Investigations towards the synthesis of (-)-coprinolone, via a thermal 8π-6π electrocyclization cascade of 1,5,7-trien-4-ones

Article abstract of DOI:10.1016/j.tetlet.2006.10.021

Herein the investigation of a thermal 8π-6π electrocyclization cascade of 1,5,7-trien-4-ones, as a key step towards the synthesis of (-)-coprinolone is described.

Full text of DOI:10.1016/j.tetlet.2006.10.021

Tetrahedron Letters 47 (2006) 8717–8720
Investigations towards the synthesis of (À)-coprinolone, via
a thermal 8p–6p electrocyclization cascade of 1,5,7-trien-4-ones
Andrew L. Lawrence, Hermann A. Wegner, Mikkel F. Jacobsen,
*
Robert M. Adlington and Jack E. Baldwin
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK
Received 9 August 2006; revised 26 September 2006; accepted 5 October 2006
Abstract—Herein the investigation of a thermal 8p–6p electrocyclization cascade of 1,5,7-trien-4-ones, as a key step towards the
synthesis of (À)-coprinolone is described.
Ó 2006 Elsevier Ltd. All rights reserved.
(
À)-Coprinolone 1 is an unusual oxygen-bridged proto-
Me
H
Me
H
illudane sesquiterpene ketol, isolated from the fungus
Coprinus psychromorbidus, which has been the subject
of many studies due to the extensive damage it causes
to overwintering cereals, grasses and legumes in western
Canada. The unusual tricyclic ether bridged structure
of (À)-coprinolone 1 with its seven chiral centres, two of
which are quaternary, makes it an attractive target for
synthetic study. Pericyclic reactions have the capacity
to fix the stereochemistry of contiguous chiral centres,
and so an electrocyclic approach may well be an attrac-
tive way to form (À)-coprinolone 1.
PO
Me
PO
HO
Me
steps
8π-6π
Me
Me
O
Δ
O
O
1
2
1
,2
(-)-coprinolone
PO
keto-enol
tautomerism
PO
Me
PO
Me
PO
OH
O
3
4
The thermal 8p–6p electrocyclic ring closure of 1,3,5,7-
Scheme 1. A proposed retrosynthetic analysis of (À)-coprinolone 1.
tetraenes has been utilized in the total synthesis of a
3
number of natural products. It is postulated that the
tricyclic structure of (À)-coprinolone 1 could be con-
structed using a thermal 8p–6p electrocyclization of a
trienone 4 (Scheme 1). To the best of our knowledge
there has only been one reported example, by Snider
et al., of the thermal 8p–6p electrocyclic ring closure
one may be a possible route to the cyclic sub-structure
of (À)-coprinolone 1. Four trienones 16–19 differing in
their ketone a-substituents have been synthesized
(Scheme 2) and their electrocyclic ring closure observed
under heating in polar solvents (DMSO, MeOH) (Table
1).
4
of a trienone. In Snider’s example a 2,5,7-trien-4-one
was postulated to first isomerize to an intermediate
1
,5,7-trien-4-one which then cyclized to a bicyclo-
[
4.2.0]octenone in a combined yield of 29% for three
The synthesis began with conversion of the commer-
cially available b-keto ester 5 to vinyl triflate 6, which
4
5
different diastereomeric products.
was then used in a Suzuki–Miyaura cross-coupling reac-
6
The electrocyclization of trienones was investigated on
model systems, to determine whether a thermal 8p–6p
electrocyclic ring closure of a preformed 1,5,7-trien-4-
tion with isopropenyl pinacolboronic ester 7, prepared
7
from the isopropenyl Grignard reagent. The resulting
ester 8 was then treated with DIBAL-H followed by
MnO2 to give the corresponding aldehyde 10. Luche
8
9
coupling was carried out with aldehyde 10 and the
appropriate allylic bromides to give alcohols 12–15.
1
0
*
0
Corresponding author. E-mail: robert.adlington@chem.ox.ac.uk
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.021

8718
A. L. Lawrence et al. / Tetrahedron Letters 47 (2006) 8717–8720
O
OTf
a
b
c
+
O
O
CO Et 95%
CO Et
B
90%
85%
CO Et
2
2
2
OH
5
6
7
8
9
R
f (R=vinyl)
g (R=Me,H,Ph)
OH
O
d
5%
e
O
+
7
Br
11
R
12, R=vinyl (87%)
R
10
16, R=vinyl (50%)
17, R=Me (63%)
18, R=H (92%)
19, R=Ph (50%)
1
3, R=Me (67%)
4, R=H (86%)
5, R=Ph (89%)
1
1
i
Scheme 2. Synthesis of 1,5,7-trien-4-ones 16–19 from b-keto ester 5. Reagents and conditions: (a) Tf
PO , DMF, 60 °C; (c) DIBAL-H, Et O, À78 °C; (d) MnO , DCM; (e) Zn, NH
2
O, Pr
2
NEt, DCM, À78 °C; (b) (dppf)PdCl
2
,
K
3
4
2
2
4
Cl(aq)–THF (1:2), 0 °C; (f) DMP, DCM; (g) IBX, DMSO.
Table 1. Electrocyclization of 1,5,7-trien-4-ones 16–19
Entry
1
Trienone
Cyclized product
Conditions
Yield (%)
4
DBU (10 equiv), DMF, 120 °C
0
Me
H
a
O
2
(i) LDA, 0 °C, TMSCl, THF
31
(
ii) Benzene, D, sealed tube
(
iii) TBAF, 0 °C
O
2
0(
Z
), 21(
E)
16
b
3
4
5
DMSO, 100 °C, 2 h
DMSO, 150 °C, 1 h
MeOH, 110 °C, 24 h
59
Me
H
9
O
O
33
22
17
Me
Me
H
O
O
6
7
MeOH, 110 °C, 3.5 h
24
O
18
23
H
Ph
c
MeOH, 120 °C, 11 h
<8
O
Ph
19
24
a
b
c
Exclusive formation of E-isomer 21.
Ratio of 11:1 for Z(20):E(21).
Yield by mass of a mixture of cyclic product 24 and unidentifiable by-products.
These alcohols were then oxidized to the corresponding
ketones 16–19 using either IBX or DMP.
tem (Scheme 3). Initially the conditions used by Snider
and Harvey were tried but resulted in no cyclic prod-
1
1
12
4
ucts (Table 1, entry 1).
The thermal 8p–6p electrocyclization of trienone 16 was
first investigated, as there are no issues regarding the
E/Z geometry of the intermediate enolate with this sys-
The formation of a TMS trapped enolate followed by
heating in benzene and subsequent TBAF deprotection

A. L. Lawrence et al. / Tetrahedron Letters 47 (2006) 8717–8720
8719
R
R
R
HO
Me
OH
O
29
Scheme 3. Required geometry of the enolic double bond for correct
orbital overlap.
γ
α
H
H
a
+
γ
H
O
OTMS
25
OTMS
26
16
Scheme 4. Possible c- versus a-deprotonation of 1,5,7-trien-4-one 16.
Reagents and conditions: (a) LDA, 0 °C, TMSCl, THF.
1
5
Figure 1. X-ray crystal structure of cyclic product 20.
was carried out, resulting in a 31% yield of the cyclic
product 21 with the double bond geometry determined
by a NOESY experiment (Table 1, entry 2). H NMR
1
DMSO as the solvent resulted in a yield of 9% of the
cyclized product 22, which was shown to have the same
relative stereochemistry as (À)-coprinolone 1 via NOE
experiments (Table 1, entry 4). The conditions were fur-
ther optimized for trienone 17, with MeOH resulting in
the best yield of 33% (Table 1, entry 5). Trienone 18 was
also cyclized to product 23 in a 24% isolated yield (Table
spectra of the crude TMS trapped enolate taken before
and after heating in benzene showed that a minor ole-
finic species was formed which was converted to 21 upon
heating. However, another major species was also pres-
ent with olefinic protons which did not undergo the elec-
trocyclization. We put forward the hypothesis that some
competing c-deprotonation may be taking place result-
ing in the formation of TMS enolate 26, which cannot
1
, entry 6).
1
3
A by-product in all the attempted cyclizations was the
corresponding trienone 31, where D-1,2 had moved to
form D-2,3, which is in conjugation with the ketone
undergo the electrocyclic ring closure (Scheme 4).
Mills and Beak reported in 1985 that the equilibrium
constant for keto-enol tautomerism is dominated by
the polarity and hydrogen bonding basicity of the sol-
(
Scheme 6). The cyclization of trienone 17 was carried
out in methanol-d , and carbon NMR showed that for-
4
1
4
mation of the conjugated trienone 31 (R = Me) was irre-
versible, as no deuterium was incorporated in the
cyclobutane ring of tricyclic ketone 22.
vent. It was envisaged that in a polar and/or hydrogen
bond acceptor solvent the enol form of trienone 16 may
directly undergo the cyclization in situ. Therefore, tri-
enone 16 was heated to 100 °C in DMSO and pleasingly
cyclic ketones 20 and 21 were isolated in 54% and 5%
yields, respectively (Table 1, entry 3). The exclusive for-
mation of the E-isomer 21 via cyclization of the TMS
trapped enolate (Table 1, entry 2) is in contrast to the
preferential formation of Z-isomer 22 by a simple heat-
ing in DMSO (Table 1, entry 3). We suggest that this
can be accounted for by kinetic formation of Z-isomer
To confirm that the formation of the conjugated tri-
enone 31 was irreversible we decided to attempt the
cyclization of a-phenyl trienone 19. Trienone 19 was
subjected to heating in MeOH and gave the cyclized ke-
tone 24 recovered in a mixture with other unidentifiable
products in a low yield of <8% by mass (Table 1, entry
2
0 by intramolecular keto-enol tautomerism of the cyc-
MeOH or
DMSO
Me
H
lized intermediate 28 (Scheme 5). A crystal structure of
Z-isomer 20 of the cyclic ketone was obtained (Fig. 1).
1
5
R
+
R
R
Δ
O
O
O
With trienone 16 successfully cyclized in a 59% yield it
was decided to attempt the cyclization of trienone 17,
which more closely resembles precursor 4, as it has a
methyl group a to the ketone. It was found that using
2
9
30
31
Scheme 6. Thermal electrocyclization of a 1,5,7-trien-4-one 29 to form
cyclic ketone 30, and the conjugated by-product 31.
MeOH or
DMSO
H
H
Δ
O
OH
27
O H
O
16
28
20
Scheme 5. Isomerizations leading to preferential formation of Z-isomer 20.

8720
A. L. Lawrence et al. / Tetrahedron Letters 47 (2006) 8717–8720
7
), and conjugated ketone 31 (R = Ph) in a 24% yield.
3. Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev.
2
005, 105, 4757–4778.
This is consistent with the facile permanent formation
of conjugated trienone 31, as a Ph substituent is more
likely to isomerize to a favourable styrene moiety.
4
5
6
7
. Snider, B. B.; Harvey, T. C. J. Org. Chem. 1994, 59, 504–
5
06.
. Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972–
975.
. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun.
979, 19, 866–867.
6
In conclusion, four 1,5,7-trien-4-ones 16–19, with differ-
ent substituents at the 3-position, have been synthesized
1
(
Scheme 2) and their 8p–6p thermal cyclization afforded,
. Nesmeyanov, A. N.; Kocheshkov, K. A. In Methods of
Elemento-Organic Chemistry; North-Holland: Amster-
dam, 1967; Vol. 1, pp 20–22.
by simple heating in polar solvents (Table 1), products
having key cyclic sub-structural features of (À)-coprino-
lone 1. Application of this enolization–electrocyclization
cascade reaction of 1,5,7-trien-4-ones towards the total
synthesis of (À)-coprinolone 1 is under investigation.
8. Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50,
443–2459.
. Gritter, R. J.; Wallace, T. J. J. Org. Chem. 1959, 24, 1051–
056.
0. Luche, J. L.; Petrier, C.; Einhorn, J. Tetrahedron Lett.
985, 26, 1445–1448.
11. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
019–8020.
12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
156.
2
9
1
1
1
Acknowledgements
8
We thank Dr. Andrew Cowley for X-ray crystal
structure determination, Roche for funding to M.F.J.
and the Ernst Schering Research Foundation for a
Fellowship for H.A.W.
4
1
3. We believe that further substitution of the cyclopentane
ring as in trienone 4 would disfavour this unwanted c-
deprotonation.
1
1
4. Mills, S. G.; Beak, P. J. Org. Chem. 1985, 50, 1216–1224.
5. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 611641. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
References and notes
1
. Starratt, A. N.; Ward, E. W. B.; Stothers, J. B. Can. J.
Chem. 1989, 67, 417–427.
2
. Starratt, A. N.; Ward, E. W. B.; Stothers, J. B. J. Chem.
Soc., Chem. Commun. 1988, 9, 590–591.