Synthesis of a 1,3-Bridged Macrobicyclic Enyne via Chemoselective Cycloisomerization Using Palladium-Catalyzed Alkyne-Alkyne Coupling

Article abstract of DOI:10.1021/acs.joc.6b01920

A unique intramolecular Pd-catalyzed alkyne-alkyne coupling is presented. This transformation generates a strained, 1,3-bridged, macrocyclic enyne. The process was readily executed on gram scale, and the structure of the product was elucidated via X-ray c

Full text of DOI:10.1021/acs.joc.6b01920

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Note
Synthesis of a 1,3-Bridged Macrobicyclic Enyne via Chemoselective
Cycloisomerization Using Palladium-catalyzed Alkyne-Alkyne Coupling
Barry M. Trost, James T Masters, Franck Le Vaillant, and Jean-Philip Lumb
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01920 • Publication Date (Web): 20 Sep 2016
Downloaded from http://pubs.acs.org on September 21, 2016
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Synthesis of a 1,3-Bridged Macrobicyclic Enyne via Chemoselective Cycloisomerization
Using Palladium-catalyzed Alkyne-Alkyne Coupling
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8
9
Barry M. Trost*, James T. Masters, Franck Le Vaillant, and Jean-Philip Lumb
Department of Chemistry, Stanford University, Stanford, CA 94305-4401.
E-mail: bmtrost@stanford.edu
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Table of Contents Graphic
H
Pd-catalyzed
Intramolecular
Alkyne-Alkyne Coupling
O
O
OAc
H
OAc
O
O
Abstract
A unique intramolecular Pd-catalyzed alkyne-alkyne coupling is presented. This
transformation generates a strained, 1,3-bridged, macrocyclic enyne. The process was readily
executed on gram-scale, and the structure of the product was elucidated via X-ray
crystallographic analysis. A mechanistic rationale for the observed chemoselectivity is provided.
Conjugated enynes constitute an important class of unsaturated compounds. 1,3-Enynes
and their derivatives have proven to be useful intermediates in the synthesis of various small
molecules,1,2 including those possessing biological activity.3 Of particular significance are
conjugated enynes that bear an element of π-unsaturation constrained within a cyclic system, as
this structural motif occurs in both natural products and natural product precursors.4 A notable
example is tricholomenyn B (Scheme 1), a macrocyclic enyne that possesses potent anti-mitotic
activity.5
Transition metal catalysis is a powerful method for the synthesis of functionalized
molecules, especially those bearing π-unsaturation. Transition metal-catalyzed sp-sp2 coupling,
in particular, has become an effective means of preparing enynes.6 Nevertheless, in the specific
context of the synthesis of enynes that contain an acetylene unit within a ring system, such
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couplings are not without limitations. In several reported cases, these reactions proceeded with
modest yields and/or required the use of stoichiometric quantities of transition metals.7,8,9,10 The
reduced effectiveness of these processes may have been a consequence of the strain associated
with the bridging of non-adjacent carbon atoms in macrocyclic structures: this strain would
necessarily develop in the transition states leading to the products, and it could potentially hinder
the efficacy of the coupling.
Relative to metal-catalyzed sp-sp2 coupling, the transition metal-catalyzed coupling of
alkynes is a distinctly different approach to the synthesis of enynes. These processes have proven
highly effective in various synthetic endeavors,11 and such catalytic addition reactions embody
the ideals of atom12 and step13 economy. Since the early 1980’s, our research group has
maintained an interest in the palladium-catalyzed coupling of alkynes as a means to generate
enynes, and we have investigated this transformation in both in its inter- and intramolecular
variants.14 In an example of the latter application, it was discovered that the combination of
palladium acetate and the electron-rich, sterically-encumbered ligand tris(2,6-
dimethoxyphenyl)phosphine (TDMPP, 1) catalyzed the intramolecular alkyne-alkyne coupling
of symmetrical diyne 2 to 14-membered macrocycle 3 (Scheme 1A).15
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Analogous reactions of unsymmetrical alkynes present an important question of
chemoselectivity, as one alkyne group must act as a donor in the coupling event and the other as
the acceptor. To this end, the observation that the unsymmetrical, propargyl alcohol-derived
diyne 4 was converted to exclusively macrocycle 5 (Scheme 1B) suggested that electronic
factors could engender chemoselectivity. In this case, it was postulated that the presence of the
oxygen substituent on the propargyl alcohol unit served to lower the energy of LUMO of the
corresponding alkyne group, thereby facilitating acetylide addition across this C−C triple bond.16
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Scheme 1: Palladium/TDMPP-catalyzed Intramolecular Alkyne-Alkyne Couplings to Generate
Macrocyclic Enynes.
(A) Symmetrical Diyne
H
6
7
8
9
H
Pd(OAc)2 (10 mol %)
TDMPP (1, 20 mol %)
PhH, reflux
(41%)
2
3
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(B) Unsymmetrical Diyne - Propargylic Alcohol Acceptor
H
H
Pd(OAc)2 (10 mol %)
TDMPP (20 mol %)
OH
OH
PhH, reflux
(46%)
4
5
(C) Unsymmetrical Diyne - Propiolate Acceptor
CO2Me
CO2Me
H
Pd(OAc)2 (5 mol %)
TDMPP (10 mol %)
O
6
O
6
PhH, reflux
(70%)
O
O
()
()
8
()
()
8
6
7
(D) Unsymmetrical Diyne - Unactivated Acceptor (This Work)
H
O
O
Pd(OAc)2 (5 mol %)
TDMPP (10 mol %)
OAc
H
OAc
O
O
PhMe, 50 °C
8
9
vs.
Me
O
O
O
OAc
O
O
HO
OAc
10
tricholomenyn B
(anti-mitotic)
Intramolecular couplings between terminal and internal alkynes have also been
examined. In these studies, the ability of an electron-withdrawing substituent to activate an
alkyne group as the acceptor was identified. Representative of this behavior was the reaction of
compound 6: in the event, the propiolate moiety of this diyne served as the acceptor alkyne, and
macrocycle 7 was obtained as the exclusive product (Scheme 1C). The utility of this process in
complex molecule synthesis was demonstrated in the synthesis of bryostatin 16.17
These examples illustrate the utility of the palladium-catalyzed alkyne-alkyne coupling in
the synthesis of enynes that contain an element of π-unsaturation constrained within a ring
system. They also demonstrate the ability of certain functional groups, such as propargylic
alcohols or propiolates, to direct the chemoselectivity of these intramolecular coupling processes.
Nevertheless, the application of this unique method of enyne synthesis to the synthesis of more
significantly strained systems—such as those that bind non-adjacent carbons in a macrocyclic
framework—has not been explored. Herein, we report an intramolecular alkyne coupling
reaction that explores this important chemoselectivity issue in an unusual metacyclophane
synthesis, a 1,3-bridged enyne, via a cross coupling between two different terminal alkynes of a
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cyclohexene-derived diyne substrate (8→9 or 10, Scheme 1D). Remarkably, the process occurs
with complete chemoselectivity, as none of isomeric compound 10 is detected. The execution of
the transformation on gram-scale is demonstrated. Additionally, the structure of the product is
unequivocally established through X-ray crystallographic analysis.
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The synthesis of the cyclohexenyl core of the diyne substrate began with the nucleophilic
epoxidation of commercially available 2-cyclohexen-1-one (11, Scheme 2). By the action of
aqueous hydrogen peroxide and a catalytic amount of aqueous sodium hydroxide, compound 11
was converted to known epoxy ketone 1218 in good yield (74%). After deprotonation with LDA,
triflation with Comin’s reagent (N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide, 13)
provided vinyl triflate 14 in 75% yield. N-Phenylbis(trifluoromethanesulfonimide) was
successfully used in place of Comin’s reagent to obtain the same product, although the reaction
yield was reduced (52%).
A regio- and stereoselective epoxide opening occurred upon dissolution of compound 14
in acetic acid in the presence of a catalytic amount of trifluoroacetic acid (13 mol %). trans-
Alcohol 15 was thus isolated cleanly and in good yield (68%). In the absence of the
trifluoroacetic acid catalyst, this solvolysis occurred at a reduced rate: 15 was obtained in 50%
yield after five days at room temperature (71% yield based on recovered 14). The Sonogashira
coupling between triflate 15 and trimethylsilyl acetylene (16) occurred in high yield (89%) to
deliver enyne 17. Esterification of the latter with 8-nonynoic acid (18) under Steglich conditions
(N,N’-dicyclohexylcarbodiimide, catalytic 4-dimethylaminopyridine) furnished ester 19 in 87%
yield, and alkyne desilylation using TBAF in THF provided the key diyne substrate 8 in 75%
yield.
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Scheme 2: Synthesis of Macrocyclization Precursor 8.
H2O2 (30% aq., 3 equiv)
O
O
LDA (1.1 equiv)
O
O
OTf
CF3CO2H (13 mol %)
NaOH (20% aq., 0.75 mol %)
THF, − 78 °C, 30 min
6
7
8
MeOH, 0 °C, 15 min
(74%)
then Comin's reagent
(13, 1.2 equiv)
THF, − 78 °C, 2 h
(75%)
AcOH, 23 °C, 48 h
(68%)
11
12
14
Without CF3CO2H:
50% yield (71% brsm)
after 5 days
With PhNTf2 : 52% yield
9
O
H
10
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OAc
TMS
OAc
TMS
HO
H
6
HO
OTf
HO
(16, 3 equiv)
(18, 1.05 equiv)
PdCl2(PPh3)2 (2.5 mol %)
CuI (5 mol %)
i-Pr2NEt (10 equiv)
THF, 0 °C to 23 °C , 17 h
(89%)
DCC (1.4 equiv)
DMAP (10 mol %)
CH2Cl2, 0 °C to 23 °C , 15 h
(87%)
15
17
H
H
Cl
O
O
OAc
TMS
OAc
H
N
TBAF (1.3 equiv)
O
O
N
THF, 0 °C, 45 min
(75%)
F3CO2S
SO2CF3
13
19
8
With diyne 8 in hand, our attention turned to the palladium-catalyzed macrocyclization
event. Performing the slow addition of a toluene solution of this compound to a mixture of
Pd(OAc)2 (5 mol %) and TDMPP (10 mol %) at room temperature afforded macrocyclic enyne 9
as the sole identifiable product after filtration of the reaction mixture through Florisil®.
Compound 9 was obtained in 47% isolated yield after chromatography on silica gel (Table 1,
entry 1). This result served as the starting point for further optimization. The use of a 2:1 ratio of
TDMPP relative to Pd(OAc)2 proved ideal: inverting the ratio (1:2 TDMPP:Pd(OAc)2) led to a
decrease in both conversion and yield (entry 2), as did the use of an equimolar ratio of these
species (entry 3).19 When the reaction was performed with the 2:1 TDMPP:Pd(OAc)2 system and
the temperature was increased from 23 °C to 50 °C, complete conversion was achieved in 13 h,
and 9 was isolated in 50% yield (entry 4).20
Table 1: Influence of Palladium to Phosphine Ratio and Reaction Temperature on the
Intramolecular Alkyne-Alkyne Coupling of 8.a
H
O
O
Pd(OAc)2 (x mol %)
TDMPP (y mol %)
OAc
H
OAc
O
O
slow addition of 8
PhMe, temperature, additive
8
9
Entry
1
Temperature
23 °C
x (mol %)
y (mol %)
Additive
--
Conversion (%)b
82
Yield (%)c
47
5
10
2
3
4
23 °C
23 °C
50 °C
10
5
5
5
--
--
--
63
80
35
34
50
5
10
> 95
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50 °C
50 °C
50 °C
50 °C
5
5
5
5
10
10
10
10
AcOH (1 equiv)
NaOAc (1.6 equiv)
Et3N (1 equiv)
< 5
N/A
52
> 95
> 95
> 95
7
8 d
53
Et3N (1 equiv)
60
a Reaction conditions: Except where otherwise indicated, a solution of 8 in PhMe (0.10 M) was added via syringe
pump to a solution of Pd(OAc)2 and TDMPP in PhMe (0.005 M in Pd(OAc)2) over the course of 4-6 h, and then the
mixture was stirred for a total of 13 h. b Determined by 1H NMR analysis of the crude reaction mixture. c Isolated
yield after chromatography. d Following the slow addition of 8, the reaction mixture was stirred for an additional 30
min (4 h 30 min total reaction time).
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The effects of reaction additives and of reaction duration were next examined. The
addition of 1 equivalent of acetic acid completely inhibited the reaction (entry 5), but a slight
improvement in yield was observed upon the introduction of base. Both sodium acetate (entry 6)
and triethylamine (entry 7) served well in this capacity. Given our goal of a readily scalable
process, we selected triethylamine as the basic additive due to its homogeneity in toluene. We
were pleased to find that, when the slow addition was performed over the standard 4 h at 50 °C
in the presence of triethylamine, complete consumption of 8 was observed after a total reaction
time of only 4 h 30 min (entry 8). From this reaction, product 9 was isolated in 60% yield.
Encouraged by this operationally convenient and expedient synthesis of macrocycle 9, we
pursued its preparation on larger scale. Thus, the reaction conditions of Table 1, entry 8 were
applied to a gram-scale (3.16 mmol) cyclization of 8 without further modification. In this event,
the intramolecular coupling proceeded smoothly to deliver macrocycle 9 as the only product
isomer and in 47% isolated yield.
From this larger-scale reaction, 9 was obtained as an amorphous solid. Its careful
crystallization from diethyl ether afforded material suitable for X-ray crystallographic analysis
(colorless, block-like crystals). This mode of analysis was employed in order to ascertain both
the relative stereochemistry of the product and the sense of chemoselectivity with which the
alkyne-alkyne coupling had proceeded. Indeed, X-ray analysis confirmed the following: (a) that
the solvolytic epoxide opening with acetic acid (14→15) had yielded the trans-product, (b) that
acetate addition occurred at the allylic position, and (c) that a chemoselective alkyne coupling
had occurred wherein the pendant terminal alkyne acted as the donor and the cyclohexenyl
alkyne acted as the acceptor (Figure 1).
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Figure 1: X-ray-Derived ORTEP Representation (50% Probability Level) of Enyne 9
A plausible mechanistic pathway for the synthesis of macrocycle 9 is illustrated in
Scheme 3. The process may commence with the formation of a palladium acetylide. To this end,
coordination of phosphine-ligated palladium to the donor alkyne and carboxylate-assisted
deprotonation would generate complex 20, with the concomitant formation of acetic acid (step
a).14 It is possible that the poor reactivity observed upon introduction of acetic acid was due to
inhibition of this stage, whereas the benefit observed upon introduction of base was due to its
acceleration. The palladium atom of complex 20 may then coordinate to the acceptor alkyne
(step b), leading to complex 21. Upon syn-carbopalladation (step c), vinylpalladium compound
22 would result. Protonolysis of the C−Pd bond by acetic acid or triethylammonium acetate (step
d) would regenerate the palladium catalyst and would release product 9.
Scheme 3: Proposed Mechanism for the Intramolecular Alkyne-Alkyne Coupling.
L
H
Pd
OAc
(a) Pd Acetylide
Formation
O
O
(b) Coordination
OAc
H
OAc
H
- HOAc
O
O
8
20
(L = TDMPP)
AcO Pd
OAc
L
(c) Carbopalladation
O
O
O
(d) Protonation
+ HOAc
H
OAc
OAc
L
O
O
Pd
O
OAc
21
22
9
The sense of chemoselectivity in this macrocyclization is remarkable and deserving of
comment. As described in prior reports,16 terminal enynes typically react preferentially as donor
alkynes when they are engaged in cross coupling reactions with other terminal alkynes. This has
been attributed to the greater acidity of enynes relative to simple acetylenes. The fact that the
enynyl moiety of compound 8 acted as the acceptor suggests that, in the present case, the
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chemoselectivity is not purely a function of alkyne acidity. Instead, the selectivity may have been
the result of subtle steric interactions. The alkyne bonded to the cyclohexene core is obstructed
by the steric bulk of the cyclohexene ring and its two carboxylate substituents, whereas the
alkyne situated on the aliphatic chain is, comparatively, more accessible. Thus, coordination of
the palladium catalyst to the latter alkyne and subsequent formation of an active palladium
acetylide may have occurred preferentially at this position, facilitating the coupling process
depicted in Scheme 3.
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Alternatively, it may have been the case that the presence of the two carboxylate
substituents was sufficient to electronically activate the enynyl alkyne as the acceptor, in the
same manner that has been observed with propargylic alcohols (i.e., by lowering the energy of
the alkyne LUMO). Indeed, both the described steric bias and this potential electronic
preference may have acted in concert to promote the selective coupling observed herein.
Additional explanations can also be envisioned, including the possibility of a Curtin-Hammett
scenario wherein palladium acetylide formation from either terminal alkyne is fast and reversible
but wherein intermediate 20 undergoes carbopalladation at a faster rate. Nevertheless, it appears
that, in the subject macrocyclization process, subtle steric and/or electronic factors beyond
simple alkyne acidity acted to influence the chemoselectivity of the coupling.
Conclusions
We report a chemoselective intramolecular alkyne-alkyne coupling that generates a
structurally unique, strained, 1,3-bridged macrocyclic enyne. Careful evaluation of the influence
of catalyst loading, reaction additives, temperature, and duration led to optimized conditions that
were highly effective on both milligram and gram scales. In all cases, only a single product
isomer was observed. The structure of this product was determined unambiguously via X-ray
crystallographic analysis. In contrast to prior examples of cross couplings between terminal
enynes and other terminal alkynes, the enyne of substrate 8 acted selectively as the acceptor in
the present case. The excellent atom economy, operational simplicity, and robustness of the
procedure compare favorably with other known methods for the synthesis of macrocycles that
contain alkyne functional groups within their ring systems.
Experimental Section
General Considerations: Unless otherwise indicated, all reactions were performed in
oven- or flame-dried glassware with magnetic stirring under a nitrogen or argon atmosphere. Air
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and moisture-sensitive liquids and solutions were transferred via oven-dried, stainless steel
syringe or cannula and were introduced into the reaction vessel through rubber septa. Anhydrous
CH2Cl2 and THF were obtained from a solvent purification system. PhMe was distilled over
CaH2.
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Analytical thin-layer chromatography was performed on pre-coated 250 µm layer
thickness silica gel 60 F254 plates. Visualization was performed by ultraviolet light fluorescence
quenching and/or by staining with potassium permanganate, ceric ammonium molybdate, or
para-anisaldehyde solutions followed by heating. Unless otherwise indicated, flash column
chromatography was performed using 40-63 µm silica gel using compressed air. The eluent
employed for flash chromatography is reported as volume/volume ratios. Proton nuclear
magnetic resonance (1H NMR) spectra were acquired using 300 MHz, 400 MHz, 500 MHz, or
600 MHz spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and are
calibrated to the residual solvent peak: proton (CHCl3, 7.26 ppm). Coupling constants (J) are
reported in Hz. Multiplicities are reported using the following abbreviations: s = singlet; d =
doublet; t = triplet; q = quartet; m = multiplet (range of multiplet is given). Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded using 75 MHz, 100 MHz, 125 MHz, or
150 MHz spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and are
calibrated to the residual solvent peak: carbon (CHCl3, 77.16 ppm).
Infrared spectroscopic data were recorded using thin films of the sample on NaCl plates.
The absorbance frequencies are recorded in wavenumbers (cm-1). Melting points are uncorrected.
HRMS data were obtained using time-of-flight electrospray ionization (ESI-TOF).
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7-Oxabicyclo[4.1.0]heptan-2-one (12): A flame-dried 500 mL round-bottom flask equipped with
a stir bar was charged with 2-cyclohexen-1-one (11, 9.60 g, 100 mmol, 1 equivalent) and
methanol (100 mL). The vessel was cooled to 0 °C, and to the homogeneous solution was added
hydrogen peroxide (30% aqueous solution, 30 mL, 300 mmol, 3 equivalents). To the reaction
mixture was added aqueous sodium hydroxide (20% aqueous solution, 0.15 mL, 0.75 mmol, 0.75
mol %). The reaction mixture was stirred for 15 min, at which point it was poured into a
separatory funnel containing ice (150 g) and brine (200 mL). The resulting suspension was
extracted with CH2Cl2 (3 x 150 mL), and the pooled organic phases were dried over MgSO4,
filtered, and concentrated. Distillation of the resulting residue under reduced pressure (11
mmHg) afforded the title compound (8.3 g, 74%, b.p. range 60-75 °C) as a clear oil (ca. 85%
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purity as judged by H NMR, with traces of residual 2-cyclohexen-1-one remaining but suitable
for use in the next step). 1H NMR (500 MHz; CDCl3): δ 3.58 (m, 1H), 3.22 (d, J = 3.9 Hz, 1H),
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MHz; CDCl3): δ 206.0, 55.9, 55.1, 36.3, 22.8, 17.0. These H and 13C NMR data were in
agreement with previously reported data.18
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7-Oxabicyclo[4.1.0]hept-2-en-2-yl trifluoromethanesulfonate (14): To a solution of freshly
distilled diisopropylamine (0.83 mL, 5.82 mmol, 1.1 equivalents) in THF (5.82 mL) at – 78 °C
was added n-BuLi (2.5 M in hexanes, 2.32 mL, 5.82 mmol, 1.1 equivalents). After 15 min, the
cooling bath was replaced with a 0 °C bath, and the solution was stirred for 30 min. The vessel
was again cooled to – 78 °C, and a solution of 7-oxabicyclo[4.1.0]heptan-2-one (12, 0.66 g, 5.3
mmol) in THF (1.5 mL) was added via cannula. After 30 min, a solution of Comin’s reagent (13,
N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide, 2.57 g, 6.35 mmol, 1.2 equivalents) was
added as a solution in THF (6 mL + 2 mL rinse), yielding a homogeneous and dark red solution.
After 2 h, the reaction mixture was poured into a separatory funnel containing water (25 mL) and
ice (50 g). The mixture was extracted with Et2O (3 x 75 mL), and the pooled organic phases were
washed with 10% aqueous KOH (20 mL) then brine (2 x 50 mL), dried over K2CO3, filtered, and
concentrated. Purification by column chromatography (10:1 hexanes:Et2O) afforded the title
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compound (969 mg, 75%) as an oil. Rf = 0.34 (10:1 hexanes:EtOAc). H NMR (400 MHz;
CDCl3): δ 5.91-5.88 (m, 1H), 3.67 (td, J = 2.7, 1.3 Hz, 1H), 3.41 (dd, J = 4.3, 2.8 Hz, 1H), 2.30
(ddq, J = 13.6, 5.1, 2.6 Hz, 1H), 2.19-2.14 (m, 2H), 1.72-1.64 (m, 1H). 13C NMR (100 MHz;
CDCl3): δ 145.0, 120.7, 118.8 (q, J = 319 Hz), 56.0, 48.7, 20.3, 19.0. IR (film): 2906, 1693,
1649, 1403, 1194, 1125, 1071, 1030, 946, 880, 811, 778 cm-1. HRMS: Calculated for
C7H8F3O4S (M+H)+: 245.0090; found 245.0093.
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trans-6-Hydroxy-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-en-1-yl acetate (15): To
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solution of 7-oxabicyclo[4.1.0]hept-2-en-2-yl trifluoromethanesulfonate (14, 1.0 g, 4.1 mmol, 1
equivalent) in acetic acid (3.0 mL) was added trifluoroacetic acid (40 µL, 0.30 mmol, 6.5 mol
%). The reaction mixture was stirred for 24 h at room temperature, after which time additional
trifluoroacetic acid (40 µL, 0.30 mmol, 6.5 mol %) was added. After an additional 24 h, the
reaction mixture was diluted with Et2O (15 mL) and poured into saturated aqueous Na2CO3 (60
mL). The phases were separated, and the aqueous phase was extracted with Et2O (3 x 70 mL).
The pooled organic phases were dried over MgSO4, filtered, and concentrated. Purification by
column chromatography (2:1 hexanes:EtOAc) afforded the title compound (842 mg, 68%) as a
yellow oil. Rf = 0.20 (2:1 hexanes:EtOAc). 1H NMR (400 MHz; CDCl3): δ 6.10 (t, J = 4.0 Hz,
1H), 5.32-5.30 (m, 1H), 4.06-4.03 (m, 1H), 2.48-2.39 (m, 1H), 2.34-2.26 (m, 1H), 2.15 (s, 3H),
1.93-1.79 (m, 2H). 13C NMR (100 MHz; CDCl3): δ 171.2, 143.2, 124.4, 118.5 (q, J = 319 Hz),
71.6, 69.1, 25.0, 20.9, 20.3. IR (film): 3400 (br), 2899, 1724, 1399, 1353, 1200, 1126, 879, 815
cm-1. HRMS: Calculated for C9H11F3NaO6S (M+Na)+: 327.0121; found 327.0122.
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trans-6-Hydroxy-2-((trimethylsilyl)ethynyl)cyclohex-2-en-1-yl acetate (17): To a solution of
trans-6-hydroxy-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-2-en-1-yl acetate (15, 5.6 g, 18.4
mmol, 1 equivalent) in THF (75 mL) was added PdCl2(PPh3)2 (322 mg, 0.46 mmol, 2.5 mol %)
and CuI (175 mg, 0.92 mmol, 5 mol %). Freshly distilled diisopropylethylamine (32 mL, 184
mmol, 10 equiv) was added, the heterogeneous mixture was cooled to 0 °C, and trimethylsilyl
acetylene (7.8 mL, 55.2 mmol, 3 equivalents) was added. The resulting heterogeneous, black
mixture was allowed to warm to room temperature and stir for 17 h, at which point it was diluted
with Et2O (50 mL) and vacuum filtered through a pad of Celite®. The pad was washed with
additional Et2O (200 mL). The filtrate was washed with saturated aqueous NH4Cl (3 x 200 mL)
then brine (200 mL), and then it was dried over MgSO4, filtered, and concentrated. Purification
by column chromatography (4:1 to 2:1 hexanes:EtOAc) afforded the title compound (4.13 g,
89%) as a viscous oil. Rf = 0.34 (1:1 hexanes:EtOAc). 1H NMR (400 MHz; CDCl3): δ 6.31-6.28
(m, 1H), 5.31 (ddt, J = 6.6, 2.7, 1.8 Hz, 1H), 3.83 (ddd, J = 10.3, 6.7, 3.6 Hz, 1H), 2.61 (br s,
1H), 2.33-2.16 (m, 2H), 2.14 (s, 3H), 1.98-1.91 (m, 1H), 1.72 (dddd, J = 13.2, 10.4, 8.9, 6.2 Hz,
1H), 0.15 (s, 9H). 13C NMR (100 MHz; CDCl3): δ 171.6, 139.2, 119.4, 102.5, 94.0, 74.9, 69.7,
27.6, 24.0, 21.2, - 0.03. IR (film): 3394 (br), 2990, 2916, 2859, 2119, 1719, 1411, 1351, 1232,
1161, 1067, 1033, 928, 898, 833, 793, 750, 688, 607 cm-1. HRMS: Calculated for C13H20NaO3Si
(M+Na)+: 275.1074; found 275.1076.
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trans-2-Acetoxy-3-((trimethylsilyl)ethynyl)cyclohex-3-en-1-yl non-8-ynoate (19): A flame-dried
50 mL flask equipped with a stir bar was charged with non-8-ynoic acid (18, 1.62 g, 10.5 mmol,
1.05 equivalents). A solution of trans-6-hydroxy-2-((trimethylsilyl)ethynyl)cyclohex-2-en-1-yl
acetate (17, 2.52 g, 10 mmol, 1 equivalent) in CH2Cl2 (15 mL) was introduced via syringe. The
homogeneous solution was cooled to 0 °C, and then DMAP (4-dimethylaminopyridine, 122 mg,
1.0 mmol, 10 mol %) was added followed by DCC (N,N’-dicyclohexylcarbodiimide, 2.89 g, 14
mmol, 1.4 equivalents). After 5 min, the cooling bath was removed, and the light yellow,
heterogeneous mixture was stirred at room temperature for 15 h. The mixture was then diluted
with 1:1 hexanes:Et2O (20 mL) and vacuum filtered through a pad of Celite®. The pad was
washed with additional Et2O, and the filtrate was concentrated. Purification by column
chromatography (8:1 hexanes:EtOAc) delivered the title compound (3.36 g, 87%) as an oil. Rf =
0.34 (2:1 hexanes:EtOAc). 1H NMR (500 MHz; CDCl3): δ 6.30 (t, J = 4.0 Hz, 1H), 5.49 (dd, J =
6.3, 1.5 Hz, 1H), 4.97 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 2.29-2.24 (m, 4H), 2.18-2.14 (m, 2H), 2.07
(s, 3H), 1.94-1.89 (m, 2H), 1.81-1.75 (m, 1H), 1.59 (quintet, J = 7.5 Hz, 2H), 1.50 (quintet, J =
7.3 Hz, 2H), 1.42-1.36 (m, 2H), 1.32-1.28 (m, 2H), 0.14 (s, 9H). 13C NMR (125 MHz; CDCl3): δ
173.0, 170.0, 138.7, 119.5, 102.3, 94.3, 84.6, 70.6, 70.1, 68.4, 34.4, 28.6, 28.4, 28.3, 24.9, 24.6,
23.4, 21.0, 18.4, − 0.10. IR (film): 3246, 2896, 2120, 1716, 1412, 1351, 1211, 1032, 904, 833,
750 cm-1. HRMS: Calculated for C22H32NaO4Si (M+Na)+: 411.1962; found 411.1956.
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trans-2-Acetoxy-3-ethynylcyclohex-3-en-1-yl non-8-ynoate (8): To a light yellow, homogeneous
solution of trans-2-acetoxy-3-((trimethylsilyl)ethynyl)cyclohex-3-en-1-yl non-8-ynoate (19, 3.04
g, 7.82 mmol, 1 equivalent) in THF (40 mL) at 0 °C was added TBAF (tetrabutylammonium
fluoride, 0.25 M in THF, 40 mL, 10 mmol, 1.3 equiv). The resulting homogeneous, red-yellow
mixture was stirred for 45 min at 0 °C, after which time it was diluted with Et2O and poured into
water (150 mL). The phases were separated, and the aqueous phase was extracted with Et2O (2 x
150 mL). The pooled organic phases were washed with brine (150 mL), dried over MgSO4,
filtered, and concentrated. Purification by column chromatography (4:1 hexanes:EtOAc)
delivered the title compound (1.86 g, 75%) as a light yellow oil. Rf = 0.29 (4:1 hexanes:EtOAc).
1H NMR (500 MHz; CDCl3): δ 6.39 (td, J = 4.0, 1.1 Hz, 1H), 5.48 (dq, J = 5.9, 1.8 Hz, 1H),
4.99 (ddd, J = 9.0, 5.9, 3.2 Hz, 1H), 2.80 (s, 1H), 2.30-2.25 (m, 4H), 2.17 (td, J = 7.0, 2.7 Hz,
2H), 2.09 (s, 3H), 1.96-1.91 (m, 2H), 1.86-1.80 (m, 1H), 1.63-1.57 (m, 2H), 1.54-1.48 (m, 2H),
1.44-1.38 (m, 2H), 1.34-1.29 (m, 2H). 13C NMR (125 MHz; CDCl3): δ 173.0, 170.2, 140.0,
118.4, 84.6, 81.3, 77.0, 70.3, 69.8, 68.4, 34.4, 28.6, 28.4, 28.3, 24.9, 24.2, 23.2, 21.0, 18.4. IR
(film): 3243, 2895, 1720, 1351, 1213, 1031 cm-1. HRMS: Calculated for C19H24NaO4 (M+Na)+:
339.1567; found 339.1567.
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Lactone of 10-(6-acetoxy-5-hydroxycyclohex-1-en-1-yl)undec-10-en-8-ynoic acid (9),
0.10 mmol-scale: Palladium acetate (5.0 mg, 0.022 mmol) and tris-2,6-
dimethoxyphenylphosphine (TDMPP, 20.0 mg, 0.044 mmol) were combined in a flame-dried 2-
dram vial equipped with a stir bar. The vial was sealed with a septum and flushed with nitrogen,
and then freshly distilled PhMe (4.4 mL) was added. The resulting homogeneous, light red
solution was stirred for 15 minutes at room temperature. A portion of this catalyst solution (1.0
mL, corresponds to 0.005 mmol palladium acetate (5 mol %) and 0.010 mmol TDMPP (10 mol
%)) was transferred via syringe to a separate flame-dried 2-dram vial equipped with a stir bar
that had previously been flushed with nitrogen. This vessel was heated to 50 °C, and then
triethylamine (14 uL, 0.10 mmol, 1 equivalent) was added. A solution of trans-2-acetoxy-3-
ethynylcyclohex-3-en-1-yl non-8-ynoate (8, 31.6 mg, 0.10 mmol, 1 equivalent) in freshly
distilled PhMe (1.0 mL) was added via syringe pump over 4 h. After 4 h 30, TLC analysis (2:1
hexanes:Et2O) indicated complete consumption of the starting material. The reaction mixture
was diluted with Et2O:CH2Cl2 (1:1, 2.5 mL) and filtered through a pipette plug of Florisil®,
which was washed with additional Et2O:CH2Cl2 (1:1). The filtrate was concentrated, and the
crude material was purified via preparative thin-layer chromatography (2:1 hexanes:Et2O) to
afford the title compound (18.9 mg, 60%) as a white solid.
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1.0 gram-scale: A flame-dried 100 mL flask equipped with a stir bar was charged with
palladium acetate (35.5 mg, 0.158 mmol, 5 mol %) and tris-2,6-dimethoxyphenylphosphine
(TDMPP, 140 mg, 0.316 mmol, 10 mol %). The vessel was purged with nitrogen, and freshly
distilled PhMe (31.6 mL) was added. The resulting homogeneous, light red solution was stirred
for 30 min at room temperature, and then the vessel was immersed in an oil bath pre-heated to 50
°C. To this solution was added freshly distilled triethylamine (0.44 mL, 3.16 mmol, 1
equivalent). A solution of trans-2-acetoxy-3-ethynylcyclohex-3-en-1-yl non-8-ynoate (8, 1.0 g,
3.16 mmol, 1 equivalent) in freshly distilled PhMe (31.6 mL) was added via syringe pump over 4
h. After 4 h 30 min, TLC analysis (2:1 hexanes:Et2O) indicated complete consumption of the
starting material. The reaction mixture was diluted with 1:1 Et2O:CH2Cl2 (2.5 mL) and filtered
through a column of Florisil®, which was rinsed with 1:1 Et2O:CH2Cl2 and then with Et2O until
TLC analysis (2:1 hexanes:Et2O) confirmed complete elution of the product. The filtrate was
concentrated. Purification of the residue by column chromatography (2:1 hexanes:Et2O) afforded
the title compound (470 mg, 47%) as a white solid. Rf = 0.40 (2:1 hexanes: Et2O). M. P. =
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64−66 °C. H NMR (500 MHz; CDCl3): δ 6.11 (dd, J = 4.8, 2.8 Hz, 1H), 5.68-5.65 (m, 1H),
5.32 (d, J = 1.9 Hz, 1H), 5.22 (q, J = 2.7 Hz, 2H), 2.45-2.29 (m, 5H), 2.21-2.15 (m, 1H), 2.03 (s,
3H), 1.94-1.84 (m, 3H), 1.63-1.46 (m, 5H), 1.37-1.27 (m, 2H). 13C NMR (100 MHz; CDCl3): δ
173.0, 169.3, 134.4, 132.7, 130.6, 119.6, 93.4, 79.8, 67.5, 65.7, 33.3, 27.93, 27.90, 27.2, 25.0,
21.17, 21.15, 21.0, 18.9. IR (film): 3413, 2891, 2819, 2191, 1722, 1576, 1421, 1344, 1293, 1261,
1208, 1153, 1114, 1055, 1039, 1007, 974, 949, 898, 835, 783, 721 cm-1. HRMS: Calculated for
C19H24NaO4 (M+Na)+: 339.1567; found 339.1563.
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Acknowledgements
We thank the NIH GM033049 and NSF CHE-1360634 for their generous support of our
programs. J.T.M. acknowledges support from an Abbott Laboratories Stanford Graduate
Fellowship.
Supporting Information
1H and 13C NMR spectra of all new compounds, a full-size ORTEP representation of compound
9, and the X-Ray crystallographic information file (CIF) associated with compound 9. This
material is available free of charge via the Internet at http://pubs.acs.org.
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7 Yoshimura, F.; Kawata, S.; Hirama, M. Tetrahedron Lett. 1999, 40, 8281−8285.
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Schneider, C. M.; Khownium, K.; Li, W.; Spletstoser, J. T.; Haack, T.; Georg, G. I. Angew.
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11
For reviews of transition metal-catalyzed couplings to form enynes, see: (a) Trost, B. M.;
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13 Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40–49.
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15 Trost, B. M.; Matsubara, S.; Caringi, J. J. J. Am. Chem. Soc. 1989, 111, 8745–8746.
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Similar results were obtained in intermolecular alkyne-alkyne couplings involving terminal
propargylic alcohols. See: Trost, B. M.; McIntosh, M. C. Tetrahedron Lett. 1997, 38, 3207–
3210.
17 Trost, B. M.; Dong, G. Nature 2008, 456, 485-488.
18
Yang, S. G.; Hwang, J. P.; Park, M. Y.; Lee, K.; Kim, Y. H. Tetrahedron 2007, 63, 5184–
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19 Although specific details regarding the impact of the metal-to-ligand ratio remain elusive, this
beneficial effect of a 2:1 phosphine:metal ratio is consistent with previous results (Cf. Ref. 15).
20 In this case and in related experiments, the mass balance of the reaction consisted of a complex
mixture of unidentified byproducts, as judged by 1H NMR analysis of the crude reaction output.
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