Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

Article abstract of DOI:10.1016/j.bmcl.2011.12.096

A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure-activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC₅₀ 0.026-0.209 μM) against Plasmodium falciparum.

Full text of DOI:10.1016/j.bmcl.2011.12.096

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1299–1307
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted
7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles
Yong-Kang Zhang a, , Jacob J. Plattner a, Yvonne R. Freund a, Eric E. Easom a, Yasheen Zhou a, Long Ye b,
⇑
Huchen Zhou b, David Waterson c, Francisco-Javier Gamo d, Laura M. Sanz d, Min Ge e, Zhiya Li e,
Lingchao Li e, Hailong Wang e, Han Cui e
a Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
b School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
c Medicines for Malaria Venture, International Center Cointrin, Block G, 20 route de Pré-Bois, PO Box 1826, CH-1215 Geneva, Switzerland
d Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain
e Acesys Pharmatech, Inc., Science and Technology Building 24B, 5 Xing Mo Fan Road, Nanjing 21009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new boron-containing benzoxaborole compounds was designed and synthesized for a contin-
uing structure–activity relationship (SAR) investigation to assess the antimalarial activity changes
derived from side-chain structural variation, substituent modification on the benzene ring and removal
of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for
the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-
Received 24 November 2011
Revised 19 December 2011
Accepted 20 December 2011
Available online 28 December 2011
1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC50 0.026–0.209
Plasmodium falciparum.
lM) against
Keywords:
Benzoxaborole
Boron-containing compound
Structure–activity relationship
Antimalarial agent
Ó 2011 Elsevier Ltd. All rights reserved.
Plasmodium falciparum
Malaria represents a continuing public health problem for close
to half of the world’s population. It is a parasitic infection that is
responsible for an estimated 250 million clinical cases and nearly
1 million deaths worldwide each year, 85% of which occur in chil-
dren under the age of five. The most important causative parasite
Plasmodium falciparum is transmitted to humans by mosquitoes
and is responsible for a majority of the mortality of the disease.
Current therapies to treat falciparum malaria are heavily reliant
on artemisinin-based combinations (ACTs). However, emergence
of resistance to the endoperoxide component of the combination
has recently been identified, and resistance to older antimalarial
drugs is already widespread. This fact has brought renewed ur-
gency to discover new medications that counter resistance and
that are safe and easy for use in the most vulnerable populations.1
Previously we have reported that screening the Anacor boron-
containing compound collection in a whole cell assay against the
malaria parasite P. falciparum identified 7-(2-carboxyethyl)-1,3-
dihydro-1-hydroxy-2,1-benzoxaborole (1 in Fig. 1) with an IC50
of 44 nM.2 In addition, we described a preliminary SAR investiga-
tion surrounding 1, including modifications on side-chain and ring
size and substitution of oxaborole ring.2 In a continuing effort to
optimize the potency of this series of antimalarial benzoxaboroles
and to further explore the SAR, additional new compounds have
been synthesized and evaluated against P. falciparum. Herein we
report the synthesis and antimalarial activity of compounds 2–21.
General methods for the preparation of a diverse number of
substituted benzoxaboroles have recently been published.3 The
chemistry for the synthesis of compound 1 was described previ-
ously2 and an improved method was also reported.4 Scheme 1
illustrates the route for the synthesis of compound 2. The ester
group in compound 22, prepared by the previous methods,2 was
reduced with excess NaBH4 and followed by hydrolysis of the ace-
tal group to provide 23. The hydroxyl group was then protected
with methoxymethyl chloride (MOMCl) to give 24. Wittig reaction
of aldehyde 24 was followed by catalytic hydrogenation to produce
26. A hydroxyl group was introduced alpha to the ester function
and this was then fluorinated using DAST to yield 28. Boronylation
of 28 was followed by successive acidic and then basic hydrolysis
to produce 2.
The methods for the syntheses of compounds 3–6 are shown in
Scheme 2. The synthesis for 3 started with aldehyde 312 which was
reacted with tetraethyl methylenebis(phosphonate) to give the
unsaturated phosphonate 32. Compound 32 was then reduced to
its saturated analog 33, which gave the desired phosphonic acid
3 after removal of the ester groups. Compound 4 was synthesized
⇑
Corresponding author.
E-mail address: yzhang@anacor.com (Y.-K. Zhang).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.096

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Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
triflated and followed by the boronylation reaction to introduce
X
COOH
the pinacolatoboron group giving 47. Reduction of the aldehyde
of 47 followed by acidification gave the benzoxaborole 48 which
was hydrolyzed to the desired compound 7.
As shown in Scheme 4, compound 49 was chlorinated with sul-
furyl dichloride to give a mixture of 50 and 51, and this was fol-
lowed by hydrolysis and separation to afford the final
compounds 8 and 19.
Y
OH
OH
B
Z
Y
B
O
O
1:
2:
3:
X=COOH, Y=H;
X
X=COOH, Y=F;
8: Z=Cl, X=Y=H;
X = P(O)(OH)2, Y=H;
9:
Z=F, X=Y=H;
4: X = C(O)NHOH,Y=H
10:
11:
12:
Z=NO2, X=Y=H;
Y=OMe, X=Z=H;
Y=Me, X=Z=H;
The chemistry for the synthesis of compound 9 is shown in
Scheme 5. The aldehyde group was installed onto 52 to give 53,
O
HN
13: Y=Cl, X=Z=H;
14: Y=F, X=Z=H;
15: X=Me, Y=Z=H;
16: X=OMe, Y=Z=H;
which was converted to the
a,b-unsaturated ester 54 by a Wittig
O
X
reaction. The methyl group in 54 was then brominated to afford
the dibromo derivative 55, which was reacted with potassium ace-
tate to yield 56. Successive boronylation and hydrolysis produced
benzoxaborole 58, which led to 9 by catalytic hydrogenation.
Scheme 6 illustrates the syntheses for compounds 10, 17 and
18. Nitration of the acid 1 gave a separable mixture of two nitro
compounds 10 and 59. Reduction of the 6-nitro compound 10
did not give the desired open-chain aniline compound, but resulted
in the cyclized compound 60. Reduction of 59 provided the amino
compound 17 that was acetylated to afford 18.
OH
B
O
17:
18:
19:
X=NH2; Y=Z=H;
X=NHAc, Y=Z=H;
X=Cl, Y=Z=H;
5:
6:
X = S;
X = NH
20: X=F, Y=Z=H;
COOH
COOH
OH
OH
O
B
O
The synthetic route for the preparation of compounds 11–15 is
shown in Scheme 7. Substituted salicylaldehydes 61–65 were re-
acted with a Wittig reagent to generate the ester extended side-
chain of 66–70, which were further formylated to install the adja-
cent aldehyde group in 71–75, respectively. The phenol group was
converted to the triflate of 76–80 in order to replace it with the
pinancolatoboron moiety of 81–85. By reduction with sodium
borohydride, the aldehyde group was transformed into the
hydroxymethyl group which spontaneously cyclized to form the
oxaborole ring in 86–90 under acidic aqueous conditions. Subse-
quent reduction of the double bond in 86–90 and hydrolysis of
the ester in 91–95 provided the final acids 11–15.
The chemistry for the preparation of compound 16 is shown in
Scheme 8. The aldehyde group in 53 was oxidized to the carboxylic
acid 96, which was then esterified to methyl ester 97. The methyl
group in 97 was di-brominated to give 98, which was treated with
NaOMe in methanol followed by treatment with aqueous acid
to generate compound 99. Protection of the aldehyde in 99 was
7
21
Figure 1. Chemical structures of the benzoxaborole compounds synthesized during
a SAR investigation for the discovery of a new class of antimalarial agents by the
side-chain variation (2–7), substituent change on the benzene ring (8–20) and
removal of boron from five-membered oxaborole ring (21).
from 1 by an amidation reaction with O-benzylhydroxylamine fol-
lowed by catalytic hydrogenation to remove benzyl group. Com-
pounds 5 and 6 were prepared by condensation of aldehyde 31
with thiazolidine-2,4-dione or imidazolid-dine-2,4-dione, respec-
tively, followed by catalytic hydrogenation of each compound.
The synthesis of compound 7 is illustrated in Scheme 3. Reac-
tion of 37 with diethyl succinate introduced the bis-carboxylic acid
side-chain of 38 that was reduced and then cyclized to provide
intermediate 40. Reduction of the ketone group in 40 gave 41 that
was dehydroxylated and demethylated to generate compound 43.
The carboxylic acid of 43 was converted to its methyl ester (44)
which was formylated to give 45. The hydroxyl group of 45 was
COOEt
O
O
CHO
CHO
Br
Br
Br
Br
O
c
a
b
OMOM
OMOM
OH
O
25
24
23
22
d
COOEt
COOEt
COOEt
COOEt
HO
F
F
O
B
Br
Br
e
g
Br
f
O
OMOM
OMOM
OMOM
OMOM
26
27
28
29
h
COOH
COOEt
F
F
OH
OH
B
B
i
O
O
2
30
Scheme 1. Synthesis of compound 2. Reagents and conditions: (a) excess NaBH4, EtOH, rt, 48 h, then 1 N HCl; (b) MOMCl, DIPEA, DCM, 50 °C, 16 h; (c) Ph3PCH2COOEt
bromide, t-BuOK, DMSO, rt, 16 h; (d) H2, 10% Pd/C, EtOAc, rt, 1 h; (e) (1) KHMDS, THF, À78 °C, 30 min, (2) 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine, À78 °C to rt, 2 h; (f)
DAST, DCM, 0 °C to rt, 16 h; (g) Pin2B2, Pd(Ph3P)2Cl2, KOAc, 1,4-dioxane, N2, 95 °C, 16 h; (h) 4 N HCl, THF, 50 °C, 4 h; (i) LiOH, THF/MeOH/H2O (3:2:1, volume ratio), 40 °C, 1 h,
then HCl acidification.

Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
1301
OEt
OEt
OEt
OH
P
COOEt
COOEt
COOH
O
P
O
O
P
OEt
O
OH
OH
OH
OH
CHO
Z
Z
B
B
B
OH
OH
OH
OH
a
b
a
O
O
O
b
c
B
B
B
B
O
O
O
O
X
(Z = Cl, X = H)
51 (Z = H, X = Cl)
X
(Z = Cl, X = H)
19 (Z = H, X = Cl)
31
32
33
3
49
50
8
H
N
H
N
O
OH
O
O
Ph
OH
Scheme 4. Syntheses of compounds 8 and 19. Reagents and conditions: (a) SO2Cl2,
AcOH, 50 °C, 16 h; (b) NaOH, THF, H2O, rt, 2 h, then 1 N HCl.
OH
OH
OH
B
B
B
d
e
O
O
O
was oxidized to the aldehyde of 105 followed by protection to give
106. Catalytic boronylation of 106 introduced pinancolatoboron
into 107, of which the ester group was reduced followed by hydro-
lysis to give 108. Wittig reaction converted the aldehyde of 108
into an extending side-chain of 109, which was hydrolyzed to
the acid 110. Compound 109 was also reduced to the saturated
side-chain of 111, which was hydrolyzed to give the final acid com-
pound 20.
Synthesis of non-boron compound 21 is shown in Scheme 10.
The carboxylic acid in 1 was transformed to its methyl ester 112,
which underwent Suzuki coupling to introduce the vinyl group in
113. Protection of the hydroxyl group in 113 was followed by oxi-
dation of the vinyl group in 114 to give 115, which was hydrolyzed
under the acidic condition to provide 116. Under mild basic
1
34
4
O
O
HN
HN
O
O
X
X
OH
OH
B
B
g
f
31
O
O
5
6
(X = S)
(X = NH)
35
(X = S)
36 (X = NH)
Scheme 2. Syntheses of compounds 3-6. Reagents and conditions: (a)
CH2[P(O)(OEt)2]2, NaH, THF, 0 °C to rt, 10 h; (b) H2, 10% Pd/C, rt, 1 h; (c) KI, Me3SiCl,
MeCN, rt, 10 h; (d) BnONH2ÁHCl, EDC, HOAt, DIPEA, THF/DCM (1:1), rt, 4 h; (e) H2,
10% Pd/C, MeOH, rt, 30 min; (f) (1) for 35: thiazolidine-2,4-dione, NaOAc, 145 °C,
1 h, (2) for 36: imidazolidine-2,4-dione, NaOAc, 145 °C, 1 h; (g) (1) for 5: from 35,
pyridine, THF, LiBH4, reflux, 2 h, (2) for 6: from 36, H2, 10% Pd/C, 5% NaOH in water,
rt, 16 h.
COOEt
COOEt
CHO
followed by boronylation to provide the bis-protected compound
101. Reduction and hydrolysis then produced 102, which reacted
with 2,2-dimethyl-1,3-dioxane-4,6-dione to generate the final
compound 16.
For the synthesis of compound 20, the chemistry is illustrated in
Scheme 9. From a common intermediate 97, compound 103 was
obtained by mono-brominating the methyl group. The bromo-
methyl moiety was then converted to hydroxylmethyl 104, which
F
Br
F
Br
F
Br
F
Br
a
c
b
Br
52
53
54
55
d
COOH
COOEt
COOH
COOEt
O
B
OH
B
OH
F
Br
F
F
F
g
B
f
e
O
O
O
OAc
9
56
58
57
OAc
COOH
COOH
COOH
CHO
Scheme 5. Synthesis of compound 9. Reagents and conditions: (a) (1) LDA, THF,
À78 °C, 2 h, (2) DMF, À78 °C, 20 min; (b) Ph3PCH2COOEt bromide, t-BuOK, DMSO,
0 °C to rt, 3 h; (c) NBS, benzoyl peroxide, CCl4, N2, 85 °C, 2 h; (d) KOAc, DMF, 50 °C,
1 h; (e) Pin2B2, Pd(Ph3P)2Cl2, KOAc, 1,4-dioxane, N2, 85 °C, 16 h; (f) NaOH, EtOH,
H2O, 50 °C, 2 h, then 6 N HCl; (g) H2, 10% Pd/C, EtOAc, rt, 1 h.
O
b
c
a
HOOC
O
HOOC
O
O
O
37
38
39
40
d
COOH
COOH
COOMe
COOMe
O
OH
R
O
O
OH
h
g
e
O
OH
CHO
OH
HO
OH
OH
a
B
1
O2N
B
+
O
42
45
i
(R = Me)
43 (R = H)
44
41
f
O
NO2
59
10
COOMe
COOMe
COOMe
COOH
b
c
O
B
OH
OH
j
k
l
O
Tf
O
OH
O
OH
B
B
O
O
O
O
CHO
CHO
OH
OH
OH
46
47
48
7
HN
B
B
B
d
O
O
O
Scheme 3. Synthesis of compound 7. Reagents and conditions: (a) diethyl
succinate, t-BuOK, t-BuOH, 75 °C, 2 h; (b) H2, 10% Pd/C, THF, HCl, rt, 5 h; (c) (1)
(COCl)2, DMF, DCM, 0 C, 1 h, (2) AlCl3, DCM, 0 °C, 30 min; (d) NaBH4, NaOH, H2O, rt,
72 h, then 6 N HCl, H2O; (e) Et3SiH, TFA, rt, 16 h; (f) AlCl3, toluene, N2, reflux, 2 h,
then 12 N HCl; (g) SOCl2, MeOH, N2, reflux, 16 h; (h) (CH2O)n, MgCl2, TEA, THF, N2,
reflux, 16 h; (i) Tf2O, pyridine, DCM, 0 °C to rt, 2 h; (j) Pin2B2, Pd(Ph3P)2Cl2, KOAc,
1,4-dioxane, N2, 80 °C, 16 h; (k) NaBH4, MeOH, 0 °C to rt, 1.5 h, then 1 N HCl; (l)
LiOHÁH2O, THF: H2O (2:1), rt, 2 h, then 1 N HCl.
HN
O
NH2
60
17
18
Scheme 6. Syntheses of compounds 10, 17 and 18. Reagents and conditions: (a)
Fuming HNO3, À30 °C, 30 min; (b) Fe, 12 N HCl, EtOH, rt. 1 h; (c) H2, 10% Pd/C,
EtOAc, rt, 1 h; (d) AcCl, TEA, DCM, THF, rt, 2 h.

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Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
COOEt
COOEt
COOEt
Br
HO
O
Br
O
CHO
X
Br
O
Br
O
a
Br
O
b
c
OH
OH
OH
OTf
a
c
O
b
O
O
O
F
Y
Y
Y
CHO
Y
CHO
F
103
F
104
F
105
X
X
X
97
61
62
(Y=OMe, X=H)
(Y=Me, X=H)
63 (Y=Cl, X=H)
66 70
71 75
76 80
-
-
-
d
COOEt
O
O
64 (Y=F, X=H)
O
O
O
B
d
CHO
F
OH
OH
65
(Y=H, X=Me)
Br
O
B
g
B
f
e
O
O
O
O
O
COOH
OH
COOEt
COOEt
COOEt
F
109
h
F
F
O
O
B
108
106
107
OH
OH
i
g
B
B
B
e
f
O
O
O
O
COOH
COOH
COOEt
Y
Y
Y
Y
CHO
X
X
X
X
OH
OH
OH
11 (Y=OMe, X=H)
91 95
-
86 90
-
81 85
-
B
B
B
j
12
13
(Y=Me, X=H)
(Y=Cl, X=H)
O
O
O
14 (Y=F, X=H)
F
20
F
110
F
111
15 (Y=H, X=Me)
Scheme 7. Syntheses of compounds 11–15. Reagents and conditions: (a)
Ph3PCH2COOEt bromide, t-BuOK, DMSO, 0 °C to rt, 3 to 16 h; (b) (CH2O)n, MgCl2,
TEA, THF, N2, reflux, 16 h; (c) Tf2O, pyridine, DCM, 0 °C to rt, 2 h; (d) Pin2B2,
Pd(Ph3P)2Cl2, KOAc, 1,4-dioxane, N2, 80–95 °C, 16 h; (e) NaBH4, MeOH, 0 °C to rt,
1.5 h, then 1 N HCl; (f) H2, 10% Pd/C, EtOAc, rt, 1 h; (g) LiOHÁH2O, THF:MeOH:H2O
(3:2:1), 40 °C, 1 h, then HCl acidification.
Scheme 9. Synthesis of compound 20. Reagents and conditions: (a) 1 equiv NBS,
benzoyl peroxide, CCl4, N2, reflux, 16 h; (b) CaCO3, H2O, 1,4-dioxane, 100 °C, 16 h;
(c) PCC, DCM, rt, 4 h; (d) Pyridinium p-toluenesulfonate (PPTS), (CH2OH)2, toluene,
reflux, 16 h; (e) Pin2B2, Pd(Ph3P)2Cl2, KOAc, 1,4-dioxane, N2, 95 °C, 16 h; (f) NaBH4,
EtOH, 0 °C to rt, 1.5 h, then 2 N HCl, rt, 30 min; (g) Ph3PCH2COOEt bromide, t-BuOK,
DMSO, 0 °C to rt, 16 h; (h) and (j) LiOHÁH2O, THF/MeOH/H2O (3:2:1), rt, 16 h, then
HCl acidification; (i) H2, 10% Pd/C, EtOAc, rt, 1 h.
Br
Br
COOMe
COOH
COOMe
COOMe
Br
Br
O
Br
O
OH
OH
a
b
c
53
16
O
O
B
B
a
O
b
c
O
O
OMOM
F
OH
F
OH
F
96
97
98
1
112
113
114
d
d
h
O
O
O
O
COOLi
COOMe
COOMe
CHO
O
B
OH
CHO
Br
O
B
Br
O
g
O
OH
O
OH
f
e
O
CHO
OMOM
O
O
e
f
O
O
O
O
O
O
O
21 (Li+ Salt)
116
115
102
101
100
99
Scheme 10. Synthesis of compound 21. Reagents and conditions: (a) MeI, K2CO3,
DMF, N2, rt, 3 h; (b) CH2@CHBr, Pd(PPh3)4, Na2CO3, H2O, toluene, THF, N2, 90 °C,
16 h; (c) MOMCl, DIPEA, DCM, 0 °C to rt, 10 h; (d) NaIO4, K2OsO4, H2O, THF, rt, 10 h;
(e) HCl, H2O, THF, rt, 1 h; (f) LiOHÁH2O, CH3CN, rt, 10 h.
Scheme 8. Synthesis of compound 16. Reagents and conditions: (a) 2-Methyl-2-
butene, NaClO2, NaH2PO4Á3H2O, t-BuOH, H2O, rt, 30 min, then 1 N HCl; (b) MeI,
K2CO3, DMF, rt, 1 h; (c) 3 equiv NBS, benzoyl peroxide, CCl4, N2, reflux, 6 h; (d)
NaOMe, MeOH, 65 °C, 4 h, then 2 N HCl; (e) Pyridinium p-toluenesulfonate,
(CH2OH)2, toluene, reflux, 16 h; (f) Pin2B2, Pd(Ph3P)2Cl2, KOAc, 1,4-dioxane, N2,
95 °C, 16 h; (g) NaBH4, MeOH, 0 °C to rt, 1.5 h, then 2 N HCl; (h) 2,2-dimethyl-1,3-
dioxane-4,6-dione, HCOOH, TEA, rt, 1 h, then 114 °C, 16 h.
Table 1
In vitro IC50 results of compounds 1–21 and 110 against the malaria parasite
Plasmodium falciparum (3D7 strain)a
conditions, the ester in 116 was hydrolyzed while the hemi-acetal
was formed in parallel to generate the desired final compound 21
as a lithium salt.
Compound IC50
(lM) (P.
Compound IC50 (lM) (P.
falciparum)
falciparum)
The experimental procedures for the preparation of compounds
1
2
3
4
5
6
7
8
0.044
0.83
>5
1.55
0.46
>5
1.82
0.75
0.209
4.12
3.48
12
13
14
15
16
17
18
19
20
21
110
0.154
1.33
0.061
1.45
0.62
>5
2–21 are described in the reference section.5
The in vitro inhibitory activities of compounds 1–21 and 110
against the malaria P. falciparum 3D7 strain were determined and
their IC50 values are summarized in Table 1. Compounds 2–4 (see
Fig. 1) were designed to examine the effect of the side-chain acidity
on antimalarial activity. The fluoro atom substituted on the alpha-
carbon of the carboxylic acid in 2 presumably increases the acidity
in comparison to 1. This structural change resulted in decrease of
>5
0.266
0.026
>5
9
10
11
>5
potency from IC50 value 0.044
ment of the carboxylic acid group with a phosphonic acid gave an
inactive compound 3 (IC50 > 5 M). The hydroxamic acid group
lM of 1 to 0.83 lM of 2. The replace-
Experimental procedure for the in vitro assay was described previously.2 The
activity of a reference compound, atovaquone, was 1 nM.
a
l

Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
1303
Table 2
antimalarial activityand that a carboxylicacid on theside-chain rep-
resents the best acidic function. In addition, four new ring-substi-
In vitro cytotoxicity results of representative compoundsa
tuted compounds inhibited P. falciparum with IC50 6 0.209
Three of the four compounds have a fluoro-substituent on the ben-
zene ring, including 6-position (9 with IC50 = 0.209 M), 5-position
(14 with IC50 = 0.061 M) or 4-position (20 with IC50 = 0.026 M).
Further investigation on these active compounds is in progress
and results will be disclosed in future publications.
lM.
Compound HeLa cells% inhibition at
25
Jurkat cells% inhibition at
25
lM
lM
l
3
4
5
6
26.0
23.8
35.2
67.7
45.3
32.5
32.6
22.8
32.3
15.3
41.1
25.3
29.3
3.0
6.3
66.0
14.1
41.2
5.3
17.2
3.8
19.5
6.8
l
l
9
10
12
16
17
19
20
21
110
References and notes
1. (a) Enserink, M. Science 2010, 328, 844; (b) Kappe, S. H. I.; Vaughan, A. M.;
Boddey, J. A.; Cowman, A. F. Science 2010, 328, 862; (c) Mackinnon, M. J.; Marsh,
K. Science 2010, 328, 866; (d) Enserink, M. Science 2010, 328, 842; (e) Rottmann,
M.; McNamara, C.; Yeung, B. K.; Lee, M. C.; Zou, B.; Russell, B.; Seitz, P.; Plouffe,
D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.;
Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.
P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler,
E. A.; Diagana, T. T. Science 2010, 329, 1175; (f) Medicines for Malaria Venture
2010 annual report, www.mmv.org.
53.6
7.1
3.1
a
Experimental procedure for the in vitro cytotoxicity assay was described
previously.2
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.
also decreased the activity of compound 4 giving an IC50 value of
3. For recent general methods for the formation of various benzoxaboroles, see: (a)
Baker, S. J.; Zhang, Y.-K.; Akama, T.; Lau, A.; Zhou, H.; Hernandez, V.; Mao, W.;
Alley, M. R. K.; Sanders, V.; Plattner, J. J. J. Med. Chem. 2006, 49, 4447; (b) 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; (c) 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; (d)
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; (e) Ding, D.; Zhao, Y.; Meng, Q.; Xie, D.; Nare, B.; Chen, D.; Bacchi, C. J.;
Yarlett, N.; Zhang, Y.-K.; Hernandez, V.; Xia, Y.; Freund, Y.; Abdulla, M.; Ang, K.
H.; Ratnam, J.; McKerrow, J. H.; Jacobs, R. T.; Zhou, H.; Plattner, J. J. ACS Med.
Chem. Lett. 2010, 1, 165; (f) Ding, C. Z.; Zhang, Y.-K.; Li, X.; Liu, Y.; Zhang, S.;
Zhou, Y.; Plattner, J. J.; Baker, S. J.; Liu, L.; Duan, M.; Jarvest, R. L.; Ji, J.;
Kazmierski, W. M.; Tallant, M. D.; Wright, L. L.; Smith, G. K.; Crosby, R. M.; Wang,
A. A.; Ni, Z.-J.; Zou, W.; Wright, J. Bioorg. Med. Chem. Lett. 2010, 20, 7317.
4. Zhang, Y.-K.; Plattner, J. J.; Easom, E. E.; Waterson, D.; Ge, M.; Li, Z.; Li, L.; Jian, Y.
Tetrahedron Lett. 2011, 52, 3909.
1.55 lM. Compounds 5 and 6 were designed to use bioisosteres
of the carboxylic group with the intention of improving the phar-
macokinetic profile while maintaining potent activity. Compound
5 containing a thiazolidine-2,4-dione showed reasonable activity
(IC50 = 0.46
2,4-dione, which is not acidic, lost activity (IC50 > 5
pound 7, with a conformationally restricted side-chain carboxylic
acid exhibited a 41-fold loss of potency (IC50 = 1.82 M).
lM) whereas compound 6 containing imidazolidine-
l
M). Com-
l
Compounds 8–20 were designed to investigate the antimalarial
effect of various substituents at the 6-, 5- or 4-position of the ben-
zene ring. At the 6-position, adjacent to the side-chain, albeit was
possible to introduce a chloro- or fluoro-group, resulting in de-
creased potency (IC50 = 0.75
tro analog 10 (IC50 = 4.12
l
M for 8 and 0.209
lM for 9). The ni-
l
M) was made with the intention to
prepare its amino and related derivatives. Interestingly, reduction
of the nitro group in 10 generated a cyclic lactam compound 60
which was inactive against the parasite (IC50 > 5 lM). At the 5-po-
sition, which is para to the boron, four different substituents meth-
oxy, methyl, chloro and fluoro (compounds 11–14) were explored.
The fluoro compound 14 and the methyl analog 12 had good po-
5. Synthesis
of
2-fluoro-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanoic acid (2): To a solution of 22 (30 g, 104.5 mmol) in EtOH (500 mL)
was added NaBH4 (9.87 g, 261.25 mmol, 2.5 equiv) at 0 °C. The reaction was
stirred at rt for 48 h, quenched with 1 N HCl and extracted with ethyl acetate
(EA). The organic phase was washed with brine and dried over anhydrous
Na2SO4. The residue after rotary evaporation was purified by column
chromatography to give 23 (14 g, yield 64%). To
a solution of 23 (7 g,
32.5 mmol) in dichloromethane (DCM, 160 mL) was added N,N-diisopropyl-N-
ethylamine (DIPEA, 12.4 mL, 71.6 mmol, 2.2 equiv) and methoxymethyl chloride
(MOMCl, 4 mL, 48.75 mmol, 1.5 equiv). The reaction was stirred at 50 °C
overnight, quenched with saturated NH4Cl and extracted with DCM. The
organic phase was washed with brine and dried over anhydrous Na2SO4. The
residue after rotary evaporation was purified by column chromatography to give
24 (6.6 g, yield 78%). To a solution of Ph3PCH2COOEt bromide (45 g, 106 mmol,
2.5 equiv) in DMSO (350 mL) was added t-BuOK (10.3 g, 85 mmol, 2 equiv). The
mixture was stirred at rt for 1 h, and then to the mixture was added a solution of
24 (11 g, 42.45 mmol, 1 equiv) in DMSO (74 mL). The reaction was stirred at rt
overnight, quenched with saturated NH4Cl and extracted with t-butyl methyl
ether (TBME). The organic phase was washed with brine and dried over
anhydrous Na2SO4. The residue after rotary evaporation was purified by column
chromatography to give 25 (13.9 g, yield 100%). To a solution of 25 (13.9 g,
42.45 mmol, 1 equiv) in EA (210 mL) was added 10% Pd/C (2.8 g). The reaction
vessel was vacuumed and backfilled with H2 for three times. After being stirred
at rt for 1 h, the reaction was filtered and evaporated. The residue was purified
by column chromatography to give 26 (6 g, yield 43%). To a solution of KHMDS
(21.7 mL, 21.7 mmol, 1.2 equiv) in THF (30 mL) was added a solution of 26 (6 g,
18.1 mmol, 1 equiv) in THF (60 mL). The mixture was stirred at À78 °C for
30 min and then 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (6.613 g,
25.34 mmol, 1.4 equiv) was added at À78 °C. After being stirred at rt for 2 h,
the reaction was quenched with saturated NaHCO3 and extracted with EA. The
organic phase was washed with brine and dried over anhydrous Na2SO4. The
residue after rotary evaporation was purified by column chromatography to give
27 (4.3 g, yield 68%). 1H NMR of 27 (500 MHz, DMSO-d6): d 7.36 (d, 1H), 7.26–
7.32 (m, 2H), 5.61 (d, 1H), 4.71 (s, 2H), 4.58 (s, 2H), 4.28 (m, 1H), 4.06 (m, 2H),
3.32 (s, 3H), 3.17 (m, 1H), 2.97 (m, 1H) 1.13 (t, 3H) ppm. To a solution of 27
(2.8 g, 8.08 mmol) in DCM (16 mL) was added DAST (1.9 g, 12.1 mmol, 1.5 equiv)
at 0 °C. The reaction was stirred at rt for 8 h, and then more DAST (1.9 g,
12.1 mmol, 1.5 equiv) was added at 0 °C. After being stirred at rt overnight, the
reaction was quenched with saturated NaHCO3 and extracted with DCM. The
organic phase was washed with brine and dried over anhydrous Na2SO4. The
residue after rotary evaporation was purified by column chromatography to give
tency (IC50 = 0.061
chloro compound 13 and methoxy analogs 11 were much less po-
tent (IC50 = 1.33 M for 13 and 3.48 M for 11). At the 4-position,
six variable substituents including methyl, methoxy, amino, acet-
amido, chloro and fluoro-group (compounds 15–20) were investi-
gated. The methyl compound 15 and the methoxy analog 16
lM for 14 and 0.154 lM for 12) while the
l
l
showed moderate antimalarial activity (IC50 = 1.45
0.62 M for 16) whereas the amino compound 17 and the acetam-
ido compound 18 lost activity (both IC50 > 5 M). The chloro analog
19 exhibited reasonable activity (IC50 = 0.266 M) while the fluoro
compound 20 demonstrated excellent potency (IC50 = 0.026 M).
lM for 15 and
l
l
l
l
Compound 21 was designed to replace the boron in 1 with car-
bon and to test whether boron is required for the antimalarial
activity. This change resulted in a complete loss of biological activ-
ity (IC50 > 5
lM). As a close analog to 20, compound 110 has a dou-
ble bond in the side-chain and showed diminished activity
(IC50 > 5 lM) indicating the importance of the flexible side-chain
in 20.
Representative compounds were selected for the in vitro cyto-
toxicity tests using human Jurkat (T cell) and human HeLa (cervical
carcinoma) cell assays. The results are summarized in Table 2.
These compounds were tested at the concentration of 25 lM and
in general this class of compounds showed low cytotoxicities
against the two human cell lines.
In summary, the SAR study described in this report demonstrated
that in this chemical series, the boron is absolutely required for the

1304
Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
28 (730 mg, yield 26%). To a solution of 28 (400 mg, 1.145 mmol) in 1,4-dioxane
5% NaOH aqueous solution (5 mL) was added 10% Pd/C (300 mg). The reaction
was stirred at rt under H2 overnight. It was filtrated and the aqueous phase was
acidified by HCl (1 N, 5 mL), extracted with EA (3 Â 5 mL). The combined organic
phase was washed with brine, dried over NaSO4 and evaporated. The solid
residue was purified by column chromatography over silica gel eluted with
DCM/MeOH/AcOH = 5:1:0.1 to give the desired product 6 as yellow solid (40 mg,
yield 40%). 1H NMR of 6 (300 MHz, DMSO-d6): d 10.50 (br s, 1H), 9.10 (br s, 1H),
7.64 (s, 1H), 7.38 (t, 1H), 7.24 (d, 1H), 7.15 (d, 1H), 4.96 (s, 2H), 4.38–4.36 (m,
1H), 3.28–3.17 (m, 1H), 3.03–2.96 (m, 1H) ppm; HPLC purity: 98.9% at 200 nm;
MS (ESI+): m/z = 269 (M+23).
(6 mL) was added KOAc (483 mg, 4.923 mmol, 4.3 equiv), Pin2B2 (349 mg,
1.37 mmol, 1.2 equiv) and Pd(Ph3P)2Cl2 (80 mg, 0.114 mmol, 0.1 equiv). The
reaction was vacuumed and backfilled with N2 for three times. Then the reaction
was stirred at 95 °C overnight. The residue after filtration and evaporation was
purified by column chromatography to give 29 (148 mg, yield 32%). To
a
solution of 29 (140 mg, 0.363 mmol) in THF (0.9 mL) was added 4 N HCl
(0.43 mL, 18.1 mmol, 5 equiv). The reaction was stirred at 50 °C for 4 h, added
with EA and the organic phase was washed with brine, dried over anhydrous
Na2SO4. The residue after rotary evaporation was purified by column
chromatography to give 30 (20 mg, yield 22%). To a solution of 30 (20 mg,
0.079 mmol) in THF/MeOH/water = 3:2:1 (0.5 mL) was added LiOHÁH2O
(13.3 mg, 0.317 mmol, 4 equiv). The reaction was stirred at 40 °C for 1 h,
quenched with 1 N HCl and extracted with EA. The organic phase was washed
with brine and dried over anhydrous Na2SO4. The residue after rotary
evaporation was purified by column chromatography to give the final
compound 2 (10 mg, yield 56%). 1H NMR of 2 (300 MHz, DMSO-d6): d 13.10
(br s, 1H), 9.10 (br s, 1H), 7.40 (t, 1H), 7.27 (d, 1H), 7.20 (d, 1H), 5.33–5.13 (dm,
1H), 4.98 (s, 2H), 3.48–3.45 (m, 2H) ppm; HPLC purity: 94% at 220 nm; MS
(ESIÀ): m/z = 223.0 (MÀ1).
Synthesis of 1-hydroxy-1,3,6,7,8,9-hexahydronaphtho[1,2-c][1,2] oxaborole-8-
carboxylic acid (7): To a solution of t-BuOK (35.08 g, 313 mmol, 1.4 equiv) in t-
BuOH (150 mL) was added a solution of 37 (30.0 g, 220.6 mmol) and diethyl
succinate (41.7 mL, 250 mmol, 1.13 equiv) in t-BuOH (23 mL). The mixture was
stirred at 75 °C for 2 h, cooled to rt and evaporated to remove t-BuOH. Then
water (333 mL) was added, followed by addition of a solution of KOH (28.6 g) in
water (95 mL). After being refluxed overnight, the reaction mixture was cooled
to rt, extracted with TBME (3 Â 100 mL). The aqueous mixture was acidified
with 6 N HCl to pH 1, cooled to 0 °C and filtered to collect the solid. The product
was washed with water (2 Â 30 mL), and then TBME (2 Â 20 mL) to give 38 as a
yellow solid (45.4 g, yield 74.0%). TLC analysis of 38 (silica gel plate, MeOH/
DCM = 5:95): Rf = 0.2. To a solution of 38 (5.0 g, 21.18 mmol) in THF (70 mL)
were added 10% Pd/C (1.25 g) and HCl (3 mL). The reaction vessel was vacuumed
and backfilled with H2. After being stirred at rt for 5 h, the mixture was filtered
and evaporated to give a dark oil. The residue was recrystallized from toluene
(15 mL) to give 39 as a white solid (2 g, yield 40%). TLC analysis of 39 (silica gel
plate, MeOH/DCM = 5:95): Rf = 0.3. To a solution of 39 (5.0 g, 21 mmol) in DCM
(50 mL) were added DMF (2 mL) and (COCl)2 (5.87 g, 46.2 mmol) at 0 °C. The
mixture was stirred for 1 h before AlCl3 (8.4 g, 63 mmol, 3 equiv) in DCM
(80 mL) was added. The mixture was stirred for 30 min and then poured into
200 mL ice-water followed by filtration. The filtrate was extracted with DCM
(3 Â 100 mL) and the organic layer was washed by brine, dried over anhydrous
sodium sulfate and concentrated. The residue was purified by column
chromatography over silica gel eluted with PE/EA = 6:4 to give 40 (2.4 g, yield
53.0%). TLC analysis of 40 (silica gel plate EA/PE = 4:6): Rf = 0.3. To a solution of
40 (3.67 g, 183.5 mmol) in H2O (50 mL) were added NaOH (0.74 g, 183.5 mmol,
1 equiv) and NaBH4 (0.694 g, 183.5 mmol, 1 equiv). The reaction mixture was
stirred at rt for 72 h. The mixture was acidified with 6 N HCl and filtered to give
41 as a solid (2.0 g, yield 55.0%). TLC analysis of 41 (silica gel plate EA/PE = 1:1):
Rf = 0.3. To a solution of 41 (2.0 g, 8.99 mmol) in TFA (50 mL) was added Et3SiH
(1.73 ml, 1.2 equiv), and the reaction mixture was stirred at rt overnight. TFA
was removed under vacuum and saturated NaHCO3 was added to adjust pH 5.
The mixture was extracted with EA (2 Â 30 mL). The organic layer was washed
with brine, dried over anhydrous sodium sulfate and concentrated. The residue
was purified by column chromatography over silica gel eluted with PE/EA = 3:1
to give 42 as a white solid (1.3 g, yield 70%). TLC analysis of 42 (silica gel plate,
EA/PE = 1:3): Rf = 0.3. To a solution of 42 (3 g, 14.4 mmol) in toluene (50 mL) was
added AlCl3 (4.85 g, 36 mmol, 2.5 equiv). The mixture was refluxed under N2 for
2 h, cooled and poured into 100 mL ice water, followed by acidification to pH 1
with 12 N HCl. Then the mixture was extracted with EA (2 Â 50 mL) and the
organic layer was washed with brine, dried over anhydrous sodium sulfate and
concentrated. The residue was purified by column chromatography over silica
gel eluted with PE/EA = 7:3 to give 43 (1.4 g, yield 52%). TLC analysis of 43 (silica
gel plate, EA/PE = 3:7): Rf = 0.3. To a solution of 43 (1.4 g, 7.28 mmol) in MeOH
(19 mL) was added SOCl2 (2.6 g, 21.8 mmol, 3 equiv) under N2. The mixture was
refluxed overnight, cooled and evaporated to give 44 (1.2 g, yield 80%). TLC
analysis of 44 (silica gel plate, EA/PE = 3:7): Rf = 0.3. To a mixture of (CH2O)n
(529 mg, 17.4 mmol, 3 equiv) in dry THF (19 mL) were added MgCl2 (1.1 g,
Synthesis
yl)ethyl)phosphonic acid (3): To
1.2 equiv) in THF (25 mL) was added
of
(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
suspension of NaH (0.3 g, 7.40 mmol,
solution of tetraethyl
a
a
methylenediphosphonate in THF (2.5 ml) at 0 °C and then a solution of 31 in
THF (12 mL) was added. The reaction was stirred at rt for 10 h, water (20 mL)
was added, and pH was adjusted to 5–7 with 1 N HCl. The mixture was extracted
with DCM, and the combined organic phase was washed with brine and dried
over anhydrous Na2SO4. The residue after rotary evaporation was purified by
column chromatography to give 32 (1.19 g, yield 65%). To a solution of 32
(1.13 g, 3.82 mmol) in EtOH (18 mL) under N2 was added 10% Pd/C (0.6 g). The
reaction vessel was vacuumed and backfilled with H2 for three times. The
reaction was stirred at rt for 1 h, filtered and evaporated. The residue was
purified by column chromatography to give 33 (1.14 g, yield 100%). To a mixture
of 33 (205 mg, 0.688 mmol) and KI (0.4 g, 3.1 mmol, 4.5 equiv) in MeCN (1.9 mL)
was added chlorotrimethylsilane (0.395 mL, 3.1 mmol, 4.5 equiv). The reaction
was stirred at rt for 10 h and LC–MS showed that all the starting material was
converted to the desired product. The reaction was evaporated and the solid was
washed with ether to give the desired product 3 as a white solid (151 mg, yield
90%). 1H NMR of 3 (300 MHz, DMSO-d6): d 7.32 (t, 1H), 7.17 (d, 1H), 7,10 (d, 1H),
4.93 (s, 2H), 4.50 (br s, 2H), 3.10–2.90 (m, 2H), 1.89–1.93 (m, 2H) ppm; HPLC
purity: 98.6% at 220 nm; MS (ESI+): m/z = 243.0 (M+1).
Synthesis
of
N-hydroxy-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanamide (4): To a solution of 1 (0.5 g, 2.42 mmol) in a mixed solvent of
THF (12 mL) and DCM (12 mL) were added DIPEA (3.4 mL, 19.36 mmol, 8 equiv),
EDC HCl (975.5 mg, 5.08 mmol, 2.1 equiv), HOAt (395 mg, 2.9 mmol, 1.2 equiv)
and BnONH2 HCl (1.742 g, 10.89 mmol, 4.5 equiv). The reaction was stirred at rt
for 4 h, evaporated and added with EA. The organic phase was washed with 1 N
HCl, brine and dried over anhydrous Na2SO4. The residue was purified by
column chromatography to give 34 (230 mg, yield 30%). 1H NMR of 34
(300 MHz, DMSO-d6): d 10.89 (s, 1H), 8.95 (s, 1H), 7.72–7.38 (m, 6H), 7.21 (d,
1H), 7.09 (d, 1H), 4.95 (s, 2H), 4.57 (s, 2H), 3.01 (t, 2H), 2.29 (t, 2H) ppm; HPLC
purity: 95.5% at 220 nm; MS (ESIÀ): m/z = 310 (MÀ1). To a solution of 34 (0.2 g,
0.643 mmol) in MeOH (3 mL) was added 10% Pd/C (80 mg), and the reaction
vessel was vacuumed and backfilled with H2 for three times. After being stirred
at rt for 30 min, the reaction mixture was filtered and evaporated. The residue
was purified by column chromatography to give the desired product 4 (55 mg,
yield 41%). 1H NMR of 4 (300 MHz, CD3OD): d 7.35 (t, 1H), 7.19 (d, 1H), 7.13 (d,
1H), 5.04 (s, 2H), 3.08 (t, 2H), 2.40 (t, 2H); HPLC purity: 96.4% at 220 nm; MS
(ESI+): m/z = 222 (M+1).
11.63 mmol, 2 equiv), TEA (1.62 mL, 2 equiv) and
a solution of 44 (1.2 g,
Synthesis
of
5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)
mixture of 31 (460 mg, 2.84 mmol),
5.8 mmol) in dry THF (10 mL) at rt under N2. The reaction mixture was refluxed
overnight, cooled to rt and extracted with EA (40 mL). The organic layer was
washed with 1 N HCl (2 Â 20 mL), water (20 mL) and brine, and was dried over
anhydrous sodium sulfate. The solvent was removed and the residue was
purified by column chromatography over silica gel eluted with PE/EA = 9:1 to
give 45 (0.7 g, yield 51%). TLC analysis of 45 (silica gel plate, EA/PE = 1:3):
Rf = 0.4. 1H NMR of 45 (300 MHz, DMSO-d6): d 11.25 (s, 1H), 9.94 (s, 1H), 7.52 (d,
1H), 6.83 (d, 1H), 3.66 (s, 3H), 2.96–2.60 (m, 5H), 2.08–1.99 (m, 1H), 1.85–1.60
(m, 1H) ppm. To a solution of 45 (0.7 g, 2.98 mmol) in DCM (9.9 mL) were added
pyridine (1.2 mL, 14.9 mmol, 5 equiv) and Tf2O (1.1 mL, 6.56 mmol, 2.2 equiv) at
0 °C. The mixture was stirred at rt for 2 h and then washed with water
(2 Â 20 mL), 0.5 N HCl (2 Â 20 mL), brine, dried and rotary evaporated. The
residue was purified by column chromatography over silica gel eluted with PE/
EA = 3:1 to give 46 (0.6 g, yield 55%). TLC analysis of 46 (silica gel plate, EA/
PE = 1:4): Rf = 0.3. 1H NMR of 46 (300 MHz, DMSO-d6): d 10.05 (s, 1H), 7.82 (d,
1H), 7.50 (d, 1H), 3.66 (s, 3H), 3.13–2.89 (m, 5H), 2.25–1.70 (m, 2H) ppm. To a
solution of 46 (0.6 g, 1.66 mmol) in 1,4-dioxane (8.3 mL) were added KOAc
(491 mg, 4.99 mmol, 3 equiv), Pin2B2 (635 mg, 2.5 mmol, 1.5 equiv). The
solution was bubbled with N2 for 15 min. Pd(PPh3)2Cl2 (117.2 mg,
0.167 mmol, 0.1 equiv) was added and the reaction was stirred under N2 at
80 °C overnight, cooled, filtrated, and evaporated. The residue was purified by
column chromatography over silica gel eluted with PE/EA = 9:1 to give 47
(550 mg, yield 95.9%). TLC analysis of 47 (silica gel plate, EA/PE = 1:9): Rf = 0.3.
To a solution of 47 (550 mg, 1.60 mmol) in MeOH (8 mL) was added NaBH4
(66.5 mg, 1.75 mmol, 1.1 equiv) at 0 °C. The mixture was stirred for 1.5 h at rt
and then 1 N HCl (4 mL) was added to adjust pH 1–2. After being stirred for
0.5 h, the mixture was extracted with EA (3 Â 20 mL) and the combined organic
methyl)thiazolidine -2,4-dione (5):
A
thiazolidine-2,4-dione (363 mg, 3.1 mmol, 1.1 equiv) and NaOAc (512 mg,
6.2 mmol, 2.2 equiv) was stirred at rt for 10 min and then at 145 °C for 1 h.
The mixture was cooled to rt and diluted with water (2 mL), HCl (1 N, 2 mL) and
EA (2 mL). After being stirred for 1 h, the solid was collected by filtration,
washed with water (5 mL) and EA (10 mL), and dried under vacuum to give the
desired product 35 as yellow solid (450 mg, yield 60%). 1H NMR of 35 (300 MHz,
DMSO-d6): d 12.58 (s, 1H), 9.35 (s, 1H), 8.30 (s, 1H), 7.64 (t, 1H), 7.49 (d, 1H),
7.44 (d, 1H), 5.04 (s, 2H) ppm; HPLC purity: 100% at 220 nm; MS (ESIÀ): m/
z = 260 (MÀ1). To a solution of 35 (70 mg, 0.27 mmol) and pyridine (2 mL) in
THF (5 mL) was added LiBH4 (22 mg, 1 mmol, 3.7 equiv) in portions. The
reaction mixture was refluxed for 2 h and then diluted with EA (10 mL) and HCl
(1 N, 20 mL). The aqueous phase was extracted with EA (3 Â 5 mL) and the
combined organic phase was washed with brine, dried over NaSO4 and
evaporated. The residue was purified by column chromatography over silica
gel eluted with DCM/MeOH/AcOH = 5:1:0.01 to give the desired product 5 as
yellow solid (21 mg, yield 22%). 1H NMR of 5 (300 MHz, DMSO-d6): d 11.97 (br s,
1H), 9.08 (s, 1H), 7.42 (t, 1H), 7.28 (d, 1H), 7.17 (d, 1H), 4.96 (s, 2H), 4.94 (t, 1H),
3.69–3.63 (m, 1H), 3.26–3.18 (m, 1H) ppm; HPLC purity: 94% at 220 nm; MS
(ESI+): m/z = 264 (M+1).
Synthesis
of
5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)
methyl)imidazoli-dine-2,4-dione (6): Intermediate 36 was synthesized from
imidazolidine-2,4-dione by a similar method described above for the synthesis
of 35. Yield 41%; 1H NMR of 36 (500 MHz, DMSO-d6): d 11.20 (s, 1H), 10.50 (s,
1H), 9.16 (s, 1H), 7.71–7.66 (m, 1H), 7.49 (t, 1H), 7.34 (d, 1H), 6.99 (s, 1H), 5.00
(s, 2H). MS (ESIÀ): m/z = 243 (MÀ1). To a solution of 36 (100 mg, 0.4 mmol) in

Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
1305
phase was washed with brine, dried and concentrated. The residue was purified
by column chromatography over silica gel eluted with PE/EA = 4:1 to give 48
(11 mg, yield 2.8%). TLC analysis of 48 (silica gel plate, EA/PE = 1:4): Rf = 0.3. To a
solution of 48 (11 mg, 0.0447 mmol) in THF/H2O = 2:1 (0.5 mL) was added
LiOHÁH2O (3.7 mg, 0.0894 mmol, 2 equiv). After being stirred at rt for 2 h, the
mixture was acidified to pH 2 with 1 N HCl and followed by extraction with EA
(3 Â 10 mL). The combined organic layer was washed with brine, dried and
evaporated. The residue was purified by column chromatography over silica gel
eluted with PE/EA = 3:7 to give the final product 7 (3.2 mg, yield 31%). 1H NMR
of 7 (300 MHz, DMSO-d6): d 12.20 (br s, 1H), 8.85 (s, 1H), 7.17–7.08 (m, 2H), 4.90
(s, 2H), 4.14 (m, 1H), 3.21–2.64 (m, 4H), 2.10–1.70 (m, 2H) ppm; HPLC purity:
90% at 220 nm; MS (ESI+): m/z = 255 (M+23).
for 20 min and extracted with EA. The organic phase was washed with brine and
dried over anhydrous Na2SO4. The residue after evaporation was purified on a
silica gel column to give 10 (720 mg, yield 30%). 1H NMR of 10 (500 MHz, DMSO-
d6): d 12.15 (s, 1H), 9.38 (s, 1H), 7.99 (d, 1H), 7.47 (d, 1H), 5.06 (s, 2H), 3.21 (t,
2H), 2.55 (t, 2H) ppm. Also separated was compound 59 (720 mg, yield 30%). 1
H
NMR of 59 (500 MHz, DMSO-d6): d 12.12 (s, 1H), 9.39 (s, 1H), 8.22 (d, 1H), 7.49
(d, 1H), 5.35 (s, 2H), 3.14 (t, 2H), 2.61 (t, 2H) ppm. To a solution of 59 (900 mg,
3.58 mmol) in EA (18 mL) was added 10% Pd/C (360 mg). The reaction vessel
was vacuumed and backfilled with H2 for three times. After being stirred at rt for
1 h, the mixture was filtered and evaporated. The residue was purified by
column chromatography to give 17 (350 mg, yield 44%). 1H NMR of 17
(500 MHz, DMSO-d6): d 11.89 (s, 1H), 8.71 (s, 1H), 6.83 (d, 1H), 6.55 (d, 1H),
4.80 (br s, 2H), 4.75 (s, 2H), 2.83 (t, 2H), 2.43 (t, 2H) ppm; HPLC purity: 99.4% at
220 nm; MS (ESI+): m/z = 222.3 (M+1). To a solution of 17 (100 mg, 0.45 mmol)
Syntheses
of
3-(6-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanoic
acid
(8) and 3-(4-chloro-1-hydroxy-1,3-dihydrobenzo[c]
[1,2]oxaborol-7-yl)propanoic acid (19): To a solution of the ethyl ester of 1 (49,
1 g, 30 mmol) in AcOH (20 mL) was added SO2Cl2 (14.4 mL, 36 mmol, 1.2 equiv)
and the mixture was stirred overnight at 50 °C. The mixture was concentrated
and the residue was purified by prep-HPLC to afford a mixture containing both
50 and 51. This mixture (0.5 g, 1.92 mmol) was mixed with 1 N NaOH (6 mL) in
THF (30 mL) and stirred at rt for 2 h. The reaction mixture was acidified with 1 N
HCl, extracted with EtOAc (100 mL) and concentrated to afford the residue
(0.377 g, yield 95%). The residue was separated by SFC chiral chromatography
in DCM/THF/MeOH (2 mL/4 mL/5 drop) was added TEA (94 lL, 0.675 mmol,
1.5 equiv) and AcCl (2 mL). The mixture was stirred at rt for 2 h and diluted with
EA (50 mL). The organic phase was washed with brine and dried over anhydrous
Na2SO4. The residue was purified by column chromatography to give 18 (30 mg,
yield 25%). 1H NMR of 18 (300 MHz, DMSO-d6): d 12.02 (br s, 1H), 9.45 (s, 1H),
8.98 (br s, 1H), 7.48 (d, 1H), 7.11 (d, 1H), 5.00 (s, 2H), 2.97 (t, 2H), 2.51 (t, 2H),
2.04 (s, 3H) ppm; HPLC purity: 94% at 220 nm; MS (ESI+): m/z = 264 (M+1). To a
solution of 10 (100 mg, 0.398 mmol) in EtOH (3.9 mL) was added Fe (220 mg,
3.98 mmol, 10 equiv) and 12 N HCl (0.66 mL, 7.96 mmol, 20 equiv). The mixture
was stirred at rt for 1 h, filtered and evaporated. The residue was purified by
column chromatography over silica gel to give 60 (30 mg, yield 34%). 1H NMR of
60 (300 MHz, DMSO-d6): d 10.05 (s, 1H), 8.98 (s, 1H), 7.14 (d, 1H), 6.96 (d, 1H),
4.90 (s, 2H), 3.05 (t, 2H), 2.44 (t, 2H) ppm; HPLC purity: 100% at 220 nm; MS
(ESI+): m/z = 204 (M+1).
over ChiralPak AD-5 l
m to give 8 (150 mg) and 19 (120 mg). 1H NMR of 8
(400 MHz, DMSO-d6): d 12.16 (s, 1H), 9.15 (s, 1H), 7.47 (d, 1H), 7.25 (d, 1H), 4.93
(s, 2H), 3.12 (t, 2H), 2.41 (t, 2H) ppm; HPLC purity: 95% at 220 nm; MS (ESIÀ): m/
z = 239 (MÀ1). 1H NMR of 19 (400 MHz, DMSO-d6): d 12.06 (s, 1H), 9.22 (s, 1H),
7.39 (d, 1H), 7.18 (d, 1H), 4.93 (s, 2H), 2.96 (t, 2H), 2.52 (t, 2H) ppm; HPLC purity:
97.5% at 220 nm; MS (ESIÀ): m/z = 239 (MÀ1).
Synthesis
of
3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
Synthesis
yl)propanoic acid (11): To
of
3-(1-hydroxy-5-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
solution of Ph3PCH2COOEt bromide (76.1 g,
yl)propanoic acid (9): To a solution of diisopropylamine (20 mL, 1.1 equiv) in
THF (250 mL) was added n-BuLi (2.5 M, 58 mL, 1.1 equiv) at À10 °C during
10 min. The mixture was stirred at À20 °C for 30 min and cooled to À78 °C. Then
2-bromo-4-fluoro-1-methylbenzene (52, 16.4 mL) was added to the solution for
10 min. After being stirred for 2 h, DMF (12 mL, 1.2 equiv) was added to the
mixture during 10 min at À78 °C and stirred for additional 10 min. The mixture
was quenched with water, extracted with EA (2 Â 500 mL), dried over Na2SO4
and evaporated to give 53 (24 g, yield 84%). TLC analysis of 53 (silica gel plate,
a
177.56 mmol, 2 equiv) in DMSO (344 mL) was added t-BuOK (23.9 g,
195.3 mmol, 2.2 equiv) under N2 and the mixture was stirred for 1 h at rt. A
solution of 2-hydroxy-5-methoxybenzaldehyde (61, 13.5 g, 88.78 mmol) in
DMSO (100 mL) was added and the mixture was stirred overnight at rt. It was
quenched with water (800 mL) and stirred for 0.5 h. The mixture was extracted
with EA (2 Â 300 mL) and the combined organic phase was washed with brine,
dried over anhydrous sodium sulfate and concentrated. The residue was purified
by column chromatography eluted with PE/EA = 4:1 to give 66 (12 g, yield 61%).
TLC analysis of 66 (silica gel plate, EA/PE = 3:7): Rf = 0.3. To a mixture of (CH2O)n
(4.9 g, 162.1 mmol, 3 equiv) in dry THF (150 mL) were added MgCl2 (10.2 g,
108 mmol, 2 equiv) and TEA (15 mL, 2 equiv) under N2. Then a solution of 66
(12.0 g, 54.0 mmol, 1 equiv) in dry THF (120 mL) was added at rt. The mixture
was refluxed overnight, cooled to rt and diluted with water and EA (400 mL).
The organic layer was washed with 1 N HCl (2 Â 200 mL), water (200 mL) and
brine, dried over anhydrous sodium sulfate. The residue after evaporation was
purified on a silica gel column eluted with PE/EA = 9:1 to give 71 (7.1 g, yield
53%). TLC analysis of 71 (silica gel plate, EA/PE = 1:9): Rf = 0.3. To a solution of 71
(6.0 g, 23.99 mmol) in DCM (160 mL) were added pyridine (9.7 ml,
119.95 mmol, 5 equiv) and Tf2O (8.9 mL, 52.8 mmol, 2.2 equiv) at 0 °C. The
mixture was stirred at rt for 2 h and then washed with water (2 Â 60 mL), 0.5 N
HCl (2 Â 70 mL), brine, dried over anhydrous sodium sulfate. The residue after
evaporation was purified on a silica gel column eluted with PE/EA=9:1 to give 76
(9.5 g, yield 89%). TLC analysis of 76 (silica gel plate, EA/PE = 1:9): Rf = 0.3. To a
solution of 76 (3 g, 7.83 mmol) in 1,4-dioxane (40 mL) were added KOAc (1.92 g,
19.57 mmol, 2.5 equiv) and Pin2B2 (2.18 mg, 8.61 mmol, 1.1 equiv). The mixture
was bubbled with N2 for 15 min and then Pd(PPh3)2Cl2 (550 mg, 0.783 mmol,
0.1 equiv) was added. The reaction mixture was stirred under N2 at 95 °C
overnight, cooled to rt and filtrated. The residue after evaporation was purified
on a silica gel column eluted with PE/EA = 9:1 to give 81 (2.5 g, yield 89%). TLC
analysis of 81 (silica gel plate, EA/PE = 1:9): Rf = 0.3. To a solution of 81 (2.5 g,
6.94 mmol) in MeOH (35 mL) was added NaBH4 (289 mg, 7.63 mmol, 1.1 equiv)
at 0 °C. The mixture was stirred for 1.5 h at rt and then 1 N HCl (5 mL) was added
to adjust pH 1–2. After being stirred for 0.5 h, the mixture was extracted with EA
(3 Â 50 mL) and the combined organic phase was washed with brine, dried over
anhydrous sodium sulfate and concentrated. The residue was purified by silica
gel column chromatography eluted with PE/EA = 4:1 to give 86 (300 mg, yield
17%). TLC analysis of 86 (silica gel plate, EA/PE = 3:7): Rf = 0.3. 1H NMR of 86
(300 MHz, DMSO-d6): d 9.12 (s, 1H), 8.01 (d, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.86
(d, 1H), 4.96 (s, 2H), 4.19 (q, 2H), 3.84 (s, 3H), 1.26 (t, 3H) ppm. Mass (ESI+): m/
z = 263 (M+H). To a solution of 86 (430 mg, 1.6 mmol) in EA (8 mL) was added
10% Pd/C (126 mg). The reaction vessel was vacuumed and backfilled with H2.
After being stirred at rt for 2 h, the mixture was filtered and evaporated to give
91 (205 mg, yield 49%). TLC analysis of 91 (silica gel plate EA/PE = 3:7): Rf = 0.6.
1H NMR of 91 (300 MHz, DMSO-d6): 8.80 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 4.90
(s, 2H), 4.03 (q, 2H), 3.76 (s, 3H), 2.96 (t, 2H), 2.61 (t, 2H), 1.15 (t, 3H) ppm. HPLC
purity: 95.1% at 220 nm; Mass (ESI+): m/z = 287 (M+23). To a solution of 91
(47.2 mg, 0.178 mmol) in MeOH/H2O = 3:1 (1.2 mL) was added LiOHÁH2O
(7.5 mg, 0.178 mmol). After being stirred at rt for 4 h, the mixture was
acidified to pH 5 with AcOH and followed by extraction with EA (3 Â 20 mL).
The combined organic layer was washed with brine, dried over anhydrous
sodium sulfate and evaporated. The residue was purified by silica gel column
chromatography eluted with PE/EA = 7:3 to give the final compound 11
(13.4 mg, yield 32%). 1H NMR of 11 (300 MHz, DMSO-d6): 11.97 (br s, 1H),
8.76 (br s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 4.90 (s, 2H), 3.76 (s, 3H), 2.94 (t, 2H),
2.51 (t, 2H). HPLC purity: 100% at 220 nm; Mass (ESI+): m/z = 237 (M+1).
PE/EA = 10:1): Rf = 0.6. To
a solution of Ph3PCH2COOEt bromide (73.7 g,
165.6 mol, 3.6 equiv) in DMSO (200 mL) was added t-BuOK (17.5 g,
156.4 mmol, 3.4 equiv) at 0 °C and the mixture was stirred for 1 h. A solution
of 53 (10 g, 46 mmol) in DMSO (50 mL) was added at 0 °C and the mixture was
stirred at rt for 3 h, quenched with water (200 mL), extracted with PE
(3 Â 200 mL), washed with brine, dried over Na2SO4 and evaporated. The
residue was purified on a silica gel column eluted from PE to PE/EA=20:1 to give
54 as an oil (10.5 g, yield 80%). TLC analysis of 54 (silica gel plate, PE/EA = 10:1):
Rf = 0.6. To a solution of NBS (3.7 g, 20 mmol) and 54 (5 g, 17.4 mmol) in CCl4
(174 mL) was added BPO (200 mg, 0.9 mmol) under N2. The mixture was stirred
at 85 °C for 2 h and cooled to rt. The organic phase was washed with water
(100 mL) and brine, dried over Na2SO4, and evaporated. The crude residue was
purified on a silica gel column eluted with PE/EA = 10:1 to give 55 (2.4 g, yield
38%). TLC analysis of 55 (silica gel plate, PE/EA = 10:1): Rf = 0.5. A mixture of 55
(1.28 g, 3.5 mmol) and KOAc in DMF (15 mL) was stirred at 50 °C for 1 h. The
reaction was diluted with EA (20 mL) and water (50 mL). The aqueous phase was
extracted with EA (2 Â 20 mL). The combined organic phase was washed with
water (100 mL) and brine, dried over Na2SO4 and evaporated. The oil residue
was purified on a silica gel column eluted with PE/EA = 20:1 to give 56 (1.2 g,
yield 100%). TLC analysis of 56 (silica gel plate, PE/EA = 10:1): Rf = 0.6. A solution
of 56 (200 mg, 0.58 mmol), Pin2B2 (181 mg, 0.7 mmol), KOAc (195 mg,
1.74 mmol) and Pd(PPh3)2Cl2 (17 mg, 0.04 equiv) in 1,4-dioxane (3 mL) was
stirred at 80 °C under N2 overnight. Then the reaction mixture was diluted with
EA (2 mL) and water (5 mL). The aqueous phase was extracted with EA
(2 Â 2 mL). The combined organic phase was washed with brine, dried over
Na2SO4, and evaporated. The residue was purified on a silica gel column eluted
with PE/EA = 10:1 to give 57 (115 mg, yield 51%). TLC analysis of 57 (silica gel
plate, PE/EA = 10:1): Rf = 0.4. To a solution of 57 (500 mg, 1.3 mmol) in THF/
MeOH/H2O = 3:2:1 (20 mL) was added NaOH (160 mg, 4 mmol) at rt and the
mixture was stirred for 2 h. It was acidified with HCl (6 N, 1 ꢀ 2 mL, pH 1 ꢀ 2)
and stirred for additional 0.5 h. Then the mixture was diluted with water
(20 mL) and EA (10 mL). The aqueous phase was extracted with EA (2 Â 10 mL).
The combined organic phase was washed with brine, dried over Na2SO4, and
evaporated to give a solid (420 mg). The solid was recrystallized from MeOH
(15 mL) and dried under high vacuum to give 58 as a white solid (150 mg, yield
70%). 1H NMR of 58 (300 MHz, DMSO-d6): d 12.48 (s, 1H), 9.45 (s, 1H), 7.97 (d,
1H), 7.37–7.50 (m, 2H), 6.77 (d, 1H), 4.99 (s, 2H) ppm. A solution of 58 (50 mg,
0.225 mmol) and 10% Pd/C (10 mg) in EA (10 mL) was stirred at rt under H2 for
1 h. The mixture was filtered and evaporated to give the desired final compound
9 as a white solid (50 mg, 100% yield). 1H NMR of 9 (500 MHz, DMSO-d6): d
12.07 (s, 1H), 9.10 (s, 1H), 7.27–7.21 (m, 2H), 4.94 (s, 2H), 3.01 (t, 2H), 2.49 (m,
2H) ppm; HPLC purity: 99.3% at 220 nm; MS (ESI+): m/z = 247 (M+23).
Syntheses
yl)propanoic acid (10), 3-(4-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborol-
7-yl)propanoic acid (17), 3-(4-acetamido-1-hydroxy-1,3-
of
3-(1-hydroxy-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborol-7-
dihydrobenzo[c][1,2]oxaborol-7-yl)propanoic acid (18) and 1-hydroxy-3,6,8,9-
tetrahydro-[1,2]oxaborolo[3,4-f]quinolin-7(1H)-one (60): To fuming HNO3
(9.6 mL, 2 mL/mmol) was added 1 (2 g, 9.7 mmol) at À30 °C and the mixture
was stirred for 0.5 h at À30 °C. The mixture was poured into ice-water, stirred
Synthesis
of
3-(1-hydroxy-5-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-7-

1306
Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
yl)propanoic acid (12): This compound was prepared by the similar method
was stirred at 100 °C overnight, filtered and extracted with EA. The organic
phase was washed with brine and dried over anhydrous Na2SO4. The residue
after rotary evaporation was purified by silica gel column chromatography to
give 104 (2.4 g, yield 83%). 1H NMR of 104 (500 MHz, DMSO-d6): d 7.67 (m, 1H),
7.43 (m, 1H), 5.55 (t, 1H), 4.51 (d, 2H), 3.91 (s, 3H) ppm. To a solution of 104
(2.4 g, 9.1 mmol) in DCM (46 mL) was added silica (2.4 g) and PCC (2.9 g,
13.6 mmol, 1.5 equiv). The mixture was stirred at rt for 4 h, filtered and
evaporated. The residue was purified by silica gel column chromatography to
give 105 (2 g, yield 84%). To a solution of 105 (2 g, 7.66 mmol) in toluene
(33 mL) was added PPTS (192 mg) and ethane-1,2-diol (0.85 mL, 15.3 mmol,
2 equiv). The mixture was stirred at 138 °C overnight and then evaporated. The
residue was purified by silica gel column chromatography to give 106 (2.23 g,
yield 96%). 1H NMR of 106 (300 MHz, DMSO-d6): d 7.72 (m, 1H), 7.47 (m, 1H),
5.96 (s, 1H), 3.91–4.11 (m, 7H) ppm. To a solution of 106 (3 g, 9.83 mmol) in 1,4-
dioxane (49 mL) was added KOAc (4.142 g, 42.269 mmol, 4.3 equiv), Pin2B2 (3 g,
11.796 mmol, 1.2 equiv) and Pd(Ph3P)2Cl2 (0.345 mL, 0.49 mmol, 0.05 equiv)
under N2. The reaction was stirred at 95 °C overnight under N2, cooled and
evaporated. The residue was purified by silica gel column chromatography to
give 107 (3.46 g, crude yield 100%). To a solution of 107 (3.46 g, 9.83 mmol) in
anhydrous EtOH (50 mL) was added NaBH4 (929 mg, 24.5 mmol, 2.5 equiv) at
0 °C. The reaction was stirred at rt for 30 min and quenched with 2 N HCl. The
mixture was stirred at rt for 30 min, followed by extraction with EA. The organic
phase was washed with brine and dried over anhydrous Na2SO4. The residue
after rotary evaporation was purified by silica gel column chromatography to
give 108 (900 mg, yield 51%). 1H NMR of 108 (300 MHz, DMSO-d6): d 10.34 (s,
1H), 9.49 (s, 1H), 7.96 (m, 1H), 7.51 (m, 1H), 5.02 (s, 2H) ppm; HPLC purity: 100%
described above for the synthesis of 11. 1H NMR of 12 (500 MHz, DMSO-d6): d
11.98 (s, 1H), 8.83 (s, 1H), 7.01 s, 1H), 6.96 (s, 1H), 4.91 (s, 2H), 2.95 (t, 2H), 2.53
(t, 2H), 2.31 (s, 3H) ppm. HPLC purity: 98.2% at 220 nm; Mass (ESI+): m/z = 243
(M+23).
Synthesis
of
3-(5-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanoic acid (13): This compound was prepared by the similar method
described above for the synthesis of 11. 1H NMR of 13 (500 MHz, DMSO-d6): d
12.06 (br s, 1H), 9.10 (s, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 4.95 (s, 2H), 2.99 (t, 2H),
2.56 (t, 2H); HPLC purity: 96.8% at 220 nm; MS (ESI+): m/z = 241 (M+1).
Synthesis
of
3-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanoic acid (14): This compound was prepared by the similar method
described above for the synthesis of 11. 1H NMR of 14 (500 MHz, DMSO-d6):
12.05 (s, 1H), 9.00 (s, 1H), 7.05 (d, 1H), 6.99 (d, 1H), 4.94 (s, 2H), 3.00 (t, 2H), 2.56
(t, 2H) ppm; HPLC purity: 97.2% at 220 nm; Mass (ESI+): m/z = 225 (M+H).
Synthesis
of
3-(1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-7-
yl)propanoic acid (15): This compound was prepared by the similar method
described above for the synthesis of 11. 1H NMR of 15 (500 MHz, DMSO-d6): d
11.97 (s, 1H), 8.88 (s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.92 (s, 2H), 2.96 (t, 2H), 2.51
(t, 2H), 2.17 (s, 3H) ppm; HPLC purity: 95.3% at 220 nm; Mass (ESI+): m/z = 243
(M+23).
Synthesis
yl)propanoic acid (16): To a solution of 53 (1 g, 4.6 mmol) in t-BuOH (33 mL)
were added 2-methyl-2-butene (3.4 mL, 32.2 mmol, 7 equiv), solution of
of
3-(1-hydroxy-4-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-
a
NaClO2 (833 mg, 9.2 mmol, 2 equiv) and NaH2PO4Á3H2O (2.15 g, 13.8 mmol,
3 equiv) in water (14 mL). The mixture was stirred at rt for 30 min and then was
quenched with 1 N HCl and extracted with EA. The organic phase was washed
with brine and dried over anhydrous Na2SO4. The residue after evaporation was
purified by silica gel column chromatography to give 96 (1.07 g, yield 100%). To
a solution of 96 (1.53 g, 6.56 mmol) in DMF (30 mL) was added K2CO3 (2.26 g,
16.4 mmol, 2.5 equiv), and the mixture was stirred at rt for 10 min. MeI
(0.815 mL, 13.1 mmol, 2 equiv) was added and then the reaction was stirred for
1 h, quenched with 1 N HCl and extracted with TBME. The organic phase was
washed with saturated NaHCO3, brine and dried over anhydrous Na2SO4. The
residue after rotary evaporation was purified by silica gel column
chromatography to give 97 (1.5 g, 94%). A mixture of 97 (7.9 g, 32 mmol), NBS
(17.1 g, 96 mmol, 3 equiv), BPO (0.78 g, 3.2 mmol, 0.1 equiv) in CCl4 (133 mL,
c = 0.24) was refluxed under N2 for 6 h, cooled and filtered. The residue after
rotary evaporation was purified by silica gel column chromatography to give 98
(11.4 g, yield 89%). To a solution of 1 N MeONa in MeOH (180 mL, 6 equiv) was
added 98 (11.5 g, 28.3 mmol) at rt. The mixture was stirred at 65 °C for 4 h,
quenched with 2 N HCl to adjust pH 2, and followed by addition of water
100 mL. The aqueous phase was extracted with EA (2 Â 200 mL) and the
combined organic phase was washed with brine and dried. The residue after
evaporation was purified by silica gel column chromatography to give 99
(2.94 g, yield 38%). 1H NMR of 99 (300 MHz, DMSO-d6): d 10.10 (s, 1H), 7.95 (d,
1H), 7.35 (d, 1H), 3.93 (s, 3H), 3.88 (s, 3H) ppm. To a solution of 99 (3.8 g,
13.97 mmol) in toluene (76 mL) were added PPTS (350 mg, 1.39 mmol,
0.1 equiv) and ethane-1,2-diol (1.73 g, 27.94 mmol, 2 equiv). The reaction was
stirred at 130 °C overnight and evaporated to give yellow oil. The residue was
purified by silica gel column chromatography eluted with PE/EA = 4:1 to give
100 (3.9 g, yield 89%). To a solution of 100 (0.5 g, 1.58 mmol) in 1,4-dioxane
(8 mL) were added KOAc (388 mg, 3.95 mmol, 2.5 equiv), Pin2B2 (442 mg,
1.74 mmol, 1.1 equiv). The solution was bubbled with N2 for 15 min and then
Pd(PPh3)2Cl2 (55.5 mg, 0.079 mmol, 0.05 equiv) was added. The mixture was
stirred under N2 at 95 °C overnight, cooled to rt and filtrated. The residue after
evaporation was purified by silica gel column chromatography eluted with PE/
at 220 nm; MS (ESI+): m/z = 203 (M+23). To
a solution of Ph3PCH2COOEt
bromide (2.98 g, 6.9 mmol, 2.5 equiv) in DMSO (20 mL) was added t-BuOK
(0.6783 g, 5.55 mmol, 2 equiv) under N2. After being stirred at rt for 1 h, to the
reaction mixture was added a solution of 108 (500 mg, 2.778 mmol) in DMSO
(8 mL). The mixture was stirred at rt overnight, quenched with water and
extracted with EA. The organic phase was washed with brine and dried over
anhydrous Na2SO4. The residue after rotary evaporation was purified by silica
gel column chromatography to give 109 (560 mg, yield 80%). 1H NMR of 109
(500 MHz, DMSO-d6): d 9.54 (s, 1H), 8.06 (d, 1H), 7.91 (m, 1H), 7.33 (m, 1H), 6.76
(d, 1H), 5.10 (s, 2H), 4.20 (q, 2H), 1.25 (t, 3H) ppm. To a solution of 109 (420 mg,
1.68 mmol) in EA (40 mL) was added 10% Pd/C (42 mg). The reaction vessel was
vacuumed and backfilled by H2 for three times. The mixture was stirred at rt for
1 h, filtered and evaporated. The residue was purified by silica gel column
chromatography to give 111 (373 mg, yield 88%). 1H NMR of 111 (500 MHz,
DMSO-d6): d 9.20 (s, 1H), 7.14–7.21 (m, 2H), 5.04 (s, 2H), 4.02 (q, 2H), 3.01 (t,
2H), 2.60 (t, 2H), 1.14 (t, 3H) ppm; HPLC purity: 100% at 220 nm; MS (ESI+): m/
z = 275 (M+23). To a solution of 111 (350 mg, 1.368 mmol) in THF/MeOH/
water = 3:2:1 (7 mL) was added LiOHÁH2O (233 mg, 5.55 mmol, 4 equiv). The
mixture was stirred at rt overnight, added with water and extracted with EA.
The organic phase was washed with brine and dried over anhydrous Na2SO4. The
residue after rotary evaporation was purified by silica gel column
chromatography to give the final compound 20 (250 mg, yield 81%). 1H NMR
of 20 (500 MHz, DMSO-d6): d 11.98 (s, 1H), 9.16 (s, 1H), 7.12–7.19 (m, 2H), 5.01
(s, 2H), 2.96 (t, 2H), 2.51 (t, 2H); HPLC purity: 98.9% at 220 nm; MS (ESI+): m/
z = 225 (M+1).
Synthesis of 3-(3-hydroxy-1,3-dihydroisobenzofuran-4-yl)propanoic acid (21):
Compound 112 was prepared from 1 as previously reported.2 To a solution of
112 (2 g, 9.09 mmol) in toluene (57 mL) were added 20% Na2CO3/H2O (5.5 mL)
and Pd(PPh3)4 (1.05 g, 0.92 mmol, 0.1 equiv) under N2. Then bromoethene in
THF (19 mL, 2 equiv) was added and the reaction was stirred at 90 °C overnight.
It was filtered and dried over anhydrous MgSO4 followed by filtration and
evaporation. The residue was purified by silica gel column chromatography to
give 113 (0.91 g, yield 41%). To a solution of 113 (910 mg, 4.05 mmol) and DIPEA
(1.53 mL, 8.91 mmol, 2.2 equiv) in DCM (20 mL) was added MOMCl (0.49 g,
6.08 mmol, 1.5 equiv) at 0 °C. The reaction was stirred at rt for 10 h, quenched
with NH4Cl-saturated aqueous solution and extracted with DCM (3 Â 15 mL).
The organic phase was washed with brine and dried over anhydrous MgSO4. The
residue after rotary evaporation was purified by silica gel column
chromatography to give 114 (0.67 g, yield 63%). To a mixture of 114 (600 mg,
2.27 mmol) and K2OsO4 (3 mg) in THF (10 mL) and water (0.8 mL) was added a
solution of NaIO4 (1.1 g) in water (3 mL) dropwise. The reaction mixture was
stirred at rt for 10 h followed by filtration. The filtrate was extracted with DCM
(3 Â 10 mL), dried over anhydrous MgSO4 and evaporated. The residue was
purified by silica gel column chromatography to give 115 (390 mg, yield 64%).
To a solution of 115 (300 mg, 1.13 mmol) in THF (2.8 mL) was added 4 N HCl
(1.4 mL). The reaction mixture was stirred at rt for 1 h and quenched with
saturated NaHCO3 (30 mL). The aqueous phase was extracted with DCM
(3 Â 10 mL). The residue after evaporation was purified by silica gel column
chromatography to give 116 (120 mg, yield 68%). 1H NMR of 116 (500 MHz,
DMSO-d6): d 7.28 (t, 1H), 7.16–7.12 (m, 2H), 6.63 (d, 1H), 6.42 (dd, 1H), 5.07 (d,
1H), 4.85 (d, 1H), 3.59 (s, 3H), 2.97-2.85 (m, 2H), 2.71–2.61 (m, 2H) ppm. To a
solution of 116 (49.8 mg, 0.224 mmol) in MeCN (1.1 mL) was added LiOHÁ2H2O
(13.5 mg, 0.224 mmol, 1 equiv). The mixture was stirred at rt for 10 h,
concentrated and dried under high vacuum to provide the final compound 21
as its lithium salt (51.5 mg, yield 100%). 1H NMR of 21 lithium salt (500 MHz,
DMSO-d6): d 7.38 (br s, 1H), 7.22 (t, 1H), 7.10 (d, 1H), 7.06 (d, 1H), 6.41 (s, 1H),
5.04 (d, 1H), 4.81 (d, 1H), 2.82–2.78 (m, 2H), 2.27–2.23 (m, 2H) ppm; HPLC
purity: 92.5% at 220 nm. MS (ESI+): m/z = 191 (MÀ17).
EA = 9:1 to give 101 (230 mg, yield 40%). To
a solution of 101 (450 mg,
1.23 mmol) in MeOH (6.2 mL) was added NaBH4 (51.4 mg, 1.36 mmol, 1.1 equiv)
at 0 °C. The reaction was stirred for 1.5 h at rt and 2 N HCl (5 mL) was added to
adjust pH 1–2. The mixture was stirred for 0.5 h and extracted with EA
(3 Â 20 mL). The organic layer was washed by brine, dried over anhydrous
sodium sulfate and concentrated. The residue after evaporation was purified by
silica gel column chromatography eluted with PE/EA = 7:3 to give 102 (190 mg,
yield 80%). 1H NMR (300 MHz, DMSO-d6): 10.19 (s, 1H), 9.10 (s, 1H), 7.97 (d, 1H),
7.27 (d, 1H), 5.03 (s, 2H), 3.94 (s, 3H) ppm; HPLC purity: 92.6% at 220 nm and
98.0% at 266 nm. Formic acid (0.32 mL, 8.85 mmol, 10 equiv) and TEA (0.49 mL,
3.54 mmol, 4 equiv) was mixed at 0 °C, and stirred at rt for 10 min. Then 102
(170 mg, 0.885 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (140 mg,
0.973 mmol, 1.1 equiv) were added. The mixture was stirred at rt for 1 h and
at 114 °C overnight, cooled to rt and acidified with 1 N HCl at 0 °C. After being
stirred for 10 min, it was extracted with EA (3 Â 20 mL). The organic layer was
washed with saturated sodium chloride and dried over anhydrous sodium
sulfate. The residue after evaporation was purified by preparative TLC to give the
final compound 16 (15.6 mg, yield 7.5%) as
a
white solid. 1H NMR of 16
(300 MHz, DMSO-d6): 11.95 (s, 1H), 8.95 (s, 1H), 7.11 (d, 1H), 6.94 (d, 1H), 4.89
(s, 2H), 3.78 (s, 3H), 2.93 (t, 2H), 2.50 (t, 2H) ppm; HPLC purity: 96.0% at 220 nm;
Mass (ESI+): m/z = 237 (M+1).
Synthesis
of
3-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-
yl)propanoic acid (20): To a solution of 97 (4.6 g, 18.6 mmol) in CCl4 (81 mL)
was added NBS (3.31 g, 18.6 mmol, 1 equiv) and BPO (225 mg, 0.93 mmol,
0.05 equiv). The reaction was stirred under N2 at 82 °C overnight, cooled to rt,
filtered and evaporated. The residue was purified to give 103 (3.6 g, yield 60%).
1H NMR of 103 (300 MHz, DMSO-d6): d 7.84 (m, 1H), 7.47 (m, 1H), 4.77 (s, 2H),
3.93 (s, 3H) ppm. To a mixture of 103 (3.6 g, 11 mmol) in 1,4-dioxane (22 mL)
and water (9 mL) was added CaCO3 (2.65 g, 26.5 mmol, 2.4 equiv). The reaction
Synthesis of 3-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-yl)acrylic
acid (110): The mixture of 109 (80 mg, 0.3199 mmol) and LiOHÁH2O (53.9 mg,

Y.-K. Zhang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1299–1307
1307
1.28 mmol, 4 equiv) in THF/MeOH/water = 3:2:1 (2 mL) was stirred at rt
overnight, added with water and extracted with EA. The organic phase was
washed with brine and dried over anhydrous Na2SO4. The residue after
evaporation was purified by silica gel column chromatography to give 110
(20 mg, yield 28%). 1H NMR of 110 (500 MHz, DMSO-d6): d 12.25 (s, 1H), 9.50 (s,
1H), 8.02 (d, 1H), 7.86 (m, 1H), 7.32 (m, 1H), 6.64 (d, 1H), 5.09 (s, 2H) ppm;
HPLC purity: 94.0% at 220 nm and 94.8% at 266 nm. MS (ESI+): m/z = 223
(M+1).