Reactivity of unsaturated sultones synthesized from unsaturated alcohols by ring-closing metathesis. Application to the racemic synthesis of the originally proposed structure of mycothiazole

Article abstract of DOI:10.1016/j.tet.2006.07.010

Unsaturated sultones have been synthesized from various primary or secondary alkenols by ring-closing metathesis of the corresponding unsaturated sulfonates. By treatment with a strong base, β,γ-unsaturated sultones can be metalated and subsequently alkylated with electrophiles. When iodomethylmagnesium chloride was selected as the electrophile, seven-membered ring β,γ-unsaturated sultones were converted into homoallylic conjugated (Z)-dienols. This methodology was applied to the racemic synthesis of the originally proposed structure of the marine natural product mycothiazole.

Full text of DOI:10.1016/j.tet.2006.07.010

Tetrahedron 62 (2006) 9017–9037
Reactivity of unsaturated sultones synthesized from unsaturated
alcohols by ring-closing metathesis. Application to the racemic
synthesis of the originally proposed structure of mycothiazole
*
Alexandre Le Flohic, Christophe Meyer and Janine Cossy
*
´
Laboratoire de Chimie Organique associe au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 28 April 2006; revised 4 July 2006; accepted 4 July 2006
Available online 28 July 2006
Abstract—Unsaturated sultones have been synthesized from various primary or secondary alkenols by ring-closing metathesis of the corre-
sponding unsaturated sulfonates. By treatment with a strong base, b,g-unsaturated sultones can be metalated and subsequently alkylated with
electrophiles. When iodomethylmagnesium chloride was selected as the electrophile, seven-membered ring b,g-unsaturated sultones were
converted into homoallylic conjugated (Z)-dienols. This methodology was applied to the racemic synthesis of the originally proposed struc-
ture of the marine natural product mycothiazole.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of the resulting allylic alcohol and subsequent methylena-
tion of the carbonyl group [route (b), Scheme 1].11 The
(Z)-alkenyl iodides of type B are generally prepared from
the aldehydes of type D by a Wittig olefination with (iodo-
methylene)triphenylphosphorane,12 but the direct conver-
sion of these latter aldehydes to the conjugated (Z)-dienols
oftypeAcanalsobeachievedbyreactionwithallylicorgano-
metallic species of type E such as an allyltitanium bearing
a diphenylphosphanyl group (Z¼PPh2) and subsequent
elimination of phosphine oxide,13 or an allylchromium14 or
an allylborane15 bearing a trimethylsilyl group (Z¼SiMe3)
followed by Peterson elimination [route (c), Scheme 1].16
Another strategy relies on a copper-promoted coupling of
the alkynylsilane moiety in the homopropargylic alcohols
of type F with vinyl iodide, followed by an intramolecular
hydrosilylation of the carbon–carbon triple bond [route (d),
Scheme 1].17 As the reduction of lactones of type G followed
by Wittig methylenation can provide access to subunits of
type A, an alternative route has been developed from homo-
allylic alcohols of type H that relies on a ring-closing meta-
thesis reaction (RCM) of the corresponding derived acrylates
[route (e), Scheme 1].18 Whereas a R3 substituent (R3sH)
can be introduced in the first two routes [routes (a) and (b),
Scheme 1], the other strategies have only been reported
for the synthesis of subunits of type A bearing a terminal
olefin (R3¼H).
Homoallylic conjugated (Z)-dienols of type A (Fig. 1) and
their derivatives are present in a variety of biologically active
natural products such as palytoxin,1 ostreocin,2 discoder-
molide,3 dictyostatin,4 neodihydrohistrionicotoxin,5 and
mycothiazole.6 As illustrated in the total synthesis of some
of these natural products or in synthetic approaches, various
strategies have been developed to synthesize conjugated (Z)-
dienols of type A in a stereoselective manner (Scheme 1).
OH
R1
R2
R3
A
Figure 1. Structure of the homoallylic conjugated (Z)-dienols of type A.
A first approach involves palladium- or nickel-catalyzed
cross-coupling reactions7 between (Z)-alkenyl iodides
(X¼I)8,9 or enol carbamates and triflates [X¼OCON(i-Pr2)
or OTf]10 of type B, respectively, with an alkenyl metal of
type C [route (a), Scheme 1]. The (Z)-alkenyl iodides of
type B (X¼I) can also undergo a Nozaki–Hiyama–Kishi
coupling with an aldehyde (R3CHO) followed by oxidation
The development of an alternative complementary route to
subunits of type A from homoallylic alcohols of type H19
was considered that would rely on an unsaturated hetero-
cyclic intermediate generated by RCM for the control of
(Z) configuration of the a,b-disubstituted double bond and
Keywords: Ring-closing metathesis; Sultones; Conjugated dienes; Natural
products.
* Corresponding authors. Tel.: +33 1 40 79 44 29; fax: +33 1 40 79 46 60
(C.M. and J.C.); e-mail addresses: christophe.meyer@espci.fr; janine.
cossy@espci.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.010

9018
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
OP
OP
O
Z
H
Ph3P=CHI
R1
R1
H
+
+
O
R3
M
R2
B
I
R2
D
E
Z = PPh2 or SiMe3
M = TiX3, CrX2, BX2
(b)
(c)
OH
OP
OP
SiMe3
+
(a)
M
(d)
I
R1
R1
R1
+
R3
R2
A
R2
B
X
R2
F
R3
C
(e)
X = I, OCONi-Pr2, OTf
M = SnR3, ZnX...
O
O
Cl
O
OH
P = protecting group
RCM
R1
R1
R2
G
R2
H
Scheme 1. Synthetic approaches toward homoallylic conjugated (Z)-dienols of type A.
would enable the introduction of a R3 substituent. Based on
literature precedents, subunits of type A should be generated
from the b-metalated sultones of type I by b-elimination of
the sulfonyl moiety and loss of sulfur dioxide.20,21 Such
intermediates of type I should be accessible from the
unsaturated sultones of type J by sequential metalation
and electrophilic trapping, first by an appropriate alkylating
reagent containing the R3 moiety and then with the carbe-
noid reagent ICH2MgCl.21 A RCM could be used to
elaborate the unsaturated sultones of type J from the corre-
sponding unsaturated sulfonates derived from homoallylic
alcohols of type H (Scheme 2).
unsaturated carbocycles as well as oxygen, nitrogen, or phos-
phorous containing heterocycles that would be difficult to
obtain by other routes.22 When we initially started our inves-
tigations on this subject, the preparation of unsaturated
sultones by RCM had not been described, although the
synthesis of sulfur-containing heterocycles by this strategy
had already been the subject of several reports.23 Thus, it
was initially reported that, unlike the more reactive Schrock’s
molybdenum carbene catalyst, the ruthenium–carbene
complex I,24 the so-called first generation Grubbs’ catalyst
(Fig. 2) was not suitable for the generation of cyclic sulfides
due to its poisoning by low-valent organosulfur com-
pounds.25,26 However, it was later demonstrated that the
second generation ruthenium catalysts bearing an N-hetero-
cyclic carbene (such as II or its dehydro analogue) could
be used successfully in some cases, depending on the substi-
tution pattern of the substrates.27 However, the ruthenium
catalysts are compatible with the higher oxidation states of
the sulfur atom as illustrated by the numerous reports con-
cerning the synthesis of unsaturated sulfoxides,28 sulfones,29
sulfonamides,30 and sulfamides31 by RCM using the ruthe-
nium–carbene catalysts I or II (Fig. 2).
MgCl
R3
O
S
O
O
OH
R1
R1
R2
R2
R3
I
A
-
-
1) B then "R3
"
+
2) B then ICH2MgCl
O
S
O
O
O
Cl
O
S
OH
In order to demonstrate that a variety of sultones could be
generated by RCM, and not only those of type J required
for our synthetic approach toward homoallylic conjugated
(Z)-dienols of type A, a variety of primary alkenols were
treated with vinyl-, allyl-, or homoallylsulfonyl chlorides32
in the presence of Et3N (CH2Cl2, 0 ꢀC to rt) to generate
the corresponding primary unsaturated sulfonates 1a–f
(40–90%). These sulfonates underwent a RCM in the
R1
R1
RCM
R2
H
R2
J
Scheme 2. Synthesis of subunits of type A from unsaturated sultones.
Herein, we would like to report a full account of our results
concerning the synthesis of unsaturated sultones by RCM,
their subsequent transformation to homoallylic conjugated
(Z)-dienols of type A as well as the application of this metho-
dology to the racemic synthesis of the originally proposed
structure of the marine natural product mycothiazole.
N
Cl
N
PCy3
Ru
Cl
Cl
Ru
Ph
2. Synthesis of unsaturated sultones by RCM
Cl
PCy3
Ph
PCy3
Catalyst II
Catalyst I
The RCM catalyzed by ruthenium–carbene complexes
is a particularly attractive strategy for the synthesis of
Figure 2. RCM catalysts.

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9019
ꢁ78 ꢀC35 and subsequent addition of methyl iodide regio-
selectively afforded the a-substituted sulfonate 1g in good
yield (84%). After treatment with catalyst II (C6H6, 70 ꢀC),
the a-methyl-b,g-unsaturated seven-membered ring sultone
2g (60%) was produced (Scheme 3).
Table 1. Synthesis of unsaturated sultones from primary alkenols
O
Cl
O
S
+
O
O
O
O
O
O
S
n
S
Et3N
Catalyst I or II
n
n
HO
CH2Cl2
0 °C to rt
C6H6, 70 °C
m
m
m
1
2
O
O
O
O
O
O
O
O
O
Catalyst II
1) n-BuLi
THF, -78 °C
m
n
Sulfonate 1 (yield%)
1a (40)
Sultone 2 (yield%)
CH3
CH3
S
S
S
(5 mol%)
O
O
O
2) MeI
84%
C6H6, 70 °C
60%
S
2a
1
0
(100)
1g
2g
1d
O
O
Scheme 3. Alkylation of acyclic unsaturated sulfonates.
S
O
2
1
0
1
1b (87)
1c (76)
2b
The synthesis of unsaturated sultones derived from second-
ary alkenols was next investigated. It turned out that the sul-
fonates 1h–l derived from secondary allylic or homoallylic
alcohols were considerably less stable than those derived
from primary ones, but their preparation could be achieved
by reaction with vinyl or allylsulfonyl chlorides in the pres-
ence of Et3N in THF at ꢁ15 ꢀC.36 The latter solvent pro-
vided better results than CH2Cl2 presumably because of
the lower solubility of triethylamine hydrochloride, which
may be responsible for side reactions. Nevertheless, the
crude intermediate secondary sulfonates 1h–l were not puri-
fied and immediately treated with catalyst II in C6H6 at
70 ꢀC. Under these conditions, the corresponding function-
alized a,b- or b,g-unsaturated sultones 2h–l were obtained
in satisfactory overall yields (54–76%) from the correspond-
ing secondary alkenols (Table 2).
(90)
O
O
O
O
S
S
2c
(51)a
(99)
O
O
2d
2
3
1
1d (90)
(60)a
(100)
O
O
S
S
O
1
2
1e (83)
1f (90)
2e
(94)a
O
O
2f
(99)a
(51)
2
O
These results demonstrate that a wide variety of sultones can
be easily synthesized by RCM of the corresponding sulfo-
nates derived from either primary or secondary alkenols.33,34
The unsaturated sultones 2 should constitute interesting
heterocyclic building blocks in organic synthesis since
they possess multiple sites of reactivity.37,38
a
Yields refer to the use of catalyst I.
presence of catalyst I or II (C6H6, 70 ꢀC) and the corre-
sponding unsaturated sultones 2a–f were obtained in good
to virtually quantitative yields (Table 1). The second gener-
ation catalyst II, which is less sensitive to steric and elec-
tronic effects compared to catalyst I,24 was used to achieve
the RCM of the unsaturated sulfonates 1a and 1b, which
provided the corresponding a,b-unsaturated five- and six-
membered ring sultones 2a (100%) and 2b (90%), respec-
tively. It was observed that catalyst I was considerably less
efficient than catalyst II for the formation of the six- and
seven-membered ring b,g-unsaturated sultones 2c (51%
compared to 99%) and 2d (60% compared to 100%), respec-
tively. Similar results were disclosed, prior to our first report,
by Metz and co-workers who achieved the formation of five-
to nine-membered and fifteen-membered ring sultones from
primary unsaturated sulfonates using catalyst II in refluxing
CH2Cl2.33 Despite the well-known difficulties associated
with the formation of medium-size rings by RCM, we
observed that the less reactive catalyst I was particularly
efficient in promoting the RCM reaction of the unsaturated
sulfonates 1e and 1f leading to the eight-membered ring
sultones 2e (94%) and 2f (99%), respectively, whereas the
latter was obtained in considerably lower yield (51%)
when catalyst II was employed (Table 1).34
Table 2. Synthesis of unsaturated sultones from secondary alkenols
O
Cl
O
O
O
O
O
S
+
S
S
n
n
O
Et3N
O
Catalyst II
n
OH
THF, -15 °C
C6H6, 70 °C
R
R
m
m
R
2
m
1
m
n
R
Sultones 2 (yield%)
O
O
O
S
2h (76)
2i (54)
1
0
0
(CH2)3OBn
CO2Et
1h
1i
BnO
O
O
O
S
1
EtO2C
O
O
O
S
2j (74)
2k (65)
0
0
1
1
1
1
CH2OPiv
1j
1k
1l
PivO
O
O
O
S
CH2OTBDPS
(CH2)3OBn
TBDPSO
BnO
O
O
O
S
It was also demonstrated that primary unsaturated sulfonates
could be substituted prior to RCM. Thus, the sulfonate
1d was metalated by treatment with n-BuLi in THF at
2l (65)

9020
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
O
O
Following our initial goal, the transformation of the b,g-
unsaturated seven-membered ring sultones of type J such
as 2d and 2l into homoallylic conjugated (Z)-dienols of
type A was investigated (Scheme 2). This operation implies
that these unsaturated sultones should be metalated at the
a-position of the sulfonyl moiety and functionalized by reac-
tion with appropriate electrophiles.
1) n-BuLi
THF, -78 °C
2) CH3I
99%
CH3
O
O
O
O
S
S
2d
2g
O
O
O
CH3
1) n-BuLi
THF, -78 °C
O
O
S
S
S
O
O
2) CH3I
85%
1) n-BuLi
THF, -78 °C
2) Br(CH2)3OBn
BnO
BnO
BnO
2l
6
3. Synthesis of conjugated (Z)-dienols of type A
O
O
O
OBn
O
O
S
Sultones can be metalated at the a-position of the sulfonyl
group using a strong base such as an alkyllithium reagent.39
In the case of b,g-unsaturated sultones of type J, the acidity
of the hydrogens at the a-position should be improved com-
pared to the saturated analogues, and the use of a milder base
such as LDA was considered for achieving the metalation.
However, when sultone 2l was treated with LDA in THF at
ꢁ78 ꢀC, the formation of the 1,3-dithietane tetraoxide 3
took place rapidly prior to the introduction of any electro-
philic agent. The latter compound was isolated in 55% yield
in the apparent form of a 60:40 mixture of trans/cis-dia-
stereomers (unassigned relative configuration) bearing dou-
ble bonds of (Z) configuration, as indicated by the analysis of
the 1H NMR spectrum. The formation of 3 may be explained
by the transformation of the a-lithiated sultone 4 into the
corresponding sulfene 5 that dimerized under these condi-
tions to 3 (Scheme 4).40
HMPA
84%
BnO
2l
7
Scheme 5. Alkylation of sultones 2d and 2l.
provided that the polar co-solvent HMPA was added. Under
these conditions, sultone 2l was effectively converted into
the a-alkylated sultone 7 (84%, single diastereomer of unas-
signed relative configuration) (Scheme 5).
In order to demonstrate that conjugated (Z)-dienols of type A
could be generated from unsaturated sultones of type J,
substrates 2l and 6 were metalated with n-BuLi in THF
at ꢁ78 ꢀC and the resulting organolithium reagents were
alkylated with ICH2MgCl41 (generated from CH2I2 and
i-PrMgCl, THF, ꢁ78 ꢀC). As anticipated, this carbenoid
reagent behaved as an electrophilic species and the Grignard
reagents initially generated by this alkylation reaction under-
went b-elimination and loss of sulfur dioxide to deliver the
homoallylic alcohols 8 (60%) and 9 (53%) bearing a 1,3-
diene unit with an internal (Z)-disubstituted double bond
and either a terminal or an a,a-disubstituted olefin, respec-
tively (Scheme 6).
O
O
LDA
S
OBn
O
THF, -78 °C
HO
BnO
55%
SO2
O2S
OH
2l
BnO
3
O
S
O
Li
O
O
OH
O
R
S
O
O
1) n-BuLi
THF, -78 °C
S
LiO
BnO
O
BnO
BnO
BnO
2) ICH2MgCl
THF, -78 °C
R
4
5
R = H
R = CH3
R = H
R = CH3
60%
53%
2l
8
Scheme 4. Metalation of sultone 2l with LDA.
6
9
Fortunately, this side-reaction was not observed when sul-
tone 2l was metalated with n-BuLi in THF at ꢁ78 ꢀC and
subsequent addition of methyl iodide cleanly provided the
a-methyl b,g-unsaturated seven-membered ring sultone 6
in 85% yield as a single diastereomer (unassigned relative
configuration) (Scheme 5). Although, the different behavior
of the a-lithiated sultone 4 under these two sets of experi-
mental conditions has not been fully elucidated, it appeared
obvious that the presence of excess LDA and/or diisopropyl-
amine modified the reactivity of the carbon–lithium bond in
the latter species and was responsible for its transformation
to sulfene 5. Indeed, when 2l was metalated with an excess
of n-BuLi, the subsequent addition of diisopropylamine
also triggered the formation of 1,3-dithietane tetraoxide 3.
Scheme 6. Synthesis of the conjugated (Z)-dienols of type A.
Having demonstrated that conjugated (Z)-dienols of type A
could be synthesized from homoallylic alcohols, we envis-
aged to highlight the interest of this methodology by its
application to the total synthesis of biologically active natu-
ral products. In order to fully benefit from the intermediacy
of an unsaturated sultone in this strategy, natural products
bearing a subunit of type Awith an a,a-disubstituted double
bond appeared rather interesting targets and the marine
natural product mycothiazole was selected.
4. Total synthesis of the originally proposed
structure of mycothiazole
Metalation of sultone 2d derived from a primary alkenol
with n-BuLi in THF at ꢁ78 ꢀC followed by addition of
methyl iodide afforded a-methylated sultone 2g, a substrate
that was previously synthesized by alkylation of the acyclic
sulfonate 1d and subsequent RCM (Scheme 3). Besides
methyl iodide, other less reactive alkylating agents such as
the alkyl bromide Br(CH2)3OBn could be used successfully
Over the past few years, natural products of marine origin
have continued to be of interest due to their wide spectrum
of biological and pharmacological properties. Mycothiazole
was first isolated in 1988 from the marine sponge Spongia
mycofijiensis collected from the Vanuatu islands.6 Its pres-
ence was also detected recently in the extracts of another

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9021
18
to the carboxylic acid of type K. The key stage would be the
elaboration of the conjugated (Z)-dienol moiety in com-
pound K from the corresponding homoallylic alcohol deriv-
ative of type L, through an intermediate sultone, using the
previously described strategy. The introduction of the side-
chain at C4 in compound L should be achieved from the
substituted 4-bromothiazole of type M. In this latter com-
pound, the secondary homoallylic alcohol at C7 would be
created by allylation of an intermediate aldehyde whose
preparation was envisaged from the readily available 2,4-
dibromothiazole 1049 (Scheme 7).
16
15
19
14
5
4
OH
N
9
6
2
7
10
11
O
S
13
1
N
H
O
20
Figure 3. Originally proposed structure of (ꢁ)-mycothiazole.
marine sponge of the genus Dactylospongia.42 Mycothiazole
was found to exhibit an antihelminthic activity in vitro.6
Moreover, screening assays by the National Cancer Institute
(NCI) in the United States indicated that mycothiazole
exhibits a rather selective toxicity against a small cell lung
cancer line.43 The originally proposed structure of mycothia-
zole was established after extensive NMR analysis and con-
firmed by the exhaustive interpretation of a HREIMS
spectrum (Fig. 3).6 The synthesis and biological evaluation
of simplified analogues of mycothiazole are still currently
being investigated.44
16
19
14
4
OH
N
9
5
6
2
10
11
7
O
S
13
N
H
O
20
Mycothiazole
(originally proposed structure)
16
14
19
19
4
OR
N
9
5
6
2
7
10
11
S
The main structural feature of this natural product is a 2,4-
disubstituted thiazole ring, which is embedded between two
acyclic dienic side chains. The C2 side-chain includes a
nitrogen substituent at C13 (methyl carbamate), a conjugated
diene moiety consisting of a (Z)-disubstituted double bond
(C9–C10) and a methylene group (C11–C20), a quaternary
carbon at C6 substituted by a gem-dimethyl group, and a sec-
ondary alcohol at C7 that constitutes the unique stereocenter
of mycothiazole having a (R) configuration. The C4 substi-
tuent is a 2,5-hexadienyl chain containing a disubstituted
double bond (C15–C16) to which an (E) configuration was
originally assigned and a terminal olefin (C18–C19). A con-
jugated (Z)-dienol subunit of type A is easily recognized in
the C7–C11 fragment of this natural product.45
13
K
COOH
20
16
14
5
4
OR
N
9
6
2
7
S
10
10
L
Br
4
OR
N
9
5
6
2
7
S
M
Br
4
N
5
2
Br
S
10
Scheme 7. Retrosynthetic analysis.
The first total synthesis of the proposed structure of myco-
thiazole features the formation of the thiazole ring by con-
densation of L-cysteine methyl ester with a carboxylic acid
followed by oxidation with activated MnO2 to form the
2,4-disubstituted thiazole, an enantioselective aldol conden-
sation for the control of configuration at the C7 stereocenter,
and the stepwise construction of the 2,5-hexadienyl side-
chain at C4 by two sequential Stille coupling reactions
(C15–C14 and C17–C18 bond formation). A third Stille cou-
pling enabled the construction of the C10–C11 bond and
hence the elaboration of the subunit of type A [according
to route (a), Scheme 1].9 The assignment of the (R) absolute
configuration to mycothiazole was based on the comparison
of the signs of optical rotations of the synthetic sample and
the natural product. The discrepancies observed between the
values were attributed to the lability of mycothiazole upon
storage.9 Synthetic approaches have also been reported
toward a C4–C7 subunit containing the 2,4-disubstituted
thiazole46 and the C8–C13 fragment containing the conju-
gated diene by an ene–yne cross-metathesis, which occurred
without stereoselectivity.47,48
The selection of this latter compound as a starting material
would also be potentially attractive for the synthesis of struc-
tural analogues of the natural product bearing a different
side-chain at C4.
4.2. Synthesis of the C4–C10 subunit
Our synthesis of the originally proposed structure of myco-
thiazole first required the chemoselective substitution of bro-
mine at C2 in 2,4-dibromothiazole 10. Prenylmagnesium
chloride chemoselectively reacted with 10 in THF at 0 ꢀC
with complete allylic transposition (SE20 process)50 to pro-
duce 2,4-disubstituted thiazole 11 (87%). The terminal ole-
fin in compound 11 was subjected to a dihydroxylation (cat.
OsO4, NMO, t-BuOH/H2O) and the resulting intermediate
1,2-diol was not purified but underwent an oxidative cleav-
age with NaIO4 in THF/H2O to afford aldehyde 12 (88%).
This compound was treated with allylmagnesium bromide
and the resulting secondary alcohol 13 (87%) was protected
as a tert-butyldimethylsilyl ether (TBSOTf, 2,6-lutidine,
CH2Cl2, 0 ꢀC) to produce compound 14 (95%) containing
the C4–C10 subunit of mycothiazole (Scheme 8).
4.1. Retrosynthetic analysis
In our retrosynthetic analysis of the originally proposed
structure of mycothiazole, the installation of the methyl car-
bamate at C13 was envisaged by a Schmidt reaction applied
The next task was to install the 2,5-hexadienyl side-chain at
C4 on the thiazole ring.

9022
Br
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
MgCl
but these reactions were initially inadverently carried out in
Br
4
1) cat.OsO4, NMO
4
N
N
THF as the solvent. In this case, subsequent formylation
with DMF afforded mixtures of products containing the
desired disubstituted thiazole 19 formylated at C4 as
the minor component, the mono-substituted thiazole 18, the
substituted 4-bromo-5-formylthiazole 20as well as the corre-
sponding regioisomeric thiazole 21 formylated at C5. The
relative proportions of these compounds differ considerably
from one experience to another and were presumably
affected by the rate of addition of alkyllithium as well as
the reaction time at ꢁ78 ꢀC before DMF was introduced,
although the aldehyde 21 (formyl group at C5) was clearly
the major component (43–72% isolated yields) (Scheme 10).
t-BuOH/H2O
5
5
6
2
2
7
Br
THF, 0 °C
87%
2) NaIO4
THF/H2O
88%
S
10
S
11
Br
Br
4
MgCl
4
O
N
OR
N
9
5
6
5
6
7
THF, -78 °C
87%
2
H
2
7
S
12
S
10
13 R = H
TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C
14 R = TBS
95%
Scheme 8. Synthesis of the C4–C10 subunit.
4.3. Installation of the unsaturated side-chain at C4
Br
Br
Br
4
4
4
N
N
N
DMF
5
Our initial plan was to create the C4–C14 bond by a cross-
coupling reaction. Thus, the substituted 4-bromothiazole
14 underwent lithium–bromine exchange with tert-butyl-
lithium in ether at ꢁ78 ꢀC.51 The corresponding organo-
lithium reagent 15a was transmetalated with zinc chloride,
but the resulting organozinc reagent 15b did not react with
the allylic acetate 1652 in the presence of a catalytic amount
of Pd(PPh3)4 in THF.53 A transmetalation of 15a with copper
cyanide was also attempted but the resulting lower order
cyanocuprate 15c did not achieve the SN20 substitution of
the allylic ester 1754 and presumably decomposed upon
warming to rt. In both cases, only the mono-substituted
thiazole 18 resulting from the protonation of the carbon–
metal bond at C4 was recovered after hydrolysis of the
reaction mixture (Scheme 9).
2
5
5
2
2
R
R
Li
R
OHC
R
R
S
14
S
22
S
20
t-BuLi
Initiation
or n-BuLi
THF, -78 °C
4
N
Li
5
4
4
5
2
R
N
N
S
18
5
2
2
Li
S
15a
S
23
Propagation
DMF
DMF
OTBS
OHC
4
4
N
N
R =
5
5
2
2
OHC
R
R
S
21
S
19
Scheme 10. Lithium–bromine exchange of 14 carried out in THF.
Indeed, the order of acidity of the hydrogens on thiazoles is
H2>H5>H4 and it is well-known that thiazol-4-yl metals
are destabilized by the adjacent nitrogen atom’s lone-pair
effect, as in the imidazole series.55 Thus, as the organolithium
15a was gradually generated by lithium–bromine exchange
of 14, it may abstract a hydrogen at C5 on the parent bromide
14 and generate the protonated compound 18, as well as the
substituted 4-bromothiazol-5-yllithium 22, which accounted
for the formation of 20 after addition of DMF. The small
amount of 18 generated during this initiation phase is then
able to subsequently catalyze the equilibration of the orga-
nolithium 15a at C4 to the thermodynamically more stable
regioisomeric thiazol-5-yllithium 23 (Scheme 10).56 This
mechanism shares some similarities with the so-called ‘halo-
gen dance reaction’ observed when 2-trimethylsilyl-4-bro-
mothiazole was deprotonated with LDA, the propagation
being ensured in this case by a 4,5-dibrominated thiazole
preferentially undergoing Br–Li exchange at C5.57 However,
such an equilibration does not take place in ether as the
organolithium 15a displays a lower basic character in this
less-coordinating solvent compared to THF. In fact, exami-
nation of literature results indicates that halogen–metal
exchange reactions on 4-halothiazoles have been generally
carried out in ether.51
Br
4
OTBS
N
9
5
6
2
7
S
10
14
t-BuLi, Et2O, -78 °C
M
4
OTBS
N
9
5
6
2
7
S
10
M = Li
15a
M = Li
M = Cu(CN)Li 15c
v
15a
ZnCl2
or
CuCN
M = ZnCl 15b
OPi
OAc
16
17
cat. Pd(PPh3)4, THF, rt
Et2O, 0 °C to rt
OTBS
4
N
9
5
6
2
7
S
10
18
Scheme 9. Attempts to form the C4–C14 bond.
These two initial unsuccessful attempts of introducing the
side-chain at C4 by direct formation of the C4–C14 bond,
although not optimized, led us to consider an alternative
plan in which the 2,5-hexadienyl side-chain at C4 would
be installed by the formation of the C14–C15 bond. This
strategy required at first the homologation of the substituted
4-bromothiazole 14 and this operation was envisaged by the
introduction of a formyl group at C4.
Thus, the substituted 4-bromothiazole 14 underwent a clean
lithium–bromine exchange with tert-butyllithium in ether
at ꢁ78 ꢀC51 and subsequent formylation with DMF
cleanly afforded aldehyde 19 (85%). Subsequent reduction
(DIBAL-H, Et2O, ꢁ78 ꢀC) afforded the primary alcohol
24 (95%), which was treated with PPh3 and CBr4 in THF.9
Under these conditions, the corresponding bromide 25 was
Thesubstituted4-bromothiazole14wassubjectedtolithium–
bromine exchange with tert-butyllithium or n-butyllithium51

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9023
obtained in modest yield (52%) due to a slow and incomplete
reaction, despite the use of a large excess of reagents. When
carried out in acetonitrile in the presence of 2,6-lutidine,58
bromination of 20 proceeded considerably faster and led to
25 in excellent yield (97%). With the aim of installing the
unsaturated side-chain of the originally proposed structure
of mycothiazole at C4 in a single operation, the bromide
25 was subjected to a Stille coupling with (E)-1-tributylstan-
nylpenta-1,4-diene 2659 in the presence of a catalytic
amount of PdCl2(MeCN)2 in N-methylpyrrolidinone
(NMP)9 and the 1,4-diene 27 was obtained in 95% yield.
Subsequent deprotection of the hindered hydroxyl group at
C7 with TBAF in THF at 50 ꢀC finally afforded the homo-
allylic alcohol 28 (94%) (Scheme 11).
reaction. After optimization, it was discovered that addition
of LiHMDS to a mixture of sultone 30 and iodide 31 in the
presence of HMPA (THF, ꢁ78 ꢀC) cleanly afforded mono-
alkylated sultone 32 (76%) as a 1:1 mixture of diastereo-
mers.61 The sultone 32 was then efficiently deprotonated
with n-butyllithium in THF at ꢁ78 ꢀC and subsequent addi-
tion of ICH2MgCl provided the desired conjugated (Z)-
dienol 33 in 60% yield (Scheme 12).
18
14
4
15
OH
N
9
5
6
2
7
S
28
10
AllylSO2Cl, DMAP, THF
18
O
O
Br
OHC
4
4
1) t-BuLi
S
OTBS
N
OTBS
N
4
Et2O, -78 °C
9
9
15
O
N
5
6
5
6
9
2
7
2
7
S
14
10
S
19
10
5
6
2) DMF
85%
2
7
S
29
10
(70% from 28)
18
catalyst II, C6H6, 70 °C
14
14
4
4
OTBS
OTBS
HO
DIBAL-H
N
Br
N
PPh3
CBr4
O
S
9
9
O
O
5
5
6
6
2
7
2
7
4
S
24
S
25
15
N
10
10
Et2O
-78 °C
95%
2,6-lutidine
MeCN
5
2
7
S
30
OMe
OMe
97%
18
SnBu3
I
LiHMDS,
19
14
5
31
76%
4
26
THF/HMPA, -78 °C
15
OR
N
9
OMe
cat. PdCl2(MeCN)2
6
18
2
7
S
10
NMP
95%
O
O
OMe
TBAF
S
27
4
R = TBS
R = H
15
O
N
THF, 50 °C
94%
28
5
2
7
S
32
Scheme 11. Synthesis of the C10–C19 subunit.
1) n-BuLi, THF, -78 °C
2) ICH2MgCl, -78 °C
60%
18
With compound 28 in hand, the formation of the conjugated
(Z)-dienol moiety (C9–C13 subunit), that constitutes the
pivotal stage of our synthetic approach toward mycothia-
zole, could be tested.
4
5
15
OH
N
9
2
7
S
33
13
11
OMe
OMe
20
4.4. Formation of the conjugated (Z)-dienol moiety
Scheme 12. Elaboration of the homoallylic conjugated (Z)-dienol.
Following our synthetic plan, the elaboration of the conju-
gated (Z)-dienol moiety of mycothiazole from the homo-
allylic alcohol 28 required at first the preparation of the key
intermediate unsaturated sultone 30. The sterically hindered
secondary alcohol 28 did not react with allylsulfonyl chloride
in the presence of triethylamine in THF at rt, but switching to
DMAP as the base enabled the synthesis of intermediate
sulfonate 29. The latter compound was not purified and
underwent RCM by treatment with catalyst II (C6H6,
70 ꢀC). Under these conditions, the unsaturated sultone 30
was obtained in 70% yield (two steps from alcohol 28).
Having successfully accomplished the key transformation of
our synthesis, only functional group manipulations were
required in order to complete the total synthesis of the
originally proposed structure of mycothiazole.
4.5. Completion of the synthesis of the originally
proposed structure of mycothiazole
Hydrolysis of the dimethyl acetal in compound 33 (PPTS,
THF/H2O, 50 ꢀC) quantitatively afforded aldehyde 34,
which was not purified but directly chemoselectively oxi-
dized by NaClO2 in the presence of amylene and excess
NaH2PO4 in t-BuOH/H2O.62 However, upon completion of
the oxidation, acidification of the reaction mixture with
hydrochloric acid should be absolutely avoided as the
decomposition of the resulting carboxylic acid 35 occurred.
This extremely sensitive compound could be in fact directly
extracted from the reaction mixture with EtOAc and imme-
diately treated with diphenylphosphoryl azide (DPPA) and
Et3N in toluene.63 After formation of the acylazide 36, the
The next task was to alkylate the unsaturated sultone 30 with
an appropriate electrophile, precursor of the (N-carbometh-
oxyamino)ethyl substituent (C12–C13) of mycothiazole.
We selected the readily available 1,1-dimethoxy-3-iodopro-
pane 3160 as the alkylating agent since the acetal moiety
could then be deprotected to the aldehyde and the latter
could be oxidized to the carboxylic acid required for the sub-
sequent Schmidt reaction. The alkylation of sultone 30 with
the functionalized alkyl iodide 31 turned out to be difficult to
achieve since dialkylation was often observed as a side-

9024
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
reaction mixture was heated at reflux in order to induce Cur-
tius rearrangement to the corresponding isocyanate 37. As
the latter was apparently not readily converted into the pro-
posed structure of mycothiazole when MeOH was added to
the reaction mixture at reflux, we initially thought that 37
had probably accidentally hydrolyzed to amine 38. How-
ever, the compound obtained after purification by prepara-
tive TLC on silica gel did not react with ClCO2Me in the
presence of Et3N. This result suggested that the rather robust
isocyanate 37 had been isolated and therefore, the reaction
mixture was treated with an excess of MeOH. Under these
conditions, a surprisingly smooth methanolysis took place,64
which produced compound 39 in 33% overall yield from
dimethyl acetal 33 (four steps) (Scheme 13).
4.6. Formal enantioselective approach
As mycothiazole contains a single stereocenter at C7, we
investigated a formal enantioselective approach relying on
the preparation of the optically active alcohol (R)-13.
Thus, addition of the chiral allylic borane III [generated
from allylmagnesium bromide and (+)-B-chlorodiisopino-
campheyl borane ((+)-DIPCl)]67 to aldehyde 12 in ether at
ꢁ78 ꢀC led to the corresponding secondary homoallylic
alcohol (R)-13 (70%) with low optical purity (ee¼54%).
Although this result could have been probably optimized
by modifying the reaction conditions, an enantioselective
allyltitanation of aldehyde 12 with the allyltitanium complex
(S,S)-IV [generated from allylmagnesium chloride and
the corresponding ((S,S)-TADDOL)CpTiCl complex]68 in
THF/Et2O at ꢁ78 ꢀC afforded (R)-13 in much better yield
and enantiomeric excess (82% yield, ee¼99%) (Scheme 14).
18
4
OH
N
15
9
5
2
7
Br
Br
S
Reagent
III or (S,S)-IV
4
4
13
O
OH
11
N
N
33
PPTS
THF/H2O, 50 °C
OMe
OMe
9
20
5
5
6
6
2
2
7
7
H
S
S
10
Et2O, -78 °C
18
(R)-13
12
4
Ph
OH
N
15
O
Ph
O
9
5
Ti
O
2
7
B
S
13
11
O
R
Ph
Ph
34
R = CHO
NaClO2, NaH2PO4
amylene
2
Reagent
III
(S,S)-IV
t-BuOH/H2O, 0 °C
35
36
R = CO2H
R = CON3
Yield of (R)-13
ee of (R)-13
70%
54%
82%
99%
DPPA, Et3N
toluene, rt
110 °C
37 R = NCO
38 R = NH2
Scheme 14. Formal enantioselective approach.
ClCO2Me, Et3N
then MeOH (see text)
(33% from 33)
The (R) configuration of the homoallylic alcohol 13 obtained
from these reactions was attributed on the basis of the known
face-selectivities of the chiral allylating reagents and parti-
cularly the allyltitanium complex IV, which displays an
extremely high face-selectivity regardless of the nature of
the aldehydes.68
OH
N
O
S
39
O
N
H
(originally proposed structure of mycothiazole)
Scheme 13. Completion of the synthesis of the originally proposed structure
of mycothiazole.
5. Conclusion
In summary, unsaturated sultones have been generated from
primary or secondary unsaturated alcohols by RCM of the
corresponding unsaturated sulfonates. The b,g-unsaturated
seven-membered ring sultones have been converted to
homoallylic conjugated (Z)-dienols by sequential metalation
and electrophilic trapping, first with an alkyl halide and then
with the carbenoid ICH2MgCl. This methodology has been
applied to the synthesis of originally proposed structure of
(ꢂ)-mycothiazole, which has been achieved in 18 steps
from 2,4-dibromothiazole with an overall yield of 5%. The
side-chain at C2 was introduced in a stepwise fashion by
using a chemoselective prenylation, an aldehyde allylation,
a chain-extension of a homoallylic alcohol to a conjugated
(Z)-dienol, proceeding through an intermediate unsaturated
sultone, and a Curtius rearrangement. The installation of
the side-chain at C4 was based on a one carbon homologa-
tion followed by a Stille coupling. A formal enantioselective
approach has also been demonstrated with the preparation of
the secondary homoallylic alcohol 13 in high enantiomeric
purity (ee¼99%). In principle, we could effectively access
to mycothiazole by a similar strategy described herein, using
1
Although the H NMR data of compound 39 were in good
agreement with those previously reported for natural myco-
thiazole,6 as well as for the synthetic material corresponding
to the originally proposed structure [compound (ꢁ)-39],9 the
13C NMR data were only in perfect agreement with those of
the synthetic material. Indeed, some discrepancies were
noted between the chemical shifts of some carbons of the
2,5-hexadienyl side-chain at C4 and those reported for the
natural product. In particular, signals corresponding to C14
and C17 (present numbering system) in compound 39
appeared significantly upfield. Differences between the
observed analytical data of mycothiazole and the synthetic
sample were initially attributed to the lability of the natural
product,6,9 but recently the configuration of the C14–C15
disubstituted double bond was reassigned to (Z) on the basis
of a 600 MHz 1H NMR spectrum and NOE experiments.65
We had thus completed a racemic synthesis of the originally
proposed structure of mycothiazole and not of the natural
product itself.66

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9025
(Z)-1-tributylstannylpenta-1,4-diene69 instead of its (E) geo-
metric isomer in Stille coupling that served to elaborate the
2,5-hexadienyl side-chain at the C4 position of the thiazole
ring.
flash chromatography (petroleum ether/EtOAc 80:20),
650 mg (87%) of 1b were obtained as a colorless oil; IR
3060, 1640, 1360, 1175, 960, 910, 835, 800, 735 cmꢁ1
;
1H NMR d 6.50 (dd, J¼16.6, 9.9 Hz, 1H), 6.34 (d,
J¼16.6 Hz, 1H), 6.11 (d, J¼9.9 Hz, 1H), 5.71 (ddt, J¼
16.9, 10.3, 6.6 Hz, 1H), 5.15–5.04 (m, 2H), 4.09 (t,
J¼6.6 Hz, 2H), 2.43 (apparent q, J¼6.6 Hz, 2H); 13C
NMR d 132.3 (d), 132.2 (d), 130.2 (t), 118.2 (t), 69.7 (t),
33.0 (t); EIMS m/z (relative intensity) 121 (MꢁC3H+5, 31),
91 (100), 55 (13), 54 (69). Anal. Calcd for C6H10O3S: C,
44.43; H, 6.21. Found: C, 44.26; H, 6.35.
6. Experimental
6.1. General procedures
IR spectra were recorded on a Perkin–Elmer 298. 1H NMR
spectra were recorded at 300 MHz in CDCl3 and data
were reported as follows: chemical shift in parts per million
from tetramethylsilane as an internal standard, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet
or overlap of nonequivalent resonances), integration. 13C
NMR spectra were recorded at 75 MHz in CDCl3 and data
were reported as follows: chemical shift in parts per million
from tetramethylsilane with the solvent as an internal indica-
tor (CDCl3 d 77.0 ppm), multiplicity with respect to proton
(deduced from DEPT experiments, s¼quaternary C,
d¼CH, t¼CH2, q¼CH3). THF and diethyl ether were dis-
tilled from sodium/benzophenone. CH2Cl2, benzene, tolu-
ene, Et3N, NMP, i-Pr2NEt, DMF, and HMPA were distilled
from CaH2. Other reagents were obtained from commercial
suppliers and used as received. TLC was performed on silica
gel plates visualized either with a UV lamp (254 nm), or by
using solutions of p-anisaldehyde/sulfuric acid/acetic acid in
EtOH or KMnO4/K2CO3 in water followed by heating. Flash
chromatography was performed on silica gel (230–400
mesh).
6.2.1.4. Allyl allylsulfonate (1c). This compound was
prepared from allyl alcohol (380 mL, 5.60 mmol,
1.05 equiv), Et3N (820 mL, 5.90 mmol, 1.1 equiv), and allyl-
sulfonyl chloride (750 mg, 5.30 mmol, 1.0 equiv) according
to the general procedure. After purification by flash chroma-
tography (petroleum ether/EtOAc 70:30), 660 mg (76%) of
1c were obtained as a colorless oil; IR 1640, 1355, 1160,
1
960, 940, 925, 880, 825 cmꢁ1; H NMR d 6.01–5.82 (m,
2H), 5.50–5.43 (m, 2H), 5.45 (dq, J¼17.0, 1.5 Hz, 1H),
5.36 (dq, J¼10.3, 1.1 Hz, 1H), 4.71 (dt, J¼5.9, 1.5 Hz,
2H), 3.86 (dt, J¼7.4, 1.1 Hz, 2H); 13C NMR d 130.4 (d),
124.3 (t and d, 2C), 120.4 (t), 70.9 (t), 55.0 (t); EIMS m/z
(relative intensity) 121 (MꢁC3H+5, 3), 106 (21), 97 (8), 83
(29), 81 (16), 80 (21), 79 (14), 69 (59), 67 (57), 57 (80),
56 (44), 55 (64), 54 (100). Anal. Calcd for C6H10O3S: C,
44.43; H, 6.21. Found: C, 44.45; H, 6.24.
6.2.1.5. But-3-enyl allylsulfonate (1d). This compound
was prepared from but-3-en-1-ol (485 mL, 5.60 mmol,
1.05 equiv), Et3N (825 mL, 5.86 mmol, 1.1 equiv), and allyl-
sulfonyl chloride (750 mg, 5.33 mmol, 1.0 equiv) according
to the general procedure. After purification by flash chroma-
tography (petroleum ether/EtOAc 75:25), 850 mg (90%) of
1d were obtained as a colorless oil; IR 3080, 1640, 1360,
6.2. Synthesis of unsaturated sultones by RCM
6.2.1. Synthesis of unsaturated sulfonates derived from
primary alcohols.
6.2.1.1. General procedure. To a solution of an
unsaturated primary alcohol (1.0–1.1 equiv) and Et3N
(1.1–1.2 equiv) in CH2Cl2 (1 M) at 0 ꢀC was added dropwise
a solution of an unsaturated sulfonyl chloride (1.0 equiv) in
CH2Cl2 (1 M). After 0.5 to 1 h at rt, the reaction mixture was
diluted with pentane and filtered through Celite. The filtrate
was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel.
1
1170, 960, 910, 820, 740, 640 cmꢁ1; H NMR d 5.88 (ddt,
J¼16.2, 10.6, 7.3 Hz, 1H), 5.76 (ddt, J¼17.2, 10.3, 6.6 Hz,
1H), 5.48–5.40 (m, 2H), 5.19–5.09 (m, 2H), 4.25 (t,
J¼6.6 Hz, 2H), 3.82 (dt, J¼7.3, 1.5 Hz, 2H), 2.47 (apparent
qt, J¼6.6, 1.3 Hz, 2H); 13C NMR d 132.3 (d), 124.3 (d),
124.0 (t), 118.0 (t), 69.4 (t), 54.3 (t), 33.2 (t). Anal. Calcd
for C7H12O3S: C, 47.71; H, 6.86. Found: C, 47.81; H, 6.94.
6.2.1.2. Allyl vinylsulfonate (1a). This compound was
prepared from allyl alcohol (300 mL, 4.35 mmol, 1.1 equiv),
Et3N (610 mL, 4.35 mmol, 1.1 equiv), and vinylsulfonyl
chloride (500 mg, 3.95 mmol, 1.0 equiv) according to the
general procedure. After purification by flash chromato-
graphy, (petroleum ether/EtOAc 80:20), 150 mg (40%) of
1a were obtained as a colorless oil; IR 3060, 1650, 1610,
6.2.1.6. Pent-4-enyl allylsulfonate (1e). This compound
was prepared from pent-4-en-1-ol (400 mL, 3.92 mmol,
1.1 equiv), Et3N (600 mL, 4.27 mmol, 1.2 equiv), and allyl-
sulfonyl chloride (500 mg, 3.56 mmol, 1.0 equiv) according
to the general procedure. After purification by flash chroma-
tography (petroleum ether/EtOAc 90:10 to 80:20), 560 mg
(83%) of 1e were obtained as a colorless oil; IR 3070,
1
1360, 1175, 940 (br), 920, 845, 810, 740 cmꢁ1; H NMR
1640, 1350, 1160, 970, 920, 830, 640 cmꢁ1 1H NMR
;
d 6.52 (dd, J¼16.5, 9.5 Hz, 1H), 6.37 (d, J¼16.5 Hz, 1H),
6.12 (d, J¼9.5 Hz, 1H), 5.89 (ddt, J¼17.3, 10.3, 5.9 Hz,
1H), 5.38 (dq, J¼17.3, 1.5 Hz, 1H), 5.31 (dq, J¼10.3,
1.5 Hz, 1H), 4.57 (dt, J¼5.9, 1.5 Hz, 2H); 13C NMR
d 132.5 (d), 130.2 (t), 130.1 (d), 120.5 (t), 71.0 (t).
d 5.86 (ddt, J¼16.9, 9.9, 7.3 Hz, 1H), 5.74 (ddt, J¼16.9,
10.3, 6.6 Hz, 1H), 5.42 (dq, J¼10.3, 1.5 Hz, 1H), 5.41
(dq, J¼16.9, 1.5 Hz, 1H), 5.05–4.95 (m, 2H), 4.19
(t, J¼6.6 Hz, 2H), 3.79 (dt, J¼7.0, 1.1 Hz, 2H), 2.13
(m, 2H), 1.79 (m, 2H); 13C NMR d 136.5 (d), 124.4 (d),
124.1 (t), 115.7 (t), 69.9 (t), 54.5 (t), 29.2 (t), 28.2 (t).
Anal. Calcd for C8H14O3S: C, 50.50; H, 7.42. Found: C,
50.36; H, 7.48.
6.2.1.3. But-3-enyl vinylsulfonate (1b). This compound
was prepared from but-3-en-1-ol (360 mL, 4.15 mmol,
1.05 equiv), Et3N (610 mL, 4.35 mmol, 1.1 equiv), and
vinylsulfonyl chloride (500 mg, 3.95 mmol, 1.0 equiv)
according to the general procedure. After purification by
6.2.1.7. But-4-enyl but-3-ene-1-sulfonate (1f). This
compound was prepared from but-3-en-1-ol (0.85 mL,

9026
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9.8 mmol, 1.0 equiv), Et3N (1.5 mL, 11 mmol, 1.1 equiv),
and (but-3-enyl)sulfonyl chloride (1.5 g, 9.8 mmol,
1.0 equiv) according to the general procedure. After purifi-
cation by flash chromatography (petroleum ether/EtOAc
70:30), 1.7 g (90%) of 1f were obtained as a colorless oil;
(33), 65 (10), 54 (22), 53 (13); HRMS (CI+, CH4) calcd
for C4H7O3S (M+H+): 135.0116. Found: 135.0118.
6.2.2.5. 2,7-3H-Dihydro-[1,2]oxathiepine-2,2-dioxide
(2d). This compound was prepared from 1d (100 mg,
0.568 mmol) by using catalyst II (24 mg, 0.028 mmol,
0.02 equiv) in C6H6 (57 mL) for 2 h at 70 ꢀC. After purifica-
tion by flash chromatography (petroleum ether/EtOAc
75:25), 84 mg (100%) of 2d were obtained as a pale brown
solid; mp 78 ꢀC; IR 1650, 1370, 1270, 1160, 975, 910, 880,
1
IR 3080, 1640, 1360, 1170, 1160, 955, 905, 825 cmꢁ1; H
NMR d 5.84–5.67 (m, 2H), 5.16–5.04 (m, 4H), 4.20 (t,
J¼6.6 Hz, 2H), 3.15–3.09 (m, 2H), 2.58–2.49 (m, 2H),
2.49–2.40 (m, 2H); 13C NMR d 133.6 (d), 132.4 (d), 118.2
(t), 117.1 (t), 68.6 (t), 49.4 (t), 33.3 (t), 27.5 (t); EIMS m/z
(relative intensity) 136 (MꢁC4H+6, 0.5), 119 (6), 108 (3),
93 (4), 79 (3), 67 (5), 55 (100), 54 (80). Anal. Calcd for
C8H14O3S: C, 50.50; H, 7.41. Found: C, 50.20; H, 7.61.
1
840, 805, 740 cmꢁ1; H NMR d 6.25–6.16 (m, 1H), 5.80–
5.71 (m, 1H), 4.52–4.48 (m, 2H), 4.02 (apparent br d,
J¼6.2 Hz, 2H), 2.65 (m, 2H); 13C NMR d 134.8 (d), 119.4
(d), 72.5 (t), 51.1 (t), 28.8 (t); EIMS m/z (relative intensity)
148 (M+, 1), 83 (4), 67 (100), 55 (18), 54 (87), 53 (14). Anal.
Calcd for C5H8O3S: C, 40.53; H, 5.44. Found: C, 40.61; H,
5.60.
6.2.2. Synthesis of unsaturated sultones derived from
primary alcohols.
6.2.2.1. General procedure. To a degassed solution of
an unsaturated sulfonate 1a–f in C6H6 (0.05–0.01 M) (argon
bubbling, 15 min) was added catalyst I or catalyst II (0.015–
0.05 equiv) and the resulting solution was heated at 70 ꢀC.
After 0.5 to 3 h, the reaction mixture was cooled to rt,
concentrated under reduced pressure, and the residue was
purified by flash chromatography on silica gel.
6.2.2.6.
dioxide (2e). This compound was prepared from 1e
(150 mg, 0.788 mmol) by using catalyst (33 mg,
3,4,7,8-Tetrahydro-[1,2]oxathiocine-2,2-
I
0.040 mmol, 0.05 equiv) in C6H6 (75 mL) for 3 h at 70 ꢀC.
After purification by flash chromatography (petroleum
ether/ether 95:5 to 90:10), 120 mg (94%) of 2e were
obtained as a pale brown waxy solid; mp<50 ꢀC; IR 1650,
1380, 1275, 1265, 1250, 1150, 1060, 990, 945, 930, 820,
6.2.2.2. 5H-[1,2]Oxathiole-2,2-dioxide (2a). This
compound was prepared from 1a (150 mg, 1.03 mmol) by
using catalyst II (21 mg, 0.025 mmol, 0.025 equiv) in
C6H6 (33 mL) at 70 ꢀC for 1 h. After purification by flash
chromatography (petroleum ether/EtOAc 70:30), 121 mg
(100%) of 2a were obtained as pale brown solid; mp
85 ꢀC; IR 1610, 1345, 1180, 1090, 1000, 920, 870,
1
790, 760 cmꢁ1; H NMR d 6.03–5.93 (m, 1H), 5.77–5.69
(m, 1H), 4.36 (t, J¼5.9 Hz, 2H), 3.91 (apparent dd, J¼7.7,
0.8 Hz, 2H), 2.42–2.32 (m, 2H), 1.99–1.91 (m, 2H); 13C
NMR d 136.6 (d), 118.6 (d), 71.0 (t), 48.5 (t), 26.6 (t), 22.9
(t); EIMS m/z (relative intensity) 162 (M+, 3), 98 (MꢁSO2+,
74), 97 (52), 80 (35), 67 (87), 57 (31), 56 (100), 53 (32);
HRMS (CI+, CH4) calcd for C6H11O3S (M+H+): 163.0429.
Found: 163.0427.
1
750 cmꢁ1; H NMR d 7.03 (dt, J¼6.6, 2.0 Hz, 1H), 6.81
(dt, J¼6.6, 2.4 Hz, 1H), 5.11 (dd, J¼2.4, 2.0 Hz, 2H); 13C
NMR d 136.8 (d), 124.3 (d), 72.2 (t); EIMS m/z (relative
intensity) 120 (M+, 40), 91 (24), 66 (100), 65 (28), 56
(10), 55 (11). Anal. Calcd for C3H4O3S: C, 29.99; H, 3.36.
Found: C, 30.10; H, 3.47.
6.2.2.7.
3,4,7,8-Tetrahydro-[1,2]oxathiocine-2,2-
dioxide (2f). This compound was prepared from 1f (650
mg, 3.42 mmol) by using catalyst I (140 mg, 0.170 mmol,
0.05 equiv) in C6H6 (350 mL) for 4 h at 70 ꢀC. After purifi-
cation by flash chromatography (petroleum ether/ether
50:50), 550 mg (99%) of 2f were obtained as a pale brown
solid; mp 62 ꢀC; IR 1350, 1165, 1010, 980, 965, 920, 880,
6.2.2.3. 5,6-Dihydro-[1,2]oxathiine-2,2-dioxide (2b).
This compound was prepared from 1b (400 mg,
2.47 mmol) by using catalyst II (42 mg, 0.049 mmol,
0.02 equiv) in C6H6 (50 mL) at 70 ꢀC for 3 h. After purifica-
tion by flash chromatography (petroleum ether/EtOAc
60:40), 300 mg (90%) of 2b were obtained as pale brown
solid; mp 90 ꢀC; IR 1620, 1355, 1345, 1180, 970, 920,
1
770, 740 cmꢁ1; H NMR d 5.97–5.79 (m, 2H), 4.25 (t,
J¼5.9 Hz, 2H), 3.31–3.27 (m, 2H), 2.63–2.52 (m, 4H); 13C
NMR d 130.4 (d), 127.8 (d), 68.9 (t), 53.7 (t), 26.9 (t),
20.8 (t); EIMS m/z (relative intensity) 162 (M+, 2), 80
(66), 79 (13), 68 (78), 67 (100), 53 (26). Anal. Calcd for
C6H10O3S: C, 44.43; H, 6.21. Found: C, 44.55; H, 6.30.
1
860, 825 cmꢁ1; H NMR d 6.60–6.49 (m, 2H), 4.79 (t,
J¼5.7 Hz, 2H), 2.57–2.51 (m, 2H); 13C NMR d 137.0 (d),
126.7 (d), 69.4 (t), 24.4 (t); EIMS m/z (relative intensity)
134 (M+, 50), 104 (100), 76 (23), 70 (15), 69 (39), 68 (11),
55 (100). Anal. Calcd for C4H6O3S: C, 35.81; H, 4.51.
Found: C, 35.86; H, 4.65.
6.2.3. Preparation of sultone 2g from 1d.
6.2.3.1. But-3-enyl but-1-ene-3-sulfonate (1g). To a
solution of sulfonate 1d (1.0 g, 5.7 mmol) in THF (30 mL)
at ꢁ78 ꢀC was added n-BuLi (2.3 mL, 2.5 M in hexanes,
5.7 mmol, 1.0 equiv). After 1.5 h at ꢁ78 ꢀC, CH3I (1.1 mL,
17 mmol, 3.0 equiv) was added. After a further 1.5 h at
ꢁ78 ꢀC, the reaction mixture was hydrolyzed with a satu-
rated aqueous solution of NH4Cl and extracted with ether.
The combined extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. After purification
by flash chromatography (petroleum ether/EtOAc 80:20),
900 mg (84%) of 1g were obtained as a colorless oil;
6.2.2.4. 3,6-Dihydro-[1,2]oxathiine-2,2-dioxide (2c).
This compound was prepared from 1c (400 mg,
2.50 mmol) by using catalyst II (52 mg, 0.06 mmol,
0.025 equiv) in C6H6 (82 mL) for 3 h at 70 ꢀC. After purifi-
cation by flash chromatography (petroleum ether/EtOAc
60:40), 335 mg (99%) of 2c were obtained as a waxy beige
solid; mp<50 ꢀC; IR 1640, 1360, 1170, 1130, 1030, 940,
1
885, 860, 800, 720 cmꢁ1; H NMR d 5.95–5.88 (m, 1H),
5.84–5.77 (m, 1H), 5.07–5.03 (m, 2H), 3.82–3.78 (m, 2H);
13C NMR d 123.6 (d), 119.0 (d), 72.5 (t), 46.6 (t); EIMS
m/z (relative intensity) 134 (M+, 1), 70 (MꢁSO2+, 100), 69
IR 3080, 1640, 1350, 1170, 960, 910, 820, 790, 650 cmꢁ1
;
1H NMR d 5.88 (ddd, J¼17.3, 10.3, 7.7 Hz, 1H), 5.74

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9027
(ddt, J¼17.0, 10.0, 6.6 Hz, 1H), 5.38 (dt, J¼17.0, 1.1 Hz,
1H), 5.37 (dt, J¼10.0, 1.1 Hz, 1H), 5.16–5.07 (m, 2H),
4.22 (t, J¼6.6 Hz, 2H), 3.80 (m, 1H), 2.44 (apparent qt,
J¼6.6, 1.5 Hz, 2H), 1.50 (d, J¼7.0 Hz, 3H); 13C NMR
d 132.4 (d), 130.9 (d), 121.3 (t), 118.1 (t), 69.3 (t), 60.1
(d), 33.5 (t), 14.2 (q); EIMS m/z (relative intensity) 148
(M+, 0.1), 136 (4), 81 (2), 71 (3), 56 (5), 55 (100), 54 (22),
53 (6). Anal. Calcd for C8H14O3S: C, 50.50; H, 7.42. Found:
C, 50.15; H, 7.63.
d 138.2 (s), 136.6 (d), 128.3 (d, 2C), 127.5 (d, 3C), 126.0
(d), 82.0 (d), 72.8 (t), 70.0 (t), 31.5 (t), 30.1 (t), 24.7 (t);
EIMS m/z (relative intensity) 282 (M+, 4), 173 (4), 161
(5), 107 (50), 105 (12), 91 (100), 79 (12), 65 (10). Anal.
Calcd for C14H18O4S: C, 59.55; H, 6.43. Found: C, 59.39;
H, 6.59.
6.2.4.3. Ethyl (2,2-dioxo-5,6-dihydro-2l6-[1,2]oxa-
thiine-6-yl)formate (2i). This compound was synthesized
according to the general procedure from ethyl 2-hydroxy-
pent-4-enoate (1.75 g, 12.2 mmol), Et3N (1.88 mL,
13.4 mmol, 1.1 equiv), and vinylsulfonyl chloride (1.69+
0.31 g, 13.4+2.4 mmol, 1.1+0.2 equiv) in THF (30 mL).
The crude sulfonate was then treated with catalyst II
(200 mg, 0.235 mmol, 0.02 equiv) in C6H6 (120 mL). After
purification by flash chromatography (petroleum ether/
EtOAc 80:20), 1.35 g (54%) of 2i were obtained as a pale
brown oil; IR 3060, 1750, 1360, 1330, 1305, 1230, 1180,
6.2.3.2. 3-Methyl-6,7-dihydro-3H-[1,2]oxathiepine-
2,2-dioxide (2g). To a solution of 1g (900 mg, 4.74 mmol)
in C6H6 (100 mL) was added catalyst II (10 mg,
0.12 mmol, 0.025 equiv). After 2 h at 70 ꢀC, the reaction
mixture was cooled to rt, concentrated under reduced pres-
sure, and the crude material was purified by flash chromato-
graphy (petroleum ether/ether 70:30) to afford 450 mg
(60%) of 2g as a colorless oil; IR 3030, 1460, 1355, 1275,
1
1170, 1005, 975, 950, 890, 840, 780, 750 cmꢁ1; H NMR
1155, 1030, 950, 910, 835, 730, 685 cmꢁ1 1H NMR
;
d 6.11 (dddd, J¼11.2, 7.7, 5.9, 1.8 Hz, 1H), 5.55 (ddd,
J¼11.2, 5.1, 1.8 Hz, 1H), 4.60–4.53 (m, 1H), 4.46–4.39
(m, 1H), 4.19–4.09 (m, 1H), 2.73–2.60 (m, 1H), 2.52–2.42
(m, 1H), 1.60 (d, J¼7.4 Hz, 3H); 13C NMR d 132.8 (d),
127.5 (d), 72.7 (t), 57.3 (d), 28.4 (t), 15.3 (q); EIMS m/z (rel-
ative intensity) 162 (M+, 0.5), 120 (10), 97 (17), 83 (36), 81
(28), 80 (16), 69 (18), 68 (100), 67 (60), 55 (16), 53 (24).
d 6.64–6.51 (m, 2H), 5.36 (dd, J¼9.2, 6.6 Hz, 1H), 4.29
(q, J¼7.2 Hz, 2H), 2.73 (m, 2H), 1.31 (t, J¼7.2 Hz, 3H);
13C NMR d 165.7 (s), 135.9 (d), 126.2 (d), 76.2 (d), 62.5
(t), 27.0 (t), 13.9 (q); EIMS m/z (relative intensity) 178
(MꢁEt+, 2), 161 (MꢁOEt+, 4), 134 (12), 133 (MꢁCO2Et+,
100), 125 (33), 115 (10), 106 (6), 97 (45), 89 (22), 87 (12), 85
(11), 69 (22), 68 (29), 57 (9); HRMS (CI+, CH4) calcd for
C7H11O5S (M+H+): 207.0327. Found: 207.0327.
6.2.4. Synthesis of unsaturated sultones derived from
secondary alcohols.
6.2.4.4.
(2,2-Dioxo-3,6-dihydro-2H-2l6-[1,2]oxa-
6.2.4.1. General procedure. To a solution of the unsatu-
rated secondary alcohols 1h–l and Et3N (1.1–2.0 equiv) in
THF at ꢁ15 ꢀC was added dropwise a solution of the appro-
priate sulfonyl chloride (1.1–1.5 equiv) in THF. After 1 h
at ꢁ15 ꢀC, an additional quantity of sulfonyl chloride
(0.2–0.5 equiv) was generally added to ensure complete
conversion. After 1 h at ꢁ15 ꢀC, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NaHCO3
and extracted with Et2O. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was filtered through a short
plug of silica gel (Et2O) and the filtrate was evaporated under
reduced pressure. The crude sulfonates 2h–l were dissolved
in benzene (0.08–0.06 M) and to the resulting degassed
solution (argon bubbling, 15 min) was added catalyst II
(0.01–0.05 equiv). After 1 h at 70 ꢀC, the reaction mixture
was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel.
thiine-6-yl)methyl-2,2-dimethyl propanoate (2j). This
compound was synthesized according to the general proce-
dure from 2-hydroxybut-3-enyl 2,2-dimethyl propanoate
(2.10 g, 12.2 mmol), Et3N (3.4 mL, 24.4 mmol, 2.0 equiv),
and allylsulfonyl chloride (1.9+0.34 g, 13.5+2.4 mmol,
1.1+0.2 equiv) in THF (30 mL). The crude sulfonate was
then treated with catalyst II (49 mg, 0.057 mmol,
0.05 equiv) in C6H6 (120 mL). After purification by flash
chromatography (petroleum ether/EtOAc 80:20), 2.24 g
(74%) of 2j were obtained as a colorless oil; IR 1730,
1625, 1480, 1360, 1280, 1160, 915, 805, 770, 740, 680,
1
630 cmꢁ1; H NMR d 5.94–5.81 (m, 2H), 5.38 (m, 1H),
4.43 (dd, J¼12.3, 6.0 Hz, 1H), 4.29 (dd, J¼12.3, 3.5 Hz,
1H), 3.91–3.80 (m, 1H), 3.78–3.66 (m, 1H), 1.20 (s, 9H);
13C NMR d 177.8 (s), 124.0 (d), 120.9 (d), 82.1 (d), 63.1
(t), 46.0 (t), 38.7 (s), 26.9 (q, 3C); EIMS m/z (relative inten-
sity) 249 (M+H+, 0.1), 233 (MꢁMe+, 0.1), 218 (1), 146
(Mꢁt-BuCO2H+, 14), 128 (5), 85 (31), 81 (6), 69 (12), 67
(9), 57 (100); HRMS (CI+, CH4) calcd for C10H17O5S
(M+H+): 249.0797. Found: 249.0798.
6.2.4.2. 6-[(3-Benzyloxy)propyl]-5,6-dihydro-[1,2]oxa-
thiine-2,2-dioxide (2h). This compound was synthesized
according to the general procedure from 7-benzyloxy-
hept-1-en-4-ol (2.0 g, 9.0 mmol), Et3N (1.5 mL, 11 mmol,
1.2 equiv), and vinylsulfonyl chloride (1.40+0.28 g,
11.0+2.2 mmol, 1.2+0.2 equiv) in THF (30 mL). The crude
sulfonate was then treated with catalyst II (55 mg,
0.070 mmol, 0.011 equiv) in C6H6 (150 mL). After purifica-
tion by flash chromatography (petroleum ether/EtOAc
70:30), 1.60 g (65%) of 2h were obtained as a pale brown
waxy solid; IR 3030, 1615, 1330, 1170, 1150, 1090, 880,
6.2.4.5. 6-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2,2-
dioxo-3,6-dihydro-2H-2l6-[1,2]oxathiine (2k). This com-
pound was synthesized according to the general procedure
from 1-(tert-butyldimethylsilyloxy)but-3-en-2-ol (1.6 g, 4.9
mmol), Et3N (1.4 mL, 10 mmol, 2.05 equiv), and allylsul-
fonyl chloride (0.78+0.34 g, 5.5+2.5 mmol, 1.1+0.5 equiv)
in THF (22 mL). The crude sulfonate was then treated with
catalyst II (42 mg, 0.05 mmol, 0.01 equiv) in C6H6
(75 mL). After purification by flash chromatography (petro-
leum ether/EtOAc 90:10 to 85:15), 1.3 g (65%) of 2k were
obtained as a white solid; mp 106–108 ꢀC; 1H NMR
d 7.71–7.66 (m, 4H), 7.50–7.39 (m, 6H), 5.97–5.91 (m,
1H), 5.89–5.82 (m, 1H), 5.27 (m, 1H), 3.95 (dd, J¼11.4,
1
820, 735, 700 cmꢁ1; H NMR d 7.40–7.26 (m, 5H), 6.54
(ddd, J¼10.7, 2.6, 1.3 Hz, 1H), 6.47 (ddd, J¼10.7, 4.4,
2.3 Hz, 1H), 4.98 (m, 1H), 4.51 (s, 2H), 3.60–3.48 (m,
2H), 2.51–2.29 (m, 2H), 1.97–1.68 (m, 4H); 13C NMR

9028
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
5.1 Hz, 1H), 3.89 (dd, J¼11.4, 5.1 Hz, 1H), 3.83 (m, 1H),
3.74–3.65 (m, 1H), 1.09 (s, 9H); 13C NMR d 135.4 (d, 4C),
132.6 (s, 2C), 129.9 (d, 2C), 127.7 (d, 4C), 125.4 (d), 119.7
(d), 84.3 (d), 64.1 (t), 46.2 (t), 26.6 (q, 3C), 19.1 (s); EIMS
m/z (relative intensity) 266 (24, MꢁSO2ꢁC4H+8), 265
(MꢁSO2ꢁt-Bu+, 100), 247 (6), 237 (11), 199 (43), 197
(12), 187 (42), 183 (12), 181 (10). Anal. Calcd for
C21H26O4SSi: C, 62.65; H, 6.51. Found: C, 62.49; H, 6.68.
Minor diastereomer: 1H NMR d 7.38–7.25 (m, 10H), 6.45 (d,
J¼9.9 Hz, 2H), 6.25 (dd, J¼10.7, 7.7 Hz, 2H), 6.06 (dd,
apparent br t, J¼10.7, 9.9 Hz, 2H), 4.51 (s, 4H), 3.70–3.61
(m, 2H), 3.55–3.44 (m, 4H), 3.16 (br s, 2H, OH), 2.33–
2.22 (m, 4H), 1.78–1.45 (m, 8H); 13C NMR d 140.4 (d,
2C), 137.8 (s, 2C), 128.3 (d, 6C), 127.7 (d, 4C), 114.7
(d, 2C), 98.8 (d, 2C), 73.0 (t, 2C), 70.1 (d, 2C), 69.8 (t,
2C), 36.2 (t, 2C), 34.6 (t, 2C), 26.2 (t, 2C).
6.2.4.6.
7-[3-(Benzyloxy)propyl]-6,7-dihydro-3H-
6.3.2. (3R* or S*,7S*)-7-[(3-Benzyloxy)propyl]-3-methyl-
3H-[1,2]oxathiepine-2,2-dioxide (6). To a solution of
sultone 2l (100 mg, 0.336 mmol) in THF (5 mL) at
ꢁ78 ꢀC was added n-BuLi (200 mL, 2.5 M in hexanes,
0.500 mmol, 1.5 equiv). After 1 h at ꢁ78 ꢀC, CH3I (84 mL,
1.34 mmol, 4.0 equiv) was added. After 15 min at ꢁ78 ꢀC,
the reaction mixture was hydrolyzed with a saturated aque-
ous solution of NH4Cl and extracted with ether. The com-
bined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether/ether
80:20) to afford 87 mg (85%) of 6 as a colorless oil and as
a single diastereomer (unassigned relative configuration);
IR 3020, 1450, 1340, 1170, 1160, 1100, 945, 910, 810,
[1,2]oxathiepine-2,2-dioxide (2l). This compound was
synthesized according to the general procedure from 7-ben-
zyloxy-hept-1-en-3-ol (1.0 g, 4.5 mmol), Et3N (1.3 mL,
9.2 mmol, 2.0 equiv), and allylsulfonyl chloride (1.0+
0.34 g, 7.1+2.4 mmol, 1.5+0.5 equiv) in THF (21 mL).
The crude sulfonate was treated with catalyst II (98 mg,
0.12 mmol, 0.025 equiv) in C6H6 (75 mL). After purification
by flash chromatography (petroleum ether/EtOAc 70:30),
0.88 g (65%) of 2l were obtained as a colorless oil; IR
3030, 1495, 1450, 1360, 1180, 1160, 1100, 965, 905, 820,
740, 705, 700 cmꢁ1; H NMR d 7.39–7.26 (m, 5H), 6.13
1
(dddd, J¼11.0, 8.8, 4.8, 2.4 Hz, 1H), 5.74 (dddd, J¼11.0,
8.1, 4.8, 2.6 Hz, 1H), 4.84–4.76 (m, 1H), 4.50 (s, 2H),
4.16–4.08 (m, 1H), 3.83 (dd, J¼15.8, 8.5 Hz, 1H), 3.57–
3.45 (m, 2H), 2.74–2.62 (m, 1H), 2.39 (ddd, apparent br d,
J¼16.6, 8.5, 1.1 Hz, 1H), 1.88–1.68 (m, 4H); 13C NMR
d 138.3 (s), 133.9 (d), 128.3 (d, 2C), 127.5 (d, 2C), 127.4
(d), 119.3 (d), 85.1 (d), 72.8 (t), 69.1 (t), 50.5 (t), 34.2 (t),
32.2 (t), 25.2 (t); EIMS m/z (relative intensity) 296 (M+,
3), 215 (MꢁSO3ꢁH+, 16), 173 (4), 161 (4), 160 (4), 131
(4), 117 (3), 108 (11), 107 (46), 92 (16), 91 (10), 80 (12),
79 (17), 71 (20), 67 (11), 54 (10). Anal. Calcd for
C15H20O4S: C, 60.79; H, 6.80. Found: C, 60.74; H, 6.94.
1
740, 700 cmꢁ1; H NMR d 7.39–7.26 (m, 5H), 5.92 (ddd,
J¼12.0, 7.7, 4.4 Hz, 1H), 5.69 (ddd, J¼12.0, 7.0, 2.0 Hz,
1H), 4.82 (m, 1H), 4.50 (s, 2H), 3.97 (apparent quintet,
J¼7.2 Hz, 1H), 3.59–3.41 (m, 2H), 2.64 (m, 1H), 2.44–
2.34 (m, 1H), 1.90–1.67 (m, 4H), 1.62 (d, J¼7.4 Hz, 3H);
13C NMR d 138.3 (s), 130.8 (d), 128.2 (d, 2C), 127.5 (d,
2C), 127.4 (d), 125.6 (d), 83.6 (d), 72.8 (t), 69.1 (t), 56.3
(d), 34.3 (t), 32.1 (t), 25.3 (t), 14.9 (q); EIMS m/z (relative
intensity) 310 (M+, 2), 229 (MꢁSO3H+, 13), 160 (8), 123
(14), 107 (40), 95 (11), 94 (12), 93 (12), 92 (15), 91 (100),
81 (16), 79 (15), 71 (18), 68 (18), 67 (16), 65 (10).
6.3. Synthesis of conjugated (Z)-dienols of type A
6.3.3. 3-Methyl-6,7-dihydro-3H-[1,2]oxathiepine-2,2-
dioxide (2g). To a solution of sultone 2d (150 mg,
1.01 mmol) in THF (15 mL) at ꢁ78 ꢀC, was added dropwise
n-BuLi (425 mL, 2.5 M in hexanes, 1.06 mmol, 1.05 equiv).
After 1 h at ꢁ78 ꢀC, CH3I (190 mL, 3.03 mmol, 3.0 equiv)
was added. After 15 min at ꢁ78 ꢀC, the reaction mixture
was hydrolyzed with a saturated aqueous solution of
NH4Cl and extracted with ether. The combined organic
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/ether 80:20) to afford
162 mg (92%) of 2g as a colorless oil. This compound has
previously been synthesized from sulfonate 1d by methyl-
ation and subsequent RCM, see Section 6.2.3.
6.3.1. trans- and cis-2,4-Bis((1Z)-7-benzyloxy-4-hydroxy-
hept-1-enyl)[1,3]dithietane-1,1,3,3-tetroxide (3). To a
solution of i-Pr2NH (0.14 mL, 1.0 mmol, 3.0 equiv) in THF
(2 mL) at ꢁ78 ꢀC was added n-BuLi (0.40 mL, 2.5 M in
hexanes, 1.0 mmol, 3.0 equiv). After 15 min at 0 ꢀC, the
resulting LDA solution was cooled to ꢁ78 ꢀC and a solution
of sultone 2l (100 mg, 0.337 mmol) in THF (2 mL) was
added. After 1 h at ꢁ78 ꢀC, the reaction mixture was hydro-
lyzed with a saturated aqueous solution of NH4Cl and
extracted with ether. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography
(petroleum ether/EtOAc 60:40 to 50:50) to afford 55 mg
(55%) of 3 as a colorless oil and as an apparent 60:40 mix-
ture of diastereomers; IR 3400 (br), 3020, 1640, 1450, 1350,
1155, 1080, 845, 740, 700 cmꢁ1; MS (CI+, NH3) m/z (rela-
tive intensity) 610 (M+NH+4, 77), 548 (10), 482 (22), 431
(20), 252 (16), 196 (100), 141 (13), 102 (55).
6.3.4. (3R* or S*,7R*)-3,7-Bis[(3-benzyloxy)propyl]-6,7-
dihydro-3H-[1,2]oxathiepine-2,2-dioxide (7). To a solution
of sultone 2l (150 mg, 0.507 mmol) in THF (10 mL) at
ꢁ78 ꢀC was added n-BuLi (250 mL, 2.5 M in hexanes,
0.625 mmol, 1.25 equiv). After 1 h at ꢁ78 ꢀC, a solution
of 3-benzyloxy-1-bromopropane (130 mL, 0.760 mmol,
1.5 equiv) and HMPA (350 mL, 2.03 mmol, 4.0 equiv) in
THF (2 mL) was added dropwise. After 1.5 h at ꢁ78 ꢀC,
the reaction mixture was hydrolyzed with a saturated aque-
ous solution of NH4Cl and extracted with ether. The com-
bined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether/ether
1
Major diastereomer: H NMR d 7.38–7.25 (m, 10H), 6.70
(d, J¼9.6 Hz, 2H), 6.27 (dd, J¼11.0, 7.7 Hz, 2H), 5.89
(dd, apparent br t, J¼11.0, 9.6 Hz, 2H), 4.51 (s, 4H), 3.70–
3.61 (m, 2H), 3.55–3.44 (m, 4H), 3.16 (br s, 2H, OH),
2.33–2.22 (m, 4H), 1.78–1.45 (m, 8H); 13C NMR d 140.0
(d, 2C), 137.8 (s, 2C), 128.3 (d, 6C), 127.7 (d, 4C), 113.3
(d, 2C), 97.0 (d, 2C), 73.0 (t, 2C), 70.2 (d, 2C), 69.8
(t, 2C), 36.4 (t, 2C), 34.7 (t, 2C), 26.2 (t, 2C).

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9029
80:20 to 75:25) to afford 188 mg (84%) of 7 as a colorless
oil and as a single diastereomer (unassigned relative
configuration); IR 3030, 1495, 1450, 1360, 1160, 1100,
(37), 105 (100), 95 (22), 93 (12), 82 (53), 79 (17), 71 (15),
67 (32).
1
910, 740, 705, 690 cmꢁ1; H NMR d 7.89–7.28 (m, 10H),
6.4. Total synthesis of the originally proposed structure
of mycothiazole
5.96 (ddd, J¼12.0, 7.5, 4.4 Hz, 1H), 5.68 (ddd, J¼12.0,
7.5, 2.2 Hz, 1H), 4.80 (m, 1H), 4.49 (s, 4H), 3.92 (m, 1H),
3.57–3.47 (m, 4H), 2.68–2.56 (m, 1H), 2.44–2.22 (m, 2H),
2.18–2.04 (m, 1H), 1.88–1.68 (m, 6H); 13C NMR d 138.3
(s), 138.1 (s), 131.4 (d), 128.3 (d, 2C), 128.2 (d, 2C),
127.5 (d, 4C), 127.4 (d, 2C), 124.6 (d), 83.6 (d), 72.9 (t),
72.8 (t), 69.4 (t), 69.1 (t), 60.7 (d), 34.4 (t), 32.1 (t), 26.8
(t, 2C), 25.3 (t).
6.4.1. Synthesis of the C4–C10 subunit.
6.4.1.1. 2,4-Dibromothiazole (10). A mixture of thia-
zolidine-2,4-dione (3.4 g, 29 mmol) and phosphorous oxy-
bromide (25 g, 87 mmol, 3.0 equiv) was heated at 110 ꢀC.
After 3 h, the reaction mixturewas cooled to rt and cautiously
hydrolyzed with crushed ice. The resulting mixture was
extracted with ether and the combined organic extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by chro-
matography (pentane/ether 99.5:0.5) to afford 4.8 g (68%)
of 10 as a white solid; mp 80–84 ꢀC; IR 3120, 1460, 1390,
1240, 1070, 1020, 880, 820, 740 cmꢁ1; 1H NMR d 7.22 (s,
1H); 13C NMR d 136.2 (s), 124.1 (s), 120.7 (d); EIMS m/z
(relative intensity) 245 (M[81Br2]+, 52), 243 (M[79Br81Br]+,
100), 241 (M[79Br]+, 52), 138 (30), 136 (30), 13 (30), 83
(13), 57 (27).
6.3.5. (6Z)-1-(Benzyloxy)nona-6,8-dien-4-ol (8). To a solu-
tion of sultone 2l (157 mg, 0.531 mmol) in THF (5 mL) at
ꢁ78 ꢀC was added n-BuLi (320 mL, 2.5 M in hexanes,
0.796 mmol, 1.5 equiv). After 1 h at ꢁ78 ꢀC, a solution of
iodomethylmagnesium chloride [prepared from CH2I2
(150 mL, 1.86 mmol, 3.5 equiv) and i-PrMgCl (930 mL,
2 M in THF, 1.86 mmol, 3.5 equiv) in THF (3 mL),
ꢁ78 ꢀC, 1 h] was transferred via a cannula into the reaction
mixture. After 1 h at ꢁ78 ꢀC, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl
and extracted with ether. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography (petroleum ether/EtOAc 80:20) to afford 79 mg
(60%) of 8 as a colorless oil; IR 3400, 3030, 1495, 1450,
6.4.1.2. 4-Bromo-2-(1,1-dimethylallyl)thiazole (11).
To a suspension of magnesium turnings (3.46 g, 142 mmol,
5.7 equiv) in THF (20 mL) was added dropwise a solution
of prenyl chloride (8.0 mL, 71 mmol, 2.9 equiv) in THF
(150 mL) (internal temperature maintained between 5–
10 ꢀC). After a further 0.5 h stirring at rt, the resulting solu-
tion of prenylmagnesium chloride was transferred via a
cannula to a solution of 10 (6.00 g, 24.7 mmol) in THF
(20 mL) at 0 ꢀC. After 1 h at 0 ꢀC, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl and
extracted with ether. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography
(pentane/ether 99.5:0.5) to afford 4.98 g (87%) of 11 as a vol-
atile colorless liquid; IR 3120, 3080, 1640, 1480, 1460, 1395,
1260, 1240, 1080, 1020, 920, 890, 840, 820, 740 cmꢁ1; 1H
NMR d 7.09 (s, 1H), 6.13 (dd, J¼17.3, 10.5 Hz, 1H), 5.17
(dd, J¼17.3, 0.7 Hz, 1H), 5.14 (dd, J¼10.5, 0.7 Hz, 1H),
1.54 (s, 6H); 13C NMR d 179.8 (s), 154.0 (s), 144.4 (d),
116.0 (d), 113.3 (t), 45.6 (s), 27.8 (q, 2C); EIMS m/z (relative
intensity) 233 (M[81Br]+, 3), 232 (M[81Br]ꢁH+, 3), 231
(M[79Br]+, 4), 230 (M[79Br]ꢁH+, 3), 218 (M[81Br]ꢁMe+,
99), 216 (M[79Br]ꢁMe+, 100), 203 (13), 201 (12), 192 (3),
190 (4), 152 (2), 138 (4), 137 (6), 136 (8).
1
1365, 1270, 1205, 1095, 1030, 910, 740, 705 cmꢁ1; H
NMR d 7.48–7.27 (m, 5H), 6.65 (dddd, J¼16.9, 11.0,
10.3, 1.1 Hz, 1H), 6.16 (dd, apparent t, J¼11.0 Hz, 1H),
5.53 (m, 1H), 5.24 (dd, J¼16.9, 1.8 Hz, 1H), 5.15 (br d,
J¼10.3 Hz, 1H), 4.53 (s, 2H), 3.68 (m, 1H), 3.52 (t,
J¼5.9 Hz, 2H), 2.59 (br s, 1H, OH), 2.41–2.36 (m, 2H),
1.82–1.62 (m, 3H), 1.58–1.43 (m, 1H); 13C NMR d 138.1
(s), 132.0 (d), 131.6 (d), 128.3 (d, 2C), 128.1 (d), 127.6 (d,
2C), 127.5 (d), 117.7 (t), 72.9 (t), 71.1 (d), 70.3 (t), 35.6
(t), 34.0 (t), 26.1 (t).
6.3.6. (6Z)-1-Benzyloxy-8-methylnona-6,8-dien-4-ol (9).
To a solution of sultone 6 (130 mg, 0.419 mmol) in THF
(4 mL) at ꢁ78 ꢀC was added n-BuLi (252 mL, 2.5 M in hex-
anes, 0.629 mmol, 1.5 equiv). After 1 h at ꢁ78 ꢀC, a solution
iodomethylmagnesium chloride [prepared from CH2I2
(120 mL, 1.46 mmol, 3.5 equiv) and i-PrMgCl (730 mL,
2M in THF 1.46 mmol, 3.5 equiv) in THF (3 mL),
ꢁ78 ꢀC, 1 h] was transferred via a cannula into the reaction
mixture. After 1 h at ꢁ78 ꢀC, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl and
extracted with ether. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography
(petroleum ether/EtOAc 85:15) to afford 58 mg (53%) of 9
as a colorless oil; IR 3400, 1595, 1580, 1490, 1450, 1360,
6.4.1.3.
2-(4-Bromothiazol-2-yl)-2-methylpropanal
(12). To a solution of 11 (3.80 g, 16.3 mmol) in t-BuOH/
H2O (1:1, 60 mL) at rt were successively added OsO4
(4.0 mL, 4% in water, 0.65 mmol, 0.04 equiv) and NMO
(2.10 g, 17.9 mmol, 1.1 equiv). After stirring overnight at
rt, a mixture of powdered Na2S2O3 (7.5 g) and Celite
(15 g) was added. After 0.5 h, the resulting mixture was fil-
tered through Celite (EtOAc). The organic layer was sepa-
rated and the aqueous phase was extracted with EtOAc.
The combined extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude result-
ing 1,2-diol was dissolved in THF/H2O (1:1, 300 mL) and
NaIO4 (8.70 g, 40.8 mmol, 2.5 equiv) was added to the
resulting solution. After 1 h at rt, the reaction mixture was
filtered through Celite (EtOAc). The filtrate was extracted
1
1275, 1205, 1175, 1100, 910, 740, 705 cmꢁ1; H NMR
d 7.39–7.27 (m, 5H), 6.00 (dd, J¼11.8, 1.1 Hz, 1H), 5.49
(dt, J¼11.8, 7.4 Hz, 1H), 4.98 (br s, 1H), 4.89 (br s, 1H),
4.53 (s, 2H), 3.71–3.64 (m, 1H), 3.52 (t, J¼5.9 Hz, 2H),
2.56–2.39 (m, 3H), 1.90 (s, 3H), 1.79–1.50 (m, 4H); 13C
NMR d 141.4 (s), 138.1 (s), 133.1 (d), 128.3 (d, 2C), 127.6
(d, 2C), 127.5 (d), 127.1 (d), 115.6 (t), 72.9 (t), 71.5 (d),
70.3 (t), 36.4 (d), 34.1 (d), 26.1 (d), 23.2 (q); EIMS m/z
(relative intensity) 260 (M+, 1), 259 (45), 152 (16), 137

9030
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
with EtOAc and the combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by filtration through
a short plug of silica gel (petroleum ether/ether 90:10) to
afford 3.37 g (88%) of aldehyde 12 as a pale yellow oil,
which was directly engaged in the next step; 1H NMR
d 9.67 (s, 1H), 7.25 (s, 1H), 1.40 (s, 6H); 13C NMR d 199.0
(d), 172.8 (s), 125.2 (s), 117.1 (d), 51.7 (s), 22.6 (q, 2C).
saturated aqueous solution of NH4Cl and extracted with ether.
The combined extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (pentane/ether 97:3 to
85:15) to afford 175 mg (22%) of 20, 200 mg (34%) of 18,
92 mg (14%) of 19, and 90 mg (14%) of 21 as pale yellow
oils.
6.4.2.1. 2-{2-[(tert-Butyldimethylsilyl)oxy]-1,1-
dimethylpent-4-enyl}thiazole (18). IR 3080, 1705, 1680,
1640, 1470, 1390, 1360, 1260, 1090, 1060, 1040, 1005,
;
910, 840, 770, 740, 725 cmꢁ1 1H NMR d 7.66 (d,
6.4.1.4. 2-(4-Bromothiazol-2-yl)-2-methylhex-5-en-3-
ol (13). To a solution of 12 (3.34 g, 14.3 mmol) in THF
(25 mL) at ꢁ78 ꢀC was added a solution of allylmagnesium
bromide (21.5 mL, 1 M in ether, 21.5 mmol, 1.5 equiv) in
ether (30 mL). After 1 h at rt, the reaction mixture was
hydrolyzed with a 1 M solution of hydrochloric acid and
extracted with ether. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromato-
graphy (pentane/ether 85:15 to 80:20) to afford 3.47 g (87%)
of 13 as a colorless oil; IR 3420, 3130, 1640, 1470, 1370,
J¼3.3 Hz, 1H), 7.14 (d, J¼3.3 Hz, 1H), 5.63 (dddd,
J¼16.5, 10.3, 7.7, 6.6 Hz, 1H), 4.89–4.80 (m, 2H), 3.99
(dd, J¼6.3, 4.6 Hz, 1H), 2.26–2.16 (m, 1H), 2.09–1.99 (m,
1H), 1.41 (s, 3H), 1.36 (s, 3H), 0.85 (s, 9H), 0.02 (s, 3H),
ꢁ0.06 (s, 3H); 13C NMR d 178.3 (s), 141.5 (d), 135.9 (d),
117.8 (d), 115.8 (t), 78.9 (d), 46.0 (s), 38.5 (t), 26.0 (q),
25.9 (q, 3C), 24.5 (q), 18.0 (s), ꢁ3.7 (q), ꢁ4.8 (q); EIMS
m/z (relative intensity) 311 (M+, 1), 296 (MꢁMe+, 5), 270
(MꢁC3H+5, 16), 256 (10), 254 (100), 198 (12), 185 (35),
180 (11), 138 (8), 127 (31), 115 (7), 99 (6), 75 (11), 73 (39).
1260, 1080, 1055, 920, 890, 845, 740 cmꢁ1 1H NMR
;
d 7.14 (s, 1H), 5.86 (dddd, J¼17.6, 9.6, 7.7, 6.3 Hz, 1H),
5.13–5.06 (m, 2H), 3.80 (m, 1H), 3.05 (m, 1H, OH), 2.31
(m, 1H), 1.98 (m, 1H), 1.45 (s, 6H); 13C NMR d 179.6 (s),
135.5 (d), 124.0 (s), 117.4 (t), 115.9 (d), 77.2 (d), 45.2 (s),
36.5 (t), 26.0 (q), 24.0 (q); EIMS m/z (relative intensity)
277 (M[81Br]+, 0.4), 275 (M[79Br]+, 0.4), 236
(M[81Br]ꢁC3H5+, 13), 234 (M[79Br]ꢁC3H+5, 13), 207 (100),
206 (39), 205 (98), 204 (32), 192 (41), 190 (36).
6.4.2.2. 2-{2-[(tert-Butyldimethylsilyl)oxy]-1,1-
dimethylpent-4-enyl}thiazole-4-carboxaldehyde (19). IR
3080, 1710, 1640, 1485, 1470, 1390, 1365, 1260, 1135,
;
1090, 1055, 1005, 915, 840, 780, 700 cmꢁ1 1H NMR
d 10.0 (s, 1H), 8.08 (s, 1H), 5.67 (dddd, J¼16.9, 10.3, 7.7,
6.6 Hz, 1H), 4.93–4.84 (m, 2H), 3.99 (dd, apparent t,
J¼5.1 Hz, 1H), 2.36–2.26 (m, 1H), 2.15–2.05 (m, 1H),
1.49 (s, 3H), 1.40 (s, 3H), 0.88 (s, 9H), 0.06 (s, 3H),
ꢁ0.08 (s, 3H); 13C NMR d 184.9 (d), 179.4 (s), 153.9 (s),
135.4 (d), 127.4 (d), 116.2 (t), 78.7 (d), 46.7 (s), 38.5 (t),
26.1 (q), 25.9 (q, 3C), 25.2 (q), 18.1 (s), ꢁ3.7 (q), ꢁ4.8
(q); EIMS m/z (relative intensity) 324 (MꢁMe+, 3), 298
(MꢁC3H+5, 21), 284 (10), 283 (20), 282 (100), 213 (13),
212 (76), 185 (34), 166 (5), 155 (5), 115 (6), 75 (10), 73 (38).
6.4.1.5. 4-Bromo-2-{2-[(tert-butyldimethylsilyl)oxy]-
1,1-dimethylpent-4-enyl}thiazole (14). To a solution of 13
(700 mg, 2.54 mmol) and 2,6-lutidine (740 mL, 6.35 mmol,
2.5 equiv) in CH2Cl2 (15 mL) at 0 ꢀC was added dropwise
TBSOTf (1.2 mL, 5.1 mmol, 2.0 equiv). After 3 h at 0 ꢀC,
the reaction mixturewas hydrolyzed with a saturated aqueous
solution of NaHCO3 and extracted with ether. The combined
organicextracts weredriedover MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (pentane/ether 99:1) to give 940 mg
(95%) of 14 as a colorless oil; IR 3120, 3080, 1640, 1465,
1390, 1365, 1255 (br), 1090, 915, 840, 780 cmꢁ1; 1H NMR
d 7.09 (s, 1H), 5.71 (m, 1H), 4.96–4.88 (m, 2H), 4.02 (t,
J¼5.3 Hz, 1H), 2.35–2.25 (m, 1H), 2.16–2.06 (m, 1H), 1.44
(s, 3H), 1.36 (s, 3H), 0.87 (s, 9H), 0.05 (s, 3H), ꢁ0.10 (s,
3H); 13C NMR d 179.6 (s), 135.8 (d), 123.8 (s), 116.2 (t),
115.9 (d), 78.7 (d), 46.6 (s), 38.6 (t), 26.0 (q, 3C), 25.3 (q),
24.9 (q), 18.1 (s), ꢁ3.6 (q), ꢁ4.8 (q); EIMS m/z (relative
intensity) 376 (M[81Br]ꢁMe+, 3), 374 (M[79Br]ꢁMe+, 3),
350 (M[81Br]ꢁC3H5+, 13), 348 (M[79Br]ꢁC3H+5, 12), 335
(M[81Br]ꢁC4H8+, 19), 334 (M[81Br]ꢁt-Bu+, 100), 333
(M[79Br]ꢁC4H8+, 19), 332 (M[79Br]ꢁt-Bu+, 96), 186 (12),
185 (70), 129 (10), 127 (13), 115 (14), 99 (12), 75 (31), 73
(61). Anal. Calcd for C16H28BrNOSSi: C, 49.22; H, 7.23;
N, 3.59. Found: C, 49.32; H, 7.23; N, 3.72.
6.4.2.3. 4-Bromo-2-{2-[(tert-butyldimethylsilyl)oxy]-
1,1-dimethylpent-4-enyl}thiazole-5-carboxaldehyde (20).
IR 3080, 1675, 1640, 1480, 1460, 1365, 1250, 1090, 1005,
915, 840, 780, 740, 680 cmꢁ1; 1H NMR d 9.94 (s, 1H), 5.70
(dddd, J¼16.9, 10.7, 7.7, 6.4 Hz, 1H), 4.97–4.88 (m, 2H),
4.03 (t, J¼5.2 Hz, 1H), 2.36–2.26 (m, 1H), 2.19–2.09
(m, 1H), 1.45 (s, 3H), 1.37 (s, 3H), 0.86 (s, 9H), 0.06 (s,
3H), ꢁ0.10 (s, 3H); 13C NMR d 186.9 (s), 182.8 (d), 135.1
(d), 133.6 (s), 131.7 (s), 116.5 (t), 78.3 (d), 47.6 (s), 38.5
(t), 25.8 (q, 3C), 25.4 (q), 24.3 (q), 18.0 (s), ꢁ3.8 (q), ꢁ4.9
(q); EIMS m/z (relative intensity) 404 (M[81Br]ꢁMe+, 2),
402 (M[79Br]ꢁMe+, 2), 378 (M[81Br]ꢁC3H+5, 14), 376
(M[79Br]ꢁC3H+5, 13), 363(M[81Br]ꢁC4H+8, 21), 362(M[81Br]ꢁ
t-Bu+, 100), 361 (M[79Br]ꢁC4H8+, 20), 360 (M[79Br]ꢁt-Bu+,
96), 185 (48), 127 (20), 115 (11), 99 (14), 75 (25), 73 (60).
6.4.2.4.
2-{2-[(tert-Butyldimethylsilyl)oxy]-1,1-
dimethylpent-4-enyl}thiazole-5-carboxaldehyde (21). IR
3080, 1680, 1640, 1510, 1470, 1420, 1390, 1360, 1260,
1100, 1040, 1005, 910, 840, 780 cmꢁ1; 1H NMR d 9.98 (s,
1H), 8.29 (s, 1H), 5.66 (dddd, J¼16.9, 10.3, 7.4, 6.6 Hz,
1H), 4.94–4.84 (m, 2H), 4.03 (dd, apparent t, J¼5.3 Hz,
1H), 2.27 (m, 1H), 2.11 (m, 1H), 1.45 (s, 3H), 1.40 (s,
3H), 0.87 (s, 9H), 0.05 (s, 3H), ꢁ0.08 (s, 3H); 13C NMR
d 187.3 (s), 182.1 (d), 150.6 (d), 138.6 (s), 135.4 (d), 116.3
6.4.2. Br–Li exchange of 14 with n-BuLi in THF and sub-
sequent formylation. To a solution of n-BuLi (1.1 mL,
2.5 M in hexanes, 2.8 mmol, 1.5 equiv) in THF (10 mL) at
ꢁ78 ꢀC was added dropwise a solution of 14 (730 mg,
1.88 mmol) in THF (10 mL). After 15 min at ꢁ78 ꢀC, freshly
distilled DMF (295 mL, 3.76 mmol, 2.0 equiv) was added.
After 0.5 h, the reaction mixture was hydrolyzed with a

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9031
(t), 78.5 (d), 47.3 (s), 38.6 (t), 25.8 (q, 3C), 25.4 (q), 25.0 (q),
18.0 (s), ꢁ3.8 (q), ꢁ4.8 (q); EIMS m/z (relative intensity)
324 (MꢁMe+, 4), 298 (MꢁC3H5+, 16), 283 (MꢁC4H+8, 21),
282 (Mꢁt-Bu+, 100), 269 (6), 256 (3), 226 (8), 185 (29),
166 (6), 156 (4), 127 (9), 115 (7), 99 (7), 75 (14), 73 (46),
59 (8).
2H), 4.57 (s, 2H), 4.04 (dd, J¼5.9, 4.8 Hz, 1H), 2.34–2.24
(m, 1H), 2.17–2.06 (m, 1H), 1.44 (s, 3H), 1.38 (s, 3H), 0.88
(s, 9H), 0.06 (s, 3H), ꢁ0.09 (s, 3H); 13C NMR d 179.2 (s),
151.1 (s), 136.0 (d), 117.0 (d), 116.0 (t), 78.9 (d), 46.4 (s),
38.6 (t), 27.6 (t), 26.0 (q, 3C), 25.5 (q), 25.0 (q), 18.3 (s),
ꢁ3.6 (q), ꢁ4.6 (q); EIMS m/z (relative intensity) 364
(M[81Br]ꢁC3H+5, 12), 362 (M[79Br]ꢁC3H+5, 12), 348
(M[81Br]ꢁt-Bu+, 87), 346 (M[79Br]ꢁt-Bu+, 83), 324 (2),
252 (7), 192 (30), 186 (17), 185 (100), 168 (31), 140 (10),
139 (13), 129 (13), 115 (15), 95 (17), 75 (14), 73 (56).
6.4.3. Installation of the unsaturated side-chain at C4.
6.4.3.1. Br–Li exchange of 14 with t-BuLi in ether and
subsequent formylation. To a solution of t-BuLi (3.1 mL,
1.7 M in pentane, 5.3 mmol, 3.0 equiv) in ether (17 mL) at
ꢁ78 ꢀC was added dropwise a solution of 14 (676 mg,
1.74 mmol) in ether (17 mL). After 5 min at ꢁ78 ꢀC, freshly
distilled DMF (410 mL, 5.22 mmol, 3.0 equiv) was added
dropwise. After 0.5 h at ꢁ78 ꢀC, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl
and extracted with ether. The combined organic extracts
were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (pentane/Et2O: 90:10) to afford 500 mg
(85%) of 19 as a yellow oil, see Section 6.4.2.2.
6.4.4. Preparation of organostannane 26.
1) EtMgBr, THF
2) CuBr.SMe2, AllylBr
1) DIBAL-H
TMS
hexanes, Et2O
TMS
2) I2, THF
THF, 60 °C
40
1) t-BuLi
Et2O, - 78°C
MeONa
I
I
26
MeOH, 40 °C
2) Bu3SnCl
41
42
TMS
6.4.3.2.
({2-[2-(tert-Butyldimethylsilyl)oxy]-1,1-
dimethylpent-4-enyl}thiazol-4-yl)methanol (24). To a
solution of aldehyde 19 (960 mg, 2.83 mmol) in ether
(35 mL) at ꢁ78 ꢀC was added DIBAL-H (4.75 mL, 1 M in
hexanes, 4.75 mmol, 1.7 equiv). After 0.5 h at ꢁ78 ꢀC, the
reaction mixture was hydrolyzed with a saturated aqueous
solution of Rochelle’s salt and diluted with ether. After 2 h
at rt, the organic layer was separated and the aqueous phase
was extracted with ether. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure to afford 910 mg (95%) of 24 as a colorless
oil, which was directly engaged in the next step without puri-
fication; IR 3300, 3070, 1640, 1470, 1390, 1365, 1260, 1100,
1040, 910, 840, 780 cmꢁ1; 1H NMR d 7.04 (s, 1H), 5.68 (m,
1H), 4.93–4.86 (m, 2H), 4.73 (br d, J¼5.0 Hz, 2H), 4.00
(dd, J¼5.9, 4.8 Hz, 1H), 3.38 (t, J¼5.0 Hz, 1H, OH), 2.31–
2.21 (m, 1H), 2.14–2.04 (m, 1H), 1.42 (s, 3H), 1.37 (s, 3H),
0.88 (s, 9H), 0.05 (s, 3H), ꢁ0.09 (s, 3H); 13C NMR d 179.3
(s), 155.3 (s), 136.1 (d), 116.0 (t), 113.7 (d), 78.9 (d), 60.8
(t), 46.4 (s), 38.6 (t), 26.0 (q, 3C), 25.8 (q), 24.8 (q), 18.3 (s),
ꢁ3.6 (q), ꢁ4.7 (q); EIMS m/z (relative intensity) 341
(M+, 1), 300 (MꢁC3H+5, 33), 285 (22), 284 (100), 262 (64),
214 (49), 192 (23), 185 (100), 183 (28), 168 (40), 157 (22),
140 (29), 115 (22), 75 (31), 73 (79). Anal. Calcd for
C17H31NO2SSi: C, 59.77; H, 9.15; N, 4.10. Found: C, 59.66;
H, 9.30; N, 4.14.
6.4.4.1. Trimethylpent-4-en-1-ylsilane (40). To a solu-
tion of EtMgBr (34 mL, 3 M in THF, 102 mmol, 1.2 equiv)
in THF (120 mL) was slowly added trimethylsilylacetylene
(12 mL, 85 mmol) (exothermic reaction, internal tempera-
ture between 25 and 30 ꢀC). The resulting mixture was
heated at 50 ꢀC for 2 h and cooled to rt. To the reaction mix-
ture was added CuBr$SMe2 (1.75 g, 8.49 mmol, 0.1 equiv)
in one portion followed by allyl bromide (11.0 mL,
127 mmol, 1.5 equiv) dropwise (exothermic reaction, inter-
nal temperature 50 ꢀC). After 2 h at 60 ꢀC, the reaction
mixture was hydrolyzed with a 1 M aqueous solution of
hydrochloric acid and extracted with ether. The combined
organic extracts were dried over MgSO4, filtered, and con-
centrated under reduced pressure. The crude material was
purified by distillation under reduced pressure to afford
9.2 g (79%) of 40 as a colorless oil; bp 45 ꢀC/15 mmHg;
IR 2180, 1640, 1420, 1250, 1030, 1000, 915, 890, 840,
700 cmꢁ1; 1H NMR d 5.82 (ddt, J¼17.0, 10.3, 5.2 Hz, 1H),
5.34 (dq, J¼17.0, 1.7 Hz, 1H), 5.13 (dq, J¼10.3, 1.7 Hz,
1H), 3.01 (dt, J¼5.2, 1.7 Hz, 2H), 0.17 (s, 9H); 13C NMR
d 132.1 (d), 116.1 (t), 103.3 (s), 87.0 (s), 24.1 (t), 0.00 (q, 3C).
6.4.4.2.
(E)-1-Iodo-1-trimethylsilylpenta-1,4-diene
(41). A solution of DIBAL-H (70 mL, 1 M in hexanes,
70 mmol, 1.2 equiv) was diluted with ether (7.2 mL,
70 mmol, 1.2 equiv) and a solution of 40 (8.00 g,
58.0 mmol) in ether (145 mL) was slowly added at 0 ꢀC.
After 1.5 h at rt and 2 h at 40 ꢀC, the reaction mixture
was cooled to ꢁ78 ꢀC and a solution of iodine (36.8 g,
145 mmol, 2.5 equiv) in THF (150 mL) was added drop-
wise. The reaction mixture was warmed to rt, hydrolyzed
with a 1 M aqueous solution of hydrochloric acid, and
extracted with ether. The combined organic extracts were
successively washed with a saturated aqueous solution of
NaHCO3 and a 25% aqueous solution of Na2S2O3, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by distillation under
reduced pressure (in the presence of a small amount of Cu
powder) to afford 11.3 g (73%) of 41 as a colorless oil; bp
85 ꢀC/10 mmHg; IR 3070, 1640, 1580, 1250, 990, 915,
6.4.3.3. 4-Bromomethyl-2-{2-[(tert-butyldimethylsilyl)-
oxy]-1,1-dimethylpent-4-enyl}thiazole (25). To a solution
of 24 (640 mg, 1.92 mmol), 2,6-lutidine (92 mL, 0.79 mmol,
0.4 equiv), and PPh3 (830 g, 3.21 mmol, 1.7 equiv) in MeCN
(16 mL) at rt was added portionwise CBr4 (1.1 g, 3.2 mmol,
1.7 equiv). After 0.5 h at rt, the reaction mixture was hydro-
lyzed with a saturated aqueous solution of NaHCO3 and
extracted with ether. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromato-
graphy (pentane/ether 95:5) to afford 740 mg (97%) of 25 as
a colorless oil; IR 3070, 1640, 1470, 1385, 1365, 1255, 1085,
1
1040, 1000, 910, 835, 775 cmꢁ1; H NMR d 7.17 (s, 1H),
5.71 (dddd, J¼16.9, 10.3, 7.3, 6.6 Hz, 1H), 4.95–4.87 (m,

9032
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
840, 760, 690 cmꢁ1; 1H NMR d 7.16 (t, J¼8.0 Hz, 1H), 5.77
(ddt, J¼17.3, 9.6, 6.1 Hz, 1H), 5.11–5.03 (m, 2H), 2.83 (ddt,
J¼8.0, 6.1, 1.5 Hz, 2H), 0.29 (s, 9H); 13C NMR d 152.7 (d),
134.6 (d), 116.0 (t), 107.8 (s), 38.8 (t), 1.0 (q, 3C); EIMS m/z
(relative intensity) 266 (M+, 21), 185 (80), 139 (MꢁI+, 4),
83 (11), 73 (100).
5.77–5.52 (m, 3H), 5.10–4.98 (m, 2H), 4.96–4.85 (m, 2H),
4.07 (dd, J¼6.0, 4.5 Hz, 1H), 3.50 (br d, J¼6.4 Hz, 2H),
2.81 (apparent br t, J¼6.4 Hz, 2H), 2.28 (m, 1H), 2.10 (m,
1H), 1.43 (s, 3H), 1.37 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H),
ꢁ0.11 (s, 3H); 13C NMR d 178.2 (s), 155.1 (s), 136.8 (d),
136.3 (d), 129.8 (d), 128.0 (d), 115.8 (t), 115.0 (t), 112.0
(d), 78.9 (d), 46.1 (s), 38.5 (t), 36.5 (t), 34.8 (t), 25.9 (q,
3C), 25.6 (q), 24.4 (q), 18.1 (s), ꢁ3.7 (q), ꢁ4.8 (q); EIMS
m/z (relative intensity) 391 (M+, 3), 376 (MꢁMe+, 4), 350
(MꢁC3H+5, 15), 336 (12), 335 (27), 334 (Mꢁt-Bu+, 100),
260 (20), 207 (41), 186 (12), 185 (72), 129 (13), 115 (14),
75 (10), 73 (54).
6.4.4.3. (E)-1-Iodopenta-1,4-diene (42). To a solution of
MeONa [prepared by portionwise addition of sodium pieces
(3.85 g, 167 mmol, 4.0 equiv) in MeOH (100 mL), 20–
45 ꢀC] at rt was added a solution of 41 (11.1 g,
41.7 mmol) in MeOH (30 mL). After 4 h at 40 ꢀC, the reac-
tion mixture was hydrolyzed with H2O (100 mL) and
extracted with pentane. The combined organic extracts
were washed with a saturated aqueous solution of NaCl,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by distillation un-
der reduced pressure (in the presence of a small amount of
Cu powder) to afford 6.0 g (74%) of 42 as a slightly yellow
oil; bp 60–70 ꢀC/35 mmHg; IR 1640, 1605, 1430, 1250,
1230, 1175, 1115, 990, 950, 915, 860, 840 cmꢁ1; 1H NMR
d 6.55 (dt, J¼14.3, 6.4 Hz, 1H), 6.07 (dt, J¼14.3, 1.5 Hz,
1H), 5.79 (ddt, J¼17.3, 10.3, 6.4 Hz, 1H), 5.12–5.05 (m,
2H), 2.81 (ddq, apparent tq, J¼6.4, 1.5 Hz, 2H); 13C NMR
d 143.6 (d), 134.2 (d), 116.5 (t), 72.8 (d), 39.7 (t).
6.4.4.6.
2-[((2E)-4-Hexa-2,5-dienyl)thiazol-2-yl]-2-
methylhex-5-en-3-ol (28). To a solution of 27 (300 mg,
0.777 mmol) in THF (10 mL) at rt was added n-Bu4NF
(2.3 mL, 1 M in THF, 2.3 mmol, 3.0 equiv). After 1.5 h at
50 ꢀC, the reaction mixture was hydrolyzed with a saturated
aqueous solution of NH4Cl and extracted with EtOAc. The
combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude mate-
rial was purified by flash chromatography (pentane/Et2O
75:25) to give 200 mg (94%) of 28 as a colorless oil; IR
3400 (br), 3070, 1640, 1520, 1470, 1430, 1365, 1050, 990,
1
970, 910, 740 cmꢁ1; H NMR d 6.75 (s, 1H), 5.91 (ddt,
J¼17.0, 10.2, 6.8 Hz, 1H), 5.82 (ddt, J¼16.9, 10.2, 6.4 Hz,
1H), 5.72–5.50 (m, 2H), 5.10–4.96 (m, 4H), 4.52 (br d,
J¼5.7 Hz, 1H), 3.73 (m, 1H), 3.46 (br d, J¼6.0 Hz, 2H),
2.78 (apparent br t, J¼6.4, 2H), 2.32–2.24 (m, 1H), 2.05–
1.94 (m, 1H), 1.44 (s, 3H), 1.40 (s, 3H); 13C NMR d 178.9
(s), 155.4 (s), 136.8 (d), 136.3 (d), 130.3 (d), 127.7 (d),
116.5 (t), 115.2 (t), 111.9 (d), 77.9 (d), 44.6 (s), 36.6 (t,
2C), 34.7 (t), 26.9 (q), 24.3 (q); EIMS m/z (relative intensity)
277 (M+, 1), 236 (MꢁC3H+5, 19), 208 (19), 207 (100), 206
(21), 192 (16), 166 (9), 139 (11), 138 (12), 126 (9), 97 (6),
71 (10); HRMS (CI+, CH4) calcd for C16H24NOS (M+H+):
278.1579. Found: 278.1575.
6.4.4.4. (E)-1-Tributylstannylpenta-1,4-diene (26). To
a solution of 42 (580 mg, 3.00 mmol) in ether (15 mL) at
ꢁ78 ꢀC was added t-BuLi (4.0 mL, 1.7 M in pentane,
6.8 mmol, 2.3 equiv). After 0.5 h at ꢁ78 ꢀC, the reaction
mixture was warmed to 0 ꢀC and n-Bu3SnCl (0.89 mL,
3.3 mmol, 1.1 equiv) was added rapidly. After 0.5 h at rt,
the reaction mixture was hydrolyzed with a saturated aque-
ous solution of NH4Cl and extracted with Et2O. The com-
bined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude alke-
nylstannane 26 was directly engaged in the next step without
further purification (purification by flash chromatography on
silica gel resulted in extensive protodestannylation). An
analytical sample of 26 was obtained by rapid filtration on
6.4.5. Synthesis of the originally proposed structure of
mycothiazole.
1
silica gel (pentane); H NMR d 6.11–5.96 (m, 2H), 5.87
6.4.5.1. 2-[1-(2,2-Dioxo-2,3,6,7-tetrahydro-2l6-[1,2]-
oxathiepin-7-yl)-1-methylethyl]-4-((2E)-hexa-2,5-dienyl)-
thiazole (30). To a solution of 28 (110 g, 0.405 mmol) and
DMAP (97 mg, 0.80 mmol, 2.0 equiv) in THF (3 mL) at rt
was added dropwise a solution of allylsulfonyl chloride
(84 mg, 0.60 mmol, 1.5 equiv) in THF (2 mL). After 2 h at
rt, a solution of DMAP (97 mg, 0.80 mmol, 2.0 equiv) and
allylsulfonyl chloride (84 mg, 0.60 mmol, 1.5 equiv) in
THF (2 mL) was added. After 1 h at rt, the reaction mixture
was hydrolyzed with a saturated aqueous solution of
NaHCO3 and extracted with ether. The combined organic
extracts were washed with an aqueous solution of CuSO4,
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was filtered through
silica gel (ether) and after evaporation of the solvent under
reduced pressure, the crude sulfonate 29 was dissolved in
C6H6 (40 mL). To the resulting degassed solution (argon
bubbling, 15 min) at 70 ꢀC was added catalyst II [(51 mg,
0.06 mmol, 0.15 equiv) in three portions at 1 h interval].
After a further 1 h at 70 ꢀC, the reaction mixture was cooled
to rt and concentrated under reduced pressure. The residue
was purified by flash chromatography (pentane/ether
70:30) to afford 98 mg (70%) of 30 as a colorless oil; IR
(ddt, J¼16.9, 10.3, 6.6 Hz, 1H), 5.05 (dq, J¼17.0, 1.5 Hz,
1H), 5.03 (dq, J¼10.3, 1.5 Hz, 1H), 2.94–2.89 (m, 2H),
1.58–1.46 (m, 6H), 1.40–1.26 (m, 6H), 0.95–0.86 (m,
15H); 13C NMR d 146.4 (d), 136.7 (d), 129.0 (d), 115.2
(t), 41.9 (t), 29.3 (t, 3C), 27.4 (t, 3C), 13.7 (q, 3C), 9.4 (t, 3C).
6.4.4.5.
2-{2-[(tert-Butyldimethylsilyl)oxy]-1,1-di-
methylpent-4-enyl}-(2E)-4-(hexa-2,5-dienyl)thiazole (27).
To a degassed solution of bromide 25 (65 mg, 0.16 mmol)
and stannane 26 (72 mg, 0.20 mmol, 1.25 equiv) in freshly
distilled NMP (2.5 mL) (argon bubbling, 10 min) at rt was
added PdCl2(CH3CN)2 (4 mg, 0.02 mmol, 0.1 equiv). After
0.5 h at rt, the reaction mixture was hydrolyzed with a 20%
aqueous solution of NH4OH, stirred for 0.5 h and extracted
with ether. The combined organic extracts were washed
with a 1 M aqueous solution of KHSO4, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash chromatography
(pentane/ether 95:5) to afford 62 mg (95%) of 27 as a color-
less oil; IR 3070, 1640, 1515, 1470, 1460, 1430, 1385, 1360,
1255, 1090, 1040, 1000, 970, 910, 835, 775, 740 cmꢁ1; 1H
NMR d 6.74 (s, 1H), 5.86 (ddt, J¼16.6, 10.2, 6.4 Hz, 1H),

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9033
3080, 3015, 3030, 1640, 1515, 1430, 1360, 1170, 1055, 970,
910, 875, 830, 740, 700, 690 cmꢁ1; 1H NMR d 6.85 (s, 1H),
6.09 (m, 1H), 5.87 (ddt, J¼17.3, 10.2, 6.4 Hz, 1H), 5.80–
5.52 (m, 3H), 5.12–5.00 (m, 3H), 4.14 (m, 1H), 3.90 (appar-
ent br dd, J¼15.5, 8.1 Hz, 1H), 3.58–3.48 (m, 2H), 2.84
(apparentbr t, J¼6.4 Hz, 2H), 2.59(m, 1H), 2.42(dd, J¼16.2,
8.5 Hz, 1H), 1.55 (s, 3H), 1.54 (s, 3H); 13C NMR d 174.5 (s),
156.0 (s), 136.9 (d), 134.5 (d), 130.3 (d), 127.8 (d), 119.1 (d),
115.2 (t), 113.1 (d), 90.1 (d), 50.5 (t), 44.6 (s), 36.6 (t), 34.8
(t), 29.8 (t), 26.9 (q), 22.4 (q); EIMS m/z (relative intensity)
353 (M+, 39), 338 (MꢁMe+, 7), 324 (10), 313 (19), 312
(MꢁC3H+5, 100), 272 (Mꢁ[CH2]CH–CH2–CH]CH]+,
12), 218 (37), 207 (58), 206 (95), 192 (22), 164 (28), 152
(22), 139 (28), 138 (58), 97 (19), 71 (23), 55 (21).
(13), 75 (31), 71 (64); HRMS (CI+, CH4) calcd for
C22H34NO5S2 (M+H+): 456.1878. Found: 456.1875.
6.4.5.3. (5Z)-2-[(4-(2E)-Hexa-2,5-dienyl)thiazol-2-yl]-
10,10-dimethoxy-2-methyl-7-methylenedec-5-en-3-ol (33).
To a solution of 32 (139 mg, 0.305 mmol) in THF (10 mL)
at ꢁ78 ꢀC was added a solution of n-BuLi (0.25 mL, 2.5 M
in hexanes, 0.625 mmol, 2.5 equiv). After 0.5 h at ꢁ78 ꢀC,
a solution of ICH2MgCl [prepared from CH2I2 (576 mg,
2.15 mmol, 7 equiv) and i-PrMgCl (1.1 mL, 2 M in THF,
2.2 mmol, 7 equiv) in THF (10 mL), ꢁ80 ꢀC, 1 h] was added
via a cannula to the reaction mixture. After 15 min at ꢁ78 ꢀC,
the reaction mixturewas hydrolyzed with a saturated aqueous
solution of NH4Cl and extracted with EtOAc. The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude material was puri-
fied by flash chromatography (pentane/ether 70:30) to
afford 74 mg (60%) of 33 as a colorless oil; IR 3420, 1640,
6.4.5.2. 2-{1-[3-(3,3-Dimethoxypropyl)-2,2-dioxo-2,3,
6,7-tetrahydro-2l6-[1,2]oxathiepin-7-yl]-1-methylethyl}-
4-((2E)-hexa-2,5-dienyl)thiazole (32). To a solution of 30
(142 mg, 0.402 mmol), iodide 31 (111 mg, 0.482 mmol,
1.2 equiv), and HMPA (280 mL, 1.61 mmol, 4.0 equiv) in
THF (10 mL) at ꢁ78 ꢀC was added dropwise LiHMDS
(0.48 mL, 1 M in THF, 0.48 mmol, 1.2 equiv). After 20
min at ꢁ78 ꢀC, the reaction mixture was hydrolyzed with
a saturated aqueous solution of NH4Cl and extracted with
EtOAc. The combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (pentane/
ether 65:35) to afford 139 mg (76%) of 30 as a colorless oil
and as a nearly 1:1 mixture of diastereomers. In order to
facilitate characterization, the two diastereomers were par-
tially separated by resubjecting an analytical sample of the
mixture to purification by flash chromatography.
1
1520, 1450, 1380, 1365, 1125, 1055, 970, 910 cmꢁ1; H
NMR d 6.77 (s, 1H), 5.92–5.53 (m, 5H), 5.18–4.98 (m, 2H),
4.98 (br s, 1H), 4.85 (br s, 1H), 4.63 (m, 1H), 4.35 (apparent
t, J¼5.8 Hz, 1H), 3.73 (m, 1H), 3.47 (apparent br d,
J¼6.4 Hz, 2H), 3.32 (s, 6H), 2.80 (apparent br t, J¼6.4 Hz,
2H), 2.49 (m, 1H), 2.24–2.09 (m, 3H), 1.75–1.66 (m, 2H),
1.44 (s, 3H), 1.40 (s, 3H); 13C NMR d 179.0 (s), 155.4 (s),
144.7 (s), 136.9 (d), 131.0 (d), 130.4 (d), 129.7 (d), 127.7
(d), 115.2 (t), 113.7 (t), 111.9 (d), 104.1 (d), 78.7 (d), 52.8
(q, 2C), 44.7 (s), 36.6 (t), 34.7 (t), 32.2 (t), 31.2 (t), 31.1 (t),
27.0 (q), 24.2 (q); MS (CI+, CH4) m/z (relative intensity)
406 (M+H+, 74), 390 (MꢁMe+, 64), 374 (37), 368 (38), 358
(35), 318 (30), 280 (26), 236 (36), 183 (28), 169 (33), 127
(29), 70 (100); HRMS (CI+, CH4) calcd for C23H36NO3S
(M+H+): 406.2416. Found: 406.2422.
First eluting diastereomer: IR 1640, 1520, 1460, 1360, 1170,
1
1130, 1055, 970, 905, 740, 690 cmꢁ1; H NMR d 6.82 (s,
6.4.5.4. (4Z)-8-[((2E)-4-Hexa-2,5-dienyl)thiazol-2-yl]-
7-hydroxy-8-methyl-3-methylenenon-4-enylmethyl car-
bamate (39) (originally proposed structure of mycothia-
zole). To a solution of 33 (15 mg, 37 mmol) in THF/H2O
(1:1, 6 mL) at rt was added PPTS (19 mg, 74 mmol,
2.0 equiv). After 18 h at 50 ꢀC, the reaction mixture was
hydrolyzed with water and extracted with EtOAc. The com-
bined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude aldehyde
34 was dissolved in t-BuOH/H2O (3:1, 2 mL) and to the
resulting solution at 0 ꢀC were successively added 2-methyl-
but-2-ene (43 mL, 0.41 mmol, 11 equiv), NaH2PO4$H2O
(69 mg, 0.44 mmol, 12 equiv), and NaClO2 (24 mg,
0.22 mmol, 6 equiv). After 1 h at 0 ꢀC, the reaction mixture
was extracted with EtOAc. The combined organic extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure to afford the crude highly sensitive carbox-
ylic acid 35, which was immediately dissolved in toluene
(5 mL). To the resulting solution at rt were successively
added Et3N (20 mL, 0.14 mmol, 3.9 equiv) and diphenyl-
phosphoryl azide (24 mL, 0.11 mmol, 3.0 equiv). After 1 h
at rt, the reaction mixture was heated at 110 ꢀC. After 1 h,
MeOH (3 mL) was added and the reaction mixture was
further heated at reflux for 1 h. After concentration under
reduced pressure, the residue was purified by preparative
chromatography on silica gel (pentane/ether 50:50) to afford
10 mg of the isocyanate 37. This compound (which was ini-
tially mistaken with the amine 38) was dissolved in CH2Cl2
(3 mL), and to the resulting solution at rt were successively
1H), 6.08 (m, 1H), 5.94–5.47 (m, 4H), 5.18–4.96 (m, 3H),
4.38 (apparent td, J¼5.5, 2.0 Hz, 1H), 4.09 (m, 1H), 3.49
(br d, J¼6.4 Hz, 2H), 3.33 (s, 6H), 2.81 (apparent br t,
J¼6.4 Hz, 2H), 2.57–2.15 (m, 4H), 2.08–1.67 (m, 2H),
1.51 (s, 6H); 13C NMR d 174.6 (s), 155.9 (s), 136.9 (d),
133.8 (d), 130.3 (d), 127.8 (d), 126.9 (d), 115.2 (t), 113.0
(d), 104.0 (d), 91.4 (d), 61.0 (d), 53.2 (q, 2C), 44.7 (s),
36.6 (t), 34.8 (t), 29.7 (t), 29.1 (t), 27.0 (q), 24.6 (t), 22.5
(q); EIMS m/z (relative intensity) 424 (MꢁOMe+, 10), 423
(38), 382 (31), 344 (20), 326 (12), 316 (15), 288 (13), 235
(13), 218 (12), 208 (15), 207 (70), 206 (57), 194 (13), 192
(15), 139 (15), 138 (27), 97 (13), 91 (14), 79 (14), 77 (13),
71 (100); HRMS (CI+, CH4) calcd for C22H34NO5S2
(M+H+): 456.1878. Found: 456.1875.
Second eluting diastereomer: IR 1640, 1520, 1460, 1420,
1360, 1170, 1125, 1060, 970, 905, 740, 690 cmꢁ1 1H
;
NMR d 6.82 (s, 1H), 5.95–5.77 (m, 2H), 5.74–5.50 (m,
3H), 5.17–4.97 (m, 3H), 4.38 (br t, J¼5.5 Hz, 1H), 3.96
(m, 1H), 3.50 (br d, J¼6.4 Hz, 2H), 3.34 (s, 3H), 3.33 (s,
3H), 2.81 (apparent br t, J¼6.4 Hz, 2H), 2.56 (m, 1H),
2.39–2.17 (m, 2H), 2.00 (m, 1H), 1.80–1.69 (m, 2H), 1.55
(s, 3H), 1.52 (s, 3H); 13C NMR d 174.5 (s), 156.0 (s),
136.9 (d), 132.2 (d), 130.3 (d), 127.8 (d), 124.1 (d), 115.2
(t), 113.1 (d), 104.0 (d), 88.2 (d), 60.4 (d), 53.2 (q), 53.1
(q), 44.5 (s), 36.6 (t), 34.8 (t), 29.7 (t), 29.6 (t), 27.0 (q),
25.0 (t), 22.5 (q); EIMS m/z (relative intensity) 384 (21),
383 (16), 336 (20), 168 (13), 167 (75), 166 (100), 97

9034
A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
added Et3N (20 mL, 0.14 mmol) and ClCO2Me (8 mL,
0.10 mmol). After 0.5 h, additional quantities of Et3N
(50 mL, 0.36 mmol) and ClCO2Me (28 mL, 0.36 mmol)
were added. As no reaction apparently occurred, MeOH
(2 mL) was added to the reaction mixture. After 1 h at rt,
the reaction mixture was concentrated under reduced pres-
sure and the residue was purified by preparative chromato-
graphy on silica gel (petroleum ether/EtOAc 50:50) to
afford 5 mg (33%) of 39; Rf (petroleum ether/EtOAc) 0.5;
1H NMR d 6.77 (s, 1H), 5.92–5.52 (m, 5H), 5.43 (br s, 1H,
NH), 5.09–4.86 (m, 4H+OH), 3.79 (br d, J¼9.8 Hz, 1H),
3.63 (s, 3H), 3.46 (d, J¼6.4 Hz, 2H), 3.35–3.14 (m, 2H),
2.80 (t, J¼6.0 Hz, 2H), 2.48–2.17 (m, 4H), 1.43 (s, 3H),
1.39 (s, 3H); EIMS 404 (M+, 5), 373 (MꢁOMe+, 2), 316
(21), 236 (42), 208 (15), 207 (100), 206 (10), 192 (6), 138
(5), 105 (8), 88 (9); HRMS (EI) calcd for C22H32N2O3S
(M+): 404.2134. Found: 404.2133.
6.5. Comparison of the 1H and 13C NMR data
See Tables 3 and 4.
6.6. Formal enantioselective approach
6.6.1. Synthesis of (R)-13 by an enantioselective allyl-
boration. To a solution of (+)-DIPCl (390 mg, 1.20 mmol,
1.2 equiv) in ether (10 mL) at ꢁ78 ꢀC was added dropwise
allylmagnesium bromide (1.1 mL, 1 M in ether, 1.1 mmol,
1.1 equiv). After 3 h at ꢁ78 ꢀC, a solution of aldehyde 12
(230 mg, 1.00 mmol) in ether (2 mL) was added. After 2 h
at ꢁ78 ꢀC, the reaction mixture was warmed to rt and hydro-
lyzed by addition of a 3 M aqueous solution of NaOH (2 mL)
and a 30% aqueous solution of H2O2 (1 mL). After 1 h at
40 ꢀC, the resulting mixture was filtered through Celite
(ether) and the filtrate was extracted with EtOAc. The
Table 3. Table of comparison of the 1H NMR data
H
Synthetic compound 39 present
study 300 MHz, CDCl3
Synthetic compound (ꢁ)-399 previous
(ꢁ)-Mycothiazole natural
total synthesis 270 MHz, CDCl3
product6 300 MHz, CDCl3
H5
H7
H8
H9
6.77 (s)
6.77 (s)
6.73 (t)
3.79 (br d, J¼9.8 Hz)
2.48–2.17 (m)
5.92–5.52 (m)
5.92–5.52 (m)
2.48–2.17 (m)
3.35–3.14 (m)
3.46 (d, J¼6.4 Hz)
5.92–5.52 (m)
5.92–5.52 (m)
2.80 (br t, J¼6.0 Hz)
5.92–5.52 (m)
5.09–4.86 (m)
5.09–4.86 (m)
1.43 (s)
3.78 (dd, J¼9.6, 3.0 Hz)
2.43–2.18 (m)
5.91–5.52 (m)
5.91–5.52 (m)
2.43–2.18 (m)
3.33–3.16 (m)
3.46 (d, J¼5.6 Hz)
5.91–5.52 (m)
5.91–5.52 (m)
2.80 (t, J¼6.0 Hz)
5.91–5.52 (m)
5.09–4.88 (m)
5.09–4.88 (m)
1.43 (s)
3.74 (dd, J¼10.2, 3.0 Hz)
2.39 (m), 2.24 (m)
5.65 (m)
H10
H12
H13
H14
H15
H16
H17
H18
H19
H20
H21
H22
H24
NH
5.83 (m)
2.29 (m), 2.18 (m)
3.23 (m), 3.14 (m)
3.46 (d, J¼7.2 Hz)
5.68 (br m)
5.50 (m)
2.84 (dt, J¼6.3, 1.5 Hz)
5.73 (m)
4.96 (m), 4.96 (m)
4.96 (m), 4.83 (m)
1.39 (s)
1.35 (s)
3.56 (s)
1.39 (s)
3.63 (s)
5.43 (br s)
5.09–4.86 (m)
1.39 (s)
3.63 (s)
5.43 (br s)
5.09–4.88 (m)
Not indicated
Not indicated
OH
Table 4. Table of comparison of the 13C NMR data
C
Synthetic compound 39 present
study 75 MHz, CDCl3
Synthetic compound (ꢁ)-39 previous
(ꢁ)-Mycothiazole natural
total synthesis9 67.5 MHz, CDCl3
product6 75 MHz, CDCl3
C2
Not accurately assigned
(low signal/noise ratio)
179.4
179.4
C4
C5
C6
C7
C8
C9
C10
C11
155.4
112.0
44.6
78.1
30.6
130.6
155.4
112.0
44.5
78.1
30.6
130.6
130.9
142.5
154.9
111.8
44.5
78.1
30.6
130.8
130.8
142.4
130.9
Not accurately assigned
(low signal/noise ratio)
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
37.1
39.4
34.7
127.6
130.5
36.6
136.8
115.2
115.9
26.7
37.1
39.4
34.7
127.6
130.4
36.6
136.8
115.2
115.8
26.7
37.1
39.4
29.4
126.7
128.8
31.5
136.4
115.0
115.8
26.6
23.9
157.2
51.8
23.9
157.1
51.8
23.9
157.1
51.8

A. Le Flohic et al. / Tetrahedron 62 (2006) 9017–9037
9035
8. For an application of a Negishi cross-coupling to the total syn-
thesis of discodermolide, see: Nerenberg, J. B.; Hung, D. T.;
Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115,
12621–12622.
9. For an application of a Stille coupling to the total synthesis of
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Org. Lett. 2000, 2, 2149–2152; (b) Sugiyama, H.; Yokokawa,
F.; Shioiri, T. Tetrahedron 2003, 59, 6579–6593.
combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (pentane/ether 90:10 to
85:15) to afford 190 mg (70%) of (R)-13 as a colorless oil.
The ee value (ee¼54%) was determined by HPLC: Chiral
OD-H column, elution rate: 1 mL/min, eluent: hexane,
detection: 230–260 nm, injection: 10 mL (of a 2 mg/mL
solution), retention times: (S)-enantiomer, 48.4 min; (R)-
enantiomer, 55.5 min.
ꢁ
10. (a) Poree, F.-H.; Clavel, A.; Betzer, J.-F.; Pancrazi, A.;
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ꢁ
Poree, F.-H.; Barbion, J.; Dhulut, S.; Betzer, J.-F.; Pancrazi,
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6.6.2. Synthesis of (R)-13 by an enantioselective allyltita-
nation. To a solution of ((S,S)-TADDOL)CpTiCl (980 mg,
1.60 mmol, 1.6 equiv) in ether (16 mL) at 0 ꢀC was added
dropwise allylmagnesium chloride (650 mL, 2 M in THF,
1.30 mmol, 1.3 equiv). After 3 h at 0 ꢀC, a solution of alde-
hyde 12 (230 mg, 1.00 mmol) in ether (4 mL) was added at
ꢁ78 ꢀC. After 5 h at ꢁ78 ꢀC, the reaction mixture was
warmed to rt and hydrolyzed with a 45% aqueous solution
of NH4F. After stirring overnight at rt, the resulting mixture
was filtered through Celite (ether). The organic layer was
separated and washed with a saturated aqueous solution of
NaCl, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was taken-up in pentane and
the precipitated (S,S)-TADDOL (634 mg, 1.36 mmol, 85%
recovery) was separated by filtration. The filtrate was evapo-
rated under reduced pressure and the residue was purified by
flash chromatography (pentane/ether 90:10 to 85:15) to
afford 226 mg (82%) of (R)-13 as a colorless oil. The ee
value (ee¼99%) was determined by HPLC with chiral
OD-H column; [a]2D0 +20.2 (c 1.0, MeOH).
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A.L.F. thanks the CNRS and Rhodia for a grant and financial
support from Rhodia is gratefully acknowledged.
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