Removable Silyl Group as a "masked Proton" in Oxy-2-oxonia(azonia)-Cope Rearrangement: Applications in Stereoselective Total Synthesis of Natural Macrolides

Article abstract of DOI:10.1002/ejoc.201500654

In the presence of a Lewis acid, trimethylsilyl-substituted β,γ-unsaturated ketones and aldehydes (imines) undergo nucleophilic addition to produce zwitterionic intermediates, followed by oxy-2-oxonia(azonia)-Cope rearrangements to give homoallylic esters (amides). In the case of TMS-containing 2-vinylcycloalkanones, the process results in ring-enlargement, providing 10- to 16-membered lactones. This protocol was applied to the total synthesis of (R)-phoracantholide I.

Full text of DOI:10.1002/ejoc.201500654

FULL PAPER
DOI: 10.1002/ejoc.201500654
Removable Silyl Group as a “Masked Proton” in Oxy-2-oxonia(azonia)-Cope
Rearrangement: Applications in Stereoselective Total Synthesis of Natural
Macrolides
Wenbo Mu,[a] Yue Zou,[b] Lijun Zhou,[a,b] Quanrui Wang,*[a] and Andreas Goeke*[b]
Dedicated to Dr. Roman Kaiser
Keywords: Total synthesis / Rearrangement / Sigmatropic rearrangement / Silicon / Protecting groups / Ring expansion /
Macrocycles
In the presence of a Lewis acid, trimethylsilyl-substituted β,γ-
homoallylic esters (amides). In the case of TMS-containing
unsaturated ketones and aldehydes (imines) undergo nucleo- 2-vinylcycloalkanones, the process results in ring-enlarge-
philic addition to produce zwitterionic intermediates, fol-
lowed by oxy-2-oxonia(azonia)-Cope rearrangements to give
ment, providing 10- to 16-membered lactones. This protocol
was applied to the total synthesis of (R)-phoracantholide I.
fashion.[5] However, the γ effect of silicon on carbocations
is much weaker than the β effect. Compared to the β- and
γ-Si effects, the hyperconjugation effect of silicon–carbon
bonds in the α positions of carbocations is less pronounced,
due to the diminished electron density of the longer C–Si
bonds. A recent computational study by Grunenberg et
al.[6] revealed the theoretical gas-phase stabilities of α-tri-
methylsilyl (TMS)-substituted tertiary carbenium ions: the
thermodynamic stabilization of a carbenium ion by a single
α-TMS group is weaker than that by a tert-butyl group, but
much stronger than that by a hydrogen–carbon bond. It is
also greater than the stabilization by a methyl group (Fig-
ure 1).
Introduction
Silyl groups are particularly useful protecting groups in
organic synthesis. They can be used to control the stereo-
chemistry of reactions taking place in their immediate vicin-
ity, for example, to control the geometry of double bonds.[1]
After they have fulfilled their purpose, they can be conve-
niently cleaved under mild conditions using a fluoride
source, which leaves other functional groups intact. This
works especially well for vinylsilanes, in which the silyl
group functions as a bulky but removable “masked proton”
in organic synthesis.[2] Although it is still a matter of debate
whether the influence of silyl groups on reaction rates and
stereochemistry should be ascribed to electronic or steric
factors, the so-called electronic β effect of a silyl group on
carbocations 1 and the γ effect of silicon on carbocations 2
are well studied.[3] The β-silyl stabilization effect of a carbo-
cation 1 is attributed to an interaction of the vacant orbital
of the carbocation with the C–Si σ bond. This β effect can
lead to carbocation formation at rates up to 1011 times
faster than those of unsilylated analogues.[4] The rate-en-
hancement effect triggered by a more remote γ-silyl group
has been attributed to the stabilization of an intermediate
carbocation by the rear lobe of the C–Si σ bond in a “W”
Figure 1. Effects of silyl groups on the stablility of carbocations.
[a] Department of Chemistry, Fudan University,
220 Handan Road, Shanghai, 200433, P. R. China
E-mail: qrwang@fudan.edu.cn
We have recently reported well-organized oxy-oxonia-
(azonia)-Cope rearrangements based on a tandem Lewis-
acid-catalysed crossed dimerization of a β,γ-unsaturated
carbonyl compound with another, different, aldehyde to
produce homoallylic esters or amides through dispropor-
tionation.[7] The reaction was successfully extended to a
new [n + 4] ring enlargement to give macrolides with 9- to
http://www.chemistry.fudan.edu.cn/
[b] Fragrance Ingredient Research Center, Givaudan Fragrances
(Shanghai) Ltd.,
298 Li Shi Zhen Road, Shanghai, 201203, P. R. China
http://www.givaudan.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500654.
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4982–4989

Removable Silyl Group as a “Masked Proton”
Scheme 1. Extension of the Lewis-acid-catalysed oxy-2-oxonia(azonia)-Cope rearrangement concept using silicon-containing substrates.
16-membered rings. The rearrangements proceeded particu- the rearrangements of unsubstituted (R1 = H) vinylcyclo-
larly well in cases where intermediate cations were stabilized alkanone substrates.[9]
by tertiary substitution patterns. α-Unsubstituted substrates
In this paper, we extend the Lewis-acid-catalysed oxy-
8 (Scheme 1, R1 = H) usually gave poor results due to com- 2-oxonia(azonia)-Cope rearrangement concept through the
petitive double-bond isomerization to more thermodynami- idea of removable silyl groups as “masked protons”. We
cally stable conjugated positions (to compound 13, also describe the application of this approach in the synthe-
Scheme 1). To address this limitation, we have investigated sis of natural macrolides.
the use of a TMS group as a bulky but removable “masked
proton” to access trisubstituted silyl-homoallylic alcohol es-
Results and Discussion
ters (amides) and macrocyclic lactones (lactams) (com-
pounds 11 and 12, Scheme 1).[8] The improved synthetic ap-
plicability can be demonstrated by the synthesis of the natu-
ral product (R)-phoracantholide I.
We began our studies by exploring the reaction between
β,γ-unsaturated ketone 8a and acetaldehyde (15a). The
TMS-substituted β,γ-unsaturated substrates were prepared
by ring-opening reactions of epoxides by 1-trimethylsilyl
vinylmagnesium bromide[10] or the corresponding vinyllith-
We envisioned that TMS substitution at the vinyl group
of β,γ-unsaturated carbonyl substrates 8 (R1 = TMS) could
serve three purposes. Firstly, TMS substitution results in a
rate enhancement of the rearrangement due to stabilization
of the intermediate tertiary carbenium ion intermediate
(i.e., 10; R1 = TMS). Furthermore, we speculated that an
accelerated reaction rate could also allow the use of formal-
dehyde as coupling aldehyde (R2 = H), a synthetic short-
coming that has not yet been otherwise overcome in the
oxy-oxonia-Cope reaction.[7a] Secondly, the steric properties
of the silyl group would be expected to suppress competitive
double-bond isomerization to the more thermodynamically
stable conjugated carbonyl by-product (i.e., 13). Finally,
conformational analysis of the transition states suggested
that the steric bulk of the silyl group would favour forma-
tion of E-silylalkene product 11 via preferred intermediate
11Ј, while unfavourable steric interactions within the n-
membered ring carbon chain in an equatorial position of
11ЈЈ should result in higher strain. The exocyclic silyl sub-
stituents on the corresponding [n + 4] ring-enlargement
lactone products (i.e., 11) would be expected to undergo
protodesilylation[2] to give macrocyclic lactones 12 with Z-
disubstituted double bonds; these structural features occur
Table 1. Lewis acid screening for the reaction.[a]
Entry
Lewis acid
Amount of
LA [mol-%]
Time [h] Conversion [%]
1
2
3
4
5
6
7
8
9
ZnCl2
10
10
10
10
10
10
10
10
10
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
0
0
46
41
La(OTf)3
Sc(OTf)3
BF3·Et2O
EtAlCl2
SnCl4
TiCl4
FeCl3
AlCl3
100[b]
87[c]
56
72
[a] Reagents and conditions: a solution of β,γ-unsaturated ketone
8a (0.78 g, 5.0 mmol), acetaldehyde 15a (0.27 g, 6.0 mmol), and a
Lewis acid (LA; 10 mol-%) in 1,2-dichloroethane (10 mL) was
stirred at room temperature for 1 h. The conversion of reaction
was monitored by GC analysis. [b] Isolated yield: 97%. [c] Complex
in several natural products, but are difficult to construct by mixtures of unidentified products.
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W. Mu, Y. Zou, L. Zhou, Q. Wang, A. Goeke
FULL PAPER
ium reagent followed by oxidation. The oxy-2-oxonia-Cope Table 2. Scope of the TMS-directed oxy-2-oxonia-Cope rearrange-
ment.[a]
rearrangement reaction was carried out in 1,2-dichloro-
ethane (0.5 m) in the presence of a range of typical Lewis
acids such as ZnCl2, La(OTf)3, and Sc(OTf)3 (Table 1, en-
tries 1–3), but none of the expected homoallylic ester (i.e.,
11a) was obtained. Further screening revealed that stronger
Lewis acids such as BF3·Et2O and EtAlCl2 could promote
the desired process, albeit with low conversions (46 and
41%; see Table 1, entries 4 and 5).
Satisfactorily, complete conversion and an excellent iso-
lated yield (97%) of ester 11a were obtained in the presence
of SnCl4 (10 mol-%) at room temperature for 1 h (Table 1,
entry 6). Reactions with other strong Lewis acids such as
TiCl4, FeCl3, and AlCl3 gave worse conversions than that
obtained with SnCl4 (Table 1, entries 7–9). Thus, the use of
SnCl4 (10 mol-%) at room temperature worked most ef-
ficiently, and these conditions were therefore used in subse-
quent investigations.
The broad scope of the rearrangement is shown in
Table 2. The stabilization of the positive charge at the posi-
tion of the intermediate TMS-substituted carbenium ion
derived from β,γ-unsaturated ketone 8 results in a high re-
activity in the oxonia-Cope rearrangement with a series of
aldehydes 15, and the desired rearranged homoallylic ad-
ducts (i.e., 11) were formed in good yields. No competitive
double-bond isomerization by-products 13 (Scheme 1) were
observed. The reactions of acyclic 8 with simple aliphatic
aldehydes were highly efficient and rapid (0.5–1.5 h; 11a–
11d). Aromatic aldehydes 15 with electron-withdrawing
groups (products 11f and 11j) seem to facilitate the trans-
formation, too. In contrast to the previous results obtained
with methyl-substituted substrates 8 (R1 = Me), the TMS-
directed cyclohexanone substrates of the [n+4] ring-en-
largement reaction gave the 10-membered ring lactones
with the double bonds preferentially occupying E configu-
rations. The more reactive substrate 4-nitrobenzaldehyde re-
[a] Reagents and conditions: a solution of β,γ-unsaturated ketone
sulted in the formation of lactone 11j exclusively with an E
configuration. The structure and double-bond configura-
tion of lactone 11j were confirmed by X-ray analysis
(Table 2). The corresponding 12-membered cyclic substrate
was converted into 11mЈ within 24 h. To drive the reaction
to complete conversion, 1.0 equiv. of the Lewis acid catalyst
was used. Notably, spontaneous cleavage of the TMS group
8 (2.0 mmol), aldehyde 15 (3.0 mmol), and SnCl4 (0.20 mmol) in
1,2-dichloroethane (5.0 mL) was stirred at room temperature for
the time indicated. [b] Isolated yields by flash chromatography or
kugelrohr distillation. [c] E/Z ratios were determined by GC and
NMR spectroscopic analysis. [d] 1.0 equiv. of SnCl4 was used.
to give lactone 11mЈ directly occurred during the reaction for an oxy-2-azonia-Cope rearrangement (Table 3). A cata-
of substrate 8m. This demonstrates that the TMS group is lytic amount of SnCl4 (10 mol-%) proved to be the best op-
unstable in the presence of high concentrations of Lewis tion. We used the same TMS-substituted β,γ-unsaturated
acid. Pentadecanolide 24, a natural macrolide isolated from ketones 8 to investigate the scope of O-methyl oximes that
galbanum, is a useful musk odorant in perfumery, and was could be used in this transformation of (Table 3). Oxime
conveniently prepared by hydrogenation of the unsaturated ethers 16 were smoothly converted into the desired homo-
16-membered lactone 11mЈ.[13] Another interesting observa- allylic amides and lactams (i.e., 17a–17f) in moderate to ex-
tion relates to the use of formaldehyde (15, R3 = H) which cellent yields. Notably, [6 + 4] ring enlargement reactions
reacted with 2-[1-(trimethylsilyl)vinyl]cyclohexanone (8b) to to give 10-membered ring lactams selectively gave the Z-
give lactone 11l in a good yield of 71%. Although this result configured products (i.e., 17d–17f), which is a similar result
was reproducible, formaldehyde remains a difficult sub- to the high diastereoselectivites observed in the carba-sub-
strate in oxonia-Cope rearrangements, and it was not gen- stituted version.[7c]
erally productive in combination with other substrates 8.
To further demonstrate the synthetic value of the new pro-
Encouraged by the efficiency of these results in the oxy- tocol, it was applied to the stereoselective synthesis of (R)-
2-oxonia-Cope rearrangement, we used similar conditions phoracantholide I, a natural macrolide isolated from the me-
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Eur. J. Org. Chem. 2015, 4982–4989

Removable Silyl Group as a “Masked Proton”
Table 3. Scope of the TMS-directed oxy-2-azonia-Cope rearrange-
ment.[a]
[a] Reagents and conditions: a solution of β,γ-unsaturated ketone
8 (2.0 mmol), imine 15 (3.0 mmol), and SnCl4 (0.20 mmol) in 1,2-
dichloroethane (5.0 mL) was stirred at room temperature for the
time indicated. [b] Isolated yields by flash chromatography or
kugelrohr distillation. [c] E/Z ratios were determined by GC and
NMR spectroscopic analysis.
Scheme 2. Application of the TMS-directed oxy-2-oxonia-Cope re-
arrangement in the total synthesis of (R)-phoracantholide I [(R)-
23]; PCC = pyridinium chlorochromate.
Conclusions
In summary, we have developed a straightforward proto-
col for the rapid assembly of homoallylic esters, lactones,
amides, and lactams carrying vinylic TMS directing groups
through Lewis-acid-catalysed oxy-2-oxonia(azonia)-Cope
rearrangements. Most of the transformations proceeded
with high E/Z selectivities and excellent yields. The effi-
ciency of this reaction was demonstrated by the total syn-
theses of (R)-phoracantholide I (23) and naturally occur-
ring macrocyclic musk 24. In these syntheses, the concept
of removable TMS groups as masked protons enabled the
formation of the key olefinically disubstituted precursors
(Z)-(R)-22 and 11mЈ. The work described here constitutes
a valuable extension of the oxy-oxonia(azonia)-Cope re-
arrangement as synthetic strategy for the preparation of
medium- and large-ring lactones and lactams without the
need for high-dilution or slow-addition methods. As shown
by the formation of lactone 11l, formaldehyde may be used
as a coupling partner in specific reactions, but it generally
remains a difficult substrate for the oxy-oxonia-Cope re-
arrangement.
tasternal gland of the eucalypt longicorn beetle, Phoracantha
synonyma, and used for the defense of the organism.[11,12]
The reaction of (R)-8b and acetaldehyde with SnCl4 gave 10-
membered lactone (R)-11g in excellent yield (E/Z = 85:15;
both E and Z isomers had optical purities of 98% ee). Subse-
quent removal of the TMS group by treatment with TFA
(trifluoroacetic acid) gave lactone (Z)-(R)-22 in 65% yield
(E/Z = 1:99). Hydrogenation of the double bond gave (R)-
phoracantholide I (23) in high yield with 93% ee. We were
not able to separate the mixture of (E)-(R)-11g and (Z)-(S)-
11g (85:15), but the fact that (Z)-(R)-22 was obtained with
high diastereselectivity shows that (Z)-(S)-11g mostly decom-
posed during the protodesilylation. Similar differences in the
rate and selectivity of the deprotection of isomers have been
reported previously.[14] We inferred that the loss of 5% ee in
the final natural product 23 was brought about by isomeriza-
tion of the double bond in (Z)-(S)-11g to give (E)-(S)-11g
during the desilylation step.[15] However, both the preference
for E configuration and the high degree of chirality transfer
in going from (R)-8b to (R)-11g instructively confirm the
mechanistic model deduced earlier.[7a] It is important to note
that in contrast to the previously reported methyl-substituted
case, silyl-substituted derivative 8b undergoes the rearrange-
ment primarily via a cis-decalin-like transition state involving
an E-oxocarbenium-ion-like species (TS-I), and the reaction
pathway via the trans-decalin-like transition state (i.e., TS-II)
becomes less preferred. The energy difference can be attrib-
uted to the larger 1,3-diaxial steric strain imparted by the
TMS group (Scheme 2).[8b]
Experimental Section
General Remarks: All reactions were carried out under argon, and
solvents and reagents from commercial suppliers were used without
further purification. Solvents for extraction and chromatography
were technical grade, and were used without further purification.
Flash chromatography was carried out using Tsingdao Haiyang
Chemical silica gel (200–300 mesh) and silica gel Merck grade
(60 Å). Unless otherwise noted, a mixture of hexane/MTBE
(methyl tert-butyl ether; 20:1) was used as eluent. NMR spectra
Eur. J. Org. Chem. 2015, 4982–4989
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4985

W. Mu, Y. Zou, L. Zhou, Q. Wang, A. Goeke
FULL PAPER
were recorded with an AW 300 MHz Bruker spectrometer. The
chemical shifts for H NMR spectra are reported in ppm on the δ
13.9, 6.8 Hz, 1 H), 2.01 (s, 3 H), 1.19 (d, J = 6.2 Hz, 3 H), 0.10 (s,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.7 (s), 148.1 (s),
127.5 (t), 70.1 (d), 42.7 (t), 21.5 (q), 19.9 (q), –1.3 (q) ppm. IR
1
scale, and are referenced to the residual proton signal of the deuter-
ated solvent; coupling constants are expressed in Hertz (Hz). 13C
NMR spectra were referenced to the carbon signals of the deuter-
ated solvent; the nature of the carbons (C, CH, CH2, or CH3) was
determined by recording DEPT-90 and DEPT-135 experiments,
and is given in parentheses. The following abbreviations are used:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd
= doublet of doublets, br. s = broad singlet. IR spectra were re-
corded with Bruker Tensor 27 and Jasco FTIR-4100 instruments.
(neat): ν = 2956, 1737, 1372, 1238, 1129, 1054, 835 cm–1. HRMS
˜
(ESI): calcd. for C10H21O2Si [M + H]+ 201.1305; found 201.1312.
2-Methyl-5-(trimethylsilyl)hex-5-en-3-yl Acetate (11b): Following
the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
2.0 mmol), aldehyde 15b (0.22 g, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
1
temp. for 1.5 h to give 11b (0.39 g, 85%) as a colourless liquid. H
NMR (300 MHz, CDCl3): δ = 5.60 (d, J = 2.2 Hz, 1 H), 5.38 (d,
J = 2.2 Hz, 1 H), 4.89–4.83 (m, 1 H), 2.41–2.25 (m, 2 H), 2.01 (s,
3 H), 1.86–1.78 (m, 1 H), 0.92 (s, 3 H), 0.89 (s, 3 H), 0.10 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 170.8 (s), 148.3 (s), 127.3
(t), 77.1 (d), 37.7 (t), 31.2 (d), 21.3 (q), 18.8 (q), 17.3 (q), –1.2 (q)
High-resolution mass spectra were obtained with
a Bruker
micrOTOF II spectrometer (ESI-MS). Melting points were deter-
mined using a SGW X-4 micro hot-stage apparatus. GCMS spec-
troscopic data were obtained from an Agilent 6890 N instrument
with a mass-selective detector 5975 using a column HP-5 MS, 30 m,
0.25 mm, 0.25 μm. The enantiomeric excess (ee) of compounds (R)-
8b, (R)-11g, and (R)-23 were determined by GC by comparing with
the corresponding racemic samples. (R)-8b and (R)-23 were
ppm. IR (neat): ν = 2961, 1736, 1372, 1239, 1021, 835 cm–1. HRMS
˜
(ESI): calcd. for C12H25O2Si [M + H]+ 229.1618; found 229.1621.
6-Methyl-2-(trimethylsilyl)hept-1-en-4-yl Acetate (11c): Following
the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
2.0 mmol), aldehyde 15c (0.26 g, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
temp. for 1 h to give 11c (0.47 g, 96%) as a colourless liquid. 1H
NMR (300 MHz, CDCl3): δ = 5.59 (d, J = 2.2 Hz, 1 H), 5.40 (d,
J = 2.2 Hz, 1 H), 5.11–5.02 (m, 1 H), 2.41 (dd, J = 13.7, 6.7 Hz, 1
H), 2.26 (dd, J = 13.7, 6.7 Hz, 1 H), 2.00 (s, 3 H), 1.63–1.58 (m, 1
H), 1.45–1.41 (m, 1 H), 1.35–1.28 (m, 1 H), 0.90 (d, J = 6.0 Hz, 3
H), 0.88 (d, J = 6.0 Hz, 3 H), 0.10 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.8 (s), 148.2 (s), 127.7 (t), 71.7 (d), 43.2
(t), 41.9 (t), 24.8 (q), 23.4 (d), 22.2 (q), 21.4 (q), –1.3 (q) ppm. IR
measured using
a
chiral HYDRODEX-β-6TBDM column
[25 mϫ0.25 mm, program 60–200 °C, 2 °C/min, Helium carrier
pressure 13.6 psi, FID detection (250 °C)]; (R)-11g was measured
using a chiral HYDRODEX-β-6TBDM column [25 mϫ0.25 mm,
program 60–230 °C, 2.5 °C/min, Helium carrier pressure 13.6 psi,
FID detection (250 °C)]. Optical rotation data were obtained with
a Rudolph AP IV589 automatic polarimeter.
General Procedure for the Lewis Acid Screening: β,γ-Unsaturated
ketone 8a (0.78 g, 5.0 mmol), acetaldehyde (15a; 0.27 g, 6.0 mmol),
and 1,2-dichloroethane (10 mL) were put into an argon-flushed
flask. The Lewis acid (see Table 1) was added at room temperature.
The mixture was stirred for 1 h. The conversion was checked by
GC analysis of aliquots of the reaction mixture that had been
quenched with saturated aq. NaHCO3. The reaction mixture was
then quenched with satd. aqueous NaHCO3 solution (20 mL). The
organic phase was separated, and the aqueous layer was extracted
with MTBE (3ϫ 20 mL). The combined organic layers were
washed with brine (20 mL) and dried (MgSO4), and the solvents
were evaporated in vacuo. The final conversion of the reaction was
measured by GC analysis. The residue was purified by kugelrohr
distillation to give the desired product (i.e., 11a).
(neat): ν = 2956, 2860, 1737, 1469, 1370, 1237, 1020, 836 cm–1.
˜
HRMS (ESI): calcd. for C13H27O2Si [M + H]+ 243.1775; found
243.1782.
2-(Trimethylsilyl)dec-1-en-4-yl Acetate (11d): Following the general
procedure, β,γ-unsaturated ketone 8a (0.32 g, 2.0 mmol), aldehyde
15d (0.34 g, 3.0 mmol), and tin tetrachloride (0.05 g, 0.2 mmol) in
1,2-dichloroethane (5 mL) reacted at room temp. for 1.5 h to give
11d (0.50 g, 93%) as a colourless liquid. 1H NMR (300 MHz,
CDCl3): δ = 5.59 (d, J = 2.9 Hz, 1 H), 5.39 (d, J = 2.9 Hz, 1 H),
5.00–4.91 (m, 1 H), 2.39 (dd, J = 13.9, 6.7 Hz, 1 H), 2.29 (dd, J =
13.9, 6.7 Hz, 1 H), 2.00 (s, 3 H), 1.25 (br. s, 10 H), 0.88 (t, J =
6.0 Hz, 3 H), 0.09 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.8 (s), 148.2 (s), 127.5 (t), 73.4 (d), 41.2 (t), 34.0 (t), 31.9 (t),
29.3 (t), 25.4 (t), 22.7 (t), 21.4 (q), 14.2 (q), –1.3 (q) ppm. IR (neat):
General Procedure for the 2-Oxonia-Cope Rearrangement: β,γ-Un-
saturated ketone 8 (2.0 mmol), aldehyde 15 (3.0 mmol), and 1,2-
dichloroethane (5 mL) were put into an argon-flushed three-necked
flask. The Lewis acid (0.2 mmol) was added dropwise under argon
at room temperature. After the addition was complete, the mixture
was stirred at room temperature. The reaction was monitored by
GC analysis of aliquots of the reaction mixture that had been
quenched with saturated aq. NaHCO3. After complete conversion,
the reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL). The organic phase was separated, and the aque-
ous layer was extracted with MTBE (2ϫ 10 mL). The combined
organic layers were washed with brine (20 mL), and dried (MgSO4),
and the solvents were evaporated in vacuo. The residue was purified
by column chromatography on silica gel (MTBE/hexane, 1:20) or
kugelrohr distillation to give compound 11.
ν = 2928, 2858, 2862, 1738, 1461, 1238, 836 cm–1. HRMS (ESI):
˜
calcd. for C15H31O2Si [M + H]+ 271.2088; found 271.2106.
1-Phenyl-4-(trimethylsilyl)pent-4-en-2-yl Acetate (11e): Following
the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
2.0 mmol), aldehyde 15e (0.36 g, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
1
temp. for 16 h to give 11e (0.37 g, 66%) as a colourless liquid. H
NMR (300 MHz, CDCl3): δ = 7.33–7.23 (m, 2 H), 7.20–7.17 (m, 3
H), 5.63 (d, J = 2.8 Hz, 1 H), 5.43 (d, J = 2.8 Hz, 1 H), 5.23–5.10
(m, 1 H), 2.83 (d, J = 6.5 Hz, 2 H), 2.49–2.28 (m, 2 H), 1.95 (s, 3
H), 0.07 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.5 (s),
148.1 (s), 137.9 (s), 139.5 (d), 128.4 (d), 127.8 (t), 126.6 (d), 73.9
(d), 40.5 (t), 40.4 (t), 21.3 (q), –1.3 (q) ppm. IR (neat): ν = 2954,
˜
4-(Trimethylsilyl)pent-4-en-2-yl Acetate (11a): Following the gene-
ral procedure, β,γ-unsaturated ketone 8a (0.32 g, 2.0 mmol),
aldehyde 15a (0.14 g, 3.0 mmol), and tin tetrachloride (0.05 g,
0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room temp. for
1 h to give 11a (0.39 g, 97%) as a colourless liquid. 1H NMR
(300 MHz, CDCl3): δ = 5.61 (br. s, 1 H), 5.41 (d, J = 2.7 Hz, 1 H),
5.04–4.98 (m, 1 H), 2.47 (dd, J = 13.9, 6.8 Hz, 1 H), 2.25 (dd, J =
1737, 1373, 1024, 835 cm–1. HRMS (ESI): calcd. for C16H25O2Si
[M + H]+ 277.1618; found 277.1618.
1-(4-Nitrophenyl)-3-(trimethylsilyl)but-3-en-1-yl Acetate (11f): Fol-
lowing the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
2.0 mmol), aldehyde 15f (0.45 g, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
4986
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4982–4989

Removable Silyl Group as a “Masked Proton”
1
temp. for 10 h to give 11f (0.49 g, 80%) as a colourless liquid. H
NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 8.6 Hz, 2 H), 7.47 (d,
J = 8.6 Hz, 2 H), 5.90–5.85 (m, 1 H), 5.53 (d, J = 2.1 Hz, 1 H),
5.44 (d, J = 2.1 Hz, 1 H), 2.71 (dd, J = 14.3, 7.0 Hz, 1 H), 2.53
(dd, J = 14.3, 7.0 Hz, 1 H), 2.07 (s, 3 H), 0.10 (s, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.1 (s), 148.0 (s), 147.6 (s), 146.6
(s), 128.7 (t), 127.5 (d), 123.8 (d), 74.3 (d), 42.4 (t), 21.2 (q), –1.4
HRMS (ESI): calcd. for C18H35O2Si [M + H]+ 331.2401; found
331.2405.
(E)-10-(4-Nitrophenyl)-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-
2H-oxecin-2-one (11j): Following the general procedure, β,γ-unsatu-
rated ketone 8b (0.39 g, 2.0 mmol), aldehyde 15f (0.45 g, 3.0 mmol),
and tin tetrachloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane
(5 mL) reacted at room temp. for 3 h to give 11j (0.52 g, 71%; E/Z
Ͼ 99:1) as a colourless solid, m.p. 78.1–79.3 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.22 (d, J = 8.6 Hz, 2 H), 7.54 (d, J =
8.6 Hz, 2 H), 6.00 (dd, J = 11.4, 2.3 Hz, 2 H), 2.70–1.50 (m, 11 H),
0.23 (s, 9 H) ppm. 13C NMR (mixture of isomers, 75 MHz, CDCl3):
δ = 174.2 (s), 149.2 (d), 147.7 (s), 147.5 (s), 135.6 (s), 126.9 (d),
123.9 (d), 75.5 (d), 47.8 (t), 36.6 (t), 32.1 (t), 30.7 (t), 25.4 (t), 0.4
(q) ppm. IR (neat): ν = 2955, 1740, 1606, 1521, 1372, 1225, 1027,
˜
835 cm–1. HRMS (ESI): calcd. for C15H21NO4SiNa [M + Na]+
330.1132; found 330.1124.
10-Methyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-2H-oxecin-2-
one (11g): Following the general procedure, β,γ-unsaturated ketone
8b (0.39 g, 2.0 mmol), aldehyde 15a (0.14 g, 3.0 mmol), and tin
tetrachloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) re-
acted at room temp. for 0.5 h to give 11g (0.47 g, 97%; E/Z = 83:17)
as a colourless liquid. 1H NMR (mixture of isomers, 300 MHz,
CDCl3): δ = 5.72 (dd, J = 10.7, 3.8 Hz, 1 H), 5.09–5.04 (m, 1 H),
2.70–1.61 (m, 10 H), 1.30 (d, J = 6.5 Hz, 3 H), 0.06 (s, 9 H) ppm.
13C NMR (mixture of isomers, 75 MHz, CDCl3): δ = 174.4 (s),
147.5 (s), 143.4 (d), 70.0 (d), 35.4 (t), 28.8 (2 C, t), 27.3 (t), 24.2
(q) ppm. IR (neat): ν = 2363, 2339, 1724, 1519, 1347, 1226, 1030,
˜
836 cm–1. HRMS (ESI): calcd. for C18H26NO4Si 348.1626; found
348.1607.
8-(Trimethylsilyl)-3,4,5,6,9,10-hexahydro-2H-oxecin-2-one (11l):
Following the general procedure, β,γ-unsaturated ketone 8b (0.39 g,
2.0 mmol), paraformaldehyde (15g; 0.10 g, 3.0 mmol), and tin tet-
rachloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted
at room temp. for 4 h to give 11l (0.32 g, 71%; E/Z = 78:22) as a
colourless liquid. 1H NMR (mixture of isomers, 300 MHz, CDCl3):
δ = 5.79 (dd, J = 16.3, 8.8 Hz, 1 H), 4.72–3.78 (m, 2 H), 2.45–1.64
(m, 10 H), 0.09 (s, 9 H) ppm. 13C NMR (mixture of isomers,
75 MHz, CDCl3): δ = 174.8 (s), 143.7 (d), 136.7 (s), 62.0 (t), 35.6
(t), 20.8 (q), –1.3 (q). IR (neat): ν = 2952, 1730, 1613, 1449, 1246,
˜
833 cm–1. HRMS (ESI): m/z: calcd. for C13H24O [M + H]+
241.1618; found 241.1616.
10-Isopropyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-2H-oxecin-2-
one (11h): Following the general procedure, β,γ-unsaturated ketone
8b (0.39 g, 2.0 mmol), aldehyde 15b (0.22 g, 3.0 mmol), and tin tet-
rachloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted
at room temp. for 0.5 h to give 11h (0.47 g, 95%; E/Z = 81:19) as
a colourless liquid. 1H NMR (mixture of isomers, 300 MHz,
CDCl3): δ = 5.68 (dd, J = 11.4, 2.7 Hz, 1 H), 4.69–4.63 (m, 1 H),
2.79–2.62 (m, 1 H), 2.57–1.58 (m, 10 H), 0.96 (d, J = 6.8 Hz, 3 H),
0.93 (d, J = 6.8 Hz, 3 H), 0.04 (s, 9 H) ppm. 13C NMR (mixture
of isomers, 75 MHz, CDCl3): δ = 174.3 (s), 143.1 (d), 137.3 (s),
78.3 (d), 35.2 (t), 32.2 (d), 31.0 (t), 28.8 (t), 27.3 (t), 24.4 (t), 19.0
(t), 28.7 (t), 27.2 (t), 26.6 (t), 23.0 (t), –1.1 (q) ppm. IR (neat): ν =
˜
2954, 1731, 1454, 1377, 1246, 1153, 1024, 903 cm–1. HRMS (ESI):
calcd. for C12H23O2Si [M + H]+ 227.1462; found 227.1463.
16-Methyloxacyclohexadec-13-en-2-one (11mЈ): Following the gene-
ral procedure, β,γ-unsaturated ketone 8d (0.56 g, 2.0 mmol), alde-
hyde 15a (0.45 g, 3.0 mmol), and tin tetrachloride (0.5 g, 2.0 mmol)
in 1,2-dichloroethane (5 mL) reacted at room temp. for 10 h to give
11nЈ (0.41 g, 82%; E/Z = 23:77) as a colourless liquid. 1H NMR
(mixture of isomers, 300 MHz, CDCl3): δ = 5.44–5.17 (m, 2 H),
4.83 (dt, J = 15.0, 6.3 Hz, 1 H), 2.39–2.29 (m, 1 H), 2.20–2.08 (m,
2 H), 2.05–1.82 (m, 3 H), 1.59–1.49 (m, 2 H), 1.34–1.03 (m, 17 H)
ppm. 13C NMR (mixture of isomers, 75 MHz, CDCl3): δ = 173.6
(s), 132.6 (d), 124.5 (d), 70.5 (d), 38.7 (t), 34.7 (t), 34.1 (t), 31.2 (t),
27.8 (t), 26.7 (t), 26.5 (t), 26.2 (t), 26.1 (t), 24.32 (t), 19.53 (q) ppm.
(q), 18.5 (q), –1.4 (q) ppm. IR (neat): ν = 2958, 1731, 1446, 1367,
˜
1246, 1027, 874 cm–1. HRMS (ESI): calcd. for C15H29O2Si [M +
H]+ 269.1931; found 269.1930.
10-Isobutyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-2H-oxecin-2-
one (11i): Following the general procedure, β,γ-unsaturated ketone
8b (0.39 g, 2.0 mmol), aldehyde 15c (0.26 g, 3.0 mmol), and tin tet-
rachloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted
at room temp. for 0.5 h to give 11i (0.54 g, 96%; E/Z = 84:16) as a
colourless liquid. 1H NMR (mixture of isomers, 300 MHz, CDCl3):
δ = 5.71 (dd, J = 11.0, 3.5 Hz, 1 H), 5.04–4.98 (m, 1 H), 2.54–1.60
(m, 12 H), 1.37–1.28 (m, 1 H), 0.92 (d, J = 6.3 Hz, 6 H), 0.07 (s, 9
H) ppm. 13C NMR (mixture of isomers, 75 MHz, CDCl3): δ =
174.5 (s), 143.3 (d), 137.1 (s), 72.3 (d), 44.3 (t), 35.3 (2 C, t), 28.8
(t), 27.3 (t), 25.0 (d), 24.4 (t), 23.3 (q), 22.2 (q), –1.3 (q). IR (neat):
IR (neat): ν = 2927, 2856, 1730, 1460, 1247, 1173, 1152, 969,
˜
727 cm–1. HRMS (ESI): calcd. for C16H29O2 253.2162; found
253.2173.
General Procedure for the 2-Azonia-Cope Rearrangement: β,γ-Un-
saturated ketone 8 (2.0 mmol), imine[3] 16 (3.0 mmol) and 1,2-
dichloroethane (5 mL) were put into an argon-flushed three-necked
flask. The Lewis acid (0.2 mmol) was added dropwise under argon
at room temperature. After the addition was complete, the mixture
was stirred at room temperature. The reaction was monitored by
GC analysis of aliquots of the reaction mixture that had been
quenched with saturated aq. NaHCO3. After complete conversion,
the reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL). The organic phase was separated, and the aque-
ous layer was extracted with MTBE (3ϫ 10 mL). The combined
organic layers were washed with brine (20 mL), and dried (MgSO4),
and the solvents were evaporated in vacuo. The residue was purified
by column chromatography on silica gel (MTBE/hexane, 1:10) or
kugelrohr distillation to give compound 17.
ν = 2954, 1730, 1613, 1447, 1246, 833 cm–1. HRMS (ESI): calcd.
˜
for C16H31O2Si [M + H]+ 283.2088; found 283.2090.
10-Hexyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-2H-oxecin-2-one
(11k): Following the general procedure, β,γ-unsaturated ketone 8b
(0.39 g, 2.0 mmol), aldehyde 15d (0.34 g, 3.0 mmol), and tin tetra-
chloride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at
room temp. for 0.5 h to give 11k (0.60 g, 96%; E/Z = 85:15) as a
colourless liquid. 1H NMR (mixture of isomers, 300 MHz, CDCl3):
δ = 5.71 (dd, J = 10.9, 3.4 Hz, 1 H), 4.85–4.93 (m, 1 H), 2.26–1.52
(m, 10 H), 1.29 (br. s, 10 H), 0.87 (t, J = 6.8 Hz, 3 H), 0.06 (s, 9 N-Methoxy-N-[4-(trimethylsilyl)pent-4-en-2-yl]acetamide (17a):
H) ppm. 13C NMR (mixture of isomers, 75 MHz, CDCl3) δ = 174.6 Following the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
(s), 143.3 (d), 137.1 (s), 74.0 (d), 35.3 (t), 35.1 (t), 34.3 (t), 31.9 (t),
29.3 (t), 28.8 (t), 27.3 (t), 25.9 (t), 24.4 (t), 22.7 (t), 14.2 (q), –1.3 CH2Cl2, 3.0 mmol), and tin tetrachloride (0.05 g, 0.2 mmol) in 1,2-
(q) ppm. IR (neat): ν = 2927, 2857, 1731, 1448, 1246, 835 cm–1.
dichloroethane (5 mL) reacted at room temp. for 1 h to give 17a
2.0 mmol), acetaldehyde O-methyl oxime (16a; 2.20 g, 10 % in
˜
Eur. J. Org. Chem. 2015, 4982–4989
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4987

W. Mu, Y. Zou, L. Zhou, Q. Wang, A. Goeke
FULL PAPER
1
(0.41 g, 90%) as a colourless liquid. H NMR (300 MHz, CDCl3):
δ = 5.59 (d, J = 1.6 Hz, 1 H), 5.38 (d, J = 1.6 Hz, 1 H), 4.65–4.55
(m, 1 H), 3.72 (s, 3 H), 2.50 (dd, J = 14.2, 7.2 Hz, 1 H), 2.23 (dd,
J = 14.2, 7.2 Hz, 1 H), 2.08 (s, 3 H), 1.18 (d, J = 6.8 Hz, 3 H), 0.07
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.6 (s), 148.7 (s),
126.8 (t), 64.7 (q), 51.0 (d), 39.9 (t), 21.0 (q), 17.9 (q), –1.4 (q) ppm.
IR (neat): ν = 2955, 1669, 1445, 1370, 1246, 835 cm–1. HRMS
˜
(ESI): calcd. for C16H32NO2Si [M + H]+ 298.2197; found 298.2197.
Ethyl
(Z)-1-Methoxy-10-oxo-4-(trimethylsilyl)-1,2,3,6,7,8,9,10-
octahydroazecine-2-carboxylate (17f): Following the general pro-
cedure, β,γ-unsaturated ketone 8b (0.39 g, 2.0 mmol), ethyl 2-
(methoxyimino)acetate (16c; 0.39 g, 3.0 mmol), and tin tetrachlo-
ride (0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at
room temp. for 4 h to give 17f (0.32 g, 48%; E/Z Ͻ 1:99) as a
IR (neat): ν = 2954, 1670, 1375, 1316, 1247, 1030, 835 cm–1. HRMS
˜
(ESI): calcd. for C11H24NO2Si [M + H]+ 230.1571; found 230.1576.
1
colourless liquid. H NMR (300 MHz, CDCl3): δ = 5.92 (dd, J =
N-Methoxy-N-[2-(trimethylsilyl)hept-1-en-4-yl]acetamide (17b):
Following the general procedure, β,γ-unsaturated ketone 8a (0.32 g,
2.0 mmol), butyraldehyde O-methyl oxime (16b; 1.52 g, 20 % in
CH2Cl2, 3.0 mmol), and tin tetrachloride (0.05 g, 0.2 mmol) in 1,2-
dichloroethane (5 mL) reacted at room temp. for 1 h to give 17b
10.3, 4.3 Hz, 1 H), 5.07 (dd, J = 9.6, 5.7 Hz, 1 H), 4.22 (q, J =
7.1 Hz, 2 H), 3.80 (s, 3 H), 2.86–2.78 (m, 1 H), 2.61–2.58 (m, 2 H),
2.27–2.16 (m, 3 H), 1.88–1.65 (m, 4 H), 1.31 (t, J = 7.1 Hz, 3 H),
0.16 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 181.3 (s), 170.8
(s), 146.9 (d), 136.6 (s), 64.4 (q), 64.0 (d), 61.3 (t), 36.3 (t), 32.4 (t),
1
(0.46 g, 89%) as a colourless liquid. H NMR (300 MHz, CDCl3):
31.9 (t), 30.2 (t), 24.0 (t), 14.3 (q), 0.2 (q) ppm. IR (neat): ν = 2934,
˜
δ = 5.62 (br. s, 1 H), 5.39 (br. s, 1 H), 4.53–4.48 (m, 1 H), 3.72 (s,
3 H), 2.51 (dd, J = 14.5, 7.3 Hz, 1 H), 2.29 (dd, J = 14.5, 7.3 Hz,
1 H), 2.11 (s, 3 H), 1.66–1.61 (m, 1 H), 1.50–1.46 (m, 1 H), 1.36–
1.20 (m, 2 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.09 (s, 9 H) ppm. 13C
NMR (75 MHz, CDCl3) δ = 173.7 (s), 148.8 (s), 126.6 (t), 64.4 (q),
56.7 (d), 48.7 (t), 34.6 (t), 20.8 (q), 19.9 (t), 14.1 (q), –1.3 (q) ppm.
1742, 1677, 1445, 1368, 1244, 1188, 835 cm–1. HRMS (ESI): calcd.
for C16H30NO4Si [M + H]+ 328.1939; found 328.1945.
Total Synthesis of (R)-Phoracantholide I
(1R,2R)-2-[1-(Trimethylsilyl)vinyl]cyclohexyl Acetate [(1R,2R)-20b]:
Vinyl acetate (230 g, 2.67 mol) and an enzyme (lipase from Pseu-
domonas fluorescens, Lot No. 2007-09-22, Shanghai Hanhong
Chemical Co., Ltd.; 1.7 g) were added to a solution of rac-trans-2-
[1-(trimethylsilyl)vinyl]cyclohexanol (19b; 8.5 g, 42.8 mmol) in dry
THF (25 mL). The suspension was stirred at room temperature for
14 d, after which time the conversion had reached 45%. The reac-
tion solution was treated with saturated aqueous NaHCO3
(25 mL), and then water (100 mL). The solvent was evaporated,
and the crude products were separated by column chromatography
on silica gel to give (1S,2S)-2-[1-(trimethylsilyl)vinyl]cyclohexanol
[(1S,2S)-19b; 4.24 g; with 78% ee] and (1R,2R)-2-[1-(trimethylsilyl)
IR (neat): ν = 2957, 1669, 1443, 1378, 1247, 835 cm–1. HRMS
˜
(ESI): calcd. for C13H28NO2Si [M + H]+ 258.1884; found 258.1904.
Ethyl 2-(N-Methoxyacetamido)-4-(trimethylsilyl)pent-4-enoate
(17c): Following the general procedure, β,γ-unsaturated ketone 4a
(0.32 g, 2.0 mmol), ethyl 2-(methoxyimino)acetate (16c; 0.39 g,
3.0 mmol), and tin tetrachloride (0.05 g, 0.2 mmol) in 1,2-dichloro-
ethane (5 mL) reacted at room temp. for 10 h to give 17c (0.35 g,
61%) as a colourless liquid. 1H NMR (300 MHz, CDCl3): δ = 5.59–
5.59 (m, 1 H), 5.40–5.39 (m, 1 H), 5.10–5.07 (m, 1 H), 4.15 (qd, J
= 7.1, 1.7 Hz, 2 H), 3.71 (s, 3 H), 2.83–2.64 (m, 2 H), 2.14 (s, 3 H),
1.24 (t, J = 7.1 Hz, 3 H), 0.08 (s, 9 H) ppm. 13C NMR (75 MHz, vinyl]cyclohexyl acetate [20b; 5.54 g; with 99% ee]. 1H NMR
CDCl3): δ = 174.4 (s), 170.5 (s), 147.3 (s), 126.0 (t), 63.9 (q), 61.5
(300 MHz, CDCl3): δ = 5.64 (d, J = 2.0 Hz, 1 H), 5.40 (d, J =
2.0 Hz, 1 H), 4.83 (td, J = 10.5, 4.3 Hz, 1 H), 2.35–2.17 (m, 1 H),
2.13–2.00 (m, 1 H), 1.93 (s, 3 H), 1.80–1.62 (m, 3 H), 1.42–1.14 (m,
4 H), 0.09 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.6
(s), 153.6 (s), 124.3 (t), 75.7 (d), 47.6 (d), 34.0 (t), 32.4 (t), 26.1 (t),
(t), 59.0 (d), 32.8 (t), 20.4 (q), 14.2 (q), –1.6 (q) ppm. IR (neat): ν
˜
= 2955, 1372, 1248, 1198, 1034, 836 cm–1. HRMS (ESI): calcd. for
C13H26NO4Si [M + H]+ 288.1626; found 288.1621.
(Z)-1-Methoxy-10-methyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-
azecin-2(1H)-one (17d): Following the general procedure, β,γ-unsat-
urated ketone 8b (0.39 g, 2.0 mmol), acetaldehyde O-methyl oxime
(16a; 2.20 g, 10 % in CH2Cl2, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
temp. for 0.5 h to give 17d (0.38 g, 70%; E/Z Ͻ 1:99) as a colourless
liquid. 1H NMR (300 MHz, CDCl3): δ = 5.77 (dd, J = 10.4, 4.0 Hz,
1 H), 4.52–4.45 (m, 1 H), 3.66 (s, 3 H), 2.83–2.74 (m, 1 H), 2.22–
2.09 (m, 5 H), 1.85–1.79 (m, 3 H), 1.44–1.35 (m, 1 H), 1.28 (d, J
= 6.9 Hz, 3 H), 0.12 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 180.5 (s), 145.4 (d), 138.1 (s), 64.7 (q), 58.2 (d), 42.0 (t), 32.4 (t),
24.9 (t), 21.4 (q), –1.2 (q) ppm. IR (neat): ν = 2954, 1731, 1454,
˜
1377, 1246, 1153, 1024, 903 cm–1. HRMS (ESI): calcd. for
C13H25O2SiNa [M + Na]+ 263.1438; found 263.1452. [α]D = –56.5
(c = 1.0, CHCl3, 25.0 °C).
Sodium hydroxide (1.32 g, 32.9 mmol), methanol (3.52 g,
110.0 mmol), and water (2.0 mL) were put into a 250 mL round-
bottomed flask. Then a solution of 2-(prop-1-en-2-yl)cyclohexyl
acetate [(1R,2R)-20b; 2.64 g, 11.0 mmol] in THF (10 mL) was
added. The solution was stirred at room temperature for 4 h. Water
(15 mL) and MTBE (15 mL) were added. The organic layer was
dried with MgSO4. Removal of the solvent gave the crude alcohol,
which was pure enough to be used in the next step.
32.2 (t), 30.3 (t), 24.0 (t), 18.5 (q), 0.3 (q) ppm. IR (neat): ν = 2927,
˜
1668, 1444, 1370, 1245, 1040, 833 cm–1. HRMS (ESI): calcd. for
C14H28NO2Si [M + H]+ 270.1884; found 270.1878.
This crude alcohol was dissolved in dichloromethane (50 mL), and
then PCC (4.73 g, 22.0 mmol) was added. The resulting solution
was stirred at room temperature for 4.5 h. Hexane (100 mL) was
added, and the precipitate was removed by filtration through a
short silica gel column. The filtrate was concentrated, and the re-
sulting residue was purified by column chromatography on silica
gel to give (R)-2-[1-(trimethylsilyl)vinyl]cyclohexanone (8b; 1.85 g,
92%; 99% ee) as a colourless liquid. [α]D = –26.0 (c = 1.0, CHCl3,
21.4 °C).
(Z)-1-Methoxy-10-propyl-8-(trimethylsilyl)-3,4,5,6,9,10-hexahydro-
azecin-2(1H)-one (17e): Following the general procedure, β,γ-unsat-
urated ketone 8b (0.39 g, 2.0 mmol), butyraldehyde O-methyl oxime
(16b; 1.52 g, 20% in CH2Cl2, 3.0 mmol), and tin tetrachloride
(0.05 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) reacted at room
temp. for 0.5 h to give 17e (0.51 g, 85%; E/Z Ͻ 1:99) as a colourless
liquid. 1H NMR (300 MHz, CDCl3): δ = 5.80 (dd, J = 10.2, 4.2 Hz,
1 H), 4.35–4.28 (m, 1 H), 3.66 (s, 3 H), 2.83–2.74 (m, 1 H), 2.22–
2.15 (m, 5 H), 1.85–1.71 (m, 5 H), 1.49–1.42 (m, 4 H), 0.95 (t, J = (R)-2-[1-(Trimethylsilyl)vinyl]cyclohexanone
[(R)-8b;
1.50 g,
7.1 Hz, 3 H), 0.13 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
181.0 (s), 145.4 (d), 137.8 (s), 64.4 (q), 63.0 (d), 39.9 (t), 34.9 (t),
32.4 (t), 32.3 (t), 30.4 (t), 24.0 (t), 20.5 (t), 14.3 (q), 0.4 (q) ppm.
7.6 mmol], acetaldehyde (15a; 0.50 g, 11.4 mmol), and 1,2-dichloro-
ethane (15 mL) were put into a 50 mL round-bottomed flask to
give a colourless solution. Tin tetrachloride (0.70 g, 2.7 mmol) was
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Eur. J. Org. Chem. 2015, 4982–4989

Removable Silyl Group as a “Masked Proton”
added dropwise. The resulting solution was stirred at room temp.
for 60 min. Saturated aq. NaHCO3 (25 mL) was added to quench
the reaction. The aqueous layer was extracted with MTBE (3ϫ
20 mL). The combined organic layers were dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography to give compound (R)-11g (1.75 g, 97%; E/Z =
85:15, both 98% ee) as a colourless liquid. [α]D = 18.1 (c = 1.0,
CHCl3, 25.0 °C).
Acknowledgments
The authors thank Dr. G. Brunner for NMR experiments, Prof.
Dr. Z. Chen at Fudan University for X-ray measurements, and G.
Tang at Fudan University for the high-resolution MS data. The
financial support from the National Natural Science Foundation
of China (NNSFC) under grant number 21372045 is gratefully ac-
knowledged.
(R)-10-Methyl-3,4,5,6,9,10-hexahydro-2H-oxecin-2-one
[(R)-22]:
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12, 564.
(R)-11g (1.75 g, 7.3 mmol) and trifluoroacetic acid (4.16 g,
36.5 mmol) were put into a 25 mL round-bottomed flask. The re-
sulting solution was heated to reflux for 3 h under argon. Saturated
aq. NaHCO3 (25 mL) was added to quench the reaction. The aque-
ous layer was extracted with MTBE (3ϫ 20 mL). The combined
organic layers were dried with MgSO4. Removal of the solvent gave
the crude lactone (0.80 g, 65%; mixture of E/Z isomers in a ratio
of 1:99), which was pure enough to be used in the next step. 1H
NMR (300 MHz, CDCl3): δ = 5.59–5.18 (m, 2 H), 5.10–5.00 (m, 1
H), 2.72 (br. s, 1 H), 2.43 (dd, J = 14.2, 7.6 Hz, 1 H), 2.19–1.91
(m, 5 H), 1.73–1.57 (m, 3 H), 1.28 (d, J = 6.5 Hz, 3 H) ppm. 13C
NMR (major isomer, 75 MHz, CDCl3): δ = 174.5 (s), 134.7 (d),
123.4 (d), 68.8 (d), 42.7 (t), 35.6 (t), 28.6 (t), 25.0 (t), 23.0 (t), 18.6
(q) ppm. IR (neat): ν = 2924, 1724, 1446, 1362, 1252, 1178, 822,
˜
726 cm–1. HRMS (ESI): calcd. for C10H17O2 [M + H]+ 169.1223;
found 169.1234.
(R)-10-Methyloxecan-2-one [(R)-23]:[12] The crude lactone (0.78 g,
4.6 mmol), Pd/C (10%; 0.12 g) and methanol (20 mL) were mixed
in a flask. The resulting suspension was then hydrogenated for 4 h.
The reaction was monitored by GC analysis. After the conversion
was complete, the organic solution was evaporated in vacuo. The
residue was purified by column chromatography on silica gel to
give (R)-10-methyloxecan-2-one (23; 0.79 g, 64% over two steps;
93% ee) as colourless liquid, which was spectroscopically identical
to the known compound.[12] 1H NMR (300 MHz, CDCl3): δ = 5.01
(qt, J = 6.6, 3.3 Hz, 1 H), 2.52–2.44 (m, 1 H), 2.22–2.17 (m, 1 H),
2.13–1.89 (m, 2 H), 1.80–1.68 (m, 1 H), 1.58–1.36 (m, 7 H), 1.27
(d, J = 6.5 Hz, 4 H), 1.12–0.96 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.0 (s), 72.6 (d), 35.2 (t), 31.4 (t), 27.1 (t), 24.3 (t),
[6] J. Grunenberg, S. Laschat, T. Dickner, Eur. J. Org. Chem. 2003,
4897.
[7] a) Y. Zou, C. Ding, L. Zhou, Z. Li, Q. Wang, F. Schoenebeck,
A. Goeke, Angew. Chem. Int. Ed. 2012, 51, 5647; Angew. Chem.
2012, 124, 5745; b) Y. Zou, H. Mouhib, W. Stahl, A. Goeke,
Q. Wang, P. Kraft, Chem. Eur. J. 2012, 18, 7010; c) L. Zhou,
Z. Li, Y. Zou, Q. Wang, I. A. Sanhueza, F. Schoenebeck, A.
Goeke, J. Am. Chem. Soc. 2012, 134, 20009; d) W. Mu, L.
Zhou, Y. Zou, Q. Wang, A. Goeke, Eur. J. Org. Chem. 2014,
2379; e) Y. Zou, L. Zhou, C. Ding, Q. Wang, P. Kraft, A.
Goeke, Chem. Biodiversity 2014, 11, 1608.
[8] For recent examples of the application of silyl groups in ring-
closing metathesis (RCM), see: a) D. Gallenkamp, A. Fürstner,
J. Am. Chem. Soc. 2011, 133, 9232; b) Y. Wang, M. Jimenez,
A. S. Hansen, E.-A. Raiber, S. L. Schreiber, D. W. Young, J.
Am. Chem. Soc. 2011, 133, 9196.
[9] a) I. Shiina, Chem. Rev. 2006, 107, 239; b) G. Rousseau, Tetra-
hedron 1995, 51, 2777; c) D. Poth, P. S. Peram, M. Vences, S.
Schulz, J. Nat. Prod. 2013, 76, 1548.
[10] L. D. Martin, J. K. Stille, J. Org. Chem. 1982, 47, 3630.
[11] B. P. Moore, W. V. Brown, Aust. J. Chem. 1976, 29, 1365.
[12] K. Hesse, Helv. Chim. Acta 1984, 67, 1713.
[13] a) R. Kaiser, D. Lamparsky, Helv. Chim. Acta 1978, 61, 2671;
b) F. Takahashi, K. Fukuda, Y. Takimura, CN102264718A,
2014.
[14] Y. Chu, D. Colclough, D. Hotchkin, M. Tuazon, J. B. White,
Tetrahedron 1997, 53, 14235.
[15] The attempted determination of the enantiomeric excess of
compound (Z)-(R)-22 by chiral GC was not successful.
Received: May 20, 2015
24.0 (t), 23.4 (t), 20.7 (t), 19.4 (q) ppm. IR (neat): ν = 2931, 1722,
˜
1468, 1363, 1239, 1144, 969 cm–1. HRMS (ESI): calcd. for
C10H19O2 [M + H]+ 171.1380; found 171.1381. [α]D = –47.5 (c =
1.0, CHCl3, 24.7 °C).
16-Methyloxacyclohexadecan-2-one (24): Compound 11nЈ (1.0 g,
4.0 mmol), Pd/C (10%; 0.1 g), and methanol (10 mL) were mixed
in a flask. The resulting suspension was then hydrogenated for 4 h
at room temperature. The reaction was monitored by GC analysis.
After the conversion was complete, the organic solution was evapo-
rated in vacuo. The residue was purified by column chromatog-
raphy on silica gel to give 24 (0.94 g, 92%) as a colourless liquid.
1H NMR (300 MHz, CDCl3): δ = 4.98–4.88 (m, 1 H), 2.30–2.24
(m, 2 H), 1.68–1.22 (m, 24 H), 1.18 (d, J = 6.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.7 (s), 70.60 (d), 35.9 (t), 34.8 (t),
27.8 (t), 27.5 (t), 27.2 (t), 26.6 (t), 26.2 (t), 26.0 (t), 25.7 (t), 25.7
(t), 25.0 (t), 24.3 (t), 20.3 (q) ppm. IR (neat): ν = 2926, 2856, 1730,
˜
1460, 1108 cm–1. HRMS (ESI): calcd. for C16H21O2 [M + H]+
255.2319; found 255.2336.
Published Online: July 1, 2015
Eur. J. Org. Chem. 2015, 4982–4989
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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