Synthesis of Butenolides via a Horner-Wadsworth-Emmons Cascading Dimerization Reaction

Article abstract of DOI:10.1021/acs.joc.9b02015

The efficient synthesis of a range of structurally related butenolides has been observed while we were exploring the substrate-scope of a Horner-Wadsworth-Emmons (HWE) reaction. While aliphatic aldehydes gave the expected HWE product, aromatic aldehydes f

Full text of DOI:10.1021/acs.joc.9b02015

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Article
Synthesis of butenolides via a Horner-Wadsworth-
Emmons cascading dimerization reaction
Jack Everson, and Milton John Kiefel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02015 • Publication Date (Web): 28 Oct 2019
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Synthesis of Butenolides via a Horner-Wadsworth-Emmons cascading dimerization reaction
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Jack Everson and Milton J Kiefel*
Institute for Glycomics, Griffith University Gold Coast Campus, Southport, Queensland, 4222, Australia
Email: m.kiefel@griffith.edu.au
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Table of Contents Graphic
ABSTRACT: The efficient synthesis of a range of structurally related butenolides has been
observed whilst we were exploring the substrate-scope of a Horner-Wadsworth-Emmons (HWE)
reaction. Whilst aliphatic aldehydes gave the expected HWE product, aromatic aldehydes
furnished butenolides, resulting from the dimerization of HWE product during desilylation of the
initially formed HWE adduct. In addition to isolating butenolides in high yield, we have also
determined precisely when dimerization occurs.
INTRODUCTION
The Horner-Wadsworth-Emmons (HWE) reaction has long been one of the favoured methods
for the olefination of carbonyl compounds, due to the robustness, high stereoselectivity, and the
varied substrate scope of the reaction. The HWE reaction forms the cornerstone of many natural
product syntheses (see for example, reviews by Kobayashi et al.,1 Burtoloso et al.,2 Al Jasem et
al.,3 and Bisceglia & Orelli,4 as well some recent examples5,6), and is particularly valuable in
carbon chain elongation, closing macrocyclic rings,7 and the coupling of synthetic segments.8 The
HWE reaction is also valuable in generating vinyl sulfones,9 and chiral sulfoxides.10
Our interest in the HWE reaction is based upon the ability to use this important carbon–carbon
bond forming reaction to generate chain elongated carbohydrate analogues. We have previously
described our efforts towards developing new synthetic approaches towards the nine-carbon acidic
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sugars known as nonulosonic acids, and have successfully described the synthesis of pseudaminic
acid and legionaminic acid analogues.11-13 Nonulosonic acids are found as key components of
glycans in several pathogenic Gram-negative bacteria, notably Campylobacter,14 Pseudomonas,15
Acinetobacter,16 Helicobacter,17 and Legionella.18,19 Significantly, nonulosonic acids are known
to be directly associated with the virulence of these pathogenic bacteria.19-22
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The synthesis of complex higher order sugars requires approaches either starting from existing
higher order sugars,23 or using approaches based on carbon–carbon bond forming reactions.24
With respect to the latter strategy, in 2015 Feng et al. described the efficient large scale synthesis
of KDO, an 8-carbon acidic sugar found in all Gram-negative bacteria, from D-mannose.25 Key
to the success of this synthesis was the use of a HWE reaction between the protected mannose
derivative 1 and the phosphonate 2, to give the HWE adduct 3 which furnished the KDO ethyl
ester derivative 4 after desilyation (Scheme 1). Previously we have reported the synthesis of a
series of structurally modified KDO derivatives, starting from ribose and using an aldol
condensation.26 The publication summarized in Scheme 1 was therefore particularly interesting
to us, and we wondered if it was possible to adapt the chemistry described by Feng et al. to include
structurally modified mannose derivatives, or indeed other types of sugars.
Scheme 1. Synthesis of the KDO ethyl ester derivative 4 using a HWE condensation.25
RESULTS AND DISCUSSION
Our initial studies into exploring the potential of using the HWE chemistry described by Feng
et al.25 for the synthesis of higher order sugars started with some mannose derivatives, notably
those modified at C-6. The preparation of these C-6 modified mannose derivatives is relatively
straightforward, commencing with the bis-isopropylidenated mannose derivative 1, selective
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removal of the 5,6-isopropylidene group (90% aq. AcOH), and subsequent selective modification
of the primary C-6 hydroxyl. In this way we prepared the modified mannose derivatives 5a-c
shown in Table 1, and then exposed each of them to the phosphate ester 2 under the HWE
conditions described by Feng et al.25 We were delighted to note that the C-8 azido KDO derivative
6b (54%) could be obtained in good yield from the corresponding 6-azido mannose derivative 5b
(Table 1), showing that an unprotected C5-OH group was not a problem. Unfortunately, the 5,6-
diol derivative (Table 1, entry 3) did not furnish any of the corresponding KDO product, which is
perhaps due to the increased acidity of the primary hydroxyl group.
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Table 1. Synthesis of KDO derivatives 6 via a HWE condensation with phosphate ester 2.
Interestingly, alternative carbohydrates such as 2,3,4-tri-O-benzylglucose and 2,3,5,6-tetra-O-
acetylgalactofuranose failed to furnish any of the corresponding 8-carbon sugar product under the
same HWE conditions as those shown in Table 1. The failure of these alternative carbohydrates
to be substrates led us to consider if this particular HWE reaction was only effective on mannose-
based substrates, since clearly the nature of the sugar substrate will reflect the preference for it to
exist in the acyclic form needed to react with the phosphate ester 2.
Given our ongoing interest in developing novel and efficient syntheses of higher order
carbohydrates,11-13 we thought it would be valuable to explore the scope of this HWE reaction on
simple aldehydes. Accordingly, a series of commercially available aromatic and aliphatic
aldehydes were reacted with the phosphonate ester 2 under the same conditions described by Feng
et al. Each of the HWE adducts 7 obtained were purified using column chromatography and
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characterized spectroscopically. As can be seen in Table 2, all the commercially available
aldehydes we used furnished the HWE adducts 7 in essentially quantitative yield after
chromatographic purification. We observed no real differences in rates of reaction or in efficiency
of the HWE condensation, irrespective of electron rich, electron deficient, aromatic, or aliphatic
aldehydes.
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Table 2. Results from the HWE condensation between phosphate ester 2 and aldehydes.
Unexpectedly, desilylation of the HWE adduct 7b (R = 4-MeOC6H4) under the conditions
described by Feng et al.25 (TBAF and aqueous AcOH) and subsequent neutralization and
purification did not give any of the expected -keto-ester product 8. Careful analysis of the
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spectroscopic data of the single product obtained, most importantly the H NMR and C NMR
spectra, clearly showed that there were two different 4-MeO-phenyl rings in the product. Key
pieces of spectroscopic evidence that led to the final structure 9b being proposed (Scheme 2)
included the observation of a single ethyl ester group ( 4.17 ppm, q, 2H, and  1.14 ppm, t, 3H)
in the 1H NMR, but the presence of two ester-type carbons ( 169.3 ppm and 169.1 ppm) in the
13C spectrum. Based on the 1H and 13C data, and a m/z of 421 (M+Na) in the ESI mass spectrum
of 9b, it was clear that we had formed a dimer of the desilylated HWE adduct with concomitant
loss of ethanol. Careful inspection of the long-range 1H–13C HMBC spectrum provided the key
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evidence to arrive at structure 9b, notably a correlation from both the ethyl ester carbonyl carbon
( 169.1 ppm) and the butenolide ring carbon ( 86.2 ppm) into the benzylic CH2 resonance (an
AB spin system centred at  3.55 ppm).
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Scheme 2. Unexpected dimerization of HWE adducts upon desilylation.
The butenolide 9b (Ar = 4-MeOC6H4) was obtained in high yield (74%) from the corresponding
HWE adduct 7b under the desilylation conditions described. Interestingly, all the aromatic-based
HWE adducts 7a-e gave the corresponding dimeric butenolide structures 9 as the only identifiable
product in modest to high yield (Scheme 2) after desilylation, whilst the aliphatic-based HWE
adducts 7f-h only furnished the expected monomeric -keto-ester products 8a-c (Scheme 2).
We believe the unexpected formation of the butenolides 9 during the desilylation of the HWE
adducts 7 that are aromatic-based, but not aliphatic, is due to the propensity of the desilylated
aromatic-based compounds to exist in both their keto and enol forms. Careful analysis (by TLC)
of the reaction mixture during desilylation clearly showed that dimerization only occurs upon
neutralization (with NaHCO3) of the reaction mixture. This observation, together with the lack of
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dimerisation observed during the desilylation of the aliphatic-based HWE adducts 7, we propose
that the formation of the butenolides 9 occurs by the mechanism depicted in Figure 1. As can be
seen, desilylation of the aromatic-based substrates leads to a mixture of the keto- and enol-forms
of the HWE adducts. Upon neutralization with NaHCO3 (to pH ≈ 8), the enol form attacks the
keto form to give the dimeric intermediate 10, which then undergoes an internal attack by the
newly generated oxygen anion, resulting in loss of ethanol to give the butenolides 9 after keto-
enol tautomerism. Whilst the dimerization of -keto esters under base catalysis is known (see
Scheme 3 and associated discussion below), it is interesting to note that we observe a difference
in behaviour between aryl and alkyl HWE adducts like 7, suggesting that perhaps this is not just a
simple case of base catalysing the dimerization.
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Figure 1. Mechanism for the formation of the butenolides 9 from the HWE adducts 7.
Butenolides such as 9 are an interesting class of natural product often isolated from fungal
sources.27,28 Of particular interest to us is the fact that several butenolides like 9 have been shown
to have biological activity. The butenolide 11 (Figure 2), isolated from Aspergillus terreus,29 is
an inhibitor of CDK2 and CDK1 kinases, showing antiproliferative activity against pancreatic and
prostate cancer cell lines.30,31 A recent study isolated 12 different butenolides from A. terreus,32
and showed that in addition to 11, the “symmetrical” butenolide 12 (i.e. a homodimer similar to
9) also showed promising activity against pancreatic cancer. Butenolides like 13, isolated from
an endophytic Aspergillus from Tripterygium wilfordii, have shown anti-inflammatory activity.28
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Figure 2. Naturally occurring butenolides with biological activity.
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It is interesting to note that butenolides with the most potent anticancer activity tend to be
asymmetrical with respect to the aromatic rings. Indeed, in the work by Braña et al.,31 the synthetic
butenolide analogue of 11 that lacked the 3-methylbut-2-enyl chain had no activity against a range
of human cancer cell lines. Since it appears that asymmetrical butenolides have more potent
biological activity, we speculated if we could obtain an unsymmetrical butenolide by exposing
two different HWE adducts to the desilylation conditions. Accordingly, exposure of an equimolar
mixture of the aryl HWE adduct 7b and the alkyl HWE adduct 7h to TBAF and aqueous AcOH,
followed by neutralization (NaHCO3, to pH ≈ 8) resulted in the isolation of, perhaps not
surprisingly, a complex mixture of products. Careful chromatographic purification showed that
we had indeed obtained the non-symmetrical butenolide 14 (m/z = 385 [M+Na]) as a mixture of
diastereomers, along with the symmetrical butenolide 9b and the -keto-ester product 8c.
Scheme 3. Formation of the unsymmetrical butenolide 14.
Obtaining only the single non-symmetrical butenolide 14 from the two HWE adducts 7b and
7h as depicted in Scheme 3 was not unexpected, since we have already shown (vide infra) that the
alkyl HWE adducts do not form butenolides. Exploring this concept of preparing non-symmetrical
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butenolides further, we exposed an equimolar mixture of the two aromatic HWE adducts 7a and
7b to the desilylation conditions (Scheme 4). After neutralisation we obtained, as expected, a
complex mixture of products in essentially statistical proportions, whereby each HWE adduct can
dimerize with itself (giving 9a and 9b), and can also dimerise with the other reactant in solution,
giving 15 and 16 as an inseparable mixture. We considered that it may be possible to control the
dimerization between two different aryl HWE adducts by desilylation of one of the components
to give the -keto-ester followed by exposure to a different aryl HWE adduct under the
desilylation/dimerization conditions. However, desilylation of the aryl HWE adduct 7b without
neutralisation gave the expected product 17 which exists, as reported by others,33 exclusively in
its enol form. Nonetheless, exposure of 17 to the HWE adduct 7a under the standard
desilylation/dimerization conditions gave the same mixture of products (Scheme 4), in comparable
ratio as to that obtained when 7a and 7b were reacted together.
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Scheme 4. Formation of the unsymmetrical butenolides 15 & 16.
Given the interesting biological activity of these butenolides, especially the activity against
pancreatic cancer, it is not surprising that several approaches towards the synthesis of analogues
of these natural products is of interest. The synthesis of butenolides has been accomplished using
metal-catalysed cyclisation approaches,34 radical cyclisations,35 acid-catalysed lactonization,36
hydrolysis and saponification of quinones,37 and in enantiomerically pure form.38,39 For
symmetrical butenolides like 9, the most common synthetic approach tends to mimic the
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postulated biosynthetic pathway,27,40 wherein simple aryl pyruvic methyl esters are dimerized in
the presence of base. A representative example is summarized in Scheme 5.31 In that work, the
aryl pyruvic methyl esters 18 themselves were obtained in either 3 or 4 steps from commercially
available aldehydes or nitriles, respectively, and then treated with either K2CO3 in acetone or DBU
in DMF to furnish the corresponding symmetric butenolides in yields typically 50-80%.31
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Scheme 5. Synthesis of butenolides via dimerization of -keto esters.31
In comparison to the current literature processes, our synthesis of butenolides 9 therefore
represents a very simple and high yielding approach towards these important natural products,
since the phosphonate ester 2 is easy to prepare, and the aromatic aldehydes are commercially
available. In order to further explore the scope of this unexpected butenolide formation, we
exposed aromatic aldehydes (benzaldehyde, 4-methoxy- and 4-chlorobenzaldehyde) to the
phosphate ester 2 under the standard HWE conditions, and then without purification treated the
crude HWE adducts 7 under desilylation conditions. In each case, the butenolides 9 were obtained
in high yield (84%, for Ar = C6H5, 75% for Ar = 4-MeOC6H4, & 67% for Ar = 4-ClC6H4).
CONCLUSIONS
In summary, our synthesis of aromatic butenolides 9 directly from the corresponding aromatic
aldehyde in 2 steps and without the need for purification of the intermediate HWE adduct 7
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represents a highly efficient and simple method for synthesizing this important class of natural
product. Further studies exploring different aldehydes and the possibility of making
unsymmetrical butenolides are in progress in our laboratory.
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EXPERIMENTAL SECTION
General Information: Unless stated otherwise, all commercially available reagents were utilized
without further purification. All “anhydrous” solvents were either purchased directly from Sigma,
or were dried following a procedure described in Armarego & Chai.41 'Flash' chromatography
using silica gel 60 was performed routinely in order to purify all products. All heating was
performed using a magnetic stirrer hotplate and an appropriate sized heating block. Low resolution
mass spectral (LRMS) analysis was performed using a Bruker esquire 3000 electrospray ionisation
mass spectrometer and high resolution mass spectrometry (HRMS) was performed using a Bruker
MaXis II quadrupole time of flight electrospray ionisation mass spectrometer. IR spectral analysis
was performed using a Bruker Alpha Fourier Transform Infra-Red spectrometer. H and 13C NMR
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spectra were obtained using a Bruker 400 MHz spectrometer at 400 and 100 MHz, respectively.
Signals are reported in terms of their chemical shift (δ in ppm) relative to the deuterated solvent
used to obtain that spectrum. All 13C NMR spectra were recorded using a DEPTQ-135 pulse
sequence resulting in quaternary and methylene carbon resonances phased negative and methine
and methyl carbons phased positive.
Ethyl ester α-(dimethylphosphinyl) glycolate t-butyldimethylsilyl ether (2)25
Dimethylphosphite (6.8 g, 5.7 mL, 62.3 mmol) was dissolved in dry toluene (70 mL) under argon.
The reaction mixture was cooled to 0oC (ice bath) and Et3N (14.5 g, 20 mL, 143.7 mmol) was
added. After 15 mins 50% ethylglyoxalate hydrate in toluene (6 g, 12 mL, 47.9 mmol) was added
and the reaction mixture was warmed to room temperature. The reaction mixture was then stirred
for 3 hours before being concentrated in vacuo. The crude residue was then dissolved in dry DMF
(60 mL) under argon. Imidazole (6.5 g, 95.8 mmol) was then added followed by TBDMSCl (11.6
g, 76.6 mmol). The reaction mixture was stirred overnight at room temperature. The reaction
mixture was then diluted with EtOAc (100 mL), washed with sat. aq. NaHCO3, dried (Na2SO4)
and filtered. The organic phase then concentrated under vacuum. The residue was purified via
column chromatography (1:2, EtOAc:hexane, v/v, Rf: 0.28) to give the known25 phosphonate (12.5
g, 38.3 mmol, 80% yield) as a clear, viscous liquid.
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1H NMR (CDCl3, 400MHz): δ (ppm) 4.60 (1H, d, J = 17.6 Hz), 4.32-4.20 (2H, m), 3.84 (3H, d, J
= 6.7 Hz), 3.81 (3H, d, J = 6.7 Hz), 1.29 (3H, t, J = 7.1 Hz), 0.91 (9H, s), 0.11 (3H, s), 0.10 (3H,
s). 13C NMR {DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 168.5 (d, J = 3.1 Hz, P split), 71.4, 69.8
(d, J = 162.0 Hz, P split), 61.8, 54.1 (t, J = 6.7 Hz, P split), 25.5, 18.4, 14.1, -5.2, -5.4. The 1H and
13C NMR data is consistent with published NMR data.25 IR (neat): 2955, 2930, 2895, 2855, 1750
cm-1. LRMS (ESI) m/z: 349 [M+Na]+.
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2,3:5,6-di-O-isopropylidene-α,β-D-mannose (1)25
D-Mannose (5.0 g, 27.8 mmol) was placed under argon and dissolved in dry DMF (50 mL). To
this was added TsOH•H2O (0.32 g, 1.7 mmol) followed by 2,2-dimethoxypropane (8.5 g, 10.0 mL,
83.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture
was then diluted with EtOAc (~100 mL) and was washed with saturated NaHCO3 (~50 mL). The
aqueous phase was then extracted with EtOAc (3x50 mL) and all organic phases were combined.
The organic phases were dried (Na2SO4), filtered and then concentrated under reduced pressure.
The crude residue was recrystallised (EtOAc/hexane) to give the known25 title compound 1 (5.5
g, 21.1 mmol, 76%) as a white crystalline powder.
1H NMR (CDCl3, 400MHz): δ (ppm) 5.38 (1H, d, J = 2.3 Hz, H1), 4.81 (1H, dd, J = 5.6 Hz, 3.6
Hz, H3), 4.62 (1H, d, J = 5.6 Hz, H2), 4.43-4.38 (1H, m, H5), 4.19 (1H, dd, J = 7.2, 3.6 Hz, H4),
4.09 (1H, dd, J = 8.7, 6.3 Hz, H6), 4.04 (1H, dd, J = 8.6, 4.8 Hz, H6’), 1.47, 1.46, 1.38, 1.33 (4 x
3H, 4 x s, 4 x (CH3)2CO). 13C NMR {DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 112.8, 109.2 (2 x
(CH3)2CO), 101.4 (C1), 85.6, 80.5, 79.8, 73.4 (all CH, C2, C3, C4, C5), 66.7 (C6), 27.0, 26.0,
25.3, 24.6 (4 x (CH3)2CO), Note that trace amounts of the anomer can be observed in both 1H and
13C NMR spectra. Our 1H and 13C NMR data is consistent with published NMR data.25 IR (neat):
3431, 2986, 2947, 2898 cm-1. LRMS (ESI) m/z: 283 [M+Na]+.
2,3-O-Isopropylidene-α,β-D-mannose (5c)42
2,3:5,6-Di-O-isopropylidene-α,β-D-mannose (1.4 g, 5.38 mmol) was dissolved in 30 mL of 90%
AcOH/H2O. The reaction mixture was stirred for 5.5 hours and was then diluted with an excess
of toluene. The reaction mixture was then placed under reduced pressure to remove solvent. The
residue was diluted with toluene and then concentrated in vacuo a number of times to remove any
remaining AcOH. The resulting residue was purified via column chromatography (9:1,
EtOAc:MeOH, v/v, Rf: 0.15) to give the known42 5,6-diol 5c (0.763 g, 3.46 mmol, 65%) as a clear,
viscous liquid.
1H NMR (CDCl3, 400MHz): δ (ppm) 5.37 (1H, brs, H1), 4.88 (1H, dd, J = 5.6, 4.0 Hz, H3), 4.61
(1H, d, J = 5.6 Hz, H2), 4.17 (1H, dd, J = 8.6, 3.7 Hz, H4), 4.00-3.95 (1H, m, H5), 3.83 (1H, dd,
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J = 11.7, 3.0 Hz, H6), 3.75 (1H, dd, J = 11.7, 4.6 Hz, H6’), 1.46, 1.33 (2 x 3H, 2 x s, 2 x (CH3)2CO).
13C NMR (CDCl3, 100MHz) δ (ppm) 112.8 ((CH3)2CO), 101.1 (C1), 85.5, 80.1, 79.1, 70.1 (all
CH, C2, C3, C4, C5), 64.1 (C6), 26.1, 24.8 (2 x (CH3)2CO), Note that trace amounts of the anomer
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can be observed in both H and C NMR spectra. Our H and C NMR data is consistent with
published NMR data.40 LRMS (ESI) m/z: 243 [M+Na]+.
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2,3-O-Isopropylidene-6-O-(p-toluenesulfonyl)-α,β-D-mannose
2,3-O-Isopropylidene-α,β-D-mannose (5c) (2.0 g, 9.08 mmol) was placed under argon and was
dissolved in pyridine (40 mL). The reaction mixture was cooled to 0oC with an ice bath and tosyl
chloride (2.6 g, 13.6 mmol) was added. The reaction mixture was warmed to room temperature
and stirred overnight, before being concentrated in vacuo. The residue was dissolved in EtOAc
(100 mL) and washed with dilute aqueous HCl (1M, 40 mL), water (40 mL), dried (Na2SO4), and
concentrated under reduced pressure. The resulting residue was purified via column
chromatography (3:2, hexane:EtOAc, v/v, Rf: 0.30) to give the 6-O-tosyl mannose derivative (1.86
g, 4.97 mmol, 55%) as a white solid.
1H NMR (CDCl3, 400MHz): δ (ppm) 7.83 (2H, d, J = 8.3 Hz, ArH), 7.35 (2H, d, J = 8.3 Hz, ArH),
5.34 (1H, d, J = 2.2 Hz, H1), 4.85 (1H, dd, J = 5.3, 3.6 Hz, H3), 4.60 (1H, d, J = 5.3 Hz, H2), 4.30
(1H, dd, J = 9.8, 2.5 Hz, H6), 4.20-4.08 (3H, m, H4, H5, H6’), 2.64 (1H, d, J = 5.3 Hz, OH5), 2.45
(3H, s, CH3Ar), 2.28 (1H, d, J = 2.5 Hz, OH1), 1.43, 1.31 (2 x 3H, 2 x s, 2 x (CH3)2CO). IR (neat):
3406, 3312, 2999, 2945 cm-1. LRMS (ESI) m/z: 397 [M+Na]+.
6-Azido-6-deoxy-2,3-O-isopropylidene-α,β-D-mannose (5b)
The 6-O-tosyl derivative (2.9 g, 7.8 mmol) was placed under argon and dissolved in DMF (30
mL). NaN3 (2.5 g, 39 mmol) was added, and the solution was heated to 55°C, and the reaction
allowed to stir for 5 days. Reaction progress was monitored by TLC (1:1 EtOAc:Hex, v/v) and
when reaction was complete, solvent was removed in vacuo, where the residue was purified by
silica gel column chromatography as solid (2:1, hexane:EtOAc, v/v, Rf: 0.17) to give the 6-azido
derivative 5b (1.5 g, 6.1 mmol, 80%) as a slightly yellow, viscous liquid.
1H NMR (CDCl3, 400MHz): δ (ppm) 5.38 (1H, s, H1), 4.88 (1H, dd, J = 5.6, 3.8 Hz, H3), 4.62
(1H, d, J = 5.6 Hz, H2), 4.15-4.06 (2H, m, H4, H5), 3.55 (1H, dd, J = 13.0, 3.5 Hz, H6), 3.44 (1H,
dd, J = 13.0, 6.5 Hz, H6’), 1.47, 1.33 (2x 3H, 2 x s, 2 x (CH3)2CO). 13C NMR {DEPTQ-135}
(CDCl3, 100MHz): δ (ppm) 113.0 ((CH3)2CO), 101.2 (C1), 85.4, 70.0, 79.8, 69.7 (all CH, C2, C3,
C4, C5), 54.3 (C6), 26.0, 24.7 (2 x (CH3)2CO), Note that trace amounts of the anomer can be
observed in both 1H and 13C NMR spectra. IR (neat): 3411, 2987, 2940, 2099cm-1. HRMS (ESI-
QTOF) m/z: [M+Na]+ Calcd for C9H15O5N3Na (268.0904), found 268.0901.
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Ethyl 4,5:7,8-di-O-isopropylidene-3-deoxy-α,β-D-manno-2-octulopyranosonate (6a)25
Following the method described by Feng et al.,25 the phosphonate 2 (9.6 g, 29.4 mmol) was placed
under argon and dissolved in dry THF (25 mL). To this was added t-BuOLi (1.9 g, 24.2 mmol)
and the suspension was stirred for 15 minutes. After this time a solution of the bis-isopropylidene
mannose derivative 1 (4.5 g, 17.3 mmol) in dry THF (15 ml) was added via syringe to the reaction
mixture. The reaction mixture was heated to ~50oC and was then stirred for 1 hour. The reaction
mixture was diluted with saturated NH4Cl (~40 mL) and any non-aqueous solvent was removed
under reduced pressure. The aqueous residue was then extracted with EtOAc (3 x 60 mL). The
organic phases were combined, dried (Na2SO4), filtered and concentrated under reduced pressure.
The resulting residue was then used in the next step without further purification.
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The residue was dissolved in THF (30 mL) and the reaction mixture was cooled to 0oC with an ice
bath. To this was added 20% AcOH/H2O (35 mL) and 1M TBAF in THF (7.1 g, 27 mL, 27 mmol).
The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The
reaction mixture was then neutralized with the addition of NaHCO3, filtered and concentrated
under reduced pressure. The residue was then dissolved in EtOAc (100 mL), washed with
saturated NaHCO3, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue
was purified via column chromatography (1:2, EtOAc:hexane, v/v, Rf: 0.20) to give the known25
KDO compound 6a (4.4 g, 12.7 mmol, 73%) as a slightly yellow, viscous liquid.
1H NMR (400MHz, CDCl3, α/β mixture): δ (ppm) α anomer (major)- 4.50 (1H, dt, J = 6.6, 5.0 Hz,
H4), 4.34 (1H, m, H7), 4.29-4.21(3H, m, H5, CO2CH2CH3), 4.07 (1H, dd, J = 8.9, 6.3 Hz, H8),
3.99 (1H, dd, J = 8.9, 4.6 Hz, H8’), 3.89 (1H, dd, J = 8.0, 2.3 Hz, H6), 2.49 (1H, dd, J = 14.5, 6.6
Hz, H3e), 1.88 (1H, dd, J = 14.5, 5.0 Hz, H3a), 1.45, 1.41, 1.36, 1.35 (4 x 3H, 4 x s, 4 x (CH3)2CO),
1.30 (3H, t, J = 7.2 Hz, CO2CH2CH3); β anomer (minor)- 4.73 (1H, dt, J = 8.0, 2.7 Hz, H4), 4.43
(dd, J = 8.1, 2.0 Hz, H7), 4.29-4.21(3H, m, H5, CO2CH2CH3), 4.09-4.04 (1H, m, H8), 4.02-3.97
(1H, m, H8’), 3.44 (1H, dd, J = 8.7, 2.0 Hz, H6), 2.32 (2H, d, J = 2.9 Hz, H3a, H3e), 1.55, 1.40,
1.38, 1.35 (4 x 3H, 4 x s, 4 x (CH3)2CO), 1.33 (3H, t, J = 7.2 Hz, CO2CH2CH3). 13C NMR
{DEPTQ-135} (100MHz, CDCl3, α/β mixture): δ (ppm) α isomer (major)- 169.8 (C1), 109.5,
109.3 (2 x (CH3)2CO), 94.5 (C2), 74.1, 71.4, 70.7, 70.0 (all CH, C3, C4, C5, C7), 67.0 (C8), 62.5
(CO2CH2CH3), 32.4 (C3), 27.2, 27.1, 25.9, 25.5 (4 x (CH3)2CO), 14.1 (CO2CH2CH3); β anomer
(minor)- 169.7 (C1), 109.71, 109.67 (2 x (CH3)2CO), 95.7 (C2), 74.0, 73.5, 72.5, 70.8 (all CH, C3,
C4, C5, C7), 67.3 (C8), 62.1 (CO2CH2CH3), 31.1 (C3), 27.2, 26.2, 25.2, 24.4 (4 x (CH3)2CO), 14.3
(CO2CH2CH3). Whilst the anomeric ratio is slightly different, our NMR data is consistent with
published 1H and 13C NMR data.25 LRMS (ESI) m/z: 369 [M+Na]+.
Ethyl 8-azido-3,8-dideoxy-4,5-O-isopropylidene-α,β-D-manno-2-octulopyranosonate (6b)
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Following the method described by Feng et al.,25 the phosphonate 2 (0.9 g, 2.7 mmol) was placed
under argon and dissolved in dry THF (15mL). To this was added t-BuOLi (0.2 g, 2.2 mmol) and
the suspension was stirred for 15 minutes. After this time a solution of the 6-azido mannose
derivative 5b (0.4 g, 1.6 mmol) in dry THF (10 ml) was added via syringe to the reaction mixture.
The reaction mixture was heated to ~50oC and was then stirred for 1 hour. The reaction mixture
was diluted with saturated NH4Cl (~20 mL) and any non-aqueous solvent was removed under
reduced pressure. The aqueous residue was then extracted with EtOAc (3 x 20 mL). The organic
phases were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. The
resulting residue was then used in the next step without further purification.
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The residue was dissolved in THF (5 mL) and the reaction mixture was cooled to 0oC with an ice
bath. To this was added 20% AcOH/H2O (5.6 mL) and 1M TBAF in THF (1.6 g, 6.0 mL, 6.0
mmol). The reaction mixture was warmed to room temperature and was stirred for 3 hours. The
reaction mixture was then neutralized with the addition of NaHCO3, filtered and concentrated
under reduced pressure. The residue was then dissolved in EtOAc (50 mL), washed with saturated
NaHCO3, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was
purified via (1:2, EtOAc:hexane, v/v, Rf: 0.19) to give the 8-azido KDO derivative 6b (292 mg,
0.88 mmol, 54%) as a slightly yellow, viscous liquid.
1H NMR (400MHz, CDCl3, α/β mixture): δ (ppm) α anomer (major) – δ 4.56-4.52 (1H, m, H4),
4.33 (1H, dd, J5,4 = 6.2, J5,6 = 2.4 Hz, H5), 4.27 (2H, q, J = 6.9 Hz, CO2CH2CH3), 4.10 (1H, ddd,
J7,6 = 8.2, J7,8’ = 5.9, J7,8 = 2.9 Hz, H7), 4.04 (1H, dd, J6,7 = 8.2, J6,5 = 2.4 Hz, H6), 3.57 (1H, dd,
J8,8’ = 12.6, J8,7 = 2.9 Hz, H8), 3.46 (1H, dd, J8’,8 = 12.6, J8’,7 = 5.9 Hz, H8’), 2.58 (1H, d, J3e,4 = 7.4
Hz, H3e), 1.93 (1H, dd, J3a,3e = 14.2, J3a,4 = 5.3 Hz, H3a), 1.48, 1.36 (2 x 3H, 2 x s, 2 x (CH3)2CO),
1.32 (3H, t, J = 6.9 Hz, CO2CH2CH3); β anomer (minor) 4.74 (1H, ddd, J4,5 = 7.9, J4,3e = J4,3a = 3.1
Hz, H4), 4.53 (1H, dd, J5,4 = 7.9, J5,6 = 1.9 Hz, H5), 4.27 (2H, q, J = 6.9 Hz, OCH2CH3), 4.00 (1H,
ddd, J7,6 = 8.8, J7,8’ = 6.0, J7,8 = 2.9 Hz, H7), 3.66 (1H, dd, J8,8’ = 12.6, J8,7 = 2.9 Hz, H8), 3.59-3.53
(1H, m, H6), 3.45 (1H, dd, J8’,8 = 12.6, J8’,7 = 6.0 Hz, H8’), 2.38 (1H, dd, J3a/3e = 14.2, J3a,4 = 3.1
Hz, H3a), 2.32 (1H, d, J3e/4 = 3.1 Hz, H3e), 1.55, 1.38 (2 x 3H, 2 x s, 2 x (CH3)2CO), 1.33 (3H, t,
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J = 6.9 Hz, CO2CH2CH3); C NMR {DEPTQ-135} (100MHz, CDCl3, α/β mixture): δ (ppm) α
isomer (major)- 169.7 (C1), 109.4 ((CH3)2CO)), 94.6 (C2), 71.1, 70.2, 70.1, 69.9 (all CH, C4, C5,
C6, C7), 62.7 (CO2CH2CH3), 53.9 (C8), 32.7 (C3), 27.6, 26.1 (2 x (CH3)2CO), 14.1 (CO2CH2CH3);
β anomer (minor)-169.0 (C1), 109.8 ((CH3)2CO)), 95.6 (C2), 72.8, 72.3, 70.9, 69.4 (all CH, C4,
C5, C6, C7), 62.3 (CO2CH2CH3), 54.0 (C8), 31.2 (C3), 26.3, 24.5 (2 x (CH3)2CO), 14.2
(CO2CH2CH3). IR (neat) 3440, 2102, 1740cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for
C13H21O7N3Na (354.1272), found 354.1269.
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General procedure for the reaction of commercially available aldehydes with the phosphonate 2
under standard HWE conditions, giving the results shown in Table 2.
Following the method described by Feng et al.,25 the phosphonate 2 (1.0 g, 3.07 mmol) was placed
under argon and dissolved in dry THF (15 mL). t-BuOLi (200 mg, 2.53 mmol) added and reaction
mixture was then stirred for 15 minutes. The commercially available aldehyde (1.81 mmol) was
then dissolved in dry THF (10 mL) and was added to reaction mixture via a syringe. The reaction
mixture then heated to ~50oC and stirred for 1 hour before being cooled to room temperature, and
quenched with sat. aq. NH4Cl (30 mL), and then the volatiles were removed in vacuo. The residue
was extracted with EtOAc (3x20 mL), the organic phases then combined, dried (Na2SO4), filtered
and concentrated under vacuum.
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The residue could be taken directly to the next step without further purification or it could be
purified via column chromatography to give:
Ethyl 2-((t-butyldimethylsilyl)oxy)-3-phenylacrylate (7a)
Obtained by the reaction of benzaldehyde with the phosphonate 2. The residue was purified via
column chromatography (1:39, EtOAc:Hexane, v/v, Rf:0.44 & 0.55) to give 7a (555 mg, 1.81
mmol, 96%) as a clear liquid obtained as an 1:1 E/Z mixture (calculated by 1H NMR integration).
1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) First isomer- 7.70 (2H, d, J = 9.62 Hz, H2’/6’),
7.37-7.22 (3H, m, H3’/5’ & H4'), 6.88 (1H, s, H3), 4.29 (2H, q, J = 7.26 Hz, OCH2CH3), 1.38 (3H,
t, J = 7.26 Hz, OCH2CH3), 0.96 (9H, s, SiC(CH3)3), 0.14 (6H, s, Si(CH3)2); Second isomer- 7.37-
7.22 (5H, m, all ArH), 6.43 (1H, s, H3), 4.13 (2H, q, J = 8.07 Hz, OCH2CH3), 1.14 (3H, t, J = 8.07
Hz, OCH2CH3), 1.01 (9H, s, SiC(CH3)3), 0.25 (6H, s, Si(CH3)2). 13C NMR {DEPTQ-135}
(CDCl3, 100MHz, E/Z mixture): δ (ppm) 165.7, 165.2 (C1), 142.3, 140.8 (C2), 134.8, 134.3 (C1’),
130.0, 128.8, 128.2 (C2’/6’ or C3’/5’), 128.1 (C4’), 128.0, 127.2 (C2’/6’ or C3’/5’), 120.4, 119.0
(C3), 61.4, 61.0 (OCH2CH3), 25.9, 25.7 (SiC(CH3)3), 18.7, 18.4 (SiC(CH3)3), 14.5, 13.9
(OCH2CH3), -3.8, -4.6 (Si(CH3)2). IR (neat): 2950, 2940, 2865, 1725, 1625 cm-1. HRMS (ESI-
QTOF) m/z: [M+Na]+ Calcd for C17H26O3SiNa (329.1543), found 329.1535.
Ethyl 2-((t-butyldimethylsilyl)oxy)-3-(4-methoxyphenyl)acrylate (7b)
Obtained by the reaction of 4-methoxybenzaldehyde with the phosphonate 2. The residue was
purified via column chromatography (1:19, EtOAc:Hexane, v/v, Rf:0.29 & 0.41) to give 7b (609
mg, 1.81 mmol, 100%) as a clear liquid obtained as a mixture of isomers (2:1, major:minor
calculated via 1H NMR integration).
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1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) Major isomer- 7.66 (2H, d, J = 8.99 Hz, H2’/6’),
6.86 (2H, d, J = 8.99 Hz, H3’/5’), 6.83 (1H, s, H3), 4.27 (2H, q, J = 7.02 Hz, OCH2CH3), 3.82
(3H, s, ArOCH3), 1.36 (3H, t, J = 7.02 Hz, OCH2CH3), 0.96 (9H, s, SiC(CH3)3), 0.13 (6H, s,
Si(CH3)2); Minor isomer- 7.23 (2H, d, J = 8.40 Hz, H2’/6’), 6.82 (2H, d, J = 8.40 Hz, H3’/5’),
6.38 (1H, s, H3), 4.15 (2H, q, J = 7.30 Hz, OCH2CH3), 3.80 (3H, s, ArOCH3), 1.19 (3H, t, J = 7.30
Hz, OCH2CH3), 0.99 (9H, s, SiC(CH3)3), 0.22 (6H, s, Si(CH3)2). 13C NMR {DEPTQ-135}
(CDCl3, 100MHz, E/Z mixture): δ (ppm) 165.9, 165.2 (C1), 159.5, 159.0 (C4’), 141.1, 139.3 (C2),
131.5, 130.3 (C2’/6’), 126.89, 126.87 (C1’), 120.9, 119.0 (C3), 113.7, 113.5 (C3’/5’), 61.3, 61.0
(OCH2CH3), 55.39, 55.37 (CarOCH3), 26.0, 25.8 (SiC(CH3)3), 18.7, 18.4 (SiC(CH3)3), 14.5, 14.1
(OCH2CH3), -3.7, -4.6 (Si(CH3)2). IR (neat): 2950, 2930, 2850, 1710, 1605, 1500 cm-1. HRMS
(ESI-QTOF) m/z: [M+Na]+ Calcd for C18H28O4SiNa (359.1649), found 359.1637.
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Ethyl 2-((t-butyldimethylsilyl)oxy)-3-(4-chlorophenyl)acrylate (7c)
Obtained by the reaction of 4-chlorobenzaldehyde with the phosphonate 2. The residue was
purified via column chromatography (1:99, EtOAc:Hexane, v/v, Rf:0.20 & 0.27) to give 7c (620
mg, 1.81 mmol, 100%) as a clear liquid obtained as a mixture of isomers (5:2, major:minor
calculated via 1H NMR integration).
1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) Major isomer- 7.62 (2H, d, J = 8.46 Hz,
H2’/6’), 7.30 (2H, d, J = 8.46 Hz H3’/5’), 6.80 (1H, s, H3), 4.28 (2H, q, J = 7.09 Hz,
OCH2CH3), 1.36 (3H, t, J = 7.09 Hz, OCH2CH3), 0.94 (9H, s, SiC(CH3)3), 0.14 (6H, s,
Si(CH3)2); Minor isomer- 7.25 (2H, d, J = 7.85 Hz, H2’/6’), 7.18 (2H, d, J = 7.85 Hz H3’/5’),
6.34 (1H, s, H3), 4.13 (2H, q, J = 7.57 Hz, OCH2CH3), 1.16 (3H, t, J = 7.57 Hz, OCH2CH3),
0.99 (9H, s, SiC(CH3)3), 0.23 (6H, s, Si(CH3)2). 13C NMR {DEPTQ-135} (CDCl3, 100MHz,
E/Z mixture): δ (ppm) 165.4, 164.9 (C1), 142.7, 141.2 (C2), 133.7, 132.8 (C4’), 131.1, 130.2,
128.5, 128.2 (C2’/6’ & C3’/5’), 119.3, 117.5 (C3), 61.6, 61.2 (OCH2CH3), 25.9, 25.7
(SiC(CH3)3), 18.7, 18.4 (SiC(CH3)3), 14.4, 14.0 (OCH2CH3), -3.7, -4.6 (Si(CH3)2), Note that
minor isomer was also observed in 13C NMR spectrum. IR (neat): 2940, 2920, 2860, 1705,
1620, 1590 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C17H25O3ClSiNa (363.1154),
found 363.1148.
Ethyl 2-((t-butyldimethylsilyl)oxy)-3-(4-methylphenyl)acrylate (7d)
Obtained by the reaction of p-tolualdehyde with the phosphonate 2. The residue was purified via
column chromatography (1:39, EtOAc:Hexane, v/v, Rf:0.34 & 0.40) to give 7d (580 mg, 1.81
1
mmol, 100%) as a clear liquid obtained as an equal E/Z mixture (calculated by H NMR
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1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) First isomer- 7.60 (2H, d, J = 8.28 Hz, H2’/6’),
7.17 (2H, d, J = 8.28 Hz, H3’/5’), 6.85 (1H, s, H3), 4.28 (2H, q, J = 7.22 Hz, OCH2CH3), 2.35
(3H, s, ArCH3), 1.37 (3H, t, J = 7.22 Hz, OCH2CH3), 0.97 (9H, s, SiC(CH3)3), 0.14 (6H, s,
Si(CH3)2); Second isomer- 7.14 (2H, d, J = 7.94 Hz, H2’/6’), 7.10 (2H, d, J = 7.94 Hz, H3’/5’),
6.39 (1H, s, H3), 4.14 (2H, q, J = 7.09 Hz, OCH2CH3), 2.33 (3H, s, ArCH3), 1.17 (3H, t, J = 7.09
Hz, OCH2CH3), 1.00 (9H, s, SiC(CH3)3), 0.23 (6H, s, Si(CH3)2). 13C NMR {DEPTQ-135}
(CDCl3, 100MHz, E/Z mixture): δ (ppm) 165.8, 165.2 (C1), 141.7, 140.1 (C2), 138.1, 137.0,
131.7, 131.5 (C1’ & C4’), 129.9, 129.0, 128.8, 128.7 (C2’/6’ & C3’/5’), 120.7, 119.2 (C3), 61.3,
61.0 (OCH2CH3), 26.0, 25.7 (SiC(CH3)3), 21.5, 21.3 (CarCH3), 18.7, 18.4 (SiC(CH3)3), 14.5, 14.0
(OCH2CH3), -3.7, -4.6 (Si(CH3)2). IR (neat): 2970, 2925, 2850, 1715, 1625 cm-1. HRMS (ESI-
QTOF) m/z: [M+Na]+ Calcd for C18H28O3SiNa (343.1700), found 343.1691.
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Ethyl 2-((t-butyldimethylsilyl)oxy)-3-(3-methoxyphenyl)acrylate (7e)
Obtained by the reaction of 3-methoxybenzaldehyde with the phosphonate 2. The residue was
purified via column chromatography (1:19, EtOAc:Hexane, v/v, Rf:0.33 & 0.42) to give 7e (559
mg, 1.66 mmol, 92%) as a clear liquid obtained as an equal E/Z mixture (calculated by 1H NMR
integration).
1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) First isomer- 7.27-7.17 (2H, m, ArH), 6.84
(1H, s, H3), 6.83-6.76 (2H, m, ArH), 4.13 (2H, q, J = 7.34 Hz, OCH2CH3), 3.79 (3H, s, ArOCH3),
1.14 (3H, t, J = 7.34 OCH2CH3), 0.99 (9H, s, SiC(CH3)3), 0.23 (6H, s, Si(CH3)2); Second isomer-
7.27-7.17 (2H, m, ArH), 6.83-6.76 (2H, m, ArH), 6.37 (1H, s, H3), 4.28 (2H, q, J = 7.27 Hz
OCH2CH3), 3.81 (3H, s, ArOCH3), 1.36 (3H, t, J = 7.27 Hz, OCH2CH3), 0.95 (9H, s, SiC(CH3)3),
0.13 (6H, s, Si(CH3)2). 13C NMR{DEPTQ-135} (CDCl3, 100MHz, E/Z mixture): δ (ppm) 165.5,
165.1 (C1), 159.4, 159.2 (C3’), 142.5, 140.8 (C2), 136.0, 135.4 (C1’), 129.0, 128.9, 122.6, 121.2,
119.6, 118.9, 115.0, 114.1, 114.0, 112.7 (C2’, C3, C4’, C5’, C6’), 61.3, 60.9 (OCH2CH3), 55.3,
55.2 (CarOCH3), 25.8, 25.6 (SiC(CH3)3), 18.6, 18.3 (SiC(CH3)3), 14.3, 13.8 (OCH2CH3), -3.8, -4.7
(Si(CH3)2). IR (neat): 2950, 2920, 2850, 1715, 1625, 1600, 1590 cm-1. HRMS (ESI-QTOF) m/z:
[M+Na]+ Calcd for C18H28O4SiNa (359.1649), found 359.1643.
Ethyl 2-((t-butyldimethylsilyl)oxy)-5-methylhex-2-enoate (7f)
Obtained by the reaction of isovaleraldehyde with the phosphonate 2. The residue was purified
via column chromatography (1:39, EtOAc:Hexane, v/v, Rf:0.17 & 0.26) to give 7f (520 mg, 1.81
mmol, 100%) as a clear liquid obtained as a mixture of isomers (13:2, major:minor calculated via
1H NMR integration).
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1H NMR (CDCl3, 400MHz, E/Z mixture): δ (ppm) Major isomer- 5.51 (1H, t, J = 7.98 Hz, H3),
4.20 (2H, q, J = 7.14 Hz, OCH2CH3), 2.35 (2H, dd, J = 7.98, 6.82 Hz, H4), 1.70-1.58 (1H, m, H5),
1.31 (2H, t, J = 7.14 Hz, OCH2CH3), 0.94 (9H, s, SiC(CH3)3), 0.91 (6H, d, J = 6.64 Hz, H6), 0.12
(6H, s, Si(CH3)2); Minor isomer- 6.04 (1H, t, J = 7.45 Hz, H3), 4.19 (2H, q, J = 7.23 Hz,
OCH2CH3), 2.08 (2H, dd, J = 7.45, 7.06, H4), 1.70-1.58 (1H, m, H5), 1.30 (3H, t, J = 7.23 Hz,
OCH2CH3), 0.96 (9H, s, SiC(CH3)3), 0.92 (6H, d, J = 6.70 Hz, H6), 0.15 (6H, s, Si(CH3)2). 13C
NMR {DEPTQ-135} (CDCl3, 100MHz): δ (ppm) 165.0 (C1), 140.7 (C2), 124.9 (C3), 60.6
(OCH2CH3), 35.8 (C4), 29.3 (C5), 25.8 (SiC(CH3)3), 22.5 (C6), 18.3 (SiC(CH3)3), 14.3
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(OCH2CH3), -4.7 (Si(CH3)2), Note that minor isomer was also observed in C NMR spectrum.
IR (neat): 2980, 2910, 2860, 1720, 1625cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for
C15H30O3SiNa (309.1856), found 309.1858.
Ethyl 2-((t-butyldimethylsilyl)oxy)-4-ethyloct-2-enoate (7g)
Obtained by the reaction of 2-ethylhexanal with the phosphonate 2. The residue was purified via
column chromatography (1:39, EtOAc:Hexane, v/v, Rf:0.19 & 0.26) to give 7g (590 mg, 1.80
mmol, 98%) as a clear liquid obtained as a mixture of isomers (20:1, major:minor calculated via
1H NMR integration).
1H NMR (CDCl3, 400MHz): δ (ppm) Major isomer- 5.18 (1H, d, J = 11.14 Hz, H3), 4.20 (2H, q,
J = 7.97 Hz, OCH2CH3), 3.05-2.95 (1H, m, H4), 1.50-1.36 (2H, m, H1’), 1.31 (3H, t, J = 7.97 Hz,
OCH2CH3), 1.30-1.19 (5H, m, H4, H5 & H6), 0.95 (9H, s, SiC(CH3)3), 0.88-0.83 (6H, m, H2’,
H8), 0.13 (6H, s, Si(CH3)2); Minor isomer- 5.77 (1H, d, J = 10.21 Hz, H3), 4.19 (2H, q, J = 7.01
Hz, OCH2CH3), 2.58-2.49 (1H, m, H4), 1.50-1.36 (2H, m, H1’), 1.33-1.19 (8H, m, OCH2CH3, H4,
H5 & H6), 0.95 (9H, s, SiC(CH3)3), 0.88-0.83 (6H, m, H2’, H8), 0.12 (6H, s, Si(CH3)2). 13C NMR
{DEPTQ-135} (CDCl3, 100MHz): δ (ppm) 165.1 (C1), 140.5 (C2), 131.0 (C3), 60.6 (OCH2CH3),
38.1 (C4), 35.5, 29.7, 28.9, (C1’, C5 & C6), 25.8 (SiC(CH3)3), 23.0 (C7), 18.4 (SiC(CH3)3), 14.3,
14.2, 11.9 (C2’, C8 & OCH2CH3), -4.7 (Si(CH3)2), Note that minor isomer was also observed in
13C NMR spectrum. IR (neat): 2950, 2925, 2855, 1720, 1620 cm-1. HRMS (ESI-QTOF) m/z:
[M+Na]+ Calcd for C18H36O3SiNa (351.2326), found 351.2318.
Ethyl 2-((t-butyldimethylsilyl)oxy)-4-methylhept-2-enoate (7h)
Obtained by the reaction of 2-methylpentanal with the phosphonate 2. The residue was purified
via column chromatography (1:39, EtOAc:Hexane, v/v, Rf:0.24 & 0.33) to give 7h (540 mg, 1.81
mmol, 100%) as a clear liquid obtained as a mixture of isomers (16:1, major:minor calculated via
1H NMR integration).
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1H NMR (CDCl3, 400MHz): δ (ppm) Major isomer- 5.25 (1H, d, J = 10.29 Hz, H3), 4.21 (2H, q,
J = 7.08 Hz, OCH2CH3), 3.21-3.11 (1H, m, H4), 1.31 (3H, t, J = 7.08 Hz, OCH2CH3), 1.29-1.18
(4H, m, H5 & H6), 0.98 (3H, d, J = 6.72 Hz, H1’), 0.94 (9H, s, SiC(CH3)3), 0.87 (3H, t, J = 6.90
Hz, H7), 0.12 (6H, s, Si(CH3)2); Minor isomer- 5.81 (1H, d, J = 10.09 Hz, H3), 4.21 (2H, q, J =
7.25 Hz, OCH2CH3), 2.75-2.66 (1H, m, H4), 1.31 (3H, t, J = 7.25 Hz, OCH2CH3), 1.29-1.18(5H,
m, H4, H5 & H6), 0.97 (3H, d, J = 6.87 Hz, H1’), 0.94 (9H, s, SiC(CH3)3), 0.86 (3H, t, J = 6.35
Hz, H7), 0.16 (6H, s, Si(CH3)2).13C NMR {DEPTQ-135} (CDCl3, 100MHz): δ (ppm) 165.0 (C1),
139.4 (C2), 132.3 (C3), 60.6 (OCH2CH3), 40.2 (C5), 31.1 (C4), 25.8 (SiC(CH3)3), 21.4 (C1’), 20.7
(C6), 18.4 (SiC(CH3)3), 14.32, 14.27 (C7 & OCH2CH3), -4.7, -4.8 (Si(CH3)2), Note that minor
isomer was also observed in 13C NMR spectrum. IR (neat): 2970, 2920, 2860, 1710, 1630cm-1.
HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C16H32O3SiNa (323.2013), found 323.2012.
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The following procedure is the typical method for the desilylation of the HWE adducts, followed by
neutralisation, as depicted in Scheme 2:
The HWE adduct 7 (1.0 mmol) or crude material from the HWE reaction described above was
dissolved in THF (5.6 mL) and cooled to ~0oC with an ice bath. 20% AcOH/H2O (6.0 mL) was
added followed by 1M TBAF/THF solution (1.2 g, 4.7 mL, 4.7 mmol). The reaction mixture was
allowed to warm to room temperature and stirred until starting material disappeared via TLC
analysis (usually ~30 minutes). The reaction mixture was then neutralised with the addition of
solid NaHCO3 (to pH ≈ 8), and then filtered to remove solids. The crude mixture was concentrated
in vacuo, and then diluted with EtOAc (50 mL), washed with sat. aq. NaHCO3, dried (Na2SO4),
and concentrated in vacuo. The residue was then purified via column chromatography, as
described below for each product.
Ethyl 5-methyl-2-oxohexanoate (8a)
Obtained 8a (139 mg, 0.81 mmol, 81%) as a clear, viscous liquid from the HWE adduct 7f after
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column chromatography (1:2, EtOAc:Hexane, v/v, Rf:0.64). H NMR (CDCl3, 400MHz): δ (ppm)
4.29 (2H, q, J = 7.08 Hz, OCH2CH3), 2.80 (2H, dd, J = 7.15, 7.79 Hz, H3), 2.24-1.99 (1H, m, H5),
1.53-1.46 (2H, m, H4), 1.34 (3H, t, J = 7.08 Hz, OCH2CH3), 0.89, 0.88 (2 x 3H, 2 x s, H1’, H6).
13C NMR {DEPTQ-135} (CDCl3, 100MHz): δ (ppm) 195.0 (C2), 161.4 (C1), 62.4 (OCH2CH3),
37.4 (C3), 31.8 (C4), 27.7 (C5), 22.3 (C1’, C6), 14.1 (OCH2CH3). Note that trace amounts of enol
tautomer can be observed in both 1H and 13C NMR spectra. HRMS (ESI-QTOF) m/z: [M+Na]+
Calcd for C9H16O3Na (195.0992), found 195.0995.
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Ethyl 4-ethyl-2-oxooctanoate (8b)
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Obtained 8b (158 mg, 0.74 mmol, 74%) as a clear, viscous liquid from the HWE adduct 7g after
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column chromatography (1:2, EtOAc:Hexane, v/v, Rf:0.61). H NMR (CDCl3, 400MHz): δ (ppm)
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4.26 (2H, q, J = 7.13 Hz, OCH2CH3), 2.69 (2H, d, J = 6.60 Hz, H3), 1.91-1.82 (1H, m, H4), 1.38-
1.15 (8H, m, H1’, H3, H5, H6 & H7), 1.32 (3H, t, J = 7.13, OCH2CH3), 0.83 (3H, t, J = 7.02 Hz,
H2’), 0.81 (3H, t, J = 7.46 Hz, H8). 13C NMR {DEPTQ-135} (CDCl3, 100MHz): δ (ppm) 195.0
(C2), 161.6 (C1), 62.3 (OCH2CH3), 43.6 (C3), 35.0 (C4), 33.2, 28.9, 26.4, 22.9 (C1’, C5, C6 &
C7), 14.04, 14.03, 10.8 (C2’, C8 & OCH2CH3). Note that trace amounts of enol tautomer can be
observed in both 1H and 13C NMR spectra. IR (neat): 2960, 2920, 2850, 1720cm-1. HRMS (ESI-
QTOF) m/z: [M+Na]+ Calcd for C12H22O3Na (237.1461), found 237.1464.
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Ethyl 4-methyl-2-oxoheptanoate (8c)
Obtained 8c (171 mg, 0.91 mmol, 91%) as a clear, viscous liquid from the HWE adduct 7h after
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column chromatography (1:2, EtOAc:Hexane, v/v, Rf:0.61). H NMR (CDCl3, 400MHz): δ (ppm)
4.27 (2H, q, J = 7.19 Hz, OCH2CH3), 2.77 (1H, dd, J = 16.69, 5.90 Hz, H3a), 2.58 (1H, dd, J =
16.69, 8.25 Hz, H3b), 2.02 (1H, m, H4), 1.32 (3H, t, J = 7.19, OCH2CH3), 1.31-1.11 (4H, m, H5
& H6), 0.88 (3H, d, J = 6.77 Hz, H1’), 0.85 (3H, t, J = 6.92 Hz, H7). 13C NMR {DEPTQ-135}
(CDCl3, 100MHz): δ (ppm) 194.7 (C2), 161.5 (C1), 62.4 (OCH2CH3), 46.4 (C3), 39.1 (C5), 28.6
(C4), 20.0 (C6), 19.8 (OCH2CH3), 14.1, 14.1 (C1’ & C7). Note that trace amounts of enol tautomer
can be observed in both 1H and 13C NMR spectra. IR (neat): 2950, 2925, 2880, 1715 cm-1. HRMS
(ESI-QTOF) m/z: [M+Na]+ Calcd for C10H18O3Na (209.1148), found 209.1148.
Ethyl 2-benzyl-4-hydroxy-5-oxo-3-phenyl-2,5-dihydrofuran-2-carboxylate (9a)
Obtained 9a (139 mg, 0.41 mmol, 82%) as a white solid from the HWE adduct 7a after column
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chromatography (1:4, EtOAc:Hexane, v/v, Rf:0.18). H NMR (CDCl3, 400MHz): δ (ppm) 7.72
(2H, d, J = 7.45 Hz, H2’/6’), 7.51-7.39 (3H, m, H3’/5’ & H4’), 7.19-7.09 (3H, m, H2’’/6’’& H4’’),
6.85 (2H, d, J = 8.11 Hz, H3’’/5’’), 4.27 (2H, q, J = 7.26 Hz, OCH2CH3) 3.69 (1H, d, J = 13.56,
H7a), 3.58 (1H, d, J = 13.56, H7b), 1.23 (3H, t, J = 7.26 Hz, OCH2CH3). 13C NMR {DEPTQ-
135} (CDCl3, 100MHz) δ (ppm) 169.2, 168.9 (C5 & C6), 138.8 (C3), 132.8 (C1’), 130.5 (C2’/6’),
129.7 (C4), 129.3 (C4’), 129.1 (C3’/C5’), 128.1 (C3’’/5’’), 127.8 (C4’’), 127.7 (C2’’/6’’), 127.4
(C4’’), 86.3 (C2), 63.1 (OCH2CH3), 39.2 (C7), 14.0 (OCH2CH3). IR (neat): 3290, 3080, 3020,
2980, 1720, 1680 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C20H18O5Na (361.1046),
found 361.1041.
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Ethyl 4-hydroxy-2-(4-methoxybenzyl)-5-oxo-3-(4-methoxyphenyl)-2,5-dihydrofuran-2-carboxylate
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(9b)
Obtained 9b (147 mg, 0.37 mmol, 74%) as a white solid from the HWE adduct 7b after column
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chromatography (1:4, EtOAc:Hexane, v/v, Rf:0.33). H NMR (CDCl3, 400MHz): δ (ppm) 7.71
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(2H, d, J = 9.23 Hz, H2’/6’), 6.99 (2H, d, J = 9.23 Hz, H3’/5’), 6.77 (2H, d, J = 8.06 Hz, H2’’/6’’),
6.65 (2H, d, J = 8.06 Hz, H3’’/5’’), 4.25 (2H, q, J = 6.90 Hz, OCH2CH3), 3.87, 3.71 (2 x 3H, 2 x
s, 2 x ArOCH3), 3.60 (1H, d, J = 14.33 Hz, H7a), 3.51 (1H, d, J = 14.33 Hz, H7b), 1.22 (3H, t, J
= 6.90 Hz, OCH2CH3). 13C NMR {DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 169.4, 169.2 (C5 &
C6), 160.2, 158.8 (C4’ & C4’’), 137.4 (C3), 131.5, 129.5 (C3’/5’ & C3’’/C5’’), 128.1 (C4), 124.8,
122.4 (C1’ & C1’’), 114.5, 113.5 (C2’/6’ & C2’’/6’’), 86.2 (C2), 63.0 (OCH2CH3), 55.5, 55.2 (2
x ArOCH3), 38.6 (C7), 14.0 (OCH2CH3). IR (neat): 3290, 3005, 2950, 2920, 2830, 1760, 1730,
1700, 1605 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C22H22O7Na (421.1258), found
421.1254.
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Ethyl 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-2-carboxylate (9c)
Obtained 9c (126 mg, 0.31 mmol, 62%) as a white amorphous mass from the HWE adduct 7c after
column chromatography (1:4, EtOAc:Hexane, v/v, Rf: 0.19). 1H NMR (CDCl3, 400MHz): δ
(ppm) 7.67 (2H, d, J = 8.75 Hz, H2’/6’), 7.44 (2H, d, J = 8.75 Hz, H3’/5’), 7.11 (2H, d, J = 8.89
Hz, H2’’/6’’), 7.01 (1H, brs, OH4), 6.77 (2H, d, J = 8.89 Hz, H3’’/5’’), 4.27 (2H, q, J = 7.12 Hz,
OCH2CH3) 3.64 (1H, d, J = 14.58 Hz, H7a), 3.51 (1H, d, J = 14.58 Hz, H7b), 1.23 (3H, t, J = 7.11
Hz, OCH2CH3). 13C NMR {DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 168.68, 168.67 (C5 & C6),
139.3, 135.5 (C4’ & C4’’), 133.6 (C3), 131.7, 129.5 (C3’/5’ & C3’’/C5’’), 131.2 (C4), 129.0,
128.5 (C2’/6’ & C2’’/6’’), 128.0, 126.3 (C1’ & C1’’), 85.9 (C2), 63.4 (OCH2CH3), 38.7 (C7), 14.0
(OCH2CH3). HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C20H16O5Cl2Na (429.0267), found
429.0266.
Ethyl 4-hydroxy-2-(4-methylbenzyl)-5-oxo-3-(4-methylphenyl)-2,5-dihydrofuran-2-carboxylate (9d)
Obtained 9d (70 mg, 0.19 mmol, 38%) as a white solid from the HWE adduct 7d after column
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chromatography (1:4, EtOAc:Hexane, v/v, Rf:0.14). H NMR (CDCl3, 400MHz): δ (ppm) 7.98
(2H, d, J = 8.06 Hz, H2’/6’), 7.62 (2H, d, J = 8.06 Hz, H3’/5’), 7.25 (2H, d, J = 8.06 Hz, H2’’/6’’),
7.09 (2H, d, J = 8.06 Hz, H3’’/5’’), 4.60 (2H, q, J = 7.19 Hz, OCH2CH3) 3.98 (1H, d, J = 14.17
Hz, H7a), 3.88 (1H, d, J = 14.17 Hz, H7b) 2.76, 2.58 (2 x 3H, 2 x s, 2 x ArCH3), 1.56 (3H, t, J =
7.08 Hz, OCH2CH3). 13C NMR {DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 169.4, 169.1 (C5 &
C6), 139.6, 138.3 (C4’ & C4’’), 136.9 (C3), 130.4, 129.8 (C3’/5’ & C3’’/C5’’), 129.7 (C4), 128.8,
127.8 (C2’/6’ & C2’’/6’’), 128.2, 126.9 (C1’ & C1’’), 86.3 (C2), 63.0 (OCH2CH3), 39.0 (C7),
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21.6, 21.2 (2 x ArCH3), 14.0 (OCH2CH3). IR (neat): 3300, 3025, 3010, 2995, 2930, 1730, 1710,
1650 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for C22H22O5Na (389.1359), found
389.1352.
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Ethyl 4-hydroxy-2-(3-methoxybenzyl)-5-oxo-3-(3-methoxyphenyl)-2,5-dihydrofuran-2-carboxylate
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(9e)
Obtained 9e (155 mg, 0.39 mmol, 78%) as an off-white amorphous mass from the HWE adduct
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7e after column chromatography (1:4, EtOAc:Hexane, v/v, Rf:0.14). H NMR (CDCl3, 400MHz):
δ (ppm) 7.38 (1H, t, J = 8.24 Hz, H5’), 7.32 (1H, brs, H2’), 7.24 (1H, m, H4’ or H6’), 7.04 (1H, t,
J = 8.04 Hz, H5’’), 6.95 (1H, m, 1.86 Hz, H4’ or H6’), 6.71 (1H, ddd, J = 8.04, 2.46 Hz, H4’’ or
H6’’), 6.46 (1H, d, J = 8.04 Hz, H4’’ or H6’’), 6.41 (1H, brs, OH4), 6.36 (1H, brs, H2’’), 4.28
(2H, q, J = 7.14 Hz, OCH2CH3), 3.84 (3H, s, ArOCH3), 3.64 (1H, d, J = 14.56 Hz, H1a), 3.59 (3H,
s, ArOCH3), 3.58 (1H, d, J = 14.56 Hz, H1b), 1.24 (3H, t, J = 7.14 Hz, OCH2CH3). 13C NMR
{DEPTQ-135} (CDCl3, 100MHz) δ (ppm) 169.00, 168.96 (C5 & C6), 160.0, 159.2 (C3’ & C3’’),
138.9 (C3), 134.4 (C1’), 130.9 (C4), 130.1 (C5’), 129.1 (C5’’), 127.4 (C1’’), 122.9 (C4’’ or C6’’),
120.0 (C4’ or C6’), 115.4 (C2’’), 115.3 (C4’ or C6’), 113.7 (C2’’ or C6’’), 113.4 (C2’), 86.3 (C2),
63.2 (OCH2CH3), 55.5, 55.1 (2 x ArOCH3), 39.4 (C7), 14.1 (OCH2CH3). IR (neat): 3280, 3060,
3000, 2940, 2840, 1750, 1725, 1700, 1600 cm-1. HRMS (ESI-QTOF) m/z: [M+Na]+ Calcd for
C22H22O7Na (421.1258), found 421.1251.
Ethyl 4-hydroxy-2-(2-methylpentyl)-5-oxo-3-(4-methoxyphenyl)-2,5-dihydrofuran-2-carboxylate (14)
A mixture of the HWE adducts 7b (200 mg, 0.59 mmol) and 7h (177 mg, 0.59 mmol) were
dissolved in THF (5.6 mL) and cooled to ~0oC with an ice bath. 20% AcOH/H2O (6.0 mL) was
added followed by 1M TBAF/THF solution (1.2 g, 4.7 mL, 4.7 mmol). The reaction mixture was
allowed to warm to room temperature and stirred until starting materials disappeared via TLC
analysis (~2 hour), and then neutralised by the addition of solid NaHCO3 (to pH ≈ 8), and stirred
for an additional 1 hour. The solid was removed by filtration and the crude mixture was
concentrated in vacuo, and then diluted with EtOAc (50 mL), washed with sat. aq. NaHCO3, dried
(Na2SO4), and concentrated in vacuo. The residue was then purified via column chromatography
(1:4, EtOAc:Hexane, v/v) to give 8c (11 mg, 0.06 mmol, 10%), 9b (56 mg, 0.14 mmol, 23%), and
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the title compound 14 (90 mg, 0.25 mmol, 42%) as a mixture of diastereomers. H NMR (CDCl3,
400MHz; where the same signal for the different diastereomer appears at a different resonance
frequency, the second signal is given in parentheses): δ (ppm) 7.76 (7.73) (2H, d, J = 9.12 Hz,
H2’/6’), 6.93 (2H, d, J = 9.12 Hz, H3’/5’), 4.20 (4.19) (2H, q, J = 7.05 Hz, OCH2CH3), 3.84 (3H,
s, ArOCH3), 2.49 (1H, dd, J = 14.85, 4.35 Hz, H1a”), 2.04 (1H, dd, J = 14.85, 6.88 Hz, H1b”),
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(2.28 (AB system, 2H, H1”)), 1.50-1.31 (1H, m, H2”), 1.28-1.05 (4H, m, H3”/H4”), 1.19 (1.19)
(3H, t, J = 7.05 Hz, OCH2CH3), 0.88 (0.71) (3H, d, J = 6.65 Hz, C2”-Me), 0.84 (0.67) (3H, t, J =
6.92 Hz, H5”). 13C NMR {DEPTQ-135} (CDCl3, 100MHz, where the same signal for the different
diastereomer appears at a different resonance frequency, the second signal is given in parentheses):
δ (ppm) 170.1, 169.5 (170.1, 169.4) (C5 & C6), 160.2 (160.1) (C4’), 137.1 (137.0) (C3), 129.6
(129.6) (C3’/5’), 129.5 (C4), 122.4 (122.2) (C1’), 114.4 (114.3) (C2’/6’), 87.6 (87.3) (C2), 62.9
(62.8) (OCH2CH3), 55.4 (55.4) (ArOCH3), 40.6 (39.9) (C1’’), 40.4 (40.4) (C3’’ or C4’’), 28.1
(28.0) (C2’’), 21.3 (21.2) (C2’’-Me), 19.8 (19.7) (C3’’ or C4’’), 14.3 (14.1) (OCH2CH3),
14.0(C5”). IR (neat): 3295, 2958, 2931, 2872, 1742, 1730 cm-1. HRMS (ESI-QTOF) m/z:
[M+Na]+ Calcd for C20H26O6Na (385.1622), found 385.1620.
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Ethyl 4-hydroxy-2-(4-methoxybenzyl)-5-oxo-3-phenyl-2,5-dihydrofuran-2-carboxylate (15) and
Ethyl 4-hydroxy-2-benzyl-5-oxo-3-(4-methoxyphenyl)-2,5-dihydrofuran-2-carboxylate (16)
A mixture of the HWE adducts 7a (330 mg, 1.08 mmol) and 7b (360 mg, 1.08 mmol) were
dissolved in THF (5.6 mL) and cooled to ~0oC with an ice bath. 20% AcOH/H2O (6.0 mL) was
added followed by 1M TBAF/THF solution (1.2 g, 4.7 mL, 4.7 mmol). The reaction mixture was
allowed to warm to room temperature and stirred until starting materials disappeared via TLC
analysis (~4 hour), and then neutralised by the addition of solid NaHCO3 (to pH ≈ 8), and stirred
for an additional 1 hour. The solid was removed by filtration and the crude mixture was
concentrated in vacuo, and then diluted with EtOAc (50 mL), washed with sat. aq. NaHCO3, dried
(Na2SO4), and concentrated in vacuo. The residue was then purified via column chromatography
(1:9, EtOAc:Hexane, v/v) to give 9a (75 mg, 0.22 mmol, 20%), 9b (80 mg, 0.20 mmol, 19%), and
a mixture of the title compounds 15 and 16 (170 mg, 0.46 mmol, 43%) as an inseparable mixture
of isomers in approximately equal amounts (as calculated via 1H NMR integration).
1H NMR (CDCl3, 400MHz, both isomers): δ (ppm) 7.73-7.68 (4H, m, 2 x H2’/6’), 7.49-7.35 (3H,
m, H3’/5’ & H4’), 7.16-7.09 (3H, m, H2’’/6’’& H4’’), 6.99 (2H, d, J = 8.14 Hz, H3’/5’), 6.85 (2H,
m, H3’’/5’’), 6.75 (2H, d, J = 8.76 Hz, H2’’/6’’), 6.66 (2H, d, J = 8.76 Hz, H3’’/5’’), 6.55, 6.38 (2
x 1H, 2 x brs, 2 x OH4), 4.30-4.22 (4H, m, 2 x OCH2CH3), 3.88, 3.72 (2 x 3H, 2 x s, 2 x ArOCH3),
3.66, 3.62 (2 x 1H, 2 x d, J = ~14.57 Hz, 2 x H7a), 3.56, 3.52 (2 x 1H, 2 x d, J = ~14.57 Hz, 2 x
H7b), 1.22 (6H, t, J = 7.38 Hz, 2 x OCH2CH3). 13C NMR {DEPTQ-135} (CDCl3, 100MHz, both
isomers): δ (ppm) 169.2, 169.2, 169.1, 169.0, (2 x C5 & C6), 160.3, 158.8 (C4’ & C4’’), 138.8,
137.3 (2 x C3), 132.9 (C1’), 131.6, 130.5 (C3’/5’ & C3’’/C5’’), 129.7 (C4), 129.5 (C2’/C6’), 129.4
(C4’), 129.1, 128.1 (C3’/C5’ & C3’’/5’’), 128.0 (C4), 127.8 (C2’’/6’’), 127.4 (C4’’), 124.8, 124.3
(C1’ & C1’’), 114.6, 113.6 (C2’/6’ & C2’’/6’’), 86.4, 86.1 (2 x C2), 63.1 (2 x OCH2CH3), 55.5,
55.2 (2 x ArOCH3), 39.5, 38.5 (2 x C7), 14.0 (2 x OCH2CH3).
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HRMS (ESI-QTOF) m/z: [M+H]+ Calcd for C21H21O6 (369.1333), found 369.1327.
ASSOCIATED CONTENT
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Supporting Information
1H & 13C NMR spectra are included.
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The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* m.kiefel@griffith.edu.au
ORCID
Milton J Kiefel: 0000-0003-1030-1440
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by a Griffith University postgraduate scholarship (GUPRA) for JE, and
the Institute for Glycomics.
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