Biomimetic studies on polyenes.

Article abstract of DOI:10.1039/b306933h

The crispatenes and SNF4435 C&D are complex polypropionate derived natural products. The core structures of these compounds along with a complex unnatural structure can be easily prepared from a common polyene precursor simply by variation of the reaction conditions. The reaction pathways provide insight into the biosynthesis of these complex natural products.

Full text of DOI:10.1039/b306933h

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Biomimetic studies on polyenes†
John E. Moses, Jack E. Baldwin,* Sébastien Brückner, Serena J. Eade and
Robert M. Adlington
The Dyson Perrins Laboratory, University of Oxford, Oxford, UK OX1 3QY.
E-mail: jack.baldwin@chem.ox.ac.uk
Received 17th June 2003, Accepted 28th July 2003
First published as an Advance Article on the web 29th August 2003
The crispatenes and SNF4435 C&D are complex polypropionate derived natural products. The core structures of
these compounds along with a complex unnatural structure can be easily prepared from a common polyene precursor
simply by variation of the reaction conditions. The reaction pathways provide insight into the biosynthesis of these
complex natural products.
diene is connected to a spirofuran unit, which in turn is
Introduction
connected to a γ-pyrone fragment, a common feature in poly-
In recent years, many structurally novel polypropionate meta-
propionates. However, the bicyclic core is also attached to a
bolites have been isolated from terrestrial and marine systems as
p-nitrophenyl ring, which is far less common.
phylogenetically diverse as bacteria and sponges. Many of the
It is believed that this class of compounds are biosynthesised
compounds isolated are biologically important, and display a
from a p-aminobenzoate and a combination of propionate and
diverse range of activity including immunosuppression, cyto-
acetate units, as demonstrated in the biosynthesis of aureothin
toxicity and antibiotic properties. Examples of such com-
3.7
pounds include erythromycin, monensin, methymycin, tylosin,
It is apparent that spectinabilin 7 is a constitutional isomer of
and nonactic acid.1
the SNF compounds 1 and 2. In addition, it has also been
As part of our continuing efforts directed towards the bio-
reported that 7 is not a very stable substrate, with about 50%
mimetic synthesis of complex natural products, we became
being converted to other substances during the course of one
interested in a range of polypropionate derived compounds. Of
month at room temperature.6 In the case of spectinabilin 7, it is
initial interest were the immunosuppressants SNF4435C 1 and
expected that a p-aminobenzoate unit 8 combines with an
equimolar amount of acetate and six propionate units as 9, the
SNF4435D 2, isolated in 2001 by Takahashi and co-workers.2
same ratio as found in the SNF compounds 1 and 2. Hence, a
clear link between these metabolites and spectinabilin 7 can be
proposed (Scheme 1).
Results and discussion
The nitrophenyl pyrones SNF4435C and SNF4435D
SNF4435C 1 and SNF4435D 2 are members of a family of
related biologically active propionate derived compounds,
known broadly as the nitrophenyl pyrones. These include
aureothin 3, luteoreticulin 4, and luteothin 5, isolated from
Streptomyces thioluteu, and S. luteoreticuli,3,4 neoaureothin 6
isolated from Streptomyces orinoci, and spectinabilin 7 isolated
as a metabolite from the same actinomycete as 1 and 2,
Streptomyces spectabilis (Fig. 1).5,6
Many biosynthetic and synthetic studies of the nitrophenyl
pyrones have been undertaken with a particular emphasis on
aureothin 3,7,8 however the more complex structures of the
family, namely 1, 2 and 7 have yet to be synthesised.
Scheme 1 Proposed biosynthesis of spectinabilin 7.
Biologically, both SNF4435 C 1 and D 2 selectively suppress
induced B-cell proliferation versus induced T-cell proliferation
and show potent immunosuppressive activity in vitro.9 This
would indicate a different mode of action from that of the
known immunosuppressants cyclosporin A (CsA) and FK-506.
This mechanistic difference, however, opens up the possibility
of developing new immunosuppressants based on these novel
compounds.10 In addition to their immunosuppressive activity,
these novel compounds have been shown to reverse multidrug
resistance in tumour cells, rendering them potentially useful in
anticancer therapy.11
The core bicyclo[4.2.0] carbon skeleton possessed by 1 and 2
had been previously identified in analogous natural products,
including the endrianic acids isolated by the groups of
Black,12 and synthesised by Nicolaou.13 The synthesis was
inspired by an intriguing hypothesis proposed by Black for
their biosynthesis, which centred around a cascade of electro-
cyclic reactions. Specifically, the appropriate (E,Z,Z,E)-tetra-
ene undergoes a thermal conrotatory 8π electrocyclisation,
immediately followed by a thermal disrotatory 6π electrocyclis-
ation, to afford the relevant bicyclo[4.2.0] carbon skeleton. This
methodology is now well established as demonstrated by the
work of Widmer and co-workers in their studies of vitamin A.14
The combination of this biosynthetic information together
with the inherent instability of spectinabilin 7 over a period of
time, prompted us to consider the possibility that spectinabilin
7 is a direct precursor of SNF4435C 1 and SNF4435D 2 via
either an in vitro or in vivo double bond isomerisation.
Structurally, SNF4435C 1 and D 2 are pentacyclic structures
exhibiting a hexasubstituted bicyclo[4.2.0] core comprising a
cyclohexadiene unit in the major ring. This bicyclo[4.2.0]octa-
† This is one of a number of contributions from the current members
of the Dyson Perrins Laboratory to mark the end of almost 90 years of
organic chemistry research in that building, as all its current academic
staff move across South Parks Road to a new purpose-built laboratory.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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Fig. 1 Examples of the nitrophenyl pyrone family of compounds
In our proposed biosynthesis, we envisaged SNF4435C 1 and
diastereoisomer 26, as established by nOe analysis. The
SNF4435D 2 as having originated from the (E,Z,Z,Z)-tetraene
10, an isomeric form of spectinabilin 7, which is necessary to
initiate a thermal conrotatory 8π electrocyclisation to generate
the cyclooctatetraene 11. A subsequent stereoselective dis-
rotatory thermal 6π electrocyclisation would afford compound
1 which could undergo epimerisation to give 2 (Scheme 2).
We have recently communicated evidence for our proposed
biosynthesis, in which the model (E,E,E,E)-tetraene 12 was
efficiently prepared using a stabilised ylide approach in good
overall yield (Scheme 3).15
The (E,E,E,E)-double-bond stereochemistry was corro-
borated by X-ray analysis, which interestingly revealed a signifi-
cant lack of planarity in the polyene backbone, due to the
strong 1,3-steric interactions between the alkene methyl substi-
tuents (Fig. 2).16 We envisaged that such a highly strained tetra-
ene (as demonstrated by the >130Њ angle between C4–C5–C6,
and the 45Њ dihedral angle of the C9–C10 bond) would be prone
to isomerisation under the right conditions.
observed product stereochemistry is consistent with a double
bond isomerisation taking place to generate the (E,Z,Z,E)-
tetraene 24, which undergoes the expected tandem double
electrocyclisation to give the product (Scheme 4). When methyl
ester 23 was treated under the same conditions, the corre-
sponding bicyclic 27 was isolated in 48% yield, whose spectral
data matched that of the identical compound prepared by
Beaudry and Trauner using a related approach.18
The same reaction sequence was observed when applied to
tetraene 28, itself prepared using the same stabilised ylide
approach starting from aldehyde 29 (Scheme 5). Thus, upon
exposure of 28 to the same metal catalysed conditions, bicyclo-
35 was formed as a single diastereoisomer in fair yield (Scheme
6). The structure of 28 was further corroborated by X-ray analy-
sis of the dinitrobenzoyl derivative 34, which also displayed a
significant lack of planarity about the polyene backbone due to
1,3-strain (Fig. 3).19
Fig. 2 X-Ray structure of tetraene 12.
Fig. 3 X-Ray structure of 34.
Our choice of conditions to effect isomerisation stemmed
from the well known ability of palladium() salts to interact
with, and isomerise conjugated double bond systems through
either a carbocation or π-allyl complex.17 Thus treatment of
tetraene 12 with dichlorobis(acetonitrile)palladium() at room
temperature effected the desired cyclisation, generating the
bicyclo[4.2.0]octadiene core in good yield, and as a single
In order to expand the scope of this methodology, we decided
to prepare pentaene 36 according to the route shown in Scheme
7. Unfortunately exposure of pentaene 36 to the same palladium
catalysed conditions gave no evidence of the desired bicyclo-
[3.2.0] core. Instead, cyclohexadiene 39 was formed in fair yield
presumably through a disrotatory 6π-electrocyclisation of the
(E,Z,E,E,E)-pentaene 40, thus providing a novel route to this
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Scheme 2 Proposed biogenesis of SNF4435C 1 and SNF4435D 2.
Scheme 3 Stabilised ylide approach to the construction of the tetraene model system.
class of structure also common in polypropionates (Scheme
8).20 The structure of 39 was implied by nOe analysis, and
further corroborated by X-ray analysis of the dinitrobenzoyl
derivative 41 (Fig. 4).21
The positive results prompted us to consider if the rel-
ationship between the linear polyene spectinabilin, and the
complex core of the SNF compounds was a general feature of
polypropionate biosynthesis. That is, we considered the possi-
bility that other complex polypropionate compounds isolated
could be tandem pericyclic reaction products of initial relatively
simple all (E)-polyenes. Thus in biosynthetic terms, units of
propionate would condense to yield a thermodynamically
favoured all (E)-polyene backbone. When provided with an
appropriate energy source reversible selective (E–Z) double
Fig. 4 X-Ray structure of 41.
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Scheme 4 Palladium catalysed tandem rearrangement.
Scheme 5 Synthesis of tetraene 28 and the crystalline derivative 34.
Scheme 6 Tandem electrocyclic reaction of tetraene 28.
Scheme 7 Synthesis of pentaene 36.
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Scheme 8 Palladium catalysed rearrangement of 36.
bond isomerisations could ensue, encouraged by 1,3 strain.
When the appropriate geometry requirements are met, a peri-
cyclic reaction could proceed, thus driving the equilibrium in
favour of the product.
In order to further substantiate our proposal we decided to
investigate marine sources, known to be rich in polypropion-
ates. In particular, we chose to concentrate on mollusc metabol-
ites which often appear to be derived from the condensation of
propionate units. Examples of such acyclic polypropionates
include cyercenes A 42 and B 43 (Fig. 5).22
cyclisation to generate photodeoxytridachione 49 directly,
which is reasonable since no racemisation was observed.26
However it could also be proposed that 9,10-deoxytridachione
46, during conversion undergoes a retro-electrocyclisation
giving tetraene 50, which undergoes a photochemical enzyme
mediated Diels–Alder reaction giving photodeoxytridachione
49 (Scheme 9).
Fig. 5 Cyercene A 42 and cyercene B 43.
As part of our investigations, we became interested in the
crispatenes and related family of compounds, which we
believed were ideally suited to our biosynthetic studies.23
Scheme 9 Two proposed mechanistic pathways for the conversion of
46 into 49.
Crispatene and related polypropionates
Many sacoglossan molluscs sequester active chloroplasts from
algae and use these organelles to carry out photosynthesis in
their own tissues. These creatures are devoid of a protective
shell and have therefore evolved with reliance on secondary
metabolites for defence against predators. Many of these
metabolites are highly unsaturated polypropionates that feature
an α-methoxy-γ-pyrone moiety; examples include crispatene
44, crispatone 45 isolated from the Californian mollusc Tri-
dachia Crispata,24 9,10-deoxytridachione 46, tridachiapyrone
47, tridachiapyrone A 48 and photodeoxytridachione 49
(Fig. 6).
Structurally, these compounds fall into two classes. The first
class which includes 46, 47 and 48 are cyclohexadiene deriv-
atives, whereas the second class, which include 44, 45 and 49
feature a bicyclo[3.1.0]hexene core. Clearly, both ring systems
are isomeric and this relationship has encouraged speculation
as to their biogenetic relationship.
It was this combination of structural complexity and bio-
synthetic information that prompted us to propose a bio-
mimetic synthesis to the crispatene family of compounds, based
upon our general biosynthetic hypothesis. In our approach, we
envisioned the bicyclo[3.1.0]hexene core of 49 as having arisen
from the photochemical transformation of 9,10-deoxytrida-
chione 46, itself arising from the corresponding (E,E,Z,E)-
tetraene pyrone 51 through a thermal 6π electrocyclisation [the
(E,E,Z,E)-tetraene pyrone itself obtained from the (E,E,E,E)-
tetraene 52 through either a thermally or photochemically
induced isomerisation]. Although tetraene 52 is not reported to
have been isolated, it is likely that it could indeed exist as a
metabolite, considering its similarity to cyercene A 42 (Scheme
10).
In order to test this hypothesis, we decided to start from the
(E,E,E,E)-tetraene 12 originally developed for our studies in
the biomimetic synthesis of SNF4435C 1 and SNF4435D 2.
As was previously found, tetraene 12 has a large degree of
strain which could provide the driving force for the initial
isomerisation.
It has been shown that 9,10-deoxytridachione 46 can be
photochemically converted in vivo and in vitro into photo-
deoxytridachione 49.25 Ireland and Faulkner have proposed
that 9,10-deoxytridachione 46 undergoes a 2a ϩ 2a electro-
σ
π
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Fig. 6 Structurally related marine polypropionates.
Scheme 10 A biomimetic inspired retrosynthetic analysis of compound 49.
Once the initial isomerisation had taken place, we expected
corroborated by X-ray analysis of the crystalline derivative 54
(Fig. 7).27
the (E,E,Z,E)-tetraene to undergo electrocyclisation. However,
treatment of tetraene ester 12 at 140 ЊC failed to afford the
desired cyclohexadiene core, affording instead the tricyclic
structure 53 in excellent yield (95%) as a single product (Scheme
11). The structure was determined by a combination of NMR
methods, including nOe and 2-D NMR analyses, and further
Formation of this product can be proposed by an isomeris-
ation of the appropriate double bond to generate the required
(E,E,Z,E)-tetraene ester 55. This ester can then undergo the
desired thermal 6π disrotatory electrocyclisation to generate
cyclohexadiene 56, which undergoes a final intramolecular
Scheme 11 Thermally induced conversion of 12 into 53.
Fig. 7 X-Ray structure of tricyclic derivative 54.
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Diels–Alder reaction to generate the tricyclic structure 53
(Scheme 12).28 Efforts to isolate the cyclohexadiene core 56 at
lower temperatures were unsuccessful.
Scheme 13 Photochemical transformation of triene 57.
Scheme 12 Proposed mechanism for the thermal conversion of
tetraene 12 into tricyclic 53.
Scheme 14 The photochemical conversion of 12 into 59.
Although disappointing from our biosynthesis point of view,
formation of the tricyclic ester 53 demonstrated the feasibility
of the selective double bond isomerisation and of the efficiency
of the 6π electrocyclisation. Furthermore, it provides us with a
rapid and efficient entry into this novel class of compounds
with yet to be determined potential.
Since we could not isolate the cyclohexadiene under thermal
conditions, we considered the possibility of a photochemically
induced double bond isomerisation. Dauben and Smith have
shown that irradiation of all (E)-1,3,4,6-tetraphenylhexa-1,3,5-
triene 57 gives rise to 1,2,4,6-tetraphenylbicyclo[3.1.0]hexene
58, whose molecular core displays a similar substitution pattern
to the crispatene type core (Scheme 13).29 With this in mind,
ester 12 was irradiated with light from a 600 W tungsten lamp
source, which successfully generated the crispatene core 59 (as
determined by 2-D NMR) in good yield (60%). The relative
stereochemistry was corroborated by a combination of NMR
methods including 1-D pulsed field gradient NOESY analysis
(Scheme 14). Interestingly, it was found that daylight also
facilitated this transformation.
formed. Tetraene 60 then undergoes another double bond
isomerisation to give the (E,E,Z,Z)-tetraene 61, which then
undergoes a photochemical 6π conrotatory electrocyclisation to
give the cyclohexadiene 56, which can then undergo a direct σ2a
ϩ π2a electrocyclisation to generate bicyclic 59 (Scheme 15).
Alternatively, the formation of 59 may be considered as
arising from an intramolecular photochemical Diels–Alder
reaction, which is consistent with the results reported by Padwa
et al. on their studies of 1,3,5-hexatrienes.30 The observed
stereochemistry can be explained by the following mechanistic
rationale. In the first instance ester 12 undergoes a photo-
chemically induced selective double bond isomerisation to yield
the (E,E,E,Z)-tetraene 60. The direct conversion of ester 60
into 59 by a photochemical Diels–Alder reaction is forbidden
by the Woodward–Hoffman rules.31 Therefore, in agreement
with Padwa’s findings, it is proposed that a two photon reaction
involving initial (E–Z) photoisomerisation about the C6–C7
double bond occurs affording the (E,E,Z,Z)-tetraene 61. This is
immediately followed by a symmetry allowed 4s ϩ 2a photo-
π
π
cycloaddition giving 59 as the thermodynamically favoured
product (Scheme 16).
Mechanistic discussion
It is possible that 59 is formed in a manner consistent with our
biomimetic hypothesis. That is, tetraene 12 undergoes a photo-
chemically induced selective double bond isomerisation to yield
the (E,E,E,Z)-tetraene 60, which was observed by NMR to
appear during irradiation and disappear as the product 59 was
Although both mechanisms are potentially feasible, we
cannot discount a highly selective diradical process for the
formation of 59.
When pentaene 36 was exposed to the same photochemical
conditions, bicyclic 62 was successfully formed in 40% yield.
Scheme 15 Possible mechanism for the conversion of tetraene 12 into 59.
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Scheme 16 An alternative mechanism for the conversion of 12 into 59.
Scheme 17 The photochemical transformation of pentaene 36 into 62.
However, cyclohexadiene 39 was also isolated from the reaction
mixture in 17% yield. Interestingly it was also found that cyclo-
hexadiene 39 could be directly converted to bicyclic 62 upon
standing in daylight, without any evidence for reversion to 36
1
by H NMR. This indicates that 39 could be a true reaction
intermediate (Scheme 17).
This observation supports Faulkner’s and our own bio-
synthetic hypothesis for the formation of the crispatene family
of compounds. Studies directed towards the total biomimetic
synthesis of photodeoxytridachione 49 are underway and shall
be reported in due course.
Conclusion
We have demonstrated that several classes of complex poly-
propionate derived core structures can be prepared from simple
polyene precursors. These tandem transformations share the
common feature that they are instigated by strain, resulting
from steric compressions of the 1,3 methyl substituents on the
polyene backbone. We believe that the same strain is the driv-
ing force in the biosynthesis of the SNF and crispatene family
of compounds, which are likely to be derived from linear all-
(E)-polyenes.
In conclusion, we have shown a diversity of high yielding
synthetic possibilities originating from this class of highly
strained polyene esters by simple modification of the reaction
conditions (Scheme 18). We are now working on ways to expand
the synthetic and mechanistic scope of these transformations,
and at the same time explore new synthetic transformations.
Scheme 18 Cascade electrocyclisation pathways of tetraene ester 12.
solvent peak. The following abbreviations are used: s, singlet; d,
doublet; t, triplet; m, multiplet; br, broad. Proton assignments
are supported by 1H–1H COSY where necessary. Data are
reported in the following manner: chemical shift (integration,
multiplicity, coupling constant if appropriate, assignment).
Coupling constants (J) are reported in Hertz to the nearest
0.5 Hz.13C NMR spectra were recorded at 50.3, 100.6 and 125.8
MHz using Varian Gemini 200, Bruker DPX400, Bruker
AM500 and Bruker AMX500 instruments. Carbon spectra
assignments are supported by DEPT-135 spectra, and 13C–1H
(HMQC and HMBC) correlations where necessary. Chemical
shifts are quoted in ppm and are referenced to the appropriate
residual solvent peak.
Experimental
1H NMR spectra were recorded at 200, 400 and 500 MHz using
Varian Gemini 200, Bruker DPX400, Bruker AM500 and
1
Bruker AMX500 instruments. For H NMR spectra recorded
in CDCl3, CD3OD and d6-DMSO, chemical shifts are quoted in
parts per million (ppm) and are referenced to the residual
Flash column chromatography was carried out using
Sorbsil C60 (40–63 mm, 230–40 mesh) silica gel. Thin layer
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chromatography was carried out on glass plates pre-coated with
Merck silica gel 60 F254 which were visualised by quenching of
UV fluorescence or by staining with 10% w/v ammonium
molybdate in 2 M sulfuric acid or 1% w/v potassium per-
manganate in aqueous alkaline solution followed by heat, as
appropriate.
Melting points were recorded using a Cambridge Instru-
ments Gallen III Kofler Block melting apparatus or a Buchi
510 capillary apparatus and are uncorrected.
Infrared spectra were recorded either as a thin film between
NaCl plates or as a KBr disc (as indicated) on a Perkin-Elmer
Paragon 1000 Fourier Transform spectrometer with internal
referencing. Absorption maxima are reported in wavenumbers
(cmϪ1) and the following abbreviations are used: w, weak; m,
medium; s, strong; br, broad.
Low resolution mass spectra were recorded on V. G. Micro-
mass ZAB 1F and V. G. Masslab instruments as appropriate
with modes of ionisation being indicated as CI, EI, ES or APCI
with only molecular ions, molecular ion fragments and major
peaks being reported. High resolution mass spectrometry was
measured on a Waters 2790-Micromass LCT electrospray
ionisation mass spectrometer and on a VG autospec chemical
ionisation mass spectrometer.
(2E )-2-Methyl-3-(4-nitrophenyl)prop-2-enal (16)35
To a stirred solution of oxalyl chloride (4.5 mL, 51.2 mmol) in
dry DCM (200 mL) was added DMSO (7.3 mL, 102.4 mmol)
dropwise at Ϫ78 ЊC under argon. After 10 minutes alcohol 15
(6.17 g, 32 mmol) in dry DCM (50 mL) was added dropwise,
and the mixture stirred for a further 20 minutes at Ϫ78 ЊC. Et3N
(28 mL, 205 mmol) was then added, and the reaction allowed
to warm up to RT over 1 hour, and then quenched with water
(100 mL). The organic layer was separated, washed with brine
(100 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure. The crude residue was purified
by flash silica gel chromatography (9 : 1 30–40 P.E. : EtOAc) to
give the title compound as a yellow solid (5.74 g, 94%). RF 0.35
(4 : 1 30–40 P.E. : EtOAc); mp 112–114 ЊC (from EtOH, lit.
value 111–112 ЊC);35 νmax/cmϪ1 (KBr) 1677, 1593, 1514, 1344;
δH (250 MHz, CDCl3) 2.10 (3H, s), 7.32 (1H, s), 7.68 (2H, d,
J 8.5 Hz), 8.31 (2H, d, J 8.5 Hz), 9.67 (1H, s); δC (62.9 MHz,
CDCl3) 11.5, 124.3, 130.9, 141.7, 141.8, 146.5, 148.1, 195.1; m/z
ϩ
(CI) 209 (MNH4 , 100%), 191 (Mϩ, 38), 174 (100), 162 (27).
Ethyl (2E,4E )-2,4-dimethyl-5-(4-nitrophenyl)penta-2,4-dienoate
(17)36
All solvents and reagents were purified by standard tech-
niques reported in ref. 32 or used as supplied from commercial
sources as appropriate.
All experiments were carried out under an inert atmosphere
unless otherwise stated.
To a stirred solution of aldehyde 16 (6.0 g, 31.4 mmol) in tolu-
ene (100 mL) was added (1-ethoxycarbonylethylidene)triphenyl-
phosphorane (11.40 g, 31.50 mol). The mixture was refluxed
overnight, then allowed to cool to RT. Pentane (100 mL) was
added, and the resultant triphenylphosphine oxide precipitate
removed by filtration. The yellow filtrate was concentrated
under reduced pressure, and purified by flash silica gel chrom-
atography (4 : 1 30–40 P.E. : EtOAc), giving the title compound
as a yellow solid (8.60 g, 99%). RF 0.45 (4 : 1 30–40 P.E. :
EtOAc); mp 80–83 ЊC (lit. value 81–83 ЊC);36 νmax/cmϪ1 (KBr)
1701, 1592, 1515, 1341, 111; δH (200 MHz, CDCl3) 1.33 (3H, t,
J 7.0 Hz), 2.1 (6H, s), 4.25 (2H, q, J 7.0 Hz), 6.62 (1H, s), 7.29
(1H, s), 7.49 (2H, d, J 8.5 Hz), 8.23 (2H, d, J 8.5 Hz); δC (50.3
MHz, CDCl3) 14.3, 14.4, 18.6, 61.0, 123.6, 128.8, 129.8, 131.4,
138.1, 142.0, 143.8, 146.8, 168.6; m/z (CIϩ) 557 (9%), 363 (44),
The star notation found in the naming of compounds * =
racemic mixture of products.
Ethyl (2E )-2-methyl-3-(4-nitrophenyl)prop-2-enoate (14)33
To a stirred solution of 4-nitrobenzaldehyde 13 (17.3 g, 115
mmol) in toluene (150 mL) was added (1-ethoxycarbonyl-
ethylidene)triphenylphosphorane (41.6 g, 115 mmol). The
mixture was refluxed overnight, then allowed to cool to RT.
Pentane (100 mL) was added, and the resulting triphenyl-
phosphine oxide precipitate removed by filtration. The yellow
filtrate was then concentrated under reduced pressure and
purified by flash silica gel chromatography (9 : 1 30–40 P.E. :
EtOAc) to give the title compound as a yellow solid (26.48 g,
98%). RF 0.7 (4 : 1 30–40 P.E. : EtOAc); mp 69–71 ЊC (from pet.
ether, lit. value 67–68 ЊC);33 νmax/cmϪ1 (KBr) 1701, 1515, 1347,
1110; δH (400 MHz, CDCl3) 1.37 (3H, t, J 7.0 Hz), 2.12 (3H, s),
4.28 (2H, q, J 7.0 Hz), 7.54 (2H, d, J 8.5 Hz), 7.68 (1H, s), 8.23
(2H, d, J 8.5 Hz); δC (100.6 MHz, CDCl3) 14.2, 14.3, 61.3,
123.6, 130.2, 132.3, 136.0, 142.5, 147.2, 167.8. m/z (CI) 253
ϩ
293 (MNH4 , 35), 279 (100).
(2E,4E )-2,4-Dimethyl-5-(4-nitrophenyl)penta-2,4-dienal (19)37
To a stirred solution of ester 17 (12.2 g, 44.4 mol) in dry Et2O
(150 mL) was added DIBAL-H (97.0 mL of a 1 M solution in
hexanes, 97.0 mmol) under argon at 0 ЊC. After 1 hour the
reaction was quenched by the cautious addition of MeOH
(1 mL). A saturated solution of potassium sodium tartrate
(200 mL) was added, and the mixture allowed to stir for several
hours until the organic and aqueous layers had completely
separated. The organic layer was separated, washed with brine
(100 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure to afford the crude alcohol 18 as
an orange oil (10.3 g, 100%), which was used without further
purification in the next step. δH (200 MHz, CDCl3) 1.90 (3H, s),
2.08 (3H, s), 4.15 (2H, s), 6.10 (1H, s), 6.44 (1H, s), 7.44, (2H, d,
J 8.5 Hz), 8.21 (2H, d, J 8.5 Hz).
To a stirred solution of oxalyl chloride (6.20 mL, 71.2 mmol)
in dry DCM (200 mL) was added DMSO (10.0 mL, 140 mmol)
dropwise at Ϫ78 ЊC under argon. After 10 min, the crude alco-
hol 18 (10.3 g, 44.2 mmol) in dry DCM (50 mL) was added
dropwise, and the mixture stirred for a further 20 minutes. Et3N
(40 mL, 285 mmol) was then added, and the reaction allowed
to warm to RT over 1 hour, then quenched with saturated
ammonium chloride solution (100 mL). The organic layer was
separated, washed with brine (100 mL), dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
crude residue was purified by flash silica gel chromatography
(9 : 1 30–40 P.E. : EtOAc) to give the title compound as a yellow
solid (9.9 g, 97%). RF 0.6 (4 : 1 30–40 P.E. : EtOAc); mp 94–95
ЊC (lit. value 94–96 ЊC);37 νmax/cmϪ1 (KBr) 1670, 1558, 1339; δH
ϩ
(MNH4 , 100%), 235 (Mϩ, 22), 206 (16).
(2E )-2-Methyl-3-(4-nitrophenyl)prop-2-en-1-ol (15)34
To a stirred solution of ester 14 (24.0 g, 0.102 mol) in dry Et2O
(150 mL) was added DIBAL-H (230 mL of a 1 M solution in
hexanes, 0.23 mol) under argon at 0 ЊC. After 1 hour the
reaction was quenched by the cautious addition of MeOH
(1 mL). A saturated solution of potassium sodium tartrate
(200 mL) was added, and the mixture was left to stir for
several hours until the organic and aqueous layers had com-
pletely separated. The organic layer was separated, washed with
brine (100 mL), dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude yellow oil
obtained was purified by flash silica gel chromatography (1:1
30–40 P.E. : EtOAc), to give the title compound as a yellow
solid (18.72 g, 95%). RF 0.2 (1 : 1 30–40 P.E. : EtOAc); mp 42–44
ЊC (lit. value 41–43 ЊC);34 νmax./cmϪ1 (KBr) 3403 (br, OH), 1515,
1343, 1110; δH (200 MHz, CDCl3) 1.93 (3H, s), 4.25 (2H, s),
6.60 (1H, s), 7.40 (2H, d, J 8.5 Hz), 8.19 (2H, d, J 8.5 Hz);
δC (50.33 MHz, CDCl3) 15.5, 68.0, 122.4, 123.5, 129.5, 142.0,
ϩ
144.6, 146.0; m/z (CI) 211 (MNH4 , 100%), 193 (Mϩ, 5), 175
(4).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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(400 MHz, CDCl3,) 2.05 (3H, s), 2.25 (3H, s), 6.89 (1H, s), 6.98
(1H, s), 7.55 (2H, d, J 8.5 Hz), 8.21 (2H, d, J 8.5 Hz), 9.5 (1H,
s); δC (100.6 MHz, CDCl3) 11.1, 18.3, 123.7, 128.4, 128.5, 130.0,
131.9, 132.0, 134.4, 153.1, 195.6; m/z (CI) 279 (100%), 249
s), 2.27 (3H, s), 6.40 (1H, s), 6.69 (1H, s), 6.82 (1H s), 7.49 (2H,
d, J 8.5 Hz), 8.25 (2H, d, J 8.5 Hz), 9.52 (1H, s); δC (100.6 MHz,
CDCl3) 10.9, 18.4, 19.11, 123.6, 129.7, 130.3, 134.9, 137.3,
138.4, 141.2, 143.9, 146.3, 154.5, 195.7; m/z (CI) 272 (MHϩ,
100), 254 (24), 244 (95). HRMS (CI) Calculated for C16H18NO3
(MHϩ): 272.1286. Found: 272.1282.
ϩ
(MNH4 , 10), 232 (MHϩ, 26).
Ethyl (2E,4E,6E )-2,4,6-trimethyl-7-(4-nitrophenyl)hepta-2,4,6-
trienoate (20)
Ethyl (2E,4E,6E,8E )-4,6,8-trimethyl-9-(4-nitrophenyl)nona-
2,4,6,8-tetraenoate (12)
To a stirred solution of aldehyde 19 (9.8 g, 42.4 mmol) in tolu-
ene (100 mL) was added (1-ethoxycarbonylethylidene)triphenyl-
phosphorane (17 g, 47 mmol). The mixture was refluxed
overnight, then allowed to cool to RT. Pentane (100 mL) was
added, and the resulting triphenylphosphine oxide precipitate
removed by filtration. The yellow filtrate was then concentrated
under reduced pressure and purified by flash silica gel chrom-
atography (9 : 1 30–40 P.E. : EtOAc), to give the title compound
as a yellow solid (12.3 g, 92%). RF 0.4 (4 : 1 30–40 P.E. : EtOAc);
mp 38–40 ЊC; νmax./cmϪ1 (KBr) 1704, 1593, 1516, 1341, 1111;
δH (400 MHz, CDCl3) 1.32 (3H, t, J 7.0 Hz), 2.05 (3H, s), 2.08
(3H, s), 2.10 (3H, s), 4.22 (2H, q, J 7.0 Hz), 6.19 (1H, s), 6.5
(1H, s), 7.21 (1H, s), 7.46 (2H, d, J 8.5 Hz), 8.21 (2H, d, J 8.5
Hz); δC (100.6 MHz, CDCl3) 14.2, 14.3, 18.72, 19.19, 60.76,
123.5, 127.3, 129.0, 129.6, 134.7, 137.8, 138.8, 142.9, 144.3,
To a stirring solution of aldehyde 22 (520 mg, 1.92 mmol) in
benzene (50 mL) was added (ethoxycarbonylmethylene)-
triphenylphosphorane (3.30 g, 9.1 mmol). The flask was fitted
with a reflux condenser and the solution heated at 80 ЊC for
2 hours, then left to cool to RT. Pentane (50 mL) was added,
and the resulting triphenylphosphine oxide precipitate was
removed by filtration. The yellow filtrate was concentrated
under reduced pressure, and the crude residue purified by flash
silica gel chromatography (9 : 1 30–40 P.E. : EtOAc), to afford
the desired tetraene ester 12 as a yellow solid (648.2 mg, 99%).
RF 0.7 (4 : 1 30–40 P.E. : EtOAc); mp = 104–107 ЊC; νmax./cmϪ1
(KBr) 1707, 1612, 1516, 1338, 1172; λmax(DCM)/nm 373.2
(ε/dm3 molϪ1 cmϪ1; δH (250 MHz, CDCl3) 1.32 (3H, t, J 7.0 Hz),
2.04 (3H, s), 2.12 (6H, s), 4.24 (2H, q, J 7.0 Hz), 5.92 (1H, d,
J 16.0 Hz), 6.16 (1H, s), 6.39 (1H, s), 6.52 (1H, s), 7.42 (1H, d,
J 16.0 Hz), 7.47 (2H, d, J 8.5), 8.26 (2H, d, J 8.5 Hz); δC (62.9
MHz, CDCl3) 14.5, 14.8, 19.6, 19.8, 60.7, 117.6, 124.0, 129.4,
130.0, 133.6, 135.2, 137.6, 138.9, 144.0, 144.8, 146.4, 150.5,
167.8; m/z (CI) 342 (MHϩ, 5%), 341 (Mϩ, 12), 340 (100), 323
(48). HRMS (CI) Calculated for C20H24NO4 (MHϩ): 342.1705.
Found: 342.1705.
ϩ
146.1, 168.8; m/z (CI) 333 (MNH4 , 100%), 316 (MHϩ, 20), 293
(12), 162. HRMS (CI) Calculated for C18H22NO4 (MHϩ):
316.1548. Found: 316.1550.
(2E,4E,6E )-2,4,6-Trimethyl-7-(4-nitrophenyl)hepta-2,4,6-trien-
1-ol (21)
To a stirred solution of ester 20 (3.15 g, 9.96 mmol) in dry Et2O
(100 mL) was added DIBAL-H (21.0 mL of a 1 M solution in
hexanes, 21.0 mmol) under argon at 0 ЊC. The reaction was
stirred at RT until completion as indicated by TLC analysis
(1 h), then quenched by the cautious addition of MeOH
(1 mL). A saturated solution of potassium sodium tartrate
(100 mL) was added, and the mixture was left to stir for several
hours until the organic and aqueous layers had completely
separated. The organic layer was separated, washed with brine
(100 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure. The crude yellow oil obtained
was purified by flash silica gel chromatography (1 : 1 30–40 P.E.
: EtOAc), to give the title compound as a yellow oil (2.46 g,
97%). RF 0.25 (1 : 1 30–40 P.E. : EtOAc); νmax/cmϪ1 (film) 3422,
1636, 1592, 1516, 1340, 1109, 1020; δH (200 MHz, CDCl3) 1.80
(3H, s), 2.03 ( 3H, s), 2.09 (3H, s), 4.10 (2H, s), 5.95 (1H, s), 6.00
(1H, s), 6.45 (1H, s), 7.45 (2H, d, J 8.5 Hz), 8.20 (2H, d, J 8.5
Hz); δC (50.3 MHz,CDCl3) 15.7, 19.3, 19.5, 69.1, 123.5, 127.7,
129.5, 129.9, 133.7, 135.6, 136.5, 139.6, 144.9, 145.8; m/z (CI)
Single crystals from diethyl ether of compound 12 suitable
for X-ray diffraction were selected.
Crystal data. C20H23NO4, M = 341.41, monoclinic, a =
15.0086(5), b = 8.0675(3), c = 15.1036(5) Å, α = 90, β =
98.916(2), γ = 90Њ, U = 1806.7 Å3, T = 150(1) K, space group
P21/a, Z = 4, µ(Mo-Kα) = 0.087mmϪ1, 12982 reflections meas-
ured, 4392 unique (Rint = 0.042) which were used in calculations.
The final wR was 0.0527.
CCDC reference number 190072. See http://www.rsc.org/
suppdata/ob/b3/b306933h/ for crystallographic files in CIF or
other electronic format.
Methyl (2E,4E,6E,8E )-4,6,8-trimethyl-9-(4-nitrophenyl)nona-
2,4,6,8-tetraenoate (23)
To a stirring solution of aldehyde 22 (32 mg, 0.118 mmol) in
benzene (10 mL) was added (methoxycarbonylmethylene)-
triphenylphosphorane (200 mg, 0.60 mmol). The flask was fit-
ted with a reflux condenser and the solution heated at 80 ЊC for
2 hours, then left to cool to RT. Pentane (50 mL) was added,
and the resulting triphenylphosphine oxide precipitate removed
by filtration. The yellow filtrate was concentrated under
reduced pressure, and the crude residue purified by flash silica
gel chromatography (9 : 1 30–40 P.E. : EtOAc), to afford the
tetraene ester 23 as a yellow solid (38 mg, 98%). RF 0.2 (5 : 1 30–
40 P.E. : EtOAc); mp = 110 ЊC; νmax/cmϪ1 (KBr disc) 1712, 1590,
1514, 1339, 1167; δH (400 MHz, CDCl3) 2.02 (3H, s), 2.10 (6H,
s), 3.77 (3H, s), 5.91 (1H, d, J 15.5 Hz), 6.12 (1H, s), 6.36 (1H,
s), 6.50 (1H, s), 7.40 (1H, d, J 15.5 Hz), 7.47 (2H, d, J 8.5 Hz),
8.20 (2H, d, J 8.5 Hz); δC (100.6 MHz, CDCl3) 14.1, 19.2, 19.3,
51.5, 116.7, 123.5, 129.0, 129.7, 133.1, 135.3, 137.3, 139.0,
ϩ
291 (MNH4 , 4%), 274 (MHϩ, 4), 256 (100), 226 (10). HRMS
(CI) Calculated for C16H18NO2 (MHϩ): 256.1337. Found:
256.1335.
(2E,4E,6E )-2,4,6-Trimethyl-7-(4-nitrophenyl)hepta-2,4,6-trienal
(22)
To a stirred solution of oxalyl chloride (0.95 mL, 10.7 mmol) in
dry DCM (100 mL) was added DMSO (1.52 mL, 21.4 mmol)
dropwise at Ϫ78 ЊC under argon. After 10 minutes a solution of
the alcohol 21 (1.71 g, 6.7 mmol) in dry DCM (50 mL) was
added dropwise, and the mixture stirred for a further 20 min-
utes at Ϫ78 ЊC. Et3N (6.0 mL, 42.8 mmol) was then added, and
the reaction allowed to warm up to RT over 1 hour, then
quenched with saturated ammonium chloride solution (100
mL). The organic layer was separated, washed with brine (100
mL), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude residue was purified by flash
silica gel chromatography (9 : 1 30–40 P.E. : EtOAc) to give the
title compound as a yellow solid (1.03 g, 57%). RF 0.65 (4 : 1 30–
40 P.E. : EtOAc); mp 94–96 ЊC; νmax/cmϪ1 (KBr) 1727, 1661,
1592, 1512, 1340; δH (400 MHz, CDCl3) 2.06 (3H, s), 2.13 (3H,
ϩ
143.8, 144.4, 146.0, 150.4, 167.8; m/z (CI) 345 (MNH4 , 49%),
328 (MHϩ, 100), 298 (64), 178 (34). HRMS (CI) Calculated for
C19H22NO4 (MHϩ): 328.1548. Found: 328.1553.
Ethyl (1R*,6S*,7R*,8R*)-1,3,5-trimethyl-8-(4-nitrophenyl)-
bicyclo[4.2.0]octa-2,4-diene-7-carboxylate (26)
Ester 12 (30.0 mg, 0.088 mmol) and (MeCN)2PdCl2 (7.6 mg,
0.029 mmol) were placed in a dry flask, which was purged with
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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argon. DMF (1 mL) was added, and the solution was stirred for
2 hours at RT, and then water (10 mL) was added. The mixture
was extracted with DCM (2 × 5 mL), and the combined organic
fractions were washed with brine (5 mL) and dried over
anhydrous MgSO4. The drying agent was removed by filtration,
and the mixture concentrated under reduced pressure. The
crude yellow residue was purified by flash silica gel chromato-
graphy (9 : 1 30–40 P.E. : EtOAc) to give the title compound as a
yellow oil (10.6 mg, 35%). RF 0.75 (9 : 1 30–40 P.E. : EtOAc);
mp 110–111 ЊC; νmax/cmϪ1 (KBr) 1709, 1518, 1346; δH (500
MHz, CDCl3) 1.24 (3H, t, J 7.0 Hz), 1.29 (3H, s), 1.64 (3H, s),
1.83 (3H, s), 2.74 (1H, d, J 9.0 Hz), 3.47 (1H, dd, J 10.0, 9.0
Hz), 3.78 (1H, d, J 10.0 Hz), 4.18 (2H, q, J 7.0 Hz), 4.45 (1H, s),
5.48 (1H, s), 7.35 (2H, m), 8.19 (2H, m); δC (125.7 MHz,
CDCl3,) 14.1, 21.5, 21.9, 28.3, 44.0, 45.7, 45.8, 55.8, 60.6, 121.1,
122.2, 123.4, 128.1, 130.9, 134.1, 145.7, 146.6, 173.3; m/z (CI)
(300 mL) was added and the mixture was left to stir for several
hours until the organic and aqueous layers had completely
separated. The organic layer was separated, washed with brine
(200 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure to give the corresponding
alcohol (13.10 g, 97%) as a colourless oil, which was used with-
out further purification in the next step. RF 0.15 (4 : 1 30–
40 P.E. : Et2O); νmax/cmϪ1 (film)39 3350, 1460, 1030; δH (400
MHz, CDCl3) 1.69 (3H, d, J 7.0 Hz), 1.76 (3H, s), 1.82
(3H, s), 4.05 (2H, s), 5.43 (1H, q, J 7.0 Hz), 5.88 (1H, br s);
δC (100.6 MHz, CDCl3) 13.7, 15.3, 16.5, 69.6, 124.7, 129.6,
133.0, 133.8.
To a stirred solution of crude alcohol (2.29 g, 18.1 mmol) in
CHCl3 (200 mL) was added MnO2 (23.65 g, 272 mmol) at RT.
After 72 h, the mixture was filtered through Celite and the fil-
trate was concentrated under reduced pressure to give the crude
product as a yellow oil (2.22 g, 99%), which needed no further
purification. RF 0.5 (4 : 1 30–40 P.E. : Et2O); νmax/cmϪ1 (film)39
2900, 1700, 1630; δH (400 MHz, CDCl3) 1.83 (3H, d, J 7.5 Hz),
1.96 (3H, s), 1.98 (3H, s), 6.00 (1H, q, J 7.5 Hz), 6.74 (1H, s),
9.38 (1H, s); δC (100.6 MHz, CDCl3) 10.6, 14.4, 15.6, 134.1,
135.0, 135.7, 155.1, 196.3.
ϩ
359 (MNH4 , 25%), 342 (MHϩ, 100), 312 (21), 279 (45), 268
(10), 192 (22), 120 (27). HRMS (CI) Calculated for C20H24NO4
(MHϩ): 342.1705. Found: 342.1709.
Methyl (1R*,6S*,7R*,8R*)-1,3,5-trimethyl-8-(4-nitrophenyl)-
bicyclo[4.2.0]octa-2,4-diene-7-carboxylate (27)18
Ethyl (2E,4E,6E )-2,4,6-trimethylocta-2,4,6-trienoate (32)40
Ester 23 (38 mg, 0.116 mmol) and (MeCN)2PdCl2 (10.0 mg,
0.029 mmol) were placed in a dry flask, which was purged with
argon. DMF (1 mL) was added, and the solution was stirred
for 2 hours at RT, and then water (10 mL) was added. The
mixture was extracted with DCM (2 × 5 mL), and the com-
bined organic fractions were washed with brine (5 mL) and
dried over anhydrous MgSO4. The drying agent was removed
by filtration, and the mixture concentrated under reduced pres-
sure. The crude yellow residue was purified by flash silica gel
chromatography (9 : 1 30–40 P.E. : EtOAc) to give the title
compound as a yellow solid (18.3 mg, 48%). RF 0.75 (9 : 1 30–40
P.E. : EtOAc); νmax/cmϪ1 (KBr) 1734, 1517, 1345; δH (400 MHz,
CDCl3) 1.25 (3H, s), 1.6 (3H, s), 1.78 (3H, s), 2.73 (1H, d, J 9.0
Hz), 3.45 (1H, dd, J 10.0, 9.0 Hz), 3.70 (3H, s), 3.74 (1H,
d, J 10.0 Hz), 4.41 (1H, s), 5.46 (1H, s), 7.33 (2H, m), 8.17
(2H, m); δC (100.6 MHz, CDCl3) 21.5, 22.0, 28.4, 44.2, 45.6,
45.8, 51.9, 55.9, 121.2, 122.3, 123.5, 128.2, 130.9, 134.2, 145.6,
To a stirred solution of aldehyde 31, (7.10 g, 57.2 mmol)
was added (1-ethoxycarbonylethylidene)triphenylphosphorane
(43.50 g, 120 mmol) in benzene (250 mL) at RT. The mixture
was refluxed for 48 hours then allowed to cool to RT and con-
centrated under reduced pressure. Et2O was added, and the
resulting triphenylphosphine oxide removed by filtration. The
yellow filtrate was then concentrated under reduced pressure
and purified by flash silica gel chromatography (19 : 1 30–40
P.E. : Et2O) to give the title compound as a colourless oil
(6.48 g, 54%). RF 0.5 (4 : 1 30–40 P.E. : Et2O); νmax/cmϪ1 (film)40
1708; δH (400 MHz, CDCl3) 1.31 (3H, t, J 7.0 Hz), 1.73 (3H, d,
J 7.0 Hz), 1.79 (3H, s), 2.00 (3H, s), 2.03 (3H, s), 4.21 (2H, q,
J 7.0 Hz), 5.54 (1H, q, J 7.0 Hz), 6.04 (1H, br s), 7.17 (1H, br s);
δC (100.6 MHz, CDCl3) 13.9, 14.1, 14.3, 16.5, 18.3, 60.6, 125.5,
127.0, 131.0, 133.2, 139.2, 144.0, 169.2.
ϩ
146.8, 173.8; m/z (CI) 345 (MNH4 , 100), 328 (MHϩ, 55),
(2E,4E,6E )-2,4,6-Trimethylocta-2,4,6-trienal (33)39
315 (15), 298 (52), 178 (88), 162 (75), 120 (40), 105 (12). HRMS
(CI) Calculated for C19H22NO4 (MHϩ): 328.1548. Found:
328.1562.
To a stirred solution of ester 32 (6.38 g, 30.7 mmol) in dry Et2O
(100 mL) was added DIBAL-H (64 mL of a 1 M solution in
hexanes, 64 mmol) under argon at 0 ЊC. After 1 h, the reaction
was quenched by the cautious addition of MeOH (1 mL). A
saturated solution of potassium sodium tartrate tetrahydrate
(100 mL) was added and the mixture was left to stir for several
hours until the organic and aqueous layers had completely sep-
arated. The organic layer was separated, washed with brine (75
mL), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give the crude alcohol (5.06 g, 99%)
as a colourless oil, which was used without further purification
in the next step. RF 0.2 (4 : 1 30–40 P.E. : Et2O); νmax/cmϪ1
(film)39 3300, 1450; δH (400 MHz, CDCl3) 1.71 (3H, d, J 7.0
Hz), 1.76 (3H, br s), 1.85 (3H, br s), 1.91 (3H, br s), 4.07 (2H,
br s), 5.45 (1H, q, J 7.0 Hz), 5.80 (1H, s), 5.94 (1H, s); δC (100.6
MHz, CDCl3) 13.8, 15.5, 16.7, 18.7, 69.6, 124.7, 130.5, 131.4,
133.4, 134.1, 134.7.
To a stirred solution of the crude alcohol (4.64 g, 27.95
mmol) in CHCl3 (100 mL) was added MnO2 (37 g, 418 mmol) at
RT. After 72 h, the mixture was filtered through Celite and the
filtrate concentrated under reduced pressure to give the crude
product as a yellow oil (4.54 g, 99%), which needed no further
purification. RF 0.45 (3 : 1 30–40 P.E. : Et2O); νmax/cmϪ1 (film)39
2970, 2930, 1690, 1630; δH (400 MHz, CDCl3) 1.76 (3H, d,
J 7.0 Hz), 1.83 (3H, br s), 1.99 (3H, s), 2.14 (3H, s), 5.64 (1H, q,
J 7.0 Hz), 6.27 (1H, s), 6.77 (1H, br s), 9.40 (1H, s); δC (100.6
MHz, CDCl3) 10.8, 14.0, 16.4, 17.9, 129.1, 131.5, 133.2, 133.7,
143.1, 156.4, 196.1.
Ethyl (2E,4E )-2,4-dimethylhexa-2,4-dienoate (30)38
To a stirred solution of tiglic aldehyde 29, (9.95 g, 118 mmol)
was added (1-ethoxycarbonylethylidene)triphenylphosphorane
(47.40 g, 131 mmol) in benzene (250 mL) at RT. The mix-
ture was refluxed for 48 hours then allowed to cool to
RT and concentrated under reduced pressure. Et2O was added,
and the resulting triphenylphosphine oxide removed by fil-
tration. The yellow filtrate was concentrated under reduced
pressure and purified by flash silica gel chromatography (19 : 1
30–40 P.E. : Et2O) to give the title compound as a colour-
less oil (17.44 g, 88%). RF 0.5 (4 : 1 30–40 P.E. : Et2O); νmax/cmϪ1
(film)38 2981, 2933, 2862, 1707, 1627, 1446, 1366, 1255, 1119,
1038, 748; δH (400 MHz, CDCl3) 1.31 (3H, t, J 7.0 Hz),
1.76 (3H, d, J 7.5 Hz), 1.85 (3H, s), 2.00 (3H, s), 4.21 (2H, q,
J 7.0 Hz), 5.73 (1H, q, J 7.5 Hz), 7.13 (1H, s); δC (100.6 MHz,
CDCl3) 14.0, 14.1, 14.3, 15.97, 60.6, 124.9, 130.9, 133.1, 143.0,
169.3.
(2E,4E )-2,4-Dimethylhexa-2,4-dienal (31)39
To a stirred solution of ester 30 (18.0 g, 107 mmol) in dry Et2O
(250 mL) was added DIBAL-H (225 mL of a 1 M solution in
hexanes, 225 mmol) under argon at 0 ЊC. After 1 h, the reaction
was quenched by the cautious addition of MeOH (1 mL). A
saturated solution of potassium sodium tartrate tetrahydrate
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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Ethyl (2E,4E,6E,8E )-4,6,8-trimethyldeca-2,4,6,8-tetraenoate
Ethyl (1R*,6S*,7S*,8S*)-1,3,5,8-tetramethylbicyclo[4.2.0]octa-
2,4-diene-7-carboxylate (35)
(28)40
To a stirred solution of aldehyde 33, (56 mg, 0.34 mmol) was
added (ethoxycarbonylmethylene)triphenylphosphorane (1.0 g,
2.87 mmol) in benzene (5 mL) at RT. The mixture was refluxed
for 48 hours then allowed to cool to RT and concentrated under
reduced pressure. Et2O was added, and the resulting triphenyl-
phosphine oxide removed by filtration. The yellow filtrate was
then concentrated under reduced pressure and purified by flash
silica gel chromatography (19 : 1 30–40 P.E. : Et2O) to give the
title compound as a yellow oil (64 mg, 80%). RF 0.65 (4 : 1 30–
40 P.E. : Et2O); νmax/cmϪ1 (film)40 1713; λmax(DCM)/nm 322.2
(ε/dm3 molϪ1 cmϪ1 11119); δH (400 MHz, CDCl3) 1.31 (3H, t,
J 7.0 Hz), 1.74 (3H, d, J 7.0 Hz), 1.80 (3H, br s), 1.97 (3H, br s),
1.99 (3H, br s), 4.22 (2H, q, J 7.0 Hz), 5.52 (1H, q, J 7.0 Hz),
5.85 (1H, d, J 15.5 Hz), 5.97 (1H, s), 6.32 (1H, s), 7.37 (1H, d,
J 15.5 Hz); δC (100.6 MHz, CDCl3) 13.8, 14.1, 14.2, 16.5, 18.5,
60.0, 115.9, 126.2, 128.2, 131.5, 133.3, 138.1, 144.8, 150.6,
167.5.
Ester 28 (239 mg, 1.02 mmol) and (MeCN)2PdCl2 (66 mg,
0.26 mmol) were dissolved in DMF (1 mL), and the mixture
stirred at RT. After 2 h another portion of catalyst (26 mg, 0.41
g) was added and stirring was continued for a further 1 h. H2O
(2.5 mL) was then added and the mixture extracted with DCM
(3 × 10 mL). The combined organic layers were washed with
brine (2 × 10 mL), dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. Purification by pre-
parative TLC (1% Et2O in 30–40 P.E.) gave the title compound
(81 mg, 34%) as a colourless oil. RF 0.7 (9 : 1 30–40 P.E. :
EtOAc); δH (500 MHz, CDCl3) 1.03 (3H, s), 1.06 (3H, d, J 7.0
Hz), 1.25 (3H, t, J 7.0 Hz), 1.73 (3H, s), 1.75 (3H, s), 2.46 (1H,
dq, J 9.5, 7.0 Hz), 2.53 (1H, d, J 9.0 Hz), 2.57 (1H, dd, J 9.5, 9.0
Hz), 4.12 (1H, q, J 7.0 Hz), 4.97 (1H, s), 5.42 (1H, br s); δC (126
MHz, CDCl3) 14.3, 14.7, 21.9, 22.7, 28.2, 40.6, 46.5, 47.9, 50.6,
60.6, 122.1, 122.8, 130.6, 134.9, 175.0. HRMS (CI) Calculated
for C15H23O2 (MHϩ): 235.1699. Found: 235.1706.
(2E,4E,6E,8E )-4,6,8-Trimethyldeca-2,4,6,8-tetraenyl
3,5-dinitrobenzoate (34)
Ethyl (2E,4E,6E,8E )-2,4,6,8-tetramethyl-9-(4-nitrophenyl)nona-
2,4,6,8-tetraenoate (37)
To a stirred solution of ester 28 (0.50 g, 2.13 mmol) in dry Et2O
(10 mL) was added DIBAL-H (4.5 mL of a 1 M solution in
hexanes, 4.5 mmol) under argon at 0 ЊC. After 1 h, the reaction
was quenched by the cautious addition of MeOH (1 mL). A
saturated solution of potassium sodium tartrate tetrahydrate
(20 mL) was added and the mixture was left to stir for several
hours until the organic and aqueous layers had completely sep-
arated. The organic layers were collected, washed with brine (10
mL), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give the crude alcohol (0.4 g, 98%) as
a colourless oil, which was used without further purification in
the next step. RF 0.15 (4 : 1 34–40 P.E. : Et2O); νmax/cmϪ1 (film)
3391, 2928, 2870; δH (500 MHz, CDCl3) 1.71 (3H, d, J 7.0 Hz),
1.78 (3H, br s), 1.93–1.95 (6H, m), 4.24 (2H, d, J 6.0 Hz), 5.48
(1H, q, J 7.0 Hz), 5.82 (1H, dt, J 15.5, 6.0 Hz), 5.83 (1H, s), 5.98
(1H, s), 6.32 (1H, d, J 15.5 Hz); δC (125.6 MHz, CDCl3) 13.7,
14.0, 16.6, 18.9, 63.9, 125.2, 126.3, 131.5, 133.4, 135.2, 135.2,
137.3, 137.6. HRMS (CI) Calculated for C13H19 (M–OH)ϩ:
175.1487. Found: 175.1488.
To a stirred solution of aldehyde 22 (0.658 g, 2.424 mmol) in
toluene (10 mL) was added (1-ethoxycarbonylethylidene)-
triphenylphosphorane (0.967 g, 2.668 mmol). The mixture was
refluxed overnight, then allowed to cool to RT. Pentane (10 mL)
was added, and the resulting triphenylphosphine oxide precipi-
tate removed by filtration. The yellow filtrate was then concen-
trated under reduced pressure and purified by flash silica gel
chromatography (9 : 1: 30–40 P.E. : EtOAc), to give the title
compound as a yellow oil (0.827 g, 96%). RF 0.6 (4 : 1 30–40
P.E. : EtOAc); νmax/cmϪ1 (CHCl3) 2983, 1698, 1594, 1517,
1343, 1111, 908, 733, 651; δH (400 MHz, CDCl3) 1.33 (3H, t,
J 7.5 Hz), 2.07 (3H, s), 2.07 (3H, s), 2.08 (3H, s), 2.10 (3H, s),
4.23 (2H, q, J 7.5 Hz), 6.05 (1H, s), 6.12 (1H, s), 6.49 (1H, s),
7.20 (1H, s), 7.45 (2H, d, J 8.0 Hz), 8.21 (2H, d, J 8.0 Hz); δC
(100.6 MHz, CDCl3) 14.2, 14.3, 18.6, 19.4, 19.4, 60.7, 123.5,
126.6, 129.5, 130.5, 133.3, 135.3, 135.4, 139.0, 139.3, 143.4,
ϩ
144.6, 145.9, 169.0; m/z (CI) 373 (MNH4 , 100%), 356 (MHϩ,
6), 343 (7), 333 (13), 326 (7). HRMS (CI) Calculated for
ϩ
C21H29N2O4 (MNH4 ): 373.2127. Found: 373.2137.
To a stirred solution of the crude alcohol (0.28 g, 1.44 mmol)
in dry DCM (2 mL) was added 3,5-dinitrobenzoyl chloride
(0.40 g, 1.73 mmol) followed by pyridine (0.14 mL) at RT. After
2.5 h, water (5 mL) was added. The layers were separated and
the aqueous layer extracted with DCM (3 × 10 mL). The com-
bined organic layers were dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude product
was recrystallised from ether to give orange crystals (0.362 g,
65%). RF 0.46 (8 : 2 30–40 P.E. : Et2O); δH (500 MHz, CDCl3)
1.70 (3H, d, J 7.0 Hz), 1.75 (3H, br s), 1.92–1.95 (6H, m), 4.99
(2H, m), 5.45 (1H, q, J 7.0 Hz), 5.72 (1H, d, J 15.5 Hz), 5.80
(1H, s), 6.05 (1H, s), 6.45 (1H, d, J 15.5 Hz), 9.10–9.24 (3H, m);
δC (125.6 MHz, CDCl3) 13.9, 14.3, 16.6, 19.0, 72.8, 119.2, 122.2,
125.7, 129.3, 131.3, 133.3, 134.1, 135.5, 139.4, 142.6, 148.6,
162.3. HRMS (CI) Calculated for C7H4N2O6 (Mϩ): 175.1487.
Found: 175.1486.
(2E,4E,6E,8E )-2,4,6,8-Tetramethyl-9-(4-nitrophenyl)nona-
2,4,6,8-tetraenal (38)
To a stirred solution of ester 37 (0.827 g, 2.33 mmol) in dry
Et2O (200 mL) was added DIBAL-H (4.89 mL of a 1 M solu-
tion in hexanes, 4.89 mmol) under argon at 0 ЊC. The reaction
was stirred at RT until completion as indicated by TLC analysis
(2 h), then quenched by the cautious addition of MeOH (2 ×
233 µL). A saturated solution of potassium sodium tartrate
(200 mL) was added, and the mixture was left to stir for several
hours until the organic and aqueous layers had completely
separated. The organic layer was separated, washed with brine
(20 mL), dried over anhydrous MgSO4, filtered and concen-
trated under reduced pressure to afford crude alcohol as a
yellow oil. RF 0.1 (4 : 1 30–40 P.E. : EtOAc). Without further
purification, this oil was used in the next step.
Single crystals of compound 53 suitable for X-ray diffraction
were selected.
To a stirred solution of crude alcohol (0.729 mg, 2.33 mmol)
in chloroform (20 mL) was added MnO2 (3.03 g, 34.9 mmol).
After stirring overnight at RT, the solution was filtered, concen-
trated under reduced pressure and purified by flash silica gel
chromatography (8 : 1 30–40 P.E. : EtOAc), to give the title
compound as an orange oil (0.688 g, 95%, 2 steps). RF 0.35 (4 : 1
30–40 P.E. : EtOAc); νmax/cmϪ1 (CHCl3) 2921, 1673, 1592, 1516,
1342, 911, 733; δH (400 MHz, CDCl3) 2.02 (3H, s), 2.12 (3H, s),
2.12 (3H, s), 2.22 (3H, s), 6.13 (1H, s), 6.35 (1H, s), 6.52 (1H s),
6.81 (1H s), 7.46 (2H, d, J 8.0 Hz), 8.22 (2H, d, J 8.0 Hz), 9.44
(1H, s); δC (100.6 MHz, CDCl3) 11.0, 18.3, 19.3, 19.3, 123.6,
Crystal data. C20H22N2O6, M = 386.40, monoclinic, a =
13.1953(2), b = 8.0054(2), c = 19.1169(4) Å, α = 90, β =
107.7083(8), γ = 90Њ, U = 1923.7 Å3, T = 150(1) K, space group
P21/n, Z = 4, µ(Mo–Kα) = 0.099 mmϪ1, 16330 reflections meas-
ured, 4625 unique (Rint = 0.026) which were used in calculations.
The final wR was 0.0513.
CCDC reference number 190073. See http://www.rsc.org/
suppdata/ob/b3/b306933h/ for crystallographic files in CIF or
other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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129.0, 129.6, 133.6, 135.0, 136.7, 139.0, 142.7, 144.4, 146.0,
reduced pressure to afford crude alcohol as a yellow oil. RF 0.15
(7 : 2 30–40 P.E. : EtOAc). Without further purification, this oil
was used in the next step.
ϩ
148.1, 155.3, 195.9; m/z (CI) 329 (MNH4 , 26%), 312 (MHϩ,
100), 294 (32), 282 (18). HRMS (CI) Calculated for C19H22NO3
(MHϩ): 312.1600. Found: 312.1612.
To a solution of crude alcohol (49.4 mg, 145.5 µmol) in dry
DCM (3 mL), was added 3,5-dinitrobenzoyl chloride (67 mg,
291.0 µmol) and pyridine (14.1 µL, 174.6 µmol). The reaction
was allowed to stir for 1 h at RT, then quenched with water
(1 mL). The layers were separated, and the aqueous layer
extracted with DCM (3 × 2 mL). The combined organic
fractions were then dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography (1 : 9 30–40 P.E. :
EtOAc), to afford the title compound as a yellow solid (59.8 mg,
75%, 2 steps) which was recrystallized from DCM. RF 0.4 (7 : 2
30–40 P.E. : EtOAc); mp = 190–192 ЊC; νmax/cmϪ1 (KBr disc)
1737, 1630, 1552, 1346, 1170; δH (500 MHz, C6D6) 1.03 (3H, s),
1.36 (3H, s), 1.47 (3H, s), 1.67 (3H, s), 2.73 (1H, s), 4.54 (1H,
dd, J 15.0, 5.0 Hz), 4.59 (1H, dd, J 15.0, 5.0 Hz), 5.24 (1H, s),
5.25 (1H, s), 5.31 (1H, dt, J 15.0, 5.0 Hz), 5.60 (1H, s), 6.12 (1H,
d, J 15.0 Hz), 6.83 (1H, d, J 10 Hz), 7.76 (1H, d, J 10.0 Hz), 8.44
(1H, d, J 5.0 Hz), 8.65 (1H, d, J 5.0 Hz); δC (125.7 MHz, C6D6)
14.1, 21.6, 22.9, 30.0, 44.1, 57.0, 67.3, 120.0, 122.3, 123.0, 124.3,
128.3, 129.0, 129.6, 131.4, 133.6, 135.4, 136.4, 141.2, 142.2,
Ethyl (2E,4E,6E,8E,10E )-4,6,8,10-tetramethyl-11-(4-nitro-
phenyl)undeca-2,4,6,8,10-pentaenoate (36)
To a stirring solution of aldehyde 38 (518 mg, 1.663 mmol)
in benzene (50 mL) was added (ethoxycarbonylmethylene)-
triphenylphosphorane (2.90 g, 8.317 mmol). The flask was fit-
ted with a reflux condenser and the solution heated at 80 ЊC for
3 hours, then left to cool to RT. Pentane (50 mL) was added,
and the resulting triphenylphosphine oxide precipitate was
removed by filtration. The filtrate was concentrated under
reduced pressure, and the crude residue purified by flash silica
gel chromatography (9 : 1 30–40 P.E. : EtOAc), to afford the
desired pentaene ester 36 as an orange oil (616 mg, 97%). RF 0.3
(7 : 1 30–40 P.E. : EtOAc); νmax/cmϪ1 (CCl4) 2979, 1708, 1615,
1590, 1515, 1444, 1340, 1298, 1166, 793; λmax(DCM)/nm 373
(ε/dm3 molϪ1 cmϪ1 35200); δH (400 MHz, C6D6) 1.08 (3H, t,
J 8.0 Hz), 1.73 (3H, s), 1.78 (3H, s), 1.85 (3H, s), 1.86 (3H, s),
4.16 (2H, q, J 8.0 Hz), 5.93 (1H, s), 5.94 (1H, s), 6.07 (1H, d,
J 16.0 Hz), 6.11 (1H, s), 6.22 (1H, s), 6.84 (2H, d, J 8.0 Hz), 7.71
(1H, d, J 16.0 Hz), 7.89 (2H, d, J 8.0 Hz); δC (100.6 MHz, C6D6)
14.3, 14.8, 19.4, 19.6, 19.8, 60.6, 118.1, 124.0, 129.2, 129.9,
133.3, 133.8, 134.6, 135.8, 136.0, 138.7, 139.4, 144.3, 144.5,
ϩ
147.4, 147.6, 148.7, 162.5; m/z (CI) 551 (MNH4 , 100%), 521
(14), 474 (16), 447 (16). HRMS (CI) Calculated for C28H30N4O8
ϩ
(MNH4 ): 551.2142. Found: 551.2134.
Single crystals from dichloromethane of compound 41 suit-
able for X-ray diffraction were selected.
ϩ
150.7, 167.3; m/z (CI) 399 (MNH4 , 44%), 382 (MHϩ, 100), 364
(15), 336 (43), 308 (40). HRMS (CI) Calculated for C23H28NO4
(MHϩ): 382.2018. Found: 382.2018.
Crystal data. C28H27N3O8, M = 533.54, triclinic, a =9.5061(2),
b = 11.9924(3), c = 12.1678(3) Å, α = 73.7785(11), β =
84.7859(9), γ = 80.7467(13)Њ, U = 1313.0 Å3, T = 150(1) K, space
Ethyl (2E,4E )-4-methyl-5-[(1R*,6R*)-1,3,5-trimethyl-6-(4-
nitrophenyl)cyclohexa-2,4-dien-1-yl]penta-2,4-dienoate (39)
Ϫ1
¯
group P1, Z = 2, µ(Mo-Kα) = 0.100 mm , 19776 reflections
measured, 5959 unique (Rint = 0.051) which were used in calcu-
lations. The final wR was 0.0427.
CCDC reference number 209300. See http://www.rsc.org/
suppdata/ob/b3/b306933h/ for crystallographic files in CIF or
other electronic format.
Ester 36 (800 mg, 2.1 mmol) and (MeCN)2PdCl2 (109 mg, 0.419
mmol) were placed in a dry flask, which was purged with argon.
DMF (20 mL) was added, and the solution was stirred for
2 days at RT, and then water (10 mL) was added. The mixture
was extracted with DCM (3 × 3 mL), and the combined organic
fractions were washed with water (3 × 3 mL), brine (5 mL) and
dried over anhydrous MgSO4. The drying agent was removed
by filtration, and the mixture concentrated under reduced pres-
sure. The crude yellow residue was purified by flash silica gel
chromatography (99.5 : 0.5 30–40 P.E. : EtOAc) to give the title
compound as a yellow oil (160 mg, 20%). RF 0.5 (3 : 1 30–40
P.E. : EtOAc); νmax/cmϪ1 (CHCl3) 2964, 2927, 2858, 1713, 1618,
1521, 1453, 1330, 1165; λmax(DCM)/nm 264 (ε/dm3 molϪ1 cmϪ1
18400); δH (400 MHz, C6D6) 0.85 (3H, s), 0.99 (3H, t, J 8.0 Hz),
1.18 (3H, s), 1.42 (3H, s), 1.64 (3H, s), 2.63 (1H, s), 4.06 (2H, q,
J 8.0 Hz), 5.12 (1H, s), 5.37 (1H, s), 5.58 (1H, s), 5.68 (1H, d,
J 16.0 Hz), 6.71 (2H, d, J 8.0 Hz), 7.42 (1H, d, J 16.0 Hz), 7.72
(2H, d, J 8.0 Hz); δC (100.6 MHz, C6D6) 13.6, 14.8, 21.6, 22.9,
29.7, 44.4, 56.5, 60.5, 117.4, 123.0, 124.3, 127.8, 129.6, 131.1,
135.5, 136.3, 146.5, 146.8, 147.6, 150.3, 167.3; m/z (CI) 399
Ethyl (1S*,2S*,5S*,6S*,7R*,8S*)-1,3,5-trimethyl-8-(4-nitro-
phenyl)tricyclo[3.2.1.02,7]oct-3-en-6-carboxylate (53)
A solution of ester 12 (0.40 g, 1.17 mmol) in xylene (80 mL) was
refluxed overnight (140–145 ЊC). The solution was allowed to
cool to RT and the solvent evaporated under reduced pressure.
The crude residue was purified by flash silica gel chromato-
graphy (9 : 1 30–40 P.E. : EtOAc) to afford the title compound
as a yellow solid (0.38 g, 95%). RF 0.65 (4 : 1 30–40 P.E. :
EtOAc); mp = 127–130 ЊC; νmax/cmϪ1 (KBr) 1718, 1593, 1514,
1343; δH (500 MHz, CDCl3) 0.91 (3H, s), 1.17 (3H, s), 1.23 (3H,
t, J 7.5 Hz), 1.76–1.79 (1H, m), 1.94–1.96 (1H, m), 1.98 (3H, s),
2.21 (1H, s), 2.8–2.82 (1H, m), 4.08 (2H, q, J 7.5 Hz), 5.36 (1H,
s), 7.27 (1H, dd, J 8.5, 2.0 Hz), 7.31 (1H, dd, J 8.5, 2.0 Hz), 8.22
(1H, dd, J 8.5, 2.5 Hz), 8.28 (1H, dd, J 8.5, 2.5 Hz); δC (125.7
MHz, CDCl3) 14.2, 17.6, 20.7, 20.9, 26.4, 27.5, 29.9, 46.1, 47.2,
58.5, 59.9, 123.2, 123.4, 125.1, 127.2, 132.7, 134.7, 146.6, 148.1,
(MNH4 , 8%), 382 (MHϩ, 100), 352 (11), 336 (43), 308 (40).
ϩ
HRMS (CI) Calculated for C23H28NO4 (MHϩ): 382.2018.
Found: 382.2026.
ϩ
172.25; m/z (CI) 359 (MNH4 , 18%), 342 (MHϩ, 100), 312 (9),
279 (13), 268 (7). HRMS (CI) Calculated for C20H24NO4
(2E,4E )-4-Methyl-5-[(1R*,6R*)-1,3,5-trimethyl-6-(4-nitro-
(MHϩ): 342.1705. Found: 342.1707.
phenyl)cyclohexa-2,4-dienyl 3,5-dinitrobenzoate (41)
[(1S*,2S*,5S*,6S*,7R*,8S*)-1,3,5-Trimethyl-8-(4-nitrophenyl)-
tricyclo[3.2.1.02,7]oct-3-en-6-yl]methyl 3,5-dinitrobenzoate (54)
To a stirred solution of ester 39 (56.6 mg, 148.3 µmol) in dry
Et2O (5 mL) was added DIBAL-H (311.4 µL of a 1 M solution
in hexanes, 311.4 µmol) under argon at 0 ЊC. The reaction was
stirred at 0 ЊC until completion as indicated by TLC analysis
(2 h), then quenched by the cautious addition of MeOH
(2 × 300 µL). A saturated solution of potassium sodium tartrate
(6 mL) was added, and the mixture was left to stir for 3 hours
until the organic and aqueous layers had completely separated.
The organic layer was separated, washed with brine (2 mL),
dried over anhydrous MgSO4, filtered and concentrated under
To a stirred solution of ester 53 (250 mg, 0.73 mmol) in dry
Et2O (50 mL) was added DIBAL-H (1.50 mL of a 1 M solution
in hexanes, 1.50 mmol) under argon at 0 ЊC. After 1 hour at 0 ЊC
the reaction was quenched by the cautious addition of MeOH
(1 mL). A saturated solution of potassium sodium tartrate
(50 mL) was added, and the mixture was left to stir at RT until
the organic and aqueous layers had completely separated (3 h).
The organic layer was separated, washed with brine (50 mL),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 7 0 – 3 6 8 4
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dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The crude yellow oil obtained was purified by
flash silica gel chromatography (1 : 1 30–40 P.E. : EtOAc) to give
the title compound as a yellow solid (213.8 mg, 98%). RF 0.10
(4 : 1 30–40 P.E. : EtOAc); mp = 99–103 ЊC; νmax/cmϪ1 (KBr)
3402, 2926, 1595, 1517, 1346; δH (400 MHz, CDCl3) 0.64 (3H,
s), 1.11 (3H, s), 1.28 (1H, s), 1.56–1.58 (1H, m), 1.78–1.80 (1H,
m), 1.89 (3H, s), 2.0–2.05 (1H, m), 2.08 (1H, s), 3.18–3.20 (1H,
m), 3.39–3.41 (1H, m), 5.27 (1H, s), 7.25 (1H, d, J 8.5 Hz), 7.29
(1H, d, J 8.5 Hz), 8.13 (1H, dd, J 8.5, 2.5 Hz), 8.19 (1H, dd,
J 8.5, 2.5 Hz); δC (100.6 MHz, CDCl3) 17.9, 20.2, 20.9, 26.9,
28.4, 29.3, 44.7, 44.8, 58.8, 61.7, 123.4, 123.6, 125.2, 127.9,
spectrum to that of 12. The other isomer was identified as
intermediate 60 by nOe, specifically, the major nOe between the
C8 methyl protons and the C9 vinylic proton. The other double
bonds were identified as having (E) configuration. δH (500
MHz, CDCl3) 1.35 (3H, t, J 7.0 Hz), 1.77 (3H, s), 2.04 (3H, s),
2.18 (3H, s), 4.28 (2H, q, J 7.0 Hz), 5.93 (1H, d, J 16.0 Hz), 6.20
(1H, s), 6.36 (1H, s), 6.50 (1H, s), 7.40 (1H, d, J 16.0 Hz), 7.49
(2H, d, J 8.5 Hz), 8.15 (2H, d, J 8.5 Hz).
Ethyl (2E,4E )-4-methyl-5-[(1S*,4R*,5S*,6S*)-1,3,6-trimethyl-
4-(4-nitrophenyl)bicyclo[3.1.0]hex-2-en-6-yl]penta-2,4-dienoate
(62)
ϩ
132.6, 134.0, 146.5, 148.2; m/z(CI) 317 (MNH4 , 10%), 300
A solution of pentaene 36 (100 mg, 0.262 mmol) in CHCl3
(15 mL) was refluxed for 2 days whilst simultaneously being
exposed to a 600 W tungsten lamp. The solution was then
allowed to cool to RT and the solvent evaporated under
reduced pressure. The crude residue was purified by flash silica
gel chromatography (99.5 : 0.5 30–40 P.E. : EtOAc) to afford 62
as a yellow oil (40 mg, 40%). RF 0.35 (7 : 1 30–40 P.E. : EtOAc);
νmax/cmϪ1 (CCl4) 2963, 2925, 2857, 1713, 1619, 1521, 1452,
1347, 1330, 1174, 1027, 812; δH (400 MHz, C6D6) 0.83 (1H, s),
0.93 (3H, s), 1.05 (3H, t, J 6.33 Hz), 1.10 (3H, s), 1.26 (3H, s),
1.61 (3H, s), 2.94 (1H, s), 4.13 (2H, q, J 6.33 Hz), 5.15 (1H, s),
5.67 (1H, s), 6.00 (1H, d, J 16.0 Hz), 6.78 (2H, d, J 10.0 Hz),
7.59 (1H, d, J 16.0 Hz), 7.89 (2H, d, J 10.0 Hz); δC (100.6 MHz,
C6D6) 13.8, 14.0, 14.1, 14.8, 16.6, 31.5, 41.1, 42.5, 55.4, 60.5,
117.5, 124.3, 129.0, 131.5, 137.0, 143.2, 144.7, 147.6, 149.3,
(MHϩ, 100), 282 (9), 270 (12), 230 (8). HRMS (CI) Calculated
for C18H22NO3 (MHϩ): 300.1600. Found: 300.1600.
To a solution of the alcohol (113.5 mg, 0.382 mmol) in dry
DCM (10 mL), was added 3,5-dinitrobenzoyl chloride (176.2
mg, 0.76 mmol) and a catalytic amount of DMAP. The reaction
was allowed to stir overnight at RT, then quenched with water
(10 mL). The layers were separated, and the aqueous layer
extracted with DCM (3 × 10 mL). The combined organic frac-
tions were then dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography (9 : 1 30–40 P.E. :
EtOAc), to afford the title compound as a yellow solid (151.8
mg, 80%). RF 0.2 (5 : 1 30–40 P.E. : EtOAc); mp = 218–220 ЊC;
νmax/cmϪ1 (KBr) 1732, 1628, 1551, 1347, 1172; δH (400 MHz,
CDCl3) 0.79 (3H, s), 1.19 (3H, s), 1.65 (1H, m), 1.83 (1H, m),
2.01 (3H, s), 2.19 (1H, s), 2.20–2.30 (1H, m), 4.07 (1H, br d,
J 11.0 Hz), 4.18 (1H, br d, J 11.0 Hz), 5.38 (1H, s), 7.29 (1H, d,
J 8.5 Hz), 7.31 (1H, d, J 8.5 Hz), 8.20 (1H, dd, J 8.5, 2.5 Hz),
8.28 (1H, dd, J 8.5, 2.5 Hz), 9.13 (2H, d, J 2.0 Hz), 9.22 (1H, t,
J 2.0 Hz); δC (100.6 MHz, CDCl3) 17.7, 20.3, 20.9, 27.1, 28.2,
29.9, 41.2, 45.0, 58.5, 66.7, 122.3, 123.2, 123.4, 124.9, 127.6,
129.3, 132.7, 133.9, 134.4, 146.7, 147.5, 148.7, 162.5.
151.0, 167.3; m/z (CI) 399 (MNH4 , 3%), 382 (MHϩ, 100), 366
ϩ
(8), 352 (29), 336 (30), 308 (27). HRMS (CI) Calculated for
C23H28NO4 (MHϩ): 382.2018. Found: 382.2023.
Compound 39 was also isolated as a yellow oil (17 mg, 17%).
Direct conversion of ethyl (2E,4E )-4-methyl-5-[(1R*,6R*)-
1,3,5-trimethyl-6-(4-nitrophenyl)cyclohexa-2,4-dien-1-yl]penta-
2,4-dienoate (39) into ethyl (2E,4E )-4-methyl-5-[(1S*,4R*,
5S*,6S*)-1,3,6-trimethyl-4-(4-nitrophenyl)bicyclo[3.1.0]hex-2-
en-6-yl]penta-2,4-dienoate (62)
Single crystals from diethyl ether of compound 53 suitable
for X-ray diffraction were selected.
A solution of hexadiene 39 (15 mg, 39.3 µmol) in benzene
(0.5 mL) was exposed to direct sunlight. Periodic observations
using 1H NMR indicated conversion to 62 without any evidence
for 36. After 2 weeks of irradiation, compound 39 has been
completely converted into bicyclic compound 62 (15 mg,
100%). The 1H NMR spectra data matched with that found for
62 given above.
Crystal data. C25H23N3O8, M = 493.47, triclinic, a =
8.0506(4), b = 12.3846(5), c = 13.2746(7) Å, α = 64.465(2), β =
86.930(2), γ = 73.060(2)Њ, U = 1138.4 Å3, T = 150(1) K, space
group P1, Z = 2, µ(Mo-Kα) = 0.109 mm , 15400 reflections
measured, 5161 unique (Rint = 0.042) which were used in calcu-
lations. The final wR was 0.0578.
CCDC reference number 209361. See http://www.rsc.org/
suppdata/ob/b3/b306933h/ for crystallographic files in CIF or
other electronic format.
Ϫ1
¯
Acknowledgements
We thank the EPSRC for funding to J. E. M. We thank
Dr B. Odell and Dr T. D. W. Claridge for NMR assistance, and
Dr Andrew Cowley for crystallographic analysis.
Ethyl (2E )-3-[(1S*,4R*,5S*,6S*)-1,3,6-trimethyl-4-(4-nitro-
phenyl)bicyclo[3.1.0]hex-2-en-6-yl]prop-2-enoate (59)
A solution of ester 12 (120 mg, 0.35 mmol) in chloroform
(25 mL) was refluxed overnight, whilst simultaneously being
exposed to the light from a 600 W tungsten lamp source. The
solution was allowed to cool to RT and the solvent evaporated
under reduced pressure. The crude residue was purified by flash
silica gel chromatography (9 : 1 30–40 P.E. : EtOAc) to afford
the title compound as a yellow oil (72 mg, 60%). RF 0.3 (4 : 1
30–40 P.E. : EtOAc); νmax/cmϪ1 (film) 1707, 1634, 1520, 1347;
δH (400 MHz, CDCl3) 1.12 (3H, s), 1.24 (3H, t, J 7.0 Hz), 1.47
(3H, s), 1.54 (3H, s), 1.59 (1H, s), 3.32 (1H, s), 4.18 (2H, q, 7.0
Hz), 5.48 (1H, s), 5.37 (1H, d, J 15.5 Hz), 6.78 (1H, d, J 15.5
Hz), 7.34 (2H, d, J 8.5 Hz), 8.19 (2H, d, J 8.5 Hz); δC (100.6
MHz, CDCl3) 10.8, 13.8, 14.3, 16.3, 33.2, 43.8, 44.2, 55.1,
60.1, 118.3, 123.9 (2C), 128.8 (2C), 131.7, 143.2, 146.8, 150.4,
153.7, 166.9. HRMS (CI) Calculated for C20H24NO4 (MHϩ):
342.1705. Found: 342.1702.
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