A chemoenzymatic total synthesis of ent-narciclasine

Article abstract of DOI:10.1016/j.tet.2008.01.113

The synthesis of the title compound [(-)-1] has been achieved, for the first time, by reacting the aryl boronic acid ester 4 with the aminoconduritol derivative 6 under Suzuki-Miyaura cross-coupling conditions then subjecting the product phenanthridinone

Full text of DOI:10.1016/j.tet.2008.01.113

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Tetrahedron 64 (2008) 4817e4826
www.elsevier.com/locate/tet
A chemoenzymatic total synthesis of ent-narciclasine
*
Maria Matveenko, Martin G. Banwell , Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
Received 3 October 2007; received in revised form 13 November 2007; accepted 10 December 2007
Available online 2 February 2008
Abstract
The synthesis of the title compound [(ꢀ)-1] has been achieved, for the first time, by reacting the aryl boronic acid ester 4 with the amino-
conduritol derivative 6 under SuzukieMiyaura cross-coupling conditions then subjecting the product phenanthridinone 23 to a global deprotec-
tion process using trimethylsilyl bromide. The aromatic building block 4 was prepared in ten steps from piperonal while compound 6 was
obtained in nine steps from the enantiomerically pure cis-1,2-dihydrocatechol 7. This last compound is available, in multi-gram quantities,
through a whole-cell-mediated biotransformation of bromobenzene using genetically engineered organisms that over-express the responsible
enzyme, namely toluene dioxygenase. Since the enantiomer of compound 7 is available by related means, the present work also represents a for-
mal total synthesis of the alkaloid narciclasine [(þ)-1]. The single-crystal X-ray analysis of compound 13 is reported.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a Japanese group identified a natural product that they named
lycoricidinol and which was shown to possess carcinostatic
properties as well as a capacity to exert a strong growth-inhib-
iting action on rice seedlings.3 Shortly thereafter it was estab-
lished that narciclasine and lycoricidinol were one and the
same compound.4 In 1972, and after some initial errors,4,5
the true structure of (þ)-narcicasine was established through
a series of synthetic, biosynthetic and X-ray crystallographic
studies.6 The biological properties of narciclasine have contin-
ued to be investigated since this time and it has been estab-
lished that the compound inhibits the growth of the
pathogenic yeast Cryptococcus neofroms while certain deriva-
tives act against the pathogenic bacterium Neisseris gonor-
rhoeae.7 The compound has also been found to inhibit the
cytotoxic properties of calprotectin, a protein found in neutro-
phils and in extracellular media during inflammation.8 It is ten
times more active, in this respect, than the alkaloids lycorine,
ungerine and hippeastrine. Some insect antifeedant properties
have also been ascribed to narciclasine9 while certain, natu-
rally-occurring glycoslyated derivatives have been shown to
possess cytotoxic and antitumour activity very similar to the
parent alkaloid.10
Narciclasine [(þ)-1, a.k.a. lycoricidinol] is an Amaryllida-
ceae alkaloid that has been isolated from various Narcissus
species including Narcissus incomparabilis Mill.1 It is struc-
turally related to lycoricidine [(þ)-2] and pancratistatin
[(þ)-3], which have been obtained from the same and/or sim-
ilar sources. All three alkaloids display a range of potentially
useful biological properties that have ensured that they con-
tinue to attract attention more than four decades after the first
of them was identified in nature.1
OH
OH
2
10b
A
3
OH
OH
HO
OH
OH
1
10a
4a
O
O
O
O
B
NH
5
6
NH
6a
7
R
O
R
O
(+)-3
(+)-1 R=OH
(+)-2 R=H
Ceriotti in Italy described the antimitotic activity of narci-
clasine [(þ)-1] in 19672 while, in the following year,
The biological properties and novel structural features asso-
ciated with narciclasine have ensured that the compound
has continued to receive attention as a synthetic target.
* 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.2008.01.113

4818
M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
Furthermore, the close structural relationship between narci-
clasine [(þ)-1] and the generally more biologically active
but much less abundant alkaloid pancratistatin [(þ)-3] has
prompted considerable effort to devise methods for converting
the former compound into the latter.11 The synthetic strategies
used in accessing narciclasine [(þ)-1] and its congeners have
been the subject of a number of reviews including two recent
and comprehensive ones.1a,b These reveal that a particularly
successful approach has involved the construction of the
C10aeC10b bond and the N5eC6 or C6eC6a bond using rel-
evant aromatic and aminosugar or related fragments, including
aminocyclitols, as building blocks.
Our own, ongoing interests in developing new protocols for
the preparation of various Amaryllidaceae alkaloids and their
congeners via16 coupled with the biological significance of
narciclasine, prompted us to develop a synthesis of the title
compound. Whilst the approach described below is amenable
to the preparation of either enantiomeric form of narciclasine
we deliberately targeted the unnatural form because this had
not been prepared previously and, as a result, nothing is known
about the biological profile of this material.
2. Results and discussion
Rigby and Mateo reported the first total synthesis of narci-
clasine in 1997.12 This involved two key steps, namely the re-
action of a 4-lithio-3-oxygenated-1,2-methylenedioxybenzene
derivative with a polyoxygenated 1-cyclohexenylisocyanate to
give, via C6eC6a bond formation, an adduct that could un-
dergo a hydrogen bond-directed aryl enamide photocyclisation
and thus establishing, via C10aeC10b bond formation, the full
framework of the target alkaloid. Nine additional steps were
then required to complete the synthesis. In 1999 Keck et al.
described the next synthesis of (þ)-1.13 This employed a ster-
eoselective 6-exo-radical cyclisation of an alkenyl radical to an
O-benzyloxime radical acceptor group and thus generating the
C4aeC10b bond of the final target. The alkenyl radical itself
was generated by regioselective addition of the PhSꢁ radical to
a disubstituted alkyne that had been constructed via a Sonoga-
shira reaction and accompanying establishment of the
C10aeC10b bond. The radical cyclisation product then engaged
in a straightforward lactam bond-forming reaction to create the
N5eC6 bond of the target framework. Hudlicky and Gonzalez
also reported a total synthesis of narciclasine in 1999.14 In the
early stages a brominated aminoconduritol derivative was
constructed from an enantiopure cis-1,2-dihydrocatechol
obtained through the whole-cell-mediated dihydroxylation of
o-dibromobenzene. This derivative was then engaged in
a SuzukieMiyaura cross-coupling reaction with 3,4-methylene-
dioxy-5-methoxyphenyl boronic acid so as to produce, via
a C10aeC10b bond-forming process, an arylated aminocon-
duritol. Various functional group interconversions followed
to provide a derivative that was engaged in a modified
BischlereNapieralski reaction. This process delivered, via
C6eC6a bond formation, a protected form of the target alkaloid.
A two-step deprotection protocol, proceeding in 20% yield,
then afforded narciclasine itself. The most recent synthesis
of this natural product was reported, in 2002, by Elango and
Yan.15 Their approach has some parallels with the one
Hudlicky used, in that an aminoconduritol building block was
again employed although this was first epoxidised then
N-alkylated with an O-protected form of 2-hydroxy-3,4-meth-
ylenedioxybenzyl bromide and so establishing the N5eC6 bond
of the final target. Subjection of the product of this process to
a SnCl4-mediated and intramolecular FriedeleCrafts alkyl-
ation resulted in C10aeC10b bond formation and the estab-
lishment of the tetracyclic framework of the target alkaloid.
Conventional FGIs were then applied to this material in com-
pleting the fourth total synthesis of narciclasine.
Our recently reported syntheses of ent-lycoricidine [(ꢀ)-2]
and various related compounds16b led us to consider the
approach defined in Figure 1 as a means for obtaining ent-narci-
clasine [(ꢀ)-1]. In particular, a tandem SuzukieMiyaura cross-
coupling/amide bond forming process involving aryl boronate 4
and the aminoconduritol 6 would be expected to result in the for-
mation of the C10aeC10b and N5eC6 bonds (no order implied)
of the target compound and concomitant formation of the lactam
ring of the target the framework. Exhaustive cleavage of the
MOM-ether residues within the product expected of this process
should then deliver the target compound (ꢀ)-1.
Whilst boronate 4 has not been reported previously, Keck
has described the preparation of closely related systems13
and so it was anticipated that this aromatic building block
could be prepared from readily available piperonal (5) using
directed o-metallation (DoM) protocols17 to establish the rele-
vant functionality on either side of the carbonyl unit within
this starting material. The aminoconduritol building block
616b was employed in our recently reported synthesis of ent-
lycoricidine and is generated, over nine rather conventional
steps, from the cis-1,2-dihydrocatechol 7. This last compound
is readily available in large quantity and enantiomerically pure
form through the whole-cell-mediated cis-1,2-dihydroxylation
of bromobenzene (8) using a genetically engineered form of
Escherichia coli that over-expresses the enzyme toluene dioxy-
genase (TDO) responsible for this fascinating biotransforma-
tion.18 Compound 7 is available on a commercial basis from
at least two sources.19 Details associated with the syntheses of
the aromatic and aminoconduritol cores, 4 and 6, respectively,
of ent-narciclasine are presented below in Parts 1 and 2.
2.1. Part 1: assembly of the aromatic core
The synthetic sequence employed in generating the aryl
boronate 4 is shown in Scheme 1. This was based, in large
part, on protocols introduced by Keck13 for the purposes of
generating the related aromatic synthon required in his synthe-
sis of narciclasine. Thus, treatment of piperonal (5) with a mix-
ture of sodium cyanide and manganese dioxide in neat
diethylamine according to protocols defined by Gilman20
resulted in the smooth formation of the diethylamide 9 (58%
yield), which is presumably formed via a reaction sequence
involving initial cyanohydrin formation then oxidation of
this species to the corresponding a-ketonitrile that engages

M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
4819
O
B
O
O
O
O
DoMs
O
(i) Suzuki–Miyaura
cross-coupling/
amide bond
CO2Me
OMOM
CHO
OH
NH
OH
OH
formation
5
4
(ii) deprotection
O
O
+
OMOM
FGIs
OH
O
OMOM
Br
OH
(–)-1
Br
OMOM
OH
NH2
7
6
whole-cell
biotrans-
formation
Br
8
Figure 1.
O
In anticipation of the next DoM event, the free hydroxyl group
with this last compound was protected, using conventional
conditions, as the corresponding TBS ether (11).21 This was ob-
tained in 94% yield after purification by flash chromatography.
Subjection of compound 11 to reaction with sec-BuLi then
molecular iodine afforded the requisite aryl iodide 1222 (90%)
that was treated with trimethyloxonium tetrafluoroborate in
the presence of dibasic sodium phosphate.23 In this manner
the diethylcarboxamide residue within compound 12 was
methanolysed and the TBS-ether moiety cleaved so as to afford
the methyl salicylate derivative 1313,23 in 62% yield. The
structure of compound 13 follows from a single-crystal
X-ray analysis, details of which are reported in Section 4. The
derived ORTEP diagram is shown in Figure 2.
NaCN, MnO2
5
Et2NH
(neat)
O
CONEt2
9
(ii) B(OMe)3
(iii) H2O2,
AcOH
(i) sec-BuLi,
TMEDA
(i) sec-BuLi,
TMEDA
5
I
O
O
O
O
6
(ii) I2
CONEt2
1
CONEt2
OTBS
OR
12
10 R=H
11 R=TBS
TBSCl
–
Me3O+BF4 Na2HPO4
The free phenolic residue within this last compound was pro-
tected, under standard conditions, as the corresponding MOM
ether 14(99%)that wasthen subjected to a Miyaura borylation re-
action24 using pinacolatoborane in the presence of PdCl2$dppf.
pinacolatoborane
PdCl2•dppf
I
O
O
4
CO2Me
OR
13 R=H
14 R=MOM
MOMCl
Scheme 1.
in a nucleophilic addition/elimination sequence with diethyl-
amine to give the observed product.
With the diethylcarboxamide moiety now installed as a di-
recting group for o-metallation,17 compound 9 was treated, suc-
cessively, with sec-BuLi, trimethyl borate then hydrogen
peroxide/acetic acid, so as to give, in a completely regio-con-
trolled manner, the phenol 10 (90% yield).21 The regiochemical
outcome of this process is fully in accord with the DoM chem-
istry displayed by related compounds17 and was readily con-
firmed through the observation of a 8.3 Hz coupling between
Figure 2. ORTEP diagram derived from the single-crystal X-ray analysis of
compound 13.
1
H5 and H6 in the 300 MHz H NMR spectrum of phenol 10.

4820
M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
By such means the required aryl boronate 4 was obtained in 44%
yield. Using a method recently described by Tønder et al.,25 the
yield of compound 4 could be raised to 54%. Inevitably this
product was accompanied by varying amounts (14e22%) of
the reductively de-iodinated material that has rather similar chro-
matographic properties to the desired compound 4.
The spectral data derived from compound 4 were in com-
plete accord with the assigned structure. In particular, the
75 MHz 13C NMR spectrum displayed the expected 14 signals
including 6 in the region above 105 ppm and attributable to
sp2-hybridised carbons within the compound. The 300 MHz
1H NMR spectrum was dominated by a 12-proton singlet at
d 1.31 that clearly arises from the 4 equivalent methyl groups
of the pinacolato residue. Distinct singlets were also observed
for all the remaining proton environments within the com-
pound. The 70 eV electron impact mass spectrum of this
material showed a molecular ion at m/z 366 and an accurate
mass measurement on this species established that it was of
the expected composition, viz. C17H2311BO8.
Various attempts were made to shorten the reaction sequence
shown in Scheme 1. In particular, and most obviously, the con-
version of phenol 10 into the corresponding MOM ether rather
than the illustrated TBS ether was investigated. While this con-
version worked the subsequent methanolysis of the ensuing io-
dinated diethylcarboxamide did not. Similarly, while the anion
derived from the reaction of compound 11 with sec-BuLi could
be intercepted by various borylating agents the ensuing aryl bor-
onate species failed to engage in SuzukieMiyaura type cross-
coupling reactions26 with the aminoconduritol 6.
commences with the conversion, under conventional condi-
tions, of cis-diol 7 into the corresponding p-methoxybenzyl-
idene acetal 15, which is obtained, predominantly, in the
illustrated diastereoisomeric form. cis-1,2-Dihydroxylation of
this last compound using the UpJohn conditions27 proceeds
with excellent levels of regio- and diastereo-control so as to
give that product, 16 (65% from 7), in which reaction has
taken place at the more nucleophilic non-halogenated double
bond and such that the hydroxyl groups are introduced
onto the sterically less congested exo-face of the substrate.
The hydroxyl groups within product 16 were each protected
as the corresponding MOM ethers and the compound, 17
(ca. 75%), so-formed was subjected to reductive cleavage of
the PMP-acetal moiety using DIBAL-H. In this manner the
tris-ether 18 was obtained as the major product of reaction
(84%). The regioselectivity observed in the conversion 17/
18 is most likely the result of selective co-ordination of the DI-
BAL-H to that acetal oxygen within the former compound that
is remote from the sterically demanding bromine. As a result
the acetal CeO bond remote from the bromine is cleaved pref-
erentially to give the observed benzyl ether 18 as the major
product of reaction. Protection of the single free hydroxyl
group within compound 18 as the corresponding MOM ether
produced the fully protected conduritol 19 in 90% yield. The
latter compound was treated with DDQ, which resulted in
oxidative cleavage of the PMB-group and so affording the
alcohol 20 in 95% yield. As a prelude to carrying out an Over-
man rearrangement,28 compound 20 was treated with trichloro-
acetonitrile in the presence of DBU. The ensuing acetimidate
21 was then subject to heating under microwave irradiation (in
the presence of potassium carbonate) and thereby undergoing
the anticipated rearrangement to give the amide 22, which was
obtained in 78% yield from precursor 20. To the best of our
knowledge, the conversion 21/22 represents a rare example
of a microwave-promoted Overman rearrangement29 as well
as the first example of such a process involving an halogenated al-
kene. Treatmentofamide22withDIBAL-Hthenaffordedthetar-
getaminoconduritol6in89%yield.Thespectral datarecordedon
this material were in full accord with the assigned structure but
2.2. Part 2: assembly of the aminoconduritol core
As noted above, the aminoconduritol 6 (Fig. 1) identified
as the second key building block for the proposed synthesis
of ent-narciclasine is a compound that we had prepared re-
cently16b for the purposes of establishing a total synthesis of
ent-lycoricidine. For the sake of completeness, however,
a discussion of the reaction sequence (Scheme 2) used in gen-
erating compound 6 from metabolite 7 is provided here. This
OR
OMOM
OMOM
p-MBDMA,
p-TsOH
OR
OsO4/NMO
DIBAL-H
7
Br
O
OR
OPMB
Br
Br
O
O
O
PMP
PMP
16 R=H
17 R=MOM
15
18 R=H
19 R=MOM
MOM-Cl
MOM-Cl
DDQ
OMOM
OMOM
OMOM
OMOM
OMOM
OMOM
Cl3CCN,
DBU
Cl3COCHN
Br
K2CO3
DIBAL-H
6
Br
OMOM
NH
µwave
165 °C
OMOM
OH
OMOM
O
Br
CCl3
21
22
20
Scheme 2.

M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
4821
final confirmation of this came from its successful transformation
into ent-lycoricidine16b and ent-narciclasine (vide infra).
OMOM
OMOM
O
B
O
O
O
+
2.3. Part 3: the endgamedcoupling of the aromatic and
aminoconduritol cores
Br
OMOM
CO2Me
OMOM
NH2
4
6
With the two key building blocks, 4 and 6, in hand the cou-
pling of them so as to generate the narciclasine framework was
pursued (Scheme 3). In the event, subjection of a toluene
solution of a ca. 3:2 mixture of these materials to Suzukie
Miyaura cross-coupling under microwave conditions, using
Pd(PPh3)4 as catalyst, aqueous K2CO3 as base and tetra-n-
butylammonium bromide (TBAB) as phase-transfer catalyst,
produced the anticipated tris-MOM ether, 23, of ent-narcicla-
sine in 63% yield after purification by flash chromatography.
The ordering of events associated with this conversion remains
unclear, viz. we do not know if the SuzukieMiyaura cross-
coupling reaction occurs before the amide bond-forming event
or vice versa. In the final step of the synthetic sequence, com-
pound 23 was subjected to reaction with ca. 30 molar equiva-
lents of trimethylsilyl bromide, in dichloromethane at ꢀ40 to
ꢀ10 ꢂC for ca. 2.5 h, and thus affording ent-narciclasine [(ꢀ)-
1] as a white crystalline solid in 48% yield.
Pd[0],
base,
µwave
OR
OR
OR
O
O
NH
O
OR
23 R=MOM
(–)-1 (R=H)
TMS-Br
Scheme 3.
available.32 Accordingly, the work described here constitutes
a formal total synthesis of the naturally occurring form of
narciclasine.
The 1H and 13C NMR spectral data derivedfrom ent-narcicla-
sine proved essentially identical with those recorded for both the
natural product30,31 and synthetic samples of (þ)-narciclasine
produced by others13 (Table 1). The specific rotation of ent-
narciclasine {[a]D ꢀ116 (c 0.21, methanol)} was of similar
magnitude but opposite sign to that reported13 for the naturally
occurring enantiomer {[a]D þ112 (c 0.57, methanol)}.
3. Summary and conclusions
A comparison of the key features of all the reported syntheses
of narciclasine, including the one detailed herein, is provided in
Table 2. While the Hudlicky synthesis14 and our own are the
The enantiomeric form, ent-7, of the cis-1,2-dihydrocatechol
(7) used as the starting material in this synthesis is also
Table 1
Comparison of the 1H and 13C NMR data recorded for synthetic [synth-1]- and naturally [nat-1]-derived samples of narciclasine with those arising from
ent-narciclasine [(ꢀ)-1]
13C NMR
1H NMR
synth-1 (dC)a
nat-1 (dC)b
(ꢀ)-1 (dC)d
synth-1 (dH)e
nat-1 (dH)f
(ꢀ)-1 (dH)h
13.26 (s, 1H)
168.9
152.4
144.8
133.4
132.1
129.3
124.8
105.6
102.1
95.9
168.9
152.3
144.9
133.4
132.1
129.3
124.6
105.6
102.8
95.7
169.0
152.4
144.8
133.5
132.2
129.3
124.8
105.6
102.2
95.9
13.3 (s, 1H)
7.91 (s, 1H)
6.86 (s, 1H)
6.15 (s, 1H)
6.08 (d, 1H)
5.21e5.19 (m, 2H)
5.04 (s, 1H)
4.20 (d, 1H)
4.01 (s, 1H)
3.79 (d, 1H)
3.70 (s, 1H)
13.24 (s, 1H)
7.88 (s, 1H)
6.84 (s, 1H)
6.15 (ddd, 1H)
6.09 (m, 2H)g
d
7.92 (s, 1H)
6.86 (s, 1H)
6.15 (m, 1H)
6.09 (m, 2H)
5.20 (m, 2H, OH)
5.04 (d, 1H, OH)
4.19 (d, 1H)
d
4.18 (ddd, 1H)
4.01 (ddd, 1H)
3.78 (dd, 1H)
3.69 (ddd, 1H)
4.01 (m, 1H)
3.78 (m, 1H)
3.69 (m, 1H)
72.4
69.2
72.4
72.4
69.2
69.2
68.8
52.9
69.8c
52.8
68.8
52.9
a
Data from Ref. 13 and recorded in DMSO-d6 at 125 MHz.
Data from Ref. 30 and recorded in DMSO-d6 at 22.5 MHz.
We believe this chemical shift is in error and should be 68.8.
b
c
d
e
f
Data arising from work reported in this paper and recorded in DMSO-d6 at 125 MHz.
Data from Ref. 13 and recorded in DMSO-d6 at 500 MHz.
Data from Ref. 31 and recorded in DMSO-d6 at 500 MHz.
In Ref. 31 this signal is actually identified as overlapping, one-proton doublets at d 6.09 and 6.08 but has been presented as ‘6.09 (m, 2H)’ in this table to
g
facilitate comparisons with the other 1H NMR data sets.
h
Data arising from work reported in this paper and recorded in DMSO-d6 at 500 MHz.

4822
M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
Table 2
Comparison of key features associated with the five reported syntheses of narciclasine or ent-narciclasine
Lead
author
Publication
date
Key bond-forming
sequence
Ring-forming
sequence
Longest linear
sequence
Overall
yield (%)
Enantiomeric form
produced
Rigby12
1997
1999
1999
2002
2008
C6eC6a then C10aeC10b
C10aeC10b, C4aeC10b then N5eC6
C10aeC10b then C6eC6a
N5eC6 then C10aeC10b
C10aeC10b/N5eC6
AþC/AC/ABC
A/AC/ABC
C/AC/ABC
C/AC/ABC
AþC/ABC
23 steps
12 steps
11 steps
15 steps
11 steps
0.15
26
(þ)
(þ)
(þ)
(þ)
(ꢀ)
Keck13
Hudlicky14
Tan15
Present work
0.7
16
7
shortest (eleven steps each), the Keck route13 to (þ)-narcicla-
sine is only one step longer and stands out for its remarkable ef-
ficiency (26% overall yield). Tan’s synthesis15 is also notable for
its rather high overall yield (16%), which is achieved over a fif-
teen-step sequence.
This study, when considered in conjunction with our earlier
work,16b,18b,33 serves to highlight the considerable utility of
microbially-derived cis-1,2-dihydrocatechols such as 7 in the
construction of a range of alkaloids and/or their analogues, in-
cluding those of the lycorine-type. Indeed, current work in our
laboratories is directed towards the total synthesis and biolog-
ical evaluation of various other members of this rather signif-
icant class of alkaloid.
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 PerkineElmer 241 polarimeter at the so-
dium-D line (589 nm) and the concentrations (c) (g/100 mL)
indicated using spectroscopic grade solvents. The measure-
ments were carried out in a cell with a path length (l) of
1 dm. Specific rotations [a]D were calculated using the equa-
tion [a]D¼100ꢃa/(cꢃl) and are given in 10ꢀ1 deg cm2 gꢀ1
.
Melting points were measured on an Optimelt automated melting
pointsystemora Reichert hot-stage microscope apparatus andare
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 visualised using
a 254 nm UV lamp and/or by treatment with a suitable dip fol-
lowed by heating. These dips included phosphomolybdic acid/
ceric sulfate/sulfuric acid (conc.)/water (37.5 g:7.5 g:37.5 g:
720 mL)orpotassiumpermanganate/potassiumcarbonate/5%so-
diumhydroxideaqueoussolution/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.34 with silica
gel 60 (0.040e0.0063 mm) as the stationary phase and using the
AR- or HPLC-grade solvents indicated. Starting materials and re-
agents were generally available from the SigmaeAldrich, Merck,
TCI, Strem or Lancaster Chemical Companies and were used as
supplied. Pinacolborane was purchased from Boron Molecular
Ltd. (Melbourne, Australia). 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 spectrometer operating at
300 MHz for proton and 75 MHz for carbon nuclei. In certain
cases, a Varian Inova 500 spectrometer, operating at 500 MHz
1
for proton and 125 MHz for carbon nuclei, was used. For H
NMR spectra, signals arising from the residual protio-forms
1
of the solvent were used as the internal standards. H NMR
data are recorded as follows: chemical shift (d) [multiplicity,
coupling constant(s) J (Hz), relative integral] where multiplic-
ity is defined as: s¼singlet; d¼doublet; t¼triplet; q¼quartet;
m¼multiplet or combinations of the above. The residual
CHCl3 peak (d 7.26), residual DMSO peak (d 2.50) and the
1
residual MeOH peak (d 3.30) were used as references for H
NMR spectra. The central peak (d 77.0) of the CDCl3 ‘triplet’
and the central peak (d 39.5) of the DMSO-d6 ‘heptet’ were
used as references for proton-decoupled 13C NMR spectra.
The data for 13C NMR spectra are given as: chemical shift
(d), (protonicity), where protonicity is defined as:
C¼quaternary; CH¼methine; CH2¼methylene; CH3¼methyl.
Assignments of signals observed in various NMR spectra were
often assisted by conducting Attached Proton Test (APT), ho-
monuclear (1H/1H) correlation spectroscopy (COSY) and/or
nuclear Overhauser effect (NOE) experiments. Infrared spec-
tra (nmax) were recorded on a PerkineElmer 1800 Series
FTIR Spectrometer. Samples were analysed as KBr disks
(for solids) or as thin films on NaCl plates (for oils). A VG Fi-
sons AutoSpec mass spectrometer was used to obtain low- and
high-resolution electron impact (EI) mass spectra. Low- and
4.2. Specific procedures
4.2.1. N,N-Diethyl-1,3-benzodioxole-5-carboxamide (9)
Following a protocol reported by Gilman,20 a magnetically
stirred suspension of sodium cyanide (12.0 g, 245 mmol) in
diethylamine (50 mL, 486 mmol), maintained under a nitrogen
atmosphere at 0 ꢂC, was treated with piperonal (9.00 g,
60 mmol), then MnO2 (85 g, 977 mmol). The resulting mix-
ture was warmed to 18 ꢂC, stirred at this temperature for
48 h then filtered through CeliteÔ (4 cm deep pad contained

M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
4823
ꢁ
in a sintered-glass funnel). The solids thus retained were
washed with CH2Cl2 (50 mL) and the combined filtrates con-
centrated under reduced pressure. The ensuing yellow oil was
subjected to column chromatography (silica, 3:7/35:65/
2:3 v/v ethyl acetate/hexane gradient elution) and concentra-
tion of the appropriate fractions (Rf¼0.3 in 1:1 v/v ethyl ace-
tate/hexane) afforded the title compound 9 (7.64 g, 58%) as
a pale-tan crystalliþne solid, mp¼66e69 ꢂC (lit.35 mp¼64e
1032, 914 cmꢀ1; MS m/z (EI, 70 eV) 237 (Mþ , 68%), 236
(40), 165 (100), 164 (85), 72 (58).
4.2.3. 4-[[1,1-(Dimethylethyl)dimethylsilyl]oxy]-N,N-
diethyl-1,3-benzodioxole-5-carboxamide (11)
Imidazole (2.29 g, 33.7 mmol) and TBSCl (2.21 g,
14.6 mmol) were added to a magnetically stirred solution of
alcohol 10 (2.67 g, 11.24 mmol) in CH2Cl2 (50 mL) main-
tained at 0 ꢂC under an atmosphere of nitrogen. After 16 h
at 18 ꢂC the reaction mixture was diluted with brine (50 mL)
and extracted with CH2Cl2 (4ꢃ50 mL). The combined organic
extracts were then dried (MgSO4), filtered and concentrated
under reduced pressure to give a pale-yellow oil. Subjection
of this material to flash chromatography (silica, 1:9/1:4 v/v
ethyl acetate/hexane gradient elution) and concentration of the
relevant fractions (Rf¼0.3 in 3:7 v/v ethyl acetate/hexane)
gave the title compound 1121 (3.70 g, 94%) as a clear, colour-
less oil, which solidified upon stanþding to give a white solid,
mp¼67e69 ꢂC. [Found: (MþH) , 352.1937. Calcd for
C18H29NO4Si (MþH)þ, 352.1944.] 1H NMR (CDCl3,
300 MHz) d 6.68 (d, J¼7.8 Hz, 1H), 6.50 (d, J¼7.8 Hz, 1H),
5.94 (br s, 1H), 5.91 (br s, 1H), 3.51 (m, 2H), 3.19 (m, 2H),
1.22 (t, J¼7.2 Hz, 3H), 1.01 (t, J¼7.2 Hz, 3H), 0.94 (s, 9H),
0.21 (br s, 3H), 0.17 (br s, 3H); 13C NMR (CDCl3, 75 MHz)
d 168.3 (C), 148.8 (C), 136.7 (C), 135.2 (C), 125.4 (C),
120.6 (CH), 102.4 (CH), 100.8 (CH2), 42.8 (CH2), 39.3
(CH2), 25.6 (3ꢃCH3), 18.1 (C), 13.9 (CH3), 13.1 (CH3),
ꢀ4.5 (CH3), ꢀ4.6 (CH3); IR nmax 2931, 1631, 1471, 1272,
1069, 1037, 840, 786 cmꢀ1; MS m/z (ESI) 374 [(MþNa)þ,
78%], 352 [(MþH)þ, 100], 279 (42).
ꢁ
ꢁ
66 ꢂC). (Found: M , 221.1051. Calcd for C12H15NO3 Mþ ,
1
221.1052.) H NMR (CDCl3, 300 MHz) d 6.90e6.78 (com-
plex m, 3H), 5.98 (s, 2H), 3.40 (br m, 4H), 1.17 (br m, 6H);
13C NMR (CDCl3, 75 MHz) d 170.6 (C), 148.2 (C), 147.4
(C), 130.8 (C), 120.4 (CH), 108.1 (CH), 107.3 (CH), 101.2
(CH2), 43.2 (br, CH2), 39.3 (br, CH2), 14.1 (br, CH3), 13.1
(br, CH3); IR nmax 2973, 2934, 1630, 1471, 1457, 1443,
1287, 1241, 1106, 1036, 917 cmꢀ1; MS m/z (EI, 70 eV) 221
ꢁ
(Mþ , 58%), 220 (65), 149 (100), 121 (34), 91 (15), 65 (30).
4.2.2. N,N-Diethyl-4-hydroxy-1,3-benzodioxole-
5-carboxamide (10)
Compound 10 was prepared using a modification of
a method described by Beak and Brown.36 Thus, sec-BuLi
(14.8 mL of a 1.4 M solution in cyclohexane, 20.7 mmol)
was added to a magnetically stirred solution of TMEDA
(3.1 mL, 20.7 mmol) in THF (130 mL) maintained under a ni-
trogen atmosphere at ꢀ78 ꢂC. The resulting yellow solution
was stirred at this temperature for 0.25 h then treated, via
a cannula, with a solution of amide 9 (3.06 g, 13.83 mmol)
in THF (70 mL) that had been precooled to ꢀ78 ꢂC. The can-
nula was then flushed with additional THF (5 mL) to ensure
that all of the substrate had been introduced into the reaction
mixture. The ensuing tan solution was stirred at ꢀ78 ꢂC for
2 h then treated, via a cannula, with a solution of trimethyl bo-
rate (3.1 mL, 27.7 mmol) in THF (50 mL) that had been pre-
cooled to ꢀ78 ꢂC. The resulting mixture was stirred at 0 ꢂC
for 0.25 h, then warmed to 18 ꢂC and stirred at this tempera-
ture for a further 2 h. After this time the reaction mixture
was cooled to 0 ꢂC and quenched with glacial acetic acid
(2.8 mL, 48.9 mmol) then H2O2 (7.0 mL of 3:7 w/v aqueous
solution). The ensuing mixture was stirred at 18 ꢂC for 16 h,
then partitioned between diethyl ether (100 mL) and H2O
(100 mL). The separated aqueous phase was extracted with
diethyl ether (3ꢃ100 mL) and the combined organic phases
were dried (MgSO4), filtered and concentrated under reduced
pressure. The ensuing residue was subjected to column chro-
matography (silica, 3:7 v/v ethyl acetate/hexane elution) to af-
ford, after concentration of the appropriate fractions (Rf¼0.3
in 1:1 v/v ethyl acetate/hexane), the title compound 1021
4.2.4. 4-[[1,1-(Dimethylethyl)dimethylsilyl]oxy]-N,N-
diethyl-6-iodo-1,3-benzodioxole-5-carboxamide (12)
Compound 12 was prepared using a modification of
a method described by Keck et al.13 Thus, sec-BuLi (9.2 mL
of a 1.4 M solution in cyclohexane, 12.8 mmol) was added
to a magnetically stirred solution of TMEDA (1.9 mL,
12.8 mmol) in THF (100 mL) maintained at ꢀ78 ꢂC under a ni-
trogen atmosphere. The resulting yellow solution was stirred
at this temperature for 0.25 h then cooled to ꢀ95 ꢂC
(MeOH/liquid N2 bath) and treated, via cannula, with a solu-
tion of amide 11 (3.01 g, 8.56 mmol) in THF (50 mL) that
had been precooled to ꢀ78 ꢂC. The cannula was then flushed
with additional THF (5 mL) to ensure that all of the substrates
had been introduced into the reaction mixture. The ensuing tan
solution was stirred at ꢀ95 ꢂC for 1 h, then treated, via can-
nula, with a solution of iodine (4.35, 17.1 mmol) in THF
(50 mL) that had been precooled to ꢀ78 ꢂC. After the addition
was complete, the reaction mixture was allowed to warm to
18 ꢂC over 16 h and after this time it was concentrated under
reduced pressure. The resulting dark-brown residue was dis-
solved in CH2Cl2 (300 mL) and the ensuing solution washed
with Na2S2O5 (3ꢃ50 mL of a saturated aqueous solution) be-
fore being dried (MgSO4), filtered and concentrated under re-
duced pressure. The ensuing yellow residue was subjected to
column chromatography (silica, 1:9 v/v ethyl acetate/hexane
elution) to afford, after concentration of the appropriate
ꢁ
(2.97 g, 90%) as a cloudy, white oil. (Found: Mþ , 237.1000.
ꢁ
Calcd for C12H15NO4 Mþ , 237.1001.) 1H NMR (CDCl3,
300 MHz) d 10.09 (br s, 1H), 6.86 (d, J¼8.3 Hz, 1H), 6.40
(d, J¼8.3 Hz, 1H), 6.03 (s, 2H), 3.52 (q, J¼7.2 Hz, 4H),
1.27 (t, J¼7.2 Hz, 6H); 13C NMR (CDCl3, 75 MHz) d 171.0
(C), 150.6 (C), 143.4 (C), 135.2 (C), 121.5 (CH), 114.4 (C),
101.9 (CH2), 99.7 (CH), 42.2 (2ꢃCH2), 13.3 (2ꢃCH3); IR
nmax 3200, 2976, 2937, 1634, 1592, 1463, 1310, 1288, 1062,

4824
M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
fractions (Rf¼0.4 in 1:4 v/v ethyl acetate/hexane), the title
compound 1222 (3.70 g, 90%) as a clear, colourless oil.
concentrated under reduced pressure to afford a pale-yellow
oil. Subjection of this material to column chromatography
(silica, 1:4 v/v ethyl acetate/hexane elution) provided, after
concentration of the appropriate fractions (Rf¼0.3 in 3:7 v/v
ethyl acetate/hexane), the title compound 14 (2.02 g, 99%)
ꢁ
ꢁ
(Found: Mþ , 477.0824. Calcd for C18H28INO4Si Mþ ,
477.0832.) 1H NMR (CDCl3, 300 MHz) d 6.92 (d, J¼
0.6 Hz, 1H), 5.96 (dd, J¼0.6 and 1.5 Hz, 1H), 5.92 (dd,
J¼1.5 and 0.6 Hz, 1H), 3.86 (m, 1H), 3.16 (m, 3H), 1.27
(t, J¼7.2 Hz, 3H), 1.11 (t, J¼7.2 Hz, 3H), 0.93 (s, 9H), 0.23
(s, 3H), 0.18 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 167.4
(C), 149.2 (C), 137.5 (C), 135.9 (C), 130.4 (C), 112.5 (CH),
101.3 (CH2), 82.2 (C), 43.0 (CH2), 39.2 (CH2), 25.5
(3ꢃCH3), 18.2 (C), 13.8 (CH3), 12.5 (CH3), ꢀ4.2 (CH3),
ꢀ4.7 (CH3); IR nmax 2930, 1638, 1616, 1461, 1262, 1087,
ꢁ
as a clear, colourless oil. (Found: Mþ , 365.9607. C11H11IO6
ꢁ
requires Mþ , 365.9600.) 1H NMR (CDCl3, 300 MHz)
d 6.98 (s, 1H), 5.98 (s, 2H), 5.24 (s, 2H), 3.92 (s, 3H), 3.48
(s, 3H); 13C NMR (CDCl3, 75 MHz) d 167.3 (C), 150.6 (C),
137.4 (C), 137.2 (C), 128.0 (C), 113.6 (CH), 102.0 (CH2),
96.7 (CH2), 81.1 (C), 57.1 (CH3), 52.8 (CH3); IR nmax 1732,
1615, 1464, 1258, 1055, 1031, 927 cmꢀ1; MS m/z (EI,
ꢁ
ꢁ
1036, 862, 839, 786 cmꢀ1; MS m/z (EI, 70 eV) 477 (Mþ ,
70 eV) 366 (Mþ , 61%), 335 (20), 305 (21), 290 (100), 45
1%), 462 (5), 421 (40), 420 (100), 405 (7), 292 (20), 264
(27), 73 (17).
(85).
4.2.7. Methyl 4-(methoxymethoxy)-6-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1,3-benzodioxole-5-
carboxylate (4)
4.2.5. Methyl 4-hydroxy-6-iodo-1,3-benzodioxole-5-
carboxylate (13)
Compound 13 was prepared according to the method of
Keck et al.13 Thus, a magnetically stirred solution of com-
pound 12 (4.22 g, 8.84 mmol) in CH3CN (45 mL) maintained
under an atmosphere of nitrogen was treated with Na2HPO4
(1.88 g, 13.26 mmol), then Me3OBF4 (3.92 g, 26.52 mmol).
The ensuing mixture was stirred at 18 ꢂC for 5 h before being
quenched with NaHCO3 (55 mL of a saturated aqueous solu-
tion then 4 g of solid material). The resulting mixture was
stirred at 18 ꢂC for 16 h, then diluted with CH2Cl2 (100 mL)
and stirred at 18 ꢂC for a further 2 h. The separated aqueous
phase was extracted with CH2Cl2 (3ꢃ100 mL) and the com-
bined organic phases were then dried (Na2SO4), filtered and
concentrated under reduced pressure. The ensuing pale-yellow
solid was subjected to column chromatography (silica, 2:3 v/v
hexane/CH2Cl2) to afford, after concentration of the appropri-
ate fractions (Rf¼0.4 in 3:7 v/v hexane/CH2Cl2), the title com-
pound 1313 (1.78 g, 62%) as a colourless, crystalline solid,
Method A: A magnetically stirred solution of iodide 14
(157 mg, 0.43 mmol) in CH3CN (2 mL) was treated with
Et3N (180 mL, 1.29 mmol) and PdCl2$dppf (35 mg,
0.04 mmol) then, dropwise, with pinacolborane (125 mL,
0.86 mmol). The ensuing red solution was heated at 100 ꢂC
in a CEM ExplorerÔ microwave reactor for 0.5 h then cooled
to 18 ꢂC and diluted with diethyl ether (30 mL). The ensuing
mixture was poured into brine (10 mL) and the separated
aqueous layer extracted with diethyl ether (3ꢃ20 mL). The
combined organic phases were dried (MgSO4), filtered and
concentrated under reduced pressure. The resulting dark-
brown oil was subjected to column chromatography (silica,
1:9/15:85 v/v ethyl acetate/hexane gradient elution) to pro-
vide two fractions, A and B.
Concentration of fraction A [Rf¼0.3(1) in 3:7 v/v ethyl ace-
tate/hexane] afforded methyl 4-(methoxymethoxy)-1,3-benzo-
dioxole-5-carboxylate (14 mg, 14%) as a clear, colourless
ꢁ
ꢁ
ꢁ
mp¼165e166 ꢂC (lit.13 mp¼154e155 ꢂC). (Found: Mþ ,
oil. (Found: Mþ , 240.0634. C11H12O6 requires Mþ ,
240.0634.) 1H NMR (CDCl3, 300 MHz) d 7.48 (d, J¼
8.4 Hz, 1H), 6.61 (d, J¼8.4 Hz, 1H), 6.03 (s, 2H), 5.28 (s,
2H), 3.86 (s, 3H), 3.57 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 165.7 (C), 152.3 (C), 140.4 (C), 139.0 (C), 126.5 (CH),
118.2 (C), 103.6 (CH), 101.9 (CH2), 97.9 (CH2), 57.1
(CH3), 51.9 (CH3); IR nmax 1723, 1624, 1601, 1466, 1274,
ꢁ
321.9338. Calcd for C9H7IO5 Mþ , 321.9338.) 1H NMR
(CDCl3, 300 MHz) d 11.03 (s, 1H), 7.20 (s, 1H), 6.08 (s,
2H), 3.96 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 168.7 (C),
152.6 (C), 146.8 (C), 135.6 (C), 115.4 (CH), 112.3 (C),
102.9 (CH2), 84.6 (C), 51.9 (CH3); IR nmax 3436, 2920,
1666, 1434, 1301, 1081, 1037, 786 cmꢀ1; MS m/z (EI,
ꢁ
ꢁ
70 eV) 322 (Mþ , 43%), 290 (100), 105 (25).
1157, 1055, 1033, 929 cmꢀ1; MS m/z (EI, 70 eV) 240 (Mþ ,
40%), 209 (23), 179 (26), 164 (89), 45 (100).
Concentration of fraction B [Rf¼0.2(9) in 3:7 v/v ethyl
4.2.6. Methyl 6-iodo-4-(methoxymethoxy)-1,3-benzodioxole-
5-carboxylate (14)
acetate/hexane] afforded the title compound 4 (69 mg, 44%)
ꢁ
A magnetically stirred solution of phenol 13 (1.78 g,
5.53 mmol) in THF (60 mL) maintained at 0 ꢂC under a nitro-
gen atmosphere was treated with NaH (290 mg of a ca. 60%
dispersion in mineral oil, 7.19 mmol) and the resulting mixture
was allowed to warm to 18 ꢂC. After 0.25 h the reaction mix-
ture was cooled to 0 ꢂC then treated, dropwise, with MOMCl
(550 mL, 7.19 mmol). The ensuing mixture was stirred at
18 ꢂC for a further 16 h then diluted with diethyl ether
(50 mL), poured into water (50 mL) and the separated aqueous
phase was extracted with diethyl ether (4ꢃ50 mL). The com-
bined organic fractions were dried (MgSO4), filtered and
as a clear, pale-tan coloured oil. (Found: Mþ , 366.1481.
ꢁ
C17H2311BO8 requires Mþ , 366.1486.) 1H NMR (CDCl3,
300 MHz) d 6.92 (s, 1H), 6.00 (s, 2H), 5.25 (s, 2H), 3.87 (s,
3H), 3.51 (s, 3H), 1.31 (s, 12H); 13C NMR (CDCl3,
75 MHz) d 168.7 (C), 150.3 (C), 139.8 (C), 137.5 (C), 127.3
(C), 109.3 (CH), 102.0 (CH2), 97.4 (CH2), 84.3 (2ꢃC), 57.3
(CH3), 52.7 (CH3), 25.0 (4ꢃCH3) (one signal obscured or
overlapping); IR nmax 2978, 1736, 1607, 1419, 1382, 1259,
1143, 1055, 1035, 971, 847 cmꢀ1; MS m/z (EI, 70 eV) 366
ꢁ
(Mþ , 7%), 335 (13), 308 (100), 290 (23), 235 (37), 208
(41), 190 (27), 83 (23), 45 (53).

M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
4825
Method B: A procedure described by Tønder et al. was em-
ployed.25 Thus, a magnetically stirred solution of iodide 14
(246 mg, 0.67 mmol) in 1,4-dioxane (2 mL) was treated with
Et3N (370 mL, 2.69 mmol) then Pd(OAc)2 (8 mg, 0.03 mmol)
and 2-(dicyclohexylphosphino)biphenyl (47 mg, 0.13 mmol).
The resulting orange-coloured mixture was heated to 80 ꢂC
then treated, dropwise, with pinacolborane (295 mL,
2.02 mmol). Heating at 80 ꢂC was continued for 1.33 h then
the reaction mixture was cooled to 18 ꢂC and treated, drop-
wise, with H2O (300 mL) before being diluted with CH2Cl2
(50 mL) and additional H2O (10 mL). The separated aqueous
layer was extracted with CH2Cl2 (2ꢃ50 mL) and the com-
bined organic phases were dried (Na2SO4) then filtered and
concentrated under reduced pressure. The resulting dark-
brown oil was subjected to column chromatography (silica,
1:9/15:85 v/v ethyl acetate/hexane gradient elution) to
provide two fractions, A and B.
Concentration of fraction A [Rf¼0.3(1) in 3:7 v/v ethyl
acetate/hexane] afforded methyl 4-(methoxymethoxy)-1,3-
benzodioxole-5-carboxylate (35 mg, 22%) as a clear, brown
oil. This material was identical, in all respects, to fraction A
obtained using Method A as detailed immediately above.
Concentration of fraction B [Rf¼0.2(9) in 3:7 v/v ethyl ace-
tate/hexane] afforded the title compound 4 (134 mg, 54%) as
a clear, brown oil. This material was identical, in all respects,
to fraction B obtained using Method A as detailed immedi-
ately above.
m, 6H), 4.43 (m, 1H), 4.29 (m, 1H), 4.14 (m, 1H), 3.93 (dd,
J¼2.1 and 8.7 Hz, 1H), 3.60 (s, 3H), 3.50 (s, 3H), 3.38 (s,
ꢁ
3H), 3.37 (s, 3H); MS m/z (EI, 70 eV) 483 (Mþ , 6%), 439
(9), 291 (13), 45 (100).
This material was used, without further purification, in the
next step of the reaction sequence.
4.2.10. (2R,4R,3S,4aS)-2,3,4,7-Tetrahydroxy-2,3,4,5,4a-
pentahydro-9H-1,3-dioxoleno[4,5-j]phenanthridin-6-one
[ent-narciclasine] [(ꢀ)-1]
A magnetically stirred solution of compound 23 (50 mg
including 14 mg of triphenylphosphine oxide, 0.074 mmol of
23) in CH2Cl2 (2 mL) maintained under a nitrogen atmosphere
at ꢀ40 ꢂC was treated with TMSBr (270 mL, 2.09 mmol). The
resulting mixture was warmed to ꢀ20 ꢂC over ca. 0.5 h, stirred
at ꢀ20 to ꢀ10 ꢂC for 2 h then treated with NaHCO3 (2 mL of
a saturated aqueous solution then 176 mg of solid material).
The ensuing mixture was warmed to 18 ꢂC, stirred at this tem-
perature for 0.5 h, then treated with TLC-grade silica (ca. 1 g).
The solvents were removed under reduced pressure, and the re-
sulting white powder loaded onto a 5 cmꢃ1.5 cm column of
TLC-grade silica that was then eluted with CH2Cl2 followed
by 2:98/4:96/5:95/1:9 v/v MeOH/CH2Cl2. Concentration
of the appropriate fractions (Rf¼0.4 in 1:4 v/v MeOH/CH2Cl2)
afforded the title compound (ꢀ)-1 (11 mg, 48%) as a white, crys-
talline solid, mp >250 ꢂC with discolouration commencing at
180 ꢂC, [a]D ꢀ116 (c 0.21, MeOH) [lit.13 (for narciclasine)
[a]D þ112 (c 0.57, MeOH)]. [Found: (MþNa)þ, 330.0599 and
(MþH)þ, 308.0768. C14H13NO7 requires (MþNa)þ, 330.0590
and (MþH)þ, 308.0770.] 1H NMR (500 MHz, CD3OD) d 6.76
(s, 1H), 6.16 (m, 1H), 6.03 (m, 2H), 4.34 (m, 1H), 4.22 (m,
1H), 3.89 (m, 2H); 1H NMR (500 MHz, DMSO-d6), see Table
1; 13C NMR (75 MHz, DMSO-d6), see Table 1; IR nmax 3429,
2918, 1676, 1472, 1379, 1262, 1231, 1089, 1031 cmꢀ1; MS
m/z (ESI) 330 [(MþNa)þ, 100%], 308 [(MþH)þ, 95].
4.2.8. (1R,4R,5S,6R)-2-Bromo-4,5,6-tris(methoxymethoxy)-
cyclohex-2-enamine (6)
Aminoconduritol 6 was prepared, over nine steps, from
commercially available cis-1,2-dihydrocatechol 7 employing
protocols we have described previously16b save for the use
of freshly distilled DBU in the conversion 20/21, which
allowed the yield for this step to be raised from 65% to 78%.
4.2.9. (2R,4R,3S,4aS)-2,3,4,7-Tetra(methoxymethoxy)-
2,3,4,5,4a-pentahydro-9H-1,3-dioxoleno[4,5-j]phen-
anthridin-6-one (23)
4.3. Crystallographic study on compound 13
4.3.1. Crystal data
C9H7IO5, M¼322.06, T¼200(1) K, orthorhombic, space group
A magnetically stirred mixture of amine 6 (42 mg,
0.12 mmol) in toluene (1.5 mL) and H2O (1.5 mL) was treated
with boronate ester 4 (68 mg, 0.19 mmol), K2CO3 (50 mg,
0.35 mmol), TBAB (10 mg, 0.03 mmol) and Pd(PPh3)4
(20 mg, 0.02 mmol). The ensuing mixture was stirred at
120 ꢂC in a CEM ExplorerÔ microwave reactor for 0.5 h
then cooled, diluted with CH2Cl2 (50 mL) and washed with
H2O (1ꢃ10 mL) before being dried (MgSO4), filtered and con-
centrated under reduced pressure to afford a dark-brown oil.
Subjection of this material to column chromatography (silica,
1:99/1.5:98.5 v/v MeOH/CH2Cl2 gradient elution) provided,
after concentration of the appropriate fractions (Rf¼0.4 in 5:95
v/v MeOH/CH2Cl2), the title compound 23 (50 mg including
14 mg of triphenylphosphine oxide, 63% of 23) as a yellow
˚
P212121, Z¼4, a¼4.1771(2), b¼6.9480(3), c¼33.0128(15) A,
3
V¼958.11(7) A , Dx¼2.233 g cmꢀ3
,
2147 unique data
˚
(2qmax¼55ꢂ), 1877 withI>3.0s(I);R¼0.030, Rw¼0.034, S¼1.12.
4.3.2. Structure determination
Images were measured on a Nonius Kappa CCD diffrac-
˚
tometer (Mo Ka, graphite monochromator, l¼0.71073 A)
and data extracted using the DENZO package.37 Structure so-
lution was by direct methods (SIR92).38 The structure of com-
pound 13 was refined using the CRYSTALS program
package.39 Atomic coordinates, bond lengths and angles, and
displacement parameters have been deposited at the Cam-
bridge Crystallographic Data Centre (CCDC no. 662224).
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
ꢁ
ꢁ
foam. (Found: Mþ , 483.1740. C22H29NO11 requires Mþ ,
1
483.1741.) H NMR (CDCl3, 300 MHz) d 6.80 (s, 1H), 6.39
(br s, 1H, NH), 6.06 (br m, 1H), 6.05 (d, J¼1.5 Hz, 1H),
6.02 (d, J¼1.5 Hz, 1H), 5.28 (m, 2H), 4.86e4.67 (complex

4826
M. Matveenko et al. / Tetrahedron 64 (2008) 4817e4826
18. For reviews on methods for generating cis-1,2-dihydrocatechols by micro-
bial dihydroxylation of the corresponding aromatics, as well as the syn-
thetic applications 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,
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033.
Acknowledgements
K. J.; Stewart, S. G.; Vogtle, M. Pure Appl. Chem. 2003, 75, 223; (c)
¨
Johnson, R. A. Org. React. 2004, 63, 117.
We thank the Institute of Advanced Studies and the Austra-
lian Research Council for generous financial support.
19. Compound 7 can be obtained from the Aldrich Chemical Co. (Catalogue
Number 489492) or from Questor, Queen’s University of Belfast, North-
ern Ireland (see: http://questor.qub.ac.uk/newsite/contact.htm).
20. Gilman, N. W. J. Chem. Soc., Chem. Commun. 1971, 733.
21. Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
22. Crich, D.; Krishnamurthy, V. Tetrahedron 2006, 62, 6830.
23. Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875.
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