Synthesis of a Highly Functionalised and Homochiral 2-Iodocyclohexenone Related to the C-Ring of the Polycyclic, Indole Alkaloids Aspidophytine and Haplophytine

Article abstract of DOI:10.1071/CH18267

The enzymatically-derived and enantiomerically pure (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (7) has been elaborated over 10 steps into cyclohexenone 8. The latter compound embodies the enantiomeric form of the C-ring associated with the hexacyclic framework of the alkaloid aspidophytine (2). As such, this work sets the stage for effecting the conversion of the enantiomeric metabolite ent-7 into compound ent-8, and thence, through previously established protocols, including a palladium-catalysed Ullmann cross-coupling reaction, into the title alkaloids.

Full text of DOI:10.1071/CH18267

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH18267
Synthesis of a Highly Functionalised and Homochiral
2-Iodocyclohexenone Related to the C-Ring of the
Polycyclic, Indole Alkaloids Aspidophytine and
Haplophytine
A
A B
,
Michael Dlugosch and Martin G. Banwell
A
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia.
Corresponding author. Email: Martin.Banwell@anu.edu.au
B
The enzymatically-derived and enantiomerically pure (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (7) has been elabo-
rated over 10 steps into cyclohexenone 8. The latter compound embodies the enantiomeric form of the C-ring associated
with the hexacyclic framework of the alkaloid aspidophytine (2). As such, this work sets the stage for effecting the
conversion of the enantiomeric metabolite ent-7 into compound ent-8, and thence, through previously established
protocols, including a palladium-catalysed Ullmann cross-coupling reaction, into the title alkaloids.
Manuscript received: 2 June 2018.
Manuscript accepted: 13 July 2018.
Published online:
17 August 2018.
Introduction
earlier biosynthetic proposals, Tokuyama and co-workers were
able to couple an advanced precursor to aspidophytine (2) with
one associated with the left-hand segment of compound 1.[9] By
such means, and after conducting a key, one-pot aerobic oxida-
tion/skeletal rearrangement cascade, the completion of a more
convergent total synthesis of haplophytine was realised.
Our own interest in constructing various Aspidosperma
alkaloids has resulted in the establishment of methods for
assembling a close structural analogue of vindoline (3)[10] as
well as total syntheses of the racemic modifications of aspidos-
permidine (4),[11] limaspermidine (5),[12] and its oxidative
cyclisation product 1-acetylaspidoalbidine (6)[12] (Fig. 2). The
analogue of vindoline was obtained in enantiomerically pure
form as a result of employing a homochiral and enzymatically
derived cis-1,2-dihydrocatechol as the starting material.[10,13]
Compounds 3–6 each embody an ABCDE-ring system that is
enantiomerically related to the one seen in aspidophytine (2)
while the last of these, namely 6, also incorporates the tetrahy-
drofuran substructure. A key step associated with all of these
syntheses was the palladium-catalyzed Ullmann cross-coupling
of a 2-iodocyclohexenone with an o-iodinated nitroarene.[14]
This was followed by reductive cyclisation of the resulting 2-
arylated cyclohexenone, often using dihydrogen in the presence
of Raney-cobalt.[15] The piperidine-annulated tetrahydrocarba-
zoles so-formed were each subjected to an annulation protocol
developed by Heathcock and co-workers[16] and thus complet-
ing the assembly of the ABCDE-ring system associated with
compounds 3–6.
The hetero-dimeric indole alkaloid haplophytine (1)[1–3] (Fig. 1)
is, as confirmed by X-ray analysis,[2] a structurally distinctive
metabolite derived from the Central American plant Haplo-
phyton cimicidum, the dried leaves of which were first employed
by the Aztecs for insecticidal purposes.[1] The right-hand seg-
ment of compound 1 embodies the aspidophytine framework 2
that is itself obtained from Haplophyton crooksii (otherwise
known as the cockroach plant) found in the Southern United
States as well as the north of Mexico. It too is used as an
insecticide, especially against cockroaches.[3]
The elaborate molecular architectures of haplophytine (1)
and aspidophytine (2) have prompted a range of synthetic
studies. In 1999 Corey and his co-workers reported the first
assembly of (–)-aspidophytine.[4] Subsequently, Fukuyama
(2003), Padwa (2006), Marino (2006), Nicolaou (2008),
Tokuyama (2013), and Qiu (2013)[5] achieved the same target.
Even more dramatically, after years of sustained effort by many
groups, total syntheses of haplophytine (1) were reported,
contemporaneously in 2009, by the Fukuyama/Tokuyama[6]
and the Nicolaou/Chen[7] groups.[8] In 2016, and inspired by
Me
N
D
N
E
N
O
N
O
O
O
O
HO
O
H
B
N
A
C-ring
H
Me
N
MeO
MeO
Me
OMe
We are now seeking to apply our earlier work in developing
total syntheses of the title alkaloids. As part of this program,
we report herein the conversion of the readily obtained and
homochiral cis-1,2-dihydrocatechol 7[13] (Fig. 3) into the
OMe
2
1
Fig. 1. The structures of haplophytine (1) and aspidophytine (2).
Journal compilation ꢀ CSIRO 2018
www.publish.csiro.au/journals/ajc

B
M. Dlugosch and M. G. Banwell
N
C
N
N
O
E
D
MeO
A
B
N
N
H
N
OAc
H
Me
X
H
H
OH
Ac
MeO2C
3
4 (X ϭ H)
6
5 (X ϭ OH)
Fig. 2. The structures of vindoline (3), aspidospermidine (4), limaspermidine (5) and 1-acetylaspidoal-
bidine (6).
CbzHN
(2). As implied above, the correct configuration at this stereo-
genic centre, and from which the ones at the others automatically
follow,[11,12] could be established by using metabolite ent-7
(rather than 7) as the starting material in this sequence.
Br
Br
CONMe2
O
OH
OH
OH
OH
C
O
I
The conversion of compound 16 into target 8 involved three
additional steps, the first of which was the cleavage of the
methoxy methyl (MOM)-ether. This was achieved using con-
centrated aqueous HBr at ambient temperatures. To prevent
accompanying hydrolysis of the associated acetonide unit, this
reaction was run in 2,2-DMP. As a result the allylic alcohol 17
was obtained, albeit in just 56 % yield. Oxidation of compound
17 was best effected with the Dess–Martin periodinane
(DMP)[21] and resulted in the formation of enone 18 (64 %).
Subjection of the latter compound to a Johnson a-iodination
reaction[22] then provided target 8 in 87 % yield. All of the
spectroscopic data acquired on compound 8 were in complete
accord with the assigned structure. In particular, a molecular-
associated ion ([M þ H]þ) was observed in the electrospray
ionisation mass spectrum and an accurate mass measurement on
this species established it was of the required composition, that
is C24H31IN2O6. In the 13C NMR spectrum the expected 22
signals were observed while in the infrared spectrum carbonyl
O
7
ent-7
8
Fig. 3. The structure of the homochiral starting material 7, its enantiomer
(ent-7) and the target 2-iodocyclohexenone 8.
2-iodocyclohexenone 8 that embodies key elements associated
with the C-ring of ent-aspidophytine (ent-2). Given that com-
pound ent-7 is also available,[17] albeit less readily, this work
should eventually allow for the synthesis of compounds 1 and 2
as well as their optical antipodes.
Results and Discussion
The route employed in the synthesis of target 8 is shown in
Scheme 1. This starts with the conversion of diol 7, using 2,2-
dimethoxypropane (2,2-DMP) in the presence of catalytic
quantities of p-toluenesulfonic acid monohydrate (p-
TsOHꢀH2O), into the corresponding and known acetonide 9.[10]
Given that the latter compound shows a ready propensity to
engage in a Diels–Alder dimerisation reaction,[18] it was
immediately subjected to a regio- and diastereo-selective dihy-
absorption bands were observed at 1697 and 1633 cmꢁ1
.
Conclusions
The reaction sequence detailed here will allow for the conversion
of the homochiral metabolite ent-7 into the cyclohexenone ent-8.
Furthermore, our earlier studies on the synthesis of aspi-
dopsermidine (4),[11] limaspermidine (5),[12] and 1-acet-
ylaspidoalbidine (6),[12] will inform us as to effective methods for
the elaboration of compound ent-8 into the structurally related
aspidophytine (2) and even, perhaps, the more elaborate haplo-
phytine (1). The conversion ent-8 - 2 is likely to involve, in the
first stages, a palladium-catalysed Ullmann cross-coupling
reaction so as to install the required dimethoxyaryl group and the
associated nitrogen. Subsequent hydrogenolysis and reductive
cyclisation stepsleading tothe B-and D-rings are likelytofollow.
A Heathcock annulation (to install the E-ring) and an oxidative
cyclisation reaction (involving an angular acetic acid group) to
form the lactone ring would then be deployed. At some point the
acetonide residue associated with compound ent-8 will need to be
converted into the corresponding cyclohexene and this is most
likely to involve a Corey–Winter olefin synthesis.[20b] Efforts
directed towards such ends will be reported in due course.
.
droxylation reaction using K2OsO4 2H2O as the catalytic oxi-
dant and N-methylamine N-oxide (NMO) as the stoichiometric
one.[19] This resulted in the formation of the bromoconduritol
mono-acetonide 10[10] (70 % from 7). The more accessible
allylic hydroxy group associated with compound 10 could be
selectively protected using tert-butyldimethylsilyl chloride
(TBS-Cl) in the presence of imidazole and thus providing the
mono-ether 11[10] in 90 % yield. Treatment of compound 11
with chloromethyl methyl ether (MOM-Cl) in the presence of
Hu¨nig’s base (N,N-diisopropylethylamine) and 4-(N,N-dime-
thylamino)pyridine (DMAP) then gave product 12[10] in 95 %
yield. Suzuki–Miyaura cross-coupling of the bromocyclohexene
12 with the previously unreported, 9-BBN-derived carbamate 13
(readily prepared in situ from 9-BBN and benzyl allylcarba-
mate) gave the anticipated product 14 (91 %). On treating
compound 14 with tetra-n-butylammonium fluoride (TBAF)
desilylation took place to give the allylic alcohol 15 (95 %). In a
critical step of the reaction sequence, compound 15 was readily
engaged in an Eschenmoser–Claisen rearrangement[10,12,20] on
treatment with dimethylacetamide dimethyl acetal (DMADMA)
in refluxing toluene and so cleanly produced the allylic ether 16
(85 % based on recovered starting material or brsm).
Experimental
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded at room temperature in base-filtered
CDCl3 on a spectrometer operating at 400 MHz for proton and
Significantly, compound 16 incorporates one of the two
quaternary carbon centres associated with the enantiomeric form
of the C-rings of the alkaloids haplophytine (1) and aspidophytine

Homochiral 2-Iodocyclohexenone
C
Br
Br
Br
2,2-DMP,
p-TsOH•H2O
K2OsO4
NMO
OH
OH
O
O
O
O
acetone/water
70 % from 7
HO
OH
7
10
9
TBS-Cl
imidazole
CH2Cl2
90 %
Br
Br
MOM-Cl
Hünig’s base
DMAP
B
O
O
O
O
NHCbz
ϩ
CH2Cl2
95 %
TBSO
TBSO
OH
11
OMOM
13
12
PdCl2dppf•CH2Cl2
aq. NaOH
THF
81 %
CbzHN
CbzHN
TBSO
CbzHN
DMADMA
CONMe2
TBAF
THF
O
O
O
O
O
toluene
O
95 %
85 %
HO
OMOM
(brsm)
OMOM
OMOM
16
15
14
conc. HBr
2,2-DMP
56 %
CbzHN
I2
CbzHN
CbzHN
CONMe2
O
CONMe2
O
CONMe2
O
DMP
CH2Cl2
CHCl3/pyridine
O
O
O
I
87 %
64 %
O
O
OH
8
18
17
Scheme 1. Conversion of metabolite 7 into the target 2-iodocyclohexenone 8.
101 MHz for carbon nuclei. The signal due to residual CHCl3
appearing at dH 7.26 and the central resonance of the CDCl3
(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.[23] with silica gel 60 (40–63 mm) as the stationary phase and
using the AR- or HPLC-grade solvents indicated. Starting
materials, reagents, drying agents, and other inorganic salts were
generally commercially available and used as supplied. Tetra-
hydrofuran (THF), methanol and, dichloromethane were dried
using a solvent purification system that is based upon a tech-
nologyoriginally described by Grubbs et al.[24] Where necessary,
reactions were performed under an atmosphere of nitrogen.
‘triplet’ appearing at dC 77.0 were used to reference 1H and 13
C
1
NMR spectra, respectively. H NMR data are recorded as fol-
lows: chemical shift (d) (multiplicity, coupling constant(s) J
(Hz), relative integral) where multiplicity is defined as: s ¼
singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, and m ¼ multiplet or
combinations of the above. Infrared spectra (nmax) were recorded
on an ATR-FTIR spectrometer. Samples were analysed in neat
form. Optical rotations were recorded in the indicated solvent at
228C. Low-resolution eletrospray ionisation (ESI) mass spectra
were recorded on a single quadrupole liquid chromatograph–
mass spectrometer while high-resolution measurements were
conducted on a time-of-flight instrument. Analytical thin-layer
chromatography (TLC) was performed on aluminium-backed
0.2 mm thick silica gel 60 F254 plates. Eluted plates were
visualised using a 254 nm UV lamp and/or by treatment with
a suitable dip followed by heating. These dips included phos-
phomolybdic acid/ceric sulfate/sulfuric acid (conc.)/water
Specific Chemical Transformations
(3aS,7aS)-4-Bromo-2,2-dimethyl-3a,7a-dihydrobenzo
[d][1,3]dioxole (9)
A magnetically stirred solution of compound 7[13b] (4.78 g,
25.0 mmol) in 2,2-DMP (50 mL) was treated with

D
M. Dlugosch and M. G. Banwell
p-TsOHꢀH2O (43 mg, 0.23 mmol, 1 mol-%) and the ensuing
mixture stirred at 228C for 2 h and then concentrated, without
heating, under reduced pressure. The residue thus obtained
was dissolved in ethyl acetate/CH2Cl2 (100 mL of a 1 : 1 v/v
mixture) and the resulting solution washed with water
(2 ꢂ 30 mL) before being dried (Na2SO4), filtered, and
then concentrated under reduced pressure (no heating) to
give compound 9[10,18] (,5.75 g) as a light-brown oil. This
material was used immediately in the next step of the reaction
sequence.
(((3aS,4S,5R,7aS)-7-Bromo-4-(methoxymethoxy)-2,2-
dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-5-yl)
oxy)(tert-butyl)dimethylsilane (12)
A magnetically stirred solution of compound 11 (1.00 g,
2.64 mmol) in CH2Cl2 (5 mL) maintained at 08C was treated
with DMAP (322 mg, 2.63 mmol, 1.0 mol equiv.) and then
Hu¨nig’s base (2.7 mL, 15.8 mmol, 6.0 mol equiv.) and MOM-
Cl[25] (2.1 mL, 19.8 mmol, 7.5 mol equiv.). The ensuing mixture
was stirred at 228C for 16 h before being quenched with NH4Cl
(30 mL of a saturated aqueous solution) and the separated
aqueous phase extracted with CH2Cl2 (3 ꢂ 20 mL). The com-
bined organic phases were dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 1 : 19 v/v
ethyl acetate/40–60 petroleum spirits elution) and thus afford-
ing, after concentration of the appropriate fractions (Rf 0.5), the
title compound 12[10] (1.06 g, 95 %) as a colourless, semi-solid,
[a]D ꢁ71.4 (c 1.0, CHCl3). dH 6.06 (br s, 1H), 4.82 (d, J 6.7, 1H),
4.72 (d, J 6.7, 1H), 4.65 (d, J 5.5, 1H), 4.47 (m, 2H), 4.08 (m,
1H), 3.40 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H), 0.91 (s, 9H), 0.12 (s,
3H), 0.10 (s, 3H). dC 132.8, 122.6, 110.3, 97.3, 77.0, 76.0, 75.6,
68.1, 55.9, 27.7, 26.4, 25.9, 18.3, ꢁ4.6 (one signal obscured or
overlapping). nmax/cmꢁ1 2988, 2953, 2930, 1644, 1464, 1381,
1371, 1253, 1133, 1115, 1078, 1037, 865, 776, 680. m/z (ESI,
þve) 447 and 445 ([M þ Na]þ, 99 and 100 %). HRMS
445.1019; calcd for C17H3179BrO5SiNa [M þ Na]þ 445.1022.
(3aS,4R,5R,7aS)-7-Bromo-2,2-dimethyl-3a,4,5,7a-
tetrahydrobenzo[d][1,3]dioxole-4,5-diol (10)
A magnetically stirred solution of the crude acetonide 9
(,5.75 g, 24. 9 mmol, 1.0 mol equiv.) in acetone/water
(100 mL of a 4 : 1 v/v mixture) was cooled to 08C and then
.
treated with K2OsO4 2H2O (158 mg, 0.25 mmol, 0.01 mol
equiv.) and NMO (6.41 g, 54.8 mmol, 2.2 mol equiv.). The
ensuing mixture was allowed to warm to 228C and then stirred
at this temperature for 16 h before being diluted with ethyl
acetate (50 mL). The separated aqueous layer was extracted
with ethyl acetate (3 ꢂ 30 mL) and the combined organic
layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was subjected to flash column
chromatography (silica, 3 : 7 v/v ethyl acetate/40–60 petro-
leum spirits elution) and thus afforded, after concentration of
the appropriate fractions (Rf ¼ 0.3 in 2 : 3 v/v ethyl acetate/40–
60 petroleum spirits), the title diol 10[10] (4.67 g, 70 % over 2
steps) as a light-brown solid, mp 1128C, [a]D ꢁ4.0 (c 1.0,
CHCl3). dH 6.16 (br s, 1H), 4.66 (m, 1H), 4.45 (t, J 5.4, 1H),
4.36 (br s, 1H), 4.19 (t, J 4.6, 1H), 2.53 (s, 2H), 1.44 (s, 3H),
1.41 (s, 3H). dC 131.1, 123.9, 110.5, 76.5, 76.4, 69.6, 67.4,
27.8, 26.3. nmax/cmꢁ1 3401, 2987, 2934, 1645, 1382, 1373,
1229, 1079, 1050, 856, 628. m/z (ESI, þve) 289 and 287
([M þ Na]þ, 95 and 100 %). HRMS 286.9880; calcd for
C9H1379BrO4Na [M þ Na]þ 286.9889.
Benzyl (3-((1S,5S)-9-Borabicyclo[3.3.1]nonan-9-yl)
propyl)carbamate (13)
Following a protocol reported by Rychnovsky,[26] benzyl
allylcarbamate[27] (500 mg, 2.61 mmol) was added to magneti-
cally stirred 9-BBN (5 mL of a 0.5 M solution in THF, 2.5 mmol)
maintained at 228C. Stirring was continued at this temperature
for 16 h and the solution thus obtained, and presumed to contain
compound 13, used directly in the Suzuki–Miyaura cross-
coupling with compound 12 as detailed immediately below.
Benzyl (3-((3aR,6R,7S,7aR)-6-((tert-Butyldimethylsilyl)
oxy)-7-(methoxymethoxy)-2,2-dimethyl-
3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)
carbamate (14)
(3aS,4S,5R,7aS)-7-Bromo-5-((tert-butyldimethylsilyl)
oxy)-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]
dioxol-4-ol (11)
A suspension of compound 10 (8.00 g, 30.2 mmol) in
CH2Cl2 (100 ml) was maintained at 08C and then imidazole
(5.28 g, 77.6 mmol, 2.56 mol equiv.) and TBS-Cl (8.19 g,
54.3 mmol, 1.8 mol equiv.) added to it. The ensuing mixture
was stirred at 228C for 1 h and then quenched with water
(50 mL). The separated aqueous layer was extracted with
CH2Cl2 (3 ꢂ 30 mL) and the combined organic phases then
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue so obtained was subjected to flash column
chromatography (silica, 1 : 15 v/v ethyl acetate/40–60 petro-
leum spirits elution) and thus afforded, after concentration of
the appropriate fractions (Rf 0.6 in 1 : 9 v/v ethyl acetate/40–60
petroleum spirits), ether 11[10] (10.34 g, 90 %) as a light-yellow
solid, mp 858C, [a]D ꢁ32.0 (c 1.0, CHCl3). dH 5.91 (m, 1H),
4.62 (m, 1H), 4.49 (t, J4.8, 1H), 4.37 (m, 1H), 4.16 (m, 1H),
2.62 (d, J1.7, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 0.92 (s, 9H), 0.15
(s 3H), 0.13 (s 3H). dC 130.8, 123.6, 110.1, 76.1, 75.8, 69.3,
68.2, 27.7, 26.3, 25.9, 18.2, ꢁ4.5, ꢁ4.7. nmax/cmꢁ1 3558, 2988,
2952, 2929, 2857, 1646, 1471, 1370, 1076, 1052, 865, 837, 777,
681. m/z (ESI, þve) 403 and 401 ([M þ Na]þ, 98 and 100 %).
HRMS 401.0761; calcd for C15H2779BrO4SiNa [M þ Na]þ)
401.0760.
A solution of compound 13 (1.04 mL of a 0.5 M solution in
THF, 0.52 mmol), prepared as described immediately above,
was dissolved in THF (1.5 ml) containing NaOH (2.3 mL of a
3 M aqueous solution). The ensuing mixture was stirred mag-
netically at 228C for 0.3 h and then added to a magnetically
stirred solution of compound 12 (200 mg, 0.47 mmol, 1.0 mol
equiv.) in THF (1 mL) maintained at 228C. The resulting
.
mixture was deoxygenated with nitrogen and then PdCl2dppf
CH2Cl2 (40 mg, 0.05 mmol, 10 mol-%) was added. The mixture
thus obtained was stirred at 228C under nitrogen for 16 h before
being quenched with NaHCO3 (5 mL of a saturated aqueous
solution). The separated aqueous layer was extracted with ethyl
acetate (3 ꢂ 15 mL) and the combined organic phases then dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The residue so obtained was subjected to flash column chroma-
tography (silica, 1 : 4 v/v ethyl acetate/40–60 petroleum spirits
elution) and thus afforded, after concentration of the appropriate
fractions (Rf 0.4), carbamate 14 (243 mg, 81 %) as a clear,
colourless oil, [a]D ꢁ72.7 (c 0.83, CHCl3). dH 7.41–7.26
(complex m, 5H), 5.51 (br s, 1H), 5.09 (s, 2H), 4.94 (br s, 1H),
4.78 (d, J 6.6, 1H), 4.71 (d, J 6.6, 1H), 4.52 (d, J 6.0, 1H), 4.41

Homochiral 2-Iodocyclohexenone
E
(t, J 6.0, 1H), 4.35 (t, J 3.7, 1H), 3.87 (m, 1H), 3.37 (s, 3H), 3.22
(m, 2H), 2.18 (m, 2H), 1.73 (m, 2H), 1.38 (s, 3H), 1.36 (s, 3H),
0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). dC 156.5, 137.2, 136.8,
128.6, 128.2(3), 128.1(7), 126.2, 109.2, 96.3, 76.3, 75.1, 74.6,
66.7, 66.5, 55.6, 40.9, 31.2, 27.7, 27.6, 26.0(2), 25.9(6), 18.3,
ꢁ4.4, ꢁ4.6. nmax/cmꢁ1 3349, 2929, 2857, 1709, 1525, 1472,
1246, 1031, 885, 775. m/z (ESI, þve) 558 ([M þ Na]þ, 100 %).
HRMS 558.2864; calcd for C28H45NO7SiNa [M þ Na]þ
558.2863.
Concentration of fraction B (Rf 0.2 in 1 : 4 v/v ethyl acetate/
diethyl ether) afforded compound16 (1.55 g, 72or 85% brsm), as
a white, crystalline solid: mp 848C, [a]D ꢁ18.3 (c 1.0, CHCl3). dH
7.36–7.20 (complex m, 5H), 5.75 (m, 2H), 5.09 (s, 2H), 5.03 (br s,
1H), 4.81 (d, J 6.7, 1H), 4.72 (d, J 6.7, 1H), 4.31 (s, 2H), 4.19 (s,
1H), 3.39(s, 3H), 3.16 (m, 2H), 3.01(s, 3H), 2.91(s, 3H), 2.50(m,
2H), 1.76–1.48 (complex m, 3H), 1.41 (s, 3H), 1.33 (s, 3H). dC
170.5, 156.5, 136.8, 135.9, 128.5, 128.1, 128.0, 125.8, 108.2,
95.5, 79.3, 78.2, 74.4, 66.5, 55.5, 41.6, 40.8, 39.1, 37.9, 35.5, 31.8,
26.8, 24.9, 24.2. nmax/cmꢁ1 3332, 2936, 1717, 1635, 1525, 1455,
1240, 1041, 731. m/z (ESI, þve) 513 ([M þ Na]þ, 100 %). HRMS
513.2578; calcd for C26H38N2O7Na [M þ Na]þ 513.2577.
Benzyl (3-((3aR,6R,7R,7aR)-6-Hydroxy-7-
(methoxymethoxy)-2,2-dimethyl-3a,6,7,7a-
tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)
carbamate (15)
Benzyl (3-((3aR,4S,7R,7aS)-4-(2-(dimethylamino)-
2-oxoethyl)-7-hydroxy-2,2-dimethyl-
3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)
carbamate (17)
A magnetically stirred solution of compound 14 (3.19 g,
5.95 mmol) in THF (14 mL) was cooled to 08C and then treated
with TBAF (12.4 mL of a 0.5 M solution in THF, 1.05 mol
equiv.). The ensuing mixture was allowed to warm to 228C over
2 h and stirring continued at this temperature for 16 h. The
reaction mixture was then diluted with NaHCO3 (20 mL of a
saturated aqueous solution) and the separated aqueous layer
extracted with ethyl acetate (3 ꢂ 15 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated under
reduced pressure and the residue thus obtained subjected to flash
column chromatography (silica, 4 : 6 - 7 : 3 - 8 : 2 v/v ethyl
acetate/40–60 petroleum spirits gradient elution). Concentration
of the appropriate fractions (Rf 0.2 in 1 : 1 v/v ethyl acetate/40–
60 petroleum elution) then gave allylic alcohol 15 (2.40 g, 95 %)
as a clear, colourless oil, [a]D ꢁ35.7 (c 0.48, CHCl3). dH 7.41–
7.27 (complex m, 5H), 5.63 (br s, 1H), 5.09 (s, 2H), 4.90 (br s,
1H), 4.77 (m, 2H), 4.51 (d, J 6.2, 1H), 4.43 (m, 1H), 4.35–4.24
(br s, 1H), 3.87 (m, 1H), 3.40 (s, 3H), 3.23 (m, 2H), 2.68 (d, J 6.1,
1H), 2.22 (m, 2H), 1.74 (m, 2H), 1.40 (s, 3H), 1.37 (s, 3H). dC
156.5, 138.3, 136.7, 128.6, 128.2(1), 128.1(8), 125.0, 109.5,
96.9, 78.0, 74.8, 74.5, 66.7, 65.5, 55.8, 40.8, 31.1, 27.8, 27.4,
26.1. nmax/cmꢁ1 3348, 2985, 2934, 1699, 1531, 1455, 1380,
1240, 1027, 916, 698. m/z (ESI, þve) 444 ([M þ Na]þ, 100 %).
HRMS 444.1192; calcd for C22H31NO7Na [M þ Na]þ
444.1998.
A magnetically stirred solution of compound 16 (47 mg,
0.09 mmol) in 2,2-DMP (1.6 mL) was cooled to 08C and then
treated with HBr (5 drops of a 48% aqueous solution). The
reaction mixture was kept at 08C for 0.1 h and then warmed to
228C, maintained at this temperature for 1.5 h and then quenched
with NaHCO3 (5 mL of a saturated aqueous solution) and the
separated aqueous layer extracted with ethyl acetate (3 ꢂ 5 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained
was subjected to flash column chromatography (silica, ethyl
acetate eltuion) and thus afforded, after concentration of the
appropriate fractions (Rf 0.2), compound 17 (24 mg, 56%) as a
clear, colourless oil, [a]D ꢁ33.8 (c 1.07, CHCl3). dH 7.45–7.28
(complex m, 5H), 5.75 (m, 1H), 5.68 (m, 1H), 5.09 (s, 2H), 4.96
(br s, 1H), 4.35 (d, J 7.3, 1H), 4.29 (dd, J 7.3 and 3.9, 1H), 4.22
(br s, 1H), 3.17 (m, 2H), 3.01 (s, 3H), 2.91 (s, 3H), 2.55 (s, 2H),
2.46 (d, J 6.2, 1H), 1.55 (br s, 4H), 1.41 (s, 3), 1.34 (s, 3H). dC
170.9, 156.5, 136.8, 134.6, 128.6, 128.2, 128.1, 128.0, 108.1,
81.0, 78.3, 69.8, 66.6, 41.6, 41.0, 40.0, 38.0, 35.6, 32.9, 26.9, 25.0,
24.4. nmax/cmꢁ1 3338, 2978, 2934, 1705, 1627, 1527, 1241, 1045,
752, 698. m/z (ESI, þve) 469 ([M þ Na]þ, 100 %). HRMS
469.2307; calcd for C24H34N2O6Na [M þ Na]þ 469.2315.
Benzyl (3-((3aR,4S,7R,7aS)-4-(2-(Dimethylamino)-
2-oxoethyl)-7-(methoxymethoxy)-2,2-dimethyl-
3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)
carbamate (16)
Benzyl (3-((3aR,4S,7aR)-4-(2-(Dimethylamino)-
2-oxoethyl)-2,2-dimethyl-7-oxo-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)
carbamate (18)
A magnetically stirred solution of compound 15 (1.86 g,
4.41 mmol,) in toluene (23 mL) was treated with DMADMA
(6.0 mL, 39.7 mmol, 9 mol equiv.) and the ensuing mixture
heated under reflux for 1 h before being cooled to 908C and the
reaction vessel vented for 0.5 h so as to allow the by-product
methanol to evaporate. The reaction mixture was then heated
again under reflux for 1 h, cooled to 908C and vented once more
for 0.5 h. Further DMADMA (3.0 mL, 19.9 mmol, 4.5 mol
equiv.) was added to the reaction mixture that was then heated
under reflux for 16 h. The cooled reaction mixture was concen-
trated under reduced pressure and the residue thus obtained
subjected to flash column chromatography (silica, 7 : 3 v/v ethyl
acetate/40–60 petroleum spirits elution) and so affording two
fractions, A and B.
A magnetically stirred solution of compound 17 (41 mg,
0.09 mmol) in CH2Cl2 (3 mL) maintained at 08C under a
nitrogen atmosphere was treated with DMP (98 mg, 0.23 mmol,
2.5 mol equiv.). The ensuing mixture was allowed to stir at 08C
for 0.1 h and then at 228C for 16 h before being quenched with
NaHCO3 (2 mL of a saturated aqueous solution) and the
separated aqueous layer extracted with ethyl acetate
(3 ꢂ 3 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue
thus obtained was subjected to flash column chromatography
(silica, ethyl acetate elution) and thus afforded, after concentra-
tion of the appropriate fractions (Rf 0.3), enone 18 (26 mg,
64 %), as a clear, colourless oil, [a]D ꢁ13.7 (c 0.9, CHCl3). dH
7.47–7.25 (complex m, 5H), 6.80 (d, J 10.4, 1H), 6.05 (d, J 10.4,
1H), 5.09 (s, 2H), 4.99 (br s, 1H), 4.48 (s, 2H), 3.20 (q, J 6.5, 2H),
2.97 (s, 3H), 2.90 (s, 3H), 2.58 (m, 2H), 1.81 (m, 1H), 1.63
(m, 3H), 1.36 (s, 3H), 1.32 (s, 3H). dC 196.0, 169.2, 156.5, 154.8,
136.7, 128.6, 128.2(3), 128.2(1), 126.4, 109.5, 78.7, 75.1, 66.7,
Concentration of fraction A (Rf 0.2 in 1 : 1 v/v ethyl acetate/
40–60 petroleum spirits) afforded allylic alcohol 15 (290 mg,
16 % recovery) as a clear, colourless oil that was identical, in all
respects, with an authentic sample.

F
M. Dlugosch and M. G. Banwell
41.4, 41.2, 40.4, 38.1, 35.7, 33.4, 27.3, 25.8, 23.8. nmax/cmꢁ1
3347, 2984, 2935, 1717, 1684, 1637, 1372, 1237, 1044, 698. m/z
(ESI, þve) 467 ([M þ Na)]þ, 100 %). HRMS 467.2159; calcd
for C24H32N2O6Na [M þ Na]þ 467.2158.
[4] F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
6771. doi:10.1021/JA9915201
[5] (a) S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama, Org. Lett.
2003, 5, 1891. doi:10.1021/OL034445E
(b) S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama, Tetrahedron
2003, 59, 8571. doi:10.1016/J.TET.2003.09.005
(c) J. M. Mej´ıa-Oneto, A. Padwa, Org. Lett. 2006, 8, 3275. doi:10.
1021/OL061137I
(d) J. P. Marino, G. Cao, Tetrahedron Lett. 2006, 47, 7711. doi:10.
1016/J.TETLET.2006.08.115
Benzyl (3-((3aR,4S,7aR)-4-(2-(Dimethylamino)-2-
oxoethyl)-6-iodo-2,2-dimethyl-7-oxo-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxol-4-yl)propyl)carbamate (8)
A magnetically stirred solution of compound 18 (72 mg,
0.16 mmol) in chloroform/pyridine (10 mL of a 1 : 1 v/v
mixture) was treated with molecular iodine (226 mg, 0.89 mmol,
5.5 mol equiv.) and the resulting mixture stirred at 228C for 16 h
and then quenched with Na2SO3 (10 mL of a saturated aqueous
solution) and the separated aqueous layer extracted with ethyl
acetate (3 ꢂ 10 mL). The combined organic phases were dried
(Na2SO4), filtered, and concentrated under reduced pressure and
the residue thus obtained subjected to flash column chromatog-
raphy (silica, ethyl acetate elution). Concentration of the appro-
priate fractions (Rf 0.5) afforded compound 8 (80 mg, 87 %) as a
clear, colourless oil, [a]D ꢁ75.6 (c 0.8, CHCl3). dH 7.49 (s, 1H),
7.42–7.27 (complex m, 5H), 5.10 (s, 2H), 4.96 (br s, 1H), 4.66 (d,
J 5.3, 1H), 4.51 (d, J 5.3, 1H), 3.21 (m, 2H), 2.98 (s, 3H), 2.89 (s,
3H), 2.56 (m, 2H), 1.88 (m, 1H), 1.77 (m, 1H), 1.63 (m, 2H),
1.36 (s, 3H), 1.29 (s, 3H). dC 189.8, 168.8, 162.4, 156.5, 136.7,
128.6, 128.2(0), 128.1(5), 109.7, 100.0, 78.9, 74.2, 66.7, 45.4,
41.2, 40.3, 38.0, 35.7, 33.4, 27.3, 25.7, 23.8. nmax/cmꢁ1 3348,
2985, 2934, 1697, 1633, 1522, 1454, 1238, 1078, 1044, 749. m/z
(ESI, þve) 593 ([M þ Na]þ, 100 %). HRMS 571.1301; calcd for
C24H32IN2O6 [M þ H]þ 571.1300.
(e) J. M. Mej´ıa-Oneto, A. Padwa, Helv. Chim. Acta 2008, 91, 285.
doi:10.1002/HLCA.200890034
(f) K. C. Nicolaou, S. M. Dalby, U. Majumder, J. Am. Chem. Soc. 2008,
130, 14942. doi:10.1021/JA806176W
(g) H. Satoh, H. Ueda, H. Tokuyama, Tetrahedron 2013, 69, 89.
doi:10.1016/J.TET.2012.10.060
(h) R. Yang, F. G. Qiu, Angew. Chem. Int. Ed. 2013, 52, 6015. doi:10.
1002/ANIE.201302442
[6] H. Ueda, H. Satoh, K. Matsumoto, K. Sugimoto, K. Sugimoto, T.
Fukuyama, H. Tokuyama, Angew. Chem. Int. Ed. 2009, 48, 7600.
doi:10.1002/ANIE.200902192
[7] K. C. Nicolaou, S. M. Dalby, S. Li, T. Suzuki, D. Y.-K. Chen, Angew.
Chem. Int. Ed. 2009, 48, 7616. doi:10.1002/ANIE.200904588
[8] For a summary of these syntheses of haplophytine see: E. Doris,
Angew. Chem. Int. Ed. 2009, 48, 7480. doi:10.1002/ANIE.
200903468
[9] H. Satoh, K. Ojima, H. Ueda, H. Tokuyama, Angew. Chem. Int. Ed.
2016, 55, 15157. doi:10.1002/ANIE.201609285
[10] L. V. White, M. G. Banwell, J. Org. Chem. 2016, 81, 1617. doi:10.
1021/ACS.JOC.5B02788
[11] M. G. Banwell, D. W. Lupton, A. C. Willis, Aust. J. Chem. 2005, 58,
722. doi:10.1071/CH05181
[12] S. H. Tan, M. G. Banwell, A. C. Willis, T. A. Reekie, Org. Lett. 2012,
14, 5621. doi:10.1021/OL3026846
[13] For some useful points of entry into the literature on cis-1,2-dihydro-
catechols see: (a) T. Hudlicky, J. W. Reed, Chem. Soc. Rev. 2009, 38,
3117. doi:10.1039/B901172M
Supplementary Material
1H and 13C NMR spectra for compounds 10–18 and 8 are
available on the Journal’s website.
(b) M. A. Vila, D. Umpie´rrez, N. Veiga, G. Seoane, I. Carrera,
S. Rodr´ıguez Giodano, Adv. Synth. Catal. 2017, 359, 2149.
doi:10.1002/ADSC.201700444
Conflicts of Interest
The authors declare no conflicts of interest.
(c) E. S. Taher, M. G. Banwell, J. N. Buckler, Q. Yan, P. Lan, Chem.
Rec. 2018, 18, 239. doi:10.1002/TCR.201700064
Acknowledgements
[14] F. Khan, M. Dlugosch, X. Liu, M. G. Banwell, Acc. Chem. Res.,
in press. doi:10.1021/ACS.ACCOUNTS.8B00169
[15] (a) M. G. Banwell, M. T. Jones, T. A. Reekie, B. D. Schwartz, S. H.
Tan, L. V. White, Org. Biomol. Chem. 2014, 12, 7433. doi:10.1039/
C4OB00917G
The authors thank the Australian Research Council and the Institute of
Advanced Studies for financial support. Dr Lorenzo White (ANU) is thanked
for stimulating discussions and suggestions.
(b) F. Tang, M. G. Banwell, R. Cobalt, in Encyclopedia of Reagents for
Organic Synthesis [Online (eEROS)] (Eds P. L. Fuchs, A. B. Charette,
T. Rovis, J. W. Bode) 2018 (John Wiley & Sons Ltd: Chichester, UK),
in press.
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