A remarkably useful sulfur bridge as synthetic lever in an approach to Javanicin B

Article abstract of DOI:10.3987/COM-16-S(S)58

A concise and efficient synthesis of a non-racemic advanced intermediate to the quassinoid javanicin B is disclosed. The strategy is centred on a triple diene-transmissive Diels-Alder cycloaddition to form the four rings of javanicin B. A sulfur bridge plays several crucial roles allowing an intramolecular cycloaddition to occur with complete stereoselectivity, controlling the stereochemical outcome of another cycloaddition, and transforming into a pivotal electrophile for the introduction of a particularly hindered methyl group.

Full text of DOI:10.3987/COM-16-S(S)58

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HETEROCYCLES, Vol. 95, No. 2, 2017
HETEROCYCLES, Vol. 95, No. 2, 2017, pp. 894-919. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2016, Accepted, 17th October, 2016, Published online, 13th December, 2016
DOI: 10.3987/COM-16-S(S)58
A REMARKABLY USEFUL SULFUR BRIDGE AS SYNTHETIC LEVER
IN AN APPROACH TO JAVANICIN B
Amélie Dion and Claude Spino*
Département de chimie, Université de Sherbrooke, 2500 Boul. Université,
Sherbrooke, QC, J1K 2R1
Abstract – A concise and efficient synthesis of a non-racemic advanced
intermediate to the quassinoid javanicin B is disclosed. The strategy is centred on
a triple diene-transmissive Diels-Alder cycloaddition to form the four rings of
javanicin B. A sulfur bridge plays several crucial roles allowing an intramolecular
cycloaddition to occur with complete stereoselectivity, controlling the
stereochemical outcome of another cycloaddition, and transforming into a pivotal
electrophile for the introduction of a particularly hindered methyl group.
INTRODUCTION
Javanicins are quassinoids isolated from the tree Picrasma javanica that grows in Indonesia and
South-East Asia.1 They possess the picrasane or the less frequently encountered 4-norpicrasane
skeletons.2,3 The structures of three members of this family of highly degraded triterpenes are displayed in
Figure 1. Many quassinoids possess strong nematicidal4 activities and anticancer properties,5 which taken
together with the recognized synthetic challenge their highly oxygenated carbon framework represents,
makes them worthwhile synthetic targets.
OMe
OMe
OMe
11
HO
Me
H
HO
Me
H
O
Me
H
O
O
O
Me Me
Me Me
Me Me
MeO
MeO
MeO
1
8
H
H
H
16
5
O
OH
O
O
O
O
H
H
H
H
H
H
HO
Me
javanicin Z
javanicin B
javanicin R
Figure 1. Three javanicins of the quassinoid family of triterpenes

HETEROCYCLES, Vol. 95, No. 2, 2017
895
We have established a Diene-Transmissive Diels-Alder Cycloadditions (DTDAC) strategy to the
picrasane framework, as summarized in Scheme 1.6 However, our first-generation approach had a fatal
flaw in that the tetrasubstituted exocyclic double bond in compound 1 (R = Me) could not be prepared
from a cyclohexane-derived starting material. Only the trisubstituted exocyclic double bond (1, R = H)
could be prepared and was shown to undergo a double DTDAC sequence to compound 3 (R = H).7 Later,
we developed a second approach involving a vinylallene 4 that not only solved the problem of the
synthesis of the tetrasubstituted exocyclic double bond (as in 5), but extended the DTDAC sequence to
three Diels-Alder reactions, thus increasing its synthetic efficiency.8 Finding a suitable linker (L) turned
out to be a difficult task as was using the tetrasubstituted endocyclic double bond contained in the product
6 to further the synthesis. We herein describe the solution to these problems and the full account of the
synthetic approach to the complete javanicin skeleton.
Scheme 1. The Diene-Transmissive Diels-Alder strategy to quassinoids
The intermolecular Diels-Alder cycloaddition on a vinylallene such as 7 proceeds to give the wrong
geometry of the exocyclic double bond (8a) because of the preferential attack on the least-hindered face
of 7 by the dienophile (Scheme 2).9 Therefore, linking the dienophile for internal delivery to the correct
face of the diene is not optional. Linking the dienophile per se was not difficult and vinylallene 9 was

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HETEROCYCLES, Vol. 95, No. 2, 2017
easily prepared, its intramolecular Diels-Alder cycloaddition proceeding in 89% to give a single
diastereomer of cycloadduct 10 (Scheme 2).10 At this stage, we believed that the entire strategy was going
to work as planned. Little did we know that a major hurdle would take years to overcome.
Scheme 2. Inter and intramolecular Diels-Alder cycloadditions of vinylallenes 7 and 9
A major obstacle was awaiting us in the form of a secondary reaction pathway competing with the third
Diels-Alder cycloaddition of compound 12 (Scheme 3).7 No matter the reaction conditions and/or what
Lewis acid was added, the unwanted reaction to give product 11 always prevailed. Much decomposition
often accompanied the unwanted reaction. On other dienes similar to 12, with some optimization, we
were in fact able to get a good yield of the unwanted adduct corresponding to 11.8
Scheme 3. Attempted intramolecular Diels-Alder cycloaddition of 11

HETEROCYCLES, Vol. 95, No. 2, 2017
897
Scheme 4 shows examples of different linkers we have investigated to replace the faulty lactone in diene
12, but none of them led to the desired cycloaddition. Cycloadducts 15 or 18 could not withstand the
reaction conditions to make them from sulfonate 14 or ether 17, respectively. They decomposed in the
reaction conditions, presumably following the mechanistic pathway shown in Scheme 3. A silyloxy linker
16 also failed to resolve the issue. We even designed a linker lacking a heteroatom at C-1 (19) thereby
blocking this decomposition pathway. The linker in the product 20 would then be released by an
elimination reaction. Strangely, we were unable to find reaction conditions to allow the intramolecular
Diels-Alder reaction of 19, decomposition occurring under forcing conditions. Most of these dienes took
months to prepare and we considered abandoning the strategy altogether.10
Scheme 4. Different linkers for the first intramolecular Diels-Alder reaction
RESULTS AND DISCUSSION
An unexpected turn of events occurred when we planned to use a sulfur linker with the intention of
removing the sulfur bridge before the problematic Diels-Alder reaction to prevent the unwanted pathway
shown in Scheme 3 (Scheme 5). Indeed, Raney nickel should readily reduce the C-S bonds in 23 before
continuing on with the DTDAC sequence.11

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HETEROCYCLES, Vol. 95, No. 2, 2017
Scheme 5. Planned use of a removable sulfur bridge in the DTDAC sequence
After exploring several different synthetic routes, a satisfactory synthesis of chiral non-racemic
vinylallene 36 was found and is presented in Scheme 6. Propargyl alcohol 25 was transformed into ynone
27 and diol 28 was converted to the phosphonium iodide 30, following standard chemistry. Their
a. n-BuLi, THF
-78 ºC
OTBDPS
TBDPS-Cl, Im.
DCM
OH
OTBDPS
26
O
b. Ac2O, rt
78% 2 steps
25
28
27
1. NaH, TBDPS-Cl
THF, 93%
PPh3
toluene
OH
I
PPh3I
OTBDPS
2. I2, PPh3, Im.
DCM, 96%
reflux, 93%
OH
OTBDPS
29
30
a. HMDSNa, THF
b. MeCN
c. 27, 66%
OTBDPS
OTBDPS
O
Oxone (cat.), 33
K2CO3/AcOH, H2O
O
O
O
O
O
O
Bu4NHSO4, Na2EDTA
DMM-MeCN, 72%
Me
OTBDPS
32
Me
OTBDPS
33
31
Br
t-BuLi, CuCN
THF
RO
AcS
Me
Me
Me
Me
DIAD, PPh3
AcSH, 70%
OTBDPS
OTBDPS
OTBDPS
OTBDPS
36
DCC, (S)-MTPA
34 R = H (94%ee)
DMAP, DCM, 50%
35 R = (+)-(O)C(CF3)(OMe)Ph
Scheme 6. Synthesis of non-racemic vinylallene 36

HETEROCYCLES, Vol. 95, No. 2, 2017
899
coupling under Wittig reaction conditions12 gave enyne 31 as a 6:1 mixture of E and Z geometrical
isomers. A carefully controlled Shi epoxidation13 of this enyne gave chiral non-racemic epoxide 32. Its
enantiomeric purity was measured at >90% by first opening it with a vinylcuprate reagent and converting
some of the resulting alcohol 34 to the corresponding Mosher ester 35. Only very small amounts of
diasteromers carried over from the E:Z mixture of enyne 31 were detected. The SN2 reaction product 36
was the sole detectable product upon treatment of alcohol 34 with thioacetic acid under the Mitsunobu
reaction conditions.
Liberation of the thiol group in 36 proved unexpectedly difficult because the free thiol is unstable.
Eventually, we found that treatment of thioacetate 36 with hydrazine in acetonitrile to uncover the free
thiol, a quick change of solvent to then react this free thiol directly with methyl propiolate, gave a
purported intermediate 37 that could not be observed as it collapsed instantly to the desired cycloadduct
38. The latter was isolated as a single diastereomer, in 83% yield for the three steps in one pot. Removal
of the two silyl protecting groups and periodane oxidation gave a sensitive dialdehyde that reacted
chemoselectively with the anion of methyl 2-(dimethoxyphosphono)acetate to give enoate 39, isolated as
a single geometrical isomer. The hetero-Diels-Alder reaction between diene 39 and ethyl vinyl ether
proceeded uneventfully to give cycloadduct 40 in an endo approach of the dienophile on the least
hindered side of the enal. No other stereoisomers could be detected.
CO2Me
Me
CO2Me
AcS
Me
Me
a. H2N-NH2•H2O
S
S
R
Me
MeCN
Me
83%
b. Et3N, DCM
CO2Me
Me
OTBDPS
OTBDPS
OTBDPS
36
OTBDPS
OTBDPS
37
38
CO2Me
Me
CO2Me
Me
S
S
H
1. TBAF, 76%
2. IBX, AcOEt
OEt
Yb(fod)3, 82%
Me
Me
O
O
OEt
3. NaH, MDPA
63%
CO2Me
39
CO2Me
40
Scheme 7. Synthesis of diene 40
Although we fully expected diene 40 to decompose upon heating or upon treatment with Lewis acids, we
nevertheless tried the intramolecular Diels-Alder reaction. To our astonishment, we obtained a 56% yield

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HETEROCYCLES, Vol. 95, No. 2, 2017
(later optimized to 66%) of the long sought-after pentacyclic compound 41. By comparison, derivatives
of 18 (c.f. Scheme 4) decomposed above 50 ºC.10 Actually, we believe that the cleavage of the
dihydrothiophene moiety does occur to give intermediate 42. However, instead of decomposing,
intermediate 42 may revert back to diene 40 for lack of competing side reactions. In the case of other
linkers, this intermediate could decarboxylate or loose SO3 or abstract protons, for example. Sulfur is
nucleophilic and may prefer to attack the oxonium system to give back diene 40. Eventually, the
intramolecular Diels-Alder cycloaddition occurs to give the stable pentacyclic compound 41. Whatever
the case may be, at last, the DTDAC strategy proved satisfactory for the synthesis of a quassinoid and
moreover, the overall synthesis looked good, promising to be very efficient and allowing for an exquisite
control of all stereocentres. The relative stereochemistry of all chiral centres in 41 was assigned beyond
doubt from the single crystal X-ray analysis of its sulfone derivative (see 44 in Scheme 9).
CO2Me
Me
CO2Me
Me
CO2Me
Me
S
S
S
11
H
Me
H
H
250 ºC
1
4
15
8
Me
Me
toluene, 66%
O
OEt
O
OEt
O
OEt
H
H
CO2Me
CO2Me
CO2Me
40
41
42
Scheme 8. Intramolecular Diels-Alder cycloaddtion of diene 40
Now remained the last major challenge imposed by this strategy, i.e. the use of the endocyclic,
tetrasubstituted, and rather severely hindered double bond in adduct 41 to introduce a methyl group at
position 8 (cf numbering in Scheme 8). A model reveals the highly hindered nature of this double bond
and we wondered if any carbon could actually be introduced at that position. Furthermore, we had not
planned on the sulfur being there at this stage, but its presence opened new synthetic opportunities.
Three main strategies were considered: using the sulfur to introduce a carbonyl at position 11; converting
the sulfur to a sulfone; converting the sulfur to a sulfonium salt. In all three cases, position 8 becomes
electrophilic thus calling for a nucleophilic methyl to be used.
Oxidizing the sulfur to the sulfone 44 was easily achieved using m-CPBA (Scheme 9). It was more
difficult, but possible, to stop the oxidation at the sulfoxide stage (43) by lowering the temperature. In any
case, there was no need to optimize this oxidation as all our attempts to convert 43 to a C-11 ketone
derivative failed, including the Pummerer reaction shown in Scheme 9. That reaction gave a 1:1 mixture
of two unusable alkenes 45 and 46 instead of the expected thioacetal.

HETEROCYCLES, Vol. 95, No. 2, 2017
901
Scheme 9. Using the sulfur atom to convert 41 to an electrophilic species
All attempts to form a palladium -complex from sulfone 44 and react it with a nucleophilic species
failed. Cuprate reagents reacted with sulfone 44 to give a 46% yield of product 47. Its structure was
proven by an X-ray analysis and a probable mechanism is shown in Scheme 10. Deprotonation  to the
MeO2C
OH
Me
CO2Me
Me
O
O
O
O
S
Me
S
Me
MeCuCNMgCl
or Me2CuLi
H
Et2O, 46%
O
OEt
H
H
H
CO2Me
CO2Me
44
47
MeO2C
O
O
CO2Me
Me
O
O
Me
O
S
Me
S
Me
H
O
OEt
H
H
H
CO2Me
49
CO2Me
48
Scheme 10. Attempted cuprate reactions of sulfone 44

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HETEROCYCLES, Vol. 95, No. 2, 2017
sulfone group (48) results in the elimination of ethanol with concomitant opening of the tetrahydropyrane
ring leading to the formation of aldehyde 49. Then, a stereoselective aldol reaction takes place to give 47.
These experiments gave an early indication of the low accessibility of the internal alkene in such a
sterically hindered and rigid pentacyclic structure.
Thinking that a sulfonium salt would be more electron-withdrawing than a sulfone for the SN2’
displacement reactions,14 we tried to prepare compound 50 by reacting it with Meerwein’s salt in DCM at
room temperature (Scheme 11). At this stage, we had no reason to believe that the compound that we had
isolated and characterized was in fact 52, not 50, possessing an epimerized -OEt group at C-16. We
submitted 52 to the action of methylcyanocuprate and to our delight, managed to get 30% yield of what
we then thought was the desired addition product 51, but was in fact adduct 53, along with a
demethylation product that, to our puzzlement, was not exactly the same as the expected starting
compound 41. Despite this problem, and an as of yet unusable yield of the cuprate adduct, we were
encouraged because no other regioisomer or diastereomer was detected in this addition reaction.
Wanting to improve on the preparation of the methylsulfonium salt, we carried out the reaction at -30 ºC
and isolated a different isomeric salt 50, which structure was secured from a single crystal X-ray
diffraction analysis. The latter was the expected methylsulfonium salt, so obviously the previous one was
not. We postulated that perhaps the two diastereomers differed by their stereochemistry at sulfur. How
CO2Me
Me
CO2Me
CO2Me
Me
BF4
Me
Me
S
Me
S
MeS
H
Me
H
Me Me
H
Me3OBF4
MeCuCNMgCl
+
41
8
DCM, -30 ºC
16
THF, rt, 30%
O
OEt
OEt
51:41 1:1
O
OEt
O
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
41
50
51
Me3OBF4
DCM, rt
CO2Me
Me
CO2Me
Me
CO2Me
Me
BF4
Me
S
S
MeS
Me
H
Me Me
H
Me
H
MeCuCNMgCl
+
8
THF, rt, 30%
16
O
OEt
53:54 2:1
OEt
O
OEt
O
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
52
53
54
Scheme 11. Cuprate reaction of sulfonium salts 50 and 52

HETEROCYCLES, Vol. 95, No. 2, 2017
903
temperature could reverse this stereochemistry, we did not know and quite frankly, there was little room
on the other face of the molecule to accommodate a methyl group.
Nonetheless, submitting the isomeric salts separately to the action of methylcyanocuprate, gave in each
case two products (Scheme 11). Methylsulfonium salt 50, obtained at -30 ºC, led to the formation of
adduct 51 and the starting sulfur 41 in a 1:1 ratio. Methylsulfonium 52, obtained at rt, led to the formation
of 53 and 54 in a 2:1 ratio. The fact that the demethylation products 41 and 54 were different in structure
invalidated the hypothesis that 50 and 52 were epimeric at sulfur. Were they epimeric at one of the
carbons bearing an ester group? We oxidized the demethylation product 54 to the corresponding sulfone
55 and were able to obtain an X-ray structure of the latter compound (Scheme 12). To our surprise, the
isomeric carbon was the acetal carbon, presumably caused by a ring-opening ring-closing event catalyzed
by traces of acid present. We can obtain either of methylsulfonium salts 50 or 52 as the major product by
carefully controlling the reaction time and temperature.
Scheme 12. Proof of the structure of the isomeric methylsulfonium 52
This serendipitous event would have remained a simple curiosity, easily avoided by keeping the
temperature low during the formation of sulfonium salt 50, had it not turned out to be crucial in the
overall scheme. We replaced the methyl group on sulfur by an ethyl group in order to reduce the SN2
reaction of the cuprate reagent at the alkyl group on sulfur. It was also possible to control the formation of
the corresponding epimeric ethylsulfonium salts 56 and 57 by regulating the temperature and reaction
time, but it was easier and more efficient to let the reaction run at rt for long enough to form epimer 56.
Moreover, upon reaction with methylcyanocuprate, the non-epimerised ethylsulfonium salt 57 still
suffered much de-ethylation to produce 41 along with the cuprate adduct 59, all in low overall yield
(30%). On the contrary, ethylsulfonium salt 56 gave a much cleaner product 58 and in higher yield.
Ultimately, the crude mixture of ethylsulfonium salts 56 prepared at rt, containing traces of 57, was made

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HETEROCYCLES, Vol. 95, No. 2, 2017
to react with the cuprate reagent issued from a mixture of methylmagnesium chloride, lithium chloride,
chlorotrimethylsilane, and copper bromide to give a 70% yield of the desired adduct 58 over two steps,
along with traces of the epimer 59 (Scheme 13). The structure of adduct 58 was secured by a single
crystal X-ray diffraction analysis.
Possibly, a subtle conformational effect may increase the desired reaction rate in the case of
ethylsulfonium 56. Alternatively, coordination of the cuprate reagent with the ethoxy oxygen could
deliver it to the reactive site, an option not available in the case of ethylsulfonium 57. It is important to
note that the presence of TMSCl is necessary in the cuprate addition,15 both to increase the yield of the
desired reaction and to reduce attack of the cuprate reagent at the S-ethyl group. Other Lewis acids
(BF3•Et2O, TMSBr) and other copper(I) sources (CuI, CuCN) were less effective.
CO2Me
CO2Me
BF4
CO2Me
Me
BF4
Et
Et
Me
Me
S
S
S
Me
Me
H
Me
H
H
Et3OBF4
+
DCM, rt, 4 h
O
OEt
O
OEt
O
OEt
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
41
56
57
MeMgCl, LiCl
CuBr•SMe2
TMSCl
76% 2 steps
CO2Me
Me
CO2Me
CO2Me
Me
Me
H
1. NaIO4
EtS
EtS
Me Me
H
Me Me
Me Me
H
H2O/MeCN/EtOAc
+
2. toluene, reflux
O
OEt
O
OEt
O
OEt
p-TsOH, EtOH
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
58 (70%)
59 (6%)
60
Scheme 13. Optimized reaction conditions for the SN2’ addition of methylcuprate to 55
The sulfur bridge had played its roles exceedingly well, providing stereoselectivity in the first
intramolecular Diels-Alder reaction, allowing the third Diels-Alder reaction to proceed with complete
stereoselectivity, being amenable to transformation into a leaving group (sulfonium salt) thus permitting a
highly diastereo- and regioselective SN2’ addition of dimethylcuprate to introduce the last carbon of the
picrasane skeleton. Last, but not least, the removal of the sulfur atom by oxidation to the sulfoxide and
elimination occurred without difficulty, providing a useful C1-C2 alkene in 60 (Scheme 13). The plan

HETEROCYCLES, Vol. 95, No. 2, 2017
905
now calls for the use of these double bonds to introduce the requisite oxygen atoms and complete the
synthesis of javanicin B.
In conclusion, we have shown that the Diene-Transmissive Diels-Alder Cycloaddition strategy is a viable
one to construct the complete javanicin framework common to many quassinoids. All stereocentres were
introduced with a high degree of stereoselectivity to provide the non-racemic advanced intermediate 60 in
only 16 linear steps (18 total) from pentanediol and propargyl alcohol. The sulfur bridge was crucial in
solving the main challenges of this synthetic approach. The completion of the synthesis of Javanicin B
and other members of this family is currently underway.
EXPERIMENTAL
Unless otherwise noted all reactions were performed under an argon atmosphere. Solvents were distilled
from potassium/benzophenone ketyl (THF, Et2O, toluene), from calcium hydride (CH2Cl2, DMF). Proton
nuclear magnetic resonance (1H NMR) spectra were recorded on a 300 MHz or 400 MHz spectrometer.
Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a 75.5 MHz or 100.7 MHz
spectrometer. NMR samples were dissolved in chloroform-d (unless specified otherwise) and chemical
shifts are reported in ppm (δ units) relative to the residual undeuterated solvent. Multiplicities are reported
as follows: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of
doublets, ddd = doublet of doublet of doublets, m = multiplet. LRMS analyses were performed on a GC
system spectrometer (30 m length, 25µ OD, DB-5 ms column) coupled with a mass spectrometer.
High-resolution mass spectrometry was performed by electrospray time-of-flight. All reactions were
monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel coated glass plate visualized under
UV (254 nm) and TLC stains such as vanillin, KMnO4, PMA, Dragen Dorff, or by 1H NMR and GCMS
analysis. Silica gel (230-400 mesh) was used for flash chromatography.
5-((tert-Butyldiphenylsilyl)oxy)pent-3-yn-2-one
(27).
The
known
tert-butyldiphenyl-
(prop-2-yn-1-yloxy)silane (26)16 (57.4 g, 0.19 mol) was dissolved in THF (380 mL) and a n-butyllithium
solution (1.96 M in pentane, 112 mL, 0.22 mol) was added slowly at -78 °C. The reaction mixture was
stirred 30 min at -78 °C, followed by 10 min at -20 °C. In a 1 L three-neck rb flask with mechanical
stirring, acetic anhydride (31.4 mL, 0.33 mol) was diluted in THF (190 mL) and the solution a was cooled
to -78 °C. The organolithium solution was added to the acetic anhydride solution and the reaction mixture
was stirred for 12 h while slowly warming up to rt. The reaction mixture was quenched with water and
the two layers were separated. The aqueous layer was extracted twice with Et2O, the organic layers were
combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give
colorless oil. The crude product was purified by column chromatography using a 1:9 mixture of Et2O and

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HETEROCYCLES, Vol. 95, No. 2, 2017
1
hexanes as eluting solvent, to give ketone 27 (49.8 g, 78%). NMR H (300 MHz, CDCl3)  (ppm) 7.70
(dd, 4H, J = 6.6, 2.2 Hz), 7.49-7.38 (m, 6H), 4.46 (s, 2H), 2.26 (s, 3H), 1.07 (s, 9H). NMR 13C (75 MHz,
CDCl3)  (ppm) 184.1 (s), 135.6 (d), 132.4 (s), 130.1 (d), 127.9 (d), 89.8 (s), 84.5 (s), 52.3 (t), 32.4 (q),
26.6 (q), 19.2 (s). IR (CHCl3)  (cm-1) 3072, 2953, 1680, 1427. LRMS (m/z, (relative intensity)) 279
((M-C4H9)+, 100), 249 (72), 241 (35). HRMS calcd for C17H15O2Si: 279.0841, found: 279.0846.
(5-((tert-Butyldiphenylsilyl)oxy)pentyl)iodotriphenylphosphane (30). tert-Butyl((5-iodopentyl)oxy)-
diphenylsilane (29)17 (115g, 0.25 mol) was dissolved in toluene (513 mL) and triphenylphosphine was
added. The reaction mixture was stirred at reflux for 12 h and after this time, cooled slowly to 0 °C. Et2O
(200 mL) was added to precipitate the phosphonium salt. The slurry was stirred for 2 h at 0 °C and
filtered. The cake was washed twice with Et2O and dried under reduced pressure to give the desired
phosphonium 30 as a white solid (167 g, 93%). 1H NMR (300 MHz, CDCl3)  (ppm) 7.81-7.64 (m, 15H),
7.58 (d, 4H, J = 7.7 Hz), 7.40-7.30 (m, 6H), 3.70-3.57 (m, 2H), 3.59 (t, 2H, J = 6.3 Hz), 1.74-1.51 (m,
6H), 0.97 (s, 9H). 13C NMR (75 MHz, CDCl3)  (ppm) 135.4 (d), 135.2 (d), 133.6 (d), 133.5 (d), 130.6
(d), 130.5 (d), 129.5 (d), 127.6 (d), 118.5 (s), 117.3 (s), 63.2 (t), 31.7 (t), 26.8 (q), 23.4 (t), 22.8 (t), 22.3
(t), 19.1 (s). IR (CHCl3)  (cm-1) 3064, 2932, 1587.
(E)-1,9-Bis((tert-butyldiphenylsilyl)oxy)-4-methylnon-4-en-2-yne (31). In a 3 L, three neck, rb flask
with a mechanical stirrer was charged phosphane 30 (175.4 g, 0.245 mol) and THF (1 L). The solution
was cooled to 0 °C and NaHMDS (259 mL, 1.0 M in THF, 0.259 mol) was added. The reaction mixture
was stirred 45 min at 0 °C and 10 min at rt. The solution was cooled to -78 °C and MeCN (37.6 mL, 0.72
mol) was added. The reaction mixture was stirred for 10 min at -78 °C. A solution of ketone 27 (48.5 g,
0.144 mol) in THF (260 mL) was added via canula to the reaction mixture at -78 °C and the mixture was
stirred for 1 h. The reaction mixture was quenched by adding a saturated solution of ammonium chloride
and the aqueous layer was extracted 3 times with Et2O. The organic layers were combined, washed with
brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified
by column chromatography using a 20:80 mixture of AcOEt and hexanes as eluting solvent, to give
alkyne 31 as colorless oil (61.2 g, 66%). 1H NMR (300 MHz, CDCl3)  (ppm) 7.75 (dd, 4H, J = 7.4, 1.9
Hz), 7.69 (dd, 4H, J = 7.4, 1.9 Hz), 7.46-7.36 (m, 12H), 5.76 (t, 1H, J = 7.2 Hz), 4.46 (s, 2H), 3.68 (t, 2H,
J = 6.1 Hz), 2.06 (q, 2H, J = 7.2 Hz), 1.71 (s, 3H), 1.71-1.44 (m, 4H), 1.08 (s, 9H), 1.07 (s, 9H). 13C
NMR (75 MHz, CDCl3)  (ppm) 138.1 (d), 135.6 (d), 134.0 (s), 133.3 (s), 129.7 (d), 129.5 (d), 127.6 (d),
117.4 (s), 88.3 (s), 83.9 (s), 63.6 (t), 53.2 (t), 32.1 (t), 28.1 (t), 26.9 (q), 26.7 (q), 25.3 (t), 19.2 (s), 17.0 (q).
IR (CHCl3)  (cm-1) 3068, 2936, 2247, 2225, 1470. LRMS (m/z, (relative intensity)) 644 (M+, 2), 587
((M-C4H9)+, 45), 237 (68), 207 (100). HRMS calcd for C42H52O2Si2: 644.3506, found: 644.3514.

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907
(+)-Epoxide 32. In a 3 L-three neck rb flask with a mechanical stirrer, was charged a solution of alkyne
31 (61.2 g, 95.0 mmol) in a 1:2 mixture of MeCN and dimethoxymethane (765 mL). An aqueous buffer
(prepared by mixing 100 mL 0.1 M aqueous K2CO3 with 0.5 mL acetic acid, pH 9.3, 484 mL),
Bu4NHSO4 (3.20 g, 9.50 mmol), and fructose-derived ketone 33 (7.36 g, 28.5 mmol) were added. The
mixture was cooled to -10 °C using a NaCl-ice bath. A solution of Oxone (87.6, 142.5 mmol) in aqueous
Na2EDTA (4 × 10-4 M, 376 mL) and a solution of K2CO3 (0.24 g, 1.73 mmol) in water (1.2 mL) were
added dropwise simultaneously through two separate syringes via syringe pump over a period of 3 h.
After stirring 1 h at -10 °C, the reaction mixture was quenched with pentane and water, the two layers
were separated, and the organic layer was extracted twice with pentane. The organic layers were
combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The
crude product was purified by column chromatography using a 5:95 mixture of Et2O and hexanes as
1
eluting solvent, to give epoxide 32 (45.4 g, 72%) as colorless oil. []D +2.9 (c 1.08, CHCl3). H NMR
(300 MHz, CDCl3)  (ppm) 7.72-7.67 (m, 8H), 7.44-7.36 (m, 12H), 4.33 (s, 2H), 3.69 (t, 2H, J = 6.1 Hz),
2.98 (t, 1H, J = 6.1 Hz), 1.60-1.48 (m, 6H), 1.39 (s, 3H), 1.07 (s, 18H). IR (CHCl3)  (cm-1) 3069, 2933,
1471. LRMS (m/z, (relative intensity)) 678 ((MNH4)+, 100), 661 ((MH)+, 30), 583 (35), 405 (77), 196
(52). HRMS calcd for C42H52Si2O3 [MH]+: 661.3533, found: 661.3518.
(+)-Vinylallene 34. tert-Butyllithium (1.7 M in pentane, 445.0 mL, 756 mmol) was added slowly to a
solution of (E)-1-bromo-1-propene (32.4 mL, 378 mmol) in THF (540 mL) at -78 °C. The mixture was
stirred 30 min at -78 °C and was then transferred via canula to a suspension of copper(I) cyanide (16.9 g,
189 mmol) in THF (300 mL) at -78 °C. The reaction mixture was stirred 30 min at -78 °C, then cooled at
-100 °C and a solution of epoxide 32 (25.0 g, 37.8 mmol) in THF (125 mL) was slowly added. The
reaction mixture was stirred 45 min at -100 °C then quenched with a saturated aqueous solution of
ammonium chloride containing 10% ammonium hydroxide. The biphasic mixture was stirred for 12 h,
after which time the two layers were separated and the organic layer was extracted three times with Et2O.
The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure to give vinylallene 34 (26.5 g, 100%), which was used in the
1
next step without purification. H NMR (300 MHz, CDCl3)  (ppm) 7.69-7.65 (m, 8H), 7.44-7.34 (m,
12H), 5.84 (dd, 1H, J = 15.9, 1.7 Hz), 5.61 (dq, 1H, J = 15.9, 6.6 Hz), 4.33 (s, 2H), 3.99 (q, 1H, J = 6.1
Hz), 3.64 (t, 2H, J = 6.1 Hz), 1.70 (t, 3H, J = 6.6 Hz), 1.69 (s, 3H), 1.61-1.40 (m, 6H), 1.04 (s, 9H), 1.03
(s, 9H). 13C NMR (75 MHz, CDCl3)  (ppm) 204.0 (s), 135.6 (d), 134.9 (d), 134.1 (s), 133.8 (s), 129.7 (d),
129.6 (d), 127.7 (d), 126.7 (d), 124.9 (d), 106.7 (s), 105.2 (s), 73.2 (s), 63.9 (t), 62.6 (t), 34.9 (t), 32.6 (t),
27.0 (q), 26.9 (q), 22.0 (t), 19.3 (s), 18.7 (q), 14.4 (q). IR (CHCl3)  (cm-1) 3633-3196, 3079, 2933, 1471.
LRMS (m/z, (relative intensity)) 700 ((M-H2)+, 4), 645 ((M-C4H9)+, 8), 199 (100), 135 (100). HRMS

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calcd for C45H56O3Si2: 700.3768, found: 700.3757. []D +9.8 (c 1.22, CHCl3).
(+)-Mosher ester 35. Vinylallene 34 (50.0 mg, 0.071 mmol) was dissolved in DCM (1.0 mL) and the
solution was cooled to 0 °C. (S)-(-)-α-Methoxy-α-(trifluoromethyl)phenylacetic acid (49 mg, 0.213
mmol), dimethylaminopyridine (8 mg, 0.06 mmol), and dicyclohexylcarbodiimide (51 mg, 0.247 mmol)
were added to the solution at 0 °C. The reaction mixture was stirred 12 h at rt and quenched with water.
The two layers were separated and the organic layer was extracted three times with DCM. The organic
layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified by column chromatography using a
20:80 mixture of AcOEt and hexanes as eluting solvent to give the Mosher ester 35 (43 mg, 50%). The
enantiomeric excess (ee = 94%) was determined by integration of the appropriate proton NMR signals in
the spectra of the crude product (methoxy signals at 3.47 and 3.5 and carbinol signals at 5.39 and 5.35
ppm). 1H NMR (300 MHz, CDCl3)  (ppm) 7.68-7.64 (m, 10H), 7.51 (d, 1H, J = 7.7 Hz), 7.43-7.29 (m,
14H), 5.75 (d, 1H, J = 15.9 Hz), 5.64 (dq, 1H, J = 15.9, 6.2 Hz), 5.39 (t, 1H, J = 6.6 Hz), 4.31 (ABq, 2H),
3.61 (t, 2H, J = 6.4 Hz), 3.47 (s, 3H), 1.76-1.71 (m, 2H), 1.68 (d, 3H, J = 6.2 Hz), 1.59 (s, 3H), 1.58-1.51
13
(m, 2H), 1.45-1.37 (m, 2H), 1.04 (s, 9H), 1.02 (s, 9H). C NMR (75 MHz, CDCl3)  (ppm) 203.0 (s),
165.9 (s), 135.5 (d), 133.9 (s), 133.5 (s), 132.2 (s), 129.5 (d), 128.2 (d), 127.6 (d), 127.4 (d), 125.8 (d),
125.2 (s), 121.4 (s), 106.4 (s), 100.0 (s), 78.1 (d), 63.6 (t), 62.6 (t), 55.4 (q), 32.5 (t), 32.2 (t), 26.8 (q),
26.7 (q), 21.8 (t), 19.2 (s), 18.6 (q), 15.1 (q). IR (CHCl3)  (cm-1) 3079, 2934, 1960, 1745, 1429. LRMS
(m/z, (relative intensity)) 918 (M+, 5), 861 ((M-C4H9)+, 22), 189 (100), 135 (74). HRMS calcd for
C55H65F3O5Si2: 918.4322, found: 918.4308. ]D +16.5 (c 0.99, CHCl3).
(-)-Thioacetate 36. Triphenylphosphine (39.6 g, 151.2 mmol) was dissolved in THF (581 mL) and the
solution was cooled at 0 ºC. Diisopropyl azodicarboxylate (29.8 mL, 151.2 mmol) was added and the
reaction mixture was stirred for 30 min at 0 °C. A solution of thioacetic acid (10.81 mL, 151.2 mmol) and
vinylallene 34 (53 g, 75.6 mmol) in THF (290 mL) was added over 60 min at -20 °C. The reaction
mixture was stirred at rt for 12 h and quenched with water. The two layers were separated and the organic
layer was extracted three times with Et2O. The organic layers were combined, washed with brine, dried
over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by column
chromatography using a 5:95 mixture of AcOEt and hexanes as eluting solvent to give thioacetate 36
(40.2 g, 70%). 1H NMR (300 MHz, CDCl3)  (ppm) 7.70-7.64 (m, 8H), 7.39-7.37 (m, 12H), 5.84 (m, 1H),
5.79-5.55 (m, 1H), 4.29 (d, 2H, J = 3.3 Hz), 3.97 (t, 1H, J = 7.2 Hz), 3.6 (t, 2H, J = 6.1 Hz), 2.30 (s, 3H),
1.76-1.24 (m, 6H), 1.73 (s, 3H), 1.70 (d, 3H, J = 6.6 Hz), 1.04 (s, 18H). 13C NMR (75 MHz, CDCl3) δ
(ppm) 202.9 (s), 195.7 (s), 135.6 (d), 134.1 (s), 133.7 (s), 129.5 (d), 127.5 (d), 126.2 (s), 125.1 (d), 106.5
(s), 102.1 (s), 63.8 (t), 62.6 (t), 47.6 (d), 34.0 (t), 30.5 (q), 26.8 (q), 23.4 (t), 19.2 (s), 18.6 (q), 17.6 (q). IR

HETEROCYCLES, Vol. 95, No. 2, 2017
909
-1
+

(CHCl3)  (cm ) 3075, 2931, 2858, 1691. LRMS (m/z, (relative intensity)) 678 ((M ), 2), 703
((M-C4H9)+, 15), 199 (90), 136 (100). HRMS calcd for C47H60Si2O3S [M]+: 760.3801, found: 760.3795.
[]D -37.2 (c 1.10, CHCl3).
(+)-Cycloadduct 38. A hydrazine hydrate solution (1.0 M in MeCN, 130 mL, 130.2 mmol) was added to
a solution of thiocacetate 36 (33.0 g, 43.4 mmol) in MeCN (435 mL), and the reaction mixture was stirred
for 12 h. The reaction mixture was concentrated under reduce pressure to remove the MeCN and
hydrazine and the concentrate were dissolved in DCM (645 mL). Triethylamine (9.7 mL, 64.4 mmol) and
a solution of methyl propiolate (5.73 mL, 64.4 mmol) in DCM (645 mL) were successively added at 0 °C.
The reaction mixture was slowly warmed to rt over a period of 4 h. The reaction mixture was then
concentrated under reduced pressure and the concentrate purified by column chromatography using a 5:95
mixture of AcOEt and hexanes as eluting solvent to give cycloadduct 38 (28.8 g, 83%) as thick colorless
oil. 1H NMR (300 MHz, CDCl3)  (ppm) 7.69-7.65 (m, 8H), 7.45-7.35 (m, 12H), 5.56 (d, 1H, J = 4.4 Hz),
4.58 (d, 1H, J = 13.2 Hz), 4.35 (d, 1H, J = 13.2 Hz), 4.26 (d, 1H, J = 12.1 Hz), 4.07 (br s, 1H), 3.72 (s,
3H), 3.66 (t, 2H, J = 6.1 Hz), 2.86 (dd, 1H, J = 6.0 Hz, 12.1 Hz), 2.67 (q, 1H, 6.6 Hz), 1.87 (s, 3H),
1.83-1.34 (m, 6H), 1.05 (s, 18H), 0.84 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm) 173.6 (s),
135.6 (d), 135.0 (s), 134.1 (s), 133.6 (s), 133.2 (s), 132.2 (d), 130.0 (s), 129.7 (d), 129.5 (d), 127.6 (d),
65.6 (t), 63.7 (t), 58.4 (q), 54.1 (d), 51.5 (q), 49.0 (d), 35.6 (t), 33.1 (d), 32.4 (d), 26.8 (q), 22.7 (t), 19.2
(q), 16.4 (t), 14.6 (s). IR (CHCl3)  (cm-1) 2939, 2857, 1735. LRMS (m/z, (relative intensity)) 802 (M+,
5), 745 ((M-C4H9)+, 50), 489 (65), 290 (65), 199 (90), 86 (100). HRMS calcd forC49H62Si2O4S: 802.3907,
found: 802.3890. []D +83.3 (c 1.55, CHCl3).
(+)-Ester 39. A solution of tetrabutylammonium fluoride (1.0 M in THF, 95.7 mL, 95.7 mmol) was
added to a solution of 38 (25.6 g, 31.9 mmol) in THF (320 mL) at rt. The reaction mixture was stirred 12
h and neutralized with a saturated aqueous solution of ammonium chloride. The two layers were
separated and the aqueous layer was extracted three times with Et2O. The organic layers were combined,
washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced
pressure. The crude product was purified by column chromatography using a 70:30 mixture of AcOEt and
hexanes as eluting solvent to give diol 61 (7.9 g, 76%), which was unstable and slowly decomposed at
ambient temperature. 1H NMR (300 MHz, CDCl3)  (ppm) 5.75 (d, 1H, J = 4.4 Hz), 4.48 (br d, 1H, J =
12.7 Hz), 4.25 (br d, 2H, J = 10.4 Hz), 4.06 (br d, 1H, J = 7.2 Hz), 3.71 (s, 3H), 3.60 (t, 2H, J = 6.1 Hz),
2.85 (dd, 1H, J = 6.6 Hz, 12.1 Hz), 2.73 (sextuplet, 1H, 6.6 Hz), 2.06 (m, 1H), 1.91 (s, 3H), 1.87 (m, 1H),
1.70-1.23 (m, 6H), 0.90 (d, 3H, J = 7.2 Hz). IR (CHCl3)  (cm-1) 3701-3099, 2939, 2874, 1735. LRMS
(m/z, (relative intensity)) 326 (M+, 10), 308 ((M-H2O)+, 25), 249 (60), 175 (50), 84 (100). HRMS calcd
for C17H26O4S: 326.1552, found: 326.1556. []D +193.6 (c 0.6, CHCl3).

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HETEROCYCLES, Vol. 95, No. 2, 2017
IBX (31.9 g, 114 mmol) was added to a solution of diol 61 (9.3 g, 28.5 mmol) in AcOEt (245 mL) and
the reaction mixture was heated to reflux for 3 h. The reaction then cooled down to rt and filtered. The
filtrate was concentrated under reduced pressure to give dialdehyde 62 (9.10 g, 100%), which was used
1
without any purification in next step. H NMR (300 MHz, CDCl3)  (ppm) 9.74 (s, 1H), 9.50 (s, 1H),
6.62 (d, 1H, J = 4.4 Hz), 4.23-4.15 (m, 1H), 4.21 (d, 1H, J = 11.8 Hz), 3.74 (s, 3H), 3.05 (dq, 1H, J = 7.3,
3.9 Hz), 2.95 (dd, 1H, J = 11.8, 6.3 Hz), 2.47-2.38 (m, 2H), 1.82-1.76 (m, 2H), 1.73 (s, 3H), 1.71-1.49 (m,
2H), 0.99 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3)  (ppm) 202.1 (d), 190.5 (d), 172.6 (s), 153.5
(d), 138.9 (s), 136.8 (s), 126.4 (s), 57.7 (d), 55.1 (d), 51.8 (q), 48.6 (d), 43.5 (t), 34.8 (t), 34.4 (d), 18.8 (t),
16.4 (q), 15.1 (q). IR (CHCl3)  (cm-1) 1730, 1447. LRMS (m/z, (relative intensity)) 322 (42), 263 (40),
163 (100), 84 (90). LRMS calcd for C17H22O4S [M]+: 322.1239, found: 322.1231.
Sodium hydride (1.43 g, 60% in mineral oil, 35.6 mmol) was added to THF (265 mL) at 0 °C. Methyl
2-(diethoxyphosphoryl)acetate (5.7 mL, 34.2 mmol) was added to the resulting suspension and the
reaction mixture was stirred for 30 min at 0 °C. The reaction mixture was cooled to -78 °C and a solution
of dialdehyde 62 (9.10 g, 28.5 mmol) in THF (20 mL) was added. The reaction mixture was stirred for a
further 12 h and then neutralized with a saturated aqueous solution of ammonium chloride. The two layers
were separated and the aqueous layer was extracted three times with Et2O. The organic layers were
combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure. The crude product was purified by column chromatography using a 20:80 mixture of
1
AcOEt and hexanes as eluting solvent to give ester 39 (6.80 g, 63%). H NMR (300 MHz, CDCl3) δ
(ppm) 9.52 (s, 1H), 6.93 (dt, J = 15.4, 7.3 Hz, 1H), 6.63 (d, J = 3.9 Hz, 1H), 5.81 (d, J = 15.4 Hz, 1H),
4.22-4.16 (m, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 3.13-3.02 (m, 1H), 2.95 (dd, J = 11.8, 6.3 Hz, 1H),
13
2.25-2.17 (m, 2H), 1.88-1.78 (m, 1H), 1.72 (s, 3H), 1.64-1.36 (m, 3H), 1.01 (d, J = 7.7 Hz, 3H). C
NMR (75 MHz, CDCl3) δ (ppm) 190.4 (d), 172.4 (s), 166.7 (s), 153.6 (d), 148.8 (d), 138.8 (s), 136.7 (s),
126.2 (s), 121.1 (d), 57.7 (d), 55.1 (d), 51.6 (q), 51.2 (q), 48.5 (d), 34.9 (t), 34.3 (d), 31.8 (t), 24.7 (t), 16.2
(q), 15.0 (q). IR (CHCl3)  (cm-1) 2948, 2934, 2856, 1724, 1697, 1436. LRMS (m/z, (relative intensity))
378 (M+, 20), 346 (50), 163 (75), 84 (100). HRMS C20H26O5S: calcd for 378.1501, found: 378.1491. []D
+136.9 (c 0.7, CHCl3).
(-)-Cycloadduct 40. Ester 39 (6.80 g, 18.0 mmol) was dissolved in ethyl vinyl ether (180 mL) and the
solution was degassed for 20 min by bubbling argon through. Then, Yb(fod)3 (1.36 g, 20% p/p) was
added and the reaction mixture was purged again 3 times with argon. The reaction mixture was stirred 16
h at rt and then concentrated under reduced pressure. The crude product was purified by column
chromatography using a 20:80 mixture of AcOEt and hexanes as eluting solvent to give cycloadduct 40
(6.66 g, 82%). 1H NMR (300 MHz, CDCl3)  (ppm) 6.96 (dt, 1H, J = 15.4, 7.2 Hz), 6.91 (s, 1H), 5.83 (d,

HETEROCYCLES, Vol. 95, No. 2, 2017
911
1H, J = 16.0 Hz), 4.97 (bd, 1H, J = 8.8 Hz), 3.94 (quint., 1H, J = 7.2 Hz), 3.83 (d, 1H, J = 8.9 Hz) 3.73 (s,
3H), 3.70 (s, 3H), 3.67 (quint., 1H, J = 7.2 Hz), 2.98 (m, 1H), 2.70 (q, 1H, J = 8.7 Hz), 2.27 (br q, 1H, J =
9.2 Hz), 2.24-2.20 (m, 2H), 2.17 (s, 3H), 1.95-1.83 (m, 1H), 1.80-1.63 (m, 3H), 1.60-1.43 (m, 3H), 1.25 (t,
3H, J = 7.2 Hz), 1.10 (d, 3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm) 174.3 (s), 167.0 (s), 149.0
(d), 139.8 (d), 130.0 (s), 129.3 (s), 121.2 (d), 112.5 (s), 99.3 (d), 64.5 (t), 58.9 (d), 56.7 (d), 51.7 (d), 51.4
(q), 35.7 (d), 35.3 (t), 34.0 (d), 32.7 (t), 32.0 (t), 24.9 (q), 15.1 (q), 14.6 (q). IR (CHCl3)  (cm-1) 2922,
1727. LRMS (m/z, (relative intensity)) 450 (M+, 70), 346 (50), 277 (50), 185 (75), 163 (100). HRMS
calcd for C24H34O6S: 450.2076, found: 450.2079. []D -51.6 (c 1.24, CHCl3).
(+)-Cycloadduct 41. Cycloadduct 40 (300 mg, 0.67 mmol) was dissolved in toluene (9 mL) and charged
in a sealable tube. The solution was degassed 5 times by freeze-thaw technique using liquid nitrogen.
Then, the tube was sealed and the reaction mixture was heated 36 h at 250 °C. After cooling to rt, the tube
was broken and the solution transferred in a rb flask and the solvent was evaporated under reduced
pressure. The crude product was purified by silica gel column chromatography eluting with
AcOEt/hexanes (30:70), to give pentacycle 41 (198 mg, 66%). Mp 164 °C. 1H NMR (300 MHz, CDCl3)
δ (ppm) 4.55 (dd, J = 9.4, 1.7 Hz, 1H), 4.12 (d, J = 9.9 Hz, 1H), 4.05 (dd, J = 6.1, 1.7 Hz, 1H), 3.78 (dq, J
= 9.9, 7.2 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.44 (dq, J = 9.6, 7.2 Hz, 1H), 3.16 (dd, J = 11.3, 5.8 Hz,
1H), 2.95 (dd, J = 12.4, 6.3 Hz, 1H), 2.50 (dd, J = 10.2, 3.6 Hz, 1H), 2.27 (dt, J = 12.4, 5.9 Hz, 1H),
2.14-2.01 (m, 3H), 1.90-1.76 (m, 3H), 1.65-1.53 (m, 2H), 1.50-1.31 (m, 1H), 1.24-1.05 (m, 1H), 1.18 (t, J
= 7.2 Hz, 3H), 0.97 (s, 3H), 0.91 (d, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 173.8 (s),
171.4 (s), 143.3 (s), 122.7 (s), 101.5 (d), 70.9 (d), 64.1 (t), 53.2 (d), 51.9 (q), 51.2 (q), 47.2 (d), 45.0 (s),
41.2 (d), 39.3 (t), 35.5 (d), 31.7 (d), 26.5 (t), 24.1 (q), 20.6 (t), 19.7 (t), 15.7 (q), 15.1 (q). IR (CHCl3) 
(cm-1) 2949, 2869, 1736, 1435. LRMS (m/z, (relative intensity)) 450 (M+, 1), 435 ((M-CH3)+, 1), 404
((M-C2H5OH)+, 100). HRMS calcd for C24H34O6S: 450.2076, found: 450.2079. []D +91.7 (c 1.11,
CHCl3).
Sulfoxide 43. Pentacyclic sulfur 41 (200 mg, 0.44 mmol) was dissolved in DCM (4.0 mL) and the
solution was cooled to -78 °C. m-CPBA (109 mg, 0.489 mmol) was added in small portions and after
stirring the resulting mixture 4 h at -78 ºC, it was neutralized by adding a saturated aqueous solution of
sodium thiosulfate. The biphasic system was vigorously stirred for 30 min at rt, the phases were separated
and the aqueous layer extracted 3 times with DCM. The organic layers were combined, washed once with
saturated aqueous NaHCO3 and once with brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified by silica gel column
chromatography using a 30:70 to 50:50 mixture of AcOEt and hexanes as eluting solvent to give
tetracyclic sulfoxide 43 (130 mg, 63%) and sulfone 44 (64 mg, 30%). For the characterisation data of

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HETEROCYCLES, Vol. 95, No. 2, 2017
sulfone 44, see the next experimental procedure. Sulfoxide 43: 1H NMR (300 MHz, CDCl3)  (ppm) 4.55
(dd, 1H, J = 9.4, 1.7 Hz), 4.15 (dt, 1H, J = 8.8, 2.5 Hz), 4.07 (dd, 1H, J = 6.3, 2.5 Hz), 3.75 (dq, 1H, J =
9.6, 6.9 Hz), 3.75 (s, 3H), 3.68 (s, 3H), 3.43 (dq, 1H, J = 9.3, 7.2 Hz), 3.00-2.93 (m, 3H), 2.22-1.75 (m,
8H), 1.60-1.42 (m, 2H), 1.41-1.03 (m, 1H), 1.20 (s, 3H), 1.17 (t, 3H, J = 7.2 Hz), 0.94 (d, 3H, J = 7.2 Hz).
IR (CHCl3)  (cm-1) 2951, 1741, 1157. LRMS (m/z, (relative intensity)) 466 (M+, 50), 449 (58), 371
(100), 335 (68), 303 (72), 225 (100). HRMS calcd for C24H34O7S: 466.2025, found: 466.2030.
Sulfone 44. Pentacyclic sulfur 41 (200 mg, 0.44 mmol) was dissolved in DCM (4.0 mL) and the solution
was cooled to 0 °C. m-CPBA (218 mg, 0.978 mmol) was added in small portions and after stirring the
resulting mixture 2 h at 0 ºC, it was neutralized by adding a saturated aqueous solution of sodium
thiosulfate. The biphasic system was vigorously stirred for 30 min at rt, the phases were separated and the
aqueous layer extracted 3 times with DCM. The organic layers were combined, washed once with
saturated aqueous NaHCO3 and once with brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified by silica gel column
chromatography using a 30:70 to 50:50 mixture of AcOEt and hexanes as eluting solvent to give
tetracyclic sulfone 44 (210 mg, 99%). The X-ray diffraction analysis data is available in this SI. 1H NMR
(300 MHz, CDCl3)  (ppm) 4.56 (dd, 1H, J = 9.3, 2.2 Hz), 4.18 (dd, 1H, J = 9.9, 2.2 Hz), 4.05 (dd, 1H, J
= 6.0, 2.2 Hz), 3.77 (s, 3H), 3.80-3.72 (m, 1H), 3.69 (m, 3H), 3.42 (dq, 1H, J = 9.4, 7.2 Hz), 3.12-3.06 (m,
2H), 2.93 (dd, 1H, J = 12.6, 6.1 Hz), 2.34-2.17 (m, 2H), 2.10-2.01 (m, 1H), 1.97-1.89 (m, 3H), 1.70-1.59
(m, 3H), 1.51-1.41 (m, 1H), 1.39-1.06 (m, 1H), 1.17 (t, 3H, J = 7.2 Hz), 1.17 (s, 3H), 0.90 (d, 3H, J = 7.2
Hz). IR (CHCl )  (cm-1) 2952, 2874, 1742, 1444. LRMS (m/z, (relative intensity)) 481 ((M-H)+, 1), 437
3
((M-EtOH)+, 10), 418 ((M-SO2)+, (20), 344 (60), 313 (55), 269 (60), 225 (100), 169 (55). HRMS calcd
for C24H33O8S: 481.1896, found: 481.1899.
Dienes 45 and 46. Sulfoxide 43 (35.0 mg, 0.075 mmol) was dissolved in MeCN (0.7 mL) and the
solution was cooled to 0 °C. Trifluoroacetic anhydride (32.0 µL, 0.225 mmol) and 2,6-lutidine (26.0 µL,
0.225 mmol) were added and the mixture was stirred 1.5 h at 0 ºC. Then, the solvent was evaporated and
the residu was filtered on a silica gel pad to give a 1:1 mixture of two inseparable regioisomeric dienes 45
and 46 (33 mg, 99%). Regioisomer 45: 1H NMR (300 MHz, CDCl3)  (ppm) 4.60-4.56 (m, 1H), 4.30 (d,
1H, J = 5.5 Hz), 3.83-3.74 (m, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.45 (dq, 1H, J = 9.3, 7.2 Hz), 3.20 (dd, 1H,
J = 11.5, 6.6 Hz), 3.04 (dd, 1H, J = 12.1, 5.5 Hz), 2.67 (q, 1H, J = 7.0 Hz), 2.37 (td, 1H, J = 12.5, 3.9 Hz),
2.32-2.04 (m, 4H), 1.96-1.71 (m, 2H), 1.65-1.24 (m, 2H), 1.18-1.14 (m, 1H), 1.18 (t, 3H, J = 7.2 Hz),
1.08 (s, 3H), 1.04 (d, 3H, J = 8.8 Hz). Regioisomer 46: 1H NMR (300 MHz, CDCl3)  (ppm) 5.23 (t, 1H,
J = 3.9 Hz), 4.60-4.56 (m, 1H), 4.44 (d, 1H, J = 10.5 Hz), 4.09 (dd, 1H, J = 5.2, 1.9 Hz), 3.83-3.74 (m,
1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.45 (dq, 1H, J = 9.3, 7.2 Hz), 2.82 (dd, 1H, J = 12.6, 5.5 Hz), 2.57 (dd,

HETEROCYCLES, Vol. 95, No. 2, 2017
913
1H, J = 11.0, 3.3 Hz), 2.32-2.04 (m, 5H), 1.96-1.71 (m, 1H), 1.65-1.24 (m, 2H), 1.18-1.14 (m, 1H), 1.18
(t, 3H, J = 7.2 Hz), 1.05 (s, 3H), 0.96 (d, 3H, J = 7.1 Hz). Both regioisomers: 13C NMR (75 MHz, CDCl3)
 (ppm) 173.9 (s), 171.3 (s), 171.0 (s), 167.9 (s), 150.1 (s), 143.9 (s), 139.6 (s), 132.1 (s), 125.7 (s), 113.4
(d), 101.8 (d), 101.4 (d), 71.9 (d), 71.7 (d), 64.2 (t), 57.1 (d), 52.0 (q), 51.4 (q), 51.3 (q), 49.2 (d), 46.5 (d),
46.2 (s), 45.9 (d), 44.3 (s), 42.7 (d), 42.1 (d), 40.8 (d), 39.9 (t), 37.6 (d), 36.0 (d), 33.6 (d), 27.1 (t), 25.8
(t), 24.9 (q), 22.0 (q), 20.2 (q), 19.4 (t), 18.6 (t), 16.4 (q), 15.1 (q). IR (CHCl3)  (cm-1) 2951, 2869, 1737,
1688, 755. LRMS (m/z, (relative intensity)) 448 (M+, 100), 112 (80). HRMS calcd for C24H32O6S:
448.1919, found: 448.1928.
Tetracyclic aldol adduct 47. A solution of methyllithium (1.4 M in Et2O, 0.68 mL, 0.96 mmol) was
slowly added to a solution of copper(I) iodide (91 mg, 0.48 mmol) in Et2O (0.8 mL) at -78 °C. The
reaction mixture was stirred 30 min at -40 °C after which time, a solution of sulfone 44 (40 mg, 0.08
mmol) in Et2O (0.4 mL) was slowly added at -78 °C. The reaction mixture was stirred while allowing it to
warm to 0 °C over a 2.5 h period. Then, it was neutralized by adding a solution of ammonium chloride
containing 10% (v/v) ammonium hydroxide. The biphasic system was vigorously stirred for 3 h at rt, the
phases were separated and the aqueous layer extracted 3 times with Et2O. The organic layers were
combined, washed once with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by silica gel column chromatography using a
50:50 mixture of AcOEt and hexanes as eluting solvent to give tetracyclic compound 47 (15 mg, 46%).
The X-ray diffraction analysis data is available in this SI. 1H NMR (300 MHz, CDCl3)  (ppm) 5.76 (d,
1H, J = 2.2 Hz), 4.54 (dd, 1H, J = 7.1, 2.8 Hz), 3.88 (s, 3H), 3.74 (s, 3H), 3.13 (dd, 1H, J = 10.7, 1.9 Hz),
3.02 (dd, 1H, J = 13.2, 5.5 Hz), 2.75-2.72 (m, 2H), 2.10-1.93 (m, 4H), 1.88 (dd, 1H, J = 14.3, 7.7 Hz),
1.75-1.47 (m, 3H), 1.43-1.33 (m, 1H), 1.26 (s, 3H), 0.98 (d, 3H, J = 6.1 Hz). 13C NMR (75 MHz, CDCl3)
 (ppm) 172.9 (s), 169.7 (s), 147.3 (s), 136.8 (s), 129.7 (s), 127.0 (d), 80.2 (d), 69.0 (d), 60.4 (s), 52.4 (t),
46.1 (d), 44.1 (d), 43.0 (q), 38.6 (d), 38.2 (d), 21.9 (q), 19.4 (t), 19.0 (t), 18.1 (t), 11.1 (q). LRMS (m/z,
(relative intensity)) 436 (M+, 7), 404 (100). HRMS calcd for C22H28O7S: 436.1556, found: 436.1544.
Methylsulfonium tetrafluoroborate 50. Cycloadduct 41 (30 mg, 0.067 mmol) was dissolved in DCM
(0.67 mL) and the reaction was cooled to -30 °C. Trimethyloxonium tetrafluoroborate (20 mg, 0.13
mmol) was added and the reaction mixture was stirred 3 h at -30 °C. Water was added and the two layers
were separated. The aqueous layer was extracted 3 times with DCM and the organic layers were
combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give
crude sulfonium 50 (36 mg, 99%) which was used without further purification for next step. The X-ray
diffraction analysis data is available in this SI. Mp 129-134 ºC. 1H NMR (300 MHz, CDCl3)  4.96 (bd,
1H, J = 10.5 Hz), 4.60 (dd, 1H, J = 9.4, 2.2 Hz), 4.14 (dd, 1H, J = 6.0, 1.7 Hz), 3.92 (dd, 1H, J = 10.5, 6.6

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HETEROCYCLES, Vol. 95, No. 2, 2017
Hz), 3.81 (s, 3H), 3.68 (s, 3H), 3.73-3.63 (m, 1H), 3.45 (dq, 1H, J = 9.9, 7.1 Hz), 3.37 (s, 3H), 3.05 (dd,
1H, J = 11.8, 6.6 Hz), 2.88 (dd, 1H, J = 10.5 Hz), 2.35 (m, 1H), 2.26-2.10 (m, 3H), 2.03-1.81 (m, 3H),
1.70-1.45 (m, 2H), 1.32 (s, 3H), 1.25-1.19 (m, 2H), 1.14 (t, 3H, J = 7.2 Hz), 0.96 (d, 3H, J = 7.1 Hz). IR
(CHCl3)  (cm-1) 3037, 2952, 1737, 1052.
Methylsulfonium tetrafluoroborate 52. Pentacyclic compound 41 (200 mg, 0.44 mmol) was dissolved
in DCM (4.4 mL) and the solution was cooled down to 0 °C. A solution of trimethyloxonium
tetrafluoroborate (130 mg, 0.88 mmol) was added and the reaction mixture was stirred 4 h while letting it
warm up to rt. After this time, the solvent was evaporated and the crude methylsulfonium salt 52 (245 mg,
0.44 mmol) was immediately used in the next step without purification.
Cuprate adduct 51. Methylmagnesium chloride (0.20 mL, 3.0 M in Et2O, 0.60 mmol) was added slowly
to a suspension of copper(I) cyanide (27 mg, 0.30 mmol) in THF (0.6 mL) at -78 °C. The reaction
mixture was stirred 30 min at -78 °C, then a solution of sulfonium 50 (45 mg, 0.08 mmol) and
trimethylsilyl chloride (76 µL, 0.60 mmol) in THF (0.4 mL) was slowly added. The reaction was slowly
warmed to rt and stirred for 12 h. The reaction mixture was then quenched with a saturated aqueous
solution of ammonium chloride containing 10% (v/v) ammonium hydroxide and the biphasic mixture was
vigorously stirred for 5 h, after which time the two layers were separated. The aqueous layer was
extracted 3 times with Et2O. The organic layers were combined, washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by
column chromatography using a 10:90 mixture of AcOEt and hexanes as eluting solvent to give the
sulfide 51 and cycloadduct 41 as a 1:1 mixture (20 mg, 52%). 1H NMR (300 MHz, CDCl3)  (ppm) 5.56
(d, 1H, J = 2.4 Hz), 4.33 (d, 1H, J = 6.5 Hz), 3.77 (dq, 1H, J = 9.3, 7.2 Hz), 3.69 (s, 3H), 3.65 (s, 3H),
3.55 (dd, 1H, J = 7.4, 2.7 Hz), 3.40-3.31 (m, 2H), 3.03 (bd, 1H), 2.86 (dd, 1H, J = 12.3 and 2.4 Hz), 2.63
(dt, 1H, J = 11.4 and 2.4 Hz), 2.50 (dd, 1H, J = 9.2, 1.9 Hz), 1.96 (s, 3H), 2.18 (t, 1H, J = 7.6 Hz),
2.12-1.93 (m, 2H), 1.80-1.00 (m, 6H), 1.34 (s, 3H), 1.25 (s, 3H), 1.17 (t, 3H, J = 7.2 Hz), 1.05 (d, 3H, J =
7.2 Hz).
Cuprate adduct 53 and demethylation product 54. To a suspension of copper(I) cyanide (27 mg, 0.30
mmol) in THF (0.6 mL) at -78 °C was slowly added a solution of methylmagnesium chloride (3.0 M in
Et2O, 0.20 mL, 0.60 mmol). After 30 min of stirring, a solution of methylsulfonium salt 52 (45 mg, 0.08
mmol) and chlorotrimethylsilane (76 µL, 0.60 mmol) in THF (0.4 mL) was added, keeping the
temperature at -78 °C. The reaction mixture was stirred while it was allowed to warm to rt over a period
of 12 h. Then, it was neutralized by adding a saturated aqueous solution of ammonium chloride
containing 10% (v/v) ammonium hydroxide. The biphasic mixture was vigorously stirred for 3 h at rt and
the phases were separated. The aqueous phase was extracted three times with Et2O the organic layers
were combined, washed once with brine, dried over anhydrous magnesium sulfate, filtered, and

HETEROCYCLES, Vol. 95, No. 2, 2017
915
concentrated under reduced pressure. The crude product was purified by column chromatography using a
10:90 mixture of AcOEt and hexanes as eluting solvent to give tetracyclic compound 53 (8 mg, 20%) and
pentacyclic sulfur 54 (4 mg, 11%). Cuprate adduct 53: 1H NMR (300 MHz, CDCl3)  (ppm) 5.58 (d, 1H,
J = 2.8 Hz), 4.87 (d, 1H, J = 2.2 Hz), 3.76 (bs, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.56 (dd, 1H, J = 7.4, 2.8
Hz), 3.49 (dq, 1H, J = 9.5, 7.2 Hz), 3.37 (dq, 1H, J = 9.9, 7.2 Hz), 3.10 (bs, 1H), 2.89 (dd, 1H J = 12.4,
2.2 Hz), 2.57 (td, 1H, J = 12.4, 2.8 Hz), 2.17-1.90 (m, 4H), 1.98 (s, 3H), 1.84-1.74 (m, 3H), 1.48-1.39 (m,
2H), 1.39 (s, 3H), 1.29-1.16 (m, 1H), 1.27 (s, 3H), 1.18 (t, 3H, J = 7.2 Hz), 1.08 (d, 3H, J = 7.2 Hz). 13C
NMR (75 MHz, CDCl3)  (ppm) 175.0 (s), 173.4 (s), 143.0 (s), 119.1 (d), 96.2 (d), 72.1 (d), 61.9 (t), 53.3
(d), 51.4 (q), 51.3 (q), 43.9 (d), 43.6 (d), 43.5 (d), 43.5 (s), 36.9 (s), 33.9 (d), 33.5 (t), 33.1 (d), 31.1 (q),
24.7 (t), 24.3 (t), 24.1 (q), 20.4 (t), 19.6 (q), 2 signals at 15.1 (q). IR (CHCl3)  (cm-1) 2950, 1738. LRMS
(m/z, (relative intensity)) 480 (M+, 45), 465 ((M-Me)+, 100). HRMS calcd for C26H40O6S: 480.2545,
1
found: 480.2555. Demethylation product 54: H NMR (300 MHz, CDCl3)  (ppm) 4.90 (bs, 1H), 4.50
(bd, 1H, J = 6.1 Hz), 4.12 (d, 1H, J = 9.9 Hz), 3.72 (s, 3H), 3.68 (s, 3H), 3.65 (dq, 1H, J = 9.9, 7.2 Hz),
3.39 (dq, 1H, J = 9.9, 7.2 Hz), 3.15 (dd, 1H, J = 11.3, 6.0 Hz), 2.92 (dd, 1H, J = 12.0, 6.3 Hz), 2.50 (dd,
1H, J = 9.9, 3.6 Hz), 2.44 (d, 1H, J = 9.4 Hz), 2.22 (dd, 1H, J = 12.0, 6.1 Hz), 2.15-2.04 (m, 1H), 1.99 (dq,
1H, J = 11.0, 3.6 Hz), 1.84-1.76 (m, 4H), 1.62-1.35 (m, 2H), 1.23 (t, 3H, J = 7.1 Hz), 1.18-1.01 (m, 1H),
0.97 (s, 3H), 0.89 (d, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3)  (ppm) 174.0 (s), 171.7 (s), 142.3 (s),
123.7 (s), 97.4 (d), 65.6 (d), 62.1 (t), 53.3 (d), 52.0 (q), 51.2 (q), 47.0 (d), 46.5 (d), 44.8 (s), 41.2 (d), 38.3
(t), 37.4 (d), 35.3 (d), 31.6 (d), 26.6 (t), 24.1 (q), 20.5 (t), 19.7 (t), 15.2 (q), 15.0 (q). IR (CHCl3)  (cm-1)
2949, 2900, 1434, 754. LRMS (m/z, (relative intensity)) 450 (M+, 75), 404 ((M-EtOH)+, 100). HRMS
calcd for C24H34O6S: 450.2076 found: 450.2088. []D +120.9 (c 0.45, CHCl3).
Pentacyclic sulfone 55. Prepared as per sulfone 44 from pentacyclic sulfur 54 (40 mg, 0.089 mmol) to
give, after purification by silica gel column chromatography using AcOEt and hexanes (50:50) as eluant,
sulfone 55 (25 mg, 58%). The X-ray diffraction analysis data is available in this SI. 1H NMR (300 MHz,
CDCl3)  (ppm) 4.87 (s, 1H), 4.48 (d, 1H, J = 5.5 Hz), 4.20 (d, 1H, J = 10.5 Hz), 3.77 (s, 3H), 3.75-3.58
(m, 1H), 3.68 (s, 3H), 3.44-3.54 (m, 1H), 3.13-3.07 (m, 2H), 2.89 (dd, 1H, J = 11.8, 5.5 Hz), 2.51 (t, 1H,
J = 8.8 Hz), 2.28-2.06 (m, 3H), 1.96-1.84 (m, 2H), 1.95 (d, 1H, J = 7.7 Hz), 1.84-1.81 (m, 1H), 1.82 (d,
1H, J = 7.7 Hz), 1.57-1.39 (m, 1H), 1.22 (t, 3H, J = 7.1 Hz), 1.17 (s, 3H), 1.20-1.05 (m, 1H), 0.88 (d, 3H,
J = 7.1 Hz). IR (CHCl3)  (cm-1) 3577-3183, 3020, 2952, 1741.
Ethylsulfonium tetrafluoroborates 56. Pentacyclic compound 41 (600 mg, 1.33 mmol) was dissolved in
DCM (13.3 mL) and the solution was cooled down to 0 °C. A solution of triethyloxonium
tetrafluoroborate (1.0 M in DCM, 4.0 mL, 4.00 mmol) was added and the reaction mixture was stirred 4 h
while letting it warm up to rt. After this time, water was added and the phases were separated. The

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HETEROCYCLES, Vol. 95, No. 2, 2017
aqueous layer was extracted 3 time with DCM and the organic layers were combined, washed once with
brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The
crude products were immediately used in the next step without purification.
Cuprate adducts (+)-58. Freshly recrystallized CuBr•Me2S (875 mg, 4.26 mmol) and lithium chloride
(180 mg, 4.26 mmol) were charged in a 25 mL dried rb flask under argon. The solids were heated using a
heat gun under a gentle stream of argon. This procedure was repeated twice, letting the solids cool in
between. Then, THF (9 mL) was added and the suspension was cooled to -78 °C. A titrated solution of
methylmagnesium chloride (3.2 M in Et2O, 1.25 mL, 3.99 mmol) was slowly added. After 30 min of
stirring at -78 °C, a solution of the crude ethylsulfoniums 56 and 57 (740 mg, 1.33 mmol) and freshly
distilled chlorotrimethylsilane (0.54 mL, 4.26 mmol) in THF (4.3 mL) were successively added. The
reaction mixture was stirred while slowly warming to rt over a 12 h period. The reaction mixture was
quenched with a saturated aqueous solution of ammonium chloride containing 10% (v/v) ammonium
hydroxide. The biphasic mixture was vigorously stirred for 3 h at rt and the phases were separated. The
aqueous phase was extracted three times with Et2O the organic layers were combined, washed once with
brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography using a 10:90 mixture of AcOEt and hexanes as
eluting solvent to give tetracyclic compound 58 (460 mg, 70%) and its C16 epimer 59 (40 mg, 6%). The
X-ray diffraction analysis data for compound 58 is available in this SI. Tetracyclic compound 58: Mp
182-186 ºC. 1H NMR (300 MHz, CDCl3)  (ppm) 5.58 (d, 1H, J = 2.8 Hz), 4.87 (d, 1H, J = 2.2 Hz), 3.75
(d, 1H, J = 1.7 Hz), 3.69 (s, 3H), 3.65 (s, 3H), 3.54 (dd, 1H, J = 7.7, 2.8 Hz), 3.49 (dq, 1H, J = 9.9, 7.2
Hz), 3.36 (dq, 1H, J = 9.9, 7.2 Hz), 3.20 (bs, 1H), 2.88 (dd, 1H J = 12.4, 2.2 Hz), 2.56 (td, 1H, J = 12.4,
2.8 Hz), 2.43 (q, 2H J = 7.2 Hz), 2.13-1.94 (m, 4H), 1.78-1.71 (m, 3H), 1.52-1.41 (m, 2H), 1.38 (s, 3H),
13
1.26 (s, 3H), 1.22-1.14 (m, 1H), 1.18 (q, 6H, J = 7.2 Hz), 1.07 (d, 3H, J = 7.2 Hz). C NMR (75 MHz,
CDCl3)  (ppm) 175.0 (s), 173.5 (s), 143.0 (s), 119.4 (d), 96.2 (d), 72.2 (d), 61.9 (t), 51.4 (q), 51.3 (q),
51.1 (d), 44.0 (d), 43.6 (d), 43.9 (d), 43.4 (s), 37.0 (s), 33.9 (d), 33.5 (t), 33.1 (d), 31.1 (q), 25.5 (t), 25.8
(t), 24.7 (t), 24.1 (q), 20.4 (t), 19.6 (q), 15.0 (q), 14.7 (q). IR (CHCl3)  (cm-1) 2949, 1739, 1434. LRMS
(m/z, (relative intensity)) 494 (M+, 50), 479 (100). HRMS calcd for C27H42O6S: 494.2702, found:
494.2697. []D +86.7 (c 1.59, CHCl3).
C16 epimer 59: 1H NMR (300 MHz, CDCl3)  (ppm) 5.57 (d, 1H, J = 2.8 Hz), 4.32 (d, 1H, J = 6.6 Hz),
3.79 (dq, 1H, J = 9.3, 7.2 Hz), 3.70 (s, 3H), 3.65 (s, 3H), 3.55 (dd, 1H, J = 7.4, 2.8 Hz), 3.42-3.32 (m, 2H),
3.37 (d, 1H, J = 2.2 Hz), 3.13 (d, 1H, J = 2.8 Hz), 2.86 (dd, 1H, J = 12.4 and 2.2 Hz), 2.59 (dt, 1H, J =
12.4 and 2.8 Hz), 2.42 (q, 1H, J = 7.2 Hz), 2.18 (t, 1H, J = 7.7 Hz), 2.11-1.94 (m, 2H), 1.78-1.48 (m, 6H),
1.33 (s, 3H), 1.25 (s, 3H), 1.19 (t, 3H, J = 7.2 Hz), 1.18 (t, 3H, J = 7.2 Hz), 1.21-1.15 (m, 1H), 1.07 (d,

HETEROCYCLES, Vol. 95, No. 2, 2017
917
3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3)  (ppm) 175.0 (s), 173.5 (s), 142.5 (s), 119.2 (d), 101.1 (d),
79.5 (d), 63.2 (t), 51.4 (q x 2), 51.3 (d), 49.9 (d), 44.8 (d), 43.4 (d), 43.4 (s), 36.6 (s), 35.7 (t), 34.2 (d),
33.3 (d), 30.6 (q), 25.8 (t), 25.4 (t), 24.9 (t), 23.9 (q), 20.3 (t), 19.4 (q), 15.1 (q), 14.7 (q). IR (CHCl3) 
(cm-1) 2949, 1739, 1434. LRMS (m/z, (relative intensity)) 494 (M+, 50), 479 (100). HRMS calcd for
C27H42O6S: 494.2702, found: 494.2697. []D +86.7 (c 1.59, CHCl3).
(+)-Diene 60. Sulfur 58 (265.0 mg, 0.536 mmol) was dissolved in a 4:4:1 mixture of AcOEt, MeCN, and
water (5.4 mL) and sodium periodate (344.0 mg, 1.61 mmol) was then added all at once. The reaction
mixture was stirred at rt for 12 h and was then neutralized with a saturated aqueous sodium thiosulfate
solution. The biphasic system was vigorously stirred for 30 min and the phases were separated. The
aqueous phase was extracted three times with AcOEt, the organic layers were combined, washed once
with saturated aqueous NaHCO3, once with brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified by column chromatography using a
1:99 mixture of MeOH and DCM as eluting solvent to give sulfoxide 63 (237 mg, 87%) as a 1:1 mixture
of 2 inseparable isomers. 1H NMR (300 MHz, CDCl3)  (ppm) 5.78 (d, 1H, J = 3.3 Hz), 5.09 (d, 1H, J =
2.8 Hz), 4.90 (br s, 1H), 3.82 (d, 1H, J = 1.7 Hz), 3.80 (d, 1H, J = 2.2 Hz), 3.68 (s, 3H), 3.66 (s, 3H), 3.65
(s, 6H), 3.60-3.41 (m, 4H), 3.40-3.31 (m, 3H), 3.17 (d, 1H, J = 2.8 Hz), 2.96-2.53 (m, 10H), 2.26-1.44 (m,
12H), 1.39-1.29 (m, 5H), 1.38 (s, 6H), 1.37 (t, 3H, J = 7.4 Hz), 1.33 (s, 3H), 1.31 (t, 3H, J = 7.4 Hz), 1.30
(s, 3H), 1.25-1.21 (m, 1H), 1.17 (t, 6H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.7 Hz), 1.07 (t, 3H, J = 7.2 Hz). 13C
NMR (75 MHz, CDCl3)  (ppm) 174.8 (s), 174.3 (s), 173.2 (s), 146.2 (s), 140.5 (s), 121.3 (d) , 118.1 (d),
96.5 (d), 95.9 (d), 72.0 (d), 67.7 (d), 66.8 (s), 64.3 (d), 61.9 (t), 51.6 (q), 51.4 (q), 45.6 (t), 44.3 (d), 43.8
(d), 43.4 (d), 43.3 (d), 43.0 (d), 37.5 (s), 37.1 (s), 34.0 (d), 33.7 (d), 33.5 (q), 33.1 (d), 31.2 (t), 30.6 (q),
25.4 (q), 24.7 (q), 24.3 (t), 24.1 (t), 21.7 (t), 21.5 (t), 21.1 (t), 20.1 (t), 19.9 (q), 19.6 (q), 15.0 (q), 8.5 (q),
7.9 (q). IR (CHCl3)  (cm-1) 2949, 1734, 1439, 1041. LRMS (m/z, (relative intensity)) 510 (M+, 5), 465
((M-EtOH)+, 15), 432 ((M-EtSOH)+, 5), 387 (60), 283 (100). HRMS calcd for C27H42O7S: 510.2651,
found: 510.2643. []D + 96.8 (c 0.47, CHCl3).
Sulfoxide 63 (195.0 mg, 0.38 mmol) was dissolved in toluene (3.8 mL) and the reaction mixture was
heated to reflux temperature and stirred for 12 h. Then the reflux was stopped, p-toluenesulfonic acid (80
mg, 0.42 mmol) and EtOH (0.15 mL) were added and the reaction mixture was stirred and extra 12 h at rt.
It was then neutralized using a saturated aqueous solution of Na2CO3. The aqueous phase was extracted 3
times with Et2O, the organic layers were combined, washed once with water and once with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product
was purified by column chromatography using a 10:90 mixture of AcOEt and hexanes as eluting solvent
to give diene 60 (123 mg, 65%). 1H NMR (300 MHz, CDCl3)  (ppm) 6.11 (d, 1H, J = 10.5 Hz), 5.83 (d,

918
HETEROCYCLES, Vol. 95, No. 2, 2017
1H, J = 4.4 Hz), 5.52 (dd, 1H, J = 10.5, 3.3 Hz), 4.81 (t, 1H, J = 4.4 Hz), 3.91 (d, 1H, J = 3.3 Hz), 3.69 (s,
3H), 3.68 (s, 3H), 3.64-3.51 (m, 1H), 3.40-3.30 (m, 1H), 3.26 (t, 1H, J = 3.3 Hz), 3.02 (dd, 1H, J = 12.9,
3.3 Hz), 2.19-2.10 (m, 2H), 2.06-1.91 (m, 3H), 1.89-1.75 (m, 2H), 1.60-1.39 (m, 1H), 1.36 (s, 3H),
13
1.21-1.16 (m, 1H), 1.20 (s, 3H), 1.19 (t, 3H, J = 7.2 Hz), 1.00 (d, 3H, J = 6.1 Hz). C NMR (75 MHz,
CDCl3)  (ppm) 174.3 (s), 173.0 (s), 145.5 (s), 135.6 (d), 123.4 (d), 117.2 (d), 96.4 (d), 73.1 (d), 62.1 (t),
51.4 (q), 51.2 (q), 44.7 (d), 44.7 (d), 43.5 (d), 40.5 (s), 38.6 (s), 37.6 (d), 33.4 (d), 29.6 (q), 25.6 (t), 24.7
(q), 21.6 (t), 18.3 (q), 15.0 (q). IR (CHCL3)  (cm-1) 2971, 1738, 755. LRMS (m/z, (relative intensity))
432 (M+, 20), 386 (48), 360 (90), 327 (74), 283 (78), 267 (85), 223 (100). HRMS calcd for C25H36O6:
432.2512, found: 432.2503. []D + 4.5 (c 1.4, CHCl3).
(+)-Triene 64. Simple reflux in toluene of the sulfoxide 63 (without subsequent treatment with acid and
EtOH) gives primarily triene 64, which could be isolated and was characterized. The X-ray diffraction
1
analysis data is available in this SI. H NMR (300 MHz, CDCl3)  (ppm) 6.45 (dd, 1H, J = 6.0, 1.7 Hz),
6.22 (d, 1H, J = 10.5 Hz), 5.88 (s, 1H), 5.52-5.48 (m, 1H), 4.43 (dd, 1H, J = 6.0, 2.2 Hz), 3.88 (d, 1H, J =
1.7 Hz), 3.72 (s, 3H), 3.71 (s, 3H), 3.39 (dd, 1H, J = 4.4, 1.1 Hz), 3.08 (dd, 1H, J = 12.4, 1.7 Hz),
2.28-1.98 (m, 5H), 1.84-1.78 (m, 1H), 1.50-1.36 (m, 1H), 1.46 (s, 3H), 1.25 (s, 3H), 1.02 (d, 3H, J = 7.0
13
Hz). C NMR (75 MHz, CDCl3)  (ppm) 175.1 (s), 172.8 (s), 144.4 (d), 140.7 (s), 136.3 (d), 123.0 (d),
117.2 (d), 104.9 (d), 80.1 (d), 51.6 (q), 51.6 (q), 47.0 (d), 44.5 (s), 42.1 (d), 40.6 (s), 38.1 (d), 36.6 (d),
34.4 (d), 29.8 (q), 26.1 (q), 25.8 (t), 21,4 (t), 16.8 (q). IR (CHCl3)  (cm-1) 3020, 2951, 2918, 1736.
LRMS (m/z, (relative intensity)) 386 (M+, 5), 354 (100), 326 (25), 267 (80), 223 (55). HRMS calcd for
C23H30O5: 386.2093, found: 386.2084. []D + 24.6 (c 0.41, CHCl3).
ACKNOWLEDGEMENTS
We thank the University of Sherbrooke and the Natural Sciences and Engineering Research Council of
Canada for financial support.
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