Biomimetic synthesis of santalin a,b and santarubin a,b, the major colorants of red sandalwood

Article abstract of DOI:10.1002/anie.201302317

Better late than never! Almost 200 years after Pelletier's pioneering studies on the chemical constituents of red sandalwood, the major santalins and santarubins have been synthesized. This efficient approach integrates a Knochel isoflavonoid synthesis with Friedel-Crafts allylations or olefin metatheses, and a final biomimetic reaction cascade that furnishes the venerable benzoxanthenone dyes in a single operation (see scheme). Copyright

Full text of DOI:10.1002/anie.201302317

Angewandte
Chemie
Communications
Biomimetic Synthesis
S. Strych, D. Trauner*
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Biomimetic Synthesis of Santalin A,B and
Santarubin A,B, the Major Colorants of
Red Sandalwood
Better late than never! Almost 200 years
after Pelletier’s pioneering studies on the
chemical constituents of red sandalwood,
the major santalins and santarubins have
been synthesized. This efficient approach
integrates a Knochel isoflavonoid syn-
thesis with Friedel–Crafts allylations or
olefin metatheses, and a final biomimetic
reaction cascade that furnishes the ven-
erable benzoxanthenone dyes in a single
operation (see scheme).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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DOI: 10.1002/anie.201302317
Biomimetic Synthesis
Biomimetic Synthesis of Santalin A,B and Santarubin A,B, the Major
Colorants of Red Sandalwood**
Sebastian Strych and Dirk Trauner*
Dedicated to the Bayer company on the occasion of its 150th anniversary
The success of organic chemistry can be largely traced back to
the fascination of humans with beautiful, bright, and persis-
tent colors. Natural dyes, such as indigo, chlorophyll, and
heme, were investigated early on in the history of the field and
are representative of some of its greatest achievements.
William Henry Perkinꢀs discovery of mauveine[1] and his
realization of its economic potential marked the beginning of
an industry that became one of the defining economic
activities of the 19th century and has been closely intertwined
with rapid advances in academic research. With their access to
chemicals and their intellectual resources, dye companies
often diversified to become producers of drugs, crop protec-
tants, and synthetic polymers. As such, the chemistry of
colorants has had an enormous impact on humanity, which
continues to this day, with biological imaging and photo-
voltaics taking center stage.
in Ayurveda medicine where it is used for treating digestive
tract problems and coughs. Chemical investigations of its
colored constituents started with Pelletierꢀs pioneering stud-
ies in 1814.[2] Subsequent attempts at structural elucidation
were complicated by the presence of many closely related
isomers and congeners. Following decades of confusion
regarding the positioning of phenolic hydroxy groups and
their methylation patterns, the constitution of the major
components, namely the santalins and santarubins, were
finally settled by Arnone et al. in 1975.[3] Santalins A and B
(1, 2) and santarubins A and B (3, 4) share a common 9H-
benzo[a]xanthen-9-one core (Figure 2). They differ in the
Among the colored materials found in nature, red sandal-
wood caught the eye of chemists early on. This rare hard-
wood, obtained from the tree Pterocarpus santalinus and
related species, has been valued for millennia, particularly in
China, where it was once reserved for the furniture of the
imperial household (Figure 1). It also plays an important role
[*] Dipl.-Chem. S. Strych, Prof. Dr. D. Trauner
Department of Chemistry and Center for Integrated Protein Science
Ludwig-Maximilians-Universitꢀt
Figure 2. Colorants isolated from red hardwoods.
Butenandtstrasse 5–13 (F4.086), 81377 Munich (Germany)
E-mail: dirk.trauner@lmu.de
Homepage: http://www.cup.uni-muenchen.de/oc/trauner/
substitution of their phenyl substituent at C5, which can either
be a resorcinol (santalins) or a catechol derivative (santar-
ubins). The reverse is true for the benzyl substituent at
position C6. In 1995, the structures of two minor components
of red sandalwood, the relatively simple isoflavonoid santa-
lin AC (5) and the complex yet racemic oxafenestrane
santalin Y (6), were reported.[4]
[**] We thank Martin Maier and Robin Meier for their assistance with the
synthesis and Dr. Peter Mayer for the X-ray structure analysis. We
thank Daniel Hog and Desiree Stichnoth for helpful discussions. We
also acknowledge SFB 749 for financial support and Chemetall for
a generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302317.
Figure 1. Objects carved from red sandalwood (Pterocarpus santalinus).
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Despite the long chemical history of the santalins and
santarubins, no total synthesis of the santalins and santarubins
has been reported to date. We now disclose our studies on the
subject, which culminated in an efficient synthesis of santa-
lins A and B as well as santarubins A and B.
Our synthetic strategies were guided by speculations
concerning the biosynthesis of these natural colorants,
exemplified by santalin A and santarubin A (Scheme 1).[4]
In the former case, nucleophilic attack of a benzylstyrene
phenolate 8a onto hypothetical isoflavylium ion 7 would
afford a reactive intermediate, shown here as a p-quinone
methide 9, which would subsequently undergo Friedel–Crafts
À
cyclization to yield compound 10. By virtue of its labile C H
bonds at position C5, C6a, and possibly C6, and a phenolic
OH bond, this intermediate would subsequently undergo
facile oxidation in the presence of air to afford the benzox-
anthenone santalin A. An analogous sequence involving the
same isoflavylium 7 and benzylstyrene 11a would afford
santarubin A. Note that benzylstyrenes 8a and 11a are O-
methylated to a different degree. It is also worth mentioning
that an analogous nucleophilic attack of a benzylstyrene onto
7, followed by a dearomatizing bond formation and Friedel–
Crafts cyclization, could account for the formation of
santalin Y.
Scheme 2. Efficient access to 18 and santalin AC (5) using an isoflavo-
noid synthesis developed by Knochel and co-workers. Im = imidazol;
DIBAL-H = diisobutylaluminum hydride; TBS = tert-butyldimethylsilyl;
TBAF = tetrabutylammonium fluoride.
that protecting phenolic hydroxy groups as silyl ethers was
indispensible to enable solubilization and purification of our
synthetic intermediates.[6,7] By using a synthetic strategy
recently published by Knochel and co-workers,[8] coumarin
13 was regioselectively deprotonated and transmetalated to
afford diorganozinc species 14, which underwent efficient
cross-coupling with aryl bromide 15 in the presence of
palladium acetate and Buchwaldꢀs SPhos ligand[9] to afford
isoflavonoid derivative 16. The brominated pyrogallol deriv-
ative 15 was available by silylation of the known phenol[10]
(see the Supporting Information). Compound 16 could then
be selectively reduced to yield lactol 17. Upon treatment with
a solution of perchloric acid in acetic acid, 17 underwent
protonation and dehydration with concomitant desilylation to
afford isoflavylium perchlorate 18, which corresponds to 7 in
Scheme 1. This benzopyrylium salt bearing phenolic hydroxy
groups was difficult to handle, but could be purified by
precipitation. The X-ray structure of 18 with the perchlorate
ion hovering over the pyrylium moiety is shown in Figure 3.
Alternatively, isoflavonoid 16 was deprotected under stan-
dard conditions to give synthetic santalin AC (5), which
proved identical to the natural product.[4]
Scheme 1. A proposed biomimetic cascade.
To explore whether this proposed biosynthetic cascade
could be achieved in the absence of enzymatic catalysis, we
developed a short synthesis of an isoflavone that could serve
as a precursor to 7 and santalin AC. It started with esculetin
(12), available in one operation from 1,3,4-trisacetoxyben-
zene and malic acid,[5] which was protected to afford bis(silyl
ether) 13 (Scheme 2). Throughout our synthesis, we found
The preparation of the benzylstyrenes, necessary to obtain
santalin A,B and santarubin A,B, is outlined in Scheme 3. It
either involved olefin cross-metathesis[11] or Friedel–Crafts-
type reactions of easily ionized alcohols.[12] To prepare
santalin A, the known allylphenol derivative 19[13] was
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the corresponding known aldehyde[14] (see the Supporting
Information). Similarly, eugenol was subjected to olefin cross-
metathesis with the same styrene 20, followed by desilylation,
to deliver building block 8b, suitable for obtaining santalin B.
To prepare santarubin A, the known benzaldehyde 22[15] was
converted into the allylic alcohol 23 by treatment with a vinyl
Grignard reagent. The resulting allylic alcohol formed
a stabilized cation upon treatment with Cu(OTf)2,[12b] which
reacted in a Friedel–Crafts-like fashion with O,O’-dimethyl-
resorcinol 24. Desilylation with a fluoride source then gave
styrene 11a as a single diastereomer. Similarly, the known
allylic alcohol 26[16] and resorcinol ether 24 gave styrene 27,
which upon treatment with TBAF yielded styrene 11b, which
is suitable for the synthesis of santarubin B.
Figure 3. X-ray structure of isoflavylium perchlorate 18. C green,
H white, O red.
With isoflavylium 18 and the various benzylstyrenes in
hand, we tested the biomimetic cascade reactions. Initial
attempts to effect this reaction by mixing isoflavylium
perchlorate 18 with its corresponding partner in the presence
of a variety of bases were met with limited success and gave
complex mixtures of unidentifiable products. Eventually, we
Scheme 3. Preparation of the benzylstyrenes 8a,b and 11a,b. Tf =
trifluoromethanesulfonyl.
subjected to olefin cross-metathesis with styrene 20, followed
by desilylation, which gave benzylstyrene 8a as a single
diastereomer. Styrene 20 was prepared as an inconsequential
2.1:1 mixture of diastereomers through Wittig-olefination of
Scheme 4. Biomimetic synthesis of santalin A,B and santarubin A,B.
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Garfield, Mauve, W. W. Norton & Co., New York, 2002; c) O.
found that it was important to deprotonate the isoflavylium
salt 18 in a separate step, which afforded the isolable
anhydrobase 28 (Scheme 4). This deprotonation was most
effective when carried out by the non-nucleophilic base 2,6-
bis-tert-butylpyridine.
Meth-Cohn, M. Smith, J. Chem. Soc. Perkin Trans. 1 1994, 5 – 7.
[2] Cited in Poggendorfꢀs Ann. Phys. Chem. 1833, 29, 102 – 107.
[3] a) A. Arnone, L. Camarda, L. Merlin, G. Nasini, J. Chem. Soc.
Perkin Trans. 1 1975, 186 – 194; b) A. Arnone, L. Camarda, L.
Merlin, G. Nasini, J. Chem. Soc. Perkin Trans. 1 1977, 2118 –
2122; c) A. Arnone, L. Camarda, L. Merlini, G. Nasini, D. A. H.
Taylor, J. Chem. Soc. Perkin Trans. 1 1977, 2116 – 2118.
[4] J. Kinjo, H. Uemura, T. Nohara, M. Yamashita, K. Yoshihira,
Tetrahedron Lett. 1995, 36, 5599 – 5602.
[5] Y. A. Jackson, Heterocycles 1995, 41, 1979 – 1986.
[6] For a recent review on polyphenolic natural products, see S.
Quideau, D. Deffieux, C. Douat-Casassus, L. Pouysꢁgu, Angew.
Chem. 2011, 123, 610 – 646; Angew. Chem. Int. Ed. 2011, 50, 586 –
621.
[7] For selected articles on the synthesis of polyphenolic natural
products, see a) K. Ohmori, T. Shono, Y. Hatakoshi, T. Yano, K.
Suzuki, Angew. Chem. 2011, 123, 4964 – 4969; Angew. Chem. Int.
Ed. 2011, 50, 4862 – 4867; b) S. A. Snyder, A. L. Zografos, Y. Lin,
Angew. Chem. 2007, 119, 8334 – 8339; Angew. Chem. Int. Ed.
2007, 46, 8186 – 8191; c) K. C. Nicolaou, Q. Kang, T. R. Wu, C. S.
Lim, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 7540 – 7548.
[8] a) S. Wunderlich, P. Knochel, Angew. Chem. 2007, 119, 7829 –
7832; Angew. Chem. Int. Ed. 2007, 46, 7685 – 7688; b) L. Klier, T.
Bresser, T. Nigst, K. Karaghiosoff, P. Knochel, J. Am. Chem. Soc.
2012, 134, 13584 – 13587.
We were pleased to find that mixing 28 with benzylstyr-
enes 8a,b or 11a,b gave santalins A,B and santarubins A,B,
respectively (Scheme 4). These were usually isolated through
precipitation and in good yields (62–83%), given the com-
plexity of the cascade. Under optimized conditions, the
reactions were carried out in the presence of air at 808C in
a methanol/acetonitrile solution by using 2.5 equivalents of
the anhydrobase 28 with respect to the benzylstyrene. It thus
appears that the anhydrobase not only serves to deprotonate
the benzylstyrene, which simultaneously provides the nucle-
ophile and the electrophile, but is also involved in the
subsequent oxidation step. The spectroscopic data of our
synthetic samples were identical in all respects with those
reported for the natural products.[3]
In summary, we have developed a unified synthetic
approach to the major dyes of red sandalwood, which yielded
five natural products. It is yet another demonstration that
complex molecular scaffolds, not easily accessible with other
methods, can be assembled along biosynthetic lines without
the necessity of enzymatic catalysis. The final reaction
sequence appears to be general and our conditions are mild,
which raises the question whether the cycloaddition/oxidation
cascade could spontaneously occur in nature as well. Our
studies concerning the biomimetic synthesis of santalin Y are
still ongoing and will be reported in due course.
[9] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685 – 4696.
[10] R. Giles, A. Hughes, M. Sargent, J. Chem. Soc. Perkin Trans.
1 1991, 1581 – 1587.
[11] a) A. Chatterjee, T. Choi, D. Sanders, R. H. Grubbs, J. Am.
Chem. Soc. 2003, 125, 11360 – 11370; b) A. Chatterjee, F. Toste,
T. Choi, R. H. Grubbs, Adv. Synth. Catal. 2002, 344, 634 – 637.
[12] a) M. Rueping, B. Nachtsheim, Beilstein J. Org. Chem. 2010, 6,
1 – 24; b) W. Rao, P. Chan, Org. Biomol. Chem. 2008, 6, 2426 –
2433.
[13] F. Fache, N. Suzan, O. Piva, Tetrahedron 2005, 61, 5261 – 5266.
[14] R. Tello-Aburto, A. Harned, Org. Lett. 2009, 11, 3998 – 4000.
[15] J. Chen, X. Chen, M. Willot, J. Zhu, Angew. Chem. 2006, 118,
8196 – 8200; Angew. Chem. Int. Ed. 2006, 45, 8028 – 8032.
[16] M. Femenꢂa-Rꢂos, C. Garcꢂa-Pajꢃn, R. Hernꢄndez-Galꢄn, A.
Macꢂas-Sꢄnchez, I. Collado, Bioorg. Med. Chem. Lett. 2006, 16,
5836 – 5839.
Received: March 19, 2013
Published online: && &&, &&&&
Keywords: biomimetic synthesis · red colorants · sandalwood
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[1] a) M. M. Sousa, M. J. Melo, A. J. Parola, P. J. T. Morris, H. S.
Rzepa, J. S. S. de Melo, Chem. Eur. J. 2008, 14, 8507 – 8513; b) S.
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