Manipulating the enone moiety of levoglucosenone: 1,3-Transposition reactions including ones leading to isolevoglucosenone

Article abstract of DOI:10.1016/j.tet.2018.03.023

The manipulation of the enone moiety associated with the biomass-derived, homochiral and now abundant compound levoglucosenone (1) is described. While the trichloroacetimidates derived from the allylic alcohols 3 and 4 failed to engage in Overman-type rea

Full text of DOI:10.1016/j.tet.2018.03.023

Accepted Manuscript
Manipulating the enone moiety of levoglucosenone: 1,3-Transposition reactions
including ones leading to isolevoglucosenone
Xinghua Ma, Xin Liu, Patrick Yates, Warwick Rafferty, Martin G. Banwell, Chenxi Ma,
Anthony C. Willis, Paul D. Carr
PII:
S0040-4020(18)30266-7
10.1016/j.tet.2018.03.023
TET 29363
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 January 2018
Revised Date: 8 March 2018
Accepted Date: 9 March 2018
Please cite this article as: Ma X, Liu X, Yates P, Rafferty W, Banwell MG, Ma C, Willis AC, Carr PD,
Manipulating the enone moiety of levoglucosenone: 1,3-Transposition reactions including ones leading
to isolevoglucosenone, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.023.
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ACCEPTED MANUSCRIPT
Graphical Abstract
O
O
dimethyl
O
O
Luche
CO2Me
CO2Me
malonate
O
O
reduction
O
MeO2C
MeO2C
O
+
O
OAc
then
NaH, Pd[0]
THF
acetylation
X-ray
X-ray
levoglucosenone

ACCEPTED MANUSCRIPT
Manipulating the Enone Moiety of Levoglucosenone:
1,3-Transposition Reactions Including Ones Leading to Isolevoglucosenone†
Xinghua Ma,a Xin Liu,a Patrick Yates,a Warwick Rafferty,b Martin G. Banwell,*,a
Chenxi Ma,a Anthony C. Willisa and Paul D. Carra
a Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
and
b Circa Group Pty Ltd,
551 Burwood Highway, Knoxfield VIC 3180, Australia
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
The manipulation of the enone moiety associated with the biomass-derived,
homochiral and now abundant compound levoglucosenone (1) is described. While the
trichloroacetimidates derived from the allylic alcohols 3 and 4 failed to engage in
Overman-type rearrangements, certain ester derivatives reacted in the presence of
Pd[0]-catalysts to give regio-isomeric mixtures of β,γ-unsaturated malonates or
ketones, the structures of which were confirmed by single-crystal X-ray analyses. In
other sequences involving 1,3-transposition reactions, an operationally simple means
for converting compound 1 into isolevoglucosenone (2) is described.
O
O
O
O
OH
O
O
O
O
O
OH
O
2
3
4
1
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
† Dedicated to the memory of Professor Sir Derek Barton and in recognition of his
seminal contributions to so many aspects of organic chemistry.
1

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INTRODUCTION
Levoglucosenone (1) can be generated through the acid-catalysed depolymerisation of
cellulose and recent refinements of this process have allowed for the production of
this homochiral material on the tonne scale from various forms of biomass including
waste paper and sawdust.1 As testimony to the scale and utility of this process, the
ketone, Cyrene™, arising from the hydrogenation of the carbon-carbon double bond
within compound 1, is now being employed in a number of countries as a replacement
for the soon-to-be banned polar aprotic solvent N-methylpyrrolidinone (NMP).2
Given both the sustainable nature and the scale of its production, levoglucosenone is
likely to become an increasingly important starting material in chemical synthesis,
and all the more so if new means for manipulating it in useful ways can be
developed.3 The most obvious site for manipulation is the enone moiety and a range
of methods for doing so has been reported in the literature,1,4 including by us.5 In
particular, and like others,3 we have sought to convert compound 1 into its quasi-
enantiomer isolevoglucosenone (2). In our work5 this was achieved using Wharton
rearrangement chemistry and these studies prompted us to consider other means by
which the required and related 1,3-transposition processes could be implemented
within the 6,8-dioxabicyclo[3.2.1]octane framework associated with levoglucosenone.
The work detailed in the following sections reveals new means for doing so.
O
O
O
O
O
O
2
1
2

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RESULTS AND DISCUSSION
The [3,3]-sigmatropic rearrangement of derivatives of the epimeric allylic alcohols
arising from the 1,2-reduction of levoglucosenone became the focal point of our
initial studies and efficient means for obtaining the first of these substrates are shown
in Scheme 1. Specifically, then, enone 1 was subjected to 1,2-reduction in methanol at
0 °C using sodium borohydride in the presence of cerium trichloride and in this way a
ca. 11:1 mixture of the anticipated and epimeric allylic alcohols 3 and 4 was obtained
in 91% combined yield.6 These could not be separated by conventional means and so
the mixture was acetylated under standard conditions and the product esters 56 (92%)
and 66 (8%) were each isolated in pure form using flash chromatographic techniques
and then fully characterized. Each was treated with potassium carbonate in methanol
and thus regenerating the corresponding and now epimerically pure allylic alcohols 3
(97%) and 4 (92%), respectively. The spectral data acquired on these were in
agreement with those reported in the literature.6 The preferential formation of epimer
3 in the initial reduction step is entirely consistent with previous observations and
necessarily arises through selective delivery of hydride from the sterically less
congested α-face of the enone moiety in substrate 1 (the corresponding β-face being
shielded by the presence of the sterically demanding 1,6-anhydro-bridge).
Scheme 1
3

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In order to secure workable quantities of the minor epimeric alcohol 4 for further
study, the straightforward reaction sequence shown in Scheme 2 was developed.
Specifically, then, the more abundant allylic alcohol 3 was subjected to a Mitsunobu
reaction using triphenylphosphine/diethyl azodicarboxylate (DEAD) for activation
and α-chloroacetic acid as the nucleophile.6,7 By such means the inverted allylic α-
chloroacetate 7 was obtained in 86% yield and when this was saponified using
potassium carbonate in methanol then the target alcohol 4 was obtained in 85% yield.
O
O
O
ClCH2CO2H
Ph3P, DEAD
OH
K2CO3
O
O
O
THF
86%
CH3OH
85%
OCOCH2Cl
OH
7
4
3
Scheme 2
The structures of all of the products of the reactions shown in Schemes 1 and 2 were
confirmed by single-crystal X-ray analyses of derivatives of compounds 3 and 4.
Details of these analyses are presented below, including in the Experimental Section
as well as in the Supplementary Information.
With allylic alcohols 3 and 4 now each available in useful quantities, an investigation
into the participation of certain derivatives in [3,3]-sigmatropic rearrangement
reactions began. Given our successes8 in applying the Eschenmoser-Claisen
rearrangement to various 2-cyclohexen-1-ols, each of compounds 3 and 4 was treated
with N,N-dimethylacetamide dimethyl acetal in refluxing toluene but to no avail.
Similarly, all attempts to effect Ireland-Claisen-type rearrangements9 of acetates 5 and
6 under standard conditions also failed. In each instance either the relevant starting
material (viz. 3-6) was returned or, under more forcing conditions (involving higher
4

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reaction temperatures), decomposition was observed. In an effort to engage allylic
alcohols 3 and 4 in Overman rearrangement reactions,10 an o-xylene/THF or
dichloromethane/THF solution of each was treated (Scheme 3) with
trichloroacetonitrile in the presence of either sodium hexamethyldisilazide
(NaHMDS) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and thereby affording the
anticipated and crystalline trichloroacetimidates 8 (87%) and 9 (78%), respectively.
The structure of each of products 8 and 9 was confirmed by single-crystal X-ray
analysis, details of which are reported in the Experimental Section. Of course, these
analyses also serve to confirm the structures of precursors 3 and 4 as well as the
corresponding acetates.
Cl3CCN
NaHMDS
O
O
OC(NH)CCl3
OH
O
O
o-xylene/THF
87%
8
3
Cl3CCN
DBU
O
O
O
O
CH2Cl2/THF
78%
OC(NH)CCl3
OH
9
4
Scheme 3
Unfortunately, all attempts thus far to induce the Overman rearrangement of
compounds 8 and 9 under a variety of conventional conditions failed. Once again,
either the starting material was returned or, under more forcing conditions,
decomposition was observed.
In light of our failures to effect [3,3]-sigmatropic rearrangements of compounds 3-6, 8
and 9, the Tsuji-Trost reactions of the allylic acetates were examined using (Ph3P)4Pd
5

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as the catalyst, the sodium salt of dimethyl malonate as the nucleophile and 1,2-
bis(diphenylphosphino)ethane (dppe) as an added ligand (Scheme 4)11,12 – in the
absence of dppe the illustrated transformations did not proceed very effectively at all.
Under such conditions compound 5 reacted to give a chromatographically separable
mixture of the regio-isomeric diesters 10 (44%) and 11 (32%), each of which was
crystalline and the structures of which could, therefore, be confirmed by single-crystal
X-ray analysis (see Experimental Section for details). Similar treatment of the
epimeric allylic acetate 6 also gave a mixture of compounds 10 (31%) and 11 (49%).
When reacted with LiCl in DMSO at 140 °C each of the product malonates was
converted, via a demethylation/decarboxylation process (Krapcho decarboxylation),13
into the corresponding methyl acetate derivatives, namely compounds 12 (79%) and
13 (82%).
O
OAc
O
5
dimethyl malonate
NaH, Pd[0], dppe
THF
LiCl
DMSO
water
LiCl
DMSO
water
O
O
O
CO2Me
CO2Me
O
CO2Me
O
MeO2C
MeO2C
O
+
O
O
79%
82%
MeO2C
10 (44% from 5
31% from 6)
11 (32% from 5
49% from 6)
12
13
dimethyl malonate
NaH, Pd[0], dppe
THF
O
O
OAc
6
Scheme 4
6

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The origins of the selectivities observed in the processes leading to malonates 10 and
11 remain to be established but the similarities of the outcomes are suggestive of the
involvement of a common intermediate. This is most likely to be the π-allyl palladium
complex in which the transition metal is co-ordinated to that face of the π-system
opposite the 1,6-anhydro-bridge. The formation of this intermediate from precursor 5
would presumably follow a conventional (inversion) pathway but precisely how this
same species is formed from epimer 6 is less obvious. It could be that interconversion
of the two possible (π-allyl)palladium complexes is taking place or that syn-
displacement of the acetate leaving group by Pd[0] is occurring.14 Regardless, of the
precise pathway involved, these results seem at odds with those of Matsumoto et al
who reported12 that the allylic and α-configured chloride corresponding to compound
6 reacts under essentially the same conditions to give a mixture of the epimeric forms
of compounds 10 and 11. Unfortunately, no spectral data were reported for
Matsumoto’s products and so relevant comparisons with our own (which are
presented in the Experimental Section) cannot be made.
A stereo-complementary outcome to the one just described was observed when the
palladium-catalysed Carroll-type rearrangement15 was applied to the β-keto-esters
derived from the epimeric alcohols 3 and 4 (Scheme 5). So, for example, treatment of
the anion derived from alcohol 3 with readily available 2,2,6-trimethyl-4H-1,3-
dioxin-4-one (14)16 afforded the β-keto-ester 15 (94%) that upon treatment with
(Ph3P)4Pd in refluxing toluene afforded a ca. 2:1 and chromatographically separable
mixture of the regio-isomeric γ,δ-unsaturated methyl ketones 16 and 17 (55%
combined yield). When the epimeric β-keto-ester 18, readily obtained in 90% by
treating the oxyanion derived from alcohol 4 with electrophile 14, was exposed to
(Ph3P)4Pd in refluxing toluene then a ca. 3:1 mixture of compounds 16 and 17 was
7

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obtained in 56% combined yield. Once again, the outcomes of this pair of reactions
suggest the involvement of a common intermediate, probably the π-allyl palladium
complex in which the metal is co-ordinated to that face of the π-system opposite the
1,6-anhydro-bridge and carrying, at the metal center, a carboxylate- or enolate-based
ligand. This intermediate is presumably generated from substrate 15 in a conventional
manner while its production from precursor 18 could involve pre-complexation of the
palladium by the α-oriented and bidentate β-keto-ester residue. Regardless of the
precise details of the Tsuji-Trost-type chemistries shown in Schemes 4 and 5, it seems
that the intermediate π-allyl complexes invariably involve α-face selective co-
ordination of the palladium.
8

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O
O
NaH
O
O
OH
O
O
O
+
O
THF
94%
O
O
3
15
14
Pd[0]
toluene
O
O
O
O
+
O
O
16 (37% from 15
41% from 18)
17 (18% from 15
15% from 18)
Pd[0]
toluene
O
O
O
NaH
O
O
+
O
THF
90%
O
O
OH
O
O
18
14
4
Scheme 5
Given the pivotal nature of these conclusions, it was crucial to unambiguously
establish the structure of each of products 16 and 17. In the case of the former
compound, this was done by the means outlined in Scheme 6. Specifically, compound
16 was treated with methylmagnesium bromide and the ensuing 3°-alcohol 19 (93%)
then converted, under standard conditions, into the corresponding 3,5-dinitrobenzoate
20 (89%). This proved to be a crystalline compound and its structure could thus be
determined by single-crystal X-ray analysis, details of which are provided in the
Experimental Section.
9

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O
O
O
O
O
O
3,5-(O2N)C6H3COCl
MeMgBr
O
O
THF
93%
pyridine, DMAP
CH2Cl2
O
OH
89%
O2N
NO2
19
16
20
Scheme 6
In an analogous manner, ketone 17 was converted into the 3°-alcohol 21 (85%)
(Scheme 7) on treatment with methylmagnesium bromide and this was, in turn,
transformed into the corresponding 3,5-dinitrobenzoate 22 (90%) on exposure to 3,5-
dinitrobenzoyl chloride in the presence of pyridine and DMAP. Compound 22 also
proved to be a crystalline material and so its structure, too, was confirmed by single-
crystal X-ray analysis.
O
O
O
O
O
O
3,5-(O2N)C6H3COCl
MeMgBr
O
O
THF
85%
pyridine, DMAP
CH2Cl2
O
OH
90%
O2N
NO2
21
22
17
Scheme 7
Another 1,3-transposition process, and one that allows for the ready formation of
isolevoglucosenone (2) from congener 1, is shown in Scheme 8. Thus, water readily
adds to levoglucosenone (1) when it is dissolved in triethylamine and so forming the
previously reported17 β-hydroxyketone 23 (72%) that could be protected as the
corresponding TBS-ether under conventional conditions. Reduction of this ether with
10

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sodium borohydride in methanol then gave a ca. 4:3 mixture of the epimeric forms of
alcohol 24 (62% combined yield), the structure of the α-configured one being
confirmed by single crystal X-ray analysis. Acetylation of each of these alcohols
using acetic anhydride in the presence of DMAP gave the corresponding and epimeric
acetates 25 (99%). On exposure of these to tetra-n-butylammonium fluoride (TBAF)
the anticipated epimeric forms of alcohol 2618 (90%) were obtained and when these
were subjected to sequential treatment with pyridinium chlorochromate (PCC) and
sodium acetate then isolevoglucosenone (2) was obtained in 53% yield. This material
was identical, in all respects, to an authentic sample prepared by our earlier route.5
(i) TBS-Cl
O
O
imidazole
THF
O
water, Et3N
72%
O
O
O
O
O
OH
(ii) NaBH4
CH3OH
62%
OH
TBSO
1
24
23
Ac2O
DMAP
THF
99%
O
TBAF
THF
O
(i) PCC
CH2Cl2
O
O
O
O
OAc
OAc
90%
(ii) NaOAc
MeCN
53%
O
TBSO
OH
26
25
2
Scheme 8
Since the reaction sequence shown in Scheme 8 represents a rather minor variation on
the route (from 1 → 2) developed sometime ago by Furneaux and co-workers,17
attempts were made to establish a more concise pathway to target 2. To such ends,
compound 23 (Scheme 9) was stereoselectively reduced to the trans-1,3-diol 2717
(70%) and on oxidation of this with a slight excess of pyridinium dichromate (PDC) a
11

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chromatographically separable mixture of the mono-oxidation products 23 (10%) and
2819 (39%) was obtained. Treatment of the latter compound with p-toluenesulfonyl
chloride (p-TsCl) and triethylamine in acetonitrile then gave, presumably via an E1cb
elimination reaction involving the intermediate tosylate, isolevoglucosenone (2) in
65% yield.
O
NaBH4
CH3OH
O
OH
O
O
O
72%
HO
HO
23
27
PDC
acetone
p-TsCl
O
O
O
Et3N
OH
O
O
O
+
O
CH2Cl2
65%
O
OH
O
28 (39%)
2
23 (10%)
Scheme 9
In an effort to improve the efficiency of this three-step reaction sequence, various
attempts were made to increase the selectivity and yield of the oxidation process
leading to compound 28 but, thus far, to no avail. As such, the longer route (Scheme
8) remains the slightly higher yielding one (21% vs 18%) despite the additional steps
involved. That said, further refinements of the shorter pathway seem warranted and
are now being investigated. The outcomes of our efforts in this area will be reported
in due course.
The ready acquisition of isolevolglucosenone by the route detailed immediately above
allowed for a further exploration of the Tsuji-Trost chemistry of these systems. In
12

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particular, and as shown in Scheme 10, compound 2 could be reduced in a completely
stereoselective manner under Luche-type conditions to give the known allylic alcohol
29. The illustrated β-configuration at the newly established stereogenic center is
assigned on the basis that the steric demands of the 1,6-anhydrobridge in substrate 2
should direct hydride deliver to the α-face of the enone moiety. Acetylation of
compound 29 was effected under standard conditions and the resulting and previously
reported ester 30 (88% over two steps) was then subjected to reaction with the sodium
salt of dimethyl malonate in the presence of (Ph3P)4Pd and dppe to afford a mixture of
the regio-isomeric di-esters 10 (42%) and 11 (53%). Thus, a similar product
distribution is seen here as was observed when the regio-isomeric allylic acetate 5
(Scheme 4) was subjected to these same Tsuji-Trost reaction conditions. Of course,
such outcomes suggest that both reactions are proceeding, as would be expected,
through a common π-allyl palladium complex.
O
NaBH4
Ac2O
O
O
CeCl3•7H2O
O
DMAP
O
O
CH3OH
pyridine
HO
AcO
O
dimethyl malonate
NaH, Pd[0], dppe
THF
2
29
30 (88%)
O
O
O
CO2Me
CO2Me
MeO2C
MeO2C
+
O
11 (53%)
10 (42%)
Scheme 10
13

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CONCLUSIONS
We have described a series of palladium-catalysed and stereocontrolled (but non-
regio-selective) 1,3-transpostion reactions of various esters of the alcohols 3 and 4
derived from levoglucosenone (1). In each case a π-allyl palladium complex wherein
the transition metal is co-ordinated to the less hindered α-face of the bicyclic
framework is likely to be involved. While the [3,3]-sigmatropic rearrangement of
various derivatives of compounds 3 and 4 could not be implemented, the facile
conjugate addition of water to enone 1 allowed for the development of simple
synthetic routes to its quasi-enantiomer isolevoglucosenone (2) and a capacity,
therefore, to study the chemistry of this less-explored isomer.
Taken together, the processes described above add to the repertoire of chemical
transformations that can be applied to levoglucosenone (1), a homochiral and
increasingly readily available building block that can be produced in a sustainable
fashion and that is, therefore, likely to continue to assume increasing importance as a
starting material in chemical synthesis.
EXPERIMENTAL SECTION
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded
at 18 °C in base-filtered CDCl3 on a spectrometer operating at 400 MHz for proton
and 100 MHz for carbon nuclei. 1H NMR data are recorded as follows: chemical shift
(δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is
defined as s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. In relevant cases, the signal due to residual CHCl3
14

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appearing at δH 7.26 and the central resonance of the CDCl3 “triplet” appearing at δC
1
77.0 were used to reference H and 13C NMR spectra, respectively. Samples were
analyzed by infrared spectroscopy (νmax) as thin films on KBr plates. Optical rotations
were recorded using the sodium D-line (589 nm) in a cell with a path length of 1 dm,
at the concentrations indicated and in the specified solvent at 22 °C. Specific rotations
were then calculated in the usual manner. Low- and high-resolution electron impact
(EI) mass spectra were recorded on a double focusing, triple sector machine. Low-
and high-resolution ESI mass spectra were recorded on a triple-quadrupole mass
spectrometer operating in positive ion mode. Melting points are uncorrected.
Analytical thin layer chromatography (TLC) was performed on aluminum-backed 0.2
mm thick silica gel 60 F254 plates. Eluted plates were visualized using a 254 nm UV
lamp and/or by treatment with a suitable dip followed by heating. These dips included
phosphomolybdic acid/ceric sulfate/sulfuric acid (conc.)/water (37.5 g : 7.5 g : 37.5 g
: 720 mL), potassium permanganate/potassium carbonate/5% sodium hydroxide
aqueous solution/water (3 g : 20 g : 5 mL : 300 mL), and p-anisaldehyde or
vanillin/sulfuric acid (conc.)/ethanol (15 g : 2.5 mL : 250 mL). Flash chromatographic
separations were carried out following protocols defined by Still et al.20 with silica gel
60 (40-63 ꢀm) as the stationary phase and using the AR- or HPLC-grade solvents
indicated. The melting points of solids purified by such means were recorded directly
(ie after they had crystallized from the concentrated chromatographic fractions).
Starting materials, reagents, drying agents, and other inorganic salts were generally
commercially available and were used as supplied. Tetrahydrofuran (THF), methanol
and dichloromethane were dried using a solvent purification system that is based upon
a technology originally described by Grubbs et al.21 Where necessary, reactions were
performed under a nitrogen atmosphere.
15

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Specific Chemical Transformations
Compounds 5 and 6. Step i: A magnetically stirred solution of compound 1 (1.00 g,
7.93 mmol) in methanol (25 mL) maintained at 0 °C was treated with CeCl3•7H2O
(3.00 g, 8.05 mmol) then, in portions, with NaBH4 (300 mg, 7.93 mmol). The ensuing
mixture was stirred at 0 °C for 1 h before being concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromatography (silica, 2:1 v/v ethyl
acetate/hexane elution) to give, after concentration of the appropriate fractions (Rf =
0.5 in 5:4:1 v/v/v ethyl acetate/hexane/methanol), an inseparable mixture of
compounds 3 and 4 (922 mg, 91%) as a white, crystalline solid.
Step ii: A magnetically stirred solution of compounds 3 and 4 (658 mg, 5.14 mmol) in
pyridine (10 mL) was treated with acetic anhydride (2.00 mL, 21.16 mmol) then
DMAP (14 mg, 0.11 mmol). After stirring the ensuing mixture at 22 °C for 2 h, the
reaction mixture was concentrated under reduced pressure and the residue thus
obtained subjected to flash chromatography (silica, gradient elution from 1:25 → 1:4
v/v ethyl acetate/petroleum benzene elution) to deliver two fractions, A and B.
Concentration of fraction A (Rf = 0.3 in 2:2.5:5.5 v/v/v ethyl acetate/dichloromethane
/hexane) gave compound 5 (802 mg, 92%) as a clear, colorless oil, [α]D = −38 (c =
0.1, CHCl3): 1H NMR (400 MHz, CDCl3) δ 6.20 (m, 1H), 5.58 (m, 2H), 5.51 (m, 1H),
13
4.69 (t, J = 4.2 Hz, 1H), 3.98 (d, J = 6.6 Hz, 1H), 3.80 (m, 1H), 2.13 (s, 3H); C
NMR (100 MHz, CDCl3) δ 170.8 (C), 132.6 (CH), 124.9 (CH), 99.3 (CH), 71.8 (CH),
71.6 (CH2), 71.5 (CH), 21.2 (CH3); IR νmax 2963, 2891, 1729, 1371, 1230, 1124,
1038, 981, 883, 802 cm–1; MS (ESI, +ve) m/z 193 [(M+Na)+, 100%]; HRMS (M+H)+
calcd for C8H11O4 171.0652, found 171.0649.
Concentration of fraction B (Rf = 0.4 in 2:2.5:5.5 v/v/v ethyl acetate/dichloromethane
/hexane) gave compound 6 (70 mg, 8%) as a clear, colorless oil, [α]D = −265 (c = 0.1,
16

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CHCl3): 1H NMR (400 MHz, CDCl3) δ 6.31 (ddd, J = 9.8, 4.7 and 1.5 Hz, 1H), 5.74
(m, 1H), 5.53 (t, J = 1.5 Hz, 1H), 4.76 (m, 2H), 3.71 (m, 2H), 2.10 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.2 (C), 132.7 (CH), 122.9 (CH), 100.4 (CH), 70.5 (CH), 69.3
(CH2), 66.5 (CH), 21.1 (CH3); IR νmax 3051, 2965, 2894, 1735, 1475, 1372, 1235,
1126, 1023, 885, 867, 800, 712 cm–1; MS (ESI, +ve) m/z 193 [(M+Na)+, 100%];
HRMS (M+Na)+ calcd for C8H10O4Na 193.0477, found 193.0476.
Compound 3. A magnetically stirred solution of compound 5 (343 mg, 2.016 mmol)
in methanol (5 mL) maintained at 22 °C was treated with K2CO3 (557 mg, 4.03
mmol). The resulting mixture was stirred for 2 h then concentrated under reduced
pressure and the residue thus obtained subjected to flash chromatography (silica, 1.5:1
v/v ethyl acetate/petroleum spirit elution) to afford, after concentration of the
appropriate fractions (Rf = 0.5 in 5:4:1 v/v/v ethyl acetate/hexane/methanol),
compound 3 (249 mg, 97%) as a white, crystalline solid, m.p. = 58-60 °C, [α]D =
1
+190 (c = 0.2, CHCl3): H NMR (400 MHz, CDCl3) δ 6.03 (m, 1H), 5.85 (m, 1H),
5.52 (m, 1H), 4.67 (m, 1H), 3.95 (m, 1H), 3.65 (m, 1H), 3.47 (m, 1H), 2.32 (broad s,
13
1H); C NMR (100 MHz, CDCl3) δ 130.3 (CH), 126.4 (CH), 95.7 (CH), 77.0 (CH),
67.3 (CH), 62.7 (CH2); IR νmax 3401, 2976, 2891, 1385, 1170, 1096, 1053, 1010, 897,
709 cm–1; MS (ESI, +ve) m/z 151 [(M+Na)+, 100%], 129 [(M+H)+, <1]; HRMS
(M+H)+ calcd for C6H9O3 129.0546, found 129.0544.
Compound 7. A magnetically stirred a solution of compound 3 (180 mg, 1.41 mmol)
in THF (20 mL) maintained at 22 °C was treated with α-chloroacetic acid (266 mg,
2.82 mmol), triphenylphosphine (737 mg, 2.81 mmol) then diethyl azodicarboxylate
(440 µL, 2.79 mmol). The ensuing mixture was stirred at 22 °C for 18 h then
concentrated under reduced pressure. Subjection of the residue thus obtained to flash
chromatography (silica, 2:25 v/v ethyl acetate/petroleum ether elution) afforded, after
17

ACCEPTED MANUSCRIPT
concentration of the appropriate fractions (Rf = 0.4 in 2:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), compound 7 (246 mg, 86%) as a white, crystalline
solid, m.p. = 61-63 °C, [α]D = −214 (c = 0.2, CHCl3): 1H NMR (400 MHz, CDCl3) δ
6.35 (ddd, J = 9.9, 4.7 and 1.1 Hz, 1H), 5.79 (ddd, J = 9.9, 3.9 and 2.0 Hz, 1H), 5.55
(m, 1H), 4.81 (m, 1H), 4.77 (m, 1H), 4.10 (d, J = 0.9 Hz, 2H), 3.71 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 166.6 (C), 133.4 (CH), 122.0 (CH), 100.0 (CH), 70.5
(CH), 69.2 (CH2), 67.9 (CH), 40.9 (CH2); IR νmax 2961, 2895, 1758, 1326, 1295,
1260, 1169, 1126, 1020, 1000, 969, 911, 892, 804 cm–1; MS (ESI, +ve) m/z 229 and
35
227 [(M+Na)+, 30 and 100%]; HRMS (M+Na)+ calcd for C8H9 ClO4Na 227.0087,
found 227.0086.
Compound 4 (from compound 6). A magnetically stirred solution of compound 6 (70
mg, 0.41 mmol) in methanol (2.0 mL) maintained at 22 °C was treated with K2CO3
(170 mg, 1.22 mmol). The resulting mixture was stirred for 2 h then concentrated
under reduced pressure. Subjection of the residue thus obtained to flash
chromatography (silica, 1.5:1 v/v ethyl acetate/petroleum ether elution) afforded, after
concentration of the appropriate fractions (Rf = 0.5 in 5:4:1 v/v/v ethyl
acetate/hexane/methanol), compound 4 (49 mg, 92%) as a white, crystalline solid,
1
m.p. = 57-59 °C, [α]D = −242 (c = 0.2, CHCl3): H NMR (400 MHz, CDCl3) δ 6.18
(ddd, J = 9.8, 4.7 and 1.0 Hz, 1H), 5.81 (ddd, J = 9.8, 4.0 and 2.0 Hz, 1H), 5.52 (m,
13
1H), 4.68 (m, 1H), 3.68 (m, 2H), 3.63 (d, J = 3.9 Hz, 1H), 1.92 (s, 1H); C NMR
(100 MHz, CDCl3) δ 131.0 (CH), 126.6 (CH), 102.8 (CH), 70.8 (CH), 69.1 (CH2),
66.0 (CH); IR νmax 3400, 2959, 2892, 1403, 1123, 1052, 1029, 921, 892, 862, 851,
796, 727 cm–1; MS (ESI, +ve) m/z 151 [(M+Na)+, 100%], 129 [(M+H)+, <1]; HRMS
(M+H)+ calcd for C6H9O3 129.0546, found 129.0544.
18

ACCEPTED MANUSCRIPT
Compound 4 (from compound 7). Following a procedure similar to that described
immediately above, ester 7 (355 mg, 1.74 mmol) was converted into alcohol 4 (189
mg, 85%). This product was identical, in all respects, with an authentic sample.
Compound 8. A magnetically stirred solution of compound 3 (500 mg, 3.90 mmol)
and trichloroacetontrile (470 µL, 4.69 mmol) in o-xylene (30 mL) maintained under a
nitrogen atmosphere at 0 °C was treated with NaHMDS (780 µL of a 1.0 M solution
in THF, 0.78 mmol). The ensuing mixture was stirred at 0 °C for 1 h then warmed to
22 °C before being concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 1:1 v/v diethyl ether/hexane elution) to
afford, after concentration of the appropriate fractions (Rf = 0.4 in 1:2.5:5.5 v/v/v
ethyl acetate/dichloromethane/hexane), compound 8 (929 mg, 87%) as a white,
crystalline solid, m.p. = 88-90 °C, [α]D = −29 (c = 0.1, CHCl3): 1H NMR (400 MHz,
CDCl3) δ 8.41 (s, 1H), 6.26 (m, 1H), 5.86 (m, 1H), 5.77 (dt, J = 9.9 and 2.2 Hz, 1H),
13
5.65 (m, 1H), 4.71 (t, J = 4.2 Hz, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.82 (m, 1H); C
NMR (100 MHz, CDCl3) δ 162.4 (C), 133.1 (CH), 124.3 (CH), 98.6 (CH), 76.1 (CH),
71.6 (CH2), 71.5 (CH) (signal due to one carbon obscured/overlapping); IR νmax 3341,
2981, 2891, 1664, 1358, 1334, 1275, 1124, 1077, 1032, 796 cm–1; MS (EI, 70 eV) m/z
275, 273 and 271 (M+•, 1, 3 and 3%), 240, 238 and 236 (12, 48 and 75), 208 (59),
206 (45), 119 (95), 117 (100), 97 (37); HRMS M+• calcd for C8H8 Cl3NO3 270.9570,
35
found 270.9562.
Compound 9. DBU (82 µL, 0.55 mmol) was added to a magnetically stirred solution
of compound 4 (351 mg, 2.74 mmol) and trichloroacetontrile (330 µL, 3.29 mmol) in
dichloromethane (25 mL) maintained under a nitrogen atmosphere at 0 °C. The
ensuing solution was stirred at 0 °C for 0.5 h then warmed to 22 °C before being
concentrated under reduced pressure. The residue thus obtained was subjected to flash
19

ACCEPTED MANUSCRIPT
chromatography (silica, 1:1 v/v diethyl ether/hexane elution) to afford, after
concentration of the appropriate fractions (Rf = 0.4 in 1:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), compound 9 (557 mg, 78%) as a white, crystalline
solid, m.p. = 89-91 °C, [α]D = −146 (c = 0.1, CHCl3): 1H NMR (400 MHz, CDCl3) δ
8.45 (broad s, 1H), 6.39 (m, 1H), 5.93 (ddd, J = 9.8, 3.8 and 1.9 Hz, 1H), 5.70 (m,
1H), 4.90 (m, 1H), 4.80 (m, 1H), 3.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.9
(C), 133.3 (CH), 122.1 (CH), 99.7 (CH), 70.6 (CH), 70.4 (CH), 69.1 (CH2) (signal
due to one carbon obscured/overlapping); IR νmax 3339, 2964, 2894, 1662, 1352,
1329, 1272, 1126, 1060, 1020, 997, 871, 831, 792, 645 cm–1; MS (EI, 70 eV) m/z 275,
273 and 271 (M+•, 0.5, 1 and 1%), 240, 238 and 236 (9, 29 and 45), 208 (60), 206
35
(65), 119 (95), 117 (100), 97 (34); HRMS M+• calcd for C8H8 Cl3NO3 270.9570,
found 270.9567.
Compounds 10 and 11 (from compound 5). Sodium hydride (76 mg of a 60%
dispersion in mineral oil, 1.90 mmol) was added, in portions, to a magnetically stirred
solution of dimethyl malonate (225 µL, 1.97 mmol) in THF (18 mL) maintained
under a nitrogen atmosphere at 0 °C. The ensuing mixture was stirred for 1 h at 0 °C
then added to a magnetically stirred solution of compound 5 (104 mg, 0.61 mmol),
Pd(Ph3P)4 (35 mg, 0.03 mmol) and ethylenebis(diphenylphosphine) (24 mg, 0.06
mmol) in THF (7 mL) maintained under a nitrogen atmosphere at 22 °C. The ensuing
mixture was heated under reflux for 18 h then cooled and concentrated under reduced
pressure. The residue thus obtained was subjected to flash chromatography (silica,
1:20 → 1:10 v/v ethyl acetate/hexane gradient elution) and so affording two fractions,
A and B.
Concentration of fraction
A
(Rf
=
0.4 in 2:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane) gave compound 10 (66 mg, 44%) as a white,
20

ACCEPTED MANUSCRIPT
crystalline solid, m.p. = 84-86 °C, [α]D = +18 (c = 0.5, CHCl3): 1H NMR (400 MHz,
CDCl3) δ 5.90 (m, 1H), 5.55 (d, J = 9.8 Hz, 1H), 5.50 (m, 1H), 4.56 (broad s, 1H),
3.88 (m, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.65 (m, 1H), 3.30 (d, J = 12.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.9 (C), 167.8 (C), 128.5 (CH), 126.5 (CH), 96.0 (CH),
73.9 (CH), 63.8 (CH2), 53.1 (CH3), 53.0 (CH3), 51.8 (CH), 40.7 (CH); IR νmax 2956,
2898, 1752, 1735, 1436, 1256, 1152, 1126, 1072, 1036, 981, 906, 712 cm–1; MS (EI,
70 eV) m/z 242 (M+•, 8%), 211 (30), 183 (30), 178 (31), 150 (27), 132 (50), 111 (57),
81 (100), 59 (43); HRMS M+• calcd for C11H14O6 242.0790, found 242.0790.
Concentration of fraction
B
(Rf
=
0.4 in 2:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane) gave compound 11 (48 mg, 32%) as a white,
1
crystalline solid, m.p. = 36-38 °C, [α]D = −7 (c = 0.5, CHCl3): H NMR (400 MHz,
CDCl3) δ 6.11 (m, 1H), 5.69 (s, 1H), 5.50 (m, 1H), 4.63 (m, 1H), 3.89 (d, J = 6.5 Hz,
1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.71 (m, 1H), 3.53 (d, J = 10.5 Hz, 1H), 3.31
(broadened d, J = 10.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.7 (C), 168.2 (C),
130.6 (CH), 125.7 (CH), 101.4 (CH), 73.0 (CH2), 70.8 (CH), 52.9 (CH3), 52.8 (CH3),
52.1 (CH), 43.0 (CH); IR νmax 2955, 2890, 1751, 1735, 1436, 1261, 1151, 1122, 1072,
1053, 1019, 988, 885 cm–1; MS (EI, 70 eV) m/z 242 (M+•, 1%), 211 (56), 153 (47),
137 (72), 132 (80), 81 (100), 79 (60), 59 (58); HRMS M+• calcd for C11H14O6
242.0790, found 242.0786.
Compounds 10 and 11 (from compound 6). Following the same procedure as
described immediately above, compound 6 (104 mg, 0.61 mmol) was converted into a
mixture of compounds 10 (46 mg, 31%) and 11 (73 mg, 49%). Each of these products
was identical with an authentic sample.
Compound 12. A magnetically stirred solution of compound 10 (62 mg, 0.26 mmol)
in DMSO (7 mL) was treated with LiCl (54 mg, 1.27 mmol) and water (5 drops). The
21

ACCEPTED MANUSCRIPT
resulting mixture was heated at 140 °C for 2 h then cooled to 22 °C and subjected to
flash chromatography (silica, 2:5 v/v ethyl acetate/hexane elution). Concentration of
the
appropriate
fractions
(Rf
=
0.3
in
2:2.5:5.5
v/v/v
ethyl
acetate/dichloromethane/hexane) afforded compound 12 (37 mg, 79%) as a clear,
1
colorless oil, [α]D = −35 (c = 1.0, CHCl3): H NMR (400 MHz, CDCl3) δ 5.84 (m,
1H), 5.58 (m, 1H), 5.49 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.70 (s, 3H), 3.37 (m,
1H), 2.36 (m, 1H), 2.27 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 171.8 (C), 128.8
(CH), 127.5 (CH), 96.0 (CH), 75.0 (CH), 63.3 (CH2), 52.0 (CH3), 37.6 (CH), 34.2
(CH2); IR νmax 2956, 2899, 1735, 1436, 1262, 1198, 1168, 1121, 1071, 1035, 969, 903
cm–1; MS (EI, 70 eV) m/z 184 (M+•, 4%), 153 (19), 124 (24), 95 (21), 81 (61), 32
(100); HRMS M+• calcd for C9H12O4 184.0736, found 184.0741.
Compound 13. A magnetically stirred solution of compound 11 (110 mg, 0.45 mmol)
in DMSO (7 mL) was treated with LiCl (96 mg, 2.26 mmol) then water (6 drops). The
resulting mixture was heated at 140 °C for 18 h then cooled to 22 °C and subjected to
flash chromatography (silica, 2:5 v/v ethyl acetate/hexane elution). Concentration of
the appropriate fractions (Rf
=
0.3 in 2:2.5:5.5 v/v/v ethyl acetate/
dichloromethane/hexane) afforded compound 13 (69 mg, 82%) as a clear, colorless
1
oil, [α]D = −46 (c = 1.0, CHCl3): H NMR (400 MHz, CDCl3) δ 6.03 (m, 1H), 5.59
(m, 1H), 5.53 (m, 1H), 4.62 (t, J = 4.4 Hz, 1H), 3.88 (d, J = 6.3 Hz, 1H), 3.72 (m,
1H), 3.70 (s, 3H), 3.02 (m, 1H), 2.53 (dd, J = 16.4 and 8.0 Hz, 1H), 2.34 (dd, J = 16.4
and 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.6 (C), 129.2 (CH), 128.1 (CH),
102.0 (CH), 73.0 (CH2), 70.8 (CH), 51.8 (CH3), 39.8 (CH), 34.3 (CH2); IR νmax 2953,
2887, 1734, 1437, 1348, 1264, 1166, 1122, 1071, 1051, 1018, 985, 880, 802 cm–1;
MS (EI, 70 eV) m/z 184 (M+•, 3%), 153 (65), 124 (73), 96 (87), 81 (100), 79 (95), 59
(57); HRMS M+• calcd for C9H12O4 184.0736, found 184.0730.
22

ACCEPTED MANUSCRIPT
Compound 15. Sodium hydride (200 mg, 60% dispersion in mineral oil, 5.0 mmol)
was cautiously added to a magnetically stirred solution compound 3 (325 mg, 2.54
mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (14)16 (0.5 mL, 3.80 mmol) in THF (15
mL) maintained under a nitrogen atmosphere at 0 °C. After a further 1 h the reaction
mixture was quenched with a small amount of ice then concentrated under reduced
pressure. The residue thus formed was subjected to flash chromatography (silica, 1:2
v/v ethyl acetate/petroleum ether elution) to afford, after concentration of the
appropriate fractions (Rf
=
0.4 in 4:2.5:5.5 v/v/v ethyl acetate/
dichloromethane/hexane), compound 15 and ca. 10% of a mono-enolic tautomer (506
mg, 94%) as a clear, colorless oil, [α]D = −27 (c = 0.2, CHCl3): 1H NMR (400 MHz,
CDCl3) δ (major tautomer) 6.21 (m, 1H), 5.69 (m, 2H), 5.64 (m, 1H), 4.69 (t, J = 4.2
Hz, 1H), 3.95 (d, J = 6.6 Hz, 1H), 3.79 (m, 1H), 3.53 (s, 2H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (major tautomer) 200.2 (C), 167.1 (C), 133.0 (CH), 124.4 (CH),
99.0 (CH), 71.6 (CH), 71.5(2) (CH2), 71.4(6) (CH), 50.1 (CH2), 30.3 (CH3); IR νmax
2965, 2894, 1742, 1715, 1647, 1411, 1359, 1261, 1149, 1124, 1038, 983, 884 cm–1;
MS (ESI, +ve) m/z 235 [(M+Na)+, 100%]; HRMS [(M+Na)+ calcd for C10H12O5Na
235.0582, found 235.0583.
Compounds 16 and 17 (from compound 15). A magnetically stirred solution of
compound 15 (177 mg, 0.83 mmol) in dry, degassed toluene (15 mL) maintained
under nitrogen was treated with (Ph3P)4Pd (96 mg, 0.08 mmol). The ensuing mixture
was heated under reflux for 18 h then cooled to 22 °C and concentrated under reduced
pressure. The residue thus obtained was subjected to flash chromatography (silica,
1:10 → 1:5 v/v ethyl acetate/hexane elution gradient elution) to deliver two fractions,
A and B.
23

ACCEPTED MANUSCRIPT
Concentration of fraction A (Rf = 0.4 in 4:2.5:5.5 v/v/v ethyl acetate/
dichloromethane/hexane) gave compound 16 (52 mg, 37%) as a clear, colorless oil,
[α]D = +157 (c = 0.2, CHCl3): 1H NMR (400 MHz, CDCl3) δ 5.87 (m, 1H), 5.62 (m,
1H), 5.44 (d, J = 3.3 Hz, 1H), 4.40 (m, 1H), 3.98 (m, 1H), 3.68 (m, 1H), 2.87 (dd, J =
18.4 and 8.9 Hz, 1H), 2.59 (dd, J = 18.4 and 4.9 Hz, 1H), 2.43 (m, 1H), 2.17 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 207.1 (C), 128.5 (CH), 128.1 (CH), 96.1 (CH), 74.8
(CH), 67.5 (CH2), 45.2 (CH2), 37.8 (CH), 30.5 (CH3); IR νmax 2971, 2894, 1713, 1638,
1477, 1362, 1155, 977, 902 cm–1; MS (ESI, +ve) m/z 191 [(M+Na)+, 100%]; HRMS
[(M+H)+ calcd for C9H13O3 169.0859, found 169.0856.
Concentration of fraction B (Rf = 0.5 in 2:2.5:5.5 v/v/v ethyl acetate/
dichloromethane/hexane) gave compound 17 (25 mg, 18%) as a clear, colorless oil,
[α]D = −206 (c = 0.2, CHCl3): 1H NMR (400 MHz, CDCl3) δ 5.99 (m, 1H), 5.57 (m,
1H), 5.38 (broad s, 1H), 4.59 (t, J = 4.3 Hz, 1H), 3.92 (d, J = 6.3 Hz, 1H), 3.71 (m,
13
1H), 2.75-2.42 (complex m, 3H), 2.15 (s, 3H); C NMR (100 MHz, CDCl3) δ 206.4
(C), 128.5 (CH), 127.9 (CH), 103.0 (CH), 72.7 (CH2), 71.2 (CH), 45.3 (CH2), 38.7
(CH), 30.4 (CH3); IR νmax 2956, 2887, 1714, 1638, 1408, 1359, 1247, 1120, 1019,
919, 870, 713 cm–1; MS (ESI, +ve) m/z 191 [(M+Na)+, 100%], 169 [(M+H)+, <1];
HRMS [(M+H)+ calcd for C9H13O3 169.0859, found 169.0855.
Compound 18. Sodium hydride (76 mg, 60% dispersion in mineral oil, 1.9 mmol)
was added, with caution, to a magnetically stirred solution of compound 4 (122 mg,
0.95 mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (14)16 (180 µL, 1.37 mmol) in THF
(10 mL) maintained under a nitrogen atmosphere at 0 °C. After stirring for 1 h the
reaction mixture was quenched with a small amount of ice then concentrated under
reduced pressure. The residue thus obtained was subjected to flash chromatography
(silica, 1:2 ethyl acetate/petroleum ether elution) to afford, after concentration of the
24

ACCEPTED MANUSCRIPT
relevant fractions (Rf = 0.3 in 4:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane),
compound 18 and ca. 15% of a mono-enolic tautomer (181 mg, 90%) as a clear,
1
colorless oil, [α]D = −261 (c = 0.2, CHCl3): H NMR (400 MHz, CDCl3) δ (major
tautomer) 6.33 (dd, J = 9.8 and 4.7 Hz, 1H), 5.78 (m, 1H), 5.55 (s, 1H), 4.82 (m, 1H),
4.75 (t, J = 4.4 Hz, 1H), 3.71 (m, 2H), 3.50 (s, 2H), 2.26 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (major tautomer) 200.2 (C), 166.3 (C), 133.1 (CH), 122.3 (CH),
100.1 (CH), 70.5 (CH), 69.2 (CH2), 67.1 (CH), 50.0 (CH2), 30.3 (CH3); IR νmax 2969,
2896, 1743, 1717, 1647, 1411, 1362, 1259, 1150, 1126, 1020, 871 cm–1; MS (ESI,
+ve) m/z 235 [(M+Na)+, 100%]; HRMS [(M+Na)+ calcd for C10H12O5Na 235.0582,
found 235.0583.
Compounds 16 and 17 (from compound 18). Following the same procedure as
described above, compound 18 (34 mg, 0.16 mmol) was converted into a mixture of
compounds 16 (11 mg, 41%) and 17 (4 mg, 15%). Each of these products was
identical with an authentic sample.
Compound 19. A magnetically stirred solution of compound 16 (69 mg, 0.410 mmol)
in THF (10 mL) maintained under a nitrogen atmosphere at 0 °C was treated
methylmagnesium bromide (280 µL of a 3.0 M solution in THF, 0.84 mmol). After
0.5 h the reaction mixture was quenched with a small amount of ice then concentrated
under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica, 2:1 v/v ethyl acetate/hexane elution). Concentration of the
appropriate fractions (Rf = 0.3 in 8:2.5:5.5 v/v/v ethyl acetate/dichloro-
methane/hexane) gave compound 19 (71 mg, 93%) as a clear, colorless oil, [α]D =
1
+203 (c = 0.1, CHCl3): H NMR (400 MHz, CDCl3) δ 5.83 (m, 1H), 5.73 (m, 1H),
5.45 (d, J = 3.2 Hz, 1H), 4.68 (m, 1H), 3.97 (m, 1H), 3.64 (dd, J = 7.4 and 2.2 Hz,
1H), 2.13 (m, 1H), 1.94 (dd, J = 14.7 and 6.8 Hz, 1H), 1.62 (dd, J = 14.7 and 5.1 Hz,
25

ACCEPTED MANUSCRIPT
13
1H), 1.41 (s, 1H), 1.28 (s, 3H), 1.26 (s, 3H); C NMR (100 MHz, CDCl3) δ 130.7
(CH), 126.6 (CH), 96.0 (CH), 76.3 (CH), 71.2 (C), 67.6 (CH2), 45.2 (CH2), 39.7
(CH), 30.7 (CH3), 29.9 (CH3); IR νmax 3447, 2959, 2895, 1638, 1472, 1380, 1171,
1141, 1107, 965, 903 cm–1; MS (EI, 70 eV) m/z 184 (M+•, 5%), 169 (79), 109 (40), 95
(51), 81 (100), 59 (73), 43 (60); HRMS M+• calcd for C10H16O3 184.1099, found
184.1104.
Compound 20. A magnetically stirred solution of compound 19 (70 mg, 0.38 mmol)
in dichloromethane (20 mL) maintained under a nitrogen atmosphere at 0 °C was
treated with pyridine (615 µL, 7.60 mmol), 3,5-dinitrobenzoyl chloride (175 mg, 0.76
mmol) and DMAP (95 mg, 0.78 mmol). The ensuing mixture warmed to 22 °C and
stirred at this temperature for 18 h then concentrated under reduced pressure. The
residue thus obtained was subjected to flash chromatography (silica, 1:5 v/v ethyl
acetate/petroleum ether elution) and concentration of the appropriate fractions (Rf =
0.4 in 2:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane) gave compound 20 (128
mg, 89%) as a white, crystalline solid, m.p. = 131-133 °C, [α]D = +94 (c = 0.1,
CHCl3): 1H NMR (400 MHz, CDCl3) δ 9.21 (t, J = 2.2 Hz, 1H), 9.10 (d, J = 2.2 Hz,
2H), 5.88 (m, 1H), 5.75 (m, 1H), 5.51 (d, J = 3.2 Hz, 1H), 4.52 (m, 1H), 4.00 (m, 1H),
3.65 (dd, J = 7.5 and 2.2 Hz, 1H), 2.30 (d, J = 6.6 Hz, 2H), 2.14 (m, 1H), 1.72 (s, 3H),
13
1.71 (s, 3H); C NMR (100 MHz, CDCl3) δ 161.4 (C), 148.8 (C), 135.5 (C), 129.4
(CH), 129.0 (CH), 127.3 (CH), 122.3 (CH), 96.2 (CH), 86.0 (C), 76.3 (CH), 67.3
(CH2), 43.7 (CH2), 39.1 (CH), 26.6 (CH3), 26.2 (CH3); IR νmax 3101, 2980, 2895,
1725, 1628, 1544, 1344, 1292, 1266, 1172, 1126, 904, 730, 722 cm–1; MS (ESI, +ve)
m/z 401 [(M+Na)+, 100%]; HRMS [(M+Na)+ calcd for C17H18N2O8Na 401.0955,
found 401.0952.
26

ACCEPTED MANUSCRIPT
Compound 21. A magnetically stirred solution of compound 17 (30 mg, 0.178 mmol)
in THF (5 mL) maintained under a nitrogen atmosphere at 0 °C was treated with
methylmagnesium bromide (120 µL of a 3.0 M solution in THF, 0.36 mmol). After
stirring for 0.5 h the reaction mixture was quenched with a small amount of ice then
concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica, 2:1 v/v ethyl acetate/hexane elution) and concentration of the
appropriate fractions (Rf = 0.3 in 8:2.5:5.5 v/v/v ethyl acetate/dichloro-
methane/hexane) gave compound 21 (28 mg, 85%) as a clear, colorless oil, [α]D =
1
−192 (c = 0.1, CHCl3): H NMR (400 MHz, CDCl3) δ 5.96 (m, 1H), 5.68 (m, 1H),
5.60 (s, 1H), 4.58 (t, J = 4.3 Hz, 1H), 3.90 (d, J = 6.2 Hz, 1H), 3.71 (m, 1H), 2.24 (m,
1H), 1.73 (dd, J = 14.7 and 6.2 Hz, 1H), 1.49 (dd, J = 14.7 and 5.5 Hz, 1H), 1.41 (s,
1H), 1.26 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 130.1 (CH), 127.0 (CH), 104.4
(CH), 72.8 (CH2), 71.1 (C), 71.0 (CH), 44.9 (CH2), 40.3 (CH), 30.2 (CH3), 30.0
(CH3); IR νmax 3448, 2969, 2885, 1638, 1471, 1364, 1115, 1018, 905, 874 cm–1; MS
(ESI, +ve) m/z 207 [(M+Na)+, 100%]; HRMS [(M+Na)+ calcd for C10H16O3Na
207.0997, found 207.0996.
Compound 22. A magnetically stirred solution of compound 21 (30 mg, 0.16 mmol)
in dichloromethane (10 mL) maintained under a nitrogen atmosphere at 0 °C was
treated with pyridine (265 µL, 3.28 mmol), 3,5-dinitrobenzoyl chloride (75 mg, 0.33
mmol) and DMAP (40 mg, 0.33 mmol). The resulting mixture was allowed to warm
to 22 °C and stirred at this temperature for 18 h then concentrated under reduced
pressure. The residue thus obtained was subjected to flash chromatography (silica, 1:5
v/v ethyl acetate/petroleum ether elution) and concentration of the appropriate
fractions (Rf = 0.5 in 2:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane) afforded
compound 22 (56 mg, 90%) as a white, crystalline solid, m.p. = 162-165 °C, [α]D =
27

ACCEPTED MANUSCRIPT
−97 (c = 0.1, CHCl3): 1H NMR (400 MHz, CDCl3) δ 9.20 (t, J = 2.1 Hz, 1H), 9.10 (d,
J = 2.1 Hz, 2H), 6.02 (m, 1H), 5.67 (m, 1H), 5.51 (d, J = 1.9 Hz, 1H), 4.65 (t, J = 4.3
Hz, 1H), 3.91 (d, J = 6.4 Hz, 1H), 3.73 (m, 1H), 2.26 (m, 1H), 2.20-2.05 (complex m,
13
2H), 1.70 (s, 6H); C NMR (100 MHz, CDCl3) δ 161.4 (C), 148.8 (C), 135.5 (C),
129.5 (CH), 128.7 (CH), 127.9 (CH), 122.3 (CH), 104.0 (CH), 86.1 (C), 72.8 (CH2),
71.2 (CH), 43.0 (CH2), 39.7 (CH), 26.6 (CH3), 26.1 (CH3); IR νmax 3099, 2935, 2895,
1722, 1631, 1544, 1346, 1130, 1116, 1023, 921, 873, 723 cm–1; MS (ESI, +ve) m/z
401 [(M+Na)+, 100%]; HRMS [(M+Na)+ calcd for C17H18N2O8Na 401.0961, found
401.0952.
Compound 23. A magnetically stirred mixture of levoglucosenone (1) (3.78 g, 30.0
mmol) and water (300 mL) maintained at 22 °C was treated with triethylamine (3.0
ml, 2.37 mmol). After 1 h the reaction mixture was concentrated under reduced
pressure and the ensuing residue subjected to flash chromatography (silica, 1:1 v/v
ethyl acetate/ petroleum ether elution). Concentration of the relevant fractions (Rf =
0.2) gave compound 2317 (3.11g, 72%) as a clear, yellow oil, [α]D = –203.9 (c = 0.1,
CH3OH) {lit.17 [α]D = –143 (water) and –255 (CHCl3)}: 1H NMR (400 MHz, CDCl3)
δ 5.07 (d, J = 1.2 Hz, 1H), 4.61 (dd, J = 5.0 and 2.2 Hz, 1H), 4.16 (d, J = 5.7 Hz, 1H),
4.04-3.74 (complex m, 2H), 3.37 (broad s, 1H), 2.83 (dd, J = 12.0 and 4.0 Hz, 1H),
13
2.46 (d, J = 12.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 199.3, 101.3, 77.4, 70.3,
65.2, 40.8; IR νmax 3446, 2971, 2912, 1734, 1114, 1008, 961, 907, 867 cm−1; MS (ESI,
+ve) m/z 199 [(M+Na+MeOH)+, 100%] 167 [(M+Na)+, 10]; HRMS [(M+Na)+ calcd
for C6H8O4Na 167.0315, found 167.0314.
TBS Ether of Compound 23. A magnetically stirred solution of compound 23 (432
mg, 3.00 mmol) and imidazole (408 mg, 6.00 mmol, 2 mole equiv.) in THF (30 mL)
maintained under nitrogen at 22 °C was treated with TBS-Cl (904 mg, 6.00 mmol, 2
28