DE102008030992A1 - Linear dendritic polyglycerol compounds, process for their preparation and their use - Google Patents

Abstract

The invention relates to novel linear dendritic polyglycerol compounds, processes for their preparation and their use for the solubilization of hydrophobic substances, in particular as a carrier or transport system for active and / or signaling substances.

Description

The The invention relates to linear dendritic polyglycerol compounds of the general formulas (1), (2) or (3), processes for their preparation as well as their use for the solubilization of hydrophobic substances, especially as a carrier or transport system for Active and / or signaling substances.

Lots newly developed, pharmaceutically interesting active ingredients have the Problem of very low water solubility and therefore poor bioavailability on. One of the biggest problems at the medicinal Treatment of diseases is the targeted transport of drugs in the diseased destination, ie in a tissue, an organ, or in the corresponding cell. Membranes are the most important barrier the destination opposite shields the active substances to be transported. Another one Problem is the degradation or derivatization of free drugs in the organism. The synthesis of water-soluble derivatives or prodrugs can in many cases not with the desired Success performed become. Another problem is particularly cytostatic in the combating tumors often a high unspecific toxicity even against healthy Tissue in vivo. At the heart of the scientific / industrial For some time now, interest has been in the search for new methods, To solubilize drugs. Another goal is passive or active accumulation of the active substance at the destination, eventual Minimize side effects on healthy tissue. For the desired effect would be in In this case, a smaller amount of therapeutic agent necessary.

Also the introduction of a signal substance, optionally coupled to an active substance, z. For example Imaging procedures such. B. for MR or IR imaging throws in usually similar Problems on. Leave chemically functionalized carriers and signaling substances consequently only limited Carrier, Signalstoff-, drug combinations too. In addition, the active substance, provided that it is covalently or coordinatively attached to the signaling substance or carrier is bound to be chemically released at the destination.

Classical Formulations for Wirkstoffsolubilisierung usually contain larger amounts on solvent mixtures from Z. For example, ethanol or polyethylene glycol. You can also find it next to it the use of phospholipids / liposomes. Nanopartikulierung and application z. B. in emulsions is used in some cases, especially for topical and non-systemic use. For use In the drug solubilization also come cyclodextrins or surfactants such as Cremophor EL ("Polyoxyl-35-Castor Oil"), a nonionic emulsifier consisting of a mixture of fatty acid glycerol polyglycol esters, fatty acid polyglycol esters and polyethylene glycols.

A new and promising way to solubilize hydrophobic substances is the use of polymeric micelles. Polymeric micelles are among the most advantageous carriers for transporting water-insoluble drugs. Polymeric micelles are characterized by a core-shell structure. Pharmaceutical research on polymeric micelles has focused primarily on (linear) copolymers having a multi-block structure. For this purpose, a variety of triblock copolymers such as Pluronics ^® and Synperonics ^® ("poloxamer"; PEO-PPO-PEO, poly (ethylene oxide) -blockpoly (propylene oxide) -block-poly (ethylene oxide) of different block length have been developed and already commercially available. Depending on their structure, composition and concentration, the amphiphilic block copolymers spontaneously form spherical, worm or lamellar aggregates.In the hydrophobic interior of polymeric micelles, water-insoluble substances can be incorporated and made bioavailable.

The shell is responsible for the stabilization of the micelles and for interactions with plasma proteins and cell membranes. It usually consists of chains of hydrophilic, biocompatible polymers such. For example, polyethylene oxide (PEO). Due to the core-shell structure, ie by the hydrophilic shell consisting z. B. from the biocompatible polyethylene oxide (in PEO block copolymers) and a lipophilic core, drugs are solubilized and stabilized, which eventually leads to prolonged circulation times in the blood ("stealth" properties of PEO). Numerous publications in this field describe the successful encapsulation of hydrophobic substances with amphiphilic block copolymers. ^1-4

So far are in the literature in addition to mostly ionic "low-weight surfactants" almost exclusively polymeric micellar nanocarriers of linear polymers are described.

A major disadvantage of linear polymeric drug carriers is that they are almost always heterogeneous and are polydispersed mixtures. The polymer molecules are contained with a variety of different molecular weights, which often also have only a limited number of functional groups and / or reactive sites. Also the linear block copolymers obtained from classical polymerization reactions like Poloxamer (Pluronics ^® ) have a broad molecular weight distribution, and are therefore polydisperse. Hyperbranched polyglycerol as a hydrophilic molecular building block is also not structurally defined. However, in order to obtain a controlled transport important in the pharmacological application, defined compounds are desirable.

There are studies on perfectly branched polyamidoamine dendrimers (PAMAM) as unimolecular transporters. However, these are very sensitive and also unstable at elevated temperatures, meaning that these macromolecules are significantly degraded. Furthermore, Noiret et al. ⁶ symmetrical polyglycerinamines showing micellar properties. On the one hand, these form no defined micelles and also have a relatively high critical micelle concentration (cmc) of> 10 ^-4 M, so that they can only be used to a limited extent for application as nanocarriers.

From Wyszogrodzka et al. ⁷ , dendritic triblock amphiphiles have been described which have a biphenyl-functionalized central unit. However, they have the disadvantage that they do not ensure an encapsulation of insoluble substances.

One remaining unresolved Problem is the generation of nonionic and structurally defined micelles, which act as active nanocarriers for hydrophobic drugs and Dyes are suitable. Therefore, there is still a need on new biocompatible and biodegradable polymeric micelle systems, which do not contain PEG (polyethylene glycol) but still have good solubilization properties demonstrate.

Of the The invention was therefore based on the object of novel systems find that are synthetically easily accessible and that can be used for Solubilization and for transport in particular of sparingly soluble Active ingredients and diagnostics z. B. for IR and MRI imaging.

The Task is achieved by the provision of nonionic, linear dendritic polyglycerol compounds with the general formulas (1), (2) or (3). All Connections have at least a glycerol dendon of the 0th to 10th generation in combination with a linear hydrophobic residue.

object The invention also relates to the synthesis of these compounds and their use, preferably as nanocarriers in aqueous Systems for the solubilization of hydrophobic dyes, active ingredients and / or Diagnostics or for the encapsulation of substances and stabilization.

worin bedeuten
PG ein Polyglycerin-Dendron der Generation 0 bis 10 [G0-G10] aus sich wiederholenden Glycerin-Einheiten, wobei
R³ = H, -C(CH₃)₂, -CH₃, -SO₃Na, -PO₃Na, oder -(CH)_ICO-ONa mit I = 1–36 sind,
Y – (Bindung) oder ein sich von PG unterscheidendes Polyglycerin-Dendron [G0-G10] aus sich wiederholenden Glycerin-Einheiten, wobei die Anzahl n im Rest (-Z-R¹-Z-R²)_n von der Generation des Dendrons abhängt,
n 1–2048
Z ausgewählt ist aus – (Bindung), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-, -S-S-,

wobei im Falle mehrerer Reste Z, diese gleich oder verschieden sein können,
X einen Linker, der im Falle mehrerer Reste X gleich oder verschieden sein kann und ausgewählt ist aus -O-, -CH₂-O-, -S-, -CH₂-S-, -COO-, -OOC-, -CH₂OOC-, -NH-CO-, -NH-COO-, -OOC-NH-, -NH-CO-, -CH₂NH-CO-, -CO-NH-, -S-S-, -CH₂-S-S-,

oder einen spaltbaren Linker bedeutet,
R¹ – (Bindung), eine lineare (gesättigte und ungesättigte) Alkylkette mit 1 bis 36 C-Atomen, einen Aryl- und/oder Heteroarylrest und/oder einen Perfluoralkyl- oder teilfluorierten Alkylrest (C1-C16) darstellt und
R² der Bedeutung von R¹ entspricht, wobei R¹ und R² gleich oder verschieden voneinander sein können, jedoch nicht beide – (Bindung) oder nur einen Arylrest bedeuten,
mit der Maßgabe, dass Verbindungen der Formel (1), in denen PG ein Polyglycerin-Dendron der Generation 0 oder 1 [G0-G1], wobei R³ = H ist,
X = -OOC,
Z = - und
R¹, R² eine Alkylkette (C1 bis C72) darstellen, ausgenommen sind.The compounds of the invention are characterized by the general formulas (1), (2) or (3).

in which mean
PG a polyglycerol dendron generation 0 to 10 [G0-G10] from repeating glycerol units, wherein
R ³ = H, -C (CH ₃ ) ₂ , -CH ₃ , -SO ₃ Na, -PO ₃ Na, or - (CH) _I CO-ONa with I = 1-36,
Y - (bond) or a polyglycerol-dendron [G0-G10] differing from PG from repeating glycerol units, the number n in the radical (-ZR ¹ -ZR ² ) _n being dependent on the generation of the dendron,
n 1-2048
Z is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-, -SS-,

in the case of several radicals Z, these may be the same or different,
X is a linker which in the case of several radicals X may be identical or different and is selected from -O-, -CH ₂ -O-, -S-, -CH ₂ -S-, -COO-, -OOC-, - CH ₂ OOC, -NH-CO, -NH-COO, -OOC-NH-, -NH-CO-, -CH ₂ NH-CO-, -CO-NH-, -SS-, -CH ₂ -SS-,

or a cleavable linker means
R ¹ - (bond), a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms, an aryl and / or heteroaryl radical and / or a perfluoroalkyl or partially fluorinated alkyl radical (C 1 -C 16) and
R ² corresponds to the meaning of R ¹ , wherein R ¹ and R ^{2 may be the} same or different from each other, but not both - (bond) or only an aryl radical,
with the proviso that compounds of formula (1) wherein PG is a generation 0 or 1 polyglycerin dendron [G0-G1] where R ^{3 is} H,
X = -OOC,
Z = - and
R ¹ , R ^{2 represent} an alkyl chain (C1 to C72) are excluded.

Aryl radicals are preferably C5-C20-aryl groups, preferably aryl is phenyl, biphenylyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, which are also represented by one or more substituents C ₁ to C ₃ -alkyl, C ₁ to C _2- alkoxy or halogen (or F, Cl) may be substituted, are preferably used as aryl phenyl, biphenylyl and Naphthylreste.

A Heteroaryl group is a monocyclic to tricyclic group with 1 to 4 heteroatoms selected from the group which consists of a nitrogen atom, oxygen atom or sulfur atom. The heterocyclic group is z. Pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl, oxazolyl, isothiazolyl, isooxazolyl, 1,3,5-triazolyl, 1,2,4-triazolyl, 1,3,5-thiadiazolyl, 1,3,5-oxadiazolyl, pyrizyl, pyridazinyl, pyrimidyl, Pyrazyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, chromenyl, Quinolyl, isoquinolyl, phthalazinyl or quinoxalinyl and the like. Preferably, it is a thiazolyl group.

In the context of the present invention, the term alkyl includes saturated or mono- or polyunsaturated linear alkyl groups. Suitable alkyl groups are, for. B. straight chain C ₄ -C ₃₆ alkyl and preferably C ₆ -C ₂₄ alkyl groups. These include in particular butyl, butenyl, butynyl, pentyl, pentenyl, pentynyl, hexyl, hexenyl, hexynyl, heptyl, heptenyl, heptynyl, octyl, octenyl, octynyl, nonyl, nonenyl, nonynyl, decyl, decenyl, decynyl, undecyl, undecenyl, undecynyl , Dodecyl, dodecenyl, dodecynyl, tridecyl, tridecenyl, tridecinyl, tetradecyl, tetradecenyl, tetradecinyl, pentadecyl, pentadecenyl, pentadecinyl, hexadecyl, hexadecenyl, hexadecinyl, heptadecyl, heptadecenyl, heptadecinyl, octadecyl, octadecenyl, octadecinyl, eicosyl, heneicosyl, docosyl or tetracosyl ,

Perfluoroalkyl or partially fluorinated alkyl (C 1 -C 16) denotes a perfluorinated or partially fluorinated alkyl radical having up to 33 fluorine atoms, preferably CF ₃ , C ₂ F ₅ , C ₃ F ₇ , C ₄ F ₉ , C ₅ F ₁₁ , C ₆ F ₁₃ , C ₇ F ₁₅ , C ₈ F ₁₇ , C ₉ F ₁₉ and C ₁₀ F ₂₁ .

preferred Compounds of the formulas (1), (2) or (3) are characterized by at least one polyglycerol dendron as head group PG from the 1. Generation. For the purposes of the invention are compounds which are a PG-Dendron head group a generation of 2 to 10 (between 2 and 10), especially prefers.

Preferred linkers X in (1), (2) or (3) are selected from -S-. -OOC-, -COO-, -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO-,

Cleavable linkers are known to the person skilled in the art and are understood as meaning compounds which are enzymatically or reductively cleavable, acid-labile, photolabile or thermolabile, preferably ester, amide, acetal, imine, disulphide or hydrazone groups. A review of cleavable linkers is z. B. by B. Rhomberg et al. before ¹⁰ .

Z in (1), (2) or (3) is preferably selected from -, -S-S-, -O-, -S-, -COO, -OOC-.

R preferably represents -, aryl, preferably phenylyl, biphenylyl or naphthyl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms,
R ² may represent a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, aryl, preferably phenylyl, biphenylyl or naphthyl, and / or perfluoryl and / or partially fluorinated alkyl (C 1 -C 16).

Especially preferred compounds of the invention (1), (2) or (3) are furthermore those which contain at least one aryl and / or heteroalkyl.

The Compounds of the invention represent macromolecular nonionic amphiphiles and draw characterized by a strictly modular design. Hydrophilic structural element is the at least one defined polyglycerol dendron (PG) different Generation as head group. The polyglycerol dendron head groups are characterized by a perfectly uniform structure, or at the core is the oxygen radical in the 2-position by another Left replaced. Preferably, the compounds of the invention possess at least one generation Dendron head G1 to G10, especially preferred from the 2nd generation.

In an embodiment variant According to the invention, preferred compounds have at least one Aryl and / or heteroaryl, the / the centrally in the immediate Near the at least one polyglycerol dione head group is / are arranged, and / or is at the end of the hydrophobic group (s).

Surprised form the compounds of the invention in aqueous Solutions uncharged definite aggregates, i. d. R. micelles, where the glycerol unit perfectly branched present. Polyglycerol is similar to polyethylene glycol good biocompatible and has a good permeability through lipid membranes.

Prefers They are compounds with a dendritic PG head group from the 2nd generation. In this case, the invention is based on the knowledge that the aggregation numbers of the dendritic amphiphiles according to the invention dependent from the dendritic head group. The forming aggregates are relatively small and their aggregation number decreases with increasing Generation of the dendritic head group.

The formed aggregates are spherical or non-spherical micelles, as vesicles or lamellae. Form a series of connections spherical Micelles made with a hydrodynamic micelle diameter, which in the Range is between 5 and 12 nm. Preferably, there are spherical micelles formed with an average diameter of 6 to 9 nm. Aggregation number and micelle formation concentration (cmc) are for each Amphiphilic characteristic sizes.

From great The advantage is that the compounds according to the invention are nonionic Represent amphiphiles, d. H. the hydrophilic group carries no Charge and so does not dissociate into ions. Nonionic amphiphiles exhibit a much better compatibility in vivo as ionic surfactants.

R' = -, Aryl, vorzugsweise Phenylyl, Biphenylyl oder Naphthyl, eine lineare (gesättigte und ungesättigte) Alkylkette mit 1 bis 36 C-Atomen,
Z = -, -S-, -COO-, -OOC- und
R² = eine lineare (gesättigte und ungesättigte) Alkylkette mit 1 bis 36 C-Atomen, Aryl, vorzugsweise Phenylyl, Biphenylyl oder Naphthyl, und/oder ein C1-C16 teilfluoriertes Alkyl
darstellen.Particular preference is given to compounds (1) in which
PG = PG dendron from the 2nd generation means, wherein R ³ is H,
X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO-,

R '= -, aryl, preferably phenylyl, biphenylyl or naphthyl, a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms,
Z = -, -S-, -COO-, -OOC- and
R ² = a linear (saturated and unsaturated) alkyl chain having 1 to 36 carbon atoms, aryl, preferably phenylyl, biphenylyl or naphthyl, and / or a C 1 -C 16 partially fluorinated alkyl
represent.

• • Verbindungen mit Alkylseitenkette,
• • Verbindungen mit Alkylseitenketten und mit (zentraler) aromatischer Einheit in Nachbarschaft zur dendritischen Polyglycerol-Kopfgruppe,
• • Verbindungen mit Alkylseitenkette und aromatischer Einheit am Ende des hydrophoben Restes

Preferred compounds (1) according to the invention having a dendritic PG head group can be classified into the following groups:

• Compounds with alkyl side chain,
• Compounds having alkyl side chains and with (central) aromatic moiety adjacent to the dendritic polyglycerol head group,
• Compounds with alkyl side chain and aromatic moiety at the end of the hydrophobic moiety

in the According to the invention, the compounds, in addition to the hydrophilic PG head group is an alkyl radical and at least one aryl and / or Heteroaryl have, particularly preferred compounds.

Particularly preferred compounds (1) according to the invention are:
1- [G1] -PG-1H- [1,2,3] triazole-4-carboxylic acid undecyl ester (22) - Example 1.1
1- [G1] -PG-1H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (21) - Example 1.2
4- (1- [G1] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (23) - Example 1.3
1- [G2] -PG-1H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (24) - Example 1.4
1- [G2] -PG-1H- [1,2,3] triazole-4-carboxylic acid undecyl ester (25) - Example 1.5
4- (1- [G2] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (26) - Example 1.6
4- (1- [G3] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (27) - Example 1.7
Hexadecanoic acid [G1] -PG amide (7) - Example 1.8
Hexadecanoic acid [G2] -PG amide (33) - Example 1.9
Bz-C11-PG [G1.0] -OH - Example 2.1
Bz-C11-PG [G2.0] -OH - Example 2.2
Bz-C18-PG [G2.0] -OH - Example 2.3
Bz-C18-PG [G3.0] -OH - Example 2.4
Na C11 PG [G2.0] OH - Example 2.5
Na-C18-PG [G2.0] -OH - Example 2.6
Na-C18-PG [G3.0] -OH - Example 2.7
Bi-C11-PG [G2.0] -OH - Example 2.8
Bi-C18-PG [G2.0] -OH - Example 2.9
Bi-C18-PG [G3.0] -OH, - Example 2.10.

R¹ = – (Bindung) oder eine lineare, gesättigte und ungesättigte Alkylkette mit 1 bis 36 C-Atomen,
Z = -, -S-, und
R² = eine lineare, gesättigte und ungesättigte Alkylkette mit 1 bis 36 C-Atomen und/oder einen teilfluorierten Alkylest C1-C16
darstellen.Preferred compounds of formula (2) are compounds in which
PG = PG dendron from the 1st generation, wherein R ³ = H or -C (CH _{3) 2,}
Y = a polyglycerol-dendron starting from the 0th generation of repeating glycerol units, different from PG, where n in the radical (-ZR ¹ -ZR ² ) _n corresponds to the number of surface groups of the generated dendron, where n = 2-2048 means
X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms,
Z = -, -S-, and
R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a partially fluorinated alkyl radical C1-C16
represent.

Particularly preferred compounds (2) are compounds with

• • Verbindungen, in denen Y n Alkenseitenketten aufweist und
• • Verbindungen, in denen Y n teilfluorierte Alkylseitenketten aufweist, die durch -S- unterbrochen sein können.

The most preferred compounds are

• Compounds in which Y n has alkene side chains and
• Compounds in which Y n has partially fluorinated alkyl side chains which may be interrupted by -S-.

Particularly preferred compounds (2) according to the invention are:
C ₆ -G 0-Ck-G1.0 - Example 3.1
C ₆ -G 0-Ck-G2.0 - Example 3.2
C ₆ -G 0-Ck-G3.0 - Example 3.3
C ₁₁ -G0-Ck-G1.0 - Example 3.4
C ₁₁ -G0-Ck-G2.0 - Example 3.5
C ₁₁ -G0-Ck-G3.0 - Example 3.6
Rf-C ₆ -G 0-Ck-G1.0 - Example 3.7
Rf-C ₆ -G 0-Ck-G2.0 - Example 3.8
Rf-C ₆ -G 0-Ck-G3.0 - Example 3.9
Rf C ₁₁ -G 0-Ck-G1.0 - Example 10.3
Rf C ₁₁ -G 0-Ck-G2.0 - Example 11.3
Rf C ₁₁ -G 0-Ck-G3.0 - Example 12.3
[G1.0] -propagyl-click [G1.5] azide-thiol (5) - Example 4.1
[G2.0] -propagyl-click [G1.5] -azide-thiol (6) - Example 4.2
[G3.0] -propagyl-click [G1.5] -azide-thiol (7) - Example 4.3
[G1.0] -propagyl-click [G1.5] -azide-OH (8) - Example 4.4
[G2.0] -propagyl-click- [G1.5] -azide-OH (9) - Example 4.5
[G3.0] -propagyl-click [G1.5] -azide-OH (10) - Example 4.6

Rf stands for the straight-chain fluoroalkyl radical.

R¹ = – (Bindung) oder eine lineare, gesättigte und ungesättigte Alkylkette mit 1 bis 36 C-Atomen,
Z = ausgewählt ist aus – (Bindung), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-,

R² = eine lineare, gesättigte und ungesättigte Alkylkette mit 1 bis 36 C-Atomen und/oder ein C1-C16 teilfluoriertes Alkyl darstellen.Preferred compounds of formula (3) are characterized by
Is PG = PG dendron from the 1st generation, wherein R ³ is H,
Y = - (bond) or glycerol unit G0, where n = 1 or 2
X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms,
Z = is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-,

R ² = represent a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a C 1 -C 16 partially fluorinated alkyl.

object The invention also relates to the preparation of the novel compounds. Of the underlying modular design as well as using easier, enable coupling reactions carried out under non-inert experimental conditions in good yield a fast and easy synthesis of structurally perfect-branched new connections.

The production takes place professionally as coupling reaction between hydrophobic and hydrophilic building blocks. The central coupling step of the two components of different polarity can, for. Example, as a Cu-catalyzed cycloaddition of the compounds, which are provided with alkyne and Azidfunktionalität and then connected by the known per se click reaction ^8,9 . In a preferred embodiment, the bond between hydrophilic and hydrophobic structural part takes place via a 1,3-dipolar cycloaddition of alkyne and azide functionality ("click" reaction, for example with the formation of a triazole ring). ^8.9

The Compounds of the invention can be prepared by either the hydrophilic ingredients with azide functionality and the hydrophobic ingredients with alkyne functionality and then the coupling of the two building blocks takes place or, conversely, the hydrophobic one Residues are provided with azide function and the hydrophilic residues with alkyne functionality, which are then subjected to the coupling reaction, optionally protecting groups can be used, which are then split off again if necessary.

Preferably, the preparation of a compound of general formula (1), (2) or (3) is characterized by using the click chemistry, the target compound as a 1,3-dipolar cycloaddition of an alkyne and azide functionality, which optionally hydrophobic and hydrophilic building block is obtained, wherein the central coupling step of the two blocks of different polarity preferably as Cu-catalyzed cycloaddition of alkyne and azide functionality in THF and / or a water / THF two-phase system with the addition of CuSO ₄ .5H ₂ O and ascorbic acid or its salts as catalysts and a base such. As NaOH or DIEPA (diisopropylethylamine) or Et ₃ N (triethylamine) takes place.

When hydrophilic moieties become the desired polyglycerol dendrons Generation synthesized. Synthesis methods to build perfectly-branched Structures of dendrimers with different generations are known to the skilled person.

The used according to the invention Hydrophilic polyglycerol dendrons are molecularly uniform macromolecules with a highly symmetrical structure. They arise from small molecules through one constantly repetitive reaction sequence, whereby ever higher branches result, at the ends of which are each the functional groups, which in turn is the starting point for further branches are. So grows with each reaction step, the number of monomer end groups exponential at the end of which a hemispherical tree structure is created. The number of reaction stages, or repeating units, is also called generation. Because of their uniform structure have the inventively used Polyglycerol head groups Dendrone a defined molecular weight on and are therefore monodisperse.

The preparation of compounds (1) can be carried out by providing the hydrophilic PG head groups with azide functionality and the hydrophobic radical with alkyne functionality:
In general, the corresponding R ³ -functionalized dendrons are first of all generations represented, which can then be converted by a simple reaction sequence preferably consisting of mesylation and azide formation in the respective azides. The synthesis of OH-functionalized dendrons requires the incorporation of protecting groups for the vicinal OH free groups, preferably acetal protecting groups are selected.

The Alkyne functionalization of the hydrophobic building block takes place, for. B. by esterification of corresponding alkyl alcohols with corresponding alkyne carboxylic acids in a suitable solvent if appropriate in the presence of a suitable catalyst and under excess alcohol.

The "click" reaction is z. B. is realized as follows: azide and alkyne are dissolved in a THF / water mixture. CuSO ₄ .5H ₂ O, ascorbic acid and NaOH are added, with the NAOH concentration being increased to 2-4-fold, in contrast to Sharpless, and the reaction mixture is preferably stirred for two to five days at room temperature. The solvent is removed, if necessary, inorganic additives are removed and any protecting groups present are eliminated, the crude product is optionally purified.

to Synthesis of amide compounds (1) are the compounds with azide functionality preferably hydrogenated by means of Pd / C and the hydrophobic portions become by reacting a corresponding carboxylic acid to the corresponding acylaminoester in the presence of a coupling reagent such. B. dicyclohexyl-carbodiimide / N-hydroxysuccinimide (DCC / NHS) prepared and then to the desired Target compound composed.

The Preparation of compounds (1) can continue to be carried out by the hydrophobic residues are provided with acitivity and the hydrophilic ones Radicals with alkyne functionality. If the hydrophobic radicals are provided with azide functionality, This functionalization z. B. on a corresponding diol with methanesulfonyl chloride and sodium azide or direct reaction an alkyl bromide with sodium azide. With the addition of appropriate Carboxylic acids, or carboxylic acid derivatives, can be a desired one hydrophobic Azidrest be prepared. The alkyne functionalization of the hydrophilic dendritic Polyglycerolbausteins z. B. over the Reaction of the protected Hydroxy-polyglycerol dendron with an alkynyl halide.

The "click" reaction is z. Example, as follows: Azide and alkyne are dissolved in THF and DIPEA is added in a concentration of 10-15 mol%. Aqueous solution of CuSO ₄ .5H ₂ O (10-15 mol%) and sodium ascorbate (20-30 mol%) are added and the reaction mixture is stirred at room temperature for a few hours to days. The solvent is removed, if necessary, inorganic additives are removed and cleaved off protecting groups, the crude product is optionally purified.

The preparation of compounds (2) takes place z. For example, as follows: In a first step, azide is reacted with a bromo-1-alkene (2 equiv per OH), optionally quenched, extracted and purified. The resulting product C _n -N ₃ is subjected to a click reaction with a polyglycerol-dentron of the desired generation, which is alkyne-functionalized, wherein catalytic amounts of DIPEA are added in THF. To prepare a perfluorinated radical R ² , the compounds are reacted after heating with the "click" reaction with RfC ₂ H ₄ SH (4 equiv. Per C = C), optionally with an initiator such as. B. AIBN is added. The GE Desired target product is cleaned if necessary.

Especially using DIPEA (diisopropylethylamine) for the click reaction be in a few minutes to hours in very good yield the Obtained target compounds.

The new compounds by at least one polyglycerol dendron are identified as a head group, form a new family of nonionic amphiphiles, which in aqueous solution undergo a controlled aggregation process subject. in particular the compounds according to the invention having a PG-dendron head group from the 2nd generation are exceptionally good water soluble. Of particular advantage is that every glycerine unit is perfect branched present. Compounds, in addition to the dendritic PG head group and a linear alkyl chain aryl and / or heteroaryl radicals either in the immediate Proximity to the head group and / or at the end of the hydrophobic alkyl radical are especially prefers.

In aqueous solution are the compounds of the invention due to their amphiphilic structure capable of defined aggregates train. Include among them spherical and non-spherical Micelles, vesicles or lamellae. Preferably, spherical micelles educated. Micelles form spontaneously from a certain concentration, the so-called critical micelle formation concentration (cmc). by virtue of The dendritic head group aligns with the hydrophilic parts (Heads) of the molecules to the adjacent water molecules whereas the hydrophobic parts (tails) are stored together and thus form a separate phase. Micelle formation is an association process, which is based on a true thermodynamic equilibrium.

The critical micelle formation concentration determines when an encapsulation of guest molecules can be done. Important for the use of micelles as transporters of hydrophobic drugs is a sufficiently low cmc to ensure that even with strong dilution while an application micellar aggregates are present. Below the critical Micelle formation concentration is only the monomeric amphiphiles before, so that already encapsulated guest molecules would be released again.

shape and size of the micelles are influenced by a number of factors. These include the chemical Structure of the amphiphiles, state of charge, polarity of the solvent, amphiphile concentration, foreign electrolyte content as well as the temperature. about Light scattering can More information about the formed aggregates are recovered. While the static light scattering information about Provides size and shape, can with the help of dynamic light scattering the hydrodynamic Radius of the micelles are determined.

Surprisingly form the compounds of the invention defined aggregates. The compounds according to the invention are in particular suitable, defined spherical To form micelles. Furthermore, the compounds of the invention monodisperse. All particles have a uniform shape and size. there they have a cmc that is significantly smaller than that of connections of the prior art, for. B. amphiphiles with polyethylene glycol head groups comparable molecular weight.

The compounds according to the invention are characterized by low micelle concentrations of ≦ 10 ^-5 mol / l. The hydrodynamic micelle diameter is 5 to 12 nm, vzw. 6 to 9 nm. The spherical shape of the micellar aggregates could be detected by KryoTEM images. Aggregation number and hydrodynamic radius were determined by static and dynamic light scattering measurements. Tensiometry, for example, makes it easy to determine the critical micelle formation concentration. The cmc is then the concentration at which the surface tension of the solution reaches a plateau and virtually no longer decreases. For this purpose, the surface tension is determined as a function of the concentration of the substance to be measured. The cmc is finally accessible via the intersection of the two curve sections

For the compounds 4- (1- [G1] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.3), 4- (1- [G2] -PG-1H- [ 1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.6) and 4- (1- [G3] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (Example 1.7 ), critical micelle concentrations of 1.5 x 10 ^-5 mol / l, 1.1 x 10 ^-5 mol / l and 7.1 x 10 ^-6 mol / l were determined.

A longer length of hydrophobic as well as the additional introduction of aromatic residues led to significantly low cmc values of ≤ 10 ^-5 mol / l, such as. For the amphiphile Bz-C18 [G2.0] -OH (Example 2.3) with the cmc of 5.3 x 10 mol / l.

comparing one the dendritic invention Amphiphiles with PEG-based representatives with otherwise the same hydrophobic Rest, so you will find surprising significantly lower cmc values in the dendritic compounds according to the invention Amphiphilic. At comparable molecular weight, these values are ten times smaller.

The Aggregation numbers were determined by static light scattering. Surprisingly the aggregation numbers are highly dependent on the size of the dendritic Head group. So is the aggregation number for the connection according to example 1.3 [G1]: 591, for the connection according to example 1.6 [G2]: 60 and for Connection according to example 1.7 [G3]: 21st Their hydrodynamic diameters were at 11.5, 8.5 and 6.5 nm.

Next the polyglycerol dendron as a hydrophilic structural unit with its defined, perfectly branched structure, have the choice of the linker X and the structure of the hydrophobic building block (eg chain length and Composition) also has a major influence on the transport properties the aggregates (micelles).

The Amphiphiles of the general formula (1), (2) and (3) are encapsulating, the transport and thus the solubilization of hydrophobic substances, such as As agents, signaling substances and other diagnostic Markers excellent.

When Active ingredients come all substances known per se, which are biologically poorly soluble Active substances are known and preferred as a drug use Find. These include in principle, all substances that are intended in the manufacture used by medicinal products as active ingredients or in their use in drug manufacture to become pharmaceutically active ingredients. These include natural and synthetic substances, such as. B. known cytostatic agents, but also proteins, enzymes, glycoproteins, polypeptides, nucleosides, Oligonucleotides, antibodies, lipids, Liposomes, phospholipids, microorganisms, human cells.

signal substances can from the group of radioactively-labeled substances or the group the dyes, such as. For example, fluorophores and chromophores may be selected.

Various hydrophobic dyes and agents have been successful as model compounds encapsulated, and the transport capacity determined by UV / VIS spectroscopy. Investigations on the encapsulation of hydrophobic substances showed a good solubilization of the water-insoluble dyes Nilrot and Pyrene, as well as the active ingredient nimodipine.

The Encapsulation of Nile Red and Pyrene with the compounds of Examples 1.3, 1.6, 1.7, 1.4 and 1.5 showed that all compounds have the desired Own transport properties. The incorporation of aromatics in the Amphiphilic structures leads to much higher transport capacity on complexed guest molecules. Links, have the biaromatic constituents (the compounds 1.3, 1.6 and 1.7) even prove to be even better than the compounds which have only one aromatic constituent (1.4 and 1.5).

A uniform size distribution the nanocarrier is also a prerequisite for optimally controlled Application. By the exclusively physical binding (hydrophobic interaction) of guest molecules in the Micelles, the release at the site of action is much less complicated and faster than, for example, dendrimers or other unimolecular, covalently linked Transportation systems.

Also Investigations with the well-known drug nimodipine confirmed the outstanding properties of the compounds of the invention. Usual formulations of the water-insoluble Active ingredients include large ones Amounts of ethanolic polyethylene glycol solutions or phospholipids. It could be shown that the macromolecular linear dendritic Amphiphiles, e.g. B. Bz-C18 [G2] -OH, up to 16 mg nimodipine per g amphiphile solubilize.

Outstanding water solubility characterizes the new dendritic polyglycerol amphiphiles. In particular, the compounds having a generation two and higher polyglycerol endonene are exceptionally well soluble in water irrespective of the group. Linear block copolymers with polyethylene glycol comparable molecular weight (PEG;. Such as at Pluronics ^®) are much worse to not water soluble.

The nonionic, macromolecular amphiphiles described in this invention, in particular the compounds (1) and (2) are excellent as described for solubilization and transport of drugs and diagnostic agents (dyes, IR / MRI markers) in vivo. Tests with water-insoluble dyes and active ingredients were successfully carried out (see also exemplary embodiments).

Not only is bioavailability and pharmacokinetics influenced by micellar nanotransport systems, but also the distribution of drugs in the body. About the size of the aggregates is a passive accumulation z. In tumor tissue, which has a dilated cell structure and a restricted lymphatic system compared to healthy tissue (enhanced permeability and retention, EPR effect). ⁵

It is noteworthy that the size of the micelles formed by the compounds of the invention with 5-12 nm, preferably 6-9 nm, on the one hand above the important renal threshold of about 5 nm, on the other hand, it is thus significantly lower than the polymeric micelles linear block copolymers (eg., Pluronics ^®) with 30-100 nm and thus profits from the EPR-effect, ie there is a better tissue penetration.

On the EPR effect leaves z. B. a passive "drug-targeting" of carcinomas or tissue with similar dilated structure like vascular tissue after balloon dilatation or massively inflamed tissue. This means a lower overall burden of the organism with potentially toxic agents. The EPR effect occurs with macromolecules 20 kDa on. For passive drug targeting will generally involve polymers 20 and 200 kDa used.

The amphiphiles according to the invention Connections can furthermore for the stabilization of emulsions, micro- and nanoemulsions as well as foams be used. They have compared to conventionally used conventional Stabilizers with low molecular weight and opposite also used linear block copolymers due to the low cmc a decisive advantage. Due to the low cmc and at low Diffusion coefficients strongly absorb colloidal particles and thus convey a good steric or electrosteric stabilization. Block copolymers, however, have the disadvantage that with increasing Although molecular weight often drops the cmc, but the diffusion coefficient also decreases sharply. In the industry, therefore, as a compromise Block copolymers having molecular weights of 1000-20000 g / mol used.

The described according to the invention linear dendritic polyglycerol amphiphiles have the great advantage that they have a very low cmc with low molecular weight of less than 1000 g / mol depending on the compound and at the same time exceptionally good Water have.

Further Fields of application of the amphiphiles described according to the invention lie z. B. in use for the encapsulation of catalysts and Formation of microreactors or for adsorption on solid surfaces, eg. B. of metal nanoparticles. Metal nanoparticles are due to their special optical and electronic properties interesting. Because of their small size they can after appropriate surface modification like molecules with each other and with surfaces react specifically. They are used as nanomarkers, as catalysts but also as components in composite materials.

literature

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• (7) Wyszogrodzka, M., Mows, K., Kamlage, S., Wodzinska, J., Plietker, B., Haag, R., New approaches towards monoamino polyglycerol dendrons and dendritic triblock amphiphiles, Eur. J. Chem. Org., 2008, 53-63 ,
• (8th) HC Kolb, MG Finn, BB Sharpless, Click Chemistry: Various Chemical Function from a Few Good Reactions, Angew. Chem. Int. Ed., 2001, 40, 2004-2021
• (9) WH Binder, R. Sachsenhofer, "Click" Chemistry in Polymer and Materials Science, Macromol. Rapid. Comm., 2007, 28, 15-54
• (10) Rhomberg, WE Hennink, G. Storm; Pharmaceutical Research, 2008, 25, 55-71

in the The following is the invention of examples explained in more detail without them limited shall be.

embodiments

Synthesis and characterization of a library of novel amphiphiles based on dendritic architectures that self-assemble into spontaneously defined micelles in water. All amphiphiles consist of a hydrophobic block with a C ₁₁ -, C ₁₆ , or C ₁₈ -alkyl chain and no or another aromatic unit (possibly next to the triazole ring). Polyglycerol dendrons of generations 1 to 3 were chosen as hydrophilic units. The coupling of hydrophobic and hydrophilic block was carried out with the help of "click" chemistry. The "click" chemistry introduced by Sharpless provides a synthetic concept consisting of some very reliable, almost perfect reactions that allow rapid synthesis of such compounds. The most widely used "click" reaction is the Cu (I) catalyzed variant of the Huisgen 1,3 cycloaddition of azides and alkynes. Amphiphiles of generations 1 and 2 without an aromatic unit were also synthesized, as were a number of compounds containing fluorine-containing alkyl side chains.

example 1

Compounds of the general formula (1) - Amphiphiles with alkyl side chain and with alkyl chain and (more central) aromatic Unit adjacent to the dendritic polyglycerol head group

in the Center point amphiphiles with an aromatic unit in direct proximity to the hydrophilic head group. In addition were also represented amphiphiles without aromatic unit. The selected hydrophobic and hydrophilic blocks are exemplified as follows.

The hydrophobic units 1-3 are synthesized by esterification of the alkyl alcohol with the acid of the respective alkyne building block. Coupling of the azide with the corresponding alkyne is followed by "click" chemistry according to the protocol of Sharpless et al. ^[8] applied. Since the synthesis is carried out with acetal-protected PG dendrons, the last step requires the cleavage of the acetal protecting groups, which ultimately leads to the amphiphile. The following retrosynthetic scheme illustrates the reaction:

to Coupling of the azide with the corresponding alkyne will be on "click" chemistry resorted. [G1] - and [G2] -PG dendrons become hydrophobic with each of the three Building blocks are functionalized, generation 3 only with the aromatic Compound 3. Generation 1 and 2 also gave amide coupling derivatives without synthesized aromatic unit. Compound 7 shows an amide [G1] -amphiphile without aromatic unit.

a) Representation of the hydrophobic alkyne building blocks

The hydrophobic alkynes 1, 2 and 3 are obtained by esterification of the alkyl alcohols 1-undecanol (8) or 1-hexadecanol (10) with propionic acid (9) or 4-ethynylbenzoic acid (11). The esterification is carried out azeotropically on a water separator. Toluene is a suitable solvent because it forms an azeotrope with the water liberated during the reaction and, moreover, all educts are soluble. To activate the carboxylic acid, catalytic amounts of PISA are added. All esterifications are carried out with a 1.75-fold excess of alcohol. This ensures that the esterification equilibrium is shifted to the product side. The esters could be isolated by column chromatography separation of the unreacted starting materials. The yields were 68% for propionic acid undecyl ester (1), 58% for propionic acid hexadecyl ester (2) and 60% for 4-ethynylbenzoic acid hexadecyl ester (3). Due to the shorter chain of the alkyl alcohol 8 compared to 10, the steric hindrance in the preparation of the ester 1 is the lowest and thus the yield is greatest. All reactions could also be carried out on a larger scale (3-10 g) without difficulty. The synthesis scheme for the esterification is shown below:

General procedure for the preparation of the hydrophobic building blocks: The carboxylic acid (1 eq) and the alcohol (1.75 eq) is dissolved in toluene. After addition of catalytic amounts of PISA, the reaction mixture is refluxed on a water separator until no more water separates (about 12 hours). It is then cooled to room temperature and the catalyst acid washed with water, aqueous sodium bicarbonate solution and water again. The organic phase is dried over sodium sulfate, the solvent is removed on a rotary evaporator and the crude product is then purified by column chromatography.

Propionic acid undecyl ester (1)

Approach: 3.00 g (42.8 mmol) of propionic acid (9), 12.91 g (74.9 mmol) of 1-undecanol (8), cat. Quantity PISA
Reaction time: 12 hours
Purification: flash column chromatography (3: 1 n-hexane / chloroform)
Yield: 6.52 g (29.1 mmol, 68%) of a colorless liquid
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 4.17 (2H, t, 3J6,5 = 7.0 Hz, H-6), 2.87 (1H, s, H-9), 1.66 (2H, quin , 3J5,4 / 5,6 = 7.0 Hz, H-5), 1.38-1.25 (16H, m, H-2, H-3, H-4), 0.87 (3H, t, 3J1.2 = 7.0 Hz , H-1).
¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 152.8 (C-7), 74.8, 74.3 (C-8, C-9), 66.4 (C-6), 31.9, 29.5, 29.4, 29.3 , 29.1, 28.3, 25.7 (C-3, C-4, C-5), 22.6 (C-2), 14.1 (C-1).
IR (KBr): (cm ^-1 ) = 3297 (m, CH (-C CH)), 2121 (m, CC (-C CH)), 2925, 2853 (s, CH (-CH ₂ , -CH ₃ )), 1714 (s, C = O), 1466, 1379 (w, CH (-CH ₂ , -CH ₃ )), 1239 (s, CO).
MS (FAB ⁺ ): m / z = 224.8 [M + H] ⁺ , 247.2 [M + Na] ⁺ .

Propionic acid hexadecyl ester (2)

Approach: 3.00 g (42.8 mmol) of propionic acid (9), 18.16 g (74.9 mmol) of 1-hexadecanol (10), cat. Quantity PISA
Reaction time: 12 hours
Purification: flash column chromatography (9: 1 n-hexane / chloroform)
Yield: 7.35 g (25.0 mmol, 58%) of a white solid
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 4.18 (2H, t, 3J6,5 = 7.0 Hz, H-6), 2.86 (1H, s, H-9), 1.67 (2H, quin , 3J5,4 / 5,6 = 7.0 Hz, H-5), 1.37-1.25 (26H, m, H-2, H-3, H-4), 0.88 (3H, t, 3J1.2 = 7.0 Hz , H-1).
¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 152.8 (C-7), 74.8, 74.3 (C-8, C-9), 66.5 (C-6), 31.9, 29.6, 29.5 (2 ×), 29.4, 29.2, 28.3, 25.7 (C-3, C-4, C-5), 22.7 (C-2), 14.1 (C-1).
IR (KBr): (cm ^-1 ) = 3298 (m, CH (-C CH)), 2121 (m, CC (-C CH)), 2925, 2854 (s, CH (-CH ₂ , -CH ₃ )), 1715 (s, C = O), 1467, 1379 (m, CH (-CH ₂ , -CH ₃ )), 1237 (s, CO).
MS (EI): m / z = 294.2 [M] ⁺ , 279.2 [M-CH ₃ ].

4-Ethynylbenzoic acid hexadecyl ester (3)

Approach: 2.17 g (12.9 mmol) of 4-ethynylbenzoic acid (11), 5.47 g (22.6 mmol) of 1-hexadecanol (10), cat. Quantity PISA
Reaction time: 12 hours
Purification: flash column chromatography (9: 1 n-hexane / chloroform)
Yield: 2.85 g (7.7 mmol, 60%) of a white solid
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 8:00 to 7:54 (4H, m, H-9, H-10), 4.31 (2H, t, ³ J 6,5 = 7.0 Hz, H-6 ), 3.22 (1H, s, H-13), 1.76 (2H, quin, 3J5.4 / 5.6 = 7.0 Hz, H-5), 1.46-1.25 (26H, m, H-2, H-3 , H-4), 0.88 (3H, t, ³ J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 166.0 (C-7), 132.0, 130.5, 129.4, 126.6, (C-8, C-9, C-10, C-11), 82.8 , 79.9 (C-12, C-13), 65.4 (C-6), 31.9, 29.7, 29.6, 29.4, 29.3, 28.7, 26.0 (C-3, C-4, C-5), 22.7 (C-) 2), 14.1 (C-1).
IR (KBr): (cm-1) = 3245 (m, CH (-C CH)), 2105 (w, CC (-C CH)), 2927, 2849 (s, CH (-CH2, -CH3)) , 1705 (s, C = O), 1471 (m, CH (-CH2, -CH3)), 1606 (m, C = C (Ar)), 1267 (s, CO).
MS (EI): m / z = 369.8 [M] ⁺ , 128.8 [C9H5O] ⁺ .

b) Representation of the hydrophilic building blocks

As hydrophilic units, polyglycerol dendrons of generations 1 to 3 were synthesized. First, the corresponding OH-functionalized dendrons are represented by all generations, which can then be converted into the respective azides by a simple reaction sequence consisting of mesylation and azide formation. The synthesis of the OH-functionalized dendrons requires the incorporation of protecting groups for the vicinal OH free groups. Since acetal protecting groups protect only vicinal diols and are also stable under the conditions required for the preparation of the dendrons, they have become selected.

outgoing of acetal protected Triglycerol (12) will be the higher Generations 2 and 3 are synthesized i-iv in repetitive synthetic sequences. The next higher generation is obtained in each case by the reaction with methallyl dichloride. First The chlorine atoms in methallyl dichloride are nucleophilic by the Oxygen atoms of the deprotonated alcohol 14 replaced. The deprotonation is achieved with the help of NaH. To reinforce the nucleophilic character will also 15-crown-5 added, which leads to the complexation of the sodium ion. By Addition of KI and 18-crown-6, the chloride is converted to a better leaving group and with it for activates the nucleophilic substitution reaction. The monosubstituted Compound and unreacted methallyl dichloride and not converted alcohol 14 are separated by HPLC. After the HPLC separation the product 15 was obtained in 73% yield.

In step iii and iv, the ozonolysis of the alkene 15 are carried out with subsequent reductive work-up. For this purpose, the alkene is dissolved in a mixture of DCM and methanol and cooled to -78 ° C. At -78 ° C, only the ozonation of C = C double bonds takes place, further side reactions can be ruled out. Ozone is introduced until the reaction mixture turns blue. The blue color indicates excess ozone in chlorinated solvents, which must then be removed by the introduction of oxygen, so that it can not lead to the formation of explosive mixtures. Since the ozonation proceeds very fast, only short reaction times of about 15 min. required. The reductive workup of the ozonides formed is achieved by addition of NaBH ₄ and 12 h stirring at room temperature. After quenching and aqueous work-up, product 16 was obtained. Since the reaction is complete, it was used without further purification for the subsequent mesylation. The mesylation of compounds 14 and 16 was carried out by adding methanesulfonyl chloride (MsCl) and triethylamine (Et ₃ N) as base. The progress of the reaction was monitored by thin-layer chromatography. First, 1 eq. MsCl and 1 eq. Et ₃ N used, after 2 h reaction time without further progress, another 0.5 eq. Et ₃ N was added and the reaction was complete within 1 h. The mesylate was converted to the azide without further work-up. 5 eq. Added NaN ₃ in DMF and heated the reaction mixture to 120 ° C for 3 h. For purification, it was filtered through silica gel. The yield of the [G2] azide 18 was 94% over two stages, the yield of the [G3] azide 20 92% over three stages (including ozonolysis). [G1] -Azide 19 could be provided analogously.

Synthesis of the [G2] - and [G3] -OH dendrons; i) NaH, 15-crown-5 (cat), methallyl dichloride, THF, 2h, RT; ii) KI, 18-crown-6 (cat), THF, 24 h, reflux, 75% overall yield of 15; iii 15) O _3, MeOH / DCM, -78 ° C, min; iv) NaBH ₄ , MeOH / DCM, RT, 12 h.

Synthesis of acetal-protected (G3) -enes (15)

9.00 g (12.9 mmol, 2.1 eq) [G 2] -OH (14), 1.48 g (61.5 mmol, 10 eq) 60% NaH in mineral oil, catalytic amounts of 18-crown-6 and absolute THF are combined in one submitted to dry round bottom flask under argon atmosphere. After the addition of 0.77 g (6.2 mmol, 1 eq) of methallyl dichloride becomes the reaction mixture Stirred for 2 hours at room temperature. Subsequently catalytic amounts of potassium iodide and 15-crown-5 are added and the reaction mixture is refluxed for 12 hours. After cooling to Room temperature will be the excess NaH quenched with water and extracted three times with DCM. The combined organic Phases are over Dried sodium sulfate and the solvent is on a rotary evaporator away. The crude product is over Silica gel filtered (6: 1 ethyl acetate / n-hexane) and then by HPLC purified (1: 1 isopropanol / n-hexane).

There was obtained 6.5 g (4.5 mmol, 73%) [G3] -en (15) as a light yellow, viscous oil.
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 5.15 (2H, s, H-1), 4:24 to 3:43 (74H, m, H- (3-10)), 1.39 / 1:33 (48H, 2s, H-12, H-13).
¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 143.1 (C-2), 109.3 (C-11), 78.4, 74.5, 72.4, 71.4, 70.6, 70.1, 66.9, 66.7 (C- (3 -10)), 26.7, 25.4 (C-12, C-13).
IR (KBr): (cm-1) = 2988 (m, CH (-CH ₂ , -CH ₃ )), 1456, 1372 (m, CH (-CH ₂ , -CH ₃ )), 1082 (s, CO ).
MS (TOF): m / z = 1467.8095 [M + Na] ⁺ , 745.3994 [M + 2Na] ²⁺ .

Synthesis of acetal protected [G3] -OH (16)

6.50 g (4.5 mmol) [G3] -en (15) are dissolved in 35 ml of dry MeOH / DCM (1: 1). solved and cooled to -78 ° C. It as long as ozone is through the solution passed until a blue tint entry. Excess ozone is subsequently removed by a strong flow of oxygen.

After the addition of 1.70 g (45 mmol) of NaBH ₄ , the reaction mixture is stirred for 12-15 hours while slowly warming to room temperature. After quenching with saturated ammonium chloride solution is stirred for an additional hour. The organic phase is separated and the aqueous extracted three times with DCM. The combined organic phases are washed three times with water, dried over sodium sulfate and the solvent is removed on a rotary evaporator.

There the reaction completely and without by-products, was [G3] -OH (16) without further purification and characterization in the next Step inserted.

It there were obtained 6.52 g (4.5 mmol, 100%) of a pale yellow, viscous oil.

working procedure for the preparation of PG azides: 1 eq [G2] -OH (14) or [G3] -OH (16) and 1.5 eq of triethylamine are initially charged in toluene and cooled to 0 ° C. Subsequently, will slowly added dropwise 1 eq methane-sulfonyl chloride. The reaction progress let yourself check with DC.

After the end of the reaction, the precipitate is filtered off and the solvent is removed on a rotary evaporator. The mesylate is dissolved in DMF and 5 eq of sodium azide are added. The reaction mixture is stirred for 3 hours at 120 ° C, the excess of sodium azide is filtered off and the DMF removed in vacuo. The crude product thus obtained is purified by filtration over silica gel (10: 1 ethyl acetate / n-hexane). Synthesis of the [G2] -azide:

Synthesis of acetal protected [G2] -N3 (18)

Preparation: 7.00 g (10.0 mmol) of [G2] -OH (14), 1.53 (15.1 mmol) of triethylamine, 1.15 g (10.0 mmol)
Methanesulfonyl chloride, 3.27 g (50.2 mmol) of sodium azide
Yield: 6.82 g (9.4 mmol, 94%) of a light yellow, viscous oil
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 4:25 to 3:45 (35H, m, H- (1-7)), 1.40 / 1:34 (24H, 2s, H-9, H-tenth
¹³ C-NMR (CDCl _3, 125 MHz): (ppm) = 109.3 (C-8), 78.7, 78.5, 74.7, 74.6, 72.5, 71.4, 70.3, 66.8, 66.7 (C (2-7)), 61.1 (C-1), 26.7, 25.4 (C-9, C-10).
IR (KBr): (cm-1) = 2987 (s, CH (-CH ₂ , -CH ₃ )), 2101 (s, azide), 1456, 1371 (s, CH, (-CH ₂ , -CH ₃ )), 1082 (s, CO).
MS (TOF): m / z = 722.4080 [M + H] ⁺ , 744.3897 [M + Na] ⁺ , 760.3638 [M + K] ⁺ .

Synthesis of acetal protected [G3] -N3 (20)

Preparation: 6.52 g (4.5 mmol) of [G3] -OH (16), 0.68 g (6.8 mmol) of triethylamine, 0.52 g (4.5 mmol)
Methanesulfonyl chloride, 1.46 g (22.5 mmol) of sodium azide
Yield: 6.11 g (4.1 mmol, 92%) of a light yellow, viscous oil
¹ H-NMR (CDCl _3, 500 MHz): (ppm) = 4:24 to 3:43 (75H, m, H- (1-9)), 1.39 / 1:33 (24H, 2s, H-11, H-12).
¹³ C-NMR (CDCl ₃ , 125 MHz): (ppm) = 109.3 (C-10), 78.6, 78.4, 74.7, 74.5, 72.4, 71.6, 71.4, 71.2, 70.4, 66.9, 66.7 (C- (2) 9)), 61.3 (C-1), 26.7, 25.4 (C-11, C-12).
IR (KBr): (cm ^-1 ) = 2987 (s, CH (-CH ₂ , -CH ₃ )), 2113 (m, azide), 1456, 1372 (s, CH, (-CH ₂ , -CH ₃ )), 1082 (s, CO).
MS (TOF): m / z = 759.8986 [M + 2Na] ⁺ , 1474.8276 [M + H] ⁺ , 1496.8084 [M + Na] ⁺ , 1512.7832 [M + K] ⁺ .

Coupling of hydrophobic and hydrophilic Building blocks through "click" chemistry

The Sharpless et al. Published conditions for successful synthesis include the addition of 5 mol% CuSO ₄ .5H ₂ O and 10 mol% ascorbic acid as catalysts. Often, 10 mol% NaOH is also added as the base. Surprisingly, only the increase of the base concentration from 10 mol% to 30 mol% led to the goal. Reaction times were shortened to two days for the [G1] azide reaction, four days for the [G2] azides, and five days for the [G3] azides.

The general synthesis of the "click" chemistry carried out is shown in the following scheme:

Cleavage of the acetal protecting groups

In the last step, the acetal protecting groups were cleaved under acidic conditions. However, the pH should not be too low, since otherwise the esters are not stable and acid ester hydrolysis may occur. The Lewatit K 1131 ion exchanger in MeOH has proven to be suitable. The cleavage took place after 24 h stirring to 100%. All products were purified by HPLC to give clean compounds for subsequent physico-chemical characterizations that are very sensitive to any contaminants. Cleavage of the acetal protecting groups by the example of the [G1] amphiphiles:

The yields of the "click" reactions after acetal cleavage and HPLC separation are summarized in Table 1 below. Table 1:

General working instructions for the "Click" reaction:

azide (1 eq) and alkyne (1.1 eq) are mixed in 4 mL of THF / water (1: 1) mixture solved. CuSO4 · 5 H2O (5 mol%), ascorbic acid (10 mol%) and NaOH (30 mol%) are added and the reaction mixture will be two to five Stirred at room temperature for days. The solvent is removed in vacuo and the inorganic additives become by filtration over Silica gel removed. The cleavage of the protective groups is the crude product dissolved in MeOH and about 100% by weight of Lewatit K 1131 ion exchangers are added. Stirring for 24 hours Deliver the deprotected Amphiphile, which is purified by HPLC.

Example 1.1

Synthesis of 1- [G1] -PG-1H- [1,2,3] triazole-4-carboxylic acid undecyl ester (22)

Approach: 750 mg (2.2 mmol) of [G1] -N3 (19), 534 mg (2.4 mmol) of undecyl propionate (1), 27 mg (0.11 mmol) of CuSO ₄ .5H ₂ O, 39 mg (0.22 mmol) ascorbic acid, 26 mg (0.66 mmol) NaOH, 1.3 g Lewatit K 1131
Reaction time: 48 hours
Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)
Yield: 510 mg (1.0 mmol, 48%) of a yellow waxy solid
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.61-8.56 (1H, m, H-9), 5.06 (1H, m, H-10), 4.28 (2H, t, ³ J6.5 = 7.0 Hz, H-6), 3.99-3.38 (14H, m, H- (11-14)), 1.72 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5), 1.43-1.25 (16H , m, H- (2-4)), 0.85 (3H, t, 3J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.2 (C-7), 140.5 (C-9), 129.8 (C-8), 73.8, 72.1, 71.1, 66.3, 64.2, 62.9 (C) 6, C- (10-14)), 33.1, 30.8, 30.5, 29.8, 27.0 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm ^-1 ) = 3387 (m, OH), 2927, 2856 (s, CH (-CH ₂ , -CH ₃ )), 1725 (m, C = O), 1543 (w, C = C (aromatic)), 1466 (w, CH (-CH ₂ , -CH ₃ )), 1042 (m, CO).
TOF-MS: m / z = 490.3124 [M + H] ⁺ , 512.2945 [M + Na] ⁺ , 979.6180 [2M + H] ⁺ , 1001.6002 [2M + Na] ⁺ .

Example 1.2

Synthesis of 1- [G1] -PG-1H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (21)

Batch: 587 mg (1.7 mmol) of [G1] -N3 (19), 551 mg (1.9 mmol) of hexadecyl propionate (2), 21 mg (0.085 mmol) of CuSO4 .5H2O, 30 mg (0.17 mmol ) Ascorbic acid, 20 mg (0.51 mmol) NaOH, 1.1 g Lewatit K 1131
Reaction time: 48 hours
Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)
Yield: 469 mg (0.84 mmol, 49%) of a white solid
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.62-8.57 (1H, m, H-9), 5.06 (1H, m, H-10), 4.29 (2H, t, ³ J6.5 = 7.0 Hz, H-6), 4.00-3.39 (14H, m, H- (11-14)), 1.73 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5), 1.44- 1.25 (26H, m, H- (2-4)), 0.86 (3H, t, ³ J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.2 (C-7), 140.5 (C-9), 129.8 (C-8), 73.8, 72.1, 71.1, 66.3, 64.2, 62.9 (C) 6, C- (10-14)), 33.1, 30.8, 30.7, 30.5 (2x), 29.8, 27.1 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3384 (s, OH), 2925, 2854 (s, CH (-CH2, -CH3)), 1724 (s, C = O), 1644, 1543 (w, C = C (aromatic)), 1466 (m, CH (-CH 2, -CH 3)), 1042 (m, CO).
TOF-MS: m / z = 560.3907 [M + H] ⁺ , 582.3722 [M + Na] ⁺ , 1119.7751 [2M + H] ⁺ , 1141.7560 [2M + Na] ⁺ .

Example 1.3

Synthesis of 4- (1- [G1] -PG-1H- [1,2,3] triazol-4-yl) benzoic acid hexadecyl ester (23)

Batch: 525 mg (1.5 mmol) of [G1] -N3 (19), 619 mg (1.7 mmol) of hexadecyl 4-ethynylbenzoate (3), 19 mg (0.075 mmol) of CuSO4 .5H2O, 26 mg (0 , 15 mmol) ascorbic acid, 18 mg (0.45 mmol) NaOH, 1.1 g Lewatit K 1131
Reaction time: 48 hours
Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)
Yield: 553 mg (0.87 mmol, 57%) of a yellowish-white solid
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.62-8.57 (1H, m, H-13), 8.07-7.95 (4H, m, H-9, H-10), 5.08 (1H, m , H-14), 4.31 (2H, t, 3J6.5 = 7.0 Hz, H-6), 4.06-3.45 (14H, m, H- (15-18)), 1.79 (2H, quin, 3J5.4 / 5.6 = 7.0Hz, H-5), 1.49-1.27 (26H, m, H- (2-4)), 0.89 (3H, t, 3J1.2 = 7.0Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.7 (C-7), 147.4 (C-11), 136.5, 131.2, 131.0, 126.6, 123.4 (C- (8-13)), 73.9, 72.2, 71.3, 66.3, 64.3, 62.6 (C-6, C- (14-18)), 33.1, 30.8 (2 ×), 30.5 (2x), 29.9, 27.2 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3415 (s, OH), 2925, 2854 (m, CH (-CH2, -CH3)), 1712 (w, C = O), 1616 (w, C = C (Aromat)), 1464 (w, CH (-CH2, -CH3)), 1112 (w, CO).
TOF-MS: m / z = 636.4228 [M + H] ⁺ , 658.4046 [M + Na] ⁺ , 1271.8383 [2M + H] ⁺

Example 1.4

Synthesis of 1- [G2] -PG-1H- [1,2,3] triazole-4-carboxylic acid hexadecyl ester (24)

Approach: 902 mg (1.3 mmol) of [G2] -N3 (18), 405 mg (1.4 mmol) of hexadecyl propionate (2), 16 mg (0.065 mmol) of CuSO4 .5H2O, 23 mg (0.13 mmol ) Ascorbic acid, 16 mg (0.39 mmol) NaOH, 1.3 g Lewatit K 1131
Reaction time: 4 days
Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)
Yield: 630 mg (0.74 mmol, 59%) of a colorless wax
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.71-8.66 (1H, m, H-9), 5.08 (1H, m, H-10), 4.34 (2H, t, ³ J6.5 = 7.0Hz, H-6), 4.19-3.40 (34H, m, H- (11-16)), 1.78 (2H, quin, ³ J5.4 / 5.6 = 7.0Hz, H-5), 1.49- 1.29 (26H, m, H- (2-4)), 0.90 (3H, t, ³ J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.3 (C-7), 140.3 (C-9), 130.1 (C-8), 80.0, 73.9, 72.4, 72.2, 71.2, 70.2, 66.4, 64.4 (C-6, C- (10-16)), 33.1, 30.8, 30.5, 29.8, 27.1 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3385 (s, OH), 2925, 2854 (s, CH (-CH2, -CH3)), 1722 (m, C = O), 1643, 1543 (w, C = C (aromatic)), 1466 (m, CH (-CH 2, -CH 3)), 1121 (m, CO).
MS (TOF): m / z = 856.5390 [M + H] ⁺ , 878.5209 [M + Na] ⁺ .

Example 1.5

Synthesis of 1- [G2] -PG-1H- [1,2,3] triazole-4-carboxylic acid undecyl ester (25)

Batch: 902 mg (1.3 mmol) of [G2] -N3 (18), 308 mg (1.4 mmol) of undecyl propionate (1), 16 mg (0.065 mmol) of CuSO ₄ .5H ₂ O, 23 mg (0 , 13 mmol) ascorbic acid, 16 mg (0.39 mmol) NaOH, 1.2 g Lewatit K 1131
Reaction time: 4 days
Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)
Yield: 441 mg (0.56 mmol, 45%) of a colorless wax
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.70-8.68 (1H, m, H-9), 5.08 (1H, m, H-10), 4.35 (2H, t, 3J6.5 = 7.0 Hz, H-6), 4.18-3.40 (34H, m, H- (11-16)), 1.78 (2H, quin, ³ J5.4 / 5.6 = 7.0 Hz, H-5), 1.48-1.29 (16H, m, H- (2-4)), 0.90 (3H, t, ³ J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 162.3 (C-7), 140.4 (C-9), 130.1 (C-8), 80.1, 73.9, 72.5, 72.2, 70.2, 66.4, 64.5, 63.5 (C-6, C- (10-16)), 33.1, 30.8, 30.5, 29.8 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3388 (s, OH), 2924 (s, CH (-CH2, -CH3)), 1720 (m, C = O), 1638 (m, C = C (Ar )), 1459 (w, CH (-CH 2, -CH 3)), 1041 (m, CO).
MS (TOF): m / z = 786.4608 [M + H] ⁺ , 808.4428 [M + Na] ⁺ .

Example 1.6

Synthesis of 4- (1- [G2] -PG-1H- [1,2,3] triazol-4-yl) -benzoic acid hexadecyl ester (26)

Batch: 752 mg (1.0 mmol) [G 2] -N 3 (18), 422 mg (1.1 mmol) 4-ethynylbenzoic acid hexadecyl ester (3), 12 mg (0.050 mmol) CuSO 4 .5H 2 O, 18 mg (0, 10 mmol) ascorbic acid, 12 mg (0.30 mmol) NaOH, 1.2 g Lewatit K 1131
Reaction time: 4 days
Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)
Yield: 423 mg (0.45 mmol, 44%) of a colorless wax
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.64-8.60 (1H, m, H-13), 8.10-7.98 (4H, m, H-9, H-10), 5.07 (1H, m , H-14), 4.32 (2H, t, ³ J6.5 = 7.0 Hz, H-6), 4.22-3.39 (34H, m, H- (15-20)), 1.79 (2H, quin, ³ J5 , 4 / 5.6 = 7.0 Hz, H-5), 1.50-1.28 (26H, m, H- (2-4)), 0.89 (3H, t, ³ J1.2 = 7.0 Hz, H-1) ,
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.8 (C-7), 147.2 (C-11), 136.5, 131.3, 131.0, 126.6, 123.7 (C- (8-13)), 80.1, 73.9, 72.5, 72.2, 70.5, 66.3, 64.4 (2x) (C-6, C- (14-20)), 33.1, 30.8, 30.7 (2x), 30.5, 29.9, 27.2 (C- (3-5) ), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3381 (s, OH), 2923, 2853 (s, CH (-CH2, -CH3)), 1716 (m, C = O), 1615 (w, C = C (Aromat)), 1466 (m, CH (-CH 2, -CH 3)), 1112 (s, CO).
MS (TOF): m / z = 932.5711 [M + H] ⁺ , 954.5531 [M + Na] ⁺ .

Example 1.7

Synthesis of 4- (1- [G3] -PG-1H- [1,2,3] triazol-4-yl) benzoic acid hexadecyl ester (27)

Approach: 1.00 g (0.68 mmol) of [G3] -N3 (20), 276 mg (0.75 mmol) of 4-ethynylbenzoic acid hexadecyl ester
(3), 8 mg (0.034 mmol) CuSO 4 .5H 2 O, 12 mg (0.068 mmol) ascorbic acid, 8 mg (0.20 mmol) NaOH,
1.3 g Lewatit K 1131
Response time: 5 days
Purification: HPLC (MeOH / DCM 1: 5, flow 64 mL / min)
Yield: 604 mg (0.40 mmol, 58%) of a colorless wax
¹ H-NMR (MeOD, 500 MHz): (ppm) = 8.66-8.65 (1H, m, H-13), 8.12-8.01 (4H, m, H-9, H-10), 5.27 (1H, m , H-14), 4.33 (2H, t, ³ J6.5 = 7.0 Hz, H-6), 4.21-3.42 (74H, m, H- (15-22)), 1.80 (2H, quin, ³ J5 , 4 / 5.6 = 7.0 Hz, H-5), 1.51-1.28 (26H, m, H- (2-4)), 0.90 (3H, t, ³ J1.2 = 7.0 Hz, H-1) ,
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 167.8 (C-7), 147.1 (C-11), 136.5, 131.3, 131.0, 126.7, 124.0 (C- (8-13)), 80.5, 79.8, 74.0, 72.9, 72.2, 71.0, 70.4, 66.4, 64.5, 63.5 (C-6, C- (14-22)), 33.1, 30.8, 30.5, 29.8, 27.2 (C- (3-5)), 23.8 (C-2), 14.5 (C-1).
MS (TOF): m / z = 1524.8621 [M + H] ⁺ , 1546.8432 [M + Na] ⁺ .

c) Synthesis of amide amphiphiles

The amide amphiphiles 7 and 33 were synthesized as shown below. The hydrogenation with Pd / C was carried out in an autoclave at 8 bar hydrogen pressure and was complete after 24 h. After filtration through silica gel, 99% [G1] -NH ₂ 28 or 96% [G ₂ ] -NH ₂ 29 were obtained. The coupling of 28 and 29 to 30 with DCC and NHS was carried out in two steps. After activation of the acid as NHS ester, the resulting DCU could be filtered off for the most part and then amine 28 or 29 were added. The progress of the coupling reaction was monitored by TLC.

General procedure for amide coupling:

Hexadecanoic acid (1 eq) and DCC (1.1 eq) are dissolved in THF and after addition of NHS (1.05 eq) is stirred for 24 hours at room temperature. The DCU precipitation is filtered off and part of the solvent away. After further crystallization of DCU overnight in the refrigerator is filtered again. The filtrate is taken up in a THF / DMF (1: 1) mixture and after addition of the amine (1 eq) stirring is continued for 2-5 days. After completion of the reaction becomes the solvent mixture removed under reduced pressure. For cleavage of the protective groups the crude product is dissolved in methanol and about 100 wt .-% ion exchanger Lewatit K 1131 is added. 24 hours stirring provides the deprotected amphiphile, which is purified by HPLC.

Example 1.8

Synthesis of hexadecanoic acid [G1] -PG amid (7)

Preparation: 0.80 g (2.5 mmol) of [G1] -NH2 (28), 641 mg (2.5 mmol) of hexadecanoic acid (30), 567 mg (2.8 mmol) of DCC, 302 mg (2.6 mmol) NHS, 1.4 g Lewatit K 1131
Reaction time: 48 hours
Purification: HPLC (MeOH / DCM 2:25, flow 64 mL / min)
Yield: 289 mg (0.61 mmol, 24%) of a white solid
¹ H-NMR (MeOD, 500 MHz): (ppm) = 4.14 (1H, m, H-8), 3.76-3.40 (14H, m, H- (9-12)), 2.17 (2H, t, 3J6 , 5 = 7.5 Hz, H-6), 1.57 (2H, m, H-5), 1.29-1.26 (24H, m, H- (2-4)), 0.87 (3H, t, 3J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 174.9 (C-7), 72.5, 72.2, 70.9, 69.9, 63.0 (C- (8-12), 35.8, 31.8, 29.5, 29.3, 29.2, 29.0, 25.8 (C- (3-6)), 22.4 (C-2), 13.1 (C-1).
IR (KBr): (cm-1) = 3357 (m, OH), 2974, 2926 (m, CH (-CH2, -CH3)), 1267 (m, CO).
MS (TOF): m / z = 478.3738 [M + H] ⁺ , 500.3557 [M + Na] ⁺ , 516.3260 [M + K] ⁺ .

Example 1.9

Synthesis of hexadecanoic acid [G2] -PG amid (33)

Approach: 1.00 g (1.4 mmol) of [G2] -NH2 (29), 359 mg (1.4 mmol) of hexadecanoic acid (30), 318 mg (1.5 mmol) of DCC, 177 mg (1.5 mmol) NHS, 1.4 g Lewatit K 1131
Response time: 5 days
Purification: HPLC (MeOH / DCM 3:20, flow 64 mL / min)
Yield: 479 mg (0.62 mmol, 44%) of a colorless wax
¹ H-NMR (MeOD, 500 MHz): (ppm) = 4.13 (1H, m, H-8), 3.79-3.46 (34H, m, H- (9-14)), 2.22 (2H, t, 3J6 , 5 = 7.5 Hz, H-6), 1.61 (2H, m, H-5), 1.33-1.29 (24H, m, H- (2-4)), 0.90 (3H, t, 3J1.2 = 7.0 Hz, H-1).
¹³ C-NMR (MeOD, 125 MHz): (ppm) = 176.3 (C-7), 79.8, 74.0, 73.0, 72.2, 71.3, 70.0, 64.5, 63.0 (C- (8-14), 37.2, 33.1, 30.9, 30.5, 30.4, 27.1 (C- (3-6)), 23.8 (C-2), 14.5 (C-1).
IR (KBr): (cm-1) = 3398 (m, OH), 2925 (m, CH (-CH2, -CH3)), 1643 (w, C = O (amide)), 1265 (s, CO) ,
MS (TOF): 774.5222 [M + H] ⁺ , 796.5036 [M + Na] ⁺ .

Example 2

Compounds of the general formula (1) - Amphiphiles with alkyl side chain and aromatic moiety at the end of the hydrophobic Remainder with dendritic polyglycerol head group

The synthesis of non-ionic, linear-dendritic, aromatic-terminated polyglycerol amphiphiles is illustrated by the example of biphenyl octadecanyl polyglycerol compound - Bi-C18-PG [G2.0] -OH. Similarly, short alkyl chain amphiphiles (C11), benzoyl (Bz), or naphthoyl (Na) structures (instead of the biphenyl moiety in the compound presented herein) and amphiphiles with generation 1.0 and 3.0 polyglycerol endo-dides were also prepared. Examples 2.1 to 2.10 Bz-C11-PG [G1.0] -OH Bz-C11-PG [G2.0] -OH Bz-C18 PG [G2.0] OH Bz-C18 PG [G3.0] OH Na C11-PG [G2.0] -OH Na-C18 PG [G2.0] OH Na-C18 PG [G3.0] OH Bi-C11-FG [G2.0] -OH Bi-C18-PG [G2.0] -OH Bi-C18-PG [G3.0] -OH Synthesis of Bi-C18-PG [G2.0] -OH Structure of biphenyl-octadecanyl-polyglycerol:

11- (4 - ((6,12-bis ((2,3-dihydroxypropoxy) methyl) -1,2,16,17-tetrahydroxy-4,7,11,14-tetraoxaheptadecan-9-yloxy) methyl) - 1H-1,2,3-triazol-1-yl) undecylbiphenyl-4-carboxylate
Chemical formula: C ₅₅ H ₉₁ N ₃ O ₁₇
Exact mass: 1065.63485
Molecular weight: 1066.3209.1 a) Representation of the hydrophobic amphiphilic building block 18-azido-1-octadecanol

Under gentle warming was 1,18-octadecanediol (18.80 g, 65.62 mmol, 1.5 equiv.) in abs. THF (800 mL) dissolved and with triethylamine (18.75 mL, 13.61 g, 134.50 mmol, 3.1 equiv.) added. about For a period of 90 minutes, methanesulfonyl chloride (3.35 mL, 4.96 g, 43.28 mmol). After 18 hours at the the reaction precipitated colorless solid separated and the solvent removed on a rotary evaporator. There were 33.80 g of a colorless, waxy solid, which without further purification was converted to the azide.

¹H-NMR (250 MHz, CDCl3): δ = 3.62 (t, 2H, 1-H), 3.25 (t, 2H, 18-H), 1.85 (OH), 1.58 (m, 6H, 2/3/17-H), 1.26 (26H, 4-16-H) ppm
¹³C-NMR (250 MHz, CDCl3): δ = 62.94 (1-C), 51.45 (18-C), 32.76 (2-C), 29.61-28.79, 26.67, 25.71 (3-17-C) ppm
HR-MS (ESI-TOF): ber. für C18H37N3ONa+: 334.2834 , gef.: 334.2807 [M+Na]+ Veresterungsreaktion

The crude product was in abs. Dissolved DMF (250 mL), treated with sodium azide (14.19 g, 218.25 mmol) and the suspension stirred at 120 ° C for three hours. After separating off the excess sodium azide, the solvent was removed in vacuo and the residue was purified by column chromatography (hexane / EA 1: 0, 8: 1 to 3: 1). There were obtained 8.25 g (61% based on mesyl chloride) of a colorless, waxy solid,

¹ H-NMR (250 MHz, CDCl3): δ = 3.62 (t, 2H, 1-H), 3.25 (t, 2H, 18-H), 1.85 (OH), 1.58 (m, 6H, 2/3 / 17-H), 1.26 (26H, 4-16-H) ppm
¹³ C-NMR (250 MHz, CDCl3): δ = 62.94 (1-C), 51.45 (18-C), 32.76 (2-C), 29.61-28.79, 26.67, 25.71 (3-17-C) ppm
HR-MS (ESI-TOF): calcd. For C18H37N3ONa +: 334.2834, found: 334.2807 [M + Na] + esterification reaction

1H-NMR (250 MHz, CDCl3): δ = 8.13 (d, 2H, 2/12-H), 7.65 (4H, 6/7/9/10-H), 7.44 (3H, 3/8/11-H), 4.35 (t, 2H, 14-H), 3.25 (t, 2H, 31-H), 1.80 (m, 2H, 15-H), 1.60 (m, 2H, 30-H), 1.28 (28H, 16-29-H) ppm
13C-NMR (250 MHz, CDCl3): δ = 166.44 (13-C), 145.44 (1-C), 140.00 (4-C), 129.99, 129.27, 128.84, 128,02, 127.19, 126.92 (2/3/5/6/7/8/9/10/11/12-C), 65.08 (14-C), 51.43 (31-C), 29.63-26.02 (15-30-C) ppm
HR-MS (ESI-TOF): ber. für C31H45N3O2Na+: 514.3409, gef.: 514.3421 b) Synthese des hydrophilen dendritischen Polyglycerolbausteins Acetalgeschütztes Alkinyl-Triglycerol

Alcohol and carboxylic acid (1.4-2 equiv.) Are dissolved in toluene and the reaction mixture after addition of p-toluenesulfonic acid (PISA, 11-15 mol%) at 118-125 ° C on a water ("Dean-Stark") heated to reflux (15-19 h). After checking by TLC, it is washed with water, saturated sodium bicarbonate solution and once more with water, and the organic phase is dried over sodium sulfate. After removal of the solvent on a rotary evaporator, the column chromatography is carried out. Bi-C18-N3 (59) Approach: 11-azido-octadecan-1-ol (3) (4.00 g, 12.84 mmol), 4-biphenylcarboxylic acid (8) (3.82 g, 19.26 mmol, 1.5 equiv.), PISA (370 mg, 1.92 mmol, 15 mol%), toluene (140 ml) Reaction: 120 ° C, 20 h Cleaning: Silica gel chromatography column, hexane / chloroform 1: 1 Yield: 5.02 g (10.50 mmol, 82%) of a colorless, loose crystalline solid

1H-NMR (250 MHz, CDCl3): δ = 8.13 (d, 2H, 2/12-H), 7.65 (4H, 6/7/9/10-H), 7.44 (3H, 3/8 / 11- H), 4.35 (t, 2H, 14-H), 3.25 (t, 2H, 31-H), 1.80 (m, 2H, 15-H), 1.60 (m, 2H, 30-H), 1.28 (28H , 16-29-H) ppm
13 C-NMR (250 MHz, CDCl 3): δ = 166.44 (13-C), 145.44 (1-C), 140.00 (4-C), 129.99, 129.27, 128.84, 128.02, 127.19, 126.92 (2/3 / 5/6/7/8/9/10/11/12-C), 65.08 (14-C), 51.43 (31-C), 29.63-26.02 (15-30-C) ppm
HR-MS (ESI-TOF): calcd. For C31H45N3O2Na +: 514.3409, prepared: 514.3421 b) Synthesis of the hydrophilic dendritic polyglycerol unit Acetal-protected alkynyl triglycerol

Triglycerol (11.51 g, 47.91 mmol) was heated to 90-100 ° C until it became a transparent liquid consistency. After addition of 2,2-dimethoxypropane (30 mL, 26.04 g, 250.00 mmol) PISA (913 mg, 4.8 mmol, 10 mol%) was slowly added with vigorous stirring and the homogeneous orange mixture was stirred at 40 ° C for 18 hours. After neutralization of the orange-black solution with triethylamine (0.7 mL, 0.51 g, 5.00 mmol), the solvent was removed in vacuo and the orange crude oil was purified by column chromatography on silica gel (hexane / EtOH 3: 1). 11.44 g (35.71 mmol, 75%) of a golden yellow oil were obtained.
¹ H-NMR (250 MHz, CDCl3): δ = 4.19-3.46 (15H, PG-H), 1.34-1.27 (2 s, 8H, acetal-H) ppm Acetal-protected polyglycerol [G2.0] - propargyl

to Representation of the second generation polyglycerol dendron the acetal protected Polyglycerol reacted with methallyl dichloride. By adding NaH deprotonation takes place (addition of 15-crown-5 for complexation sodium ion). Addition of KI and 18-crown-6 converts the chloride into a better leaving group.

In the further steps are carried out with the ozonolysis of the double bond followed by Reductive workup with sodium borohydride (for more details see also example 1).

Subsequently, the alkyne functionality was introduced by reaction with propargyl bromide. To this was added sodium hydride (3 equiv.) To the hydroxy compound in THF and the suspension was stirred at 40 ° C for 2 h. At 0 ° C, propargyl bromide (2.5 equiv.) Was added to the reaction and allowed to thaw slowly to RT over 18 h. Coupling by the "click" reaction

alkyne and azide (1.1 equiv.) are dissolved in a little THF and diisopropylethylamine (DIPEA, 10-20 mol%) added. After a few minutes, the addition of aqueous solutions of sodium ascorbate takes place (20-40 mol%) and copper (II) sulfate pentahydrate (10-20 mol%). After setting a THF / water solvent ratio from 1: 1, the reaction is at RT for 12 hours to seven days touched. For workup, the batch is diluted with water, the phases separated and the aqueous phase washed three times with DCM. The combined organic phases are over sodium sulfate dried, the solvent removed in vacuo and the crude product by column chromatography on silica gel cleaned. The "click" reaction takes place here, unlike the synthesis of linear dendritic Amphiphiles with central aromatics (see Example 1) with copper (II) sulfate pentahydrate, Sodium ascorbate and DIPEA as base. Lower reaction times and higher Can yield be observed here.

Bi-C18 [G2]

¹H-NMR (400 MHz, CDCl3): δ = 8.07 (d, 2H, 2/12-H), 7.63-7.55 (5H, 6/7/9/10/18-H), 7.42 (t, 2H, 3/11-H), 7.35 (1H, 8-H), 4.77 (2H, 20-H), 4.30 (4H, 14/17-H), 4.20-3.45 (35H, PG-H), 1.85 (2H, 15-H), 1.75 (2H, 16-H), 1.37-1.22 (44H, Alkyl-, Acetal-H) ppm
13C-NMR (400 MHz, CDCl3): δ = 166.36 (13-C), 145.34 (19-C), 139.88 (1-C), 129.90, 129.14, 128.76, 127.95, 127.10, 126.84, 122.20 (2/3/4/5/6/7/8/9/10/11/12/18-C),) 109.18 (Acetal-C), 78.31, 74.51, 74.48, 72.36, 66.61, 64.99, 63.87 (14/PG-C), 50.13 (17-C), 30.22-25.28 (Alkyl-, Acetal-H) ppm
HR-MS (ESI-TOF): ber. für C67H107N3O17Na+: 1248.7498 , gef.: 1248.7456Approach: [G2] -Propargyl 14 (1.54 g, 2.10 mmol), Bi-C18-N3 59 (1.14 g, 2.31 mmol, 1.1 equiv.), DIPEA (54.9 μL, 0.32 mmol, 15 mol%), sodium ascorbate (0.63 mmol, 30 mol%), copper sulfate pentahydrate (0.32 mmol, 15 mol%), THF / water (1: 1, 8.1 ml)
Reaction: 4 d
Purification: silica gel flash column, hexane / THF 3: 1, 1.5: 1
Yield: 2.27 g (1.85 mmol, 88%) of viscous oil

¹ H-NMR (400 MHz, CDCl3): δ = 8.07 (d, 2H, 2/12-H), 7.63-7.55 (5H, 6/7/9/10/18-H), 7.42 (t, 2H , 3/11-H), 7.35 (1H, 8-H), 4.77 (2H, 20-H), 4.30 (4H, 14/17-H), 4.20-3.45 (35H, PG-H), 1.85 ( 2H, 15-H), 1.75 (2H, 16-H), 1.37-1.22 (44H, alkyl, acetal-H) ppm
13 C-NMR (400 MHz, CDCl 3): δ = 166.36 (13-C), 145.34 (19-C), 139.88 (1-C), 129.90, 129.14, 128.76, 127.95, 127.10, 126.84, 122.20 (2/3 / 4/5/6/7/8/9/10/11/12/18-C),) 109.18 (acetal-C), 78.31, 74.51, 74.48, 72.36, 66.61, 64.99, 63.87 (14 / PG- C), 50.13 (17-C), 30.22-25.28 (alkyl, acetal-H) ppm
HR-MS (ESI-TOF): calcd for C67H107N3O17Na +: 1248.7498, found: 1248.7456

Remove the acetal protecting group

to Cleavage of the acetal protecting groups of the polyglycerol endones is the protected Product dissolved in methanol and after addition of 100% by weight of Lewatit K 1131, it is stirred at RT for 24 hours. Subsequently, will the ion exchanger was separated and washed with methanol.

Bi-C18 [G2] -OH (51)

¹H-NMR (400 MHz, MeOD): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/11-H), 7.65 (2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17-H), 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10, 130.10, 128.22, 125.13 (2/3/4/5/6/7/8/9/10/11/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49, (14/PG-C), 51.38 (17-C), 31.38-27.17 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C55H91N3O17Na+: 1088.6246, gef.: 1088.6192 Spektroskopische Daten aller Amphiphile mit endständigem Aromaten Bz-C11-[G1]-OH (46)

¹H-NMR (400 MHz, MeOD): δ = 7.99 (3H, 2/6/12-H), 7.59 (1H, 4-H), 7.47 (m, 2H, 3/5-H), 4.78 (2H, 14-H), 4.38 (t, 2H, 8-H), 4.30 (t, 2H, 11-H), 3.75-3.49 (15H, PG-H), 1.88 (2H, 8-H), 1.76 (2H, 9-H), 1.45-1.29 (14H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 168.09 (7-C), 134.21 (13-C), 131.63, 130.45, 129.61, 125.14 (1/2/3/4/5/6/12-C), 78.76, 73.98, 72.42, 66.24, 64.44 (8-C/PG-C), 51.37 (11-C), 31.32-27.13 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C30H49N3O9Na+: 618.3366, gef.: 618.3358 Bz-C11-[G2]-OH (47)

¹H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (m, 1H, 4-H), 7.48 (m, 2H, 3/5-H), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.49 (35H, PG-H), 1.90 (2H, 9-H), 1.77 (2H, 10-H), 1.46-1.31 (14H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 168.11 (7-C), 146.40 (13-C), 134.23, 131.62, 130.49, 129.62, 125.17 (1/2/3/4/5/6/12-C), 79.88, 74.00, 72.45, 66.25, 64.49, 63.02 (8-C, PG-C), 51.39 (11-C), 33.67-26.96 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C42H73N3O17Na+: 914.4838, gef.: 914.4853 Na-C11-[G2]-OH (48)

¹H-NMR (400 MHz, MeOD): δ = 8.58 (1H, 10-H), 8.02-7.98 (3H, 2/8/16-H), 7.93 (d, 2H, 3/5-H), 7.63-7.56 (2H, 6/7-H), 4.78 (2H, 18-H), 4.36 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.87-1.78 (4H, 13/14-H), 1.47-1.28 (14H, Alkylkette) ppm
13C-NMR (400 MHz, MeOD): δ = 168.18 (11-C), 137.00, 133.93, 131.89, 130.39, 129.54, 128.88, 127.97, 126.04 (1/2/3/4/5/6/7/8/9/10/16/17-C), 79.87, 74.00, 72.45, 66.40, 65.11, 64.49 (12/PG-C), 51.36 (15-C), 30.56-26.95 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C46H75N3O17Na+: 964.4994, gef.: 964.5013 Bi-C11-[G2]-OH (49)

¹H-NMR (400 MHz, MeOD): δ = 8.07 (d, 2H, 2/12-H), 7.99 (1H, 18-H), 7.73 (d, 2H, 3/11-H), 7.67 (2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.78 (2H, 20-H), 4.37-4.32 (4H, 14/17-H), 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.29 (14H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 167.96 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10, 130.35, 130.11, 128.24, 127.98, 128.10 (2/3/4/5/6/7/8/9/10/11/12/18-C),), 79.88, 74.01, 72.47, 72.21, 66.27, 64.49, (14/PG-C), 51.37 (17-C), 30.60-26.96 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C48H77N3O17Na+: 990.5151, gef.: 990.5111 Bz-C18-[G2]-OH (45)

¹H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.47 (m, 2H, 3/5-H), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.50 (35H, PG-H), 1.90 (2H, 9-H), 1.77 (2H, 10-H), 1.46-1.27 (28H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 168.02 (7-C), 146.37 (13-C), 134.20, 131.60, 130.45, 129.60, 125.16 (1/2/3/4/5/6/12-C), 79.90, 73.97, 72.44, 66.22, 64.46 (8-C, PG-C), 51.37 (11-C), 30.81-27.16 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C49H87N3O17Na+: 1012.5933, gef.: 1012.5951 Na-C18-[G2]-OH (50)

¹H-NMR (400 MHz, MeOD): δ = 8.57 (1H, 10-H), 8.02-7.96 (3H, 2/8/16-H), 7.91 (d, 2H, 3/5-H), 7.62-7.53 (2H, 6/7-H), 4.78 (2H, 18-H), 4.37-4.35 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.86-1.79 (4H, 13/14-H), 1.47-1.22 (28H, Alkylkette) ppm
13C-NMR (400 MHz, MeOD): δ = 168.12 (11-C), 136.97, 133.89, 131.87, 130.35, 129.49, 128.84, 127.91, 126.02 (1/2/3/4/5/6/7/8/9/10/16/17-C), 79.84, 73.96, 72.27, 66.37, 64.45 (12/PG-C), 51.35 (15-C), 30.76-27.15 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C53H89N3O17Na+: 1062.6090, gef.: 1062.6030 Bi-C18-[G2]-OH (51)

¹H-NMR (400 MHz, MeOD): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/11-H), 7.65 (2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17-H), 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10, 130.10, 128.22, 125.13 (2/3/4/5/6/7/8/9/10/11/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49, (14/PG-C), 51.38 (17-C), 31.38-27.17 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C55H91N3O17Na+: 1088.6246, gef.: 1088.6192 Bz-C18-[G3]-OH (52)

¹H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.48 (m, 2H, 3/5-H), 4.81 (2H, 14-H), 4.40 (t, 2H, 8-H), 4.31 (t, 2H, 11-H), 3.76-3.50 (75H, PG-H), 1.91 (2H, 9-H), 1.78 (2H, 10-H), 1.46-1.28 (28H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 168.12 (7-C), 146.58 (13-C), 134.22, 131.65, 130.46, 129.62 (1/2/3/4/5/6/12-C), 79.89, 74.03, 72.23, 66.26, 64.54 (8-C, PG-C), 51.42 (11-C), 30.81-27.15 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C73H135N3O33Na+: 1604.8876, gef.: 1604.8855 Na-C18-[G3]-OH (53)

¹H-NMR (400 MHz, MeOD): δ = 8.59 (1H,10-H), 8.03-8.01 (3H, 2/8/16-H), 7.94 (d, 2H, 3/5-H), 7.64-7.55 (2H, 6/7-H), 4.81 (2H, 18-H), 4.39-4.37 (4H, 12/15-H), 3.77-3.49 (75H, PG-H), 1.88-1.82 (4H, 13/14-H), 1.49-1.25 (28H, Alkylkette) ppm
13C-NMR (400 MHz, MeOD): δ = 168.21 (11-C), 146.56, 137.03, 133.96, 131.90, 130.40, 129.55, 128.88, 127.97, 126.05 (1/2/3/4/5/6/7/8/9/10/16/17-C), 79.87, 74.03, 72.45, 66.42, 64.55 (12/PG-C), 51.41 (15-C), 31.43-24.76 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C77H137N3O33Na+: 1654.9032, gef.: 1654.9035 Bi-C18-[G3]-OH (54)

¹H-NMR (400 MHz, MeOD): δ = 8.08 (d, 2H, 2/12-H), 8.01 (s, 1H, 18-H), 7.73 (d, 2H, 3/11-H), 7.67 (2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.80 (2H, 20-H), 4.39 (t, 2H, 14-H), 4.32 (t, 2H, 17-H), 3.77-3.49 (75H, PG-H), 1.89 (2H, 15-H), 1.78 (2H, 16-H), 1.47-1.26 (28H, Alkyl-H) ppm
13C-NMR (400 MHz, MeOD): δ = 167.95 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10, 130.11, 128.23 (2/3/4/5/6/7/8/9/10/11/12/18-C), 79.86, 74.02, 72.43, 66.27, 64.53, (14/PG-C), 51.41 (17-C), 31.43-27.15 (Alkyl-C) ppm
HR-MS (ESI-TOF): ber. für C79H139N3O33Na+: 1680.9189, gef.: 1680.9251Yield: 1.79 g (1.68 mmol, 91%) wax

¹ H-NMR (400 MHz, MeOH): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/11-H), 7.65 ( 2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17-H). , 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10, 130.10, 128.22, 125.13 (2/3/4/5/6 / 7/8/9/10/11/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49, (14 / PG-C), 51.38 (17-C), 31.38-27.17 (alkyl-C ) ppm
HR-MS (ESI-TOF): calcd. For C55H91N3O17Na +: 1088.6246, made: 1088.6192 Spectroscopic data of all aromatic-terminated amphiphiles Bz-C11- [G1] -OH (46)

¹ H-NMR (400 MHz, MeOD): δ = 7.99 (3H, 2/6/12-H), 7.59 (1H, 4-H), 7.47 (m, 2H, 3/5-H), 4.78 ( 2H, 14-H), 4.38 (t, 2H, 8-H), 4.30 (t, 2H, 11-H), 3.75-3.49 (15H, PG-H), 1.88 (2H, 8-H), 1.76 (2H, 9-H), 1.45-1.29 (14H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.09 (7-C), 134.21 (13-C), 131.63, 130.45, 129.61, 125.14 (1/2/3/4/5/6/12-C) , 78.76, 73.98, 72.42, 66.24, 64.44 (8-C / PG-C), 51.37 (11-C), 31.32-27.13 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C30H49N3O9Na +: 618.3366, found: 618.3358 Bz-C11- [G2] -OH (47)

¹ H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (m, 1H, 4-H), 7.48 (m, 2H, 3/5-H ), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.49 (35H, PG-H), 1.90 (2H, 9-H) , 1.77 (2H, 10-H), 1.46-1.31 (14H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.11 (7-C), 146.40 (13-C), 134.23, 131.62, 130.49, 129.62, 125.17 (1/2/3/4/5/6 / 12- C), 79.88, 74.00, 72.45, 66.25, 64.49, 63.02 (8-C, PG-C), 51.39 (11-C), 33.67-26.96 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C42H73N3O17Na +: 914.4838, Found: 914.4853 Na-C11- [G2] -OH (48)

¹ H-NMR (400 MHz, MeOD): δ = 8.58 (1H, 10-H), 8.02-7.98 (3H, 2/8/16-H), 7.93 (d, 2H, 3/5-H), 7.63-7.56 (2H, 6/7-H), 4.78 (2H, 18-H), 4.36 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.87-1.78 (4H, 13/14-H), 1.47-1.28 (14H, alkyl chain) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.18 (11-C), 137.00, 133.93, 131.89, 130.39, 129.54, 128.88, 127.97, 126.04 (1/2/3/4/5/6/7/8 / 9/10/16/17-C), 79.87, 74.00, 72.45, 66.40, 65.11, 64.49 (12 / PG-C), 51.36 (15-C), 30.56-26.95 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C46H75N3O17Na +: 964.4994, found: 964.5013 Bi-C11- [G2] -OH (49)

¹ H-NMR (400 MHz, MeOH): δ = 8.07 (d, 2H, 2/12-H), 7.99 (1H, 18-H), 7.73 (d, 2H, 3/11-H), 7.67 ( 2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.78 (2H, 20-H), 4.37-4.32 (4H, 14/17-H) , 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.29 (14H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 167.96 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10, 130.35, 130.11, 128.24, 127.98, 128.10 (2/3/4 / 5/6/7/8/9/10/11/12/18-C),), 79.88, 74.01, 72.47, 72.21, 66.27, 64.49, (14 / PG-C), 51.37 (17-C) , 30.60-26.96 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd for C48H77N3O17Na +: 990.5151, found: 990.5111 Bz-C18- [G2] -OH (45)

¹ H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.47 (m, 2H, 3/5-H), 4.79 (2H, 14-H), 4.39 (2H, 8-H), 4.31 (t, 2H, 11-H), 3.77-3.50 (35H, PG-H), 1.90 (2H, 9-H), 1.77 (2H, 10-H), 1.46-1.27 (28H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.02 (7-C), 146.37 (13-C), 134.20, 131.60, 130.45, 129.60, 125.16 (1/2/3/4/5/6 / 12- C), 79.90, 73.97, 72.44, 66.22, 64.46 (8-C, PG-C), 51.37 (11-C), 30.81-27.16 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd for C49H87N3O17Na +: 1012.5933, found: 1012.5951 Na-C18 [G2] -OH (50)

¹ H-NMR (400 MHz, MeOD): δ = 8.57 (1H, 10-H), 8.02-7.96 (3H, 2/8/16-H), 7.91 (d, 2H, 3/5-H), 7.62-7.53 (2H, 6/7-H), 4.78 (2H, 18-H), 4.37-4.35 (4H, 12/15-H), 3.76-3.49 (35H, PG-H), 1.86-1.79 ( 4H, 13/14-H), 1.47-1.22 (28H, alkyl chain) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.12 (11-C), 136.97, 133.89, 131.87, 130.35, 129.49, 128.84, 127.91, 126.02 (1/2/3/4/5/6/7/8 / 9/10/16/17-C), 79.84, 73.96, 72.27, 66.37, 64.45 (12 / PG-C), 51.35 (15-C), 30.76-27.15 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C53H89N3O17Na +: 1062.6090, found: 1062.6030 Bi-C18 [G2] -OH (51)

¹ H-NMR (400 MHz, MeOH): δ = 8.06 (d, 2H, 2/12-H), 8.00 (1H, 18-H), 7.71 (d, 2H, 3/11-H), 7.65 ( 2H, 6/10-H), 7.45 (2H, 7/9-H), 7.38 (1H, 8-H), 4.79 (2H, 20-H), 4.37-4.31 (4H, 14/17-H). , 3.76-3.49 (35H, PG-H), 1.87-1.77 (4H, 15/16-H), 1.46-1.24 (28H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 167.90 (13-C), 147.00 (1-C), 141.05 (19-C), 131.10, 130.10, 128.22, 125.13 (2/3/4/5/6 / 7/8/9/10/11/12/18-C), 79.91, 74.00, 72.21, 66.26, 64.49, (14 / PG-C), 51.38 (17-C), 31.38-27.17 (alkyl-C ) ppm
HR-MS (ESI-TOF): calcd for C55H91N3O17Na +: 1088.6246, found: 1088.6192 Bz-C18 [G3] -OH (52)

¹ H-NMR (400 MHz, MeOD): δ = 8.02-8.00 (3H, 2/6/12-H), 7.60 (1H, 4-H), 7.48 (m, 2H, 3/5-H), 4.81 (2H, 14-H), 4.40 (t, 2H, 8-H), 4.31 (t, 2H, 11-H), 3.76-3.50 (75H, PG-H), 1.91 (2H, 9-H) , 1.78 (2H, 10-H), 1.46-1.28 (28H, alkyl-H) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.12 (7-C), 146.58 (13-C), 134.22, 131.65, 130.46, 129.62 (1/2/3/4/5/6/12-C) , 79.89, 74.03, 72.23, 66.26, 64.54 (8-C, PG-C), 51.42 (11-C), 30.81-27.15 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C73H135N3O33Na +: 1604.8876, Found: 1604.8855 Na-C18 [G3] -OH (53)

¹ H-NMR (400 MHz, MeOD): δ = 8.59 (1H, 10-H), 8.03-8.01 (3H, 2/8/16-H), 7.94 (d, 2H, 3/5-H), 7.64-7.55 (2H, 6/7-H), 4.81 (2H, 18-H), 4.39-4.37 (4H, 12/15-H), 3.77-3.49 (75H, PG-H), 1.88-1.82 ( 4H, 13/14-H), 1.49-1.25 (28H, alkyl chain) ppm
13 C-NMR (400 MHz, MeOD): δ = 168.21 (11-C), 146.56, 137.03, 133.96, 131.90, 130.40, 129.55, 128.88, 127.97, 126.05 (1/2/3/4/5/6/7 / 8/9/10/16/17-C), 79.87, 74.03, 72.45, 66.42, 64.55 (12 / PG-C), 51.41 (15-C), 31.43-24.76 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd. For C77H137N3O33Na +: 1654.9032, prepared: 1654.9035 Bi-C18 [G3] -OH (54)

¹ H-NMR (400 MHz, MeOD): δ = 8.08 (d, 2H, 2/12-H), 8.01 (s, 1H, 18-H), 7.73 (d, 2H, 3/11-H), 7.67 (2H, 6/10-H), 7.48 (2H, 7/9-H), 7.39 (1H, 8-H), 4.80 (2H, 20-H), 4.39 (t, 2H, 14-H) , 4.32 (t, 2H, 17-H), 3.77-3.49 (75H, PG-H), 1.89 (2H, 15-H), 1.78 (2H, 16-H), 1.47-1.26 (28H, alkyl-H ) ppm
13 C-NMR (400 MHz, MeOD): δ = 167.95 (13-C), 147.04 (1-C), 141.07 (19-C), 131.10, 130.11, 128.23 (2/3/4/5/6/7 / 8/9/10/11/12/18-C), 79.86, 74.02, 72.43, 66.27, 64.53, (14 / PG-C), 51.41 (17-C), 31.43-27.15 (alkyl-C) ppm
HR-MS (ESI-TOF): calcd for C79H139N3O33Na +: 1680.9189, found: 1680.9251

Example 3

Compounds of the general formula (2) - Amphiphiles with alkyl radicals and partially fluorinated alkyl side chains and dendritic Polyglycerol head groups

1. Experimental part

1.1. General

preparative methods:

All reactions requiring dry conditions were carried out under argon atmosphere in dried glassware. The compounds (x), (x), (x) and (x) were prepared and purified within the Haag group, the solvents for the column chromatography were purified by distillation. All other chemicals and reagent grade dry solvents were commercially available Purchased and used without further purification. Column and flash chromatography were performed on silica gel 60 (230-400 mesh).

spectroscopy:

The ¹ H NMR and ¹³ C NMR spectra were recorded with BRUKER AC 250 (250 MHz), BRUKER DRX 500 (500 MHz) and JOEL ECLIPSE 400 (400 MHz), with the proton and carbon signals from residual solvent for calibration CDCl ₃ (δ = 7.26 ppm for ¹ H and δ = 77.0 ppm for ¹³ C) and CD ₃ OD (δ = 4.84 ppm for ¹ H). The ¹³ C NMR spectra were recorded with ¹ H broadband decoupling. The chemical shifts are given in parts per million (ppm) and the coupling constants in Hertz (Hz).

The Mass spectrometry was performed on an Agilent 6210 ESI-TOF instrument carried out.

1.2. General procedure

General Procedure for the Synthesis of C _n -N ₃ : The azide (x) was dissolved in DMSO and KOH powder (4 equivalents per OH) was added all at once to give a brown suspension. After stirring at room temperature for 10 min, the olefinic bromide (2 equiv. Per OH) was added via syringe and the reaction mixture was then stirred for a further 40 min. The reaction was quenched with H ₂ O and then extracted with DCM. The combined organic layers were washed with H ₂ O and dried over anhydrous Na ₂ SO ₄ . The DCM was evaporated in vacuo and the residual DMSO was removed by cryogenic distillation. The resulting liquid was purified by column chromatography on silica gel with 2% EA in hexane as eluent to give the desired product.

General procedure for the synthesis of C _n -GO-Ck-G _m : propargyl-G _m (1.0 equivalents) and the azide C _n -N ₃ (1.1 equivalents) were dissolved in very small amounts of THF to give a clear to give concentrated solution. Subsequently, catalytic amounts of DIPEA (10-30 mol%) and freshly prepared aqueous solutions of sodium ascorbate (10-30 mol%) and CuSO ₄ .5H ₂ O (5-15 mol%) were added sequentially with Eppendorf pipettes. Additional amounts of H ₂ O were added to give a total THF / H ₂ O ratio of 1: 1. Subsequently, the reaction mixture was stirred vigorously for 3 to 5 days at room temperature until the TLC analysis indicated that the propargyl G _{m was} completely consumed. H ₂ O was added for dilution and then extracted with DCM. The combined organic layers were washed with small amounts of saturated EDTA solution and dried over anhydrous Na ₂ SO ₄ . The DCM was evaporated in vacuo and the residual oil was purified by column chromatography or filtration on silica gel with a mixture of EA or isopropanol and hexane as eluent to give the desired product.

General procedure for the synthesis of RfC _{n -G0-Ck-m} G: C _{n -G0-Ck-m} G was dissolved in RfC ₂ H ₄ SH (4 equivalents per C = C) and refluxed at 90 ° C , A spatula tip AIBN was added and after stirring for 2 hours a second. The reaction mixture was stirred at 90 ° C for at least 22 more hours until TLC analysis indicated that the C _n -G0-Ck-G _{m was} completely consumed. A large part of the unused RfC ₂ H ₄ SH was (if appropriate) removed by means of cryogenic distillation. The residual oil was purified by filtration through silica gel with a mixture of PE and DCM (7: 1) and a subsequent mixture of EE or isopropanol and hexane as eluent to give the desired product.

1.3. Reaction method and analytical Specifications

2-azido-propane-1,3-diol (xx):

¹H-NMR (CD₃OD, 400 MHz, 2,5°C): δ = 3,51 (m, 4H, 2-H), 3,42-3,36 (m, 1H, 1-H) ppm.Acetal deprotection on azide (x1) to give the azide (x2): The azide (x1) (9.57 g, 47.57 mmol) was dissolved in ethanol (100 ml). After addition of 2.5 equivalents of K ₂ CO ₃ (16.44 g, 199 mmol) in one portion, the suspension was stirred for 30 min at room temperature. The formed precipitate was separated by filtration and washed with ethanol. The solvent of the combined filtrates was evaporated under vacuum and the remaining liquid was dried under high vacuum to give the azide (x2) as a pale yellow oil (5.699 g, 47.57 mmol, 99%).

¹ H-NMR (CD ₃ OD, 400 MHz, 2.5 ° C): δ = 3.51 (m, 4H, 2-H), 3.42 to 3.36 (m, 1H, 1H) ppm.

C ₆ -N ₃ (xx):

¹H-NMR (CDCl₃, 500 MHz, 26°C): δ = 5,79 (tdd, J = 16,95, 10,20, 6,66 Hz, 2H, 2-H), 5,01, 4,98 (2 dd, J = 3,62, 1,59 Hz, jeweils 1H, 1-H), 4,95, 4,93 (2 td, J = 2,16, 1,21 Hz, jeweils 1H, 1-H), 3,66 (tt, J = 6,62, 4,61 Hz, 1H, 8-H), 3,51, 3,45 (2 m, jeweils 4H, 6-H, 7-H), 2,06 (m, 4H, 3-H), 1,58 (m, 4H, 5-H), 1,45 (m, 4H, 4-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 26°C): δ = 138,58 (s, C-2), 114,48 (s, C-1), 71,36 (s, C-6), 70,34 (s, C-7), 60,56 (s, C-8), 33,41 (s, C-3), 28,96 (s, C-5), 25,23 (s, C-4) ppm. MS (ESI-TOF): berechnet für C₁₅H₂₇N₃O₂: (281,2103); gefunden: m/z = 304,2001 [M+Na]⁺. Synthesis of C ₆ -N ₃ : The reaction was carried out with the azide (x) (1.871 g, 15.98 mmol), KOH powder (7.17 g, 128 mmol), and 6-bromohex-1-ene (x). (10.0 g, 61 mmol) in 50 ml of DMSO as described above. Extraction with DCM (3 × 100 ml) and purification by column chromatography gave C ₆ -N ₃ (x) as a colorless liquid (4.05 g, 14.39 mmol, 90%).

¹ H-NMR (CDCl _3, 500 MHz, 26 ° C): δ = 5.79 (tdd, J = 16.95, 10.20, 6.66 Hz, 2H, 2H), 5.01, 4.98 (2 dd, J = 3.62, 1.59 Hz, each 1H, 1-H), 4.95, 4.93 (2 td, J = 2.16, 1.21 Hz, each 1H , 1-H), 3.66 (tt, J = 6.62, 4.61 Hz, 1H, 8-H), 3.51, 3.45 (2 m, 4H, 6-H, 7, respectively). H), 2.06 (m, 4H, 3-H), 1.58 (m, 4H, 5-H), 1.45 (m, 4H, 4-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 26 ° C): δ = 138.58 (s, C-2), 114.48 (s, C-1), 71.36 (s, C-6) , 70.34 (s, C-7), 60.56 (s, C-8), 33.41 (s, C-3), 28.96 (s, C-5), 25.23 (s , C-4) ppm. MS (ESI-TOF): calculated for C ₁₅ H ₂₇ N ₃ O _2: (281.2103); Found: m / z = 304,2001 [M + Na] ⁺ .

C ₁₁ -N ₃ (xx):

¹H-NMR (CDCl₃, 500 MHz, 26°C): δ = 5,80 (tdd, J = 16,93, 10,18, 6,68 Hz, 2H, 2-H), 5,00, 4,96 (2 dd, J = 3,72, 1,60 Hz, jeweils 1H, 1-H), 4,93, 4,91 (2 td, J = 2,28, 1,21 Hz, jeweils 1H, 1-H), 3,67 (tt, J = 6,55, 4,61 Hz, 1H, 13-H), 3,51 (ddd, J = 16,65, 10,04, 5,60 Hz, 4H, 12-H), 3,43 (m, 4H, 11-H), 2,03 (m, 4H, 3-H), 1,56 (qd, J = 13,42, 6,59 Hz, 4H, 10-H), 1,36 (m, 4H, 4-H), 1,27 (s, 20H, H-5, H-6, H-7, H-8, H-9) ppm.
¹³C-NMR (CDCl₃, 500 MHz, 2,5°C): δ = 139,13 (s, C-2), 114,05 (s, C-1), 71,64, 70,37 (2 s, C-11, C-12), 60,60 (s, C-13), 33,76 (s, C-3), 29,55, 29,48, 29,38, 29,08, 28,89 (6 s, C-4, C-5, C-6, C-7, C-8, C-9, C-10) ppm. MS (ESI-TOF): berechnet für C₂₅H₄₇N₃O₂: (421,3668); gefunden: m/z = 444,3574 [M+Na]⁺, 460,3318 [M+K]⁺. Synthesis of C ₁₁ -N ₃ : The reaction was carried out with the azide (x) (1.018 g, 9.23 mmol), KOH powder (4.14 g, 73.8 mmol), and 11-bromoundec-1-ene ( x) (8.61 g, 36.9 mmol) in 15 mL of DMSO as described above. Extraction with DCM (3 x 70 ml) and purification by column chromatography gave C ₁₁ -N ₃ (x) as a colorless liquid (3.41 g, 8.09 mmol, 88%).

¹ H-NMR (CDCl _3, 500 MHz, 26 ° C): δ = 5.80 (tdd, J = 16.93, 10.18, 6.68 Hz, 2H, 2H), 5.00, 4.96 (2 dd, J = 3.72, 1.60 Hz, each 1H, 1-H), 4.93, 4.91 (2 td, J = 2.28, 1.21 Hz, each 1H , 1-H), 3.67 (t, J = 6.55, 4.61 Hz, 1H, 13-H), 3.51 (ddd, J = 16.65, 10.04, 5.60 Hz , 4H, 12-H), 3.43 (m, 4H, 11-H), 2.03 (m, 4H, 3-H), 1.56 (qd, J = 13.42, 6.59 Hz , 4H, 10-H), 1.36 (m, 4H, 4-H), 1.27 (s, 20H, H-5, H-6, H-7, H-8, H-9) ppm ,
¹³ C NMR (CDCl _3, 500 MHz, 2.5 ° C): δ = 139.13 (s, C-2), 114.05 (s, C-1), 71.64, 70.37 ( 2s, C-11, C-12), 60.60 (s, C-13), 33.76 (s, C-3), 29.55, 29.48, 29.38, 29.08, 28.89 (6s, C-4, C-5, C-6, C-7, C-8, C-9, C-10) ppm. MS (ESI-TOF): calculated for C ₂₅ H ₄₇ N ₃ O ₂ : (421.3668); Found: m / z = 444.3574 [M + Na] ⁺ , 460.3318 [M + K] ⁺ .

Example 3.1

C ₆ -G0-Ck-G1.0 (xx):

Synthesis of C ₆ -Go-Ck-G1.0: The reaction was carried out with propargyl G1.0 (x) (1.392 g, 3.833 mmol), C ₆ -N ₃ (x) (1.202 g, 4.272 mmol), DIPEA (100 mg, 0.777 mmol), sodium ascorbate (154 mg, 0.777 mmol) and CuSO ₄ .5H ₂ O (97 mg, 0.388 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by column chromatography on silica gel with a mixture of EA and hexane (1: 1, then 2: 1) gave C ₆ -G 0 -Ck-G1.0 (x) as a pale yellow oil ( 1.941 g, 3.029 mmol, 78%).

¹H-NMR (CDCl₃, 500 MHz, 26°C): δ = 7,69 (s, 1H, 9-H), 5,74 (tdd, J = 16,95, 6,66, 10,18 Hz, 2H, 2-H), 4,98, 4,94 (2 dd, J = 3,40, 1,74 Hz, jeweils 1H, 1-H), 4,93, 4,92 (2 m, jeweils 1H, 1-H), 4,83 (tt, J = 9,84, 4,84 Hz, 1H, 8-H), 4,76 (t, J = 1,74 Hz, 2H, 11-H), 4,21 (m, 2H, 15-H), 4,00 (ddd, J = 10,55, 6,35, 4,16 Hz, 2H, 16-H), 3,79 (d, J = 3,79 Hz, 4H, 7-H), 3,69, 3,57, 3,52, 3,46, 3,40 (5 br m, 15H, 6-H, 12-H, 13-H, 14-H, 16-H), 2,00 (dd, J = 7,22, 14,29 Hz, 4H, 3-H), 1,37 (m, 4H, 4-H), 1,38, 1,32 (2 s, 12H, 18-H, 19-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 28°C): δ = 144,75 (s, C-10), 138,45 (s, C-2), 122,70 (s, C-9), 114,55 (s, C-1), 109,24 (s, C-17), 78,55 (s, C-12), 74,54 (s, C-15), 72,40 (s, C-14), 71,47, 71,28 (m, C-6, C-13), 69,30 (s, C-7), 66,66 (s, C-16), 63,83 (t, J = 3,85 Hz, C-11), 60,51 (s, C-8), 32,29 (s, C-3), 28,77 (s, C-5), 26,68, 25,32 (2 s, C-18, C-19), 25,12 (s, C-4) ppm. MS (ESI-TOF): berechnet für C₃₃H₅₇N₃O₉: (639,4095); gefunden: m/z = 640,4175 [M+H]⁺, 662,3999 [M+Na]⁺, 678,3738 [M+K]⁺. The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 26 ° C): δ = 7.69 (s, 1H, 9-H), 5.74 (tdd, J = 16.95, 6.66, 10.18 Hz, 2H, 2-H), 4.98, 4.94 (2 dd, J = 3.40, 1.74 Hz, each 1H, 1-H), 4.93, 4.92 (2 m, each 1H, 1-H), 4.83 (t, J = 9.84, 4.84Hz, 1H, 8-H), 4.76 (t, J = 1.74Hz, 2H, 11-H ), 4.21 (m, 2H, 15-H), 4.00 (ddd, J = 10.55, 6.35, 4.16 Hz, 2H, 16-H), 3.79 (d, J = 3.79 Hz, 4H, 7-H), 3.69, 3.57, 3.52, 3.46, 3.40 (5 br, 15H, 6H, 12H, 13H , 14-H, 16-H), 2.00 (dd, J = 7.22, 14.29 Hz, 4H, 3-H), 1.37 (m, 4H, 4-H), 1.38 , 1.32 (2 s, 12H, 18-H, 19-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 28 ° C): δ = 144.75 (s, C-10), 138.45 (s, C-2), 122.70 (s, C-9) , 114.55 (s, C-1), 109.24 (s, C-17), 78.55 (s, C-12), 74.54 (s, C-15), 72.40 (s , C-14), 71.47, 71.28 (m, C-6, C-13), 69.30 (s, C-7), 66.66 (s, C-16), 63.83 (t, J = 3.85Hz, C-11), 60.51 (s, C-8), 32.29 (s, C-3), 28.77 (s, C-5), 26, 68, 25.32 (2 s, C-18, C-19), 25.12 (s, C-4) ppm. MS (ESI-TOF): calculated for C ₃₃ H ₅₇ N ₃ O ₉ : (639.4095); Found: m / z = 640.4175 [M + H] ⁺ , 662.3999 [M + Na] ⁺ , 678.3738 [M + K] ⁺ .

Example 3.2

C ₆ -G0-Ck-G2.0 (xx):

¹H-NMR (CDCl₃, 500 MHz, 26°C): δ = 7,68 (s, 1H, 9-H), 5,75 (tdd, J = 16,92, 10,19, 6,66 Hz, 2H, 2-H), 4,98, 4,95 (2 dd, J = 3,45, 1,64 Hz, jeweils 1H, 1-H), 4,93, 4,91 (2 td, J = 2,04, 1,09 Hz, jeweils 1H, 1-H), 4,82 (dp, J = 5,70, 1,60 Hz, 1H, 8-H), 4,75 (s, 2H, 11-H), 4,21 (m, 4H, 17-H), 4,00 (m, 4H, 18-H), 3,79 (d, J = 5,69 Hz, 4H, 7-H), 3,68, 3,64, 3,53, 3,46 (4 br m, 27H, 12-H, 13-H, 14-H, 15-H, 16-H, 18-H), 3,41 (m, 4H, 6-H), 2,01 (dd, J = 14,29, 7,20 Hz, 4H, 3-H), 1,52 (m, 4H, 5-H), 1,35 (m, 4H, 4-H), 1,37, 1,32 (2 s, jeweils 12H, 20-H, 21-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 25°C): δ = 144,86 (s, C-10), 138,44 (s, C-2), 122,70 (s, C-9), 114,58 (s, C-1), 109,24 (s, C-19), 78,40, 78,34 (2 s, C-12, C-14,), 74,52 (s, C-17), 72,40 (s, C-15, C-16), 71,40, 71,27 (m, C-6, C-13), 69,30 (s, C-7), 66,67 (s, C-18), 63,83 (d, J = 4,41 Hz, C-11), 60,46 (s, C-8), 33,31 (s, C-3), 28,76 (s, C-5), 26,70, 25,34 (2 s, C-20, C-21), 25,18 (C-4) ppm. MS (ESI-TOF): berechnet für C₅₁H₈₉N₃O₁₇: (1015,6192); gefunden: m/z = 1016,6282 [M+H]⁺, 1038,6099 [M+Na]⁺, 1054,5840 [M+K]⁺. Synthesis of C ₆ -Go-Ck-G2.0: The reaction was carried out with propargyl G2.0 (x) (2.391 g, 3.256 mmol), C ₆ -N ₃ (x) (1.008 g, 3.581 mmol), DIPEA (126 mg, 0.977 mmol), sodium ascorbate (194 mg, 0.977 mmol) and CuSO ₄ .5H ₂ O (122 mg, 0.488 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by column chromatography on silica gel with a mixture of EA and hexane (1: 1, then 6: 1) gave C ₆ -G 0 -Ck-G 2 O (x) as a pale yellow oil ( 2.538 g, 2.497 mmol, 76%).

¹ H-NMR (CDCl _3, 500 MHz, 26 ° C): δ = 7.68 (s, 1H, 9-H), 5.75 (tdd, J = 16.92, 10.19, 6.66 Hz, 2H, 2-H), 4.98, 4.95 (2 dd, J = 3.45, 1.64 Hz, each 1H, 1-H), 4.93, 4.91 (2 td, J = 2.04, 1.09 Hz, each 1H, 1-H), 4.82 (dp, J = 5.70, 1.60 Hz, 1H, 8-H), 4.75 (s, 2H , 11-H), 4.21 (m, 4H, 17-H), 4.00 (m, 4H, 18-H), 3.79 (d, J = 5.69 Hz, 4H, 7-H ), 3.68, 3.64, 3.53, 3.46 (4 br, 27H, 12H, 13H, 14H, 15H, 16H, 18H), 3 , 41 (m, 4H, 6-H), 2.01 (dd, J = 14.29, 7.20 Hz, 4H, 3-H), 1.52 (m, 4H, 5-H), 1 , 35 (m, 4H, 4-H), 1.37, 1.32 (2 s, each 12H, 20-H, 21-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 25 ° C): δ = 144.86 (s, C-10), 138.44 (s, C-2), 122.70 (s, C-9) , 114.58 (s, C-1), 109.24 (s, C-19), 78.40, 78.34 (2 s, C-12, C-14,), 74.52 (s, C-17), 72.40 (s, C-15, C-16), 71.40, 71.27 (m, C-6, C-13), 69.30 (s, C-7), 66.67 (s, C-18), 63.83 (d, J = 4.41 Hz, C-11), 60.46 (s, C-8), 33.31 (s, C-3) , 28.76 (s, C-5), 26.70, 25.34 (2 s, C-20, C-21), 25.18 (C-4) ppm. MS (ESI-TOF): calculated for C ₅₁ H ₈₉ N ₃ O ₁₇ : (1015.6192); Found: m / z = 1016.6282 [M + H] ⁺ , 1038.6099 [M + Na] ⁺ , 1054.5840 [M + K] ⁺ .

Example 3.3

C ₆ -G0-Ck-G3.0 (xx):

Synthesis of C ₆ -G 0 Ck G3.0: The reaction was carried out with propargyl G3.0 (x) (1.536 g, 1.032 mmol), C ₆ -N ₃ (x) (0.320 g, 1.137 mmol), DIPEA (40 mg, 0.310 mmol), sodium ascorbate (61 mg, 0.310 mmol) and CuSO ₄ .5H ₂ O (39 mg, 0.155 mmol) in 3 mL THF as described above. Extraction with DCM (3 x 75 mL) and purification by filtration over silica gel with 5% EA in hexane, then 35% isopropanol in hexane gave C ₆ -G 0 C k -G 3 O (x) as a pale brown oil (1.050 g, 0.594 mmol, 58%).

¹H-NMR (CDCl₃, 500 MHz, 27°C): δ = 7,68 (s, 1H, 9-H), 5,75 (tdd, J = 16,93, 10,23, 6,65, Hz, 2H, 2-H), 4,99 (dd, J = 3,31, 1,66 Hz, 1H, 1-H), 4,95 (dd, J = 3,39, 1,74 Hz, 1H, 1-H), 4,94, 4,91 (2 m, jeweils 1H, 1-H), 4,82 (qd, J = 11,28, 5,53 Hz, 1H, 8-H), 4,76 (s, 2H, 11-H), 4,21 (m, 8H, 19-H), 4,01 (dd, J = 12,82, 6,21 Hz, 8H, 20-H), 3,80 (m, 4H, 7-H), 3,69 (m, 8H, 20-H), 3,62, 3,57, 3,53, 3,47 (4 br m, 51H, 12-H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H), 3,39 (m, 4H, 6-H), 2,02 (dd, J = 14,39, 7,11 Hz, 4H, 3-H), 1,53 (td, J = 14,64, 6,63 Hz, 4H, 5-H), 1,38 (s, 24H, 23-H), 1,36 (m, 4H, 4-H), 1,32 (s, 24H, 23-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 25°C): δ = 144,93 (s, C-10), 138,43 (s, C-2), 122,71 (s, C-9), 114,59 (s, C-1), 109,23 (s, C-21), 78,55, 78,30, 78,28 (3 s, C-12, C-14, C-16), 74,53 (s, C-19), 72,41 (s, C-15, C-17, C-18), 71,36, 71,28 (m, C-6, C-13), 69,33 (s, C-7), 66,71 (s, C-20), 63,93 (s, C-11), 60,43 (s, C-8), 33,33 (s, C-3), 28,79 (s, C-5), 26,73, 25,36 (2 s, C-22, C-23), 25,20 (C-4) ppm. MS (ESI-TOF): berechnet für C₈₇H₁₅₃N₃O₃₃: (1768,0386); gefunden: m/z = 907,0101 [M+2Na]^{2 +}, 1791,0324 [M + Na]⁺. The resulting from the click coupling regioisomers ratio is 87:13 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 27 ° C): δ = 7.68 (s, 1H, 9-H), 5.75 (tdd, J = 16.93, 10.23, 6.65 , Hz, 2H, 2-H), 4.99 (dd, J = 3.31, 1.66 Hz, 1H, 1-H), 4.95 (dd, J = 3.39, 1.74 Hz , 1H, 1-H), 4.94, 4.91 (2 m, each 1H, 1-H), 4.82 (qd, J = 11.28, 5.53 Hz, 1H, 8-H) , 4.76 (s, 2H, 11-H), 4.21 (m, 8H, 19-H), 4.01 (dd, J = 12.82, 6.21 Hz, 8H, 20-H). , 3.80 (m, 4H, 7-H), 3.69 (m, 8H, 20-H), 3.62, 3.57, 3.53, 3.47 (4 br m, 51H, 12 -H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H), 3.39 (m, 4H, 6-H), 2.02 (dd, J = 14 , 39, 7.11 Hz, 4H, 3-H), 1.53 (td, J = 14.64, 6.63 Hz, 4H, 5-H), 1.38 (s, 24H, 23-H ), 1.36 (m, 4H, 4-H), 1.32 (s, 24H, 23-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 25 ° C): δ = 144.93 (s, C-10), 138.43 (s, C-2), 122.71 (s, C-9) , 114.59 (s, C-1), 109.23 (s, C-21), 78.55, 78.30, 78.28 (3 s, C-12, C-14, C-16) , 74.53 (s, C-19), 72.41 (s, C-15, C-17, C-18), 71, 36, 71, 28 (m, C-6, C-13), 69.33 (s, C-7), 66.71 (s, C-20), 63.93 (s, C-11), 60.43 (s, C-8), 33.33 (s, C-3), 28.79 (s, C-5), 26.73, 25.36 (2 s, C-22, C-23), 25.20 (C-4) ppm. MS (ESI-TOF): Calcd. for C ₈₇ H ₁₅₃ N ₃ O ₃₃ : (1768.0386); Found: m / z = 907.0101 [M + 2Na] ^{2 +} , 1791.0324 [M + Na] ⁺ .

Example 3.4

C ₁₁ -G0-Ck-G1.0 (xx):

Synthesis of C ₁₁ -G 0 Ck G1.0: The reaction was treated with propargyl G1.0 (x) (0.762 g, 2.126 mmol), C ₁₁ N ₃ (x) (0.990 g, 2.338 mmol), DIPEA (55 mg, 0.425 mmol), sodium ascorbate (84 mg, 0.425 mmol) and CuSO ₄ .5H ₂ O (53 mg, 0.213 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by column chromatography on silica gel with a mixture of EA and hexane (5:95, then 1: 1) gave C ₁₁ -G 0 -Ck-G1.0 (x) as a colorless oil ( 1.335 g, 1.711 mmol, 80%).

¹H-NMR (CDCl₃, 500 MHz, 25°C): δ = 7,70 (s, 1H, 14-H), 5,77 (tdd, J = 16,92, 10,17, 6,67 Hz, 2H, 2-H), 4,97, 4,94 (2 dd, J = 3,64, 1,62 Hz, jeweils 1H, 1-H), 4,90, 4,88 (2 td, J = 2,24, 1,19 Hz, jeweils 1H, 1-H), 4,84 (tq, J = 9,78, 4,82 Hz, 1H, 13-H), 4,76 (t, J = 1,70 Hz, 2H, 16-H), 4,21 (m, 2H, 20-H), 4,00 (m, 2H, 21-H), 3,78 (d, J = 5,67 Hz, 4H, 12-H), 3,69 (m, 2H, 21-H), 3,60 (m, 1H, 17-H), 3,57, 3,46 (2 br m, 8H, 18-H, 19-H), 3,37 (m, 4H, 11-H), 2,00 (m, 4H, 3-H), 1,49 (m, 4H, 10-H), 1,38 (s, 6H, 24-H), 1,34 (m, 4H, 4-H) 1,32 (s, 6H, 23-H), 1,23 (s, 20H, 5-H, 6-H, 7-H, 8-H, 9-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 27°C): δ = 144,72 (s, C-15), 139,04 (s, C-2), 122,72 (s, C-14), 114,05 (s, C-1), 109,25 (s, C-22), 78,56 (s, C-17), 74,55 (s, C-20), 72,40 (s, C-19), 71,54, 71,48 (m, C-11, C-18), 69,27 (s, C-12), 66,67 (s, C-21), 63,83 (s, C-16), 60,51 (s, C-13), 33,70 (s, C-3), 29,43, 29,35, 29,29, 29,02, 28,82 (5 s, C-5, C-6, C-7, C-8, C-9, C-10), 26,69 (s, C-23), 25,93 (s, C-4), 25,33 (s, C-24) ppm. MS (ESI-TOF): berechnet für C₄₃H₇₇N₃O₉: (779,5660); gefunden: m/z = 780,5767 [M+H]⁺, 802,5585 [M+Na]⁺, 818,5335 [M+K]⁺. The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 25 ° C): δ = 7.70 (s, 1H, 14-H), 5.77 (tdd, J = 16.92, 10.17, 6.67 Hz, 2H, 2-H), 4.97, 4.94 (2 dd, J = 3.64, 1.62 Hz, each 1H, 1-H), 4.90, 4.88 (2 td, J = 2.24, 1.19 Hz, each 1H, 1-H), 4.84 (tq, J = 9.78, 4.82 Hz, 1H, 13-H), 4.76 (t, J = 1.70 Hz, 2H, 16-H), 4.21 (m, 2H, 20-H), 4.00 (m, 2H, 21-H), 3.78 (d, J = 5.67 Hz, 4H, 12-H), 3.69 (m, 2H, 21-H), 3.60 (m, 1H, 17-H), 3.57, 3.46 (2 br m, 8H, 18 -H, 19-H), 3.37 (m, 4H, 11-H), 2.00 (m, 4H, 3-H), 1.49 (m, 4H, 10-H), 1.38 (s, 6H, 24H), 1.34 (m, 4H, 4H), 1.32 (s, 6H, 23H), 1.23 (s, 20H, 5H, 6H , 7-H, 8-H, 9-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 27 ° C): δ = 144.72 (s, C-15), 139.04 (s, C-2), 122.72 (s, C-14) , 114.05 (s, C-1), 109.25 (s, C-22), 78.56 (s, C-17), 74.55 (s, C-20), 72.40 (s , C-19), 71.54, 71.48 (m, C-11, C-18), 69.27 (s, C-12), 66.67 (s, C-21), 63.83 (s, C-16), 60.51 (s, C-13), 33.70 (s, C-3), 29.43, 29.35, 29.29, 29.02, 28.82 ( 5s, C-5, C-6, C-7, C-8, C-9, C-10), 26,69 (s, C-23), 25,93 (s, C-4), 25.33 (s, C-24) ppm. MS (ESI-TOF): calculated for C ₄₃ H ₇₇ N ₃ O ₉ : (779.5660); Found: m / z = 780.5767 [M + H] ⁺ , 802.5585 [M + Na] ⁺ , 818.5335 [M + K] ⁺ .

Example 3.5

C ₁₁ -G0-Ck-G2.0 (xx):

Synthesis of C ₁₁ -G0-Ck-G2.0: The reaction was treated with propargyl-G2.0 (x) (1.442 g, 1.962 mmol), C ₁₁ -N ₃ (X) (0.910 g, 2.158 mmol), DIPEA (76 mg, 0.589 mmol), sodium ascorbate (117 mg, 0.589 mmol) and CuSO ₄ .5H ₂ O (73 mg, 0.294 mmol) in 3 mL THF as described above. Extraction with DCM (3 × 75 ml) and purification by filtration through silica gel with a mixture of EA and hexane (1: 2, then 1: 6) gave C ₁₁ -G 0 -Ck-G 2 O (x) as a brown oil ( 1.953 g, 1.689 mmol, 86%).

¹H-NMR (CDCl₃, 500 MHz, 28°C): δ = 7,69 (s, 1H, 14-H), 5,79 (tdd, J = 16,96, 10,17, 6,68 Hz, 2H, 2-H), 4,99, 4,95 (2 td, J = 2,04, 1,58 Hz, jeweils 1H, 1-H), 4,92, 4,90 (2 td, J = 2,33, 1,21 Hz, jeweils 1H, 1-H), 4,83 (m, 1H, 13-H), 4,76 (s, 2H, 16-H), 4,27 (m, 4H, 22-H), 4,01 (ddt, J = 7,35, 4,07, 2,37 Hz, 4H, 23-H), 3,80 (m, 4H, 12-H), 3,70 (m, 4H, 23-H), 3,64, 3,54, 3,46 (3 br m, 23H, 17-H, 18-H, 19-H, 20-H, 21-H), 3,40 (m, 4H, 11-H), 2,01 (m, 4H, 3-H), 1,51 (p, J = 6,72 Hz, 4H, 10-H), 1,39 (s, 12H, 25-H), 1,35 (m, 4H, 4-H), 1,33 (s, 12H, 26-H), 1,25 (s, 20H, 5-H, 6-H, 7-H, 8-H, 9-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 2,5°C): δ = 144,87 (s, C-15), 139,09 (s, C-2), 122,72 (s, C-14), 114,09 (s, C-1), 109,28 (s, C-24), 78,57, 78,42 (2 s, C-17, C-19), 74,57 (s, C-22), 72,45 (s, C-20, C-21), 71,59, 71,45, (m, C-11, C-18), 69,32 (s, C-12), 66,72 (s, C-23), 63,83 (s, C-16), 60,49 (s, C-13), 33,74 (s, C-3), 29,48, 29,40, 29,34, 29,07, 28,88, (5 s, C-5, C-6, C-7, C-8, C-9, C-10), 26,74 (s, C-25), 25,96 (s, C-4), 25,37 (s, C-26) ppm. MS (ESI-TOF): berechnet für C₆₁H₁₀₉N₃O₁₇: (1155,7757); gefunden: m/z = 1156,7920 [M+H]⁺, 1178,7736 [M+Na]⁺, 1194,7622 [M+K]⁺, 1218,7144 [M+Cu]⁺. The resulting from the click coupling regioisomers ratio is 89: 7 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 28 ° C): δ = 7.69 (s, 1H, 14-H), 5.79 (tdd, J = 16.96, 10.17, 6.68 Hz, 2H, 2-H), 4.99, 4.95 (2 td, J = 2.04, 1.58 Hz, each 1H, 1-H), 4.92, 4.90 (2 td, J = 2.33, 1.21 Hz, each 1H, 1-H), 4.83 (m, 1H, 13-H), 4.76 (s, 2H, 16-H), 4.27 (m, 4H, 22-H), 4.01 (ddt, J = 7.35, 4.07, 2.37 Hz, 4H, 23-H), 3.80 (m, 4H, 12-H), 3.70 (m, 4H, 23-H), 3.64, 3.54, 3.46 (3 br m , 23H, 17H, 18H, 19H, 20H, 21H), 3.40 (m, 4H, 11H), 2.01 (m, 4H, 3H), 1.51 (p, J = 6.72 Hz, 4H, 10-H), 1.39 (s, 12H, 25-H), 1.35 (m, 4H, 4-H), 1.33 ( s, 12H, 26H), 1.25 (s, 20H, 5H, 6H, 7H, 8H, 9H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 2.5 ° C): δ = 144.87 (s, C-15), 139.09 (s, C-2), 122.72 (s, C 14), 114.09 (s, C-1), 109.28 (s, C-24), 78.57, 78.42 (2 s, C-17, C-19), 74.57 (s , C-22), 72.45 (s, C-20, C-21), 71.59, 71.45, (m, C-11, C-18), 69.32 (s, C-12 ), 66.72 (s, C-23), 63.83 (s, C-16), 60.49 (s, C-13), 33.74 (s, C-3), 29.48, 29.40, 29.34, 29.07, 28.88, (5s, C-5, C-6, C-7, C-8, C-9, C-10), 26.74 (s , C-25), 25.96 (s, C-4), 25.37 (s, C-26) ppm. MS (ESI-TOF): calculated for C ₆₁ H ₁₀₉ N ₃ O ₁₇ : (1155.7757); Found: m / z = 1156.7920 [M + H] ⁺ , 1178.7736 [M + Na] ⁺ , 1194.7622 [M + K] ⁺ , 1218.7144 [M + Cu] ⁺ .

Example 3.6

C ₁₁ -G0-Ck-G3.0 (xx):

Synthesis of C ₁₁ -G 0 Ck G3.0: The reaction was carried out with propargyl G3.0 (x) (2.204 g, 1.481 mmol), C ₁₁ N ₃ (x) (0.687 g, 1.629 mmol), DIPEA (57 mg, 0.444 mmol), sodium ascorbate (88 mg, 0.444 mmol) and CuSO ₄ .5H ₂ O (55 mg, 0.222 mmol) in 5 mL THF as described above. Extraction with DCM (3 x 75 mL) and purification by column chromatography on silica gel with 5% EA in hexane, then 25% isopropanol in hexane gave C ₁₁ -G 0 C k -G 3 O (x) as a colorless oil (1.472 g, 0.771 mmol, 52%).

¹H-NMR (CDCl₃, 500 MHz, 25°C): δ = 7,68 (s, 1H, 14-H), 5,78 (tdd, J = 16,95, 10,19, 6,67 Hz, 2H, 2-H), 4,98, 4,94 (2 dd, J = 3,65, 1,61 Hz, jeweils 1H, 1-H), 4,91, 4,89 (2 td, J = 2,24, 1,18 Hz, jeweils 1H, 1-H), 4,81 (p, J = 5,85 Hz, 1H, 13-H), 4,75 (s, 2H, 16-H), 4,21 (m, 8H, 24-H), 4,00 (m, 8H, 25-H), 3,79 (m, 4H, 12-H), 3,68 (m, 8H, 25-H), 3,62, 3,57, 3,52, 3,45 (4 br m, 51H, 17-H, 18-H, 19-H, 20-H, 21-H, 22-H, 23-H), 3,39 (m, 4H, 11-H), 2,00 (m, 4H, 3-H), 1,51 (p, J = 6,82 Hz, 4H, 10-H), 1,38 (s, 24H, 27-H), 1,34 (m, 4H, 4-H), 1,32 (s, 24H, 28-H), 1,24 (s, 20H, 5-H, 6-H, 7-H, 8-H, 9-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 30°C): δ = 144,91 (s, C-15), 139,06 (s, C-2), 122,68 (s, C-14), 114,08 (s, C-1), 109,23 (s, C-26), 78,59, 78,35, 78,04 (3 s, C-17, C-19, C-21), 74,55 (s, C-24), 72,48 (s, C-20, C-22, C-23), 71,57, 71,39 (m, C-11, C-18), 69,33 (s, C-12), 66,88 (s, C-25), 63,92 (s, C-16), 60,43 (s, C-13), 33,71 (s, C-3), 29,48, 29,38, 29,34, 29,05, 28,85, (5 s, C-5, C-6, C-7, C-8, C-9, C-10), 26,74 (s, C-27), 25,95 (s, C-4), 25,37 (s, C-28) ppm. MS (ESI-TOF): berechnet für C₉₇H₁₇₃N₃O₃₃: (1908,1951); gefunden: m/z = 977,0871 [M+2Na]²⁺ 1931,1844 [M+Na]⁺. The resulting from the click coupling Regioisomerenverhältnis is 32: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 25 ° C): δ = 7.68 (s, 1H, 14-H), 5.78 (tdd, J = 16.95, 10.19, 6.67 Hz, 2H, 2-H), 4.98, 4.94 (2 dd, J = 3.65, 1.61 Hz, each 1H, 1-H), 4.91, 4.89 (2 td, J = 2.24, 1.18 Hz, each 1H, 1-H), 4.81 (p, J = 5.85 Hz, 1H, 13-H), 4.75 (s, 2H, 16-H ), 4.21 (m, 8H, 24-H), 4.00 (m, 8H, 25-H), 3.79 (m, 4H, 12-H), 3.68 (m, 8H, 25 -H), 3.62, 3.57, 3.52, 3.45 (4 br, 51H, 17H, 18H, 19H, 20H, 21H, 22H, 23-H), 3.39 (m, 4H, 11-H), 2.00 (m, 4H, 3-H), 1.51 (p, J = 6.82 Hz, 4H, 10-H) , 1.38 (s, 24H, 27-H), 1.34 (m, 4H, 4-H), 1.32 (s, 24H, 28-H), 1.24 (s, 20H, 5- H, 6-H, 7-H, 8-H, 9-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 30 ° C): δ = 144.91 (s, C-15), 139.06 (s, C-2), 122.68 (s, C-14) , 114.08 (s, C-1), 109.23 (s, C-26), 78.59, 78.35, 78.04 (3 s, C-17, C-19, C-21), 74.55 (s, C-24), 72.48 (s, C-20, C-22, C-23), 71.57, 71.39 (m, C-11, C-18), 69.33 (s, C-12), 66 , 88 (s, C-25), 63.92 (s, C-16), 60.43 (s, C-13), 33.71 (s, C-3), 29.48, 29.38 , 29.34, 29.05, 28.85, (5s, C-5, C-6, C-7, C-8, C-9, C-10), 26.74 (s, C 27), 25.95 (s, C-4), 25.37 (s, C-28) ppm. MS (ESI-TOF): Calcd. for C ₉₇ H ₁₇₃ N ₃ O ₃₃ : (1908, 1951); Found: m / z = 977.0871 [M + 2Na] ²⁺ 1931.1844 [M + Na] ⁺ .

Example 3.7

Rf-C ₆ -G0-Ck-G1.0 (xx):

Synthesis of Rf-C ₆ -Go-Ck-G1.0: The reaction was carried out with C ₆ -Go-Ck-G1.0 (x) (1.299 g, 2.030 mmol) in RfC ₂ H ₄ SH (7.80 g , 16.24 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 L, 7: 1) followed by a mixture of EA and hexane (1.5 L, 2: 1) gave Rf-C ₆ -G 0 Ck -G1.0 (x) as a colorless oil (2.619 g, 1.637 mmol, 81%) which, after storage in the refrigerator, formed a milky wax.

¹H-NMR (CDCl₃, 500 MHz, 2,5°C): δ = 7,70 (s, 1H, 19-H), 4,84 (m, 1H, 18-H), 4,77 (t, J = 1,70 Hz, 2H, 21-H), 4,23 (m, 2H, 25-H), 4,01 (m, 2H, 26-H), 3,81 (d, J = 5,62 Hz, 4H, 17-H), 3,71 (m, 2H, 26-H), 3,61, 3,58, 3,47 (3 br m, 9H, 22-H, 23-H, 24-H), 3,40 (m, 4H, 16-H), 2,70 (m, 4H, 10-H), 2,52 (t, J = 7,35 Hz, 4H, 11-H), 2,34 (m, 4H, 9-H), 1,54 (m, 8H, 12-H, 15-H), 1,38 (s, 6H, 28-H), 1,35 (m, 4H, 14-H), 1,33 (s, 6H, 29-H), 1,29 (m, 4H, 13-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 25°C): δ = 144,82 (s, C-20), 122,75 (s, C-19), 121-107 (m, C-F), 109,33 (s, C-27), 78,61 (s, C-22), 74,59 (s, C-25), 72,45 (s, C-24), 71,53, 71,37 (2 s, C-16, C-23), 69,40 (s, C-17), 66,70 (s, C-26), 63,88 (s, C-21), 60,55 (s, C-18), 32,25 (s, C-11), 31,81 (t, J = 21,90 Hz, C-9), 29,27, 29,19 (2 s, C-12, C-15), 28,47 (s, C-13), 26,70 (s, C-28), 25,59 (s, C-14), 25,32 (s, C-19), 22,54 (s, C-10) ppm.
¹⁹F-NMR (CDCl₃, 400 MHz, 24°C): δ = –80,80 (t, J = 9,94 Hz, 6 F, 1-F), –114,31 (m, 4 F, 2-F), –121,70, –121,92 (2 s, 12 F, 3-F, 4-F, 5-F), –122,72 (s, 4 F, 6-F), –123,35 (s, 4 F, 7-F), –126,13 (m, 4 F, 8-F) ppm. MS (ESI-TOF): berechnet für C₅₃H₆₇F₃₄N₃O₉S₂: (1599,3776); gefunden: m/z = 1120,4051 [(M–RfC₂H₄SH)+H]⁺, 1142,3867 [(M–RfC₂H₄SH)+Na]⁺, 1158,3623 [(M–RfC₂H₄SH)+K]⁺, 1600,3901 [M+H]'⁺ 1622,3717 [M+Na]⁺, 1638,3469 [M+K]⁺. The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 2.5 ° C): δ = 7.70 (s, 1H, 19-H), 4.84 (m, 1H, 18-H), 4.77 ( t, J = 1.70 Hz, 2H, 21-H), 4.23 (m, 2H, 25-H), 4.01 (m, 2H, 26-H), 3.81 (d, J = 5.62Hz, 4H, 17H), 3.71 (m, 2H, 26H), 3.61, 3.58, 3.47 (3 br, 9H, 22H, 23H , 24-H), 3.40 (m, 4H, 16-H), 2.70 (m, 4H, 10-H), 2.52 (t, J = 7.35 Hz, 4H, 11-H ), 2.34 (m, 4H, 9-H), 1.54 (m, 8H, 12-H, 15-H), 1.38 (s, 6H, 28-H), 1.35 (m , 4H, 14-H), 1.33 (s, 6H, 29-H), 1.29 (m, 4H, 13-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 25 ° C): δ = 144.82 (s, C-20), 122.75 (s, C-19), 121-107 (m, CF), 109 , 33 (s, C-27), 78.61 (s, C-22), 74.59 (s, C-25), 72.45 (s, C-24), 71, 53, 71, 37 (2s, C-16, C-23), 69.40 (s, C-17), 66.70 (s, C-26), 63.88 (s, C-21), 60.55 ( s, C-18), 32.25 (s, C-11), 31.81 (t, J = 21.90 Hz, C-9), 29.27, 29.19 (2 s, C-12 , C-15), 28.47 (s, C-13), 26.70 (s, C-28), 25.59 (s, C-14), 25.32 (s, C-19), 22.54 (s, C-10) ppm.
¹⁹ F-NMR (CDCl _3, 400 MHz, 24 ° C): δ = -80.80 (t, J = 9.94 Hz, 6 F, 1-F), -114.31 (m, 4 F, 2-F), -121.70, -121.92 (2 s, 12 F, 3-F, 4-F, 5-F), -122.72 (s, 4 F, 6-F), 123.35 (s, 4 F, 7-F), -126.13 (m, 4 F, 8-F) ppm. MS (ESI-TOF): calculated for C ₅₃ H ₆₇ F ₃₄ N ₃ O ₉ S ₂ : (1599.3776); Found: m / z = 1120.4051 [(M-RfC ₂ H ₄ SH) + H] ⁺ , 1142.3867 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 1158.3623 [(M-RfC ₂ H ₄ SH) + K] ⁺ , 1600.3901 [M + H] ' ⁺ 1622.3717 [M + Na] ⁺ , 1638.3469 [M + K] ⁺ .

Example 3.8

Rf-C ₆ -G0-Ck-G2.0 (xx):

¹H-NMR (CDCl₃, 500 MHz, 22°C): δ = 7,69 (s, 1H, 19-H), 4,83 (m, 1H, 18-H), 4,76 (s, 2H, 21-H), 4,22 (m, 4H, 27-H), 4,01 (m, 4H, 28-H), 3,80 (d, J = 5,61 Hz, 4H, 17-H), 3,69 (m, 4H, 28-H), 3,64, 3,56, 3,53, 3,46 (4 br m, 23H, 22-H, 23-H, 24-H, 25-H, 26-H), 3,40 (m, 4H, 16-H), 2,70 (m, 4H, 10-H), 2,52 (t, J = 7,35 Hz, 4H, 11-H), 2,34 (m, 4H, 9-H), 1,53 (m, 8H, 12-H, 15-H), 1,38 (s, 12H, 30-H), 1,35 (m, 4H, 14-H), 1,32 (s, 12-H, 31-H), 1,29 (m, 4H, 13-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 2,5°C): δ = 144,95 (s, C-20), 122,68 (s, C-19), 121-107 (m, C-F), 109,29 (s, C-29), 78,59, 78,47 (2 s, C-22, C-24), 74,59 (s, C-27), 72,47 (s, C-25, C-26), 71,46, 71,37 (m, C-16, C-23), 69,42 (s, C-17), 66,72 (s, C-28), 63,89 (s, C-21), 60,50 (s, C-18), 32,14 (s, C-11), 32,06 (t, J = 21,90 Hz, C-9), 29,27, 29,20 (2 s, C-12, C-15), 28,47 (s, C-13), 26,70 (s, C-30), 25,58 (s, C-14), 25,32 (s, C-31), 22,56 (s, C-10) ppm.
¹⁹F-NMR (CDCl₃, 400 MHz, 25°C): δ = –80,74 (t, J = 9,99 Hz, 6 F, 1-F), –114,30 (m, 4 F, 2-F), –121,66, –121,88 (2 s, 12 F, 3-F, 4-F, 5-F), –122,68 (s, 4 F, 6-F), –123,31 (s, 4 F, 7-F), –126,08 (m, 4 F, 8-F) ppm. MS (ESI-TOF): berechnet für C₇₁H₉₉F₃₄N₃O₁₇S₂: (1975,5873); gefunden: m/z = 1010,7823 [M+2Na]^{2 +}, 1518,5926 [(M–RfC₂H₄SH)+ Na]⁺, 1998,5762 [M+Na]⁺. Synthesis of ₆ RfC -G0-Ck-G2.0: The reaction was charged with C ₆ -G0-Ck-G2.0 (x) (1.510 g, 1.486 mmol) in RfC ₂ H ₄ SH (5.70 g , 11.89 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 L, 7: 1) followed by a mixture of EE and hexane (1 L, 5: 1) gave Rf-C ₆ -Go-Ck-G2 .0 (x) as a colorless oil (2.421 g, 1.224 mmol, 82%) that formed a milky wax in the refrigerator after storage.

¹ H-NMR (CDCl _3, 500 MHz, 22 ° C): δ = 7.69 (s, 1H, 19-H), 4.83 (m, 1H, 18-H), 4.76 (s, 2H, 21-H), 4.22 (m, 4H, 27-H), 4.01 (m, 4H, 28-H), 3.80 (d, J = 5.61 Hz, 4H, 17- H), 3.69 (m, 4H, 28-H), 3.64, 3.56, 3.53, 3.46 (4 br, 23H, 22H, 23H, 24H, 25-H, 26-H), 3.40 (m, 4H, 16-H), 2.70 (m, 4H, 10-H), 2.52 (t, J = 7.35 Hz, 4H, 11-H), 2.34 (m, 4H, 9-H), 1.53 (m, 8H, 12-H, 15-H), 1.38 (s, 12H, 30-H), 1, 35 (m, 4H, 14-H), 1.32 (s, 12-H, 31-H), 1.29 (m, 4H, 13-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 2.5 ° C): δ = 144.95 (s, C-20), 122.68 (s, C-19), 121-107 (m, CF) , 109.29 (s, C-29), 78.59, 78.47 (2 s, C-22, C-24), 74.59 (s, C-27), 72.47 (s, C -25, C-26), 71,46, 71,37 (m, C-16, C-23), 69,42 (s, C-17), 66,72 (s, C-28), 63 , 89 (s, C-21), 60.50 (s, C-18), 32.14 (s, C-11), 32.06 (t, J = 21.90 Hz, C-9), 29.27, 29.20 (2 s, C-12, C-15), 28.47 (s, C-13), 26.70 (s, C-30), 25.58 (s, C) 14), 25.32 (s, C-31), 22.56 (s, C-10) ppm.
¹⁹ F-NMR (CDCl _3, 400 MHz, 25 ° C): δ = -80.74 (t, J = 9.99 Hz, 6 F, 1-F), -114.30 (m, 4 F, 2-F), -121.66, -121.88 (2 s, 12 F, 3-F, 4-F, 5-F), -122.68 (s, 4 F, 6-F), 123.31 (s, 4 F, 7-F), -126.08 (m, 4 F, 8-F) ppm. MS (ESI-TOF): Calcd. for C ₇₁ H ₉₉ F ₃₄ N ₃ O ₁₇ S ₂ : (1975.5873); Found: m / z = 1010.7823 [M + 2Na] ^{2 +} , 1518.5926 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 1998.5762 [M + Na] ⁺ .

Example 3.10

Rf-C ₁₁ -Go-Ck-G 1.0 (xx):

Synthesis of Rf-C ₁₁ -Go-Ck-G1.0: The reaction was carried out with C ₁₁ -Go-Ck-G1.0 (x) (0.681 g, 0.873 mmol) in RfC ₂ H ₄ SH (3.35 g , 6.98 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1 L, 7: 1) followed by a mixture of EE and hexane (1 L, 1: 1) gave Rf-C ₁₁ -Go-Ck-G1.0 (x) as a colorless oil (1.335 g, 0.767 mmol, 88%) which formed a milky wax in the refrigerator after storage.

¹H-NMR (CDCl₃, 500 MHz, 27°C): δ = 7,72 (s, 1H, 24-H), 4,85 (m, 1H, 23-H), 4,78 (t, J = 1,63 Hz, 2H, 26-H), 4,25 (m, 2H, 30-H), 4,03 (m, 2H, 31-H), 3,81 (d, J = 5,69 Hz, 4H, 22-H), 3,72 (m, 2H, 31-H), 3,62, 3,59, 3,48 (3 br m, 9H, 27-H, 28-H, 29-H), 3,40 (m, 4H, 21-H), 2,72 (m, 4H, 10-H), 2,53 (t, J = 7,5 Hz, 4H, 11-H), 2,34 (m, 4H, 9-H), 1,58 (td, J = 14,99, 7,35 Hz, 4H, 12-H), 1,51 (m, 4H, 20-H), 1,40 (s, 6H, 33-H), 1,37 (m, 4H, 14-H), 1,34 (s, 6H, 34-H), 1,25 (s, 24H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 27°C): δ = 144,81 (s, C-25), 122,80 (s, C-24), 109,35 (s, C-32), 78,65 (s, C-27), 74,63 (s, C-30), 72,50 (s, C-29), 71,64, 71,39 (2 s, C-21, C-28), 69,38 (s, C-22), 66,76 (s, C-31), 63,92 (s, C-26), 60,61 (s, C-23), 32,27 (s, C-11), 31,46 (t, J = 32,15 Hz, C-9), 29,56, 29,53, 29,48, 29,45, 29,39, 29,35, 29,19, 28,79 (8 s, C-12, C-13, C-15, C-16, C-17, C-18, C-19, C-20), 26,75 (s, C-33), 26,01 (s, C-14), 25,38 (s, C-34), 22,58 (s, C-10) ppm.
¹⁹F-NMR (CDCl₃, 400 MHz, 27°C): δ = –80,70 (t, J = 9,85 Hz, 6 F, 1-F), –114,27 (m, 4 F, 2-F), –121,63, –121,88 (2 s, 12 F, 3-F, 4-F, 5-F), –122,65 (s, 4 F, 6-F), –123,31 (s, 4 F, 7-F), –126,04 (m, 4 F, 8-F) ppm. MS (ESI-TOF): berechnet für C₆₃H₈₇F₃₄N₃O₉S₂: (1739,5341); gefunden: m/z = 1298,5322 [(M–RfC₂H₄SH)+K]⁺, 1740,5399 [M+H]⁺, 1762,5205 [M+Na]⁺, 1778,5110 [M+K]⁺. The regioisomer ratio resulting from the click coupling is 7: 3 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 27 ° C): δ = 7.72 (s, 1H, 24-H), 4.85 (m, 1H, 23-H), 4.78 (t, J = 1.63 Hz, 2H, 26-H), 4.25 (m, 2H, 30-H), 4.03 (m, 2H, 31-H), 3.81 (d, J = 5, 69 Hz, 4H, 22-H), 3.72 (m, 2H, 31-H), 3.62, 3.59, 3.48 (3 br m, 9H, 27-H, 28-H, 29 -H), 3.40 (m, 4H, 21-H), 2.72 (m, 4H, 10-H), 2.53 (t, J = 7.5 Hz, 4H, 11-H), 2.34 (m, 4H, 9-H), 1.58 (td, J = 14.99, 7.35 Hz, 4H, 12-H), 1.51 (m, 4H, 20-H), 1.40 (s, 6H, 33H), 1.37 (m, 4H, 14H), 1.34 (s, 6H, 34H), 1.25 (s, 24H, 13H , 15-H, 16-H, 17-H, 18-H, 19-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 27 ° C): δ = 144.81 (s, C-25), 122.80 (s, C-24), 109.35 (s, C-32) , 78.65 (s, C-27), 74.63 (s, C-30), 72.50 (s, C-29), 71.64, 71.39 (2 s, C-21, C -28), 69.38 (s, C-22), 66.76 (s, C-31), 63.92 (s, C-26), 60.61 (s, C-23), 32, 27 (s, C-11), 31.46 (t, J = 32.15 Hz, C-9), 29.56, 29.53, 29.48, 29.45, 29.39, 29.35 , 29.19, 28.79 (8s, C-12, C-13, C-15, C-16, C-17, C-18, C-19, C-20), 26.75 (s , C-33), 26.01 (s, C-14), 25.38 (s, C-34), 22.58 (s, C-10) ppm.
¹⁹ F-NMR (CDCl _3, 400 MHz, 27 ° C): δ = -80.70 (t, J = 9.85 Hz, 6 F, 1-F), -114.27 (m, 4 F, 2-F), -121.63, -121.88 (2 s, 12 F, 3-F, 4-F, 5-F), -122.65 (s, 4 F, 6-F), 123.31 (s, 4 F, 7-F), -126.04 (m, 4 F, 8-F) ppm. MS (ESI-TOF): calculated for C ₆₃ H ₈₇ F ₃₄ N ₃ O ₉ S _2: (1739.5341); Found: m / z = 1298.5322 [(M-RfC ₂ H ₄ SH) + K] ⁺ , 1740.5399 [M + H] ⁺ , 1762.5205 [M + Na] ⁺ , 1778.5110 [M + K] ⁺ .

Example 3.11

Rf-C ₁₁ -G0-Ck-G2.0 (xx):

Synthesis of RfC ₁₁ -G0-Ck-G2.0: The reaction was charged with C ₁₁ -G0-Ck-G2.0 (x) (1.346 g, 1.164 mmol) in RfC ₂ H ₄ SH (4.47 g , 9.31 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 L, 7: 1) followed by a mixture of EE and hexane (1 L, 5: 1) gave Rf-C ₁₁ -GO-Ck-G2 .0 (x) as a pale yellow oil (2.170 g, 1.029 mmol, 88%) which formed a milky wax in the refrigerator after storage.

¹H-NMR (CDCl₃, 500 MHz, 22°C): δ = 7,70 (s, 1H, 24-H), 4,84 (m, 1H, 23-H), 4,76 (s, 2H, 26-H), 4,22 (m, 4H, 32-H), 4,01 (m, 4H, 33-H), 3,80 (d, J = 5,60 Hz, 4H, 22-H), 3,70 (m, 4H, 33-H), 3,64, 3,57, 3,54, 3,47 (4 br m, 23H, 27-H, 28-H, 29-H, 30-H, 31-H), 3,40 (m, 4H, 21-H), 2,70 (m, 4H, 10-H), 2,53 (t, J = 7,5 Hz, 4H, 11-H), 2,35 (m, 4H, 9-H), 1,57, 1,51 (2 m, jeweils 4H, 12-H, 20-H), 1,39 (s, 12H, 35-H), 1,36 (m, 4H, 14-H), 1,33 (s, 12H, 36-H), 1,24 (s, 24H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 29°C): δ = 144,89 (s, C-25), 122,73 (s, C-24), 121-107 (m, C-F), 109,21 (s, C-34), 78,59, 78,41 (2 s, C-27, C-29), 74,60 (s, C-32), 72,47 (s, C-30, C-31), 71,59, 71,46 (2 s, C-21, C-28), 69,35 (s, C-22), 66,73 (s, C-33), 63,88 (s, C-26), 60,52 (s, C-23), 32,32 (s, C-11), 32,10 (t, J = 22,33 Hz, C-9), 29,53, 29,50, 29,45, 29,42, 29,36, 29,31 29,15, 28,75 (8 s, C-12, C-13, C-15, C-16, C-17, C-18, C-19, C-20), 26,71 (s, C-35), 25,97 (s, C-14), 25,34 (s, C-36), 22,53 (s, C-10) ppm.
¹⁹F-NMR (CDCl₃, 400 MHz, 2,5°C): δ = –80,77 (t, J = 9,81 Hz, 6 F, 1-F), –114,32 (m, 4 F, 2-F), –121,67, –121,90 (2 s, 12 F, 3-F, 4-F, 5-F), –122,70 (s, 4 F, 6-F), –123,35 (s, 4 F, 7-F), –126,10 (s, 4 F, 8-F) ppm. MS (ESI-TOF): berechnet für C₈₁H₁₁₉F₃₄N₃O₁₇S₂: (2115,7438); gefunden: m/z = 1658,7513 [(M–RfC₂H₄SH)+Na]⁺, 2116,7520 [M+H]⁺, 2138,7349 [M+Na]⁺. The resulting from the click coupling Regioisomerenverhältnis is 23: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 22 ° C): δ = 7.70 (s, 1H, 24-H), 4.84 (m, 1H, 23-H), 4.76 (s, 2H, 26-H), 4.22 (m, 4H, 32-H), 4.01 (m, 4H, 33-H), 3.80 (d, J = 5.60 Hz, 4H, 22- H), 3.70 (m, 4H, 33-H), 3.64, 3.57, 3.54, 3.47 (4 br, 23H, 27H, 28H, 29H, 30-H, 31-H), 3.40 (m, 4H, 21-H), 2.70 (m, 4H, 10-H), 2.53 (t, J = 7.5 Hz, 4H, 11-H), 2.35 (m, 4H, 9-H), 1.57, 1.51 (2 m, each 4H, 12-H, 20-H), 1.39 (s, 12H, 35 -H), 1.36 (m, 4H, 14-H), 1.33 (s, 12H, 36-H), 1.24 (s, 24H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 29 ° C): δ = 144.89 (s, C-25), 122.73 (s, C-24), 121-107 (m, CF), 109 , 21 (s, C-34), 78.59, 78.41 (2 s, C-27, C-29), 74.60 (s, C-32), 72.47 (s, C-30 , C-31), 71.59, 71.46 (2 s, C-21, C-28), 69.35 (s, C-22), 66.73 (s, C-33), 63, 88 (s, C-26), 60.52 (s, C-23), 32.32 (s, C-11), 32.10 (t, J = 22.33 Hz, C-9), 29 , 53, 29.50, 29.45, 29.42, 29.36, 29.31, 29.15, 28.75 (8s, C-12, C-13, C-15, C-16, C -17, C-18, C-19, C-20), 26.71 (s, C-35), 25.97 (s, C-14), 25.34 (s, C-36), 22 , 53 (s, C-10) ppm.
¹⁹ F-NMR (CDCl _3, 400 MHz, 2.5 ° C): δ = -80.77 (t, J = 9.81 Hz, 6 F, 1-F), -114.32 (m, 4 F, 2-F), -121.67, -121.90 (2 s, 12 F, 3-F, 4-F, 5-F), -122.70 (s, 4 F, 6-F) , -123.35 (s, 4F, 7-F), -126.10 (s, 4F, 8-F) ppm. MS (ESI-TOF): Calcd. for C ₈₁ H ₁₁₉ F ₃₄ N ₃ O ₁₇ S ₂ : (2115.7438); Found: m / z = 1658.7513 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 2116.7520 [M + H] ⁺ , 2138.7349 [M + Na] ⁺ .

Example 3.12

Rf-C ₁₁ -G0-Ck-G3.0 (xx):

Synthesis of Rf-C ₁₁ -Go-Ck-G3.0: The reaction was carried out with C ₁₁ -Go-Ck-G3.0 (x) (0.860 g, 0.450 mmol) in RfC ₂ H ₄ SH (1.73 g , 3.60 mmol) as described above. Purification by filtration through silica gel with a mixture of PE and DCM (1.5 L, 7: 1) and a subsequent mixture of isopropanol and hexane (1.5 L, 1: 4) gave Rf-C ₁₁ -G 0 Ck -G3.0 (x) as a colorless oil (0.863 g, 0.301 mmol, 60%) that formed a milky wax in the refrigerator after storage.

Unused C ₁₁ -G0-Ck-G3.0 (x) was also obtained (6%).

¹H-NMR (CDCl₃, 500 MHz, 25°C): δ = 7,69 (s, 1H, 24-H), 4,81 (m, 1H, 23-H), 4,76 (s, 2H, 26-H), 4,21 (m, 8H, 34-H), 4,01 (m, 8H, 35-H), 3,79 (m, 4H, 22-H), 3,69 (m, 8H, 35-H), 3,63, 3,58, 3,53, 3,40 (4 br m, 51H, 27-H, 28-H, 29-H, 30-H, 31-H, 32-H, 33-H) 3,39 (m, 4H, 21-H), 2,70 (m, 4H, 10-H), 2,53 (t, J = 7,5 Hz, 4H, 11-H), 2,35 (m, 4H, 9-H), 1,57 (td, J = 15,00, 7,38 Hz, 4H, 12-H), 1,52 (m, 4H, 20-H), 1,38 (s, 24H, 37-H), 1,36 (m, 4H, 14-H), 1,32 (s, 24H, 38-H), 1,25 (s, 24H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H) ppm.
¹³C-NMR (CDCl₃, 400 MHz, 30°C): δ = 144,93 (s, C-25), 122,70 (s, C-24), 121-107 (m, C-F), 109,26 (s, C-36), 78,61, 78,33 (m, C-27, C-29 C-31), 74,56 (s, C-34), 72,46 (s, C-30, C-32, C-33), 71,59, 71,41 (m, C-21, C-28), 69,36 (s, C-22), 66,76 (s, C-35), 63,93 (s, C-26), 60,44 (s, C-23), 32,32 (s, C-11), 32,10 (t, J = 22,17 Hz, C-9), 29,53, 29,48, 29,41, 29,32, 29,17, 28,78 (6 s, C-12, C-13, C-15, C-16, C-17, C-18, C-19, C-20), 26,74 (s, C-37), 25,98 (s, C-14), 25,37 (s, C-38), 22,54 (s, C-10) ppm.
¹⁹F-NMR (CDCl₃, 400 MHz, 22°C): δ = –80,70 (t, J = 9,57 Hz, 6 F, 1-F), –114,33 (m, 4 F, 2-F), –121,68, –121,89 (2 s, 12 F, 3-F, 4-F, 5-F), –122,68 (s, 4 F, 6-F), –123,34 (s, 4 F, 7-F), –126,08 (m, 4 F, 8-F) ppm. MS (ESI-TOF): berechnet für C₁₁₇H₁₈₃F₃₄N₃O₃₃S₂: (2868,1632); gefunden: m/z = 1217,5799 [(M–RfC₂H₄SH)+Na]^{2 +}, 1457,0715 [M+ 2Na]^{2 +}, 2412,1465 [(M–RfC₂H₄SH)+Na]⁺, 2891,1572 [M+Na]⁺. The resulting from the click coupling Regioisomerenverhältnis is 32: 1 (calculated from ¹ H-NMR).

¹ H-NMR (CDCl _3, 500 MHz, 25 ° C): δ = 7.69 (s, 1H, 24-H), 4.81 (m, 1H, 23-H), 4.76 (s, 2H, 26-H), 4.21 (m, 8H, 34-H), 4.01 (m, 8H, 35-H), 3.79 (m, 4H, 22-H), 3.69 ( m, 8H, 35-H), 3.63, 3.58, 3.53, 3.40 (4 br, 51H, 27H, 28H, 29H, 30H, 31H , 32-H, 33-H) 3.39 (m, 4H, 21-H), 2.70 (m, 4H, 10-H), 2.53 (t, J = 7.5 Hz, 4H, 11-H), 2.35 (m, 4H, 9-H), 1.57 (td, J = 15.00, 7.38 Hz, 4H, 12-H), 1.52 (m, 4H, 20-H), 1.38 (s, 24H, 37-H), 1.36 (m, 4H, 14-H), 1.32 (s, 24H, 38-H), 1.25 (s, 24H, 13H, 15H, 16H, 17H, 18H, 19H) ppm.
¹³ C-NMR _(CDCl3, 400 MHz, 30 ° C): δ = 144.93 (s, C-25), 122.70 (s, C-24), 121-107 (m, CF), 109 , 26 (s, C-36), 78.61, 78.33 (m, C-27, C-29 C-31), 74.56 (s, C-34), 72.46 (s, C -30, C-32, C-33), 71.59, 71.41 (m, C-21, C-28), 69.36 (s, C-22), 66.76 (s, C-) 35), 63.93 (s, C-26), 60.44 (s, C-23), 32.32 (s, C-11), 32.10 (t, J = 22.17 Hz, C -9), 29.53, 29.48, 29.41, 29.32, 29.17, 28.78 (6s, C-12, C-13, C-15, C-16, C-17 , C-18, C-19, C-20), 26.74 (s, C-37), 25.98 (s, C-14), 25.37 (s, C-38), 22.54 (s, C-10) ppm.
¹⁹ F-NMR (CDCl _3, 400 MHz, 22 ° C): δ = -80.70 (t, J = 9.57 Hz, 6 F, 1-F), -114.33 (m, 4 F, 2-F), -121.68, -121.89 (2 s, 12 F, 3-F, 4-F, 5-F), -122.68 (s, 4 F, 6-F), 123.34 (s, 4 F, 7-F), -126.08 (m, 4 F, 8-F) ppm. MS (ESI-TOF): Calcd. for C ₁₁₇ H ₁₈₃ F ₃₄ N ₃ O ₃₃ S ₂ : (2868.1632); Found: m / z = 1217.5799 [(M-RfC ₂ H ₄ SH) + Na] ^{2 +} , 1457.0717 [M + 2Na] ^{2 +} , 2412,1465 [(M-RfC ₂ H ₄ SH) + Na] ⁺ , 2891,1572 [M + Na] ⁺ .

Example 4

Compounds of the general formula (2) - Amphiphiles with partially fluorinated alkyl side chains and dendritic polyglycerol head groups

Experimental part

General: All reactions in which dry conditions are required were performed in Schlenk glassware under argon. Dry and reagent grade solvents were purchased from Acros or Aldrich and used as supplied. The ¹ H NMR and ¹³ C NMR spectra were recorded at 25 ° C using the Bruker AB 250 spectrometers (250 and 67.5 MHz for ¹ H and ¹³ C, respectively), ECX 400 (400 and 100 MHz for ¹ H or ¹³ C) and Delta JEOL ECLIPSE 500 (500 and 125 MHz for ¹ H and 130, respectively).

The ECX 400 was used to record high-resolution ¹³ C NMR. The spectra were calibrated for the solvent peak (CDCl ₃ : 7.26 ppm for ¹ H and 77.0 ppm for ¹³ C; CD ₃ OD: 4.84 ppm for ¹ H and 49.05 ppm for ¹³ C). Flash chromatography was performed on silica gel 60 (230-400 mesh) using compression pressure with the aid of compressed air. For the ESI-TOF measurements, an Agilent 6210 ESI-TOF, Agilent Technologies, Santa Clara, USA, was used. HPLC was performed on a Knauer HPLC (K-1800 pump) using a Knauer RI detector K-2401 and a Nucleosil 50-5 column (32x240).

General Procedure for Coupling Propargyl Dendrones with the [G1.5] Azide: 1.0 equivalent of [Gn] propargyl and 1.1 equivalents of [G1.5] azide per triple bond dissolved in THF were mixed with 15 mol% DIPEA (diisopropylethylamine) added per triple bond. After stirring for 5 minutes, 30 mol% sodium ascorbate per triple bond was added, followed by 15 mol% CuSO ₄ .5H ₂ O per triple bond. The THF / H ₂ O mixture must be 1: 1 (v / v). The heterogeneous mixture was vigorously stirred to the point where TLC analysis showed that the starting material was completely consumed. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with a small amount of a saturated EDTA solution, dried with Na ₂ SO ₄ and concentrated in vacuo. Purification by column chromatography gives the desired product (a stock solution of sodium ascorbate and CuSO ₄ .5H ₂ O in water was prepared at a concentration of 100 mg / ml).

[G1.0] -Propargyl-click- [G1.5] -azide (2): Reaction conditions and work up were as described above, with [G1.0] -propargyl (0.385 g, 1.107 mmol, 1.0 equivalents), [G1.5] azide (0.518 g, 1.218 mmol, 1.05 equiv.), DIPEA (27.45 μL, 0.166 mmol, 0.15 equiv.), Sodium ascorbate (65.8 mg, 0.332 mmol, 0.3 equiv and copper (II) sulfate pentahydrate (41.5 mg, 0.166 mmol, 0.15 equivalents) in THF / H ₂ O (6 mL). Purification by column chromatography (10% isopropanol in n-hexane and 20% isopropanol in n-hexane) gave the desired product 2 (0.468 g, 54%).
¹ H NMR (500 MHz, CDCl _3, 25 ° C): δ = 7.71 (s, 1H, H-3), 5.84 (m, 4H, H-10), 5.28 to 5.08 (m, 8H, H-11), 4.86 (m, 1H, H-4), 4.74, 4.60 (s, 2H, H-1), 4.22 (m, 2H, H) 15), 4.05 (m, 4H, H-6), 4.00 (m, 2H, H-7), 3.94 (m, 4H, H-8), 3.87 (m, 4H, H-5), 3.82-3.30 (br m, 21H, H-16, H-14-H-12, H-9), 1.38, 1.32 (2 x s, 12H, H -19, H-18) ppm.
¹³ C-NMR (500 MHz, CDCl _3, 25 ° C): δ = 144.78 (C-2), 134.90, 134.51 (C-10), 122.75 (C-3), 116 , 98, 116.89 (C-11), 109.23 (C-17), 77.18, 76.70, 72.42, 71.56, 69.60 (C-16, C-14-C -12, C-9, C-8), 74.55 (C-15), 72.26 (C-9), 71.22 (C-6), 70.12 (C-5), 66, 67 (C-7, C-16), 63.85 (C-1), 60.40 (C-4), 26.72, 25.35 (C-19, C-18) ppm. ESI-TOF-MS: Calcd. for C ₃₉ H ₆₅ N ₃ O ₁₃ : (783.4517); found: 784.4553 [M + H] ⁺ , 806.4374 [M + Na] ⁺ , 822.4114 [M + K] ⁺ .

[G3.0] -propargyl-click- [G1.5] -azide (3): Reaction conditions and workup were as described above with [G3.0] -propargyl (1.0 g, 0.672 mmol, 1.0 equiv ), [G1.5] azide (0.314 g, 0.739 mmol, 1.1 equivalents), DIPEA (16.65 μl, 0.101 mmol, 0.15 equivalents), sodium ascorbate (39.9 mg, 0.202 mmol, 0, 3 equivalents) and cupric sulfate pentahydrate (25.2 mg, 0.101 mmol, 0.15 equiv.) In THF / H ₂ O (10 mL). Purification by column chromatography (ethyl acetate / n-hexane 8: 1 and 2% MeOH in CH ₂ Cl ₂ ) gave the desired product 3 (0.96 g, 75%).
¹ H-NMR (500 MHz, CDCl _3, 25 ° C): δ = 7.69 (s, 1H, H-3), 5.90 to 5.80 (m, 4H, H-10), 5, 26-5.10 (m, 8H, H-11), 4.84 (m, 1H, H-4), 4.74 (s, 2H, H-1), 4.25-4.16 (m , 8H, H-19), 4,12-3,97 (m, 12H, H-20, H-9), 3,95, 3,94 (m, 4H, H-9), 3,88, 3.86 (m, 4H, H-5), 3.75-3.40 (br m, 69H, H-20, H-18-H-12, H-8-H-6), 1.37 , 1.32 (2xS, 48H, H-23, H-22) ppm.
¹³ C-NMR (500 MHz, CDCl _3, 25 ° C): δ = 144.95 (C-2), 134.96, 134.55 (C-10), 122.69 (C-3), 116 , 93, 116.83 (C-11), 109.23 (C-21), 74.69, 74.54 (C-19), 70, 52, 70, 12, 69, 97 (C-5) , 78, 58, 78, 30, 72, 43, 72, 25, 71, 61, 71, 19, 69, 66 (C-18-C-12, C-9-C-6), 66, 86, 66.73 (C-20), 63.89 (C-1), 60.32 (C-4), 26.73, 25.36 (C-23, C-22) ppm. ESI-TOF-MS: calculated for C ₉₃ H ₁₆₁ N ₃ O ₃₇ : (1912.0809); found: 1936.0733 [M + H + Na] ⁺ , 1951.0452 [M + K] ⁺ , 979.5307 [M + H + Na] ²⁺ .

General procedure for the thiol coupling to the "click" compounds: The click compounds (2-4) were mixed with 4 equivalents of RfCH ₂ CH ₂ SH per allyl group. The solution was stirred under reduced pressure (3 mbar) to remove the oxygen from the solution. After heating to 80 ° C, a catalytic amount of AIBN (azobisisobutyronitrile) was added under argon atmosphere, and the reaction mixture was stirred for 2 hours. After further addition of the same amount of AIBN, the mixture was stirred for an additional 24 hours at 80 ° C and then the solvent was evaporated. Further purification was achieved by column chromatography.

Example 4.1

[G1.0] propargyl-click-[G1.5] azide-thiol (5):

Reaction conditions and work-up were as described above with 2 (0.46 g, 0.611 mmol, 1.0 equiv.), RfCH ₂ CH ₂ SH (4.70 g, 9.799 mmol, 16 equiv.) And a catalytic amount of AIBN. Purification by flash column (petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 1: 2) gave the desired product 5 (0.66 g, 40%).
¹ H-NMR (500 MHz, CDCl _3, 25 ° C): δ = 7.70, 7.67 (s, 1H, H-3), 4.86 (m, 1H, H-4), 4, 77, 4.63 (s, 2H, H-1), 4.24 (m, 2H, H-7), 4.02 (m, 2H, H-25), 3.88 (d, 4H, J = 4.63 Hz, H-5), 3.80 (m, 1H, H-22), 3.76-3.32 (br m, 28H, H-26, H-24, H-23, H -9, H-8, H-6), 2.70 (m, 8H, H-12), 2.61 (t, 8H, J = 6.94 Hz, H-11), 2.35 (m , 8H, H-13), 1.81 (m, 8H, H-10), 1.39, 1.33 (2 x s, 12H, H-29, H-28) ppm.
¹³ C-NMR (500 MHz, CDCl _3, 25 ° C): δ = 144.92 (C-2), 122.73 (C-3), 109.36 (C-27), 77.84 (C -22), 74.77, 74.63 (C-7), 70.25 (C-5), 66.71 (C-25), 64.91, 63.89 (C-1), 60, 53 (C-4), 31.99 (C-13), 29.60, 29.32 (C-10), 28.81, 22.46 (C-12, C-11), 26.70, 25,32 (C-29, C-28), 78,65, 77,86, 72,50, 71,50, 71,38, 70,64, 69,57, 68,42 (C-26, C -24, C-23, C-9-C-6), 122.00-107.00 (C-21-C-14) ppm.
¹⁹ F-NMR (400 MHz, CDCl _3, 25 ° C): δ = -114.41 (F-20) -121.79, -122.00 (F-17, F-19, F-18) , -122.82 (F-16), -123.39 (F-15), -126.24 (F-14) ppm. ESI-TOF-MS: calculated for C ₇₉ H ₈₅ F ₆₈ N ₃ O ₁₃ S _4: (2703.3879); Found: 2726.3645 [M + Na] ⁺ , 2742.3448 [M + K] ⁺ .

Example 4.2

[G2.0] propargyl-click-[G1.5] azide-thiol (6):

Reaction conditions and workup were as described above with 4 (0.5 g, 0.431 mmol, 1.0 equiv.); RfCH ₂ CH ₂ SH (3.31 g, 6.894 mmol, 16 equiv.) And a catalytic amount of AIBN. Purification by flash column (petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 4: 1) gave the desired product 6 (0.80 g, 69%).
¹ H-NMR (500 MHz, CDCl _3, 25 ° C): δ = 7.68 (s, 1H, H-3), 4.86 (m, 1H, H-4), 4.77 (s, 2H, H-1), 4.23 (m, 4H, H-28), 4.03 (m, 4H, H-27), 3.89, 3.88 (d, 4H, J = 5.6 Hz, H-5), 3.82-3.30 (br m, 45H, H-28, H-26-H-22, H-9-H-6), 2.72 (m, 8H, H -12), 2.62 (t, 8H, J = 7.2 Hz, H-11), 2.36 (m, 8H, H-13), 1.83 (m, 8H, H-10), 1.40, 1.34 (2xS, 24H, H-31, H-30) ppm.
¹³ C NMR (500 MHz, CDCl _3, 25 ° C): δ =
¹⁹ F-NMR (400 MHz, CDCl _3, 25 ° C): δ = -80.79 (F-21) -114.34 (F-20) -121.70, -121.93 (F- 19, F-18, F-17), -122.73 (F-16), -123.32 (F-15), -126.14 (F-14) ppm. ESI-TOF-MS: calculated for C ₉₇ H ₁₁₇ F ₆₈ N ₃ O ₂₇ S _4: (3079.3879); found: 3103.6002 [M + H + Na] ⁺ , 3081.6176 [M + 2H] ⁺ , 1552.3016 [M + 2H + Na] ^{2 +} , 1512.7896

Example 4.3

[G3.0] propargyl-click-[G1.5] azide-thiol (7):

Reaction conditions and work up were as described above with 3 (0.6 g, 0.313 mmol, 1.0 equiv.), RfCH ₂ CH ₂ SH (2.41 g, 5.017 mmol, 16 equiv.) And a catalytic amount of AIBN. Purification by flash column (petroleum ether (40-60 ° C) / CH ₂ Cl ₂ 7: 1 and ethyl acetate / n-hexane 10: 1) gave the desired product 7 (0.89 g, 74%).
¹ H-NMR (500 MHz, CDCl _3, 25 ° C): δ = 7.65 (s, 1H, H-3), 4.82 (m, 1H, H-4), 4.74 (s, 2H, H-1), (m, 2H, H-7), 4.21 (m, 8H, H-30) 4.01 (m, 8H, H-29), 3.88 (m, 4H, H-5), 3.75-3.34 (br m, 75 H, H-30, H-28-H-22, H-9, H-8, H-6), 2.70 (m, 8H, H-12), 2.60 (m, 8H, H-11), 2.34 (m, 8H, H-13), 1.82 (m, 8H, H-10), 1.38- 1.32 (2xS, 48H, H-32, H-33) ppm.
¹³ C-NMR (500 MHz, CDCl _3, 25 ° C): δ = 144.95 (C-2), 122.63 (C-3), 109.27 (C-31), 77.83 (C -22), 74.70, 74.55 (C-7), 70.01 (C-5), 66.73 (C-29), 63.87, 63.74 (C-1), 60, 28 (C-4), 31.90 (C-13), 29.60 (C-10), 28.79, 28.68 (C-12, C-11), 26.75, 25.33 ( C-33, C-32), 78.82, 78.58, 78.30, 77.20, 72.44, 71.43, 71.15, 70.71, 69.53, 68.40, 66 , 71 (C-30, C-28-C-23, C-9, C-8, C-6), 122.00-107.00 (C-21-C-14) ppm.
¹⁹ F-NMR (400 MHz, CDCl _3, 25 ° C): δ = -80.85 (F-21) -114.40 (F-20) -121.76, -121.98 (F- 19, F-18, F-17), -122.79 (F-16), -123.35 (F-15), -126.21 (F-14) ppm. QFT-ESI-MS: calculated for C ₁₃₃ H ₁₈₁ F ₆₈ N ₃ O ₃₇ S _4: 3832.0171; Found: 3834.0390 [M + 2H] ⁺ .

General procedure for the deprotection of the alcohol function: 1.0 equivalent of the acetal protected compounds (5-7) dissolved in a mixture of dichloromethane / methanol 1: (vol./vol.) 3 was Dowex ^® 50WX2-100 ion-exchange resin with the mixed and stirred for 12-24 h at room temperature. Thereafter, the Dowex ^® 50WX2-100 was removed by filtration, and the residue was concentrated under vacuum to give the desired compounds (8-10).

Example 4.4

[G1.0] -propargyl-CLICK [G1.5] azide-OH (8th):

Reaction conditions and workup were as described above with 5 (0.6 g, 0.222 mmol) in CH ₂ Cl ₂ / MeOH (30 mL). Evaporation of the solvent gave the desired product 8 (0.28 g, 0.1067 mmol, 48%).

Example 4.5

[G2.0] -propargyl-CLICK [G1.5] azide-OH (9):

Reaction conditions and workup were as described above with 6 (0.8 g, 0.259 mmol) in CH ₂ Cl ₂ / MeOH (30 mL). Evaporation of the solvent gave the desired product 9 (0.59 g, 0.2020 mmol, 78%).

Example 4.6

[G3.0] -propargyl-CLICK [G1.5] azide-OH (10):

Reaction conditions and workup were as described above with 7 (0.89 g, 0.232 mmol) in CH ₂ Cl ₂ / MeOH (30 mL). Evaporation of the solvent gave the desired product 10 (0.76 g, 0.2163 mmol, 93%).

Example 5

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) nach 24 h. Werte in Klammern nach 7 Tagen. [Amphiphil] = 1.0 g/L. ^b mg transportiertes Nilrot pro g Amphiphil. ^c mmol transportiertes Nilrot pro mol Amphiphil. ^d Zentrifugiert. Die Fehler der Messungen liegen jeweils im Bereich von 10%.

Tabelle 3 Ergebnisse der Farbstofftransportmessungen mit Nilrot bei 0.1 g/l Amphiphilkonzentration in Wasser.^a Amphiphil mg/g^b mmol/mol^c Bz-C11-[G2]-OH 47 14.9^d 41.7^d Bz-C18-[G2]-OH 45 68.9 214.3 Na-C11-[G2]-OH 48 23.5 69.5 Na-C18-[G2]-OH 50 39.5^d 128.9^d Bi-C11-[G2]-OH 49 114.8 349.1 Bi-C18-[G2]-OH 51 50.2 168.1

• ^a Filtration (PTFE, 0.45 μm, Rotilabo) nach 24 h. Werte in Klammern nach 7 Tagen. [Amphiphil] = 0.1 g/L. ^b mg transportiertes Nilrot pro g Amphiphil. ^c mmol transportiertes Nilrot pro mol Amphiphil. ^d Zentrifugiert. Die Fehler der Messungen liegen jeweils im Bereich von 10%.

b) Transportuntersuchungen der Amphiphile mit Aromaten in der Mitte der linear-dendritischen Struktur gemäß Beispiel 1 Tabelle 4 Ergebnisse der Farbstofftransportmessungen mit Nilrot (und Pyren) und 1 g/l der PG-Dendron-basierten Amphiphile ^a

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) nach 24 h. [Amphiphil] = 1.0 g/L. ^b mg transportiertes Nilrot pro g Amphiphil. ^c mmol transportiertes Nilrot pro mol Amphiphil. ^d Zentrifugiert.

Investigations of suitability as a nanotransporter / Determination of the transport capacity of selected linear dendritic polyglycerol compounds according to the invention according to Examples 1 and 2 on the basis of the dyes Nile Red and Pyrene and of the active ingredient nimodipine (the latter in comparison to PEG-based surfactants known per se) a) Transport studies of the amphiphiles with aromatics at the end of the hydrophobic residue according to Example 2. TABLE 2 Results of the dye transport measurements with Nile Red and 1 g / l of the PG-dendron-based amphiphiles ^a amphiphilic mg / g ^b mmol / mol ^c Bz-C11 [G2] -OH 47 11.4 32.0 Bz-C18 [G2] -OH 45 19.2 (74.8) 59.8 (232.4) Bz-C18 [G3] -OH 52 15.0 74.3 Na-C11 [G2] -OH 48 20.2 (100.2) 59.6 (296.7) Na C18 [G2] OH 50 17.9 ^d 58.5 ^d Na C18 [G3] OH 53 12.3 63.1 Bi-C11 [G2] -OH 49 18.9 (87.2) 57.6 (265.1) Bi-C18 [G2] -OH 51 17.4 (72.4) 58.4 (242.5) Bi-C18 [G3] -OH 54 12.6 65.5

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) after 24 h. Values in parentheses after 7 days. [Amphiphile] = 1.0 g / L. ^b mg transported Nile red per g amphiphile. ^c mmol transported Nile red per mole of amphiphile. ^d Centrifuged. The errors of the measurements are each in the range of 10%.

Table 3 Results of dye transport measurements with Nile red at 0.1 g / l amphiphile concentration in water. ^a amphiphilic mg / g ^b mmol / mol ^c Bz-C11 [G2] -OH 47 14.9 ^d 41.7 ^d Bz-C18 [G2] -OH 45 68.9 214.3 Na-C11 [G2] -OH 48 23.5 69.5 Na C18 [G2] OH 50 39.5 ^d 128.9 ^d Bi-C11 [G2] -OH 49 114.8 349.1 Bi-C18 [G2] -OH 51 50.2 168.1

• ^a Filtration (PTFE, 0.45 μm, Rotilabo) after 24 h. Values in parentheses after 7 days. [Amphiphile] = 0.1 g / L. ^b mg transported Nile red per g amphiphile. ^c mmol transported Nile red per mole of amphiphile. ^d Centrifuged. The errors of the measurements are each in the range of 10%.

b) Transport studies of amphiphiles with aromatics in the middle of the linear dendritic structure according to Example 1. TABLE 4 Results of dye transport measurements with Nile red (and pyrene) and 1 g / l of PG-dendron-based amphiphiles ^a

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) after 24 h. [Amphiphile] = 1.0 g / L. ^b mg transported Nile red per g amphiphile. ^c mmol transported Nile red per mole of amphiphile. ^d Centrifuged.

c) encapsulation and transport capacity of nimodipine with compounds according to example Second

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) nach 24 h. [Amphiphil] = 1.0 g/L. ^b mg transportiertes Nimodipin pro g Amphiphil. ^c mmol transportiertes Nimodipin pro mol Amphiphil.

Nimodipine is an active ingredient in the dihydropyridine class. It is used under the trade names Nimotop ^® and Periplum ^® as a calcium antagonist for the treatment of heart disease and nerve damage in the central and peripheral nervous system. Table 5 Results of drug delivery measurements with nimodipine ^a amphiphilic mg / g ^b mmol / mol ^c Bz-C11 [G2] -OH 47 4.9 10.4 Bz-C18 [G2] -OH 45 15.6 36.9 Bi-C11 [G2] -OH 49 10.0 23.1 Bi-C18 [G2] -OH 51 13.2 33.7

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) after 24 h. [Amphiphile] = 1.0 g / L. ^b mg transported nimodipine per g amphiphile. ^c mmol transported nimodipine per mole of amphiphile.

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) nach 24 h. [Amphiphil] = 1.0 g/L. ^b mg transportiertes Nimodipin pro g Amphiphil. ^c mmol transportiertes Nimodipin pro mol Amphiphil.

The errors of the measurements are each in the range of 10%. Table 6 Drug transport measurements with nimodipine of mPEG _x -based amphiphiles ^a amphiphilic CMC / uM mg / g ^b mmol / mol ^c Bz-C11-mPEG ₁₁₀₀ 34 - 5.6 19.5 Bz-C18-mPEG ₇₅₀ 37 8.3 9.1 26.2 Bi-C11-mPEG ₇₅₀ 36 8.9 9.8 27.8 Bi-C11-mPEG ₁₁₀₀ 41 - 10.0 36.6 Bi-C18-mPEG ₇₅₀ 39 62.0 11.2 34.6

• ^a Filtration (PTFE, 0.45 μM, Rotilabo) after 24 h. [Amphiphile] = 1.0 g / L. ^b mg transported nimodipine per g amphiphile. ^c mmol transported nimodipine per mole of amphiphile.

The Errors of the measurements are in the range of 10%.

In summary It should be noted that the encapsulation of Nile Red, Pyrene and Nimodin with the compounds of the invention showed that the new compounds have the desired transport properties have. All PG amphiphiles according to the invention spontaneously form micelles in water. The micelles have a low Size between 5 and 12 nm, preferably from 5.6 to 8.2 nm. Surprised leads the Incorporation of aromatics in the amphiphilic structures to significantly higher transport capacities of complexed guest molecules.

The advantages of the linear dendritic polyglycerol amphiphiles in comparison to the PEG amphiphiles also investigated here are their defined structure (monodispersed), the small size of the micelles formed, which ensure better tissue penetration and above all the outstanding water solubility in comparison with the known structures with PEG as a hydrophilic unit (eg., Pluronics ^®). In particular, all second generation polyglycerol amphiphiles (PG [G2.0]) are exceptionally soluble in water. Here presented PEG amphiphiles with mPEG750 (comparable molecular weight to PG [G2.0] are poor, amphiphiles with mPEG1100 only satisfactorily water-soluble.

Claims (25)

Linear dendritic polyglycerol compounds characterized by the general formulas (1), (2) or (3)

wherein PG represents a polyglycerol dendron generation 0 to 10 [G0-G10] of repeating glycerol units, wherein R ³ = H, -C (CH _{3) 2,} -CH _3, -SO ₃ Na, -PO ₃ Na, or - (CH) _I CO-ONa where I = 1-36, Y - (bond), or a polyglycerol-dendron [G0-G10] other than PG, of repeating glycerol units, the number n being the number Surface group (-ZR ¹ -ZR ² ) _n depends on the generation of the dendron, n 1-2048 Z is selected from: - (bond), -O-, -S-, -COO-, -OOC-, -NH- CO-, -CO-NH-, -SS-,

where, in the case of a plurality of radicals Z, these may be identical or different, X is a linker which in the case of several radicals X may be identical or different and is selected from -O-, -CH ₂ -O-, -S-, -CH ₂ -S-, -COO-, -OOC-, -CH ₂ OOC-, -NH-CO-, -NH-COO-, -OOC-NH-, -NH-CO-, -CH ₂ NH-CO-, -CO-NH-, -SS, -CH ₂ -SS-,

or a cleavable linker, R ¹ - (bond), a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms, an aryl and / or heteroaryl radical and / or a perfluoroalkyl or partially fluorinated alkyl radical (C 1 -C 16), and R ² corresponds to the meaning of R ¹ , wherein R ¹ and R ^{2 may be the} same or different from each other, but not both - or may only represent an aryl radical, with the proviso that compounds of formula (1) in which PG is a generation 0 or 1 polyglycerin dendron [G0-G1] where R ³ = H, X = -OOC, Z = - and R ¹ , R ² an alkyl chain (C1 to C72) are excluded. Polyglycerol compounds according to claim 1, characterized in that the polyglycerol-dendron PG is a PG from the 1. Generation is, preferably from the 2nd generation. Polyglycerol compounds according to one of claims 1 or 2, characterized in that the linker X is selected from -S-. Is -OOC-, -COO-, -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or a triazole radical

represents. Polyglycerol compounds according to any one of claims 1 to 3, characterized in that Z is selected from -, -S-S-, -S-, -COO, or -OOC- is. Polyglycerol compounds according to any one of claims 1 to 4, characterized in that R ¹ = -, aryl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms. Polyglycerol compounds according to any one of claims 1 to 5, characterized in that R ² = linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, aryl radical and / or partially fluorinated alkyl (C 1 -C 16). Polyglycerol compounds according to any one of claims 1 to 6, characterized in that R ¹ and / or R ² = comprise an aryl radical, preferably a phenyl, biphenyl or naphthyl radical. Polyglycerol compounds according to one of claims 1 to 7, characterized by the formula (1), in which PG = a PG-dendron starting from the 2nd generation, where R ³ = H, X = -OOC-NH-, -NH-COO- , -CO-NH-, -NH-CO- or

R ¹ = -, aryl and / or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, Z = -, -S-, -COO-, -OOC- and R ² = a linear, saturated and unsaturated alkyl chain with 1 to 36 C atoms, aryl and / or partially fluorinated C 1 to C 16 alkyl. Polyglycerolverbindungen according to one of claims 1 to 7 characterized by the formula (2) in which PG = PG dendron from the 1st generation (G1-G10), where R ³ = H, or -C (CH _{3) 2,} Y = a polyglycerol dendron differing from PG starting from the 0th generation (G0-G10) of repeating glycerol units, n in (-ZR ¹ -ZR ² ) _n, corresponding to the number of surface groups of the generated dendron, where n = 2-2048 X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 C atoms, Z = -, -S-, and R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, and / or a partially fluorinated alkyl radical C1-C16. Polyglycerol compounds according to claim 9, characterized in that

means. Polyglycerol compounds according to any one of claims 1 to 7, characterized by formula (3), wherein PG = PG-Dendron is from the 1st generation, wherein R ³ = H, Y = - (bond) or glycerol unit G0, where n = 1 or 2 X = -OOC-NH-, -NH-COO-, -CO-NH-, -NH-CO- or

R ¹ = - (bond) or a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms, vzw. C8 to C36 alkyl, Z = is selected from - (bond), -O-, -S-, -COO-, -OOC-, -NH-CO-, -CO-NH-

R ² = a linear, saturated and unsaturated alkyl chain having 1 to 36 carbon atoms and / or a C 1 -C 16 partially fluorinated alkyl. Polyglycerol compounds according to any one of claims 1 to 11, characterized in that R ¹ and / or R ² = include an aryl radical. Polyglycerol compounds according to any one of claims 1 to 12, characterized in that the aryl radical is a phenyl, biphenyl or naphthyl radical which connects directly to X or which is terminal in R ² . Polyglycerol compounds according to any one of claims 1 to 13, characterized in that they are perfectly branched and in aqueous solutions Aggregates, preferably micelles, form. Aggregates comprising polyglycerol compounds according to any one of claims 1 to 14, characterized in that they have a critical micelle concentration ≤ 10 ^-5 mol / l. Aggregates according to claim 15, characterized in that they are micelles having a diameter average of 5 to 12 nm. Aggregates according to one of Claims 14 to 16, characterized that these with radioactive-labeled signal substances from the group Derivatives or from the group of dyes loaded or bound. Aggregates according to one of Claims 14 to 17, characterized that this with a diagnostic or therapeutic agent possibly loaded or bound in combination with a signal substance. Process for the preparation of a compound of the general Formula (1), (2) or (3) according to a the claims 1 to 13, characterized in that using the click chemistry the destination connection via 1,3-dipolar cycloaddition of an alkyne and azide functionality, which optionally produced on the hydrophobic and hydrophilic building block, wins. A method according to claim 19, characterized in that the central coupling step of the two components of different polarity as Cu-catalyzed cycloaddition of alkyne and azide functionality in THF and / or a water / THF two-phase system with the addition of CuSO ₄ .5H ₂ O and ascorbic acid or its salts as catalysts and NaOH or DIEPA (diisopropylethylamine) takes place. Use of a polyglycerol compound according to one the claims 1 to 13 for the preparation of water-soluble and isolatable aggregates comprising at least one substance. Use of a polyglycerol compound according to claim 21 for the encapsulation and solubilization of hydrophobic substances. Use according to claim 21 or 22, characterized that the substance is an active ingredient, color and / or signaling material. Use of a polyglycerol compound according to one the claims 1 to 13 for the stabilization of emulsions, micro- and nanoemulsions as well as foams. Use of a polyglycerol compound according to one the claims 1 to 13 for the encapsulation of catalysts, for the formation of microreactors, for adsorption on solid surfaces.