Diastereoselective Weitz-Scheffer epoxidation of levoglucosenone for the synthesis of isolevoglucosenone and derivatives

Article abstract of DOI:10.1016/j.tet.2018.08.041

High-yielding epoxidation conditions for the cellulose pyrolysis product (?)-levoglucosenone (LGO) and 3-aryl derivatives of LGO have been developed. The reaction of LGO with hydrogen peroxide/base is known to give a Baeyer-Villiger reaction, however, it was found that the reactions of LGO or derivatives with tert-butylhydroperoxide/base affords solely epoxides through the Weitz-Scheffer reaction. A critical parameter in the successful isolation of the epoxide from LGO was to avoid all contact with water or alcohols during the reaction and workup. The epoxide products were reacted under Wharton conditions affording allylic alcohols and subsequent oxidation led to isolevoglucosenone or 3-arylisolevoglucosenone derivatives. Previously unreported reactions on isolevoglucosenone were then investigated.

Full text of DOI:10.1016/j.tet.2018.08.041

Accepted Manuscript
Diastereoselective Weitz-Scheffer epoxidation of levoglucosenone for the synthesis of
isolevoglucosenone and derivatives
Edward T. Ledingham, Ben W. Greatrex
PII:
S0040-4020(18)31007-X
10.1016/j.tet.2018.08.041
TET 29761
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 July 2018
Revised Date: 20 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Ledingham ET, Greatrex BW, Diastereoselective Weitz-Scheffer epoxidation
of levoglucosenone for the synthesis of isolevoglucosenone and derivatives, Tetrahedron (2018), doi:
10.1016/j.tet.2018.08.041.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Diastereoselective Weitz-Scheffer Epoxidation of Levoglucosenone for the Synthesis of
Isolevoglucosenone and Derivatives
Edward T. Ledingham and Ben W. Greatrex*
School of Science and Technology, University of New England, Armidale, NSW, 2351,
Australia
ben.greatrex@une.edu.au
Ph: +61 406650161
1

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Abstract
High-yielding epoxidation conditions for the cellulose pyrolysis product (−)-levoglucosenone
(LGO) and 3-aryl derivatives of LGO have been developed. The reaction of LGO with
hydrogen peroxide/base is known to give a Baeyer-Villiger reaction, however, it was found
that the reactions of LGO or derivatives with tert-butylhydroperoxide/base affords solely
epoxides through the Weitz-Scheffer reaction. A critical parameter in the successful isolation
of the epoxide from LGO was to avoid all contact with water or alcohols during and after the
reaction. The epoxide products were reacted under Wharton conditions affording allylic
alcohols and subsequent oxidation led to isolevoglucosenone or 3-arylisolevoglucosenone
derivatives. Previously unreported reactions on isolevoglucosenone were then investigated.
Keywords:
Levoglucosenone,
epoxide,
diastereoselective,
hydroperoxide,
isolevoglucosenone
2

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1. Introduction
The cellulose pyrolysis product (−)-levoglucosenone (1) has generated interest as a chiral
synthon due to its selective formation under acidic conditions and as non-food biomass is
used in its production.1,2,3 It has been used to synthesize chiral materials including catalysts,4
ligands5 and auxiliaries,6 intermediates for the production of pharmaceuticals,7 and has been
used as a scaffold for drug discovery.8 The high degree of functionality in 1 has allowed for
the development of a large set of transformations generating diverse structures. In particular,
oxidation chemistry involving the alkene in 1 can be used to produce rare carbohydrates.9
Recent reports from the Banwell group have explored epoxidation and allylic transposition
reactions on 1 (Scheme 1).10 The group have used the Wharton reaction as the key step
leading to isolevoglucosenone (2), a compound which has been investigated by a number of
groups,11 and once readily available may find new applications in synthesis. The authors
reported that the attempted Weitz‐Scheffer epoxidation of 1 using hydrogen peroxide to give
5 resulted in a Baeyer-Villiger reaction affording 6, which matches results in our group, and
is consistent with recent reports on the Baeyer-Villiger oxidation of 1 using hydrogen
peroxide in water.12 Success in this reaction would have led to an efficient three-step
synthesis of the transposition product 2. The synthesis of α-ketoepoxide 5 was instead
achieved by reducing the ketone in 1 to alcohol 3a, protection as the acetate 3b,
diastereoselective epoxidation affording 4b, deprotection and subsequent oxidation of alcohol
4a.10 The process could be carried out without protection, however the epoxidation was not
diastereoselective. Recently, we reported a series of aryl substituted derivatives 8 which were
prepared from 1 via Suzuki chemistry.13 These compounds underwent Johnson-Corey-
Chaykovsky cyclopropanation via 1,4-addition of a sulfoxonium ylide and none of the
competing epoxidation via 1,2-addition was observed (Scheme 1).13a The selectivity observed
for the 1,4-addition suggested that these derivatives might also serve as Weitz‐Scheffer
3

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epoxidation substrates, and could be used to prepare 3-arylisolevoglucosenone derivatives in
a concise manner using Banwell’s approach.10 An investigation into this chemistry has
identified Weitz‐Scheffer epoxidation conditions compatible with 1 and 3-aryl derivatives 8,
and subsequently, Wharton chemistry has been used for the production of isolevoglucosenone
2 and derivatives.
Scheme 1
2. Results and Discussion
2.1 Weitz‐Scheffer epoxidation of levoglucosenone
A series of reactions was performed on 1 to determine whether the Weitz‐Scheffer
epoxidation could be achieved using literature variants and representative results are
presented in Table 1. The reaction of aqueous hydrogen peroxide with 1 using catalytic
base afforded the butenolide 6 as expected and no epoxidation product 5 was observed.
The epoxidation of isolevoglucosenone can be carried out using H2O2 and NaOH, and
derivatives have been epoxidised using tert-butylhydroperoxide (TBHP) with DBU, a
reagent combination known for its selectivity in the epoxidation of cyclic α,β-unsaturated
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ketones.14 Furthermore, kinetic isotope studies of the epoxidation of cyclohex-2-en-1-one
have shown that axial approach of the tert-butylhydroperoxide nucleophile is favored,
which matches nucleophilic additions to the ring-locked conformation of 1.15 Switching
the oxidant to 70% aqueous TBHP, an encouraging 23% yield of epoxide 5 was obtained
without evidence of Baeyer-Villiger reaction. The remaining material was mostly
unreacted 1, and a mixture of epoxides where the ketone had hydrated or formed
hemiacetals. These hemiacetals did not revert to ketone with attempted drying by
coevaporation with toluene. An improved 82% yield of 5 was obtained using anhydrous
TBHP combined with DBU. In the reaction, hemiacetal and hydrate formation was
avoided by omitting an aqueous workup, and instead using catalytic 10% Pd/C to
decompose residual hydroperoxide and avoiding all contact of solutions of 5 with water
or alcohols. The base had a small influence and it was found that DBU was superior to
NEt3 in the epoxidation reaction under the anhydrous reaction conditions. Both possible
epoxide diastereomers from the reaction are known and so the diastereoselectivity of the
1
reaction could be readily investigated. There was no evidence in the H NMR spectra of
the crude materials of the other diasteromer, presumably due to the high facial selectivity
of 1,4-additions to 1. These results are significant when considering the production of
isomer 2 from 1. The direct epoxidation of 1 removes the need for the
reduction/protection/oxidation steps on the carbonyl, which although high yielding, add
considerable time and handling to the published route to 2.
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Table 1. Epoxidation of 1 and aryl derivatives 8a-f.
Entrya
R
Peroxide (equiv)b
27% H2O2 (1.0)
Base (equiv)
KOH (0.4)
-
t (hr)
4
Product
Yield, (conv.)c
1
H
H
H
H
H
H
H
H
H
H
Ph
Ph
(24)d
-
6
2
m-CPBA (1.5)
16
15
24
21
16
16
16
16
16
3
5
3
70% TBHP (1.0)
70% TBHP (1.0)
70% TBHP (1.0)
70% TBHP (1.0)
70% TBHP (2.0)
Anhyd. TBHP (1.1)
Anhyd. TBHP (1.0)
Anhyd. TBHP (1.0)
Anhyd. TBHP (1.5)
70% TBHP (1.1)
70% TBHP (1.1)
-
-
5
4
KOH (0.1)
KOH (1.0)
K2CO3 (1.0)
DBU (1.2)
DBU (0.2)
Et3N (1.0)
TMG (1.0)
DBU (0.2)
KOH (0.4)
KOH (0.4)
(3)
(23)
(25)
20
5
5
5
6
5
7
5
8
82e
(44)d
74
5
9
5
10
11
12
13
5
84
11a
11a
11b
3
93f
84
3
14
15
70% TBHP (1.1)
70% TBHP (1.1)
KOH (0.4)
KOH (0.4)
2
2
84
56
11c
11d
16
17
18
70% TBHP (1.1)
Anhyd. TBHP (1.0)
70% TBHP (1.1)
KOH (0.4)
DBU (0.2)
KOH (0.4)
2
2
2
31
79
93
11e
11e
11f
9-Phenanthryl
a Reactions performed using 1 (1.0-2.0 mmol) in CH2Cl2 (10 mL) at 25 °C. b 70% TBHP (tert-butylhydroperoxide) solution
was in water and anhydrous TBHP was prepared by drying a CH2Cl2 solution with anhydrous MgSO4.c Isolated yield,
percentage conversion determined by 1H NMR relative to unreacted 1. d Remaining material mainly unreacted 1. e 40 mmol
scale. f 5.0 mmol scale.
The observation of hydration products using aqueous tert-butyl hydroperoxide needed
confirmation although hydration in this ring-system is well known.16 The NMR spectra of 5
in D2O, CDCl3 and d6-acetone provided conclusive evidence that hydration occurs. Notable
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13
among the changes in the D2O spectra, the C spectrum lacked the carbonyl resonance at δ
192 ppm seen in CDCl3 and had a resonance at δ 88.9 ppm assigned to the ketone hydrate 12
(Scheme 2). The addition of a drop of D2O to a solution of 5 in CDCl3 immediately resulted
in a complex 1H NMR spectra, containing ketone, hydrate and possibly hemiacetal dimers or
oligomers. Hydration of 5 in a d6-acetone solution in a capped NMR tube was also nearly
complete over 8 hours (see Electronic Supporting Information).
Scheme 2
With the success achieved in the epoxidation of 1, and the lack of the Baeyer-Villiger
reaction using TBHP as oxidant, the epoxidations of other aryl derivatives 8a-f were
examined. The epoxidations of electron rich aryl derivatives 8a-d,f were more tolerant to
water and aqueous TBHP using KOH as base afforded excellent yields of the epoxides 11a-
d,f. In all cases, a single stereoisomer was observed due to the facial selectivity enforced by
the steric hindrance of the oxymethylene bridge. In the case of the fluoro-substituted 8e,
aqueous TBHP resulted in the formation of hemiacetals which were difficult to separate from
the desired product. Substituting the aqueous conditions with anhydrous TBHP gave a good
yield of the desired product 11e, indicating that substrates with electron poor aryl substituents
may form hydrates similar to the unsubstituted product 5.
2.2 Wharton reactions of epoxides
With efficient methods developed allowing for the scalable synthesis of epoxide 5 and aryl
substituted epoxides 11a-e, the Wharton reactions could be examined (Table 2). The
reactions were mainly performed in acetonitrile, and methanol was avoided due to the
7

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potential formation of hemiacetals. The rearrangement reaction of 5 with anhydrous
hydrazine/acetic acid has been reported by Banwell and coworkers and our result of 67%
yield starting with 5 mirrored those of the previous report. All attempts at improving the yield
using base promoted Wharton conditions failed and only trace amounts of allylic alcohol 7
were obtained. In the case of unsubstituted epoxide 5, the use of hydrazine hydrate afforded
less of the desired rearrangement product, possibly due to the susceptibility of the carbonyl to
hydration. An acceptable yield of 13a was obtained using phenyl substituted epoxide 8a with
hydrazine hydrate (entry 11), and anhydrous conditions slightly improved yields in this
reaction (entry 10). The electron-rich substrates 11b,c and the electron-poor substrate 11e
both afforded good yields of the allylic alcohol products 13b,c and 13e.
8

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Table 2. Wharton reactions on epoxide 5 and aryl derivatives 11a-e.
entry
1
R
NH2NH2 (equiv)
anhyd. (4.0)
anhyd. (2.0)
hydrate (2.0)
anhyd. (2.0)
anhyd. (2.0)
anhyd. (2.0)
hydrate (2.0)
anhyd. (1.1)
anhyd. (2.0)
anhyd. (2.0)
hydrate (2.0)
anhyd. (2.0)
Acid (equiv)
AcOH (5.0)
AcOH (0.2)
AcOH (0.2)
AcOH (2.0)
AcOH (2.0)
TFA (2.0)
Solvent
MeOH
MeCN
MeCN
MeCN
CH2Cl2
MeCN
MeCN
MeOH
MeOH
MeCN
MeOH
MeCN
t (hrs)
Product Yield (%)
H
2
5
5
2
2
2
2
2
3
2
2
2
Lit 45
31
7
2
H
7
3
H
<5
67
7
4
H
7
5
H
26
7
6
H
17
7
7
H
AcOH (2.0)
AcOH (1.1)
AcOH (2.0)
AcOH (2.0)
AcOH (2.0)
AcOH (2.0)
<5
41
7
8
Ph
Ph
Ph
Ph
13a
13a
13a
13a
13b
9
51
10
11
12
79
65
64
13
14
15
anhyd. (2.0)
hydrate (2.0)
anhyd. (2.0)
AcOH (2.0)
AcOH (2.0)
AcOH (2.0)
MeCN
MeCN
MeCN
2
2
2
62
<5
68
13c
13d
13e
9

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The allylic alcohol products 7 and 13a-e formed in the Wharton reaction were acid sensitive
and underwent rearrangement in CDCl3 (Scheme 3). Near quantitative conversion to furan 17
(R = H)17 was observed after 8 days, presumably promoted by traces of acid in the solvent.
Allylic alcohols 13a-e with aryl substituents were more stable, taking up to 3 weeks for most
of the allylic alcohol to react at ambient temperature. A plausible mechanism for the
formation of 17 involves a series of stabilized oxocarbenium ions, with acid-catalyzed ring-
opening of the acetal centre in 7 or 13 giving the delocalized oxocarbenium ion 14, which is
then trapped as the intermediate 5,7-dioxabicyclo[2.2.1]hept-2-ene system 15. Further ring-
opening through 16 and aromatisation gives the observed diols.
Scheme 3
The oxidation of allylic alcohol 7 to isolevoglucosenone (2) has been reported using activated
MnO2 in CH2Cl2.10b In our hands, improved reliability of the oxidation was obtained using
Dess-Martin periodinane (DMP). The oxidation of 7 with DMP afforded isolevoglucosenone
(2) and likewise, oxidation of the 3-substituted derivatives 13a-c,e gave 18a-c,e in moderate
to excellent yield (Table 3). Starting with 1, the three-step process gave an overall yield of 2
of 43%, while phenyl substituted 18a was obtained in 65% yield for the three steps starting
with 8a, which can be obtained from 1 in excellent yield.13b
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Table 3. The oxidation of allylic alcohols 7 and 13.
entry
R
product
yield
1
2
3
H
78
88
64
2
Ph
18a
18b
4
5
42
52
18c
18e
As gram scale quantities of 2 and 18e were available, several reactions that could generate
novel chiral derivatives were performed (Scheme 4). Aza-Michael addition of aniline to 2
proceeded to give mainly exo-addition product 20 and some of the epimer 21 in moderate
yield. The stereochemistry was assigned on the basis of coupling constants and NOESY
interactions in the major isomer 20. The equatorial H-3α proton at δ 2.55 ppm had 4J W-path
couplings to H-1 and H-5 and had interactions with the ortho-protons on the aromatic ring in
the 2D NOESY NMR spectrum. Attempted cyclopropanation of 2 using the Corey-
Chaykovsky sulfoxonium ylide18 with 1,1,3,3-tetramethylguanidine (TMG) gave virtually
none of the cyclopropane product 22a, however, aryl substituted 18a afforded an excellent
yield of a single diastereomer 22b. The outcomes from the aza-Michael and cyclopropanation
reactions agreed with the preferred stereochemical outcome of additions to 2.19 The
hydrogenation of 2 to give the known dihydrolevoglucosenone 2316c proceeded in near
quantitative yield and subsequent reaction with benzaldehyde and TMG afforded the Z-aldol
condensation product 24. The alkene geometry was assigned on the basis of crosspeaks
11

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between the vinylic CH and the methylene adjacent to the double bond in the NOESY NMR
spectrum. The outcome of this reaction differs to the reaction of the pseudo-enantiomer
dihydrolevoglucosenone, which affords the E-aldol condensation products.7b, 20
Scheme 4.
The results presented here provide a method for the direct epoxidation of 1 and some 3-aryl
derivatives 8 and their subsequent conversion to substituted isolevoglucosenone derivatives.
Levoglucosenone (1) is emerging as a versatile starting material in synthesis and this single
step, scalable and high yielding synthesis of the epoxide derivative 5 is an important addition
to its known reactivity. The exploration of ring-opening reactions of 5 for the preparation of
carbohydrate derivatives, and some further transformations on 2 are currently underway.
3. Experimental
3.1 General Experimental
1
Solvents were dried using literature procedures. H NMR spectra recorded in CDCl3 were
13
recorded at 298 K referenced to TMS (δH 0 ppm) and C NMR spectra were referenced to
1
13
residual solvent (δC 77.0 ppm). H and C NMR spectra in D2O were referenced to the
1
internal reference 1,4-dioxane (δH 3.75 ppm, δH 67.19 ppm). H NMR spectra in d6-acetone
12

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were referenced to residual solvent (δH 2.05 ppm). MS were recorded using an Agilent 6120
Quadrupole detector. Melting points are uncorrected. HRMS were recorded in positive ESI V
mode (source temperature 80 °C, desolvation temperature 150 °C, capillary 2.5 kV). HRMS
were recorded on an AB SCIEX 5600 Triple-TOF mass spectrometer. Aryl derivatives 8a-e
were prepared as previously described.13
3.2 General procedure for Epoxidation Reactions. Anhydrous tert-butylhydroperoxide
(TBHP) solution was prepared by adding 70% TBHP in water (1.00 mL) to CH2Cl2 (20 mL),
standing over anhydrous MgSO4 (~2 grams) for 15 minutes and then decanting the solution.
The anhydrous TBHP solution (1.1 eq) was added to a stirred solution of α,β-unsaturated
ketone (1.59 - 39.6 mmol) in CH2Cl2 (total volume specified below). Alternatively, 70%
aqueous TBHP (1.1 eq) was added to the solution of α,β-unsaturated ketone without drying.
The solution was cooled via ice bath to 0 °C and then DBU (0.2 eq) or KOH (0.4 eq) was
added and the mixture allowed to warm to room temperature over 2-3 hrs and stirring
continued as set out in Table 1. When no starting material remained by TLC, the reaction was
quenched by the addition of 10% Pd/C (25 mg), the mixture stirred until the evolution of
oxygen ceased and a negative test for peroxide was obtained (starch/iodide paper). The
solution was then concentrated under reduced pressure and purified as specified below.
(1R,2R,4R,6R)-3,7,9-Trioxatricyclo[4.2.1.02,4]nonan-5-one (5).11c The reaction of
anhydrous TBHP prepared from 70% aqueous TBHP (6.00 mL, 43.3 mmol) with 1 (5.00 g,
39.6 mmol) in CH2Cl2 (200 mL) and DBU (1.18 mL, 7.91 mmol) was performed according
to the general procedure. Purification by flash chromatography (1:4 MeCN/EtOAc) afforded
1
5 as colorless crystals (4.59 g, 82%); Rf (1:4 MeCN/EtOAc) 0.50; H NMR (500 MHz,
CDCl3) δ 5.18 (d, J = 1.8 Hz, 1H, H-6), 5.00 (br dd, J = 4.8, 1.9 Hz, 1H, H-1), 4.04 (dd, J =
13

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7.4, 0.6 Hz, 1H, H-8β), 3.90 (dd, J = 7.4, 4.8 Hz, 1H, H-8α), 3.52 (dd, J = 3.7, 1.8 Hz, 1H, H-
13
4), 3.31 (ddd, J = 3.7, 1.9, 0.6 Hz, 1H, H-2); C NMR (125 MHz, CDCl3) δ 192.1 (C-5),
99.8 (C-6), 70.2 (C-1), 65.1 (C-8), 49.9 (C-2), 49.1 (C-4). (1R,2R,4R,6R)-3,7,9-
1
Trioxatricyclo[4.2.1.02,4]nonane-5,5-diol (12). H NMR (500 MHz, D2O) δ 5.00 (br d, J =
2.5 Hz, 1H, H-6), 4.89 (ddd, J = 4.6, 1.6, 0.6 Hz, 1H, H-1), 4.08 (d, J = 7.9 Hz, 1H, H-8β),
3.84 (dd, J = 7.9, 4.6 Hz, 1H, H-8α), 3.47 (dd, J = 4.3, 1.6 Hz, 1H, H-2), 3.18 (ddd, J = 4.3,
2.5, 0.6 Hz, 1H, H-4); 13C NMR (125 MHz, D2O) δ 101.6 (C-6), 88.9 (C-5), 70.4 (C-1), 67.1
(C-8), 53.1 (C-4), 50.5 (C-2).
(1S,5R)-3-(Phenanthren-9-yl)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-one
(8f).
3-
Iodolevoglucosenone13b (1.5 g, 5.95 mmol), 9-phenanthrylboronic acid (1.98 g, 8.92 mmol),
K3PO4 (2.53 g, 11.92 mmol), SPhos (49 mg, 0.12 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol)
were combined in toluene (15 mL) and refluxed at 110 °C for 45 min in a microwave reactor.
The mixture was diluted with H2O (20 mL), extracted with DCM (30 mL x 3) and the organic
phase concentrated. The organic residue was isolated via flash chromatography (1:1
EtOAc:hexanes) then recrystallized from EtOH to afford the product as colorless crystals
(1.39 g, 77%); Rf (1:1 EtOAc:hexanes) 0.89; mp 163-172 °C; [α]D25 −168 (c 0.6, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 8.74-8.63 (m, 2H, ArH), 7.88-7.83 (m, 1H, ArH), 7.70-7.53 (m,
6H, ArH), 7.30 (d, J = 4.8 Hz, 1H, H-2), 5.61 (s, 1H, H-5), 5.20 (dd, J = 4.8, 4.8 Hz, 1H, H-
13
1), 4.10-3.98 (m, 2H, H-7); C NMR (125 MHz, CDCl3) δ 188.2 (C-4), 146.1 (C-2), 138.6
(C-3), 131.2 (ArC), 130.7 (ArC), 130.62 (ArC), 130.58 (ArC), 130.4 (ArC), 128.9 (ArC),
128.2 (ArC), 127.3 (ArC), 127.0 (ArC), 126.91 (ArC), 126.89 (ArC), 126.0 (ArC), 123.1
(ArC), 122.7 (ArC), 101.9 (C-5), 72.6 (C-1), 67.0 (C-7); FT-IR (neat) 3062, 2963, 2899,
1699, 1492, 1449, 1351, 1292, 1239, 1106, 1069, 1041, 1003, 748 cm-1; MS (ESI) m/z 325.0
[M+Na]+; HRMS (ESI) calc. for C20H14O3Na [M + H]+, 325.0841; found 325.0839.
14

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(1R,2R,4R,6R)-4-Phenyl-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one (11a). The reaction of
70% aqueous TBHP (0.75 mL, 5.5 mmol) with α,β-unsaturated ketone 8a (1.00 g, 5.0 mmol)
and KOH (0.11 g, 2.0 mmol) in CH2Cl2 (12 mL) was performed as per the general procedure.
The crude product was purified by flash chromatography (2:3 EtOAc/hexanes) then
recrystallized from EtOH to afford the epoxide as colorless crystals (1.01 g, 93%); Rf (2:3
24
EtOAc/hexanes) 0.60; mp 139-141 °C (EtOH); [α]D −22 (c 0.78, CHCl3); FT-IR (neat)
1
1736, 1496, 1485, 1447, 1410, 1335, 1253, 1124, 1096, 1075, 1022 cm-1; H NMR (500
MHz, CDCl3) δ 7.39-7.36 (m, 3H, ArH), 7.33-7.30 (m, 2H, ArH), 5.31 (s, 1H, H-6), 5.05 (dd,
J = 4.6, 1.9 Hz, 1H, H-1), 4.14 (d, J = 7.5 Hz, 1H, H-8β), 3.94 (dd, J = 7.5, 4.6 Hz, 1H, H-
8α), 3.39 (d, J = 1.9 Hz, 1H, H-2); 13C NMR (125 MHz, CDCl3) δ 192.3 (C-5), 131.7 (ArC),
128.9 (ArC), 128.5 (ArC), 126.5 (ArC), 99.8 (C-6), 70.8 (C-1), 65.5 (C-8), 58.5 (C-4), 58.1
(C-2); MS (EI) m/z = 218.1 (M+, trace), 162.1 (43%), 145.1 (47), 133.1 (46), 115.1 (52),
106.1 (28), 105.1 (100), 89.1 (35), 77.1 (85), 63.1 (26), 51.1 (35); HRMS (ESI) calc. for
C12H9O4 [M − H]−, 217.0501; found 217.0497.
(1R,2R,4R,6R)-4-(4-Methoxyphenyl)-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one
(11b).
The reaction of 70% aqueous TBHP (0.389 mL, 2.84 mmol) with α,β-unsaturated ketone 8b
(600 mg, 2.58 mmol) and KOH (58 mg, 1.03 mmol) in CH2Cl2 (10 mL) was performed as per
the general procedure. The crude product was purified by flash chromatography (1:1
EtOAc/hexanes) to afford the epoxide as colorless crystals (539 mg, 84%); Rf (1:1
EtOAc/hexanes) 0.74; mp 144-146 °C; [α]D23 −31 (c 0.16, CHCl3); FT-IR (neat) 2973, 1736,
1
1609, 1510, 1244, 1185, 1127, 1096, 1016, 978, 922 cm-1; H NMR (500 MHz, CDCl3) δ
7.26-7.23 (m, 2H, ArH), 6.92-6.89 (m, 2H, ArH), 5.30 (s, 1H, H-6), 5.05 (dd, J = 4.5, 2.0 Hz,
15

ACCEPTED MANUSCRIPT
1H, H-1), 4.13 (d, J = 7.5 Hz, 1H, H-8β), 3.94 (dd, J = 7.5, 4.5 Hz, 1H, H-8α), 3.81 (s, 3H,
13
OCH3), 3.39 (d, J = 2.0 Hz, 1H, H-2); C NMR (125 MHz, CDCl3) δ 192.6 (C-5), 160.1
(ArC), 128.0 (ArC), 123.6 (ArC), 113.9 (ArC), 99.8 (C-6), 70.8 (C-1), 65.5 (C-8), 58.4 (C-4),
58.1 (C-2), 55.3 (OCH3); MS (EI) m/z = 248.0 (M+, 19%), 202 (25), 175.1 (29), 174 (34),
163.1 (33), 159.1 (55), 147.1 (31), 145.1 (31), 135 (100), 115 (23), 77 (36); HRMS (ESI)
calc. for C13H11O5 [M − H]−, 247.0606; found 247.0601.
(1R,2R,4R,6R)-4-(Benzo[d][1,3]dioxol-5-yl)-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one
(11c). The reaction of anhydrous TBHP prepared from 70% aqueous TBHP (0.15 mL, 1.07
mmol), α,β-unsaturated ketone 8c (0.240 g, 0.97 mmol) and DBU (29 µL, 0.19 mmol) in
CH2Cl2 (10 mL) was performed as per the general procedure. The crude product was purified
by flash chromatography (1:1 EtOAc/hexanes) then recrstallized from EtOH to afford the
22
epoxide as a light yellow wax (0.215 g, 84%); Rf (1:1 EtOAc/hexanes) 0.70; [α]D −10 (c
0.50, CHCl3); FT-IR (neat) 3479, 1971, 2902, 1738, 1609, 1504, 1491, 1445, 1408, 1354,
1
1300, 1233, 1123, 1097, 1035 cm-1; H NMR (500 MHz, CDCl3) δ 6.80-6.79 (m, 3H, ArH),
5.97 (s, 2H, OCH2O), 5.29 (s, 1H, H-6), 5.04 (dd, J = 4.5, 1.9 Hz, 1H, H-1), 4.12 (d, J = 7.4
Hz, 1H, H-8β), 3.94 (dd, J = 7.4, 4.5 Hz, 1H, H-8α), 3.37 (d, J = 1.9 Hz, 1H, H-2); 13C NMR
(125 MHz, CDCl3) δ 192.3 (C-5), 148.2 (ArC), 147.8 (ArC), 125.3 (ArC), 120.5 (ArC), 108.3
(ArC), 107.2 (ArC), 101.3 (OCH2O), 99.7 (C-6), 70.8 (C-1), 65.5 (C-8), 58.5 (C-4), 58.0 (C-
2); MS (EI) m/z = 262 (M+, 42%), 188 (61), 173 (40), 159 (35), 149 (100), 147 (40), 131
(37), 121 (28), 103 (32), 63 (26); No molecular ion observed by ESI-HRMS.
(1R,2R,4R,6R)-4-(Naphthalen-2-yl)-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one (11d). The
reaction of 70% aqueous TBHP (0.600 mL, 4.38 mmol), α,β-unsaturated ketone 8d (1.0 g,
16

ACCEPTED MANUSCRIPT
3.96 mmol) and KOH (90 mg, 1.58 mmol) in CH2Cl2 (20 mL) was performed as per the
general procedure. The crude product was purified by flash chromatography (2:3
EtOAc/hexanes) to afford the epoxide as colorless crystals (0.596, 56%); Rf (2:3
25
EtOAc/hexanes) 0.60; mp 191-193 °C; [α]D −8 (c 0.62, CHCl3); FT-IR (neat) 3064, 2974,
2910, 1736, 1602, 1505, 1481, 1411, 1338, 1284, 1130, 1099, 1061, 817, 746 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.85-7.81 (m, 4H, ArH), 7.52-7.48 (m, 2H, ArH), 7.36-7.34 (m, 1H,
ArH), 5.36 (s, 1H, H-6), 5.08 (dd, J = 4.6, 1.9 Hz, 1H, H-1), 4.17 (d, J = 7.5 Hz, 1H, H-8β),
13
3.97 (dd, J = 7.5, 4.6 Hz, 1H, H-8α), 3.45 (d, J = 1.9 Hz, 1H, H-2); C NMR (125 MHz,
CDCl3) δ 192.4 (C-5), 133.3 (ArC), 132.8 (ArC), 129.2 (ArC), 128.3 (ArC), 128.1 (ArC),
127.7 (ArC), 126.7 (ArC), 126.6 (ArC), 126.1 (ArC), 123.6 (ArC), 99.8 (C-6), 70.9 (C-1),
65.6 (C-8), 58.7 (C-4), 58.3 (C-2); MS (EI) m/z = 268.1 (M+, 47%), 195.1 (38), 194.1 (32),
179.1 (25), 165.1 (47), 155.1 (100), 152.1 (33), 139.1 (36), 128.1 (31), 127.1 (91); HRMS
(ESI) calc. for C16H11O4 [M − H]−, 267.0657; found 267.0654.
(1R,2R,4R,6R)-4-(2-Fluorophenyl)-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one (11e). The
reaction of anhydrous TBHP prepared from 70% aqueous TBHP (0.483 mL, 3.52 mmol),
α,β-unsaturated ketone 8e (0.706 g, 3.21 mmol) and DBU (96 µL, 0.64 mmol) in CH2Cl2 (10
mL) was performed as per the general procedure. The crude product was purified by flash
chromatography (2:3 EtOAc/hexanes) then recrystallized from i-Pr2O to afford colorless
26
crystals (0.600, 79%); Rf (2:3 EtOAc/hexanes) 0.50; mp 134-136 °C (i-Pr2O); [α]D −150 (c
0.44, CHCl3); FT-IR (neat) 2968, 2910, 1744, 1618, 1582, 1491, 1451, 1404, 1334, 1259,
1213, 1172, 1124, 1104, 1093, 1056, 1024, 968, 822, 765 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.47-7.44 (m, 1H, ArH), 7.40-7.35 (m, 1H, ArH), 7.20-7.18 (m, 1H, ArH), 7.08-7.04 (m,
1H, ArH), 5.31 (s, 1H, H-6), 5.07 (br dd, J = 4.8, 1.9 Hz, 1H, H-1), 4.23 (d, J = 7.4 Hz, 1H,
13
H-8β), 3.98 (dd, J = 7.4, 4.8 Hz, 1H, H-8α), 3.51 (d, J = 1.9 Hz, 1H, H-2); C NMR (125
17

ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 191.2 (C-5), 160.3 (d, JCF = 247.6 Hz, ArC), 131.0 (d, JCF = 8.1 Hz, ArC),
129.1 (d, JCF = 2.8 Hz, ArC), 124.3 (d, JCF = 3.5 Hz, ArC), 119.8 (d, JCF = 15.0 Hz, ArC),
115.1 (d, JCF = 20.3 Hz, ArC), 99.7 (C-6), 70.4 (C-1), 65.3 (C-8), 56.5 (C-2), 56.1 (C-4); MS
(EI) m/z = 236.0 (M+, trace), 163 (33%), 151.1 (22), 147.1 (48), 146.1 (24), 133 (42), 123
(100), 120 (19), 107 (17), 95 (30), 75 (15); HRMS (ESI) calc. for C12H8O4F [M − H]−,
235.0407; found 235.0399.
(1R,2R,4R,6R)-4-(Phenanthren-9-yl)-3,7,9-trioxatricyclo[4.2.1.02,4]nonan-5-one
(11f).
The reaction of 70% aqueous TBHP (0.862 mL, 6.29 mmol), α,β-unsaturated ketone 8f (1.73
g, 5.72 mmol) and KOH (0.128 g, 2.29 mmol) in CH2Cl2 (40 mL) was performed as per the
general procedure. The crude product was purified by flash chromatography (2:3
EtOAc/hexanes) to afford the epoxide as a light brown wax (1.70 g, 93%); Rf (3:7
17
EtOAc/hexanes) 0.56; [α]D −95 (c 0.21, CHCl3); FT-IR (neat) 2964, 2921, 1784, 1736,
1450, 1340, 1249, 1209, 1127, 1098, 748 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 8.1
Hz, 1H, ArH), 8.67 (d, J = 8.2 Hz, 1H, ArH), 7.99 (br s, 1H, ArH), 7.91 (br m, 2H, ArH),
7.70-7.60 (m, 4H, ArH), 5.45 (br s, 1H, H-6), 5.18 (br d, J = 4.6 Hz, 1H, H-1), 4.42 (d, J =
7.7 Hz, 1H, H-8β), 4.11 (dd, J = 7.7, 4.6 Hz, 1H, H-8α), 3.54 (br s, 1H, H-2); 13C NMR (125
MHz, CDCl3) δ 192.5 (C-5), 130.9 (ArC), 130.7 (ArC), 130.3 (ArC), 129.3 (ArC), 129.1
(ArC), 127.5 (ArC), 127.3 (ArC), 127.2 (ArC), 127.15 (ArC), 127.0 (ArC), 126.8 (ArC),
123.5 (ArC), 123.4 (ArC), 122.5 (ArC), 100.1 (C-6), 70.9 (C-1), 65.3 (C-8), 59.0 (C-4), 57.2
(C-2); MS (ESI) m/z = 341.1 [M+Na]+; HRMS (ESI) calc. for C20H13O4 [M − H]−, 317.0814;
found 317.0810.
18

ACCEPTED MANUSCRIPT
3.3 General Procedure for the Wharton Reaction. A stirred solution of epoxide 5 or 11a-
c,e in MeCN (4.0 - 6.0 mL/mmol) was cooled to 0 °C using an ice bath and a 1.0 M solution
of hydrazine (2 equiv) in THF was added. The solution was allowed to stir for 5 min before
addition of glacial AcOH (2 equiv) then subsequently allowed to warm to room temperature.
After the time specified in Table 2, the reaction was diluted with sat. NaHCO3 solution, and
extracted exhaustively with CH2Cl2 (TLC), dried with MgSO4 then concentrated under
reduced pressure. The crude product was further purified as specified below.
(1R,2S,5R)-6,8-Dioxabicyclo[3.2.1]oct-3-en-2-ol (7).10b The reaction of epoxide 5 (1.00 g,
7.0 mmol) with 1M hydrazine in THF (14 mL, 14.0 mmol) and AcOH (0.80 mL, 14.0 mmol)
in MeCN (40 mL) was performed as per the general procedure. Purification by flash
chromatography (1:1 EtOAc/hexanes) afforded the title product as a yellow oil which
crystallized upon standing at 4 °C (0.60 g, 67%); mp 43-45 °C (Lit. mp 59-60 °C); Rf (4:1
24
1
EtOAc/hexanes) 0.61; [α]D +138 (c 1.0, MeOH) (Lit.10b [α]D +209 (c 0.6, MeOH)) H
NMR (500 MHz, CDCl3) δ 6.03 (ddd, J = 9.6, 3.4, 0.6 Hz, 1H, H-4), 5.85 (dddd, J = 9.6, 4.4,
1.9, 0.8 Hz, 1H, H-3), 5.52 (br d, J = 3.4 Hz, 1H, H-5), 4.67 (dddd, J = 6.6, 2.2, 1.9, 1.4 Hz,
1H, H-1), 3.95 (dd, J = 7.9, 6.6 Hz, 1H, H-7α), 3.67 (ddd, J = 4.4, 1.4, 0.8 Hz, 1H, H-2), 3.46
13
(dd, J = 7.9, 2.2 Hz, 1H, H-7β), 2.25 (br s, 1H, OH); C NMR (125 MHz, CDCl3) δ 130.0
(C-3), 126.3 (C-4), 95.4 (C-5), 76.8 (C-1), 67.1 (C-2), 62.6 (C-7). A CDCl3 solution of 7 was
observed to react over 8 days to give furan 17 (R = H). (R)-1-(Furan-2-yl)ethane-1,2-diol
(17, R = H).17 [α]D15 +26 (c 1.48, CHCl3); Lit17 +32.0 (c 2.17, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.39 (dd, J = 1.9, 0.9 Hz, 1H, H-5′), 6.36 (dd, J = 3.3, 1.9 Hz, 1H, H-4′), 6.32 (ddd,
J = 3.3, 0.9, 0.6 Hz, 1H, H-3′), 4.81 (ddd, J = 6.4, 4.7, 0.6 Hz, 1H, H-1), 3.87 (dd, J = 11.4,
13
6.4 Hz, 1H, H-2), 3.86 (dd, J = 11.4, 4.7 Hz, 1H, H-2), 2.66 (br s, 2H, OH); C NMR (125
MHz, CDCl3) δ 153.6 (C-2′), 142.3 (C-5′), 110.3 (C-4′), 107.0 (C-3′), 68.3 (C-1), 65.1 (C-2);
19

ACCEPTED MANUSCRIPT
MS (EI) m/z = 128 (M+, 67%), 98 (20), 97.1 (M-CH2OH+, 100), 95 (15), 81 (14), 69.1 (37),
53.1 (13), 51.1 (12), 41.1 (74), 39.1 (39).
(1R,2S,5R)-3-Phenyl-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol (13a). The reaction of epoxide
11a (200 mg, 0.92 mmol) with 1M hydrazine in THF (1.83 mL, 1.83 mmol) and AcOH (105
µL, 1.83 mmol) in MeCN (4 mL) was performed as per the general procedure. Purification
by flash chromatography (2:3 EtOAc/hexanes) and then recrystallization from
acetone/hexanes afforded the title product as fine yellow crystals (149 mg, 79%); Rf (2:3
28
EtOAc/hexanes) 0.70; mp 108-110 °C (acetone/hexanes); [α]D −22 (c 0.88, CHCl3); FT-IR
(neat) 3380, 2971, 2892, 1632, 1494, 1446, 1358, 1113, 1098, 1072, 1034, 1013, 897, 750
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.56-7.55 (m, 2H, ArH), 7.39-7.31 (m, 3H, ArH), 6.31
(d, J = 3.6 Hz, 1H, H-4), 5.71 (d, J = 3.6 Hz, 1H, H-5), 4.82 (ddd, J = 6.6, 2.0, 1.8 Hz, 1H, H-
1), 4.19 (br. d, J = 8.7 Hz, 1H, H-2), 3.99 (dd, J = 7.9, 6.6 Hz, 1H, H-7β), 3.53 (dd, J = 7.9,
13
2.1 Hz, 1H, H-7α), 2.40 (br d, J = 8.7 Hz, 1H, OH); C NMR (125 MHz, CDCl3) δ 136.38
(ArC), 136.35 (C-3), 128.7 (ArC), 128.6 (ArC), 125.9 (ArC), 124.0 (C-4), 95.7 (C-5), 77.2
(C-1), 68.4 (C-2), 62.4 (C-7); MS (EI) m/z = 204.1 (M+, 21%), 157.1 (57), 148 (83), 147
(100), 115.1 (49), 105 (20), 103.1 (29), 102.1 (20), 91.1 (22), 77.1 (30); No molecular ion
observed by ESI-HRMS.
(1R,2S,5R)-3-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol (13b). The reaction
of epoxide 11b (248 mg, 1.0 mmol) with 1M hydrazine in THF (2.00 mL, 2.0 mmol) and
AcOH (0.114 mL, 2.0 mmol) in MeCN (4 mL) was performed as per the general procedure.
Purification by flash chromatography (3:2 EtOAc/hexanes) afforded the title product as a pale
22
yellow oil (150 mg, 64%); Rf (3:2 EtOAc/hexanes) 0.80; [α]D −17 (c 0.53, CHCl3); FT-IR
20

ACCEPTED MANUSCRIPT
(neat) 3269, 2958, 2896, 2837, 1729, 1605, 1573, 1512, 1462, 1418, 1357, 1307, 1276, 1243,
1
1181, 1111, 1098, 1074, 901 cm-1; H NMR (500 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 6.92-
6.89 (m, 2H), 6.21 (d, J = 3.7 Hz, 1H, H-4), 5.69 (d, J = 3.7 Hz, 1H, H-5), 4.81 (ddd, J = 6.7,
2.2, 1.4 Hz, 1H, H-1), 4.16 (br dd, J = 10.2, 1.4 Hz, 1H, H-2), 3.98 (dd, J = 8.0, 6.7 Hz, 1H,
H-7α), 3.82 (s, 3H, OCH3), 3.52 (dd, J = 8.0, 2.2 Hz, 1H, H-7β), 2.33 (d, J = 10.2 Hz, 1H,
13
OH); C NMR (125 MHz, CDCl3) δ 159.9 (ArC), 135.7 (C-3), 128.7 (ArC), 127.1 (ArC),
122.1 (C-4), 114.1 (ArC), 95.9 (C-5), 77.2 (C-1), 68.5 (C-2), 62.4 (C-7), 55.3 (OCH3); MS
(EI) m/z = 234.1 (M+, 46%), 203.1 (21), 187.1 (100), 178.1 (84), 177.1 (36), 161 (20), 159.1
(22), 147.1 (20), 133.1 (24), 109.1 (24); HRMS (ESI) calc. for C13H14O4Na [M + H]+,
257.0790; found 257.0786. A CDCl3 solution of 13b was observed to react over 21 days to
give furan 17 (R = 4-MeOPh). (R)-1-(3-(4-Methoxyphenyl)furan-2-yl)ethane-1,2-diol (17,
R = 4-MeOPh). 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 1.9 Hz, 1H, H-5′), 7.38-7.35 (m,
2H, ArH), 6.96-6.93 (m, 2H, ArH), 6.51 (d, J = 1.9 Hz, 1H, H-4′), 4.91 (dd, J = 7.7, 4.3 Hz,
1H, H-1), 4.06 (dd, J = 11.5, 7.7 Hz, 1H, H-2), 3.86 (dd, J = 11.5, 4.3 Hz, 1H, H-2), 3.83 (s,
13
3H, OCH3); C NMR (125 MHz, CDCl3) δ 159.0 (ArC), 147.7 (C-2′), 142.0 (C-5′), 129.3
(ArC), 125.1 (ArC), 124.6 (C-3′), 114.2 (ArC), 111.8 (C-4′), 66.6 (C-1), 65.0 (C-2), 55.3
(OCH3); MS (EI) m/z = 234.1 (M+,12%), 216.1 (9), 204.1 (13), 203.1 (M-CH2OH+, 100),
187.1 (23), 160 (10), 134.1 (44), 115.1 (17), 91.1 (11), 77.1 (9).
(1R,2S,5R)-3-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol (13c). The
reaction of epoxide 11c (256 mg, 0.98 mmol) with 1M hydrazine in THF (1.95 mL, 1.95
mmol) and AcOH (0.112 mL, 1.95 mmol) in MeCN (5 mL) was performed as per the general
procedure. Purification by flash chromatography (2:3 EtOAc/hexanes) afforded the title
26
product as a yellow oil (150 mg, 62%); Rf (2:3 EtOAc/hexanes) 0.38; [α]D −19 (c 0.21,
CHCl3); FT-IR (neat) 3432, 2963, 2898, 1729, 1606, 1503, 1488, 1443, 1361, 1245, 1224,
21

ACCEPTED MANUSCRIPT
1099, 1070, 1035 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.06 (dd, J = 8.1, 1.9 Hz, 1H, 6-ArH),
7.03 (d, J = 1.9 Hz, 1H, 2-ArH), 6.80 (d, J = 8.1 Hz, 1H, 5-ArH), 6.17 (d, J = 3.7 Hz, 1H, H-
4), 5.98-5.96 (m, 2H, OCH2O), 5.68 (d, J = 3.7 Hz, 1H, H-5), 4.80 (ddd, J = 6.7, 2.2, 1.2 Hz,
1H, H-1), 4.10 (d, J = 1.2 Hz, 1H, H-2), 3.98 (dd, J = 8.0, 6.7 Hz, 1H, H-7α), 3.51 (dd, J =
13
8.0, 2.2 Hz, 1H, H-7β), 2.33 (br s, 1H, OH); C NMR (125 MHz, CDCl3) δ 148.1 (ArC),
148.0 (ArC), 136.0 (C-3), 130.7 (ArC), 122.8 (C-4), 119.9 (ArC), 108.4 (ArC), 106.3 (ArC),
101.3 (OCH2O), 95.8 (C-5), 77.1 (C-1), 68.6 (C-2), 62.4 (C-7); MS (EI) m/z = 248.1 (M+,
89%), 217.1 (25), 201 (100), 192 (94), 191 (33), 188 (30), 147 (29), 123 (50), 115.1 (25),
89.1 (29); No molecular ion observed by ESI-HRMS. A CDCl3 solution of 13c was observed
to react over 21 days to give furan 17 (R = 3,C-4H2O2Ph). (R)-1-(3-(Benzo[d][1,3]dioxol-5-
1
yl)furan-2-yl)ethane-1,2-diol (17, R = 3,4-CH2O2Ph). H NMR (500 MHz, CDCl3) δ 7.40
(d, J = 1.5 Hz, 1H, C-5′), 6.93-6.84 (m, 3H, ArH), 6.48 (d, J = 1.5 Hz, C-4′), 5.99 (s, 2H,
OCH2O), 4.89 (dd, J = 7.7, 4.2 Hz, 1H, H-1), 4.05 (dd, J = 11.4, 7.7, 1H, H-2), 3.85 (dd, J =
13
11.4, 4.2 Hz, 1H, H-2); C NMR (125 MHz, CDCl3) δ 147.9 (C-2′ & ArC), 147.0 (ArC),
142.0 (C-5′), 126.6 (ArC), 124.8 (C-3′), 121.7 (ArC), 111.8 (C-4′), 108.7 (ArC), 108.6 (ArC),
101.1 (OCH2O), 66.5 (C-1), 65.0 (C-2); MS (EI) m/z = 248.1 (M+, 26%), 218 (14), 217 (M-
CH2OH+, 100), 207 (25), 187.1 (26), 171.1 (22), 159.1 (27), 131.1 (23), 115.1 (16), 77.1 (15).
(1R,2S,5R)-3-(2-Fluorophenyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol (13e) The reaction of
epoxide 11e (75 mg, 0.34 mmol) with 1M hydrazine in THF (680 µL, 0.68 mmol) and AcOH
(39 µL, 0.68 mmol) in MeCN (4 mL) was performed as per the general procedure.
Purification by flash chromatography (1:1 EtOAc/hexanes) afforded the title product as a
colorless wax (48 mg, 68%); Rf (1:1 EtOAc/hexanes) 0.43; [α]D23 +25 (c 0.12, CHCl3); FT-IR
(neat) 3415, 2975, 2894, 1731, 1611, 1574, 1488, 1448, 1355, 1294, 1238, 1205, 1115, 1098,
1
1072, 1036, 1013, 758 cm-1; H NMR (500 MHz, CDCl3) δ 7.39 (ddd, J = 8.2, 7.7, 1.8 Hz,
22

ACCEPTED MANUSCRIPT
1H, ArH), 7.32-7.27 (m, 1H, ArH), 7.15 (ddd, J = 7.7, 7.6, 1.2 Hz, 1H, ArH), 7.07 (ddd, J =
11.4, 8.2, 1.2 Hz, 1H, ArH), 6.24 (d, J = 3.7 Hz, 1H, H-4), 5.68 (d, J = 3.7 Hz, 1H, H-5), 4.79
(ddd, J = 6.7, 2.2, 1.6 Hz, 1H, H-1), 4.19 (br s, 1H, H-2), 4.01 (dd, J = 8.0, 6.7 Hz, 1H, H-
7α), 3.62 (dd, J = 8.0, 2.2 Hz, 1H, H-7β), 2.41 (br s, 1H, OH); 13C NMR (125 MHz, CDCl3) δ
160.5 (d, JCF = 248.7 Hz, ArC), 133.2 (d, JCF = 1.8 Hz, H-3), 129.9 (d, JCF = 9.0 Hz, ArC),
129.8 (d, JCF = 3.6 Hz, ArC), 128.5 (d, JCF = 5.7 Hz, H-4), 124.9 (d, JCF = 12.7 Hz, ArC),
124.3 (d, JCF = 3.6 Hz, ArC), 116.1 (d, JCF = 22.7 Hz, ArC), 95.5 (C-5), 76.9 (C-1), 68.9 (d,
JCF = 3.2 Hz, C-2), 62.5 (H-7); MS (EI) m/z = 222.1 (M+, 18%), 175.1 (65), 166 (100), 165
(53), 147.1 (68), 146.1 (39), 133 (68), 121 (36), 120 (34), 109 (29), 101 (29); HRMS (ESI)
calc. for C12H11O3FNa [M+Na]+, 245.0590; found 245.0567. A CDCl3 solution of 13e was
observed to react over 21 days to give furan 17 (R = 2-FPh). (R)-1-(3-(2-
1
Fluorophenyl)furan-2-yl)ethane-1,2-diol (17, R = 2-FPh). H NMR (500 MHz, CDCl3) δ
7.46 (H-5′), 7.40-7.37 (ArH), 7.34-7.29 (ArH), 7.20-7.17 (ArH), 7.16-7.12 (ArH), 6.53 (H-
13
4′), 4.81 (H-1), 4.03 (H-2), 3.83 (H-2); C NMR (125 MHz, CDCl3) δ 149.4 (C-2′), 142.2
(C-5′), 131.1 (ArC), 129.3 (ArC), 124.3 (ArC), 120.4 (ArC), 118.2 (C-3′), 115.8 (ArC), 112.4
(C-4′), 66.6 (C-1), 64.8 (C-2); MS (EI) m/z = 222.1 (M+, 27%), 192.1 (61), 191.1 (M-
CH2OH+, 100), 175.1 (24), 173 (20), 171.1 (45), 146.1 (21), 133.1 (62), 115.1 (58), 109.1
(24).
3.4 General procedure for the Oxidation of Allylic Alcohols. Dess-Martin periodinane
(DMP) (1.05 eq) was added to a solution of allylic alcohol 7, 13a-c,e in CH2Cl2 (20
mL/mmol) and the mixture stirred at ambient temperature for 2-5 hrs as specified in Table 3.
The resulting solution was washed with sat. NaHCO3 solution, dried over MgSO4, filtered
and concentrated under reduced pressure and the residue was purified by flash
chromatography.
23

ACCEPTED MANUSCRIPT
(1R,5R)-6,8-Dioxabicyclo[3.2.1]oct-3-en-2-one (isolevoglucosenone) (2).10 As per the
general procedure, the reaction of allylic alcohol 7 (1.00 g, 7.80 mmol) and DMP (3.48 g,
8.20 mmol) afforded the title product as a yellow oil (0.77 g, 78%); Rf (1:1 EtOAc/hexanes)
23
1
0.80; [α]D +250 (c 1.0, CHCl3) (Lit.10 [α]D +445 (c 1.0, CHCl3)); H NMR (500 MHz,
CDCl3) δ 7.13 (dd, J = 9.8, 3.2 Hz, 1H, H-4), 6.11 (ddd, J = 9.8, 1.5, 0.9 Hz, 1H, H-3), 5.82
(dd, J = 3.2, 0.9 Hz, 1H, H-5), 4.79 (ddd, J = 6.3, 1.5, 1.5 Hz, 1H, H-1), 4.11 (dd, J = 8.2, 6.3
13
Hz, 1H, H-7α), 3.66 (dd, J = 8.2, 1.5 Hz, 1H, H-7β); C NMR (125 MHz, CDCl3) δ 194.5
(C-2), 147.3 (C-3), 127.1 (C-4), 96.0 (C-5), 79.6 (C-1), 62.7 (C-7).
(1R,5R)-3-Phenyl-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one (18a). As per the general
procedure, the reaction of allylic alcohol 13a (0.574 g, 2.81 mmol) and DMP (1.25 g, 2.95
mmol) afforded the title product as a colorless oil (0.500 g, 88%); Rf (1:4 EtOAc/hexanes)
22
0.63; [α]D +133 (c 1.67, CHCl3); FT-IR (neat) 3057, 2961, 2893, 1698, 1612, 1576, 1492,
1
1445, 1356, 1325, 1275, 1159, 1112, 1075, 1038, 986, 905, 756, 695 cm-1; H NMR (500
MHz, CDCl3) δ 7.43-7.36 (m, 5H, ArH), 7.14 (d, J = 3.5 Hz, 1H, H-4), 5.96 (d, J = 3.5 Hz,
1H, H-5), 4.94 (dd, J = 6.3, 1.4 Hz, 1H, H-1), 4.15 (dd, J = 8.2, 6.3 Hz, 1H, H-7α), 3.75 (dd,
13
J = 8.2, 1.4 Hz, 1H, H-7β); C NMR (125 MHz, CDCl3) δ 193.6 (C-2), 142.3 (C-4), 137.4
(C-3), 132.5 (ArC), 128.9 (ArC), 128.4 (ArC), 128.3 (ArC), 97.1 (C-5), 79.7 (C-1), 62.7 (C-
7); MS (EI) m/z = 202.1 (M+,100%), 171.1 (48), 159.1 (33), 145.1 (21), 131.1 (20), 117.1
(24), 115.1 (58), 105.1 (19), 103.1 (65), 77.1 (25); HRMS (ESI) calc. for C12H10O3Na [M +
Na]+, 225.0528; found 225.0505.
24

ACCEPTED MANUSCRIPT
(1R,5R)-3-(4-Methoxyphenyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one (18b). As per the
general procedure, the reaction of allylic alcohol 13b (94 mg, 0.40 mmol) and DMP (179 mg,
0.42 mmol) afforded the title product as a yellow oil (60 mg, 64%); Rf (2:4 EtOAc/hexanes)
21
0.50; [α]D +129 (c 0.21, CHCl3); FT-IR (neat) 2958, 2893, 2837, 1763, 1696, 1606, 1572,
1
1510, 1461, 1356, 1326, 1292, 1268, 1246, 1180, 1158, 1108, 1033 cm-1; H NMR (500
MHz, CDCl3) δ 7.41-7.38 (m, 2H, ArH), 7.08 (d, J = 3.6 Hz, 1H, H-4), 6.93-6.90 (m, 2H,
ArH), 5.94 (d, J = 3.6 Hz, 1H, H-5), 4.92 (dd, J = 6.3, 1.4 Hz, 1H, H-1), 4.13 (dd, J = 8.2, 6.3
13
Hz, 1H, H-7α), 3.82 (s, 3H, OCH3), 3.73 (dd, J = 8.2, 1.4 Hz, 1H, H-7β); C NMR (125
MHz, CDCl3) δ 194.1 (C-2), 160.2 (ArC), 140.9 (C-4), 136.8 (C-3), 129.6 (ArC), 124.8
(ArC), 113.9 (ArC), 97.2 (C-5), 79.8 (C-1), 62.7 (C-7), 55.3 (OCH3); MS (EI) m/z = 232.1
(M+, 100%), 202 (37), 201 (65), 187.1 (22), 171 (34), 161 (23), 159 (24), 135 (26), 133.1
(49), 89.1 (22); HRMS (ESI) calc. for C13H12O4Na [M + Na]+, 255.0633; found 255.0634.
(1R,5R)-3-(Benzo[d][1,3]dioxol-5-yl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one (18c). As per
the general procedure, the reaction of allylic alcohol 13c (130 mg, 0.52 mmol) and DMP (233
mg, 0.55 mmol) afforded the title product as a pale yellow wax (54 mg, 42%); Rf (1:4
20
EtOAc/hexanes) 0.53; [α]D +77 (c 0.39, CHCl3); FT-IR (neat) 2959, 2898, 1697, 1608,
1
1488, 1440, 1360, 1230, 1166, 1107, 1032 cm-1; H NMR (500 MHz, CDCl3) δ 7.06 (d, J =
3.6 Hz, 1H, H-4), 6.94-6.92 (m, 2H, ArH), 6.82 (d, J = 8.5 Hz, 1H, ArH), 5.98 (s, 2H,
OCH2O), 5.94 (d, J = 3.6 Hz, 1H, H-5), 4.92 (dd, J = 6.3, 1.5 Hz, 1H, H-1), 4.13 (dd, J = 8.2,
13
6.3 Hz, 1H, H-7α), 3.72 (dd, J = 8.2, 1.5 Hz, 1H, H-7β); C NMR (125 MHz, CDCl3) δ
193.8 (C-2), 148.3 (ArC), 147.6 (ArC), 141.4 (C-4), 136.9 (C-3), 126.3 (ArC), 122.3 (ArC),
108.7 (ArC), 108.3 (ArC), 101.3 (OCH2O), 97.1 (C-5), 79.7 (C-1), 62.7 (C-7); MS (EI) m/z =
246 (M+, 100%), 216 (28), 215 (76), 188.1 (23), 159 (22), 147 (22), 131.1 (23), 117 (23),
102.1 (17), 89.1 (28); HRMS (ESI) calc. for C13H11O5 [M + H]+, 247.0606; found 247.0535.
25

ACCEPTED MANUSCRIPT
(1R,5R)-3-(2-Fluorophenyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one (18e). As per the
general procedure, the reaction of allylic alcohol 13e (86 mg, 0.39 mmol) and DMP (172 mg,
0.41 mmol) afforded the title product as a colorless wax (45 mg, 52%); Rf (1:4
21
EtOAc/hexanes) 0.54; [α]D +92 (c 0.64, CHCl3); FT-IR (neat) 2961, 2900, 1703, 1625,
1
1572, 1489, 1452, 1353, 1255, 1218, 1158, 1109, 1032, 757 cm-1; H NMR (500 MHz,
CDCl3) δ 7.38-7.33 (m, 1H, ArH), 7.27-7.24 (m, 1H, ArH), 7.18 (dd, J = 3.5, 0.7, 1H Hz, H-
4), 7.16-7.14 (m, 1H, ArH), 7.13-7.09 (m, 1H, ArH), 5.96 (d, J = 3.5 Hz, 1H, H-5), 4.95 (dd,
J = 6.3, 1.5 Hz, 1H, H-1), 4.18 (dd, J = 8.3, 6.3 Hz, 1H, H-7α), 3.79 (dd, J = 8.3, 1.4 Hz, 1H,
13
H-7β); C NMR (125 MHz, CDCl3) δ 192.3 (C-2), 159.9 (d, JCF = 250 Hz, ArC), 145.0 (d,
JCF = 2.7 Hz, C-4), 133.5 (C-3), 130.8 (d, JCF = 2.8 Hz, ArC), 130.6 (d, JCF = 8.2 Hz, ArC),
124.0 (d, JCF = 3.6 Hz, ArC), 120.4 (d, JCF = 15.2 Hz, ArC), 115.8 (d, JCF = 22.1 Hz, ArC),
96.8 (C-5), 79.5 (C-1), 62.8 (C-7); MS (EI) m/z = 220.1 (M+, 100%), 189 (29), 177 (33),
163.1 (22), 135.1 (21), 133 (60), 123 (15), 121 (68), 120 (21), 101 (37); HRMS (ESI) calc.
for C12H9FO3Na [M + Na]+, 243.0433; found 243.0431.
(1R,4S/R,5R)-4-(Phenylamino)-6,8-dioxabicyclo[3.2.1]octan-2-one
(20).
Isolveoglucosenone 2 (0.250 g, 1.98 mmol) was dissolved in a 0.1 M K2CO3 aqueous
solution (10 mL) and aniline (199 ꢀL, 2.18 mmol) was added. The mixture was stirred at
ambient temperature for 2 hrs and then extracted with CH2Cl2 (20 mL × 3). The organic
phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (1:49 NH4OH/CH2Cl2), giving a 4:1 mixture of
20/21 as a yellow solid (0.248 g, 57%); Rf (1:49 NH4OH/CH2Cl2) 0.37; FT-IR (neat) 3373,
2958, 2894, 1729, 1598, 1499, 1311, 1256, 1172, 1121, 1023, 749 cm-1; MS (EI) m/z = 219.1
26

ACCEPTED MANUSCRIPT
(M+, 17%), 174.1 (41), 126 (33), 119.1 (50), 118.1 (62), 93.1 (100), 83 (40), 68 (32), 66 (47),
55 (36), 39.1 (30); HRMS (ESI) calc. for C12H14NO3 [M + H]+, 220.0974; found 220.0969.
1
20: H NMR (500 MHz, CDCl3) δ 7.21-7.17 (m, 2H, ArH), 6.79-6.75 (m, 1H, ArH), 6.61-
6.59 (m, 2H, ArH), 5.61 (br s, 1H, H-5), 4.55 (br d, J = 5.3 Hz, 1H, H-1), 4.06 (d, J = 8.2 Hz,
1H, H-7β), 4.06-4.04 (m, 1H, C-4), 3.96 (dd, J = 8.4, 5.3 Hz, 1H, H-7α), 2.80 (dd, J = 17.3,
13
6.8 Hz, 1H, H-3), 2.52 (dddd, J = 17.3, 2.0, 1.5, 1.5 Hz, 1H, H-3); C NMR (125 MHz,
CDCl3) δ 203.2 (C-2), 145.4 (ArC), 129.6 (ArC), 118.7 (ArC), 113.6 (ArC), 102.1 (C-5), 79.5
1
(C-1), 66.9 (C-7), 54.1 (C-4), 38.9 (C-3); 21: H NMR (500 MHz, CDCl3) δ 7.25-7.23 (m,
2H, ArH), 6.96-6.93 (m, 1H, ArH), 6.64-6.63 (m, 1H, ArH), 5.67 (d, J = 2.2 Hz, 1H, H-5),
4.54 (m, 1H, H-1), 4.11 (m, 1H, H-4), 4.00 (br d, J = 8.4 Hz, 1H, H-7), 3.94 (m, 1H, H-7),
2.99 (br dd, J = 17.2, 7.5 Hz, 1H, H-3), 2.24 (dd, J = 17.2, 7.8 Hz, 1H, H-3); 13C NMR (125
MHz, CDCl3) δ 202.7 (C-2), 145.5 (ArC), 129.6 (ArC), 118.6 (ArC), 113.6 (ArC), 100.7 (C-
5), 78.5 (C-1), 67.1 (C-7), 53.9 (C-4), 40.7 (C-3).
(1R,2R,5S,6R)-4-Phenyl-8,9-dioxatricyclo[4.2.1.02,4]nonan-5-one (22). To a solution of 2
(0.500 g, 2.47 mmol) and trimethylsulfoxonium iodide (0.652 g, 2.96 mmol) in DMSO (6
mL) was added 1,1,3,3-tetramethlyguanadine (0.371 mL, 2.96 mmol) and the mixture stirred
at room temperature for 4 hrs. The resulting solution was diluted with brine (15 mL), then
extracted with CH2Cl2 (3 × 20 mL), dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (1:4 EtOAc/hexanes), then
recrystallized from i-Pr2O to afford the title compound as fine white crystals (0.490 g, 92%);
Rf (1:4 EtOAc/hexanes) 0.55; mp 104-106 °C; [α]D27 +62 (c 0.13, CHCl3); FT-IR (neat) 2957,
2890, 1706, 1600, 1496, 1472, 1445, 1377, 1351, 1319, 1273, 1224, 1184, 1155, 1127, 1098,
1
1078, 1066, 1051, 1018, 754, 698 cm-1; H NMR (500 MHz, CDCl3) δ 7.34-7.26 (m, 5H,
ArH), 5.94 (d, J = 1.4 Hz, 1H, H-6), 4.56 (dd, J = 5.9, 1.8 Hz, 1H, H-1), 4.01 (dd, J = 8.2, 1.8
27

ACCEPTED MANUSCRIPT
Hz, 1H, H-8), 3.99 (dd, J = 8.2, 5.9 Hz, 1H, H-8), 1.99 (ddd, J = 7.5, 5.3, 1.4 Hz, 2H, H-5),
1.90 (dd, J = 5.3, 4.8 Hz, 1H, H-3), 1.50 (dd, J = 7.5, 4.8 Hz, 1H, H-3); 13C NMR (125 MHz,
CDCl3) δ 202.8 (C-2), 137.6 (ArC), 129.9 (ArC), 128.5 (ArC), 127.8 (ArC), 100.2 (C-6), 78.5
(C-1), 67.0 (C-8), 38.4 (C-4), 25.0 (C-5), 17.6 (C-3); MS (EI) m/z = 216.1 (M+, 35%), 173.1
(90), 160.1 (29), 145.1 (100), 129.1 (41), 128.1 (59), 127.1 (45), 117.1 (54), 115.1 (89), 91.1
(31); HRMS (ESI) calc. for C13H12O3Na [M + Na]+, 239.0684; found 239.0666.
(1R,5R)-6,8-Dioxabicyclo[3.2.1]octan-2-one (23).16c A stirred solution of 2 (0.500 g, 3.96
mmol) and 10% Pd/C (0.843 g, 0.79 mmol) in EtOAc (20 mL) was placed under a H2
atmosphere and stirred at 50 °C for 4 days. The mixture was filtered and concentrated under
20
reduced pressure to afford the title compound as a yellow oil (0.498 g, 98%); [α]D −40 (c
1.0, CHCl3) (Lit.16c [α]D25 −83 (c 0.4, CHCl3)); 1H NMR (500 MHz, CDCl3) δ 5.74 (d, J =2.7
Hz, 1H, H-5), 4.51 (d, J = 5.6 Hz, 1H, H-1), 3.97 (br d, J = 8.2, 1H, H-7β), 3.88 (dd, J = 8.2,
5.6 Hz, 1H, H-7α), 2.49-2.46 (m, 2H, H-3), 2.17 (dddd, J = 14.0, 8.8, 7.9, 3.0 Hz, 1H), 2.07-
13
2.02 (m, 1H, H-4); C NMR (125 MHz, CDCl3) 205.6 (C-2), 100.8 (C-5), 79.3 (C-1), 67.2
(C-7), 31.5 (C-3), 30.7 (C-4).
(1R,5R)-3-((Z)-Benzylidene)-6,8-dioxabicyclo[3.2.1]octan-2-one (24). To a stirred solution
of ketone 23 (200 mg, 1.56 mmol) and benzaldehyde (188 ꢀL, 1.87 mmol) in dioxane (15
mL) was added TMG (196 ꢀL, 1.56 mmol) and the mixture heated to reflux for 24 hrs. The
solution was concentrated under reduced pressure then purified via flash chromatography
(1:4 EtOAc/hexanes) to afford the title compound as a colorless wax (118 mg, 35%); Rf (1:4
20
EtOAc/hexanes) 0.51; [α]D +16 (c 0.62, CHCl3); FT-IR (neat) 2955, 2891, 1697, 1595,
1
1572, 1492, 1446, 1423, 1281, 1253, 1201, 1174, 1125, 1088, 1032 cm-1; H NMR (500
28