Chemoenzymatic approaches to the montanine alkaloids: a total synthesis of (+)-nangustine

Article abstract of DOI:10.1016/j.tet.2008.04.070

The synthesis of (+)-nangustine [(+)-2] has been achieved, for the first time, using the enantiomerically pure cis-1,2-dihydrocatechol 3 as starting material. The latter compound is available, in multi-gram quantities, through a whole-cell-mediated biotransformation of chlorobenzene using genetically engineered organisms that over-express the responsible enzyme, namely toluene dioxygenase. Since the enantiomer of compound 3 is available by related means, the present work also represents a formal total synthesis of the montanine alkaloid (-)-nangustine [(-)-2]. Single-crystal X-ray analyses of compounds 13 and (+)-2 are reported.

Full text of DOI:10.1016/j.tet.2008.04.070

Tetrahedron 64 (2008) 6444–6451
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoenzymatic approaches to the montanine alkaloids: a total synthesis
of (þ)-nangustine
Okanya J. Kokas, Martin G. Banwell , Anthony C. Willis
*
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of (þ)-nangustine [(þ)-2] has been achieved, for the first time, using the enantiomerically
pure cis-1,2-dihydrocatechol 3 as starting material. The latter compound is available, in multi-gram
quantities, through a whole-cell-mediated biotransformation of chlorobenzene using genetically en-
gineered organisms that over-express the responsible enzyme, namely toluene dioxygenase. Since the
enantiomer of compound 3 is available by related means, the present work also represents a formal total
synthesis of the montanine alkaloid (ꢀ)-nangustine [(ꢀ)-2]. Single-crystal X-ray analyses of compounds
13 and (þ)-2 are reported.
Received 30 January 2008
Received in revised form 31 March 2008
Accepted 17 April 2008
Available online 22 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
OH
1. Introduction
OH
OH
OH
1
2
3
11a
4
(ꢀ)-Brunsvigine [(ꢀ)-1]1–3 is a representative member of the
montanine class of Amaryllidaceae alkaloid, a small group of
natural products characterised by the presence of a 5,11-meth-
anomorphanthridinone framework.4 These compounds, which
normally incorporate hydroxy and/or methoxy groups at C2 and C3
11
12
10
H
H
N
N
6
O
O
7
O
O
(–)-2
(in varying configurations) as well as a
D
1(11a)-double bond, have
(–)-1
been isolated from a variety of plant sources. The isolation of
(þ)-montabuphine from the Amaryllidaceae species Boophane flava
found in Southern Africa suggests that both enantiomeric forms of
the framework can be encountered within this class of natural
product.5 A modest number of biological properties have been at-
tributed to such alkaloids including anxiolytic, antidepressive, an-
ticonvulsive and (weak) hypotensive activities.5,6 As a result,
various efforts have been made to develop syntheses of these
compounds with notable successes having been reported by
Overman,7 Pearson,8 Weinreb,9 Sha10 and Hoshino.11 Our own
contributions to the area have involved the development of a for-
mal total synthesis of the racemic modification of pancracine (an-
other member of the montanine alkaloid family)12 and a total
synthesis of (þ)-brunsvigine [(þ)-1].13 Each of these involved
the same end-game as originally established by Overman,7 namely
the preparation of the relevant 3a-arylhexahydroindole and the
subjection of such species to a Pictet–Spengler reaction so as to
introduce C6 and thus complete the assembly of the required
5,11-methanomorphanthridinone framework.
2
OH
1
3
E
4
H
OH
D
N
Cl
OH
C
B
O
OH
A
O
(+)-2
3
The montanine alkaloid nangustine [(ꢀ)-2]14 is the most re-
cently characterised member of the class. It was isolated from the
bulbs of Narcissus angustifolius subsp. transcarpathicus collected in
Ukraine and has been assigned the illustrated structure on the basis
of extensive NMR analytical studies. Significantly, this compound
differs from its congeners in that it possesses a C3,C4- rather than
a C2,C3-dioxygenation pattern in the E-ring. Furthermore, the
compound has been shown14 to possess modest but selective ac-
tivity (IC50 0.7–7.1 mg/mL) against Trypanosoma brucei rhodesiense,
Trypanosoma cruzi and Plasmodium falciparum. In contrast, co-oc-
curring pancracine, which incorporates the more conventional
C2,C3-dioxygenation pattern, is essentially inactive against the first
two of these same parasitic species. On this basis we have sought to
adapt our recently reported13 synthesis of (þ)-brunsvigine to the
* Corresponding author. Tel.: þ61 2 6125 8202; fax: þ61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M.G. Banwell).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.070

O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
6445
preparation of (þ)-nangustine [(þ)-2]. If successful, such endeav-
ours should serve to confirm the structure assigned to this most
unusual member of the montanine alkaloid family. Details of our
studies of this matter are reported herein. The reaction sequence
used exploits the enantiomerically pure cis-1,2-dihydrocatechol 3
as starting material.15 This compound is available, in multi-gram
quantities, through a whole-cell-mediated biotransformation of
chlorobenzene using genetically engineered organisms that over-
express toluene dioxygenase.16
and the PMB unit within the resulting tris-ether 7 (86%) was se-
lectively cleaved with DDQ to give the allylic alcohol 8 in 81% yield.
This last compound was converted into the corresponding mesylate
9 (100%) using modifications of the Crossland and Servis20 pro-
cedure and this ester was then engaged in an SN2 reaction with
sodium azide in DMF. By such means the allylic azide 10 was
obtained in 90% yield. The Staudinger reduction21 of compound 10
was best carried out using polymer-supported triphenylphosphine
in aqueous THF because of the ease of separation of the co-pro-
duced, and polymer-bound, phosphine oxide from the desired
amine 11 (84%). Following protocols established during our syn-
thesis of (þ)-brunsvigine, compound 11 was subjected to reductive
amination using p-methoxybenzaldehyde (p-MBA) as electrophile
and sodium triacetoxyborohydride as the reducing agent. By such
means the secondary amine 12 was obtained in 63% yield. In con-
trast, if DIBAL-H was used to reduce the intermediate imine then
this process was accompanied by cleavage of one or other of the
associated MOM-ethers such that a chromatographically separable
and 2:5 mixture of compounds 13 and 14 was obtained.
2. Results and discussion
2.1. Part 1: assembly of the 4-deoxyaminoconduritol core
Following the strategy employed in our recently reported13
synthesis of (þ)-brunsvigine, the early stages of our approach to the
title compound involved assembling the 4-deoxyaminoconduritol
residue corresponding to the E-ring of the target. The route by
which this was achieved is outlined in Scheme 1 and started with
the readily available PMP-acetal 4 of the cis-1,2-dihydrocatechol 3.
Epoxidation of the acetal 417 using m-chloroperbenzoic acid (m-
CPBA) proceeded in both a regio- and diastereo-selective manner to
give epoxide 5 (75% from 3). In a critical step of the reaction se-
quence, compound 5 was exposed to ca. seven molar equivalents of
DIBAL-H and so resulting in reductive cleavage of both the epoxide
and acetal residues within the substrate and thus delivering the
mono-protected triol 6 (42%) as the only characterisable product of
the reaction. The structure of this compound follows from the
single-crystal X-ray analysis of a derivative (vide infra). The seem-
ingly selective formation of 4-deoxyconduritol 6 by this means is
presumably driven by two factors, namely the preferential cleavage
of the allylic C–O bond of the epoxide ring18 and that benzylic C–O
bond of the PMP-acetal remote from the sterically demanding
chlorine.19
OMOM
OH
OH
Cl
Cl
OMOM
NHPMB
NHPMB
13
14
The former product was a solid material that was subjected to
a single-crystal X-ray analysis. The derived ORTEP plot is shown in
Figure 1 and served to confirm the structures assigned to these
compounds and their precursors.
2.2. Part 2: the end-gamedcoupling of the aromatic
and aminocyclitol cores of (D)-nangustine
The two free hydroxy groups within diol 6 were protected as the
corresponding MOM-ethers using MOM-Cl in the presence of base
Compound 12 embodies the E-ring of (þ)-nangustine so its an-
nulation with the ABCD-substructure of the target molecule was
pursued using the same sorts of protocols as employed in our re-
cently reported synthesis of (þ)-brunsvigine.13 Thus, as shown in
Scheme 2, the racemic modification of the known and readily
availableacid1522 wasconverted, usingstandardconditions, intothe
O
DIBAL-H,
toluene
42%
OH
OH
m-CPBA
75%
Cl
Cl
Cl
O
O
(from 3)
O
OPMB
O
C8
PMP
PMP
O2
C7
4
5
6
MOM-Cl,
NaH, Et3N
C6
86%
O1
C1
C2
C5
C4
OMOM
OMOM
OMOM
OMOM
DDQ
81%
O3
Cl1
C3
N1
Cl
Cl
OR
OPMB
8 R=H
MsCl, Et3N
quant.
7
9 R=Ms
C9
C10
C15
C14
OMOM
OMOM
NaN3, DMF
90%
C11
C12
Cl
C13
X
10 X=N3
11 X=NH2
12 X=NHPMB
Ph3P
84%
p-MBA,
O4
C16
NaBH(OAc)3
63%
Scheme 1.
Figure 1. ORTEP plot derived from the single-crystal X-ray analysis of compound 13.

6446
O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
OMOM
C1
C5
SOCl2,
then 12
Cl
O
OMOM
PMB
SPh
O13
O11
C2
C3
O
OH
C15
C16
C19
N
and NaOH
C14
C10
C17
O
O
78%
O20
SPh
O
O
C12
C18
C4
15
16
N6
C8
C9
Bu6Sn2, Bu3SnH, AIBN 88%
O
C7
O21
OMOM
OMOM
LiAlH4, AlCl3
Figure 2. ORTEP plot derived from the single-crystal X-ray analysis of compound
(þ)-2.
O
98%
H
N
origins of the lower intensities of the fragment ions observed in the
spectrum of the synthetic material remain unclear at the present
time but such variations between these types of data sets are not
uncommon. An accurate mass measurement on the molecular ion
observed in the electron impact-induced mass spectrum of the
synthetic material established that it was of the expected molecular
composition, viz. C16H17NO4.
PMB
O
O
OMOM
OMOM
17
O
HCl, H2O
H
N
X
18 X=PMB
19 X=COCl
The 1H and 13C NMR spectral data derived from (þ)-nangustine
(ent-2) proved essentially identical with those recorded for the
natural product14 (Table 2). Furthermore, the specific rotation of
triphosgene
76%
O
O
OMOM
OMOM
(H2CO)n, HCO2H
(+)-2
Table 1
H
40%
N
Comparison of the 70 eV electron impact-induced mass spectral fragmentation
patterns for naturally occurring (ꢀ)-nangustine [(ꢀ)-2] and synthetically-derived
(þ)-nangustine [(þ)-2]
(from 19)
H
20
Scheme 2.
Synthetically-derived (þ)-2a
Naturally occurring (ꢀ)-2b,c
m/z
% of base peak
m/z
% of base peak
corresponding acidchloride andthis was thenreacted withamine 12
under Schotten–Baumann conditions so as to produce the amide 16,
ꢁ
ꢁ
287 (Mþ
270
241
226
223
215
214
212
199
197
186
185
173
154
141
129
128
127
116
115
103
102
91
89
83
77
76
73
72
69
65
64
63
60
57
55
53
51
)
100
6
5
287 (Mþ
270
243
226
223
215
214
212
199
197
186
185
173
154
141
129
128
127
116
115
103
102
91
89
83
77
76
73
71
69
65
64
63
60
57
55
53
51
)
100
7
1
as a ca.1:1 mixture of diastereoisomers, in 78% yield. The 1H and 13
C
NMR spectra of this mixture proved to be exceptionally complex and
rather uninformative due to the presence of amide rotamers. Nev-
ertheless, subjecting this material to reaction with a combination of
hexa-n-butylditin and tri-n-butyltin hydride resulted in the expec-
ted radical addition/elimination reaction13,23 to form, in 88% yield
and as a single diastereoisomer, the lactam 17 containing what will
8
19
22
22
16
22
35
24
20
87
19
20
43
29
50
30
19
72
19
20
31
32
22
62
32
19
26
24
32
21
40
27
48
60
30
46
10
14
8
10
17
6
8
29
5
3
9
5
9
5
4
12
2
2
3
3
1
7
2
1
3
2
3
2
3
2
2
5
2
2
become the
D
1(11a)-doublebond of (þ)-nangustine. Theorigins of the
pleasing diastereoselectivity associated with the conversion 16/17
are the subject of ongoing mechanistic and theoretical studies, the
results of which will be reported in due course.
In anticipation of carrying out a Pictet–Spengler reaction to es-
tablish the C-ring of target (þ)-2, compound 17 was reduced to the
corresponding amine 18 (98%) using in situ generated AlH3. Re-
action of the latter compound with triphosgene24 in CH2Cl2 resul-
ted in cleavage of the PMB-residue within this substrate and
formation of the carbamoyl chloride 19 that was obtained in 76%
yield after chromatographic purification. Acid-catalysed hydrolysis
of compound 19 resulted in the formation of the secondary amine
20 that was immediately subjected to a Pictet–Spengler reaction
using a mixture of paraformaldehyde and formic acid. Since this
process appeared to produce a mixture of the two mono-formate
ester derivatives of (þ)-nangustine [(þ)-2] the crude material
obtained on workup was saponified using aqueous potassium hy-
droxide. The solid material thus produced was then recrystallised
from n-propanol/hexane to give compound (þ)-2 (40% from 19),
the structure of which follows from a single-crystal X-ray analysis.
The derived ORTEP plot is shown in Figure 2.
The MS, NMR and IR spectral data obtained on compound (þ)-2
were fully consistent with the assigned structure and in excellent
agreement with those reported for the natural product (ꢀ)-2.14 For
example, the electron impact-induced mass spectral fragmentation
patterns of the two materials were very similar (Table 1). The
a
Data recorded at 70 eV.
Data derived from Ref. 14.
Data recorded at 70 eV.
b
c

O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
6447
Table 2
Comparison of the 1H and 13C NMR data recorded for naturally occurring (ꢀ)-nangustine [(ꢀ)-2] and synthetically-derived (þ)-nangustine [(þ)-2]
13C NMR (dC
)
1H NMR (dH
)
(ꢀ)-2a
(þ)-2b
(ꢀ)-2c
(þ)-2d
148.3
147.6
147.5
133.6
125.2
114.7
108.3
107.8
102.1
75.5
148.2
147.8
147.6
133.7
125.4
114.5
108.3
107.7
102.1
75.6
6.56 (s, 1H)
6.51 (s, 1H)
6.55 (s, 1H)
6.50 (s, 1H)
5.86 (d, J¼1.5 Hz, 1H)
5.85 (d, J¼1.2 Hz, 1H)
5.84 (d, J¼1.2 Hz, 1H)
5.50 (q, J¼3.0 Hz, 1H)
4.29 (d, J¼16.2 Hz, 1H)
3.80 (d, J¼16.2 Hz, 1H)
3.61 (m, 1H)
5.85 (d, J¼1.5 Hz, 1H)
5.52 (dt, J¼3.5 and 2.5 Hz, 1H)
4.32 (d, J¼16.5 Hz, 1H)
3.83 (d, J¼16.5 Hz, 1H)
3.62 (ddd, J¼9.0, 9.0 and 7.0 Hz, 1H)
3.33 (br d, J¼2.5 Hz, 1H) and 3.31 (t, J¼9.0 Hz, 1H)
3.16 (br d, J¼9.0 Hz, 1H)
3.30 (br s, 2H) partially obscured by signals due to CD3OD
3.12 (br d, J¼9.6 Hz, 1H)
72.3
70.0
62.0
56.9
72.3
69.9
62.1
56.9
3.03 (d, J¼11.0 Hz, 1H)
3.00 (d, J¼11.4 Hz, 1H)
2.94 (dd, J¼11.0 and 2.0 Hz, 1H)
2.57 (dddd, J¼18.0, 7.0, 3.5 and 2.0 Hz, 1H)
2.05 (ddt, J¼18.0, 9.0 and 3.5 Hz, 1H)
Signals due to OHs not observed
2.91 (dd, J¼10.8 and 2.4 Hz, 1H)
2.56 (dddd, J¼18.0, 6.9, 3.6 and 1.8 Hz, 1H)
2.04 (m, 1H)
46.4
46.5
Signals due to OHs not observed
35.5
35.5
a
Data from Ref. 14 (recorded in CD3OD at 50 MHz).
Data from work reported in this paper (recorded in CD3OD at 150 MHz).
Data from Ref. 14 (recorded in CD3OD at 600 MHz).
b
c
d
Data from work reported in this paper (recorded in CD3OD at 600 MHz).
(þ)-nangustine {[
a
]
þ80.4 (c 0.44, methanol)} was of similar
oils). A VG Fisons AutoSpec mass spectrometer was used to obtain
low- and high-resolution electron impact (EI) mass spectra. Low-
and high-resolution electrospray (ESI) mass spectra were obtained
on a VG Quattro II triple-quadrupole MS instrument operating in
positive ionisation mode. Optical rotations were measured at 18 ꢂC
with a Perkin–Elmer 241 polarimeter at the sodium-D line (589 nm)
and the concentrations (c) (g/100 mL) indicated using spectroscopic
grade solvents. The measurements were carried out in a cell with a
D
magnitude but opposite sign to that reported14 for the naturally
occurring or (ꢀ)-enantiomer {[ D ꢀ69.6 (c 0.35, methanol)}.
a
]
3. Summary and conclusions
The work presented herein serves to confirm that the structure of
the novel montanine alkaloid (ꢀ)-nangustine has been correctly
assigned. Furthermore, since the enantiomeric form, ent-3, of the
cis-1,2-dihydrocatechol used as the starting material in this syn-
thesis is also available,25 the work described herein constitutes
a formal total synthesis of the naturally occurring (ꢀ)-form of nan-
gustine. It is also worth noting that the results of the present study,
when considered alongside our related earlier work,13,16b,17–19
highlight the considerable utility of microbially-derived cis-1,
2-dihydrocatechols such as 3 in the construction of a range of
alkaloids and/or their analogues, including those of the montanine-
type. Current efforts in our laboratories are directed towards the
total synthesis and biological evaluation of various other members
of this rather interesting class of alkaloid.
path length (l) of 1 dm. Specific rotations [a]D were calculated using
the equation [
a
]D¼100 a/(c l) and are given in 10ꢀ1 deg cm2 gꢀ1
.
Melting points were measured on an Optimelt automated melting
point system or a Reichert hot-stage microscope apparatus and are
uncorrected. Analytical thin layer chromatography (TLC) was per-
formed on aluminium-backed 0.2 mm thick silica gel 60 F254 plates
as supplied by Merck. Eluted plates were visualised 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 (concd)/water (37.5 g:7.5 g:37.5 g:720 mL) or potas-
sium permanganate/potassium carbonate/5% sodium hydroxide
aqueous solution/water (3 g:20 g:5 mL:300 mL). The retardation
factor (Rf) values cited here have been rounded at the first decimal
point. Flash chromatographic separations were carried out
following protocols defined by Still et al.26 with silica gel 60 (0.040–
0.0063 mm) 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. Tetrahydrofuran (THF) and diethyl
ether (ether) were distilled from sodium benzophenone ketyl.
Methanol was distilled from its magnesium alkoxide salt. Benzene
and toluene were distilled from sodium wire. Dichloromethane was
distilled from calcium hydride. Triethylamine was distilled from and
stored over potassium hydroxide pellets. Where necessary,
reactions were performed under a nitrogen or argon atmosphere.
4. Experimental section
4.1. General experimental procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded at 18 ꢂC in base-filtered CDCl3 on a Varian
Mercury or Inova 300 spectrometeroperating at 300 MHz for proton
and 75 MHz for carbon nuclei. In certain cases, a Varian Inova 600
spectrometer, operating at 600 MHz for proton and 150 MHz for
carbon nuclei, was used. For 1H NMR spectra, signals arising from
the residual protio-forms of the solvent were used as the internal
standards. 1H NMR data are recorded as follows: chemical shift (
d)
[multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s¼singlet; d¼doublet; t¼triplet;
q¼quartet; m¼multiplet or combinations of the above. The residual
CHCl3 peak (
MeOH peak (
central peak (
d
7.26), residual DMSO peak (
d
2.50) and the residual
4.2. Specific procedures
d
3.30) were used as references for 1H NMR spectra. The
77.0) of the CDCl3 ‘triplet’ and the central peak (
d
d
4.2.1. (2S,3aS,5aR,6aR,6bS)-4-Chloro-3a,5a,6a,6b-tetrahydro-
2-(4-methoxyphenyl)-7-oxabicyclo[4.1.0]hepta-1(6),2-dieno[5,
4-d][1,3]dioxole (5)
A magnetically stirred suspension of cis-1,2-dihydrocatechol 3
(10.0 g, 68.3 mmol) and p-methoxybenzaldehyde dimethyl acetal
49.3) of the CD3OD ‘heptet’ were used as references for proton-
decoupled 13C NMR spectra. Infrared spectra (nmax) were recorded
on a Perkin–Elmer 1800 Series FTIR Spectrometer. Samples were
analysed as KBr disks (for solids) or as thin films on NaCl plates (for

6448
O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
(p-BDMA) (12.8 mL, 75.1 mmol) in anhydrous CH2Cl2 (150 mL) was
cooled to ꢀ20 ꢂC then treated with (1S)-(þ)-camphor-10-sulfonic
acid monohydrate (CSA$H2O) (1.58 g, 6.82 mmol). After 1 h, at
which point TLC analysis indicated that all of the starting material
had been consumed, the reaction mixture was quenched with
sodium hydroxide (200 mL of a 2 M aqueous solution) and the
separated aqueous phase was extracted with CH2Cl2 (2ꢃ200 mL).
The combined organic fractions were then washed with brine
(1ꢃ100 mL) before being dried (MgSO4) and filtered to give a clear
and transparent solution that was cooled to 0 ꢂC, treated with m-
CPBA (30.6 g, 136.5 mmol) then stirred at 0–18 ꢂC for 18 h. The en-
suing mixture was treated with sodium metabisulfite (300 mL of
a 20% w/v aqueous solution) and the separated aqueous fractionwas
extracted with CH2Cl2 (2ꢃ100 mL). The combined organic fractions
were washed with NaHCO3 (1ꢃ200 mL of a saturated aqueous so-
lution) and brine (1ꢃ200 mL) before being dried (MgSO4), filtered
and concentrated under reduced pressure to give an oily residue.
Subjection of this material to flash chromatography (silica, 1:9 v/v
ethyl acetate/hexane elution) and concentration of appropriate
fractions (Rf¼0.5; silica, 3:7 v/v ethyl acetate/hexane elution)
afforded the title compound 5 (14.2 g, 75%) as a white, crystalline
18 ꢂC, with sodium hydride (60 mg of a 60% w/w mixture with
paraffin oil, 1.40 mmol) then triethylamine (194 mL, 1.47 mmol).
The ensuing mixture was heated to 65 ꢂC then, after 10 min at this
temperature, cooled to 0 ꢂC and methoxymethyl chloride (MOM-
Cl) (106 mL, 1.40 mmol) was added dropwise. After the addition
was complete, the reaction mixture was re-warmed to 18 ꢂC then
kept at this temperature for 0.5 h. This protocol was repeated once
more and the resulting mixture then quenched with water (25 mL)
[Caution: exothermic reaction]. The separated aqueous phase was
extracted with ethyl acetate (2ꢃ30 mL) and the combined organic
fractions were then dried (MgSO4), filtered and concentrated un-
der reduced pressure to give a yellow residue. This material was
subjected, once more, to the reaction conditions outlined above
and, after workup in the usual fashion, a yellow residue was
obtained. Subjection of this material to flash chromatography
(silica, hexane/2:3 v/v ethyl acetate/hexane gradient elution) and
concentration of appropriate fractions (Rf¼0.3; silica, 2:3 v/v ethyl
acetate/hexane elution) under reduced pressure afforded the title
compound 7 (214 mg, 86%) as clear, light-yellow oil, [
a
]
ꢀ64.8 (c
D
35
1.02, CHCl3). [Found: (MþNa)þ, 395.1235. C18
H ClO6 requires
25
(MþNa)þ, 395.1237]. 1H NMR (300 MHz, CDCl3) dH 7.35 (2H, d,
J¼8.6 Hz), 6.86 (2H, d, J¼8.6 Hz), 5.79 (1H, m), 4.91–4.62 (6H,
complex m), 4.18–4.02 (2H, complex m), 3.87 (1H, m), 3.78 (3H, s),
3.40 (3H, s), 3.34 (3H, s), 2.64 (1H, dm, J¼18.0 Hz), 2.14 (1H, dm,
J¼18.0 Hz); 13C NMR (75 MHz, CDCl3) dC 159.1, 130.3, 129.8, 129.6,
125.3, 113.5, 96.7, 96.6, 77.6, 77.4, 74.1, 72.1, 55.6, 55.3, 55.1, 32.0;
nmax (NaCl) 2933, 2894, 1612, 1514, 1465, 1441, 1302, 1249, 1151,
1118, 1038, 917, 824 cmꢀ1; m/z (ESI) 397 and 395 [(MþNa)þ, 14 and
39%], 241 (4), 121 (100).
solid, mp¼67–69 ꢂC. [Found: (MþH)þ, 281.0590; C, 60.31; H, 4.69.
35
C
H
ClO4 requires (MþH)þ, 281.0581; C, 59.90; H, 4.67%]. 1H NMR
14 13
(300 MHz, CDCl3) dH 7.39 (2H, d, J¼8.9 Hz), 6.91 (2H, d, J¼8.9 Hz),
6.28 (1H, dd, J¼4.2 and 0.9 Hz), 5.96 (1H, s), 4.93 (1H, m), 4.47 (1H,
dd, J¼7.5 and 0.3 Hz), 3.81 (3H, s), 3.64 (1H, m), 3.41 (1H, m); 13C
NMR (75 MHz, CDCl3) dC 160.7,136.7,128.3,128.0,122.6,113.8,105.4,
73.8, 72.9, 55.2, 48.9, 47.7; nmax (NaCl) 3005, 2906, 2838, 1648, 1614,
1589, 1518, 1463, 1437, 1399, 1360, 1304, 1251, 1172, 1082, 1031, 989,
829 cmꢀ1; m/z (ESI) 283 and 281 [(MþH)þ, both <1%], 147 and 145
(4 and 13), 137 (57), 109 (100), 81 (25).
4.2.4. (1S,5R,6R)-2-Chloro-5,6-bis(methoxymethoxy)cyclohex-2-
enol (8)
4.2.2. (1R,2S,3S)-3-(4-Methoxybenzyloxy)-4-chlorocyclohex-
4-ene-1,2-diol (6)
A magnetically stirred solution of PMB ether 7 (190 mg,
0.51 mmol) in CH2Cl2/water (50 mL of a 3:1 v/v mixture) main-
tained at 18 ꢂC was treated with DDQ (162 mg, 0.71 mmol) and
after 18 h, at which point TLC analysis indicated that all of the
starting material had been consumed, the reaction mixture was
treated with water (40 mL) and extracted with CH2Cl2 (3ꢃ40 mL).
The combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure to give an orange oil.
Subjection of this material to flash chromatography (silica, hex-
ane/3:7 v/v ethyl acetate/hexane gradient elution) and con-
centration of the appropriate fractions (Rf¼0.3; silica, 2:3 v/v
ethyl acetate/hexane elution) afforded the title alcohol 8 (104 mg,
A magnetically stirred solution of epoxide 5 (14.2 g, 50.6 mmol)
in anhydrous toluene (300 mL) was cooled to ꢀ60 ꢂC then treated
with DIBAL-H (350 mL of a 1 M solution in toluene, 350 mmol). The
ensuing solution was allowed to warm to ꢀ30 ꢂC and after 7 h, at
which point TLC analysis indicated that all the starting material had
been consumed, the reaction mixture was quenched with sodium
potassium tartrate (200 mL of a saturated aqueous solution) [Cau-
tion: exothermic reaction] and the ensuing mixture was then
allowed to warm to 18 ꢂC over a period of 10 h. The separated
aqueous fraction was extracted with toluene (3ꢃ200 mL) and the
combined organic fractions were then dried (MgSO4), filtered and
concentrated under reduced pressure to give a clear, colourless oil.
Subjection of this material to flash chromatography (silica, hex-
ane/3:2 v/v ethyl acetate/hexane gradient elution) and concen-
tration of appropriate fractions (Rf¼0.4; silica, 3:2 v/v ethyl acetate/
81%) as a clear, colourless oil, [
a
]
ꢀ15.9 (c 0.98, CHCl3). [Found:
D
ꢁ
ꢁ
35
(MꢀH2O)þ , 234.0664. C10
H
17
ClO5 requires (MꢀH2O)þ , 234.0659].
1H NMR (300 MHz, CDCl3) dH 5.81 (1H, m), 4.84–4.64 (4H, com-
plex m), 4.32 (1H, m), 4.00 (1H, m), 3.82 (1H, m), 3.40 (3H, s),
3.34 (3H, s), 2.99 (1H, br s), 2.58 (1H, dm, J¼18.3 Hz), 2.15 (1H,
dm, J¼18.3 Hz); 13C NMR (75 MHz, CDCl3) dC 130.7, 124.9, 97.1,
96.4, 78.3, 71.4, 70.1, 55.8, 55.4, 31.1; nmax (NaCl) 3450, 2930,
2897, 1654, 1441, 1215, 1151, 1111, 1038, 988, 917 cmꢀ1; m/z (EI,
hexane elution) afforded the title compound 6 (6.1 g, 42%) as a clear,
ꢁ
colourless oil, [
a
]
D
ꢀ56.3 (c 2.4, CHCl3). [Found: Mþ , 284.0815.
ꢁ
35
C
H
14 17
ClO4 requires Mþ , 284.0815]. 1H NMR (300 MHz, CDCl3) dH
ꢁ
7.23 (2H, d, J¼8.6 Hz), 6.83 (2H, d, J¼8.6 Hz), 5.81 (1H, m), 4.89 (1H,
d, J¼11 Hz), 4.59 (1H, d, J¼11 Hz), 4.04 (1H, d, J¼4.8 Hz), 3.78–3.71
(1H, obscured m), 3.74 (3H, s), 3.49 (1H, m), 2.56 (2H, partially
obscured m), 2.51 (1H, partially obscured m), 1.99 (1H, m); 13C NMR
(75 MHz, CDCl3) dC 159.5, 129.9, 129.6, 126.6, 113.9, 78.6, 75.0, 73.7,
66.7, 55.2, 32.4 (one signal obscured or overlapping); nmax (NaCl)
3401, 2909, 1612, 1514, 1464, 1440, 1341, 1302, 1249, 1174, 1102,
70 eV) 236 and 234 [(MꢀH2O)þ , <1 and 2%], 221 (5), 207 (10),
190 (35), 175 (29), 161 (33), 148 (100), 145 (43), 129 (40), 119 (43),
101 (35), 95 (20), 89 (13), 81 (16), 72 (35), 65 (30), 53 (28), 45
(91), 39 (23).
4.2.5. (1S,5R,6S)-2-Chloro-5,6-bis(methoxymethoxy)cyclohex-2-
enyl methanesulfonate (9)
ꢁ
1034, 823 cmꢀ1; m/z (EI, 70 eV) 286 and 284 (Mþ , 2 and 8%), 137
A magnetically stirred solution of alcohol 8 (4.0 g, 15.9 mmol),
triethylamine (5.5 mL, 39.7 mmol) and DMAP (194 mg, 1.58 mmol)
in anhydrous CH2Cl2 (160 mL) was cooled to 0 ꢂC then treated,
dropwise, with methanesulfonyl chloride (MsCl) (3.1 mL,
39.7 mmol). After 3 h, at which point TLC analysis indicated that all
starting material had been consumed, the reaction mixture was
warmed to 18 ꢂC then treated with NaHCO3 (300 mL of a saturated
(21), 121 (100), 109 (7), 78 (8), 77 (8), 65 (5).
4.2.3. 1-{[(1S,5R,6S)-2-Chloro-5,6-bis(methoxymethoxy)cyclohex-
2-enyloxy]methyl}-4-methoxybenzene (7)
A magnetically stirred solution of diol 6 (190 mg, 0.67 mmol) in
anhydrous THF (40 mL) was treated, whilst being maintained at

O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
6449
aqueous solution) and the resulting mixture was extracted with
CH2Cl2 (2ꢃ100 mL). The combined organic fractions were dried
(MgSO4), filtered and concentrated under reduced pressure to give
the crude title compound 9 as viscous, yellow oil (Rf¼0.4; silica, 2:3
(100 mL) maintained at 18 ꢂC was treated with activated molecular
sieves 4 Å (w2 g) and the ensuing mixture heated at 120 ꢂC in an
apparatus fitted with a Dean–Stark trap. After 34 h, at which point
TLC analysis indicated that all the starting material had been con-
sumed, the reaction mixture was cooled to 18 ꢂC, filtered through
a pad of CeliteÒ and the resulting filtrate concentrated under re-
duced pressure to give a yellow oil containing the imine derivative
of compound 11. A magnetically stirred solution of this material in
anhydrous CH2Cl2 (20 mL) was cooled to 0 ꢂC then treated with
NaBH(OAc)3 (930 mg, 4.92 mmol) and the ensuing mixture allowed
to warm to 18 ꢂC. After 20 h at this temperature the reaction mix-
ture was treated with water (20 mL) and sodium hydroxide (20 mL
of a 2 M aqueous solution) then stirred for 5 min at 18 ꢂC. The
separated aqueous phase was extracted with CH2Cl2 (3ꢃ20 mL) and
the combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure to give a yellow oil. Sub-
jection of this material to flash chromatography (silica, hexane/
2:3 v/v ethyl acetate/hexane gradient elution) and concentration of
appropriate fractions (Rf¼0.8; silica, 2:3 v/v ethyl acetate/hexane
elution) afforded the title compound 12 (578 mg, 63%) as a viscous,
v/v ethyl acetate/hexane elution). [Found: (MþNa)þ, 353.0489.
35
C
H
11 19
ClO7S requires (MþNa)þ, 353.0438]. 1H NMR (300 MHz,
CDCl3) dH 5.97 (1H, m), 5.21 (1H, d, J¼3.0 Hz), 4.75–4.60 (4H,
complex m), 3.93 (2H, m), 3.38 (3H, s), 3.31 (3H, s), 3.11 (3H, s), 2.65
(1H, dm, J¼18.6 Hz), 2.17 (1H, dm, J¼18.6 Hz); m/z (ESI) 355 and 353
[(MþNa)þ, <1 and 1%], 257 (4), 123 (99), 102 (100), 74 (47).
This rather unstable material was used, without purification, in
the next step of the reaction sequence.
4.2.6. (4R,5R,6R)-6-Azido-1-chloro-4,5-bis(methoxymethoxy)-
cyclohex-1-ene (10)
A magnetically stirred solution of mesylate 9 in anhydrous DMF
(200 mL) was kept at 18 ꢂC then treated with sodium azide (3.1 g,
47.6 mmol). After 15 h, at which point TLC analysis indicated that
staring material had been consumed, the reaction mixture was
treated with water (600 mL) and extracted with diethyl ether
(4ꢃ200 mL). The combined organic fractions were then dried
(MgSO4), filtered and concentrated under reduced pressure to give
an orange oil. Subjection of this material to flash chromatography
(silica, neat hexane/1:9 v/v ethyl acetate/hexane gradient elution)
and concentration of appropriate fractions (Rf¼0.6; silica, 3:2 v/v
ethyl acetate/hexane elution) afforded the title compound 10
colourless oil, [
a
]Dþ48.9 (c 2.00, CHCl3). [Found: (MþH)þ, 372.1580.
35
C H
18 26
ClNO5 requires (MþH)þ, 72.1578]. 1H NMR (300 MHz, CDCl3)
dH 7.31 (2H, d, J¼8.7 Hz), 6.84 (2H, d, J¼8.7 Hz), 5.83 (1H, m), 4.76
(2H, q, J¼6.6 Hz), 4.71 (1H, d, J¼6.9 Hz), 4.65 (1H, d, J¼6.9 Hz), 3.98
(1H, m), 3.87 (1H, m), 3.81 (1H, m), 3.77 (3H, s), 3.71 (1H, d,
J¼12.1 Hz), 3.36 (3H, s), 3.35 (3H, s), 3.32 (1H, m), 2.49 (1H, dm,
J¼17.7 Hz), 2.22 (1H, dm, J¼17.7 Hz), 2.11 (1H, br s); 13C NMR
(75 MHz, CDCl3) dC 158.5, 132.8, 132.1, 129.5, 123.2, 113.6, 96.8, 95.8,
75.7, 73.3, 62.0, 55.7, 55.4, 55.1, 49.0, 29.8; nmax (NaCl) 3347, 2933,
2894, 2836, 1611, 1513, 1464, 1442, 1301, 1247, 1150, 1106, 1036, 917,
833 cmꢀ1; m/z (ESI) 396 and 394 [(MþNa)þ, 38 and 80%], 378 (19),
360 (50), 338 (26), 306 (5), 201 (11), 181 (10), 121 (100).
(3.97 g, 90%) as a clear, colourless oil, [
a
]Dþ144.8 (c 1.26, CHCl3).
35
[Found: (MþNa)þ, 300.0734. C10
H
16
ClN3O4 requires (MþNa)þ,
300.0727]. 1H NMR (300 MHz, CDCl3) dH 5.90 (1H, m), 4.78–4.61
(4H, complex m), 3.79 (3H, m), 3.37 (3H, s), 3.32 (3H, s), 2.48 (1H,
dm, J¼17.7 Hz), 2.20 (1H, dm, J¼17.7 Hz); 13C NMR (75 MHz, CDCl3)
dC 127.9, 125.9, 97.1, 95.9, 78.1, 72.0, 65.5, 56.0, 55.6, 30.0; nmax
(NaCl) 2934, 2895, 2105, 1467, 1445, 1329, 1152, 1109, 1039, 1011,
918 cmꢀ1; m/z (ESI) 302 and 300 [(MþNa)þ, 5 and 14%], 258 (5), 220
and 218 (8 and 22), 188 (12), 158 and 156 (28 and 42), 128 (65), 101
(100), 99 (42), 93 (39), 65 (70), 60 (85).
4.2.9. (1R,2R,6R)-2-(4-Methoxybenzylamino)-3-chloro-
6-(methoxymethoxy)cyclohex-3-enol (13) and (1R,5R,6R)-5-
(4-methoxybenzylamino)-4-chloro-6-(methoxymethoxy)cyclohex-
3-enol (14)
4.2.7. (1R,5R,6R)-2-Chloro-5,6-bis(methoxymethoxy)cyclohex-2-
enamine (11)
A magnetically stirred solution of primary amine 11 (1.00 g,
3.97 mmol) and p-MBA (482 mL, 3.97 mmol) in anhydrous benzene
A magnetically stirred solution azide 10 (400 mg, 1.44 mmol) in
THF/water (50 mL of a 4:1 v/v mixture) maintained at 18 ꢂC was
treated with polymer-supported PPh3 (886 mg, 1.90 mmol) then
heated at 65 ꢂC. After 15 h, when TLC analysis indicated that all
the starting material had been consumed, the reaction mixture
was cooled to 18 ꢂC and filtered through a pad of CeliteÒ. The
resulting filtrate was diluted with water (100 mL), extracted with
diethyl ether (3ꢃ100 mL) and the combined organic fractions
were dried (MgSO4), filtered and concentrated under reduced
pressure to give the title compound 11 (305 mg, 84%) as a clear,
(100 mL) maintained at 18 ꢂC was treated with activated molecular
sieves 4 Å (w10 g) and the ensuing mixture heated at 80 ꢂC in an
apparatus fitted with a Dean–Stark trap. After 14 h, at which point
TLC analysis indicated that all the starting material had been con-
sumed, the reaction mixture was cooled to 18 ꢂC, filtered through
a pad a CeliteÒ and the resulting filtrate was concentrated under
reduced pressure to give a yellow oil containing the imine de-
rivative of compound 11. A magnetically stirred solution of this
material in anhydrous toluene (100 mL) was cooled to 0 ꢂC then
treated with DIBAL-H (20 mL of a 1 M solution in toluene,
20.0 mmol) and the ensuing mixture allowed to warm to 18 ꢂC.
After 14 h at this temperature the reaction mixture was quenched
with sodium potassium tartrate (40 mL of a saturated aqueous
solution) [Caution: exothermic reaction]. Stirring was continued at
18 ꢂC for 16 h then the separated aqueous phase was extracted with
toluene (2ꢃ50 mL) and the combined organic fractions were dried
(MgSO4), filtered and concentrated under reduced pressure to give
a yellow residue. Subjection of this material to flash chromato-
graphy (silica, hexane/2:3 v/v ethyl acetate/hexane gradient elu-
tion) provided fractions A and B.
light-yellow oil, [
a
]Dþ75.7 (c 1.87, CHCl3) (Rf¼0.3; silica, 1:11:8 v/v
MeOH/ethyl acetate/CHCl3 elution). [Found: (MþH)þ, 252.1000.
35
C
H
ClNO4 requires (MþH)þ, 252.1003]. 1H NMR (300 MHz,
10 18
CDCl3) dH 5.74 (1H, m), 4.77 (2H, d, J¼1.2 Hz), 4.71 (1H, d,
J¼6.8 Hz), 4.65 (1H, d, J¼6.8 Hz), 3.92 (1H, m), 3.85 (1H, m), 3.40
(3H, s), 3.37 (3H, s), 2.52 (1H, dm, J¼18.0 Hz), 2.26 (1H, dm,
J¼18.0 Hz), 2.10 (2H, br s) (one signal obscured or overlapping);
13C NMR (75 MHz, CDCl3) dC 134.1, 120.8, 96.8, 95.5, 80.1, 72.2,
56.3, 55.6, 55.3, 29.4; nmax (NaCl) 3384, 3307, 2931, 2894, 1653,
1586, 1469, 1441, 1214, 1150, 1104, 1035, 992, 917 cmꢀ1; m/z (ESI)
254 and 252 [(MþH)þ, 6 and 20%], 222 and 220 (32 and 100), 190
(49), 188 (49), 178 and 176 (7 and 21).
Concentration of fraction A (Rf¼0.5; silica, 2:3 v/v ethyl acetate/
hexane elution) afforded the title compound 13 (190 mg, 22%) as
a white, crystalline solid, mp¼85–87 ꢂC, [
]Dþ59.7 (c 1.60, CHCl3).
a
35
4.2.8. (1R,5R,6R)-N-(4-Methoxybenzyl)-2-chloro-5,6-bis-
(methoxymethoxy)cyclohex-2-enamine (12)
A magnetically stirred solution of primary amine 11 (620 g,
2.46 mmol) and p-MBA (894 mL, 7.38 mmol) in anhydrous toluene
[Found: (MþH)þ, 328.1316. C16
H
ClNO4 requires (MþH)þ,
22
328.1316]. 1H NMR (300 MHz, CDCl3) dH 7.29 (2H, d, J¼8.7 Hz), 6.85
(2H, d, J¼8.7 Hz), 5.86 (1H, m), 4.81 (1H, d, J¼6.8 Hz), 4.74 (1H, d,
J¼6.8 Hz), 3.85–3.62 (7H, complex m), 3.43 (1H, m), 3.40 (3H, s),

6450
O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
2.55 (1H, dm, J¼17.4 Hz), 2.18 (1H, dm, J¼17.4 Hz) (two signals
obscured or overlapping); 13C NMR (75 MHz, CDCl3) dC 158.6, 132.5,
132.0, 129.6, 124.2, 113.7, 96.6, 76.6, 72.4, 63.8, 55.6, 55.2, 47.8, 31.1;
nmax (NaCl) 3436, 3350, 2930, 2905, 2836, 1612, 1513, 1464, 1301,
1248, 1106, 1034, 842 cmꢀ1; m/z (ESI) 352 and 350 [(MþNa)þ, 45
and 100%], 330 and 328 [(MþH)þ, 5 and 15], 121 (70).
and AIBN (26 mg, 0.159 mmol) in anhydrous benzene (3 mL). The
resulting mixture was cooled and concentrated under reduced
pressure to give a yellow residue. Subjection of this material to
flash chromatography (silica, hexane/2:3 v/v ethyl acetate/
hexane gradient elution) and concentration of appropriate frac-
tions (Rf¼0.2; silica, 2:3 v/v ethyl acetate/hexane elution) pro-
vided the title compound 17 (142 mg, 88%) as an opaque, viscous
oil. [Found: (MþH)þ, 498.2132. C27H31NO8 requires (MþH)þ,
498.2128]. 1H NMR (300 MHz, CDCl3) dH (CDCl3) 7.19 (2H, d,
J¼8.6 Hz), 6.77 (2H, d, J¼8.6 Hz), 6.66 (1H, d, J¼8.0 Hz), 6.57 (1H,
d, J¼1.5 Hz), 6.53 (1H, d, J¼8.0 Hz), 5.90 (2H, m), 5.65 (1H, m),
5.06 (1H, d, J¼14.4 Hz), 4.88 (2H, q, J¼5.7 Hz), 4.72 (2H, q,
J¼6.9 Hz), 4.52 (1H, d, J¼14.4 Hz), 4.09 (1H, m), 4.02 (1H, s), 3.81
(1H, m), 3.77 (3H, s), 3.70 (1H, m), 3.46 (3H, s), 3.37 (3H, s), 3.69
(1H, m), 2.28 (1H, m); 13C NMR (75 MHz, CDCl3) dC 174.8, 158.8,
147.9, 146.7, 133.1, 131.8, 129.8, 129.0, 121.9, 120.2, 113.6, 108.2,
107.8, 101.0, 98.6, 96.5, 81.9, 59.9, 57.0, 55.6, 55.2, 51.4, 44.4, 33.1,
29.6; nmax (NaCl) 2954, 2925, 2853, 1707, 1686, 1611, 1512, 1488,
1441, 1247, 1176, 1151, 1109, 1035, 930, 812 cmꢀ1; m/z (ESI) 520
[(MþNa)þ, 100%], 498 [(MþH)þ, <1].
Concentration of fraction B (Rf¼0.7; silica, 2:3 v/v ethyl acetate/
hexane elution) afforded the title compound 14 (510 mg, 58%) as
a clear, colourless oil, [
a
]Dþ33.1 (c 0.88, CHCl3). [Found: (MþH)þ,
35
328.1318.
C H
16 22
ClNO4 requires (MþH)þ, 328.1316]. 1H NMR
(300 MHz, CDCl3) dH 7.25 (2H, d, J¼8.7 Hz), 6.87 (2H, d, J¼8.7 Hz),
5.93 (1H, m), 4.68 (2H, q, J¼6.8 Hz), 4.08 (1H, m), 4.02 (1H, m), 3.92
(1H, d, J¼12.9 Hz), 3.80 (3H, s), 3.73 (1H, d, J¼12.9 Hz), 3.36 (3H, s),
2.52 (1H, dm, J¼18.3 Hz), 2.33 (1H, dm, J¼18.3 Hz) (three signals
obscured or overlapping); 13C NMR (75 MHz, CDCl3) dC 159.0, 130.4,
129.6, 129.5, 125.4, 113.9, 96.3, 73.5, 66.4, 61.2, 55.7, 55.2, 50.6, 32.0;
nmax (NaCl) 3306, 2904, 2837, 1611, 1513, 1463, 1248, 1177, 1150,
1106, 1037, 990, 917, 832 cmꢀ1; m/z (ESI) 352 and 350 [(MþNa)þ, 35
and 100%], 330 and 328 [(MþH)þ, <1 and 2], 122 (2).
4.2.10. N-(4-Methoxybenzyl)-2-{benzo[d][1,3]dioxol-6-yl}-N-
[(1R,5R,6R)-2-chloro-5,6-bis(methoxymethoxy)cyclohex-2-enyl]-2-
(phenylthio)acetamide (16)
4.2.12. (3R,6R,7R,7aS)-1-(4-Methoxybenzyl)-3-{benzo[d]-
[1,3]dioxol-6-yl}-2,3,5,6,7,7a-hexahydro-6,7-bis(methoxymethoxy)-
1H-indole (18)
A magnetically stirred solution of acid 1522 (210 mg, 0.72 mmol)
in anhydrous toluene (10 mL) maintained at 18 ꢂC was treated with
A magnetically stirred suspension of aluminium trichloride
(AlCl3) (860 mg, 6.44 mmol) in anhydrous THF (20 mL) was cooled
to ꢀ20 ꢂC then treated, dropwise, with LiAlH4 (6.44 mL of a 1 M
solution in THF, 6.44 mmol) before being allowed to warm to 18 ꢂC.
After 2 h at this temperature a solution of lactam 17 (210 mg,
0.42 mmol) in anhydrous THF (10 mL) was added, dropwise, and
the ensuing mixture was stirred at 18 ꢂC for 13 h. TLC analysis of the
reaction mixture after this time indicated that all the starting ma-
terial had been consumed so it was treated with sodium potassium
tartrate (10 mL of a saturated aqueous solution) [Caution: exo-
thermic reaction] and stirring continued at 18 ꢂC for 2 h. The sep-
arated aqueous phase was extracted with diethyl ether (3ꢃ60 mL)
and the combined organic fractions were washed with brine
(1ꢃ20 mL) and ammonium chloride (1ꢃ20 mL of a saturated
aqueous solution) before being dried (MgSO4), filtered and con-
centrated under reduced pressure to afford title compound 18
(201 mg, 98%) as an opaque, viscous oil (Rf¼0.4; silica, 2:3 v/v ethyl
acetate/hexane elution). [Found: (MþH)þ, 484.2329. C27H33NO7
requires (MþH)þ, 484.2335]. 1H NMR (300 MHz, CDCl3) dH 7.20 (2H,
d, J¼8.7 Hz), 6.75 (2H, d, J¼8.7 Hz), 6.60 (1H, d, J¼8.0 Hz), 6.53 (1H,
d, J¼1.8 Hz), 6.50 (1H, dd, J¼8.0 and 1.8 Hz), 5.82 (2H, s), 5.22 (1H,
m), 4.93 (1H, d, J¼6.2 Hz), 4.85 (1H, d, J¼6.2 Hz), 4.73 (1H, d,
J¼6.8 Hz), 4.66 (1H, partially obscured d, J¼6.8 Hz), 4.63 (1H, par-
tially obscured m), 3.85–3.72 (2H, complex m), 3.70 (3H, s), 3.56
(1H, br m), 3.36 (3H, s), 3.32 (3H, s), 3.23–3.10 (3H, complex m),
thionyl chloride (SOCl2) (210 mL, 2.89 mmol) and the ensuing
mixture heated at 120 ꢂC for 3 h. The reaction mixture was then
cooled to 18 ꢂC and concentrated under reduced pressure to give
a brown residue containing the acid chloride derivative of com-
pound 15. A solution of this material in CH2Cl2 (3 mL) was then
added, via syringe pump over 0.25 h, to a magnetically stirred
mixture of secondary amine 12 (179 mg, 0.48 mmol) and sodium
hydroxide (5 mL of a 2.5 M aqueous solution) in CH2Cl2 (10 mL) that
had been cooled to 0 ꢂC. After stirring at this temperature for 1 h,
the reaction mixture was allowed to warm to 18 ꢂC and kept stirring
at this temperature for 40 h at which point TLC analysis indicated
that all of secondary amine 12 had been consumed. Accordingly, the
reaction mixture was treated with CH2Cl2 (50 mL) and water
(20 mL) then sufficient HCl (2 M aqueous solution) to establish a pH
of ca. 0–1 (ca. 5 mL required). The mixture was then treated with
sufficient sodium hydroxide (2 M aqueous solution) to establish
a pH of ca. 9–10 (ca. 6 mL required). The separated aqueous phase
was extracted with CH2Cl2 (2ꢃ40 mL) and the combined organic
fractions were then dried (MgSO4), filtered and concentrated under
reduced pressure to give a yellow residue. Subjection of this
material to flash chromatography (silica, hexane/3:7 v/v ethyl
acetate/hexane gradient elution) and concentration of appropriate
fractions (Rf¼0.4; silica, 3:7 v/v ethyl acetate/hexane elution) then
afforded the title compound 16 (242 mg, 78%) as a white foam.
[Found: (MþH)þ, 642.1931. C33
H
36
ClNO8S requires (MþH)þ,
2.58 (1H, m), 2.15 (1H, m) (one signal obscured or overlapping); 13
C
35
642.1928]. nmax (NaCl) 2933, 2896, 2837, 1649, 1611, 1512, 1486,
1441, 1407, 1303, 1247, 1176, 1152, 1108, 1037, 919, 734 cmꢀ1; m/z
(ESI) 666 and 664 [(MþNa)þ, 43 and 100%], 644 and 642 [(MþH)þ,
40 and 88], 534 and 532 (7 and 20), 502 and 500 (5 and 18), 490 and
488 (4 and 12), 458 and 456 (4 and 11), 382 and 380 (1 and 3), 130
(8), 121 (13), 102 (24).
NMR (75 MHz, CDCl3) dC 158.5, 147.6, 145.9, 142.6, 137.1, 130.1, 127.0,
120.9,118.6,113.5,108.0,100.8, 98.6, 96.4, 83.2, 68.5, 63.4, 59.7, 56.7,
55.4, 55.1, 45.7, 33.2, 29.6 (one signal obscured or overlapping); nmax
(NaCl) 2924, 2851,1611,1511, 1487,1441,1374,1247,1148, 1107, 1035,
918, 810 cmꢀ1; m/z (ESI) 484 [(MþH)þ, 100%], 452 (10), 362 (10),
332 (5), 300 (7), 254 (6), 121 (83).
4.2.11. (3R,6R,7R,7aS)-1-(4-Methoxybenzyl)-3-{benzo[d]-
[1,3]dioxol-6-yl}-5,6,7,7a-tetrahydro-6,7-bis(methoxymethoxy)-
1H-indol-2(3H)-one (17)
4.2.13. (3R,6R,7R,7aS)-3-{Benzo[d][1,3]dioxol-6-yl}-2,3,5,6,7,7a-
hexahydro-6,7-bis(methoxymethoxy)indole-1-carbonyl
chloride (19)
A
magnetically stirred mixture of amide 16 (205 mg,
A magnetically stirred solution of tertiary amine 18 (200 mg,
0.312 mmol) and n-Bu6Sn2 (400 L, 0.798 mmol) in anhydrous
m
0.413 mmol) and pyridine (134 mL, 1.65 mmol) in anhydrous CH2Cl2
benzene (750 mL) was degassed (3ꢃfreeze-pump-thaw method)
and then maintained under an argon atmosphere. The ensuing
mixture was heated to 80 ꢂC then treated, via syringe pump over
(20 mL) was cooled to 0 ꢂC then treated with triphosgene (245 mg,
0.826 mmol). The ensuing mixture was allowed to warm to 18 ꢂC
and after 10 h at this temperature it was concentrated under re-
duced pressure to give a brown residue that was subjected to flash
3 h, with a degassed solution of n-Bu3SnH (127 mL, 0.479 mmol)

O.J. Kokas et al. / Tetrahedron 64 (2008) 6444–6451
6451
chromatography (silica, 1:9/3:7 v/v ethyl acetate/hexane gradient
elution). Concentration of appropriate fractions (Rf¼0.2; silica, 3:7
v/v ethyl acetate/hexane elution) then afforded the title compound
4.3.3. Structural determinations
Images were measured on a Nonius Kappa CCD diffractometer
(Mo K , graphite monochromator,
a
l¼0.71073 Å) and data extracted
19 (134 mg, 76%) as an opaque, viscous oil. [Found: (MþNa)þ,
using the DENZO package.27 Structure solution was by direct
methods (SIR92).28 The structures of compounds (þ)-2 and 13 were
refined using the CRYSTALS program package.29 Crystallographic
data (excluding structure factors) for these compounds have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. 675210 and 675211, respectively.
Copies of the data can be obtained free-of-charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0) 1223
336033, email: data_request@ccdc.cam.ac.uk or web: www.ccdc.
cam.ac.uk/data_request/cif).
35
448.1145. C
H
ClNO7 requires (MþNa)þ, 448.1139]. 1H NMR
20 24
(300 MHz, CDCl3) dH 6.75 (1H, d, J¼7.8 Hz), 6.65 (1H, d, J¼1.5 Hz),
6.61 (1H, dd, J¼7.8 and 1.5 Hz), 5.94 (2H, s), 5.76 (1H, m), 4.86 (1H,
d, J¼6.8 Hz), 4.80 (1H, d, J¼7.1 Hz), 4.74 (1H, d, J¼7.1 Hz), 4.68 (1H,
d, J¼6.8 Hz), 4.51 (1H, br s), 4.33 (1H, d, J¼10.8 Hz), 3.98 (1H, m),
3.75 (3H, br s), 3.41 (3H, s), 3.37 (3H, s), 2.75 (1H, br m), 2.31 (1H, m)
(one signal obscured or overlapping); 13C NMR (75 MHz, CDCl3) dC
148.1, 146.6, 137.9, 133.5, 121.5, 119.1, 108.4, 106.9, 101.0, 97.1, 96.4,
78.4, 74.9, 61.6, 57.4, 56.0, 55.4, 47.2, 32.3 (one signal obscured or
overlapping); nmax (NaCl) 2895, 1746, 1503, 1489, 1440, 1366, 1320,
1253, 1235, 1149, 1105, 1032, 918 cmꢀ1; m/z (ESI) 450 and 448
[(MþNa)þ, 15 and 45%], 444 (100), 394 (5), 390 (20), 314 (28), 298
(30), 284 (10), 101 (10), 80 (39).
Acknowledgements
We thank the Institute of Advanced Studies and the Australian
Research Council for generous financial support.
4.2.14. (þ)-Nangustine [(þ)-2]
A
magnetically stirred solution of carbamoyl chloride 19
References and notes
(130 mg, 0.305 mmol) in dioxane/water (20 mL of a 1:1 v/v mix-
ture) maintained at 18 ꢂC was treated with HCl (drop of a concen-
trated aqueous solution) then heated at 70 ꢂC. After 21 h at this
temperature, the reaction mixture was cooled to 18 ꢂC, treated with
water (20 mL) and sodium hydrogen carbonate (20 mL of a satu-
rated aqueous solution) then extracted with ethyl acetate
(3ꢃ30 mL). The combined organic fractions were dried (MgSO4),
filtered and concentrated under reduced pressure to afford a grey
residue presumably containing compound 20. A magnetically stir-
red solution of this material in formic acid (10 mL) maintained at
18 ꢂC was treated with paraformaldehyde (80 mg, 2.54 mmol) and
the ensuing mixture heated at 80 ꢂC for 16 h then cooled to 18 ꢂC,
diluted with water (100 mL), treated with sufficient sodium hy-
droxide (2 M aqueous solution) to attain a pH of ca. 9 then extracted
with ethyl acetate (5ꢃ50 mL). The combined organic fractions were
dried (MgSO4), filtered and concentrated under reduced pressure to
give a brown residue. A magnetically stirred solution of this ma-
terial in MeOH (20 mL) maintained at 18 ꢂC was treated with po-
tassium hydroxide (5 mL of a 2.5 M aqueous solution) and after 3 h
the reaction mixture was diluted with water (100 mL) and treated
with sufficient HCl (1 M) aqueous solution to attain a pH of ca. 7–8
then extracted with ethyl acetate (5ꢃ50 mL). The combined organic
fractions were dried (MgSO4), filtered and concentrated under re-
duced pressure to give a light-brown solid. Recrystallisation (n-
propanol/hexane) of this material then afforded the title compound
(þ)-2 (35 mg, 40%) as a white, crystalline solid, mp¼255–257 ꢂC
1. Dry, L. J.; Poynton, M.; Thompson, M. E.; Warren, F. L. J. Chem. Soc. 1958, 4701.
2. Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J. Org. Chem. 1960, 25,
2153.
3. Clark, R. C.; Warren, F. L.; Pachler, K. G. R. Tetrahedron 1975, 31, 1855.
4. For reviews dealing with this class of alkaloid see: (a) Martin, S. F. The Alkaloids;
Brossi, A., Ed.; Academic: San Diego, CA, 1987; Vol. 30, p 251; (b) Hoshino, O.
The Alkaloids; Cordell, G. A., Ed.; Academic: San Diego, CA, 1998; Vol. 51, p 323;
(c) Lewis, J. R. Nat. Prod. Rep. 2000, 17, 57 and previous reviews in the series.
5. Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.; Mathee, S. Phytochemistry
1995, 40, 307.
6. Schu¨rmann da Silva, A. F.; de Andrade, J. P.; Bevilaqua, L. R. M.; da Souza, M. M.;
Izquierdo, I.; Henriques, A. T.; Zuanazzi, J. A. S. Pharmacol., Biochem. Behav. 2006,
85, 148.
7. Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005.
8. Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724.
9. Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773.
10. Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
11. Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992, 57, 7285.
12. Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Kemmler, M. J. Chem. Soc., Perkin
Trans. 1 2001, 1345.
13. Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2007, 9, 3503.
14. Labran˜a, J.; Machocho, A. K.; Kricsfalusy, V.; Brun, R.; Codina, C.; Viladomat, F.;
Bastida, J. Phytochemistry 2002, 60, 847.
15. Compound
3 can be obtained from the Aldrich Chemical Co. (Catalogue
Number 489492) or from Questor, Queen’s University of Belfast, Northern
Ireland (see http://questor.qub.ac.uk/newsite/contact.htm).
16. For reviews on methods for generating cis-1,2-dihydrocatechols by microbial
dihydroxylation of the corresponding aromatics, as well as the synthetic ap-
plications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T.
Aldrichimica Acta 1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.;
Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vo¨gtle, M. Pure Appl.
Chem. 2003, 75, 223; (c) Johnson, R. A. Org. React. 2004, 63, 117.
17. Banwell, M. G.; McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin Trans. 1 2001, 2194.
18. For an example of a closely related cleavage process see: Banwell, M. G.; McRae,
K. J. Org. Lett. 2000, 2, 3583.
19. For examples of related cleavage processes see: (a) Ref. 13; (b) Matveenko, M.;
Kokas, O. J.; Banwell, M. G.; Willis, A. C. Org. Lett. 2007, 9, 3683; (c) Banwell, M.
G.; McLeod, M. D.; Riches, A. G. Aust. J. Chem. 2004, 57, 53; (d) Ref. 18.
20. Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195.
{lit.14 mp [for (ꢀ)-2]¼261 ꢂC}, [
a
]
D
þ80.4 (c 0.44, MeOH). [Found:
ꢁ
ꢁ
Mþ
,
287.1158. C16H17NO4 requires Mþ
,
287.1158]. 1H NMR
(600 MHz, CD3OD) dH see Table 2; 13C NMR (150 MHz, CD3OD) dC
see Table 2; nmax (NaCl) 3435, 2898, 1632, 1502, 1483, 1337, 1235,
1039, 930 cmꢀ1; m/z (EI, 70 eV) see Table 1.
21. For a useful point-of-entry into the literature on the Staudinger reaction see:
´
Ku¨ rti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis;
Elsevier Academic: Burlington, MA, 2005; pp 428–429.
22. Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.; Ishibashi, H. J. Chem.
Soc., Perkin Trans. 1 1999, 1949.
4.3. X-ray crystallographic studies
23. For related examples of this type of radical reaction see: (a) Stanislawski, P. C.;
Willis, A. C.; Banwell, M. G. Chem. Asian J. 2007, 2, 1127; (b) Stanislawski, P. C.;
Willis, A. C.; Banwell, M. G. Org. Lett. 2006, 8, 2143.
24. Banwell, M. G.; Coster, M. J.; Harvey, M. J.; Moraes, J. J. Org. Chem. 2003, 68, 613.
25. Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Dalton, H.; Chima, J.; Whited, G.; See-
mayer, R. J. Am. Chem. Soc. 1994, 116, 1147.
26. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
27. DENZO–SMN: Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data
Collected in Oscillation Mode. In Methods in Enzymology; Carter, C. W., Jr.,
Sweet, R. M., Eds.; Macromolecular Crystallography, Part A; Academic: New
York, NY, 1997; Vol. 276, pp 307–326.
4.3.1. Crystal data for compound (þ)-2
C
16H17NO4$1.25H2O, M¼309.83, T¼200(1) K, orthorhombic,
space
group
C2221,
Z¼8,
a¼7.4746(2),
b¼17.1338(5),
c¼24.0329(6) Å, V¼3077.85(14) Å3, Dx¼1.337 g cmꢀ3, 1545 unique
data (2qmax¼50ꢂ), 1213 with I>1.5
(I); R¼0.039, Rw¼0.041, S¼1.19.
s
4.3.2. Crystal data for compound 13
16H22ClNO4, M¼327.81, T¼200(1) K, monoclinic, space group
C
28. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
29. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.
P21, Z¼2, a¼12.5255(4), b¼5.0041(1), c¼13.5776(4) Å,
b
¼
106.574(1), V¼815.67(4) Å3, Dx¼1.335 g cmꢀ3, 3726 unique data
(2qmax¼55ꢂ), 3108 with I>3.0
(I); R¼0.026, Rw¼0.027, S¼1.13.
s