Biomimetic synthesis and structure elucidation of rubicordifolin, a cytotoxic natural product from Rubia cordifolia

Article abstract of DOI:10.1021/ja042375g

The biomimetic synthesis and full structural elucidation of rubicordifolin, a cytotoxic natural product isolated from Rubia cordifolia, is described. Copyright

Full text of DOI:10.1021/ja042375g

Published on Web 02/12/2005
Biomimetic Synthesis and Structure Elucidation of Rubicordifolin, a Cytotoxic
Natural Product from Rubia cordifolia
Jean-Philip Lumb and Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720-1460
Received December 19, 2004; E-mail: trauner@cchem.berkeley.edu
Cycloadditions are unmatched in their ability to generate
molecular diversity and stereochemical complexity. Hence, it is no
surprise that they are widely found in biosynthetic pathways.1 While
some naturally occurring cycloadditions have been shown to require
enzyme catalysis,2 many proceed spontaneously, often yielding
complex racemic products.
Racemic natural products with intricate structures have indeed
been found in certain plants of the genus Rubiaceae (Figure 1).3
Rubioncolin A (1) and rubioncolin B (2) were isolated from Rubia
oncotricha.4 The latter compound was also found in the Chinese
medical plant Rubia cordifolia.5 An unnamed natural product, 3,
Figure 1. Complex natural products isolated from Rubiaceae.
was isolated from this source as well, whose relative configuration
was not reported. Compound 3 showed significant cytotoxic activity
both in vitro and in vivo, inhibiting the growth of sarcoma ascites
in mice at low concentrations.5
Scheme 1. Biosynthetic Hypothesis
We now report a concise synthesis of 3 resulting somewhat
serendipitously from our systematic investigations of the Rubiaceae
natural products. In the course of our studies, the structure of 3
has been fully elucidated, prompting us to name this intriguing
compound “rubicordifolin”.
Biosynthetic and retrosynthetic analysis suggests that the dimeric
natural products shown in Figure 1 ultimately stem from prenylated
naphthoquinone 4 through a series of oxidations, electrocyclizations,
and cycloadditions (Scheme 1).
Scheme 2. Synthesis of Building Blocks 5, 6, and Furomollugin
(11)a
Naphthoquinone 4 is a known natural product previously isolated
from various Rubiaceae.6 Oxidation with concomitant allylic
transposition would afford the reactive vinyl quinone 5 as a
hypothetical biosynthetic intermediate. Acid-catalyzed or photo-
chemical isomerization of this material would yield naphthofuran
6.7 A [4 + 2] cycloaddition involving 5 and 6 would then give
rubioncolin A (1).8 Similar, yet more elaborate, biosynthetic
schemes can be devised to account for the formation of 2 and 3.
Inspired by this biosynthetic hypothesis, we set out to synthesize
vinyl quinone 4 and to study its isomerization to naphthofuran 5
and subsequent dimerization (Scheme 2). Conjugate addition of a
vinyl cuprate derived from vinyl stannane 79 to 2-carbomethoxy-
naphthoquinone 8,10 followed by tautomerization, gave vinyl
naphthohydroquinone 9. Oxidation with aqueous cerium ammonium
nitrate not only restored the quinone moiety but also resulted in
cleavage of the silyl ether to afford 5.
Upon standing at room temperature, the unstable vinyl quinone
5 underwent conversion into naphthofuran 6 and furomollugin (11).
This reaction presumably proceeds through cation 10, which
undergoes either deprotonation to afford 6 or retro-Friedel-Crafts
hydroxyalkylation to yield 11.11 Furomollugin (11) is a biologically
active natural product that has been isolated from several members
of the Rubiaceae family.12
a Reagents and conditions: (a) 7, n-BuLi, CuCN, THF, f 8, f NH4Cl/
NH4OH (67%); (b) CAN, MeCN, H2O (99%); (c) THF, rt (23% of 6; 24%
of 11).
of rubicordifolin (3) (Scheme 3). Attempting to promote the
dimerization by transiently tethering the tertiary alcohol moieties
of 5 and 6 with phenylboronic acid,13 we isolated 3 in low yield,
along with elimination product 12.
Mechanistically, this result can be interpreted as follows (Scheme
4). Phenylboronic acid-mediated cyclization of 5 affords 13, whose
intramolecular demethylation gives ortho-quinone methide 14.14
Simultaneously, dehydration of naphthofuran 6 occurs. The resultant
electron-rich alkene 12 then undergoes regioselective hetero-Diels-
Alder reaction with ortho-quinone methide 14, followed by
hydrolysis, to afford the natural product 3. The stereochemical
With vinyl quinone 5 and naphthofuran 6 in hand, we studied
their dimerization to afford rubioncolin A (1). While these studies
have so far not afforded 1, they have resulted in a concise synthesis
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C O M M U N I C A T I O N S
Scheme 5. Direct Synthesis of Rubicordifolin (3) and
Scheme 3. Synthesis of Rubicordifolin (3)
Furomollugin (11)
Synthetic studies on these analogues, as well as rubioncolins A (1)
and B (2), and other naphthoquinone derivatives isolated from
Rubiaceae are well underway in our laboratories and will be
reported in due course.
Acknowledgment. This work was supported in part by NSF
Grant CHE-0348770. Financial support by Glaxo Smith Kline, Eli
Lilly, Astra Zeneca, Amgen, and Merck & Co. is also gratefully
acknowledged.
Scheme 4. Mechanistic Interpretation
Note Added after ASAP Publication: In the version published
on the Internet February 12, 2005, naphthofuran was mistakenly
identified as compound 4 in Scheme 4 and in the fourth line of the
last paragraph on the first page. The final version published
February 15, 2005 and the print version correctly identify it as
compound 6.
Supporting Information Available: Synthetic procedures and
spectroscopic data for compounds 3, 5, 6, 7, 9, 11, and 12. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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outcome of this cycloaddition is compatible with an endo-transition
state, whose induced diastereoselection is governed by the bulky
hydroxyisopropyl group.
Synthetic rubicordifolin (3) is identical in all respects (1H NMR,
13C NMR, IR, UV, and MS) with the previously unnamed cytotoxic
natural product isolated from Rubia cordifolia.5,15 Its relative
stereochemistry was elucidated by detailed nOe measurements (see
Supporting Information).
Since both heterodiene 14 and dienophile 12 ultimately stem from
vinyl naphthoquinone 5, it was tempting to investigate the direct
conversion of 5 into 3. Indeed, under carefully optimized conditions,
5 underwent cyclization and dimerization to afford rubicordifolin
in 45% yield. In this case, furomollugin (11) was formed as the
major byproduct. Given the multitude of individual steps and
associated rate constants that need to be orchestrated for this reaction
to occur, the yield of 45% is remarkably high. Note that the vinyl
substituent of 5 has to engage in cyclizations with both proximate
carbonyl groups at a comparable rate to afford the dimerization
partners 14 and 12.
In summary, we have achieved a concise, biomimetic synthesis
of rubicordifolin and fully established the structure of the natural
product.16 The synthesis yields hundreds of milligrams of the
biologically active natural product and could be easily modified to
produce analogues of rubicordifolin for further biological testing.
(9) Vinyl stannane 7 was prepared by silyl protection of the corresponding,
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(14) For a review on the chemistry of ortho-quinone methides, see: Van de
Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
(15) Unfortunately, an authentic sample of natural 3 was not available to us.
(16) For other examples of dimeric phenolic natural products obtained through
biomimetic synthesis, see: (a) Chapman, O. L.; Engel, M. R.; Springer,
J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971, 93, 6696. (b) Nicolaou, K.
C.; Simonsen, K. B.; Vassilikogiannakis, G.; Baran, P. S.; Vidali, V. P.;
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pp 1-49.
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