Total synthesis of cyercene A and the biomimetic synthesis of (±)-9,10-deoxytridachione and (±)-ocellapyrone A

Article abstract of DOI:10.1016/j.tet.2007.03.057

This paper summarises our detailed study towards the biomimetic synthesis of the complex polypropionate derived natural product (±)-9,10-deoxytridachione. A previous study based on the elaboration of functionalised γ-pyrones allowed us to synthesise cyerc

Full text of DOI:10.1016/j.tet.2007.03.057

Tetrahedron 63 (2007) 4500–4509
Total synthesis of cyercene A and the biomimetic synthesis
of ( )-9,10-deoxytridachione and ( )-ocellapyrone A
a
Raphael Rodriguez, Robert M. Adlington, Serena J. Eade, Magnus W. Walter,
a,
a
c
*
€
Jack E. Baldwina and John E. Mosesb,
*
aThe Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bThe School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK
cLilly Research Centre, Eli Lillyand Company Ltd, Erl Wood Manor, Sunninghill Road, Windlesham GU20 6PH, UK
Received 23 November 2006; revised 19 February 2007; accepted 8 March 2007
Available online 13 March 2007
Dedicated to the memory of Professor D. John Faulkner
Abstract—This paper summarises our detailed study towards the biomimetic synthesis of the complex polypropionate derived natural prod-
uct (ꢀ)-9,10-deoxytridachione. A previous study based on the elaboration of functionalised g-pyrones allowed us to synthesise cyercene A.
The same efficient methodology has been applied for the elaboration of a more complex fully conjugated g-pyrone polyene. Our approach
centred on a key tandem Suzuki-coupling/electrocyclisation reaction, which supports a possible biosynthetic pathway for this class of natural
products. A related compound was obtained during our studies, which we identified as the correct structure of ocellapyrone A.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
a range of structures including unsaturated conjugated poly-
enes such as cyercene A (1),3 1,3-cyclohexadiene core units
such as 9,10-deoxytridachione (2)4 and tridachiahydro-
pyrone (5),5 bicyclo[3.1.0]hexene metabolites including
photodeoxytridachione (7),6 bicyclo[4.2.0]octadiene (e.g.,
ocellapyrone A (10)7–9) and their corresponding oxidised
metabolites such as tridachione (3),10 tridachiapyrone I
(4),11 tridachiahydropyrone B (6),11,5b tridachiapyrone E
(8),12 tridachiapyrone F (9),12 ocellapyrone B (11)8,9 and
elysiapyrone B (12).13 It is noteworthy that the nitrophenyl
pyrones spectinabilin (13)14 and SNF compounds15 14 and
15 isolated from the actinomycete Streptomyces spectabilis
exhibit similar structural complexities.
1.1. Background
Over the last 30 years, many structurally novel polypropio-
nate derived metabolites have been isolated from marine or-
ganisms as diverse as bacteria, sponge and molluscs. Pyrone
containing polypropionate compounds are characteristically
produced by a restricted group of marine molluscs of the or-
der Sacoglossan.1 These creatures have developed a symbi-
otic relationship with active chloroplasts from algae in order
to synthesise, in their own tissue, secondary metabolites
involved in defence against predators. Such compounds,
which are formally derived from a polyketide pathway, are
associated with specific ecophysiological functions of the
molluscs, and may also act as mediators in tissue regenera-
tion.2 The diverse range of biological activities expressed
is the consequence of the impressive structural diversity
associated with this superfamily of natural products.
Fascinated by the structural diversity of the natural products
created by these astonishing marine organisms, Faulkner un-
dertook a research programme in the late 1970s dedicated to
the isolation and characterisation of new metabolites.4 This
pioneering work uncovered many interesting compounds
and their chemical relationships. A most representative ex-
ample was provided independently by Scheuer and Faulkner,
both demonstrating the in vivo6 and in vitro4 photochemical
conversion of (ꢁ)-9,10-deoxytridachione (2) into (ꢁ)-pho-
todeoxytridachione (7). Ireland and Faulkner proposed that
(ꢁ)-9,10-deoxytridachione (2) undergoes a [s2a+p2a] rear-
rangement to (ꢁ)-photodeoxytridachione (7), which is
chemically reasonable since optical activity was retained
in the product. However, it could also be proposed
that during the in vivo conversion, (ꢁ)-2 undergoes a
Indeed, these metabolites display an unusual and diverse ar-
ray of molecular architectures, often comprising compounds
with pyrone units appended to a polyene or polyene derived
carbon-frame/side chain. For example, Figure 1 displays
Keywords: Total synthesis; Natural products; Electrocyclisation; Reaction
cascade.
* Corresponding authors. Tel.: +44 (0)20 7753 5804; fax: +44 (0)20 7753
5935 (J.E.M.); e-mail: john.moses@pharmacy.ac.uk
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.03.057

R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
4501
O
O
OMe
OMe
OMe
O
O
O
O
O
OMe
O
O
O
Cyercene A (1)
9,10-Deoxytridachione (2)
Tridachiapyrone I (4)
Tridachione (3)
O
O
OMe
O
O
OMe
O
O
OMe
O
H
O
Tridachiahydropyrone (5) Tridachiahydropyrone B (6)
Photodeoxytridachione (7)
(Revised structure)5b
O
O
OMe
OMe
O
H
H
O
O
O
O
O
O
H
H
H
O
O
H
O
O
OMe
OMe
Tridachiapyrone F (9)
Tridachiapyrone E (8)
Ocellapyrone A (10) Ocellapyrone B (11)
O
O
H
O
O
O2N
O
H
O
O
OMe
OMe
Elysiapyrone B (12)
Spectinabilin (13)
O
O
O2N
O2N
O
O
O
O
OMe
OMe
SNF4435C (14)
Figure 1. Representative structural diversity of polypropionate metabolites containing g-pyrones.
SNF4435D (15)
retro-electrocyclisation providing an achiral tetraene, which
subsequently undergoes a photochemical enzyme mediated
Diels–Alder cycloaddition giving 7 in enantiopure form.
Jones, however, has recently proposed a diradical process
to be involved in this transformation.16
diverse scaffolds from relatively simple (E,E,E,E)-tetraene
precursors. In the examples illustrated in Scheme 1, polyene
(ꢀ)-16 was encouraged to undergo selective E/Z double
bond isomerisation under a variety of reaction conditions, re-
sulting in the necessary geometry for cascade electrocyclisa-
tions to ensue. Several of the model core structures such as
(ꢀ)-17, (ꢀ)-19 and (ꢀ)-20 shared common features with
the Sacoglossan polypropionate metabolites described
above, which led us to propose a general biosynthetic ratio-
nale to explain the origin of these natural products through
cascade electrocyclisations.17 We proposed that many com-
plex polypropionate metabolites may be biosynthetically de-
rived from conjugated linear polyenes via double bond
isomerisations, thermal and/or photochemical electrocycli-
sations, [4+2] cycloadditions and photoinduced [2+2] con-
certed rearrangements, generating significant structural
diversity. Scheme 2 describes our proposed hypothesis of
a general biosynthetic pathway for representative polypropi-
onate metabolites containing g-pyrones and describes possi-
ble chemical relationship existing between them. A single
polyene precursor (E,E,E,E)-21 could, after photochemical
or thermal selective double bond isomerisation, convert
1.2. Previous study
Intrigued by the noteworthy [s2a+p2a] transformation of
(ꢁ)-2 into (ꢁ)-7 and the possible chemical relationship
existing between other polypropionate metabolites, we in-
vestigated model reactions involving simple polyene sub-
strates.17 This study allowed us to demonstrate the ability
of conjugated polyenes to undergo selective cascade isomer-
isations–pericyclisations, forming a range of complex core
structures under a judicious choice of reaction conditions.
Such polyenes were found to be versatile reactive substrates
and highly sensitive to their environment such as light,
temperature or the presence of a palladium catalyst.
Thus, we have demonstrated several different modes of
thermal and photochemical reactions affording structurally

4502
R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
into the polyene intermediates (E,Z,E,E)-22, (E,Z,Z,E)-23,
(Z,E,E,E)-24 and (Z,Z,E,E)-25, which could subsequently
undergo photochemically or thermally allowed pericyclic
processes to provide metabolites 2, 7 and 5, respectively.
Furthermore, selective late stage oxidation could lead to
the related metabolites including 3, 4, 6, 8 and 9.
transformations.4,10 We have recently reported the first total
synthesis of this natural product in racemic form, which in-
volved a tandem Suzuki cross coupling/disrotatory electro-
cyclisation process.7 We now report a complete account of
our studies, which includes an efficient preparation of cyer-
cene A (1) using a novel methodology, and its application to
the biomimetic synthesis of both natural products (ꢀ)-9,10-
deoxytridachione (2) and (ꢀ)-ocellapyrone A (10).
R1
R2
con = conrotatory
dis = disrotatory
double bond isomerisation
R1 =
H
NO2
2. Results and discussion
R2
=
CO2Et
( )-17
2.1. Model study: synthesis of cyercene A (1)
E /Z2 and E /Z
3
8πcon, 6πdis
2
3
Pd
Cyerce cristallina is a Sacoglossan species whose body
volume is mainly due to the presence of dorsal appendages
aposematically coloured in red and white. When attacked
by predators, this mollusc secretes presumably toxic mucus
and, if molested further, detaches its cerata, which then
exhibit prolonged contractions and carry on secreting large
amount of mucus. After the autonomic process, the mollusc
providesa striking exampleof regeneration by completely re-
producing the cerata within a week. Intrigued by the unusual
display of tissue regeneration for such a complex organism,
Di Marzo and co-workers undertook a research programme,
aimed at characterising some of the chemical substances in-
volved in both chemical defence and regenerative process.3
Several products were isolated and cyercene A (1) was found
to be central in the tissue regeneration phenomena.3,20
E
E
E
E
1
2
3
4 R2
( )-16
R1
E /Z1 and E /Z
1
2
2
[
E /Z
6π dis
π4s + π2a]
2
2
Δ
h
Δ
Δ
H
R1
h
R2
R2
[σ2a
+
π2a]
R2
[π4s + π2s]
H
H
R1
( )-18
R1
( )-19
( )-20
Scheme 1. Complex core structures derived from polyene precursors.
As part of our continuing efforts directed towards the
biomimetic synthesis of natural products,18,19 we became
interested in the polypropionate derived (ꢀ)-9,10-deoxy-
tridachione (2) due to its unusual molecular architecture
and biological activity. Compound (ꢁ)-2 was isolated as
a single enantiomer by Faulkner and has attracted much
attention with respect to understanding the chemical
processes involved in its biosynthesis and biosynthetic
A retrosynthetic analysis of this very interesting natural prod-
uct reveals the commercially available aldehyde 26 (Scheme
3) and the phosphono-g-pyrone unit (ꢀ)-27, which we be-
lieved could be coupled in a stereoselective manner to furnish
O
[O]
3
Δ
O
O
OMe
6π disrotatory
[O]
4
2
R
R
Δ
7
O
OMe
[π4a
+ π2a]
Z
24
22
R
E
Δ
Δ
O
O
E
Z
6π disrotatory
Δ
O
X
O
O
OMe
O2/h
6
E
E
E
[4 + 2]
R
O
OMe
OMe
25
H
O
O
5
21
Z
Selective
Isomerisation
h
X
h
6π conrotatory
OMe
R
Z
h
x =
O
9
h
7
[π4s
+ π2a]
OMe
O
R
OMe
[O]
Isomerisation
O
Z
h
h
8
R
2
23
Z
6π conrotatory
[σ2a
+ π2a]
H
O
7
Scheme 2. Proposed biosynthetic relationship between several g-pyrone containing compounds.

R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
4503
the target compound in a single step. Structurally related non-
methylatedphosphono-pyroneshavebeenreportedbyKoester
and Hoffmann, however there are no reports of their use in
Horner–Wadsworth–Emmons olefinations.21 Further discon-
nection of the functionalised pyrone building block gives rise
to the known pyrone 28. Our desire to utilise a Horner–
Wadsworth–Emmons type approach for the coupling was
based upon the well-known ability of such reagents to gener-
ate E-trisubstituted olefins stereoselectively.22 It was also
desirable to install the double bond in one step, thus avoiding
additional dehydration protocols necessary in existing
aldol-type methodology utilised in related studies with
a-pyrones.23
involved the corresponding iodo-pyrone rather than the
Horner–Wadsworth–Emmons reagent. Unfortunately, such
protocols were abandoned, suffering from very low yields.
Withtheaboveexample, wehadsynthesisedanovelg-pyrone
Horner–Wadsworth–Emmons reagent, which we anticipated
could be employed in the synthesis of more complex polypro-
pionate derived natural products. Having this methodology in
hand, and our expertise in polyene rearrangements,17 we next
engaged in the biomimetic synthesis of the more complex
polyene derived metabolite (ꢀ)-9,10-deoxytridachione (2).
2.2. Application of methodology to the synthesis of
complex metabolites
O
O
(ꢁ)-9,10-Deoxytridachione (2) was isolated from the mol-
luscs Tridachiella diomedea4 (Mexican dancer) and Placo-
branchus ocellatus.6 This natural product seemed suitable
for our continuing studies since we envisaged that relatively
simple chemical manipulations may allow access to a range
of related metabolites including 3, 4, 7, 8 and 9 (Scheme 2).
Scheme 5 depicts a retrosynthetic rationale towards (ꢀ)-2.
Thus, a retro thermal 6p-disrotatory electrocyclisation re-
veals the (E,Z,E,E)-conjugated g-pyrone-tetraene 22, which
we, Ireland and Faulkner,4 have considered as a possible bio-
synthetic precursor to 2. However, we also appreciated that 2
H
O
OMe
HWE Olefination
26
1
+
O
O
O
O
(EtO)2P
O
OMe
OMe
28
( )-27
Scheme 3. Cyercene A retrosynthetic analysis.
Our synthesis of cyercene A (1) commenced with the readily
available 2-ethyl-6-methoxy-3,5-dimethylpyran-4-one (28)
shown in Scheme 4.21,23 Deprotonation of 28 using lithium
hexamethyldisilazide at ꢁ78 ꢂC in tetrahydrofuran, fol-
lowed by quenching of the resulting anion with the Davis ox-
aziridine,24 lead to the functionalised hydroxypyrone (ꢀ)-33
in good yield. The product was then smoothly converted into
the corresponding mesylate in high yield and was easily pu-
rified by flash silica gel chromatography to provide (ꢀ)-34.
Treatment of the latter with the sodium salt of diethyl phos-
phite in DMF at 0 ꢂC successfully generated the desired
Horner–Wadsworth–Emmons reagent (ꢀ)-27 in good yield.
Finally, treatment of the commercially available aldehyde 26
with the lithium salt of (ꢀ)-27 at ꢁ78 to 20 ꢂC successfully
yielded the target natural product cyercene A (1) as the ma-
jor stereoisomer [E:Z>16:1] in excellent yield.25 All spec-
tral data were in agreement with those described for the
natural product.3 We have also investigated several other
olefination protocols using similar enals, including a Julia-
type coupling and a Reformatsky approach. Both strategies
6π Retro-
electrocyclisation
Suzuki Cross
Coupling
OMe
OMe
O
O
O
O
2
22
O
HWE
Olefination
O
B
I
+
O
O
OMe
35
36
I
37
+
( )-27
O
Scheme 5. (ꢀ)-9,10-Deoxytridachione retrosynthetic analysis.
OMe
OH
O
O
O
a
b, c
d
28
+
O
32
O
h
O
O
29
30
31
O
O
O
e
f
g
28
( )-27
1
MsO
HO
OMe
O
OMe
( )-33
( )-34
Scheme 4. Reagents and conditions: (a) NaH, Et2O, then ethyl propionate, 0 ꢂC to rt, 12 h, 52%; (b) DIPA, nBuLi, THF, 0 ꢂC, 30 min, then solid CO2; (c) Ac2O,
rt, 12h, 59% over two steps; (d) Me2SO4, Li2CO3, refluxing acetone, 48 h, 42% for 32, 55% for 28; (e) LHMDS, THF, ꢁ78 ꢂC, 30 min, then Davis’s reagent,
10 min, 76%; (f) Et3N, MsCl, DCM, 0 ꢂC, 30 min, 92%; (g) NaH, diethylphosphite, DMF, 0 to 60 ꢂC, then (ꢀ)-34, 0 ꢂC to rt, 12 h, 84%; (h) LHMDS, DMF,
ꢁ78 ꢂC then 26, then ꢁ78 ꢂC to rt over 1 h, 87%.

4504
R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
may be biosynthetically derived through a photochemical
6p-conrotatory electrocyclisation process17c,d of the corre-
sponding (E,Z,Z,E)-tetraene 23 (Scheme 2). Although both
thermal and photochemically induced 6p-electrocyclisation
processes have been reported with related polyene systems,
to our knowledge, such transformations had not been dem-
onstrated with conjugated g-pyrone containing polyenes.
Considering the known photochemical relationship between
2 and 7,4,6 we assumed that polyene 22 was more suitable for
our study. Avoiding photochemical conditions would allow
us to prepare (ꢀ)-2 selectively without its subsequent con-
version into (ꢀ)-7.
Wadsworth–Emmons olefination reagent (ꢀ)-27, which was
previously used in the preparation of cyercene A (1), and the
known readily available iodo-aldehyde 37.28
Our synthesis commenced with the condensation of alde-
hyde 37, obtained in two steps from propargyl alcohol,28
with the lithium salt of (ꢀ)-27, at ꢁ78 to 20 ꢂC in THF, to
give the conjugated vinyl iodide 36 as the major stereoiso-
mer [E:Z>6:1] in an unoptimised 39% yield (Scheme 6).
Subsequent Suzuki cross coupling between 36 and boronic
ester 35, the latter obtained efficiently in three steps from
26,26 was performed using standard conditions at 80 ꢂC.29
The insoluble palladium salts were removed from the reac-
1
Thus, disconnection of 22 revealed the known conjugated
vinyl-boronic ester 3526 and vinyl iodide 36, which we
believed would be ideal partners for a Suzuki coupling reac-
tion.27 Further analysis of fragment 36 revealed the Horner–
tion mixture by a quick filtration on florisilÒ. H NMR of
the crude reaction mixture showed the presence of four
new alkenyl signals [dH (CDCl3) 5.32–5.41 (br m), 5.85
(br s), 5.98 (br s) and 6.42 (br s)] characteristic of
O
I
I
I
OH
a
c
b
OH
O
OMe
O
38
39
37
36
H
O
B
Br
d
e
f
O
O
Br
26
40
41
35
OMe
OMe
O
Z
E
E/Z
O
O
Z
E
E
E
g
Isomerisation
36
O
Δ
Z
E
23
22
8π-Conrotatory
Electrocyclisation
Δ
O
H
O
H
O
6π-Disrotatory
Electrocyclisation
Δ
O
OMe
endo-( )-42
OMe
exo-( )-42
6π-Disrotatory
Electrocyclisation
Δ
not observed
OMe
O
O
H
H
O
O
H
O
H
O
OMe
OMe
( )-10
( )-2
( )-43
15%
31%
Scheme 6. Reagents and conditions: (a) MeMgBr, CuI, Et2O, ꢁ10 ꢂC to rt, then ICl, ꢁ10 ꢂC to rt, 16 h, 45%; (b) MnO2, DCM, rt, 12 h, 99%; (c) (ꢀ)-27,
LHMDS, THF, ꢁ78 ꢂC to rt, 1 h, 39%; (d) PPh3, CBr4, DCM, rt, 2 h, 96%; (e) BuLi, THF, then MeI, ꢁ78 ꢂC to rt over 2 h, then stirred 16 h, 40%; (f) cate-
cholborane neat, 90 ꢂC, 4 h, 99%; (g) Pd(PPh3)4, 35, THF, then aqueous KOH, 80 ꢂC, 2 h, 65% (crude product 22), then benzene, 120 ꢂC, 1 h, 31% for (ꢀ)-2,
15% for (ꢀ)-10.

R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
4505
a conjugated tetraene,17d,e leading us to conclude the major
constituent of the crude mixture to be compound 22.
the same mollusc P. ocellatus. This successful, flexible meth-
odology previously created for the synthesis of cyercene A
will be further optimised in our laboratory, and used to probe
for the preparation of other polypropionate metabolites. This
example further demonstrates the power of such biomimetic
approaches, which allowed us in this particular case to obtain
the unexpected, recently isolated natural product (ꢀ)-10.
Crude 22 was heated in a sealed tube in benzene at 120 ꢂC
for 1 h in the absence of light. A mixture comprising two
main compounds was obtained, which we were unable to
separate by silica gel chromatography. However, purification
by reverse phase C-18 HPLC facilitated the separation of the
two compounds.30 The spectral data for the major compound
isolated (31% yield), corresponded to the natural product
(ꢀ)-2,4 and was presumably formed via a 6p-disrotatory
electrocyclisation from polyene 22.
4. Experimental
4.1. General procedures
The other unexpected compound obtained in 15% yield pos-
sesses the same structural bicyclo[4.2.0]octadiene core as the
spectinabilin (13) derived immunosuppressants SNF 4435 C
(14) and D (15) (Fig. 1), and is formally derived from iso-
merisation of (E,Z,E,E)-22 to (E,Z,Z,E)-23, followed by
thermally allowed consecutive 8p-conrotatory and sterically
favoured 6p-disrotatory electrocyclisations.17f,19a,c,31,32 The
exo-structure (ꢀ)-10 proposed for this compound was based
upon extensive NOE measurements. Recently, two natural
products were isolated from the mollusc P. ocellatus by
Manzo et al.8 for which structures 43 and 11 were proposed.
The endo-structure of 43 had indirectly been assigned by
structural comparison with 11 for which 2D NMR analysis
has been carried out.8 However, the NMR data (1H and 13C)
collected by us for compound (ꢀ)-10 were identical to those
described for43byManzoet al. We didnotobserve any traces
of (ꢀ)-43 during our synthesis and a structural reassignment
for the newly isolated natural product ocellapyrone A was
suggested. More recently, in a similarstudy, Trauner observed
similar results and confirmed the structure correction after
X-ray analysis of a related compound derived from (ꢀ)-43.9
In his recent report, Trauner observed the formation of (ꢀ)-
43 as the major isomer along with small quantities of (ꢀ)-
10 starting from the same polyene 22 at lower temperature
(45 ꢂC). A higher temperature (120 ꢂC) used during our ex-
periment allowed us to isolate compound (ꢀ)-10 as a single
product. However, if formed, (ꢀ)-43 could convert into the
endo-(ꢀ)-42 intermediate at high temperature via a 6p
retro-electrocyclisation and subsequently displaces the equi-
librium towards the most stable exo conformer, the latter
yielding natural product (ꢀ)-10. In a comparable study,
Trauner also reported the conversion of (ꢀ)-43 into ocella-
pyrone B ((ꢀ)-11) via a [4+2] cycloaddition with singlet
oxygen. However, 43 has still not been isolated itself as a
natural product.
All reagents were purified by standard techniques reported in
Ref. 35 or used as supplied from commercial sources, as ap-
propriate. Solvents were distilled before use, unless other-
wise stated. Anhydrous dichloromethane was obtained by
heating to reflux over calcium hydride for an hour followed
by distillation under argon. Anhydrous diethyl ether and
anhydrous THF were obtained by heating to reflux over
sodium–benzophenone for 1 h followed by distillation under
argon. Anhydrous DMF was purchased from the Sigma–
Aldrich Company and used without any further purification.
Solvents were removed under reduced pressure using a Buchi
R110 or R114 Rotavapor. Final traces of solvent were re-
moved from samples using an Edwards E2M5 high vacuum
pump with pressure below 2 mmHg. All experiments were
carried out under inert atmosphere unless otherwise stated.
1H NMR spectra were recorded using Bruker DPX 200,
1
DQX 400, AMX 500 and DRX 500 instruments. For H
spectra recorded in CDCl3, CD3OD and C6D6, chemical
shifts are quoted in parts per million (ppm) and are refer-
enced to the residual solvent peak. The following abbrevia-
tions are used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Proton assignments and stereochemistry
1
are supported by H–1H COSY and NOESY where neces-
sary. Data are reported in the following manner: chemical
shift (integration, multiplicity, coupling constant if appropri-
ate). Coupling constants (J) are reported in hertz to the near-
est 0.5 Hz. 13C NMR spectra were recorded using Bruker
DPX 200, Bruker DQX 400 and Bruker AMX 500 instru-
ments. Carbon spectra assignments are supported by
DEPT-135 spectra, 13C–1H (HMQC and HMBC) correla-
tions where necessary. Flash column chromatography was
carried out using SorbsilÔ C60 (40–63 mm, 230–400
mesh) silica gel. Thin layer chromatography was carried
out on glass plates pre-coated with Merck silica gel 60
F254, which was visualised either by quenching of UV fluo-
rescence or by dipping in a solution of KMnO4 (KMnO4
(3 g), KOH (0.3 g), K2CO3 (20 g) and water (300 mL)) fol-
lowed by heating, as appropriate. Melting points were re-
corded using a Cambridge Instruments GallenÔ III Kofler
Block melting apparatus or a Buchi 510 capillary apparatus
and are uncorrected.
3. Conclusion
In conclusion, we have described the first total synthesis of
cyercene A (1) and (ꢀ)-9,10-deoxytridachione ((ꢀ)-2) in
a biomimetic fashion, demonstrating experimentally a chem-
ical relationship between a fully conjugated polyene-g-
pyrone and a complex natural product. The results from
this study strengthen our general biosynthetic proposal that
compounds of these classes are most likely derived through
pericyclic processes of linear polyene precursors. The co-
isolation of (ꢀ)-ocellapyrone A ((ꢀ)-10) during our synthe-
sis also strongly supports this biosynthetic hypothesis on the
grounds that both natural products have been isolated from
Infrared spectra were recorded either as a thin film between
NaCl plates or KBr disc on a Perkin-Elmer Paragon 1000
Fourier Transform spectrometer with internal referencing.
Absorption maxima are reported in wavenumbers (cmꢁ1
)
and the following abbreviations are used: s, strong; br, broad;
m, medium; w, weak. Low-resolution mass spectra were
recorded on V. G. Micromass ZAB 1F and V. G. Masslab
instruments as appropriate with modes of ionisation being

4506
R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
indicated as CI, EI, ES or APCI with only molecular ions.
High-resolution mass spectrometry was performed on a
Waters 2790-Micromass LCT electrospray ionisation mass
spectrometer, on a V. G. autospec chemical ionisation
mass spectrometer and a Thermo Electron LTQ-FT Mass
Spectrometer.
the addition of satd aq NH4Cl (20 mL). The crude mixture
was extracted with EtOAc (2ꢃ50 mL), followed by washing
of the organic fraction with brine (2ꢃ50 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure to give a yellow
oil. The crude residue was purified by flash silica gel
chromatography (1:1, 30–40 PE/EtOAc) to give the title
compound as a white powder (2.48 g, 76%). Rf 0.20
(EtOAc); mp 78–80 ꢂC; nmax/cmꢁ1 (KBr disc) 3301br s,
4.1.1. 4-Methyl-3,5-heptanedione (30).33 Compound 30
was prepared according to the procedure of Konopelski
et al.33
1
1660s, 1569s; H NMR (400 MHz, CDCl3): dH 1.49 (3H,
d, J¼6.5 Hz), 1.84 (3H, s), 1.92 (3H, s), 4.02 (3H, s), 4.97
(1H, q, J¼6.5 Hz); 13C NMR (100.6 MHz, CDCl3): dC 6.8,
9.1, 20.1, 55.4, 64.1, 99.4, 117.7, 158.2, 162.3, 181.4;
HRMS [(ES)+] calculated for C10H15O4 [MH+]: 199.0970,
found 199.0971.
Colourless oil; bp 188 ꢂC/766 mmHg [lit.,33 190 ꢂC/
1
750 mmHg]; nmax/cmꢁ1 (film) 1710s; H NMR (400 MHz,
CDCl3): dH 1.01 (6H, t, J¼7.0 Hz), 1.29 (3H, d, J¼7.0 Hz),
2.47 (4H, q, J¼7.0 Hz), 3.67 (1H, q, J¼7.0 Hz); 13C NMR
(100.6 MHz, CDCl3): dC 7.5, 12.7, 34.7, 60.0, 207.3.
4.1.5. ( )-Methanesulfonic acid 1-(6-methoxy-3,5-di-
methyl-4-oxo-4H-pyran-2-yl)ethyl ester (( )-34). Et3N
(1.13 mL, 8.11 mmol) was slowly added to a solution of
g-hydroxypyrone (ꢀ)-33 (1.00 g, 5.07 mmol) in DCM
(10 mL) at 0 ꢂC under argon. The solution was allowed to
stir for 2 min, followed by the slow dropwise addition of
methane sulfonyl chloride (0.87 g, 7.60 mmol). The reaction
mixture was allowed to stir for a further 30 min at 0 ꢂC, by
which time a white precipitate of Et3N$HCl had formed.
The reaction was then quenched by the addition of satd aq
NH4Cl (20 mL), and the mixture was extracted with DCM
(2ꢃ40 mL), followed by washing of the organic fraction
with brine (2ꢃ40 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give a yellow solid. The crude
residue was purified by flash silica gel chromatography
(4:1, 30–40 PE/EtOAc) to give the title compound as a white
solid (1.29 g, 4.67 mmol, 92%). Rf 0.50 (EtOAc); mp 100–
103 ꢂC; nmax/cmꢁ1 (KBr disc) 1672s, 1584s, 1349s, 1180s;
1H NMR (400 MHz, CDCl3): dH 1.72 (3H, d, J¼6.5 Hz),
1.84 (3H, s), 2.09 (3H, s), 2.99 (3H, s), 4.03 (3H, s), 5.86
(1H, q, J¼6.5 Hz); 13C NMR (100.6 MHz, CDCl3): dC 6.9,
9.5, 18.9, 38.9, 55.6, 72.9, 100.5, 120.7, 151.6, 162.2,
180.1; HRMS [(ES)+] calculated for C11H17O6S [MH+]:
277.0746, found 277.0750.
4.1.2. 6-Ethyl-4-hydroxy-3,5-dimethyl-2H-pyran-2-one
(31).21 Compound 31 was prepared according to the proce-
dure of Koester and Hoffmann.21 White powder; nmax/cmꢁ1
(KBr disc) 2975br, 1684s, 1552s; 1H NMR (400 MHz,
CDCl3): dH 1.16 (3H, t, J¼7.5 Hz), 1.95 (3H, s), 1.98 (3H, s),
2.51 (2H, q, J¼7.5 Hz); 13C NMR (100.6 MHz, CDCl3):
dC 8.6, 9.6, 11.6, 24.2, 98.3, 106.9, 159.9, 165.9, 166.9.
4.1.3. 2-Ethyl-6-methoxy-3,5-dimethyl-4H-pyran-4-one
(28) and 6-ethyl-4-methoxy-3,5-dimethyl-2H-pyran-2-
one (32).23 Compounds 28 and 32 were prepared according
to a modified route of Takano et al.23 A mixture of pyrone 31
(10.0 g, 59.5 mmol), dimethyl sulfate (15.0 g, 119.0 mmol)
and Li2CO3 (13.3 g, 180.0 mmol) in acetone (100 mL) was
heated to reflux for 48 h. After cooling, the reaction mixture
was diluted with Et2O (100 mL) and filtered through Cel-
iteÒ. The filtrate was concentrated under reduced pressure
and purified by flash silica gel chromatography (4:1, 30–
40 PE/EtOAc).
Elution first yielded a-pyrone 32 (4.54 g, 42%) as a yellow
oil. Rf 0.35 (4:1, 30–40 PE/EtOAc); nmax/cmꢁ1 (film) 1705s,
1573s, 1360m, 1067w; 1H NMR (400 MHz, CDCl3): dH 1.11
(3H, t, J¼7.5 Hz), 1.85 (3H, s), 1.93 (3H, s), 2.44 (2H, q,
J¼7.5 Hz), 3.73 (3H, s); 13C NMR (100.6 MHz, CDCl3):
dC 9.7, 10.0, 11.6, 24.2, 60.1, 108.5, 109.0, 160.0, 166.2,
168.4.
4.1.6. ( )-[1-(6-Methoxy-3,5-dimethyl-4-oxo-4H-pyran-
2-yl)-ethyl]phosphonic acid diethyl ester (( )-27). To
a stirred suspension of sodium hydride (155 mg of 60% dis-
persion in paraffin oil, 3.8 mmol) in DMF (1 mL) at 0 ꢂC
was slowly added diethyl phosphite (426 mL, 3.31 mmol).
The solution was allowed to stir for 30 min at 0 ꢂC, and
then for a further 30 min at 60 ꢂC. The solution was then
cooled in an ice bath to 0 ꢂC, followed by the cautious addi-
tion of a solution of mesylate (ꢀ)-34 (760 mg, 2.75 mmol) in
DMF (1 mL). The reaction mixture was warmed to rt and al-
lowed to stir overnight, then quenched by the addition of satd
aq NH4Cl (1 mL). The crude mixture was extracted with
EtOAc (2ꢃ5 mL), followed by washing of the organic frac-
tion with water (2ꢃ5 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give a yellow oil. The crude resi-
due was purified by flash silica gel chromatography (EtOAc)
to give the title compound as a pale yellow oil (738 mg,
84%). Rf 0.15 (EtOAc); nmax/cmꢁ1 (oil) 2984s, 1666s,
1600s; 1H NMR (400 MHz, CDCl3): dH 1.24 (3HA, t,
J¼7.0 Hz), 1.30 (3HB, t, J¼7.0 Hz), 1.54 (3H, dd, J¼18.0,
Further elution yielded g-pyrone 28 (5.95 g, 55%) as a white
crystalline solid. Rf 0.15 (4:1, 30–40 PE/EtOAc); mp 46–
47 ꢂC; nmax/cmꢁ1 (KBr disc) 1668s, 1592s, 1464m, 1175w;
1H NMR (400 MHz, CDCl3): dH 1.26 (3H, t, J¼7.5 Hz),
1.82 (3H, s), 1.91 (3H, s), 2.60 (2H, q, J¼7.5 Hz), 3.94
(3H, s); 13C NMR (100.6 Hz, CDCl3): dC 6.8, 9.7, 11.2,
24.1, 55.2, 99.2, 117.6, 159.1, 162.1, 181.1.
4.1.4. ( )-2-(1-Hydroxy-ethyl)-6-methoxy-3,5-dimethyl-
pyran-4-one (( )-33). To a solution of THF (30 mL) con-
taining g-pyrone 28 (3.00 g, 16.5 mmol) at ꢁ78 ꢂC under
an atmosphere of argon was slowly added LHMDS
(18.1 mL of a 1 M solution, 18.1 mmol) with stirring. The
solution changed from colourless to a bright red whilst
allowed to stir at ꢁ78 ꢂC for 30 min. A solution of Davis’s
reagent24 (5.17 g, 19.8 mmol) in THF (15 mL) was then
added cautiously to the pyrone anion, and allowed to stir
for a further 10 min. The reaction was then quenched by

R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
4507
7.0 Hz), 1.83 (3H, s), 1.96 (3H, br s), 3.41 (1H, dq, J¼23.5,
7.0 Hz), 3.99 (3H, s), 4.01–4.18 (4HAB, m); 13C NMR
(100.6 MHz, CDCl3): dC 6.8, 10.1, 11.9, 16.4, 34.9 (d,
J¼141.0 Hz), 55.5, 62.7 (CA), 63.4 (CB), 99.3, 119.9,
153.3, 162.1, 180.4; HRMS [(ES)+] calculated for
C14H24O6P [MH+]: 319.1311, found 319.1314.
by flash silica gel chromatography (9:1, 30–40 PE/EtOAc)
to give the title compound as a white solid (143 mg,
0.39 mmol, 39%) [E:Z>6:1]. Rf 0.50 (1:1, 30–40 PE/EtOAc);
mp 88–91 ꢂC; nmax/cmꢁ1 (KBr disc) 1654s, 1589s, 1464s,
1
1325m, 1255m, 1169w; H NMR (500 MHz, CDCl3): dH
1.88 (3H, s), 1.99 (3H, br d, J¼1.5 Hz), 2.08 (3H, br s), 2.12
(3H, s), 3.98 (3H, s), 6.17 (1H, br s), 6.26 (1H, q, J¼1.5 Hz);
13C NMR (100.6 MHz, CDCl3): dC 7.3, 12.5, 16.8, 24.6,
55.8, 80.2, 99.8, 118.9, 130.8, 137.1, 143.7, 157.8, 162.3,
181.6; HRMS [(ES)+] calculated for C14H18IO3 [MH+]:
361.0301, found 361.0308.
4.1.7. Cyercene A (1).3 To a solution of DMF (1 mL) con-
taining phosphono-pyrone (ꢀ)-27 (35.0 mg, 0.11 mmol) at
ꢁ78 ꢂC was added LHMDS (120 mL of a 1 M solution in
THF, 0.12 mmol). The solution was allowed to stir for
10 min, by which time the solution had attained a bright yel-
low colour, followed by the dropwise addition of aldehyde
26 (10.7 mg, 12 mL, 0.11 mmol). The mixture was allowed
to warm to rt over 1 h, then quenched by the addition of
satd aq NH4Cl (1 mL). The crude mixture was extracted
with EtOAc (2ꢃ5 mL), followed by washing of the organic
fraction with water (2ꢃ5 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give a yellow oil. The crude resi-
due was purified by flash silica gel chromatography (4:1, 30–
40 PE/EtOAc) to give the title compound as a colourless oil
(25.0 mg, 0.095 mmol, 87%). All spectral data were identi-
cal in all respects to the natural material.3 nmax/cmꢁ1 (oil)
1650s, 1605s, 1585s; 1H NMR (500 MHz, CDCl3): dH
1.04 (3H, t, J¼7.5 Hz), 1.84 (3H, br s), 1.87 (3H, br s),
2.01 (3H, br s), 2.04 (3H, br s), 2.16 (2H, m), 3.96 (3H, s),
5.53 (1H, br t, J¼7.0 Hz), 6.11 (1H, s); 13C NMR
(125.7 MHz, CDCl3): dC 6.8, 11.8, 13.7, 16.0, 16.2, 21.4,
55.1, 99.2, 117.6, 125.5, 130.8, 135.8, 139.4, 159.1, 161.8,
181.5; HRMS [(ES)+] calculated for C16H23O3 [MH+]:
263.1647, found 263.1651.
4.1.11. 1,1-Dibromo-3-methylhexa-1,3-diene (40).26
Compound 40 was prepared according to the procedure of
Paterson and Perkins.26 nmax/cmꢁ1 (KBr disc) 1716s, 1643s;
1H NMR (400 MHz, CDCl3): dH 1.02 (3H, t, J¼7.5 Hz),
1.87 (3H, s), 2.09 (2H, qd, J¼7.5, 7.5 Hz), 5.63 (1H, t,
J¼7.5 Hz), 6.94 (1H, s); 13C NMR (62.9 MHz, CDCl3): dC
13.5, 15.2, 21.4, 85.3, 131.0, 137.6, 140.9.
4.1.12. (E)-4-Methylhept-4-en-2-yne (41).26 Compound 41
was prepared according to the procedure of Paterson and
Perkins.26 nmax/cmꢁ1 (film) 2970m, 2935m, 2252m; 1H
NMR (500 MHz, CDCl3): dH 0.95 (3H, t, J¼7.5 Hz), 1.73
(3H, d, J¼0.5 Hz), 1.92 (3H, s), 2.05 (2H, qd, J¼7.5,
7.5 Hz), 5.73 (1H, br t, J¼7.5 Hz); 13C NMR (100.6 MHz,
CDCl3): dC 3.9, 13.4, 17.0, 21.4, 81.5, 82.6, 117.3, 138.1.
4.1.13. 2-(1,3-Dimethylhexa-1,3-dienyl)benzo[1,2,3]di-
oxaborole (35).26 Compound 35 was prepared according
to a modified procedure of Paterson and Perkins.26 In a dry
Schlenk tube was placed alkyne 41 (500 mg, 4.63 mmol)
and freshly distilled catecholborane (555 mg, 4.63 mmol).
The mixture was heated at 90 ꢂC for 4 h, then cooled to rt.
The resulting yellow oil needed no further purification
(1.06 g, >99%). nmax/cmꢁ1 (oil) 2965s, 1595s, 1474m,
1411s; 1H NMR (500 MHz, CDCl3): dH 1.04 (3H, t,
J¼7.5 Hz), 1.96 (3H, s), 2.10 (3H, s), 2.24 (2H, qd, J¼7.5,
7.0 Hz), 5.70 (1H, t, J¼7.0 Hz), 7.08–7.17 (3H, m), 7.24
(2H, m); 13C NMR (125.7 MHz, CDCl3): dC 13.7, 15.2, 16.2,
21.5, 95.7, 112.2, 122.3, 132.9, 137.4, 148.5, 149.6; HRMS
[(CI)+] calculated for C14H18 11BO2 [MH+]: 229.1399,
found 229.1389.
4.1.8. (Z)-3-Iodo-2-methylprop-2-en-1-ol (39).28 Com-
ꢀ
pound 39 was prepared according to the procedure of Henaff
and Whiting.28 nmax/cmꢁ1 (oil) 3300br, 3010s, 2980s, 1600s,
1050m; 1H NMR (200 MHz, CDCl3): dH 1.92 (3H, d,
J¼1.5 Hz), 4.20 (2H, s), 5.95 (1H, q, J¼1.5 Hz); 13C
NMR (125.7 MHz, CDCl3): dC 21.6, 66.8, 74.9, 146.6.
4.1.9. (Z)-3-Iodo-2-methylprop-2-enal (37).28,34 The title
compound was prepared according to a procedure of Porco
et al.34 as unstable yellow crystals, which were conserved
in the dark at ꢁ20 ꢂC, and used in the next step without fur-
1
ther purification; nmax/cmꢁ1 (NaCl plate) 2940s, 1680s; H
4.1.14. ( )-9,10-Deoxytridachione (( )-2)4 and ocellapyr-
one A (( )-10).8 In a dry Schlenk tube, vinyl-iodide 36
(207 mg, 0.57 mmol) and tetrakis(triphenylphospine) palla-
dium(0) (33 mg, 5 mol %) were stirred for 10 min in the
dark, at 20 ꢂC in THF (2 mL). To the reaction mixture was
then added borane 35 (154 mg, 0.67 mmol) in THF (1 mL)
via cannula, and the reaction heated at 80 ꢂC under argon.
After 5 min, KOH aq (1.2 mL, 1M) was added. The reaction
was stirred for 2 h at 80 ꢂC, cooled to rt, and extracted with
diethyl ether (3ꢃ50 mL). The combined organic layers were
washed with brine (2ꢃ50 mL), dried over magnesium sul-
fate, then concentrated under reduced pressure to give
a brown oil. The oil was quickly subjected to chromato-
graphy over florisilÒ, to remove the catalyst mixture, which
gave crude tetraene 22 as the major product (130 mg, 66%).
Compound 22 (for which the 1H NMR displays four new al-
kenyl signals in the NMR spectra [dH (CDCl3) 5.32–5.41 (br
m), 5.85 (br s), 5.98 (br s), 6.42 (br s)] characteristic of a con-
jugated tetraene), was taken immediately in a sealed tube,
NMR (200 MHz, CDCl3): dH 2.52 (3H, d, J¼1.5 Hz), 7.24
(1H, q, J¼1.5 Hz), 9.26 (1H, s).
4.1.10. 2-(4-Iodo-1,3-dimethylbuta-1,3-dienyl)-6-me-
thoxy-3,5-dimethylpyran-4-one (36). To a dry flask con-
taining a magnetic stirrer bar were added pyrone (ꢀ)-27
(320 mg, 1.01 mmol) and dry THF (2 mL). The flask was
purged with argon, and cooled to ꢁ78 ꢂC, followed by the
addition of a solution of LHMDS (1.10 mL of a 1 M THF
solution, 1.10 mmol). The mixture was allowed to stir for
30 min by which time the solution became bright red. A so-
lution of aldehyde 37 (290 mg, 1.48 mmol) in THF (2 mL)
was added and the reaction allowed to warm to rt over the
course of 1 h. The reaction was quenched by the addition
of brine (5 mL), and extracted with EtOAc (2ꢃ10 mL).
The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure
to give a crude brown solid. The crude residue was purified

4508
R. Rodriguez et al. / Tetrahedron 63 (2007) 4500–4509
and heated in benzene (2 mL) at 120 ꢂC under argon for 1 h
in the dark. After evaporation of the solvent under reduced
pressure, the brown oil obtained was purified by silica gel
(preparative TLC; 90:10, 30–40 PE/EtOAc) to afford a
mixture of compounds (60 mg), including the title com-
pounds (ꢀ)-2 and (ꢀ)-10 (by 1H NMR).30 Following separa-
tion of the isomers by reverse phase C-18 HPLC [CH3CN/
H2O, 6:4] both compounds ((ꢀ)-2, 31% and (ꢀ)-10, 15%)
were fully characterised by NMR and mass spectrometry.
All spectral data recorded were identical in all respects
to the natural material for both compounds (ꢀ)-24 and
(ꢀ)-10.8
5. (a) Gavanin, M.; Mollo, E.; Cimino, G.; Ortea, J. Tetrahedron
Lett. 1996, 37, 4259–4262; (b) Jeffery, D. W.; Perkins, M. V.;
White, J. M. Org. Lett. 2005, 7, 1581–1584.
6. Ireland, C.; Scheuer, P. J. Science 1979, 205, 922–923.
7. Moses, J. E.; Adlington, R. M.; Rodriguez, R.; Eade, S. J.;
Baldwin, J. E. Chem. Commun. 2005, 1687–1689.
8. Manzo, E.; Ciavatta, M. L.; Gavagnin, M.; Mollo, E.;
Wahidulla, S.; Cimino, G. Tetrahedron Lett. 2005, 46, 465–
468.
9. Miller, A. K.; Trauner, D. Angew. Chem., Int. Ed. 2005, 44,
4602–4606.
10. Ireland, C.; Faulkner, D. J.; Solheim, B. A.; Clardy, J. J. Am.
Chem. Soc. 1978, 100, 1002–1003.
For (ꢀ)-2: Rf 0.60 (3:1, 30–40 PE/EtOAc); nmax/cmꢁ1 (film)
2960s, 2929s, 2873m, 2859m, 1729s, 1662m, 1616m,
1599w, 1462m, 1404w, 1378w, 1274m, 1166w, 1123w,
11. Fu, X.; Hong, E. P.; Schmitz, F. J. Tetrahedron 2000, 56, 8989–
8993.
12. Ksebati, M. B.; Schmitz, F. J. J. Org. Chem. 1985, 50, 5637–
5642.
1
1072m, 1040m, 984w; H NMR (500 MHz, CDCl3): dH
ꢀ
ꢀ
13. Cueto, M.; D’CroZ, L.; Mate, J. L.; San-Martın, A.; Darias, J.
0.71 (3H, t, J¼7.5 Hz), 1.33 (3H, s), 1.44 (3H, s), 1.73
(3H, s), 1.74–1.80 (2H, m), 1.79 (3H, d, J¼1.5 Hz), 1.83
(3H, s), 2.06 (3H, s), 2.72 (1H, s), 3.99 (3H, s), 5.06 (1H,
t, J¼7.0 Hz), 5.59 (1H, s), 5.68 (1H, s); 13C NMR
(125.6 MHz, CDCl3): dC 6.8, 12.2, 13.7, 14.1, 21.0, 21.5,
22.3, 26.8, 47.5, 55.3, 59.4, 98.6, 119.9, 122.3, 124.2,
127.7, 130.8, 132.0, 134.8, 161.0, 161.6, 181.1; HRMS
[(ESI)+] calculated for C22H31O3 [MH+]: 343.2268, found
343.2268.
Org. Lett. 2005, 7, 415–418.
14. Kakinuma, K.; Hanson, C. A.; Rinehart, K. L., Jr. Tetrahedron
1976, 32, 217–222.
15. (a) Kurosawa, K.; Takahashi, K.; Tsuda, E. J. Antibiot. 2001,
54, 541–547; (b) Takahashi, K.; Tsuda, E.; Kurosawa, K.
J. Antibiot. 2001, 54, 548–553.
16. Zuidema, D. R.; Miller, A. K.; Trauner, D.; Jones, P. B. Org.
Lett. 2005, 7, 4959–4962.
17. (a) Br€uckner, S.; Baldwin, J. E.; Adlington, R. M.; Claridge,
T. D. W.; Odell, B. Tetrahedron 2004, 60, 2785–2788; (b)
Moses, J. E.; Baldwin, J. E.; Adlington, R. M.; Cowley,
A. R.; Marquez, R. Tetrahedron Lett. 2003, 44, 6625–6627;
(c) Br€uckner, S.; Baldwin, J. E.; Moses, J.; Adlington, R. M.;
Cowley, A. R. Tetrahedron Lett. 2003, 44, 7471–7473; (d)
For compound (ꢀ)-10: Rf 0.55 (3:1, 30–40 PE/EtOAc); nmax
/
cmꢁ1 (film) 2959m, 2929m, 2874w, 2857w, 1728w, 1661s,
1616s, 1459m, 1405m, 1375m, 1317m, 1290m, 1246m,
1168m, 1129w, 1036w; H NMR (500 MHz, CDCl3): dH
1
0.89 (3H, t, J¼7.5 Hz), 1.15 (3H, s), 1.25 (3H, s), 1.55–
1.61 (1H, m), 1.70–1.81 (1H, m), 1.74 (3H, d, J¼1.5 Hz),
1.77 (3H, s), 1.88 (3H, s), 1.97 (3H, s), 2.41 (1H, dd, J¼
11.5, 3.0 Hz), 3.12 (1H, s), 4.01 (3H, s), 5.07 (1H, s), 5.62
(1H, s); 13C NMR (125.6 MHz, CDCl3): dC 7.2, 9.8, 13.3,
15.5, 18.9, 22.2, 23.5, 32.5, 38.1, 47.3, 49.2, 57.2, 57.3,
100.6, 116.7, 122.9, 125.4, 129.9, 130.2, 162.2, 164.9,
182.0; HRMS [(ES)+] calculated for C22H31O3 [(MH)+]:
343.2268, found 343.2266.
€
Moses, J. E.; Baldwin, J. E.; Bruckner, S.; Eade, S. J.;
Adlington, R. M. Org. Biomol. Chem. 2003, 1, 3670–3684;
(e) Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington,
R. M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5, 661–
663; (f) Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington,
R. M.; Cowley, A. R. Org. Lett. 2002, 4, 3731–3734.
18. For a recent review, see: Moses, J. E.; Adlington, R. M. Chem.
Commun. 2005, 5945–5952.
19. For recent examples, see: (a) Jacobsen, M. F.; Moses, J. E.;
Adlington, R. M.; Baldwin, J. E. Tetrahedron 2006, 62,
1675–1689; (b) Rodriguez, R.; Moses, J. E.; Adlington,
R. M.; Baldwin, J. E. Org. Biomol. Chem. 2005, 3, 3488–
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Acknowledgements
We thank Lilly Research Center, Erl Wood Manor, Windle-
sham for their assistance in purification and characterisation
of compounds (ꢀ)-2 and (ꢀ)-10. We would also like to thank
ꢀ
€
Dr. Sebastien Bruckner, Dr. Tim Claridge and Dr. Babara
Odell for helpful discussions. Thanks to the EPSRC for
funding J.E.M.
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