Total synthesis of blennolide mycotoxins: Design, synthetic routes and completion

Article abstract of DOI:10.1002/ejoc.201402083

Mycotoxins of the tetrahydroxanthone class of natural products possess a large number of interesting biological properties. In this full paper, we present our synthetic strategy to some members of this class of compounds, namely the blennolides A and C. We disclose the scope and limitations of the functionalization of various xanthones derived from a domino oxa-Michael-aldol condensation and pursue dimerization of these xanthones. Furthermore, the first crystal structure of blennolide C has been obtained.

Full text of DOI:10.1002/ejoc.201402083

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
FULL PAPER
DOI: 10.1002/ejoc.201402083
Total Synthesis of Blennolide Mycotoxins: Design, Synthetic Routes and
Completion
Anne C. Meister,[a][‡] Arantxa Encinas,[a]
Hülya Sahin,[a][‡‡] Emilie M. C. Singer,[a][‡‡‡] Carl F. Nising,[a][‡‡‡‡] Martin Nieger,[b] and
Stefan Bräse*[a,c]
Dedicated to the memory of Professor Karsten Krohn
Keywords: Total synthesis / Natural products / Domino reactions / Michael addition / Lactones
Mycotoxins of the tetrahydroxanthone class of natural prod-
ucts possess a large number of interesting biological proper-
ties. In this full paper, we present our synthetic strategy to
some members of this class of compounds, namely the
blennolides A and C. We disclose the scope and limitations
of the functionalization of various xanthones derived from a
domino oxa-Michael-aldol condensation and pursue dimeri-
zation of these xanthones. Furthermore, the first crystal struc-
ture of blennolide C has been obtained.
tetrahydroxanthones. They possess a huge variety of bio-
logical activities including antibacterial, toxic, mutagenic,
teratogenic, and HIV protease inhibiting activities.[3–10]
Xanthonol (4), an unsymmetrical dimeric tetrahydroxan-
thone, has insecticidal and anthelmintic activities.[11] The
symmetrical dimer rugulotrosin A (5) has antibacterial ac-
tivities.[12] So far, several monomeric tetrahydroxanthones
have been synthesized. Blennolide C has been synthesized
by our group,[13] Nicolaou and Li,[14] and by Porco et al.[15]
Blennolide B has also been synthesized by Porco et al.
through the same synthetic pathway used for blennolide C.
Blennolide A has recently been synthesized by Tietze et
al.[16] The first route to homodimeric tetrahydroxanth-
enones has been published very recently by Porco et al.,
who synthesized secalonic acids A and D through a cop-
per(I)-mediated dimerization of stannanes.[17] Another di-
meric xanthone derivative, paecilin A, has also recently
been synthesized by Tietze et al.[18]
In the present work, we focus on the synthesis of blennol-
ides A and C and present several attempts to access the
homo- and hetero-dimeric natural products 3–5. As an ex-
ample, our retrosynthesis of secalonic acid E (3) is shown
in Scheme 1. The dimer could be formed either by cross
coupling (X = halide, triflate) or by enzymatic oxidative
coupling (X = H) from the highly substituted tetra-
hydroxanthone 7. The substituent on position C-4a can be
introduced by nucleophilic addition to compound 8, which
is accessible from the simple building blocks 9 and 10
through a domino oxa-Michael-aldol condensation,[19] fol-
lowed by functionalization steps.
Introduction
Tetrahydroxanthones are a family of monomeric and di-
meric natural products with interesting biological activities.
The family of blennolides consists of seven members (A–
G), of which only blennolide G is dimeric. All the com-
pounds were isolated in 2008 from a fungus from Blennoria
sp. Blennolides A (1) and B show antifungal, antibacterial,
and antialgal activity (Figure 1).[1] The dimeric secalonic
acids (3), isolated about 100 years ago from the fungus Cla-
viceps purpura, also known as ergot,[2] were the first known
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
http://www.ioc.kit.edu/braese/
[b] Laboratory of Inorganic Chemistry, Department of Chemistry,
University of Helsinki,
P. O. Box 55, 00014 Helsinki, Finland
[c] Institute of Toxicology and Genetics, Karlsruhe Institute of
Technology,
Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-
Leopoldshafen, Germany
[‡] Present address: Institut de Science et d’Ingénierie
Supramoléculaires, Université Strasbourg,
8 allée Gaspard Monge, 67083 Strasbourg, France
[‡‡] Present address: IoLiTec Ionic Liquids Technologies GmbH,
Salzstrasse 184, 74076 Heilbronn, Germany
[‡‡‡] Née Gérard; Present address: Symrise AG,
Mühlenfeldstr. 1, 37603 Holzminden, Germany
[‡‡‡‡] Present address: Bayer Pharma AG,
Friedrich-Ebert-Straße 475, 42117 Wuppertal, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402083.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
Figure 1. Some tetrahydroxanthone natural products: blennolide A (1), blennolide C (2), secalonic acid E (3), xanthonol (4), rugulotro-
sin A (5) and diversonol (6).
Scheme 2. Synthesis of model systems 13–15 for the Michael ad-
dition at C-4a. Reactions (a)–(d) have been previously re-
ported.[21,31] Reagents and conditions: (a) DABCO, H2O, sonic-
Scheme 1. Retrosynthetic analysis of dimeric tetrahydroxanthone 3.
ation, 48 h, 83%; (b) NBS, DMSO, room temp., 3 h, 80%;
(c) DABCO, dioxane, room temp., 14 h, 74%; (d) TPAP, NMO,
MeCN, CH2Cl2, sonication, 12 h, 79%; (e) NaBH4, CeCl3, MeOH,
0 °C, 46%.
Results and Discussion
Funtionalization of Tetrahydroxanthenones in the C-4a
Position
Tetrahydroxanthones such as those shown in Figure 1,
bear a substituent in position C-4a, the introduction of
which is challenging. Gabbutt et al. reported a method to
install an ester moiety at this position[20] with moderate
yield (35%), but its reproduction was not possible with a
yield better than 11%. For this reason, we investigated fur-
ther 1,4-addition methods to improve the yield and to allow
for a variety of substituents at this position.
Figure 2. Molecular structure of dione 14 (one crystallographic in-
dependent molecule is shown, displacement parameters are drawn
at 50% probability level).[22]
To this end, we first synthesized three model systems
(13–15; Scheme 2). Known Michael acceptor 13 (Scheme 2)
was synthesized in three steps from commercially available
salicylic aldehyde (11) and cyclohexenone (12).[21] Oxi-
dation to known dione 14 gave the second Michael
To afford the ester group at the C-4a position, nucleo-
acceptor,[21] and reduction of the C-1 ketone gave 15 as the philes that can easily be converted into the desired function-
third model system for 1,4-addition. It was also possible to ality were required for the 1,4-addition reaction. Among
obtain a crystal structure of dione 14 (Figure 2).
the appropriate nucleophiles considered for this kind of re-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
action, masked ketone, nitrile or olefin derivatives appeared was isolated as the only product. To selectively conduct the
to be the most likely to undergo this transformation. We 1,4-addition, the corresponding cuprate was prepared (reac-
tested the 1,4-addition methods with these nucleophiles first tion pathway e), but it proved to be unreactive and only
with dione 14, because it was expected to be most active starting material was recovered.
toward this reaction.
Addition of Sulfur-Stabilized Anions
We first tried to reproduce the 1,4-addition with tris-
(methylthio)methanide described by Gabbutt et al., but we
were not able to obtain the yield described (Scheme 3, reac-
tion pathway a). However, it was possible to convert 16 into
the corresponding methyl ester 17 (reaction pathway b) in
quantitative yield. The regioselectivity of the addition was
established by a crystal structure (Figure 3). Nevertheless,
due to the low yield of the 1,4-addition, we tested other
sulfur-stabilized carbanions as reagents for the Michael ad-
dition. The ethyl glyoxalate derivative 20, which is known
Figure 3. Molecular structure of ester 17 (displacement parameters
to add to poor Michael acceptors,[23] gave no reaction with
dione 14 and only starting material was recovered. To test
the viability of this method, masked acyl anions derived
from 1,3-dithianes were investigated next. Although their
addition to α,β-unsaturated ketones normally proceeds
through 1,2-addition, 1,4-addition reactions should be fa-
vored in polar solvents, at higher temperatures, and with
longer reaction times.[24] Thus, the lithium anion of 1,3-di-
thiane was reacted with dione 14 (reaction pathway d), but
1,2-addition took place and alcohol 21 (instead of enol 19)
are drawn at 50% probability level).[22]
Summarizing, only the previously reported tris(methyl-
thio)methanide reacted in a 1,4-addition to Michael ac-
ceptor 14.
Addition of Nitrile Derivatives
Hydrocyanation of the α,β-unsaturated carbonyl com-
pound 14 should open up a possibility to obtain carboxylic
acid 25 after hydrolysis of nitrile 24 (Scheme 4). First, KCN
was tested as a nucleophile in ethanol heated to reflux (reac-
tion pathway a), because this method had been reported for
sterically hindered enones.[25] However, after basic hydroly-
sis, only destruction of the tetrahydroxanthone was ob-
served (in spite of modification of the reaction parameters:
H2O/EtOH, H2O/DMF, H2O/DMF + NH4Cl, addition of
crown ether 18-crown-6). For this reason, the milder
TMSCN was then used. It has been reported that this ni-
trile undergoes 1,4-addition in the presence of Lewis acids
such as AlEt2CN,[26] AlEt3,[27] AlCl3, or SnCl2.[28] We first
tried the 1,4-addition without the use of a Lewis acid (reac-
tion pathway c) and observed an addition product that
proved to be unstable. In a second attempt, the addition
product was directly subjected to methanolic hydrolysis, but
only nitrile 23 was obtained. Clearly, 1,2-addition of the
nitrile anion took place and gave the unstable cyanhydrin
22. After cleavage of the TMS protecting group, methyl
ether 23 was formed. A crystallographic analysis confirmed
this outcome (Figure 4). Surprisingly, conducting the same
reaction in the presence of the Lewis acid AlEt3 (reaction
pathway e) also gave 1,2-addition (instead of the nitrile, an
ethyl group was added, leading to alcohol 26). This out-
come was also obtained by employing a transition-metal-
catalyzed reaction with TMSCN and catalytic amounts of
PdII (reaction pathway f). Only 1,2-addition product 22 was
formed.
Scheme 3. Attempts of 1,4-addition by sulfur-stabilized carbanions.
Reactions (a) and (b) were reported by Gabbutt et al.[20,31] Reagents
and conditions: (a) nBuLi, HC(SMe)3, THF, –78 °C, 12 h, 11%;
(b) HgCl2, HgO, MeOH, room temp., 18 h, 99%; (c) LDA, 20,
THF, –78 °C to 0 °C, 18 h; (d) 1,3-dithiane, DMPU, nBuLi, THF,
–78 °C to 0 °C, 5 h, 67%; (e) 1,3-dithiane, nBuLi, CuCN, THF,
–78 °C, 2 h.
In conclusion, KCN ad TMSCN, which are both classi-
cal reagents for the hydrocyanation of enones, failed to add
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
Scheme 4. Addition of nitriles to dione 14. Reagents and conditions: (a) KCN, EtOH, 80 °C, 14 h; (b) KOH, EtOH, 60 °C, 4 d; (c) TMSCN,
MeCN, 0 °C to room temp., 18 h, 50% 22; (d) HCl, MeOH, room temp. to –30 °C, 16 h, 76% 23; (e) AlEt3, TMSCN, hexane, room
temp., 18 h, 26% 26; (f) TMSCN, Pd(OAc)2 (cat.), DMF, room temp., 18 h, 57% 22.
yllithium (reaction pathway c). After conversion into the
corresponding cuprate with copper(I) cyanide, the desired
1,4-addition product 29 was obtained with 66% yield. The
X-ray structure of this molecule proved the regioselectivity
of the addition (Figure 5). The addition of other cuprates
such as furyl cuprate could be advantageous because its
cleavage to the acid moiety was expected to be straightfor-
ward.[29] Regrettably, only the 1,2-addition product (alcohol
27, reaction pathway d) was obtained. A plausible explana-
tion to account for this unexpected selectivity is that the
furyllithium did not completely react with the CuCN to
form the cuprate. Hence, the remaining lithiated species is
more likely to attack the α,β-unsaturated ketone at the 2-
position. With ethyl vinyl ether[30] no reaction occurred and
the starting material was reisolated (reaction pathway e).
Figure 4. Molecular structure of nitrile 23 (one crystallographic in-
dependent molecule is shown, displacement parameters are drawn
at 50% probability level).[22]
to dione 14 in a 1,4-addition manner. The deactivation of
the 4a position, due to the presence of the heteroatom in
the α-position as well as the high reactivity of the carbonyl
group at the C-1, represents a major challenge for the intro-
duction of a substituent through 1,4-addition.
Addition of Olefin Moieties
Olefins can be transformed into other oxidized function-
alities such as aldehydes, acids and esters by, for example,
ozonolysis and corresponding work-up. The simplest olefin
that can be introduced is a vinyl moiety. In a first attempt,
vinylmagnesium bromide was treated with copper(I) brom-
ide to give the corresponding cuprate. This reacted with di-
one 14 (Scheme 5), but only the 1,2-addition product 30
was obtained in low yield (reaction pathway a). Using vinyl-
lithium instead offered access to another cuprate by conver-
sion with copper(I) cyanide (reaction pathway b). In this
case, the desired 1,4-addition product 31 was formed but it
was contaminated with tetraphenyltin, as a byproduct of
the synthesis of vinyllithium. Purification of the product
proved to be difficult and for these practical reasons the
addition of other olefins was examined. To this end, we
focused on the homologue propenyllithium, which was
Scheme 5. Additions of different vinyl reagents to dione 14. Reac-
tions (b)–(d) have been previously reported.[13,31] Reagents and con-
ditions: (a) CuBr·SMe2, vinylmagnesium bromide, TMEDA, THF,
–78 °C, 5 h, 26%; (b) tetravinyltin, phenyllithium, CuCN, Et2O,
–50 °C, 4 h, 51%; (c) propenyl bromide, tBuLi, CuCN, THF,
–78 °C, 5 h, 66%; (d) furyllithium, CuCN, THF, –78 °C, 5 h, 29%;
(e) ethyl vinyl ether, tBuLi, CuCN, THF, –78 °C, 5 h.
The most promising result from the experiments de-
much easier to access from propenyl bromide and tert-but- scribed above was the addition of propenyl cuprate, from
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
Figure 5. Molecular structure of olefin 29 (displacement param-
eters are drawn at 50% probability level).[22]
which olefin 29 was obtained. An efficient conjugated ad-
dition of a propenyl group at the 4a-position of a xanthone
core was thus achieved in 66% yield, in spite of the steric
hindrance and the sensitivity of the substrate.
Scheme 6. Different attempts to functionalize dione 29: ozonolysis
reactions. Reagents and conditions: (a) i. O3, CH2Cl2, –78 °C,
15 min; ii. NaBH4, room temp., 1 h; (b) i. O3, CH2Cl2, –78 °C,
15 min; ii. SMe2 or PPh3, room temp., 1 h; (c) i. O3, CH2Cl2,
–78 °C, 15 min; ii. NaOH/MeOH, room temp., 1 h; (d) (tBu)2Si-
(OTf)2, 2,6-lutidine, CH2Cl2, room temp., 6 h, 90%; (e) i. O3,
CH2Cl2, –78 °C, 15 min; ii. PPh3, room temp., 1 h; (f) mCPBA,
CH2Cl2, room temp., 1 h, 96%.
Oxidative Cleavage of the Olefin Moiety
We then conducted further experiments with 29 to inves-
tigate the oxidative cleavage of the olefin moiety. First, we
examined ozonolysis with different work-ups: reductive
(NaBH4 Ǟ32), semi-reductive (SMe2 or PPh3 Ǟ33), and
oxidative (NaOH/MeOH Ǟ17) to obtain the alcohol, the
aldehyde or the ester moiety, respectively (Scheme 6). How-
ever, because all these experiments resulted in destruction
of the molecule, protection of the sensitive enol moiety of
olefin 29 with a di-tert-butylsilyl group (35; reaction path-
way d) was pursued first. However, after ozonolysis, no
product 36 could be observed (reaction pathway e). Ozon-
olysis conditions seem to be too harsh for this molecule.
Thus, we tried a different approach: epoxidation of olefin
35.
iodate (reaction pathway b)[34] no product was isolated. As-
suming that these reaction conditions might be too harsh,
Epoxides can be converted into the corresponding alde-
hydes by treatment with periodic acid,[32] which would offer
another possibility to obtain aldehyde 33. However, when
35 was subjected to mCPBA, only the undesired silyl enol
ether 34 was formed (reaction pathway f). Probably, the silyl
ether is partially cleaved and the enol double bond is sub-
sequently epoxidized. The epoxide is opened when the
ketone forms again. This shows that the enol double bond
is more reactive than the olefinic double bond even through
the former is sterically more hindered. Therefore, this reac-
tion pathway was abandoned and other possibilities to ox-
idize the olefin moiety of 29 were investigated.
Scheme 7. Different oxidation reactions of olefin 29. Reaction (c)
has been previously reported.[13,31] Reagents and conditions:
(a) KMnO4, NaIO4, K2CO3, H2O/dioxane, room temp., 22 h;
(b) RuCl3 (cat.), NaIO4, MeCN/CCl4/H2O, room temp., 2 h;
(c) K2OsO4 (cat.), NaIO4, 2,6-lutidine, THF, H2O, room temp.,
24 h, 57%; (d) i. K2OsO4 (cat.), NaIO4, 2,6-lutidine, THF, H2O,
room temp., 24 h; ii. Me2NNH2, acetone, H2O, room temp., 2 h,
23%; (e) K2OsO4 (cat.), NMO, 2,6-lutidine, acetone, H2O, room
We then tried several transition-metal-mediated conver-
sions to oxidize olefin 29 into the corresponding carboxylic
acid or ester (Scheme 7). With potassium permanganate
and sodium periodate[33] (reaction pathway a) or with cata-
lytic amounts of ruthenium trichloride and sodium per- temp., 5 h.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
we pursued a two-step oxidation strategy. First, cleavage of addition to the Michael system a more stable molecule
the olefin into the aldehyde and second, oxidation to the would be formed, which would support harsher reaction
carboxylic acid (ester). With catalytic amounts of potas- conditions (e.g., ozonolysis). First, addition of 1,3-dithiane
sium osmate and sodium periodate,[35] aldehyde 33 was iso- anion to 13 and 15 was carried out (Scheme 9, reaction
lated in 57% yield. Presumably, the aldehyde is unstable, pathway a), but no desired product (43a or 45a) could be
because no starting material remained after the reaction. obtained. Subjecting Michael acceptors 13 and 15 to ad-
Therefore, in situ formation of hydrazone 37 was performed dition of propenyl cuprate [analogous to reaction pathway
after aldehyde formation (reaction pathway d). Regrettably, c) in Scheme 5], did not result in the formation of adducts
the yield was much lower, so the hydrazone formation does 43b or 45b. This was surprising because high yield of ad-
not seem to be a viable alternative. Another two-step pro- dition product was obtained with model system 14. The ad-
cedure involving dihydroxylation[36] of olefin 29 followed by dition of nitrile to both model systems also failed, and only
oxidative cleavage to obtain the aldehyde (reaction pathway protected silyl ethers 42 and 44 were formed. The reactivity
e) was then tested. Unfortunately, it was not even possible of these Michael acceptors seems to be too low for a suc-
to obtain the diol. The one-step procedure (reaction path- cessful 1,4-addition.
way c) therefore seemed to offer the best possibility of ob-
taining the desired aldehyde 33.
Derivatization of the Aldehyde Functionality
For natural products such as 1–5, a methyl ester is neces-
sary instead of the aldehyde. Therefore, several oxidation
methods were tested with aldehyde 33 (Scheme 8). Alkaline
iodine mediated oxidation[37] gave only aromatized com-
pound 40 (the regioselectivity could not be determined).
With NIS,[38] which is a milder reagent, the same undesired
product was obtained but in lower yield. By employing cal-
cium hypochlorite[39] only a small amount of acetal 39 was
formed. Finally, oxidation with oxone in methanol[40] gave
a very small amount of dimethyl acetal 41. With vanadium
pentoxide/hydrogen peroxide[41] or N-heterocyclic carb-
Scheme 9. Different 1,4-addition methods carried out on model
systems 13 and 15. Reagents and conditions: (a) 1,3-dithiane,
enes,[42] which are both methods that have been used to ox-
DMPU, nBuLi, THF, –78 °C to 0 °C, 5 h; (b) propenyl bromide,
tBuLi, CuCN, THF, –78 °C, 5 h; (c) TMSCN, MeCN, 0 °C to room
temp., 18 h, 52% 42; 81% 44.
idize aromatic aldehydes, only destruction of aldehyde 33
was observed.
In conclusion, a method has been developed to introduce
an aldehyde moiety at position C-4a in good yield through
the addition of propenyl cuprate to Michael acceptor 14
(Scheme 5 and Scheme 7). Unfortunately, no suitable meth-
ods for the subsequent oxidation of the aldehyde 33 into
the desired methyl ester 17 were found. Nevertheless, the
strategy developed is very modular and may be applied in
the preparation of other members of the tetrahydroxan-
thenone family.
Diastereoselective Synthesis of Blennolide C
The highly functionalized building block 47, the synthe-
sis of which has been described for the synthesis of di-
versonol,[43] was subjected to 1,4-addition with propenyl
cuprate (Scheme 10, reaction pathway a). The desired ad-
duct 46 could be obtained diastereoselectively, but with
lower yield than in the addition to the model system 14
(Scheme 5). This is probably due to the higher steric hin-
drance in dione 47 because of the adjacent polyether group.
Regrettably, it was not possible to oxidize olefin 46 into the
corresponding aldehyde by employing the method devel-
Scheme 8. Oxidation experiments for aldehyde 33. Reagents and
conditions: (a) I2, KOH, MeOH, room temp., 1 h, 50%; (b) NIS,
K2CO3, MeOH, room temp., 1 h, 39%; (c) Ca(ClO)2, AcOH, MS,
MeCN, MeOH, room temp., 1 h, 10%; (d) oxone, MeOH, 70 °C,
4 h, 5%.
1,4-Additions on Other Michael Acceptors
1,4-Additions were also carried out on the other model oped with the model system. It was also not possible to
systems 13 and 15 (Scheme 2). It was thought that after obtain an oxidation product of olefin 46 by other oxidation
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
methods such as those shown in the Schemes 6 and 7. The Building blocks for this natural product were salicylalde-
building block 47 was therefore subjected to the action of hyde 51 and the substituted cyclohexenone 52 (Scheme 11).
tris(methylthio)methanide anion, yielding orthothioester 48 The synthesis of aldehyde 51 is possible in two steps from
diastereoselectively.[20] Removal of the aromatic bromide by dimethoxybenzene,[44] whereas cyclohexenone 52 is access-
action of tBuLi (Ǟ49) and subsequent cleavage of the or- ible through a known, seven-step synthesis from d-quinic
thothioester with mercury salts, gave methyl ester 50. After acid.[45] Both building blocks were used in a domino oxa-
deprotection of the alcohol moieties with boron tribromide, Michael-aldol condensation and yielded the tetrahydroxan-
the resulting product was, according to analytical data, thone scaffold 53 as a mixture of two separable epimers.
identical to the natural product blennolide C (2).[1] In ad-
dition, crystal structure analysis proved that the synthesized
product was indeed the same as the natural product (Fig-
ure 6). Thus, a diastereoselective method has been devel-
oped to obtain the racemic natural product blennolide C.
Scheme 10. Addition of propenyl cuprate to building block 47 and
the total synthesis of blennolide C (2). Reactions already re-
ported.[13,31] Reagents and conditions: (a) propenyl bromide, tBuLi,
CuCN, THF, –78 °C, 5 h, 36%; (b) HC(SMe)3, nBuLi, THF,
–78 °C, 12 h, 20%; (c) tBuLi, THF, –78 °C, 30 min, 96%; (d) HgO,
HgCl, MeOH/H2O, room temp., 18 h; (e) BBr3, CH2Cl2, room
temp., 5 h, 23% over two steps.
Scheme 11. First steps of the total synthesis of blennolide A. Reac-
tion (a) was previously reported.[31,51] Reagents and conditions:
(a) N-methylimidazole, dioxane, H2O, sonication, 60 °C, 72 h, 38%
cis-53, 26% trans-53; (b) MEMCl, DIPEA, CH2Cl2, 40 °C, 1 h,
95% cis-54; 95% trans-54; (c) TBATB, THF, H2O, room temp.,
20 h, 56% trans-57; (d) DABCO, dioxane, room temp., 18 h, 48%
cis-56 over two steps.
Starting with the cis-epimer (cis-53), the alcohol was pro-
tected as MEM (methoxyethoxymethyl) ether (Ǟcis-54)
and bromohydrin formation (Ǟcis-55) was achieved by
using tetrabutylammonium tribromide (TBATB). In the
course of this reaction, bromination of the aromatic ring
also took place; however, this was not considered problem-
atic because removal with tBuLi in a later step was consid-
ered feasible. Tetrahydroxanthone trans-53 was subjected to
the same reactions and gave the protected species trans-54
in good yield. However, treatment with TBATB did not re-
sult in bromohydrin formation but in bromination of the
cyclohexanone ring (Ǟtrans-57). Consequently, further re-
actions were only carried out with the cis-epimer.
Elimination of HBr from cis-55 under basic conditions
yielded the α,β-unsaturated alcohol cis-56. Subsequent oxi-
dation to diketone 58 was performed under Ley conditions
by using tetrapropylammonium perruthenate (TPAP,
Scheme 12).[46] The so-formed diketone was then subjected
to 1,4-addition by the action of tris(methythio)methanide,
Figure 6. Molecular structure of blennolide C (2) (displacement pa-
rameters are drawn at 50% probability level).[22]
Total Synthesis of Blennolide A
The synthetic procedure towards blennolide C (2) was analogous to the 1,4-addition conducted for blennolide C
next applied to the total synthesis of blennolide A (1). (2) (Scheme 10). Unlike in the synthesis of blennolide C, in
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
this case the 1,4-addition did not proceed diastereoselec- synthesis of blennolide C (2) could be applied to the synthe-
tively and an inseparable mixture of trans-60 and cis-60 was sis of blennolide A (1), although its C-3-epimer was ob-
obtained (Scheme 12). In addition, this reaction did not tained. In the case of blennolide A, the method lacks both
show complete regioselectivity. HPLC analysis of the prod- diastereoselectivity and regioselectivity.
uct after purification by chromatography showed, besides
the two epimers of 1,4-addition product 60, the two possible
1,2-addition products 59 and 61. Both were also obtained
as a mixture of epimers, which explains the low yield of 1,4-
addition product 60. This diastereomeric mixture was used
for further reactions, analogous to those for blennolide C
(2).
Towards the Synthesis of Dimeric Tetrahydroxanthenones
To obtain the monomer of secalonic acid E (hemi-3, Fig-
ure 1), inversion of the stereogenic center C-4 of tetra-
hydroxanthone trans-53 was investigated. After inversion,
the same synthetic pathway used for the synthesis of epi-
blennolide A could be pursued to obtain hemi-3. With this
purpose, alcohol trans-53 was first mesylated to form a bet-
ter leaving group for a SN2 reaction (Scheme 14). Mesylated
compound 64, which was obtained in good yield, was then
subjected to substitution with different carboxylate salts.
Unfortunately, only elimination of the leaving group (Ǟ66)
took place and no inversion product 65 could be obtained.
This strategy did not seem to be target-oriented, therefore,
Mitsunobu inversion was envisaged. However, under dif-
ferent reaction conditions, substrate trans-53 decomposed
and no inversion (Ǟ65b) was observed.
Scheme 12. Synthesis of 1,4-addition product 60. Reagents and con-
ditions: (a) TPAP (cat.), NMO, MS, CH2Cl2, MeCN, 60 °C, 6 h,
76%; (b) HC(SMe)3, nBuLi, THF, –78 °C, 14 h, 2% cis-60, 12%
trans-60.
Debromination of the aromatic ring using tBuLi afforded
the desired product 62, again as a mixture of two insepa-
rable epimers (Scheme 13). Subsequent methanolysis of the
orthothioester using mercury salts gave methyl ester 63 as
the crude product, which was subjected directly to final de-
protection by BBr3. Thereby a mixture of two epimers was
formed, in which the main isomer (trans-1) corresponded
to C-3-epi-blennolide A (Figure 1).
Scheme 14. Different conditions for the inversion of stereogenic
center C-4. Reagents and conditions: (a) MsCl, pyridine, room
temp., 27 h, 69%; (b) CsOAc, DMF, room temp. to 80 °C;
(c) CsOAc, DMAP, toluene, 110 °C; (d) PhCO2H, CsF, DMF,
90 °C; (e) PhCO2Na; DMF, room temp. to 80 °C; (f) DEAD, PPh3,
p-nitrobenzoic acid, THF; (g) DIAD, PPh3, p-nitrobenzoic acid,
THF; (h) DEAD, polymer bound PPh3, p-nitrobenzoic acid, THF.
Scheme 13. Synthesis of natural product blennolide A (1) as a mix-
ture of epimers (C-4a). Reagents and conditions: (a) tBuLi, THF,
–78 °C, 30 min, 68%; (b) HgO, HgCl, MeOH/H2O, room temp.,
18 h; (c) BBr3, CH2Cl2, room temp., 5 h, 19% over two steps.
An explanation for the failure of the inversion reactions
(Scheme 14) could be the ring strain. If the substituents at
Unfortunately, it was not possible to obtain pure trans- positions C-3 and C-4 are arranged trans to each other, they
1, either by column chromatography or by preparative TLC can be in a pseudo-equatorial position (pseudo because the
or HPLC. In conclusion, the method developed for the total six-membered ring in trans-53 or 64 does not form a perfect
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
chair due to two sp2 centers). Inversion would result in tion of simple model systems by phenolic oxidation with
higher ring strain and it is therefore disfavored.
[K2Fe(CN)6] or by Suzuki coupling.[50] Now we focused on
Another possibility to invert the stereogenic center at C- dimerization with functionalized tetrahydroxanthones to
4 is oxidation of the alcohol to the corresponding ketone proceed towards dimeric natural products. First, natural
(Ǟ68)
and
subsequent
stereoselective
reduction product xanthonol (4) was envisaged. To this end, a methyl-
(Scheme 15). Before this, the carbonyl group at position C- ene alcohol was required in position C-4a for one of the
1 had to be protected by conversion into the enol and sub- monomers. On the model system 33, it was possible to per-
sequent protection by a silyl ether (Ǟ67). With TBDMS form a reduction of the aldehyde to alcohol 72 (Scheme 16,
triflate and the base DIPEA or 2,6-lutidine, twice protected reaction pathway a). For the natural product, fully func-
product 69 was obtained together with the C-4-OH pro- tionalized orthothioester 48 was chosen (Scheme 10). This
tected 70. However, decreasing the reaction temperature to compound already carries a bromide substituent at position
0 °C instead of room temperature gave the desired silyl C-7, where the later dimerization should take place. Dimer-
ether 67 in quantitative yield. Next, several oxidation meth- ization through Suzuki coupling should therefore be pos-
ods were tested to obtain ketone 68. Under Swern condi- sible. First, the orthothioester functionality was converted
tions[47] or with DMP[48] decomposition of the substrate into the corresponding ester 73 in the presence of mer-
was observed. Under Ley conditions,[46] no reaction oc- cury(II) salts. Subsequent reduction of the ester moiety to
curred and the substrate was reisolated. 2,2,6,6-Tetrameth- the alcohol 74 was not possible under different conditions
ylpiperidine-1-oxyl (TEMPO) mediated oxidation in the and only destruction of the substrate was observed. For this
presence of bromide[49] also did not result in oxidation of reason, we abandoned this route to obtain the natural prod-
the alcohol, but bromination of the enol (Ǟ71). Probably, uct xanthonol.
position C-4 is sterically too hindered for an oxidation,
which could also be a reason for the failure of the inversion duce a methylene alcohol at position C-4a.[51] Currently,
reactions. further investigation towards the synthesis of xanthonol,
We have recently presented a different method to intro-
The next step towards the total synthesis of dimeric employing this method, are being carried out in our group.
tetrahydroxanthone natural products such as the secalonic In addition, ester 73, which could be obtained in good yield
acids (3) or xanthonol (4) was the investigation of dimeriza- from 48, is a valuable building block for the synthesis of
tion possibilities. In the past, we have shown the dimeriza- dimeric natural product rugulotrosin A (5; Figure 1).
Scheme 15. Protection of carbonyl group of trans-53 and subsequent oxidation trials of the secondary alcohol in 67. Reagents and
conditions: (a) TBDMSOTf, 2,6-lutidine, 0 °C, 1.5 h, 99%; (b) DMSO, (COCl)2, NEt3, –78 °C; (c) DMP, CH2Cl2, 0 °C to room temp.;
(d) TPAP, NMO, CH2Cl2, MeCN, 60 °C; (e) KBr, NaOCl, TEMPO, CH2Cl2, 0 °C to room temp., 45% 71.
Scheme 16. Synthesis of alcohol 72 and of the highly functionalized ester 73. Reaction (a) was previously reported.[31] Reagents and
conditions: (a) NaBH4, MeOH/EtOH, 0 °C, 67%; (b) HgCl2, HgO, MeOH/H2O, room temp., 18 h, 99%.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
For secalonic acids, the corresponding brominated build-
ing block is necessary. It is not formed in the synthesis of
epi-blennolide A, because bromination takes place at posi-
tion C-5 instead of position C-7 (Scheme 11). Therefore, it
was necessary to introduce the desired bromine substituent
at the very beginning of the synthesis. Starting with 6-meth-
oxysalicylaldehyde (51), brominated compound 76 was syn-
thesized in three steps by silylation of the alcohol (Ǟ75),
regioselective bromination of the aromatic ring with N-
bromosuccinimide (NBS) and final deprotection of the silyl
ether (Scheme 17).
Figure 7. Molecular structure of cis-77 (displacement parameters
are drawn at 50% probability level).[22]
Scheme 17. Synthesis of brominated building block 76. Reagents
and conditions: (a) TBDPSCl, DIPEA, CH2Cl2, room temp., 24 h,
53%; (b) NBS, CH2Cl2, 40 °C, 4 h, 35%; (c) TBAF, THF, room
temp., 2 h, 56%.
opening, followed by elimination in situ was anticipated to
provide the desired Michael system 81 (Scheme 19). Epox-
idation of MEM-protected cis-79 was achieved with
hydrogen peroxide in good yield (Ǟ80). The epoxide open-
ing (Ǟ81) is currently under investigation.
With the brominated salicylaldehyde 76 in hand, we con-
ducted the domino oxa-Michael-aldol condensation
(Scheme 18). The yield was much higher than for other
domino oxa-Michael-additions and a separable mixture of
the two isomers trans-77 and cis-77 was obtained. The abso-
lute configuration of the enantiopure cis-77 could be deter-
mined by X-ray crystal structure determination, by using
the effects of anomalous dispersion (Figure 7).[52] Sepa-
rately, both isomers were subjected to MEM protection,
yielding trans-79 and cis-79. Bromohydrin formation by the
action of tetrabutylammonium tribromide (TBATB) failed,
not only with the MEM-protected trans-isomer (as already
experienced with the model system, see Scheme 11), but
also with its epimer cis-79. Instead, bromination in the α-
position to the carbonyl group took place (Scheme 11).
Scheme 19. Epoxidation of MEM-protected 79. Reagents and con-
ditions: (a) H2O2, NaOH, CH2Cl2, room temp., 2 h, 71%.
To investigate dimerization conditions, we synthesized
first some model systems (Scheme 20). Thus, domino oxa-
Michael-aldol condensation was performed with different
salicylaldehydes and cyclohexenones. Because bromination
of the aromatic ring occurred automatically during bromo-
hydrin formation (Scheme 11), we assumed that it could
be possible to start from unsubstituted salicyl aldehydes 51
and 82. The corresponding tetrahydroxanthones 83 and 84
were obtained in moderate yield. We then tried to form the
bromohydrin and, in the same step, brominate the aromatic
ring at position C-7. With tetrahydroxanthone 83, bromina-
tion at the aromatic ring took place, but at C-5 instead of
C-7 (Ǟ85). This could be a precursor for other dimeric
tetrahydroxanthones such as the phomoxanthones,[53] but it
was not useful for the synthesis of secalonic acids and its
further conversions were therefore not investigated. Methyl-
Scheme 18. Domino oxa-Michael-aldol condensation with brom-
inated salicylaldehyde 76 and subsequent conversions. Reagents and
conditions: (a) N-methylimidazole, dioxane/H2O (1:2), sonication,
60 °C, 18 h, 53% cis-77; 27% trans-77; (b) MEMCl, DIPEA,
CH2Cl2, 60 °C, 1 h, 85% cis-79; 82% trans-79; (c) TBATB, THF/
H2O, room temp., 16 h.
Because bromohydrin formation was not successful, an- substituted tetrahydroxanthone 84 was also subjected to
other reaction sequence was investigated. Introduction of bromohydrin formation and both the C-5 and the C-7 posi-
the oxygen moiety at position C-9 was expected to be tion were brominated (Ǟ86). Although it was possible to
achieved by epoxidation of the double bond. Basic epoxide perform elimination to the Michael system 87, this model
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
system was not further studied because two bromo substitu- meric product. We focused on two model systems: one for
ents at the aromatic ring did not seem to be useful for the the secalonic acids (3) and a second for rugulotrosin A (5).
synthesis of dimeric tetrahydroxanthones.
The syntheses of these model systems are shown in
Scheme 22 (R = H: secalonic acid system; R = Me: rugulo-
trosin A system). First, the tetrahydroxanthone scaffolds
were built from the corresponding salicyl aldehydes 51 or 82
and cyclohex-2-enone (12) (see also Scheme 20). The labile
Michael system of compounds 83 and 84 was converted
into less reactive alcohols 99 and 100 by two reduction steps
via enols 95 and 96. Finally, the aromatic alcohol was de-
protected to yield the free phenols 97 and 98 for enzymatic
coupling. Laccases are known to perform phenolic coupling
in the presence of oxygen, also with complex molecules.[55]
Dimerization with this kind of enzymes are currently under
investigation in our group.
Scheme 20. Synthesis of two model systems for cross coupling reac-
tions. Reagents and conditions: (a) DABCO, dioxane/H2O (1:2),
sonication, 60 °C, 2 d, 39% 83, 28% 84; (b) TBATB, THF/H2O,
room temp., 14 h, 62%; (c) NBS, DMSO/H2O, room temp., 14 h,
47%; (d) DABCO, dioxane, room temp., 16 h, 93%.
Due to the fact that bromination of the aromatic ring
during bromohydrin formation was not selective towards
the C-7 position, the domino oxa-Michael-aldol condensa-
tion was performed with commercially available brominated
salicylaldehyde 88 (Scheme 21). Two cyclohexenones, 12
and 89 were employed to yield tetrahydroxanthones 90 and
91. As the yield of hydroxy substituted 91 was very low,
further reactions were only carried out with simple model
system 90. Bromohydrin formation (Ǟ92), followed by eli-
mination, gave Michael system 94 in good yield. Subse-
quent Ley-type oxidation furnished dione 93, which is cur-
rently being used in ongoing dimerization experiments.
Scheme 22. Synthesis of two model systems for enzymatic phenol
coupling. Synthesis of 83 has already been reported.[56] Reagents
and conditions: (a) DABCO, dioxane/H2O (1:2), sonication, 60 °C,
2 d, 39% 83, 28% 84; (b) NaBH4, MeOH, 0 °C to room temp., 2 h,
84% 95; 86% 96; (c) Pd/C (cat.), H2, MeOH, room temp., 18 h,
70% 99 (two diastereomers cis-(1,9a)/trans-(1,9a) = 1:2), 94% 100
[two diastereomers cis-(1,9a)/trans-(1,9a) = 1:6]; (d) BBr3, CH2Cl2,
–78 °C to room temp., 6 h, 42% 97 [two diastereomers cis-(1,9a)/
trans-(1,9a) = 1:2], 61% 98 [two diastereomers cis-(1,9a)/trans-
(1,9a) = 1:6].
In the course of performing the above reactions, we also
prepared other tetrahydroxanthones (not shown). Their
synthesis is described in the Supporting Information.
Conclusions
Scheme 21. Synthesis of model system 93 for Suzuki coupling. Re-
action (a) was previously reported.[56] Reagents and conditions:
(a) for 90: DABCO, dioxane/H2O, room temp., 2 d, 60%; for 91:
N-methylimidazole, dioxane/H2O, room temp., 3 d, 12% (cis/trans
In this full paper, we have presented our journey towards
the total syntheses of blennolides epi-A (1) and C (2). Based
on the domino oxa-Michael-aldol condensation of salicyl-
aldehydes and cyclohexenones, the frameworks of these nat-
ural products were readily assembled. However, the instal-
=
1.0:2.8); (b) NBS, THF/H2O, room temp., 14 h, 82%;
(c) DABCO, dioxane, room temp., 18 h, 88%; (d) TPAP (cat.),
NMO, CH2Cl2, MeCN, sonication, 60 °C, 12 h, 46%.
Another possibility to perform dimerization of tetra- lation of a methyl ester in the C-4a position imposed chal-
hydroxanthones is enzymatic phenol coupling.[54] Enzy- lenges. Nevertheless, the goal was achieved through nucleo-
matic reactions have some advantages over cross-coupling philic addition, diastereomerically in the case of blennol-
reactions in that no functionalization is needed and the re- ide C. Thereby, blennolides epi-A (1) and C (2) are access-
action conditions are very mild. In addition, enzymes can ible. Furthermore, efforts towards the dimerization of
react very selectively, which could increase the yield of di- xanthones have been made. We continue along this road, to
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
8.3 Hz, 1 H, ArH), 7.77 (d, 4J = 2.1 Hz, 1 H, 9-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.1 (+, CH3), 30.9 (+, CH), 45.5 (–, CH2),
55.6 (+, OCH3), 58.9 (+, OCH3), 67.6 (–, OCH2CH2O), 71.7 (–,
OCH2CH2O), 79.4 (+, C-4), 80.4 (+, C-4a), 96.3 (–, OCH2O), 103.7
(+, CAr), 108.5 (+, CAr), 111.8 (Cq), 125.3 (Cq), 128.6 (+, CAr),
132.7 (+, C-9), 156.2 (Cq), 158.0 (Cq), 194.8 (Cq, C=O) ppm. IR
synthesize secalonic acids (3) and other dimers, having a
similar xanthone moiety.
Experimental Section
(KBr): ν = 2889 (m), 1679 (m) cm–1. MS (EI): m/z (%) = 348 (2)
˜
General: 1H NMR spectra were recorded with a Bruker AM 400
(400 MHz), or a Bruker DRX 500 (500 MHz) spectrometer. Chem-
ical shifts are expressed in parts per million (ppm, δ) downfield
from tetramethylsilane (TMS) and are referenced to CHCl3 (δ
=7.26 ppm) or [D5]DMSO (δ =2.50 ppm) as internal standard. All
coupling constants are absolute values and J values are expressed
in Hertz [Hz]. The description of signals include: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublet, ddd = doublet of dd, dt = doublet of triplet, td = triplet
of doublet, br. s = broad singlet, mc = centered multiplet. The spec-
tra were analyzed according to first order. 13C NMR spectra were
recorded with a Bruker AM 400 (100 MHz), or a Bruker DRX 500
(125 MHz) spectrometer. Chemical shifts are expressed in parts per
million (ppm, δ) downfield from tetramethylsilane (TMS) and are
referenced to CDCl3 (δ =77.2 ppm) or to [D6]DMSO (δ =39.5 ppm)
as internal standard. The multiplicity of 13C NMR signals is given
as follows: DEPT: + = primary or tertiary (positive DEPT-sig-
nal), – = secondary (negative DEPT-signal), Cq = quaternary C-
atoms no DEPT-signal. The spectra were analyzed according to
first order. MS (EI) were obtained with a Finnigan MAT 90
(70 eV). The peaks are given as mass-to-charge-ratio (m/z). The
molecule peak is given as [M]+ and characteristic fragment peaks
are given as [M – fragment]+ or [fragment]+. The signal intensities
are given in percent, relatively to the intensity of the base signal
(100%). FTIR spectra were obtained with Bruker IFS 88 and
Bruker alpha spectrometers. IR spectra of solids were recorded in
KBr or by Attenuated Total Reflection (ATR), and as thin films
on KBr for oils and liquids; absorption bands was described in
[M]+, 259 (100), 242 (50). HRMS (EI): m/z calcd. for C19H24O6
348.1573; found 348.1570.
(3R,4S,4aR,9S,9aR)-5,9a-Dibromo-9-hydroxy-8-methoxy-4-[(2-
methoxyethoxy)methoxy]-3-methyl-2,3,4,4a,9,9a-hexahydro-1H-
xanthen-1-one (55): To a solution of cis-54 (1.84 g, 5.29 mmol, 1.
00 equiv.) in THF/H2O (96 mL, 1:1) was added tetrabutylammo-
nium tribromide (5.10 g, 10.6 mmol, 2.00 equiv.). After stirring
20 h at room temp., water was added and the mixture was extracted
with diethyl ether (3ϫ 70 mL). The organic phase was washed with
a saturated aqueous solution of sodium thiosulfate, dried with so-
dium sulfate, and the solvents evaporated. The sensitive crude
product (2.57 g) was used for the next step without any purifica-
tion.
(3R,4S)-5-Bromo-9-hydroxy-8-methoxy-4-[(2-methoxyethoxy)-
methoxy]-3-methyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (56): To a
solution of crude 55 (2.57 g, 4.92 mmol, 1.00 equiv.) in dioxane
(40 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.67 g,
14.8 mmol, 3.00 equiv.). After stirring 18 h at room temp., water
was added and the mixture was extracted with diethyl ether (4ϫ
50 mL). The organic phase was dried with sodium sulfate, evapo-
rated, and purified by flash column chromatography (cyclohexane/
ethyl acetate, 2:1 + 5% NEt3) to give a yellow solid (1.12 g, 48%
over two steps). Rf = 0.36 (cyclohexane/ethyl acetate, 1:1 + 5%
NEt3). 1H NMR (400 MHz, CDCl3): δ = 1.10 (d, 3J = 6.8 Hz, 3
H, CH3), 2.20 (dd, 2J = 16.6, 3J = 8.4 Hz, 1 H, CH2), 2.33–2.48
2
3
(m, 1 H, CH), 2.77 (dd, J = 16.6, J = 4.5 Hz, 1 H, CH2), 3.32 (s,
3 H, OCH3), 3.48–3.62 (m, 2 H, OCH2CH2O), 3.68–3.83 (m, 2 H,
OCH2CH2O), 3.84 (s, 3 H, OCH3), 4.28 (d, 3J = 6.5 Hz, 1 H, 4-
wave numbers ν in cm–1 between 3600 and 500 cm–1. Band inten-
˜
sities were characterized as follows: vs = very strong [0–10% trans-
mission (T)], s = strong (11–30% T), m = medium (31–70% T), w
= weak (71–90% T), vw = very weak (91–100% T).
2
2
H), 4.97 (d, J = 7.3 Hz, 1 H, OCH2O), 5.23 (d, J = 7.3 Hz, 1 H,
3
OCH2O), 5.91 (s, 1 H, 9-H), 6.56 (d, J = 8.8 Hz, 1 H, ArH), 7.43
(d, J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ
3
Only procedures for the syntheses of 54–56, 58, 60, 62, 63 and 1
are described here. For further procedures, NMR spectra and X-
ray data, see the Supporting Information.
= 17.9 (+, CH3), 33.9 (+, CH), 41.8 (–, CH2), 54.1 (+, C-9), 56.2
(+, OCH3), 59.1 (+, OCH3), 67.9 (–, OCH2CH2O), 71.8 (–,
OCH2CH2O), 75.4 (+, C-4), 96.3 (–, OCH2O), 101.5 (Cq), 107.6
(+, CAr), 113.3 (Cq), 113.6 (Cq), 132.8 (+, CAr), 147.2 (Cq), 157.7
Experimental Procedures for the Total Synthesis of Blennolide (A)
(C ), 164.1 (C ), 196.1 (C , C=O) ppm. IR (KBr): ν = 3462 (m),
˜
q
q
q
cis-(3R,4S,4aS)-8-Methoxy-4-[(2-methoxyethoxy)methoxy]-3-
methyl-2,3,4,4a-tetrahydro-1H-xanthen-1-one (cis-54): To a solution
of cis-(3R,4S)-4-hydroxy-8-methoxy-3-methyl-2,3,4,4a-tetrahydro-
1H-xanthen-1-one (0.658 g, 2.53 mmol, 1.00 equiv.) in dichloro-
methane (16 mL) were added N,N-diisopropylethylamine (2.17 mL,
12.7 mmol, 5.00 equiv.) and 1-chloromethoxy-2-methoxyethane
(1.45 mL, 12.7 mmol, 5.00 equiv.) under an argon atmosphere. Af-
ter stirring for 1 h and heating to reflux the reaction was quenched
with water and extracted with dichloromethane (4ϫ 70 mL). The
organic phase was dried with sodium sulfate, evaporated, and puri-
fied by flash column chromatography (cyclohexane/acetone, 2:1 +
1% NEt3) to give a yellow oil (0.836 g, 95%). Rf = 0.49 (cyclohex-
1656 (m) cm–1. MS (EI): m/z (%) = 442/444 (6/6) [M]+, 335/337 (33/
38), 43 (100). HRMS (EI): m/z calcd. for C19H23BrO7 442.0627;
found 442.0625.
(3R,4S)-5-Bromo-8-methoxy-4-[(2-methoxyethoxy)methoxy]-3-
methyl-3,4-dihydro-1H-xanthen-1,9(2H)-dione (58): To a solution of
56 (0.670 g, 1.52 mmol, 1.00 equiv.) in dichloromethane (38 mL)
and acetonitrile (7.6 mL), were added N-methylmorpholino-N-ox-
ide (0.534 g, 4.55 mmol, 3.00 equiv.) and molecular sieves (4 Å,
1.50 g) under an argon atmosphere. After stirring 30 min at room
temp. tetrapropylammonium perruthenate (0.107 g, 303 μmol,
0.200 equiv.) was added and the mixture was heated to reflux for
ane/acetone, 2:1 + 1% NEt3). 1H NMR (400 MHz, CDCl3): δ = 6 h. The solvent was evaporated and the crude product was purified
3
1.13 (d, J = 6.5 Hz, 3 H, CH3), 1.93–2.05 (m, 1 H, CH), 2.21 (dd,
by flash column chromatography (chloroform/ethyl acetate, 1:1, +
2J = 17.8, 3J = 13.2 Hz, 1 H, CH2), 2.59 (dd, 2J = 17.8, 3J = 4.2 Hz,
2 % MeOH) to give a yellow solid (0.507 g, 76 %). Rf = 0.19
1 H, CH2), 3.42 (s, 3 H, OCH3), 3.59–3.63 (m, 2 H, OCH2CH2O), (CHCl3/ethyl acetate, 1:1 + 2 % MeOH). 1H NMR (500 MHz,
3
3.79 (s, 3 H, OCH3), 3.85–3.93 (m, 3 H, OCH2CH2O and 4-H), [D6]DMSO): δ = 1.13 (d, J = 6.1 Hz, 3 H, CH3), 2.34–2.42 (m, 2
3
3
2
4.77 (dd, J = 8.3, J = 2.3 Hz, 1 H, 4-Ha), 4.93 (d, J = 6.8 Hz, 1 H, CH2), 2.56–2.64 (m, 1 H, CH), 3.25 (s, 3 H, OCH3), 3.46–3.52
H, OCH2O), 5.18 (d, 2J = 6.8 Hz, 1 H, OCH2O), 6.44 (d, 3J = (m, 2 H, OCH2CH2O), 3.68–3.75 (m, 1 H, OCH2CH2O), 3.78–3.84
3
3
3
8.3 Hz, 1 H, ArH), 6.47 (d, J = 8.3 Hz, 1 H, ArH), 7.16 (t, J = (m, 1 H, OCH2CH2O), 3.87 (s, 3 H, OCH3), 4.67 (d, J = 7.7 Hz,
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
1 H, 4-H), 5.09 (d, 2J = 7.1 Hz, 1 H, OCH2O), 5.21 (d, 2J = 7.1 Hz,
1 H, OCH2O), 7.04 (d, 3J = 9.1 Hz, 1 H, ArH), 8.00 (d, 3J = 9.0 Hz,
1 H, ArH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 17.8 (+,
CH3), 33.7 (+, CH), 43.4 (–, CH2), 57.0 (+, OCH3), 58.6 (+,
OCH3), 68.0 (–, OCH2CH2O), 71.6 (–, OCH2CH2O), 76.2 (+, C-
After stirring 30 min at this temperature, tert-butyllithium was
again added until the TLC showed no starting material. The reac-
tion mixture was quenched with saturated aqueous solution of so-
dium hydrogen carbonate and extracted with ethyl acetate
(3 ϫ 20 mL). The organic phase was dried with sodium sulfate,
4), 96.6 (–, OCH2O), 101.0 (Cq), 110.1 (+, CAr), 116.4 (Cq), 116.5 evaporated, and purified by flash column chromatography (cyclo-
(Cq), 137.9 (+, CAr), 152.6 (Cq), 159.4 (Cq), 172.0 (Cq), 173.8 (Cq, hexane/ethyl acetate, 2:1) to give a yellow oil (64 mg, 68%) as two
C=O), 196.1 (C , C=O) ppm. IR (KBr): ν = 3449 (w), 1710 (w),
inseparable epimers: trans-4,4a/cis-4,4a in a ratio of 4:1. Rf = 0.29
˜
q
1655 (w) cm–1. MS (EI): m/z (%) = 440/442 (6/2) [M]+, 351/353 (21/
14), 59 (100). HRMS (EI): m/z calcd. for C19H21BrO7 440.0471;
found 440.0468.
(cyclohexane/ethyl acetate, 2:1). IR (KBr): ν = 2920 (w), 1601
˜
(m) cm–1. FAB-MS (3-NBA): m/z (%) = 517 (3) [M + H]+, 363
(100). HRMS (FAB): m/z calcd. for C23H33S3O7 517.1384; found
517.1393.
(3R,4S)-5-Bromo-1-hydroxy-8-methoxy-4-[(2-methoxyethoxy)-
methoxy]-3-methyl-4a-[tris(methylthio)methyl]-4,4a-dihydro-2H-
xanthen-9(3H)-one (60): To a solution of tris(methylthio)methane
(0.208 g, 1.35 mmol, 1.10 equiv.) in THF (10 mL) at –78 °C was
added n-butyllithium (1.6 m in hexane, 842 μL, 1.35 mmol,
1.10 equiv.) over 30 min. After stirring 1 h at this temperature, 58
(0.540 g, 1.22 mmol, 1.00 equiv.), diluted in THF (10 mL), was
added slowly. The resulting red solution was stirred for 14 h at
–78 °C and then poured carefully onto ice and extracted with ethyl
acetate (3ϫ 40 mL). The organic phase was dried with sodium sulf-
ate, evaporated, and purified by flash column chromatography (cy-
clohexane/ethyl acetate, 2:1) to give a yellow oil (0.100 g, 14%) of
two inseparable epimers: trans-4,4a/cis-4,4a in a ratio of 6:1. Rf =
Isomer trans-62: 1H NMR (400 MHz, CDCl3): δ = 1.28 (d, 3J =
6.5 Hz, 3 H, CH3), 1.91–2.06 (m, 1 H, CH), 2.12 (s, 9 H, 3ϫSCH3),
3
2
3
2.30 (dd, 2J = 17.3, J = 4.8 Hz, 1 H, CH2), 2.84 (dd, J = 17.2, J
= 13.5 Hz, 1 H, CH2), 3.40 (s, 3 H, OCH3), 3.56–3.64 (m, 2 H,
OCH2CH2O), 3.82–3.90 (m, 2 H, OCH2CH2O), 3.94 (s, 3 H,
3
2
OCH3), 4.47 (d, J = 9.8 Hz, 1 H, 4-H), 5.07 (d, J = 6.5 Hz, 1 H,
OCH2O), 5.30 (d, 2J = 6.5 Hz, 1 H, OCH2O), 6.42 (d, 3J = 8.4 Hz,
3
3
1 H, ArH), 6.51 (d, J = 8.4 Hz, 1 H, ArH), 7.33 (t, J = 8.4 Hz,
1 H, ArH), 16.42 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 15.8 (+, 3ϫSCH3), 18.8 (+, CH3), 34.3 (+, CH), 38.4 (–, CH2),
56.3 (+, OCH3), 59.0 (+, OCH3), 68.1 (–, OCH2CH2O), 71.8 (–,
OCH2CH2O), 84.1 (+, C-4), 84.6 (Cq, C-4a), 88.9 (Cq), 95.7 (–,
OCH2O), 101.9 (Cq), 103.8 (+, CAr), 108.8 (+, CAr), 135.7 (+, CAr),
159.9 (Cq), 160.2 (Cq), 176.8 (Cq, C-1), 187.2 (Cq, C=O) ppm.
0.38 (cyclohexane/ethyl acetate, 2:1). IR (KBr): ν = 2920 (w), 1586
˜
(m) cm–1. FAB-MS (3-NBA): m/z (%) = 597/595 (7/7) [M +
H]+, 443/441 (100/93). HRMS (FAB): m/z calcd. for C23H32BrS3O7
595.0494; found 595.0496.
Isomer cis-62: 1H NMR (400 MHz, CDCl3): δ = 1.12 (d, 3J =
6.6 Hz, 3 H, CH3), 1.91–2.06 (m, 1 H, CH), 2.14 (s, 9 H, 3ϫSCH3),
2.57 (dd, 2J = 19.0, 3J = 7.2 Hz, 1 H, CH2), 2.94–3.07 (m, 1 H,
CH2), 3.35 (s, 3 H, OCH3), 3.45–3.51 (m, 2 H, OCH2CH2O), 3.74–
Isomer trans-60: 1H NMR (400 MHz, CDCl3): δ = 1.27 (d, 3J =
6.5 Hz, 3 H, CH3), 1.90–2.04 (m, 1 H, CH), 2.10 (s, 9 H, 3ϫSCH3),
3
2
3
2.31 (dd, 2J = 17.5, J = 5.1 Hz, 1 H, CH2), 2.88 (dd, J = 17.4, J 3.81 (m, 2 H, OCH2CH2O), 3.92 (s, 3 H, OCH3), 4.32 (d, 3J =
2
2
= 13.4 Hz, 1 H, CH2), 3.38 (s, 3 H, OCH3), 3.55–3.60 (m, 2 H, 2.1 Hz, 1 H, 4-H), 4.73 (d, J = 7.0 Hz, 1 H, OCH2O), 5.00 (d, J
OCH2CH2O), 3.74–3.81 (m, 1 H, OCH2CH2O), 3.86–3.94 (m, 1 H,
= 7.0 Hz, 1 H, OCH2O), 6.36 (d, 3J = 8.3 Hz, 1 H, ArH), 6.45–
6.50 (m, 1 H, ArH), 7.26–7.31 (m, 1 H, ArH), 16.21 (s, 1 H,
OCH2CH2O), 3.91 (s, 3 H, OCH3), 4.46 (d, 3J = 9.3 Hz, 1 H, 4-
2
2
H), 5.08 (d, J = 7.0 Hz, 1 H, OCH2O), 5.51 (d, J = 7.0 Hz, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.7 (+, 3ϫSCH3),
3
3
OCH2O), 6.42 (d, J = 9.0 Hz, 1 H, ArH), 7.53 (d, J = 9.0 Hz, 1 18.1 (+, CH3), 29.1 (+, CH), 37.4 (–, CH2), 56.3 (+, OCH3), 59.0
H, ArH), 16.35 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): (+, OCH3), 68.0 (–, OCH2CH2O), 71.7 (–, OCH2CH2O), 81.1 (+,
δ = 15.6 (3ϫSCH3), 18.8 (+, CH3), 34.4 (+, CH), 38.1 (–, CH2),
56.4 (+, OCH3), 59.0 (+, OCH3), 67.9 (–, OCH2CH2O), 71.7 (–,
C-4), 84.6 (Cq, C-4a), 91.7 (Cq), 97.7 (–, OCH2O), 100.9 (Cq), 104.0
(+, CAr), 108.4 (+, CAr), 134.9 (+, CAr), 160.1 (Cq), 160.3 (Cq),
OCH2CH2O), 83.1 (+, C-4), 83.4 (Cq, C-4a), 89.6 (Cq), 96.3 (–, 180.4 (Cq, C-1), 189.3 (Cq, C=O) ppm.
OCH2O), 100.7 (Cq), 101.5 (Cq), 104.9 (+, CAr), 110.3 (Cq), 138.5
Methyl (3R,4S)-1-Hydroxy-8-methoxy-4-[(2-methoxyethoxy)-
methoxy]-3-methyl-9-oxo-3,4,4a,9-tetrahydro-2H-xanthene-4a-
carboxylate (63): A suspension of 62 (70.0 mg, 0.135 mmol,
(+, CAr), 155.7 (Cq), 159.4 (Cq), 180.0 (Cq, C-1), 187.4 (Cq,
C=O) ppm.
Isomer cis-60: 1H NMR (400 MHz, CDCl3): δ = 1.12 (d, 3J = 1.00 equiv.), mercury(II) chloride (148 mg, 0.543 mmol, 4.00 equiv.)
6.6 Hz, 3 H, CH3), 1.90–2.04 (m, 1 H, CH), 2.16 (s, 9 H, 3ϫSCH3), and mercury(II) oxide (50.0 mg, 0.227 mmol, 1.70 equiv.) in meth-
2.56 (dd, 2J = 19.0, 3J = 7.1 Hz, 1 H, CH2), 2.94–2.99 (m, 1 H, anol/water (3.1 mL/0.3 mL) was stirred for 18 h at room temp. The
CH2), 3.34 (s, 3 H, OCH3), 3.45–3.52 (m, 2 H, OCH2CH2O), 3.81– suspension was then filtered through Celite and washed with
3.41 (m, 1 H, OCH2CH2O), 3.88 (s, 3 H, OCH3), 3.95–4.00 (m, 1 dichloromethane. The organic phase was washed with a 60% aque-
H, OCH2CH2O), 4.32 (d, 3J = 2.1 Hz, 1 H, 4-H), 4.71 (d, 2J = ous solution of ammonium acetate (2ϫ15 mL) and a saturated
7.1 Hz, 1 H, OCH2O), 5.16 (d, 2J = 7.1 Hz, 1 H, OCH2O), 6.41 (d,
solution of ammonium chloride (2ϫ15 mL), dried with sodium
3
3J = 9.1 Hz, 1 H, ArH), 7.49 (d, J = 9.1 Hz, 1 H, ArH), 16.27 (s, sulfate and the solvents evaporated. The sensitive crude product
1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.9 (+, (63.0 mg) was used for the next step without any purification.
3ϫSCH3), 17.9 (+, CH3), 29.0 (+, CH), 37.5 (–, CH2), 56.5 (+,
Methyl (3R,4S)-1,4,8-Trihydroxy-3-methyl-9-oxo-3,4,4a,9-tetra-
OCH3), 58.9 (+, OCH3), 67.8 (–, OCH2CH2O), 71.6 (–, OCH2-
hydro-2H-xanthene-4a-carboxylate (epi-1): To a solution of crude
CH2O), 77.2 (+, C-4), 81.6 (Cq, C-4a), 92.2 (Cq), 98.3 (–, OCH2O),
63 (63.0 mg, 0.135 mmol, 1.00 equiv.) in CH2Cl2 (10 mL) was
100.7 (Cq), 100.7 (Cq), 105.1 (+, CAr), 109.3 (Cq), 137.7 (+, CAr),
added dropwise boron tribromide (1 m in CH2Cl2, 1.35 mL,
155.9 (Cq), 159.5 (Cq), 175.1 (Cq, C-1), 190.9 (Cq, C=O) ppm.
1.35 mmol, 10.0 equiv.) under an argon atmosphere. After stirring
(3R,4S)-1-Hydroxy-8-methoxy-4-[(2-methoxyethoxy)methoxy]-3-
methyl-4a-[tris(methylthio)methyl]-4,4a-dihydro-2H-xanthen-9-
(3H)-one (62): To a solution of 60 (0.108 g, 0.182 mmol,
1.00 equiv.) in THF (5 mL) at –78 °C, was added dropwise tert-
butyllithium (1.6 m in pentane, 340 μL, 0.545 mmol, 3.00 equiv.).
for 5 h at room temp., the reaction mixture was quenched with
water (20 mL) and extracted with CH2Cl2 (3ϫ20 mL). The organic
phase was dried with sodium sulfate and the solvents evaporated.
The crude product was purified by preparative TLC (cyclohexane/
ethyl acetate, 10:1, 5:1, 3:1, 1:1) to give a yellow solid (8 mg, 19%
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
1
[21]
[22]
B. Lesch, S. Bräse, Angew. Chem. Int. Ed. 2004, 43, 115–118;
Angew. Chem. 2004, 116, 118–120.
over two steps). H NMR (400 MHz, CDCl3): δ (main epimer) =
3
2
3
1.04 (d, J = 7.3 Hz, 3 H, CH3), 2.15 (dd, J = 18.6, J = 5.2 Hz,
1 H, CH2), 2.30–2.38 (m, 1 H, CH), 2.82 (dd, 2J = 18.6, 3J =
CCDC-982384 (for 14), -982385 (for 17), -982386 (for 23),
-982387 (for 29), -982388 (for 2), and -982389 (for cis-77) con-
tain the supplementary crystallographic 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.
M. Amat, M. Pérez, N. Llor, C. Escolano, F. J. Luque, E. Mol-
ins, J. Bosch, J. Org. Chem. 2004, 69, 8681–8693.
a) P. C. Ostrowski, V. V. Kane, Tetrahedron Lett. 1977, 40,
3549–3552; b) D. J. Ager, M. B. East, J. Org. Chem. 1986, 51,
3983–3992; c) T. Cohen, W. D. Abraham, M. Myers, J. Am.
Chem. Soc. 1987, 109, 7923–7924; d) P. C. B. Page, M. B.
van Niel, J. C. Prodger, Tetrahedron 1989, 45, 7643–7677; e)
W. H. Sikorski, H. J. Reich, J. Am. Chem. Soc. 2001, 123, 6527–
6535; f) E. Juaristi, M. Hernández-Rodríguez, H. López-Ruiz,
J. Aviña, O. Muñoz-Muñiz, M. Hayakawa, D. Seebach, Helv.
Chim. Acta 2002, 85, 1999–2008.
3
5.8 Hz, 1 H, CH2), 3.66 (s, 3 H, CO2CH3), 4.16 (dd, J = 2.1, 6.0,
3.7 Hz, 1 H, 4-H), 6.51 (dd, 3J = 8.2, J = 0.9 Hz, 1 H, ArH), 6.56
4
3
4
3
(dd, J = 8.4, J = 0.9 Hz, 1 H, ArH), 7.34 (d, J = 8.3 Hz, 1 H,
ArH), 11.32 (s, 1 H, OH), 13.45 (s, 1 H, OH) ppm. 13C NMR
(100 MHz, CDCl3): δ (main epimer) = 17.0 (+, CH3), 31.4 (+, CH),
33.3 (–, CH2), 53.3 (+, CO2CH3), 73.4 (+, C-4), 81.8 (Cq, C-4a),
100.9 (Cq), 107.6 (Cq), 107.9 (+, CAr), 111.3 (+, CAr), 137.7 (+,
CAr), 157.2 (Cq), 162.1 (Cq), 171.0 (CO2CH3), 177.5 (Cq, C-1),
188.1 (Cq, C=O) ppm. MS (EI): m/z (%) = 320 (5) [M]+, 261 (100).
HRMS (EI): m/z calcd. for C16H16O7 320.0896; found 320.0898.
[23]
[24]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures of all compounds, detailed spec-
troscopic data and crystallographic data.
[25]
a) W. Nagata, I. Kikkawa, K. Takeda, Chem. Pharm. Bull.
1961, 9, 79–81; b) U. R. Ghatak, D. K. Datta, S. C. Ray, J. Am.
Chem. Soc. 1960, 82, 1728–1734; c) U. R. Ghatak, J. Charkrav-
arty, A. K. Banerjee, Tetrahedron 1968, 24, 1577–1593; d) A. K.
Ghosh, J. K. Mukhopadhyaya, U. R. Ghatak, J. Chem. Soc.
Perkin Trans. 1 1997, 2747–2754.
Acknowledgments
The authors acknowledge the Fonds der Chemischen Industrie and
the Deutsche Forschungsgemeinschaft (DFG) (BR 1750-12-1) for
financial support.
[26]
[27]
W. Nagata, M. Onaka, Org. React. 1977, 25, 255–476.
K. Utimoto, M. Obayashi, Y. Shishiyama, M. Inoue, H. No-
zaki, Tetrahedron Lett. 1980, 21, 3389–3392.
K. Utimoto, Y. Wakabayashi, T. Horiie, M. Inoue, Y. Shishi-
yama, M. Obayashi, H. Nozaki, Tetrahedron 1983, 39, 967–
973.
a) M. Kasai, H. Ziffer, J. Org. Chem. 1983, 48, 2346–2349; b)
M. E. Jung, J. Gervay, J. Am. Chem. Soc. 1991, 113, 224–232.
R. K. Boeckman Jr., K. J. Bruza, J. Org. Chem. 1979, 44, 4781–
4788.
Syntheses of molecules 2, 13, 14, 16, 17, 27, 29, 31, 33, 46–50,
53, 74 and 85 have already been reported, see ref.[13,17,18,48,53]
J. P. Nagarkatti, K. R. Ashley, Tetrahedron Lett. 1973, 46,
4599–4600.
a) R. U. Lemieux, E. von Rudloff, Can. J. Chem. 1955, 33,
1701–1710; b) E. von Rudloff, Can. J. Chem. 1955, 33, 1714–
1719.
a) H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J.
Org. Chem. 1981, 46, 3936–3938; b) T. K. Jones, S. E. Den-
mark, J. Org. Chem. 1985, 50, 4037–4045.
[1] W. Zhang, K. Krohn, U. Flörke, G. Pescitelli, L. Di Bari, S.
Antus, T. Kurtán, J. Rheinheimer, S. Draeger, B. Schulz, Chem.
Eur. J. 2008, 14, 4913–4923.
[2] F. Kraft, Arch. Pharm. 1906, 244, 336–359.
[3] I. Kurobane, S. Iwahashi, A. Fukuda, Drugs Exp. Clin. Res.
1987, 13, 339–344.
[4] C. S. Reddy, A. W. Hayes, R. V. Hayes, A. Ciegler, J. Toxicol.
Environ. Health 1981, 7, 445–455.
[5] C. S. Reddy, A. W. Hayes, W. L. Williams, A. Ciegler, J. Tox-
icol. Environ. Health 1979, 5, 1159–1169.
[6] F. McPhee, P. S. Caldera, G. W. Bemis, A. F. McDonagh, I. D.
Kuntz, C. S. Craik, Biochem. J. 1996, 320, 681–686.
[7] B. H. Wang, G. M. Polya, Planta Med. 1996, 62, 111–114.
[8] K. Mayura, A. W. Hayes, W. O. Berndt, Toxicology 1982, 25,
311–322.
[28]
[29]
[30]
[31]
[32]
[33]
[9] R. Zeng, S. Luo, Y. Shi, M. Shi, C. Tu, Agric. J. 2001, 93, 72–
79.
[34]
[10] a) C. C. Howard, R. A. W. Johnstone, J. Chem. Soc. Perkin
Trans. 1 1973, 2440–2444; b) C. C. Howard, R. A. W. John-
stone, I. D. Entwistle, J. Chem. Soc., Chem. Commun. 1973,
464.
[11] J. G. Ondeyka, A. W. Dombrowski, J. P. Polishook, T. Felcetto,
W. L. Shoop, Z. Guan, S. B. Singh, J. Antibiot. 2006, 59, 288–
292.
[35]
[36]
[37]
W. Yu, Y. Mei, Y. Kang, Z. Hua, Z. Jin, Org. Lett. 2004, 6,
3217–3219.
Y. Nishikimi, T. Iimori, M. Shibasaki, J. Org. Chem. 1989, 54,
3354–3359.
a) S. Yamada, D. Morizono, K. Yamamoto, Tetrahedron Lett.
1992, 33, 4329–4332; b) K. Yamamoto, M. Shimizu, S. Yam-
ada, J. Org. Chem. 1992, 57, 33–39; c) J. Yu, X. Z. Wearing,
J. M. Cook, J. Org. Chem. 2004, 70, 3963–3979; d) T. K. Trul-
linger, J. Qi, W. R. Roush, J. Org. Chem. 2006, 70, 6915–6922.
C. McDonald, H. Holcomb, K. Kennedy, E. Kirkpatrick, T.
Leathers, P. Vanemon, J. Org. Chem. 1989, 54, 1213–1215.
C. E. McDonald, L. E. Nice, A. W. Shaw, N. B. Nestor, Tetra-
hedron Lett. 1993, 34, 2741–2144.
B. J. Travis, M. Sivakumar, G. O. Hollist, B. Borhan, Org. Lett.
2003, 5, 1031–1034.
R. Gopinath, B. K. Patel, Org. Lett. 2000, 2, 577–579.
A. Schmidt, T. Habeck, B. Snovydovych, W. Eisfeld, Org. Lett.
2007, 9, 3515–3518.
C. F. Nising, U. K. Ohnemüller, S. Bräse, Angew. Chem. Int.
Ed. 2006, 45, 307–309; Angew. Chem. 2006, 118, 313–315.
A. R. Haight, A. E. Bailey, W. S. Baker, M. H. Cain, R. R.
Copp, J. A. DeMattei, K. L. Ford, R. F. Henry, M. C. Hsu,
R. F. Keyes, S. A. King, M. A. McLaughlin, L. M. Melcher,
W. R. Nadler, P. A. Oliver, S. I. Parekh, H. H. Patel, L. S. Seif,
[12] M. Stewart, R. J. Capon, J. M. White, E. Lacey, S. Tennant,
J. H. Gill, M. P. Shaddock, J. Nat. Prod. 2004, 67, 728–730.
[13] E. M. C. Gérard, S. Bräse, Chem. Eur. J. 2008, 14, 8086–8089.
[14] K. C. Nicolaou, A. Li, Angew. Chem. Int. Ed. 2008, 47, 6579–
6582; Angew. Chem. 2008, 120, 6681–6684.
[38]
[39]
[40]
[15] T. Qin, R. P. Johnson, J. A. Porco Jr., J. Am. Chem. Soc. 2011,
133, 1714–1717.
[16] L.-F. Tietze, L. Ma, J. R. Reiner, S. Jackenkroll, S. Heidemann,
Chem. Eur. J. 2013, 19, 8610–8614.
[17] a) T. Qin, J. A. Porco Jr., Angew. Chem. Int. Ed. 2014, 53, 3107–
3110; for a review, see: T. Wezeman, K. Masters, S. Bräse, An-
gew. Chem. 2014, 53, 4524–4526.
[18] L. F. Tietze, L. Ma, S. Jackenkroll, J. R. Reiner, J. Hierold, B.
Gnanaprakasam, S. Heidemann, Heterocycles 2014, 88, 1101–
1119.
[19] For a general overview of domino reactions, see: Domino Reac-
tions: Concepts for Efficient Organic Synthesis (Ed.: L. F.
Tietze), Wiley VCH, Weinheim, Germany, 2014.
[20] C. D. Gabbutt, J. D. Hepworth, M. W. J. Urquhart, L. M. Vas-
quez de Miguel, J. Chem. Soc. Perkin Trans. 1 1997, 1819–1824.
[41]
[42]
[43]
[44]
14
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
Total Synthesis of Blennolide Mycotoxins
M. A. Staeger, G. S. Wayne, S. J. Wittenberger, W. Zhang, Org.
Process Res. Dev. 2004, 8, 897–902.
[45] U. K. Ohnemüller, C. F. Nising, A. Encinas, S. Bräse, Synthesis
2007, 2175–2185.
[46] W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J.
Chem. Soc., Chem. Commun. 1987, 1625–1627.
[47] A. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43,
2480–2482.
[48] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[49] P. L. Anelli, F. Montanari, S. Quici, Org. Synth. 1990, 69.
[50] H. Sahin, M. Nieger, S. Bräse, Eur. J. Org. Chem. 2009, 5576–
5586.
J. Aust, S. Draeger, B. Schulz, S. Antus, T. Kurtán, Eur. J. Org.
Chem. 2005, 4563–4570.
[54] a) J. B. Hewgley, S. S. Stahl, M. C. Kozlowski, J. Am. Chem.
Soc. 2008, 130, 12232–12233; b) S. J. Brooks, L. Coulombel, D.
Ahuja, D. S. Clark, J. S. Dordick, Adv. Synth. Catal. 2008, 350,
1517–1525; c) R. Gazák, P. Sedmera, M. Marzorati, S. Riva,
ˇ
V. K rˇen, J. Mol. Catal. B 2008, 50, 87–92; d) A. Pezzella, L.
Lista, A. Napolitano, M. d’Ischia, J. Org. Chem. 2004, 69,
5652–5659; e) H. Agematu, T. Tsuchida, K. Kominato, N. Shi-
bamoto, T. Yoshioka, H. Nishida, R. Okamoto, J. Antibiot.
1992, 46, 141–148.
[55] For examples of enzyme-catalyzed phenol coupling reactions,
see: a) A. Intra, S. Nicotra, S. Riva, B. Danieli, Adv. Synth.
Catal. 2005, 347, 973–977; b) C. Navarra, C. Goodwin, S. Bur-
ton, B. Danieli, S. Riva, J. Mol. Catal. B 2010, 65, 52–57.
[56] U. K. Ohnemüller, C. F. Nising, M. Nieger, S. Bräse, Eur. J.
Org. Chem. 2006, 1535–1546.
[51] A. C. Meister, M. Nieger, S. Bräse, Chem. Eur. J. 2013, 19,
10836–10839.
[52] Flack’s parameter x = –0.02(2); C3R, C4S, C4aS; see: H. D.
Flack, Acta Crystallogr., Sect. A 1983, 39, 876–881.
[53] a) M. Isaka, A. Jaturapat, K. Rukseree, K. Danwisetkanjana,
M. Tanticharoen, Y. Thebtaranonth, J. Nat. Prod. 2001, 64,
1015–1018; b) B. Elsässer, K. Krohn, U. Flörke, N. Root, H.-
Received: February 15, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15

Job/Unit: O42083
/KAP1
Date: 30-06-14 17:49:06
Pages: 16
S. Bräse et al.
FULL PAPER
Natural Products
Two total syntheses of monomeric tetra-
hydroxanthone natural products are pre-
sented. The introduction of various func-
tional groups by nucleophilic addition is
extensively examined, and efforts towards
the dimerization of these xanthones are re-
ported.
A. C. Meister, A. Encinas, H. Sahin,
E. M. C. Singer, C. F. Nising, M. Nieger,
S. Bräse* ......................................... 1–16
Total Synthesis of Blennolide Mycotoxins:
Design, Synthetic Routes and Completion
Keywords: Total synthesis
/
Natural
products / Domino reactions / Michael
addition / Lactones
16
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0