МСОС Лекции с поиском и закладками
.pdfMeTOAbl aKTMBaU.MM Kap60KCMnbHOH rpynnbl 3. A3MAHbtM MeTOA (Kyp4Myca)
MeTOAbl nonyYeHHR a3HAOB
r |
.., |
MeTOAbl aKTMBaU.MM Kap60KCMnbHOM rpynnbl
npHMeHeHHe a3HAHOro MeTOAa B CHHTe3e aMHAOB H nenTHAOB
O |
0 |
'<. |
|
R- |
|
N=N=N
|
H |
|
R,,,,,,,. |
N |
'R |
2 |
|
1 )Ill |
-HN3
0 |
|
R-1(_ |
|
N-R |
|
/ |
1 |
R2 |
|
0
1/oMe
NHCbz Cbz-Val-OMe
1. NH2NH2 |
|||||
2. |
N |
a |
NO2 ► |
||
|
|
° |
C |
||
|
HCI/0 |
|
1/ =®9=N |
H N |
||
0 |
|
||
|
|
2 |
OBn |
|
N N |
|
H-Gly-OBn |
NHCbz |
|
-HN3 |
|
Cbz-Val-N3 |
|
|
OBn |
► |
|
OH |
|
NHCbz |
O |
Pd/C |
NH2 |
0 |
|
|
H-Val-Gly- H |
||
HeAOCT3TKM Cbz-Val-Gly-OBn |
|
|
O |
-HL-13KVIIII BblXOA <80%; cryneHYaTaR a1<TV1Ba41-1R; HeCTa6V1/lbHOCTb a3"1P,OB AoCTOHHCTea
-OTCyTCTBll1e pa4eM1-13aLJ. t1,1; AOCTynHOCTb peareHTOB
C00/1b3VIOT AJIR CMHTe3a t<OpOTKMX nenTMAOB M/1H CWHBKM nenTMAHblX 6110KOB
MeTOAbl aKTHBa4HM Kap60KCMnbHOM rpynnbl 3. A3MAHbtH MeTOA(Kypl.\Myca)
nplttMeHeHltte a3lt1AOB B ClttHTe3e aMlttHOB lt1 Kap6aMaTOB (neperpynnlttpOBKa Kypu. yca)
R
|
N-N |
|
;f' |
r,:, |
|
\ |
|
"' |
0N
◄
•
R |
N / |
||||||
|
|
T |
• |
||||
|
|
_-_ """'" |
|
|
|
|
|
R- |
|
|
|
|
---►►a |
||
|
|
|
|
||||
___N |
|
|
|
||||
|
N=C=O " |
|
|
R'OH |
|||
isocyanate |
|
|
|
T |
|||
|
|
R-+1z';".,,:
nitre •
II
R-HN/'-..OR'
R'=Me, Bn, t-Bu
neperpynn"1poeKa Kypu_"1yca crepeoce11eKn1aHa (c coxpaHeH"1eM cTepeox"1M"1"1)
|
|
o |
o |
|
|
c |
|
|
|
A |
|
|
|
N |
HN Ot-Bu |
|
|
► |
|
|
DPPA |
• |
|
|
► |
||
|
|
t-BuOH |
t-BuOH |
|
|
|
|
|
NEt3 |
T |
|
■ |
|
|
|
MeTOAbl aKTHB3U.MM Kap6oKCMnbHOM rpynnbl 3. A3MAHblM MeTOA (Kypu,Myca)
npv1MeHeHv1e a3v1AOB B Cv1HTe3e aMv1HOB v1 Kap6aMaTOB (neperpynnv1po0Ka Kyp4v1yca)
0 |
◄ ► R Gi) T ► |
R . • |
|
R--{ (£) 0 |
|||
N=N=N |
N-N |
|
N . |
|
. |
||
|
_____ / |
nitre |
R-NH2
H2O
◄◄----- -CO2
r R-N=C=O
'" |
isocyanate |
|
- ►► |
)l |
R'OH |
|
-- |
R-N OR' |
T |
H |
|
R'=Me, Bn, t-Bu |
neperpynnl
Ph_/JII
-1pOBK YP'-'l-1yca crepeoce11eKn1eHa (c coxpaHeHt.1eM crepeoxl-1M"1l-1) |
|
|||||||||
0@ \._OEl |
|
1.NaOH |
|
|
DPPA/NEt3 |
|||||
N=N |
|
|
|
OH |
||||||
► |
Ph OEt |
|
+► |
Ph |
T |
Jia |
||||
|
|
|
|
|
||||||
|
Cu or Rh |
2. H |
|
|||||||
|
N |
|
trans-O |
|
O |
|
|
|
||
- 2 |
|
|
|
|
|
|
|
|
|
|
|
|
H20/H+ |
Ph |
|
|
|
|
► |
|
|||
Ph....._v-"' ,, |
|
......V-'NH2 |
|
|||
|
N |
C |
|
Tranylcypromine |
|
|
•......__ |
|
'o |
|
|
||
|
|
|
|
|
_ |
nenTMAHblM CMHTe3
|
|
|
|
|
|
|
|
|
|
upom OIITJeT MB&Kle. ffO OIRT88 n8IrrJDlOB |
|
|
|||||||||
|
|
|
|
|
|
|
-Opt'8HJO(OB |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
"CpeJDI DNPJHJB |
|
|
|
|
,_o1'BOM 00 CBOel oodoTBeHKOI |
OIIMBMJt- |
|
||||||||||||||
11BJU18'!0I SOIJOCTBOII 11.D ..... |
|
||||||||||||||||||||
|
JC!O |
|
|
||||||||||||||||||
1(()1, |
|
ll3IIIOM |
K |
plTJ&IOII, |
|
B81'TO |
OOB8p118KKO 1fY'U08 |
JIBT8pe08M |
Tex, |
|
|
||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||
dOT&8T B A.PJX'&X 06JlaoT,at' |
|
|
-1963 r |
|
|
|
|
|
|
|
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||
OcHOBHaA 4enb nenTHAH0ro Cll1HTe3a - o6pa30BaHHe nenTHAHOM CBR3"1 |
C-KOHe4 |
||||||||||||||||||||
|
|
|
|
O |
. |
|
|
0 |
|
|
|
|
:·o |
.. |
|
R |
C |
||||
|
|
|
|
|
|
|
|
|
|
.. |
|
|
|
|
|
||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||
|
|
|
-N,,,,n Jl |
|
|
|
|
\Jl.\j__ a |
|
c |
|||||||||||
|
|
|
|
|
|
|
|
|
|
e |
|
|
|
y\__ |
|
|
II |
||||
R |
|
|
|
|
|
|
|
|
|
|
|
c |
► |
R a |
|
|
|
|
|
OPG |
|
a |
|
|
|
|
( 'OPG |
|
|
|
|
N1 |
|
|
|
|
|||||||
|
T 'LG |
+ |
|
-HLG |
|
|
|
|
|
|
|||||||||||
|
|
NHPGN |
|
R |
|
|
|
|
PGNHN ··. .: 0 |
|
|
||||||||||
|
|
|
|
|
PG - 3au,u,1THas:i rpynna |
|
|
|
|
nenntAHaR |
|
|
|||||||||
|
|
|
|
|
|
|
|
N-KOHeu, |
ca Jb |
|
|
|
|||||||||
|
|
|
|
|
LG - YXOA a rpynna |
|
|
|
|
|
|
|
|
|
|
|
|||||
CS>opMHPOBaHHe nenTHAHOM CBff3H BK/ltOl.faeT HeCKO/lbKOOCHOBHblX 3Tanos: |
|
|
|||||||||||||||||||
- |
|
3aLLii&i1Ta N-KoH4eso1A AK no aM&i1Horpynne (PGN = Boe, Fmoc) |
|
|
|
|
|
|
|
||||||||||||
- |
|
3aLLii&itTa C-KOH4eBOIA AK no Kap60KC"1 rpynne (PGC = Me, Bn, t-Bu) |
|
|
|
|
|
||||||||||||||
- |
|
KOHAeHca41-1R aM&itHO K&itC/lOT nyreM aKT&,1Ba41,11,1 N-KOH4eBOIA AK (BBeAeH&,1e LG) |
|
-YAalleH1-1e 3aLLii&itTHblX rpynn
-KpoMe Toro, He06XOA&,1Ma 3al.Ui"1Ta Q>YHK4"10HaJlbHblX rpynn 60KOBblX 4ene1A
■
nenTMAHblM CHHTe3
Pa38111Tll1e nenTll1AHOLII X"1Mil1"1 np111ee110 K nORB/leHiltK) 111 pa38"1T"1K) HOBblX nOAXOAOB l-1 MeTOAOB 3aw_111Tbl cpyHK4"10HallbHblX rpynn AK, aKTll1Ba41,11,1 Kap6oKC"1llbHOLII rpynnbl, KOTOpble CefOAHR Wl-1POKO "1CnO/lb3YK)T B pa3/1111'-1Hb1X 0611aCT.RX opraHl-1'-leCKOLII 1,1 MeAL-14"1HCKOi'.1 X"1Mil1"1.
1. 3aU4 1THble rpynnbt
Am t\.1HTe3a no11111nenn1AOB pa3pa6oraHa KOH4enu,111R «oproroHa/lbHOM 3aW.MTbl>> (P. Mep1,1cp1,111A): Ka>t<AaR 3aL1.1i111THaR rpynna MO>KeT 6b1Tb vAa11eHa He3ae111c1,1Mo or APvr111x
|
|
|
H |
O |
I - TFA► |
|
0 |
|
|||
|
|
|
O N |
|
O |
|
|
OH |
)I, I |
|
|
|
|
0 |
|
|
|
|
|
|
|
Pip |
|
|
,.N, |
|
|
|
|
H |
H |
|
|
|
|
|
|
|
|
||
H-Lys-OH |
-9' |
|
|
||
H2 |
Fmoc |
|
|||
|
|
|
c |
|
|
|
|
|
Cbz-L I s-O-t-Bu |
|
B npou,ecce nenr111AHOro Cl-1HTe3a y
5 Ha Ka>KAOM U,1-1Klle Hapaw_1-1aaHl-1R u,en1,1 npl-1XOAv1TCR vAamHb PG Ca -aMvtHorpynnbl («epeMeHHaA» 3aW.MTHaA rpynna"};
-pe>Ke YAallRK)T PG CL -Kap60KCLII rpynnbl (npLit CWLIIBKe 0/lLitronenTLIIAOB);
-PG 6oKOBbtX 4eneH YAa,rneTCR Ha 3aK11t01.11i1re11bHOM 3Tane cvtHTe3a («cra61rtnbHaA» 3aUJ.MTHaA rpynna)
nenTMAHblM C"1HTe3
Bb16op 3au.v1THblX rpynn onpeAem:ieTcR cxeM0111 c&.1HTe3a nenn1A.a.
B 3aev1C&.1MOCT&.1 OT l-1CnO/lb3yeMOi1 «epeMeHH0'1» 3a1.4&.1THO rpynnbl Hav16011ee pacnpocrpaHeHbl:
1.Boe- cTparerHR (Nci - Boe, c« 111 PG-60Koeb1x u_ene vAallRIOTCR a ocHoeaH111RM&.1)
2.Fmoc- CTparerHR (Nci - Fmoc, cci 1,1 PG-6oKOBblX 4enei1 vAaJ1RJOTCR e K"1CJ10TaMv1)
np1.1 n11aH1.1posaHl.1&.1 cxeMbl nenTIIIAHOro C"1HTe3a np"1MeHRIOT ABe TaKTv1K"'1 3at.4v1Tbl 60KOBblX u,ene (e 3a8"1Cl,1MOCTl,1 OT MeTOAOB aKn1eau,1,11,1 Kap60KCv1/lbHO rpynnbl}
-MaKCMManbHaR 3aU4MTa - 3al4&.1t.4a10T see <f>YHKU,1.10Ha/1bHble rpynnbl 60KOBblX u_enei:1
-(cMewaHHble aHrl.1AP111Ab1, Kap60A&.1&.1M&.1AHbl MeTOA}
-M.-tHMMa/lbHaR 33LL\MTa - 3aw,1-1l4at0T "10Hv13v1pyeMble rpynnbl (KOHAeHcv1pyt0l4v1e areHTbl}.
2. MeTOAbl 3KTMBal.\MH Kap6ot<CH/lbHOH rpynnbt
2.1. A3MAHblM MeTOA (npMMeHfleTCfl cpaBHMTeJlbHO peAKO)
■
nenTMAHblM cMHTe3
2.2. MeTOA cMewaHHblX aHrMAPHAOB
|
CMewaHHbte aHntAPHAbt |
o |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||||||||
|
o |
o |
|
Nu: |
o |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||
|
R 1Aa)lR2 |
|
|
|
|
R1 )l0..,R2 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
|
R1=Et. |
i-Bu |
|
|
|
|
|
|
|
|
|
|
|
|
|
||
|
Kap60H08blX K-T |
|
|
|
|
|
|
Kap60HOBO / |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||||||
|
\. |
|
|
|
|
|
|
|
yronbHOt'.1 K-T |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
8: NMP |
|
NMM |
DIEA |
|
||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
o |
o |
H2N |
|
|
|
II |
|
|
yo |
|
|
|
|
|
|
|
|
|
|
CiC02-iB\:, |
|
|
|
|
|
|
|
OMe |
|
|
|
|
OMe |
|||||||||||
|
JOH |
|
|
|
|
|
|
|
H- |
- |
OMe |
|
|
|
|
|
||||||||||||
|
|
|
|
MPITHF |
|
|
|
|
|
|
|
|
B |
|
|
|
|
|
|
|
|
|||||||
|
HBoci |
|
|
c |
|
|
|
NHBoc I-Bu |
iy |
|
|
► |
NHBoc |
|
|
O |
|
|||||||||||
|
-20 |
° |
|
|
|
|
?, -i- |
u |
|
|
|
|
||||||||||||||||
|
Boe-Ala-OH |
|
|
O |
|
|
|
Yo |
|
|
|
|
|
|
|
|
|
|
|
|
OM |
o |
||||||
|
|
|
|
|
|
|
|
OMe |
|
|
|
|
|
|
|
|
|
l |
|
|
|
|||||||
|
TFA |
-....... )lN |
|
1.NaOH/MeOH |
|
|
|
|
|
|
:: •• |
G |
iy- |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
||||||||||||||||||
|
|
►TFA• NH2 |
H |
|
|
|
II |
|
|
2· H |
|
|
N 2 |
|
|
|
|
|
|
|||||||||
|
|
|
|
|
|
O |
|
|
|
|
|
|
|
|
|
|||||||||||||
|
|
|
|
T |
|
|
|
|
|
|
|
|
|
|
|
H |
|
|
|
|
|
|
|
|||||
|
|
|
TFA.. H-Ala-Gly-OMe |
|
|
|
|
|
|
|
|
|
|
|||||||||||||||
|
|
|
|
|
|
|
H-Ala-Gly-OH |
|
|
|
|
|
||||||||||||||||
|
-Hlt13Klt1 BblXOA <80%; cryneH4aTa.A at<Tl-1BaU.1t1.A; Hecra61-1J1bHOCTb aHflilAP"1AOB |
|||||||||||||||||||||||||||
|
AocTOMHCTBa |
|
|
|
|
|
|
|
BblCOt<a.A CKOpOCTb peaKLJ."1"1, AOCrynHOCTb peareHTOB |
|||||||||||||||||||
|
-OTCYfCTB&iie pa4eM1it3aU."1"1; |
|
||||||||||||||||||||||||||
■ |
WHpot<o Hcnonb3yior AnR CHHTela aMMAOS "' KopoTt<M>< nenntAOB |
|
|
|
|
|
nenTMAHblM CHHTe3 2.3. Kap6oAMMMMAHblM MeTOA
npoH3B0.QHble
Kap6o.QHHMH.Qa
o+
R1 -N=C=N-R2 |
EDC (>t<HAKOQ)a3Hbl c1-1Hre3) |
Nu:/ |
DIC (TBepAo¢a3Hbl c1-1Hre3) |
|
TFA •
Hf!AOCTaTK
Ph',,,-..... |
JL |
rs:: |
HF/PhOMe |
||
|
,•··y |
n |
|||
T |
|
o |
|
|
|
NHBoc Bzh |
|
|
|
H8oc-Phe•Cys-0Bn
H Phe•Cys-OH
- Pau,eM"13aU,"1fl <20%; Heycroi'.14"1BOCTb ype"1AOB, no604Hble peaKU,"1"1 o6pa3oBaH"1e A""l.J.""K11oreKc"111Mo4eB"1Hbl, a1111epreHHOCTb DCC AocroHHCTBa
- BblXOA >90%, BblCOKaR CKOPOCTb peaKU,"1"1, AOCTYnHOCTb peareHTOB
■ WHpOKO HCOO/lb3YtoT AJIR CJ,1HTe3a aMHAOB 111 nenTHAOB
npMMeHeHMe npOM3BOAHblX Kap60AMMMMAa B opraHM"leCKOM CMHTe3e
Kap60AHHMHAbt WHPOKO HCnOnb3YtoT A/1.R CHHTe3a aMHAOB, naKTaMOB, 34>Hpoe, aKTMBHpoeaHHbtX 34>Mpoe, aHrHAPHAOB, AerHApaTal,\HM, OKMCneHHff cnMpTOB
|
|
|
|
|
|
|
|
|
H |
|
|
|
|
|
|
|
|
|
|
|
|
|
1 EDC |
|
|
|
|
2 |
|
DCC/RT |
|
[ U |
Jl |
|
|
|
______ F |
||||
U |
|
] H-Ser-OB; HO\ |
|
|
|
||||||||
|
|
|
|
|
|
H |
J°Bn |
||||||
|
|
|
• |
|
|
|
|
|
|
|
|||
|
H H |
|
H |
H |
|
|
|
OLO |
CH |
||||
|
|
|
|
|
|
||||||||
|
|
|
|
0 |
|
|
|
|
,--NH |
|
|
|
|
|
|
|
|
|
|
N..,..OH H |
|
|
|
||||
3. Aen1Aparat..1i"1H |
R)lNH2 1-1m,R H |
DCC/RT• |
R |
_N |
|
||||||||
|
4.OK"1CJ1eH111e
(MeTOA Mocp4>a1a)
0
CyreHT
er-OBn |
|
|
|
Y"l111TbJB8Tb s nenr111,t\HOM C111Hre3e |
An · |
||
0 |
|
H2N 0 |
|
H2N |
|
|
|
O |
Gin |
|
|
Asn H2N |
|
||
OH |
H2N |
|
|
|
|
|
[ |
HO\ |
//O |
r,. |
||
Se H;iN |
OH |