumbie, R. Tetrahe-
dron Lett. 1999, 40, 3071–3074.
2. (a) Congreve, M. S.; Holmes, A. B.; Hughes, A. B.;
Looney, M. G. J. Am. Chem. Soc. 1993, 115, 5815–5816;
(b) Lindquist, N.; Fenical, W. Tetrahedron Lett. 1989, 30,
2735–2738; (c) McNaughton-Smith, A. G.; Taylor, R. J.
K. Tetrahedron 1996, 52, 2113–2124.
3. (a) Niva, H.; Inagaki, H.; Yamada, K. Tetrahedron Lett.
1991, 32, 5127–5128; (b) Niva, H.; Watanabe, M.; Inagaki,
H.; Yamada, K. Tetrahedron 1994, 50, 7385–7400.
[a]D = +140( c 2.0CHCl ).
3
4.15. (3R,2S)-1-(p-Tolylsulfenyl)-1-(acetoxy)-2-tert-
butyl-dimethylsilyloxy-3-methoxyethoxymethyl-5-
hexene 30
To a solution of 29 (84 mg, 0.18 mmol) in Ac2O (4 mL)
was added AcONa (177 mg, 2.16 mmol). The mixture
4. Furstner, A.; Schlede, M. Adv. Synth. Catal. 2002, 344,
¨
657–665.

I. Izzo et al. / Tetrahedron: Asymmetry 16(2005) 1503–1511
1511
5. Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem.
Soc. 1980, 102, 7984–7985.
9. Mitsunobu, O. Synthesis 1981, 1–28.
10. Sibi, M. P.; Marwin, M.; Sharma, R. J. Org. Chem. 1995,
60, 5016–5023.
11. Hubbard, J. S.; Harris, M. J. Org. Chem. 1981, 46, 2566–
2570.
12. The relative configuration of the monoprotected diol 23
was determined by 13C NMR analysis of the correspond-
ing acetonide.1b
13. Bravo, P.; Frigero, M.; Resnati, G. J. Org. Chem. 1990,
55, 4216–4218.
6. Optimum yields of b-ketosulfoxides from ester displace-
ment by the lithium anion of methyl-p-tolylsulfoxide have
previously been found to occur with 2 equiv of sulfinyl
anion (better conversions were generally observed under
these conditions rather than using 1 equiv of methyl-p-
tolylsulfoxide and 2 equiv of lithium amide). Such an
excess was necessary because of the acidity of the
methylene protons of the b-ketosulfoxide. Initial experi-
ments in this work carried out under these conditions led
to a mixture of products, with the a-diketo-b-disulfoxide
being formed in highest yield.
14. Soai, K.; Ooakawa, A. J. Org. Chem. 1986, 51, 4216–4218.
15. Takebuchi, K.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1994, 35, 5239–5242.
7. Silica gel chromatography of the b-ketosulfoxide 11
resulted in decomposition, even when the silica gel was
deactivated. Separation from the excess of the starting
diethyloxalate was achieved using a two layer column; the
lower layer being deactivated silica gel, the upper, Celite.
The crude product was dissolved in dichloromethane and
loaded onto the column, which had been prepared with
hexane. b-Ketosulfoxide 11 precipitated in the Celite layer
in the non-polar solvent, whilst the diethyloxalate could be
washed through. Some other impurities were then
removed by changing to a 50% ether–hexane mixture,
then the product was isolated by rapid flushing with ether.
8. The relative configuration of the monoprotected diol 10
was determined by 13C NMR analysis of the correspond-
ing acetonide 15.
16. Corey, E. J.; Hua, D. H.; Seitz, S. P. Tetrahedron Lett.
1984, 25, 3–6.
17. Boeckman, B. K.; Potenza, J. C. Tetrahedron Lett. 1985,
26, 1411–1414.
´
18. Solladie, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
19. A common work-up procedure for Dibal-H reduction of
b-ketosulfoxides is the precipitation of aluminium salts as
their tartrate. For this substrate, this led to poor recovery
and it was found that a pH of 3–4 was best to obtain the
highest yields of alcohol 12. This was achieved by initially
quenching the reaction with saturated ammonium chloride
solution, followed by the careful addition of dilute sulfuric
acid to the mixture so as to avoid lowering the pH too
dramatically, since it was found that the alcohol readily
epimerized at lower pH.