Investigation of an acrylate lynchpin approach toward the synthesis of stolonidiol

Article abstract of DOI:10.1055/s-0032-1316589

An acrylate lynchpin approach toward the synthesis of stolonidiol has been investigated. To access the key macrocyclization precursor we adapted the silylcupration reaction of alkynes, facilitating attack of the intermediate vinylcuprate on a trisubstituted epoxide. With all of the required carbons of stolonidiol in place, macrocyclization reactions to provide the 11-membered ring were attempted using either a nickel-mediated cyclization of a bromo aldehyde, intercepting methyl acrylate, or an intramolecular Baylis-Hillman cyclization. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316589

2770▌
PAPER
paper
Investigation of an Acrylate Lynchpin Approach toward the Synthesis of
Stolonidiol
Acrylate Lynchpin Approach toward the Synthesis of Stolonidiol
Thomas Barton, Dionicio Siegel*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, USA
Fax +1(512)4716835; E-mail: dsiegel@cm.utexas.edu
Received: 28.03.2012; Accepted after revision: 05.06.2012
fledgling cells.6 In the absence of these contacts, as seen
Abstract: An acrylate lynchpin approach toward the synthesis of
in Alzheimer’s disease, neurogenesis is attenuated.7,8 Im-
stolonidiol has been investigated. To access the key macrocycliza-
portantly, cholinergic agonists have been shown to in-
tion precursor we adapted the silylcupration reaction of alkynes, fa-
cilitating attack of the intermediate vinylcuprate on a trisubstituted
crease the rate of neurogenesis.9 Fortification of the
epoxide. With all of the required carbons of stolonidiol in place, cholinergic system by increasing ChAT activity has the
macrocyclization reactions to provide the 11-membered ring were
attempted using either a nickel-mediated cyclization of a bromo al-
dehyde, intercepting methyl acrylate, or an intramolecular Baylis–
ing existing degeneration.10 Structure–activity relation-
Hillman cyclization.
potential to favorably shift the balance of cell production
and cell loss, slowing cognitive decline or possibly revers-
ships (SAR) for stolonidiol, based on compounds that
could be prepared from the natural product, demonstrated
that compounds without epoxide functionality lack the
Key words: stolonidiol, epoxides, silylcupration, macrocycliza-
tion, acrylate lynchpin approach
ability to potently induce ChAT activity, providing evi-
dence for potential covalent modification of protein tar-
gets.1 Yamada and co-workers, the group which isolated
stolonidiol from Clavularia viridis, achieved the sole syn-
thesis of stolonidiol to date.11 Work toward the synthesis
of the functionalized cyclopentane core of stolonidiol has
also been reported.12,13
Stolonidiol (1) induces the biosynthesis of choline acetyl-
transferase (ChAT) mRNA at concentrations of 27 nM re-
sulting in an increased biosynthesis of acetylcholine.1
Owing to limited access from the marine soft coral Clavu-
laria sp., the mode of action leading to this transcriptional
regulation is currently unknown.2 Neurogenesis, produc-
ing newborn cells, in the mature brain occurs continuous-
ly in the hippocampal dentate gyrus and stimulation of the
developing cells by the actions of acetylcholine has been
strongly implicated in the production and the survival of
neural progenitors during early development and adult-
hood.3–5 The new cells’ contacts with cholinergic projec-
tions are associated with the growth and development of
Our synthetic studies have investigated an acrylate lynch-
pin approach to stolonidiol utilizing either a nickel-medi-
ated conjugate addition/aldol sequence with methyl
acrylate or a Heck reaction, also with methyl acrylate, fol-
lowed by an intramolecular Baylis–Hillman macrocycli-
zation to form the 11-membered ring (Scheme 1). These
approaches should provide efficient sequences toward the
Me
Me
Me
Me
O
CO2Me
H
H
H
+
H
OH
OH
Me
CHO
OH
Me
HO
Me
OH
Me
Me
4
Br
Me
Me
Me
O
O
OH
MeO
OH
stolonidiol (1)
stolonitriene (2)
3
5
methyl
acrylate
Ni(cod)2
additive
Me
Me
Me
Me
Me
Heck coupling
methyl acrylate
Me
Me
Me
Me
Baylis–Hillman
OH
H
H
H
CHO
H
H
OH
OH
CHO
CHO
Me
OH
OH
HO
HO
Br
Br
Me
Me
Me
Me
Me
O
O
MeO
MeO
MeO
O
5
6
5
7
8
Scheme 1 Acrylate lynchpin strategy for the formation of the fully functionalized bicyclic ring system, 6 and 8, of stolonidiol
SYNTHESIS 2012, 44, 2770–2778
Advanced online publication: 27.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316589; Art ID: SS-2012-M0321-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acrylate Lynchpin Approach toward the Synthesis of Stolonidiol
2771
assembly of the appropriately functionalized bicyclic ring employed. The optimized procedure for our purposes en-
system 6 and 8. In addition, the formation of both cycliza- tailed the addition of a tetrahydrofuran solution of epoxy-
tion precursors can be traced back to single compound, alkyne 13 to 1.15 equivalents of dilithium
bromo aldehyde 5.
bis[dimethyl(phenyl)silyl]cyanocuprate in tetrahydrofu-
ran [prepared by adding 2.3 equiv of a deep red dimeth-
To examine the acrylate lynchpin strategies, a synthesis of
bromo aldehyde 5 was required. Proceeding from gerani-
ol, optically active aldehyde 9 was prepared over three
steps on a 50-gram scale (Scheme 2).14 Alkynylation of al-
dehyde 9 using the Bestmann–Ohira reagent 10 (1.5
equiv) with potassium carbonate in methanol at 23 °C
provided alkyne 11 in 91% yield.15,16 Epoxidation of the
trisubstituted olefin of alkyne 11 using the Shi catalyst 12
(1.1 equiv) with slow addition of aqueous, buffered
Oxone® solution resulted in the formation of epoxyalkyne
13 in a 9:1 ratio of diastereomers.17–19
Ac
PO(OMe)2
OH
Me CH2OTBS
OHC
N2
10
3-steps
Me
Me
K2CO3
MeOH, 23 °C
91%
Me
Me
9
Me
geraniol
Me CH2OTBS
Using dilithium bis(dimethyl(phenyl)silyl)cyanocuprate
to induce the cyclization of epoxyalkyne 13 to form the
desired cyclopentane led predominantly to hydrosi-
lylation of the alkyne, generating vinylsilane 14 with none
of the cyclized products 15 or 16 (Table 1). Challenges in
inducing cyclization following silylcupration reactions
have been previously noted by Fleming and co-workers.20
A variety of conditions, summarized in Table 1, were ex-
amined and the addition of boron trifluoride–diethyl ether
complex was found to promote the formation of cyclized
products, generating vinylsilanes 15 and 16.
Me
Me
11
O
O
O
Me
Me
O
O
Me CH2OTBS
Me
Me
O
12
oxone, pH 10
O
Me
Me
dimethoxymethane, MeCN, 0 °C
86%
13
The ratio of vinylsilanes 15 and 16 changed depending on
the amount of boron trifluoride–diethyl ether complex
Scheme 2 Synthesis of epoxide 13 from geraniol
Table 1 Optimization of Conditions for the Silylcupration Reaction of Epoxyalkyne 13 to Cyclopentane 15a
TBSO
Me
Me CH2OTBS
Me CH2OTBS
TBSO
Me
1. (PhMe2Si)2CuCNLi2
2. Lewis acid
+
+
H
H
PhMe2Si
Me
OH
O
Me
O
Me
Si
Me
Me
PhMe2Si
O
Me
Me
Me
Me
Me
13
14
15
16
Entry
Lewis acid (equiv)
Temp (°C) of Lewis acid addition
Time (h) after addition
Yield (%) of 14/15/16
1
2
–
0
0
6
6
82: 0: 0
32: 0: 0
28: 0: 0
46: 0: 0
31:32:12
8:14:51
21:11:45
6:17:65
5:81: 0
7:64: 0
5:84: 0
TMSCl (1.5)
TMSOTf (1.5)
Me3Al (1.5)
BF3·OEt2 (1.5)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (5.0)
BF3·OEt2 (5.0)
BF3·OEt2 (3.0)
3
0
6
4
0
6
5
0
6
6
0
2
7
–78
0
2
8
18
18
6
9
0
10
11
0
0
12
a Conditions: All reactions were performed in THF (0.1 M). The epoxyalkyne 13 was added at –78 °C and warmed to 0 °C. TLC (hexanes–
EtOAc, 9:1) indicated that starting material was consumed within 2 h at 0 °C, at which point the Lewis acid was introduced, where indicated.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2770–2778

2772
T. Barton, D. Siegel
PAPER
yl(phenyl)silyllithium solution to CuCN (1.15 equiv) Bromo diene 21 was prepared over a five-step sequence
suspended in THF at 0 °C, followed by stirring for 20 min, from bromide 17 as outlined in Scheme 4. Cleavage of the
which gave a brown solution] at –78 °C and warming to silyl groups using tetrabutylammonium fluoride (2.5
0 °C for 2 hours, followed by the addition of boron triflu- equiv) in tetrahydrofuran at 23 °C followed by oxidation
oride–diethyl ether complex (3 equiv) and stirring at 0 °C of the resulting diol using Dess–Martin periodinane gave
for 12 hours, generating 15 in 84% yield. Notably, this re- aldehyde 18 on a 10-gram scale. Horner–Wadsworth–
action proved reliable on a 15-gram scale.
Emmons olefination of aldehyde 18 using lithium hexa-
methyldisilazide and the known ketophosphonate 19 in
toluene heated to 100 °C provided enone 20 in 77%
yield.23 Conjugate reduction of enone 20 was achieved by
combining copper(II) acetate monohydrate (5 mol%), 1,2-
bis(diphenylphosphino)benzene (BDPPB, 5 mol%), and
tert-butyl alcohol (1.5 equiv) in toluene (0.2 M), provid-
ing a clear blue solution, followed by addition of poly-
methylhydrosiloxane (PMHS, 1.5 equiv), transitioning
the color of the solution to bright yellow; after 30 minutes,
enone 20 was introduced in a toluene solution and after 18
hours the reaction mixture was worked up to provided the
corresponding saturated ketone.24 Wittig methylenation of
the ketone with methylenetriphenylphosphorane in tetra-
hydrofuran at 23 °C provided bromo diene 21 in 46%
yield over two steps.
Protection of the tertiary alcohol of 15 was necessary21
and achieved in dichloromethane using trimethylsilyl tri-
fluoromethanesulfonate (3.0 equiv) and 2,6-lutidine (6.0
equiv) at –78 °C with warming to 23 °C (Scheme 3). Ad-
dition of solid N-bromosuccinimide (2.0 equiv) to a solu-
tion of the resulting trimethylsilyl ether in acetonitrile
provided bromide 17 with retention of the olefin geometry
(confirmed by X-ray crystallography of the p-bromoben-
zoate derived from the parent alcohol by treatment with p-
bromobenzoyl chloride and pyridine).22 The correspond-
ing vinyl iodide of 17 could also be prepared in 62% yield
using N-iodosuccinimide.
Me CH2OTBS
TBSO
Me
The tert-butyldimethylsilyl group of bromo diene 21 was
removed with tetrabutylammonium fluoride (1.5 equiv) in
tetrahydrofuran, which was followed by oxidation of the
primary alcohol with Dess–Martin periodinane (1.1
equiv) in dichloromethane, generating the desired bromo
aldehyde 5 in 53% yield over two steps (Scheme 5). Heck
reaction using bromo diene 21 was accomplished using
methyl acrylate (8 equiv), triethylamine (10 equiv), tri-
phenylphosphane (20 mol%), and tetrabutylammonium
bromide (1 equiv) in degassed N,N-dimethylformamide
followed by the addition of palladium(II) acetate (0.2
equiv).25 After combination of the components was com-
plete, the reaction mixture was placed in a 100 °C oil bath
and stirred for 16 hours yielding, after purification, dieno-
ate 22 (Scheme 5). Subjecting this material to deprotec-
tion with fluoride and oxidation with Dess–Martin
periodinane afforded dienoate aldehyde 7 in 82% yield
over two steps.
(PhMe2Si)2CuCNLi2
BF3•OEt2
THF, –78 °C to 0 °C
84%
H
O
OH
Me
PhMe2Si
Me
Me
Me
13
15
TBSO
Me
H
OTMS
1. TMSOTf, 2,6-lutidine
CH2Cl2, –78 to 23 °C
Me
Br
Me
17
2. NBS, MeCN, 23 °C
2 steps 88%
Scheme 3 Synthesis of bromide 17 from epoxyalkyne 13
TBSO
O
O
Me
TBSO
Me
P(OMe)2
OHC
19
1. TBAF, THF, 23 °C
H
H
LiHMDS
toluene, 100 °C
77%
2. DMP, NaHCO3
CH2Cl2, 23 °C
OH
OTMS
Me
Br
Me
Br
Me
Me
2 steps 92%
18
17
O
Me
Me
1. BDPPB, Cu(OAc)2, PMHS
t-BuOH, toluene, 0 °C
TBSO
H
H
2. Ph3P=CH2
THF, 23 °C
OH
OH
Me
Br
OTBS
Me
Br
20
Me
2 steps 45%
Me
21
Scheme 4 Synthesis of bromo diene 21 from bromide 17
Synthesis 2012, 44, 2770–2778
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acrylate Lynchpin Approach toward the Synthesis of Stolonidiol
2773
Access to bromo aldehyde 5 allowed examination of the dure gave rise to no discernable conjugate addition
nickel-catalyzed conjugate addition/aldol sequence to product. Variation of the acrylate species, reductants (al-
form the 11-membered ring of stolonidiol (Scheme 6). kylzincs, boranes), reaction times, and temperature failed
Following conditions reported by Subburaj and Mont- to generate the desired product. The corresponding iodo
gomery,26 bis(cyclooctadiene)nickel (20 mol%) was aldehyde of 5 showed similar reactivity under these con-
transferred in a glovebox to a flame-dried flask and sus- ditions.
pended in tetrahydrofuran. A solution of the bromo alde-
Intramolecular Baylis–Hillman ring closures using dieno-
hyde 5 in tetrahydrofuran was added to the nickel
ate 7 were examined under a variety of conditions
solution, turning the yellow solution orange, followed by
(Scheme 7), including the use of triphenyl- and tribu-
the addition of methyl acrylate (2 equiv). To the resulting
tylphosphane, 1,4-diazabicyclo[2.2.2]octane, and the an-
deep red solution, dimethylzinc (1.0 M soln, 2 equiv) was
ion of thiophenol, none of which generated the desired
added and the reaction mixture was stirred at 23 °C, tran-
macrocycle. Intermolecular examples of the reaction with
sitioning the color to brown after 30 minutes. This proce-
dienoates have been shown previously.27
In addition to the typical nucleophiles used in the reaction,
Me
Me
Me
methyl acrylate
Pd(OAc)2, Ph3P
Et3N, TBAB
the tertiary alkoxide of 7, anion 23, was examined in an ef-
fort to promote the ring closure (Scheme 8). Attempts at
macrocyclization using this approach did not succeed;
only the conjugate addition product (protio quench of an-
ion 24) was isolated.
H
H
OH
DMF, 100 °C
61%
Me
OTBS
OH
Br
21
Me
OTBS
Me
O
OMe
22
1. HFn•py
THF, 23 °C
2. DMP
CH2Cl2, 23 °C
2 steps 82%
Me
From the same scaffold, a reductive aldol pathway was in-
vestigated. Copper hydride reagents were examined to in-
duce conjugate reduction of the dienoate 7, which would
provide an enolate that could be used to engage the
aldehyde in an intramolecular aldol reaction.28,29 Use of
Stryker’s reagent gave no reaction. Switching to the same
copper hydride/phosphane system used earlier (see
Scheme 4), conjugate reduction was effected but the de-
sired accompanying cyclization did not occur, only reduc-
tion of the aldehyde to form alcohol 28 after prolonged
reaction (Scheme 9).
1. TBAF
THF, 23 °C
2. DMP
CH2Cl2, 0 °C
2 steps 79%
Me
H
CHO
OH
H
Me
CHO
O
Br
OH
Me
Me
5
Me
In summary, we have reported an efficient route to con-
struct the cyclopentane ring of (–)-stolonidiol and all of
the carbons of the natural product with appropriate func-
tionalization. The use of boron trifluoride–diethyl ether
complex to promote the silylcuprate-mediated cyclization
of epoxyalkyne 13 was key in accessing the cyclization
precursors. With access to the key intermediates for mac-
rocyclizations, 5 and 7, the strategies employed to date
have failed to successfully form the large 11-membered
ring. Future efforts using these same types of substrates
will employ related aldol and Horner–Wadsworth–
Emmons strategies for the late-stage cyclizations.
OMe
7
Scheme 5 Synthesis of the cyclization precursors bromo aldehyde 5
and dienoate 7
Me
methyl
Me
acrylate
Ni(cod)2
additive
H
H
OH
CHO
Me
OH
HO
Me
Br
Me
Me
O
MeO
5
6
All reactions were run under an atmosphere of argon or nitrogen us-
ing anhydrous conditions, unless otherwise indicated. Toluene,
CH2Cl2, Et2O, and THF were purified using a solvent purification
system. All other reagents were used directly from the supplier
without further purification, unless noted. Analytical thin-layer
chromatography (TLC) was carried out using commercial 0.2-mm
silica gel plates (silica gel 60, F254, EMD Chemicals). Infrared
spectra were recorded using neat thin-film technique. High-resolu-
tion mass spectra (HRMS) are reported as m/z; accurate masses are
reported for the molecular ion [M + Na]+, [M + H]+, or [M+]. Nucle-
ar magnetic resonance spectra (1H and 13C NMR) were recorded at
400 MHz (1H) and 100 MHz (13C). For CDCl3 the chemical shifts
are reported as parts per million (ppm) referenced to residual proti-
um or carbon of the solvent: CHCl3, δ H (7.26 ppm); CDCl3, δ C
(77.0 ppm). Coupling constants are reported in hertz (Hz). Data for
1H NMR spectra are reported as follows: chemical shift (ppm, ref-
Scheme 6 Attempted nickel-catalyzed conjugate addition/intramolec-
ular aldol reaction of bromo aldehyde 5
Me
Me
various
conditions
H
H
CHO
O
OH
OH
Me
Me
HO
Me
Me
O
OMe
MeO
7
8
Scheme 7 Attempted Baylis–Hillman macrocyclization of dienoate 7
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2770–2778

2774
T. Barton, D. Siegel
PAPER
Me
O
Me
O
Me
Me
Me
RO–
H
H
H
H
CHO
O
CHO
O
CHO
Me
O–
Me
OH
Me
Me
Me
–O
Me
Me
O
OMe
O
OMe
MeO
OMe
7
23
24
25
Me
Me
Me
O
Me
ROH
H
H
H
Me
O–
OH
Me
–
Me
HO
HO
HO
Me
Me
O
O
O
MeO
MeO
MeO
8
27
26
Scheme 8 Proposed internal-alkoxide-induced Baylis–Hillman macrocyclization of 7
Me
Me
Me
Cu(OAc)2•H2O
PMHS, BDPPB
H
H
H
CHO
O
OH
Me
OH
OH
toluene, 23 °C
Me
HO
Me
HO
O
Me
Me
Me
O
MeO
OMe
28
OMe
6
7
Scheme 9 Conjugate reduction/aldol cyclization strategy
erenced to protium), multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, dd = doublet of doublets, td = triplet of doublets, m =
multiplet), coupling constant (in Hz), integration.
tert-Butyl{[(R)-2-{2-[(R)-3,3-dimethyloxiran-2-yl]ethyl}-2-
methylbut-3-yn-1-yl]oxy}dimethylsilane (13)
Alkyne 11 (3.04 g, 10.8 mmol, 1.0 equiv) dissolved in dimethoxy-
methane–MeCN (2:1, 160 mL) was added to a 3-neck 1-L flask, fol-
lowed by aq Na2B4O7 soln (0.5 M with 4 mM Na2EDTA, 105 mL),
solid Bu4NHSO4 (0.294 g, 0.867 mmol, 0.08 equiv), and the Shi cat-
alyst 12 (3.08 g, 11.9 mmol, 1.1 equiv). Then Oxone® (16.66 g, 27.1
mmol, 2.5 equiv) dissolved in a 4 mM Na2EDTA soln (100 mL) in
one addition funnel, and K2CO3 (14.98 g, 108 mmol, 10.0 equiv) in
H2O (100 mL) in a second addition funnel, were added simultane-
ously at 0 °C over 1.5 h. After the addition, the reaction mixture was
diluted with pentane (300 mL) and H2O (300 mL). The organic
phase was collected and the aqueous layer was extracted with pen-
tane (2 × 250 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure; NMR
spectroscopy showed a 9:1 ratio of diastereomers. The crude mate-
rial was purified by silica gel chromatography (hexanes–EtOAc,
99:1 to hexanes–EtOAc, 95:5) to afford 13 as a clear, colorless oil;
yield: 2.79 g (86%).
tert-Butyl{[(R)-2-ethynyl-2,6-dimethylhept-5-en-1-yl]oxy}di-
methylsilane (11)
The aldehyde 914 (3.66 g, 12.86 mmol, 1.0 equiv) was dissolved in
anhyd MeOH (120 mL) and the solution was cooled to 0 °C. Solid
K2CO3 (4.44 g, 32.2 mmol, 2.5 equiv) was added, followed by neat
Bestmann–Ohira reagent (dimethyl 1-diazo-2-oxopropylphospho-
nate, 10) (3.70 g, 19.3 mmol, 1.5 equiv). The reaction mixture was
allowed to warm to 23 °C and was stirred for 14 h. Over this period
the solution changed from a clear yellow to green. The reaction mix-
ture was poured into pentane (200 mL), and the organic layer was
separated and washed with H2O (400 mL) then brine (200 mL). The
organic extract was dried (Na2SO4) and concentrated under reduced
pressure. The crude material was purified by silica gel chromatog-
raphy (hexanes–EtOAc, 100:1) to provide 11 as a clear oil; yield:
3.20 g (91%).
Rf = 0.73 (hexanes–EtOAc, 9:1).
IR (neat): 2111, 1103, 851 cm–1.
Rf = 0.42 (hexanes–EtOAc, 9:1).
IR (neat): 1251, 1100 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.07 (t, J = 8.6 Hz, 1 H), 3.49 (d,
J = 9.4 Hz, 1 H), 3.41 (d, J = 9.4 Hz, 1 H), 2.08–2.02 (m, 2 H), 2.03
(s, 1 H), 1.63 (s, 3 H), 1.57 (s, 3 H), 1.51–1.44 (m, 1 H), 1.35–1.27
(m, 1 H), 1.12 (s, 3 H), 0.84 (s, 9 H), 0.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 131.5, 124.5, 89.2, 69.5, 69.4,
37.2, 25.9, 25.7, 23.8, 23.6, 18.4, 17.7, –5.3.
1H NMR (400 MHz, CDCl3): δ = 3.55 (d, J = 9.5 Hz, 1 H), 3.46 (d,
J = 9.5 Hz, 1 H), 2.73 (t, J = 6.1 Hz, 1 H), 2.09 (s, 1 H), 1.74–1.55
(m, 4 H), 1.31 (s, 3 H), 1.28 (s, 3 H), 1.17 (s, 3 H), 0.89 (s, 9 H), 0.05
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 88.6, 69.9, 69.5, 64.5, 58.4, 37.1,
33.6, 25.9, 25.0, 24.7, 23.6, 18.7, 18.3, –5.3.
HRMS (EC-CI+): m/z [M – H]+ calcd for C17H31OSi: 279.2144;
found: 279.2148.
HRMS (EC-CI+): m/z [M + H]+ calcd for C17H33O2Si: 297.2250;
found: 297.2251.
Synthesis 2012, 44, 2770–2778
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acrylate Lynchpin Approach toward the Synthesis of Stolonidiol
2775
Dimethyl(phenyl)silyllithium20c
1H NMR (400 MHz, CDCl3): δ = 7.51–7.49 (m, 2 H), 7.31–7.30 (m,
3 H), 5.51 (s, 1 H), 3.34 (d, J = 10.2 Hz, 1 H), 3.24 (d, J = 9.2 Hz, 1
H), 2.32–2.30 (m, 1 H), 1.85–1.81 (m, 1 H), 1.74–1.70 (m, 2 H),
1.58–1.53 (m, 1 H), 1.14 (s, 3 H), 1.11 (s, 3 H), 1.03 (s, 3 H), 0.89
(s, 9 H), 0.34 (s, 3 H), 0.33 (s, 3 H), 0.05 (s, 9 H), 0.02 (s, 3 H), 0.01
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 140.2, 133.9, 128.7, 127.6,
118.7, 76.6, 72.8, 56.2, 49.6, 34.7, 30.3, 30.3, 30.2, 26.9, 26.0, 23.7,
18.4, 2.7, –0.5, –0.6, –5.4.
A 50-mL flask equipped with a large stir bar was dried in an oven
overnight. Lithium wire (0.540 g, 78.0 mmol, 2.0 equiv) was cut
into 0.5-cm sections and added to the flask. The flask was then
equipped with septa, evacuated, and backfilled with argon three
times before placing the contents under argon. Anhyd THF (30 mL)
was added to the flask which was placed in a 0 °C bath before
PhMe2SiCl (6.0 mL, 39 mmol, 1.0 equiv) was added. After 15 min
of stirring, the clear solution developed a red color. After 30 min,
the solution obtained a dark red color. The flask was stirred at 0 °C
for 2 h then placed in a –4 °C freezer to stand for 12 h. Such a solu-
tion proved stable at –4 °C for 2–3 weeks maintaining a titer of 0.5
M.
HRMS (ESI+): m/z [M + Na]+ calcd for C28H52O2Si3Na: 527.3181;
found: 527.3169.
{[(1R,3R,E)-2-(Bromomethylene)-1-methyl-3-{2-[(trimethylsi-
lyl)oxy]propan-2-yl}cyclopentyl]methoxy}(tert-butyl)dimethyl-
silane (17)
2-[(1R,3R,E)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-{[di-
methyl(phenyl)silyl]methylene}-3-methylcyclopentyl]propan-
2-ol (15)
The vinylsilane (3.92 g, 7.76 mmol, 1.0 equiv) was dissolved in
MeCN–CH2Cl2 (20:1, 78 mL) and solid NBS (2.76 g, 15.5 mmol,
2.0 equiv) was added in a single portion. The reaction mixture was
stirred at 23 °C for 2 h and excess NBS was quenched with sat. aq
Na2S2O3 soln (50 mL) and sat. aq NaHCO3 soln (50 mL). The or-
ganic layer was collected and the aqueous layer was extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed
with brine (150 mL), dried (Na2SO4), and concentrated under re-
duced pressure. The crude material was purified by silica gel chro-
matography (hexanes) to provide 17 as a pale yellow oil; yield: 3.21
g (92%).
Solid CuCN (1.04 g, 11.6 mmol, 1.15 equiv) was added to a flame-
dried flask then purged with argon and flame-dried again under re-
duced pressure. The CuCN was suspended in THF (90 mL) and the
flask was placed in a 0 °C bath. Dimethyl(phenyl)silyllithium (0.5
M in THF; 46.6 mL, 23.3 mmol, 2.3 equiv) was added via syringe.
The reaction mixture was allowed to stir at 0 °C until all the CuCN
had dissolved (indicated by the red color from PhMe2SiLi turning
to a darker red-brown opaque solution, ~20 min). The reaction mix-
ture was cooled to –78 °C, and epoxyalkyne 13 (3.0 g, 10.1 mmol,
1.0 equiv) was added as a solution in THF (20 mL) via cannula. The
reaction mixture was warmed to 0 °C and allowed to stir for 2 h.
Neat BF3·OEt2 (3.73 mL, 30.4 mmol, 3.0 equiv) was added and the
mixture was allowed to stir for 12 h, then poured into sat. NH4Cl
soln (100 mL) and extracted with Et2O (2 × 100 mL). The combined
organic extracts were washed with brine (150 mL), dried (Na2SO4),
and concentrated under reduced pressure. The crude material was
purified by silica gel chromatography (hexanes–EtOAc, 99:1 to
hexanes–EtOAc, 95:5) to provide 15 as a yellow oil; yield: 3.68 g
(84%).
Rf = 0.76 (hexanes).
IR (neat): 1612, 1250, 1106, 1030, 837 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.18 (d, J = 1.3 Hz, 1 H), 3.30 (d,
J = 11.3 Hz, 1 H), 3.29 (d, J = 11.6 Hz, 1 H), 2.69 (d, J = 8.2 Hz, 1
H), 1.95–1.83 (m, 2 H), 1.73–1.59 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3
H), 1.12 (s, 3 H), 0.88 (s, 9 H), 0.11 (s, 9 H), 0.027 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 156.5, 101.8, 78.2, 77.3, 71.7,
57.2, 49.6, 36.9, 30.5, 30.4, 26.8, 25.9, 24.1, 18.3, 2.7, –5.3, –5.4.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H41BrO2Si2Na:
471.1741; found: 471.1726.
Rf = 0.52 (hexanes–EtOAc, 9:1).
IR (neat): 1599, 1249, 1093 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 6.2, 2.7 Hz, 2 H),
7.32–7.30 (m, 3 H), 5.62 (d, J = 1.5 Hz, 1 H), 3.28 (d, J = 9.3 Hz, 1
H), 3.14 (d, J = 9.3 Hz, 1 H), 2.65 (dd, J = 8.2, 1.2 Hz, 1 H), 1.87–
1.79 (m, 2 H), 1.47–1.44 (m, 2 H), 1.13 (s, 3 H), 1.05 (s, 3 H), 0.98
(s, 3 H), 0.87 (s, 9 H), 0.41 (s, 3 H), 0.35 (s, 3 H), 0.01 (s, 3 H), 0.00
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.0, 140.4, 133.8, 128.7, 127.8,
121.7, 72.7, 72.5, 54.8, 50.5, 34.6, 29.1, 27.4, 27.2, 26.0, 23.0, 18.3,
–0.3, –1.2, –5.4.
2-[(1R,3R,E)-2-(Bromomethylene)-3-(hydroxymethyl)-3-meth-
ylcyclopentyl]propan-2-ol
Vinyl bromide 17 (1.0 g, 2.24 mmol, 1.0 equiv) was dissolved in
THF (22 mL) at 23 °C and 1.0 M TBAF in THF (5.56 mL, 5.56
mmol, 2.5 equiv) was added in a single portion. The reaction mix-
ture was stirred for 18 h, then diluted with sat. aq NH4Cl soln (30
mL). The mixture was extracted with EtOAc (2 × 30 mL) and the
combined organic layers were washed with brine (100 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude ma-
terial was purified by silica gel chromatography (hexanes–EtOAc,
9:1 to hexanes–EtOAc, 4:1) to provide the diol as a viscous, clear
yellow oil; yield: 0.574 g (98%).
HRMS (EC-CI+): m/z [M + H]+ calcd for C25H45O2Si2: 433.2958;
found: 433.2958.
tert-Butyl{[(1R,3R,E)-2-{[dimethyl(phenyl)silyl]methylene}-1-
methyl-3-{2-[(trimethylsilyl)oxy]propan-2-yl}cyclopentyl]-
methoxy}dimethylsilane
Rf = 0.31 (hexanes–EtOAc, 1:1).
IR (neat): 3370, 1611, 1037, 949 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.22 (d, J = 1.7 Hz, 1 H), 3.45 (d,
J = 10.9 Hz, 1 H), 3.37 (d, J = 10.9 Hz, 1 H), 2.93 (dd, J = 6.1, 1.4
Hz, 1 H), 1.89–1.77 (m, 4 H), 1.38 (s, 3 H), 1.28 (s, 3 H), 1.19 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 102.4, 75.1, 71.7, 55.9, 49.9,
36.8, 30.0, 28.9, 27.1, 23.7.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H19BrO2Na: 285.0441;
found: 285.0463.
To a soln of the tertiary alcohol 15 (3.50 g, 8.09 mmol, 1.0 equiv)
in CH2Cl2 (80 mL) was added 2,6-luitdine (5.65 mL, 48.5 mmol, 6.0
equiv) and the solution was cooled to –78 °C in a dry ice–acetone
bath. Neat TMSOTf (4.38 mL, 24.2 mmol, 3.0 equiv) was then add-
ed dropwise via syringe and the reaction mixture was stirred for 30
min before the cooling bath was removed and the solution was al-
lowed to warm to 23 °C. Excess TMSOTf was quenched by the ad-
dition of MeOH (5 mL) and the mixture was concentrated under
reduced pressure. The crude material was purified by silica gel
chromatography (hexanes) to provide the TMS ether as a clear, col-
orless oil; yield: 3.92 g (96%).
(1R,3R,E)-2-(Bromomethylene)-3-(2-hydroxypropan-2-yl)-1-
methylcyclopentanecarbaldehyde (18)
The diol (0.480 g, 1.82 mmol, 1.0 equiv) was dissolved in CH2Cl2
(20 mL) and cooled to 0 °C. Solid NaHCO3 (0.460 g, 5.47 mmol,
3.0 equiv) was added followed by Dess–Martin periodinane (0.851
g, 2.00 mmol, 1.1 equiv) in portions over 30 min. After an addition-
Rf = 0.82 (hexanes).
IR (neat): 1604, 1250, 1033, 837 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2770–2778

2776
T. Barton, D. Siegel
PAPER
al 30 min, the excess periodinane was quenched by addition of sat.
aq Na2S2O3 soln (20 mL) followed by 10 min of vigorous stirring.
The mixture was extracted with CH2Cl2 (2 × 20 mL) and the com-
bined organic extracts were washed with brine (50 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude ma-
terial was purified by silica gel chromatography (hexanes–EtOAc,
20:1 to hexanes–EtOAc, 10:1) to provide 18 as a viscous, clear yel-
low oil; yield: 0.438 g (92%).
Rf = 0.52 (hexanes–EtOAc, 4:1).
IR (neat): 3480, 1713, 1257, 1096, 836 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.10 (d, J = 1.7 Hz, 1 H), 3.61 (t,
J = 6.1 Hz, 2 H), 2.90–2.88 (m, 1 H), 2.48 (t, J = 7.5 Hz, 2 H), 2.44–
2.28 (m, 2 H), 1.86–1.56 (m, 9 H), 1.37 (s, 3 H), 1.27 (s, 3 H), 1.17
(s, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 210.9, 157.2, 102.8, 74.9, 62.2,
55.6, 47.5, 39.2, 39.0, 38.1, 37.7, 30.4, 29.1, 27.8, 27.1, 26.9, 26.0,
18.4, –5.2.
Rf = 0.44 (hexanes–EtOAc, 1:1).
IR (neat): 3481, 1722, 1684, 1094 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 1 H), 6.11 (s, 1 H), 2.92
(d, J = 7.8 Hz, 1 H), 2.17–2.12 (m, 1 H), 2.06–1.97 (m, 2 H), 1.81–
1.77 (m, 1 H), 1.39 (s, 3 H), 1.31 (s, 3 H), 1.30 (s, 3 H).
HRMS (ESI+): m/z [M + H]+ calcd for C22H42BrO3Si: 461.2081;
found: 461.2083.
2-[(1R,3S,E)-2-(Bromomethylene)-3-{6-[(tert-butyldimethylsi-
lyl)oxy]-3-methylenehexyl}-3-methylcyclopentyl]propan-2-ol
(21)
13C NMR (100 MHz, CDCl3): δ = 198.8, 151.2, 105.8, 74.7, 58.7,
55.0, 34.6, 30.5, 29.4, 27.6, 20.7.
Solid methyltriphenylphosphonium bromide (0.495 g, 1.38 mmol,
5.0 equiv) was suspended in THF (2.0 mL) at 23 °C and 1.8 M n-
BuLi in hexanes (0.755 mL, 1.36 mmol, 4.9 equiv) was added. A
color change to bright red was observed and the reaction mixture
became homogeneous over 20 min. To this clear red-yellow solu-
tion, the ketone (0.128 g, 0.277 mmol, 1.0 equiv) in THF (1 mL)
was added dropwise. During addition the reaction mixture became
opaque. After the mixture was stirred for 12 h, excess anion was
quenched by careful addition of sat. aq NH4Cl soln (10 mL) and the
resulting mixture was extracted with EtOAc (3 × 10 mL). The com-
bined organic extracts were washed with brine (20 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude ma-
terial was purified by silica gel chromatography (hexanes–EtOAc,
10:1) to provide 21 as a clear yellow oil; yield: 0.092 g (72%).
HRMS (CI+): m/z [M – OH]+ calcd for C11H16BrO: 243.0385;
found: 243.0388.
(E)-1-[(1S,3R,E)-2-(Bromomethylene)-3-(2-hydroxypropan-2-
yl)-1-methylcyclopentyl]-6-[(tert-butyldimethylsilyl)oxy]hex-1-
en-3-one (20)
The ketophosphonate 1923 (0.560 g, 1.72 mmol, 1.5 equiv) was dis-
solved in toluene (10.0 mL) and 1.0 M LiHMDS in toluene (1.72
mL, 1.72 mmol, 1.5 equiv) was added. The mixture was stirred for
20 min then aldehyde 18 (0.300 g, 1.14 mmol, 1.0 equiv) was added
at 23 °C as a solution in toluene (1.0 mL). The reaction mixture was
placed in a 100 °C oil bath for 18 h. After cooling, the mixture was
diluted with sat. aq NH4Cl soln (20 mL) and extracted with EtOAc
(2 × 20 mL). The combined organic extracts were washed with
brine (50 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude material was purified by silica gel chromatog-
raphy (hexanes–EtOAc, 20:1 to hexanes–EtOAc, 10:1) to provide
20 as a viscous, clear yellow oil; yield: 0.407 g (77%).
Rf = 0.78 (hexanes–EtOAc, 4:1).
IR (neat): 3472, 1644, 1613, 1256, 1101, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.10 (d, J = 1.7 Hz, 1 H), 4.70 (s,
2 H), 3.60 (t, J = 6.5 Hz, 2 H), 2.91–2.89 (m, 1 H), 2.07–1.50 (m, 12
H), 1.37 (s, 3 H), 1.27 (s, 3 H), 1.18 (s, 3 H), 0.89 (s, 9 H), 0.05 (s,
6 H).
Rf = 0.47 (hexanes–EtOAc, 4:1).
IR (neat): 3488, 1666, 1617, 1256, 1099, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.79 (d, J = 16.0 Hz, 1 H), 6.07 (d,
J = 15.7 Hz, 1 H), 6.00 (d, J = 1.7 Hz, 1 H), 3.63 (t, J = 6.2 Hz, 2
H), 2.91–2.89 (m, 1 H), 2.63 (t, J = 7.1 Hz, 1 H), 2.04–1.75 (m, 6
H), 1.61 (s, 1 H), 1.38 (s, 3 H), 1.38 (s, 3 H), 1.30 (s, 3 H), 0.88 (s,
9 H), 0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 200.8, 155.4, 153.7, 124.7, 105.8,
74.6, 62.2, 55.0, 50.5, 39.9, 37.0, 30.6, 29.3, 27.5, 27.0, 26.0, 24.1,
18.3, –5.2.
13C NMR (100 MHz, CDCl3): δ = 157.8, 149.8, 108.8, 102.4, 75.0,
62.9, 55.7, 48.1, 43.1, 38.1, 32.4, 31.7, 31.0, 30.4, 28.9, 27.8, 27.2,
26.0, 18.4, –5.1.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H43BrO2SiNa: 481.2110;
found: 481.2109.
6-[(1S,3R,E)-2-(Bromomethylene)-3-(2-hydroxypropan-2-yl)-
1-methylcyclopentyl]-4-methylenehexan-1-ol
Vinyl bromide 21 (15 mg, 0.033 mmol, 1.0 equiv) was dissolved in
THF (0.500 mL) at 23 °C and 1.0 M TBAF in THF (0.050 mL, 0.05
mmol, 1.5 equiv) was added. The reaction mixture was stirred for 2
h and diluted with 1 M pH 7 phosphate buffer (10 mL). The result-
ing solution was extracted with EtOAc (2 × 5 mL) and the com-
bined organic extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude ma-
terial was purified by silica gel chromatography (hexanes–EtOAc,
9:1 to hexanes–EtOAc, 4:1) to provide the diol as a viscous, clear
yellow oil; yield: 10 mg (89%).
HRMS (ESI+): m/z [M + H]+ calcd for C22H40BrO3Si: 459.1946;
found: 459.1928.
1-[(1S,3R,E)-2-(Bromomethylene)-3-(2-hydroxypropan-2-yl)-
1-methylcyclopentyl]-6-[(tert-butyldimethylsilyl)oxy]hexan-3-
one
Solid Cu(OAc)2·H2O (4.34 mg, 5 mol%) and 1,2-bis(diphe-
nylphosphino)benzene (9.72 mg, 5 mol%) were combined in a flask
equipped with a septum and the flask was evacuated and backfilled
with argon three times; then, the solids were suspended in toluene
(2 mL) at 23 °C. t-BuOH (0.062 mL, 0.653 mmol, 1.5 equiv) was
added to the heterogeneous mixture which was allowed to stir until
a faint blue color persisted. Neat polymethylhydrosiloxane (0.041
mL, 0.653 mmol, 1.5 equiv) was added and the reaction mixture
was stirred until it turned bright yellow. At this point the reaction
mixture became homogeneous. Enone 20 (0.200 g, 0.435 mmol, 1.0
equiv) was added as a solution in toluene (2 mL) and the reaction
mixture was stirred for 18 h. After concentration under reduced
pressure, the crude material was purified by silica gel chromatogra-
phy (hexanes–EtOAc, 9:1) to provide the desired ketone as a clear,
pale yellow oil; yield: 0.128 g (64%).
Rf = 0.42 (hexanes–EtOAc, 1:1).
IR (neat): 3393, 1643, 1613, 1383, 1057 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.10 (d, J = 1.7 Hz, 1 H), 4.73 (s,
2 H), 3.66 (t, J = 6.5 Hz, 2 H), 2.91–2.89 (m, 1 H), 2.11–1.91 (m, 4
H), 1.84–1.66 (m, 6 H), 1.58–1.48 (m, 2 H), 1.37 (s, 3 H), 1.27 (s, 3
H), 1.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.7, 149.6, 109.0, 102.3, 74.9,
62.7, 55.6, 48.0, 43.0, 38.1, 32.4, 31.5, 30.7, 30.3, 28.9, 27.8, 27.1.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H29BrO2Na: 367.1250;
found: 367.1246.
Synthesis 2012, 44, 2770–2778
© Georg Thieme Verlag Stuttgart · New York

PAPER
Acrylate Lynchpin Approach toward the Synthesis of Stolonidiol
2777
6-[(1S,3R,E)-2-(Bromomethylene)-3-(2-hydroxypropan-2-yl)-
1-methylcyclopentyl]-4-methylenehexanal (5)
stirred for 8 h. Sat. aq NaHCO3 soln (3 mL) was carefully added to
the reaction mixture. The resulting mixture was then extracted with
EtOAc (3 × 5 mL). The combined organic layers were washed with
brine (15 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude material was purified by silica gel chromatog-
raphy (hexanes–EtOAc, 4:1 to hexanes–EtOAc, 1:1) to provide the
diol as a pale yellow oil; yield: 29 mg (98%).
The diol (10 mg, 0.029 mmol, 1.0 equiv) was dissolved in CH2Cl2
(0.500 mL) and the flask was placed in a 0 °C bath. Solid NaHCO3
(7 mg, 0.087 mmol, 3.0 equiv) was then added. Dess–Martin peri-
odinane (14 mg, 0.032 mmol, 1.1 equiv) was added as a solid in a
single portion. After 30 min of stirring, excess periodinane was
quenched by addition of sat. aq Na2S2O3 soln (2 mL) followed by
10 min of vigorous stirring. The mixture was extracted with CH2Cl2
(2 × 5 mL) and the combined organic extracts were washed with
brine (15 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude material was purified by silica gel chromatog-
raphy (hexanes–EtOAc, 9:1 to hexanes–EtOAc, 4:1) to provide 5 as
a viscous, clear yellow oil; yield: 8.6 mg (60%).
Rf = 0.25 (hexanes–EtOAc, 1:1).
IR (neat): 3420, 1717, 1700, 1628, 1275, 1145 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J = 15.0, 11.2 Hz, 1 H),
6.19 (d, J = 11.2 Hz, 1 H), 5.80 (d, J = 15.0 Hz, 1 H), 4.71 (s, 2 H),
3.72 (s, 3 H), 3.64 (t, J = 6.5 Hz, 2 H), 3.05 (t, J = 4.1 Hz, 1 H), 2.09–
1.96 (m, 3 H), 1.89–1.76 (m, 3 H), 1.71–1.64 (m, 4 H), 1.51–1.45
(m, 2 H), 1.29 (s, 3 H), 1.18 (s, 3 H), 1.16 (s, 3 H).
Rf = 0.69 (hexanes–EtOAc, 1:1).
IR (neat): 3433, 1721, 1643, 1266, 1094 cm–1.
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.0, 149.6, 144.0, 122.8,
118.6, 109.0, 74.1, 62.7, 54.0, 51.4, 46.8, 42.9, 36.8, 32.4, 31.5,
30.6, 30.0, 28.4, 27.4, 26.7.
HRMS (ESI+): m/z [M + Na]+ calcd for C21H34O4Na: 373.2349;
found: 373.2349.
1H NMR (400 MHz, CDCl3): δ = 9.78 (t, J = 1.3 Hz, 1 H), 6.10 (d,
J = 1.3 Hz, 1 H), 4.78 (s, 1 H), 4.69 (s, 1 H), 2.91–2.89 (m, 1 H),
2.57 (dt, J = 7.5, 1.3 Hz, 2 H), 2.34 (t, J = 7.5 Hz, 2 H), 2.01–1.67
(m, 6 H), 1.56–1.52 (m, 2 H), 1.37 (s, 3 H), 1.27 (s, 3 H), 1.18 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 202.0, 157.6, 147.9, 109.4, 102.3,
74.8, 55.6, 48.0, 42.9, 41.8, 38.1, 31.9, 30.3, 28.9, 28.2, 27.8, 27.1.
Methyl (2E,4E)-4-[(2S,5R)-5-(2-Hydroxypropan-2-yl)-2-meth-
yl-2-(3-methylene-6-oxohexyl)cyclopentylidene]but-2-enoate
(7)
HRMS (ESI+): m/z [M + Na + H]+ calcd for C17H27BrO2Na:
366.1128; found: 366.1121.
To a soln of the diol (15 mg, 0.043 mmol, 1.0 equiv) in CH2Cl2
(0.500 mL) at 23 °C was added solid NaHCO3 (14 mg, 0.171 mmol,
4.0 equiv) in a single portion. Solid Dess–Martin periodinane (20
mg, 0.047 mmol, 1.1 equiv) was added in small portions over 20
min. After 10 min, the reaction mixture was diluted with sat. aq
Na2S2O3 soln (5 mL) followed by 10 min of vigorous stirring. The
mixture was extracted with CH2Cl2 (3 × 5 mL) and the combined
organic extracts were washed with brine (15 mL), dried (Na2SO4),
and concentrated under reduced pressure. The crude material was
purified by silica gel chromatography (hexanes–EtOAc, 9:1 to hex-
anes–EtOAc, 4:1) to provide 7 as a viscous, clear yellow oil; yield:
12 mg (83%).
Methyl (2E,4E)-4-[(2S,5R)-2-{6-[(tert-Butyldimethylsilyl)oxy]-
3-methylenehexyl}-5-(2-hydroxypropan-2-yl)-2-methylcyclo-
pentylidene]but-2-enoate (22)
To a soln of vinyl bromide 21 (0.120 g, 0.263 mmol, 1.0 equiv) in
DMF (2.0 mL), Ph3P (14 mg, 0.052 mmol, 0.2 equiv), TBAB (84
mg, 0.263 mmol, 1.0 equiv), methyl acrylate (0.237 mL, 2.61 mmol,
10.0 equiv), and Et3N (0.294 mL, 2.08 mmol, 8.0 equiv) were add-
ed. The reaction mixture was sparged with argon and stirred for 20
min. Solid Pd(OAc)2 (12 mg, 0.052 mmol, 0.20 equiv) was added
and the reaction mixture was sparged with argon again; the flask
was placed in an oil bath heated to 100 °C for 16 h. The mixture was
cooled and diluted with H2O (10 mL), then extracted with EtOAc
(10 mL). The organic layer was washed with brine (4 × 15 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude material was purified by silica gel chromatography (hexanes–
EtOAc, 20:1 to hexanes–EtOAc, 4:1) to provide 22 as a clear yellow
oil; yield: 74 mg (61%).
Rf = 0.38 (hexanes–EtOAc, 1:1).
IR (neat): 3489, 1717, 1629, 1604, 1274, 1143 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.76 (t, J = 1.7 Hz, 1 H), 7.69 (dd,
J = 15.0, 11.2 Hz, 1 H), 6.19 (dd, J = 11.2, 1.7 Hz, 1 H), 5.80 (d, J =
15.0 Hz, 1 H), 4.75 (s, 1 H), 4.67 (s, 1 H), 3.72 (s, 3 H), 3.06–3.04
(m, 1 H), 2.55 (dt, J = 7.5, 1.7 Hz, 2 H), 2.32 (t, J = 7.5 Hz, 2 H),
2.04–1.96 (m, 1 H), 1.89–1.83 (m, 1 H), 1.81–1.75 (m, 1 H), 1.70–
1.66 (m, 1 H), 1.52–1.48 (m, 4 H), 1.29 (s, 3 H), 1.19 (s, 3 H), 1.17
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 202.0, 167.9, 165.8, 147.9, 143.9,
122.8, 118.7, 109.4, 74.2, 54.0, 51.4, 46.7, 42.8, 41.8, 36.8, 31.9,
30.0, 28.4, 28.1, 27.3, 26.7.
Rf = 0.28 (hexanes–EtOAc, 4:1).
IR (neat): 3468, 1719, 1705, 1629, 1604, 1100, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J = 15.0, 11.2 Hz, 1 H),
6.19 (dd, J = 11.2, 1.4 Hz, 1 H), 5.79 (d, J = 15.0 Hz, 1 H), 4.68 (s,
2 H), 3.72 (s, 3 H), 3.59 (t, J = 6.5 Hz, 2 H), 3.06–3.03 (m, 1 H),
2.04–1.91 (m, 3 H), 1.84–1.76 (m, 3 H), 1.69–1.57 (m, 4 H), 1.51–
1.46 (m, 2 H), 1.29 (s, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H), 0.89 (s, 9
H), 0.04 (s, 6 H).
HRMS (CI+): m/z [M + H]+ calcd for C21H33O4: 349.2379; found:
349.2373.
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.1, 149.8, 144.1, 122.9,
118.7, 108.7, 77.3, 74.2, 62.8, 54.1, 51.5, 46.9, 43.0, 36.8, 32.4,
31.7, 31.0, 30.1, 28.5, 27.4, 26.8, 26.0, 18.4, –5.1.
HRMS (ESI+): m/z [M + Na]+ calcd for C27H48O4SiNa: 487.3214;
found: 487.3214.
Acknowledgment
The authors are grateful for the financial support of the Robert A.
Welch Foundation (F-1694), the Texas Institute of Diagnostic and
Drug Development (H-F-0032), and The University of Texas at
Austin. T.B. acknowledges financial assistance from the Myasthe-
nia Gravis Foundation of America.
Methyl (2E,4E)-4-[(2S,5R)-2-(6-Hydroxy-3-methylenehexyl)-5-
(2-hydroxypropan-2-yl)-2-methylcyclopentylidene]but-2-eno-
ate
To a soln of TBS ether 22 (40 mg, 0.086 mmol, 1.0 equiv) in THF
(1.0 mL) at 23 °C was slowly added neat HF·py (70% HF; 0.039
mL, 0.430 mmol, 5.0 equiv) and the resulting cloudy solution was
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2770–2778

2778
T. Barton, D. Siegel
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Synthesis 2012, 44, 2770–2778
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