Organocatalytic Alkyne Isomerizations under Flow Conditions Using Heterogeneous Bifunctional Polystyrene Bearing Phosphine and Phenol Groups

Article abstract of DOI:10.1055/s-0036-1588589

A heterogeneous bifunctional polymer bearing phosphine and phenol groups was developed to catalyze the isomerization of electronically activated alkynes. This organocatalytic process provided the corresponding (E,E)-dienes and was shown to work under both batch and flow conditions.

Full text of DOI:10.1055/s-0036-1588589

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
S. Ceylan et al.
Paper
Synthesis
Organocatalytic Alkyne Isomerizations under Flow Conditions
Using Heterogeneous Bifunctional Polystyrene Bearing Phosphine
and Phenol Groups
Sascha Ceylana
Henry Chun-Hin Lawb
Andreas Kirschning*a
Patrick H. Toy*b
O
N
1
1
5
a Institute of Organic Chemistry and Center of Biomolecular
Drug Research (BMWZ), Leibniz Universität Hannover,
Schneiderberg 1b, 30167 Hannover, Germany
andreas.kirschning@oci.uni-hannover.de
b Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong, P. R. of China
phtoy@hku.hk
= JandaJel = cross-linked
polystyrene
OH
PPh2
O
O
1 M, toluene, 100 °C
0.005 mL/min
Ph
O
OTIPS
Ph
O
TIPSO
59% (full conversion under flow)
Received: 27.06.2016
Accepted after revision: 05.08.2016
Published online: 10.10.2016
catalyze the rearrangement of a wide range of ester-activat-
ed alkynes (Figure 1).8 We now wish to report on the syn-
thesis of the heterogeneous analogue 2, which is based on
the rasta resin architecture (Figure 1). Here, the functional
groups are attached to linear polystyrene grafts anchored
onto a heterogeneous cross-linked polystyrene core.9 We
included its use as a catalyst in the isomerization of alky-
noates under flow conditions into our studies.
DOI: 10.1055/s-0036-1588589; Art ID: ss-2016-z0440-op
Abstract A heterogeneous bifunctional polymer bearing phosphine
and phenol groups was developed to catalyze the isomerization of elec-
tronically activated alkynes. This organocatalytic process provided the
corresponding (E,E)-dienes and was shown to work under both batch
and flow conditions.
Key words rearrangement, organocatalysis, polymer-supported cata-
lyst, phosphine, phenols, flow chemistry
O
N
1
1
1
5
1
5
The organocatalytic phosphine-catalyzed isomerization
of electron-withdrawing group activated alkynes to the
corresponding (E,E)-dienes is a highly stereoselective pro-
cess that occurs under mild reaction conditions.1,2 It was in-
dependently reported by the groups of Trost3 and Lu4 for
the isomerization of alkynones. Shortly thereafter Rych-
novsky and Kim showed that the addition of phenol as a co-
catalyst allows to extend this methodology to alkynoates
(Scheme 1).5 Recently, such reactions have been used in the
synthesis of a variety of natural products.6
OH
PPh2
OH
PPh2
1
2
= JandaJel
R
living radical polymerization
initiation groups
heterogeneous
core
O N
n
O
O
PPh3, PhOH
flexible functionalized
grafts
OR2
(catalysts)
R1
OR2
R1
Figure 1 Bifunctional polymers 1 and 2 and the rasta resin concept
Scheme 1 The Trost–Lu isomerization of alkynes
For the synthesis of 2, the rasta resin architecture was
used since the attachment of the catalytic phosphine and
phenol groups on the flexible grafts rather than in the more
rigid heterogeneous core would eliminate the need for
polymer swelling in the solvent to achieve high catalytic ef-
ficiency. We felt that this was important since previous re-
sults from our group indicated that the presence of phenol
groups in more traditional Merrifield-type resins reduced
Several years ago we reported on the synthesis of 1, a
bifunctional non-cross-linked polystyrene bearing phos-
phine and phenol groups. This bifunctionalized polymer
served as a catalyst for the Morita–Baylis–Hillman reac-
tion,7 and its linear backbone meant that it functions as a
homogeneous catalyst. Thus, it was difficult to recover and
recycle it. However, more recently we used 1 to efficiently
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
S. Ceylan et al.
Paper
Synthesis
their ability to swell, and thus would reduce substrate ac-
cessibility to the catalytic sites.10 Thus, heterogeneous core
39 was heated in the presence of a ternary monomer mix-
ture of styrene, phosphine monomer 4,11 and phenol mono-
mer 59 (5:1:1 molar ratio) thus initiating living radical po-
lymerization to afford 6 (Scheme 2). Subsequent treatment
of 6 with TBAF liberated the phenol groups to form polymer
2. The loading level of the phosphine groups was deter-
mined by elemental analysis to be 0.95 mmol/g, compared
to a theoretical value of 0.90 mmol/g. Furthermore, gel-
phase 31P NMR analysis of 2 confirmed that the phosphine
groups were not oxidized. Scanning electron microscopy
images of the resins are shown in Figure 2. A dramatic in-
crease in average bead size was observed in 6 compared to 3
and the beads of 2 and 6 were approximately equal in size.
In continuation of our work on flow chemistry and en-
abling techniques for organic synthesis14 we investigated
the performance of the bifunctional heterogeneous organo-
catalyst 2 as fixed bed material inside microstructured flow
reactors. For this purpose we first had to optimize the cata-
lytic process with respect to the nature of the immobilized
catalyst, the amount of catalyst employed, and the concen-
tration of the solution (Table 1).
Table 1 Trost–Lu Isomerization Using Mono- and Bifunctional Organo-
catalysts 1, 2, and 13
O
conditionsa
O
(batch mode)
OR2
R1
OR2
R1
10–12
7 R1 = Ph, R2 = Bn
8 R1 = n-Bu, R2 = Bn
9 R1 = n-Bu, R2 = Et
O
N
+
+
+
O
1
N
5
130 °C
PPh2
OTBS
3
4
5
PPh2
O
N
13
1
1
5
Entry
Alkyne
Conditionsa,b
Product
Yieldc (%)
OR
PPh2
1
2
7
7
7
8
9
7
9
8
8
9
13, PhOH, 29 h
1, 29 h
10
10
10
11
12
10
12
11
11
12
50
75
85
90
85
0
6: R = OTBS, 60% yield
2: R = H, 97% yield
TBAF, THF, rt
3
2, 24 h
Scheme 2 Synthesis of rasta resin 2
4
2 (0.5 equiv), 24 h
2 (0.2 equiv), 24 h
2, 0.5 M, 24 h
0.2 M, PPh3, PhOH, 2 h
2, 2 h
5
6
7
91
46
81
80
8
9
2, 4 h
Figure 2 The SEM images of resins 3 (left), 6 (middle), and 2 (right)
10
2, 7 h
a 13 Resembles functionalized polymer 2, but it is only monofunctionalized
lacking the phenol moiety.
Interest in miniaturized flow devices (meso- or micro-
structured reactors) has seen a dramatic increase lately.12
By combining them with chemically functionalized fixed
bed materials based on inorganic or polymeric supports
synthetic technology platforms are created which simplify
synthesis and work-up protocols.13 Catalytic processes us-
ing heterogenized homogeneous catalysts are ideally suited
for being operated under the regime of flow protocols. For
example the catalytic reaction can be carried out in a con-
tinuous mode, which is particularly beneficial when a
chemically robust catalyst is immobilized. Importantly, the
local catalyst concentration is very high, which has an im-
pact on the kinetics of a catalytic process, allowing for high
substrate concentrations and higher degrees of conversion
with shorter reaction times.
b Conditions if not otherwise stated: 1 M solution in toluene, catalyst (1
equiv), 80 °C.
c Isolated yield.
We chose activated alkynes 7–9 as substrates and the
reactions were conducted in the batch mode in a vial. Clear-
ly, the insoluble rasta resin 2 showed superior activity com-
pared to simple phosphine functionalized resin 139 and sol-
uble non-cross-linked bifunctional polymer 17 (compare
entries 1–3), which is a prerequisite for the following flow
experiments. The reduced activity of the monofunctional-
ized resin in the presence of phenol indicates that both
groups act cooperatively, when closely attached onto the
polymeric backbone. With respect to the catalyst concen-
tration, we investigated the possibility of lowering the ini-
tial amount of 2 from a stoichiometric quantity down to 0.2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
S. Ceylan et al.
Paper
Synthesis
equivalents (entries 3–5). Gratifyingly, we found that 2 tru-
ly acts as an organocatalyst, and can be used at 20 mol%
loading levels. Regarding the concentrations of the sub-
strates we observed that concentrations below 1 M led to
no conversion with catalyst 2 (entry 6). In contrast, the use
of traditional conditions with PhOH and PPh3 allowed the
use of 0.2 M concentrations (entry 7). Obviously, catalyst 2
is limited to high concentrations although in the context of
flow reactions this is not a concern. Next, we varied the re-
action time to gain an understanding of the kinetics (en-
tries 8–10). We found that after 4–7 hours the conversion
was almost as high as in the case of 20 hours. Thus, we
could collect important information and facts for the de-
sired flow reactions described below.
First, we studied the reusability of resin 2 and as a test
reaction we chose the isomerization of alkyne 14 to diene
15 (Scheme 3). To be useful as fixed bed materials in flow
processes the heterogenized catalyst must prove to be ro-
bust with respect to leaching, which is an immense prob-
lem in metal-catalyzed reactions. We13e,15 and other
groups16 have encountered that the strong convective flow
inside microstructured flow reactors leads to enhanced
leaching of metals from its ligand, when attached to a solid
phase compared to corresponding batch reactions. Mechan-
ical stability and stress are other issues when low cross-
linked polymers are exposed to different solvents because
solvents cause swelling and shrinking.
based on glass rods, used earlier by our group.14a The flow
reactor (length: 12 cm, i.d. 5.0 mm, void volume when filled
with catalyst 2: 1 mL) was filled with the heterogeneous
catalyst and heated by an external oil bath while the reac-
tion mixture was pumped through, and finally collected at
the reactor outlet.
We next optimized three reaction parameters in order
to achieve full conversion in a single pass. The investiga-
tions included the impact of the flow rate, the reaction
temperature, and the influence of toluene. All reactions
were conducted with the same fixed bed reactor; thus the
same batch of functionalized polymer 2 was used for all re-
actions. The residence time, which correlated with the flow
rate, has a strong influence on the degree of conversion (en-
tries 1–4). Clearly, at a flow rate of 0.005 mL/min good re-
sults were obtained and the isolated yield of 81% demon-
strates that the transformation provides a true picture of
the efficacy of the process. When the temperature was
raised to 100 °C, good yields are achievable at higher flow
rates (entry 5). At temperatures well above 100 °C we en-
Table 2 Isomerization of Alkyne 15 under Flow Conditions and Sche-
matic Presentation of Flow Setupa
O
O
1 M, toluene
O
O
2
15
14
O
PPh3 (1 equiv), PhOH (1 equiv) 69%a
O
pump
2 (1 equiv) 1st run: 80%a
14
catalyst 2
6-port valve
2nd run: 85%a
3rd run: 86%a
4th run: 83%a
5th run: 74%a
1 M, toluene, 80 °C, 9 h
(batch)
1
5 4 3 2
starting materials
and washing solutions
reaction/
collection vessel
O
valve
waste
O
15
Entry
Flow rate
(mL/min)
Residence time Temp
Transformation
(%)
Scheme 3 Recyclability studies with rasta resin 2; a full conversion, iso-
lated yield
(min)
(°C)
1
2
3
4
5
6
7
8
9c
0.05
20
50
80
43
When alkyne 14 was subjected to the homogeneous
Trost–Lu conditions, diene 15 was isolated in 69% yield.
Rasta resin 2 gave a similar yield after filtration and solvent
removal. The polymer was resubjected to a new batch of
alkyne furnishing diene 15 in 85% yield. This procedure was
repeated three more times with similar results. In essence,
we did not observe any degradation or loss of activity of the
functionalized polymer 2, even after four reuses.
Next, we optimized the isomerization reaction of
alkyne 14 under flow conditions. The technical setup is de-
picted in Table 2; it allows for conducting the flow synthe-
sis in a circular mode, or alternatively as a continuous pro-
cess. In the present study we utilized a reactor design,
0.02
80
80
55
0.01
100
200
50
81
0.005
0.02
80
87 (81)b
78
100
100
105
110
100
0.005
0.005
0.005
0.005
200
200
200
200
92
60
69
86
a Conditions if not otherwise stated: 1 M solution in toluene, catalyst (1
equiv), 80 °C.
b Isolated yield.
c Neat conditions.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
S. Ceylan et al.
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Synthesis
countered degradation of the rasta resin 2 which led to re-
duced yields (compare entries 4, 6–8). Interestingly, the re-
action can also be conducted in the absence of toluene as
solvent at 100 °C and a flow rate of 0.005 mL/min (resi-
dence time approximately 200 min) which could be of par-
ticular importance for continuous industrial processes (en-
try 9).
Compared to the reaction times for isomerization under
batch conditions, the residence time calculated for the opti-
mized flow process (100 °C, 0.005 mL/min) is much shorter,
which demonstrates another advantage of flow processes
over the batch mode. This can be ascribed to the fact that
local catalyst concentration is higher when used as fixed
bed material inside the flow device.
Finally, we planned to show that the Trost–Lu isomeri-
zation can be a powerful synthetic tool in natural product
synthesis using more complex substrates. As a representa-
tive example we prepared alkyne 18 starting from bromide
1617 (Scheme 4). Alkynylation of bromide 16 with lithium
acetylide afforded 17, which was further functionalized af-
ter deprotonation and trapping of the acetylide with benzyl
chloroformate to afford alkyne 18.
groups for applying this new methodology to asymmetric
organocatalysis, and the results of these experiments will
be reported in due course.
1H NMR spectra were recorded at 400 MHz with a Bruker AVS-400
spectrometer referenced to CHCl3 (δ = 7.26). 13C NMR spectra were re-
corded at 100 MHz with a Bruker AVS-400 referenced to CHCl3 (δ =
77.16). Mass spectra (EI) were obtained at 70 eV with a type VG Auto-
spec apparatus (Micromass) or with a type LCT (ESI) (Micromass).
Analytical TLC was performed using precoated silica gel 60 F254 plates
(Merck, Darmstadt), and the spots were visualized with UV light at
254 nm or by staining with H2SO4/4-methoxybenzaldehyde in EtOH.
Flash column chromatography was performed on Merck silica gel 60
(230–400 mesh). All reagents were used as received from the suppli-
ers. THF was dried over Na wire with benzophenone as indicator. Spe-
cific optical rotations [α] were measured at 20 °C with a polarometer
type 341 from Perkin-Elmer with a 10 cm cuvette at λ = 589.3 mm
(sodium D line). As HPLC pumps Smartline Pump 100 from Knauer
were used. The employed glass reactors were constructed from com-
mercially available parts. Analytical data of dienes 10–12 were previ-
ously reported.8
Preparation of Catalyst 2
A suspension of 3 (0.41 g, 1.5 mmol), 4 (4.2 g, 14.6 mmol), 5 (3.42 g,
14.6 mmol), and styrene (7.6 g, 72.9 mmol) was heated at 130 °C un-
der N2 for 48 h. After cooling to r.t., the resulting polymer was shaken
with CH2Cl2 (25 mL) for about 5 min until the resin beads floated free-
ly. The resin was collected by filtration, placed in a Soxhlet extractor,
and washed with refluxing THF for 24 h. The beads were then washed
sequentially with MeOH, THF, Et2O, and hexanes, and dried in vacuo
to afford 6 (9.4 g, 60%).
DMPU, THF, 0 °C
Li
Br
OTIPS
TIPSO
47%
16
17
n-BuLi, THF, CbzCl, –78 °C
40%
Polymer 6 was mixed with 1.0 M TBAF solution in THF (34.4 mL, 34.4
mmol), shaken overnight at r.t. for 12 h, and then washed sequentially
with MeOH, THF, Et2O and hexane and dried in vacuo to afford 2 (9.1
g, 97%). Elemental analysis was used to determine the phosphine con-
tent (3.0%), and thus a loading level of 0.95 mmol PPh3/g. Gel-phase
31P NMR of 2 indicated only the presence of unoxidized phosphine at
δ = –6.13.
O
O
1 M, toluene, 100 °C
Ph
O
2
Ph
O
TIPSO
TIPSO
0.005 mL/min
18
19 59% (full conversion)
Benzyl Hept-2-ynoate (14)
Scheme 4 Synthesis of alkyne 18 from bromide 16 and Trost–Lu isom-
erization of alkyne 18 under flow conditions using rasta resin 2
Hex-1-yne (5.2 mL, 3.6 g, 44.1 mmol) was dissolved in dry THF (140
mL) and cooled to –78 °C under an argon atmosphere. Subsequently,
n-BuLi (2.5 M in hexane, 17.64 mL, 1.25 equiv) was added dropwise
over 30 min and the resulting solution further stirred for 30 min. Ben-
zyl chloroformate (5.0 mL, 6.0 g, 35.3 mmol, 1.0 equiv) was added
dropwise and stirring was continued for 45 min. The mixture was hy-
drolyzed by the addition of sat. NH4Cl solution, the organic phase was
separated, and the aqueous phase was extracted with EtOAc. The
combined organic phases were washed with brine, dried (Na2SO4),
and concentrated in vacuo. The crude product was purified by Kugel-
rohr distillation at 150 °C and 14 (6.03 g, 27.9 mmol, 79%) was ob-
tained as a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.33 (m, 5 H, Ar-H), 5.19 (s, 2 H,
Bn-H), 2.33 (t, J = 7.0 Hz, 2 H, H-4), 1.59–1.51 (m, 2 H, H-5), 1.47–1.37
(m, 2 H, H-6), 0.92 (t, J = 7.3 Hz, 3 H, H-7).
13C NMR (100 MHz, CDCl3): δ = 153.7 (q, C-1), 135.1 (q, Ar-C), 128.6 (t,
Ar-C), 128.53 (t, Ar-C), 128.50 (t, Ar-C), 90.2 (q, C-3), 73.0 (q, C-2),
67.4 (s, Bn-C), 29.5 (s, C-5), 21.9 (s, C-6), 18.4 (s, C-4), 13.5 (p, C-7).
When alkyne 18 was subjected to the optimized isom-
erization conditions using rasta resin 2, full conversion at a
flow rate of 0.005 mL/min was achieved. These conditions
are comparable to those used for simpler alkynes (Scheme
4).
In conclusion, we described the first example of an or-
ganocatalytic flow process using a heterogeneous bifunc-
tionalized polymer as catalyst. The process described paves
the way to perform the Trost–Lu isomerization of alky-
noates to dienoates under continuous flow conditions with
minimal work up. We are currently developing heteroge-
neous bifunctional polymers that bear chiral catalytic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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S. Ceylan et al.
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Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C14H16O2Na: 239.1048; found:
239.1053.
dried (Na2SO4), and concentrated in vacuo. Purification by column
chromatography (EtOAc/petroleum ether 1:50) afforded 18 (21 mg,
0.05 mmol, 40%) as a colorless oil; [α]D20 –34.0 (c 0.9, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.40–7.33 (m, 5 H, Ar-H), 5.18 (s, 2 H,
Bn-H), 3.53–3.46 (m, 2 H, H-4), 2.34–2.30 (m, 2 H, H-8), 1.66–1.50 (m,
5 H, H-5, H-6, H-7), 1.05 (s, 21 H, TIPS-H), 0.89 (d, J = 8.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 153.8 (q, C-1), 135.2 (q, Ar-C), 128.7
(Ar-C), 128.67 (Ar-C), 128.64 (Ar-C), 90.3 (q, C-3), 73.1 (q, C-2), 68.5 (s,
Bn-CH2), 67.5 (s, C-8), 35.7 (t, C-7), 32.7 (s, C-6), 25.4 (s, C-5), 19.2 (s,
C-4), 18.2 (p, TIPS-C), 12.1 (t, TIPS-C).
Benzyl (2E,4E)-Hepta-2,4-dienoate (15)
Batch reaction: Catalyst 2 (625 mg, 0.50 mmol) was added to a solu-
tion of 14 (108 mg, 0.50 mmol, 1 equiv) in toluene (0.5 mL). The mix-
ture was shaken at 80 °C for 9 h. The polymer beads were filtered off
and washed with EtOAc. The filtrate was concentrated in vacuo to af-
ford 15 (86.4 mg, 0.40 mmol, 80%) as a yellow oil.
Flow reaction: A glass reactor (length: 12 cm, i.d. 5.0 mm) was filled
with catalyst 2 (1.6 g, 1.28 mmol) and flushed with toluene. The reac-
tor was placed in a preheated oil bath (80 °C) and a flow rate of 0.005
mL/min was employed. After a steady state was reached 14 (215 mg,
1.0 mmol) in toluene (1 mL) was pumped through the reactor. The
crude product was collected, concentrated in vacuo and purified by
column chromatography (EtOAc/petroleum ether 1:40) to afford 15
(175 mg, 0.81 mmol, 81%) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 6 H, Ar-H, H-3), 6.18–
6.17 (m, 2 H, H-2, H-4), 5.84 (d, J = 15.0 Hz, 1 H, H-5), 5.19 (s, 2 H, Bn-
H), 2.23–2.16 (m, 2 H, H-6), 1.05 (t, 3 H, H-7).
13C NMR (100 MHz, CDCl3): δ = 167.1 (q, C-1), 146.4 (q, C-Ar), 145.7 (t,
C-3), 136.3 (t, C-5), 128.5 (t, Ar-C9, 128.2 (t, Ar-C), 128.1 (t, Ar-C),
127.4 (t, C-4), 118.8 (t, C-2), 66.0 (s, Bn-C), 26.1 (s, C-6), 12.9 (p, C-7).
HRMS (ESI): m/z [M + Na]+ calcd for C14H16O2Na: 239.1048: found:
239.1047.
HRMS (ESI): m/z [M + H]+ calcd for C25H41O3Si: 417.2825; found:
417.2839.
Benzyl (S,2E,4E)-7-Methyl-8-(triisopropylsilyloxy)octa-2,4-die-
noate (19)
Batch reaction: Catalyst 2 (30 mg, 0.024 mmol) was added to a solu-
tion of 18 (10 mg, 0.024 mmol, 1 equiv) in toluene (24 μL). The mix-
ture was shaken at 80 °C for 20 h. The polymer beads were filtered
and washed by EtOAc. The filtrate was concentrated in vacuo and af-
ter purification by column chromatography (EtOAc/petroleum ether
1:50) afforded 19 (86.4 mg, 0.40 mmol, 80%) as a colorless oil.
Flow reaction: A glass reactor (length: 12 cm, i.d. 5.0 mm) was filled
with catalyst 2 (1.6 g, 1.28 mmol) and flushed with toluene. The reac-
tor was placed in a preheated oil bath (80 °C) and a flow rate of 0.005
mL/min was employed. After a steady state was reached, 18 (39 mg,
0.094 mmol) in toluene (0.1 mL) was pumped through the reactor.
The crude product was collected, concentrated in vacuo, and purified
by column chromatography (EtOAc/petroleum ether 1:50) to afford
19 (23 mg, 0.055 mmol, 59%) as a colorless oil.
(S)-Triisopropyl(2-methylhept-6-ynyloxy)silane (17)
Lithium acetylide–ethylenediamine complex (85%, 105 mg, 1.13
mmol, 2.0 equiv) was suspended in dry THF (5 mL) under an argon
atmosphere and cooled to 0 °C. 2-Methylhept-6-ynyl bromide (16,
190 mg, 0.57 mmol, 1 equiv) in DMPU (1.5 mL) was added dropwise
and stirring was continued at r.t. for 17 h. The mixture was hydro-
lyzed by addition of ice cold water and extracted with Et2O. The com-
bined organic phases were washed with water, dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatography
(EtOAc/petroleum ether 1:50) afforded 17 (75 mg, 0.27 mmol, 47%) as
a colorless oil; [α]D20 –43.4 (c 1.1, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 3.55–3.46 (m, 2 H, H-1), 2.19–2.16 (m,
2 H, H-5), 1.94–1.93 (m, 1 H, H-7), 1.66–1.49 (m, 4 H, H-3, H-4), 1.23–
1.16 (m, 1 H, H-2), 1.06 (s, 21 H, TIPS-H), 0.90 (d, J = 6.5 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 84.9 (q, C-6), 68.6 (s, C-1), 68.3 (t, C-7),
35.8 (t, C-2), 32.6 (s, C-3), 26.3 (s, C-4), 18.9 (s, C-5), 18.2 (p, TIPS-C),
16.9 (p, CH3), 12.2 (t, TIPS-C).
[α]D20 –21.6 (c 0.6, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.38–7.30 (m, 6 H, Ar-H, H-3), 6.22–
6.10 (m, 2 H, H-5, H-4), 5.83 (d, J = 15.7 Hz, 1 H, H-2), 5.19 (s, 2 H, Bn-
H), 3.56–3.47 (m, 2 H, H-8a, H-8b), 2.40–2.34 (m, 1 H, H-6a), 2.05–
1.97 (m, 1 H, H-6b), 1.80–1.72 (m, 1 H, H-7), 1.05 (s, 21 H, TIPS-H),
0.89 (d, J = 6.5 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.3 (q, C-1), 145.7 (t, C-3), 143.8 (t,
C-5), 136.4 (q, Ar-C), 129.8 (t, C-4), 128.7 (t, Ar-C), 128.3 (t, Ar-C),
128.2 (t, Ar-C), 118.9 (t, C-2), 68.0 (s, C-8), 66.2 (s, Bn-C), 37.0 (s, C-6),
36.3 (t, C-7), 18.2 (p, TIPS-C), 16.6 (p, CH3), 12.3 (t, TIPS-C).
HRMS (ESI): m/z [M + H]+ calcd for C25H41O3Si: 417.2825; found:
417.2839.
HRMS (ESI): m/z [M + H]+ calcd for C17H35OSi: 283.2457; found:
283.2543.
Acknowledgement
This research was funded in part by the Research Grants Council of
the Hong Kong S. A. R., P. R. of China (Project No. HKU 704108P and G-
HK 031/07), and the Deutscher Akademischer Austauschdienst
(DAAD). Ms. Yan Teng provided technical assistance in recording the
SEM images shown in Figure 2, and Mr. Jun Ou performed some pre-
liminary experiments.
Benzyl (S)-7-Methyl-8-(triisopropylsilyloxy)oct-2-ynoate (18)
Alkyne 17 (35 mg, 0.12 mmol, 1.0 equiv) was dissolved in dry THF
(0.5 mL) under an argon atmosphere and cooled to –78 °C. n-BuLi (2.5
M in hexane, 53 μL, 0.13 mmol, 1.1 equiv) was added dropwise and
stirring was continued for 40 min. Benzyl chloroformate (21 μL, 24.6
mg, 0.14 mmol, 1.2 equiv) was subsequently added dropwise and the
mixture was stirred for an additional 90 min at –78 °C. The mixture
was hydrolyzed by the addition of sat. NH4Cl solution and extracted
with EtOAc. The combined organic phases were washed with brine,
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588589.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F