Synthesis of fused-β-lactams through selective gold-catalyzed oxycyclization of dioxolane-tethered enynes

Article abstract of DOI:10.1021/jo401390k

The gold-catalyzed preparation of 2-azetidinone-fused oxacycles was accomplished from β-lactam-linked enynes through heterocyclization reaction taking advantage of the acetonide pendant group. While the synthesis of fused tetrahydrofuran-β-lactams from 1,

Full text of DOI:10.1021/jo401390k

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Synthesis of Fused-β-Lactams through Selective Gold-Catalyzed
Oxycyclization of Dioxolane-Tethered Enynes
Benito Alcaide,*,† Pedro Almendros,*,‡ Teresa Martínez del Campo,† and M. Rosario Torres§
†Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organ
Química, Universidad Complutense de Madrid, 28040 Madrid, Spain
‡Instituto de Química Organ
ica General, IQOG, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
§CAI Difraccion
de Rayos X, Facultad de Química, Universidad Complutense de Madrid, 28040 Madrid, Spain
́
ica I, Unidad Asociada al CSIC, Facultad de
́
́
S
* Supporting Information
ABSTRACT: The gold-catalyzed preparation of 2-azetidinone-fused oxacycles was accomplished from β-lactam-linked enynes
through heterocyclization reaction taking advantage of the acetonide pendant group. While the synthesis of fused
tetrahydrofuran-β-lactams from 1,3-enynes could be considered as an unusual metal-catalyzed cyclization of enynols, α-alkoxy
dioxolane-tethered 1,3-enynes exclusively undergo bis-oxycyclization to afford tricyclic bridged acetals.
through tandem addition of tethered dioxolane moieties by use
of an equivalent of water.8 Interestingly, under otherwise
identical conditions, α-alkoxy dioxolane-tethered 1,3-enynes
exclusively undergo bis-oxycyclization to afford tricyclic bridged
acetals.
INTRODUCTION
■
β-Lactam antibiotics are among the most commonly prescribed
antibacterial drugs.1 In addition, β-lactams further exhibit some
other biological activities.2 2-Azetidinones are also used as
valuable intermediates in organic synthesis.3 Thus, the search
for new syntheses of β-lactam derivatives is of interest because
of their important role in synthetic and pharmaceutical
chemistry. On the other hand, because of its chemical inertness
as a bulk metal, gold has not fascinated chemists working in
catalysis until recently. However, the last two decades have
witnessed dramatic growth in the number of reactions catalyzed
by gold complexes, notably in its homogeneous catalysis
manifestation,4 because of their powerful soft Lewis acidic
nature. In particular, activation of alkynes toward attack by
oxygen nucleophiles such as carbonyls, carboxylic acids, and
alcohols is an important C−O bond-forming reaction.5 Despite
the use of functionalized 1,3-enynes as building blocks for the
preparation of bioactive molecules or organic electronic
materials,6 the gold-catalyzed cyclization of enynols has been
scarcely reported.7 In terms of developing a new synthetic
method for fused β-lactams based on selective cycloether-
ification reactions, we hypothesized that a substrate bearing a
dioxolane group with a tethered 1,3-enyne moiety should be
ideal. We report here an efficient gold-catalyzed fused
tetrahydrofuran-β-lactam synthesis from 1,3-enyne β-lactams
RESULTS AND DISCUSSION
■
Starting materials for oxycyclization reactions, functionalized
1,3-enynes 2, were readily prepared in good yields from the
corresponding β-lactam-tethered α-allenols 1 by treatment with
the AcCl/NaOH (aqueous) system (Scheme 1).9 Bromoal-
kynes 3a and 3b were smoothly achieved from enynes 2a and
2b in excellent yield by reaction with NBS and AgOAc
(Scheme 1). Terminal alkyne 2a was functionalized as its
corresponding aryl alkyne 4 and phenylbuta-1,3-diynyl alkyne 5
under Sonogashira or Cadiot−Chodkiewicz conditions
(Scheme 1). Terminally deuterated alkyne [D]-2a was accessed
through base-promoted deuteration of the enyne 2a with D2O,
adapting a reported mild protocol to our substrate (Scheme
1).10
To validate the concept, an intramolecular hydroalkoxylation
of enynic acetonide 2a was first explored using metal catalysis.
Received: June 27, 2013
Published: September 5, 2013
© 2013 American Chemical Society
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a
Scheme 1. Preparation of Dioxolane-Tethered 1,3-Enynes 2a−d, [D]-2a, and 3−5
a
Conditions: (i) CH3COCl, NaOH, 5 mol % of TBAI, H2O/CH2Cl2 (1:1), rt, 24 h, (ii) 1-iodo-4-methoxybenzene, 1 mol % of Pd(PPh3)2Cl2, 2 mol
% of CuI, Et3N, MeCN, rt, 1.5 h, (iii) D2O, K2CO3, MeCN, rt, 1.5 h, (iv) NBS, AgOAc, acetone, darkness, rt, 3 h, (v) phenylacetylene, MeOH/
CH2Cl2, CuCl, NH2OH·HCl, EtNH2, 0 °C, 3 h. PMP = 4-MeOC6H4. TBAI = tetrabutylammonium iodide.
Initially, the use of AuCl3 and AuCl were tested, but both failed
to catalyze the reaction in the presence or absence of any
additive. Nicely, it was found that [AuClPPh3] along with
AgOTf and a Brønsted acid (PTSA monohydrate) could be a
promising cooperative catalytic system for our purpose, even
though total conversion was not obtained. Interestingly, enyne
2a was converted into the bicyclic tetrahydrofuran-fused β-
lactam 6a (Scheme 2). Unfortunately, under the above
conditions 2a gave low yields of the reaction products. On
the basis of the structure of 2a, we believed that ambient H2O
in the reaction system was involved in this Au(I)-catalyzed
reaction. Obviously, bicycle 2a could be more easily available if
we could directly perform the reaction in the presence of
external water as nucleophile. Happily, the addition of 1.0 equiv
of H2O raised the yield of 6a up to 67% (Scheme 2). This
conversion is remarkable as it implies a rare reactivity of the
1,3-enyne moiety. As such, the alkyne functionality would
behave as a latent carbonyl group giving a reactive α,β-
unsaturated ketone, while the alkene moiety undergoes metal-
catalyzed hydroalkoxylation. As earlier attempts to employ
other metal catalysts such as AuCl3 and AuCl met with failure,
we switched our attention to PtCl2. We performed the gold-
catalyzed reaction of enyne 2a under otherwise identical
conditions, but replaced [AuClPPh3] with PtCl2. The dramatic
decrease of yield in the formation of bicycle 6a (from 67 to
23%) did clearly establish the essential role of the gold salt for
this transformation. In addition, the Au-catalyzed reaction
afforded 6a as the sole product, while an epimeric byproduct 7a
was also obtained in the Pt-catalyzed reaction (Scheme 2).11
The two products obtained from the Pt-catalyzed reaction, 6a
and 7a, are not identical but rather stand in an epimeric
relationship at the α-carbonylic position. Interestingly, product
6a is converted into its epimer 7a after prolonged treatment
with the platinum catalyst.
Having established the optimum catalytic system, next we
investigated the scope and limitations of the process. Tolerance
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Scheme 2. Hydration/Oxycyclization Reaction of Dioxolane-Tethered 1,3-Enyne 2a under Modified Metal-Catalyzed
a
Conditions
a
Conditions: (i) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, CH2Cl2, sealed tube, 80 °C, 72 h, (ii) 2.5 mol % of PtCl2, 2.5
mol % of AgOTf, 10 mol % of PTSA, 100 mol % of H2O, CH2Cl2, sealed tube, 80 °C, 4 h, (iii) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10
mol % of PTSA, 100 mol % of H2O, CH2Cl2, sealed tube, 80 °C, 4 h. PMP = 4-MeOC6H4.
a
Scheme 3. Oxycyclization Reactions of Dioxolane-Tethered 1,3-Enynes 2b−d under Gold-Catalyzed Conditions
a
Conditions: (i) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, 100 mol % of H2O, CH2Cl2, sealed tube, 80 °C, 2b: 2.5 h; 2c: 3
h; 2d: 1 h. PMP = 4-MeOC6H4.
toward different substituents at the alkene and β-lactam
moieties was demonstrated starting from enynes 2b and 2c
(Scheme 3). While adduct 6b was formed as the sole product,
reaction of 2c afforded an inseparable mixture (60:40) of
diastereomers 6c/7c. The reason for the poor diastereoselec-
tivity moving from phenyl derivative 2b to the 4-bromophenyl
derivative 2c may be the presence of the bulkier bromoaryl
substituent, which makes the approach of the incoming
nucleophile to the less hindered face difficult. Surprisingly,
the cationic gold-catalyzed reaction of α-alkoxy dioxolane-
tethered 1,3-enyne 2d proceeded smoothly but gave adduct 8
with no expected bicycle 6d (Scheme 3). Formation of tricyclic
bridged acetal 8 implies cycloketalization of the acetonide
group toward the alkyne. The structure of fused tetrahydrofur-
an-β-lactam 6b was unambiguously assigned through its X-ray
structure (Figure 1, see the Supporting Information).12 X-ray
analysis of 6b reveals that there exist intramolecular hydrogen
bonds between hydroxyl group on the tetrahydrofuran ring and
carbonyl from the newly created ketone moiety, helping to
further stabilize the structure of the products.
We also tested the reactivity of 1,3-enynes 3−5 bearing an
additional substituent at the distal alkyne position. The results,
reported in Scheme 4, show that these substrates could not be
all converted into the corresponding tetrahydrofuran-β-lactam.
Tetrahydrofuran-β-lactams 6e and 6f were formed from
bromoalkynes 3a and 3b as major or exclusive products.
Adduct 6e was accompanied by tricyclic bridged acetal 9a along
with fused 3,6-dihydro-2H-pyran 10. The skeletal reorganiza-
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a
Scheme 4. Reactions of Dioxolane-Tethered 1,3-Enynes 3−5 under Gold-Catalyzed Conditions
a
Conditions: (i) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, 100 mol % of H2O, CH2Cl2, sealed tube, 80 °C, 3a: 1.5 h; 3b:
2.5 h; 4: 4.5 h; 5: 21 h, (ii) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, CH2Cl2, sealed tube, 80 °C, 2 h. PMP = 4-
MeOC6H4.
tion of 3a under gold catalysis but in absence of water resulted
in total selectivity with the exclusive formation of tricycle 9a.
While aryl-substituted enyne 4 underwent β-lactam cleavage,
alkynyl-substituted enyne 5 was nearly inert. This study
demonstrated that a subtle structural variation of dioxolane-
tethered 1,3-enyne β-lactams could result in completely
different product patterns in their gold-catalyzed cyclizations.
The above studied reaction makes use of starting enynes. These
enyne substrates have three points of diversity. Notably,
substituted and unsubstituted alkynes at the terminal position
followed different reactivity patterns. The presence of an aryl or
ethynylbenzene substituent at the terminal alkyne position does
not allow the oxycyclization reaction to proceed. Normally,
changing from an aryl to a benzyl substituent at the N1-β-
lactam nitrogen has little effect in the reactivity. By examining
the influence of the R2 substituent on the alkene side chain, we
found that substrates which contain bulky aryl groups were
smoothly transformed into tetrahydrofuran-β-lactam products
but with diminished stereoselectivity. In addition, when
applicable the presence of water favored the formation of
bicycles of type 6, while the absence of water directed the
reaction to the cycloketalization path.
Several experiments were performed to gain a mechanistic
insight into the present reaction. When H218O was added to the
gold-catalyzed reaction of enyne 2b, product [18O]-6b with
100% 18O content was formed in 62% yield (Scheme 5). A
similar trend was observed for compound [18O]-6a, but the
efficiency of the labeling process was lower (Scheme 5). H218O-
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a
Scheme 5. Control and 18O-Labeling Experiments of Dioxolane-Tethered 1,3-Enynes under Gold-Catalyzed Conditions
a
Conditions: (i) 2.5 mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, 200 mol % of H218O, CH2Cl2, sealed tube, 80 °C, 2.5 h, (ii) 2.5
mol % of [AuClPPh3], 2.5 mol % of AgOTf, 10 mol % of PTSA, 100 mol % of H2O, CH2Cl2, sealed tube, 80 °C, 2 h, (iii) 10 mol % of PTSA, 100
mol % of H2O, CH2Cl2, sealed tube, 80 °C, 5 h. PMP = 4-MeOC6H4.
labeling experiments unambiguously established that the
oxygen atom in the resulting ketone carbonyl group of adducts
6 originated from water.13 When [D]-2a, a deuterated alkyne,
reacted under otherwise identical gold-catalyzed reaction
conditions to those for 2a, nondeuterated tetrahydrofuran-β-
lactam 6a and tricyclic bridged acetal 9b were obtained
(Scheme 5). This absence of deuteration may be due to a fast
hydrogen−deuterium exchange on the enolic form of
intermediate species. A control experiment that would clarify
the participation of the gold species as the active catalyst in the
oxycyclization reaction was undertaken. A marked difference of
reactivity using gold salts or PTSA as catalysts was observed
because when enyne 2b was treated with PTSA under metal-
free reaction conditions bicycles 13 and 7b were obtained along
with the major component 6b. Unfortunately, diol 12c was not
available by acid treatment (PTSA or AcOH) of enyne 3a
because the reactions were not clean. However, taking into
account that the reaction of acetonide 3a under gold catalysis in
the absence of water proceeded to afford the corresponding
ketal 9a as the exclusive product (see Scheme 4) would suggest
that water is not necessarily needed for the cycloketalization
reaction to proceed.
AgOTf.15 The reaction of 1,3-enynes to yield tetrahydrofur-
an-β-lactams may be catalyzed by the Au(I) salt. The catalytic
reaction is likely divided into six parts. The initial formation of
the 1,2-diol 14 assisted by the Brønsted acid is followed by
coordination of the carbon−carbon triple bond of enyne diol
14 to the Au(I) salt, giving gold-π-alkynyl complex 15.
Regioselective nucleophilic addition of water to the alkyne
triple bond in gold-enynyl complex 15 provides the α,β-
unsaturated ketonic gold complex 16. Species 16 evolves
through a chemo- and regioselective 5-exo-dig oxyauration of
the diol moiety to form oxonium 17.16 Loss of proton generates
neutral species 18, which followed by protonolysis of the
carbon−gold bond afforded tetrahydrofuran-β-lactams 6 with
concurrent regeneration of the gold catalyst (Scheme 6).
A possible pathway for the gold-catalyzed formation of
bridged acetals 8 and 9 from dioxolane-tethered 1,3-enynes
may or may not involve an α,β-unsaturated ketone
intermediate. Using [D]-2a as starting material (Scheme 5),
we argued that it would be possible to determine wheter the
reaction occurs through an α,β-unsaturated ketone intermedi-
ate or direct bis-oxycyclization of the acetonide group toward
the alkyne. The direct bis-oxycyclization pathway would lead to
formation of deuterated tricyclic bridged acetal [D]-9b. The
absence of deuteration in compound 9b may be due to a fast
hydrogen−deuterium exchange on the enolic form of the α,β-
unsaturated ketone intermediate. This leads us to propose a
mechanism that is exemplified in Scheme 7 by the obtention of
adduct 8 from enyne 2d. The reaction may tentatively be
classified as cooperative concurrent catalysis, involving a
There is general agreement that the role of the silver salt just
consists in the activation of the precatalyst through formation
of cationic gold species by anion exchange.14 AgOTf alone does
not catalyze the reaction, thus indicating that a gold complex is
the active catalyst. Consequently, AgOTf cannot be considered
a cocatalyst, and in our case the catalytic system may consist of
[Au(OTf)PPh3], generated in situ from [AuClPPh3] and
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Scheme 6. Mechanistic Explanation for the Gold-Catalyzed Oxycyclization Reaction of Dioxolane-Tethered 1,3-Enynes into
Fused Tetrahydrofuran-β-lactams
11H), 6.97 (m, 2H), 5.13 (d, 1H, J = 12.3 Hz), 5.00 (d, 1H, J = 12.1
Hz), 4.86 (d, 1H, J = 6.3 Hz), 4.82 (d, 1H, J = 2.6 Hz), 4.64 (d, 1H, J
= 11.3 Hz), 4.13 (m, 3H), 3.92 (dd, 1H, J = 8.0, 6.1 Hz), 3.84 (d, 1H, J
= 8.0 Hz), 3.76 (d, 1H, J = 8.2 Hz), 1.38 (s, 3H), 1.32 (s, 3H); 13C
NMR (CDCl3) δ 207.4, 168.4, 137.8, 135.3, 132.6, 131.7, 128.7 (2C),
128.6 (2C), 128.5 (2C), 128.3 (2C), 127.8 (2C), 109.2, 106.0, 84.3,
80.1, 79.2, 76.7, 74.5, 66.2, 62.3, 45.5, 31.6, 31.0, 26.3, 25.2, 22.7, 14.2;
IR (CHCl3) ν 3339, 2987, 1940, 1739 cm−1; HRMS (ES) calcd for
C32H33NO5 [M]+ 511.2359, found 511.2381.
Previously unreported 1,3-enyne 2d. (E)-1,3-Enyne (−)-2d
was prepared according to the generalprocedure.9b From 80 mg (0.16
mmol) of the α-allenol (+)-1d and after chromatography of the
residue using hexanes/ethyl acetate (3:1) as eluent compound (−)-2d
(63 mg, 50%) was obtained as a colorless oil: [α]D = −75.4 (c 0.6,
CHCl3); 1H NMR (CDCl3) δ 8.06 (dd, 2H, J = 8.2, 1.9 Hz), 7.32 (d,
2H, J = 7.6 Hz), 7.21 (m, 11H), 4.91 (d, 1H, J = 15.6 Hz), 4.64 (d, 1H,
J = 11.4 Hz), 4.46 (m, 2H), 4.26 (d, 1H, J = 15.3 Hz), 4.08 (d, 1H, J =
6.7 Hz), 3.96 (m, 2H), 3.62 (m, 1H), 3.33 (s, 1H), 1.28 (s, 3H), 1.20
(s, 3H); 13C NMR (CDCl3) δ 161.0, 144.4, 136.6, 135.0, 132.2, 128.7,
127.8 (2C), 127.6 (2C), 127.4 (2C), 127.3 (2C), 127.2 (2C), 127.0
(2C), 126.9, 126.5, 120.1, 108.5, 83.8, 79.2, 76.1, 74.8, 73.8, 67.0, 59.3,
45.6, 25.7, 24.2; IR (CHCl3) ν 3030, 1735, 1607 cm−1; HRMS (ES)
calcd for C32H31NO4 [M]+ 493.2253, found 493.2276.
catalytic action by the Au(I) salt on the alkynic site (Scheme 7,
right catalytic cycle) and by the Brønsted acid on the activation
of the transient ketonic intermediate (Scheme 7, left catalytic
cycle).
CONCLUSION
■
In conclusion, a hydrative oxycyclization of dioxolane-tethered
enynes has been developed for the preparation of fused
tetrahydrofuran-β-lactams under gold catalysis. By contrast,
under otherwise identical conditions, α-alkoxy dioxolane-
tethered 1,3-enynes exclusively undergo bis-oxycyclization to
afford tricyclic bridged acetals.
EXPERIMENTAL SECTION
■
General Methods. NMR spectra were recorded at 25 °C on a 300
1
MHz instrument: H NMR (300 MHz) and 13C NMR (75 MHz).
Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm), or
CDCl3 (13C, 76.9 ppm). Low and high resolution mass spectra were
taken on a QTOF LC/MS spectrometer using the electronic impact
(EI) or electrospray modes (ES). Specific rotation [α]D is given in
10−1 deg cm2 g−1 at 20 °C, and the concentration (c) is expressed in g
per 100 mL.
Procedure for the Synthesis of Deutero-enyne (−)-[D]-2a.
Deuterium oxide (36 mmol) was added at room temperature under
argon atmosphere to a stirred solution of the (E)-1,3-enyne (−)-2a
(280 mg, 0.72 mmol) and K2CO3 (1.08 mmol) in acetonitrile (0.15
mL). The reaction was stirred for 1 h before being partitioned between
dichloromethane and water. The aqueous phase was extracted with
dichloromethane (3 × 10 mL). The organic extract was washed with
Previously Unreported α-Allenic Alcohol 1d. α-Allenol (+)-1d
was prepared according to the general prcedure.9a From 200 mg (0.51
mmol) of the corresponding azetidine-2,3-dione and after chromatog-
raphy of the residue using hexanes/ethyl acetate (2:1) as eluent
compound (+)-1d (166 mg, 64%) was obtained as a colorless oil: [α]D
= +156.3 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 7.62 (m, 2H), 7.32 (m,
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Scheme 7. Mechanistic Explanation for the Gold-Catalyzed Oxycyclization Reaction of Dioxolane-Tethered 1,3-Enyne 2d into
Tricyclic Bridged Acetal 8
1
water and brine, dried (MgSO4), and concentrated under reduced
pressure to give 258 mg (92%) of analytically pure compound
(−)-[D]-2a.
obtained as a colorless oil: [α]D = −7.8 (c 0.4, CHCl3); H NMR
(CDCl3) δ 7.96 (dd, 2H, J = 8.2, 1.9 Hz), 7.28 (m, 8H), 4.95 (d, 1H, J
= 14.9 Hz), 4.32 (d, 1H, J = 6.6 Hz), 4.27 (d, 1H, J = 14.9 Hz), 4.11
(dd, 1H, J = 8.6, 6.6 Hz), 3.96 (d, 1H, J = 6.5 Hz), 3.81 (dd, 1H, J =
8.6, 6.3 Hz), 1.37 (s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3) δ 161.1,
143.7, 135.9, 133.2, 129.9, 129.9 (2C), 128.8 (2C), 128.7 (2C), 128.3
(2C), 127.8, 122.8, 109.7, 81.3, 78.0, 77.3, 67.5, 60.8, 45.8, 26.5, 25.4;
IR (CHCl3) ν 1734, 1608 cm−1; HRMS (ES) calcd for C24H22BrNO3
[M]+ 451.0783, found 451.0803.
Deuterated alkyne (−)-[D]-2a: colorless oil; [α]D = −12.0 (c 0.8,
CHCl3); 1H NMR (CDCl3) δ 8.00 (dd, 2H, J = 8.0, 1.8 Hz), 7.48 (d,
2H, J = 9.1 Hz), 7.34 (m, 3H), 6.81 (d, 2H, J = 9.1 Hz), 4.74 (d, 1H, J
= 5.7 Hz), 4.51 (dd, 1H, J = 12.6, 6.7 Hz), 4.12 (2H, J = 6.7 Hz), 3.73
(s, 3H), 1.36 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3) δ 158.6, 156.6,
142.1, 133.4, 131.3, 130.0, 129.2 (2C), 128.3 (2C), 123.2, 119.7 (2C),
114.2 (2C), 109.7, 83.0, 80.0, 77.3, 67.0, 61.9, 55.5, 26.4, 25.5; IR
(CHCl3) ν 1733, 1602 cm−1; HRMS (ES) calcd for C24H22DNO4
[M]+ 390.1690, found 390.1671.
Palladium-Catalyzed Reaction between 1-Iodo-4-methox-
ybenzene and Terminal Enyne (−)-2a. Procedure for the
Synthesis of Aryl-Substituted Enyne (+)-4. PdCl2(PPh3)2 (7 mg,
0.01 mmol), CuI (3.8 mg, 0.02 mmol), and triethylamine (60.6 mg,
0.6 mmol) were sequentially added to a solution of the enyne (−)-2a
(400 mg, 1.0 mmol) and the iodoarene (1.0 mmol) in acetonitrile (0.8
mL) under argon atmosphere. The reaction mixture was stirred at
room temperature. After completion of the reaction as indicated by
TLC, the mixture was poured into water (5 mL) and extracted with
ethyl acetate (3 × 5 mL). The organic layer was washed with water (2
× 10 mL) and brine (2 × 10 mL), dried over MgSO4, and
concentrated under reduced pressure. Chromatography of the residue
eluting with hexanes/ethyl acetate (2:1) gave 324 mg (64%) of
analytically pure compound (+)-4.
General Procedure for the Synthesis of Bromoalkynes 3. To
a solution of the corresponding enyne 2 (120 mg, 0.50 mmol) in
acetone (3.4 mL) were added NBS (111 mg, 0.63 mmol) and silver
acetate (25 mg, 0.15 mmol). The reaction mixture was stirred at room
temperature in the dark until disappearance (TLC) of the starting
material. The solids were removed by filtration through a Celite pad
(washing with ethyl acetate). The combined organic filtrates were
washed with water and brine, dried (Na2SO4), concentrated under
reduced pressure, and then purified by column chromatography
eluting with ethyl acetate/hexanes mixtures to give analytically pure
bromoalkynes 3.
Bromoenyne (+)-3a. From 300 mg (0.77 mmol) of the 1,3-enyne
(−)-2a and after chromatography of the residue using hexanes/ethyl
acetate (2:1) as eluent compound (+)-3a (325 mg, 90%) was obtained
Aryl-substituted enyne (+)-4: colorless oil; [α]D = +10.0 (c 0.2,
CHCl3); 1H NMR (CDCl3) δ 8.10 (dd, 2H, J = 8.1, 1.6 Hz), 7.62 (d,
2H, J = 9.0 Hz), 7.53 (d, 2H, J = 8.8 Hz), 7.44 (m, 3H), 6.94 (d, 2H, J
= 8.8 Hz), 6.90 (d, 2H, J = 9.1 Hz), 4.86 (d, 1H, J = 6.3 Hz), 4.58 (dd,
1H, J = 13.3, 6.5 Hz), 4.30 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 1.47 (s,
3H), 1.36 (s, 3H); 13C NMR (CDCl3) δ 160.6, 159.1, 156.4, 139.1,
134.1, 133.5 (2C), 131.6, 131.4, 130.0, 129.8. 129.3 (2C), 128.2 (2C),
125.0, 119.5 (2C), 114.4 (2C), 114.1 (2C), 109.7, 98.3, 86.1, 78.1,
67.2, 62.2, 55.5, 26.5, 25.5; IR (CHCl3) ν 1735, 1603 cm−1; HRMS
(ES) calcd for C31H29NO5 [M]+ 495.2046, found 495.2038.
Copper(I) Chloride Promoted Heterocoupling Reaction
between Bromoenyne (+)-3a and Phenylacetylene. Procedure
for the Synthesis of Phenylbuta-1,3-diynylalkene (−)-5. A few
crystals of hydroxylamine hydrochloride, a 70% EtNH2 (0.25 mL)
aqueous solution, and CuCl (0.0072 mmol, 0.002 equiv) were
1
as a colorless oil: [α]D = +16.7 (c 0.9, CHCl3); H NMR (CDCl3) δ
7.95 (dd, 2H, J = 8.0, 1.7 Hz), 7.49 (d, 2H, J = 9.2 Hz), 7.34 (m, 3H),
6.81 (d, 2H, J = 9.2 Hz), 4.73 (d, 1H, J = 5.9 Hz), 4.45 (m, 1H), 4.14
(dd, 1H, J = 8.6, 6.2 Hz), 4.03 (m, 1H), 3.73 (s, 3H), 1.39 (s, 3H),
1.28 (s, 3H); 13C NMR (CDCl3) δ 158.8, 157.0, 142.2, 133.7, 131.7,
130.4, 129.5 (2C), 128.7 (2C), 124.2, 120.0 (2C), 114.5 (2C), 110.2,
78.2, 77.7, 67.5, 62.1, 59.4, 55.9, 26.8, 25.9; IR (CHCl3) ν 1735, 1605
cm−1; HRMS (ES) calcd for C24H22BrNO4 [M]+ 467.0732, found
467.0752.
Bromoenyne (−)-3b. From 110 mg (0.29 mmol) of the 1,3-enyne
(−)-2b and after chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent compound (−)-3b (124 mg, 94%) was
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sequentially added at room temperature to a solution of the
bromoenyne (+)-3a (175 mg, 0.36 mmol) in methanol (1.8 mL).
Then phenylacetylene (0.36 mmol) in CH2Cl2 (5 mL) was added to
the above acetylide suspension cooled at 0 °C. More crystals of
hydroxylamine hydrochloride were added throughout the reaction as
necessary to prevent the solution from turning blue or green. The
reaction mixture was stirred until disappearance (TLC) of the starting
materials. The products were extracted with ethyl acetate (3 × 5 mL),
dried over MgSO4, and concentrated under reduced pressure.
Purification by column chromatography eluting with hexanes/ethyl
acetate (4:1) gave 154 mg (85%) of analytically pure phenylbuta-1,3-
diynyl alkene (−)-5.
Phenylbuta-1,3-diynylalkene (−)-5: colorless oil; [α]D = −32.5 (c
0.6, CHCl3); 1H NMR (CDCl3) δ 7.98 (dd, 2H, J = 8.0, 1.7 Hz), 7.48
(m, 4H), 7.32 (m, 6H), 6.80 (dd, 2H, J = 7.0, 2.0 Hz), 4.77 (d, 1H, J =
5.6 Hz), 4.51 (m, 1H), 4.17 (dd, 1H, J = 8.6, 6.3 Hz), 4.09 (m, 1H),
3.71 (s, 3H), 1.38 (s, 3H), 1.28 (s, 3H); 13C NMR (CDCl3) δ 158.3,
156.7, 142.9, 133.3, 132.8 (2C), 131.3, 130.1, 129.9, 129.2 (2C), 128.6
(2C), 128.4 (2C), 123.4, 121.1, 119.6 (2C), 114.2 (2C), 109.8, 85.1,
81.9, 78.4, 77.1, 73.4, 67.0, 61.7, 55.5, 26.4, 25.5; IR (CHCl3) ν 1737,
1605 cm−1; HRMS (ES) calcd for C32H27NO4 [M]+ 489.1940, found
489.1965.
General Procedure for the Gold-Catalyzed Reactions of
Enynyldioxolanes 2−5. [AuClPPh3] (0.0093 mmol), AgOTf
(0.0093 mmol), p-toluenesulfonic acid (0.037 mmol), and water
(0.37 mmol) were sequentially added to a solution of the
corresponding enynyldioxolane 2−5 (0.37 mmol) in dichloromethane
(0.37 mL). The resulting mixture was heated in a sealed tube at 80 °C
until disappearance of the starting material (TLC). The reaction was
allowed to cool to room temperature and filtered through a pack of
Celite. The filtrate was extracted with ethyl acetate (3 × 5 mL), and
the combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue eluting with ethyl acetate/hexanes
mixtures gave analytically pure adducts 6 and 8−12.
Tetrahydrofuran-Fused β-Lactam (+)-6a. From 30 mg (0.08
mmol) of the enynyldioxolane (−)-2a and after chromatography of
the residue using hexanes/ethyl acetate (2:1) as eluent compound
(+)-6a (19 mg, 67%) was obtained as a colorless oil: [α]D = +51.0 (c
0.7, CHCl3); 1H NMR (CDCl3) δ 7.23 (m, 5H), 7.10 (d, 2H, J = 9.1
Hz), 6.69 (d, 2H, J = 8.9 Hz), 4.76 (br s, 1H), 4.60 (s, 1H), 4.45 (s,
1H), 4.32 (br s, 1H), 4.17 (d, 1H, J = 10.7 Hz), 3.92 (dd, 1H, J = 10.7,
3.0 Hz), 3.65 (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3) δ 208.4, 162.5,
156.7, 134.2, 131.0, 129.5 (2C), 129.2 (2C), 129.0, 118.3 (2C), 114.5
(2C), 96.8, 76.1, 70.5, 65.0, 56.7, 55.5, 30.8; IR (CHCl3) ν 3056, 1746,
1702 cm−1; HRMS (ES) calcd for C21H21NO5 [M]+ 367.1420, found
367.1402.
(M), 123.0 (m), 118.3 (2C), 114.7 (2C), 96.5 (M), 94.2 (m), 76.1
(M), 75.7 (m), 70.6, 67.3 (m), 65.0 (M), 57.8 (m), 56.0 (M), 55.5,
30.9 (M), 29.6 (m); IR (CHCl3) ν 3055, 1746, 1703 cm−1; HRMS
(ES) calcd for C21H20BrNO5 [M]+ 445.0525, found 445.0531.
Reaction of Enynyldioxolane (+)-3a. From 100 mg (0.21 mmol)
of enynyldioxolane (+)-3a, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent, 27 mg (29%) of
compound (+)-6e, 25 mg (27%) of compound (+)-9a, and 16 mg
(18%) of compound (+)-10 were obtained.
Tetrahydrofuran-fused β-lactam (+)-6e: colorless oil; [α]D
=
1
+110.0 (c 0.7, CHCl3); H NMR (CDCl3) δ 7.36 (m, 5H), 7.21 (d,
2H), 6.80 (d, 2H), 5.04 (s, 1H), 4.54 (s, 1H), 4.43 (dd, 1H, J = 12.3,
2.5 Hz), 4.29 (td, 2H, J = 12.3, 1.3 Hz), 4.06 (d, 1H, J = 13.6 Hz), 4.05
(dd, 1H, J = 11.1, 3.1 Hz), 3.97 (d, 1H, J = 13.9 Hz), 3.76 (s, 3H); 13C
NMR (CDCl3) δ 201.4, 162.0, 156.7, 130.1, 129.7 (2C), 129.4, 129.2,
129.1 (2C), 118.4 (2C), 114.5 (2C), 96.7, 76.2, 70.4, 65.1, 55.5, 53.7,
34.3; IR (CHCl3) ν 3477, 1749, 1706 cm−1; HRMS (ES) calcd for
C21H20BrNO5 [M]+ 445.0525, found 445.0547.
Tricyclic Bridged Acetal (+)-9a: colorless oil; [α]D = +122.0 (c 0.5,
CHCl3); 1H NMR (CDCl3) δ 7.42 (m, 5H), 7.15 (d, 2H, J = 8.9 Hz),
6.80 (d, 2H, J = 9.1 Hz), 5.14 (m, 1H), 4.90 (d, 1H, J = 3.5 Hz), 4.04
(dd, 1H, J = 8.3, 7.3 Hz), 3.77 (m, 3H), 3.71 (s, 3H); 13C NMR
(CDCl3) δ 156.4, 134.3 (2C), 134.1 (2C), 132.0, 131.9, 29.4 (2C),
129.2 (2C), 128.6, 128.5, 117.2, 114.8, 105.3, 75.3, 63.2, 56.0, 55.5,
29.3; IR (CHCl3) ν 1746, 1583 cm−1; HRMS (ES) calcd for
C21H18BrNO4 [M]+ 427.0419, found 427.0433.
Fused 3,6-dihydro-2H-pyran (+)-10: colorless oil; [α]D = +56.0 (c
1
0.5, CHCl3); H NMR (CDCl3) δ 7.53 (d, 2H, J = 9.1 Hz), 7.41 (m,
2H), 7.35 (m, 3H), 6.82 (d, 2H, J = 9.0 Hz), 5.62 (s, 1H), 4.74 (d, 1H,
J = 4.7 Hz), 4.31 (m, 2H), 4.16 (m, 1H), 3.71 (s, 3H), 2.63 (d, 1H, J =
7.7 Hz); 13C NMR (CDCl3) δ 157.9, 157.3, 156.4, 134.5, 133.2, 132.7,
131.6, 129.9 (2C), 129.8, 128.8 (2C), 118.3 (2C), 114.6 (2C), 99.5,
76.8, 73.2, 65.6, 55.5; IR (CHCl3) ν 3439, 1729, 1511 cm−1; HRMS
(ES) calcd for C21H18BrNO4 [M]+ 427.0419, found 427.0414.
Tetrahydrofuran-Fused β-Lactam (+)-6f. From 120 mg (0.27
mmol) of the enynyldioxolane (−)-3b and after chromatography of
the residue using hexanes/ethyl acetate (3:2) as eluent compound
(+)-6f (71 mg, 61%) was obtained as a colorless oil: [α]D = +160.1 (c
1
0.9, CHCl3); H NMR (CDCl3) δ 7.34 (m, 3H), 7.20 (m, 2H), 7.07
(m, 3H), 6.43 (d, 2H, J = 7.2 Hz), 4.90 (s, 1H), 4.37 (d, 1H, J = 15.2
Hz), 4.16 (dd, 1H, J = 10.4, 0.9 Hz), 3.87 (m, 6H); 13C NMR
(CDCl3) δ 201.3, 165.2, 134.2, 130.3, 129.8 (2C), 129.5 (2C), 129.2,
128.8 (2C), 127.8, 127.5 (2C), 97.9, 76.5, 70.3, 64.7, 53.5, 43.8, 34.4;
IR (CHCl3) ν 3479, 1756, 1710 cm−1; HRMS (ES) calcd for
C21H20BrNO4 [M]+ 429.0576, found 429.0585.
Tricyclic Bridged Acetal (+)-8. From 20 mg (0.04 mmol) of the
enynyldioxolane (−)-2d and after chromatography of the residue using
hexanes/ethyl acetate (3:1) as eluent compound (+)-8 (17 mg, 92%)
was obtained as a colorless oil: [α]D = +36.3 (c 0.8, CHCl3); 1H NMR
(CDCl3) δ 7.56 (m, 2H), 7.23 (m, 13H), 4.51 (d, 1H, J = 7.5 Hz),
4.40 (d, 1H, J = 12.0 Hz), 4.33 (t, 1H, J = 7.2 Hz), 4.11 (m, 4H), 3.60
(dd, 1H, J = 8.5, 6.3 Hz), 3.40 (d, 1H, J = 7.5 Hz), 1.97 (s, 3H); 13C
NMR (CDCl3) δ 160.9, 136.6, 136.1, 135.5, 133.4, 133.1, 132.2, 128.0
(2C), 127.9, 127.7 (2C), 127.6 (2C), 127.4 (2C), 127.1, 127.0 (3C),
126.6, 110.0, 86.2, 77.5, 70.7, 67.3, 59.9, 44.9, 21.9; IR (CHCl3) ν
1742 cm−1; HRMS (ES) calcd for C29H27NO4 [M]+ 453.1940, found
453.1942.
Tetrahydrofuran-Fused β-Lactam (+)-6b. From 86 mg (0.23
mmol) of the enynyldioxolane (−)-2b and after chromatography of
the residue using hexanes/ethyl acetate (3:2) as eluent compound
(+)-6b (49 mg, 61%) was obtained as a colorless solid: mp 163−164
°C; [α]D = +312.6 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.33 (m, 3H),
7.22 (m, 2H), 7.07 (m, 3H), 6.42 (d, 2H, J = 7.0 Hz), 4.61 (d, 1H, J =
11.7 Hz), 4.56 (s, 1H), 4.37 (d, 1H, J = 15.3 Hz), 4.14 (dd, 1H, J =
10.4, 1.2 Hz), 3.95 (m, 2H), 3.72 (d, 1H, J = 15.3 Hz), 2.11 (s, 3H);
13C NMR (CDCl3) δ 208.4, 165.7, 134.3, 131.2, 129.6 (2C), 129.5
(2C), 128.8, 128.8 (2C), 127.7, 127.5 (2C), 97.9, 76.3, 70.3, 64.6, 56.4,
43.7, 30.9; IR (CHCl3) ν 3052, 1745, 1704 cm−1; HRMS (ES) calcd
for C21H21NO4 [M]+ 351.1471, found 351.1482.
Diarylenyne 11. From 60 mg (0.12 mmol) of the enynyldioxolane
(+)-4 and after chromatography of the residue using hexanes/ethyl
acetate (2:1) as eluent compound 11 (25 mg, 86%) was obtained as a
Tetrahydrofuran-Fused β-Lactam (+)-6c. From 63 mg (0.13
mmol) of the enynyldioxolane (−)-2c and after chromatography of the
residue using hexanes/ethyl acetate (2:1) as eluent compound (+)-6c
(37 mg, 63%; 60:40 mixture of epimers) was obtained as a colorless
oil: [α]D = +104.0 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 7.47 (d, 0.8H,
J = 8.5 Hz), 7.40 (d, 1.2H, J = 8.5 Hz), 7.31 (d, 0.8H, J = 9.1 Hz), 7.17
(m, 3.2H), 6.81 (d, 0.8H, J = 9.1 Hz), 6.72 (d, 1.2H, J = 9.1 Hz), 4.59
(m, 1.2H), 4.36 (m, 1.8H), 4.17 (m, 1.2H), 3.92 (m, 1.8H), 3.72 (s,
1.2H), 3.67 (s, 1.8H), 2.15 (s, 1.8H), 2.04 (s, 1.2H); 13C NMR
(CDCl3) δ 208.0 (M), 207.0 (m), 162.7 (m), 162.3 (M), 156.8, 132.8
(2C), 132.2 (M), 131.8 (m), 130.8 (2C), 130.0 (M), 129.9 (m), 123.4
1
colorless oil: H NMR (CDCl3) δ 7.79 (d, 2H, J = 8.9 Hz), 7.58 (m,
2H), 7.44 (m, 3H), 6.92 (d, 2H, J = 9.1 Hz), 6.79 (d, 1H, J = 1.5 Hz),
6.34 (d, 1H, J = 1.4 Hz), 3.81 (s, 3H); 13C NMR (CDCl3) δ 163.0,
161.9, 160.6, 156.0, 136.3, 130.6, 129.2, 127.5 (2C), 126.8 (2C), 124.1,
114.4 (2C), 108.1, 100.0, 55.5; IR (CHCl3) ν 3061 cm−1; HRMS (ES)
calcd for C17H14O [M]+ 234.1045, found 234.1037.
Diol (+)-12a. From 55 mg (0.11 mmol) of the enynyldioxolane
(−)-5 and after chromatography of the residue using hexanes/ethyl
acetate (2:1) as eluent compound (+)-12a (37 mg, 75%) was obtained
1
as a colorless oil: [α]D = +17.5 (c 0.4, CHCl3); H NMR (CDCl3) δ
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8.02 (dd, 2H, J = 8.2, 2.0 Hz), 7.50 (dd, 2H, J = 8.0, 1.6 Hz), 7.30 (m,
8H), 6.84 (d, 2H, J = 8.9 Hz), 4.87 (d, 1H, J = 2.9 Hz), 4.42 (br s,
1H), 3.75 (m, 2H), 3.73 (s, 3H), 2.41 (s, 1H), 1.93 (s, 1H); 13C NMR
(CDCl3) δ 158.5, 156.9, 143.4, 133.1, 132.8 (2C), 130.9, 130.1, 129.9,
129.1 (2C), 128.6 (2C), 128.4 (2C), 123.3, 121.0, 119.7 (2C), 114.6
(2C), 81.8, 78.2, 77.2, 73.2, 71.7, 64.2, 61.5, 55.6; IR (CHCl3) ν 3448,
1727 cm−1; HRMS (ES) calcd for C29H23NO4 [M]+ 449.1627, found
449.1633.
Reaction of Deuterated Alkyne (−)-[D]-2a. From 250 mg (0.64
mmol) of enynyldioxolane (−)-[D]-2a, and after chromatography of
the residue using hexanes/ethyl acetate (2:1) as eluent, 60 mg (27%)
of the less polar compound (+)-9b and 96 mg (41%) of the more
polar compound (+)-6a were obtained.
and concentrated under reduced pressure. Chromatography of the
residue using hexanes/ethyl acetate (3:2) as eluent gave 19 mg (23%)
of the less polar compound (+)-6a and 8 mg (9%) of the more polar
compound (−)-7a.
Tetrahydrofuran-fused β-lactam (−)-7a: colorless oil; [α]D
=
−80.2 (c 0.7, CHCl3); 1H NMR (CDCl3) δ 7.33 (m, 7H), 6.81 (d, 2H,
J = 9.1 Hz), 4.40 (d, 1H, J = 0.9 Hz), 4.29 (s, 1H), 4.11 (dd, 1H, J =
10.8, 1.2 Hz), 3.89 (dd, 1H, J = 10.8, 3.1 Hz), 3.72 (s, 3H), 3.44 (d,
1H, J = 11.7 Hz), 2.05 (s, 3H); 13C NMR (CDCl3) δ 207.3, 163.0,
156.7, 133.4, 130.1 (2C), 129.1 (2C), 128.6, 118.2 (2C), 114.7 (2C),
94.6, 76.1, 75.4, 70.6, 67.0, 58.4, 55.6, 29.6; IR (CHCl3) ν 3054, 1745,
1703 cm−1; HRMS (ES) calcd for C21H21NO5 [M]+ 367.1420, found
367.1430.
Tricyclic bridged acetal (+)-9b: colorless oil; [α]D = +252.1 (c 0.7,
Procedure for the Gold-Catalyzed Reaction of Enynyldiox-
olane (+)-3a in the Absence of Water. [AuClPPh3] (0.0080
mmol), AgOTf (0.0080 mmol), and p-toluenesulfonic acid (0.032
mmol) were sequentially added to a solution of the enynyldioxolane
(+)-3a (150 mg, 0.32 mmol) in dichloromethane (0.32 mL). The
resulting mixture was heated in a sealed tube at 80 °C until
disappearance of the starting material (TLC). The reaction was
allowed to cool to room temperature and filtered through a pack of
Celite. The filtrate was extracted with ethyl acetate (3 × 5 mL), and
the combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using hexanes/ethyl acetate (3:2) as
eluent gave 64 mg (58%) of compound (+)-9a as a colorless oil.
Procedure for the Metal-Free PTSA-Catalyzed Reaction of
Enynyldioxolane (−)-2b. p-Toluenesulfonic acid (0.032 mmol) was
added to a solution of the enynyldioxolane (−)-2b (120 mg, 0.32
mmol) in dichloromethane (0.32 mL). The resulting mixture was
heated in a sealed tube at 80 °C until disappearance of the starting
material (TLC). The reaction was allowed to cool to room
temperature and filtered through a pack of Celite. The filtrate was
extracted with ethyl acetate (3 × 5 mL), and the combined extracts
were washed twice with brine. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using hexanes/ethyl acetate (2:1) as eluent gave 12 mg (12%)
of the less polar compound 13, 26 mg (23%) of compound (+)-6b,
and 19 mg (17%) of the more polar compound (−)-7b.
1
CHCl3); H NMR (CDCl3) δ 7.50 (m, 2H), 7.33 (m, 3H), 7.15 (d,
2H, J = 8.9 Hz), 6.79 (d, 2H, J = 8.9 Hz), 5.03 (m, 1H), 4.81 (d, 1H, J
= 3.7 Hz), 3.90 (dd, 1H, J = 8.3, 6.7 Hz), 3.69 (s, 3H), 3.59 (dd, 1H, J
= 8.6, 2.8 Hz), 1.69 (s, 3H); 13C NMR (CDCl3) δ 158.9, 156.3, 141.2,
132.7, 132.0, 130.4, 129.5, 129.0 (2C), 128.3 (2C), 117.2 (2C), 114.8
(2C), 105.6, 74.9, 62.1, 56.2, 55.6, 19.2; IR (CHCl3) ν 1747, 1585
cm−1; HRMS (ES) calcd for C21H19NO4 [M]+ 349.1314, found
349.1301.
General Procedure for the Gold-Catalyzed Reaction of
Enynyldioxolanes 2 in the Presence of H218O. Preparation of
18O-Labeled Tetrahydrofuran-Fused β-Lactams 6. [AuClPPh3]
(0.0093 mmol), AgOTf (0.0093 mmol), p-toluenesulfonic acid (0.037
mmol), and H218O (0.37 mmol) were sequentially added to a solution
of the corresponding enynyldioxolane 2 (0.37 mmol) in dichloro-
methane (0.37 mL). The resulting mixture was heated in a sealed tube
at 80 °C until disappearance of the starting material (TLC). The
reaction was allowed to cool to room temperature and filtered through
a pack of Celite. The filtrate was extracted with ethyl acetate (3 × 5
mL), and the combined extracts were washed twice with brine. The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with ethyl acetate/
hexanes mixtures gave analytically pure 18O-labeled compounds 6.
β-Alkoxy Ketone [18O]-6a. From 65 mg (0.17 mmol) of the
enynyldioxolane (−)-2a and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent 31 mg (52%) of compound
(+)-[18O]-6a (16O 30%) was obtained as a colorless oil: [α]D = +77.2
Tetrahydrofuran-fused β-lactam (−)-7b: pale yellow oil; [α]D
=
−45.8 (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.35 (m, 10H), 4.42 (dd,
2H, J = 30.3, 14.9 Hz), 4.30 (s, 1H), 4.01 (d, 1H, J = 11.1 Hz), 4.00 (s,
1H), 3.87 (dd, 1H, J = 10.6, 2.9 Hz), 3.80 (d, 1H, J = 6.7 Hz), 2.75 (br
s, 1H), 2.14 (s, 3H); 13C NMR (CDCl3) δ 206.9, 166.1, 135.5, 133.5,
129.9 (2C), 129.0 (3C), 128.6 (2C), 128.5, 128.2 (2C), 96.0, 75.1,
70.6, 67.4, 58.3, 45.1, 29.7; IR (CHCl3) ν 3049, 1744, 1705 cm−1;
HRMS (ES) calcd for C21H21NO4 [M]+ 351.1471, found 351.1472.
Bicycle 13: pale yellow oil; 1H NMR (CDCl3) δ 7.29 (m, 9H), 6.94
(d, 2H, J = 6.6 Hz), 6.34 (d, 1H, J = 5.7 Hz), 5.17 (s, 2H), 2.18 (s,
3H); 13C NMR (CDCl3) δ 159.5, 145.5, 138.3, 136.0, 133.1, 131.1,
130.6 (2C), 129.2 (2C), 128.1, 127.8 (2C), 126.8, 125.9 (2C), 121.2,
106.7, 96.5, 47.7, 10.7; IR (CHCl3) ν 1730 cm−1; HRMS (ES) calcd
for C21H17NO2 [M]+ 315.1259, found 315.1259.
1
(c 0.9, CHCl3); H NMR (CDCl3) δ 7.26 (m, 5H), 7.11 (d, 2H, J =
9.1 Hz), 6.70 (d, 2H, J = 9.0 Hz), 4.60 (broad s, 1H), 4.44 (broad s,
1H), 4.32 (broad s, 1H), 4.18 (dd, 1H, J = 10.7, 1.2 Hz), 3.93 (dd, 1H,
J = 10.7, 2.9 Hz), 3.66 (s, 3H), 2.15 (s, 3H); 13C NMR (CDCl3) δ
208.3 [δC(18O) = −7 ppb, CO], 162.5, 156.7, 131.0, 129.5 (2C),
129.4 (2C), 129.2, 129.0, 118.3 (2C), 114.5 (2C), 96.7, 76.1, 70.5,
65.0, 56.6, 55.5, 30.8; IR (CHCl3) ν 3055, 1745, 1704 cm−1; HRMS
(ES) calcd for C21H20N16O418O [M]+ 369.1462, found 369.1455.
β-Alkoxy Ketone [18O]-6b. From 75 mg (0.20 mmol) of the
enynyldioxolane (−)-2b and after chromatography of the residue using
hexanes/ethyl acetate (1:1) as eluent 44 mg (62%) of compound
(+)-[18O]-6b was obtained as a colorless oil: [α]D = +205.3 (c 0.6,
1
CHCl3); H NMR (CDCl3) δ 7.43 (m, 3H), 7.32 (m, 2H), 7.17 (m,
3H), 6.53 (d, 2H, J = 7.1 Hz), 4.66 (s, 1H), 4.47 (d, 1H, J = 15.3 Hz),
4.24 (dd, 1H, J = 10.5, 1.2 Hz), 4.11 (m, 1H), 4.05 (m, 2H), 3.82 (d,
1H, J = 15.2 Hz), 2.21 (s, 3H); 13C NMR (CDCl3) δ 208.3 [δC(18O)
= −73 ppb, CO], 165.7, 134.3, 131.2, 129.6 (2C), 129.5 (2C),
128.8, 128.7 (2C), 127.7, 127.5 (2C), 97.9, 76.3, 70.3, 64.6, 56.4, 43.7,
30.8; IR (CHCl3) ν 3056, 1747, 1705 cm−1; HRMS (ES) calcd for
C21H21N16O318O [M]+ 353.1573, found 353.1549.
Procedure for the Platinum-Catalyzed Reaction of Enynyl-
dioxolane (−)-2a. [PtCl2] (0.0058 mmol), AgOTf (0.0058 mmol),
p-toluenesulfonic acid (0.023 mmol), and water (0.23 mmol) were
sequentially added to a solution of the enynyldioxolane (−)-2a (90
mg, 0.23 mmol) in dichloromethane (0.23 mL). The resulting mixture
was heated in a sealed tube at 80 °C until disappearance of the starting
material (TLC). The reaction was allowed to cool to room
temperature and filtered through a pack of Celite. The filtrate was
extracted with ethyl acetate (3 × 5 mL), and the combined extracts
were washed twice with brine. The organic layer was dried (MgSO4)
ASSOCIATED CONTENT
■
S
* Supporting Information
1
ORTEP drawing of compound 6b as well as copies of the H
NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alcaideb@quim.ucm.es, palmendros@iqog.csic.es.
Notes
The authors declare no competing financial interest.
8964
dx.doi.org/10.1021/jo401390k | J. Org. Chem. 2013, 78, 8956−8965

The Journal of Organic Chemistry
Featured Article
Rossi, E. Org. Biomol. Chem. 2011, 9, 7836 We thank a reviewer for
calling this to our attention..
ACKNOWLEDGMENTS
■
Support for this work by MINECO (Projects CTQ2012-33664-
C02-01 and CTQ2012-33664-C02-02) and Comunidad
(12) X-ray data of 6b: crystallized from ethyl acetate/n-hexane at 20
°C; C21H21NO4 (Mr = 351.39); orthorhombic; space group = P2(1)
2(1)2(1); a = 6.4739(6) Å, b = 15.5769(15) Å; c = 18.5242(17) Å; α
= 90°; β = 90°; γ = 90°; V = 1868.0(3) Å3; Z = 4; cd = 1.249 mg m−3;
μ = 0.087 mm−1; F(000) = 744. A transparent crystal of 0.19 × 0.13 ×
0.06 mm3 was used. 4058 [R(int) = 0.0803] independent reflections
were collected on a difractomer using graphite-monochromated Mo
Kα radiation (λ = 0.71073 Å) operating at 50 Kv and 35 mA. Data
were collected over a hemisphere of the reciprocal space by
combination of three exposure sets. Each exposure of 20s covered
0.3 in ω. The cell parameters were determined and refined by a least-
squares fit of all reflections. The first 100 frames were recollected at
the end of the data collection to monitor crystal decay, and no
appreciable decay was observed. The structure was solved by direct
methods and Fourier synthesis. It was refined by full-matrix least-
squares procedures on F2 (SHELXL-97). All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were included in the
calculated positions and refined riding on the respective carbon atoms.
Final R(Rw) values were R1 = 0.0393, wR2 = 0.0798. CCDC-881465
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge via the www.ccdc.can.ac.uk/
deposit, (or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, UK; Fax (+44)1223-336033; or
deposit@cccdc.cam.ac.uk).
Auton
acknowledged.
́
oma de Madrid (Project S2009/PPQ-1752) is gratefully
REFERENCES
■
(1) See, for example: (a) Payne, D. J. Science 2008, 321, 1644.
(b) Spencer, J.; Walsh, T. Angew. Chem., Int. Ed. 2006, 45, 1022.
(c) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. Rev. 2005, 105,
395.
(2) (a) Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.;
Lukevics, E. Curr. Med. Chem. 2003, 10, 1741. (b) Miller, T. M.;
Cleveland, D. W. Science 2005, 307, 361. (c) Banik, B. K.; Banik, E.;
Becker, F. F. In Topics in Heterocyclic Chemistry; Banik, B. K., Ed.;
Springer-Verlag: Berlin, Heidelberg, 2010; Vol. 22, p 349.
(3) (a) Kamath, A.; Ojima, I. Tetrahedron 2012, 68, 10640.
(b) Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311. (c) Alcaide,
B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437.
(4) (a) Modern Gold Catalyzed Synthesis; Hashmi, A. S. K., Toste, F.
D., Eds.; Wiley-VCH: Weinheim, 2012. (b) Rudolph, M.; Hashmi, A.
́
S. K. Chem. Soc. Rev. 2012, 41, 2448. (c) Corma, A.; Leyva-Perez, A.;
Sabater, M. J. Chem. Rev. 2011, 111, 1657. (d) Alcaide, B.; Almendros,
P.; Alonso, J. M. Org. Biomol. Chem. 2011, 9, 4405. (e) Hashmi, A. S.
K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(13) Our gold-catalyzed reaction is suited for the synthesis of 18O-
labeled β-lactam ketones. Here, the use of isotopic labels has been
used with mechanistic purposes, but the preparation of 18O-labeled
compounds may be of pharmaceutical interest because the use of
labeled compounds becomes increasingly interesting for the develop-
ment of new drugs; for example, labeled derivatives are necessary for
metabolite studies as well as for production of novel radiotracers
intended for complex imaging studies in humans. For example, see:
(a) Shao, X.; Carpenter, G. M.; Desmond, T. J.; Sherman, P.; Quesada,
C. A.; Fawaz, M.; Brooks, A. F.; Kilbourn, M. R.; Albin, R. L.; Frey, K.
A.; Scott, P. J. H. ACS Med. Chem. Lett. 2012, 3, 936. (b) Cai, L.; Lu,
S.; Pike, V. W. Eur. J. Org. Chem. 2008, 2853. (c) Allard, M.; Fouquet,
E.; James, D.; Szlosek-Pinaud, M. Curr. Med. Chem. 2008, 15, 235.
(d) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem., Int.
Ed. 2007, 46, 7744.
(5) For leading references on alkynes, see: (a) Science of Synthesis;
Thomas, E. J., Ed.; Thieme: Stuttgart, 2008; Vol. 43. (b) Acetylene
Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-
VCH: New York, 2005. For reviews on the construction of
heterocycles by alkyne π-activation, see: (c) Rudolph, M.; Hashmi,
A. S. K. Chem. Commun. 2011, 47, 6536. (d) Das, A.; Sohel, S. M. A.;
Liu, R.-S. Org. Biomol. Chem. 2010, 8, 960. (e) Yamamoto, Y.; Gridnev,
I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075. (f) Kirsch, S. F.
Synthesis 2008, 3183. (g) McDonald, F. E. Chem.Eur. J. 1999, 5,
3103.
(6) See, for instance: (a) Yu, X.; Zhang, J. Chem.Eur. J. 2012, 18,
12945. (b) Bender, G.; Wiegand, T.; Eckert, H.; Frohlich, R.; Daniliuc,
̈
C. G.; Muck-Lichtenfeld, C.; Ndambuki, S.; Ziegler, T.; Kehr, G.;
̈
Erker, G. Angew. Chem., Int. Ed. 2012, 51, 8846. (c) Dateer, R. B.; Pati,
K.; Liu, R.-S. Chem. Commun. 2012, 48, 7200. (d) Gai, B. M.; Stein, A.
L.; Roehrs, J. A.; Bilheri, F. N.; Nogueira, C. W.; Zeni, G. Org. Biomol.
Chem. 2012, 10, 798. (e) Zhong, M.-J.; Wang, X.-C.; Zhu, H.-T.; Hu,
J.; Liu, L.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2012, 77, 10955.
(7) (a) Han, Z.-Y.; Chen, D.-F.; Wang, Y.-Y.; Guo, R.; Wang, P.-S.;
Wang, C. J. Am. Chem. Soc. 2012, 134, 6532. (b) Hashmi, A. S. K.;
Ghanbari, M.; Rudolph, M.; Rominger, F. Chem.Eur. J. 2012, 18,
8113. (c) Kotikalapudi, R.; Swamy, K. C. K. Tetrahedron Lett. 2012, 53,
3831. (d) Du, X.; Song, F.; Lu, Y.; Chen, H.; Liu, Y. Tetrahedron 2009,
65, 1839.
(14) (a) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47,
́
5703. (b) Gaillard, S.; Bosson, J.; Ramon, R. S.; Nun, P.; Slawin, A. M.
Z.; Nolan, S. P. Chem.Eur. J. 2010, 16, 13729.
(15) However, despite proving that the silver activators themselves
are unreactive, there are examples of gold(I)-catalyzed reactions where
Ag(I) salts affected either activity or selectivity: Wang, D.; Cai, R.;
Sharma, S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang,
H.; Liu, X.; Petersen, J. L.; Shi, X. J. Am. Chem. Soc. 2012, 134, 9012.
(16) In the presence of electrophilic transition metals, intermediate
α,β-unsaturated ketones look like ideal substrates for the formation of
complexes of type 16. However, a Michael addition process catalyzed
by a Brønsted acid cannot be completely ruled out.
(8) Very few examples of tetrahydrofuro[2,3-c]azetidinones are
known in the literature. See: (a) Mollet, K.; D’hooghe, M.; De Kimpe,
N. Tetrahedron 2012, 68, 10787. (b) Zhang, Z.; Zhang, Q.; Ni, Z.; Liu,
Q. Chem. Commun. 2010, 1269. (c) Alcaide, B.; Almendros, P.;
Martínez del Campo, T.; Carrascosa, R. Eur. J. Org. Chem. 2010, 4912.
(d) Leemans, E.; D’hooghe, M.; Dejaegher, Y.; Tornroos, K. W.; De
̈
Kimpe, N. Eur. J. Org. Chem. 2010, 352. (e) Alcaide, B.; Almendros, P.;
Martínez del Campo, T.; Soriano, E.; Marco-Contelles, J. L. Chem.
Eur. J. 2009, 15, 1901.
(9) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2000, 2,
1411. (b) Alcaide, B.; Almendros, P.; Martínez del Campo, T. Org.
Biomol. Chem. 2012, 10, 7603.
(10) (a) Bew, S. P.; Hiatt-Gipson, G. D.; Lovell, J. A.; Poullain, C.
Org. Lett. 2012, 14, 456. (b) Yabe, Y.; Sawama, Y.; Monguchi, Y.;
Sajiki, H. Chem.Eur. J. 2013, 19, 484.
(11) It is very interesting and strange that the observed epimerization
occurs at the α position of CO in the presence of Pt but not in the
presence of Ag, when it is well known that AgOTf is able to speed up
tautomeric equilibria; e.g., see: Dell’Acqua, M.; Abbiati, G.; Arcadi, A.;
8965
dx.doi.org/10.1021/jo401390k | J. Org. Chem. 2013, 78, 8956−8965