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-
Chem. Eur. J. 2011, 17, 2633 – 2641
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