Furanyl Cyclic Ethers: Single and Double Diastereoselectivity in the Synthesis of 2,4-Di and 2,4,5-Trisubstituted Tetrahydropyrans

Article abstract of DOI:10.1021/acs.joc.6b02831

Combining the desymmetrization of a prochiral bis-hydroxymethyl group with the epimerization of a chiral furanyl ether in a single transformation, high levels of double diastereoselectivity have been achieved in a synthesis of 2,4,5-trisubstituted tetrahy

Full text of DOI:10.1021/acs.joc.6b02831

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Article
Furanyl Cyclic Ethers: Single and Double Diastereoselectivity in
the Synthesis of 2,4-di and 2,4,5-tri-substituted tetrahydropyrans.
Dennis A Cooper, Emma Robbins, Graham J. Tizzard, Simon J. Coles, and Matthew O'Brien
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02831 • Publication Date (Web): 28 Feb 2017
Downloaded from http://pubs.acs.org on March 3, 2017
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Furanyl Cyclic Ethers: Single and Double Diastereoselectivity in the Synthesis of 2,4-di
and 2,4,5-tri-substituted tetrahydropyrans.
a
a
b
b
Dennis A. Cooper , Emma Robbins , Graham J. Tizzard , Simon J. Coles and Matthew
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a
O’Brien *
a
Lennard-Jones Building, School of Chemical and Physical Sciences, Keele University,
b
Borough of Newcastle-under-Lyme, Staffordshire, ST5 5BG, UK. National Crystallography
Service, University of Southampton, SO17 1BJ, UK.
m.obrien@keele.ac.uk
ABSTRACT: Combining the desymmetrization of a prochiral bis-hydroxymethyl group with
the epimerization of a chiral furanyl ether in a single transformation, high levels of double
diastereoselectivity have been achieved in a synthesis of 2,4,5-trisubstituted tetrahydropyrans
which proceeds under thermodynamic control.
Introduction
The tetrahydropyran moiety is found in a large number of biologically active natural and non-
1
natural products and can rightly be classed as a privileged scaffold. Examples include
1
a
1b
zincophorin (ionophore antibiotic) , sorangicin-A (antibiotic) , polycarvernoside-A (algal
1
c
1d,e
1f,g
toxin) , the bryostatins (cytotoxins)
,
salinomycin (coccidiostat ionophore) ,
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h
halichondrin-B (cytotoxin) , eribulin (simplified synthetic analogue of halichondrin-B and
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clinical cancer chemotherapeutic) , swinholide-A (actin-binding cytotoxin) and the
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tubulexins (modulators of mitosis) . Due to the importance of these and other compounds,
the development of new stereoselective methodologies for tetrahydropyran construction has
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been, and continues to be, the focus of intense research activity. Building on our previous
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research into the use of epimerizable furanyl ethers in cyclic scaffolds, we here report the
diastereoselective formation of 2,4-syn-disubstituted tetrahydropyrans and the doubly
diastereoselective formation of 2,4,5-syn,anti-trisubstituted tetrahydropyrans. Our conceptual
plan is outlined in Scheme 1.
Scheme 1: Conceptual Outline
Using the ability of 2-furanyl ethers to epimerize under acidic conditions (via furanyl cations,
4
2
), we reasoned that a suitably placed substituent at the 4 position of a tetrahydropyran
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formed through the reversible cyclization of either diastereisomer of diol 1 would favor
formation of the 2,4-syn product syn-3. This would place both the 4-substituent and the
furanyl group in favored equatorial positions on a chair conformation. Each diastereisomer of
diol 1, present as a diastereisomeric mixture, would thus be converted to the same product
diastereisomer, irrespective of the original C-2/C-4 stereochemical relationship. Building on
this basic idea, the inclusion of a second hydroxymethyl group at C-5 would provide a
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prochiral bis(hydroxymethyl) center in 4 that would undergo desymmetrization upon
cyclization by the same reversible mechanism. The primary alcohol selected for inclusion in
the tetrahydropyran ring would be such that the remaining uncyclized hydroxymethyl group
at C-5 was left in an equatorial position.
Under thermodynamic conditions, syn-anti-5, in which all substituents are in
equatorial positions, would accordingly be favored. The chiral center at C-4 would thus
control the configuration at both C-2 and C-5 (Scheme 1). In addition to facilitating the key
cyclization/epimerization mechanism, the furan moiety is also synthetically versatile and can
be converted into a number of useful functional motifs (e.g. oxidative cleavage to the
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a
6b
6c
carboxylic acid , Achmatowicz-type oxidations , hydrogenation to the tetrahydrofuran,
6d
6e
Diels-Alder cycloadditions , [4+3] cycloadditions etc).
Results and Discussion
Scheme 2: Synthetic Route to Diol and Triol Substrates
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Our investigation began with the synthesis of diol substrates 1a-k (Scheme 2). Claisen-
Schmidt aldol condensation of either 2-acetylfuran 6a or 5-methyl-2-acetyl furan 6b with a
series of substituted benzaldehydes (which avoid self-aldol condensation) afforded the enones
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a-k, from which Michael addition of dimethylmalonate furnished the keto-diesters 8a-k.
Subsequent Krapcho decarboxylation led to the ketoesters 9a-k, which were purified by
column chromatography. LiAlH reduction provided the diols 1a-k (formed as approximately
4
1
:1 diastereisomeric mixtures) which were used without chromatographic purification.
Table 1: Diol Cyclization Results.
Entry
Ar
R
Diol (d.r.)
Yld
Prod (d.r.)
1
2
3
4
5
6
7
8
9
C
6
H
5
H
H
1a (1:0.7)
1b (1:0.75)
1b (4:1)
76 %
80 %
76 %
78 %
60 %
83 %
95 %
96 %
93 %
70 %
88 %
86 %
68 %
3a (16:1)
3b (21:1)
3b (19:1)
3b (20:1)
3c (11:1)
3d (20:1)
3e (20:1)
3f (12:1)
3g (25:1)
3h (21:1)
3i (18:1)
3j (19:1)
3k (20:1)
4-C
6
H
4
-Cl
-Cl
-Cl
4-C
4-C
6
6
H
4
4
H
H
H
1b (1:6)
4-C
4-C
3,4-C
4-C
2,4,5-C
4-C
6
H
4
-OMe
-Me
-(OMe)
-Br
-(OMe)
H
1c (1:0.75)
1d (1:0.74)
1e (1:0.8)
1f (1:0.76)
1g (1:0.65)
1h (1:0.67)
1i (1:0.65)
1j (1:0.7)
1k (1:0.75)
6
H
3
H
6
H
3
2
H
6
H
4
H
6
H
2
3
H
1
1
1
0
1
2
6
H
4
-Br
Me
Me
Me
Me
C
H
6 5
4-C
6
H
4
-CH
3
13
4-C
6
H
4
-Cl
With these diols in hand we investigated their acid catalyzed cyclizations. A brief screen of
solvents and acids identified acetonitrile and polymer supported sulfonic acid as satisfactory,
combining clean and rapid cyclization/epimerization with ease of workup (Table 1). Initial
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investigation focused on phenyl substrate 1a. The cyclization reaction itself was relatively
rapid. Loss of starting material was almost complete after 10 minutes (as judged by TLC and
NMR analysis of an aliquot). The initial ratio of syn and anti diastereomers syn-3a and anti-
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a at this time was 2.2:1. After 10 hours, a diastereomeric ratio of 16:1 was obtained.
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Analysis of chemical shifts, coupling constants and NOESY correlations in the H NMR
spectra indicated that the major product was the syn-3a diastereomer. Using the same
conditions, the cyclization reaction was carried out on a series of diol substrates 1a-k to
afford the 2,4-syn tetrahydropyran products 3a-k in high yields and with diastereoselectivities
ranging from 11:1 to 25:1 (Table 1). Adventitiously, we found that careful chromatography of
para-chloro diol 1b afforded diastereomerically enriched samples, both of which cyclized to
essentially the same ratio of tetrahydropyran diastereisomers as the original 1:0.75 mixture
(Table 1, entries 2-4). Pleasingly, tetrahydropyrans syn-3e and syn-3g formed crystals from
which we were able to obtain X-ray structures, confirming the stereochemistry (Figure 1,
syn-3g structure in Supp Info.) To explore our mechanistic hypothesis, and to obtain more of
the minor diastereisomer for NMR analysis, we carried out the cyclization under base
mediated conditions (Scheme 3). Treatment of the 1:0.7 syn/anti diastereisomeric mixture of
diols 1a with NaH and toluenesulfonyl chloride led to the formation of tetrahydropyrans syn-
3
a and anti-3a in the same 1:0.7 diastereomeric ratio, presumably via 10.
Scheme 3: Base Promoted Cyclization (Avoiding Epimerization).
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It is therefore unlikely that stereochemical equilibration at the furanyl center occurs under
these basic conditions. Syn-3a and anti-3a could be separated (at length) by careful column
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chromatography. The 2,4-anti diastereomer had an identical H NMR spectrum to the minor
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component from the acid catalyzed cyclization. The isolated anti-3a, when exposed to the
polymer supported sulfonic acid resin in acetonitrile, was cleanly converted to syn-3a,
consistent with the proposed mechanism. Having established that the C-4 substituent could
exert control of the configuration at C-2, we next investigated simultaneous control over the 2
and 5 positions.
Figure 1. X-Ray Structure of syn-3e (Thermal Ellipsoids Drawn at 50%)
LiAlH reduction of ketodiesters 8a-k afforded triols 4a-k (Scheme 2). Using the same acidic
4
conditions established for the diol substrates, cyclization of triol 4a (d.r.=1:0.8) proceeded
smoothly and, after equilibration, the product 5a was formed in high yield and with high
diastereoselectivity. The two major diastereomers were formed in a ratio of 26:1. Similar
results were also obtained for a number of other triol substrates, present as approximately 1:1
mixtures of diastereomers (Table 2). In each case, key NMR signals for major and minor
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diastereomers closely mirrored those of 5a. H NMR coupling constants, chemical shifts and
NOESY correlations were consistent with the major products having 2,4,5-syn,anti
stereochemistry with all substituents in equatorial positions, as predicted. This was confirmed
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by single crystal X-ray analysis of syn,anti-5g (Figure 2). The main observable minor
diastereomer had a significantly higher chemical shift for the C-2 hydrogen, consistent with
an equatorial orientation, indicating that this diastereomer was epimeric at the furanyl ether
center. Although the reaction was clearly very diastereoselective, we sought clarity as to the
nature and distribution of all minor diastereomers (several NMR peaks of which were
dwarfed and obscured by those of the major product).
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Table 2. Triol Cyclization Results.
Entry
Ar
R
Triol (d.r.)
Yld
Prod (d.r.)
1
2
C
6
H
5
H
H
4a (1:0.8)
4b (1:0.8)
anti-4b
99%
95%
92%
94%
87%
89%
89%
86%
96%
63%
84%
75%
87%
5a (26:1)
5b (21:1)
5b (21:1)
5b (21:1)
5c (20:1)
5d (25:1)
5e (24:1)
5f (20:1)
5g (20:1)
5h (19:1)
5i (20:1)
5j (21:1)
5k (20:1)
4-C
4-C
4-C
6
H
H
H
4
-Cl
-Cl
-Cl
3
6
6
4
4
H
4
H
syn-4b
5
4-C
4-C
3,4-C
4-C
2,4,5-C
4-C
6
H
4
-OMe
-Me
-(OMe)
-Br
-(OMe)
H
4c (1:0.65)
4d (1:0.75)
4e (1:1)
6
6
H
3
H
7
6
H
3
2
H
8
6
H
4
H
4f (0.8:1)
4g (1:0.5)
4h (1:0.6)
4i (1:0.5)
4j (1:0.6)
4k (1:0.6)
9
6
H
2
3
H
10
6
H
4
-Br
Me
Me
Me
Me
1
1
1
1
2
3
C
H
6 5
4-C
6
H
4
-CH
3
4-C
6
H
4
-Cl
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Figure 2. X-ray structure of 2,4,5-syn,anti-5g (thermal ellipsoids shown at 50%)
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Chromatographic isolation of minor diastereomers eluded our efforts. Fortuitously, we found
that the anti diastereomer of the para-chloro triol compound, anti-4b, was crystalline whilst
syn-4b was an oil. This discovery suggested a possible means of accessing all four possible
cyclization products and, by comparison of spectra, of determining the product distribution
obtained during the triol cyclization. At length, repeated cycles of recrystallization from ethyl
acetate furnished useful quantities of the diastereomerically pure triols, anti-4b and syn-4b.
In addition to facilitating this separation, the crystalline nature of anti-4b provided, through
X-ray crystallography, unambiguous determination of its relative stereochemistry (and
therefore the relative stereochemistry of syn-4b also), Figure 3.
Figure 3. X-ray structure of Anti-4b (thermal ellipsoids at 50%)
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Consistent with the proposed mechanism, either of these pure triol diastereomers, when
exposed to the cyclization conditions, furnished the same 21:1 ratio of products as obtained
from cyclization of the original 1:0.8 mixture of diastereomers (Table 2, entries 3 and 4).
Triols anti-4b and syn-4b could be converted to the corresponding mixtures of mono-TBDPS
ethers 11a,b and 11c,d where, in each case, the TPDPS ether was formed at one of the two
primary alcohols (Scheme 4). The pair of mono-TBDPS ethers, 11a and 11b, were separated
from each other by careful column chromatography on silica gel, as were 11c and 11d.
Following their isolation, each of these diastereomerically pure diols was then independently
cyclized under the established acidic conditions. With one hydroxymethyl group now tied up
as a TBDPS ether, epimerization of the bis(hydroxymethyl) group was no longer possible,
thus fixing the C-4/C-5 relative stereochemistry. Epimerization was limited to the furanyl
center at C-2. As expected, the stereochemistry at the configurationally labile furanyl center
in the starting material had no bearing on the stereochemical outcome of the reaction. Each
diol 11a-d produced only one of the two possible pairs of products (12a,b or 12c,d),
depending only on the C-4/C-5 relative stereochemistry. Thus, 11a and 11c, whose relative
stereochemistries differ only at the C-2 furanyl alcohol, both afforded the same mixture of
tetrahydropyrans 12a,b, epimeric at C-2, in the same diastereomeric ratio. Likewise, when
either 11b or 11d were cyclized, the same mixture of C-2 epimers 12c and 12d was formed.
These cyclization reactions were left for only 3 hours in order to obtain observable NMR
peaks for the minor products rather than attempt to achieve greater diastereoselectivity. In
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each pair, the H NMR spectrum of the major component was consistent with having an axial
hydrogen at C-2. Once the TBDPS groups of the 12a,b and 12c,d mixtures were removed,
using TBAF, the NMR spectra of the resulting mixtures of alcohols ([syn,anti-5b + anti,anti-
5b] from 12a,b and [syn,syn-5b + anti,syn-5b] from 12c,d) were compared with that
obtained following the cyclization of triol 4b. It was found that syn,anti-5b, anti,anti-5b, and
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syn,syn-5b were present in the triol cyclization product, in a ratio of 25:1:0.9, whilst the
remaining diastereomer, anti,syn-5, was not present at all. Interestingly, cyclization of either
11b or 11d to the mixture of products 12c,d was also diastereoselective (d.r. = 6:1,
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unoptimized). Once the restraining TPDPS group was removed from each pair of
tetrahydropyrans, acid catalyzed equilibration of either [syn,syn-5b + anti,syn-5b] or
[
syn,anti-5b + anti,anti-5b] led cleanly to the same 25:1:0.9 mixture of diastereomers as
obtained from cyclization of triol 4b (Scheme 4).
Scheme 4. Stereochemical correlations
In conclusion, the formation of 2,4-disubstituted tetrahydropyrans occurs via a highly
diastereoselective acid mediated cyclization-epimerization reaction which favors the 2,4-syn
diastereomer capable of adopting the energetically favorable diequatorial chair conformation.
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The reaction harnesses the propensity of the furanyl ether moiety to epimerize in the presence
of a suitable acid catalyst, presumably via a furanyl cation intermediate. Extending the
concept further, 2,4,5-trisubstituted tetrahydropyrans are also formed in a reaction which
displays very high levels of double diastereoselectivity favoring the 2,4,5-syn,anti
diastereomer.
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Experimental Section
NMR spectra were recorded in CDCl , CD CN or CD OD solutions at room temperature with
3
3
3
1
13
a 400 MHz spectrometer (400 MHz for H, 100 MHz for C) or a 300 MHz spectrometer
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13
(
300 MHz for H, 75 MHz for C). CDCl was stored over granular anhydrous potassium
3
1
13
carbonate in a brown glass bottle. The H and C chemical shifts are reported relative to
tetramethylsilane (0.0 ppm). Coupling constants (J-values) are reported in Hz. In a few
instances, apodization was used to facilitate J-value determination. Protons coupling to two
other non-identical protons but with identical coupling constants are generally referred to as
doublets of doublets, rather than triplets (or apparent triplets). Assignment of peaks in the
proton NMR spectra was carried out using chemical-shift values, coupling constants, COSY,
1
TOCSY, HMBC and HSQC. Peak assignments given in the H NMR data follow the
numbering scheme used for THP rings in the manuscript (see diagrams in Supporting
Information for details). Melting point temperatures are uncorrected. TLC analysis was
carried out using silica gel impregnated with fluorescent indicator on aluminium backed
plates. Plates were visualized either by UV fluorescence (254 nm) or by staining with acidic
vanillin solution or alkaline potassium permanganate solution. Column chromatography was
carried out using silica gel. Where anhydrous tetrahydrofuran was required, this was either
purchased in anhydrous form or was obtained by passing reagent grade unstabilized solvent
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through alumina packed columns under nitrogen (Grubbs system). Where anhydrous diethyl
ether was required, this was obtained by stirring reagent grade diethyl ether with calcium
hydride under a nitrogen atmosphere. All other solvents were used as supplied without further
purification. HRMS measurements were carried out on an LCMS mass spectrometer using
electrospray ionization and a TOF analyzer. Infrared spectra were obtained using a thin film
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(evaporated from solution) on an ATR spectrometer. Single-crystal X-ray diffraction analyses
of 3e, 3g, anti-4b and 5g were performed using an area detector mounted at the window of a
rotating anode generator with a Mo anode (λ=0.71075Å) and equipped with a cryostream
device. The crystals were mounted on loops and the data were collected at 100 K. Data were
processed and empirical absorption corrections were carried out using CrystalClear SM-
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Expert. The structures were solved by charge-flipping using SUPERFLIP and refined on F
o
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by full-matrix least squares refinement using SHELXL-2014. All non-hydrogen atoms were
refined with anisotropic displacement parameters. Hydrogen atoms were added at calculated
positions to carbon atoms with isotropic displacement parameters based on the equivalent
isotropic displacement parameter (Ueq) of the parent atom. The CIF files for the crystal
structures have been deposited with the CCDC and been given the deposition numbers
1
410355 (3e), 1410356 (5g), 1410357 (3g) and 1410358 (anti-4b).
General Procedure for Malonate Additions to form 8a-k
Sodium hydride (60% dispersion in mineral oil, 221 mg, 5.52 mmol, 2 equiv.) was suspended
in anhydrous tetrahydrofuran (14 mL), under an atmosphere of dry nitrogen. The mixture was
then cooled to −18 °C (ice/acetone bath). Dimethyl malonate (632 μL, 729 mg, 5.52 mmol, 2
equiv.) was then added dropwise (causing effervescence) and the reaction mixture was then
stirred for 15 minutes at room temperature. The mixture was again cooled to −18 °C and the
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corresponding enone 7a-k (2.76 mmol, 1 equiv.) was added dropwise as a solution in
anhydrous tetrahydrofuran (5 mL). The reaction was stirred for approximately 4 hours at
room temperature. Upon completion, the reaction mixture was partitioned between diethyl
ether (20 mL) and saturated ammonium chloride (20 mL). The aqueous phase was extracted
with diethyl ether (3 × 20 mL) and the combined organic phases were washed with water (50
mL) and brine (50 mL). The organic phase was then dried over magnesium sulfate and
concentrated under reduced pressure. Material was then taken through to the next step
without further purification. A small portion of each ketodiester product was purified by
column chromatography for spectroscopic characterization, using silica gel and a solvent
gradient starting at petroleum ether and reaching 1:1 petroleum ether-diethyl ether.
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Dimethyl 2-(3-(furan-2-yl)-3-oxo-1-phenylpropyl)malonate 8a
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, dd, J = 1.7, 0.7, 11-H), 7.30 - 7.16 (5H, m, Ar-H),
3
7
5
.15 (1H, dd, J = 3.6, 0.7, 9-H), 6.48 (1H, dd, J = 3.6, 1.7, 10-H), 4.16 (1H, ddd, J = 9.6, 8.3,
.8, 4-H), 3.86 (1H, d, J = 9.6, 5-H), 3.73 (3H, s, OMe), 3.51 (3H, s, OMe), 3.39 (1H, dd, J =
1
3
16.5, 8.3, 3-H), 3.32 (1H, dd, J = 16.5, 5.8, 3-H’); C NMR (75 MHz, CDCl ) δ 186.4,
3
1
68.5, 168.0, 152.4, 146.3, 146.3, 140.0, 128.4, 128.0, 127.2, 117.2, 112.2, 57.1, 52.6*, 52.4*
(show very fine splitting, 3 Hz), 42.1, 40.5; IR (thin film) νmax 3125, 3097, 2957, 1724,
1664, 1563, 1473, 1455, 1430, 1403, 1352, 1332, 1294, 1268, 1236, 1218, 1195, 1152, 1095,
-1
1
071, 1044, 1018, 1002, 980, 950, 918, 881, 860, 771, 759, 699, 683, 618, 564, 531 cm ;
+
HRMS MNa (C H O Na) calcd 353.1001, found 353.1017.
18 18
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Dimethyl 2-(1-(4-chlorophenyl)-3-(furan-2-yl)-3-oxopropyl)malonate 8b
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, dd, J = 1.7, 0.7, 11-H), 7.21 (4H, s, Ar-H), 7.15 (1H,
3
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2
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dd, J = 3.6, 0.7, 9-H), 6.49 (1H, dd, J = 3.6, 1.7, 10-H), 4.14 (1H, ddd, J = 9.5, 8.1, 6.0, 4-H),
3.82 (1H, d, J = 9.5, 5-H), 3.74 (3H, s, OMe), 3.53 (3H, s, OMe), 3.35 (1H, dd, J = 16.7, 8.1,
1
3
3
1
-H) , 3.29 (1H, dd, J = 16.7, 6.0, 3-H’); C NMR (75 MHz, CDCl ) δ 186.2, 168.3, 167.8,
3
52.5, 146.4, 138.7, 133.0, 129.5, 128.6, 117.2, 112.3, 56.9, 52.7, 52.5, 41.9, 39.9; IR (thin
film) νmax 3131, 2956, 2853, 1743, 1726, 1662, 1562, 1491, 1467, 1433, 1417, 1399, 1307,
-1
1
274, 1251, 1199, 1157, 1113, 1090, 1069, 1039, 1022, 993, 945, 928, 910, 831 cm ; HRMS
+
MNa (C H O NaCl) calcd 387.0611, found 387.0619.
18 17
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Dimethyl 2-(3-(furan-2-yl)-1-(4-methoxyphenyl)-3-oxopropyl)malonate 8c
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, dd, J = 1.7, 0.7, 11-H), 7.17 (2H, d, J = 8.7, Ar-H),
3
7
.15 (1H, m, 9-H), 6.77 (2H, d, J = 8.7, Ar-H’), 6.48 (1H, dd, J = 3.6, 1.7, 10-H), 4.11 (1H,
ddd, J = 9.6, 8.2, 6.1, 4-H), 3.81 (1H, d, J = 9.6, 5-H), 3.74 (3H, s, OMe), 3.73 (3H, s, OMe),
1
3
3.51 (3H, s, OMe), 3.40-3.38 (2H, m, 3-H,H’); C NMR (75 MHz, CDCl ) δ 186.6, 168.7,
3
1
68.1, 158.5, 152.5, 146.3, 131.9, 129.1, 117.2, 113.8, 112.2, 57.4, 55.1, 52.7, 42.3, 40.0; IR
thin film) νmax 3126, 3098, 2956, 2838, 1727, 1665, 1612, 1583, 1515, 1474, 1431, 1421,
1402, 1289, 1270, 1252, 1233, 1192, 1179, 1159, 1115, 1089, 1078, 1045, 1032, 998, 981,
(
-1
+
9
3
51, 919, 881, 827, 769, 734, 677, 598, 563, 533 cm ; HRMS MNa (C H O Na) calcd
19 20 7
83.1107, found 383.1094.
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Dimethyl 2-(3-(furan-2-yl)-3-oxo-1-(p-tolyl)propyl)malonate 8d
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, d, J = 1.6, 11-H), 7.15 (1H, d, J = 3.6, 9-H), 7.13
3
10
11
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(
2H, d, J = 8.0, Ar-H), 7.04 (2H, d, J = 8.0, Ar-H’), 6.48 (1H, dd, J = 3.6, 1.6, 10-H), 4.12
(1H, ddd, J = 9.5, 8.1, 6.0, 4-H), 3.82 (1H, d, J = 9.5, 5-H), 3.73 (3H, s, OMe), 3.51 (3H, s,
OMe), 3.21 (1H, dd, J = 16.6, 8.1, 3-H), 3.32 (1H, dd, J = 16.6, 6.0, 3-H’), 2.26 (3H, s, Ar-
1
3
Me); C NMR (75 MHz, CDCl ) δ 186.6, 168.6, 168.1, 152.5, 146.3, 136.9, 136.8, 129.2,
3
127.8, 117.2, 112.2, 57.3, 52.7, 52.4, 42.2, 40.2, 21.0; IR (thin film) νmax 3126, 3097, 2948,
1
1
743, 1730, 1665, 1565, 1516, 1473, 1433, 1401, 1347, 1319, 1306, 1273, 1250, 1241, 1194,
116, 1089, 1076, 1044, 1022, 992, 974, 951, 929, 912, 882, 854, 820, 778, 770, 735, 720,
-1
+
596, 552 cm ; HRMS MNa (C H O Na) calcd 367.1158, found 367.1174.
1
9
20
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Dimethyl 2-(1-(3,4-dimethoxyphenyl)-3-(furan-2-yl)-3-oxopropyl)malonate 8e
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, dd, J = 1.7, 0.7, 11-H), 7.14 (1H, dd, J = 3.6, 0.7, 9-
3
H), 6.81 – 6.70 (3H, m, Ar-H), 6.48 (1H, dd, J = 3.6, 1.7, 10-H), 4.10 (1H, ddd, J = 9.3, 8.9,
5.3, 4-H), 3.83 (1H, d, J = 9.3, 5-H), 3.82 (3H, s, OMe), 3.80 (3H, s, OMe), 3.72 (3H, s,
OMe), 3.52 (3H, s, OMe), 3.35 (1H, dd, J = 16.4, 8.9, 3-H) , 3.26 (1H, dd, J = 16.4, 5.3, 3-
1
3
H’); C NMR (75 MHz, CDCl ) δ 186.6, 168.6, 168.1, 152.5, 148.5, 147.9, 146.3, 132.5,
3
119.8, 117.2, 112.2, 111.4, 110.9, 57.3, 55.8, 55.7, 52.7, 52.5, 42.1, 40.3; IR (thin film) νmax
2
953, 2838, 1732, 1671, 1592, 1568, 1518, 1465, 1435, 1394, 1257, 1236, 1195, 1142, 1025,
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-1
+
9
4
10, 883, 766, 728, 646, 595 cm ; HRMS MNa (C H O Na) calcd 413.1212, found
20 22 8
13.1216.
0
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Dimethyl 2-(1-(4-bromophenyl)-3-(furan-2-yl)-3-oxopropyl)malonate 8f
1
H NMR (300 MHz, CDCl ) δ 7.51 (1H, dd, J = 1.6, 0.7, 11-H), 7.34 (2H, d, J = 8.5, Ar-H),
3
7.15 - 7.11 (3H, m, Ar-H’, 9-H), 6.46 (1H, dd, J = 3.6, 1.6, 10-H), 4.12 (1H, ddd, J = 9.3, 8.5,
5
1
.7, 4-H), 3.80 (1H, d, J = 9.3, 5-H), 3.70 (3H, s, OMe), 3.49 (3H, s, OMe), 3.34 (1H, dd, J =
1
3
6.7, 8.5, 3-H) , 3.27 (1H, dd, J = 16.7, 5.7, 3-H’); C NMR (75 MHz, CDCl ) δ 186.0,
3
168.2, 167.7, 152.2, 146.4, 139.1, 131.4, 129.8, 121.0, 117.2, 112.2, 56.7, 52.6, 52.4, 41.7,
3
1
8
4
9.8; IR (thin film) νmax 3131, 2955, 2924, 2854, 1740, 1724, 1660, 1561, 1488, 1466, 1432,
411, 1332, 1306, 1253, 1217, 1200, 1155, 1084, 1065, 1021, 1011, 991, 944, 927, 909, 875,
-
1
+
46, 827, 813, 793, 765, 554 cm ; HRMS MNa (C H O NaBr) calcd 431.0106, found
18
17
6
31.0119.
Dimethyl 2-(3-(furan-2-yl)-3-oxo-1-(2,4,5-trimethoxyphenyl)propyl)malonate 8g
1
H NMR (300 MHz, CDCl ) δ 7.53 (1H, dd, J = 1.7, 0.6, 11-H), 7.16 (1H, dd, J = 3.6, 0.6, 9-
3
H), 6.71 (1H, s, Ar-H), 6.48 (1H, dd, J = 3.6, 1.7, 10-H), 6.43 (1H, s, Ar-H’), 4.23 – 4.13
(
2H, m, 5-H,4-H), 3.83 (3H, s, OMe), 3.81 (3H, s, OMe’), 3.76 (3H, s, OMe’’), 3.73 (3H, s,
1
3
OMe’’’), 3.54 – 3.44 (4H, m, OMe’’’’, 3-H), 3.22 (1H, dd, J = 15.9, 4.0, 3-H’); C NMR (75
MHz, CDCl ) δ 187.1, 169.0, 168.4, 152.6, 151.6, 148.6, 146.2, 142.3, 118.6, 117.1, 114.3,
3
112.1, 97.3, 56.4, 56.1, 55.9, 54.9, 52.5, 52.3, 40.5, 37.8; IR (thin film) νmax 2953, 2837,
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-1
33, 702 cm
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Dimethyl 2-(1-(4-bromophenyl)-3-(5-methylfuran-2-yl)-3-oxopropyl)malonate 8h
1
H NMR (300 MHz, CDCl ) δ 7.36 (2H, d, J = 8.5, Ar-H), 7.14 (2H, d, J = 8.5, Ar-H’), 7.07
3
(1H, d, J = 3.4, 9-H), 6.10 (1H, dd, J = 3.4, 0.9, 10-H), 4.10 (1H, ddd, J = 9.6, 8.5, 5.7, 4-H),
3
3
1
.82 (1H, d, J = 9.6, 5-H), 3.73 (3H, s, OMe), 3.52 (3H, s, OMe), 3.25 (1H, dd, J = 16.4, 8.5,
13
-H), 3.23 (1H, dd, J = 16.4, 5.7, 3-H’), 2.34 (3H, s, 11-Me); C NMR (75 MHz, CDCl ) δ
3
85.3, 168.3, 167.9, 157.9, 151.1, 139.2, 131.5, 129.9, 121.1, 119.4, 109.0, 56.8, 52.8, 52.5,
41.5, 40.2, 14.0; IR (thin film) νmax 2953, 2923, 2852, 1730, 1660, 1514, 1488, 1433, 1241,
-1
+
1
206, 1159, 1074, 1038, 992, 960, 909, 826, 795, 765, 718, 692, 556 cm ; HRMS MNa
(
C H O NaBr) calcd 445.0263, found 445.0278.
1
9
19
6
Dimethyl 2-(3-(5-methylfuran-2-yl)-3-oxo-1-phenylpropyl)malonate 8i
1
H NMR (300 MHz, CDCl ) δ 7.27 – 7.23 (5H, m, Ar-H), 7.07 (1H, d, J = 3.4, 9-H), 6.09
3
(
1H, d, J = 3.4, 10-H), 4.14 (1H, ddd, J = 9.6, 8.3, 5.7, 4-H), 3.86 (1H, d, J = 9.6, 5-H), 3.73
3H, s, OMe), 3.49 (3H, s, OMe), 3.28 (1H, dd, J = 16.1, 8.3, 3-H), 3.26 (1H, dd, J = 16.1,
(
1
3
5.7, 3-H’), 2.35 (3H, s, 11-Me); C NMR (75 MHz, CDCl ) δ 185.7, 168.6, 168.1, 157.7,
3
1
51.3, 140.1, 128.4, 128.1, 127.2, 119.3, 108.9, 57.2, 52.7, 52.4, 41.8, 40.9, 14.0; IR (thin
film) νmax 2954, 2922, 1746, 1727, 1659, 1516, 1456, 1433, 1417, 1293, 1252, 1205, 1149,
-1
+
1074, 1040, 1027, 977, 956, 925, 904, 788, 764, 702, 564, 530 cm ; HRMS MNa
(
C H O Na) calcd 367.1158, found 367.1140.
1
9
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Dimethyl 2-(3-(5-methylfuran-2-yl)-3-oxo-1-(p-tolyl)propyl)malonate 8j
0
1
2
3
4
5
6
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8
9
0
1
2
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8
9
0
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7
8
9
0
1
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4
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6
7
8
9
0
1
H NMR (300 MHz, CDCl ) δ 7.13 (2H, d, J = 8.1, Ar-H), 7.08 (1H, d, J = 3.4, 9-H), 7.04
3
(2H, d, J = 8.1, Ar-H), 6.09 (1H, dd, J = 3.4, 0.8, 10-H), 4.09 (1H, ddd, J = 9.5, 7.9, 6.0, 4-
H), 3.83 (1H, d, J = 9.5, 5-H), 3.73 (3H, s, OMe), 3.51 (3H, s, OMe), 3.26-3.10 (2H, m, 3-
13
H,H’), 2.34 (3H, s, 11-Me), 2.25 (3H, s, Ar-Me); C NMR (75 MHz, CDCl ) δ 185.8, 168.7,
3
1
2
68.1, 157.7, 151.3, 137.0, 136.7, 129.1, 127.9, 119.3, 108.9, 57.3, 52.6, 52.4, 41.9, 40.5,
1.0, 14.0; IR (thin film) νmax 2953, 2922, 2852, 1749, 1729, 1660, 1515, 1432, 1360, 1379,
-
1
301, 1239, 1221, 1196, 1144, 1115, 1081, 1041, 983, 959, 906, 816, 794, 722, 560, 533 cm
1
+
; HRMS MNa (C H O Na) calcd 381.1314, found 381.1311.
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Dimethyl 2-(1-(4-chlorophenyl)-3-(5-methylfuran-2-yl)-3-oxopropyl)malonate 8k
1
H NMR (300 MHz, CDCl ) δ 7.13 (4H, s, Ar-H), 7.06 (1H, d, J = 3.5, 9-H), 6.08 (1H, d, J =
3
3
.5, 10-H), 4.07 (1H, ddd, J = 9.7, 8.6, 5.6, 4-H), 3.79 (1H, d, J = 9.7, 5-H), 3.71 (3H, s,
OMe), 3.49 (3H, s, OMe), 3.22 (1H, dd, J = 16.3, 8.6, 3-H), 3.20 (1H, dd, J = 16.3, 5.6, 3-
1
3
H’), 2.30 (3H, s, 11-Me); C NMR (75 MHz, CDCl ) δ 185.5, 168.4, 167.9, 158.0, 151.0,
3
1
38.5, 132.9, 129.4, 128.5, 119.6, 109.0, 57.0, 52.7, 52.5, 41.5, 40.1, 13.9; IR (thin film) νmax
2
954, 1728, 1660, 1515, 1491, 1435, 1272, 1239, 1221, 1164, 1082, 1039, 1015, 960, 907,
-1
828, 795, 728, 648, 559 cm
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General Procedure for Krapcho Decarboxylations of ketodiesters 8a-k to form
ketoesters 9a-k
A portion of crude keto-diester 8a-k (2.00 mmol, 1 equiv.) was dissolved in a 5:1 mixture of
10
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dimethyl sulfoxide and water (30 mL). To this was added lithium chloride (3.39 g, 80 mmol,
4
0 equiv.) and the mixture was heated at 110 °C for 36 hours. Upon completion the reaction
mixture was partitioned between diethyl ether (50 mL) and water (50 mL). The aqueous
phase was extracted with diethyl ether (3 × 30 mL). The combined organic phases were then
washed with water (2 × 100 mL) and brine (100 mL) and dried over magnesium sulfate. The
solution was then concentrated under reduced pressure and the crude product purified by
column chromatography using silica gel and a solvent gradient from hexane to 1:1
hexane:diethyl ether, affording the product 9a-k.
Methyl 5-(furan-2-yl)-5-oxo-3-phenylpentanoate 9a
1
2
45 mg from 396 mg 7a (45%, 2 steps), m.p. 85.2-85.6 C; H NMR (300 MHz, CDCl ) δ
3
7.52 (1H, m, 11-H), 7.28 – 7.14 (5H, m, Ar-H), 7.13 (1H, d, J = 3.6, 9-H), 6.47 (1H, m, 10-
H), 3.83 (1H, dddd, J = 7.3, 7.3, 7.3, 7.3, 4-H), 3.55 (3H, s, OMe), 3.19 (2H, d, J = 7.3, 3-H,
1
3
3
-H’), 2.78 (1H, dd, J = 15.5, 7.3, 5-H), 2.67 (1H, dd, J = 15.5, 7.3, 5-H’); C NMR (75
MHz, CDCl ) δ 187.2, 172.1, 152.6, 146.3, 142.9, 128.5, 127.2, 126.8, 117.1, 112.2, 51.5,
3
4
4.3, 40.4, 37.4; IR (thin film) νmax 3128, 3100, 2950, 1726, 1660, 1565, 1466, 1430, 1396,
-1
1354, 1288, 1245, 1219, 1197, 1064, 1086, 1064, 1043, 1007, 985, 952, 919, 882 cm ;
+
HRMS MNa (C H O Na) calcd 295.0946, found 295.0945.
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Methyl 3-(4-chlorophenyl)-5-(furan-2-yl)-5-oxopentanoate 9b
1
6
7
4 mg from 442 mg 7b (11%, 2 steps), m.p. 83.3-84.2 C; H NMR (300 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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3
4
5
6
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9
0
1
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3
4
5
6
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8
9
0
.55 (1H, m, 11-H), 7.25 (2H, d, J = 8.2, Ar-H), 7.19 (2H, d, J = 8.2, Ar-H’), 7.17 (1H, dd, J
= 3.6, 0.4, 9-H), 6.51 (1H, dd, J = 3.6, 1.7, 10-H), 3.78 (1H, m, 4-H), 3.58 (3H, s, OMe), 3.18
2H, d, J = 7.2, 3-H, 3-H’), 2.78 (1H, dd, J = 15.6, 6.8, 5-H), 2.66 (1H, dd, J = 15.6, 8.2, 5-
(
1
3
H’); C NMR (75 MHz, CDCl ) δ 186.9, 171.9, 152.6, 146.4, 141.4, 132.5, 128.7 (2xC) ,
3
1
1
17.3, 112.3, 51.7, 44.1, 40.3, 36.8; IR (thin film) νmax 3124, 3098, 2952, 1721, 1661, 1563,
494, 1473, 1430, 1398, 1362, 1327, 1306, 1290, 1267, 1216, 1195, 1155, 1106, 1089, 1066,
-
1
1042, 1014, 1000, 986, 950, 920, 906, 881, 873, 827, 770, 730, 709, 597, 536, 519 cm ;
+
HRMS MNa (C H O NaCl) calcd 329.0557, found 329.0566.
16
15
4
Methyl 5-(furan-2-yl)-3-(4-methoxyphenyl)-5-oxopentanoate 9c
1
1
08 mg from 479 mg 7c (17%, 2 steps), viscous oil; H NMR (300 MHz, CDCl ) δ 7.54 (1H,
3
m, 11-H), 7.19 – 7.13 (3H, m, Ar-H, 9-H), 6.80 (2H, d, J = 8.57, Ar-H’), 6.49 (1H, dd, J =
3
7
.5, 1.2, 10-H), 3.83 (1H, m, 4-H), 3.75 (3H, s, OMe), 3.57 (3H, s, OMe), 3.16 (2H, d, J =
1
3
.2, 3-H, 3-H’), 2.76 (1H, dd, J = 15.4, 6.9, 5-H), 2.64 (1H, dd, J = 15.4, 8.1, 5-H’); C
NMR (75 MHz, CDCl ) δ 186.9, 171.8, 157.9, 152.2, 146.1, 146.1, 134.6, 127.9, 116.9,
3
1
1
1
3
13.5, 111.9, 54.7, 54.6, 51.1, 51.0, 44.1, 40.2, 36.4; IR (thin film) νmax 2952, 2837, 1731,
669, 1611, 1583, 1567, 1512, 1466, 1435, 1394, 1364, 1300, 1278, 1245, 1177, 1152, 1112,
-1
+
085, 1029, 915, 882, 829, 763, 729, 594, 557 cm ; HRMS MNa (C H O Na) calcd
17
18
5
25.1052, found 325.1059.
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Methyl 5-(furan-2-yl)-5-oxo-3-(p-tolyl)pentanoate 9d
1
2
01 mg from 425 mg 7d (35 %, 2 steps), viscous oil; H NMR (300 MHz, CDCl ) δ 7.54
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
1H, dd, J = 1.7, 0.7, 11-H), 7.17 – 7.06 (5H, m, Ar-H, 9-H), 6.50 (1H, dd, J = 3.6, 1.7, 10-
H), 3.83 (1H, dddd, J = 7.6, 7.3, 7.3, 7.3, 4-H), 3.58 (3H, s, OMe), 3.18 (2H, d, J = 7.3, 3-H,
-H’), 2.78 (1H, dd, J = 15.5, 7.3, 5-H), 2.66 (1H, dd, J = 15.5, 7.6, 5-H’), 2.28 (3H, s, Ar-
3
1
3
Me); C NMR (75 MHz, CDCl ) δ 187.3, 172.2, 152.6, 146.3, 139.8, 136.3, 129.2, 127.0,
3
117.2, 112.2, 51.5, 44.4, 40.5, 37.0, 21.0; IR (thin film) νmax 3131, 3022, 2951, 2921, 1732,
1
1
670, 1592, 1568, 1515, 1467, 1449, 1435, 1394, 1362, 1314, 1276, 1211, 1193, 1154, 1085,
-1
019, 990, 914, 883, 816, 762, 722, 695 cm
Methyl 3-(3,4-dimethoxyphenyl)-5-(furan-2-yl)-5-oxopentanoate 9e
1
1
17 mg from 480 mg 7e (19%, 2 steps), m.p. 94.4-95.6 C; H NMR (300 MHz, CDCl ) δ
3
7.55 (1H, dd, J = 1.7, 0.6, 11-H), 7.13 (1H, dd, J = 3.6, 0.6, 9-H), 6.75 (3H, s (br), Ar-H),
6
3
.48 (1H, dd, J = 3.6, 1.7, 10-H), 3.83 (3H, s, OMe), 3.80 (3H, s, OMe), 3.78 (1H, m, 4-H),
.56 (3H, s, OMe), 3.16 (2H, d, J = 7.4, 3-H, 3-H’), 2.75 (1H, dd, J = 15.4, 7.0, 5-H), 2.65
1
3
(1H, dd, J = 15.4, 8.0, 5-H’); C NMR (75 MHz, CDCl ) δ 187.3, 172.1, 152.6, 148.7, 147.6,
3
1
46.3, 135.5, 118.9, 117.1, 112.2, 111.1, 110.7, 55.7, 55.7, 51.5, 44.4, 40.6, 37.1; IR (thin
film) νmax 3130, 3100, 3008, 2957, 2836, 1735, 1658, 1589, 1562, 1519, 1465, 1438, 1425,
1
8
397, 1329, 1293, 1281, 1254, 1230, 1187, 1160, 1142, 1087, 1039, 1019, 999, 974, 919,
-1
+
95, 881, 859, 847, 805, 776, 763, 734, 642, 661, 596, 566, 538, 520 cm ; HRMS MNa
(C H O Na) calcd 355.1158, found 355.1166.
1
8
20
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Methyl 3-(4-bromophenyl)-5-(furan-2-yl)-5-oxopentanoate 9f
1
1
90 mg from 571 mg 7f (26 %, 2 steps), m.p. 83.9-95 C; H NMR (300 MHz, CDCl ) δ 7.55
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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6
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(1H, dd, J = 1.6, 0.7, 11-H), 7.40 (2H, d, J = 8.5, Ar-H), 7.17 – 7.12 (3H, m, Ar-H’, 9-H),
6.51 (1H, dd, J = 3.6, 1.6, 10-H), 3.82 (1H, dddd, J = 7.9, 7.2, 7.2, 7.0, 4-H), 3.59 (3H, s,
OMe), 3.18 (2H, d, J = 7.2, 3-H, 3-H’), 2.78 (1H, dd, J = 15.7, 7.0, 5-H), 2.65 (1H, dd, J =
1
3
1
1
1
5.7, 7.9, 5-H’); C NMR (75 MHz, CDCl ) δ 186.9, 171.9, 152.5, 146.4, 141.9, 131.6,
3
29.1, 120.6, 117.3, 112.3, 51.7, 44.0, 40.2, 36.8; IR (thin film) νmax 3124, 3097, 2951, 1722,
662, 1563, 1488, 1472, 1430, 1398, 1361, 1326, 1306, 1290, 1267, 1214, 1193, 1160, 1105,
1077, 1065, 1041, 1010, 1000, 986, 950, 920, 906, 881, 873, 824, 769, 724, 703, 610, 535,
-1
+
5
18 cm ; HRMS MNa (C H O NaBr) calcd 373.0051, found 373.0069.
16 15 4
Methyl 5-(furan-2-yl)-5-oxo-3-(2,4,5-trimethoxyphenyl)pentanoate 9g
1
3
47 mg from 499 mg 7g (55 %, 2 steps), gum; H NMR (300 MHz, CDCl ) δ 7.55 (1H, dd, J
3
=
1.6, 0.6, 11-H), 7.16 (1H, dd, J = 3.6, 0.6, 9-H), 6.73 (1H, s, Ar-H), 6.49 (1H, dd, J = 3.6,
1
3
.6, 10-H), 6.47 (1H, s, Ar-H’), 4.00 (1H, m , 4-H), 3.84 (3H, s, OMe), 3.80 (3H, s, OMe),
.79 (3H, s, OMe), 3.58 (3H, s, OMe), 3.26 (1H, dd, J = 14.7, 6.0, 3-H), 3.18 (1H, dd, J =
1
3
14.7, 6.2, 3-H’), 2.83 (1H, dd, J = 13.2, 4.9, 5-H), 2.76 (1H, dd, J = 13.2, 5.2, 5-H’); C
NMR (75 MHz, CDCl ) δ 188.0, 172.7, 152.7, 151.3, 148.2, 146.3, 142.6, 121.8, 117.2,
3
1
12.8, 112.1, 97.6, 56.5, 56.2, 56.0, 51.5, 42.8, 38.6, 33.4; IR (thin film) νmax 2950, 2835,
1733, 1671, 1611, 1568, 1511, 1467, 1438, 1397, 1314, 1276, 1206, 1163, 1122, 1031, 916,
-1
8
83, 830, 767 cm
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Methyl 3-(4-bromophenyl)-5-(5-methylfuran-2-yl)-5-oxopentanoate 9h
1
2
7
62 mg from 585 mg 7h (36 %, 2 steps), m.p. 77.6-79.0 C; H NMR (300 MHz, CDCl ) δ
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
.39 (2H, d, J = 8.4, Ar-H), 7.14 (2H, d, J = 8.4, Ar-H’), 7.06 (1H, d, J = 3.4, 9-H), 6.12 (1H,
dd, J = 3.4, 0.8, 10-H), 3.76 (1H, m, 4-H), 3.58 (3H, s, OMe), 3.11 (2H, d, J = 7.3, 3-H, 3-
H’), 2.78 (1H, dd, J = 15.7, 8.3, 5-H), 2.65 (1H, dd, J = 15.7, 8.3, 5-H’), 2.36 (3H, s, 11-Me);
1
3
C NMR (75 MHz, CDCl ) δ 186.1, 171.9, 158.0, 151.3, 142.0, 131.6, 129.1, 120.6, 119.4,
3
1
1
09.1, 51.7, 43.8, 40.2, 37.1, 14.1; IR (thin film) νmax 2952, 2916, 1735, 1654, 1590, 1516,
489, 1448, 1437, 1421, 1407, 1386, 1366, 1306, 1291, 1220, 1209, 1195, 1178, 1165, 1104,
1087, 1070, 1036, 1025, 1010, 987, 959, 950, 933, 910, 873, 823, 792, 725, 706, 670, 526
-1
+
cm ; HRMS MNa (C H O NaBr) calcd 387.0208, found 387.0225.
1
7
17
4
Methyl 5-(5-methylfuran-2-yl)-5-oxo-3-phenylpentanoate 9i
1
1
54 mg from 374 mg 7i (31%, 2 steps), m.p. 99.3-100.6C; H NMR (300 MHz, CDCl ) δ
3
7.36 – 7.12 (5H, m, Ar-H), 7.06 (1H, d, J = 3.5, 9-H), 6.11 (1H, dd, J = 3.5, 0.8, 10-H), 3.83
(1H, m, 4-H), 3.57 (3H, s, OMe), 3.13 (2H, d, J = 7.2, 3-H, 3-H’), 2.80 (1H, dd, J = 15.5, 6.8,
13
5
-H), 2.69 (1H, dd, J = 15.5, 8.1, 5-H’), 2.36 (3H, s, 11-Me); C NMR (75 MHz, CDCl ) δ
3
1
86.5, 172.2, 157.8, 151.5, 143.1, 128.6, 127.3, 126.8, 119.2, 109.0, 51.5, 44.1, 40.4, 37.8,
1
4.0; IR (thin film) νmax 2952, 1730, 1659, 1515, 1495, 1436, 1456, 1372, 1360, 1284, 1248,
-1
1226, 1211, 1161, 1090, 1074, 1034, 989, 978, 954, 931, 882, 796, 783, 761, 699, 559 cm
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2
2
2
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Methyl 5-(5-methylfuran-2-yl)-5-oxo-3-(p-tolyl)pentanoate 9j
1
1
7
77 mg from 434 mg 7j (31 %, 2 steps), m.p. 79.3-80.2 C; H NMR (300 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.16 – 7.06 (5H, m, Ar-H, 9-H), 6.10 (1H, dd, J = 3.5, 0.8, 10-H), 3.79 (1H, dddd, J = 7.6,
7.3, 7.3, 7.0, 4-H), 3.56 (3H, s, OMe), 3.10 (2H, d, J = 7.3, 3-H, 3-H’), 2.77 (1H, dd, J =
13
1
5.5, 7.0, 5-H), 2.65 (1H, dd, J = 15.5, 7.6, 5-H’), 2.34 (3H, s, Me), 2.27 (3H, s, Me); C
NMR (75 MHz, CDCl ) δ 186.5, 172.2, 157.7, 151.3, 138.9, 136.1, 129.1, 127.0, 119.2,
3
1
1
08.8, 51.4, 44.1, 40.3, 37.2, 20.9, 13.9; IR (thin film) νmax 2951, 2920, 1729, 1659, 1515,
448, 1435, 1422, 1385, 1368, 1334, 1312, 1296, 1270, 1223, 1211, 1180, 1162, 1113, 1085,
-1
+
1072, 1037, 1026, 991, 958, 873, 816, 795, 755, 722, 666, 528 cm ; HRMS MNa
C H O Na) calcd 323.1259, found 323.1248.
(
1
8
20
4
Methyl 3-(4-chlorophenyl)-5-(5-methylfuran-2-yl)-5-oxopentanoate 9k
1
1
77 mg from 466 mg 7k (29 %, 2 steps), m.p. 65.7-66.5 C; H NMR (300 MHz, CDCl ) δ
3
7.23 – 7.14 (4H, m, Ar-H), 7.04 (1H, d, J = 3.5, 9-H), 6.09 (1H, dd, J = 3.5, 0.8, 10-H), 3.79
(1H, dddd, J = 7.6, 7.2, 7.2, 7.0, 4-H), 3.54 (3H, s, OMe), 3.09 (2H, d, J = 7.2, 3-H, 3-H’),
1
3
2
.76 (1H, dd, J = 15.6, 7.0, 5-H), 2.63 (1H, dd, J = 15.6, 7.9, 5-H’), 2.32 (3H, s, 11-Me); C
NMR (75 MHz, CDCl ) δ 186.0, 171.8, 157.8, 151.2, 141.4, 132.3, 128.6, 128.5, 119.3,
3
1
08.9, 51.5, 43.7, 40.1, 36.9, 13.9; IR (thin film) νmax 2998, 2953, 2920, 1735, 1654, 1591,
1514, 1492, 1448, 1438, 1423, 1411, 1385, 1369, 1329, 1306, 1291, 1271, 1220, 1209, 1196,
1
7
178, 1164, 1105, 1088, 1071, 1036, 1026, 1014, 987, 959, 912, 887, 873, 825, 791, 729,
-1
+
11, 672, 537, 526 cm ; HRMS MNa (C H O NaCl) calcd 343.0713, found 343.0706.
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General Procedure for the reduction of ketoesters 9a-k to form diols 1a-k
Solid lithium aluminium hydride (304 mg, 8.00 mmol, 10 equiv.) was suspended in
anhydrous tetrahydrofuran (4 mL) under dry nitrogen. The reaction mixture was cooled to
−15 °C. Keto-ester 9a-k (0.80 mmol, 1 equiv.) was added dropwise in anhydrous
tetrahydrofuran (5 mL) at this temperature. The reaction mixture was then stirred at room
temperature for a further 15 minutes after which TLC analysis indicated that reaction was
complete. The reaction was quenched by adding diethyl ether (10 mL) followed by the slow
dropwise addition of a 4:1 mixture of diethyl ether and acetone (15 mL). The reaction
mixture was then diluted in ethyl acetate (40 mL) and washed with water (100 mL) and 2.0 M
aqueous sodium hydroxide (150 mL). The combined aqueous phase was extracted with ethyl
acetate (5 × 50 mL). The combined organic phases were then washed with water (2 × 100
mL) and brine (100 mL) before being dried over magnesium sulfate. The organic phase was
then concentrated under reduced pressure to afford the product 1a-k as a colorless oil which
was used without any further purification (except in the case of 1b, whose diastereomers
were able to be partly separated by careful column chromatography, using a solvent gradient
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from petroleum ether to diethyl ether). In general, H NMR data for each diastereomer in the
mixtures are listed sequentially, although signals from each diastereomer were often
1
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significantly overlapped. For 1b, the H, C, IR and MS data for each diastereomer is listed
separately.
1-(Furan-2-yl)-3-phenylpentane-1,5-diol 1a
1
1
95 mg from 218 mg 9a, 99 %, d.r. = 1:0.7; H NMR (300 MHz, CD CN) δ major
3
diastereomer: 7.44 (1H, dd, J = 1.8, 0.8, 11-H), 7.36 – 7.23 (5H, m, Ar-H), 6.37 (1H, dd, J =
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.2, 1.8, 10-H), 6.20 (1H, d, J = 3.2, 9-H), 4.33 (1H, dd, J = 7.3, 7.3, 2-H), 3.45 – 3.15 (3H,
m, 6-H,H’,OH), 2.69 – 2.54 (2H, m, 4-H,OH), 2.24 – 1.64 (4H, m, 3-H,H’, 5-H,H); minor
diastereomer: 7.36 (1H, dd, J = 1.8, 0.8, 11-H), 7.36 – 7.23 (5H, m, Ar-H), 6.31 (1H, dd, J =
0
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0
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.2, 1.8, 10-H), 6.14 (1H, d, J = 3.2, 9-H), 4.18 (1H, dd, J = 10.0, 3.2, 2-H), 3.45 – 3.15 (3H,
m, 6-H,H’,OH), 3.03 (H, m, b-4-H), 2.69 – 2.54 (1H, m, OH), 2.24 – 1.64 (4H, m, 3-H’,H’,
1
3
5
1
-H,H’); C NMR (75 MHz, CD CN) δ 159.0, 157.9, 145.9, 145.5, 142.8, 142.5, 129.3,
3
28.8, 128.5, 127.1, 111.0, 110.9, 107.0, 105.9, 65.7, 65.2, 60.4, 60.2, 43.2, 43.1, 40.6, 39.9,
39.3, 39.0; IR (thin film) νmax 3318 (br), 2921, 2850, 1494, 1453, 1260, 1145, 1043, 1009,
-1
+
9
2
13, 884, 808, 762, 740, 701, 634, 598, 533 cm ; HRMS MNa (C H O Na) calcd
15 18 3
69.1154, found 269.1145.
3
-(4-Chlorophenyl)-1-(furan-2-yl)pentane-1,5-diol 1b
55 mg from 61 mg 9b, 99 %, d.r. = 1:0.75, separable by column chromatography;
1
major diastereomer: H NMR (300 MHz, CDCl ) δ 7.38 (1H, dd, J = 1.8, 0.8, 11-H), 7.27
3
(2H, d, J = 8.4, Ar-H), 7.08 (2H, d, J = 8.4, Ar-H’), 6.33 (1H, dd, J = 3.2, 1.8, 10-H), 6.17
(1H, d, J = 3.2, 9-H), 4.49 (1H, dd, J = 6.2, 6.2, 2-H), 3 52 (1H, m, 6-H), 3.39 (1H, m, 6-H’),
13
2
.71 (1H, m, 4-H), 2.30 – 1.70 ([4H, m, 3-H,H’, 5-H,H’); C NMR (75 MHz, CDCl ) δ
3
155.7, 142.7, 142.2, 132.1, 128.9, 128.7, 110.2, 106.7, 65.6, 60.5, 42.1, 38.8, 38.0; IR (thin
film) νmax 3328 (br), 2938, 2885, 1489, 1467, 1450, 1412, 1146, 1091, 1042, 1012, 940, 908,
-1
8
83, 824, 730, 597, 566 cm
1
minor diastereomer: H NMR (300 MHz, CDCl ) δ 7.32 (1H, dd, J = 1.8, 0.8, 11-H), 7.28
3
(
2H, d, J = 8.5, Ar-H), 7.17 (2H, d, J = 8.5, Ar-H’), 6.29 (1H, dd, J = 3.2, 1.8, 10-H), 6.14
1H, ddd, J = 3.2, 0.8, 0.7, 9-H), 4.33 (1H, d, J = 10.4, 2-H), 3.65 – 3.40 (2H, m, 6-H,H’),
(
3
.14 (1H, m, 4-H), 2.22 (1H, ddd, J = 14.2, 10.4, 4.2, 3-H), 2.05 – 1.80 (3H, m, 3-H’, 5-
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H,H’); C NMR (75 MHz, CDCl ) δ 156.7, 155.7, 142.7, 142.3, 141.93, 141.87, 132.1,
3
1
3
1
29.2, 128.9, 128.77, 128.75, 110.2, 110.1, 106.8, 105.6, 65.7, 65.0, 60.6, 60.5, 42.1, 41.8,
9.6, 38.9, 38.0, 37.7; IR (thin film) νmax 3314 (br), 2932, 1489, 1434, 1412, 1320, 1146,
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-1
090, 1043, 1012, 884, 824, 737, 634, 598, 534 cm
1
-(Furan-2-yl)-3-(4-methoxyphenyl)pentane-1,5-diol 1c
1
188 mg from 215 mg 9c, 96 %, d.r. = 1:0.75; H NMR (300 MHz, CDCl ) δ major
3
diastereomer: 7.39 (1H, d, J = 1.7, 11-H), 7.07 (2H, d, J = 8.3, Ar-H), 6.87 – 6.84 (2H, m,
Ar-H’), 6.33 (1H, dd, J = 2.7, 1.7, 10-H), 6.19 (1H, d, J = 2.7, a-9-H), 4.51 (1H, dd, J = 11.2,
5
.9, a-2-H), 3.80 (3H, s(br), Ar-OMe), 3.62 – 3.38 (2H, m, 6-H,H’), 2.68 – 2.59 (1H, m, a-4-
H), 2.29 – 1.79 (4H, m, a-3-H,H’, 5-H,H’); minor diastereomer: 7.32 (1H, m, 11-H), 7.15
(2H, d, J = 8.5, Ar-H), 6.87 – 6.84 (2H, m, Ar-H’), 6.29 (1H, dd, J = 3.0, 1.6, 10-H), 6.15
(1H, d, J = 3.0, 9-H), 4.37 (1H, dd, J = 8.8, 3.6, 2-H), 3.80 (3H, s(br), Ar-OMe), 3.62 – 3.38
1
3
(2H, m, 6-H,H’), 3.13 – 3.02 (1H, m, 4-H), 2.29 – 1.79 (4H, m, 3-H’,H’, 5-H,H’); C NMR
(75 MHz, CDCl ) δ 158.3, 157.1, 156.0, 142.2, 141.8, 136.0, 135.6, 128.7, 128.5, 114.12,
3
1
14.10, 110.1, 106.7, 105.4, 66.1, 65.3, 61.1, 60.9, 55.3, 42.6, 42.3, 40.0, 39.4, 38.2, 37.7; IR
(thin film) νmax 3347(br), 2933, 1609, 1510, 1441, 1365, 1301, 1243, 1177, 1146, 1029, 1008,
-1
+
830, 736, 598, 574 cm ; HRMS MNa (C H O Na) calcd 299.1259, found 299.1273.
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-(furan-2-yl)-3-(p-tolyl)pentane-1,5-diol 1d
1
6
2 mg from 101 mg 9d, 68 %, d.r. = 1:0.74; H NMR (300 MHz, CDCl ) δ major
3
0
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diastereomer: 7.38 (1H, dd, J = 1.8, 0.8, 11-H), 7.13 – 7.02 (4H, m, Ar-H), 6.33 (1H, dd, J =
3.2, 1.8, 10-H), 6.18 (1H, d, J = 3.2, 9-H), 4.52 (1H, dd, J = 7.2, 7.2, 2-H), 3.61 – 3.38 (2H,
m, 6-H,H), 2.66 (1H, m, 4-H), 2.33 (3H, s(br), Ar-Me), 2.28 – 1.72 (4H, m, 3-H,H’, 5-H,H’);
minor diastereomer: 7.32 (1H, dd, J = 1.8, 0.8, 11-H), 7.13 – 7.02 (4H, m, Ar-H), 6.28 (1H,
dd, J = 3.2, 1.8, 10-H), 6.14 (1H, d, J = 3.2, 9-H), 4.36 (1H, ddd, J = 10.2, 2.8, 2-H), 3.61 –
3
.38 (2H, m, 6-H,H’), 3.08 (1H, m, 4-H), 2.33 (3H, s(br), Ar-Me), 2.28 – 1.72 (4H, m, 3-
1
3
H’,H’, 5-H,H’); C NMR (75 MHz, CDCl ) δ 157.0, 155.9, 142.2, 141.8, 140.9, 140.6,
3
136.11, 136.08, 129.4, 127.6, 127.4, 110.11, 110.08, 106.7, 105.4, 66.0, 65.2, 61.1, 60.9,
4
1
2
2.4, 42.0, 39.8, 39.2, 38.5, 38.0, 21.0; IR (thin film) νmax 3317 (br), 2924, 1512, 1145, 1042,
-1
+
008, 884, 814, 735, 598, 572, 491 cm ; HRMS MNa (C H O Na) calcd 283.1310, found
16 20
3
83.1320.
3
-(3,4-dimethoxyphenyl)-1-(furan-2-yl)pentane-1,5-diol 1e
1
9
2 mg from 105 mg 9e, 95 %, d.r. = 1:0.8; H NMR (300 MHz, CDCl ) δ major
3
diastereomer: 7.44 (1H, dd, J = 1.8, 0.8, 11-H), 6.84 (1H, d, J = 8.2, Ar-H), 6.70 (1H, d, J =
2.0, Ar-H’), 6.65 (1H, dd, J = 8.2, 2.0, Ar-H’’), 6.37 (1H, dd, J = 3.2, 1.8, 10-H), 6.20 (1H, d,
J = 3.2, 9-H), 4.33 (1H, ddd, J = 8.3, 6.0, 6.0, 2-H), 3.77 (6H, s, OMe,OMe’), 3.41 – 3.16
(
3H, m, 6-H,H’,OH), 2.60 – 2.44 (2H, 4-H,OH), 2.20 – 1.60 (4H, m, 3-H,H’, 5-H,H’); minor
diastereomer: 7.36 (1H, dd, J = 1.8, 0.8, 11-H), 6.86 (1H, d, J = 8.1, Ar-H), 6.79 (1H, d, J =
.9, Ar-H’), 6.75 (1H, dd, J = 8.1, 1.9, Ar-H’’), 6.31 (1H, dd, J = 3.2, 1.8, 10-H), 6.14 (1H, d,
1
J = 3.2, 9-H), 4.20 (1H, m, 2-H), 3.774 (3H, s, OMe), 3.767 (3H, s, OMe’), 3.41 – 3.16 (3H,
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m, 6-H,H’,OH), 2.95 (1H, m, 4-H), 2.60 – 2.44 (1H, OH), 2.20 – 1.60 (4H, m, 3-H’,H’, 5-
1
3
H,H’); C NMR (75 MHz, CDCl ) δ 159.1, 158.1, 150.0, 148.4, 142.8, 142.5, 138.4, 138.0,
3
1
4
20.7, 120.4, 112.4, 112.2, 112.0, 111.0, 107.1, 105.9, 65.8, 65.2, 60.5, 60.4, 56.1, 43.4, 43.3,
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0.6, 40.0, 39.0, 38.7; IR (thin film) νmax 3344(br), 2935, 2835, 1591, 1513, 1463, 1420,
-
1
+
1256, 1232, 1139, 1024, 912, 884, 808, 763, 727, 649, 599 cm ; HRMS MNa (C H O Na)
1
7
22
5
calcd 329.1365, found 329.1358.
3-(4-bromophenyl)-1-(furan-2-yl)pentane-1,5-diol 1f
1
1
47 mg from 160 mg 9f, 99 %, d.r. = 1:0.76; H NMR (300 MHz, CDCl ) δ major
3
diastereomer: 7.46 – 7.40 (2H, m, Ar-H), 7.39 (1H, dd, J = 1.8, 0.8, 11-H), 7.03 (2H, d, J =
8
6
.4, Ar-H’), 6.33 (1H, dd, J = 3.2, 1.8, 10-H), 6.18 (1H, d, J = 3.2, 9-H), 4.49 (1H, dd, J =
.7, 8.0, 2-H), 3.62 (2H, m, 6-H,H), 2.69 (1H, m, 4-H), 2.30 – 1.70 (4H, m, 3-H,H’, 5-H,H’);
minor diastereomer: 7.46 – 7.40 (2H, m, Ar-H), 7.32 (1H, dd, J = 1.8, 0.8, 11-H), 7.12 (2H,
d, J = 8.4, Ar-H’), 6.29 (1H, dd, J = 3.2, 1.8, 10-H), 6.14 (1H, d, J = 3.2, 9-H), 4.33 (1H, dd,
J = 10.4, 3.2, 2-H), 3.62 (2H, m, 6-H,H’), 3.13 (1H, m, 4-H), 2.30 – 1.70 (4H, m, 3-H’,H’, 5-
1
3
H,H’); C NMR (75 MHz, CDCl ) δ 156.7, 155.7, 143.2, 142.8, 142.3, 141.9, 131.74,
3
1
31.71, 129.6, 129.3, 120.2, 110.2, 110.1, 106.8, 105.6, 65.7, 65.1, 60.7, 60.5, 42.1, 41.9,
39.6, 38.9, 38.2, 37.9; IR (thin film) νmax 3312(br), 2929, 1486, 1431, 1230, 1146, 1069,
-1
+
1
3
042, 1008, 883, 818, 737, 598, 565, 494 cm ; HRMS MNa (C H O NaBr) calcd
15 17 3
47.0259, found 347.0245.
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