AuCl3-catalyzed hydroalkoxylatlon of conjugated alkynoates: Synthesis of five- and six-membered cyclic acetals

Article abstract of DOI:10.1002/ejoc.200801221

ing acetals can be obtained by simply choosing the appropriate reaction solvent. NMR spectroscopic studies were carried out to determine the kinetics and pathway of the latter domino 5-exo cyclization-hydroalkoxylation reaction. Wiley-VCH Verlag GmbH & Co

Full text of DOI:10.1002/ejoc.200801221

FULL PAPER
DOI: 10.1002/ejoc.200801221
AuCl3-Catalyzed Hydroalkoxylation of Conjugated Alkynoates: Synthesis of
Five- and Six-Membered Cyclic Acetals
Alejandro Diéguez-Vázquez,*[a] C. Christoph Tzschucke,[a] José Crecente-Campo,[a]
Sally McGrath,[a] and Steven V. Ley[a]
Dedicated to Professor Alain Krief
Keywords: Cyclization / Gold / Homogenous catalysis / Hydroalkoxylation / Oxygen heterocycles
The AuCl3-catalyzed double hydroalkoxylation of conju-
gated 7-hydroxyheptynoates offers a convenient route for the
synthesis of six-membered cyclic acetals, which are common
substructures of polyketide natural products. When conju-
gated 6-hydroxyhexynoates are used as starting materials,
ing acetals can be obtained by simply choosing the appropri-
ate reaction solvent. NMR spectroscopic studies were carried
out to determine the kinetics and pathway of the latter
domino 5-exo cyclization–hydroalkoxylation reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
either five-membered cyclic E-enol ethers or the correspond- Germany, 2009)
Introduction
Pyran rings are substructures contained in numerous
polyketide natural products, some of which display useful
biological activities, such as (+)-acutiphycin or the callipel-
toside family (Figure 1).[1] The embedded β-pyranoacetal
ester unit 2 (Scheme 1) in these compounds has been syn-
thesized by a variety of methods including acid-catalyzed
cyclization of δ-hydroxyketones,[1] addition of acetic ester
enolates to δ-lactones,[2] or more recently, Pd-catalyzed alk-
oxycarbonylation of δ-alkynols.[3]
Scheme 1. Synthetic plan.
The conjugate addition of oxygen nucleophiles to α,β-
unsaturated ketones and esters has generally suffered from
reversibility and low reactivity, especially in the second step
of the hydroalkoxylation process. Only recently has an in-
creasing number of catalytic systems for oxy-Michael reac-
tions emerged.[4] Nevertheless, examples of additions to tri-
ple bonds remain sparse and are largely limited to ynones[5]
or dimethyl acetylene dicarboxylate (DMAD).[6] In con-
trast, the thiol double conjugate addition to a wide variety
of propargylic carbonyl-containing compounds has been
exploited more extensively.[7]
Although transition-metal-catalyzed activation of ter-
minal alkynes towards hydroalkoxylation is well pre-
cedented,[8] the use of alkynoates in these reactions has only
been described in a few isolated examples.[9] This might be
due to the fact that electron-deficient alkynes are less prone
to coordinate to electrophilic transition metals and, thus,
are less readily activated towards nucleophilic attack.
Recently, we reported the PtCl4-catalyzed formation of
fused bicyclic acetals from enantiopure 1,2-heptynediols or
directly from the corresponding butane-2,3-diacetal (BDA)
derivatives.[10] Whereas electron-rich aryl-substituted triple
bonds led to 7-endo cyclization, substitution with electron-
poor aromatic rings decreased the reactivity and favored
Figure 1. Pyran-containing polyketide natural products.
As an alternative disconnection, we investigated a double
hydroalkoxylation reaction of 7-hydroxy-2-alkynoate deriv-
atives 1 as a new method for the preparation of β-pyrano-
acetal esters 2 by a metal-mediated process (Scheme 1).
[a] Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44-122-333-6442
E-mail: ad431@cam.ac.uk
1698
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AuCl3-Catalyzed Hydroalkoxylation of Conjugated Alkynoates
initial 6-exo cyclization (conjugate addition relating to the
On the basis of these results, AuCl3 (2 mol-%) was se-
aromatic ring). Following a similar concept, we reasoned lected as the best catalyst to explore the scope of the double
that transition-metal-catalyzed hydroalkoxylation of elec- hydroalkoxylation reaction of 7-hydroxyhept-2-ynoate de-
tron-deficient alkynes, particularly 7-hydroxyheptynoate de- rivatives 1 (Table 2). In general, good to excellent isolated
rivatives 2, would allow rapid access to desired cyclic acetals
1.
Table 2. Double oxy-Michael addition to 7-hydroxyalkynoates 1.
Results and Discussion
Initially, we investigated the cyclization of ethyl 7-hy-
droxyhept-2-ynoate (1a; R1, R2 = H, R3 = Et) with different
catalytic systems in methanol/THF (1:1) at room tempera-
ture (Table 1). A catalyst screen revealed that AuCl3 or
[AuCl(PPh3)] combined with AgSbF6 led to complete con-
version to desired six-membered cyclic acetal 2a within less
than 4 h at room temperature (Table 1, Entries 16 and 10).
In the absence of the AgI salt, [AuCl(PPh3)] showed no ac-
tivity (Table 1, Entry 9). Although PtII-, PtIV-, and PdII-
based catalysts also gave quantitative conversion, signifi-
cantly longer reaction times were required (Table 1, En-
tries 12, 14, and 15). In contrast, DABCO[5c] or TBAF did
not effect any conversion to the desired product (Table 1,
Entries 1 and 2). Brønsted or Lewis acids such as TfOH,
[11]
HCl, TFA, CSA, and FeCl3 were likewise ineffective un-
der these reaction conditions (Table 1, Entries 3–7). Re-
ported conditions for the IrIV-catalyzed hydroalkoxylation
of methyl 2-butynoate[9e] led to the formation of desired
product 2a but in only 20% after 5 days (!) (Table 1, En-
try 8).
Table 1. Optimization of the double hydroalkoxylation of ethyl 7-
hydroxyhept-2-ynoate (1a).
Entry Catalyst
Time Yield[a]
[h]
[%]
1
2
3
4
5
6
7
8
10 mol-% DABCO
120
120
120
120
120
120
120
144
25
0
0
0
0
0
100 mol-% TBAF
10 mol-% TMSOTf[b]
10 mol-% TMSCl[c]
10 mol-% TFA
10 mol-% CSA
5 mol-% FeCl3
5 mol-% [Na(18-C6)]2[IrCl6]
2 mol-% [AuCl(PPh3)]
2 mol-% [AuCl(PPh3)], 2 mol-% AgSbF6
2 mol-% [PdCl2(CH3CN)2]
2 mol-% [PdCl2(CH3CN)2], 2 mol-% AgSbF6 26
2 mol-% AgSbF6
2 mol-% PtCl4
0
0
20
0
98
60
98
3
99
99
96
9
10
11
12
13
14
15
16
4
26
26
26
4
1 mol-% [PtCl2(CH2CH2)]2
2 mol-% AuCl3
1
[a] Yield determined by GC–MS vs. nC14H30. [b] Formation of
TfOH is assumed under the reaction conditions. [c] Formation of
HCl is assumed under the reaction conditions. Tf = trifluoro-
methanesulfonyl.
[a] Yield of isolated product based on ω-hydroxyalkynoate 1.
[b] THF instead of MeOH was used as solvent. [c] 2.5 equiv. of
AllylOH was used. [d] 5 equiv. of AcOH was used. Bn = benzyl;
PMB = p-methoxybenzyl.
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A. Diéguez-Vázquez et al.
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yields of products were obtained as single diastereoiso-
Remarkably, the secondary silyl ether was not cleaved
mers.[12] Notably, alkynoates 1 bearing substituents R1 such during the hydroalkoxylation reaction, which further illus-
as vinyl, phenyl, or benzyl gave excellent conversion to the trates the mild conditions of this method. The structure of
desired product (Table 2, Entries 6–8).[13] It is also note- 5 was unambiguously established by X-ray crystallography
worthy that transesterification was not observed and PMB (Figure 2).[16]
ether cleavage did not occur under the reaction conditions
(Table 2, Entry 11).
We then investigated reducing the amount of R4OH in
order to vary the acetal formed and make the process more
economic. Accordingly, hydroalkoxylation of 1b in THF as
solvent by using allyl alcohol (2.5 equiv.) was studied
(Table 2, Entry 9). The corresponding 2-allyloxytetra-
hydropyran 2i was obtained in good yield; however, further
reduction of the amount of alcohol in these reactions led
to mixtures of cyclic acetal 2i and hemiacetal 2j. The latter
could be isolated as the exclusive product in the presence
of AcOH (5 equiv.) in THF as solvent (Table 2, Entry 10).
The formation of the hemiacetal in this example probably
occurred during the aqueous workup.
Taking into account the above results, we anticipated
that the use of enantiopure 1,3-diols as starting materials
should afford natural-product-like compounds (Scheme 2).
Pleasingly, the corresponding cyclic acetals 2l and 2m were
obtained in high yield and as single diastereoisomers under
the reaction conditions described previously. As before, the
vinyl group did not participate in any side reactions and
the PMB protecting group was stable under the reaction
conditions.
Figure 2. X-ray structure of BDA-derivative 5.
Although the hydroalkoxylation of 3 did not give the cor-
responding acetal, this result suggests the intermediacy of
cyclic (Z)-β-alkoxyenoates in the formation of alkoxytetra-
hydropyrans 2. Moreover, this observation is in agreement
with the commonly accepted mechanism for the Au-cata-
lyzed hydroalkoxylation of triple bonds.[8p,10a]
We briefly investigated the formation of seven-membered
cyclic acetals. From the reaction of benzyl 8-hydroxy-2-oc-
tynoate (6) in methanol, cyclic acetal 7 was isolated in 18%
yield along with 15% of acyclic enol ether 8, 35% of di-
methylacetal 9, and
a small amount of ketone 10
(Scheme 4). This result clearly illustrates the thermo-
dynamic instability of 7 in comparison to that of the acyclic
products. The yield of cyclic acetal 7 could be improved to
34% when the reaction was performed in THF in the pres-
ence of MeOH (1.1 equiv.). When the reaction was carried
out in pure THF as the solvent, exocyclic enol ether 11 was
isolated as a 1.6:1 mixture of isomers in 60% yield
(Scheme 4).
Scheme 2. Reagents and conditions: (a) AuCl3 (2 mol-%), MeOH,
r.t., 3 h, then sat. NaHCO3, 2l, 88%; 2m, 82%.
By applying the same protocol, BDA-protected ethyl 7-
hydroxyheptynoate 3[14] gave exclusively Z-exocyclic enol
ether 4, which could be stereoselectively hydrogenated to
pyran derivative 5 (Scheme 3).[15]
Scheme 4. Reagents and conditions: (a) AuCl3 (2 mol-%), MeOH,
r.t., 2.5 h, then sat. NaHCO3, 7, 18%; 8, 15%; 9, 35%, 10, 5%; or
(a) AuCl3 (2 mol-%), MeOH (1.1 equiv.), r.t., 2.5 h, then sat.
NaHCO3, 11, 34%; (b) AuCl3 (2 mol-%), THF, r.t., 2.5 h, then sat.
NaHCO3, 60% (1:1.6).
We next turned our attention to the synthesis of the five-
membered cyclic acetals. When we applied the previously
optimized reaction conditions, AuCl3 (2 mol-%) in MeOH,
to benzyl 6-hydroxy-2-hexynoate (12a), cyclic acetal 13a
Scheme 3. Reagents and conditions: (a) AuCl3 (2 mol-%), MeOH,
r.t., 4 h, then sat. NaHCO3, 88%; (b) H2, Pd/C, EtOAc, r.t., 12 h,
99%.
1700
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AuCl3-Catalyzed Hydroalkoxylation of Conjugated Alkynoates
Table 3. Hydroalkoxylation of 6-hydroxy-2-hexynoate derivatives 12.
Entry
12
R1
R2
R3
R4
Solvent
Time [min] Product
Yield[a] [%]
1
2
3
4
5
6
7
8
9
12a
12b
12c
12d
12d
12a
12b
12c
12d
H
Tol
H
H
H
H
H
Bn
Et
Et
Bn
Bn
Bn
Et
MeOH
MeOH
MeOH
MeOH
MeOH
THF
THF
THF
THF
150
150
150
120
20
150
150
150
15
13a + 14a
13b[b]
80 + 7
92
86
–(CH2)4–
13c
–(CH2)4–[c]
–(CH2)4–[c]
H
H
H
H
H
13d[d]
82
15d[e] + 13d 47 + 30[d]
H
H
14a
80
82
93
91
Tol
14b
H
–(CH2)4–
Et
Bn
14c
–(CH2)4–[d]
H
14d[e]
[a] Yield of isolated product based on alkynoate 12. [b] 1:1.75 mixture of epimers. [c] (R*,S*) isomer. [d] 1:1.6 mixture of epimers. [e] Struc-
ture unambiguously established by X-ray crystallography. Tol = p-MeC6H4.
was isolated in good yield together with a small amount of tration of 15a reached a maximum approximately 5 min af-
E-enol ether 14a (Table 3, Entry 1). Noteworthy, the E- ter the beginning of the reaction. At this time, only a small
double bond geometry of 14a is unexpected in view of the amount of cyclic acetal 13a and E-enol ether 14a had been
commonly accepted mechanism for the Au-catalyzed hy- formed. Intermediate Z-enol ether 15a evolved slowly, fol-
droalkoxylation of triple bonds.[8p,10a] Similarly, other 6-hy- lowing first-order kinetics, to an 8:1 equilibrium mixture of
droxy-2-hexynoate derivatives 12 gave the corresponding 13a and 14a. Analysis of the NMR spectroscopic data
cyclic acetals 13 in good isolated yields as mixtures of epi- showed that the first step of the reaction (formation of 15a)
mers at the acetal carbon atom (Table 3, Entries 2–4). is approximately 10 times faster than the second step (for-
Moreover, when we conducted the reaction in THF, corre- mation of 13a and 14a).
sponding E-enol ether 14 was obtained as the major prod-
uct and as single isomer in good yield (Table 3, Entries 6–
9). Interestingly, when we treated 12d with AuCl3 (2 mol-%)
in MeOH for 20 min, Z-enol ether 15d was isolated as the
major product along with an epimeric mixture of the corre-
sponding cyclic acetal 13d (Table 3, Entry 5). This result in-
dicates that expected Z-enol ether 15d is initially formed
as the kinetic product, which, depending on the reaction
conditions, evolves into thermodynamically more-stable E-
enol ether 14d and/or cyclic acetal 13d. The structures of
both enol ethers 14d and 15d were confirmed by single-
crystal X-ray diffraction analysis (Figure 3).[16]
Figure 4. Hydroalkoxylation of 12a in CD3OD. Concentration ver-
sus reaction time.
In [D8]THF the reaction displayed different kinetic be-
havior. After an induction period, exclusive formation of E-
Figure 3. X-ray structure of E- and Z-enol ethers 14d and 15d.
enol ether 14a was detected. In comparison to the reaction
In order to clarify the mechanism of these transforma- in CD3OD the rate of reaction is smaller and does not fol-
tions, we monitored the AuIII-catalyzed hydroalkoxylation low first-order kinetics.
of 12a by 1H NMR spectroscopy by using CD3OD and
These results are in agreement with the following mech-
[D8]THF as solvents. In CD3OD we observed rapid con- anistic proposal (Scheme 5).[17] Coordination of the AuIII
sumption of the starting material, by a first-order decay, species to the triple bond (A) promotes the intramolecular
and formation of Z-enol ether 15a (Figure 4). The concen- trans addition of the hydroxy group and leads to Z-enol
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A. Diéguez-Vázquez et al.
FULL PAPER
pad of silica gel (previously deactivated with PE 30–40/Et2O/Et3N,
7.5:1.5:1) by using a mixture of PE 30–40/Et2O (8:2) as eluent.
Concentration in vacuo afforded the desired cyclic acetal.
ether 15 after protodemetalation of B. Subsequent forma-
tion of acetal 13 and equilibration with enol ethers 14 and
15 might be AuIII- or proton-catalyzed (via C).[18]
Ethyl (2-Methoxytetrahydro-2H-pyran-2-yl)acetate (2a): Colorless
oil. R = 0.52 (PE 40–60/EtOAc, 2:1). IR (neat): ν = 1031, 1200,
˜
f
1734 (C=O), 2943 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.18–
4.10 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.64–3.59 (m, 2 H, 6Ј-H),
3.28 (s, 3 H, OCH3), 2.70 (d, J = 13.5 Hz, 1 H, 2-Hb), 2.52 (d, J
= 13.5 Hz, 1 H, 2-Ha), 1.92–1.47 (m, 6 H, 3Ј,4Ј,5Ј-H), 1.25 (t, J =
7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.5, 97.4, 61.6, 60.5, 47.9, 42.4, 33.5, 24.8, 18.5, 14.2 ppm.
HRMS (ESI): calcd. for C10H18O4Na [M + Na]+ 225.1103; found
225.1098.
Benzyl (2-Methoxytetrahydro-2H-pyran-2-yl)acetate (2b): Colorless
oil. R = 0.66 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 697, 737, 1031,
˜
f
1090, 1198, 1735 (C=O), 2943 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.37–7.32 (m, 5 H, Ar-H), 5.16 (d, J = 12.4 Hz, 1 H, CHHPh),
5.12 (d, J = 12.4 Hz, 1 H, CHHPh), 3.64–3.61 (m, 2 H, 6Ј-H), 3.28
(s, 3 H, OCH3), 2.76 (d, J = 13.5 Hz, 1 H, 2-Hb), 2.61 (d, J =
13.5 Hz, 1 H, 2-Ha), 1.92–1.47 (m, 6 H, 3Ј,4Ј,5Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.3, 135.9, 128.5, 128.2, 97.5, 66.4, 61.6,
48.0, 42.4, 33.5, 24.8, 18.5 ppm. HRMS (ESI): calcd. for
C15H20O4Na [M + Na]+ 287.1262; found 287.1259.
Scheme 5. Proposed mechanism for the hydroalkoxylation of 12a
in MeOH.
In THF, the situation is less clear as there are at least
three mechanistic scenarios that can account for the experi-
mental observation: (a) The initial cyclization occurs with
Ethyl
[(2S*,6S*)-2-Methoxy-6-methyltetrahydro-2H-pyran-2-yl]-
acetate (2c): Colorless oil. Rf = 0.29 (PE 40–60/EtOAc, 10:1). IR
(neat): ν = 1003, 1032, 1082, 1735 (C=O), 2937 cm–1. 1H NMR
˜
trans addition but more slowly and becomes the rate-de- (400 MHz, CDCl3): δ = 4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.71–
3.63 (m, 1 H, 6Ј-H), 3.26 (s, 3 H, OCH3), 2.74 (d, J = 13.5 Hz, 1
H, 2-Hb), 2.49 (d, J = 13.5 Hz, 1 H, 2-Ha), 1.91–1.52 (m, 6 H,
3Ј,4Ј,5Ј-H), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.12 (d, J =
6.2 Hz, 3 H, 7Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.6,
98.0, 66.7, 60.4, 47.8, 42.6, 33.0, 32.2, 21.7, 18.85, 14.17 ppm.
HRMS (ESI): calcd. for C11H20O4Na [M + Na]+ 239.1257; found
239.1254.
termining step, which prevents accumulation of Z-enol
ether 15. (b) Protodemetalation occurs through a different
mechanism, which directly forms E-enol ether 14. (c) The
initial cyclization proceeds by cis alkoxymetalation.[8j]
Ethyl
[(2S*,6S*)-6-Ethyl-2-methoxytetrahydro-2H-pyran-2-yl]-
Conclusions
acetate (2d): Colorless oil. Rf = 0.36 (PE 40–60/EtOAc, 10:1). IR
In conclusion, the AuIII-catalyzed intramolecular hy-
droalkoxylation of acetylenic esters offers a convenient
route for the synthesis of five- and six-membered cyclic ace-
tals, which are common substructures of polyketide natural
products. In the case of five-membered rings, exocyclic enol
ethers can be accessed selectively by changing the reaction
solvent from MeOH to THF. Ongoing work in our labora-
tory is focused on the application of this new method
towards the synthesis of complex pyran-containing poly-
ketide natural products.
˜
(neat): ν = 1028, 1086, 1201, 1736 (C=O), 2939 cm–1. H NMR: δ
1
= (400 MHz, CDCl3) 4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.50–
3.38 (m, 1 H, 6Ј-H), 3.26 (s, 3 H, OCH3), 2.75 (d, J = 13.5 Hz, 1
H, 2-Hb), 2.50 (d, J = 13.5 Hz, 1 H, 2-Ha), 1.93–1.39 (m, 8 H,
4,5,6,8-H), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 0.92 (t, J = 7.5 Hz,
3 H, 8Ј-H) ppm. 13C NMR: δ = (100 MHz, CDCl3) 170.0, 98.3,
72.3, 60.8, 48.2, 43.1, 33.8, 30.5, 29.4, 19.3, 14.6, 10.3 ppm. HRMS
(ESI): calcd. for C12H22O4Na[M + Na]+ 253.1412; found 253.1410.
Ethyl [(2S*,6R*)-6-Isopropyl-2-methoxytetrahydro-2H-pyran-2-yl]-
acetate (2e): Colorless oil. Rf = 0.52 (PE 40–60/EtOAc, 8:2). IR
(neat): ν = 1029, 1095, 1205, 1234, 1309, 1737 (C=O), 2946 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 4.13 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.25 (s, 3 H, OCH3), 3.25–3.20 (m, 1 H, 6Ј-H), 2.70
(d, J = 13.5 Hz, 1 H, 2-Hb), 2.52 (d, J = 13.5 Hz, 1 H, 2-Ha), 1.89–
1.55 (m, 7 H, 3Ј,4Ј,5Ј,7Ј-H), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3),
0.93 (d, J = 6.6 Hz, 3 H, 8Ј-H), 0.89 (d, J = 6.9 Hz, 3 H, 9Ј-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8, 97.9, 75.3, 60.4,
47.8, 42.6, 33.4, 32.9, 27.1, 18.9, 18.5, 18.2, 14.2 ppm. HRMS
(ESI): calcd. for C13H24O4Na [M + Na]+ 267.1563; found 267.1567.
Experimental Section
General Procedure for the Synthesis of Cyclic Acetals 2 and 13: A
freshly prepared 0.01  solution of AuCl3 (0.02 equiv. relative to
the ω-hydroxyalkynoate) in anhydrous MeOH was added to the
substrate, and the reaction mixture was stirred at room temperature
until TLC analysis indicated complete conversion of the starting
material. The resulting mixture was diluted with petroleum ether
(PE) 30–40 and Et2O (8:2), and quenched with saturated aqueous
NaHCO3. The organic layer was washed with water (2ϫ) and brine
Ethyl
[(2S*,6R*)-6-Benzyl-2-methoxytetrahydro-2H-pyran-2-yl]-
acetate (2f): Colorless oil. Rf = 0.71 (PE 40–60/EtOAc, 1:1). IR
(neat): ν = 700, 1030, 1079, 1198, 1234, 1736 (C=O), 2942 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.29–7.17 (m, 5 H, Ar-H), 4.14
(2ϫ) and dried with Na2SO4. Solvents were removed by rotary (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.74–3.67 (m, 1 H, 6Ј-H), 3.04 (s,
evaporation, and the resultant residue was filtered through a small 3 H, OCH3), 2.78 (dd, J = 13.4, 7.5 Hz, 1 H, 7Ј-Ha), 2.69 (d, J =
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AuCl3-Catalyzed Hydroalkoxylation of Conjugated Alkynoates
13.5 Hz, 1 H, 2-Hb), 2.65 (dd, J = 13.9, 6.2 Hz, 1 H, 7Ј-Hb) 2.52
(d, J = 13.9 Hz, 1 H, 2a-H), 1.91–1.56 (m, 6 H, 3Ј,4Ј,5Ј-H), 1.26 (t,
J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 169.5, 138.8, 129.5, 128.0, 126.0, 98.1, 71.8, 60.3, 47.7, 42.6, 42.5,
3 H, CH3O), 3.62–3.53 (m, 1 H, H-6Ј), 3.23 (s, 3 H, CH3O), 2.76
(d, J = 13.9 Hz, 1 H, H-2), 2.59 (d, J = 13.5 Hz, 1 H, H-2), 2.43
(ddd, J = 12.8, 4.4, 1.8 Hz, 1 H, H-3Ј), 1.94 (ddd, J = 12.8, 4.2,
2.0 Hz, 1 H, H-5Ј), 1.65–1.49 (m, 2 H, H-3Ј, H-5Ј), 1.27 (t, J =
33.2, 30.1, 18.8, 14.2 ppm. HRMS (ESI): calcd. for C17H24O4Na 7.1 Hz, 3 H, OCH2CH3). 13C NMR (100 MHz, CDCl3): δ = 169.5,
[M + Na]+ 315.1570; found 315.1570.
159.5, 131.2, 129.6, 114.2, 99.8, 71.5, 70.0, 61.0, 60.2, 55.7, 48.3,
42.5, 40.5, 32.2, 14.6. HRMS (ESI): calcd. [M + Na]+ calculated
for C18H26O6Na: 361.1651; found 361.1660.
Ethyl [(2S*,6R*)-2-Methoxy-6-vinyltetrahydro-2H-pyran-2-yl]acet-
ate (2g): Colorless oil. Rf = 0.64 (PE 30–40/Et2O, 1:1). IR (neat):
ν = 1021, 1092, 1201, 1311, 1735 (C=O), 2943 cm–1. 1H NMR
˜
Methyl
{4-Hydroxy-2-methoxy-6-[(4-methoxybenzyloxy)methyl]-
(400 MHz, CDCl3): δ = 5.82 (ddd, J = 17.1, 10.7, 6.1 Hz, 1 H, 7Ј-
H), 5.24 (d, J = 17.2 Hz, 1 H, 8-HtransЈ), 5.09 (d, J = 10.6 Hz, 1 H,
8-HcisЈ), 4.14 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.06–4.01 (m, 1 H,
6-HЈ), 3.28 (s, 3 H, OCH3), 2.78 (d, J = 13.5 Hz, 1 H, 2-Hb), 2.54
(d, J = 13.5 Hz, 1 H, 2-Ha), 1.95–1.62 (m, 6 H, 3Ј,4Ј,5Ј-H), 1.26 (t,
J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 169.5, 138.9, 114.9, 98.1, 71.4, 60.5, 48.0, 42.5, 33.0, 30.4, 18.6,
14.2 ppm. HRMS (ESI): calcd. for C12H20O4Na [M + Na]+
251.1256; found 251.1254.
tetrahydro-2H-pyran-2-yl}acetate (2l): Colorless oil. Rf = 0.50 (PE
40–60/EtOAc, 1:1). [α]2D5 = –42 (c = 11, CHCl3). 1H NMR
(500 MHz, C6D6): δ = 7.30 (d, J = 6.6 Hz, 2 H, ArH), 6.89 (d, J
= 6.6 Hz, 2 H, ArH), 4.46 (s, 2 H, H-9), 4.25–4.18 (m, 1 H, H-6Ј),
4.15–4.08 (m, 1 H, H-4Ј), 3.92 (d, J = 9.6 Hz, 1 H, OH), 3.49 (dd,
J = 10.2, 6.2 Hz, 1 H, H-7aЈ), 3.39 (s, 3 H, ArOMe), 3.37 (dd, J =
10.2, 3.8 Hz, 1 H, H-7bЈ), 3.34 (s, 3 H, CO2Me), 3.11 (s, 3 H, OMe),
2.68 (d, J = 13.9 Hz, 1 H, H-2a), 2.47 (d, J = 13.9 Hz, 1 H, H-2b),
2.32 (dt, J = 14.4, 2.5 Hz, 1 H, H-3axЈ), 1.88 (dd, J = 14.4, 3.6 Hz,
1 H, H-3eqЈ), 1.82 (dq, J = 13.4, 3.1 Hz, 1 H, H-5eqЈ), 1.41 (td, J
= 13.4, 2.8 Hz, 1 H, H-5axЈ) ppm. 13C NMR (125 MHz, C6D6): δ
= 168.8, 159.7, 131.0, 129.3, 114.0, 100.1, 73.2, 73.1, 65.6, 64.1,
54.7, 51.2, 47.7, 42.1, 38.6, 34.4 ppm. HRMS (ESI): calcd. for
C18H26O7Na [M + Na]+ 377.1576; found 377.1593.
Ethyl
[(2S*,6R*)-2-Methoxy-6-phenyltetrahydro-2H-pyran-2-yl]-
acetate (2h): Colorless oil. Rf = 0.61 (PE 30–40/Et2O, 1:1). IR
(neat): ν = 698, 1026, 1091, 1206, 1234, 1734 (C=O), 2943 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 5 H, Ar-H), 4.61
(dd, J = 11.7, 2.2 Hz, 1 H, 6Ј-H), 4.18 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.32 (s, 3 H, OCH3), 2.80 (d, J = 13.9 Hz, 1 H, 2-Hb),
2.67 (d, J = 13.5 Hz, 1 H, 2-Ha), 2.06–1.45 (m, 6 H, 3Ј,4Ј,5Ј-H),
1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.6, 142.7, 128.3, 127.4, 126.0, 98.5, 72.8, 60.5, 48.1,
42.5, 33.0, 32.8, 19.2, 14.2 ppm. HRMS (ESI): calcd. for
C16H22O4Na [M + Na]+ 301.1415; found 301.1410.
Methyl
(4-Hydroxy-2-methoxy-6-vinyltetrahydro-2H-pyran-2-yl)-
acetate (2m): Colorless oil. Rf = 0.48 (PE 40–60/EtOAc, 1:1). [α]2D5
1
= –41 (c = 9, CHCl3). H NMR (400 MHz, C6D6): δ = 5.85 (ddd,
J = 17.0, 10.5, 5.3 Hz, 1 H, H-8Ј), 5.30 (d, J = 17.0 Hz, 1 H, H-
7aЈ), 5.07 (d, J = 10.5 Hz, 1 H, H-7bЈ), 4.45–4.41 (m, 1 H, H-6Ј),
4.09–4.06 (m, 1 H, H-4Ј), 3.89 (d, J = 9.4 Hz, 1 H, OH), 3.36 (s, 3
H, CO2Me), 3.02 (s, 3 H, OMe), 2.64 (d, J = 13.9 Hz, 1 H, H-2a),
2.46 (d, J = 13.9 Hz, 1 H, H-2b), 2.29 (dt, J = 14.5, 2.3 Hz, 1 H,
H-3axЈ), 1.87 (dd, J = 14.5, 3.7 Hz, 1 H, H-3eqЈ), 1.88–1.86 (m, 1
H, H-5eqЈ), 1.37 (td, J = 13.7, 2.5 Hz, 1 H, H-5axЈ) ppm. 13C NMR
(125 MHz, C6D6): δ = 168.5, 138.6, 114.2, 99.9, 66.1, 63.9, 50.9,
47.4, 41.9, 38.2, 37.8 ppm. HRMS (ESI): calcd. for C11H18O5Na
[M + Na]+ 253.1052; found 253.1056.
Benzyl (2-Allyloxytetrahydro-2H-pyran-2-yl)acetate (2i): Colorless
oil. R = 0.69 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 697, 737, 1025,
˜
f
1084, 1197, 1225, 1736 (C=O), 2943 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.31 (m, 5 H, Ar-H), 5.92 (ddd, J = 17.2, 10.4,
5.1 Hz, 1 H, CH=), 5.30 (dd, J = 17.2, 1.5 Hz, 1 H, =CHH), 5.17–
5.10 (m, 3 H, =CHH, CH2Ph), 4.06 (d, J = 5.1 Hz, 2 H, CH2-
Allyl), 3.66–3.63 (m, 2 H, H-6Ј), 2.75 (d, J = 13.9 Hz, 1 H, H-2a),
2.65 (d, J = 13.9 Hz, 1 H, H-2b), 1.98–1.47 (m, 6 H, H-3Ј,4Ј,5Ј)
ppm. 13C NMR (100 MHz, CDCl3) = 169.2, 135.9, 134.8, 128.4,
128.1, 115.8, 97.6, 66.3, 61.8, 61.2, 43.3, 33.6, 24.8, 18.5 ppm.
HRMS (ESI): calcd. for C17H22O4Na [M + Na]+ 313.1421; found
313.1410.
(Z)-Ethyl {8-(tert-Butyldimethylsilyloxy)-2,3-dimethoxy-2,3-dimeth-
yldihydro-2H-pyrano[4,3-b][1,4]dioxin-7(3H,8H,8aH)-ylidene}-
ethanoate (4): White solid. M.p. 99–102 °C. Rf = 0.43 (PE 40–60/
1
EtOAc, 4:1). [α]2D5 = –205 (c = 6.5, CHCl3). H NMR (500 MHz,
CDCl3) = 5.09 (s, 1 H, CH=), 4.46 (td, J = 10.6, 5.6 Hz, 1 H, H-
4a), 4.35 (dd, J = 10.3, 5.6 Hz, 1 H, H-5eq), 4.17–4.10 (m, 3 H,
OCH2, H-8), 3.69 (t, J = 10.6 Hz, 1 H, H-5ax), 3.58 (dd, J = 10.2,
2.7 Hz, 1 H, H-8a), 3.24 (s, 3 H, OCH3), 3.22 (s, 3 H, OCH3), 1.27
(s, 3 H, CH3), 1.26 (s, 3 H, CH3), 1.25 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 0.87 (s, 9 H, tBuSi), 0.11 [s, 3 H, Si(CH3)2], 0.05 [s, 3
H, Si(CH3)2] ppm. 13C NMR (125 MHz, CDCl3) = 166.1, 165.2,
101.8, 100.3, 99.7, 71.9, 70.6, 70.1, 61.3, 60.2, 48.3, 48.1, 25.9, 18.6,
18.1, 18.0, 14.7, –4.8, –4.9 ppm. HRMS (ESI): calcd. for
C21H39O8Si [M + H]+ 447.2330; found 447.2327. C21H38O8Si
(446.62): calcd. C 56.48, H 8.58; found C 56.09, H 8.66.
Benzyl (2-Hydroxytetrahydro-2H-pyran-2-yl)acetate (2j): Colorless
oil. R = 0.48 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 698, 1014,
˜
f
1157, 1204, 1717 (C=O), 2945, 3478 (OH) cm–1. 1H NMR
(400 MHz, CDCl3) = 7.38–7.30 (m, 5 H, Ar-H), 5.22 (d, J =
12.4 Hz, 1 H, CHHPh), 5.15 (d, J = 12.4 Hz, 1 H, CHHPh), 4.68
(d, J = 2.2 Hz, 1 H, OH), 3.98 (td, J = 10.9, 4.1 Hz, 1 H, H-6Јa),
3.64–3.60 (m, 1 H, H-6Јb), 2.70 (d, J = 15.7 Hz, 1 H, H-2b), 2.59
(d, J = 15.4 Hz, 1 H, H-2a), 1.96–1.85 (m, 1 H, H-5Јa), 1.79–1.74
(m, 1 H, H-5Јb), 1.70–1.42 (m, 4 H, H-3Ј,4Ј) ppm. 13C NMR
(100 MHz, CDCl3) = 172.1, 135.4, 128.6, 128.3, 128.2, 94.6, 66.6,
61.3, 45.2, 34.7, 25.0, 18.5 ppm. HRMS (ESI): calcd. for
C14H18O4Na [M + Na]+ 273.1103; found 273.1108. The spectro-
scopic data match those reported previously.[19]
Ethyl 2-{(2R,3R,4aS,7R,8S,8aR)-8-(tert-Butyldimethylsilyloxy)-2,3-
dimethoxy-2,3-dimethylhexahydro-2H-pyrano[4,3-b][1,4]dioxin-7-
yl}ethanoate (5): White solid. M.p. 92–95 °C. Rf = 0.35 (PE 40–60/
EtOAc, 4:1). [α]2D5 = –81 (c = 6.5, CHCl3). 1H NMR (400 MHz,
CDCl3) = 4.16–4.10 (m, 2 H, OCH2CH3), 4.06 (td, J = 10.3,
5.0 Hz, 1 H, H-4a), 3.93 (dd, J = 2.6, 0.7 Hz, 1 H, H-8), 3.89 (dd,
Ethyl [2-Methoxy-4-(4-methoxybenzyloxy)tetrahydro-2H-pyran-2-
yl]acetate (2k): Colorless oil. Rf = 0.43 (PE 40–60/EtOAc, 7:3). IR
(neat): ν = 2940 (w), 1733 (s), 1612 (m), 1513 (s), 1464 (m), 1364
˜
(s), 1315 (m), 1303 (m), 1246 (s), 1172 (m), 1142 (m), 1098 (s), 1072 J = 10.6, 5.0 Hz, 1 H, H-5eq), 3.82 (ddd, J = 7.0, 6.3, 0.7 Hz, 1 H,
1
(s), 1032 (s), 980 (m), 816 (s) cm–1. H NMR (400 MHz, CDCl3):
H-7), 3.58 (dd, J = 10.3, 2.6 Hz, 1 H, H-8a), 3.33 (t, J = 10.6 Hz,
1 H, H-5ax), 3.24 (s, 3 H, OCH3), 3.18 (s, 3 H, OCH3), 2.62 (dd, J
δ = 7.25 (2 H, ArH), 6.82 (2 H, ArH), 4.48 (d, J = 11.3 Hz, 1 H,
CHH-4-MeOC6H4), 4.46 (d, J = 11.3 Hz, 1 H, CHH-4-MeOC6H4), = 16.2, 7.1 Hz, 1 H, CH2CO2), 2.55 (dd, J = 16.2, 6.1 Hz, 1 H,
4.16 (m, 2 H, OCH2CH3), 3.88–3.72 (m, 2 H, H-4Ј, H-6Ј), 3.79 (s, CH2CO2), 1.27 (s, 3 H, CH3), 1.25 (t, J = 16.2, 7.1 Hz, 3 H,
Eur. J. Org. Chem. 2009, 1698–1706
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1703

A. Diéguez-Vázquez et al.
FULL PAPER
OCH2CH3), 1.23 (s, 3 H, CH3), 0.91 (s, 9 H, tBuSi), 0.14 [s, 3 H, 7.0 Hz, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.37 (s, 3 H), 3.34 (s, 3 H),
Si(CH3)2], 0.04 [s, 3 H, Si(CH3)2] ppm. 13C NMR (100 MHz,
CDCl3) = 170.3, 99.0, 98.2, 75.3, 71.4, 69.4, 67.2, 61.7, 59.5, 46.8,
3.04 (d, J = 13.9 Hz, 1 H), 3.03 (d, J = 14.3 Hz, 1 H), 2.81 (d, J =
14.3 Hz, 1 H), 2.72 (d, J = 14.6 Hz, 1 H), 2.20–2.12 (m, 8 H), 2.34
46.4, 35.6, 25.0, 17.5, 16.7, 16.6, 13.2, –5.3, –5.9 ppm. HRMS (br. s, 6 H), 1.89–1.80 (m, 1 H), 1.29 (t, J = 7.1 Hz, 6 H) ppm. 13C
(ESI): calcd. for C21H41O8Si [M + H]+ 449.2571; found 449.2564.
C21H40O8Si (448.63): calcd. C 56.22, H 8.99; found C 56.17, H
8.62.
NMR (100 MHz, CDCl3) = 169.7, 169.6, 139.3, 139.1, 137.2, 137.1,
129.0, 126.5, 125.8, 107.3, 107.1, 83.3, 80.1, 60.5, 49.0, 48.8, 40.8,
40.3, 38.0, 36.6, 33.6, 21.1, 14.2 ppm. HRMS (ESI): calcd. for
C16H22O4Na [M + Na]+ 301.1416; found 301.1425.
Benzyl 2-(2-Methoxyoxepan-2-yl)acetate (7): Colorless oil. Rf
=
0.68 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 1065, 1099, 1187, 1736 Ethyl (3-Methoxy-2-oxaspiro[4.5]decan-3-yl)acetate (13c): Colorless
˜
(C=O), 2929 cm–1. 1H NMR (400 MHz, CDCl3) = 7.37–7.31 (m, 5
H, Ar-H), 5.13 (s, 2 H, OCH2Ph), 3.76–3.69 (m, 1 H, H-7Јa), 3.59– 1225, 1641, 1703, 1737 (C=O), 2925 cm–1. 1H NMR (400 MHz,
oil. R = 0.37 (PE 40–60/AcOEt, 8:2). IR (neat): ν = 1034, 1119,
˜
f
3.54 (m, 1 H, H-7Јb), 3.25 (s, 3 H, OCH3), 2.76 (d, J = 13.5 Hz, 1
H, H-2a), 2.65 (d, J = 13.9 Hz, 1 H, H-2b), 2.43 (dd, J = 15.2,
8.2 Hz, 1 H, H-3Јa), 1.83–1.79 (m, 1 H, H-3Јb), 1.70–1.27 (m, 6 H,
CDCl3) = 4.14 (q, J = 7.5 Hz, 2 H, OCH2CH3), 3.67 (d, J = 8.4 Hz,
1 H, H-1Јa), 3.55 (d, J = 8.4 Hz, 1 H, H-1Јb), 3.22 (s, 3 H, OCH3),
2.93 (d, J = 13.9 Hz, 1 H, H-2a), 2.57 (d, J = 14.0 Hz, 1 H, H-2b),
H-4Ј,5Ј,6Ј) ppm. 13C NMR (100 MHz, CDCl3) = 169.4, 135.9, 2.06 (d, J = 13.5 Hz, 1 H, H-4Јa), 1.93 (d, J = 13.5 Hz, 1 H, H-
128.5, 128.2, 128.1, 102.6, 66.3, 62.0, 48.5, 40.7, 37.8, 30.5, 29.7,
22.6 ppm. HRMS (ESI): calcd. for C16H22O4Na [M + Na]+
301.1412; found 301.1410.
4Јa), 1.58–1.31 (m, 10 H), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3)
ppm. 13C NMR (100 MHz, CDCl3) = 169.6, 107.3, 77.8, 60.5, 48.2,
43.2, 40.6, 37.9, 36.6, 25.7, 24.2, 23.6, 23.4, 14.2 ppm. HRMS
(ESI): calcd. for C14H24O4Na [M + Na]+ 279.1572; found 279.1567.
(Z)-Benzyl 8-Hydroxy-3-methoxyoct-2-enoate (8): Colorless oil. Rf
= 0.34 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 1048, 1131, 1616
Benzyl [(3aR*,7aS*)-2-Methoxyoctahydrobenzofuran-2-yl]acetate
˜
(C=C), 1710 (C=O), 2937, 3378 (OH) cm–1. 1H NMR = (400 MHz,
(13d): Colorless oil. R = 0.62 (PE 40–60/EtOAc, 1:1). IR (neat): ν
˜
f
CDCl3) 7.37–7.31 (m, 5 H, Ar-H), 5.13 (s, 2 H, OCH2Ph), 5.05 (s, = 698, 980, 1034, 1073, 1215, 1456, 1736 (C=O), 2936 cm–1. 1H
1 H, H-2), 3.63–3.61 (m, 5 H, H-8, OCH3), 2.77 (t, J = 7.7 Hz, 2 NMR (400 MHz, CDCl3) = 7.37–7.32 (m, 5 H, Ar-H), 5.16 (d, 1
H, H-4), 1.63–1.56 (m, 4 H, H-5, H-7), 1.44–1.36 (m, 2 H, H-6),
1.26 (br. s, 1 H, OH) ppm. 13C NMR = (100 MHz, CDCl3) 171.5,
168.4, 137.1, 128.5, 128.1, 128.0, 90.3, 65.3, 62.9, 55.5, 32.5, 31.9,
27.6, 25.4 ppm. HRMS (ESI): calcd. for C16H22O4Na [M + Na]+
301.1421; found 301.1410.
H, J = 12.4 Hz, OCH2Ph), 5.12 (d, 1 H, J = 12.1 Hz, OCH2Ph),
3.32–3.29 (m, 1 H, H-7aЈ), 3.31 (s, 3 H, OCH3), 2.90 (d, 1 H, J =
13.5 Hz, H-2a), 2.72 (d, J = 13.5 Hz, 1 H, H-2b), 2.55 (dd, J =
12.8, 7.7 Hz, 1 H, H-3Јa), 2.07–2.03 (m, 1 H, H-3Јb), 1.83–1.78
(m, 2 H), 1.68–1.59 (m, 3 H), 1.37–1.10 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3) 169.5, 135.8, 128.5, 128.3, 128.2, 106.6, 82.2,
66.4, 49.3, 45.4, 42.1, 41.5, 30.6, 28.6, 25.6, 24.2 ppm. HRMS
(ESI): calcd. for C18H24O4Na [M + Na]+ 327.1572; found 327.1568.
Benzyl 8-Hydroxy-3,3-dimethoxyoctanoate (9): Colorless oil. Rf =
0.32 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 697, 746, 1047, 1173,
˜
1
1736 (C=O), 2938, 3436 (OH) cm–1. H NMR (400 MHz, CDCl3)
= 7.36–7.33 (m, 5 H, Ar-H), 5.13 (s, 2 H, OCH2Ph), 3.60(t, 2 H, J General Procedure for the Synthesis of Cyclic Enol Ethers: For the
= 6.2 Hz, H-8), 3.20 (m, 6 H, 2ϫOCH3), 2.71 (s, 2 H, H-2), 1.75–
1.72 (m, 2 H), 1.54–1.52 (m, 2 H), 1.41–1.32 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3) = 169.2, 135.8, 128.5, 128.2, 128.2, 101.8,
66.4, 62.8, 48.1, 38.6, 33.5, 32.5, 25.8, 23.6 ppm. HRMS (ESI):
calcd. for C17H26O5Na [M + Na]+ 333.1674; found 333.1672.
synthesis of cyclic enol ethers 11, 14, and 15 THF was used as
solvent following the same procedure described above.
(E/Z)-Benzyl (Oxepan-2-ylidene)acetate (11): Colorless oil. Rf
=
0.66 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 696, 734, 1053, 1116,
˜
1621 (C=C), 1706 (C=O), 2929 cm–1. 1H NMR (400 MHz, CDCl3)
= 7.37–7.29 (m, 10 H), 5.30 (s, 1 H), 5.13–5.10 (m, 4 H), 5.09 (s, 1
H), 4.14 (m, 2 H), 3.79 (m, 2 H), 3.17 (m, 2 H), 2.94 (m, 2 H),
Benzyl 8-Hydroxy-3-oxooctanoate (10): Colorless oil. Rf = 0.31 (PE
40–60/EtOAc, 1:1). IR (neat): ν = 699, 1057, 1263, 1316, 1713
˜
1
(C=O), 1741 (C=O), 2936, 3442 (OH) cm–1. H NMR (400 MHz, 1.75–1.44 (m, 12 H) ppm. 13C NMR (100 MHz, CDCl3) = 177.9,
CDCl3) = 7.37–7.33 (m, 5 H, Ar-H), 5.18 (s, 2 H, OCH2Ph), 3.65–
175.5, 168.1, 167.6, 136.9, 136.7, 128.5, 128.4, 128.2, 95.5, 91.4,
3.60 (m, 2 H, H-8), 3.48 (s, 2 H, H-2), 2.53 (t, J = 7.1 Hz, 2 H, H- 69.2, 66.1, 65.2, 65.0, 30.5, 29.9, 29.2, 27.8, 26.9, 26.3, 24.6,
4), 1.65–1.52 (m, 4 H, H-5,7), 1.38–1.31 (m, 2 H, H-6), 1.25 (br. s,
23.8 ppm. HRMS (ESI): calcd. for C15H18O3Na [M + Na]+
1 H, OH) ppm. 13C NMR (100 MHz, CDCl3) = 202.3, 160.9, 131.1, 296.1154; found 269.1159.
128.6, 128.5, 128.4, 67.1, 62.6, 49.3, 42.9, 37.4, 25.1, 23.1 ppm.
(E)-Benzyl Dihydrofuran-2(3H)-ylideneacetate (14a): Colorless oil.
HRMS (ESI): calcd. for C15H20O4Na [M + Na]+ 287.1258; found
287.1254.
R = 0.54 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 1043, 1107, 1641,
˜
f
1702 (C=O) cm–1. H NMR (400 MHz, CDCl3) = 7.38–7.27 (m, 5
1
Benzyl (2-Methoxytetrahydrofuran-2-yl)acetate (13a): Colorless oil.
H, Ar-H), 5.38 (s, 1 H, H-2), 5.14 (s, 2 H, CH2Ph), 4.23 (t, J =
7.0 Hz, 2 H, H-5Ј), 3.12 (td, J = 7.8, 1.7 Hz, 2 H, H-3Ј), 2.09 (quint,
J = 7.3 Hz, 2 H, H-4Ј) ppm. 13C NMR (100 MHz, CDCl3) = 177.2,
R = 0.57 (PE 40–60/EtOAc, 1:1). IR (neat): ν = 697, 737, 1041,
˜
f
1204, 1735 (C=O) cm–1. H NMR (400 MHz, CDCl3) = 7.37–7.32
1
(m, 5 H, Ar-H), 5.14 (d, J = 2.6 Hz, 2 H, CH2Ph), 3.87 (m, 2 H, 168.4, 136.9, 128.5, 128.0, 127.8, 89.3, 71.9, 65.1, 30.3, 23.8 ppm.
H-5Ј), 3.24 (s, 3 H, OCH3), 3.02 (d, J = 14.3 Hz, 1 H, H-2a), 2.70 HRMS (ESI): calcd. for C13H14O3Na [M + Na]+ 241.0847; found
(d, J = 14.3 Hz, 1 H, H-2b), 2.13–2.07 (m, 2 H, H-3Ј), 2.04 (m, 1 H, 241.0835.
H-4Јa), 1.88 (m, 1 H, H-4Јb) ppm. 13C NMR (100 MHz, CDCl3) =
(E)-Ethyl [5-(4-Tolyl)dihydrofuran-2(3H)-ylidene]acetate (14b): Col-
169.5, 135.9, 128.5, 128.2, 106.8, 67.8, 66.4, 48.6, 40.2, 36.2,
orless oil. R = 0.44 (PE 40–60/AcOEt, 8:2). IR (neat): ν = 816,
˜
f
24.3 ppm. HRMS (ESI): calcd. for C14H18O4Na [M + Na]+
273.1096; found 273.1097.
1045, 1103, 1349, 1371, 1638 (C=C), 1700 (C=O) cm–1. H NMR
1
(400 MHz, CDCl3) = 7.20 (d, J = 8.8 Hz, 2 H, Ar-H), 7.17 (d, J =
8.4 Hz, 2 H, Ar-H), 5.41 (br. s, 1 H, H-2), 5.35 (t, J = 7.5 Hz, 1 H,
H-5Ј), 4.16 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.41 (1 H, J = 18.3,
Benzyl (2-Methoxy-5-p-tolyltetrahydrofuran-2-yl)acetate (13b): Col-
orless oil. R = 0.44 (PE 40–60/Et O, 8:2). IR (neat): ν = 816, 1032,
˜
f
2
1111, 1212, 1735 (C=O), 2978 cm–1. H NMR (400 MHz, CDCl3) 8.7, 4.3, 1.2 Hz, dddd, H-3Јa), 3.08 (1 H, J = 18.3, 9.2, 2.0 Hz, dtd,
1
= 7.28–7.14 (m, 10 H, ArH), 5.05–4.99 (m, 2 H), 4.19 (q, J = H-3Јb), 2.53–2.45 (m, 1 H, H-4Јa), 2.35 (s, 3 H, Ar-CH3), 2.03 (dq,
1704
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1698–1706

AuCl3-Catalyzed Hydroalkoxylation of Conjugated Alkynoates
J = 12.6, 8.7 Hz, 1 H, H-4Јb), 1.28 (t, J = 7.1 Hz, 3 H, OCH2CH3)
terio de Educación y Ciencia and FICYT (Spain) for a postdoc-
toral fellowship (A. D. V.), the Deutsche Forschungsgemeinschaft
ppm. 13C NMR (100 MHz, CDCl3) = 176.1, 168.6, 138.1, 136.8,
129.3, 125.6, 89.9, 86.9, 59.2, 32.3, 30.6, 21.1, 14.5 ppm. HRMS for a postdoctoral fellowship (C. C. T.), and the Universidade de
(ESI): calcd. for C15H18O3Na [M + Na]+ 269.1154; found 269.1160.
Santiago de Compostela (Spain) for a PhD fellowship (J. C. C.). We
also thank Dr. John Davies at the Cambridge University Chemistry
Laboratory for X-ray crystallography.
(E)-Ethyl (2-Oxaspiro[4.5]decan-3-ylidene)acetate (14c): Colorless
oil. R = 0.38 (PE 40–60/AcOEt, 8:2). IR (neat): ν = 821, 1049,
˜
f
1083, 1097, 1118, 1639 (C=C), 1701 (C=O), 2927 cm–1. H NMR
1
(400 MHz, CDCl3) = 5.24 (br. s, 1 H, H-2), 4.10 (q, J = 7.1 Hz, 2
H, OCH2CH3), 3.91 (s, 2 H, H-1Ј), 2.92 (d, J = 1.5 Hz, 2 H, H-
4Ј), 1.54–1.40 (m, 10 H), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm.
13C NMR (100 MHz, CDCl3) = 177.6, 168.6, 90.4, 80.9, 59.1, 42.4,
41.8, 34.6, 25.7, 23.3, 14.5 (OCH2CH3) ppm. HRMS (ESI): calcd.
for C13H21O3 [M + H]+ 225.1491; found 225.1492.
[1] For a review, see: K.-S. Yeung, I. Paterson, Chem. Rev. 2005,
105, 4237–4313.
[2] A. B. Smith III, S. S.-Y. Chen, F. C. Nelson, J. M. Reichert,
B. A. Salvatore, J. Am. Chem. Soc. 1995, 117, 12013–12014.
[3] a) K. Kato, A. Nishimura, Y. Yamamoto, H. Akita, Tetrahe-
dron Lett. 2001, 42, 4203–4205; b) J. A. Marshall, M. M.
Yanik, Tetrahedron Lett. 2000, 41, 4717–4721. For a recent ap-
plication in total synthesis, see: c) J. Carpenter, A. B. Northrup,
D. Chung, J. J. M. Wiener, S.-G. Kim, D. W. C. McMillan, An-
gew. Chem. Int. Ed. 2008, 47, 3568–3572.
(E)-Benzyl [(3aR*,7aR*)-Hexahydro-1-benzofuran-2(3H)-ylidene]-
acetate (14d): White solid. M.p. 70–72 °C. Rf = 0.42 (PE 40–60/
Et O, 8:2). IR (neat): ν = 1040, 1075, 1109, 1138, 1346, 1637
˜
2
(C=C), 1705 (C=O), 2936 cm–1. 1H NMR (400 MHz, CDCl3) =
7.37–7.28 (m, 5 H, Ar-H), 5.39 (d, 1 H, J = 1.1 Hz, H-2), 5.13 (s,
2 H, CH2Ph), 3.55–3.51 (m, 1 H, H-7aЈ), 2.73 (ddd, J = 17.4, 12.8,
2.3 Hz, 1 H, H-3Јa), 2.24–2.20 (m, 1 H, H-3Јb), 2.02–2.00 (m, 1
H), 1.91–1.89 (m, 1 H), 1.78–1.71 (m, 2 H), 1.63–1.54 (m, 1 H),
1.46 (ddd, J = 23.7, 11.7, 3.7 Hz, 1 H), 1.36–1.19 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3) = 176.3, 168.2, 136.8, 128.5, 127.9,
127.8, 90.6, 86.9, 65.1, 44.3, 36.4, 30.3, 28.3, 25.3, 24.0 ppm.
HRMS (ESI): calcd. for C17H20O3Na [M + Na]+ 295.1310; found
295.1299.
[4] For a review, see: C. F. Nising, S. Bräse, Chem. Soc. Rev. 2008,
37, 1218–1228.
[5] Double intramolecular oxy-Michael addition with the use of a
Brønsted acid as catalyst: a) J. Aiguade, J. Hao, C. J. Forsyth,
Org. Lett. 2001, 3, 979–982; hydration with the use of PtCl4/
CO as catalyst: b) W. Baidossi, M. Lahav, J. Blum, J. Org.
Chem. 1997, 62, 669–672; for the DABCO-catalyzed addition
of phenols to activated alkynes, see: c) M.-J. Fan, G.-Q. Li, L.-
H. Li, S.-D. Yang, Y.-M. Liang, Synthesis 2006, 14, 2286–2292.
[6] PtII or PdII/AgI-catalyzed monohydroalkoxylation: a) Y. Ka-
taoka, O. Matsumoto, K. Tani, Organometallics 1996, 15,
5246–5249; b) Y. Kataoka, O. Matsumoto, M. Ohashi, T. Yam-
agata, K. Tani, Chem. Lett. 1994, 1283–1284.
(Z)-Benzyl [(3aR*,7aR*)-Hexahydro-1-benzofuran-2(3H)-ylidene]-
acetate (15d): White solid. M.p. 101–103 °C. Rf = 0.42 (PE 40–60/
[7] H. F. Sneddon, A. v. d. Heuvel, A. K. H. Hirsch, R. A. Booth,
D. M. Shaw, M. J. Gaunt, S. V. Ley, J. Org. Chem. 2006, 71,
2715–2725.
Et O, 8:2). IR (neat): ν = 731, 1028, 1039, 1197, 1213, 1648 (C=C),
˜
2
1717 (C=O), 2935 cm–1. H NMR (400 MHz, CDCl3) = 7.39–7.26
1
(m, 5 H, Ar-H), 5.16 (d, J = 12.4 Hz, 1 H, OCHHPh), 5.12 (d, J
= 12.8 Hz, 1 H, OCHHPh), 4.97 (d, J = 1.5 Hz, 1 H, H-2), 3.72
(td, J = 11.0, 3.7 Hz, 1 H, H-7aЈ), 2.64 (dd, J = 15.7, 6.2 Hz, 1 H,
H-3Јa), 2.40–2.33 (m, 2 H, H3Јb, H-3aЈ), 2.00–1.89 (m, 2 H). 1.78–
1.75 (m, 1 H), 1.69–1.53 (m, 2 H), 1.39–1.15 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3) 177.1, 165.4, 136.9, 128.3, 128.0, 127.7,
89.3, 88.9, 65.0, 43.9, 38.2, 30.5, 28.3, 25.2, 24.1 ppm. HRMS
(ESI): calcd. for C17H20O3Na [M + Na]+ 295.1310; found 295.1319.
[8] For selected examples, see: a) Y.-Y. Yeung, E. J. Corey, Org.
Lett. 2008, 10, 3877–3878; b) B. M. Trost, A. H. Weiss, Angew.
Chem. 2007, 119, 7808–7810; Angew. Chem. Int. Ed. 2007, 46,
7664–7666; c) Y. Li, F. Zhou, C. Forsyth, Angew. Chem. 2007,
119, 283–286; Angew. Chem. Int. Ed. 2007, 46, 279–282; d) H.
Harkat, J.-M. Weibel, P. Pale, Tetrahedron Lett. 2007, 48, 1439–
1442; e) V. Belting, N. Krause, Org. Lett. 2006, 8, 4489–4492;
f) B. Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907–4910;
g) J. Barluenga, A. Diéguez, A. Fernández, F. Rodríguez, F. J.
Fañanás, Angew. Chem. 2006, 118, 2145–2147; Angew. Chem.
Int. Ed. 2006, 45, 2091–2093; h) E. Genin, S. Antoniotti, V.
Michelet, J.-P. Gênet, Angew. Chem. 2005, 117, 5029–5033; An-
gew. Chem. Int. Ed. 2005, 44, 4949–4953; i) S. Antoniotti, E.
Genin, V. Michelet, J.-P. Gênet, J. Am. Chem. Soc. 2005, 127,
9976–9977; for some recent reviews, see: j) A. Arcadi, Chem.
Rev. 2008, 108, 3266–3325; k) Z. Li, C. Brouwer, C. He, Chem.
Rev. 2008, 108, 3239–3265; l) N. T. Patil, Y. Yamamoto, Chem.
Rev. 2008, 108, 3395–3442; m) J. Muzart, Tetrahedron 2008, 64,
5815–5849; n) S. F. Kirsch, Synthesis 2008, 3183–3204; o) E.
Jimenez-Núñez, A. M. Echavarren, Chem. Commun. 2007,
333–346; p) A. Fürstner, P. W. Davies, Angew. Chem. 2007, 119,
3478–3519; Angew. Chem. Int. Ed. 2007, 46, 3410–3449; q) D. J.
Gorin, F. D. Toste, Nature 2007, 446, 395–403; r) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180–3211; s) A. S. K. Hashmi,
G. J. Hutchings, Angew. Chem. 2006, 118, 8064–8105; Angew.
Chem. Int. Ed. 2006, 45, 7896–7936; t) F. Alonso, I. P. Belets-
kaya, M. Yus, Chem. Rev. 2004, 104, 3079–3160; u) G. Zeni,
R. Larock, Chem. Rev. 2004, 104, 2285–2309.
NMR Spectroscopic Experiments: Compound 4b (70.0 mg,
0.321 mmol) was dissolved in [D4]MeOH (892 µL) resulting in a
0.333  solution. Of this solution, a 750 µL aliquot was transferred
to a dry NMR tube and an initial 1H NMR spectrum was re-
corded. A 0.02  solution of AuCl3 in [D4]MeOH (250 µL; pre-
pared from 15.3 mg of AuCl3 and 2.52 mL of [D4]MeOH) was
added and the NMR tube was inverted repeatedly to achieve mix-
ing. The NMR tube was returned to the spectrometer and spectra
(single pulse) were recorded in 33.7 s intervals over a period of
approx. 60 min. Well-resolved resonances of the starting material
and the products were integrated and normalized relative to the
integral of all aromatic signals (the absolute value of this integral
changed less than 3% between the first and last spectrum). The
thus derived concentrations of the components of the reaction mix-
ture were plotted against time for visualization. The experiment in
[D8]THF was carried out as described above, except that [D8]THF
was used as the solvent: 750 µL of 0.333  benzyl 6-hydroxyhex-2-
ynoate (60.3 mg in 769 µL [D8]THF), 250 µL of 0.02  AuCl3
(4.4 mg in 725 µL [D8]THF).
[9] An isolated example of AuI-catalyzed double intramolecular
hydroalkoxylation starting from an epoxyalkynoate has been
recently reported, see: a) L.-Z. Dai, M.-J. Qi, Y.-L. Shi, X.-G.
Liu, M. Shi, Org. Lett. 2007, 9, 3191–3194; for monohydro-
alkoxylation reactions catalyzed by PdMo3 clusters, see: b) T.
Murata, Y. Mizobe, H. Gao, Y. Ishii, T. Wakabayashi, F. Nak-
ano, T. Tanase, S. Yano, M. Hidai, I. Echizen, H. Nanikawa,
S. Motomura, J. Am. Chem. Soc. 1994, 116, 3389–3398; for
Acknowledgments
The authors thank Merck Research Laboratories for support
through the Academic Development Program (S. V. L.), the Minis-
Eur. J. Org. Chem. 2009, 1698–1706
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1705

A. Diéguez-Vázquez et al.
FULL PAPER
reactions catalyzed by HgII, see: c) M. Bassetti, B. Floris, J.
Chem. Soc. Perkin Trans. 2 1998, 227–233; for CuI-catalyzed
bishydroalkoxylation of methyl propiolate, see: d) S. H. Bertz,
G. Dabbagh, P. Cotte, J. Org. Chem. 1982, 47, 2216–2217; for
IrIV-catalyzed hydration of methyl propiolate, see: e) M. Kon-
kol, H. Schmidt, D. Steinborn, J. Mol. Catal. A 2007, 261, 301–
305; for some selected examples of metal-catalyzed carboalkox-
ylation of alkynoates, see: f) P. Dubé, F. D. Toste, J. Am. Chem.
Soc. 2006, 128, 12062–12063; g) A. Fürstner, F. Stelzer, H. Szil-
lat, J. Am. Chem. Soc. 2001, 123, 11863–11869.
Cheong, D. T. Thangadurai, I.-C. Hwang, Y. H. Rhee, Angew.
Chem. 2008, 120, 2295–2298; Angew. Chem. Int. Ed. 2008, 47,
2263–2266; considering that these starting materials are 1,7-
enynes, a skeletal rearrangement might take place, see: b) E.
Jiménez-Núñez, A. M. Echavarren, Chem. Rev. 2008, 108,
3326–3350; when R1 = Bn, a domino hydoalkoxylation–hy-
droarylation could take place, see: c) J. Barluenga, A.
Fernández, A. Satrústegui, A. Diéguez, F. Rodríguez, F. J.
Fañanás, Chem. Eur. J. 2008, 14, 4153–4156.
For the preparation of 3, see: L.-G. Milroy, G. Zinzalla, G.
Prencipe, P. Michel, S. V. Ley, M. Gunaratnam, M. Beltran, S.
Neidle, Angew. Chem. 2007, 119, 2545–2548; Angew. Chem. Int.
Ed. 2007, 46, 2493–2496.
The configuration of the products was unequivocally estab-
lished by NMR spectroscopy (including HMQC, HMBC,
COSY, and NOESY).
CCDC-704953 (for 5), -699405 (for 14d), and -699406 (for 15d)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[14]
[10] a) A. Diéguez-Vázquez, C. C. Tzschucke, W. Y. Lam, S. V. Ley,
Angew. Chem. Int. Ed. 2008, 47, 209–212; Angew. Chem. 2008,
120, 216–219. For recent reviews on BDA chemistry, see: b) E.
Lence, L. Castedo, C. González-Bello, Chem. Soc. Rev. 2008,
37, 1689–1708; c) S. V. Ley, A. Polara, J. Org. Chem. 2007, 72,
5943–5959; d) S. V. Ley, T. D. Sheppard, R. M. Myers, M. S.
Chorghade, Bull. Chem. Soc. Jpn. 2007, 80, 1451–1472; e) S. V.
Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince,
H. W. M. Priepke, D. J. Reynolds, Chem. Rev. 2001, 101, 53–
80.
[11] FeCl3 (5 mol-%) in AcOH was also ineffective for the hydro-
alkoxylation of 7,8-dihydroxy-2-octynoate derivatives, see:
C. C. Tzschucke, N. Pradidphol, A. Diéguez-Vázquez, B.
Kongkathip, N. Kongkathip, S. V. Ley, Synlett 2008, 9, 1293–
1296.
[15]
[16]
[17] For a similar mechanistic proposal, see: I. Nakamura, C. S.
Chan, T. Araki, M. Terada, Y. Yamamoto, Org. Lett. 2008, 10,
309–312.
[18] When 13a was treated with AuCl3 (0.02 equiv., 0.01  in
CD3OD), [D1]-14a was obtained after 1 h by just removing the
solvent (without previous neutralization with sat. NaHCO3).
[19] B. Loubinoux, J. L. Sinnes, A. C. O’Sullivan, J. Chem. Soc. Per-
kin Trans. 1 1995, 521–525.
[12] The diastereomer formed is the more-stable epimer with the
alkoxy group in an axial position as a consequence of the an-
omeric effect, whereas the bulkier alkyl substituents are placed
in a favorable equatorial orientation. The formation of the
thermodynamic product could be a consequence of the revers-
ibility of the second hydroalkoxylation step.
Received: December 5, 2008
[13] When R1 = vinyl or phenyl, a [3,3] sigmatropic rearrangement
could take place, see: a) H. J. Bae, B. Baskar, S. E. An, J. Y.
Published Online: February 13, 2009
1706
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