Thieme Chemistry Journal Awardees - Where
are They Now? A Convenient Route for Introduction of Lipophilic
Side Chains in Polyamine Backbones by Solid-Phase Synthesis

Frank Hahn; Ute Schepers

doi:10.1055/s-0029-1217987

LETTER

Thieme Chemistry Journal Awardees - Where are They Now? A Convenient Route for Introduction of Lipophilic Side Chains in Polyamine Backbones by Solid-Phase Synthesis

Frank Hahn^a, Ute Schepers*^a,b
^a LIMES-Institute Program Unit Membrane Biology and Lipid Biochemistry and Kekulé-Institut für Organische Chemie and Biochemie, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
^b Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Hermann-von Helmholtzplatz 1, 76344 Eggenstein-Leopoldshafen, Germany
Fax: +49(7247)823354; e-Mail: ute.schepers@itg.fzk.de; e-Mail: ute.schepers@kit.edu;

Abstract

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Abstract

The synthesis of polyamines is often a laborious task that usually requires the use of complex protection schemes in combination with harsh alkylation steps. Here, we report the development of a convenient strategy for the generation of various linear as well as branched lipophilic polyamine structures on solid phase. The sequential use of Aloc-, o-nosyl-, and Dde groups for differentiation between the primary and secondary amines and Fukuyama alkylation and reductive amination for elongation and modification of the backbone enabled the synthesis of both, linear as well as branched polyamines. The mild deprotection conditions facilitated the synthesis of acid- and base-labile conjugates. This strategy was applied for the synthesis of a range of fluorescently labelled polyamine conjugates with varying degrees of lipophilic substitution.

Key words

solid-phase synthesis - drug delivery - polyamines - alkylations - protecting groups - polycations

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Referenzen

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

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<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

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<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

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The highly amphiphilic structure of this molecule avoided purification either on silica gel or on usual reversed-phase materials.

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.

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.

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 (C_q), 170.0 (C_q), 157.6 (C_q), 140.3 (C_q), 137.3 (C_q), 135.6 (C_q), 132.3 (+), 132.1 (C_q), 130.2 (+), 116.0, 114.6, 112.5 (C_q), 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 (C_q), 169.7 (C_q), 146.4, 146.1, 146.1, 145.6, 139.2, 137.1, 128.5, 128.3, 128.2, 121.0, 115.9, 113.6 (C_q, +), 143.4 (C_q), 130.5 (C_q), 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