МСОС Методичка

		O		DCC
22.	2	R
		OH
		O		N		OH
23.	R		or	R			DCC
		NH		H
		2
		O
	R		HNR R
24.				2 3
		X
	X= O-NP or O-PFP or O-Su or O-Bt
		O
25.	R		BOP or PyBOP or TBTU or HBTU
		OH		DIEA or NEt		3	/ DMSO
		O
				HNR R
26.	R			1	2
		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; PGС= Me or t-Bu or Bn

ClCO

-i-Bu

C

C

N

N

H-AA

-OPG

-OH

2

PG

-AA

...

28.

NMO or NMP

N

С

PG = Boc or Cbz or Fmoc; PG = 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; PGС= 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; PGС= Me or t-Bu or Bn

C

Cl

PS

TFA

...

31.

Boc-AA

-OH

Cs CO

or DBU / DMF

2

3

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

N

-OH / DCC or DIC

C

Fmoc-AA

-O

33.

H-AA

HO-Bt / DMF or DMSO

PS

= метиленполистирол

(Merrifild's resin)

PS

N

Fmoc-AA -OSu

C

-O

34.

H-AA

DMF

PS

=

метиленполистирол

(Merrifild's resin)

TFA

PS

HF(liq.) or TfOH

35.

Boc-PP-O

PhOMe

PS

= метиленполистирол

(Merrifild's resin)

PS

NH /

MeOH

3

36.

Boc-PP-O

PS

= метиленполистирол

(Merrifild's resin)

C

-OH

Cl

.P

Pip

37.

Fmoc-AA

DIEA / DCM ...

DMF

.P

= (2-Cl-Trt resin)

C

-OH

Br

.P

Pip

38.

Fmoc-AA

...

DIEA / DCM

DMF

.P

= (Wang resin)

HO

.P

Pip

C

...

39.

Fmoc-AA

-OH

DMF

DIC / DMAP / DMF

.P

= (Wang resin)

N

DCC or DIC

C

Fmoc-AA -OH /

-O

P

40.

H-AA

HO-Bt

/ DMF

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

N

C

Fmoc-AA -OSu

-O

P

41.

H-AA

DMF

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

N

PyBOP or TBTU

42.

C

-O

Fmoc-AA

-OH /

P

H-AA

DIEA / DMF

Pip

Fmoc-PP-O

TFA

P

43.

DMF

DCM

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

31

					H N	.P			Pip
					2
		C						...
	Fmoc-AA		-OH						DMF
44.				PyBOP or TBTU
					DIEA / DMF
	H2N	.P		= (MBHA resin)
						N	-OH
	C	-NH			Fmoc-AA
				P
	H-AA				PyBOP or TBTU
45.
					DIEA / DMF
		HN		.P	= (MBHA resin)
	Pip		Fmoc-PP-NH					HF(liq.) or MsOH
46.	DMF					P		PhOMe
		HN		.P	= (MBHA resin)

Приведите схемы синтеза пептидов твердофазным (смолы Меррифилда, третильная, MBHA) и жидкофазным методом с

47.использованием Boc- и Fmoc-стратегий:

a.H-Met-Glu-Ala-Phe-Lys-OH;

b.H-Val-Asp-Tyr-Gly-Cys-OH;

c.H-Ile-Asn-Arg-Ser-Pro-NH2.

H

PS

2

HF(liq.) or TfOH

48.

Pd/C, DMF

R-O

PhOMe

PS

= метиленполистирол

R= Alk or Ar or Acyl

(Merrifild's resin)

NH

O

NaOH

3

PS

R

49.

MeOH

O

PS

= метиленполистирол

(Merrifild's resin)

NaOMe

O

LiBH

R

PS

4

50.

MeOH

O

THF

PS

= метиленполистирол

(Merrifild's resin)

HF(liq.)

PS

Na / NH3 (liq.)

51.

R-S

PhOMe

52.

PS

H

/ Pd/C

2

R-NH

DMF

O

OH

or R-NH or N

53.

Cl

.P

R

2

N

H

DIEA / DCM

.P

= (2-Cl-Trt resin)

Ar-OH or Alk-OH or R-SH

54.

Cl

.P

Py / THF

.P

= (2-Cl-Trt resin)

TFA

R

X

.P

1

DCM

55.

.P

= (2-Cl-Trt resin)

X= O, NH, NR or S

2

O

OH

56.

R

HO

.P

DIC / DMAP / DMF

.P

= (Wang resin)

O

OH

or R-OH or RNH

2

57.

R

Br

.P

Cs

CO or DBU or DIEA

2

3

DMF

.P = (Wang resin)

CAN

TFA

R

O

.P

58.

DCM

.P

= (Wang resin)

H

R

O

.P

2

59.

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
62.	Cl	NaCN

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 CF

or Ph

EtONa or NaH

3

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

R

-X

R

2

1

67.

OEt

NaOH / PhH / TEBAC

R = Ac or CO Et or CN

R =Alk or Bn or All

2

1

2

X=Hal or OTs or OMs

O

NaOEt

R

-X

R

2

1

...

68.

OEt EtOH(abs.)

R =Alk or Bn or All

2

R

X=Hal or OTs or OMs

2

R = Ac or CO Et or CN

1

2

O

O

1. NaOH

...

69.

R

OEt

2. H

R

R

R=OEt or Me

1

2

O

R

NaCl or LiI

70.

OEt

O

DMSO, 150 C

R

R

R= Ac or CO Et or CN

1

2

2

O

R

TsOH or DMAP(cat.)

71.

OEt

6

4

2

PhMe or C H Me

O

R

R

110-150 C

1

2

R= Ac or CO Et or CN

2

O

O

NaOH (conc.)

72.

Me

OEt

R1 R2

73.

74.

75.

76.

77.

78.

79.

80.

81.

R

1

O

R

NaOEt

R

O

...

2

OEt

EtOH(abs.)

R= Ac or CO Et or CN

2

O

O

Me

O

HBr(conc.)

O

O

X

X

n

R

OEt

EtONa or NaH (ex.)

R=OEt or Me

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

O

O

O

R

Cl

OEt Mg(OEt)

EtO

or MgCl

2

/ NEt

2

3

O

O

TsOH or DMAP(cat.)

EtO

OEt

PhMe or C H Me

6

4

2

O

110-150 C

O

R

O

O

EtO

OEt

1. NaOH (ex.)

...

2. H

O

R

O

O

O

R

2 BuLi

Cl

OH

...

...

EtO

O

O

O

R

H

HO

OH

Py,

O

O

R2

R

R1

3

OEt

Pip / AcOH,

R1= CO2Et or СN

33

O

O

H

-Pd/C

NaCl or LiI

2

82.

EtO

OEt

...

O

DMSO, 150 C

R

R

1

2

O

O

HCN / NaCN(cat)

H O / H

...

2

83.

EtO

OEt

R

R

1

2

O

O

R -M

H O / H

2

3

84.

EtO

OEt

CuI

...

M=MgBr or Li

R

R

1

2

O

O

85.

R

R

H

1. NaOH

2

1

2

OEt

HNEt , ...

2. H ,

2

R = CO Et or CN

1

2

O

O

O

86.

2

R

H

1. NaOH (conc.)

Me

OEt

NaOEt

...

2. H ,

O

O

87.

NH (anh.)

/ EtOH

3

Me

OEt

O

O

O

R

/

NH

88.

3

2

H

Me

OEt

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

Ac

O

/

ZnCl

R=OEt or Me or Ar

2

2

O

O

HNR1R2

91.

R

OEt

OEt

R

EWG

1

O

O

92.

R

R

2

3

EtO

OEt

Na or NaH

EWG = CN or Ac or CO Et

2

O

O

CN

93.

2H /

Ni

2

Ra

EtO

OEt

Na or NaH

...

(-C H OH)

2

5

O

O

O

R

/ NH

94.

3

H

HO

OH

EtOH,

O

O

NaNO2 / AcOH

95.

R

OEt

R= Me or OEt

O

O

Zn / Ac

O

96.

EtO

2

OEt

N

OH

O

O

1. NaOEt

97.

EtO

OEt

2. R-X

NHAc

R = Alk or All or Bn;

X= Hal or OTs or OMs

O

O

98.

1. NaOH

...

EtO

OEt

2. H

R

NHAc

O

O

NaOH (1eq.)

1. DPPA / NEt3

99.

...

2. ROH,

EtO

OEt

R1

R2

X

O

100. R

H2N

NH2

OEt NaOEt / EtOH,

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

34

O

101.
	EtO
	R
	1
	N
102.
	R
	O
103.
	Me
	O
104.	EtO
	R
	1
	O
105.	Me
	MeO

N

106.

X

O

H N

NH

2

2

OEt

NaOEt / EtOH,

R

X= O or NH

2

O

X

H N

NH

OEt

2

2

NaOEt / EtOH,

X= O or NH

O

OEt

H2N

NH

R

EtOH,

O

H N

NH

R

2

OEt

EtOH,

R

2

O

H N

X

2

OEt

EtOH,

X= OH or NH

2

O

OEt

H2N

NH2

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

(PPh )

RhCl /

NMP, T

3 3

or (PPh

)

RhCl(cat.) / DPPA /

THF, RT

110.

R

3 3

H

O

O

>

NO

2

>

>

>

Cl

O

H

X

H

>

>

>

2

111.

>

Ar

CH

Cat

2

O

>

N

>

>

O

R

1

H (ex.)

112.

2

R

2

Rh/Al O or RhO / PtO

(3:1)

2

2

3

2

R

R

1

1

R1

R

H (ex.)

113.

2

> >

2

>

R2

R2

PtO or Pt/C

N

2

N

H

R

2

R

>

>

R

R

>

H

1

1

2

R

2

114.

1

R

R

R

R

Pt/C or PtO

2

3

3

4

2

>

>

>>

R

R

R

R

R

1

1

2

1

2

N

OH

H

/ Pt/C

115.

R

or

R

N

2

H

EtOH / HCl

H

2

R

R

116.

1

2

Pd/CaCO /Pb(OAc)

2

3

or Pd/BaSO

4

/ S-хинолин

O

O

H

117.

Alk

>

Ar

2

Cl

Pd/BaSO

/ S-хинолин,

Cl

4

,

C H Me

6

4

2

R

H

2

118.

Pd/C

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

119. R

or R

H2

NO

N

N

N

2

Pd/C

120. R

N

H2

Pd/C / EtOH / HCl or NH3

35

R		R	R1
		3			R		H
1
		or		O		3	2
121.	N				H N
							Pd/C/ EtOH
			R		2
R
	2		2

122.

123.

Ar
O	H N
	2
Alk

		H
		2
R	X	Pd/C
R = Ar or HetAr or Alkenyl
X = OR or NR R or Hal (I,
	1	2

Me

H2

Pd/C

Ph

Br, Cl)

H

Ar

Hal

or

HetAr

Hal

2

124.

Pd/C

Hal = I or Br or Cl

H

/ Pd/C

2

125.

X

X= CH

or O or NH

2

H

R

N

2

126.

Ni

/ EtOH / NH

Ra

3

H or NH NH

R

NO

2

2

2

127.

2

Ni

/ EtOH

Ra

R

H

/

Ni

/ EtOH

1

Ra

2

128.

O

R

2

R

H

/

Ni

/ EtOH

1

Ra

2

129.

O

H N

R

2

3

R

2

130.	R		SH		or
					R2
	R1	>
131.					R1
				R2	R3

> >

R1	R1
	O
Ar
132.
O	NH

H

/

Ni

Ra

/ EtOH

2

R

R

1

2

S

> R1

R2

>

H2 / (PPh3)3RhCl

>>

R3

R4

R2

R1

R2

H2

OMe

Rh[(S-)BINAP]ClO4

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

Me

O

H

133.

2

OH

Rh[(S-)BINAP]ClO

4

R

or Rh[(R-)BINAP]ClO

4

(cat.)

HO

HO

R

O

R

H

1

134.

1

2

or

Rh[(S-)BINAP]ClO

4

R

R

or Rh[(R-)BINAP]ClO

4

(cat.)

2

2

O

H

135.

2

Rh[(S-)BINAP]ClO

R

R

4

or Rh[(R-)BINAP]ClO

(cat.)

2

1

4

O

O

NaBH

R

>

4

136.

R

1

H

R

THF or EtOH

2

NaBH

/ NiCl or

4

2

NaBH

/ Pd/C

137.

Ar

NO

or

Ar

NO

4

2

EtOH

O

O

O

NaBH

/ TiCl

4

138.

R

or

R

or

4

1

1

R

OH

OR

NR R

2

2

3

O

R

R

NaBH

/ СeCl

1

4

139.

4

3

MeOH

R

R

2

3

O

O

NaBH

/ СeCl

140.

R

>

R

4

3

1

R

H

MeOH

2

O

LiBH

4

or NaBH

/ LiI

141.

R

4

1

OR

MeOH

2

R1

H2N

R3

or

R4

N

R3

142.

O

H

R2

Na[BH3CN] - MeOH

(R)n

n(R)

143.

Na[BH3CN]

or

AcOH,

N

N

H

36

R

LiBH

2

Na[BH CN]

4

or

NaBH

/ LiI

144.

3

4

BF *Et O

R

1

MeOH

3

2

O

O

O

Na[BH(OAc)

]

145.

R

>>

R

3

1

H

R

THF

2

OH

O

OH

O

Na[BH(OAc)

]

3

146.

or

THF

R

R

R

R

2

1

2

1

R

R

R

H N

R

or

4

N

3

1

2

3

H

147.

O

R

Na[BH(OAc)

] / DCE or DCM

2

3

O

R

(ex.)

148.

1

OH

R

R

H N

R

4

N

3

or

2

2

NaBH

(ex.),

H

4

Li[AlH(OMe)]

149.

3

B(s-Bu)

3

n

L-selectride

R O or K-selectride

150. m

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

O

R

2

151.

L-selectride

or K-selectride

R

R

2

1

O

R

3

1. L-selectride

or K-selectride

152.

R

R

2

2.R-X

1

R= Alk or Bn or All;

X = I or Br or Cl or OTs or OMs

BF *Et O

153.

3

2

NaBH

4

O

O

BH3

>

>

>

or BH3*THF

154.

OH

O

or BMS

> > >

O O

BH3 or BH3*THF or BMS (ex.)

155.

R

H O

/ NaOH

HCO H / H O

2

2

156.

R

2

2

BH2

I

2

/ MeOH

157.

R

BH

2

R

BH

or BH *THF or BMS (ex.)

3

3

158.

or

R

R

1

2

R

H

R

R

H O / NaOH

1

2

2

2

159.

or

H

BH2

H

BH

2

R

H

R1

R2

HCO2H / H2O

160.

or

H

BH2

H

BH

2

R

H

R

R

1

2

I

/ MeOH

161.

or

2

H

BH

H

BH

2

2

BH

Me

Me

3

or BH *THF

3

162.

or BMS

Me

(ex.)

Me

Me

BH

3

or BH *THF

163.

3

or BMS (eq.)

Me

Me

BH

3

164.

or BH *THF

3

COD

or BMS

R

R

R

Sia BH or 9-BBN

L

S

L

2

165.

or

R

S

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

1. Ipc2BH

168.

R

R

2. H O

/ NaOH

1

2

2

2

Me

169.

Me

=

Me

9-BBN

Me

THF

Me

Me

O

(R-)-alpine-boran

170.

R

R

THF

S

L

R

= Ar or alkynyl

L

O

1. 2PheMgBr

2. TFA

171.

N

3. MeB(OH)2

Boc

OMe

O

BH *THF

3

172.

R

R

(S-)-2-Me-CBS-оксазаборолидин (cat.)

L

S

R

L

= 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

LiAlH

or

R

N

4

176.

R

1

Et O or THF or dioxane

NR R

2

2

3

LiAlH

Ar

4

177.

Et O or THF or dioxane

Hal

2

Hal = I or Br or Cl or OTs

OH

LiAlH

178.

4

R

Et O or THF or dioxane

2

O

O

O

AlH or

3

179. R

or

R1

or

R1

LiAlH4 / AlCl3

Et2O

OH

OR2

R

2

O

AlH or

3

/

AlCl

LiAlH

or

R

N

4

3

180.

R1

Et O

NR R

2

2

3

R2

AlH3 or

181.

LiAlH4 / AlCl3

R

O

Et2O or THF or dioxane

1

O

O

182.

R

or

R

DIBAL

1

1

OR

Et O or THF

R

2

2

2

R

O

3

DIBAL

183.

Et

O

O or THF, -78 C

R

R

2

2

1

O

DIBAL

184.

O

O

Et O or THF, -78 C

R

2

O

1. DIBAL

O

R

Me

Et O or THF, -78 C

185.

2

N

O

or R

N

2. H O / H

Me

2

O

186.

R

DIBAL

1

NR R

Et O or THF

2

2

3

R

DIBAL

187.

Et O or THF

2

R

DIBAL

188.

O

Ph-Me -20 C

R

H

I

MeOH

2

189.

H

Al(s-Bu)

2

190.

t-BuOH (ex.)

LiAlH

4

O

O

LTBA

191.

R

or

R

Cl

OPh

O

(ex.)

192.

HO

NaAlH

4

O

O

O

SMEAH

or

193. R

R1

or

R1

Et2O or THF

OH

OR2

R

or dioxane

2

38

		O				SMEAH
194.	R		or		R	N
	1					Et O or THF
						2
		NR R				or dioxane
		2	3
					OH	SMEAH
195.	R					Et O or THF
						2
						or dioxane
						R
		SMEAH				2	DIBAL
196.					R		OH
							Et O or THF
		Et O or THF				1
							2
		2				O	or dioxane
		or dioxane
		1. (R-) or (S-)-BINOL
197.	LiAlH
		4
		2. MeOH
		O	(R-) or (S-)-BINAL-H
198.	R	R
	L	S
	R	= Ar or alkenyl or alkynyl
	L
		O				Na
199.
	Ar1	Ar2			Et2O or THF
					or dioxane (abs.)
		O				O
						Na
200.	R	or	R
	1		1			EtOH or BuOH
		OR
						R
		2
						2
201.					Na
	R	N
				EtOH or BuOH
		EDG				EWG
202.						Na (Li)	/ NH (liq.)
							3
		or				EtOH(abs.)

				R			OR
		OR			1
								1. Na (Li) / NH (liq.)
			or						3
206.	Ar
				R			R		EtOH
					2		3
	R = H or Ac or Alk or Ar or CO Alk
							2
		1. Na (Li)			/ NH (liq.)
	Alk-X					3
207.
				EtOH
	X = I or Br or Cl or OTs or OMs
				1. Na (Li) / NH (liq.)
	Alk-Hal						3
208.						EtOH
	Hal = I or Br or Cl
	O				Zn/Hg
209.
	R	R	2			HCl
	1
	O			1. NH NH
					2	2
210.				2. KOH		/ HO-(CH )			O
	R	R						OH, >150 C
			2				2 2
	1
									Zn
211.	Ar-Hal	or	HetAr-Hal			or	Alk-Hal
									AcOH
	Hal = I			> Br >> Cl
		or					Zn or Sn or Fe
212.	Ar-NO2			Alk-NO
					2		AcOH or HCl
							N	OH
213.	2					1			Zn or Sn or Fe
	R-NO	or	R-NO		or	R			AcOH or HCl
							R
							2
							SnCl / HCl,		O
									-10 C
							2
214.							or NaHSO / H O,
								3	2
	Ar	N		N	X

203.

		Na (Li) / NH (liq.)
R	R	3
1	2	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

39

Контрольная работа № 2

I. Приведите структуру продуктов,

			O
1.	i			OH	DCC, HOSu
		Bu
			Me		DCM

Вариант 0 в реакциях 8*-10* укажите их стереохимию (10 балов):

OH

H2N

	O	H
2.		Me N OMe
O	OH	CDI
		O
3.		OH	1. DPPA/NEt 3
O			2. BnOH, T

4.

5.

6.

7.

8*.

9*.

		1. H-Pro-OBn, PyBop, DIEA
Boc-Met-OH		2. TFA
				O
O	O				NaCN
			N	H		H+
EtO		OEt	Pip*AcOH			T
		Me
O	O		Me	O
Me		OEt	NaOEt
	O
		H /RhO -PtO
	Me	2	2	2
		4 атм,	EtOH
		Me
O	NBoc	H N	Ph
		2
		H -Pd/C
		2
		O
	O			(R)-альпинборан
				H

10*.

O	SMEAH
	OH

II. Заполните схему превращений (5 балов):

							O
O	O	H	-Pd/C				OH
				DIBAL-H	EtNH	NBoc		HCl
NC		2
					2
OH								Et2O
AcONH	, T				NaBH(OAc)	TBTU
4					3
					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