Synthesis of a novel class of antitubercular peptidomimetics based on β-aminoboronates.

(1)

β

(2)

(3)

1 Synthesis of a novel class of

antitubercular peptidomimetics

based on β-aminoboronates.

(4)

2

(5)

3 A CKNOWLEDGEMENTS

(6)

4

(7)

5 A ^BSTRACT

β

β α

β

(8)

6 L IST OF ABBREVIATIONS

(9)

7 T ABLE OF CONTENTS

β β

α β

β β

α β β

α β

α β β

β

(10)

8 α β

β β

α β β

α β

(11)

9 1. I NTRODUCTION

β

(12)

10

(13)

11 β

β

(14)

12 α

α

α β α γ

β α

α β



β

β α

β

(15)

13 β

β

α β

β

    

α β

β β

β

(16)

14 β

β

(17)

15 β

β

1.24Å

1.29Å 1.48Å

bonds lengths for benzoic acid 1.568Å

1.378Å

1.362Å bonds lengths for phenylboronic acid

120°

~ 109°

(18)

16 Ser

195

Ser

195

Ser

195

Ser

195

(19)

17

*

(20)

18 α

α

β β

α

(21)

19 -

- -

LiCHCl

2

ZnCl

2

1.1 1.2

1.3 1.4

(22)

20 1.5 1.6

[1,2]-rearrangement

ZnCl

2

1.7

1.8

Scheme 1.4 1.9

(23)

21 α

(24)

22 OsO

4

OsO

4

4-Me-morpholine-4-oxide 4-Me-morpholine-4-oxide

(-)-α-pinene (+)-α-pinene

(1 R ,2 R ,3 S ,5 R )-(-)-pinanediol (1 S ,2 S ,3 R ,5 S )-(+)-pinanediol

α α

(+)-pinanediol (-)-pinanediol

1.10 1.11

(25)

23 A IMS OF THE PROJECT

β β

β

α β

(26)

24 β

(27)

25

(28)

26 2. R ESULTS AND DISCUSSION

β β

β

(29)

27 A

C B

α β

β β α β β

(30)

28 α β

a b c

d e

f

2.1 2.2 2.3

2.4 2.5 2.6

2.7

α β

(31)

29 β

(32)

30 β

α

*

(33)

31 α β

(34)

32 β β

2.8 2.9 2.10

2.11 2.12

2.13 2.14

2.15

d

e f

g

a b

c

β β

(35)

33 β β

α β

β β

(36)

34 α

α β β

β β

β α

α α

β

α

(37)

35

2.18 2.9

2.19 a

b

2.16 c

2.17

α α

α

α α

(38)

36

2.19

c a

2.16

2.20 b

2.16 2.9e

α

(39)

37 2.22 60% conversion

2.16 a

b

2.16 2.20

β β 2.21

(40)

38

(41)

39 α β β

2.11 2.23

2.24 2.25

2.26 a

b c

d

α β β

(42)

40 α β β

α

2.23

(43)

41 β

α

(44)

42 tetrahedral 1.638Å

α

β

α

α β

(45)

43 Bz

t-Boc-NH H

H

Me pin-B

HH

MeB-pin

NH-t-Boc Bz

a b

α β β

(46)

44 α β β

β

α β β

α

α α

α,β

(47)

45

2.11

α

(48)

46

a b

c d e

f

2.11 2.27 2.28

78% 50%

2.29 2.30

2.31 2.32

α β β β

(49)

47

2.33 α

(50)

48 α β

2.30 2.31a

α β β

β

α β

(51)

49 A B C

R1

R1 pin R1

pin pin

α β β

β



α β

(52)

50 α β

α β

R1

R2

COOR

NH2

R1

R2

(53)

51 β α

2.34 2.35

2.36

a

b

HRMS found: 795.3936

Exact Mass : 795,3924

Formula : C

47

H

52

BN

4

O

7

(54)

52 α β

β

(55)

53 α

2.10c 2.37

(-)-pinanediol

KHF

2

(56)

54

H H R1 R3

N B

N H R1 R3

H B

N R3 R1 H

H B

(-)-pinanediol (+)-pinanediol

(+)-pinanediol

H (-)-pinanediol

R3 R1 H

N B

A B

C D

deprotection

esterification

(57)

55

(58)

56 α

(59)

57 α

β

(60)

58 2.38 Mosher acid

2.5c

(61)

59 α β

2.28 2.39

(62)

60

(63)

61 α β

β

β β

2.40 2.41

a b

1 2 3 4

2.4c Scheme 2.17

a:

(64)

62

(65)

63

(66)

64 The α β

β

(67)

65

(68)

66 β β

Ph Ph

Ph

Ph Ph Ph

- N2

H2O Ph Ph Ph

Ph Ph

Ph

Ph Ph

Ph

(69)

67 β β

2.42

2.43 2.12c

2.13c Ph

?

not detected Ph

.

Ph

H

2

O

Ph

Ph Ph

Ph

Ph Ph Ph

Ph

β

(70)

68

(71)

69 α

α

(72)

70

2.10c

Scheme 2.20 R

α

β

α β

β

(73)

71

(74)

72 3. M ICROBIOLOGICAL INVESTIGATIONS

β

(75)

73 α β

α β

α

β

α

(76)

74 α β

2.6 2.7

(77)

75

(78)

76 α

α

(79)

77 β β

β

α -

- - - - -

β α β

(80)

78 β β

2.14 2.15

(81)

79 α β β

α β

α β β

α β

α

(82)

80 α,β β

2.25

(83)

81 α β

α β

2.32a 2.29

α

(84)

82

(85)

83 α

(86)

84

SMI ID INH SM RIF EMB OFX CAP AMI KM Rif range: 0.25-2

mg/L 2.7-11 2.14-3 2.7-17 2.6-23 2.6-8 2.6-12 2.6-25range: 6.875-55

mg/L XTB10-

215 R R R R R R R R >2 >128 >128 >128 64 128 128 27.5

XTB10-

213 R R R S S S S S >2 >128 >128 >128 64 128 128 27.5

XTB10-

212 R R R R S R R R >2 >128 >128 >128 64 128 128 27.5

XTB10-

210 S S S S S S S S ≤0,25 >128 >128 >128 64 128 128 27.5

XTB10-

208 S S S S S S S S ≤0,25 >128 >128 >128 64 128 128 27.5

XTB10-

207 S S S S S S S S ≤0,25 128 128 >128 64 128 128 27.5

XTB10-

206 S S S S S S S S ≤0,25 >128 >128 >128 64 128 128 27.5

XTB11-

176 R R R R R S S S >2 >128 >128 >128 64 128 128 27.5

XTB11-

177 R R R S S S S S >2 >128 >128 >128 64 >128 128 27.5

XTB11-

180 R R R S S S S R >2 >128 >128 >128 64 128 128 27.5

XTB11-

181 S S S S S S S S ≤0,25 128 >128 >128 64 128 128 27.5

XTB11-

182 R R R R S S S S >2 >128 >128 >128 64 128 128 27.5

XTB11-

183 S S S S S S S S ≤0,25 >128 >128 >128 64 128 128 27.5

XTB11-

184 R R R S S S S R >2 >128 >128 >128 64 128 128 27.5

XTB11-

189 S S S S S S S S ≤0,25 128 >128 >128 64 128 128 27.5

XTB11-

190 S S S S S S S S ≤0,25 128 >128 >128 64 128 128 27.5

XTB11-

191 S S S S S S S S ≤0,25 >128 >128 >128 64 128 128 27.5

XTB11-

192 S S S S S S S S ≤0,25 >128 64 >128 64 64 128 27.5

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85

XTB11-

193 R R R R S S S S 2 >128 >128 >128 64 >128 128 27.5

XTB11-

194 R R R S S S S S >2 >128 >128 >128 32 128 128 27.5

XTB11-

195 R R R S S S S S >128 >128 >128 64 >128 128 27.5

BTB 11-

299 R R R R R S S S >2 >128 >128 >128 64 128 128 27.5

BTB 10-

092 R R R R R S S S no growth no

growth no growth

no growth

no

growth no growth

BTB 10-

344 R R S R R S R R ≤0,25 >128 >128 >128 64 >128 128 27.5

BTB 10-

349 R R S R R S S S ≤0,25 >128 >128 >128 64 >128 128 27.5

H37Rv S S S S S S S S ≤0,25 >128 >128 >128 64 >128 128 27.5

(88)

86

(89)

87

(90)

88 μ

μ

(91)

89

(92)

90

(93)

91 4. M ECHANISTIC INVESTIGATION AND

TOXICITY TESTING

(94)

92 α β

α

β

α

β

(95)

93 μ μ

μ

0 0,2 0,4 0,6 0,8 1

0 10 20 30 40 50 60 70 80 90

Relative fluorescence

Temperature [°C]

A02 (0 ˚C)-reference A03 (9,3 ˚C)-8 mM TSA B02 (-3,5 ˚C)-8 mM tlo281 *MtCM

C02 (-3,7 ˚C)-8 mM tlo281 *MtCM D02 (-3,1 ˚C)-8 mM tlo281 *MtCM B04 (3,6 ˚C)-8 mM tlo173 *MtCM C04 (3 ˚C)-8 mM tlo173 *MtCM D04 (2,7 ˚C)-8 mM tlo173 *MtCM

*

β

(96)

94

0 0,2 0,4 0,6 0,8 1

0 10 20 30 40 50 60 70 80 90

Relative fluorescence

A02 (0 ˚C)-reference A03 (9,3 ˚C)-8 mM TSA B05 (-0,4 ˚C)-8 mM tlg116 *MtCM

C05 (-0,1 ˚C)-8 mM tlg116 *MtCM D05 (-1,6 ˚C)-8 mM tlg116 *MtCM

0 0,2 0,4 0,6 0,8 1

0 10 20 30 40 50 60 70 80 90

Relative fluorescence

E02 (0 ˚C)-reference F01 (2 ˚C)-8 mM tlo289 MtCM H01 (-2,2 ˚C)-8 mM tlo289 MtCM F04 (-1,3 ˚C)-8 mM tlo173 MtCM G04 (-1,3 ˚C)-8 mM tlo173 MtCM H04 (-0,8 ˚C)-8 mM tlo173 MtCM F05 (-32,1 ˚C)-8 mM tlg116 MtCM G05 (-32 ˚C)-8 mM tlg116 MtCM H05 (-31,6 ˚C)-8 mM tlg116 MtCM

μ μ

μ

(97)

95 μ

μ

(98)

96 5. C ^ONCLUSIONS

- α β

- β β

- α β β

β

α β

α-

β

(99)

97 6. S UMMARY OF SYNTHESIZED

PEPTIDOMIMETICS

(100)

98 7. E XPERIMENTAL SECTION

α

μ

α α α α

α

(101)

99

CH²Br²

n-BuLi (+)- or (-)-pinanediol

2.1

NaN3

tetrabutylammonium bromide dichloromethane/H2O

2.1 2.2

(102)

100

CH2Cl2

n-BuLi

THF

2.2 2.3

lithium triethylborohydride

THF

2.3 2.4a

α

δ

(103)

101

2.4

R1MgCl

ZnCl2

THF

2.3 α

δ

α

(104)

102 δ

δ

(105)

103 δ

δ

(106)

104 δ

δ

(107)

105 2.HCl/MeOH

2.4 2.5

1.LiAlH

4

/THF

β

δ

α

(108)

106 δ

δ

α

δ

α

δ

(109)

107 δ

α

δ

α

(110)

108 δ

δ

α

δ

α

(111)

109 δ

δ

α

δ

α

(112)

110 2.5 2.6

′

δ

α

(113)

111 δ

δ

α

δ

α

(114)

112 δ

δ

α

δ

α

(115)

113 δ

δ

α

δ

(116)

114 α

δ

α

δ

(117)

115 δ

α

δ

α

δ

(118)

116 δ

α

δ

α

δ

(119)

117 δ

α

δ

α

(120)

118 δ

δ

(121)

119 δ

δ

α

(122)

120 δ

δ

α

(123)

121 δ

δ

α

δ

(124)

122 δ

α

δ

α

(125)

123 δ

δ δ

α

δ

α

(126)

124 δ

δ

α

δ

(127)

125 δ

α

δ

α

6 7

(128)

126 δ

δ

α

δ

(129)

127 δ

α

δ

α

δ

α

(130)

128 δ

δ

α

δ

α

(131)

129 δ

δ

α

δ

α

(132)

130 δ

δ

(133)

131 δ

δ

(134)

132 δ

δ

α

δ

(135)

133 δ

δ

(136)

134 δ

δ

(137)

135 δ

δ

α

δ

(138)

136 δ

δ

α

(139)

137 δ

δ

α

δ

(140)

138 δ

δ

α

(141)

139 β

δ

α

(142)

140 δ

δ

α

β β

α

(143)

141 δ

δ

(144)

142 δ

60% conversion

a b

2.16 2.20 2.21

α α

δ

(145)

143 α

δ

α

δ

(146)

144 δ

α

δ

α

δ

(147)

145 δ

α

δ

α

(148)

146 δ

δ

α

(149)

147 δ

δ

α

δ

(150)

148 δ

δ

α

δ

α

(151)

149 δ

δ

α

δ

(152)

150 δ

δ

2.11 2.23

α

(153)

151 δ

δ

α

(154)

152 δ

δ

α

(155)

153 δ

δ

α

0.23

11

21

7’’ 7’ 10

16 5’’ 4

1 2

5’

9_me

6

17

16

0.06 0.08 0.05 10 17

9me 13 11

1 7

14 12

2 3 21

8 4 9 5 10

6

15 17 16

18 19 20

9me 13 11

1 7

14 12

2 3 21

8 4 9 5 10

6

15 17 16

18 19 20



(156)

154

3

J

_16/10

~4.5 Hz 10

16

3

J

_16/17

~6 Hz

3

J

_16/18

~9 Hz

3

J

_16/10

~4.5 Hz

3

J

_16/17

~6 Hz

3

J

_16/18

~9 Hz 10

16

(157)

155



(158)

156

(159)

157

(160)

158

(161)

159

(162)

160

(163)

161

(164)

162

(165)

163

(166)

164

(167)

165 δ

δ

α

δ

(168)

166

(169)

167 δ

δ

α

δ

(170)

168 δ

α

δ

α

(171)

169 δ

δ

(172)

170 δ

(173)

171

(174)

172 δ

δ

(175)

173

(176)

174 (

α

(177)

175 Patent

(178)

176

(179)

177

(180)

178

(181)

189

(182)

190

(183)

201 β

(184)

202

(185)

207 Syntheses and anti-tubercular activity of -substituted and -disubstituted

 -aminoboronates and boronic acids

Alexey S. Gorovoy, Olga Gozhina, John-Sigurd Svendsen, George V. Tetz, Anna Domorad,

Victor V. Tetz and Tore Lejon

(186)

208

(187)

ISBN xxx-xx-xxxx-xxx-x

Synthesis of a novel class of antitubercular peptidomimetics based on β-aminoboronates.

β

1