The first stereoselective synthesis of a dithiane derivative of the C18 β-diketodiene system proposed for an active compound isolated from Cantharellus cibarius (chanterelle)

Article abstract of DOI:10.1055/s-0034-1379984

A stereocontrolled synthesis of a thioketal system that is a direct precursor of an active compound isolated from chanterelle was accomplished by using readily available methyl 11-[2-(2-oxoethyl)-1,3-dithian-2-yl]undec-9-ynoate as a key intermediate. The synthesis involves simple and straightforward reactions, such as addition of a lithiated alkyne to an aldehyde, alkyne hydrogenation using nickel boride, alcohol oxidation with Dess-Martin periodinane, and Z-to-E enone isomerization.

Full text of DOI:10.1055/s-0034-1379984

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1181–1189
paper
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Paper
Synthesis
The First Stereoselective Synthesis of a Dithiane Derivative of the
C18 β-Diketodiene System Proposed for an Active Compound Iso-
lated from Cantharellus cibarius (Chanterelle)
Jacek Grodnera
W. Marek Gołębiewski*a
Michael C. Willisb
oxidation of hydroxy group
with Dess–Martin
periodinane
James D. Osborneb
Mirosław Gucmaa
OTBS
MeO2C
(
)
6
OH
O
S
S
a lnstitute of Industrial Organic Chemistry, Annopol 6,
03-236 Warsaw, Poland
(
)
6
MeO2C
golebiewski@ipo.waw.pl
isomerization reaction of
Z-double bond in
enone system
b Department of Chemistry, University of Oxford, Chemical
Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
michael.willis@chem.ox.ac.uk
oxidation and double
Michael addition of
propane-1,3-dithiol
Received: 02.10.2014
Accepted after revision: 19.12.2014
Published online: 27.01.2015
spectrometry, 1H and 13C NMR spectroscopy, and UV and IR
spectroscopy to be that of (9Z,13Z,15E)-14,18-dihydroxy-
12-oxo-9,13,15-octadecatrienoic acid, and the trivial name
cibaric acid has been proposed.2 The promising biological
activities and interesting molecular architecture of this un-
saturated fatty acid make it an attractive target for synthe-
sis.
The low abundance and novel structure of cibaric acid
prompted us to undertake its total synthesis. In planning
our approach, we chose a versatile, practical, and stereo-
controlled route, and we adopted a platform that might
lead to a variety of cibaric acid analogues. Scheme 1 shows
our initial disconnections for cibaric acid. Our retrosynthet-
ic analysis revealed that the target molecule can be derived
from methyl 11-[2-(2-oxoethyl)-1,3-dithian-2-yl]undec-9-
ynoate (4) and but-3-yn-1-ol by a rhodium-catalyzed hy-
droacylation reaction as the key coupling operation.3 Fur-
ther, we surmised that stereoselective Z-selective reduction
of enyne 3 and removal of the protecting groups from
enone 2 should deliver the desired fatty acid 1.
DOI: 10.1055/s-0034-1379984; Art ID: ss-2014-z0587-op
Abstract A stereocontrolled synthesis of a thioketal system that is a
direct precursor of an active compound isolated from chanterelle was
accomplished by using readily available methyl 11-[2-(2-oxoethyl)-1,3-
dithian-2-yl]undec-9-ynoate as a key intermediate. The synthesis in-
volves simple and straightforward reactions, such as addition of a lithi-
ated alkyne to an aldehyde, alkyne hydrogenation using nickel boride,
alcohol oxidation with Dess–Martin periodinane, and Z-to-E enone
isomerization.
Key words total synthesis, stereoselective synthesis, hydroacylations,
cross-coupling, organometallic reagents, thioketals
Plant organisms have proved to be a unique source of
novel and diverse bioactive compounds.1 A new compound
1 has been isolated from injured fruiting bodies of the edi-
ble mushroom Cantharellus cibarius (chanterelle), and is
suggested to act as a component of the mushroom’s chemi-
cal defense system.2 The structure of the isolated com-
pound was elucidated by means of high-resolution mass
O
S
O
OH
S
MeO2C
HO2C
OR
OH
5
5
cibaric acid (1)
2
O
S
S
MeO2C
O
S
5
S
MeO2C
H
5
4
OR
3
OR
Scheme 1 Initial retrosynthetic analysis of cibaric acid (1)
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Synthesis
a–c
d
OTHP
MeO2C
g–j
OH
CO2Me
5
5
5
7
5
6
8
e, f
OTHP
k,l
5
Br
O
S
S
MeO2C
5
H
4
Scheme 2. Synthesis of aldehyde 4 from ether 5. Reagents and conditions: (a) 5% aq H2SO4, MeOH, 5 °C to r.t., 24 h; (b) Jones reagent, acetone, 0 °C to
r.t., 95 min; (c) CH2N2, Et2O, 0 °C, 90% (from 5); (d) HOCH2C≡CCH2Cl, Cs2CO3, NaI, CuI, DMF, 0 °C to r.t., 21 h, 69%; (e) BuLi, –10 °C, THF, 60 min, then
paraformaldehyde, 0 °C to 66 °C, 145 min, 90%; (f) CBr4, Ph3P, DMF, 0 °C, 40 min, 86%; (g) 5% H2SO4, MeOH, 5 °C to r.t., 24 h; (h) Jones reagent, ace-
tone, 0 °C to r.t., 1 h; (i) CH2N2, Et2O, 0 °C; (j) HC≡CCH2OH, Cs2CO3, NaI, CuI, DMF, 0 °C to r.t., 20 h, 73% (from 8); (k) Dess–Martin periodinane, CH2Cl2,
8 °C to r.t., 25 min; (l) HS(CH2)3SH, NaOMe, MeOH–CH2Cl2, –10 °C to –2 °C, 17 h, 54% (2 steps).
Our synthesis of the required aldehyde 4 began with the
hydrolysis of the tetrahydropyranyl ether 5 (previously pre-
pared from octane-1,8-diol);4 this was followed by sequen-
tial oxidation of the resultant alcohol with Jones reagent
and esterification with diazomethane (Scheme 2). Coupling
of the alkynyl ester 6 with 4-chlorobut-2-yn-1-ol5 in the
presence of copper iodide, cesium carbonate, and sodium
iodide in N,N-dimethylformamide gave diyne 7 in 69%
yield.6 The diyne 7 was also obtained by an alternative se-
quence starting from ether 5. One-carbon homologation of
5 with butyllithium and paraformaldehyde,7 followed by
bromination of the resultant alcohol under Appel condi-
tions8 gave bromoalkyne 8. Cleavage of the tetrahydropyra-
nyl ether with 5% aqueous sulfuric acid and methanol, oxi-
dation of the resultant alcohol with Jones reagent (CrO3 +
dil. H2SO4), esterification of the carboxylic acid with diazo-
methane, and, finally, copper-catalyzed cross-coupling with
propargyl alcohol gave diyne 7.9 Oxidation of alcohol 7 with
Dess–Martin periodinane [1,1,1-triacetoxy-1,1-dihydro-
1,2-benziodoxol-3(1H)-one]10 gave the corresponding ynal,
which, without purification, was converted directly into the
β-carbonyl 1,3-dithiane 4 by treatment with sodium meth-
oxide and propane-1,3-dithiol in 54% yield (two steps).11
Next, we examined the key hydroacylation3 of but-3-
yn-1-ol with aldehyde 4 in the presence of various rhodium
catalysts (Scheme 3). Unfortunately, the expected product
of intermolecular alkyne hydroacylation, enone 3a, was not
obtained under any of the conditions that we examined.
When a second-generation hydroacylation catalyst incor-
porating an [oxybis(2,1-phenylene)]bis(diphenylphos-
phine) (DPEphos) ligand12 was used, the product of intra-
molecular alkyne hydroacylation, cyclopentanone 9, was
isolated in low yield.
Kishi coupling13 of aldehyde 4 with tert-butyl{[(3E)-4-io-
dobut-3-en-1-yl]oxy}dimethylsilane (10). Iodide 10 is
available from but-3-yn-1-ol by O-protection followed by
hydrozirconation/iodine trapping.14 Unfortunately, once
more intermolecular coupling did not occur, and the cyclo-
pentanol 11 was the sole product of this reaction (53%
yield). This suggested that the presence of a triple bond in
the ynal 4 hinders the intermolecular coupling reaction. Ac-
cordingly, in our next approach we protected the triple
bond in ynal 4 as its hexacarbonyl dicobalt complex,15 and
we once more explored the Nozaki–Hiyama–Kishi coupling.
However, this resulted only in triple-bond deprotection and
formation of the same spiroalkylidene cyclopentanol deriv-
ative 11. After the failure of the Nozaki–Hiyama–Kishi cou-
plings, we next investigated the nucleophilic addition of or-
ganometallic reagents to the aldehyde group in ynal 4. In
our first approach, treatment of ynal 4 with the Grignard
reagent (1-[tert-butyl(dimethyl)siloxy]but-3-yn-1-yl)mag-
nesium bromide gave only traces of the expected alcohol
12.16 Fortunately, the yield was increased by use of the
more nucleophilic organolithium reagent.17 Treatment of
tert-butyl(but-3-yn-1-yloxy)dimethylsilane with butyllithi-
um in tetrahydrofuran at –78 °C and subsequent combina-
tion of the resulting acetylenic anion with ynal 4 gave the
desired diyne alcohol 12 in 60% yield as a chromatographi-
cally separable colorless oil.
Next, we attempted to transform the methyl ester 12
into the cyclic orthoester 14 (Scheme 4), as a preparation
for reduction of the triple bond with lithium aluminum hy-
dride according to the Corey procedure.18 However, during
isomerization of the intermediate oxetane ester 13, formed
by saponification of the ester 12 and reaction with (3-
methyloxetan-3-yl)methanol (54% yield, two steps), an un-
expected decomposition of the product occurred. Changing
the reaction conditions failed to remedy this problem.19
These disappointing results prompted us to explore an
alternative strategy. We surmised that the carbon skeleton
of 1 might be synthesized by means of a Nozaki–Hiyama–
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O
S
S
MeO2C
O
S
a
S
MeO2C
5
6
H
OH
4
3a
c
b
d
OH
O
MeO2C
MeO2C
OH
S
MeO2C
S
6
7
7
S
S
11
9
S
12
S
OTBS
PPh2
PPh2
O
DPEphos =
nbd = norbornadiene
dppe = 1,2-bis(diphenylphosphino)ethane
Scheme 3 Linking of but-1-yn-4-ol derivatives with ynal 4. Reagents and conditions: (a) HC≡C(CH2)2OH, [Rh(dppe)(nbd)][ClO4], acetone, 55 °C; (b)
HC≡CCH2OH, [Rh(DPEphos)(nbd)][ClO4], DCE, 70 °C, 4 h, 26%; (c) (E)-ICH=CH(CH2)2OTBS (10), CrCl2, bis(acetylacetonato)nickel(II) (cat.), DMF, r.t., 7.5
h, 53%; (d) HC≡C(CH2)2OTBS, BuLi, THF, –78 °C to –70 °C, 30 min, then 4, –78 °C to 10 °C, 60%.
O
a, b
OH
S
O
OH
S
S
S
MeO2C
7
7
O
12
OTBS
13
OTBS
c
O
O
OH
S
S
7
O
14
OTBS
Scheme 4 Attempted conversion of methyl ester 12 into the orthoester 14. Reagents and conditions: (a) LiOH, THF, H2O, 0 °C to r.t., 19 h; (b) (3-
methyloxetan-3-yl)methanol, DCC, DMAP, CH2Cl2, 0 °C to r.t., 1 h, 54% (2 steps); (c) BF3∙OEt2 (0.25 equiv), CH2Cl2, –15 °C or BF3∙OEt2 (0.045 equiv),
CH2Cl2, 0 °C to r.t.
Our final experiments involved catalytic reduction of
both the triple bonds in diyne 12, oxidation of the hydroxy
group, and isomerization of the conjugated Z-double bond
(Scheme 5). Diyne 12 was hydrogenated with nickel
boride,20 generated in situ from nickel acetate and an aque-
ous ethanolic solution of sodium borohydride, to give the
(Z,Z)-diene 16 as the main product in 66% yield. Enyne 15
was also isolated from the reaction mixture in 3% yield. By
using freshly prepared Dess–Martin reagent, the hydroxy
groups in 15 and 16 were then oxidized to form the corre-
sponding ketones 17 and 18 in 41% and 46% yield, respec-
tively.10 Diene 18 was then subjected to a number of isom-
erization conditions, including the use of dilute acid21 and
treatment with tributylphosphine.22 Acid treatment result-
ed in decomposition; however, the reaction with tributyl-
phosphine gave the desired E-enone 20 in low yield (27%).
An improved yield for the isomerization was achieved by
using enyne 17 as the substrate; in this case, treatment
with tributylphosphine provided E-enone 19 in 38% yield.
Removal of the 1,3-dithiane unit proved to be problem-
atic. Attempts at cleavage by using mild chemoselective
methods, such as treatment with iodine/sodium hydrogen
carbonate,23 sodium chlorite, sodium dihydrogen phos-
phate, or 2-methylbut-2-ene,24 were unsuccessful; the sub-
strates decomposed or gave unidentified compounds in low
yields. A possible explanation for this is the reactivity of the
ketone–enol system unmasked upon dithiane cleavage;
these molecules contain both nucleophilic sites and elec-
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MeO2C
CO2Me
6
MeO2C
S
6
6
S
S
S
OH
a
S
S
OH
OTBS
OH
OTBS
12
15
16
OTBS
b
b
CO2Me
MeO2C
6
6
S
S
S
S
O
O
OTBS
OTBS
17
18
c
c
MeO2C
CO2Me
6
6
S
S
S
S
O
O
19
20
OTBS
OTBS
Scheme 5 Preparation of the 1,3-dithiane derivative with E- and Z-double bond geometry from the diynenol 12. Reagents and conditions: (a) Ni2B (P-2),
H2, EtOH 95%, NaOH, r.t., 1.25 h, 15: 3%, 16: 66%; (b) Dess–Martin periodinane, CH2Cl2, 8 °C to r.t., 25 min, 17: 41%, 18: 46%; (c) Bu3P, THF, 5 °C, 30
min, 19: 38%, 20: 27%.
trophilic enone and ester groups. In support of this, it is in-
teresting to note that, to the best of our knowledge, the un-
saturated enolic β-diketone system proposed for cibaric
acid has not been described in the literature.
es. Column chromatography was performed on Merck silica gel 60
(0.04–0.063 mm). TLC was performed on Alufolien coated with Merck
silica gel 60 F254. 1H and 13C spectra (with DEPT experiments) were re-
corded on a Varian UNITYplus-200 spectrometer (200 MHz for 1H, 50
MHz for 13C) or a Varian UNITYinova-500 spectrometer (500 MHz for
1H, 125 MHz for 13C) with TMS as the internal standard. IR spectra
were recorded on a Jasco model FT/IR-420 spectrophotometer. Mass
spectra were measured on an API 365 or AMD M-40W spectrometer.
The purity of the synthesized compounds was estimated by GC using
a Varian STAR 3400 CX chromatograph equipped with a flame-ioniza-
tion detector (250 °C), an injector on column (230 °C), and a DB1 cap-
illary column (30 m, 0.53 mm i.d., 0.25 μm); the inert carrier gas was
N2. The oven temperature was programmed from 90 °C (3 min hold)
at 20 °C min–1 to 180 °C (0 min hold) and then at 5 °C min–1 to 230 °C
(10 min hold). 2-(Dec-9-yn-1-yloxy)tetrahydro-2H-pyran,4 4-chloro-
but-2-yn-1-ol,5 tert-butyl(but-3-yn-1-yloxy)dimethylsilane,26 and
tert-butyl{[(3E)-4-iodobut-3-en-1-yl]oxy}dimethylsilane27 were pre-
pared as described previously. Precatalysts [Rh(dppe)(nbd)][ClO4] and
[Rh(DPEphos)(nbd)][ClO4] were synthesized according to the meth-
ods described in the literature.28
In summary, we have developed a simple route for the
synthesis of the carbon skeleton of cibaric acid 1 by the ad-
dition of a suitable four-carbon unit to the β-formyl-l,3-
dithiane 4. This synthetic route should permit the prepara-
tion of a variety of C18 polyunsaturated fatty acid analogues.
In addition, the use of a DPEphos-containing rhodium cata-
lyst in the hydroacylation reaction of β-formyl-1,3-dithiane
4 permitted cyclization to the spiro cyclopentanone 9. This
is a new application of a rhodium catalyst for conversion of
linear β-S-substituted aldehydes containing a triple bond in
the 5-position into cyclic enones, which should find appli-
cation in natural product synthesis.
All solvents and chemicals were obtained from commercial sources.
Anhydrous solvents and reagents were prepared from reagent-grade
materials by conventional methods.25 Reactions of air- and moisture-
sensitive materials were carried out in oven-dried (150 °C) glassware
under argon; solutions were transferred by using hypodermic syring-
Methyl Dec-9-ynoate (6)
2-(Dec-9-yn-1-yloxy)tetrahydro-2H-pyran4 (5; 3.2 g, 13.4 mmol) was
dissolved in MeOH (66 mL), and 5% aq H2SO4 (13.4 mL) was slowly
added to the stirred solution at 5 °C. The mixture was stirred for a
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further 24 h at r.t. then neutralized with sat. aq NaHCO3 (12 mL), and
concentrated in vacuo to remove the MeOH. The residue was extract-
ed with Et2O (3 × 60 mL). The organic extract was washed with cold
H2O (30 mL) and brine (60 mL), dried (MgSO4) and concentrated in
vacuo to give a crude oily product (2.1 g). This was dissolved in ace-
tone (24 mL) at 0 °C and treated by dropwise addition of Jones re-
agent29 (11.2 mL) over 50 min with vigorous stirring. The ice bath was
removed, and the mixture was stirred for 45 min. The mixture was
then poured into ice–water (70 mL) and extracted with Et2O (3 × 65
mL). The organic layers were combined, washed with brine (2 × 60
mL), dried (MgSO4), and concentrated in vacuo. The residue was dis-
solved in Et2O (50 mL) and a ~0.2 M solution of diazomethane30 in
Et2O (70 mL) at 0 °C was added dropwise. Removal of the solvent gave
an oil that was purified by column chromatography [silica gel, hex-
ane–Et2O, (20:1)] as a colorless oil; yield: 2.2 g (90%).
Ph3P (44.5 g, 170 mmol) in several portions over 10 min, maintaining
a reaction temperature of 0 °C. Stirring was continued for 0.5 h at
0 °C, then 3% aq NaHCO3 (200 mL) was added to the mixture. The
product was extracted with hexane (3 × 200 mL) and the organic lay-
ers combined, washed successively with H2O (100 mL) and brine (100
mL), dried (MgSO4), and concentrated in vacuo. The residue was puri-
fied by column chromatography [silica gel, hexane–EtOAc (9:1)] to
give a yellowish oil; yield: 32.4 g (86%; GC purity 94%).
IR (neat): 2933, 2857, 1457, 1351, 1205, 1119, 1079, 1031, 609 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.30–1.40 (m, 8 H, 4CH2), 1.48–1.60
(m, 8 H, 4CH2), 1.71–1.83 (m, 2 H, CH2), 2.23 (tt, J = 7.1, 2.4 Hz, 2 H,
CH2–C≡C), 3.38 [dt, J = 9.5, 6.8 Hz, 1 H, OCHH–(CH2)6], 3.51 (m, 1 H,
HeqC–O–CH–O), 3.73 [dt, J = 10.0, 6.5 Hz, 1 H, OCHH–(CH2)6], 3.87 (m,
1 H, HaxC–O–CH–O), 3.93 (t, J = 2.4 Hz, 2 H, CH2–Br), 4.58 (m, 1 H, O–
CH–O).
IR (neat): 1740 (C=O), 2110 (C≡C) cm–1
.
Spectral data were in accordance with those reported in the litera-
ture.8
1H NMR (200 MHz, CDCl3): δ = 1.20–1.74 (m, 10 H, 5CH2), 1.94 (t, J =
2.7 Hz, 1 H, H–C≡C), 2.12–2.24 (m, 2 H, C≡CCH2), 2.31 (t, J = 7.4 Hz, 2
H, CH2CO2Me), 3.67 (s, 3 H, OCH3).
Methyl 11-Bromoundec-9-ynoate
Spectral data were in accordance with those reported in the litera-
ture.31
Bromo ether 8 (10 g, 30.2 mmol) was dissolved in MeOH (240 mL),
and 5% aq H2SO4 (50 mL) was slowly added to the stirred solution at
5 °C. The mixture was stirred for 24 h at r.t. then neutralized with sat.
aq NaHCO3 (45 mL) and concentrated in vacuum to remove MeOH.
The residue was extracted with Et2O (3 × 130 mL). The organic ex-
tracts were combined, washed successively with cold H2O (100 mL)
and brine (200 mL), dried (MgSO4), and concentrated in vacuo. The
residue (7 g) was dissolved in acetone (200 mL) at 0 °C, and Jones re-
agent (50 mL) was added dropwise with vigorous stirring over 10
min. The reaction was allowed to continue for 40 min at 0 °C before
the mixture was slowly warmed to r.t. (10 min), poured into ice–
water (150 mL), and extracted with Et2O (3 × 130 mL). The organic
layers were combined, washed with brine (2 × 150 mL), dried
(MgSO4), and concentrated in vacuo. The residue was dissolved in
Et2O (100 mL), and a ~0.2 M solution of diazomethane in Et2O (150
mL) at 0 °C was added dropwise. Removal of the solvent gave an oil
that was purified by column chromatography [silica gel, hexane–Et2O
(40:1)] to give a colorless oil; yield: 6.7 g (81%).
Methyl 14-Hydroxytetradeca-9,12-diynoate (7)
The compound was synthesized from alkyne 6 (2.6 g, 14.3 mmol) by a
known procedure6 as a clear colorless oil; yield: 2.5 g (69%)
IR (neat): 3340 (OH), 1736 (C=O) cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.20–1.72 (m, 10 H, 5CH2), 2.15 (tt, J =
6.8, 2.2 Hz, 2 H, CH2–C≡C), 2.31 (t, J = 7.4 Hz, 2 H, CH2CO2Me), 3.16–
3.24 (m, 2 H, C≡CCH2C≡C), 3.67 (s, 3 H, OCH3), 4.27 (t, J = 2.1 Hz, 2 H,
CH2OH).
Spectral data were in accordance with those reported in the litera-
ture.6
11-(Tetrahydro-2H-pyran-2-yloxy)undec-2-yn-1-ol
2-(Dec-9-yn-1-yloxy)tetrahydro-2H-pyran (5; 23.8 g, 100 mmol) was
slowly added in a dropwise manner to a mixture of dry THF (80 mL)
and a 2.5 M solution of BuLi in hexane (40 mL, 100 mmol) at –10 °C
under N2, and the mixture was stirred at –10 °C for 1 h. A suspension
of paraformaldehyde (3.6 g, 120 mmol) in dry THF (100 mL) was add-
ed, and the mixture was warmed to 0 °C with stirring, and then
stirred for a further 45 min at 0 °C. The mixture was then refluxed for
90 min, cooled to r.t., poured into ice–water (300 mL), and extracted
with Et2O (2 × 150 mL). The organic extracts were combined, dried
(MgSO4), and concentrated in vacuo. The crude product was purified
by column chromatography [silica gel, hexane–EtOAc (4:1)] to give a
straw-colored oil; yield: 24.1 g (90%; GC purity 96%).
IR (neat): 1740, (C=O), 2110 (C≡C) cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.20–1.74 (m, 10 H, 5CH2), 2.24 (tt, J =
2.2, 7.0 Hz, 2 H, CH2C≡C), 2.31 (t, J = 7.4 Hz, 2 H, CH2CO2Me), 3.67 (s, 3
H, OCH3), 3.93 (t, J = 2.5 Hz, 2 H, CH2Br).
Spectral data were in accordance with those reported in the litera-
ture.33
Methyl 14-Hydroxytetradeca-9,12-diynoate (7); Alternative Syn-
thesis
Methyl 11-bromoundec-9-ynoate (0.55 g, 2.0 mmol) and HC≡CCH2OH
(0.14 mL, 135 mg, 2.4 mmol) were added successively to a suspension
of Cs2CO3 (1.08 g, 3.3 mmol), CuI (0.81 g, 4.3 mmol), and NaI (0.64 g,
4.3 mmol) in DMF (2 mL) at 0 °C. The mixture was stirred at r.t. for 20
h then treated with sat. aq NH4Cl (10 mL) at 5 °C. The aqueous layer
was extracted with Et2O (3 × 25 mL), and the organic layers were
combined, washed successively with cold H2O (20 mL) and brine (40
mL), dried (MgSO4), and concentrated in vacuo. The residue (0.45 g)
contained 92% of alcohol 7 (GC); yield: 90%.
1H NMR (200 MHz, CDCl3): δ = 1.30–1.40 (m, 8 H, 4CH2), 1.50–1.60
(m, 8 H, 4CH2), 1.70–1.85 (m, 2 H, CH2), 2.21 (tt, J = 6.8, 2.2 Hz, 2 H,
CH2–C≡C), 3.39 [dt, J = 9.6, 6.5 Hz, 1 H, OCHH–(CH2)6], 3.40–3.50 (m, 1
H, CHeqO–CH–O), 3.74 [dt, J = 9.5, 7.0 Hz, 1 H, OCHH(CH2)6], 3.80 (ddd,
J = 10.9, 7.4, 3.5 Hz, 1 H, CHaxO–CH–O), 4.25 (td, J = 2.0, 6.0 Hz, 2 H,
C≡CCH2–OH), 4.53–4.62 (m, 1 H, O–CH–O), 5.30 (s, 1 H, OH).
Spectral data were in accordance with those reported in the litera-
ture.32
Spectral data were in accordance with those reported above.
2-[(11-Bromoundec-9-yn-1-yl)oxy]tetrahydro-2H-pyran (8)
To
a vigorously stirred mixture of 11-(tetrahydro-2H-pyran-2-
yloxy)undec-2-yn-1-ol (30.6 g, 0.114 mol) and CBr4 (55.0 g, 170
mmol) in anhyd DMF (200 mL) cooled to 0 °C (ice bath) was added
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Methyl 11-[2-(2-Oxoethyl)-1,3-dithian-2-yl]undec-9-ynoate (4)
Methyl (9E)-9-(3-Hydroxy-6,10-dithiaspiro[4.5]dec-2-
ylidene)nonanoate (11)
CrCl2 (140 mg, 1.1 mmol) was added from a Schlenk addition flask to
solution of aldehyde (130 mg, 0.36 mmol), (E)-
Dess–Martin periodinane (2.86 g, 6.7 mmol) was added in one por-
tion to a solution of alcohol 7 (1.03 g, 4.1 mmol) in CH2Cl2 (50 mL) at
8 °C. The cooling bath was removed and the mixture was stirred for
25 min. A solution of Na2S2O3·5H2O (6.4 g, 26 mmol) in sat. aq NaHCO3
(26 mL) was then slowly added, and the combined mixture was ex-
tracted with Et2O (80 mL). The organic layer was washed successively
with sat. aq NaHCO3 (30 mL) and brine (2 × 30 mL), and the aqueous
layer was extracted with Et2O (2 × 30 mL). The organic layers were
combined, dried (MgSO4), and concentrated in vacuo. The resulting
crude methyl 14-oxotetradeca-9,12-diynoate (1.07 g) was used in the
next step without purification.
a
4
ICH=CH(CH2)2OTBS27 (10; 135 mg, 0.43 mmol), and Ni(acac)2 (0.8 mg,
0.003 mmol) in degassed DMF (2.5 mL). The mixture was stirred at r.t.
for 7.5 h, and then the reaction was quenched with 0.5 M aq EDTA (pH
8.0, 5 mL) and the mixture was diluted with EtOAc (10 mL). The re-
sulting deep-purple solution was stirred for 15 min, the layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 15
mL). The organic layers were combined, washed successively with
H2O (2 × 20 mL) and sat. aq NaCl (30 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash chromatography
[silica gel, hexane–EtOAc (3:1)] to give a colorless oil; yield: 68 mg
(53%). Additionally, the starting dithiane 4 (20 mg) was also isolated.
NaOMe (0.46 g, 8.5 mmol) was added in one portion to a stirred solu-
tion of the crude methyl 14-oxotetradeca-9,12-diynoate (1.73 g, 7
mmol) in MeOH (104 mL), CH2Cl2 (26 mL), and HS(CH2)3SH (0.75 mL)
at about –10 °C (ice–acetone bath). The mixture was stirred for 17 h
while the temperature was allowed to rise to –2 °C. The reaction was
quenched by adding sat. aq NH4Cl (60 mL), and the mixture was ex-
tracted with Et2O (3 × 80 mL). The organic fractions were combined,
washed successively with cold H2O (100 mL) and brine (3 × 100 mL),
dried (MgSO4), and concentrated. The residue was purified by column
chromatography [silica gel, PE–Et2O (5:2)] to give a colorless oil;
yield: 1.3 g (54%, 2 steps).
IR (neat): 3430 (OH), 1736 (C=O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.24–1.44 (m, 8 H, 4CH2), 1.62 (tt, J =
7.0, 7.8 Hz, 2 H, CH2), 1.94–2.15 (m, 4 H, SCH2CH2CH2S and CH2CH=C),
2.30 (t, J = 7.8 Hz, 2 H, CH2CO2Me), 2.45–2.49 (m, 2 H, CH2CHOH), 2.65
(br d, J = 17.0 Hz, 1 H, CH=CCHH), 2.82–2.90 (m, 2 H, CH2), 2.94 (br d,
J = 17.0 Hz, 1 H, CH=CCHH), 2.95–3.05 (m, 2 H, CH2), 3.67 (s, 3 H,
OCH3), 4.55 (t, J = 2.0 Hz, 1 H, CHOH), 5.71 (m, 1 H, CH=C).
13C NMR (125 MHz, CDCl3): δ = 24.9 (CH2), 25.2 (CH2), 28.1 (CH2), 28.3
(CH2), 29.1 (CH2), 29.1 (2 SCH2), 29.1 (CH2), 29.5 (CH2), 34.1 (CH2),
44.0 (CH2), 49.5 (CH2), 51.5 (OCH3), 52.4 (SCS), 74.1 (CHOH), 128.2
(CH=C), 141.9 (C=CH), 174.3 (C=O).
IR (neat): 1713, 645, 558 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.20–1.72 (m, 10 H, 5CH2), 1.92–2.08
(m, 2 H, SCH2CH2CH2S), 2.18 (tt, J = 2.5, 6.9 Hz, 2 H, CH2C≡C), 2.30 (t,
J = 7.5 Hz, 2 H, CH2CO2Me), 2.80–3.02 (m, 4 H, 2CH2), 2.94–3.02 (m, 4
H, 2CH2), 3.67 (s, 3 H, OCH3), 9.84 (t, J = 2.6 Hz, 1 H, CHO).
HRMS (ESI): m/z [M + Na]+ calcd for C18H30NaO3S2: 381.1528; found:
381.1518.
13C NMR (50 MHz, CDCl3): δ = 18.9 (CH2), 24.6 (CH2), 25.1 (CH2), 26.6
(2 SCH2), 28.8 (2CH2), 28.9 (CH2), 29.2 (CH2), 32.1 (CH2), 34.3 (CH2),
48.4 (SCS), 50.7 (CH2CHO), 51.7 (OCH3), 74.3 (C≡), 85.7 (C≡), 174.5
(C=O), 199.5 (CHO).
Methyl 11-[2-(2-Oxoethyl)-1,3-dithian-2-yl]undec-9-ynoate–Dico-
balt Hexacarbonyl Complex [4·Co2(CO)6]
A soln of alkyne 4 (164 mg, 0.46 mmol) in degassed CH2Cl2 (10 mL)
was added dropwise over 40 min to a stirred solution of Co2(CO)8
(170 mg, 0.5 mmol) in degassed CH2Cl2 (10 mL). The dark solution
was stirred at r.t. until the reaction was complete (TLC; 3 h). The sol-
vent was removed under vacuum, and the residue was purified by
column chromatography [silica gel, hexane–EtOAc (3:1)] to give a
dark-red oil; yield: 176 mg (60%).
1H NMR (200 MHz, CDCl3): δ = 1.18–1.82 (m, 10 H, 5CH2), 1.92–2.10
(m, 2 H, SCH2CH2CH2S), 2.32 (br t, J = 7.2 Hz, 2 H, CH2CO2Me), 2.78–
3.10 (m, 6 H, 3CH2), 3.03 (br d, J = 2.0 Hz, 2 H, CH2CHO), 3.67 (br s, 3 H,
OCH3), 3.72 (br s, 2 H, C≡CCH2CS), 9.85 (br s, 1 H, CHO).
HRMS (EI): m/z [M+] calcd for C18H28O3S2: 356.1480; found: 356.1471.
Methyl (9E)-9-(3-Oxo-6,10-dithiaspiro[4.5]dec-2-ylidene)nona-
noate (9)
DCE (2.0 mL) was added to precatalyst [Rh(DPEphos)(nbd)]ClO4 (13
mg, 0.015 mmol) under argon, and the catalyst was activated in situ
by bubbling H2 gas though the solution for 2 min or until its color
changed from orange to red. The H2 atmosphere was then purged by
passing argon through the solution for 0.5 min. Aldehyde 4 (53 mg,
0.15 mmol) and HC≡CCH2OH (17 mg, 0.3 mmol) were added, and the
mixture was stirred and heated at 70 °C for 4 h. The solution was then
cooled to r.t., filtered through a silica plug, concentrated in vacuo, and
purified by flash chromatography [silica gel, PE–Et2O (1:1 to 1:2)] to
give a colorless oil; yield: 14 mg (26%).
Methyl 11-(2-{6-[tert-Butyl(dimethyl)siloxy]-2-hydroxyhex-3-yn-
1-yl}-1,3-dithian-2-yl)undec-9-ynoate (12)
A solution of HC≡C(CH2)2OTBS26 (244 mg, 1.3 mmol) in THF (7 mL)
was cooled to –78 °C and treated with a 2 M soln of BuLi (0.65 mL, 1.3
mmol) in hexane with stirring for 40 min at –70 °C. A soln of alde-
hyde 4 (380 mg, 1.05 mmol) in THF (2 mL) was then slowly added at
–78 °C. The mixture was stirred at –78 °C for 15 min and then slowly
warmed to 10 °C (1.5 h). The mixture was cooled to 0 °C and sat. aq
NH4Cl (2 mL) was added dropwise. The mixture was extracted with
Et2O (4 × 10 mL), and the organic layers were combined, washed with
brine (15 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography [silica gel, PE–Et2O (2:1)] to
give a colorless oil; yield: 340 mg (60%).
IR (neat): 2932, 1721, 1653, 1472, 1380, 910, 733 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.21–1.34 (m, 6 H, 3CH2), 1.38–1.50
(m, 2 H, CH2CH2C=CH), 1.61 (app p, J = 7.4 Hz, 2 H, CH2CH2CO2Me),
1.94–2.10 (m, 2 H, SCH2CH2CH2S), 2.10–2.19 (m, 2 H, CH2CH=C), 2.29
(t, J = 7.5 Hz, 2 H, CH2CO2Me), 2.89–2.94 (m, 4 H, 2SCH2), 2.95 (s, 2 H,
CO–CH2), 3.06 (td, J = 2.5, 1.4 Hz, 2 H, CH=CCH2), 3.66 (s, 3 H, OCH3),
6.65 (tt, J = 7.7, 2.5 Hz, 1 H, CH=C).
13C NMR (100 MHz, CDCl3): δ = 24.8 (CH2), 24.9 (CH2), 27.8 (2 SCH2),
28.2 (CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 29.7 (CH2), 34.0 (CH2),
42.2 (CH2), 49.0 (SCS), 51.5 (OCH3), 53.5 (CH2), 134.6 (C=CH), 138.6
(C=CH), 174.2 (C=O), 201.1 (C–C=O).
IR (neat): 2460 (OH), 2237 (C≡C), 1739 (C=O), 1253 (C–O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.08 (s, 6 H, 2CH3), 0.90 (s, 9 H, t-Bu),
1.20–1.74 (m, 10 H, 5CH2) 1.88–2.10 (m, 2 H, SCH2CH2CH2S), 2.18 (tt,
J = 2.5, 7.0 Hz, 2 H, CH2C≡C), 2.30 (t, J = 7.5 Hz, 2 H, CH2CO2Me), 2.44
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(dt, J = 2.0, 7.8, 2 H, C≡CCH2CH2O), 2.45 (dd, J = 3.0, 15.2 Hz, 1 H, CHH-
CHOH), 2.56 (dd, J = 9.0, 15.2 Hz, 1 H, CHHCHOH), 2.78–3.04 (m, 6 H,
3CH2), 3.67 (s, 3 H, OCH3), 3.73 (t, J = 7.5 Hz, 2 H, CH2OSi), 4.74–4.88
(m, 1 H, CHOH).
13C NMR (125 MHz, CDCl3): δ = –5.25 [(CH3)2Si], 18.3 [C(CH3)3], 18.8
(CH2), 23.2 (CH2), 24.7 (CH2), 24.9 (CH2), 25.9 (3 CH3), 26.4 (CH2), 26.5
(CH2), 28.6 (CH2), 28.7 (2 SCH2), 29.0 (CH2), 31.4 (CH2), 34.1 (CH2),
45.8 (CH2), 50.6 (SCS), 51.5 (OCH3), 60.3 (CHOH), 61.8 (CH2O), 74.4
(C≡), 82.0 (C≡), 82.2 (C≡), 84.9 (C≡), 174.3 (C=O).
3CH2), 3.73 (t, J = 7.5 Hz, 2 H, CH2OSi), 4.16 (s, 2 H, CH2OCO), 4.38 (d,
J = 6.0 Hz, 2 H, 2CHHoxetane), 4.52 (d, J = 6.0 Hz, 2 H, 2CHHoxetane), 4.76–
4.84 (m, 1 H, CHOH).
13C NMR (125 MHz, CDCl3): δ = –5.0 [(CH3)2Si], 18.3 [C(CH3)3], 18.8
(CH2), 21.2 (CH3), 23.2 (CH2), 24.7 (CH2), 24.9 (CH2), 25.9 (3 CH3), 26.4
(CH2), 26.5 (CH2), 28.6 (CH2) 28.7 (2 SCH2), 29.0 (CH2), 31.4 (CH2), 34.2
(CH2), 39.1 [CH2C(CH3)CH2], 45.8 (CH2), 50.7 (SCS), 60.3 (CHOH), 61.8
(CH2OSi), 68.5 (CH2OCO), 74.4 (C≡), 79.6 (CH2OCH2), 82.0 (C≡), 82.2
(C≡), 84.9 (C≡), 173.9 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C28H48NaO4SiS2: 563.2661; found:
HRMS (ESI): m/z [M + Na]+ calcd for C32H54NaO5SiS2: 633.3080; found:
563.2666.
633.3083.
11-(2-{6-[tert-Butyl(dimethyl)siloxy]-2-hydroxyhex-3-yn-1-yl}-
1,3-dithian-2-yl)undec-9-ynoic Acid
Methyl (9Z)-11-(2-{(3Z)-6-[tert-Butyl(dimethyl)siloxy]-2-hydroxy-
hex-3-en-1-yl}-1,3-dithian-2-yl)undec-9-enoate (16) and Methyl
11-(2-{(3Z)-6-[tert-Butyl(dimethyl)siloxy]-2-hydroxyhex-3-en-1-
yl}-1,3-dithian-2-yl)undec-9-ynoate (15)
A 1 M soln of aq LiOH (7.5 mL) was added over 20 min to a solution of
methyl ester 12 (260 mg, 0.48 mmol) in THF (24 mL) at 0 °C. After 5
min, the mixture was brought to r.t. and stirred for 19 h. The solution
was then acidified to pH 2 with 1 M aq HCl and the mixture was ex-
tracted with EtOAc (4 × 50 mL). The organic extracts were combined,
washed with cold H2O (50 mL), dried (Na2SO4), and concentrated to
give a colorless oil (310 mg). This crude acid was purified by column
chromatography [silica gel, hexane–EtOAc (1:1)] to give a colorless
oil; yield: 185 mg (73%).
1H NMR (500 MHz, acetone-d6): 0.09 (s, 6 H, 2CH3), 0.91 (s, 9 H, t-Bu),
1.30–1.42 (m, 4 H, 2CH2), 1.44–1.54 (m, 4 H, 2CH2), 1.61 (tt, J = 7.0, 7.5
Hz, 2 H, CH2), 1.82–2.02 (m, 2 H, SCH2CH2CH2S), 2.17 (tt, J = 2.5, 6.5
Hz, 2 H, CH2C≡C), 2.27 (t, J = 7.5 Hz, 2 H, CH2CO2Me), 2.39 (td, J = 2.0,
6.9 Hz, 2 H, C≡CCH2CH2O), 2.40–2.50 (m, 2 H, CH2), 2.78–2.99 (m, 6 H,
3CH2), 3.73 (t, J = 7.0 Hz, 2 H, CH2OSi), 4.67 (br t, J = 6.0 Hz, 1 H,
CHOH), 10.40 (br s, 1 H, CO2H).
A 1 M soln of NaBH4 was prepared by dissolving NaBH4 (0.2 g, 5
mmol) in EtOH (4.75 mL) and 1.2 M aq NaOH (0.25 mL). The filtered
solution (0.45 mL) was added to a stirred solution of Ni(OAc)2 (107
mg, 0.43 mmol) in 95% ethanol (4 mL) saturated with argon.
H2N(CH2)2NH2 (0.07 mL, 63 mg, 1 mmol) was added, and the resulting
mixture was saturated with H2. A solution of diyne 12 (92 mg, 0.17
mmol) in 95% ethanol (0.6 mL) was added, maintaining the H2 atmo-
sphere immediately after addition. When the reaction was complete
(TLC; 75 min), the reaction was quenched with Et2O (6 mL). The mix-
ture was then filtered through a pad of Celite with suction, and the
filtrate was concentrated in vacuo. The residue was suspended in Et2O
(8 mL), filtered through a second pad of Celite, and concentrated. The
crude product (86 mg) was purified by column chromatography [sili-
ca gel, PE–Et2O (2:1)] to give diene 16 as a colorless oil; yield: 61 mg
(66%). Additionally, enyne 15 was also isolated as a colorless oil; yield:
~3 mg (3%).
13C NMR (125 MHz, acetone-d6): –5.0 [(CH3)2Si], 18.9 [C(CH3)3], 19.3
(CH2), 23.8 (CH2), 25.7 (CH2), 25.9 (CH2), 26.4 (3 CH3), 26.9 (CH2), 27.0
(CH2), 29.4 (CH2), 29.7 (SCH2) 29.7 (SCH2), 29.9 (CH2), 31.8 (CH2), 34.3
(CH2), 46.7 (CH2), 51.9 ( SCS), 60.2 (CHOH), 62.7 (CH2OSi), 76.3 (C≡),
82.0 (C≡), 84.4 (C≡), 84.5 (C≡), 174.8 (C=O).
16
IR (neat): 3450 (OH), 1735 (C=O), 1622 (C=C), 1253 (C–O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.06 (s, 6 H, 2CH3), 0.89 (s, 9 H, t-Bu),
1.22–1.46 (m, 8 H, 4CH2), 1.58–1.66 (m, 2 H, CH2), 1.88–2.12 (m, 4 H,
SCH2CH2CH2S and CH2CH=CH), 2.00 (dd, J = 2.8, 15.2 Hz, 1 H,
CHHCHOH), 2.26–2.48 (m, 2 H, CH2), 2.30 (t, J = 7.5 Hz, 2 H, CH2-
CO2Me), 2.36 (dd, J = 8.6, 15.2 Hz, 1 H, CHHCHOH), 2.68–2.84 (m, 4 H,
2CH2), 2.88–3.04 (m, 2 H, CH2), 3.58–3.70 (m, 2 H, CH2OSi), 3.66 (s, 3
H, OCH3), 4.81 (br td, J = 2.4, 8.4 Hz, 1 H, CHOH), 5.44–5.62 (m, 4 H,
2CH=CH).
13C NMR (125 MHz, CDCl3): δ = –5.3 [(CH3)2Si], 18.4 [C(CH3)3], 24.8
(CH2), 24.9 (CH2), 26.0 (3 CH3), 26.1 (CH2), 26.3 (CH2), 27.7 (CH2), 29.0
(CH2), 29.1 (2 SCH2), 29.3 (CH2), 31.3 (CH2), 34.0 (CH2), 37.3 (CH2),
44.7 (CH2), 51.4 (OCH3), 52.1 (SCS), 62.5 (CH2OSi), 65.0 (CHOH), 123.0
(CH=), 127.7 (CH=), 133.5 (CH=), 134.3 (CH=), 174.2 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C27H46NaO4SiS2: 549.2505; found:
549.2518.
(3-Methyloxetan-3-yl)methyl 11-(2-{6-[tert-Butyl(dimethyl)sil-
oxy]-2-hydroxyhex-3-yn-1-yl}-1,3-dithian-2-yl)undec-9-ynoate
(13)
A solution 11-(2-{6-[tert-butyl(dimethyl)siloxy]-2-hydroxyhex-3-yn-
1-yl}-1,3-dithian-2-yl)undec-9-ynoic acid (155 mg, 0.29 mmol) in
CH2Cl2 (1.2 mL) was added to a stirred solution of DCC (96 mg, 0.47
mmol), (3-methyloxetan-3-yl)methanol (614 mg, 6 mmol) and DMAP
(4 mg, 0.03 mmol) in CH2Cl2 (1.2 mL) at –2 °C under argon, and the
mixture was kept for 15 min at 0 °C. The mixture was then slowly
warmed to r.t. over 1 h and the precipitated dicyclohexylurea was col-
lected by filtration and washed with CH2Cl2. The filtrate was washed
successively with 1% aq NH4Cl (2 × 3 mL) and 5% aq NaHCO3 (3 mL),
dried (MgSO4), and concentrated in vacuo. The residue was purified
by column chromatography [silica gel, hexane–EtOAc (3:1)] to give a
colorless oil; yield: 130 mg (74%).
HRMS (ESI): m/z [M + Na]+ calcd for C28H52NaO4SiS2: 567.2968; found:
567.2999.
15
IR (neat): 3460 (OH), 2230 (C≡C), 1740 (C=O), 1254 (C–O) cm–1
.
IR (neat): 3426 (OH), 2236 (C≡C), 1738 (C=O), 1252 (C–O) cm–1
.
1H NMR (200 MHz, CDCl3): δ = 0.06 (s, 6 H, 2CH3), 0.90 (s, 9 H, t-Bu),
1.20–1.72 (m, 10 H, 5CH2), 1.90–2.06 (m, 2 H, CH2C≡C), 2.06–2.60 (m,
6 H, 3CH2), 2.30 (t, J = 7.4 Hz, 2 H, CH2CO2Me), 2.70–3.04 (m, 6 H,
3CH2), 3.54–3.78 (m, 2 H, CH2OSi), 3.66 (s, 3 H, OCH3), 4.85 (br tt, J =
2.8, 8.0 Hz, 1 H, CHOH), 5.38–5.70 (m, 2 H, CH=CH).
1H NMR (500 MHz, CDCl3): δ = 0.08 (s, 6 H, 2CH3), 0.90 (s, 9 H, t-Bu),
1.30–1.44 (m, 6 H, 3CH2), 1.34 (s, 3 H, CH3), 1.46–1.54 (m, 2 H, CH2),
1.60–68 (m, 2 H, CH2), 1.88–2.06 (m, 2 H, SCH2CH2CH2S), 2.18 (tt, J =
2.5, 7.0 Hz, 2 H, CH2C≡C), 2.35 (t, J = 7.5 Hz, 2 H, CH2CO2CH2), 2.44 (dt,
J = 2.0, 7.0 Hz, 2 H, C≡CCH2CH2O), 2.45 (dd, J = 3.0, 15.0 Hz, 1 H, CHH-
CHOH), 2.56 (dd, J = 8.5, 15.0 Hz, 1 H, CHHCHOH), 2.78–3.02 (m, 6 H,
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13C NMR (50 MHz, CDCl3): δ = –5.1 [(CH3)2Si], 18.6 [C(CH3)3], 19.0
(CH2), 25.0 (CH2), 25.1 (CH2), 26.2 (3 CH3), 26.6 (CH2), 26.7 (CH2), 28.8
(CH2), 28.9 (2 SCH2), 29.2 (CH2), 31.4 (CH2), 31.5 (CH2), 34.3 (CH2),
45.0 (CH2), 51.2 (SCS), 51.6 (OCH3), 62.7 (CH2OSi), 65.2 (CHOH), 74.9
(C≡), 84.8 (C≡), 128.0 (CH=), 134.4 (CH=), 174.5 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C28H50NaO4SiS2: 565.2818, found:
565.2808.
HRMS (ESI): m/z [M + Na]+ calcd for C28H50NaO4SiS2: 565.2817;
found: 565.2813.
Isomerization of the Z-Double Bond in Enones 17 and 18; General
Procedure
Bu3P (1 μL, 0.81 mg, 0.004 mmol) was added to a solution of Z-enone
17 or 18 (0.012 mmol) in anhyd THF (0.2 mL) at 5 °C, and the resulting
solution was stirred at 5–10 °C for 30 min. It was then diluted with
EtOAc (1 ml), washed with brine (2 × 0.5 mL), dried MgSO4, and puri-
fied by column chromatography [silica gel, PE–Et2O].
β-Keto Dithianes 17 and 18; General Procedure
Alcohol 15 or 16 (0.12 mmol) was dissolved in CH2Cl2 (2 mL), and the
solution was cooled to 8 °C. Dess–Martin periodinane (88 mg, 0.23
mmol) and anhyd NaHCO3 (31 mg, 0.37 mmol) were added, the ice
bath was removed, and the mixture was stirred for 25–30 min. The
mixture was then cooled to 2 °C and the reaction was quenched with
Na2S2O3·5 H20 (207 mg, 0.83 mmol) in sat. aq NaHCO3 (0.83 mL). The
mixture was then diluted with Et2O (3 mL) and stirred until clear. The
organic phase was washed with sat. aq NaHCO3 (1 mL) and brine (2 ×
1 mL), and the aqueous washes were extracted with Et2O (2 × 3 mL).
The organic extracts were combined, washed with brine, dried
(MgSO4), and concentrated in vacuo to give a colorless oil that was pu-
rified by flash column chromatography [silica gel, hexane–EtOAc
(6:1)].
Methyl 11-(2-{(3E)-6-[tert-Butyl(dimethyl)siloxy]-2-oxohex-3-en-
1-yl}-1,3-dithian-2-yl)undec-9-ynoate (19)
Clear, colorless oil; yield: 2.5 mg (38%).
IR (neat): 2230 (C≡C), 1733, 1685 (C=O), 1627 (C=C), 1256 (C–O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.05 (s, 6 H, 2CH3), 0.89 (s, 9 H, t-Bu),
1.22–1.54 (m, 8 H, 4CH2), 1.56–1.66 (m, 2 H, CH2), 1.92–2.06 (m, 2 H,
SCH2CH2CH2S), 2.17 (tt, J = 2.5, 7.0 Hz, 2 H, CH2C≡C), 2.28 (t, J = 7.5 Hz,
2 H, CH2CO2Me), 2.44 (ddt, J = 1.2, 6.5, 7.0 Hz, 2 H, CH2), 2.80–2.92 (m,
4 H, 2CH2), 3.09 (t, J = 2.5 Hz, 2 H, C≡CCH2CS), 3.27 (s, 2 H, CH2), 3.66
(s, 3 H, OCH3), 3.74 (t, J = 6.5 Hz, 2 H, CH2OSi), 5.48–5.62 (m, 2 H,
CH=CH), 6.24 (dt, J = 1.5, 15.5 Hz, 1 H, CH=), 6.90 (dt, J = 7.0, 15.5 Hz, 1
H, CH=).
13C NMR (125 MHz, CDCl3): δ = –5.2 [(CH3)2Si], 18.5 [C(CH3)3], 18.9
(CH2), 25.0 (CH2), 25.2 (CH2), 26.2 (3 CH3), 26.8 (2 SCH2), 29.2 (CH2),
29.4 (CH2), 29.5 (CH2), 29.9 (CH2), 31.6 (CH2), 33.5 (CH2), 35.9 (CH2),
47.4 (CH2), 50.0 (SCS), 51.8 (OCH3), 62.0 (CH2OSi), 75.2 (C≡), 84.8 (C≡),
132.5 (C=), 144.9 (C=), 174.4 (C=O), 195.7 [CH2C(O)CH=].
Methyl 11-(2-{(3Z)-6-[tert-Butyl(dimethyl)siloxy]-2-oxohex-3-en-
1-yl}-1,3-dithian-2-yl)undec-9-ynoate (17)
Prepared from alcohol 15 (25 mg, 0.046 mmol) as a clear colorless oil;
yield: 10 mg (41%).
1H NMR (500 MHz, CDCl3): δ = 0.05 (s, 6 H, 2CH3), 0.88 (s, 9 H, t-Bu),
1.24–1.54 (m, 8 H, 4CH2), 1.58–1.66 (m, 2 H, CH2), 1.90–2.08 (m, 2 H,
SCH2CH2CH2S), 2.18 (tt, J = 2.5, 7.0 Hz, 2 H, CH2C≡C), 2.30 (t, J = 7.5 Hz,
2 H, CH2CO2Me), 2.82–2.90 (m, 6 H, 3CH2), 3.06 (t, J = 2.5 Hz, 2 H, CH2),
3.20 (br s, 2 H, CH2), 3.66 (s, 3 H, OCH3), 3.71 (t, J = 6.2 Hz, 2 H,
CH2OSi), 6.22–6.33 (m, 2 H, CH=CH).
13C NMR (125 MHz, CDCl3): δ = –5.1 [(CH3)2Si], 18.5 [C(CH3)3], 19.0
(CH2), 25.0 (CH2), 25.1 (CH2), 26.2 (3 CH3), 26.8 (2 SCH2), 28.9 (CH2),
29.0 (2 CH2), 29.3 (CH2), 30.7 (CH2), 33.4 (CH2), 34.3 (CH2), 50.1 (SCS),
50.7 (CH2), 51.7 (OCH3), 62.4 (CH2OSi), 75.1 (C≡), 84.7 (C≡), 128.5 (C=),
146.6 (C=), 174.5 (C=O), 197.0 [CH2C(O)CH=].
HRMS (ESI): m/z [M + Na]+ calcd for C28H48NaO4SiS2: 563.2661; found:
563.2637.
Methyl (9Z)-11-(2-{(3E)-6-[tert-butyl(dimethyl)siloxy]-2-oxohex-
3-en-1-yl}-1,3-dithian-2-yl)undec-9-enoate (20)
Clear colorless oil; yield: 1.8 mg (27%).
IR (neat): 1733, 1686 (C=O), 1627 (C=C), 1258 (C–O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.05 (s, 6 H, 2CH3), 0.89 (s, 9 H, t-Bu),
1.24–1.42 (m, 8 H, 4CH2), 1.58–1.66 (m, 2 H, CH2), 1.90–2.10 (m, 4 H,
SCH2CH2CH2S and CH2CH=CH), 2.30 (t, J = 7.5 Hz, 2 H, CH2CO2Me),
2.42 (ddt, J = 1.5, 6.5, 7.0 Hz, 2 H, CH2), 2.82–2.92 (m, 6 H, 3CH2), 3.14
(s, 2 H, CH2), 3.66 (s, 3 H, OCH3), 3.73 (t, J = 6.5 Hz, 2 H, CH2OSi), 5.48–
5.62 (m, 2 H, CH=CH), 6.21 (dt, J = 1.5, 15.8 Hz, 1 H, CH=), 6.85 (dt, J =
7.0, 15.8 Hz, 1 H, CH=).
HRMS (ESI): m/z [M + Na]+ calcd for C28H48NaO4SiS2: 563.2661; found:
563.2655.
Methyl (9Z)-11-(2-{(3Z)-6-[tert-butyl(dimethyl)siloxy]-2-oxohex-
3-en-1-yl}-1,3-dithian-2-yl)undec-9-enoate (18)
13C NMR (125 MHz, CDCl3): δ = –5.3 [(CH3)2Si], 18.3 [C(CH3)3], 24.9
(CH2), 25.0 (CH2), 25.9 ((3 CH3)), 26.5 (2 SCH2), 27.8 (CH2), 29.4 (CH2),
29.5 (CH2), 29.7 (CH2), 32.0 (CH2), 34.1 (CH2), 36.0 (CH2), 36.4 (CH2),
47.2 (CH2), 50.6 (SCS), 51.5 (OCH3), 61.6 (CH2OSi), 123.1 (C=), 132.4
(C=), 134.1 (C=), 144.3 (C=), 174.3 (C=O), 195.6 [CH2C(O)CH=].
HRMS (ESI): m/z [M + Na]+ calcd for C28H50NaO4SiS2: 565.2818; found:
565.2832.
Clear colorless oil; yield: 30 mg (46%)
IR (neat): 1739, 1690 (C=O), 1623 (C=C), 1258 (C–O) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.04 (s, 6 H, 2CH3), 0.88 (s, 9 H, t-Bu),
1.22–1.40 (m, 8 H, 4CH2), 1.56–1.66 (m, 2 H, CH2), 1.88–2.10 (m, 4 H,
SCH2CH2CH2S and CH2CH=CH), 2.29 (t, J = 7.5 Hz, 2 H, CH2CO2Me),
2.78–2.96 (m, 8 H, 4CH2), 3.08 (s, 2 H, CH2), 3.66 (s, 3 H, OCH3), 3.70 (t,
J = 6.2 Hz, 2 H, CH2OSi), 5.48–5.62 (m, 2 H, CH=CH), 6.18–6.30 (m, 2 H,
CH=CH). Homodecoupling was carried out; irradiation of the allylic
proton signal at 2.8 ppm resulted in two doublets with 3J = 11.2 Hz,
confirming the Z-configuration of the enone double bond.
Acknowledgment
13C NMR (125 MHz, CDCl3): δ = –5.3 [(CH3)2Si], 18.3 [C(CH3)3], 24.9
(2CH2), 25.9 (3 CH3), 26.5 (2 SCH2), 27.7 (CH2), 29.1 (3 CH2), 29.4
(CH2), 33.1 (CH2), 34.1 (CH2), 36.4 (CH2), 50.4 (CH2), 50.7 (SCS), 51.4
(OCH3), 62.1 (CH2OSi), 123.0 (C=), 128.5 (C=), 134.0 (C=), 146.1 (C=),
174.3 (C=O), 196.9 [CH2C(O)CH=].
This work was supported by the Polish State Committee for Scientific
Research (Grant No. 20503032/1852), which is gratefully acknowl-
edged.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1181–1189

1189
J. Grodner et al.
Paper
Synthesis
Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379984.
S
u
p
p
ortioInfgrmoaitn
S
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p
p
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1181–1189