Atropo-enantioselective total synthesis of knipholone and related antiplasmodial phenylanthraquinones

Article abstract of DOI:10.1021/jo020189s

The "lactone concept" has been efficiently employed for the first atropo-enantioselective synthesis of knipholone and related natural phenylanthraquinones. Besides the regio- and stereoselective construction of the biaryl axis, another important step was the "synthetically late" introduction of the C-acetyl group, either by a Friedel-Crafts type acetylation or by an ortho-selective Fries rearrangement first tested on simplified model systems and subsequently applied to the highly atroposelective preparation of the natural products and of simplified analogs thereof for biotesting. The synthetic availability of these natural biaryls, their precursors, and their unnatural analogs permitted a broader investigation of the antiplasmodial activities of these interesting biaryls.

Full text of DOI:10.1021/jo020189s

Atr op o-En a n tioselective Tota l Syn th esis of Kn ip h olon e a n d
Rela ted An tip la sm od ia l P h en yla n th r a qu in on es†
Gerhard Bringmann,*,‡ Dirk Menche,‡ J u¨rgen Kraus,‡ J o¨rg Mu¨hlbacher,‡ Karl Peters,§
Eva-Maria Peters,§ Reto Brun,| Merhatibeb Bezabih, and Berhanu M. Abegaz
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany,
Max-Planck-Institut fu¨r Festko¨rperforschung, Heisenbergstrasse 1, D-70506 Stuttgart, Germany,
Schweizerisches Tropeninstitut, Socinstrasse 57, CH-4002 Basel, Switzerland, and Department of
Chemistry, University of Botswana, Private Bag 0022, Gaborone, Botswana
bringman@chemie.uni-wuerzburg.de
Received March 18, 2002
The “lactone concept” has been efficiently employed for the first atropo-enantioselective synthesis
of knipholone and related natural phenylanthraquinones. Besides the regio- and stereoselective
construction of the biaryl axis, another important step was the “synthetically late” introduction of
the C-acetyl group, either by a Friedel-Crafts type acetylation or by an ortho-selective Fries
rearrangement first tested on simplified model systems and subsequently applied to the highly
atroposelective preparation of the natural products and of simplified analogs thereof for biotesting.
The synthetic availability of these natural biaryls, their precursors, and their unnatural analogs
permitted a broader investigation of the antiplasmodial activities of these interesting biaryls.
In tr od u ction
regarded as a taxonomic marker for the plant.6 Recently,
however, 1a has been found in Bulbine and Bulbinella
species (likewise Aphodelaceae) too,7 and a number of
closely related compounds, differing only in the O-
methylation pattern of the acetylphloroglucinol unit and/
or in the oxidation state of the tricyclic portion (an-
thraquinone vs anthrone), such as 1b,8 1c,9 and 1d 10 have
been described.11 All of these constitutionally unsymmet-
About 2 million people per year worldwide, mostly in
developing countries, die of malaria,1 making the search
for new remedies against this most important tropical
infectious disease an urgent task.2 As a result of not only
the rapid spreading of malaria but also the increasing
resistance to the still widely used chloroquine, new
antimalarials are urgently needed.3 Recently, natural
phenylanthraquinones such as 1a -d have been shown
to possess good to high antiplasmodial activity in vitro
against Plasmodium falciparum,4 the carrier of the most
lethal malaria tropica, making them a new potential lead
structure against this tropical disease.
ric natural biaryls12 are optically active ([R]20 > 0) and
D
thus configurationally stable, but only for 1a and 1b has
the axial configuration recently been elucidated using
Boltzman-weighted quantum chemical CD calculations.13
In this article, we describe the elaboration of a synthetic
strategy for the atropo-enantiodivergent construction of
such phenylanthraquinones leading to the first total
synthesis of these axially chiral natural products and
simplified analogs and report on their antiplasmodial
The occurrence of knipholone [(M)-1a ], first isolated
from Kniphofia foliosa,5 has long been considered to be
confined to this Asphodelaceae species and has even been
* To whom correspondence should be addressed. Phone: +49 931
888 5323. Fax: +49 931 888 4755.
(6) van Wyk, B.-E.; Yenesew, A.; Dagne, E. Biochem. Syst. Ecol.
1995, 23, 277 and references therein.
(7) (a) van Staden, F.; Drewes, E. S. Phytochemistry. 1994, 35, 685.
(b) Bringmann, G.; Menche, D.; Brun, R.; Msuta, T.; Abegaz; B. M.
Eur. J . Org. Chem. 2002, 1107.
(8) Dagne, E.; Yenesew, A. Phytochemistry 1993, 34, 1440.
(9) Bezabih, M.; Motlhagodi, S.; Abegaz, B. M. Phytochemistry 1997,
46, 1063.
† Dedicated to Professor Ekkehard Winterfeldt on the occasion of
his 70th birthday. Part 100 of the series “Novel Concepts in Directed
Biaryl Synthesis”. For part 99, see: Tasler, S.; Bringmann, G. Chem.
Rec. 2002, 2, 114-127.
‡ Universita¨t Wu¨rzburg.
§ Max-Planck-Institut, Stuttgart.
| Schweizerisches Tropeninstitut.
University of Botswana.
(10) Bezabih, M.; Abegaz, B. M. Phytochemistry 1998, 48, 1071.
(11) Some of these plants have considerable importance in tradi-
tional medicine: (a) Watt, J . M.; Breyer-Brandwijk, M. G. The
Medicinal and Poisonous Plants of Southern and Eastern Africa, 2nd
ed.; Livingstone: Edinburgh, 1962; pp 568-574, 695, 707. (b) Gelfand,
M.; Mavi, S.; Drummond, R. B.; Ndemera, B. The Traditional Medical
Practitioner in Zimbabwe; Mambo Press: Gweru, 1993; p 89.
(12) For a first comprehensive review on naturally occurring biaryls,
see: Bringmann, G.; Gu¨nther, C.; Ochse, M.; Schupp, O., Tasler, S.
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Moore, R. E., Tamm, C., Eds.; Springer-Verlag: Wien,
New York, 2001; Vol. 82, pp 1-249.
(1) (a) Backmund, M. Fortschr. Med. 1999, 117, 20. (b) Backmund,
M.; von Zielonka, M.; Hartmann, W. J .; Hesse, J .; Eichenlaub, D.
Fortschr. Med. 1999, 117, 24.
(2) WHO. Malaria Weekly; 1996, J une 3, 11.
(3) For a selection of promising new antimalarials, see: (a) J omaa,
H.; Wiesner, J .; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz,
M.; Tu¨rbachova, I.; Eberl, M.; Zeidler, J .; Lichtenthaler, H. K.; Soldati,
D.; Beck, E. Science 1999, 285, 1573. (b) Bringmann, G.; Feineis, D.
Act. Chim. The´rapeut. 2000, 26, 151. (c) Ying, L.; Zhu, Y.-M.; J iang,
H.-J .; Pan, J .-P.; Wu, G.-S.; Wu, J .-M. J . Med. Chem. 2000, 43, 1635.
(4) Bringmann, G.; Menche, D.; Bezabih, M.; Abegaz, B. M.; Ka-
minsky, R. Planta Med. 1999, 65, 757.
(13) Bringmann, G.; Kraus, J .; Menche, D.; Messer, K. Tetrahedron
1999, 55, 7563.
(5) Dagne, E.; Steglich, W. Phytochemistry 1984, 23, 1729.
10.1021/jo020189s CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/03/2002
J . Org. Chem. 2002, 67, 5595-5610
5595

Bringmann et al.
activities. Part of this work has previously been reported
in preliminary form.4,14
whether lactone structures of type 4 would be accessible
in the usual way from 5, despite the additional steric
hindrance and electronic impact exerted by the carbonyl
function at C-10,17 and whether the lactone would (hope-
fully) be configurationally unstable, to permit the atro-
poselective ring cleavage to occur economically, with
dynamic kinetic resolution.
Using a very simplified synthetic model (Scheme 2),
we first investigated at what stage an efficient introduc-
tion of the C-acetyl group might best be achieved, for
which we considered two main strategies. The first
approach, an early introduction of the acetyl group,
implied an ester such as 10 as a key intermediate, while
the second one, to first build up the biaryl bond and then
to incorporate the acetyl group at a later stage, just
required the “standard” lactone 6 as a building block.
Resu lts a n d Discu ssion
SCHEME 2
A characteristic structural feature of knipholone (1a )
is the rotationally hindered and thus stereogenic biaryl
axis. The substitution pattern of 1a and related an-
thraquinones, in particular the presence of a C1 substitu-
ent (the methyl group at C-3) and an oxygen function
(e.g., the OH group at C-2′) next to the axis, suggested
to build up 1a according to the “lactone method”, a
strategy for the regioselective and atropo-enantiodiver-
gent construction of even highly hindered biaryls, which
has already been used for the synthesis of numerous
bioactive natural biaryls and useful biaryl reagents.15,16
The corresponding retrosynthetic concept is shown in
Scheme 1. A key intermediate of our approach would thus
be a biaryl lactone of type 4, either already equipped with
the ultimate C-acetyl group as in 4b or being still without
it as in 4a . These bridged biaryls were planned to be
obtained by intramolecular coupling of the corresponding
esters 5 (e.g., with X ) Br), which in turn should best be
accessible from chrysophanol (2) and a suitably function-
alized phloroglucinol part, 3a or 3b. Before embarking
on a total synthesis, a number of issues had to be
addressed beforehand, among them the question of when
to introduce the acetyl group and the general problem of
SCHEME 1
To test the first approach, ester 10, as prepared from
2-hydroxy-4,6-dimethoxyacetophenone18 and 1-bromo-2-
naphthoic acid19 (not shown, see Experimental Section),
was submitted to the conditions of a Heck-type intramo-
(14) Bringmann, G.; Menche, D. Angew. Chem., Int. Ed. 2001, 40,
1687.
(15) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525.
(16) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615.
(17) For an easier comparison of the compounds presented herein,
the numbering of the “free” anthraquinone chrysophanol (2) was
applied to the quinoid moiety of the respective phenylanthraquinones
5, 17, 30, and 35. In the Experimental Section, the correct numbering
according to the IUPAC nomenclature has been used.
(18) Cunningham, B. D. M.; Lowe, P. R.; Threadgill, M. D. J . Chem.
Soc., Perkin Trans. 2 1989, 1275.
(19) Cornejo, J . J .; Ghodsi, S.; J ohnson, R. D.; Woodling, R.;
Rickborn, B. J . Org. Chem. 1983, 48, 3869.
5596 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
SCHEME 3
lecular coupling reaction that had previously been ef-
ficiently used in numerous syntheses of a broad variety
of most different biaryl lactones.15,16 A number of other
catalysts, additives, and reaction conditions were also
tried, but none of them produced the desired lactone 11.
Attempts to first protect the ketone function of 10 before
the coupling reaction, either as an acetal or as a thio-
acetal, likewise failed. With 1,2-ethanediol there was no
reaction, whereas with 1,2-ethanedithiol cleavage of the
ester occurred, making it feasible to try the second
strategy, introducing the acetyl group at a later stage
starting from lactone 6.20 As previously shown,21 this
bridged biaryl is configurationally unstable and can be
cleaved highly atropo-enantioselectively by a number of
chiral nucleophiles, leading to the corresponding open
biaryls, which are configurationally stable. For a first
proof of concept concerning the introduction of the
C-acetyl group, however, no optically active material was
required, so that it sufficed to cleave the ring with the
achiral and thus cheap reducing agent LAH to give, after
stepwise deoxygenation of the side chain, the racemic
biaryl 7. Using this substrate, the introduction of the
C-acetyl group succeeded both directly, by Friedel-Crafts
acetylation,22 and in a two-step procedure, by an ortho-
selective Fries reaction23 on ester 8, and provided the
C-acetyl compound 9 in good yields, without any cleavage
of the methyl ether.
We then proceeded to test the applicability of our
lactone methodology to phenylanthraquinone-type struc-
tures such as 4a at the level of the still simplified and
easily accessible but closer model compound 17 (Scheme
3). Both, the bromo- and the iodoacid 16a and 16b were
prepared by the corresponding Sandmeyer reaction from
13, which was in turn accessible from 2-methylan-
thraquinone (12).24 Cyclization of the resulting bro-
moester 14 under typical Heck conditions, with the
reagent combination Pd(OAc)2/PPh3/NaOAc, proceeded
smoothly and in good yield, to give the desired key
intermediate 17, which was obtained as the only detect-
able product, so that a further optimization of the
reaction by using the corresponding iodoester was not
required. An X-ray analysis of 17, besides confirming the
constitution, revealed the expectedly highly distorted
helicene-like structure, as a consequence of the steric
constraints exerted by the ortho substituents next to the
newly generated biaryl bond. In particular the carbonyl
oxygen at C-1017 is largely twisted out of the previously
planar anthraquinone system.
TABLE 1. Resu lts of th e Red u ctive Rin g Clea va ge
Rea ction of 17
Initial attempts using achiral nucleophiles such as
LAH to test the reactivity of 17 soon revealed that the
lactone functionality can be selectively reduced without
attacking the quinoid system. For an atroposelective
cleavage of the bridge, chiral H-nucleophiles, such as the
H
(P):(M)
(R)-15‚BH3, 25 °C
(S)-15‚BH3, 0 °C
LAH
25:75
85:15
50:50
analytical scale
67% yield
71% yield
(20) Bringmann, G.; Hartung, T.; Go¨bel, L.; Schupp, O.; Ewers, C.
L. J .; Scho¨ner, B.; Zagst, R.; Peters, K.; von Schnering, H. G.; Burschka,
C. Liebigs Ann. Chem. 1992, 225.
(21) Bringmann, G.; Heubes, M.; Breuning, M.; Go¨bel, L.; Ochse,
M.; Scho¨ner, B.; Schupp, O. J . Org. Chem. 2000, 65, 722.
(22) For a similar Friedel-Crafts acylation, see ref 18.
(23) For related Fries rearrangements, see: (a) Harowven, D. C.;
Dainty, R. F. Tetrahedron Lett. 1996, 37, 7659. (b) Lin, G.-Q.; Zhong,
M. Tetrahedron Lett. 1997, 38, 1087.
oxazaborolidine-borane system, seemed particularly
promising. The CBS reaction,25 originally developed for
the enantioselective reduction of ketones, has proven to
be an efficient tool for the stereoselective cleavage of
biaryl lactones15,16,26 and of related nonbiarylic hetero-
(24) For the synthesis of 13 a three-step procedure according to the
following references was used: (a) Locher, A.; Fierz, H. E. Helv. Chim.
Acta 1927, 10, 642. (b) BASF, Fortschr. Teerfarbenfabr. Verw. Indus-
triezweige 1909, 10, 601. (c) Morley, J . O. Synthesis 1976, 528.
(25) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37, 1986.
(26) Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J .; Peters, K.;
Peters, E.-M.; Rycroft, D. S.; Connolly, J . D. J . Am. Chem. Soc. 2000,
122, 9127.
J . Org. Chem, Vol. 67, No. 16, 2002 5597

Bringmann et al.
cycles with stereogenic centers.26 As in all those cases
before, reduction proceeded smoothly, permitting access
atropodivergently both to the (P)- or, optionally, to the
corresponding (M)-alcohol 19, depending on the ox-
azaborolidine enantiomer used, (S)-18 or (R)-18. The
enantiomeric ratios and yields obtained indicate that this
cleavage reaction proceeds according to the principle of
a dynamic kinetic resolution (e.g., er 85:15, 67% yield),
showing that, despite the molecular distortion, lactone
17 is configurationally unstable and thus allows the
efficient conversion of the entire (racemic!) lactone mate-
rial into essentially one (or, optionally, the other) enan-
tiomeric ring cleavage product, which constitutes one of
the advantages of the lactone approach.
SCHEME 4
The absolute configurations of the atropo-enantiomeric
ring cleavage products 19 became evident from the
analogous products of the authentic, correctly substituted
lactones subsequently prepared (see below), leading to
the genuine natural products. For an additional confir-
mation already at this stage of the synthesis and at the
level of a biaryl derivative with an entirely different,
nonquinoid chromophore, 19 was converted into the
correspondingly configured phenylanthracene leuco-di-
acetate 20 (Figure 1), whose absolute configuration was
established by quantum chemical circular dichroism (CD)
calculations, a valuable stereoanalytical tool as already
demonstrated in numerous previous cases.27,28 The CD
spectrum calculated for (M)-20 showed a good agreement
with the experimental one for the enantiomer of 19 that
had been obtained when using (S)-18 as the H-nucleo-
phile for the ring cleavage of 17, whereas the spectrum
calculated for (P)-20 was nearly opposite to the experi-
mental one, especially in the diagnostically significant27
short-wavelength part (Figure 1).
For the preparation of the knipholone model analog
23 (at this level again racemic; see Scheme 4), neither
the reduction of the side chain nor the introduction of
the C-acetyl group succeeded by using the protocols
established above (see Scheme 2). Thus, attempted side-
chain deoxygenation of 19 by hydroxy/bromine exchange
with subsequent LAH reduction predominantly reduced
the quinoid system, and the previous conditions for the
C-acetylation of 7 (see Scheme 2) did not give any
reaction for 21. The reduction of the side chain of 19
finally succeeded by hydrogenolysis of the intermediate
bromide with Pd/C as the catalyst; an additional im-
provement in the hydroxy/halogen exchange was achieved
by the use of polymer-bound triphenylphosphine, which
can readily be discarded by simple filtration, further
increasing the yield up to 72%. For the introduction of
the C2 unit at C-3′ of the target molecule, the stronger
acetylating reagent combination TiCl4/Ac2O had to be
applied or, for the corresponding Fries rearrangement,
higher reaction temperatures, to give the (still deoxy-
genated) model knipholone 23.
For the synthesis of the authentic, genuine natural
phenylanthraquinones, a 1,8-dioxygenated anthraquino-
ne building block was required. A broad variety of
synthetic pathways to natural and unnatural hydroxy-
anthraquinones are known,29,30 of which, because of the
cheap commercial availability of the starting materials
and the convergence of the synthesis, the cycloaddition
of naphthoquinones such as juglone (24) and dienes such
as 2530 (see Scheme 5) was chosen for the straightforward
(29) (a) Eder, R.; Widmer, C. Helv. Chim. Acta 1923, 6, 419. (b)
Mu¨hlemann, H. Pharm. Acta Helv. 1948, 23, 257. (c) Birch, A. J .;
Powell, V. H. Tetrahedron Lett. 1970, 40, 3467. (d) Banville, J .;
Brassard, P. J . Chem. Soc., Perkin Trans. 1 1976, 613. (e) Krohn, K.
Tetrahedron Lett. 1980, 21, 3557. (f) Savard, J .; Brassard, P. Tetra-
hedron 1984, 40, 3455. (g) J ung, M.; Lowe, J . A., III.; Lyster, M. A.;
Node, M.; Pfluger, R. W.; Brown, R. W. Tetrahedron 1984, 40, 4751.
(h) Watanabe, M.; Fukuda, T.; Miyashita, T.; Furukawa, S. Fac.
Pharm. Sci. 1985, 105, 11. (i) Cameron, D. W.; Feutrill, G. I.; Gamble,
G. B.; Stavrakis, J . Tetrahedron Lett. 1986, 27, 4999. (j) Khanapure,
S. P.; Reddy, R. T.; Biehl, E. R. J . Org. Chem. 1987, 52, 5685. (k) Krohn,
K.; Khanbabaee, K. Liebigs Ann. Chem. 1993, 905.
F IGURE 1. Elucidation of the absolute configuration of (P)-
19 by comparison of the experimental CD spectrum of its leuco-
acetate 20 (s) with the CD data calculated for the two atropo-
enantiomeric forms of 20 (- - -).
(27) Bringmann, G.; Busemann, S. In Natural Product Analysis;
Schreier, P., Herderich, M., Humpf, H.-U., Schwab, W., Eds.; Vieweg:
Braunschweig 1998; pp 195-212.
(28) Bringmann, G.; Mu¨hlbacher, J .; Repges, C.; Fleischhauer, J .
J . Comput. Chem. 2001, 22, 1273.
(30) Khan, A. T.; Blessing, B.; Schmidt, R. R. Synthesis 1994, 255.
5598 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
SCHEME 5
SCHEME 7
construction of chrysophanol (2). For the already side-
chain oxygenated building block aloe-emodin (27), which
is likewise a natural product, a direct, partial synthesis
from the likewise commercially available (though quite
expensive) natural C-glycoside aloin (26)31 was preferred.
As shown in this paper, chrysophanol and aloe-emodin
can easily be interconverted, by benzylic halogenation of
2 with subsequent hydrolysis and by the above-men-
tioned two-step hydrogenolysis procedure for the side-
chain deoxygenation of 27, giving the presented synthesis
a high flexibility.
Likewise simple seemed the halogenation at the re-
quired coupling position, since a three-step procedure for
the introduction of bromine into the 4-position of aloe-
emodin (27) had already been reported in the literature,32
by bromination of the diacetate 28 (see Scheme 6).33 The
product now obtained by the published protocol, however,
although displaying the same physical data as those
reported in the literature (and also the same yield),
turned out not to be the postulated 4-bromo derivative
3017 but the respective 2-isomer, 29, as was unambigu-
ously shown by NMR, in particular by HMBC inter-
actions of both, H-4 and H-5, to C-10 (see Scheme 6). The
likewise attempted direct bromination of free, unpro-
tected aloe-emodin (27) itself preferentially took place in
the undesired 2- and 7-positions. This inherent reactivity
could not be overcome even by a variety of different
brominating reagents and solvent systems or by applying
most different reaction conditions.
the molecule by converting the phenolic OH groups into
isopropyl ethers as in 31 and subsequent treatment with
Br2 to produce 33, whose correct bromination site was
unambiguously deduced from NMR experiments (see
Scheme 7) and X-ray data.34 As a result of the formation
of further regioisomeric or over-reacted bromination
products and the sensitivity of the side chain toward
oxidation, however, the obtained yields were only moder-
ate (32%) and could not be improved by using other
SCHEME 6
(31) Rychener, M.; Steiger, W. Pharm. Acta Helv. 1989, 64, 8.
(32) Alexander, J .; Bhatia, A. V.; Mitscher, L. A.; Omoto, S.; Suzuki,
T. J . Org. Chem. 1980, 45, 20.
(33) In the literature, a direct bromination of chrysophanol (2) has
also been described, yet leading to a variety of products: (a) Chum-
balov, T. K.; Muzychkina, R. A.; Zhusupova, G. E.; Nazarova, V. D.;
Chanysheva, I. S. S. Rab. Khim., Kaz. Univ. 1973, 3, 57; Chem. Abstr.
1974, 81, 135801. (b) Chumbalov, T. K.; Chanysheva, I. S.; Zhusupova,
G. E.; Muzychkina, R. A.; Sheinchenko, V. I. Zh. Fiz. Khim. 1979, 53,
186; Chem. Abstr. 1979, 90, 185882.
The desired functionalization of 27 was finally at-
tained after sterically shielding the “Northern” part of
(34) Peters, K.; Peters, E.-M.; Menche, D.; Bringmann, G. Unpub-
lished results.
J . Org. Chem, Vol. 67, No. 16, 2002 5599

Bringmann et al.
TABLE 2. Resu lts of th e In tr a m olecu la r Cou p lin g
Rea ction s of 35
SCHEME 8
time 37a 37b 37c
catalyst
base
[h]
[%] [%] [%]
PdCl2(PPh3)2 (0.5 equiv)
PdCl2(PPh3)2 (0.5 equiv)
Pd(OAc)2 (0.2 equiv), PPh3
Pd(OAc)2 (0.4 equiv), PPh3
Pd(OAc)2 (0.6 equiv), PPh3
Pd(OAc)2 (0.8 equiv), PPh3
NaOAc 10
5.4 46
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
2
6
5
4.5
2
17
6
12
36 12
32
59
22
14
6
7
8
Pd(OAc)2/P(o-tolyl)3 (0.6 equiv) NaOAc
Pd(OAc)2 (0.6 equiv), PPh3
2
NaOPiv 1-2 68
5
procedures. Different from the model compounds de-
scribed above, a regioselective nitration (in this case for
1-O,8-O-dimethylchrysophanol and 1-O,8-O-dimethyl-
aloe-emodin) failed because of formation of chromato-
graphically very similar regioisomeric products or de-
composition, as did attempts to introduce the bromine
by a DOM (directed ortho metalation) strategy either on
31 or on the corresponding aldehyde or acid (not shown).
All of these problems were overcome by protecting the
oxidation-sensitive side chain by O-acetylation and then
using bromine in excess, thus directly giving the dibromo
derivative 34 in a reliably high yield. By saponification
and stepwise oxidation (MnO2, NaClO2) to the respective
acid 36, followed by esterification with the dimethoxy-
phenol 15 using Steglich’s procedure,35 which proved to
be superior to the alternative to proceed via the corre-
sponding acid chloride as above for 16a , the dibromo ester
35 became available on a multigram scale (Scheme 7).
Despite the additional bromine substituent at C-5,17
the intramolecular coupling of 35 proceeded smoothly to
give the desired, still monobrominated lactone 37a
(Scheme 7, Table 2), proving the applicability of the
lactone methodology even to substrates with two elec-
tronically similar aryl-bromine bonds. For this cycliza-
tion, the use of Pd(II)acetate was most efficient, while
entirely unexpectedly PdCl2(PPh3)2 produced significant
quantities (up to 46%) of the additionally phenylated
derivative 37c. Short reaction times and the use of
sodium pivalate as a sterically more demanding base,36
as compared to sodium acetate, further improved the
yields, whereas in contrast to previous cases37 the use of
the Herrmann-Beller catalyst38 was less effective.
The stereochemical key step of the synthesis, the
atroposelective reductive ring cleavage of 37a , was
thoroughly optimized with respect to nucleophiles, sol-
vents, and reaction temperatures. As for the model
lactone 17 (see Scheme 3), the best results were obtained
using Corey’s oxazaborolidine-borane system, providing
the phenylanthraquinone (P)-38 in very good optical (er
98:2) and chemical (81%) yields (Scheme 8). Its enantio-
meric purity was further enhanced by a simple crystal-
lization step. The possibility to reoxidize (MnO2, NaClO2)
and subsequently recycle (DCC, DMAP) the undesired
enantiomer (practically spoken, the mother liquor mate-
rial), literally by recyclization back to the lactone 37a ,
as exemplarily shown for (M)-38 in Scheme 8, permitted
transformation of an even larger portion of the starting
material into the desired product enantiomer, here into
(P)-38.
A remaining synthetic problem was the reductive
elimination of the additional bromine substituent at C-5.
One of the methods for such aromatic hydrodehalogena-
tion reactions in the field of anthraquinones, the use of
Na2S2O4,39 led to the cleavage40 of the biaryl bond as
shown for (P)-38 to give 31 and 15 (Scheme 9), while
formic acid in combination with Pd/C41 preferentially
reduced the quinoid system, e.g., converting 37a to 41.
The desired transformation could finally be effected by
Pd-catalyzed hydrogenolysis in the presence of a mild
buffer (NaOAc) to avoid an acid-induced cleavage of the
O-isopropyl groups by the HBr formed. The conditions
were optimized such that via (M)-39 simultaneously the
desired methyl group at C-2 was obtained to give (P)-40
in a one-pot reaction. Thus, the additional bromine at
C-5 ultimately had not required any additional steps for
its introduction or for its reductive elimination but had
significantly increased the efficacy of the synthesis.
Stronger bases, such as NEt3, gave the undesired cyclic
ether 42. From the diastereotopic character of the ben-
zylic portions in the bridge (partially overlayed by the
OCH(CH3)2 multiplet (see Scheme 9), this bridged biaryl
was shown to be chiral on the NMR time scale but (as
expected from the similarity to the corresponding lactone
37a ) should be configurationally unstable from DNMR
investigations.21
Initial attempts to achieve the last synthetic key step,
the introduction of the still required C2 unit, by acety-
lating (P)-40 directly or by a Fries rearrangement of its
2′-O-acetate ester (not shown) as above for (rac)-7 (see
(35) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(36) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J . Am.
Chem. Soc. 1994, 116, 1004.
(37) (a) Bringmann, G.; Hinrichs, J .; Kraus, J .; Wuzik, A.; Schulz,
T. J . Org. Chem. 2000, 65, 2508. (b) Bringmann, G.; Ochse, M.; Go¨tz,
R. J . Org. Chem. 2000, 65, 2069.
(38) Herrmann, W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 25, 1844.
(39) (a) Yosioka, I.; Yamauchi, H.; Morimoto, K.; Kitagawa, I.
Tetrahedron Lett. 1968, 9, 1149. (b) Banville, J .; Grandmaison, J .-L.;
Lang, G.; Brassard, P. Can. J . Chem. 1974, 52, 80.
(40) For related biaryl cleavage reactions, see refs 5 and 8.
(41) (a) Cortese, N. A.; Heck, R. F. J . Org. Chem. 1977, 42, 3491.
(b) Pandey, P. N.; Purkayastha, M. L. Synthesis 1982, 876.
5600 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
SCHEME 9
from Bulbine capitata and Kniphofia foliosa8-10 in all
their chromatographic, physical, spectral, and chiroptical
data. Thus, 1c and 1d must be stereochemically identi-
cal44 both with knipholone and its anthrone, i.e., all of
them with the COCH3 portion “above” the anthraquinone
plane, and must have the stereostructures shown in
Scheme 10 now established by the synthetic work pre-
sented here.
SCHEME 10
The absolute configurations of knipholone (1a ) and its
anthrone (1b) in turn had previously been established
by Boltzmann-weighted quantum chemical CD calcula-
tions13 and were now confirmed to be M by molecular
dynamics based quantum chemical CD calculations.
The MD simulations were performed using the MM3
force field,45 arbitrarily starting with the (M)-enantiomers
of the compounds. The simulations were calculated for a
total time period of 500 ps, recording the structure every
0.5 ps for further calculations.
For the 1000 structures thus collected for each com-
pound, single CD spectra were calculated and then,
differently from the previous13 Boltzmann-weighting,
averaged arithmetically to give theoretical overall spec-
tra. To take into account systematic shifts of the calcu-
lated CD spectra, a “UV correction” was carried out for
each calculated spectrum as introduced earlier.27 The
good agreements between the calculated overall CD
spectra for the (M)-compounds with the experimental
ones (Figure 2) permitted an unambiguous attribution
of the absolute configuration of both 1a and 1b as M.
The synthetic availability of the compounds presented
herein permitted the evaluation of their antimalarial
potential in vitro against Plasmodium falciparum. The
authentic natural products 1a -d , but also some of their
synthetic biarylic precursors, e.g., 38 and 40, and to a
smaller degree the dideoxy analogs 19, 21, and 23,
Scheme 2), only led to a cleavage of the O-isopropyl
ethers. After a complete directed O-deprotection in the
anthraquinone part, however, acetylation proceeded
smoothly and in high yields, this time necessitating a
2-fold excess in both the lewis acid (TiCl4) and the
acetylating agent (Ac2O) (Scheme 10), to give 6′-O-
methylknipholone (1c), the first natural phenylan-
thraquinone synthetically attained. Selective mono-O-
demethylation of 1c at C-6′42 using AlBr3 gave the target
molecule knipholone (1a ), whose reduction using a stan-
dard procedure for anthraquinones43 provided its an-
throne 1b. The fully O-demethylated derivative 1d was
obtained when using AlBr3 in excess. All of the phenyl-
anthraquinones 1a -d are natural products and were
found to be completely identical to authentic samples
(42) For a related regioselective cleavage of xanthoxylline (2-acetyl-
3,5-dimethoxyphenol), but under more drastic conditions, see: J ain,
A. C.; Gupta, S. M.; Bambah, P. Indian J . Chem., Sect. B 1985, 24,
393.
(43) For related reductions of anthraquinones, see: Auterhoff, H.;
Scherff, F. C. Arch. Pharm. (Weinheim, Ger.) 1960, 293, 918.
(44) Note that the opposite descriptor of 1c as compared to those of
1a , 1b, and 1d is only due to the CIP formalism.
(45) Cui, W.; Li, F.; Allinger, N. L. J . Am. Chem. Soc. 1993, 115,
2943.
J . Org. Chem, Vol. 67, No. 16, 2002 5601

Bringmann et al.
TABLE 3. Activities of Selected P h en yla n th r a qu in on es
a n d Com p ou n d s Der ived Th er eof a ga in st P . fa lcipa r u m
(str a in K1), T. cr u zi, T. br u cei r h od esien se, a n d
L. d on ova n i a n d Cytotoxicities a ga in st Ra t Sk eleta l
Myobla st Cells (L6)
IC50 [µg/mL]
IC50/MIC
P.
T.
T. b.
L.
[µg/mL]
compd falciparum
cruzi
rhodes donova cytotoxicity (L6)
e
std
0.141a
0.398b
0.0024c
48.2d
2.8 (IC50)
>90 (MIC)
33 (MIC)
3.7 (MIC)
ndg
1a
1b
1c
0.672
0.149
1.06
7.61
1.5
ndg
9.31
13.12
ndg
>30
nef
ndg
1d
2
3b
(rac)-9
13
0.512
>5.00
13.65
5.7
>10
30 (MIC)
>90 (MIC)
nah
ndg
ndg
>30
>30
>30
>10
>30
>30
>30
>5.00
>5.00
>5.00
>5.00
>5.00
1.05
86.0
ndg
44.1
ndg
38.6
13.13
13.26
>90
>90
4.84
85.8
2.27
16.8
24.2
32.25
2.86
ndg
3.34
15.05
2.91
4.6
11.36
10.68
2.765
4.185
2.875
5.505
29.48
6.31
90 (MIC)
88.0 (IC50
)
15
>90 (MIC)
>90 (IC50)
90
67.4 (MIC)
>90 (MIC)
>90 (MIC)
(M)-20
(rac)-19
(rac)-21
(rac)-23
26
27
32
37a
0.677
1.17
22.7i
>30
>30
>5.00
>5.00
>5.00
>5.00
0.714
0.326
>5.00
0.739
>3.3
10 (IC50
>90 (IC50
58.2 (IC50
18.9 (IC50
10.3 (IC50
)
)
)
)
)
>30
>30
>10
>10
>30
>10
(M)-38
(P)-38
41
7.58
82.82
8.52
31.4 (MIC)
16.9 (MIC)
(P)-40
a
d
Chloroquine. b Benznidazole. c Melarsoprol. Pentostam. e Me-
floquine. f Not evaluated due to cytotoxicity. Not determined.
Not applicable, activity did not substantiate cytotoxicity. Mac-
g
F IGURE 2. Confirmation of the absolute configuration of 1a
and 1b (- - -), by comparison of the CD spectra calculated for
both (M)- and (P)-1a , as well as (M)- and (P)-1b, with the
experimental data (s).
h
i
rophages infected with axenic amastigotes.
compound (IC50 1.5 µg/mL). It is interesting to note that
in this case likewise the mere anthraquinone building
block 27, which had no effect against P. falciparum (see
above), was now shown to be active against this pathogen
also. Only very low activities of the compounds studied
were observed against T. b. rhodesiense, with mostly no
activity against L. donovani, showing again the above-
reported antiplasmodial activities to be quite pathogen
specific.
showed moderate to good activities with IC50 values from
1.17 µg/mL for (rac)-21 to 0.326 µg/mL for (P)-38. The
best results were obtained for the anthrone 1b (IC50 0.149
µg/mL), being in the range of the standard chloroquine
(IC50 0.141 µg/mL), while its quinoid synthetic precursor
(P)-38 was less active (IC50 0.326 µg/mL). As revealed by
comparing 21 and 40 with the corresponding acetyl
derivatives 23 and 1d , the C-acetyl group in the lower
part of the molecule does not seem to be important to
achieve good activities. The presence of an intact, full
phenylanthraquinone molecular framework, however,
appears to be essential. Not only the lactone-type struc-
tures 41 and 37a but also all of the phenyl-devoid
anthraquinones (e.g., 2, 13, 26, 27, and 32) and the
acetylphloroglucinol building blocks (e.g., 3b), as well as
the simplified phenylnaphthalenes (e.g., 9), are com-
pletely inactive. Likewise inactive is the biarylic but
nonquinoid phenylanthracene (M)-20. None of the phen-
ylanthraquinones showed any cytotoxicity on mammalian
cells, revealing this antiplasmodial activity to be quite
specific.
With respect to these activities, further investigations
of other antiprotozoal properties, viz., against Trypano-
soma cruzi (the pathogen of Chagas disease), T. brucei
rhodesiense (causing the African sleeping sickness), and
Leishmania donovani (responsible for leishmaniasis),
seemed promising. Knipholone (1a ), its natural deriva-
tives, and some of its synthetic biphenylic precursors such
as 37, 38, and 40, as well as their dideoxy analogs 19
and 21, displayed moderate to good activities against T.
cruzi, with the anthrone 1b being the most potent
Con clu sion s
Based on the lactone concept, the first successful
synthetic approach toward natural knipholone-type phen-
ylanthraquinones is described. After the elaboration of
solutions to the main synthetic problems using simplified
model compounds, key steps of the synthesis were the
regioselective 2-fold halogenation of the respective an-
thraquinone building block, the intramolecular biaryl
coupling of the respective trioxyphenyl dibromoan-
thraquinone carboxylate ester, the atropo-enantiodiver-
gent ring cleavage of the configurationally unstable biaryl
lactone using chiral H-nucleophiles with dynamic kinetic
resolution, and the introduction of the C-acetyl group.
By this strategy, knipholone (1a ), knipholone anthrone
(1b ), 6′-O-methylknipholone (1c), and 4′-O-demeth-
ylknipholone (1d ) were obtained. This first total synthesis
of natural phenylanthraquinones simultaneously permit-
ted a stereochemical correlation among the compounds.
On the basis of the now attained synthetic availability
of these natural products, their precursors, and structural
analogs, the antiplasmodial activities of such knipholone-
5602 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
of dry THF was treated dropwise at 0 °C with a solution of
(rac)-7 (50 mg, 170 µmol) in 0.5 mL of dry THF. After 2 h a
solution of AcCl (15 µL, 16.6 mg, 210 µmol) in 1 mL of CH2Cl2
was added within 20 min at 0 °C. The mixture was stirred for
3 h. Evaporation of the solvent and filtration of the residue
through a silica gel column (petroleum ether/Et2O ) 3:1)
afforded (rac)-8 (54.9 mg, 163 µmol, 96%) as a yellow powder,
which was crystallized from CH2Cl2/petroleum ether: mp 111
°C; IR (KBr) ν 3020, 2980, 2940, 2920, 1745, 1600, 1560, 1200,
type phenylanthraquinones were broadly tested and were
shown to result from a combination of the anthraquinone
portion and the acetylphloroglucinol unit being fixed
together via the biaryl bond. The highest antiplasmodial
activity has so far been obtained for the natural pheny-
lanthrone 1b.
Exp er im en ta l Section
1
1185, 1145, 1080; H NMR (250 MHz, CDCl3) δ 1.55 (s, 3H),
Gen er a l Meth od s. HPLC-UV: HPLC with syringe load-
ing sample injector, UV detector, and integrator. Column:
Chiralcel OD-H, 4.6 mm × 250 mm, 0.5 mL/min, hexane/i-
PrOH ) 70:30 for 19 [tR ) 30 min for (M)-19, tR ) 35 min for
(P)-19] and 65:35 for 38 [tR ) 29 min for (P)-38, tR ) 46 min
for (M)-38]. For preparative HPLC an LC 25 mm module with
two Nova-Pak C-18 column segments (25 mm × 100 mm) and
a pump with a flow of 4.0 mL min-1 and UV detection at 254
nm was used (solvent MeOH/H2O ) 75:25, acidified with 0.1%
TFA). Source of compounds: 2,30 6,20 13,24 16b,48 27,31 28,32
2-acetyl-3,5-dimethoxyphenol,18 and 1-bromo-2-naphthoic acid19
were prepared according to literature procedures. All pal-
ladium-catalyzed coupling reactions were performed in care-
fully baked flasks (heating by a heatgun for 5 min under
vacuum). For further general procedures (i.e., [R]D, mp, NMR,
IR, MS) see ref 7b.
(r a c)-1-(2′,4′-Dim et h oxy-6′-h yd r oxyp h en yl)-2-m et h yl-
n a p h th a len e [(r a c)-7]. A solution of 6 (800 mg, 2.61 mmol)
in 25 mL of dry THF was treated with 198 mg (5.22 mmol) of
LAH at 0 °C and stirred for 30 min at 0 °C and for 30 min at
room temperature. The reaction mixture was cautiously
hydrolyzed with 1 M HCl. The aqueous phase was thoroughly
extracted with Et2O. The combined organic phases were dried
(MgSO4) and the solvent evaporated. Filtration through a short
silica gel column (CH2Cl2) and subsequent recrystallization
from CH2Cl2/petroleum ether afforded colorless crystals of
(rac)-2-hydroxymethyl-(2′,4′-dimethoxy-6′-hydroxyphenyl)-naph-
thalene (674 mg, 2.17 mmol, 83%): mp 165-166 °C (lit.46 165-
166 °C).
A solution of this phenol (301 mg, 971 µmol) in 25 mL of
CH2Cl2 was treated at 0 °C under nitrogen with PPh3 (382
mg, 1.46 mmol) and stirred at 0 °C for 30 min. (CBrCl2)2 (475
mg, 1.46 mmol) was added and the reaction mixture was
allowed to warm to room temperature within 3 h and stirred
for further 5 h at this temperature. After evaporation of the
solvent the residue was passed through a short silica gel
column (petroleum ether/Et2O ) 3:1) to afford a white solid
(320 mg) which was dissolved in 10 mL of dry Et2O, subse-
quently treated with LAH (61.2 mg, 1.61 mmol), and stirred
at room temperature for 3 h. After cautious hydrolysis of the
reaction mixture with H2O and 2 M HCl, the aqueous phase
was thoroughly extracted with CH2Cl2. Drying of the combined
organic phases (MgSO4) and evaporation of the solvent under
reduced pressure afforded (rac)-7 (230 mg, 781 µmol, 81%) as
a slightly yellow solid, which was obtained as colorless crystals
from CH2Cl2/petroleum ether: mp 153 °C; IR (KBr) ν 3400,
3020, 2930, 2900, 2820, 1605, 1560, 1135, 1090 cm-1; 1H NMR
(250 MHz, CDCl3) δ 2.26 (s, 3H), 3.62 (s, 3H), 3.88 (s, 3H),
6.25 (d, J ) 2.9 Hz, 1H), 6.31 (d, J ) 2.9 Hz, 1H), 7.32-7.49
(m, 4H), 7.82-7.87 (m, 2H); 13C NMR (63 MHz, CDCl3) δ 20.2,
55.4, 55.7, 91.7, 92.7, 106.3, 125.2, 126.5, 127.3, 128.1, 128.5,
128.8, 132.4, 133.3, 137.2, 154.5, 158.7, 161.3; MS (EI) m/z 294
(100) [M+•], 279 (18), 263 (10). Anal. Calcd for C19H18O3: C,
77.53; H, 6.17. Found: C, 77.17; H, 6.03.
2.22 (s, 3H), 3.89 (s, 3H), 3.66 (s, 3H), 6.44 (d, J ) 2.3 Hz,
1H), 6.55 (d, J ) 2.3 Hz, 1H), 7.31-7.41 (m, 4H), 7.73-7.81
(m, 2H); 13C NMR (63 MHz, CDCl3) δ 20.2, 20.2, 55.5, 55.9,
96.8, 99.6, 114.0, 124.6, 125.6, 125.7, 127.5, 127.7, 128.4, 129.1,
131.8, 132.9, 135.6, 150.3, 156.0, 160.5, 168.8; MS (EI) m/z 336
(26) [M+•], 294 (100), 279 (13). Anal. Calcd for C21H20O4: C,
74.98; H, 5.99. Found: C, 75,68; H, 5,72.
(r a c)-1-(5′-Acetyl-2′,4′-d im eth oxy-6′-h yd r oxyp h en yl)-2-
m eth yln aph th alen e [(r a c)-9]. (A) By Fr iedel-Cr afts Acyl-
a tion of (r a c)-7. BCl3 (102 µL, 1 M solution in hexane) was
treated dropwise with a solution of (rac)-7 (30.0 mg, 102 µmol)
in 1 mL of CH2Cl2 at -10 °C. After 5 min AcCl (120 µL of a 1
M solution in CH2Cl2) was added and the mixture was heated
under reflux for 3 h and then allowed to cool to room
temperature. After cautious hydrolysis with 1 M HCl, the
aqueous phase was thoroughly extracted with CH2Cl2 and the
combined organic phases were dried (MgSO4). Evaporation of
the solvent, column chromatography, and recrystallization
from CH2Cl2/petroleum ether afforded (rac)-7 (33.3 mg, 99.0
µmol, 97%) as fine colorless needles. (B) By F r ies Rea r -
r a n gem en t of (r a c)-8 Usin g Zr Cl4. A suspension of ZrCl4
(28.0 mg, 120 µmol) in 1 mL of dry CH2Cl2 was treated
dropwise with (rac)-8 (10.0 mg, 29.7 µmol) in 500 µL of CH2-
Cl2. The reaction mixture was stirred vigorously at room
temperature for 15 h. Evaporation of the solvent and flash
chromatography afforded (rac)-8 (7.11 mg, 21.1 µmol, 71%) as
a colorless powder, identical to the material obtained above.
(C) By F r ies Rea r r a n gem en t of (r a c)-8 Usin g TiCl4. A 50-
µL portion of a 1 M solution of TiCl4 in benzene was treated
dropwise with (rac)-8 (7.00 mg, 20.8 µmol) in 200 µL of dry
benzene and refluxed for 1 h. Evaporation of the solvent,
column chromatography, and crystallization from CH2Cl2/
petroleum ether afforded (rac)-8 (5.88 mg, 17.5 µmol, 84%) as
colorless needles, identical to the material obtained above: mp
202 °C; IR (KBr) ν 3400, 3020, 2980, 2945, 2920, 1600, 1580,
1
1550, 1265, 1205, 1120, 1105; H NMR (250 MHz, CDCl3) δ
2.25 (s, 3H), 2.70 (s, 3H), 3.73 (s, 3H), 4.03 (s, 3H), 6.15 (s,
1H), 7.28-7.46 (m, 4H), 7.77-7.84 (m, 2H), 13.87 (s, 1H); 13
C
NMR (63 MHz, CDCl3) δ 20.3, 55.5, 55.7, 86.1, 106.1, 108.0,
124.5, 125.2, 125.7, 127.5, 128.1, 128.5, 129.4, 132.1, 132.9,
135.1, 163.3, 163.5, 163.7, 203.4; MS (EI) m/z 336 (60) [M+•],
321 (100). Anal. Calcd for C21H20O4: C, 74.98; H, 5.99. Found:
C, 75.63; H, 6.13.
2′-Acetyl-3′,5′-d im eth oxyp h en yl 1-Br om o-2-n a p h th oa te
(10). A solution of 2-acetyl-3,5-dimethoxyphenol18 (645 mg,
3.29 mmol) in 8 mL of THF was added within 20 min to a
suspension of NaH (86.9 mg, 3.62 mmol) in 4 mL of dry THF
at 0 °C and stirred at 0 °C for 1 h. A solution of 1-bromo-2-
naphthoyl chloride20 (887 mg, 3.29 mmol) in 12 mL of CH2Cl2
was added dropwise within 25 min and the mixture was stirred
for 3 h at room temperature. The residue as obtained after
evaporation of the solvent was dissolved in 20 mL of CH2Cl2
and washed twice with 5 mL of H2O. The organic phase was
separated and dried (MgSO4). Evaporation of the solvent and
recrystallization from CH2Cl2/petroleum ether yielded 8 (1.23
g, 2.87 mmol, 87%) as colorless crystals: mp 146 °C; IR (KBr)
ν 3050, 3000, 2960, 2920, 2830, 1740, 1660, 1595, 1555, 1245,
1220, 1140, 1110, 1065; 1H NMR (250 MHz, CDCl3) δ 2.54 (s,
3H), 3.87 (s, 3H), 3.89 (s, 3H), 6.46 (d, J ) 2.2 Hz, 1H), 6.43
(d, J ) 2.2 Hz, 1H), 7.58-7.71 (m, 2H), 7.84-7.99 (m, 3H),
8.45-8.50 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 32.0, 55.7,
55.9, 96.8, 100.1, 117.0, 123.3, 126.2, 128.1, 128.1, 128.3, 128.3,
(r a c)-1-(2′-Acet oxy-4′,6′-d im et h oxyp h en yl)-2-m et h yl-
n a p h th a len e [(r a c)-8]. A suspension of NaH (net weight:
4.48 mg, 187 µmol, from ca. 7.5 mg in mineral oil) in 0.5 mL
(46) Bringmann, G.; Hartung, T.; Go¨bel, L.; Schupp, O.; Peters, K.;
von Schnering, H. G. Liebigs Ann. Chem. 1992, 769.
(47) Whitmore, F. C.; Carnahan, F. L. J . Am. Chem. Soc. 1929, 51,
856.
(48) Scholl, R. Monatsh. Chem. 1913, 34, 1011.
J . Org. Chem, Vol. 67, No. 16, 2002 5603

Bringmann et al.
128.6, 130.2, 132.2, 135.5, 149.7, 159.5, 162.4, 165.3, 199.3;
MS (EI) m/z 430/428 (3/2) [M+•], 349 (16), 235/233 (82/82), 126
(100). Anal. Calcd for C19H18O3: C, 58.76; H, 3.99. Found: C,
59.05; H, 3.79.
1-Br om oan th r aqu in on e-2-car boxylic Acid (16a). CuSO4‚
5H2O (41.6 g, 165 mmol) and NaBr (25.7 g, 250 mmol) were
dissolved with gentle heating in 150 mL of H2O and treated
dropwise with a solution of Na2SO3‚7H2O (7.00 g, 17 mmol)
in 50 mL of H2O. The white precipitate of CuBr was filtered,
washed twice with 50 mL of H2O, and dissolved in 65 mL of
HBr (48%).
(90), 315/313 (75/75), 150 (100). Anal. Calcd for C23H15BrO6:
C, 59.12; H, 3.24. Found: C, 59.22; H, 3.25.
1,3-Dim eth oxy-6H-a n th r a [2,1-c]ben zop yr a n -6,9,14-tr i-
on e (17). A mixture of ester 14 (200 mg, 428 µmol), PPh3 (22.5
mg, 85.6 µmol), Pd(OAc)2 (9.7 mg, 42.8 µmol), and NaOAc (70.2
mg, 82.0 µmol) was heated at 60 °C for 1 h at 10-2 mbar.
Freshly distilled DMA (4 mL) was added and the reaction
mixture was stirred at 120 °C for 1 h. Evaporation of the
solvent, column chromatography on silica gel (petroleum ether/
EtOAc ) 2:1), and recrystallization from CH2Cl2/petroleum
ether afforded 17 (147 mg, 381 mmol, 89%) as a red powder:
mp 279-280 °C; IR (KBr) ν 2930, 2900, 2830, 1730, 1660, 1600,
A solution of 13 (4.00 g, 15.0 mmol) in 60 mL of concentrated
H2SO4 was diluted with H2O until the acid began to precipi-
tate. The acid was then redissolved by adding concentrated
H2SO4. NaNO2 (1.24 g, 18 mmol) was added at 0 °C and the
mixture was stirred for 10 min and subsequently added
dropwise at 0 °C to the above prepared solution of CuBr. The
mixture was allowed to warm to room temperature, stirred 1
h at 60 °C, and afterward cooled to 0 °C. The precipitated solid
was filtered and washed twice with 10 mL of H2O to afford
16a (4.56 g, 13.8 mmol, 93%) as a brown solid, which was
crystallized from EtOH: mp 262-263 °C (lit.47 267-268 °C);
IR (KBr) ν 3040, 1690, 1660, 1560; 1H NMR (250 MHz, DMSO-
d6) δ 7.91-7.94 (m, 2H), 7.93 (d, J ) 7.9 Hz, 1H), 8.14-8.20
(m, 2H), 8.28 (d, J ) 7.9 Hz, 1H); 13C NMR (63 MHz, DMSO-
d6) δ 117.4, 126.2, 126.9, 127.0, 131.1, 131.9, 131.9, 134.1,
134.2, 134.8, 136.1, 144.6, 168.1, 181.1, 181.4; MS (EI) m/z 332/
330 (58/57) [M+•], 304/302 (14/13), 287/285 (18/18) [M -
CO2H]+, 150 (100).
1-Iod oa n th r a qu in on e-2-ca r boxylic Acid (16b). H2O was
added to a solution of 13 (100 mg, 374 µmol) in 1.5 mL of
concentrated H2SO4 until the acid began to precipitate. The
acid was then redissolved by addition of concentrated H2SO4,
subsequently treated with NaNO2 (31.0 mg, 449 µmol), and
stirred at room temperature for 10 min. This solution was
cooled to 0 °C and a solution of KI (200 mg, 1.2 mmol) in 2 mL
of H2O was added. The reaction mixture was allowed to warm
to room temperature and stirred at 60 °C for 1 h. After cooling
to 0 °C precipitated 16b was filtered and recrystallized from
EtOH to afford 16b (96.0 mg, 254 µmol, 68%) as a yellow
powder: mp 266-268 °C (lit.48 266-267 °C); IR (KBr) ν 3040,
2990, 1720, 1560, 1550; 1H NMR (250 MHz, DMSO-d6) δ 7.43
(d, J ) 7.8 Hz, 1H) 7.84-7.95 (m, 2H), 8.11-8.19 (m, 2H), 8.13
(d, J ) 7.9 Hz, 1H); 13C NMR (63 MHz, DMSO-d6) δ 92.6,
126.0, 127.0, 127.3, 129.9, 132.1, 132.5, 132.6, 133.9, 134.0,
134.5, 171.2, 181.2, 182.2; MS (EI) m/z 378 (45) [M+•], 333 (3),
305 (4), 43 (100).
3′,5′-Dim eth oxyp h en yl 1-Br om oa n th r a qu in on e-2-ca r -
boxyla te (14). A suspension of NaH (35.0 mg, 1.45 mmol) in
1 mL of THF was treated dropwise with a solution of 15 (186
mg, 1.21 mmol) in 2 mL of THF at 0 °C and stirred for 1 h at
room temperature. A mixture of 16a (400 mg, 1.20 mmol) was
treated under nitrogen with 1.5 mL (2.22 g, 17.5 mmol) of
(COCl)2 in 8 mL of dry CH2Cl2 and 5 drops of dry DMF and
refluxed for 1 h. The solvent and unreacted (COCl)2 were
evaporated. The residue was suspended in 10 mL of dry CH2-
Cl2 and added dropwise to the above prepared solution of the
phenolate of 15. The resulting mixture was stirred at room
temperature for 3 h after which 2 mL of H2O and 2 mL of 1 M
HCl were cautiously added. The mixture was thoroughly
extracted with CH2Cl2. Drying of the combined organic phases
(MgSO4), filtration through a silica gel column (petroleum
ether/EtOAc ) 8:2), and recrystallization from CH2Cl2/
petroleum ether afforded 14 (378 mg, 810 µmol, 67%) as a
yellow powder: mp 164-165 °C; IR (KBr) ν 3030, 2980, 2930,
2810, 1725, 1650, 1600, 1575, 1145, 1130 cm-1; 1H NMR (200
MHz, CDCl3) δ 3,79 (s, 6H), 6.37 (t, J ) 2.2 Hz, 1H), 6.46 (d,
J ) 2.2 Hz, 2H), 7.76-7.82 (m, 2H), 7.89 (d, J ) 8.0 Hz, 1H),
8.20-8.28 (m, 2H), 8.40 (d, J ) 8.0 Hz, 1H); 13C NMR (63 MHz,
CDCl3) δ 55.6, 98.7, 99.9, 119.9, 126.4, 126.9, 127.3, 127.8,
132.1, 132.7, 133.4, 134.2, 134.5, 134.9, 137.0, 142.5, 151.8,
161.3, 165.1, 181.4, 181.6; MS (EI) m/z 468/466 (2/2) [M+•], 387
1580, 1250, 1145, 1100 cm-1 1H NMR (200 MHz, CDCl3) δ
;
3,71 (s, 3H), 3.90 (s, 3H), 6.36 (d, J ) 2.4 Hz, 1H), 6.55 (d, J
) 2.4 Hz, 1H), 7.81-7.87 (m, 2H), 8.13-8.17 (m, 1H), 8.28-
8.32 (m, 1H), 8.31 (d, J ) 8.1 Hz, 1H), 8.54 (d, J ) 8.1 Hz,
1H); 13C NMR (63 MHz, CDCl3) δ 55.3, 55.8, 93.6, 96.1, 102.5,
124.7, 125.5, 126.5, 127.2, 132.7, 132.9, 133.6, 134.6, 134.7,
135.6, 137.3, 153.7, 157.2, 160.3, 162.9, 182.3, 185.4; MS (EI)
m/z 386 (10) [M+•], 355 (100), 340 (14). Anal. Calcd for
C
23H14O6: C, 71.51; H, 3.65. Found: C, 71.27; H, 3.52.
(r a c)-2-Hyd r oxym eth yl-1-(2′,4′-d im eth oxy-6′-h yd r oxy-
p h en yl)-a n th r a qu in on e [(r a c)-19]. A solution of 70.0 mg
(181 µmol) of lactone 17 in 10 mL of dry THF was treated
dropwise at 0 °C with 400 µmol of LAH (1.0 M solution in
THF). After 3 h of stirring at this temperature, H2O (10 mL)
and aqueous HCl (1 M, 10 mL) were cautiously added and the
suspension was thoroughly extracted with EtOAc (20 mL).
Evaporation of the dried (MgSO4) solvent and flash chroma-
tography (silica gel, CH2Cl2/EtOAc ) 7:3) afforded (rac)-19
(50.2 mg, 128 µmol, 71%), which was crystallized from CH2-
Cl2/petroleum ether: mp 201 °C; IR (KBr) ν 3450, 2900, 1650,
1560, 1480, 1340, 1250, 1140, 1080 cm-1; 1H NMR (250 MHz,
CDCl3/DMSO-d6) δ 3.44 (s, 3H), 3.69 (s, 3H), 4.24 (d, J ) 15.0
Hz, 1H), 4.34 (d, J ) 15.0 Hz, 1H), 6.01 (d, J ) 2.1 Hz, 1H),
6.12 (d, J ) 2.5 Hz, 1H), 7.54-7.59 (m, 2H,), 7.92-7.97 (m,
2H,), 8.07-8.10 (m, 1H), 8.24 (d, J ) 7.9 Hz, 1H); 13C NMR
(63 MHz, CDCl3/DMSO-d6) δ 54.8, 55.2, 61.9, 90.3, 94.0, 107.1,
126.0, 126.7, 126.7, 131.3, 131.6, 132.5, 132.9, 133.1, 133.5,
133.7, 134.5, 149.7, 154.6, 157.2, 160.2, 183.1, 183.4; MS (EI)
m/z 390 (36) [M+•], 359 (4) [M - CH3O]+, 341 (100). Anal. Calcd
for C23H18O6: C, 70.76; H, 4.65. Found: C, 70.20; H, 4.52.
Atr oposelective Rin g Cleavage of 17 (An alytical Scale).
The solvent was removed in vacuo from a commercial solution
of (R)-18 (1.0 M in toluene, 39 µL, 39 µmol) and the residue
was dissolved in dry THF (500 µL). This solution was treated
under argon with a solution of the BH3-THF complex (1.0 M
in THF, 52 µL) and stirred for 30 min at room temperature.
After dropwise addition of a suspension of the lactone 17 (5.00
mg, 12.9 µmol) in dry THF (500 µL), the solution was stirred
for 21 h at this temperature, then H2O (1 mL) and 2 M HCl (1
mL) were added, and the aqueous phase was extracted with
EtOAc. The organic phase was purified by TLC (petroleum
ether/EtOAc ) 4:2) and the enantiomeric ratio of the product
alcohols (P)- and (M)-19 was determined by analytical HPLC
to be 25:75.
At r op oselect ive R in g Clea va ge of 17 (P r ep a r a t ive
Sca le). As described above, a solution of (S)-18 (715 µmol) and
the BH3-THF complex (1.0 M in THF, 950 mL) in 1 mL of
dry THF was prepared and stirred for for 30 min at room
temperature. A solution of 17 (92.0 mg, 238 µmol) in dry THF
(1 mL) was added dropwise at 0 °C, the solution was stirred
for 2 h at this temperature, then H2O (1 mL) and 2 M HCl (1
mL) were added, and the aqueous phase was thoroughly
extracted with EtOAc. The combined organic phases were
dried (MgSO4) and the solvents were removed in vacuo. After
flash chromatography of the residue on silica gel (CH2Cl2/
EtOAc ) 2:1), (P)-19 (62.2 mg, 159 µmol, 67%) was obtained
as a red powder (er 85:15): mp 193-202 °C; [R]22 ) +26.1 (c
D
0.01, MeOH); the spectroscopic data were identical to those of
(rac)-19.
5604 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
(M)-9,10-Dia cetoxy-2-a cetoxym eth yl-1-(2′-a cetoxy-4′,6′-
d im eth oxyp h en yl)-a n th r a cen e [(M)-20]. A solution of (P)-
19 (47.0 mg, 120 µmol, er 85:15) in 1.5 mL of Ac2O and 2 mL
of pyridine was stirred at 50 °C for 10 min and then treated
with zinc dust (150 mg, 2.29 mmol). After further stirring for
15 min at this temperature, the zinc was removed by filtration,
the mixture was poured onto ice (5 g), and 2 M HCl (5 mL)
was added. Thorough extraction with EtOAc, drying of the
combined organic extracts (MgSO4), evaporation of the solvent,
and subsequent flash chromatography (CH2Cl2/EtOAc ) 10:
1) yielded (M)-20 (43.0 mg, 76.7 µmol, 64%) as a colorless solid,
fluorescent at 366 nm: mp 185-190 °C; IR (KBr) ν 2958, 2927,
µmol) in 1 mL of dry CH2Cl2 was treated with 6 µL (10.3 mg,
54.4 µmol) of TiCl4 at -10 °C and 2 µL (2.18 mg, 21.2 µmol) of
Ac2O and was stirred at this temperature for 30 min. After
addition of H2O (1 mL) and aqueous HCl (2 M, 1 mL) the
aqueous phase was extracted thoroughly with EtOAc (5 mL).
The combined organic phases were dried (MgSO4) and the
solvent was evaporated. Flash chromatography (CH2Cl2/EtOAc
) 100:1) afforded (rac)-23 (4.23 mg, 10.2 µmol, 76%) as a yellow
powder. (B) By F r ies Rea r r a n gem en t of (r a c)-22. A solu-
tion of (rac)-22 (6.00 mg, 14.4 µmol) in 2 mL of dry toluene
was treated under argon with 5 µL (8.65 mg, 45.6 µmol) of
TiCl4 and refluxed for 2 h. After hydrolysis with 2 mL of H2O
and 2 mL of aqueous HCl (2 M), the mixture was thoroughly
extracted with EtOAc. The combined organic extracts were
dried (MgSO4), the solvent was evaporated, and the crude
product was purified by flash chromatography (CH2Cl2/EtOAc
) 100:1) to afford (rac)-23 (3.84 mg, 9.21 µmol, 64%), identical
to the material obtained above. Mp 188 °C; IR (KBr) ν 3448,
2856, 1766, 1735, 1619, 1365, 1263, 1197, 1090, 800; [R]22
)
D
1
+30.9 (c 0.01, MeOH); H NMR (400 MHz, CDCl3) δ 1.53 (s,
3H), 1.84 (s, 3H), 2.07 (s, 3H), 2.65 (s, 3H), 3.67 (s, 3H), 3.89
(s, 3H), 4.82-5.00 (m, 2H), 6.52-6.54 (m, 2H), 7.44-7.52 (m,
2H), 7.60 (d, J ) 8.8 Hz, 1H), 7.7 (m, 1H), 7.91 (d, J ) 8.1 Hz,
1H), 8.02 (d, J ) 9.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
19.9, 20.8, 21.0, 55.7, 55.9, 64.1, 96.5, 114.3, 121.5, 122.00,
122.3, 124.6, 125.1, 126.6, 140.6, 168.4, 169.4, 170.7; MS (EI)
m/z 560 (15) [M+•], 518 (90), 476 (65), 374 (100). Anal. Calcd
for C31H28O10: C, 66.43; H, 5.00. Found: C, 66.23; H, 5.12.
1
2927, 2852, 1673, 1619, 1277, 1125, 716 cm-1; H NMR (400
MHz, CDCl3) δ 2.18 (s, 3H), 2.69 (s, 3H), 3.76 (s, 3H), 4.02 (s,
3H), 6.15 (s, 1H), 7.66-7.73 (m, 3H), 8.08-8.11 (m, 1H), 8.24-
8.26 (m, 1H), 8.31 (d, J ) 7.8 Hz, 1H), 13.89 (s, 1H); 13C NMR
(101 MHz, CDCl3) δ 20.6, 33.3, 55.4, 55.7, 86.3, 106.3, 109.6,
126.5, 127.3, 127.3, 132.1, 133.0, 133.0, 133.3, 133.8, 134.5,
134.8, 135.1, 146.8, 162.2, 162.3, 163.1, 183.6, 183.9, 203.6;
MS (EI) m/z 416 (83) [M+•], 401 (100), 385 (27). Anal. Calcd
for C25H20O6: C, 72.11; H, 4.84. Found: C, 72.14; H, 4.56.
3-Hyd r oxym eth yl-1,8-d ih yd r oxya n th r a qu in on e (Aloe-
em od in , 27) fr om 2. A solution of 2 (1.00 g, 3.94 mmol) in 30
mL of dry CCl4 was treated under argon with NBS (771 mg,
4.33 mmol) and (PhCO2)2 (104 mg, 433 µmol) and refluxed for
6 h, after which the reaction mixture was allowed to cool to
room temperature. The crude bromomethyl derivative as
obtained after filtration and evaporation of the solvent was
dissolved in 20 mL of dioxane. CaCO3 (1.50 g, 15 µmol) and
H2O (20 mL) were added and the resulting mixture was stirred
at 120 °C for 7 h. Evaporation of the solvent and subsequent
flash chromatography on silica gel (CH2Cl2/EtOAc ) 100:1)
afforded 27 (756 mg, 2.80 mmol, 71%), which crystallized from
EtOH: mp 223-224 °C (lit.31 213-214 °C).
(r a c)-1-(2′,4′-Dim et h oxy-6′-h yd r oxyp h en yl)-2-m et h yl-
a n th r a qu in on e [(r a c)-21]. A solution of (rac)-21 (15.0 mg,
38.4 µmol) in 600 µL of dry CH2Cl2 was treated at room
temperature with polymer-bound PPh3 (52.0 mg, 153.7 µmol)
and stirred at this temperature for 15 min. Then 24.0 mg (73.7
µmol) of (CBrCl2)2 was added and the suspension was stirred
for 10 min at room temperature. The mixture was filtered
through a pad of Celite, which was subsequently thoroughly
washed with CH2Cl2. The solvent of the combined organic
phases was evaporated and the residue was dissolved in 4 mL
of dry MeOH, after which Pd/C (10%, 5.00 mg) and 6.20 mg
(75.6 µmol) NaOAc were added and the mixture was hydro-
genated for 2 h at 2 bar. Filtration, evaporation of the solvent,
and flash chromatography on silica gel (CH2Cl2/EtOAc ) 7:3)
afforded (rac)-21 as a yellow oil (7.62 mg, 20.4 µmol, 53%),
which was crystallized from CH2Cl2/petroleum ether: mp 180
°C; IR (KBr) ν 3400, 2960, 1650, 1575, 1310, 1280, 1140, 810
1
cm-1; H NMR (200 MHz, CDCl3) δ 2.17 (s, 3H), 3.62 (s, 3H),
3.87 (s, 3H), 6.25 (d, J ) 2.1 Hz, 1H,), 6.28 (d, J ) 2.3 Hz,
1H), 7.70-7.73 (m, 3H), 8.10-8.15 (m, 1H), 8.22-8.26 (m, 1H),
8.32 (d, J ) 8.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 20.6,
55.3, 55.7, 92.0, 93.6, 108.5, 126.6, 126.6, 127.4, 127.8, 132.8,
132.9, 133.2, 133.6, 134.0, 134.7, 135.5, 148.0, 153.1, 157.4,
160.9, 183.4, 183.8; MS (EI) m/z 374 (100) [M+•], 343 (47) [M
- CH3O]+, 315 (27). Anal. Calcd for C23H18O5: C, 73.79; H,
4.85. Found: C, 74.07; H, 4.90.
1,8-Dih yd r oxy-3-m et h yla n t h r a q u in on e (Ch r ysop h a -
n ol, 2) fr om 27. A solution of 27 (1.00 g, 3.70 mmol) in 50
mL of dry CH2Cl2 was treated at room temperature with
polymer-bound PPh3 (1.89 g, 5.55 mmol) and stirred at this
temperature for 15 min. (CBrCl2)2 (1.81 g, 5.55 mmol) was
added and the suspension was stirred for 30 min at room
temperature. The mixture was filtered through a pad of Celite
and the Celite was washed thoroughly with CH2Cl2. The
solvent of the combined organic phases was evaporated and
the residue was suspended in 20 mL of dry MeOH. Pd/C (10%,
500 mg) was added and the mixture was hydrogenated for 1
h at 4 bar. Filtration and recrystallization from EtOH yielded
2 as a yellow solid (780 mg, 3.07 mmol, 83%): mp 196-197
°C (lit.30 194-195 °C).
8-Acetoxy-3-a cetoxym eth yl-2-br om o-1-h yd r oxya n th r a -
qu in on e (29) (i.e., original protocol for the postulated syn-
thesis of 30 from 2832). A solution of 28 (100 mg, 282 µmol) in
3 mL of dry CHCl3 and 1 mL of glacial HOAc was treated with
acetamide (190 mg, 3.17 mmol) and 190 µL (592 mg, 3.70
mmol) of Br2 in 1 mL of glacial HOAc. The mixture was
refluxed for 9 h. After cooling to room temperature the organic
phase was washed twice with 2 mL of H2O and dried (Na2-
SO4). Evaporation of the solvent afforded 29 (120 mg, 276 µmol,
98%) (lit.32 for 30, 97%) as a yellow powder, which was
crystallized from toluene: mp 205-206 °C (lit.32 for 30, 207-
209 °C); IR (KBr) ν 3400, 3060, 2940, 2920, 1750, 1725, 1660,
1620, 1575, 1240, 1180; 1H NMR (600 MHz, CDCl3) δ 2.24 (s,
3H), 2.47 (s, 3H), 5.28 (s, 2H), 7.45 (dd, J ) 8.2 Hz, J ) 1.2
Hz, 1H), 7.84 (s, 1H), 7.85 (dd, J ) 7.9 Hz, J ) 7.9 Hz, 1H),
8.28 (dd, J ) 7.9 Hz, J ) 1.2 Hz, 1H), 13.34 (s, 1H); 13C NMR
(63 MHz, CDCl3) δ 20.8, 21.2, 65.3, 116.0, 117.9, 119.2, 124.3,
126.1, 130.5, 131.0, 135.1, 136.0, 145.0, 150.7, 159.1, 169.5,
(r a c)-1-(2′-Acetoxy-4′,6′-d im eth oxyp h en yl)-2-m eth yla n -
th r a qu in on e [(r a c)-22]. A solution of (rac)-21 (18.1 mg, 48.4
µmol), 10.0 µL (9.52 mg, 159 µmol) of HOAc, and a catalytic
quantity of DMAP in 500 µL of dry CH2Cl2 was treated at 0
°C with 32.8 mg (159 µmol) DCC. The mixture was stirred for
5 min at 0 °C and 1 h at room temperature. After filtration
the solution was washed twice with aqueous HCl (0.5 M, 1
mL) and twice with a saturated solution of NaHCO3 (1 mL)
and subsequently dried (MgSO4). Evaporation of the solvent
and flash chromatography (silica gel, CH2Cl2/MeOH ) 100:
0.2) yielded (rac)-22 (15.0 mg, 36.0 µmol, 75%) as a yellow
solid: mp 218-220 °C; IR (KBr) ν 2910, 1740, 1650, 1570,
1310, 1280, 1190, 1140, 1115 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.73 (s, 3H), 2.16 (s, 3H), 3.71 (s, 3H), 3.88 (s, 3H), 6.40 (s,
1H), 6.54 (s, 1H), 7.65-7.74 (m, 3H), 8.12-8.17 (m, 1H), 8.24-
8.27 (m, 1H), 8.30 (d, J ) 8.0 Hz, 1H); 13C NMR (63 MHz,
CDCl3) δ 21.2, 21.9, 55.5, 56.2, 90.9, 92.2, 93.3, 127.1, 127.2,
127.4, 127.4, 131.2, 133.3, 133.5, 133.5, 133.9, 134.0, 134.9,
145.3, 154.1, 156.8, 160.5, 171.7, 183.0, 183.4; MS (EI) m/z 417
(42) [M+•], 375 (100), 344 (35). Anal. Calcd for C25H20O6: C,
72.11; H, 4.84. Found: C, 72.10; H, 4.72.
(r a c)-1-(5′-Acetyl-2′,4′-d im eth oxy-6′-h yd r oxyp h en yl)-2-
m eth yla n th r a qu in on e [(r a c)-23]. (A) By F r ied el-Cr a fts
Acyla tion of (r a c)-21. A solution of (rac)-21 (5.00 mg, 13.4
J . Org. Chem, Vol. 67, No. 16, 2002 5605

Bringmann et al.
170.3, 181.1, 187.5; MS (EI) m/z 434/432 (0.3/0.5) [M+•], 353
(6), 348/346 (8/10), 311 (8), 269 (20), 43 (100). Anal. Calcd for
13C NMR (63 MHz, CDCl3) δ 20.9, 22.0, 65.3, 73.2, 73.4, 118.2,
119.4, 121.4, 122.8, 125.6, 125.9, 133.3, 135.0, 135.2, 141.7,
157.9, 158.2, 170.6, 181.7, 184.0; MS (EI) m/z 396 (0.3) [M+•],
353 (76), 270 (100). Anal. Calcd for C23H24O6: C, 69.68; H, 6.10.
Found: C, 69.18; H, 6.36.
C
19H13BrO7: C, 52.67; H, 3.02. Found: C, 52.57; H, 3.14.
3-Hydr oxym eth yl-1,8-diisopr opoxyan th r aqu in on e (31).
A suspension of 27 (1.00 g, 3.70 mmol) in 10 mL of acetone
was treated with Cs2CO3 (7.30 g, 22.2 mmol) and i-PrI (10 mL,
5.88 g, 35.0 mmol) and refluxed for 12 h. Evaporation of the
solvent and column chromatography on silica gel (petroleum
ether/EtOAc ) 7:3) afforded 3-isopropoxymethyl-1,8-diisopro-
poxyanthraquinone (103 mg, 259 µmol, 7%) as a yellow oil and
31 (1.08 g, 3.03 mmol, 82%), which was obtained from CH2-
Cl2/petroleum ether as a yellow powder.
2-Acetoxym eth yl-1,8-d ibr om o-4,5-d iisop r op oxya n th r a -
qu in on e (34). A mixture of 32 (10.7 g, 27.1 mmol) and NaOAc
(11.1 g, 136 mmol) in 75 mL of CHCl3 and 75 mL of CCl4 was
treated with Br2 (11.2 mL, 34.7 g, 217 mmol) and refluxed for
3 h. After cooling to room temperature the reaction mixture
was washed twice with a saturated aqueous NaHSO3 solution
(50 mL) and twice with H2O (50 mL). The organic phase was
dried (MgSO4) and the solvent was evaporated. Recrystalli-
zation of the residue from EtOH afforded 34 (11.7 g, 21.1
mmol, 89%) as a yellow powder: mp 148 °C; IR (KBr) ν 2950,
1750, 1720, 1600, 1250, 1200, 1020 cm-1; 1H NMR (250 MHz,
CDCl3) δ 1.40 (d, J ) 6.1 Hz, 6H), 1.41 (d, J ) 6.1 Hz, 6H),
2.18 (s, 3H), 4.51-4.63 (m, 2H), 5.26 (s, 2H), 7.03 (d, J ) 9.3
Hz, 1H), 7.24 (s, 1H), 7.71 (d, J ) 9.0 Hz, 1H); 13C NMR (63
MHz, CDCl3) δ 21.0, 22.0, 65.9, 73.8, 74.0, 110.6, 111.1, 121.2,
121.9, 127.3, 127.9, 135.6, 136.2, 139.1, 142.4, 155.8, 156.0,
170.4, 180.6, 184.7; MS (EI) m/z 556/554/552 (1/2/1) [M+•], 513/
511/509 (23/44/20), 349/347 (79/89), 43 (100). Anal. Calcd for
3-Isop r op oxym eth yl-1,8-d iisop r op oxya n th r a qu in on e.
IR (CCl4) ν 3400, 2940, 2900, 2840, 1710, 1655, 1580, 1570,
1
1270, 1100 cm-1; H NMR (250 MHz, CDCl3) δ 1.22 (d, J )
6.1 Hz, 6H), 1.42 (d, J ) 6.0 Hz, 6H), 1.43 (d, J ) 6.1 Hz, 6H),
3.68 (sept, J ) 6.1 Hz, 1H), 4.52-4.68 (m, 2H), 4.56 (s, 2H),
7.27 (dd, J ) 8.4 Hz, J ) 0.8 Hz, 1H), 7.31-7.32 (m, 1H), 7.54
(dd, J ) 7.8 Hz, J ) 7.6 Hz, 1H), 7.73 (d, J ) 1.5 Hz, 1H), 7.79
(dd, J ) 7.6 Hz, J ) 1.2 Hz, 1H); 13C NMR (63 MHz, CDCl3)
δ 22.1, 68.2, 69.2, 73.1, 73.2, 118.6, 119.7, 120.5, 123.2, 128.6,
130.9, 133.2, 134.9, 135.1, 145.5, 157.9, 158.2, 182.8, 184.2;
MS (EI) m/z 353 (12) [M - C3H7]+, 311 (2), 149 (100). Anal.
Calcd for C24H28O5: C, 72.71; H, 7.12. Found: C, 72.41; H,
7.30.
C
23H22Br2O6: C, 49.84; H, 4.00. Found: C, 49.71; H, 4.00.
1,8-Dibr om o-4,5-diisopr opoxyan th r aqu in on e-2-car box-
ylic Acid (36). A mixture of 34 (10.0 g, 18.1 mmol) and 10
mL of aqueous NaOH (5%) in 400 mL of MeOH was stirred at
70 °C for 2 h. After evaporation of the solvent the residue was
dissolved in 100 mL of EtOAc and washed twice with 70 mL
of H2O. Drying (MgSO4) of the organic phase and evaporation
of the solvent yielded 1,8-dibromo-4,5-diisopropoxy-2-hydroxym-
ethylanthraquinone (8.43 g, 16.7 mmol, 91%) as a red oil,
which was crystallized from CH2Cl2/petroleum ether: mp 114-
116 °C; IR (KBr) ν 3400, 2940, 1650, 1550, 1250, 1180, 1090,
3-Hydr oxym eth yl-1,8-diisopr opoxyan th r aqu in on e (31).
Mp 118-119 °C; IR (KBr) ν 3400, 2940, 2900, 2840, 1710, 1655,
1580, 1570, 1270, 1100; 1H NMR (250 MHz, CDCl3) δ 1.43 (d,
J ) 6.1 Hz, 6H), 1.45 (d, J ) 6.0 Hz, 6H), 4.62 (sept, J ) 6.1
Hz, 1H), 4.63 (sept, J ) 6.0 Hz, 1H), 4.77 (s, 2H), 7.29 (dd, J
) 8.5 Hz, J ) 1.0 Hz, 1H), 7.33 (d, J ) 0.9 Hz, 1H), 7.56 (dd,
J ) 8.2 Hz, J ) 7.8 Hz, 1H), 7.69 (m, 1H, 4-H), 7.79 (dd, J )
7.6 Hz, J ) 1.2 Hz, 1H, 5-H); 13C NMR (63 MHz, CDCl3) δ
21.7, 63.6, 72.5, 72.8, 116.5, 118.9, 119.4, 122.2, 123.6, 125.2,
133.1, 134.2, 134.5, 147.9, 157.5, 157.8, 182.0, 183.5; MS (EI)
m/z 311 (55) [M - C3H7]+, 270 (73), 241 (100). Anal. Calcd for
1
1020 cm-1; H NMR (250 MHz, CDCl3) δ 1.38 (d, J ) 6.0 Hz,
6H), 1.39 (d, J ) 6.1 Hz, 6H), 4.81 (s, 2H), 4.50-4.67 (m, 2H),
7.02 (d, J ) 9.0 Hz, 1H), 7.44 (s, 1H), 7.69 (d, J ) 9.0 Hz, 1H);
13C NMR (63 MHz, CDCl3) δ 21.0, 63.8, 72.5, 72.7, 108.4, 109.5,
118.5, 120.9, 125.3, 126.9, 134.5, 134.5, 137.9, 146.4, 154.9,
155.0, 179.9, 183.7; MS (EI) m/z 514/512/510 (2/4/3) [M+•], 471/
469/467 (41/76/42), 430/428/426 (50/100/62). Anal. Calcd for
C
21H22O5: C, 71.17; H, 5.97. Found: C, 71.08; H, 6.09.
1-Br om o-2-h yd r oxym et h yl-4,5-d iisop r op oxya n t h r a -
qu in on e (33). A solution of 32 (54.0 mg, 152 µmol), 13.0 mg
(158 µmol) NaOAc, and one crystal of I2 in 6 mL of CHCl3 was
treated dropwise with 160 µL (160 µmol) of a solution of Br2
in CCl4 (1 M) and heated under reflux for 3 h. Evaporation of
the solvent and column chromatography on silica gel (petro-
leum ether/EtOAc ) 6:4) afforded 33 (21.1 mg, 48.6 µmol, 32%),
which was crystallized from CH2Cl2/petroleum ether: mp 152-
C
21H20Br2O5: C, 49.25; H, 3.94. Found: C, 49.11; H, 3.68.
A solution of 1,8-dibromo-4,5-diisopropoxy-2-hydroxymethyl-
anthraquinone (8.00 g, 15.6 mmol) in 200 mL of CH2Cl2 was
treated with activated MnO2 (6.81 g, 78.1 mmol) and stirred
at room temperature for 1 h, after which more activated MnO2
(2.72 g, 31.2 mmol) was added. Filtration of the mixture over
a Celite pad and evaporation of the solvent afforded 7.40 g
(14.5 mmol, 93%) 1,8-dibromo-3-formyl-4,5-diisopropoxyan-
thraquinone, which was crystallized from EtOH: mp 169-
171 °C; IR (KBr) ν 2950, 2940, 2850, 1675, 1555, 1270, 1190,
153 °C; IR (CCl4) ν 3040, 2940, 2910, 1710, 1115, 1065 cm-1
;
1H NMR (250 MHz, CDCl3) δ 1.42 (d, J ) 6.1 Hz, 6H), 1.44 (d,
J ) 6.0 Hz, 6H), 4.64 (sept, J ) 6.1 Hz, 1H), 4.66 (sept, J )
6.1 Hz, 1H), 4.72 (s, 2H), 7.21 (dd, J ) 8.4 Hz, J ) 1.2 Hz,
1H), 7.51 (s, 1H), 7.54 (dd, J ) 8.1 Hz, J ) 7.7, 1H), 7.63 (dd,
J ) 7.7 Hz, J ) 1.3, 1H); 13C NMR (63 MHz, CDCl3) δ 22.0,
65.0, 73.3, 73.6, 119.1, 120.6, 121.6, 125.7, 127.3, 128.8, 130.9,
133.4, 136.7, 156.7, 156.8, 181.9, 184.4; MS (EI) m/z 391/389
(100/97) [M - C3H7]+, 350/348 (68/81) 269 (70). HRMS calcd
for C21H21BrO5 442.2354, found: 442.2355.
1
960, 920 cm-1; H NMR (250 MHz, CDCl3) δ 1.39 (d, J ) 6.1
Hz, 6H), 1.41 (d, J ) 6.1 Hz, 6H), 4.66 (sept, J ) 6.1 Hz, 1H),
4.69 (sept, J ) 6.1 Hz, 1H), 7.04 (d, J ) 8.2 Hz, 1H), 7.64 (s,
1H), 7.72 (d, J ) 9.1 Hz, 1H), 10.54 (s, 1H, CHO); 13C NMR
(63 MHz, CDCl3) δ 21.8, 21.9, 73.4, 73.7, 110.4, 114.1, 119.3,
121.7, 127.5, 131.1, 135.4, 136.7, 137.5, 139.3, 155.7, 156.0,
180.2, 183.7, 191.4; MS (EI) m/z 512/510/508 (1/2/1) [M+•], 469/
467/465 (17/33/18), 428/426/424 (53/100/45). Anal. Calcd for
3-Acetoxym eth yl-1,8-d iisop r op oxya n th r a qu in on e (32).
A mixture of 27 (14.8 g, 54.8 mmol), Cs2CO3 (258 g, 785 mmol),
and i-PrI (200 mL, 340 g, 2.00 mol) in 200 mL of acetone was
refluxed for 48 h. The crude product, as obtained after
filtration and evaporation of the solvent, was dissolved in 150
mL of Ac2O and treated with 5 mL of pyridine. The mixture
was stirred for 5 h at 70 °C and subsequently poured onto 500
g of crushed ice for hydrolysis of the Ac2O. The suspension
was then stirred at 50 °C for 30 min. After cooling to room
temperature crystallization was completed at 0 °C. Filtration
and subsequent recrystallization from EtOH afforded 32 (17.0
g, 42.8 mmol, 78%) as a yellow powder: mp 155 °C; IR (KBr)
ν 2940, 2900, 1715, 1655, 1585, 1570, 1420, 1270, 1220, 1030
C
21H20Br2O5: C, 49.44; H, 3.56. Found: C, 49.21; H, 3.57.
A solution of the above prepared 1,8-dibromo-3-formyl-4,5-
diisopropoxyanthraquinone in 300 mL of dioxane was treated
with a solution of NaOAc (4.42 g, 53.9 mmol) in 100 mL of
H2O and 100 mL of HOAc, a solution of amidosulfuric acid
(2.62 g, 27.0 mmol) in 200 mL of H2O, and with a solution of
NaClO2 (80% technical grade, 2.44 g, 27.0 mmol) in 200 mL
of H2O and stirred at room temperature for 90 min. The
solution was concentrated in vacuo to 200 mL and extracted
twice with 50 mL of CH2Cl2. The combined organic extracts
were dried (MgSO4), the solvent was evaporated, and the
residue was crystallized from EtOH to afford 36 (7.09 g, 13.5
mmol, 97%) as a yellow powder: mp 191-192 °C; IR (KBr) ν
1
cm-1; H NMR (250 MHz, CDCl3) δ 1.45 (d, J ) 6.1 Hz, 6H),
1.45 (d, J ) 6.0 Hz, 6H), 2.16 (s, 3H), 4.58-4.68 (m, 2H), 5.16
(s, 2H), 7.25 (m, 1H, 2-H), 7.30 (dd, J ) 8.2 Hz, J ) 1.2 Hz,
1H), 7.57 (dd, J ) 8.2 Hz, J ) 8.4 Hz, 1H), 7.79-7.83 (m, 2H);
5606 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
2950, 2900, 1690, 1675, 1435, 1320, 1190, 920 cm-1; 1H NMR
(250 MHz, CDCl3) δ 1.38 (d, J ) 6.2 Hz, 6H), 1.39 (d, J ) 6.1
Hz, 6H), 4.50-4.64 (m, 2H), 7.02 (d, J ) 9.2 Hz, 1H), 7.38 (s,
1H), 7.70 (d, J ) 8.6 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ
21.9, 73.7, 73.7, 107.9, 110.4, 120.8, 121.7, 127.6, 128.6, 135.6,
136.7, 139.1, 141.0, 155.4, 155.9, 168.1, 180.3, 184.3; MS (EI)
m/z 527/525/523 (3/4/2) [M+•], 485/483/481 (17/30/15), 444/442/
440 (56/100/51). Anal. Calcd for C21H18Br2O6: C, 47.94; H, 3.45.
Found: C, 47.68; H, 3.42.
(15/11), 183 (100). Anal. Calcd for C29H25BrO8: C, 59.91; H,
4.33. Found: C, 59.66; H, 4.25.
1,3-Dim eth oxy-8,10-d iisop r op oxy-6H-a n th r a [2,1-c]ben -
zop yr a n -6,9,14-tr ion e (37b): mp 175 °C; IR (KBr) ν 2950,
1
2910, 1708, 1660, 1602, 1576, 1214, 1100,732 cm-1; H NMR
(400 MHz, CDCl3) δ 1.43-1.55 (m, 12H), 3.66 (s, 3H), 3.87 (s,
3H), 4.67 (sept, J ) 6.0 Hz, 1H), 4.78 (sept, J ) 6.0 Hz, 1H),
6.33 (d, J ) 2.5 Hz, 1H), 6.52 (d, J ) 2.5 Hz, 1H), 7.28 (dd, J
) 7.8 Hz, J ) 2.0 Hz), 7.57-7.64 (m, 2H), 7.99 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 21.8, 22.0, 22.0, 22.1, 55.5, 55.7,
72.9, 73.1, 93.7, 96.0, 102.4, 117.7, 118.0, 120.8, 124.0, 125.3,
125.5, 129.3, 133.6, 136.6, 136.7, 152.7, 156.2, 156.3, 157.6,
160.4, 161.7, 180.6, 186.7; MS (EI) m/z 502 (22) [M+•], 471 (8),
429 (60), 387 (100). Anal. Calcd for C29H26O8: C, 69.31; H, 5.21.
Found: C, 69.48; H, 5.18.
3′,5′-Dim eth oxyp h en yl 1,8-Dibr om o-4,5-d iisop r op oxy-
a n th r a qu in on e-2-ca r boxyla te (35). A solution of 36 (6.00
g, 11.4 mmol), 15 (2.11 g, 13.7 mmol), and DMAP (100 mg,
819 µmol) in 5 mL of dry CH2Cl2 and 1 mL of dry DMF was
treated at 0 °C under argon with 2.82 g (13.7 mmol) DCC. The
mixture was stirred for 5 min at 0 °C and 30 min at room
temperature. After filtration the solution was washed twice
with aqueous HCl (0.5 M, 1 mL) and twice with a saturated
solution of NaHCO3 (1 mL). The organic phase was dried
(MgSO4), the solvent evaporated and the residue crystallized
from EtOH to yield 35 (6.67 g, 10.3 mmol, 90%) as a yellow
powder: mp 155-156 °C; IR (KBr) ν 2960, 2905, 1730, 1675,
(P )-8-Br om o-4,5-d iisop r op oxy-1-(2′,4′-d im eth oxy-6′-h y-
d r oxyp h en yl)-2-h yd r oxym eth yla n th r a qu in on e [(P )-38].
As described for 17, a solution of (S)-18 (360 µmol) and the
BH3-THF complex (1.0 M in THF, 480 µL) in 1 mL of dry
THF was prepared and stirred for 30 min at room temperature.
After dropwise addition of a solution of the lactone 37a (69.8
mg, 120 µmol) in dry THF (1 mL) at 0 °C, the mixture was
stirred for 1 h at this temperature, then H2O (1 mL) and 2 M
HCl (1 mL) were added, and the aqueous phase was thoroughly
extracted with EtOAc. The combined organic phases were
dried (MgSO4) and the solvents were removed in vacuo. After
flash chromatography of the residue on silica gel (CH2Cl2/
EtOAc ) 7:3), (P)-38 (56.9 mg, 97.2 mmol, 81%) was obtained
as a yellow solid (er 98:2). Crystallization from CH2Cl2/Et2O/
hexane yielded yellow crystals (45.6 mg, 77.9 mmol, 65%; er
1600, 1480, 1370, 1145 cm-1 1H NMR (250 MHz, CDCl3) δ
;
1.41 (d, J ) 5.9 Hz, 6H), 1.43 (d, J ) 5.9 Hz, 6H), 3.75 (s, 3H),
4.52-4.71 (m, 2H), 6.40 (t, J ) 2.3 Hz, 1H), 6.46 (d, J ) 2.1
Hz, 2H), 7.04 (d, J ) 9.1 Hz, 1H), 7.43 (s, 1H), 7.73 (d, J ) 8.9
Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 21.9, 55.6, 73.6, 74.0,
98.7, 99.9, 108.1, 110.5, 120.9, 121.7, 127.5, 129.2, 135.5, 136.7,
139.3, 139.9, 151.9, 155.6, 156.0, 161.3, 164.6, 180.9, 183.9;
MS (EI) m/z 649/647/645 (0.2/0.5/0.2) [M+ - CH3]+, 621/619/
617 (1/2/1), 583/581 (100/93). Anal. Calcd for C21H20Br2O5: C,
52.59; H, 3.96. Found: C, 52.06; H, 3.97.
> 99.5:0.5): mp 122-124 °C; [R]20 ) -28 (c 0.01, MeOH); IR
D
(KBr) ν 3120, 2950, 1660, 1570, 1190, 1090 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.37-1.44 (m, 12H), 3.59 (s, 3H), 3.76 (s, 3H),
4.33 (d, J ) 13.7 Hz, 1H), 4.42 (d, J ) 13.7 Hz, 1H), 4.55 (sept,
J ) 5.8 Hz, 1H), 4.67 (sept, J ) 5.8 Hz, 1H), 6.12 (d, J ) 1.8
Hz, 1 H), 6.20 (d, J ) 1.8 Hz, 1H), 6.97 (d, J ) 8.8 Hz, 1H),
7.43 (s, 1H), 7.60 (d, J ) 8.8 Hz, 1 H); 13C NMR (63 MHz,
CDCl3) δ 21.9, 22.0, 55.1, 55.6, 62.8, 72.7, 73.5, 91.3, 94.1,
105.7, 109.8, 118.9, 121.3, 122.4, 124.6, 128.0, 135.6, 137.4,
138.4, 148.0, 154.9, 155.8, 155.8, 157.2, 160.7, 182.4, 186.3;
MS (EI) m/z 586/584 (54/54) [M+•], 543/541 (44/39), 495/493
(20/19), 453/451 (100/100). Anal. Calcd for C29H29BrO8: C,
59.50; H, 4.99. Found: C, 59.59; H, 4.74.
Oxid a tion a n d Recycliza tion of 38 Ba ck to La cton e
37a . A solution of 38 (10.0 mg, 17.1 µmol, as obtained from
the mother liquor) in 10 mL of CH2Cl2 was treated with MnO2
(50.0 mg, 581 µmol) and stirred at room temperature for 2 h.
After filtration through a Celite pad the solvent was evapo-
rated in vacuo and the residue was dissolved in 1 mL of
dioxane. A solution of NaOAc (13.0 mg, 158 µmol) in 0.5 mL
of HOAc and 0.5 mL of H2O, 6.2 mg (63.8 µmol) amidosulfuric
acid, and 6.0 mg (66.4 µmol) NaClO2 (80% technical grade)
were added and the resulting mixture was stirred at room
temperature for 30 min. The solvent was evaporated, and the
residue was dissolved in 5 mL of CH2Cl2 and washed twice
with 5 mL of H2O. After evaporation of the dried (MgSO4)
solvent the residue was dissolved in 2 mL of CH2Cl2 and
treated under argon at 0 °C with 6.0 mg (29.1 µmol) DCC and
a catalytic quantity of DMAP, and the mixture was stirred
for 1 h at room temperature. Evaporation of the solvent and
purification by flash chromatography (silica gel, CH2Cl2/EtOAc
) 100:2) yielded 37a (7.1 mg, 12.2 µmol, 71%) as a red solid,
identical to the material obtained above.
Gen er a l P r oced u r e for th e In tr a m olecu la r Cou p lin g
of 35 (Ta ble 2). A flame-dried flask was charged with 35 (1.0
equiv), the specified catalyst [PdCl2(PPh3)2 or Pd(OAc)2/PPh3
(ratio 1/2)], and the specified base (2 equiv) and dried in vacuo
(10-2 mbar) for 1-2 h at 60 °C. Dry DMA was added to yield
a suspension approximately 0.05 M of 35. The mixture was
degassed three times and heated under argon for the specified
time at 120-130 °C before it was allowed to cool to room
temperature. The mixture was diluted with EtOAc, washed
sequentially with 2 M HCl and saturated aqueous NaCl
solution, dried (MgSO4), and concentrated in vacuo. Flash
chromatography on silica gel (CH2Cl2/EtOAc ) 100:2) gave the
lactones 37c, 37a , and 37b in this order of elution with the
specified yields.
13-P h en yl-1,3-dim eth oxy-8,10-diisopr opoxy-6H-an th r a-
[2,1-c]ben zop yr a n -6,9,14-tr ion e (37c): mp 174-182 °C; IR
(KBr) ν 3050, 3030, 2950, 2905, 1715, 1665, 1605, 1430, 1300,
1095, 815 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.48 (d, J ) 6.1
Hz, 12H), 3.20 (s, 3H), 3.78 (s, 3H), 4.64-4.81 (m, 2H), 5.94
(d, J ) 2.3 Hz, 1H), 6.42 (d, J ) 2.3 Hz, 1H), 7.26-7.36 (m,
3H), 7.29 (d, J ) 8.7 Hz, 1H), 7.48 (d, J ) 8.6 Hz, 1H), 7.57-
7.59 (m, 2H), 7.93 (s, 1H,); 13C NMR (101 MHz, CDCl3) δ 22.1,
21.9, 55.6, 57.4, 73.1, 73.2, 93.5, 96.7, 102.9, 116.8, 124.1, 125.4,
126.8, 127.4, 128.1, 129.3, 131.2, 132.2, 134.9, 137.8, 138.5,
139.6, 152.2, 155.5, 156.3, 156.4, 160.6, 161.4, 182.0, 184.5;
MS (EI) m/z 578 (25) [M+•], 547 (35), 505 (61), 463 (100). Anal.
Calcd for C35H30O8‚1/2CH2Cl2 (content of CH2Cl2 confirmed by
1H NMR on material freshly dissolved in CDCl3): C, 68.65;
H, 5.03. Found: C, 68.40; H, 5.25.
13-Br om o-1,3-dim eth oxy-8,10-diisopr opoxy-6H-an th r a-
[2,1-c]ben zop yr a n -6,9,14-tr ion e (37a ): mp 138 °C; IR (KBr)
ν 2950, 1710, 1660, 1190, 1100 cm-1 1H NMR (200 MHz,
;
13-Br om o-1,3-d im eth oxy-8,10-d iisop r op oxy-9-h yd r oxy-
6H-a n th r a [2,1-c]ben zop yr a n -6,14-d ion e (41). A mixture of
37a (20.0 mg, 34.4 µmol) and Pd/C (10%, 3.67 mg) in 0.8 mL
of NEt3 and 0.1 mL of DMF was treated under argon with 1.45
µL of formic acid, stirred at 50 °C for 135 min, and allowed to
cool to room temperature. After addition of 1 mL of 1 M HCl,
the mixture was thoroughly extracted with EtOAc. Drying of
the combined organic phases (MgSO4), evaporation of the
solvent, and flash chromatography (silica gel, CH2Cl2/EtOAc
CDCl3) δ 1.40-1.56 (m, 12H), 3.67 (s, 3H), 3.87 (s, 3H), 4.64
(sept, J ) 6.1 Hz, 1H), 4.77 (sept, J ) 6.1 Hz, 1H), 6.35 (d, J
) 2.3 Hz), 6.53 (d, J ) 2.3 Hz, 1H), 7.12 (d, J ) 9.2 Hz, 1H),
7.80 (d, J ) 8.9 Hz, 1H), 7.94 (s, 1H); 13C NMR (63 MHz,
CDCl3) δ 19.2, 21.9, 22.4, 55.8, 57.7, 73.1, 73.3, 93.8, 96,4,
102.5, 110.2, 116.7, 121.3, 123.6, 125.6, 128.0, 128.7, 133.0,
137.9, 139.2, 152.4, 155.6, 155.9, 156.9, 160.4, 161.8, 180.1,
184.4; MS (EI) m/z 582/580 (5/5) [M+•], 509/507 (9/6), 467/465
J . Org. Chem, Vol. 67, No. 16, 2002 5607

Bringmann et al.
) 100:2) afforded 41a (13.0 mg, 22.3 µmol, 65%), which
crystallized from CH2Cl2/petroleum ether as yellow needles:
mp 174 °C; IR (KBr) ν 3463, 3097, 2979, 2932, 1731, 1686,
1619, 1450, 1272, 1112, 947, 815; 1H NMR (250 MHz, CDCl3)
δ 1.43-1.57 (m, 12H), 3.70 (s, 3H), 3.86 (s, 3H), 4.70 (sept, J
) 6.0 Hz, 1H), 4.87 (sept, J ) 6.0 Hz, 1H), 6.33 (d, J ) 2.4 Hz,
1H), 6.41 (s, 1H), 6.52 (d, J ) 2.3 Hz, 1H), 7.02 (d, J ) 9.4 Hz,
1H), 7.71 (d, J ) 9.9 Hz, 1H), 7.86 (s, 1H); 13C NMR (63 MHz,
CDCl3) δ 22.3, 22.5, 22.7, 56.1, 57.9, 58.7, 72.1, 72.3, 94.0, 96.4,
103.3, 111.3, 113.6, 118.2, 123.3, 125.3, 132.6, 133.8, 136.1,
136.2, 152.9, 154.4, 155.7, 156.6, 161.7, 161.9, 185.4; MS (EI)
m/z 584/582 (46/60) [M+•], 553/551 (55/55), 536/534 (47/46), 493/
491 (76/72), 451/449 (100/88). Anal. Calcd for C29H27BrO8: C,
59.70; H, 4.66. Found: C, 59.63; H, 4.38.
m/z 490 (54) [M+•], 447 (100), 405 (27). Anal. Calcd for C29H27
-
BrO7: C, 71.01; H, 6.16. Found: C, 70.62; H, 5.95.
(P )-6′-O-Meth ylk n ip h olon e [(P )-1c]. A solution of (P)-40
(25.0 mg, 50.9 µmol) in 1 mL of CH2Cl2 was cooled to -20 °C,
treated with TiCl4 (35 µL, 60.1 mg, 334 µmol), and then
allowed to warm to room temperature over a period of 2 h.
H2O (1 mL) and 2 M HCl (1 mL) were added and the mixture
was thoroughly extracted with EtOAc. Drying (MgSO4) of the
combined organic phases, evaporation of the solvent, and flash
chromatography (silica gel, CH2Cl2/EtOAc ) 10:2) yielded
(P)-4,5-dihydroxy-1-(2′,4′-dimethoxy-6′-hydroxyphenyl)-2-methyl-
anthraquinone (18.4 mg, 45.3 µmol, 89%) as a red amorphous
solid: [R]23 ) -31 (c 0.021, MeOH); IR (KBr) ν 3443, 2927,
D
2852, 1629, 1583, 1459, 1098, 800 cm-1; H NMR (400 MHz,
1
CDCl3) δ 2.09 (s, 3H), 3.62 (s, 3H), 3.85 (s, 3H), 6.22 (d, J )
2.3 Hz, 1H), 6.25 (d, J ) 2.3 Hz, 1H), 7.21 (dd, J ) 8.1 Hz, J
) 1.5 Hz, 1H), 7.23 (s, 1H), 7.58 (dd, J ) 7.8, J ) 7.8, 1H),
7.62 (dd, J ) 7.5 Hz, J ) 1.5 Hz, 1H), 11.99 (s, 1H), 12.58 (s,
1H); 13C NMR (101 MHz, CDCl3) δ 21.0, 55.3, 55.7, 91.9, 93.7,
108.0, 115.1, 115.6, 120.0, 123.6, 125.4, 127.3, 132.4, 152.5,
153.5, 157.5, 160.8, 161.8, 162.8, 182.6, 192.9; MS (EI) m/z 406
(7.3) [M+•], 375 (5) [M+ - OCH3], 56 (100). Anal. Calcd for
Red u ctive Clea va ge of (M)-38. To a solution of (M)-38
(20.0 mg, 34.2 µmol) in 2 mL of 5% NaOH was added Na2S2O4
(180 mg, 1.03 mmol) and the mixture was stirred at 50 °C for
1 h. The solution was acidified and thoroughly extracted with
EtOAc. Evaporation of the dried extract and purification by
flash chromatography on silica gel (CH2Cl2/MeOH ) 100:0 f
100:2) afforded 15 (2.8 mg, 18.1 µmol, 53%) and 31 (4.6 mg,
13.0 µmol, 38%). Compounds 15 and 31 were found to be
identical to an authentic sample (Fluka) and synthetic mate-
rial (see above) by TLC and 1H NMR.
C
23H18O7: C, 67.98; H, 4.46. Found: C, 67.72; H, 4.17.
A solution of (P)-4,5-dihydroxy-1-(2′,4′-dimethoxy-6′-hydroxy-
phenyl)-2-methylanthraquinone (20.0 mg, 49.2 µmol) in 1 mL
of dry CH2Cl2 was treated at -20 °C with 11 µL (18.7 mg, 99.3
µmol) of TiCl4 and 9 µL (10.1 mg, 98.4 µmol) of Ac2O, stirred
at this temperature for 10 min, and allowed to warm to room
temperature over 110 min. After addition of H2O (1 mL) and
aqueous HCl (2 M, 1 mL) the aqueous phase was extracted
thoroughly with EtOAc (5 mL). The combined organic phases
were dried (MgSO4) and the solvent was evaporated. Flash
chromatography (silica gel, CH2Cl2/EtOAc ) 10:2) afforded (P)-
1c (18.0 mg, 40.3 µmol, 82%) as red solid: mp 262-263 °C
13-Br om o-1,3-dim eth oxy-8,10-diisopr opoxy-6H-an th r a-
[2,1-c]ben zop yr a n -9,14-d ion e (42). A solution of (P)-38 (20.0
mg, 34.2 µmol) in 1 mL of dry CH2Cl2 was treated at room
temperature with polymer-bound PPh3 (46.3 mg, 136 µmol)
and stirred at this temperature for 15 min. (CBrCl2)2 (21.4 mg,
65.6 µmol) was added and the suspension stirred for 10 min
at room temperature. The mixture was filtered through a pad
of Celite, which was washed thoroughly with CH2Cl2. The
solvent of the combined organic phases was evaporated and
the residue was dissolved in 4 mL of dry MeOH. Pd/C (10%,
5.00 mg) and 20 µL of NEt3 were added and the mixture was
hydrogenated for 15 min at 3.5 bar. Filtration, evaporation of
the solvent, and flash chromatography on silica gel (CH2Cl2/
EtOAc ) 7:3) afforded 42 as a yellow oil (10.5 mg, 18.5 µmol,
54%), which was crystallized from CH2Cl2/petroleum ether:
mp 123 °C; IR (KBr) ν 2940, 2900, 1660, 1590, 1430, 1260,
1190, 1140, 1090, 1040; 1H NMR (600 MHz, CD3SOCD3) δ 1.28
(d, J ) 6.1 Hz, 3H), 1.31 (d, J ) 6.0 Hz, 3H), 1.34 (d, J ) 6.0
Hz, 3H), 1.39 (d, J ) 6.1 Hz, 3H), 3.58 (s, 3H), 3.80 (s, 3H),
4.65-4.71 (m, 2H), 4.66 (d, J ) 13.4 Hz, 1H), 4.99 (d, J ) 14.1
Hz, 1H), 6.26 (d, J ) 2.3 Hz, 1H), 6.34 (d, J ) 2.3 Hz, 1H),
7.37 (s, 1H), 7.38 (d, J ) 9.2 Hz, 1H), 7.89 (d, J ) 9.0 Hz, 1H);
coalescence of the diastereotopic benzylic protons at 4.66 and
4.99 ppm was nearly reached at 140 °C; 13C NMR (101 MHz,
CDCl3) δ 21.9, 22.1, 22.2, 55.5, 57.0, 69.5, 73.6, 73.8, 94.2, 94.8,
106.6, 110.5, 115.8, 119.4, 121.9, 124.5, 129.5, 133.4, 135.9,
138.7, 141.7, 155.6, 156.1, 156.6, 158.1, 161.2, 181.2, 184.9;
MS (EI) m/z 568/566 (53/53) [M+•], 526/524 (13/13), 495/493
(77/75), 453/451 (100/97). HRMS calcd for C29H27BrO7 566.0940,
found: 566.0933.
(lit.9 255-260 °C); [R]22 ) +121 (c 0.01, CHCl3) (lit.9 +130, c
D
0.2, CHCl3); IR (KBr) ν 2925, 2847, 1616, 1593, 1461, 1278,
1
1211, 1128, 796 cm-1; H NMR (400 MHz, CDCl3) δ 2.11 (s,
3H), 2.67 (s, 3H), 3.77 (s, 3H), 4.00 (s, 3H), 6.13 (s, 1H), 7.21
(dd, J ) 8.1 Hz, J ) 1.7 Hz, 1H), 7.24 (d, J ) 0.8 Hz, 1H), 7.56
(dd, J ) 7.8 Hz, J ) 7.6 Hz, 1H), 7.60 (dd, J ) 7.6 Hz, J ) 1.7
Hz, 1H), 12.07 (s, 1H), 12.59 (s, 1H), 13.88 (s, 1H); 13C NMR
(101 MHz, CDCl3) δ 21.0, 33.3, 55.4, 55.7, 86.3, 106.3, 109.0,
115.0, 115.7, 119.7, 123.5, 125.2, 128.4, 131.4, 134.7, 136.8,
151.5, 161.8, 162.4, 162.5, 162.6, 163.1, 182.5, 193.0, 199.2;
MS (EI) m/z 448 (99) [M+•], 433 (100).
(M)-4′-O-Dem eth ylk n ip h olon e [(M)-1d ]. A solution of 1c
(5.00 mg, 11.2 µmol) in 1 mL of chlorobenzene was treated
under argon with AlBr3 (30.0 mg, 112 µmol) and stirred at 80
°C for 1.5 h. After cooling to room temperature H2O (1 mL)
and 2 M HCl (1 mL) were added and the mixture was
thoroughly extracted with EtOAc. Drying (MgSO4) of the
combined organic extracts, evaporation of the solvent, and
purification by preparative HPLC afforded (M)-1d (2.92 mg,
6.94 µmol, 62%) as a red solid: mp 216-217 °C (lit.10 210-
212 °C); [R]23 ) +113 (c 0.01, MeOH) (lit.10 +104, c 0.02,
D
(P )-4,5-Diisopr opoxy-1-(2′,4′-dim eth oxy-6′-h ydr oxyph en -
yl)-2-m eth yla n th r a qu in on e [(P )-40]. Crude (M)-39, pre-
pared as described above for 42 from (P)-38 (80.0 mg, 137
µmol), polymer-bound PPh3 (185 mg, 544 µmol), and (CBrCl2)2
(85.6 mg, 262 µmol), was dissolved in 10 mL of dry MeOH.
Pd/C (10%, 20.0 mg) and 26.8 mg (151 µmol) NaOAc were
added and the mixture was hydrogenated for 2 h at 3.5 bar.
Filtration, evaporation of the solvent, and flash chromatog-
raphy on silica gel (CH2Cl2/EtOAc ) 7:3) afforded (P)-40 (32.2
MeOH); IR (KBr) ν 3431, 2928, 2840, 1676, 1622, 1282, 1200,
1
1135 cm-1; H NMR (400 MHz, CD3OD) δ 2.14 (s, 3H), 2.66
(s, 3H), 6.05 (s, 1H), 7.24 (dd, J ) 8.3 Hz, J ) 1.3 Hz, 1H),
7.26 (s, 1H), 7.54 (dd, J ) 7.6 Hz, J ) 1.0 Hz, 1H), 7.65 (dd, J
) 8.3 Hz, J ) 7.6 Hz, 1H), 8.85 (s, 1H), 11.97 (s, 1H), 12.51 (s,
1H), 14.19 (s, 1H); 13C NMR (101 MHz, CD3OD) δ 21.4, 33.4,
95.9, 103.5, 107.6, 116.8, 120.2, 120.5, 124.6, 125.7, 130.1,
133.2, 136.0, 138.5, 153.3, 160.8, 162.5, 162.7, 163.1, 163.3,
183.6, 194.0, 204.4; MS (EI) m/z 420 (56) [M+•], 405 (26), 44
(100).
mg, 65.6 µmol, 48%) as a yellow oil: [R]22 ) +88 (c 0.01,
D
MeOH); IR (KBr) ν 3380, 2940, 2903, 1650, 1580, 1305, 1220,
1
905 cm-1; H NMR (400 MHz, CDCl3) δ 1.40-1.49 (m, 12H),
(M)-Kn ip h olon e [(M)-1a ]. To a solution of (P)-1c (10.0 mg,
22.3 µmol) in 1 mL of chlorobenzene was added AlBr3 (36.0
mg, 134 µmol) in four equal portions over a period of 2 h in a
way that after each addition at room temperature, the reaction
mixture was heated to 80 °C for 15 min, after which it was
cooled again down to room temperature in order to add the
next portion of AlBr3 and then the mixture was again stirred
2.08 (s, 3H), 3.60 (s, 3H), 3.84 (s, 3H), 5.52-4.70 (m, 2H), 6.18
(d, J ) 2.3 Hz, 1H), 6.27 (d, J ) 2.1 Hz, 1H), 6.97 (s, 1H), 7.06
(d, J ) 9.1 Hz, 1H), 7.73 (d, J ) 8.8 Hz, 1H); 13C NMR (63
MHz, CDCl3) δ 21.9, 22.0, 22.1, 55.5, 56.3, 73.2, 92.4, 93.2,
119.4, 120.1, 122.9, 123.5, 123.7, 126.0, 127.5, 133.1, 134.8,
135.1, 144.3, 153.9, 156.8, 157.8, 158.0, 160.7, 181.2; MS (EI)
5608 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of Natural Phenylanthraquinones
at 80 °C. After cooling to room temperature, H2O (1 mL) and
2 M HCl (1 mL) were added and the mixture was thoroughly
extracted with EtOAc. Drying (MgSO4) of the combined organic
extracts, evaporation of the solvent, and purification by
preparative HPLC afforded (M)-1a (3.84 mg, 9.14 µmol, 41%)
as a red solid, which was crystallized from CH2Cl2/petroleum
2-mercaptoethanol and 15% heat-inactivated horse serum was
added to each well of a 96-well microtiter plate. Serial drug
dilutions were added to the wells. Then 50 µL of trypanosome
suspension (T. b. rhodesiense STIB 900) were added to each
well and the plate incubated at 37 °C under a 5% CO2
atmosphere for 72 h. Alamar Blue (10 µL) was added to each
well and incubation was continued for a further 2-4 h. The
plate was then read at an excitation wavelength of 530 nm
and an emission wavelength of 590 nm.52 Fluorescence devel-
opment was expressed as percentage of the control, and IC50
values were determined.
Leish m a n ia d on ova n i. Mouse peritoneal macrophages
were seeded in RPMI 1640 medium with 10% heat-inactivated
FBS into 16-chamber slides. After 24 h L. donovani amastig-
otes (strain MHOM-ET-67/L82) were added at a ratio of 3:1
(amastigotes to macrophages). The medium containing free
amastigotes was replaced by fresh medium 4 h later. The next
day the medium was replaced by fresh medium containing
different drug concentrations. The slides were incubated at
37 °C under a 5% CO2 atmosphere for 96 h. Then the medium
was removed, and the slides were fixed mith MeOH and
stained with Giemsa. The ratio of infected to noninfected
macrophages was determined microscopically, expressed as
percentage of the control, and the IC50 value was calculated
by linear regression.
Com p u ta tion a l Meth od s. The conformational analysis of
(P)-19 was performed using the semiempirical AM153 method
as implemented in the program package Vamp 6.554 starting
from geometries preoptimized by the Tripos55 force field.
The molecular dynamics simulations of 1a and 1b were
performed using the MM345 force field as implemented in the
molecular modeling package Sybyl 6.7,55 with a time step of 2
fs. Bond lengths were constrained using the SHAKE algo-
rithm.56 The molecule was weakly coupled to a virtual thermal
bath at T ) 300 K,57 with a temperature relaxation time τ )
0.2 ps.
The wave functions for the calculation of the rotational
strengths for the electric transitions from the ground state to
excited states were obtained by CNDO/S-CI calculations58,59
with a CI expansion including 576 singly occupied configura-
tions and the ground state determinant. These calculations
were carried out by the use of the BDZDO/MCDSPD59 program
package. For a better visualization, the rotational strengths
were transformed into ∆ꢀ values and superimposed with a
Gaussian band shape function.
ether: mp 219-220 °C (lit.5 225 °C); [R]22 ) + 78 (c 0.01,
D
MeOH) (lit.5 +80, c 0.01, MeOH); IR (KBr) ν 3442, 2928, 1682,
1397, 1200, 1135 cm-1; 1H NMR (400 MHz, CD3OD) δ 2.14 (s,
3H), 2.66 (s, 3H), 6.05 (s, 1H), 7.24 (dd, J ) 8.3 Hz, J ) 1.3
Hz, 1H), 7.26 (s, 1H), 7.54 (dd, J ) 7.6 Hz, J ) 1.0 Hz, 1H),
7.65 (dd, J ) 8.3 Hz, J ) 7.6 Hz, 1H), 8.85 (s, 1H), 11.97 (s,
1H), 12.51 (s, 1H), 14.19 (s, 1H); 13C NMR (101 MHz, CD3OD)
δ 21.4, 33.4, 95.9, 103.5, 107.6, 116.8, 120.2, 120.5, 124.6, 125.7,
130.1, 133.2, 136.0, 138.5, 153.3, 160.8, 162.5, 162.7, 163.1,
163.3, 183.6, 194.0, 204.4; MS (EI) m/z 434 (100) [M+•], 419
(79), 401 (14).
(M)-Kn ip h olon e An th r on e [(M)-1b]. To a solution of (M)-
1a (2.12 mg, 4.88 µmol) in 2 mL of glacial HOAc was added 2
mL of 40% SnCl2 solution in concentrated HCl. The resulting
solution was refluxed for 2 h, cooled, and poured into 20 mL
of brine and the whole was thoroughly extracted with EtOAc.
Evaporation of the combined dried extracts and chromatog-
raphy on silica gel (CH2Cl2/MeOH ) 100:0.5) afforded (M)-1b
(1.32 mg, 3.14 µmol, 64%) as a red solid, which was crystallized
from acetone/petroleum ether: mp 236-237 °C (lit.8 240-242
°C); [R]23D ) +183 (c 0.001, acetone) (lit.8 +200, c 0.001, Me2O);
IR (KBr) ν 3200, 1605, 1450, 1410, 1360, 1265, 1110 cm-1; 1H
NMR (600 MHz, CD3SOCD3) δ 2.03 (s, 3H), 2.61 (s, 3H), 3.92
(s, 3H), 3.94 (s, 1H), 3.97 (s, 1H), 6.26 (s, 1H), 6.87 (dd, J )
8.2 Hz, J ) 0.7 Hz, 1H), 6.90 (s, 1H), 6.92 (dd, J ) 7.7 Hz, J
) 1.0 Hz, 1H), 7.52 (dd, 3J ) 8.0 Hz, 3J ) 7.8 Hz, 1H), 10.6 (s,
1H), 12.2 (s, 1H), 12.3 (s, 1H), 14.2 (s, 1H); 13C NMR (151 MHz,
CD3SOCD3) δ 20.5, 30.9, 32.6, 55.7, 91.1, 95.9, 103.5, 104.8,
114.8, 115.0, 115.9, 119.3, 124.0, 136.4, 141.2, 142.4, 148.8,
161.4, 161.7, 162.3, 162.7, 163.7, 193.4, 202.6; MS (EI) m/z 420
(100) [M+•], 405 (15), 378 (7), 239 (93).
Biologica l Exp er im en ts. P la sm od iu m fa lcipa r u m . An-
tiplasmodial activity was determined using the K1 strain
(resistant to chloroquine and pyrimethamine). A modification
of the [3H]-hypoxanthine incorporation assay49 was used.50
Briefly, infected human red blood cells were exposed to serial
drug dilutions in microtiter plates for 48 h at 37 °C in a gas
mixture with reduced oxygen and elevated CO2. [3H]-Hypox-
anthine was added to each well and after further incubation
for 24 h the wells were harvested on glass fiber filters and
counted in a liquid scintillation counter. From the sigmoidal
inhibition curve the IC50 value was calculated. The assays were
run in duplicate and repeated at least once.
Tr ypa n osom a cr u zi. Rat skeletal myoblasts (L-6 cells)
were seeded in 96-well microtiter plates at 2000 cells/well/100
µL in RPMI 1640 medium with 10% FBS and 2 mM L-
glutamine. After 24 h 5000 trypomastigotes of T. cruzi (Tu-
lahuen strain C2C4 containing the galactosidase (Lac Z) gene)
were added. The plates were incubated at 37 °C in 5% CO2
for 2 d before the medium was removed and replaced by a
serial 3-fold drug dilution. After another incubation period of
4 d, the substrate CPRG/Nonidet was added to the wells. The
color reaction that developed during the following 2-4 h was
read photometrically at 540 nm. IC50 values were calculated
from the sigmoidal inhibition curve. Cytotoxicity was assessed
in the same assay using noninfected L-6 cells and the same
serial drug dilution. The MIC was determined microscopically
after 4 d.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 347 and Gra-
duiertenkolleg “Elektronendichte”), the Fonds der Che-
mischen Industrie, the DAAD (fellowship to D.M.), and
the UNDP/World Bank/WHO Special Programme. Par-
ticular thank is due to Elke Gobright and Christian
Scheurer for carrying out the in vitro assays and to
(51) Baltz, T.; Baltz, D.; Giroud, C.; Crockett, J . EMBO J . 1985, 4,
1273.
(52) Ra¨z, B.; Iten, M.; Grether-Bu¨hler, Y.; Kaminsky, R.; Brun, R.
Acta Trop. 1997, 68, 139.
(53) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E.; Stewart, J . J . P. J .
Am. Chem. Soc. 1985, 107, 3902.
(54) Rauhut, G.; Chandrasekhar, J .; Alex, A.; Beck, B.; Sauer, W.;
Clark, T. VAMP 6.5; Oxford Molecular Ltd., The Medewar Centre,
Oxford Science Park, Sandford-on-Thames, Oxford, OX4 4GA, England.
(55) SYBYL; Tripos Associates, 1699 St. Hanley Road, Suite 303,
St. Louis, MO 63144.
Tr ypa n osom a b. r h od esien se. Minimum Essential Me-
dium (50 µL) supplemented according to Baltz et al.51 with
(56) van Gunsteren, W. F.; Berendsen, H. J . C. Mol. Phys. 1977,
34, 1311.
(57) Berendsen, H. J . C.; Postma, J . P. M.; van Gunsteren, W. F.;
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(59) Downing, J . W., Program Packet BDZDO/MCDSPD, Depart-
ment of Chemistry and Biochemistry, University of Colorado, Boulder,
USA.; modified by Fleischhauer, J .; Schleker, W.; Kramer; B.; ported
to Linux by Gulden, K.-P.
(49) Desjardins, R. E.; Canfield, C. J .; Haynes, D.; Chulay, J .
Antimicrob. Agents Chemother. 1979, 16, 710.
(50) Ridley, R. G.; Hofheinz, W.; Matile, H.; J acquet, C.; Dorn, A.;
Masciadri, R.; J olidon, S.; Richter, W. F.; Guenzi, A.; Girometta, M.
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J . Org. Chem, Vol. 67, No. 16, 2002 5609

Bringmann et al.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for 33 and 42 and X-ray crystallographic data
for 17. This material is available free of charge via the Internet
at http://pubs.acs.org.
Valeska Barthel for technical support. B.M.A. is grateful
to the University of Botswana for a useful grant, and
M.B. thanks Deutscher Akademischer Austauschdi-
enst-Natural Products Research Network for Eastern
and Central Africa (DAAD-NAPRECA) for a fellowship.
J O020189S
5610 J . Org. Chem., Vol. 67, No. 16, 2002