An enantioselective synthesis of the epoxyquinol (+)-isoepiepoformin

Article abstract of DOI:10.1002/ejoc.201000642

The epoxyquinol natural product: (+)-isoepiepoformin (1) has been synthesized for the first time and in an unambiguous fashion by using the scalemic cis-l,2-dihydrocatechol 2 as starting material. The spectroscopic data derived from the synthetic sample o

Full text of DOI:10.1002/ejoc.201000642

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000642
An Enantioselective Synthesis of the Epoxyquinol (+)-Isoepiepoformin
Lorenzo V. White,[a] Christine E. Dietinger,[a] David M. Pinkerton,[a] Anthony C. Willis,[a]
and Martin G. Banwell*[a]
Keywords: C–C coupling / cis-1,2-Dihydrocatechol / Enones / (+)-Isoepiepoformin / Total synthesis / Natural products
The epoxyquinol natural product (+)-isoepiepoformin (1) has
been synthesized for the first time and in an unambiguous
fashion by using the scalemic cis-1,2-dihydrocatechol 2 as
starting material. The spectroscopic data derived from the
synthetic sample of compound 1 match those reported in the
literature for the natural product and thereby confirm the
structure assigned to the latter.
all of which incorporate a substituent on the α-carbon atom
of the enone moiety or a derived substructure.[5] Accord-
ingly, we were interested in determining if our synthetic pro-
tocols could be modified so as to allow for the preparation
of isoepiepoformin (1). The outcome of our successful stud-
ies of this matter is detailed here.
Introduction
In 1986 Jarvis and Yatawara reported that, under certain
conditions, cultures of the fungus Myrothecium roridum
CL-514 (ATCC 20605) produced a new antibiotic to which
they assigned the epoxyquinol-type structure 1 and which
they named isoepiepoformin.[1] Their structural assignment
was based on 1H and 13C NMR analyses, while the absolute
stereochemistry of the compound was established by CD
spectroscopy. Isoepiepoformin differs from the related ep-
oxyquinol natural products epoformin and epiepoformin in
that the methyl group is located on the β- rather than the
α-carbon atom of the enone moiety. Despite this unusual
structural feature and the demonstrated antibacterial effects
exerted by compound 1, it has not been the subject of any
synthetic studies.
Results and Discussion
The reaction sequence used to establish the first total
synthesis of isoepiepoformin (1) is shown in Scheme 1, and
this began with the ready conversion of the iodobenzene-
derived cis-1,2-dihydrocatechol 2 (X = I) into the corre-
sponding p-methoxyphenyl (PMP) acetal 3 (97%). This ace-
tal was obtained exclusively in the illustrated epimeric form,
presumably because the reaction leading to it operates un-
der kinetic control.[6] In keeping with our recently reported
studies on its bromo analogue,[7] when a tert-butyl methyl
ether (TBME) solution of compound 3 was treated at
–78 °C with 6.5 mol-equiv. of DIBAl-H, then a ca. 2.5:1
Recently we reported[2,3] the ready preparation of a series
of enantiomerically pure epoxyquinol synthons from cis-
1,2-dihydrocatechols of the general form 2 (X = Cl, Br or
I) – the latter compounds being available in large quantity
and enantiomerically pure form through the whole-cell bio-
transformation of the corresponding halobenzene.[4] The
acquisition of these synthons enabled us to develop highly
abbreviated total syntheses of (–)-bromoxone, (–)-brom-
oxone acetate, (–)-epiepoformin, (–)-harveynone, (+)-pane-
pophenanthrin, (+)-hexacyclinol and (–)-tricholomenyn A,
1
mixture (as determined by H NMR analysis) of the ex-
pected p-methoxybenzyl (PMB) ethers 4 and 5 was ob-
tained. The structures of these chromatographically insepa-
rable products follow from a single-crystal X-ray analysis
(vide infra) of a derivative of ether 4, the preferential gener-
ation of which presumably derives from selective coordina-
tion of DIBAl-H to the acetal oxygen atom of substrate 3
that is remote from the sterically demanding iodine atom.
As a result of such coordination, the O-1–C-2 bond within
compound 3 is cleaved preferentially. Several attempts to
improve the selectivity of this reductive cleavage process,
including those involving an examination of variations in
reaction solvent and temperature as well as the nature of
the reducing agent, failed. Treatment of the 2.5:1 mixture
of monoethers 4 and 5 with N-bromosuccinimide (NBS) in
wet THF under conditions used in our earlier studies[2,3]
[a] Research School of Chemistry, Institute of Advanced Studies,
The Australian National University,
Canberra, ACT 0200, Australia
Fax: +61-2-6125-8114
E-mail: mgb@rsc.anu.edu.au
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000642.
Eur. J. Org. Chem. 2010, 4365–4367
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4365

M. G. Banwell et al.
SHORT COMMUNICATION
Scheme 1.
presumably generated both of the expected bromohydrins 6 compound 10 could be accumulated so as to allow for the
and 7 (37% yield of a Ͼ2.5:1 mixture), but only the latter completion of the synthesis. To this end, the PMB residue
product was readily isolated from the reaction mixture in within compound 10 was cleaved by using 2,3-dichloro-5,6-
pure form. In keeping with earlier observations,[2,3] reaction dicyano-1,4-benzoquinone (DDQ), and the structure of the
of compound 7 with freshly prepared sodium methoxide in alcohol 11 thus obtained (in 48% yield) was confirmed by
THF at ambient temperatures gave epoxide 8, which was single-crystal X-ray analysis (see Supporting Information
obtained as a white, crystalline solid in 99% yield. The for details). Subjection of compound 11 to a Mitsunobu
selectivity of this epoxide-forming step is attributed to the reaction by using chloroacetic acid as nucleophile[2] then
more favorable orientation of the non-allylic hydroxy group gave the chloroacetate derivative 12 of target 1 in 73% yield.
(over its allylic counterpart) for participation in the re- Finally, treatment of a methanolic solution of ester 12 with
quired internal nucleophilic displacement reaction.
zinc(II) acetate dihydrate at 18 °C afforded target 1, which
With the pivotal epoxide 8 in hand, the closing stages was obtained as a light-yellow oil in 66% yield.
of the total synthesis of (+)-isoepiepoformin (1) could be
undertaken. Thus, reaction of this compound with the
Dess–Martin periodinane[8] (DMP) proceeded smoothly to
give the crystalline β-iodo enone 9 (92%), the structure of
which was secured through a single-crystal X-ray analysis
that also served to confirm the structures of all of its pre-
cursors. The derived ORTEP is shown in Figure 1, while
additional details of this analysis are provided in the Sup-
porting Information. Subjection of compound 9 to a Stille
cross-coupling with tetramethyltin and in the presence of
Pd2(dba)3/Ph3As mixtures as catalyst precursors[2,3] resulted
in formation of the crucial β-methylated enone 10. This was
obtained in 63% yield after purification by flash
chromatography. Several attempts, including those involv-
Figure 1. ORTEP derived from the single-crystal X-ray analysis of
ing variations in catalyst and solvent, were made to improve
compound 9. Anisotropic displacement ellipsoids display 30%
the outcome of this cross-coupling reaction, but all were
without useful effect. Nevertheless, sufficient quantities of radii.
probability levels. Hydrogen atoms are drawn as circles with small
4366
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Eur. J. Org. Chem. 2010, 4365–4367

Enantioselective Synthesis of the Epoxyquinol (+)-Isoepiepoformin
Table 1. Comparison of the 13C and 1H NMR spectroscopic data (CDCl3; δ [ppm]) recorded on naturally and synthetically derived
samples of (+)-isoepiepoformin (1).
13C
Synthetic 1 (125 MHz)
1H
Natural 1 (100 MHz)
Natural 1 (400 MHz)[a]
Synthetic 1 (500 MHz)[b]
193.3
156.0
124.1
66.6
56.9
52.2
193.8 (C, C-2)
156.6 (C, C-4)
123.8 (CH, C-3)
66.5 (CH, C-5)
56.9 (CH, C-6)
52.2 (CH, C-1)
21.5 (CH3)
5.75 (m, 1 H)
5.77 (br. s, 1 H, H-3)
4.46 (d, J = 8.8 Hz, 1 H, H-5)
3.80 (dd, J = 3.4, 1.0 Hz, 1 H, H-1)
3.40 (m, 1 H, H-6)
4.43 (dd, J = 1.3 and 0.7 Hz, 1 H)[c]
3.75 (dd, J = 3.3 and 1.3 Hz, 1 H)
3.38 (ddd, J = 3.3, 3.0 and 0.7 Hz, 1 H)
2.03 (d, J = 1.3 Hz, 3 H)
2.06 (d, J = 1.5 Hz, 3 H, CH3)
–
2.99 (d, J = 8.8 Hz, 1 H, OH)[d]
21.4
[a] Data derived from ref.[1] The field strengths of the spectrometers used in acquiring the cited 1H and 13C NMR spectra are ambiguous
1
and could have been generated by using a machine operating at 200 MHz (for H spectra). [b] Data derived from present work. [c] After
H/D exchange. [d] This signal disappears upon treatment of the sample with D2O.
1
The 13C and H NMR spectroscopic data derived from
CCDC-774424 (for 9) and -774425 (for 11) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
the synthetic sample of compound 1 are in complete accord
tained free of charge from The Cambridge Crystallographic Data
with the assigned structure and, with one minor exception
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(vide infra), match those reported[1] for the natural product
(Table 1). The only apparent discrepancy between the two
data sets is seen in the resonances of H-5. In the natural
product this appears as a doublet of doublets at δ =
4.43 ppm with J = 1.3 and 0.7 Hz, whereas in the synthetic
material it appears at δ = 4.46 ppm as a doublet with J =
8.8 Hz. This difference arises because the former signal was
recorded after an H/D exchange experiment had been car-
ried out, whereas the latter was recorded without the analo-
gous exchange process having taken place. As a result, in
the spectrum of the synthetic material a significant three-
bond coupling is observed between H-5 and the hydroxy
group proton. This coupling obscures the other smaller
ones that are reported for the natural product.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, 1H NMR, 13C NMR, IR
spectroscopic together with mass spectrometric data for com-
pounds 1, 3–5 and 7–12, as well as single-crystal X-ray analyses
data for compounds 9 and 11 and an ORTEP of compound 11.
Acknowledgments
We thank the Australian Research Council and the Institute of Ad-
vanced Studies, ANU for generous financial support and Mr. Pat
Sharp (Research School of Chemistry, ANU) for helpful advice.
[1] B. B. Jarvis, C. S. Yatawara, J. Org. Chem. 1986, 51, 2906.
[2] D. M. Pinkerton, M. G. Banwell, A. C. Willis, Org. Lett. 2009,
11, 4290.
[3] D. M. Pinkerton, M. G. Banwell, A. C. Willis, Aust. J. Chem.
2009, 62, 1639.
[4] Compound 2 (X = I) can be obtained from Questor, Queen’s
University of Belfast, Northern Ireland. Questor Centre Con-
tact Page: http://questor.qub.ac.uk/contact (accessed June 21,
2010). For reviews on methods for generating cis-1,2-dihy-
drocatechols by microbial dihydroxylation of the correspond-
ing aromatic compounds, as well as the synthetic applications
of these metabolites, see: a) T. Hudlicky, D. Gonzalez, D. T.
Gibson, Aldrichim. Acta 1999, 32, 35; b) M. G. Banwell, A. J.
Edwards, G. J. Harfoot, K. A. Jolliffe, M. D. McLeod, K. J.
McRae, S. G. Stewart, M. Vögtle, Pure Appl. Chem. 2003, 75,
223; c) R. A. Johnson, Org. React. 2004, 63, 117; d) T. Hud-
licky, J. W. Reed, Synlett 2009, 685.
The specific rotation of the synthetic material {[α]D
=
+430.2 (c = 0.6, CHCl3)} proved to be more than ten times
larger than that recorded[1] for naturally derived (+)-iso-
epiepoformin (1) {[α]D = +36.4 (c = 0.5, CHCl3)}. Given
that the natural product (+)-epiepoformin, the α-methylated
congener of compound 1, is reported[9] to have a specific
rotation of [α]D = +310 (c = 0.46, ethanol), it is conceivable
that the reported value for the (+)-isoepiepoformin may
have been miscalculated and is, in fact, +364 or thereabouts.
That being so, then the structure originally assigned to (+)-
isoepiepoformin seems to be supported by the present
study.
The antibacterial effects of compound 1 and certain of
its precursors will be reported in due course.
[5] For a very useful introduction to this class of compounds, see:
J. Marco-Contelles, M. T. Molina, S. Anjum, Chem. Rev. 2004,
104, 2857.
[6] Y. Oikawa, T. Nishi, O. Yonemitsu, Tetrahedron Lett. 1983, 24,
Conclusions
4037.
The first total synthesis of (+)-isoepiepoformin (1) has
been achieved, thereby confirming the structure assigned to
this natural product. More broadly speaking, this work
highlights the continued utility of microbially derived and
enantiomerically pure cis-1,2-dihydrocatechols as starting
materials in chemical synthesis.[2–4]
[7] A. D. Findlay, A. Gebert, I. A. Cade, M. G. Banwell, Aust. J.
Chem. 2009, 62, 1173.
[8] R. E. Ireland, L. Liu, J. Org. Chem. 1993, 58, 2899.
[9] H. Okamura, H. Shimizu, N. Yamashita, T. Iwagawa, M. Nak-
atani, Tetrahedron 2003, 59, 10159.
Received: May 6, 2010
Published Online: June 25, 2010
Eur. J. Org. Chem. 2010, 4365–4367
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4367