Synthesis and reactivity of a putative biogenetic precursor to tricholomenyns B, C, D and E

Article abstract of DOI:10.1016/j.tetlet.2010.11.139

A chemoenzymatic synthesis of the putative biogenetic precursor, 6, to the epoxy-quinol type natural products, tricholomenyns B, C, D and E (2-5, respectively), has been achieved. However, treatment of compound 6 under a variety of conditions failed to ef

Full text of DOI:10.1016/j.tetlet.2010.11.139

Tetrahedron Letters 52 (2011) 2192–2194
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Tetrahedron Letters
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Synthesis and reactivity of a putative biogenetic precursor to tricholomenyns
B, C, D and E
⇑
Xinghua Ma, Jasmine C. Jury, Martin G. Banwell
Research School of Chemistry, The Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 2 December 2010
A chemoenzymatic synthesis of the putative biogenetic precursor, 6, to the epoxy-quinol type natural
products, tricholomenyns B, C, D and E (2–5, respectively), has been achieved. However, treatment of
compound 6 under a variety of conditions failed to effect its conversion into any of the natural products
2–5. In contrast, the simple model system 22 reacts with acetic acid in the presence of stoichiometric
quantities of Ti(OPr-i)4 to give the diacetate 23.
Dedicated to Professor Harry Wassermann
on the occasion of his 90th birthday and in
recognition of his profound and wide-
ranging contributions to the discipline of
organic chemistry
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chemoenzymatic
Epoxy-quinol
Sonogashira reaction
Synthesis
Tricholomenyns
Studies carried out in the mid-1990s by Vidari and co-
workers1,2 resulted in the isolation of the highly oxygenated
cyclohexanoid natural products, tricholomenyns A–E (1–5, respec-
tively), from the fruiting bodies of the Basidiomycetes species
Tricholoma acerbum (Bull.: Fr) Quel collected in the Italian
Apennines. Their structures were elucidated using NMR spectro-
scopic and mass spectrometric techniques. Compounds 1 and 2
were found to act as anti-mitotic agents and proved more potent
in this respect than Colcemid™ (deacetyl N-methylcolchicine), a
clinically effective cytotoxic agent.1 It has been suggested2 that
the biosynthesis of tricholomenyns C–E ‘proceeds via a not yet
isolated intermediate arising from the regiospecific oxidation of
congener 1 at the C-14 methyl group.’ Presumably, the monomeric
tricholomenyn B (2) could also arise via cyclization of the same
intermediate, the most obvious form of which is carboxylic acid 6.
As part of an ongoing program directed towards the synthesis of
epoxyquinol-type natural products,3,4 we have recently completed
an enantioselective synthesis of tricholomenyn A.3b As an exten-
sion of these efforts we are pursuing the synthesis of tricholome-
nyn
B (2), the first example of a natural cyclohexenoid
containing an acetylenic ansa bridge. To this end we now describe
the preparation, in enantiomerically pure form, of its potential
biogenetic (and synthetic) precursor, acid 6, and report on the
chemical reactivity of this compound.
⇑
Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M.G. Banwell).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.139

X. Ma et al. / Tetrahedron Letters 52 (2011) 2192–2194
2193
(87%). Treatment of compound 14 with tert-butyl hydroperoxide
in the presence of 0.5 mol equiv of selenium dioxide9 afforded a
chromatographically separable mixture of aldehyde 15 (18%) and
alcohol 16 (32%). The former product could be converted into the
latter (97%) using sodium borohydride in methanol. Treatment of
compound 16 with tetra-n-butylammonium fluoride (TBAF) then
afforded the terminal acetylene 17 (99%) which was converted, un-
der standard conditions, into the corresponding TBS ether 18 (94%)
ready for coupling to the core molecule 10.
In the final stage (Scheme 3) of the synthesis of target acid 6,
compounds 10 and 18 were subjected to a Sonogashira cross-cou-
pling reaction and the product 19 (85%) thereby obtained was trea-
ted with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to afford
aldehyde 20 in 72% yield. Pinnick oxidation10 of compound 20 gave
acid 21 (89%) that was then subjected to reaction with Dess–Mar-
tin periodinane (DMP)11 so as to effect oxidation of the remaining
free hydroxy group and complete the synthesis of acid 612 (55%).
The {1H}13C NMR spectrum of compound 6 displayed the expected
eighteen signals including nine due to sp2-hybridized and two due
to sp-hybridized carbons. The illustrated E-configuration about the
Scheme 1.
D
2,3-double bond in target 6, which is that expected based on the
selectivity rules for such SeO2-mediated hydroxylation reactions,13
and the likely mechanism of this process,14 was confirmed through
the observation of an NOE of the C-4 methylene protons (resonat-
ing at dH 2.47) upon irradiation of the C-2 methyl group protons
(which resonate at dH 1.86). The chemical shift of the resonance
due to H-3 (dH 6.87) is also consistent with the geometry assigned
The preparation of target 6 involved three distinct stages,
namely the synthesis of the core and the side-chain and then, in
the final stage, the linking of these two units followed by some
simple functional group interconversions. The first stage is shown
in Scheme 1 and starts with the conversion of the readily available
and enantiomerically pure cis-1,2-dihydrocatechol 75 into bro-
mohydrin 83a (68%) through reaction with N-bromosuccinimide
in wet THF. Treatment of compound 8 with sodium methoxide re-
sulted in the regioselective formation of epoxide 93a (85%) that was
subjected to Mitsunobu reaction6 with di-iso-propyl diazoacetate
(DIAD)/Ph3P using acetic acid as the nucleophile6 and thus produc-
ing, in a completely regioselective manner, acetate 10 in 64% yield.
The acetylene-containing side-chain associated with target 6
was synthesized from the commercially available ketone 11 using
the reaction sequence shown in Scheme 2. Thus, compound 11 was
converted, under standard conditions, into the corresponding enol
triflate 123b,7 (88%) that was subjected to Sonogashira cross-cou-
pling8 with trimethylsilylacetylene (13) to give the dienyne 147a,b
to the
D
2,3-double bond.9
Acid 6 proved to be a remarkably stable species and thus far we
have been unable to engage it in any productive thermal-, acid- or
Scheme 2.
Scheme 3.

2194
X. Ma et al. / Tetrahedron Letters 52 (2011) 2192–2194
References and notes
1. Garlaschelli, L.; Magistrali, E.; Vidari, G.; Zuffardi, O. Tetrahedron Lett. 1995, 36,
5633.
2. Garlaschelli, L.; Vidari, G.; Vita-Finzi, P. Tetrahedron Lett. 1996, 37, 6223.
3. (a) Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Org. Lett. 2009, 11, 4290; (b)
Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Aust. J. Chem. 2009, 62, 1639; (c)
Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Acta Crystallogr., Sect. E: Struct. Rep.
Online 2010, 66, o342.
Scheme 4.
4. For a very useful introduction to this class of compound, see: Marco-Contelles,
J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004, 104, 2857.
5. For reviews on methods for generating compounds such as 7 by microbial
dihydroxylation of the corresponding aromatics, as well as the synthetic
applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D.
T. Aldrichim. Acta 1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.;
Jolliffe, K. A.; McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vögtle, M. Pure Appl.
Chem. 2003, 75, 223; (c) Johnson, R. A. Org. React. 2004, 63, 117; (d) Hudlicky,
T.; Reed, J. W. Synlett 2009, 685.
6. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234.
7. (a) Kamikubo, T.; Ogasawara, K. Chem. Commun. 1996, 1679; (b) Graham, A. E.;
Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1997, 1087; (c) Miller, M. W.;
Johnson, C. R. J. Org. Chem. 1997, 62, 1582.
base-promoted isomerization or dimerization processes regardless
of the concentration of the substrate used. In contrast, the model
system 22, which is readily obtained in 95% yield by oxidation of
alcohol 10 with DMP (Scheme 4), reacted with acetic acid in the
presence of 1.1 mol equiv of Ti(OPr-i)4 to give the diacetate 2315
(26%) as the only characterizable product of reaction. Under the
same conditions, compound 6 was consumed but no identifiable
products could be isolated from the reaction mixture.
The origin of the divergent reactivities of compounds 6 and 22
remains unclear at the present time. There are various explana-
tions for our failure to observe the conversion of the former com-
pound into any of tricholomenyns B–E. Thus, for example, it is
possible that epoxy-acid 6 is not a biogenetic precursor to these
natural products or that the relevant conversions (of 6) are en-
zyme-mediated processes unable to be mimicked under strictly
chemical (i.e., non-biological) conditions.
8. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
9. For an example of a related oxidation, see: Banwell, M. G.; Jury, J. C. Org. Prep.
Proced. Int. 2004, 36, 87.
10. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
11. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
12. Selected spectral data for compound 6: [
a
]
D = À213.4 (c 0.5, CHCl3); 1H NMR
(CDCl3, 500 MHz) d 6.87 (m, 1H), 6.77 (dd, J = 5.5 and 2.5 Hz, 1H), 5.82 (m, 1H),
5.47 (d, J = 1.0 Hz, 1H), 5.38 (d, J = 1.0 Hz, 1H), 3.75 (m, 1H) 3.59 (dd, J = 4.0 and
1.5 Hz, 1H), 2.47 (dd, J = 14.0 and 7.0 Hz, 2H), 2.35 (br t, J = 7.0 Hz, 2H), 2.13 (s,
3H), 1.86 (d, J = 1.0 Hz, 3H) (signal due to carboxylic acid proton not observed);
13C NMR (CDCl3, 125 MHz) d 189.5 (C), 173.5 (C), 169.8 (C), 143.5 (CH), 140.8
(CH), 129.6 (CH2 or C), 128.1 (C), 124.9 (C), 124.4 (CH2 or C), 95.2 (C), 82.7 (C),
64.2 (CH), 54.9 (CH), 53.0 (CH), 35.7 (CH2), 27.5 (CH2), 20.7 (CH3), 12.2 (CH3); IR
mmax 2928, 2204, 1757, 1740, 1698, 1643, 1422, 1371, 1289, 1218, 1024,
910 cmÀ1; MS m/z (ESI, Àve ionization) 329 [(MÀH+)À, 19%], 287 (99), 243
(100), 225 (27); HRMS Found: (MÀH+)À, 329.1021. C18H17O6 requires (MÀH+)À,
329.1025.
Acknowledgements
We thank the Australian Research Council and Institute of Ad-
vanced Studies for generous financial support. J.C.J. is the grateful
recipient of an ANU Ph.D. Scholarship.
13. Bhalerao, U. T.; Rapoport, H. J. Am. Chem. Soc. 1971, 93, 4835.
14. Arigoni, D.; Vasella, A.; Sharpless, K. B.; Jensen, H. P. J. Am. Chem. Soc. 1973, 95,
7917.
15. Selected spectral data for compound 23: [
a
]
D = À51.0 (c 0.5, CHCl3); 1H NMR
Supplementary data
(CDCl3, 500 MHz) d 7.49 (d, J = 2.5 Hz, 1H), 5.66 (dd, J = 8.5 and 2.5 Hz, 1H), 5.44
(d, J = 8.5 Hz, 1H), 4.20 (m, 1H), 2.72 (br s, 1H), 2.24 (s, 3H), 2.20 (s, 3H); 13C
NMR (CDCl3, 125 MHz) d 186.2 (C), 170.5 (C), 170.0 (C), 153.6 (CH), 102.1 (C),
75.0 (CH), 74.5 (CH), 73.0 (CH), 20.9 (CH3), 20.7 (CH3); IR mmax 3468, 2923,
2852, 1752, 1710, 1373, 1223, 1071, 1036, 800, 737 cmÀ1; MS m/z (EI, 70 eV)
Supplementary data (including experimental procedures and
product characterization for compounds 6, 10 and 15–23) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.139.
354 (M+Å, 5%), 312 (20), 252 (100), 223 (16), 210 (32); HRMS Found: M+Å
353.9597. C10H11IO6 requires M+Å, 353.9600.
,