Further explorations on bridged 1,2,4-trioxanes

Article abstract of DOI:10.1016/j.tet.2007.07.090

Three new bicyclo[3.2.1]-type 1,2,4-trioxanes have been designed and synthesized. One of them demonstrates better tolerance of the intramolecular hemiketals to steric crowding in hydroperoxidation. The other represents a prototype for possible manipulation of the transient radicals generated in cleavage reactions. A new substitution pattern in the bridged system is explored through synthesis of the third molecule. The configurations of all stereogenic centers in the bridged system can be effectively controlled by the chirality of the allyl alcohol as illustrated by the enantioselective synthesis of the fourth molecule. Finally, similar bicyclo[3.3.1]-type 1,2,4-trioxanes are shown very difficult to be synthesized because of the involvement of a conformer with two substituents at axial positions at the same time.

Full text of DOI:10.1016/j.tet.2007.07.090

Tetrahedron 63 (2007) 10189–10201
Further explorations on bridged 1,2,4-trioxanes
*
Qi Zhang and Yikang Wu
State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 6 June 2007; revised 23 July 2007; accepted 24 July 2007
Available online 31 July 2007
Abstract—Three new bicyclo[3.2.1]-type 1,2,4-trioxanes have been designed and synthesized. One of them demonstrates better tolerance of
the intramolecular hemiketals to steric crowding in hydroperoxidation. The other represents a prototype for possible manipulation of the tran-
sient radicals generated in cleavage reactions. A new substitution pattern in the bridged system is explored through synthesis of the third mol-
ecule. The configurations of all stereogenic centers in the bridged system can be effectively controlled by the chirality of the allyl alcohol as
illustrated by the enantioselective synthesis of the fourth molecule. Finally, similar bicyclo[3.3.1]-type 1,2,4-trioxanes are shown very difficult
to be synthesized because of the involvement of a conformer with two substituents at axial positions at the same time.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
in different molecular systems has become the most com-
mon practice in the synthesis of organic peroxides.
World-wide recognition of qinghaosu1 (artemisinin) and its
derivatives as effective weapons in the battle against malaria
has led to a dramatically renewed interest in organic per-
oxides, a rather old class of organic compounds known2a
since 1850s, and thus has greatly stimulated the studies2b–x
on such compounds.
One of the practical methodologies for incorporating per-
oxy bond(s) into organic molecules is that introduced by
Kobayashi3 and co-workers, which utilizes UHP (urea–
hydrogen peroxide complex) as the source of the peroxy
functionality. By employing this protocol we have made
a range of new organic peroxides, including monocyclic,
fused bicyclic, spiro, and bridged ones.4 In this paper we
describe our further explorations on the bridged trioxanes.
H
O
Qinghaosu
O
O
H
H
(Artemisinin)
O
2. Results and discussions
O
One of the major purposes of our studies here is to exploit the
facile formation of intramolecular hemiketal in the incorpo-
ration of a hydroperoxyl group. In the previous molecular
setups we already demonstrated that intramolecular hemike-
tals were superior to the intermolecular ones. These observa-
tions encouraged us to re-examine the possibility to include
a bulky isopropyl group at ketone carbonyl group, which was
shown4b to be impossible in an intermolecular hemiketal
system (Scheme 1) with either 1 or its dimethyl ketal as
the starting material.
Peroxy bonds are the central functionality of organic perox-
ides. Compared with other covalent bonds commonly found
in organic compounds, peroxy bonds are very fragile be-
cause their average bond energy is only approximately half
of that for a C–C single bond. This decides that peroxy bonds
cannot survive a range of reaction conditions as well as re-
agents commonly employed in organic synthesis and thus
makes synthesis of organic peroxides more difficult than
otherwise. Besides, peroxy bonds are practically impossible
to form from two alkoxyls or related species. It is therefore
not surprising that the existing methods for ‘making’ peroxy
bond(s) in an organic molecular framework are rather lim-
ited in number. Under such circumstances, making use of
one of the known methods for introducing peroxy bonds
UHP
MeO
O
O OH
CO2Et
CO2Et
1
2
CO2Et
MeO
3
Keywords: Antimalarials; Hemiketals; Peroxides; Cyclization; Hetero-
cycles.
* Corresponding author. E-mail: yikangwu@mail.sioc.ac.cn
O O
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.090

10190
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
An additional thing that we wish to examine through this
molecule is whether the cis/trans ratio of the hydroperoxyl
intermediate could be improved by a bulkier substituent so
that more desired cis isomer (with –OOH cis to the Michael
acceptor) could be formed in the hydroperoxidation.
species induced cleavage reaction (a likely model for in vivo
antimalarial action) to evolve further into a secondary radi-
cal through an intramolecular addition3c and thus improve
the antimalarial potency.
The synthesis is shown in Scheme 3. Reaction of the known
iodide 128 with 1-phenyl-1H-tetrazole-5-thiol followed by
oxidation with m-CPBA led to sulfone 14. Deprotonation
of 14 with NaHMDS and reaction with cyclohexanone af-
forded 15. The TBS protecting group was readily removed
by treatment with TBAF. The resulting alcohol (169) was
then converted into the corresponding iodide 17.
The synthesis of the first target (4) of this work is outlined in
Scheme 2. The known dithiane 55 was deprotonated with n-
BuLi at ꢀ25 ꢁC followed by treatment with I(CH2)4OTBS6
to give 6 in 84% yield. The TBS protecting group was then
removed with TBAF to afford alcohol 7. A SO3$Py oxida-
tion gave the corresponding aldehyde 8, which on treatment
with PhSOCH2CO2Et via the SPAC7 reaction (Sulfoxide
Piperidine And Carbonyl reaction) yielded alcohol 9.
I
a
b
S
OTBS
SO2 OTBS
Ph
e
Ph
N
N
N
N
N
N N
N
TBSO
12
b
S
S
a
S
S
14
S
S
13
OH
OTBS
CO2Et
OH
I
OTBS
7
6
c
5
c
d
S
S
d
S
S
H
17
15
16
e
CHO
8
9
Scheme 3. (a) NaH/1-phenyl-1H-tetrazole-5-thiol/rt/overnight, 97%; (b)
m-CPBA/NaHCO3/rt/1 d, 91%; (c) NaHMDS/cyclohexanone/ꢀ78 ꢁC/6 h,
74%; (d) TBAF/THF/0 ꢁC/1 h, 96%; and (e) I2/imid./PPh3/0 ꢁC/30 min, 85%.
OH
O
HOO
CO2Et
O
With the side chain in hand, we set out to build up the frame-
work of the second target molecule (Scheme 4). The known
dithiane 1810 was first converted into the corresponding
dianion by treatment with slightly more than 2 equiv of
n-BuLi at ꢀ20 ꢁC. The above mentioned iodide 17 was then
introduced along with HMPA. After reaction at ambient tem-
perature for 15 h, the desired alcohol 19 was obtained in
70% overall yield.
f
CO2Et
trans-11
10
OH
H
H
H
g
O
O
O
O
CO2Et
O
OH
cis-11
CO2Et
4
Scheme 2. (a) (i) n-BuLi/ꢀ25 ꢁC/4 h; (ii) HMPA/I(CH2)4OTBS/0 ꢁC/17 h,
84%; (b) TBAF/THF/rt/4 h, 70%; (c) SO3$Py/DMSO/NEt3/CH2Cl2/0 ꢁC/
0.5 h, 86%; (d) PhSOCH2CO2Et/piperidine/CH3CN/rt/17 h, 62%; (e) I2/
NaHCO3/acetone–H2O/0 ꢁC/0.5 h, 82%; (f) UHP (ca. 7.5 equiv)/
p-TsOH$H2O/DME/rt/12 h, 90% (trans-11/cis-11¼1.3:1); (g) cat. HNEt2/
CF3CH2OH/rt/24 h, 30%.
OH
S
S
S
S
S
S
b
CHO
a
3
3
HO
The sulfur protecting group was then removed to release the
carbonyl group to set up a stage for incorporation of a hydro-
peroxyl group. To our gratification, when treating 10 with
p-TsOH/UHP4d the reaction did take place as anticipated,
giving 11 as a 1.3:1 mixture of the trans and cis isomers.
This result proves again that with a transient intramolecular
hemiketal as an immediate precursor, the driving force for
the incorporation of the hydroperoxyl group is significantly
increased compared with those in intermolecular cases.
Thus, for the first time we are able to include an isopropyl
at the carbonyl group in the ketal exchange reaction. And
the content of the desired cis isomer (with the –OOH cis
to the C–C double bond) in the product mixture reached
an unprecedented 44%. Further treatment of cis-11 with
HNEt2 in CF3CH2OH at ambient temperature for 24 h led
to the desired end product 4 in 30% yield.
20
18
19
c
O
OH
OH
S
S
d
2
3
CO2Et
2
3
e
CO2Et
22
21
CO2Et
+
CO2Et
f
H
H
R
H
H
R
O
R
3
O
O
O
R =
O
HOO
OOH
EtO2C
trans-23
cis-23
24
Scheme 4. (a) (i) n-BuLi/ꢀ20 ꢁC/4 h, (ii) HMPA/17/rt/15 h, 70%; (b)
SO3$Py/NEt3/DMSO/0 ꢁC, 30 min, 89%; (c) PhSOCH2CO2Et/piperidine/
CH3CN/rt/overnight, 63%; (d) I2/NaHCO3/acetone–H2O/0 ꢁC/0.5 h, 78%;
(e) UHP/p-TsOH$H2O/rt/20 h, total yield 88% (trans-23/cis-23¼1.6:1);
and (f) HNEt2/CF3CH2OH/rt/15 h, 28%.
We also designed a similar trioxane that carries a different
substituent in place of the isopropyl group in 4. The side
chain in this case is a substituted pentyl group with a cyclo-
hexylidene group at the terminal, which may allow the car-
bon-centered radical generated in a single electron reducing
A subsequent SO3$Py/DMSO oxidation transformed the
terminal alcohol into an aldehyde, which on exposure to

Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
10191
PhSOCH2CO2Et/piperidine underwent SPAC reaction
smoothly yielding the ester 21. The sulfur protecting group
was then hydrolyzed with iodine to release the carbonyl
group. Further reaction of 22 with UHP in the presence of
p-TsOH$H2O led to peroxy hemiketal 23 as a 1.6:1 mixture
of the trans/cis isomers. The cis isomer was separated from
the trans one on silica gel and treated with HNEt2 in
CF3CH2OH to give the end product 24 in 28% yield.
with MeI in the presence of HMPA, a methyl group was in-
troduced at the a position as reported in the literature.12 The
resultant 26 was converted into the corresponding methyl
ketone by reaction with MeLi in Et2O at ꢀ78 ꢁC. The ketone
carbonyl group was then masked with ethanedithiol before
the hydroxyl group was oxidized into an aldehyde. An
SPAC reaction converted 28 into 29, completing the whole
molecular framework for the target structure.
Ring substitution was also examined in this work. Introduc-
tion of a substituent in the THF ring at the position a to the
ketal carbon might lead to interesting consequences in later
biotesting and cleavage studies. This is because in a single
electron reducing species induced cleavage,11 a substituent
at the a position would give a secondary carbon-centered rad-
ical at the position indicated in Scheme 5 instead of a primary
one as might occur with other trioxanes mentioned above.
The sulfur protecting group was removed with iodine. Under
the same conditions employed above for incorporating a hy-
droperoxyl group, 30 afforded the hydroperoxy hemiketal 31
in 90% yield as a mixture of diastereomers. These isomers
are rather difficult to separate from each other. Therefore,
in an initial run we directly utilized the mixture of all iso-
mers in the subsequent ring-closure reaction. Because of
larger difference in polarity, the end products 32 could be
readily separated from the unreacted precursors 31 (presum-
ably mainly the isomers with –OOH trans to the C–C double
bond, which possibly cannot undergo the Michael addition).
secondary radical
H
R'
R'
R'
H
H
H
H
R
R
1
RCOO
O
O
H
The H NMR spectrum clearly showed that 32 was a 2.4:1
O
O
O
O
O
O
mixture of two diastereomers. However, it was not possible
to assign whether the major isomer is 32a or 32b. Fortu-
nately, after exhaustive efforts we managed to obtain a small
sample of a single diastereomer of 31 by chromatography on
silica gel using 1:3 Et2O/petroleum ether as eluant. The ring-
closure product from this precursor was shown by 1H NMR
to be a single diastereomer, with the two methyl groups trans
e
CO2Et
CO2Et
CO2Et
Primary radical
H
H
H
H
H
R
R
H
RCOO
O
O
O
O
O
O
1
e
EtO2C
EtO2C
to each other as shown by the structure 32a. And, the H
EtO2C
NMR data were consistent with the major isomer in the
above mentioned 2.4:1 mixture. The minor isomer therefore
must have the structure of 32b.
Scheme 5.
Synthesis of a target molecule of this substitution pattern is
shown in Scheme 6. Starting from the commercially avail-
able lactone 25 via deprotonation with LDA and methylation
As already mentioned in a previous4d paper, the Michael ad-
dition (closing of the peroxy ring) proceeds in a highly
stereoselective way. Consequently, the relative configuration
of the whole molecule should be dictated by the first stereo-
genic center—the one generated in the SPAC reaction. It
therefore seems possible to make optically active bridged tri-
oxanes by employing a single enantiomer of the allyl alcohol
(e.g., 9, 21, and 29 above).
HO
O
b
a
O
25
O
O
e
O
c
26
S
S
S
S
S
S
d
One of the potential ways to obtain optically active alco-
hol is the enzymatic resolution reported by Burgess and
co-workers.13 As we still have 334d in hand, we tried
that approach first. The progress of the acetylation
CO2Et
CHO
29
28
OH
27
HO
O
1
g
f
(Scheme 7) was monitored by H NMR. After 4 h of reac-
O
H
CO2Et
tion about half of the starting 33 was transformed into the
corresponding acetate. However, the optical rotation for
the recovered alcohol (34) was very small ([a]2D0 ꢀ1.1),
suggesting a failure in differentiating the two isomers.
Chiral HPLC analysis further confirmed that the ee value
of 34 was only 15%.
HOO
CO2Et
31
h
30
HO
H3C
H3C
H3C
H
H
H3C
+
H
O
O
O
O
O
O
32a
CO2Et
32b
CO2Et
2.4:1
CO2Et
CO2Et
CO2Et
a
HO
AcO
HO
O
Scheme 6. (a) (i) LDA/HMPA/ꢀ15 ꢁC, 15 min; (ii) MeI/0 ꢁC, 6 h, 70%; (b)
MeLi/Et2O/ꢀ78 ꢁC/30 min; (c) HS(CH2)2SH/BF3$Et2O/rt/15 h, 64% from
26; (d) SO3$Py/NEt3/DMSO/0 ꢁC/30 min, 91%; (e) PhSOCH2CO2Et/piperi-
dine/CH3CN/rt/15 h, 64%; (f) I2/NaHCO3/acetone–H2O/0 ꢁC/0.5 h, 78%;
(g) UHP/p-TsOH$H2O/rt/20 h, 90%; and (h) HNEt2/CF3CH2OH/rt/1 d,
10% (32a and 32b).
O
O
+
5
5
5
35
33
34
15% e.e.
Scheme 7. (a) Pseudomonas AK/vinyl acetate/hexane/25 ꢁC.

10192
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
The desired enantiomerically pure allyl alcohols are also
accessible from asymmetric SPAC reaction, which uses an
optically active sulfoxide reagent. To obtain the desired re-
agent, we tried to make use of Evans auxiliary to resolve a ra-
cemic sulfoxide.14 As shown in Scheme 8, sequential
treatment of 36 with SOCl2 and lithiated (R)-4-phenyl-oxa-
zolidin-2-one gave an N-sulfinyloxazolidinone 37 as a 1.5:1
mixture separable on silica gel. At that time we were not able
to assign the configurations of these two compounds. For
convenience, the major component was used in the follow-
ing transformations.
After completing several bicyclo[3.2.1]-type trioxanes, we
also attempted to extend the methodology to [3.3.1] bridged
system. This requires building a tetrahydropyran instead of
the tetrahydrofuran in the intermediate hemiketal. In the be-
ginning it seemed that we only needed to increase one more
CH2 unit in the carbon chain.
Thus, the known aldehyde 4317 was converted into alcohol
44 by reaction with MeMgBr (Scheme 10). The allyl
protecting group was removed with PdCl2/MeOH. The
resultant diol 4518 was oxidized into the corresponding
aldehyde–ketone and treated with PhSOCH2CO2Bn4d/
piperidine with the hope that the SPAC reaction would
take place preferentially at the aldehyde group. However,
probably because of the interference of the intramolecular
aldol reaction of the dicarbonyl intermediate, no expected
46 was formed at all. This result made us to adopt a slightly
longer route, with the ketone group masked at the SPAC
reaction.
O
O
O
S
O
S
O
S
a
O
c
N
O
N
+
Ph
Ph
Ph
ONa
36
37a
Ph
Ph 37b
b
O
S
O
S
CO2Et
Ph
Ph
39
38
OH
Scheme 8. (a) (i) SOCl2/rt/2 h, (ii) (R)-4-phenyl-oxazolidin-2-one/n-
BuLi/ꢀ78 ꢁC/25 min, 87% from 36 (37a/37b¼1:1.5); (b) MeMgBr/THF/
ꢀ78 ꢁC/20 min, 96%; and (c) (i) LDA/ꢀ78 ꢁC/40 min, (ii) ClCO2Et/
ꢀ78 ꢁC/5 h, 47%.
O
O
a
b
CHO
OH
c
45
43
44
OH
Removal of the chiral auxiliary using a Reformatsky reac-
tion to directly obtain 3915 was not very successful (10–
20% yields). Therefore, we next turned to an indirect
way—to cut off the auxiliary with MeMgBr first to yield
the desired optically active sulfoxide 3816 with concurrent
configuration inversion as reported previously by Evans.14
The absolute configuration of 38 was assigned by compari-
son with the known (S)-isomer16 in the literature. Further
treatment of 38 with LDA followed by ClCO2Et resulted
in 39 in 47% yield.
CO2Bn
HO
CHO
d
46
O
O
Scheme 10. (a) MeMgBr/Et2O/0 ꢁC, 75%; (b) PdCl2/MeOH, 62%; (c)
Swern oxidation; and (d) PhSOCH2CO2Bn/piperidine/rt, 15 h.
Starting from the known alcohol 4719 via oxidation and
MeMgBr addition, we obtained alcohol 4820 in 75% yield
(Scheme 11). A SO3$Py/DMSO oxidation gave the methyl
ketone 49,20 which on treatment with HS(CH2)2SH/
F3B$OEt2 in CH2Cl2 led to carbonyl protection with
With 39 in hand, we went on with the same route used in the
synthesis of racemic 424d (Scheme 9). Treatment of alde-
hyde 404d with the optically active reagent 39 gave 34 in
59% yield with an ee value of 95% as determined by chiral
HPLC. The absolute configuration of 34 was assigned ac-
cording to the rule13 in the literature. Incorporation of hydro-
peroxyl group under the UHP/p-TsOH conditions gave
trans-41 and cis-41 as observed before in the racemic syn-
thesis. Finally, reaction of the isolated cis-41 with HNEt2
in F3CCH2OH gave the optically active bridged trioxane
42 as planned.
TBSO
TBSO
TBSO
OH
b
a
49
O
47
CO2Bn
48 OH
c
HO
CHO
HO
e
d
h
S
S
S
S
CO2Et
51
S
S
52
f
50
HOO
H
a
b
HO
O
CHO
CO2Bn
n-Hex
O
O
5
CO2Et
trans-41
g
5
H
40
O
HO
34
+
O
O
HOO
O
H
H
H
BnO2C
n-Hex
55
n-Hex
CO2Bn
53
54
c
O
O
H
O
cis-41
O
O
CO2Et
Scheme 11. (a) (i) SO3$Py/DMSO/NEt3/0 ꢁC, 30 min; (ii) MeMgBr/Et2O/
0 ꢁC, 75%; (b) SO3$Py/DMSO/NEt3/0 ꢁC, 3 h, 86%; (c) HS(CH2)2SH/
F3B$OEt2/CH2Cl2/rt, 97%; (d) SO3$Py/DMSO/NEt3/0 ꢁC, 30 min, 82%;
(e) PhSOCH2CO2Bn/piperidine/rt/15 h, 57%; (f) I2/NaHCO3/acetone–
H2O/0 ꢁC/15 min, 80%; (g) UHP (ca. 7.5 equiv)/p-TsOH$H2O/DME/rt/
12 h, 95%; and (h) cat. HNEt2/F3CCH2OH/rt/2 d.
O
O
CO2Et
42
cis-41
Scheme 9. (a) Piperidine/39/CH3CN/rt/10 h, 59%; (b) UHP (ca. 7.5 equiv)/
p-TsOH$H2O/DME/rt/overnight, 35%; and (c) cat. HNEt2/F3CCH2OH/rt/
12 h, 32%.

Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
10193
concurrent removal of the TBS protecting group. The
newly-freed hydroxyl group was oxidized with SO3$Py/
DMSO, giving aldehyde 51. Without the interference of
the ketone group, the SPAC reaction occurred smoothly,
affording the expected allyl alcohol 52 in 57% yield.
The sulfur protecting group was then removed. The hy-
droxy ketone was treated with UHP/p-TsOH to produce
hydroperoxy hemiketal 54 as a ca. 9:1 mixture of two di-
astereomers in an unprecedented 95% yield. However, the
final ring-closure reaction did not occur as planned. Stir-
ring with HNEt2 in F3CCH2OH did not result in any an-
ticipated 55.
in the side chain and thus allows for possible evolution of
the initial radical generated in a cleavage reaction. The syn-
thesis of the third trioxane explores a new substitution pattern
in the present bridged framework. To demonstrate the possi-
bility of performing enantioselective synthesis of these
trioxanes, a single enantiomer of a previously reported
trioxane with an n-hexyl as side chain was synthesized.
Finally, through exhaustive efforts it is proven that similar bi-
cyclo[3.3.1]-type trioxanes are difficult to be synthesized
probably because of the involvement of the conformation
with two substituents in axial positions at the same time.
Prolonged reaction time (55 h) still did not make any dis-
cernible change. Raising the temperature (55 ꢁC or reflux
for 24 h), on the other hand, led to a complex mixture
without organic peroxide (visualization with Fe(SCN)2
on TLC). Replacing the heating with microwave (3 min)
also gave a complex mixture. Using KOH, LiOH,
Me4N+OHꢀ, DBU, DMAP, NEt3 or pyridine to replace
HNEt2 did not lead to any improvement. At ambient tem-
perature, no reaction took place. At 55 ꢁC, all the runs led
to complex mixtures but still without peroxide. We also
tried to initiate the cyclization with NBS, NIS, I2 or
Hg(OAc)2. Unfortunately, none of these gave useful re-
sults.
4. Experimental
4.1. General
Unless otherwise stated, the 1H NMR and 13C NMR spectra
were recorded in deuterochloroform at ambient temperature
using a Varian Mercury 300 or a Bruker Avance 300 instru-
ment (operating at 300 MHz for proton). The FTIR spectra
were scanned with a Nicolet Avatar 360 FTIR spectrometer.
EIMS and EIHRMS were recorded with an HP 5989A and
a Finnigan MAT 8430 mass spectrometer, respectively.
The ESIMS and ESIHRMS were recorded with a PE Mari-
ner API-TOF and an APEX III (7.0 T) FTMS mass spec-
trometer, respectively. MALDIHRMS were recorded on an
IonSpec 4.7 T FTMS instrument. Elemental analyses were
performed on an Elementar VarioEL III instrument. The
melting point was uncorrected. Dry THF was distilled
from Na/Ph2CO under N2. Dry HMPA, DMF, and DMSO
were stirred with CaH2 at ambient temperature under N2
for 4 d before being distilled under reduced pressure and
Repeated failure prompted us to look into the molecular
structure to seek possible reasons. Close inspection of
the stereo-model of 54 revealed that there are four possi-
ble conformations (Fig. 1) for the two sets of diastereo-
mers of 54 (A and B for trans-54, C and D for cis-54).
Among these, only conformer C of the cis isomer is
able to undergo the intramolecular Michael addition to
give the ring-closure product 55. However, in this con-
former, both –OOH and C–C double bond are in axial po-
sitions and thus may be of rather high energy. This seems
to explain why 55 could not be formed under a variety of
conditions.
˚
kept under N2 over activated 4 A molecular sieves. Dry
CH2Cl2 was distilled over CaH2 and kept over activated
˚
4 A molecular sieves. UHP was purchased from Acros. All
other solvents and reagents were commercially available
and used as received without any further purification. PE
stands for petroleum ether (bp 60–90 ꢁC).
HO
O
4.1.1. Alkylation of 5 (6). n-BuLi (1.6 M in hexanes,
11.0 mL, 17.6 mmol) was added dropwise to a solution of
5 (2.618 g, 16.16 mmol) in dry THF (45 mL) stirred at
ꢀ78 ꢁC under N2. After completion of the addition, the stir-
ring was continued at ꢀ25 ꢁC for 4 h. Dry HMPA (3.2 mL)
and a solution of I(CH2)4OTBS (5.075 g, 16.16 mmol) in dry
THF (10 mL) were introduced. The mixture was stirred at
0 ꢁC for 17 h before being diluted with Et2O (50 mL),
washed in turn with satd aq NH4Cl, water, and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by ro-
tary evaporation and column chromatography (1:12 EtOAc/
PE) on silica gel afforded 6 as a colorless oil (4.736 g,
13.61 mmol, 84% yield). FTIR (film) 2953, 2930, 2857,
O
O
H
CO2Bn
A (trans)
O
H
B (trans)
CO2Bn
OH
HO
O
O
H
O
O
C (cis)
CO2Bn
D (cis)
OH
H
CO2Bn
Figure 1. The four possible conformers of 54.
3. Conclusions
1471, 1462, 1255, 1102, 835, 775 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 3.64 (t, J¼5.4 Hz, 2H), 2.92–2.84
(m, 2H), 2.77–2.69 (m, 2H), 2.15 (heptet, J¼6.6 Hz, 1H),
2.02–1.87 (m, 4H), 1.59–1.49 (m, 4H), 1.18 (d, J¼6.6 Hz,
6H), 0.90 (s, 9H), 0.069 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 63.0, 59.0, 35.6, 34.2, 33.2, 26.0, 25.7, 25.5,
20.9, 18.3, 17.7, ꢀ5.2; EIMS m/z (%) 348 (M+, 2.49), 333
(M+ꢀCH3, 1.72), 75 (100); EIHRMS calcd for C17H36OS2Si
(M+) 348.1977, found 348.1976.
Three new bicyclo[3.2.1]-type 1,2,4-trioxanes have been syn-
thesized. One of them carries an isopropyl group at the ketal
carbon, demonstrating that such intramolecular hemiketals as
in the present systems are indeed more tolerable to steric
crowding than those intermolecular hemiketals involved in
monocyclic peroxides in the hydroperoxidation. The second
trioxane reported above contains a cyclohexylidene group

10194
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
4.1.2. Deprotection of 6 (7). TBAF (1 M in THF, 13.61 mL,
13.61 mmol) was added dropwise to a solution of 6 (4.736 g,
13.61 mmol) in THF (27 mL) stirred at 0 ꢁC. The stirring
was then continued at ambient temperature for 17 h. The
mixture was diluted with Et2O, washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:6
EtOAc/PE) on silica gel afforded 7 as a colorless oil
(2.230 g, 9.53 mmol, 70% yield). FTIR (film) 3371, 1460,
15 min before the excess I2 was destroyed by addition of satd
aq Na2S2O3 (2 mL). The mixture was extracted with EtOAc
(3ꢂ30 mL). The combined organic phases were washed
with satd aq Na2S2O3, water, and brine, and dried over anhy-
drous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:5 EtOAc/PE) on silica gel
afforded 10 as a yellowish oil (105 mg, 0.46 mmol, 81%
yield). FTIR (film) 3482, 1716, 1658, 1468, 1369, 1304,
1
1273, 1176, 1041, 982 cmꢀ1; H NMR (300 MHz, CDCl3)
1385, 1274, 1168 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d 6.91 (dd, J¼4.6, 15.3 Hz, 1H), 6.07 (d, J¼15.8 Hz, 1H),
4.37 (br s, 1H), 4.20 (q, J¼7.2 Hz, 2H), 2.84 (d, J¼4.5 Hz,
1H), 2.68–2.59 (m, 2H), 2.01–1.76 (m, 3H), 1.29 (t,
J¼6.9 Hz, 3H), 1.10 (d, J¼7.0 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 215.5, 166.5, 149.6, 120.6, 70.2, 60.4,
41.0, 35.9, 29.8, 18.3, 18.2,21 14.2; EIMS m/z (%) 228
(M+, 0.11), 210 (M+ꢀH2O, 3.37), 43 (100); EIHRMS calcd
for C12H18O3 ([M+ꢀH2O]) 210.1256, found 210.1259.
d 3.68 (t, J¼6.1 Hz, 2H), 2.87 (ddd, J¼3.4, 9.6, 14.0 Hz,
2H), 2.75 (ddd, J¼3.6, 6.0, 10.4 Hz, 2H), 2.17 (heptet,
J¼6.8 Hz, 1H), 2.02–1.87 (m, 4H), 1.65–1.54 (m, 5H),
1.12 (d, J¼6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 62.8, 58.9, 35.3, 34.0, 33.0, 25.7, 25.4, 20.9, 17.7; EIMS
m/z (%) 234 (M+, 7.19), 191 (100); EIHRMS calcd for
C11H22OS2 (M+) 234.1112, found 234.1105.
4.1.3. Oxidation of 7 (8). A solution of SO3$Py (850 mg,
5.34 mmol) in DMSO (7.5 mL) was added dropwise to a so-
lution of 7 (500 mg, 2.13 mmol) and NEt3 (1.47 mL,
10.65 mmol) in dry CH2Cl2 (10 mL) was stirred in an ice-
water bath. The stirring was continued at the same tempera-
ture for 30 min. The mixture was diluted with Et2O, washed
with water and brine, and dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (1:15 EtOAc/PE) on silica gel afforded 8
as a colorless oil (425 mg, 1.83 mmol, 86% yield). FTIR
4.1.6. Synthesis of 4. A solution of 10 (47 mg, 0.21 mmol),
UHP (148 mg, 1.58 mmol), and p-TsOH (monohydrate,
53 mg, 0.28 mmol) in MeO(CH2)2OMe (4 mL) was stirred
at ambient temperature overnight. The mixture was diluted
with Et2O, washed with water and brine, and dried over an-
hydrous Na2SO4. Removal of the solvent by rotary evapora-
tion and column chromatography (1:8 EtOAc/PE) on silica
gel afforded cis-11 (colorless oil, 20 mg, 0.082 mmol) and
trans-11 (colorless oil, 26 mg, 0.11 mmol). Total yield:
1
90%. Data for cis-11 (the less polar component): H NMR
(film) 1732, 1457, 1418, 1386, 1275 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 7.90 (s, 1H), 6.99 (dd, J¼15.6,
6.1 Hz, 1H), 6.06 (d, J¼15.7 Hz, 1H), 4.64–4.61 (m, 1H),
4.21 (q, J¼7.1 Hz, 2H), 2.36 (heptet, J¼7.0 Hz, 1H),
2.13–1.96 (m, 4H), 1.30 (t, J¼7.1 Hz, 3H), 0.97 (d,
J¼6.7 Hz, 3H), 0.96 (d, J¼7.3 Hz, 3H). Data for trans-11
(300 MHz, CDCl3) d 9.80 (s, 1H), 2.89 (ddd, J¼3.5, 9.9,
14.0 Hz, 2H), 2.73 (ddd, J¼3.8, 5.7, 14.4 Hz, 2H), 2.50 (t,
J¼6.5 Hz, 2H), 2.17 (heptet, J¼6.7 Hz, 1H), 2.03–1.80
(m, 6H), 1.12 (d, J¼6.8 Hz, 6H); 13C NMR (75 MHz,
CDCl3) d 202.2, 58.6, 43.9, 35.0, 34.1, 25.7, 25.3, 17.7,
17.4; ESIMS m/z 233.2 ([M+H]+); EIHRMS calcd for
C11H20OS2 (M+) 232.0956, found 232.0957.
1
(the more polar component): H NMR (300 MHz, CDCl3)
d 8.12 (s, 1H), 6.93 (dd, J¼15.4, 5.3 Hz, 1H), 6.06 (d,
J¼15.9 Hz, 1H), 4.82–4.76 (m, 1H), 4.21 (q, J¼7.2 Hz,
2H), 2.42 (7, J¼6.9 Hz, 1H), 2.33–12.22 (m, 1H), 2.05
(ddd, J¼4.1, 9.5, 13.7 Hz, 1H), 2.09–2.00 (m, 1H), 1.68–
1.55 (m, 1H), 1.30 (t, J¼7.2 Hz, 3H), 0.99 (d, J¼6.8 Hz,
3H), 0.97 (d, J¼6.8 Hz, 3H).
4.1.4. Synthesis of 9. A solution of 8 (188 mg, 0.81 mmol)
in CH3CN (3 mL) was added to a solution of PhSOCH2-
CO2Et (173 mg, 0.81 mmol) and piperidine (0.081 mL,
0.81 mmol) in CH3CN (2 mL). The mixture was stirred at
ambient temperature overnight before being diluted with
Et2O, washed with water and brine, and dried over anhy-
drous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:6 EtOAc/PE) on silica gel
afforded 9 as a yellowish oil (160 mg, 0.50 mmol, 62%
yield). FTIR (film) 3465, 1718, 1656, 1368, 1304, 1274,
A solution of cis-11 (37 mg, 0.15 mmol) and HNEt2 (2 mL,
0.019 mmol) in CF3CH2OH (4 mL) was stirred at ambient
temperature for 1 d. The solvent was removed by rotary
evaporation. The residue was chromatographed (1:12
EtOAc/PE) on silica gel to give 4 as colorless oil (11 mg,
0.045 mmol, 30% yield). FTIR (film) 2925, 2854, 1741,
1
1174, 1038 cmꢀ1; H NMR (300 MHz, CDCl3) d 6.97 (dd,
1462, 1185, 1026 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
J¼4.7, 15.6 Hz, 1H), 6.07 (d, J¼15.6 Hz, 1H), 4.36 (br s,
1H), 4.21 (q, J¼7.1 Hz, 2H), 2.89 (ddd, J¼2.8, 9.7,
13.9 Hz, 2H), 2.73 (ddd, J¼3.3, 5.5, 13.9 Hz, 2H), 2.21–
1.68 (m, 8H), 1.30 (t, J¼7.1 Hz, 3H), 1.12 (d, J¼6.8 Hz,
6H); 13C NMR (75 MHz, CDCl3) d 166.4, 149.7, 120.6,
71.1, 60.5, 58.6, 34.2, 31.67, 31.0, 25.7, 25.23, 17.6, 14.2;
EIMS m/z (%) 318 (M+, 0.89), 300 (M+ꢀH2O, 0.51), 41
(100); EIHRMS calcd for C15H26O3S2 (M+) 318.1323,
found 318.1329.
d 4.87 (t, J¼6.7 Hz, 1H), 4.34–4.33 (m, 1H), 4.16 (q,
J¼7.1 Hz, 2H), 2.37–2.23 (m, 3H), 1.99–1.87 (m, 4H),
1.27 (t, J¼7.1 Hz, 3H), 0.99 (d, J¼5.5 Hz, 3H), 0.98 (d,
J¼5.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 169.0,
114.7, 80.2, 77.2, 61.1, 34.9, 32.6, 30.2, 23.9, 17.1, 16.8,
14.1; ESIMS m/z 267.2 ([M+Na]+); MALDIHRMS calcd
for C12H20O5Na ([M+Na]+) 267.1203, found 267.1211.
4.1.7. Synthesis of 13. A solution of 1-phenyl-1H-tetrazole-
5-thiol (PTTS, 5.764 g, 32.38 mmol) in dry THF (12 mL)
was added to a mixture of NaH (60% in mineral oil, washed
with hexanes before use, 1.3 g, 32.38 mmol) in dry THF
(48 mL) and dry DMF (8 mL). The mixture was stirred at
ambient temperature for 30 min. A solution of 12 (5.31 g,
16.19 mmol) in dry THF (12 mL) was then introduced.
4.1.5. Deprotection of
9 (10). NaHCO3 (409 mg,
4.87 mmol) and I2 (498 mg, 1.96 mmol) were added to a so-
lution of 9 (180 mg, 0.57 mmol) in CH3COCH3–H2O (3 mL,
5:1 v/v) stirred in an ice-water bath. After completion of the
addition, the mixture was stirred at the same temperature for

Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
10195
The stirring was continued at ambient temperature over-
night. Excess hydride was quenched by addition of satd aq
NH4Cl. The mixture was diluted with Et2O, washed with wa-
ter and brine, and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromato-
graphy (1:10 EtOAc/PE) on silica gel afforded 13 as a color-
less oil (5.940 g, 15.71 mmol, 97% yield). FTIR (film) 1500,
1471, 1462, 1387, 1250, 1103, 835, 776, 760 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 7.58–7.51 (m, 5H), 3.57 (t, J¼5.8 Hz,
2H), 3.37 (t, J¼7.3 Hz, 2H), 1.81 (quintet, J¼7.1 Hz, 2H),
1.54–1.44 (m, 4H), 0.84 (s, 9H), 0 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 154.5, 133.8, 130.1, 129.8, 123.9,
62.8, 33.3, 32.1, 28.9, 26.0, 25.0, 18.4, ꢀ5.3; ESIMS m/z
([M+H]+) 379.2; EIHRMS calcd for C18H30N4OSiS (M+)
378.1910, found 378.1906.
solvent by rotary evaporation and column chromatography
(1:3 EtOAc/PE) on silica gel afforded 169 as a colorless oil
(460 mg, 2.74 mmol, 96% yield). 1H NMR (300 MHz,
CDCl3) d 5.06 (t, J¼7.2 Hz, 1H), 3.64 (t, J¼6.0 Hz, 2H),
2.14–1.98 (m, 6H), 1.60–1.37 (m, 11H).
4.1.11. Conversion of alcohol 16 into iodide 17. I2
(775 mg, 3.05 mmol) was added in portions to a mixture
of 16 (426 mg, 2.54 mmol), PPh3 (799 mg, 3.05 mmol),
and imidazole (207 mg, 3.05 mmol) in Et2O–CH3CN (5:1
v/v, 12 mL) stirred in an ice-water bath. After completion
of the addition, the stirring was continued at the same tem-
perature for 30 min. The mixture was diluted with n-hexane.
Solids were filtered off. The filtrate was concentrated on a ro-
tary evaporator. The residue was chromatographed (PE) on
silica gel to give 17 as a colorless oil (600 mg, 2.16 mmol,
85% yield). FTIR (film) 2925, 2852, 1446, 1218,
4.1.8. Oxidation of 13 (14). A mixture of 13 (3.218 g,
8.51 mmol), m-CPBA (70%, 5.25 g, 21.28 mmol), and
NaHCO3 (3.547 g, 42.55 mmol) in CH2Cl2 (42 mL) was
stirred at ambient temperature for 24 h. Satd aq Na2S2O3was
added. The mixture was stirred vigorously before being ex-
tracted with CH2Cl2 (3ꢂ30 mL). The combined organic
phases were washed with satd aq NaHCO3 and brine before
being dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:10
EtOAc/PE) on silica gel afforded 14 as a colorless oil
(3.175 g, 7.74 mmol, 91% yield). FTIR (film) 1596, 1498,
1197 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 5.06 (t,
J¼7.2 Hz, 1H), 3.19 (t, J¼7.2 Hz, 2H), 2.13–1.97 (m, 6H),
1.83 (quintet, J¼7.4 Hz, 2H), 1.54–1.38 (m, 8H); 13C
NMR (75 MHz, CDCl3) d 140.4, 120.5, 32.2, 33.1, 31.0,
28.7, 27.9, 27.0, 25.9, 7.2; EIMS m/z (%) 278 (M+, 5.04),
67 (100); EIHRMS calcd for C11H19I (M+) 278.0532, found
278.0536.
4.1.12. Alkylation of dithiane 18 with iodide 17 (19).
n-BuLi (1.6 M in hexanes, 6.9 mL, 11 mmol) was added
dropwise to a solution of 18 (960 mg, 5.00 mmol) in dry
THF (20 mL) stirred at ꢀ78 ꢁC under N2. After completion
of the addition, the stirring was continued at ꢀ25 ꢁC for 4 h.
Dry HMPA (2 mL) and a solution of 17 (1.390 g,
5.00 mmol) in dry THF (5 mL) were introduced. The mix-
ture was stirred at 0 ꢁC for 15 h before being diluted with
Et2O (50 mL), washed in turn with satd aq NH4Cl, water,
and brine, and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromato-
graphy (1:5 EtOAc/PE) on silica gel afforded 19 as a color-
less oil (1.193 g, 3.94 mmol, 70% yield). FTIR (film) 3391,
1471, 1463, 1342, 1256, 1154, 1103, 836, 776, 668 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 77.67–7.54 (m, 5H), 3.73–
3.67 (m, 2H), 3.53 (t, J¼5.9 Hz, 2H), 1.99–1.88 (m, 2H),
1.59–1.50 (m, 4H), 0.84 (s, 9H), 0 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 153.5, 133.1, 131.5, 129.7, 125.1,
62.4, 56.0, 32.0, 26.0, 24.7, 21.8, 18.3, ꢀ5.3; ESIMS m/z
411.2 ([M+H]+); MALDIHRMS calcd for C18H30N4O3-
SiSNa ([M+Na]+) 433.1700, found 433.1705.
4.1.9. Julia coupling of 14 with cyclohexanone (15).
NaHMDS (2.0 M in THF, 3 mL, 5.93 mmol) was added to
a solution of 14 (2.114 g, 5.16 mmol) in dry THF (18 mL)
stirred at ꢀ78 ꢁC under N2. After stirring for another
30 min at the same temperature, the reaction was quenched
by addition of satd aq NH4Cl (2 mL). Most of the solvent
was removed on a rotary evaporator. The residue was ex-
tracted with Et2O (3ꢂ30 mL), washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:50
EtOAc/PE) on silica gel afforded 15 as a colorless oil
(1.077 g, 3.82 mmol, 74% yield). FTIR (film) 1472, 1462,
1
2928, 2852, 1446, 1274, 1067 cmꢀ1; H NMR (300 MHz,
CDCl3) d 5.06 (t, J¼7.2 Hz, 1H), 3.68 (t, J¼6.1 Hz, 2H),
2.83–2.79 (m, 4H), 2.13–1.83 (m, 12H), 1.72 (br s, 1H),
1.64–1.25 (m, 14H); 13C NMR (75 MHz, CDCl3) d 139.8,
121.0, 62.7, 53.3, 38.2, 38.0, 37.2, 32.8, 30.4, 28.7, 27.9,
27.0, 26.9, 26.0, 25.6, 23.7, 20.5; ESIMS m/z 343.2
([M+H]+); MALDIHRMS calcd for C19H35OS2 ([M+H]+)
343.2124, found 343.2128.
4.1.13. Oxidation of alcohol 19 (20). A solution of SO3$Py
(111 mg, 0.70 mmol) in DMSO (1 mL) was added to a solu-
tion of 19 (95 mg, 0.28 mmol) and NEt3 (0.19 mL,
1.38 mmol) in dry CH2Cl2 (1.5 mL) stirred in an ice-water
bath. The stirring was continued at the same temperature
for 30 min. The mixture was diluted with Et2O, washed
with water and brine, and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chro-
matography (1:10 EtOAc/PE) on silica gel afforded 20 as
a colorless oil (85 mg, 0.25 mmol, 89% yield). FTIR (film)
1447, 1255, 1104, 835, 774 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 5.01 (t, J¼7.2 Hz, 1H), 3.56 (t, J¼6.5 Hz, 2H),
2.08–1.90 (m, 6H), 1.52–1.40 (m, 8H), 1.35–1.25 (m, 2H),
0.85 (s, 9H), 0 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 139.7, 121.3, 63.2, 37.2, 32.5, 28.7, 27.9, 27.0, 26.8,
26.4, 26.0, 18.4, ꢀ5.2; EIMS m/z (%) 282 (M+, 0.20), 267
(M+ꢀCH3, 1.47), 67 (100); EIHRMS calcd for C16H31OSi
(M+ꢀCH3) 267.2144, found 267.2137.
1
4.1.10. Deprotection of 15 (16). TBAF (1 M in THF,
2.9 mL, 2.86 mmol) was added dropwise to a solution of
15 (806 mg, 2.86 mmol) in THF (5 mL) stirred at 0 ꢁC.
The stirring was then continued at ambient temperature for
1 h. The mixture was diluted with Et2O, washed with water
and brine, and dried over anhydrous Na2SO4. Removal of the
2927, 2851, 1725, 1447, 1275 cmꢀ1; H NMR (300 MHz,
CDCl3) d 9.79 (s, 1H), 5.06 (t, J¼7.5 Hz, 1H), 2.89–2.73
(m, 4H), 2.48 (t, J¼7.4 Hz, 2H), 2.13–1.73 (m, 14H),
1.52–1.26 (m, 10H); 13C NMR (75 MHz, CDCl3) d 202.0,
139.9, 121.0, 53.1, 43.7, 38.4, 37.4, 37.2, 30.3, 28.7, 27.9,
27.0, 26.9, 26.0, 25.4, 23.6, 17.2; ESIMS m/z 341.2

10196
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
([M+H]+); EIHRMS calcd for C19H32OS2 (M+) 340.1895,
found 340.1893.
1H), 4.20 (q, J¼7.1 Hz, 2H), 2.18–1.92 (m, 11H), 1.72–
1.62 (m, 1H), 1.57–1.19 (m, 10H), 1.29 (t, J¼7.2 Hz, 3H).
Data for compound trans-23 (the more polar component):
1H NMR (300 MHz, CDCl3) d 7.89 (s, 1H), 6.91 (dd,
J¼15.8, 5.1 Hz, 1H), 6.05 (d, J¼15.6 Hz, 1H), 5.06 (t,
J¼7.3 Hz, 1H), 4.79–4.77 (m, 1H), 4.21 (q, J¼7.1 Hz,
2H), 2.32–2.26 (m, 1H), 2.13–1.91 (m, 10H), 1.74–1.63
(m, 2H), 1.51–1.25 (m, 9H), 1.30 (t, J¼7.1 Hz, 3H).
4.1.14. Synthesis of 21. A solution of 20 (445 mg,
1.31 mmol) in CH3CN (3 mL) was added to a solution of
PhSOCH2CO2Et (278 mg, 1.31 mmol) and piperidine
(0.13 mL, 1.31 mmol) in CH3CN (5 mL). The mixture was
stirred at ambient temperature overnight before being di-
luted with Et2O, washed with water and brine, and dried
over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (1:6 EtOAc/PE)
on silica gel afforded 21 as a colorless oil (353 mg,
0.83 mmol, 63% yield). FTIR (film) 3458, 1720, 1657,
A solution of cis-23 (60 mg, 0.17 mmol) and HNEt2 (6 mL,
0.055 mmol) in CF3CH2OH (10 mL) was stirred at ambient
temperature for 15 h. The solvent was removed by rotary
evaporation. The residue was chromatographed (1:20
EtOAc/PE) on silica gel to give 24 as colorless oil (17 mg,
0.048 mmol, 28% yield). FTIR (film) 1740, 1460, 1378,
1447, 1368, 1273, 1174 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 6.96 (dd, J¼15.7, 5.0 Hz, 1H), 6.06 (d,
J¼15.5 Hz, 1H), 5.06 (t, J¼7.3 Hz, 1H), 4.36–4.34 (m,
1H), 4.21 (q, J¼7.1 Hz, 2H), 2.90–2.75 (m, 4H), 2.13–
2.04 (m, 11H), 1.84–1.67 (m, 4H), 1.52–1.25 (m, 10H),
1.30 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 166.4, 149.6, 139.9, 121.0, 120.6, 71.0, 60.5, 53.0, 38.5,
37.2, 33.4, 31.4, 30.3, 28.7, 27.9, 27.0, 26.9, 26.0, 25.4,
23.5, 14.3; ESIMS m/z 449.3 ([M+Na]+); MALDIHRMS
calcd for C23H38O3S2Na ([M+Na]+) 449.2155, found
449.2168.
1331, 1278, 1184, 1025, 969, 913 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 5.04 (t, J¼7.2 Hz, 1H), 4.87 (t,
J¼6.9 Hz, 1H), 4.38 (d, J¼5.1 Hz, 1H), 4.16 (q, J¼7.1 Hz,
2H), 2.37–2.22 (m, 3H), 2.11–2.04 (m, 4H), 2.00–1.87 (m,
5H), 1.76–1.69 (m, 2H), 1.52–1.38 (m, 8H), 1.36–1.30 (m,
2H), 1.26 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 169.0, 139.8, 121.0, 112.5, 80.1, 77.0, 61.1, 37.2, 34.9,
34.1, 32.6, 30.3, 28.7, 27.8, 27.0, 26.8, 24.1, 23.1, 14.1;
ESIMS m/z ([M+Na]+) 375.3; MALDIHRMS calcd for
C20H32O5Na ([M+Na]+) 375.2142, found 375.2155.
4.1.15. Deprotection of 21 (22). NaHCO3 (548 mg,
6.53 mmol) and I2 (666 mg, 2.63 mmol) were added to a
solution of 21 (320 mg, 0.75 mmol) in CH3COCH3–H2O
(7.5 mL, 5:1 v/v) stirred in an ice-water bath. After comple-
tion of the addition, the mixture was stirred at the same tem-
perature for 15 min before the excess I2 was destroyed by
addition of satd aq Na2S2O3 (2 mL). The mixture was ex-
tracted with EtOAc (3ꢂ30 mL). The combined organic
phases were washed with satd aq Na2S2O3, water, and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:5
EtOAc/PE) on silica gel afforded 22 as a yellowish oil
(196 mg, 0.58 mmol, 78% yield). FTIR (film) 3481, 1718,
4.1.17. Synthesis of 27. MeLi$LiBr (1.6 M in Et2O,
3.12 mL, 5 mmol) was added dropwise to a solution of 26
(570 mg, 5.0 mmol) in dry Et2O (25 mL) stirred at ꢀ78 ꢁC
under N2. After completion of the addition, the stirring
was continued at the same temperature for 15 min before
the mixture was diluted with Et2O, washed with satd aq
NH4Cl, water, and brine, and dried over anhydrous
Na2SO4. The solvent was removed on a rotary evaporator
and the residue was dissolved in CH2Cl2 (25 mL). To this so-
lution were added in turn HS(CH2)2SH (0.49 mL, 5.0 mmol)
and BF3$Et2O (0.12 mL, 1.0 mmol) with cooling (ice-water
bath) and stirring. The mixture was then stirred at ambient
temperature. When TLC showed completion of the reaction,
acetone was added. The mixture was stirred at ambient tem-
perature overnight before being diluted with Et2O, washed
with water and brine, and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chro-
matography (1:6 EtOAc/PE) on silica gel afforded 27 as
a yellowish oil (660 mg, 3.2 mmol, 64% yield from 26).
1658, 1447, 1386, 1303, 1271, 1175 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 6.90 (dd, J¼15.9, 4.4 Hz, 1H), 6.07
(d, J¼16.2 Hz, 1H), 5.04 (t, J¼7.8 Hz, 1H), 4.37 (br s,
1H), 4.20 (q, J¼7.1 Hz, 2H), 2.80 (s, 1H), 2.59 (dt, J¼3.4,
6.7 Hz, 2H), 2.43 (t, J¼6.9 Hz, 2H), 2.12–1.93 (m, 7H),
1.85–1.75 (m, 2H), 1.62–1.46 (m, 7H), 1.36–1.25 (m, 2H),
1.30 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 212.1, 166.5, 149.6, 128.6, 120.7, 120.7, 70.2, 42.9,
38.3, 37.2, 29.7, 29.7, 28.7, 27.9, 27.9, 27.0, 28.5, 14.3;
ESIMS m/z 359.3 ([M+Na]+); MALDIHRMS calcd for
C20H32O4Na ([M+Na]+) 359.2193, found 359.2211.
1
FTIR (film) 3361, 1444, 1371, 1277, 1094, 1055 cmꢀ1; H
NMR (300 MHz, CDCl3) d 3.66 (t, J¼6.3 Hz, 2H), 3.35–
3.25 (m, 4H), 1.97–1.68 (m, 4H), 1.71 (s, 3H), 1.57–1.44
(m, 1H), 1.31–1.19 (m, 1H), 1.12 (d, J¼7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 72.9, 62.7, 45.9, 39.5, 39.5,
31.2, 30.8, 28.9, 17.4; EIMS m/z (%) 206 (M+, 0.41), 119
(100); EIHRMS calcd for C9H18OS2 (M+) 206.0799, found
206.0806.
4.1.16. Synthesis of 24. A solution of 22 (175 mg,
0.52 mmol), UHP (367 mg, 3.90 mmol), and p-TsOH
(monohydrate, 119 mg, 0.64 mmol) in MeO(CH2)2OMe
(10 mL) was stirred at ambient temperature overnight. The
mixture was diluted with Et2O, washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:10
EtOAc/PE) on silica gel afforded cis-23 (colorless oil,
62 mg, 0.18 mmol) and trans-23 (colorless oil, 100 mg,
0.28 mmol). Total yield: 88%. Data for compound cis-23
4.1.18. Oxidation of 27 (28). A solution of SO3$Py (1.50 g,
9.38 mmol) in DMSO (13 mL) was added to a solution of 27
(735 mg, 3.57 mmol) and NEt3 (2.5 mL, 17.85 mmol) in dry
CH2Cl2 (12 mL) stirred in an ice-water bath. The stirring
was continued at the same temperature for 30 min. The mix-
ture was diluted with Et2O, washed with satd aq CuSO4, wa-
ter, and brine, and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromato-
graphy (1:15 EtOAc/PE) on silica gel afforded 28 as
1
(the less polar component): H NMR (300 MHz, CDCl3)
d 8.02 (s, 1H), 6.98 (dd, J¼16.3, 6.1 Hz, 1H), 6.05 (d,
J¼16.0 Hz, 1H), 5.06 (t, J¼7.1 Hz, 1H), 4.68–4.66 (m,

Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
10197
a colorless oil (665 mg, 3.26 mmol, 91% yield). FTIR (film)
following data: 1H NMR (300 MHz, CDCl3) d 7.81 (s,
1H), 6.95 (dd, J¼5.9, 15.4 Hz, 1H), 6.05 (d, J¼15.8 Hz,
1H), 4.68–4.64 (m, 1H), 4.21 (q, J¼7.4 Hz, 2H), 2.26–
2.18 (m, 2H), 1.84–1.75 (m, 1H), 1.49 (s, 3H), 1.13 (t,
J¼7.4 Hz, 3H), 1.11 (d, J¼6.2 Hz, 3H).
1
2965, 2922, 1742, 1372, 1277 cmꢀ1; H NMR (300 MHz,
CDCl3) d 9.79 (s, 1H), 3.35–3.25 (m, 4H), 2.56–2.44 (m,
2H), 2.22–2.17 (m, 1H), 1.94–1.85 (m, 1H), 1.73 (s, 3H),
1.54–1.47 (m, 1H), 1.10 (d, J¼6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 202.4, 72.5, 45.9, 42.7, 39.8, 39.7,
29.3, 26.9, 17.1; ESIMS m/z ([M+H]+) 205.1; EIHRMS
calcd for C9H16OS2 (M+) 204.0643, found 204.0641.
A solution of 31 (the mixture of four diastereomers, 390 mg,
1.70 mmol) and HNEt2 (22 mL, 0.21 mmol) in CF3CH2OH
(53 mL) was stirred at ambient temperature for 1 d. The sol-
vent was removed by rotary evaporation. The residue was
chromatographed (1:10 EtOAc/PE) on silica gel to give
32a and 32b as colorless oil (1:2.4 mixture of two diastereo-
mers, 39 mg, 0.17 mmol, 10% yield). FTIR (film) 2983,
4.1.19. Synthesis of 29. A solution of 28 (612 mg,
3.0 mmol) in CH3CN (3 mL) was added to a solution of
PhSOCH2CO2Et (636 mg, 3.0 mmol) and piperidine
(0.3 mL, 3.0 mmol) in CH3CN (10 mL). The mixture was
stirred at ambient temperature for 15 h before being diluted
with Et2O, washed with water and brine, and dried over an-
hydrous Na2SO4. Removal of the solvent by rotary evapora-
tion and column chromatography (1:4 EtOAc/PE) on silica
gel afforded 29 as a yellowish oil (1:1 mixture of two diaste-
reomers, 557 mg, 1.92 mmol, 64% yield). FTIR (film) 3443,
1
2879, 1738, 1455, 1381, 1183, 997, 861 cmꢀ1; H NMR
(300 MHz, CDCl3) d 4.88–4.81 (m, 1H), 4.32–4.27 (m,
1H), 4.16 (q, J¼7.1 Hz, 2H), 2.35–2.19 (m, 4H), 1.56–
1.51 (m, 1H), 1.33 (s, 2.13H), 1.32 (s, 0.87H), 1.29–1.21
(m, 5.13H), 0.87 (d, J¼7.2 Hz, 0.87H); ESIMS m/z 231.2
([M+H]+); Anal. calcd for C11H18O5 C 57.38, H 7.88; found
C 57.29, H 7.89.
1717, 1656, 1446, 1370, 1302, 1276, 1177, 1038, 982 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.00–6.91 (m, 1H), 6.11–6.03
(m, 1H), 4.49–4.29 (m, 1H), 4.21 (q, J¼7.0 Hz, 2H), 3.35–
3.26 (m, 4H), 2.33–2.23 (m, 0.5H), 2.13–1.89 (m, 2.5H),
1.72 (s, 3H), 1.63–1.50 (m, 1H), 1.30 (t, J¼7.7 Hz, 3H),
1.18–1.15 (m, 3H); ESIMS m/z 313.1 ([M+Na]+); Anal.
calcd for C13H22O3S2 C 53.76, H 7.63, found C 53.82, H
7.54.
4.1.22. Synthesis of 32a. A solution of cis-31 (the isolated
diastereomer mentioned above, 51 mg, 0.22 mmol) and
HNEt2 (6 mL, 0.07 mmol) in CF3CH2OH (6 mL) was stirred
at ambient temperature overnight. The solvent was removed
by rotary evaporation. The residue was chromatographed
(1:10 EtOAc/PE) on silica gel to give 32a as a colorless
oil (16 mg, 0.07 mmol, 32% yield). FTIR (film) 1738,
4.1.20. Deprotection of 29 (30). NaHCO3 (2.54 g,
30.28 mmol) and I2 (3.094 g, 12.18 mmol) were added to
a solution of 29 (1:1 mixture of the two diastereomers,
1.010 g, 3.48 mmol) in CH3COCH3–H2O (20 mL, 5:1 v/v)
stirred in an ice-water bath. After completion of the addition,
the mixture was stirred at the same temperature for 15 min
before the excess I2 was destroyed by addition of satd aq
Na2S2O3 (5 mL). The mixture was extracted with EtOAc
(3ꢂ30 mL). The combined organic phases were washed
with satd aq Na2S2O3, water, and brine, and dried over anhy-
drous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:4 EtOAc/PE) on silica gel
afforded 30 as a colorless oil (580 mg, 2.71 mmol, 78%
yield). FTIR (film) 3420, 1720, 1656, 1461, 1369, 1305,
1455, 1381, 1183, 997, 861 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 4.85 (t, J¼6.9 Hz, 1H), 4.30 (d, J¼7.2 Hz, 1H),
4.16 (q, J¼7.1 Hz, 2H), 3.11–2.91 (m, 4H), 1.55–1.51 (m,
1H), 1.33 (s, 3H), 1.28–1.21 (m, 6H); 13C NMR (75 MHz,
CDCl3) d 169.0, 111.3, 79.5, 76.3, 61.1, 40.9, 34.7, 31.8,
18.9, 14.1, 12.5; ESIMS m/z 231.15 ([M+H]+); EIHRMS
calcd for C11H18O5 (M+) 230.1154, found 230.1160.
4.1.23. Synthesis of 37a and 37b. Sodium benzenesulfinate
(10 g, 50 mmol) was added in portions to SOCl2 (10.9 mL,
150 mmol) stirred at ambient temperature. After completion
of the addition, the stirring was continued for 2.5 h. Excess
SOCl2 was removed by rotary evaporation. The residue
was diluted with Et2O and re-evaporated to dryness. The res-
idue (crude PhSOCl) was dissolved in dry THF to form a
solution (25 mL) for the subsequent reaction.
1273, 1181, 1036, 981, 864 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.00–6.85 (m, 1H), 6.11–5.95 (m, 1H), 4.75–
4.33 (m, 1H), 4.32–4.11 (m, 2H), 2.80–1.88 (m, 5H),
1.76–1.00 (m, 8H); ESIMS m/z 237.2 ([M+Na]+); Anal.
calcd for C11H18O4 C 61.66, H 8.47, found C 61.27, H 8.80.
n-BuLi (1.6 M, 3.13 mL, 5 mmol) was added to a solution of
(R)-4-phenyl-oxazolidin-2-one (815 mg, 5 mmol) in dry
THF (10 mL) stirred in an ice-water bath under N2. After
stirring for 5 min, the cooling bath was replaced with an ace-
tone-dry ice bath (ꢀ78 ꢁC). The above prepared PhSOCl so-
lution (5.5 mL from the 25 mL stock solution) was added
quickly. The stirring was continued at ꢀ78 ꢁC for 25 min be-
fore satd aq NH4Cl was introduced. The mixture was diluted
with EtOAc, washed first with satd aq NaHCO3 to pH¼7,
then with brine, and dried over anhydrous Na2SO4. Removal
of the solvent by rotary evaporation and column chromato-
graphy (1:3.3 EtOAc/PE) on silica gel afforded 37a
(500 mg, 1.74 mmol) and 37b (749 mg, 2.61 mmol). Total
yield: 87%. Data for compound 37a: [a]2D0 ꢀ362.8 (c 1.12,
CHCl3); mp 119–121 ꢁC. FTIR (film) 1738, 1455, 1381,
4.1.21. Synthesis of 32 (mixture). A solution of 30 (1:1
mixture of the two diastereomers, 546 mg, 2.55 mmol),
UHP (1.798 g, 19.13 mmol), and p-TsOH (monohydrate,
582 mg, 3.06 mmol) in MeO(CH2)2OMe (50 mL) was
stirred at ambient temperature for 20 h. The mixture was
diluted with Et2O (100 mL), washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:6
EtOAc/PE) on silica gel afforded 31 as a colorless oil
(a 1:1.9:2.3:3.4 mixture of four diastereomers, 530 mg,
2.30 mmol, 90% yield in total). This mixture was used in
the next step.
1183, 997, 861 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
Further chromatography (1:3 Et2O/PE) on silica gel led to
a single diastereomer (a priori, cis-31), which gave the
d 7.63–7.48 (m, 5H), 7.36–7.32 (m, 3H), 7.15–7.11 (m,
2H), 4.56–4.49 (m, 2H), 4.14 (t, J¼10.5 Hz, 1H); ESIMS

10198
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
288.2 ([M+H]+), 310.1 ([M+Na]+); Anal. calcd for
C15H13NO3S C 62.70, H 4.56, N 4.87, found C 62.84, H
4.66, N 4.65. Data for compound 37b: [a]2D0 ꢀ92.6 (c 0.78,
CHCl3); mp 117–118 ꢁC. FTIR (film) 2983, 2879, 1738,
214 nm). [a]2D0 ꢀ122.4 (c 1.20, CHCl3). FTIR (film)
3447, 2925, 2855, 1720, 1661, 1466, 1272 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 6.91 (dd, J¼15.5, 4.3 Hz,
1H), 6.07 (d, J¼15.4 Hz, 1H), 4.37 (s, 1H), 4.20 (q,
J¼7.2 Hz, 2H), 2.71 (d, J¼4.1 Hz, 1H), 2.60 (t,
J¼5.9 Hz, 2H), 2.43 (t, J¼7.5 Hz, 2H), 2.03–1.95 (m,
2H), 1.35–1.28 (m, 11H), 0.86 (t, J¼9.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 211.9, 166.5, 149.6, 120.6,
70.0, 60.4, 42.9, 38.1, 31.5, 29.8, 28.8, 23.8, 22.4, 14.2,
13.9; ESIMS m/z 271.2 ([M+H]+); ESIHRMS calcd for
C15H26O4Na ([M+Na]+) 293.1729, found 293.1720.
1455, 1381, 1183, 997, 861 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.39–6.86 (m, 10H), 5.29 (t, J¼7.8 Hz, 1H),
4.71 (t, J¼9.8 Hz, 1H), 4.21 (t, J¼8.2 Hz, 1H); ESIMS
m/z 288.2 ([M+H]+), 310.1 ([M+Na]+); Anal. calcd for
C15H13NO3S C 62.70, H 4.56, N 4.87, found C 62.75, H
4.56, N 4.67.
4.1.24. Synthesis of 38. MeMgBr (1.7 M in Et2O, 1.4 mL,
2.31 mmol) was added dropwise to a solution of 37b
(311 mg, 1.08 mmol) in dry THF (8 mL) stirred at ꢀ78 ꢁC
under N2. The mixture was stirred at the same temperature
for 20 min. Satd aq NH4Cl (5 mL) was added, followed by
Et2O (60 mL). The phases were separated. The aqueous
layer was back-extracted with Et2O. The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography (2.5:1 EtOAc/PE) on silica gel
afforded 3816 as a colorless oil (146 mg, 1.04 mmol, 96%
yield). [a]2D0 ꢀ136.2 (c 1.49, acetone), (lit.16 [a]2D0 ꢀ143 (c
4.1.27. Synthesis of 42. A solution of ent-34 (50 mg,
0.19 mmol), UHP (130 mg, 1.35 mmol), and p-TsOH
(monohydrate, 43 mg, 0.22 mmol) in MeO(CH2)2OMe
(2 mL) was stirred at ambient temperature overnight. The
mixture was diluted with Et2O, washed with water and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:8
EtOAc/PE) on silica gel afforded cis-41 as a colorless oil
(19 mg, 0.066 mmol, 35% yield). [a]2D0 ꢀ22.1 (c 1.05,
CHCl3). FTIR (film) 3386, 2979, 2940, 1718, 1659, 1304,
1
1271 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.99 (s, 1H),
1
1.0, acetone)); H NMR (300 MHz, CDCl3) d 7.63–7.68
6.78 (dd, J¼6.1, 15.3 Hz, 1H), 6.05 (d, J¼15.4 Hz, 1H),
4.69–4.66 (m, 1H), 4.21 (q, J¼6.9 Hz, 2H), 2.15–2.11 (m,
4H), 1.70–1.25 (m, 13H), 0.86 (t, J¼9.3 Hz, 3H).
(m, 2H), 7.50–7.57 (m, 3H), 2.73 (s, 3H).
4.1.25. Synthesis of 39. n-BuLi (1.6 M in hexanes, 0.81 mL,
1.3 mmol) was added dropwise to a solution of i-Pr2NH
(0.17 mL, 1.3 mmol) in dry THF (4.5 mL) stirred at 0 ꢁC un-
der N2. The mixture was stirred at the same temperature for
30 min before the bath was cooled to ꢀ78 ꢁC. A solution of
38 (138 mg, 0.99 mmol) in THF (4 mL) was then added
slowly. After completion of the addition, the mixture was
stirred at the same temperature for 40 min. ClCO2Et
(0.12 mL, 1.1 mmol) was then introduced while the bath
temperature remained at ꢀ78 ꢁC. The stirring was continued
at the same temperature for 5 h. Satd aq NH4Cl (5 mL) was
added, followed by Et2O (60 mL). The phases were sepa-
rated. The aqueous layer was back-extracted with EtOAc
(20 mLꢂ3). The combined organic layers were washed first
with 1 N HCl to pH 7, then with brine and dried over anhy-
drous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (1:2 EtOAc/PE) on silica gel
afforded 3915 as a colorless oil (100 mg, 0.47 mmol, 47%
A solution of cis-41 (19 mg, 0.066 mmol) and HNEt2
(2 mL, 0.021 mmol) in CF3CH2OH (2 mL) was stirred at
ambient temperature for 12 h. The solvent was removed
by rotary evaporation. The residue was chromatographed
(1:20 EtOAc/PE) on silica gel to give 42 as colorless oil
(6 mg, 0.02 mmol, 32% yield). [a]2D0 ꢀ40.0 (c 0.31,
CHCl3). FTIR (film) 2925, 2854, 1741, 1462, 1185,
1026 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 4.89 (t,
J¼7.2 Hz, 1H), 4.34 (d, J¼4.3 Hz, 1H), 4.16 (q,
J¼7.1 Hz, 2H), 2.33–2.27 (m, 3H), 1.99–1.87 (m, 3H),
1.77–1.68 (m, 2H), 1.16–1.09 (m, 2H), 1.04–0.98 (m,
9H), 0.70 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 169.1, 112.6, 80.2, 77.1, 61.2, 35.0, 34.3,
32.7, 31.7, 29.8, 24.13, 23.5, 22.6, 14.2, 14.1; EIMS m/z
(%) 286 (M+, 2.8), 113 (100); MALDIHRMS calcd for
C15H26O5Na ([M+Na]+) 309.1674, found 309.1666.
1
yield). [a]2D0 ꢀ132.7 (c 0.95, CHCl3); H NMR (300 MHz,
4.1.28. Synthesis of 44. MeMgBr (2.4 M, 4.0 mL,
9.64 mmol) was added dropwise to a solution of 43
(1.504 g, 9.64 mmol) in dry Et2O (44 mL) stirred at 0 ꢁC un-
der argon. After completion of the addition, the stirring was
continued at the same temperature until TLC showed com-
pletion of the reaction. Satd aq NH4Cl was added. The mix-
ture was extracted with Et2O (50 mLꢂ3), washed with satd
aq NH4Cl, water, and brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography (1:5 EtOAc/PE) on silica gel af-
forded 44 as a colorless oil (1.245 g, 7.24 mmol, 75% yield).
CDCl3) d 7.72–7.54 (m, 5H), 4.16 (q, J¼6.8 Hz, 2H), 3.86
(d, J¼13.6 Hz, 1H), 3.67 (d, J¼13.6 Hz, 1H), 1.22 (t,
J¼7.4 Hz, 3H).
4.1.26. Synthesis of 34. A solution of 404d (51 mg,
0.27 mmol) in CH3CN (1 mL) was added to a solution
of optically active sulfoxide 39 (58 mg, 0.27 mmol) and
piperidine (27 mL, 0.27 mmol) in CH3CN (10 mL). The
mixture was stirred at ambient temperature for 10 h before
being diluted with Et2O, washed first withaq NH4Cl then
with water and brine, and dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (1:4.5 EtOAc/PE) on silica gel afforded
34 as a colorless oil (43 mg, 0.16 mmol, 59% yield).
This sample was of 95% ee as shown by chiral HPLC
1
FTIR (film) 3407, 2931, 2857, 1460, 1101 cmꢀ1; H NMR
(300 MHz, CDCl3) d 5.92 (ddt, J¼7.1, 10.1, 1.6 Hz, 1H),
5.26 (br d, J¼7.1 Hz, 1H), 5.17 (br d, J¼10.1 Hz, 1H),
3.97 (t, J¼1.6 Hz, 1H), 3.96 (t, J¼1.6 Hz, 1H), 3.82–3.76
(m, 1H), 3.43 (t, J¼6.6 Hz, 2H), 1.64–1.31 (m, 9H), 1.18
(d, J¼6.4 Hz, 3H); ESIMS m/z 173.3 ([M+H]+); ESIHRMS
calcd for C10H20O2Na ([M+Na]+) 195.1356, found
195.13586.
analysis (performed on
a
Chiralpak OD column
(4.6ꢂ250 mm), eluting 9:1 n-hexane/isopropanol (v/v) at
a flow rate of 0.7 mL/min with the detector set to

Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
10199
4.1.29. Deprotection of 44 (45). PdCl2 (155 mg,
0.87 mmol) was added to a solution of 44 (617 mg,
3.59 mmol) in anhydrous MeOH (20 mL). The mixture
was stirred at ambient temperature overnight. Most of the
solvent was removed by rotary evaporation. The residue
was diluted with Et2O, washed with water and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by ro-
tary evaporation and column chromatography (1:1 EtOAc/
PE) on silica gel afforded 4518 as a colorless oil (294 mg,
2.23 mmol, 62% yield); 1H NMR (300 MHz, CDCl3)
d 3.86–3.75 (m, 1H), 3.65 (t, J¼6.3 Hz, 2H), 1.61–1.33
(m, 10H), 1.19 (d, J¼8.7 Hz, 3H).
(m, 4H), 1.98–1.92 (m, 2H), 1.76 (s, 3H), 1.45–1.35 (m,
7H); 13C NMR (75 MHz, CDCl3) d 66.8, 62.9, 45.7, 39.7,
32.6, 32.3, 27.1, 25.8; ESIMS m/z 224.1 ([M+NH4]+);
ESIHRMS calcd for C9H18ONa ([M+Na]+) 229.0688, found
229.0691.
4.1.33. Synthesis of 51. A solution of SO3$Py (1.769 g,
11.1 mmol) in DMSO (16 mL) was added to a solution of
50 (746 mg, 3.62 mmol) and NEt3 (2.57 mL, 18.6 mmol)
in CH2Cl2 (10 mL) stirred in an ice-water bath. After com-
pletion of the addition, the mixture was stirred at ambient
temperature for 0.5 h before being diluted with Et2O
(200 mL), washed first with satd aq CuSO4, then with water
and brine, and dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography
(1:17 EtOAc/PE) on silica gel afforded 51 as a colorless
oil (606 mg, 2.97 mmol, 82% yield). FTIR (film) 3392,
4.1.30. Synthesis of 48. A solution of SO3$Py (5.15 g,
32.4 mmol) in DMSO (46 mL) was added to a solution of
4719 (2.504 g, 10.8 mmol) and NEt3 (7.47 mL, 54 mmol)
in CH2Cl2 (30 mL) stirred in an ice-water bath. After com-
pletion of the addition, the mixture was stirred at ambient
temperature for 1 h before being diluted with Et2O
(150 mL), washed first with satd aq CuSO4, then with water
and brine, and dried over anhydrous Na2SO4. The solvent
was removed on a rotary evaporator. The residue was dis-
solved in dry Et2O (30 mL) and stirred in an ice-water
bath under argon. MeMgBr (2.4 M, 4.5 mL, 10.8 mmol)
was introduced dropwise. The stirring was continued in an
ice-water bath until TLC showed completion of the reaction.
Satd aq NH4Cl was added. The mixture was extracted with
Et2O (50 mLꢂ3). The combined organic layers were washed
with water and brine, and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chro-
matography (1:9 EtOAc/PE) on silica gel afforded 4820 as
1
2922, 1734, 1447, 1041, 756 cmꢀ1; H NMR (300 MHz,
CDCl3) d 9.78 (s, 1H), 3.27–3.18 (m, 4H), 2.45 (t,
J¼4.9 Hz, 2H), 1.88–1.81 (m, 2H), 1.75 (s, 3H), 1.54–1.43
(m, 4H); 13C NMR (75 MHz, CDCl3) d 202.5, 66.5, 45.4,
43.7, 39.8, 32.4, 26.8, 22.1; ESIMS m/z 205.1 ([M+H]+);
EIHRMS calcd for C9H16OS2 (M+) 204.0636, found
204.0635.
4.1.34. Synthesis of 52. A solution of 51 (518 mg,
2.54 mmol) in CH3CN (4 mL) was added to a solution of
PhSOCH2CO2Bn4d (704 mg, 2.57 mmol) and piperidine
(0.25 mL, 2.57 mmol) in CH3CN (6 mL). The mixture was
stirred at ambient temperature for 15 h before being diluted
with Et2O, washed with water and brine, and dried over an-
hydrous Na2SO4. Removal of the solvent by rotary evapora-
tion and column chromatography (1:5 EtOAc/PE) on silica
gel afforded 52 as a colorless oil (510 mg, 1.45 mmol,
57% yield). FTIR (film) 3446, 1715, 1656, 1456, 1271,
1
a colorless oil (1.992 g, 8.1 mmol, 75% yield); H NMR
(300 MHz, CDCl3)
d 3.77–3.75 (m, 1H), 3.57 (t,
J¼5.8 Hz, 2H), 1.49–1.13 (m, 12H), 0.85 (s, 9H), 0.00 (s,
6H).
1
1160, 982, 752, 697 cmꢀ1; H NMR (300 MHz, CDCl3)
4.1.31. Oxidation of 48 (49). A solution of SO3$Py
(1.148 g, 7.22 mmol) in DMSO (10 mL) was added to
d 7.32–7.23 (m, 5H), 6.93 (dd, J¼5.1, 15.8 Hz, 1H), 6.04
(d, J¼15.5 Hz, 1H), 5.13 (s, 2H), 4.28 (br s, 1H), 3.32–
3.21 (m, 4H), 1.95–1.43 (m, 7H), 1.69 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 166.3, 150.6, 135.8, 128.5, 128.2,
128.2, 119.9, 70.8, 66.6, 66.3, 45.4, 39.9, 36.4, 32.3,
23.0; ESIMS m/z 370.1 ([M+NH4]+); ESIHRMS calcd
for C18H24O3S2Na ([M+Na]+) 375.1059071, found
375.1053470.
a
solution of 48 (587 mg, 2.39 mmol) and NEt3
(1.67 mL, 12.1 mmol) in CH2Cl2 (6 mL) stirred in an
ice-water bath. After completion of the addition, the mix-
ture was stirred at ambient temperature for 3 h before be-
ing diluted with Et2O (200 mL), washed first with satd aq
CuSO4, then with water and brine, and dried over anhy-
drous Na2SO4. Removal of the solvent by rotary evapora-
tion and column chromatography (1:50 EtOAc/PE) on
silica gel afforded 4920 as a colorless oil (503 mg,
2.06 mmol, 86% yield); 1H NMR (300 MHz, CDCl3)
d 3.56 (t, J¼6.2 Hz, 2H), 2.39 (t, J¼7.2 Hz, 2H), 2.10
(s, 3H), 1.62–1.20 (m, 6H), 0.83 (s, 9H), 0.00 (s, 6H).
4.1.35. Deprotection of 52 (53). NaHCO3 (935 mg,
11.13 mmol) and I2 (1.139 g, 4.48 mmol) were added to a so-
lution of 52 (450 mg, 1.28 mmol) in CH3COCH3 (13 mL)
and H2O (2.6 mL) stirred in an ice-water bath. After comple-
tion of the addition, the mixture was stirred at the same
temperature for 30 min before the excess I2 was destroyed
by addition of satd aq Na2S2O3 (10 mL). The mixture was
extracted with EtOAc (3ꢂ30 mL). The combined organic
phases were washed with satd aq Na2S2O3, water, and brine,
and dried over anhydrous Na2SO4. Removal of the solvent
by rotary evaporation and column chromatography (1:3
EtOAc/PE) on silica gel afforded 53 as a colorless oil
(238 mg, 1.03 mmol, 80% yield). FTIR (film) 3446, 1718,
4.1.32. Synthesis of 50. A solution of HS(CH2)2SH
(0.11 mL, 1.12 mmol), BF3$Et2O (0.03 mL, 0.25 mmol),
and 49 (169 mg, 0.69 mmol) was stirred at ambient temper-
ature for 5 h. Acetone was added to eliminate the excess
thiol. The stirring was continued at ambient temperature
overnight. The mixture was diluted with CH2Cl2, washed
with water and brine, and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chro-
matography (1:6 EtOAc/PE) on silica gel afforded 50 as
a colorless oil (138 mg, 0.67 mmol, 97% yield). FTIR
(film) 3376, 2925, 1460, 1375, 1275, 1052 cmꢀ1; 1H NMR
(300 MHz, CDCl3) d 3.65 (t, J¼6.5 Hz, 2H), 3.36–3.29
1
1656, 1455, 1275, 1163, 980, 697, 666 cmꢀ1; H NMR
(300 MHz, CDCl3) d 7.37 (br s, 5H), 6.79 (dd, J¼4.4,
15.9 Hz, 1H), 6.04 (d, J¼15.7 Hz, 1H), 5.19 (s, 2H), 4.57
(br s, 1H), 4.33–4.29 (m, 1H), 2.50 (t, J¼8.0 Hz, 2H),
2.21 (s, 3H), 1.75–1.65 (m, 4H); ESIMS m/z 294.2

10200
Q. Zhang, Y. Wu / Tetrahedron 63 (2007) 10189–10201
([M+NH4]+); MALDIHRMS calcd for C16H20O4Na
([M+Na]+) 299.1254, found 299.1270.
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4.1.36. Hydroperoxidation of 53 (54). A solution of
53 (265 mg, 0.96 mmol), UHP (683 mg, 6.79 mmol), and
p-TsOH (monohydrate, 224 mg, 1.18 mmol) in MeO-
(CH2)2OMe (15 mL) was stirred at ambient temperature
overnight. The mixture was diluted with Et2O, washed
with water and brine, and dried over anhydrous Na2SO4. Re-
moval of the solvent by rotary evaporation and column chro-
matography (1:5 EtOAc/PE) on silica gel afforded 54 as
a colorless oil (a 9:1 mixture, 265 mg, 0.91 mmol, 95%
yield). FTIR (film) 3400, 1717, 1660, 1456, 1379, 1219,
1
1174, 976, 739 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.65
(s, 1H), 7.37–7.32 (m, 5H), 6.96 (dd, J¼15.7, 4.4 Hz,
0.9H), 6.89 (dd, J¼15.7, 4.5 Hz, 0.1H), 6.14 (d,
J¼15.7 Hz, 0.9H), 6.09 (d, J¼15.7 Hz, 0.1H), 5.19 (s, 2H),
4.44 (dt, J¼11.7, 2.2 Hz, 1H), 1.84–1.54 (m, 6H), 1.47 (s,
3H). (Because of its unstable/reactive nature, it was not pos-
sible to obtain HRMS or elemental analysis data for 54).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20025207, 20272071, 20372075,
20321202, 20672129, 20621062) and the Chinese Aca-
demy of Sciences (‘Knowledge Innovation’ project,
KJCX2.YW.H08).
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