The synthesis of polyfunctionalized, cyclohexene-based chirons from tartaric acid

Article abstract of DOI:10.3987/COM-16-S(S)18

Compound ent-1 as well as certain related homochiral and polyfunctionalized cyclohexenes have been prepared from the 1,2-diacetal 4 that is itself readily derived from L-tartaric acid (3). Grignard addition and ring-closing metathesis processes constitute the key steps associated with the reaction sequences involved. This work provides a method for obtaining a range of potentially useful cyclohexenone-containing chirons that are enantiomerically related to those that have been prepared from the homochiral cis-1,2-dihydrocatechol 2, the product of the microbial biotransformation of bromobenzene.

Full text of DOI:10.3987/COM-16-S(S)18

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HETEROCYCLES, Vol. 95, No. 1, 2017
HETEROCYCLES, Vol. 95, No. 1, 2017, pp. 290-303. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 20th July, 2016, Accepted, 9th August, 2016, Published online, 11th October, 2016
DOI: 10.3987/COM-16-S(S)18
THE
SYNTHESIS
OF
POLYFUNCTIONALIZED,
CYCLOHEXENE-BASED CHIRONS FROM TARTARIC ACID†
Joshua N. Buckler, Brett D. Schwartz, and Martin G. Banwell*
Research School of Chemistry, Institute of Advanced Studies, The Australian
National
University,
Canberra,
ACT
2601,
Australia;
E-mail:
Martin.Banwell@anu.edu.au
† Dedicated to Professor Masakatsu Shibasaki on the occasion of his 70th
birthday and in recognition of his sustained and outstanding contributions to
chemical synthesis
Abstract – Compound ent-1 as well as certain related homochiral and
polyfunctionalized cyclohexenes have been prepared from the 1,2-diacetal 4 that
is itself readily derived from L-tartaric acid (3). Grignard addition and
ring-closing metathesis processes constitute the key steps associated with the
reaction sequences involved. This work provides a method for obtaining a range
of potentially useful cyclohexenone-containing chirons that are enantiomerically
related to those that have been prepared from the homochiral
cis-1,2-dihydrocatechol 2, the product of the microbial biotransformation of
bromobenzene.
INTRODUCTION
In connection with a study focused on acetylcholine esterase (AChE) inhibitors, we prepared, over five
steps, the polyfunctionalized and homochiral α-bromocyclohexenone 1 from the enantiomerically pure
cis-1,2-dihydrocatechol 2.1 Compound 2 is the product of the microbial dihydroxylation of bromobenzene,
a transformation that can be achieved particularly effectively with a genetically-engineered strain of E.
coli that over-expresses the enzyme toluene dioxygenase (TDO).2 In order to fully explore the biological
profiles of the AChE inhibitors in question, we required the enantiomer of compound 1, namely ent-1.
While a logical precursor to this brominated cyclohexene is the cis-1,2-dihydrocatechol ent-2, the latter is
not as readily accessible, especially in homochiral form, as congener 2.3 Accordingly, we sought another
means for obtaining chiron ent-1 as well as related systems that could serve as valuable building blocks
for the synthesis of various polyoxygenated cyclohexenes and their saturated counterparts.

HETEROCYCLES, Vol. 95, No. 1, 2017
291
OMe
MeO
O
HO
O
OH
HO
HO
Br
Br
1
2
OMe
O
OMe
O
MeO
MeO
HO
HO
O
OH
O
OH
Br
HO
HO
Br
Br
ent-1
ent-2
ent-1
The groups of Madsen,4 Sulikowski5 and Yan6 have each demonstrated that the acetonide derived from
D- or L-tartaric acid can be elaborated, via manipulation of the derived ester residues using reduction,
vinyl Grignard addition and then ring-closing metathesis (RCM) steps, into various conduritols or amino
pseudosugars. Prasad has described7 closely related chemistries. The RCM products so formed
incorporate rather unstable acetonide-protected cyclohex-4-ene-trans-1,2-diol moieties. On the other hand,
and during the course of establishing a total synthesis the macrolide antascomicin B (a potential
immunosuppressive agent), Ley8 and co-workers used a butanediacetal-protected dimethyl tartrate to
construct, via a late-stage RCM, a complex cyclohexene annulated to a 1,4-dioxane and that embodies a
stable masked trans-1,2-diol moiety. Herein we report on the exploitation of these types of protocols in
the synthesis of the target chiron ent-1 as well as a range of analogues that are likely to be of value in the
synthesis of a variety of biologically active systems.
RESULTS AND DISCUSSION
The preparation of a series of poly-oxygenated and homochiral cyclohexenes from L-tartaric acid (3) is
shown in Scheme 1 and started with the formation, under standard and operationally simple conditions, of
diacetal diester 4 (72%). Reduction of the latter compound to the corresponding dialdehyde was achieved
using di-iso-butylaluminium hydride (DIBAl-H) in toluene at –78 °C and this was immediately reacted
with vinylmagnesium bromide5 to give the bis-olefin 5 as an inseparable mixture of diastereoisomers in
88% combined yield. This mixture was treated with the Grubbs’-II catalyst in dichloromethane and so
effecting a RCM reaction and thus forming a ca. 10:6:3 mixture of the three possible stereoisomeric
forms of the anticipated cyclohexene 6 in 99% combined yield.

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HETEROCYCLES, Vol. 95, No. 1, 2017
OMe
O
(i) DIBAl-H
(MeCO)2,
HC(OMe)3
p-TsOH•H2O
OMe
OMe
O
toluene, –78 °C
2 h
Grubbs'-II
catalyst
OH
MeO
O
MeO
MeO
HO
O
OH
CO2H
O
O
OH
(ii) H2C=CHMgBr
toluene, THF
CO2Me
MeOH
ca. 65 °C
24 h, 72%
CH2Cl2,
40 °C
CO2H
MeO2C
HO
HO
–78 to ca. 22 °C, 16 h
88%
15 h, 99%
3
4
5
6
DMP
CH2Cl2
0 °C, 2 h
88%
OMe
OMe
OMe
Br2 then Et3N
CH2Cl2
NaBH4,
O
MeO
O
MeO
O
CeCl3•7H2O
MeO
O
O
O
O
O
O
O
–5 to ca. 22 °C, 5 h
MeOH, –78 °C
2 h, 94%
79%
HO
Br
HO
9
8
7
Scheme 1
This mixture of cyclohexenes, which was characterized as such, was subjected to a two-fold oxidation
with the Dess-Martin periodinane (DMP) and so affording the corresponding enedione 7 in 88% yield.
While enedione 7 was prone to two-fold enolization and concomitant formation of the isomeric
hydroquinone,9 this C2-symmetric compound could be stereoselectively reduced to the γ-hydroxyenone 8
(94%) under Luche-type conditions. Confirmation of the stereochemical outcome associated with this
conversion, which involves axial delivery of hydride,10 was achieved through the single-crystal X-ray
analysis of a halogenated derivative. Specifically, successive treatment of compound 8 with molecular
Figure 1. ORTEP derived from the single-crystal X-ray analysis of compound 9 (CCDC No. 1491822).
Anisotropic displacement ellipsoids display 30% probability levels. Hydrogen atoms are drawn as circles
with small radii.

HETEROCYCLES, Vol. 95, No. 1, 2017
293
bromine then triethylamine at 0 °C11 afforded the crystalline α-bromoenone 9 (79% yield) that was
subjected to such an analysis. The derived ORTEP is shown in Figure 1 while other results of this
analysis are provided in the Experimental Section.
The completion of the synthesis of the target synthon ent-1 followed the pathway shown in Scheme 2 and
involved the conversion of the γ-hydroxyenone 9 into the corresponding acetate, 10 (97%), under
standard conditions. Luche reduction of compound 10 afforded a diastereoisomeric and
chromatographically separable mixture of compounds 11 (7%) and 12 (79%). Subjection of the latter
product to a Mitsunobu reaction, using p-methoxybenzoic acid as nucleophile and the
N,N,N’,N’-tetramethylazodicarboxamide (TMAD)/tri-n-butylphosphine reagent combination,12 then
afforded ester 13 (79%). Finally, cleavage of this ester using potassium hydroxide in methanol gave the
target ent-1 in 96% yield.
OMe
O
MeO
O
OH
Br
AcO
OMe
O
OMe
O
11 (7%)
Ac2O
NaBH4,
MeO
pyridine
CeCl3•7H2O
MeO
+
O
O
O
O
ca. 22 °C,
1 h
MeOH, –78 °C
1 h
OMe
O
HO
Br
AcO
Br
97%
MeO
9
10
O
OH
Br
AcO
12 (79%)
compound 12
p-MeOC6H4CO2H
TMAD, Bu3P
C6H6, 0 to 80 °C
48 h, 79%
OMe
OMe
KOH
O
MeO
O
O
MeO
MeOH
OPMBz
Br
O
OH
Br
ca. 22 °C
48 h
AcO
HO
96%
13
ent-1
Scheme 2

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HETEROCYCLES, Vol. 95, No. 1, 2017
The minor product, 11, derived from the reduction of α-bromoenone 10 was readily and nearly
quantitatively converted into compound ent-1 through treatment (Scheme 3) with potassium carbonate in
methanol. All the spectral data acquired on compound ent-1 were consistent with the assigned structure
and matched those recorded1 on its enantiomer (viz. 1) save for the specific rotation that was of similar
magnitude but opposite in sign {viz. –76.5 (c 1.0 in CHCl3) for ent-1 vs +72.6 (c 1.1 in CHCl3) for 1}.
Given this relationship and that the structure of compound 1 has been established through the
single-crystal X-ray analysis of a derivative,1 the illustrated stereochemical array within compound ent-1
is secure.
OMe
OMe
O
MeO
O
MeO
K2CO3
MeOH
O
OH
Br
O
OH
Br
ca. 22 °C
16 h
HO
AcO
quant.
ent-1
11
Scheme 3
Considering the ready availability of both D- and L-tartaric acid and the demonstrated utility of
polyoxygenated and halogenated cyclohexenes in the synthesis,2 the simple protocols defined above
should provide a useful new means for the assembly of biologically active systems, especially various
conduritols and related compounds.15 Work directed towards such ends is now underway in our
laboratories. Results will be reported in due course.
EXPERIMENTAL
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded at 18 °C in
base-filtered CDCl3 on a Varian spectrometer operating at 400 MHz for proton and 100 MHz for carbon
nuclei. For 1H NMR spectra, signals arising from the residual protio-forms of the solvent were used as the
1
internal standards. H NMR data are presented 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. The signal due to residual CHCl3 appearing at δH
1
7.26 and the central resonance of the CDCl3 “triplet” appearing at δC 77.1(6) were used to reference H
and 13C NMR spectra, respectively. Infrared spectra (νmax) were recorded on a Perkin–Elmer UTAR Two
FTIR Spectrometer. Samples were analyzed as either thin films or finely divided solids. Low-resolution
ESI mass spectra were recorded on a Micromass LC-ZMD single quadrupole liquid chromatograph-mass
spectrometer while high-resolution measurements were conducted on an LCT Premier time-of-flight

HETEROCYCLES, Vol. 95, No. 1, 2017
295
instrument. Low- and high-resolution EI mass spectra were recorded on an Autospec Premier Micromass
magnetic-sector machine. Optical rotations were recorded in CHCl3 at 20 °C on a Perkin Elmer Model
343 Polarimeter. Melting points were measured on an Optimelt™ automated melting point system and are
uncorrected. Analytical thin layer chromatography (TLC) was performed on aluminium-backed 0.2 mm
thick silica gel 60 F254 plates as supplied by Merck. 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) or potassium
permanganate : potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g : 5 mL :
300 mL). Flash chromatographic separations were carried out following protocols defined by Still et al.13
with silica gel 60 (40–63 µm) as the stationary phase and using the AR- or HPLC-grade solvents
indicated. Starting materials and reagents were generally available from the Sigma–Aldrich, Merck, TCI,
Strem or Lancaster Chemical Companies and were used as supplied. Drying agents and other inorganic
salts were purchased from the AJAX, BDH or Unilab Chemical Companies. Diethyl ether,
N,N-dimethylformamide (DMF), CH2Cl2 and EtOAc were dried using a Glass Contour solvent
purification system that is based upon a technology originally described by Grubbs et al.14 Where
necessary, reactions were performed under an inert atmosphere.
Specific Experimental Procedures and Product Characterization
Dimethyl (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-dicarboxylate (4)
Using a modification of a procedure reported16 by Maycock and co-workers, a magnetically stirred
solution of L–tartaric acid (11.87 g, 79.09 mmol), 2,3-butanedione (7.25 mL, 80 mmol) and trimethyl
orthoformate (50 mL, 466 mmol) in dry MeOH (100 mL) was treated with p-toluenesulfonic acid
monohydrate (710 mg, 5 mol%). The resulting solution was heated under reflux for 24 h and the ensuing
deep-red mixture then cooled to room temperature and neutralized with NaHCO3 (4.00 g). Stirring was
continued for 0.5 h then the reaction mixture was concentrated under reduced pressure. The residue thus
obtained was diluted with EtOAc (100 mL) then NaHCO3 (30 mL of a saturated aqueous solution) added
and the separated organic phase washed with NaHCO3 (1 × 30 mL of a saturated aqueous solution) then
water (1 × 30 mL). The combined aqueous layers were extracted with EtOAc (3 × 30 mL) and the
combined organic phases then washed with brine (2 × 20 mL) before being dried (Na2SO4), filtered and
concentrated under reduced pressure. The yellow solid thus obtained was recrystallized (hexane/EtOAc)
and the resulting solid collected and washed successively with ice-cold hexane and ice-cold EtOAc to
give bis-ester 416,17 (16.73 g, 72%) as an off-white, crystalline solid, mp 107–108 ºC (lit.17 mp 106–
108 °C), [α]D –135.7 (c 1.1, CHCl3) {lit.17 [α]D –139.6 (c 1.0, CHCl3)} [Found: (M + K)+, 331.0777.
C12H20KO8 requires (M + K)+, 331.0795]. 1H NMR (CDCl3, 400 MHz) δH 4.54 (s, 2H), 3.77 (s, 6H), 3.32

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13
(s, 6H), 1.36 (s, 6H); C NMR (CDCl3, 100 MHz) δC 168.6, 99.4, 68.9, 52.7, 48.6, 17.5; IR (solid) νmax
2992, 1736, 1443, 1377, 1282, 1202, 1139, 1110, 1026, 898, 886, 810, 744 cm–1; MS (ESI, +ve) m/z 315
[(M + Na)+, 100%].
1,1'-((2S,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-diyl)bis(prop-2-en-1-ol) (5)
A magnetically stirred solution of bis-ester 4 (3.10 g, 10.63 mmol) in dry toluene (30 mL) was cooled to
–78 ºC then DIBAl-H (22.3 mL of a 1 M solution in toluene, 22.3 mmol) added, via syringe-pump, over
0.75 h. The ensuing mixture was stirred at –78 ºC for 2 h then vinylmagnesium bromide (74.4 mL of a 1
M solution in THF, 74.4 mmol) was added dropwise over 0.5 h. The solution thus formed was stirred at
–78 ºC for 0.5 h then allowed to warm to room temperature. After 16 h the reaction mixture was cooled to
0 ºC, quenched with Rochelle salt (100 mL of a saturated solution: CAUTION slow addition required)
then re-warmed to room temperature and stirring continued for 3 h. The resulting biphasic mixture was
transferred to a separating funnel and the organic layer separated then washed with water (1 × 100 mL).
The combined aqueous layers were extracted with EtOAc (3 × 30 mL) and the combined organic phases
then washed with brine (3 × 30 mL) before being dried (Na2SO4), filtered and concentrated under reduced
pressure. The ensuing thick, orange oil was subjected to flash column chromatography (silica, hexane →
1:1 v/v EtOAc/hexane gradient elution) and concentration of appropriate fractions (Rf = 0.5 in 1:1 v/v
EtOAc/hexane) afforded bis-allylic alcohol 5 (2.69 g, 88%) as a clear, colorless oil and a mixture of
1
diastereoisomers [Found: (M + Na)+, 311.1465. C14H24NaO6 requires (M + Na)+, 311.1471]. H NMR
(CDCl3, 400 MHz) δH (mixture of three diastereoisomers) 6.12–5.94 (complex m, 2H), 5.40–5.15 (series
of m, 4H), 4.31–4.17 (complex m, 2H), 4.03–3.65 (series of m, 2H), 3.24–3.19 (4 × s, 6H), 2.70–2.30
(series of m, 2H), 1.28–1.27 (3 × s, 6H); 13C NMR (CDCl3, 100 MHz) δC (mixture of three
diastereoisomers) 138.1, 138.0, 136.7(2), 136.6(8), 117.2, 116.8, 116.1, 115.8, 99.0, 98.9, 98.8(1), 98.7(9),
72.6, 72.3, 72.1, 71.6, 71.3, 70.5, 48.1(0), 48.0(6), 17.6(1), 17.5(9), 17.5; IR (film) νmax 3407, 2991, 2949,
2833, 1375, 1121, 1036, 997, 921, 852 cm–1; MS (ESI, +ve) m/z 311 [(M + Na)+, 100%].
(2R,3R,4aS,8aS)-2,3-Dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxine-5,8-diol
(6)
A solution of the bis-allylic alcohol 5 (2.67 g, 9.25 mmol) in CH2Cl2 (200 mL) was sonicated under an
atmosphere of nitrogen for 0.5 h then Grubbs’-II catalyst (157 mg, 2 mol%) was added in one portion.
The ensuing mixture was heated under reflux for 1.5 h then cooled to room temperature and the solvent
removed under reduced pressure. The resulting brown solid was subjected to flash column
chromatography (silica, 1:1 v/v EtOAc/hexane → EtOAc gradient elution) and concentration of
appropriate fractions (Rf = 0.3 in 2:1 v/v EtOAc/hexane) afforded cyclohexene 6 (2.39 g, 99%) as a white,
amorphous solid and a mixture of diastereoisomers [Found: (M + Na)+, 283.1165. C12H20NaO6 requires
1
(M + Na)+, 283.1158]. H NMR (CDCl3, 400 MHz) δH (mixture of three diastereoisomers) 6.07–5.62

HETEROCYCLES, Vol. 95, No. 1, 2017
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(series of m, 2H), 4.51–4.20 (complex m, 2H), 4.10–3.57 (series of m, 2H), 3.49 (broad m, 1H), 3.36–
3.24 (4 × s, 6H), 2.64–2.09 (series of broad m, 1H), 1.39–1.28 (4 × s, 6H). 13C NMR (CDCl3, 100 MHz)
δC 132.9, 130.0, 129.3, 126.6, 100.0, 99.8, 99.3, 99.1, 72.5, 70.6, 70.3, 69.7, 67.9, 65.9, 65.5, 65.3, 48.3,
48.2, 48.1(3), 48.0(7), 17.9(4), 17.9(0), 17.8(2), 17.8(0); IR (solid) νmax 3313, 2948, 1465, 1373, 1204,
1117, 1030, 971, 915, 886, 847 cm–1; MS (ESI, +ve) m/z 283 [(M + Na)+, 100%].
(2R,3R,4aR,8aR)-2,3-Dimethoxy-2,3-dimethyl-2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxine-5,8-dione
(7)
Dess-Martin periodane (23.80 g, 53.31 mmol) was added, in portions, to a magnetically stirred solution of
compound 6 (4.63 g, 17.78 mmol) in CH2Cl2 (25 mL) maintained at 0 ºC. After addition was complete
(0.25 h) the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h
before being concentrated under reduced pressure at 20 ºC. The residue thus obtained was subjected to
rapid flash chromatography (silica, 2:8 v/v pentane/Et2O elution) and concentration of the relevant
fractions (Rf = 0.7 in 1:2 v/v CH2Cl2/Et2O) at 20 ºC afforded enedione 7 (4.01 g, 88%) as a bright yellow,
crystalline solid, mp 115–117 ºC (dec.), [α]D –121.0 (c 0.9 in CHCl3) [Found: (M + Na)+, 279.0850.
1
C12H16NaO6 requires (M + Na)+, 279.0845]. H NMR (CDCl3, 400 MHz) δH 6.84 (s, 2H), 4.73 (s, 2H),
13
3.26 (s, 6H), 1.41 (s, 6H); C NMR (CDCl3, 100 MHz) δC 192.1, 140.1, 100.6, 73.9, 48.7, 17.6; IR
(solid) νmax 2954, 2849, 1699, 1380, 1133, 1113, 1027, 823, 543 cm–1; MS (ESI, +ve) m/z 343 [(M + 2 ×
CH3OH + Na)+, 100%], 311 [(M + CH3OH + Na)+, 50], 279 [(M + Na)+, 10].
(2R,3R,4aR,8R,8aS)-8-Hydroxy-2,3-dimethoxy-2,3-dimethyl-2,3,8,8a-tetrahydrobenzo[b][1,4]dioxin-
5(4aH)-one (8)
Sodium borohydride (770 mg, 20.35 mmol) was added, in portions over 0.08 h, to a magnetically stirred
solution of CeCl3•7H2O (7.60 g, 20.40 mmol) in MeOH (50 mL) maintained at 0 ºC. The ensuing mixture
was stirred at this temperature for 0.25 h then transferred to a pressure-equalized dropping funnel and
added dropwise to a magnetically solution of endione 7 (4.01 g, 15.67 mmol) in MeOH (150 mL) that had
been cooled to –78 ºC. After 1.5 h further portions of NaBH4 (5 × 10 mg, 1.32 mmol) were slowly added
until the yellow reaction mixture became colorless and at which point it was quenched with acetone (20
mL). NH4Cl (100 mL of a saturated aqueous solution) was added to the reaction mixture so-formed that
was then allowed to warm to room temperature. The ensuing mixture was concentrated under reduced
pressure and the residue thus obtained diluted with EtOAc (100 mL) and water (50 mL). The separated
aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic phases then washed with
brine (2 × 50 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The
residue thus generated was subjected to flash column chromatography (silica, CH2Cl2 → 1:2 v/v
Et2O/CH2Cl2 gradient elution) and concentration of appropriate fractions (Rf = 0.2 in 1:1 v/v
EtOAc/hexane) afforded enone 8 (3.79 g, 94%) as a clear, colorless oil, [α]D –215.0 (c 0.5, CHCl3)

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1
[Found: (M + Na)+, 281.1006. C12H18NaO6 requires (M + Na)+, 281.1001]. H NMR (CDCl3, 400 MHz)
δH 6.85 (dd, J = 10.5 and 2.0 Hz, 1H), 6.07 (dd, J = 10.5 and 2.6 Hz, 1H), 4.67 (m, 1H), 4.25 (d, J = 11.4
Hz, 1H), 3.96 (dd, J = 11.4 and 8.7 Hz, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 2.55 (d, J = 3.9 Hz, 1H), 1.42 (s,
3H), 1.36 (s, 3H); 13C NMR (CDCl3, 100 MHz) δC 193.5, 148.6, 128.4, 100.3, 99.4, 74.3, 72.3, 70.1, 48.7,
48.2, 17.7(3), 17.6(6); IR (film) νmax 3452, 2958, 1683, 1379, 1118, 1028, 967, 947, 881, 806, 634, 585,
540 cm–1; MS (ESI, +ve) m/z 281 [(M + Na)+, 100%].
(2R,3R,4aR,8R,8aS)-6-Bromo-8-hydroxy-2,3-dimethoxy-2,3-dimethyl-2,3,8,8a-tetrahydrobenzo[b][1,
4]dioxin-5(4aH)-one (9)
Molecular bromine (400 µL of a 10% v/v solution in CH2Cl2, 0.79 mmol) was added, dropwise, to a
magnetically stirred solution of enone 8 (185 mg, 0.72 mmol) in CH2Cl2 maintained at –5 ºC. The
resulting solution was stirred at this temperature for 1 h then triethylamine (300 µL, 2.15 mmol) added
dropwise. The cooling bath was then removed and the reaction mixture stirred at room temperature for 16
h before being quenched with sodium sulfite (2 mL of a saturated aqueous solution). The separated
organic layer was washed successively with sodium sulfite (3 × 5 mL of a saturated aqueous solution) and
NH4Cl (3 × 5 mL of an aqueous solution) then the combined aqueous washings were extracted with
EtOAc (3 × 10 mL). The combined organic phases were washed with brine (2 × 10 mL) before being
dried (Na2SO4), filtered and concentrated under reduced pressure. The ensuing residue was subjected to
flash column chromatography (silica, CH2Cl2 → 1:9 v/v Et2O/CH2Cl2 gradient elution) and concentration
of appropriate fractions (Rf = 0.2 in 1:9 v/v Et2O/CH2Cl2) afforded bromoenone 9 (190 mg, 79 %) as a
white, crystalline solid, mp 178–181 °C, [α]D –146.6 (c 0.5, CHCl3) [Found: (M + Na)+, 359.0100.
C12H1779BrNaO6 requires (M + Na)+, 359.0106]. 1H NMR (CDCl3, 400 MHz) δH 7.29 (d, J = 2.3 Hz, 1H),
4.63 (ddd, J = 8.6, 4.1 and 2.3 Hz, 1H), 4.28 (d, J = 11.4 Hz, 1H), 3.98 (dd, J = 11.4 and 8.6 Hz, 1H),
13
3.31 (s, 3H), 3.28 (s, 3H), 2.57 (d, J = 4.1 Hz, 1H), 1.42 (s, 3H), 1.35 (s, 3H); C NMR (CDCl3, 100
MHz) δC 186.3, 148.6, 123.2, 100.5, 99.3, 73.6, 71.6, 70.5, 48.8, 48.3, 17.6(3), 17.5(9); IR (solid) νmax
3480, 2945, 1712, 1601, 1450, 1373, 1334, 1279, 1205, 1141, 1110, 1023, 907, 888, 870, 858, 606, 782,
663, 606, 517, 440 cm–1; MS (ESI, +ve) m/z 361 and 359 [(M + Na)+, 98 and 100%, respectively].
(2R,3R,4aS,5R,8aR)-7-Bromo-2,3-dimethoxy-2,3-dimethyl-8-oxo-2,3,4a,5,8,8a-hexahydrobenzo[b][1,
4]dioxin-5-yl acetate (10)
Acetic anhydride (120 µL, 1.25 mmol) was added to a magnetically stirred solution of bromoenone 9
(140 mg, 0.416 mmol) in pyridine (5 mL). Stirring was continued at room temperature for 1 h then the
reaction mixture was concentrated under reduced pressure to afford acetate 10 (153 mg, 97%) as a white
foam, [α]D –366.5 (c 0.6, CHCl3) [Found: (M + Na)+, 401.0217. C14H1979BrNaO7 requires (M + Na)+,
1
401.0212]. H NMR (CDCl3, 400 MHz) δH 7.13 (d, J = 2.4 Hz, 1H), 5.67 (dd, J = 8.9 and 2.4 Hz, 1H),

HETEROCYCLES, Vol. 95, No. 1, 2017
299
4.39 (d, J = 11.2 Hz, 1H), 4.18 (dd, J = 11.2 and 8.9 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 2.16 (s, 3H), 1.40
(s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 100 MHz) δC 185.9, 170.1, 144.8, 124.3, 100.5, 99.3, 71.7, 71.0,
70.6, 48.7, 48.1, 20.9, 17.6, 17.5; IR (solid) νmax 2952, 1751, 1720, 1377, 1220, 1135, 1113, 1028, 979,
918, 886, 853, 786, 662 cm–1; MS (ESI, +ve) m/z 467 and 465 [(M + 2 × CH3OH + Na), 98 and 100%,
respectively], 403 and 401 [(M + Na)+, 30 and 29, respectively].
(2R,3R,4aS,5R,8aR)-7-Bromo-2,3-dimethoxy-2,3-dimethyl-8-oxo-2,3,4a,5,8,8a-hexahydrobenzo[b][1,
4]dioxin-5-yl acetate (11) and (2R,3R,4aS,5R,8S,8aS)-7-Bromo-8-hydroxy-2,3-dimethoxy-2,3-
dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxin-5-yl acetate (12)
Sodium borohydride (211 mg, 5.59 mmol) was added, in portions over 0.08 h, to a magnetically stirred
solution of CeCl3•7H2O (1.09 g, 2.93 mmol) in MeOH (20 mL) maintained at 0 ºC. The ensuing mixture
was stirred at this temperature for 0.25 h then transferred to a pressure-equalized dropping funnel and
added dropwise to a magnetically solution of acetate 10 (1.06 g, 2.79 mmol) in MeOH (100 mL)
maintained at –78 ºC. After 1 h the reaction mixture was allowed to warm to room temperature, quenched
with water (5 mL) and concentrated under reduced pressure. The residue thus obtained was diluted with
EtOAc (100 mL) and NH4Cl (50 mL of a saturated aqueous solution). The separated aqueous layer was
extracted with EtOAc (3 × 50 mL) and the combined organic phases then washed with brine (2 × 50 mL)
before being dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained
was subjected to flash column chromatography (silica, 1:19 v/v Et2O/CH2Cl2) to afford two fractions, A
and B.
Concentration of fraction A (Rf = 0.3 in 1:19 v/v Et2O/CH2Cl2) afforded compound 11 (76 mg, 7%) as a
clear, colorless oil, [α]D –160.0 (c 0.9, CHCl3) [Found: (M + Na)+, 403.0373. C14H2179BrNaO7 requires
(M + Na)+, 403.0368]. 1H NMR (CDCl3, 400 MHz) δH 6.12 (d, J = 2.5 Hz, 1H), 5.30 (dd, J = 8.4 and 2.5
Hz, 1H), 4.35 (d, J = 4.0 Hz, 1H), 4.16 (dd, J = 11.0 and 8.4 Hz, 1H), 3.78 (dd, J = 11.0 and 4.0 Hz, 1H),
3.27 (s, 3H), 3.26 (s, 3H), 2.74 (broad s, 1H), 2.09 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3,
100 MHz) δC 170.5, 130.6, 123.8, 100.1, 99.3, 72.2, 72.1, 67.6, 65.1, 48.4, 48.0, 21.1, 17.8, 17.7; IR
(film) νmax 3475, 2950, 1750, 1733, 1371, 1230, 1135, 1116, 1033, 970, 933, 886, 851, 732 cm–1; MS
(ESI, +ve) m/z 405 and 403 [(M + Na)+, 100 and 98%, respectively].
Concentration of fraction B (Rf = 0.2 in 1:19 v/v Et2O/CH2Cl2) afforded compound 12 (840 mg, 79%) as
a clear, colorless oil, [α]D –204.7 (c 0.9, CHCl3) [Found: (M + Na)+, 403.0367. C14H2179BrNaO7 requires
1
(M + Na)+, 403.0368]. H NMR (CDCl3, 400 MHz) δH 6.04 (app. t, J = 2.1 Hz, 1H), 5.38 (m, 1H), 4.35
(m, 1H), 3.90 (dd, J = 11.0 and 8.3 Hz, 1H), 3.81 (dd, J = 11.0 and 7.8 Hz, 1H), 3.31 (s, 3H), 3.27 (s, 3H),
2.53 (s, 1H), 2.09 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3, 100 MHz) δC 170.3, 128.5, 127.1,
99.4, 99.2, 72.1, 71.8, 71.4, 68.6, 48.2, 48.0, 21.1, 17.7, 17.6; IR (film) νmax 3474, 2919, 2850, 1737,
1369, 1229, 1118, 1020, 969, 914, 886, 852, 795, 736 cm–1; MS (ESI, +ve) m/z 405 and 403 [(M + Na)+,

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HETEROCYCLES, Vol. 95, No. 1, 2017
100 and 98%, respectively].
(2R,3R,4aR,5R,8R,8aS)-8-Acetoxy-6-bromo-2,3-dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahydro-
benzo[b][1,4]dioxin-5-yl 4-methoxybenzoate (13)
Tri-n-butylphosphine (520 µL, 2.08 mmol) was added to a magnetically stirred solution of allylic alcohol
12 (397 mg, 1.04 mmol) and p-methoxybenzoic acid (316 mg, 2.08 mmol) in benzene (7 mL). The
solution thus obtained was cooled to 0 ºC then N,N,N′,N′-tetramethylazodicarboxamide (TMAD) (376 mg,
2.08 mmol) was added in one portion. The ensuing mixture was stirred at 0 °C for 0.25 h then heated
under reflux for 48 h. The cooled solution was filtered through a short pad of diatomaceous earth and the
filtrate concentrated under reduced pressure. The residue thus obtained was subjected to flash column
chromatography (silica, CH2Cl2 → 1:19 v/v Et2O/CH2Cl2 gradient elution) and concentration of
appropriate fractions (Rf = 0.5 in 1:9 v/v Et2O/CH2Cl2) afforded ester 13 (422 mg, 79%) as a white,
amorphous solid, [α]D –28.3 (c 1.1, CHCl3) [Found: (M + Na)+, 537.0734. C22H2779BrNaO9 requires (M +
Na)+, 537.0736]. 1H NMR (CDCl3, 400 MHz) δH 8.05 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.24
(d, J = 2.5 Hz, 1H), 5.97 (d, J = 4.2 Hz, 1H), 5.37 (dd, J = 8.5 and 2.5 Hz, 1H), 4.28 (dd, J = 11.1 and 8.5
Hz, 1H), 3.95 (dd, J = 11.1 and 4.2 Hz, 1H), 3.88 (s, 3H), 3.30 (s, 3H), 3.25 (s, 3H), 2.14 (s, 3H), 1.27 (s,
3H), 1.10 (s, 3H); 13C NMR (CDCl3, 100 MHz) δC 170.4, 165.8, 163.6, 132.6, 132.3, 122.5, 121.0, 113.7,
99.6, 99.3, 72.2, 71.9, 66.7, 66.0, 55.6, 48.4, 47.9, 21.1, 17.7, 17.4; IR (film) νmax 2980, 1724, 1605, 1511,
1372, 1254, 1226, 1166, 1117, 1083, 1051, 1028, 971, 933, 765, 699, 663, 611 cm–1; MS (ESI, +ve) m/z
539 and 537 [(M + Na)+, 100 and 98%, respectively].
(2R,3R,4aS,5R,8R,8aS)-6-Bromo-2,3-dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]-
dioxine-5,8-diol (ent-1)
Method i (ex. Compound 13): Potassium hydroxide (60 mg, 1.07 mmol) was added to a magnetically
stirred solution of compound 13 (103 mg, 0.20 mmol) in MeOH (10 mL) and the ensuing mixture stirred
at room temperature for 48 h. The MeOH was then removed under reduced pressure and the residue thus
obtained diluted with EtOAc (10 mL) and NH4Cl (10 mL of a saturated aqueous solution). The separated
aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic phases washed with brine
(2 × 5 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting
white solid was subjected to flash column chromatography (silica, → 1:24 v/v Et2O/CH2Cl2 gradient
elution) and concentration of appropriate fractions (Rf = 0.3 in 1:19 v/v MeOH/CH2Cl2) afforded enediol
ent-1 (65 mg, 96%) as a white foam, [α]D –76.5 (c 1.0, CHCl3) [Found: (M + Na)+, 361.0260.
C12H1979BrNaO6 requires (M + Na)+, 361.0263]. H NMR (CD3OD, 400 MHz) δH 6.05 (d, J = 2.5 Hz,
1
1H), 4.22 (d, J = 4.1 Hz, 1H), 4.06 (dd, J = 7.9 and 2.5 Hz, 1H), 3.87 (dd, J = 11.1 and 7.9 Hz, 1H), 3.63
(dd, J = 11.1 and 4.1 Hz, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H) (signals due to
hydroxyl group protons not observed); 13C NMR (CD3OD, 100 MHz) δC 135.3, 124.0, 100.8, 100.2, 73.1,

HETEROCYCLES, Vol. 95, No. 1, 2017
301
71.8, 69.9, 69.2, 48.3(1), 48.2(5), 18.1, 18.0; IR (film) νmax 3236, 3007, 2954, 2905, 2834, 1114, 1074,
1054, 1030, 985, 912, 884, 852, 760, 665, 617, 599 cm–1; MS (ESI, +ve) m/z 363 and 361 [(M + Na)+, 98
and 100%, respectively].
Method ii (ex. Compound 11): Potassium carbonate (50 mg, 0.36 mmol) was added to a magnetically
stirred solution of ester 11 (76 mg, 0.20 mmol) in MeOH (10 mL) and the resulting mixture stirred at
room temperature for 12 h then concentrated under reduced pressure. The residue thus obtained was
diluted with EtOAc (10 mL) and water (10 mL) then the separated aqueous layer extracted with EtOAc (3
× 5 mL). The combined organic phases were washed with brine (2 × 5 mL) before being dried (Na2SO4),
filtered and concentrated under reduced pressure to give enediol ent-1 (67 mg, 99%) as a white foam.
This material was identical, in all respects, with that obtained by Method i.
X-Ray Crystallographic Study
Crystallographic Data
Compound 9: C12H17BrO6, M = 337.17, T = 150 K, orthorhombic, space group P212121, Z = 4, a =
6.8265(1), b = 11.4217(1), c = 17.8288(1) Å; V = 1390.12(1) Å3; Dx = 1.611 g cm–3; 2750 unique data
(2θmax 144.6°), R = 0.021 [for 2718 reflections with I > 2.0σ(I)]; Rw = 0.052 (all data), S = 1.03.
Structure Determination
Images were measured on an Agilent SuperNova CCD diffractometer (CuKα, mirror monochromator,
λ = 1.54184 Å) and data extracted using the CrysAlis package.18 Structure solution was by direct methods
(SIR92).19 The structure of compound 9 was refined using the CRYSTALS program package.20 Atomic
coordinates, bond lengths and angles, and displacement parameters have been deposited at the Cambridge
Crystallographic Data Centre (CCDC no. 1491822). These data can be obtained free-of-charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
Supplementary Material
The 1H and 13C NMR spectra of compounds 4–13 and ent-1 are available on the Journal’s website.
ACKNOWLEDGEMENTS
We thank the Research School of Chemistry, the Australian Research Council and Institute of Advanced
Studies for support. JNB is the grateful recipient of an Australian Postgraduate Award (APA) provided by
the Australian Government.

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