Ti(III)-Mediated Radical-Induced Approach to a Bicyclic δ-Lactone with a Bridgehead β-Hydroxy Group

Article abstract of DOI:10.1055/s-0037-1609586

Herein, we portray a synthetic route to a bicyclic lactone containing a bridgehead hydroxy group, a structure that is present in many natural products of biological and medicinal relevance. Ethyl (E)-3-(dimethylphenylsilyl)-7,8-epoxyoct-2-enoate underwent

Full text of DOI:10.1055/s-0037-1609586

SYNTHESIS
0
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1
1
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
special topic
A
en
D. Das et al.
Special Topic
Synthesis
Ti(III)-Mediated Radical-Induced Approach to a Bicyclic δ-Lactone
with a Bridgehead β-Hydroxy Group
Dipendu Das
H
H
Tamao–Fleming
Hina P. A. Khan
CO2Et
Cp2TiCl
oxidation (R = Ph)
O
O
Tushar Kanti Chakraborty*
O
O
SiMe2R
Department of Organic Chemistry, Indian Institute of Science,
Bengaluru 560012, India
tushar@iisc.ac.in
OH
SiMe2R
both E & Z-isomers
R = Me, Ph
Published as part of the Special Topic Modern Radical Methods
and their Strategic Applications in Synthesis
Received: 21.06.2018
Accepted after revision: 25.06.2018
Published online: 05.07.2018
more substituted carbon.10 The designed tactic was extend-
ed later in the stereoselective construction of chiral quater-
nary stereocenters by trapping the radical intermediate
with suitable acceptors, particularly in an intramolecular
mode, to provide carbocycles,11 oxacycles,12 azacycles,13 and
dioxafenestranes.14
After successful implementation of the titanocene(III)
chemistry for the construction of quaternary centers, we
next intended to extend our iterative methodology to build
hydroxylated bridgehead chiral centers in bicyclic ring sys-
tems, structural features of various natural products and
natural product inspired synthons.15
DOI: 10.1055/s-0037-1609586; Art ID: ss-2018-c0115-st
Abstract Herein, we portray a synthetic route to a bicyclic lactone
containing a bridgehead hydroxy group, a structure that is present in
many natural products of biological and medicinal relevance. Ethyl (E)-
3-(dimethylphenylsilyl)-7,8-epoxyoct-2-enoate underwent radical-
mediated reductive epoxide opening with concomitant intramolecular
cyclization using Cp2Ti(III)Cl to give cis-6-(dimethylphenylsilyl)-3-oxabi-
cyclo[4.3.0]nonan-4-one, a bicyclic lactone with a bridgehead silyl
group serving as a masked hydroxy group. Furthermore, the bridge-
head C–Si bond underwent stereoretentive oxidative cleavage to give
cis-6-hydroxy-3-oxabicyclo[4.3.0]nonan-4-one in high yield under
Tamao–Fleming oxidation conditions; this demonstrates the potential
utility of this strategy in the synthesis of many natural products bearing
similar hydroxylated bridgehead chiral center embedded in a bicyclic
lactone framework.
O
O
O
O
H
O
O
O
O
O
O
Key words quaternary center, bridgehead hydroxy, Cp2TiCl, bicyclic
H
OH
OH
OH
lactone, radical cyclization, Tamao–Fleming oxidation
O
O
cis-hexahydrocyclopenta-
[c]pyran-3(1H)-one (1)
Picrotoxinin (2)
Picrotin (3)
The development of methodologies that employ reac-
tive species that enable the synthesis of valuable molecules
and advanced synthons owing to their unique reactivity is
of significant importance in synthetic organic chemistry. A
plethora of useful and elegant chemistry has been devel-
oped over the years using radical intermediates, despite the
accepted notion that these species are chaotic, uncontrolla-
ble, and non-stereoselective.1,2
O
O
O
H
HO
HO
O
this work
O
O
O
O
OH
OH
HO
CO2Me
O
Corianin (4)
Methyl Picrotoxate (5)
6
Figure 1 Bioactive natural products containing hydroxylated bridge-
head chiral centers in bicyclic ring systems and our designed β-hydroxy
cyclopentano lactone
In these endeavors, methods based on Cp2Ti(III)Cl3 me-
diated radical epoxide-opening reactions, first reported by
Nugent and RajanBabu,4 have been used by several research
groups, including ours, as the key step in the synthesis of
many natural products5–7 and medicinally relevant com-
pounds.8,9 We began our journey with Cp2Ti(III)Cl with the
development of an iterative synthetic strategy that allowed
the synthesis of chiral 2-methyl-1,3-diols by selective
opening of a trisubstituted chiral 2,3-epoxy alcohol at the
As the process of isolation, structure elucidation, and bi-
ological evaluation of new natural products is rather labori-
ous and time consuming, the concept of the development of
natural product hybrids and analogues, containing two or
more different pharmacophoric subunits, is being actively
pursued.16 Cyclopentano-monoterpene lactone
1 rep-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
D. Das et al.
Special Topic
Synthesis
resents one of the parent frameworks common to a large
number of plant families and in various species of Iridomyr-
mex17 known to exhibit highly excitative activity towards
cats and other Felidae animals and used by ants as agents of
defense against preying insects.18 Insertion of a bridgehead
hydroxy group into the core scaffold of 1 leads to the struc-
ture 6, which can be regarded as a biologically pre-validated
scaffold owing to the fact that many natural products based
on this hydroxylated bicyclic ring system possess a wide ar-
ray of densely functionalized structures 2–515,19 with di-
verse biological activities (Figure 1).
O
O
O
O
ref. 21
OEt
OEt
11
12
m-CPBA, CH2Cl2
0 °C to r.t., 3.5 h
87%
see
Table 1
OPG
O
O
O
O
O
OEt
OEt
13
7
Scheme 2 Preparation of the epoxide 13
Herein, we disclose the viability of the Ti(III)-mediated
reductive epoxide opening–cyclization sequence to build
hydroxylated bridgehead stereogenic centers following two
approaches summarized in Scheme 1. The direct approach
(A) employing an epoxy-β-alkoxy-α,β-unsaturated ester
was backed up by an alternate strategy (B) starting with an
epoxy-β-(triorganosilyl)-α,β-unsaturated ester in which
the silyl group could serve as a surrogate for the eventual
oxygen functionality. The stereoretentive oxidative cleavage
of the C–Si bond using the Tamao–Fleming method20 was
expected to provide a synthetic strategy to access the de-
sired bridgehead-oxygenated bicyclic ring systems (Scheme
1). We report here the full detail of our systematic study to-
ward the target scaffold.
Table 1 Attempted Preparation of the Silyl Enol Ethera
O
O
EtO2C
H
reagent
solvent
14
O
O
O
or
O
0 °C to r.t.,
12 h
OEt
TBSO
CO2Et
13
15
Entry Reagents
Solvent
Product
Yield (%)b
1
2
3
4
5
6
7
DIPEA/TBSOTf
CH2Cl2
THF
14
14
14
–
88
72
81
K2CO3/18-crown-6/TBSOTf
Et3N/TBSOTf
(A) 1st Approach:
H
H
CH2Cl2
toluene
CH2Cl2
CH2Cl2
hexane
CO2Et
OPG
Cp2TiCl
O
c
deprotection
O
imidazole/TBSCl
DBU/TBSCl
–
O
c
O
O
–
–
OH
OPG
7
2,6-lutidine/TBSOTf
Et3N/TBSOTf
15
15
63
57
both E & Z-isomers
PG = protecting group
6
8
(B) 2nd Approach:
a Reaction conditions: 13 (1.0 equiv), base (2.0 equiv), silylating agent (1.5
equiv), solvent (3 mL/mmol).
H
H
Tamao–Fleming
oxidation (R = Ph)
b Isolated yield after silica gel column chromatography.
c No reaction; starting material was recovered.
CO2Et
Cp2TiCl
O
O
O
O
O
SiMe2R
SiMe2R
OH
9
both E & Z-isomers
Next, epoxide 13 was synthesized from 12 in 87% yield
using m-CPBA (Scheme 2) and was subsequently subjected
to various reaction conditions to deliver the desired silyl
enol ether 7a. A summary of these efforts using different
bases and additives is documented in Table 1.
To begin with, when epoxide 13 was treated with
DIPEA/TBSOTf in CH2Cl2 for 12 h, it furnished an unusual bi-
cyclic ketal moiety 1422 (Table 1, entry 1), failing to provide
the desired silyl enol ether 7a. The use of K2CO3/18-crown-
6/TBSOTf in THF and Et3N/TBSOTf in CH2Cl2 led to the same
result (Table 1, entries 2 and 3). Treatment of 13 with
TBSCl/imidazole or TBSCl/DBU did not initiate any reaction
and led to the recovery of starting material (Table 1, entries
4 and 5). Whereas formation of the THP derivative 15 (E/Z
1:5) resulted from the use of 2,6-lutidine and Et3N with
TBSOTf in CH2Cl2 and hexane, respectively (Table 1, entries
6 and 7).
6
10
R = Me, Ph
Scheme 1 Generalized scheme of our approach
To evolve an approach efficaciously, at the outset, we
devised a simple strategy to access epoxide 7 with a teth-
ered enol ether serving as a precursor for the key Ti(III)-
mediated reductive epoxide opening–cyclization to access
the bridgehead-oxygenated bicyclic ring in one go (Scheme
1, A).
The reaction of the dianion of ethyl acetoacetate (11)
with 4-bromobut-1-ene afforded ethyl 3-oxooct-7-enoate
(12) by following the procedure documented in literature
(Scheme 2).21
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
D. Das et al.
Special Topic
Synthesis
the fact that the occupancy of the O-silyl group probably
made the β-carbon less prone to the radical attack. With
the aim to optimize the electron density at the β-carbon, it
was decided to switch to the acetyl enol carbonate 7b, enol
sulfonate ester 7c, and enol ester 7d following the optimum
conditions developed for 7a using (Boc)2O, TsCl, and BzCl,
respectively (Scheme 3).
Compounds 7b–d were subjected to the key Cp2Ti(III)Cl-
mediated reductive epoxide cleavage and radical cyclization
(Table 2, entries 2–4). Optimization of the electron density
at the β-carbon with the aim to achieve the cyclize product
worked out for 7b and 7c, but with the loss of the oxygen
functionality present at the β-carbon leading to the forma-
tion of cyclopentylidene derivative 17.23 While subjection
of 7d to the Cp2TiCl-reaction resulted in a complex mixture
of products.
OPG
Et3N, HMPA, DMAP, CH2Cl2
TBSOTf/(Boc)2O/TsCl/BzCl
O
O
O
O
OEt
r.t., 4–12 h
CO2Et
13
7
OBoc
OTBS
O
O
CO2Et
CO2Et
7a
7b
81% yield
75% yield
OBz
O
OTs
O
CO2Et
7d
CO2Et
E/Z = 14:1 (separable)
7c
86% yield
71% yield
Scheme 3 Preparation of the protected enol ethers 7a–d
The failure to furnish the expected bicyclic lactone 6
with a bridgehead hydroxy group directly from 7 led us to
try the alternative route starting with the epoxy-β-(triorga-
nosilyl)-α,β-unsaturated ester 9 in which the silyl group
was expected to serve as a surrogate for the bridgehead ox-
ygen functionality (Scheme 1, B).
Gratifyingly, the reaction occurred to produce the de-
sired silyl enol ether 7a in 81% yield when epoxide 13 in
CH2Cl2 was stirred with Et3N/HMPA/TBSOTf/DMAP at room
temperature for 12 h (Scheme 3). The synthesis of the epox-
ide with a tethered enol ether 7a set the stage for the imple-
mentation of our crucial epoxide opening–cyclization step.
CAN, Celite, NaHCO3
CH2Cl2–MeCN–H2O
–30 °C, 5 min (for 20a)24a
n-BuLi, THF, RMe2SiCl
–78 °C to r.t., 2–12 h
S
S
Table 2 Ti(III)-Mediated Reductive Cyclization of Epoxy Estersa
R
S
S
then
n-BuLi, THF
5-bromopent-1-ene
–78 °C to r.t., 2–12 h
or
Si
CaCO3, MeI, MeCN–H2O
r.t., 12 h (for 20b)25
OPG
18
O
Cp2TiCl2, Zn, THF
r.t., 12 h
19a R = Me, 87%
19b R = Ph, 83%
CO2Et
O
7
CO2Et
O
TMS
m-CPBA, CH2Cl2
OEt
Entry
1
Compound (PG)
Product
Yield (%)b
72
R
R
0 °C to r.t.,
Si
Si
LiHMDS,
THF
–78 °C to 0 °C, 18 h
3 h
OTBS
CO2Et
20a R = Me, 71%
20b R = Ph, 81%
60–61% over 2 steps
21a R = Me (E/Z = 1:7)
21b R = Ph (E/Z = 1:9)
7a (TBS)
16
17
17
CO2Et
EtO2C
Z
E
O
O
+
CO2Et
R
R
Si
Si
2
7b (Boc)
43
47
9a R = Me, 60%
9b R = Ph, 61%
9a' R = Me, 10%
9b' R = Ph, 9%
OH
Scheme 4 Preparation of the epoxy esters
CO2Et
3
4
7c (Ts)
7d (Bz)
Synthesis of 9 started with 1,3-dithiane (18) which, fol-
lowing a modified literature procedure,24a,b was silylated
with triorganosilyl chloride followed by alkylation using 5-
bromopent-1-ene to deliver the dithianes 19a and 19b in
one pot. The desired acylsilane 20a was synthesized by a re-
ported procedure24a using the oxidizing agent CAN, while
20b24c,d resulted with a poor yield. After investigating a
number of alternative methods, removal of the thioketal
was performed using CaCO3/MeI (Scheme 4).25 The Peter-
son olefination reaction26 of acylsilanes 20a and 20b with
the lithium enolate of ethyl (trimethylsilyl)acetate pro-
duced the (Z)-α,β-unsaturated ester predominantly togeth-
OH
c
complex mixture
–
a Reaction conditions: epoxide (1.0 equiv), Cp2TiCl2 (3.0 equiv), Zn (9.0
equiv), THF (45 mL/mmol).
b Isolated yield after silica gel column chromatography.
c Not determined.
Compound 7a failed to undergo reductive epoxide cleav-
age mediated by [Cp2Ti(III)Cl] with cyclization onto the
pendant enol ether and instead provided the deoxygenated
product 16 (Table 2, entry 1). The outcome sheds light onto
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
D. Das et al.
Special Topic
Synthesis
O
CO2Et
EtO2C
H
O
Cp2TiCl2, Zn, THF
r.t., 40 h
Cp2TiCl2, Zn, THF
r.t., 40 h
Z
E
O
O
R
Si
Si
Si
R
9a R = Me
9b R = Ph
10a R = Me, 81–84%
10b R = Ph, 78%
9a'
Scheme 5 Ti(III)-mediated reductive epoxide opening and radical cyclization
O
O
H
H
O
O
O
H
HBF4•OEt2, CH2Cl2
reflux, 24 h
KF, KHCO3, aq H2O2
O
THF–MeOH, 0 °C to r.t.
12 h, 93% (2 steps)
Si
Si
OH
Ph
10b
F
22
6
Scheme 6 Construction of the hydroxy-substituted quaternary center
er with an inseparable mixture the of E-isomer and residual
reagents (21a E/Z = 1:7; 21b E/Z = 1:9). Exploration of the
Horner–Wadsworth–Emmons reaction27 on 20a using tri-
ethyl phosphonoacetate also gave the required product, but
with reverse stereoselectivity (21a E/Z = 4:1) and in lower
yield (53%). Among the alternate possible routes available
for the synthesis of 21b, hydrosilylation reaction of ethyl
oct-7-en-2-ynoate28 with PhMe2SiH catalyzed by cyclopen-
tadienyl-ruthenium complex [Cp*Ru(MeCN)3]PF6 was also
explored.29 But for scaling up purposes, we continued with
the route depicted in Scheme 4. With better stereoselectivi-
ty and yield, the crude products of Peterson olefination re-
action 21a and 21b were subjected to epoxidation with m-
CPBA which resulted in a separable mixture of the pure (Z)-
epoxy-α,β-unsaturated esters 9a and 9b (Z-isomer 9a =
60%, E-isomer 9a′ = 10%; Z-isomer 9b = 61%, E-isomer 9b′ =
9%) (Scheme 4).
Next, the Z-isomers 9a and 9b were subjected to reduc-
tive epoxide cleavage mediated by Cp2Ti(III)Cl (generated in
situ from Cp2TiCl2and activated Zn dust) with concomitant
5-exo-trig cyclization onto the pendant β-silyl-α,β-unsatu-
rated ester to successfully give the bicyclic lactones with
the cis ring junction embedded with bridgehead C–Si bond
10a and 10b (Scheme 5) in good yields. Further, inspection
of the stereochemical outcome led us to set up the Cp2Ti(III)Cl
reaction also with the E-isomer 9a′. 1H NMR and 13C NMR of
the product from the reaction of the E-isomer 9a′ showed
that it was identical to that from the Z-isomers 9a and 9b.
NOE experiments were carried out to establish the stereo-
chemical outcome of the ring junction (see the Supporting
Information).
hydroxy group in 10a, although it was effective for other
molecular frameworks. The same conversion of the TMS
group into the hydroxy group could possibly be achieved in
a multistep sequence through a recently reported proce-
dure which involves an initial iridium-catalyzed C(sp3)–H
borylation of the methyl group on silicon.31
An alternate two-step protocol, shown in Scheme 6, re-
quired the use of the dimethylphenylsilyl group in place of
trimethylsilyl. To render this transformation, the non-hy-
drolysable dimethylphenylsilane in 10b was first activated
to a fluorosilane 22 followed by the oxidation of the result-
ing functionalized silicon atom using H2O2 to install the de-
sired bridgehead hydroxyl group to furnish hydroxylated-
cyclopentano lactone 6 in 93% overall yield. The stereo-
structure of 6 was confirmed by 2D NMR and NOE studies
(see the Supporting Information).
Subsequently, an extension of the aforementioned strat-
egy to access 6,6-fused ring systems was also attempted. In
this regard, the requisite epoxy-β-(triorganosilyl)-α,β-un-
saturated ester was synthesized by dimethylphenylsilyla-
tion of 1,3-dithiane, alkylation using 6-bromohex-1-ene
and then following the same strategy used for synthesizing
compound 9 as shown in Scheme 4. However, implementa-
tion of the key Cp2Ti(III)Cl-mediated reaction resulted in a
mixture of deoxygenated and reduced products with no
trace of the required 6,6-fused bicyclic product.
In conclusion, as part of our ongoing research endeavor,
we successfully widen the viability of Ti(III)-mediated ep-
oxide opening cyclization protocol to forge a hydroxylated
bridgehead chiral center, the structural feature observed in
a countless number of natural products and natural product
inspired synthons. The β-silyl functionality turned out to be
very effective to fix the bridgehead stereocenters in the 6,5-
fused bicyclic β-hydroxy lactone and serve as a valuable
synthon for later stage functionalization to give the hydroxy
group and build the desired hydroxylated bridgehead ste-
reocenter with excellent diastereoselectivity and in reason-
able overall yield, amenable to scale up. Further application
The next crucial step was the Tamao–Fleming oxida-
tion,20 which permits silyl group to be used as ‘masked hy-
droxy group’. Although the TMS group shows extremely
high tolerability to a range of reaction conditions, its use in
Tamao–Fleming oxidation is limited. The single step reac-
tion protocol documented in the literature for this transfor-
mation using TBHP and KH30 failed to install the bridgehead
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
D. Das et al.
Special Topic
Synthesis
of the strategy will be demonstrated in due course by the
successful synthesis of natural products containing similar
6,5-fused ring systems.
13C NMR (CDCl3, 100 MHz): δ = 169.07, 106.37, 75.10, 69.10, 60.55,
43.44, 33.76, 27.93, 16.65, 14.15.
HRMS (ESI): m/z [M + Na]+ calcd for C10H16O4Na: 223.0946; found:
223.0948.
All the reactions were carried out under an inert atmosphere in oven-
dried glassware using dry solvents, unless otherwise stated. All chem-
icals purchased from commercial suppliers were used as received un-
less otherwise stated. Reactions and chromatography fractions were
monitored by Merck silica gel 60 F-254 glass TLC plates and visualized
using UV light, 7% ethanolic phosphomolybdic acid/heat or 2.5% etha-
nolic anisaldehyde (with 1% AcOH and 3.3% concd H2SO4)/heat as de-
veloping agents. Flash column chromatography was performed with
100–200 mesh silica gel and yields refer to chromatographically and
spectroscopically pure compounds.
Ethyl 6-[(tert-Butyldimethylsiloxy)methyl]tetrahydro-2H-pyran-
2-ylideneacetate (15); General Procedure
To a solution of 13 (1.0 equiv) in CH2Cl2 or hexane (3 mL/mmol) at
0 °C were added 2,6-lutidine (2.0 equiv) or Et3N (2.0 equiv) and
TBSOTf (1.5 equiv). Then the mixture was stirred at r.t. for 12 h and
quenched with sat. aq NH4Cl. The mixture was extracted with EtOAc
and the combined extracts were washed with water and brine, dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography [silica gel, 15% EtOAc/hexane; Rf = 0.60 (sili-
ca gel, 10% EtOAc/hexane)] gave 15 (57–63%) as a colorless oil.
All NMR spectra were recorded in CDCl3 or in DMSO-d6 on a 400 MHz
instrument at 300 K and are calibrated to residual solvent peaks
[CHCl3 δ = 7.26 (1H) and 77.0 (13C), DMSO δ = 2.50 (1H) and 40.0 13C).
FT-IR spectra were recorded as neat liquid or KBr pellets using Perkin-
Elmer Spectrum BX spectrophotometer. HRMS was performed on Mi-
cromass Q-TOF Micro instrument.
IR (neat): 3439, 2924, 2852, 2361, 1729, 1644, 1460, 1369, 1279,
1252, 1166, 1028 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 4.67–4.60 (m, 1 H), 4.14 (q, J = 7.1 Hz, 2
H), 3.91–3.84 (m, 1 H), 3.73 (dd, J = 10.5, 5.2 Hz, 1 H), 3.62 (dd, J =
10.5, 6.0 Hz, 1 H), 2.99 (br s, 2 H), 2.16–1.96 (m, 2 H), 1.90–1.76 (m, 1
H), 1.64–1.52 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.05 (s, 6
H).
Ethyl 7,8-Epoxy-3-oxooctanoate (13)
13C NMR (CDCl3, 100 MHz): δ = 170.54, 147.49, 98.89, 76.09, 65.26,
60.67, 40.34, 25.86, 23.55, 19.78, 18.33, 14.15, –5.30, –5.35.
HRMS (ESI): m/z [M + Na]+ calcd for C16H30O4SiNa: 337.1811; found:
337.1815.
To a solution of 12 (1.0 g, 5.43 mmol, 1.0 equiv) in CH2Cl2 (15 mL) at 0
°C was added portionwise m-CPBA (77%, 2.43 g, 10.86 mmol, 2.0
equiv); the mixture was warmed to r.t. and stirred for 3.5 h. The reac-
tion was then quenched with sat. aq Na2SO3 and extracted with
EtOAc. The combined extracts were washed with sat. aq NaHCO3 solu-
tion, water, and brine, dried (anhyd Na2SO4), and concentrated. Purifi-
cation by column chromatography [silica gel, 20% EtOAc/hexane; Rf =
0.52 (silica gel, 40% EtOAc/hexane)] afforded epoxide 13 (945 mg,
87%) as a colorless oil.
Ethyl (E)-3-(tert-Butyldimethylsiloxy)-7,8-epoxyoct-2-enoate (7a)
To a stirred solution of 13 (100 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (2.5
mL) at r.t., Et3N (0.42 mL, 3.0 mmol, 6.0 equiv) and HMPA (0.4 mL)
were added. After 15 min, TBSOTf (0.23 mL, 1.0 mmol, 2.0 equiv) and
DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added sequentially. After
stirring for 12 h at r.t., the mixture was quenched with sat. aq NH4Cl
and extracted with Et2O. The combined organic layers were washed
with 1 M aq HCl, water, and brine, dried (Na2SO4), filtered, and con-
centrated in vacuo. The resulting residue [Rf = 0.43 (silica gel, 20%
EtOAc/hexane)] was subjected to the Cp2TiCl-mediated cyclization re-
action without any further purification.
IR (neat): 3403, 2983, 2934, 1742, 1715, 1638, 1318, 1022 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 4.18 (q, J = 7.1 Hz, 2 H), 3.43 (s, 2 H),
2.91–2.86 (m, 1 H), 2.75–2.71 (m, 1 H), 2.65–2.59 (m, 2 H), 2.45 (dd,
J = 4.9, 2.7 Hz, 1 H), 1.81–1.73 (m, 2 H), 1.67–1.59 (m, 1 H), 1.49–1.39
(m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 202.34, 167.15, 61.35, 51.88, 49.28,
46.71, 42.27, 31.48, 19.85, 14.05.
HRMS (ESI): m/z [M + Na]+ calcd for C10H16O4Na: 223.0946; found:
223.0944.
Ethyl (E)-3-(tert-Butoxycarbonyloxy)-7,8-epoxyoct-2-enoate (7b)
To a stirred solution of 13 (100 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (2.5
mL) at r.t., Et3N (0.21 mL, 1.5 mmol, 3.0 equiv) and HMPA (0.2 mL)
were added. After 15 min, Boc2O (0.23 mL, 1.0 mmol, 2.0 equiv) and
DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added sequentially. After
stirring for 5 h at r.t., the mixture was quenched with sat. aq NH4Cl
and extracted with Et2O. The combined organic layers were washed
with water and brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The resulting residue was purified by flash column chromatog-
raphy [silica gel, 10% EtOAc/hexane; Rf = 0.70 (silica gel, 20% EtO-
Ac/hexane)] to afford 7b (113 mg, 75%) as a colorless liquid.
Ethyl 6,8-Dioxabicyclo[3.2.1]octan-5-ylacetate (14); General Pro-
cedure
To a solution of 13 (1.0 equiv) in CH2Cl2 or in THF (3 mL/mmol) at 0 °C
were added Et3N (2 equiv), DIPEA (2 equiv), or K2CO3 (2.0 equiv)/18-
crown-6 (2.0 equiv) and TBSOTf (1.5 equiv). Then the mixture was
stirred at r.t. for 12 h and quenched with sat. aq NH4Cl. The mixture
was extracted with EtOAc and the combined extracts were washed
with water and brine, dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by column chromatography [silica gel, 15% EtOAc/
hexane; Rf = 0.43 (silica gel, 32% EtOAc/hexane)] afforded 14 (72–88%)
as a colorless oil.
IR (neat): 3419, 2361, 1763, 1644, 1456, 1399, 1372, 1253, 1221,
1114, 1017 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 5.79 (s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H),
2.96–2.85 (m, 3 H), 2.76–2.72 (m, 1 H), 2.47 (dd, J = 4.9, 2.6 Hz, 1 H),
1.79–1.55 (m, 4 H), 1.51 (s, 9 H), 1.27 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 166.04, 165.92, 150.10, 109.46, 84.08,
60.23, 51.86, 47.02, 31.78, 30.36, 27.57, 23.12, 14.18.
IR (neat): 3432, 2943, 2859, 2361, 1731, 1643, 1451, 1367, 1253,
1171, 1109, 1028 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 4.58–4.54 (m, 1 H), 4.16 (q, J = 7.1 Hz, 2
H), 3.95–3.91 (m, 1 H), 3.88–3.83 (m, 1 H), 2.73 (s, 2 H), 1.96–1.74 (m,
4 H), 1.69–1.60 (m, 1 H), 1.51–1.44 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C15H24O6Na: 323.1471; found:
323.1476.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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D. Das et al.
Special Topic
Synthesis
Ethyl (E)-7,8-Epoxy-3-(tosyloxy)oct-2-enoate (7c)
with water and brine, dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by column chromatography (silica gel) afforded
the product.
To a stirred solution of 13 (100 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (2.5
mL) at r.t., Et3N (0.21 mL, 1.5 mmol, 3.0 equiv) and HMPA (0.2 mL)
were added. After 15 min, TsCl (143 mg, 0.75 mmol, 1.5 equiv) and
DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added sequentially. After
stirring for 12 h at r.t., the mixture was quenched with sat. aq NH4Cl
and extracted with Et2O. The combined organic layers were washed
with water and brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The resulting residue was purified by flash column chromatog-
raphy [silica gel, 8% EtOAc/hexane; Rf = 0.50 (silica gel, 40% EtOAc/
hexane)] to afford 7c (126 mg, 71%) as a light-yellow oil.
Ethyl (E)-3-(tert-Butyldimethylsiloxy)octa-2,7-dienoate (16)
Following the general procedure using 7a (90 mg, 0.29 mmol) with
purification by column chromatography [100–200 mesh silica gel, 5%
EtOAc/hexane; Rf = 0.80 (silica gel, 20% EtOAc/hexane)] gave 16 as a
colorless oil; yield: 62 mg (72%).
IR (neat): 3443, 2930, 2361, 1709, 1626, 1464, 1368, 1259, 1134,
1044, 913, 837 cm–1
.
IR (neat): 3435, 2929, 2361, 1719, 1650, 1596, 1455, 1373, 1218,
1H NMR (CDCl3, 400 MHz): δ = 5.87–5.76 (m, 1 H), 5.07 (s, 1 H), 5.04–
4.92 (m, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 2.76–2.70 (m, 2 H), 2.09 (dd, J =
14.6, 7.1 Hz, 2 H), 1.68–1.59 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.94 (s, 9
H), 0.23 (s, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 173.18, 167.67, 138.46, 114.66, 99.05,
59.27, 33.35, 32.81, 26.27, 25.45, 18.04, 14.39, –4.67.
1185, 1122, 1032, 980, 879 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.85–7.80 (m, 2 H), 7.40–7.36 (m, 2 H),
5.82 (s, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 2.89–2.82 (m, 1 H), 2.79–2.73 (m,
2 H), 2.73–2.70 (m, 1 H), 2.47 (s, 3 H), 2.42 (dd, J = 5.0, 2.6 Hz, 1 H),
1.70–1.41 (m, 4 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 165.22, 165.10, 145.83, 132.82,
130.00, 128.19, 110.13, 60.55, 51.70, 46.91, 31.52, 30.92, 22.79, 21.72,
14.10.
HRMS (ESI): m/z [M + Na]+ calcd for C16H30O3SiNa: 321.1862; found:
321.1863.
HRMS (ESI): m/z [M + Na]+ calcd for C17H22O6SNa: 377.1035; found:
377.1036.
Ethyl 2-(Hydroxymethyl)cyclopentylideneacetate (17)
Following the general procedure using 7b (80 mg, 0.27 mmol) or 7c
(80 mg, 0.22 mmol) with purification by column chromatography
[100–200 mesh silica gel, 15% EtOAc/hexane; Rf = 0.40 (silica gel, 20%
EtOAc/hexane)] gave 17 as a colorless oil; yield: 22 mg (43% from 7b);
23 mg (47% from 7c).
Ethyl (E)-3-(Benzoyloxy)-7,8-epoxyoct-2-enoate (7d)
To a stirred solution of 13 (100 mg, 0.5 mmol, 1.0 equiv) in CH2Cl2 (2.5
mL) at r.t., Et3N (0.21 mL, 1.5 mmol, 3.0 equiv) and HMPA (0.2 mL)
were added. After 15 min, BzCl (0.12 mL, 1.0 mmol, 2.0 equiv) and
DMAP (12 mg, 0.1 mmol, 0.2 equiv) were added sequentially. After
stirring for 4 h at r.t., the mixture was quenched with sat. aq NH4Cl
and extracted with Et2O. The combined organic layers were washed
with water and brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The resulting crude (mixture of E/Z isomer 14:1) was purified
by flash column chromatography [silica gel, 5% EtOAc/hexane; Rf =
0.43 (silica gel, 20% EtOAc/hexane)] to afford 7d (E-isomer) (131 mg,
86%) as a light-yellow oil.
IR (neat): 3436, 2959, 2361, 1709, 1647, 1463, 1371, 1201, 1129,
1032, 957, 863 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 5.83 (dd, J = 4.5, 2.2 Hz, 1 H), 4.15 (q, J =
7.1 Hz, 2 H), 3.71–3.62 (m, 2 H), 3.00–2.89 (m, 1 H), 2.81–2.68 (m, 2
H), 1.95–1.78 (m, 2 H), 1.72–1.56 (m, 2 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 168.27, 166.77, 112.69, 64.46, 59.66,
48.91, 33.14, 28.67, 24.26, 14.29.
HRMS (ESI): m/z [M + Na]+ calcd for C10H16O3Na: 207.0997; found:
IR (neat): 3424, 2361, 1739, 1717, 1647, 1453, 1372, 1254, 1224,
207.0995.
1179, 1122, 1088, 1020 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.09–8.05 (m, 2 H), 7.66–7.60 (m, 1 H),
7.52–7.46 (m, 2 H), 5.85 (s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.06–2.97 (m,
2 H), 2.96–2.90 (m, 1 H), 2.74 (t, J = 4.5 Hz, 1 H), 2.46 (dd, J = 4.9, 2.7
Hz, 1 H), 1.86–1.54 (m, 4 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 166.47, 165.74, 163.89, 133.88,
130.08, 128.89, 128.66, 110.77, 60.28, 51.85, 47.03, 31.87, 30.66,
23.17, 14.19.
2-(Pent-4-enyl)-2-(silyl)-1,3-dithianes (19a and 19b)
Dithianes 19a and 19b were synthesized by modifying the literature
procedure.24a,b A solution of 1,3-dithiane (3.0 g, 24.95 mmol, 1.0
equiv) in dry THF (75 mL) was cooled to –78 °C and treated with 1.3 M
n-BuLi in hexane (20.2 mL, 26.2 mmol, 1.05 equiv). After stirring for
30 min at 0 °C, the solution was cooled to –78 °C and treated with
TMSCl (3.5 mL, 27.44 mmol, 1.1 equiv) or Me2PhSiCl (4.6 mL, 27.44
mmol, 1.1 equiv). The resulting solution was stirred for 2 h at r.t. and
then cooled to –78 °C, and additional of n-BuLi (20.2 mL) was added.
After stirring for 30 min at 0 °C, the solution was cooled to –78 °C and
treated with 5-bromopent-1-ene (3.6 mL, 29.94 mmol, 1.2 equiv).
Then the mixture was warmed to r.t. and stirred for 12 h. The reaction
was quenched with sat. aq NH4Cl and extracted with Et2O. The com-
bined organic layers were washed with water and brine, dried
(Na2SO4), filtered, and concentrated in vacuo. The resulting residue
was purified by chromatography (neutral alumina, 5% EtOAc/hexane)
to afford 19a (5.6 g, 87%) or 19b [6.9 g, 83%; Rf = 0.63, (silica gel, 8%
EtOAc/hexane)] as light-yellow oils.
HRMS (ESI): m/z [M + Na]+ calcd for C17H20O5Na: 327.1208; found:
327.1208.
Cp2TiCl-Mediated Radical Cyclization of 7a–d, 9a,b and 9a′; Gener-
al Procedure
In a flame-dried round-bottom flask containing THF (30 mL/mmol)
were added Zn (9.0 equiv) and Cp2TiCl2 (3.0 equiv) under an inert at-
mosphere and the mixture was stirred for 1 h at r.t. (the color
changed from deep red to green). The epoxide (1.0 equiv) in THF (15
mL/mmol) was cannulated into this solution at r.t. under N2 atmo-
sphere. The mixture was brought to r.t. and continuously stirred for
40 h. The mixture was quenched with sat. aq NH4Cl and stirred for an
additional 15 min. The solvent was evaporated in vacuo and the resi-
due was extracted with Et2O; the combined extracts were washed
Data for 19a
The spectroscopic data were in full accord with those reported in the
literature.24a,b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
D. Das et al.
Special Topic
Synthesis
Data for 19b
ed with Et2O. The combined organic extracts were washed with water
and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give
the crude products as light-yellow oils, which were used in the next
step without further purification.
IR (neat): 3739, 2314, 1645, 1543, 1516, 1421, 1253, 1111, 912, 821
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.69–7.64 (m, 2 H), 7.43–7.34 (m, 3 H),
5.78–5.67 (m, 1 H), 4.99–4.91 (m, 2 H), 3.01–2.92 (m, 2 H), 2.47–2.39
(m, 2 H), 2.12–2.06 (m, 2 H), 2.05–1.95 (m, 3 H), 1.94–1.82 (m, 1 H),
1.55–1.45 (m, 2 H), 0.53 (s, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 138.41, 135.58, 134.79, 129.55,
127.55, 114.77, 39.00, 36.59, 33.94, 26.59, 24.85, 23.68, –3.94.
Compound 21a
Following the general procedure using 20a (500 mg, 2.94 mmol) gave
21a; Rf = 0.63 (silica gel, 5% EtOAc/hexane); E/Z 1:7 (1H NMR of the
crude product).
HRMS (ESI): m/z [M + Na]+ calcd for C17H26S2SiNa: 345.1143; found:
345.1145.
Compound 21b
Following the general procedure using 20b (500 mg, 2.15 mmol) gave
21b; Rf = 0.53 (silica gel, 5% EtOAc/hexane); E/Z 1:9 (1H NMR of the
crude product).
Hex-5-enoyltrimethylsilane (20a)
Acylsilane 20a was synthesized by using CAN following the literature
procedure24a and the spectroscopic data were in full accord with
those reported.
Ethyl (Z)- and (E)-7,8-Epoxy-3-(trimethylsilyl)oct-2-enoates (9a
and 9a′)
To a solution of 21a (500 mg, 2.08 mmol, 1.0 equiv) in CH2Cl2 (10 mL)
at 0 °C was added portionwise m-CPBA (77%, 1.16 g, 5.2 mmol, 2.5
equiv). The mixture was warmed to r.t. and stirred for 3 h. The reac-
tion was then quenched with sat. aq Na2SO3 and extracted with Et2O.
The combined extracts were washed with sat. aq NaHCO3 solution,
water, and brine, dried (anhyd Na2SO4), and concentrated. Purifica-
tion by flash column chromatography (silica gel, 3% EtOAc/hexane) af-
forded the epoxide 9a [Z-isomer, 320 mg, 60%; Rf = 0.46 (silica gel, 8%
EtOAc/hexane)] and 9a′ [E-isomer, 52 mg, 10%; Rf = 0.38 (silica gel, 8%
EtOAc/hexane)] as colorless oils.
Hex-5-enoyldimethylphenylsilane (20b)
To a solution of 19b (3.0 g, 9.3 mmol, 1.0 equiv) in CH3CN/H2O (4:1, 50
mL) were added CaCO3 (2.79 g, 27.9 mmol, 3.0 equiv) and MeI (11.5
mL, 186 mmol, 20.0 equiv). After stirring at r.t. for 12 h, the resulting
mixture was diluted with Et2O and H2O. The layers were separated,
and the aqueous layer was extracted with Et2O. The combined organic
layers were washed with water and brine, dried (Na2SO4), filtered,
and concentrated in vacuo. The resulting crude was purified by flash
column chromatography [silica gel, 5% EtOAc/hexane; Rf = 0.50 (silica
gel, 5% EtOAc/hexane)] to afford the acylsilane 20b (1.75 g, 81%) as a
light-yellow oil (synthesis adapted from ref. 25).
Ethyl (Z)-7,8-Epoxy-3-(trimethylsilyl)oct-2-enoate (9a)
IR (neat): 3072, 2933, 1726, 1641, 1429, 1251, 1111, 997, 912, 831
IR (neat): 2937, 2358, 1717, 1597, 1336, 1250, 1197, 1033, 846 cm–1
.
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 6.05–6.02 (m, 1 H), 4.15 (q, J = 7.1 Hz, 2
H), 2.96–2.91 (m, 1 H), 2.76–2.68 (m, 3 H), 2.46 (dd, J = 5.0, 2.7 Hz, 1
H), 1.66–1.52 (m, 4 H), 1.28 (t, J = 7.1 Hz, 3 H), 0.14 (s, 9 H).
13C NMR (CDCl3, 100 MHz): δ = 165.86, 165.28, 126.80, 59.71, 52.07,
47.04, 32.79, 30.94, 26.08, 14.28, –1.83.
1H NMR (CDCl3, 400 MHz): δ = 7.57–7.52 (m, 2 H), 7.43–7.32 (m, 3 H),
5.74–5.61 (m, 1 H), 4.95–4.88 (m, 2 H), 2.61–2.54 (m, 2 H), 1.98–1.89
(m, 2 H), 1.61–1.51 (m, 2 H), 0.48 (m, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 246.21, 138.09, 134.46, 133.94,
129.84, 128.12, 114.94, 47.85, 33.04, 21.13, –4.78.
HRMS (ESI): m/z [M + Na]+ calcd for C13H24O3SiNa: 279.1392; found:
279.1391.
HRMS (ESI): m/z [M + Na]+ calcd for C14H20OSiNa: 255.1181; found:
255.1184.
Ethyl (E)-7,8-Epoxy-3-(trimethylsilyl)oct-2-enoate (9a′)
Ethyl (E/Z)-3-(Trimethylsilyl)octa-2,7-dienoate (21a) by HWE Ole-
fination
IR (neat): 2919, 2850, 2362, 2336, 1735, 1644, 1337, 1251, 1199,
1036, 820 cm–1
.
A mixture of triethyl phosphonoacetate (278 mg, 1.24 mmol, 2.1
equiv) and NaH (60%, 47 mg, 1.18 mmol, 2.0 equiv) in THF (3 mL) was
stirred at 0 °C for 1 h. Then the solution of 20a (100 mg, 0.59 mmol,
1.0 equiv) in THF (2 mL) was cannulated into the mixture at the same
temperature. After stirring for 15 min, the mixture was brought to r.t.
and stirred for 12 h. The mixture was then quenched with sat. aq
NH4Cl and extracted with Et2O. The combined organic extracts were
washed with water and brine, dried (Na2SO4), filtered, and concen-
trated in vacuo to give the crude product of 21a (75 mg, 53%; E/Z 4:1)
as light-yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 6.28–6.22 (m, 1 H), 4.15 (q, J = 7.1 Hz, 2
H), 2.98–2.82 (m, 1 H), 2.78–2.72 (m, 1 H), 2.46 (dd, J = 4.9, 2.6 Hz, 1
H), 2.36–2.27 (m, 2 H), 1.65–1.47 (m, 4 H), 1.28 (t, J = 7.1 Hz, 3 H), 0.19
(s, 9 H).
13C NMR (CDCl3, 100 MHz): δ = 166.74, 165.45, 130.34, 60.03, 51.99,
46.99, 38.60, 32.09, 25.89, 14.25, –0.53.
HRMS (ESI): m/z [M + Na]+ calcd for C13H24O3SiNa: 279.1392; found:
279.1391.
Ethyl (Z)- and (E)-3-(Dimethylphenylsilyl)-7,8-epoxyoct-2-enoates
(9b and 9b′)
Ethyl 3-(Silyl)octa-2,7-dienoates 21a,b; General Procedure for the
Peterson Olefination Reaction
To a solution of 21b (500 mg, 1.65 mmol, 1.0 equiv) in CH2Cl2 (8 mL)
at 0 °C was added portionwise m-CPBA (77%, 924 mg, 4.12 mmol, 2.5
equiv). The mixture was warmed to r.t. and stirred for 3 h. The reac-
tion was then quenched with sat. aq Na2SO3 and extracted with Et2O.
The combined extracts were washed with sat. aq NaHCO3 solution,
water, and brine, dried (anhyd Na2SO4), and concentrated. Purifica-
To a solution of ethyl (trimethylsilyl)acetate (1.3 equiv) in THF (3
mL/mmol) was added 1.0 M LiHMDS in THF (1.2 equiv) at –78 °C un-
der argon. After stirring for 20 min at –78 °C, a solution of acylsilane
20a or 20b (1.0 equiv) in THF (2 mL/mmol) was cannulated at –78 °C.
The mixture was warmed to 0 °C and stirred for 18 h. The reaction
was quenched by the addition of sat. aq NaHCO3 solution and extract-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
D. Das et al.
Special Topic
Synthesis
tion by flash column chromatography (silica gel, 3% EtOAc/hexane) af-
forded the epoxide 9b [Z-isomer, 320 mg, 61%; Rf = 0.45 (silica gel, 5%
EtOAc/hexane)] and 9b′ [E-isomer, 46 mg, 9%; Rf = 0.33, silica gel (5%
EtOAc/hexane)] as colorless oils.
1H NMR (CDCl3, 400 MHz): δ = 7.54–7.50 (m, 2 H), 7.41–7.34 (m, 3 H),
4.04 (dd, J = 11.4, 3.7 Hz, 1 H), 3.83 (dd, J = 11.4, 3.7 Hz, 1 H), 2.47–
2.39 (m, 2 H), 2.22 (d, J = 14.9 Hz, 1 H), 1.98–1.89 (m, 1 H), 1.72–1.54
(m, 3 H), 1.50–1.41 (m, 1 H), 1.36–1.24 (m, 1 H), 0.37–0.34 (m, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 174.11, 135.49, 134.24, 129.63,
127.96, 70.49, 39.20, 36.89, 36.79, 30.95, 29.54, 25.32, –6.14, –6.16.
Ethyl (Z)-3-(Dimethylphenylsilyl)-7,8-epoxyoct-2-enoate (9b)
HRMS (ESI): m/z [M + Na]+ calcd for C16H22O2SiNa: 297.1287; found:
297.1285.
IR (neat): 2981, 2935, 1716, 1597, 1456, 1369, 1336, 1251, 1197,
1109, 1037, 918, 823 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.54–7.49 (m, 2 H), 7.34–7.30 (m, 3 H),
6.40–6.36 (m, 1 H), 4.00 (q, J = 7.1 Hz, 2 H), 2.79–2.74 (m, 1 H), 2.70–
2.67 (m, 1 H), 2.37 (dd, J = 5.0, 2.6 Hz, 1 H), 2.29–2.24 (m, 2 H), 1.58–
1.39 (m, 4 H), 1.15 (t, J = 7.1 Hz, 3 H), 0.51–0.48 (m, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 166.52, 162.59, 138.83, 133.75,
131.75, 128.65, 127.52, 60.08, 51.88, 46.99, 38.90, 32.03, 25.72, 14.07,
–1.73.
cis-6-Hydroxy-3-oxabicyclo[4.3.0]nonan-4-one (6) by Tamao–
Fleming Oxidation of the Cycloadduct 10b
To a solution of 10b (200 mg, 0.73 mmol, 1.0 equiv) in CH2Cl2 (10 mL)
was added HBF4·OEt2 (1.49 mL, 10.95 mmol, 15.0 equiv) at 0 °C. When
the addition was complete, the ice bath was removed, and the mix-
ture was refluxed for 48 h. Then the reaction was quenched by drop-
wise addition of sat. aq NaHCO3 (at 0 °C). The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc. The combined
organic extracts were dried (anhyd Na2SO4), filtered, and concentrat-
ed under vacuo to give the crude fluorosilane 22, which was dissolved
in THF/MeOH (1:1, 14 mL). The solution was cooled to 0 °C and KF
(212 mg, 3.65 mmol, 5.0 equiv) and KHCO3 (365 mg, 3.65 mmol, 5.0
equiv) were added followed by 30% aq H2O2 (1.7 mL, 14.6 mmol, 20.0
equiv). The resulting mixture was allowed to warm to r.t. and stirred
for 12 h. Then the reaction was quenched with 1 M aq HCl and ex-
tracted with EtOAc. The combined organic extracts were dried (anhyd
Na2SO4), filtered, and concentrated under reduced pressure. Purifica-
tion by flash column chromatography [silica gel, 60% EtOAc/hexane;
Rf = 0.33 (silica gel, 80% EtOAc/hexane)] gave the alcohol 6 (106 mg,
93%) as a colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O3SiNa: 341.1549; found:
341.1549.
Ethyl (E)-3-(Dimethylphenylsilyl)-7,8-epoxyoct-2-enoate (9b ′)
IR (neat): 2953, 2929, 1714, 1641, 1600, 1456, 1369, 1340, 1255,
1172, 1111, 1039, 918, 823 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.52–7.48 (m, 2 H), 7.41–7.33 (m, 3 H),
6.09 (s, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 2.83–2.77 (m, 1 H), 2.72–2.64 (m,
3 H), 2.36 (dd, J = 5.0, 2.7 Hz, 1 H), 1.53–1.37 (m, 4 H), 1.28 (t, J = 7.1
Hz, 3 H), 0.45–0.42 (m, 6 H).
13C NMR (CDCl3, 100 MHz): δ = 165.18, 163.89, 136.41, 133.99,
129.47, 128.31, 127.94, 59.82, 51.99, 46.97, 32.65, 31.13, 25.96, 14.26,
–3.34, –3.37.
IR (neat): 3413, 2955, 2925, 2866, 2362, 2336, 1736, 1388, 1257,
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O3SiNa: 341.1549; found:
341.1549.
1180, 1060, 1033 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 4.38 (dd, J = 11.6, 5.4 Hz, 1 H), 3.92 (dd,
J = 11.6, 7.6 Hz, 1 H), 2.75 (d, J = 14.9 Hz, 1 H), 2.67 (d, J = 14.9 Hz, 1 H),
2.54 (br s, 1 H), 2.34–2.26 (m, 1 H), 2.11–2.00 (m, 1 H), 1.95–1.86 (m,
1 H), 1.85–1.74 (m, 1 H), 1.73–1.61 (m, 2 H), 1.40–1.29 (m, 1 H).
cis-6-(Silyl)-3-oxabicyclo[4.3.0]nonan-4-ones (10a and 10b)
Following the general procedure for Cp2TiCl-mediated radical cycliza-
tion using 9a/9a′ (100 mg, 0.39 mmol) or 9b (300 mg, 0.94 mmol)
gave 10a and 10b, respectively.
13C NMR (CDCl3, 100 MHz): δ = 172.27, 80.18, 69.52, 46.75, 43.16,
42.75, 29.16, 24.59.
cis-6-(Trimethylsilyl)-3-oxabicyclo[4.3.0]nonan-4-one (10a)
1H NMR (DMSO-d6, 400 MHz): δ = 5.01 (s, 1 H), 4.26 (dd, J = 11.4, 5.8
Hz, 1 H), 3.89 (dd, J = 11.4, 9.2 Hz, 1 H), 2.68 (d, J = 14.6 Hz, 1 H), 2.52
(d, J = 14.6 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.93–1.83 (m, 1 H), 1.76–1.68
(m, 1 H), 1.68–1.44 (m, 3 H), 1.22–1.13 (m, 1 H).
Purification by flash column chromatography [100–200 mesh silica
gel, 8% EtOAc/hexane; Rf = 0.47 (silica gel, 16% EtOAc/hexane)] gave
10a as a colorless liquid; yield: 72 mg (84% from 9a); 69 mg, (81%
from 9a′).
13C NMR (DMSO-d6, 100 MHz): δ = 172.65, 79.58, 69.41, 46.63, 43.34,
IR (neat): 2949, 2358, 1745, 1254, 1186, 1023, 843 cm–1
.
42.57, 28.88, 24.81.
HRMS (ESI): m/z [M + Na]+ calcd for C8H12O3Na: 179.0684; found:
179.0681.
1H NMR (CDCl3, 400 MHz): δ = 4.11 (d, J = 4.3 Hz, 2 H), 2.42 (d, J = 15.0
Hz, 1 H), 2.33–2.26 (m, 1 H), 2.24 (d, J = 15.0 Hz, 1 H), 1.87–1.62 (m, 4
H), 1.53–1.40 (m, 2 H), 0.03 (s, 9 H).
13C NMR (CDCl3, 100 MHz): δ = 174.24, 70.62, 39.09, 36.71, 36.47,
31.09, 29.26, 25.35, –4.41.
Acknowledgment
HRMS (ESI): m/z [M + Na]+ calcd for C11H20O2SiNa: 235.1130; found:
235.1132.
Authors gratefully acknowledge the financial support by SERB, New
Delhi, India for JC Bose Fellowship (T.K.C., SERB No.: SR/S2/JCB-
30/2007). The authors are also thankful to the Department of Organic
Chemistry, IISc for providing the spectroscopic and analytical data.
cis-6-(Dimethylphenylsilyl)-3-oxabicyclo[4.3.0]nonan-4-one (10b)
Purification by flash column chromatography [100–200 mesh silica
gel, 8% EtOAc/hexane; Rf = 0.46 (silica gel, 20% EtOAc/hexane)] gave
10b as a colorless liquid; yield: 201 mg (78%).
Supporting Information
IR (neat): 2953, 1743, 1427, 1382, 1257, 1186, 1112, 1082, 1035, 947,
Supporting information for this article is available online at
835 cm–1
.
https://doi.org/10.1055/s-0037-1609586.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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D. Das et al.
Special Topic
Synthesis
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