Synthesis of medium-sized lactones from siloxy alkynes via ring expansion

Article abstract of DOI:10.1016/j.tet.2020.131163

Synthesis of medium ring lactones remains as a challenging topic in organic synthesis due to the disfavored kinetic and thermodynamic features. Herein we detail an efficient intermolecular process using siloxy alkynes as substrates and oxetene ring expansion as the key strategy. With extension to a new silyl-masked alkyne, this reaction now features a broad scope, high efficiency, and mild conditions.

Full text of DOI:10.1016/j.tet.2020.131163

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Synthesis of medium-sized lactones from siloxy alkynes via ring expansion
An Wu, Wanxiang Zhao, Jianwei Sun
PII:
S0040-4020(20)30298-2
https://doi.org/10.1016/j.tet.2020.131163
TET 131163
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 March 2020
Revised Date: 25 March 2020
Accepted Date: 27 March 2020
Please cite this article as: Wu A, Zhao W, Sun J, Synthesis of medium-sized lactones from siloxy
alkynes via ring expansion, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131163.
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Synthesis of Medium-Sized Lactones from
Siloxy Alkynes via Ring Expansion
Leave this area blank for abstract info.
An Wu, Wanxiang Zhao, and Jianwei Sun
Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China

1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Medium-Sized Lactones from Siloxy Alkynes via Ring Expansion
An Wu, Wanxiang Zhao, and Jianwei Sun
Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of medium ring lactones remains as a challenging topic in organic synthesis due to the
disfavored kinetic and thermodynamic features. Herein we detail an efficient intermolecular
process using siloxy alkynes as substrates and oxetene ring expansion as the key strategy. With
extension to a new silyl-masked alkyne, this reaction now features a broad scope, high
efficiency, and mild conditions.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
medium-sized lactones
siloxy alkynes
ring expansion
———
Corresponding author. Tel.: +852-2358-7351; fax: +842-2358-1594; e-mail: sunjw@ust.hk

2
Tetrahedron
1. Introduction
efficient intermolecular strategies for this purpose remain in high
demand. Herein, we describe our recent detailed efforts in the
design and realization of an improved intermolecular strategy
employing siloxy alkynes.8
Medium ring (typically 8~11-membered ring) lactones are
important substructures in a range of bioactive molecules and
natural products.1 They constitute the core of many of these
useful molecules (e.g., I, II) and contribute significantly to their
unique bioactivities (Figure 1).2 Despite their substantial
significance, medium-ring (particularly 8-membered) lactones
are not straightforward to synthesize when compared with their
counterparts of other ring sizes.3 The challenge mainly lies in the
disfavored kinetic and thermodynamic profiles during their
formation resulting from the disfavored ring strain and
transannular interactions.3 Consequently, the development of
efficient strategies for the synthesis of medium-ring lactones has
been a long-standing topic receiving substantial attention from
the synthetic community.4-6
2. Results and discussion
We envisioned that the expansion of a strained ring
intermediate embedded in a bicyclic system could be potentially
employed to overcome the disfavored high barrier typically
encountered in the cyclization strategy.9 For example, upon
activation a six-membered cyclic acetal 1 can form a cyclic
oxonium intermediate A, which can react with a siloxy alkyne 2
(via ynolate intermediate) to form the [2+2] cycloadduct C
(Scheme 2). The cycloaddition might be stepwise via the
intermediacy of ketene B. The key bicyclic oxetenium
intermediate C then undergoes electrocyclic opening with
concomitant ring expansion to form the 8-membered ring lactone
3. This strategy excludes the possibility of intermolecular
dimerization. Therefore, low concentration or slow addition is
not necessary in principle. It is also worth noting that, although
electrocyclic opening of oxetene is a known process in a bicyclic
context, previously all the cases did not result in ring
enlargement.10 The desired expansion can only take place when
the two rings are fused at the C‒O bond (Scheme 3).
Figure 1. Selected natural products and bioactive molecules
containing medium-sized lactone motif.
R'
R'
OTIPS
O
LA
+
O
O
LG
Among the various existing approaches, the most general one
is intramolecular cyclization from a linear substrate. Specifically,
intramolecular lactonization from the corresponding seco-acids
and ring-closing metathesis from the corresponding dienes
represent the two major approaches (Scheme 1).4,5 However, the
intramolecular cyclization is known to encounter competition
with the intermolecular dimerization process, since the latter does
not suffer from ring strain or transannular interactions. By
manipulating the conditions, such as a low concentration
(typically at μM level) or slow addition of substrate, the desired
intramolecular ring formation could be enhanced to some degree.
This effect is owing to the first-order substrate kinetics for the
intramolecular reaction, which is less sensitive to concentration
decrease than the second-order dimerization process. However,
this improvement is not always predictable or satisfactory.
Moreover, it is at the cost of solvent, operational simplicity, and
applicability in large-scale synthesis.
R
R
3
1
2
R'
R'
R'
R
O
O
O
R
R
A
O
C
B
O
O
LA
LA
LA
Scheme 2. Design of the ring expansion strategy.
Scheme 3. Oxetene ring opening in a bicyclic context.
Scheme 1. Current general synthetic strategies.
While intramolecular cyclization for medium ring synthesis
has been already challenging, it is a more formidable task to
realize intermolecular reaction to achieve this goal, although it is
highly desirable for convergent synthesis. Indeed, there are only
very limited examples of intermolecular reactions for the
assembly of medium-ring lactones.7 In this context, more
We began our study with cyclic acetal 1a and siloxy alkyne 2a
as the model substrates. After considerable efforts in studying the
reaction conditions, we were able to achieve the desired lactone
formation in 91% yield as a single isomer without high dilution
(0.1 M concentration in DCM, Table 1, entry 1). Under the
standard conditions, BF3-OEt2 was found to be the best Lewis

3
acid promoter. Various other Lewis acids were not effective.
Brønsted acid HNTf2 did not lead to the desired product 3a. It is
worth noting that two equivalents of BF3-OEt2 have to be used in
combination with one equivalent of 2,4,6-collidine as an additive
to achieve the best efficiency. Removing or decreasing the
loading of either of them resulted in low yield (entries 4‒6).
Replacing the additive to pyridine completely shut down the
reactivity (entry 7), and the use of 2,6-di(tert-butyl)pyridine led
to a significantly lower yield (entry 8).
This ring expansion process is general in terms of various
cyclic acetals and siloxy alkyne partners. A range of 8-membered
lactones with diverse substituents at different positions were
successfully synthesized (Table 2). The mild conditions also
tolerated a range of functional groups. Notably, the cyclic ketal
substrate 1q was also successfully employed to form 2,3-
disubstituted lactone 3q in good yield.
Table 2. Scope for eight-membered lactone synthesis a
Table 1. Evaluation of reaction conditions
a Other Lewis acids (1 equiv) in place of BF3-OEt2 and collidine:
TiCl4, TMSOTf, SnCl4, Sc(OTf)3 (5 mol%), AgNTf2 (5 mol%),
Au(PPh3)NTf2 (5 mol%). b NMR yield with CH2Br2 as an internal
standard.
a Isolated yield, Z/E >20:1. b Run at r.t.
The dramatic influence of the collidine additive could be
explained by its ability in reversible stabilization of the oxonium
intermediate A (Scheme 4). In the absence of collidine, oxonium
A underwent facile deprotonation to form D followed by
oligomerization (path a), which is competing with the desired
path toward lactone 3 (path b). When collidine is added, it forms
an adduct E with oxonium A (path c), which prevents it from
decomposition. The presence of a characteristic peak at ~6.0 ppm
in 1HNMR spectroscopy is in agreement with its formation
according to the observation of Fujioka and Kita.11 Moreover, it
is important to note that the presence of two ortho-methyl groups
in collidine makes this process reversible. The oxonium A can
still be regenerated when needed, for example, when the alkyne
nucleophile is ready. Thus, this reversible stabilization is crucial
to the observed high efficiency. In contrast, the pyridine adduct F
is highly stable, which makes this step irreversible and thus leads
to no lactone product formation (path d).
In addition to 8-membered lactone formation, this protocol is
also applicable to the synthesis of other-sized lactones (Table 3).
Starting from 5-, 7-, 8-, 16-membered acetals, their
corresponding expanded lactone products were all formed in
moderate to good yields. It is worth noting that the acetal 1v
derived from 2-deoxy-D-ribose, an important sugar unit in DNA,
was also expanded to the corresponding chiral 7-membered
lactone 3v in 46% yield (entry 5). This experiment implied new
applications of natural sugar molecules in asymmetric synthesis.
Notably, only Z-alkene configuration was observed in 7- to 9-
membered lactones made from this protocol, but an E/Z mixture
was formed for 10-membered product 3x and only the E isomer
was observed in the case of 18-membered lactone 3y. These
observations indicated that the product configuration might be
determined by the thermodynamic stability of the isomers in each
case via the torquoselective electrocyclic opening of the
oxetenium intermediate.8a,12 It is also worth noting that acetate
(OAc) also served as a good leaving group in the acetal substrates
(1w-1y). The reactivity of these acetals was essentially the same
as those with methoxide (MeO) as leaving group.
Scheme 4. Role of the collidine additive

4
Tetrahedron
Table 3. Synthesis of other-sized lactones a
Indeed, we were pleased to find that, with slight modification
o
of the reaction temperature (starting from ‒78 C), siloxy alkyne
4c reacted with various cyclic acetals (mostly bearing an acetate
leaving group) smoothly to form a range of α-silyl lactones 5 in
moderate to good yields (Table 4). Thus, the scope of this
reaction is now further expanded and expected to be more
practically useful.
Table 4. Synthesis of α-TMS lactones a
a Same conditions as in Table 2. Isolated yield, Z/E >20:1. b Run
at r.t.
a
b
Isolated yield, Z/E >20:1, LG = OAc unless otherwise noted.
LG = OMe.
While the reaction scope with respect to cyclic acetals and the
product ring sizes is generally good, it is worth noting that the
lactones made so far all have an alkyl or an aryl group substituted
at the α-position. Since many useful medium lactones are
unsubstituted in this position (Figure 1), the current protocol
represents a significant drawback. Moreover, due to the limited
synthetic protocol of siloxy alkynes, which typically used strong
base, siloxy alkynes bearing base-labile functional groups could
not be easily prepared. In this context, we envisioned that the
terminal version or a masked terminal siloxy alkyne should be
developed to address the current limitations. Therefore, we spent
a great amount of effort to make the terminal siloxy alkyne 4a
using various synthetic approaches. Unfortunately, this alkyne
was not stable enough to be obtained in reasonable purity, nor its
analogues with a bulkier silyl group reported by Danheiser.13
Next, we resorted to other masked alkynes, such as bromo- and
silyl-substituted siloxy alkynes (4b and 4c). While the former
was still not successfully prepared, it is gratifying that the TMS-
masked alkyne 4c could be made in good purity. It is expected
that the TMS group can be easily removed or transformed to
groups to serve the above purpose, provided that it can participate
in this lactone formation process.
To further demonstrate the utility of the α-silyl lactones 7, we
carried out some derivatizations of the model compound 5a
(Scheme 5). For example, the TMS group could be easily
removed to form α-unsubstituted 6 or halogenated to form 7 and
8. The α-iodo lactone 8 could easily undergo Suzuki coupling to
form 9 and Sonogashira reaction to form enyne-lactone 10,
respectively. It is worth noting that direct synthesis of 10 using
the corresponding siloxy 1,3-diyne and a cyclic acetal was not
successful. This example represents a remedy of the drawbacks
of the standard protocol. To the best of our knowledge, it is the
first demonstration of using a silyl-substituted siloxy alkyne (4c)
to serve as a masked alternative to the unavailable terminal or
halogenated siloxy alkynes.

5
CsF
NBS
TMS
Br
O
MeCN
60 °C
O
O
DMF
rt
O
5a
O
O
7, 71%
6, 49%
MeCN
rt
I2, AgNO3
PhB(OH)2
Pd(PPh3)4
K2CO3
1-hexyne
CuI, Pd(PPh3)4
Ph
I
O
O
8, 63%
O
nBu
THF/H2O = 1:1
80 °C
Et3N, rt
O
O
O
10, 81%
9, 61%
Scheme 7. Proposed mechanism
Scheme 5. Derivatizations of the α-TMS lactone 5a
To substantiate this mechanism, we also carried out some
control experiments (Scheme 8). Considerable efforts were paid
to examine whether ketene B is a viable intermediate. Thus,
ketene B-Ph was separately prepared in situ from the
corresponding acid B’. Upon treatment of BF3-OEt2, the 8-
membered lactone 3c was formed as the major product. This
observation is an important evidence for the chemical
competence of the ketene B intermediate. Next, the reactivity of
some special acetals were examined. For example, acetals 13 and
15 were subjected to the standard reaction with 2a. The
corresponding linear esters 12 and 14 were both formed with
good efficiency, which agrees well with the proposed mechanism
via intermediates H and J, respectively. Furthermore, orthoester
17 also participated in the ring expansion (via intermediate K) to
form lactone 18 successfully. Finally, we found that the linear 7-
hydroxy ester 19 could not be converted to lactone 3a, which
suggested that this reaction should not involve ring-opening
followed by olefination and then cyclization.
In view of the structural relationship between the cyclic acetal
substrate and the lactone product, we envisioned iterative ring
expansions (Scheme 6a). For example, the lactone product can be
reduced and converted to a cyclic acetal, which can serve as the
substrate for a further expansion step to afford the formal
[n+2+2]-membered lactone product. In principle, this ring can be
further expanded by repeating the same steps. Therefore, lactones
of all sizes, both odd- and even-membered ones, can be
potentially obtained from 5- and 6-membered acetals as the
starting substrates, respectively. To demonstrate the feasibility,
we carried out an iterative expansion of acetal 1r′ (Scheme 6b).
After expansion twice and two steps for functional group
conversion, the 9-membered lactone 12 was successfully
obtained (via 3r and 11).
Scheme 6. Iterative ring expansions
A plausible mechanism is proposed in Scheme 7. We believe
that the Lewis acid promoter BF3 initially activates the acetal to
form oxonium A and trifluoroborate F, which then activates the
siloxy alkyne to form the highly nucleophilic ynolate G and
TIPSF. The latter was observed from the reaction. The following
steps as well as the reversible stabilization are same as discussed
earlier.
Scheme 8. Control experiments

6
Tetrahedron
o
t
3. Conclusions
(60 mL) was cooled to −78 C. BuOOH (6.77 mL, 22 mmol,
3.25 M in toluene) was added over 10 min followed by adding
LHMDS (57.5 mL, 46 mmol, 0.8 M in THF) over 16 min.
In summary, we have developed an efficient intermolecular
n
process for the synthesis of medium-sized lactones. It takes
advantage of the versatile siloxy alkynes as the key reaction
partner as well as the expansion of oxetene as the key strategy to
overcome the disfavored kinetic and thermodynamic profile
typically encountered from medium ring synthesis. As a result,
this protocol does not need to use low concentration or slow
addition of substrates to disfavor the intermolecular competition.
In particular, the failure to prepare terminal siloxy alkynes
prompted us to realize this goal by a TMS-masked analogue.
This process, featuring high efficiency, mild conditions, a broad
scope, and operational simplicity, is expected to find applications
in organic synthesis.
LHMDS was made previously by adding BuLi (a solution in
hexane) to a solution of HMDS in THF at 0 C. The reaction
o
o
o
mixture was stirred at −78 C for 45 min and then at 0 C for 45
min. Next, the mixture was cooled to −78 oC, and TIPSOTf (5.19
mL, 22 mmol) was added over 6 min. The mixture was stirred at
−78 oC for 15 min and then at 0 C for 10 min. The mixture was
o
then diluted with hexanes (140 mL) and poured into a saturated
aqueous NaHCO3 solution (90 mL). Hexanes (70 mL) were used
to wash the flask. The layers were separated. The aqueous layer
was extracted with hexanes (3×60 mL). The combined organic
layers were washed with a saturated aqueous Na2S2O4 solution
(60 mL) and brine (2×60 mL), dried with anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by bulb-to-
bulb distillation to give the desired product in 77% yield (4.15 g).
1H NMR (400 MHz, CDCl3) δ 1.33 - 1.21 (m, 3H), 1.12 (d, J =
7.1 Hz, 18H), 0.09 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 107.7,
29.6, 17.2, 11.9, 0.8. IR (thin film) 2956, 2869, 2459, 2187,
1463, 1398, 1243 cm-1. HRMS (CI) calcd for C14H30OSi2 (M+):
270.1835, found: 270.1841.
4. Experimental section
4.1. General
All air or moisture sensitive reactions were conducted in oven-
dried glassware under nitrogen atmosphere using dry solvents.
Flash column chromatography was performed over silica gel
(230-400 mesh) purchased from Qindao Puke Co., China.
Anhydrous dichloromethane was distilled with calcium hydride.
1H and 13C NMR spectra were collected on a Bruker AV 400
MHz NMR spectrometer using residue solvent peaks as an
internal standard (1H NMR: CDCl3 at 7.26 ppm, C6D6 at 7.16
ppm, CD3CN at 1.94 ppm, 13C NMR: CDCl3 at 77.0 ppm, C6D6
at 128.06 ppm, CD3CN at 118.26 ppm). Mass spectra were
collected on an Agilent GC/MS 5975C system, or a MALDI
Micro MX mass spectrometer, or an API QSTAR XL System.
The synthetic procedures and characterization data for
compounds 1–3 (except 3v) and 11–19 have been reported
previously.9
4.2.3. General procedure for the synthesis of α-TMS lactones
(5a-5m). At room temperature under N2, an oven-dried 25-mL
Schlenk tube was charged with the acetal 1 (0.5 mmol, 1.0
equiv), the alkyne 4c (0.6 mmol, 1.2 equiv), 2,4,6-collidine (0.5
mmol, 1.0 equiv), and CH2Cl2 (5.0 mL). The reaction mixture
o
was cooled to −78 C followed by addition of BF3-OEt2 (126.7
μL, 1.0 mmol, 2.0 equiv). The reaction mixture was then warmed
slowly to room temperature and stirred overnight. Next, the
reaction was quenched by addition of a saturated aqueous
NaHCO3 solution (8 mL). The layers were separated, and the
organic layer was extracted by DCM (10 mL×3). The combined
organic layers were washed with brine (10 mL), dried with
anhydrous Na2SO4, filtered, and concentrated. The crude product
was purified by silica gel to afford the pure product 5.
4.2. Procedures
4.2.3.1. (E)-3-(Trimethylsilyl)-5,6,7,8-tetrahydro-2H-oxocin-
2-one (5a) was prepared as a colorless oil according to the
General Procedure (12 h, eluent: hexanes/EtOAc = 20:1) in 81%
4.2.1
dihydrooxepin-2(5H)-one (3v). Under N2 atmosphere, to an oven-
dried flask was added (2R,3S)-3,5-Dimethoxy-2-
(6S,7R)-3-Butyl-6-methoxy-7-(methoxymethyl)-6,7-
1
yield (79.8 mg). H NMR (400 MHz, CDCl3) δ 6.32 (t, J = 5.9
(methoxymethyl)tetrahydrofuran (1v) (88.1 mg, 0.5 mmol), the
siloxy alkyne 2 (181.8 mg, 0.6 mmol), 2,4,6-collidine (0.5 mmol)
and anhydrous DCM (2.5 mL). The flask was cooled to 0 oC, and
BF3·OEt2 (1.0 mmol) was added. The reaction mixture was
stirred for 23 h. Upon completion, the reaction was quenched
with saturated NaHCO3 aqueous solution (5 mL) and then diluted
with DCM (15 mL). The organic layer was separated and
extracted by DCM (10 mL) for 3 times. Washed with brine (10
mL) and dried with Na2SO4, filtered and concentrated. The
residue was purified by silica gel chromatography (eluent:
hexanes/EtOAc = 10:1) to afford the desired product 3v as
yellow oil in 46% yield (55.9 mg). 1H NMR (400 MHz, CDCl3) δ
6.19 - 6.10 (m, 1H), 4.08 (ddd, J = 9.3, 5.3, 2.3 Hz, 1H), 3.78 -
3.61 (m, 3H), 3.42 (s, 3H), 3.36 (s, 3H), 2.65 - 2.55 (m, 1H), 2.51
- 2.40 (m, 1H), 2.34 - 2.16 (m, 2H), 1.52 - 1.39 (m, 2H), 1.39 -
1.29 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 170.7, 137.7, 131.4, 79.9, 78.8, 71.5, 59.3, 57.1, 32.6,
30.6, 27.4, 22.3, 13.8. IR (neat) 3056, 2930, 2871, 2828, 1720,
1457, 1100, 732 cm-1. HRMS (CI) calcd for C13H23O4 (M+H+):
243.1596, found: 243.1595.
Hz, 1H), 4.29 (t, J = 5.6 Hz, 2H), 2.39 - 2.24 (m, 2H), 1.92 - 1.78
(m, 2H), 1.71 - 1.61 (m, 2H), 0.16 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 174.3, 145.3, 133.9, 67.1, 31.9, 30.4, 19.8, −1.7. IR
(thin film) 2951, 1704, 1617, 1240, 1170 cm-1. HRMS (CI) calcd
for C10H19O2Si (M+H+): 199.1154, found: 199.1153.
4.2.3.2. (E)-8-Methyl-3-(trimethylsilyl)-5,6,7,8-tetrahydro-2H-
oxocin-2-one (5b) was prepared as a white solid according to the
General Procedure (12 h, eluent: hexanes/EtOAc = 40:1) in 62%
1
yield (66.3 mg). H NMR (400 MHz, CDCl3) δ 6.30 - 6.22 (m,
1H), 4.71 - 4.61 (m, 1H), 2.46 - 2.35 (m, 1H), 2.27 - 2.13 (m, 1H),
1.87 - 1.72 (m, 2H), 1.68 - 1.48 (m, 2H), 1.26 (d, J = 6.4 Hz, 3H),
0.13 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 174.1, 144.8, 134.2,
74.1, 38.0, 32.6, 21.7, 19.9, −1.8. IR (thin film) 2945, 1700, 1623,
1241, 1207 cm-1. HRMS (CI) calcd for C11H21O2Si (M+H+):
213.1311, found: 213.1313.
4.2.3.3.
(E)-6,6-Dimethyl-3-(trimethylsilyl)-5,6,7,8-
tetrahydro-2H-oxocin-2-one (5c) was prepared as a white solid
according to the General Procedure (12 h, eluent: hexanes/EtOAc
1
= 40:1) in 77% yield (69.4 mg). H NMR (400 MHz, CDCl3) δ
6.26 (t, J = 8.3 Hz, 1H), 4.47 - 3.99 (m, 2H), 2.26 - 1.92 (m, 2H),
1.83 - 1.51 (m, 2H), 0.95 (s, 6H), 0.17 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 173.3, 143.5, 137.5, 65.0, 44.4, 41.7, 30.4, 17.7,
4.2.2. Triisopropyl(((trimethylsilyl)ethynyl)oxy)silane (4c). A
solution of trimethylsilylacetylene (2.77 mL, 20.0 mmol) in THF

7
−1.9. IR (thin film) 2957, 2914, 2869, 1697, 1253 cm-1. HRMS
(CI) calcd for C12H23O2Si (M+H+): 227.1467, found: 227.1473.
Procedure (12 h, eluent: hexanes/EtOAc = 40:1) in 72% yield
1
(94.1 mg). H NMR (400 MHz, CDCl3) δ 7.45 - 7.26 (m, 5H),
6.67 (dd, J = 7.2, 5.6 Hz, 1H), 5.16 (dd, J = 11.4, 4.1 Hz, 1H),
2.60 - 2.41 (m, 2H), 2.28 (dddd, J = 14.5, 11.3, 8.0, 3.3 Hz, 1H),
2.09 (dddd, J = 14.4, 10.5, 7.7, 4.1 Hz, 1H), 0.22 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 171.6, 145.5, 139.8, 139.4, 128.5,
128.0, 126.2, 78.7, 34.7, 26.5, −1.4. IR (thin film) 3029, 2956,
2866, 1708, 1330, 1241 cm-1. HRMS (CI) calcd for C15H21O2Si
(M+H+): 261.1311, found: 261.1315.
4.2.3.4. (E)-8-Oxo-7-(trimethylsilyl)-3,4,5,8-tetrahydro-2H-
oxocin-3-yl benzoate (5d) was prepared as a white solid
according to the General Procedure (12 h, eluent: hexanes/EtOAc
1
= 40:1) in 69% yield (110.4 mg). H NMR (400 MHz, CDCl3) δ
8.11 - 8.03 (m, 2H), 7.63 - 7.53 (m, 1H), 7.50 - 7.40 (m, 2H),
6.34 (t, J = 4.6 Hz, 1H), 5.23 - 5.17 (m, 1H), 4.53 - 4.35 (m, 2H),
2.69 - 2.56 (m, 1H), 2.43 - 2.28 (m, 1H), 2.21 - 1.99 (m, 2H),
0.19 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 173.7, 165.5, 144.1,
133.2, 129.7 (2C), 128.3 (2C), 72.8, 67.9, 28.4, 24.0, −1.7. IR
(thin film) 3067, 2957, 2894, 1715, 1612, 1456, 1268 cm-1.
HRMS (CI) calcd for C17H23O4Si (M+H+): 319.1366, found:
319.1356.
4.2.3.10. 5,5-Diphenyl-3-(trimethylsilyl)-6,7-dihydrooxepin-
2(5H)-one (5j) was prepared as a white solid according to the
General Procedure (46 h, eluent: hexanes/EtOAc = 40:1) in 46%
1
yield (62.4 mg). H NMR (400 MHz, CDCl3) δ 7.37 - 7.29 (m,
4H), 7.28 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.18 - 7.11 (m, 4H),
6.90 (s, 1H), 4.30 - 4.23 (m, 2H), 2.80 - 2.73 (m, 2H), 0.24 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 170.6, 153.7, 146.1, 134.9,
128.7, 127.7, 126.8, 64.1, 57.0, 40.4, −1.0. IR (thin film) 3060,
3029, 2956, 2903, 2861, 1691, 1250, 1207 cm-1. HRMS (CI)
calcd for C21H23O2Si (M-H+): 335.1467, found: 335.1454.
4.2.3.5. (E)-7-((tert-Butyldimethylsilyl)oxy)-3-(trimethylsilyl)-
5,6,7,8-tetrahydro-2H-oxocin-2-one (5e) was prepared as a white
solid according to the General Procedure (11 h, eluent:
1
hexanes/EtOAc = 100:1) in 55% yield (71.6 mg). H NMR (400
MHz, CDCl3) δ 6.32 (t, J = 5.0 Hz, 1H), 4.18 - 4.08 (m, 1H), 4.08
- 3.97 (m, 2H), 2.54 (dddd, J = 18.0, 11.0, 4.8, 2.0 Hz, 1H), 2.21
(dddd, J = 18.6, 8.6, 5.2, 1.8 Hz, 1H), 1.99 - 1.88 (m, 1H), 1.68 -
1.52 (m, 1H), 0.88 (s, 9H), 0.16 (s, 9H), 0.06 (s, 6H). 13C NMR
(101 MHz, CDCl3) δ 174.0, 145.7, 132.9, 69.9, 27.6, 26.8, 25.7,
18.0, −1.7, −4.89, −4.90. IR (thin film) 2950, 2893, 2861, 1712,
1623, 1462, 1251 cm-1. HRMS (CI) calcd for C16H33O3Si2
(M+H+): 329.1968, found: 329.1971.
4.2.3.11.
(E)-3-(Trimethylsilyl)-6,7,8,9-tetrahydrooxonin-
2(5H)-one (5k) was prepared as a yellow oil according to the
General Procedure (20 h, eluent: hexanes/EtOAc = 100:1) in 47%
yield (49.7 mg). H NMR (400 MHz, CDCl3) δ 6.45 (t, J = 7.2
Hz, 1H), 4.31 (t, J = 5.6 Hz, 2H), 2.39 (td, J = 7.0, 3.3 Hz, 2H),
1.83 - 1.73 (m, 2H), 1.64 - 1.52 (m, 4H), 0.16 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ 172.8, 150.7, 138.2, 67.3, 30.1, 28.3, 27.8,
26.5, -1.6. IR (thin film) 2946, 2862, 1710, 1458, 1216 cm-1.
HRMS (CI) calcd for C11H21O2Si (M+H+): 213.1311, found:
213.1310.
1
4.2.3.6. (E)-7-(Allyloxy)-3-(trimethylsilyl)-5,6,7,8-tetrahydro-
2H-oxocin-2-one (5f) was prepared as a pale yellow oil from
according to the General Procedure (12 h, eluent: hexanes/EtOAc
1
= 20:1) in 81% yield (102.5 mg). H NMR (400 MHz, CDCl3) δ
4.2.3.12. 3-(Trimethylsilyl)oxacyclooctadec-3-en-2-one (5l)
was prepared as a colorless oil according to the General
Procedure (20 h, eluent: hexanes/EtOAc = 100:1) in 84% yield
(t, J = 5.0 Hz, 1H), 5.88 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H), 5.27
(dd, J = 17.2, 1.6 Hz, 1H), 5.18 (dd, J = 10.3, 1.3 Hz, 1H), 4.26 -
4.15 (m, 2H), 4.09 - 3.95 (m, 2H), 3.71 - 3.63 (m, 1H), 2.52
(dddd, J = 18.6, 10.3, 4.9, 2.2 Hz, 1H), 2.21 (dddd, J = 18.6, 9.1,
5.2, 2.0 Hz, 1H), 1.93 (dddd, J = 15.7, 10.3, 3.6, 2.0 Hz, 1H),
1.84 - 1.71 (m, 1H), 0.16 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
173.9, 145.2, 134.5, 133.2, 117.3, 76.2, 70.0, 67.6, 27.3, 24.2,
−1.72. IR (thin film) 3083, 2954, 2891, 1707, 1616, 1459, 1248
cm-1. HRMS (CI) calcd for C13H23O3Si (M+H+): 255.1416, found:
255.1418.
1
(141.6 mg, Z/E = 1:1.25). H NMR (400 MHz, CDCl3) δ 7.10 (t,
J = 7.4 Hz, 1H), 6.05 (t, J = 7.3 Hz, 1.25H), 4.21 - 4.09 (m, 4.5H),
2.37 - 2.23 (m, 4.5H), 1.70 - 1.59 (m, 4.5H), 1.51 - 1.22 (m,
49.5H), 0.22 (s, 9H), 0.12 (s, 11.25H). 13C NMR (101 MHz,
CDCl3) δ 171.3, 156.5, 149.2, 136.8, 135.0, 64.1, 63.9, 31.8, 30.8,
28.8, 28.6, 28.4, 28.28, 28.25, 28.1, 27.78, 27.76, 27.74, 27.63
(2C), 27.61, 26.8, 26.7, 26.6, 26.34, 26.30, 26.1, 26.0, 25.2, 25.1,
0.6, -1.5. IR (thin film) 2929, 2857, 1705, 1608, 1457, 1249 cm-1.
HRMS (CI) calcd for C20H38O2Si (M+H+): 338.2641, found:
338.2630.
4.2.3.7. (E)-7-(Prop-2-yn-1-yloxy)-3-(trimethylsilyl)-5,6,7,8-
tetrahydro-2H-oxocin-2-one (5g) was prepared as a white solid
according to the General Procedure (12 h, eluent: hexanes/EtOAc
4.2.3.13.
(E)-5-(Trimethylsilyl)-1,2-dihydro-4H-
benzo[d]oxocin-4-one (5m) was prepared as a white solid
1
= 20:1) in 83% yield (104.7 mg). H NMR (400 MHz, CDCl3) δ
6.31 (t, J = 5.0 Hz, 1H), 4.31 - 4.23 (m, 2H), 4.22 - 4.17 (m, 2H),
3.93 - 3.84 (m, 1H), 2.53 (dddd, J = 18.7, 10.1, 4.9, 2.2 Hz, 1H),
2.44 (t, J = 2.4 Hz, 1H), 2.23 (dddd, J = 18.7, 9.2, 5.1, 2.1 Hz,
1H), 1.95 (dddd, J = 15.8, 10.2, 3.7, 2.1 Hz, 1H), 1.88 - 1.75 (m,
1H), 0.16 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 173.7, 145.1,
133.2, 79.4, 75.9, 74.7, 67.3, 56.2, 27.4, 24.0, −1.7. IR (thin film)
3298, 2955, 2894, 1702, 1644, 1457, 1247 cm-1. HRMS (CI)
calcd for C13H21O3Si (M+H+): 253.1260, found: 253.1250.
according to the General Procedure (20 h, eluent: hexanes/EtOAc
= 40:1) in 88% yield (108.9 mg). H NMR (400 MHz, CDCl3) δ
1
7.23 - 7.16 (m, 2H), 7.16 - 7.09 (m, 2H), 7.09 - 7.04 (m, 1H),
4.57 (t, J = 6.7 Hz, 2H), 3.24 (t, J = 6.7 Hz, 2H), 0.28 (s, 9H). 13
C
NMR (101 MHz, CDCl3) δ 173.5, 142.5, 139.9, 136.4, 132.9,
132.2, 129.6, 128.9, 126.2, 67.0, 36.4, −1.7. IR (thin film) 3061,
2959, 2904, 1710, 1601, 1251, 1172 cm-1. HRMS (CI) calcd for
C14H18O2Si (M+): 246.1076, found: 246.1071.
4.2.3.8. 3-(Trimethylsilyl)-6,7-dihydrooxepin-2(5H)-one (5h)
was prepared as a pale yellow solid according to the General
Procedure (12 h, eluent: hexanes/EtOAc = 40:1) in 77% yield
(71.0 mg). 1H NMR (400 MHz, CDCl3) δ 6.56 (t, J = 6.3 Hz, 1H),
4.14 (t, J = 5.9 Hz, 2H), 2.39 (td, J = 7.4, 6.2 Hz, 2H), 1.96 (tt, J
= 7.3, 5.8 Hz, 2H), 0.18 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
173.2, 145.6, 139.1, 65.7, 26.5, 26.1, −1.4. IR (thin film) 2960,
2865, 1710, 1470, 1329, 1244 cm-1. HRMS (CI) calcd for
C9H17O2Si (M+H+): 185.0998, found: 185.0993.
4.2.4. (Z)-5,6,7,8-Tetrahydro-2H-oxocin-2-one (6). At room
temperature under N2, to an oven-dried 25-mL Schlenk tube were
added cesium fluoride (227.9 mg, 1.5 mmol), acetonitrile (5 mL)
and lactone 5a (99.2 mg, 0.5 mmol). The mixture was heated to
o
60 C and stirred at the same temperature overnight. Next, water
(5 mL) was added. The layers were separated, and the aqueous
layer was extracted by diethyl ether (5 mL×3). The combined
organic layers were washed with brine (10 mL), dried with
Na2SO4, filtered, and concentrated. The crude product was
purified by silica gel flash chromatography (eluent:
4.2.3.9. 7-Phenyl-3-(trimethylsilyl)-6,7-dihydrooxepin-2(5H)-
one (5i) was prepared as a white solid according to the General

8
Tetrahedron
hexanes/EtOAc = 10:1) to afford the desired product 6 as
colorless oil in 49% yield (30.6 mg). 1H NMR (400 MHz, CDCl3)
δ 6.26 (dt, J = 12.8, 4.9 Hz, 1H), 5.72 (dt, J = 12.7, 2.0 Hz, 1H),
4.45 - 4.35 (m, 2H), 2.38 - 2.29 (m, 2H), 1.89 - 1.83 (m, 2H),
1.83 - 1.70 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.4, 141.7,
116.9, 67.3, 30.6, 29.8, 18.8. IR (thin film) 2934, 2878, 1705,
1638, 1180 cm-1. HRMS (CI) calcd for C7H11O2 (M+H+):
127.0759, found: 127.0754.
4.2.8. (Z)-3-(Hex-1-yn-1-yl)-5,6,7,8-tetrahydro-2H-oxocin-2-
one (10). At room temperature under N2, a 25-mL Schlenk tube
was charged with CuI (4.76 mg, 0.025 mmol), Pd(PPh3)4 (28.9
mg, 0.025 mmol) and Et3N (4 mL). Next, iodolactone 8 (126.0
mg, 0.5 mmol) and 1-hexyne (82.1 mg, 1.0 mmol) were added.
The reaction mixture was stirred at room temperature. Upon
completion (~ 42 h), the mixture was filtered, and the filtrate was
concentrated. The crude product was purified by silica gel
chromatography (eluent: hexanes/EtOAc = 20:1) to afford the
desired product 10 as brown oil in 81% yield (83.8 mg). 1H NMR
(400 MHz, CDCl3) δ 6.41 (t, J = 7.2 Hz, 1H), 4.46 - 4.38 (m, 2H),
2.34 - 2.24 (m, 4H), 1.94 - 1.83 (m, 2H), 1.70 - 1.57 (m, 2H),
1.56 - 1.44 (m, 2H), 1.44 - 1.34 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 168.6, 142.5, 115.4, 91.1, 76.7,
68.6, 30.5, 29.7, 28.7, 21.9, 20.4, 19.0, 13.5. IR (thin film) 2938,
2869, 1726, 1462, 1156 cm-1. HRMS (CI) calcd for C13H19O2
(M+H+): 207.1385, found: 207.1381.
4.2.5. (E)-3-Bromo-5,6,7,8-tetrahydro-2H-oxocin-2-one (7).
At room temperature under N2, to an oven-dried 25-mL Schlenk
tube wrapped with a piece of tin foil paper were added NBS
(222.5 mg, 1.25 mmol), DMF (2 mL), and lactone 5a (99.2 mg,
0.5 mmol). The mixture was stirred for about 3.5 days before
water (3 mL) was added. The layers were separated, and the
aqueous layer was extracted by EtOAc (4 mL×4). The combined
organic layers were sashed with water (5 mL×2) and brine (5
mL), dried with anhydrous Na2SO4, filtered, and concentrated.
The crude product was purified by silica gel flash
chromatography (eluent: hexanes/EtOAc = 20:1) to afford the
desired product 7 as a pale yellow solid in 71% yield (73.1 mg).
1H NMR (400 MHz, CDCl3) δ 6.61 (t, J = 6.8 Hz, 1H), 4.45 (t, J
= 5.4 Hz, 2H), 2.34 - 2.25 (m, 2H), 1.96 - 1.85 (m, 2H), 1.71 -
1.62 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 166.5, 139.8, 106.4,
68.7, 30.2, 29.5, 19.5. IR (thin film) 2938, 2872, 1713, 1635,
1462, 1266, 1178 cm-1. HRMS (CI) calcd for C7H10BrO2 (M+H+):
204.9864, found: 204.9868.
Acknowledgments
Financial support was provided by NSFC (21572192,
21490570) and Hong Kong RGC (16302318) and Shenzhen
Science
and
Technology
Innovation
Committee
(JCYJ20170818113708560).
Supplementary data
4.2.6. (E)-3-Iodo-5,6,7,8-tetrahydro-2H-oxocin-2-one (8). At
room temperature, under N2, an oven-dried 25-mL Schlenk tube
was wrapped with tin foil paper and charged with AgNO3 (79.6
mg, 1.5 mmol) in acetonitrile (3 mL). The mixture was stirred for
5~10 min and then cooled to 0 oC. The starting materials 5a (62.0
mg, 0.31 mmol) was added, followed by I2 (103.1 mg, 0.41
mmol). The reaction mixture was stirred in the dark for 13 h.
Diluted with diethyl ether (5 mL) and filtered. Washed with
saturated Na2S2O3 (8 mL). The aqueous layer was separated and
extracted by EtOAc (8 mL) for 3 times. The organic layers were
collected and dried with Na2SO4. Filtered and concentrated. The
crude product was purified by silica gel chromatography (eluent:
hexanes/EtOAc = 20:1) to afford the desired product 8 as a
yellow solid in 63% yield (49.7 mg). 1H NMR (400 MHz, CDCl3)
δ 6.82 (t, J = 6.7 Hz, 1H), 4.42 (t, J = 5.2 Hz, 2H), 2.33 - 2.24 (m,
2H), 1.96 - 1.85 (m, 2H), 1.69 - 1.61 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 167.9, 147.7, 78.6, 68.5, 32.5, 29.6, 19.4. IR
(thin film) 2935, 2873, 1715, 1622, 1462, 1176 cm-1. HRMS (CI)
calcd for C7H10IO2 (M+H+): 252.9725, found: 252.9729.
The procedures for the synthesis of substrates together with 1H
and 13C NMR spectra for compounds the new compounds.
Supplementary data associated with this article can be found in
the online version.
References and notes
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4.2.7. (Z)-3-Phenyl-5,6,7,8-tetrahydro-2H-oxocin-2-one (9).
At room temperature, under N2, a 25-mL Schlenk tube was
charged with PhB(OH)2 (91.5 mg, 0.75 mmol), Pd(PPh3)4 (28.9
mg, 0.025 mmol), K2CO3 (138.2 mg, 1.0 mmol), THF (2.5 mL)
and water (2.5 mL). Followed by addition of the starting
materials 8 (126.0 mg, 0.5 mmol). The reaction mixture was
o
heated to 80 C and stirred overnight. Upon completion, diethyl
ether (3 mL) was added and the aqueous layer was separated and
extracted by diethyl ether (3 mL) for 3 times. Washed with brine
(10 mL) and dried with Na2SO4. Filtered and concentrated. The
crude product was purified by silica gel chromatography (eluent:
hexanes/EtOAc = 15:1) to afford the desired product 9 as a
yellow solid in 61% yield (61.4 mg). The characterization data
match the reported data.9

9
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: