Evolution of a synthetic strategy for the variecolortides

Article abstract of DOI:10.1002/ejoc.201200712

The variecolortides are a family of unusual natural products that combine motifs from a variety of biosynthetic streams. Herein, we present the gradual evolution of a convergent synthetic strategy that ultimately culminated in a reaction cascade featuring a hydrogen shift and a cycloaddition followed by a spontaneous air oxidation. Attempts to link an anthrone building block with an exo-methylene diketopiperazine using radical chemistry were ultimately unsuccessful, but led to interesting observations that shaped our successful strategy. The total synthesis of variecolortide C is presented for the first time. Copyright

Full text of DOI:10.1002/ejoc.201200712

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FULL PAPER
DOI: 10.1002/ejoc.201200712
Evolution of a Synthetic Strategy for the Variecolortides
Christian A. Kuttruff,[a] Peter Mayer,[a] and Dirk Trauner*[a]
Dedicated to the memory of Ernesto Fattorusso
Keywords: Total synthesis / Natural products / Cycloaddition / Biomimetic synthesis / Domino reactions / Cascade
reactions
The variecolortides are a family of unusual natural products
that combine motifs from a variety of biosynthetic streams.
Herein, we present the gradual evolution of a convergent
synthetic strategy that ultimately culminated in a reaction
cascade featuring a hydrogen shift and a cycloaddition fol-
lowed by a spontaneous air oxidation. Attempts to link an
anthrone building block with an exo-methylene diketo-
piperazine using radical chemistry were ultimately unsuc-
cessful, but led to interesting observations that shaped our
successful strategy. The total synthesis of variecolortide C is
presented for the first time.
Introduction
tolerant fungal strain Aspergillus variecolor B-17, and their
structures and biological activities were reported by Wang
et al. in 2007.[6] They feature a tetracyclic pyrano-anthrone
moiety, which is connected to a central diketopiperazine
Nature remains a major source of inspiration for syn-
thetic chemists not only in terms of the structures it pro-
duces but also with respect to the strategies it uses for their
construction. These have been mimicked with remarkable
success in the laboratory, yielding many elegant and ef-
ficient syntheses of natural products.[1] Many of these “bio-
mimetic” syntheses incorporate reaction cascades, whose
role in the origin of natural products has been increasingly
recognized. Cascade reactions allow for the formation of
many bonds in a single operation and can create several
stereocenters, which also allows for the spontaneous con-
struction of complex chiral molecules from achiral precur-
sors.[2] However, in the absence of an asymmetric environ-
ment, such as the active site of an enzyme, there is no
reason why one enantiomer should be preferred over the
other. Hence, complex natural products that have been iso-
lated in racemic form can be suspected to spontaneously
arise through cascade reactions and, thus, are prime candi-
dates for biomimetic total synthesis.
In recent years, our group has published several synthe-
ses of racemic natural products, including rubicordifolin
(1),[3] rubioncolin B (2),[4] and exiguamines A (3) and B
(4)[5] (see Figure 1) that were based on pericyclic reaction
cascades. More recently, the variecolortides attracted our
attention.Theseunusualcompoundswereisolatedfromthehalo-
[a] Department of Chemistry and Center of Integrated Protein
Science (CIPSM), LMU Munich,
Butenandtstr. 5–13, 81377 München, Germany
Fax: +49-89-2180-77972
E-mail: dirk.trauner@lmu.de
Homepage: http://www.cup.uni-muenchen.de/oc/trauner/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200712.
Figure 1. Racemic natural products that have been synthesized in
our laboratory.
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moiety through a spirocyclic N,O-acetal. Notably, this now disclose the full details of our studies that eventually
structural motif can also be found in the exiguamines. The led to the total syntheses of variecolortide A and B and
diketopiperazine moiety of the variecolortides is also con- report our previously unpublished synthesis of variecolor-
nected to a reversely prenylated indole, which can be further tide C.
prenylated on the benzene ring. Variecolortide A (5), B (6),
and C (7) are distinguished by different prenylation patterns
(prenyl = 3-methyl-but-2-en-1-yl) as well as differences in
Results and Discussion
the O-methylation of the pyrano-anthrone unit.
In a recent communication, our group published the syn-
Our initial plan for the synthesis of the variecolortides is
theses of variecolortide A and B that hinged once again on depicted in Scheme 1. We reasoned that the spirobicyclic
a pericyclic reaction cascade.[7] However, our eventual suc- N,O-acetal moiety, which also represents the sole stereo-
cessful synthetic strategy was not our initial choice, but genic center of the racemic molecules, could be formed by
gradually evolved in the course of our investigations. We means of an oxa-6π-electrocyclization (oxa-6π-EC) reac-
Scheme 1. First-generation retrosynthesis of variecolortide A (5).
Scheme 2. Syntheses of different diketopiperazines. Reagents and conditions: (a) Boc2O, DMAP [4-(dimethylamino)pyridine], DMF (di-
methylformamide), room temp., 1.5 h, 69%; (b) NaH, PMBCl, 0 °C to room temp., 12 h, 53%; (c) NH4F, MeOH, 40 °C, 5 d, 99%.
2
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Evolution of a Synthetic Strategy for the Variecolortides
tion. This type of reaction has been successfully used in
other total syntheses published by our group, for instance,
in the synthesis of exiguamine A (3) and B (4) and micro-
phyllaquinone.[8] In the retrosynthetic sense, variecolor-
tide A (5) would arise from the corresponding hydro-
quinone 8, which would stem from anthraquinone methide
9 through a tautomerization (see Scheme 1). The key inter-
mediate 9 could be further dissected into a “northern” an-
thracene portion (i.e., 10) or an analogous anthrone moiety
(i.e., 11), a “central” diketopiperazine building block (i.e.,
12 or 13), and a “southern” indole building block 14.
Our initial approach for the connection of the northern
and central part of the variecolortides called for a conden-
sation reaction between the formyl diketopiperazine 12 and
the anthracene 10 or anthrone 11. As we did not find litera-
ture precedence for formyl diketopiperazines of type 12, we
planned to synthesize them from their corresponding ser-
ine-derived diketopiperazine precursors by simple oxidation
(see Scheme 2). To this end, silyl ether 15 was first prepared
in three steps from protected amino acids, according to a
procedure published by Chai et al.[9] The former was then
Boc-protected to give 16, whose structure and absolute ste-
reochemistry were unambiguously assigned by X-ray crystal
structure analysis. However, subsequent attempts to remove
the silyl protecting group and oxidize to the resulting
alcohol 17 failed. We reasoned that the Boc protecting
groups might not survive the deprotection conditions and,
therefore, switched to the more stable PMB (p-meth-
oxybenzyl) protecting group. Thus, 15 was doubly alkylated
to give the corresponding bis(PMB) derivative,[10] which
could be desilylated by using ammonium fluoride in meth-
anol. With the desired alcohol 18 in hand, we next screened
a variety of different oxidation conditions, again with no
success.
The failure to obtain aldehydes of type 12 left us to re-
consider our approach, opting instead for electrophiles
other than a carbonyl group. As the hydroxymethyl group
present in 18 can easily be converted into an exo-methylene
group, we decided to synthesize a diketopiperazine that
could potentially function as a Michael acceptor. To this
end, piperazinedione 15 was converted into exo-methylene
diketopiperazine 20 in three steps, following a known litera-
ture procedure.[9] The structure of this compound was also
confirmed by X-ray crystal structure analysis.
Next, the synthesis of the southern indole portion was
addressed. As variecolortide A is the only member of the
family whose indole moiety bears an additional prenyl
group at C-22, we had to devise a strategy for this building
block (see Scheme 3). Originally, we planned to synthesize
Scheme 3. Syntheses of formyl indoles. Reagents and conditions:
(a) allyl(tributyl)stannane, PdCl2, PPh3, DMF, 110 °C, 24 h, 90%;
(b) 2-methyl-2-butene, Grubbs second-generation catalyst, CH2Cl2,
room temp., 1.5 h, 79%, (c) NCS (N-chlorosuccinimide), DMF,
room temp., 3.5 h, 73%; (d) prenyl-9-BBN (BBN = 9-borabicy-
clo[3.3.1]nonane), Et3N, THF (tetrahydrofuran), room temp., 3.5 h,
96%; (e) Vilsmeier reagent, DMF, room temp., 3 h; then NaOH,
20 min, 84%; (f) NaH, MOMCl (methoxymethyl chloride), DMF,
0 °C to room temp., 20 h, 86%; (aa) NCS, DMF, room temp., 1 h,
91%; (bb) prenyl-9-BBN, Et3N, THF, room temp., 5 h, 74%;
(cc) Vilsmeier reagent, DMF, room temp., 2.5 h; then NaOH,
20 min, 93%; (dd) NaH, MOMCl, DMF, 0 °C to room temp., 25 h,
58%.
Therefore, we decided to install the prenyl group follow-
26 from 5-bromoindole derivative 21 by direct prenylation ing a stepwise approach that we previously used in the syn-
and subsequent formylation. Although direct prenylations thesis of microphyllaquinone.[8] Accordingly, 5-bromo-
of arenes using Stille couplings have been reported,[11] the indole (22) was subjected to a Stille cross-coupling reaction
direct coupling of a prenyl stannane to 21 failed in our with allyl(tributyl)stannane to give indole 23 in excellent
hands. We reasoned that the double bond of the reverse- yield. Subsequent cross-metathesis with 2-methyl-2-butene
prenyl group present in 21 might interfere with the transi- afforded the prenylated indole 24. A reverse prenylation was
tion-metal catalysts and thus attempted to couple the prenyl carried out following a literature protocol to yield 25.[12]
stannane to unsubstituted 5-bromoindole (22), but again Vilsmeier formylation then gave compound 26, whose struc-
our efforts were unsuccessful.
ture was confirmed by X-ray crystal structure analysis. Fi-
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nally, 26 was protected to give MOM ether 27. Analogously, nucleophile that could undergo addition to the exo-methyl-
formyl indole 32, required for the synthesis of variecolor- ene group of diketopiperazine 20, we found that none of
tide B and C, was prepared in four steps starting from in- the conditions tested yielded any of the desired addition
dole (28, see Scheme 3).
product 37.
Our synthesis of the northern anthrone building block,
In addition to enabling the reoxidation of 36 to 34, the
compound 34, closely followed the pioneering work of Cali- phenolic hydroxy group in the 4-position could also inter-
skan[13] and is shown in Scheme 4. It started from known fere with the desired reaction through an unfavorable peri
anhydride 33,[14] which was treated with sodium hydride to interaction. Therefore, we decided to remove it and try the
generate the corresponding enolate that underwent a regio- critical linkage with the sterically less hindered emodin
controlled cycloaddition reaction with 2-chloro-5-methyl- anthrone 40 (see Scheme 6). Our synthesis of this building
benzoquinone. An aromatization of this intermediate, ac- block commenced with the triple methylation of the natural
companied by the loss of CO2 and HCl, provided hydroxy- product emodin.[15] To allow for the planned oxidation of
viocristin dimethyl ether (34) in good yield as a single re- the phenol into the corresponding quinone, we had to selec-
gioisomer. The structure of the product was confirmed by tively deprotect the methoxy group at C-8. This was
X-ray crystal structure analysis. The required reduction of achieved in good yield by treatment with BBr3 at lower tem-
quinone 34 into the corresponding hydroquinone turned peratures. Finally, the chemoselective reduction of anthra-
out to be rather difficult, since 34 was found to be insoluble quinone 39 using tin(II) chloride yielded anthrone 40 (see
in most solvents. Eventually, we found that the reduction of Scheme 6).
34 in a mixture of chloroform, acetone, and water using
sodium dithionite under sonication gave rise to a mixture
of the desired anthrone 35 and its tautomer 36 (see
Scheme 4). We found that 35 and 36 were extremely prone
to reoxidize and give quinone 34. As such, they could not
be isolated and stored under ambient atmosphere, but in-
Scheme 6. Synthesis of emodin anthrone 40. Reagents and condi-
tions: (a) K2CO3, Me2SO4, acetone, room temp., 30 min; then
90 °C, 16 h, 76%; (b) BBr3, CH2Cl2, from –5 °C to room temp.,
1 h, 73%; (c) SnCl2·2H2O, HCl, AcOH, 65 °C, 1 h, 82%.
stead had to be freshly prepared and used directly in the
next step.
With the desired partially deoxygenated anthrone 40 in
hand, we set out to screen for conditions that would effect
a Michael addition to diketopiperazine 20 (see Scheme 7).
Unfortunately, neither the use of bases, such as K2CO3,
Et3N, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and
nBuLi, nor the use of Lewis acids facilitated the required
transformation. This led us to conclude that the exo-meth-
ylene diketopiperazines of type 20 are poor electrophiles,
even with additional electron-withdrawing substituents on
the nitrogen.
Scheme 4. Synthesis of 35/36 and attempted linkage. Reagents and
conditions: (a) 2-chloro-5-methyl-benzoquinone, NaH, THF, 0 °C
to room temp., 52%; (b) Na2S2O4, CHCl3/acetone/H2O (1:1:2, de-
gassed), sonication, 40 °C, 10 min.
We next explored the Michael-type addition of anthrone
36 to diketopiperazine 20 (see Scheme 5). Although we had
hoped that the deprotonation of 36 would give rise to a
Scheme 7. Attempted monoalkylation of emodin anthrone 40 un-
der nucleophilic conditions.
At that point, we became aware of the possibility of
using radical chemistry, since anthrones are well known to
form radicals in the presence of oxygen. We hypothesized
that the central spirocycle of the variecolortides could arise
from emodin anthrone 40 and exo-methylene diketopiper-
azine 20 by radical addition and subsequent oxidation reac-
tion. To pursue such a biomimetic approach, we mixed both
building blocks and stirred them under an oxygen atmo-
Scheme 5. Attempted linkage of anthrone 36 and diketopiperazine
20.
4
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Evolution of a Synthetic Strategy for the Variecolortides
sphere (see Scheme 8). To our surprise, this led to a double Diels–Alder disconnection to yield the ortho-quinone
addition reaction to give the doubly alkylated anthrone 42, methide 44 and exo-methylene diketopiperazine 45. The lat-
which proved to be crystalline. Its X-ray crystal structure is ter is a natural product known as isoechinulin B.[16] The re-
also shown in Figure 2. Remarkably, this unusual com- active heterodiene 44, in turn, would be formed by an intra-
pound features a nonstereogenic chirotopic center. It is pre- molecular 1,5-hydrogen shift from an anthrone that is also
sumably formed through an initial hydrogen abstraction a known natural product, hydroxyviocristin (46).
from 40, followed by addition to 20. This is followed by
another hydrogen abstraction, another addition reaction,
and a final abstraction. It is likely that stereoisomers of 42
are formed in the course of this process, but they could not
be isolated.
Scheme 8. A surprising double-radical addition reaction. Reagents
and conditions: (a) O2, DMSO/H2O (2:1), room temp., 20 h, 40%.
Scheme 9. Second-generation retrosynthetic analysis of variecolor-
tide A (5).
Figure 2. X-ray crystal structure of bis(diketopiperazine) 42.
To test our revised plan, we first heated a mixture of
hydroxyviocristin dimethyl ether (34) and benzyl-protected
exo-methylene diketopiperazine 47 in an aerated ortho-
dichlorobenzene solution inside a pressure tube (see
Scheme 10). Indeed, under these conditions, we isolated
compound 48, which displays the crucial pyrano-anthrone
core of the variecolortides. Next, we tested the analogous
reaction with the unprotected exo-methylene diketopiperaz-
ine 49[7] and also obtained the corresponding cycloadduct
50 in good yield. The synthesis of 47, an analogue of exo-
Subsequently, we tried to achieve a monoaddition reac-
tion by varying several of the reaction parameters, such as
stoichiometry, reaction time, the speed of the addition of
the reagent, and so forth, but none of these changes led
to the desired monoalkylated product 41. Interestingly, if
solvents other than DMSO (dimethyl sulfoxide) or other
radical-generating conditions such as AIBN [azobis(iso-
butyronitrile)]/nBu3SnH were attempted, the dialkylated
product 42 was not observed. Attempts to remove one of
the diketopiperazines by using a base-induced elimination
proved equally unsuccessful.
At this stage, we chose to abandon our original synthetic
plan and adopt a different approach for the linkage of our
building blocks. This eventually led us to consider one of
our favorite reactions, that is, a hetero-Diels–Alder reac-
tion, which had also played a prominent role in our total
synthesis of rubioncolin B. The implementation of this reac-
tion in the retrosynthesis of variecolortide A (5) is shown
in Scheme 9. We hypothesized that the natural product
could stem from the reduced anthrone precursor 43, which
could easily undergo an oxidative unsaturation in the pres-
ence of oxygen by virtue of its extremely labile C–H bond
in the bis(benzylic) position. Compound 43, a benzopyran,
Scheme 10. Model system for the cycloaddition approach. Reagents
and conditions: (a) ortho-dichlorobenzene, air, 210 °C, 1 h, 39%;
could then be retrosynthetically disassembled through a (b) ortho-dichlorobenzene, air, 180 °C, 1.5 h, 73%.
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methylene diketopiperazine 20 is detailed in the Supporting isoechinulin B (45), albeit in poor quality (see Supporting
Information.
Information).
Encouraged by these model studies, we proceeded to syn-
When neoechinulin 51 was heated with readily available
thesize the three variecolortides, using isoechinulin B (45) viocristin dimethyl ether 34 in a sealed tube in the presence
or its desprenyl derivative neoechinulin B (51)[17] as dieno- of molecular oxygen, the corresponding dimethyl ether 52
philes. The syntheses of these naturally occurring diketo- of the natural product variecolortide B was obtained as de-
piperazines using well-established routes are shown in picted in Scheme 12. What remained to be done in order to
Scheme 11.[7] We also obtained an X-ray crystal structure of finish the total synthesis was simply deprotection of the
methyl groups. Considering the vast number of methods
suitable for the deprotection of phenolic methyl ethers, we
felt that this final step should be straightforward. However,
under all of the conditions examined, we observed either
decomposition or obtained a mixture of monodemethylated
product and starting material.
Consequently, we decided to first carry out the deprotec-
tion of hydroxyviocristin dimethyl ether (34) and use the
resulting resorcinol 46 in the key step of the synthesis. This
could be achieved using a procedure published by Caliskan
et al. (see Scheme 13).[13]
Scheme 11. Synthesis of isoechinulin B (45) and neoechinulin B
Scheme 13. Demethylation of hydroxyviocristin dimethyl ether
(34). Reagents and conditions: (a) AlCl3/NaCl, 180 °C, 2 min, 75%.
(51). Reagents and conditions: (a) piperidine, 110 °C, 7 h, 39%;
(b) piperidine, 110 °C, 7 h, 36%.
With the requisite northern building block 46 in hand,
we were finally in a position to synthesize variecolortide A
and B (see Scheme 14). As in the model systems, the natural
products could be isolated in decent yields, considering the
complexity of the reaction cascade. Whether the conditions
used (air, o-dichlorobenzene, 180 °C) can be deemed “bio-
mimetic”, however, is questionable.
Variecolortide C (7) was the final member of the family
to succumb to total synthesis. It differs from variecolor-
tide B in that it bears a methoxy group at C-7. As we antici-
pated that a selective methylation of variecolortide B in the
required position would be difficult, we decided to synthe-
size acetyl variecolortide C (55), which could subsequently
be deprotected (see Scheme 15). To this end, we first pre-
pared the known anhydride 53.[13] Treatment with sodium
hydride generated the corresponding enolate, which under-
went a regiocontrolled cycloaddition reaction to 2-chloro-
5-methyl-benzoquinone. An aromatization reaction ac-
companied by the loss of CO2 and HCl provided acetyl vi-
ocristin 54 in 55% yield. Heating of 54 and neoechinulin B
(51) in ortho-dichlorobenzene at 180 °C in the presence of
oxygen afforded acetyl variecolortide C (55), which was
subsequently converted into the desired natural product 7
by hydrolysis of the acetyl group. With this, we achieved a
six-step synthesis of variecolortide C. Synthetic variecolor-
tide C (7) exhibited spectroscopic data consistent with its
structure and in accordance with those reported for the nat-
ural product.[6]
Scheme 12. Synthesis of dimethylvariecolortide B (52) and at-
tempted demethylation. Reagents and conditions: (a) ortho-di-
chlorobenzene, air, 180 °C, 1.25 h, 34%.
6
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Evolution of a Synthetic Strategy for the Variecolortides
reactivities of exo-methylene diketopiperazines and
anthrones. In addition, during these unsuccessful studies,
several building blocks were assembled that could ulti-
mately be used in our successful cycloaddition–oxidation
approach that also yielded variecolortide C as a final mem-
ber of the variecolortide family.
Experimental Section
General Methods: Unless stated otherwise, all of the reactions were
performed in oven-dried or flame-dried glassware under a positive
pressure of nitrogen. Commercial reagents and solvents were used
as received with the following exceptions. Tetrahydrofuran was dis-
tilled from benzophenone and sodium immediately prior to use.
Triethylamine, diisopropylamine, and diisopropylethylamine were
distilled from calcium hydride immediately before use. The reac-
tions were magnetically stirred and monitored by NMR spec-
troscopy or analytical thin-layer chromatography (TLC) using E.
Merck 0.25 mm silica gel 60 F254 precoated glass plates. The TLC
plates were visualized by exposure to ultraviolet light (UV, 254 nm)
and exposure to either an aqueous solution of ceric ammonium-
molybdate (CAM), an aqueous solution of potassium permanga-
nate (KMnO4), an acidic solution of vanillin, or a solution of
ninhydrin in ethanol followed by heating with a heat gun. Flash
column chromatography was performed as described by Still et al.
employing silica gel (60 Å, 40–63 μm, Merck) and a forced flow of
the eluent at 1.3–1.5 bar pressure.[18] The yields refer to chromato-
graphically and spectroscopically (1H and 13C NMR) pure mate-
rial.
Scheme 14. Synthesis of variecolortide A (5) and B (6). Reagents
and conditions: (a) ortho-dichlorobenzene, 180 °C, 0.5 h, 48%;
(b) ortho-dichlorobenzene, 180 °C, 1 h, 32%.
Instrumentation: Proton nuclear magnetic resonance (1H NMR)
spectroscopic data were recorded with Varian VNMRS 300,
VNMRS 400, INOVA 400, or VNMRS 600 spectrometers. Proton
chemical shifts are expressed in parts per million (δ scale) and are
calibrated by using the residual undeuterated solvent as an internal
reference (CDCl3, δ = 7.26 ppm; [D6]DMSO, δ = 2.50 ppm). The
data for the 1H NMR spectra are reported as chemical shift (δ,
ppm) [multiplicity, coupling constant (Hz), integration]. The multi-
plicities are reported by s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br. = broad, app = apparent, or combina-
tions thereof. The carbon nuclear magnetic resonance (13C NMR)
spectroscopic data were recorded with Varian VNMRS 300,
VNMRS 400, INOVA 400, or VNMRS 600 spectrometers. The car-
bon chemical shifts are expressed in parts per million (δ scale) and
are referenced to the carbon resonances of the solvent (CDCl3, δ
= 77.0 ppm; [D6]DMSO, δ = 39.5 ppm). The infrared (IR) spectra
were recorded with a Perkin–Elmer Spectrum BX II (FTIR Sys-
tem). IR data are reported in frequency of absorption (cm–1). The
mass spectroscopy (MS) experiments were performed with a
Thermo Finnigan MAT 95 (EI) or a Thermo Finnigan LTQ FT
(ESI) instrument.
Scheme 15. Synthesis of variecolortide C (7). Reagents and condi-
tions: (a) 2-chloro-5-methyl-benzoquinone, NaH, THF, 0 °C to
room temp., 55%; (b) neoechinulin B (51), ortho-dichlorobenzene,
air, 180 °C, 1 h; (c) K2CO3, MeOH, room temp., 1 h, 28% over 2
steps.
Bis(Boc)-diketopiperazine 16: To a white suspension of 15 (200 mg,
0.77 mmol. 1.0 equiv.) in dry DMF (2 mL) was added Boc2O
(356 mg, 1.63 mmol, 2.1 equiv.) and DMAP (199 mg, 1.63 mmol,
2.1 equiv.) at room temp. The resulting clear, yellow solution was
stirred for 1.5 h, and then EtOAc (2 mL) and a saturated aqueous
solution of KHSO4 (4 mL) were added. The mixture was extracted
with EtOAc (3ϫ8 mL), and the combined organic layers were
washed with a saturated aqueous solution of NaCl (8 mL), dried
with sodium sulfate, filtered, and concentrated in vacuo. Purifica-
Conclusions
In summary, we have presented a detailed account of our
recent work on the variecolortides. Initial attempts to
implement an oxa-6π-electrocyclization reaction proved
unsuccessful, but led to important insights concerning the tion of the crude product by flash column chromatography (silica
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gel, hexanes/EtOAc, 10:1) afforded the title compound 16 (244 mg,
0.53 mmol, 69%) as a white solid; m.p. 98–102 °C. Rf = 0.58 (hex-
anes/EtOAc, 10:1; KMnO4). 1H NMR (600 MHz, CDCl3): δ = 4.74
(dd, J = 2.9, 1.8 Hz, 1 H), 4.50 (d, J = 17.9 Hz, 1 H), 4.31 (d, J =
17.9 Hz, 1 H), 4.21 (dd, J = 10.6, 1.8 Hz, 1 H), 4.02 (dd, J = 10.6,
2.9 Hz, 1 H), 1.53 (s, 9 H), 1.53 (s, 9 H), 0.85 (s, 9 H), 0.03 (s, 3
H), 0.03 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 167.2,
165.3, 150.3, 149.9, 84.7, 84.7, 65.7, 62.4, 49.3, 27.9, 27.9, 25.8,
18.4, –5.7, –5.9 ppm. IR [diamond-ATR (attenuated total reflec-
1362, 1321, 1264, 1247, 1177, 1165, 1102, 1073, 1026, 976, 960,
938, 892, 852, 823, 813, 766, 703, 668 cm–1. HRMS (EI): calcd. for
C21H24N2O5 [M]+· 384.1685; found 384.1676.
MOM-Protected Indole 27: A solution of indole 26 (427 mg,
1.52 mmol, 1.0 equiv.) in dry DMF (5 mL) was added to a suspen-
sion of sodium hydride (60% dispersion in mineral oil, 608 mg,
15.2 mmol, 10 equiv.) in dry DMF (5 mL) at 0 °C. After stirring the
suspension at 0 °C for 30 min, chloromethyl methyl ether (1.15 mL,
15.2 mmol, 10 equiv.) was added dropwise. The reaction mixture
was warmed to room temp., stirred for another 20 h, and then
quenched by the addition of a saturated aqueous solution of
NH4Cl (20 mL). The orange suspension was extracted with EtOAc
(3ϫ50 mL), and the combined organic layers were dried with so-
dium sulfate, filtered, and concentrated under reduced pressure. Pu-
rification of the crude orange oil by flash column chromatography
(silica gel, hexanes/EtOAc, 5:1) afforded the title compound 27
(426 mg, 1.31 mmol, 86%) as a yellow oil. Rf = 0.74 (hexanes/
EtOAc, 2:1; UV/CAM). 1H NMR (600 MHz, CDCl3): δ = 10.67
(s, 1 H), 8.33 (dd, J = 1.5, 0.6 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H),
7.13 (dd, J = 8.4, 1.7 Hz, 1 H), 6.28 (dd, J = 17.5, 10.6 Hz, 1 H),
5.52 (s, 2 H), 5.39–5.36 (m, 1 H), 5.15 (d, J = 10.6 Hz, 1 H), 5.08
(d, J = 17.5 Hz, 1 H), 3.46 (d, J = 7.3 Hz, 2 H), 3.36 (s, 3 H), 1.76
(d, J = 0.9 Hz, 3 H), 1.75 (s, 6 H), 1.74 (d, J = 1.2 Hz, 3 H) ppm.
13C NMR (150 MHz, CDCl3): δ = 188.6, 153.7, 146.9, 137.2, 136.2,
131.8, 126.4, 124.7, 124.2, 121.9, 117.4, 112.5, 109.7, 75.6, 55.8,
tance), neat]: νmax = 2981, 2934, 2885, 2859, 1773, 1724, 1697, 1472,
˜
1393, 1368, 1279, 1250, 1226, 1144, 1115, 1086, 1054, 1035, 995,
940, 878, 834, 811, 776, 709 cm–1. HRMS (EI): calcd. for
C21H38N2O7Si [M]+· 458.2448; found 458.2450.
(S)-3-{[(tert-Butyldimethylsilyl)oxy]methyl}-1,4-bis(4-methoxy-
benzyl)piperazine-2,5-dione (S1): To a suspension of sodium hydride
(60% dispersion in mineral oil, 173 mg, 4.33 mmol, 2.05 equiv.) in
dry DMF (40 mL) was added piperazinedione 15 (546 mg,
2.11 mmol, 1.0 equiv.) at 0 °C. After 10 min, 4-methoxybenzyl
chloride (661 mg, 4.22 mmol, 2.0 equiv.) was added dropwise, and
the reaction mixture was stirred for another 2 h at 0 °C. The re-
sulting light yellow solution was warmed to room temp., and the
stirring was continued for another 12 h. Water (150 mL) was added,
and the white mixture was extracted with EtOAc (3ϫ100 mL). The
combined organic layers were dried with sodium sulfate, filtered,
and concentrated in vacuo. Purification of the residue by flash col-
umn chromatography (silica gel, hexanes/EtOAc, 5:1) afforded the
title compound S1 (561 mg, 1.12 mmol, 53%) as a white solid; m.p.
112 °C. Rf = 0.52 (hexanes/EtOAc, 1:1; UV/CAM). 1H NMR
(600 MHz, CDCl3): δ = 7.18 (dd, J = 10.9, 8.6 Hz, 4 H), 6.85–6.83
(m, 4 H), 5.15 (d, J = 14.8 Hz, 1 H), 4.78 (d, J = 14.4 Hz, 1 H),
4.24 (d, J = 14.4 Hz, 1 H), 4.05–4.04 (m, 1 H), 4.02 (s, 1 H), 3.96
(d, J = 14.8 Hz, 1 H), 3.88 (s, 1 H), 3.84 (dd, J = 10.4, 2.7 Hz, 1
H), 3.79 (s, 3 H), 3.79 (s, 3 H), 3.74 (d, J = 16.9 Hz, 1 H), 0.78 (s,
9 H), –0.05 (s, 3 H), –0.06 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 165.9, 165.4, 159.4, 159.4, 129.8, 129.7, 127.5, 127.2,
114.3, 114.2, 62.8, 61.5, 55.3, 55.3, 49.6, 49.0, 46.4, 25.7, 18.2, –5.7,
42.0, 34.5, 30.8, 25.8, 17.9 ppm. IR (diamond-ATR, neat): ν
=
˜
max
2973, 2927, 1644, 1478, 1456, 1374, 1347, 1316, 1223, 1196, 1178,
1148, 1084, 1041, 1024, 966, 914, 874, 844, 799, 726, 679 cm–1.
HRMS (EI): calcd. for C21H27NO2 [M]+· 325.2042; found
325.2032.
MOM-Protected Indole 32: Sodium hydride (60% dispersion in
mineral oil, 936 mg, 23.4 mmol, 10 equiv.) was added to a solution
of indole 31 (500 mg, 2.34 mmol, 1.0 equiv.) in dry DMF (12 mL)
at 0 °C, and the resulting suspension was stirred at this temperature
for 30 min. Chloromethyl methyl ether (1.78 mL, 23.4 mmol,
10 equiv.) was added dropwise, and the reaction mixture was
warmed to room temp. and then stirred for 25 h. A saturated aque-
ous solution of NH4Cl (50 mL) was added, and the mixture was
extracted with EtOAc (4ϫ35 mL). The combined organic layers
were washed with a saturated aqueous solution of NaCl (50 mL),
dried with sodium sulfate, filtered, and concentrated in vacuo. Puri-
fication of the crude product by flash column chromatography (sil-
ica gel, hexanes/EtOAc, 10:1) yielded the title compound 32
(349 mg, 1.36 mmol, 58%) as a yellow oil. Rf = 0.57 (hexanes/
EtOAc, 5:1; UV/CAM). 1H NMR (300 MHz, CDCl3): δ = 10.70
(s, 1 H), 8.53–8.48 (m, 1 H), 7.42–7.36 (m, 1 H), 7.34–7.28 (m, 1
H), 6.30 (dd, J = 17.5, 10.6 Hz, 1 H), 5.55 (s, 2 H), 5.17 (d, J =
10.6 Hz, 1 H), 5.09 (d, J = 17.5 Hz, 1 H), 3.38 (s, 3 H), 1.77 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.6, 153.5, 146.9,
146.8, 137.6, 126.3, 124.0, 123.3, 122.7, 117.5, 112.6, 109.8, 75.5,
–5.8 ppm. IR (diamond-ATR, neat): νmax = 2930, 2853, 2360, 2341,
˜
1651, 1612, 1584, 1512, 1467, 1434, 1354, 1322, 1306, 1247, 1210,
1179, 1164, 1123, 1110, 1087, 1059, 1033, 1011, 952, 912, 868, 842,
826, 810, 781, 769, 728, 702, 668 cm–1. HRMS (EI): calcd. for
C27H38N2O5Si [M]+· 498.2550; found 498.2537.
Alcohol 18: To a solution of S1 (245 mg, 0.49 mmol, 1.0 equiv.) in
dry MeOH (20 mL) was added NH4F (0.5 m solution in MeOH,
14.7 mL, 7.35 mmol, 15 equiv.), and the solution was heated to
40 °C and stirred at this temperature for 5 d. After cooling to room
temp., the reaction mixture was concentrated to half of its volume,
and an equal amount of saturated aqueous NaHCO3 was added.
The mixture was extracted with EtOAc (3ϫ25 mL), and the com-
bined organic extracts were dried with sodium sulfate and filtered.
The solvent was evaporated under reduced pressure. Purification
of the residue by flash column chromatography (silica gel, CHCl3/
acetone, 2:1) afforded the title compound 18 (188 mg, 0.49 mmol,
99%) as a white solid. Rf = 0.37 (CHCl3/acetone, 2:1; UV/CAM).
1H NMR (600 MHz, CDCl3): δ = 7.17–7.15 (m, 4 H), 6.85 (d, J =
8.3 Hz, 4 H), 5.12 (d, J = 14.8 Hz, 1 H), 4.61 (d, J = 14.6 Hz, 1
H), 4.41 (d, J = 14.6 Hz, 1 H), 4.06 (d, J = 6.5 Hz, 1 H), 4.03 (d,
J = 4.1 Hz, 1 H), 4.00 (dd, J = 10.8, 1.4 Hz, 1 H), 3.89–3.85 (m, 2
H), 3.78 (s, 3 H), 3.78 (s, 3 H), 3.73 (d, J = 17.2 Hz, 1 H), 2.83 (br.
55.8, 42.0, 30.8 ppm. IR (diamond-ATR, neat): νmax = 2974, 2934,
˜
2900, 1640, 1584, 1511, 1501, 1467, 1406, 1375, 1349, 1221, 1204,
1191, 1125, 1082, 1064, 1040, 990, 964, 921, 818, 798, 749, 740,
718, 688, 668 cm–1. HRMS (ESI): calcd. for C16H19NO2Na [M +
Na]+ 280.1308; found 280.1309.
1,3-Dimethoxy-8-hydroxy-6-methyl-9,10-anthraquinone (39): To a
solution of 1,3,8-trimethoxy-6-methylanthracene-9,10-dione[15]
s, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 165.9, 165.4, 159.4, (288 mg, 0.92 mmol, 1.0 equiv.) in CH2Cl2 (13 mL) was added BBr3
159.3, 129.6, 129.5, 127.3, 127.0, 114.4, 114.2, 62.1, 61.3, 55.3, 55.2,
(1.0 m in CH2Cl2, 2.86 mL, 2.86 mmol, 3.1 equiv.) dropwise at
–5 °C. The dark red reaction mixture was warmed to room temp.
and stirred for 1 h. The mixture was then poured into ice/H2O, and
49.2, 48.8, 46.5 ppm. IR (diamond-ATR, neat): νmax = 3403, 2924,
˜
2837, 2360, 2342, 1901, 1650, 1611, 1584, 1511, 1468, 1440, 1417,
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
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Pages: 12
Evolution of a Synthetic Strategy for the Variecolortides
the resulting mixture was stirred for an additional 30 min. The lay-
ers were separated, and the aqueous layer was extracted with
CH2Cl2 (3ϫ15 mL). The combined organic layers were dried with
sodium sulfate, filtered, and concentrated under reduced pressure.
The resulting red-brown solid was then purified by flash column
chromatography (silica gel, CHCl3/acetone, 100:1 Ǟ 25:1) to afford
39 (200 mg, 0.67 mmol, 73%) as a bright orange solid; m.p. 202–
205 °C. Rf = 0.64 (CHCl3/acetone, 20:1; UV/CAM). 1H NMR
(600 MHz, CDCl3): δ = 7.55 (dd, J = 1.5, 0.4 Hz, 1 H), 7.44 (d, J
= 2.5 Hz, 1 H), 7.06 (dd, J = 1.6, 0.8 Hz, 1 H), 6.77 (d, J = 2.5 Hz,
1 H), 4.02 (s, 3 H), 3.98 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 187.4, 182.9, 165.2, 162.9, 162.6, 146.9,
137.6, 132.3, 124.8, 120.0, 115.2, 114.7, 104.7, 103.9, 56.6, 56.0,
1165, 1136, 1039, 983, 949, 896, 851 cm–1. HRMS (ESI): calcd. for
C35H37N4O12 [M + H]+ 705.2402; found 704.2406.
1-Benzyl-3-methylenepiperazine-2,5-dione (47): To a solution of
(S)-1-benzyl-3-(hydroxymethyl)piperazine-2,5-dione
(400 mg,
1.7 mmol, 1.0 equiv.) in dry pyridine (17 mL) was added meth-
anesulfonyl chloride (224 μL, 2.9 mmol, 1.7 equiv.) dropwise at
0 °C. The resulting yellow reaction mixture was stirred at this tem-
perature for 2 h, and then MeOH (5 mL) was added. The solution
was warmed to room temp., and the solvent was removed in vacuo.
To the residue was added water (10 mL), and the aqueous layer
was extracted with CHCl3 (3ϫ 10 mL). The combined organic lay-
ers were dried with sodium sulfate, filtered, and concentrated under
reduced pressure to give the crude (S)-(4-benzyl-3,6-dioxopipera-
zin-2-yl)methyl methanesulfonate, which was directly used in the
next step without further purification. The crude mesylate was dis-
solved in dry CH2Cl2 (25 mL), and triethylamine (547 μL) was
added dropwise at room temp. The solution was stirred at room
temp. for 20 h, and then a saturated aqueous solution of NH4Cl
(25 mL) was added. The organic layer was separated, dried with
sodium sulfate, filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography (silica gel, hexanes/
EtOAc, 1:2) provided 47 (270 mg, 1.25 mmol, 73% over 2 steps) as
a white solid; m.p. 163 °C dec. Rf = 0.33 (hexanes/EtOAc, 1:3; UV/
22.0 ppm. IR (diamond-ATR, neat): νmax = 2946, 2845, 1669, 1626,
˜
1592, 1553, 1493, 1362, 1322, 1263, 1218 cm–1. HRMS (ESI): calcd.
for C17H15O5 [M + H]+ 299.0914; found 299.0914.
8-Hydroxy-1,3-dimethoxy-6-methyl-10H-anthracen-9-one (40):
A
solution of 39 (573 mg, 1.92 mmol, 1.0 equiv.) in glacial acetic acid
(75 mL) was heated to 65 °C. After the addition of a solution of
SnCl·2H2O (3.47 g, 15.4 mmol, 8 equiv.) in concentrated aqueous
HCl (15 mL), the resulting mixture was stirred at 65 °C. After 1 h,
the reaction mixture was poured into ice/H2O (100 mL), and the
resulting mixture was stirred for an additional hour. The mixture
was then extracted with CHCl3 (2ϫ 70 mL), and the combined
organic layers were washed with water (100 mL), dried with sodium
sulfate, and concentrated in vacuo. Purification of the residue by
flash column chromatography (silica gel, CHCl3/acetone, 100:1 Ǟ
5:1) provided 40 (450 mg, 1.58 mmol, 82%) as a brown solid; m.p.
176–180 °C. Rf = 0.54 (CHCl3/acetone, 20:1; UV/CAM). 1H NMR
(600 MHz, CDCl3): δ = 13.32 (s, 1 H), 6.66–6.61 (m, 2 H), 6.47–
6.44 (m, 2 H), 4.23 (s, 2 H), 3.97 (s, 3 H), 3.89 (s, 3 H), 2.33 (s, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 188.7, 164.2, 163.3,
162.8, 146.0, 145.7, 139.8, 118.5, 115.7, 115.3, 114.6, 104.2, 97.7,
1
CAM). H NMR (300 MHz, CDCl3): δ = 9.19 (br. s, 1 H), 7.39–
7.27 (m, 5 H), 5.70 (s, 1 H), 4.92 (d, J = 0.6 Hz, 1 H), 4.66 (s, 2
H), 3.99 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.4,
157.3, 134.8, 132.8, 129.0, 128.6, 128.3, 103.4, 50.0, 49.5 ppm. IR
(diamond-ATR, neat): ν
= 3183, 3063, 3028, 2923, 1675, 1622,
˜
max
1494, 1472, 1454, 1417, 1328, 1220, 1176, 1081, 1026, 978, 942,
855, 829, 800, 780, 756, 696, 654 cm–1. HRMS (EI): calcd. for
C12H12N2O2 [M]+· 216.0899; found 216.0891.
Diels–Alder Adduct 48: No precautions were taken to exclude oxy-
gen from the reaction vessel. To a mixture of 1,4-anthraquinone
34 (15 mg, 50.3 μmol, 1.0 equiv.) and diketopiperazine 47 (11 mg,
50.9 μmol, 1.01 equiv.) in a pressure tube was added ortho-dichloro-
benzene (1.5 mL), and the dark purple reaction mixture was heated
to 210 °C. After 1 h, the mixture was cooled to room temp. and
directly subjected to flash column chromatography (silica gel, elut-
ing first with hexanes to remove o-dichlorobenzene and then
CHCl3/acetone, 10:1 Ǟ 5:1 Ǟ 1:1) to afford the title compound 48
(10 mg, 19.5 μmol, 39%) as an orange solid. Rf = 0.50 (CHCl3/
MeOH, 10:1; UV/CAM). 1H NMR (400 MHz, [D6]DMSO): δ =
13.02 (s, 1 H), 9.68 (s, 1 H), 7.42–7.38 (m, 3 H), 7.35–7.31 (m, 3
H), 7.25 (s, 1 H), 6.87 (d, J = 0.7 Hz, 1 H), 6.81 (d, J = 2.2 Hz, 1
H), 4.82 (d, J = 15.0 Hz, 1 H), 4.55 (d, J = 15.0 Hz, 1 H), 4.29 (d,
J = 17.8 Hz, 1 H), 3.99 (s, 3 H), 3.96 (d, J = 17.8 Hz, 1 H), 3.92
(s, 3 H), 2.18 (d, J = 0.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 186.4, 166.5, 164.5, 163.3, 162.6, 156.2, 138.0,
137.6, 135.8, 134.2, 128.7, 127.4, 126.4, 120.5, 119.1, 116.6, 112.4,
110.4, 100.5, 100.3, 83.8, 56.2, 56.1, 49.5, 48.8, 15.5 ppm. IR (dia-
56.2, 55.5, 33.9, 21.9 ppm. IR (diamond-ATR, neat): ν
= 3018,
˜
max
2951, 1630, 1599, 1504, 1334, 1257, 1224, 1094, 825 cm–1. HRMS
(EI): calcd. for C17H16O4 [M]+· 284.1043; found 284.1043.
Radical Adduct 42: To a solution of 40 (10 mg, 35 μmol, 1.0 equiv.)
in a mixture of DMSO (1.0 mL) and water (0.5 mL) was added 20
(8.1 mg, 38.5 μmol, 1.1 equiv.). The inner atmosphere of the flask
was exchanged with oxygen, and then the reaction mixture was
allowed to stir under an O2 atmosphere (double-layer balloon) at
room temp. After 20 h, the reaction mixture was concentrated in
vacuo, and the residue was purified by flash column chromatog-
raphy (silica gel, CHCl3/acetone, 50:1 Ǟ 1:1) to afford 42 (9.8 mg,
1.39 μmol, 40%) as a 1:1 mixture of diastereoisomers. Rf = 0.36
(CHCl3/acetone, 3:1; UV/CAM). 1H NMR (600 MHz, CDCl3): δ
= 13.98 (s, 1 H), 13.89 (s, 1 H), 6.77 (d, J = 2.2 Hz, 1 H), 6.75–
6.74 (m, 2 H), 6.68–6.66 (m, 4 H), 6.59 (d, J = 2.2 Hz, 1 H), 4.90–
4.84 (m, 3 H), 4.82 (s, 1 H), 4.72 (dd, J = 8.8, 6.6 Hz, 1 H), 4.69
(dd, J = 10.6, 5.9 Hz, 2 H), 4.61 (dd, J = 11.2, 5.6 Hz, 1 H), 4.07
(s, 3 H), 4.05 (s, 3 H), 4.04 (s, 3 H), 3.98 (s, 3 H), 3.82 (dd, J =
18.7, 5.8 Hz, 2 H), 3.79 (d, J = 18.7 Hz, 2 H), 2.67–2.60 (m, 4 H),
2.53–2.48 (m, 4 H), 2.41 (s, 3 H), 2.37 (s, 6 H), 2.36 (s, 3 H), 2.27
(s, 3 H), 2.27 (s, 3 H), 2.19 (s, 3 H), 2.10 (s, 6 H), 2.08 (s, 3 H) ppm.
mond-ATR, neat): νmax = 2922, 2852, 1672, 1599, 1490, 1453, 1376,
˜
1329, 1246, 1226, 1161, 1043, 1027, 979, 950, 926, 869, 822, 800,
732, 699 cm–1. HRMS (EI): calcd. for C29H24N2O7 [M]+· 512.1584;
found 512.1575.
13C NMR (150 MHz, CDCl3): δ = 187.5, 187.5, 170.8, 170.7, 170.7, Dimethyl Variecolortide B (52): No precautions were taken to ex-
170.5, 170.1, 165.8, 165.7, 165.7, 165.4, 165.3, 165.0, 164.6, 164.4,
163.7, 163.7, 163.4, 163.3, 146.5, 145.9, 145.6, 145.1, 141.0, 140.2,
118.0, 117.9, 117.7, 116.6, 116.3, 115.4, 115.4, 114.2, 102.3, 102.0,
99.7, 98.7, 56.5, 56.4, 55.9, 55.8, 55.0, 54.8, 54.3, 48.3, 48.0, 47.5,
46.7, 46.6, 46.6, 42.3, 42.3, 26.6, 26.6, 26.5, 26.5, 26.5, 26.3, 22.1,
clude oxygen from the reaction vessel. A pressure tube was charged
with hydroxyviocristin dimethyl ether (34, 12.7 mg, 42.4 μmol,
1.0 equiv.), neoechinulin B (51, 15 mg, 46.7 μmol, 1.1 equiv.), and
ortho-dichlorobenzene (1.5 mL). The pressure tube was sealed, and
the reaction mixture was heated at 180 °C for 1.25 h and then sub-
sequently cooled to room temp. The crude product was subjected
directly to flash column chromatography (silica gel, eluting first
22.0 ppm. IR (diamond-ATR, neat): νmax = 3009, 2938, 2846, 1706,
˜
1631, 1597, 1568, 1498, 1453, 1416, 1366, 1325, 1310, 1253, 1201,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O20712
/KAP1
Date: 13-08-12 12:17:49
Pages: 12
C. A. Kuttruff, P. Mayer, D. Trauner
FULL PAPER
with hexanes to remove o-dichlorobenzene and then CHCl3/acet-
one, 20:1 Ǟ 10:1 Ǟ 1:1) to afford the title compound 52 (8.8 mg,
9.98 (s, 1 H), 9.55 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.44 (d, J =
8.0 Hz, 1 H), 7.17 (d, J = 2.9 Hz, 1 H), 7.17 (s, 1 H), 7.11–7.09 (m,
1 H), 7.06–7.03 (m, 1 H), 6.87 (s, 1 H), 6.87 (s, 1 H), 6.68 (d, J =
14.2 μmol, 34%) as an orange solid. Rf = 0.52 (CHCl3/acetone, 5:1;
1
UV/CAM). H NMR (600 MHz, [D6]DMSO): δ = 13.04 (s, 1 H), 2.0 Hz, 1 H), 6.11 (dd, J = 17.6, 10.3 Hz, 1 H), 5.09 (dd, J = 10.4,
11.14 (s, 1 H), 10.00 (s, 1 H), 9.56 (s, 1 H), 7.46–7.45 (m, 1 H),
7.45–7.44 (m, 1 H), 7.38 (d, J = 2.3 Hz, 1 H), 7.24 (s, 1 H), 7.17 (s, 3 H), 1.53 (s, 3 H), 1.49 (s, 3 H) ppm. 13C NMR (150 MHz,
(s, 1 H), 7.10 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H), 7.05 (ddd, J = 7.9, [D6]DMSO): δ = 186.3, 163.7, 163.6, 161.6, 161.5, 156.2, 145.1,
7.1, 1.0 Hz, 1 H), 6.89 (d, J = 0.8 Hz, 1 H), 6.82 (d, J = 2.2 Hz, 1 144.9, 137.8, 137.6, 135.1, 134.1, 126.8, 126.3, 123.8, 120.8, 119.4,
H), 6.11 (dd, J = 17.6, 10.3 Hz, 1 H), 5.09 (dd, J = 17.6, 1.2 Hz, 1 119.4, 119.1, 118.9, 117.0, 114.5, 111.8, 111.5, 111.1, 110.4, 104.0,
1.1 Hz, 1 H), 5.09 (dd, J = 17.6, 1.1 Hz, 1 H), 3.88 (s, 3 H), 2.24
H), 5.09 (dd, J = 10.3, 1.2 Hz, 1 H), 3.99 (s, 3 H), 3.93 (s, 3 H), 102.4, 100.9, 83.9, 55.9, 40.0, 27.9, 27.3, 15.7 ppm. IR (diamond-
2.25 (d, J = 0.7 Hz, 3 H), 1.53 (s, 3 H), 1.49 (s, 3 H) ppm. 13C ATR, neat): νmax = 3220, 2967, 2925, 2360, 2342, 1685, 1615, 1578,
˜
NMR (150 MHz, [D6]DMSO): δ = 186.5, 164.5, 163.3, 161.4,
161.4, 156.2, 145.1, 144.9, 137.9, 137.8, 135.2, 134.3, 126.6, 126.3,
123.7, 120.8, 120.0, 119.4, 119.4, 119.1, 116.9, 114.5, 112.4, 111.8,
111.5, 110.5, 103.9, 100.5, 100.3, 84.0, 56.2, 56.0, 40.4, 27.9, 27.4,
15.7 ppm. HRMS (ESI): calcd. for C36H33N3O7 [M – H]– 616.2089;
found 616.2073.
1456, 1365, 1333, 1239, 1222, 1207, 1170, 1121, 1049, 1022, 1001,
915, 899, 882, 820, 748 cm–1. HRMS (ESI): calcd. for C35H30N3O7
[M + H]+ 604.2078; found 604.2089.
CCDC-883797 (for 16), -883798 (for 20), -883796 (for 26), -883856
(for 34), -883799 (for 42) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acetyl Viocristin 54: To a suspension of sodium hydride (60% dis-
persion in mineral oil, 22 mg, 0.55 mmol, 2.4 equiv.) in dry THF
(5 mL) was added anhydride 53[13] (57 mg, 228 μmol, 1.0 equiv.) at
0 °C, and the resulting suspension was stirred at this temperature
for 20 min. Then, a solution of 2-chloro-5-methyl-1,4-benzoquin-
one (42.8 mg, 273 μmol, 1.2 equiv.) in dry THF (5 mL) was added
at 0 °C. The red suspension was warmed to room temp., and a
saturated aqueous solution of NH4Cl (10 mL) was added. The re-
action mixture was extracted with CHCl3 (3ϫ15 mL), and the
combined organic layers were dried with sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (silica gel, CHCl3/acetone, 10:1) to yield 54
(41.2 mg, 126 μmol, 55%) as a purple solid; m.p. Ͼ 215 °C dec.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all of the key
intermediates and final products as well as the X-ray crystal struc-
tures.
Acknowledgments
We thank Dr. Mario Waser (Johannes Kepler University Linz) for
his generous donation of emodin.
1
Rf = 0.33 (CHCl3/acetone, 80:1; UV/CAM). H NMR (400 MHz,
CDCl3): δ = 14.86 (s, 1 H), 7.91 (s, 1 H), 7.26 (s, 1 H), 6.87 (q, J
= 1.5 Hz, 1 H), 6.79 (d, J = 2.1 Hz, 1 H), 4.03 (s, 3 H), 2.37 (s, 3
H), 2.19 (d, J = 1.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 188.5, 184.4, 168.7, 164.8, 161.2, 153.0, 149.8, 139.1, 137.2,
128.5, 121.5, 116.2, 114.3, 109.0, 104.7, 56.5, 21.2, 16.6 ppm. IR
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(diamond-ATR, neat): ν
= 3093, 3009, 2975, 2945, 2920, 2848,
˜
max
2362, 2341, 1760, 1667, 1640, 1589, 1446, 1427, 1394, 1341, 1276,
1242, 1190, 1146, 1121, 1025, 1001, 975, 912, 890, 873, 824, 811,
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Variecolortide C (7): Note: no precautions were taken to exclude
oxygen from the reaction vessel. To a mixture of acetyl viocristin 54
(23.7 mg, 72.6 μmol, 1.1 equiv.) and neoechinulin B (51, 21.2 mg,
65.9 μmol, 1.0 equiv.) in a pressure tube was added o-dichloroben-
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180 °C (in a preheated oil bath). After 1 h, the reaction mixture was
cooled to room temp. and then directly subjected to flash column
chromatography (silica gel, eluting first with hexanes to remove o-
dichlorobenzene and then CHCl3/acetone, 40:1 Ǟ 20:1 Ǟ 10:1Ǟ
1:1) to afford acetyl variecolortide C (55), which was used directly
in the next step without further purification. To an orange solution
of 55 in MeOH (3 mL) was added potassium carbonate (8 mg) at
room temp. The resulting brown reaction mixture was stirred for
1 h, and then saturated aqueous NH4Cl (1.5 mL) and water
(1.5 mL) were added. The mixture was extracted with CHCl3
(3ϫ15 mL), and the combined organic extracts were dried with
sodium sulfate, filtered, and concentrated under reduced pressure.
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gel, CHCl3/acetone, 10:1 Ǟ CHCl3/MeOH, 10:1) afforded variecol-
ortide C (7, 11 mg, 18.2 μmol, 28% over 2 steps) as an orange solid.
Rf = 0.39 (CHCl3/MeOH, 5:1; UV/CAM). 1H NMR (600 MHz,
[D6]DMSO): δ = 13.12 (s, 1 H), 11.14 (s, 1 H), 10.89 (br. s, 1 H),
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10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20712
/KAP1
Date: 13-08-12 12:17:49
Pages: 12
Evolution of a Synthetic Strategy for the Variecolortides
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Received: May 28, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20712
/KAP1
Date: 13-08-12 12:17:49
Pages: 12
C. A. Kuttruff, P. Mayer, D. Trauner
FULL PAPER
Total Synthesis
Variations on a theme by Aspergillus varie-
color: The concise total syntheses of the va-
riecolortides, in particular of variecolor-
tide C, are presented.
C. A. Kuttruff, P. Mayer,
D. Trauner* ..................................... 1–12
Evolution of a Synthetic Strategy for the
Variecolortides
Keywords: Total synthesis / Natural prod-
ucts / Cycloaddition / Biomimetic syn-
thesis
/ Domino reactions / Cascade
reactions
12
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Eur. J. Org. Chem. 0000, 0–0