The cobalt way to angucyclinones: Asymmetric total synthesis of the antibiotics (+)-rubiginone B2, (-)-tetrangomycin, and ( - ) -8- O-Methyltetrangomycin

Article abstract of DOI:10.1002/chem.201000804

A cobalt(I)-mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)-rubiginone B₂

Full text of DOI:10.1002/chem.201000804

FULL PAPER
DOI: 10.1002/chem.201000804
The Cobalt Way to Angucyclinones: Asymmetric Total Synthesis of the
Antibiotics (+)-Rubiginone B2,
N
Christian Kesenheimer, Aris Kalogerakis, Anja Meißner, and Ulrich Groth*[a]
Abstract: A cobalt(I)-mediated conver-
gent and asymmetric total synthesis of
angucyclinones with an aromatic B ring
has been developed. In the course of
our research, we synthesized three nat-
urally occurring anguclinone deriva-
tives, namely, (+)-rubiginone B2 (1),
(ꢀ)-8-O-methyltetrangomycin (2), and
(ꢀ)-tetrangomycin (3). By combining
3-hydroxybenzoic acid, 3-methoxyben-
zoic acid, citronellal, and geraniol as
starting materials in a convergent way,
we were able to synthesize chiral triyne
chains, which were cyclized with
[CpCo(C2H4)2] (Cp=cyclopentadienyl)
by means of an intramolecular
AHCTUNGTRENNUNG
[2+2+2] cycloaddition to their corre-
sponding
tetrahydrobenzo[a]anthra-
cenes. Successive oxidation and depro-
tection steps led to the above-men-
tioned natural products 1–3.
Keywords: angucyclinone · cataly-
sis · cobalt · cycloaddition · natural
products
Introduction
action was studied by Hamagishi et al.,[4,5] who found that
the effect was synergistic. Furthermore, he concluded that,
in combination with cytotoxic agents, rubiginone B1 and
congeners could serve as efflux blockers (like verapamil) in
cancer therapy for the treatment of a variety of protein-in-
volved multi-drug-resistant tumor cells. Moreover, it was
found that the rubiginones can potentiate the cytotoxicity of
colchicine against colchicine resistant cancer kB cell lines in
vitro.[6] However, the naturally occurring rubiginones show
no potentiation effect on doxorubicin.
Angucycline antibiotics have stimulated great interest be-
cause of their wide range of biological properties such as an-
titumor, antibiotic, and anti-HIV activity.[1,2] The angucycli-
nones represent a group of angucyclines that show the same
angular, quinoide aglycon, but differ in their sugar moieties.
A characteristic feature of the angucyclines is the existence
of at least one O-glycosidic bonded sugar, whereas the angu-
cyclinones usually have none or so-called ꢀnoncleavableꢁ C-
glycosidic bonded sugars. Among this simpler group are, for
example, the tetrangomycins 2 and 3, and the rubiginones
such as 1. The rubiginones A1, A2, B1, B2, C1, and C2, which
were isolated by Oka et al.,[3] are secondary microbial me-
tabolites produced by the strain Streptomyces griseorubigi-
nosus Q144-2. All of these antibiotics have been shown to
potentiate the cytotoxicity of the chemotherapeutic agent
vincristine against vincristine resistent P 388 leukaemia and
human Moser cells in vitro as well as in vivo. The most
active member of this group is rubiginone B1, which can
easily be obtained from rubiginone B2 (1). Its mode of
From the synthetical point of view, the stereogenic center
in the C3 position of the aglyca in the nonaromatic A ring,
which is a widespread feature of the angucyclines, is one of
the major challenges. In addition to our approach, other
[a] Dr. C. Kesenheimer, Dr. A. Kalogerakis, Dr. A. Meißner,
Prof. Dr. U. Groth
Fachbereich Chemie and
Konstanz Research School Chemical Biology
Universitꢂt Konstanz
Universitꢂtsstrasse 10, Postfach 720, 78457 Konstanz (Germany)
Fax : (+49)7531-884155
E-mail: ulrich.groth@uni-konstanz.de
methods have already successfully been applied for the total
synthesis of angucyclinones to yield the natural products in
moderate to excellent optical purity. Therefore it is necessa-
ry to mention the groups of Krohn,[7–11] Suzuki,[12,13]
Larsen,[14–17] and Sulikowski,[18–21] all of whom considerably
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contributed to the research work done in the field of natural
product synthesis. Whereas all of these groups focused their
research on creating building blocks for an intermolecular
Diels–Alder reaction, we decided to choose another ap-
proach. Our synthetic approach towards enantiomerically
pure (+)-rubiginone B2 (1), (ꢀ)-8-O-methyltetrangomycin
(2), and (ꢀ)-tetrangomycin (3) is demonstrated in the fol-
lowing retrosynthetic analysis (Scheme 1).
boxylic acid 8 with thionyl chloride (Scheme 2) followed by
transfer into the respective amide 10 with diethylamine.
This amide was alkylated by ortho metalation with sec-butyl-
lithium and a twofold transmetalation into a so-called ꢀKno-
chel-cuprateꢁ,[23] which was reacted with 3-trimethylsilylpro-
pargyl bromide. Without transmetalation of the lithiated
Scheme 1. Retrosynthetic analysis of (+)-rubiginone (1), (ꢀ)-8-O-methyl-
tetrangomycin 2, and (ꢀ)-tetrangomycin 3.
Scheme 2. Synthesis of benzaldehyde 6a.
This highly convergent synthetic strategy is based on an
intramolecular catalytic [2+2+2] cycloaddition[22] of a triyne
following an A!ABCD approach.[22i,l] The A-ring building
block 6 and the side chain 7 were synthesized independently
and connected with each other during a very late stage of
the synthesis to triyne 5. Cobalt-catalyzed [2+2+2] cycload-
dition to 4, spontaneous aromatization, anthracene oxida-
tion, and finally photooxidation at C1 should afford (+)-ru-
biginone B2 (1), (ꢀ)-8-O-methyltetrangomycin (2), and (ꢀ)-
tetrangomycin (3).
The major advantages of our methodology are 1) the com-
plete regioselectivity during the [2+2+2] cycloaddition as a
result of the intramolecular mode of the reaction, 2) the
configurative stability of the asymmetric center under the
conditions of a cobalt(I)-mediated reaction, and 3) a high
tolerance of functional groups inside the triyne as long as
the reactivity of the acetylene groups are not affected. By
employing this method, we are able to synthesize natural
products of the angucyclinone family with an exceptionally
high enantiomeric purity regarding the C3 center of the A
ring.
benzamide into its cuprate, it was impossible to isolate any
desired product. The resulting alkylated amide 11 was re-
duced to the respective benzaldehyde 6a following a one-
pot procedure developed by Kim et al.[24] (Scheme 2). There-
fore, the ꢀateꢁ-complex was used; it was obtained by mixing
diisobutylaluminum hydride (DIBAl-H) with equimolar
amounts of n-butyllithium in THF at 08C, thus leading to
benzaldehyde 6a, a main building block for the synthesis of
(+)-rubiginone B2 (1) and (ꢀ)-8-O-methyltetrangomycin
(2).
For the second benzaldehyde, 6b (R4 =methoxymethyl
ether (MOM)), the synthesis had to be changed to introduce
the MOM protecting group (Scheme 3). Starting with 3-hy-
droxybenzoic acid (9), the phenolic hydroxy group was pro-
tected with acetic acid anhydride, which first led to 3-
acetoxyACHTUNGTRNEUNG
benzoic acid.[25] After chlorination and further con-
version into the corresponding amide with diethylamine,
N,N-3-acetoxydiethyl amide (12) was isolated. Deprotection
of the phenolic hydroxy group with sodium bicarbonate in
methanol afforded the 3-hydroxybenzamide, which was con-
verted into the MOM acetale 13 by reaction with MOM-Cl
and diisopropylethylamine in dichloromethane heated at
reflux. The resulting benzamide 13 was alkylated following
the procedure described before for the synthesis of 11. Un-
fortunately, the subsequent reduction of the alkylated amide
14 by applying the ꢀateꢁ-complex led to no measurable
amount of aldehyde 6b. Thus, several reduction methods for
benzamides were tested, whereby the use of the Schwartz
reagent [Cp2Zr(H)Cl][26,27] (Cp=cyclopentadienyl) showed
the highest yields under comparably mild conditions. Reduc-
tion with the Schwartz reagent was performed at room tem-
Results and Discussion
Preparation of 2,3-disubstituted benzaldehydes 6a and 6b:
The main starting material for the synthesis of the benzalde-
hydes 6a and 6b was 3-methoxybenzoic acid (8) or 3-hy-
droxybenzoic acid (9), respectively, in the case of the (ꢀ)-
tetrangomycin synthesis. The synthesis of the methoxy deriv-
ative 6a (R4 =Me) was conducted by chlorination of the car-
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Angucyclinones
FULL PAPER
Scheme 3. Synthesis of benzaldehyde 6b.
Scheme 5. Preparation of 7b.
perature in THF and showed relatively short reaction times
of about 35–40 min also in scaled-up experiments. After a
short-column filtration, the analytically pure benzaldehyde
6b was obtained in a yield of 69% (Scheme 3).
which can be isolated from rose oil in its natural form. The
enantiomeric excess of the starting material was confirmed
to be 94% ee by comparison of the measured values with
the values known from literature.[28,29] Starting with the syn-
thesis of 7a (Scheme 4), we employed the Corey–Fuchs re-
action[30] to transform aldehyde 15 into its geminal dibro-
mide. Elimination with a surplus of n-butyllithium in THF
led to a lithiated alkyne, which was quenched with trime-
thylsilyl chloride, thereby leading to the trimethylsilyl
(TMS)-protected enyne 17. Subsequent ozonolysis of 17 in
dichloromethane at ꢀ808C yielded aldehyde 18 after acidic
workup with dimethylsulfide and acetic acid. A final Corey–
Fuchs reaction followed by an elimination reaction with n-
butyllithium and final aqueous workup led to the desired
diyne 7a.
Preparation of the diynes 7a and 7b: Diynes 7a and 7b—
the second building blocks—were prepared starting from
the natural products citronellal (15) (Scheme 4) and geraniol
(16) (Scheme 5), respectively.
For the synthesis of diyne 7a (R3 =H), we started from
the commercially available natural product citronellal (15),
For the synthesis of diyne 7b (R3 =OTBS (TBS=tert-bu-
tyldimethylsilyl)), we had to follow a more complicated
route to achieve our desired side chain. Therefore, we start-
ed from the natural product geraniol (16) (Scheme 5), which
is also a part of rose oil. With geraniol as the starting mate-
rial, we began the synthesis with a catalytic asymmetric ep-
oxidation following the original literature of Sharpless
et al.,[31] which yielded epoxy alcohol 19 in 94% yield and
with an enantiomeric excess of 91% ee. During our work on
the synthesis of diyne 7b, it could be shown that raising the
amount of the catalytically active titanium complex from 5
Scheme 4. Preparation of the diyne 7a.
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U. Groth et al.
to 10% led to more reproducible results with regards to the
enantiomeric excess without an influence on the chemical
yield. The second step in our synthetic pathway to 7b was a
reductive ring opening with sodium bis(methoxyethoxy)alu-
minumhydride (Red-Al). This reaction was conducted ac-
cording to another procedure published by Sharpless
et al.,[32] whereby diole 20a was isolated after aqueous
workup. Due to the fact that three different rotation values
for compound 20 exist in the literature, we measured its
enantiomeric excess by means of gas chromatography with
the aid of a chiral GC column. Afterwards, diole 20a was
subjected to a three-step protection/deprotection sequence
to get the mono-protected diole 20d. The primary hydroxy
function was thereby esterified with benzoyl chloride in di-
chloromethane first, followed by silylation of the tertiary hy-
droxy function with TBS triflate and 2,6-lutidine in dichloro-
methane. The third and last step of the sequence was the
cleavage of the ester function with sodium hydroxide in
methanol at room temperature. The mono-protected diole
20d was then transformed into the respective aldehyde 21
by a so-called Parikh–Doering oxidation,[33,34] a Swern-ana-
logue reaction with a sulfur trioxide–pyridine complex and
dimethylsulfoxide as reagents. With aldehyde 21 in hand, we
had a compound comparable to citronellal (15; Scheme 4),
which was suitable for the synthesis of diyne 7b. Unfortu-
nately, we noticed that with the introduction of R2 =OTBS
the reactivity of aldehyde 21 changed tremendously. By ap-
plying standard Corey–Fuchs conditions as we used for the
synthesis of 7a, it was not possible to convert aldehyde 21
into its geminal dibromide. The addition of triethylamine
and conduction of the reaction at ꢀ808C enabled us to
transfer the aldehyde into the dibromide. Elimination with a
small excess amount of n-butyllithium in THF and quench-
ing with TMS-Cl led to the TMS-protected enyne 22. Ozo-
nolysis of enyne 22 under basic conditions with pyridine as
cosolvent afforded aldehyde 23 after workup with dimethyl-
sulfide. It is remarkable to note that in the case of the ozo-
nolysis due to the OTBS group under standard conditions
without pyridine, the yield of 23 was much lower. By the ad-
dition of pyridine, we were able to increase the yield up to
85%. Under modified Corey–Fuchs conditions with Et3N as
described before and an elimination reaction with n-butyl-
lithium, aldehyde 23 was converted into the substituted oc-
tadiyne 7b.
Preparation of the triynes 5: With benzaldehydes 6 and
octadiynes 7 in hand, we could now combine benzaldehyde
6a with both diynes 7a and b and benzaldehyde 6b with oc-
tadiyne 7b. By combining these building blocks, we were
able to accomplish the total syntheses of three different nat-
urally occurring antibiotics: (+)-rubiginone B2 (1), (ꢀ)-8-O-
methyltetrangomycin (2), and (ꢀ)-tetrangomycin (3).
We started with the addition of the lithiated octadiyne 7a
to benzaldehyde 6a. For this addition reaction, octadiyne 7a
was dissolved in THF, cooled to ꢀ808C, and then treated
with n-butyllithium. The deprotonated octadiyne was then
stirred for 50 min, whereby the temperature increased slight-
ly to ꢀ408C. After cooling the solution again to ꢀ808C, it
was transferred into another flask containing a solution of
the aldehyde 6a in THF at ꢀ808C. The combined solutions
were stirred for 2 h until the solution reached a temperature
of 08C, whereupon an aqueous workup followed. When the
same reaction was conducted with 6a and 7b, the yield was
much lower. This problem was solved by adding boron tri-
fluoride etherate to the solution of the aldehyde to increase
the reactivity of the carbonyl group. When benzaldehyde 6b
and octadiyne 7b were finally brought to reaction, we again
had the problem of very poor yields. Due to the fact that
the addition of strong Lewis acids to acetals is often prob-
lematic, we decided to search for another solution. The best
way to increase the reactivity without adding a Lewis acid
was to raise the reaction temperature. By conducting the ad-
dition reaction at ꢀ158C we were able to achieve a yield of
93% for this coupling reaction (Table 1).
Through this method, we could build up the terminally
protected triynes 25 (Scheme 6). However, these were not
suitable for the cobalt-mediated [2+2+2] cycloaddition in
this form. Therefore, we had to deprotect the terminal ace-
Table 1. Reaction conditions for the addition of octadiynes 7 to alde-
hydes 6.
Entry Octadiyne
Aldehyde
Reaction conditions
Yield
[%]
1
2
3
7a (R2 =H) 6a
a) nBuLi, THF, ꢀ808C!
ꢀ308C, 1 h b) 6a, THF,
ꢀ808C!RT, 4 h
98
70
93
(R1 =Me)
7b
6a
a) nBuLi, Et2O, ꢀ808C!
ꢀ308C, 1 h b) 6a, BF3·Et2O,
Et2O, ꢀ808C!RT, 2 h
a) nBuLi, THF, ꢀ808C!
(R2 =OTBS) (R1 =Me)
7b
6b
(R2 =OTBS) (R1 =MOM) ꢀ308C, 1 h b) 6b, Et2O,
ꢀ158C, 1 h
After optimization of this sequence, we were able to syn-
thesize octadiyne 7b in an overall yield of 49% over 11
linear steps. To ensure the enantiomeric purity, we decided
to cleave the tertiary TBS group (Scheme 5) to measure the
enantiomeric excess of the monoprotected octadiyne 24 by
means of chiral gas chromatography in comparison with the
racemic octadiyne rac-24, which was synthesized from 5-hex-
ynone and a Grignard reagent prepared from 3-TMS-prop-
argyl bromide. As a result of this comparative measurement,
we could show that the enantiomeric excess was unchanged
and remained at 91% ee.
Scheme 6. Addition of octadiynes 7 to aldehydes 6.
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Angucyclinones
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Table 2. Cobalt-mediated [2+2+2]-cycloaddition of triynes 5.
tylenes and to protect the free hydroxy functionality
(Scheme 7). Thus, we first removed the trimethylsilyl groups
from the acetylenic groups. In the case of the rubiginone B2
Catalyst
Yield
[%]
Entry Triyne Type
Amount Reaction conditions
[mol%]
1
2
3
4
5a
5a
5a
5b
N
5
10
5
hn, toluene, reflux,
4 h
hn, toluene, reflux,
4 h
61
74
G
Et2O, ꢀ808C!08C, 76
4 h
10
slow addition of the 23
catalyst, hn, toluene,
reflux, 40 h
5
5b
[CpCo(CO)2]
20
slow addition of the 44
catalyst, hn, toluene,
reflux, 8 h
6
5b
5b
5b
5b
5b
5c
5c
N
20
40
hn, toluene, reflux,
4 h
hn, toluene, reflux,
4 h
hn, toluene, reflux,
4 h
31
38
58
7
8
9
R
Et2O, ꢀ808C!08C, 45
4 h acidic workup
10
11
12
E
Et2O, ꢀ808C!08C, 80
4 h acidic workup
hn, toluene, reflux,
38
4 h
G
Et2O, ꢀ608C!08C, 93
4 h
reaction conditions given for the cyclization with the biscar-
bonyl complex, we could only isolate the aromatic tetrahy-
drobenzo[a]anthracenes 4. In contrast, after cyclization with
the bis-ethene complex, we isolated a mixture of the aro-
matic products 4 and the direct cyclization products 27 with
a OTBS group situated at the C12 position. By choosing an
acidic workup with acetic acid, we were able to convert the
primer cyclization products 27 into the desired aromatic tet-
rahydrobenzo[a]anthracenes 4.[22i]
Afterwards, the aromatic systems were oxidized with a
silver permanganate complex to their corresponding tetrahy-
drobenzo[a]anthraquinones.[35] The oxidation was accom-
plished in dichloromethane at room temperature with a
huge excess amount of oxidant mixed thoroughly with silica
gel prior to use. As a typical workup, the brown suspension
was filtered, whereby an intensive yellow solution was ob-
tained. This solution was concentrated in vacuo and the re-
sulting solid was purified by means of flash column chroma-
tography over silica gel to give the pure compounds 28 in
48–65% yield. At this stage, the reaction pathway split
(Scheme 8). Whereas the rubiginone B2 precursor 28a was
directly converted into the natural product 1 by photooxida-
tion with light and air,[36] compounds 28b and 28c had to be
deprotected before they could be oxidized to their corre-
sponding natural products. Compound 28b was deprotected
with hydrofluoric acid in acetonitrile to lead to compound
29, which was subsequently oxidized to 2 following the pro-
cedure given for the photooxidation to 1. For the synthesis
of 3 from compound 28c, two different deprotection steps
Scheme 7. Preparation of the tetrahydrobenzo[a]anthracenes 4.
precursor 25a, we used ammonium fluoride in a two-phase
system of water and dichloromethane for this reaction. In
the cases in which a TBS-protected tertiary alcohol was
present (25b and c) we used potassium carbonate in metha-
nol to remove the terminal TMS groups without affecting
the TBS group.
The second step to accomplish the precursor synthesis
was to protect the secondary alcohol with tert-butyldimethyl-
silyltrifluoromethanesulfonate (OTBSTf). For this reaction,
the triynes 26 were dissolved in dichloromethane together
with 2,6-lutidine, cooled to 08C, and OTBSTf was slowly
added with a syringe. After aqueous workup and column
chromatography, we obtained analytically pure triynes 5, the
starting material for the [2+2+2] cycloaddition.
The cobalt-mediated [2+2+2] cycloaddition of triynes 5a–
c was tested and performed under various conditions using
[CpCo(CO)2] and [CpCoACHTNUTRGNE(UNG C2H4)] as catalysts (Table 2).
Whereas the cycloaddition of 5a with catalytic amounts of
either the carbonyl complex or the ethene complex gave ex-
cellent yields, triyne 5b afforded only low yields under these
conditions. In the case of 5b and 5c, only stoichiometric
amounts of the cobalt–ethene yielded the tetrahydroben-
zo[a]anthracene in good yields. We observed that, under the
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U. Groth et al.
Conclusion
In the end, we were able to
complete the synthesis of three
representative members of the
angucyclinone natural product
class. (+)-rubiginone B2 (1) has
been synthesized in 15 steps
(longest linear synthesis se-
quence was 11 steps) with an
overall yield of 15% and an
enantiomeric excess of 92% ee.
(ꢀ)-8-O-methyltetrangomycin
(2) was synthesized in 22 steps,
whereby the longest linear se-
quence had 18 steps, in 9%
overall yield and an enantio-
meric excess of 91% ee. And,
finally, (ꢀ)-tetrangomycin (3)
has been obtained by a synthe-
sis containing 26 steps (19
linear steps); it afforded the
product in 9% overall yield and
with an enantiomeric excess of
90% ee.
Experimental Section
General remarks: Infrared (IR) spec-
tra were obtained using
a Perkin–
Elmer 1600 spectrometer. NMR spec-
tra were obtained using a JEOL 400
GX JNM or a Bruker Advance DRX
600 spectrometer for 1H and 13C NMR
spectroscopy. Chemical shifts are
given in parts per million (d) using tet-
ramethylsilane as internal standard for
1H and 13C NMR spectroscopy. Mass
spectra were recorded using a Varian
MAT 312 spectrometer. GC–MS anal-
yses were recorded using an HP-6890
GC system with an HP 5973 MSD.
HPLC analyses were performed using
Scheme 8. Synthesis of the antibiotics (+)-rubiginone B2 (1), (ꢀ)-8-O-methyl-tetrangomycin (2), and (ꢀ)-tet-
rangomycin (3).
a MERCK/HITACHI L4000 HPLC system with UV detection at 254 nm.
Optical rotations were measured using a Perkin–Elmer Mod. 241 MC po-
larimeter. The melting points were measured in open capillary tubes
using a Gallenkamp melting-point apparatus and are not corrected. TLC
analyses were performed using Polygram Sil G/UV254 silica gel plates
(Macherey & Nagel). Merck silica gel 60 (0.040–0.063 mm, 230–400
mesh) was used for flash chromatography. Combustion analyses were car-
ried out by the microanalytical laboratory of the University of Konstanz.
All reactions were carried out under an argon atmosphere except those
involving hydrolysis. All reagents were purified and dried if necessary
before use.
were necessary. At first we removed the MOM group in po-
sition C8 with acetyl chloride in dry methanol for an excel-
lent yield of 96%. The resulting monoprotected compound
30 was treated with hydrofluoric acid in acetonitrile at ele-
vated temperatures to remove the TBS group. By this
means, we obtained 31 as precursor for the synthesis of the
natural product 3. Successful photooxidation in chloroform
with a tungsten lamp in air afforded natural product 3 in a
yield of 60% and with an enantiomeric excess of 91% ee.
Noticeable are the differences in reaction time for the pho-
tooxidation between the different natural products. Whereas
oxidation of 29 needed only 1 h, oxidation of 28a took 18 h,
and oxidation of 31 even 48 h, whereas the yields of the dif-
ferent photooxidations are in the same range.
N,N-Diethyl-3-methoxybenzamide (10): 3-Methoxybenzoic acid (31.4 g,
0.206 mol) was heated to reflux in thionyl chloride (65 mL) for 3 h. Com-
pletion of the reaction was controlled by TLC. The excess amount of
thionyl chloride was removed by distillation. The residue was dissolved in
dichloromethane (100 mL). Diethylamine (40.4 mL, 0.392 mol) in di-
chloromethane (150 mL) was added dropwise to this solution and was
stirred overnight at room temperature. For workup, the solution was di-
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Angucyclinones
FULL PAPER
luted with dichloromethane (250 mL) and poured into an aqueous
NaHCO3 solution (300 mL). Phases were separated, the organic layer
was washed with HCl (1m, 300 mL) and water (300 mL), dried over
MgSO4, and concentrated in vacuo, thereby providing 10 (35.8 g,
rial was detected by TLC. The reaction mixture was extracted with dieth-
yl ether (3ꢄ300 mL). The combined organic layers were washed with
brine (300 mL), dried over MgSO4, and concentrated in vacuo. The vis-
cous brown oil was dissolved in boiling ethyl acetate (100 mL) and
cooled overnight in a refrigerator to provide colorless crystals (27.8 g,
0.144 mol, 73%). M.p. 848C; Rf =0.09 (petroleum ether/diethyl ether
0.173 mol, 84%). B.p. 1238C (1 mbar); Rf =0.18 (petroleum ether/ethyl
1
ꢀ
acetate 5:1); H NMR (400 MHz, CDCl3): d=1.11 (m, 3H; CH3), 1.25
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1:2); 1H NMR (400 MHz, CDCl3): d=1.08 (t, 3J
ACHTUNGTRENNUNG
(m, 3H; CH3), 3.25 (m, 2H; CH2 ), 3.54 (m, 2H; CH2 ), 3.82 (s, 3H;
ꢀ
CH3), 1.23 (t, 3J
G
ACHTUNGTRENNUNG
OCH3), 6.92 (m, 3H; H2, H3, H5), 7.30 ppm (t, 3J
(H,H)=8.2 Hz, 1H;
ꢀ
ꢀ
ꢀ
2H; NCH2 ), 3.53 (q, 3J
ACTHNGUTER(NNUG H,H)=6.6 Hz, 2H; NCH2 ), 6.76 (m, 2H;
13
ꢀ
ꢀ
ꢀ
ꢀ
H4); C NMR (100 MHz, CDCl3): d=12.8 and 14.1 (2ꢄ CH3), 39.0 and
43.1 (2ꢄ CH2 ), 55.2 ( OCH3), 111.5, 114.8, 118.2, 129.4 (CH arom.),
138.4 (C1), 159.4 (C3), 170.8 ppm (C=O).
H4 and H6), 6.85 (s, 1H; H2), 7.13 (t, 3J
ACTHNUTRGNEUNG(H,H)=7.8 Hz, 1H; H5),
ꢀ
ꢀ
ꢀ
8.76 ppm (brs, 1H; Ar OH); 13C NMR (100 MHz, CDCl3): d=12.7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
A
3-Acetoxybenzoic acid: 3-Hydroxybenzoic acid (100.0 g, 0.724 mol) was
dissolved in a solution of sodium hydroxide (96.1 g, 0.796 mol) in distilled
water (400 mL) at room temperature. After the acid had been dissolved
completely, ice (500 g) was added and stirred vigorously for 10 min.
Acetic anhydride (88 mL, 0.94 mol) was quickly added in one portion to
this water/ice mixture, and the reaction mixture stirred overnight at am-
bient temperature. The aqueous solution was extracted with diethyl ether
(3ꢄ250 mL). The combined organic phases were dried over MgSO4 and
concentrated in vacuo to provide colorless crystals (97.4 g, 0.541 mol,
75%). M.p. 1148C; Rf =0.35 (petroleum ether/diethyl ether 1:1);
(C4), 117.1 (C6), 129.4 (C5), 137.0 (C1), 157.1 (C3), 172.1 ppm
(CONEt2); IR (CCl4): n˜ =3606.6 (w), 3237.2 (brm), 3072.0 (m), 2979.0
(m), 2937.7 (m), 2876.3 (m), 1613.1 (s), 1592.0 (s), 1509.6 (m), 1506.5 (m),
1475.4 (s), 1446.7 (s), 1383.1 (m), 1366.1 (m), 1349.1 (m), 1314.8 (s),
1294.4 (s), 1262.2 (m), 1232.2 (m), 1219.5 (m), 1177.8 (m), 1158.8 (m),
1102.1 (m), 1079.8 (w), 1070.2 (w), 1012.6 (w), 998.9 (w), 949.7 (w),
927.1 cmꢀ1 (w); MS (GC–MS): m/z (%): 194 (4), 193 (30) [M+], 192 (53),
164 (6), 122 (9), 121 (100) [M+ꢀNEt2], 120 (3), 107 (1), 94 (2), 93 (19)
[121ꢀCO], 92 (3), 72 (3), 66 (1), 65 (11), 64 (2), 63 (2), 56 (1), 53 (1); ele-
mental analysis calcd (%) for C11H15NO2: C 68.37, H 7.82, N 7.25; found:
C 67.93, H 7.76, N 7.13.
1H NMR (400 MHz, CDCl3): d=2.27 (s, 3H; CH3), 7.38 (d, 3J
ACHTUNGTRENNUNG
7.8 Hz, 1H; H4), 7.53 (t, 3J
ACHTUNGTRENNUNG
7.82 ppm (d, 3J
ACHTUNGTRENNUNG
N,N-Diethyl-3-methoxymethoxybenzamide (13): Diisopropylethylamine
(44 mL, 0.263 mol) and MOM-Cl (14.4 mL, 0.193 mol) were added con-
ꢀ
d=20.9 ( CH3), 122.8 (C2), 126.5 (C4), 126.8 (C6), 129.9 (C5), 132.3
secutively to
a solution of N,N-diethyl-3-hydroxybenzamide (33.9 g,
ꢀ
ꢀ
(C1), 150.6 (C3), 166.6 ( CO2H), 169.3 ppm ( COCH3); IR (CCl4): n˜ =
3711.5 (w), 3608.9 (w), 3538.4 (w), 3079.7 (m), 3018.7 (m), 2888.1 (m),
2674.3 (m), 2559.2 (m), 1773.9 (s), 1745.3 (m), 1700.4 (s), 1589.1 (s),
1489.2 (m), 1452.7 (s), 1414.3 (m), 1369.6 (s), 1302.2 (s), 1288.1 (s), 1269.7
(s), 1200.0 (s), 1106.8 (w), 1076.8 (w), 1012.7 (m), 942.1 cmꢀ1 (m); MS
(GC–MS): m/z (%): 180 (11.4) [M+], 163 (0.8), 140 (1), 139 (8), 138
(100) [M+ꢀAc], 122 (3), 121 (42) [M+ꢀOAc], 110 (1), 93 (8), 81 (3), 66
(1), 65 (7), 63 (7), 53 (3), 50 (1); elemental analysis calcd (%) for
C9H8O4: C 60.00, H 4.48; found: C 59.11, H 4.68.
0.175 mol) in absolute dichloromethane (500 mL) by means of a dropping
funnel at room temperature. The reaction mixture was left at reflux for
12 h whereupon the colorless solution turned orange. The reaction was
quenched by the addition of
a half-concentrated NaHCO3 solution
(300 mL) and vigorous stirring for 3 min. Phases were separated, and the
aqueous layer was extracted with dichloromethane (2ꢄ50 mL). The com-
bined organic layers were washed with brine (300 mL), dried over
MgSO4, and concentrated in vacuum. Chromatography (petroleum ether/
diethyl ether 1:2) of the residue, an orange oil, provided a colorless oil
(40.7 g, 0.172 mol, 98%). Rf =0.32 (petroleum ether/diethyl ether 1:2);
N,N-Diethyl-3-acetoxybenzamide (12): A suspension of 3-acetoxybenzoic
acid (97.4 g, 0.541 mol) in thionyl chloride (180 mL) was heated at reflux
for 4.5 h to give a colorless solution. Distillation (1108C, 0.5 mbar) of the
solution provided a colorless oil (105.3 g, 0.530 mol, 98%). The benzoyl
chloride was dissolved in absolute dichloromethane (500 mL), cooled to
08C, and treated dropwise with diethylamine (120 mL, 1.16 mol). The re-
action mixture was stirred overnight while slowly warming to ambient
temperature. The mixture was diluted with water (300 mL) and made
acidic with hydrochloric acid (450 mL, 2m). Phases were separated, and
the aqueous layer was extracted with dichloromethane (2ꢄ300 mL). The
combined organic layers were washed with brine (300 mL), dried over
MgSO4, and concentrated in vacuo. Drying the orange oil in vacuum
(<0.1 mbar) provided pure 12 (122.0 g, 0.519 mol, 98%). Rf =0.15 (petro-
leum ether/diethyl ether 1:1); 1H NMR (400 MHz, CDCl3): d=1.12 (brs,
1H NMR (400 MHz, CDCl3): d=0.95 (brs, 3H; CH3), 1.08 (brs, 3H;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
CH3), 3.09 (brs, 2H; NCH2 ), 3.30 (s, 3H; OCH3), 3.36 (brs, 2H;
NCH2), 5.02 (s, 2H; OCH2 OCH3), 6.83 (d, 3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
H4), 6.89 (m, 2H; H2 and H6), 7.14 ppm (t, 3J
ACHTUNGTRENNUNG
13C NMR (100 MHz, CDCl3): d=12.7 ( CH3), 14.0 ( CH3), 39.0
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
( NCH2), 43.1
U
(C2), 116.7 (C4), 119.4 (C6), 129.4 (C5), 138.4 (C1), 157.0 (C3),
ꢀ
170.6 ppm ( CONEt2); IR (CCl4): n˜ =3263.2 (w), 3070.5 (m), 2974.1 (s),
2935.5 (s), 2900.5 (s), 2845.8 (m), 2837.3 (m), 2786.6 (w), 2360.7 (w),
2336.6 (w), 2073.8 (w), 2000.8 (w), 1930.8 (w), 1856.5 (w), 1771.8 (w),
1647.7 (s), 1609.4 (s), 1581.0 (s), 1489.4 (s), 1456.9 (s), 1382.2 (s), 1365.7
(s), 1348.7 (m), 1315.6 (s), 1289.9 (s), 1239.8 (s), 1220.7 (s), 1206.7 (s),
1151.9 (s), 1100.6 (s), 1982.7 (s), 1015.1 (s), 979.1 (m), 925.8 cmꢀ1 (s); MS
(GC–MS): m/z (%): 238 (8), 237 (54) [M+], 236 (34), 208 (1), 207 (3),
206 (7), 193 (9), 192 (71) [M+ꢀC2H5O], 190 (1), 178 (2), 176 (3) [M+
ꢀOMOM], 166 (12), 165 (100) [M+ꢀNEt2], 164 (20), 151 (1), 149 (3),
137 (4) [165ꢀCO], 136 (2), 135 (12), 133 (3), 121 (16) [165ꢀC2H5O], 120
(10), 107 (7), 105 (3), 104 (3), 93 (9) [137ꢀC2H5O], 92 (15), 77 (6), 76 (7)
[C6H4+], 72 (5) [NEt2+], 65 (5), 64 (6), 63 (4), 45 (45); elemental analysis
calcd (%) for C13H19NO3: C 65.80, H 8.07, N 5.90; found: C 65.31, H
8.13, N 6.03.
ꢀ
ꢀ
ꢀ
3H; CH3), 1.25 (brs, 3H; CH3), 2.30 (s, 3H; CH3), 3.28 (brs, 2H;
ꢀ
ꢀ
ꢀ
ꢀ
NCH2 ), 4.64 (brs, 2H; NCH2 ), 7.15 (m, 2H; H2 and H4), 7.25 (d,
3J
ACHTUNGTRENNUNG ACHTUNGTNER(NUGN H,H)=7.8 Hz, 1H; H5);
(H,H)=7.8 Hz, 1H; H6), 7.41 ppm (t, 3J
C NMR (100 MHz, CDCl3): d=12.7 ( CH3), 14.0 ( CH3), 21.0 ( CH3),
39.2 and 43.2 (2ꢄ NCH2 ), 119.7 (C2), 122.2 (C4), 123.5 (C6), 129.4
13
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(C5), 138.3 (C1), 150.3 (C3), 169.0 ( CONEt2), 169.9 ppm ( COCH3); IR
(CCl4): n˜ =3264.8 (w), 3073.1 (w), 2977.3 (s), 2936.9 (s), 2876.1 (m),
2360.8 (w), 1772.1 (s), 1635.6 (s), 1585.8 (s), 1490.1 (s), 1470.2 (s), 1456.7
(s), 1425.9 (s), 1382.7 (s), 1368.5 (s), 1348.8 (m), 1314.9 (s), 1290.4 (s),
1203.6 (s), 1157.1 (s), 1097.8 (s), 1079.0 (m), 1045.7 (w), 1015.0 (m),
1002.6 (m), 949.3 (m), 934.5 cmꢀ1 (m); MS (GC–MS): m/z (%): 235 (48)
[M+], 234 (51), 220 (2), 206 (1), 194 (4), 193 (33), 192 (63) [M+ꢀAc],
178 (1), 176 (2) [M+ꢀOAc], 165 (5), 164 (19), 163 (54) [M+ꢀNEt2], 150
(3), 136 (1), 122 (13), 121 (100) [163ꢀAc], 120 (9), 107 (3), 94 (3), 93
(22), 92 (15), 76 (2), 72 (4), 65 (11), 64 (7), 63 (5), 56 (2); elemental anal-
ysis calcd (%) for C13H17NO3: C 66.36, H 7.28, N 5.95; found: C 65.25, H
7.73, N 6.79.
General procedure for the synthesis of the alkylated benzamides 11 and
14: A solution of sec-BuLi (100.0 mL, 0.140 mmol, 1.4m in cyclohexane)
was added dropwise at ꢀ808C to a solution of N,N,N’,N’-tetramethylethy-
lenediamine (TMEDA; 19.0 mL, 0.126 mol) in THF (100 mL). After
30 min of stirring, a solution of the N,N-diethylbenzamide (0.120 mol) in
THF (70 mL) was added dropwise at ꢀ80 C. After 90 min of stirring at
ꢀ808C, a solution of ZnCl2 (18.0 g, 0.132 mol) in THF (100 mL) was
added through a cannula and the resulting mixture was allowed to warm
to 08C under stirring. The reaction was again cooled to ꢀ808C and a so-
lution of CuCN (11.8 g, 0.132 mol) and LiCl (11.2 g, 0.264 mol) in THF
(150 mL) was added through a cannula. The mixture was allowed to
warm to 08C, stirred for 10 min and cooled again to ꢀ808C. Then 3-tri-
N,N-Diethyl-3-hydroxybenzamide:
A
saturated NaHCO3 solution
(250 mL) was added to a solution of 12 (46.4 g, 0.197 mol) in methanol
(400 mL) and stirred for 5 h at room temperature until no starting mate-
Chem. Eur. J. 2010, 16, 8805 – 8821
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8811

U. Groth et al.
methylsilylpropargyl bromide (25.2 g, 0.132 mol) was added dropwise,
and the resulting mixture was slowly allowed to warm to room tempera-
ture over 18 h. Then the mixture was poured into half-saturated aqueous
NH4Cl (1 L). The organic layer was separated, and the aqueous phase
was extracted with diethyl ether (5ꢄ350 mL). The combined organic
layers were washed with brine (1 L), dried over MgSO4, and concentrated
in vacuum. Chromatography on silica gel (diethyl ether/petroleum ether
1:1) provided the alkylated benzamide as a yellow solid.
THF (70 mL) was added quickly to this white suspension and stirred for
30–35 min until the white suspension turned into a clear yellow solution.
The volume of the solution was then reduced to 5% of its original
volume. The concentrated solution was transferred onto a prepacked
column (silica gel) and purified with a mixture of petroleum ether/diethyl
ether (3:1) as eluent to give a bright-brown oil (1.28 g, 4.6 mmol, 69%
yield). Rf =0.63 (petroleum ether/diethyl ether 2:1); 1H NMR (400 MHz,
ꢀ
ꢀ
CDCl3): d=0.15 (s, 9H; TMS), 3.57 (s, 3H; OCH3), 4.13 (s, 2H; H1’),
5.33 (s, 2H; OCH2-OMe), 7.42 (m, 2H; H4 and H6), 7.58 (t, 3J
A
ꢀ
N,N-Diethyl-3-methoxy-2-(3-trimethylsilyl-prop-2-ynyl)benzamide (11):
4.4 Hz, 1H; H5), 10.43 ppm (s, 1H; CHO); 13C NMR (100 MHz,
M.p. 738C; Rf =0.3 (diethyl ether/petroleum ether 1:1); 1H NMR
ꢀ
(400 MHz, CDCl3): d=0.09 (s, 9H; TMS), 1.08 (t, 3J
G
ꢀ
ꢀ
CDCl3): d=ꢀ0.1 ( TMS), 15.4 (C1’), 56.2 ( OCH3), 84.8 (C3’), 94.7
ꢀ
3H; CH3), 1.28 (t, 3J
(H,H)=7.8 Hz, 3H; CH3), 3.1–3.3 (m, 4H; 2ꢄ
ꢀ
( OCH2-OMe), 104.5 (C2’), 120.0 (C4), 124.3 (C6), 128.1 (C2), 128.4
ꢀ
ꢀ
CH2 ), 3.46 and 3.75 (2ꢄd, 2J
E
ꢀ
(C5), 134.8 (C1), 155.0 (C3), 191.8 ppm ( CHO); IR (CCl4): n˜ =2175.0
ꢀ
ꢀ
ꢀ1
+
OCH3), 6.80 (d, 3J
G
ꢀ
ꢀ
ꢀ
( CꢁC Si), 1707.8 cm ( CHO); MS (GC–MS): m/z (%): 276 (29) [M
ꢀ
], 246 (11) [M+ꢀH2CO], 245 (29) [M+ꢀOMe], 244 (100) [M+ꢀMeOH],
231 (24) [M+ꢀC2H5O], 217 (7) [246ꢀOMe], 215 (8) [M+ꢀOMOM], 203
(14) [M+ꢀTMS], 185 (32) [285ꢀH2CO], 175 (10) [203ꢀH2CO], 73 (93)
[TMS+]; elemental analysis calcd (%) for C15H20O3Si: C 65.18, H 7.29;
found: C 65.08, H 7.21.
AHCTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
ꢀ
(2ꢄ N-CH2 ), 55.7 ( OCH3), 83.3 (C3’), 104.2 (C2’), 111.0 (C4), 117.5
(C6), 121.6 (C2), 128.0 (C5), 138.2 (C1), 157.4 (C3), 169.8 ppm (C=O);
ꢀ1
ꢀ
IR (CCl4): n˜ =2172 (CꢁC Si), 1636 cm (C=O); MS (EI, 70 eV): m/z
(%): 317 (100) [M+], 302 (67) [M+ꢀCH3], 288 (36) [M+ꢀC2H5], 243 (61)
[M+ꢀTMS], 229 (92) [M+ꢀC5H13O], 215 (18); elemental analysis calcd
(%) for C18H27NO2Si: C 68.09, H 8.57, N 4.41; found: C 68.13, H 8.71, N
4.41.
(ꢀ)-[4R]-2,6-Dimethyl-9-trimethylsilylnon-2-ene-8-yne (17): CBr4 (21.5 g,
65.0 mmol) was added slowly to a solution of PPh3 (34.0 g, 0.13 mol) in
CH2Cl2 (500 mL) at 08C and stirring was continued for 30 min. A solu-
tion of (+)-citronellal (15) (5.0 g, 32.4 mmol) in CH2Cl2 (20 mL) was
added dropwise at the same temperature and stirring was continued at
room temperature for 2 h. The reaction mixture was filtered through a
silica gel column with diethyl ether. The solvent was removed in vacuum
and the residue—crude dibromo alkene—was dissolved in THF
(100 mL). The solution was cooled to ꢀ808C, a solution of nBuLi (2.7m
in heptane, 24 mL, 64.8 mmol) was added slowly, and stirring was contin-
ued for 1 h. Chlorotrimethylsilane (7.0 g, 64.9 mmol) was added with a
cannula, and the resulting mixture was allowed to warm to room temper-
ature within 18 h. The mixture was poured then into saturated aqueous
NH4Cl (150 mL). The organic layer was separated and the aqueous phase
extracted with diethyl ether (3ꢄ50 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Column chromatog-
raphy on silica gel (diethyl ether/petroleum ether 1:10) provided the
enyne 17 (5.47 g, 25.0 mmol, 76%) as a colorless liquid. [a]2D3 =ꢀ7.9 (c=
1.0 in CHCl3); Rf =0.26 (diethyl ether/petroleum ether 1:9); 1H NMR
ꢀ
N,N-Diethyl-3-methoxymethoxy-2-(3-trimethylsilyl-prop-2-ynyl)benza-
mide (14): M.p. 608C (petroleum ether/diethyl ether); Rf =0.32 (petro-
leum ether/diethyl ether 1:2); 1H NMR (400 MHz, CDCl3): d=0.05 (s,
9H; TMS), 1.05 (t, 3J
G
G
ꢀ
ꢀ
ꢀ
7.4 Hz, 3H; CH3), 3.1–3.85 (m, 6H; 2ꢄN CH2 and H1’), 3.48 (s, 3H;
OCH3), 5.19–5.26 (m, 2H; OCH2 OMe), 6.82 (d, 3J
ꢀ
1H; H4), 7.07 (d, 3J
N
13
7.4 Hz, 1H; H5); C NMR (100 MHz, CDCl3): d=ꢀ0.06 ( TMS), 12.6
ꢀ
ꢀ
ꢀ
( CH3), 13.9 ( CH3), 17.6 (C1’), 38.6 (N CH2 ), 43.3 (N CH2 ), 56.0
ꢀ
ACHTUNGTRENNUNG( OCH3), 83.6 (C3’), 94.0 ( OCH2 OMe), 104.3 (C2’), 114.2 (C4), 118.6
(C6), 122.4 (C2), 128.0 (C5), 138.4 (C1), 155.0 (C3), 169.7 ( CONEt2);
ꢀ
IR (CCl4): n˜ =2172.9 ( CꢁC Si), 1635.9 cm (C=O); MS (GC-MS): m/z
(%): 347 (93) [M+], 332 (24) [M+ꢀMe], 316 (85) [M+ꢀOMe], 302 (49)
[M+ꢀC2H5O], 286 (4) [M+ꢀOMOM], 275 (6) [M+ꢀNEt2], 274 (25)
G
(400 MHz, CDCl3): d=0.12 (s, 9H; TMS), 0.95 (d, 3J
ACTHNUGRTENUNG(H,H)=6.6 Hz,
[286ꢀNEt2], 187 (11) [246ꢀOMOM], 73 (26) [TMS+]; elemental analysis
calcd (%) for C19H29NO3Si: C 65.67, H 8.41, N 4.03; found: C 65.41, H
8.34, N 3.98.
ꢀ
3H; C4-CH3), 1.19–1.39 (m, 2H), 1.58 and 1.67 (2ꢄs, 6H; 2ꢄ CH3),
ACTHNUTRGNEUNG
1.93–2.20 (m, 4H), 5.08 ppm (t, 3J(H,H)=6.1 Hz, 1H; H7); 13C NMR
ꢀ
(100 MHz, CDCl3): d=0.17 ( TMS), 17.65, 19.39, 25.51, 25.71, 27.07,
3-Methoxy-2-(3-trimethylsilyl-prop-2-ynyl)benzaldehyde (6a): A solution
of nBuLi (5.1 mL, 8.14 mmol, 1.6m in hexane) was added dropwise to a
solution of diisobutylaluminum (DIBAL; 1.2 g, 8.14 mmol) in THF
(30 mL) at 08C. After 30 min, a solution of amide 11 (2.6 g, 8.14 mmol)
in THF (25 mL) was added with a cannula, and the resulting mixture was
allowed to warm up slowly to room temperature over 18 h. The mixture
was then poured into aqueous hydrochloric acid (0.5m, 50 mL). The or-
ganic layer was separated and the aqueous phase was extracted with di-
ethyl ether (3ꢄ100 mL). The combined organic layers were then extract-
ed with brine (0.5 L), dried over MgSO4, and concentrated in vacuo.
Chromatography on silica gel (diethyl ether/petroleum ether 1:10) pro-
vided benzaldehyde 6a (1.36 g, 5.54 mmol, 68%) as a yellow solid.
M.p.=538C; Rf =0.55 (petroleum ether/diethyl ether 5:1); 1H NMR
32.15, 36.11, 85.35 and 86.44 (CꢁC), 124.46 and 131.40 ppm (C=C); IR
(CCl4): n˜ =2173 cmꢀ1 (CꢁC Si); MS (GC–MS): m/z (%): 222 (2) [M ],
+
ꢀ
207 (20) [M+ꢀCH3], 149 (18) [M+ꢀSi
ACHTUNGTRENNUNG
A
(CH3)3ꢀCH4], 73 (100) [Si
(CH3)3+].
ACHTUNGTRENNUNG
(ꢀ)-[4R]-4-Methyl-7-trimethylsilyl-hept-6-yneal (18): A solution of enyne
17 (2.0 g, 9.01 mmol) in CH2Cl2/MeOH (10:1, 20 mL) was cooled to
ꢀ788C and an ozone/oxygene stream was bubbled through this solution
until the solution stayed dark blue for more than 10 s. This indicates an
excess of ozone. The excess of ozone was removed with an oxygen
stream and then dimethyl sulfide (1.12 g, 18.00 mmol) and acetic acid
(7 drops) were added at ꢀ788C and the solution was stirred at room tem-
perature for 18 h. The solvent was removed in vacuo and crude aldehyde
18 (1.86 g, 9.49 mmol, 105%) was obtained, which was used directly for
the next reaction step without any further purification. A small sample of
18 was purified by column chromatography (diethyl ether/petroleum
ether 1:20) for analytical purposes. [a]2D2 =ꢀ1.54 (c=1.17 in CHCl3); Rf =
0.21 (diethyl ether/petroleum ether 1:20); 1H NMR (400 MHz, CDCl3):
ꢀ
ꢀ
(400 MHz, CDCl3): d=0.10 (s, 9H; TMS), 3.90 (s, 3H; OCH3), 4.04 (s,
2H; H1’), 7.13 (d, 3J(H,H)=8.2 Hz, 1H; H4), 7.38 (t, 3J
ACHTUNGTRENNUNG ACHTUGNTREN(NUGN H,H)=8.2 Hz,
1H; H5), 7.5 (d, 3J
(H,H)=8.2 Hz, 1H; H6), 10.46 ppm (s, 1H; CHO);
C NMR (100 MHz, CDCl3): d=0.01 ( TMS), 15.1 (C1’), 56.2 ( OCH3),
85.0 (C3’), 104.6 (C2’), 116.6 (C4), 122.2 (C6), 127.51 (C2), 128.1 (C5),
ꢀ
13
ꢀ
ꢀ
(CH3)3), 0.97 (d, 3J
ACHUTGTNRENNGU ACHTUNTGREN(NUGN H,H)=6.6 Hz, 3H; 4-CH3), 1.57
ꢀ
d=0.12 (s, 9H; Si
(m, 1H), 1.75 (m, 2H), 2.18 (m, 2H), 2.49 (m, 2H), 9.79 ppm (s, 1H;
CHO); 13C NMR (100 MHz, CDCl3): d=0.10 (Si
(CH3)3), 19.25, 26.89,
134.80 (C1), 157.09 (C3), 191.91 ppm ( CHO); IR (CCl4): n˜ =2838 (m,
ꢀ1
ꢀ
ꢀ
ꢀ
OCH3), 2174 (m, CꢁC Si), 1708 cm (s, C=O); MS (EI, 70 eV): m/z
(%): 246 (22) [M+], 231 (58) [M+ꢀCH3], 216 (24) [M+ꢀC2H6], 201 (18)
[M+ꢀC3H9], 73 (100) [TMS+]; elemental analysis calcd (%) for
C14H18O2Si: C 68.25, H 7.36; found: C 68.18, H 7.62.
AHCTUNGTRENNUNG
27.89, 31.99, 41.59 (CH, CH2, CH3), 86.05 and 105.313 (CꢁC),
ꢀ1
ꢀ
202.44 ppm (C=O); IR (CCl4): n˜ =2173 (CꢁC Si), 1713 cm (C=O);
MS (GC–MS) m/z (%): 195 (3) [M+ꢀH], 181 (69) [M+ꢀCH3], 163 (19)
3-Methoxymethoxy-2-(3-trimethylsilylprop-2-ynyl)benzaldehyde (6b): In
a flame-dried Schlenk flask, the Schwartz complex ([CpZr(H)Cl]) (2.6 g,
10.1 mmol) was suspended under a nitrogen atmosphere in absolute THF
(25 mL). A solution of the benzamide 14 (2.33 g, 6.7 mmol) in absolute
[M+ꢀCH3ꢀH2O], 123 (18) [M+ꢀSi
(CH3)3+].
ACHTUGTNRENUNG(CH3)3], 73 (100) [SiACHUTNGTRENNUGN
(ꢀ)-[4R]-4-Methyl-1-trimethylsilylocta-1,7-diyne (7a): CBr4 (15.43 g,
47 mmol) was added slowly to a solution of PPh3 (24.41 g, 93 mmol) in
8812
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8805 – 8821

Angucyclinones
FULL PAPER
CH2Cl2 (300 mL) at 08C with stirring, and this stirring was continued for
30 min. A solution of aldehyde 18 (4.56 g, 23 mmol) in CH2Cl2 (20 mL)
was added dropwise at the same temperature and stirring was continued
at room temperature for 2 h. The reaction mixture was filtered through a
silica gel column with diethyl ether. The solvent was removed in vacuum
and the residue—crude dibromo alkene (6.96 g, 20 mmol)—was dissolved
in THF (100 mL). The solution was cooled down to ꢀ788C, a solution of
nBuLi in heptane (2.7n, 17 mL, 47 mmol) was added dropwise, and stir-
ring was continued for 1 h. H2O (2 mL, 0.11 mol) was added dropwise
with a cannula, and the resulting mixture was allowed to warm up to
room temperature over 10 min. Then the mixture was poured into satu-
rated aqueous NH4Cl (100 mL). The organic layer was separated and the
aqueous phase was extracted with diethyl ether (3ꢄ50 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in
vacuum. Distillation in vacuo afforded the octa-1,7-diyne 7a (3.19 g,
2m). After phase separation, the aqueous phase was extracted with dieth-
yl ether (3ꢄ250 mL), the combined organic layers were dried over
MgSO4 and concentrated in vacuo. Distillation using Kugelrohr (170–
1808C, 10ꢀ1 mbar) yielded
a colorless oil (26.5 g, 0.154 mol, 92%,
91% ee). B.p. 170–1808C (10ꢀ1 mbar) Kugelrohr distillation; [a]2D0 =+3.18
(c=3 in CHCl3); Rf =0.05 (petroleum ether/diethyl ether 1:1); 1H NMR
(400 MHz, CDCl3): d=1.18 (s, 3H; C3-CH3), 1.45–1.60 (m, 2H; H4), 1.56
3
(s, 3H; C7-CH3), 1.6–1.75 (m, 2H; H2), 1.62 (s, 3H; C7-CH3), 1.97 (qi, J-
ꢀ
ꢀ
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(100 MHz, CDCl3): d=17.5 (C7-CH3), 22.6 (C5), 25.6 (C7-CH3), 26.4
(C3-CH3), 41.3 (C4), 42.2 (C2), 59.5 (C1), 73.7 (C3), 124.1 (C6),
131.6 ppm (C7); IR (CCl4): n˜ =3536.2 (m), 3382.9 (m), 2969.3 (s), 2928.8
(s), 2883.4 (s), 1557.3 (m), 1451.3 (m), 1376.3 (s), 1342.5 (m), 1216.9 (m),
1116.0 (s), 1067.6 cmꢀ1 (s); MS (GC–MS): m/z (%): 155 (4) [M+ꢀOH],
154 (31) [M+ꢀH2O], 139 (9), 123 (9), 122 (7), 121 (74), 112 (6), 111 (15),
110 (16), 109 (100) [M+ꢀEtOHꢀH2O], 95 (23), 93 (17), 89 (20)
[C4H9O2+], 84 (9), 83 (8), 81 (20), 79 (8), 71 (39), 69 (67) [C5H9+], 68
(12), 67 (28), 57 (5), 56 (8), 55 (20), 53 (11); elemental analysis calcd (%)
for C10H20O2: C 69.72, H 11.70; found: C 69.07, H 10.92.
17.00 mmol, 74%) as a colorless liquid. B.p.=808C (12 mbar); [a]D26
ꢀ9.4 (c=1.17, CHCl3); Rf =0.35 (diethyl ether/petroleum ether 1:9);
1H NMR (400 MHz, CDCl3): d=0.12 (s, 9H; Si(CH3)3), 0.97 (d, 3J-
=
AHCTUNGTRENNUNG
4
ACHTUNGTRENNUNG(H,H)=6.7 Hz, 3H; 4-CH3), 1.43–1.82 (m, 4H), 1.92 (t, JACHUTNGTREN(NNGU H,H)=2.7 Hz,
1H; CꢁC H), 2.11–2.26 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=
ꢀ
0.21 (SiACHTUNGTRENNUNG(CH3)3), 16.26, 26.84, 34.52 (3ꢄCH2), 19.08, 31.43 (CH and 4-
(3S)-3-Hydroxy-3,7-dimethyl-oct-6-enyl benzoate (20b): After addition
of absolute triethylamine (31.0 mL, 0.222 mol) to a solution of 20a
(25.5 g, 0.148 mol) in absolute dichloromethane (500 mL), the solution
was cooled to 08C. Then benzoyl chloride (21.0 mL, 0.178 mol) was
added dropwise. After addition was completed, the reaction mixture was
stirred for 12 h at ambient temperature. The reaction was quenched by
the addition of water (300 mL) and aqueous HCl (75 mL, 2m) and vigo-
rous stirring for 3 min. Phases were separated, and the aqueous layer was
extracted with dichloromethane (3ꢄ150 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue
was subjected to chromatography (petroleum ether/ethyl acetate 6:1) to
provide a pale yellow oil (40.0 g, 0.145 mol, 98%). [a]2D0 =ꢀ1.48 (c=3 in
CHCl3); Rf =0.14 (petroleum ether/diethyl ether 2:1); 1H NMR
ꢀ
CH3), 68.38 (CꢁC H), 84.22, 85.83, 105.57 ppm (Cquart, 3ꢄCꢁC); IR
ꢀ1
ꢀ
ꢀ
(CCl4): n˜ =3311 (CꢁC H), 2172 cm (CꢁC Si); MS (EI, 70 eV): m/z
(%): 177 (6) [M+ꢀCH3], 73 (100) [Si
ACHTUNGTRENNUNG(2S,3S)-3,7-Dimethyl-2,3-epoxy-6-octenol (19): l-(+)-Tartaric acid
(CH3)3+].
ACHTUNGTRENNUNG
(5.1 mL, 29.9 mmol) was added to a stirred suspension of 4 ꢅ molecular
sieves (5.4 g) in absolute dichloromethane (150 mL) at 08C, followed by
titanium isopropoxide (5.8 mL, 19.5 mmol). The reaction mixture was
cooled to ꢀ208C using a cryostat, whereupon a solution of tert-butyl hy-
droperoxide (54.5 mL, 0.292 mol, 5.5m in CH2Cl2) was added slowly. The
resulting suspension was stirred for 35 min at ꢀ208C before cooling to
ꢀ258C. At this temperature, a solution of geraniol 16 (30 g, 0.195 mol,
50% in dichloromethane) was slowly added with a syringe and stirred for
2.5 h at ꢀ258C until complete conversion of the starting material was ob-
served by TLC. The reaction mixture was slowly warmed to 08C, diluted
with water (100 mL), and stirred at ambient temperature until the reac-
tion mixture had also reached room temperature. NaOH (30 mL, 30% in
water saturated with NaCl) was added and the mixture stirred for 20 min
until phase separation was observed. The solution was filtered, phases
were separated, and the aqueous layer was extracted with dichlorome-
thane (3ꢄ100 mL). The combined organic phases were dried over
MgSO4 and concentrated in vacuo. Distillation of the residue using a Ku-
gelrohr (1508C, 7ꢄ10ꢀ2 mbar) provided a colorless oil (29.8 g, 0.174 mol,
(400 MHz, CDCl3): d=1.29 (s, 3H; C3’-CH3), 1.59 (m, 2H; H4’), 1.62 (s,
3
3H; C7’-CH3), 1.68 (s, 3H; C7’-CH3), 1.98 (dt, J
A
H5’), 2.08 (d, 3J
H2’), 2.27 (brs, 1H; OH), 4.50 (t, J
(H,H)=7.0 Hz, 1H; H6’), 7.42 (t, 3J
7.55 (t, 3J(H,H)=7.4 Hz, 1H; H4), 8.03 ppm (d, 3J
ACHTUNGTRENNUNG
(H,H)=7.4 Hz, 1H; H2’), 2.12 (d, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
3
3
ꢀ
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
U
H2 and H6); 13C NMR (100 MHz, CDCl3): d=17.7 (C7’-CH3), 22.7 (C5’),
25.7 (C7’-CH3), 27.0 (C3’-CH3), 39.9 (C2’), 42.3 (C4’), 61.8 (C1’), 71.9
(C3’), 124.1 (C6’), 128.4 (C3 and C5), 129.6 (C2 and C6), 130.2 (C1),
132.0 (C7’), 133.0 (C4), 166.7 ppm (C=O); IR (CCl4): n˜ =3544.4 (m),
3091.0 (w), 3063.6 (m), 3033.7 (m), 2969.3 (s), 2928.3 (s), 2856.2 (m),
2730.1 (w), 2361.5 (w), 2336.0 (w), 1961.6 (w), 1907.5 (w), 1722.4 (ss),
1602.8 (m), 1585.0 (m), 1490.6 (m), 1451.1 (s), 1376.9 (s), 1314.8 (s),
1272.2 (ss), 1248.3 (s), 1175.9 (s), 1110.9 (s), 1097.2 (s), 1069.9 (s), 1026.8
(s), 981.9 (m), 963.7 (m), 933.2 (m), 914.3 (w), 909.1 (w), 906.4 (w),
900.2 cmꢀ1 (m); MS (GC–MS): m/z (%): 258 (<1) [M+ꢀH2O], 139 (2),
137 (2), 136 (18), 123 (4), 122 (16), 121 (100) [C7H5O2+], 109 (9), 105
(73) [C7H5O+], 93 (15), 91 (2), 81 (3), 77 (25) [C6H5+], 71 (8), 69 (12), 68
(5), 67 (5), 55 (5), 51 (5); elemental analysis calcd (%) for C17H24O3: C
73.88, H 8.75; found: C 73.98, H 8.75.
90%). B.p. 115–1208C (0.5ꢄ10ꢀ2 mbar) Kugelrohr distillation; [a]2D0
=
ꢀ5.08 (c=3 in CHCl3); Rf =0.23 (petroleum ether/diethyl ether 1:1);
1H NMR (400 MHz, CDCl3): d=1.24 (s, 3H; C3-CH3), 1.43 (m, 1H; H4),
1.55 (s, 3H; C7-CH3), 1.59 (m, 1H; H4), 1.62 (s, 3H; C7-CH3), 2.02 (q, 3J-
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
d=16.6 (C7-CH3), 17.5 (C3-CH3), 23.6 (C5), 25.6 (C7-CH3), 38.4 (C4),
61.2 (C3), 61.3 (C1), 63.1 (C2), 123.2 (C6), 132.0 ppm (C7); IR (CCl4):
n˜ =3484.6 (m), 2968.5 (s), 2929.5 (s), 2858.2 (s), 1739.8 (w), 1672.7 (w),
1451.5 (s), 1383.9 (s), 1342.7 (m), 1247.4 (m), 1199.1 (m), 1152.0 (w),
1093.8 (m), 1076.6 (m), 1027.9 (s), 1009.0 (m), 986.0 (w), 951.0 cmꢀ1 (w);
MS (GC–MS): m/z (%): 155 (<1) [M+ꢀCH3], 152 (<1) [M+ꢀH2O], 139
(3), 121 (7), 111 (11), 110 (37), 109 (98) [C8H13+], 101 (<1), 97 (8), 95
(39), 93 (13), 91 (8), 88 (8), 83 (28), 82 (46), 81 (33), 79 (18), 77 (8), 71
(26), 69 (87), 67 (81), 61 (34), 55 (41), 53 (19), 43 (86), 41 (100) [C3H5+];
elemental analysis calcd (%) for C10H18O2: C 70.55, H 10.66; found: C
70.75, H 10.83.
(3S)-3-(tert-Butyldimethylsilyloxy)-3,7-dimethyl-oct-6-enyl
benzoate
(20c): Absolute 2,6-lutidin (23.3 mL, 0.2 mol) was added to a solution of
20b (27.6 g, 99.0 mmol) in dichloromethane (500 mL) and the mixture
was stirred for 5 min at room temperature before being cooled to 08C.
At this temperature, OTBSTf (25.0 mL, 0.109 mol) was added slowly
with a dropping funnel. The reaction mixture was stirred overnight while
it was allowed to warm to room temperature. The reaction was quenched
by addition of water (500 mL) and vigorous stirring for 10 min until the
color of the organic layer changed from brown to orange. Phases were
separated, and the aqueous layer was extracted with dichloromethane
(3ꢄ300 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The brown residue was purified by column chro-
matography (petroleum ether/ethyl acetate 10:1) to provide a colorless
oil (37.0 g, 94.7 mmol, 96%). [a]2D0 =ꢀ2.38 (c=3 in CHCl3); Rf =0.66 (pe-
(3S)-3,7-Dimethyloct-6-ene-1,3-diol (20a): At 08C, a solution of Red-Al
(35.5 g, 0.176 mol, 70% in toluene) was added dropwise to a solution of
epoxide 19 (28.5 g, 0.167 mol) in absolute tetrahydrofuran (500 mL) in
such a way that only slow evolution of gas was observed. After complete
addition of Red-Al, the reaction mixture was stirred for 5 h at ambient
temperature. The mixture was diluted with diethyl ether (200 mL) and
the reaction carefully quenched with water (200 mL) to result in a white
precipitate. The precipitate was dissolved using aqueous HCl (100 mL,
1
troleum ether/diethyl ether 5:1); H NMR (400 MHz, CDCl3): d=0.11 (s,
ꢀ
ꢀ
6H; SitBuACHTUNTRGENN(UG CH3)2), 0.86 (s, 9H; SiMe2CAHCUTNGTRENN(UGN CH3)3), 1.30 (s, 3H; C3’-CH3),
Chem. Eur. J. 2010, 16, 8805 – 8821
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8813

U. Groth et al.
ꢀ
ꢀ
1.54 (m, 2H; H4’), 1.60 (s, 3H; C7’-CH3), 1.67 (s, 3H; C7’-CH3), 1.94 (m,
2H; H5’), 2.05 (m, 2H; H2’), 4.44 (t, 3J
(H,H)=7.0 Hz, 2H; H1’), 5.08 (t,
3J(H,H)=7.0 Hz, 1H; H6’), 7.41 (t, 3J
(H,H)=7.6 Hz, 2H; H3 and H5),
7.53 (t, 3J(H,H)=7.6 Hz, 1H; H4), 8.03 ppm (d, 3J
(H,H)=7.4 Hz, 2H;
H2 and H6); C NMR (100 MHz, CDCl3): d=ꢀ3.0 ( SitBu
CAHUTNGTREN(UNG SiMe2C(Me)3), 22.9 (C7-CH3), 25.7 ( SiMe2CCAHTUTGNERN(NUGN CH3)3), 26.9 (C7-CH3),
G
28.3 (C3-CH3), 43.5 (C4), 55.0 (C2), 74.8 (C3), 123.7 (C6), 131.9 (C7),
203.4 ppm (C1); IR (CCl4): n˜ =2956.4 (s), 2929.2 (s), 2856.7 (s), 2734.2
(w), 1723.6 (s), 1471.6 (m), 1462.1 (m), 1376.4 (m), 1360.1 (w), 1254.6 (s),
1171.0 (w), 1136.6 (m), 1120.5 (m), 1098.8 (w), 1050.7 (s), 1005.5 (m),
982.9 cmꢀ1 (w); MS (GC–MS): m/z (%): 269 (<1) [M+ꢀCH3], 241 (5),
227 (10), 209 (2), 201 (7), 185 (2), 171 (6), 159 (11), 152 (3), 151 (5), 145
(53), 135 (49), 123 (4), 115 (20), 107 (23), 101 (19), 93 (18), 84 (3), 77 (6),
75 (48), 73 (19), 69 (100), 59 (13), 45 (6).
R
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
13
ꢀ
AHCTUNGTRENNUNG
ꢀ
ꢀ
( SitBu
ACHTUNGTRENNUNG
(C7’-CH3), 25.9 (SiMe2tBu), 27.9 (C3’-CH3), 40.5 (C4’), 43.0 (C2’), 62.0
(C1’), 74.6 (C3’), 124.3 (C6’), 128.3 (C3 and C5), 129.5 (C2 and C6), 130.4
(C1), 131.3 (C7’), 132.7 (C4), 166.6 ppm (C=O); IR (CCl4): n˜ =2955.3 (s),
2928.4 (s), 2855.9 (s), 1722.3 (s), 1471.2 (m), 1462.1 (m), 1451.2 (m),
1387.3 (w), 1376.1 (w), 1360.1 (w), 1314.8 (m), 1274.0 (s), 1253.3 (s),
1175.9 (m), 1143.8 (m), 1111.8 (m), 1097.2 (m), 1069.7 (s), 1048.9 (s),
1026.9 (m), 1005.3 cmꢀ1 (m); MS (GC–MS): m/z (%): 333 (<1) [M+
ꢀtBu], 258 (1), 253 (2), 241 (7), 221 (<1), 197 (2), 185 (12), 179 (47)
[C10H11O3+], 145 (2), 137 (14), 136 (5), 135 (4), 121 (16) [Ph+ꢀCO2], 106
(8), 105 (100) [Ph+ꢀCO], 95 (5), 81 (13), 77 (11) [C6H5+], 75 (13), 73
(12), 69 (9) [C5H9+], 55 (2); elemental analysis calcd (%) for C23H34O3Si:
C 70.72, H 9.81; found: C 70.56, H 9.70.
(1S)-tert-Butyl-[1-(3,3-dibromoallyl)-1,5-dimethylhex-4-enyloxy]dimethyl-
silane: Tetrabromocarbon (53.6 g, 0.162 mol, 2 equiv) was carefully added
portionwise (in large-scale preparation, the reaction is very exothermic)
at room temperature to
a solution of triphenylphosphane (85 g,
0.324 mol, 4 equiv) in dry dichloromethane (500 mL), which gave a deep
orange solution after stirring for 30 min at room temperature. Then dry
triethylamine (90 mL, 0.648 mol, 8 equiv) was added slowly at RT, fol-
lowed by cooling the solution to ꢀ808C (isopropanol/liquid nitrogen),
whereupon
a 50 vol% solution of the aldehyde 21 (23 g, 81 mmol,
(3S)-3-(tert-Butyl-dimethylsilyloxy)-3,7-dimethyloct-6-en-1-ol
NaOH (4.1 g, 0.103 mol) dissolved in absolute MeOH (250 mL) was
slowly added with dropping funnel to solution of 20c (35.6 g,
(20d):
1 equiv) in dichloromethane was added with a syringe to the reaction so-
lution. The reaction was then stirred in a cooling bath overnight under
warming to room temperature. On the next day, silica gel (300 g) was
added to the solution, followed by evaporation of the solvent with a
rotary evaporator. The resulting yellow solid was pounded in a mortar
and the yellow powder was put onto the top of an already packed
column (1 kg of silica gel, petroleum ether/diethyl ether 10:1) and puri-
fied by means of column chromatography with petroleum ether/diethyl
ether (10:1), which gave a colorless oil (32.1 g, 72.9 mmol, 90% yield).
[a]2D0 =ꢀ4.38 (c=3 in CHCl3); Rf =0.84 (petroleum ether/diethyl ether=
ꢀ
a
a
91.0 mmol) in absolute MeOH (250 mL) at room temperature, where-
upon the reaction mixture slowly turned yellow. After stirring for 5 h at
ambient temperature no starting material was observed by TLC. The re-
action was quenched by addition of water (1.5 L) and 5 min vigorous stir-
ring. The aqueous phase was extracted with diethyl ether (3ꢄ600 mL).
The combined organic layers were washed with brine (350 mL), dried
over MgSO4, and concentrated in vacuum. The yellow oil was subjected
to chromatography (petroleum ether/ethyl acetate 5:1) to yield a color-
less oil (24.8 g, 86.5 mmol, 95%) . [a]2D0 =+8.98 (c=3 in CHCl3); Rf =0.21
(petroleum ether/diethyl ether 5:1); 1H NMR (400 MHz, CDCl3): d=
10:1); 1H NMR (400 MHz, CDCl3): d=0.075 (s, 3H; SitBu
ACHTUNGTRENNUNG
ꢀ
ꢀ
0.078 (s, 3H; SitBuACTHNUGTERNN(UGN CH3)2), 0.86 (s, 9H; SiMe2CACHTUNGTRENNUNG
ꢀ
ꢀ
0.08 (s, 6H; SitBu
CH3), 1.45 (m, 2H; H4), 1.56 (s, 3H; C7-CH3), 1.64 (s, 3H; C7-CH3),
G
N
ACHTUNGTRENNUNG
ACHUTNGRENNUG CAHTUNGTREN(NUNG H,H)=7.0 Hz, 1H; H4), 6.48 ppm (t,
(H,H)=6.7 Hz, 2H; H1’), 5.7 (t, 3J
1.71 (m, 2H; H2), 1.93 (q, 3J
(H,H)=8.0 Hz, 2H; H5), 2.80 (brs, 1H;
(H,H)=6.2 Hz, 2H; H1), 5.04 ppm (t, 3J
(H,H)=7.0 Hz,
(CH3)2), ꢀ1.89
3J
ACHTUNGTRENNUNG
OH), 3.74 (t, 3J
A
ꢀ
ꢀ
13
ꢀ
1H; H6); C NMR (100 MHz, CDCl3): d=ꢀ1.91 ( SitBu
ꢀ
( SitBu
U
ꢀ
CH3), 25.8 ( SiMe2tBu), 27.6 (C3-CH3), 42.6 (C4), 42.8 (C2), 59.6 (C1),
78.0 (C3), 124.1 (C6), 131.4 ppm (C7); IR (CCl4): n˜ =3527.7 (m), 2956.1
(s), 2929.1 (s), 2856.8 (s), 2734.9 (w), 2361.9 (w), 1471.7 (m), 1462.3 (m),
1408.4 (m), 1387.7 (m), 1375.7 (m), 1360.1 (m), 1339.9 (m), 1305.6 (w),
1254.7 (s), 1215.8 (m), 1158.2 (m), 1114.8 (s), 1094.4 (s), 1072.6 (m),
1027.9 cmꢀ1 (s); MS (GC–MS): m/z (%): 271 (<1) [M+ꢀCH3], 242 (3),
241 (13), 203 (5) [M+ꢀC6H11], 187 (2), 173 (5), 161 (2), 154 (7) [M+
ꢀOTBSH], 145 (8), 137 (22) [154ꢀH2O], 133 (10), 121 (10), 115 (7)
[TBS+], 111 (7) [C8H15+], 109 (13), 105 (27), 95 (28), 89 (13), 81 (50), 75
(88), 73 (29), 70 (6), 69 (100) [C5H9+], 67 (9), 57 (6) [tBu+], 55 (8). 45
(6); elemental analysis calcd (%) for C16H34O2Si: C 67.07, H 11.96;
found: C 66.83, H 11.34.
(+)-[3S]-3-(tert-Butyldimethylsilanyloxy)-3,7-dimethyl-oct-6-enal
Dry triethylamine (96.8 mL, 0.7 mol, 8 equiv) was added at room temper-
ature to a solution of the alcohol 20d (25 g, 87.3 mmol) in methyl sulfox-
ide (500 mL). Afterwards, the sulfurtrioxidepyridine complex (55.6 g,
0.35 mol, 4 equiv) was added portionwise, and the brownish solution was
then stirred for 3 h at room temperature under TLC control. After com-
plete conversion, the reaction solution was diluted with water (around
1.5 L; exothermic reaction) and extracted 4 times with diethyl ether
(300 mL portions). The combined organic phases were then dried over
magnesium sulfate, and the solvent was evaporated to give a brown oil
(with an intense odor). The oily residue was purified then by means of
column chromatography over silica gel with petroleum ether/diethyl
ether (20:1) to give a colorless oil (23.0 g, 93% yield). [a]2D0 =+8.32 (c=3
in CHCl3); Rf =0.6 (petroleum ether/diethyl ether=5:1); 1H NMR
ꢀ
ꢀ
(400 MHz, CDCl3): d=0.08 (s, 3H; SitBu
(CH3)2), 0.84 (s, 9H; SiMe2C
ꢀ
ꢀ
T
(CH3)3), 1.32 (s, 3H; C3-CH3), 1.55 (m,
G
(CH3)2), 0.12 (s, 9H; Si
E
ꢀ
2H; H4), 1.57 (s, 3H; H8), 1.65 (s, 3H; C7-CH3), 2.03 (m, 2H; H5), 2.45
N
(dd, 2J
7.2 Hz, 1H; H6), 9.84 ppm (t, 3J
(100 MHz, CDCl3): d=ꢀ2.0 and ꢀ1.9 ( SitBu
(H,H)=14.6 Hz, 3J
R
3J
ACHTUNGTRENNUNG
ꢀ
8814
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8805 – 8821

Angucyclinones
FULL PAPER
ꢀ
ꢀ
ꢀ
ꢀ1.9 ( SitBu-(CH3)2), 0.1 ( Si
N
E
371 (70), 369 (35), 269 (4), 226 (3), 211 (4), 170 (20), 169 (100), 155 (4),
147 (11), 139 (11), 115 (7), 97 (4), 75 (21), 73 (59), 59 (4), 45 (2).
ꢀ
E
33.8 (C3), 42.0 (C5), 75.0 (C4), 86.3 (C1), 104.8 (C2), 124.5 (C7),
131.3 ppm (C8); IR (CCl4): n˜ =2957.7 (s), 2928.6 (s), 2855.5 (s), 2359.9
(w), 2336.0 (w), 2174.5 (m), 1471.6 (m), 1461.8 (m), 1374.9 (m), 1359.6
(m), 1310.1 (w), 1250.1 (ss), 1215.9 (w), 1188.2 (w), 1168.0 (m), 1128.7
(m), 1114.3 (m), 1096.6 (m), 1050.2 (s), 1005.0 cmꢀ1 (m); MS (GC–MS):
m/z (%): 337 (2), 297 (6), 296 (16), 295 (62), 269 (6), 241 (100), 221 (3),
207 (6), 197 (2), 183 (5), 170 (18), 169 (89), 157 (5), 147 (21), 139 (4), 127
(4), 115 (9), 109 (22), 97 (6), 83 (4), 75 (24), 73 (56), 69 (36), 59 (8), 45
(2).
(4S)-4-(tert-Butyldimethylsilanyloxy)-4-methyl-1-trimethylsilanyl-octa-
1,7-diyne (7b): nBuLi (70 mL, 0.110 mmol, 2.2 equiv, 1.6m in hexane)
was added with a dropping funnel to a solution of (5S)-1,1-dibromo-5-
(tert-butyldimethylsilanyloxy)-5-methyl-8-trimethylsilanyl-oct-1-en-7-yne
(24.0 g, 50 mmol, 1 equiv) in dry THF (500 mL) at ꢀ808C. The brownish
solution was then stirred for 2 h under warming to room temperature,
followed by cooling the solution again to 08C. After quenching the solu-
tion with saturated NH4Cl solution (100 mL), additional H2O (400 mL)
was added, and the resulting solution was then stirred for 5 min at 08C.
After phase separation, the aqueous phase was extracted 3 times with di-
ethyl ether (200 mL portions), and the combined organic phases were
then dried over magnesium sulfate. Evaporation of the solvent gave a
brown oil, which was purified by means of column chromatography with
petroleum ether/diethyl ether (50:1) to give a yellowish oil (15.3 g,
47.5 mmol, 95% yield). [a]D20 =ꢀ5.3 (c=3 in CHCl3); Rf =0.84 (petro-
leum ether/diethyl ether 10:1); 1H NMR (400 MHz, CDCl3): d=0.069 (s,
(4S)-4-(tert-Butyldimethylsilanyloxy)-4-methyl-7-trimethylsilanylhept-6-
ynal (23): Ozone was introduced at ꢀ808C for 30 min into a solution of
enyne 22 (22.0 g, 62.4 mmol, 1 equiv) and pyridine (11.1 g, 0.14 mol,
2.25 equiv) in dry dichloromethane (1 L) until the color of the solution
turned purple. A TLC analysis showed that enyne 22 reacted completely,
so dimethyl sulfide (66 mL) was added at ꢀ808C to the solution, which
was stirred overnight under warming to room temperature. The next day,
silica gel (around 200 g) was added to the orange solution, and the sol-
vent was evaporated. The orange solid was then purified by means of
column chromatography with petroleum ether/diethyl ether (20:1!10:1)
to give a yellow oil (17.3 g, 53.1 mmol, 85% yield). [a]2D0 =ꢀ5.6 (c=3,
CHCl3); Rf =0.42 (petroleum ether/diethyl ether 10:1); 1H NMR
ꢀ
ꢀ
ꢀ
3H; SitBu
G
R
ACHTUNGTRENNUNG(CH3)3),
0.84 (s, 3H; C4-CH3), 1.82 (m, 2H; H5), 1.90 (t, 4J
ACHTUNGTRENNUNG
H8), 2.25 (dt, 3J
(H,H)=8.2 Hz, 4J
U
13
ꢀ
2H; H3); C NMR (100 MHz, CDCl3): d=ꢀ2.17 and ꢀ2.22 ( SitBu-
ꢀ
A
ACHTUGNTRNEN(UNG CH3)3), 25.8
ꢀ
ꢀ
(400 MHz, CDCl3): d=0.05 (s, 3H; SitBu
ACHTUNGTRENNUNG
ꢀ
( SiMe2C
U
ꢀ
ꢀ
A
N
(CH3)3), 1.29 (s,
(C4), 84.9 (C7), 87.1 (C1), 104.0 ppm (C2); IR (CCl4): n˜ =3313.4 (m),
2956.8 (s), 2929.3 (s), 2897.3 (m), 2856.1 (m), 2175.1 (m), 1471.5 (m),
1462.1 (m), 1375.5 (w), 1359.9 (w), 1250.4 (s), 1171.5 (w), 1133.3 (m),
1112.2 (s), 1046.8 (s), 1019.8 (m), 1006.0 cmꢀ1 (w); MS (GC–MS): m/z
(%): 307 (1), 269 (5), 265 (14), 249 (<1), 235 (<1) 221 (2), 212 (20), 211
(100), 191 (4), 177 (3), 170 (10). 169 (52), 157 (4), 147 (22), 133 (15), 115
(6), 97 (4), 83 (4), 75 (18), 73 (54), 59 (5), 45 (2).
3H; C4-CH3), 1.88 (m, 2H; H3), 2.35 (s, 2H; H5), 2.50 (dt, 3J=7.7,
1.6 Hz, 2H; H2), 9.76 ppm (t, 3J=1.6 Hz, 1H; H1). 13C NMR (100 MHz,
ꢀ
ꢀ
CDCl3): d=ꢀ2.2 and ꢀ2.16 ( SitBu
G
ACHTUGNTRNEN(UNG CH3)3), 18.2
ꢀ
ꢀ
ACHTUNGTRENNUNG( SiMe2CACHTUNGTRENNUNG(CH3)3), 25.8 ( SiMe2CACTHUGNTRENNNGU
(C3), 39.1 (C5), 74.3 (C4), 87.1 (C7), 103.7 (C6), 202.5 ppm (C1). MS
(GC–MS): m/z (%): 311 (<1%), 269 (15.0), 216 (12.8), 215 (100.0), 195
(6.4), 179 (4.9), 169 (10.8), 157 (32.8), 147 (27.9), 133 (6.4), 123 (2.0), 115
(5.4), 105 (12.7), 97 (2.9), 83 (5.9), 75 (28.9), 73 (62.7), 59 (5.9), 45 (2.9).
IR (CCl4): n˜ =3534.7 (w), 2956.8 (s), 2929.3 (s), 2898.0 (s), 2856.2 (s),
2711.3 (m), 2175.0 (s), 1756.2 (m), 1728.23 (s), 1711.3 (ss), 1471.5 (m),
1462.1 (m), 1412.8 (m), 1388.3 (m), 1376.1 (m), 1360.1 (m), 1304.3 (m),
1250.3 (s), 1170.5 (m), 1112.6 (s), 1042.8 (s), 1005.6 cmꢀ1 (m).
(4S)-4-Methyl-1-trimethylsilanylocta-1,7-diyn-4-ol (24): Caution! Concen-
trated hydrofluoric acid is toxic and harmful in addition to its corrosive
properties toward glassware. Personal safety equipment is an absolute ne-
cessity as well as a good working fume hood. We decided to use polytetra-
fluoroethylene (PTFE) flasks for this reaction. Hydrofluoric acid (3 mL,
70 mmol, 40% in H2O, p.a.) was added dropwise with a plastic pipette to
a solution of the substituted octadiyne 7b (0.48 g, 1.5 mmol, 1 equiv) in
HPLC-grade acetonitrile (60 mL). The reaction mixture was then stirred
under TLC control for 6 h at 508C. During the reaction, the color of the
originally colorless solution turned yellow. For workup, the reaction solu-
tion was poured into a saturated CaCl2 solution (200 mL) and stirred for
5 min at room temperature. The aqueous phase was then extracted
3 times with diethyl ether (150 mL portions). NaHCO3 (1 g) was added
to the combined organic phases, followed by magnesium sulfate. After fil-
tering and evaporation of the solvent, the brown oily residue was purified
by column chromatography with petroleum ether/diethyl ether (5:1) to
give a colorless oil (0.15 g, 0.73 mmol, 49% yield). [a]2D0 =+5.3 (c=1 in
CHCl3); Rf =0.06 (petroleum ether/diethyl ether 10:1), 0.17 (petroleum
ether/diethyl ether 5:1); 1H NMR (400 MHz, CDCl3): d=0.28 (s, 9H;
ꢀ
(5S)-1,1-Dibromo-5-(tert-butyldimethylsilanyloxy)-5-methyl-8-trimethylsi-
lanyl-oct-1-en-7-yne: Tetrabromocarbon (34.2 g, 0.103 mol, 2 equiv) was
carefully (exothermic reaction!) added portionwise to a solution of tri-
phenylphosphane (54.0 g, 0.206 mol, 4 equiv) in dry dichloromethane
(500 mL) and then stirred for 30 min at room temperature. After adding
dry triethylamine (57 mL, 0.411 mol, 8 equiv), the solution was cooled to
ꢀ808C in a cooling bath (isopropanol/liquid nitrogen). After reaching
ꢀ808C a 50 vol% solution of aldehyde 23 (16.8 g, 51.4 mmol, 1 equiv) in
dichloromethane was added with a syringe to the reaction mixture. The
solution was then stirred in a cooling bath overnight under warming to
room temperature. The next day, silica gel (ꢂ250 g) was added to the so-
lution, whereby the solvent was then removed with a rotary evaporator.
The orange solid was then pounded in a mortar followed by purification
by means of column chromatography over a prepacked column with
silica gel (0.75 kg) with petroleum ether/diethyl ether (75:1) to give a col-
orless oil (24.2 g, 50.2 mmol, 98% yield) . Please note: The dibromide
(CH3)3), 1.40 (s, 3H; C4-CH3), 1.96 (m, 2H; H5), 2.10 (t, 4J
SiACTHNUGTRENNGNU ACHTUNGTRENNUNG
2.7 Hz, 1H; H8), 2.21 (brs, 1H; C4-OH), 2.45 (dt, 3J
G
4J
(H,H)=2.7 Hz, 1H; H6), 2.55 ppm (d, 2J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
tends toward decomposition, even under an inert gas in
a freezer
13
ꢀ
C NMR (100 MHz, CDCl3): d=0.02 ( SiACHTNUGTRENNUNG
(ꢀ258C), so the elimination to the acetylenic compound 7b was done on
the same day as the column chromatography. Rf =0.88 (petroleum ether/
diethyl ether 10:1); 1H NMR (400 MHz, CDCl3): d=0.509 (s, 3H;
CH3), 33.9 (C3), 39.4 (C5), 68.6 (C8), 71.3 (C4), 84.5 (C7), 88.3 (C1),
102.7 (C2); IR (CCl4): n˜ =3614.7 (m), 3568.1 (m), 3312.5 (ss), 2961.5 (ss),
2930.2 (s), 2902.6 (s), 2172.9 (ss), 2120.5 (m), 1740.9 (m), 1722.7 (m),
1451.2 (m), 1431.71 (m), 1420.5 (m), 1408.0 (m), 1390.4 (m), 1374.3 (s),
1250.1 (ss), 1198.5 (m), 1160.2 (m), 1116.1 (s), 1034.7 (s), 985.3 (m), 974.9
(m), 915.0 (s), 904.7 cmꢀ1 (m); MS (GC–MS): m/z (%): 208 (1), 193 (2),
175 (2), 170 (9), 169 (57), 135 (4), 119 (3), 112 (22), 97 (78), 91 (2), 83
(12), 75 (29), 73 (100), 69 (9), 67 (6), 59 (5), 53 (9), 45 (8).
ꢀ
ꢀ
ꢀ
SitBu
(s, 9H; SiMe2C
G
E
ACHTUGNTRNEN(UNG CH3)3), 1.28
ꢀ
G
(q, 3J
(H,H)=7.4 Hz, 2H; H3), 2.80 (d, 2J
N
6.82 ppm (t, 3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
d=ꢀ2.12 and ꢀ2.09 ( SitBu
ACHUTNGTNERN(UG CH3)2), 0.05 ( SiCAHTUNTGRENN(GUN CH3)3), 18.2 ( SiMe2-C-
(CH3)3), 27.2 (C3), 28.0 (C5-CH3), 33.9 (C6), 39.5
ꢀ
(CH3)3), 25.8 ( SiMe2-C
N
(6R)-1-[3-Methoxy-2-(3-trimethylsilylprop-2-ynyl)-phenyl]-6-methyl-9-tri-
methylsilylnona-2,8-diyn-1-ol (25a): nBuLi (3.2 mL, 8.54 mmol, 2.7m in
hexanes) was added dropwise at ꢀ808C to a solution of 7a (1.72 g,
8.94 mmol) in THF (10 mL). At this temperature the solution was stirred
for 1 h before it was added with a cannula to a solution of 6a (2.00 g,
8.13 mmol) in THF (20 mL) cooled to ꢀ808C. The reaction mixture was
(C4), 74.6 (C5), 86.9 (C8), 88.6 (C1), 104.1 (C7), 138.7 ppm (C2); IR
(CCl4): n˜ =2957.0 (s), 2929.3 (s), 2897.4 (m), 2856.1 (s), 2174.7 (m),
1628.1 (w), 1471.4 (m), 1462.1 (m), 1435.7 (m), 1407.5 (m), 1388.2 (m),
1375.5 (m), 1360.0 (m), 1312.0 (m), 1295.3 (m), 1170.9 (m), 1139.2 (s),
1119.5 (s), 1063.71 (s), 1041.5 (s), 1004.9 cmꢀ1 (m); MS (GC–MS): m/z
(%): 469 (<1), 467 (1), 465 (<1), 427 (19), 425 (35), 423 (13), 373 (36),
Chem. Eur. J. 2010, 16, 8805 – 8821
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8815

U. Groth et al.
stirred for 4 h and allowed to warm to ꢀ308C until no further starting
material could be detected by TLC. The mixture was poured into an ice-
cold NH4Cl solution (20 mL). The aqueous phase was extracted thrice
with diethyl ether (10 mL), the combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuum. The residue
was purified by column chromatography (petroleum ether/diethyl ether
1:5) to provide the alcohol as a colorless oil (3.53 g, 8.04 mmol, 94%).
[a]2D2 =ꢀ5.11 (c=0.705 in CHCl3); Rf =0.56 (petroleum ether/diethyl
ether 2:1); 1H NMR (400 MHz, CDCl3): d=0.11 and 0.15 (s, 18H; 2ꢄSi-
to warm slowly to ꢀ308C. After cooling to ꢀ808C again, the reaction
mixture was added with a cannula to a solution of 6b (8.7 g, 31.5 mmol)
in diethyl ether (200 mL) cooled to ꢀ158C. The solution was stirred for
1 h at ꢀ158C until TLC showed complete conversion of the starting ma-
terial. At room temperature the reaction was quenched with water
(250 mL). After phase separation, the aqueous layer was extracted with
diethyl ether (3ꢄ250 mL). The combined organic layers were washed
with brine (300 mL), dried over MgSO4, and concentrated in vacuo to
give an orange viscous oil, which was purified by column chromatography
(petroleum ether/ethyl acetate 4:1). Thus, a yellow oil (18.1 g, 30.2 mmol,
96%) could be isolated. [a]D20 =ꢀ4.38 (c=1.1 in CHCl3); Rf =0.63 (petro-
leum ether/diethyl ether 2:1); 1H NMR (400 MHz, CDCl3): d=0.08 (s,
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
changeable), 3.72 and 4.00 (2ꢄd, AB signal, JCAHTUNGTRENNNUG
CH2-CꢁC), 3.87 (s, 3H; OCH3), 5.87 (dt, 3J
G
(H,H)=
3H; SitBu
G
ꢀ
ꢀ
ꢀ
ꢀ
2 Hz, 1H; Ar-CH-OH), 6.90 and 7.39 (d, J0 =7.8 Hz, 2H; H-arom.),
TMS), 0.85 (s, 9H; SiMe2tBu), 1.29 (s, 3H; C6-CH3), 1.85 (m, 2H;
7.30 ppm (t, J0 =7.8 Hz, 1H; H-5); 13C NMR (100 MHz, CDCl3): d=
H5), 2.37 (m, 4H; H4 and H7), 3.49 (s, 3H; OCH3), 3.73 (d, 2J
ꢀ
ꢀ0.08, 0.21 (2ꢄSi
N
17.2 Hz, 1H; H1’’), 3.96 (d, 2J
(H,H)=17.2 Hz, 1H; H1’’), 5.22 (s, 2H;
OCH2O ), 5.82 (s, 1H; H1), 7.08 (d, 3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
(t, 3J
A
13
123.17, 140.78, 156.85 ppm (Cquart-arom.); IR (CCl4): n˜ =3602–3513 (OH),
C NMR (100 MHz, CDCl3): d=ꢀ2.21 ( SitBu(CH3)2), ꢀ2.17 ( SitBu-
ꢀ1
ꢀ
ꢀ
ꢀ ꢀ ꢀ
(CH3)2), ꢀ0.05 ( TMS), ꢀ0.01 ( TMS), 13.7 (C4), 16.0 ( SiMe2CMe3),
2172 (CꢁC Si),1263 and 1250 cm (C O); MS (EIMS, 70 eV): m/z (%):
R
438 (3) [M+], 423 (6) [M+ꢀCH3], 408 (4) [M+ꢀ2CH3], 365 (69)
18.2 (C1’’), 25.8 ( SiMe2tBu), 27.0 (C6-CH3), 33.9 (C7), 40.9 (C5), 56.0
[M+ꢀSi
(CH3)3], 350 (11) [365ꢀCH3]; elemental analysis calcd (%) for
ACHTUNGRTEN(NUGN OCH3), 62.4 (C1), 74.4 (C6), 79.0 (C2), 84.7 (C3), 87.0 (C3’’), 87.6
ꢀ
ꢀ
C26H38O2Si2: C 71.17, H 8.73; found: C 70.92, H 8.97.
(C9), 94.5 ( OCH2O ), 104.1 (C8), 105.3 (C2’’), 114.5 (C4’), 121.1 (C6’),
124.1 (C2’), 128.0 (C5’), 140.6 (C1’), 154.5 ppm (C3’); IR (CCl4): n˜ =
3603.3 (w), 2958.7 (s), 2931.1 (m), 2899.5 (m), 2857.5 (m), 2173.4 (m),
1587.9 (w), 1471.7 (m), 1376.1 (m), 1360.4 (w), 1311.1 (w), 1250.9 (ss),
1205.5 (w), 1155.0 (s), 1111.2 (m), 1089.7 (m), 1044.1 (s), 1017.5 cmꢀ1 (s);
MS (EIMS, 70 eV): m/z (%): 599 (0.1) [M+], 566 (0.2), 542 (0.9)
(6S)-6-(tert-Butyldimethylsilyloxy)-1-[3-methoxy-2-(3-trimethylsilylprop-
2-ynyl)phenyl]-6-methyl-9-trimethylsilylnona-2,8-diyn-1-ol (25b): nBuLi
(9.0 mL, 14.4 mmol, 1.6m in hexanes) was added dropwise with a syringe
at ꢀ808C to a solution of 7b (4.4 g, 13.7 mmol) in absolute diethyl ether
(120 mL). The mixture was stirred for 30 min at this temperature, then
for a further 30 min at room temperature. After cooling to ꢀ808C again,
the reaction mixture was added with a cannula to a solution of 6a (3.1 g,
12.5 mmol) and BF3·Et2O (1.7 mL, 13.1 mmol) in absolute diethyl ether
(120 mL). The reaction mixture was stirred for 3 h at ambient tempera-
ture, diluted with distilled water (250 mL), and stirred vigorously for a
further 3 min. Phases were separated, and the aqueous layer was extract-
ed with diethyl ether (3ꢄ200 mL). The combined organic layers were
washed with brine (200 mL), dried over MgSO4, and concentrated in
vacuo. Column chromatography (petroleum ether/diethyl ether 10:1) pro-
vided the asymmetric product (5.0 g, 8.8 mmol, 70%). [a]2D0 =ꢀ3.88 (c=2
in CHCl3); Rf =0.17 (petroleum ether/diethyl ether 10:1); 1H NMR
[M+ꢀtBu], 526 (0.6), 512 (0.3), 497 (0.7) [541ꢀC2H5O], 488 (2), 469 (17),
437 (4), 429 (1), 417 (2), 404 (3), 397 (1), 389 (1), 377 (4), 365 (1), 345
(7), 340 (4), 305 (9), 269 (5), 253 (3), 229 (3), 185 (3), 169 (17), 155 (3),
149 (5), 147 (12), 133 (3), 115 (7), 89 (7), 77 (3), 75 (23), 74 (11), 73 (100)
[TMS+], 59 (5), 45 (40) [C2H5O+], 41 (1); elemental analysis calcd (%)
for C33H54O4Si3: C 66.16, H 9.09; found: C 66.14, H 8.96.
(6R)-1-(3-Methoxy-2-prop-2-ynylphenyl)-6-methylnona-2,8-diyn-1-ol
(26a): The alcohol 25a (3.01 g, 6.86 mmol) was dissolved in dichlorome-
thane (50 mL). Tetrabutylammonium hydrogensulfate (1.17 g, 3.43 mmol)
and ammonium fluoride solution (60 mL, 45% in water) were added,
and the mixture was stirred intensively for 24 h at ambient temperature.
Additional ammonium fluoride solution (20 mL, 45% in water) was
added and the solution was stirred for another 24 h. Phases were separat-
ed, the aqueous layer was extracted thrice with dichloromethane
(100 mL). The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. The residue was purified by column chromatography
ꢀ
ꢀ
(400 MHz, CDCl3): d=0.09 (s, 3H; SitBuACHTNUTRGEN(UNG CH3)2), 0.10 (s, 3H; SitBu-
ꢀ
ꢀ
ꢀ
N
Me2tBu), 1.30 (s, 3H; C6-CH3), 1.86 (m, 2H; H5), 2.36 (m, 2H; H4), 2.38
(s, 2H; H7), 2.71 (d, 3J
2J
(H,H)=17.6 Hz, 1H; H1’’), 3.85 (s, 3H; C3’-OMe), 5.87 (m, 1H; H1),
6.87 (d, 3J(H,H)=8.2 Hz, 1H; H4’), 7.28 (t, 3J
(H,H)=8.2 Hz, 1H; H5’),
7.38 ppm (d, 3J(H,H)=8.2 Hz, 1H; H6’); 13C NMR (100 MHz, CDCl3):
ACHTUNGTRENNUNG(H,H)=5.8 Hz, 1H; C1-OH), 3.70 and 3.98 (d,
ACHTUNGTRENNUNG
A
U
(petroleum ether/diethyl ether 3:1) to yield a colorless oil (1.94 g,
G
6.60 mmol, 96%). [a]2D3 =ꢀ3.47 (c=0.98 in CHCl3); Rf =0.31 (petroleum
d=ꢀ2.17 and ꢀ2.14 ( SitBu
N
ACHTUGNTRNEN(UNG CH3)3), 13.7
(CH3)3), 25.8 ( SiMe2tBu), 26.9 (C6-
ether/diethyl ether 2:1); 1H NMR (400 MHz, CDCl3): d=0.98 (d,
ꢀ
ꢀ
N
3J
ACHTUNGTRENN(NUG H,H)=6.6 Hz, 3H; 3-CH3), 1.41–1.81 and 2.14–2.25 (m, 8H; 3ꢄCH2,
ꢀ
ꢀ
H-3 and OH, D2O-exchangeable), 1.94 (t, 4J
(H,H)=2.3 Hz; CꢁC H),
ꢀ
CH3), 34.0 (C7), 41.0 (C5), 56.0 (C3’-OCH3), 62.3 (C1), 74.5 (C6), 79.1
(C2), 84.8 (C3), 87.0 (C3’’), 87.5 (C9), 104.1 (C2’’), 105.7 (C8), 111.0
(C4’), 123.2 (C2’), 128.1 (C6’), 136.1 (C5’), 140.8 (C1’), 156.9 ppm (C3’);
IR (CCl4): n˜ =3516.0 (w), 3313.4 (w), 2957.2 (s), 2929.5 (s), 2898.2 (m),
2855.8 (m), 2172.1 (s), 1587.3 (m), 1471.8 (s), 1461.8 (m), 1439.4 (m),
1407.4 (w), 1375.5 (m), 1359.8 (m), 1321.3 (w), 1262.3 (ss), 1250.4 (ss),
1212.9 (w), 1171.5 (m), 1111.01 (s), 1074.7 (m), 1045.6 (s), 1016.6 (s),
1005.1 (s), 981.3 (m), 976.1 (m), 939.0 (w), 908.1 cmꢀ1 (s); MS (EIMS,
70 eV): m/z (%): 569 (<1) [M+], 553 (<1) [M+ꢀMe], 535 (<1) [M+
vMeOH], 511 (6) [M+ꢀtBu], 496 (7) [M+ꢀTMS], 482 (<1), 457 (13)
[M+ꢀC6H11Si], 439 (100) [496ꢀtBu], 419 (8), 404 (20), 347 (21), 345 (14),
331 (28), 316 (14), 291 (12), 275 (20), 269 (22) [M+ꢀC14H29OSi], 247 (9),
235 (10), 231 (9), 209 (10), 195 (20), 171.0 (12), 169 (34), 149 (41), 147
(56), 133 (13) [OTBSH+], 115 (17) [TBS+], 75 (64) 74 (30) [C6H3+], 74
(12), 73 (99) [TMS+]; elemental analysis calcd (%) for C32H54O3Si3: C
67.55, H 9.21; found: C 67.33, H 9.15.
4
ꢀ
1.97 (t, J
E
ꢀ ꢀ
(H,H)=2.8 Hz, 2H; Ar CH2 CꢁC), 3.87 (s, 3H;
J
A
U
ꢀ
ꢀ
U
6.86 and 7.29 (d, J0 =7.8 Hz, 2H; H-arom.), 7.25 ppm (t, J0 =7.8 Hz, 1H;
H-5); 13C NMR (100 MHz, CDCl3): d=14.41, 16.60, 25.21, 34.08 (4ꢄ
CH2), 18.90, 31.70, 55.82, 62.38 (C-3, 3-CH3, OCH3, ArCHO), 67.97,
ꢀ
69.55 (2ꢄCꢁC H), 79.64, 82.61, 82.90, 87.21 (4x C-alkyne), 110.93,
119.52, 128.13 (CH-arom.), 122.93, 140.28, 157.03 ppm (Cquart- arom.); IR
(CCl4): n˜ =3601–3510 (OH), 3312 cmꢀ1 (CꢁC H); MS (EIMS, 70 eV):
ꢀ
m/z (%): 294 (7) [M+], 251 (7) [M+ꢀCH2CꢁCHꢀH2O], 237 (11)
[251ꢀCH2]; elemental analysis calcd (%) for C21H24O2: C 81.60, H 7.53;
found: C 79.42, H 7.47.
(6S)-6-(tert-Butyldimethylsilyloxy)-1-(3-methoxy-2-prop-2-ynylphenyl)-6-
methylnona-2,8-diyn-1-ol (26b): A solution of 25b (7.1 g, 12.5 mmol) in
absolute methanol (150 mL) was stirred with dried potassium carbonate
(3.5 g, 25.0 mmol) for 6.5 h at room temperature until no further starting
material could be detected by TLC. The reaction mixture was diluted
with diethyl ether (150 mL) and distilled water (400 mL). Phases were
separated, and the aqueous layer was extracted thrice with diethyl ether
(250 mL). The combined organic layers were dried over MgSO4 and con-
(6S)-6-(tert-Butyldimethylsilyloxy)-1-[3-methoxymethoxy-2-(3-trimethyl-
silylprop-2-ynyl)phenyl]-6-methyl-9-trimethylsilylnona-2,8-diyn-1-ol
(25c): At 08C, nBuLi (25.0 mL, 39.5 mmol, 1.6m in hexanes) was quickly
added to a solution of 7b (10.63 g, 32.9 mmol) in absolute tetrahydrofur-
an (200 mL) with a syringe. The solution was stirred for 1 h and allowed
8816
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8805 – 8821

Angucyclinones
FULL PAPER
centrated in vacuo. The remaining yellow oil was subjected to chromatog-
raphy (petroleum ether/diethyl ether 10:1) to yield a pale yellow oil
(4.8 g, 11.3 mmol, 90%). [a]D20 =ꢀ5.98 (c=2 in CHCl3); Rf =0.28 (petro-
leum ether/diethyl ether 2:1); 1H NMR (400 MHz, CDCl3): d=0.09 (s,
(200 mL) and vigorous stirring for 3 min. After phase separation, the
aqueous layer was extracted thrice with dichloromethane (150 mL). The
combined organic layers were washed with brine (250 mL), dried over
MgSO4, and concentrated in vacuo. Column chromatography of the resi-
due provided the product as a colorless to pale yellow oil.
ꢀ
ꢀ
ꢀ
3H; SitBu
1.32 (s, 3H; C6-CH3), 1.87 (m, 2H; H5), 1.99 (t, 4J
H9), 2.0 (t, 4J
(H,H)=2.8 Hz, 1H; H3’’), 2.36 (m, 4H; H4 and H7), 3.72
ACHTUNGTRENNUNG(CH3)2), 0.10 (s, 3H; SitBuCAHTUNGTRENNNUG
AHCTUNGTRENNUNG
AHCTUNGTRENGN(UN 6’R)-1-[1’-(tert-Butyldimethylsilyloxy)-6’-methylnona-2’,8’-diynyl]-3-me-
thoxy-2-prop-2-ynyl benzene (5a): [a]2D2 =ꢀ1.36 (c=0.59 in CHCl3); Rf =
ACHTUNGTRENNUNG
2
4
0.28 (petroleum ether/diethyl ether 40:1); 1H NMR (400 MHz, CDCl3):
and 3.85 (dd, JACHTUNGTRENNUNG(H,H)=16.0 Hz, JCAHTUNGTRENNUNG
C3’-OCH3), 5.79 (m, 1H; H1), 6.88 (d, 3J
ACHTUNGTRENNUNG
d=0.13 and 0.15 (2ꢄs, 6H; Si
CH3), 1.45–1.82 and 2.13 to 2.29 (m, 7H; 3ꢄCH2, H-3), 1.93 (t, JACHTUNGTRENNUNG
(CH3)2), 1.00 (d, 3J
ACHUTGTNRENNGU ACHTUNGTERN(NUGN H,H)=6.6 Hz, 3H; 3-
(t, 3J
A
A
4
13
ꢀ
C NMR (100 MHz, CDCl3): d=ꢀ2.21 and ꢀ2.17 ( SitBu
ACHTUNGTRENNUNG
4
ꢀ
ꢀ
2.3 Hz, 1H; CꢁC H), 1.96 (t, J
ACHTUNGTRENNUNG
ꢀ
ꢀ
(C4), 14.4 (C1’’), 18.1 ( SiMe2CACHTUNGTRENNUNG
3.82 (2ꢄdd, AB signal, JACTHNUGRTNENUG HCATUNGTRENN(UGN H,H)=2.8 Hz, 2H; Ar
(A,B)=17.13 Hz, 4J
ꢀ
CH3), 32.4 (C7), 40.5 (C5), 56.0 (C3’-OCH3), 67.9 (C1), 70.6 (C3’’), 74.3
(C9), 79.2 (C2’’), 81.3 (C2), 82.9 (C8), 87.7 (C3), 111.0 (C4’), 119.5 (C2’),
123.0 (C6’), 128.1 (C5’), 140.3 (C1’), 157.1 ppm (C3’); IR (CCl4): n˜ =
3516.0 (w), 3312.2 (s), 2955.6 (s), 2929.5 (s), 2894.8 (m), 2856.1 (m),
2836.8 (w), 2231.0 (w), 2119.1 (w), 1588.2 (m), 1472.0 (s), 1462.0 (s),
1439.7 (m), 1375.9 (m), 1360.0 (m), 1312.2 (w), 1264.2 (ss), 1213.5 (w),
1171.7 (m), 1133.0 (m), 1111.8 (s), 1085.6 (m), 1074.8 (m), 1043.7 cmꢀ1
(s); MS (EIMS, 70 eV): m/z (%): 424 (1) [M+], 385 (17) [M+ꢀC3H3], 367
(30) [M+ꢀtBu], 349 (7), 328 (8) [367ꢀC3H3], 313 (7), 293 (6)
CH2 CꢁC), 3.88 (s, 3H; OCH3), 5.87 (t, 5J
AHCTUNGTREG(NNNU H,H)=2 Hz, 1H; Ar CH
ꢀ
ꢀ
ꢀ
OTBDMS), 6.85 (m, 1H; H-arom.), 7.26 ppm (m, 2H; H-arom.);
13C NMR (100 MHz, CDCl3): d=ꢀ4.89, ꢀ4.61 (Si
ACHTUGNTRENUN(GN CH3)2), 14.50, 16.66,
25.24, 34.19 (4ꢄCH2), 18.90, 31.27, 55.82, 62.64 (C-3, 3 CH3, OCH3,
ꢀ
ArCHO), 67.35, 69.39 (2ꢄCꢁC H), 80.66, 82.64, 82.66, 85.52 (4ꢄC-
alkyne), 110.15, 118.53, 127.71 (CH-arom.), 121.89, 141.85, 156.96 ppm
(Cquart-arom.); IR (CCl4): n˜ =3312 cmꢀ1 (CꢁC H); MS (EIMS, 70 eV):
ꢀ
m/z (%): 408 (0.2) [M+], 351 (26) [M+ꢀtBu], 336 (28) [351ꢀCH3], 335
ꢀ
(6) [336 H]; elemental analysis calcd (%) for C27H38O2Si: C 76.42, H
A
8.88; found: C 75.56, H 8.77.
195 (46), 171 (17), 165 (28), 153 (19), 152 (19), 145 (16) [C10H9O+], 115
(34), 97 (59), 77 (16), 75 (100) [C6H3+], 73 (93), 69 (12); elemental analy-
sis calcd (%) for C26H36O3Si: C 73.54, H 8.54; found: C 73.58, H 8.49.
AHCTUNGTRENGN(UN 6’S)-1-[1’,6’-Bis-(tert-butyldimethylsilyloxy)-6’-methylnona-2’,8’-diynyl]-
3-methoxy-2-prop-2-ynyl benzene (5b): [a]2D0 =ꢀ5.28 (c=2 in CHCl3);
Rf =0.65 (petroleum ether/diethyl ether 10:1); 1H NMR (400 MHz,
(6S)-6-(tert-Butyldimethylsilyloxy)-1-(3-methoxymethoxy-2-prop-2-ynyl-
phenyl)-6-methylnona-2,8-diyn-1-ol (26c): Compound 25c (17.84 g,
29.8 mmol) was dissolved in absolute methanol (500 mL). After the addi-
tion of dry potassium carbonate (9.23 g, 66.8 mmol), the mixture was
stirred for 5 h at room temperature until TLC showed complete conver-
sion. The solvent was evaporated and the residue dissolved in distilled
water (250 mL) and diethyl ether (250 mL). Phases were separated, and
the aqueous layer was extracted with diethyl ether (3ꢄ200 mL). The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. The remaining orange oil was subjected to chromatography (pe-
ꢀ
ꢀ
CDCl3): d=0.07 (s, 3H; SitBu
G
ACHTUGNTRNEN(UNG CH3)2), 0.12
ꢀ
ꢀ
ꢀ
(s, 3H; SitBu
G
(CH3)2), 0.84 ( SiMe2tBu),
ꢀ
0.92 ( SiMe2tBu), 1.29 (s, 3H; C6’-CH3), 1.81 (m, 2H; H5’), 1.93 (t,
4J
(H,H)=2.7 Hz, 1H; H9’), 1.97 (t, 4J
R
4H; H4’ and H7’), 3.70 (dd, 2J
G
ACHTUNGTRENNUNG
H2’’), 3.82 (dd, 2J
A
ACHTUNGTRENNUNG
3H; C3-OCH3), 5.76 (m, 1H; H1’), 6.84 (t, 3J
ACTHNUTRGNEUNG(H,H)=5.4 Hz, 1H; H5),
7.25 ppm (m, 2H; H4 and H6); 13C NMR (100 MHz, CDCl3): d=ꢀ4.53
ꢀ
ꢀ
and ꢀ4.24 ( SitBu
N
ACHTUGNTRENUN(NG CH3)2), 14.0 (C4’),
(CH3)3), 26.1 and 26.2 ( SiMe2tBu),
ꢀ
ꢀ
14.9 (C1’’), 18.5 and 18.6 ( SiMe2C
G
troleum ether/ethyl acetate 3:1) to provide
a yellow oil (12.97 g,
27.3 (C6’-CH3, 32.8 (C7’), 40.8 (C5’), 56.2 (C3-OCH3, 63.0 (C1’), 67.7
(C6’), 70.8 (C3’’), 74.7 (C9’), 80.5 (C2’’), 81.6 (C8’), 83.0 (C2’), 86.5 (C3’),
110.5 (C4), 119.0 (C2), 122.3 (C6), 128.1 (C5), 142.2 (C1), 157.3 ppm
(C3); IR (CCl4): n˜ =3312.6 (s), 2955.7 (s), 2929.1 (s), 2894.8 (m), 2856.3
(s), 2360.8 (w), 2224.8 (w), 2118.8 (w), 1588.7 (m), 1471.6 (s), 1462.3 (s),
1439.4 (m), 1406.5 (w), 1388.4 (m), 1376.1 (m), 1360.8 (m), 1257.1 (s)
1215.4 (m), 1199.8 (m), 1170.6 (m), 1132.7 (s), 1111.7 (s), 1058.2 (s),
1004.9 (s), 938.5 (m), 906.1 cmꢀ1 (m); MS (EIMS, 70 eV): m/z (%): 538
(<1) [M+], 523 (3) [M+ꢀMe], 499 (17) [M+ꢀC3H3], 482 (59), 481 (86)
[M+ꢀtBu], 407 (22) [M+ꢀOTBS], 368 (18), 367 (54), 350 (27)
[480ꢀOTBS], 349 (70), 334 (33), 327 (33), 309 (28), 294 (22), 289 (53)
[C17H23OSi+], 275 (89), 269 (31), 260 (27), 259 (17), 247 (47), 235 (53)
[C14H23OSi+], 231 (56), 211 (17), 209 (20), 195 (47), 181 (17), 165 (31),
153 (38), 149 (22), 147 (72), 141 (26), 115 (55) [TBS+], 97 (69), 75 (90)
[C6H3+], 74 (48), 73 (100), 59 (32); elemental analysis calcd (%) for
C32H50O3Si2: C 71.32, H 9.35; found: C 71.04, H 8.76.
28.5 mmol, 96%). [a]2D0 =ꢀ5.48 (c=1.08 in CHCl3); Rf =0.43 (petroleum
ether/diethyl ether 2:1); 1H NMR (400 MHz, CDCl3): d=0.09 (s, 3H;
ꢀ
ꢀ
ꢀ
SitBuACHTUNGTRENNUNG(CH3)2), 0.10 (s, 3H; SitBuACHUTNTGREN(NGUN CH3)2), 0.85 (s, 9H; SiMe2tBu), 1.32
(s, 3H; C6-CH3), 1.81 and 1.93 (m, 2H; H5), 2.00 (t, 4J
ACTHNUGRTENUNG(H,H)=2.7 Hz,
ꢀ
2H; H9 and H3’’), 2.24 (s, 1H; OH), 2.36 (m, 4H; H4 and H7), 3.50 (s,
3H; OCH3), 3.75 (dd, 2J
(H,H)=17.1 Hz, 4J
N
ꢀ
3.86 (dd, 2J
(H,H)=17.1 Hz, 4J
N
OCH2O ), 5.78 (s, 1H; H1), 7.09 (d, 3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
(t, 3J
U
ACHTUNGTRENNUNG
13
ꢀ
ꢀ
C NMR (100 MHz, CDCl3): d=ꢀ2.03 ( SitBu
ACHTUNGTRENNUNG
ꢀ
ꢀ
(CH3)2), 13.8 (C4), 15.0 ( SiMe2CMe3), 18.3 (C1’’), 25.9 ( SiMe2tBu),
ꢀ
27.2 (C6-CH3), 32.6 (C7), 40.7 (C5), 56.3 ( OCH3), 62.7 (C1), 68.3 (C3’’),
ꢀ
ꢀ
74.5 (C9), 79.3 (C2), 81.5 (C2’’), 82.9 (C8), 88.1 (C3), 94.7 ( OCH2O ),
114.7 (C4’), 120.9 (C6’), 124.0 (C2’), 128.3 (C5’), 140.5 (C1’), 155.0 ppm
(C3’); IR (CCl4): n˜ =3604.0 (w), 3313.9 (s), 2957.4 (s), 2931.0 (s), 2898.3
(m), 2857.8 (m), 2827.4 (w), 2120.3 (w), 1588.0 (m), 1471.9 (s), 1442.2
(m), 1404.2 (w), 1376.7 (m), 1360.6 (m), 1312.3 (m), 1253.1 (s), 1205.0
(m), 1172.9 (m), 1155.1 (s), 1133.2 (m), 1113.3 (s), 1088.8 (m), 1042.9 (s),
1015.2 (s), 1006.0 cmꢀ1 (s); MS (EIMS, 70 eV): m/z (%): 454 (0.02) [M+],
415 (7), 397 (11) [M+ꢀtBu], 379 (2) [397ꢀH2O], 366 (1), 365 (2), 335 (2)
[397ꢀOMOM], 325 (1), 307 (1), 306 (2), 305 (7), 273 (14), 261 (8), 258
(10), 251 (4), 245 (12), 243 (9), 233 (19), 229 (8), 219 (9), 215 (10), 205
(9), 197 (10), 181 (12), 165 (12), 152 (8), 115 (14) [TBS+], 97 (31), 77
(11), 75 (68) [C6H3+], 73 (69), 45 (100) [C2H5O+], 43 (20), 41 (3); ele-
mental analysis calcd (%) for C27H38O4Si: C 71.32, H 8.42; found: C
71.23, H 8.34.
AHCTUNGTRENGN(UN 6’S)-1-[1’,6’-Bis(tert-butyldimethylsilyloxy)-6’-methylnona-2’,8’-diynyl]-3-
methoxymethoxy-2-prop-2-ynyl benzene (5c): [a]2D0 =ꢀ4.88 (c=1.16,
CHCl3); Rf =0.75 (petroleum ether/diethyl ether 2:1); 1H NMR
ꢀ
ꢀ
(400 MHz, CDCl3): d=0.08 (s, 3H; SitBu
(CH3)2), 0.13 (s, 3H; SitBu
ACHTUNGTRENNUNG
ꢀ
ꢀ
G
(CH3)2), 0.16 (s, 3H; SitBu
(CH3)2), 0.85 (s,
ꢀ
ꢀ
9H; SiMe2tBu), 0.93 (s, 9H; SiMe2tBu), 1.30 (s, 3H; C6-CH3), 1.77 (m,
1H; H5), 1.87 (m, 1H; H5), 1.94 (t, 4J
4J
(H,H)=2.7 Hz, 1H; H3’’), 2.31 (m, 4H; H4 and H7), 3.51 (s, 3H;
ACHTUNGTNER(NUNG H,H)=2.3 Hz, 1H; H9), 1.98 (t,
AHCTUNGTRENNUNG
OCH3), 3.74 (dd, 2J
(H,H)=17.0 Hz, 4J
(H,H)=2.7 Hz, 1H; H1’’), 5.24 (s, 2H;
(H,H)=7.6 Hz, 1H; H4’), 7.22
(H,H)=7.6 Hz, 1H; H5’), 7.27 ppm (d, 3J
(H,H)=7.6 Hz, 1H; H6’);
ACHTUNGTNER(NUNG H,H)=2.7 Hz, 1H; H1’’), 3.83
ꢀ
(dd, 2J(H,H)=17.0 Hz, 4J
A
ACHTUNGTRENNUNG
OCH2O ), 5.74 (s, 1H; H1), 7.05 (d, 3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
General procedure for the synthesis of the TBS ether of the triynes (5a–
c): 2,6-Lutidine (2.9 g, 27.1 mmol) was added at room temperature to a
solution of the alcohol 26 (11.3 mmol) in absolute dichloromethane
(150 mL). After cooling the solution to 08C, OTBSTf (3.6 g, 13.6 mmol)
was added dropwise. The reaction mixture was stirred and allowed to
warm to room temperature slowly until no starting material could be de-
tected by TLC. The reaction was quenched by the addition of water
(t, 3J
N
ACHTUNGTRENNUNG
13
ꢀ
ꢀ
C NMR (100 MHz, CDCl3): d=ꢀ4.9 ( SitBu(CH3)2), ꢀ4.6 ( SitBu-
G
ꢀ
ꢀ
G
E
ACHTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
(C1’’), 18.1 ( SiMe2CMe3), 18.3 ( SiMe2CMe3), 25.8 ( SiMe2tBu), 25.9
( SiMe2tBu), 27.0 (C6-CH3), 32.4 (C7), 40.5 (C5), 56.1 ( OCH3), 62.8
(C1), 67.5 (C6), 70.4 (C3’’), 74.3 (C9), 80.1 (C2’’), 81.3 (C8), 82.6 (C2),
ꢀ
ꢀ
Chem. Eur. J. 2010, 16, 8805 – 8821
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8817

U. Groth et al.
ꢀ
ꢀ
86.4 (C3), 94.6 ( OCH2O ), 113.7 (C4’), 119.9 (C6’), 122.9 (C2’), 127.8
(C5’), 141.8 (C1’), 154.7 ppm (C3’); IR (CCl4): n˜ =3314.0 (s), 2957.3 (s),
2930.4 (s), 2897.3 (m), 2857.7 (s), 2827.1 (w), 2336.6 (w), 2120.1 (w),
1588.1 (m), 1472.0 (s), 1463.4 (m), 1442.1 (m), 1404.6 (w), 1389.4 (m),
1376.8 (m), 1361.3 (m), 1312.9 (m), 1253.0 (s), 1211.1 (m), 1155.1 (s),
1133.4 (m), 1112.3 (m), 1090.2 (m), 1029.9 cmꢀ1 (s); MS (EIMS, 70 eV):
m/z (%): 569 (0.1) [M+], 554 (1) [M+ꢀMe], 530 (6), 512 (45) [M+ꢀtBu],
479 (5), 451 (1), 437 (4) [M+ꢀOTBS], 421 (2), 409 (1), 405 (5), 397 (8),
379 (11) [512ꢀOTBSH], 347 (15), 325 (6), 319 (13) [C18H27O3Si+], 305
(11), 299 (8), 287 (6), 273 (27), 251 (7), 245 (16), 233 (10), 229 (8), 217
(5), 197 (7), 193 (7) [C11H16OSi+], 181 (7), 165 (8), 153 (8), 147 (15), 115
(14) [TBS+], 99 (6), 97 (36), 89 (21), 75 (41) [C6H3+], 74 (12), 73 (100),
59 (9), 45 (61) [C2H5O+], 43 (6); elemental analysis calcd (%) for
C33H52O4Si2: C 69.67, H 9.21; found: C 69.66, H 9.12.
202 (9), 191 (14), 153 (8), 136 (4), 107 (8), 89 (10), 77 (22), 76 (9), 75
(96), 73 (37), 59 (6), 57 (12) [tBu+], 52 (7), 44 (8); elemental analysis
calcd (%) for C26H34O2Si: C 76.80, H 8.43; found: C 76.54, H 8.44.
(3S)-3-(tert-Butyldimethylsilyloxy)-8-methoxymethoxy-3-methyl-1,2,3,4-
tetrahydrobenzo[a]anthracene (4c): M.p. 1268C (from petroleum ether/
diethyl ether); [a]2D0 =ꢀ42.58 (c=1.4 in CHCl3); Rf =0.53 (petroleum
ether/diethyl ether 10:1); 1H NMR (400 MHz, CDCl3): d=ꢀ0.05 (s, 3H;
ꢀ
ꢀ
ꢀ
SitBuACTHNUTRGENN(UG CH3)2), 0.13 (s, 3H; SitBuACHUTNTGREN(NGUN CH3)2), 0.74 (s, 9H; SiMe2tBu), 1.42
(s, 3H; C3-CH3), 1.93 and 2.09 (m, 2H; H2), 2.97 and 3.00 (d, 2J
ACHTUNGTRENNUNG(H,H)=
ꢀ
23.0 Hz, 2H; H4), 3.25 and 3.36 (m, 2H; H1), 3.60 (s, 3H; OCH3), 5.48
(s, 2H; OCH2O ), 7.02 (d, 3J
G
ꢀ
ꢀ
3J
3J
(H,H)=7.8 Hz, 1H; H11), 7.35 (t, 3J
ACHUTNGTRENNUG AHCTUNGTRENN(GUN H,H)=7.8 Hz, 1H; H10), 7.68 (d,
ACHUTNGRENNUG CAHTUNGTREN(NGUN H,H)=8.4 Hz, 1H; H6), 8.47 (s,
(H,H)=8.4 Hz, 1H; H5), 7.84 (d, 3J
1H; H12), 8.78 ppm (s, 1H; H7); 13C NMR (100 MHz, CDCl3): d=ꢀ2.4
ꢀ
ꢀ
ꢀ
General procedure for the cycloaddition to 4a–c with [CpCo(CO)2]: For
reaction details, see Table 2. A solution of the catalyst in toluene was
added with a cannula to a solution of the triynes in dry and degassed tol-
uene. The mixture was heated to reflux while being irradiated with a
tungsten lamp (Osram Vitalux 300 W) for the time indicated in Table 2.
The solvent was evaporated and the residue was purified by column chro-
matography.
( SitBu
ꢀ
G
ACHTUNGTRENNUNG
ꢀ
( SiMe2tBu), 28.8 (C3-CH3), 36.9 (C2), 45.1 (C4), 56.3 ( OCH3), 71.4
(C3), 94.7 ( OCH2O ), 105.3 (C9), 121.0 (C12), 121.2 (C7a), 121.9 (C11),
124.3 (C6a), 125.1 (C7), 126.7 (C6), 128.2 (C10), 129.7 (C5), 130.5
(C11a), 131.1 (C12a), 132.1 (C12b), 132.7 (C4a), 152.8 ppm (C8); IR
(CCl4): n˜ =3059.2 (w), 2956.9 (s), 2929.8 (s), 2897.8 (m), 2856.9 (s), 2827.2
(w), 1626.7 (m), 1563.5 (m), 1472.6 (s), 1462.9 (m), 1431.8 (w), 1399.7
(m), 1374.0 (m), 1350.0 (m), 1328.9 (w), 1292.6 (w), 1258.4 (s), 1222.7
(m), 1194.9 (s), 1170.0 (m), 1153.0 (s), 1137.2 (m), 1114.1 (s), 1078.2 (s),
1050.6 (s), 1024.27 (s), 1005.8 (m), 984.6 (s), 944.4 (w), 926.9 cmꢀ1 (m);
MS (EIMS, 70 eV): m/z (%): 436 (100) [M+], 380 (16), 379 (51)
General procedure for the cycloaddition to 4a–c with [CpCoACTHNUTRGNE(UNG C2H4)] as
catalyst: For reaction details, see Table 2. The catalyst in toluene at
ꢀ808C was added to a solution of the triynes in dry and degassed tolu-
ene. This solution was stirred for 4 h and allowed to warm slowly to 08C.
The solvent was evaporated, and the residue was dissolved in glacial
acetic acid and stirred for several minutes. The solvent was removed in
vacuo and the residue was purified by column chromatography.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
107 (16), 89 (14), 77 (24), 75 (48) [C6H3+], 73 (17), 57 (14) [tBu+], 51 (6),
45 (65) [C2H5O+]; elemental analysis calcd (%) for C27H36O3Si: C 74.27,
H 8.31; found: C 74.17, H 8.32.
(+)-(3R)-8-Methoxy-3-methyl-1,2,3,4-tetrahydrobenzo[a]anthracene
(4a): M.p. 1368C; [a]2D2 =+86.43 (c=0.14 in CHCl3); Rf =0.31 (petroleum
ether/diethyl ether 100:1); 1H NMR (400 MHz, CDCl3): d=1.16 (d,
3J
2.14 (m, 1H; H-2), 2.60 (dd, 2J
H-4), 2.95 (dd, 2J(H,H)=16.5 Hz, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
General method for the oxidation to the benzo[a]anthracenediones 28a–
c: A well-ground mixture of [Ag(py)2MnO4] (3.8 g, 9.89 mmol) and silica
gel (5.0 g) was added in one portion at room temperature to a solution of
4 (1.24 mmol) in absolute dichloromethane (100 mL). Excluding light,
the reaction mixture was stirred until the conversion of the starting mate-
rial was completed. The suspension was filtered over Celite and the fil-
trate was concentrated after addition of silica gel (25.0 g). The residue
was purified by column chromatography.
A
ACHTUNGTRENNUNG
G
2
1H; H-1), 3.40 (d, JACHTUNGTRENNUNG
(d, J0 =8.0 Hz, 1H; H-9), 7.18 (d, J0 =8.6 Hz, 1H; H-5), 7.37 (t, J0 =
8.0 Hz, 1H; H-10), 7.62 (d, J0 =8.0 Hz, 1H; H-11), 7.82 (d, J0 =8.6 Hz,
1H; H-6), 8.44 (s, 1H; H-12), 8.78 ppm (s, 1H; H-7); 13C NMR
(100 MHz, CDCl3): d=21.79 (3-CH3), 25.83 (C-1), 28.88 (C-3), 31.35 (C-
2), 39.14 (C-4), 55.45 (OCH3), 101.34 (C-9), 120.75 (C-12), 120.83 (C-11),
121.35 (C-7), 125.06 (C-10), 126.58 (C-6), 128.05 (C-5), 124.09, 130.34,
131.42, 132.64, 133.57, 155.38 ppm (Cquart-arom.); IR (CCl4): n˜ =2935–
(+)-(3R)-8-Methoxy-3-methyl-1,2,3,4-tetrahydrobenz[a]anthracen-7,12-
dione (28a): M.p. 1708C; [a]2D3 =+64.00 (c=0.14 in CHCl3); Rf =0.28
1
(petroleum ether/diethyl ether 1:1); H NMR (400 MHz, CDCl3): d=1.01
2810 cmꢀ1 (C H of OCH3); MS (EIMS, 70 eV): m/z (%): 276 (100)
(d, 3J
ACHTUNGTRENNUNG
ꢀ
[M+], 261 (15) [M+ꢀCH3], 246 (7) [261ꢀCH3], 233 (77) [261ꢀC2H4].
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(3S)-3-(tert-Butyldimethylsilyloxy)-8-methoxy-3-methyl-1,2,3,4-tetrahy-
drobenzo[a]anthracene (4b): [a]2D0 =ꢀ49.18 (c=0.75 in CHCl3); Rf =0.80
(petroleum ether/diethyl ether 10:1); 1H NMR (400 MHz, CDCl3): d=
1H; H-1), 3.45 (m 1H; H-1), 3.97 (s, 3H; OCH3), 7.20 (d, J0 =8.2 Hz,
1H; H-arom.), 7.36 (d, J0 =7.8 Hz, 1H; H-arom.), 7.61 (t, J0 =8.2, 7.8 Hz,
1H; H-10), 7.77 (d, J0 =7.8 Hz, 1H; H-arom.), 8.01 ppm (d, J0 =7.8 Hz,
1H; H-arom.); 13C NMR (100 MHz, CDCl3): d=21.62 (3-CH3), 27.91 (C-
3), 29.22, 31.73, 39.82 (3ꢄCH2), 56.75 (OCH3), 116.72, 119.64, 124.97,
ꢀ
ꢀ
ꢀ0.06 (s, 3H; SitBu
ACHTUNGTRENNUNG(CH3)2), 0.12 (s, 3H; SitBuCAHTUNGTRENNNUG
SiMe2tBu), 1.40 (s, 3H; C3-CH3), 2.00 (m, 2H; H2), 2.95 (d, 2J
N
ꢀ
25 Hz, 1H; H4), 2.99 (d, 2J
U
4.06 (s, 3H; C8-OCH3), 6.70 (d, 3J
A
134.86 (CH-arom.), 120.96, 130.35, 134.73, 137.61, 139.99, 159.55 (Cquart
-
arom.), 183.22, 185.85 ppm (C=O); IR (CCl4): n˜ =1671, 1722 cmꢀ1 (C=
O); MS (EIMS, 70 eV): m/z (%): 306 (13) [M+], 291 (10) [M+ꢀCH3],
277 (25) [M+ꢀCHO].
3J
3J
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG ACHTUNGTRENN(UGN H,H)=8.2 Hz, 1H; H9), 8.43 (s,
(H,H)=9.2 Hz, 1H; H6), 7.81 (d, 3J
1H; H12), 8.75 ppm (s, 1H; H7); 13C NMR (100 MHz, CDCl3): d=ꢀ2.7
ꢀ
ꢀ
ꢀ
and ꢀ2.3 ( SitBu
(CH3)2), 18.0 ( SiMe2CMe3), 24.3 (C1), 25.7 ( Si-
(3S)-3-tert-Butyldimethylsilyloxy-8-methoxy-3-methyl-1,2,3,4-tetrahydro-
benzo[a]anthracene-7,12-dione (28b): M.p. 1158C; [a]2D0 =ꢀ61.18 (c=1 in
MeOH); Rf =0.17 (petroleum ether/diethyl ether 2:1); 1H NMR
Me2tBu), 28.8 (C3-CH3), 36.8 (C2), 45.2 (C4), 55.5 (C8-OCH3), 71.5 (C3),
101.4 (C9), 120.9 (C7a), 121.4 (C11 and C12), 124.2 (C7), 125.2 (C6a),
126.9 (C6), 128.0 (C10), 129.7 (C5), 130.4 (C11a), 131.3 (C12a), 132.2
(C12b), 132.7 (C4a), 155.5 ppm (C8); IR (CCl4): n˜ =3056.7 (w), 2956.6
(s), 2929.0 (s), 2855.6 (m), 1625.6 (w), 1585.2 (w), 1542.9 (m), 1471.9 (s),
1471.9 (m), 1462.6 (m), 1430.7 (w), 1405.6 (m), 1387.8 (w), 1373.0 (m),
1351.1 (m), 1328.6 (w), 1290.8 (w), 1260.3 (ss), 1223.9 (m), 1205.5 (m),
1187.1 (w), 1107.2 (s), 1071.6 (m), 1045.1 (s), 1023.9 cmꢀ1 (s); MS (EIMS,
70 eV): m/z (%): 406 (81) [M+], 392 (6) [M+ꢀMe], 365 (11), 350 (23),
349 (66) [M+ꢀtBu], 334 (9), 290 (6) [M+ꢀTBS], 289 (6), 277 (10), 276
(11), 275 (63) [M+ꢀOTBS], 274 (100), 273 (44), 261 (6), 260 (17)
[391ꢀOTBS], 259 (28), 258 (8), 246 (8), 245 (11), 235 (8), 234 (23)
[C7H14O+], 231 (11), 228 (7), 219 (8), 217 (8), 216 (10), 215 (13), 203 (8),
ꢀ
ꢀ
(400 MHz, CDCl3): d=ꢀ0.05 (s, 3H; SitBu
ACHTUGNTRENUN(GN CH3)2), 0.08 (s, 3H; SitBu-
(CH3)2), 0.68 (s, 9H; SiMe2tBu), 1.35 (s, 3H; C3-CH3), 1.71 (m, 1H;
ꢀ
G
H2), 1.96 (m, 1H; H2), 2.87 (d, 2J
(H,H)=27.3 Hz, 1H; H4), 2.91 (d,
2J
7.25 (d, 3J
7.67 (t, 3J(H,H)=7.6 Hz, 1H; H10), 7.84 (d, 3J
8.07 ppm (d, 3J(H,H)=8.6 Hz, 1H; H6); 13C NMR (100 MHz, CDCl3):
d=ꢀ2.4 and ꢀ2.3 ( SitBu
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
ACHTNUTGREGNN(UN CH3)2), 18.0 ( SiMe2CMe3), 25.5 ( SiMe2tBu),
26.7 (C1), 28.8 (C3-CH3), 36.7 (C2), 45.5 (C4), 56.3 (C8-OCH3), 70.2
(C3), 116.7 (C11), 119.6 (C7a), 120.7 (C9), 125.1 (C6), 129.7 (C6a), 134.8
(C10 and C11a), 134.9 (C12a), 137.4 (C5), 139.4 (C12b), 143.2 (C4a),
8818
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8805 – 8821

Angucyclinones
FULL PAPER
159.5 (C8), 183.3 (C12), 185.6 ppm (C7); IR (CCl4): n˜ =3546.2 (w), 2955.8
(m), 2929.2 (m), 2895.1 (w), 2856.1 (m), 1670.1 (s), 1588.1 (s), 1571.7 (m),
1470.9 (m), 1447.3 (m), 1435.6 (w), 1417.9 (m), 1374.8 (m), 1359.8 (w),
1270.2 (ss), 1216.0 (m), 1186.0 (w), 1160.1 (m), 1133.6 (m), 1117.0 (m),
1098.6 (m), 1075.8 (m), 1050.8 (m), 1029.9 (s), 1005.0 (w), 989.6 cmꢀ1
(m); MS (EIMS, 70 eV): m/z (%): 436 (0.6) [M+], 421 (3) [M+ꢀMe], 393
(6), 382 (5), 381 (23), 380 (64), 379 (100) [M+ꢀtBu], 361 (4), 348 (6), 347
(14), 346 (40), 331 (3), 305 (11) [M+ꢀOTBS], 304 (6), 289 (9), 288 (10),
287 (31), 259 (3), 121 (4), 119 (12), 117 (13), 77 (7), 75 (47), 73 (18), 61
(25), 47 (4), 44 (32); elemental analysis calcd (%) for C26H32O4Si: C
71.52, H 7.39; found: C 71.44, H 7.45.
to a solution of 28b or 30 (0.69 mmol), respectively, in acetonitrile
(75 mL) at room temperature. The reaction mixture was stirred for 6 h at
508C until complete conversion was observed by TLC. The yellow solu-
tion was poured into a half-concentrated CaCl2 solution (200 mL) and
stirred for 5 min at ambient temperature. Phases were separated, and the
aqueous layer was extracted thrice with diethyl ether (200 mL). The com-
bined organic layers were washed with saturated NaHCO3 solution
(150 mL) and brine (100 mL), dried over MgSO4, and concentrated in
vacuo. The residue was subjected to chromatography to provide a yellow
solid.
(3S)-3-Hydroxy-8-methoxy-3-methyl-1,2,3.4-tetrahydrobenzo[a]anthra-
cene-7,12-dione (29): M.p. 1908C; [a]2D0 =ꢀ65.78 (c=1 in CHCl3); Rf =0.2
(diethyl ether); 1H NMR (400 MHz, CDCl3): d=1.36 (s, 3H; C3-CH3),
1.80 (m, 1H; H2), 1.94 (m, 1H; H2), 2.92 (s, 2H; H4), 3.44 (m, 2H; H1),
(3S)-3-tert-Butyldimethylsilyloxy-8-methoxymethoxy-3-methyl-1,2,3,4-tet-
rahydrobenzo[a]anthracene-7,12-dione (28c): M.p. 1058C (from petrole-
um ether/diethyl ether); [a]D20 =ꢀ37.58 (c=0.6 in CHCl3); Rf =0.49 (pe-
troleum ether/diethyl ether 1:1); 1H NMR (400 MHz, CDCl3): d=ꢀ0.03
4.00 (s, 3H; C8-OCH3), 7.24 (d, 3J
N
G
3J
3J
ACHTUNGTRENNUNG
ꢀ
ꢀ
ꢀ
(s, 3H; SitBuACHTUNGTRENNUNG(CH3)2), 0.10 (s, 3H; SitBuCAHTUNGTNERN(UGN CH3)2), 0.70 ( SiMe2tBu),
1.37 (s, 3H; C3-CH3), 1.75 and 1.97 (m, 2H; H2), 2.88 and 2.96 (d,
G
ACHTUNGTRENNUNG
13C NMR (100 MHz, CDCl3): d=26.3 (C1), 28.6 (C3-CH3), 35.7 (C2),
44.6 (C4), 56.4 (C8-OCH3), 68.2 (C3), 116.8 (C11), 119.7 (C7a), 120.7
(C9), 125.4 (C6), 130.1 (C6a), 134.9 (C10), 135.1 (C11a), 135.2 (C12a),
137.4 (C5), 138.6 (C12b), 142.3 (C4a), 159.6 (C8), 183.1 (C12), 185.7 ppm
(C7); IR (CCl4): n˜ =3708.0 (w), 3611.6 (w), 3546.6 (w), 2961.1 (w), 2927.9
(w), 2335.8 (w), 1670.0 (s), 1588.4 (s), 1571.4 (m), 1466.3 (m), 1447.2 (m),
1435.3 (w), 1419.9 (w), 1376.2 (w), 1322.1 (m), 1270.6 (ss), 1216.0 (m),
1185.8 (w), 1159.2 (w), 1109.9 (m), 1096.7 (m), 1028.5 (m), 994.9 (m),
985.0 cmꢀ1 (m); MS (EIMS, 70 eV): m/z (%): 323 (34) [M++H], 322
(100) [M+], 318 (7), 307 (7), 305 (14), 304 (27) [M+ꢀH2O], 293 (9), 290
(10) [M+ꢀMeOH], 289 (30), 280 (23), 279 (48), 277 (9), 266 (12), 265
(40), 264 (42), 247 (21), 235 (11), 219 (7), 202 (8), 189 (13), 178 (12), 167
(15), 165 (12), 149 (33), 71 (10), 58 (14), 44 (27); elemental analysis calcd
(%) for C20H18O: C 74.52, H 5.63; found: C 74.47, H 5.44.
2J
(H,H)=17.0 Hz, 2H; H4), 3.43 (m, 2H; H1), 3.57 (s, 3H; OCH3),
ꢀ
5.39 (s, 2H; OCH2O ), 7.40 (d, 3J
(H,H)=7.8 Hz, 1H; H9), 7.50 (d,
ꢀ
ꢀ
3J
ACHTUNGTRENNUNG
3J
ACHTUNGTRENNUNG
13
ꢀ
ꢀ
C NMR (100 MHz, CDCl3): d=ꢀ2.3 ( SitBu(CH3)2), ꢀ2.2 ( SitBu-
N
ꢀ
ꢀ
ACHTUNGTRENNUNG(CH3)2), 18.0 ( SiMe2CMe3), 25.6 ( SiMe2tBu), 26.8 (C1), 28.9 (C3-CH3),
ꢀ
ꢀ
ꢀ
36.8 (C2), 45.6 (C4), 56.6 ( OCH3), 70.3 (C3), 95.2 ( OCH2O ), 121.1
(C9), 121.3 (C11), 122.0 (C7a), 125.1 (C6), 129.9 (C6a), 134.5 (C11a),
134.9 (C10), 135.0 (C5), 137.4 (C12a), 139.6 (C12b), 143.3 (C4a), 157.0
(C8), 183.1 (C12), 185.5 ppm (C7); IR (CCl4): n˜ =3684.4 (s), 3620.4 (s),
3473.4 (m), 3018.8 (ss), 2435.0 (s), 1668.8 (m), 1517.5 (s), 1476.3 (s),
1424.0 (s), 1334.4 (m), 1218.1 (ss), 1047.7 (s), 928.0 cmꢀ1 (s); MS (EIMS,
70 eV): m/z (%): 466 (0.4) [M+], 451 (2) [M+ꢀMe], 423 (4), 411 (10),
410 (35), 409 (100) [M+ꢀtBu], 365 (6), 348 (10), 347 (29), 332 (9), 321
(2), 305 (3), 303 (4), 289 (3), 273 (7), 245 (3), 234 (2), 215 (1), 202 (2),
189 (1), 153 (2), 107 (4), 89 (4), 77 (7), 75 (38), 73 (17), 57 (5) [tBu+], 45
(50) [C2H5O+]; elemental analysis calcd (%) for C27H34O5Si: C 69.49, H
7.34; found: C 69.24, H 7.32.
(3S)-3,8-Dihydroxy-3-methyl-1,2,3,4-tetrahydrobenzo[a]anthracene-7,12-
dione (31): M.p.=1958C (decomposition, from petroleum ether/diethyl
ether); [a]2D0 =ꢀ9.68 (c=0.28 in CHCl3); Rf =0.55 (diethyl ether);
1H NMR (400 MHz, CDCl3): d=1.39 (s, 3H; C3-CH3), 1.70 and 1.84 (m,
2H; H2), 2.89 (s, 2H; H4), 3.35 (m, 2H; H1), 7.34 (d, 3J
1H; H9), 7.59 (d, 3J(H,H)=8.5 Hz, 1H; H5), 7.65 (d, 3J
1H; H11), 7.8 (t, 3J(H,H)=7.8 Hz, 1H; H10), 8.06 (d, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(3S)-3-(tert-Butyldimethylsilyloxy)-8-hydroxy-3-methyl-1,2,3,4-tetrahy-
drobenzo[a]anthracene-7,12-dione (30): Acetyl chloride (0.3 mL,
4.2 mmol) was added dropwise to a solution of 28c (0.25 g, 0.59 mmol) in
absolute methanol (75 mL) and stirred for 2 h at ambient temperature,
until no further starting material was detected by TLC. The solvent was
evaporated, and the residue was purified by column chromatography (pe-
troleum ether/diethyl ether 2:1) to yield an orange solid (0.24 g,
0.57 mmol, 96%). M.p. 1338C (from petroleum ether/diethyl ether);
A
ACHTUNGTRENNUNG
G
1H; H6), 12.38 ppm (s, 1H; C8-OH); 13C NMR (100 MHz, CDCl3): d=
26.3 (C1), 29.0 (C3-CH3), 35.0 (C2), 44.3 (C4), 65.6 (C3), 115.2 (C7a),
119.0 (C11), 122.7 (C9), 124.4 (C6), 130.3 (C9a), 132.2 (C11a), 134.8
(C12a), 135.2 (C5), 137.0 (C10), 140.2 (C12b), 145.6 (C4a), 160.5 (C8),
184.2 (C12), 188.2 ppm (C7); IR (CCl4): n˜ =3612.1 (w), 2961.2 (w), 2927.7
(w), 2845.8 (w), 2360.8 (w), 2336.4 (w), 1670.7 (m), 1639.1 (s), 1577.0 (m),
1456.5 (m), 1418.6 (w), 1367.0 (m), 1321.7 (w), 1269.3 (s), 1245.5 (m),
1159.7 (m), 1111.4 (w), 1072.7 (m), 1053.6 cmꢀ1 (w); MS (EIMS, 70 eV):
m/z (%): 308 (100) [M+], 291 (23), 290 (87) [M+ꢀH2O], 275 (26), 272
(11), 266 (42), 265 (61), 263 (16), 251 (60), 245 (55), 247 (16), 237 (14),
202 (14), 194 (13), 189 (26), 165 (29), 153 (24), 152 (19), 139 (12), 136
(13), 115 (21), 107 (39), 97 (10), 89 (24), 81 (12), 78 (10), 77 (81), 73 (10),
69 (41), 60 (12), 57 (21), 55 (19), 51 (16), 45 (14), 43 (67), 41 (9); elemen-
tal analysis calcd (%) for C19H16O4: C 74.01, H 5.23; found: C 74.17, H
5.30.
[a]2D0 =ꢀ56.78 (c=0.3 in CHCl3); Rf =0.82 (petroleum ether/diethyl ether
1
ꢀ
2:1); H NMR (400 MHz, CDCl3): d=ꢀ0.03 (s, 3H; SitBu
ACHTUGNTRNEN(UNG CH3)2), 0.10
ꢀ
ꢀ
(s, 3H; SitBu
1.98 (m, 2H; H2), 2.88 and 2.93 (d, J
2H; H1), 7.21 (d, 3J(H,H)=8.2 Hz, 1H; H9), 7.40 (d, 3J
(H,H)=8.2 Hz, 1H; H10), 7.70 (d, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(CH3)2), 0.69 (s, 9H; SiMe2tBu), 1.38 (C3-CH3), 1.74 and
2
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1H; H5), 7.61 (t, 3J
N
1H; H11), 8.11 (d, 3J
(H,H)=8.0 Hz, 1H; H6), 12.53 ppm (s, 1H; OH);
ꢀ
13
ꢀ
ꢀ
C NMR (100 MHz, CDCl3): d=ꢀ2.3 ( SitBu(CH3)2), ꢀ2.2 ( SitBu-
G
ꢀ
ꢀ
ACHTUNGTRENNUNG(CH3)2), 18.0 ( SiMe2CMe3), 25.6 ( SiMe2tBu), 27.0 (C1), 28.9 (C3-CH3),
36.6 (C2), 45.6 (C4), 70.1 (C3), 115.5 (C7a), 119.2 (C9), 122.9 (C11),
124.8 (C6), 130.7 (C6a), 132.8 (C11a), 134.9 (C10), 135.0 (C12a), 136.4
(C5), 141.0 (C12b), 145.2 (C4a), 161.7 (C8), 184.7 (C12), 188.8 ppm (C7);
IR (CCl4): n˜ =3735.8 (w), 2957.7 (m), 2929.6 (m), 2857.4 (m), 2363.4 (w),
1700.4 (m), 1684.4 (m), 1669.3 (m), 1653.2 (s), 1638.0 (s), 1472.2 (m),
1456.9 (m), 1419.4 (m), 1369.1 (m), 1363.2 (m), 1319.4 (w), 1269.3 (s),
1244.6 (m), 1159.7 (m), 1135.3 (w), 1118.2 (m), 1073.7 (m), 1049.8 (w),
1029.1 (w), 1012.3 cmꢀ1 (m); MS (EIMS, 70 eV): m/z (%): 422 (0.3)
[M+], 407 (1), 389 (1), 381 (1), 379 (5), 367 (8), 366 (32), 365 (100)
General procedure for the oxidation to the benzo[a]anthracene-1,7,12-
triones (1–3): Compound 28a, 29, or 31 (0.31 mmol) was dissolved in
chloroform (150 mL). During irradiation with a tungsten lamp (Osram
Vitalux 300 W), the solution was stirred at room temperature in an open
round-bottomed flask until the conversion of starting material was com-
pleted. The solvent was evaporated and the residue was purified by
column chromatography.
(+)-Rubiginone B2 (1): M.p.>2628C (decomposition); [a]2D5 =+71.64
A
(c=0.275 in CHCl3); Rf =0.14 (petroleum ether/diethyl ether 4:1);
1H NMR (400 MHz, CDCl3): d=1.20 (d, 3J
ACHTUNGTRENNUNG
E
(3), 165 (2), 153 (2), 107 (3), 77 (10), 75 (72), 73 (27), 57 (8) [tBu+], 51
(3), 43 (2), 41 (4); elemental analysis calcd (%) for C25H30O4Si: C 71.05,
H 7.16; found: C 70.93, H 7.16.
2.45 (m, 1H; H-3), 2.55 (dd, 2J
2), 2.67 (dd, 2J
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
H-2 and H-4), 4.04 (s, 3H; OCH3), 7.24 (d, J0 =8.2 Hz, 1H; H-9), 7.45 (d,
J0 =8.0 Hz, 1H; H-5), 7.65 (dd, J0 =8.2, 7.8 Hz, 1H; H-10), 7.71 (d, J0 =
7.8 Hz, 1H; H-11), 8.20 ppm (d, J0 =8.0 Hz, 1H; H-6); 13C NMR
General procedure for the deprotection of 3-TBS ether to 29 and 31:
Concentrated hydrofluoric acid (5.0 mL, 45% in water, p.a.) was added
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8819

U. Groth et al.
(100 MHz, CDCl3): d=21.43 (3-CH3), 30.82 (C-3), 38.33 (C-4), 47.55 (C-
2), 56.50 (OCH3), 117.15 (C-9), 119.68 (C-11), 129.60 (C-6), 132.99 (C-5),
135.34 (C-10), 120.56, 134.98, 135.07, 137.67, 149.13, 159.81 (Cquart-arom.),
181.59, 184.51, 198.89 ppm (C=O); IR (CCl4): n˜ =1673, 1677, 1708 cmꢀ1
(C=O); MS (EIMS, 70 eV): m/z (%): 320 (100) [M+], 305 (15)
[7] K. Krohn, K. Khanbabaee, Angew. Chem. 1994, 106, 100–102;
Angew. Chem. Int. Ed. Engl. 1994, 33, 99–100.
[8] K. Krohn, K. Khanbabee, Liebigs Ann. Chem. 1994, 1109–1112.
[9] K. Krohn, K. Khanbabee, J. Micheel, Liebigs Ann. Chem. 1995,
1529–1537.
[10] K. Krohn, Tetrahedron Lett. 1980, 21, 3557–3560.
[11] K. Krohn, K. Khanbabee, P. G. Jones, Liebigs Ann. Chem. 1995,
1981–1985.
[12] T. Matsumoto, T. Sohma, H. Yamaguchi, S. Kurata, K. Suzuki, Syn-
lett 1995, 263–266.
[13] T. Matsumoto, T. Sohma, H. Yamaguchi, S. Kurata, K. Suzuki, Tetra-
hedron 1995, 51, 7347–7360.
[14] D. S. Larsen, M. D. OꢁShea, Tetrahedron Lett. 1993, 34, 1373–1376.
[15] D. S. Larsen, M. D. OꢁShea, Tetrahedron Lett. 1993, 34, 3769–3772.
[16] D. S. Larsen, M. D. OꢁShea, J. Chem. Soc. Perkin Trans. 1 1995,
1019–1028.
[17] D. S. Larsen, M. D. OꢁShea, S. Brooker, J. Chem. Soc. Chem.
Commun. 1996, 203–204.
[18] K. Kim, J. Reibenspies, G. A. Sulikowski, J. Org. Chem. 1992, 57,
5557–5559.
A
[292ꢀOCH3], 233 (24) [261ꢀCO].
(ꢀ)-8-O-Methyltetrangomycin (2): M.p. 1698C; [a]2D0 =ꢀ89.28 (c=1 in
MeOH); Rf =0.05 (diethylether); 1H NMR (400 MHz, CDCl3): d=1.49
2
(s, 3H; C3-CH3), 1.81 (brs, 1H; C3-OH), 2.97 (d, J
N
H2), 3.08 (d, 2J
C8-OCH3), 7.28 (d, 3J
1H; H5), 7.69 (t, 3J(H,H)=8.2 Hz, 1H; H10), 7.74 (d, 3J
1H; H11), 8.27 ppm (d, 3J(H,H)=7.8 Hz, 1H; H6); 13C NMR (100 MHz,
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CDCl3): d=29.9 (C3-CH3), 44.0 (C4), 53.8 (C2), 56.5 (C8-OCH3), 72.6
(C3), 117.1 (C9), 119.6 (C11), 120.5 (C7a), 130.0 (C6), 133.8 (C5), 134.3
(C6a), 135.1 (C12a), 135.2 (C10), 135.4 (C11a), 137.8 (C12b), 146.3
(C4a), 159.7 (C8), 181.5 (C12), 184.7 (C7), 196.9 ppm (C1); IR (CCl4):
n˜ =3709.2 (w), 3607.2 (w), 2963.0 (m), 2928.3 (w), 2855.0 (w), 1709.7 (m),
1674.2 (s), 1588.4 (s), 1470.9 (m), 1444.0 (m), 1436.0 (m), 1299.9 (m),
1269.8 (ss), 1216.1 (m), 1154.0 (m), 1101.3 (m), 1074.0 (m), 1025.7 cmꢀ1
(m); MS (EIMS, 70 eV): m/z (%): 336 (4) [M+], 320 (5), 319 (33), 318
(100) [M+ꢀH2O], 301 (10), 290 (4), 289 (8), 273 (8), 272 (9), 245 (7), 244
(14), 231 (9), 216 (7), 215 (9), 203 (8), 202 (14), 190 (5), 189 (16), 153 (4),
107 (4), 89 (5), 77 (10), 58 (5), 45 (7), 44 (5); elemental analysis calcd
(%) for C20H16O5: C 71.42, H 4.79; found: C 71.32, H 4.71.
[19] K. Kim, Y. Guo, G. A. Sulikowski, J. Org. Chem. 1995, 60, 6866–
6871.
[20] V. A. Boyd, J. Reibenspies, G. A. Sulikowski, Tetrahedron Lett.
1995, 36, 4001–4004.
[21] V. A. Boyd, G. A. Sulikowski, J. Am. Chem. Soc. 1995, 117, 8472–
8473.
(ꢀ)-Tetrangomycin (3): [a]2D0 =ꢀ89.6 (c=0.2 in MeOH); literature:
[a]2D0 =ꢀ1008 (c=0.2 in MeOH) for 99% ee; Rf =0.18 (diethyl ether);
1H NMR (400 MHz, CDCl3): d=1.52 (s, 3H; C3-CH3), 1.74 (brs, 1H;
[22] For [2+2+2] cycloadditions in general, see: a) K. P. C. Vollhardt,
R. G. Bergman, J. Am. Chem. Soc. 1974, 96, 4996–4998; b) R. L.
Hillard, K. P. C. Vollhardt, J. Am. Chem. Soc. 1977, 99, 4058–4069;
c) Y. Wakatsuki, H. Yamazaki, J. Organomet. Chem. 1977, 139, 169–
177; d) K. P. C. Vollhardt, Angew. Chem. 1984, 96, 525–541; Angew.
Chem. Int. Ed. Engl. 1984, 23, 539–644; e) S. H. Lecker, N. H.
Nguyen, K. P. C. Vollhardt, J. Am. Chem. Soc. 1986, 108, 856–858;
f) C. Saꢇ, D. D. Crotts, G. Hsu, K. P. C. Vollhardt, Synlett 1994, 487–
489; g) M. Malacria, Chem. Rev. 1996, 96, 289–306; h) U. Groth, N.
Richter, A. Kalogerakis, Eur. J. Org. Chem. 2003, 4634–4639; i) A.
Kalogerakis, U. Groth, Synlett 2003, 1886–1888; j) J. A. Varela, C.
Saꢇ, Chem. Rev. 2003, 103, 3787–3801; k) G. Chouraqui, M. Petit, C.
Aubert, M. Malacria, Org. Lett. 2004, 6, 1519–1521; l) C. Kesen-
heimer, U. Groth, Org. Lett. 2006, 8, 2507–2510; m) V. Gandon, C.
Aubert, M. Malacria, Chem. Commun. 2006, 21, 2209–2217; n) P.
Chopade, J. Louie, Adv. Synth. Catal. 2006, 348, 2307–2327; o) B.
Heller, M. Hapke, Chem. Soc. Rev. 2007, 36, 1085–1094; p) M.
Koegl, L. Brecker, R. Warrass, J. Mulzer, Angew. Chem. 2007, 119,
9480–9482; Angew. Chem. Int. Ed. 2007, 46, 9320–9322; q) B.
Heller, A. Gutnov, C. Fischer, H.-J. Drexler, A. Spannenberg, D.
Redkin, C. Sundermann, B. Sundermann, Chem. Eur. J. 2007, 13,
1117–1128; r) J. A. Varela, C. Saꢇ, Synlett 2008, 2571–2578; s) I.
Omae, Appl. Organomet. Chem. 2008, 22, 149–166; t) T. Shibata, K.
Tsuchikama, Org. Biomol. Chem. 2008, 6, 1317–1323; u) N. Nico-
laus, S. Strauss, J.-M. Neudçrfl, A. Prokop, H.-G. Schmalz, Org. Lett.
2009, 11, 341–344; v) T. Shibata, T. Uchiyama, K. Endo, Org. Lett.
2009, 11, 3906–3908.
C3-OH), 3.02 and 3.13 (d, 2J
7.28 (d, 3J(H,H)=7.4 Hz, 1H; H9), 7.56 (d, 3J
7.67 (m, 2H; H10 and H11), 8.31 (d, 3J
(H,H)=8.5 Hz, 1H; H6),
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
12.26 ppm (s, 1H; C8-OH); 13C NMR (100 MHz, CDCl3): d=30.2 (C3-
CH3), 44.0 (C4), 53.9 (C2), 72.6 (C3), 115.3 (C7a), 119.6 (C11), 123.7
(C9), 129.4 (C6), 133.6 (C12a), 133.8 (C10), 135.1 (C6a), 135.7 (C12b),
136.1 (C11a), 137.1 (C5), 147.6 (C4a), 162.0 (C8), 183.1 (C12), 187.4
(C7), 197.0 ppm (C1); H,H COSY correlation (CDCl3): d=3.03 (H2)–
3.13 (H2), 7.08 (H9)–7.67 (H10 and H11), 7.56 (H5)–8.31 (H6); IR
(CCl4): n˜ =3706.7 (w), 3606.6 (w), 2957.5 (m), 2927.6 (s), 2855.3 (m),
2361.2 (w), 2334.3 (w), 1712.9 (m), 1682.2 (m), 1639.9 (s), 1593.4 (m),
1456.5 (s), 1362.1 (m), 1269.4 (s), 1216.8 (m), 1158.9 (m), 1075.3 (m),
1051.0 cmꢀ1 (m); MS (EIMS, 70 eV): m/z (%): 322.2 (31) [M+], 305.1 (6),
304.1 (27) [M+ꢀH2O], 278.9 (16), 264.9 (20), 263.9 (100) [M+ꢀC2H4O],
235.9 (7), 208.0 (10), 189.0 (4), 179.9 (6), 165.0 (7), 152.1 (31), 151.0 (12),
126.2 (7), 116.2 (11), 107.2 (3), 89.2 (4), 77.1 (6), 57.1 (4), 55.1 (3), 43.1
(18); elemental analysis calcd (%) for C19H14O5: C 74.80, H 4.38; found:
C 74.55, H 4.49.
Acknowledgements
A.M. thanks the Landesgraduiertenfçrderung Baden-Wꢆrttemberg for a
doctoral fellowship. A.M. thanks the Konstanz Research School Chemi-
cal Biology (KoRS-CB) for scientific encouragement and academic train-
ing. We are grateful to Bayer AG, Merck KGaA, and Wacker AG for
generous gifts of reagents.
[23] For Knochel cuprates in general, see, for example: P. Knochel, P.
Jones, Organozinc reagents—A Practical Approach (Eds.: P. Kno-
chel, P. Jones), Oxford Medical Publications, Oxford, 1999.
[24] S. Kim, K. H. Ahn, J. Org. Chem. 1984, 49, 1717–1724.
[25] F. D. Chattaway, J. Chem. Soc. 1931, 3, 2495–2496.
[26] D. J. A. Schedler, B. Ganem, J. Org. Chem. 1996, 61, 4115–4119.
[27] J. M. White, A. R. Tunoori, G. I. Georg, J. Am. Chem. Soc. 2000,
122, 11995–11996.
[1] J. Rohr, R. Thiericke, Nat. Prod. Rep. 1992, 9, 103–137.
[2] K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 127–195.
[3] M. Oka, H. Kamei, Y. Hamagishi, K. Tomita, T. Miyaki, M. Konishi,
T. Oki, J. Antibiot. 1990, 43, 8, 967–976.
[28] L.-F. Tietze, G. V. Kiedrowski, K.-G. Fahlbusch, E. Voss, Org. Synth.
1993, 8, 353–357.
[29] C. Chapuis, M. Barthe, J.-Y.de Saint Laumer, Helv. Chim. Acta 2001,
84, 230–242.
[4] H. Kamei, M. Oka, Y. Hamagishi, K. Tomita, M. Konishi, T. Oki, J.
Antibiot. 1990, 43, 1018–1020.
[30] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
[31] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, K. B.
Sharpless, J. Am. Chem. Soc. 1987, 109, 5765–5780.
[5] M. Ogasawara, M. Hasegawa, Y. Hamagishi, H. Kamei, T. Oki, J.
Antibiot. 1992, 45, 129–132.
[6] Y. Hayakawa, S.-C. Ha, Y. J. Kim, K. Furihata, H. Seto, J. Antibiot.
1991, 44, 1179–1186.
[32] Y. Gao, K. B. Sharpless, J. Org. Chem. 1988, 53, 4081–4084.
8820
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Angucyclinones
FULL PAPER
[33] J. R. Parikh, W. von Doering, J. Am. Chem. Soc. 1967, 89, 5505–
5507.
[36] K. Krohn, F. Ballwanz, W. Baltus, Liebigs Ann. Chem. 1993, 911–
913.
[34] T. T. Tidwell, Synthesis 1990, 857–869.
[35] a) M. A. Tius, J. G. Galeno, X. Gu, J. H. Zaid, J. Am. Chem. Soc.
1991, 113, 5775–5783; b) H. Firouzabadi, B. Vessel, M. Naderi, Tet-
rahedron Lett. 1982, 23, 1847–1850.
Received: March 30, 2010
Published online: June 23, 2010
Chem. Eur. J. 2010, 16, 8805 – 8821
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8821