Straightforward synthesis of highly hydroxylated phloroglucinol-type 3-deoxyanthocyanidins

Article abstract of DOI:10.1055/s-2007-977433

Phloroglucinol-type 3-deoxyanthocyanidins were synthesized through the interaction between phloroglucinol derivatives and arylethynylketones in acetic acid in the presence of aqueous hexafluorophosphoric acid. This methodology was applied to achieve the synthesis of natural apigeninidin, luteolinidin and tricetanidin with high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977433

LETTER
1067
Straightforward Synthesis of Highly Hydroxylated Phloroglucinol-Type
3-Deoxyanthocyanidins
Synthesis of
H
ighly H
y
a
droxylated
r
Phlorog
i
lucinol
e
-Type 3-Deoxyan
K
thocyanidins ueny-Stotz, Géraldine Isorez, Stefan Chassaing,* Raymond Brouillard
Laboratoire de Chimie des Polyphénols, Université Strasbourg I, CNRS, LC3 UMR 7177, 4 Rue Blaise Pascal, 67008 Strasbourg, France
E-mail: stefanchassaing@mac.com
Received 5 January 2007
R5'
Abstract: Phloroglucinol-type 3-deoxyanthocyanidins were syn-
R4'
1: R5 = R7 = R3' = R4' = R5' = H
thesized through the interaction between phloroglucinol derivatives
2: R3' = R5' = H and R5 = R7 = R4' = OH
+
O
and arylethynylketones in acetic acid in the presence of aqueous
hexafluorophosphoric acid. This methodology was applied to
achieve the synthesis of natural apigeninidin, luteolinidin and
tricetanidin with high yields.
R7
3: R5' = H and R5 = R7 = R3' = R4' = OH
4: R5 = R7 = R3' = R4' =R5' = OH
R3'
A
3
R5
Key words: acid-mediated condensation, heterocycles, ketones,
phenols, 3-deoxyanthocyanidins
Figure 1 The flavylium chromophore 1 and the major representati-
ves of natural 3-deoxyanthocyanidins
Flavylium-derived salts (anthocyanins) represent an im-
portant family of natural pigments, being responsible for
the color of most flowers, fruits and leaves of angio-
sperms. Such pigments are also found in other plant
tissues (roots, tubers, stems, bulbs) and in various gymno-
sperms, ferns and some bryophytes.1 Structurally, this
family of pigments is characterized by the presence of the
flavylium chromophore 1 diversely substituted with hy-
droxyl, alkyloxy, acyl or glycosyloxy groups (Figure 1).
Most of the natural flavylium pigments possess a phloro-
glucinol-type cycle A (R5 = R7 = OH). The 3-oxygenated
derivatives (anthocyanidins), are red-colored pigments
that are color-unstable and therefore seldom found natu-
rally in their free form. In contrary, the 3-deoxyanalogues
(3-deoxyanthocyanidins) are yellow-orange pigments
quite stable in acidic media. Apigeninidin (2), luteolinidin
(3) and tricetanidin (4) are major representatives of this
group of pigments, as they were isolated from various
food plants like corn, sorghum and black tea leaves
(Figure 1).2
acid-mediated aldol condensation between a salicylalde-
hyde derivative and an acetophenone (Scheme 1: discon-
nection a).9 In this case, it is well established that, if
nonprotected phloroglucinaldehyde is involved, these
conditions lead to a hard-to-purify mixture of organic salts
where the targeted flavylium cation is present in small
amounts at best (5–20% yield). Nevertheless, two suc-
cessful alternatives were recently published.10,11
In the present work, we report an efficient and straightfor-
ward procedure for the preparation of phloroglucinol-type
3-deoxyanthocyanidins via an acid-mediated condensa-
tion between phenolic derivatives and arylethynylketones
(Scheme 1: disconnection b).
+
O
R'
R
Although being suggested for long as food colorants,3 3-
deoxyanthocyanidins recently attracted an increasing
interest in many other areas due to the discovery of their
potential use as hair dyes,4 laser dyes,5 molecular-level
memory systems6 and also as nutraceuticals for humans.7
+ H+/– H2O
HO
R'
O
R
From a synthetic point of view, some attractive approach-
es towards anthocyanidins have already been reported in
the literature.8 However, it is worth noting that the prepa-
ration of 3-deoxyanthocyanidins possessing such a phlo-
roglucinol-type cycle A still constitutes a real synthetic
challenge. Until now, only a few methods are known and
they all exhibit inherent limitations. Pratt and Robinson
described, in the early twenties, a method consisting in an
β
α
OH
O
R'
OH
O
R
R'
R
O
Scheme 1 Retrosynthetic analyses of the 3-deoxyanthocyanidin
skeleton: ‘a’ is the classical disconnection10 and ‘b’ is the disconnec-
tion investigated herein
SYNLETT 2007, No. 7, pp 1067–1070
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977433; Art ID: D03307ST
© Georg Thieme Verlag Stuttgart · New York
2
4.
0
4.
2
0
0
7

1068
M. Kueny-Stotz et al.
LETTER
Since phloroglucinol derivatives can easily react as C- This reaction is probably driven by the precipitation of the
and/or O-nucleophile, we reasoned that under acidic con- flavylium salt in the medium. We actually noticed upon a
ditions, they could add on ynones and then cyclize to the counter-anion screening that flavylium hexafluorophos-
3-deoxyanthocyanidin salts.12 Therefore, in order to check phates exhibit the lowest solubility in acetic acid among
–
–
the potential of this synthetic tool, we initially prepared Cl–, Br–, HSO4 , and BF4 , highlighting probably the
different arylethynylketone patterns 6a–g via a nucleo- formation of the most intimate ion pair in the case of the
philic addition–oxidation sequence starting from the cor- interaction between a flavylium cation and an hexafluoro-
responding benzaldehydes 5a–g (Scheme 2). We then phosphate anion.13 Moreover, it should be noted that
investigated the acid-mediated interaction of 6a–g with whereas flavylium chlorides,11 tetrafluoroborates10,14 or
phloroglucinol derivatives and after optimization of the triflates14 have been already described, no report of
reaction conditions, we found that aqueous HPF6 nicely flavylium hexafluorophosphates was so far mentioned.
promotes the expected condensation process (providing
flavylium hexafluorophosphates in high yields, Table 1).
Table 1 Scope of the Acid-Mediated Condensation between an Arylethynylketone and a Phloroglucinol Derivativea
Entry
Phloroglucinol derivative
Arylethynylketone
Product
Yield (%)b
O
OH
O
O+
O+
O+
O
1
99
O
O
7
6a
9
O
O
OH
O
O
O
O
2
93
7
O
6b
10
O
OH
O
O
O
O
O
O
3
O
94
7
O
6c
11
O
OH
O
O
O
O
O
O+
O
O
O
4
95
O
7
O
6d
12
HO
OH
O+
O
HO
5
91
OH
8
OH
6a
13
Synlett 2007, No. 7, 1067–1070 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Hydroxylated Phloroglucinol-Type 3-Deoxyanthocyanidins
1069
Table 1 Scope of the Acid-Mediated Condensation between an Arylethynylketone and a Phloroglucinol Derivativea (continued)
Entry
Phloroglucinol derivative
Arylethynylketone
Product
Yield (%)b
HO
OH
OH
OH
OTBS
OH
HO
O+
O
6
82
84
OH
OH
OH
8
OH
6e
2
HO
OH
OH
OTBS
OTBS
HO
O+
O
7
8
OH
6f
3
HO
OH
OTBS
OH
OH
OTBS
OTBS
HO
O+
O
8
82
8
OH
6g
4
a Reaction conditions: HPF6 (50% in H2O), AcOH, r.t., 48 h.
b Isolated yield of pure product obtained, when necessary, after recrystallization.
ether (11), and tricetanidin pentamethylether (12) being
prepared with excellent yields (entries 1–4).
R'
RO
OH
O
RO
HPF6 (aq)
O+
R'
Nevertheless, as the deprotection of permethylated 3-
deoxyanthocyanidins is generally effective in only mod-
erate yields,10,14 we envisaged the access to polyhydroxy-
lated structures by directly involving phloroglucinol (8) in
the condensation process (Scheme 2). Fortunately, when
first involving 8 and 6a in the condensation–cyclization
process, our conditions proved to be very effective for the
condensation, 13 being prepared with an excellent yield of
91% (entry 5).17 In order to check the compatibility of our
conditions with different protective groups, we submitted
the arylethynylketones 6e–g bearing acid-labile tert-
butyldimethylsilyl groups to the condensation process.
Interestingly enough, an efficient synthesis of natural
apigeninidin (2), luteolinidin (3), and tricetanidin (4) was
achieved without any further deprotection step (entries
6–8).18
–
PF6
AcOH, r.t.
OR
OR
7: R = Me
8: R = H
6a–g
(1)
(2) IBX, AcOEt, 80 °C
(86–90%, 2 steps)
MgBr, THF, 0 °C to r.t.
R'
O
5a–g
Scheme 2 Synthetic route to phloroglucinol-type 3-deoxyantho-
cyanidins
In summary, the interaction of phloroglucinol derivatives
with arylethynylketones in the presence of HPF6 appears
indeed as a simple and efficient synthetic method for the
preparation of polymethylated and above all polyhydrox-
ylated 3-deoxyanthocyanidins. We also developed an or-
thogonal protective-group strategy allowing a direct and
efficient access to highly hydroxylated derivatives. More-
over, the total synthesis of natural 2, 3, and 4 have been
achieved in only four steps with high overall yields start-
ing from commercially available unprotected benzalde-
hydes (respectively 69%, 72% and 61%).
At first, since permethylated 3-deoxyanthocyanidins are
generally regarded as the more convenient synthetic pre-
cursors of their phenolic analogues, we precisely checked
our conditions for the access to such permethylated
salts.10,15 We thus considered the interaction between
phloroglucinol dimethylether 7 and the arylethynylke-
tones 6a–d (Scheme 2). It clearly appeared that the use of
aqueous HPF6 significantly facilitated the condensation–
cyclization process, chrysinidin dimethylether (9), apige-
ninidin trimethylether (10),16 luteolinidin tetramethyl-
Synlett 2007, No. 7, 1067–1070 © Thieme Stuttgart · New York

1070
M. Kueny-Stotz et al.
LETTER
(7) (a) Mas, T.; Susperregui, J.; Berké, B.; Chèze, C.; Moreau,
S.; Nuhrich, A.; Vercauteren, J. Phytochemistry 2000, 53,
679. (b) Clifford, M. N. J. Sci. Food Agric. 2000, 80, 1063.
(c) Kong, J. M.; Chia, L. S.; Goh, N. K.; Chia, T. F.;
Brouillard, R. Phytochemistry 2003, 64, 923. (d) Hou, D. X.
Curr. Mol. Med. 2003, 3, 149.
Further work is now underway to expand the scope of this
synthetic tool for the preparation of more sophisticated
flavylium derivatives such as flavylium-benzopyrilium
and oligoflavylium skeletons.
(8) For a review on the synthesis of anthocyanidins, see:
Iacobucci, G. A.; Sweeny, J. G. Tetrahedron 1983, 39, 3005.
(9) (a) Pratt, D. D.; Robinson, R. J. Chem. Soc. 1922, 1577.
(b) Pratt, D. D.; Robinson, R. J. Chem. Soc. 1923, 745.
(c) Pratt, D. D.; Robinson, R. J. Chem. Soc. 1924, 188.
(d) Pratt, D. D.; Robinson, R. J. Chem. Soc. 1924, 199.
(e) Pratt, D. D.; Robinson, R. J. Chem. Soc. 1925, 1128.
(10) Kuhnert, N.; Clifford, M. N.; Radenac, A.-G. Tetrahedron
Lett. 2001, 42, 9261.
Typical Procedure for the Acid-Mediated Condensation of
Phloroglucinol Derivatives with Arylethynylketones
To a solution of arylethynylketone 6 (5 mmol, 1.0 equiv) and phlo-
roglucinol derivative 7 or 8 (5 mmol, 1.0 equiv) in 10 mL of AcOH
were added 2 mL of hexafluorophosphoric acid (50% in H2O). The
solution, becoming immediately dark red, was stirred during 48 h at
r.t. The resulting mixture was then plunged in 100 mL of Et2O
where the flavylium salt precipitated. The orange–red solid was
recovered by filtration, washed with Et2O and finally dried under
vacuum to give the expected 3-deoxyanthocyanidin. Recrystalliza-
tion from AcOH was performed when necessary.
(11) Mas, T. Synthesis 2003, 1878.
(12) A similar approach, using sulfuric acid, was mentioned in
the early fifties and was, surprisingly, reported only once
thereafter: (a) Johnson, A. W.; Melhuish, R. R. J. Chem. Soc.
1947, 346. (b) Gramshaw, J. W.; Johnson, A. W.; King, T. J.
J. Chem. Soc. 1958, 4040. (c) Costantino, L.; Rastelli, G.;
Rossi, M. C.; Albasini, A. J. J. Chem. Soc., Perkin Trans. 2
1995, 227.
(13) Marcus, Y.; Hefter, G. Chem. Rev. 2006, 106, 4585.
(14) (a) Katritzky, A. R.; Czerney, P.; Level, J. R.; Du, W. Eur. J.
Org. Chem. 1998, 2623. (b) Fichtner, C.; Remennikov, G.;
Mayr, H. Eur. J. Org. Chem. 2001, 4451.
Acknowledgment
The authors thank the CNRS and the MNERT for funding. Three of
us (S.C., M.K. and G.I.) thank the MNERT for PhD fellowships.
References and Notes
(15) Doxsee, K. M.; Feigel, M.; Kent, D. S.; Canary, J. W.;
Knobler, C. B.; Cram, D. J. Am. Chem. Soc. 1987, 109, 3098.
(16) Apigeninidin Trimethylether Hexafluorophosphate (8)
Purple powder; yield 93%; mp 201 °C. IR (KBr): 1652, 1640
(s, C=O), 1600, 1569, 1506, 1456, 1436, 1378, 1339, 1241,
1124, 1052, 834 (m, P–F) cm–1. UV/Vis (MeOH/5% 1 N
HCl): lmax (e) = 266 (24900), 394 (18000), 460 nm (13600
M–1cm–1). 1H NMR [300 MHz, CD3CN–TFA-d1 (1%)]:
d = 3.96 (3 H, s, OCH3), 4.07 (3 H, s, OCH3), 4.09 (3 H, s,
OCH3), 6.80 (1 H, d, J = 2.2 Hz), 7.19 (2 H, m), 7.23 (1 H,
dd, J = 2.2, 0.7 Hz), 8.05 (1 H, d, J = 8.5 Hz), 8.32 (2 H, m),
9.07 (1 H, dd, J = 8.5 Hz, 5J = 0.7 Hz). 13C NMR [75 MHz,
CD3CN–TFA-d1 (1%)]: d = 55.9, 57.0, 57.2 (OCH3), 93.4,
99.8, 111.3, 113.4, 115.8, 120.8, 131.9, 148.7, 158.8, 159.0,
167.0, 171.4, 171.7. MS (ESI, positive mode): 297 (100)
[M+]. HRMS (ESI): m/z calcd: 297.1121; found: 297.1109.
(17) Chrysinidin Hexafluorophosphate (12)
(1) (a) Timberlake, C. F.; Bridle, P. The Flavonoids; Academic
Press: New York, 1975, 214–266. (b) Hrazdina, G. The
Flavonoids: Advances in Research; Chapman and Hall:
London, 1982, 135–188. (c) Harborne, J. B.; Grayer, R. J.
The Flavonoids: Advances in Research since 1980;
Chapman and Hall: London, 1988, 1–20. (d) Strack, D.;
Wray, V. The Flavonoids: Advances in Research since 1986;
Chapman and Hall: London, 1994, 1–22. (e) Harborne, J.
B.; Williams, C. A. Nat. Prod. Rep. 1998, 15, 631.
(f) Harborne, J. B.; Williams, C. A. Nat. Prod. Rep. 2001,
18, 310. (g) Williams, C. A.; Grayer, R. J. Nat. Prod. Rep.
2004, 21, 539. (h) Andersen, O. M.; Jordheim, M.
Flavonoids: Chemistry, Biochemistry and Applications;
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(2) (a) Coggon, P.; Moss, G. A.; Graham, H. N.; Sanderson, G.
W. J. Agric. Food Chem. 1973, 21, 727. (b) Mazza, G.;
Miniati, E. Anthocyanins in Fruits, Vegetables and Grains;
CRC Press: Boca Raton, 1993, 225.
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(4) (a) Darmenton, P.; Philippe, M. FR 2757383, 1996; Chem.
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Brouillard, R.; Fougerousse, A.; Roehri-Stoeckel, C. WO
03/000214 A1, 2003.
Orange powder; yield 91%. IR (KBr): 3412 (s, br, OH), 1642
(s, C=O), 1580, 1563, 1541, 1381, 1340, 1269, 1239, 1203,
1193, 835 (m, P–F) cm–1. UV/Vis (MeOH/5% 1 N HCl):
l
max (e) = 274 (35400), 474 nm (36200 M–1cm–1). 1H NMR
[300 MHz, CD3CN–TFA-d1 (1%)]: d = 6.81 (1 H, d, J = 2.2
Hz), 7.11 (1 H, dd, J = 2.2, 0.7 Hz), 7.72 (2 H, m), 7.84 (1 H,
m), 8.13 (1 H, d, J = 8.4 Hz), 8.35 (2 H, m), 9.25 (1 H, dd,
J = 8.4, 0.7 Hz). 13C NMR [75 MHz, CD3CN–TFA-d1
(1%)]: d = 95.7, 102.9, 111.2, 114.4, 128.9, 129.1, 130.0,
135.8, 150.5, 158.4, 159.4, 171.1, 171.4. MS (ESI, positive
mode): 239 (100) [M+]. HRMS (ESI): m/z calcd: 239.0703;
found: 239.0696.
(5) Czerney, P.; Graness, G.; Birckner, E.; Vollmer, F.; Rettig,
W. J. Photochem. Photobiol. A 1995, 89, 31.
(6) (a) Pina, F.; Melo, M. J.; Maestri, M.; Passaniti, P.;
Comaioni, N.; Balzani, V. Eur. J. Org. Chem. 1999, 3199.
(b) Roque, A.; Lodeiro, C.; Pina, F.; Maestri, M.; Ballardini,
R.; Balzani, V. Eur. J. Org. Chem. 2002, 2699.
(18) All synthesized compounds exhibit NMR spectroscopic data
identical to those previously reported in the literature.10–12
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