Efficient synthetic methodology for the construction of dihydronaphthalene and benzosuberene molecular frameworks

Article abstract of DOI:10.1016/j.tetlet.2018.12.033

Benzosuberene analogues (1 and 2) and dihydronaphthalene analogues (3 and 4) function as potent inhibitors of tubulin polymerization, demonstrate pronounced cytotoxicity (low nM to pM range) against human cancer cell lines, and are promising vascular disrupting agents (VDAs). As such, these compounds represent lead anticancer agents with potential translatability towards the clinic. Methodology previously established by us (and others) facilitated synthetic access to a variety of structural and functional group modifications necessary to explore structure activity relationship considerations directed towards the development of these (and related) molecules as potential therapeutic agents. During the course of these studies it became apparent that the availability of synthetic methodology to facilitate direct conversion of the phenolic-based compounds to their corresponding aniline congeners would be beneficial. Accordingly, modified synthetic routes toward these target phenols (benzosuberene 1 and dihydronaphthalene 3) were developed in order to improve scalability and overall yield [45-57% (1) and 32% (3)]. Moreover, benzosuberene-based phenolic analogue 1 and separately dihydronaphthalene-based phenolic analogue 3 were successfully converted into their corresponding aniline analogues 2 and 4 in good yield (>60% over three steps) using a palladium catalyzed amination reaction.

Full text of DOI:10.1016/j.tetlet.2018.12.033

Accepted Manuscript
Efficient Synthetic Methodology for the Construction of Dihydronaphthalene
and Benzosuberene Molecular Frameworks
Deboprosad Mondal, Haichan Niu, Kevin G. Pinney
PII:
S0040-4039(18)31475-8
https://doi.org/10.1016/j.tetlet.2018.12.033
TETL 50496
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 October 2018
8 December 2018
14 December 2018
Please cite this article as: Mondal, D., Niu, H., Pinney, K.G., Efficient Synthetic Methodology for the Construction
of Dihydronaphthalene and Benzosuberene Molecular Frameworks, Tetrahedron Letters (2018), doi:https://doi.org/
10.1016/j.tetlet.2018.12.033
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Efficient Synthetic Methodology for the Construction of Dihydronaphthalene
and Benzosuberene Molecular Frameworks
1, †
Deboprosad Mondal , Haichan Niu
1, †
1, *
, and Kevin G. Pinney
1
Department of Chemistry and Biochemistry, Baylor University, One Bear Place # 97348,
Waco, Texas 76798-7438, United States
†
Authors contributed equally to the work.
* Corresponding author: Tel.: +1 254 710 4117
e-mail address: Kevin_Pinney@baylor.edu

Keywords: Benzosuberene analogues; Dihydronaphthalene analogues; Direct conversion of
phenolic moieties to aniline moieties; Small-molecule inhibitors of tubulin polymerization.

ABSTRACT
Benzosuberene analogues (1 and 2) and dihydronaphthalene analogues (3 and 4) function as
potent inhibitors of tubulin polymerization, demonstrate pronounced cytotoxicity (low nM to pM
range) against human cancer cell lines, and are promising vascular disrupting agents (VDAs). As
such, these compounds represent lead anticancer agents with potential translatability towards the
clinic. Methodology previously established by us (and others) facilitated synthetic access to a
variety of structural and functional group modifications necessary to explore structure activity
relationship considerations directed towards the development of these (and related) molecules as
potential therapeutic agents. During the course of these studies it became apparent that the
availability of synthetic methodology to facilitate direct conversion of the phenolic-based
compounds to their corresponding aniline congeners would be beneficial. Accordingly, modified
synthetic routes toward these target phenols (benzosuberene 1 and dihydronaphthalene 3) were
developed in order to improve scalability and overall yield [45% (1) and 35% (3)]. Moreover,
benzosuberene-based phenolic analogue 1 and separately dihydronaphthalene-based phenolic
analogue 3 were successfully converted into their corresponding aniline analogues 2 and 4 in
good yield (>60% over three steps) using a palladium catalyzed amination reaction.

The discovery and development of small-molecule inhibitors of tubulin polymerization as
anticancer therapeutics represents an important field of research inquiry that often draws
structural inspiration from natural products. We have previously reported benzosuberene (1 and
2) and dihydronaphthalene (3 and 4) analogues (phenolic and aniline-based, respectively) that
function as potent inhibitors of tubulin polymerization and demonstrate enhanced cytotoxicity
against a variety of human cancer cell lines [low nM to pM range (Fig. 1)].1–7 The structures of
these molecules are reminiscent of the natural products colchicine and combretastatin A-4 (Fig.
1),8–10 which are potent inhibitors of tubulin polymerization.11 These molecules interact with the
tubulin-microtubule protein system at the colchicine binding site (situated on the tubulin
heterodimer) and inhibit microtubule formation. Associated with their tubulin-based mechanism
of action, these compounds also disrupt tumor-associated vasculature and thus function as
vascular disrupting agents (VDAs).1,3,4,12,13 Solid tumors increasingly require nutrients and
oxygen provided by a network of vasculature, which has distinct structural and architectural
differences compared with vasculature associated with normal healthy tissue.14 Tumor-associated
vasculature is highly disorganized with abnormal bulges, blind ends and shunts.15 It is also
characterized as leaky and discontinuous. Collectively, these physiological dissimilarities offer a
therapeutic advantage for the selective targeting and disruption of tumor-associated vasculature
with VDAs.13
Figure 1. Natural products (colchicine and combretastatin A-4), and synthetic benzosuberene
and dihydronaphthalene analogues as small-molecule inhibitors of tubulin polymerization.
Synthetic routes to each of the four key molecules (1 - 4) were previously established by our
laboratory.1,3–6 The synthesis of compounds 1 and 3 was later reported by other groups utilizing
different synthetic approaches to these molecular scaffolds.16–18 Our reported1,3,7 synthetic routes

towards compounds 1 and 2 were quite similar and involved a Wittig reaction followed by
Eaton’s reagent mediated intramolecular Friedel-Crafts acylation to provide the six-seven fused
ring system (Scheme 1). One of the critical steps in the synthesis of compound 1 involved
microwave assisted regioselective demethylation of an aromatic methoxy group using an ionic
liquid [TMAH][Al2Cl7] to generate the corresponding free phenol. In the case of amino
functionalized benzosuberene 2, a nitro group was carried through the synthesis and ultimately
reduced to reveal the aniline functionality. While these synthetic routes proved to be robust and
reproducible, they proceeded in relatively low overall yield [compound 1 (12% over seven steps)
and compound 2 (18% over six steps)]. Our original synthetic routes (Scheme 1) to the
functionalized dihydronaphthalene analogues were somewhat laborious and involved
regioselective oxidation of 6-methoxytetralin to sequentially introduce a hydroxy group and a
benzylic ketone in the case of phenolic-based dihydronaphthalene 3. In the case of amino-
dihydronaphthalene 4, a regioselective nitration of 6-methoxytetralone was followed by
reduction. The overall reported yields for the dihydronaphthalene series were also fairly low
[compound 3 (8% over ten steps) and compound 4 (17% over three steps)]. Therefore, we sought
to modify our methodology to improve both overall yield and atom economy. We recently
described one example of an improved synthesis of dihydronaphthalene 3 that proceeds through
an aryl bromide intermediate.19

Scheme 1. Previously reported synthetic route by Pinney and co-workers toward benzosuberene
and dihydronaphthalene analogues 1, 2, 3, and 4.1,3,6,7
Our modified methodology directed towards the synthesis of benzosuberene 1 along with
methodology to facilitate the direct conversion of phenolic benzosuberene 1 to its corresponding
aniline congener 2 (in three steps using a palladium catalyzed amination reaction) is detailed in
Scheme 2. In this revised methodology an isopropyl protecting group replaced the methoxy
group utilized previously. The isopropyl group undergoes facile deprotection using fairly mild
reaction conditions whereas demethylation requires relatively harsh reaction conditions.

Scheme 2. Modified synthetic routes to compounds 1 and 2. Reagents and reaction conditions:
o
(a) compound 5 (1.0 eq.), K2CO3 (1.5 eq.), 2-iodopropane (2.0 eq.), DMF, 50-60 C, 20 h, 98%.
(b) (i) 3-(carboxypropyl)triphenylphosphonium bromide (1.5 eq.), potassium tert-butoxide (3.5
o
eq.), compound 6 (1.0 eq.), DMF, 0 C to RT, 24 h; (ii) Pd-C (0.1 eq., 10 wt%), H2 balloon,
CH3OH, 24 h, 85-94% (two steps). (c) (i) compound 7 (1.0 eq.), oxalyl chloride (2.0 eq.), DMF
o
(0.2 eq.), CH2Cl2, RT, 2 h; (ii) SnCl4 (1.2 eq.), CH2Cl2, -10 C, 40 min, 75-80% (two steps). (d)
o
(i) 5-bromo-1,3,4-trimethoxybenzene (2.0 eq.), n-BuLi (2.0 eq.), THF, -78 C, 30 min. (ii)
o
compound 8 (1.0 eq.), -78 C, 4 h, RT, 16 h, 84%. (e) compound 9 (1.0 eq.), boron trichloride
o
(1.1 eq.), CH2Cl2, 0 C, 2 h, 85-92%. (f) compound 1 (1.0 eq.), triethylamine (2.0 eq.), triflic
o
anhydride (1.5 eq.), CH2Cl2, 0 C to RT, 5 h, 80-92%. (g) (i) compound 10 (1.0 eq.),
benzophenone imine (1.5 eq.), Cs2CO3 (1.5 eq.), palladium(II) acetate (0.1 eq.), racemic-BINAP
(0.15 eq.), toluene, 110-115 oC, 36 h; (ii) 2 M HCl, RT, 1 h, THF, 75-93% (two steps).
Benzaldehyde 6 was prepared by protection of the free phenolic moiety of commercially
available (and inexpensive) benzaldehyde 5 by a nucleophilic substitution reaction with 2-
iodopropane in quantitative yield. Installation of the side chain using a Wittig reaction
proceeded in an analogous fashion to our original synthetic route with minor improvements in
yield realized by switching the solvent from THF to DMF and carrying the Wittig reaction
product forward to the next step prior to purification. Benzaldehyde 6, upon treatment with (3-
carboxypropyl)-triphenylphosphonium bromide generated a mixture of alkenes (E and Z) that
were subjected to hydrogenation to afford carboxylic acid 7 (up to 94% yield over two steps
without the need for purification of the intermediate alkene mixture). The core benzosuberone 8
was obtained over two steps in a one-pot reaction. Initially, carboxylic acid 7 was converted to
its corresponding acyl chloride using oxalyl chloride. Subsequently, an intramolecular Friedel-
acid conditions
Crafts acylation reaction utilizing the crude acyl chloride under mild Lewis

(SnCl generated the requisite
(80% yield over two steps) with preservation
benzosuberone 8
)
4
of the isopropyl protecting group.20 This one-pot, two-step reaction sequence was preferred
over the one step cyclization using Eaton’s reagent (in our previously reported route), which
resulted in concomitant (undesirable) cleavage of the isopropyl group (up to 30% yield of
deprotected phenolic ketone, from a reaction mixture that included deprotected phenolic
carboxylic acid). There were also practicality and safety considerations (due to highly
exothermic work up procedure) associated with the use of Eaton’s reagent on large scale.
Compound
9 was obtained (84% yield) through an addition-elimination reaction between in situ
generated 3, 4, 5-trimethoxyphenyllithium and ketone 8, which was beneficial since it obviated
the need for a separate elimination reaction (through acidic work-up or a separate AcOH
mediated elimination) of the intermediate tertiary alcohol that was necessary in our original
procedure. Finally, target compound 1 was obtained (90% yield) by selective deprotection of
the isopropyl group with boron trichloride followed by acidic (HCl) work-up.. This modified
procedure facilitated the preparation of phenolic-based benzosuberene 1 in an overall yield of
45-55% which is four times higher than our previously reported procedure.1,7
Compound 1 was successfully converted (via triflate 10) directly to compound 2 through an
optimized palladium catalyzed amination reaction. Triflate 10 was initially synthesized by
reaction of compound 1 with triflic anhydride in 92% yield. Subsequently, triflate 10 was
converted to the target aniline-based benzosuberene analogue 2 through application of the well-
known Buchwald-Hartwig cross coupling reaction, which we optimized for our specific
o
substrate.21 Triflate 10 was heated (toluene at 110 C) with benzophenone imine in the presence
of catalytic palladium acetate and racemic-BINAP under basic conditions for 36 h in a sealed
tube. The corresponding benzophenone-based imine was formed initially, which under acidic
condition hydrolyzed to generate compound 2 in 75-80% yield (over two steps). The overall
yield of compound 2 from compound 1 varied from 60-72% (over three steps) which is three to
four times higher than the original procedure (Scheme 1).

Scheme 3. Unsuccessful Wittig reaction using (2-carboxyethyl)triphenylphosphonium bromide.

Scheme 4. New synthetic routes to compounds 3 and 4. Reagents and reaction conditions: (a)
compound 11 (2.0 eq.), triphenylphosphine (1.0 eq.), toluene, reflux, 24 h, 96%. (b) (i)
o
o
compound 12 (1.5 eq.), n-BuLi (3.0 eq.), THF, 0 C, 15 min; TMSCl (1.5 eq.), 0 C, 30 min;
o
compound 6 (1.0 eq.), 0 C, 1.0 h, RT, 2 h (ii) Pd-C (0.1 eq., 10 wt%), H2 balloon, CH3OH, 24
h, 92% (two steps, compound 13). (c) compound 13 (1.0 eq.), Oxone® (1.5 eq.), IBX (0.3 eq.)
ACN/H2O, 70 oC, 20 h, 46%. (d) (i) compound 14 (1.0 eq.), oxalyl chloride (2.0 eq.), DMF (0.2
o
eq.), CH2Cl2, RT, 2 h; (ii) SnCl4 (1.2 eq.), CH2Cl2, -10 C, 40 min, 92% (two steps). (e) (i) 5-
bromo-1,3,4-trimethoxybenzene (2.0 eq.), n-BuLi (2.0 eq.), THF, -78 oC, 30 min. (ii) compound
o
15 (1.0 eq.), -78 C, 4 h, RT, 16 h, 65%. (f) compound 16 (1.0 eq.), boron trichloride (1.1 eq.),
CH2Cl2, 0 oC, 3 h, 85%. (g) compound 3 (1.0 eq.), Triethylamine (2.0 eq.), triflic anhydride (1.5
o
eq.), 0 C to RT, 5 h, 100%. (h) (i) compound 17 (1.0 eq.), benzophenone imine (1.5 eq.),
Cs2CO3 (1.5 eq.), palladium(II) acetate (0.1 eq.), racemic-BINAP (0.15 eq.), toluene, 110-115
oC, 36 h; (ii) 2 M HCl, RT, 1 h, THF, 72% (two steps).
While our original synthetic methodology towards dihydronaphthalene analogues involved
reactions that initiated from existing fused aromatic-cycloalkane or -alkanone six-membered
ring systems,5,6 we subsequently envisioned the synthesis of dihydronaphthalene analogues 3
and 4 through ring-forming methodology similar to that depicted in Scheme 1 for the related
benzosuberene analogues.3,4 Unfortunately, efforts to coax the requisite Wittig reaction (Scheme
3) to proceed using (2-carboxyethyl)triphenylphosphonium bromide with NaH or KOtBu in
various solvents (THF, CH3OH, and DMF) mimicking our previous methodology1 proved
unsuccessful. The reaction was typically complicated by the formation of a mixture of various
by-products which appeared to result primarily from decomposition of the Wittig salt under
basic conditions. The reported yield (by Aubé and co-workers) for a similar type of Wittig
reaction using (2-carboxyethyl)triphenylphosphonium bromide was also low (23%), which
further confirmed our observations.22

Although we did not fully characterize each of these various decomposition by-products, one
by-product was identified as acrylic acid, which was obtained by elimination of
triphenylphosphine. We postulated that a possible driving force for the elimination was the
formation of stable α, β-unsaturated acrylic acid. Therefore, to solve the problem, instead of
using
(2-carboxyethyl)triphenylphosphonium
bromide,
we
employed
(3-
hydroxypropyl)triphenylphosphonium bromide as the Wittig salt 12 (Scheme 4), which was
readily synthesized in high yield (95%) by treatment of 3-bromo-1-propanol with
triphenylphosphine at reflux in toluene.23 Wittig salt 12 (as its corresponding in situ TMS
protected ylide) was reacted with benzaldehyde 6 following a similar protocol as reported.24
The TMS group was deprotected under acidic workup conditions to generate the intermediate
alkene (mixture of E/Z isomers) that contained a primary alcohol moiety. The crude alkene was
subjected to hydrogenation (hydrogen gas, Pd-C catalyst) to afford compound 13 (92% over
two steps). Alcohol 13 was oxidized (Oxone® and IBX) to its corresponding carboxylic acid 14
(46% yield). Cyclic ketone 15 was prepared (92% yield) under Friedel-Crafts acylation
conditions by conversion of carboxylic acid 14 to its corresponding acyl chloride (using oxalyl
chloride) followed by exposure to SnCl4. The remaining steps (Scheme 4) to prepare
dihydronaphthalene analogues 3 and 4 are akin to that described for the synthesis of related
benzosuberene analogues 1 and 2 (Scheme 3). Phenolic dihydronaphthalene analogue 3 was
obtained in an overall yield of 40% over seven steps. Amino dihydronaphthalene analogue 4
was obtained directly from phenolic compound 3 in three steps with an overall yield of 60%.
These modified procedures proved highly scalable, which facilitated the preparation of each of
these compounds in 2-5 gram amounts without any significant change in overall yields.

In conclusion, a general and highly efficient synthetic route has been developed for
functionalized benzosuberene (1 and 2) and dihydronaphthalene (3 and 4) analogues.
Importantly, an efficient three steps procedure was optimized and employed to synthesize
aniline-based congeners 2 and 4 directly from their corresponding phenolic-based counterparts
using a well-established palladium catalyzed amination reaction. These synthetic methodologies
should be amendable to the synthesis of a wide variety of benzosuberene and
dihydronaphthalene analogues with potential extension to other fused ring systems.

Acknowledgements:
The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT, Grant
#RP140399 and Grant #170696 to K.G.P., the National Cancer Institute of the National Institutes
of Health (Grant # 5R01CA140674 to K.G.P.), and Mateon Therapeutics, Inc. (grant to K.G.P.)
for their financial support of this project.
Appendix A. Supplementary data:
Supplementary data (1H, 13C NMR of compounds 1-4, 6-10, 13-17, HRMS spectra, HPLC traces
of compounds 1-4, and X-ray crystallography for compound 2) associated with this article can be
found, in the online version, at https://XXXXXXXXXXXXXXXXXXXX.

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Highlights:
Efficient synthetic methodology for benzosuberene and dihydronaphthalene analogues
Methodology accommodated larger scale reactions
Palladium catalyzed amination converted phenolic analogues to aniline congeners