Total synthesis of the epoxyquinol dimer (+)-panepophenanthrin: application of a diastereospecific biomimetic Diels-Alder dimerisation

Article abstract of DOI:10.1016/j.tet.2006.08.010

An asymmetric total synthesis of the novel and structurally complex epoxyquinol natural product (+)-panepophenanthrin has been accomplished, in which a biomimetic Diels-Alder dimerisation is a key step. The key monomeric precursor was assembled by an effi

Full text of DOI:10.1016/j.tet.2006.08.010

Tetrahedron 62 (2006) 9892–9901
Total synthesis of the epoxyquinol dimer (D)-panepophenanthrin:
application of a diastereospecific biomimetic Diels–Alder
dimerisation
a,y
a
a, ,z
a
Robert M. Adlington, Jack E. Baldwin,
a
*
Laurent Comm ꢀe iras, John E. Moses,
Andrew R. Cowley, Christopher M. Baker, Birgit Albrecht and Guy H. Grant
b,x
b
b,x
a
The Chemistry Research Laboratory, University of Oxford, OX1 3TA, UK
Department of Chemistry, Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ, UK
b
Received 23 June 2006; accepted 3 August 2006
Available online 1 September 2006
Abstract—An asymmetric total synthesis of the novel and structurally complex epoxyquinol natural product (+)-panepophenanthrin has been
accomplished, in which a biomimetic Diels–Alder dimerisation is a key step. The key monomeric precursor was assembled by an efficient
Stille cross coupling of two readily available building blocks that upon standing underwent a diastereospecific dimerisation cascade in excel-
lent yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
terrestrial and marine systems as phylogenetically diverse
as fungi, bacteria and worms. The degree of structural com-
plexity displayed by this family ranges from the lower order
epoxyquinols, including (+)-epiepoformin (2), (+)-isoepoxy-
In 2002 Sekizawa et al. reported the isolation of (+)-panepo-
phenanthrin (1), from the culture broth of the mushroom
strain Panus rudis IF08994. Until the recent isolation of
Himeic acid A, by Tsukamoto et al. in 2005 from Aspergillus
sp., (+)-(1) was the only known natural product inhibitor of
the ubiquitin activating enzyme E1. The fascinating molec-
ular architecture assigned to (+)-1 was fully elucidated by
complementary spectroscopic and X-ray crystallographic
techniques, revealing a complex, densely functionalised
core consisting of a highly oxygenated tricyclic ABC ring
system, containing 11 contiguous stereocentres and a trans-
fused lactol functionality (Fig. 1). Although (+)-1 displayed
no significant inhibitory effect in whole cells, the in vitro
activity alone make 1 a promising tool for investigating
ubiquitin functions linked to serious disease and serve as
1
5
don (3) and (+)-bromoxone (4) and its acetylated derivative
(+)-5. Increasing in structural complexity belong the natu-
6
2
ral products (ꢀ)-jesterone (6), a biologically active antifun-
3
7
gal isolated from Panus jesteri, and (ꢀ)-manumycin A (7),
8
isolated from Streptomyces sp., and identified as a novel
Ras farnesyltransferase inhibitor. Structurally higher order
9
members of the epoxyquinoid family include (+)-torreyanic
acid (8), a metabolite isolated from the endophytic fungus
1
0
Pestalotiopsis microspora, and epoxyquinols (+)-A (9)
and (+)-B (10), metabolites isolated from an uncharacterised
1
1
fungus (Fig. 1). Biosynthetically, compounds 8, 9 and 10
are believed to arise from Diels–Alder pseudo-dimerisation
pathways of monomeric epoxyquinol units. Experimental
evidence to support the proposed biosynthetic dimerisations
has been provided through several elegant synthetic stud-
4
a platform for future drug development.
1
2,13
Structurally, (+)-1 belongs to a family of related epoxy-
quinoid natural products, which have been isolated from
ies.
Related prenylated epoxyquinols are also known,
including enantiomers (+)-harveynone (11) and (ꢀ)-harvey-
1
4
none (12), isolated from Pestalotiopsis thea and Curvu-
laria harveyi, respectively.
1
5
Keywords: Total synthesis; Biomimetic synthesis; Stille coupling; Dimer-
isation cascade; Epoxyquinol; Ubiquitin activating enzyme E1.
1
6
In a previous report, we described a highly efficient syn-
thesis of racemic (ꢁ)-panepophenanthrin (1), demonstrating
the feasibility of a key biomimetic Diels–Alder dimerisation
cascade. Herein, we report a full account of our studies on
the total synthesis of (+)-1 and provide a discussion sup-
ported by molecular modelling to explain the mechanisms
controlling the biomimetic reaction.
*
Corresponding author. Tel.: +44 20 7753 5804; fax: +44 20 7753 5935;
e-mail: john.moses@pharmacy.ac.uk
Present address: UMR-CNRS 6178 Symbio, ꢀe quipe SVO, Universit ꢀe Paul
C ꢀe zanne (Aix-Marseille III), Marseille cedex 20, France.
Present address: The School of Pharmacy, University of London, WC1N
y
z
x
1AX, UK.
Present address: Unilever Centre for Molecular Informatics, The Univer-
sity Chemical Laboratory, Cambridge CB2 1EW, UK.
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.010

L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
9893
OH
4
1
15
13
11
12
17
16
5
O
OH
3
O
O
OH
O
5
a
1
0c
6
a
3a
C
Br
B
10b
10a
X
HO
O
6
7
O
O
O
O
2
1
H
H
A
8
OH
1
9
0
OX
OH
OH
X = CH , (+)-Epiepoformin (2)
O
3
2
X = H, (+)-Bromoxone (4)
X = CH OH, (+)-Isoepoxydon (3) X = Ac, (5)
(
+)-Panepophenanthrin (1)
(–)-Jesterone (6)
O
H
N
nBu
2
O
HO C
O
2
O
O
O
HO
OH
O
HO
O
O
H
nBu
3
O
O
O
O
HO C
2
CH3
OH
O
H
HN
O
H
O
O
CH3
O
H
O
Bun
(
–)-Manumycin A (7)
(+)-Torreyanic acid (8)
(+)-Epoxyquinol A (9)
O
HO
O
OH
O
O
O
O
O
O
O
CH3
H
OH
CH3
O
OH
(–)-Harveynone (12)
(+)-Harveynone (11)
(+)-Epoxyquinol B (10)
Figure 1. Members of the epoxyquinoid family of natural products.
1
.1. Synthetic plan
products, which include the afore mentioned compounds
1 and 12 (Fig. 1). Biosynthetically, monomer 15 can
1
As part of our ongoing studies towards the biomimetic syn-
thesis of complex natural products, we became interested in
be thought of as arising through a biochemical reduction
of epoxyquinone 16, itself derived from a facially selective
enzyme catalysed epoxidation of prenylated hydroxyqui-
(
+)-1 for its unique molecular architecture and biological
2
0
profile. Our biomimetic-retrosynthesis towards the target
compound is depicted in Scheme 1. Dimer (+)-1 was thought
as arising through an unusual exo-[4+2] Diels–Alder cyclo-
addition of two monomeric counterparts 15 (the carbonyl
group of the dienophile is used to define exo/endo).
none 18, through intermediate 17. Compound 18, itself
having been isolated along with its oxidised counterpart 21
2
1
from the fungus Acremoniu, may arise from the coupling
of 4-hydroxybenzoate (19) and DMAPP (dimethylallyl
pyrophosphate) (20).
A key assumption in this biomimetic approach was that the
molecular framework of 1 arises in nature, through an intrin-
Monomer 15 had been reported by Wood and co-workers, as
an undesirable side product isolated during their synthetic
studies towards (+)-panepoxydone (22). Compound 15 was
formed through an acid catalysed rearrangement, during
the attempted desilylation of TBS-protected panepoxydone
1
7
sically favourable chemical pathway. Thus, if monomer 15
could be realised, then a ‘pre-disposed’ dimerisation might
proceed unaided to yield the target dimer. Thus, (+)-1 may
be thought of having occurred through hemiketal formation
of the corresponding hydroxy ketone dimer 14. It is known
that epoxyquinoid derivatives form both hydrates and hemi-
ketals by reaction of water and alcohols with the electro-
2
2
(23) (Scheme 2). However, no comment regarding the sta-
bility of 15 or any noted dimerisation/decomposition path-
ways was reported. Interestingly, both (+)-1 and (+)-22
1
23
have been isolated from the common producing fungal
species P. rudis indicating a probable common biosynthetic
pathway.
1
8
philic carbonyl group. The open-form precursor of 14
may be derived from an exo-Diels–Alder dimerisation of
the epoxyquinol monomer 15. Alternatively, hemiketal
1
9
formation followed by Diels–Alder cycloaddition was
considered as another possibility. The endo-Diels–Alder
is thought to be disfavoured due to steric factors.
Synthetic approaches towards such prenylated epoxyqui-
noids often involve late stage pseudo-prenylation of a fully
elaborated epoxyquinoid nucleus. For example, Taylor
et al. have reported an efficient synthesis of racemic harvey-
none, employing a palladium/copper catalysed coupling of
1
6
The complexity of the primary synthetic target, although re-
duced to that of the lower order epoxyquinol monomer 15,
itself posed a relatively complex challenge. Compound 15
belongs to the prenylated epoxyquinol family of natural
2
4
an alkynylstannane and fully elaborated epoxyiodoenone.
Attracted by this logical strategy, and based upon analogous
2
5–27
studies,
we chose to adopt a Stille cross coupling

9894
L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
OH
Hemiketal
HO
OH
O
O
O
OH
OH
O
O
exo-Diels-Alder
H
2 x O
O
H
OH
O
O
HH
OHHO
OH
OH
O
(1)
(14)
(15)
OH
O
OH
OH
OH
OH
O
O
OH
O
O
OH
(18)
(17)
(16)
CO2-
O
OH
+
OPP
(21)
OH
O
(19)
(20)
Scheme 1. Proposed biosynthesis of (+)-panepophenanthrin (1).
O
validity of the proposed dimerisation. A previously reported
synthesis of 4 by Altenbach et al. was conveniently chosen,
OH
3
0
O
since this was amenable to large scale production. The
synthesis began with the bromination of p-benzoquinone
to (ꢁ)-bromoquinone (25) in near quantitative yield,
(
15)
20%
O
OTBS
i
OH
O
OH
followed by reduction with NaBH to (ꢁ)-diol (26) as the
O
4
ii
only isolated diastereoisomer. Internal substitution (S i) of
N
O
OTBS
23)
a single bromo group gave (ꢁ)-epoxide (27), followed by
(
(+)-(22) 77%
directed epoxidation with m-CPBA to give (ꢁ)-bis-epoxide
OH
(
28). The synthesis was completed upon oxidation with
DMP and subsequent basic workup to give (ꢁ)-bromoxone
4) in good overall yield (Scheme 4). Synthesis of the corre-
sponding vinylstannane fragment 24 was achieved following
e et al. with efficient hydrostannation
Scheme 2. (i) H
2
SiF ; (ii) TREAT/HF.
6
(
the protocol of Guib
ꢀ
approach towards 15. Thus, further retrosynthetic planning
led us to the known building blocks (ꢀ)-bromoxone 4
2
8
of commercially available 2-methylbut-3-yn-1-ol with
Bu SnH and a catalytic quantity of PdCl (PPh ) in
3 2 3 2
2
9
n
and vinylstannane 24, as suitable coupling partners
Scheme 3).
2
9
(
THF. This afforded the desired (E)-vinylstannane (24) in
good yield and as the only observed diastereoisomer
(
Scheme 4).
Cross coupling
OH
O
O
OH
Our initial attempt at the Stille cross coupling of (ꢁ)-4 and
vinylstannane 24 was performed using 7 mol % of Pd dba
and 22 mol % of AsPh in toluene at 110 C. The reaction
3
Br
+
2
3
O
+
O
ꢂ
Bu Sn
3
was monitored by TLC analysis, which indicated rapid con-
sumption of the (ꢁ)-bromoxone (4) starting material and
formation of several new products. Purification of the crude
reaction mixture by flash silica gel chromatography yielded
a small quantity (6%) of the desired epoxyquinol monomer
OH
OH
(–)-(4)
(
15)
(24)
Scheme 3. Retrosynthetic analysis of epoxyquinol monomer 15.
(
ꢁ)-15, along with approximately 10% of the reduced side
2
. Results and discussion
product (ꢁ)-29 (Scheme 5). Upon standing at room temper-
ature overnight, monomer (ꢁ)-15 was completely trans-
formed into racemic (ꢁ)-panepophenanthrin (1) as the
only observable product. The spontaneous conversion of
(ꢁ)-15 into target (ꢁ)-panepophenanthrin (1) provided solid
evidence to support our biosynthetic proposal and completed
2
.1. Feasibility study for exo-Diels–Alder dimerisation
Racemic bromoxone (ꢁ)-(4) was chosen in order to inves-
tigate optimum coupling conditions and to evaluate the

L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
9895
O
O
O
O
OH
OH
Br
Br
Br
Br
Br
i
ii
iii
84%
9
8%
85%
O
OH
OH
vi
5%
(
±)-(27)
(
±)-(25)
(±)-(26)
OH
6
Bu Sn
3
O
O
(24)
OH
Br
Br
O
Br
iv
v(a)
v(b)
O
O
O
6
2%
77%
O
OH
(±)-(28)
(±)-(4)
ꢂ ꢂ
3 4 2 2
, CHCl , 0 C; (ii) NaBH (aq), Et O, 0 C; (iii) LiOH, Et O/MeOH (3:1); (iv) m-CPBA,
Scheme 4. Synthesis of (ꢁ)-bromoxone 4 and vinylstannane 24: (i) Br
2
ꢂ
ꢂ
CH
2
Cl , 0 C; (v) (a) DMP, CH
2
Cl
2 2
, 0 C, (b) NaHCO , Na
3
2
S
2
O
3
, rt; (vi) 2 mol % PdCl
2
(PPh
3
)
2
, Bu
3
SnH, THF, rt.
OH
O
O
OH
ii
OH
O
>
99%
O
H
O
OH
O
H
OH
OH
OH
Br
(±)-(15), 6%
i
O
+
O
+
(
±)-(1)
Bu Sn
3
O
OH
HB
OH
HA
ii
(
±)-(4)
(24)
No dimerisation
HO
H
H
H
1
1
OH
H- H COSY
(±)-(29), 10%
ꢂ
2 3 3
Scheme 5. (i) Pd dba (7 mol %), AsPh (22 mol %), 1 h, 110 C, toluene; (ii) neat, rt, overnight.
the target synthesis, albeit in low overall yield (Scheme 5).
Although such complexity generating cascade reactions
of the TES-protected bromoxone (ꢁ)-30 with vinylstannane
24 proved successful, furnishing the TES-protected mono-
mer (ꢁ)-31 along with a small quantity of TES-
protected dimer (ꢁ)-32, in a combined yield of 75%. As
with the unprotected monomer, compound (ꢁ)-31 dimerised
completely upon standing to yield (ꢁ)-32 as a single
diastereoisomer. Smooth deprotection of silyl protected
1
7
are often a signature of biomimetic strategies, the remark-
able diasterospecific nature of the dimerisation cascade was
1
2c
somewhat unexpected. Improved yields in coupling reac-
tions with protected epoxyquinols had been reported, thus
offering a potential solution towards monomer synthesis
2
6
1
strate, since desilylation could be facilitated under mild
5. Triethyl silane (ꢁ)-30 was chosen as a suitable sub-
(ꢁ)-32 by NH F in methanol cleanly generated racemic
4
(ꢁ)-1 in good yield (85%) (Scheme 6). The remarkable
diastereospecificity observed in the reaction sequence re-
sulted from an exclusive homochiral dimerisation process.
The absence of any observable diastereoisomeric products
was suprising and indicative of some important stereochem-
ical control elements in the reaction cascade.
3
1
conditions, without detriment to the sensitive epoxyquinol.
Compound (ꢁ)-30 was obtained in 93% yield by action of
ꢂ
chlorotriethylsilane and 2,6-lutidine in CH Cl at 0 C,
2
2
followed by purification of the delicate substrate by flash-
Florisil mediated chromatography. Gratifyingly, coupling
iii
OH
CH3
H3C
H
H3C
H C
H
O
O
3
O
OH
OH
H
OH
Br
H
ii
O
+
O
+
H
O
7
5%
O
Bu3Sn
Observed
H
H
NOE's
OX
OTES
OX
OX
O
H
X = H, (±)-(4)
(24)
(±)-(31)
X = TES, (±)-(32)
X = H, (±)-(1)
i
93%
iv. 85%
X = TES, (±)-(30)
ꢂ
ꢂ
Scheme 6. (i) SiEt
3
Cl, 2,6-lutidine, CH
Cl
2 2
, 0 C; (ii) 10 mol % Pd
2
dba
3
, 30 mol % AsPh
3
, toluene, 110 C, 1 h; (iii) neat, rt, overnight; (iv) NH
4
F, MeOH, rt.

9896
L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
2
.2. Asymmetric synthesis of (D)-panepophenanthrin (1)
Our racemic synthesis was shortly complemented by an
asymmetric synthesis of (+)-1 by Porco et al. and more re-
cently by Mehta et al.
3
2
3
3
From the outset of our studies, we had appreciated that enan-
tiomerically pure bromoxone (ꢀ)-(4) was readily accessible,
prepared in an analogous manner to the racemic counterpart
with the addition of a kinetic resolution of (ꢁ)-diacetate
Figure 2. Stereo-representation of the crystal structure of synthetic (+)-pan-
epophenanthrin (1).
30
3
3. Thus, upon enzyme catalysed hydrolysis of (ꢁ)-33
by pig pancreas lipase (PPL), (+)-diacetate 33 and (+)-diol
6 were recovered, after recrystallisation in 35% yield
>99% ee (by HPLC)] and 39% yield [>99% ee (by
HPLC)], respectively. Furnishing the total synthesis of
+)-1 with enantiomerically pure building blocks yielded
.73 g of the target compound (Scheme 7). All spectral
was reasoned that such reversible tethering would result in
a highly organised transition state favouring homochiral
dimerisation (Scheme 8, Path A). An alternative suggested
2
[
3
2,33
mechanism
involves normal mode Diels–Alder cyclo-
(
addition to give intermediate 14, followed by subsequent
ring closure to form the five-membered ring hemiketal lead-
ing to (+)-(1) (Scheme 8, Path B). The latter pathway is
supported by dimerisation studies with monomers lacking
1
1
13
25
D
data ( H and C NMR) and specific rotation ([a] +146.0
(
1
26
c 1.0, MeOH), lit. [a]D +149.8 (c 1.0, MeOH)) for syn-
3
2
thetic (+)-1 were found to be in good agreement with natu-
rally occurring (+)-1. Furthermore, slow crystallisation of
compound (+)-1 from a mixture of dichloromethane and
methanol (1:1) resulted in the X-ray crystal structure, thus
tertiary hydroxyl residues.
The dimerisation cascade was also found to be sensitive to
the stereochemistry of the peripheral functional groups.
For example, the presence of the TES-protecting group
attached to the hydroxyl moiety of the epoxyquinoid nucleus
had no influence on the dimerisation process. This was
further demonstrated by synthesising the bulky TBS-
protected analogue (ꢁ)-35, which underwent dimerisation
in an identical diastereospecific fashion to yield (ꢁ)-36
(Scheme 9).
3
4
corroborating our success (Fig. 2).
The pre-disposed nature of the dimerisation sequence
enabled the formation of an extremely complex structure
from relatively simple building blocks. Moreover, the
observed diastereospecificity of the reaction indicated that
there were some very important stereocontrol elements in-
herent in the process. Intrigued by these results, we sought
to develop a greater understanding of the dynamics of the
dimerisation cascade.
These observations ruled out any hydrogen bonding effects,
which may have arisen from the free secondary hydroxyl. On
the other hand, it had been demonstrated that the relative
stereochemistry of the secondary hydroxyl group to be a very
Our initial rationalisation for the dimerisation evolved
because it provided an explanation for the high degree of
diastereospecificity observed in the racemic synthesis. Orig-
inally, we had considered that initial, reversible hemiketal
formation between two monomer units to give complex
3
2
important factor in the dimerisation process. Preparation
of the related syn-epoxyquinol monomer 37 yielded no
dimerisation product under the same conditions as those
applied to the corresponding anti-isomer. The epoxide motif
itself was also found to be essential for dimerisation, since
reduced diol side product 29 did not undergo any observable
34, followed by an intramolecular inverse electron demand
Diels–Alder reaction may lead to compound (+)-1. It
1
6
OAc
OAc
OH
OH
OH
O
Br
Br
Br
Br
Br
Br
Br
Br
Br
i
ii
2%
iii
85%
iv
+
O
O
7
55%
O
O
OAc
OAc
OH
OH
(
±)-(33)
(+)-(33), 35% (+)-(26), 39%
(+)-(27)
(+)-(28)
(–)-bromoxone (4)
90%
e.e. > 99%
e.e. > 99%
vii
99%
OH
OH
v
OH
OH
>
O
O
O
O
OH
Br
vi
92%
viii
9%
O
H
O
O
+
O
H
H
O
8
O
H
OTES
OH
OH
OTES
OTES
O
OTES
O
(
+)-Panepophenanthrin (1)
(+)-(32)
(31)
(–)-(30)
Cl
ꢂ
ꢂ
Scheme 7. (i) Pig pancreas lipase, pH 7.0 phosphate buffer, 3 days, rt; (ii) LiOH, Et
ꢂ
2
O/MeOH (3:1), 0 C to rt; (iii) m-CPBA, CH
2
2
, 0 C; (iv) (a) DMP,
ꢂ
ꢂ
CH
2
Cl
2
, 0 C, (b) NaHCO
rt, overnight; (viii) NH
3
, Na
2
S
2
O
F, MeOH, rt.
3
; (v) SiEt
3
Cl, 2,6-lutidine, CH
2
Cl
2
, 0 C; (vi) 10 mol % Pd
2
dba , 30 mol % AsPh
3
3
, 24, toluene, 110 C, 1 h; (vii) neat,
4

L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
9897
HO
Inverse demand
O
O
[
4+2] exo-Diels-Alder
Path A
OH
O
(
15)
(+)-(1)
O
OH
HO
34)
(
OH
O
HO
OH
Normal demand [4+2]
HO
O
O
exo-Diels-Alder
Path B
O
(
15)
(+)-(1)
H
O
O
O
OH
H
HO
OH
OH
O
2
x (15)
(14)
Scheme 8. Proposed mechanisms for the biomimetic dimerisation.
OH
was identified. All stationary points were characterised via
analysis of vibrational modes. For all pathways except
(
+)–(+) the stationary points were minimised at the HF/
O
O
6-31+G* level of theory before single point energy calcula-
tions were performed at the B3LYP/6-31+G* level.
OH
OH
3
6
O
H
O
O
H
OR
The results of our simulations are broadly in agreement with
OR
OR
3
2
those of Lei et al. favouring the reaction pathway that pro-
ceeds by a Diels–Alder reaction followed by cyclisation to
form the five-membered hemiketal ring (Fig. 3). In the pro-
posed alternative mechanism, the intermediate that would
result from initial hemiketal formation (34, Scheme 8) is
O
R = H (15),TES (31),
TBS (35).
O
R = H (1), TES (32),
TBS (36).
OH
[ref 32]
No Dimerisation
No Dimerisation
O
ꢀ1
found to have an energy of 11.92 kcal mol relative to the
energy of the starting materials, whereas that of intermediate
OH
ꢀ
1
(
37)
14 is ꢀ4.99 kcal mol . The transition state search that was
performed for both possible pathways also supports the pro-
posal of an initial Diels–Alder reaction followed by an intra-
molecular hemiketal formation. In the alternative pathway
proceeding via initial hemiketal formation, no transition
state could be identified.
O
OH
HO
OH
29)
(
These results provide some explanation for the observed
diastereospecificity resulting from the cascade reaction. It
is considered that the second-stage hemiketal formation is
essentially irreversible under the given conditions, which
would then effectively render the (potentially reversible)
first-stage Diels–Alder cycloaddition irreversible, by ‘lock-
ing’ the core structure in place. The alignment required to
facilitate such hemi-ketal bridging is provided by intermedi-
ate 14, itself resulting from a homochiral exo-Diels–Alder
Scheme 9. Factors affecting the biomimetic dimerisation.
reaction under similar conditions. These results clearly
indicate that both steric and stereoelectronic effects are
controlling factors in the dimerisation process.
2
.3. Transition state analysis of dimerisation cascade
1
cycloaddition (Scheme 8). The crystal structure of (+)-1
To further understand the biomimetic dimerisation and
explain the observed diastereospecificity of the reaction,
a series of theoretical calculations were undertaken. These
simulations were performed by disconnecting (+)-1 in
a retro-[4+2] fashion. Each of the structures on the proposed
reaction pathways were minimised at the B3LYP/6-31+G*
level of theory. Transition state searches were performed
by moving the molecules along the reaction co-ordinate, at
the HF/STO-3G level of theory, until an energy maximum
reveals the close proximity of the tertiary hydroxyl group
and ketone, which should substantially favour the formation
of the hemiketal bridge (Fig. 2). Whether diastereoisomers
resulting from endo-heterochiral, endo-homochiral or from
exo-heterochiral Diels–Alder cycloadditions are feasible re-
action products is uncertain. However, steric or conforma-
tional constraints would seem to disfavour their hemiketal
formation, thereby driving the overall equilibrium in favour
of conformationally ‘locked’ 1.
3
5

9898
L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
Figure 3. Reaction profile for formation of (+)-panepophenanthrin (1).
3
. Conclusion
necessary. HMQC analysis was used in selected cases to aid
assignment. Low-resolution mass spectra (m/z) were re-
corded using a V.G.TRIO (GC/MS) spectrometer, a Micro-
mass Platform (APCI) spectrometer, Micromass Autospec
We have achieved a concise and efficient asymmetric syn-
thesis of (+)-panepophenanthrin (1) employing a biomimetic
dimerisation of an epoxyquinol monomer (+)-15. A key
feature of our racemic synthesis was the observed diastereo-
specificity of the reaction sequence, which resulted from
exclusive homochiral dimerisation. Our choice of building
blocks allowed ready access to enantiomerically pure (+)-
+
spectrometer (CI ) and a Micromass ZAB spectrometer
+
+
(CI , ESI). Only molecular ions (M ) and other major frag-
ments are reported, with intensities quoted as percentages of
the base peak. High resolution mass spectra were recorded
on a VG Autospec spectrometer by chemical ionisation or
on a Micromass LCT electro spray ionisation mass spec-
trometer operating at a resolution of 5000 full width half
height. The quoted masses are accurate to ꢁ5 ppm. All
reagents were used as obtained from commercial sources
unless otherwise stated. Melting points (mp) were obtained
using a Buchi 510 Cambridge instruments GallenÔ III hot
stage melting point apparatus.
(
1), through an enzyme mediated kinetic resolution of di-
acetate (ꢁ)-33, which is amenable to large-scale synthesis.
Computational analysis assisted our interpretation of the
dimerisation process.
4
. Experimental
4
.1. General experimental
4.1.1. Additional supporting data for known compounds.
ꢂ
30c
ꢂ
Compounds (ꢁ)-27, mp 81–82 C (lit. mp 79 C); (+)-27
ꢂ
mp 113–115 C (from CHCl /hexane) (lit. mp 114–
3
37
All reagents were used as obtained from commercial sources
unless otherwise stated. Measurement of pH was carried out
using Prolabo RotaÔ pH 1–10 paper. Infrared (IR) spectra
were recorded on Perkin–Elmer Paragon Fourier Transform
ꢂ
22
37
25
115 C), [a]D +168 (c 1.0, CHCl ) (lit. [a]D +174 (c 1.0,
3
ꢂ
ꢂ
CHCl )); (ꢁ)-28 mp 92–94 C; (+)-28 mp 137–138 C
3
2
2
(from CCl /CHCl ), [a] +198 (c 1.0, acetone); (ꢁ)-bro-
4
3
D
1
ꢂ
spectrometer. Proton magnetic resonance spectra ( H NMR)
moxone (4) mp 95–97 C (from CCl ); (ꢀ)-bromoxone (4)
ꢂ
4 3
4
28
were recorded on Br €u ker DPX400 (400 MHz), Br €u ker
DRX500 (500 MHz) and Br €u ker AMX500 (500 MHz) spec-
trometers at ambient temperatures. Chemical shifts (dH)
are quoted in parts per million (ppm) and are referenced
to the residual solvent peak. J values are given in hertz.
Carbon magnetic resonance spectra ( C NMR) were re-
corded on Br €u ker DPX400 (100.6 MHz), Br €u ker DRX500
(
125.8 MHz) and Br €u ker AMX500 (125.8 MHz) spectrome-
ters at ambient temperature. Chemical shifts (d ) are quoted
mp 135–136 C (from CCl /CHCl ) (lit.
mp 137–
ꢂ
22
28
22
139 C), [a]D ꢀ189 (c 1.0, acetone) (lit. [a] ꢀ188
D
ꢂ
109 C), [a]D +12.6 (c 1.00, CH Cl ) (lit. [a]D +11.3
30a
(c 1.85, acetone)); (+)-33 mp 108–109 C (lit. mp 107–
ꢂ
25
30a
25
2
2
(c 5.1, CH Cl )), ee >99% (chiral HPLC: heptane/2-propa-
2
2
1
3
ꢀ1
nol (90:10), flow 0.8 mL min ) t¼9.06 min and (+)-26 mp
ꢂ ꢂ
D
30a
25
164–165 C (lit. mp 164–165 C), [a] +51.3 (c 1.00,
3
0a
25
acetone) (lit. [a]D +49.5 (c 1.22, acetone)), ee >99% (chi-
ral HPLC: heptane/2-propanol (90:10), flow 0.8 mL min )
ꢀ
1
C
in parts per million (ppm) and are referenced to CDCl3
unless otherwise stated. Carbon spectral assignments are
supported by DEPT analysis and H– C correlations where
t¼10.15 min were prepared according to the procedure of
30
3
0a
1
13
Altenbach et al. The spectral data ( H and C NMR) for
these compounds were in agreement with those reported.
1
13

L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
9899
4
.1.2. (±)-(1S*,5R*,6R*)-5-Hydroxy-3-(3-hydroxy-3-
methylbut-1-enyl)-7-oxa-bicyclo[4.1.0]hept-3-en-2-one
15), (±)-(4R*,5S*)-4,5-dihydroxy-2-(3-hydroxy-3-meth-
(SiCH CH ), 53.6 (C(O)CH), 58.3 (–OCHCHOH), 65.4
2 3
(CH–OSiEt ), 123.0 (]CBr), 144.7 (]CH), 186.5 (CO);
3
+
(
MS (ESI) m/z¼338/336 (MNH ) , (100), 210 (50), 91 (19).
4
ylbut-1-enyl)cyclohex-2-enone (29) and (±)-panepophe-
nanthrin (1). (ꢁ)-Bromoxone (4) (0.50 g, 2.44 mmol) was
4.1.4. (±)-(1S*,5R*,6R*)-3-(3-Hydroxy-3-methylbut-1-
enyl)-5-triethylsilanyloxy-7-oxabicyclo[4.1.0]hept-3-en-
one (31) and (±)-TES-protected panepophenanthrin
3
dissolved in degassed toluene (10 cm ) with stirring. Vinyl-
stannane 24 (1.13 g, 3.01 mmol) was added and the mixture
ꢂ
.17 mmol) and AsPh (165 mg, 0.54 mmol) were stirred
16
heated to 110 C. In a separate flask, Pd dba (160 mg,
2
0
in degassed toluene (5 cm ) for 20 min. The catalyst solution
was added to the above reaction drop-wise over 10 min and
the reaction mixture was stirred for an additional 1 h at
(32).
3.40 mmol) was dissolved in degassed toluene (20 cm )
TES-protected bromoxone (ꢁ)-30 (1.10 g,
3
3
3
3
with stirring. Vinylstannane 24 (1.65 g, 4.40 mmol) was
ꢂ
added and the mixture was heated to 110 C. In a separate
flask, Pd dba (320 mg, 0.35 mmol) and AsPh (330 mg,
2
3
3
ꢂ
3
1
10 C. The solvent was removed under reduced pressure.
1.08 mmol) were stirred in degassed toluene (10 cm ) for
20 min. The catalyst solution was then added to the above
reaction drop-wise over 10 min and the reaction mixture
TLC analysis of the crude mixture indicated several minor
products, which upon silica gel chromatography (1:99,
ꢂ
MeOH/CHCl ) yielded two clear oils: monomer (ꢁ)-15
stirred for an additional 1 h at 110 C. The solvent was
3
(
(
31.00 mg, 6%) and diol (ꢁ)-29 (51.0 mg, 10%). Compound
removed by rotary evaporation and the crude mixture sub-
jected to flash silica gel chromatography (1:99, MeOH/
ꢁ)-15 was found to be unstable and dimerised completely
to give (ꢁ)-panepophenanthrin (1) (30.7 mg, 6%). Com-
CHCl ) to afford two products: monomer (ꢁ)-31 and dimer
3
ꢀ
1
pound (ꢁ)-29: n /cm
(film) 3435 (br, OH), 3100,
980, 1690 (s, CO), 1600; dH (500 MHz, MeOD) 1.30
(ꢁ)-32. Overnight, (ꢁ)-31 was completely transformed into
max
2
(ꢁ)-32. Finally (ꢁ)-32 was obtained as a white powder
(
2
1
6H, s, 2ꢃCH ), 2.47 (1H, dd, J 16.0 and 11.5, CH (H )),
(827 mg, 75%). Compound (ꢁ)-31: d (MeOD, 400 MHz)
3
2
A
H
.74 (1H, dd, J 16.0 and 4.5, CH (H )), 3.83 (1H, ddd, J
2
0.63 (6H, q, J 8.0, SiCH ), 0.98 (9H, t, J 8.0, SiCH CH ),
3
B
2
2
1.5, 7.5 and 4.5, CH CHOH), 4.30 (1H, dd, J 7.5 and 2.5,
2
1.30 (3H, br s, CH ), 1.31 (3H, br s, CH ), 3.49 (1H, br
3 3
CHOH), 6.34 (1H, d, J 16.0, C]CHC(CH ) OH), 6.40
3
dd, J 4.0 and 1.0, C(O)CH), 3.74 (1H, m, –OCHCHOH),
4.62 (1H, br d, J 5.0, CH–OSiEt ), 6.32 (1H, d,
2
(
1H, d, J 16.0, HC]CHC(CH ) OH), 6.83 (1H, br d, J
3
2
3
2
4
.5, ]CHCHOH)); d (125.7 MHz, MeOD) 29.7 (2ꢃCH ),
J 16.0, C]CHC(CH ) OH), 6.44 (1H, d, J 16.0,
3 2
HC]CHC(CH ) OH), 6.63 (1H, br dd, J 5.0 and 2.5,
3 2
C
3
6.1 (CH ), 71.4 (C(CH ) OH), 73.2 (CH CHOH), 73.6
2
3 2
2
(
1
(
2
CHOH), 120.3 (]CHC(CH ) OH), 136.6 (C(O)C]),
3
]CH); dC (100.6 MHz, MeOD) 4.8 (SiCH2), 6.9
(SiCH CH ), 29.7 (2ꢃCH ), 55.2 (C(O)CH), 58.7 (–OCH-
2
42.3 (C]CHC(CH ) OH), 146.5 (]CHCHOH), 198.5
3 2
2
3
3
ꢀ
C]O); HRMS (ESI) m/e calcd for C H O (MꢀH ):
CHOH), 64.1 (CH–OSiEt ), 71.4 (C(CH ) OH), 120.7
3 3 2
1
1
15
4
ꢀ
1
11.0970. Found: 211.0969; compound (ꢁ)-15: n /cm
max
(C]CHC(CH ) OH), 134.3 (C(O)C]), 139.7 (]CH),
3 2
(
(
film) 3435 (br, OH), 3105, 2982, 1685 (s, CO), 1602; dH
400 MHz, MeOD) 1.32 (6H, s, 2ꢃCH ), 3.48 (1H, br dd,
143.4 (C]CHC(CH ) OH), 195.2 (C-2); compound (ꢁ)-
3 2
ꢂ
ꢀ1
(32) (see Fig. 1 for numbering): mp 89–91 C; n /cm
max
3
J 3.5 and 1.0, C(O)CH), 3.75–3.77 (1H, m, J 3.5 and 2.5,
–OCHCHOH), 4.64 (1H, br d, J 5.0, CHOH), 6.31 (1H, d,
J 16.0, C]CHC(CH ) OH), 6.45 (1H, d, J 16.0, HC]
(KBr) 3435, 1691 (s, C]O), 1599; d (500 MHz, CDCl )
H 3
0.68 (12H, q, J 8.0, Si–CH CH ), 1.0 (18H, m, J 8.0 and
2 3
8.0, Si–CH CH ), 1.21 (3H, s, H-14), 1.24 (3H, s, H-15),
2
3
2
3
CHC(CH ) OH), 6.66 (1H, dd, J 5.0 and 2.5, ]CH); d
C
1.39 (3H, s, H-17), 1.46 (3H, s, H-16), 2.11 (1H, d, J 11.5,
H-10b), 2.54 (1H, br d, J 11.5, H-10a), 3.42–3.47 (3H, m,
H-2, 3, 5a), 3.49 (1H, d, J 4.5, H-8), 3.74 (1H, br t, J 4.5,
H-9), 4.53 (1H, d, J 3.5, H-1), 4.59 (1H, d, J 3.5, H-10),
5.69 (1H, d, J 16.5, H-12), 6.14 (1H, d, J 16.5, H-11), 6.82
(1H, dd, J 5.5 and 2.5, H-6); d (125.7 MHz, CDCl ) 4.7
3
2
(
(
100.6 MHz, MeOD) 29.7 (2ꢃCH ), 55.2 (C(O)CH), 58.7
3
–OCHCHOH), 64.1 (CHOH), 71.4 (C(CH ) OH), 120.7
3
2
(
]CHC(CH ) OH)), 134.3 (C(O)C]), 139.7 (]CH),
3 2
1
experimental data given below.
43.4 (C]CHC(CH ) OH), 195.2 (CO); compound (ꢁ)-1:
3
2
C
3
(Si–CH CH ), 6.6 (Si–CH CH ), 25.2 (C-16), 29.3 (C-14),
2 3 2 3
4.1.3. (±)-(1S*,5R*,6R*)-3-Bromo-5-triethylsilanyloxy-7-
oxabicyclo[4.1.0]hept-3-en-2-one (30). To a solution of
29.9 (C-15), 31.9 (C-17), 48.0 (C-10b), 49.4 (C-10a), 54.2
(C-8), 55.0 (C-10c), 55.2 (C-2), 55.7 (C-3), 55.9 (C-5a),
59.3 (C-9), 65.4 (C-10), 68.4 (C-1), 71.1 (C-13), 78.4
(C-5), 101.1 (C-3a), 129.3 (C-11), 138.2 (C-6a), 138.5
(C-6), 141.6 (C-12), 194.6 (CO); HRMS (ESI) calcd for
1
6
(
(
1
ꢁ)-bromoxone (4) (200 mg, 0.98 mmol) in CH Cl
2
2
3
ꢂ
10 cm ) at 0 C was added 2,6-lutidine (170 mL,
.46 mmol) with stirring. After 5 min chlorotriethylsilane
220 mg, 1.46 mmol) was added and the mixture was
ꢀ
(
C H O Si (MꢀH ): 647.3436. Found: 647.3457.
3
4
55
8
2
3
allowed to stir for 30 min. EtOAc was added (20 cm ) and
the mixture was washed with NH Cl (30 cm ) and brine
3
16
4.1.5. (±)-ꢀanepophenanthrin (1). To a round-bottomed
flask containing methanol (5 cm ) was added (ꢁ)-32
4
3
3
(
30 cm ). Drying of the mixture followed by removal of
the solvent under reduced pressure gave a crude brown solid,
which could be purified by flash chromatography on Florisil
(199 mg, 0.31 mmol) followed by stirring for 5 min. NH F
4
(45.5 mg, 1.23 mmol) was then added and the mixture was
allowed to stir until the reaction had completed as indicated
by TLC analysis (approx 2 h). The solvent was removed
under reduced pressure and the crude mixture subjected to
(
(
(
60–100 mesh) (4:1, 30–40 PE/EtOAc), to give compound
ꢁ)-30 as a pale yellow oil (290 mg, 93%); nmax/cm
ꢀ
1
film) 2957, 2878 (s, C–H), 1705 (s, C]O), 1611 (m,
C]C); d (400 MHz, CDCl ) 0.69 (6H, q, J 8.0, Si–CH ),
H
silica gel chromatography (97:3, CHCl /MeOH) to give the
3
3
2
0
.99 (9H, t, J 8.0, Si–CH CH ), 3.65 (1H, dd, J 3.5 and
2
title compound as a white solid (110 mg, 85%) (see Fig. 1
3
1
ꢂ
1.0, C(O)CH), 3.68–3.70 (1H, m, –OCHCHOH), 4.70
1H, br d, J 5.0, CH–OSiEt ), 6.96 (1H, dd, J 5.0 and
for numbering); R ¼0.3 (9:1, CHCl /MeOH); mp 81 C
ꢀ
3 max
f
3
1
(
(from CH Cl); n /cm (KBr) 3435, 1672 (s, CO), 1600
3
2
.5, ]CH); dC (101.6 MHz, CDCl ) 4.9 (Si–CH ), 6.8
3
(m, C]C); d (500 MHz, MeOH) 1.23 (3H, s, H-14), 1.26
H
2

9900
L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
(
(
3H, s, H-15), 1.41 (3H, s, H-17), 1.51 (3H, s, H-16), 2.10
1H, br d, J 10.0, H-10b), 2.40 (1H, br d, J 10.0, H-10a),
.39 (1H, d, J 4.0, H-3), 3.41 (1H, dd, J 5.0 and 2.0, H-
a), 3.49 (1H, d, J 4.0, H-8), 3.56 (1H, br t, J 3.5, H-2),
.90 (1H, br t, J 3.5, H-9), 4.41 (1H, br t, J 2.0, H-1), 4.61
1H, br t, J 2.0, H-10), 5.75 (1H, d, J 16.0, H-12), 6.05
1H, d, J 16.0, H-11), 6.88 (1H, dd, J 5.0 and 3.0, H-6); dC
125.7 MHz, MeOD) 26.3 (C-16), 29.6 (C-14), 30.5
C-15), 32.5 (C-17), 50.2 (C-10b), 51.3 (C-10a), 55.2
C-8), 55.8 (C-10c), 57.3 (C-2), 57.4 (C-3), 57.5 (C-5a),
4.1.7. (L)-(4R,5S,6S)-2-Bromo-4-triethylsilanoxy-5,6-
epoxy-2-cyclohexen-1-one (30). To a solution of (ꢀ)-bro-
3
3
5
3
(
(
(
(
(
moxone (4) (4.00 g, 19.51 mmol) in CH Cl (100 cm )
2
2
ꢂ
3
at 0 C was added 2,6-lutidine (3.40 cm , 29.26 mmol)
with stirring. After 5 min chlorotriethylsilane (4.40 g,
29.26 mmol) was added and the mixture was allowed to
3
stir for 30 min. EtOAc was added (100 cm ) and the mixture
was washed with NH Cl (2ꢃ100 cm ) and brine
3
4
3
(2ꢃ100 cm ). Drying of the mixture followed by removal
of the solvent under reduced pressure gave a crude brown
solid, which could be purified by flash chromatography on
Florisil (60–100 mesh) (4:1, 30–40 PE/EtOAc) to give com-
6
(
(
0.8 (C-9), 66.4 (C-10), 69.2 (C-1), 71.9 (C-13), 79.3
C-5), 102.8 (C-3a), 129.4 (C-11), 138.9 (C-6a), 140.1
2
2
C-6), 143.2 (C-12), 196.4 (C-7); HRMS (ESI) calcd for
pound (ꢀ)-30 as a clear oil (5.61 g, 90%); [a] ꢀ145 (c 1.0,
D
ꢀ
1
13
C H O (MꢀH ): 419.1704. Found: 419.1706.
acetone). The spectral data ( H and C NMR) for (ꢀ)-30
were in agreement with racemic (ꢁ)-30.
2
2 27 8
4
3
.1.6. (±)-5-(1S*,5R*,6R*)-(tert-Butyldimethylsilanoxy)-
-(3-hydroxy-3-methylbut-1-enyl)-7-oxabicyclo[4.1.0]-
4.1.8. (D)-TES-protected panepophenanthrin (32). TES-
protected bromoxone (ꢀ)-30 (3.50 g, 10.96 mmol) was
hept-3-en-2-one (35) and (±)-TBS-protected panepophe-
nanthrin (36). To a round-bottomed flask was added
TBS-protected bromoxone (1.08 g, 3.38 mmol) and was
3
dissolved in degassed toluene (60 cm ) with stirring. Vinyl-
stannane 24 (5.32 g, 14.17 mmol) was added and the mixture
3
ꢂ
dissolved in degassed toluene (20 cm ). Vinylstannane 24
was heated to 110 C. In a separate flask, Pd dba (1.03 g,
2
3
(
to 110 C. In
0
in degassed toluene (10 cm ) for 20 min. The catalyst solu-
tion was then added to the above reaction drop-wise over
1.65 g, 4.39 mmol) was added and the mixture was heated
a
1.13 mmol) and AsPh (1.06 mg, 3.48 mmol) were stirred
3
ꢂ
.35 mmol) and AsPh (330 mg, 1.07 mmol) were stirred
3
separate flask, Pd dba (320 mg,
2
in degassed toluene (30 cm ) for 20 min. The catalyst solu-
tion was then added to the above reaction drop-wise over
10 min and the reaction mixture stirred for an additional
3
3
3
ꢂ
1 h at 110 C. The solvent was removed by rotary evapora-
1
1
0 min and the reaction mixture was stirred for an additional
ꢂ
tion and the crude mixture left to stand overnight. Purifica-
tion of the crude oil by flash silica gel chromatography
(1:99, MeOH/CHCl ) afforded compound (+)-32 as an off-
h at 110 C. The solvent was removed by rotary evapora-
tion and the crude product subjected to silica gel chromato-
graphy (1:99, MeOH/CH Cl ) to afford two products:
3
2
2
white powder (3.27 g, 92%); [a] +182 (c 1.0, CHCl3).
The spectral data ( H and C NMR) for (+)-32 were in
agreement with racemic (ꢁ)-32.
2
2
D
1
13
monomer (ꢁ)-35 and dimer (ꢁ)-36. Upon standing over-
night monomer (ꢁ)-35 was completely transformed into
the dimer. Finally (ꢁ)-36 was obtained in 66% yield
(
728 mg) as an off yellow powder. Compound (ꢁ)-35: d
4.1.9. (D)-ꢀanepophenanthrin (1). To a round-bottomed
flask containing methanol (100 cm ) was added (+)-32
H
3
(
SiCH ), 0.16 (3H, s, SiCH ), 0.90 (9H, s, SiC(CH ) ),
CDCl , 400 MHz) 0.65 (6H, q, J 8.0, SiCH ), 0.13 (3H, s,
3
2
(3.00 g, 4.63 mmol) followed by stirring for 5 min. NH4F
(685 mg, 18.50 mmol) was then added and the mixture
was allowed to stir until the reaction had gone to completion
as indicated by TLC analysis (approx 2–3 h). The solvent
was removed under reduced pressure and the crude mixture
subjected to silica gel chromatography (97:3, CHCl3/
MeOH) to give the title compound as a white solid (1.73 g,
3
3
3 3
1
.33 (3H, s, CH ), 1.35 (3H, s, CH ), 3.51 (1H, br d,
3 3
J 4.0 and 1.0, C(O)CH), 3.63 (1H, m, J 4.0 and 2.5,
OCHCHOH), 4.71 (1H, br d, J 5.0, CH–OTBS), 6.27
1H, d, J 16.0, C]CHC(CH ) OH), 6.36–6.40 (1H, m,
–
(
3
2
]
(
2
CH), 6.41 (1H, d, J 16.0, HC]CHC(CH ) OH); d
3 2 C
CDCl , 100.6 MHz) ꢀ4.7, ꢀ4.5 (SiCH ), 18.0 (Si–C),
3
3
ꢂ ꢂ
89%); mp 145–148 C (CHCl ) (lit. mp 144–146 C);
3
1
5.6 (SiC–(CH ) ), 29.6 (2ꢃCH ), 54.1 (C(O)CH), 57.9
3
3
3
2
2
1
26
(
–OCHCHOH), 64.1 (CH–OTBS), 70.9 (C(CH ) OH),
3
[a] +146 (c 1.0, MeOH) (lit. [a]D +149.8 (c 1.0,
D
2
ꢀ
1
1
1
19.7 (]CHC(CH ) OH), 132.8 (C(O)C]), 137.9 (]CH),
3
MeOH); nmax/cm (KBr) 2988, 1672 (s, CO), 1600 (m,
C]C); d (500 MHz, MeOH) (see Fig. 1 for numbering)
2
1
42.3 (C]CHC(CH ) OH), 193.2 (CO); compound (ꢁ)-36:
3
2
H
ꢂ
ꢀ1
mp 169–170 C (from CH Cl ); n /cm (KBr) 3454 (br,
2
1.17 (3H, s, H-14), 1.21 (3H, s, H-15), 1.36 (3H, s, H-17),
1.45 (3H, s, H-16), 2.04 (1H, br d, J 10.0, H-10b), 2.32
(1H, br d, J 10.0, H-10a), 3.31 (1H, d, J 4.0, H-3), 3.35
(1H, dd, J 5.0 and 2.0, H-5a), 3.42 (1H, d, J 4.0, H-8),
3.50 (1H, br t, J 3.5, H-2), 3.84 (1H, br t, J 3.5, H-9), 4.35
(1H, br t, J 2.0, H-1), 4.55 (1H, br t, J 2.0, H-10), 5.69
(1H, d, J 16.0, H-12), 5.99 (1H, d, J 16.0, H-11), 6.81 (1H,
2
max
OH), 2930, 2858, 1687 (s, C]O); d (400 MHz, MeOD)
H
0
1
1
.18 (12H, br s, Si–CH ), 0.87 (18H, br s, Si–C(CH ) ),
3 3 3
.09 (3H, s, H-14), 1.16 (3H, s, H-15), 1.31 (3H, s, H-17),
.43 (3H, s, H-16), 2.09 (1H, d, J 11.5, H-10b), 2.37 (1H,
br d, J 11.5, H-10a), 3.29–3.48 (4H, m, H-2, 3, 5a, 8), 3.87
1H, br t, J 3.5, H-9), 4.52 (1H, d, J 3.5, H-1), 4.66 (1H, d,
(
J 3.5, H-10), 5.64 (1H, d, J 16.0, H-12), 6.01 (1H, d,
J 16.0, H-11), 6.73 (1H, dd, J 5.5 and 3.0, H-6); d (CDCl ,
dd, J 5.0 and 3.0, H-6); d (125.7 MHz, MeOD) 26.1 (C-
C
16), 29.4 (C-14), 30.4 (C-15), 32.3 (C-17), 50.1 (C-10b),
51.2 (C-10a), 55.2 (C-8), 55.6 (C-10c), 57.1 (C-2), 57.2
(C-3), 57.5 (C-5a), 60.8 (C-9), 66.2 (C-10), 69.0 (C-1),
71.9 (C-13), 79.2 (C-5), 102.6 (C-3a), 129.2 (C-11), 138.9
(C-6a), 139.9 (C-6), 143.1 (C-12), 196.2 (C-7); HRMS
C
3
1
2
25.7 MHz) ꢀ4.7, ꢀ4.5 (SiCH ), 17.9 (Si–C), 24.9 (C-16),
3
5.1 (Si–C), 28.9 (C-14), 29.2 (C-15), 31.5 (C-17), 48.5
(
(
C-10b), 48.6 (C-10a), 49.0 (C-8), 49.4 (C-10c), 54.3
C-2), 55.6 (C-3), 56.0 (C-5a), 59.5 (C-9), 66.4 (C-10),
ꢀ
ꢀ
6
(
8.8 (C-1), 70.8 (C-13), 77.8 (C-5), 102.1 (C-3a), 128.6
C-11), 138.2 (C-6a), 138.5 (C-6–C), 141.9 (C-12), 194.6
[(EI) ] calcd for C H O [(MꢀH) ]: 419.1704. Found:
2
2 27 8
419.1706. Crystal Data for 1: C H O , M¼438.47,
22 30 9
ꢀ
˚
(
6
CO); HRMS (ESI) calcd for C H O Si (MꢀH ):
monoclinic, a¼8.9012(2), b¼22.7413(5), c¼10.3797(3) A,
˚
1
3
4
55
8
2
3
47.3436. Found: 647.3448.
U¼2100.82(9) A , T¼150 K, space group P2 , Z¼2,

L. Comm eꢀ iras et al. / Tetrahedron 62 (2006) 9892–9901
9901
ꢀ
1
m(Mo Ka)¼0.107 mm , 17,072 reflections measured, 4871
18. Wipf, P.; Jeger, P.; Kim, Y. Bioorg. Med. Chem. Lett. 1998, 8,
351.
19. For Diels–Alder dimerisation reactions of 2-vinylcyclohexe-
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Angew. Chem., Int. Ed. 1998, 37, 3262.
unique (R ¼0.053), which were used in calculations. The
int
final wR was 0.0442. CCDC no. 247818.
Acknowledgements
2
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We thank the EPSRC for funding J.E.M. and Roche for
funding Laurent Commeiras. We thank Dr. B. Odell for
NMR assistance.
21. Lindsey, C. C.; G ꢀo mez-Dı
Tetrahedron 2002, 58, 4559.
´
az, C.; Villalba, J. M.; Pettus, T. R. R.
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2