Total synthesis of cyclo-mumbaistatin analogues through anionic homo-fries rearrangement

Article abstract of DOI:10.1002/chem.201003166

The structurally unique polyketide mumbaistatin is the strongest naturally occurring inhibitor of glucose-6-phosphate translocase-1 (G6P-T1), which is a promising target for drugs against type-2 diabetes mellitus and angiogenic processes associated with brain tumor development. Despite its high relevance, mumbaistatin has so far withstood all attempts towards its total synthesis. In the present study an efficient total synthesis of a deoxy-mumbaistatin analogue containing the complete carbon skeleton and a spirolactone motif closely resembling the natural product in its cyclized form was elaborated. Key steps of the synthesis are a Diels-Alder cycloaddition for the construction of the fully functionalized anthraquinone moiety and an anionic homo-Fries rearrangement to build up the tetra-ortho-substituted benzophenone core motif, from which a spiroketal lactone forms in a spontaneous process. The elaborated strategy opens an entry to a variety of new analogs of mumbaistatin and cyclo-mumbaistatin and may be exploited for the total synthesis of the natural product itself in the future.

Full text of DOI:10.1002/chem.201003166

FULL PAPER
DOI: 10.1002/chem.201003166
Total Synthesis of cyclo-Mumbaistatin Analogues through Anionic
Homo-Fries Rearrangement
Stefan Neufeind,[a] Nils Hꢀlsken,[a] Jçrg-Martin Neudçrfl,[a] Nils Schlçrer,[b] and
Hans-Gꢀnther Schmalz*[a]
Abstract: The structurally unique poly-
ketide mumbaistatin is the strongest
naturally occurring inhibitor of glu-
cose-6-phosphate translocase-1 (G6P-
T1), which is a promising target for
drugs against type-2 diabetes mellitus
and angiogenic processes associated
with brain tumor development. Despite
its high relevance, mumbaistatin has so
far withstood all attempts towards its
total synthesis. In the present study an
efficient total synthesis of a deoxy-
mumbaistatin analogue containing the
complete carbon skeleton and a spiro-
lactone motif closely resembling the
natural product in its cyclized form was
elaborated. Key steps of the synthesis
are a Diels–Alder cycloaddition for the
construction of the fully functionalized
anthraquinone moiety and an anionic
homo-Fries rearrangement to build up
the tetra-ortho-substituted benzophe-
none core motif, from which a spiroke-
tal lactone forms in a spontaneous pro-
cess. The elaborated strategy opens an
entry to a variety of new analogs of
mumbaistatin and cyclo-mumbaistatin
and may be exploited for the total syn-
thesis of the natural product itself in
the future.
Keywords: natural products · phos-
phatase inhibitor
· polyketides ·
spirolactones · total synthesis
Introduction
and by single crystal X-ray analysis of a trimethylated dehy-
dration product.[2] Based on these studies, mumbaistatin is
supposed to exist in an equilibrium between the “open”
diketo (1a) and a “closed” spiroketal lactone form (1b, re-
ferred to as cyclo-mumbaistatin). The absolute configuration
of the only stereocenter in the alkyl side chain of 1 could
not be determined. However, the stereocenter is supposed
to be S-configured based on the comparison with the known
naphthoquinone antibiotic juglomycin D[3] and its quasi-di-
merization product juglorubin,[4] which were both isolated as
fermentation products from the same Streptomyces strain
and assumed to be formed in a related biosynthetic path-
way.
In 1997, Ramakrishna and co-workers discovered a novel
natural product by cultivation of the microorganism Strepto-
myces sp. DSM 11641, isolated from a soil sample from the
Hiranyakeshi river bed near Amboli, in Maharashtra,
India.[1] According to the north Indian metropolis Mumbai
(formerly Bombay) the compound was named mumbaistatin
(1, Scheme 1). The unique structure of this polyketide was
elucidated two years later by extensive 2D NMR studies
Biological studies unveiled mumbaistatin to be the stron-
gest naturally occurring inhibitor of glucose-6-phoshate
translocase 1 (G6P-T1) known to date (IC50 =5 nm).[2] G6P-
T1 is part of the glucose-6-phosphatase (G6Pase) enzyme
complex, which catalyzes the breakdown of glucose-6-phos-
phate (G6P) into glucose and phosphate. This process repre-
sents the terminal step in both pathways of the hepatic glu-
cose production, gluconeogenesis and glucogenolysis. The
activity of G6Pase is several folds higher in diabetic animals
and probably in diabetic humans, which results in an in-
creased hepatic glucose production and an elevated blood
sugar level. Hence, the regulation of this enzyme is a highly
interesting target for pharmacological intervention in the
treatment of the non-insulin dependent type II diabetes mel-
litus (NIDDM).[5] Moreover, recent studies revealed G6P
translocase to play a crucial role in the proliferation of brain
tumors.[6] Since glioma growth often cannot be suspended by
conventional methods, for example, surgical resection or ra-
diation, the selective regulation of G6P activity offers a
Scheme 1. Equilibrium between the “open” diketo form (1a) and the
“closed” spirocyclic form (1b) of mumbaistatin.
[a] Dr. S. Neufeind, N. Hꢀlsken, Dr. J.-M. Neudçrfl,
Prof. Dr. H.-G. Schmalz
Department of Chemistry, Institute of Organic Chemistry
University of Cologne, Greinstrasse 4, 50939 Kçln (Germany)
schmalz @uni-koeln.de
[b] Dr. N. Schlçrer
Department of Chemistry, NMR Department
University of Cologne, Greinstrasse 4, 50939 Kçln (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003166.
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promising therapeutic approach. In this sense, the elabora-
tion of a synthetic access to mumbaistatin (1) and deriva-
tives thereof would constitute an important contribution to-
wards the development of new and improved antidiabetic
drugs as well as in the fight against cancer.
General synthetic concept: Our new synthetic strategy
(Scheme 3) is based on the consideration that the intrinsic
propensity of the natural product to undergo spiro-lactoni-
zation might be exploited in a beneficial manner. Thus, we
The outstanding biological properties of mumbaistatin
have stimulated extensive efforts towards the total synthesis
of this natural product and its structural analogues. First
studies in the groups of Schmalz[7] and Krohn[8] led to the
preparation of the tri-ortho-substituted benzophenones 2
and 3 (Scheme 2) following different strategies. While the
anthraquinone 2 was synthesized through nucleophilic addi-
Scheme 3. Retrosynthetic analysis of cyclo-mumbaistatin (1b).
Scheme 2. Mumbaistatin analogues synthesized in previous studies.
tion of an aryllithium species to a 1-formyl anthracene de-
rivative and subsequent oxidation of the resulting benzhy-
drol,[7] the benzophenone scaffold of 3 was constructed in a
base-catalyzed aldol-type cyclization, followed by bromine-
mediated photooxidation of the resulting diarylmethane in-
termediate.[8] In a second-generation approach, we later suc-
ceeded in the synthesis of lactone rac-4, which for the first
time displayed the complete carbon skeleton of mumbaista-
tin.[9] Key steps of the elaborated sequence were a Pd-cata-
lyzed Stille cross-coupling to generate a tetra-ortho-substi-
tuted diarylmethane intermediate and a titanium-mediated
alkynylation of an aldehyde to introduce the upper (alkyl)
side chain. Some semi-synthetic mumbaistatin analogues
were also prepared by Khosla and co-workers starting from
a fermentation-derived anthraquinone precursor.[10] In the
course of subsequent structure activity relationships studies,
the simplified derivative AD4-015 (5) was identified as a
fairly potent G6P-T1 inhibitor (IC50 =2.5 mm).
envisioned a spiro compound of type A to be a suitable pre-
target structure from which the natural product would arise
upon benzylic oxidation (e.g., via radical bromination) and
global deprotection. Conceiving the pivotal spiroketal-lac-
tone scaffold of A as a masked tetra-ortho-substituted ben-
zophenone subunit, its construction by means of an anionic
homo-Fries rearrangement of a diester of type B seemed
feasible.[11] The required dimethoxyanthracene B in turn
could be derived from a “Southern” anthraquinone carbox-
ylic acid D, and a “Northern” building block C through
simple esterification.
To examine the general feasibility of the synthetic con-
cept, our first studies (presented in this work) focused on
the most challenging task, that is, the construction of the spi-
rolactone core motif, as represented by the model system
rac-6 (see below). Subsequently, we intended to probe the
developed protocols also in the synthesis of deoxy-cyclo-
Despite all efforts, none of the synthetic strategies devel-
oped so far allowed to construct the tetra-ortho-substituted
benzophenone core of mumbaistatin (or the spiroketal lac-
tone system, respectively) with the proper functionalization
pattern. We herein disclose the results of a study, which (fol-
lowing a new strategy) has led to the development of an ef-
ficient total synthetic access to close structural analogs of
cyclo-mumbaistatin (1b).
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Mumbaistatin Analogues
FULL PAPER
mumbaistatin (rac-7). Noteworthy, these two model com-
pounds by themselves constitute potentially active agents
and would be of value to gain insights into structure–activity
relationships (SAR) of mumbaistatin-related compounds.
dehyde intermediate furnished the carboxylic acid 11. This
way, the anthraquinone building block 11 was obtained in
six steps from naphthoquinone 8 with a satisfying overall
yield of 31%.
As model “Northern” building blocks the haloarenes 12[27]
and 13[28] were both prepared from 3-methoxy-benzylic alco-
hol through ortho-lithiation/halogenation. The reaction of
the alcohols 12 and 13 with the acid 11 under Mitsunobu
conditions then afforded the esters 14 and 15, respectively,
in good yield.[29]
Evaluation of the strategy in the model series: According to
our synthetic plan, a first goal was the preparation of the an-
thraquinone 11 as a simplified “Southern” building block of
type D lacking one oxy-substituent (Scheme 4). As an ap-
propriate precursor of 11 we considered the anthraquinone
9 which we had previously synthesized from naphthoqui-
none 8 exploiting a Diels–Alder cycloaddition to assemble
the carbon skeleton.[9,12]
At this point, we asked ourselves whether 14 or 15 could
possibly be used as substrates for the planned anionic
homo-Fries rearrangement (in order to save additional pro-
tection–deprotection operations). The question was whether
the halogen–metal exchange could be performed in the pres-
ence of the unprotected anthraquinone substructure.[30,31]
For that reason, bromide 14 was treated with tBuLi
(2 equiv) at À1008C in the expectation that the resulting ar-
yllithium species would undergo the envisioned rearrange-
ment. Much to our delight, the benzophenone rac-16 could
indeed be isolated (as a mixture of two atropisomers) after
protic workup. However, this encouraging initial result was
impaired by a poor yield (25%) and low reproducibility. At-
tempts to optimize the reaction by varying the amount of
tBuLi or to substitute it by nBuLi or mesityllithium (THF,
À788C)[34] were not successful. Hoping that a more rapid
iodine/lithium exchange[32] could possibly suppress side reac-
tions, the aryl iodide 15 was subjected to the same condi-
tions as before (2.0 equiv of tBuLi, THF, À1008C). Howev-
er, only a complex mixture was formed. Attempts to gener-
ate an aryl–magnesium (instead of an aryl–lithium) inter-
mediate by reacting 15 either with magnesium or with neo-
pentylmagnesium bromide[34] also failed. In the latter case,
only nucleophilic addition of the Grignard reagent to an an-
thraquinone carbonyl group was observed.
Scheme 4. Preparation of the diesters 14 and 15 and initial studies on the
anionic homo-Fries rearrangement. a) NBS (1.95 equiv), BP (20 mol%),
CCl4, reflux, hn (vis), 24 h, 93%; b) NMO, RT, 16 h, 66%; c) NaClO2,
NaH2PO4, 2-methylbut-2-ene, THF/H2O, 0 8C to RT, 21 h, 83%; d) 12,
DIAD, PPh3, THF, 08C, then RT, 6 h, 64% of 14; e) 13, DIAD, PPh3,
THF, 08C, then RT, 2 h, 88% of 15; f) 14, tBuLi (2.0 equiv), THF, À100
to À788C, 45 min, 25%.
We therefore returned to our original plan (Scheme 3)
and protected the reactive anthraquinone moiety as a 9,10-
dimethoxyanthracene derivative. The reductive methylation
of 15 with Na2S2O4/KOH/MeI (in THF/water) was achieved
under phase-transfer catalysis to furnish the rearrangement
precursor 17 in good yield (Scheme 5).[35]
Initial attempts to directly convert the anthraquinone 9
into the monoester 11 failed. No conversion could be de-
tected on treatment of 9 with various common reagents for
To induce the key rearrangement of 17 through halogen–
metal exchange several reagents were tested (tBuLi, nBuLi,
MeLi, PhLi and iPrMgCl). Among those, Knochelꢂs “Turbo
Grignard” solution gave the best results.[36] Thus, when the
anthracene 17 was treated slowly with a commercial solution
of iPrMgCl·LiCl in THF at À158C followed by heating the
mixture to 508C the spirolactone rac-21 was isolated in 63%
yield after workup with aqueous NH4Cl. We suppose that
the deprotonated hemiacetal rac-20 (resulting as an inter-
mediate from the homo-Fries rearrangement of 18) under-
goes spontaneous lactonization to give rac-21 as indicated in
Scheme 5. It should be emphasized that heating the dark re-
action mixture (508C, 2 h) proved to be essential to initiate
the rearrangement. When the reaction mixture was stirred
at ambient temperature for one day, only proto-dehalogen-
ated starting material was recovered after aqueous workup.
benzylic
(Bu4N)MnO4/pyridine,[14] Na2Cr2O7·2H2O,[15] CrO3/H5IO6,[16]
N-hydroxyphthalimide/Co
(OAc)2/O2,[17] RuCl3·H2O/NaOCl/
oxidation,
such
as
KMnO4/pyridine,[13]
AHCTUNGTRENNUNG
Bu4NBr,[18] NaIO4/LiBr/H2SO4,[19] FeCl3·6H2O/tBuOOH.[20]
We therefore had to perform the oxidation of the methyl
substituent stepwise. After light-induced radical bromination
of 9 using NBS in the presence of dibenzoyl peroxide
(BP),[9,10] the resulting benzylic bromide 10 was converted
into the corresponding aldehyde by reaction with N-methyl-
morpholine-N-oxide (NMO) in DMSO.[21] Other oxidation
reagents such as NaHCO3/DMSO,[22] IBX,[23] NaIO4/DMF[24]
or trimethylamine-N-oxide[25] turned out to be less effective.
Finally, Pinnick oxidation[26] of the air- and light-sensitive al-
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H.-G. Schmalz et al.
Scheme 6. Benzylic oxidation and mono-demethylation of rac-22. a) i)
NBS, BP (10 mol%), benzene, hn (vis), RT, 16 h, ii) KOH/H2O, RT, 12 h,
iii) HCl/H2O, 35%; b) BBr3 (10 equiv), CH2Cl2, À788C, 1.5 h, 81%.
for aryl-methyl ether cleavage became apparent. For exam-
ple, treatment of rac-22 with BBr3 at À788C[39] furnished the
mono-demethylated product rac-24 (Scheme 6). The one
methoxy group remained unaffected by BBr3 even after 1 d
at ambient temperature. Also, treatment of rac-22 with
BF3·Me2S[40] only afforded rac-24, while a significant degree
of decomposition was observed with other protocols (AlI3/
Bu4NI in refluxing benzene;[41] LiSEt in DMF under micro-
wave heating[42]). The inertness of the methoxy group at C-7’
towards demethylation becomes plausible by regarding the
Scheme 5. Synthesis of the spirolactone rac-22 through anionic homo-
Fries rearrangement of the anthracene 17 and subsequent oxidation. a)
Na2S2O4, KOH, MeI, Bu4NBr, THF/H2O, 0 8C to RT, over night, 78%; b)
iPrMgCl·LiCl 1:1 (1.05 equiv), THF, À15 to RT, then 508C, 2 h, 63%; c)
AgO, HNO3, 1,4-dioxane, RT, 20 min, 86%.
X-ray structure of rac-22 (Figure 1).[56] The anthra
ACHTUNGTRENNUNG[2,1-
This indicates that the iodine–magnesium exchange pro-
ceeds smoothly at lower temperatures, but the reaction of
the arylmagnesium intermediate 18 (i.e., the key rearrange-
ment) takes place only at elevated temperature. After treat-
ment of the trimethoxyanthracene rac-21 with silver(II)
c]furan-3,6,11-trione “paddle” seems to effectively shield the
methoxy oxygen towards coordination of a Lewis acid, thus
preventing the required activation of the O-aryl fragment as
a leaving group.
Using rac-22 as a model, we have demonstrated the gener-
al possibility to achieve benzylic oxidation. Also, we learned
that an easier removable phenol protecting group (such as
MOM) will be required to allow a late deprotection of the
[37]
oxide in dioxane/4n HNO3 the anthraquinone derivative
rac-22 was obtained in high yield. This compound represents
the first synthetic mumbaistatin analog possessing the spiro-
lactone substructure of the natural product.
For the completion of the synthesis of pseudo acid rac-6
we next intended to introduce the benzylic hydroxyl group
by means of a radical bromination-substitution sequence.[38]
Hence, spiro compound rac-22 was reacted with NBS
(2.2 equiv) and benzyol peroxide (10 mol%) under irradia-
tion with visible light (Scheme 6). After hydrolysis of the
crude product with aqueous KOH the “spiro-anhydride”
rac-23 was isolated in moderate yield, probably emerging
from a dibrominated intermediate. Since the introduction of
the hydroxy group (preparation of rac-6) could also not be
achieved with 1 equiv of NBS or with cerium ammonium ni-
trate (CAN) as an oxidant, we decided to focus our efforts
on the synthesis of the deoxy-cyclo-mumbaistatin derivative
rac-7. In this context, we used anthraquinone rac-22 as a
model system to probe the deprotection of the phenol func-
tions. During these investigations a remarkable resistance of
the “Northern” methoxy group towards common reagents
Figure 1. Structure of spirolactone rac-22 in the crystalline state (C black,
H white, O red).[56]
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Mumbaistatin Analogues
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“Northern” molecule part. With this knowledge, we next
turned towards the application of the developed strategy in
the preparation of more complex compounds related to the
deoxy-cyclo-mumbaistatin derivative rac-7.
Synthesis of a deoxy-cyclo-mumbaistatin analogue: As a
fully functionalized “Southern” building block we selected
the anthraquinone 34, exhibiting a second methoxy group at
C-8. For its synthesis we intended to follow the established
Diels–Alder cycloaddition pathway shown in Scheme 7. For
this purpose, a short access to chlorojuglone 30 was elabo-
rated. In the first step the aerobic oxidation of 1,5-dihydroxy-
naphthalene (28) using substoichiometric amounts of freshly
recrystallized copper(I) chloride to furnish juglone (29) was
achieved in yields according to those reported in the litera-
ture.[43] Dichlorination of 29
Figure 2. Structure of chlorojuglone 30 (top) and the anthraquinone car-
boxylic acid ester 31 (bottom) in the crystalline state (C black, H white,
O red, Cl green).[56]
and subsequent thermal elimi-
nation of HCl afforded chloro-
juglone 30[44] and its regioiso-
mer as a mixture, the separa-
tion of which could not be ac-
complished by column chroma-
tography.
Fortunately,
the
desired naphthoquinone 30
could be obtained in pure form
by recrystallization of the crude
material from chloroform at
room temperature. X-ray analy-
sis[56] of suitable
crystals
(Figure 2) confirmed the consti-
tution of 30 as the regioisomer
needed in the subsequent cyclo-
addition. The required electron-
rich diene 27[9] was obtained as
a moisture-sensitive mixture of
E- and Z-isomers after C-acety-
lation of tert-butyl acetoacetate
(25) with AcCl in the presence
of MgCl2 and pyridine followed
Scheme 7. Synthesis of the anthraquinone dicarboxylic acid monoester 34 through a Diels–Alder cycloaddition.
a) AcCl, pyridine, MgCl2, CH2Cl2, 08C to RT, 2 h, 98%; b) BSA, 08C to RT, 2.5 d, 84%; c) CuCl, air, CH3CN,
RT, 9 h, 52%; d) Cl2, AcOH, 30 min, RT; then EtOH, reflux, 30 min, 56%; e) toluene, 1108C, 40 h; then THF/
H2O, RT, SiO2; then K2CO3, MeOH, 58%; f) K2CO3, MeI, acetone, reflux, 20 h, 97%; g) NBS (2.2 equiv), BP
(20 mol%), CCl4, reflux, 48 h, 72%; h) NMO, DMSO, RT, 20 h, 61%; i) NaClO2, NaH2PO4, 2-methylbut-2-
ene, THF/H2O, 0 8C to RT, 17 h, 74%.
by treatment of the resulting di-b-keto ester 26 with N,O-
bis(trimethylsilyl)acetamide (BSA).[12c–e,i] The key cycloaddi-
tion between the dienophile 30 and 27 was accomplished by
heating in toluene to 1108C for 40 h. The crude cycloaddi-
tion product was stirred with wet THF followed by treat-
ment of the (chromatographed) mixture with K2CO3 in
methanol to complete aromatization and O-desilylation.
This way, the pure anthraquinone 31 was isolated in good
yield. Its constitution was assigned by 2D NMR spectrosco-
py and additionally confirmed by X-ray crystallography of a
sample recrystallized from chloroform (Figure 2).[56]
After protection of both hydroxyl groups present in 31
(MeI, K2CO3) the resulting di-O-methylated compound 32
was subjected to benzylic bromination. The mono-bromide
33 was finally converted into the acid 34 under the proven
conditions (compare Scheme 4) by treatment with NMO
and subsequent oxidation of the aldehyde intermediate with
sodium chlorite (Scheme 7).
Noteworthy is the fact that the conversion of 32 into the
mono-bromide 33 required special optimization. Initially, we
conducted the radical bromination of 32 under the same
conditions as used before for the preparation of the anthra-
quinone 10 (1.95 equiv of NBS, 20 mol% of benzoylperox-
ide, reflux, irradiation with light), however, an inseparable
1:1.3 mixture of the mono- and the dibrominated com-
pounds 33 and 35 was obtained (Scheme 8). While the di-
bromide 35 could be separated from the aldehyde 36 after
the subsequent step (reaction with NMO), all our efforts to
transform 35 into 36 (e.g., by hydrolysis in the presence of
[45]
AgNO3 or by reaction with DMSO[46]) failed. This forced
us to optimize the conditions for the bromination of 32. Re-
duction of the amounts of NBS to one equivalent or even
less still resulted in the formation of a mixture of 33 and 35,
alongside with starting material. Finally, we found that the
pure mono-brominated compound 33 is exclusively formed
in good yield when the radical bromination is performed in
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H.-G. Schmalz et al.
Scheme 8. Photo-induced benzylic dibromination of anthraquinone 32. a)
NBS (1.95 equiv), BP (20 mol%), CCl4, reflux, hn (vis), 24 h; b) NMO,
DMSO, RT, 20 h, 30% of 35 and 34% of 36 (yields over 2 steps).
the dark (CCl4, reflux), even if an excess of NBS is used
(Scheme 7).
To rationalize the different behavior of substrates 9 and
32 under the light-induced bromination conditions we had
to consider the different reactivity of the primarily formed
mono-bromides. It is known that 1-alkyl-9,10-anthraqui-
nones can undergo a photo-induced H atom transfer accord-
ing to a Norrish type II process (Scheme 9).[47,48] The formed
species of type 37a (diradical) or 37b (photoenol) may then
react with NBS (or bromine) to give a dibromide of type 35.
An explanation why only the dimethoxyanthraquinone 33
(but not the monomethoxy analogue 10) further reacts
under the photochemical bromination conditions can be
gained by comparison of the UV/Vis absorption spectra of
the two substrates (Figure 3). Obviously, the second me-
thoxy group present in 33 gives rise to an additional band of
absorption between 360 and 430 nm. Thus, in contrast to 10
compound 33 can absorb visible light and is prone to a sub-
sequent Norrish type II-initiated bromination according to
Scheme 9.
Scheme 9. Formation of dibromide 35 in the presence of light.
clude the synthesis of a deoxy-cyclo-mumbaistatin deriva-
tive. As a promising “Northern” building block we chose
the benzylic alcohol rac-43 (Scheme 10) containing an easier
removable methoxymethyl (MOM) protecting group for the
phenolic OH to facilitate the final deprotection.
Scheme 10. Synthesis of the “Northern” deoxy building block rac-43. a)
NaH, TIPSCl, THF, 08C to RT, 30 min, 53%; b) DMSO, (COCl)2, NEt3,
CH2Cl2, À788C to RT, 90 min, 81%; c) 41
+
nBuLi, THF, À788C,
15 min, CeCl3, À788C, 45 min, then addn. of 40, À788C to RT, 12 h,
83%; d) nBuLi, toluene, À508C to RT, 4 h, then I2, À508C to RT, 12 h,
79%.
The carbon skeleton of rac-43 was assembled by addition
of an arylmetal nucleophile derived from bromide 41 to al-
deyde 40. The latter was prepared by mono-TIPS protection
of 1,6-hexandiol (39)[49,50] followed by Swern oxidation.[51]
Metalation of 41 was performed with nBuLi and the lithiat-
ed intermediate was slowly added to a solution of CeCl3 in
THF.[52,53] The resulting solution of the less-basic organoceri-
um reagent was then reacted with the aldehyde 40 to afford
the benzylic alcohol rac-42 in good yield. ortho-Lithiation of
rac-42 with nBuLi followed by addition of an ethereal solu-
tion of iodine finally furnished the iodide building block rac-
43.
Figure 3. UV/Vis spectra of the monobrominated anthraquinones 10
(c) and 33 (a), both recorded at 258C using DMSO as solvent.
Having succeeded in the optimization of the bromination
and the preparation of the anthraquinone carboxylic acid 34
on a gram scale (Scheme 7), the remaining task was to con-
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Mumbaistatin Analogues
FULL PAPER
As shown in Scheme 11, the coupling of the “Northern”
and the “Southern” fragments 34 and rac-43 was then ach-
ieved satisfactorily again under Mitsunobu conditions. After
conversion of the anthraquinone rac-44 into the rearrange-
ment precursor rac-45[54] by reductive methylation the
anionic homo-Fries rearrangement was probed applying the
elaborated reaction conditions. In fact, when iodide rac-45
was reacted with a slight excess of iPrMgCl·LiCl 1:1 the ex-
pected spirolactone rac-46 was formed in even higher yield
(76%) as compared to the simpler analogue rac-15. The
transformation proceeded with a pronounced diastereoselec-
tivity (d.r. 8:1 to 13:1). The relative configuration of the
major diastereomer (rac-46) was assigned by NOESY NMR
spectroscopy (NOE between the protons of the OMe group
at C-11 and H-3’). Global oxidation of rac-46 with Jones re-
agent[55] at 08C directly afforded the cyclo-mumbaiststain
derivative rac-47 in 59% yield under liberation of the an-
thraquinone substructure and installation of the carboxyl
group at the end of the side chain.
Scheme 12. Attempted hydroxylation of rac-47. a) NBS (2.7 equiv), BP
(10 mol%), benzene, hn, RT, 30 h, then KOH, THF/H2O, 1 h.
Conclusion
We have developed a new and efficient strategy for the total
synthesis of compounds containing the complete carbon
skeleton and the functional core motif (spiroketal-lactone)
of the naturally occurring G6P-T1 inhibitor mumbaistatin in
its cyclic form (1b). The study disclosed here has culminated
in the preparation of the deoxydealkyl derivative rac-24 and
the more elaborated cyclo-mumbaistatin analogue rac-47.
Key elements of the strategy include: i) The generation of
the anthraquinone part by Diels–Alder cycloaddition, ii) the
pre-attachment of a “Northern” building block to the
“Southern” anthraquinone fragment through Mitsunobu
esterification, and iii) the construction of the tetra-ortho-
substituted benzophenone substructure by means of an
anionic homo-Fries rearrangement which leads directly to
the spiroketal-lactone moiety in a domino-type process. We
are confident that the strategy developed and the experience
collected in the course of this study form a promising basis
for the synthesis of mumbaistatin and further relevant ana-
logs in the future.
Acknowledgements
This work was supported by Sanofi-Aventis. We would like to thank Dr.
Lothar Schwink from Sanofi-Aventis for valuable and fruitful discussions.
Moreover, we are grateful to Dr. David Sucunza and Dr. Daniel Demb-
kowski for initial experiments. We also thank Chemetall for generous
gifts of organolithium and Grignard reagents.
Scheme 11. Coupling of the “Northern” and the “Southern” building
block and final steps to complete the cyclo-mumbaistatin derivative rac-
47. a) PPh3, DIAD, THF, 08C, then RT, 2.5 h, 73%; b) Na2S2O4, KOH,
MeI, Bu4NBr, THF/H2O, 0 8C to RT, 15 h, 53%; c) iPrMgCl·LiCl 1:1,
THF, À158C to 1.5 h, then 508C, 2 h, 76%, d.r. 13:1; d) Jones reagent,
acetone, 08C, 30 min, 59%.
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products (Scheme 12).
Chem. Eur. J. 2011, 17, 2633 – 2641
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2640
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Chem. Eur. J. 2011, 17, 2633 – 2641

Mumbaistatin Analogues
FULL PAPER
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Received: November 3, 2010
Published online: January 27, 2011
Chem. Eur. J. 2011, 17, 2633 – 2641
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2641