Development of an iron(II)-catalyzed aerobic catechol cleavage and biomimetic synthesis of betanidin

Article abstract of DOI:10.1002/chem.201403436

An aerobic iron(II)-catalyzed cleavage of catechols was developed. This reaction allows for the preparation of 2-methoxy-2H-pyrans that can be employed as versatile building blocks for synthesis. The utility of this biomimetic oxidative cleavage is featured in the synthesis of betanidin, a natural colorant with antioxidant properties. Cut and paste: An aerobic iron(II)-catalyzed oxidative cleavage of catechol was developed. This reaction allows the preparation of 2H-pyrans that can be employed as versatile building blocks for synthesis. The utility of this biomimetic cleavage is featured in the synthesis of betanidin, the aglycone of red beets' principal colorant and itself a valuable antioxidant (see scheme).

Full text of DOI:10.1002/chem.201403436

DOI: 10.1002/chem.201403436
Communication
&
Biomimetic Synthesis
Development of an Iron(II)-Catalyzed Aerobic Catechol Cleavage
and Biomimetic Synthesis of Betanidin
Nicolas Guimond, Peter Mayer, and Dirk Trauner*[a]
tion of betalamic acids with a variety of amines, often also de-
Abstract: An aerobic iron(II)-catalyzed cleavage of cate-
rived from l-DOPA, then gives rise to a family of dyes known
chols was developed. This reaction allows for the prepara-
as betalains.[4] In the plant order Caryophyllales, which includes
tion of 2-methoxy-2H-pyrans that can be employed as
cacti, beets, amaranths, and many insectivores, these have re-
versatile building blocks for synthesis. The utility of this
placed the otherwise predominant anthocycanins. One of their
biomimetic oxidative cleavage is featured in the synthesis
best-known representatives, betanin, is responsible for the in-
of betanidin, a natural colorant with antioxidant proper-
tense color of red beets (Beta vulgaris) and is widely employed
ties.
in the food industry. Similar to its aglycone, betanidin, it has
been investigated for its antioxidant properties, which adds to
its value as a food additive.[5] Indicaxanthin is found in the
Oxidative transformations of the amino acid l-DOPA account
for some of the most important colorants found in Nature. De-
hydrogenation of the catechol moiety to the corresponding
ortho-quinone, for instance, fol-
fruits of prickly pear cacti and is a condensation product of be-
talamic acid with l-proline. Muscapurpurin and muscaaurin II,
in turn, account for the bright red orange color of the fly
lowed by intramolecular nucleo-
philic attack gives l-dopaqui-
none, which can undergo further
transformations and polymeri-
zation to afford melanin in its
many varieties (Figure 1a). The
exact structures of these evolu-
tionarily
ancient
pigments,
which are mostly synthesized to
prevent DNA damage, are still
unknown. This does not distract
from the significance of this
chemistry, however, which ac-
counts for skin, eye, and hair
color in humans and plays a criti-
cal role in our visual system.[1]
An alternative biosynthetic
pathway found in certain plants
and higher fungi involves the so-
called extradiol cleavage of l-
DOPA catalyzed by catechol-2,3-
dioxygenases.[2] One of the two
possible modes, shown in Fig-
ure 1b, leads to the formation of
betalamic acid (1).[3] Condensa-
Figure 1. Oxidative chemistry of l-DOPA and representative members of betalain natural products
agaric (Amanita muscaria). Their variable “northern” part re-
[a] Dr. N. Guimond, Dr. P. Mayer, Prof. Dr. D. Trauner
Department of Chemistry, Ludwig-Maximilians University Munich
and Center for Integrated Protein Science
flects the two different modes of extradiol cleavage that l-
DOPA can undergo, namely, 2,3- and 1,6-cleavage, respectively
(DOPA nomenclature).
Butenandstrasse 5–13, 81377 Munich (Germany)
Fax: (+49)89-2180-77972
Over the years, chemists have been trying to mimic the ac-
tivity of catechol-2,3-dioxygenases by using simple systems. In
that regard, important advances were made by the groups of
E-mail: dirk.trauner@cup.uni-muenchen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403436.
Chem. Eur. J. 2014, 20, 9519 – 9523
9519
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Funabiki,[6] Dei,[7] Bugg,[8] Palaniandavar,[9] and Que.[10] They
showed that it was possible to perform extradiol cleavages by
using a stoichiometric iron(II)/fac-tridentate ligand system.
Based on the results obtained by Bugg in 2001 with an iron(II)/
1,4,7-triazacyclononane (TACN) system (Figure 2), we ques-
tion giving a 2-methoxy-2H-pyran. We presume that the
higher concentration of acidic catechol is responsible for the
cyclic acetal formation under these conditions. By considering
the mechanism that was put forth to account for these oxida-
tive cleavages,[8] we reasoned that catalytic turnover should be
possible. We thus attempted a re-
action using only 5 mol% of
FeBr2/TACN complex (Table 1,
entry 3). Gratifyingly, turnover
occurred and a separable 5:1
mixture of 1,6:2,3 cleavage prod-
ucts could be isolated in 69%
combined yield. Upon further re-
action development (see the
Supporting Information), the
yield of 2a could be increased
to 77%.[12]
Evaluation of the reaction
scope revealed that several 4- or
4,5-alkyl-substituted
catechols
were tolerated,[13] the 1,6-cleav-
age product being consistently
Figure 2. Prior art in extradiol cleavage and present work.
the major one (Table 2). In terms
tioned whether it would be possible to access the structure of
betalamic acid in a biomimetic fashion. This would grant us
a rapid access to natural colorants that would otherwise be dif-
ficult to obtain in a pure form from the natural source. Litera-
ture precedents suggested that a number of difficulties would
have to be addressed to reach this goal. First, the cleavage se-
lectivity of a 4-substituted catechol had not been thoroughly
assessed and it was initially proposed to occur at the unde-
sired 2,3-position.[8b] To obtain a betalamic acid derivative, the
cleavage would have to take place at the 1,6-position (DOPA
nomenclature). Also, the conditions employed previously, with
the exception of one very recent contribution from Paine,[11]
used a stoichiometric amount of iron complex, and the extra-
diol cleavage products obtained had either undergone carbon
monoxide release, over-oxidation to an a-pyrone,
of functional-group compatibility, molecules 2e–g showed that
protected amines, protected alcohols, and esters were tolerat-
ed. In the case of l-DOPA, a 1:1 mixture of epimers with re-
spect to the 2-methoxy 2H-pyran moiety was obtained in 56%
yield. One of these, 2 f gave crystals suitable for X-ray diffrac-
tion analysis, which confirmed our structural assignment
(Figure 3).[14] For now, the reaction does not tolerate electron-
withdrawing groups or substituents at the 3- or 6-position of
the starting catechol, that is, ortho to the phenolic hydroxyl
groups.
The surprising site selectivity of this cleavage prompted us
to revisit the conditions reported by Bugg et al. in 2001, in
which the cleavage was proposed to occur at the 2,3-position
exclusively.[8b] Given the instability of the extradiol cleavage
and/or were not isolated.[7–9] Herein, we describe
a catalytic method that performs the desired extra-
diol cleavage while providing versatile and isolable
heterocyclic building blocks. We then feature the util-
ity of this biomimetic cleavage by synthesizing beta-
nidin, starting from l-DOPA.
Table 1. Key observations during reaction development.[a]
As was mentioned, the exploration of this iron-cat-
alyzed catechol extradiol cleavage began with modi-
fication of the conditions reported by Bugg in
2001.[8b] Therein, the reaction was studied by UV/Vis
spectroscopy and thus conducted at low concentra-
tion (0.2 mm) due to the highly colored nature of the
oxidation products obtained. When repeating the
original protocol, but under more concentrated con-
ditions (Table 1, entry 2), a colorless cleavage product
was obtained instead of the expected conjugated
system. Isolation and structure elucidation of this
new compound revealed that it was the result of an
extradiol cleavage followed by a cyclic acetal forma-
Entry
FeBr2 loading
[mol%]
Catechol
Yield[b] [%]
Notes
concentration[b]
(selectivity 2,3:1,6)[c]
1
100
100
5
0.2 mm
3 mm
60 (1:3)
86 (1:3)
69 (1:5)
77 (1:5)
2H-pyran was
not formed[c]
2H-pyran was
obtained
2H-pyran was
obtained
2
3
0.06 m
0.06 m
4[d]
5
2H-pyran was
obtained
[a] Conditions: FeBr2, TACN (same amount as FeBr2), pyridine (3 equiv), MeOH, O2,
room temperature, 16 h. [b] Isolated yields are reported. [c] Isolated as the corre-
sponding pyridine [d] Using chloral hydrate (1 equiv) as an additive.
Chem. Eur. J. 2014, 20, 9519 – 9523
www.chemeurj.org
9520
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
tained after the cleavage reaction with a source of
ammonia (Scheme 1). This gave stable pyridines with
a substitution pattern informative of the cleavage se-
lectivity. Opposed to the results initially reported, the
cleavage seems to occur at the same position under
Bugg’s conditions as under our newly developed
ones, that is the 1,6-position.
Table 2. Scope of FeII-catalyzed oxidative cleavage of catechol.[a,b]
Noteworthy is that the cyclic acetals obtained in
our system can also be treated with ammonium for-
mate to form carbomethoxy pyridines in one pot
(Scheme 2). Additionally, reaction with secondary
amines gave conjugated systems analogous to the
Zincke aldehyde.[15] The synthesis of betanidin pre-
sented herein feature the use of such an intermedi-
ate.
As was stated in the introduction, our main moti-
vation for the development of a practical extradiol
cleavage was the development of a general and bio-
mimetic route to betalains starting from l-DOPA.[16]
We first targeted the natural product betanidin, the
aglycon of betanin, which is biosynthetically made of
two parts originating from oxidative transformations
of l-DOPA (Scheme 3). Hence, the sequence was initi-
[a] Conditions: FeBr2 (5 mol%), TACN (5 mol%), pyridine (3 equiv), chloral hydrate
(1 equiv), MeOH, O2, 508C, 16 h. [b] Isolated yields are reported. [c] Separable 5:1 mix-
ture of 1,6- and 2,3-cleavage products (2,3-cleavage product not shown). [d] Insepara-
ble 5:1 mixture of 1,6 and 2,3-cleavage products (2,3-cleavage product not shown).
[e] FeBr2/TACN (7.5 mol%) was used and the reaction was run at 358C.
ated with the protection of the amino acid moiety of l-DOPA
to obtain N-Boc-l-DOPA methyl ester 5. Aerobic iron(II)-cata-
lyzed oxidative cleavage on this substrate by using 7.5 mol%
FeBr2/TACN gave the desired 2-methoxy-2H-pyran 2 f in 56%
yield on a 2.5g scale. Initial attempts of making betalamic acid
dimethyl ester from this intermediate via the deprotection of
the amine and condensation onto the a-keto ester were un-
successful due to preferential condensation of the nitrogen
onto the acetal/aldehyde carbon. To circumvent this problem,
we modified our strategy and installed the “northern” amino
acid directly at this stage. Thus, exposing (S)-cyclo-DOPA
methyl ester (6)[17] to 2 f gave a deep-red-colored intermediate
with the presumed structure 7, which could be detected by
LC-MS (lmax =490 nm) but could not be isolated. Therefore, we
avoided purification and replaced the solvent of this reaction
mixture by TFA to trigger the amine deprotection and its con-
densation onto the a-ketoester. This procedure allowed the
isolation of air-sensitive betanidin trimethylester (8) in 48%
yield as a single diastereoisomer. We finally applied the condi-
tions reported by Hilpert and Dreiding to hydrolyze the three
methyl esters and obtained betanidin together with its C-15
epimer isobetanidin in 31%
Figure 3. X-ray structure of 2-methoxy-2H-pyran 2 f.
products obtained in their report, isolation and proper charac-
terization could not be carried out. To address this issue, we re-
peated the same experiment, but we treated the mixture ob-
combined yield (d.r.ꢀ1:1; the
previously unreported 13C NMR
spectra of betanidin and isobeta-
nidin can be found in the Sup-
porting Information).[16c]
In conclusion, a biomimetic
aerobic iron(II)-catalyzed cate-
chol extradiol cleavage reaction
that provides cyclic 2H-pyran
acetals in synthetically useful
yields was developed. These het-
Scheme 1. Cleavage selectivity under previously reported conditions.
erocycles can easily be viewed
Chem. Eur. J. 2014, 20, 9519 – 9523
www.chemeurj.org
9521
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
tert-butyl-catechol (250 mg, 1.50 mmol, 1.00 equiv). O2
was then bubbled through the mixture for 20 min. The
reaction mixture was allowed to stir under an O2 atmos-
phere for 16 h. Silica gel (ca. 3.5 g) was then added to
the mixture, and the volatiles were evaporated under re-
duced pressure. Purification was made by flash-column
chromatography by using 12% EtOAc in hexanes as
eluent. The product was obtained as a clear oil (260 mg,
77%) containing a 5:1 mixture of 1,6- versus 2,3 extradiol
cleavage that can be separated by
Scheme 2. One-pot synthesis of a carbomethoxy pyridine from a catechol.
flash chromatography by using the
same conditions.
Acknowledgements
N.G. thanks NSERC for a postdoc-
toral fellowship. We thank the
Deutsche
Forschungsgemein-
schaft (SFB 749) for financial sup-
port.
Keywords: aerobic oxidation
·
betalain · biomimetic synthesis ·
green chemistry · iron
[1] For selected reviews, see: a) J. D.
Simon, D. N. Peles, Acc. Chem. Res.
2010, 43, 1452; b) M. d’Ischia, A.
Napolitano, A. Pezzella, P. Mere-
dith, T. Sarna, Angew. Chem. 2009,
121, 3972; Angew. Chem. Int. Ed.
2009, 48, 3914.
[2] For reviews on catechol dioxyge-
nases, see: a) L. Que, Jr., R. Y. N. Ho,
Chem. Rev. 1996, 96, 2607;
b) T. D. H. Bugg, C. J. Winfield, Nat.
Prod. Rep. 1998, 15, 513.
Scheme 3. Synthesis of betanidin.
as pyrylium-ion precursors and therefore be converted to
other valuable structures, such as pyridines. We also demon-
strated the utility of this oxidative cleavage by synthesizing be-
tanidin in five steps starting from two molecules of l-DOPA.
This strategy constitutes a rapid entry into the chemistry of be-
talains and may revive the interest for their use in the food in-
dustry. The synthesis and full structural elucidation of musca-
purpurin, which requires a different selectivity of the extradiol
cleavage or a non-biomimetic strategy to access the top por-
tion of the molecule, is under active investigation and will be
reported in due course. The synthesis of muscaaurin from two
molecules of 2 f is also being pursued in our laboratories.
[3] N. Fischer, A. Dreiding, Helv. Chim. Acta 1972, 55, 649.
[4] For reviews on betalains, see: a) W. Steglich, D. Strack, The Alkaloids:
Chemistry and Pharmacology, Vol 39, (Ed.: A. Brossi), Academic Press, Or-
lando, FL, 1990, p.1; b) D. Strack, T. Vogt, W. Schliemann, Phytochemistry
2003, 62, 247.
[5] a) L. Tesoriere, M. Fazzari, F. Angileri, C. Gentile, M. A. Livrea, J. Agric.
Food Chem. 2008, 56, 10487; b) D. Butera, L. Tesoriere, F. Di Gaudio, A.
Bongiorno, M. Allegra, A. M. Pintaudi, R. Kohen, M. A Livrea, J. Agric.
Food Chem. 2002, 50, 6895.
[6] T. Funabiki, A. Mizoguchi, T. Sugimoto, S. Tada, M. Tsiji, H. Sakamoto, S.
Yoshida, J. Am. Chem. Soc. 1986, 108, 2921.
[7] A. Dei, D. Gatteschi, L. Pardi, Inorg. Chem. 1993, 32, 1389.
[8] a) G. Lin, G. Reid, T. D. H. Bugg, Chem. Commun. 2000, 1119; b) G. Lin, G.
Reid, T. D. H. Bugg, J. Am. Chem. Soc. 2001, 123, 5030; c) M. Xin, T. D. H.
Bugg, J. Am. Chem. Soc. 2008, 130, 10422.
[9] a) R. Mayilmurugan, K. Visvaganesan, E. Suresh, M. Palaniandavar, Inorg.
Chem. 2009, 48, 8771; b) R. Mayilmurugan, H. Stoeckli-Evans, M. Pala-
niandavar, Inorg. Chem. 2008, 47, 6645; c) K. Visvaganesan, R. Mayilmur-
ugan, E. Suresh, M. Palaniandavar, Inorg. Chem. 2007, 46, 10294.
[10] a) D.-H. Jo, L. Que, Jr. Angew. Chem. 2000, 112, 4454; Angew. Chem. Int.
Ed. 2000, 39, 4284; b) M. Ito, L. Que Jr., Angew. Chem. 1997, 109, 1401;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1342; Angew. Chem. Int. Ed. Engl.
1997, 36, 1342.
[11] This work was published during the preparation of this manuscript: S.
Chatterjee, D. Sheet, T. K. Paine, Chem. Commun. 2013, 49, 10251.
[12] Chloral hydrate was used to scavenge potential carboxylate ions that
could result from an undesired intradiol cleavage through hydrogen-
bonding interactions.
Experimental Section
Representative procedure for the oxidative cleavage of 4-
tert-butyl catechol
FeBr2 (16 mg, 0.075 mmol, 5.0 mol%) and TACN (10 mg,
0.075 mmol, 5.0 mol%) were stirred in dry MeOH (25 mL) under
a N2 atmosphere until the mixture became clear and homogene-
ous. Pyridine (363 mL, 4.50 mmol, 3.00 equiv) was then added fol-
lowed by chloral hydrate (248 mg, 1.50 mmol, 1.00 equiv) and 4-
Chem. Eur. J. 2014, 20, 9519 – 9523
www.chemeurj.org
9522
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[13] Formation of the corresponding cyclic ketal did not occur starting from
3-substituted catechols.
Chim. Acta 1977, 60, 673; c) H. Hilpert, A. S. Dreiding, Helv. Chim. Acta
1984, 67, 1547; d) G. H. Bꢁchi, H. Fliri, R. Shapiro, J. Org. Chem. 1977, 42,
2192; e) G. H. Bꢁchi, H. Fliri, R. Shapiro, J. Org. Chem. 1978, 43, 4765.
[17] Prepared according to a literature procedure: H. Wyler, J. Chiovini, Helv.
Chim. Acta 1968, 51, 1476.
[14] Quality of the crystal obtained allowed the establishment of atom con-
nectivity, but may not display accurate bond lengths and angles.
[15] For seminal reports, see: a) T. Zincke, Justus Liebigs Ann. Chem. 1903,
330, 361; b) T. Zincke, Justus Liebigs Ann. Chem. 1904, 333, 296; c) T.
Zincke, W. Wurker, Justus Liebigs Ann. Chem. 1904, 338, 107; d) W.
Kçnig, J. Prakt. Chem. (Leipzig) 1904, 69, 105.
Received: May 7, 2014
[16] For previous syntheses of betalains, see: a) K. Hermann, A. S. Dreiding,
Helv. Chim. Acta 1975, 58, 1805; b) K. Hermann, A. S. Dreiding, Helv.
Published online on June 24, 2014
Chem. Eur. J. 2014, 20, 9519 – 9523
www.chemeurj.org
9523
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim