БЛОК E

3 схемы синтеза алкалоида А.

7
NO2
O H
O NO2

1) BH2Cl*DMS, Et2O, 0oC,

O P
O 1) LiHDMS, TESCl, Et3N,
, then NaOH/H2O2, NaBH4,
THF, -78 to 0oC; OH
77% + (7% of regioisomer) CeCl3*7H2O, 1) 9-BBN, THF;
O 1 Al2O3 2 o
LiHMDS, THF, -10 C, 71%
3 4 2) Eschenmoser salt, CH2Cl2, 91%; 5 MeOH, 99%
6 2) NaOH/H2O2, 88%
mCPBA C19H21NO4 OH
C11H16O2 C11H16O2 C18H21NO3 C18H21NO4 C19H23NO4 C19H25NO5
2) (COCl)2, DMSO, Et3N, 3) MeI, CH2Cl2/Et2O;
CH2Cl2, 99% 4) Al2O3, CH2Cl2, 95%; 1) MsCl, 1 eq, Et3N,
C11H16O
6 O CH2Cl2, -78oC;
O N
O 2) NaHMDS, THF,
1) KOH, EtOH/H2O, 90oC -78 to 0oC, 91%
CH2=CHCO2Me,
2) (ClCO)2, CH2Cl2, 0oC 1) ClCH2CN, Bu4NI (2 mol%), H 8
Si AlCl3, CH2Cl2, Br2, 1,2,2,6,6-pentamethyl-
O 1 1) SeO2, dioxane, 100oC 2 3) NaN3, acetone/H2O 3 iPr2NEt, THF, 67oC 4 1) KH, [18]crown-6, THF, RT 5 Br
C19H23NO4
-78oC, 83% piperidine, CH2Cl2, - 78oC
C20H36O3Si C21H36O3Si C19H35NOSi C12H16N2O C13H17NO3 C13H16BrNO3
2) Ph3P=CH2, THF, 4) toluene, reflux 2) Bu4NF, THF, 0oC, 90% 2) ClCO2Me, DTBMP, -78oC to RT
TFA/CH2Cl2,
-78 to 0oC, 90% 5) KOH, dioxane/H2O, 23oC, 64% 3) KOH, MeOH, H2O, RT, 81% 5 O
H 0oC 81%
C16H30OSi O
O N
TFA, reflux, 67%
9
1) NaBH4, MeOH, 0oC NH
C15H15NO4
[Cu(acac)2] (cat.), 2) Ac2O, pyridine, 23oC I O ,
O
1) NaH, THF, 0oC; then BuLi 2 CuSO4, benzene, 3) TsOH, iPrOH/H2O, 23oC, 74% 4
O O 1 TsN3, Et3N, 3 piperidine (cat.), HO O
I
7
85oC, 3h, 68% C15H22O5 C13H16BrNO3 (COCl)2, DMSO, Et3N,
C15H24O5 C15H22N2O5 C11H14O6
OCH3 C19H18INO6 CH2Cl2, -78oC, 81%
C5H8O3 2) O, 0 to 23oC; CH2Cl2, 0oC, 83% 4) O3, MeOH/CH2Cl2 (10%), -78oC, MeOH, 23oC, 89%
ethyl vinyl ether, POCl3, then Me2S -78 to 23oC, 89% 1) DCC, DMSO, pyridinium
o 10
CH2Cl2, 0 to 23oC, 53% trifluoroacetate, 23 C C15H13NO4
1) KHMDS, Et3SiCl,
2) Et3N, CH2Cl2, 23oC, 91% o
THF, -78 C
6 2) (PhIO)n, BF3*OEt2, triethyl phosphonoacetate,
1) Hg(OTf)2*N,N-dimethylaniline, C17H12INO4
30 MeOH, CH2Cl2, -78 to 0oC NaH, THF, 0oC, E/Z 3:2, 92%
28 CH3NO2, 60-90% 29 NaOH (10%), THF, 91% LiAlH4, THF, 0-25oC, 81%
C29H28N2O6 C29H28N2O6 C21H22N2O4 toluene/CH3CN (1:1), 3) KHDMS, Comins' reagent,
o 11
2) NaBH4, NaOH, BnEt3NCl, 90 C, 45 min, 98%
THF, -78oC, 61% C19H19NO5
CH2Cl2/H2O, 60%
7
TBAF/HOAc C17H12INO4
8 DIBALH, 1 eq,
1:1, THF, 80% Target structure
16 1) HCl (conc.), (MeOCH2)2, 55oC 17 1) (iBu)2AlH, 1eq, toluene, 0oC to RT Bu3SnH, AlBN (cat.), C15H17BrF3NO6S CH2Cl2, -78oC, 88%
C22H24N2O4 C20H20N2O3 C20H22N2O2 o
toluene, 95 C, 1 h, 85%
27 12
C35H42N2O6Si 2) (iPr)2NEt, MeOH, 55oC, 90% 2) Et3SiH, TFA, CH2Cl2, reflux, 65%
8 C17H17NO4
C17H13NO4 CO (3.5 bar),

17 TMSCl, NaI, CH3CN, 18 [PdCl2(dppf)2]*CH2Cl2, CH3C(OEt)3, propionic

NEt3, MeOH, 63% DIBALH, toluene, 90% (Et2O)P(O)CH2CO2tBu,
1) NaOMe, MeOH C20H20N2O3 acid (cat.), toluene,
1) DBU, PhMe, C22H24N2O4 MeOH, (nBu)3N,
2) TPAP, NMO, CH2Cl2,
reflux, 80% BuLi, THF, 65oC, reflux, 64%
4A molecular sieves, 50% DMF, 80oC, 94%
2) H2O then MOMCl, tBuOK,
23oC, 70% 13
1) Hg(OTf)2*N,N-dimethylaniline, CH3NO2, 60-90% C21H23NO5
9 9
26 2) NaBH4, NaOH, CH2Cl2, EtOH, 80% Alloc=allyloxycarbonyl EE=ethoxyethyl C16H20BrNO5
C36H44N2O7Si C25H27NO6
15 BBN= 9-borabicyclo[3.3.1]nonane Eschenmoser salt= (CH3)2 N=CH2I NaOH/THF/EtOH, 86%
C22H25N3O3 Bn=benzyl MOM=methoxymethyl MeNH2, MeOH,
16 Cbz= benzyloxycarbonyl 14
NBS= N-bromosuccinimide 23oC, 100%
TESOTf, Et3N, CH2Cl2,
C22H24N2O4 Comins reagent= Tf2NPh 1) 2-iodoaniline, Me3Al, C19H19NO5
NMO= 4-methylmorpholine N-oxide
o
0 C, 80% DBU= 1,8-diazabicyclo[5.4.0]undec-7-ene Piv= pivalyl= 2,2,2-trimethylacetyl 10 CH2Cl2, 0oC to RT, 91%
[Cp2TiMe2], THF, DMS= dimethyl sulfide TES= triethylsilyl C26H32N2O6 2) NaH, MOMCl, THF, 86%
dppf= 1,1-bis(diphenylphosphanyl)ferrocene 1) diphenylphosphoryl
-40 to 0oC, 3 h, 65% TFA= trifluoroacetic acid
25 1) MeOTf, DTBMP, DTBMP= 2,6-di-tert-butyl-4-methylpyridine TPAP= tetrapropylammonium perruthenate 1) ClCO2CH2CH=CH2, pyridine, azide, Et3N, benzene,
C30H30N2O7 CH2Cl2, 0oC; 15 DMAP, CH2Cl2, 0oC 10 25oC to reflux;
C21H22N2O5 2) LiBH4, LiBEt3H (cat.), THF, 23 C o C23H26BrIN2O5 2) MeOH, reflux, 89%
NaCN, Me2SO,
90oC, 85% 1) HCO2H, 23oC, 79% 3) Ac2O, pyridine,73%
1) OsO4, THF, -25oC 11 O
[Pd2(dba)3]*CHCl3, 15
HCl (3N), THF, 23oC, 18 h 2) ClCO2Et, Et3N, THF, 0oC H
2) TsOH*H2O, CH2Cl2, 1) [Pd(PPh3)4], PPh3, O O Ag3PO4, Et3N, THF, C20H22N2O5
2) aqeous Na2SO3 O
MeOH, RT, 99% 14 13 o
pyrrolidine, CH2Cl2, 23 C 12 3) nBu4NN3 N reflux, 73%
3) NaIO4, THF/H2O, 45% AgOTf, Ag2CO3, CH2Cl2, 45oC,15 min, 52% O N
C26H31N3O8 C26H30ClN3O7 C29H35N3O8
O BF3*Et2O, CH2Cl2,
2) COCl2, 2,6-lutidine, CH2Cl2, 0oC, 95% 4) toluene, Et3N (cat.), reflux, then EtOH, 23oC, 76% 11
24 O -78 to 12oC, 64%
N O
O
C30H30N2O5
14 NaCN, Me2SO, 150oC, 99%
13 ethyl vinyl ether, PPTS, CH2Cl2, RT, 85% 12 1) HCl (conc.), MeOH, RT, 98% C31H38N2O8 16
O
C24H30N2O4 C26H33BrN2O6 C22H25BrN2O5 O
C20H22N2O5
o O N
2) (iBu)3Al, PhMe, -78 C to RT, 71% Br
TsOH*H2O, CH2Cl2, PivCl, Et3N, DMAP,
O
reflux, 50%
CH2Cl2, 0 to 25oC, 92%
C23H25BrN2O5
NO2
23 22 21 CH3C(OMe)2NMe2,
20 19 18 17 H
DIBALH, CH2Cl2, -78oC silica gel m-xylene, 45% K2CO3, MeOH, 90% 1) zinc dust, THF/HOAc 1) NBS, AIBN, hv, CCl4/CH2Cl2, 55-60oC, 60%
C30H32N2O6 C35H38N2O7 C37H45N3O7 C33H38N2O7 C35H40N2O8 C27H32N2O8
2) CbzCl, NaHCO3, CH2Cl2, 2) AgOAc, HOAc, 52%
94% N
O

O O

O
C25H30N2O6