Studies towards the total synthesis of mumbaistatin: Synthesis of highly substituted benzophenone and anthraquinone building blocks

Article abstract of DOI:10.1016/S0040-4020(03)00427-7

Model compounds and building blocks for a planned total synthesis of the highly potent glucose-6-phosphate (G6P) translocase inhibitor mumbaistatin (1) and structural analogs were elaborated: compound 1 represents a lead structure in the development of po

Full text of DOI:10.1016/S0040-4020(03)00427-7

Tetrahedron 59 (2003) 3201–3217
Studies towards the total synthesis of mumbaistatin:
synthesis of highly substituted benzophenone
and anthraquinone building blocks
Florian Kaiser,a Lothar Schwink,b Janna Veldera and Hans-Gu¨nther Schmalza
,
*
a
¨
¨
¨
¨
Institut fur Organische Chemie, Universitat zu Koln, Greinstrasse 4, D-50939 Koln, Germany
bAventis Pharma Deutschland GmbH, Industriepark Hoechst, G838, D-65926 Frankfurt am Main, Germany
Received 9 January 2003; revised 18 March 2003; accepted 19 March 2003
Abstract—Model compounds and building blocks for a planned total synthesis of the highly potent glucose-6-phosphate (G6P) translocase
inhibitor mumbaistatin (1) and structural analogs were elaborated: compound 1 represents a lead structure in the development of potential
new antidiabetic drugs. With the model substrate 20 it was demonstrated that highly functionalized, tetra-ortho-substituted benzophenones
can be prepared by nucleophilic addition of an aryllithium-building block to a benzaldehyde followed by oxidation. For compound 37, a
potential precursor of the anthraquinone part of mumbaistatin, various approaches via aryne/phthalide annulations were developed and
evaluated. The required functionalized arenes were prepared exploiting, among others, regioselective bromination and ortho-lithiation
reactions. Coupling reactions of the anthracene–carbaldehyde 44 derived from 37 with various metalated arenes proved to be unexpectedly
difficult and failed so far. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. General strategy
Mumbaistatin (1), an aromatic anthraquinone polyketide
isolated from a culture of streptomyces DSM 11641, is the
strongest naturally occurring inhibitor of glucose-6-phos-
phate translocase (G6P-T1) known today.1 G6P-T1 is a part
of the glucose-6-phosphatase (G6Pase) enzyme complex,2
which catalyzes the release of glucose from glucose-6-
phosphate (G6P) in both pathways of endogenous hepatic
glucose production, gluconeogenesis and glucogenolysis.
Inhibitors of G6Pase3 are therefore of high interest for the
regulation of blood glucose and thus for the treatment of the
non-insulin-dependent type II diabetes mellitus (NIDDM).4
Because the control of hyperglycemia in NIDDM cannot
satisfactorily be achieved by pharmacological interventions
with common antidiabetic drugs, the development of new
improved therapeutic approaches represents an important
goal. Taking 1 as a lead structure, the elaboration of
synthetic approaches to this and related compounds
(mumbaistatin analogs) would pave the way for further
biological studies (incl. SAR) and the discovery of new
compounds as potential antidiabetic drugs.
Our strategy for the synthesis of mumbaistatin and analogs
thereof is based on the retrosynthetic analysis shown in
Scheme 1. Because the diketoacid functionality tends to
irreversibly form spiroketals with the secondary alcohol
under acidic conditions,1b it seemed advisable to set up the
sensitive functionalities in a late stage of the synthesis.
Therefore, we envisioned to employ a pre-target molecule
of type 3 in which all the carbonyl groups are masked as
protected or free alcohols and could be set free in the final
stage of the synthesis through an oxidation/deprotection
cascade. The connection of the two aromatic parts to the
benzhydrol 3 could possibly be achieved by nucleophilic
addition of a lithiated arene intermediate of type 4 to an
anthracene carbaldehyde 5. Such arylanion-benzaldehyde
couplings have been successfully used before in the
synthesis of various sterically hindered tetra-ortho-substi-
tuted benzophenones including the prominent PKC inhibitor
balanol.5 To set up the heavily functionalized anthraquinone
structure, we intended to employ an aryne-phthalide
annulation, which we had utilized previously in the
synthesis of the decarboxy-mumbaistatin analog 2 (Fig. 1)
following a related strategy.6
3. Synthesis of a tetra-ortho-substituted benzophenone
Keywords: mumbaistatin; benzophenones; anthraquinones; arynes; total
synthesis; G6Pase; diabetes.
For the planned synthesis of mumbaistatin, we selected a
bis-ortho-substituted aldehyde building block bearing a
*
Corresponding author. Tel.: þ49-2214703063; fax: þ49-2214703064;
e-mail: schmalz@uni-koeln.de
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00427-7

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F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
Scheme 2. Synthesis of the benzaldehyde 16. (a) NBS, CH3CN, 2 h, rt,
84%; (b) Ac2O, pyridine, 2 h, rt, 90%; (c) NBS, CCl4, hn, 3.5 h, reflux,
95%; (d) AcOH, NaOAc, 20 h, reflux, 88%; (e) 1N LiOH, dioxane, 1 h, rt,
95%; (f) NaH, MOMCl, DMF, 1 h, rt, 31% (52% rec. s.m.); (g) NEt3,
TBSCl, CH2Cl2, 2158C to rt, 1.5 h, 51%; (h) DMSO, (COCl)2, NEt3,
CH2Cl2, 2788C to rt, 90%.
protected hydroxymethyl substituent as a precursor of the
benzoic acid functionality. To evaluate whether such an
electrophile could be successfully coupled with a nucleo-
phile of type 4, we applied the aldehyde 16 as a model
substrate, which was synthesized in eight steps starting from
2,3-dimethylphenol 8 as follows (Scheme 2): bromination
of 8 with NBS in acetonitrile7 and acetylation was followed
by benzylic photo-bromination using NBS in carbon
tetrachloride.8 The tribromide 11 was converted into triol
13 in a two-step procedure by acetolysis using NaOAc/
Ac2O and subsequent saponification with LiOH in dioxane.
This efficient five-steps sequence afforded the triol 13 in
total yield of 60%. Selective protection of the phenol as a
MOM–ether was achieved in only moderate yield of 31%
(52% based on recovered starting material) using NaH/
MOMCl. The following silylation showed a 4.1:1 regio-
selectivity towards the desired isomer, giving TBS–ether 15
in 51% yield. Final oxidation of the remaining benzylic
alcohol under Swern-conditions produced benzaldehyde 16
in 90% yield (Scheme 3).
Scheme 1. Retrosynthetic analysis for mumbaistatin (1).
To test the coupling reaction, we used the o-bromobenzylic
alcohol derivative 176 as a model substrate. Treatment of 17
with 2 equiv. of n-BuLi generated the corresponding lithio-
dianion 18, which was reacted with aldehyde 16. The crude
product, i.e. an inseparable mixture of the diastereomeric
benzhydrols 19 and debrominated 17, was directly oxidized
using IBX in DMSO.9 The tetra-ortho-substituted benzo-
phenone 20 was isolated in 38% yield (two steps). Thus,
with this model system it was clearly demonstrated that
sterically hindered benzophenones related to mumbaistatin
can be prepared (albeit in a moderate yield) using the
arylanion/benzaldehyde approach.
Figure 1. Structure of mumbaistatin (1) and the simplified analog 2
previously synthesized.6

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3203
Therefore, we wanted to investigate the possibility to couple
the ‘northern’ nucleophile with an anthraquinone building
block of type 5 (Scheme 1). For the construction of the
corresponding structurally complex anthraquinone moiety,
a convergent annulation strategy seemed to be attractive,10
in which the central ring is constructed from two arene
building blocks. As in our earlier study, we intended to use
the aryne-phthalide annulation reaction developed by
Sammes11 and Biehl.12 We therefore had to prepare
phthalides (as precursors of 7) and a fully functionalized
bromide-building block as a precursor of an aryne of type 6
with the aldehyde function masked as an acetal.
4.1. Preparation of phthalides
For the aryne-phthalide-annulation, either unsubstituted
isobenzofuranones or phthalides bearing a cyano-sub-
stituent in the benzylic position can be applied (vide
infra). The MOM-protected phthalides (25 and 28) were
synthesized applying ortho-lithiation13 strategies (Scheme
4). For the synthesis of the cyanophthalide 25 we used an
iterative double metallation/alkylation approach: lithiation
of MOM-phenol 22 followed by addition of N,N-diethyl-
carbamoylchloride gave 23, which was then subjected to a
second directed ortho-metallation by treatment with s-BuLi
under Beak/Snieckus14 conditions. Subsequent addition of
DMF and aqueous workup gave the corresponding benz-
aldehyde 24, which was directly converted into the
cyanophthalide 25 with TMSCN following the procedure
of Yoshii.15
Scheme 3. Synthesis of the model benzophenone 20. (a) 17, 2 equiv.
n-BuLi, THF, 2788C; (b) 16, 2788C to rt; (c) IBX, DMSO, 6 h, rt, 38%
(two steps).
This four-step sequence produced 25 in an overall yield of
63%. The non-cyano substituted phthalide 28 was synthe-
sized in two steps from the commercial diol 26 by
chemoselective MOM-protection of the more acidic phenol
functionality, lithiation of the resulting intermediate 27
(under modified literature conditions) and quenching of
the resulting dianion with dry ice. After acidic workup, the
isobenzofuranone 28 was obtained in 54% overall yield
(Scheme 4).
4. Synthesis of an anthraquinone building block
While 20 represents a useful intermediate for the synthesis
of some mumbaistatin analogues, a fully elaborated
anthraquinone building block would be needed for the
total synthesis of the natural product itself following the
convergent approach developed earlier.6
Scheme 4. Synthesis of the phthalides 25 and 28. (a) NaH, MOMCl, DMF, rt, 94%; (b) n-BuLi, TMEDA, then ClCONEt2, THF, 2788C to rt, 91%; (c) s-BuLi,
TMEDA, then DMF, THF, 2788C to rt, 78%; (d) TMSCN, cat. KCN/18-C-6, CH2Cl2, 08C to rt, then AcOH, rt, 74% (94% rec. s.m.); (e) NaH, MOMCl, THF,
08C to rt, 84%; (f) n-BuLi, benzene, rt, then dry ice, THF, 2788C to rt, then AcOH, rt, 64%.

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F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
4.2. Synthesis of the aromatic building blocks 33 and 36
We next turned to the preparation of the coupling partner
for the envisioned anthraquinone annulation. Because the
sequence for the synthesis of bromide 16 was rather long
(Scheme 2), we developed a new approach towards such
compounds: as shown in Scheme 5, bromide 33 was
prepared in a short sequence by alkylation of the protected
3-hydroxy-benzaldehyde 31 with a suitable C1-electrophile
followed by regioselective bromination. Starting from 29, a
highly practical two-step procedure was developed for the
synthesis of the protected derivative 31. Treatment of 29
with 1,3-propandiol in the presence of pTsOH in a refluxing
benzene/THF mixture (6þ1) under azeotropical removal of
water gave the corresponding crystalline 1,3-dioxane
derivative 30 in significantly higher yield (90%) as
compared to the literature procedures. After MOM-protec-
tion of the phenol functionality, regioselective ortho-
lithiation of 3116 with n-BuLi was best performed in
benzene as a solvent. Reaction of the lithiated intermediate
with MOMCl gave the methoxymethyl-substituted product
32a. Alternatively, alkylation with SEMCl afforded the
(2-TMS-ethyl)-protected benzylic alcohol 32b also in good
yield. The subsequent (regioselective) bromination proved
to be much more difficult than expected: reaction of 32a
with bromine or NBS in various chlorinated or polar aprotic
solvent systems (tetrachloromethane, chloroform, dichloro-
methane, DMF, acetonitrile, 1,4-dioxane and mixtures of
these solvents) gave only low yields of 33 due to incomplete
conversion, inseparability of starting material and product,
and, most seriously, cleavage of the acid-labile 1,3-dioxane
protective group. After considerable experimentation it was
Scheme 5. Synthesis of the aromatic building blocks 33 and 36 as aryne- or
arynophile precursors. (a) HO(CH2)3OH, cat. pTsOH, benzene/THF 6:1,
24 h reflux, 90%; (b) NaH, MOMCl, DMF, 1 h, 08C to rt, 99%; (c) n-BuLi,
benzene, rt, then MOMCl (for 32a) or SEMCl (for 32b), THF, 2208C to rt,
74% (32a) or 68% (32b); (d) 3 equiv. NBS, AcOH, NaOAc, 10 h, rt, 81%;
(e) t-BuLi, THF, 21008C, then ClCONEt2, 21008C to rt, 75%; (f) s-BuLi,
TMEDA, THF, 2208C, then DMF, 45%; (g) TMSCN, cat. KCN/18-C-6,
CH2Cl2, 08C to rt, then AcOH, rt, 71%.
Scheme 6. Synthesis of anthraquinone 37 using aryne/phthalide annulation reactions. (a) 25, 4 equiv. LiTMP, THF, 2788C, then 2 equiv. 33, 2438C to rt, 27%
or 28, 4 equiv. LiTMP, THF, 2788C, then 2 equiv. 33, 2438C to rt, then air, 32%; (b) 36, 6 equiv. LiTMP, THF, 2788C, then 5 equiv. 38, 2438C to rt, 43%.

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3205
found that this challenging bromination could be achieved
with an excess of NBS in a saturated solution of sodium
acetate in glacial acetic acid. Under these (unusual)
conditions17 the brominated product 33 was obtained in
81% yield after chromatographic purification as a pure
regioisomer (Scheme 5).
We also investigated the possibility of switching the
retrosynthetic disconnection for the anthraquinone core.
For this purpose, the bromide 33 was converted into the
phthalide 36 (Scheme 5), which could then be employed as
an ‘arynophil’ in the reaction with an aryne derived from
MOM-protected 2-bromophenol (38). Starting from 33,
bromine–lithium exchange followed by addition of diethyl-
carbamoylchloride gave benzamide 34 in 75% yield
together with 21% of the debrominated starting material
(32a). The rather moderate yield of this transformation
(compared to the reaction 22!23) may reflect the high
sterical hindrance within the bis-ortho-substituted 2-phenyl-
1,3-dioxane system. This hindrance also leads to a reduced
conformational mobility of the 1,3-dioxane substituent,
1
which is indicated in the H NMR spectrum of 34 by the
splitting of the two methylene hydrogens of the CH2OMe
group, which disappears upon warming. Moreover, the
benzamide 34 proved to be rather reluctant towards
further deprotonation (DoM). Even with 3–4 equiv. of a
base (s-BuLi/TMEDA) at 2208C (higher temperatures led
to decomposition) the aldehyde 35 was obtained only in
45% yield after trapping the anion with DMF. Other
electrophiles such as TMSCl or BrF2C–CF2Br (vide infra)
gave similar yields for the respective products. All attempts
to improve the yield of 35 by varying the base and other
reaction parameters (temperature, solvent, additives) were
not successful, and even the LICKOR ‘superbase’ (KOtBu/
n-BuLi)18 was not able to deprotonate the benzamide 34. It
seems that 34 strongly prefers a conformation, which
disfavors the ortho-lithiation (shielding of the aromatic
ortho-proton by the N,N-diethylamide substituent). Follow-
ing the established protocol, 35 was converted into the
cyanophthalide 36 in good yield.
Scheme 7. Synthesis of anthraquinone 37 using an anionic cyclisation.
(a) t-BuLi, TMEDA, THF, 2788C, then C2Br2F4, 71%; (b) s-BuLi,
TMEDA, THF, 2308C, then C2Br2F4, 41%; (c) 1.1 equiv. n-BuLi,
1.2 equiv. MeNHCH2CH2NMe2, benzene, 08C to rt, 30 min, 41, 08C to
rt, 30 min, 3 equiv. PhLi, rt, 10 h, 4 equiv. C2B2F4, THF, 83%; (d) 39,
n-BuLi, THF, 2788C, then 42, 2308C, 2 h, then 2 equiv. t-BuLi, 2788C to
rt, then water, air, 2 h, max. 14%.
When 28 was employed, a stream of air was bubbled
through the crude reaction mixture in order to oxidize the
primary product to the anthraquinone. To our disappoint-
ment, all the reactions proceeded rather sluggishly affording
the desired product (37) in only low yield. With 2 equiv. of
the aryne-precursor 33, moderate yields could be achieved.
The unsubstituted, easier accessible phthalide 28 gave
slightly better yields (32%) than the cyanophthalide 25
(27%). The annulation proved to be highly regioselective,
giving the ‘head to head’ product 37 as the only detected
product. The observed regioselectivity, which was secured
by NOE and long range NMR measurements, corresponds
to an attack of the phthalide anion at the less electron-rich
position of the aryne as indicated in Scheme 6. In the second
aryne-phthalide route, the cyanophthalide 36 was (as its
anion) reacted with a large excess (5 equiv.) of the
intermediate aryne derived from 2-bromo-MOM-phenol
38. Even the key reaction to form the anthraquinone 37
did now proceed with an appreciable yield of 43%, the
efficiency of the overall sequence for the preparation of
cyanophthalide 36 was not competitive, due to the low
reactivity of benzamide 34 with respect to deprotonation
and the resulting low yield of 35 (Scheme 5). Thus, this
route did not provide any advantage compared to the first
approach towards 37 (coupling of 28 and 33).
4.3. Assembly of the anthraquinone building block 37
Having succeeded in preparing the building block 33 and
the phthalides 25, 28 and 36, we next investigated the
synthesis of the anthraquinone 37 (Scheme 6). For the
planned anthraquinone (see Scheme 1) formation, which is
based on the early work of Hauser, Kraus, Kelly and others
about annulation reactions using phthalide anions or
cycloadditions involving isobenzofuranes,19 two alternative
protocols involving arynes are known in the literature: while
Sammes11 employs deprotonated phthalides (such as 28) in
the reaction with the aryne, Biehl12 introduced stabilized
anions derived from cyanophthalides (such as 25 and 36)
for the same purpose. For the first approach towards 37,
we employed the phthalides 25 and 28 (Scheme 6). The
‘cycloaddition’ reactions were performed under the con-
ditions optimized earlier6 by pre-formation of the respective
phthalide anion at 2788C (4 equiv. of LiTMP as base)
followed by addition of bromide 33 and allowing the
mixture to warm up to room temperature. Under these
conditions, 33 forms an aryne20 by 1,2-elimination of HBr,
while the phthalides are deprotonated in benzylic position.

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F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
Scheme 8. Synthesis of the anthracene carbaldehyde 44 from anthraquinone 37 and unsuccessful coupling experiments of 44 with various organometallic
nucleophiles. (a) Na2S2O4, KOH, cat. Bu4NBr, (Me)2SO4, THF/H2O, 18 h, rt, 63%; (b) 10% H2SO4 absorbed on silica, CH2Cl2, 3 days, rt, 72%.
As a third convergent approach towards the anthraquinone
building block 37 we also considered to probe the Snieckus
‘anionic Friedel–Crafts equivalent’ strategy.21,22 In this
tandem-sequence, a lithiated benzamide is first fused to a
second aromatic system, which, after lithiation, undergoes
an anionic (Parham-) cyclisation. This methodology has
been successfully used in the synthesis of various aromatic
and heteroaromatic ring systems.21,22 Applied to the
preparation of anthraquinones, a lithiated benzamide must
first be reacted with a 2-bromobenzaldehyde. In the second
step, bromine–lithium exchange initiates an intramolecular
nucleophilic attack to the amide functionality. Final air-
oxidation gives the anthraquinones. Metallation of benz-
amide 34 under the conditions mentioned above and
reaction with BrF2C–CF2Br gave bromide 39 in a moderate
yield of 41% (Scheme 7). Attempts to improve the yield by
using t-BuLi/TMEDA at 2788C gave a surprising result: in
this case the regioisomeric bromide 40, arising from ortho-
lithiation directed by the MOM instead of the benzamide
group, was cleanly formed in 71% as the sole regioisomer.
This unique regioselectivity, which is in contrast to the
normal hierarchy of DMG’s,23 may be attributed again to
the sterical crowding within the system: at low temperature
the usually stronger directing benzamide cannot easily
adopt the conformation required for the directed metallation
process, and the more flexible MOM group takes over the
directing business. The constitutional assignment of both
bromides (39 and 40) is based on 1H and 13C NMR
spectroscopy including NOE and long range coupling
measurements. The second aromatic building block for the
planned tandem-lithiation reaction, the 2-bromobenzalde-
hyde derivative 42, was prepared from the MOM-protected
3-hydroxybenzaldehyde 41 in a one-step procedure using the
in situ protection/ortho-lithiation methodology developed
by Comins.24 Employing 39, the tandem key transformation
was carried out by bromine–lithium exchange (using BuLi)
followed by addition of aldehyde 42, addition of further
BuLi and final aerial oxidation. To our disappointment, only
low yields of anthraquinone 29 were obtained in numerous
attempts, 14% being the best result (Scheme 7). In all
experiments, the debrominated starting material (34) was
isolated as the main product in 70–80% yield. This
indicated that the metallation of 39 must have taken place,
but the further reaction of the sterically hindered aryllithium
species with the aldehyde 42 did obviously not proceed to a
significant extend. Variation of the metallation conditions
(n-BuLi, t-BuLi, cosolvents, etc.) and the reaction tempera-
ture (up to room temperature) gave no improvement. In
conclusion, the aryne-phthalide reaction between 28 and 33
(Scheme 6) until now seems to be the method of choice for
the preparation of anthraquinone 37, although the overall
yield starting from 3-hydroxybenzaldehyde is only around
10%.
5. Attempts to prepare the anthracenophenones 47/48
To prepare an anthracene carbaldehyde of type 5 for the
crucial coupling reaction, the quinone moiety of 37 had to
be protected by reductive methylation and the aldehyde had
to be set free selectively (Scheme 8). The method of Kraus25
(Na2S2O4/KOH/Me2SO4 in THF/H2O in the presence of a
phase-transfer catalyst) afforded the 9,10-dimethoxy-
anthracene 43. The final hydrolysis of the 1,3-dioxane
protective group was selectively achieved using 10% H2SO4
adsorbed on silica26 without effecting the MOM groups. The
aldehyde 44 proved to be unstable towards light and air,
longer standing times in solution led to rapid degradation.

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3207
1
For the anticipated construction of the anthracenophenone
system, various organometallic arene nucleophiles related
to the upper part of mumbaistatin were tested as coupling
partners for the aldehyde 44. First, we used nucleophiles
derived from bromide 17, which were generated by
bromine–lithium exchange and (appropriate) trans-metalla-
tion. The reactions were performed under the optimized
conditions we developed for the preparation of the
benzophenone 20 (Scheme 3). The soft arylcopper- and
the almost non-basic arylcerium nucleophile showed no
reaction, leaving the aldehyde unchanged. When the
aldehyde was treated with the lithium compound 18, part
of the material reacted (judged from the TLC of the crude
reaction mixture), but due to fast decomposition during
workup and chromatography, we were unable to isolate the
new compound. Finally we moved to the resorcinol lithium
nucleophile 46 (synthesized with high yield in four
steps from resorcinol monobenzoate by MOM-protection,
saponification of the benzoate, alkylation with PMB-Cl and
final ortho-lithation using n-BuLi in hexane). Reaction of 46
with 44 proceeded under formation of a coupling product,
but again minutes after chromatography the product
fractions changed color, and only decomposed material
was isolated. It seems that the coupling products derived
from aldehyde 44 are even more unstable than the starting
material itself.
13C chemical shifts were determined using H-decouplet
spectra, the number of protons bound directly was
determined employing the DEPT sequence (q¼CH3;
t¼CH2; d¼CH; s¼quaternary carbon). Some assignments
are based on two-dimensional spectra additionally recorded.
IR-spectra were recorded on a Perkin–Elmer Paragon 1000
FT-IR spectrometer using the ATR-technique. Gas-chroma-
tography (GC) and low-resolution mass spectra (EI, 70 eV)
were recorded on an Agilent HP 6890 GC–MS system
using an Optima 1 MS column with H2 as carrier-gas (flow
10 psi). Temperature programs are presented as following:
starting temperaturelength
(min)!(8C/min)!end
of stay
temperaturelength of stay (min). Given are the retention times
and the purities calculated from the uncorrected FID-
integrations. High-resolution mass spectra (HRMS) were
recorded on a Finnigan MAT 900S (ESI). Analytical thin-
layer chromatography (TLC) was performed on silica
coated alumina plates. Flash chromatography was per-
formed on Merck silica gel 60 (230–400 mesh). Reagents
were supplied by Aldrich, Merck, Fluka, Acros and
Chemetall and were used without further purification
unless otherwise noted. THF and toluene were freshly
distilled from sodium benzophenone ketyl, and dichloro-
methane was distilled from CaH2. Other solvents (aceto-
nitrile, benzene, hexane, DMF, DMSO) were purchased
in HPLC-pure quality and stored under argon over
molecular sieves. Bulk solvents for chromatography
and extraction were distilled prior to use. All reactions
with organometallic reagents were carried out under a
positive atmosphere of dry argon in oven-dried glassware
by using Schlenk techniques. Solvents and solutions
were added with syringes through rubber septa. organo-
metallic reagents (n-, sec-, t-BuLi, PhLi) were titrated with
menthol in THF in the presence of 1,10-phenanthroline
prior to use.
6. Conclusion
Following a convergent strategy towards the potent G6Pase
inhibitor mumbaistatin (1), we have elaborated synthetic
schemes allowing the preparation of various aromatic and
anthraquinone building blocks. While the key-assembly of
the northern and ‘southern’ molecule parts to form a tetra-
ortho-substituted bezophenone was successfully probed in
the model series (preparation of compound 20), a related
transformation employing the sensitive anthracene aldehyde
44 failed so far. Nevertheless, we are optimistic that the
developed strategies and building blocks will prove their
value for the synthesis of the natural product and structural
analogs thereof in the future. For example, by changing the
order of the steps during the connection of the building
blocks, a benzhydrol of type 19 could be protected and used
in an aryne/phthalide-annulation with isobenzofuranones 25
or 28 to produce the anticipated pre-target molecule of type
3. This is subject of current investigations in these
laboratories.
7.1.1. 4-Bromo-2,3-dimethylphenol (9). To a solution of
10.995 g (90 mmol) of 2,3-dimethylphenol (8) in 300 ml of
dry acetonitrile was added 15.218 g (85.5 mmol) of NBS.
The solution was stirred for 1.5 h. Then for 2–3 times
portions of 800 mg (4.5 mmol) of NBS were added followed
by stirring for another 30 min and TLC-control, until the
starting material was completely consumed. The solvent
was evaporated, and 50 ml of carbon tetrachloride were
added. The succinimide precipitate was removed by
filtration. After evaporation of the solvent, the product
started to crystallize out of the mixture. Recrystallization
gave 15.201 g (75.6 mmol, 84%) of compound 9 as
colorless needles. Mp 84–858C. TLC (cyclohexane/ethyl
acetate 6:1) R ¼0.35. IR (ATR): n (cm21)¼3270 (br, m),
˜
f
1772 (m), 1700 (s), 1573 (m), 1455 (m), 1427 (m), 1272 (s),
1175 (s), 1067 (s), 998 (m). 1H NMR (300 MHz, CDCl3): d
(ppm)¼2.20 (s, 3H, H at C7 or C8), 2.35 (s, 3H, H at C7 or
7. Experimental
7.1. General information
3
3
C8), 6.52 (d, 1H, J¼8.5 Hz, H at C6), 7.21 (d, 1H, J¼
8.5 Hz, H at C5). 13C NMR (75 MHz, CDCl3): d (ppm)¼
19.9, 29.5 (each q, C7, C8), 113.9 (d, C6), 116.3, 124.6
(each s, C1, C4), 129.8 (d, C5), 137.4 (s, C3), 152.7 (s, C1).
GC–MS (Optima 1 MS, 10 psi, 5082!(108/min)!300810):
tRet¼14.74 min, GC-purity 98%. MS (EI, 70 eV): 202/204
(79, [M]þ), 185/187 (8, [M2OH]þ), 171/173 (4, [M2OH,
–CH3]þ), 121/123 (100), 107 (95), 91 (72), 77 (67), 63 (23),
39 (29). HR-MS (EI): calcd 199.9837 for C8H9BrO, found
199.984.
Melting points (MP) were determined in open capillary
tubes measured on a Bu¨chi Melting Point B-545 apparatus
and are uncorrected. 1H and 13C NMR spectra were
recorded on Bruker 250, 300 or 500 MHz instruments and
are referenced to the non-deuterated impurities of the used
solvents (CDCl3, CD3OD, d6-DMSO) as internal standard.
The spectra are reported in ppm using the following
abbreviations to express the multiplicities: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; m¼multiplet; b¼broad.

3208
F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
7.1.2. 4-Bromo-2,3-dimethylphenyl-1-acetate (10). A
solution of 14.074 g (70 mmol) of phenol 9 in 60 ml of
pyridine was treated with 29.8 ml (315 mmol) of acetic acid
anhydride. The resulting solution was stirred for 2 h at rt.
The pyridine and the Ac2O were removed under reduced
pressure. The residue was purified by flash chromatography
(500 g of silica, cyclohexane/ethyl acetate 4:1) to give
15.315 g (63 mmol, 90%) of 10 as a white crystalline solid.
Mp: 50–518C. TLC (cyclohexane/ethyl acetate 4:1) Rf¼
(m), 1375 (m), 1289 (m), 1229 (s), 1195 (s), 1174 (s), 1062
(w), 1025 (s). 1H NMR (300 MHz, CDCl3): d (ppm)¼1.99,
2.06 (each s, 3H, CH3 of OAc), 2.09 (s, 3H, CH3 of OAc),
5.21 (d, 2H, J¼9.5 Hz, H at C7 or C8), 5.35 (d, 2H, J¼
11.5 Hz, H at C7 or C8), 6.94 (dd, 1H, J¼36 Hz, 3J¼8.5 Hz,
3
H at C4), 7.56 (dd, 1H, J¼40 Hz, J¼8.5 Hz, H at C5).
GC–MS (Optima 1 MS, 10 psi, 5082!(258/min)!30085):
tRet¼11.1 min, purity 99%. MS (EI, 70 eV): 316/318
(3, [M2CH2CvO]þ), 279 (15, [M2Br]þ), 256/258 (9,
[M2Ac, –OAc]þ), 237 (14, [M2Br, –Ac]þ), 214/216 (13,
[M22Ac, –OAc]þ), 187 (5), 177 (39, [M2Br, –OAc]þ),
135 (21), 122 (6), 107 (16), 91 (8), 77 (8), 43 (100). HR-MS
(EI): calcd 317.9927 for C12H13O5Br [M2CH2CvO],
found 317.992.
0.45. IR (ATR): n (cm21)¼2359 (w), 1759 (s), 1456 (m),
˜
1364 (s), 1215 8 (s), 1204 (s), 1171 (s), 1065 (m), 1009 (w),
878 (w). 1H NMR (300 MHz, CDCl3): d¼2.15 (s, 3H, CH3
of C1–OAc), 2.28 (s, 3H, H at C7 or C8), 2.36 (s, 3H, H at
3
C7 or C8), 6.74 (d, 1H, J¼8.5 Hz, H at C6), 7.39 (d, 1H,
3J¼8.5 Hz, H at C5). 13C NMR (75 MHz, CDCl3): d¼13.83
(q, CH3 of C1–OAc), 20.01, 20.77 (each q, C7, C8), 120.72
(d, C6), 122.39 (s, C2), 130.25 (d, C5), 130.67 (s, C4),
137.86 (s, C3), 148.26 (s, C1), 169.19 (s, C(O)OMe of
C1–OAc). GC–MS (Optima 1 MS, 10 psi, 5082!(108/
min)!30085): tRet¼15.45 min, purity 99%. MS (EI, 70 eV):
242/244 (12, [M]þ), 202/202 (100, [M2COCH3]þ), 185/
187 (4, [M2Ac–OH]þ), 164 (8), 121 (85), 107 (50), 91
(54), 77 (33), 63 (19), 43 (48). HR-MS (EI): calcd 199.9837
for C8H9BrO [M2CH2CvO], found 199.984.
7.1.5. 4-Bromo-2,3-bis(hydroxymethyl)phenol (13). A
solution of 17.959 g (50 mmol) of compound 12 in 250 ml
of 1,4-dioxane was treated with 250 ml of a 1 M aqueous
solution of LiOH. The mixture was stirred for 1 h at rt. The
dioxane was removed under reduced pressure. The aqueous
solution was cooled to 08C and acidified with 2N HCl.
The reaction mixture was extracted with ethyl acetate. The
organic layer was washed with brine and dried over MgSO4.
After evaporation of the solvent, the product solidified upon
standing overnight. After recrystallization from hexane/
ethyl acetate and intensive drying in high vacuum, 11.210 g
(47.5 mmol, 95%) of triol 13 was achieved as yellow solid.
Mp: 179–1808C. TLC (cyclohexane/ethyl acetate 1:1) Rf¼
7.1.3. 4-Bromo-2,3-bis(bromomethyl)phenyl-1-acetate
(11). A solution of 14.586 g (60 mmol) of compound 10
dissolved in 350 ml of dry carbon tetrachloride was refluxed
for 3.5 h under irradiation of a 150 W photolight. After the
succinimide was filtered off, the solvent was evaporated.
The residue was recrystallized from cyclohexane/ethyl
acetate to give 22.850 g (57 mmol, 97%) of tribromide 11
as colorless needles. Mp: 80–818C. TLC (cyclohexane/
0.1. IR (ATR): n (cm21)¼3271 (br, s), 2902 (m), 1579 (s),
˜
1441 (s), 1347 (m), 1285 (s), 1172 (s), 1126 (m), 1045 (m),
1
995 (s). H NMR (300 MHz, CDCl3): d¼4.84 (s, 2H, H at
C7), 4.85 (s, 2H, H at C8), 6.71 (d, 1H, H at C6), 7.34 (d, 1H,
H at C5). 13C NMR (75 MHz, CDCl3): d¼57.2 (t, C7), 62.3
(t, C8), 118.0 (d, C6), 115.5 (s, C4), 129.7 (s, C2), 133.8 (d,
C5), 140.6 (s, C3), 157.1 (s, C1). MS (EI, 70 eV)): 234/232
(18/20, [M]þ), 216/214 (33/30, [M2H2O]þ), 199 (4), 185/
187 (17/19), 168 (7), 157 (10), 135 [M2Br–H2O]þ), 107
(100), 89 (17), 79 (62), 77 (65), 63 (23). HR-MS (EI): calcd
233.9715 for C8H9BrO3, found 233.971.
ethyl acetate 2:1) R ¼0.3. IR (ATR): n (cm21)¼1746 (s),
˜
f
1580 (m), 1455 (s), 1436 (s), 1286 (s), 1204 (s), 1178 (s),
1156 (s), 1119 (s), 1098 (m), 1019 (m). 1H NMR (300 MHz,
CDCl3): d¼2.37 (s, 3H, CH3 of C1–OAc), 4.58, 4.76 (each
s, 2H, H on C7, C8), 7.01 (d, 1H, 3J¼8.5 Hz, H on C6), 7.57
(d, 1H, 3J¼8.5 Hz, H on C5). 13C NMR (75 MHz, CDCl3):
d¼21.0 (q, CH3 of C1–OAc), 24.0, 29.3 (each t, C7, C8),
117.5 (d, C6), 124.7, 125.6 (each s, C2, C4), 134.0 (d, C5),
137.1 (s, C3), 153.7 (s, C1), 168.9 (s, C(O)OMe of
C1–OAc). GC–MS (Optima 1 MS, 10 psi, 5082!(258/
min)!300810): tRet¼11.1 min, purity 99%. MS (EI, 70 eV):
402 (4, [M]þ), 358 (35, [M2Ac]þ), 321 (8, [M2Br]þ), 279
(69, [M2Br–Ac]þ), 200 (46, [M22Br–Ac]þ), 171 (13),
145 (6), 122 (26), 107 (21), 91 (47), 77 (9), 63 (27), 43
(100). HR-MS (EI): calcd 399.8132 for C10H9Br3O2, found
399.813.
7.1.6. 4-Bromo-2,3-bis(hydroxymethyl)methoxy-meth-
oxybenzene (14). 880 mg of a 60% dispersion of sodium
hydride in oil were placed in a flask under argon. After
washing with dry hexane, the NaH was suspended in 40 ml
of dry DMF. The cooled (08C) suspension was slowly
treated with a solution of 4.720 g (20 mmol) of phenol 13 in
30 ml of dry DMF. After the emission of hydrogen had
ceased, the mixture was stirred for 30 min at rt. The cooled
(08C) reaction mixture was treated with 1.65 ml (22 mmol)
of MOMCl [CAUTION: Due to the carcinogenity of
MOMCl all operations involving this reagent should be
performed in a well working fume hood!]. Stirring was
continued for 1 h at rt, before 100 ml of an ice cooled NH4Cl
solution was added. The mixture was extracted with MTBE.
The combined organic layers were washed with 1N NaOH
solution, water and brine and dried over MgSO4. After
evaporation of the solvent, the residue was purified by flash-
chromatography (200 g of silica, cyclohexane/ethyl acetate
1:1) to give 1.718 g (6.2 mmol, 31%) of MOM–ether 14 as
a white oil which solidified upon standing. Up to 40% of the
starting material 13 could be recovered by acidifying the
NaOH washing layers and extraction with MTBE. Mp:
69–708C. TLC (cyclohexane/ethyl acetate 1:1) Rf¼0.15. IR
7.1.4. Acetic acid 2,3-diacetoxy-6-bromophenylester
(12). 22.850 g (57 mmol) of tribromide 11 were dissolved
in 300 ml of glacial acetic acid. After addition of 18.705 g
(228 mmol) of sodium acetate the reaction mixture was
refluxed for 20 h. Afterwards the acetic acid was evapo-
rated. The residue was dissolved in ethyl acetate. The
organic phase was filtered, washed with 1N HCl, water and
brine and dried over MgSO4. The solvent was evaporated,
and the residue, which solidified overnight, was recrystal-
lized from hexane/ethyl acetate to give 18.016 g
(50.2 mmol, 88%) of triacetate 12 as colorless crystalline
solid. Mp: 75–768C. TLC (cyclohexane/ethyl acetate 1:1)
R ¼0.25. IR (ATR): n (cm21)¼2356 (w), 1737 (s), 1455
˜
f

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3209
(ATR): n (cm21)¼3338 (br, m), 2932 (m), 2896 (m), 1574
1248 (s), 1201 (s), 1180 (s), 1154 (s), 1064 (s), 985 (s), 921
1
˜
(m), 1453 (s), 1254 (s), 1203 (s), 1178 (s), 1151 (s), 1132 (s),
(s), 837 (s). H NMR (300 MHz, d6-Benzol): d¼0.097 (s,
1
1088 (s), 1050 (s), 989 (s), 919 (s). H NMR (300 MHz,
6H, CH3 of Si(Me)2), 0.93 (s, 9H, CH3 of SiC(CH3)3), 3.06
(s, 3H, CH3 of C3–OMOM), 4.65 (s, 2H, C8), 5.00 (s, 2H,
CH2 of C3–OMOM), 6.70 (d, 1H, 3J¼9 Hz, H at C4), 7.06
(d, 1H, 3J¼9 Hz, H at C5), 10.38 (s, 1H, H at C7). 13C NMR
(75 MHz, d6-Benzol): d¼25.33 (q, CH3 of Si(CH3)2),
18.55 (s, Si–C), 25.95 (q, CH3 of SiC(CH3)3), 40.59 (t,
C8), 55.76 (q, CH3 of C3–OMOM), 94.86 (t, CH2 of
C3–OMOM), 115.38 (s, C2), 119.08 (d, C4), 132.37 (s,
C6), 133.37 (d, C5), 136.49 (s, C1), 154.67 (s, C3), 192.74
(d, C7).-GC (HP 1, 25 psi, 10085!(108/min)!30085):
tRet¼14.7 min, purity 98%. MS (ESI): 389.3/391.3 ([M]þ),
411.3/413.3 ([MþNa]þ). HR-MS (ESI): calcd 332.9981 for
C16H25BrSiO4, found 332.998.
CD3OD): d (ppm)¼3.46 (s, 3H, CH3 of C1–OMOM), 4.85,
4.89 (each s, 2H, C7, C8), 5.22 (s, 2H, CH2 of C3–OMOM),
7.06 (d, 1H, 3J¼9 Hz, H at C6), 7.49 (d, 1H, 3J¼9 Hz, H at
C5). MS (EI, 70 eV): 276 (15, [M]þ), 244/246 (36/34,
[M2H–OCH3]þ), 226/228 (45/50, [M2H–OCH3–
H2O]þ), 216 (70), 214 (85), 187 (25), 135 (68), 108 (35),
107 (100), 77 (82). HR-MS (EI): calcd 275.9997 for
C10H13BrO4, found 275.998.
7.1.7. 6-Bromo-2-tertbutyldimethylsilanyloxymethyl-3-
methoxymethoxybenzylic alcohol (15). A solution of
1.998 g (7.2 mmol) of compound 14 in 25 ml of dry
dichloromethane was cooled to 2158C and treated with
2.0 ml of triethylamine. A solution of 1.296 g (8.6 mmol) of
TBSCl was slowly added, and the resulting mixture was
stirred for 1 h at 2158C. The temperature was raised to
rt, and 1 ml of methanol was added. After stirring was
continued for 1 h, 100 ml of water was added. After phase
separation, the aqueous solution was extracted with
MTBE. The combined organic layers were washed with
brine and dried over MgSO4. After evaporation of the
solvent, the residue was purified by flash chromatography
(150 g of silica, cyclohexane/ethyl acetate 6:1) to give
1.410 g (3.6 mmol, 51%) of silylether 15 and 0.335 g
(0.86 mmol, 12%) of the regioisomer. TLC (cyclohexane/
ethyl acetate 6:1) Rf¼0.45. 1H NMR (300 MHz, CD3OD): d
(ppm)¼0.12 (s, 6H, CH3 of Si(Me)2), 0.90 (s, 9H, CH3 of
Si–C(Me)3), 3.46 (s, 3H, CH3 of C3–OMOM), 4.88 (s,
2H, H at C7), 4.97 (s, 2H, H at C8), 5.21 (s, 2H, CH2 of
C3–OMOM), 7.05 (d, 1H, 3J¼9 Hz, H at C4), 7.49 (d, 1H,
3J¼9 Hz, H at C5). 13C NMR (75 MHz, CD3OD): d
(ppm)¼25.2 (q, 2CH3 of Si(Me)2), 19.2 (s, C of Si–
C(Me)3), 26.4 (q, 3CH3 of Si–C(Me)3), 56.6 (q, CH3 of
C3–OMOM), 57.6 (t, C8), 62.0 (t, C7), 96.2 (t, CH2 of
C3–OMOM), 117.3 (d, C4), 118.7 (s, C6), 132.1 (s, C2),
134.2 (d, C5), 141.5 (s, C1), 156.2 (s, C3). MS (EI, 70 eV):
335/335 (38/44, [M2tBu]þ), 303 (45), 275 (50), 273 (85),
243 (8), 227 (32), 197 (23), 177 (7), 171 (12), 139 (5),
89 (30), 75 (100). HR-MS (EI): calcd 333.0157 for
C12H18BrO4Si ([M2tBu]þ), found 333.015.
7.1.9. 1-(2-{[6-Bromo-2-(tertbutyldimethylsilanyloxy-
methyl)-3-methoxymethoxyphenyl]-hydroxy-methyl}-3-
methoxymethoxy-phenyl)-6-(tert-butyldimethyl-silanyl-
oxy)-hexan-1-ol (19). 920 mg (2.06 mmol) of bromide 176
was dissolved in 10 ml of dry THF under argon. The
solution was cooled to 2788C, and 2.65 ml of n-BuLi
(1.6 M solution in hexane) was added. After 10 min a
solution of 535 mg of benzaldehyde 16 in 10 ml of dry THF
was added slowly via syringe. The mixture was stirred
overnight, while the temperature slowly raised to rt.
After addition of 20 ml of sat. NH4Cl-solution the THF
was distilled of the mixture, and the aqueous residue was
extracted with ethyl acetate. The organic layer was washed
with brine and dried over MgSO4. The solution was filtered
through a pad of silica, and the solvent was evaporated.
The resulting crude product containing 19 was directly used
in the following oxidation reaction.
7.1.10. 1-(2-{[6-Bromo-2-(tertbutyldimethyl-silanyloxy-
methyl)-3-methoxymethoxy-phenyl]-hydroxy-methyl}-
3-methoxymethoxy-phenyl)-6-(tert-butyl-dimethyl-sila-
nyloxy)-hexan-1-ol (20). The crude product of the coupling
reaction was dissolved in 15 ml of dry DMSO. 1.40 g
(5 mmol) of IBX were added in one portion, and the mixture
was stirred for 6 h. After addition of 2 ml of water the
mixture was filtered through a bed of Na2SO4/celite and
rinsed with 30 ml of MTBE. The solution was washed with
water and brine and dried over MgSO4. After evaporation of
the solvent, the residue was purified by flash chroma-
tography (50 g of silica, cyclohexane/ethyl acetate 9:1) to
give 385 mg (0.51 mmol, 38% over two steps) of the
benzophenone 20 as a brown oil. TLC (cyclohexane/ethyl
7.1.8. 6-Bromo-3-methoxymethoxy-2-tertbutyldimethyl-
siloxymethylbenzaldehyde (16). A solution of 1.130 g
(2.9 mmol) of benzylic alcohol 15 in 40 ml of dry
dichloromethane was cooled to 2788C and 0.45 ml
(6.4 mmol) of dry DMSO was added. After 5 min 0.27 ml
(3.2 mmol) of oxalylchloride was added, and the solution
turned milky white. After being stirred for 1.5 h at 2788C,
2.0 ml (14.5 mmol) of triethylamine was added, and stirring
was continued for 30 min while the temperature was
allowed to rise to rt. After addition of 50 ml of sat. NH4Cl
solution the phases where separated, and the aqueous layer
was extracted with MTBE. The combined organic layers
where washed with brine and dried over MgSO4.
After evaporation of the solvent, the residue was purified
by flash chromatography (50 g of silica, cyclohexane/ethyl
acetate 6:1) to give 1.016 g (2.6 mmol, 90%) of aldehyde 16
as a pale yellow oil. TLC (cyclohexane/ethyl acetate 6:1)
acetate 9:1) R ¼0.15. IR (ATR): n (cm21)¼2924 (s), 2894
˜
f
(s), 2851 (s), 1698 (s), 1651 (s), 1573 (s), 1462 (s), 1449 (s),
1402 (m), 1273 (s), 1250 (s), 1201 (m), 1183 (m), 1153 (s),
1
1131 (s), 1079 (s), 985 (s), 922 (s). H NMR (300 MHz,
d6-Benzol): d (ppm)¼20.15, 20.04 (each s, 3H, CH3 of
C20–OSi(Me)2), 0.04 (s, 6H, CH3 of C1–OSi(Me)2), 0.79
(s, 9H, CH3 of C20–OSi–tBu), 0.96 (s, 9H, CH3 of
C1–OSi–tBu), 1.48–1.57 (m, 6H, H at C2, C3, C4), 1.90–
2.00 (m, 2H, H at C5), 2.99 (s, 3H, CH3 of C11–OMOM),
3.07 (s, 3H, CH3 of C16–OMOM), 3.53 (t, 2H, 3J¼6 Hz, H
3
at C1), 4.50, 4.62 (each d, 1H, J¼7 Hz, H at C20), 4.68,
4.72 (each d, 1H, J¼7 Hz, CH2 of C11–OMOM), 4.84
3
4
(s, 2H, CH2 of C16–OMOM), 6.69 (dd, 1H J¼7 Hz, J¼
R ¼0.2. IR (ATR): n (cm21)¼2948 (s), 2924 (s), 2850 (m),
1.2 Hz, H at C10), 6.75 (d, 1H, J¼9 Hz, H at C17), 6.95
3
˜
1704 (s), 1571 (m), 1450 (s), 1386 (m), 1359 (m), 1305 (w),
f
3
4
(dd, 1H, J¼8.5 Hz, J¼1.2 Hz, H at C8), 7.03 (dd, 1H,

3210
F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3J¼8.5, 7 Hz, H at C9), 7.19 (d, 1H, J¼9 Hz, H at C18).
13C NMR (75 MHz, d6-Benzol): d (ppm)¼25.8, 25.6
(each q, (CH3)2Si of C20–OTBS), 25.1 (q, (CH3)2Si of
C1–OTBS), 18.5 (s, (Me)3CSi of C20–OTBS), 18.7 (s,
(Me)3CSi of C1–OTBS), 24.4 (t, C3), 25.8 (t, C4), 26.15,
26.2 (each q, 3C, (CH3)3CSi of C1–OTBS, C20–OTBS),
33.2 (t, C2), 43.2 (t, C5), 55.7 (q, CH3 of C11–OMOM),
56.0 (q, CH3 of C16–OMOM); 57.6 (t, C20), 63.2 (t, C1),
94.8 (t, 2C: CH2 of C1–OMOM, C20–OMOM), 111.1 (d,
C17), 115.8 (d, C10), 119.8 (d, C8), 125.7 (s, C15), 128.8 (d,
C9), 132.2, 134.4, 145.2 (s, C14), 147.7 (s, C7), 154.7 (s,
C16), 158.2 (s, C11), 193.5 (s, C6), 205.3 (s, C13). MS
(ESI): 777/775 (55/45, [MþNa]þ), 707 (16), 663 (100), 633
(20), 529 (12), 339 (64). HR-MS (ESI): calcd 775.2673 for
C36H57BrO8Si2þNa, found 775.266.
J¼6.5 Hz, H at C8 or C9), 5.14 (br d, 2H, J¼3 Hz, CH2 of
C2–OMOM), 6.99 (dt, 1H, 3J¼7.5 Hz, 4J¼1 Hz, H at C3),
3
3
7.08–7.19 (m, 2H, H at C4, C5), 7.27 (dt, 1H, J¼8 Hz,
4J¼12 Hz, H at C6). 13C NMR (63 MHz, CDCl3): d¼12.8,
14.0 (each q, C10, C11), 38.7, 42.7 (each t, C8, C9), 56.1 (q,
CH3 of C2–OMOM), 94.8 (t, CH2 of C2–OMOM), 114.9
(d, C3), 122.0, 127.4 (each d, C4, C5), 127.9 (s, C1), 129.8
(d, C6), 152.8 (s, C2), 168.5 (s, C7). GC–MS (Optima 1
MS, 10 psi, 5082!(108/min)!30085): tRet¼8.5 min, 99%
pure; MS(EI): 237 (35, [M]þ), 222 (19, [M2CH3]þ), 206
(17, [M2OCH3]þ),192 (19, [M2CH2OCH3]þ), 176 (22,
[M2OCH2OCH3]þ), 165 (58, [M2NEt2]þ), 149 (14), 135
(40), 121 (46), 107 (10), 92 (28), 72 (65), 45 (100). HR-MS
(EI): calcd 237.1365 for C13H19NO3, found 237.137.
7.1.13. 2-Formyl-6-methoxymethoxy-N,N-diethyl-benz-
amide (24). 83.5 ml of sBuLi (1.3 M in hexane,
108.8 mmol) were dissolved in 200 ml of dry THF. At
2788C 16.3 ml (108.8 mmol) of TMEDA were added,
followed by a solution of 18.430 g (77.7 mmol) of
benzamide 23 in 50 ml of THF 15 min later. The reaction
mixture was stirred for 1 h at 2788C and for 2 h at 2308C.
The red suspension was cooled to 2788C, and 12.0 ml
(155 mmol) of anhydrous DMF were added dropwise. The
mixture was stirred overnight while slowly warming up to
rt. After the reaction was quenched by addition of 50 ml of
saturated NH4Cl solution, the THF was distilled off under
reduced pressure. The aqueous residue was extracted with
dichloromethane (3£100 ml). The combined organic layers
were washed with brine and dried over MgSO4. Evaporation
of the solvent under reduced pressure and purification of
the residue by flash chromatography (400 g of silica, cyclo-
hexane/ethyl acetate 1:3) afforded 16.075 g (60.6 mmol,
78%) of 2-formyl-6-methoxymethoxy-N,N-diethyl-benz-
amide 24 as an orange oil. TLC(cyclohexane/ethyl acetate
7.1.11. MOM-phenol (22). 4.40 g of a 60% sodium hydride
oil dispersion (110 mmol NaH), 9.411 g (100 mmol) of
phenol (21) and 8.2 ml (110 mmol) of MOMCl in 350 ml
of dry THF were reacted under the same conditions as
described above (prepn of 14) to give 12.988 g (94 mmol,
94%) of MOM-phenol (22) as colorless liquid which did not
need further purification. TLC (cyclohexane/ethyl acetate
1:1) R ¼0.7. IR (ATR): n¼2894 (w), 2359 (w), 1597 (w),
˜
1274 (s), 1259 (s), 1006 (w), 920 (w), 763 (s). H NMR
f
1
(250 MHz, CDCl3): d¼3.48 (s, 3H, CH3 of C1–OMOM),
5.16 (s, 2H, CH2 of C1–OMOM), 6.97–7.07 (m, 3H, H at
C
C2, C4, C6), 7.25–7.33 (m, 2H, 3J¼8 Hz, H at C3, C5). 13
NMR (63 MHz, CDCl3): d¼55.9 (q, CH3 of C1–OMOM),
94.4 (t, CH2 of C1–OMOM), 116.2 (d, C2/C4), 121.8 (d,
C4), 129.4 (d, C3/C5), 157.2 (s, C1). GC–MS (Optima 1
MS, 10 psi, 5082!(258/min)!30058): tRet¼4.95 min, 99%
pure; MS(EI): 138 (36, [M]þ), 108 (18, [MþH–OCH3]þ),
93 (3), 77 (23, [M2OCH2OCH3]þ), 65 (16), 49 (16), 45
(100), 39 (14). HR-MS (EI): calcd 138.068 for C8H10O2,
found 138.068.
1:3) R ¼0.2. IR (ATR): n¼3355 (br, s), 1697 (m), 1633 (s),
˜
1557 (m), 1538 (m), 1505 (m), 1456 (m), 1252 (m), 1152
f
1
7.1.12. 2-Methoxymethoxy-N,N-diethylbenzamide (23).
8.874 g (64.2 mmol) of MOM2phenol 22 were dissolved in
250 ml of anhydrous THF. At 08C 12.5 ml (83.5 mmol) of
TMEDA followed by 52.2 ml of n-Buli (1.6 M in hexane,
83.5 mmol) were added slowly via syringe. The solution
was stirred for 2.5 h at 08C. After being cooled to 2788C,
a solution of 12.2 ml (96.3 mmol) of freshly distilled
N,N-diethylcarbamoylchloride in 40 ml of THF were
added slowly to the reaction mixture. The yellow solution
was stirred overnight while the reaction was allowed to
slowly come to rt. The reaction was quenched by addition
of 100 ml of a saturated NH4Cl solution. The mixture was
extracted with ethyl acetate (3£300 ml). The combined
organic layers were washed with brine and dried over
MgSO4. After evaporation of the solvent under reduced
pressure the residue was purified by flash chromatography
(400 g of silica, cyclohexane/ethyl acetate 3:2) to give
13.858 g (58.4 mmol, 91%) of the benzamide 23 as a yellow
oil. TLC (cyclohexane/ethyl acetate 3:2) Rf¼0.2. IR (ATR):
(m), 1019 (m), 921 (m). H NMR (250 MHz, CDCl3): d¼
3
3
1.01 (t, 3H, J¼7 Hz, H at C10 or C11), 1.28 (t, 3H, J¼
7 Hz, H at C10 or C11), 3.10 (q, 2H, 3J¼7 Hz, 2H at C8 or
C9), 3.46 (s, 3H, CH3 of C6–OMOM), 3.61 (q, 2H,
3J¼7 Hz, H at C8 or C9), 5.18 (s, 2H, CH2 of C6–OMOM),
7.37–7.46 (m, 2H, H at C4 and C3 or C5), 7.56 (dd, 1H,
4
3J¼6.5 Hz, J¼2.5 Hz, H at C3 or C5), 9.97 (s, 1H, H at
C12). 13C NMR (63 MHz, CDCl3): d¼12.6, 13.8 (each q,
C10, C11), 38.9,42.7 (each t, C8, C9), 56.4 (q, CH3 of
C6–OMOM), 95.0 (t, CH2 C6–OMOM), 120.5, 122.8
(each d, C3, C5), 129.9 (d, C4), 133.7 (s, C2), 153.4 (s, C6),
165.6 (s, C7), 190.4 (s, C12). GC–MS (Optima 1 MS,
10 psi, 5082!(258/min)!30085): tRet¼9.5 min, 98% pure;
MS(EI): 265 (7, [M]þ), 251 (3), 236 (29, [M2C2H5]þ), 220
(2), 204 (4), 193 (13, [M2NEt2]þ), 179 (7), 163 (6), 149
(23), 134 (6), 121 (10), 86 (11), 72 (51), 45 (100). HR-MS
(EI): calcd 265.1314 for C14H19NO4, found 265.131.
7.1.14. 3-Cyano-7-methoxymethoxy-1(3H)isobenzo-fura-
none (25). 13.265 g (50 mmol) of 2-formyl-6-methoxy-
methoxy-N,N-diethylbenzamide 24 was dissolved in 250 ml
of dry CH2Cl2. At 08C 650 mg (10 mmol) of KCN and
2.043 g (10 mmol) of 18-crown-6 were added followed by
9.4 ml of TMSCN 10 min later. The reaction mixture was
stirred for 30 min at 08C and for additional 3 h at rt. The
solvent was evaporated under reduced pressure. The flask
n¼2969 (m), 2932 (m), 1628 (s), 1599 (s), 1489 (m), 1472
˜
(s), 1456 (s), 1427 (s), 1378 (m), 1362 (m), 1311 (m), 1291
(m), 1273 (m), 1232 (s), 1200 (m), 1152 (s), 1120 (m), 1075
(s), 1041 (m), 988 (s), 941 (m). 1H NMR (250 MHz,
3
CDCl3): d¼1.01 (t, 3H, J¼7 Hz, H at C10 or C11), 1.22
(t, 3H, 3J¼7 Hz, H at C10 or C11), 3.14 (q, 2H, 3J¼7 Hz, H
at C8, C9), 3.44 (s, 3H, CH3 of C2–OMOM), 3.61 (br d, 1H,

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3211
was closed with a rubber septum, and 40 ml of glacial acetic
acid were added. [CAUTION: This reaction should be
performed in a well working, closed fume hood due to the
danger of exposure of HCN] The solution was stirred
overnight at rt. After addition of 100 ml of 1N NaOH
solution the mixture was extracted with dichloromethane
(3£100 ml). The combined organic layers were washed with
brine and dried over MgSO4. After evaporation of the
solvent under reduced pressure, the residue was purified by
flash chromatography (400 g of silica, cyclohexane/ethyl
acetate 3:1) to give 8.070 g (36.8 mmol, 74%; 93% based on
recovered starting material) of cyanophthalide 25 as an
orange oil, which slowly crystallized at 48C.-MP: 67–688C-
TLC (cyclohexane/ethyl acetate 2:1) Rf¼0.35. IR (ATR):
perature was allowed to raise to rt. The solvent was
evaporated under reduced pressure. The residue was
dissolved in 100 ml of glacial acetic acid and stirred for
3 h at rt. The acetic acid was distilled off under reduced
pressure. The residue was dissolved in 200 ml of MTBE and
washed with saturated K2CO3 solution, water and brine.
After drying over MgSO4, the solvent was evaporated under
reduced pressure. The residue was purified by flash
chromatography (200 g of silica, cyclohexane/ethyl acetate
3:1) to give 2.486 g (12.8 mmol, 64%, 85% based on
recovered starting material) of 28 as a yellow solid. An
analytical sample was recrystallized from hexane/chloro-
form to give colorless crystals. Mp: 788C. TLC (cyclo-
hexane/ethyl acetate 3:1) R ¼0.12. IR (ATR): n¼3502 (br,
˜
f
n¼2936 (m), 1772 (s), 1602 (s), 1483 (s), 1453 (m), 1279
m), 2932 (m), 1757 (s), 1611 (s), 1600 (s), 1483 (s), 1454
(m), 1315 (m), 1268 (m), 1250 (s), 1202 (s), 1151 (s), 1051
(m), 1019 (s), 922 (s). 1H NMR (250 MHz, CDCl3): d¼3.42
(s, 3H, CH3 of C7–OMOM), 5.15 (s, 2H, H at C3), 5.28 (s,
2H, CH2 of C7–OMOM), 7.00 (dd, 1H, 3J¼7.5 Hz,
4J¼0.5 Hz, H at C4 or C6), 7.09 (dd, 1H, 3J¼8.5 Hz,
4J¼0.5 Hz, H at C4 or C6), 7.50 (dd, 1H, 3J¼8.5, 7.5 Hz, H
at C5). 13C NMR (63 MHz, CDCl3): d¼56.3 (q, CH3 of
C7–OMOM), 68.5 (t, C3), 94.5 (t, CH2 of C7–OMOM),
114.3, 114.7 (each d, C4, C6), 135.8 (d, C5), 148.9 (s, C3a),
156.0 (s, C7), 168.7 (s, C1); the signal for C7a was not
detectable. GC–MS (Optima 1 MS, 10 psi, 5082!(258/
min)!3008): tRet¼8.5 min, 96%, MS: 193 (13, [M21]þ),
179 (9, [M2CH3]þ), 163 (40, [M2OCH3]þ), 149 (6), 134
(45), 119 (10), 105 (25), 91 (8), 45 (100). HR-MS (EI):
calcd 194.0579 for C10H10O4, found 194.058.
˜
(s), 1265 (s), 1234 (s), 1196 (s), 1152 (s), 1092 (s), 1075 (m),
1060 (m), 994 (s), 955 (s), 921 (s). H NMR (250 MHz,
1
CDCl3): d¼3.47 (s, 3H, CH3 of C7–OMOM), 5.34 (s, 2H,
CH2 of C7–OMOM), 6.03 (s, 1H, H at C3), 7.24 (d, 1H,
3J¼7.5 Hz, H at C6), 7.29 (d, 1H, 3J¼8.5 Hz, H at C4), 7.69
3
(dd, 1H, J¼8.5, 7.5 Hz, H at C5). 13C NMR (63 MHz,
CDCl3): d¼56.6 (q, CH3 of C7–OMOM), 64.7 (d, C3), 94.7
(t, CH2 of C7–OMOM), 112.2 (s), 114.0 (s), 115.2, 116.6
(each d, C4, C6), 137.5 (d, C5), 143.8 (s), 156.5 (s, C7),
165.2 (s, C1). GC–MS (Optima 1 MS, 10 psi, 5082!(258/
min)!30058): tRet¼9.2 min, 98% pure; MS(EI): 219 (3,
[M]þ), 188 (12), 159 (13), 130 15), 119 (5), 114 (3), 45
(100).- HRMS (EI): calcd 219.0531 for C11H9NO4, found
219.052.
7.1.15. 3-Methoxymethoxybenzylic alcohol (27). 4.40 g of
a 60% sodium hydride oil dispersion (55 mmol NaH),
6.207 g (50 mmol) of 3-hydroxybenzylic alcohol 26 and
8.2 ml (55 mmol) of MOMCl in 170 ml of dry THF were
reacted under the same conditions as described for 14 to give
7.056 g (42 mmol, 84%) of 3-methoxymethoxy-benzylic
alcohol 27 as a colorless liquid after purification with flash
chromatography (250 g of silica, cyclohexane/ethyl acetate
2.1). TLC (cyclohexane/ethyl acetate 2:1) Rf¼0.25. IR
7.1.17. 20-(3-Hydroxyphenyl)-[10,30]-dioxane (30). In a
flask equipped with reflux condenser and dean-stark device
12.212 g (100 mmol) of 3-hydroxybenzaldehyde (29) was
dissolved in 250 ml of benzene and 50 ml of THF. 22 ml
(300 mmol) of 1,3-propandiol and 570 mg (3 mol%) of
p-toluenesulfonic acid was added and the reaction mixture
was refluxed for 24 h. After being transferred into a
separatory funnel, 100 ml of water was added. After phase
separation, the aqueous phase was extracted with ethyl
acetate (3£100 ml). The combined organic layers were
washed with brine and dried over MgSO4. Evaporation of
the solvent under reduced pressure gave a yellow oil which
crystallized overnight at 48C. The material was purified by
recrystallization from hexane/ethyl acetate. The mother
liquor was concentrated in vacuo and the residue was
purified by flash chromatography. All in all0 16.150 g
(90 mmol, 90%) of 20-(3-hydroxyphenyl)-[10,3 ]-dioxane
30 were obtained as white crystalline solid. Mp: 1088C.
TLC (cyclohexane/ethyl acetate 4:1) Rf¼0.13. IR (ATR):
(ATR): n¼3389 (br, m), 2930 (m), 2898 (m), 2824 (m),
˜
1585 (s), 1486 (s), 1451 (s), 1403 (m), 1362 (m), 1314 (m),
1250 (s), 1206 (s), 1149 (s), 1077 (s), 1006 (s), 921 (s). H
1
NMR (250 MHz, CDCl3): d¼1.91 (br s, 1H, OH), 3.39 (s,
3H, CH3 of C3–OMOM), 4.64 (s, 2H, H at C7), 5.16 (s, 2H,
CH2 of C3–OMOM), 6.92–7.03 (m, 3H), 7.22–7.28 (m,
1H). 13C NMR (63 MHz, CDCl3): d¼56.0 (q, CH3 of
C3–OMOM), 65.1 (t, C7), 94.3 (t, CH2 of C3–OMOM),
114.6, 115.4 (each d, C2, C4), 120.3 (d, C6), 129.6 (d, C5),
142.6 (s, C1), 157.4 (s, C3). GC–MS (Optima 1 MS, 10 psi,
5082!(258/min)!30085): tRet¼7.2 min, 97% pure; MS(EI):
168 (30, [M]þ), 153 (2), 138 (12), 123 (2), 107 (7), 92 (8),
77 (16), 45 (100). HR-MS (EI): calcd 168.0786 for
C9H12O3, found 168.078.
n¼3348 (br, m), 2965 (m), 2856 (m), 2359 (w), 1603 (m),
˜
1592 (m), 1456 (m), 1427 (w), 1393 (m), 1377 (m), 1337
(m), 1307 (m), 1281 (m), 1236 (m), 1172 (m), 1156 (m),
1
1145 (s), 1099 (s), 998 (m), 928 (m), 916 (m). H NMR
7.1.16. 7-Methoxymethoxy-(3H)isobenzofuran-1-one
(28). 3.304 g (20 mmol) of 3-methoxymethoxybenzylic
alcohol 27 was dissolved in 200 ml of dry benzene. 32 ml
of n-BuLi (1.6 M solution in hexane) was added via syringe,
and the solution was stirred for 3 h at rt. The solution turned
orange. An argon-flushed flask was charged with a handful
of dry ice in 200 ml of dry THF. The aryllithium solution
was added slowly via transfer cannula. The yellow
suspension was stirred overnight during which the tem-
(250 MHz, CDCl3): d¼1.43 (ttd, 1H, J¼13.5, 13 Hz, Heq at
C50), 2.11–2.31 (m, 1H, Hax at C50), 3,95, 4.00 (each d, 1H,
Hax at C40, C60), 4.22–4.29 (m, 2H, each 1Heq at C40, C60),
5.28 (s, 1H, OH), 5.45 (s, 1H, H at C20), 6.74 (ddd, 1H,
4
3J¼8 Hz, J¼2.5, 1 Hz, H at C4), 6.93 (ct, 1H, H at C2),
7.00 (d, 1H, 3J¼8 Hz, H at C6), 7.19 (t, 1H, 3J¼8 Hz, H at
C5). 13C NMR (63 MHz, CDCl3): d¼25.7 (t, C40), 67.4 (t,
2C, C40, C60), 101.4 (d, C20), 113.0 (d, C4), 115.9 (d, C2),
118.4 (d, C6), 129.6 (d, C5), 140.0 (s, C1), 155.6 (s, C3).

3212
F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
GC–MS (Optima 1 MS, 10 psi, 5082!(258/min)!30085):
tRet¼9.5 min, 97% pure; MS(EI): 180 (43, [M]þ), 179 (85,
[M2H]þ), 163 (23), 138 (7), 122 (50), 121 (100), 107 (6),
87 (35), 65 (26), 39 (22).
(63 MHz, CDCl3): d¼25.8 (t, C50), 56.0, 57.2 (each q, CH3
of C7–OMe, C3–OMOM), 64.4 (t, C7), 67.5 0(t, 2C, C40,
C60), 94.8 (t, CH2 of C3–OMOM), 99.4 (d, C2 ), 115.1 (d,
C4), 119.8 (d, C6), 124.4 (s, C2), 129.3 (d, C5), 139.5
(s, C1), 155.7 (s, C3). GC–MS (Optima 1 MS, 10 psi,
5082!(108/min)!30085): tRet¼19.8 min, 96% pure, MS(EI):
268 (18, [M]þ), 236 (18, [M2H–OCH3]þ), 221 (13,
[M2H–OCH3–CH3]þ), 206 (2), 191 (10), 176 (13), 165
(13), 150 (6), 135 (10), 120 (19), 105 (10), 45 (100). HR-MS
(EI): calcd 268.131 for C14H20O5, found 268.131.
7.1.18. 20-(3-Methoxymethoxyphenyl)-[10,30]-dioxane
(31). 7.00 g of a 60% sodium hydride o0il dispersion
(175 mmol NaH), 26.300 g (1460 mmol) of 2 -(3-hydroxy-
phenyl)-[10,30]-dioxane 30 and 13.3 ml (175 mmol) of
MOMCl in 400 ml of anhydrous DMF were reacted under
the same conditions as described for 14 to give 32.499 g
(145 mmol, 99%) of MOM protected dioxane 31 as a yellow
oil. TLC (cyclohexane/ethyl acetate 3:1) Rf¼0.3. IR (ATR):
7.1.20. 20-[6-Bromo-3-methoxymethoxy-2-methoxy-
methyl-phenyl]-[10,30]-dioxane (33). 9.927 g (37 mmol)
of 32a was dissolved in a solution of 18.3 g (225 mmol)
sodium acetate in 300 ml of glacial acetic acid. The solution
was cooled to 58C, and 19.760 g of NBS was added in
portions. The solution turned clear orange after 1 h and
was stirred at rt overnight. After addition of 100 ml of
dichloromethane the mixture was cooled in an ice bath,
and 300 ml of 2 M NaOH was added. Then solid NaOH and
later K2CO3 were added in portions, until the aqueous phase
was almost neutralized. The phases were separated, and
the aqueous layer was extracted with dichloromethane
(4£200 ml). The combined organic layers were washed with
saturated K2CO3 solution, saturated Na2S2O3 solution and
brine and dried over MgSO4. After evaporation of the
solvent the residue was purified by flash chromatography
(400 g of silica, cyclohexane/ethyl acetate 3:1) to give
10.413 g (30 mmol, 81%) of bromide 33 as an orange oil.
TLC (cyclohexane/ethyl acetate 3:1) Rf¼0.15. IR (ATR):
n¼2956 (s), 2849 (s), 1676 (m), 1588 (s), 1488 (s), 1453 (s),
˜
1376 (s), 1315 (m), 1275 (s), 1236 (s), 1208 (m), 1151 (s),
1
1100 (s), 989 (s), 921 (s). H NMR (250 MHz, CDCl3):
d¼1.41 (br d, 1H, J¼13.5 Hz, Heq at C50), 2.10–2.29 (m,
1H, Hax at C50), 3.95, 3.99 (each m, 1H, Hax at C40, C60),
4.20–4.27 (m, 2H, each 1Heq at C40, C60), 3.45 (s, 3H, CH3
of C3–OMOM), 5.16 (s, 2H, CH2 of C3–OMOM), 5.45 (s,
1H, H at C20), 6.97 (ddd, 1H, 3J¼8 Hz, J¼2.5, 1 Hz),
4
7.07–7.16 (m, 2H), 7.22–7.30 (m, 1H). 13C NMR (63 MHz,
CDCl3): d¼25.7 (t, C40), 55.9 (q, CH3 of C3–OMOM), 67.3
(t, 2C: C40, C60), 94.3 (t, CH2 C3–OMOM), 101.3 (d, C20),
113.5, 115.9, 119.5 (each d, C2, C4, C6), 129.3 (d, C5),
140.2 (s, C1), 157.2 (s, C3). GC–MS (Optima 1 MS, 10 psi,
5082!(258/min)!30085): tRet¼9.9 min, 98%. MS(EI): 224
(29, [M]þ), 223 (28), 193 (7, [M2OCH3]þ), 179 (8,
[M2CH2OCH3]þ), 163 (10, [M2OCH2OCH3]þ), 136 (18,
[M2CH3–dioxane]þ), 121 (7), 103 (6), 87 (20), 65 (10), 45
(100).
n¼2959 (m), 2921 (m), 2847 (m), 1575 (m), 1457 (s), 1393
˜
(m), 1374 (m), 1258 (s), 1234 (m), 1151 (s), 1115 (s), 1088
(s), 1059 (s), 989 (s), 950 (s), 900 (m). 1H NMR (2050 MHz,
CDCl3): d¼1.44 (br d, 1H, J¼13.5 Hz, Heq at C5 ), 2.19–
2.34 (m, 1H, Hax at C50), 3.41 (s, 3H, CH3 of C7–OMe),
3.44 (s, 3H, CH3 of C3–OMOM), 3.97 (dt, 2H, J¼12.5,
2.5 Hz, each 1Hax at C40, C60), 4.24–4.30 (m, 2H, each 1Heq
at C40, C60), 4.87 (s, 2H, H at C7), 5.17 (s, 2H, CH2 of
C3–OMOM), 6.14 (s, 1H, H at C20), 6.97 (d, 1H, 3J¼9 Hz,
H at C4), 7.43 (d, 1H, 3J¼9 Hz, H at C5). 13C NMR
(63 MHz, CDCl3): d¼25.8 (t, C50), 56.0 (q, CH3 of C3–
OMOM), 58.4 (q, CH3 of C7–OMe), 65.4 (t, C7), 67.9 (t,
2C, C40, C60), 94.7 (t, CH2 of C3–OMOM), 103.6 (d, C20),
115.5 (s, C6), 117.3 (d, C4), 129.3 (s, C2), 133.4 (d, C5),
136.4 (s, C1), 156.6 (s, C3). GC–MS (Optima 1 MS, 10 psi,
5082!(258/min)!30085): tRet¼11.7 min, 95% pure; MS
(EI): 346/348 (18.5/18, [M]þ), 316 (10), 301 (16), 286 (4),
271 (4), 256 (7), 243 (12), 228 (5), 213 (18), 170 (9), 133
(9), 105 (16), 87 (17), 75 (19), 45 (100). HR-MS (EI): calcd
346.042 for C14H19O5Br, found 346.042.
7.1.19. 20-[2-Methoxymethyl-3-(methoxymethoxy)-phenyl]-
[10,30]-dioxane (32a). 11.210 g (50 mmol) of dioxane 31
was dissolved in 200 ml of anhydrous benzene. Under
cooling (ice bath) 46.9 ml of n-BuLi (75 mmol, 1.6 M in
hexane) was added slowly via syringe. After the solution
was stirred for 4 h at rt turning brown, 50 ml of dry THF
was added, and the solution was cooled with an 2438C
cooling bath. When the solution started to freeze, a solution
of 6.50 ml (85 mmol) of MOMCl (which was stored 30 min
over K2CO3 prior to use) in 20 ml of dry THF was added.
The resulting yellow mixture was stirred overnight while
the temperature was allowed to rise to rt. After quenching
with 100 ml of saturated NH4Cl solution, the phases were
separated, and the aqueous layer was extracted with ethyl
acetate (3£100 ml). The combined organic layers were
washed with brine and dried over MgSO4. After evaporation
of the solvent under reduced pressure the residue was
purified by flash chromatography (500 g of silica, cyclo-
hexane/ethyl acetate 7:2) to give 9.926 g (37 mmol, 74%) of
32a as a yellow oil. TLC (cyclohexane/ethyl acetate 4:1)
7.1.21. 2-[10,30]Dioxane-20-yl-N,N-diethyl-4-methoxy-
methoxy-3-methoxymethyl-benzamide (34). In a 500 ml
argon-flushed three-necked flask 10.063 g (mmol) of
arylbromide 33 was dissolved in 200 ml of dry THF. At
2958C 35.0 ml t-BuLi (1.7 M in pentane, 59.5 mmol) was
added via syringe. The solution turned dark brown. After
5 min a solution of 12.9 ml (101.5 mmol) of freshly distilled
N,N-diethylcarbamoylchloride in 40 ml of dry THF was
added. After 60 min at 2958C the solution was allowed to
rise to rt over 3 h. After stirring for 1 h at rt, the reaction was
quenched by addition of 10 ml of ethanol. The solvent
was evaporated under reduced pressure. The residue was
R ¼0.13. IR (ATR): n¼2355 (w), 1692 (w), 1588 (m), 1462
˜
f
(m), 1375 (m), 1247 (m), 1148 (s), 1111 (m), 1086 (s), 1055
(s), 982 (s), 949 (m), 921 (m), 860 (w). 1H NMR (250 MHz,
CDCl3): d¼1.42 (septd, 1H, J¼13.5, 1.5 Hz, Heq at C50),
2.13–2.32 (m, 1H, Hax at C50), 3.36 (s, 3H, CH3 of
C7–OMe), 3.45 (s, 3H, CH3 of C3–OMOM), 3.99 (dt,
J¼13.5, 2 Hz, 2H, each 1Hax at C40, C60), 4.21–4.28 (m,
2H, each 1Heq at C40, C60), 4.65 (s, 2H, H at C7), 5.17 (s, 2H,
CH2 of C3–OMOM), 5.80 (s, 1H, H at C20), 7.08 (dd, 1H,
4
3
3J¼8 Hz, J¼1.5 Hz, H at C4), 7.26 (t, 1H, J¼8 Hz, H at
C5), 7.35 (dd, 1H, 3J¼8 Hz, 4J¼1.5 Hz, H at C6). 13C NMR

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3213
purified by flash chromatography (300 g of silica, ethyl
acetate/ethanol 20:1) to give 7.987 g (21.8 mmol, 75%) of
benzamide 34 as a red viscous oil, which became a brown
glassy solid after a few days at 48C. 1.637 g (6.1 mmol,
21%) of the debrominated starting material 20 could also be
isolated, which could be reused. Mp: 76.58C. TLC (ethyl
(63 MHz, CDCl3): d¼12.4 (q, C10), 13.4 (q, C9), 25.6
(t, C50), 38.8 (t, C8), 43.0 (t, C9), 56.3 (q, CH3 of C4–
OMOM), 58.7 (q, CH3 of C12–OMe), 65.2 (t, C12), 67.5,
67.6 (each t, C40, C60), 94.5 (t, CH2 of C4–OMOM), 100.3
(d, C20), 113.9 (d, C5), 133.0, 133.0, 133.1, 135.8 (each s,
C1, C2, C3, C5), 157.0 (s, C4), 167,1 (s, C7), 190.1 (s, C13).
GC–MS (Optima 1 MS, 10 psi, 5082!(258/min)!30085):
tRet¼13.8 min, 98% pure; MS(EI): 395 (5, [M]þ), 380 (3),
366 (30), 348 (9), 323 (30),3 22 (29), 306 (3), 292 (5), 262
810), 247 (40), 232 (20), 218 (8), 189 (25), 161 (15), 133
(15), 45 (100). HRMS (EI): calcd 395.1944 for C16H29NO7,
found 395.194.
acetate/ethanol 20:1): R ¼0.2. IR (ATR): n¼2965 (m), 2929
˜
f
(m), 1626 (s), 1596 (m), 1455 (m), 1427 (m), 1377 (m),
1287 (m), 1253 (m), 1210 (m), 1150 (s), 1115 (s), 1089 (s),
1
1059 (s), 988 (s), 926 (m). H NMR (300 MHz, CDCl3):
d¼0.95 (t, 3H, J¼7 Hz, H at C10), 1.24 (t, 3H, J¼7 Hz, H at
C11), 1.38 (br d, 1H, J¼13.5 Hz, Heq at C50), 2.19 (m, 1H,
Hax at C50), 3.02 (sex, 1H, J¼7 Hz, H at C9), 3.20 (sex, 1H,
J¼7 Hz, H at C9), 3.21 (sex, 1H, J¼7 Hz, H at C8), 3.40 (s,
3H, CH3 of C12–OMe), 3.45 (s, 3H, CH3 of C4–OMOM),
3.83 (m, 1H, Hax at C60), 3.86 (br d, 1H, J¼7 Hz, H at C8),
3.87 (m, 1H, Hax at C40), 4.18 (t, 1H, J¼11 Hz, Heq at C40),
4.22 (t, 1H, J¼11 Hz, Heq at C60), 4.71/4.82 (each d, 1H,
J¼10 Hz, H at C12), 5.19 (s, 2H, CH2 of C4–OMOM), 5.68
(s, 1H, H at C20), 7.07 (s, 1H, H at C6), 7.09 (s, 1H, H at C5).
13C NMR (75 MHz, CDCl3): d¼12.4 (q, C10), 13.5 (q,
C11), 25.7 (t, C50), 38.5 (t, C8), 42.8 (t, C9), 56.0 (q, CH3 of
C4–OMOM), 58.4 (q, CH3 of C12–OMe), 65.2 (t, C12),
67.4 (t, C40), 67.6 (t, C60), 94.6 (t, CH2 of C4–OMOM),
100.6 (d, C20), 115.3 (d, C5), 126.4 (s, C3), 127.4 (d, C6),
130.6 (s, C1), 134.9 (s, C2), 156.6 (s, C4), 170.4 (s, C7).
GC–MS (Optima 1 MS, 10 psi, 5082!(258/min)!30085):
tRet¼13.0 min, 98% pure; MS(EI): 367 (2, [M]þ), 352 (8),
336 (7), 320 (9), 295 (33), 266 (20), 237 (18), 219 (21), 204
(13), 177 813), 161 (16), 133 (15), 105 (15), 45 (100). HR-
MS (EI): calcd 367.1995 for C19H29NO6, found 367.199.
7.1.23. 4-[10,30]Dioxan-20-yl-6-methoxymethoxy-5-meth-
oxymethyl-3-oxo-1,3-dihydroisobenzo-furan-1-carbo-
nitrile (36). 160 mg (0.4 mmol) of benzaldehyde 35 was
dissolved in 5 ml of dry CH2Cl2. At 08C 4 mg (0.05 mmol)
of KCN and 10 mg (0.05 mmol) of 18-crown-6 was added,
followed by 0.2 ml of TMSCN 10 min later. The reaction
mixture was stirred for 30 min at 08C and for additional 3 h
at rt. The solvent was evaporated under reduced pressure.
The flask was closed with a rubber septum, and 3 ml of
glacial acetic acid were added. The solution was stirred
overnight at rt. After addition of 1N NaOH solution the
mixture was extracted with dichloromethane (3£10 ml).
The combined organic layers were washed with brine and
dried over MgSO4. After evaporation of the solvent under
reduced pressure, the residue was purified by flash
chromatography (30 g of silica, ethyl acetate/ethanol 70:1)
to give 89 mg (0.25 mmol, 64%; 92% based on recovered
starting material) of cyanophthalide 35 as an orange oil.
TLC (ethyl acetate/ethanol 70:1) R ¼0.45. IR (ATR): n¼
˜
f
7.1.22. 2-[10,30]Dioxan-20-yl-N,N-diethyl-6-formyl-4-
3319 (br, m), 2924 (m), 1772 (s), 1600 (s), 1456 (m), 1416
(m), 1307 (s), 1251 (m), 1235 (m), 1151 (s), 1081 (s), 1063
methoxymethoxy-3-methoxymethyl-benzamide
(35).
1
9.6 ml of s-BuLi (1.3 M in cyclohexane) was dissolved
in 40 ml of dry THF. At 2788C, 1.5 ml (12.5 mmol) of
TMEDA was added, followed by a solution of 1.836 g
(5 mmol) of benzamide 34 in 20 ml of dry THF 15 min later.
The solution turned dark brown. After 1 h at 2788C and
3 h at 2308C, the mixture was recooled to 2788C, and a
solution of 1.2 ml (15 mmol) of anhydrous DMF in 10 ml of
THF was added. The yellow solution was stirred overnight
while the temperature was allowed to rise to rt. After
addition of 20 ml of saturated NH4Cl solution the THF was
distilled off under reduced pressure. The aqueous residue
was extracted with ethyl acetate (3£30 ml). The combined
organic layers were washed with brine and dried over
MgSO4. After evaporation of the solvent under reduced
pressure the residue was purified by flash chromatography
(60 g of silica, ethyl acetate/ethanol 30:1) to give 1.005 g
(2.25 mmol, 45%) of 35 as a red oil. TLC (ethyl acetate/
(s), 991 (s), 955 (s), 925 (s). H NMR (250 MHz, CDCl3):
d¼1.48 (br d, 1H, J¼13.5 Hz, Heq at C50), 2.29 (m, 1H, Hax
at C50), 3.42, 3.45 (each s, 3H, CH3 of C9–OMe,
C6–OMOM), 3.98–4.09 (m, 2H, each 1Hax at C40, C60),
4.21–4.27 (m, 2H, each 1Heq at C40, C60), 4.87/4.98 (each d,
1H, J¼10 Hz, H at C9), 5.28/5.36 (each d, 1H, J¼7 Hz, CH3
of C6–OMOM), 5.94 (s, 1H, H at C20), 6.80 (s, 1H, H at
C1), 7.29 (s, 10H, H at C7). 13C NMR (63 MHz, CDCl3):
d¼25.8 (t, C5 ), 56.5, 58.7 (each q, CH3 of C9–OMe,
C60–OMOM), 64.4 (d, C1), 65.5 (t, C9), 67.8 (t, 2C: C40,
C6 ), 94.4 (t, CH2 of C6–OMOM), 95.8 (d, C20), 107.9 (d,
C7), 113.7, 113.8 (each s, C5, C8), 131.3, 139.0, 144.0 (each
s, C1a, C3a, C4), 163.1 (s, C6), 166.5 (s, C3). GC–MS
(Optima 1 MS, 10 psi, 15082!(108/min)!30085): tRet¼12.9
min, 95% pure; MS(EI): 349 (19, [M]þ), 317 (2), 302 (5),
261 (2), 246 (8), 231 (4), 215 (8), 186 (5), 147 (2), 103 (6),
75 (13), 45 (100). HR-MS(EI): calcd 349.1161 for
C17H19NO7, found 349.116.
ethanol 30:1) R ¼0.25. IR (ATR): n¼2966 (s), 2928 (s),
˜
f
1692 (s), 1626 (s), 1591 (s), 1432 (s), 1380 (s), 1314 (s),
1289 (s), 1234 (s), 1151 (s), 1126 (s), 1096 (s), 1061 (s), 998
7.1.24. 1-[10,30]Dioxan-20-yl-3,8-bismethoxymethoxy-2-
methoxymethylanthraquinone (37). Method A. 3.4 ml
(20 mmol) of freshly distilled 2,2,6,6-tetramethylpiperidin
was dissolved in 10 ml of dry THF. At 2788C 12.5 ml of
n-BuLi (1.6 M in hexane, 20 mmol) was added. The mixture
was stirred for 30 min before 0.971 g (5 mmol) of phthalide
28 in 10 ml of THF was added slowly via syringe. After
30 min at 2788C the solution had turned intensive red. After
allowing the mixture to warm to 2438C (by changing the
cooling bath), a solution of 3.471 g (10 mmol) of bromide
1
(s), 951 (s). H NMR (250 MHz, CDCl3): d¼0.93 (t, 3H,
J¼7 Hz, H at C11), 1.22 (t, 3H, J¼7 Hz), 1.42 (br d, 2H,
J¼13.5 Hz, Heq at C50), 2.12–2.29 (m, 1H, Hax at C50),
2.92–3.23 (m, 3H, H at C8, C9), 3.42, 3.45 (each s, 3H, CH3
of C12–OMe, C4–OMOM), 3.77–3.94 (m, 3H, H 0at C8,
each 1Hax at C40, C60); 4.22 (m, 2H, each 1Heq at C4 , C60);
4.75 (d, 1H, J¼10 Hz, H at C12), 4.91 (d, 1H, J¼10 Hz, H at
C12), 5.26 (s, 2H, CH2 of C4–OMOM), 5.69 (s, 1H, H at
C20), 7.64 (s, 1H, H at C5), 9.92 (s, 1H, H at C13). 13C NMR

3214
F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
33 in 15 ml of THF was added via syringe. After 2 h the
cooling bath was removed and the solution was stirred
overnight. Then the flask was opened and the brown mixture
was stirred for 2 h while a slight steam of air was passed
through it. After addition of 20 ml of saturated NH4Cl
solution the THF was distilled off the mixture under reduced
pressure. The aqueous residue was extracted with dichloro-
methane (4x30 ml). The combined organic layers were
washed with brine and dried over MgSO4. The solvent was
evaporated under reduced pressure. The residue was
purified by flash chromatography (50 g of silica, cyclo-
hexane/ethyl acetate 1:3) to give 733 mg (1.6 mmol, 32%)
of anthraquinone 37 as a yellow oil.
(12.5 mmol) of TMEDA was added, followed by 1.836 g
(5 mmol) of benzamide 34 in 20 ml of dry THF 15 min later.
The solution turned dark brown. After 1 h at 2788C and 3 h
at 2308C, the mixture was recooled to 2788C, and 1.8 ml
(15 mmol) of tetrafluorodibromoethane in 10 ml of THF
was added. The yellow solution was stirred overnight while
the temperature was allowed to rise to rt. After addition of
20 ml of saturated NH4Cl solution the THF was distilled off
under reduced pressure. The aqueous residue was extracted
with ethyl acetate (3£30 ml). The combined organic layers
were washed with brine and dried over MgSO4. After
evaporation of the solvent under reduced pressure the
residue was purified by flash chromatography (60 g of silica,
ethyl acetate/ethanol 30:1) to give 0.915 g (2.05 mmol,
41%) of bromide 39 as a red oil. TLC (ethyl acetate/ethanol
Method B. 3.4 ml (20 mmol) of freshly distilled 2,2,6,6-
tetramethylpiperidin was dissolved in 10 ml of dry THF. At
2788C 12.5 ml of n-BuLi (1.6 M in hexane, 20 mmol) was
added. The mixture was stirred for 30 min before 1.095 g
(5 mmol) of cyanophthalide 25 in 10 ml of THF was added
slowly via syringe. After 30 min at 2788C the solution had
turned intensive red, and the mixture was allowed to warm
to 2438C. A solution of 3.478 g (10 mmol) of bromide 33 in
15 ml of THF was added via syringe. After 2 h the cooling
bath was removed and the solution was stirred overnight.
The reaction was quenched by addition of 50 ml of saturated
NH4Cl solution. Isolation and purification of the product
following the procedure described in method A gave
618 mg (1.35 mmol, 27%) of anthraquinone 37 as a yellow
oil.
30:1) R ¼0.25. IR (ATR): n¼2966 (s), 2928 (s), 1632 (s),
˜
f
1583 (s), 1430 (s), 1379 (s), 1284 (s), 1234 (s), 1207 (s),
1150 (s), 1121 (s), 1090 (s), 1060 (s), 989 (s), 946 (s), 927
(s). 1H NMR (250 MHz, CDCl3): d¼1.04 (t, 3H, J¼7 Hz, H
at C11), 1.26 (t, 3H, J¼7 Hz, H at C10), 1.38 (br d, 1H,
J¼13.5 Hz, Heq at C50), 2.12–2.27 (m, 1H, Hax at C50),
3.00–3.24 (m, 2H, each 1H at C8, C9), 3.38 (s, 3H, CH3 of
C12–OMe), 3.43 (s, 3H, CH3 of C4–OMOM), 3.46–3.65
(m, 2H, each 1H at C8, C9), 3.73–3.90 (m, 2H, each 1Hax at
C40, C60), 4.14–4.26 (m, 2H, each 1Heq at C40, C60), 4.67 (d,
1H, J¼10 Hz, H at C12), 4.85 (d, 1H, J¼10 Hz, H at C12),
5.17 (s, 2H, CH2 of C4–OMOM), 5.55 (s, 1H, H at C20),
7.31 (s, 1H, H at C5). 13C NMR (63 MHz, CDCl3): d¼12.3
(q, C10), 13.2 (q, C11), 25.6 (t, C50), 38.5 (t, C8), 42.9
(t, C9), 56.1 (q, CH3 of C4–OMOM), 58.4 (q, CH2 of
C12–OMe), 65.2 (t, C12), 67.5, 67.6 0(each t, C40, C60), 94.6
(t, CH2 of C4–OMOM), 101.0 (d, C2 ), 119.6 (d, C6), 119.9
(s, C5), 126.4, 131.2, 136.4 (each s, C1, C2, C3), 157.1 8s,
C4), 167.4 (s, C7). GC–MS (Optima 1 MS, 10 psi, 15082!
(108/min)!30085): tRet¼11.9 min, purity 97%; MS(EI):
447, 445 (1, [M]þ), 432, 430 (1), 415 (5), 400 (7), 373
(15), 344 (8), 315 (10), 299 (18), 284 (8), 257 (6), 45 (100).
HR-MS(EI): calcd 445.1100 for C19H28NO6Br, found
445.110.
Method C. 70 mg (0.2 mmol) of cyanophthalide 36, 217 mg
(1 mmol) of 2-methoxymethoxyphenylbromide 38 and
1.5 mmol of LiTMP in 6 ml of dry THF were reacted
under the same conditions as described in Method
B. Isolation and purification by flash chromatography gave
37 mg (0.08 mmol, 43%) of anthraquinone 37 as a yellow
oil. TLC (cyclohexane/ethyl acetate 1:3) Rf¼0.2. IR (ATR):
n¼2922 (s), 2823 (m), 1768 (m), 1730 (s), 1667 (s), 1579
˜
(s), 1464 (s), 1407 (s), 1248 (s), 1151 (s), 752 (s). 1H NMR
(500 MHz, CDCl3): d¼1.48 (br d, 1H, J¼12.5 Hz, Heq on
C50), 2.34 (m, 1H, Hax on C50), 3.45 (s, 3H, CH3 of
C11–OMe), 3.46 (s, 3H, CH3 of C3–OMOM), 3.54 (s, 3H,
CH3 of C8–OMOM), 4.09 (br dt, 2H, J¼12.5, 2.5 Hz, each
1Hax on C40, C60), 4.28 (m, 2H, each 1Heq on C40, C60), 5.06
(s, 2H, H on C11), 5.33 (s, 2H, CH2 of C8–OMOM), 5.37
(s, 2H, CH2 of C3–OMOM), 6.56 (s, 1H, H on C20), 7.48
7.1.26. 5-Bromo-2-[10,30]dioxan-20-yl-N,N-diethyl-4-
methoxymethoxy-3-methoxymethyl-benzamide (40). To
a solution of 1.836 g (5 mmol) of benzamide 39 in 60 ml of
dry THF at 2788C was added 1.5 ml (10 mmol) of TMEDA
followed by 5.9 ml of t-BuLi (1.7 M in pentane) 5 min later.
The solution turned dark red. After stirring for 1 h at 2788C
and 2 h at 2308C the solution was cooled to 2788C, and
1.8 ml (15 mmol) of tetrafluorodibromoethane in 10 ml of
THF was added. The yellow solution was stirred overnight
while the temperature was allowed to slowly rise to rt.
Workup and purification as described for 39 gave 1.584 g
(3.55 mmol, 71%) of bromide 40 as a red gum. TLC (ethyl
3
4
(dd, 1H, J¼8.5 Hz, J¼1 Hz, H on C7), 7.57 (dd, 1H,
3J¼8.5 Hz, 4J¼7.5 Hz, H on C6), 7.84 (dd, 1H, 3J¼7.5 Hz,
4J¼1 Hz, H on C5), 7.88 (s, 1H, H on C4). 13C NMR
(125 MHz, CDCl3): d¼25.9 (t, C50), 56.3 (q, CH3 of
C3–OMOM), 56.5 (q, CH3 of C8–OMOM), 58.7 (q, CH3
of C11–OMe), 66.1 (t, C11), 67.8 (t, 2C, C40, C60), 94.0
(t, CH2 of C3–OMOM), 95.6 (t, CH2 of C8–OMOM), 99.3
(d, C20), 111.9 (d, C4), 120.6 (d, C5), 123.0 (d, C7), 125.8
(s, C8a), 129.5 (s, C9a), 133.6 (d, C6), 134.4 (s, C4a), 134.6
(s, C5a), 134.9 (s, C2), 139.6 (s, C1), 156.4 (s, C8), 160.1 8s,
C3), 182.9 (s, C10), 184.9 (s, C9). HR-MS(EI): calcd
458.1577 for C24H26O9, found 458.157.
acetate/ethanol 30:1) R ¼0.25. IR (ATR): n¼2965 (s), 2928
˜
f
(s), 1631 (s), 1580 (m), 1556 (m), 1455 (s), 1426 (s), 1378
(s), 1346 (m), 1290 (s), 1235 (s), 1203 (s), 1154 (s), 1114 (s),
1
1090 (s), 1025 (m), 1004 (s), 943 (s). H NMR (250 MHz,
CDCl3): d¼0.98 (t, 3H, J¼7 Hz, H at C11), 1.23 (t, 3H,
J¼7 Hz, H at C10), 1.37 (br d, 1H, J¼12.5 Hz, Heq at C50),
2.16 (m, 1H, Hax at C50), 3.03 (m, 1H, H at C9), 3.17 (m, 1H,
H at C9), 3.22 (m, 1H, H at C8), 3.41 (s, 3H, CH3 of
C12–OMe), 3.65 (s, 3H, CH3 of C4–OMOM), 3.82 (m, 1H,
H at C8), 3.83 (m, 2H, each 1Hax at C40, C60), 4.19 (br dt,
2H, J¼12, 4.5 Hz, each 1Hax at C40, C60), 4.70/4.74 (each d,
7.1.25. 6-Bromo-2-[10,30]dioxan-20-yl-N,N-diethyl-4-
methoxymethoxy-3-methoxymethyl-benzamide
(39).
9.6 ml of s-BuLi (1.3 M in cyclohexane) was placed
in 40 ml of dry THF under argon. At 2788C, 1.5 ml

F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
3215
1H, J¼10 Hz, H at C12), 5.09/5.11 (each d, 1H, J¼5 Hz,
CH2 of C4–OMOM), 5.64 (s, 1H, H at C20), 7.35 (s, 1H H at
C6). 13C NMR (63 MHz, CDCl3): d¼12.4 (q, C10), 13.5 (q,
C11), 25.6 (t, C50), 38.6 (t, C8), 42.8 (t, C9), 58.0 (q, CH2 of
C4–OMOM), 58.4 (q, CH2 of C12–OMe), 66.0 (t, C12),
67.4, 67.5 (each t, C40, C60), 100.0 (d, C30), 100.7 (t, CH2 of
C4–OMOM), 118.4 (s, C5), 131.2 (d, C6), 132.9 (s, C1),
134.5 (s, C3), 134.6 (s, C2), 154.1 (s, C4), 168.6 (s, C7).
GC–MS (Optima 1 MS, 10 psi, 5082!(258/min)!30085):
tRet¼13.9 min, 94% pure; MS(EI): 447, 445 (1, [M]þ), 432,
430 (10), 415 (8), 400 (7), 373 (15), 344 (8), 328 (22), 312
(28), 297 (18), 284 (8), 257 (6), 241 (12), 213 (10), 45 (100).
HR-MS(EI): calcd 445.1100 for C19H28NO6Br, found
445.110.
cooling bath was removed and the solution was stirred
overnight at rt. Then the flask was opened and the brown
mixture was stirred for 2 h while a slight steam of air was
passed through it. Isolation and purification as described in
method A gave 43 mg (0.09 mmol, 14%) of anthraquinone
37 as a yellow oil.
7.1.29. 20-(9,10-Dimethoxy-3,8-bismethoxymethoxy-2-
methoxymethylanthracen-1-yl)-[10,30]-dioxane
(43).
916 mg (2 mmol) of the anthraquinone 37 and 80 mg of
tetrabutylammoniumbromide were dissolved in 8 ml of
THF and 4 ml of water. 1.567 g (9 mmol) of sodium
dithionite and 5 min later 1.650 g (30 mmol) of KOH
was added. After additional 5 min 2.85 ml (30 mmol) of
dimethylsulfate was added dropwise. The mixture
was stirred for 18 h at rt, until the starting material was
completely consumed (TLC-control). The mixture was
poured into a separatory funnel charged with 10 ml of
saturated NH4Cl solution and extracted with ethyl acetate
(5£20 ml). The combined organic layers were washed with
brine and dried over MgSO4. After evaporation of the
solvent under reduced pressure, the residue was purified
by flash chromatography (50 g silica, cyclohexane/ethyl
acetate 1:1) to give 615 mg (1.26 mmol, 63%) of the
methoxyanthracene 43 as yellow foam. TLC (cyclohexane/
7.1.27. 2-Bromo-3-methoxymethoxybenzaldehyde (42).
To a solution of 3.4 ml (26 mmol) of N,N,N0-trimethylethyl-
endiamine and 40 ml of anhydrous benzene was added
15 ml of n-BuLi (1.6 M in hexane, 24 mmol) slowly at 08C.
The solution was stirred for 30 min at rt. At 08C 3.324 g
(20 mmol) of 3-methoxymethoxybenzaldehyde 41 in 20 ml
of benzene was added and the resulting solution was stirred
for 30 min at rt. 35 ml PhLi (1.8 M in cyclohexane/ether,
60 mmol) was added and the reaction mixture was stirred
for 24 h at rt. 40 ml of dry THF was added to the resulting
brown suspension. The mixture was cooled to 2438C, and
9.6 ml (80 mmol) of tetrafluorodibromoethane was added
dropwise. The cooling bath was removed and the solution
was stirred for 2 h during which the temperature was
allowed to rise to rt. After additional 2 h at rt the reaction
was quenched by addition of 50 ml of saturated NH4Cl
solution. The solvent was distilled off the mixture under
reduced pressure. The aqueous residue was extracted with
dichloromethane (3£100 ml). The combined organic layers
were washed with brine and dried over MgSO4. The solvent
was evaporated under reduced pressure. The residue was
purified by flash chromatography (250 g of silica, cyclo-
hexane/ethyl acetate 5:1) to give 4.080 g (16.6 mmol, 83%)
of bromide 42 as an orange oil. TLC (cyclohexane/ethyl
ethyl acetate 1:1): R ¼0.2. IR (ATR): n¼2927 (s), 2839 (s),
˜
f
2243 (m), 1730 (m), 1609 (s), 1556 (s), 1523 (s), 1448 (s),
1394 (s), 1352 (s), 1313 (s), 1223 (s), 1145 (s), 1124 (s), 854
1
(s). H NMR (250 MHz, CDCl3): d¼1.48 (br d, 1H, J¼
13.5 Hz, Hax on C50), 2.28–2.46 (m, 1H, Heq on C50), 3.52
(s, 3H, CH3), 3.54 (s, 3H, CH3), 3.63 (s, 3H, CH3), 3.79 (s,
3H, CH3), 3.97 (s, 3H, CH3), 4.00–4.13 (m, 2H, each 1Heq
on C40, C60), 4.28–4.35 (m, 2H, each 1Hax on C40, C60),
5.20 (s, 2H, H on C11), 5.40 (s, 3H, CH3 of C2–OMOM),
5.40 (s, 3H, CH3 of C8–OMOM), 7.02 (dd, 1H, 3J¼7.5 Hz,
4J¼1 Hz, H on C7), 7.23 (s, 1H, H on C20), 7.32 (dt, 1H,
3J¼8.5, 7.5 Hz, H on C6), 7.71 (s, 1H, H on C4), 7.88 (dd,
3
4
1H J¼8.5 Hz, J¼1 Hz, H on C5). 13C NMR (63 MHz,
CDCl3): d¼26.0 (t, C50), 56.1 (q), 56.5 (q,), 58.5 (q), 62.1
(q), 63.6 (q), 67.3 (t, C11), 67.9 (t, 2C, C40, C60), 94.3, 96.1
(each t, CH2 of C3–OMOM, C8–OMOM), 101.3, 103.4
(each d, C4, C7), 109.5 (d), 116.1 (d), 118.3 (s), 121.0 (s),
125.4 (d), 126.4 (s), 127.4 (s), 132.0 (s), 135.3 (s), 146.3
(s, C3/8), 150.5 (s, C3/8), 153.6, 154.3 (each s, C9, C10).
GC–MS (Optima 1 MS, 10 psi, 15082!(108/min)!30085):
tRet¼17.9 min, 94% pure; MS(EI): 488 (65, [M]þ), 473
(11), 457 (10), 413 (24), 384 (16), 339 (50), 279 (46), 251
(16), 223 (8), 181 (6), 152 (10), 75 (12). HR-MS (EI):
488.2046 calcd for C26H32O9, found 488.205.
acetate 5:1) R ¼0.2. IR (ATR): n¼2897 (w), 1689 (s), 1566
˜
f
(s), 1459 (m), 1434 (m), 1379 (m), 1257 (s), 1235 (s), 1203
(m), 1150 (s), 1083 (s), 1006 (s), 920 (s). 1H NMR
(250 MHz, CDCl3): d¼3.51 (s, 3H, CH3 of C3–OMO), 5.27
(s, 2H, CH2 of C3–OMOM), 7.31–7.36 (m, 2H), 7.55 (dd,
1H, 3J¼7 Hz, 4J¼2.5 Hz), 10.40 (s, 1H, H at C7). 13C NMR
(63 MHz, CDCl3): d¼56.5 (q, CH3 of C3–OMOM), 95.2 (t,
CH2 of C3–OMOM), 118.0 (s, C2), 121.1, 122.8, 128.3
(each d, C4, C5, C6), 134.8 (s, C1), 154.2 (s, C3), 192.1
(d, C7). GC–MS (Optima 1 MS, 10 psi, 15082!(108/
min)!30085): tRet¼4.8 min, 96% pure; MS(EI): 246, 244
(9, [M]þ), 213 (3), 143 (4), 92 (4), 75 (6), 63 (9), 45 (100).
HRMS (EI): calcd 243.9735 for C9H9BrO3, found 243.975.
7.1.30. 9,10-Dimethoxy-3,8-methoxymethoxy-2-methoxy-
methylanthracene-1-carbaldehyde (44). 2.54 g of silica
was suspended in 11 ml of dichloro-methane. 250 mg of a
10% aqueous H2SO4 solution was added dropwise under
stirring, and the mixture was stirred for 30 min until the
aqueous phase was fully absorbed on the silica. 254 mg
(0.52 mmol) of anthracenyl-[1.3]dioxane in 4 ml of dichloro-
methane was added dropwise. The yellow suspension soon
turned red. The flask was closed, and the mixture was stirred
for 72 h at rt. After addition of some potassium carbonate
the mixture was stirred for further 30 min before it was
filtered through a sintered funnel. The silica was washed
with ethyl acetate and methanol. The solution was collected
7.1.28. 1-[10,30]Dioxan-20-yl-3,8-bismethoxymethoxy-2-
methoxymethylanthraquinone (37). Method D. In a
25 ml argon-flushed schlenk flask 300 mg (0.67 mmol) of
bromobenzamide 39 was dissolved in 5 ml of dry THF. At
2788C 0.42 ml of n-BuLi (1.6 M, 0.67 mmol) was added,
and the mixture was stirred for 15 min. Then 328 mg
(1.34 mmol) of bromobenz-aldehyde 42 in 5 ml of THF was
added, and the solution was stirred for 1 h at 2788C and for
2 h at 2308C. The solution was recooled to 2788C, and
0.84 ml of n-BuLi (1.34 mmol) was added. After 2 h the

3216
F. Kaiser et al. / Tetrahedron 59 (2003) 3201–3217
Chem. 1994, 59, 6703–6709. (b) Townsend, C. A.; Graybill,
T. L.; Casillas, E. G.; Pal, K. J. Am. Chem. Soc. 1999, 34,
7729–7746. (c) Katoh, T.; Ohmuri, O. Tetrahedron Lett. 2000,
41, 465–469. (d) Katoh, T.; Ohmuri, O.; Iwasaki, K.; Inoue,
M. Tetrahedron 2002, 58, 1289–1299. (e) Iikubo, K.;
Ishikawa, Y.; Ando, N.; Umezawa, K.; Nishiyama, S.
Tetrahedron Lett. 2002, 43, 291–293.
and the solvent was removed under reduced pressure. The
residue was dissolved in 50 ml of dichloromethane. The
solution was washed with 1 M NaOH solution, water and
brine and dried over MgSO4. After evaporation of the
solvent the residue was purified by flash chromatography
(25 g silica, cyclohexane/ethyl acetate 3:2) to give 161 mg
of 44 (0.375 mmol, 72%) as a brown solidified oil. TLC
6. Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-G. J. Org.
Chem. 2002, 67, 9248–9256.
(cyclohexane/ethyl acetate 3:2): R ¼0.2. IR (ATR): n¼3371
˜
f
(br, m), 2930 (m), 2896 (m), 2824 (m), 1692 (s), 1608 (s),
1561 (m), 1526 (s), 1449 (s), 1431 (s), 1397 (m), 1355 (s),
1225 (s), 1206 (s), 1150 (s), 1038 (s), 1013 (s), 973 (s), 920
(s). 1H NMR (300 MHz, CDCl3): d¼3.40 (s, 3H, CH3), 3.52
(s, 3H, CH3), 3.59 (s, 3H, CH3), 3.69 (s, 3H, CH3), 4.00
(s, 3H, CH3), 4.71 (s, 2H, CH2), 5.27 (s), 5.37 (s, 2H, CH2 of
OMOM), 5.39 (s, 2H, CH2 of OMOM), 7.06 (d, 1H,
7. Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.;
Urbano, A. J. Org. Chem. 1995, 60, 5328–5331.
8. Gruter, G.-J. M.; Akkerman, O. S.; Bickelhaupt, F. J. Org.
Chem. 1994, 59, 4475–4481.
9. (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G.
J. Org. Chem. 1995, 60, 7272–7276. (b) Frigerio, M.;
Santagosti-no, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537–4538. review: Wirth, T. Angew. Chem., Int. Ed. 2001,
40, 2812–2814.
3
J¼7.5 Hz, H on C7), 7.35 (dd, 1H, J¼8.5, 7.5 Hz, H on
3
C6), 7.70 (s, 1H, H on C4), 7.90 (d, 1H, J¼8.5 Hz, H on
C5), 10.68 (s, 1H, H on C11). 13C NMR (75 MHz, CDCl3):
d¼56.3, 56.6 (each q, CH3 of C3–OMOM, C8–OMOM),
58.6 (q, CH3 of C12–OMe), 62.4, 63.0 (each q, CH3 of
C9–OMe, C10–OMe), 65.2 (t, C12), 94.6, 96.1 (each t,
CH2 of C3–OMOM, C8–OMOM), 103.0, 109.4 (each d,
C4, C7), 116.2 (d, C5), 117.1 (s), 120.5 (s), 125.4 (s), 126.0
(d, C6), 127.5 (s), 128.1 (s), 138.5 (s, C1), 146.9, 148.7
(each s, C9, C10), 153.0, 153.3 (each s, C3, C8), 193.9
(d, C11). GC–MS (Optima 1 MS, 10 psi, 20082!(108/
min)!30085): tRet¼8.0 min, 95% pure; MS(EI): 430 (17,
[M]þ), 401 (2), 386 (7), 354 (10), 339 (24), 310 (11), 295
(26), 279 (16), 251 (14), 223 (7), 208 (5), 181 (5), 152 (11),
115 (5), 75 (34), 45 (100). HRMS (EI): calcd 430.1628 for
C23H26O8, found 430.163.
10. For reviews about the synthesis of anthraquinones/anthra-
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Acknowledgements
This work was supported by Aventis Pharma GmbH and the
Fonds der Chemischen Industrie. We thank Dr Hans
Schmickler for NMR spectroscopic support and Dr Mathias
¨
Schafer for MS spectroscopic measurements. Generous gifts
of chemicals from Chemetall AG are highly appreciated.
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