Palladium-mediated fragmentation of meta photocycloadducts using carbon based electrophiles. Part 1

Article abstract of DOI:10.1016/j.tet.2006.01.042

Substituted benzene derived meta photocycloadducts have been shown to undergo a fragmentation/arylation reaction under Heck reaction conditions to give bridged bicyclo[3.2.1] compounds in a highly atom-efficient manner. When an anisole derived meta photoc

Full text of DOI:10.1016/j.tet.2006.01.042

Tetrahedron 62 (2006) 3423–3434
Palladium-mediated fragmentation of meta photocycloadducts
using carbon based electrophiles. Part 1
a
b
c
a
Clive S. Penkett,a, Rupert O. Sims, Paul W. Byrne, Lee Kingston, Richard French,
*
Lauriane Dray,a Simon Berritt,a Jason Lai,a Anthony G. Aventa and Peter B. Hitchcocka
aDepartment of Chemistry, University of Sussex, Brighton BN1 9QJ, UK
bTocris-Cookson Ltd, Avonmouth, Bristol BS11 8TA, UK
cAstraZeneca R&D Charnwood, Loughborough LE11 5RH, UK
Received 29 September 2005; revised 19 December 2005; accepted 12 January 2006
Available online 8 February 2006
Abstract—Substituted benzene derived meta photocycloadducts have been shown to undergo a fragmentation/arylation reaction under Heck
reaction conditions to give bridged bicyclo[3.2.1] compounds in a highly atom-efficient manner. When an anisole derived meta
photocycloadduct is used, a bridgehead ketone is generated. However, if an alkylbenzene derived meta photocycloadduct is used, a
bridgehead alkene is formed. This strategy has been used to create novel enol ether and transient allyl silane compounds.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
resulting cationic intermediate fragments to give a [3.2.1]
bridged bicyclic ketone (Scheme 1).
The remarkable meta photocycloaddition reaction1
between an alkene and an arene has inspired considerable
interest for the formation of complex polycyclic mole-
cules.2 Although generally stable under ambient con-
ditions, meta photocycloadducts are highly strained
chemical entities and hence are inclined to undergo relief
of ring strain in the presence of certain reagents. Wender
and co-workers1d–f have been the greatest exponent of this
reaction’s synthetic potential and they have used a variety
of strategies to cleave the strained three-membered ring.
Radical based methods involving dissolving metal condi-
tions3 and thiophenol4 have been used to prepare the
angular and linear fused triquinanes silphinene and
coriolin, respectively. More commonly electrophiles have
been employed in conjunction with anisole derived meta
photocycloadducts, which add to the electron rich olefin
portion of the oxygen-substituted photocycloadduct and the
In this context an acid5 has acted as a source of HC,
bromine6 or N-bromosuccinimide7 as a source of BrC and
mCPBA7 as a source of OHC (via an epoxide), however, the
synthetic potential of this reaction would be significantly
enhanced if a carbocation-mediated equivalent could be
developed. We reasoned that an aryl halide would behave as
a carbon based electrophile in the presence of a palladium
catalyst to cause an analogous fragmentation8 and we now
describe the Heck reaction of meta photocycloadducts.
2. Results and discussion
2.1. Arylation of anisole derived photoadducts
The palladium-mediated Heck reaction9 has become one of
the most versatile carbon–carbon bond forming methods
OMe
OMe
OMe
O
E
hν
E
E
1
2
3
4
5
Scheme 1.
Keywords: Photoaddition; Palladium; Heck reaction; Tandem reaction; Atom efficiency; Allylsilane formation.
*
Corresponding author. Tel.: C44 1273 877374; e-mail: c.s.penkett@sussex.ac.uk
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.042

3424
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
Pd(0)
H
Ar
.
Et3N HX
Ar
X
Et3N
R
R
Scheme 2.
known to synthetic chemists. During this process an aryl
halide is commonly coupled to an alkene in the presence of a
palladium catalyst and a base to yield an arylated olefin
along with a salt bi-product (Scheme 2).
photoadduct 8 was separated from the crude photolysis
mixture by distillation under reduced pressure and used
without any further purification during the modified Heck
reaction. Our initial attempt at a palladium-mediated
arylation reaction involved heating a solution of the
photoadduct 8 and 1-iodo-2-nitrobenzene in DMF with
palladium(II) acetate and dppe ligand as the catalyst and
triethylamine as the base.10 The reaction mixture was
heated at 80 8C until the starting material was no longer
observed by TLC analysis and we were delighted to find
that our predictions about the reactivity of the meta
photocycloadduct proved correct for the formation of the
desired fragmentation/arylation product 9 (Scheme 6). This
compound was obtained in 20% yield as a yellow
crystalline solid8 and as expected the aryl group had
been introduced onto the exo-face of the bridged bicyclic
ketone 9 (Scheme 4).
A modified version of the generally accepted catalytic cycle
can be proposed for the reaction of an anisole derived meta
photoadduct with an aryl halide in the presence of a
palladium(0) catalyst (Scheme 3). The initial steps
involving oxidative addition of the aryl halide with the
palladium(0) catalyst and syn carbopalladation of the alkene
portion are common to the classic mechanism, however, the
rigid structure of 6 does not allow the carbon–palladium
s-bond to align syn with a b hydrogen atom. This prevents
b-hydride elimination from taking place and cyclopropane
ring fragmentation occurs as a consequence. The final stages
of the catalytic cycle involve the formation of an arylated
bicyclic ketone product and the regeneration of the
palladium(0) catalyst with the assistance of the base.
A second series of compounds was prepared from the
photoadducts derived from anisole and cis-4,7-dihydro-1,3-
dioxepin 10. A solution of anisole and the alkene in
cyclohexane was irradiated using 254 nm UV light and both
exo and endo photoadducts (11 and 12) were isolated
separately. These were then subjected to the same Heck
reaction conditions using 1-iodo-2-nitrobenzene to afford
the arylation/fragmentation products 13 and 14, whose
structures were again confirmed by X-ray crystallo-
graphy11a,b (Scheme 5).
To verify this proposed mechanism we carried out some
preliminary studies using the simple anisole/cyclopentene
sourced meta photocycloadduct 8.5 This was prepared
predominantly as the endo isomer by irradiating a solution
of anisole and cyclopentene in cyclohexane using 254 nm
UV light, with the powerful electron donating properties of
anisole’s methoxy group directing the addition of the olefin
between the 2- and 6- positions of the aromatic ring. This
.
Et3N MeX
Ar X
Pd[0]L2
O
Ar
X
Ar
Pd[II]L2
OMe
Et3N
X
MeO Pd[II]L2
Ar
OMe
Ar
Pd[II]L2
H
H
X
6
Scheme 3.
OMe
OMe
O
(i)
(ii)
NO2
1
8
9
7
Scheme 4. Reagents and conditions: (i) hn, cyclohexane, 19%; (ii) 1-iodo-2-nitrobenzene, Pd(OAc)2 (5 mol%), dppe (5 mol%), NEt3, DMF, 80 8C, 32 h, 20%.

C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3425
OMe
O
O
O
O
O
(ii)
OMe
NO2
11
13
(4.1%)
(23%)
(i)
1
OMe
O
O
O
(ii)
NO2
10
12
(4.8%)
14
(20%)
O
O
O
O
Scheme 5. Reagents and conditions: (i) hn, cyclohexane; (ii) 1-iodo-2-nitrobenzene, Pd(OAc)2 (5 mol%), dppe (5 mol%), NEt3, DMF, 80 8C, 32 h.
OMe
OMe
OMe
OMe
OMe
OH
OH
h
ν
MeO
H
OH
cyclohexane
OH
1
17
18
19
OH
20
21
0.5%
OH
8%
16
4%
9%
Scheme 6.
2.2. A gelsemine model
is difficult to conceive of a more straight-forward synthetic
route to these complex products.
One of the initial aims of this research was to establish a
rapid method of assembling the core structure of the
alkaloid gelsemine 15.7,12 Gelsemine provides a unique
challenge to the synthetic organic chemist, as six rings (one
spirofused with another) and seven chiral centres (two of
which are quaternary) are contained within its compact
structure. The level of interest shown towards this alkaloid
is probably more a reflection of its complex molecular
architecture than any intrinsic biological activity and the
varied strategies used for its assembly have been the focus
of a recent review by Danishefsky and Lin.13
In our approach to gelsemine a nitrogen-substituted aryl
group needed to be introduced onto the alkene of an
appropriate meta photoadduct at what would become the C7
position of gelsemine (see Fig. 1). Fortunately the more
plentiful 7-endo photocycloadduct 17 was also the isomer
most closely related to the structure of gelsemine. When the
same arylation conditions as before were used (heating a
solution of the photoadduct 17, 1-iodo-2-nitrobenzene,
palladium(II) acetate, dppe and triethylamine in DMF at
80 8C), the familiar arylation/fragmentation reaction
occured to provide compound 228 in 21% yield (Scheme 7).
It was interesting to note that an unprotected hydroxyl group
in the substrate did not appear to significantly hinder the
palladium(0) catalysed process.
The basic carbon framework of gelsemine lends itself to
being assembled by the fragmentation of an appropriate
meta photocycloadduct. Preliminary studies were aimed at
the formation of its core structure and were focused on the
use of meta photocycloadducts derived from anisole and
allyl alcohol. These were prepared by the irradiation of a
solution of anisole and allyl alcohol in cyclohexane using
254 nm UV light. The electron donating properties of
anisole’s methoxy group directed the addition of the olefin
between the 2- and 6- positions of the aromatic ring during
the photochemical reaction and four meta photocycloadduct
isomers were formed (Scheme 6). The 7-endo and the 6-exo
isomers 17 and 18 could be obtained as single compounds,
but the 6-endo and the 7-exo isomers 19 and 20 co-eluted as
a mixture. In addition to these compounds a small amount of
the ortho photoadduct 21 was also obtained. Although the
percentage yields of products for this process tended to be
low, multigram quantities of the desired photoadducts could
be easily separated from the simple starting materials and it
O
20
NH
N
5
7
16
3
14
17
O
Figure 1. The alkaloid gelsemine 15 with its numbering system shown.
Various experiments were then undertaken with a view to
improving the yield of 22 from 17 by altering the ligand,
base, solvent, temperature and time of the reaction with the
results being summarised in Table 1. Initially reactions were
carried out at 80 8C and doubling the reaction time from 32
to 64 h had a detrimental effect on the yield of 22. Silver
salts are known to improve the reactivity of electron rich

3426
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
OMe
O2N
O
17
OH
22
OH
Scheme 7. Reagents and conditions: 1-iodo-2-nitrobenzene, Pd(OAc)2 (5 mol%), dppe (5 mol%), NEt3, DMF, 80 8C, 32 h, 21%.
Table 1. Optimisation studies for the conversion of 17 to 22
OMe
O2N
I
O2N
O
17
22
Pd(OAc)2
(5 mol%)
OH
OH
Variables: ligand, base, solvent, temperature, time, solvent.
Entry
Ligand
Base
Solvent
Temperature (8C)
Time (h)
Yield of 22 (%)
1
2
3
4
5
6
7
8
Dppe
Dppe
Dppe
PPh3
NEt3
NEt3
AgCO3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
Acetonitrile
80
80
80
80
32
68
32
32
32
32
24
12
8
4
2
0.5
12
12
12
21
8
11
28
36
17
24
42
37
37
35
28
35
0
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
80
120
120
120
120
120
120
120
120
120
120
9
10
11
12
13
14
15
!5%
alkenes during Heck reactions,14 but the use of silver
carbonate as a base led to less 22 being obtained. Using the
monodentate ligand triphenylphosphine instead of the
bidentate dppe ligand brought about an improvement in
yield indicating that cyclopropane fragmentation required a
vacant coordination site, as the bidentate ligand appeared to
slow down the rate of catalysis. The yield of 22 was further
improved by the use of tri-ortho-tolylphosphine, which was
advantageous as this ligand was known to exhibit good
thermal stability at elevated temperatures.9c After raising
the reaction temperature to 120 8C it was found that the
highest yield of 22 was obtained after 12 h. Other solvents
were used, but DMF remained the solvent of choice.
The presence of 23 in the product mixture indicates that the
proposed mechanism in Scheme 4 is either flawed or
another mechanism is operating, which may involve the
formation of a p-allyl palladium species 2415 (Fig. 3). It
may also be that this alternative reaction pathway only
becomes significant at higher reaction temperatures.
Me
I
O
Pd[II]Ar
OH
It was interesting to note that at the higher temperature of
120 8C another isomeric compound 23 (Fig. 2) was obtained
and in the case of entry 8 (Table 1) 23 was obtained in 9%
yield.
Figure 3. The proposed p-allyl palladium species 24.
2.3. Formation of a bridgehead alkene using an alkyl-
benzene derived photoadduct
O
O2N
So far we had shown that meta photocycloadducts obtained
from oxygen-substituted benzene derivatives would
undergo a palladium-catalysed arylation/fragmentation
process in the presence of an aryl halide. This transform-
ation can be summarised as the conversion of 25a to 26a
(Scheme 8) with Xa as oxygen and Ya as methyl.
OH
Figure 2. The minor isomeric compound 23.

C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3427
2.4. Tandem formation of an allylsilane and an enol
ether
Y
X
X
X
Y
Ar
I
Ar
Inspired by Fleming’s allylsilane approach16 to create the
key quaternary centre at the C20 position of gelsemine
(Fig. 1), we contemplated a novel strategy for preparing
a similar bridgehead allylsilane using a version of the
chemistry described above. We have shown that the
arylation/fragmentation of a simple methylbenzene-derived
photoadduct would give rise to a [3.2.1] bicycle with an
alkene at the bridgehead position and conceived that a
similar alkene could also form part of an allylsilane unit
(see compound 33, Fig. 4).
25a
O
Me
H
Pd cat.
25b CH2
25
26
Scheme 8.
We wondered if Xb could be CH2 and Yb could be H and
then employ palladium’s versatile reactivity to initiate a
similar arylation/fragmentation process of an alkyl substi-
tuted meta photoadduct 25b to generate an alkenyl
bridgehead compound 26b (Scheme 9). To test this
hypothesis a simple alkyl substitued meta photoadduct
system was prepared by irradiating a solution of toluene and
allyl alcohol in cyclohexane using 254 nm UV light. The
electron donating methyl group directed meta addition of
the alkene across the 2,6 positions of toluene during the
photoreaction, however, only the 6 and 7-endo photoadducts
28 and 29 were obtained on this occasion (Scheme 9) and
the 6-endo isomer 28 proved inseparable from a co-eluting
impurity.
SiMe3
Ar
OH
Figure 4. Compound 33 with a bridgehead allylsilane unit.
Me
An appropriate photoadduct to attempt this arylation/
fragmentation reaction was prepared by the irradiation of
a solution of trimethyl phenethyl silane 3417 and allyl-
alcohol in cyclohexane using 254 nm UV light. Two meta
photoadducts were isolated from the crude reaction mixture
after chromatographic separation and their structures were
identified as the 6 and 7-endo isomers 35 and 36 using NMR
techniques (Scheme 11).
Me
Me
h
ν
cyclohexane
OH
27
16
28
(<2%)
29
(2%)
HO
HO
Scheme 9.
The 7-endo photoadduct 29 was reacted with a variety of
aryl halides 30 using the best yielding conditions from the
anisole variant 17 (Table 1, entry 8) and as predicted a range
of [3.2.1] bicyclic dienes were formed that exhibited a
methylene group at the bridgehead position instead of a
ketone (Scheme 10). Again a major isomer 31 and a minor
isomer 32 were formed in a similar fashion to the anisole
variants 22 and 23 and we found the reaction to be equally
tolerant of electron rich bromides as to electron-poor
iodides, but the less reactive chlorobenzene failed to afford
any arylation products. The spectroscopic details of the
minor 1-bromo-3-methylbenzene derivative 32b are not
quoted in the Section 4 as it could not be obtained free of
co-eluting impurities.
SiMe3
SiMe3
SiMe3
34
hν
cyclohexane
OH
35
(2.4%)
36
(2.2%)
HO
HO
16
Scheme 11.
After subjecting the 7-endo isomer (36) to the arylation/
fragmentation process, compound 37 was obtained after
chromatographic separation from the crude reaction mixture
(Scheme 12). It would appear that a bridgehead allylsilane
similar to compound (Fig. 4) had formed, but underwent
H
H
H
H
Me
R2
SiMe3
R1
X
R2
NOE 1.8%
R2
H
H
R1
R1
29
OH
OH
30
31
32
OH
X
I
R1
R2
H
NO2
30a
30b
30c
NO2
H
31a 29%
31b 30%
32a
13%
36
37
OH
Br
Cl
Me
H
32b <10%
32c 0%
OH
H
31c
0%
Scheme 10. Reagents and conditions: Pd(OAc)2 (5 mol%), P(o-Tol)3,
(10 mol%), NEt3, DMF, 120 8C, 12 h.
Scheme 12. Reagents and conditions: 1-iodo-2-nitrobenzene, Pd(OAc)2
(5 mol%), P(o-Tol)3, (10 mol%), NEt3, DMF, 120 8C, 12 h, 15%.

3428
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
proto-desilylation to give the vinyl group under the reaction
conditions. It is interesting to note that the hydrogen atom at
the bridgehead position had been introduced on to what was
the more sterically encumbered face of the allylsilane next
to the aryl group during the proto-desilylation stage. This
reaction was repeated in the presence of Eschenmoser’s salt
in the hope of trapping the in situ formed allylsilane 33 with
an iminium ion, but the same proto-desilylated compound
37 was obtained again. In an attempt to form a more stable
allylsilane variant during the arylation/fragmentation stage,
triisopropyl phenethyl silane was prepared using the same
procedure as for compound 34 and irradiated in the presence
of allylalcohol, however, no evidence could be found of
meta photocycloaddition between the two.
4. Experimental
4.1. General
1H NMR spectra were recorded on Bruker DPX300, Varian
unityINOVA-400 or Bruker AMX500 Fourier transform
spectrometers at 300, 400 or 500 MHz, respectively.
Chemical shifts (d) are quoted in ppm using tetramethyl-
silane or residual chloroform as internal reference (dZ
0.00 ppm), and coupling constants (J) are quoted in Hz. 13C
NMR spectra were recorded using the same instruments,
and chemical shifts (d) are quoted in ppm using CDCl3 as
internal reference (dZ77.0 ppm).
IR spectra were recorded on Perkin-Elmer Spectrum One
Fourier transform instruments and frequencies (nmax) are
quoted in wavenumbers (cmK1).
During the course of studying enantioselective intra-
molecular versions of the Heck reaction, Overman and
Shibasaki showed how silyl enol ethers could be prepared in
high yield from silyl protected allylic alcohols.18 The
apparent stability of these functional groups under Heck
reaction conditions led us to contemplate the formation of
an enol ether at the bridgehead position after initiating an
arylation/fragmentation procedure on an appropriate meta
photocycloadduct. Various benzyl silyl ethers were pre-
pared and irradiated in the presence of allyl alcohol, but no
evidence of meta photocycloaddition could be detected.
However, benzyl methyl ether did undergo meta photo-
cycloaddition with allyl alcohol, although the 2,6 meta
photoadduct isomer of interest (40) co-eluted with what was
tentatively assigned as the 2,4 meta photoadduct isomer 39.
This mixture was subjected to the arylation/fragmentation
process and afforded the bridgehead methyl enol ether
compound 41 (Scheme 13).
Low- and high-resolution electron impact (EI) and chemical
impact (CI) mass spectra were recorded using a Fisons
Autospec instrument. High-resolution electrospray ioni-
sation (ESI) mass spectra were recorded using a Bruker
Daltonics APEXIII instrument.
The starting materials for the synthesis of the compounds
were obtained from the usual suppliers (Sigma–Aldrich–
Fluka, Lancaster, Fisher etc.) unless otherwise stated. The
anhydrous solvents were obtained from Aldrich Chemicals
in Sure/Seale bottles and were used without further
purification. Petrol refers to petroleum ether with a boiling
range of 40–60 8C. Flash column chromatography was
performed using Fisher Matrex 60 (35–70 mm) silica.
Analytical thin-layer chromatography (TLC) was per-
˚
formed using Whatman K6F silica gel plates (60 A porosity)
developed with UV light or an alkaline solution of
potassium permanganate followed by heating to give yellow
spots.
OMe
H
O2N
OMe
MeO
38
(i)
(ii)
Irradiations were carried out in quartz immersion-well
reactors fitted with 6 or 16 W low-pressure mercury vapour
lamps or 125 or 400 W medium-pressure mercury vapour
lamps as supplied by Photochemical Reactors Ltd, Reading,
UK. Oxygen free solvent for the irradiation experiments was
simply obtained by passing a vigorous stream of nitrogen
gas through a sintered glass tube into the solvent for 15 min
at rt. Experiments were conducted with gentle stirring of the
reaction solution under an atmosphere of nitrogen and with
cold-water cooling of the lamp and vessel contents
throughout.
39
OMe
2:1
40
41
OH
OH
OH
OH
16
Scheme 13. Reagents and conditions: (i) hn, cyclohexane, 6.8%; (ii) 1-iodo-
2-nitrobenzene, Pd(OAc)2 (5 mol%), P(o-Tol)3 (10 mol%), NEt3, DMF,
120 8C, 12 h, 15%.
3. Conclusion
A unique fragmentation/carbon–carbon bond forming
process has been shown to occur when a Heck reaction is
performed with various meta photocycloadducts for the
formation of complex polycyclic compounds. The degree of
added molecular complexity after only two synthetic
operations is remarkable and, depending on the nature of
the substituted benzene used during the photoaddition stage,
[3.2.1] bicycles can be prepared with either a ketone or an
alkene at the bridgehead position. This methodology has
been shown to be tolerant of unprotected hydroxyl groups
and its versatility has been demonstrated for the formation
of bridgehead ketones, alkenes, enol ethers and in situ
generated allylsilanes.
4.1.1. rac-(1R,2S,6R,7R,10S)-10-(20-Nitrophenyl)tri-
cyclo[5.3.1.02,6]undec-8-en-11-one 9. A solution of anisole
(34.5 g, 320 mmol) and cyclopentene (21.8 g, 320 mmol) in
cyclohexane (270 ml) was added to a quartz immersion-well
photoreactor and degassed by passing a stream of nitrogen
through it for 10 min. This solution was then irradiated with
short wavelength UV light for 35 h using a 400 W medium-
pressure mercury vapour lamp. The solvent and unreacted
starting materials were removed in vacuo and the residue
was distilled under reduced pressure using an oil rotary
pump to yield the photoadduct as a colourless oil (10.7 g,
19%). This photoadduct was primarily the 2,6 endo adduct

C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3429
and was used without further purification during the
arylation reaction.
(1H, dd, JZ2.7, 12.4 Hz, H-3a), 4.04 (1H, t, JZ11.7 Hz, H-
7b), 4.77 (1H, d, JZ4.5 Hz, H-5b), 4.78 (1H, d, JZ4.6 Hz,
H-5a), 5.58 (1H, ddd, JZ1.4, 2.7, 5.7 Hz, H-10), 5.64 (1H,
dd, JZ2.4, 5.7 Hz, H-11); 13C NMR (125 MHz, CDCl3) d
36.5, 37.4, 40.7, 52.7, 56.0, 56.4, 66.6, 67.6, 89.9, 95.5,
127.5, 131.9; IR 1645, 2935, 3053 cmK1; HRMS (ESI) m/z
calcd C12H16NaO3 [MCNa]C 231.0992, found 231.0989.
A mixture of the endo meta photoadduct (4.00 g,
23.4 mmol), 2-iodo-1-nitrobenzene (5.80 g, 23.4 mmol),
triethylamine (89 mg, 0.88 mmol), palladium (II) acetate
(260 mg, 1.16 mmol) and 1,2-bis(diphenylphosphine)
ethane (466 mg, 1.17 mmol) and dry DMF (70 ml) was
heated at 80 8C for 32 h. The reaction was poured into 2 M
hydrochloric acid (150 ml) and the aqueous portion was
washed with ethyl acetate (3!150 ml). The combined
organics were washed with brine (150 ml), water (150 ml)
and dried over magnesium sulfate. The solvent was
removed under reduced pressure and the residue subjected
to column chromatography to afford the product 9 (1.32 g,
20%) as a yellow crystalline solid (for crystallographic
details see Ref. 8) mp 147–149 8C.
Compound 12
OCH
3
13
8
10
9
12
1
7
2
11
3
6
5
O
4 O
5'
4'
1H NMR (500 MHz, CDCl3) d 1.71 (1H, ddd, JZ1.2, 2.4,
8.4 Hz, H-12), 1.77 (1H, dd, JZ6.3, 8.4 Hz, H-1), 2.07 (1H,
ddd, JZ1.6, 2.6, 5.7 Hz, H-9), 2.89 (1H, m, H-8b), 2.94
(1H, m, H-2b), 3.07 (3H, s, OCH3), 3.20 (1H, dd, JZ9.1,
12.5 Hz, H-7a), 3.51 (1H, ddd, JZ0.4, 3.8, 12.0 Hz, H-3b),
3.58 (1H, dd, JZ10.6, 12.0 Hz, H-3a), 3.65 (1H, dd, JZ5.5,
12.5 Hz, H-7b), 4.22 (1H, d, JZ6.3 Hz, H-5a), 4.93 (1H, d,
JZ6.3 Hz, H-5b), 5.42 (1H, ddd, JZ0.4, 2.4, 5.8 Hz, H-11),
5.48 (1H, ddd, JZ1.2, 2.6, 5.8 Hz, H-10); 13C NMR
(125 MHz, CDCl3) d 36.3, 37.7, 47.6, 53.1, 54.1, 56.5, 70.3,
O
6'
11
3'
1'
10
2'
2
1
NO2
7
6
9
8
3
4
5
1H NMR (300 MHz, CDCl3) d 1.3–1.9 (6H, m, H-3, H-4, H-
5), 2.4–2.6 (4H, m, H-1, H-2, H-6, H-7), 4.60 (1H, m, H-10),
5.51 (1H, ddd, JZ1.2, 3.4, 9.2 Hz, H-9), 5.94 (1H, dd,
JZ6.2, 9.2 Hz, H-8), 7.23–7.32 (2H, m, H-40, H-60), 7.44
(1H, t, JZ7.6 Hz, H-50), 7.83 (1H, d, JZ8.1 Hz, H-30); 13C
NMR (75 MHz, CDCl3) d 26.6, 27.7, 28.0, 40.3, 43.7, 47.2,
48.2, 52.0, 124.9, 127.9, 129.1, 130.6, 133.2, 133.5, 136.1,
148.2, 214.8; IR 1605, 1740, 2923 cmK1; HRMS (ESI) m/z
calcd C17H17NNaO3 [MCNa]C 306.1101, found 306.1083.
71.4, 92.0, 99.8, 131.0, 134.3; IR 1644, 2930, 3051 cmK1
;
HRMS (EI) m/z calcd C12H17O3 [MCH]C 209.1178, found
209.1170.
4.1.3. rac-(1S,2R,8S,9R,12S)-12-(20-Nitrophenyl)-4,6-
dioxatricyclo[7.3.1.02,8]tridec-10-en-13-one 13. A mixture
of the exo meta photoadduct 11 (171 mg, 0.822 mmol),
2-iodo-1-nitrobenzene (222 mg, 0.891 mmol), triethylamine
(89 mg, 0.88 mmol), palladium (II) acetate (7 mg,
0.03 mmol) and 1,2-bis(diphenylphosphine) ethane (57 mg,
0.14 mmol) and dry DMF (3.5 ml) was added to a re-sealable
reaction tube. The tube was flushed with a stream of dry
nitrogen, sealed and the mixture heated at 80 8C for 32 h. The
reaction was poured into water (50 ml) and acidified with
2 M HCl. The aqueous portion was washed with ethyl acetate
(5!10 ml) and the combined organics washed with brine
(50 ml), water (50 ml) and dried over magnesium sulfate.
The solvent was removed under reduced pressure and the
residue subjected to column chromatography (silica, eluting
with petrol/ethyl acetate 3:1) to afford the product 13 (60 mg,
23%) as an off-white crystalline solid (for crystallographic
details see Ref. 11a) mp 190.6–191.3 8C.
4.1.2. rac-(1S,2S,8R,9S,13R)-13-Methoxy-4,6-dioxatetra-
cyclo[7.3.1.0.2,8012,13]tridec-10-ene (exo isomer) 11 and
rac-(1S,2R,8S,9S,13R)-13-methoxy-4,6-dioxatetracyclo-
[73.1.0.2,8012,13]tridec-10-ene (endo isomer) 12. A solution
of anisole (1.35 g, 12 mmol) and cis-4,7-dihydro-1,3-
dioxepin (1.29 g, 12 mmol) in cyclohexane (175 ml) was
added to a quartz immersion-well photoreactor and
degassed by passing a stream of nitrogen through it for
10 min. This solution was then irradiated with 254 nm UV
light for 161⁄2 h using a 6 W low-pressure mercury vapour
lamp. The solvent was removed in vacuo and the residue
subjected to column chromatography (silica, petrol/ether
3:1) to obtain the exo isomer 11 (0.105 g, 4.1%) and endo
isomer 12 (0.113 g, 4.5%) as light green oils.
Compound 11
5'
O 4
4'
O
5
6
OCH3
13
6'
5
O
13
6 O
3'
3
1'
12
11
4 O
7
2
2'
8
1
7
10
9
NO
3
2
9
1
12
8
10
11
2
1H NMR (500 MHz, CDCl3) d 1.92 (1H, m, H-2a), 2.09
(1H, dd, JZ1.6, 8.4 Hz, H-1), 2.21 (1H, m, H-8a), 2.22 (1H,
ddd, JZ1.4, 2.4, 8.4 Hz, H-12), 2.79 (1H, d, JZ2.7 Hz,
H-9), 3.30 (3H, s, OCH3), 3.72 (1H, ddd, JZ0.9, 4.5,
12.0 Hz, H-7a), 3.90 (1H, dd, JZ3.4, 12.4 Hz, H-3b), 3.97
1H NMR (500 MHz, CDCl3) d 2.44 (1H, m, H-1), 2.45 (1H,
dd, JZ2.0, 7.2 Hz, H-9), 2.87 (2H, m, H-2a, H-8a), 3.81
(1H, ddm, JZ6.6, 13.0 Hz, H-3), 3.86 (1H, ddm, JZ3.8,
13.0 Hz, H-3), 4.01 (1H, ddm, JZ5.7, 12.9 Hz, H-7), 4.06
(1H, ddm, JZ3.1, 12.8 Hz, H-7), 4.64 (1H, d, JZ6.7 Hz,

3430
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
H-5b), 4.70 (1H, m, H-12a), 4.74 (1H, d, JZ6.7 Hz, H-5a),
5.60 (1H, ddd, JZ1.3, 3.5, 9.1 Hz, H-11), 6.27 (1H, ddd,
JZ1.3, 7.2, 8.9 Hz, H-10), 7.33 (1H, dd, JZ1.4, 7.8 Hz, H-
60), 7.41 (1H, ddd, JZ1.4, 7.4, 8.1 Hz, H-40), 7.54 (1H, ddt,
JZ0.4, 1.4, 7.4 Hz, H-50) 7.94 (1H, dd, JZ1.4, 8.1 Hz, H-
30); 13C NMR (125 MHz, CDCl3) d 45.6, 48.2, 51.4, 53.3,
55.0, 72.0, 73.4, 99.2, 125.0, 127.2, 128.3, 130.1, 133.3,
134.5, 135.0, 148.3, 213.5; IR 1599, 1630, 1744, 2855,
2922 cmK1; HRMS (ESI) m/z calcd C17H18NO5 [MCH]C
316.1185, found 316.1196.
254 nm UV light for 120 h using a 16 W low-pressure
mercury vapour lamp. The unreacted starting materials and
solvent were removed in vacuo and the residue subjected to
column chromatography to obtain the ortho photoadduct 21
(350 mg, 0.5%), the 6-exo isomer 18 (2.65 g, 4%), a mixture
of the 6-endo and 7-exo isomers 19 and 20 (6.0 g, 9%) and the
7-endo isomer 17 (5.3 g, 8%).
Compound 17
OCH
3
8
4.1.4. rac-(1S,2S,8R,9R,12S)-12-(20-Nitrophenyl)-4,6-
dioxatricyclo[7.3.1.02,8]tridec-10-en-13-one 14. A mixture
of the endo meta photoadduct 12 (474 mg, 2.28 mmol),
2-iodo-1-nitrobenzene (615 mg, 2.46 mmol), triethylamine
(474 mg, 2.43 mmol), palladium (II) acetate (19 mg,
0.084 mmol) and 1,2-bis(diphenylphosphine) ethane
(157 mg, 0.394 mmol) and dry DMF (9 ml) was added to a
re-sealable reaction tube. The tube was flushed with a stream
of dry nitrogen, sealed and the mixture heated at 80 8C for
32 h. The reaction was poured into water (100 ml) and
acidified with 2 M HCl. The aqueous portion was washed
with ethyl acetate (5!25 ml) and the combined organics
washed with brine (100 ml), water (100 ml) and dried over
magnesium sulfate. The solvent was removed under reduced
pressure and the residue subjected to column chromatog-
raphy (silica, eluting with petrol/ether 1:1) to afford the
product 14 (143 mg, 20%) as a white crystalline solid (for
crystallographic details see Ref. 11b) mp 198.0–198.4 8C.
6
4
5
1
2
7
3
OH
1H NMR (500 MHz, CDCl3) d 1.52 (1H, dd, JZ1.3, 12.9 Hz,
H-6a), 2.05 (1H, br s, –OH), 2.09 (1H, ddd, JZ0.6, 2.2,
8.5 Hz, H-2), 2.15 (1H, dd, JZ6.2, 8.5 Hz, H-1), 2.43 (1H,
ddd, JZ6.6, 11.4, 12.9 Hz, H-6b), 2.75 (1H, m, H-7b), 3.18
(1H, ddd, JZ1.3, 2.7, 6.8 Hz, H-5), 3.37 (3H, s, OCH3), 3.51
(1H, dd, JZ7.2, 10.3 Hz, –CHHO–), 3.59 (1H, dd, JZ8.4,
10.3 Hz, –CHHO–), 5.57 (1H, dddd, JZ0.6, 1.3, 2.7, 5.6 Hz,
H-4), 5.65 (1H, dd, JZ2.2, 5.6 Hz, H-3); 13C NMR
(125 MHz, CDCl3) d 36.7, 38.9, 40.0, 44.9, 51.2, 56.2,
65.7, 91.4, 129.1, 136.5; IR 1645, 2933, 3403 cmK1; HRMS
(EI) m/z calcd C10H14O2 [M]C 166.0994, found 166.0996.
Compound 18
5'
4'
O
OCH
3
6'
13
HO
3'
8
1'
2
2'
6
1
12
11
4
5
NO2
8
7
6 O
9
3
1
2
10
7
3
4
O
5
1H NMR (500 MHz, CDCl3) d 1.47 (1H, ddd, JZ1.4, 6.3,
13.9 Hz, H-7a), 1.68 (1H, dddd, JZ0.5, 1.7, 6.7, 13.9 Hz,
H-7b), 2.05 (1H, ddd, JZ1.4, 6.3, 8.4 Hz, H-1), 2.06 (1H,
dddd, JZ0.5, 6.3, 7.0, 7.9 Hz, H-5), 2.10 (1H, br s, –OH),
2.18 (1H, dddd, JZ0.6, 1.4, 2.4, 8.4 Hz, H-2), 3.12 (1H, dd,
JZ1.7, 2.7 Hz, H-5), 3.32 (3H, s, OCH3), 3.58 (1H, dd,
JZ7.0, 10.6 Hz, –CHHO–), 3.69 (1H, dd, JZ7.9, 10.6 Hz,
–CHHO–), 5.55 (1H, ddd, JZ1.4, 2.7, 5.7 Hz, H-4), 5.60
(1H, dd, JZ2.4, 5.7 Hz, H-3); 13C NMR (125 MHz, CDCl3)
d 25.0, 34.5, 36.6, 52.3, 53.1, 56.4, 63.6, 89.8, 126.8, 132.2;
IR 1645, 2931, 3409 cmK1; HRMS (ESI) m/z calcd
C10H14NaO2 [MCNa]C 189.0891, found 189.0885.
1H NMR (400 MHz, CDCl3) d 2.69 (1H, dd, JZ5.6, 6.4 Hz,
H-9), 2.75 (1H, d, JZ7.6 Hz, H-1), 2.87 (1H, m, H-8a), 3.00
(1H, m, H-2a), 4.05 (2H, t, JZ12.0 Hz, H-7b, H-3b), 4.27
(1H, dd, JZ4.8, 12.8 Hz, H-7a), 4.53 (1H, d, JZ7.2 Hz, H-
5b), 4.59 (1H, dd, JZ3.6, 12.0 Hz, H-3a), 4.75 (1H, m,
H-12a), 5.18 (1H, d, JZ7.2 Hz, H-5a), 5.69 (1H, dd, JZ2.4,
8.8 Hz, H-11), 6.12 (1H, dd, JZ7.2, 8.8 Hz, H-10), 7.27
(1H, d, JZ8.2 Hz, H-60), 7.43 (1H, dt,0 JZ1.2, 7.8 Hz, H-
40), 7.56 (1H, dt, JZ1.2, 7.6 Hz, H-5 ) 7.99 (1H, d, JZ
8.4 Hz, H-30); 13C NMR (100 MHz, CDCl3) d 39.1, 43.6,
46.6, 47.9, 52.5, 71.1, 72.0, 100.0, 125.3, 128.4, 129.2,
130.4, 132.5, 133.3, 134.9, 148.1, 211.1; IR 1602, 1641,
1753, 2876, 2956 cmK1; HRMS (ESI) m/z calcd
C17H17NNaO5 [MCNa]C 338.1004, found 338.1000.
Compound 21
OH
MeO
3
4
8
2
5
1
6
4.1.5. rac-(1S,2R,5R,7R,8S)-7-Hydroxymethyl-8-methoxy-
tricyclo[3.2.1.02,8]oct-3-ene 17 and rac-(1S,2R,5S,6R,
8R)-6-hydroxymethyl-8-methoxytricyclo[32.1.02,8]oct-3-
ene 18 and rac-(1S,2R,6R)-1-methoxy-2-hydroxymethyl-
bicyclo[42.0]octa-4,7-diene 21. A solution of anisole
(43.2 g, 400 mmol) and allyl alcohol (46.4 g, 800 mmol) in
cyclohexane (302 ml) was added to a quartz immersion-well
photoreactor and degassed by passing a stream of nitrogen
through it for 20 min. This solution was then irradiated with
7
H
1H NMR (500 MHz, CDCl3) d 1.20 (1H, br s, –OH), 1.60–
1.69 (1H, m, H-3), 1.94–2.06 (1H, m, H-2b, H-3), 3.35 (3H,
s, –OCH3), 3.36 (1H, dd, JZ0.9, 5.7 Hz, H-6b), 3.54 (1H,
dd, JZ4.5, 10.6 Hz, –CHHO–), 3.71 (1H, dd, JZ8.5,
10.6 Hz, –CHHO–), 5.70 (1H, dddd, JZ0.5, 3.3, 5.9,

C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3431
9.7 Hz, H-5), 5.87 (1H, ddd, JZ2.1, 6.8, 9.6 Hz, H-4), 6.11
(1H, dd, JZ0.9, 2.9 Hz, H-7), 6.15 (1H, d, JZ2.9 Hz, H-8);
13C NMR (125 MHz, CDCl3) d 24.7, 42.3, 46.4, 50.9, 64.8,
2.43 (1H, s, –OH), 2.6–2.7 (3H, m, H-1, H-5, H-7b), 3.81
(1H, dd, JZ6.4, 10.9 Hz, –CHHO–), 4.09 (1H, dd, JZ8.2,
10.9 Hz, –CHHO–), 4.79 (1H, dm, JZ3.5 Hz, H-2a), 5.55
(1H, ddd, JZ1.2, 3.6, 9.1 Hz, H-3), 6.27 (1H, ddd, JZ1.1,
7.0, 9.1 Hz, H-4), 7.33 (1H,0dd, JZ1.4, 7.9 Hz, H-60), 7.40
(1H, dt, JZ1.4, 7.8 Hz, H-4 ), 7.54 (1H, dt, JZ1.4, 7.7 Hz,
H-50), 7.90 (1H, dd, JZ1.4, 8.1 Hz, H-30); 13C NMR
(125 MHz, CDCl3) d 31.5, 36.7, 44.8, 46.1, 50.9, 64.1,
124.9, 127.6, 128.2, 130.6, 133.1, 135.1, 136.4, 148.3,
88.1, 126.1, 129.4, 134.2, 139.6; IR 1644, 3419 cmK1
;
HRMS (ESI) m/z calcd C10H14NaO2 [MCNa]C 189.0891,
found 189.0889.
4.1.6. rac-(1R,4S,5R,7R)-4-(20-Nitrophenyl)-7-hydroxy-
methylbicyclo[3.2.1]oct-2-en-8-one 22 and rac-(1R,
2R,5R,7R)-2-(20-nitrophenyl)-7-hydroxymethylbicyclo-
[3.2.1]oct-3-en-8-one 23. A mixture of the 7-endo allyl
alcohol/anisole derived meta photoadduct 17 (330 mg,
1.21 mmol), 2-iodo-1-nitrobenzene (303 mg, 1.22 mmol),
triethylamine (123 mg, 1.22 mmol), palladium (II) acetate
(13 mg, 0.060 mmol) and tri-ortho-tolylphosphine (37 mg,
0.12 mmol) and dry DMF (4 ml) was added to a re-sealable
reaction tube. The tube was flushed with a stream of dry
nitrogen, sealed and the mixture heated at 120 8C for 12 h.
The reaction was poured into 2 M hydrochloric acid (50 ml)
and the aqueous portion was washed with ethyl acetate (5!
40 ml) and the combined organic portions were washed with
brine (100 ml), water (100 ml) and dried over magnesium
sulfate. The solvent was removed under reduced pressure
and the residue subjected to column chromatography (silica,
eluting with petrol/EtOAc 1:1) to afford 22 (139 mg, 42%)
as a yellow oil that became crystalline upon standing (for
crystallographic details see Ref. 8) (mp 118.5–119.4 8C) and
23 (33 mg, 10%) as a pale yellow oil.
214.2; IR 1606, 1635, 1748, 2874, 2936, 3406 cmK1
;
HRMS (ESI) m/z calcd C15H15NNaO4 [MCNa]C
296.0899, found 296.0885.
4.1.7.
rac-(1R,2R,5R,7R,8R)-7-Hydroxymethyl-8-
methyltricyclo[3.2.1.02,8]oct-3-ene 29. A solution of total
volume (400 ml) containing toluene (36.8 g, 400 mmol),
allyl alcohol (46.4 g, 800 mmol) and cyclohexane was
added to a quartz immersion-well photoreactor and
degassed by passing a stream of nitrogen through it for
20 min. This solution was then irradiated with 254 nm UV
light for 120 h using a 16 W low-pressure mercury vapour
lamp. The unreacted starting materials and solvent were
removed in vacuo and the residue subjected to column
chromatography to obtain the 7-endo isomer 29 as a pale
yellow oil (1.23 g, 2%).
CH
3
8
6
4
5
1
2
7
3
Compound 22
OH
O N
O
2
3'
4'
5'
2'
8
4
1H NMR (500 MHz, CDCl3) d 1.44 (3H, s, –CH3), 1.48 (1H,
br s, –OH), 1.48 (1H, d, JZ12.8 Hz, H-6a), 1.53 (1H, dd,
JZ6.3, 7.1 Hz, H-1), 1.56 (1H, dm, JZ7.2 Hz, H-2), 2.36
(1H, ddd, JZ6.2, 11.3, 12.8 Hz, H-6b), 2.72–2.78 (1H, m,
H-7b), 2.78 (1H, dm, JZ6.0 Hz, H-5), 3.64 (1H, dd, JZ7.3,
10.3 Hz, –CHHO–), 3.74 (1H, dd, JZ8.4, 10.2 Hz,
–CHHO–), 5.45 (1H, dddd, JZ0.8, 0.8, 2.4, 5.3 Hz, H-4),
5.66 (1H, dd, JZ2.0, 5.3 Hz, H-3); 13C NMR (125 MHz,
CDCl3) d 18.5, 37.6, 37.9, 41.3, 45.6, 46.4, 54.6, 66.4,
129.8, 136.7; IR 1596, 2923, 3308 cmK1; HRMS (EI) m/z
calcd C10H14O [M]C 150.1045, found 150.1045.
6
5
1'
6'
1
3
7
2
OH
1H NMR (500 MHz, CDCl3) d 1.53 (1H, ddd, JZ1.5, 7.7,
13.5 Hz, H-6a), 1.67 (1H, br s, –OH), 2.44 (1H, ddd, JZ8.4,
9.8, 13.5 Hz, H-6b), 2.54 (1H, dm, JZ8.4 Hz, H-5), 2.59
(1H, m, H-7b), 2.83 (1H, ddd, JZ1.5, 5.3, 6.8 Hz, H-1),
3.79–3.83 (2H, m, –CH2O–), 4.56 (1H, ddm, JZ1.1, 3.6 Hz,
H-4a), 5.72 (1H, ddd, JZ1.3, 3.6, 9.2 Hz, H-3), 6.14 (1H,
ddd, JZ1.1, 6.8, 9.1 Hz, H-2), 7.32 (1H, dd, JZ1.4, 7.8 Hz,
H-60), 7.42 (1H, dt, JZ1.4, 8.2 Hz, H-40), 7.55 (1H, dt,
JZ1.3, 7.6 Hz, H-50), 7.94 (1H, dd, JZ1.4, 8.1 Hz, H-30);
13C NMR (100 MHz, CDCl3) d 28.9, 43.1, 47.4, 48.7, 55.0,
63.3, 124.8, 128.2, 129.1, 130.0, 131.0, 133.0, 134.9, 148.4,
4.1.8. rac-(1R,4S,5R,7R)-4-(20-Nitrophenyl)-7-hydroxy-
methyl-8-methylenebicyclo[3.2.1]oct-2-ene 31a and
rac-(1R,2R,5R,7R)-2-(20-nitrophenyl)-7-hydroxymethyl-
8-methylenebicyclo[3.2.1]oct-3-ene 32a. A mixture of the
7-endo allyl alcohol/toluene-derived meta photoadduct 29
(150 mg, 1.00 mmol), 2-iodo-1-nitrobenzene (299 mg,
1.20 mmol), triethylamine (121 mg, 1.20 mmol), palladium
(II) acetate (11 mg, 0.050 mmol) and tri-ortho-tolylphos-
phine (30 mg, 0.10 mmol) and dry DMF (3 ml) was added
to a re-sealable reaction tube. The tube was flushed with a
stream of dry nitrogen, sealed and the mixture heated at
120 8C for 12 h. The reaction was poured into 2 M
hydrochloric acid (50 ml) and the aqueous portion was
washed with ethyl acetate (5!40 ml) and the combined
organic portions were washed with brine (100 ml), water
(100 ml) and dried over magnesium sulfate. The solvent was
removed under reduced pressure and the residue subjected
to column chromatography (silica, eluting with petrol/Et2O
214.5; IR 1606, 1632, 1751, 2871, 2931, 3415 cmK1
;
HRMS (ESI) m/z calcd C15H15NNaO4 [MCNa]C
296.0899, found 296.0901.
Compound 23
O
3'
O N
8
2
2'
4'
5'
4
6
5
1'
6'
7
1
3
2
OH
1H NMR (500 MHz, CDCl3) d 1.68 (1H, dd, JZ4.7,
12.8 Hz, H-6a), 2.19 (1H, ddd, JZ6.4, 10.6, 12.7 Hz, H-6b),

3432
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3:2) to afford 31a (78 mg, 29%) as a yellow oil and 32a
(35 mg, 13%) as a yellow oil.
hydrochloric acid (50 ml) and the aqueous portion was
washed with ethyl acetate (5!40 ml) and the combined
organic portions were washed with brine (100 ml), water
(100 ml) and dried over magnesium sulfate. The solvent was
removed under reduced pressure and the residue subjected
to column chromatography (silica, eluting with petrol/Et2O
2:1) to afford 31b (71 mg, 30%) as a yellow oil. The minor
isomer 32b (24 mg, !10%) was also obtained but could not
be separated from some co-eluting impurites.
Compound 31a
O N
2
3'
4'
5'
2'
8
4
6
1'
5
6'
3
7
1
2
OH
5'
4'
6'
8
1H NMR (500 MHz, CDCl3) d 1.27 (1H, ddd, JZ1.2, 7.2,
13.4 Hz, H-6a), 1.65 (1H, br s, –OH), 2.29 (1H, ddd, JZ7.8,
10.0, 13.3 Hz, H-6b), 2.42–2.49 (1H, m, H-7b), 2.66
(1H, dm, JZ7.9 Hz, H-5), 2.96 (1H, ddd, JZ1.1, 5.2,
6.4 Hz, H-1), 3.69 (1H, dd, JZ9.2, 10.4 Hz, –CHHO–),
3.74 (1H, dd, JZ6.1, 10.4 Hz, –CHHO–), 3.98 (1H, m, H-
4a), 4.17 (1H, d, JZ1.1 Hz, ]CHH), 4.74 (1H, d, JZ
0.7 Hz, ]CHH), 5.49 (1H, ddd, JZ1.6, 3.6, 9.4 Hz, H-3),
6.13 (1H, 0ddd, JZ1.7, 6.4, 9.3 Hz, H-2), 7.34–7.37 (2H, m,
H-40, H-6 ), 7.50 (1H, ddd, JZ1.4, 7.1, 8.4 Hz, H-50), 7.87
(1H, ddd, JZ0.7, 1.4, 7.8 Hz, H-30); 13C NMR (125 MHz,
CDCl3) d 33.1, 44.0, 46.4, 49.1, 50.3, 64.4, 102.9, 124.1,
127.2, 127.7, 131.7, 132.0, 132.5, 136.3, 148.8, 150.3; IR
1606, 1634, 2866, 2926, 3469 cmK1; HRMS (ESI) m/z
calcd C16H17NNaO3 [MCNa]C 294.1106, found 294.1101.
4
6
1'
3'
5
CH
3
2'
1
3
7
2
OH
1H NMR (500 MHz, CDCl3) d 1.25 (1H, ddd, JZ1.0, 7.1,
13.0 Hz, H-6a), 1.60 (1H, br s, –OH), 2.23 (1H, ddd, JZ7.8,
10.1, 13.0 Hz, H-6b), 2.33 (3H, s, –CH3), 2.39–2.46 (1H, m,
H-7b), 2.51 (1H, dm, JZ8.0 Hz, H-5), 2.89 (1H, ddd, JZ
1.0, 5.1, 6.4 Hz, H-1), 3.43 (1H, m, H-4a), 3.73–3.75 (2H,
m, –CH2O–), 4.20 (1H, d, JZ1.4 Hz, ]CHH), 4.71 (1H, d,
JZ0.8 Hz, ]CHH), 5.59 (1H, ddd, JZ1.5, 3.6, 9.4 Hz,
H-3), 6.02 (1H, ddd, JZ1.6, 6.4, 9.6 Hz, H-2), 6.98 (3H, m,
H-20, H-40, H-60), 7.17 (1H, t, JZ7.5 Hz, H-50); 13C NMR
(125 MHz, CDCl3) d 21.4, 33.4, 43.9, 47.5, 49.3, 56.3, 64.7,
102.0, 125.4, 127.0, 127.7, 129.0, 129.1, 130.8, 137.3,
142.7, 150.8; IR 1637, 2924, 3433 cmK1; HRMS (ESI) m/z
calcd C17H20NaO [MCNa]C 263.1412, found 263.1414.
Compound 32a
3'
O N
2
2'
4'
5'
8
4
6
4.1.10. rac-(1S,2R,5S,6S,8S)-6-Hydroxymethyl-8-(20-tri-
methylsilanylethyl)tricyclo[3.2.1.02,8]oct-3-ene 35 and
rac-(1R,2R,5R,7R,8R)-7-hydroxymethyl-8-(20-trimethyl-
silanylethyl)tricyclo[32.1.02,8]oct-3-ene 36. A solution of
total volume (400 ml) containing phenethyltrimethyl
silane16 (14.2 g, 80 mmol), allyl alcohol (14 g, 240 mmol)
and cyclohexane was added to a quartz immersion-well
photoreactor and degassed by passing a stream of nitrogen
through it for 20 min. This solution was then irradiated with
UV light for 13 h using a 400 W medium-pressure mercury
vapour lamp. The solvent and unreacted allyl alcohol were
removed in vacuo and the residue subjected to column
chromatography to obtain the 6-endo isomer 35 (453 mg,
2.4%) and the 7-endo isomer 36 (415 mg, 2.2%).
5
1'
6'
1
7
3
2
OH
1H NMR (500 MHz, CDCl3) d 1.43 (1H, dd, JZ4.7,
12.2 Hz, H-6a), 1.60 (1H, br s, –OH), 2.06 (1H, dddd, JZ
0.8, 6.4, 11.3, 12.2 Hz, H-6b), 2.57–2.64 (1H, m, H-7b),
2.76 (1H, ddm, JZ1.4, 6.9 Hz, H-1), 2.81 (1H, ddd, JZ1.2,
5.8, 6.6 Hz, H-5), 3.75 (1H, dd, JZ6.3, 11.1 Hz, –CHHO–),
3.97 (1H, dd, JZ9.0, 11.1 Hz, –CHHO–), 4.22 (1H, m,
H-2a), 4.23 (1H, d, JZ1.1 Hz, ]CHH), 4.74 (1H, m,
]CHH), 5.34 (1H, ddd, JZ1.5, 3.7, 9.2 Hz, H-3), 6.27 (1H,
ddd, JZ1.40, 6.6, 9.2 Hz, H-4), 7.37 (1H, ddd, JZ1.5, 7.3,
8.1 Hz, H-4 ), 7.41 (1H, dd, JZ1.5, 7.9 Hz, H-60), 7.52 (1H,
ddd, JZ1.4, 7.5, 7.5 Hz, H-50), 7.88 (1H, ddd, JZ0.3, 1.4,
8.1 Hz, H-30); 13C NMR (125 MHz, CDCl3) d 36.3, 41.5,
41.7, 42.7, 48.5, 64.8, 103.2, 124.3, 125.6, 127.3,
132.1, 132.5, 136.5, 137.8, 148.5, 150.6; IR 1640, 2955,
3422 cmK1; HRMS (ESI) m/z calcd C16H17NNaO3
[MCNa]C 294.1106, found 294.1102.
Compound 35
1'
8
2'
Me Si
3
6
4
5
1
2
7
3
OH
4.1.9. rac-(1R,4S,5R,7R)-4-(30-Methylphenyl)-7-hydro-
xymethyl-8-methylenebicyclo[3.2.1]oct-2-ene
31b.
A mixture of the 7-endo allyl alcohol/toluene-derived
meta photoadduct 29 (150 mg, 1.00 mmol), 3-bromotoluene
(205 mg, 1.20 mmol), triethylamine (121 mg, 1.20 mmol),
palladium (II) acetate (11 mg, 0.050 mmol) and tri-ortho-
tolylphosphine (30 mg, 0.10 mmol) and dry DMF (3 ml)
was added to a re-sealable reaction tube. The tube was
flushed with a stream of dry nitrogen, sealed and the mixture
heated at 120 8C for 12 h. The reaction was poured into 2 M
1H NMR (500 MHz, CDCl3) d K0.03 (9H, s, –Si(CH3)3),
0.47 (1H, ddd, JZ5.0, 12.5, 14.2 Hz, Si–CHH–), 0.53 (1H,
ddd, JZ5.0, 12.5, 14.2 Hz, Si–CHH–), 1.22 (1H, ddd, JZ
1.5, 10.7, 13.0 Hz, H-7a), 1.44 (1H, ddd, JZ1.5, 7.0,
7.0 Hz, H-1), 1.55 (1H, ddd, JZ5.0, 12.6, 14.1 Hz, C(8)–
CHH–), 1.61 (1H, m, H-2), 1.63 (1H, ddd, JZ5.0, 12.6,
14.1 Hz, C(8)–CHH–), 1.78 (1H, br s, –OH), 1.89 (1H,
dddd, JZ1.4, 6.6, 7.9, 12.9 Hz, H-7b), 2.53–2.68 (1H, m,

C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
3433
H-6b), 2.87 (1H, ddd, JZ1.3, 2.4, 5.1 Hz, H-5), 3.42 (2H, d,
JZ7.5 Hz, –CH2O–), 5.47 (1H, dd, JZ2.4, 5.5 Hz, H-4),
5.69 (1H, dd, JZ2.3, 5.5 Hz, H-3); 13C NMR (125 MHz,
CDCl3) d K1.8, 13.5, 26.2, 26.8, 30.2, 35.7, 53.1, 53.2,
57.1, 63.2, 129.8, 130.1; IR 2952, 3429 cmK1; HRMS (EI)
m/z calcd C14H24OSi [M]C 236.1608, found 236.1596.
JZ6.1, 10.3 Hz, –CHHO–), 3.91 (1H, ddd, JZ1.8, 1.8,
3.6 Hz, H-4a), 4.94 (1H, dd, JZ1.7, 17.2 Hz, ]CHH), 4.96
(1H, dd, JZ1.6, 10.7 Hz, ]CHH), 5.56 (1H, ddd, JZ1.7,
3.6, 9.5 Hz, H-3), 5.73 (1H, ddd, JZ5.8, 10.7, 17.2 Hz,
C(8)–CH]), 6.26 (1H, ddd, JZ2.0, 6.8, 9.5 Hz, H-2), 7.39
(1H, ddd, JZ1.5, 7.3, 8.1 Hz, H-40), 7.45 (1H, dd, JZ1.5,
7.8 Hz, H-60), 7.56 (1H, ddd, JZ1.4, 7.7, 7.7 Hz, H-50), 7.92
(1H, dd, JZ1.3, 8.1 Hz, H-30); 13C NMR (125 MHz,
CDCl3) d 32.9, 42.1, 43.9, 44.3, 47.6, 48.1, 64.8, 114.4,
124.9, 126.9, 127.3, 131.2, 132.6, 134.6, 138.3, 139.7,
149.0; IR 1606, 1637, 2929, 3365 cmK1; HRMS (ESI) m/z
calcd C17H19NNaO3 [MCNa]C 308.1263, found 308.1260.
Compound 36
1'
2'
Me Si
3
8
6
4
5
1
2
7
3
4.1.12. rac-(1R,4S,5R,7R)-4-(20-Nitrophenyl)-7-hydroxy-
methyl-8(Z)-methoxymethylenebicyclo[3.2.1]oct-2-ene
41. A solution of total volume (400 ml) containing
benzylmethylether (4.89 g, 40 mmol), allyl alcohol
(6.96 g, 120 mmol) and cyclohexane was added to a quartz
immersion-well photoreactor and degassed by passing a
stream of nitrogen through it for 20 min. This solution was
then irradiated with 254 nm UV light for 87 h using a 16 W
medium-pressure mercury vapour lamp. The solvent and
unreacted starting materials were removed in vacuo and the
residue subjected to column chromatography to obtain a 2:1
mixture of the 2,4 meta photoadduct 39 and the 2,6 meta
photoadduct 40 (487 mg, 6.8%) as a pale green oil.
OH
1H NMR (500 MHz, CDCl3) d K0.02 (9H, s, –Si(CH3)3),
0.52 (1H, ddd, JZ5.0, 12.6, 14.2 Hz, Si–CHH–), 0.57 (1H,
ddd, JZ4.9, 12.6, 14.2 Hz, Si–CHH–), 1.48 (1H, dd, JZ
1.2, 12.8 Hz, H-6a), 1.58 (2H, m, H-1, C(8)–CHH–), 1.63
(1H, ddd, JZ5.1, 12.6, 14.1 Hz, C(8)–CHH–), 1.69 (1H, br
s, –OH), 1.72 (1H, ddd, JZ5.2, 12.6, 14.2 Hz, C(8)–CHH–),
2.31 (1H, ddd, JZ6.2, 11.3, 12.8 Hz, H-6b), 2.69–2.76 (1H,
m, H-7b), 2.85 (1H, ddd, JZ1.3, 2.5, 6.0 Hz, H-5), 3.64
(1H, dd, JZ7.3, 10.3 Hz, –CHHO–), 3.74 (1H, dd, JZ8.4,
10.2 Hz, –CHHO–), 5.47 (1H, dddd, JZ0.8, 0.8, 2.4,
5.3 Hz, H-4), 5.66 (1H, dd, JZ1.9, 5.3 Hz, H-3); 13C NMR
(125 MHz, CDCl3) d K1.8, 13.4, 26.7, 36.0, 36.2, 41.6,
45.6, 52.7, 53.7, 66.4, 130.0, 136.9; IR 1597, 1637, 2922,
3350 cmK1; HRMS (ESI) m/z calcd C14H24NaOSi [MC
Na]C 259.1494, found 259.1489.
This inseparable mixture of photoadducts 39 and 40
(487 mg, 2.70 mmol) was added to a re-sealable reaction
tube along with 2-iodo-1-nitrobenzene (674 mg,
2.70 mmol), triethylamine (328 mg, 3.25 mmol), palladium
(II) acetate (30 mg, 0.135 mmol) and tri-ortho-tolylpho-
sphine (82 mg, 0.27 mmol) and dry DMF (10 ml). The tube
was flushed with a stream of dry nitrogen, sealed and the
mixture heated at 120 8C for 2 h. The reaction was poured
into 2 M hydrochloric acid (75 ml) and the aqueous portion
was washed with ethyl acetate (5!50 ml) and the combined
organic portions were washed with brine (100 ml), water
(100 ml) and dried over magnesium sulfate. The solvent was
removed under reduced pressure and the residue subjected
to column chromatography (silica, eluting with petrol/
EtOAc 2:1) to afford 41 (54 mg, 15% with respect to the
mixture of photoadducts 39 and 40) as an orange oil.
4.1.11.
rac-(1R,4R,5S,7R,8R)-4-(20-Nitrophenyl)-7-
hydroxymethyl-8-vinylbicyclo[3.2.1]oct-2-ene 37. A mix-
ture of the 7 endo phenethyltrimethyl silane derived meta
photoadduct 36 (300 mg, 1.27 mmol), 2-iodo-1-nitroben-
zene (380 mg, 1.53 mmol), triethylamine (154 mg,
1.53 mmol), palladium (II) acetate (14 mg, 0.060 mmol)
and tri-ortho-tolylphosphine (39 mg, 0.13 mmol) and dry
DMF (8 ml) was added to a re-sealable reaction tube. The
tube was flushed with a stream of dry nitrogen, sealed and
the mixture heated at 80 8C for 12 h. The reaction was
poured into 2 M hydrochloric acid (75 ml) and the aqueous
portion was washed with ethyl acetate (5!50 ml) and the
combined organic portions were washed with brine
(100 ml), water (100 ml) and dried over magnesium sulfate.
The solvent was removed under reduced pressure and the
residue subjected to column chromatography (silica, eluting
with petrol/EtOAc 5:1) to afford 37 (54 mg, 15%) as a
yellow oil.
H CO
3
H
5'
4'
3'
6'
8
4
6
7
1'
5
2'
1
3
NO
2
2
OH
1H NMR (500 MHz, CDCl3) d 1.25 (1H, ddm, JZ6.7,
13.2 Hz, H-6a), 1.65 (1H, br s, –OH), 2.26 (1H, ddd, JZ7.8,
10.1, 13.2 Hz, H-6b), 2.38–2.46 (1H, m, H-7b), 2.59 (1H,
tm, JZ7.9 Hz, H-5), 3.44 (1H, tm, JZ5.7 Hz, H-1), 3.47
(3H, s, –OCH3), 3.68 (1H, dd, JZ9.2, 10.5 Hz, –CHHO–),
3.74 (1H, dd, JZ6.2, 10.5 Hz, –CHHO–), 3.88 (1H, m, H-
4a), 5.19 (1H, s, ]CHO–), 5.47 (1H, ddd, JZ1.6, 3.7,
9.4 Hz, H-3), 6.15 (1H, ddd, JZ1.7, 6.4, 9.3 Hz, H-2), 7.34–
7.37 (2H, m, H-40, H-60), 7.52 (1H, ddd, JZ1.4, 7.6, 7.6 Hz,
H-50), 7.86 (1H, dd, JZ1.3, 8.0 Hz, H-30); 13C NMR
(125 MHz, CDCl3) d 33.7, 36.7, 43.2, 49.6, 49.9, 59.6,
64.5, 119.4, 124.1, 127.1, 127.9, 131.9, 132.1, 132.3, 135.1,
5'
4'
H
6'
8
4
3'
6
1'
5
2'
3
7
1
NO
2
2
OH
1H NMR (500 MHz, CDCl3) d 1.16 (1H, dd, JZ6.3,
13.8 Hz, H-6a), 1.58 (1H, br s, –OH), 2.27 (1H, ddd, JZ7.7,
10.0, 13.9 Hz, H-6b), 2.37 (1H, dm, JZ7.7 Hz, H-5), 2.51
(1H, dm, JZ5.8 Hz, H-8), 2.53–2.59 (2H, m, H-1, H-7b),
3.69 (1H, dd, JZ8.5, 10.3 Hz, –CHHO–), 3.74 (1H, dd,

3434
C. S. Penkett et al. / Tetrahedron 62 (2006) 3423–3434
136.5, 148.8; IR 1636, 2930, 3417 cmK1; HRMS (ESI) m/z
calcd C17H19NNaO4 [MCNa]C 324.1212, found 324.1204.
7. Avent, A. G.; Byrne, P. W.; Penkett, C. S. Org. Lett. 1999, 1,
2073.
8. Penkett, C. S.; Sims, R. O.; French, R.; Dray, L.; Roome, S. J.;
Hitchcock, P. B. Chem. Commun. 2004, 1932.
9. (a) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl.
1995, 33, 2379. (b) Gibson, S. E.; Middleton, R. J. Contemp.
Org. Synth. 1996, 3, 447. (c) Crisp, G. T. Chem. Soc. Rev.
1998, 27, 427. (d) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000, 100, 3009. (e) Poli, G.; Giambastiani, G.;
Heumann, A. Tetrahedron 2000, 56, 5959. (f) Link, J. T. In
Organic Reactions, Vol. 60; Wiley: Hoboken, NJ, 2002;
Chapter 2. (g) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945.
Acknowledgements
We gratefully acknowledge the funding for this research
from Tocris-Cookson Ltd and the EPSRC (GR/T08807/01).
We have appreciated the opportunity to discuss this
chemistry with Professor P. J. Parsons and Professor P. A.
Wender. L.K. would like to thank AstraZeneca for the
opportunity to undertake a part-time MSc course at the
University of Sussex. We would also like to thank Dr. A.
Abdul Sada for mass spectroscopy studies.
10. We thank Mark Charles, DPhil thesis, University of Sussex,
2003 for suggesting these initial reaction conditions.
11. (a) The crystallographic data for compound 13 have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 283162. Formula:
C17H17N1O5 Unit cell parameters: a 7.1064(12) b 9.7290(16) c
References and notes
˚
11.6227(16) A alpha 110.028(8) beta 106.858(8) gamma
ꢀ
91.824(6)8 space group P1. (b) The crystallographic data for
1. (a) Wilzbach, K. E.; Kaplan, L. J. Am. Chem. Soc. 1966, 88,
2066. (b) Bryce-Smith, D.; Gilbert, A.; Orger, B. H. J. Chem.
Soc., Chem. Commun. 1966, 512. (c) Cornelisse, J. Chem. Rev.
1993, 93, 615. (d) Wender, P. A.; Siggel, L.; Nuss, J. M. In
Padwa, A., Ed.; Organic Photochemistry; Marcel-Dekker:
New York, 1989; Vol. 10; Chapter 4. (e) Wender, P. A.;
Siggel, L.; Nuss, J. M. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 5, p 645. (f) Wender, P. A.; Ternansky, R.; de Long, M.;
Singh, S.; Olivero, A.; Rice, K. Pure Appl. Chem. 1990,
62, 1597.
compound 14 have been deposited with Cambridge Crystallo-
graphic Data Centre as supplementary publication number
CCDC 283163. Formula: C17H17N1O5 Unit cell parameters: a
˚
9.1079(17) b 12.352(2) c 13.656(2) A beta 107.328 space
group P21/n.
12. Penkett, C. S.; Byrne, P. W.; Teobald, B. J.; Rola, B.;
Ozanne, A.; Hitchcock, P. B. Tetrahedron 2004, 60, 2771.
13. Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003,
42, 36.
14. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
2. De Keukeleire, D.; He, S.-L. Chem. Rev. 1993, 93, 359.
3. Wender, P. A.; Ternansky, R. J. Tetrahedron Lett. 1985, 26,
2625.
¨
15. Wilhelm, D.; Backvall, J. E.; Nordberg, R. E.; Norin, T.
Organometallics 1985, 4, 1296.
16. Clarke, C.; Fleming, I.; Fortunak, J. M. D.; Gallagher, P. T.;
Honan, M. C.; Mann, A.; Nu¨bling, C. O.; Raithby, P. R.;
Wolff, J. J. Tetrahedron 1988, 44, 3931.
4. Wender, P. A.; Howbert, J. J. Tetrahedron Lett. 1983, 24,
5325.
5. Srinivasan, R.; Merritt, V. Y.; Subrahmanyam, G. Tetrahedron
Lett. 1974, 15, 2715.
17. Gilman, M. J. Am. Chem. Soc. 1949, 71, 2066.
18. Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Org. Chem. 1993, 58, 6949.
6. Wender, P. A.; Howbert, J. J. J. Am. Chem. Soc. 1981,
103, 688.