A synthetic approach to C-nor-D-homosteroids based on a cascade of radical cyclisations from a vinylcyclopropane-substituted acyl radical precursor

Article abstract of DOI:10.1016/j.tet.2009.05.020

Treatment of the arylvinylcyclopropane-substituted seleno ester 5 with Bu₃SnH-AIBN, under high dilution in benzene at 80 °C, led to a 1:1 mixture of C10 methyl epimers of the C-nor-D-homosteroid ring system 24/25. The homosteroid was formed fro

Full text of DOI:10.1016/j.tet.2009.05.020

Tetrahedron 65 (2009) 5767–5775
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A synthetic approach to C-nor-D-homosteroids based on a cascade of radical
cyclisations from a vinylcyclopropane-substituted acyl radical precursor
*
Gerald Pattenden , Davey A. Stoker, Johan M. Winne
School of Chemistry, The University of Nottingham, Nottingham, NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of the arylvinylcyclopropane-substituted seleno ester 5 with Bu3SnH–AIBN, under high di-
lution in benzene at 80 ꢀC, led to a 1:1 mixture of C10 methyl epimers of the C-nor-D-homosteroid ring
system 24/25. The homosteroid was formed from 5 via a cascade of sequential acyl 13-endo trig radical
macrocyclisation, benzyl radical 5-exo trig transannulation and alkyl radical transannulation reactions
(Scheme 1). The macrocyclic dienone 23 was also isolated as an intermediate in the radical cascade
between 5 and 24/25, and the dioxolanes 29 were interesting by-products. The cascade of radical cyc-
lisations leading to the homosteroid 24/25 from the acyl radical precursor 5 is compared and contrasted
with similar radical cascades from arylvinylcyclopropane-substituted alkyl radical precursors, i.e, 30/31
and 32b/38.
Received 23 February 2009
Received in revised form 17 April 2009
Accepted 7 May 2009
Available online 13 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
H
O
H
N
H
O
The C-nor-D-homosteroids comprise a small group of in-
teresting and unusual steroids where the D-ring in the normal
steroid nucleus has been expanded by one carbon, at the same time
as the C-ring is contracted from a six- to a five-membered ring.
Examples of these nor-homosteroids include veratramine 1 and
jervine 2, which are found in Veratrum grandiflorum1 and Veratrum
califoricum,2 respectively, and nakiterpiosin 3 isolated recently
from the marine sponge Terpios hashinota.3 Veratramine and jer-
vine, together with related metabolites found in species of Vera-
trum are responsible for severe teratogenic effects, whilst other
veratrum alkaloids have been used in medicine as hypotensive
agents.4 The biological profile of nakiterpiosin has not yet been
determined, but the compound does display cytotoxicity against
P388.
NH
H
H
H
HO
H
H
H
HO
O
O
H
O
1
2
R
D
CHCl2
OH
O
R'
H
H
H
H
A
O
O
O
H
The total synthesis of veratramine 1 was first described some 40
years ago,5,6 and recently Chen et al.7 presented a total synthesis of
nakiterpiosin 3, at the same time revising the stereochemistry
originally assigned to the natural product.8 In this paper we de-
scribe a synthetic approach to the C-nor-D-homosteroid ring sys-
tem in 1 and 3, which uses a new cascade of radical cyclisations
from a 1,2-disubstituted aromatic precursor as its basis.
Br
OH
3
4
a, R=Me; R'=CO2Me
b, R=R'=H
stepwise manner starting from a ring D precursor. This strategy led
to the tetracyclic A-ring ketone 4a as a key intermediate, which was
then elaborated to the natural product. We conceived an approach
to the tetracyclic compound 4 whereby the A, B and C rings were
produced in a single step, using a cascade of radical cyclisations
starting from an acyl radical intermediate.9,10 The specific precursor
In the synthesis of veratramine 1 described by Johnson et al.,5
the A, B and C rings of the tetracycle were elaborated in a linear,
* Corresponding author. Tel.: þ44 115 9513530; fax: þ44 115 9513564.
E-mail address: gp@nottingham.ac.uk (G. Pattenden).
we designed was compound 5, which accommodated a
g,d-
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.020

5768
G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
unsaturated seleno ester, as the source of the acyl radical 6, and also
a vinylcyclopropane unit designed to accept the aforementioned
acyl radical as the first step in the radical cascade (Scheme 1). Thus,
a 13-endo trig radical macrocyclisation within the acyl radical in-
termediate 6 would first lead to the benzylic radical intermediate 7.
Sequential 5-exo trig (to 8) and 6-exo trig (8 to 9) transannular
cyclisations in 7, should then produce the tetracyclic core 4b in
veratramine in a single step event. To our knowledge acyl radical
intermediates have not previously been studied in such cascade
macrocyclisation–transannulation processes, and applications of
vinylcyclopropanes as electrophores, i.e. radical acceptors, in carbon-
to-carbon bond forming reactions are relatively sparse.
O
i
ii,iii
OH
I
I
I
12
13
14
iv
10
SnBu3
SnBu3
vii
v
11
R
OH
15
16
a, R=CH2OH
b, R=CHO
vi
PhSe
EtO
EtO
O
O
ix
15
x
10
O
O
HO
5
6
R
19
20
13-endo
trig
a, R=CH2OH
b, R=CHO
5-exo
trig
xi
H
xii
H
O
O
O
EtO
EtO
7
8
viii
11
+
O
O
Bu
6-exo
trig
H
H
quench
H
4b
17
18
H
xiii, xiv
5
9
Scheme 2. Reagents and conditions: (i) isopropyltriphenylphosphonium iodide, BuLi,
THF, 0 ꢀC, 3 h, 82%; (ii) m-CPBA, DCM, 0 ꢀC/rt, 24 h, 84%; (iii) Al(OiPr)3, tol, reflux,
12 h, 83%; (iv) propionic acid, triethyl orthoacetate, 100 ꢀC, Dean–Stark, 4 days, 91%; (v)
Et2Zn, CH2I2, DCM, ꢁ50 ꢀC/ꢁ20 ꢀC, 48 h, 74%; (vi) IBX, DMSO, rt, 20 h, 96%; (vii)
MePPh3Br, NaHMDS, THF, ꢁ78 ꢀC/rt, 12 h, 97%; (viii) Pd(OAc)2, AsPh3, CuI, CsF, LiCl,
NMP, 80 ꢀC, 48 h, 20%; (ix) (a) PdCl2(PPh3)2, LiI, LiCl, DMF, 80 ꢀC, 16 h, (b) iodine on
Scheme 1. Strategy for a cascade of radical cyclisations from the seleno ester 5 leading
to the C-nor-D-homosteroid 4b.
2. Results and discussion
silica, hn, benzene, rt, 12 h, 60%; (x) Et2Zn, CH2I2, DCM, rt, 48 h, 82%; (xi) IBX, DMSO, rt,
12 h, 70%; (xii) MePPh3Br, NaHMDS, THF, ꢁ78 ꢀC/rt, 12 h, 93%; (xiii) LiOH, H2O, rt,
24 h, 96%; (xiv) N-(phenylselenyl)phthalimide, PBu3, rt, 24 h, 55%.
2.1. Synthesis of the arylvinylcyclopropane-substituted
seleno ester 5
The route we designed to synthesise the arylvinylcyclopropane-
substituted seleno ester 5 was based on preparing the ortho-
substituted iodobenzene 10, followed by a Stille cross-coupling
reaction11,12 between 10 and the E-1,2-vinylcyclopropylstannane 11,
as the key step.
A Stille cross-coupling reaction between the iodobenzene 10
and the vinylcyclopropylstannane 11,17 using Pd(OAc)2–AsPh3 in
the presence of CuI, CsF, NMP and LiCl at 80 ꢀC led to the anticipated
arylvinylcyclopropane 17 in 20% yield, but the product 18 resulting
from
a competitive aryl–butyl cross-coupling reaction was
obtained concurrently (up to 41%). The competitive migration of an
alkyl (sp3) group in Stille reactions involving vinyl and aryl (sp2)
trialkylstannanes is very rare indeed, which is why, of course, Stille
cross-coupling reactions involving sp2 centres are so revered in
synthesis. We suggest that the incidence of competitive migration
of the butyl group in the stannane 11, is associated with the
‘pseudo’ sp2/sp3 character of the carbon centres in the cyclopro-
pane ring in 11, and also possibly due to steric impedance between
the stannane 11 and the ortho-substituted side-chain in the iodo-
benzene 10.18 Whatever the reason, it was frustrating to find that
we were not able to separate the co-product 18 from the required
arylvinylcyclopropane 17 by chromatography, on a scale sufficient
to justify continuing with this particular route to the target com-
pound 5.
SnBu3
EtO
5
+
O
I
10
11
Thus, a Wittig reaction between the known phenylacetaldehyde
1213 and isopropyltriphenylphosphonium iodide, using n-BuLi as
base, first gave the alkene 13 in 82% yield. Epoxidation of 13, using
m-CPBA, followed by rearrangement of the resulting epoxide14 in
the presence of Al(OiPr)3 next led to the allyl alcohol 14 (84%)
(Scheme 2). Rearrangement of the orthoester15 derived by treating
14 with triethyl orthoacetate and propionic acid at 100 ꢀC then gave
the E-
g
-unsaturated ester 10 in 91% yield. The vinyl-
We therefore modified our approach to the vinylcyclopropane
intermediate 17, and instead first coupled the iodobenzene 10 to
the E-vinylstannane 15, which led to the aryl-substituted propenol
19 in 60% yield (Scheme 2). A Simmons–Smith reaction between 19
and diiodomethane in the presence of Et2Zn next gave the trans-
cyclopropylmethanol 20a, which, in two straightforward steps was
cyclopropylstannane 11, required for coupling to 10, was syn-
thesised from the known E-vinylstannane 15,16 following
a Simmons–Smith cyclopropanation reaction, leading to 16a, oxi-
dation of 16a to the aldehyde 16b, and a Wittig reaction between
16b and methylenetriphenylphosphoranylide (Scheme 2).

G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
5769
H
then converted into the same arylvinylcyclopropane 17 to that
12.5Hz
prepared earlier from 10 and 11. Finally, saponification of the ethyl
ester group in 17, followed by treatment of the resulting carboxylic
acid with N-(phenylseleno)phthalimide and PBu3 gave the phe-
nylseleno ester 5.
H
13
16
O
H
11
H
18
12.0Hz
H
1
4
8
H
14.5Hz
6.5Hz
H
O
12.5Hz
13.0Hz
6
H
2.2. Cascade radical cyclisations leading to the C-nor-D-
homosteroid 24/25
H
H
H
H
24
2.5Hz
When a solution of the seleno ester 5 in benzene at 80 ꢀC was
treated with Bu3SnH and catalytic AIBN over 8 h under high di-
lution, work up and chromatography resulted in the isolation of
two major products, each in ca. 25% yield. The structure of one of
these products, i.e. the macrocyclic dienone 23, followed conclu-
sively from examination of its proton and carbon NMR spectro-
scopic data, alongside a 2D NMR analysis. A COSY correlation
analysis established pertinent proton coupling data in the macro-
cycle and, most importantly, confirmed that both of the alkene
bonds in 23 had the E-configuration. The formation of the macro-
cyclic dienone 23 from the seleno ester 5 is the result of a 13-endo
trig cyclisation of the acyl radical intermediate 6 into the alkene
bond of the vinylcyclopropane unit in 5 producing 21, followed by
a cyclopropylmethyl-to-butenyl radical rearrangement, leading to
the benzylic radical 22, which then becomes quenched by an Hꢂ
source (Scheme 3).
12.0Hz
H
13
16
11
H
18
H
12.5Hz
H
1
13.5Hz
8
H
12.0Hz
H
12.5Hz
O
H
O
6
4
H
H
H
25
4.0Hz
Figure 1. Pertinent vicinal proton coupling data in the 1H NMR spectra of the isomeric
tetracyclic ketones 24 and 25.
compatible with a trans B/C ring fusion. Furthermore, the absence
of diaxial vicinal coupling between the hydrogen atoms at C4 and
C5, i.e. observed (J 6.5 and 2.5 Hz), demonstrated that the A/B ring
junction cannot be trans-fused, and must therefore be cis-fused.
Comparisons between the observed J-values shown in Figure 1,
and those calculated for all possible configurations and confor-
mations added additional support to the cis, syn, trans stereo-
chemical assignment 24 to this isomer.
12-endo
trig
5
O
A similar analysis of the proton-to-proton coupling data be-
tween relevant vicinal hydrogen atoms in the 1H NMR spectrum of
the second isomeric tetracyclic ketone produced during the radical
cascade from 5, established that this compound had the alternative
trans, anti, trans stereochemistry 25 (Fig. 1, with pertinent vicinal
coupling data). Thus, the coupling of 12.5 Hz between the vicinal
hydrogens at C8 and C9, established that the B/C ring junction is
trans-fused. However, unlike the isomeric ketone 24, the trans
diaxial coupling of 13.5 Hz between the hydrogen atoms at C4 and
C5 in this second isomer demonstrated that its A/B ring junction
must also be trans-fused.
O
6
21
H
quench
O
O
22
23
Scheme 3. Formation of the macrocyclic dienone 23 from the acyl radical inter-
mediate 6.
The isomeric tetracyclic ketones 24 and 25 are related as methyl
group epimers at C10.19 They are produced from the macrocyclic
(benzylic) radical intermediate 22 as a result of a 5-exo trig trans-
annulation reaction, which leads to the trans ring-fused radical
intermediate 8 (cf. Scheme 1). Presumably, the methyl substituted
sp3 carbon radical centre embedded in the ten-membered ring in 8
has no stereochemical integrity, yet has sufficient conformational
flexibility to present itself to the transannular double bond in the
two extreme conformations 26 and 27, which lead to the C10
methyl epimers of the tetracyclic ketone by 6-exo trig transannular
cyclisation.
The second major product isolated from treatment of the
seleno ester 5 with Bu3SnH–AIBN was obtained as a crystalline
solid, and preliminary analysis of its NMR spectroscopic and other
data indicated that it was a 1:1 mixture of isomeric tetracyclic
ketones of similar constitution to the expected C-nor-D-homo-
sterane 4b. Separation of the isomeric tetracycles by HPLC allowed
their structures and stereochemistries to be analysed in detail by
NMR spectroscopy. The 13C NMR spectrum of one of the isomers
showed the expected 18 carbon atoms, i.e., 6 aromatic, 11 aliphatic
and 1 carbonyl resonance. A DEPT analysis then established the
presence of four aromatic and three aliphatic CH signals, six CH2
and one CH3 signal, together with one aliphatic and two aromatic
quaternary carbon centres, in the structure. The 1H NMR spectrum
was complex, showing a multiplet in the aromatic proton region,
H
H
22
O
H
O
H
and several overlapping proton resonances between
d 1.3 and
26
27
1.9 ppm, including a double doublet (J 7 and 2 Hz). However, all of
the proton resonances could be correlated with their carbon
centres, and the carbon connectivity was established by carrying
out HMQC and COSY experiments. Pertinent proton-to-proton
coupling data determined between several vicinal hydrogen
atoms in the 1H NMR spectrum are collected in Figure 1, and these
data allowed us to assign a cis, syn, anti stereochemistry 24 to this
isomer of the tetracyclic ketone. Significantly, the coupling of
12 Hz between the vicinal hydrogen atoms at C8 and C9 in 24 is
25
24
Minor products that were isolated and characterised from
treatment of the seleno ester 5 with Bu3SnH–AIBN were the com-
pounds resulting from quenching and decarbonylation of the first-
formed acyl radical species, i.e. 28a and 28b, together with the
interesting dioxolanes 29a and 29b, resulting from additions of

5770
G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
oxygen across the cyclopropane rings of the vinylcyclopropane
R
units in 28b and 5, respectively.20
30/32
R
R
R'
R
H
O
O
H
28
29
H
R
a, R=CHO
b, R=H
a, R=H
R'
5-exo
H
b, R=COSePh
35
R
H
2.3. Comparisons with related cascades leading to oestranes
R'
5-endo
H
34
H
The cascade of cyclisations from the acyl radical 6 leading to the
tetracycle 24/25 complements some of our earlier studies with
the structurally related substituted vinylcyclopropanes 30 where
the multiple cyclisations were triggered from alkyl, rather than acyl
radical species.21 The substituted vinylcyclopropanes 30 also differ
from the seleno ester substrate 5 used in the present study by
having two methylene groups separating the Z-disubstituted dou-
ble bond from the aryl ring, and one less methylene group between
the same double bond and the terminal CH2I group. The substituted
alkyl iodides 30a and 30b both underwent cascades of radical
cyclisations in the presence of Bu3SnH–AIBN, leading to the ‘normal’
oestrane steroid ring system products 31a and 31b, respectively. By
contrast, when the analogous substituted iodovinylcyclopropane
32a was treated with Bu3SnH–AIBN, it underwent a sequence of
radical cyclisations leading to the C-nor-D-homosteroid 33a at the
expense of the normal oestrane steroid by-product. The differing
outcomes in the radical cascades from the iodovinylcyclopropanes
30 and 32 occur at the terminating, transannular cyclisation, event,
by competing 5-exo/6-endo ring closures, viz. 34 to 35/36 (Scheme 4).
R'
36
Scheme 4. Dichotomous radical transannulations leading to oestranes 35 and C-nor-
D-homosteroids 36.
?
32b
37
H
H
H
H
H
H
H
H
H
H
H
38
39
40
3. Conclusion
R
We have developed a new approach to C-nor-D-homosteroids,
whereby the A, B and C rings are produced in a single step, using
a cascade of radical cyclisations starting from an acyl radical in-
termediate. To our knowledge acyl radical intermediates have not
previously been applied in such cascade macrocyclisation–trans-
annulation sequences, particularly where unusual vinyl-
cyclopropanes are used as electrophores. The outcome of the
investigation has been compared and contrasted with similar,
earlier, studies involving alkyl, rather than acyl, radical cascade
cyclisations many of which lead to oestranes, e.g., oestrone. The
research emphasises the subtle effects that substitution on the
vinylcyclopropane electrophores, and the positioning of the react-
ing alkene bonds in the starting materials, play in determining the
competition between the modes of transannular cyclisations, par-
ticularly in the final steps, in these radical cascades.
R
H
Bu3SnH
AIBN
H
H
I
MeO
MeO
30
31
a, R=H
b, R=OMe
R
R
H
Bu3SnH
AIBN
H
I
32
33
a, R=Me
b, R=H
In averyearly study of the scope for iodovinylcyclopropanes in the
synthesis of oestranes by cascades of radical reactions,22 we tenta-
tively assigned the ‘normal’ steroid structure 37 with no defined
stereochemistry to the polycycle resulting from treatment of 32b
with Bu3SnH–AIBN. Over the ensuing years, and with results from
other, related studies this outcome became less credulous. We
therefore sought to put our minds at rest, and repeat this particular
radical cascade and analyse the structures of the product in more
detail. Thus, when a newly prepared sample of the iodovinyl-
cyclopropane 32bwastreated with Bu3SnH–AIBN, one majorand two
minor tetracyclic products were produced, which could be separated
by reverse phase HPLC. Detailed analysis (see Supplementary data) of
their NMR spectroscopic data now revealed that the major product
was the C-nor-D-homo steroid 38 with the trans, anti, trans stereo-
chemistry, and that the corresponding isomers 39 and 40 of the
‘normal’ steroid were actually minor products of the radical cascade.
4. Experimental
4.1. General
For general details see Ref. 23. Preparative HPLC was performed
on a Polaris 5 C18-A 10 mmꢃ250 mm column using a Varian Prostar
210 binary solvent delivery system and a Varian Prostar 325 UV
detector.
4.2. 1-Iodo-2-(3-methylbut-2-enyl)benzene 13
Tetrahydrofuran (2 ml) was added to a flask containing dried
(high vacuum at 80 ꢀC for 1 h) isopropyltriphenylphosphonium
iodide (0.35 g, 0.8 mmol) at room temperature, under an argon
atmosphere. n-Butyllithium (2.5 M, 0.28 ml, 0.7 mmol) was added
dropwise over 5 min, to the stirred solution at 0 ꢀC, and the mixture

G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
5771
was then stirred at 0 ꢀC for 30 min. A solution of 2-(2-iodophenyl)-
acetaldehyde 1213 (0.10 g, 0.4 mmol) in tetrahydrofuran (2 ml) was
added dropwise over 5 min, at 0 ꢀC and the mixture was stirred at
0 ꢀC for a 3 h and then diethyl ether (5 ml) and water (5 ml) were
added. The separated aqueous phase was extracted with diethyl
ether (5ꢃ5 ml) and the combined organic extracts were then
washed with brine (10 ml), dried and concentrated in vacuo. The
residue was purified by flash column chromatography (100% pet-
rol) on silica gel, to give the olefin 13 (0.10 g, 82%) as a colourless oil.
nmax (sol CHCl3)/cmꢁ1, 2916 (s), 1562 (m); dH (400 MHz, CDCl3), 1.76
(3H, s, C]CMeMe), 1.77 (3H, d, J 1.0 Hz, C]CMeMe), 3.42 (2H, d, J
7.0 Hz, ArCH2), 5.27 (1H, tq, J 7.0 and 1.0 Hz, Me2C]CH), 6.88 (1H,
ddd, J 8.0, 7.5 and 2.0 Hz, ArH), 7.20 (1H, dd, J 7.5 and 2.0 Hz, ArH),
7.27 (1H, ddd, J 8.0, 7.5 and 1.0 Hz, ArH), 7.82 (1H, dd, J 7.5 and
1.0 Hz, ArH); dC (100 MHz, CDCl3), 18.2 (q), 25.8 (q), 39.7 (t), 100.8
(s), 121.7 (d), 127.6 (d), 128.3 (d), 129.3 (d), 133.6 (s), 139.4 (d), 144.3
(s); m/z (EI) 272.0069 (C11H11237I requires 272.0062).
under Dean–Stark conditions for 4 days, then cooled to room
temperature and concentrated in vacuo. Diethyl ether (20 ml) and
water (20 ml) were added, and the separated aqueous phase was
then extracted with diethyl ether (3ꢃ20 ml). The combined organic
extracts were washed with saturated sodium hydrogen carbonate
solution (20 ml), then dried and concentrated in vacuo. The residue
was purified by flash column chromatography (2% EtOAc, 98%
petrol) on silica gel, to give the unsaturated ester 10 (2.9 g, 91%) as
a colourless oil. nmax (sol CHCl3)/cmꢁ1, 2984 (m), 1727 (s), 1562 (m);
dH (400 MHz, CDCl3), 1.23 (3H, t, J 7.0 Hz, OCH2CH3), 1.74 (3H, app s,
C]CCH3), 2.34–2.41 (2H, m, O]CCH2CH2), 2.42–2.48 (2H, m,
O]CCH2CH2), 3.41 (2H, d, J 7.0 Hz, ArCH2), 4.10 (2H, q, J 7.0 Hz,
OCH2CH3), 5.30 (1H, tq, J 7.0 and 1.0 Hz, C]CH), 6.88 (1H, ddd, J 8.0,
7.5 and 2.0 Hz, ArH), 7.16 (1H, dd, J 7.5 and 2.0 Hz, ArH), 7.26 (1H,
ddd, J 8.0, 7.5 and 1.5 Hz, ArH), 7.81 (1H, dd, J 7.5 and 1.5 Hz, ArH); dC
(100 MHz, CDCl3),14.2 (q),16.4 (q), 33.1 (t), 34.6 (t), 39.5 (t), 60.3 (t),
100.7 (s), 122.4 (d), 127.7 (d), 128.3 (d), 129.1 (d), 135.5 (s), 138.3 (d),
143.8 (s), 173.3 (s); m/z (ES) 359.0499 (MþHþ, C15H20O127 I requires
2
4.3. ( )-1-(2-Iodophenyl)-3-methylbut-3-en-2-ol 14
359.0508).
A solution of 3-chloroperbenzoic acid (75% in H2O, 100 mg,
0.4 mmol) in dichloromethane (2 ml) was added dropwise over
5 min, to a stirred solution of the olefin 13 (100 mg, 0.4 mmol) in
dichloromethane (2 ml) at 0 ꢀC, under a nitrogen atmosphere. The
mixture was stirred at room temperature for 24 h and then satu-
rated sodium hydrogen carbonate (5 ml) was added. The separated
aqueous phase was extracted with dichloromethane (3ꢃ5 ml) and
the combined organic extracts were then washed with brine
(10 ml), dried over sodium sulfate and concentrated in vacuo. The
residue was purified by flash column chromatography (100% petrol)
on silica gel, to give the corresponding epoxide (89 mg, 84%) as
a colourless oil. nmax (sol CHCl3)/cmꢁ1, 2965 (s); dH (400 MHz,
CDCl3), 1.36 (3H, s, C]CMeMe), 1.42 (3H, s, C]CMeMe), 2.92–3.05
(3H, m, ArCH2CH), 6.94 (1H, ddd, J 8.0, 7.0 and 2.0 Hz, ArH), 7.28–
7.34 (2H, m, 2ꢃArH), 7.85 (1H, dd, J 8.0 and 1.0 Hz, ArH); dC
(100 MHz, CDCl3), 19.1 (q), 24.8 (q), 40.0 (t), 58.7 (s), 63.4 (d), 100.8
(s), 128.3, 128.5 (2ꢃd), 129.6 (d), 139.5 (d), 141.4 (s); m/z (ES)
310.9891 (MþNaþ, C11H13O127INa requires 310.9909).
4.5. [2E-(Tributylstannyl)cyclopropyl]methanol 16a
Diethylzinc (1.1 M in Tol, 32 ml, 35 mmol) was added dropwise
over 10 min, to a stirred solution of (E)-3-(tributylstannyl)prop-2-
en-1-ol 15 (6.09 g, 18 mmol)16 and diiodomethane (4.2 ml,
52 mmol) in dichloromethane (250 ml) at ꢁ50 ꢀC, under a nitrogen
atmosphere. The solution was warmed slowly to ꢁ20 ꢀC over 2 h
and stirred at this temperature for a further 48 h, before triethyl-
amine (20 ml) was added. After warming to room temperature,
water (100 ml) was added and the separated aqueous phase was
then extracted with dichloromethane (3ꢃ100 ml). The combined
organic extracts were washed with brine (20 ml), dried over so-
dium sulfate and concentrated in vacuo. The residue was purified
by flash column chromatography (10% EtOAc, 90% petrol) on silica
gel, to give the cyclopropane 16a (4.66 g, 74%) as a colourless oil.
nmax (sol CHCl3)/cmꢁ1, 3611 (br m), 3029 (m); dH (400 MHz, CDCl3),
0.29–0.36 (1H, m, SnCH), 0.50–0.55 (2H, m, CHCH2CH), 0.81 (6H, t, J
8.0 Hz, SnCH2), 0.89 (9H, t, J 7.5 Hz, CH2CH3), 1.02–1.14 (1H, m,
HOCH2CH), 1.24–1.36 (6H, m, CH3CH2), 1.41–1.56 (6H, m,
SnCH2CH2), 3.39 (1H, dd, J 10 and 7.5 Hz, CHHOH), 3.55 (1H, dd, J 10
and 6.5 Hz, CHHOH0); dC (100 MHz, CDCl3), ꢁ2.6 (d), 7.4 (t), 8.7 (t),
13.7 (q), 18.1 (d), 27.3 (t), 29.1 (t), 69.6 (t); m/z (ES) 385.1539
(MþNaþ, C16H34O120SnNa requires 385.1529). These data agree
with those published previously for the chiral material.24
Aluminium triisopropoxide (75 mg, 0.4 mmol) was added in one
portion, to a stirred solution of the epoxide (100 mg, 0.3 mmol) in
toluene (2 ml) at room temperature, under a nitrogen atmosphere.
The mixture was heated to reflux for 12 h, and then cooled to room
temperature and diethyl ether (5 ml) was added. The mixture was
poured onto hydrochloric acid (2 M, 5 ml) and the separated
aqueous phase was then extracted with diethyl ether (3ꢃ5 ml). The
combined organic extracts were washed with saturated sodium
hydrogen carbonate (10 ml), then dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column
chromatography (5% EtOAc, 95% petrol) on silica gel, to give the
allylic alcohol 14 (83 mg, 83%) as a colourless oil. nmax (sol CHCl3)/
cmꢁ1, 3604 (s), 3468 (br w), 2958 (s), 1651 (m); dH (400 MHz,
CDCl3), 1.57 (1H, d, J 9.0 Hz, OH), 1.86 (3H, s, C]CMe), 2.84 (1H, dd, J
14.0 and 9.0 Hz, ArCHH), 3.06 (1H, dd, J 14.0 and 4.0 Hz, ArCHH),
4.36 (1H, app br d, J 9.0 Hz, HOCH), 4.88 (1H, app t, J 1.5 Hz,
C]CHH), 5.03 (1H, app t, J 1.5 Hz, C]CHH), 6.92 (1H, ddd, J 8.0, 7.0
and 2.0 Hz, ArH), 7.22–7.32 (2H, m, 2ꢃArH), 7.84 (1H, dd, J 8.0 and
1.0 Hz, ArH); dC (100 MHz, CDCl3), 18.3 (q), 46.7 (t), 74.8 (d), 101.0
(s), 111.2 (t), 128.2, 128.4 (2ꢃd), 131.1 (d), 139.7 (d), 141.2 (s), 146.9
(s); m/z (ES) 310.9892 (MþNaþ, C11H13O127INa requires 310.9909).
4.6. 2E-(Tributylstannyl)cyclopropanecarbaldehyde 16b
2-Iodoxybenzoic acid (5.0 g, 17.9 mmol) was added portionwise,
to a stirred solution of the alcohol 16a (4.0 g, 11.1 mmol) in
dimethylsulfoxide (80 ml) at room temperature, under a nitrogen
atmosphere. The solution was stirred at room temperature for 20 h,
then water (40 ml) was added and the resulting precipitate was
filtered through Celite with diethyl ether (50 ml). The separated
aqueous phase was extracted with diethyl ether (3ꢃ20 ml) and the
combined organic extracts were washed with brine (10 ml), dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (20% Et2O, 80% petrol) on
silica gel, to give the aldehyde 16b (3.8 g, 96%) as a colourless oil.
nmax (sol CHCl3)/cmꢁ1, 3029 (s), 1696 (s); dH (400 MHz, CDCl3), 0.58
(1H, ddd, J 11.0, 8.5 and 5.5 Hz, SnCH), 0.88 (6H, t, J 8.5 Hz, SnCH2),
0.89 (9H, t, J 7.0 Hz, CH2CH3), 1.04 (1H, ddd, J 8.5, 7.0 and 4.5 Hz,
CHCHHCH), 1.24–1.37 (7H, m, CHCHHCHþCH3CH2), 1.43–1.54 (6H,
m, SnCH2CH2), 1.68–1.76 (1H, m, O]CHCH), 8.52 (1H, d, J 6.5 Hz,
O]CH); dC (100 MHz, CDCl3), 1.7 (d), 9.0 (t), 11.2 (t), 13.7 (q), 26.9
(d), 27.3 (t), 28.9 (t), 201.6 (d); m/z (ES) 383.1359 (MþNaþ,
C16H32O120SnNa requires 383.1373).
4.4. (E)-Ethyl 6-(2-iodophenyl)-4-methylhex-4-enoate 10
Propionic acid (0.1 ml, 1.3 mmol) was added dropwise over
2 min, to a stirred solution of the alcohol 14 (2.6 g, 9.0 mmol) in
triethyl orthoacetate (35 ml, 185.0 mmol) at room temperature
under a nitrogen atmosphere. The solution was heated to 100 ꢀC

5772
G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
4.7. Tributyl(2-vinyl-E-cyclopropyl)stannane 11
tq, J 7.0 and 1.0 Hz, C]CH), 6.25 (1H, dt, J 15.5 and 5.5 Hz,
ArCH]CH), 6.79 (1H, dt, J 15.5 and 1.0 Hz, ArCH]CH), 7.13 (1H, dd, J
6.0 and 2.0 Hz, ArH), 7.15–7.20 (2H, m, 2ꢃArH), 7.46 (1H, dd, J 6.5
and 1.5 Hz, ArH); dC (100 MHz, CDCl3),14.1 (q),16.2 (q), 32.3 (t), 33.0
(t), 34.5 (t), 60.4 (t), 63.9 (t), 123.9 (d), 125.9 (d), 126.3 (d), 127.7 (d),
128.5 (d), 129.3 (d), 130.1 (d), 133.9, 135.6 (2ꢃs), 138.7 (s), 173.4 (s);
m/z (ES) 311.1619 (MþNaþ, C18H24O3Na requires 311.1618).
Tetrahydrofuran (60 ml) was added to freshly dried (100 ꢀC,
1 mmHg, 5 h) methyltriphenylphosphonium bromide (7.0 g,
19.6 mmol) at room temperature. Sodium hexamethyldisilazane
(2.0 M in THF, 6.0 ml, 12.0 mmol) was added dropwise over 10 min,
to the stirred solution at ꢁ78 ꢀC, under a nitrogen atmosphere. The
yellow solution was stirred at ꢁ78 ꢀC for 30 min and then a solution
of the aldehyde 16b (3.4 g, 9.5 mmol) in tetrahydrofuran (30 ml)
was added dropwise over 5 min. The mixture was stirred at ꢁ78 ꢀC
for 2 h and then allowed to warm to room temperature over 12 h.
Saturated aqueous ammonium chloride solution (10 ml) was
added, and the separated aqueous phase was then extracted with
diethyl ether (3ꢃ20 ml). The combined organic extracts were dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (100% petrol) on silica
gel, to give the alkene 11 (3.3 g, 97%) as a colourless oil. nmax (sol
CHCl3)/cmꢁ1, 3083 (w), 1631 (m); dH (400 MHz, CDCl3), 0.11 (1H,
ddd, J 10.5, 8.5 and 5.5 Hz, SnCH), 0.70–0.76 (2H, m, CHCH2CH), 0.81
(6H, t, J 8.0 Hz, SnCH2), 0.89 (9H, t, J 7.5 Hz, CH2CH3), 1.25–1.36 (6H,
m, CH3CH2), 1.36–1.44 (1H, m, H2C]CHCH), 1.44–1.56 (6H, m,
SnCH2CH2), 4.80 (1H, dd, J 10.0 and 1.5 Hz, CH]CHH), 5.05 (1H, dd, J
17.0 and 1.5 Hz, CH]CHH), 5.29 (1H, ddd, J 17.0, 10.0 and 9.0 Hz,
CH]CH2); dC (100 MHz, CDCl3), 2.6 (d), 8.7 (t), 11.5 (t), 13.7 (q), 19.4
(d), 27.3 (t), 29.1 (t), 110.5 (t), 144.6 (d); m/z (EI) 301.0986 (MꢁBu,
C13H12250Sn requires 301.0978).
4.9. (E)-Ethyl-6-(2-(2-(hydroxymethyl)cyclopropyl)phenyl)-4-
methylhex-4-enoate 20a
Diethylzinc (1.0 M in hexanes, 520
dropwise over 20 min, to a stirred solution of the olefin 19 (100 mg,
0.3 mmol) and diiodomethane (84 l, 1.0 mmol) in dichloro-
ml, 0.5 mmol) was added
m
methane (10 ml) at room temperature, under an argon atmosphere.
The mixture was stirred at room temperature for 4 h and then more
diethylzinc (1.0 M in hexanes, 520
ml, 0.5 mmol) and diiodo-
methane (84 l, 1.0 mmol) were added dropwise, over 20 min. The
m
mixture was stirred at room temperature for 14 h and then ethyl
acetate (50 ml) and water (50 ml) were added. The separated
aqueous phase was extracted with ethyl acetate (3ꢃ20 ml), and the
combined organic extracts were then washed with brine (10 ml),
dried over sodium sulfate and concentrated in vacuo. The residue
was purified by flash column chromatography (30% Et2O, 70%
petrol) on silica gel, to give the cyclopropane 20a (86 mg, 82%) as
a colourless oil. nmax (sol CHCl3)/cmꢁ1, 3613 (w), 3520 (br w), 3009
(m), 1726 (s), 1602 (w); dH (400 MHz, CDCl3), 0.87–0.94 (2H, m,
ArCHCH2), 1.19 (3H, t, J 7.0 Hz, OCH2CH3), 1.38–1.45 (1H, m,
HOCH2CH), 1.75 (3H, d, J 1.0 Hz, C]CCH3), 1.84 (1H, app dt, J 9.0 and
5.0 Hz, ArCH), 2.10 (1H, app br s, OH), 2.37 (2H, t, J 7.0 Hz,
O]CCH2CH2), 2.44 (2H, t, J 7.0 Hz, O]CCH2CH2), 3.47 (1H, dd, J 16.0
and 7.0 Hz, ArCHH), 3.53 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 3.66
(2H, d, J 6.5 Hz, HOCH2), 4.07 (2H, q, J 7.0 Hz, OCH2CH3), 5.34 (1H,
app tq, J 7.0 and 1.0 Hz, C]CH), 6.99 (1H, dd, J 6.0 and 2.0 Hz, ArH),
7.10–7.15 (3H, m, 3ꢃArH); dC (100 MHz, CDCl3),12.0 (t),14.2 (q),16.2
(q), 19.0 (d), 23.4 (d), 31.8 (t), 33.1 (t), 34.7 (t), 60.4 (t), 66.6 (t), 123.9
(d), 125.8, 126.1, 126.2 (3ꢃd), 128.6 (d), 134.3 (s), 139.6 (s), 140.7 (s),
173.5 (s); m/z (ES) 325.1784 (MþNaþ, C19H26O3Na requires
325.1774).
4.8. (4E)-Ethyl-6-(2-((E)-3-hydroxyprop-1-enyl)phenyl)-4-
methylhex-4-enoate 19
A solution of the aryl iodide 10 (2.50 g, 7.0 mmol) and (E)-3-
(tributylstannyl)prop-2-en-1-ol16 (2.60 g, 7.5 mmol) in N-dimethyl-
formamide (20 ml) was added dropwise over 1 min, to flame-dried
lithium chloride (0.58 g, 13.5 mmol) and lithium iodide (1.80 g,
13.0 mmol) in a Schlenk flask at room temperature, under an argon
atmosphere. The mixture was degassed and bis-triphenylphos-
phinepalladium dichloride (0.24 g, 0.3 mmol) was added in one
portion, and the mixture was then degassed again. The mixture was
heated to 80 ꢀC for 16 h, and then cooled to room temperature and
poured onto water (50 ml) and ethyl acetate (50 ml). The separated
aqueous phase was extracted with ethyl acetate (3ꢃ100 ml) and the
combined organic extracts were then washed with water
(3ꢃ20 ml), hydrochloric acid (2 M, 10 ml) and brine (50 ml), dried
over sodium sulfate and concentrated in vacuo to leave a residue,
which consisted of a 6:1 mixture of Z/E isomers of the allylic al-
cohol. Data for major Z-isomer: dH (400 MHz, CDCl3), 1.20 (3H, t, J
7.0 Hz, OCH2CH3), 1.73 (3H, app s, C]CCH3), 2.37 (2H, t, J 7.0 Hz,
O]CCH2CH2), 2.43 (2H, t, J 7.0 Hz, O]CCH2CH2), 3.36 (2H, d, J
7.5 Hz, ArCH2), 4.09 (2H, q, J 7.0 Hz, OCH2CH3), 4.27 (2H, dd, J 6.5
and 1.5 Hz, HOCH2), 5.39 (1H, tq, J 7.5 and 1.0 Hz, C]CH), 5.94 (1H,
dt, J 11.5 and 6.5 Hz, ArCH]CH), 6.65 (1H, dt, J 11.5 and 1.5 Hz,
ArCH]CH), 7.07 (1H, dd, J 6.0 and 2.0 Hz, ArH), 7.12–7.20 (2H, m,
2ꢃArH), 7.46 (1H, dd, J 6.5 and 1.5 Hz, ArH).
4.10. (E)-Ethyl 6-(2-(2-formylcyclopropyl)phenyl)-4-
methylhex-4-enoate 20b
2-Iodoxybenzoic acid (2.75 g, 9.8 mmol) was added portion-
wise, to a stirred solution of the alcohol 20a (1.85 g, 6.1 mmol) in
dimethylsulfoxide (25 ml) at room temperature, under an argon
atmosphere. The solution was stirred at room temperature for 12 h
and then water (25 ml) was added. The mixture was filtered
through Celite using diethyl ether (50 ml), and the separated
aqueous phase was then extracted with diethyl ether (3ꢃ20 ml).
The combined organic extracts were washed with brine (30 ml),
then dried over sodium sulfate and concentrated in vacuo. The
residue was purified by flash column chromatography (20% EtOAc,
80% petrol) on silica gel, to give the aldehyde 20b (1.31 g, 70%) as
a colourless oil. nmax (sol CHCl3)/cmꢁ1, 3011 (m), 1715 (br s), 1603
(w); dH (400 MHz, CDCl3), 1.21 (3H, t, J 7.0 Hz, OCH2CH3), 1.52–1.58
(1H, m, ArCHCHH), 1.67–1.70 (1H, m, ArCHCHH), 1.71 (3H, app s,
C]CCH3), 2.05 (1H, ddd, J 9.0, 7.0 and 5.0 Hz, ArCH), 2.35 (2H, t, J
7.0 Hz, O]CCH2CH2), 2.43 (2H, t, J 7.0 Hz, O]CCH2CH2), 2.62–2.70
(1H, m, O]CHCH), 3.42 (2H, d, J 7.0 Hz, ArCH2), 4.09 (2H, q, J 7.0 Hz,
OCH2CH3), 5.28 (1H, tq, J 7.0 and 1.0 Hz, C]CH), 7.00 (1H, dd, J 7.5
and 1.5 Hz, ArH), 7.12–7.23 (3H, m, 3ꢃArH), 9.34 (1H, d, J 5.0 Hz,
O]CH); dC (100 MHz, CDCl3), 14.1 (q), 15.0 (t), 16.2 (q), 24.3 (d), 31.6
(t), 32.3 (d), 33.0 (t), 34.5 (t), 60.2 (t), 122.9 (d), 125.9, 126.2, 127.1
(3ꢃd), 128.8 (d), 134.9 (s), 136.3 (s), 140.9 (s), 173.2 (s), 199.9 (s); m/z
(ES) 323.1617 (MþNaþ, C19H24O3Na requires 323.1618).
The mixture of Z- and E-isomers was dissolved in benzene
(50 ml), and approximately 10 grains of iodine on silica (iodine
adsorbed onto chromatographic silica with dichloromethane) were
added. The mixture was left in direct sunlight for 12 h, then satu-
rated sodium thiosulphate (50 ml) was added and the organic
phase was separated and concentrated in vacuo. The residue was
purified by flash column chromatography (40% Et2O, 60% petrol) on
silica gel, to give the E-allyl alcohol 19 (1.25 g, 60%) as a colourless
oil. nmax (sol CHCl3)/cmꢁ1, 3611 (w), 3502 (br w), 3011 (m), 1725 (s),
1601 (w); dH (400 MHz, CDCl3), 1.15 (3H, t, J 7.0 Hz, OCH2CH3), 1.76
(3H, app s, C]CMe), 2.34 (2H, t, J 7.0 Hz, O]CCH2CH2), 2.43 (2H, t, J
7.0 Hz, O]CCH2CH2), 3.38 (2H, d, J 7.0 Hz, ArCH2), 4.04 (2H, q, J
7.0 Hz, OCH2CH3), 4.32 (2H, dd, J 5.5 and 1.0 Hz, HOCH2), 5.24 (1H,

G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
5773
4.11. (E)-Ethyl 4-methyl-6-(2-(2-vinylcyclopropyl)phenyl)hex-
4-enoate 17
aqueous phase was extracted with ethyl acetate (3ꢃ10 ml), and the
combined organic extracts were dried over sodium sulfate and
concentrated in vacuo, to leave the corresponding carboxylic acid
(135 mg, 96%) as a colourless oil, which was used in the next step
without further purification. nmax (sol CHCl3)/cmꢁ1, 3059 (s), 2929
(s), 1709 (w), 1600 (m); dH (400 MHz, CDCl3), 1.05 (1H, app dt, J 8.5
and 5.0 Hz, ArCHCHH), 1.25 (1H, ddd, J 8.5, 6.0 and 5.0 Hz,
ArCHCHH),1.53–1.61 (1H, m, H2C]CHCH), 1.73 (3H, app s, C]CMe),
1.96 (1H, ddd, J 8.5, 5.5 and 5.0 Hz, ArCH), 2.37 (2H, t, J 7.0 Hz,
O]CCH2CH2), 2.49 (2H, t, J 7.0 Hz, O]CCH2CH2), 3.44 (1H, dd, J 16.0
and 7.0 Hz, ArCHH), 3.49 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 4.96
(1H, dd, J 10.0 and 1.5 Hz, HC]CHH), 5.13 (1H, dd, J 17.0 and 1.5 Hz,
HC]CHH), 5.37 (1H, app tq, J 7.0 and 1.5 Hz, C]CH), 5.57 (1H, ddd, J
17.0, 10.0 and 8.5 Hz, H2C]CH), 6.99 (1H, dd, J 6.0 and 2.0 Hz, ArH),
7.12–7.15 (3H, m, 3ꢃArH); dC (100 MHz, CDCl3), 14.6 (t), 16.2 (q),
23.0 (d), 25.7 (d), 31.7 (t), 32.7 (t), 34.3 (t), 112.5 (t), 123.8 (d), 125.7,
126.0, 126.1 (3ꢃd), 128.5 (d), 134.0 (s), 139.5 (s), 140.8 (s), 141.1 (d),
179.0 (s); m/z (ES) 271.1693 (MþHþ, C18H23O2 requires 271.1693).
N-(Phenylselenyl)phthalimide (200 mg, 0.5 mmol) was added,
in one portion, to a stirred solution of the carboxylic acid (110 mg,
0.4 mmol) and tributylphosphine (0.27 ml, 1.2 mmol) in benzene
(1 ml) at room temperature, under an argon atmosphere. The
mixture was stirred at room temperature for 24 h, then poured
onto silica and purified by flash column chromatography (100%
petrol) on silica gel to give the seleno ester 5 (90 mg, 55%) as a pale
yellow oil. nmax (sol CHCl3)/cmꢁ1, 2924 (m), 1717 (s), 1634 (m); dH
(400 MHz, CDCl3), 1.05 (1H, app dt, J 8.5 and 5.0 Hz, ArCHCHH), 1.26
(1H, ddd, J 8.5, 6.0 and 5.0 Hz, ArCHCHH), 1.54–1.60 (1H, m,
H2C]CHCH), 1.73 (3H, app s, C]CMe), 1.96 (1H, ddd, J 8.5, 6.0 and
5.0 Hz, ArCH), 2.43 (2H, t, J 7.5 Hz, O]CCH2CH2), 2.84 (2H, t, J 7.5 Hz,
O]CCH2CH2), 3.44 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 3.50 (1H, dd, J
16.0 and 7.0 Hz, ArCHH), 4.97 (1H, dd, J 10.0 and 1.5 Hz, HC]CHH),
5.14 (1H, dd, J 17.0 and 1.5 Hz, HC]CHH), 5.38 (1H, app tq, J 7.0 and
1.5 Hz, C]CH), 5.58 (1H, ddd, J 17.0, 10.0 and 8.5 Hz, H2C]CH), 7.00
(1H, dd, J 6.0 and 2.0 Hz, ArH), 7.13–7.16 (3H, m, 3ꢃArH), 7.34–7.41
(3H, m, 3ꢃArH), 7.46–7.51 (2H, m, 2ꢃArH); dC (100 MHz, CDCl3),
14.6 (t), 16.3 (q), 23.0 (d), 25.8 (d), 31.7 (t), 34.9 (t), 46.1 (t), 112.5 (t),
124.4 (d), 125.7, 126.0, 126.1 (3ꢃd), 126.4 (s), 128.5 (d), 128.8 (d),
129.3 (2C d), 133.5 (s), 135.8 (2C d), 139.5 (s), 140.7 (s), 141.1 (d),
199.8 (s); m/z (ES) 433.1031 (MþNaþ, C24H26O80SeNa requires
433.1041).
4.11.1. Prepared from the aldehyde 20b
Tetrahydrofuran (40 ml) was added to freshly dried (100 ꢀC,
1 mmHg, 5 h) methyltriphenylphosphonium bromide (4.3 g,
12.0 mmol) at room temperature, under an argon atmosphere. A
solution of sodium hexamethyldisilazane (1.0 M) in THF (5.6 ml,
5.6 mmol) was added dropwise over 15 min to the stirred solution
at ꢁ78 ꢀC. The mixture was stirred at ꢁ78 ꢀC for 15 min and then
a solution of the aldehyde 20b (1.4 g, 4.7 mmol) in tetrahydrofuran
(20 ml) was added dropwise, via canula, over 15 min. The mixture
was stirred at ꢁ78 ꢀC for a further 2 h and then allowed to warm to
room temperature over 12 h. Diethyl ether (50 ml) and water
(50 ml) were added, and the separated aqueous phase was then
extracted with diethyl ether (3ꢃ20 ml). The combined organic ex-
tracts were dried over sodium sulfate and then concentrated in
vacuo. The residue was purified by flash column chromatography
(5% EtOAc, 95% petrol) on silica gel, to give the vinylcyclopropane 17
(1.3 g, 93%) as a colourless oil. nmax (sol CHCl3)/cmꢁ1, 3011 (s), 1727
(s), 1634 (m), 1602 (w); dH (400 MHz, CDCl3), 1.05 (1H, app dt, J 8.5
and 5.0 Hz, ArCHCHH),1.22 (3H, t, J 7.0 Hz, OCH2CH3),1.24–1.27 (1H,
m, ArCHCHH), 1.54–1.59 (1H, m, H2C]CHCH), 1.72 (3H, app s,
C]CCH3), 1.96 (1H, ddd, J 8.5, 5.5 and 5.0 Hz, ArCH), 2.36 (2H, t, J
7.0 Hz, O]CCH2CH2), 2.43 (2H, t, J 7.0 Hz, O]CCH2CH2), 3.43 (1H,
dd, J 16.0 and 7.0 Hz, ArCHH), 3.49 (1H, dd, J 16.0 and 7.0 Hz,
ArCHH), 4.10 (2H, q, J 7.0 Hz, OCH2CH3), 4.96 (1H, dd, J 10.0 and
1.5 Hz, HC]CHH), 5.13 (1H, dd, J 17.0 and 1.5 Hz, HC]CHH), 5.34
(1H, app tq, J 7.0 and 1.5 Hz, C]CH), 5.58 (1H, ddd, J 17.0, 10.0 and
8.5 Hz, H2C]CH), 6.99 (1H, dd, J 6.0 and 2.0 Hz, ArH), 7.12–7.15 (3H,
m, 3ꢃArH); dC (100 MHz, CDCl3), 14.2 (q), 14.6 (t), 16.2 (q), 23.0 (d),
25.7 (d), 31.6 (t), 33.2 (t), 34.7 (t), 60.3 (t), 112.4 (t), 123.6 (d), 125.7,
126.0, 126.1 (3ꢃd), 128.4 (d), 134.4 (s), 139.5 (s), 140.9 (s), 141.0 (d),
173.4 (s); m/z (ES) 321.1817 (MþNaþ, C20H26O2Na requires
321.1825).
4.11.2. Prepared by a Stille coupling reaction between the
iodobenzene 10 and the stannane 11
The iodobenzene 10 was coupled to the vinylcyclopropyl-
stannane 11, using the same reagents and conditions as those used
to couple 10 to the E-vinylstannane 15 (for the synthesis of 19).
Work up and chromatography gave the arylvinylcyclopropane 17
(20%) and the corresponding substituted n-butylbenzene 18 (41%).
The vinylcyclopropane 17 had identical spectroscopic properties to
those recorded under section 4.11.1. The butylbenzene 18 showed:
dH (360 MHz, CDCl3), 0.96 (3H, t, J 7 Hz, (CH2)2CH3), 1.30 (3H, t, J
7.5 Hz, OCH2CH3), 1.33 (2H, m, CH2CH2CH3), 1.62 (2H, app. pentet, J
w7 Hz, CH2CH2CH2), 1.71 (3H, s, CH]CMe), 2.2–2.4 (4H, m,
CH2CH2CO2Et), 2.55 (2H, t, J 7 Hz, ArCH2), 3.22 (2H, d, J 6 Hz,
ArCH2CH]), 4.12 (2H, q, J 7.5 Hz, OCH2CH3), 5.80 (1H, t, J 6 Hz,
]CHCH2), 6.9–7.05 (4H, m. ArH); dC (90 MHz, CDCl3), 14.1 (2ꢃq),
17.1 (q), 22.4 (t), 29.6 (t), 31.9 (t), 33.8 (t), 34.6 (t), 35.2 (t), 61.3 (t),
122.8 (d), 125.6 (d), 125.9 (d), 128.1 (d), 128.9 (d), 135.5 (s), 136.5 (s),
136.6 (s), 173.1 (s).
4.13. 1,2,4a,5,6,6a,11,11a-Octahydro-11b-methyl-4H-
benzo[a]fluoren-3(11bH)-ones 24 and 25, and (6E,12E)-
8,9,14,15-tetra hydro-7-methyl-5H-benzo[13]annulen-
10(11H)-one 23
A solution of tri-n-butyltin hydride (92 m
l, 0.34 mmol) and 2,20-
azobis(isobutyronitrile) (2 mg, 0.01 mmol) in degassed benzene
(20 ml), was added dropwise over 8 h via syringe pump, to a stirred
solution of the seleno ester 5 (110 mg, 0.26 mmol) and 2,20-azobis-
(isobutyronitrile) (2 mg, 0.01 mmol) in degassed benzene (200 ml),
at 80 ꢀC under an argon atmosphere. The mixture was heated under
reflux for a further 12 h, and then allowed to cool to room tem-
perature and concentrated in vacuo. The residue was purified by
flash column chromatography on silica (0–25% Et2O, 100–75%
petrol) to give: (i) a 1:1 mixture of angular methyl epimers of the
tetracyclic ketone 24/25 (16.5 mg, 25%) (eluted fourth) as a crys-
talline solid, mp 128–129 ꢀC (ethanol). nmax (sol CHCl3)/cmꢁ1, 2928
(s), 1704 (s). The epimers were separated by reverse phase pre-
parative HPLC (MeCN/H2O) and showed the following data: trans,
anti, trans isomer 25 (contaminated by w20% of the other epimer)
dH (400 MHz, CDCl3) (see numbering system on structure), 1.13 (3H,
s, CH3, H-18), 1.36 (1H, dddd, J 12.5, 12.0, 12.0 and 4.5 Hz, ArCH-
CHaxHeq, H-7ax), 1.43–1.53 (1H, m, O]CCH2CHCHaHb, H-6a), 1.51–
4.12. (E)-Phenyl-4-methyl-6-(2-(2-vinylcyclopropyl)-
phenyl)hex-4-eneselenoate 5
A solution of lithium hydroxide (40 mg, 1.7 mmol) in water
(2 ml) was added dropwise over 2 min, to a stirred solution of the
ester 17 (150 mg, 0.5 mmol) in acetonitrile (4 ml) at room tem-
perature. The mixture was stirred at room temperature for 24 h,
then diethyl ether (1 ml) was added and the separated organic
phase was extracted with water (2ꢃ5 ml) and sodium hydroxide
(2 M, 5 ml). Hydrochloric acid (2 M) was added to the combined
aqueous extracts until pH 1 (approximately 10 ml). The acidified
1.60 (1H, m, O]CH2CHaxHeq
,
H-1ax), 1.56–1.62 (1H, m,

5774
G. Pattenden et al. / Tetrahedron 65 (2009) 5767–5775
O]CCH2CHCHaHb, H-6b), 1.60–1.68 (1H, m, O]CCH2CH, H-4), 1.67
(1H, ddd, J 12.5, 12.0 and 7.0 Hz, ArCHCH, H-9), 1.96 (1H, ddd, J 13.0,
6.5 and 2.0 Hz, O]CCH2CHaxHeq, H-1eq), 2.21 (1H, ddd, J 14.5, 4.0
and 2.0 Hz, O]CCHaxHeqCH, H-4eq), 2.31 (1H, dd, J 14.5 and 13.5 Hz,
O]CCHaxHeqCH, H-4ax), 2.34–2.42 (2H, 2ꢃm, O]CCHaxHeqCH2, H-
2eqþArCHCHaxHeq, H-7eq), 2.49 (1H, ddd, J 15.0, 13.5 and 6.5 Hz,
O]CCHaxHeqCH2, H-2eq), 2.65 (1H, dd, J 14.0 and 12.0 Hz, ArCH-
axHeq, H-11ax), 2.73 (1H, dd, J 14.0 and 7.0 Hz, ArCHaxHeq, H-11eq),
2.93 (1H, ddd, J 12.5, 12.0 and 3.5 Hz, ArCH, H-8), 7.12–7.17 (3H, m,
3ꢃArH, H-14,15,16), 7.23 (1H, dd, J 7.0 and 2.0 Hz, ArH, H-13); dC
(100 MHz, CDCl3), 11.6 (q, C-18), 28.8 (t, C-7), 29.5 (t, C-6), 31.3 (t, C-
11), 35.6 (s, C-10), 38.0 (t, C-2), 38.4 (t, C-1), 44.0 (d, C-8), 44.3 (t, C-
4), 46.6 (d, C-5), 60.7 (d, C-9), 122.0 (d, C-16), 124.6 (d, C-13), 126.2
(2ꢃd, C-14,15), 143.0 (s, C-12), 146.6 (s, C-17), 211.4 (s, C-3); cis, syn,
trans isomer 24 dH (400 MHz, CDCl3) (see numbering system on
structure), 1.33 (1H, dddd, J 14.5, 13.0, 12.0 and 3.5 Hz, ArCH-
CHaxHeq, H-7ax), 1.37 (3H, s, CH3, H-18), 1.45 (1H, dddd, J 14.0, 13.0,
12.5 and 3.5 Hz, O]CCH2CHCHaxHeq, H-6ax), 1.66–1.72 (1H, m,
O]CCH2CHaxHeq, H-1eq), 1.68–1.74 (1H, m, O]CCH2CHCHaxHeq, H-
6eq), 1.81 (1H, ddd, J 12.5, 12.0 and 6.5 Hz, ArCHCH, H-9), 1.81–1.89
(1H, m, ArCH2CH, H-5), 2.10 (1H, ddd, J 14.5, 2.5 and 2.0 Hz,
O]CCHaHbCH, H-4a), 2.17 (1H, ddd, J 14.0, 13.5 and 5.0 Hz,
O]CCH2CHaxHeq, H-1ax), 2.29–2.36 (1H, m, O]CCHaxHeqCH2, H-
2eq), 2.32–2.38 (1H, m, ArCHCHaxHeq, H-7eq), 2.53 (1H, dddd, J 14.5,
14.0, 7.0 and 0.5 Hz, O]CCHaxHeqCH2, H-2ax), 2.56 (1H, dd, J 14.0
and 12.5 Hz, ArCHaxHeq, H-11ax), 2.81 (1H, dd, J 14.0 and 6.5 Hz,
ArCHaxHeq, H-11eq), 2.82 (1H, dd, J 14.5 and 12.0 Hz, ArCH, H-8), 2.87
(1H, ddd, J 14.5, 6.5 and 0.5 Hz, O]CCHaHbCH, H-4b), 7.11–7.18 (3H,
m, 3ꢃArH, H-14,15,16), 7.23 (1H, dd, J 7.0 and 2.0 Hz, ArH, H-13); dC
(100 MHz, CDCl3), 24.8 (q, C-18), 27.1 (t, C-1), 29.2 (t, C-7), 30.2 (t, C-
6), 31.7 (t, C-11), 35.1 (s, C-10), 37.5 (t, C-2), 43.2 (d, C-8), 44.2 (t, C-
4), 46.2 (d, C-5), 59.8 (d, C-9), 122.0 (d, C-16), 124.5 (d, C-13), 126.1
(2ꢃd, C-14,15), 143.0 (s, C-12), 146.6 (s, C-17), 212.1 (s, C-3); m/z (ES)
277.1570 (MþNaþ, C18H22ONa requires 277.1568); and (ii) the
macrocyclic dienone 23 (16 mg, 25%) (eluted third) as a colourless
oil; nmax (sol CHCl3)/cmꢁ1, 2920 (s), 1710 (s), 1605 (w); dH (400 MHz,
CDCl3), 1.72 (3H, d, J 1.5 Hz, HC]CCH3, H-15), 2.33 (2H, app dd, J 6.0
and 4.5 Hz, O]CCH2CH2, H-16), 2.48 (2H, app dtd, J 7.5, 5.5 and
1.0 Hz, ArCH2CH2, H-4), 2.51 (1H, app d, J 12.0 Hz, O]CCHaHbCH2,
H-17a), 2.52 (1H, app td, J 4.5 and 1.0 Hz, O]CCHaHbCH2, H-17b),
2.69 (1H, app d, J 5.5 Hz, ArCHaCHbCH2, H-5a), 2.70 (1H, app dd, J 6.0
and 5.5 Hz, ArCHaCHbCH2, H-5b), 2.91 (2H, app dd, J 7.0 and 1.0 Hz,
O]CCH2, H-1), 3.27 (2H, app d, J 7.0 Hz, ArCH2CH]C, H-12), 5.05
(1H, app tq, J 7.0 and 1.5 Hz, ArCH2CH]C, H-13), 5.26 (1H, app dtt, J
15.5, 7.5 and 1.0 Hz, O]CCH2CH]CH, H-3), 5.47 (1H, app dtt, J 15.5,
7.0 and 1.0 Hz, O]CCH2CH]CH, H-2), 7.07–7.12 (2H, m, 2ꢃArH, H-
7,8), 7.17 (1H, ddd, J 7.5, 7.0 and 2.0 Hz, ArH, H-9), 7.24 (1H, dd, J 7.5
and 1.0 Hz, ArH, H-10); dC (100 MHz, CDCl3), 17.1 (q, C-15), 31.0 (t, C-
12), 32.3 (t, C-16), 32.7 (t, C-5), 33.7 (t, C-4), 40.1 (t, C-17), 45.1 (t, C-
1), 121.2 (d, C-13), 125.0 (d, C-2), 126.0, 126.3 (2ꢃd, C-8,9), 128.7 (d,
C-7), 130.2 (d, C-10), 131.9 (s, C-11), 134.6 (d, C-3), 139.0 (s, C-14),
139.8 (s, C-6), 207.9 (s, C-18); m/z (ES) 277.1575 (MþNaþ, C18H22ONa
requires 277.1568).
(<1 mg, 1%), as a yellow oil; dH (400 MHz, CDCl3), 1.03 (3H, t, J
7.5 Hz, CH2CH3), 1.75 (3H, app s, C]CCH3), 2.06 (2H, q, J 7.5 Hz,
CH2CH3), 2.39 (1H, app dt, J 12.0 and 7.5 Hz, ArCHCHH), 3.23 (1H,
app dt, J 12.0 and 7.5 Hz, ArCHCHH), 3.35 (1H, dd, J 16.0 and 7.0 Hz,
ArCHH), 3.41 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 4.89 (1H, app dt, J
7.5 and 7.0 Hz, H2C]CHCH), 5.21 (1H, app tq, J 7.0 and 1.5 Hz,
C]CH), 5.30 (1H, dd, J 10.0 and 1.5 Hz, HC]CHH), 5.41 (1H, dd, J
17.0 and 1.5 Hz, HC]CHH), 5.55 (1H, app t, J 7.5 Hz, ArCH), 5.93 (1H,
ddd, J 17.0, 10.0 and 7.0 Hz, H2C]CH), 7.19 (1H, dd, J 6.0 and 1.5 Hz,
ArH), 7.25–7.31 (3H, m, 3ꢃArH); (ii) the saturated aldehyde 28a
(3 mg, 4%) as a yellow oil; nmax (sol CHCl3)/cmꢁ1, 2928 (s), 1720 (s),
1634 (m), 1605 (m); dH (400 MHz, CDCl3), 1.05 (1H, app dt, J 8.5 and
5.0 Hz, ArCHCHH), 1.24–1.28 (1H, m, ArCHCHH), 1.52–1.63 (1H, m,
H2C]CHCH), 1.73 (3H, d, J 1.0 Hz, C]CCH3), 1.95 (1H, ddd, J 8.5, 6.0
and 5.0 Hz, ArCH), 2.38 (2H, t, J 7.5 Hz, O]CCH2CH2), 2.56 (2H, td, J
7.5 and 2.0 Hz, O]CCH2CH2), 3.45 (1H, dd, J 16.0 and 7.0 Hz,
ArCHH), 3.49 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 4.96 (1H, dd, J 10.0
and 1.5 Hz, HC]CHH), 5.13 (1H, dd, J 17.0 and 1.5 Hz, HC]CHH),
5.35 (1H, tq, J 7.0 and 1.0 Hz, C]CH), 5.58 (1H, ddd, J 17.0, 10.0 and
8.5 Hz, H2C]CH), 7.00 (1H, dd, J 6.0 and 2.0 Hz, ArH), 7.11–7.17 (3H,
m, 3ꢃArH), 9.77 (1H, t, J 2.0 Hz, O]CH); m/z (ES) 277.1565 (MþNaþ,
C18H22ONa requires 277.1568); (iii) recovered seleno ester 5 (5 mg,
5%); (iv) the dioxolane 29b (10 mg, 8%) as a colourless oil; dH
(400 MHz, CDCl3), 1.74 (3H, d, J 0.5 Hz, HC]CCH3), 2.36 (1H, app dt,
J 12.0 and 7.0 Hz, ArCHCHH), 2.42 (2H, t, J 7.5 Hz, O]CCH2CH2), 2.83
(2H, t, J 7.5 Hz, O]CCH2CH2), 3.18 (1H, app dt, J 12.0 and 7.5 Hz,
ArCHCHH), 3.34 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 3.39 (1H, dd, J
16.0 and 7.0 Hz, ArCHH), 4.85 (1H, app dtt, J 7.5, 7.0 and 1.0 Hz,
H2C]CHCH), 5.27 (1H, app dt, J 10.0 and 1.0 Hz, HC]CHH), 5.28
(1H, app tq, J 7.0 and 0.5 Hz, C]CH), 5.38 (1H, app dt, J 17.0 and
1.0 Hz, HC]CHH), 5.49 (1H, app t, J 7.5 Hz, ArCH), 5.89 (1H, ddd, J
17.0, 10.0 and 7.5 Hz, H2C]CH), 7.14 (1H, dd, J 7.5 and 1.5 Hz, ArH),
7.33–7.40 (3H, m, 3ꢃArH), 7.44–7.47 (3H, m, 3ꢃArH), 7.57 (2H, dd, J
7.5 and 7.0 Hz, 2ꢃArH); dC (100 MHz, CDCl3), 16.3 (q), 31.5 (t), 34.8
(t), 45.9 (t), 48.8 (t), 79.6 (d), 82.3 (d), 119.0 (t), 124.2 (d), 125.7,
126.7, 128.1, 128.9 (4ꢃd), 126.4 (s), 129.3 (2C d), 129.4 (d), 134.0 (s),
135.0 (d), 135.7 (2C d), 136.7 (s), 138.4 (s), 199.7 (s); m/z (ES)
465.0956 (MþNaþ, C24H26O80SeNa requires 465.0945).
3
Acknowledgements
We thank the EPSRC (studentship to D.A.S. and fellowship to
J.M.W.) and Astra Zeneca for support. We also thank Mr. Robert
Kempton and Mr. Joseph Rogers for their collaboaration in rein-
vestigating the radical cyclisation of 32b, and Mr. Dane Toplis for
HPLC analyses and separations of oestrane and C-nor-D-homoste-
roid isomers.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.05.020.
The following minor compounds were also separated by chro-
matography: (i) the vinylcyclopropane hydrocarbon 28b (<1 mg,
1%) as a colourless oil; dH (400 MHz, CDCl3), 1.01 (3H, t, J 7.5 Hz,
CH2CH3), 1.05 (1H, app dt, J 8.5 and 5.0 Hz, ArCHCHH), 1.24–1.32
(1H, m, ArCHCHH), 1.50–1.61 (1H, m, H2C]CHCH), 1.71 (3H, app s,
C]CCH3), 1.99 (1H, ddd, J 8.5, 6.0 and 5.0 Hz, ArCH), 2.04 (2H, q, J
7.5 Hz, CH2CH3), 3.44 (1H, dd, J 16.0 and 7.0 Hz, ArCHH), 3.49 (1H,
dd, J 16.0 and 7.0 Hz, ArCHH), 4.95 (1H, dd, J 10.0 and 1.5 Hz,
HC]CHH), 5.13 (1H, dd, J 17.0 and 1.5 Hz, HC]CHH), 5.29 (1H, app
tq, J 7.0 and 1.5 Hz, C]CH), 5.58 (1H, ddd, J 17.0, 10.0 and 8.5 Hz,
H2C]CH), 6.98 (1H, dd, J 6.0 and 1.5 Hz, ArH), 7.11–7.18 (3H, m,
3ꢃArH). Upon leaving in the open air, for 5 min, the vinyl-
cyclopropane became oxidised producing the dioxolane 29a
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