Samia R Lima1, Fernando Coelho1. 1. Institute of Chemistry-Laboratory of Synthesis of Natural Products and Drugs, University of Campinas, P.O. Box 6154, 13083-970 Campinas, São Paulo, Brazil.
Abstract
We report a direct, straightforward, and regioselective hydration of 1,4-enynes designed from Morita-Baylis-Hillman adducts. Under smooth conditions and short reaction times, gold-catalyzed hydration of internal alkynes provides synthetically useful ketones as single regioisomers in yields higher than 90%. The synthetic usefulness of this protocol was demonstrated by the conversion of selected ketones into biologically valuable α-alkylidene-γ-lactones upon reduction with sodium borohydride. In the course of the scope evaluation, we discovered that this methodology could also furnish α-arylidene-β,γ-butenolides.
We report a direct, straightforward, and regioselective hydration of 1,4-enynes designed from Morita-Baylis-Hillman adducts. Under smooth conditions and short reaction times, gold-catalyzed hydration of internal alkynes provides synthetically useful ketones as single regioisomers in yields higher than 90%. The synthetic usefulness of this protocol was demonstrated by the conversion of selected ketones into biologically valuable α-alkylidene-γ-lactones upon reduction with sodium borohydride. In the course of the scope evaluation, we discovered that this methodology could also furnish α-arylidene-β,γ-butenolides.
The
carbonyl functional group has a central role in modern organic
synthesis because its vastly developed reactivity makes it very synthetically
useful. Similarly, polycarbonylated compounds are valuable motifs.
In particular, 1,3- and 1,4-dicarbonyl compounds are important building
blocks in the synthesis of heterocycles.[1] 1,4-Dicarbonyl compounds are mainly employed in the synthesis of
pyrroles,[2] furans,[3] and thiophenes[4] via the Paal–Knorr
reaction (Scheme A–C).
This framework is also present in diverse natural products and drugs,
such as the cytotoxicditerpenoidmaoecrystal V,[5] the anticancer drug batimastat,[6] and the antineoplastic food additive quassin[7] (Scheme D).
Scheme 1
Importance of 1,4-Dicarbonyl Compounds
Highly efficient strategies exist for achieving 1,3-dicarbonyl
compounds, usually by exploiting the inherent polarity of the carbonyl
group.[8] On the other hand, although several
methodologies helpful in achieving different levels of complexity
were developed to access 1,4-dicarbonyl compounds, they are often
operationally difficult (e.g., by demanding anhydrous conditions),
require multistep preparation of two starting materials, or even undergo
undesired homoreactions. Most of these methodologies rely on the formation
of a C–C bond via enolate alkylation,[9] NHC-catalyzed Stetter reaction,[3c,10] and oxidative
coupling reactions.[11] A few examples of
more straightforward strategies involving alkynes have been reported
for the synthesis of 1,4-dicarbonyl compounds, including hydration
of 3-alkynoatescatalyzed by gold(III),[12] hydration of 3-en-1-ynescatalyzed by zinc(II) and gold(I) in the
presence of Selectfluor,[13] hydration of
alkynonescatalyzed by palladium(II),[14] formal hydration of 4-alkynones mediated by KOMe,[15] and enantioselective formal dehydration of ynamides.[8]In this scenario, gold catalysis, which
allows a rapid increase
in molecular complexity from alkynes as starting materials,[16] is an outstanding alternative for accessing
the carbonyl group because the addition of water to alkynes, when
catalyzed by gold(I) and gold(III), is a mild, atom-economic, and
operationally simple transformation.[17] However,
gold-catalyzed hydration of internal alkynes suffers from a notable
lack of regioselectivity.[18] In fact, to
the best of our knowledge, no general method exists for achieving
regioselectivity in hydration or hydroalkoxylation of internal alkynes
by means of gold catalysis.[19] Reported
strategies rely on the presence of electron-withdrawing groups[20] or, more frequently, on O- and N-based nucleophiles
attached to the triple bond.[21−23] These nucleophiles can act as
directing groups that form cycliccationic intermediates from intramolecular
attack to the triple bond. Subsequently, water attacks a specific
position on this intermediate, and the attached nucleophile becomes
a leaving group. Because the formation of a cyclic intermediate is
controlled by Baldwin’s rules, ketonescan be obtained with
great regioselectivity. This strategy of using a carbonyl group as
a neighboring nucleophile was first applied by Hammond and co-workers
for the synthesis of γ-keto esters (Scheme A).[12] A similar
strategy was used by Mohapatra and co-workers for the synthesis of
γ-acetoxy β-keto esters (Scheme B).[24] The acetoxy
group was claimed to be responsible for the observed selectivity.
Scheme 2
Strategies for Regioselective Au-Catalyzed Alkyne Hydration
We hypothesized that 1,4-enynes (3) prepared from
Morita–Baylis–Hillman (MBH) adducts could readily furnish
the access to a new pattern of highly functionalized 1,4,6-tricarbonylcompounds. We explored this possibility by exploiting the exceptional
ability of cationicgold(I)complexes to activate triple C≡C
bonds toward nucleophilic attack under mild conditions.[25] An electron-withdrawing fragment attached to
the triple bond could differentiate the two C sp atoms favoring water
attack at the distal carbon. Furthermore, the presence of an additional
carbonyl group could speed up the reaction through anchimeric assistance.
Should this assumption be correct, this strategy would allow rapid
and high regioselective access to polyfunctionalized ketones (Scheme C).
Results and Discussion
In order to test our hypothesis, we prepared MBH adducts 1 using a methodology previously developed by our group.[26] These adducts were then transformed into allylic
bromides 2. Most of these allylic bromides were prepared
in good yields by treatment of MBH adducts with aqueous HBr solution
in the presence of concentrated H2SO4.[27] However, under these conditions, we observed
degradation of some starting materials. In these cases, Appel conditions
furnished the desired allylic bromides.[28] Alkynylation of 2 with alkyl propiolates (3a–c) or but-3-yn-2-one (3d), in presence of 0.2 equiv of
CuI and 1.0 equiv of K2CO3, led to enynes 4 in 44–88% yield (Scheme ).[29] The alkynylation
conditions employed to prepare 4 were adapted from the
methodology described by Kim and co-workers for the synthesis of substituted
naphthalenes from allylic bromides in the presence of excess of base,
through propargyl–allenyl isomerization of 1,4-enynes generated
in situ. Unfortunately, the naphthalenes and the 1,4-enynes have the
same R (on TLC plates)
and could not be separated by column chromatography. We therefore
avoided naphthalene formation by first reducing the original amount
of the base (2.0 equiv) to 1.0 equiv. Under these conditions, enynes4aa–da and 4ae–ap were obtained
in typically good yields, at 60 °C. Enynes 4ab–ad, bearing halogens in their aromatic moieties, could only be prepared
at room temperature and only in moderate yields (Scheme ).
Scheme 3
Preparation of Substrates 1,4-Enynes (3),
Reaction conditions
for the alkynylation
step: aMBH bromide 2 (1.0 mmol), 3 (1.2 equiv), copper iodide (0.2 equiv), potassium carbonate (1.0
equiv), and 10 mL of CH3CN (0.1 M). bIsolated
yields after column chromatography. cIsolated yields based
on recovery of the starting materials.
Preparation of Substrates 1,4-Enynes (3),
Reaction conditions
for the alkynylation
step: aMBH bromide 2 (1.0 mmol), 3 (1.2 equiv), copper iodide (0.2 equiv), potassium carbonate (1.0
equiv), and 10 mL of CH3CN (0.1 M). bIsolated
yields after column chromatography. cIsolated yields based
on recovery of the starting materials.Once
the substrates were prepared, enyne4aa was chosen
as a model for optimizing the reaction conditions. The key results
are summarized in Table .
Table 1
Screening of Reaction Conditionsa
conversion
(%)b
entry
cat. (mol %)
solvent (v/v)
T (°C)
1 h
2 h
3 h
1
C1 (5)
CH3CN/H2O (2/1)
Rt
89 (83)c
2
C1 (5)
CH2Cl2/H2O (2/1)
Rt
83
3
C1(5)
CH3CN/H2O (1/1)
Rt
27
4
C1(5)
CH3CN/H2O (1/2)
Rt
29
5
C2 (5)
CH3CN/H2O (2/1)
Rt
94
6
C3 (5)
CH3CN/H2O (2/1)
Rt
95
7
C4 (5)
CH3CN/H2O (2/1)
Rt
94
8
C5 (5)
CH3CN/H2O (2/1)
Rt
94
9
C6 (5)
CH3CN/H2O (2/1)
Rt
82
10
C7 (5)
CH3CN/H2O (2/1)
Rt
76
11
C2 (1)
CH3CN/H2O (2/1)
Rt
50
79
92
12
C2 (2)
CH3CN/H2O (2/1)
Rt
53
79
94
13
C2 (1)
CH3CN/H2O(2/1)
50
94
96
>99
14
C2 (0.2)
CH3CN/H2O (2/1)
50
21
15d
CH3CN/H2O (2/1)
50
Reaction conditions: 0.2 mmol of 4aa, in 1 mL of solvent (0.2 M), [AgOTf] = 2[catalyst].
Estimated by 1H NMR of
the crude reaction mixture.
Isolated yields after column chromatography.
The reaction was carried out in
the absence of gold catalyst, with 10 mol % of AgOTf, only 6% of conversion
after 15 h.
Reaction conditions: 0.2 mmol of 4aa, in 1 mL of solvent (0.2 M), [AgOTf] = 2[catalyst].Estimated by 1H NMR of
the crude reaction mixture.Isolated yields after column chromatography.The reaction was carried out in
the absence of gold catalyst, with 10 mol % of AgOTf, only 6% of conversion
after 15 h.We first ran
the hydration of 4aa in CH3CN/H2O (2/1, v/v) at room temperature, in the presence
of 5 mol % of gold(I)-catalyst C1 and 10 mol % of AgOTf.
To our delight, under these conditions and just after 1 h, a conversion
of 89% was observed (Table , entry 1). The expected product 5aa was isolated
in 83% yield as a single regioisomer. The structure of 5aa was confirmed by 1H and 13C nuclear magnetic
resonance (NMR) spectra as well as by high-resolution mass spectrometry
(HRMS) analysis. Subsequently, CH3CN was replaced by CH2Cl2, keeping the initial proportion with water
(2:1, v/v). Under these conditions, the conversion of 4aa was reduced from 89% to 83% (entry 2). Because CH3CN
furnished a better result, we moved toward investigating the proportion
of solvents. Whereas 4aa was converted at 89% with CH3CN/H2O (2:1, v/v), only 27% was achieved with CH3CN/H2O (1/1, v/v) (entry 3) and 29% with CH3CN/H2O (1:2, v/v) (entry 4), confirming CH3CN/H2O (2:1, v/v) as the most suitable solvent
mixture for this transformation. We determined the best catalyst for
this reaction by testing complexes C2–C7. Gold(I)-catalysts C2–C4 and Au(III)-catalyst C5 satisfactorily
furnished conversions of 94–95% (entries 5–8). Conversely,
the use of Au(III)-catalyst C6 and Au(I)-catalyst C7 yielded conversions of only 82 and 76%, respectively (entries
9 and 10). These results confirmed that this transformation was very
smooth and fast; hence, we decided to investigate the possibility
of reducing the catalyst loading. For this, we chose to use catalyst C2, based on its availability in our laboratory. Initially,
the reaction was carried out using 1 mol % of C2; however,
by 3 h, the conversion was poorer than in the previous conditions
(entry 11). Similar results were observed with the use of 2 mol %
of C2 (entry 12). In an attempt to improve the reactivity of 4aa, the reaction temperature was increased to 50 °C.
At this temperature, using 1 mol % of C2, full conversion
(>99%) of 4aa was observed in 3 h (entry 13). An additional
reduction of catalyst loading to 0.2 mol % led to a conversion of
only 21% (entry 14). To rule out the possibility of silver-catalysis,
we run the hydration of 4aa in the presence of 10 mol
% of AgOTf and in the absence of any gold catalyst. Under these conditions,
a conversion of only 6% was observed after 15 h (Entry 15). Although
a few examples of efficient silver(I)-catalyzed hydration of internal
alkynes have been reported, they normally require harsh conditions
(the use of strong acids or high temperatures).[30]Having established the optimized conditions (Table , entry 13), we evaluated
the hydration scope.
The 1,4-enynescontaining aliphatic, styryl, heteroaryl, and halogenated
aryl substituents at R1 position and 1,4-enynes with methyl
ketone and different alkyl esters directly bonded to the triple bond
(R3) were all found to be suitable substrates for this
transformation, readily furnishing the hydrated product. Substrates
containing R2 = OEt, OMe, and Me furnished corresponding
poly-carbonylated compounds 5aa–an in excellent
yields (>90%) and regioselectivities (Scheme A). A different reactivity pattern was observed
when enynes bearing a R2 = OBu were employed. To these enynes, the tert-butyl
group was lost to form unexpected α-arylidene-butyrolactones6a and 6b. Under the optimized hydration conditions,
enyne4ao furnished cyclic enol ester6a′ in excellent yields after filtration on a plug of Celite. However,
when placed on silica, 6a′ was quantitatively
converted into its endocyclicolefinic isomerized form 6a. Similar behavior was observed with enyne 4ap, although
the exocyclicenolic double bond isomer could not be isolated with
proper purity (Scheme B).
Scheme 4
Substrate scope,
Reaction conditions: 4 (0.1 mmol), Et3PAuCl
(1.0 mol %), AgOTf (2.0 mol %) in
CH3CN/H2O 2:1 (v/v) (0.5 mL), stirred at 50
°C for 3 h. bIsolated yields after column chromatography. cIsolated yield after filtration. dConverted from 6a′ after column chromatography.
Substrate scope,
Reaction conditions: 4 (0.1 mmol), Et3PAuCl
(1.0 mol %), AgOTf (2.0 mol %) in
CH3CN/H2O 2:1 (v/v) (0.5 mL), stirred at 50
°C for 3 h. bIsolated yields after column chromatography. cIsolated yield after filtration. dConverted from 6a′ after column chromatography.We then endeavored to gain further insights into the mechanism
and influence of substituents on regioselectivity of the hydration
reaction by preparing substrate 7 and performing a control
experiment under our optimized conditions (Scheme ). Because 7 lacks one of the
carbonyl moieties (the one that comes from the MBH adduct) that could
work as a neighboring nucleophile, we were able to analyze the role
of this carbonyl group on the rate of the hydration reaction and to
determine whether the presence of the carbonyl group attached to the
triple bond would be sufficient to provide selectivity on water attack,
resulting in a regioselective hydration.
Scheme 5
Investigation of
Carbonyl Moiety Effects on Regioselectivity and
the Rate of the Hydration Reaction
Product 8 was obtained as a single regioisomer after
3 h. In agreement with our prediction, we verified that the reaction,
in the absence of the carbonyl moiety coming from MBH adduct, required
a higher catalytic loading for completion in 3 h (5 mol % of Et3PhAuCl), indicating that the reaction is slower for 7 than for the other substrates.Based on the control
experiment results and preliminary works,[12,21] we propose a plausible mechanism involving a cationiccyclic intermediate
(Scheme ). First,
gold(I)catalyst C2 coordinates with triple bond of alkyne4aa leading to complex A. The activated alkyne
moiety, in this complex, is then attacked by the nucleophiliccarbonyl
group, which is placed on the substrate to increase the rate of hydration,
leading to cyclic vinyl gold intermediate B or B′, in which both favored processes according to Baldwin’s
rules. The B′ type intermediate was proposed by
Oh and co-workers in the regioselective hydration of 1-arylalkynes
through carbonyl group participation.[21a] Because ketone5aa′ was not observed, 5-exo-dig cyclization should be the preferential pathway because
of the presence of an electron-withdrawing group attached at the triple
bond. The intermediate B is, in sequence, attacked by
water to form the ring-opened enol–gold species D, which undergoes protodeauration and leads to intermediate enol E. Finally, isomerization of E affords ketone5aa as a single product. This mechanistic proposal also accounts
for the formation of 6a and 6b; upon nucleophilic
attack of a water molecule, species B″ furnishes
a tetrahedral intermediate C″, which then loses BuOH to form the cyclicenol-gold ester D’’ (Scheme , path a). Alternatively, species D″ could be produced via direct formation of a tert-butyl cation (Scheme , path b). Protodeauration of D″ then generates 6a’. To investigate these mechanistic proposals, we
performed the reactions to form 5aa and 6a′ using a 3:2 (v/v) mixture of H2O[16]/H2O[18] under the optimized
conditions. HRMS(ESI) analysis of 6a′ did not
show any peak consistent with incorporation of O.[18] This result indicates that 6a′ is formed
according to path b in Scheme , with direct loss of a tert-butyl cation
and no inclusion of water. On the other hand, HRMS (ESI) analysis
of 5aa showed the presence of a peak at m/z 329.1252, two mass units more than that found
for the product hydrated by H2O.[16] Additionally, a quantitative NOE-decoupled 13C NMR experiment
showed a new signal at δ = 167.3 ppm (see Supporting Information). Because this new signal is compatible
with the chemical shift of a carboxyl carbon from an ester functional
group and substantially different from the original ketonecarbonyl
signal (δ = 200.5 ppm), it is reasonable that the incorporation
of O[18] happened in the α,β-unsaturated
ester moiety. Finally, the integration of the new signal is about
40% of the carboxyl carbon of the α,β-unsaturated ester
(proportional to the amount of H2O[18] used in the experiment). Besides supporting our mechanistic proposal
of water attack on the cationiccyclic intermediate B, these results suggest that this is the only path in the reaction,
without competition with a direct attack of water on the electrophilicalkynecarbon.
Scheme 6
Proposed Mechanism for the Au(I)-Catalyzed 1,4-Enyne
Hydration
We demonstrated the synthetic
importance of the polyfunctionalized
ketones achieved in this work by preparing a set of biologically valuable[31] α-arylidene-γ-lactones9a–g in good yields through reduction of the corresponding
ketones with sodium borohydride (Scheme ). Reduction of 5ah led to a
5:1 inseparable mixture of α-alkylidene-γ-lactone 9g and its endocyclicolefinic analogue 9g′ in 73% yield. Attempts to convert this mixture into the endocyclic
regioisomer 9g′ as a single product by using rhodium(III)chloride
hydrate[32] was unsuccessful.
Scheme 7
Synthesis
of α-Alkylidene-γ-lactones from Tricarbonyl
Compounds 5
Reaction conditions: 5 (0.1 mmol) and NaBH4 (1.2 equiv) in MeOH (1.3 mL), stirred
at 0 °C for 30 min. b9g + 9g′ (0.1
mmol), RhCl3·3H2O (1 mol %) in EtOH at
80 °C.
Synthesis
of α-Alkylidene-γ-lactones from Tricarbonyl
Compounds 5
Reaction conditions: 5 (0.1 mmol) and NaBH4 (1.2 equiv) in MeOH (1.3 mL), stirred
at 0 °C for 30 min. b9g + 9g′ (0.1
mmol), RhCl3·3H2O (1 mol %) in EtOH at
80 °C.
Conclusions
In summary, we have
developed an efficient and highly regioselective
gold(I)-catalyzed hydration of internal alkynes in a short reaction
time and with low catalytic loading. The substrates, which were designed
to provide regiocontrol and acceleration of the reaction, furnished
polyfunctionalized ketones5aa–ap with a long
carbonchain in excellent yields. The products are valuable intermediates
in organic synthesis, as exemplified by the formation of lactones9a–g upon reduction. In the course of the scope development,
we discovered that this methodology could also give the polyfunctionalized
α-arylidene-β and γ-butenolides 6a and 6b in excellent yields.
Experimental Section
General
Information
Unless otherwise noted, the commercially
available reagents were used without any further purification. All
experiments were monitored by thin-layer chromatography (TLC) on Merck
silica gel 60 F254 precoated plates. The TLC plates were visualized
under UV light (254 nm) or by exposure to sulfuricvanillin/dinitrophenylhydrazine/cerium
molybdate stains, followed by brief heating with a heat gun. Purification
by flash chromatography was performed on silica gel (230–400
mesh). NMR spectra were obtained in CDCl3 at 25 °C
using 250/400/500/600 spectrometers. For 1H NMR spectra,
the peak due to residual solvent (δ 7.26 ppm) was used as the
internal reference. For proton-decoupled 13C NMR spectra,
the reference was the central peak of the CDCl3 signal
(δ 77.16 ppm). The data are reported as follows: chemical shift
in ppm (relative to TMS), multiplicity (s = singlet, brs = broad singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet
of doublets, ddd = doublet of doublet of doublets, and qd = quartet
of doublets), coupling constants (J) in Hz, and integration.
The absorption spectra in the infrared region (IR) were obtained with
an Fourier transform infrared spectrophotometer fitted with a Ge crystal.
The IR absorbance frequencies were expressed in cm–1. High resolution mass spectrometry (HRMS) was performed using electrospray
ionization (ESI) (Synapt Q-TOF.). Melting points were measured and
were not corrected. Compounds were named according to IUPAC rules
using the MarvinSketch 15.9.21.0 program.
General Procedures for
the Synthesis of Allylic Bromides 2a–l
To a stirred solution of MBH adduct 1 in CH2Cl2 (0.1 M), at 0 °C, was
added dropwise 48% aqueous HBr solution (6.0 equiv) and then concentrated
aqueous H2SO4 solution (5.5 equiv). After stirring
overnight at room temperature, the mixture was cooled to 0 °C
and diluted with H20. The aqueous phase was extracted with
CH2Cl2 (3×), and the combined organic phase
was washed with H2O. After removal of solvent under reduced
pressure, the residue was purified by flash silica gelcolumn chromatography
using a mixture of ethyl acetate/hexane as eluent to afford the corresponding
allylic bromide. The spectral data of known allylic bromides are the
same as described.[25]
General Procedures
for the Synthesis of Allylic Bromides 2m–p
To a stirred solution of MBH adduct 1 in dry CH2CI2 (0.1 M), PPh3 (2.0 equiv) and CBr4 (2.0 equiv) were added under a nitrogen
atmosphere. The colored mixture was stirred at room temperature until
TLC analysis showed complete consumption of the start material (1–2
h). After completion, the reaction mixture was quenched with cold
water and extracted with CH2CI2 (3×). After
removal of solvent under reduced pressure, the residue was purified
by flash silica gelcolumn chromatography using a mixture of ethyl
acetate/hexane as eluent to afford the corresponding allylic bromide.
The spectral data of known allylic bromides are the same as described.[26]
General Procedure for the
Synthesis of Enynes (4aa–ap)
The corresponding
MBH bromide 2 (1.0 mmol),
copper iodide (0.2 mmol, 0.2 equiv), and potassium carbonate (1.0
mmol, 1.0 equiv) were added in a round-bottom flask containing a stir
bar. The flask was equipped with a rubber septum and was purged with
nitrogen using a needle. Dry acetonitrile (10 mL) and appropriate
terminal alkyne (1.2 equiv) were then added. The reaction was stirred
under a nitrogen atmosphere at the optimized temperature. After 2
or 24 h, 15 mL of saturated aqueous ammonium chloride solution was
added, and the resulting mixture was extracted at room temperature
with ethyl acetate (3 × 15 mL). After removal of the solvent
under reduced pressure, the residue was purified by flash silica gelcolumn chromatography, using a gradient mixture of ethyl acetate/hexane
as the eluent, to afford the corresponding enyne.
Enyne 7 was prepared according
to a literature procedure:[33] to an oven-dried
nitrogen purged flask containing a stir bar, E-(2-methyl-pent-1-en-4-ynyl)-benzene
(6.4 mmol) and dry THF (10.5 mL) were added. The system was cooled
to −78 °C using a dry ice-acetonecold bath. Then n-butyllithium (2.92 mL of 2.3 M in hexanes, 1.05 equiv)
was added dropwise to the solution and stirred for 30 min. Next, freshly
distilled ethyl chloroformate (0.396 mL, 4.02 mmol, 1.0 equiv) was
added dropwise. The reaction temperature was held at −78 °C
for 6 h and allowed to warm to room temperature overnight. The reaction
was quenched with saturated aqueous ammonium chloride (30 mL) and
extracted with CH2Cl2 (3 × 10 mL). After
removal of solvent under reduced pressure, the residue was purified
by flash silica gelcolumn chromatography using a gradient mixture
of ethyl acetate/hexane as eluent to afford the desired product 7 as pale yellow oil, 51% (68% brsm). 1H NMR (250
MHz, CDCl3): δ 7.37–7.20 (m, 5H), 6.54 (br
s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.22 (d, J = 1.0 Hz, 2H), 1.94 (d, J = 1.2 Hz, 3H),
1.33 (t, J = 7.1 Hz, 3H). 13C NMR (63
MHz, CDCl3): δ 153.9, 137.5, 131.2, 128.9 (2C), 128.2
(2C), 127.7, 126.7, 86.0, 75.5, 62.0, 29.6, 17.9, 14.2. IR (ATR, νmax): 2988, 2235, 1706, 1246, 1069, 752. HRMS (ESI) m/z calcd for C15H17O2+ [M + H]+, 229.1223; found, 229.1237.
General Procedure for the Synthesis of Hydrated Products (5aa–ap, 6a,6b)
In a 10 mL round-bottom
flask containing a stir bar, enyne4aa–ap (0.2
mmol), chloro(triethylphosphine)gold(I) (0.01 equiv), silver triflate
(0.02 equiv), acetonitrile (0.33 mL), and distilled water (0.17 mL)
were added. The reaction mixture was stirred at 50 °C for 3 h.
After reaction time, the solvent was removed under reduced pressure.
The residue was purified by flash silica gelcolumn chromatography
using a gradient mixture of ethyl acetate/hexane as eluent to afford
the corresponding product.
General Procedure for the
Synthesis of Lactones (9a–g)
In a 10
mL round-bottom flask containing a stir bar was
added ketone 5 (0.1 mmol), methanol (1.3 mL), and sodium
borohydride (0.12 mmol, 1.2 equiv). The reaction mixture was stirred
for 30 min at 0 °C. After complete consumption of the standard
material, the reaction was quenched with H2O (10 mL) and
extracted with ethyl acetate (3 × 10 mL) to afford pure lactones9a–g.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7