Towards a total synthesis of the new anticancer agent mensacarcin: Synthesis of the carbocyclic core

Article abstract of DOI:10.1002/chem.200400342

A synthesis of the carbocyclic core associated with the new anti-cancer agent mensacarcin (1) is reported. The strategy involves the synthesis of several novel highly substituted aromatic compounds, such as 12 and 23. The lithium derivative of 12 readily

Full text of DOI:10.1002/chem.200400342

FULL PAPER
Towards a Total Synthesis of the New Anticancer Agent Mensacarcin:
Synthesis of the Carbocyclic Core
Lutz F. Tietze,* Scott G. Stewart, Marta E. Polomska, Andrea Modi, and Axel Zeeck[a]
Dedicated to Professor Karsten Krohn on the occasion of his 60th birthday
Abstract: Asynthesis of the carbocy-
clic core associated with the new anti-
cancer agent mensacarcin (1) is report-
ed. The strategy involves the synthesis
of several novel highly substituted aro-
matic compounds, such as 12 and 23.
The lithium derivative of 12 readily
engages in a nucleophilic addition to
benzaldehyde 4 to provide the diphenyl-
carbinol rac-15. The analogous benzyl
ether rac-16 undergoes an intramolecu-
lar Heck reaction to provide the re-
quired tetrahydroanthracene rac-17,
which can be transformed into the key
benzaldehyde 23 to give the diphenyl-
carbinol rac-35. Subsequent methyla-
tion to rac-36 followed by an intramo-
lecular Heck reaction provides tricycle
rac-37. Similarly, the oxidised com-
pound 40 provides an electronically
more suitable intramolecular Heck
partner to afford compound 41. Fur-
ther transformations of these substrates
leads to rac-43, which incorporates the
core structure of mensacarcin (1).
tricyclic methyl ether rac-20. In
a
second approach, the lithium derivative
of 21 is added to the hexasubstituted
Keywords:
antibiotics
carbocycles
anthracenes
antitumor agents
Heck reactions
·
·
·
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Introduction
Mensacarcin (1) is a novel polyfunctionalised hexahydroan-
thracene isolated from a strain of Streptomyces (Gö C4/4)
by Zeeck and Arnold.[1] Mensacarcin (1) shows cytostatic
and cytotoxic activity comparable to doxorubicin (2), anoth-
er anticancer agent currently used in the treatment of malig-
nant lymphomas and leukemias.[2,3] Interestingly, mensacar-
cin (1) has a high level of oxygenation, similar to that found
in compound 2, along with some other structural similarities.
At present, the only known natural product with a closely
related structure to mensacarcin (1) is cavicarcin (3), which
displays a much lower biological activity.[4] The challenges
involved with the highly substituted tricyclic core of mensa-
carcin (1) along with its pronounced bioactivity make it an
attractive target for organic synthesis. When the prevalence
of anthraquinone-type frameworks in a variety of natural
products is considered, it is not surprising that many ap-
proaches have been developed for their synthesis.[5] However,
only a few methods exist for the formation of the hydroxy-
or methoxy-substituted dihydroanthracenone, either by re-
gioselective reduction of anthraquinone or by other synthet-
ic pathways.[6] For this reason, and because of our interest in
preparation of natural products by transition-metal-catalysed
transformations,[7] we have devised a synthesis of the tricy-
clic core of 1 by means of an intramolecular Heck reaction.
The strategy for the synthesis of the carbocyclic core of
mensacarcin (1) is outlined in Scheme 1. In an initial retro-
synthesis analysis, it was envisaged that the tricyclic com-
pound 1 could be broken up into the two aromatic frag-
ments, 4 and 5. Nucleophilic addition of the aryllithium spe-
cies 5 to the aldehyde 4 should afford the diphenylcarbinol
6. An intramolecular Heck reaction involving a protected
[a] Prof. Dr. L. F. Tietze, Dr. S. G. Stewart, M. E. Polomska,
Dr. A. Modi, Prof. Dr. A. Zeeck
Institut für Organische und Biomolekulare Chemie
Georg-August Universität
Tammannstrasse 2, Göttingen 37077 (Germany)
Fax : (+49)551-399-476
E-mail: ltietze@gwdg.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 5233 – 5242
DOI: 10.1002/chem.200400342
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Results and Discussion
The synthesis of 2-iodo-3-methoxybenzaldehyde (4) was
achieved, in 52% yield, by converting the commercially
available benzaldehyde 13 into the corresponding ortho-ar-
yllithium compound by using nBuLi, TriMEDAand PhLi
and then quenching with iodine (Scheme 2).[8] The C-ring
Scheme 1. Retrosynthesis analysis of the carbocyclic core of mensacarcin
(1).
Scheme 2. Synthesis of tricycle rac-20. a) TriMEDA, C6H6, nBuLi, 08C,
then 13, 08C, PhLi, 7 h, then THF, ꢀ788C, I2, 12 h, 55%; b) 12, tBuLi,
THF, ꢀ788C, 10 min, then 4, Et2O, 20 8C, 30 min, 80%; c) NaH, THF,
BnBr, 408C, 12 h, 65%; d) Pd(OAc)2, PPh3, nBu4NCl, K2CO3, DMF,
408C, then 16, 808C, 12 h, 85%; e) RuCl3, NaIO4, CCl4, MeCN, H2O,
208C, 20 min, 81%; f) LiAlH4, THF, 08C, 30 min, 91%; g) NaH, MeI,
THF, 408C, 12 h, 96%. Bn=benzyl, TriMEDA=N’,N,N-trimethylethyl-
enediamine.
derivative of diphenylcarbinol 6 would then provide the re-
quired tetrahydroanthracene compound 7 (Pathway 1). In a
second retrosynthesis approach, the building blocks 8 and 9
were utilised (Pathway 2). Nucleophilic addition of the lithi-
um compound 8 to the aldehyde 9 would provide the diphe-
nylcarbinol 10, which should then lead to the tetrahydroan-
thracene 11, again by way of an intramolecular Heck reac-
tion. However, before such retrosynthesis approaches were
realised, the synthesis of the corresponding highly substitut-
ed building blocks 4 and 9 had to be performed. Additional-
ly, at this stage it was not clear whether the planned Heck
reactions would be at all feasible, due to the high electron
density in rings Aand C. For the synthesis of mensacarcin
(1), we initially focussed on the preparation of building
block 12, assuming that the missing methyl group at C-3
could be introduced by addition of a methyl cuprate to an
epoxide in ring C; this reaction would also allow the intro-
duction of a hydroxy group at C-2 (mensacarcin number-
ing). As a second building block, 2-iodo-3-methoxybenzalde-
hyde (4) had to be prepared.
building block 12 was synthesised in 12 steps from p-
methoxyphenol 14 in 12% overall yield.[9] Treatment of 12
with tBuLi at ꢀ788C generated the corresponding aryllithi-
um compound, which was in turn treated with aldehyde 4.
The resulting alcohol from this reaction, rac-15, was not iso-
lated but was protected under standard conditions with
NaH, BnBr and THF at 408C to provide the benzyl ether 16
as a racemic mixture in 52% yield over two steps. Com-
pound rac-16 was subsequently employed in the key ring-
closure step. Thus, intramolecular Heck reaction with
Pd(OAc)2, PPh3, nBu4NCl and K2CO3 in DMF allowed a
smooth transformation to form the desired methylene tetra-
hydroanthracene rac-17 in an excellent yield of 85%. As an-
ticipated, none of the seven-membered endo product was
detected, due to the highly favoured and less sterically de-
manding six-exo-trig cyclisation.[10]
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Chem. Eur. J. 2004, 10, 5233 – 5242

Synthesis of the Mensacarcin Carbocyclic Core
5233 – 5242
Once we had succeeded in forming the carbocyclic core of
mensacarcin (1), our attention was then focussed on instal-
ling the methoxy substituent at C-12 (mensacarcin number-
ing: C-10). To this end, the methylene group within the tri-
cyclic rac-17 was initially oxidatively cleaved with a mixture
of RuCl3 (5 mol%) and NaIO4 to give the ketone rac-18 in
81% yield.[11] The latter compound was then stereoselective-
ly reduced to afford the alcohol rac-19. The anti-orientated
substituents at C-7 and C-12 within rac-19 probably arise
from a neighbouring-group effect of the benzyloxy moiety
at the C-7 position during reduction. Final methylation of
the hydroxy group in rac-19 provided the racemic ether 20,
in 96% yield, which was characterised by standard spectro-
1
scopic techniques as well as H-NOESY NMR spectroscopy.
This compound contains the desired ABC ring system as
well as the C-12 functionality as found in mensacarcin (1)
but is missing the methyl group at C-5 (mensacarcin num-
bering: C-10 and C-3, respectively).
In addition to compound 12, we also prepared the C-ring
building block 23, which already contains the necessary
methyl group at C-5. The connection of this compound with
ring Awas envisaged according to retrosynthesis pathway 2
(Scheme 1), for which the building blocks 21 and 22
(Scheme 3) were needed. For the synthesis of the first
Scheme 4. Synthesis of bromobenzenes 23 and 34. a) Br2, CH2Cl2,
NaOAc, 08C, 2 h, 85%; b) Mg, THF, Et2O, reflux, 1 h 30 min, then 208C,
CO2, 2 h, 82%; c) Br2, dioxane, 208C, 7 d, 84%; d) LiAlH4, THF, Et2O,
08C, 1 h, 72%; e) MnO2, CH2Cl2, 208C, 12 h, 87%; f) m-CPBA, CH2Cl2,
208C, then K2CO3, MeOH, 208C, 15 min, 68%; g) HCHO, H2O, CaO,
208C, 5 d, 69%; h) (CH3)2CO, p-TsOH, 208C, 18 h, 91%; i) DMSO,
ClCOCOCl, CH2Cl2, ꢀ788C, 30 min, then 32/33, ꢀ788C, 1.5 h, then NEt3,
5 min, 208C, 30 min, 83%. DMSO=dimethylsulfoxide, m-CPBA=meta-
chloroperoxybenzoic acid, p-TsOH=para-toluenesulfonic acid.
and this functionality subsequently needed to be “un-
masked” as the phenol to allow the introduction of two
ortho-hydroxymethyl units.[14] This transformation first re-
quired an acid to aldehyde reduction, which was achieved in
2 steps by initial treatment of 27 with LiAlH4 to give the al-
cohol 28 in 72% yield and subsequent oxidation with MnO2
to afford aldehyde 29 in 87% yield. Baeyer–Villiger oxida-
tion of 29 to give the corresponding formate was followed
by solvolysis with K2CO3 and MeOH to furnish phenol 30 in
reasonable yield (68%).[15] The 1H NMR spectrum of 30
shows two meta-coupled resonances (J=1.2 Hz), which are
characteristic for the aromatic substitution pattern in this
compound. In a final transformation, the last two nonsubsti-
tuted positions within phenol 30 were hydroxymethylated by
exposure to formaldehyde and calcium oxide in water to
give the novel hexasubstituted aromatic compound 31 in
69% yield.[16]
Scheme 3. Synthesis of iodobenzenes 21 and 22. a) Ph3PCH3Br,
NaHMDS, THF, 208C, 1 h, then 4, 1 h, 90%; b) 1,3-propanediol, Amber-
lyst 15 H+, C6H6, reflux, 5 h, 66%. NaHMDS=sodium hexamethyldisila-
zanide.
Acetonide protection of triol 31 by using acetone and cat-
alytic amounts of p-TsOH gave a mixture of regioisomers 32
and 33 in a 1:1.1 ratio,[17] respectively, and in 91% overall
yield.[18] Unfortunately, at this stage alcohols 32 and 33
could not be separated by conventional chromatography.
Therefore, the mixture was carried through the synthesis se-
quence and oxidised under Swern conditions to give the cor-
responding aldehydes 23 and 34 in 83% overall yield. Here,
the two aromatic regioisomers could be chromatographically
separated and individually characterised by using standard
spectroscopic techniques, as well as NOE difference mea-
surements to determine their substitution pattern. Aldehyde
23, which represented the desired C-ring building block, was
used for the anticipated ring coupling, while compound 34
was used for another independent pathway to mensacarcin
(1).
Aring building block, the previously synthesised aldehyde 4
was subjected to a Wittig reaction with PPh3CH3Br and
NaHMDS to give 21 in 90% yield. Furthermore, the pre-
sumably more stable acetal-protected derivative 22 was also
prepared in a single step, in 66% yield, by using 1,3-pro-
panediol. Synthesis of the more complex aldehyde 23 started
with bromination in the para position of the commercially
available anisole 24 by using Br2 and NaOAc in CH2Cl2 to
give 25 (Scheme 4). This step was followed by preparation
of the corresponding magnesium compound, which was CO2
(dry) quenched to produce the carboxylic acid 26 in 70%
yield over 2 steps.[12] Reaction of carboxylic acid 26 with
2.0 equivalents of Br2 in dioxane furnished compound 27, in
84% yield, containing a bromine atom in the ortho position
to the methoxy substituent.[13] As intended, the carboxylic
acid at C-1 in 26 was successful in directing the bromination
The crucial connection of the two Aand C-ring aromatic
fragments was performed as previously anticipated in the
Chem. Eur. J. 2004, 10, 5233 – 5242
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L. F. Tietze et al.
FULL PAPER
retrosynthesis analysis (Pathway 2, Scheme 2). The aryllithi-
um was prepared in situ from 21 by a lithium–iodine ex-
change with nBuLi (Scheme 5). This was followed by addi-
acetone/water (81%) and olefination with PPh3CH3Br and
NaHMDS (81%) to give the desired alkene rac-36. Howev-
er, due to the additional steps, the overall yield of this path-
way does not exceed the previously mentioned direct and
shorter approach to rac-36 by using compound 21 as the
substrate.
The intramolecular Heck reaction of olefin rac-36, with
the Herrmann–Beller catalyst,[19] provided the desired meth-
ylene tetrahydroanthracene rac-37 in a low yield of 24%
(54% based on recovery of starting material). After similar
poor yields with several other palladium catalysts, the highly
electron-donating C-ring within substrate rac-36 was
deemed to negatively effect the initial insertion process of
the Heck reaction cycle and hence lower the turnover rate
of this transformation. With this in mind, a new precursor,
benzophenone 40, was devised to accelerate the Heck trans-
formation. It was thought that such a substrate would lower
the C-ring aromatic electron density as well as bring the
olefin and the organopalladium intermediate in close prox-
imity to each other through conjugation. Benzophenone 40
was synthesised from rac-35 by using Dess–Martin periodi-
nane in 81% yield (Scheme 6). As predicted, the intramo-
Scheme 5. Synthesis of tricycle rac-37. a) 21, nBuLi, THF, ꢀ788C, 20 min,
then 23, THF, ꢀ788C, 20 min, 208C, 58%; b) KH, THF, 08C, 40 min,
then MeI, 208C, 1 h, 87%; c) nBu4NOAc, DMF/CH3CN/H2O, 60 8C, then
Herrmann–Beller catalyst, 1208C, 4 h, 24%; d) 22, nBuLi, THF, ꢀ788C,
10 min, then 23, THF, 208C, 35 min, 74%; e) KH, THF, 08C, 40 min,
then MeI, 208C, 2 h, 91%; f) PPTS, (CH3)2O, H2O, 20 8C!reflux, 3 h,
81%; g) Ph3PCH3Br, NaHMDS, THF, 208C, 1 h, then the aldehyde from
(f), 208C, 1 h, 81%. PPTS=pyridinium p-toluenesulfonate.
tion of the aldehyde 23 which led to formation of the diphe-
nylcarbinol rac-35 in a reasonable yield of 58%. Initial evi-
dence for the success of this reaction was obtained upon
H1 NMR spectral analysis by observation of a new reso-
nance at d=6.82 ppm (d, J=8.1 Hz), which was attributed
to the 1-H proton. Subsequent installation of what would
become the C-10 methoxy substituent in mensacarcin (1)
was achieved by subjection of rac-35 to KH and MeI in
THF to give rac-36 in 87% yield. In an effort to improve
the aryllithium to aldehyde addition and hence the overall
yields, an alternative pathway to compound rac-36, the in-
tramolecular Heck reaction precursor, was devised. Thus,
the aryllithium of acetal 22 was added in the same manner
to the aldehyde 23 to give the diphenylcarbinol rac-38 with
a superior yield (74%). The reasons for the protected iodo
compound 22 performing better under these conditions than
its styrene counterpart 21 are unknown. However, one could
assume that the oxygen atoms within the acetal moiety at
the ortho position facilitate the lithiation and stabilise the
formed metal organic compound. Alcohol rac-38 was then
methylated by using KH and MeI to give rac-39 (91%); this
was followed by cleavage of the acetal moiety with PPTS in
Scheme 6. Synthesis of tricycle rac-43. a) Dess–Martin periodinane,
CH2Cl2, 208C, 15 min, 81%; b) nBu4NOAc, DMF/CH3CN/H2O, 60 8C,
then Herrmann–Beller catalyst, 1108C, 17 h, 74%; c) LiAlH4, THF, 08C,
10 min; d) NaH, MeI, THF, 08C!208C, 14 h, 37% over two steps;
e) RuCl3, NaIO4, CCl4, MeCN, H2O, 0 8C, 15 min, 69%.
lecular Heck reaction of this compound proceeded smoothly
under the previously described conditions with the Herr-
mann–Beller catalyst to afford the anthracenone derivative
41 in 74% yield. This latter tricyclic derivative could be con-
verted into the required compound rac-37. This conversion
was achieved through a reduction with LiAlH4 and a meth-
ylation sequence in 37% overall yield. This poor yield was
due to the susceptibility of the intermediate tetrahydroan-
thracene rac-42 to rearomatise. Finally, an oxidative cleav-
age of the methylene moiety within anthracene rac-37 by
using RuCl3 (5 mol%) and NaIO4 allowed the formation of
rac-43, in 69% yield, containing the correct ABC tricyclic
core and the AB ring functionality as found in mensacarcin
(1).
An essential factor of the described synthesis pathways to
provide a viable route to the natural product mensacarcin
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Chem. Eur. J. 2004, 10, 5233 – 5242

Synthesis of the Mensacarcin Carbocyclic Core
5233 – 5242
136.7, 158.2, 196.4 ppm; UV/Vis (CH3CN): lmax (loge)=222.0 (4.4167),
326.5 nm (3.7352); IR (KBr): n˜ =2849, 1950, 1562, 1466, 1270, 1013,
787 cmꢀ1; MS (EI, 70 eV): m/z (%): 261 (100) [M]+, 133.0 (10), 104.0 (8),
76.0 (12); HRMS: calcd for C8H7IO2: 261.9491; confirmed.
(1) is the ability to dearomatise the C-ring. Methods for car-
rying out this transformation include oxidation by using
ceric ammonium nitrate (CAN),[16] hypervalent iodine re-
agents[20] or anodic methods.[21] Initial efforts in this area
have been fruitful with the successful CAN oxidation of
compound rac-20.
(1’RS)-7-[1’-Benzyloxy-(2’-iodo-3’-methoxyphenyl)-methyl]-6-methoxy-
2,2-dimethyl-8-vinyl-4H-benzo[1,3]dioxine (16): Amagnetically stirred
solution of bromobenzene 12 (500 mg, 1.76 mmol) in Et2O (20 mL) at
ꢀ788C was treated with tBuLi (2.18 mL, 1.7m in hexane, 3.7 mmol). The
resulting mixture was stirred at this temperature for 10 min before being
treated with aldehyde 4 (507 mg, 1.94 mmol) in Et2O (2 mL). Stirring was
continued at ꢀ788C for 30 min and the ensuing solution was warmed to
208C. The resulting mixture was diluted with Et2O (20 mL) and washed
with water (2”5 mL), then the organic phases were dried (Na2SO4), fil-
tered and concentrated under reduced pressure to afford alcohol 15 as a
yellow oil (684 mg, 1.42 mmol, approximately 80%).[23]
Conclusion
In summary, we have developed an efficient pathway to the
tricyclic carbocycles 17, 37 and 41. Furthermore, compounds
37 and 41 could be readily converted into the 12-methoxydi-
hydroanthracenone 43 which contains the desired ABC tri-
cyclic core found in mensacarcin (1), the correct AB func-
tionality and the carbon pattern of ring C. It is also expected
that, following alternative transformations, compounds 41
and 43 will serve as useful precursors to mensacarcin (1).
This work demonstrates the value of intramolecular Heck
transformations in organic synthesis. The utility of this syn-
thetic pathway for the synthesis of the natural product men-
sacarcin (1) and biologically active analogues is currently
being explored within this group.
Amagnetically stirred solution of alcohol 15 in THF (20 mL) was treated
with NaH (141 mg, 60% in oil, 3.52 mmol) and benzyl bromide (418 mL,
3.52 mmol) at 208C. The resulting mixture was warmed to 408C and stir-
ring was continued for 12 h. The ensuing cloudy solution was diluted with
Et2O (40 mL), washed with water (2”10 mL), dried (Na2SO4), filtered
and concentrated under reduced pressure to afford a pale oil. Subjection
of this material to flash chromatography (pentane/methyl tert-butyl ether
3:1) and concentration of the appropriate fractions afforded benzyl ether
16 as
a
yellow foam (654 mg, 1.14 mmol, 65%). Rf =0.4; 1H NMR
(300 MHz, C6D6): d=1.42 (s, 3H; CH3), 1.44 (s, 3H; CH3), 3.18 (s, 6H;
2”OCH3), 4.59 (s, 2H; 4-H), 4.62 (d, J=11.0 Hz, 1H; OCH2Ph), 4.83 (d,
J=11.0 Hz, 1H; OCH2Ph), 5.43 (dd, J=12.0, 2.6 Hz, 1H; 2’’-H), 6.01
(dd, J=17.7, 2.6 Hz, 1H; 2’’-H), 6.03 (s, 1H; 7-H), 6.19 (dd, J=8.3,
1.3 Hz, 1H; 4’-H), 6.64 (s, 1H; 5-H), 6.88 (t, J=8.0 Hz, 1H; 5’-H), 7.03–
7.20 (m, 3H; Ar-H), 7.30 (dd, J=7.8, 1.4 Hz, 1H; 6’-H), 7.40–7.51 ppm
(m, 3H; Ar-H, 1’’-H); 13C NMR (50.3 MHz, C6D6): d=24.7, 25.1, 55.9,
55.9, 61.2, 71.7, 82.1, 94.0, 99.5, 106.6, 110.1, 119.9, 120.8, 126.1, 123.0,
127.8, 128.2, 128.3, 128.9, 132.0, 139.2, 144.2, 145.7, 152.6, 158.7 ppm; IR
(KBr): n˜ =3442, 3029, 2938, 2838, 1726, 1603, 1584, 1463, 1425, 1340,
1385, 1279, 1202, 1065, 851, 797 cmꢀ1; MS (EI, 70 eV): m/z (%): 572.0
(28) [M]+, 513.9 (20) [MꢀC3H6O]+, 422.9 (100), 387.1 (38), 279.0 (24),
165.0 (20), 91.0 (100) [C7H7]+; HRMS: calcd for C28H29IO5: 572.1059;
confirmed.
Experimental Section
General: All reactions were performed in flame-dried glassware under
an argon atmosphere. Solvents were dried and purified according to the
method defined by Perrin and Armarego.[22] TLC chromatography was
performed on precoated aluminium silica gel SIL G/UV254 plates (Ma-
cherey, Nagel Co.), and silica gel 32–63 (0.032–0.064 mm; Macherey,
Nagel Co.) was used for column chromatography. Apparatus used: melt-
ing points: Mettler FP61; IR spectroscopy: Brucker IFS25; UV/Vis spec-
troscopy: Perkin-Elmer Lambda 9; NMR spectroscopy: Varian VXR-200
(7RS)-7-Benzyloxy-6,11-dimethoxy-2,2-dimethyl-12-methylene-7,12-dihy-
dro-4H-1,3-dioxabenzo[a]anthracene (17): Amagnetically stirred so-
lution of Pd(OAc)2 (16 mg, 5 mol%, 77 mmol), PPh3 (36 mg, 10 mol%,
1.4 mmol), nBu4NCl (793 mg, 2.86 mmol) and K2CO3 (395 mg,
2.86 mmol) in DMF (30 mL) was heated at 408C for 30 min. The result-
ing solution was treated with olefin 16 (818 mg, 1.43 mmol) in one por-
tion and the mixture was immediately degassed and heated to 808C. Stir-
ring was continued at this temperature for 12 h, before the solution was
cooled to 208C. The ensuing mixture was diluted with Et2O (60 mL),
washed with water (1”10 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The resulting crude oil was subjected to flash
chromatography (pentane/methyl tert-butyl ether 1:1) and concentration
of the appropriate fractions afforded anthracene 17 as a yellow foam
(540 mg, 1.22 mmol, 85%). Rf =0.6; 1H NMR (300 MHz, C6D6): d=1.28
(s, 3H; CH3), 1.46 (s, 3H; CH3), 3.21 (s, 3H; OCH3), 3.33 (s, 3H; OCH3),
4.56 (d, J=15.3 Hz, 1H; 4-H), 4.62 (d, J=15.3 Hz, 1H; 4-H), 4.62 (d, J=
12.0 Hz, 1H; OCH2Ph), 4.68 (d, J=12.0 Hz, 1H; OCH2Ph), 6.01 (s, 1H;
5-H), 6.20 (s, 1H; 7-H), 6.54 (dd, J=7.3, 2.5 Hz, 1H; 10-H), 6.78 (s, 2H;
1’-H), 6.97–7.13 (m, 5H; Ar-H), 7.31–7.38 ppm (m, 2H; Ar-H); 13C NMR
(150.8 MHz, C6D6): d=24.1, 25.5, 55.1, 55.6, 61.3, 69.8, 71.4, 99.4, 105.5,
111.5, 120.1, 122.0, 122.2, 127.2, 127.6, 127.9, 128.2, 125.4, 127.7, 129.6,
132.0, 137.9, 140.1, 142.8, 150.9, 157.4 ppm; IR (KBr): n˜ =3424, 2937,
1601, 1461, 1434, 1384, 1265, 1139, 858, 799 cmꢀ1; UV/Vis (CH3CN): lmax
(loge)=191.0 (4.8328), 306.0 nm (3.7432); MS (EI, 70 eV): m/z (%):
444.0 (8) [M]+, 386.0 (5) [MꢀC3H6O]+, 279.0 (100), 249.0 (8), 91.0 (1)
[C7H7]+; HRMS: calcd for C28H28O5: 444.519; confirmed; elemental anal-
ysis calcd (%) for C28H28O5: C 75.65, H 6.35; found: C 75.71, H 6.20.
1
1
(200 MHz, H) or Bruker AM-300 (300 MHz, 75 MHz, for H and 13C, re-
spectively); MS: Varian MAT 731. For 1H and 13C NMR spectroscopy,
CDCl3 and C6D6 were used as solvents. HRMS was performed by using a
modified peak-matching technique, with an error of ꢁ2 ppm and a reso-
lution of approximately 10000. Elemental analysis was performed at the
Mikroanalytisches Labor des Institutes für Organische und Biomoleku-
lare Chemie der Universität Göttingen.
2-Iodo-3-methoxybenzaldehyde (4): Asolution of N,N’,N’-trimethyleth-
ylenediamine (3.22 g, 31.5 mmol) in benzene (100 mL) was treated drop-
wise with nBuLi (12.60 mL, 2.5m in hexane, 31.5 mmol) at 08C. The re-
sulting solution was warmed to 208C while being continuously stirred for
15 min. The mixture was then cooled again to 08C and 3-methoxybenzal-
dehyde (13; 4.00 g, 29.4 mmol) was added in one portion. The resulting
yellow solution was stirred for another 15 min at 208C before being
cooled again to 08C and treated with
a solution of phenyllithium
(44.1 mL, 2.0m in dibutyl ether, 88.2 mmol). After the mixture was stirred
at 208C for 7 h, THF (50 mL) was added while the mixture was cooled to
ꢀ788C. This solution was then treated with freshly sublimed iodine
(29.9 g, 118 mmol) in THF (50 mL), the cooling bath was removed and
the reaction mixture was allowed to warm to 208C. After being stirred
for a further 12 h, the slurry was diluted with ethyl acetate (100 mL),
washed with HCl (1”20 mL, 1m) and Na2S2O3 (3”50 mL, saturated so-
lution), dried (MgSO4), filtered and concentrated under reduced pres-
sure. Subjection of the resulting crude oil to flash chromatography (pen-
tane/EtOAc 19:1) and concentration of the appropriate fractions afford-
ed iodobenzene 4 as a yellow solid (4.23 g, 16.2 mmol, 55%), recrystal-
lised from EtOAc/hexane. Rf =0.5; m.p. 848C; 1H NMR (200 MHz,
CDCl3): d=3.95 (s, 3H; OCH3), 7.05 (d, J=7.9 Hz, 1H; 4-H), 7.39 (t, J=
7.9 Hz, 1H; 5-H), 7.50 (d, J=7.9 Hz, 1H; 6-H), 10.19 ppm (s, 1H;
CHO); 13C NMR (50.3 MHz, CDCl3): d=56.8, 93.9, 116.0, 122.2, 129.4,
(7RS)-7-Benzyloxy-6,11-dimethoxy-2,2-dimethyl-4,7-dihydro-1,3-dioxa-
benzo[a]anthracen-12-one (18): Amagnetically stirred solution of com-
pound 17 (293 mg, 0.66 mmol) in CCl4/MeCN/H2O 1:1:1.5 (10.5 mL) at
208C was treated in one portion with a mixture of RuCl3 (6.8 mg,
5 mol%, 0.03 mmol) and NaIO4 (705 mg, 3.0 mmol). After being stirred
for 20 min, the suspension was diluted with CH2Cl2 (10 mL), washed with
Chem. Eur. J. 2004, 10, 5233 – 5242
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5237

L. F. Tietze et al.
FULL PAPER
water (1”5 mL), dried (MgSO4), filtered and concentrated under re-
duced pressure. The resulting brown solid was diluted with pentane
(10 mL), filtered and washed further with pentane (1”5 mL) to afford
crude anthracenone 18 as a brown solid (254 mg, 0.57 mmol, 81%).
1H NMR (300 MHz, C6D6): d=1.37 (s, 3H; CH3), 1.53 (s, 3H; CH3), 3.25
(s, 3H; OCH3), 3.28 (s, 3H; OCH3), 4.45 (d, J=12.0 Hz, 1H; OCH2Ph),
4.50 (s, 2H; 4-H), 4.52 (d, J=12.0 Hz, 1H; OCH2Ph), 5.98 (s, 1H; 7-H),
6.09 (brs, 1H; 5-H), 6.42 (d, J=8.6 Hz, 1H; 10-H), 6.86 (d, J=7.3 Hz,
1H; 8-H), 6.96–7.11 (m, 4H; Ar-H), 7.18–7.24 ppm (m, 2H; Ar-H);
13C NMR (75.5 MHz, C6D6): d=24.7, 24.9, 55.4, 55.8, 61.0, 69.2, 69.6,
100.0, 110.5, 112.7, 121.2, 121.6, 127.3, 127.9, 128.2, 132.2, 125.8, 126.8,
139.3, 141.4, 144.9, 150.1, 159.3, 183.2 ppm; IR (KBr): n˜ =3424, 3002,
2941, 2841, 1680, 1472, 1431, 1384, 1270, 1196, 1141, 1087, 1020, 865,
742 cmꢀ1; UV/Vis (CH3CN): lmax (loge)=191.0 (4.8334), 287.5 (3.4882),
332.0 (3.6248), 357.0 nm (3.6562); MS (EI, 70 eV): m/z (%): 446.4 (24)
[M]+, 388.4 (16) [MꢀC3H6O]+, 282.2 (100), 267.2 (30), 253.2 (20), 239.2
(24), 167.1 (30), 149.1 (50), 108.1 (20), 91.0 (28) [C7H7]+; HRMS: calcd
for C27H26O6: 446.1729; confirmed.
2-Iodo-3-vinyl-anisole (21): Asolution of Ph 3PCH3Br (1.38 g, 3.87 mmol)
in THF (50 mL) was treated with sodium bis(trimethylsilyl) amide
(3.87 mL, 1m in THF, 3.87 mmol) and stirred for 1 h at 208C. The reac-
tion mixture was then treated with a solution of 2-iodo-3-methoxybenzal-
dehyde 4 (676 mg, 2.58 mmol) in THF (20 mL) and stirred for 1 h, before
silica gel was added and the suspension concentrated under reduced pres-
sure. Subjection of the resulting yellow solid to the flash chromatography
(pentane/EtOAc 9:1) and concentration of the appropriate fractions af-
forded styrene 21 as a white solid (601 mg, 2.31 mmol, 90%) recrystal-
lised from EtOAc/hexane. Rf =0.8; m.p. 648C; 1H NMR (200 MHz,
CDCl3): d=3.87 (s, 3H; OCH3), 5.30 (d, J=11.0 Hz, 1H; 2’-H), 5.62 (d,
J=17.3 Hz, 1H; 2’-H), 6.71 (d, J=7.5 Hz, 1H; 6-H), 7.00 (dd, J=17.3,
11.0 Hz, 1H; 1’-H), 7.12 (d, J=7.5 Hz, 1H; 4-H), 7.24 ppm (t, J=7.5 Hz,
1H; 5-H); 13C NMR (50.3 MHz, CDCl3): d=56.5, 92.0, 100.7, 116.9,
122.2, 129.4, 136.7, 158.2, 196.4 ppm; IR (KBr): n˜ =3081, 2962, 2935,
1616, 1558, 1465, 1057, 786 cmꢀ1; UV/Vis (CH3CN): lmax (loge)=222.0
(4.4427), 296.5 (3.3006), 249.0 nm (3.9419); MS (EI, 70 eV): m/z (%):
260.0 (100) [M]+, 245.0 (8) [MꢀCH3]+, 104.0 (8), 133.1 (4) [MꢀI]+;
HRMS: calcd for C9H9IO: 259.9698; confirmed.
(7RS,12RS)-7-Benzyloxy-6,11-dimethoxy-2,2-dimethyl-7,12-dihydro-4H-
1,3-dioxabenzo[a]anthracen-12-ol (19): Amagnetically stirred solution of
ketone 18 (251 mg, 0.56 mmol) in THF (10 mL) at 08C was treated drop-
wise with LiAlH4 (674 mL, 1m in THF, 674 mmol). Stirring was continued
for 30 min before the solution was warmed to 208C. The ensuing suspen-
sion was then quenched dropwise with water (2 mL), extracted with Et2O
(3”10 mL), washed with brine (2 mL), dried (Na2SO4), filtered and con-
centrated under reduced pressure to give a yellow oil. Subjection of this
material to flash chromatography (pentane/methyl tert-butyl ether 1:1)
and concentration of the appropriate fractions gave anthracenol 19 as a
yellow foam (223 mg, 0.51 mmol, 91%). Rf =0.4; 1H NMR (300 MHz,
CDCl3): d=1.52 (s, 3H; CH3), 1.60 (s, 3H; CH3), 3.22 (d, J=10.1 Hz,
1H; OH), 3.75 (s, 3H; OCH3), 3.89 (s, 3H; OCH3), 4.46 (d, J=12.2 Hz,
1H; OCH2Ph), 4.52 (d, J=12.2 Hz, 1H; OCH2Ph), 4.77 (d, J=15.5 Hz,
1H; 4-H), 4.84 (d, J=15.5 Hz, 1H; 4-H), 5.70 (s, 1H; 7-H), 6.29 (d, J=
10.1 Hz, 1H; 12-H), 6.44 (s, 1H; 5-H), 6.88 (d, J=8.5 Hz, 1H; 10-H),
6.97 (d, J=7.2 Hz, 1H; 8-H), 7.19–7.39 ppm (m, 6H; Ar-H); 13C NMR
(75.5 MHz, CDCl3): d=24.7, 24.8, 55.7, 55.9, 57.2, 61.0, 69.9, 70.3, 99.7,
106.2, 111.0, 120.2, 121.3, 126.3, 128.7, 130.5, 138.2, 139.1, 127.4, 127.9,
128.1, 128.5, 142.7, 150.6, 157.3 ppm; IR (KBr): n˜ =3430, 2937, 2872,
1588, 1482, 1434, 1375, 1303, 1281, 1248, 1201, 1098, 1024, 994, 954, 851,
2-(2’-Iodo-3’-methoxyphenyl)-[1,3]dioxane (22): Amagnetically stirred
solution of aldehyde 4 (1.73 g, 6.65 mmol) in benzene (60 mL) was treat-
ed with 1,3-propanediol (961 mL, 13.30 mmol) and amberlyst 15 (192 mg)
at 208C. The resulting mixture was heated to reflux for 5 h with a Dean–
Stark apparatus. After cooling, the mixture was diluted with Et2O
(60 mL), washed with H2O (4”10 mL), dried (MgSO4), filtered and con-
centrated under reduced pressure. The resulting white solid was recrystal-
lised (EtOAc/hexane) to afford acetal 22 as white solid (1.40 g,
4.39 mmol, 66%). M.p. 1348C; 1H NMR (200 MHz, C6H6): d=0.58–0.78
(m, 1H; 5-H), 1.70–2.00 (m, 1H; 5-H), 3.15 (s, 3H; OCH3), 3.51–3.68 (m,
2H; 4-H/6-H), 3.33–3.97 (m, 2H; 4H/6-H), 5.79 (s, 1H; 2-H), 6.19 (d, J=
8.3 Hz, 1H; 4’-H), 6.99 (t, J=8.0 Hz, 1H; 5’-H), 7.65 ppm (d, J=7.7 Hz,
1H; 6’-H); 13C NMR (50.3 MHz, CDCl3): d=25.6, 56.6, 67.5, 90.1, 105.2,
111.4, 120.0, 129.3, 142.0, 157.7 ppm; IR (KBr): n˜ =2972, 1571, 1433,
1379, 1267, 1105, 1065, 991, 781 cmꢀ1; UV/Vis (CH3CN): lmax (loge)=
204.5 (4.5436), 280.0 (3.5111), 287.0 (3.5195), 227.0 nm (0.3184); MS (EI,
70 eV): m/z (%): 320.1 (100) [M]+, 319.2 (76) [MꢀH]+, 261.1 (17)
[MꢀC3H6O]+; HRMS: calcd for C11H13IO3: 320.1240; confirmed.
3-Bromo-4-methoxy-5-methylbenzoic acid (27): Amagnetically stirred
solution of carboxylic acid 26 (88.0 g, 0.53 mol) in dioxane (850 mL) was
treated dropwise with bromine (54.0 mL, 1.06 mol) at 208C. Stirring was
continued in the absence of light for 7 days before the reaction mixture
was diluted with diethyl ether (300 mL), transferred to a separating
funnel and washed vigorously with an aqueous saturated solution of
Na2S2O3 until the solution changed from orange to yellow (approximately
2”100 mL). The remaining organic layer was dried (MgSO4), filtered and
concentrated under reduced pressure to give bromobenzene 27 as a pale
yellow solid (109.1 g, 0.44 mol, 84%) recrystallised from EtOAc/pentane.
M.p. 1608C; 1H NMR (300 MHz, CDCl3): d=2.35 (s, 3H; CH3), 3.81 (s,
3H; OCH3), 7.84 (d, J=1.1 Hz, 1H; Ar-H), 8.11 ppm (d, J=1.1 Hz, 1H;
Ar-H); 13C NMR (75.5 MHz, CDCl3): d=16.6, 61.5, 64.0, 117.3, 130.2,
132.5, 133.0, 159.9, 170.5 ppm; IR (KBr): n˜ =2950, 1603, 1416, 1104, 775,
661 cmꢀ1; UV/Vis: lmax (loge)=208 (4.4228), 245 nm (3.7995); MS (EI,
70 eV): m/z (%): 246.1 (96), 244.1 (100) [M]+, 229.1 (68), 227.1 (55)
[MꢀH2O]+, 166.1 (30) [MꢀBr]+; HRMS: calcd for C9H9BrO3: 243.9735;
confirmed.
799 cmꢀ1
; UV/Vis (CH3CN): lmax (loge)=192.5 (4.8358), 307.0 nm
(3.7024); MS (EI, 70 eV): m/z (%): 448.1 (20) [M]+, 430.1 (4) [MꢀH2O]+,
390.1 (8) [MꢀC3H6O]+, 372.1 (20), 282.0 (100), 266.0 (74), 254.0 (20),
91.0 (20) [C7H7]+; HRMS: calcd for C27H28O6: 448.1886; confirmed.
(7RS,12RS)-7-Benzyloxy-6,11,12-trimethoxy-2,2-dimethyl-7,12-dihydro-
4H-1,3-dioxabenzo[a]anthracene (20): Amagnetically stirred solution of
alcohol 19 (210 mg, 0.47 mmol) in THF (10 mL) at 208C was treated with
NaH (37 mg, 60% in oil, 0.94 mmol) and methyl iodide (59 mL,
0.94 mmol). The resulting mixture was warmed to 408C and stirred for a
further 12 h. After this time, the reaction was cooled to 208C, diluted
with Et2O (10 mL) and washed with water (5 mL). The water layer was
extracted further with Et2O (3”10 mL) and the combined organic phases
were dried (Na2SO4), filtered and concentrated under reduced pressure.
Subjection of the resulting crude oil to flash chromatography (pentane/
methyl tert-butyl ether 2:1) and concentration of the appropriate frac-
tions afforded anthracenol 20 as a yellow oil (208 mg, 0.45 mmol, 96%).
Rf =0.2; 1H NMR (300 MHz, CDCl3): d=1.55 (s, 3H; CH3), 1.61 (s, 3H;
CH3), 3.54 (s, 3H; OCH3), 3.76 (s, 3H; OCH3), 3.91 (s, 3H; OCH3), 4.53
(d, J=12.5 Hz, 1H; OCH2Ph), 4.64 (d, J=12.5 Hz, 1H; OCH2Ph), 4.80
(d, J=14.5 Hz, 1H; 4-H), 4.87 (d, J=14.5 Hz, 1H; 4-H), 5.69 (s, 1H; 12-
H), 6.02 (s, 1H; 7-H), 6.47 (s, 1H; 5-H), 6.89 (d, J=8.2 Hz, 1H; 10-H),
6.97 (d, J=7.9 Hz, 1H; 8-H), 7.17–7.31 (m, 4H; Ar-H), 7.33–7.39 ppm
(m, 2H; Ar-H); 13C NMR (150.8 MHz, CDCl3): d=24.7, 25.1, 55.7, 55.9,
55.9, 64.7, 61.1, 69.1, 69.4, 99.5, 111.4, 119.4, 122.3, 126.5, 127.8, 127.0,
127.7, 128.1, 128.7, 138.7, 139.4, 143.2, 151.3, 157.8 ppm; IR (KBr): n˜ =
3449, 2992, 2936, 2838, 1603, 1589, 1464, 1434, 1384, 1279, 1100, 990, 864,
(3-Bromo-4-methoxy-5-methylphenyl)-methanol (28): Amagnetically
stirred solution of carboxylic acid 27 (60.5 g, 0.25 mol) in THF/Et2O 1:1
(300 mL) was treated with LiAlH4 (70.0 mL, 2.64m in Et2O, 0.185 mol)
through a cannula over 30 min at 08C. Stirring was continued for a fur-
ther 30 min before the reaction mixture was treated with MgSO4 (51 g)
and with water (38 mL) dropwise. The resulting suspension was filtered
and washed thoroughly with Et2O (6”50 mL). The combined organic
fractions were dried (MgSO4), filtered and concentrated under reduced
pressure to give a yellow oil. Subjection of the resulting crude oil to flash
chromatography (pentane/EtOAc 9:1) and concentration of the appropri-
ate fractions afforded alcohol 28 as a pale yellow oil (41.6 g, 0.18 mmol,
72%). Rf =0.3; 1H NMR (300 MHz, CDCl3): d=2.29 (s, 3H; CH3), 3.80
(s, 3H; OCH3), 4.55 (s, 2H; 1’-H), 7.07 (d, J=0.8 Hz, 1H; Ar-H),
7.35 ppm (d, J=0.8 Hz, 1H; Ar-H); 13C NMR (75.5 MHz, CDCl3): d=
16.6, 60.1, 64.2, 117.2, 128.5, 129.4, 133.2, 137.9, 154.6 ppm; IR (KBr): n˜ =
2931, 1736, 1478, 1276, 821 cmꢀ1; UV/Vis: lmax (loge)=201.5 (4.6209),
798, 739 cmꢀ1
; UV/Vis (CH3CN): lmax (loge)=190.5 (4.8915), 192.0
(4.8935), 94.5 (4.8872), 199.0 (4.8685), 307.0 nm (3.7363); MS (EI, 70 eV):
m/z (%): 462.1 (26) [M]+, 430.1 (2) [MꢀCH3OH]+, 373.1 (8), 266.1
(100), 223 (8), 91.0 (20) [C7H7]+; HRMS: calcd for C28H30O6: 462.2042;
confirmed.
5238
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5233 – 5242

Synthesis of the Mensacarcin Carbocyclic Core
5233 – 5242
272.5 nm (2.8340); MS (EI, 70 eV): m/z (%): 232.1 (98), 230.1 (100) [M]+,
215.1 (25), 213.1 (20) [MꢀOH]+, 153.2 (33), 151.2 (30) [MꢀBr]+;
HRMS: calcd for C9H11BrO2: 229.9943; confirmed.
(7-Bromo-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxin-8-carbaldehyde
(23) and (5-bromo-6-methoxy-2,2,7-trimethyl-4H-benzo[1,3]dioxin-8-car-
baldehyde (34): Asolution of oxalyl chloride (436 mL, 5.06 mmol) in
CH2Cl2 (20 mL) at ꢀ788C was added through a cannula over 30 min to a
magnetically stirred solution of DMSO (719 mL, 0.01 mol) in CH2Cl2
(20 mL), also maintained at ꢀ788C. The resulting clear solution was
treated dropwise with a mixture of 32 and 33 (1.0 g, 3.16 mmol in 6 mL
of CH2Cl2) from the above reaction, stirred at ꢀ788C for 1.5 h and then
treated dropwise with NEt3 (1.9 mL). The solution was stirred at this
temperature for 5 min before being warmed to 208C and stirred for a fur-
ther 30 min. The ensuing solution was quenched with water (20 mL) and
extracted with CH2Cl2 (3”20 mL). The combined organic fractions were
dried (MgSO4), filtered and concentrated under reduced pressure to
afford a pale oil. Subjection of the crude oil to flash chromatography
(pentane/EtOAc 20:1) and concentration of the appropriate fractions af-
forded aldehydes 23 and 34.
3-Bromo-4-methoxy-5-methylbenzaldehyde (29): Amagnetically stirred
solution of alcohol 28 (17.8 g, 0.08 mol) in CH2Cl2 (400 mL) was treated
with MnO2 (67.0 g, 0.80 mol) in one portion at 208C. Stirring was contin-
ued for 12 h before the reaction mixture was filtered and washed thor-
oughly with CH2Cl2 (3”100 mL). The organic filtrate was concentrated
under reduced pressure to give a yellow oil. Subjection of the resulting
crude oil to flash chromatography (pentane/EtOAc 19:1) and concentra-
tion of the appropriate fractions afforded the aldehyde 29 as a yellow oil
1
(16.1 g, 0.07 mol, 87%). Rf =0.3; H NMR (300 MHz, CDCl3): d=2.36 (s,
3H; CH3), 3.84 (s, 3H; OCH3), 7.61 (d, J=1.8 Hz, 1H; Ar-H), 7.87 (d,
J=1.8 Hz, 1H; Ar-H), 9.82 ppm (s, 1H; CHO); 13C NMR (75.5 MHz,
CDCl3): d=16.5, 60.2, 118.1, 131.5, 132.6, 133.2, 134.1, 160.4, 189.8 ppm;
IR (KBr): n˜ =1695, 1271, 1110, 740 cmꢀ1; UV/Vis: lmax (loge)=217.0
(4.3877), 261 nm (4.0649); MS (EI, 70 eV): m/z (%): 230.1 (100), 228.1
(97) [M]+, 213.1 (8), 215.1 (6) [MꢀCH3]+, 187.1 (6), 185.0 (8)
[MꢀC2H3O]+, 171.0 (5), 77.1 (44) [C6H5]+; HRMS: calcd for
C9H979BrO2: 227.9786; confirmed.
Compound 23: Acolourless solid (420 mg, 1.33 mmol, 42%), recrystal-
lised from pentane/EtOAc; Rf =0.3; m.p. 1228C; 1H NMR (300 MHz,
CDCl3): d=1.55 (s, 6H; 2”CH3), 2.17 (s, 3H; CH3), 3.75 (s, 3H; OCH3),
4.71 (s, 2H; CH2), 10.32 ppm (s, 1H; CHO); 13C NMR (75.5 MHz,
CDCl3): d=12.1, 24.6, 59.7, 60.7, 100.1, 117.3, 118.9, 121.4, 134.4, 149.1,
150.7, 189.4; IR (KBr): n˜ =2986, 1697, 1580, 1396, 1005 cmꢀ1; UV/Vis:
lmax (loge) 195.5 (4.3540), 268.5 (3.8656), 334.0 nm (0.1779); MS (EI,
70 eV): m/z (%): 316.1 (45), 314.1 (44) [M]+, 258.0 (98), 256.0 (100)
[MꢀC3H6O]+, 243.0 (45), 241.0 (40) [MꢀC3H6OꢀCH3]+; HRMS: calcd
for C13H15BrO4: 314.0154; found: 314.0154; elemental analysis: calcd (%)
for C13H15BrO4: C 49.54, H 4.80; found: C 49.68, H 4.62.
3-Bromo-4-methoxy-5-methylphenol (30): Amagnetically stirred solution
of aldehyde 29 (2.6 g, 11.4 mmol) in CH2Cl2 (100 mL) was treated with
m-CPBA(4.1 g, 70% in water, 17.0 mmol) in one portion at 20 8C. Stir-
ring was continued for 12 h before the CH2Cl2 was removed under re-
duced pressure. The ensuing white solid was diluted with MeOH
(150 mL), treated with K2CO3 (2.3 g, 17.0 mmol) and stirred at 208C for
15 min. The resulting mixture was treated with silica gel (3.5 g), concen-
trated under reduced pressure and subjected to flash chromatography
(pentane/EtOAc 9:1). Concentration of the appropriate fractions afford-
ed phenol 30 as colourless solid (1.68 g, 7.7 mmol, 68%) recrystallised
from EtOAc/pentane. Rf =0.2; m.p. 1148C; 1H NMR (300 MHz, CDCl3):
d=2.25 (s, 3H; CH3), 3.82 (s, 3H; OCH3), 7.61 (d, J=1.2 Hz, 1H; Ar-H),
7.87 (d, J=1.2 Hz, 1H; Ar-H), 9.82 ppm (s, 1H; OH); 13C NMR
(75.5 MHz, CDCl3): d=16.7, 60.5, 117.1, 117.2, 117.5, 133.6, 148.8,
152.2 ppm; IR (KBr): n˜ =2951, 1602, 1456, 1418, 1225, 760 cmꢀ1; UV/Vis:
lmax (loge)=199.5 (4.6526), 289.0 nm (3.5079); MS (EI, 70 eV): m/z (%):
218.0 (90), 216.0 (89) [M]+, 203.0 (95), 201.0 (100) [MꢀCH3]+; HRMS:
calcd for C8H9BrO2: 215.9786; confirmed; elemental analysis calcd (%)
for C8H9BrO2: C 44.27, H 4.18; found: C 44.27, H 3.95.
Compound 34: Acolourless solid (410 mg, 1.30 mmol, 41%), recrystal-
lised from pentane/EtOAc; Rf =0.5; m.p. 1078C; 1H NMR (300 MHz,
CDCl3): d=1.56 (s, 6H; 2”CH3), 2.53 (s, 3H; CH3), 3.72 (s, 3H; OCH3),
4.74 (s, 2H; CH2), 10.49 ppm (s, 1H; CHO); 13C NMR (75.5 MHz,
CDCl3): d=13.6, 24.5, 60.6, 61.9, 100.4, 118.2, 121.7, 122.4, 133.7, 148.9,
151.9, 191.1 ppm; IR (KBr): n˜ =2996, 2938, 1685, 1563, 1451, 839 cmꢀ1
;
UV/Vis: lmax (loge)=220.0 (4.4725), 332.0 nm (4.3181); MS (EI, 70 eV):
m/z (%): 316.1 (45), 314.1 (44) [M]+, 258.0 (98), 256.0 (100)
[MꢀC3H6O]+, 243.0 (45), 241.0 (40) [MꢀC3H6OꢀCH3]+; HRMS: calcd
for C13H15BrO4: 314.0154; confirmed.
(1’RS)-(7-Bromo-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxin-8-yl)-
(3’-methoxy-7’-vinylphenyl)-methanol (35): Amagnetically stirred so-
lution of iodobenzene 21 (240 mg, 0.92 mmol) in THF (10 mL) at ꢀ788C
was treated dropwise with nBuLi (406 mL, 2.5m in hexane, 1.01 mmol).
The resulting mixture was stirred at this temperature for 20 min before
being treated with aldehyde 23 (264 mg, 0.84 mmol) in THF (5 mL). Stir-
ring was continued at this temperature for 20 min then the solution was
warmed to 208C and quenched immediately with a saturated aqueous so-
lution of NH4Cl (4 mL). The resulting mixture was extracted with diethyl
ether (3”10 mL) and washed with brine (1”2 mL), then the combined
organic fractions were dried (MgSO4), filtered and concentrated under
reduced pressure to afford a clear yellow oil. Subjection of the resulting
crude oil to flash chromatography (pentane/EtOAc 9:1) and concentra-
tion of the appropriate fractions afforded diphenylcarbinol 35 as a col-
ourless solid (220 mg, 0.49 mmol, 58%) recrystallised from EtOAc/
hexane. Rf =0.3; m.p. 1288C; 1H NMR (300 MHz, CDCl3): d=0.95 (s,
3H; Me) 1.33 (s, 3H; CH3), 2.10 (s, 3H; CH3), 3.74 (s, 3H; OCH3), 3.79
(s, 3H; OCH3), 4.61 (dd, J=22.5, 7.2 Hz, 2H; 4-H), 5.15 (dd, J=10.8,
1.8 Hz, 1H; 2’’-H), 5.39 (dd, J=17.1, 1.8 Hz, 1H; 2’’-H), 6.48 (d, J=
9.0 Hz, 1H; Ar-H), 6.82 (d, J=8.1 Hz, 1H; 1’-H), 6.92 (d, J=17.1,
10.8 Hz, 1H; 1’’-H), 7.00 (d, J=7.5 Hz, 1H; Ar-H), 7.18 ppm (t, J=
8.4 Hz, 1H; Ar-H); 13C NMR (50.3 MHz, CDCl3): d=11.3, 22.6, 25.0,
55.9, 60.1, 60.6, 73.0, 98.6, 110.9, 116.2, 118.4, 119.1, 120.0, 126.8, 127.5,
128.2, 129.1, 135.8, 138.4, 146.2, 148.7, 158.1 ppm; IR (KBr): n˜ =3500,
3-Bromo-2,6-bis(hydroxymethyl)-4-methoxy-5-methylphenol (31):
A
magnetically stirred solution of phenol 30 (2.0 g, 9.2 mmol), formalde-
hyde (1.76 mL, 30% in water, 23.4 mmol) in water (7.6 mL) was treated
with CaO (258 mg, 4.6 mmol) at 208C. The resulting mixture was stirred
for 30 min before being left unstirred in the dark for 5 days. The resulting
suspension was dissolved in warm CHCl3 (50 mL) and acetic acid
(10 mL) and then diluted twofold with CHCl3. The organic phase was
washed with a saturated aqueous solution of NaHCO3 until the acetic
acid was removed. The mixture was concentrated under reduced pressure
to afford a yellow solid. This crude solid was washed with pentane/
EtOAc 4:1 to afford triol 31 as a colourless solid (1.67 g, 6.4 mmol,
69%), recrystallised from EtOAc/hexane. Rf =0.4; m.p. 1328C; 1H NMR
(300 MHz, CDCl3): d=2.26 (s, 3H; CH3), 2.76 (brs, 1H; OH), 2.81 (brs,
1H; OH), 3.68 (s, 3H; OCH3), 4.77 (s, 2H; CH2), 4.96 (s, 2H; CH2),
8.89 ppm (s, 1H; OH); 13C NMR (75.5 MHz, CDCl3): d=12.5, 58.2, 60.5,
62.9, 109.9, 117.7, 124.2, 126.7, 131.5, 153.2 ppm; IR (KBr): n˜ =3384,
3259, 2959, 1453, 1005, 760 cmꢀ1; UV/Vis: lmax (loge)=205.5 nm (4.6195);
MS (EI, 70 eV): m/z (%): 278.1 (58), 276.1 (60) [M]+, 260.1 (57), 258.1
(59) [MꢀH2O]+, 245.1 (100), 243.1 (90) [MꢀH2OꢀCH3]+, 229.1 (45), 231
(40); HRMS: calcd for C10H13BrO4: 275.9997; confirmed.
1569, 1408, 1261, 1044 cmꢀ1
; UV/Vis: lmax (loge)=207.5 (4.7345),
(7-Bromo-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxin-8-yl)-methanol
(32) and (5-bromo-6-methoxy-2,2,7-trimethyl-4H-benzo[1,3]dioxin-8-yl)-
methanol (33): Amagnetically stirred solution of triol 31 (1.92 g, 7.0 mol)
in acetone (100 mL) at 208C was treated with a few crystals of p-TsOH.
The resulting mixture was stirred for 18 h then concentrated under re-
duced pressure to afford a colourless oil. Subjection of the resulting
crude oil to flash chromatography (pentane/EtOAc 4:1) and concentra-
tion of the appropriate fractions afforded a mixture of two regioisomeric
acetonides 32 and 33 as a colourless oil (2.02 g, 6.37 mmol, 91%); Rf =
0.3.
293.5 nm (3.7238); MS (EI, 70 eV): m/z (%): 450.2 (1), 448.2 (1) [M]+,
392.1 (88) [MꢀC3H6O]+, 390.1 (92), 311.2 (100) [MꢀC3H6OꢀBr]+, 293
(36), 148.1 (47); HRMS: calcd for C22H25BrO5: 448.0885; confirmed.
(1’RS)-7-Bromo-6-methoxy-8-[1’-methoxy-(3’-methoxy-7’-vinylphenyl)-
methyl]-2,2,5-trimethyl-4H-benzo[1,3]dioxine (36): Amagnetically stir-
red solution of diphenylcarbinol 35 (145 mg, 0.32 mmol) in THF (5 mL)
was treated with KH (26 mg, 0.65 mmol) in one portion at 08C. Stirring
was continued for 40 min before the reaction mixture was treated drop-
wise with MeI (40 mL, 0.64 mmol). The ensuing solution was warmed to
Chem. Eur. J. 2004, 10, 5233 – 5242
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5239

L. F. Tietze et al.
FULL PAPER
208C and stirred for a further 1 h before being treated with water (2 mL)
and extracted with diethyl ether (3”5 mL). The combined organic frac-
tions were dried (MgSO4), filtered and concentrated under reduced pres-
sure to afford a colourless solid. Subjection of this material to flash chro-
matography (pentane/EtOAc 19:1) and concentration of the appropriate
fractions afforded methyl ether 36 as colourless solid (130 mg, 0.28 mmol,
87%) recrystallised from EtOAc. Rf =0.4; m.p. 2028C; 1H NMR
(300 MHz, CDCl3): d=0.72 (s, 3H; CH3), 1.29 (s, 3H; CH3), 2.06 (s, 3H;
CH3), 3.36 (s, 3H; OCH3), 3.58 (s, 3H; OCH3), 3.75 (s, 3H; OCH3), 4.65
(dd, J=26.5, 15.6 Hz, 2H; 4-H), 5.12 (dd, J=10.8, 1.8 Hz, 1H; 2’’-H),
5.43 (dd, J=17.5, 1.8 Hz, 1H; 2’’-H), 6.17 (s, 1H; 1’-H), 6.67 (dd, J=8.1,
0.9 Hz, 1H; 4’-H), 7.06 (t, J=8.4 Hz, 1H; Ar-H), 7.14 (t, J=7.8 Hz, 1H;
Ar-H), 7.81 ppm (dd, J=17.5, 10.8 Hz, 1H; 1’’-H); 13C NMR (75.5 MHz,
CDCl3): d=11.3, 21.7, 25.4, 55.7, 57.6, 60.0, 60.5, 80.4, 98.5, 109.6, 112.5,
118.6, 120.0, 121.2, 126.7, 127.0, 127.1, 127.2, 139.9, 140.1, 146.2, 148.5,
156.9 ppm; IR (KBr): n˜ =2937, 1408, 1071 cmꢀ1; UV/Vis: lmax (loge)=
294.5 (3.7312), 206.5 nm (4.5609); MS (EI, 70 eV): m/z (%): 464.2 (1),
462.0 (>1) [M]+, 384.2 (12), 374.1 (13), 294.2 (100); HRMS: calcd for
C23H27BrO5: 462.1042; confirmed; elemental analysis calcd (%) for
C23H27BrO5: C 59.62, H 5.87; found: C 59.38, H 5.71.
201.5 nm (4.7676); MS (EI, 70 eV): m/z (%): 510.3 (10) [M]+, 508.0 (9),
452.0 (4) [MꢀC3H6O]+, 450.2 (3), 374.1 (42), 371.3, (67) 312.3 (58), 295.2
(100), 222.2 (50), 163.1 (61); HRMS: calcd for C24H29BrO7: 508.1097; con-
firmed.
(1’RS)-7-Bromo-8-{[7’-(1’’,3’’)dioxan-2’’-yl-3’-methoxyphenyl]-1’-methoxy-
methyl}-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxine (39): Amagnet-
ically stirred solution of alcohol 38 (480 mg, 0.943 mmol) in THF (15 mL)
was treated with KH (75 mg, 1.89 mmol) in one portion at 08C. Stirring
was continued for 40 min before the reaction mixture was treated with
MeI (118 mL, 1.89 mmol) and stirred at 208C for a further 2 h. The result-
ing mixture was treated with water (5 mL) and extracted with diethyl
ether (3”15 mL). The combined organic fractions were dried (MgSO4),
filtered and concentrated under reduced pressure to afford a colourless
solid. Subjection of this material to flash chromatography (pentane/
EtOAc 17:3) and concentration of the appropriate fractions afforded
olefin 39 as colourless solid (451 mg, 0.862 mmol, 91%). Rf =0.3;
1H NMR (200 MHz, CDCl3): d=1.37 (s, 3H; CH3), 1.42 (m, 1H; H-5’’),
1.55 (s, 3H; CH3), 2.10–2.40 (m, 1H; H-5’’), 2.30 (s, 3H; CH3), 3.56 (s,
6H; 2”OCH3), 3.78 (s, 3H; OCH3), 3.83–4.04 (m, 2H; 4’’-H), 4.11–4.27
(m, 2H; 6’’-H), 4.57 (d, J=6.0, Hz, 2H; 4-H), 6.26 (s, 1H; 2’’-H), 6.59 (s,
1H; 1’-H), 6.68 (d, J=4.8 Hz, 1H; Ar-H), 7.19 (m, 1H; Ar-H), 7.45 ppm
(d, J=8.2 Hz, 1H; Ar-H); 13C NMR (75.5 MHz, CDCl3): d=11.3, 21.3,
25.2, 26.0, 55.8, 58.5, 59.9, 60.5, 67.1, 67.4, 80.7, 98.9, 99.8, 99.8, 110.8,
118.8, 118.9, 127.0, 127.2, 127.3, 127.4, 139.4, 146.3, 148.5, 156.4 ppm; IR
(12RS)-6,11,12-Trimethoxy-2,2,5-trimethyl-7-methylene-7,12-dihydro-4H-
1,3-dioxabenzo[a]anthracene (37): Amagnetically stirred solution of
olefin 36 (70 mg, 0.15 mmol) and nBu4NOAc (46 mg, 0.15 mmol) in a
previously degassed mixture of DMF/CH3CN/H2O 5:5:1 (2 mL) at 608C
was treated with trans-di(m-acetato)-bis[ortho(di-ortho-tolylphosphino)-
benzyl]-dipalladium(ii) catalyst (14 mg, 0.015 mmol) in one portion. The
resulting suspension was heated to 1208C and stirring was continued for
4 h. The ensuing brown mixture was diluted with diethyl ether (20 mL)
and washed with water (3”3 mL). The organic layer was dried (MgSO4),
filtered and concentrated under reduced pressure to afford a crude
brown solid. Subjection of this material to flash chromatography (pen-
tane/EtOAc19:1) and concentration of the appropriate fractions afforded
tetrahydroanthracene 37 as a yellow solid (14 mg, 0.004 mmol, 24%) and
starting material 36 (40 mg, 0.086 mmol).
37: Rf =0.2; 1H NMR (300 MHz, CDCl3): d=1.57 (s, 3H; CH3), 1.61 (s,
3H; CH3), 2.11 (s, 3H; CH3), 3.30 (s, 3H; OCH3), 3.57 (s, 3H; OCH3),
9.92 (s, 3H; OCH3), 4.77 (s, 2H; 4-H), 5.95 (d, J=1.2 Hz, 1H; 1’-H), 6.16
(s, 1H; 12-H), 6.34 (d, J=1.2 Hz, 1H; 1’-H), 6.85–6.89 (m, 1H; Ar-H),
7.26–7.30 ppm (m, 2H; Ar-H); 13C NMR (75.5 MHz, CDCl3): d=10.7,
24.5, 25.0, 55.7, 56.3, 59.7, 60.2, 64.0, 98.9, 109.5, 116.6, 117.2, 117.8, 122.2,
123.4, 127.0, 128.8, 129.2, 137.9, 140.8, 145.1, 148.9, 157.0 ppm; UV/Vis:
lmax (loge)=201.5 (4.4756), 290.5 (4.5398), 306.0 ppm (3.5456); IR (KBr):
n˜ =2929, 1456, 1269, 1065, 742 cmꢀ1; MS (EI, 70 eV): m/z (%): 382 (32)
[M+], 324 (100) [MꢀC3H6O]+, 293 (86) [MꢀC3H6OꢀCH3O]+, 278 (65)
[MꢀC3H6OꢀCH3OꢀCH3]+, 265 (29); HRMS: calcd for C23H26O5:
382.1780; confirmed.
(KBr): n˜ =2942, 1456, 1255, 1074 cmꢀ1
; UV/Vis: lmax (loge)=285.5
(3.7228), 199.0 nm (4.7657); MS (EI, 70 eV): m/z (%): 524.3 (24), 522.0
(20) [M]+, 443.0 (14) [MꢀBr]+, 385.3 (37) [MꢀBrꢀC3H6O]+, 326.2 (25),
236 (38), 206.1 (100); HRMS: calcd for C25H31BrO7: 464.0835; confirmed.
(1’RS)-7-Bromo-6-methoxy-8-[1’-methoxy-(3’-methoxy-7’-vinylphenyl)-
methyl]-2,2,5-trimethyl-4H-benzo[1,3]dioxine (36): Amagnetically stir-
red solution of acetal 39 (140 mg, 0.269 mmol) in a water/acetone mixture
(2.5:5 mL) was treated with a few crystals of pyridinium p-toluenesulfo-
nate in one portion at 208C. The resulting suspension was heated at
reflux for 3 h before being extracted with diethyl ether (3”15 mL). The
combined organic fractions were washed with brine (1”2 mL), dried
(MgSO4), filtered and concentrated under reduced pressure to afford a
crude solid. Subjection of this material to flash chromatography (pen-
tane/EtOAc 17:3) and concentration of the appropriate fractions afforded
the corresponding aldehyde as a colourless solid (101 mg, 0.217 mmol,
81%) recrystallised from EtOAc/hexane. Rf =0.3; m.p. 1408C; 1H NMR
(300 MHz, CDCl3): d=0.78 (s, 3H; CH3), 1.30 (s, 3H; CH3), 2.11 (s, 3H;
CH3), 3.45 (s, 3H; OCH3), 3.66 (s, 3H; OCH3), 3.79 (s, 3H; OCH3), 4.60
(dd, J=28.8, 15.6 Hz, 2H; 4-H), 6.33 (s, 1H; 1’-H), 6.92 (d, J=8.1,
1.2 Hz, 1H; Ar-H), 7.30 (d, J=8.1 Hz, 1-H, Ar-H), 7.42 (dd, J=8.1,
1.2 Hz, 1H; Ar-H), 11.07 ppm (s, 1H; CHO); 13C NMR (75.5 MHz,
CDCl3): d=11.4, 22.0, 25.3, 55.8, 57.1, 59.9, 60.6, 80.6, 98.8, 114.2, 118.8,
119.3, 121.5, 125.3, 127.6, 127.9, 131.1, 138.3, 146.4, 148.6, 156.3,
197.4 ppm; IR (KBr): n˜ =1685, 1578, 1455, 1267, 1047 cmꢀ1; UV/Vis: lmax
(loge)=206.0 (4.7348), 296.0 nm (3.7415); MS (EI, 70 eV): m/z (%):
466.3 (5), 464.3 (5) [M]+, 408.2 (7), 406.2 (6) [MꢀC3H6O]+, 376.2 (100),
374.2 (97) [MꢀC7H6]+, 295.3 (16) [MꢀC7H6ꢀBr]+, 178.2 (7); HRMS:
calcd for C22H25BrO6: 465.0835; confirmed.
(1’RS)-(7-Bromo-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxin-8-yl)-
(7’-[1’’,3’’]dioxan-2’’-yl-2’-methoxyphenyl)-methanol (38): Amagnetically
stirred solution of iodobenzene 22 (448 mg, 1.40 mmol) in THF (20 mL)
at ꢀ788C was treated dropwise with nBuLi (560 mL, 2.5m in hexane,
1.40 mmol). The resulting mixture was stirred at this temperature for
10 min before being treated dropwise with aldehyde 23 (400 mg,
1.27 mmol) in THF (7 mL). Stirring was continued at this temperature
for 35 min then the solution was warmed to 208C and immediately
quenched with a saturated aqueous solution of NH4Cl (4 mL). The result-
ing mixture was extracted with diethyl ether (3”20 mL) and washed with
brine (1”5 mL). The combined organic fractions were dried (MgSO4),
filtered and concentrated under reduced pressure to afford a clear yellow
oil. Subjection of the resulting crude oil to flash chromatography (pen-
tane/EtOAc 19:1 ! pentane/EtOAc 9:1) and concentration of the appro-
priate fractions (Rf =0.3 in pentane/EtOAc 9:1) afforded alcohol 38 as a
Amagnetically stirred solution of PPh 3CH3Br (399 mg, 1.12 mmol) in
THF (5 mL) at 208C was treated dropwise with sodium bis(trimethylsilyl)
amide (1.12 mL, 1m in THF, 1.12 mmol). The resulting yellow suspension
was stirred for 1 h before being treated with above-mentioned aldehyde
(260 mg, 0.56 mol) in THF (5 mL). The resulting suspension was stirred
for 1 h, treated with silica gel (1 g) and concentrated under reduced pres-
sure. The resulting white solid was subjected to column chromatography
(pentane/EtOAc 19:1) and concentration of the appropriate fractions af-
forded olefin 36 as a colourless solid (210 mg, 0.45 mmol, 81%). Rf =0.4;
m.p. 2028C. This material was identical in all respects with that obtained
previously.
1
colourless solid (481 mg, 0.945 mmol, 74%). H NMR (200 MHz, CDCl3):
d=0.70 (s, 3H; CH3), 1.28 (s, 3H; CH3), 1.40 (m, 1H; 5’’-H), 2.07 (s, 3H;
CH3), 2.10–2.32 (m, 1H; 5’’-H), 3.64 (s, 3H; OCH3), 3.75 (s, 3H; OCH3),
3.80–4.02 (m, 2H; 4’’-H/6’’-H), 4.02–4.25 (m, 2H; 6’’-H/4’’-H), 4.58 (d, J=
4.6 Hz, 2H; 4-H), 4.78 (s, 1H; OH), 6.20 (s, 1H; 2’’-H), 6.66 (d, J=
4.8 Hz, 1H; Ar-H), 6.76 (d, J=8.2 Hz, 1H; Ar-H), 7.20 ppm (d, J=4.8,
1H; Ar-H); 13C NMR (75.5 MHz, CDCl3): d=11.2, 21.4, 25.4, 25.5, 55.9,
60.0, 60.5, 67.2, 67.3, 72.5, 98.5, 99.3, 111.7, 118.4, 118.7, 119.8, 126.9,
127.2, 128.9, 129.3, 137.6, 146.2, 148.6, 157.1 ppm; IR (KBr): n˜ =3455,
2991, 2960, 1456, 1257, 1046 cmꢀ1; UV/Vis: lmax (loge)=285.0 (3.7282),
(7-Bromo-6-methoxy-2,2,5-trimethyl-4H-benzo[1,3]dioxin-8-yl)-(3’-meth-
oxy-7’-vinylphenyl)methanone (40): Amagnetically stirred solution of
alcohol 35 (125 mg, 0.278 mmol) in CH2Cl2 (10 mL) at 208C was treated
with Dess–Martin periodinane (177 mg, 0.417 mmol) in one portion. The
resulting mixture was stirred for 15 min before being treated with a satu-
rated solution of NaHCO3 (2 mL) and a 1m solution of Na2S2O3 (2 mL).
Stirring was continued until the cloudy solution became clear (approxi-
mately 1 h). The resulting mixture was transferred to a separating funnel
5240
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 5233 – 5242

Synthesis of the Mensacarcin Carbocyclic Core
5233 – 5242
and extracted with CH2Cl2 (3”10 mL). The combined organic fractions
were subjected to flash chromatography (pentane/EtOAc 10:1) and con-
centration of the appropriate fractions afforded benzophenone 40 as a
colourless solid (101 mg, 0.225 mmol, 81%). Rf =0.3; m.p. 1298C;
1H NMR (300 MHz, CDCl3): d=1.14 (brs, 6H; 2”CH3), 2.13 (s, 3H;
CH3), 3.58 (s, 3H; OCH3), 3.78 (s, 3H; OCH3), 4.64 (s, 2H; 4-H), 5.28
(dd, J=10.8, 1.2 Hz, 1H; 2’’-H), 5.70 (dd, J=17.4, 1.2 Hz, 1H; 2’’-H),
6.75 (d, J=8.1 Hz, 1H; Ar-H), 6.93 (dd, J=17.4, 10.8 Hz, 1H; 1’’-H),
7.22 (d, J=7.8 Hz, 1H; Ar-H), 7.31 ppm (t, J=7.8 Hz, 1H; Ar-H);
13C NMR (75.5 MHz, CDCl3): d=11.5, 23.6, 24.0, 55.9, 59.8, 60.7, 98.9,
110.4, 114.7, 115.9, 118.0, 118.1, 129.4, 129.9, 130.2, 130.8, 135.1, 138.8,
145.9, 148.9, 157.8, 195.4 ppm; IR (KBr): n˜ =1680, 1471, 1400, 1271, 1045,
881 cmꢀ1; UV/Vis: lmax (loge)=207.5 (4.6472), 313.0 nm (3.6938); MS
(EI, 70 eV): m/z (%): 448.3 (10) 446.3 (9) [M]+, 390.2 (43), 388.2 (40)
[MꢀC3H6O]+, 309.3 (100) [MꢀBrꢀC3H6O]+, 281.2 (20), 255.2 (24);
HRMS: calcd for C22H23BrO5: 446.0729; confirmed.
3H; OCH3), 3.97 (s, 3H; OCH3), 4.81 (s, 2H; CH2), 6.15 (s, 1H; 12-H),
7.10 (dd, J=8.4, 0.9 Hz, 1H; Ar-H), 7.43 (t, J=8.1 Hz, 1H; Ar-H),
7.64 ppm (dd, J=7.8, 0.9 Hz, 1H; Ar-H); 13C NMR (75.5 MHz, CDCl3):
d=10.3, 24.5, 24.9, 55.9, 60.2, 61.8, 62.6, 99.4, 114.3, 119.0, 124.6, 125.6,
126.6, 127.0, 129.1, 129.5, 136.4, 145.2, 151.3, 157.0, 184.8 ppm; IR (KBr):
n˜ =2932, 1673, 1591, 1271, 1054, 861, 747 cmꢀ1; MS (EI, 70 eV): m/z (%):
384.2 (14) [M]+, 326.2 (100) [MꢀC3H6O]+, 298.2 (25), 267.1 (24), 149.1
(40); HRMS: calcd for C22H24O6: 384.1573; confirmed.
Acknowledgement
The authors would like to thank the Deutsche Forshungsgemeinschaft
(Grant: SFB416), the Fonds der Chemische Industrie and the Alexan-
der von Humboldt-Stiftung for the scholarship for S.G.S. Gifts of chemi-
cals from BASF AG, Bayer AG, Degussa, Wacker Fine Chemicals and Eli
Lilly are gratefully acknowledged.
6,11-Dimethoxy-2,2,5-trimethyl-7-methylene-4,7-dihydro-1,3-dioxaben-
zo[a]anthracen-12-one (41): Amagnetically stirred solution of benzophe-
none 40 (215 mg, 0.481 mmol) and nBu4NOAc (290 mg, 0.961 mmol) in a
previously degassed mixture of DMF/CH3CN/H2O 5:5:1 (10 mL) at 608C
was treated with trans-di(m-acetato)-bis[ortho(di-ortho-tolylphosphino)
benzyl]dipalladium (ii) (45 mg, 0.048 mmol) in one portion. The resulting
suspension was heated at 1108C for 17 h, cooled to 208C, diluted with di-
ethyl ether (30 mL) and washed with water (3”3 mL). The organic layer
was dried (MgSO4), filtered and concentrated under reduced pressure to
afford a crude brown solid. Subjection of this material to flash chroma-
tography (pentane/EtOAc 9:1) and concentration of the appropriate frac-
tions afforded anthracenone 41 as yellow solid (130 mg, 0.355 mmol,
74%). Rf =0.3; 1H NMR (300 MHz, CDCl3): d=1.60 (s, 6H; 2”CH3),
2.14 (s, 3H; CH3), 3.61 (s, 3H; OCH3), 3.94 (s, 3H; OCH3), 4.77 (s, 2H;
CH2), 6.07 (s, 1H; 1’-H), 6.53 (s, 1H; 1’-H), 6.95 (d, J=8.2 Hz, 1H; Ar-
H), 7.31–7.44 ppm (m, 2H; Ar-H); 13C NMR (150.8 MHz, CDCl3): d=
11.3, 24.7, 56.2, 59.8, 60.1, 67.0, 99.2, 111.2, 116.0, 119.3, 120.0, 121.7,
122.4, 129.3, 131.9, 132.5, 136.2, 141.1, 146.6, 147.9, 158.3, 183.5 ppm; IR
(KBr): n˜ =1672, 1456, 1273, 1058, 842 cmꢀ1; UV/Vis: lmax (loge)=194.0
(4.6834), 229.0 nm (4.6089); MS (EI, 70 eV): m/z (%): 366.2 (10) [M]+,
308.1 (23) [MꢀC3H6O]+, 293.1 (100) [MꢀC3H6OꢀCH3]+, 265.1 (6), 165.1
(6); HRMS: calcd for C22H22O5: 366.1467; confirmed.
[1] A. Zeeck, M. Arnold, unpublished results.
[2] Antitumour activity was carried out by Prof. W. Beil at the Medizi-
nische Hochschule, Hannover, unpublished results.
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[14] The bromination of the more accessible 3-bromo-4-methoxy-5-
methyl-benzaldehyde was unsuccessful with several literature proce-
dures.
(12RS)-6,11,12-Trimethoxy-2,2,5-trimethyl-7-methylene-7,12-dihydro-4H-
1,3-dioxabenzo[a]anthracene (37): Amagnetically stirred solution of
LiAlH4 (2 mg, 0.05 mmol) in THF (1 mL) at 08C was treated dropwise
with ketone 41 (20 mg, 0.05 mmol) in THF (0.5 mL). The resulting so-
lution was stirred for 10 min before being treated with a saturated aque-
ous solution of NH4Cl (1 mL) and extracted with diethyl ether (3 mL).
The combined organic fractions were dried (MgSO4), filtered and con-
centrated under reduced pressure to afford a yellow solid. The resulting
alcohol 42 was not isolated but was immediately subjected to the next re-
action.
The crude solid from the above reaction (approximately 20 mg) in THF
(1 mL) at 08C was treated with KH (4 mg, 0.11 mmol) and then immedi-
ately with MeI (6 mL, 0.11 mmol). The resulting solution was stirred at
this temperature for 30 min before being warmed to 208C and stirred for
a further 14 h. The resulting mixture was treated with water (1 mL) and
extracted with diethyl ether (3”3 mL), then the combined organic frac-
tions were dried (MgSO4), filtered and concentrated under reduced pres-
sure to afford a colourless solid. Subjection of this material to flash chro-
matography (pentane/EtOAc 19:1) and concentration of the appropriate
fractions afforded 37 as a yellow solid (7.7 mg, 0.02 mmol, 37%). Rf =0.2.
This material was identical in all respects to that obtained previously.
(12RS)-6,11,12-Trimethoxy-2,2,5-trimethyl-11a,12-dihydro-4H,7aH-1,3-di-
oxabenzo[a]anthracen-7-one (43): Amagnetically stirred solution of
compound 37 (10 mg, 0.026 mmol) in CCl4/MeCN/H2O 1:1:1.5 (350 mL)
at 208C was treated with a mixture of RuCl3 (0.2 mg, 5 mol%, 1.3”
10ꢀ3 mmol) and NaIO4 (28 mg, 0.139 mmol). The ensuing solution was
stirred for 15 min and the suspension was diluted with CH2Cl2 (10 mL).
The organic layer was washed with water (2”1 mL), dried (MgSO4), fil-
tered and concentrated under reduced pressure. Subjection of the result-
ing brown solid to flash chromatography through a small plug of silica
(pentane/EtOAc 9:1) afforded crude anthracenone 43 as a yellow foam
(7 mg, 0.018 mmol, 69%). 1H NMR (300 MHz, CDCl3): d=1.60 (s, 3H;
CH3), 1.63 (s, 3H; CH3), 2.14 (s, 3H; CH3), 3.25 (s, 3H; OCH3), 3.87 (s,
[15] The best yields for this transformation were obtained in reactions
up to a 4.0 g scale; larger batches resulted in lower yields.
Chem. Eur. J. 2004, 10, 5233 – 5242
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5241

L. F. Tietze et al.
FULL PAPER
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[17] Ratio determined by crude 1H NMR spectroscopy and upon later
oxidation to aldehydes 23 and 34.
[18] Protection of triol 31 by using other more common methods, that is,
2,2-dimethoxypropane, gave a preference for regioisomer 32, which
could not be used in this approach but can be employed in another
soon to be published synthesis.
[23] The crude product from this reaction was deemed to be unstable
1
and was only partially characterised by H NMR spectroscopy.
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ermeier, M. Beller, H. Fisher, Angew. Chem. 1995, 107, 1989;
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W. A. Herrmann, K. Öfele, C. Broßmer, Angew. Chem. 1995, 107,
1992; Angew. Chem. Int. Ed. Engl. 1995, 34, 1848.
Received: April 6, 2004
Published online: September 13, 2004
5242
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5233 – 5242