Rapid Access to Orthogonally Functionalized Naphthalenes: Application to the Total Synthesis of the Anticancer Agent Chartarin

Article abstract of DOI:10.1002/anie.201605071

We report the synthesis of orthogonally functionalized naphthalenes from simple, commercially available indanones in four steps. The developed method proceeds through a two-step process that features a thermally induced fragmentation of a cyclopropane indanone with simultaneous 1,2-chloride shift. Migration of the chloride substituent occurs in a regioselective manner to preferentially afford the para-chloronaphthol substitution pattern. The obtained naphthols are versatile building blocks that can be selectively modified and used for the efficient construction of biologically active molecules. This has enabled the total synthesis of the potent anticancer natural product chartarin through a highly convergent retrosynthetic bond disconnection.

Full text of DOI:10.1002/anie.201605071

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International Edition: DOI: 10.1002/anie.201605071
German Edition: DOI: 10.1002/ange.201605071
Total Synthesis
Hot Paper
Rapid Access to Orthogonally Functionalized Naphthalenes: Appli-
cation to the Total Synthesis of the Anticancer Agent Chartarin
Teresa A. Unzner, Adriana S. Grossmann, and Thomas Magauer*
Abstract: We report the synthesis of orthogonally functional-
ized naphthalenes from simple, commercially available inda-
nones in four steps. The developed method proceeds through
a two-step process that features a thermally induced fragmen-
tation of a cyclopropane indanone with simultaneous 1,2-
chloride shift. Migration of the chloride substituent occurs in
a regioselective manner to preferentially afford the para-
chloronaphthol substitution pattern. The obtained naphthols
are versatile building blocks that can be selectively modified
and used for the efficient construction of biologically active
molecules. This has enabled the total synthesis of the potent
anticancer natural product chartarin through a highly con-
vergent retrosynthetic bond disconnection.
S
ubstituted naphthalenes are common substructural units in
many biologically active molecules.[1,2] These include the
antiproliferative natural products chartarin (1), the aglycon of
chartreusin (2) and elsamicin,[3] justicidin A (3),[4] furomollu-
gin (4)[5] and drugs such as the dopamine antagonist
nafadotride (5)[6] and the nonsteroidal anti-inflammatory
drug naproxene (Figure 1a).[7] Traditional strategies for the
functionalization of this structural motif hinge on a stepwise
approach, that is the electrophilic aromatic substitution of
partially substituted naphthalene building blocks.[8] Owing to
the inherent low substrate selectivity and the complex
substitution pattern found in many natural products, stepwise
functionalization from readily available naphthalene precur-
sors is rather inefficient and thus inapplicable for polyfunc-
tionalized molecules. In recent years, methods based on
annelation,[2,9] cycloaddition[10] or ring expansion[11] reactions
have emerged as possible alternatives to access the bicyclic
aromatic system. However, these concepts often require the
use of expensive catalysts, involve relatively harsh reaction
conditions with inherent lack of functional group compati-
bility or are dependent on multistep sequences to access the
substrates. As a consequence, their application in the syn-
thesis of more complex molecules has remained rather
restricted.
Figure 1. a) Occurrence of naphthalene pharmacophores and b) syn-
thetic design.
limitations in a highly efficient manner (Figure 1b). After
considering various options, we identified indanone-cyclo-
propane A, readily accessible from a plethora of commer-
cially available, inexpensive indanones via oxidation and
cyclopropanation,[13] as the ideal substrate. The envisaged
thermally induced disrotatory 2p-electrocyclic ring opening[14]
of A was expected to be operationally simple on large-scale
without requiring additional promoters and requires tempo-
rary carbon-halogen bond cleavage. This step produces the
benzylallyl cation B. Regioselective attack by the chloride
anion at the benzylic position affords enone C that should
spontaneously isomerize to the orthogonally functionalized
naphthol D. By virtue of the orthogonal functionalization
present in D, rapid access to selectively modified products
would be possible.
As part of our ongoing program to develop practical and
scalable methods for the synthesis of polysubstituted, highly
functionalized arenes and heteroarenes,[12] we designed
a strategy that would allow us to address the current
[*] M. Sc. T. A. Unzner, M. Sc. A. S. Grossmann, Dr. T. Magauer
Department of Chemistry and Pharmacy, Ludwig-Maximilians-Uni-
versity Munich
Butenandtstrasse 5–13, 81377 Munich (Germany)
E-mail: thomas.magauer@lmu.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605071.
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At the outset, we were curious if conditions that were
previously developed in our group for the preparation of
methyl 3-hydroxybenzoates[12a] could be adapted to this novel
substrate class. After a short evaluation of possible reaction
conditions, we were pleased to see that the envisaged ring-
opening/1,2-migration could be successfully promoted for
a panel of compounds upon heating a 0.5m solution of our
substrates in sulfolane at 1908C (Table 1).
(compound 9) or the ortho-position (compound 12). Within
this context it is interesting to note that the observed lower
yield for 12 might be a result of the inherent substrate
preference for the para-position. While steric hindrance was
expected to affect the regioselectivity to a minor extent, a low
degree of delocalization that results in the predominance of
the highly stabilized mesomeric resonance structure B might
account for this observation.
Having established a robust platform for the synthesis of
several polyfunctionalized naphthalenes, we evaluated differ-
ent strategies to further increase the chloride attack at the
para-position. As illustrated in Scheme 1a, site-selective
Table 1: Evaluation of substituents in the electrocyclic ring opening to
give orthogonally functionalized naphthalenes.[a]
Scheme 1. a) Directed chlorine migration with concomitant carbon-
silicon cleavage and b) ring opening of bicyclo[3.1.0]hex-3-en-2-ones to
give chlorinated benzoates.
lithiation of the ring opening precursor 20 followed by
quenching with trimethylsilyl chloride[16] afforded 21, which,
upon exposure to the standard reaction conditions, was
smoothly opened to afford 6a in excellent yields (93%).
This transformation is viewed to proceed via 22, which
undergoes a spontaneous Brook rearrangement at elevated
temperatures.[17] The developed transformation was not only
limited to bicyclic ring systems, but could also be realized for
bicyclo[3.1.0]hex-3-en-2-one substrates as shown in Sche-
me 1b.
Having synthesized a library of polysubstituted naphtha-
lenes, we wanted to evaluate the selective modification of our
products by taking advantage of the orthogonal reactivity of
the hydroxy, chloro and ester substituents. We found out that
allyl ether 26 could be converted to tricycle 31 via an
unprecedented cascade cyclization (Scheme 2). This sequence
is initiated by thermal Claisen rearrangement of 26 to 27,
which then reacts in a subsequent Cope rearrangement to the
thermally unstable chloride 28. Elimination of hydrogen
[a] Yield of the isolated product.
At this temperature, the reaction went cleanly to full
conversion within less than 30 minutes in most cases.
Removal of sulfolane could be best accomplished by repeat-
edly washing an ethereal (diethyl ether; tert-butyl methyl
ether) product solution with water. We then investigated the
scope of this transformation by varying the substitution
pattern of our substrates and evaluated the observed regio-
selectivity.[15] For the majority of substrates, moderate to high
yields were obtained with a strong preference for the
formation of the para-chloronaphthol substitution pattern.
The choice of substituents along the ring junction enabled us
to fully direct the migration of the chloride to either the para-
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Scheme 2. One-pot functionalization of naphthyl allyl ether 26 through
sequential Claisen–Cope lactonization. Reagents and conditions:
a) allylBr, K2CO3, acetone, 89%, b) sulfolane, p-TsOH·H2O, 1908C,
15 min, 40%. p-Ts=para-toluenesulfonyl.
chloride generates a para-quinone methide structure 29 and
its tautomeric form 30, respectively. Termination of the
sequence could be facilitated by capture of residual water to
give a benzylic alcohol that undergoes an acid catalyzed (p-
TsOH·H2O) lactonization to afford 31. Since formation of 31
was also observed under anhydrous conditions, a competing
pathway that involves direct attack of the ester might be also
operative. The realization of this one-pot cyclization method
gives rapid access to annulated naphthalene lactones, an
important structural motif that is also part of dioscorealide B
(32).[18]
An additional remarkable feature of the developed ring-
expansion reaction is the possibility to design powerful
retrosynthetic bond disconnections for the construction of
highly substituted, sterically hindered biaryl compounds. The
first application of this strategy could be realized in the
convergent total synthesis of the potent anticancer natural
product chartarin (1).[3b] We began our synthesis with the
coupling of indanone 33, derived from commercially available
7-methoxy-1-indanone in one synthetic operation, to the
known para-quinone 34 (Scheme 3).[19] For the conjugate
addition of 33 to 34, we relied on a previously reported
protocol by Jørgensen.[20] Thus, in the presence of catalytic
amounts of hydroquinidine (20 mol%), immediate consump-
tion of the equimolar mixture of reactants occurred. Trapping
of the formed hydroquinone as its bis-pivalate ester prevented
oxidation to the quinone, and subsequent addition of
trifluoroacetic acid promoted decarboxylation of the tert-
butyl ester to afford the 2-arylated indanone 35 in good
overall yield on gram scale. Next, oxidation of 36 to the
indenone could be accomplished using Stahlꢀs palladium-
catalyzed aerobic dehydrogenation conditions.[21] In order to
overcome the low reactivity of the 2-substituted indenone in
the following cyclopropanation reaction, we had to modify
Scheme 3. Application of the ring opening protocol to the total syn-
thesis of chartarin (1). Reagents and conditions: a) 33 (1 equiv), 34
(1 equiv), HQ (20 mol%), CH2Cl2, À208C; NEt3, PivCl, 238C, 70%;
b) TFA, CH2Cl2, 238C, 89%; c) Pd(TFA)2 (20 mol%), 4,5-diazafluoren-
9-one (20 mol%), O2 (1 atm), DMSO, 808C, 67%, 24% 35;
d) KHMDS, MDCA, 18-crown-6 (10 mol%), THF, À78 to 238C, 75%;
e) K2CO3, MeOH, 238C, 74%; f) Tf2O, NEt3, CH2Cl2, À788C to 238C,
98%; g) sulfolane, 2008C, 15 min, 75%; h) Pd(dppf)Cl2, Me2Zn, 1,4-
dioxane, 958C, 83%; i) NaOH, CH2Cl2, MeOH, 238C; p-TsOH·H2O,
toluene, 808C, 98%; j) Pd(CH3CN)2Cl2 (5 mol%), SPhos (8 mol%),
KB(OMe)4, 1,4-dioxane, 908C, 87%; k) pyridine·HCl, 1958C, 69%.
dppf=1,1’-bis(diphenylphosphino)ferrocene, HQ=hydroquinidine,
KHMDS=potassium hexamethyldisilazane, MDCA=methyl dichloroa-
cetate, Piv=pivaloyl, Tf=trifluoromethanesulfonyl, TFA=trifluoroace-
tic acid.
the standard reaction conditions. Replacement of lithium
hexamethyldisilazane (LHMDS) by its potassium derivative
KHMDS in the presence of 18-crown-6 allowed us to improve
the initial low yield of 36 to 75%. Sequential treatment of 36
with methanolic potassium carbonate and then triflic anhy-
dride provided 37. Having prepared sufficient amounts of the
crucial intermediate (1.6 g), we turned our attention to the
key-step of the synthesis. Heating a solution of triflate 37 in
sulfolane at 2008C for 15 min induced the desired ring
opening reaction and led to clean conversion to the biaryl
intermediate 38 (75%, 1.2 g). For the installation of the
methyl group, a site-selective coupling of the triflate had to be
developed. Careful experimentation revealed that, upon
exposure of 38 to an excess of dimethyl zinc in the presence
of Pd(dppf)Cl2 at 958C for 1 h, the chloride was left unreacted
and exclusive insertion at the triflate occurred.[22]
Lactone formation with loss of the biaryl axis was
promoted upon hydrolysis of the remaining pivalate
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[2] X. Zhang, S. Sarkar, R. C. Larock, J. Org. Chem. 2006, 71, 236 –
243.
(NaOH, MeOH) and acid catalyzed (p-TsOH·H2O) ring
closure at elevated temperature (toluene, 808C) gave 39.
Substitution of the chloride with a hydroxyl group was
initially investigated with a model substrate that was lacking
the methoxy substituent (see Supporting Information for
further details). To our surprise, this seemingly trivial
coupling reaction was not successful under a variety of
reaction conditions[23] and, in most cases, only dehalogenation
of the starting material was observed. Fortunately, when
a solution of the more electron rich naphthalene 39 in 1,4-
dioxane (0.05m) was exposed to potassium tetramethoxybo-
rate in the presence of bis(acetonitrile)dichloropalladium(II)
(5 mol%) and SPhos (8 mol%) at 908C for 3 h, efficient
incorporation of the desired methoxy group occurred
(87%).[24] For the completion of the synthesis, simultaneous
removal of both methyl substituents was accomplished by
treatment of 39 with pyridine hydrochloride at elevated
temperature (1958C) for 16 h. Chartarin (1) crystallized from
methanol as a yellow-brownish powder whose spectroscopic
data (1H and 13C NMR, mp, HRMS) were in full agreement
with those reported for the naturally occurring substance.[3b,25]
In conclusion, we have developed an efficient and
practical ring opening/1,2-migration transformation for the
synthesis of orthogonally functionalized naphthalenes. The
reaction is operationally simple, does not require any
additives, occurs in a regioselective manner with a strong
preference for the para-chloronaphthol substitution pattern
and enables novel, powerful retrosynthetic bond disconnec-
tions. A translation of this method to natural product
synthesis was realized for the preparation of the potent
anticancer agent chartarin (1). The developed route can be
conducted on gram scale, provides efficient access to the
highly substituted, polycyclic carbon framework and enables
rapid diversification by standard transformations. Further
applications of this concept in the synthesis of complex
naphthalene containing molecules are currently underway in
our laboratories.
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Acknowledgements
We gratefully acknowledge financial support from the FCI
(Sachkostenzuschuss to T.M.) and the DFG (grant number
SFB 749 and Emmy Noether Fellowship to T.M.). We thank
Benjamin Williams (LMU Munich) for helpful discussions
during the preparation of this manuscript and Johannes
Feierfeil (LMU Munich) for providing individual substrates.
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Keywords: arenes · naphthalenes · natural products ·
ring expansion · total synthesis
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Received: May 24, 2016
Published online: && &&, &&&&
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Communications
Total Synthesis
T. A. Unzner, A. S. Grossmann,
T. Magauer*
&&&& — &&&&
Rapid Access to Orthogonally
Functionalized Naphthalenes:
Application to the Total Synthesis of the
Anticancer Agent Chartarin
Substituted naphthalenes: Orthogonally
functionalized naphthalenes were syn-
thesized from commercially available
indanones in four steps. The developed
method proceeds through the thermally
induced fragmentation of cyclopropane
indanones and involves a regioselective
1,2-chloride shift. This transformation
enables the synthesis of the anticancer
agent chartarin.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!