A Catalytic Oxidative Quinone Heterofunctionalization Method: Synthesis of Strongylophorine-26

Article abstract of DOI:10.1002/anie.201805580

The preparation of heteroatom-substituted p-quinones is ideally performed by direct addition of a nucleophile followed by in situ reoxidation. Albeit an appealing strategy, the reactivity of the p-quinone moiety is not easily tamed and no broadly applicable method for heteroatom functionalization exists. Shown herein is that Co(OAc)₂ and Mn(OAc)₃?2 H₂O act as powerful catalysts for oxidative p-quinone functionalization with a collection of O, N, and S nucleophiles, using oxygen as the terminal oxidant. Preliminary mechanistic observations and the first synthesis of the cytotoxic natural product strongylophorine-26 is presented.

Full text of DOI:10.1002/anie.201805580

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: A Catalytic Oxidative Quinone Heterofunctionalization Method -
Synthesis of Strongylophorine-26
Authors: Wanwan Yu, Per Hjerrild, Kristian Jacobsen, Henriette
Tobiesen, Line Clemmensen, and Thomas Bjørnskov Poulsen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805580
Angew. Chem. 10.1002/ange.201805580
Link to VoR: http://dx.doi.org/10.1002/anie.201805580
http://dx.doi.org/10.1002/ange.201805580

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
A Catalytic Oxidative Quinone Heterofunctionalization Method –
Synthesis of Strongylophorine-26
Wanwan Yu+, Per Hjerrild+, Kristian M. Jacobsen, Henriette N. Tobiesen, Line Clemmensen, Thomas
B. Poulsen*[a]
Abstract: The preparation of heteroatom-substituted p-quinones is
ideally performed by direct addition of a nucleophile followed by in situ
reoxidation. Albeit an appealing strategy, the reactivity of the p-
quinone moiety is not easily tamed and no broadly applicable method
for heteroatom functionalization exists. Here, we show that Co(OAc)2
and Mn(OAc)3•2H2O act as powerful catalysts for oxidative p-quinone
functionalization with a collection of O, N, and S-nucleophiles using
oxygen as the terminal oxidant. Preliminary mechanistic observations
and the first synthesis of the cytotoxic natural product
strongylophorine-26 is presented.
ostensibly an attractive option (Scheme 1C, Pathway-B), the
advantage of applying this approach had not been exploited.
Indeed, a literature survey revealed the lack of a general method
for p-benzoquinone alkoxylation.
Quinones have a strong propensity for undergoing proton-
coupled electron-transfer reactions,[1] which has spurred
numerous applications within materials/polymer science[2] and
chemical biology.[3] While redox cycling of quinones has been
harnessed for powerful oxidative transformations,[4] the redox
characteristics of unprotected quinones limit their utility as
chemical reactants. The introduction of heteroatoms onto the
quinone ring affords increased stability and these groups are
prevalent in bioactive natural products (Scheme 1A),[5]
underscoring the value of efficient synthetic methods. Here, we
report
a
novel
and
broadly
applicable
quinone-
heterofunctionalization reaction, which we have employed in the
first synthesis of the cytotoxic meroterpenoid strongylophorine-26
(STR-26, 1).
We earlier achieved the first synthesis of strongylophorine-2
(STR-2, 2, Scheme 1B)[6] – a potential synthetic precursor to other
STR natural products. In this respect, STR-26 (1, Scheme 1B) is
of particular interest as 1 has been reported to depolarize cancer
cells by actin-remodeling.[7,8] These effects likely underlie the
potent cytotoxicity of 1, but the detailed mechanism is unknown.
In solution, STR-26 (1) exists in an equilibrium between the 6´-
methoxy-quinone and two diastereomeric hemiketals involving
the C3-hydroxyl group (Scheme 1B).[7] To prepare 1 from 2,
oxidative opening of the 4’-phenoxychromane ring and installation
of the methoxy substituent are required. We initially aimed for
functionalization of the chromane moiety prior to oxidative
opening (Scheme 1C, Pathway-A), but despite considerable
efforts this strategy could not be realized (see Table S1 and
Scheme S1, Supporting Information).
Scheme 1. Heteroatom-functionalized quinone natural products and strategies
for constructing STR-26 from STR-2.
Recently, the Lumb lab reported an excellent method for the
aerobic coupling of phenols to o-quinones, but this system was
unable to functionalize p-quinones.[9] In fact, the evaluation of the
methods known to us[10] in a simple quinone test system (4) was
not encouraging (Figure 1), as we observed either no reactivity,
or complex mixtures containing only small quantities of mono-
methoxyquinone 6a.
These discouraging results likely reflect the propensity of p-
benzoquinones to dimerize and oligomerize under both acidic and
basic conditions.[11] Interestingly, a control experiment revealed
that simply heating 4 in MeOH under oxygen was superior to all
other conditions that we had tested at this point affording 6a in
mediocre yield at full conversion of 4 (Figure 1). While somewhat
encouraging, this reactivity is not general.[12] We hypothesized
Next, we considered direct methoxylation of p-benzoquinone
3, which can be generated by NaIO4-oxidation of 2.[6] While
[a]
Dr. W. Yu,[+] P. Hjerrild,[+] K. M. Jacobsen, H. N. Tobiesen, L.
Clemmensen, Prof. Dr. T. B. Poulsen
Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
*E-mail: thpou@chem.au.dk.
[+]
The authors contributed equally to this work
Supporting information and the ORCID identification number(s) for
the author(s) are given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
that an additive could be identified which would accelerate both
nucleophilic addition and reoxidation of a putative hydroquinone
intermediate, leading us to perform a broad screen of metal salts
for promoting mono-methoxylation of 4 (representative results in
Figure 1 – complete data in Table S2, Supporting Information).[12]
This led to the discovery that Mn(OAc)3•2H2O and in particular
Co(OAc)2 afford good to excellent yields of 6a as a mixture of
regioisomers.[13] Other metal-salts displayed disparate effects,
most prominently Fe(OAc)2, which completely blocked conversion
of 4. Catalytic quantities of the respective metal salts were
sufficient to enhance or suppress reactivity.
Figure 1. Methoxylation of 2-methyl-p-benzoquinone. Yield and isomer ratio
determined by 1H NMR of the reaction mixture. [a] 4% of C3-isomer observed.
[b] Conditions: O2 (1 bar), MeOH, 60 °C, 22 h. [c] Isolated yield.
To probe the mechanism, we investigated the kinetic profiles
of methoxylation of 4 (Figure 2A, 2B). With no catalyst, the
reaction affords a mixture of 6a and 4a in a ratio that is clearly
correlated, suggesting involvement of 4 as the kinetically favoured
oxidant of a hydroquinone intermediate (5a). Catalytic amounts of
Co(OAc)2 facilitates reoxidation of 4a and ultimately allows
productive funnelling to the product 6a. In accord, the
hydroquinone intermediate 5a undergoes spontaneous redox
exchange with 4 at ambient temperature (Figure 2C). The
disubstituted quinone 5g, generated upon oxidation of
hydroquinone 5b, does not undergo spontaneous methoxylation
in methanol at 60 ºC and thus can test the ability of the catalysts
to facilitate both nucleophilic addition and hydroquinone
reoxidation (Figure 2D). Partial oxidation of hydroquinone 5b to
quinone 5g was evident by 1H-NMR analysis of the crude reaction
mixtures, however, catalytic Co(OAc)2, Co(acac)2, or
Mn(OAc)3•2H2O were required for formation of product 6g. Thus,
the metal is needed for quinone activation. The nature of the
counterion is decisive in tuning the properties as CoCl2, Co(OAc)2
and Co(acac)2 afford differing reactivity in this system. Combined
addition of CoCl2 and NaOAc effectively mimics the reactivity of
the corresponding Co(OAc)2 reaction. Catalytic amount of
Fe(OAc)2 provided quantitative oxidation of 5b however without
the formation of 6g, further substantiating a specific interaction
Figure 2. Proposed mechanism and mechanistic elaboration.
between the quinoid compounds and Fe(OAc)2. Cyclic
voltammetry measurements of the metal salts in methanolic
solution indicate a correlation between the oxidation potential and
the catalytic activity of the corresponding metal salt (Figure 2D).
The generality of the catalytic system was probed (Figure 3).
Methoxylation and ethoxylation are generally possible and in
sterically biased systems high regiocontrol is observed (6b and
6c). Addition of isopropanol was possible (6d) but tert-butanol and
phenol did not couple. Highly efficient 2,5-dialkoxylation was
This article is protected by copyright. All rights reserved.

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
performed on p-benzoquinone (6e and 6f) and 2-Ph-p-
benzoquinone (6m). In general, reactions can also be initiated
from the corresponding hydroquinone (6g and 6h) as discussed
above. Methoxylation of chlorinated quinones was challenging
due to competing vinylic substitution (6i and 6j), however the
presence of Co(OAc)2 was required for reactivity. p-
Naphthoquinone underwent alkoxylation in good yields (6k and
6l) and naturally occurring quinone compounds or analogs (6n,
6o) may be produced.
excellent outcomes for the majority of applied substrates
(Supporting Information, Scheme S2 displays examples (7a-h,
7m-q) of mono-addition of amines). Notably, the method
delivered 2,5-diamino-p-benzoquinones (7i, 7j) or mixed 2,5-
aminoalkyl-methoxy-p-benzoquinones (7k, 7l) with very high
regioselectivities (Figure 3). As a further application, we prepared
2,5-diaminoalkyl-p-benzoquinone 7p in excellent yield (Figure 3).
Ring-closing metathesis afforded atropisomeric macrocycle 12a
in nearly quantitative yield.[15]
We investigated the addition of amine-nucleophiles to p-
Thiol-addition was also facile as exemplified with the
thioethylation of p-naphthoquinone (8a). Selective bis-
thioethylation proceeded albeit in low yield (8b) and tri-substituted
benzoquinones.
Prior
studies
have
reported
similar
transformations,[14] but the use of catalytic Co(OAc)2 provided
Figure 3. Scope of the quinone heterofunctionalization conditions. i Mn(OAc)3•2H2O was applied; ii decomposition was observed during purification. Abbreviations:
no cat = no catalyst was applied; no conv. = no conversion was observed by TLC analysis; no prod. = no product formation was observed by TLC analysis; rsm =
recovered starting materials; [HPLC] = preparative HPLC purification was applied; from HQ = the corresponding hydroquinone was used as the substrate.
This article is protected by copyright. All rights reserved.

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
compounds such as 8c could also be prepared.[16]
Finally, we explored the preparation of unsymmetric
benzoquinones based on mono-aminated starting materials 9a
and 9b, which we serendipitously found can be accessed
efficiently using catalytic Fe(OAc)2. This enabled construction of
a series of 2,5-disubstituted quinone derivatives (10a-j) with
excellent regiocontrol. The unanimous tendency for 2,5-
substitution found in compounds with two heteroatom
substituents (6e-f, m,o; 7i-l; 8b; 10a-j) is indicative of a Lewis acid
activation mode through chelate-coordination of the mono-
functionalized quinone.
We evaluated the robustness of the methoxylation reaction of
5b in the presence of nine stoichiometric additives (Figure 3).[17]
A functional group was deemed tolerated if the methoxylation
proceeded in 90% in comparison to the standard reaction, with
conversion of the additive being below 10%. Aniline, being itself a
substrate (7q, Scheme S2), was not tolerated but all other
functional group sampled were compatible (Figure 3).
We now returned to the initial synthetic target – STR-26 (1).
Chromane-oxidation of 2 using NaIO4•SiO2 afforded quinone 3.
We did not attempt purification of this rather unstable species, but
immediately subjected it to the methoxylation-conditions using
Co(OAc)2 in methanol at reflux for 44 h. We used 40 mol%
Co(OAc)2 to facilitate conversion, as the amount of 2 disallowed
mimicking the substrate concentration previously utilized.
Gratifyingly, this afforded a mixture of 1 and the tentative 5’-
regioisomer (13) in 61% yield (ca. 85% purity) over two steps
(Scheme 2A). Further purification by preparative HPLC afforded
1, however 13 could not be obtained cleanly. The spectroscopic
data for synthetic 1 matched the data reported for STR-26 isolated
from the natural source (Table S3,4, Supporting Information).[7]
We also conducted the methoxylation on a non-lactone
analog (see Supporting Information) to generate a mixture of
methoxy-quinones 15 and 16 (53% yield, ca. 90% purity)
(Scheme 2A). Again, only the 6´-isomer (15) could be obtained
cleanly following HPLC purification, and NMR analysis revealed
that this analog also equilibrates to the hemiketal. We validated
the previously reported ability of 1 to depolarize cancer cells and
to kill MDA-MB-231 breast cancer cells at low micromolar
concentrations (Scheme 2B).
Comparison of the cytotoxicity of 1 with 2 and analog 15
demonstrates that both the δ-lactone and the methoxyquinone
functionalities of 1 are needed for potency (Scheme 2C).
Preliminary evaluation of additives for ability to modulate toxicity
of 1 and 2 was performed (Figure S7, Supporting Information).
In conclusion, we have developed a simple and broadly
applicable method for functionalization of p-quinones with a
variety of heteroatom nucleophiles under aerobic catalytic
conditions. Mechanistic features have been evaluated in an effort
to understand the intricacies of the reaction. For many substrates,
the reaction proceeds in good yields and high selectivities and
application in a late-stage setting was demonstrated. The method
does not translate directly to o-quinones and more studies will be
required to understand this limitation. With access to STR-26, as
well as unnatural analogs, further biological studies are now
possible.
Scheme 2. A. Synthetic route to STR-26 (1) and analog (15). B. Cell
polarization was assessed in MDA-MB-231 cells by visual inspection (N > 300
for each condition). C. Viability of MDA-MB-231 cells. Curves from
a
representative experiment are shown.
Acknowledgements
We thank the Lundbeckfoundation, the Danish Research
Foundation, and the Carlsberg Foundation for financial support.
Jacob Overgaard is acknowledged for X-Ray analysis of 12a.
Access to the 950 MHz NMR spectrometer at the Danish Center
for Ultrahigh-Field NMR Spectroscopy (Ministry of Higher
Education and Science grant AU-2010-612-181) is acknowledged.
The K. A. Jørgensen group is acknowledged for technical
assistance. The Collins Pine Company of Chester, California is
acknowledged for supplying Pinus Ponderosa bark.
Keywords: Quinones • Catalysis • Oxygen • Oxidative coupling
• Natural Products
[1]
N. Song, C. J. Gagliardi, R. A. Binstead, M.-T. Zhang, H. Thorp, T. Meyer,
J. Am. Chem. Soc. 2012, 134, 18538-18541.
[2]
[3]
W. Ma, Y.-T. Long, Chem. Soc. Rev. 2014, 43, 30-41.
a) D. P. Walton, D. A. Dougherty, J. Am. Chem. Soc, 2017, 139, 4655-
4658; b) M. N. Levine, R. T. Raines, Chem. Sci. 2012, 3, 2412-2420.
For a review, see: a) A. E. Wendlandt, S. S. Stahl, Angew. Chem. Int. Ed.
2015, 54, 14638-14658; Recent examples: b) X. Chen, J.-J. Li, X.-S. Hao,
C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 78-79; c) K. L.
[4]
This article is protected by copyright. All rights reserved.

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904-11905; d) C.
C. Pattillo, I. I. Strambeanu, P. Calleja, N. A. Vermeulen, T. Mizuno, M.
C. White, J. Am. Chem. Soc. 2016, 138, 1265-1272; e) S. H. Hong, D. P.
Sanders, C. W. Lee, R. H. Grubbs, J. Am. Chem. Soc. 2005, 127, 17160-
17161.
Gašić, W. Muster, J. J. Csanádi, B. A. Šolaja, Tetrahedron 1997, 53,
14073-14084; e) L. Garuti, M. Roberti, D. Pizzirani, A. Pession, E.
Leoncini, V. Cenci, S. Hrelia, Farmaco 2004, 59, 663-668; f) T. Ling, E.
Poupon, E. J. Rueden, S. H. Kim, E. A. Theodorakis, J. Am. Chem. Soc.
2002, 124, 12261-12267; For alkoxylations of 2-acyl quinones, see e.g.:
g) F. Farina, J. Valderrama, Synthesis, 1971, 315-316; h) P. Capdeville,
M. Maumy, Tetrahedron, 2001, 57, 379-384.
[5]
For a review, see: a) S. N. Sunassee, M. T. Davies-Coleman, Nat. Prod.
Rep. 2012, 29, 513-535; recent examples: b) C. Xing, J. P. LaPorte, J.
K. Barbay, A. G. Myers, Proc. Natl. Acad. Sci. USA, 2004, 101, 5862-
5866; c) M. T. Hoyt, R. Palchaudhuri, P. J. Hergenrother, Invest. New
Drugs, 2011, 29, 562-573.
[11] a) P. Jacob III, P. S. Callery, A. T. Shulgin, N. Castagnoli Jr., J. Org.
Chem. 1976, 41, 3627-3629; b) S. I. Sadykh-Zade, A. V. Ragimov, S. S.
Suleimanova, V. I. Liogon’kii, Polym. Sci. (USSR) (Engl. Transl.), 1972,
14, 1395-1403.
[6]
[7]
[8]
W. Yu, P. Hjerrild, J. Overgaard, T. B. Poulsen, Angew. Chem. Int. Ed.
2016, 55, 8294-8298.
[12] Alkoxylation of mono-alkyl quinones under neutral conditions was
observed previously: a) J. M. Singh, A. B. Turner, J. Chem. Soc., Perkin
Trans. 1 1974, 2556-2559. In these studies Zn(II) was also tested as a
Lewis acid, with limited advantage over the uncatalyzed reaction. This is
in accord with our observation that Zn(OAc)2 is not able to facilitate
methoxylation of 4. For even earlier studies, see: b) Knoevenagel, E.;
Bückel, C. Chem. Ber. 1901, 34, 3993-3998.
K. Warabi, L. M. McHardy, L. Matainaho, R. Van Soest, C. D. Roskelley,
M. Roberge, R. J. Andersen, J. Nat. Prod. 2004, 67, 1387-1389.
a) L. M. McHardy, K. Warabi, R. J. Andersen, C. D. Roskelley, M.
Roberge, Mol. Cancer Ther. 2005, 4, 772-778; b) K. Warabi, B. O. Patrick,
P. Austin, C. D. Roskelley, M. Roberge, R. J. Andersen, J. Nat. Prod.
2007, 70, 736-740.
[9]
a) Z. Huang, J.-P. Lumb, Angew. Chem. Int. Ed. 2016, 55, 11543-11547;
see also: b) K. V. N. Esguerra, Y. Fall, L. Petitjean, J.-P. Lumb, J. Am.
Chem. Soc. 2014, 136, 7662-7668; c) Z. Hunag, M. S. Askari, K. N.
Esguerra, T.-Y. Dai, O. Kwon, X. Ottenwaelder, J.-P. Lumb, Chem. Sci.
2016, 7, 358-369. For alkylation and arylation of quinones, see: d) D.
Dixon, J. W. Lockner, Q. Zhou, P. S. Baran, J. Am. Chem. Soc. 2012,
134, 8432-8435; e) X.-L. Xu, Z. Li, Angew. Chem. Int. Ed. 2017, 56, 8196-
8200; f) Á. Gutiérrez-Bonet, C. Remeur, J. K. Matsui, G. A. Molander, J.
Am. Chem. Soc. 2017, 139, 12251-12258.
[13] Anhydrous and hydrate-forms of Mn(OAc)3 and Co(OAc)2 afforded
similar outcomes.
[14] See e.g.: a) C. J. Cavallto, A. E. Soria, J. O. Hoppe, J. Am. Chem. Soc.
1950, 72, 2661-2665; b) A. H. Crosby, R. E. Lutz, J. Am. Chem. Soc.
1956, 78, 1233-1235; c) H. Zhang, L. Liu, Y. Chen, D. Wang, C. Li, Adv.
Synth. Catal. 2006, 348, 229-235.
[15] CCDC 1548695 (12a) contains the supplementary crystallographic data.
The data are provided free of charge by The Cambridge Crystallographic
Data Centre.
[10] a) G. A. Kraus, I. Kim, J. Org. Chem. 2003, 68, 4517-4518; b) M. Kidwai,
P. Kumar, S. J. Kohli, Chem. Res. 1997, 24-25; c) Z.-E. Yan, Y. Xiao, L.
Zhang, Angew. Chem. Int. Ed. 2012, 51, 8624-8627; d) D. R. Milić, M. J.
[16] Thiophenol derivatives did not couple to 5b under standard conditions.
[17] K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597-601.
This article is protected by copyright. All rights reserved.

10.1002/anie.201805580
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Sine qua non: Heteroatom-
functionalized p-quinones are
Wanwan Yu+, Per Hjerrild+, Kristian
Mark Jacobsen, Henriette N. Tobiesen,
Line Clemmensen, Thomas B. Poulsen*
important within the chemical sciences
and recurring elements of bioactive
natural products. A powerful catalytic
method employing transition metal
salts and molecular oxygen as
terminal oxidant for direct coupling of
p-quinones to O, N, S-nucleophiles is
reported. The value of the method is
demonstrated by the first preparation
of the terpenoid strongylophorine-26.
Page No. – Page No.
A Catalytic Oxidative Quinone
Heterofunctionalization Method –
Synthesis of Strongylophorine-26
This article is protected by copyright. All rights reserved.