Gold(I)-, palladium(II)-, platinum(II)-, and mercury(II)-catalysed spirocyclization of 1,3-enynediols: Reaction scope

Article abstract of DOI:10.1002/ejoc.201402029

The spirocyclization of different 1,3-enynediols was investigated. The reaction was only efficient for the synthesis of [5,6]-spiroacetals. In this case, the reaction was characterized by almost quantitative yields, short reaction times, and low catalyst loadings (0.5-1%). When the synthesis of [6,6]-spiroacetals was attempted, the reaction suffered from poor regioselectivity and a higher propensity of the intermediate dienol ethers to decompose under the acidic conditions, and it became no longer viable. But it is possible to generate the dienol ethers cleanly under milder conditions as a mixture of regioisomers. This striking difference in reaction efficiency was explained by the unstable dienol ethers cyclizing more quickly to give [5,6]-spiroacetals than to give [6,6]-spiroacetals. In this study, the successful application of a new cationic palladium pincer complex for electrophilic alkyne activation at room temperature has been demonstrated for the first time. Copyright

Full text of DOI:10.1002/ejoc.201402029

FULL PAPER
DOI: 10.1002/ejoc.201402029
Gold(I)-, Palladium(II)-, Platinum(II)-, and Mercury(II)-Catalysed
Spirocyclization of 1,3-Enynediols: Reaction Scope
Alexander Zhdanko*[a] and Martin E. Maier*[a]
Keywords: Spiro compounds / Enynes / Acetals / Cyclization / Oxygen heterocycles / Homogeneous catalysis
The spirocyclization of different 1,3-enynediols was investi-
gated. The reaction was only efficient for the synthesis of
[5,6]-spiroacetals. In this case, the reaction was characterized
by almost quantitative yields, short reaction times, and low
catalyst loadings (0.5–1%). When the synthesis of [6,6]-
spiroacetals was attempted, the reaction suffered from poor
regioselectivity and a higher propensity of the intermediate
dienol ethers to decompose under the acidic conditions, and
it became no longer viable. But it is possible to generate the
dienol ethers cleanly under milder conditions as a mixture of
regioisomers. This striking difference in reaction efficiency
was explained by the unstable dienol ethers cyclizing more
quickly to give [5,6]-spiroacetals than to give [6,6]-spiro-
acetals. In this study, the successful application of a new cat-
ionic palladium pincer complex for electrophilic alkyne acti-
vation at room temperature has been demonstrated for the
first time.
Introduction
The spiroketal unit is frequently found in natural prod-
ucts of various types, including insect pheromones and
polyether antibiotics.[1] Prominent and recent examples in-
clude the spongistatins/altohyrtins.[2] Some of them, like
avermectin A1a,[3] salinomycin,[4] and okadaic acid,[5] have
a double bond in one of the rings. A double bond can be
an important functional group for the introduction of ad-
ditional substituents into a spiroketal substructure. During
investigations towards the total synthesis of natural prod-
ucts in our laboratory, the question arose as to whether
monounsaturated spiroketal structures can be synthesized
by a transition-metal-catalysed double cyclization of 1,3-
enyne diols.[6] A similar cyclization of propargylic triols was
reported by Aponick,[7] and later extended by Deslong-
champs[8] (Scheme 1). In these cases, the double bond is
formed by the elimination of water during the spirocycliza-
tion.
Scheme 1. Routes to unsaturated spiroacetals. The arrows indicate
the formal cyclization modes.
not an exception.[12] In our case, this would lead to two
possible regioisomers, 3 and 4 (Scheme 1). Therefore, we
investigated whether the regioselectivity is controlled, and
to what extent, by the double bond. The double bond might
have a purely electronic effect, but it may also have confor-
mational effects, since the two hydroxy groups at the left
and right sides of the alkyne have different approaches to
the reaction centre.
Our approach would be a good alternative for the syn-
thesis of this type of structure because the starting materials
are easily available by Sonogashira coupling between ter-
minal alkynes and cis-vinyl bromides under mild condi-
tions. It is also well known that transition-metal-catalysed Results and Discussion
addition to internal alkynes suffers from poor regioselectiv-
Starting enynediols 10a–10i were obtained in a straight-
ity; the addition can occur at either atom of the triple bond,
forward manner by the general strategy shown in Scheme 2.
The five-step sequence is illustrated with the preparation of
enynediol 10a. Thus, (Z)-vinyl bromide 8a was obtained
from alkynol 5a by converting it into the corresponding
bromoalkyne[13] (i.e., 6a), followed by protection of the
hydroxy function, subsequent hydroboration with dicyclo-
hexylborane,[14] and acidic work-up.[15] As protecting
groups, acetate, tetrahydropyranyl (THP), and tert-butyldi-
resulting in a mixture of products.[9–11] Spirocyclization is
[a] Institut für Organische Chemie, Universität Tübingen,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
E-mail: vinceeero@gmail.com
martin.e.maier@uni-tuebingen.de
http://www.uni-tuebingen.de/uni/com/welcome.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402029.
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A. Zhdanko, M. E. Maier
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methylsilyl (TBS) were used. Vinyl bromide 8a was then THP protecting group instead. Alkynol 5g[18] and protected
subjected to Sonogashira coupling[16] with alkynol 5b to alkynol 5d[19] were prepared as described in the literature.
give enyne 9a. Final deprotection delivered enynediol 10a.
The alkynols that were used for the cross-coupling reac-
tion are shown in Figure 2. Compound 5a was bought,
whereas alkynols 5b,[20] 5c,[21] 5d,[19] 5e, and 5f[22] were pre-
pared according to the literature.
Scheme 2. General approach to starting enynediols 10 used in this
study; NBS = N-bromosuccinimide.
Figure 2. Alkynols used for the Sonogashira coupling with (Z)-
vinyl bromides. TBDPS = tert-butyldiphenylsilyl.
Figure 1 shows the (Z)-vinyl bromides (i.e., 8a–8d) that
were prepared and used in this study. In addition, aryl iod-
ide[17] 8e also served as a substrate for the Sonogashira cou-
pling reaction.
Classical conditions were used for the coupling reaction,
i.e., catalytic amounts of Pd(PPh3)2Cl2 (0.6 mol-%) and CuI
(1.2 mol-%) in a mixture of THF and diethylamine. The
yields ranged from 77 to 90%. Subsequently, the protecting
group was removed under appropriate conditions (NaOH
in THF/MeOH/H2O for acetate, HCl in MeOH for THP
and TBS).
Enynediols 10 that were prepared for this study are
shown in Figure 3. They can be divided into enynediols
with either two or three carbon atoms on the alkyne ter-
minus. On the side of the alkene, there are always two car-
bon atoms between the alkene and the hydroxy terminus.
Figure 1. (Z)-Vinyl bromides 8a–8e prepared according to
Scheme 2.
The yields for the individual steps leading to the vinyl
bromides are listed in Table 1. As can be seen, the yields
were generally high. In case of the homoallylic acetates (i.e.,
8a, 8c) a small amount (4–8%) of the corresponding (E)-
isomer was also present. This can be explained by intra-
molecular addition of the acetate to the vinylborane, bond
rotation, and anti elimination (see Supporting Infor-
mation). The isomerization could be avoided by using the
Table 1. Yields for the transformation of alkynols 5a, 5d, and 5g
into (Z)-vinyl bromides 8a–8f.
Vinyl
bromide
Bromination
product
Protection
product
R
Hydroboration
yield [%]
Figure 3. Enynediols 10a–10i prepared in this study.
(yield [%])
(yield [%])
8a
8b
8c
8d
6a (88)
6a (88)
6c (99)
6d (95)
7a (96)
7b (99)
7c (98)
Ac
THP
83
80
97
91
The yields for the individual steps leading to the enynedi-
ols are listed in Table 2. Both the coupling and the depro-
tection steps proceeded in good yield.
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Spirocyclization of 1,3-Enynediols
Table 2. Yields for the preparation of enynediols 10a–10i by Sono-
gashira coupling and deprotection.
Alkynol
Vinyl
Coupling yield Deprotection yield
Enynediol
bromide
[%]
[%]
5b
5b
5a
5d
5a
5c
5e
5a
5f
8a
8c
8b
8d
8c
8c
8c
8d
8a
8e
80
77
79
79
89
68
79
90
87
70
99
99
71
81
99
99
99
91
90
10a
10b
10c
10d
10e
10f
10g
10h
10i
5a
10j
Scheme 3. Competitive spirocyclization and decomposition of di-
enol ether intermediates.
With the substrates in hand, we began our studies with
the spiroketalization of diols 10a and 10b, with the aim of
synthesizing 1,7-dioxaspiro[5.5]-undec-4-ene ring systems 3
([6,6]-acetals). This is probably the most important olefin-
containing spiroketal structure found in natural products.
Some of the catalysts used in this study are shown in
Figure 4. This includes Zeise’s dimer, new pincer complex
11, and gold(I) complex[23] 12.
Obviously, the conjugated double bond in 2 has little or
no impact on the regioselectivity of the alcohol addition to
the triple bond (the reaction remains unselective). This is
somewhat surprising: the hydroxy group coming from the
alkene substituent (alkenol hydroxy group) and being ap-
parently well preorganized for cyclization generally ap-
peared to be the least reactive, so ca. 90% of the cyclization
originated from the saturated side (alkynol hydroxy group).
It appears that the rule about the preference for 5-exo over
6-exo cyclization is valid also here.[28]
Besides Au, Pt, and Hg catalysts, we tried to solve the
regioselectivity problem by using a Pd catalyst. Since the
Pd(MeCN)2Cl2-catalysed reaction was found to be inef-
ficient, we supposed that cationic palladium pincer com-
plexes might work better. Prompted by the fact that com-
plexes of this kind have been already used for the electro-
philic activation of alkenes, but not of alkynes,[29] we syn-
Figure 4. Catalysts for the spirocyclization.
But using various gold, platinum, and mercury catalysts
in different solvents, we could not achieve an efficient syn-
thesis of the desired [6,6]-acetals.[24,25] This screening is dis-
cussed in more detail in the Supporting Information. Our
results show that the failure to synthesize [6,6]-acetals is
associated with the poor regioselectivity of the first cycliza-
tion event, and decomposition of the intermediate dienol
ethers competing with the second cyclization event, as
exemplified in Scheme 3. It is possible to cleanly generate
the dienol ethers (e.g., 13a and 14a) as a mixture of
regioisomers under less acidic conditions in situ, but the
higher level of acidity required for the second cyclization
causes unavoidable competitive decomposition, making the
spiroacetals isolable only in a low yield. We think that the
decomposition of 13a and 14a is facilitated by the ad-
ditional unsaturation, which makes them more vulnerable
towards competitive side-reactions (carbocation is more
stable, lives longer, and becomes more susceptible to inter-
molecular processes such as cationic polymerization and/or
Diels–Alder reactions). Such processes should decrease the
–
thesized a new catalyst, PdPCP-ac+ SbF6 (Figure 1, avail-
able in two easy steps), and investigated its ability to cata-
lyse the spirocyclization. To our delight, this catalyst ap-
peared to be very active, giving a mixture of dienol ethers.
However, this catalyst favours the 5-exo product with high
selectivity (ca. 90%, determined in situ by NMR spec-
troscopy). This makes the reaction synthetically valuable,
but again unsuitable for [6,6]-spiroacetal synthesis
(Scheme 4). The successful application of this well-defined
1
level of unsaturation, which is indeed observed in the H
NMR spectra.[26] This is supported also by the fact that a
saturated analogue (non-3-yne-1,9-diol) gave no decompo-
sition in Au-, Pd-, and Pt-catalysed reactions, even when
the reaction mixture was left overnight.[27]
Scheme 4. Pd pincer catalyst 11 provided 5-exo dienol ether 13b
most selectively.
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A. Zhdanko, M. E. Maier
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catalyst in this reaction opens new perspectives for the Table 4. Efficient formation (in situ) of spiroacetal 3d with various
catalysts.
chemistry of alkynes that could become complementary to
modern gold catalysis.
Having failed to achieve the synthesis of [6,6]-acetals, we
continued to search for another type of unsaturated spiro-
acetal system that could be formed more efficiently. We
found that the cyclization of (3Z)-oct-3-en-5-yne-1,8-diol
10c occured cleanly to give the corresponding [5,6]-
spiroacetal (i.e., 3c; Table 3). The reaction is applicable to a
wide range of differently substituted diols, and occurs
equally well in CH2Cl2, CHCl3, THF, and MeOH in the
presence of different Au, Pd, Pt, and Hg catalysts. Gen-
erally, the reaction is fastest in CH2Cl2 or CHCl3, solvents
that neither solvate H+ nor coordinate to a catalyst. The
overall process is characterized by short reaction times, and
Entry Catalyst
Amount Time
[mol-%] [min]
Yield of
3d [%]
–
1
L2AuNCMe+ SbF6 (12)
0.8
1.0
4.6
7
10
7
95
95
–
2
PdPCP-ac+ SbF6– (11)
3[a]
PdPCP-ac+ SbF6 (11)
25[b]
[a] Reaction in CD3OD. [b] 95% after reaction overnight.
the initial monocyclization products are detectable by TLC diol contained a chiral centre, the spiroacetal products were
as reaction intermediates that eventually completely disap- obtained as thermodynamic mixtures of epimers at the
pear. For example, the cyclization of model substrate 10c in acetal carbon. Thus, some substrates provided mixtures of
the presence of various catalysts was monitored by NMR both epimers (Table 5, entries 8, 9, and 11), while all other
spectroscopy, and a quantitative in situ yield of the corre- substrates provided a single isomer, due to the strong con-
sponding spiroacetal product (i.e., 3c) was achieved within trol from the side-chain, which favours an equatorial posi-
4 min (Table 3, entries 1–4). The less active Hg(OTFA)2 cat- tion in the ring (Table 5, entries 1–6, and 8). From a practi-
alyst (OTFA = trifluoroacetate) also gave a quantitative cal point of view, all the catalysts gave equally good yields.
yield, but the reaction was slower (Table 3, entry 5). The Interestingly, AuCl3, which could not be used in the pre-
reaction catalysed by gold catalyst L2AuNCMe+ (12; Fig- vious reaction at all, now appears to be one of the most
ure 4) was slower in methanol than in CDCl3 (Table 3, en- active catalysts! The catalyst loading could be further re-
tries 1 and 6).
duced to 0.1 mol-% without the addition of an extra acidic
promoter (see Supporting Information).[34] However, for
preparative purposes, we recommend a catalyst loading of
0.2–1 mol-%, and a substrate concentration of Ͼ0.1 m.
From our experiments, it follows that the striking efficacy
of [5,6]-3c formation over [6,6]-3a or [5,7]-4a relies on the
faster cyclization of the intermediate monocyclization prod-
ucts, Scheme 5. As we will show later,[35] formation of the
[5,6]-3c spiroacetal occurs via either 5-endo-16c dienol ether
(for Au, Pd, and Pt) or 6-exo-17c ether (for Hg), and both
of these intermediates appear to ring-close to form the sec-
ond cycle faster than do the previously described examples
5-exo-13a and 6-endo-14a (Scheme 3).[36] This difference is
explained as follows: 5-endo enol ether 16c suffers from
some ring strain because of the deviation from the 120°
angle for both sp2 carbons, and this strain is released upon
the second cyclization. 6-exo Enol ether 16c does not suffer
Table 3. Efficient formation (in situ) of spiroacetal 3c with various
catalysts.
Entry Catalyst
Amount Time Yield of
[mol-%]
[min]
3c [%]
–
1
2
L2AuNCMe+ SbF6 (12)
0.8
1.0
1.1
0.7
4.1
0.8
4
4
4
4
26
18
99
99
99
99
99
95
–
Ph3PAuNCMe+ SbF6
3
4
Zeise’s dimer
–
PdPCP-ac+ SbF6 (11)
5
Hg(OTFA)2
6[a]
L2AuNCMe+ SbF6 (12)
–
[a] Reaction in CD3OD.
Similarly, reaction of a chiral substrate 10d led to the from this strain, but then formation of a five-membered
formation of spirocycle 3d as a thermodynamic mixture of ring occurs, which is faster than six- or seven-membered
diastereomers (Table 4, entries 1–3). Notably, catalysis by ring formation to give [6,6]-3a or [5,7]-4a. This further sup-
PdPCP-ac+ (11) was rather slow in methanol (Table 4, ports our viewpoint that the inability of 5-exo-13a and 6-
entry 3).[30] The parent spiroacetal 3c is known in the litera- endo-14a to cyclize quickly enough makes them more sus-
ture. Originally, it was prepared from the saturated ceptible to decomposition, which may become a major pro-
spiroacetal by bromination and elimination.[31] In another cess, while 5-endo-16c and 6-exo-17c avoid decomposition
route, a dihydrofuran with an alkenol side-chain was sub- due to a fast cyclization to give more stable spiroacetal
jected to proton-catalysed acetalization.[32] While natural [5,6]-3c (Scheme 5). It can be also pointed out that due to
products with a double bond in a pyran ring of a spiro- the “harsher” conditions required for the cyclization of 5-
acetal are rare, derivatives of compounds 3c have been used exo-13a and 6-endo-14a, their [6,6]-3a or [5,7]-4a products
as synthetic intermediates en route to bis-spiroacetals.[33]
Some preparative examples are given in Table 5. Gen- equilibration.
may open reversibly and decompose as a result of such an
erally, these reactions gave the spiroacetals in high yield
Although these explanations are quite clear, it was rather
with virtually no decomposition. When the starting enyne- surprising to find that simply shortening the substrate by
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Spirocyclization of 1,3-Enynediols
Table 5. Spirocyclization of (3Z)-oct-3-en-5-yne-1,8-diols. Preparative examples.
[a] The yield is lower because of the presence of a trans-alkene impurity (ca. 10%) in the starting substrate. [b] Volatile compound.
poor regioselectivity of the first cyclization event, and the
high propensity of the dienol ether intermediates (i.e., 5-
exo-13a and 6-endo-14a) to decomposition under acidic
conditions (which is necessary to complete the spirocycliza-
tion sequence). But it is possible to generate dienol ethers
5-exo-13a and 6-endo-14a cleanly under milder conditions
in situ as a mixture of regioisomers. In contrast, enol ethers
5-endo-16c or 6-exo-17c are much more difficult to generate
in situ, because of their higher propensity to undergo the
second ring closure.
Thus, spirocyclization of (3Z)-oct-3-en-5-yne-1,8-diols is
a very convenient new route to unsaturated [5,6]-spiroacet-
als. The starting materials are easily available in high yield
Scheme 5. Fast ring closure saves dienol ether intermediates from
decomposition.
by Sonogashira coupling of two subunits. The yields of the
just one methylene unit may dramatically change the situa-
tion so that a low-yielding and unselective reaction becomes
an efficient process.
[5,6]-spiroacetals are close to quantitative, and are achiev-
able with a broad range of Au, Pd, Pt, and Hg electrophilic
catalysts used at low catalyst loadings (Ͻ1 mol-%). The re-
action provides a thermodynamic mixture of epimers at the
acetal carbon, and the reaction product is therefore influ-
enced by the side-chain substituents.
Conclusions
In conclusion, we investigated gold(I)-, palladium(II)-,
platinum(II)-, and mercury(II)-catalysed spirocyclizations
of 1,3-enynediols 10, and found that the reaction is only
efficient for the synthesis of [5,6]-spiroacetals. The failure
Experimental Section
4-Bromobut-3-yn-1-ol (6a): Silver nitrate (0.6 g, 6mol-%) was added
to efficiently provide [6,6]-spiroacetals is due to both the to a solution of but-3-yn-1-ol (4.20 g, 60 mmol) in acetone (60 mL).
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A. Zhdanko, M. E. Maier
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Then NBS (11.0 g, 1.03 equiv.) was added in portions. The reaction
was exothermic, and the reaction flask was cooled in a water bath.
After the addition of NBS, the reaction mixture was stirred at room
temperature for 1 h (TLC control: EtOAc/petroleum ether, 1:1 or
1:2). The resulting milky solution was concentrated in vacuo, then
diethyl ether (50 mL) was added, and the mixture was washed with
water (60 mL). The aqueous phase was extracted with diethyl ether
(2ϫ 30 mL). The combined organic phases were washed with satu-
rated NaCl solution, dried with MgSO4, filtered, and concentrated.
The residue was purified by chromatography on a silica column
(13ϫ3 cm) to give bromoalkyne 6a (7.9 g, 88%) as a colourless
1.811 g, 12.2 mmol) and dihydropyran (1.33 mL) in CH2Cl2
(10 mL). An exothermic reaction soon started. The solution was
cooled in a water bath. When the reaction was complete (ca.
30 min, TLC control: petroleum ether/EtOAc, 2:1), the reaction
mixture was quenched with Et3N (0.02 mL), and the solvents evap-
orated to dryness in vacuo. The crude compound 7b was used for
the hydroboration without further purification.
1-[(Benzyloxy)methyl]-4-bromobut-3-ynyl Acetate (7c): AcCl (3.3 mL,
1.2 equiv.) was added to a solution of crude 1-(benzyloxy)-5-
bromopent-4-yn-2-ol (6c; 10.5 g, 39.0 mmol) in Et2O (60 mL) and
petroleum ether (40 mL). The solution was cooled to –10 °C, and
Et3N (7.6 mL, 1.4 equiv.) was added. Initially, a thick, heavy oil
precipitated. The flask was shaken, and the temperature was al-
lowed to rise, whereupon the oil slowly disappeared, and a solid
precipitate formed. At this stage, the reaction mixture was stirred
for a few min at room temperature. If necessary, additional AcCl
and Et3N can be added to achieve complete conversion of the
alcohol into the ester (TLC control: petroleum ether/EtOAc, 2:1).
When complete conversion was achieved, the reaction mixture
(with precipitate) was directly passed through a short column of
silica gel (1.5ϫ3.5 cm), which was further eluted with petroleum
ether/Et2O, 3:1. The fractions containing the acetate were evapo-
rated to give pure acetate (11.89 g, 98%) as a yellow oil. The combi-
nation petroleum ether/Et2O is probably not the best solvent for
the filtration, because of the precipitation of polar components as
an oil that must be crystallized by scratching with a spatula, but it
allows very easy separation of the product when the reaction is
finished and no oil is left (no need to extract, wash and purify). 1H
NMR (400 MHz, CDCl3): δ = 2.08 (s, 1 H, CH3), 2.57 (dd, J =
5.6, 16.8 Hz, 1 H, CH2), 2.63 (dd, J = 6.6, 16.8 Hz, 1 H, CH2),
3.60 (dd, J = 4.6, 10.4 Hz, 1 H, CH2), 3.64 (dd, J = 5.1, 10.4 Hz,
1 H, CH2), 4.52 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.58 (dd, J =
12.2 Hz, 1 H, CH2Ph), 5.06 (app. quint, 1 H, CH), 7.26–7.37 (m,
5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 22.0
(CH2), 40.4 (quat.), 69.4, 70.3, 73.3, 75.3 (quat.), 127.6, 127.8,
128.4, 137.7 (quat.), 170.3 ppm.
1
liquid. The H NMR spectroscopic data were in accordance with
the literature.[13]
1-(Benzyloxy)-5-bromopent-4-yn-2-ol (6c): Silver nitrate (0.199 g,
3mol-%) was added to a solution of 5g (7.61 g, 39.0 mmol) in acet-
one (40 mL). Then NBS (7.15 g, 1.03 equiv.) was added in portions.
The reaction was exothermic, and the reaction flask was cooled in
a water bath. After the addition of NBS, the reaction mixture was
stirred at room temperature for 1 h (TLC control: EtOAc/petro-
leum ether, 1:1 or 1:2). The resulting milky solution was concen-
trated in vacuo, then diethyl ether (20 mL) was added, and the mix-
ture was washed with water (20 mL). The aqueous phase was ex-
tracted with diethyl ether (2ϫ10 mL). The combined organic
phases were washed with saturated NaCl solution, dried with
MgSO4, filtered, and concentrated. The residue was purified by
chromatography on a silica column to give bromoalkyne 6c (10.6 g,
99%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 2.45 (d,
1 H, OH), 2.47 (d, J = 6.1 Hz, 2 H, CH2), 3.48 (dd, J = 6.4, 9.4 Hz,
1 H, CH2), 3.59 (dd, J = 4.1, 9.4 Hz, 1 H, CH2), 3.92–3.99 (m, 1
H, CH), 4.56 (s, 2 H, CH2), 7.28–7.38 (m, 5 H, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.7 (CH2), 40.3 (quat.), 68.7, 72.7, 73.4,
76.1 (quat.), 127.7, 127.8, 128.5, 137.7 (quat.) ppm.
{[(2S)-4-Bromo-2-methylbut-3-ynyl]oxy}(tert-butyl)dimethylsilane (6d):
Silver nitrate (0.061 g, 3.5mol-%) and NBS (1.91 g, 1.05 equiv.)
were added to a solution of alkyne 5d (2.02 g, 10.2 mmol) in acet-
one (10 mL), and the mixture was stirred at room temperature for
1 h (TLC control: petroleum ether/Et2O, 40:1). The resulting milky
solution was concentrated in vacuo, then diethyl ether (20 mL) was
added, and the mixture was washed with water (20 mL). The aque-
ous phase was extracted with diethyl ether (2ϫ10 mL). The com-
bined organic phases were washed with saturated NaCl solution,
dried with MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography to give bromoalkyne 6d (2.69 g,
95%) as a colourless liquid. Rf (petroleum ether/Et2O, 40:1): 0.66.
1H NMR (400 MHz, CDCl3): δ = 0.05 (s, 6 H), 0.89 (s, 9 H), 1.15
(d, J = 6.9 Hz, 3 H), 2.58 (app. sext, 1 H), 3.46 (dd, J = 9.7, 7.6 Hz,
1 H), 3.65 (dd, J = 9.7, 5.9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = –5.4, –5.3, 16.9, 18.3, 25.8, 30.3, 39.1, 66.9, 82.4 ppm.
Dicyclohexylborane:
A
three-necked round-bottomed flask
equipped with a magnetic stirrer, a gas inlet, and a thermometer
was flushed with nitrogen, and cyclohexene (5.8 mL, 4.70 g,
57.7 mmol, 2.4 equiv.) and absolute Et2O (15 mL) were added. The
flask was immersed in an ice–water bath. At +10 °C, borane di-
methyl sulfide complex (2.65 mL, 27.9 mmol, 1.15 equiv.) was
added in one portion by syringe to the stirred mixture. The flask
was partially removed from the bath to prevent further cooling, but
to keep the temperature around +10 °C. The reaction mixture was
stirred in this position until a precipitate began to form (ca. 5 min).
The reaction was exothermic. Then the reaction mixture was al-
lowed to stir without cooling for ca. 20 min (during this time, the
mixture may reach room temperature; moreover, a lot of precipitate
was already formed).
4-Bromobut-3-ynyl Acetate (7a): Et3N (9.5 mL, 1.3 equiv.) was
added to
a solution of 4-bromobut-3-yn-1-ol (6a; 6.11 g,
52.6 mmol) and AcCl (4.3 mL, 1.15 equiv.) in EtOAc (30 mL) at
0 °C. A white precipitate formed immediately. An additional small
amount of AcCl (0.1 mL) was added to reach full conversion (TLC
control: petroleum ether/EtOAc, 2:1). The precipitate was removed
by filtration and washed with Et2O. The filtrate was concentrated
in vacuo, and the residue was purified by flash chromatography
(Et2O/petroleum ether, 1:1) on a short column to give 7a (9.64 g,
96%) as a colourless oil. Rf (petroleum ether/Et2O, 5:1): 0.37. H
NMR (400 MHz, CDCl3): δ = 2.07 (s, 1 H, CH3), 2.54 (t, J =
6.7 Hz, 2 H, CH2), 4.14 (t, J = 6.7 Hz, 2 H, CH2) ppm.
(3Z)-4-Bromobut-3-enyl Acetate (8a): The slurry of dicyclohexyl-
borane in Et2O prepared as described above was cooled again to
+15 °C. Starting from this temperature, a solution of bromoalkyne
7a (4.66 g, 24.3 mmol, 1 equiv.) in petroleum ether (15 mL) was
added from a dropping funnel. The reaction was exothermic, and
it started to occur actively in the region of 17–22 °C. The rate of
addition and depth of immersion of the reaction flask in the cool-
ing bath can be regulated so as to keep the temperature within this
region. The initially formed precipitate dissolved. Following this
regime, the exothermic phase of the reaction lasted ca. 5 min. After
the addition was complete, and when most of the precipitate had
dissolved, the cooling bath was removed, and the temperature was
1
2-[(4-Bromobut-3-yn-1-yl)oxy]tetrahydro-2H-pyran (7b): pTsOH·H2O
(23 mg) was added to a solution of 4-bromobut-3-yn-1-ol (6a;
3416
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3411–3422

Spirocyclization of 1,3-Enynediols
1
allowed to rise to ca. 25–27 °C. The mixture was stirred for some
10 min to form an almost clear solution (higher temperatures were
avoided). Then the solution was cooled back to ca. 20 °C, and
acetic acid (1.5 mL, 1.1 equiv.) was added by pipette. The solution
was stirred for ca. 5 min (this step was only slightly exothermic).
Then ethanolamine (H2NCH2CH2OH; 3.16 mL, 2.3 equiv.) was
added by pipette at ca. 20 °C, and the mixture was stirred for an-
other 30 min. Eventually, a sticky crystalline precipitate formed.
Then the reaction mixture (with the precipitate) was passed
through a short column of flash silica gel (1.5ϫ3.5 cm), and fur-
ther eluted with petroleum ether/Et2O, 4:1. The filtrate was evapo-
rated to give the crude vinyl bromide (3.9 g, 83%) as a sufficiently
pure yellow oil. Alternatively, purification by flash column
chromatography (petroleum ether/Et2O, 5:1) can be performed. Rf
8d (2.33 g, 91%) as a colourless oil. H NMR (400 MHz, CDCl3):
δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.01 (d, J = 6.9 Hz, 3 H), 2.79–2.89
(m, 1 H), 3.47 (dd, J = 9.8, 5.7 Hz, 1 H), 3.53 (dd, J = 9.8, 6.3 Hz,
1 H), 5.95 (dd, J = 8.9, 6.9 Hz, 1 H), 6.14 (d, J = 7.1 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = –5.4, 15.9, 18.3, 25.9, 37.5,
66.4, 107.3, 137.6 ppm.
(Z)-9-Hydroxynon-3-en-5-yn-1-yl Acetate (9a): THF (19 mL) and
diethylamine (5 mL) were added to alkenyl bromide 8a (2.46 g,
12.7 mmol) and pentynol (5b; 1.18 g, 14.03 mmol, 1.1 equiv.) under
a nitrogen atmosphere. The mixture was stirred to dissolve the
starting materials. Then Pd(PPh3)2Cl2 (55 mg, 0.6 %) and CuI
(30 mg, 1.2%) were added, the flask was closed, and the nitrogen
flow was disconnected. The reaction mixture was stirred for 24 h
at room temperature (TLC control: petroleum ether/EtOAc, 2:1).
The white precipitate was removed by filtration and washed with
portions of EtOAc, the filtrate was evaporated in vacuo, and the
residue was purified by flash chromatography (petroleum ether/
EtOAc, 2:1Ǟ1:1) to give 9a (1.99 g, 80%) as a slightly orange oil.
Rf (petroleum ether/EtOAc, 1:1): 0.38. 1H NMR (400 MHz,
CDCl3): δ = 1.74 (br. s, 1 H, OH), 1.78 (ap. quint., J = 6.6 Hz, 2
H, 8-H), 2.04 (s, 3 H, CH3), 2.46 (dt, J = 2.0, 6.9 Hz, 2 H, 7-H),
2.60 (ap. dq, J = 1.2, 6.9 Hz, 2 H, 2-H), 3.76 (t, J = 6.1 Hz, 2 H,
9-H), 4.12 (t, J = 6.9 Hz, 2 H, 1-H), 5.54 (br. d, J = 10.7 Hz, 1 H, 4-
H), 5.81 (dt, J = 7.1, 10.7 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.0 (C-7), 21.0 (CH3), 29.5, 31.3, 61.5 (C-9), 63.1 (C-
1), 77.3, 94.5, 112.1, 137.0, 171.2 ppm. HRMS (ESI): calcd. for
C11H16O3 [M + Na]+ 219.09917; found 219.09920.
1
(petroleum ether/Et2O, 5:1): 0.37. H NMR (400 MHz, CDCl3): δ
= 6.28 (dt, J = 7.1, 1.3 Hz, 1 H), 6.12 (app. q, J = 7.1 Hz, 1 H),
4.13 (t, J = 6.6 Hz, 2 H), 2.54 (app. dq, 2 H), 2.05 (s, 3 H) ppm.
HRMS (ESI): calcd. for C6H9BrO2 [M + Na]+ 214.96781; found
214.96795.
2-[(4-Bromobut-3-yn-1-yl)oxy]tetrahydro-2H-pyran (8b): This com-
pound was prepared by a similar method to that described for 8a.
Thus, dicyclohexylborane was prepared from cyclohexene (2.30 g,
2.84 mL, 28.0 mmol, 2.3 equiv.) and borane dimethyl sulfide com-
plex (1.27 mL, 13.4 mmol) in Et2O (10 mL). A solution of crude
bromoalkyne 7b (2.84 g, 12.2 mmol) in petroleum ether (10 mL)
was added to the resulting suspension. Flash chromatography
(pentane/Et2O, 10:1) gave alkenyl bromide 8b (2.27 g, 80% over two
steps) as a colourless oil. Rf (petroleum ether/Et2O, 5:1): 0.4. 1H
NMR (400 MHz, CDCl3): δ = 1.47–1.61 (m, 4 H), 1.68–1.73 (m, 1
H), 1.77–1.85 (m, 1 H), 2.46–2.52 (m, 2 H), 3.48 (dt, J = 6.6,
9.6 Hz, 1 H, CH2), 3.48–3.53 (m, 1 H), 3.78 (dt, J = 6.8, 9.6 Hz, 1
H, CH2), 3.85 (ddd, J = 3.3, 7.8, 11.1 Hz, 1 H), 4.60 (dd, J = 2.8,
4.3 Hz, 1 H, OCHO), 6.19 (app. q, J = 6–7 Hz, 1 H, =CH), 6.23
(d, J = 7.1 Hz, 1 H, =CH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 19.5, 25.4, 30.5, 30.6, 62.3, 65.4, 98.7, 109.2, 131.7 ppm. HRMS
(Z)-1-(Benzyloxy)-10-hydroxydec-4-en-6-yn-2-yl Acetate (9b): Benz-
ene (16 mL) and diethylamine (4.2 mL, 2.97 g, 40.6 mmol, 3 equiv.)
were added to alkenyl bromide 8c (4.21 g, 13.5 mmol) and pentynol
(1.20 g, 14.3 mmol, 1.1 equiv.) under a nitrogen atmosphere. The
mixture was stirred to dissolve the starting materials. After that,
Pd(PPh3)2Cl2 (57 mg, 0.6%) and CuI (43 mg, 1.7%) were added,
the flask was closed, and the nitrogen flow was disconnected. The
reaction mixture was stirred for 5 h at room temperature (TLC con-
trol: petroleum ether/EtOAc, 2:1; the reaction was slightly exother-
mic, the initial light solution darkened, and a precipitate formed).
(ESI): calcd. for C9H15BrO2 [M
257.01469.
+
Na]+ 257.01476; found
(3Z)-1-[(Benzyloxy)methyl]-4-bromobut-3-enyl Acetate (8c): This After that, the precipitate was removed by filtration and washed
compound was prepared by a similar method to that described for
8a, starting from cyclohexene (6.15 g, 4.99 g, 60.7 mmol, 2.3 equiv.)
and borane dimethyl sulfide complex (2.76 mL, 29.1 mmol,
1.1 equiv.) in Et2O (25 mL), and bromoalkyne 7c (8.21 g,
26.4 mmol, 1 equiv.) in petroleum ether (25 mL). Flash chromatog-
raphy (petroleum ether/Et2O, 4:1) gave alkenyl bromide 8c (7.85 g,
95%) as a colourless oil. Rf (petroleum ether/Et2O, 4:1): 0.4. 1H
NMR (400 MHz, CDCl3): δ = 2.06 (s, 1 H, CH3), 2.56 (dt, J = 1.5,
with portions of EtOAc, the filtrate was evaporated in vacuo, and
the residue was purified by flash chromatography (petroleum ether/
EtOAc, 2:1Ǟ1:1) to give 9b (3.28 g, 77%) as a slightly orange oil.
The yield was higher if pure substrate was used. The use of 5 equiv.
of Et2NH instead of 3 equiv. is recommended. Rf (petroleum ether/
EtOAc, 1:1): 0.40. H NMR (400 MHz, CDCl3): δ = 1.75 (quint.,
J = 6.6 Hz, 2 H), 2.06 (s, 1 H, CH3), 2.44 (dt, J = 2.0, 6.8 Hz, 2
H, CH2), 2.57–2.69 [m (ddt), 2 H, CH2], 3.53 (d, J = 5.1 Hz, 2 H,
1
6.9 Hz, 2 H, CH2), 3.52 (dd, J = 4.6, 10.5 Hz, 1 H, CH2), 3.55 (dd, CH2), 3.73 (t, J = 6.3 Hz, 2 H, CH2), 4.50 (d, J = 12.2 Hz, 1 H,
J = 5.6, 10.5 Hz, 1 H, CH2), 4.51 (d, J = 12.1 Hz, 1 H, CH2), 4.58 CH2), 4.58 (dd, J = 12.2 Hz, 1 H, CH2), 5.12 [tt (almost quint), 1
(dd, J = 12.1 Hz, 1 H, CH2), 5.14 (app. quint, 1 H, CH), 6.09 (q, H, CH], 5.53 (br. d, J = 10.7 Hz, 1 H, =CH), 5.81 (dt, J = 7.3,
J = 7.1 Hz, 1 H, =CH), 6.26 (dt, J = 1.5, 7.1 Hz, 1 H, =CH), 7.26–
10.7 Hz, 1 H, =CH), 7.26–7.36 (m, 5 H, Ph) ppm. 13C NMR
7.36 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1 (100 MHz, CDCl3): δ = 16.0, 21.2 (CH3), 31.2, 31.5, 61.4, 70.6,
(CH3), 31.6 (CH2), 70.5, 71.1, 73.2, 110.6 (=CH), 127.6 (Ph), 127.7 71.9, 73.2, 77.4, 94.6, 112.6 (=CH), 127.6 (Ph), 127.7 (Ph), 128.4
(Ph), 128.4 (Ph), 129.7 (=CH), 137.9 (Phquat), 170.5 ppm. HRMS
(ESI): calcd. for C14H17BrO3 [M
335.02540.
(Ph), 136.2 (=CH), 138.0 (Phquat), 170.7 ppm. HRMS (ESI): calcd.
+
Na]+ 335.02533; found
for C19H24O4 [M + Na]+ 339.15668; found 339.15662.
(Z)-8-[(Tetrahydro-2H-pyran-2-yl)oxy]oct-5-en-3-yn-1-ol (9c): This
compound was prepared similarly to 9b starting from alkenyl
bromide 8b (0.224 g, 0.952 mmol), butynol 5a (78 mg, 1.11 mmol),
diethylamine (0.5 mL, 0.354 g, 4.84 mmol), toluene (1 mL),
Pd(PPh3)2Cl2 (4.2 mg), and CuI (3.2 mg). The residue was purified
by flash chromatography (petroleum ether/EtOAc, 2:1Ǟ1:1) to give
{[(2S,3Z)-4-Bromo-2-methylbut-3-enyl]oxy}(tert-butyl)dimethylsil-
ane (8d): This compound was prepared by a similar method to that
described for 8a, starting from cyclohexene (2.36 mL, 23.3 mmol,
2.4 equiv.) and borane dimethyl sulfide complex (1.06 mL,
11.2 mmol, 1.15 equiv.) in Et2O (7 mL), and bromoalkyne 6d
(2.692, 9.7 mmol, 1 equiv.) in petroleum ether (10 mL). Flash enynol 9c (0.475 g, 79%) as a slightly yellow oil. Rf (petroleum
chromatography (petroleum ether/Et2O, 4:1) gave alkenyl bromide
ether/EtOAc, 1:1): 0.39. 1H NMR (400 MHz, CDCl3): δ = 1.49–
Eur. J. Org. Chem. 2014, 3411–3422
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3417

A. Zhdanko, M. E. Maier
FULL PAPER
1.61 (m, 4 H), 1.66–1.73 (m, 1 H), 1.78–1.86 (m, 1 H), 2.04 (t, J = 71.8, 73.2, 79.6, 91.7, 112.4 (=CH), 127.6 (Ph), 127.7 (Ph), 128.4
6.4 Hz, 2 H), 2.54–2.64 (m, 4 H), 3.46–3.52 (m, 2 H), 3.71–3.88 (m, (Ph), 136.8 (Phquat), 138.0 (=CH), 170.7 ppm.
4 H), 4.61 (dd, J = 3.0, 3.0 Hz, 1 H), 5.52 (br. d, J = 10.9 Hz, 1
(3Z)-9-(Benzyloxy)-8-hydroxy-8-methylnon-3-en-5-ynyl Acetate
H), 5.94 (dt, J = 7.3, 10.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
(9g): Prepared from alkenyl bromide 8a (0.255 g, 1.14 equiv.), alk-
CDCl3): δ = 19.5, 24.0, 25.4, 30.6, 61.2, 62.3, 66.1, 79.1, 91.1, 98.6,
ynol 5e (238 mg, 1.16 mmol), diethylamine (2 mL), Pd(PPh3)2Cl2
110.8 (=CH), 139.4 (=CH) ppm. HRMS (ESI): calcd. for C13H20O3
(8.1 mg), and CuI (4.4 mg). The residue was purified by flash
chromatography (petroleum ether/EtOAc, 4:1Ǟ2:1) to give enynol
[M + Na]+ 247.13047; found 247.13041.
9g (0.289 g, 79 %) as a slightly yellow oil. Rf (petroleum ether/
(3Z,7S)-8-{[tert-butyl(dimethyl)silyl]oxy}-7-methyloct-3-en-5-ynyl
Acetate (9d): This compound was prepared from alkenyl bromide
8a (0.169 g, 0.876 mmol), alkyne 5d (191 mg, 1.1 equiv.), dieth-
ylamine (2 mL), Pd(PPh3)2Cl2 (6.1 mg), and CuI (3.3 mg). The resi-
due was purified by flash chromatography (petroleum ether/EtOAc,
15:1Ǟ10:1) to give enynol 9d (0.215 g, 79%) as a slightly yellow
1
EtOAc, 2:1): 0.38. H NMR (400 MHz, CDCl3): δ = 1.29 (s, 3 H,
CH3), 2.03 (s, 3 H), 2.53–2.63 (m, 5 H), 3.37 (d, J = 9.0 Hz, 1 H),
3.49 (d, J = 9.0 Hz, 1 H), 4.10 (t, J = 6.7 Hz, 2 H), 4.58 (s, 2 H),
5.55 (d, J = 10.6 Hz, 1 H), 5.83 (dt, J = 10.6, 7.3 Hz, 1 H), 7.27–
7.36 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.9, 23.7,
oil. Rf (petroleum ether/EtOAc, 10:1): 0.42. 1H NMR (400 MHz,
CDCl3): δ = 0.05 (s, 6 H, CH3), 0.89 (s, 9 H), 1.18 (d, J = 6.8 Hz,
3 H), 2.04 (s, 3 H), 2.61 (app. q, 2 H), 2.67–2.76 (m, 1 H), 3.47 (dd,
J = 9.4, 7.5 Hz, 1 H), 3.68 (dd, J = 9.4, 5.7 Hz, 1 H), 4.11 (t, J =
6.7 Hz, 2 H), 5.55 (d, J = 10.7 Hz, 1 H), 5.81 (dt, J = 7.2, 10.8 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.3, 17.4, 18.3, 21.0,
25.9, 29.5, 29.9, 63.2, 67.2, 77.5, 97.4, 112.0, 137.1, 171.0 ppm.
29.6, 30.6, 63.1, 71.8, 73.5, 75.9, 79.0, 91.3, 112.0, 127.6, 127.7,
128.4, 137.5, 171.1 ppm.
(5Z,7S)-8-{[tert-Butyl(dimethyl)silyl]oxy}-7-methyloct-5-en-3-yn-1-
ol (9h): Prepared from alkenyl bromide 8d (0.319 g, 1.14 mmol),
alkynol 5a (88 mg, 1.1 equiv.), diethylamine (2 mL), Pd(PPh3)2Cl2
(8.1 mg), and CuI (4.5 mg). The residue was purified by flash
chromatography (petroleum ether/EtOAc, 4:1) to give enynol 9h
(0.276 g, 90%) as a slightly yellow oil. Rf (petroleum ether/EtOAc,
4:1): 0.33. 1H NMR (400 MHz, CDCl3): δ = 0.04 (s, 3 H, CH3),
0.04 (s, 3 H, CH3), 0.88 (s, 9 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.84
(br., 1 H), 2.59 (dt, J = 6.1, 2.0 Hz, 2 H), 2.85–2.96 (m, 1 H), 3.45
(dd, J = 6.6, 9.9 Hz, 1 H), 3.51 (dd, J = 6.1, 9.9 Hz, 1 H), 3.73 (t,
J = 6.4 Hz, 2 H), 5.44 (d, J = 11.4 Hz, 1 H), 5.69 (dd, J = 10.4,
9.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.37, –5.31,
16.5, 18.4, 24.0, 25.9, 37.7, 61.2, 67.3, 79.5, 90.2, 109.1, 146.0 ppm.
(Z)-1-(Benzyloxy)-9-hydroxynon-4-en-6-yn-2-yl Acetate (9e): This
compound was prepared similarly to 9b starting from alkenyl
bromide 8c (0.626 g, 2.0 mmol), butynol (5a; 0.154 g, 2.20 mmol,
1.1 equiv.), benzene (2.4 mL), and diethylamine (1 mL, 0.71 g,
9.67 mmol, 4.8 equiv.). The mixture was stirred to dissolve the
starting materials. After that, Pd(PPh3)2Cl2 (8.4 mg, 0.6 mol-%)
and CuI (6.6 mg, 1.7 mol-%) were added, the reaction flask was
closed, and the nitrogen flow was disconnected. The components
of the catalytic system soon dissolved to give a yellow-green solu-
tion. The reaction mixture was stirred overnight at room tempera-
ture (TLC control: petroleum ether/EtOAc, 2:1; almost complete
conversion was observed already after 2.5 h, when a precipitate was
formed). After that, the precipitate was removed by filtration and
washed with portions of EtOAc, the filtrate was evaporated on a
rotary evaporator, and the residue was purified by flash chromatog-
raphy (petroleum ether/EtOAc, 2:1Ǟ1:1) to give enynol 9e (0.535 g,
89%) as a slightly yellow oil. Rf (petroleum ether/EtOAc, 1:1): 0.41.
1H NMR (400 MHz, CDCl3): δ = 2.06 (s, 1 H, CH3), 2.28 (t, 1 H,
OH), 2.58 (dt, J = 2.0, 6.1 Hz, 2 H, CH2), 2.65 (t, J = 7.3 Hz, 2
H, CH2), 3.53 (d, J = 5.1 Hz, 2 H, CH2), 3.70 (q, J = 6.1 Hz, 2 H,
CH2), 4.52 (d, J = 12.2 Hz, 1 H, CH2), 4.58 (dd, J = 12.2 Hz, 1 H,
CH2), 5.10 (app. quint, 1 H, CH), 5.55 (br. d, J = 10.7 Hz, 1 H,
=CH), 5.81 (dt, J = 7.6, 10.7 Hz, 1 H, =CH), 7.26–7.36 (m, 5 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.2 (CH3), 24.0, 31.5,
61.1, 70.4, 71.9, 73.2, 78.6, 92.0, 112.4 (=CH), 127.6 (Ph), 127.7
(Ph), 128.4 (Ph), 136.7 (=CH), 137.9 (Phquat), 170.8 ppm. HRMS
(ESI): calcd. for C18H22O4 [M + Na]+ 325.14103; found 325.14109.
Acetate 9i: Prepared from alkenyl bromide 8a (14.3 mg, 1.2 equiv.),
alkynol 5f (32.4 mg, 0.0617 mmol), diethylamine (0.5 mL),
Pd(PPh3)2Cl2 (0.5 mg), and CuI (0.3 mg). The residue was purified
by flash chromatography (petroleum ether/EtOAc, 10:1) to give en-
ynol 9i (39.3 mg, 87%) as a slightly yellow oil. Rf (petroleum ether/
EtOAc, 4:1): 0.55. 1H NMR (400 MHz, CDCl3): δ = –0.19 (s, 3 H,
CH3), –0.03 (s, 3 H), 0.78 (s, 9 H), 1.00 (d, J = 7.3 Hz, 3 H), 1.03
(s, 9 H), 1.19 (d, J = 7.1 Hz, 3 H), 2.04 (s, 3 H), 2.14–2.19 (m, 1
H), 2.65 (app. q, 2 H), 2.73–2.83 (m, 1 H), 3.51–4.13 (m, 7 H), 5.62
(d, J = 10.9 Hz, 1 H), 5.82 (dt, J = 10.8, 7.1 Hz, 1 H), 7.37–7.44
(m, 6 H), 7.62–7.66 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = –5.2, –4.7, 10.2, 17.6, 17.8, 19.2, 21.0, 25.7, 26.8, 29.6, 31.3,
34.6, 63.3, 64.3, 73.8, 77.7, 98.0, 112.4, 127.8, 129.9, 133.2, 135.48,
135.53, 137.0, 177.8 ppm.
General Procedure for the Synthesis of Diols 10 from Acetates 9:
Typically, methanol (0.4 mL) and water (1 mL) were added to a
solution of acetate (1 mmol) in THF (2 mL). Solid NaOH or KOH
(1.5–2 equiv.) was then added to this mixture with stirring. The
resulting biphasic mixture was stirred at room temperature. The
reaction was normally finished within 2 h, but it can be left to stir
overnight. When TLC (petroleum ether/EtOAc, 1:1) showed com-
plete conversion, the mixture was diluted with diethyl ether and
water. The organic phase was separated, washed with a small
amount of saturated NaCl solution, and dried with Na2SO4. After
filtration, the solvent was evaporated, and the residue was purified
by chromatography to give the diols as sticky oils in quantitative
yields.
(Z)-1-(Benzyloxy)-9-hydroxy-9-methyldec-4-en-6-yn-2-yl Acetate
(9f): Prepared from alkenyl bromide 8c (0.313 g, 1.0 mmol), 2-
methylpent-4-yn-2-ol 5c (78 mg, 0.79 mmol), diethylamine (0.5 mL,
354 mg, 4.8 mmol), THF (1.3 mL), Pd(PPh3)2Cl2 (4.9 mg), and CuI
(2.7 mg). The residue was purified by flash chromatography (petro-
leum ether/EtOAc, 2:1Ǟ1:1) to give enynol 9f (0.178 g, 68%) as a
slightly yellow oil. Rf (petroleum ether/EtOAc, 2:1): 0.25. 1H NMR
(400 MHz, CDCl3): δ = 1.30 (s, 6 H, CH3), 2.05 (s, 3 H, CH3), 2.12
(br. s, 1 H, OH), 2.50 (d, J = 1.8 Hz, 2 H, CH2), 2.66 (app. t, J =
(Z)-Non-3-en-5-yne-1,9-diol (10a): This diol was prepared from
7.3 Hz, 2 H, CH2), 3.51 (dd, J = 4.8, 10.6 Hz, 1 H, CH2), 3.55 (dd, acetate 9a in quantitative yield as a colourless oil. Rf (EtOAc): 0.32.
J = 5.3, 10.6 Hz, 1 H, CH2), 4.50 (s, J = 12.1 Hz, 1 H, CH2), 4.56 1H NMR (400 MHz, CDCl3): δ = 1.78 (ap. quint., J = 6.5 Hz, 2
(s, J = 12.1 Hz, 1 H, CH2), 5.10 (tt, J = 5.1, 6.3 Hz, 1 H, CH), 5.57 H, 8-H), 2.09 (br. s, 1 H, OH), 2.46 (dt, J = 2.0, 6.9 Hz, 2 H, 7-
(br. d, J = 10.9 Hz, 1 H, =CH), 5.82 (dt, J = 7.6, 10.9 Hz, 1 H,
H), 2.55 (ap. dq, J = 1.2, 6.4 Hz, 2 H, 2-H), 3.68 (t, J = 6.9 Hz, 2
H, 1-H), 3.76 (t, J = 6.1 Hz, 2 H, 9-H), 5.56 (br. d, J = 10.7 Hz, 1
=CH), 7.26–7.36 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.2 (CH3CO), 28.70 (CH3), 28.73 (CH3), 31.7, 35.2, 70.0, 70.5, H, 4-H), 5.85 (dt, J = 7.4, 10.7 Hz, 1 H, 3-H) ppm. 13C NMR
3418
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3411–3422

Spirocyclization of 1,3-Enynediols
(100 MHz, CDCl3): δ = 16.1 (C-7), 31.2, 33.6, 61.6, 61.8, 77.6, 94.2,
112.0, 138.1 ppm.
= –5.2, –4.7, 10.2, 17.5, 17.8, 19.1, 25.7, 26.8, 31.2, 33.7, 34.4, 61.9,
64.2, 74.0, 77.7, 78.4, 97.6, 112.4 (=CH), 127.77 (Ph), 127.80 (Ph),
129.83 (Ph), 129.86 (Ph), 133.06 (Ph), 133.06 (Phquat), 133.22
(Phquat), 135.48 (Ph), 135.52 (Ph), 138.21 (=CH) ppm. HRMS
(ESI): calcd. for C35H54O4Si2 [M + Na]+ 617.34528; found
617.34561.
(Z)-10-(Benzyloxy)dec-6-en-4-yne-1,9-diol (10b): Prepared from
acetate 9b in quantitative yield as a colourless oil. Rf (EtOAc): 0.5.
1H NMR (400 MHz, CDCl3): δ = 1.76 (quint., J = 6.6 Hz, 2 H,
CH2), 2.44 (dt, J = 6.8, 2.0 Hz, 2 H, CH2), 2.50 (t, J = 7.0 Hz, 2
H, CH2), 3.39 (dd, J = 7.3, 9.6 Hz, 1 H, CH2), 3.52 (dd, J = 3.5,
General Procedure for the Synthesis of Diols 10 from Alkoxytetra-
9.6 Hz, 1 H, CH2), 3.73 (t, J = 6.2 Hz, 2 H, CH2), 3.92 (app. dq, hydro-2H-pyrans 9 or tert-Butyldimethylsilyl Ethers 9: Deprotection
1 H, CH), 4.56 (s, 2 H, CH2), 5.55 (br. d, J = 10.7 Hz, 1 H, =CH), of THP acetals or tert-butyldimethylsilyl ethers 9 can be carried
5.90 (dt, J = 7.4, 10.7 Hz, 1 H, =CH), 7.27–7.37 (m, 5 H, Ph) ppm. out in MeOH (0.4–0.5 m) in the presence of a few drops of concd.
HCl (about 2 drops for 3 mL of MeOH) at room temperature in
high yield (ca. 90%). Reactions were monitored by TLC (petroleum
ether/EtOAc, 1:1), and aqueous HCl was used in such amounts
that the reactions were complete within 5–30 min. The HCl was
neutralized by adding Et3N (about 4 drops for 3 mL of MeOH),
and then the mixture was concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/EtOAc, 1:1 to
0:1) to give enynediols 10.
(Z)-9-(Benzyloxy)non-5-en-3-yne-1,8-diol (10e): Prepared from acet-
ate 9e (0.245 g, 0.810 mmol), dissolved in THF (1.5 mL) and
MeOH (0.3 mL). Compound 10e (0.211 g, 99%) was obtained as a
colourless oil. Rf (EtOAc): 0.54. 1H NMR (400 MHz, CDCl3): δ =
2.14 (br. s, 2 H, OH), 2.51 [m (app. t), 2 H, CH2], 2.57 (dt, J = 2.0,
6.1 Hz, 2 H, CH2), 3.39 (dd, J = 7.3, 9.6 Hz, 1 H, CH2), 3.52 (dd,
J = 3.5, 9.6 Hz, 1 H, CH2), 3.70 (q, J = 6.1 Hz, 2 H, CH2), 3.92
(app. dq, 1 H, CH), 4.55 (s, 2 H, CH2), 5.57 (br. d, J = 10.7 Hz, 1
H, =CH), 5.94 (dt, J = 7.6, 10.7 Hz, 1 H, =CH), 7.27–7.37 (m, 5 (Z)-Oct-3-en-5-yne-1,8-diol (10c): Prepared from 9c (0.289 g,
H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.9, 34.0, 61.1,
70.0, 73.4, 73.9, 79.0, 91.7, 111.8 (=CH), 127.7 (Ph), 127.8 (Ph),
128.5 (Ph), 137.9 (Phquat), 138.2 (=CH) ppm. HRMS (ESI): calcd.
for C16H20O3 [M + Na]+ 283.13047; found 283.13034.
1.29 mmol) in MeOH (3 mL), and concd. aqueous HCl (2 drops).
The reaction time was 20 min. The acid was quenched with Et3N
(4 drops). Diol 10c (0.126 g, 71%) was obtained as a colourless oil.
1
Rf (EtOAc): 0.3. H NMR (400 MHz, CDCl3): δ = 1.63 (br., 1 H),
2.19 (t, 1 H), 2.54–2.62 (m, 4 H), 3.70–3.77 (m, 4 H), 5.60 (dtt, J
= 10.7, 2.2, 1.3 Hz, 1 H), 5.92 (dt, J = 10.7, 7.5 Hz, 1 H) ppm.
(Z)-1-(Benzyloxy)-9-methyldec-4-en-6-yne-2,9-diol (10f): Prepared
from acetate 9f in quantitative yield as a colourless oil. H NMR
1
(400 MHz, CDCl3): δ = 1.29 (s, 6 H, CH3), 2.19 (br. s, 2 H, OH), (S,Z)-7-Methyloct-3-en-5-yne-1,8-diol (10d): MeOH (0.5 mL) and
2.50 (s, 2 H, 8-H), 2.51 (t, J = 7.1 Hz, 2 H, 3-H), 3.39 (dd, J = 7.3, concd. aqueous HCl (0.02 mL) were added to a solution of 9d
9.6 Hz, 1 H, 1-H), 3.51 (dd, J = 3.5, 9.6 Hz, 1 H, 1-H), 3.92 (app. (0.2 g, 0.64 mmol) in THF (1 mL). The reaction mixture was stirred
dq, J = 3.5, 7.1 Hz, 1 H, 2-H), 4.55 (s, 2 H, CH2Ph), 5.57 (br. d, J
= 10.9 Hz, 1 H, 5-H), 5.94 (dt, J = 7.6, 10.9 Hz, 1 H, 4-H), 7.26–
7.36 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.7,
34.1, 35.2, 70.0, 70.1, 73.4, 73.9, 79.9, 91.5, 111.8 (=CH), 127.7
(Ph), 127.8 (Ph), 128.4 (Ph), 137.9 (Phquat), 138.1 (=CH) ppm.
HRMS (ESI): calcd. for C18H24O3 [M + Na]+ 311.16178; found
311.16195.
at room temperature for 30 min to achieve complete removal of the
TBS group (TLC petroleum ether/EtOAc, 1:1). Then H2O (0.5 mL)
and NaOH (52 mg) were added to the reaction mixture. The reac-
tion mixture was stirred further at room temperature until the acet-
ate had been completely saponified. The mixture was diluted with
diethyl ether and water. The organic phase was separated, washed
with a small amount of saturated NaCl solution, and dried with
Na2SO4. After filtration, the solvent was evaporated, and the resi-
due was purified by chromatography (petroleum ether/EtOAc,
1:1Ǟ1:2) to give diol 10d (79 mg, 81 %) as a colourless oil. Rf
(EtOAc): 0.44. 1H NMR (400 MHz, CDCl3): δ = 1.19 (d, J =
7.1 Hz, 3 H, 9-H), 1.54 (br. s, 1 H, OH), 2.10 (br. s, 1 H, OH), 2.56
(ddt, J = 1.2, 6.8, 7.3 Hz, 2 H, 2-H), 2.77–2.86 (m, 1 H, 7-H), 3.53
(dd, J = 10.1, 7.2 Hz, 1 H, 8-H), 3.61 (dd, J = 10.1, 5.3 Hz, 1 H,
8-H), 3.73 (t, J = 6.1 Hz, 2 H, 1-H), 5.61 (br. d, J = 10.7 Hz, 1 H, 4-
H), 5.92 (dt, J = 7.4, 10.7 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.9, 30.3, 33.5, 61.8, 67.0, 78.9, 96.4, 112.0,
138.8 ppm.
(Z)-9-(Benzyloxy)-8-methylnon-3-en-5-yne-1,8-diol (10g): Prepared
from acetate 9g (0.270 g, 0.853 mmol) in THF (1.2 mL), MeOH
(0.2 mL), KOH (76 mg, 1.6 equiv.), and H2O (0.8 mL) according to
the general procedure. Compound 10g (0.225 g, 99%) was obtained
as a colourless oil. Rf (petroleum ether/EtOAc, 1:1): 0.27. 1H NMR
(400 MHz, CDCl3): δ = 1.29 (s, 3 H, CH3), 2.53 (app. q, 2 H, CH2),
2.62 (s, 2 H, CH2), 3.38 (d, J = 9.1 Hz, 1 H, CH2), 3.49 (d, J =
9.1 Hz, 1 H, CH2), 3.68 (t, J = 6.3 Hz, 1 H, CH2), 4.58 (s, 2 H,
CH2), 5.57 (br. d, J = 10.6 Hz, 1 H, =CH), 5.89 (dt, J = 7.3,
10.6 Hz, 1 H, =CH), 7.27–7.37 (m, 5 H, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.7, 30.5, 33.6, 61.8, 71.9, 73.4, 76.0, 79.4,
91.0, 112.0 (=CH), 127.6 (Ph), 127.7 (Ph), 128.4 (Ph), 138.0
(Phquat), 138.6 (=CH) ppm. HRMS (ESI): calcd. for C17H22O3 [M
+ Na]+ 297.14612; found 297.14603.
(S,Z)-2-Methyloct-3-en-5-yne-1,8-diol (10h): Prepared from silyl
ether 9h (0.276 g, 1.02 mmol) in MeOH (3 mL), and concd. aque-
ous HCl (2 drops). The acid was quenched with Et3N. Diol 10h
(0.140 g, 91%) was obtained as a colourless oil. Rf (EtOAc): 0.44.
1H NMR (400 MHz, CDCl3): δ = 1.00 (d, J = 6.8 Hz, 3 H), 1.72
(t, 1 H), 2.35 (t, 1 H), 2.59 (t, 2 H), 2.97–3.06 (m, 1 H), 3.41–3.49
(m, 1 H), 3.55–3.61 (m, 1 H), 3.74 (app. q, 2 H), 5.56 (d, J =
10.6 Hz, 1 H), 5.68 (dd, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 16.2, 24.0, 37.7, 61.2, 67.6, 79.2, 91.4, 110.7, 145.3 ppm.
(7S,8S,9R,10R,Z)-10-[(tert-Butyldimethylsilyl)oxy]-11-[(tert-butyl-
diphenylsilyl)oxy]-7,9-dimethylundec-3-en-5-yne-1,8-diol (10i): Pre-
pared from acetate 9i. Compound 10i (32 mg, 90%) was obtained
as a colourless oil. Rf (petroleum ether/EtOAc, 2:1): 0.45. 1H NMR
(400 MHz, CDCl3): δ = –0.20 (s, 3 H, SiCH3), –0.04 (s, 3 H,
SiCH3), 0.79 (s, 9 H), 1.00 (d, J = 7.4 Hz, 3 H, CH3), 1.03 (s, 9 H),
1.18 (d, J = 6.9 Hz, 3 H, CH3), 1.72 (br. s, 2 H, OH), 2.17 (app.
br. q, 1 H, CH), 2.50 (s, 2 H, CH2), 2.58 (q, J = 6.6 Hz, 2 H, CH2),
2.76 (app. quint., 1 H, CH), 3.58 (dd, J = 9.4, 14.2 Hz, 1 H, CH2),
3.71 (t, J = 6.4 Hz, 2 H, CH2), 3.71–3.77 (overlapped m, 2 H, CH),
3.93 (d, J = 1.5, 8.7 Hz, 1 H, CH), 5.65 (br. d, J = 10.7 Hz, 1 H,
4-[2-(2-Hydroxyethyl)phenyl]but-3-yn-1-ol (10j): Prepared from aryl
iodide 8e (0.347 g, 1.4 mmol), alkynol 5a (108 mg, 1.1 equiv.), di-
ethylamine (2 mL), Pd(PPh3)2Cl2 (7.1 mg), and CuI (3.8 mg). The
residue was purified by flash chromatography (EtOAc) to give en-
ynol 10j (0.186 g, 70%) as a slightly yellow oil. Rf (EtOAc): 0.25. 1H
=CH), 5.89 (dt, J = 7.5, 10.7 Hz, 1 H, =CH), 7.35–7.46 (m, 6 H, NMR (400 MHz, CDCl3): δ = 2.42 (br., 1 H), 2.67 (t, J = 5.9 Hz, 2
Ph), 7.64 (app. t, 4 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ
H), 3.04 (t, J = 6.8 Hz, 2 H), 3.07 (br., 1 H), 3.80 (br., 2 H), 3.86
Eur. J. Org. Chem. 2014, 3411–3422
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3419

A. Zhdanko, M. E. Maier
FULL PAPER
(t, J = 6.7 Hz, 2 H), 7.13–7.24 (m, 3 H), 7.38 (d, J = 8.3 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.9, 38.0, 61.1, 63.4, 80.9,
91.1, 123.5, 126.4, 128.1, 129.4, 131.9, 140.7 ppm.
CDCl3): δ = 1.23 (m, 3 H), 1.38 (m, 3 H), 1.80 (m, 1 H), 1.89–1.97
(m, 2 H), 2.02–2.17 (m, 3 H), 3.50 (dd, J = 10.5, 4.5 Hz, 1 H), 3.57
(dd, J = 10.5, 5.6 Hz, 1 H), 4.20–4.26 (m, 1 H), 4.56 (d, J = 12.4 Hz,
1 H), 4.61 (d, J = 12.4 Hz, 1 H), 5.60 (d, J = 9.9 Hz, 1 H), 5.95
(ddd, J = 9.9, 5.6, 2.0 Hz, 1 H), 7.23–7.33 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 26.9, 29.1, 30.3, 37.3, 38.1, 66.9, 72.7, 73.1,
82.3, 103.7, 127.4, 127.5, 128.2, 129.0, 138.5 ppm.
General Procedure. [5,6]-Spiroacetals 3 from Enynediols 10: Enyne-
diol 10 was dissolved in CH2Cl2 or another solvent, and the catalyst
was added, either as a solid or in solution (in CH2Cl2 or MeCN
or a mixture of these two solvents). The progress of reaction was
monitored by TLC, and when the conversion was complete, the
reaction was quenched by the addition of Et3N (about 1 drop per
0.1 mmol of substrate). The mixture was directly loaded onto a
small silica column and further eluted with petroleum ether/EtOAc,
4:1 (or pentane/Et2O, 4:1 for volatile compounds) to give spiro-
acetal 3.
2-[(Benzyloxy)methyl]-2-methyl-1,6-dioxaspiro[4.5]dec-9-ene (3g): A
solution of 10g (32.5 mg, 0.118 mmol) in a mixture of CH2Cl2
(1.2 mL) and acetonitrile (0.024 mL) containing mercury(II) tri-
fluoromethanesulfonate [Hg(OTf)2] (0.29 mg, 0.59 μmol, 0.5 mol-
%) was stirred for 5 min at room temperature. Et3N was added, the
mixture was concentrated in vacuo, and the residue was purified
by flash chromatography to give spiroacetal 3g (27.0 mg, 83%) as
a mixture of epimers (1:1.1 mol ratio). Rf (petroleum ether/EtOAc,
4:1): 0.5. 1H NMR (400 MHz, CDCl3): δ = 1.29 (s, minor, 3 H),
1.35 (s, major, 3 H), 1.72–2.03 (m, 4 H), 2.06–2.18 (m, 1 H), 2.19–
2.31 (m, 1 H), 3.29 (d, J = 9.5 Hz, major, 1 H), 3.34 (d, J = 9.5 Hz,
major, 1 H), 3.43 (d, J = 9.1 Hz, minor, 1 H), 3.48 (d, J = 9.1 Hz,
minor, 1 H), 3.69 (dd, J = 11.2, 6.1 Hz, minor, 1 H), 3.75 (dd, J =
11.2, 6.1 Hz, major, 1 H), 3.93 (ddd, J = 11.6, 11.6, 3.8 Hz, minor,
1 H), 4.01 (ddd, J = 11.6, 11.6, 3.7 Hz, major, 1 H), 4.53 (d, J =
12.1 Hz, major, 1 H), 4.57 (d, J = 12.1 Hz, major, 1 H), 4.57 (d, J
= 12.1 Hz, minor, 1 H), 4.61 (d, J = 12.1 Hz, minor, 1 H), 5.60 (d,
major, minor, 1 H), 5.96–6.00 (m, major, minor, 1 H), 7.24–7.36
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.5, 26.1, 33.6,
33.9, 37.3, 38.4, 58.46, 57.51, 73.41, 76.8, 78.2, 83.8, 83.9, 103.0,
103.2, 127.4, 128.3, 128.5, 128.2, 128.3, 128.78, 128.83, 128.87,
129.03, 138.7, 138.7 ppm.
7-[(Benzyloxy)methyl]-1,6-dioxaspiro[4.5]dec-9-ene (3e)
Method A: A solution of 10e (26.5 mg, 0.102 mmol) in CH2Cl2
(1 mL) containing Hg(O2CCF3)2 (0.47 mg, 1 mol-%) was stirred for
24 h at room temperature. Et3N was added, the mixture was con-
centrated in vacuo, and the residue was purified by flash
chromatography to give spiroacetal 3e (24.4 mg, 92%) as a colour-
less oil.
Method B: A solution of 10e (50.7 mg, 0.195 mmol) in CH2Cl2
–
(1.3 mL) containing L2AuNCMe+ SbF6 (0.75 mg, 0.975 μmol,
0.5 mol-%) was stirred for 10–15 min at room temperature. Et3N
was added, the mixture was concentrated in vacuo, and the residue
was purified by flash chromatography to give spiroacetal 3e
(47.2 mg, 93%).
Method C: A solution of 10e (43.0 mg, 0.165 mmol) in CH2Cl2
–
(1.4 mL) containing [PdPCP-ac]+ SbF6 (1.16 mg, 0.132 μmol,
(8S)-8-Methyl-1,6-dioxaspiro[4.5]dec-9-ene (3h): A solution of 10h
(32.7 mg, 0.212 mmol) in CH2 Cl2 (0.8 mL) containing
L2AuNCMe+ SbF6– (0.655 mg, 0.848 μmol, 0.4 mol-%) was stirred
for 4 min at room temperature. Et3N was added, the mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography to give spiroacetal 3h (27.1 mg, 83%) as a mixture
of epimers (2:1 mol ratio). Rf (petroleum ether/EtOAc, 4:1): 0.5. 1H
NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 7.1 Hz, major, 3 H),
1.05 (d, J = 7.1 Hz, minor, 3 H), 1.76–1.84 (m, major, minor, 1 H),
1.88–2.18 (m, major, minor, 3.3 H), 2.33–2.43 (m, major, 1 H),
3.43–3.51 (m, major, minor, 1 H), 3.67 (ddd, J = 11.1, 5.7, 1.4 Hz,
major, 1 H), 3.87–4.00 (m, major, minor, 2 H), 4.04 (dd, J = 11.4,
3.8 Hz, minor, 1 H), 5.53–5.59 (m, major, minor, 1 H), 5.82 (ddd,
J = 10.0, 1.6, 1.5 Hz, major, 1 H), 5.95 (ddd, J = 10.0, 5.2, 1.3 Hz,
major, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.8 (major),
17.7 (minor), 24.5 (minor), 24.6 (major), 28.8 (minor), 29.0 (major),
37.4 (major, minor), 65.2 (minor), 65.8 (major), 67.4 (major), 67.5
(minor), 102.5 (major), 102.6 (minor), 127.2 (minor), 127.4 (major),
134.5 (minor), 135.5 (major) ppm.
0.8 mol-%) was stirred for 10–15 min at room temperature. Et3N
was added, the mixture was concentrated in vacuo, and the residue
was purified by flash chromatography to give spiroacetal 3e
(38.7 mg, 90%).
Method D: A solution of 10e (32.1 mg, 0.123 mmol) in THF
(1.1 mL) and acetonitrile (0.074 mL) containing Hg(O2CCF3)2
(0.85 mg, 1.5 mol-%) was stirred for 10–15 min at room tempera-
ture. Et3N was added, the mixture was concentrated in vacuo, and
the residue was purified by flash chromatography to give
spiroacetal 3e (38.7 mg, 90%). Rf (petroleum ether/EtOAc, 4:1):
0.5. 1H NMR (400 MHz, CDCl3): δ = 1.82 (ddd, J = 12.1, 9.3,
8.3 Hz, 1 H), 1.89–1.98 (m, 2 H), 2.01–2.19 (m, 3 H), 3.51 (dd, J
= 10.4, 4.6 Hz, 1 H), 3.51 (dd, J = 10.4, 5.6 Hz, 1 H), 3.89–3.99
(m, 2 H), 4.14–4.20 (m, 1 H), 4.58 (d, J = 12.1 Hz, 1 H), 4.60 (d,
J = 12.1 Hz, 1 H), 5.63 (ddd, J = 9.9, 2.7, 1.5 Hz, 1 H), 5.99 (ddd,
J = 9.9, 5.6, 2.2 Hz, 1 H), 7.26–7.34 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.6, 26.9, 37.4, 67.3, 67.7, 72.6, 73.1,
103.5, 127.5, 127.6, 128.3, 128.5, 138.5 ppm.
7-[(Benzyloxy)methyl]-2,2-dimethyl-1,6-dioxaspiro[4.5]dec-9-ene (3f)
4,5-Dihydro-3H-spiro[furan-2,1Ј-isochroman] (3j): A solution of 10j
(20.1 mg, 0.212 mmol) in CH2 Cl2 (0.8 mL) containing
Method A: A solution of 10f (28.8 mg, 0.100 mmol) in a mixture of
CH2Cl2 (1.0 mL) and acetonitrile (0.02 mL) containing mercury(II)
trifluoromethanesulfonate [Hg(OTf)2] (0.25 mg, 0.5 μmol, 0.5 mol-
%) was stirred for 10–15 min at room temperature. Et3N was
added, the mixture was concentrated in vacuo, and the residue was
purified by flash chromatography to give spiroacetal 3f (25.9 mg,
90%).
–
L2AuNCMe+ SbF6 (0.4 mol-%) was stirred for 10 min at room
temperature. Et3N was added, the mixture was concentrated in
vacuo, and the residue was purified by flash chromatography to
give spiroacetal 3j (19.1 mg, 95%) as a colourless oil. Rf (petroleum
ether/EtOAc, 4:1): 0.56. 1H NMR (400 MHz, CDCl3): δ = 2.04–
2.17 (m, 1 H), 2.18–2.34 (m, 3 H), 2.60 (ddd, J = 16.0, 2.5, 2.4 Hz,
1 H), 3.03 (ddd, J = 16.0, 12.1, 5.8 Hz, 1 H), 3.90 (ddd, J = 11.1,
5.8, 1.8 Hz, 1 H), 4.01–4.13 (m, 3 H), 7.07–7.11 (m, 1 H), 7.18–
7.29 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.1, 28.8,
39.5, 59.5, 68.0, 105.6, 126.4, 127.7, 128.4, 135.2, 136.3 ppm.
Method B: A solution of 10f (23.7 mg, 0.082 mmol) in CH2Cl2
–
(1.0 mL) containing L2AuNCMe+ SbF6 (0.51 mg, 0.656 μmol,
0.8 mol-%) was stirred for 10 min at room temperature. Et3N was
added, the mixture was concentrated in vacuo, and the residue was
purified by flash chromatography to give spiroacetal 3f (21.8 mg,
(5R)-2,2,3,3,9,9-Hexamethyl-5-{(1R)-1-[(2S,3S)-3-methyl-1,6-di-
oxaspiro[4.5]dec-9-en-2-yl]ethyl}-8,8-diphenyl-4,7-dioxa-3,8-disila-
1
92%). Rf (petroleum ether/EtOAc, 4:1): 0.5. H NMR (400 MHz,
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Spirocyclization of 1,3-Enynediols
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decane (3i): A solution of 10i (13.6 mg, 0.0313 mmol) in CH2Cl2
(0.3 mL) containing L2AuNCMe+ SbF6 (0.242 mg, 0.313 μmol,
–
1.0 mol-%) was stirred for 10 min at room temperature. Et3N was
added, the mixture was concentrated in vacuo, and the residue was
purified by flash chromatography to give spiroacetal 3i (12.8 mg,
94%) as a mixture of epimers (0.56:0.44 mol ratio). Rf (petroleum
[10]
1
ether/Et2O, 10:1): 0.41 and 0.49. H NMR (400 MHz, CDCl3): δ =
–0.04 (s, minor, 3 H), –0.03 (s, major, 3 H), 0.04 (s, major, 3 H),
0.08 (s, minor, 3 H), 0.80 (d, minor, 3 H), 0.84 (d, major, 3 H), 0.88
(s, major, 9 H), 0.89 (s, minor, 9 H), 0.98 (d, major, 3 H), 1.04 (d,
minor, 3 H), 1.04 (s, major, minor, 9 H), 1.47 (dd, J = 12.1, 11.9 Hz,
major, 1 H), 1.63 (dd, J = 12.9, 6.8 Hz, minor, 1 H), 1.73–1.89 (m,
2 H), 1.95–2.13 (m), 2.16–2.26 (m, major, minor, 1 H), 2.30–2.40
(m, major, H), 3.61–3.87 (m, 6 H), 5.53 (d, 1 H), 5.86–5.93 (m, 1
H), 7.33–7.41 (m, 6 H), 7.66–7.70 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = –5.1, –5.0, –4.1, –4.0, 8.5, 9.4, 16.7, 17.7,
18.10, 18.13, 19.25, 24.4, 24.5, 25.9, 26.0, 26.89, 26.92, 34.8, 36.1,
38.8, 39.3, 46.4, 47.0, 58.4, 59.5, 66.5, 66.6, 75.5, 75.7, 84.0, 86.3,
101.4, 102.4, 127.2, 127.5, 128.1, 129.4, 129.5, 129.6, 133.7, 133.8,
133.84, 133.9, 135.70, 135.73, 135.77, 135.79 ppm.
[11]
[12]
[13]
[14]
[15]
[16]
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of some starting materials, synthesis of pincer com-
plex 11, description of unselective cyclization reactions with enyne-
diol 10b, description of in situ NMR experiments, copies of 1H and
13C NMR spectra of key intermediates and final products.
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[17]
[18]
Acknowledgments
Financial support by the German Federate State of Baden-
Württemberg is greatly acknowledged. The authors thank Dr. D.
Wistuba (Univ. Tübingen) for HRMS analysis.
[19]
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Decomposition was evident from the 1H NMR spectrum: an
increase was seen in the multiplets in the regions 3–4.5 and 1–
2 ppm, while the unsaturated region 5–6 ppm was left clear.
It was claimed that the mercury-catalysed cyclization of non-
3-yne-1,9-diol gave the corresponding saturated [6,6]-spi-
roacetal as a single product.[8] However, in our hands, treat-
ment of this substrate with Hg(OTf)2 in either CDCl3 or
MeCN (under identical conditions) gave a mixture of regioiso-
mers. Secondly, in relation to the same ref.[8] we would like to
comment that Hg(OTf)2 is so active that there is no need to
use 10 mol-% catalyst loading, as was done in that work. An
amount of 1 mol-% or less is enough. It appears that this toxic
but cheap compound is also a useful catalyst for the activation
of C–C triple bonds and, as it may be used in very small
amounts, it may indeed find practical applications in Synthesis
despite its toxicity.
[26]
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Eur. J. Org. Chem. 2014, 3411–3422
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3421

A. Zhdanko, M. E. Maier
FULL PAPER
2048–2076; c) R. Chinchilla, C. Nájera, Chem. Rev. 2014, DOI:
10.1021/cr400133p.
of the dienol ether into the final spiroacetal. When a transition
metal catalyst is used alone, the necessary Brønsted acid arises
naturally in the catalytic cycle. It is clear that lowering the cata-
lyst loading can be compensated by the addition of external
Brønsted acid to speed up the overall process.
[30] The catalysis by PdPCP+ is slow in methanol because the li-
gand-exchange equilibrium PdPCP-MeOH+
+ alkyne h
PdPCP-alkyne+ + MeOH is strongly on the left, so alkyne co-
ordination is suppressed. More mechanistic details will be pub-
lished separately.
[35] A. Zhdanko, M. E. Maier, unpublished results. We note here
that 6-exo-17c is not a product of the direct and selective 6-
exo-cyclization, but the product of rearrangement of a vinyl
mercury intermediate with subsequent transformations.
[36] The difference in reactivity of both 5-endo-16c and 6-exo-17c
compared with 5-exo-13a and 6-endo-14a is very pronounced.
Thus, a mixture 5-exo-13a and 6-endo-14a is reliably obtained
even under unbuffered catalytic conditions (simple use of active
Pd, Au, or Pt catalysts, as mentioned). The generation of 5-
endo-16c or 6-exo-17c, on the other hand, is very challenging,
and requires buffered conditions (use of a weak base like
tBu2Py), otherwise they are all transformed into the final spi-
roacetals within minutes.
[31] E. N. Lawson, W. Kitching, C. H. L. Kennard, K. A. Byriel, J.
Org. Chem. 1993, 58, 2501–2508.
[32] P. Kocienski, S. Wadman, K. Cooper, J. Am. Chem. Soc. 1989,
111, 2363–2365.
[33] For a review of such spiroacetals, generated by intramolecular
hydrogen abstraction, see: J. Sperry, Y.-C. W. Liu, M. A. Brim-
ble, Org. Biomol. Chem. 2010, 8, 29–38.
[34] A control experiment with 10e (0.1 m in CH2Cl2) indicated that
cyclization of enynediols is not catalysed by Brønsted acid
alone (3% TfOH, room temp., 1 d gave 0% conversion). How-
ever, a Brønsted acid (H+) is required for a) the turnover of a
transition metal catalyst, because it is necessary for protodeme-
talation of organometallic intermediates; b) the transformation
Received: February 7, 2014
Published Online: April 17, 2014
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Eur. J. Org. Chem. 2014, 3411–3422