Synthesis of the bicyclic core of tagetitoxin

Article abstract of DOI:10.1039/b600819d

A synthesis of the 9-oxa-3-thiabicyclo[3.3.1]nonane ring system, which constitutes the core of the RNA polymerase inhibitor tagetitoxin, has been achieved through cyclisation of a thiol onto an electrophilic ketone. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600819d

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Synthesis of the bicyclic core of tagetitoxin{
Julien R. H. Plet and Michael J. Porter*
Received (in Cambridge, UK) 19th January 2006, Accepted 31st January 2006
First published as an Advance Article on the web 14th February 2006
DOI: 10.1039/b600819d
and heterolytic C–S bond cleavage to give zwitterion 4; rather than
A synthesis of the 9-oxa-3-thiabicyclo[3.3.1]nonane ring system,
which constitutes the core of the RNA polymerase inhibitor
tagetitoxin, has been achieved through cyclisation of a thiol
onto an electrophilic ketone.
the desired C–C bond formation, this intermediate is presumed to
undergo a ring-flip to the more stable conformer followed by
proton transfer to afford the observed product.
To circumvent this difficulty, a conformationally constrained
substrate was designed whose derived zwitterion (analogous to 4)
would be incapable of ring-flipping. 3-Methyl-D-glucose was
converted to bicycle 6, then the acetate groups were cleaved and
Tagetitoxin is a phytotoxin which was isolated from the plant
pathogenic bacterium Pseudomonas syringae pv. tagetis in 1981.1
The compound induces chlorosis in the apex of infected plants, an
effect which has been traced to inhibition of RNA polymerase in
chloroplasts.2 Furthermore, tagetitoxin inhibits bacterial RNA
polymerase,2 and is the only natural product known to inhibit
eukaryotic RNA polymerase III in a specific manner.3 Recently, a
crystal structure of the RNA polymerase from Thermus thermo-
philus with tagetitoxin bound to the active site was published;4
consideration of this structure led the authors to postulate that
tagetitoxin acts by stabilisation of an inactive intermediate in the
transcription process.
a
bridging di-tert-butylsilylene protecting group installed.
Treatment of the resulting tricycle 7 with ethyl diazo(triethylsilyl)-
acetate in the presence of rhodium(II) heptafluorobutyrate gave a
low yield of primary alcohol 9 as the only isolable product. In this
case, the sulfur ylid 8 forms as required but this, rather than
undergoing C–S bond heterolysis and ring expansion, is trapped
by adventitious water to give the bicyclic alcohol 9.
Due to the failure of our initial approach to the tagetitoxin
skeleton, a new strategy was adopted in which the 1,4-oxathiane
ring of the natural product would be formed by cyclisation of a
thiol onto an electron-deficient ketone, rather than through a
carbene-mediated ring expansion.
The structure which was assigned to the compound shortly after
its isolation5 was later rejected in favour of a bicyclic structure
based on the 9-oxa-3-thiabicyclo[3.3.1]nonane ring system.
Structure 1 was favoured, although the spectroscopic data did
not rule out the closely related structure 2 (Fig. 1).6
To date, limited work has been published detailing synthetic
approaches to tagetitoxin and its analogues,7 and none has yet
been successful in generating the bicyclic ring system. In this
communication we describe a synthesis of this bicyclic core
structure, starting from a carbohydrate precursor.
Our initial strategy focused on the use of a carbene-mediated
ring expansion of 1,3-oxathiolanes.8 D-Glucose was converted to
the bicyclic monothioacetal 39 through displacement of an
anomeric bromide and
a
6-tosylate with potassium
O-ethylxanthate (Scheme 1).10 Ring expansion was then attempted
using ethyl diazo(triethylsilyl)acetate and catalytic rhodium(II)
acetate;8 this led not to the anticipated bridged bicycle, but instead
to glycal 5. This product may arise through sulfur ylid formation
Fig. 1 Proposed structures of tagetitoxin.
Scheme 1 Reagents and conditions: i. TsCl, pyridine; Ac2O; ii. HBr,
AcOH; iii. KSCSOEt, DMF, 50 uC (46% 3 over 3 steps) or KSCSOEt,
acetone, reflux (47% 6 over 3 steps); iv. Et3SiC(N2)CO2Et, Rh2(OAc)4,
Department of Chemistry, University College London, Christopher
Ingold Building, 20 Gordon Street, London, UK WC1H 0AJ.
E-mail: m.j.porter@ucl.ac.uk; Fax: +44 20 7679 7463;
Tel: +44 20 7679 4710
{ Electronic supplementary information (ESI) available: HMQC and
HMBC spectra for 21. See DOI: 10.1039/b600819d
t
benzene, reflux, 34%; v. NH3, MeOH, H2O, 50%; vi. Bu2SiCl2, Et3N,
CH2Cl2, 86%; vii. Et3SiC(N2)CO2Et, Rh2(O2CC3F7)4, benzene, reflux,
21%.
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Scheme 3 Reagents and conditions: i. TBAF, THF, 99%; ii. MsCl, Et3N,
DMAP, CH2Cl2, 95%; iii. KSAc, DMF, 99%; iv. NBS, AgNO3, acetone,
98%; v. KMnO4, NaHCO3, MgSO4, aq. MeOH, 71%; vi. N2H4?H2O,
MeOH, 88%.
Scheme 2 Reagents and conditions: i. TBDPS-Cl, imidazole, DMF, 99%;
ii. BnBr, NaH, DMF, 87%; iii. NBS, aq. acetone, 95%; iv. Dess–Martin
periodinane, pyridine, CH2Cl2, 69%; v. TMSCMCH, n-BuLi, CeCl3?7H2O,
THF, 278 uC to rt, 96%; vi. Et3SiH, TMSOTf, CH2Cl2, 74%; vii. NaOH,
MeOH, CH2Cl2, 100%; viii. NBS, AgNO3, acetone, 98%; ix. KMnO4,
NaHCO3, MgSO4, aq. MeOH, 84%; x. HF?py, THF, 278 uC to rt, 77%.
In conclusion, we have carried out the first synthesis of the
tagetitoxin skeleton, by unmasking of a thiol in the presence of an
electrophilic a-ketoester, triggering spontaneous cyclisation to a
hemithioacetal. Efforts towards synthesis of the fully functionalised
tagetitoxin structure are under way and will be reported in due
course.
We thank EPSRC and UCL for financial support of this work.
Phenyl 1-thio-b-D-glucopyranoside (10) was converted to the
fully protected analogue 1111 before NBS-promoted hydrolysis of
the thioglycoside linkage (Scheme 2). Oxidation to the d-lactone 12
was accomplished using Dess–Martin periodinane. Cerium-
mediated addition of trimethylsilylacetylene followed by deox-
ygenation and desilylation then afforded terminal alkyne 14.
Bromination to give 15 was followed by oxidation with potassium
permanganate in aqueous methanol12 to yield a-ketoester 16.
On cleavage of the silyl ether with TBAF, concomitant
elimination of the 2-benzyloxy group (glucose numbering) to form
an enol ether was observed. However, when silyl ether 16 was
treated with HF–pyridine, the sole product was tricyclic acetal 17,
in which not only the silyl ether but also the 3- and 4-benzyl ethers
had been cleaved, and an acetal had formed between the ketone
and the 3- and 6-OH groups.
Notes and references
{ Data for 21: [a]1D7 +3.1 (c 1.07 in EtOH); nmax/cm21 (film) 3445 (OH),
2928 (CH), 1736 (CLO); dH (500 MHz, C6D6) 7.38–6.99 (15H, m, ArH),
5.01 (1H, d, J 11.3), 4.92 (1H, d, J 11.3), 4.82 (1H, d, J 11.6), 4.75 (1H, d, J
11.6) and 4.65 (1H, d, J 12.0, 5 of PhCH2), 4.43 (1H, dd, J 9.3, 2.8, H-2),
4.39 (1H, J 12.0, 1 of PhCH2), 4.36 (1H, br d, J 2.8, H-1), 4.22 (1H, t, J 9.4,
H-3), 4.19 (1H, td, J 3.6, 1.9, H-5), 4.11 (1H, s, OH), 4.03 (1H, dd, J 9.6,
3.7, H-4), 3.30 (1H, dd, J 13.4, 3.6, 1 of CH2S), 3.24 (3H, s, CH3), 1.57 (1H,
br d, J 13.4, 1 of CH2S); dC (125 MHz, C6D6) 173.4 (CLO), 139.1, 138.9
and 138.6 (3 6 aromatic C), 82.2 (C-3), 80.0 (C-4), 79.8 (C-2), 79.5 (C-1),
75.0 (PhCH2), 73.3 (C-5), 73.2 (PhCH2), 72.4 (PhCH2), 71.9 (SCOH), 52.5
(OCH3), 40.9 (C-6), other aromatic carbons obscured by solvent; m/z
(FAB+) 559 (MNa+, 2%), 326 (21), 199 (26), 176 (100); HRMS (FAB+)
found 559.1784; C30H32O6SNa (MNa+) requires 559.1766.
1 R. E. Mitchell and R. D. Durbin, Physiol. Plant Pathol., 1981, 18,
157–168.
Formation of the tricyclic acetal 17 precluded introduction of a
sulfur atom at C6, but alteration of the order of steps allowed
completion of the synthesis of the tagetitoxin skeleton; thus double
desilylation of 13 could be achieved with TBAF to give primary
alcohol 18 (Scheme 3). Activation as the mesylate was followed by
displacement with potassium thioacetate, and bromination of the
alkyne afforded 19. Oxidation as for compound 15 gave the
a-ketoester 20, and removal of the S-acetyl protecting group using
hydrazine hydrate in methanol led directly to the bicyclic
hemithioacetal 21.
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346–347; (b) M. Ioannou, M. J. Porter and F. Saez, Tetrahedron, 2005,
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The structure of 21 was confirmed by mass spectrometry and
NMR;{ in particular, an HMBC correlation was observed
between the hemithioacetal carbon at 71.9 ppm and one of the
CH2S protons at 1.57 ppm. Vicinal coupling constants of 9.3 and
9.6 Hz between the pairs of CHOBn protons indicated a boat
conformation for the tetrahydropyran ring, as depicted in 21. The
hemithioacetal was obtained as a single stereoisomer, although the
configuration of this centre was not determined.
1198 | Chem. Commun., 2006, 1197–1199
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