Synthetic studies towards tragoponol: Preparation of a highly functionalized resorcylate

Article abstract of DOI:10.1016/j.tetlet.2013.05.044

Studies on the synthesis of racemic tragoponol are described. The western resorcylate unit of tragoponol was efficiently constructed from appropriate diketo-dioxinone and secondary alcohol intermediates using a ketene generation-trapping and aromatization

Full text of DOI:10.1016/j.tetlet.2013.05.044

Tetrahedron Letters 54 (2013) 4817–4820
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies towards tragoponol: preparation of a highly
functionalized resorcylate
⇑
Hideki Miyatake-Ondozabal, Anthony G. M. Barrett
Department of Chemistry, Imperial College, England SW7 2AZ, London
a r t i c l e i n f o
a b s t r a c t
Article history:
Studies on the synthesis of racemic tragoponol are described. The western resorcylate unit of tragoponol
was efficiently constructed from appropriate diketo-dioxinone and secondary alcohol intermediates
using a ketene generation–trapping and aromatization sequence. Further functionalization provided an
Received 12 March 2013
Accepted 10 May 2013
Available online 17 May 2013
advanced diketo-dioxinone intermediate which upon desilylation resulted in the formation of
dihydroisocoumarin.
a
Keywords:
Resorcylic acid lactones
Resorcylate unit
Ó 2013 Elsevier Ltd. All rights reserved.
Retro-Diels–Alder
Intermolecular ketene trapping
Diketo-dioxinones
Numerous bioactive natural products, including resorcylic acid
lactones (RALs), contain a key 6-alkyl-2,4-dihydroxybenzoic ester
unit.1 Two examples are shown in Figure 1, the antifungal agent
15G256b (1)2 and the TAK-kinase inhibitor LL-Z1640-2 (2).3 Due
to their notable biological activities, these natural products have
been the subject of extensive synthetic studies. In 2008, inspired
by the earlier work of Harris,4 Hyatt5 and Boeckmann,6 the first
biomimetic synthesis of 15G256b (1)7 was completed. The meth-
odology, based on the use of diketo-dioxinones,8 was extended to
other macrocyclic lactones by intermolecular ketene trapping
including cruentaren A,9 the fungal metabolites W1278AÀC10
and aigialomycin D,11 and by intramolecular trapping and concur-
rent macrocyclization applied to the total syntheses of (À)-zearal-
enone12 and LL-Z1640-2 (2).13 Tragoponol (3) represents the first
dimeric dihydroisocoumarin isolated from the roots of Tragopon
porrifolius by Zidorn and co-workers in 2010.14 This natural prod-
uct consists of a novel 12-membered dilactone system and it can
also be recognized as an unsymmetrical resorcylic dimer (Fig. 1).
The monomeric subunits of tragoponol (3) are found in other nat-
ural products including scorzocreticin (4),15 thunberginol C (5)16
and hongkongenin (6),17 which are known to possess anti-allergic,
anti-microbial and anti-oxidant activities. The biological activity of
tragoponol (3) has not yet been investigated in detail. To date, no
total synthesis of 3 has been reported.
Following our successful total synthesis of LL-ZI640-2 (2) which
employed macrocyclization by intramolecular ketene trapping
with an alcohol,13 we considered that tragoponol (3) should be
available from hydroxy-diketo-dioxinone 7 by an equivalent trap-
ping and subsequent transannular aromatization and regioselec-
tive demethylation. Dioxinone
7 should be available from
Weinreb amide 8 via C-acylation of keto-dioxinone and desilyla-
tion. We sought to synthesize the western resorcylate part of 8
by thermolysis of diketo-dioxinone 9 in the presence of secondary
OH
O
O
OH
OH
O
HO
O
O
O
O
O
O
O
O
O
OH
MeO
O
OH
OH
2
1
OH
OR4
O
OH
R2O
MeO
O
O
O
OH
OR3
2
O
Herein we report our studies towards the synthesis of racemic
tragoponol (3) and its racemic diastereoisomer using a ketene-gen-
eration, trapping and aromatization sequence. The retrosynthetic
analysis is shown in Scheme 1.
OH
O
: R = R3 = H, R4 = CH3
4
5
: R = R3 = R4 = H
2
6: R2 = CH3, R3 = R4 = H
OMe
3
⇑
Corresponding author. Tel.: +44 020 7594 5766; fax: +44 020 7594 5805.
E-mail address: agm.barrett@imperial.ac.uk (A.G.M. Barrett).
Figure 1. 15G256b (1), LL-Z1640-2 (2), tragoponol (3), scorzocreticin (4), thun-
berginol C (5) and hongkongenin (6).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.044

4818
H. Miyatake-Ondozabal, A. G. M. Barrett / Tetrahedron Letters 54 (2013) 4817–4820
OH
OH
O
O
O
OH
i. Intramolecular
ketene trapping
MeO
MeO
O
O
OH
O
O
OH
ii. Transannular
aromatization
OH
O
OMe O
O
O
iii. Regioselective
demethylation
OMe
OMe
3
7
i. C-acylation with
keto-dioxinone
ii. Silyl deprotection
OTBS
OTBS
O
O
O
O
9
O
OTBS
i. Intermolecular
ketene trapping
O
OTBS Me
Me
+
O
N
Me
N
OMe
ii. Aromatization
HO
O
O
O
iii. Bis-methylation
OMe
10
Me
O
OMe
8
OMe
Scheme 1. Retrosynthetic analysis of tragoponol (3).
Weinreb amide 14 in 74% yield, using iso-propylmagnesium chlo-
ride and N,O-dimethylhydroxylamine. Reaction of the zinc enolate
dianion,13,20,21 derived from keto-dioxinone 1520 with lithium di-
iso-propylamide and diethylzinc, and Weinreb amide 14 gave dike-
to-dioxinone 9 in excellent yield and in gram quantities.22
b-Ketoester 11 was allowed to react with sodium borohydride
to give alcohol 1623 in 77% yield. Following t-butyldimethylsilyla-
tion, Weinreb amide formation and tetrabutylammonium fluoride
mediated desilylation gave hydroxamate 1024 in 92% yield over
three-steps (Scheme 3).
O
O
HO
OEt
CO2Et
CO2Et
O
BBr3, CH2Cl2
NaBH4
−78 °C to 0 °C
EtOH, 0 °C
60%
90%
OMe
11
OH
12
OH
13
1) TBSCl,
Imidazole,
CH2Cl2
.
2) MeNHOMe HCl,
i-PrMgCl, THF,
− 40 °C
As expected, thermolysis of diketo-dioxinone 9 resulted in ret-
ro–hetero-Diels–Alder fragmentation5 to generate the diketo-ke-
tene intermediate, which was efficiently trapped in situ by
alcohol 10 to provide triketo-ester 17 (Scheme 4). Subsequent aro-
matization at elevated temperature yet under mild conditions25
gave resorcylate 18 in 81% yield over two-steps. It is noteworthy
that the use of both methanol and iso-propanol (1:1 mixture)
was crucial for obtaining a high yield in this transformation. A sig-
nificant amount of transesterified byproduct was observed in the
absence of iso-propanol, whereas the reaction was extremely slow
and low yielding when performed solely in iso-propanol.
74% over 2 steps
OTBS
OTBS
O
O
O
O
O
O
O
O
O
15
MeO
O
OTBS
N
Me
OTBS
i-Pr2NLi, Et2Zn, THF,
−
°C to − °C
89%
78
5
9
14
Scheme 2. Synthesis of diketo-dioxinone 9.
alcohol 10 to give the triketo-ester intermediate, which in turn
should aromatize to give our target molecule. Bis-methylation of
the resulting resorcinol unit should provide intermediate 8.
The synthesis of diketo-dioxinone 9 was achieved in five-steps
from commercially available starting materials (Scheme 2). b-Keto-
ester 11 was allowed to react with boron tribromide to provide
phenol 1218 in 90% yield, which was reduced with sodium borohy-
dride to give the corresponding alcohol 13.19 Following t-buty-
ldimethyldisilylation, the carboxylic ester was converted into
Diol 18 was dimethylated by reaction with excess methyl iodide
in the presence of potassium carbonate to furnish resorcylate 8 in
71% yield (Scheme 4). Subsequent addition of the zinc enolate
dianion,13,20,21 derived from dioxinone 15, to
smoothly to yield diketo-dioxinone 19 (76%).
8 proceeded
The projected final steps included secondary alcohol silyl
ether deprotection followed by intramolecular ketene trapping
and transannular aromatization to produce the macrocyclic
bis-resorcylate. A range of conditions was screened for the desi-
Me
O
HO
HO
N
Me
CO2Et
CO2Et
O
1) TBSCl, Imidazole,
CH2Cl2
NaBH4
O
.
EtOH, 0 °C
77%
2) MeNHOMe HCl,
i-PrMgCl, THF,
−40 °C
OMe
11
OMe
16
OMe
10
3) Bu4NF, THF
92% over 3 steps
Scheme 3. Synthesis of alcohol 10.

H. Miyatake-Ondozabal, A. G. M. Barrett / Tetrahedron Letters 54 (2013) 4817–4820
4819
OTBS
OTBS
O
O
O
OTBS
Me
10
, PhMe, 110 °C
1)
O
O
O
O
O
N
Me
O
O
OTBS
O
O
9
OMe
17
2) CH2Cl2, 4 Å MS,
MeOH, i-PrOH (1:1)
sealed tube, 110 °C
81% over 2 steps
OTBS
OTBS
MeO
HO
MeI (excess)
OTBS Me
O N
OTBS Me
O
N
K2CO3, acetone,
45 °C
OMe
OMe
OH
O
O
OMe O
O
71%
OMe
8
OMe
18
O
O
O
O
15
i-Pr2NLi, Et2Zn, THF,
−78 °C to −5 °C
76%
OTBS
O
O
MeO
O
OTBS
O
OMe O
O
O
OMe
19
Scheme 4. Synthesis of resorcylate 18 and diketo-dioxinone 19.
OTBS
OTBS
OH
O
O
O
O
MeO
O
O
MeO
OTBS
conditions
O
O
OMe O
O
O
OMe O
O
O
OMe
19
OMe
20
O
O
O
OTBS
HO
MeO
+
O
O
O
OMe O
21
22
OMe
Scheme 5. Six-membered lactonization of 20 to form dihydroisocoumarin 21.

4820
H. Miyatake-Ondozabal, A. G. M. Barrett / Tetrahedron Letters 54 (2013) 4817–4820
lylation step (Scheme 5). The use of hydrogen fluoride initially
gave the desired product 20, however rapid d-lactonization gave
dihydroisocoumarin 21 in quantitative yield. Dioxinone 22
decomposed during attempted purification. Deprotection of the
silyl ether 19 was examined using zirconium tetrachloride,
which resulted in the recovery of unreacted starting material
19. Tetrabutylammonium fluoride mediated selective deprotec-
tion of the aryl silyl ether. Finally, desilylation with hexafluoro-
silicic acid did result in completely selective secondary silyl
ether deprotection. However upon work-up, rapid d-lactoniza-
tion again could not be suppressed and only isochromanone
21 was isolated. All efforts to induce ketene generation during
silyl deprotection to trigger the desired cyclization also failed
to produce the triketo-ester-macrocycle. It is noteworthy that
d-lactonization during the synthesis of W1278AÀC10 could be
significantly suppressed and the total synthesis completed. Pre-
sumably the 16-membered macrocyclic triketo-lactone from
alcohol 20 was formed at too slow a rate to overcome competi-
tion from d-lactonization.
In conclusion, attempted macrocyclization of the triketo-ketene
derived from dioxinone 20 was less efficient than fragmentation
via a d-lactonization pathway. It is noteworthy that the study did
provide the polyfunctional resorcylate 19 in 13 steps and with an
overall yield of 11%. The key transformations in its synthesis were
the mild aromatization of triketo-ester 17–18 under neutral condi-
tions and the late-stage incorporation of keto-dioxinone unit 15 via
dianion addition to Weinreb amide 8.
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We thank P.R. Haycock and R.N. Sheppard (Imperial College
London) for help with high-resolution NMR spectroscopy and the
Engineering and Physical Sciences Research Council (EPSRC) for
financial support (to H.M.O.). We also thank Professor Dr. Christian
Zidorn (University of Innsbruck) for kindly providing us with an
authentic sample of tragoponol.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.044.