A convergent total synthesis of the telomerase inhibitor (±)-γ-rubromycin

Article abstract of DOI:10.1002/anie.201400315

The total synthesis of the human telomerase inhibitor γ-rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid-catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well-balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl-substituted aldehyde, an α-methoxyallyl-γ-silyl-substituted phosphonate as the central C₃ building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late-stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ-rubromycin. 3 building blocks + 3 acids→natural product: After the assembly of the crucial precursor from three highly functionalized building blocks, the pivotal spiroketalization was achieved with trifluoromethanesulfonic acid, the isocoumarin formation with fluoroboric acid, and the O-demethylation with the Lewis acid boron tribromide. (±)-γ-Rubromycin was thus synthesized in 18 steps with an overall yield of 3.8 % from commercially available precursors.

Full text of DOI:10.1002/anie.201400315

Angewandte
Chemie
DOI: 10.1002/anie.201400315
Natural Product Synthesis
A Convergent Total Synthesis of the Telomerase Inhibitor
(ꢀ)-g-Rubromycin**
Michael Wilsdorf and Hans-Ulrich Reissig*
Dedicated to Professor Axel Zeeck on the occasion of his 75th birthday
Abstract: The total synthesis of the human telomerase
inhibitor g-rubromycin in its racemic form was accomplished
in 3.8% overall yield. The key feature of this synthesis is an
efficient acid-catalyzed spiroketalization for the construction
of the spiroketal core. The required electronically well-bal-
anced spiroketal precursor was obtained by the convergent
assembly of a naphthyl-substituted aldehyde, an a-methoxy-
allyl-g-silyl-substituted phosphonate as the central C3 building
block, and a highly functionalized aryl Grignard reagent.
Another key feature is the late-stage construction of the
isocoumarin moiety and a simultaneous protodesilylation
furnishing the known methyl aryl ether protected precursor
of g-rubromycin.
T
he history of the rubromycins started with the isolation of
b-rubromycin (1) from the mycelia of the actinomycetes
strain Streptomyces collinus by Brockmann and Renneberg in
the 1950s.[1] Shortly after, the structure of the isolated natural
product was elucidated by chemical derivatizations, degrada-
tion experiments, and NMR spectroscopic studies; a first
proposal suggested an ortho-quinoid structure.[2] However, in
2000 Zeeck and co-workers could unequivocally confirm
a para-quinoid structure of the naphthoquinone moiety with
the aid of modern NMR methods and 13C-labeling experi-
ments, thus correcting the originally proposed formula.[3] In
addition to b-rubromycin, other representatives of this
interesting class of natural products have been described
over the years, including the structurally closely related
g-rubromycin (2), purpuromycin (3), and heliquinomycin (4,
Figure 1).[4] Biological studies reveal, that—in addition to
their role as effective antibiotics and HIV-1-RT inhibi-
tors[1,3]—the rubromycins display potent activity against
human telomerase, and their high biological activity signifi-
cantly depends on the presence of the [5,6]-bisbenzannulated
spiroketal moiety as a central structural motif.[5,6]
Figure 1. Prominent members of the rubromycin family of natural
products. * The absolute configuration of 3 is not known.
and only two total syntheses of (ꢀ)-g-rubromycin by Kita
(2007)[9] and Pettus (2011)[10] and the total synthesis of (ꢀ)-d-
rubromycin by Li (2013)[11] are known. Notably, none of these
total syntheses relies on an obvious acid-mediated ketaliza-
tion[12] for the generation of the spiroketal core. The failure of
this strategy can be attributed to the electronic properties of
the spiroketal precursors used, which has been experimentally
confirmed by Kozlowski[13] and our group.[14] Thus, the acid-
catalyzed spiroketalization is almost completely inhibited in
the case of isocoumarin-substituted substrates due to the
decreased nucleophilicity of the phenolic oxygen atom.[4,15]
The replacement of the isocoumarin fragment by a synthetic
equivalent allowed Brimble (2009)[16] and Li (2012)[17] to
achieve acid-induced spiroketalizations which led to formal
total syntheses of (ꢀ)-g-rubromycin.[18] We here report our
route to this natural product, which afforded the target
molecule in larger quantities by a convergent approach and
highly efficient reaction steps.
From the outset, our concept envisaged an acid-catalyzed
spiroketalization as a key step, but it should take place at
a late stage of the synthetic sequence. Additionally, according
to Brimbleꢀs strategy the lactonization for completing the
isocoumarin fragment should occur after the spiroketaliza-
tion. Owing to our experience in previous model studies[14,19]
we were confident that rubromycin could be derived from
spiroketal precursors such as 5 (Scheme 1). Compounds of
this type are attractive due to the presence of all functional
groups required for the construction of the isocoumarin
fragment and the naphthoquinone oxidation level. Target
Since the discovery of the rubromycins various synthetic
approaches towards [5,6]-bisbenzannulated spiroketals have
been developed.[4,7] To date only the total synthesis of the
racemic aglycone of heliquinomycin by Danishefsky (2001)[8]
[*] Dr. M. Wilsdorf, Prof. Dr. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
E-mail: hans.reissig@chemie.fu-berlin.de
[**] Support of this work by Bayer HealthCare AG is most gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400315.
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To escape from this dead end we directed our attention to
the a-methoxyallyl-substituted phosphonate 13.[22] The metal-
ation of 13 generates an ambident allyl anion which upon
addition to aryl aldehydes reacts in a Horner–Wittig reaction
to afford 2-methoxybuta-1,3-dienes. They should be conver-
tible into the corresponding enones by acidic hydrolysis of
their enol ether moiety. In our case, we solved the expected
problem of a- versus g-addition by silylation of the g-
position[23] with chloro(4-methoxyphenyl)dimethylsilane[24]
to yield phosphonate 14. The 4-methoxyphenyl-substituted
silyl group was chosen since a smoother removal of this group
by an acid-induced protodesilylation was expected at a later
stage. The metalation of 14 with potassium bis(trimethylsilyl)-
amide (KHMDS) and the subsequent addition to naphthyl
aldehyde 15—obtained by oxidation of alcohol 10—afforded
(Z,E)-2-methoxybuta-1,3-diene 16 in good yield. Hydrolysis
of the enol ether moiety furnishing the b-silyl-substituted
enone 17 was achieved under acidic conditions using tri-
chloroacetic acid in wet dichloromethane (Scheme 3). As
illustrated by the sequence 15!17, the reagent 14 provides an
interesting alternative to methoxyallene as a C3 building
block and should also be valuable for other synthetic
endeavors.
Scheme 1. Retrosynthetic analysis of (ꢀ)-g-rubromycin based on an
acid-catalyzed spiroketalization of precursor 5.
compound 5 was traced back to the pentamethoxynaphthyl-
substituted enone 6, which serves as acceptor for a Normant
cuprate, generated from aryl iodide 7. Enone 6 should be
generated by reaction of bromide 8 with lithiated methoxy-
allene (9)[20] (Scheme 1).
Our synthesis started with the preparation of pentameth-
oxynaphthyl-substituted alcohol 10 which was accessible from
2,4,5-trimethoxybenzaldehyde over 10 steps on a multigram
scale following a procedure described by Kozlowski.[21]
Unfortunately, we were not able to convert alcohol 10 into
a compound with a suitable leaving group such as bromide 8;
due to the extraordinarily electron-rich naphthalene ring the
electrophile to be generated is apparently too labile
(Scheme 2). As a consequence, the planned strategy could
not be applied to the synthesis of enone 6, although this
approach was successful for simpler benzyl-substituted model
substrates (e.g. conversion 11!12) employing lithiated
methoxyallene 9 as an acyl anion equivalent (Scheme 2).
Scheme 3. Reagents and conditions: a) nBuLi, ꢁ788C, 10 min, then
chloro(4-methoxyphenyl)dimethylsilane, ꢁ788C!RT, 64%; b) IBX,
DMF, RT, 1 h, 85%; c) KHMDS, THF, ꢁ408C, 15 min, then aldehyde
15, ꢁ788C!RT, 82%; d) TCA, CH2Cl2/H2O (25:1), RT, 45 min, 94%.
IBX=2-iodoxybenzoic acid, KHMDS=potassium bis(trimethylsilyl)-
amide, TCA=trichloroacetic acid.
Enone 17 represents an equivalent of the required
building block 6 (Scheme 1), albeit being functionalized
with a sterically demanding silyl group whose compatibility
with the next steps was uncertain at this point. The second
component, the highly substituted aryl iodide 7, was readily
available with standard reactions: starting from vanillin, the
aldehyde 18[25] was prepared in four known steps and
subjected as methoxymethyl ether 19 to the carbanion of
phosphonate 20[26] efficiently leading to compound
7
(Scheme 4).
Grignard reagent 21 was generated following a procedure
described by Knochel et al.[27] by reaction of 7 with iPrMgBr
at ꢁ408C in a mixture of Et2O/THF (4:1).[28] The quantitative
halogen–metal exchange proceeded rapidly (< 5 min). The
Scheme 2. Attempts to synthesize enone 6 and model reaction 11!
12. Reagents and conditions: a) NBS, Ph3P, CH2Cl2, 08C, 1 h, 98%;
b) H2C=C=C(OMe)Li, ꢁ78!08C, then H2SO4 (5%, aq.), 86%.
NBS=N-bromosuccinimide.
2
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Scheme 6. Reagents and conditions: a) 0.2 equiv TfOH, MeCN,
ꢁ258C!RT, 90 min, 80%, d.r.>97:3. TfOH=trifluoromethanesulfonic
acid.
Scheme 4. Reagents and conditions: a) MOMCl, iPr2NEt, DMF, RT,
1 h, 83%; b) 1.2 equiv 20, LiHMDS, ꢁ788C, 5 min; then addition of
19, ꢁ788C!RT, 90%. MOMCl=chloromethyl methyl ether,
LiHMDS=lithium bis(trimethylsilyl)amide.
alents TfOH, MeCN, ꢁ258C!RT). The latter was an
important prerequisite for the success of this transformation.
Remarkably the conversion of 23 to spiroketal 24 occurred
with high diastereoselectivity (d.r. > 97:3) and could reliably
be conducted even on a 1.0 g scale. Moreover, this is the first
example in which the spiroketalization of a rubromycin
derivative was successfully achieved at the naphthoquinone
oxidation level (Scheme 6).
The final lactonization to the isocoumarin was carried out
under acidic reaction conditions:[32] the treatment of 24 with
fluoroboric acid etherate (ca. 10 equivalents of HBF4·Et2O) in
CH2Cl2 at 508C resulted in immediate hydrolysis of the TBS
enol ether, followed by formation of the isocoumarin. This
process was accompanied by complete dearylation of the silyl
substituent (Scheme 7).[33] The treatment of the intermediate
fluorosilane 26 with peracids (e.g. with m-CPBA), however,
CuI-catalyzed 1,4-addition[29] of 21 to b-silylated enone 17
furnished the arylated product 22 after acidic hydrolysis of the
intermediate silyl enol ether in excellent yield. Remarkably,
the highly functionalized aryl iodide 7 proved to be fully
compatible with the reaction conditions for the halogen–
metal exchange. The generated Grignard reagent displays
sufficient stability which is probably due to the complexation
of the metal by the methoxymethyl ether group in ortho-
position. The subsequent oxidation of the pentamethoxy-
substituted naphthyl fragment of 22 with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone occurred regioselectively afford-
ing g-naphthoquinone 23. With this substrate, we have
prepared a spiroketal precursor that is stable towards
oxidation and, in contrast to the originally envisaged target
5, bears a silyl substituent in b-position (Scheme 5).
Scheme 5. Reagents and conditions: a) iPrMgBr, Et2O/THF (4:1),
ꢁ408C, 5 min; b) 1.4 equiv 21, 0.15 equiv CuI·2LiCl (0.20m in THF),
6.0 equiv TMSCl, Et2O/HMPA (10:1), ꢁ408C!RT, 30 min; then H2SO4
(5%, aq.), THF, RT, 20 min (85%, over 2 steps); c) DDQ, MeCN/H2O
(4:1), 08C, 20 min, 91%. HMPA=hexamethylphosphoric acid tri-
amide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Scheme 7. Lactonization and protodesilylation of compound 24 to
g-rubromycin precursor 25: Reagents and conditions: a) 10.0 equiv
HBF4·Et2O, CH2Cl2, 508C, 15 min; then 08C, MeOH/NEt3, 08C!RT,
15 min, 66%.
The synthesis should now be continued with the pivotal
spiroketalization of 23 to compound 24. In model studies we
had already discovered that catalytic amounts of trifluoro-
methanesulfonic acid in MeCN efficiently promote the
smooth spiroketalization of MOM-protected substrates.[30,31]
Ketone 23 was converted into highly functionalized spiroketal
24 in very good yield and with high chemo- and diastereo-
selectivity (Scheme 6). The cleavage of the MOM ether was
chemoselective while the potentially acid-labile TBS enol
ether remained untouched under these conditions (0.2 equiv-
did not lead to a Tamao–Fleming-type oxidation, but resulted
in the rapid protodesilylation to g-rubromycin precursor 25.
This unexpected behavior may be explained by the electron-
withdrawing effect of the isocoumarin fragment facilitating
the desilylation by formation of the stabilized enolate 27.[34]
The yield of the transformation of the spiroketal 24 to g-
rubromycin precursor 25 could be significantly increased by
employing a one-pot procedure: after acid-induced dearyl-
ation, isolation of compound 26 was omitted and the mixture
was worked-up under basic conditions (MeOH/Et3N) result-
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chromatography the desired spiroketal 25 was obtained as
yellow solid in 66% overall yield and with high purity.
The synthesis of (ꢀ)-g-rubromycin (2) was completed by
selective O-demethylation of the methylaryl ether moieties of
25 by treatment with an excess of boron tribromide. Hence,
the natural product was obtained in several experiments in
40–50% yield (purity approximately 90%)[35] in its racemic
1
form as an intensively red solid (Scheme 8). The H NMR
spectroscopic data of (ꢀ)-(2) match perfectly with the data
published by Kita,[9] Pettus,[10] and Zeeck.[3] In addition, the
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Scheme 8. Demethylation of precursor 25 to (ꢀ)-g-rubromycin (2).
Reagents and conditions: a) 6.0 equiv BBr3, CH2Cl2, ꢁ78!08C,
90 min, 40–50%.
[11] W. Wang, J. Xue, T. Tian, J. Zhang, L. Wei, J. Shao, Z. Xie, Y. Li,
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[15] So far, only two examples of an acid-catalyzed spiroketalization
with a complete isocoumarin fragment are known. In our studies
towards the total synthesis of rubromycins the synthesis of
dimethylated (ꢀ)-3-hydroxy-b-rubromycin could only be ach-
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With this route to (ꢀ)-g-rubromycin (2) we have de-
scribed a new total synthesis of this natural product. The
synthesis is convergent and very efficient in its single steps
and makes 2 accessible in 18 steps (longest linear sequence)
with an overall yield of 3.8%. The key steps of this synthesis
are: the chemoselective 1,4-addition of highly functionalized
Grignard reagent 21, the efficient ketalization of intermediate
23 to spiroketal 24, and the subsequent acid-induced proto-
desilylation with concurrent isocoumarin formation to give g-
rubromycin precursor 25. The developed protocols are very
robust and also feasible on a larger scale and should be
suitable for the synthesis of analogues of rubromycin. In
addition, our strategy should allow an asymmetric synthesis of
g-rubromycin, since enantioselective 1,4-additions of func-
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known.[36]
[16] D. C. K. Rathwell, S.-H. Yang, K. Y. Tsang, M. A. Brimble,
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Received: January 11, 2014
Published online: && &&, &&&&
[18] Both formal total syntheses led to an intermediate of Kitaꢀs
synthesis of (ꢀ)-g-rubromycins, see Ref. [9].
Keywords: 1,4-addition · natural product synthesis ·
spiroketalization · telomerase inhibitors · g-rubromycin
.
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4
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naphthyl-substituted enone 17 a change to a mixture of Et2O/
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Communications
Natural Product Synthesis
3 building blocks + 3 acids!natural
product: After the assembly of the crucial
precursor from three highly functional-
ized building blocks, the pivotal spiro-
ketalization was achieved with trifluoro-
methanesulfonic acid, the isocoumarin
formation with fluoroboric acid, and the
O-demethylation with the Lewis acid
boron tribromide. (ꢀ)-g-Rubromycin was
thus synthesized in 18 steps with an
overall yield of 3.8% from commercially
available precursors.
M. Wilsdorf,
H.-U. Reissig*
&&&& — &&&&
A Convergent Total Synthesis of the
Telomerase Inhibitor (ꢀ)-g-Rubromycin
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