An efficient synthesis for a new class antimalarial agent, 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

Article abstract of DOI:10.1016/j.tetlet.2011.05.088

Efficient synthesis is essential for antimalarial therapeutics. A four-step route has been established for the synthesis of 7-(2-carboxyethyl)-1,3-dihydro- 1-hydroxy-2,1-benzoxaborole 1 that is a potent new class boron-containing antimalarial agent in pre

Full text of DOI:10.1016/j.tetlet.2011.05.088

Tetrahedron Letters 52 (2011) 3909–3911
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Tetrahedron Letters
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An efficient synthesis for a new class antimalarial agent,
7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
Yong-Kang Zhang a, , Jacob J. Plattner a, Eric E. Easom a, David Waterson b, Min Ge c, Zhiya Li c, Lingchao Li c,
⇑
Yong Jian c
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
b Medicines for Malaria Venture, International Center Cointrin, Block G, 20 Route de Pré-Bois, POB 1826, CH-1215 Geneva, Switzerland
c Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthesis is essential for antimalarial therapeutics. A four-step route has been established for the
synthesis of 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole 1 that is a potent new class
boron-containing antimalarial agent in preclinical development with IC50 = 26 nM against the malaria
parasite Plasmodium falciparum.
Received 23 April 2011
Revised 17 May 2011
Accepted 19 May 2011
Available online 27 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Benzoxaborole
Antimalarial therapeutics
Malaria
Plasmodium falciparum
1. Introduction
because of low reproducibility and difficult scalability. In order to
establish a shorter and scalable synthetic methodology, which is
Malaria represents a continuing public health problem for just
under half of the world’s population. Plasmodium falciparum, the
principal malarial parasite, is transmitted by mosquitoes and is
estimated to infect 250 million people worldwide and causes
nearly 1 million deaths each year. Sadly, 85% of these infections oc-
cur in children under the age of five. Current therapies to treat fal-
ciparum malaria are heavily reliant on artemisinin-based
combinations. However, resistance to artemisinins has recently
been identified, and resistance to key artemisinin partner drugs
is already widespread. Therefore, there is a great need for new anti-
malarial drugs with improved attributes over older therapies.1
These new medicines need to be orally active, rapidly efficacious,
safe in all age groups, including children and pregnant women,
and inexpensive to produce.
Recently we identified a potent new class of boron-containing
antimalarial agent, 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-
2,1-benzoxaborole 1, with an IC50 of 26 nM against the malaria
parasite P. falciparum.2 The initial route was lengthy and included
nine chemical steps starting from 2-bromo-3-methylbenzoic acid
2 (Scheme 1).2 An aryl nitrile reduction (3 to aldehyde 4) with Ra-
ney nickel in aqueous formic acid was particularly problematic
a requirement for a new antimalarial drug, we have investigated
alternative syntheses of compound 1, and wish to report an effi-
cient, four-step synthesis of this compound.
2. Results and discussion
In order to avoid the cyano reduction from 3 to 4, the second
synthetic strategy shown in Scheme 2 was designed and investi-
gated at a scale of 0.7 mol level. The methyl group in 5 was bromi-
nated with N-bromosuccinimide (NBS) to the bromomethyl
derivative 6, which was converted into the hydroxymethyl com-
pound 7. The benzyl alcohol 7 was oxidized with pyridinium chlo-
rochromate (PCC) to the aldehyde 8, which was further protected
to give the acetal derivative 9. Compound 9 was converted to the
pinacolato boron compound 10 in a good yield by the catalytical
boronylation method with bis(pinacolato)diboron (Pin2B2) as a
boron-introducing agent and Pd(PPh3)2Cl2 as a catalyst. The ester
group in 10 was reduced resulting in a spontaneous cyclization
with removal of pinacolato group forming the benzoxaborole moi-
ety. This was followed by the acetal deprotection with the aqueous
acid to provide 4.3 The aldehyde in 4 reacted with 2,2-dimethyl-
1,3-dioxane-4,6-dione in the presence of formic acid and triethyl-
amine to afford the carboxyethyl side chain of 1. This reaction
was remarkably efficient, which gave a convenient way for the
conversion of 4 to 1 in a single step.
⇑
Corresponding author. Tel.: +1 650 543 7513; fax: +1 650 543 7660.
E-mail address: yzhang@anacor.com (Y.-K. Zhang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.088

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Y.-K. Zhang et al. / Tetrahedron Letters 52 (2011) 3909–3911
reduction of the cyano group, the challenge for developing the
CN
COOH
Br
OH
second route into a practical manufacturing process for the final
product API still remained high because of the seven step process
and the use of a toxic solvent (carbon tetrachloride—CCl4) in the
bromination step. It was very clear that a more efficient and short-
er process for the preparation of compound 1 was required.
In order to shorten the synthetic route, a new building block, 2-
bromoisophthalaldehyde 11, was identified as the starting point
for the third synthetic strategy, shown in Scheme 3. In the new
route, one of the two aldehyde groups in 11 was protected with
ethylene glycol to give 12, and this compound was catalytically
boronylated to produce the pinacolato boron intermediate 13. Sim-
ple reduction of 13 followed by acidification generated 4, which
was further converted to the final product 1. This synthetic scheme
provided a short four-step route. The main problem of this route
was the low yield of the first step because of concomitant reaction
of the second aldehyde group in 11 to form a diacetal by-product. It
was attempted to minimize this side-reaction by very slow addi-
tion of ethylene glycol to the reaction mixture, but the best yield
obtained was 52%.
7 steps
B
O
2
3
Raney Ni
HCOOH, H2O
100oC, 1h
COOH
CHO
OH
OH
1 step
B
B
O
O
4
1
Scheme 1. An early method for the synthesis of 1.
Although the second strategy was better than the first one in
terms of fewer reaction steps and avoidance of the Raney nickel
OH
NBS, BPO
CCl4, N2
Br
CaCO3
THF, H2O
Br
Br
Br
80-85 oC, 5 h
100oC, 5 h
(crude 100%)
(53%)
COOMe
COOMe
COOMe
7
8
5
6
PCC, silica gel
DCM, 0-30 oC,
4.5 h (94%)
Pin2B2
O
O
Ethylene glycol
PPTS, toluene
reflux 5 h (95%)
O
Pd(PPh3)2Cl2
KOAc
O
O
O
B
Br
Br
COOMe
1,4-dioxane
N2, 91-95 o
30-35 h
(crude 100%)
O
C
COOMe
COOMe
9
10
NaBH4, EtOH
30oC, 4 h, then
2N HCl,10 oC,
0.5 h (60%)
O
O
HCOOH, TEA
110-115oC, 15 h
(47%)
O
O
4
1
Scheme 2. Second strategy for the synthesis of 1.
Pin2B2
Pd(PPh3)2Cl2
KOAc, N2
O
O
O
O
CHO
Ethylene glycol
O
B
p
-TsOH
Br
Br
Toluene
O
1,4-dioxane
100oC for 16h
Yield 71%
Reflux 4h
Yield 52%
CHO
CHO
CHO
11
12
13
2. 2N HCl
EtOH
1. NaBH4
EtOH
r.t., 1h
25 oC, 1h
Yie ld 77%
1
4
Scheme 3. Third strategy for the synthesis of 1.

Y.-K. Zhang et al. / Tetrahedron Letters 52 (2011) 3909–3911
3911
Pin2B2
Pd(PPh3)2Cl2
KOAc, N2
HO
1. NaBH4
CHO O
EtOH
OH
B
0-5oC, 3h
O
B
11
O
2. 2N HCl
CHO
1,4-dioxane
EtOH
90-95oC for 5-7h
14
15
4
20 min, r.t.
PCC
silica, DCM
5-30oC, 3h
48%
O
O
O
O
yield over
3 steps
1
HCOOH, TEA
110-115oC, 15 h
Yield 47%
Scheme 4. Fourth strategy for the synthesis of 1.
A fourth strategy was designed to further improve the overall
yield. As shown in Scheme 4, compound 11 was subjected to a bor-
onylation reaction to provide the boron intermediate 14. The
dialdehyde groups in 14 were reduced with sodium borohydride
followed by acidification to produce 15. Complete purification of
the intermediate 15 was not performed because once the material
was pure and solidified, it had very poor solubility in many
solvents, even in DMSO or DMF. The crude oily 15 was soluble in
organic solvents such as DCM and was then oxidized with PCC to
give the aldehyde 4. This compound was converted to the final
compound as described above. This four-step synthetic route gave
a better overall yield and provided an efficient methodology for the
synthesis of 1. This method has been used for a scale-up to more
than a hundred grams of 1 in one batch, and further optimization
of the reaction conditions is expected to provide kilogram quanti-
ties of 1.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.088.
References and notes
1. (a) Enserink, M. Science 2010, 328, 844; (b) Mackinnon, M. J.; Marsh, K. Science
2010, 328, 866; (c) Enserink, M. Science 2010, 328, 842; (d) Medicines for Malaria
Venture 2009 Annual Report, www.mmv.org.
2. Zhang, Y.-K.; Plattner, J. J.; Freund, Y.; Easom, E. E.; Zhou, Y.; Gut, J.; Rosenthal, P.
J.; Waterson, D.; Gamo, F.-J.; Angulo-Barturen, I.; Ge, M.; Li, Z.; Li, L.; Jian, Y.; Cui,
H.; Wang, H.; Yang, J. Bioorg. Med. Chem. Lett. 2011, 21, 644.
3. For recent general methods for the formation of various benzoxaboroles, see: (a)
Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Crépin, T.; Zhou, H.; Zhang, Y.-
K.; Hernandez, V.; Akama, T.; Baker, S. J.; Plattner, J. J.; Shapiro, L.; Martinis, S. A.;
Benkovic, S. J.; Cusack, S.; Alley, M. R. K. Science 2007, 316, 1759; (b) Akama, T.;
Baker, S. J.; Zhang, Y.-K.; Hernandez, V.; Zhou, H.; Sanders, V.; Freund, Y.;
Kimura, R.; Maples, K. R.; Plattner, J. J. Bioorg. Med. Chem. Lett. 2009, 19, 2129; (c)
Zhang, Y.-K.; Plattner, J. J.; Akama, T.; Baker, S. J.; Hernandez, V.; Sanders, V.;
Freund, Y.; Kimura, R.; Bu, W.; Hold, K. M.; Lu, X. S. Bioorg. Med. Chem. Lett. 2010,
20, 2270.
In summary, an efficient four-step route was established
for the synthesis of 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1
-benzoxaborole 1, which is a pre-clinical candidate being devel-
oped for the treatment of malaria.