Efficient preparation of chiral non-racemic sulfur compounds

Article abstract of DOI:10.1139/V07-091

p-Menthane-3-carboxaldehyde serves as an efficient chiral auxiliary in the preparation of chiral non-racemic S-alkylthiocarbamates or 5-dithiocarbonates via the 3,3-sigmatropic rearrangement of the corresponding alkylthionocarbamates or xanthates. The tra

Full text of DOI:10.1139/V07-091

603
Efficient preparation of chiral non-racemic sulfur
compounds
Joannie Minville, Mélina Girardin, and Claude Spino
Abstract: p-Menthane-3-carboxaldehyde serves as an efficient chiral auxiliary in the preparation of chiral non-racemic
S-alkylthiocarbamates or S-dithiocarbonates via the 3,3-sigmatropic rearrangement of the corresponding
alkylthionocarbamates or xanthates. The transfer of chirality during rearrangement is complete, and the final products
possess a chiral tertiary or quaternary carbon bearing sulfur. The rearranged products are then transformed into
enantiopure cyclic or acyclic sulfur-containing products, depending on the means of clivage of the auxiliary. The syn-
thesis of a potent MMP-13 inhibitor is presented.
Key words: 3,3-sigmatropic rearrangement, p-menthane-3-carboxaldehyde, S-alkylthiocarbamate, S-dithiocarbonate,
alkylthionocarbamate, xanthate, ring-closing metathesis.
Résumé : Le p-menthane-3-carboxaldéhyde est un auxiliaire chiral efficace dans la préparation de S-alkylthiocarbama-
tes ou de S-dithiocarbonates non chiraux par le biais d’un réarrangement sigmatropique-3,3 des alkylthionocarbamates
ou des xanthates correspondants. Le transfert de chiralité durant ce réarrangement est total et les produits finaux possè-
dent un atome de carbone tertiaire ou quaternaire chiral portant un atome de soufre. Suivant les méthodes utilisées pour
cliver l’auxiliaire, es produits réarrangés sont alors transformés en produits cycliques ou acycliques énantiopurs conte-
nant du soufre. On rapporte la synthèse d’un puissant inhibiteur MMP-13.
Mots-clés : réarrangement sigmatropique-3,3, p-menthane-3-carboxaldéhyde, S-alkylthiocarbamate, S-dithiocarbonate, al-
kylthionocarbamate, xanthate, métathèse accompagnant une fermeture de cycle.
[Traduit par la Rédaction] Minville et al. 618
Introduction
In that regard, we viewed our chiral scaffold derived from
p-menthane-3-carboxaldehyde 7 as ideal to implement a
methodology aimed at preparing chiral sulfur-containing
compounds (Scheme 1) (11). First, the bulky menthyl moi-
ety allows rearrangements reactions to occur at low tempera-
tures (11b). Thus, the 3,3-sigmatropic rearrangement of
allylic thionocarbamates (12, 13), phosphonothionates (12b),
xanthates (14), or similar precursors should proceed smoothly
to give the desired chiral C–S bond, even in the case of
trisubstituted double bonds. Second, the chiral auxiliary is
cleavable by two completely different methods, giving rise
to cyclic or acyclic products. Last, either stereochemistry of
the targeted chiral C–S bond can be selected by controlling
the stereochemistry of the alcohol (both are easily obtained)
and (or) the geometry of the alkene and (or) the absolute
configuration of 7 (both enantiomers are readily available
and inexpensive). This flexibility is a great asset for synthe-
sis.
Many natural and man-made products, containing a sulfur
atom, have huge potential in medicinal chemistry (1). Fig-
ure 1 lists some examples. Montelukast 1 (singulair) is a po-
tent antagonist of the cysteinyl leukotriene receptor and
serves as a prophylactic, once-a-day, anti-asthma agent (2).
Compound 3 is a potent inhibitor of phosphodiesterases
(PDE4) at nanomolar concentrations (3). Natural products,
containing a chiral sulfide moiety, include the fatty-acid
synthetase inhibitors thiolactomycin 4 and thiotetromycin 5
(4), gliotoxin 6 (5), with antiviral, antibacterial, and
immunosuppressive activities, and biotin 2 (6).
The construction of chiral C–O and C–N bonds has
reached a higher level of sophistication than the making of
chiral C–S bonds (7). In fact, chiral C–S bonds are often
made by displacement of the corresponding chiral C–O
bonds (8). When displacing a chiral allylic C–O bond,
transposition may or may not occur. With Mitsunobu reac-
tions, transposition is usually not observed (9), whereas 3,3-
sigmatropic rearrangements provide products with a trans-
posed double bond (10).
Results and discussion
Building the thiocarbamates and xanthates
Our strategy starts with the synthesis of allylic alcohols 8,
which were prepared by one of methods A, B, or C
(Scheme 2). Method A involves the preparation of vinyl io-
dides 17 using Schwartz’ hydrozirconation or hydroboration
of the substituted acetylenes 13. After submitting vinyl io-
dides 17 to a metal-halogen exchange using t-butyllithium,
the resulting vinyllithiums 18a were stereoselectively added
to (–)-p-menthane-3-carboxaldehyde 7 in the presence of
Received 18 May 2007. Accepted 03 July 2007. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
21 August 2007.
J. Minville, M. Girardin, and C. Spino.1 Département de
Chimie, Université de Sherbrooke, Sherbrooke, QC J1K 2R1,
Canada.
1Corresponding author (email: Claude.Spino@USherbrooke.ca).
Can. J. Chem. 85: 603–618 (2007)
doi:10.1139/V07-091
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Can. J. Chem. Vol. 85, 2007
Fig. 1. Biologically active sulfur-containing natural and unnatural products.
CO2Na
O
S
S
HN
NH
H
H
Cl
N
(CH2)5CO2H
HO
Me Me
1
2
O
O
R
N
S
S
N
S
Me
HOHN
H
HO
HO
O O2S
OMe
OMe
O
R
OH
3
4 R = Me
5
6
R = Et
Scheme 1. Strategy to obtain chiral sulfur compounds.
i-Pr
i-Pr
i-Pr
H
R1
R1
R2
O
OH R2
RS
Me
Me
Me
β
7
8 -OH
10
9 α
-OH
X
S
R1
O
R1 R2
RS R2
11
12
trimethylaluminium (15). The major alcohols 8a, c, d, and f
result from the addition of the vinyllithiums to aldehyde 7
following Felkin–Ahn’s model of stereoselectivity (16).
Trimethylaluminium renders this addition highly stereo-
selective, and the Felkin adducts 8 were isolated essentially
as a single isomer (52 to 200:1; Table 1, entries 1, 3, 4, and
6). Method B uses the stereoselective addition of vinylalanes
18b, made from the zirconium-catalyzed carboalumination
(17) of alkynes 13, to aldehyde 7. While this method is
slightly less stereoselective than method A, it is nonetheless
the excess trimethylaluminium used during the carbolu-
mination process that provides this level of stereoselection
(11 to 30:1; Table 1, entries 2, 7, and 8). Evaporation of the
excess trimethylaluminium prior to addition to 7 leads to
lower stereoselectivities. Method C involves the addition of
lithium acetylides 14 to 7. Propargyl alcohol 15, isolated as
a 2:1 mixture of diastereomers, was then converted to the
desired allylic alcohol 8 using Red-Al. All mixtures of alco-
hols 8 and 9 were easily separated by flash chromatography,
and the sequence was continued with isomerically pure alco-
hols as determined by GC or HPLC.
The minor diastereomer 9 (α-OH) could be prepared in
sufficient quantities first by oxidizing the major isomer 8 to
the corresponding enone 19 and then by reducing the latter
using Super-Hydride™ (Scheme 3). This reduction is com-
pletely diastereoselective and gives 9 as the sole diastereo-
mer (11a). Having access to both alcohols 8 and 9 in large
quantities allowed us to measure the diastereoselectivities of
the subsequent reactions. Moreover, both enantiomers of the
final chiral sulfur compounds can be prepared from a single
enantiomer of the chiral auxiliary 7 via alcohols 8 or 9, since
they lead to enantiomeric products after cleavage of the
chiral auxiliary, respectively.
Starting from the allylic alcohols 8 or 9, we procured the
allylic thionocarbamates as intermediates (not shown), using
N-phenylisothiocyanate as reagent to make them. They rear-
ranged to the S-allylthiocarbamates 20 or 21, respectively,
upon acidification of the reaction mixture with PPTS
(Table 2). The rearrangement does not proceed (or proceeds
very slowly) while the allylthionocarbamates are still under
basic conditions. However, once the solution is acidified, the
rearrangement takes place within a few hours at 66 °C.
© 2007 NRC Canada

Minville et al.
605
Scheme 2. Preparation of alcohols 8.
Method C
R1
i-Pr
n-BuLi, THF
7
R1
Li
R1
Et2O, CeCl3
Me
OH
15 β
13
14
-OH
α
16 -OH
Cp2ZrCl2, AlMe3
CH2Cl2
CpZrHCl or
Br2BH·SMe2
I2
Method B
Red-AlTM
THF
i-Pr
R2
R2
7
t-BuLi, Et2O
Method A
R1
I
M
Et2O, AlMe3
R1
R1
OH R2
Me
β
17
18a M = Li
18b M = AlMe2
8 -OH
9 α
-OH
Table 1. Yields and % de of alcohols 8.
Entry
13
R1
R2
Method
Yield (%)a
de (%)b
98
94
>99
>99
90
1
2
3
4
5
6
a
b
c
d
e
f
n-Pr
n-Pr
t-Bu
Me3Si
Ph
H
Me
H
H
H
A
B
A
A
C
A
72
87
66
46
97
68
Ph(CH2)4
H
96
7
8
g
Ph(CH2)4
Bn
Me
Me
B
B
82
81
88
92
h
aIsolated yield.
bMeasured by GC or HPLC on crude mixtures.
Scheme 3. Preparation of the diastereomeric alcohols 9.
TPAP
NMO
i-Pr
i-Pr
i-Pr
R1
R1
R1
Et3BHLi
THF
OH R2
O
R2
OH R2
Me
Me
Me
CH2Cl2
8
19
9
Many substrates underwent the rearrangement slowly at
room temperature within several days. This sequence al-
lowed us to prepare various S-allylthiocarbamates 20a–20h
and 21a–21h in good to excellent yields with diastereomeric
excesses (de) > 90%. We believe that the de of compound
21f reported in Table 2, entry 12 is > 76%. The lower-than-
expected value may be due to an impurity that co-elutes with
the diastereomer of 21f, and that we could neither identify
nor remove. The structure of 20c was confirmed by single
crystal X-ray diffraction analysis, and it was consistent with
a concerted rearrangement of 8c via a chair-like transition
state (TS) 20-E-chair (Scheme 4).
one. Indeed, a close look at the possible transition states
(Scheme 4, only the chair-like TS are represented) (19) leads
us to the conclusion that to attack the alkene face leading to
the minor S-thiocarbamate, the thionocarbamate must maxi-
mize its A1,3 strain, which would give a product having a Z
double bond. There is no concerted pathway leading to 21
from 8 or to 20 from 9. Ionic intermediates, on the other
hand, would collapse to a mixture of 20 and 21 regardless of
their origin.
One might wonder why we did not observe the formation
of regioisomers 23 as a minor product if ionic intermediates
are involved. However, it is our experience that the menthyl
moiety is very efficient at preventing attack at the β position.
For example, when alcohol 8g is submitted to an acidic envi-
ronment, some regioisomer 24g was isolated as a mixture of
diastereomers, but the recovered alcohol 8g was diastereo-
The minor S-thiocarbamates in the rearrangement of the
thionocarbamates derived from 8 or 9 do not come from a
competing concerted transition state (18) but must instead be
derived from ionic pathways competing with the concerted
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Can. J. Chem. Vol. 85, 2007
Table 2. Yields and % de of thiocarbamates 20 and 21.
i-Pr
i-Pr
R1
i) NaH, THF, 0 ºC
R1
R2
OH R2
∆
ii) PhN=C=S,
2.5–3 h
Me
S
Me
NHPh
∆
iii) PPTS, , 1-3 h
O
8 β
20 β
-OH
-SC(O)NHPh
α
21 -SC(O)NHPh
α
-OH
9
Entry
Alcohol
R1
R2
Product
Yield (%)a
de (%)b
98
>99
>99
98
98
>99
>99
1
2
3
4
5
6
7
8a
9a
8b
9b
8c
9c
8d
n-Pr
H
H
Me
Me
H
20a
21a
20b
21b
20c
21c
20d
97
99
75
65
96
99
99
n-Pr
n-Pr
n-Pr
t-Bu
t-Bu
Me3Si
H
H
8
9
9d
8e
Me3Si
Ph
H
H
21d
20e
87
81
>99
93
10
11
9e
8f
Ph
H
H
21e
20f
97
99
90
97
Ph(CH2)4
Ph(CH2)4
Ph(CH2)4
Ph(CH2)4
12
13
14
9f
H
21f
20g
21g
94
87
67
76c
8g
9g
Me
Me
98
>99
15
16
8h
9h
Bn
Bn
Me
Me
20h
21h
88
85
99
>99
aIsolated yield.
bMeasured by GC or HPLC on crude mixture.
cPresence of impurity with same retention time as diastereomer makes % de appear lower than actual value.
Scheme 4. Chair-like transition state for the rearrangement.
X
X
NPh
S
H
H
R2
O
O
NHPh
NPh
Aux
R1
H
Aux
O
δ
-
δ
+
S
S
)(
R1
Aux
R2
20-E-chair
22-Z -chair
R1 R2
β
γ
α
Aux
R2
Aux
SR
R2 R1
20
SR
R2 R1
SR R1
Aux
22
23
i-Pr
i-Pr
SiO2
(CH2)4Ph
(CH2)4Ph
Me
Me
OH Me
HO
24g
Me
8g
© 2007 NRC Canada

Minville et al.
607
Table 3. Yields and % de of S-thiocarbonates 25 and 26 and S-thiocarbamates 27 and 28.
i-Pr
i-Pr
R1
R1
R2
i) NaH, THF, 0ºC
OH R2
S
Me
Me
∆
ii) CS2, , 2 h
∆
iii) MeI, , 2 h
SMe
O
β
β
8 -OH
9
25 -SC(O)SMe
26
α
α
-OH
-SC(O)SMe
Entry
Alcohol
R1
R2
Product
Yield (%)a
de (%)b
99
98
>99
98
1
2
3
4
5
8b
9b
8c
9c
8f
n-Pr
n-Pr
t-Bu
t-Bu
Me
Me
H
H
H
25b
26b
25c
26c
25f
59
39
99
90
85
Ph(CH2)4
>99
6
9f
Ph(CH2)4
H
26f
85
96
7
8
9
10
8c
9c
8e
9e
t-Bu
t-Bu
Ph
H
H
H
H
27c
28c
27e
28e
78
42
0
97
99
—
Ph
0
—
aIsolated yield.
bMeasured by GC or HPLC on crude mixture.
Scheme 5. Imidazole variant of the thiocarbamate rearrangement.
O
S
N
N
i-Pr
i-Pr
R1
N
R1
N
R2
N
OH R2
Me
S
PhMe, RT, 3 d
Me
N
O
β
β
8
9
27
-SC(O)imid
28 -SC(O)imid
-OH
α
-OH
α
merically pure. This implies that the ionic intermediates col-
lapsed exclusively to the regioisomer 24g.
24 h. The analogous thionocarbamates made from 8f and 9f
did not rearrange after the same time at room temperature.
Several days later, some rearrangement was observed for 8f
and 9f, but the reaction had not reached completion. This
same trend was observed for 8a and 8c.
Xanthates derived from alcohols 8 or 9 rearranged to al-
lylic dithiocarbonates 25 or 26 (Table 3, entries 1–6). The
reaction conditions and times were very similar to the ones
used for the thionocarbamates. Table 3 reveals that yields
and diastereoselectivities are also comparable. The main dif-
ference resides in the subsequent cleavage of the chiral aux-
iliary (see later).
We also tested the rearrangement on the imidazole variant
of thionocarbamates because they are supposed to proceed at
lower temperatures, which could be an advantage for some
thermally unstable substrates (Scheme 5 and Table 3, entries
7–10) (20). Indeed, we obtained a 78% yield of 27c from 8c
after stirring for 3 days at room temperature (Table 3, entry
7). However, while the rearrangements were somewhat faster
than their N-phenyl carbamate analogs, it proved to be less
general. For example, alcohols 8e and 9e yielded only elimi-
Our observation that the thionocarbamates (Scheme 4,
X = H) rearrange much faster than the metallated thiono-
carbamates (X = Na) is in line with observations by Nakai
and Zaim that electron donors (e.g., R2N) at that position
slowed the rearrangement, while an electron-withdrawing
group such as Cl increased the reaction rate (18). Possibly,
the proton sits exclusively on the nitrogen atom in the
thionocarbamate, while the metal is perhaps on sulfur. Ac-
cording to Nakai and Ari-Izumi, a higher bond order for the
thiocarbonyl is found in precursors that undergo fast reac-
tions (18a).
Also, these authors found that substitution on the allylic
fragment increased the reaction rate. Although we have not
measured the actual rate constants of our reactions, we have
qualitatively observed that the thionocarbamates derived
from the trisubstituted allylic alcohols 8b, g, h and 9b, g, h
rearranged substantially faster than the others. For example,
the thionocarbamates derived from 8g and 9g rearranged in
53% and 67% yield, respectively, at room temperature in
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608
Can. J. Chem. Vol. 85, 2007
Scheme 6. Oxidative cleavage of the S-thiocarbamate 20c.
O
NHPh
S
O
NHPh
i) O3, CH2Cl2, -78 oC
Ph
i-Pr
N
S
O
S
+
HO
ii) Reducing agent
H
t-Bu
HO
Me
20c
29
30
NaBH4
BH SMe
<16%
57%
>64%
0%
·
3
2
Scheme 7. Oxidative cleavage of S-thiocarbonates 25c, 25f, and 26f.
SMe
S
O
SMe
a) O3, CH2Cl2, -78 ºC
b) NaBH4, 89%
i-Pr
O
S
HO
t-Bu
H
25c
t-Bu
Me
31
O
SMe
SMe
S
a) O3, CH2Cl2, -78 ºC
b) NaBH4, 0% or
i-Pr
S
O
HO
H
(CH2)4Ph
b) BH SMe
·
3 2
Me
Ph
83%, >95% ee
25f
(R)-32
O
SMe
SMe
S
a) O3, CH2Cl2, -78 ºC
i-Pr
S
H
O
b) BH SMe
·
3
57%, >95% ee
2
HO
Ph(H2C)4
Me
Ph
(S)-32
26f
nation and other decomposition products under those condi-
tions.
thiazolidinone 30 in 80% combined yield (Scheme 6). When
BH3·SMe2 was used as the reducing agent, only alcohol 29
was formed in 57% yield. The Lemieux protocol (OsO4/NaIO4)
or similar methodologies are less efficient and often lead to
a mixture of products.
The yields of cleavage products were consistently better
from S-thiocarbonates 25 or 26. Here too, the use of
BH3·SMe2 usually gives superior results, though sodium
borohydride can give good yields of products (Scheme 7).
This is the protecting group of choice for sulfur if oxidative
cleavage is needed. We verified the stereochemical integrity
of the alcohols 32 by making the Mosher ester derivatives on
both enantiomers and found no racemization. Aldehydes can
be prepared using dimethylsulfide as reducing agent but α-
thioaldehydes are sensitive to racemization and must be used
without purification, unless of course the α-position is
dialkylated (see later).
The low temperature at which all of these rearrangements
take place is noteworthy and likely the result of the steric
volume of the menthyl fragment (steric decompression).2
Some thionocarbamates derived from 8 or 9 undergo rear-
rangement at room temperature, albeit rather slowly.
Usually, such compounds require heating in excess of
100 °C for the rearrangement to take place. For example,
Thomas and co-workers used, in their synthesis of thio-
tetronic acids, a xanthate to thiocarbonate rearrangement that
occurred at 145 °C during distillation (10).
Cleaving the chiral auxiliary
Oxidative cleavage
Cleavage of the auxiliary in S-thiocarbamate 20c with ozone,
the usual method by which we cleave this chiral auxiliary
(11), resulted in the efficient conversion of the starting mate-
rial. Indeed, a reductive work-up with NaBH4 led to the for-
mation of a mixture of the desired alcohol 29 and
Cleavage by ring-closing metathesis
We have recently discovered that it is possible to generate
2 We have observed the same phenomenon for the Claisen rearrangement, see ref. 11.
© 2007 NRC Canada

Minville et al.
609
Scheme 8. RCM cleavage of allylic sulfide 33c and 34c.
0.01 mol/L, CH2Cl2
reflux, 86%
n
R
S
i-Pr
S
i-Pr
+
10%
MesN
NMes
Cl
t-Bu
Me
H
t-Bu
Me
35
Cs2CO3
Ru
20c
R = OCNHPh
38
36c n=1
37c n=2
∆
Br
MeOH,
Ph
Cl
PCy3
33c R = CH2CH=CH2
34c R = (CH2)2CH=CH2
n
Scheme 9. RCM cleavage of allylic sulfide 33a.
R
S
i-Pr
0.01 mol/L, CH2Cl2
reflux, 86%
S
H
n-Pr
Me
10% 35
no L.A. : 0%
((C6H6)RuCl2)2 : 97%
n-Pr
36a
Cs2CO3
20a R = OCNHPh
33a
∆
Br
MeOH,
R = CH2CH=CH2
n
Scheme 10. RCM cleavage of allylic sulfones 39a and 39c.
O
m-CPBA
i-Pr
0.01 mol/L, CH2Cl2
reflux
S
O
CH2Cl2
O
S
33a
33c
O
0 ºC
Me
39a
72%
39c 77%
H
R
R
10% 35
40a
40c
97%
84%
39a
R = n-Pr
39c R = t-Bu
40a
R = n-Pr
40c R = t-Bu
chiral nonracemic cycloalkenes by ring-closing metathesis
(21) starting from dienes that still possess the menthyl moi-
ety (22). To the best of our knowledge, this was the first ex-
ample of a chiral auxiliary that could be cleaved by RCM.
However, several heteroatoms, sulfur in particular (21, 23),
may cause problems by coordinating to the metal center, and
it was unclear at the onset if chiral S-heterocycles could be
prepared by this method.
Thus, the carbamate functionality in 20c was hydrolyzed
and the resulting thiol alkylated in a one-pot procedure to
give the precursor 33c in 84% yield. To our delight, 2,5-
dihydrothiophene (24) 36c was obtained in 86% yield from
33c using the Grubbs–Nolan catalyst 35 (25) (Scheme 8). It
appeared that catalyst poisoning was not going to be a prob-
lem, or so we thought. Compound 38 is very conveniently
recovered by evaporation and distillation. It can be converted
back to the chiral auxiliary 7 by ozonolysis.
To our surprise, the very similar precursor 33a, prepared
in the same way from 20a, gave no cyclic product under
identical conditions (Scheme 9). Instead, some dimer (not
shown) was isolated. We had to add an external Lewis acid
to get the reaction to go (97% conversion by NMR).3 A ru-
thenium(II) dimer was the Lewis acid that gave the best re-
sults.
3,6-Dihydrothiopyrans 37c could not be prepared from of
the corresponding precursors 34c, after testing several sol-
vents, catalysts, Lewis acids, and other additives (Scheme 8).
Sulfolenes 40a and 40c were efficiently prepared by RCM
cleavage of 39a and 39c, respectively (Scheme 10). The low
temperature used for RCM cleavage in this case was essen-
tial, since higher temperatures lead to the slow cheletropic
extrusion of SO2 in the sulfolene product to give the corre-
sponding 1,3-dienes. Again, we were unable to prepare the
analogous six-membered cyclic sulfones.
There seem to be several factors controlling the rate of
RCM in our system. It is plausible that the formation of 3,6-
dihydrothiopyrans 37 is prevented by the formation of a sta-
ble chelate II between sulfur and ruthenium (Fig. 2). The al-
lylic sulfides do not form a stable chelate (cf. I in Fig. 2),
and in those cases, poisoning of the catalyst probably occurs
intermolecularly. In this case, bulky R groups such as t-Bu
in 33c or external Lewis acids are enough to allow the reac-
tion to proceed.
We have shown previously that the formation of six-
membered carbo- or N-heterocycles is kinetically less fa-
vored than the formation of the analogous five-membered
rings (22). We suggest that under the reaction conditions and
time used, the RCM reaction does not reach equilibrium and
3 Isolated yield was low because of the high volatility of the product.
© 2007 NRC Canada

610
Can. J. Chem. Vol. 85, 2007
Fig. 2. Possible chelates in RCM of allylic sulfides and sulfones.
tained and could be purified. Its treatment with Jones’ re-
agent gave 47 in 53% yield for the two steps. Carrying out
the two previoulsy reported steps (27) completed the synthe-
sis of 42 for a total of eight steps and 12% overall yield
from 43.
In conclusion, we have successfully extended our p-
menthane-3-carboxaldehyde based methodology to include
the formation of chiral sulfur-bearing tertiary and quaternary
carbons. This methodoly is becoming highly versatile and
compares favorably to methodologies based on the classical
alkylation of chiral enolates (30). Furthermore, carbo-, N-
hetero-, and S-heterocyclic compounds are now directly ac-
cessible using RCM without the need for an extra step to
cleave the auxiliary.
Ru(L)n
Aux
Aux
S
Aux
S
Ru(L)n
H
H
H
H
R
R
I
II
Ru(L)n
O
O
S
Aux
S
Ru(L)n
O
O
R
R
III
IV
that the difference in efficiency of formation of
dihydrothiophenes and dihydrothiopyrans is kinetically
driven. We think that perhaps the longer C–S bond (>1.8 Å)
hampers the ring-closing metathesis for six-membered ring
formation and that poisoning of the catalyst is not the sole
problem in this case, since a fair amount of dimer was iso-
lated in each case.
Experimental4
General
Sulfones do form internal chelates with ruthenium, but the
oxygen–ruthenium bond is weaker such that allylic sulfones
(III, Fig. 2) undergo RCM fast enough, while homoallylic
sulfones yield mostly dimer because of the slower rate of
six-membered ring formation (IV, Fig. 2).
Flash chromatography was performed using Merck silica
gel (230–400 Mesh ASTM) with solvents distilled prior to
use. NMR spectra were recorded on a Bruker AC-300 spec-
trometer (1H NMR at 300 MHz, 13C NMR at 75.5 MHz). In-
frared spectra were recorded on a PerkinElmer 1600 FTIR
spectrometer with a thin layer of the product on a NaCl disc.
HPLC analyses were performed on a HP 1100 apparatus;
GC analyses were performed on a Agilent 6890 series appa-
ratus; GCMS analyses were performed on a HP 5890 serie II
instrument (25 m length, 25µ OD, capillary Stabiliwax-DB5
column) coupled with a mass spectrometer (HP 5971). High-
resolution spectrometry was performed on a ZAB-1F
Synthesis of a potent MMP inhibitor
Several sulfonylhydroxamic acids are potent matrix
metalloproteinase (MMP) inhibitors that have been studied
in the clinic for the treatment of cancer and osteoarthritis
(Fig. 3) (26). The overexpression of MMPs may result in the
degradation of cartilage and may lead to medical conditions,
such as osteoarthritis and rheumatoid arthritis. Compounds
41 and 43 are two highly selective inhibitors of MMP-13 in
the nanomolar concentration (27) that may offer protection
against cartilage degradation and potentially better treatment
of osteoarthritis (28). Compounds 41 and 42 were previously
prepared as racemic mixtures, but a small amount of 41 was
resolved by preparative HPLC on a chiral column, and it
was shown that (+)–41 was 20 times as active as (–)–41
(27). Their asymmetric synthesis thus becomes interesting.
We synthesized 42 as shown in Scheme 11. Alcohol 8h
was easily prepared in two steps from the commercially
available propynylbenzene 43. The ratio of β- and α-alcohols
8h and 9h was excellent, and their chromatographic separa-
tion was easy. Diastereomerically pure alcohol 8h was sub-
mitted to the rearrangement conditions to give 20h in 88%
micromass spectrometer. Optical rotations [α]20 were mea-
D
sured on a PerkinElmer 343 polarimeter.
Alcohol 8f (method A)
Vinyliodide 17f (5.50 g, 19.2 mmol) was dissolved in di-
ethyl ether (70.0 mL), and the solution was cooled to –
78 °C. A solution of t-BuLi in pentane (38.4 mmol) was
added dropwise to the mixture. The reaction mixture was
stirred at –78 °C for 30 min and then at RT for 1 h. It was
again cooled to –78 °C before the addition of
trimethylaluminium (2.0 mol/L in hexanes, 24.0 mL,
48.0 mmol) followed by a solution of (–)-p-menthane-3-
carboxaldehyde 7 (2.70 g, 16.0 mmol) in diethyl ether
(10.0 mL). The reaction mixture was stirred at –78 °C for
2 h and then at RT overnight. The reaction was quenched
with an aqueous solution of sodium bicarbonate (100 mL) at
0 °C. The two phases were separated, and the aqueous phase
was extracted with diethyl ether (3 × 100 mL). The com-
bined organic portions were washed with brine, dried with
anhyd. magnesium sulfate, and evaporated under reduced
pressure. The crude product (8f:9f 52:1 by GC) was purified
by flash chromatography on silica gel eluting with a mixture
of hexanes/ethyl acetate (100: 0 to 95:5). A colorless oil was
obtained (3.44 g, 55%).
yield as essentially
a
single diastereomer. The S-
thiocarbamate function could be directly coupled to iodide
45 using Tamaru’s allylsulfenylation conditions to give a
good yield of 46 (29). The synthesis was continued by first
oxidizing the sulfur in 46, then oxidatively cleaving the
chiral auxiliary with ozone. Acid 47 could be obtained di-
rectly in one step by treating 46 with ozone, but this proce-
dure led to lower yield of 47 and many decomposition
products. Alternatively, when dimethylsulfide was used in
the ozonolysis work-up, the α-sulfonylaldehyde was ob-
4 Supplementary data for this article are available on the journal Web site (canjchem.nrc.ca) or may be purchased from the Depository of Un-
published Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5199. For more in-
formation on obtaining material, refer to cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
© 2007 NRC Canada

Minville et al.
611
Fig. 3. Biologically active sulfonylhydroxamic acids.
N
O
N
O2S
N
O
O
O
HOHN
S
O2
HOHN
S
Prinomastat
OR1
CGS-27023
O
O
R2
O2S
Me
Cl
NHOH
S
O2
O
NHOH
O
1
2
O
43
41 R =Et, R =
N
42 R1 =Me, R2 =H
Scheme 11. Synthesis of MMP-13 inhibitor 42.
i) Cp2ZrCl2, AlMe3
CH2Cl2, 0 oC
n-BuLi (2.5 eq)
i-Pr
Et2O
Ph
Ph
Ph
o
ii) , THF, -78 C
0 oC, 80%
Me
OH Me
7
81%, 24:1
43
44
8h
OMe
OMe
O
NHPh
i) NaH, THF, 0 oC
45
ii) PhNCS, THF, reflux
Aux
I
S
Aux
S
Pd(PPh3)4, PPh3
Cs2CO3, PhMe
111 ºC, 72%
Me
20h
Me
iii) PPTS, THF, reflux
88%, 99% de
46
OMe
OMe
O
1. Cl2(CO)2, DMF/CH2Cl2
1. mCPBA, 85%
O S
O2S
Me
2. NH2OH, CH2Cl2
65% for 2 steps
2. a) O3, CH2Cl2
b) DMS
c) Jones', 51%
O
Ph
O
NHOH
OH
47
42
6.6 Hz), 0.76 (d, 3H, J = 7.2 Hz). 13C NMR (75.5 MHz,
CDCl3) δ (ppm): 142.7 (s), 132.5 (d), 130.4 (d), 128.4 (d),
128.2 (d), 125.7 (d), 71.3 (d), 44.8 (d), 43.0 (d), 35.8 (q),
35.1 (t), 33.8 (q), 32.8 (d), 32.2 (t), 31.0 (t), 28.9 (t), 26.3
(d), 24.3 (q), 22.8 (t), 21.6 (t), 15.5 (t). IR (neat) ν (cm–1):
3395, 2927, 2857, 1454, 966, 698. LRMS (m/z, relative in-
Compound 8f
1H NMR (300 MHz, CDCl3) δ (ppm): 7.30–7.25 (m, 2H),
7.19–7.15 (m, 3H), 5.66–5.49 (m, 2H), 4.41–4.31 (m, 1H),
2.61 (t, 2H, J = 7.5 Hz), 2.15–2.06 (m, 3H), 1.70–1.58 (m,
5H), 1.44 (dt, 2H, J = 14.9, 7.5 Hz), 1.35–1.21 (m, 4H),
1.06–0.78 (m, 2H), 0.93 (d, 3H, J = 7.2 Hz), 0.87 (d, 3H, J =
© 2007 NRC Canada

612
Can. J. Chem. Vol. 85, 2007
tensity) 328 (M+, 18), 285 (4), 171 (95), 83 (100). HRMS
15.6 (q). IR (neat) ν (cm–1): 3362, 2927, 2857, 1453, 1001,
698. LRMS (m/z, relative intensity) 342 (M+, 8), 324 (M+ -
H2O, 4), 203 (81), 185 (49), 91 (100). HRMS calcd. for
calcd. for C23H36O: 328.2766, found: 328.2769. [α]20 –9.2
D
(c = 1.39, CHCl3).
C24H38O: 342.2922, found: 342.2924. [α]20 –25.9 (c =
D
Compound 9f
1.01, CHCl3).
1H NMR (300 MHz, CDCl3) δ (ppm): 7.36–7.31 (m, 2H),
7.26–7.21 (m, 3H), 5.75–5.66 (m, 1H), 5.61–5.53 (m, 1H),
4.45–4.41 (m, 1H), 2.69 (t, 2H, J = 7.7 Hz), 2.23–2.13 (m,
3H), 2.08–1.99 (m, 2H), 1.81–1.62 (m, 3H), 1.56–1.32 (m,
2H), 1.13–0.70 (m, 6H), 1.01 (d, 3H, J = 6.6 Hz), 0.94 (d,
3H, J = 6.6 Hz), 0.88 (d, 3H, J = 6.6 Hz). 13C NMR
(75.5 MHz, CDCl3) δ (ppm): 142.6 (s), 132.7 (d), 129.3 (d),
128.4 (d), 128.3 (d), 125.7 (d), 72.1 (d), 44.7 (d), 44.0 (d),
35.9 (q), 35.3 (t), 34.0 (q), 32.6 (d), 32.4 (t), 31.0 (t), 29.1
(t), 26.1 (d), 24.3 (q), 23.0 (t), 21.6 (t), 15.3 (t). IR (neat) ν
(cm–1): 3342, 2929, 2856, 1453, 971, 698. LRMS (m/z, rela-
tive intensity) 328 (M+, 20), 267 (12), 171 (100), 91 (90).
HRMS calcd. for C23H36O: 328.2766, found: 328.2762.
Compound 9g
1H NMR (300 MHz, CDCl3) δ (ppm): 7.36–7.25 (m, 2H),
7.19–7.16 (m, 3H), 5.32 (d, 1H, J = 9.4 Hz), 4.59 (dd, 1H,
J = 9.4, 3.9 Hz), 2.62 (t, 2H, J = 7.7 Hz), 2.06 (t, 2H, J =
7.1 Hz), 1.94 (dd, 1H, J = 12.7, 2.8 Hz), 1.84–1.77 (m, 1H),
1.69 (s, 3H), 1.72–1.18 (m, 8H), 1.07–0.70 (m, 10H), 0.90
(d, 3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm):
142.5 (s), 140.5 (s), 128.4 (d), 128.2 (d), 125.6(d), 123.4 (d),
67.8 (d), 44.5 (d), 44.1 (d), 39.7 (t), 35.7 (t), 35.2 (t), 34.0
(t), 32.6 (d), 30.8 (t), 27.3 (t), 26.4 (d), 24.1 (t), 22.8 (q),
21.5 (q), 16.4 (q), 15.3 (q). IR (neat) ν (cm–1): 3355, 2931,
2858, 1453, 1020, 698. LRMS (m/z, relative intensity) 342
(M+, 14), 324 (M+ – H2O, 4), 203 (100), 185 (75), 91 (79).
HRMS calcd. for C24H38O: 342.2922, found: 342.2924.
[α]20 –20.5 (c = 1.71, CHCl3). 98% de (GC).
D
[α]20 –27.3 (c = 0.70, CHCl3).
Alcohol 8g (method B)
D
A flask containing a solution of bis(cyclopentadienyl)zir-
conium dichloride (129 mg, 0.44 mmol) in 6.3 mL of di-
chloromethane was put under vacuum and then filled with
argon (3×). Trimethylaluminium (545 µL, 5.69 mmol) was
added using a sass equipped with a syringe under an argon
atmosphere. The solution was stirred 10 min at RT and then
5 min at 0 °C before the dropwise addition of hex-5-
ynylbenzene (300 mg, 1.90 mmol). The mixture was stirred
General procedure for the preparation of S-
allylthiocarbamates
To a solution of the allylic alcohol 8 or 9 (0.198 mmol) in
THF (2 mL) at 0 °C was added NaH 60% w/w in oil (15 mg,
0.372 mmol), and the mixture was stirred for 1 h at this tem-
perature before the addition of phenylisothiocyanate (47 µL,
0.396 mmol). The reaction was heated to reflux and stirred
for 3 h. It was then cooled down to RT before the addition of
pyridinium p-toluenesulfonate (124 mg, 0.495 mmol) in
THF (3.3 mL). The reaction was then heated to reflux for 2–
3 h. Then, the reaction was stopped by the addition of water
(5 mL) and Et2O (5 mL). The two phases were separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were washed with brine, dried
with anhyd. MgSO4, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatogra-
phy on silica gel (100% hexanes to 5% EtOAc in hexanes)
to afford the desired product.
at RT overnight.
A
solution of (–)-p-menthane-3-
carboxaldehyde 7 (246 mg, 1.46 mmol) in 4.9 mL of
tetrahydrofuran was added dropwise to the reaction mixture
at –78 °C. The reaction was warmed to RT and stirred over-
night. A saturated aqueous solution of potassium carbonate
was added dropwise until gas evolution stopped. The white
precipitate was dissolved in a 1 N aq. solution of HCl. Then
a 5 N aq. solution of HCl was added until the two layers
were clear. The two phases were separated, and the aqueous
layer was extracted three times with dichloromethane
(50 mL). The organic layers were combined, washed with a
saturated aqueous solution of sodium bicarbonate, dried over
MgSO4, filtered, and evaporated under reduced pressure.
The crude compound was determined to be a mixture of the
two diastereomers 8g and 9g in a ratio of 94:6 (88% de).
The crude product was purified by flash chromatography on
silica gel (100% hexanes to 5% EtOAc in hexanes). Two
colorless oils were isolated (major diastereomer 8g, 132 mg,
75%, >99% de by HPLC.; minor diastereomer 9g, 12 mg,
7%, >99% de).
S-allylthiocarbamate 20c
Prepared following the general procedure for the synthesis
of S-allylthiocarbamates. Reaction time after the addition of
pyridinium p-toluenesulfonate: 2 h. Compound 20c was iso-
lated as a white solid (74 mg, 96%, 98% de by GC), mp
1
102–103 °C. H NMR (300 MHz, CDCl3) δ (ppm): 7.41 (d,
2H, J = 8.3 Hz), 7.30 (t, 2H, J = 8.0 Hz), 7.11–7.07 (m, 2H),
5.50–5.47 (m, 2H), 3.97–3.94 (m, 1H), 1.91–1.78 (m, 2H),
1.70 (dm, 1H, J = 12.1 Hz), 1.62–1.53 (m, 2H), 1.36–1.21
(m, 1H), 1.01 (s, 9H), 0.98–0.78 (m, 4H), 0.85 (d, 3H, J =
7.2 Hz), 0.82 (d, 3H, J = 6.6 Hz), 0.70 (d, 3H, J = 7.2 Hz).
13C NMR (75.5 MHz, CDCl3) δ (ppm): 165.1 (s), 138.1 (d),
137.9 (s), 129.0 (d), 127.0 (d), 124.1 (d), 119.5 (d), 59.9 (d),
47.0 (s), 44.9 (d), 42.9 (t), 35.1 (t), 34.4 (d), 32.5 (d), 28.2
(d), 27.9 (q), 23.9 (t), 22.5 (q), 21.4 (q), 15.1 (q). IR
(CHCl3) ν (cm–1): 3395–3210 (br), 2958, 2922, 2869, 1659,
1440, 1143, 750. LRMS (m/z, relative intensity) 387 (M+, 5),
330 ((M – C4H9)+, 3), 177 (64), 97 (100). HRMS calcd. for
Compound 8g
1H NMR (300 MHz, CDCl3) δ (ppm): 7.30–7.25 (m, 2H),
7.19–7.15 (m, 3H), 5.34 (d, 1H, J = 7.7 Hz), 4.67 (d, 1H, J =
8.3 Hz), 2.62 (t, 2H, J = 7.7 Hz), 2.23–2.14 (m, 1H), 2.04 (t,
2H, J = 7.4 Hz), 1.71–1.42 (m, 7H), 1.63 (s, 3H), 1.35–1.24
(m, 3H), 1.14 (br s, 1H), 1.04–0.79 (m, 2H), 0.94 (d, 3H, J =
7.1 Hz), 0.88 (d, 3H, J = 6.6 Hz), 0.79 (d, 3H, J = 6.6 Hz).
13C NMR (75.5 MHz, CDCl3) δ (ppm): 142.7 (s), 136.5 (s),
128.4 (d), 128.2 (d), 127.2(d), 125.7 (d), 67.6 (d), 44.9 (d),
43.2 (d), 39.5 (t), 35.8 (t), 35.2 (t), 34.1 (t), 32.8 (d), 31.0
(t), 27.2 (t), 26.3 (d), 24.3 (t), 22.9 (q), 21.7 (q), 16.5 (q),
20
C24H37ONS: 387.2596, found: 387.2591. [α]D –118.7 (c =
1.31, CHCl3).
© 2007 NRC Canada

Minville et al.
613
for C24H37ONS: 387.2596, found: 387.2591. [α]20 –165.1
S-allylthiocarbamate 20g
D
(c = 1.03, CHCl3).
Prepared following the general procedure for the synthesis
of S-allylthiocarbamates. Reaction time after the addition of
pyridinium p-toluenesulfonate: 3 h. Compound 21g was iso-
S-allylthiocarbamate 21g
1
lated as a colorless oil (83 mg, 87%, 80% de by HPLC). H
Prepared following the general procedure for the synthesis
of S-allylthiocarbamates. Reaction time after the addition of
pyridinium p-toluenesulfonate: 3 h. Compound 21g was iso-
NMR (300 MHz, CDCl3) δ (ppm): 7.39 (d, 2H, J = 7.7 Hz),
7.32–7.24 (m, 4H), 7.18–7.03 (m, 5H), 5.66 (d, 1H, J =
15.6 Hz), 5.39 (dd, 1H, J = 15.6, 9.1 Hz), 2.61 (t, 2H, J =
7.7 Hz), 2.07–1.94 (m, 2H), 1.93–1.55 (m, 6H), 1.62 (s, 3H),
1.45–1.32 (m, 3H), 1.04–0.71 (m, 5H), 0.85 (d, 3H, J =
7.2 Hz), 0.84 (d, 3H, J = 6.1 Hz), 0.67 (d, 3H, J = 6.6 Hz).
13C NMR (75.5 MHz, CDCl3) δ (ppm): 165.0 (s), 142.5 (s)
137.7 (s), 135.7 (d), 133.2 (d), 129.0 (d), 128.2 (d), 125.7
(d), 124.2 (d), 119.6 (d), 55.3 (s), 47.1 (d), 45.0 (d), 43.2 (t),
40.6 (t), 35.9 (t), 35.1 (t), 32.4 (d), 31.6 (t), 28.2 (d), 24.5
(q), 24.0 (t), 22.5 (q), 21.4 (q), 15.2 (q). IR (neat) ν (cm–1):
3456, 2925, 2865, 1660, 1436, 1139, 750. LRMS (m/z, rela-
tive intensity) 477 (M+, 4), 325 (60), 137 (60), 119 (100).
HRMS calcd. for C31H43ONS: 477.3065, found: 477.3056.
1
lated as a colorless oil (64 mg, 67%, 98% de by HPLC). H
NMR (300 MHz, CDCl3) δ (ppm): 7.37 (d, 2H, J = 7.7 Hz),
7.32–7.24 (m, 4H), 7.18–7.14 (m, 3H), 7.08 (t, 1H, J =
7.7 Hz), 6.98 (br s, 1H), 5.62 (d, 1H, J = 15.7 Hz), 5.39 (dd,
1H, J = 15.7, 9.4 Hz), 2.61 (t, 2H, J = 7.7 Hz), 2.04–1.79
(m, 3H), 1.73–1.45 (m, 6H), 1.64 (s, 3H), 1.43–1.25 (m,
3H), 1.04–0.78 (m, 4H), 0.85 (d, 3H, J = 6.6 Hz), 0.81 (d,
3H, J = 7.2 Hz), 0.64 (d, 3H, J = 7.2 Hz). 13C NMR
(75.5 MHz, CDCl3) δ (ppm): 164.9 (s), 142.5 (s) 137.6 (s),
135.7 (d), 133.2 (d), 129.0 (d), 128.4 (d), 128.2 (d), 125.6
(d), 124.1 (d), 119.4 (d), 53.6 (s), 47.2 (d), 44.8 (d), 43.2 (t),
40.7 (t), 35.7 (t), 35.1 (t), 32.4 (d), 31.6 (t), 28.0 (d), 24.5
(q), 24.3 (t), 24.0 (t), 22.5 (q), 21.4 (q), 15.2 (q). IR (neat) ν
(cm–1): 3302, 2947, 2928, 2869, 1660, 1513, 1435, 1137,
749. LRMS (m/z, relative intensity) 477 (M+, 1), 357 (1),
325 (95), 119 (100). HRMS calcd. for C31H43ONS:
[α]20 –37.0 (c = 1.30, CHCl3).
D
S-allylthiocarbamate 20h
Prepared following the general procedure for the synthesis
of S-allylthiocarbamates. Reaction time after the addition of
pyridinium p-toluenesulfonate: 3 h. Compound 21h was iso-
477.3065, found: 477.3056. [α]20 –175.6 (c = 0.52,
D
CHCl3).
1
lated as a colorless oil (77 mg, 88%, 99% de by HPLC). H
NMR (300 MHz, CDCl3) δ (ppm): 7.44 (d, 2H, J = 8.3 Hz),
7.34 (d, 2H, J = 7.2 Hz), 7.35–7.22 (m, 4H), 7.15–7.09 (m,
2H), 5.82 (d, 1H, J = 15.4 Hz), 5.32 (dd, 1H, J = 15.4,
9.4 Hz), 3.35 (ABq, 2H), 2.01–1.90 (m, 1H), 1.76–1.57 (m,
4H), 1.61 (s, 3H), 1.46–1.30 (m, 1H), 1.08–0.78 (m, 4H),
0.86 (d, 3H, J = 6.6 Hz), 0.83 (d, 3H, J = 7.1 Hz), 0.74 (d,
3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm):
165.1 (s) 137.7 (s), 137.1 (s), 136.2 (d), 132.4 (d), 131.0 (d),
129.1 (d), 127.7 (d), 126.5 (d), 124.3 (d), 119.7 (d), 55.6 (s),
47.0 (d), 46.6 (t), 44.9 (d), 43.3 (t), 35.1 (t), 32.4 (d), 28.0
(d), 24.3 (q), 24.0 (t), 22.5 (q), 21.4 (q), 15.5 (q). IR (neat) ν
(cm–1): 3310, 3029, 2922, 1666, 1514, 1438, 1139. LRMS
(m/z, relative intensity) 435 (M+, 1), 344 (8), 283 (23), 145
(85), 84 (100). HRMS calcd. for C28H37ONS: 435.2596,
General procedure for the preparation of
thiocarbonates
To a solution of the allylic alcohol 8 or 9 (0.099 mmol) in
THF (1 mL) at 0 °C was added NaH 60% w/w in oil (7 mg,
0.198 mmol), and the mixture was stirred for 1 h at this tem-
perature before the addition of carbon disulfide (24 µL,
0.396 mmol). The reaction was heated to reflux and stirred
for 2 h. It was then cooled down to RT before the addition of
methyl iodide (25 µL, 0.396 mmol) and was again heated to
reflux for 45 min. Then, the reaction was stopped by the ad-
dition of water (5 mL) and Et2O (5 mL). The two phases
were separated, and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic layers were
washed with brine, dried with anhyd. MgSO4, and concen-
trated under reduced pressure. The crude product was puri-
fied by flash chromatography on silica gel (100% hexanes to
2% EtOAc in hexanes) to afford the desired product.
found: 435.2593. [α]20 –49.2 (c = 1.03, CHCl3).
D
S-allylthiocarbamate 21c
Prepared following the general procedure for the synthesis
of S-allylthiocarbamates. Reaction time after the addition of
pyridinium p-toluenesulfonate: 2 h. Compound 21c was iso-
Thiocarbonate 25b
Prepared following the general procedure for the synthesis
of thiocarbonates. Compound 25b was isolated as a colorless
1
lated as a colorless oil (77 mg, >99%, >99% de by GC). H
1
NMR (300 MHz, CDCl3) δ (ppm): 7.40 (d, 2H, J = 7.7 Hz),
7.30 (t, 2H, J = 7.7 Hz), 7.08 (t, 1H, J = 7.7 Hz), 7.04 (s,
1H), 5.47–5.44 (m, 2H), 3.94–3.91 (m, 1H), 1.87–1.78 (m,
2H), 1.69 (d, 1H, J = 12.1 Hz), 1.61–1.54 (m, 2H), 1.38–
1.26 (m, 1H), 1.01 (s, 9H), 0.98–0.80 (m, 4H), 0.86 (d, 3H,
J = 6.6 Hz), 0.71 (d, 3H, J = 7.2 Hz), 0.62 (d, 3H, J =
6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm): 164.9 (s),
138.0 (s), 138.0 (d), 129.0 (d), 126.9 (d), 124.1 (d), 119.4
(d), 60.2 (d), 47.2 (s), 44.8 (d), 43.1 (t), 35.1 (t), 34.2 (d),
32.5 (d), 28.0 (d), 27.8 (q), 24.0 (t), 22.6 (q), 21.2 (q), 15.1
(q). IR (neat) ν (cm–1): 3298, 2954, 2914, 2869, 1659, 1499,
1439, 1147, 749. LRMS (m/z, relative intensity) 387 (M+,
12), 330 ((M – C4H9)+, 8), 177 (71), 97 (100). HRMS calcd.
oil (90 mg, 59%, >99% de by HPLC). H NMR (300 MHz,
CDCl3) δ (ppm): 5.56 (d, 2H, J = 16.0 Hz), 5.34 (dd, 1H, J =
15.7, 9.1 Hz), 2.33 (s, 3H), 1.94–1.68 (m, 6H), 1.62–1.52
(m, 2H), 1.58 (s, 3H), 1.38–1.23 (m, 2H), 1.01–0.76 (m,
7H), 0.86 (d, 6H, J = 6.6 Hz), 0.67 (d, 3H, J = 7.1 Hz). 13C
NMR (75.5 MHz, CDCl3) δ (ppm): 188.7 (s), 135.7 (d),
132.4 (d), 58.0 (s), 47.1 (d), 44.9 (d), 43.1 (t), 35.1 (t), 32.4
(d), 30.9 (t), 28.2 (d), 24.5 (q), 24.0 (t), 22.5 (q), 21.4 (q),
18.0 (t), 15.2 (q), 14.4 (q), 12.8 (q). IR (neat) ν (cm–1):
2955, 2927, 2871, 1641. LRMS (m/z, relative intensity) 343
(MH+, 4), 250 (8), 235 (100). HRMS calcd. for C19H35OS2
(MH+): 343.2129, found: 343.2135. [α]20 –46.9 (c = 0.73,
CHCl3).
D
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Can. J. Chem. Vol. 85, 2007
phy on silica gel (100% hexanes to 5% EtOAc in hexanes)
to afford the desired product.
Thiocarbonate 25c
Prepared following the general procedure for the synthesis
of thiocarbonates. Compound 25c was isolated as a colorless
1
Imidazoyl thiocarbonate 27c
oil (135 mg, 99%, >99% de by GC). H NMR (300 MHz,
Prepared following the general procedure for the synthesis
of imidazoyl thiocarbonates. Compound 27c was isolated as
CDCl3) δ (ppm): 5.43–5.40 (m, 2H), 4.04–4.06 (m, 1H),
2.40 (s, 3H), 1.87–1.75 (m, 2H), 1.74–1.68 (m, 1H), 1.62–
1.50 (m, 3H), 1.36–1.25 (m, 1H), 0.99–0.77 (m, 3H), 0.95
(s, 9H), 0.85 (d, 3H, J = 7.2 Hz), 0.84 (d, 3H, J = 6.6 Hz),
0.68 (d, 3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ
(ppm): 188.8 (s), 138.7 (d), 126.1 (d), 59.8 (d), 47.0 (d),
44.9 (d), 42.8 (t), 35.1 (t), 34.4 (s), 32.4 (d), 28.3 (d), 27.7
(q), 23.9 (t), 22.5 (q), 21.4 (q), 15.0 (q), 13.1 (q). IR (neat) ν
(cm–1): 2956, 2927, 2869, 2360, 2340, 1646, 1366, 861.
LRMS (m/z, relative intensity) 342 (M+, 6), 267 (23), 235
(84), 177 (82), 97 (100). HRMS calcd. for C19H34OS2:
342.2051, found: 342.2044. [α]20D +85.3 (c = 0.83, CHCl3).
1
a colorless oil (28 mg, 78% yield, 97% de by HPLC). H
NMR (300 MHz, CDCl3) δ (ppm): 8.18 (s, 1H), 7.45 (s, 1H),
7.06 (s, 1H), 5.58–5.41 (m, 2H), 4.10 (d, 1H, J = 9.3 Hz),
1.91–1.66 (m, 3H), 1.60–1.45 (m, 2H), 1.34–1.23 (m, 2H),
1.02 (s, 9H), 1.01–0.62 (m, 3H), 0.84 (d, 3H, J = 7.2 Hz),
0.81 (d, 3H, J = 6.6 Hz), 0.68 (d, 3H, J = 6.6 Hz). 13C NMR
(75.5 MHz, CDCl3) δ (ppm): 165.3 (s), 140.0 (d), 135.4 (d),
130.6 (d), 125.3 (d), 115.9 (d), 60.9 (d), 47.0 (d), 44.9 (d),
42.7 (t), 35.0 (t), 34.5 (s), 32.4 (d), 28.3 (d), 27.8 (q), 23.9
(t), 22.5 (q), 21.4 (q), 15.0 (q). IR (neat) ν (cm–1): 3125,
2954, 2924, 1762, 1693. LRMS (m/z, relative intensity) 362
(M+, 3), 306 (39), 107 (100). HRMS calcd. for C21H34ON2S:
362.2392, found: 362.2386. [α]20D –47.3 (c = 0.64, CHCl3).
Thiocarbonate 26b
Prepared following the general procedure for the synthesis
of thiocarbonates. Compound 26b was isolated (60 mg,
39%, >96% de by HPLC) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ (ppm): 5.55 (d, 2H, J = 15.4 Hz), 5.35
(dd, 1H, J = 15.4, 9.4 Hz), 2.32 (s, 3H), 1.98–1.72 (m, 6H),
1.70–1.50 (m, 2H), 1.60 (s, 3H), 1.43–1.24 (m, 2H), 1.01–
0.66 (m, 7H), 0.86 (d, 6H, J = 6.6 Hz), 0.66 (d, 3H, J =
7.2 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm): 188.6 (s),
135.7 (d), 132.5 (d), 58.0 (s), 47.2 (d), 44.8 (d), 43.3 (t),
35.1 (t), 32.4 (d), 30.9 (t), 28.0 (d), 24.3 (q), 24.0 (t), 22.5
(q), 21.4 (q), 18.0 (t), 15.2 (q), 14.3 (q), 12.7 (q). IR (neat) ν
(cm–1): 2955, 2927, 2871, 1642. LRMS (m/z, relative inten-
sity) 343 (MH+, 3), 250 (5), 235 (100). HRMS calcd. for
Imidazoyl thiocarbonate 28c
Prepared following the general procedure for the synthesis
of imidazoyl thiocarbonates. Compound 27c was isolated as
1
a colorless oil (17 mg, 42% yield, 99% de by HPLC). H
NMR (300 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 7.48 (s, 1H),
7.08 (s, 1H), 5.58–5.41 (m, 2H), 4.10 (d, 1H, J = 9.3 Hz),
1.93–1.81 (m, 1H), 1.72–1.52 (m, 4H), 1.39–1.22 (m, 2H),
1.04 (s, 9H), 0.98–0.65 (m, 3H), 0.86 (d, 3H, J = 6.6 Hz),
0.76 (d, 3H, J = 7.2 Hz), 0.57 (d, 3H, J = 7.2 Hz). 13C NMR
(75.5 MHz, CDCl3) δ (ppm): 165.4 (s), 139.8 (d), 135.6 (d),
130.6 (d), 125.2 (d), 116.1 (d), 61.1 (d), 47.2 (d), 44.7 (d),
42.9 (t), 35.1 (t), 34.4 (s), 32.4 (d), 28.0 (d), 27.8 (q), 24.0
(t), 22.5 (q), 21.2 (q), 15.1 (q). IR (neat) ν (cm–1): 2955,
2927, 2869, 1695, 1467. LRMS (m/z, relative intensity) 362
(M+, 10), 306 (62), 95 (100). HRMS calcd. for C21H34ON2S:
362.2392, found: 362.2386. [α]20D –98.8 (c = 1.42, CHCl3).
C19H35OS2 (MH+): 343.2129, found: 343.2135. [α]20 –22.9
(c = 0.74, CHCl3).
D
Thiocarbonate 26c
Prepared following the general procedure for the synthesis
of thiocarbonates. Compound 26c was isolated as a colorless
Alcohol 31
1
oil (122 mg, 90%, 98% de by GC). H NMR (300 MHz,
Thiocarbonate 25c (50 mg, 0.146 mmol) was solubilized
in 4.9 mL of dichloromethane and Sudan III (1 mg) was
added. The mixture was cooled down to –78 °C. Ozone was
bubbled through the solution until the indicator color passed
from red to pale pink or from red to violet. Then, dry nitro-
gen was bubbled through the solution for 5 min before so-
dium borohydride (55 mg, 1.459 mmol) was added. The
mixture was stirred at –78 °C for 30 min and was slowly
warmed to RT overnight. Then, the reaction was stopped by
the addition of water (5 mL) and dichloromethane (5 mL).
The two phases were separated, and the aqueous layer was
extracted with dichloromethane (3 × 10 mL). The combined
organic layers were washed with brine, dried with anhyd.
MgSO4, and concentrated under reduced pressure without
heating. The crude product was purified by flash chromatog-
raphy on silica gel (100% hexanes to 10% EtOAc in hex-
anes) to afford the desired product. Menthyl alcohol was
also recovered in 80% yield. Compound 31 was isolated as a
CDCl3) δ (ppm): 5.41–5.38 (m, 2H), 4.05 (dd, 1H, J = 5.5,
3.3 Hz), 2.38 (s, 3H), 1.95–1.75 (m, 2H), 1.73–1.60 (m, 1H),
1.58–1.51 (m, 3H), 1.36–1.28 (m, 1H), 0.99–0.78 (m, 9H),
0.96 (s, 9H), 0.65 (d, 3H, J = 6.6 Hz). 13C NMR (75.5 MHz,
CDCl3) δ (ppm): 188.7 (s), 138.7 (d), 126.0 (d), 60.0 (d),
47.2 (d), 44.7 (d), 43.0 (t), 35.1 (t), 34.2 (s), 32.4 (d), 27.8
(d), 27.8 (q), 24.0 (t), 22.5 (q), 21.4 (q), 15.3 (q), 13.0 (q).
IR (neat) ν (cm–1): 2955, 2927, 2869, 1647. LRMS (m/z, rel-
ative intensity) 342 (M+, 5), 235 (38), 177 (35), 97 (100).
HRMS calcd. for C19H34OS2: 342.2051, found: 342.2044.
[α]20 –157.3 (c = 0.49, CHCl3).
D
General procedure for the preparation of S-
allylimidazoyl thiocarbonates
To a solution of the allylic alcohol (0.099 mmol) in
acetonitrile (0.5 mL) was added thiocarbonyldiimidazole
(53 mg, 0.297 mmol), and the mixture was stirred for 3 days
at RT. Then, the reaction was stopped by the addition of wa-
ter (5 mL) and Et2O (5 mL). The two phases were separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were washed with brine, dried
with anhyd. MgSO4, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatogra-
1
colorless oil (27 mg, 89%, 93% ee by HPLC). H NMR
(300 MHz, CDCl3) δ (ppm): 4.00 (dd, 1H, J = 11.3, 3.6 Hz),
3.72 (dd, 1H, J = 8.8, 3.9 Hz), 3.62 (dd, 1H, J = 11.6,
8.8 Hz), 2.44 (s, 3H), 1.90–1.50 (br s, 1H), 1.02 (s, 9H). 13C
NMR (75.5 MHz, CDCl3) δ (ppm): 190.3 (s), 62.6 (t), 60.3
(d), 34.4 (s), 28.1 (q), 13.3 (q). IR (neat) ν (cm–1): 3430,
© 2007 NRC Canada

Minville et al.
615
2962, 2931, 1646. LRMS (m/z, relative intensity) 266 (M +
tensity) 308 (M+, 6), 267 ((M – C3H5)+, 24), 257 ((M –
C4H9)+, 100), 177 (78), 97 (88). HRMS calcd. for C20H36S:
+
NH4 , 7), 209 (MH+, 1), 195 (24), 178 (100). HRMS calcd.
for C8H16O2S2: 209.0670, found: 209.0667. [α]20 +9.5 (c
308.2538, found: 308.2543. [α]20 +9.6 (c = 1.31, CHCl3).
D
D
0.86, CHCl3).
Sulfide 34c
Alcohol (R)-32
Prepared following the general procedure for the synthesis
of RCM precursors. Compound 34c was isolated as a color-
The substrate (68 mg, 0.239 mmol) was solubilized in
2.4 mL of dichloromethane. The mixture was cooled down
to –78 °C. Ozone was bubbled through the solution until
TLC showed completion. Nitrogen was then bubbled
through the solution for 5 min before a borane-methylsulfide
solution (2 mol/L in THF, 0.48 mL, 0.955 mmol) was slowly
added. The mixture was stirred at –78 °C for 30 min and
was slowly warmed to RT overnight. Then, the reaction was
stopped by the addition of water (5 mL) and dichloro-
methane (5 mL). The two phases were separated, and the
aqueous layer was extracted with dichloromethane (3 ×
10 mL). The combined organic layers were washed with
brine, dried with anhyd. MgSO4, and concentrated under re-
duced pressure without heating. The crude product was puri-
fied by flash chromatography on silica gel (100% hexanes to
20% EtOAc in hexanes) to afford 56 mg of the desired prod-
1
less oil (54 mg, 75% yield.) H NMR (300 MHz, CDCl3) δ
(ppm): 5.82 (ddt, 1H, J = 16.8, 10.3, 6.6 Hz), 5.31 (dd, 1H,
J = 15.1, 10.3 Hz), 5.15–5.07 (m, 2H), 5.02–4.99 (m, 1H),
2.88 (d, 1H, J = 10.3 Hz), 2.48–2.38 (m, 2H), 2.36–2.21 (m,
2H), 1.98–1.80 (m, 2H), 1.74–1.70 (m, 1H), 1.65–1.56 (m,
3H), 1.40–1.25 (m, 1H), 0.98–0.77 (m, 3H), 0.97 (s, 9H),
0.87 (d, 3H, J = 7.2 Hz), 0.86 (d, 3H, J = 6.6 Hz), 0.71 (d,
3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm):
137.3 (d), 137.1, (d), 127.6 (d), 115.5 (t), 60.1 (d), 47.2 (d),
45.0 (d), 44.0 (s), 35.1 (t), 34.0 (t), 33.8 (q), 32.5 (d), 29.8
(t), 28.2 (d), 28.0 (q), 23.9 (t), 22.5 (q), 21.4 (t), 15.0 (q).
LRMS (m/z, relative intensity) 322 (M+, 25), 265 (95), 205
(69), 177 (72), 127 (100). HRMS calcd. for C21H38S:
322.2694, found: 322.2705. [α]20D –12.3 (c = 0.86, CHCl3).
1
uct (83%) as a colorless oil. H NMR (300 MHz, CDCl3) δ
(S)-2-tert-Butyl-2,5-dihydrothiophene 36c
(ppm): 7.28 (m, 2H), 7.20–7.16 (m, 3H), 3.79–3.66 (m, 3H),
2.62 (t, 2H, J = 7.7 Hz), 2.43 (s, 3H), 1.97 (s, 1H), 1.84–
1.72 (m, 1H), 1.70–1.37 (m, 5H). 13C NMR (75.5 MHz,
CDCl3) δ (ppm): 190.2 (s), 142.3 (s), 128.3 (d), 125.7 (d),
65.4 (t), 48.9 (d), 35.7 (t), 31.1 (t), 30.5 (t), 26.6 (t), 13.3 (q)
IR (neat) ν (cm–1): 3600–3200 (br), 3025, 2931, 2857, 1644,
869. LRMS (m/z, relative intensity) 285 (MH+, 15), 159
(70), 117 (75), 91 (100). HRMS calcd. for C14H21O2S2
A solution of sulfide 33c (92 mg, 0.30 mmol) in dichloro-
methane (30 mL, 0.01 mol/L), was brought to reflux and
then degassed by passing a stream of argon for 15 min while
refluxing. The Grubbs–Nolan catalyst 35 (25 mg, 10 mol%)
was quickly added while the solution was still under reflux.
The resulting pale pink solution was refluxed for 18 h. It
was cooled to room temperature, and volatiles were removed
under reduced pressure without heating. Analysis of the
crude reaction mixture showed complete conversion to 36c
and auxiliary by-product 38. The crude product was purified
by flash chromatography on silica gel (100% pentane) to af-
ford the desired product 36c (36 mg, 85%) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ (ppm): 5.86 (tt, 1H, J = 6.6,
2.2 Hz), 5.77 (tt, 1H, J = 6.6, 2.2 Hz), 4.12 (br s, 1H), 3.64
(br s, 2H), 0.94 (s, 9H). 13C NMR (75.5 MHz, CDCl3) δ
(ppm): 130.9 (d), 128.9 (d), 68.0 (d), 38.4 (t), 35.5 (s), 27.1
(q). IR (neat) ν (cm–1): 2956, 2868, 1712, 1691, 1463.
LRMS (m/z, relative intensity) 142 (M+, 20), 85 (100), 77
(10). HRMS calcd. for C8H14S: 142.0816, found: 142.0814.
(MH+): 285.0983, found: 285.0980. [α]20 +4.5 (c = 2.37,
D
CHCl3).
General procedure for the preparation of RCM
precursors
The thiocarbamate (0.064 mmol) and the bromide
(0.322 mmol) were solubilized in 1 mL of methanol, and ce-
sium carbonate (0.322 mmol) was added. The mixture was
stirred and heated overnight at 80 °C in a sealed tube. Water
(5 mL) and diethyl ether (5 mL) were added to the reaction
mixture. The two layers were separated, and the aqueous
layer was extracted three times with diethyl ether. The com-
bined organic layers were washed with brine, dried over
anhyd. MgSO4, filtered, and evaporated under reduced pres-
sure. The crude product was purified by flash chromatogra-
phy on silica gel (100% hexanes to 4% EtOAc in hexanes).
[α]20 –43.1 (c = 1.23, CHCl3).
D
Sulfone 39c
The allylic sulfide 33c (192 mg, 0.622 mmol) was
solubilized in
3
mL of dichloromethane, and m-
chloroperbenzoic acid (215 mg, 1.24 mmol) was added to
the solution. The mixture was stirred for 10 min at RT and
was then cooled to 0 °C before the addition 5 mL of a satu-
rated aqueous solution of NaHCO3 and 5 mL of dichloro-
methane. The two layers were separated. The aqueous layer
was extracted with dichloromethane (3 × 5 mL). The com-
bined organic layers were washed with brine, dried over
anhyd. MgSO4, filtered, and evaporated under reduced pres-
sure. The crude product was purified by flash chromatogra-
phy on silica gel (5% to 10% EtOAc in hexanes). The
desired product was isolated as a white solid (163 mg, 77%),
Sulfide 33c
Prepared following the general procedure for the synthesis
of RCM precursors. Compound 33c was isolated as a color-
less oil (54 mg, 79% yield). H NMR (300 MHz, CDCl3) δ
1
(ppm): 5.76 (dddd, 1H, J = 15.9, 10.6, 8.4, 5.7 Hz), 5.31
(dd, 1H, J = 15.9, 10.6 Hz), 5.12–5.04 (m, 3H), 3.07 (dd,
1H, J = 13.9, 5.7 Hz), 2.99 (dd, 1H, J = 13.9, 8.4 Hz), 2.83
(d, 1H, J = 9.9 Hz), 2.03–1.56 (m, 4H), 1.43–1.32 (m, 1H),
1.25–0.67 (m, 11H), 0.97 (s, 9H), 0.71 (d, 3H, J = 7.2 Hz).
13C NMR (75.5 MHz, CDCl3) δ (ppm): 137.6 (d), 135.2, (d),
127.5 (d), 116.5 (t), 58.8 (d), 47.2 (d), 45.2 (d), 44.2 (t), 35.1
(t), 33.8 (t), 33.2 (s), 32.6 (d), 28.2 (q), 28.1 (d), 23.8 (t),
22.6 (q), 21.4 (q), 15.0 (q). IR (neat) ν (cm–1): 2955, 2920,
2871, 1641, 1458, 1366, 971, 912. LRMS (m/z, relative in-
1
mp 107–108 °C. H NMR (300 MHz, CDCl3) δ (ppm): 5.88
(dddd, 1H, J = 16.0, 10.3, 9.0, 6.1 Hz), 5.60 (dd, 1H, J =
15.1, 10.3 Hz), 5.49–5.31 (m, 3H), 3.85 (dd, 1H, J = 13.8,
9.0 Hz), 3.41 (dd, 1H, J = 13.8, 6.1 Hz), 3.32 (d, 1H, J =
© 2007 NRC Canada

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Can. J. Chem. Vol. 85, 2007
10.5 Hz), 2.11–2.00 (m, 1H), 1.76–1.59 (m, 4H), 1.43–1.17
(m, 1H), 1.14 (s, 9H), 1.05–0.78 (m, 4H), 0.86 (d, 3H, J =
6.1 Hz), 0.85 (d, 3H, J = 7.7 Hz), 0.69 (d, 3H, J = 6.6 Hz).
IR (CHCl3) ν (cm–1): 3028, 2957, 1310, 1126. LRMS (m/z,
2934, 2845, 1656, 1595, 1141. LRMS (m/z, relative inten-
sity) 349 (M+, 3), 285 (20), 155 (100). HRMS calcd. for
C17H19NO5S (M+): 349.0984, found: 349.0990. [α]20 –12.9
D
(c = 1.80, CHCl3).
+
relative intensity) 358 (MNH4 , 30), 235 (100), 97 (70).
+
HRMS calcd. for C20H40NO2S (MNH4 ): 358.2780, found:
Arylsulfide 46
358.2784. [α]20 –73.5 (c = 0.73, CHCl3).
Thiocarbamate 20h (94 mg, 0.22 mmol) and the aryl io-
dide 45 (66 mg, 0.28 mmol) were dissolved in toluene
(1.0 mL). Cesium carbonate (91 mg, 0.28 mmol) and
triphenylphosphine (17 mg, 0.065 mmol) were added, and
argon was bubbled through the solution for 5 min prior to
the addition of Pd(PPh3)4 (25 mg, 0.022 mmol). The reac-
tion mixture was stirred and heated to reflux temperature
overnight. The mixture was filtered through Celite®, and the
filtrate was concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel
(100% hexanes to 10% EtOAc in hexanes). A colorless oil
D
Sulfolene 40c
A solution of 39c (50 mg, 0.15 mmol) in dichloromethane
(147 mL, 0.001 mol/L) was brought to reflux and then de-
gassed by passing a stream of argon for 15 min while
refluxing. The Grubbs–Nolan catalyst 35 (12 mg, 10 mol%)
was quickly added while the solution was still under reflux.
The resulting pale pink solution was refluxed for 18 h. It
was cooled to room temperature, and volatiles were removed
under reduced pressure without heating. Analysis of the
crude reaction mixture showed complete conversion to 40c
and auxiliary by-product 38. The crude product was purified
by flash chromatography on silica gel (100% hexanes to
30% EtOAc in hexanes) to afford the desired product 40c
(21 mg, 84%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ (ppm): 6.17–6.06 (m, 2H), 3.75–3.56 (m, 2H),
3.55–3.53 (m, 1H), 1.18 (s, 9H). 13C NMR (75.5 MHz,
CDCl3) δ (ppm): 129.1 (d), 124.0 (d), 74.4 (d), 56.4 (t), 34.5
(s), 27.1 (q). IR (neat) ν (cm–1): 2963, 2868, 1298, 1245,
1
was isolated (66 mg, 72%). H NMR (300 MHz, CDCl3) δ
(ppm): 7.39 (d, 2H, J = 8.5 Hz), 7.24–7.11 (m, 5H), 6.81 (d,
2H, J = 8.5 Hz), 5.56 (d, 1H, J = 15.5 Hz), 4.62 (dd, 1H, J =
15.5, 9.1 Hz), 3.80 (s, 3H), 3.03 (d, 1H, J = 12.9 Hz), 2.87
(d, 1H, J = 12.9 Hz), 1.92–1.81 (m, 1H), 1.67 (br d, 1H, J =
12.1 Hz), 1.54–1.21 (m, 4H), 1.18 (s, 3H), 1.07–0.51 (m,
4H), 0.84 (d, 3H, J = 6.6 Hz), 0.72 (d, 3H, J = 6.6 Hz), 0.68
(d, 3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) δ (ppm):
160.2 (s), 139.2 (d), 137.4 (s), 134.9 (d), 133.7 (d), 130.6
(d), 127.5 (d), 126.2 (d), 122.9 (s), 113.7 (d), 55.2 (q), 54.1
(s), 48.0 (t), 47.0 (d), 44.7 (d), 43.0 (t), 35.0 (t), 32.4 (d),
27.7 (d), 23.9 (t), 23.6 (q), 22.5 (q), 21.4 (q), 15.5 (q). IR
(neat) ν (cm–1): 2953, 2923, 1588, 1493, 1246. LRMS (m/z,
relative intensity) 422 (M+, 1), 283 (18), 145 (100). HRMS
+
1109. LRMS (m/z, relative intensity) 192 (MNH4 , 40), 175
(MH+, 5), 110 (100), 96 (95). HRMS calcd. for C8H15SO2
(MH+): 175.0793, found: 175.0790. [α]20 –15.2 (c = 1.96,
D
CHCl3).
Sulfonylhydroxamic acid 42
calcd. for C28H38OS: 422.2643, found: 422.2637. [α]20
42.2 (c = 1.45, CHCl3).
–
D
Carboxylic acid 47 (45 mg, 0.135 mmol) was dissolved in
dichloromethane (20 mL), and one drop of N,N-dimethyl-
formamide was added. The mixture was cooled to 0 °C, and
oxalyl chloride (151 µL, 1.73 mmol) was added dropwise.
The reaction mixture was stirred at 0 °C for 1 h. The solu-
tion was concentrated under reduced pressure, and the resi-
due was taken up in dichloromethane (2 mL).
Carboxylic acid 47
Arylsulfide 46 was treated as per the preparation of
sulfone 39c. A white solid was obtained after chromatogra-
1
phy (834 mg, 85%), mp 137–138 °C. H NMR (300 MHz,
CDCl3) δ (ppm): 7.76 (d, 2H, J = 8.8 Hz), 7.26–7.18 (m,
3H), 7.11–7.08 (m, 2H), 6.95 (d, 2H, J = 8.8 Hz), 5.73 (d,
1H, J = 15.8 Hz), 4.81 (dd, 1H, J = 15.8, 9.3 Hz), 3.86 (s,
3H), 3.34 (d, 1H, J = 12.9 Hz), 3.23 (d, 1H, J = 12.9 Hz),
2.02–1.90 (m, 1H), 1.67 (br d, 1H, J = 12.6 Hz), 1.55–1.19
(m, 4H), 1.16 (s, 3H), 0.84 (d, 3H, J = 6.6 Hz), 0.80–0.47
(m, 4H), 0.68 (d, 3H, J = 6.0 Hz), 0.66 (d, 3H, J = 6.0 Hz).
IR (CHCl3) ν (cm–1): 2922, 1595, 1497, 1458, 1289. LRMS
(m/z, relative intensity) 455 (MH+, 1), 437 (8), 283 (100),
145 (85). HRMS calcd. for C28H39O3S (MH+): 455.2620,
In a separate flask, the hydrochloride salt of hydroxyl-
amine (435 mg, 6.26 mmol) was dissolved in a 5:1 mixture
of tetrahydrofuran and water (6.2 mL), and it was cooled to
0 °C. Triethylamine (1.1 mL, 7.9 mmol) was added
dropwise, and the reaction mixture was stirred 1 h at 0 °C.
The acyl chloride solution previously prepared was added
to the hydroxylamine solution at 0 °C. The resulting mixture
was stirred 2 h, then water (10 mL) and chloroform (10 mL)
were added. The two phases were separated, and the aque-
ous phase was extracted with chloroform (3 × 10 mL). The
combined organic phases were washed with brine, dried over
anhyd. magnesium sulfate, and concentrated under reduced
pressure. Flash chromatography on silica gel, eluting with
ethyl acetate, gave a white solid (31 mg, 65%), mp 48–
51 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.72 (br s, 1H),
7.77 (d, 2H, J = 8.5 Hz), 7.23–7.22 (m, 3H), 7.13–7.11 (m,
2H), 7.02 (d, 2H, J = 8.5 Hz), 3.88 (s, 3H), 3.58 (d, 1H, J =
13.8 Hz), 3.10 (d, 1H, J = 13.8 Hz), 1.65 (br s, 1H), 1.35 (s,
3H). 13C NMR (75.5 MHz, CDCl3) δ (ppm): 164.8 (s), 164.5
(s), 133.5 (s), 132.4 (d), 130.3 (d), 128.6 (d), 127.6 (d),
125.7 (s), 114.5 (d), 71.6 (s), 55.7 (q), 38.7 (t), 16.1 (q). IR
(CHCl3) ν (cm–1): 3650–3500 (br), 3500–3175 (br), 3028,
found: 455.2622. [α]20 –75.9 (c = 0.69, CHCl3).
D
The resulting sulfone (35 mg, 0.079 mmol) was
solubilized in dichloromethane (1.0 mL). The mixture was
cooled down to –50 °C, then ozone was bubbled through the
solution for 4 h. Nitrogen was then bubbled through the so-
lution for 10 min before Jones’ reagent was added dropwise
until the orange color persisted. The reaction mixture was
stirred for 60 min at RT. Then, 2-propanol was added
dropwise until the solution became blue-green. The mixture
was concentrated under reduced pressure, and the resulting
solids were dissolved in a minimum amount of water
(1 mL). Dichloromethane (1 mL) was added, and the two
phases were separated. The aqueous layer was extracted
© 2007 NRC Canada

Minville et al.
617
6. (a) P. V. Attwood and J. C. Wallace. Acc. Chem. Res. 35, 113
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amides has been successfully utilized for the stereoselective
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with dichloromethane (3 × 1 mL). The combined organic
fractions were washed with brine, dried over anhyd. magne-
sium sulfate, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on sil-
ica gel (10% methanol in dichloromethane). A colorless oil
1
was isolated (13 mg, 51%). H NMR (300 MHz, CD3OD) δ
(ppm): 7.89–7.85 (m, 2H), 7.19 (br s, 5H), 7.11 (d, 2H, J =
9.3 Hz), 3.90 (s, 3H), 3.72 (d, 1H, J = 12.6 Hz), 2.86 (d, 1H,
J = 12.7 Hz), 1.24 (s, 3H). IR (neat) ν (cm–1): 3700–3100
(br), 2925, 2851, 1709, 1595, 1265, 1141. LRMS (m/z, rela-
tive intensity) 335 (MH+, 5), 317 (10), 163 (70), 91 (100).
HRMS calcd. for C17H19O5S (MH+): 335.0953, found:
335.0946. [α]20 –17.7 (c = 0.56, CHCl3).
D
Acknowledgements
Financial support from Bristol-Myers Squibb, the Natural
Sciences and Engineering Research Council of Canada
(NSERC), and the Université de Sherbrooke is gratefully ac-
knowledged.
8. For a review on the preparation of sulfides, sulfoxides, sul-
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and T. Mitsudo. Chem. Rev. 100, 3205–3220 (2000).
9. For example, see: A. Dion, P. Dubé, and C. Spino. Org. Lett.
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