References and Notes
<A NAME="RS07009ST-1A">1a</A>
Cohen SS.
A
Guide to the Polyamines
New York;
Oxford
University Press:
1998.
<A NAME="RS07009ST-1B">1b</A>
Hahn F.
Schepers U. In Combinatorial
Chemistry on Solid Supports
Vol. 278:
Bräse S.
Springer;
Berlin/Heidelberg:
2007.
p.135-208
<A NAME="RS07009ST-2A">2a</A>
Wender PA.
Galliher WC.
Goun EA.
Jones LR.
Pillow TH.
Adv.
Drug Deliv. Rev.
2008,
60:
452
<A NAME="RS07009ST-2B">2b</A>
Lebleu B.
Moulton HM.
Abes R.
Ivanova GD.
Abes S.
Stein DA.
Iversen PL.
Arzumanov AA.
Gait MJ.
Adv. Drug Deliv. Rev.
2008,
60:
517
<A NAME="RS07009ST-3A">3a</A>
Umezawa N.
Gelman MA.
Haigis MC.
Raines
RT.
Gellman SH.
J.
Am. Chem. Soc.
2002,
124:
368
<A NAME="RS07009ST-3B">3b</A>
Seebach D.
Beck AK.
Bierbaum DJ.
Chem. Biodiversity
2004,
1:
1111
<A NAME="RS07009ST-4A">4a</A>
Wender PA.
Mitchell DJ.
Pattabiraman K.
Pelkey ET.
Steinman L.
Rothbard JB.
Proc. Natl. Acad. Sci., U.S.A.
2000,
97:
13003
<A NAME="RS07009ST-4B">4b</A>
Schröder T.
Schmitz K.
Niemeier N.
Balaban TS.
Krug HF.
Schepers U.
Bräse S.
Bioconjugate Chem.
2007,
18:
342
<A NAME="RS07009ST-5A">5a</A>
Olsen CA.
Witt M.
Hansen SH.
Jaroszewski JW.
Franzyk H.
Tetrahedron
2005,
61:
6046
<A NAME="RS07009ST-5B">5b</A>
Manov N.
Bienz S.
Tetrahedron
2001,
57:
7893
<A NAME="RS07009ST-5C">5c</A>
Hahn F.
Müllen K.
Schepers U.
Synlett
2008,
2785
<A NAME="RS07009ST-5D">5d</A>
Kan T.
Kobayashi H.
Fukuyama T.
Synlett
2002,
1338
<A NAME="RS07009ST-5E">5e</A>
Hone ND.
Payne LJ.
Tetrahedron
Lett.
2000,
41:
6149
<A NAME="RS07009ST-5F">5f</A>
Chhabra SR.
Khan AN.
Bycroft BW.
Tetrahedron Lett.
2000,
41:
1095
<A NAME="RS07009ST-5G">5g</A>
Manku S.
Laplante C.
Kopac D.
Chan T.
Hall DG.
J.
Org. Chem.
2001,
66:
874
<A NAME="RS07009ST-5H">5h</A>
Picard S.
Le Roch M.
Renault J.
Uriac P.
Org. Lett.
2004,
6:
4711
<A NAME="RS07009ST-6">6</A>
Hahn F.
Schepers U.
J. Comb. Chem.
2008,
10:
267
<A NAME="RS07009ST-7">7</A>
Hahn F.
Schmitz K.
Balaban TS.
Bräse S.
Schepers U.
ChemMedChem
2008,
3:
1185
<A NAME="RS07009ST-8">8</A>
The highly amphiphilic structure of
this molecule avoided purification either on silica gel or on usual
reversed-phase materials.
<A NAME="RS07009ST-9">9</A>
The coupling of NBD allows the time
lapse monitoring
(up to 24 h) of living cells without
much bleaching of the fluorophore. Unpublished results of our group.
<A NAME="RS07009ST-10">10</A>
Experimental ProceduresIntroduction
of Aloc Group
The resin was swollen in CH2Cl2 and
after removal of the solvent a solution of of allylchloroformate
(10 equiv) and Et3N (10 equiv) in CH2Cl2 was
added. The suspension was agitated overnight, the solvent was removed,
and the resin was washed with CH2Cl2-MeOH
and CH2Cl2.
Aloc
Deprotection
The resin was swollen in CH2Cl2 in
a lock-up vial and N,N′-dimethylbarbituric
acid (8 equiv) and Pd(PPh3)4 (10 mol%) in
CH2Cl2 (1.5 mL) were added. The suspension
was agitated for at least 6 h at 35 ˚C in the
absence of light. The resin was transferred to a glas frit and washed
with a solution of sodium diethylaminodithiocarbamate in CH2Cl2-MeOH and
CH2Cl2.
o
-Nosyl Removal
The resin was swollen
in DMF, and after removal of the solvent a solution of β-mercaptoethanol
(10 equiv) and DBU (5 equiv) in DMF was added. The suspension was
agitated for 1 h. After removal of solvent the resin was washed
with DMF until the filtrate was colourless. The procedure was repeated
in steps of 30 min until the supernatant stays colourless after
the reaction. The resin was washed with DMF.
Dde Removal
The resin was swollen
in DMF, and after removal of the solvent a solution of N2H4˙H2O
(10 equiv, 80% in H2O) and allyl alcohol (100
equiv) of in DMF was added. The suspension was agitated (3 × 15
min), and after removal of the solvent the resin was washed with
DMF in each case.
Fukuyama Alkylation
Compound 1 (1 equiv) and K2CO3 (13
equiv) were suspended in DMF, and after 5 min N-Dde-3-aminopropyl-iodide
(13 equiv) was added. The suspension was agitated at 60 ˚C
for 18 h. The resin was washed with H2O, THF-MeOH
(2:1)/MeOH, and CH2Cl2. Compound 1 (1 equiv) was swollen in DMF for 5 min,
and DBU (20 equiv) and halide (20 equiv) were added. The suspension
was agitated at r.t. for 16 h. The resin was washed with DMF, THF-MeOH
(2:1)/MeOH, and CH2Cl2.
Reductive Amination
The resin
was placed in a frit with a plastic cap and 3% HOAc in
DMF (3 mL) was added. The suspension was shortly agitated, heated
to 40 ˚C, and capronaldehyde (6 equiv) was added.
The suspension was left for 30 min under occasional stirring, and
then NBu4BH4 (6 equiv) was added. The suspension
was again left for 30 min under occasional stirring or overnight
and was then cooled to r.t. The resin was washed with DMF. The alkylation
was twice repeated. The resin was washed with DMF, THF-MeOH,
and CH2Cl2.
<A NAME="RS07009ST-11">11</A>
Spectroscopic
Data
Compound 5a: ¹H
NMR (400 MHz, CD3OD): δ = 8.00-7.95 (m,
1 H), 7.67-7.59 (m, 2 H), 7.52-7.46 (m, 2 H),
7.25-7.11 (m, 3 H), 6.99-6.91 (m, 2 H), 3.64 (q, J = 7.0 Hz,
8 H), 3.35 (t, J = 6.4
Hz, 2 H), 3.15 (t, J = 7.7
Hz, 2 H), 3.12-2.98 (m, 6 H), 2.92 (t, J = 6.5
Hz, 2 H), 2.12 (tt, J
1 = 7.7
Hz, J
2 = 7.3 Hz,
2 H), 1.88-1.78 (m, 4 H), 1.54 (tt, J
1 = 6.8
Hz, J
2 = 6.5 Hz,
2 H), 1.30 and 1.16 (t, J = 7.0
Hz, 12 H). ESI-HRMS:
m/z calcd [M + H]+:
627.4381; found: 627.4362.
Compound 5b: ¹H
NMR (400 MHz, CD3OD): δ = 7.69 (d, J = 8.4 Hz,
2 H), 7.55 (d, J = 8.4
Hz, 2 H), 7.02 (d, J = 2.5 Hz,
1 H), 6.94 (d, J = 9.0
Hz, 1 H), 6.69 (dd, J
1 = 9.0
Hz, J
2 = 2.5
Hz, 1 H), 3.80 (s, 3 H), 3.65 (s, 2 H), 3.32 (t, J = 6.7 Hz,
2 H), 3.12 (t, J = 7.7
Hz, 2 H), 3.06 (t, J = 7.8
Hz, 2 H), 3.07-3.00 (m, 4 H), 2.95 (t, J = 7.1
Hz, 2 H), 2.32 (s, 3 H), 2.09 (tt, J
1 = 7.8
Hz, J
2 = 7.7
Hz, 2 H), 1.88 (tt, J
1 = 7.1
Hz, J
2 = 6.7
Hz, 2 H), 1.81-1.67 (m, 4 H). ¹³C
NMR (75 MHz, CD3OD): δ = 174.4 (Cq),
170.0 (Cq), 157.6 (Cq), 140.3 (Cq), 137.3
(Cq), 135.6 (Cq), 132.3 (+), 132.1
(Cq), 130.2 (+), 116.0, 114.6, 112.5 (Cq),
102.6 (+), 56.2 (+), 48.2, 48.0 (-), 46.3
(-), 45.8 (-), 37.8, 37.1 (-, 2 C), 32.3
(-), 27.5 (-), 25.3 (-), 24.2 (-,
3 C), 13.6 (+). ESI-HRMS: m/z calcd [M + H]+: 542.2892;
found: 542.2890.
Compound 5c: ¹H
NMR (400 MHz, CD3OD): δ = 8.50 (d, J = 8.8 Hz,
1 H), 6.39 (d, J = 8.8
Hz, 1 H), 3.74-3.64 (m, 2 H), 3.20 (t, J = 7.9
Hz, 2 H), 3.17-3.03 (m, 8 H), 2.18 (tt, J
1 = 7.8
Hz, J
2 = 7.4
Hz, 2 H), 2.08 (tt, J
1 = 7.8
Hz, J
2 = 7.7 Hz,
2 H), 1.84-1.78 (m, 4 H). ESI-HRMS: m/z calcd [M + H]+:
366.2248; found: 366.2252.
Compound 5d: ¹H
NMR (400 MHz, CD3OD): δ = 9.64 (s,
4 H), 9.56 (d, J = 4.9
Hz, 2 H), 8.80 (d, J = 4.9
Hz, 2 H), 8.60 (d, J = 8.2
Hz, 2 H), 8.44 (d, J = 8.2
Hz, 2 H), 5.10 (m, 6 H), 3.57 (t, J = 7.1
Hz, 2 H), 3.34 (t, J = 6.4
Hz, 2 H), 3.16 (t, J = 7.7
Hz, 2 H), 2.97-3.11 (m, 8 H), 2.50-2.60 (m, 6
H), 2.34 (t, J = 6.5
Hz, 2 H), 2.10 (tt, J
1 = 9.0
Hz, J
2 = 6.4
Hz, 2 H), 1.93 (tt, J
1 = 6.9
Hz, J
2 = 6.8
Hz, 2 H), 1.73-1.86 (m, 10 H), 1.47-1.58 (m, 8
H), 1.20-1.38 (m, 40 H), 0.87 (t, J = 7.0 Hz,
9 H). ¹³C NMR (75 MHz, CD3OD): δ = 177.3
(Cq), 169.7 (Cq), 146.4, 146.1, 146.1, 145.6,
139.2, 137.1, 128.5, 128.3, 128.2, 121.0, 115.9, 113.6 (Cq, +),
143.4 (Cq), 130.5 (Cq), 124.6, 124.5 (+),
48.3, 48.2 (-), 46.5, 45.9 (-), 41.2 (-),
37.8, 37.0 (-, 3 C), 33.1 (-), 31.4, 31.3 (-),
30.9, 30.8, 30.5, 30.4 (-), 27.9 (-), 26.8 (-),
27.8, 25.4 (-), 24.4, 24.3 (-), 23.8 (-), 14.5
(+). ESI-HRMS: m/z calcd [M + 2
H]²+: 595.9816; found: 595.9816.
Compound 13: ¹H NMR (400 MHz,
CD3OD): δ = 8.53 (d, J = 8.7
Hz, 1 H), 6.40 (d, J = 8.7
Hz, 1 H), 3.75-3.65 (m, 2 H), 3.23-3.03 (m, 14
H), 2.17 (tt, J
1 = 8.1
Hz, J
2 = 6.9
Hz, 2 H), 2.19-2.11 (m, 2 H), 2.08 (tt, J
1 = 7.8
Hz, J
2 = 7.8
Hz, 2 H), 1.83-1.77 (m, 4 H). ESI-HRMS: m/z calcd [M + H]+: 423.2827;
found: 423.2820.
Compound 17a: ¹H
NMR (400 MHz, CD3OD): δ = 8.46 (d, J = 8.8 Hz,
1 H), 6.38 (d, J = 8.8
Hz, 1 H), 3.74-3.63 (m, 2 H), 3.30 (t, J = 6.6
Hz, 2 H), 3.22 (t, J = 7.2
Hz, 2 H), (3.12 (t, J = 7.1
Hz, 2 H), 2.95 (t, J = 7.1
Hz, 2 H), 3.04 (t, J = 6.8 Hz,
2 H), 2.20 (tt, J
1 = 7.8
Hz, J
2 = 6.8
Hz, 2 H), 2.03-1.98 (m, 3 H), 1.88 (tt, J
1 = 7.2
Hz, J
2 = 6.6
Hz, 2 H), 1.87-1.67 (m, 16 H). ESI-HRMS: m/z calcd [M + H]+:
528.3293; found: 528.3304.
Compound 17b:
ESI-HRMS: m/z calcd [M + H]+:
646.5014; found: 646.4998.
Compound 23: ¹H
NMR (400 MHz, CDCl3): δ = 8.38-8.30 (m,
1 H), 6.71 (m, 1 H), 3.75-3.62 (m, 2 H), 3.38-3.30
(m, 2 H), 3.27-3.22 (m, 4 H), 3.16-2.94 (m, 8
H), 2.32-2.21 (m, 2 H), 2.04-1.97 (m, 5 H), 1.90-1.86
(m, 4 H), 1.85-1.81 (m, 4 H), 1.76-1.60 (m, 12
H), 1.45-1.22 (m, 12 H), 0.90-0.81 (m, 6 H). ESI-HRMS: m/z calcd [M + H]+:
696.5171; found: 696.5167.
Compound 27: ¹H
NMR (400 MHz, CD3OD): δ = 8.42 (d, J = 8.7 Hz,
1 H, 12 H), 7.40-7.16 (m, 5 H), 6.29 (d, J = 8.7 Hz,
1 H), 4.62 (s, 2 H), 3.68-3.58 (m, 2 H), 3.42 (t, J = 7.0 Hz,
2 H), 3.12-2.84 (m, 12 H), 2.40 (t, J = 7.6
Hz, 2 H, 17-H), 2.11 (tt, J
1 = 7.1
Hz, J
2 = 7.1
Hz, 2 H), 1.89 (tt, J
1 = 7.3 Hz, J
2 = 7.0
Hz, 2 H), 1.77-1.69 (m, 4 H), 1.69-1.52 (m, 6 H),
1.35-1.19 (m, 28 H), 0.91-0.83 (m, 9 H). ESI-HRMS:
m/z calcd [M + H]+:
806.6266; found: 806.6249.
Compound 31: ¹H
NMR (400 MHz, CDCl3): δ = 8.44-8.33 (m,
1 H), 6.31-6.26 (m, 1 H), 6.09-6.01 (m, 1 H),
3.66-3.54 (m, 2 H), 3.42-3.34 (m, 2 H), 3.34-3.22
(m, 4 H), 3.16-2.84 (m, 8 H), 2.78-2.60 (m, 4
H), 2.30 (t, J = 7.1
Hz, 2 H), 2.22-2.15 (m, 2 H), 2.08-1.96 (m, 7
H), 1.88-1.81 (m, 6 H), 1.72-1.66 (m, 6 H), 1.66-1.50
(m, 12 H), 1.34-1.16 (m, 28 H), 0.90-0.79 (m,
9 H). ESI-HRMS: m/z calcd [M + H]+: 935,7420;
found: 936.7415.
<A NAME="RS07009ST-12">12</A>
Olsen CA.
Jorgensen MR.
Witt M.
Mellor IR.
Usherwood PNR.
Jaroszewski JW.
Franzyk H.
Eur. J. Org. Chem.
2003,
17:
3288