Методы современного органического синтеза

O

DCC

22.

2

R

OH

O

N

OH

DCC

23.

R

or

R

NH2

H

O

24.

R

HNR2R3

X

X= O-NP or O-PFP or O-Su or O-Bt

O

BOP or PyBOP or TBTU or HBTU

25. R

DIEA or NEt3 / DMSO

OH

O

HNR1R2

26. R OH BOP or PyBOP or TBTU or HBTU

2.2. Пептидный и твердофазный синтез

PGN-AAN-OH

DPPA

H-AAC-OPGC

27.

NEt3 or EDIA

...

PGN= Boc or Cbz or Fmoc; PGN= Me or t-Bu or Bn

N N

ClCO -i-Bu

H-AAC-OPGC

2

PG -AA

-OH

28.

NMO or NMP ...

PGN= Boc or Cbz or Fmoc; PGN= Me or t-Bu or Bn

PGN-AAN-OH

DCC or EDC

H-AAC-OPGC

29.

HO-Bt or HO-Su ...

PGN= Boc or Cbz or Fmoc; PGN= Me or t-Bu or Bn

PGN-AAN-OH

H-AAC-OPGC

30.

PyBOP or TBTU or HBTU / DIEA

PGN= Boc or Cbz or Fmoc; PGN= Me or t-Bu or Bn

31.

Boc-AAC-OH

Cl

PS

TFA

Cs2CO3 or DBU / DMF ...

Cl

= хлорметилполистирол

PS

(Merrifild's resin)

PS

Boc-AAN-OH / DIEA / DMF

32.

H-AAC-O

PyBOP or TBTU

PS

= метиленполистирол

(Merrifild's resin)

PS

H-AAC-O

Fmoc-AAN-OH / DCC or DIC

33.

HO-Bt / DMF or DMSO

PS = метиленполистирол

(Merrifild's resin)

PS

Fmoc-AAN-OSu

34.

H-AAC-O

DMF

PS = метиленполистирол

(Merrifild's resin)

TFA

PS

HF(liq.) or TfOH

35.

Boc-PP-O

PhOMe

PS

= метиленполистирол

(Merrifild's resin)

PS

NH3 / MeOH

36.

Boc-PP-O

= метиленполистирол

PS

(Merrifild's resin)

Fmoc-AAC-OH

Cl

.P

Pip

37.

...

DIEA / DCM

DMF

.P

= (2-Cl-Trt resin)

Fmoc-AAC-OH

Br

.P

Pip

38.

DIEA / DCM ...

DMF

.P

= (Wang resin)

Fmoc-AAC-OH

HO

.P

Pip

39.

... DMF

DIC / DMAP / DMF

.P

= (Wang resin)

H-AAC-O

Fmoc-AAN-OH / DCC or DIC

40.

P

HO-Bt / DMF

.P = (2-Cl-Trt resin or Wang resin)

H-AAC-O

Fmoc-AAN-OSu

41.

P

DMF

.P = (2-Cl-Trt resin or Wang resin)

42.H-AAC-O

Pip

43.DMF

Fmoc-AAN-OH / PyBOP or TBTU

P

DIEA / DMF

TFA Fmoc-PP-O P

DCM

.P = (2-Cl-Trt resin or Wang resin)

31

H2N		.P	Pip

44.Fmoc-AAC-OH PyBOP or TBTU... DMF

DIEA / DMF

H2N

.P

= (MBHA resin)

H-AAC-NH

Fmoc-AAN-OH

P

45.

PyBOP or TBTU

DIEA / DMF

HN

.P

= (MBHA resin)

Pip

HF(liq.) or MsOH

Fmoc-PP-NH P

46.

DMF

PhOMe

HN

.P

= (MBHA resin)

Приведите схемы синтеза пептидов твердофазным и жидкофазным методом с

использованием Boc- и Fmoc-стратегий:

47. a. H-Met-Glu-Ala-Phe-Lys-OH; b. H-Val-Asp-Tyr-Gly-Cys-OH; c. H-Ile-Asn-Arg-Ser-Pro-NH2.

H2

PS

HF(liq.) or TfOH

48.

Pd/C, DMF R-O

PhOMe

PS = метиленполистирол

R= Alk or Ar or Acyl

(Merrifild's resin)

NH3

O

NaOH

PS

R

49.

MeOH

O

PS

= метиленполистирол

(Merrifild's resin)

NaOMe

O

LiBH4

R

PS

50.

MeOH

O

THF

PS

= метиленполистирол

(Merrifild's resin)

HF(liq.)

PS

Na / NH3 (liq.)

51.

R-S

PhOMe

52.

PS

H2 / Pd/C

R-NH

DMF

O

OH or R-NH

2

or N

N

H

53.

Cl

.P

R

DIEA / DCM

.P = (2-Cl-Trt resin)

Cl

54.

.P

R1

55.

Ar-OH or Alk-OH or R-SH

.P

Py / THF

= (2-Cl-Trt resin)

TFA

X .P DCM

.P = (2-Cl-Trt resin) X= O, NH, NR2 or S O

OH

56.

R

HO

.P

DIC / DMAP / DMF

.P

= (Wang resin)

O

OH

or R-OH or RNH2

57.

R

Br

.P

Cs2CO3 or DBU or DIEA

DMF

.P

= (Wang resin)

CAN

TFA

R

O

.P

58.

DCM

.P = (Wang resin)

H2

59.

R

O

.P

Pd/C

.P

= (Wang resin)

O

O

OSu

OH

60.

R

R

H2N

.P

DMF

PyBOP or TBTU

(MBHA resin) DIEA, DMF

O

R

HF(liq.) or MsOH

61.

HN

.P

PhOMe

.P

= (MBHA resin)

HN

2.3. Синтезы на основе малонового и ацетоуксусного эфира

O

NaCN

62. Cl

OEt DMF

32

O

63.

NC

EtOH / HCl

OEt

O

64.

EtONa

2

Me

OEt

O

O

65.

Me

OEt

R

OEt

R= Ph or CF3 or Ph

EtONa or NaH

O

R1

NaOEt

...

R2-X

66.

OEt

EtOH(abs.)

R =Alk or Bn or All

2

R1= Ac or CO2Et or CN

X=Hal or OTs or OMs

O

R2-X

R1

67.

OEt

NaOH / PhH / TEBAC

R1= Ac or CO2Et or CN

R2=Alk or Bn or All

X=Hal or OTs or OMs

O

R1

NaOEt

R2-X

68.

OEt EtOH(abs.)

... R =Alk or Bn or All

2

X=Hal or OTs or OMs

R2

R1= Ac or CO2Et or CN

O

O

1. NaOH

...

69.

R

OEt

2. H

R1

R2

R=OEt or Me

O

R

NaCl or LiI

70.

OEt

DMSO, 150OC

R1 R2

R= Ac or CO2Et or CN

O

TsOH or DMAP(cat.)

R

71. OEt PhMe or C6H4Me2

	R1	R2	110-150OC
			R= Ac or CO2Et or CN

O O

NaOH (conc.)

72.MeOEt

R1 R2

				R1
	O
73. R		NaOEt		R2	O
			...
	OEt	EtOH(abs.)

R= Ac or CO2Et or CN

OO

74.MeO HBr(conc.)

O

O

X

75.

X

n

R

OEt

EtONa or NaH (ex.)

R=OEt or Me

X=Hal, OTs, OMs; n= 1-4

O

O

O

R

76.

Cl

EtO

OEt Mg(OEt)2 or MgCl2 / NEt3

O

O

TsOH or DMAP(cat.)

77.

EtO

OEt

PhMe or C6H4Me2

110-150OC

O

R

O

O

78.

OEt

1. NaOH (ex.)

EtO

...

2. H

O

R

O

O

O

R

79.

2 BuLi

Cl

...

...

EtO

OH

O

O

O

R

80.

H

HO

OH

Py,

O

O

81.

R2

R

R1

3

OEt

Pip / AcOH,

R1= CO2Et or СN

33

O

O

H2-Pd/C

NaCl or LiI

82. EtO

OEt

...

DMSO, 150O

C

R1

R2

O

O

HCN / NaCN(cat)

H2O / H

83.EtOOEt ...

R1 R2

O O

R3-M

H2O / H

84.EtO OEt CuI ...

M=MgBr or Li

R1

R2

O

O

85.

2

R

R

2

H

1. NaOH

1

OEt

...

HNEt2,

2. H ,

R1= CO2Et or CN

O

O

O

86.

2

R

H

1. NaOH (conc.)

...

Me

OEt

NaOEt

2. H

,

O

O

87.

NH3(anh.)

/ EtOH

Me

OEt

O

O

O

R

/ NH3

88.

2

OEt

H

Me

EtOH,

O

R

O

89.

EtO

OEt

HNO3 or DDQ

Me

N

Me

H

O

O

90.

CH(OMe)3 or CH(OEt)3

R

OEt

Ac2O / ZnCl2

R=OEt or Me or Ar

O O

HNR1R2

91.ROEt

OEt

	R1	EWG
O	O

92.

OEt

R2

R3

EtO

Na or NaH

EWG = CN or Ac or CO2Et

O

O

CN

93.

2H2 / NiRa

EtO

OEt

Na or NaH

...

(-C H OH)

2 5

O

94.

O

O

R

/ NH3

H

HO

OH

EtOH,

O

O

NaNO2 / AcOH

95.

R

OEt

R= Me or OEt

O

O

Zn / Ac2O

96.

EtO

OEt

N

OH

OO

97.EtO OEt

NHAc

OO

98.EtOOEt

R NHAc

1.NaOEt

2.R-X

R = Alk or All or Bn; X= Hal or OTs or OMs

1. NaOH
					...
2. H

O

O

NaOH (1eq.)

1. DPPA / NEt3

99.

...

2. ROH,

EtO

OEt

R1

R2

X

O

H2N

NH2

100. R

OEt NaOEt / EtOH,

R= Ac, CO2Et, CN; X= O or NH

34

X

O

O

101.

H2N

NH2

EtO

OEt

NaOEt / EtOH,

R1

R2

X= O or NH

O

X

N

102.

OEt

H2N

NH2

NaOEt / EtOH,

R

X= O or NH

O

O

103.

H2N

NH

R

Me

OEt

EtOH,

O

O

H2N

NH

R

104. EtO

OEt

EtOH,

R1

R2

O

O

H2N

X

105. Me

OEt

EtOH,

X= OH or NH2

MeO

O

N

H2N

NH2

106.

OEt

EtOH,

MeO

O

O

1.[Ar-N

N] Cl

HCl / AcOH

...

107. Me

OEt 2. NaOH

R

1. Zn / AcOH

O

O

O

O

2.

/ EtOH,

108. Me

OEt

Me

R

N

OH

R = OEt or Alk or Ar

2.4. Методы восстановления органических соединений

O

Cu2O*Cr2O3

109. R

хинолин,

OH

O(PPh3)3RhCl / NMP, T

110.or (PPh3)3RhCl(cat.) / DPPA / THF, RT R

H

O

O

>

NO2

>

>

>

Cl

O

H

X

H2

111.

>

>

>

>

O

Ar

CH2

Cat

>

N

>

O

>

R1

112.

R2

H2(ex.)

Rh/Al2O3 or RhO2 / PtO2 (3:1)

R1

R1

R1

R

H (ex.)

113.

2

R > >

2

>

R

2

2

PtO2 or Pt/C

N

N

H

R2

>

>

>

R1

R1

R2

H

R1

2

114.

R2

R3

R3

R4

Pt/C or PtO2

>

>

>>

R1

R1

R2

R1

R2

115. R

N

OH

H2 / Pt/C

or

R

N

H

EtOH / HCl

H2

116.

R1

R2

Pd/CaCO3/Pb(OAc)2

or Pd/BaSO4 / S-хинолин

O

O

117. Alk

> Ar

H2

Cl

Pd/BaSO4 / S-хинолин,

Cl

C6H4Me2,

R H2

118. Pd/C

R= EWG (with -I, -M) or Ar

119.

or

H2

R

NO

R N

N

N

2

Pd/C

120.

R

N

H2

Pd/C / EtOH / HCl or NH3

35

R1

R

R1

3

R

H2

121.

N

or

O

3

H2N

Pd/C/ EtOH

R2

R2

Ar

Me

H2

122.

O

H2N

Pd/C

Alk

Ph

H2

R

X

Pd/C

123.

R = Ar or HetAr or Alkenyl

X = OR or

NR1R2 or Hal (I, Br, Cl)

124. Ar

Hal

or HetAr Hal

H2

Pd/C

Hal = I or Br or Cl

H

/ Pd/C

125.

X

2

X= CH2 or O or NH

H2

126. R N NiRa / EtOH / NH3

	127. R NO2	H2 or NH2NH2
		NiRa / EtOH
	R1	H2 / NiRa / EtOH

128. O

R2

R1

H2

/ NiRa / EtOH

129.

O

H2N

R3

R2

130. R

H2 / NiRa / EtOH

SH or

R1

S

R2

R2

R1

>

>

R1

R2

>

H2 / (PPh3)3RhCl

131.

R1

R2

R3

R3

R4

>

>

>>

R1

R1

R2

R1

R2

O

Ar

OMe

H2

132.

Rh[(S-)BINAP]ClO4

O

NH

or Rh[(R-)BINAP]ClO4 (cat.)

Me

133.

R1

134.

R2

135.

R2

O

H2

OH

Rh[(S-)BINAP]ClO

4

R

or Rh[(R-)BINAP]ClO4

(cat.)

HO

HO

O

R1

H2

or

Rh[(S-)BINAP]ClO4

R2

or Rh[(R-)BINAP]ClO4

(cat.)

O

H2

Rh[(S-)BINAP]ClO4

R1 or Rh[(R-)BINAP]ClO4 (cat.)

O

O

NaBH4

136. R

>

R1

H

R2

THF or EtOH

NaBH4

/ NiCl2 or

137. Ar

NO

or

NaBH4

/ Pd/C

2

Ar NO

EtOH

O

O

O

138.

R

or

R

or

NaBH4 / TiCl4

OH

1

OR2

R1

NR R

2

3

O

139.

R1

R4

NaBH4

/ СeCl3

MeOH

R2

R3

O

O

NaBH4 / СeCl3

140. R1

>

R

R2

H

MeOH

OLiBH4

or NaBH4 / LiI

141.R1

MeOH

OR2

R1

H2N

R3 or

R4

R3

N

142.

O

H

R2

Na[BH3CN] - MeOH

(R)n

n(R)

143.

or

Na[BH3CN]

AcOH,

N

N

H

36

R2

LiBH4

Na[BH3CN]

144.

or NaBH / LiI

4

BF3*Et2O

R1

O

MeOH

O

O

Na[BH(OAc)3]

145. R

>>

R1

THF

H

R2

OH

O

OH

O Na[BH(OAc)3]

146.

or

THF

R2

R

R

R1

2

1

R1

H2N

R3 or

R4

R3

N

147.

O

H

R2

Na[BH(OAc)3] / DCE or DCM

O

148.

R1

(ex.)

OH

R4 N

R3 or

H2N

R2

NaBH4 (ex.),

H

Li[AlH(OMe)]3

149. B(s-Bu)3

n

L-selectride

R O or K-selectride

150. m

n, m = 0-2; R = bulky substituent

O

R2

L-selectride

151.

or K-selectride

R

R2

1

O

R3

1. L-selectride

or K-selectride

152.

R

R2

1

2.R-X

R= Alk or Bn or All;

X = I or Br or Cl or OTs or OMs

153. NaBH

BF3*Et2O

4

O

O

BH3

>

>

>

or BH3*THF

154.

OH

O

or BMS

> > >

O O

BH3 or BH3*THF or BMS (ex.)

155.

R

H2O2	/ NaOH				HCO2H / H2O
156.		R		BH2

157. R BH2

I2 / MeOH

R

158.

R1

R

159.

H

R

160.

H

R

161.

H

Me

162.

Me

Me

163.

Me

BH3 or BH3*THF or BMS (ex.)

or

R2

H

R1

R2

H2O2 / NaOH

or

BH2

H

BH

2

H

R1

R2

HCO2H / H2O

or

BH2

H

BH

2

H

R1

R2

or

I2

/ MeOH

BH2

H

BH

2

Me

BH3

or BH3*THF

or BMS

(ex.)

Me

BH3

or BH3*THF

or BMS (eq.)

Me

BH3

164.

or BH3*THF

or BMS

COD

RL

RL

RS

Sia2BH or 9-BBN

165.

or

RS

n

R

O

Sia2BH

166.

m

n, m = 0-2; R = bulky substituent

Me

Me

Me

BMS

167. 2

=

Me

THF, 0OC

Me

Me

37

168. R1

R2

1. Ipc2BH

2. H O / NaOH

2

2

Me

169.

Me

9-BBN

=

Me

Me

THF

Me

Me

O

(R-)-alpine-boran

170. RS

RL

THF

RL = Ar or alkynyl

O

1. 2PheMgBr

2. TFA

171.

N

3. MeB(OH)2

OMe

Boc

O

BH3*THF

172.

RL

RS

(S-)-2-Me-CBS-оксазаборолидин (cat.)

RL = Ar

O

O

O

LiAlH4

173. R

or

or R

R1

Et2O or THF

OH

OR2

H

or dioxane

O

R2

or

LiAlH4

174. R1

R

R

O

Et2O or THF or dioxane

1

2

R1

NO2

LiAlH4

175. Alk

NO2 or

R2

Et2O or THF or dioxane

R3

O

LiAlH4

or

R

N

176. R1

Et2O or THF or dioxane

NR2R3

Ar

LiAlH4

177.

Hal

Et2O or THF or dioxane

Hal = I or Br or Cl or OTs

OH

LiAlH4

178. R

Et2O or THF or dioxane

O

O

O

AlH or

3

179. R

or

R1

or

R1

LiAlH4 / AlCl3

Et2O

OH

OR2

R

2

O

AlH3 or

or R

N

LiAlH4 / AlCl3

180. R1

Et2O

NR2R3

R2

AlH3 or

181.

LiAlH4 / AlCl3

R

O

Et2O or THF or dioxane

1

O

O

182. R1

or

R1

DIBAL

Et2O or THF

OR2

R

2

O

R3

DIBAL

183.

R

R2

Et2O or THF, -78OC

1

O

DIBAL

184.

O

R

Et2O or THF, -78OC

O

1. DIBAL

185.

R

N

O

Me

or

R

N

Et2O or THF, -78OC

2. H2O / H

Me

O

186. R1

DIBAL

NR2R3

Et2O or THF

187. R

DIBAL

Et2O or THF

188. R

DIBAL

Ph-Me -20OC

R

H

I2

MeOH

189.

H Al(s-Bu)2

t-BuOH (ex.) 190. LiAlH4

O

O

LTBA

191.

R

or

R

Cl

OPh

O

(ex.)

192.

HO

NaAlH4

O

O

O

SMEAH

or R1

193.

R

or

R1

Et2O or THF

OH

OR2

R

or dioxane

2

38

O

SMEAH

or R

N

194. R1

Et2O or THF

NR2R3

or dioxane

OH

SMEAH

195. R

Et2O or THF

or dioxane

SMEAH

R2

DIBAL

OH

196.

R1

Et2O or THF

Et O or THF

or

2dioxane

O

or dioxane

1.(R-) or (S-)-BINOL

197.LiAlH4

2.MeOH

O(R-) or (S-)-BINAL-H

198.RL RS

RL = Ar or alkenyl or alkynyl

O

Na

199.

Ar1

Ar2

Et2O or THF

or dioxane (abs.)

O

O

Na

200.

R1

or

R1

EtOH or BuOH

OR2

R

2

Na

201.

R

N

EtOH or BuOH

EDG

EWG

202.

Na (Li) / NH3(liq.)

or

EtOH(abs.)

203.

R1

R2

Na (Li) / NH3(liq.)

EtOH

O

R3

Na (Li) / NH3(liq.)

204.

R2

EtOH

R

1

O

R3

1. Na (Li) / NH3(liq.) / EtOH

205.

2. Alk-X

R2

R

1

X = I or Br or Cl or OTs or OMs

OR

R1

OR

1. Na (Li) / NH3(liq.)

206.

Ar

or

R2

R3

EtOH

R = H or Ac or Alk or Ar or CO2Alk

Alk-X

1. Na (Li) / NH3(liq.)

207.

EtOH

X = I or Br or Cl or OTs or OMs

Alk-Hal

1. Na (Li) / NH3(liq.)

208.

EtOH

Hal = I or Br or Cl

O

Zn/Hg

209.

R1

R2

HCl

O

1. NH2NH2

210.

R1

2. KOH / HO-(CH2)2OH, >150OC

R2

Zn

211.

Ar-Hal

or

HetAr-Hal

or Alk-Hal

AcOH

Hal = I > Br >> Cl

or Alk-NO2

Zn or Sn or Fe

212.

Ar-NO2

AcOH or HCl

N

OH

213.

or

R-NO

or

R1

Zn or Sn or Fe

R-NO2

AcOH or HCl

R2

SnCl2 / HCl, -10OC

214.

or NaHSO3 / H2O,

Ar

N

N

X

39

Контрольная работа № 2

Вариант 0

I. Приведите структуру продуктов, в реакциях 8*-10* укажите их стереохимию (10 балов):

				O		OH
				OH
1.	i				DCC, HOSu	H2N
		Bu
				Me	DCM
			O	H
2.				Me N OMe
		O	OH	CDI

3.

4.

O

1. DPPA/NEt3

OH

2. BnOH, T

O

1. H-Pro-OBn, PyBop, DIEA

Boc-Met-OH

2. TFA

O

5.

6.

7.

8*.

9*.

10*.

O	O			NaCN
		N	H		H+
EtO	OEt	Pip*AcOH			T
		Me
O	O	Me	O
Me	OEt	NaOEt
	O
	H2/RhO2-PtO2
	Me
	4 атм, EtOH
		Me
O	NBoc H2N	Ph
	H2-Pd/C
	O
	O		(R)-альпинборан

H

O SMEAH

OH

II. Заполните схему превращений (5 балов):

						O
O	O	H2-Pd/C				OH
			DIBAL-H	EtNH2	NBoc		HCl
NC
	OH
							Et2O
	AcONH4, T			NaBH(OAc)3	TBTU
				DCM	DIEA

III. Приведите схему твердофазного синтеза пептида с использованием Fmocстратегии и полимера c MBHA-спейсером (5 балов):

H –– Met –– Leu –– Lys –– Val –– Gly –– NH2

40