Synthesis of the C1-C15 fragment of apicularen A through a regioselective electron-transfer-initiated cyclization reaction

Article abstract of DOI:10.1055/s-2007-983776

In this paper we report the preparation of the benzyltetrahydropyran fragment of the vacuolar ATPase inhibitor apicularen A through an oxidative cyclization protocol. In this reaction regioselective cleavage of one homobenzylic ether in the presence of another homobenzylic ether is achieved by selectively weakening one carbon-carbon σ-bond through substitution. This work demonstrates that oxidative fragmentation reactions can be used to generate stable cations selectively, even in the presence of other readily oxidized groups, provided that bond cleavage is sufficiently rapid following oxidation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983776

PAPER
2291
Synthesis of the C1–C15 Fragment of Apicularen A through a Regioselective
Electron-Transfer-Initiated Cyclization Reaction
Regioselective
Ox
l
idative
eCleavage xander J. Poniatowski, Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
E-mail: florean@pitt.edu
Received 8 March 2007
Dedicated to Professor Paul Wender on the occasion of his 60th birthday
oxidative cleavage of one homobenzylic ether in the pres-
Abstract: In this paper we report the preparation of the benzyltet-
rahydropyran fragment of the vacuolar ATPase inhibitor apicularen
A through an oxidative cyclization protocol. In this reaction regio-
selective cleavage of one homobenzylic ether in the presence of an-
other homobenzylic ether is achieved by selectively weakening one
carbon–carbon s-bond through substitution. This work demon-
strates that oxidative fragmentation reactions can be used to gener-
ate stable cations selectively, even in the presence of other readily
oxidized groups, provided that bond cleavage is sufficiently rapid
following oxidation.
ence of another can be achieved en route to the prepara-
tion of a substantial subunit of the potent vacuolar ATPase
inhibitor apicularen A (1) (Figure 1).4
Isolated from the myxobacterial genus Chondromyces,
apicularen A is a member of the benzolactone enamide
class of natural products that also includes the salicyli-
halamides,5 lobatamides,6 and oximidines.7 Apicularen A
is a potent cytotoxin, with IC50 values ranging from 0.2 to
20 nM for several cancer cell lines. This activity most
likely results from inhibition of the vacuolar ATPase (V-
ATPase).8 V-ATPase inhibition has also been implicated
as being useful for treating a host of other maladies, such
as Alzheimer’s disease9 and osteoporosis.10
Key words: acetals, cations, cyclizations, electron transfer, oxida-
tions
Selectively activating one functional group toward reac-
tion in the presence of another structurally similar group
is a significant challenge for complex molecule synthesis.
Approaches to this problem can exploit subtle differences
in reactivity or steric environment, but more commonly
rely on the use of protecting groups that lengthen the syn-
thetic scheme. An alternative approach employs function-
al groups that have orthogonal reactivity patterns as
precursors to reactive intermediates. We have studied this
approach extensively through the use of radical cation
fragmentation reactions in the preparation of stabilized
carbocations.1 These processes proceed through single-
electron oxidations of homobenzylic ethers and amides
which are completely inert toward the acidic conditions
that are conventionally used for carbocation formation.
Moreover, common cation precursors such as acetals are
inert to most single-electron oxidants, creating the possi-
bility for the use of oxidative cleavage to generate electro-
philes through carbon–carbon bond activation in the
presence of acid-sensitive groups, and through acetal acti-
vation in the presence of homobenzylic ethers and amides.
We have reported several examples in which oxocarbeni-
um and acyliminium ions can be formed through oxida-
tive cleavage in the presence of acid-sensitive acetals2 and
epoxides.3 Conducting oxidative cleavage reactions in the
presence of other functional groups that can undergo sin-
gle-electron oxidation, however, has been studied much
less thoroughly. In this paper we report that, with appro-
priate substitution patterns, excellent selectivity for the
OH
O
O
N
H
O
O
OH
1
Figure 1 Apicularen A
Several total11 and formal syntheses12 of 1 have been re-
ported. Most of these routes have established the 2,6-
trans-relationship around the tetrahydropyran ring prior
to formation of the macrocycle; however, an intriguing
study by Rizzacasa and co-workers12c has suggested that a
2,6-cis-disubstituted tetrahydropyrone could isomerize to
the trans-isomer following lactone formation. This led us
to consider the possibility (Scheme 1) that tetrahydropy-
rone 2 could be a suitable precursor to apicularen A. The
tetrahydropyrone would be derived from an electron-
transfer-initiated cyclization from homobenzylic ether 3.
Successful implementation of this strategy is contingent
upon selective generation of the C13 carbocation in prefer-
ence to oxidative cleavage of the C8–C9 bond. The pres-
ence of the geminal methyl groups weakens the benzylic
carbon–carbon bond,13 resulting in preferential cleavage14
provided that the radical cation intermediate can localize
on the appropriate arene. The cyclization precursor can be
accessed from acetal 4, which can be prepared from alde-
hyde 5 and diol 6.
SYNTHESIS 2007, No. 15, pp 2291–2296
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983776; Art ID: C01307SS
© Georg Thieme Verlag Stuttgart · New York

2292
A. J. Poniatowski, P. E. Floreancig
PAPER
OP
sulting adduct to a one-pot sequence of ozonolysis and so-
dium borohydride reduction provided diol 6. Although 6
was prepared as a racemic mixture for experimental con-
venience, several methods have been reported20 that will
allow for the preparation of enantiomerically enriched
material.
OP
CO2Me
O
9
R
8
CO2Me
13
1
O
R
AcO
OP
OP
1. KHMDS, ∆
O
F
H
94%
OMe
3
+
2
2. DIBAL-H
97%
O
CN
MeO
MeO
12
PO
10
11
MeO2C
1. allylmagnesium
bromide, 95%
O
O
OH OH
2. O3, then NaBH4
68%
OMe
MeO
R
6
Scheme 3 Diol preparation
4
OH
The union of 5 and 6 (Scheme 4) was achieved through
Noyori’s acetalization method.21 Diol 6 was converted
into its bis(trimethylsilyl ether) under standard conditions,
and added without purification to aldehyde 5 and a cata-
lytic amount of TMSOTf, to provide acetal 13 in 86%
overall yield. The use of acetalization as a fragment cou-
pling method in complex molecule synthesis is attractive
because of its general efficiency and its mutual protection
of diol and carbonyl groups.22 The Lewis acid mediated23
propargylation of 13 proved to be challenging due to com-
petition between the desired bimolecular addition to the
intermediate oxocarbenium ion to form 14 and an in-
tramolecular Friedel–Crafts reaction to yield 15. Optimal
conditions employed allenyltrimethylsilane, prepared as a
solution in pentane according to Myers’ protocol,24 an un-
protected phenolic hydroxy group, and the addition of
precooled titanium(IV) chloride to form the desired ether
14 in 50% yield as a 6.8:1 ratio of diastereomers. The se-
lectivity for acetal ionization in the presence of the ho-
mobenzylic ether under Lewis acidic conditions
highlights one useful aspect of using oxidative cleavage to
generate oxocarbenium ions. Methylation of the phenol
followed by acylation of the primary alcohol provided 16.
Cyclization precursor 17 was obtained by subjecting 16 to
a ruthenium-mediated Markovnikov addition of acetic
acid across the alkyne group.25
HO
HO
CO2Me
+
H
OMe
O
5
6
Scheme 1 Retrosynthetic analysis
For the preparation of 5 (Scheme 2) we employed a de
novo approach to arene construction that employed a
cycloaddition15 between hydroxypyrone 716 and allenedi-
carboxylate 8,17 both available in one step from inexpen-
sive commercially available sources, to form diester 9.
Selective reduction of the aliphatic ester group18 provided
aldehyde 5.
OH
∆
+
MeO2C
CO2Me
92%
O
O
7
8
OH
OH
DIBAL-H
78%
CO2Me
H
CO2Me
CO2Me
In considering the critical cyclization of 17, we became
concerned about the selectivity of arene oxidation. While
1H NMR analysis indicates that the ester group in the
trisubstituted arene acts to withdraw electrons when the
phenolic hydroxy group is unprotected, the chemical
shifts of the arene hydrogens move significantly upfield
upon methyl ether formation. Clearly the conjugation be-
tween the ester group and the ring is disrupted, resulting
in higher electron density that could compromise selectiv-
ity in the single-electron-oxidation step. Exposure of 17 to
cerium(IV) ammonium nitrate, however, cleanly resulted
O
9
5
Scheme 2 Arene synthesis
The synthesis of the diol component (Scheme 3) com-
menced with a base-mediated coupling of p-fluoroanisole
(10) and isobutyronitrile (11) according to the Pfizer pro-
tocol,19 followed by nitrile reduction to yield aldehyde 12.
Adding allylmagnesium bromide and subjecting the re-
Synthesis 2007, No. 15, 2291–2296 © Thieme Stuttgart · New York

PAPER
Regioselective Oxidative Cleavage
2293
HO
i. TMSCl, imidazole
MeO2C
6
O
ii. 5, TMSOTf
86%
13
9
15
O
OMe
13
OH
SiMe3
1. K2CO3, MeI, 96%
CO2Me
15
O
OH
2. Ac2O, DMAP,
py, 95%
TiCl4, 50%
13
9
11
Ar
14
OMe
OMe
CO2Me
O
CO2Me
O
HOAc, (furyl)3P
OAc
OAc
[(p-cymene)RuCl2]2
∆, 78%
Ar
Ar
OAc
16
17
OH
CO2Me
O
OH
MeO
15
Scheme 4 Synthesis of the cyclization precursor
in the isolation of tetrahydropyrone 18 as a single stereo- bon–carbon bond, a single-cleavage process can be
isomer in 73% yield (Scheme 5). The cis relationship was realized in the presence of multiple redox-active groups.
established through a 2D NOESY NMR experiment. The Demonstrating that electron-transfer-initiated reactions
reaction required heating to 40 °C, which is not generally are not necessarily product-determining events in chemi-
required for these cyclizations, indicating that reversible cal reactions is essential in establishing oxidative frag-
and nondestructive trisubstituted arene oxidation could be mentation reactions as versatile, predictable tools for
a competitive process.
complex molecule synthesis.26
We have reported a convergent approach to the C1–C15
fragment of apicularen A. Key steps include a cycloaddi-
tion reaction to form the trisubstituted arene, fragment
coupling through acetal formation, and a diastereoselec-
tive acetal opening to form a highly substituted ether
group. The oxidative fragmentation reaction demonstrates
the ability to use rationally designed substitution patterns
to achieve selective bond activation in the presence of oth-
er groups that can undergo single-electron oxidation. Ef-
forts to elaborate this sequence to complete the total
synthesis are in progress and will be reported in due
course.
OMe
OMe
CO2Me
CO2Me
CAN, NaHCO3
40 °C, 73%
9
13
O
OAc
O
OAc
9
13
11
11
Ar
OAc
O
17
18
Scheme 5 Tetrahydropyrone construction
This cyclization provides evidence that the outcomes of
oxidative cleavage reactions can be controlled by the rate
of processes that follow the initial single-electron oxida-
tion. By using benzylic substitution to weaken the car-
1H and 13C NMR spectra were recorded on Bruker Avance 300
spectrometers at 300 and 75 MHz, respectively. The chemical shifts
are given in parts per million (ppm) on the delta (d) scale. The sol-
Synthesis 2007, No. 15, 2291–2296 © Thieme Stuttgart · New York

2294
A. J. Poniatowski, P. E. Floreancig
PAPER
vent peak or the internal standard tetramethylsilane was used as ref-
erence value; for 1H NMR: CDCl3 = 7.27 ppm, TMS = 0.00 ppm;
for 13C NMR: CDCl3 = 77.23 ppm, TMS = 0.00 ppm. For proton da-
ta: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, dt =
doublet of triplets, ddd = doublet of doublet of doublets, br = broad,
m = multiplet, app t = apparent triplet. High-resolution and low-res-
olution mass spectra were recorded on a VG 7070 spectrometer. IR
spectra were collected on a Mattson Gygnus 100 spectrometer. An-
alytical GC was performed using a Hewlett–Packard 6850 Series
gas chromatograph fitted with an FID. Analytical TLC was per-
formed on E. Merck precoated (25 nm) silica gel 60F-254 plates; vi-
sualization was done under UV light (254 nm). Flash column
chromatography was performed using ICN SiliTech 32–63 60-Å
silica gel. Reagent grade EtOAc and hexanes (commercial mixture)
were purchased from EM Science and used as supplied for chroma-
tography. Reagent grade CH2Cl2 was distilled from CaH2. Et2O and
THF were dried by passage through an aluminum drying column.
Anhyd MeOH and MeCN were purchased from Aldrich and used as
supplied. All reactions were conducted under an argon or nitrogen
atmosphere, unless otherwise specified.
EtOAc (3 × 100 mL), and the combined organic layers were washed
with brine (400 mL), dried (MgSO4), filtered, and concentrated to
yield a crude brown oil. The oil was distilled at 2 mmHg and the title
compound was collected at 98 °C as a colourless oil (26.0 g, 94%).
IR (neat): 2980, 2838, 2234, 1610, 1512, 1463, 1301, 1254, 1185,
1032 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40 (d, J = 8.7 Hz, 2 H), 6.91 (d,
J = 8.7 Hz, 2 H), 3.82 (s, 3 H), 1.71 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 159.8, 133.6, 126.4, 125.0, 114.3,
55.5, 36.6, 29.4.
MS (EI): m/z (%) = 175 (22) [C11H13NO+].
2-(4-Methoxyphenyl)-2-methylpropionaldehyde (12)
To 2-(4-methoxyphenyl)-2-methylpropionitrile (12.93 g, 73.7
mmol) in CH2Cl2 (150 mL) at –78 °C was added 1 M DIBAL-H in
hexanes (81 mL, 81 mmol) over the course of 2 h. The reaction was
stirred at –78 °C for an additional 45 min, then was quenched with
0.5 M H2SO4 (150 mL), warmed to r.t., and stirred overnight. The
contents were extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were washed with sat. aq NaHCO3 (100 mL), then
brine (100 mL), and then dried (MgSO4), filtered, and concentrated
to yield the title compound as a colourless oil (12.77 g, 97%).
IR (neat): 2970, 1723, 1513, 1253, 1185, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.46 (s, 1 H), 7.21 (dd, J = 6.7, 2.2
Hz, 2 H), 6.92 (dd, J = 6.7, 2.2 Hz, 2 H), 3.82 (s, 3 H), 1.45 (s, 6 H).
Methyl 2-Hydroxy-6-(methoxycarbonylmethyl)benzoate (9)
Allene 8 (8.37 g, 53.6 mmol) and pyrone 7 (6.62 g, 59.0 mmol) were
dissolved in toluene (150 mL) and heated to 80 °C for 78 h. The sol-
vent was evaporated under reduced pressure and the crude material
was purified via flash column chromatography (EtOAc–hexanes,
3:7) to yield the desired salicylate as a colourless oil (11.1 g, 92%).
IR (neat): 2954, 1739, 1668, 1611, 1580, 1452, 1439, 1357, 1258,
1171 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.2 (s, 1 H), 7.37 (dd, J = 7.5, 0.6
Hz, 1 H), 6.97 (dd, J = 7.5, 1.2 Hz, 1 H), 6.73 (ddd, J = 7.5, 1.2, 0.6
Hz, 1 H), 3.90 (s, 5 H), 3.69 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.8, 171.0, 162.8, 136.5, 134.4,
123.8, 117.4, 112.1, 51.9, 51.7, 42.3.
13C NMR (75 MHz, CDCl3): d = 201.6, 158.6, 132.9, 127.7, 114.1,
54.8, 49.4, 22.2.
+
MS (EI): m/z (%) = 178 (35) [C11H14O2 ].
2-(4-Methoxyphenyl)-2-methylhex-5-en-3-ol
To aldehyde 12 (10.08 g, 56.6 mmol) in CH2Cl2 (115 mL) at –78 °C
was added 1 M allylmagnesium bromide in Et2O (62 mL, 62 mmol)
dropwise. The reaction was stirred at –78 °C for 1 h, then was
quenched with sat. aq NH4Cl and warmed to r.t. The contents were
extracted with CH2Cl2 (3 × 70 mL). The combined organic layers
were washed with brine (50 mL), then dried (MgSO4), filtered, and
concentrated to yield the title compound as a colourless oil (11.84
g, 95%).
HRMS (EI): m/z calcd for C11H12O5 [M+]: 224.0685; found:
224.0684.
Methyl 2-Hydroxy-6-(2-oxoethyl)benzoate (5)
To ester 9 (8.06 g, 35.9 mmol) in CH2Cl2 (180 mL) at –78 °C was
added, dropwise, 1.0 M DIBAL-H in hexanes (54 mL, 54 mmol).
The reaction was warmed to 0 °C and stirred for 1 h, then it was
quenched with 1 M HCl (200 mL). The biphasic mixture was vigor-
ously stirred for 1 h. The layers were separated and the aqueous lay-
er was extracted with CH2Cl2 (3 × 100 mL). The combined organic
layers were washed with H2O (200 mL), then brine (200 mL), and
then dried (MgSO4), filtered, and concentrated. The resulting crude
oil was purified via flash column chromatography (EtOAc–hex-
anes, 3:7) to yield the title compound as a colourless oil (5.45 g,
78%).
IR (neat): 3481, 2970, 2835, 1611, 1252, 1185 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32 (d, J = 8.9 Hz, 2 H), 6.88 (d,
J = 8.9 Hz, 2 H), 5.8 (m, 1 H), 5.09 (d, J = 1.0 Hz, 1 H), 5.05 (d, J
= 1.1 Hz, 1 H), 3.81 (s, 3 H), 3.64 (d, J = 10.4 Hz, 1 H), 2.18 (m, 1
H), 1.9 (m, 1 H), 1.6 (m, 2 H), 1.34 (2 s, 6 H).
13C NMR (75 MHz, CDCl3) d = 157.8, 138.9, 136.5, 127.6, 117.3,
113.5, 78.5, 55.2, 41.7, 36.6, 24.5, 24.0.
HRMS (EI): m/z calcd for C14H20O2 [M+]: 220.1463; found:
220.1462.
IR (neat): 3052, 2956, 1719, 1670, 1609, 1577, 1449, 1319, 1247,
1219 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.18 (s, 1 H), 9.70 (s, 1 H), 7.40
(app t, J = 7.8 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 7.2
Hz, 1 H), 3.94 (s, 2 H), 3.91 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.4, 171.1, 163.5, 135.5, 135.2,
124.4, 118.2, 112.6, 52.6, 51.6.
4-(4-Methoxyphenyl)-4-methylpentane-1,3-diol (6)
A steady stream of ozone was bubbled through a soln of 2-(4-meth-
oxyphenyl)-2-methylhex-5-en-3-ol (3.09 g, 14.0 mmol) in CH2Cl2
(30 mL) at –78 °C for 20 min. The soln was purged with N2, then
MeOH (30 mL) was added while the temperature was maintained at
–78 °C. NaBH4 (2.65 g, 70.3 mmol) was added and the reaction was
warmed to 0 °C for 2 h and to r.t. for 16 h. The reaction was
quenched by a careful addition of H2O (5 mL), then the solvent was
concentrated under reduced pressure. The residue was dissolved in
EtOAc (200 mL) and washed with brine (2 × 30 mL). The organic
layer was collected, dried (MgSO4), filtered, and concentrated. The
residue was purified by flash chromatography (hexane–EtOAc, 4:6)
to yield the title compound as a colourless oil (2.13 g, 68%).
HRMS (EI): m/z calcd for C10H10O4 [M+]: 194.0579; found:
194.0577.
2-(4-Methoxyphenyl)-2-methylpropionitrile
To fluoroanisole 10 (20.0 g, 158 mmol) and isobutyronitrile (56.8
mL, 634 mmol) in THF (250 mL) was added KHMDS (47.4 g, 238
mmol). The reaction was heated to reflux for 6 d, then quenched at
0 °C with 1 M HCl (200 mL). The contents were extracted with
IR (neat): 3371, 2960, 1610, 1513, 1295, 1252, 1186, 1035 cm–1.
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Regioselective Oxidative Cleavage
2295
1H NMR (300 MHz, CDCl3): d = 7.28 (dd, J = 8.4, 3.0 Hz, 2 H),
6.88 (dd, J = 8.4, 3.0 Hz, 2 H), 3.80 (m, 6 H), 2.66 (br s, 1 H), 2.21
(br s, 1 H), 1.50 (m, 2 H), 1.33 (s, 3 H), 1.31 (s, 3 H).
crude oil was purified via flash column chromatography (EtOAc–
hexanes, 3:7) to yield the title compound as a colourless oil (1.74 g,
50%; dr = 6.8:1).
13C NMR (75 MHz, CDCl3): d = 157.8, 138.8, 127.6, 113.6, 79.9,
IR (neat): 3427, 3303, 2955, 1663, 1609, 1512, 1449, 1252 cm–1.
62.3, 55.2, 41.8, 32.8, 24.1, 23.7.
1H NMR (300 MHz, CDCl3): d = 11.31 (s, 1 H), 7.35 (app t, J = 8.1,
7.5 Hz, 1 H), 6.95 (dd, J = 7.5, 0.9 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2
H), 6.79 (dd, J = 7.5, 0.9 Hz, 1 H), 6.70 (d, J = 8.7 Hz, 2 H), 3.81 (s,
3 H), 3.79 (s, 3 H), 3.75–3.65 (m, 2 H), 3.35–3.25 (m, 2 H), 2.84
(dd, J = 13.8, 9.6 Hz, 1 H), 2.41 (dd, J = 4.8, 2.7 Hz, 1 H), 2.06 (app
t, J = 2.7, 2.4 Hz, 1 H), 1.7–1.5 (m, 2 H), 1.35–1.20 (m, 3 H), 1.04
(s, 3 H), 0.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.1, 162.8, 157.7, 141.6, 140.7,
134.1, 127.4, 125.6, 116.7, 113.5, 113.1, 81.6, 81.4, 76.9, 71.0,
60.6, 55.4, 52.4, 42.2, 41.9, 34.3, 26.4, 24.0, 23.3.
HRMS (EI): m/z calcd for C13H20O3 [M+]: 224.1412; found:
224.1402.
1-[1,1-Dimethyl-2,4-bis(trimethylsilyloxy)butyl]-4-methoxy-
benzene
To diol 6 (5.04 g, 22.5 mmol) and imidazole (6.13 g, 90.0 mmol) in
CH2Cl2 (110 mL) was added TMSCl (7.33 g, 8.48 mL, 67.5 mmol)
dropwise. The reaction was warmed to r.t. and stirred for 16 h, then
was quenched with H2O (25 mL). The organic layer was isolated,
then washed with 1 M HCl (25 mL), then brine (25 mL). The organ-
ic material was collected, dried (MgSO4), filtered, and concentrated
to yield the title compound as a colourless oil (7.43 g, 90%).
HRMS (ESI): m/z calcd for C26H32O6Na [M + Na+]: 463.2097;
found: 463.2085.
IR (neat): 2958, 1611, 1513, 1250, 1088 cm–1.
Methyl 2-{2-[1-(2-Hydroxyethyl)-2-(4-methoxyphenyl)-2-meth-
ylpropoxy]pent-4-ynyl}-6-methoxybenzoate
1H NMR (300 MHz, CDCl3): d = 7.22 (d, J = 8.7 Hz, 2 H), 6.84 (d,
J = 8.7 Hz, 2 H), 3.80 (m, 4 H), 3.53 (m, 1 H), 3.42 (m, 1 H), 1.53
(m, 1 H), 1.38 (m, 1 H), 1.21 (s, 3 H), 1.19 (s, 3 H), 0.2 (s, 18 H).
13C NMR (75 MHz, CDCl3): d = 157.9, 140.5, 128.0, 113.5, 77.9,
60.7, 55.5, 42.4, 36.1, 26.5, 23.9, 0.9, –0.1.
To phenol 14 (603 mg, 1.37 mmol) and K2CO3 (567 mg, 4.10
mmol) in anhyd acetone (30 mL) was added MeI (389 mg, 171 mL,
2.74 mmol). The reaction was heated to reflux for 14 h. The con-
tents were partitioned between H2O (100 mL) and EtOAc (100 mL),
and the layers were separated. The aqueous layer was extracted with
EtOAc (3 × 20 mL), and the combined organic layers were washed
with brine (50 mL), dried (MgSO4), filtered, and concentrated. The
resulting oil was purified via flash column chromatography
(EtOAc–hexanes, 3:7) to yield the title compound as a colourless oil
(582 mg, 96%).
Methyl 2-Hydroxy-6-{4-[1-(4-methoxyphenyl)-1-methylethyl]-
1,3-dioxan-2-ylmethyl}benzoate (13)
To a soln of aldehyde 5 (25 mg, 129 mmol) and 1-[1,1-dimethyl-2,4-
bis(trimethylsilyloxy)butyl]-4-methoxybenzene (48 mg, 129 mmol)
in CH2Cl2 (2 mL) at –78 °C was added TMSOTf (3 mg, 3 mL, 13
mmol). The reaction was warmed to 0 °C and stirred for 10 min, then
was quenched with pyridine (5 drops). The contents were poured
into sat. aq NaHCO3 (4 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 4 mL). The combined organic layers were washed with
brine (10 mL), dried (MgSO4), filtered, and concentrated. The re-
sulting crude oil was purified via flash column chromatography
(EtOAc–hexanes, 4:6) to yield the title compound as a colourless oil
(49 mg, 95%).
IR (neat): 3538, 3289, 2952, 2837, 1727, 1584, 1513, 1470, 1267,
1073 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25 (app t, J = 8.1, 7.8 Hz, 1 H),
7.19 (d, J = 8.7 Hz, 2 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.80–6.72 (m, 3
H), 3.89 (s, 3 H), 3.81 (s, 3 H), 3.76 (s, 3 H), 3.75–3.50 (m, 4 H),
2.82 (d, J = 6.6 Hz, 2 H), 2.42 (ddd, J = 17.0, 5.4, 2.7 Hz, 1 H), 2.30
(ddd, J = 17.0, 6.9, 2.7 Hz, 1 H), 2.06 (app t, J = 2.7, 2.4 Hz, 1 H),
1.84 (br s, 1 H), 1.60–1.50 (m, 2 H), 1.19 (s, 3 H), 1.15 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.9, 157.9, 156.7, 140.2, 137.0,
130.4, 127.7, 124.5, 123.7, 113.6, 109.5, 82.0, 81.7, 77.9, 71.1,
60.3, 56.2, 55.4, 52.6, 42.7, 38.1, 34.8, 26.4, 24.0, 23.5.
IR (neat): 2956, 2851, 1663, 1610, 1513, 1449, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.06 (s, 1 H), 7.30 (app t, J = 7.8
Hz, 1 H), 7.25 (d, J = 9.0 Hz, 2 H), 6.89 (dd, J = 8.4, 1.2 Hz, 1 H),
6.80 (m, 3 H), 4.61 (dd, J = 5.1, 4.8 Hz, 1 H), 4.04 (dd, J = 11.4, 4.2
Hz, 1 H), 3.89 (s, 3 H), 3.79 (s, 3 H), 3.58 (app td, J = 12.1, 11.4,
2.4 Hz, 1 H), 3.41 (dd, J = 11.4, 1.8 Hz, 1 H), 3.31 (dd, J = 13.5, 5.1
Hz, 1 H), 3.23 (dd, J = 13.5, 4.8 Hz, 1 H), 1.57 (ddd, J = 24.0, 12.0,
5.0 Hz, 1 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 1.07 (d, J = 12.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.0, 162.5, 157.9, 139.0, 134.2,
127.9, 124.5, 116.6, 113.4, 112.9, 102.7, 84.7, 67.2, 55.4, 52.3,
42.2, 40.9, 26.1, 25.6, 23.2.
MS (ESI): m/z (%) = 477 (100) [C27H34O6Na+].
Methyl 2-{2-[1-(2-Acetoxyethyl)-2-(4-methoxyphenyl)-2-meth-
ylpropoxy]pent-4-ynyl}-6-methoxybenzoate (16)
To methyl 2-{2-[1-(2-hydroxyethyl)-2-(4-methoxyphenyl)-2-meth-
ylpropoxy]pent-4-ynyl}-6-methoxybenzoate (48 mg, 106 mmol) in
CH2Cl2 (1 mL) was added DMAP (1.3 mg, 10.6 mmol), then pyri-
dine (17 mg, 17 mL, 211 mmol), and then Ac2O (32 mg, 30 mL, 30
mmol). The reaction was stirred at r.t. for 1 h, then was partitioned
between H2O (20 mL) and CH2Cl2 (20 mL). The organics were
washed with 1 M HCl (20 mL), then brine (20 mL), and then dried
(MgSO4), filtered, and concentrated to yield the title compound as a
colourless oil (50 mg, 95%).
HRMS (ESI): m/z calcd for C23H29O6 [M + H+]: 401.1964; found:
401.1969.
Methyl 2-Hydroxy-6-{2-[1-(2-hydroxyethyl)-2-(4-methoxy-
phenyl)-2-methylpropoxy]pent-4-ynyl}benzoate (14)
To acetal 13 (3.13 g, 7.82 mmol) and allenyltrimethylsilane (24
wt% soln in pentane, 10.97 g, 23 mmol) in CH2Cl2 (30 mL) at –78
°C was added a –78 °C soln of TiCl4 (4.44 g, 23.4 mmol) in CH2Cl2
(20 mL) via cannula. The reaction had consumed all starting mate-
rial within 10 min and was quenched with pyridine (10 mL), fol-
lowed by MeOH (10 mL). The quenched mixture was warmed to r.t.
and the contents were poured into 1 M HCl (50 mL). The layers
were separated, the aqueous layer was extracted with CH2Cl2 (3 ×
30 mL), and the combined organic layers were washed with brine
(50 mL), dried (MgSO4), filtered, and concentrated. The resulting
IR (neat): 3286, 2953, 2838, 1734, 1584, 1513, 1471, 1250, 1074
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29 (app t, J = 9.0, 7.8 Hz, 1 H),
7.19 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 7.8 Hz, 1 H), 6.85–6.75 (m, 3
H), 4.10–3.95 (m, 2 H), 3.90 (s, 3 H), 3.82 (s, 3 H), 3.78 (s, 3 H),
3.70 (m, 1 H), 3.59 (dd, J = 7.8, 3.3 Hz, 1 H), 2.86 (d, J = 6.9 Hz, 2
H), 2.38 (ddd, J = 16.8, 5.4, 2.7 Hz, 1 H), 2.28 (m, 1 H), 2.06 (app
t, J = 2.7, 2.1 Hz, 1 H), 1.99 (s, 3 H), 1.7–1.5 (m, 2 H), 1.19 (s, 3 H),
1.14 (s, 3 H).
Synthesis 2007, No. 15, 2291–2296 © Thieme Stuttgart · New York

2296
A. J. Poniatowski, P. E. Floreancig
PAPER
13C NMR (75 MHz, CDCl3): d = 171.1, 168.8, 158.0, 156.8, 139.8,
137.0, 130.4, 128.0, 127.7, 124.6, 123.8, 113.6, 109.5, 81.6, 81.3,
78.2, 71.2, 62.5, 56.2, 55.4, 52.5, 42.8, 38.2, 31.5, 26.7, 23.6, 21.3.
HRMS (ESI): m/z calcd for C29H36O7Na [M + Na+]: 519.2359;
found: 519.2335.
References
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Methyl 2-{4-Acetoxy-2-[1-(2-acetoxyethyl)-2-(4-methoxyphe-
nyl)-2-methylpropoxy]pent-4-enyl}-6-methoxybenzoate (17)
A soln of n-decyne (114 mg, 148 mL, 821 mmol), Na2CO3 (13 mg,
123 mmol), dichloro(p-cymene)ruthenium(II) dimer (20 mg, 33
mmol), tri-2-furylphosphine (15 mg, 66 mmol), and AcOH (99 mg,
94 mL, 1.64 mmol) in toluene (10 mL) was heated to 80 °C for 45
min. Alkyne 16 (408 mg, 821 mmol) in toluene (10 mL) was added
in 10 portions. A further 2 equiv of AcOH (99 mg, 94 mL, 1.64
mmol) were added and the reaction was stirred at 80 °C for 14 h.
The solvent was evaporated and the crude solid was purified via
flash column chromatography (EtOAc–hexanes, 3:7) to yield the ti-
tle compound as a colourless oil (358 mg, 78%).
IR (neat): 2959, 2838, 1740, 1735, 1513, 1250, 1074 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29 (app t, J = 8.1 Hz, 1 H), 7.12
(d, J = 9.0 Hz, 2 H), 6.83 (d, J = 7.8 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1
H), 6.77 (d, J = 8.7 Hz, 2 H), 4.79 (d, J = 1.2 Hz, 1 H), 4.73 (d, J =
1.2 Hz, 1 H), 4.0–3.9 (m, 2 H), 3.89 (s, 3 H), 3.83 (s, 3 H), 3.79 (s,
3 H), 3.65–3.50 (m, 2 H), 2.75 (dd, J = 13.8, 7.2 Hz, 1 H), 2.59 (m,
2 H), 2.19 (d, J = 6.6 Hz, 1 H), 2.13 (s, 3 H), 2.02 (s, 3 H), 1.70–1.50
(m, 2 H), 1.15 (s, 3 H), 1.11 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.3, 169.2, 168.8, 157.9, 156.8,
153.6, 140.0, 137.4, 130.3, 127.7, 124.6, 123.8, 113.8, 109.4, 104.1,
80.4, 76.6, 62.6, 56.3, 55.4, 52.4, 42.5, 38.9, 38.7, 31.4, 26.5, 23.9,
21.4, 21.3.
HRMS (ESI): m/z calcd for C31H40O9Na [M + Na+]: 579.2570;
found: 579.2521.
Methyl 2-{[6-(2-Acetoxyethyl)-4-oxotetrahydro-2H-pyran-2-
yl]methyl}-6-methoxybenzoate (18)
To a soln of enol acetate 17 (33 mg, 59 mmol), NaHCO3 (66 mg),
and powdered 4-Å molecular sieves (66 mg) in DCE (4 mL) at 40
°C was added a soln of CAN (130 mg, 237 mmol) in MeCN (1 mL)
in one portion. The reaction turned a murky green color and was
stirred for 10 min at 40 °C. The contents were filtered through a plug
of silica gel (EtOAc), concentrated, and purified via flash column
chromatography (EtOAc–hexanes, 4:6) to yield the title compound
as a colourless oil (16 mg, 73%).
(16) Wiley, R. H.; Jarboe, C. H. J. Am. Chem. Soc. 1956, 78,
2398.
(17) Node, M.; Fujiwara, T.; Ichihashi, S.; Nishide, K.
Tetrahedron Lett. 1998, 39, 6331.
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(20) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
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3899.
IR (neat): 2954, 1732, 1585, 1471, 1267, 1073 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30 (m, 1 H), 6.88 (d, J = 7.8 Hz,
1 H), 6.83 (d, J = 8.4 Hz, 1 H), 4.2–4.1 (m, 2 H), 3.94 (m, 1 H), 3.91
(s, 3 H), 3.83 (s, 3 H), 3.79 (m, 1 H), 3.67 (m, 1 H), 2.97 (dd, J =
13.8, 7.2 Hz, 1 H), 2.75 (dd, J = 14.1, 5.1 Hz, 1 H), 2.4–2.2 (m, 4
H), 2.02 (s, 3 H), 2.0–1.8 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 206.8, 171.3, 168.9, 156.9, 136.2,
130.7, 123.1, 109.8, 77.6, 74.0, 61.1, 56.3, 52.6, 47.9, 47.7, 40.1,
35.5, 21.3.
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68, 7143. (b) Aubele, D. L.; Wan, S.; Floreancig, P. E.
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Soc. 1983, 105, 2088. (b) Denmark, S. E.; Willson, T. M.;
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Org. Chem. 1991, 56, 6458. (e) Denmark, S. E.; Almstead,
N. G. J. Org. Chem. 1991, 56, 6485. (f) Sammakia, T.;
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HRMS (ESI): m/z calcd for C19H24O7Na [M + Na+]: 387.1420;
found: 387.1432.
Acknowledgment
We thank the National Institutes of Health (GM62924) for generous
support of this work.
(26) For another illustrative example, see: Duan, S.; Moeller, K.
D. J. Am. Chem. Soc. 2002, 124, 9368.
Synthesis 2007, No. 15, 2291–2296 © Thieme Stuttgart · New York