The succinct synthesis of AT13387, a clinically relevant Hsp90 inhibitor

Article abstract of DOI:10.1080/00397911.2019.1602654

AT13387 is an orally bioavailable clinical candidate developed to inhibit heat shock protein 90 (Hsp90). This article describes a modified synthetic route for the multi-gram production of AT13387 in 46% overall yield. The modified synthetic route is short

Full text of DOI:10.1080/00397911.2019.1602654

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
The succinct synthesis of AT13387, a clinically
relevant Hsp90 inhibitor
Jatinder Kaur, Atul Bhardwaj, Bruce J. Melancon & Brian S. J. Blagg
To cite this article: Jatinder Kaur, Atul Bhardwaj, Bruce J. Melancon & Brian S. J. Blagg (2019):
The succinct synthesis of AT13387, a clinically relevant Hsp90 inhibitor, Synthetic Communications,
DOI: 10.1080/00397911.2019.1602654
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1602654
The succinct synthesis of AT13387, a clinically relevant
Hsp90 inhibitor
Jatinder Kaur, Atul Bhardwaj, Bruce J. Melancon, and Brian S. J. Blagg
Warren Family Research Center for Drug Discovery and Development, Department of Chemistry and
Biochemistry, University of Notre Dame, Notre Dame, IN, USA
ABSTRACT
ARTICLE HISTORY
Received 11 January 2019
AT13387 is an orally bioavailable clinical candidate developed to
inhibit heat shock protein 90 (Hsp90). This article describes a modi-
fied synthetic route for the multi-gram production of AT13387 in
46% overall yield. The modified synthetic route is short, avoids strin-
gent reaction conditions and difficult purifications, which led to an
increase in overall yield.
KEYWORDS
AT13387; cost-effective
synthetic route; Hsp90; iso-
indoline; proteostasis
GRAPHICAL ABSTRACT
Introduction
Eukaryotic cells have evolved to express the molecular chaperone family of heat shock
proteins (Hsp) to ensure the conformational function of client proteins as well as their
degradation via the proteasome. In fact, molecular chaperones are responsible for the
maturation, maintenance and proper folding of nascent polypeptides into their biologic-
ally active three-dimensional structures.[1–4] However, Hsp’s can also serve a detrimental
role in cancer, neurodegeneration, and/or autoimmune/inflammatory diseases.[5–11] In
fact, cancer cells utilize the chaperone machinery to increase their survival and prolifer-
ation by stabilizing mutant and overexpressed oncoproteins, such as protein kinase B
(Akt), cyclin-dependent kinases 4 (Cdk4), epidermal growth factor receptor (EGFR),
Her-2 and c-Met among others. Since cancer cells are highly dependent upon the chap-
erone machinery, inhibition of the heat shock proteins is widely sought as a promising
strategy for the treatment of cancer.[12–14] The 90 kDa heat shock protein, Hsp90, is an
extensively studied chaperone that modulates proteostasis activity[15–18] and prevents
CONTACT Brian Blagg
bblagg@nd.edu
University of Notre Dame, South Bend, Notre Dame, IN, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
J. KAUR ET AL.
Scheme 1. Reagents and reaction conditions: (a) Ac2O, BF3.OEt2, 75 ꢀC, 3 h; (b) benzyl bromide,
K2CO3, acetone, reflux, 8 h; (c) MePPh3Br, KOC(CH3)3, THF, rt, 1 h; (d) NaOH, MeOH/H2O, 70 ꢀC, 3 h; (e)
MeOH, SO2Cl; (f) NBS, benzoyl peroxide; (g) acetone, Na2CO3; (h) anisole, TFA, microwave; (i) EDC,
HOBt; (j) NaOH, 48 h; (k) N, O-dimethylhydroxylamine hydrochloride, EDC, HOBt, NEt3, DMF; (l) LiAlH4,
THF; (m) NaBH(OAc)3, DCE, AcOH; (n) 10% Pd/C, EtOH, H2.
apoptosis via the stabilization of oncogenic signaling proteins.[13,19–21] As a consequence
of these roles, Hsp90 inhibitors have been developed and have advanced to clinical
evaluation.[22–26] One such compound, AT13387, is orally bioavailable and currently
undergoing phase II clinical trials. AT13387 was developed by researchers at Astex
Pharmaceuticals[27,28] using a fragment-based drug design approach and the utilization
of extensive SAR studies (Hsp90 Kd ¼ 0.71 nM, LE ¼ 0.42).[27,29] The original synthesis
of AT13387 was achieved in thirteen steps and in an overall yield of 2.6%
(Scheme 1).[27] As illustrated in Scheme 1, resorcylic acid 6 and the isoindoline inter-
mediates (5 and 10) were synthesized, and then coupled to afford 11. The 1-methylpi-
perazine moiety was introduced through a lengthy sequence of transformations.
Although this route was useful for the preparation of AT13387, it required several
laborious steps and long reaction times (>3 days) in addition to the chromatographic
separation of highly polar intermediates (Scheme 1).[27] After the identification of
AT13387 as a clinical candidate, attempts to reduce the complexity of its preparation
and to improve the overall yield were pursued (Schemes 1 and 2).[30,31] Patel et al.
reduced the number of steps and improved the overall yield to 13.3% via an alternative
synthetic procedure (Scheme 2, route B) that involved the preparation of dioxinone-
resorcylate 21 utilizing a base-mediated cyclization/aromatization process, as well as iso-
indoline 27 via a Suzuki-Miyaura cross-coupling reaction. Both units (21 and 27) were
combined through a Grignard-mediated amine dioxinone transacylation. Despite an
improvement in the overall yield, the reported procedure required the use of hazardous
reagents and stringent reaction conditions, which is challenging to implement on large-
scale. The Liang team reported another procedure, wherein the piperazino-isoindoline-
(27) was prepared via a [2 þ 2þ2] cycloaddition of dipropargylamine derivative 29 and

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SYNTHETIC COMMUNICATIONSV
3
Scheme 2. Retrosynthetic routes developed for AT13387.
propargyl alcohol, while resorcylate 6 was prepared following the synthetic route devel-
oped by Astex researchers (Scheme 2, route C). Although, the Liang team was able to
produce an alternative synthetic route to prepare the piperazino-isoindoline scaffold, the
synthesis of AT13387 remained lengthy, and required challenging purifications with a
low overall yield of 9.3%.
Therefore, to address these synthetic concerns and to improve the overall yield, a syn-
thetic procedure for the multigram synthesis of AT13387 was pursued, which ultimately
led to a 46% overall yield. As compared to the other procedures, this method produced
AT13387 in seven steps, many of which did not require a protection/deprotection
protocol nor column purification of the highly polar and weakly UV active, t-butyl 5-
((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate (26).
Results and discussion
2,4-Bis(benzyloxy)-5-(prop-1-en-2-yl) benzoic acid (6) was prepared by modification of
the previously reported route[27] as noted in Scheme 3. The phenols of 4-dihydroxyben-
zoic acid (32) were masked as the benzyl ethers using benzyl bromide in acetonitrile,
which was then treated with N-bromosuccinimide (NBS) to give benzyl 2,4-bis(benzy-
loxy)-5-bromobenzoate (34) as a colorless solid in high yield. A palladium-mediated
cross coupling reaction was then utilized along with potassium trifluoro(prop-1-en-2-
yl)borate to produce 35 as an amorphous solid (88% yield), which was then hydrolyzed
with lithium hydroxide to give the corresponding benzoic acid 6 in excellent yield. The
synthesis of 6 did not require column purification throughout its preparation, except
for intermediate 35.
Benzoic acid 6 was then subjected to an 1-ethyl-3-[3-dimethylaminopropyl]carbodii-
mide hydrochloride (EDC) mediated amide coupling reaction with 5-bromoisoindoline

4
J. KAUR ET AL.
Scheme 3. Reagents and reaction conditions: (a) Benzyl bromide, K2CO3, CH3CN, 70 ꢀC, 5 h; (b) NBS,
CH3CN, rt; (c) potassium trifluoro(prop-1-en-2-yl)borate, Pd(OAc)2, XPhos, Cs2CO3, THF:H2O (9:1), 90 ꢀC,
8 h; (d) LiOH, THF:MeOH:H2O (2:1:1), rt, 3 h; (e) 5-bromoisoindoline, EDC.HCl, HOBt, DIPEA, DCM, 0 ꢀC
to rt, 13 h; (f) potassium 4-methylpiperazinomethyl-trifluoroborate, Pd(OAc)2, t-Bu3P-HBF4, Cs2CO3,
Toluene:H2O (10:3), 100 ꢀC, 14 h; (g) 10% Pd/C, CH3OH, H2, rt, 12 h.
Table 1. Optimization of amide coupling reaction conditions.
Entry
Coupling reagent
Basea
Solventb
Temperature
Time (hrs)
Isolated Yield (%)c
1
2
3
4
5
6
7
8
EDC/HOBt
EDC/HOBt
EDC/HOBt
EDC/HOBt
EDC/HOAt
EDC/HOAt
EDC/HOAt
EDC/HOAt
Et3N
Et3N
DIPEA
DIPEA
Et3N
Et3N
DIPEA
DIPEA
DCM
DMF
DCM
DMF
DCM
DMF
DCM
DMF
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
20
18
13
12
30
18
18
16
81
76
95
83
75
70
76
78
aAll reactions involve the use of anhydrous base.
bAll reactions performed in anhydrous solvent.
cIsolated yield, average of three independent reactions (n ¼ 3).
to afford (2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-bromoisoindolin-2-yl)metha-
none (36). Optimization of these coupling conditions led to the use of EDC with
hydroxybenzotriazole (HOBt) in anhydrous N,N-diisopropylethylamine (DIPEA) and
dichloromethane (DCM), which gave 36 in 95% yield (Table 1, entry 3).
The next key step that required optimization was the palladium-catalyzed cross
coupling reaction between (2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-bromoisoin-
dolin-2-yl)methanone (36) and potassium 4-methylpiperazinomethyl-trifluoroborate
(25). After extensive screening of reagent combinations (Table 2), (2,4-bis(benzy-
loxy)-5-(prop-1-en-2-yl)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)me-
thanone (17) was produced in good yield (85%) via palladium acetate (5 mol%), tri-
tert-butylphosphoniumtetrafluoroborate (10 mol%) and cesium carbonate (3 equiva-
lents) in a heterogeneous mixture of toluene and water (10:3). As shown in Table 2,
the reaction time was minimized via the use of a sealed tube and under microwave
irradiation, however, the yields were modest at best (38–67%, Table 2). It is note-
worthy to mention that in comparison to previously reported methods, the late stage
installation of 1-methylpiperazine avoided the need to prepare the weakly UV active
intermediate 26, which also contributed to an increase in the overall yield. For the
final step, we observed that hydrogenolysis was cleaner when methanol was used as

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SYNTHETIC COMMUNICATIONSV
5
Table 2. Optimization of the palladium-catalyzed cross coupling reaction for the preparation of 17.
Entry
Catalysta
Solvents (ratio)
Temp.
Time (hrs)
Isolated yieldb (%)
1
2
3
4
5
6
8
9
10
11
12
13
Pd(OAc)2, XPhos
Pd(OAc)2, XPhos
Pd(OAc)2, t-Bu3P-HBF4
Pd(OAc)2, t-Bu3P-HBF4
Pd(PPh)4
THF: H2O (7:3)
Toluene: H2O (10:3)
THF: H2O (7:3)
Toluene: H2O (10:3)
THF: H2O (7:3)
Toluene: H2O (10:3)
THF: H2O (7:3)
Toluene: H2O (10:3)
THF: H2O (7:3)
Toluene: H2O (10:3)
THF: H2O (7:3)
110 ꢀC
18
18
14
14
18
18
0.5
0.5
0.5
0.5
0.5
0.5
52
55
63
85
47
35
46
51
40
67
41
38
110 ꢀC
100 ꢀC
100 ꢀC
100 ꢀC
Pd(PPh)4
100 ꢀC
Pd(OAc)2, XPhos
Pd(OAc)2, XPhos
Pd(OAc)2, t-Bu3P-HBF4
Pd(OAc)2, t-Bu3P-HBF4
Pd(PPh)4
110 ꢀC#
110 ꢀC#
100 ꢀC#
100 ꢀC#
100 ꢀC#
100 ꢀC#
Pd(PPh)4
Toluene: H2O (10:3)
aAll reactions performed using Pd-catalyst (5 mol%), ligand (10 mol%), and Cs2CO3 (3 equivalents).
bIsolated yield, average of three independent reactions (n ¼ 3).
#Reactions performed under microwave irradiations in a sealed tube.
a solvent in lieu of ethanol under the presence of a hydrogen atmosphere and 10%
palladium on carbon. However, silica chromatography was required to achieve >98%
purity of AT13387. Overall, in comparison to route
A (13 steps, overall
yield ¼ 2.6%), route B (8 steps, overall yield ¼ 13.3%), or route C (>12 steps, overall
yield ¼ 9.3%), the synthetic route described herein requires 7 steps to produce
AT13387 in an overall yield of 46%.
Conclusions
In conclusion, a synthetic method for the multigram synthesis of the Hsp90 inhibitor
AT13387 was achieved in high yield. In fact, the route is very succinct,
producing AT13387 in high yields which may be useful for assessing the clinical utility
of AT13387 or the generation of analogs. Since, many of the intermediates do not
require chromatographic purification, which further enhances the usefulness of this
method for the large scale synthesis of AT13387.
Experimental section
1H NMR and 13C NMR spectra were recorded on Bruker AVIIIHD 400 MHz NMR
with a broadband X-channel detect gradient probe using CDCl3 as a solvent. Chemical
shifts were recorded in d (ppm) with tetramethylsilane (TMS) as an internal reference.
J (coupling constant) values were estimated in Hertz (Hz). The following notations are
used: br: broad; s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; dd: doublet of
doublets. Mass spectra (MS) were recorded on a Waters 2695 mass spectrometer using
ESI ionization mode. Thin layer chromatography was performed using TLC silica gel
60 F254. Normal phase column chromatography was performed on a flash chromatog-
raphy system (AI-580S, Yamazen) using 30 mm silica gel column. All solvents were
reagent grade and used without further purification. Compound 1, 6, 17, and 33–36 are
already reported.[27,32,33]

6
J. KAUR ET AL.
Procedure for the synthesis of (2,4-Dihydroxy-5-isopropylphenyl)(5-((4-
methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (1)[27]
Palladium on carbon (10%) (214.6 mg, 2.01 mmol, 0.3 eq.) was added to a solution of
(2,4-Bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoin-
dolin-2-yl)methanone (3.95 g, 6.72 mmol, 1 eq.) in methanol (30 mL). The reaction mix-
ture was then stirred under a hydrogen atmosphere for 12 h. The mixture was filtered
through a pad of celite, eluted with ethyl acetate and the eluent was concentrated. The
resulting residue was purified by silica chromatography (0–10% MeOH: DCM) to afford
(2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-
1
yl)methanone as a colorless solid (2.2 g, 81%): H NMR (400 MHz, CDCl3) d 7.38 (s,
1H), 7.23–7.18 (br m, 3H), 6.33 (s, 1H), 5.01 (s, 2H), 4.98 (s, 2H), 3.55 (s, 2H),
3.26–3.19 (m, 1H), 2.89–2.68 (br m, 8H), 2.57 (s, 3H), 1.24 (d, J ¼ 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d 171.22, 159.93, 158.76, 136.71, 136.46, 135.72, 128.97, 126.20,
126.07, 123.47, 122.53, 108.48, 103.62, 62.10, 54.12 (2C), 53.69 (2C), 50.92 (2C), 44.43,
26.58, 22.87 (2C); HRMS (ESIþ): m/z [M þ Hþ]calcd. for C24H31N3O3, 410.2438;
found: 410.2438.
Supporting information
1
Full experimental detail, H and 13C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
Funding
The authors gratefully acknowledge the Ara Parseghian Medical Research Fund, the National
Institutes of Health [CA167079], and National Cancer Institute for support.
ORCID
Brian S. J. Blagg
http://orcid.org/0000-0002-6200-3480
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