Atom transfer radical cyclization reactions (ATRC): Synthetic applications

Article abstract of DOI:10.1016/j.tet.2006.01.038

Atom transfer cyclization reactions (ATRC) provide rapid access to functionalized γ-butyrolactones.

Full text of DOI:10.1016/j.tet.2006.01.038

Tetrahedron 62 (2006) 3004–3015
Atom transfer radical cyclization reactions (ATRC):
synthetic applications
Chris D. Edlin,a James Faulkner,b Madeleine Helliwell,b Christopher K. Knight,b
b
Jeremy Parker,c Peter Quayleb, and James Raftery
*
aMedicinal Chemistry 1, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, UK
bSchool of Chemistry, The University of Manchester, Manchester M13 9PL, UK
cAstraZeneca Process R&D, Avlon Works, Severn Road, Hallen Bristol BS10 7ZE, UK
Received 7 November 2005; revised 21 December 2005; accepted 12 January 2006
Available online 13 February 2006
Abstract—Atom transfer cyclization reactions (ATRC) provide rapid access to functionalized g-butyrolactones.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
which the (planar) benzylic radical adopts a conformation in
which the bulky aromatic residue takes up an ‘outside-’
orientation with respect to the lactone ring, thereby
minimizing unfavorable steric interactions. Halogen
abstraction from the copper (II) complex 4, generated in
the first step of the reaction, proceeds in a direction anti- to
the bulky geminal dichloromethylene residue6 (steric
approach control). Given that structurally related g-butyro-
lactones, for example, 6 have found application7 in the
synthesis of a variety of lignans we wondered whether an
ATRC approach8 could be employed in the preparation of
these synthetically useful intermediates.
Transition metal catalyzed atom transfer radical cyclization
reactions1 (ATRC) provide a useful alternative to the more
widely adopted2 ‘tin hydride’ variants of this process.
ATRC reactions are of interest in that they generate
intermediates, which possess a potentially useful carbon–
halogen bond for manipulation after cyclization has
taken place. Although a number of groups1 have reported
on the ATRC of polyhaloacetates and amides, leading to
g-butyrolactones and g-butyrolactams, there are scant
reports concerning their use in target-oriented synthesis.3
In this paper, we detail our preliminary results in this area.
Cl
4
a
O
O
O
O
OCOCCl3
2. Results and discussion
Cl
Cl
Cl
Cl
2
3
5
In previous reports,4 we demonstrated that a range of
catalysts including the 1st generation Grubbs catalyst
promotes cyclization of the ester 2 affording the lactone 5
in high yield. Of note was the observation that the reaction
proceeds with very high levels of diastereoselectivity
affording the threo-isomer 5 as the sole product. Subsequent
studies established that the stereochemical outcome of this
radical reaction is essentially independent of the catalyst
used, the same result being obtained with, for example,
copper catalysts. This stereochemical result may be
rationalized5 in terms of an ‘allylic strain model’ depicted
below (Scheme 1). Cyclization of 2 initially generates 3 in
Cu(II)ClLn
4
O
OR
Cl2C
O
via
O
Ar
H
H
X
6
O
II
[Cu]
Cl
Scheme 1. Reagents and conditions: (a) CuCl (5 mol%), dHbipy (5 mol%),
DCE, 80 8C, 89% (drO95:5).
Initial studies were concerned with the synthesis of the
trichloroacetate 8, which was readily accomplished9 in three
steps from piperonal (Scheme 2). Purely fortuitously
we also observed that attempted trichloroacetylation of
10-hydroxysafrole 7 also resulted in the isolation of
Keywords: Atom; Transfer; Cyclization; Radical; ATRC; Copper.
*
Corresponding author. Tel.: C44 161 275 4619; fax: C44 161 275 4598;
e-mail: peter.quayle@manchester.ac.uk
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.038

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3005
CHO
O
O
O
O
O
O
OCOCCl3
OH
a
b
8
7
8
Cl
d
Cl
c
O
O
O
+
O
O
O
O
O
Cl
9T
Cl
9E
Cl
Cl
Scheme 2. Reagents and conditions: (a) i. Ph3P]CHCO2Et (1 equiv), THF,
20 8C, 89%, ii. Dibal-H (2.2 equiv), THF, K78 8C, 88% (cf. Ref. 9), iii.
ClCOCCl3 (1 equiv), Et3N (1 equiv), Et2O, 0 8C, 85%; (b) H2CCHMgBr,
THF, K78 8C, (c) ClCOCCl3 (1 equiv), Et3N (1 equiv), Et2O, 0 8C, 91%
(over two steps); (d) CuCl (5 mol%); dHbipy (5 mol%); DCE, 80 8C; 90%.
the rearranged ester 8. This facile high-yielding reaction
(O90% over two steps) sequence could be conducted very
simply on a preparative scale and became the route of
choice to this particular substrate. Surprisingly exposure of
the ester 8 (3 mmol) to a preformed solution of a Cu(I)–
dHbipy catalyst10 (5 mol%) in degassed 1,2-dichloroethane
for 3.5 h at reflux was almost stereo-random and afforded
the diastereoisomeric chlorolactones 9T and 9E (9T:9EZ3:2)
in 90% isolated yield. Stereochemical assignments in this
series were secured on the basis of a single crystal X-ray
structure11 carried out on the major diastereisomer 9T
(Fig. 1). On scaling-up this reaction (46 mmol) we observed
that the initial product of the reaction was indeed the threo-
isomer 9T, as predicted (9T:9EZ19:1), suggesting that
equilibration had taken place after cyclization in our initial
experiments. That this was the case was confirmed when it
was found that subjecting either of the isomers 9T or 9E
separately to mild thermolysis in DCE again afforded 9T and
9E as a 3:2 mixture at equilibrium. This isomerisation is
apparently thermally driven and does not necessitate the
addition of a copper catalyst, Scheme 2.
Figure 2. X-ray structure of 11a (crystallographic numbering).
generating a planar benzylic cation 10 whose interception
by benzyl alcohol would, as in the case of the radical
chemistry, affords the threo-product 11aT (drO95:5).
Replacing benzyl alcohol with allyl alcohol or methanol
in this reaction also resulted in the isolation of the ethers 11b
(91%) and 11c (75%), both with reasonable levels of
diastereoselectivity (dr ca. 9:1; stereochemistry by analogy,
vide supra). Dechlorination of 11a (Bu3SnH, AIBN, PhH,
80 8C) proved uneventful and afford the known13 lactone 12
in 83% isolated yield. Regioselective catalytic hydrogeno-
lysis (10% Pd–C, H2, EtOAc, of 12 followed by in situ
protection (TBDMSCl, imidazole, DMAP, TBAB, CH2Cl2)
led directly to the known14 TBS ether 13 in 72% overall
yield from 12. The spectral data for 13 were identical to that
reported by Coelho14 thereby providing additional support
for our stereochemical assignments (Scheme 3).
With a practical synthesis of the intermediate 12 to hand we
have briefly investigated its chemistry. In keeping with
Brown’s13 earlier work, enolate generation (LDA,
1.2 equiv, THF; K78 8C; 1 h) followed by reaction with
3,4,5-trimethoxybenzaldehyde afforded the aldol products
14 as a 1:1 mixture of diastereoisomers at the newly created
benzylic centre (76% yield). Exposure of the diastereoiso-
meric mixture 14 to a Lewis acid (BF3$OEt2, 1.0 equiv;
CH2Cl2; K78 8C, 30 min) resulted in the isolation15a of the
retro-lignan 15 (71%) together with the bis-epipodophyllo-
toxin15b derivative 16 as a minor component (12%).
Molecular models indicate that the cyclohexene ring of 15
adopts a half-boat conformation in which the aromatic
substituent at C-4 is pseudo-equatorially disposed (3JH3a–H4
15 Hz), Figure 3.
This conformational bias places the aromatic ring of the C-1
substituent over the C-5 methoxy group, a situation which
Figure 1. X-ray structure of 9T (crystallographic numbering).
1
With the chlorolactones 9T and 9E in hand their solvolysis12
was next attempted. After some experimentation it was
discovered that dissolution of a diastereoisomeric mixture
of lactones 9T,9E (9T:9EZ3:2) in CH2Cl2 containing benzyl
alcohol (2 equiv of a 1.7 M soln) at 50 8C resulted in a clean
conversion into a single crystalline threo-ether 11a in 85%
yield. Again stereochemical assignments were based upon
single crystal X-ray analysis (Fig. 2). We presume that these
reactions proceed via heterolysis of the C–Cl bond,
results in a large upfield shift16 of this substituent in its H
NMR spectrum compared to 14 (Ddz0.5 ppm). Catalytic
hydrogenation of 15 (10% Pd–C; EtOAc; H2) proved to be
highly stereoselective17 (drO95:5), as depicted in Figure 3,
and afforded the tetrahydronaphthalene 17 possessing
a cis-fused lactone in high yield (86%). Reduction of
the D9,9a-double bond of 15 results in a conformational
change in ring B of 17. Detailed NOE experiments led us
to conclude that whilst the cyclohexane ring of 17 still

3006
C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
adopts a half-boat conformation18a the aryl residue at
OR
Cl
Cl
O
O
O
O
O
O
the C-1 substituent is now pseudo axially disposed
(3JH3a–H4z1 Hz). Presumably this conformational change
occurs in order to minimize a potentially destabilizing peri-
interaction between the bulky substituent at C-4 and the C-5
methoxy group (Fig. 4). Reaction of the enolate derived
from 17 was highly stereoselective19a resulting in attack
from the exo-face of the cup-shaped enolate. Hence, enolate
generation (KHMDS, 1 equiv; THF, K78 8C) followed by
reaction with (1R)-camphorsulfonyloxaziridine (2.2 equiv;
THF; K78 8C) afforded the diastereoisomerically pure
hydroxylated lactone 1819b in good yield (67%).
a
+
O
O
O
O
O
Cl
Cl
9T
Cl
9E
Cl
Cl
Cl
O
11a; R = Bn
11b; R = Me
11c; R = Allyl
O
OBn
Cl2C
O
O
10
O
R
O
O
Ar
H
b
H
H
O
OBn
MeO
OMe
O
OR
O
O
OMe
O
O
O
d
e
16
O
HO
O
14
12, R = Bn
+
9
c
O
MeO
OMe
MeO
MeO
13, R = TBDMS
OMe
HO
1
O
5
4
HO
O
O
OH
H
H
MeO
MeO
MeO
MeO
H
3a
O
j
MeO
i
O
O
H
MeO
MeO
O
f
15
O
O
O
O
20
21a,b
OH
O
O
O
O
OH
OH
H
H
H
MeO
MeO
MeO
MeO
MeO
MeO
O
B
g
H
h
MeO
MeO
MeO
O
O
O
O
O
O
19
18
17
Scheme 3. Reagents and conditions: (a) ROH (2.0 equiv), CH2Cl2, 50 8C,
85% (R]Bn) or ROH (excess), 20 8C, 82% (RZAllyl); 78% (RZMe); (b)
TBTH (2.0 equiv), AIBN (20 mol%), PhH, 80 8C, 83%; (c) i. 10% Pd–C,
H2, EtOAc, ii. TBDMSCl (1.0 equiv), imidazole (1 equiv), DMAP (cat.),
CH2Cl2, RT, 72% overall; (d) i. LDA (1.2 equiv), THF, K78 8C, ii. ArCHO
(1.2 equiv), THF, K78 8C, 76% (1:1 mixture of isomers), (e) BF3.Et2O
(1.0 equiv), CH2Cl2, RT, 15 (71%) and 16 (12%), (f) 10% Pd–C; H2,
EtOAc, 86%; (g) i. KHMDS (1.0 equiv), THF, K78 8C, ii. (1R)-(K)-
(10-camphorsulfonyl)oxaziridine (2.2 equiv), K78 8C; 67%; (h) LiAlH4
(2.4 equiv), THF, 0 8C; 87%; (i) i. OsO4 (1.2 equiv), pyridine, 20 8C, 12 h,
ii. Na2SO3, 65%; (j) SmI2: 3 equiv, THF:H2O (98:2), 20 8C, 15 min, 86%.
Figure 4. Chem 3D representation of 17.
Again, NOE studies infer that ring B of 18 exists in a half-
boat conformation in which the aryl substituent at C-4 is
pseudo-axially disposed (3JH3a–H4 1.5 Hz). Reduction20 of
the lactone 18 (LiAlH4, 2.4 equiv; THF; 0 8C; 5 min)
afforded the lactol 19 as a single diastereoisomer in 87%
yield, which we have tentatively assigned as the b-epimer
on the basis of NOE measurements. The lactol 19 is related
to other oxygenated lignans such as the africanal21 and the
triol cycloovitol22 which, notwithstanding their interesting
biological activity, have received scant attention from
synthetic chemists.22 In addition, dihydroxylation of the
electron deficient D9,9a-bond of 15 proved sluggish but
proceeded cleanly following the procedure adopted by
Criegee,23a which is stoichiometric in osmium tetroxide.
This reaction also proved to be highly stereoselective,
affording the diol 20 in 65% yield, again as a result of the
reagent approaching from the b-face of 15 as depicted in
Figure 3. In passing it is also noteworthy that the intermediate
osmate ester, 200 (Fig. 5), formed during this reaction, proved
to be quite stable towards hydrolysis and survived chromato-
graphy although its demetallation could be readily achieved
using Sarrett’s procedure.23b Analysis of the coupling
1
constant data derived from the H NMR spectrum of 200
suggests that this molecule rapidly interchanges18b between
two boat conformations on the NMR time scale and that the
resulting coupling pattern differs from that which would be
expected for the conformationally constrained isomer 2000,
Figure 3. Chem 3D representation of 15.

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3007
Figure 5. Conformational analysis of 200 and 2000.
Scheme 4. Interconversion of 21a,b.

3008
C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
the product of a-attack by the oxidizing agent on lactone 15,
Figure 5.
subsequent intramolecular Friedel–Crafts alkylation, a
process presumably aided by the Lewis acidity of the
oxidizing agent.30
Whilst the deoxygenation of the diastereoisomerically pure
diol 20 was readily achieved, in high isolated yield, using
the conditions reported by Hanessian24 (SmI2 in wet THF;
86%) we were surprised to find that this reaction afforded an
inseparable mixture of isomeric alcohols, tentatively
assigned as 21a,b25 (drZ3:1). Specifically, NOE measure-
ments support the assertion that both isomers possess a cis-
lactone moiety, with the b-isomer, 21a, exhibiting an
additional mutual enhancement between C8–H and C9–Ha.
Molecular models suggest these substituents in 21a are
almost co-planar, whilst in 21b, the C9–OH group is
coplanar with the C8–H resulting in a down-field shift of
C8–H (Ddz0.1 ppm) in this isomer. We presume that the
formation of 21b during this reaction proceeds via an aldol–
retroaldol reaction26 involving the intermediacy of an
enolate anion 21c or its equivalent, Scheme 4.
3. Conclusion
This work demonstrates that ATRC reactions can be utilized
in the rapid, stereoselective synthesis of functionalized
g-butyrolactones (Scheme 5).
O
O
O
O
OAc
OR
MeO
O
MeO
O
O
O
MeO
MeO
[O] ?
22; R = Ac
23; R = Bn
MeO
MeO
(-)-Steganacin
The synthesis of steganone and related lignans has been a
popular target27 in recent years and we mused whether a
direct approach to the steganacin system could be
accomplished via a bi-aryl coupling reaction28 of the
lactone 22. In order to investigate this strategy we therefore
embarked upon the synthesis of the model substrate 23.
Unfortunately, attempts to alkylate the enolate derived from
12 were fraught with problems and resulted in the
preferential formation of the di-alkylated lactone 24.
Nevertheless enough of 24 could be prepared in order to
investigate the pivotal oxidative coupling reaction. Wald-
vogel29 has recently advocated the use of MoCl5 for the
promotion of such reactions, demonstrating it to be superior
to other oxidizing agents more commonly employed in
intramolecular oxidative coupling of aromatics. However,
exposure of the lactone 24 to MoCl5 (2 equiv; CH2Cl2; 0 8C)
resulted not in oxidative coupling of the aromatic rings but
rather in the isolation of the cyclolignan 25, as a single
diatereosisomer, in 50% yield. Again stereochemical
assignments were established on the basis of NOE
experiments, Figure 6. It would appear that the intended
bi-aryl coupling reaction is again dogged by the proclivity
of the benzylic substituents to undergo ionization and
OBn
Ar
Ar
O
O
OBn
O
MeO
b
O
O
O
O
a
O
O
O
MeO
H
Ar
MeO
12
(Ar = 3,4,5-(MeO)3C6H2–)
O
O
24
25
Scheme 5. Reagents and conditions: (a) i. KHMDS (2 equiv); THF; 2 h;
K78 8C, ii. ArCH2Br (2.0 equiv); THF; K78 8C; 55%; (b) MoCl5
(2.0 equiv); CH2Cl2; 0 8C; 50%.
4. Experimental
4.1. General
All non-aqueous reactions were performed under an
atmosphere of dry nitrogen at temperatures, which were
those of the external bath. Proton nuclear magnetic
resonance (1H) spectra were recorded on Varian INOVA
400 (400 MHz) or Varian INOVA Unity 300 (300 MHz)
spectrometers, with residual non-deuterated solvent as
internal standard. All chemical shifts are quoted in parts
per million downfield from tetramethylsilane. J values are
given in Hz. Splitting patterns were abbreviated as follows:
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
broad (br). Carbon NMR spectra (13C NMR) were recorded
on a Varian INOVA unity 300 spectrometer at 75 MHz.
Infrared spectra were recorded on a Perkin-Elmer 1710 FT
spectrometer as evaporated films unless otherwise stated.
Absorption maxima (nmax) are reported in wavenumbers
(cmK1). Mass spectra were recorded on a Micromass Trio
200 spectrometer (low resolution). High-resolution mass
spectra were recorded on a Kratos Concept IS spectrometer
using electron impact (EI), chemical ionization (CI;
ammonia) or electrospray in positive mode (ESC) modes
of ionization. Microanalysis was performed at the Univer-
sity of Manchester. Melting points were recorded on a
Kofler heated stage microscope, and are uncorrected.
Hexanes refers to that fraction of light petroleum ether,
which distills between 40 and 60 8C, and was redistilled
Figure 6. Chem 3D representation of 25.

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3009
prior to use. Tetrahydrofuran (THF) was dried over sodium-
benzophenone ketyl and distilled under an atmosphere of
dry nitrogen. Dichloromethane was dried over phosphorus
pentoxide and distilled. Triethylamine and pyridine were
dried over potassium hydroxide pellets and redistilled under
nitrogen. Where ether is mentioned it refers to diethyl ether.
n-Butyllithium was supplied as solution in hexanes.
Trichloroacetyl chloride and tri-n-butyltin hydride were
distilled prior to use. Chromatography refers to flash column
chromatography and was carried out using Merck silica gel
60H (40–63 mm, 230–400 mesh) as stationary phase. Thin-
layer chromatography was carried out on plates pre-coated
with Kieselgel 60 F254 silica. Visualization was achieved by
ultraviolet absorption or treatment with an ethanolic
solution of dodecamolybdophosphoric acid followed by
heating. 4,40-Di-n-heptyl-2,20-bipyridine (dHbipy) was
prepared according to the literature31 procedure.
and concentrated in vacuo to afford the title compound 8 as a
low-melting solid, which was used in subsequent ATRC
reactions without further purification. Crude overall yield
4.04 g (91%).
4.1.2.
(4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(chloro)-
methyl]-3,3-dichlorodihydrofuran-2(3H)-one and 9T
and (4R*)-4-[(S*)-1,3-benzodioxol-5-yl(chloro)methyl]-
3,3-dichlorodihydrofuran-2(3H)-one, 9E. A dry Schlenck
tube was charged with CuCl (0.014 g, 5 mol%), dHbipy
(0.046 g; 5 mol%) and anhydrous 1,2-DCE (3 mL) and the
resulting brown solution was allowed to stir for 10 min at
room temperature. The contents of the flask were then
degassed (three times using freeze–thaw cycle). To this
solution was added, by syringe, a solution of trichloroace-
tate 8 (0.91 g, 2.8 mmol) in 1,2-DCE (1 mL). After
degassing (three times freeze–thaw cycle), the Schlenck
tube was placed in a pre-heated oil bath (90 8C) and was
allowed to stir for 3.5 h under an atmosphere of argon. Upon
cooling, the solvent was removed in vacuo and the residue
chromatographed (silica; 1:19 EtOAc/hexanes) to give the
diastereoisomeric lactones 9T and 9E. The major product 9T
(Rf 0.2; silica; 1:19 EtOAc/hexanes) was isolated as a white
solid. Yield 0.30 g (31%), mp 165–166 8C (from DCE–
hexanes). dH (300 MHz, CDCl3) 3.59 (1H, td, JZ10, 8 Hz,
C4–H), 3.75 (1H, apparent t, JZ10 Hz, C5–H), 3.90 (1H,
dd, JZ9, 8 Hz, C5–H), 5.12 (1H, d, JZ10 Hz, CHCl), 5.95
(2H, s, OCH2O), 6.82 (1H, d, JZ8 Hz, ArH), 6.88 (1H, dd,
JZ8, 1.5 Hz, ArH), 6.93 (1H, d, JZ1.5 Hz, ArH) ppm; dC
(75 MHz, CDCl3) 167.9, 149.1, 149.0, 130.6, 121.4, 108.8,
107.4, 102.0, 79.3, 67.5, 58.4, 57.8 ppm; nmax (Nujol) 2906,
1803 (s), 1609, 1503, 1447, 1374, 1250 cmK1; m/z (EI) 323
(MC10%), 287 (20%), 169 (100%), 135 (40%), 122 (40%);
m/z (CI) 341 ([MCNH4]C10%), 287 (50%), 236 (70%),
168 (100%). HRMS (EI) C12H395Cl3O (MC) requires:
321.9561; found: 321.9569. The minor isomer 9E (Rf 0.35;
silica; 1:19 EtOAc/hexanes), was isolated as a white solid.
Yield 0.192 g (21%), mp 159–160 8C (from DCE–hexanes).
dH (300 MHz, CDCl3) 3.50–3.64 (1H, m, C4–H), 4.20 (1H,
apparent t, JZ7 Hz, C5–H), 4.75–4.85 (1H, m, C5–H), 5.20
(1H, d, JZ10 Hz, CHCl), 5.95 (2H, s, OCH2O), 6.72 (1H,
dd, JZ8, 2 Hz, ArH), 6.95–7.05 (2H, m, ArH) ppm; dC
(75 MHz, CDCl3) 167.8, 149.1, 148.4, 130.6, 122.5, 108.4,
108.2, 101.8, 78.8, 69.1, 60.5, 57.7 ppm; nmax (Nujol) 2925,
1810 (s), 1613, 1528 cmK1; m/z (EI) 323 (MC10%), 287
(20%), 169 (100%), 135 (40%), 122 (40%); m/z (CI) 341
([MCNH4]C10%), 287 (50%), 236 (70%), 168 (100%).
HRMS (EI) C12H395Cl3O4 (MC) requires: 321.9561; found:
321.9563.
4.1.1. (2E)-3-(10,30-Benzodioxol-5-yl)prop-2-enyl tri-
chloroacetate, 8. a. To a solution of (2E)-3-(10,30-
benzodioxol-5-yl)prop-2-en-1-ol9 4.63 g, 26 mmol) and
triethylamine (3.61 mL, 26 mmol) in dry ether (90 mL)
was slowly added, at 0 8C, freshly redistilled trichloroacetyl
chloride (2.89 mL, 26 mmol) and the mixture was allowed
to stir at 0 8C for 3 h. After stirring for 3 h, the reaction was
quenched with water (100 mL) and the organic phase was
extracted with ether (2!100 mL). The combined organic
phases were washed with saturated sodium hydrogencarbo-
nate solution (10%, 50 mL), brine (200 mL), dried (MgSO4)
and the solvent removed in vacuo to afford the title
compound as a pale yellow, chromatographically unstable
oil which solidified on standing, which was used without
further purification. Yield 7.15 g, (85%). dH (300 MHz,
CDCl3) 6.95 (1H, s), 6.70–6.90 (2H, m, ArH), 6.66 (1H, br
d, JZ16 Hz, alkene), 6.20 (1H, dt, JZ16, 7 Hz, alkene),
6.0 (2H, s, O–CH2–O), 5.00 (2H, dd, JZ7, 1 Hz, CH2–
OCOCCl3) ppm; dC (75 MHz, CDCl3) 162.1, 148.4, 148.3,
136.8, 130.3, 122.3, 118.8, 108.6, 106.2, 101.7, 90.2,
70.2 ppm; nmax (evaporated film) 2896, 1763 (s), 1607,
1503, 1491, 1447, 1250 cmK1; m/z (ES) 323, 325, 329.
b. To a solution of piperonal (2.0 g, 1.3 mmol) in anhydrous
THF (50 mL) at K78 8C was added, under an atmosphere of
nitrogen, vinylmagnesium bromide (14.6 mL of a 1 M
solution in THF ex Aldrich; 14.7 mmol) and the reaction
mixture allowed to warm up to room temperature. On re-
cooling to 0 8C the reaction was quenched by the addition of
saturated aqueous ammonium chloride (20 mL), the organic
phase was extracted with ether (3!30 mL), the combined
extracts dried (MgSO4) and concentrated in vacuo to afford
10-hydroxysafrole 7 [dH (300 MHz, CDCl3) 3.00 (1H, br s,
OH), 5.07 (1H, br d, JZ6 Hz, CH2O), 5.18 (1H, dt, JZ10,
1.5 Hz, alkene), 5.32 (1H, dt, JZ16, 1.5 Hz, alkene), 5.94
(2H, s, OCH2O), 5.96–6.06 (1H, m, alkene), 6.76–6.88 (3H,
m, ArH) ppm] in an essentially pure state (yield 2.27 g,
95%), which was used in the next step without further
purification. The crude product, 7, was redissolved in dry
ether (100 mL), to which was added, at 0 8C, triethylamine
(1.8 mL, 12.8 mmol) followed by trichloroacetyl chloride
(1.4 mL, 12.8 mmol). The reaction mixture was left to stir at
0 8C for 1 h after which time it was quenched by the addition
of water (30 mL). The aqueous layer was extracted (ether,
3!20 mL), the combined organic extracts dried (MgSO4)
4.1.3. (4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(benzyloxy)-
methyl]-3,3-dichlorodihydrofuran-2(3H)-one, 11a. The
trichlorolactone 9E,T (0.56 g, 1.73 mmol) and benzyl
alcohol (0.374 g, 3.46 mmol, 2.0 equiv) were dissolved in
a minimum volume of anhydrous dichloromethane (2 mL).
The resulting solution was placed in a preheated oil-bath
(50 8C), which was maintained at this temperature until TLC
analysis indicated that all of the starting material had been
consumed. The solvent was removed in vacuo and the
residue was purified by chromatography (silica, 1:17
EtOAc/hexanes) affording the title compound as a white
solid. Yield 0.622 g (91%), 152–154 8C (from DCM–
hexanes). dH (300 MHz, CDCl3) 3.20 (1H, q, JZ7 Hz,

3010
C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
C4–H), 4.28 (1H, d, JZ11 Hz, CH2Ph), 4.34 (1H, dd, JZ9,
7 Hz, C5–H), 4.48 (1H, d, JZ11 Hz, CH2Ph), 4.62 (1H, dd,
JZ9, 7 Hz, C5–H), 4.80 (1H, d, JZ7 Hz, CHOCH2Ph),
6.05 (2H, s, OCH2O), 6.85–6.95 (3H, m, ArH), 7.22–7.40
(5H, m, ArH) ppm; dC (75 MHz, CDCl3) 168.3, 148.6,
148.4, 142.2, 137.2, 131.0, 128.8, 128.2, 128.0, 121.6,
108.7, 107.5, 101.6, 79.3, 79.1, 70.5, 68.1, 60.6, 57.1 ppm;
nmax (evaporated film) 2900, 1803, 1502, 1489, 1241, 1182,
1038 cmK1; m/z (EI); 394 (MC, 5%), 324 (5%), 287 (10%),
241 (10%), 169 (20%), 149 (30%), 91 (100%); m/z (CI); 412
([MCNH4]C, 25%), 340 (20%), 246 (30%), 230 (60%),
4.1.6. (4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(allyloxy)-
methyl]-3,3-dichlorodihydrofuran-2(3H)-one, 11c.
Dissolution of 9E,T (100 mg) in allyl alcohol (2 mL) for
12 h at ambient temperature followed by removal of the
solvent in vacuo and column chromatography afforded the
title compound as a colourless oil. Yield 88 mg (82%). dH
(300 MHz, CDCl3) 3.75 (1H, ddt, JZ13, 6, 1.5 Hz, CH2O),
3.15 (1H, q, JZ7 Hz, C4–H), 3.95 (1H, ddt, JZ13, 6,
1.5 Hz, CH2O), 4.38 (1H, dd, JZ9, 7 Hz, C5–H), 4.58
(1H, dd, JZ9, 7 Hz, C5–H), 4.77 (1H, d, JZ7 Hz, ArCH),
5.16–5.25 (2H, m, alkene), 5.76–5.84 (1H, m, alkene), 6.00
(2H, s), 6.78–6.90 (3H, m, ArH); dC (75 MHz, CDCl3)
168.4, 148.6, 148.3, 133.8, 131.1, 131.0, 121.4, 117.8,
107.0, 101.7, 79.5, 78.7, 69.5, 68.0, 57.0 ppm; nmax
(evaporated film) 2901, 1803 (s), 1504, 1489, 1445, 1242,
1182, 1039 cmK1; m/z (ES) 367 ([MCNa]C, 100%).
126 (100%). HRMS (EI) C19H Cl2O5 (MC) requires:
35
16
394.0369; found: 394.0360.
4.1.4. (4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(benzyloxy)-
methyl]-dihydrofuran-2(3H)-one, 12.13 To a stirred
solution of the lactone 11a (1.04 g, 2.65 mmol) and AIBN
(88 mg, 0.53 mmol, 20 mol%) in benzene (35 mL) was
added tri-n-butyltin hydride (1.42 mL, 5.30 mmol). The
resulting mixture was placed in an oil bath at 80 8C and
heated for 6 h. The solvent was removed in vacuo and the
residue was chromatographed (silica, 1:9 EtOAc/hexanes)
to afford the title compound as a white solid. Yield 0.717 g
(83%), mp 126–128 8C (from DCM–hexanes; lit.13 mp 120–
123). dH (300 MHz, CDCl3) 2.28 (1H, dd, JZ18, 8 Hz,
C3–H), 2.32 (1H, dd, JZ18, 8 Hz, C3–H), 2.85–2.95 (1H,
m, C4–H), 4.15 (1H, d, JZ8 Hz, ArCHO), 4.20 (1H, d, JZ
11 Hz, CH2Ph), 4.34 (1H, dd, JZ10, 6 Hz, C5–H), 4.42
(1H, dd, JZ10, 6 Hz, C5–H), 4.48 (1H, d, JZ11 Hz,
CH2Ph), 6.0 (2H, s, OCH2O), 6.75–6.85 (3H, m, ArH),
7.22–7.40 (5H, m, ArH) ppm; dC (75 MHz, CDCl3) 176.4,
148.4, 147.8, 137.4, 132.8, 128.5, 127.9, 120.9, 108.3,
106.7, 101.2, 81.7, 70.9, 70.3, 42.3, 31.3 ppm; nmax
(evaporated film) 1778, 1505, 1487, 1253 cmK1; m/z (EI);
326 (MC, 20%), 219 (40%); m/z (CI) 344 ([MCNH4]C,
25%) 246 (30%), 230 (60%), 126 (100%). HRMS (CI)
C19H18O5 (MC) requires: 326.1145; found: 326.1149.
HRMS (ES) C15H Cl2NaO5 ([MCNa]C) requires:
35
14
367.0111; found: 367.0109.
4.1.7. (4R*)-4-{(R*)-Benzo[1,3]dioxol-5-yl(tert-butyldi-
methy-lsilyloxy)methyl}-dihydrofuran-2(3H)-one, 13. A
solution of 12 (0.102 g, 0.312 mmol) in ethyl acetate (5 mL)
was hydrogenolysed over 5% Pd–C (0.051 g, 50 wt%) at
20 8C under atmospheric pressure for 5 h. The reaction
mixture was filtered through a pad of Celitew, the cake was
washed (EtOAc, 2!20 mL), and the combined filtrates
concentrated in vacuo to afford the crude product, (4R*)-4-
[(R*)-benzo-1,3-dioxol-5yl)hydroxymethyl]dihyd-rofuran-
2-one,32 as a viscous oil, which was used in the next step
without further purification. Yield 0.065 g (82%). dH
(300 MHz, CDCl3) 2.25 (1H, dd, JZ18, 7 Hz, C3–H),
2.38 (1H, dd, JZ18, 9 Hz, C3–H), 2.42–2.52 (1H, br s, OH),
2.78–2.90 (1H, m, C4–H), 4.38 (2H, apparent d, JZ7 Hz,
C5–H), 4.55 (1H, d, JZ8 Hz, CHO), 5.98 (2H, s, OCH2O),
6.75–6.85 (3H, m, ArH) ppm; dC (75 MHz, CDCl3) 177.2,
148.4, 147.9, 136.0, 119.9, 108.6, 106.5, 101.5, 75.4, 70.8,
42.8, 31.6 ppm; nmax (evaporated film) 3600–3200, 1771 (s),
1457, 144, 1243 cmK1; m/z (ES) 235 (100%). HRMS (ES)
C12H12NaO5 ([MCNa]C) requires: 259.0577; found:
259.0575.
Treatment of 9E,T with methanol or allyl alcohol similarly
afforded the ethers 11b and 11c, respectively.
To a suspension of imidazole (0.018 g, 0.26 mmol) in DCM
(3 mL) was added tert-butyldimethylsilylchloride (0.038 g,
0.26 mmol) before cooling to 0 8C. A solution of crude
(4R*)-4-[(R*)-benzo-1,3-dioxol-5-yl)hydroxyme-thyl]dihy-
drofuran-2-one (0.051 g, 0.22 mmol) in DCM (2 mL) was
added by syringe and the resulting mixture was allowed to
warm to room temperature. DMAP (cat.) and TBAI (cat.)
were added before stirring for 14 h, dilution with DCM
(20 mL), and filtration. The filtrate was partitioned with
water (10 mL), the organic layer separated and the aqueous
layer re-extracted (DCM; 3!10 mL). The combined
organic extracts were washed (brine; 10 mL), dried
(MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (1:9 EtOAc/
hexanes) affording the title compound 13, as a colourless
oil. Yield 0.079 g (88%). dH (300 MHz, CDCl3) K0.21 (3H,
s, SiMe2), 0.04 (3H, s, SiMe2), 0.92 (9H, s, SiC (CH3)3),
2.28 (1H, dd, JZ18, 8 Hz, C3–H), 2.36 (1H, dd, JZ18,
8 Hz, C3–H), 2.71–2.84 (1H, m, C4–H), 4.24–4.36 (2H, m,
OCH2), 4.49 (1H, d, JZ7 Hz, CHOSi), 5.96–5.98 (2H, m,
OCH2O), 6.70 (1H, dd, JZ8, 1.5 Hz, ArH), 6.76 (1H, d, JZ
8 Hz, ArH), 6.77 (1H, br s, ArH) ppm; dC (75 MHz, CDCl3)
4.1.5. (4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(methoxy)-
methyl]-3,3-dichlorodihydrofuran-2(3H)-one, 11b.
Dissolution of 9E,T (50 mg) in methanol (2 mL) for 12 h
at ambient temperature, followed by removal of the solvent
in vacuo and column chromatography afforded the title
compound as a colourless oil. Yield 38 mg (78%). dH
(300 MHz, CDCl3) 3.09–3.13 (1H, m, C4–H), 3.25 (3H, s,
OMe), 4.40 (1H, dd, JZ9, 6 Hz, C5–H), 4.56 (1H, dd, JZ
10, 7 Hz, C5–H), 4.63 (1H, d, JZ6 Hz, ArCH), 6.05 (2H, s,
OCH2O), 6.88–6.90 (3H, m, ArH); dC (75 MHz, CDCl3)
168.4, 148.6, 148.3, 131.0, 121.3, 108.7, 107.3, 101.6, 81.4,
79.5, 67.8, 57.0, 56.8 ppm; nmax (evaporated film) 2904,
1802 (s), 1505, 1489, 1242 cmK1; m/z (ES) 341, 343, 345
([MCNa]C). HRMS (ES) C13H Cl2NaO5 ([MCNa]C)
35
12
requires: 340.9954; found: 340.9956. The presence of
a minor amount of an isomeric compound, presumably
(4R*)-4-[(S*)-1,3-benzodioxol-5-yl(methoxy)methyl]-3,3-
dichlorodihydrofuran-2-(3H)-one, was also apparent from
the 1H NMR spectrum of 11b: dH (300 MHz, CDCl3)
3.30 (3H, s, OMe), 3.75–3.85 (2H, m, C5–H), 4.49 (1H, d,
JZ9 Hz, ArCH).

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3011
176.9, 148.1, 147.4, 136.3, 119.7, 108.2, 106.4, 101.3, 75.8,
70.2, 44.3, 31.5, 25.9, 18.2, K4.2, K5.0 ppm; nmax
(evaporated film) 1769, 1515, 1468 cmK1; m/z (CI) 368
([MCNH4]C, 100%) 351 ([MCH]C, 20%), 219 (60%), 91
(20%). HRMS C18H26O5Si (MC) requires: 350.1544;
found: 350.1539
209 (15%); m/z (CI) 540 ([MCNH4]C, 10%). HRMS (CI)
C29H34NO9 ([MCNH4]C) requires: 540.2228; found:
540.2221.
4.1.9. (3aR*,4S*)-4-{(1,3-Benzodioxol-5-yl)-5,6,7-tri-
methoxy-3a,4-dihydronaphtho[2,3-c]}furan-1(3H)-one,
15 and O-benzyl-isoepipodophyllotoxin, 16.15a To a
solution of the aldol adducts 14a,b (0.10 g, 0.19 mmol) in
anhydrous dichloromethane (5 mL) was added, at 20 8C,
boron trifluoride diethyl ether complex (0.023 mL,
0.19 mmol, 1.0 equiv) and the resulting solution was stirred
for 30 . The reaction was quenched by the addition of
saturated sodium hydrogencarbonate solution (1 mL) and
the aqueous phase was extracted with dichloromethane (3!
5 mL). The combined organic extracts were washed (brine;
2!10 mL), dried (MgSO4) and concentrated in vacuo.
Purification of the residue by column chromatography
(silica, 1:4 EtOAc/hexanes) afforded two products, the less
polar of which was identified as the olefin 15, a white
crystalline solid. Yield 0.051 g (71%), mp 171–173 8C
(from DCM–hexanes), (lit. mp15a 170–172 8C), Rf 0.19
(silica, 1:4 EtOAc–hexanes). dH (300 MHz, CDCl3) 3.25
(3H, s, OCH3), 3.30–3.41 (1H, m, C3a–H), 3.94 (1H, d, JZ
15 Hz, C4–H), 3.82 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.98
(1H, t, JZ9 Hz, C3–H), 4.36 (1H, t, JZ7 Hz, C3–H), 5.98
(2H, m, OCH2O), 6.73 (1H, dd, JZ7, 2 Hz, ArH), 6.73 (1H,
s, ArH), 6.76 (1H, s, ArH), 6.78 (1H, d, JZ8 Hz, ArH), 7.32
(1H, d, JZ3.5 Hz, alkene) ppm; dC (75 MHz, CDCl3)
169.9, 153.1, 153.0, 148.1, 146.3, 138.8, 132.5, 129.4,
125.6, 124.2, 120.1, 109.6, 108.5, 107.7, 101.2, 72.6, 61.0,
60.2, 60.7, 56.3, 48.1, 44.0 ppm; nmax (evaporated film)
1771, 1510, 1472, 1287 cmK1; m/z (EI); 396 (MC, 100%);
m/z (CI) 414 ([MCNH4]C, 100%). HRMS C22H20O7 (MC)
requires: 396.1209; found: 396.1204. The more polar
product was identified as the aryltetralin, 16, an amorphous,
white solid. Yield 0.011 g (12%), Rf 0.31 (silica, 1:4
EtOAc–hexanes). dH (300 MHz, CDCl3) 2.66–2.80 (1H, m,
C8a–H), 3.48 (1H, dd, JZ14, 11 Hz, C5a–H), 3.75 (6H, 2!
overlapping s, OCH3), 3.92 (3H, s, OCH3), 4.05 (1H, d, JZ
11 Hz, C5–H), 4.34–4.44 (2H, m, 2!C8–H), 4.55 (1H, d,
JZ2 Hz, C9–H), 4.62 (1H, d, JZ12 Hz, OCH2Ph) 4.75
(1H, d, JZ12 Hz, OCH2Ph), 5.98–6.00 (2H, m, OCH2O),
6.46 (2H, s, ArH), 6.51 (1H, s, ArH), 6.74–6.80 (2H, m,
ArH), 7.34–7.40 (5H, m, ArH) ppm; dC (75 MHz, CDCl3)
176.3, 153.3, 148.6, 146.1, 139.6, 138.1, 136.9, 134.4,
132.5, 129.4, 128.7, 128.3, 128.1, 127.5, 111.0, 109.9,
106.3, 101.6, 101.2, 73.2, 70.3, 67.4, 61.0, 60.2, 56.2, 48.1,
46.5, 45.1, 42.4 ppm; m/z (EI) 504 (MC, 5%), 230 (50%);
m/z (CI) 522 ([MCNH4]C, 100%), 414 (40%). HRMS (CI)
C29H32NO8 ([MCNH4]C) requires: 522.2122; found:
522.2116
4.1.8. (3S*,4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(benzyl-
oxy)-methyl]-3-[(R*S*)-hydroxy(3,4,5-trimethoxy-
phenyl)-methyl]dihydrofuran-2(3H)-one, 14a,b. To a
solution of di-isopropylamine (0.31 mL, 2.21 mmol,
1.20 equiv) in anhydrous tetrahydrofuran (2 mL) was
added, at K78 8C, n-butyllithium (1.26 mL, 2.02 mmol,
1.1 equiv, 1.6 M in hexanes) and the resulting mixture was
stirred at K78 8C for 5 . After this time the solution was
allowed to warm to 0 8C and was stirred for 30 min then
re-cooled to K78 8C. The resulting solution of lithium
di-isoproplyamide was then added by cannula to a solution
of the benzylether 12 (0.60 g, 1.84 mmol, 1.0 equiv) in
anhydrous tetrahydrofuran (5 mL). The resulting solution
was stirred for 1 h, at K78 8C, and a solution of 3,4,5-
trimethoxybenzaldehyde (0.433 g, 2.21 mmol, 1.20 equiv)
in anhydrous tetrahydrofuran (1 mL) was added dropwise
over 10 min by syringe. The solution was stirred for 2 h at
K78 8C and allowed to warm to 20 8C over 2 h after which
time the reaction was quenched by addition of saturated
aqueous ammonium chloride solution (2 mL). The aqueous
layer was extracted (DCM, 3!10 mL) and the combined
organic extracts were washed (brine, 2!10 mL), dried
(MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (silica, 7:13 EtOAc/
hexanes) affording the diastereomeric products 14a,b. The
less polar isomer, Rf 0.43 (silica, 7:13 EtOAc/hexanes) was
isolated as a white foam, yield 0.394 g (41%): dH (300 MHz,
CDCl3) 2.50 (1H, br s, OH), 2.62 (1H, dd, JZ8, 3 Hz,
C3–H), 2.77–2.87 (1H, m, C4–H), 3.80 (6H, 2!overlap-
ping s, 2!OCH3), 3.85 (3H, s, OCH3), 3.90 (1H, dd, JZ9,
4 Hz, OCH2), 4.0 (1H, d, JZ12 Hz, OCH2Ph), 4.30 (1H, d,
JZ12 Hz, OCH2Ph), 4.39 (1H, apparent triplet, JZ9 Hz,
CHOCH2Ph), 4.52 (1H, dd, JZ9, 4 Hz, OCH2), 5.20 (1H, d,
JZ2 Hz, CHOH), 5.98 (1H, d, JZ1 Hz, OCH2O), 6.08 (1H,
d, JZ1 Hz, OCH2O), 6.32–6.36 (3H, m, ArH), 6.44 (1H, dd,
JZ8, 2 Hz, ArH), 6.63 (1H, d, JZ8 Hz, ArH), 7.20–7.40
(5H, m, ArH) ppm; dC (75 MHz, CDCl3) 178.7, 153.5,
148.6, 147.9, 137.7, 137.3, 136.6, 132.2, 128.8, 128.2,
121.2, 107.5, 106.1, 101.9, 81.4, 72.7, 70.9, 70.6, 61.1, 56.2,
50.7, 42.0, 28.1, 27.1 ppm; m/z (EI); 522 (MC, 5%), 405
(10%) 209 (20%); m/z (CI) 540 (MCNHC4 , 20%). HRMS
C29H34O9N ([MCNH4]C) requires: 540.2228; found:
540.2215. The more polar isomer, Rf 0.38 (silica, 7:13
EtOAc/hexanes) was isolated as a white foam, yield 0.336 g
(35%): dH (300 MHz, CDCl3) 2.58 (1H, ddd, JZ13, 8, 5 Hz,
C4–H), 2.92 (1H, t, JZ8 Hz, C3–H), 3.58 (1H, d, JZ5 Hz,
OCHAr), 3.82 (6H, 2!overlapping s, 2!OCH3), 3.84 (3H,
s, OCH3), 3.88 (1H, d, JZ12 Hz, OCH2Ph), 4.00–4.18 (1H,
m, C5–H), 4.32 (1H, d, JZ12 Hz, OCH2Ph), 4.45 (1H, dd,
JZ9, 8 Hz, C5–H), 4.76 (1H, d, JZ9 Hz, CHOH), 6.0 (2H,
dd, JZ8, 1 Hz, OCH2O), 6.44–6.50 (2H, m, ArH), 6.56 (2H,
s, ArH), 6.75 (1H, d, JZ8 Hz, ArH), 7.20–7.40 (5H, m,
ArH) ppm; dC (75 MHz, CDCl3) 178.9, 153.7, 148.6, 147.9,
137.6, 136.0, 132.4, 128.8, 128.2, 127.7, 120.2, 108.4,
106.2, 103.7, 101.6, 79.0, 74.6, 71.2, 68.0, 61.1, 60.6, 56.3,
48.6, 45.2, 21.3 ppm; m/z (EI); 522 (MC, 10%), 405 (15%)
4.1.10. (3aR*,4S*,9aS*)-4-(1,3-Benzodioxol-5-yl)-5,6,7-
trimethoxy-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-
1(3H)-one, 17. A solution of the unsaturated lactone 15
(0.050 g, 0.132 mmol) in ethyl acetate (2 mL) was
hydrogenated over 5% Pd–C (0.025 g, 50 wt%) at room
temperature and atmospheric pressure for 2 h. The reaction
mixture was filtered through a pad of Celitew, and the filtrate
concentrated in vacuo. Chromatography of the crude
product (silica, 17:3 EtOAc/hexanes) afforded the title
compound as a colourless oil. Yield 0.043 g (86%). dH
(500 MHz, CDCl3) 2.83 (1H, dd, JZ15, 8 Hz, C9–H), 2.95

3012
C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
(1H, JZ15, 2 Hz, C9–H), 3.03 (1H, ddd, JZ11, 7, 2 Hz,
C9a–H), 3.55–3.64 (1H, ddt, JZ11, 7, 2 Hz, C3a–H), 3.64
(1H, dd, JZ7, 3 Hz, C3–H), 3.78 (3H, s, OCH3), 3.88 (6H,
2!overlapping s, 2!OCH3), 4.48 (1H, br s, C4–H), 4.60
(1H, t, JZ7 Hz, C3–H), 5.95 (2H, s, OCH2O), 6.45 (1H,
ddd, JZ8, 1.5, 1 Hz, ArH), 6.47 (1H, br s, ArH), 6.53 (1H,
d, JZ1.5 Hz, ArH), 6.63 (1H, d, JZ8 Hz, ArH) ppm; dC
(75 MHz, CDCl3) 178.5, 153.0, 152.2, 148.2, 146.3, 141.3,
135.9, 131.3, 122.4, 120.3 108.4, 108.2, 101.3, 72.9, 61.4,
61.1, 59.2, 40.1, 39.5, 38.8, 29.9, 29.6 ppm; nmax (evapor-
ated film); 1765, 1501, 1379 cmK1; m/z (EI); 398 (MC,
100%), 277 (20%), 135 (50%); m/z (CI); 416 ([MCNH4]C,
100%), 399 ([MCH]C, 20%). HRMS C22H22O7 (MC)
requires: 398.1365; found: 398.1360.
was extracted with dichloromethane (3!5 mL) and the
combined organic extracts were washed with brine, dried
over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica, 3:7 EtOAc/
hexanes) affording compound 25 as an oil. Yield (0.030 g,
50%). dH (300 MHz, CDCl3) 2.22 (1H, d, JZ15 Hz, ArCH),
2.75 (1H, d, JZ15 Hz, ArCH), 3.08 (1H, d, JZ15 Hz,
ArCH), 3.25 (1H, d, JZ15 Hz, ArCH), 3.30–3.40 (1H, m,
C3a–H), 3.45–3.55 (1H, m, C3–H), 3.76 (3H, s, OCH3),
3.86–3.95 (15H, m, OCH3), 4.08 (1H, t, JZ9 Hz, C3–H),
4.50 (1H, br s, C4–H), 6.0 (2H, s, O–CH2–O), 6.35 (2H, s,
ArH), 6.46 (1H, d, JZ9 Hz, ArH), 6.65 (2H, d, JZ4 Hz,
ArH), 6.75 (1H, d, JZ9 Hz, ArH) ppm; dC (75 MHz,
CDCl3) 182.7, 153.3, 153.1, 152.4, 148.3, 146.4, 141.4,
137.1, 135.0, 132.3, 131.4, 122.2, 120.6, 108.3, 108.1,
107.0, 101.4, 71.7, 61.6, 61.2, 61.1, 56.3, 56.2, 51.2, 45.4,
42.3, 41.1, 39.0, 24.0, 21.3 ppm; nmax 2938, 1763, 1590,
1488, 1462 cmK1; m/z (CI); 596 ([MCNH4]C, 50%), 578
(MC, 40%). APCI 579 (30%), 491 (30%), 458 (100%), 411
(65%). HRMS (APCI) C32H34O10 ([MCH]C) requires:
579.2225; found: 579.2225.
4.1.11. (4R*)-4-[(R*)-1,3-Benzodioxol-5-yl(benzyloxy)-
methyl]-3,3-bis[3,4,5-trimethoxyphenyl)methyl]dihydro-
furan-2(3H)-one, 24. To potassium hexamethyldisilazide
(3.92 mL, 1.96 mmol, 0.5 M solution in toluene) was added
slowly by syringe, at K78 8C, a solution of the lactone 12
(0.32 g, 0.98 mmol) in anhydrous tetrahydrofuran (3 mL)
and the resulting mixture was stirred for 2 h whilst warming
up to 20 8C. To this solution was added, slowly by syringe
at 0 8C, 3,4,5-trimethoxybenzyl bromide33 (0.512 g,
1.96 mmol) in anhydrous tetrahydrofuran (3 mL) and the
resulting mixture was stirred for 2 h at 20 8C. The reaction
was quenched by the addition of saturated ammonium
chloride solution (5 mL) and the aqueous phase was
extracted with dichloromethane (3!10 mL). The combined
organic extracts were washed with brine, dried MgSO4 and
concentrated in vacuo and the residue was purified by
column chromatography (silica, 40% EtOAc/hexanes)
affording the bisalkylated lactone, 24 as a glass (0.370 g,
55%). dH (300 MHz, CDCl3) 2.19 (1H, d, JZ12 Hz,
CH2Ar), 2.90–2.98 (1H, m, C4–H), 2.95 (1H, d, JZ
12 Hz, CH2Ar), 3.16 (2H, dd, JZ14, 7 Hz, CH2Ar), 3.78–
3.85 (1H, m, C5–H), 3.85 (6H, s, OCH3), 3.86 (6H, s,
OCH3), 3.88 (6H, s, OCH3), 4.18 (1H, d, JZ12 Hz,
OCH2Ph), 4.31 (1H, t, JZ7 Hz, C5–H), 4.40 (1H, d, JZ
12 Hz, OCH2Ph), 4.72 (1H, d, JZ7 Hz, CHOCH2Ph), 6.08
(2H, s, O–CH2–O), 6.38 (2H, s, ArH), 6.46 (2H, s, ArH),
6.95–7.00 (3H, m, ArH), 7.18–7.24 (2H, m, ArH), 7.32–7.38
(3H, m, ArH) ppm; dC (75 MHz, CDCl3) 179.8, 171.4,
153.2, 153.1, 148.8, 148.3, 137.5, 137.4, 137.1, 133.6,
132.2, 131.7, 129.1, 129.0, 128.8, 128.3, 128.1, 121.6,
108.6, 107.9, 107.8, 107.7, 101.8, 78.5, 70.2, 67.9, 61.2,
61.1, 60.6, 56.4, 56.4, 56.1, 51.5, 46.6, 41.1, 40.5, 34.1,
28.7, 24.1 ppm; nmax (evaporated film) 3067, 2937, 2838,
1766, 1590, 1505, 1459 cmK1; m/z (EI); 686 (MC, 5%), 578
(5%), 455 (5%), 399 (25%), 314 (20%), 181 (100%). HRMS
(CI) C39H46NO11 ([MCNH4]C) requires: 704.3065; found:
704.3079.
4.1.13. (3aS*,4S*,9aR*)-4-(Benzo-1,3-dioxol-5-yl)-5,6,7-
trimethoxy-9a-hydroxy-3a,4,9,9a-tetrahydro-naphtho-
[2,3-c]furan-1(3H)-one, 18. To a stirred solution of 17
(0.067 g, 0.17 mmol) in THF (5 mL) was added potassium
hexamethyldisilazide (0.034 mL, 0.17 mmol of a 2.0 M
soln in THF), at K78 8C. After 1 h at 78 8C a solution of
(1R)-(K)-(10-camphorsulfonyl)oxaziridine
(0.085 g,
0.37 mmol) in THF (1 mL) was added dropwise by syringe
before stirring for a further 3 h. The reaction was quenched
by the addition of saturated ammonium chloride solution
(5 mL), the phases separated, and the aqueous phase
extracted repeatedly with ethyl acetate (3!20 mL). The
combined organic phases were washed with brine (10 mL),
dried (MgSO4), the solvent removed under reduced pressure
and the crude residue residue chromatographed (3:7 ethyl
acetate/hexanes) affording the title compound as a colour-
less viscous oil. Yield 0.046 g (67%). Rf 0.25 (3:7 EtOAc/
hexanes). dH (300 MHz, CDCl3) 2.88 (1H, d, JZ2 Hz, OH),
2.95 (1H, dd, JZ13, 1 Hz, C9–H), 3.12 (1H, d, JZ13 Hz,
C9–H), 3.48–3.55 (1H, m, C3a–H), 3.62 (1H, dd, JZ9,
7 Hz, C3–H), 3.84 (3H, s, OCH3), 3.88 (3H, s, OCH3), 3.92
(3H, s, OCH3), 4.58 (1H, d, JZ2 Hz, C4–H), 4.68 (1H, t,
JZ9 Hz, C3–H), 5.95 (2H, apparent t, JZ2 Hz, OCH2O),
6.54 (1H, s, ArH), 6.75–80 (3H, m, ArH) ppm; dC (75 MHz,
CDCl3) 180.4, 153.2, 152.1, 148.1, 146.3, 141.5, 135.1,
128.8, 122.6, 120.7, 108.5, 108.3, 108.2, 101.2, 71.4,
61.4, 61.1, 56.2, 49.6, 46.5, 43.0, 41.0, 38.8 ppm; nmax
(evaporated film) 3458 (br), 2960, 1772 (s), 1646, 1600,
1489 cmK1; m/z (EI); 414 (MC, 5%), 398 (5%), 108 (60%);
m/z (CI); 432 ([MCNH4]C, 50%), 231 (100%). HRMS (CI)
C22H26NO8 ([MCNH4]C) requires: 432.1662; found:
432.1653.
4.1.12. (3aR*,4S*,9aR*)-4-[(1,3-Benzodioxol-5-yl)-
((3,4,5-trimethoxyphenyl)methyl)]-5,6,7-trimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one, 25.
To a solution of the bis-alkylated lactone 24 (0.071 g,
0.1035 mmol) in anhydrous dichloromethane (2 mL) was
added, at 0 8C, a solution of molybdenum pentachloride
(0.056 g, 0.207 mmol) in anhydrous dichloromethane
(1 mL). The resulting solution was stirred for 2 h and was
then quenched by the addition of saturated sodium
hydrogencarbonate solution (2 mL). The aqueous layer
4.1.14. (1S*,3aS*,4S*,9aR*)-4-(Benzo-1,3-dioxol-5-yl-
5,6,7-trimethoxy)-3,3a,4,9-tetrahydronaphtho[2,3-c]-
furan-1,9a-diol, 19. To a solution of 18 (0.030 g,
0.072 mmol) in anhydrous THF (1 mL) was added lithium
aluminium hydride (0.072 ml, 0.072 mmol, 1.0 M in THF)
at 0 8C. After 15 min the reaction was quenched by the
addition of saturated aqueous sodium potassium tartrate
solution (1 mL) and diluted with ethyl acetate (10 mL).

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3013
The organic layer was separated and the aqueous phase
extracted repeatedly with ethyl acetate (3!5 mL). The
combined organic extracts were washed (brine; 10 mL),
dried (MgSO4) and the solvent removed under reduced
pressure. The residue was chromatographed (silica; 2:3
ethyl acetate/hexanes) affording the title compound as a
colourless, viscous oil. Yield 0.026 g (87%). dH (300 MHz,
CDCl3) 2.80 (1H, d, JZ13 Hz, C9–H), 2.93 (1H, dd, JZ13,
1 Hz, C9–H), 3.02 (1H, td, JZ8.5, 2 Hz, C3a–H), 3.17 (1H,
apparent triplet, JZ9 Hz, C3–H), 3.76 (3H, s, OCH3), 3.89
(6H, 2!overlapping s, OCH3), 4.35 (1H, apparent t, JZ
9 Hz, C3–H), 4.40 (1H, br s, C4–H), 4.62 (1H, s, C1–H),
5.95 (2H, s, OCH2O), 6.54 (1H, s, ArH), 6.67 (1H, ddd, JZ
8, 2, 1 Hz ArH), 6.74 (1H, d, JZ8 Hz, ArH), 6.74–6.76 (1H,
m, ArH) ppm; dC (75 MHz, CDCl3) 153.3, 151.8, 149.4,
145.9, 141.3, 135.2, 127.4, 123.5, 120.7, 108.6, 108.3,
108.1, 101.2, 101.1, 69.5, 61.2, 61.1, 56.2, 51.0, 46.5, 40.0,
37.8 ppm; nmax (evaporated film) 3449 (br), 2945, 1659,
1639, 1475, 1372 cmK1; m/z (CI); 434 (MCNHC4 , 30%),
416 (MC, 30%), 221 (40%), 161 (100%). HRMS (CI)
C22H28NO8 ([MCNH4]C) requires: 434.1809; found:
434.1796.
as a brown amorphous solid. Attempted purification of
200 by column chromatography led to its partial
decomposition. Crude yield 0.072 g (87%). dH
(300 MHz, CDCl3) 8.89 (4H, apparent t, JZ5 Hz, py),
7.92 (2H, apparent q, JZ7 Hz, py), 7.53 (4H, apparent q,
JZ8 Hz, py), 6.98 (1H, d, JZ2 Hz, ArH), 6.85 (1H, dd,
JZ8, 2 Hz, ArH), 6.72 (1H, d, JZ8 Hz, ArH), 5.94 (1H,
d, JZ1.5 Hz, OCH2O), 5.90 (1H, d, JZ1.5 Hz, OCH2O),
5.65 (1H, s, ArCHO), 4.78 (1H, dd, JZ10, 6 Hz, C3–H),
4.28 (1H, dd, JZ9, 2.5 Hz, C3–H), 4.25 (1H, d, JZ5 Hz,
C4–H), 3.91 (3H, s, OMe), 3.82 (3H, s, OMe), 3.38 (3H,
s, OMe), 3.25–3.30 (1H, m, C3a–H) ppm; dC (75 MHz,
CDCl3) 175.5, 153.1, 151.7, 150.0, 149.9, 147.7, 145.7,
143.2, 141.8, 141.1, 141.0, 129.9, 125.7, 125.6, 124.7,
121.7, 109.3, 109.1, 107.8 100.9, 91.3, 90.5, 74.7, 60.8,
60.4, 56.1, 46.6, 46.1 ppm; nmax (evaporated film) 2937,
1774, 1608, 1486, 1413, 1245, 1035, 838 cmK1
.
4.1.17. (3aR*,4S*,9S*R*,9aR*)-4-(1,3-Benzodioxol-5-
yl)-9-hydroxy-5,6,7-trimethoxy-3a,4,9,9a-tetrahydro-
naphtho[2,3-c]furan-1(3H)-one, 21a,b. A dry Schlenck
tube was charged with 15 (0.030 g, 0.070 mmol and
‘wet’ THF (1 mL) and the resulting solution degassed
(three times using freeze–thaw cycle) to which was
added, by syringe, a 0.1 M solution SmI2 in THF (1.5 ml,
0.15 mmol, 3 equiv). The deep blue solution of Sm(II)
was immediately discharged, turning first to a red and
then a pale-yellow coloured solution within 5 min. This
solution was allowed to stir for a further 30 min at 20 8C
and then quenched by the addition of water (20 mL). The
organic layer was separated, the aqueous layer extracted
(EtOAc, 2!20 mL) and the combined organic extracts
dried (MgSO4) and concentrated in vacuo. Chromatog-
raphy of the residue (silica; 100% ethyl acetate) afforded
the title compound (3:1 mixture of diastereoisomers) as
an off-white crystalline solid. Yield 0.025 g (86%), mp
138–140 8C (from DCM–hexanes). Major isomer, 21a: dH
(300 MHz, CDCl3) 3.31 (1H, dd, JZ9, 2.5 Hz, C9a–H),
3.40–3.50 (1H, m, C3a–H), 3.62 (3H, s, OMe), 3.88 (3H,
s, OMe), 3.91 (3H, s, OMe), 4.15 (1H, dd, JZ9, 5 Hz,
C3–H), 4.35 (1H, d. JZ2.5 Hz), 4.59 (1H, dd, JZ9,
7.5 Hz, C3–H), 5.01 (1H, d, JZ2.5 Hz, C9–H), 5.95 (2
H, s, OCH2O), 6.62 (1H, br d, JZ7 Hz, ArH), 6.74 (1H,
d, JZ7 Hz, ArH), 6.77 (2H, 2!overlapping s, ArH); dC
(75 MHz, CDCl3) 177.0, 153.4, 152.3, 152.2, 148.4,
146.6, 139.4, 143.1, 131.5, 122.7, 120.4, 108.5, 108.4,
101.4, 73.8, 69.2, 61.0, 60.9, 56.3, 46.8, 40.8, 39.6 ppm;
nmax (evaporated film) 3418, 2915, 1775, 1501, 1487,
1243, 1122, 1036 cmK1; m/z (ESC) 437 (100%). HRMS
(ESC) C22H22NaO8 ([MCNa]C) requires 437.1207;
found: 437.1200. Minor isomer 21b exhibits resonances
at dH (300 MHz, CDCl3) 6.86 (1H, s, ArH), 4.76 (1H, br
s, C9–H), 4.70 (1H, t, JZ9 Hz, C3–H), 4.30 (1H, d, JZ
2 Hz, C4–H), 3.86–3.96 (1H, m, C3–H), 3.57 (3H, s,
4.1.15. (3aS*,4S*,9R*,9aS*)-4-(1,3-Benzodioxol-5-yl)-
9,9a-dihydroxy-5,6,7-trimethoxy-3a,4,9,9a-tetrahydro-
naphtho[2,3-c]furan-1(3H)-one, 20. To a solution of 15
(0.050 g, 0.126 mmol) in anhydrous pyridine (2 mL) was
added OsO4 (0.038 g, 0.15 mmol, 1.2 equiv) (CARE) at
room temperature. The solution was allowed to stir overnight
and was then quenched by the addition saturated aqueous
sodium sulfite (10 mL) and left to stir at ambient temperature
for 3 h. Ether (20 mL) was then added and the organic phase
was separated, washed [satd sodium sulfite (5 mL), copper
(II) sulfate (5 mL) then and brine (5 mL)], dried (MgSO4)
and the solvent removed under reduced pressure. Chromato-
graphy of the residue (silica; 4:5 ethyl acetate/hexanes)
afforded the title compound as an off-white crystalline
compound. Yield 0.035 g (65%), mp 152–154 8C (from
DCM–hexanes). dH (300 MHz, CDCl3) 2.81 (1H, br s, OH),
3.25 (1H, td, JZ9, 2 Hz, C3a–H), 3.54 (3H, s, C5–OMe),
3.86 (3H, s, C6–OMe), 3.92 (3H, s, C7–OMe), 3.93 (1H, t
JZ8 Hz, C3–H), 4.28 (1H, d, JZ2 Hz, C4–H), 4.70 (1H, t,
JZ9 Hz, C3–H), 4.80 (1H, s, C9–H), 5.95, (2 H, s, OCH2O),
6.62 (1H, dd, JZ8, 1.5 Hz, ArH), 6.73 (1H, d, JZ8 Hz,
ArH), 6.75 (1H, d, JZ2 Hz, ArH), 6.88 (1H, s, ArH); dC
(75 MHz, CDCl3) 40.5, 46.9, 56.3, 60.8, 60.9, 69.8, 71.5,
75.2, 101.4, 108.1, 108.4, 108.5, 120.7, 122.7, 129.9, 139.0,
143.1, 146.5, 148.2, 152.1, 153.6, 177.8 ppm; nmax (evapor-
ated film) 3368, 1709 (s), 1504, 1491, 1449, 1251 cmK1; m/z
(EI) 430 (MC, 98%), 412 (20%), 395 (30%), 313 45%); m/z
(CI) 448 ([MCNH4]C). HRMS (CI) C22H26NO9 ([MC
NH4]C) requires: 448.1602; found: 448.1605.
4.1.16. Isolation of osmate ester 200. To a stirred solution
of 15 (0.050 g, 0.13 mmol) in anhydrous pyridine (2 mL)
was added OsO4 (0.038 g, 0.15 mmol, 1.2 equiv) (CARE)
at room temperature. This solution was allowed to stir
overnight at 20 8C and then the reaction was quenched
by the addition of a saturated aqueous solution of sodium
sulfite (10 mL) and ethyl acetate (10 mL). The organic
phase was separated then washed with sodium sulfite
(5 mL), brine (5 mL) and dried (MgSO4). Removal of
the solvent in vacuo afforded the crude osmate ester 200
OMe); nmax (evaporated film) 1769 cmK1
.
Acknowledgements
We thank the EPSRC (C.K.K.; J.F.), AstraZeneca and GSK
for the provision of a research studentship through the
Industrial CASE Scheme.

3014
C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
and wR2Z0.0806 (all data); Crystal data for 12: C19H16Cl2O5,
References and notes
MrZ395.22, orthorhombic, aZ11.446(3), bZ10.168(2), cZ
3
˚
29.897(7), VZ3479.5(14) A , TZ100(2) K, space group
Pbca, ZZ8, Mo Ka radiation, 0.71073 A, 3580 independent
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exceptions see: Glinski, M. B.; Freed, J. C.; Durst, T. J. Org.
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et al.22 have prepared the isomeric lactone i
δ
3.05 and 3.22 ppm
δ
2.95 and 3.12 ppm
(d, J 13 Hz)
(d, J 17 Hz)
HH
OH
O
HH
OH
O
MeO
MeO
9
9
O
O
MeO
MeO
H
H
MeO
MeO
O
O
O
O
Iwasaki lactone, i
This work, 18
8. For approaches utilising TBTH-mediated radical cyclisations
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194–206. Belletire, J. L.; Mahmoodi, N. O. Tetrahedron Lett.
1989, 30, 4363–4366.
ˆ
9. Galland, J.-C.; Dias, S.; Savignac, M.; Genet, J.-P. Tetra-
hedron 2001, 57, 5137–5148.
whose spectral data exhibits minor, yet significant, differences
compared to that for lactone 18.
20. cf. Nishibe, S.; Tsukamoto, H.; Hisada, S.; Yamanouchi, S.;
Takido, M. Chem. Pharm. Bull. 1981, 29, 2082–2085.
21. Viviers, P. M.; Ferreira, D.; Roux, D. G. Tetrahedron Lett.
1979, 20, 3773.
10. This and related catalyst systems have found use in the relarted
ATRP polymerization reactions, see: Patten, T. E.; Xia, J.;
Abernathy, T.; Matyjaszewski, K. Science 1996, 272,
866–868.
22. Moritani, Y.; Ukita, T.; Hiramatsu, H.; Okamura, K.;
Ohmizu, H.; Iwasaki, T. J. Chem. Soc., Perkin Trans. 1
1996, 2747–2753.
11. Crystal data: 9T C12H9Cl3O4, MrZ323.54, monoclinic, aZ
23. (a) Criegee, R.; Marchand, B.; Wannowius, H. Ann. 1942, 550,
99–133. See also: Hashimoto, S.-I.; Sakata, S.; Sonegawa, M.;
Ikegami, S. J. Am. Chem. Soc. 1988, 110, 3670–3672. (b) Sarett,
L. H. J. Am. Chem. Soc. 1948, 70, 1454–1458.
3
˚
6.9064(6), bZ20.7797(18), cZ9.2375(8), VZ1306.6(2) A ,
TZ100(2) K, space group P2(1)/n, ZZ4, Mo Ka radiation,
˚
0.71073 A, 3056 independent reflections. Final R1Z0.0352

C. D. Edlin et al. / Tetrahedron 62 (2006) 3004–3015
3015
24. Hanessian, S.; Girard, C. Synlett 1994, 861–862.
Quideau, S.; Pouysegu, L.; Deffieux, D. Curr. Org. Chem.
2004, 8, 113–148.
29. Kramer, B.; Averhoff, A.; Waldvogel, S. R. Angew. Chem., Int.
25. Tobinaga et al.16 previously reported the isolation of a
compound assigned as ii, which has identical spectroscopic
data to 21a. We tentatively suggest, on the basis of NOE and
other data, that its structure be more correctly represented as
the 9b-alcohol, 21a and not the 9a-epimer, 21b.
¨
Ed. 2002, 41, 2981–2982. Mirk, D.; Wibbeling, B.; Frohlich,
R.; Waldvogel, S. R. Synlett 2005, 1970–1974.
30. cf. Tanaka, M.; Mitsuhashi, H.; Wakamatsu, T. Tetrahedron
Lett. 1992, 33, 4161–4164. Eklund, P. C.; Rainer, E. S.
Tetrahedron 2003, 59, 4515–4523.
OH
H
O
O
MeO
MeO
31. Matyjaszewski, K.; Patten, T. E.; Xia, J. J. Am. Chem. Soc.
1997, 119, 674–680.
1
32. The H NMR spectrum of our sample is in agreement with
9
H
MeO
that previously reported (although stereochemical assignments
were not made by these groups): Ishiguro, T.; Mizuguchi, H.;
Tomioka, K.; Koga, K. Chem. Pharm. Bull. 1985, 33,
609–617. Lewis, S. N.; Popper, T. L. Tetrahedron 1967, 23,
4197–4208. Curiously Coelho’s14 data for this compound
does not match that in the literature or that from our study
whilst his data for the silylether derivative 13 is identical to
that reported here.
O
O
ii
26. For a related aldol reaction see: Suryawanshi, S. N.;
Fuchs, P. L. J. Org. Chem. 1986, 51, 902–921.
27. See: Abe, H.; Takeda, S.; Fujita, T.; Nishioka, K.; Takeuchi, Y.;
Harayama, T. Tetrahedron Lett. 2004, 45, 2327–2329 and
references therein.
33. Ohta, A.; Tonomura, Y.; Sawaki, J.; Sato, N.; Akiike, H.;
Ikuta, M.; Shimazaki, M. Heterocycles 1991, 32,
965–973.
28. Lessene, G.; Feldman, K. S. In Modern Arene Chemistry;
Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; pp 479–538.