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Synthesis 2013; 45(11): 1452-1461
DOI: 10.1055/s-0033-1338470
feature article
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized Adamantane Derivatives: (3 + 1)-Scaffolds for Applications in Medicinal and Material Chemistry

Carsten Fleck
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany   Fax: +49(40)42838-3477   Email: maison@chemie.uni-hamburg.de
,
Elisa Franzmann
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany   Fax: +49(40)42838-3477   Email: maison@chemie.uni-hamburg.de
,
Dorith Claes
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany   Fax: +49(40)42838-3477   Email: maison@chemie.uni-hamburg.de
,
Aljona Rickert
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany   Fax: +49(40)42838-3477   Email: maison@chemie.uni-hamburg.de
,
Wolfgang Maison*
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany   Fax: +49(40)42838-3477   Email: maison@chemie.uni-hamburg.de
› Author Affiliations
Further Information

Publication History

Received: 16 March 2013

Accepted after revision: 05 April 2013

Publication Date:
24 April 2013 (online)

 
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Abstract

Due to its rigid cage structure, adamantane has received considerable interest as a scaffold with a defined tetrahedral geometry. In this paper we describe orthogonally functionalized tetrasub­stituted adamantane derivatives. These compounds may be conjugated to other functional molecules by standard techniques such as amide formation or click chemistry and are thus useful (3 + 1) scaffolds for medicinal and material chemistry.


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Key words

adamantane - multivalency - dendrimers - C 3 symmetry - diamandoids

Biographical Sketches

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Carsten Fleck studied chemistry at the Justus-Liebig­-University Gießen where he obtained his M.Sc. degree in 2010. Subsequently, he moved to the University of Hamburg and joined the research group of Prof. Maison for his Ph.D. studies. He is interested in carbohydrate chemistry and the synthesis of adamantane-based carbohydrate mimics.

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Elisa Franzmann studied chemistry at the Justus-Liebig­-University Gießen and obtained her Diploma degree in 2009. Currently, she is a Ph.D. candidate supervised­ by Professor Wolfgang Maison. Her research interests are focused on biomimetic strategies for the functionalization of metal surfaces.

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Dorith Claes studied chemistry at the Justus-Liebig-University of Gießen and obtained her M.Sc. degree in 2010 under the guidance of Prof. Maison. She joined his group for her Ph.D. studies and moved from Gießen to the University of Hamburg. Her research interests are multivalent benzoboroxoles for carbohydrate recognition.

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Aljona Rickert studied chemistry at the Justus-Liebig­-University in Gießen. She obtained her M.Sc. degree in 2010 on a research project about synthetic multivalent ligands for cell recognition. Since 2010 she has worked on her Ph.D. under the guidance of Prof. Wolfgang Maison and Prof. Holger Zorn. Her research focuses on enzymatic allylic oxidations.

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Wolfgang Maison studied chemistry at the University of Oldenburg and obtained his Ph.D. degree in 2000 under the guidance of Prof. Jürgen Martens. He joined the group of Prof. Daniel S. Kemp at MIT for a one-year postdoc. From 2001–2006 he was a junior group leader at the University of Hamburg, before he accepted a W2-Professorship at the JLU-Giessen. Since 2011 he has been a full professor at the University of Hamburg. His research interests are linked to natural product syntheses and drug development.

Introduction

Adamantane was first isolated from crude oil in Czechoslovakia in 1933.[1] It is the lowest diamandoid followed by diamantane, triamantane etc. and has, like the others, unique chemical properties.[2] The first synthesis of adamantane was achieved by Prelog and Steinwerth in 1941.[3] [4] Schleyer published in 1957 a practical method to synthesize adamantane from tetrahydrodicyclopentadiene.[5]

Due to its rigid cage structure, the adamantyl scaffold is an interesting tetrahedral building block in many fields, such as catalysis,[6] [7] supramolecular chemistry,[8–10] material science,[11–14] and medicinal chemistry.[15] [16] Many bridgehead-substituted adamantane derivatives have been described because they are readily accessible by nucleophilic substitution or radical reactions.[17] [18] A number of mono- and disubstituted derivatives are commercially available and have been used frequently in medicinal chemistry as a bulky and lipophilic structural element in drugs. Tri- and tetrabridgehead functionalized derivatives are less common, because they are often more difficult to synthesize. Functionalization of adamantane at the bridgehead positions requires the activation of a tertiary C–H bond and does, therefore, often imply drastic reaction conditions.[19] This is particularly problematic with substituted adamantane derivatives, because the reactivity at each bridgehead position is strongly influenced by the substituents at the other bridgeheads. A good example is the bromination of adamantane 1 (Scheme [1]),[20] [21] [22] which is often the first step in the synthesis of more complex adamantane derivatives. The introduction of each additional bromine lowers the reactivity of the system for the next bromination significantly.[18] In consequence each bromine derivative 2–5 is easy to prepare selectively by a slightly modified protocol. However, the conditions required for the synthesis of tribromoadamantane 4 and tetrabromoadamantane 5 are quite harsh.

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Scheme 1 Mono-, di-, tri- and tetrabromoadamantanes 2–5 by selectively bromination of adamantane (1)

A particularly interesting feature of tetrasubstituted adamantanes is the ability to align rigidly four substituents in a tetrahedral arrangement. The adamantane core may thus be considered a large replacement for a sp3-carbon.

Tetrasubstituted adamantanes of general type 6 are (3 + 1) scaffolds for applications in medicinal and material chemistry. Known examples of these scaffolds include the amino acids 7–9.

Our group started in 2003 with the design of tetrahedral scaffolds based on the general structure 6 with three functional groups X in a tripodal arrangement and a fourth orthogonal functionality Y pointing in opposite direction (Scheme [2]).[13] [23] [24] [25] These scaffolds offer various fields of applications because threefold rotational symmetry plays a crucial role in various natural molecular recognition systems.[26–28] Among them are important cell surface receptors,[29–33] enzymes,[34] siderophores, and natural adhesives.[35] [36] For these applications a number of tripodal scaffolds are known such as 1,3,5-substituted cyclohexanes,[37] 1,3,5-substituted benzenes,[38] or cyclopeptides.[39] However, these scaffolds lack a fourth position for the conjugation of effector molecules, which is an essential component for many fields of application such as surface functionalization and imaging. Like a central sp3-carbon,[40] adamantane has three bridgehead positions for conjugation of ligands and one additional position for further conjugation (‘3 + 1 system’) of effectors, for example dyes,[41] polymers,[42] or other functional molecules.[15] We have described synthetic routes to three adamantyl-based (3 + 1) scaffolds 7,[43] 8,[43] and 9 [23] with orthogonal functionality and have reported their application in tumor imaging,[15] [41] targeted tumor therapy,[44] and material chemistry.[42] In this paper we extend this molecular toolbox and describe the synthesis of additional (3 + 1) scaffolds with different functionality and spacing.

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Scheme 2

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Results and Discussion

Variations at the Ligand-Conjugation Site

Scaffolds 7–9 are restricted to the conjugation of ligands either with a reactive amine functionality via amide formation or with an alcohol moiety via ester formation.

An example is depicted in Scheme [3] with the coupling of dopamine as a ligand to the scaffold Boc-8. The resulting triscatecholate 10 is a strong metal binder and may be used for the functionalization of metal surfaces. To increase the range of suitable ligands to be conjugated, we aimed for tetraamines like 12 that would be easily addressed by ligands bearing carboxylic acids or carbonyls.

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Scheme 3 Synthesis of triscatecholate 10 via EDC/HOBt coupling

A Curtis reaction of the known tricarboxylic acid Cbz-9 [42] with diphenylphosphoryl azide (DPPA)[45] gave the orthogonally protected tetraamine 11. Acidic deprotection gave the target amine 12 ready for conjugation of ligands (Scheme [4]). A similar trisamine 14 was prepared from tris(cyanoethyl)adamantane 13,[46] via diisobutylaluminum hydride reduction. The trisamine 14 was conjugated to 2,3-dihydroxybenzaldehyde and 3,4-dihydroxybenzaldehyde via imine formation. The resulting triscatecholates 15 and 16 precipitate from ethanol and are analogues of bacterial siderophores such as enterobactin (Scheme [5]).[25]

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Scheme 4 Synthesis of tetraamine 12 via Curtius degradation of tricarboxylic acid Cbz-9
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Scheme 5 Synthesis of trisamine 14 and triscatecholates 15 and 16

For many applications of our scaffolds it is interesting to vary the spacing of the tripodal conjugation site. Starting from scaffold Cbz-9, we have thus coupled mono Boc-protected ethylenediamine (Scheme [6]). Trifluoroacetic acid deprotection of the resulting trimeric coupling product gave the free trisamine 17. In a similar approach, tris(cyanoethyl)adamantane 13 was hydrolyzed to the corresponding tricarboxylic acid, which was then coupled to mono-Boc-protected 1,4-diaminobutane using standard peptide coupling conditions. The resulting product was deprotected with trifluoroacetic acid to give the trisamine 18. A similar protocol was used for the synthesis of trisalcohol 19, which was obtained by peptide coupling of the protected amino acid Cbz-9 with ethanolamine.

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Scheme 6 Preparation of spaced trisamines 17, 18, and trisalcohol 19

For the coupling of densely functionalized and/or polar ligands[47] it is often advantageous to use the Huisgen cycloaddition of alkynes and azides.[48] [49] Trisazides like 20 and 22 are thus interesting scaffolds for click conjugations of alkyne functionalized ligands. Trisazide 20 was prepared from the tricarboxylic acid Cbz-9 via borane reduction, mesylation of the resulting triol, and subsequent nucleophilic displacement with sodium azide (Scheme [7]). In addition, the amino acid functionalized derivative 22 was prepared from scaffold Boc-9 by peptide coupling with azidohomoalanine. Trisazide 22 is particularly interesting for the assembly of complex multivalent structures, because it has three orthogonal functionalities which might be addressed selectively.

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Scheme 7 Synthesis of trisazides 20 and 22

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Variations at the Effector-Conjugation Site

Conjugation of effector molecules like dyes to the sterically hindered bridgehead amines of adamantyl scaffolds such as 7 or 9 can be problematic if nonactivated or weakly activated carboxylic acids need to be coupled. Spaced amino groups or alternative functionalities in this position are therefore attractive. The bromo-substituted tricarboxylic acid 23 is an excellent precursor for the introduction of a functional group orthogonal to the three carboxylic acids, because the bridgehead bromine is easily substituted using radical chemistry (Scheme [8]). Treatment of 23 with acrylonitrile gave the cyanoethyl derivative 24, which was reduced to the spaced amine 27. Alternatively, bromide 23 was treated with methacrylate to give the methyl ester 26. Both, the methyl ester 26 and the cyanoethyl derivative 24 were also hydrolyzed to tetrakis(carboxyethyl)adamantane 25, which is an interesting tetrahedral building block for the synthesis of dendritic structures.

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Scheme 8 Bromide 23 as a versatile precursor for the synthesis of (3 + 1) scaffolds 24, 26, and 27 and the tetrahedral scaffold 25 via radical chemistry

Additional (3 + 1) scaffolds were available starting from amino acid 9 (Scheme [9]). Methyl ester 28 was prepared in 80% yield using thionyl chloride in methanol with catalytic amounts of N,N-dimethylformamide. This triester was coupled to propiolic acid with N,N′-dicyclohexylcarbodiimide to give the alkyne 29 ready for click conjugation of effector molecules with an azide moiety.

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Scheme 9 Synthesis of the alkyne-functionalized triester 29

Alternatively, the free amino acid 9 may be directly acylated with N-hydroxysuccinimide (NHS) benzylglutarate to give benzyl ester 31 (Scheme [10]). A spaced amino group in 33 was prepared by NHS ester coupling of Cbz-protected aminohexanoic acid 32.

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Scheme 10 Elongation of the effector conjugation site via NHS ester coupling to amino acid 33

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Conclusion

We described the synthesis of several new tri- and tetrafunctionalized adamantane derivatives. These compounds belong to a molecular toolbox for applications in medicinal and material chemistry.[50] Most derivatives described are (3 + 1) scaffolds with different orthogonal functionalities such as alcohols, amines, carboxylic acids, azides, or alkynes. They may thus easily be conjugated to other functional molecules by standard coupling techniques such as amide formation or copper catalyzed click reactions.


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The following compounds were prepared according to literature protocols: 7,[43] Boc-8,[43] 9,[23] Boc-9,[23] Cbz-9,[42] 13,[46] 14,[51] 21,[52] 23,[23] 30,[53] and 32.[54]

TLC was performed on silica gel aluminum sheets. Reagents used for developing plates were cerium-stain [phosphomolybdic acid (5.00 g), Ce(SO4)2·4 H2O (2.50 g), H2SO4 (25 mL, and H2O (225 mL)], KMnO4 soln (0.5% KMnO4–1 M aq NaOH), and detection by UV light was used when applicable. Flash column chromatography was performed on silica gel (60–200 μm). 1H NMR are referenced to residual non-deuterated solvent (CDCl3, δH = 7.26; DMSO-d 6, δH = 2.50; CD3OD, δH = 3.31). 13C NMR are referenced to the solvent signal (CDCl3, δC = 77.16; DMSO-d 6, δC = 39.52; CD3OD, δH = 49.0). NMR spectra were recorded on 200 (50), 400 (100), or 600 (150) MHz instruments. ESI MS were recorded on a TOF instrument operated in positive or negative mode. Samples were dissolved in MeCN–MeOH mixtures and directly injected via syringe. If indicated with as anhyd solvents, these were dried according to standard procedures prior to use.[55] [56]


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7-[3-(tert-Butoxycarbonylamino)propyl]-N,N′,N′′-tris[2-(3,4-dihydroxyphenyl)ethyl]adamantane-1,3,5-tricarboxamide (10)

Compound Boc-8 (0.10 g, 0.24 mmol) was dissolved in DMF (30 mL) and the soln was cooled to 0 °C (ice bath). Et3N (0.39 mL, 2.82 mmol) was added and the soln was stirred for 5 min. EDC·HCl (0.21 g, 1.06 mmol) and HOBt (0.14 g, 1.06 mmol) were added and the soln was stirred for 5 min. Dopamine hydrochloride (0.20 g, 1.06 mmol) was added and the soln was stirred for 72 h at r.t. The mixture was concentrated and dissolved in a mixture of EtOAc (30 mL) and 1 M HCl (5 mL); the soln was washed with sat. aq KHSO4 soln (3 ×). The organic layer was dried (Na2SO4), filtered, and concentrated. Evaporation of the solvent gave a colorless solid that was suspended in Et2O (100 mL) and stirred for 30 min in a water bath at 30 °C. The resulting slurry was filtered and the procedure was repeated (6 ×) to give 10 (99 mg, 0.12 mmol, 50%) as a colorless sticky solid.

IR (KBr): 3374, 2936, 1633, 1526, 1366, 1285, 1285, 1196–1046 cm–1.

1H NMR (400 MHz, MeOH-d 4): δ = 7.74–7.42 (m, 3 H), 6.67–6.65 (m, 3 H), 6.61 (s, 3 H), 6.50–6.48(m, 3 H), 3.31–3.29 (m, 6 H), 3.01–2.98 (m, 2 H), 2.64–2.59 (m, 6 H), 1.76–1.69 (m, 6 H), 1.40–1.35 (m, 17 H), 1.14–1.12 (m, 2 H).

13C NMR (100 MHz, MeOH-d 4): δ = 178.9, 146.2, 144.8, 132.0, 121.2, 117.1, 116.3, 80.0, 43.7, 43.4, 42.3, 40.7, 39.4, 35.8, 35.1, 28.8, 24.2, 12.8.

HRMS (ESI): m/z [M + Na]+ calcd for C45H58N4NaO11: 853.3994; found: 853.3992.


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7-(Benzyloxycarbonylamino)-N,N′,N′′-tris(tert-butoxycarbonyl)adamantane-1,3,5-triethanamine (11)

Compound Cbz-9 (0.31 g, 0.61 mmol) was dissolved in anhyd CH2Cl2 (5 mL). DPPA (0.60 mL, 2.38 mmol) and Et3N (0.60 mL, 4.32 mmol) were added and the soln was stirred at r.t. for 8 h. The mixture was concentrated; the resulting crude product was dissolved in t-BuOH (50 mL) and heated under reflux for 24 h (N2 atmosphere). The soln was concentrated, the residue was dissolved in CH2Cl2 (50 mL), and the soln washed with 2 M NaOH (3 × 20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting crude product was purified by flash chromatography (silica gel, EtOAc–MeOH, 10:1; Rf  = 0.69) to give 11 (0.25 g, 0.35 mmol, 58%) as a yellow oil.

IR (KBr): 3404, 2898–2841, 1644, 1544–1521, 1463, 1359, 1232, 1025, 738 cm–1.

1H NMR (400 MHz, CDCl3, broad signals due to carbamate rotational isomerism): δ = 7.21–7.12 (m, 5 H), 4.90 (s, 2 H), 3.04–2.92 (m, 6 H), 1.57–1.55 (m, 6 H), 1.45 (s, 18 H), 1.35–1.34 (m, 6 H), 1.16–1.14 (m, 6 H).

13C NMR (100 MHz, CDCl3, broad signals due to carbamate rotational isomerism): δ = 155.9, 154.3, 136.5, 129.6, 128.4, 127.9, 78.4, 65.8, 52.3, 45.5, 42.7, 35.6, 35.6, 34.0, 28.4.

MS (ESI): m/z [M + Na]+ calcd for C39H62N4NaO8: 737.4460; found: 737.4463.


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7-(Benzyloxycarbonylamino)adamantane-1,3,5-triethanamine (12)

A soln of 11 (0.25 g, 0.35 mmol) in CH2Cl2 (40 mL) and TFA (10 mL) was stirred at r.t. for 24 h. The mixture was concentrated in vacuo and the resulting oil was co-evaporated with CH2Cl2 (3 × 20 mL) to give 12 (0.14 g, 0.34 mmol, 99%) as a colorless oil.

IR (film): 2916, 1689, 1520–1365, 1248–1025, 798–720 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 7.92–7.70 (m, 6 H), 7.35–7.17 (m, 5 H), 4.92 (s, 2 H), 1.52–1.41 (m, 12 H), 1.21–1.13 (m, 6 H), 1.10–0.94 (m, 6 H).

13C-MR (100 MHz, DMSO-d 6): δ 154.1, 137.2, 128.3, 127.7, 64.6, 51.6, 44.7, 44.5, 34.2 34.0, 33.8.

HRMS (ESI): m/z [M + H]+ calcd for C24H39N4O2: 415.3068; found: 415.3060.


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N,N′,N′′-Tris(3,4-dihydroxybenzylidene)adamantane-1,3,5-tripropaneamine (15)

Compound 14 (50 mg, 0.16 mmol) was dissolved in anhyd EtOH (10 mL) and 3,4-dihydroxybenzaldehyde (76 mg, 0.49 mmol) dissolved in a small amount of EtOH was added and the soln was stirred for 24 h under N2 atmosphere. The precipitate was separated by centrifugation, washed with cold Et2O and a small amount of EtOH, and dried in vacuo to give 15 (104 mg, 0.16 mmol, 100%) as a sticky solid.

IR (KBr): 3410, 2901–2842, 1583, 1450, 1383, 1285, 1116, 816 cm–1.

1H NMR (400 MHz, MeOH-d 4): δ = 8.05–8.02 (m, 3 H), 7.16–7.14 (m, 3 H), 6.92.6.89 (m, 3 H), 6.72–6.69 (m, 3 H), 3.40–3.10 (br s, 6 H), 1.90 (s, 1 H), 1.50–1.48 (m, 6 H), 1.29–1.27 (m, 6 H), 1.08–1.05 (m, 12 H).

HRMS (ESI): m/z [M + H]+ calcd for C40H50N3O6: 668.3694; found: 668.3691.


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N,N′,N′′-Tris(2,3-dihydroxybenzylidene)adamantane-1,3,5-tripropaneamine (16)

Compound 14 (50 mg, 0.16 mmol) was dissolved in anhyd EtOH (10 mL) and 2,3-dihydroxybenzaldehyde (76 mg, 0.49 mmol) dissolved in a small amount of EtOH was added and the soln was stirred for 24 h under N2 atmosphere. The precipitate was separated by centrifugation and washed with cold Et2O and a small amount of EtOH. The solid was dried in vacuo to give 16 (103 mg, 0.16 mmol, 100%) as a sticky solid.

1H NMR (400 MHz, MeOH-d 4): δ = 8.47–8.44 (m, 3 H), 6.80–6.75 (m, 6 H), 6.59–6.50 (m, 3 H), 3.53–3.50 (m, 6 H), 1.91 (br s, 1 H), 1.57–1.50 (m, 6 H), 1.31–1.29 (m, 6 H), 1.13–1.10 (m, 12 H).

HRMS (ESI): m/z [M + H]+ calcd for C40H50N3O6: 668.3694; found: 668.3691.


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N,N′,N′′-tris(2-Aminoethyl)-7-(benzyloxycarbonylamino)adamantane-1,3,5-tripropanamide (17)

Compound Cbz-9 (0.21 g, 0.41 mmol) and 0.54 g (1.4 mmol) HATU were dissolved in anhyd DMF (5 mL). DIPEA (0.25 mL, 1.49 mmol) was added and the soln was stirred at 0 °C for 20 min. Boc-protected ethylenediamine (0.21 mL, 1.33 mmol) was added and the soln was stirred for 20 h at r.t. The mixture was concentrated and the residue was dissolved in EtOAc (50 mL). This soln was washed with sat. aq NaHCO3 (3 ×) and sat. aq KHSO4 (3 ×). The organic layer was dried (Na2SO4), filtered, and concentrated to give the Boc-protected trisamine (345 mg, 0.37 mmol, 91%) as a colorless solid.

1H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 5 H), 5.00 (s, 2 H), 3.33–3.32 (m, 6 H), 3.23 (s, 6 H), 2.11 (t, 3 J = 7.5 Hz, 6 H), 1.54–1.53 (m, 12 H), 1.43 (s, 27 H), 1.11 (d, 2 J = 12.2 Hz, 3 H), 1.04 (d, 2 J = 12.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.4, 157.0, 136.8, 128.7, 128.2, 128.1, 79.7, 66.1, 52.9, 45.3, 45.0, 40.6, 40.6, 38.2, 35.2, 30.3, 28.6.

HRMS (ESI): m/z [M + H]+ calcd for C48H78N7O11: 928.5754; found: 928.5759.

A soln of the Boc-protected trisamine (345 mg, 0.37 mmol) in CH2Cl2 (10 mL) and TFA (2.5 mL) was stirred at 0 °C for 2 h and allowed to warm to r.t. The mixture was concentrated in vacuo and the resulting oil was co-evaporated with CH2Cl2 (3 ×) and then with 1 M aq HCl to give 17 (0.25 g, 0.34 mmol, 95%) as the hydrochloride salt. Trisamine 17 should be used for functionalization without further purification and is unstable upon storage.

1H NMR (400 MHz, CDCl3): δ = 7.36–7.30 (m, 5 H), 5.01 (s, 2 H), 3.45 (t, 3 J = 6.3 Hz, 6 H), 3.08–3.04 (m, 6 H), 2.27–2.23 (m, 6 H), 1.59 (s, 6 H), 1.54–1.50 (m, 6 H), 1.21 (d, 2 J = 12.2 Hz, 3 H), 1.12 (d, 2 J = 12.2 Hz, 3 H).


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N,N′,N′′-Tris(4-aminobutyl)adamantane-1,3,5-tripropanamide (18)

A soln of 13 (7.00 g, 23.7 mmol), concd HCl (40 mL), and H2O (5 mL) was heated to reflux for 20 h. The resulting mixture was poured into ice-H2O; the product was filtered off, washed with cold H2O and crystallized (MeCN) to give the tricarboxylic acid (8.00 g, 22.7 mmol, 95%) as a colorless solid.

The tricarboxylic acid (0.30 g, 0.85 mmol) was dissolved in distilled DMF (60 mL). Et3N (1.52 mL, 11.0 mmol) was added and the soln was stirred at 0 °C for 5 min. EDC·HCl (63 mg, 2.81 mmol) and HOBt (0.38 g, 2.81 mmol) were added to the mixture, which was stirred for 15 min. Mono-Boc-protected 1,4-diaminobutane (0.53 g, 2.81 mmol) was then added and the soln was stirred for 72 h at r.t. The mixture was concentrated and the residue was dissolved in EtOAc. This soln was washed with sat. aq NaHCO3 (3 ×) and sat. aq NaHSO4 (3 ×). The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting crude product was purified by flash chromatography (silica gel, 10% MeOH–EtOAc) to give the Boc-protected trisamine (0.33 g, 0.39 mmol, 46%) as a colorless solid.

IR (KBr): 3425, 2918–2849, 2416, 1687, 1536, 1450, 1391–1381, 1271–1109 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.05–6.94 (m, 3 H), 5.27–5.19 (m, 3 H), 3.31–3.30 (m, 6 H), 3.20–2.17 (m, 6 H), 2.23–2.06 (m, 7 H), 1.64–1.52 (m, 12 H), 1.52–1.40 (m, 33 H), 1.40–1.30 (m, 6 H), 1.21–1.03 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 174.5, 156.6, 79.3, 46.6, 41.5, 40.5, 39.8, 39.5, 33.7, 30.6, 29.4, 28.2, 27.8, 27.1.

HRMS (ESI): m/z [M + Na]+ calcd for C46H82N6NaO3: 885.6035; found: 885.6045.

A soln of the Boc-protected trisamine (0.16 g, 0.19 mmol) in CH2Cl2 (40 mL) and TFA (15 mL) was stirred at r.t. for 24 h. The mixture was concentrated in vacuo and the resulting oil was co-evaporated with CH2Cl2 (3 ×) to give 18 (0.10 g, 0.18 mmol, 94%) as a colorless oil. Trisamine 18 should be used for functionalization without further purification and is unstable upon storage.

MS (ESI): m/z [M + H]+ calcd for C31H58N6O3: 563.4643; found: 563.4641.


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7-(Benzyloxycarbonylamino)-N,N′,N′′-tris(2-hydroxyethyl)adamantane-1,3,5-tripropanamide (19)

Compound Cbz-9 (0.10 g, 0.19 mmol) and HATU (0.274 g, 0.72 mmol) were dissolved in anhyd DMF (5 mL). DIPEA (0.1 mL, 0.6 mmol) was added and the soln was stirred at 0 °C for 20 min. Ethanolamine (0.045 mL, 0.72 mmol) was added and the soln was stirred for 20 h at r.t. The mixture was concentrated and the residue was dissolved in H2O. This soln was washed with CH2Cl2 (3 ×) and concentrated to give 19 (0.063 g, 0.10 mmol, 49%) as a colorless solid.

1H NMR (400 MHz, CDCl3): δ = 7.28–7.23 (m, 5 H), 4.96 (s, 2 H), 3.56 (t, 3 J = 5.3 Hz, 6 H), 3.30–3.24 (m, 6 H), 2.12 (m, 6 H), 1.48–1.39 (m, 12 H), 1.06–0.96 (m, 6 H).

MS (ESI): m/z [M + H]+ calcd for C33H50N4O8: 653.3521; found: 653.3520.


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3,5,7-Tris(3-azidopropyl)-N-(benzyloxycarbonyl)adamantan-1-amine (20)

Compound Cbz-9 (0.48 g, 0.96 mmol) was dissolved in anhyd THF and 1 M BH3 in THF (9.57 mL, 9.57 mmol) was slowly added. The soln was stirred at r.t. for 24 h. H2O (10 mL) and sat. aq NaHCO3 (10 mL) were added to the mixture. The solvent was removed in vacuo and the remaining solid was extracted with hot EtOH (3 × 50 mL). The combined extracts were concentrated to give the intermediate triol (0.50 g), which was used in the next step without further purification.

The crude triol was dissolved in anhyd CH2Cl2 (50 mL) and cooled to 0 °C. Freshly distilled Et3N (0.95 mL, 4.31 mmol) was added and the soln was stirred at r.t. for 15 min. MsCl (0.33 mL, 4.31 mmol) was added and the soln was stirred at r.t. for 20 h. MeOH (20 mL) was added to the mixture and the soln was concentrated. The resulting crude product was dissolved in CH2Cl2 (60 mL). The resulting soln was washed with H2O, sat. aq NaHCO3, and sat. aq NaHSO4, and dried (Na2SO4). The reaction soln was concentrated to give the intermediate mesylate, which was again used without further purification in the next step.

The crude mesylate was dissolved in anhyd DMF (40 mL), NaN3 (0.28 g, 4.31 mmol) was added and the soln was stirred at 60 °C for 26 h. The mixture was concentrated, the resulting crude product was dissolved in EtOAc (30 mL), washed with the same amount of H2O and sat. aq NaCl soln, dried (Na2SO4), filtered, and concentrated. The resulting crude product was purified by flash chromatography (silica gel, CH2Cl2–MeOH, 10:1) to give 20 (0.15 g, 0.27 mmol, 30% over 3 steps) as a yellowish oil.

IR (film): 3339, 2908–2844, 2096, 1725, 1507, 1453, 1351–1150, 1118, 1025, 737 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.30–7.21 (m, 5 H), 4.97 (s, 2 H), 4.62 (s, 1 H), 3.16 (t, 3 J = 8.6 Hz, 6 H), 1.51–1.45 (m, 12 H, 5–H), 1.12–0.95 (m, 12 H).

13C NMR (100 MHz, CDCl3): δ = 158.5, 136.4, 128.3, 127.9, 65.9, 52.6, 51.9, 45.5, 45.2, 39.8, 34.9, 22.3.

HRMS (ESI): m/z [M + Na]+ calcd for C27H38N10NaO: 557.3071; found: 557.3067.


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N,N′,N′′-Tris[(S)-3-azido-1-(benzyloxycarbonyl)propyl]-7-benzyloxycarbonylaminoadamantane-1,3,5-tripropanamide (22)

Boc-9 (90 mg, 0.19 mmol), HATU (469 mg, 1.20 mmol), and DIPEA­ (0.22 mL, 1.20 mmol) were dissolved in anhyd DMF (8 mL) at 0 °C. After 10 min azidoamine 21 (333 mg, 1.20 mmol) and DIPEA (0.22 mL, 1.20 mmol) in anhyd DMF (5 mL) were added. The reaction was warmed to r.t. and stirred for 69 h. The solvent was evaporated in vacuo and the crude product dissolved in EtOAc (20 mL). The organic layer was washed with 1 M aq HCl (3 × 10 mL) and sat. NaHCO3 (3 × 10 mL). The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated. The crude product was purified by column chromatography (silica gel, PE–EtOAc, 1:2; Rf  = 0.4) to give 22 (110 mg, 0.10 mmol, 52%) as a colorless oil.

1H NMR (400 MHz, CD3OD): δ = 7.27–7.42 (m, 15 H), 5.18 (d, 2 J = 12.3 Hz, 3 H), 5.13 (d, 2 J = 12.3 Hz, 3 H), 4.54 (d, 3 J = 5.1 Hz, 1.5 H), 4.52 (d, 3 J = 5.1 Hz, 1.5 H), 3.32–3.45 (m, 6 H), 2.15–2.30 (m, 6 H), 2.02–2.15 (m, 3 H), 1.85–1.97 (m, 3 H), 1.53 (s, 6 H), 1.44–1.51 (m, 6 H), 1.42 (s, 9 H), 1.13 (d, 2 J = 12.1 Hz, 3 H), 1.04 (d, 2 J = 12.1 Hz, 3 H).

13C NMR (100 MHz, CD3OD): δ = 177.0, 172.9, 137.1, 129.6, 129.4, 129.3, 79.3, 68.1, 53.4, 51.5, 49.0, 46.4, 46.0, 39.8, 36.1, 31.6, 30.1, 28.9.

HRMS (ESI): m/z [M + Na]+ calcd for C57H73N13NaO11: 1138.5445; found: 1138.5445.


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7-(2-Cyanoethyl)adamantane-1,3,5-tripropanoic Acid (24)

A soln of bromide 23 (0.315 g, 0.73 mmol), acrylonitrile (0.14 mL, 2.12 mmol), Bu3SnH (0.38 mL, 1.44 mmol), and AIBN (0.012 g, 0.07 mmol) in THF–toluene (1:1, 20 mL) was heated to reflux for 6 h. The resulting mixture was poured into 2 M NaOH (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was washed with EtOAc (2 ×). The aqueous phase was acidified with 4 M HCl and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated to give 24 (0.262 g, 0.65 mmol, 79%) as a yellowish solid; mp 216 °C.

IR (KBr): 2923, 2261, 1707, 1453, 1411, 1315, 1224, 1153 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 2.42 (t, 3 J = 7.9 Hz, 2 H), 2.14 (t, 3 J = 7.9 Hz, 6 H), 1.42 (t, 3 J = 7.7 Hz, 2 H), 1.35 (t, 3 J = 8.1 Hz, 6 H), 1.01 (d, 2 J = 9.5 Hz, 12 H).

13C NMR (100 MHz, DMSO-d 6): δ = 175.2, 121.7, 44.9, 44.5, 38.0, 37.8, 33.8, 33.5, 27.8, 10.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H30NO6: 405.2151; found: 405.2168.


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Adamantane-1,3,5,7-tetrapropanoic Acid (25)

Method A: A soln of 24 (0.073 g, 0.18 mmol), concd HCl (0.5 mL), and H2O (0.1 mL) was heated to reflux for 48 h. The solvent was evaporated to yield 25 (0.045 g, 0.11 mmol, 59%) as a colorless solid.

Method B: A soln of bromide 23 (0.10 g, 0.23 mmol), methyl acrylate (0.06 mL, 0.68 mmol), Bu3SnH (0.130 mL, 0.49 mmol), and AIBN (0.004 g, 0.02 mmol) in THF–toluene (1:1, 20 mL) was heated under reflux for 6 h. The resulting mixture was poured into aq 10% NaOH (50 mL) and EtOAc (50 mL). The phases were separated and the organic phase was extracted with 10% aq NaOH (2 ×). The aqueous phase was acidified with HCl and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated to give 25 (0.068 g, 0.16 mmol, 63%) as a yellowish solid; mp 229 °C.

IR (KBr): 2896, 2843, 1691, 1406, 1310, 1209, 1149 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 12.05 (s, 4 H), 2.14 (t, 3 J = 7.8 Hz, 8 H), 1.35 (t, 3 J = 7.6 Hz, 8 H), 0.99 (s, 12 H).

13C NMR (100 MHz, DMSO-d 6): δ = 175.1, 45.0, 37.8, 33.4, 27.8.

HRMS (ESI): m/z [M + Na]+ calcd for C22H32NNaO8: 447.1989; found: 447.1988.


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7-[2-(Methoxycarbonyl)ethyl]adamantane-1,3,5-tripropanoic Acid (26)

A soln of bromide 23 (0.10 g, 0.23 mmol), methyl acrylate (0.06 mL, 0.68 mmol), Bu3SnH (0.130 mL, 0.49 mmol), and AIBN (0.004 g, 0.02 mmol) in THF–toluene (1:1, 20 mL) was heated under reflux for 6 h. The resulting mixture was poured into sat. aq NaHCO3 (50 mL) and EtOAc ((50 mL). The phases were separated and the aqueous phase was washed with EtOAc (2 × 50 mL). The aqueous phase was acidified with HCl and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated to give 26 (0.099 g, 0.22 mmol, 88%) as a yellowish solid; mp 150 °C.

IR (KBr): 2962, 2846, 1709, 1453, 1261, 1058 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ = 11.99 (s, 3 H), 3.57 (s, 3 H), 2.24 (t, 3 J = 8.0 Hz, 2 H), 2.14 (t, 3 J = 7.7 Hz, 6 H), 1.37–1.33 (m, 6 H), 0.99 (s, 12 H), 0.87 (t, 3 J = 7.3 Hz, 2 H).

13C NMR (100 MHz, DMSO-d 6): δ = 175.2, 174.0, 51.3, 48.5, 45.0, 44.7, 37.8, 35.4, 33.5, 32.8, 27.8.

HRMS (ESI): m/z [M + Na]+ calcd for C23H34NNaO8: 461.2151; found: 461.2153.


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7-(3-Aminopropyl)adamantane-1,3,5-tripropanoic Acid Hydrochloride (27)

A soln of nitrile 24 (0.10 mg, 0.25 mmol) and PtO2 (0.011 mg, 0.05 mmol) in glacial AcOH–concd HCl (1:1, 14 mL) was hydrogenated (30 bar H2) for 6 d. The resulting mixture was filtered through celite and the solvent was evaporated in vacuo to give 27 (99 mg, 0.22 mmol, 80%) as a colorless oil.

1H NMR (400 MHz, DMSO-d 6): δ = 2.87 (s, 2 H), 1.87 (s, 2 H), 1.71 (br s, 8 H), 1.59–1.54 (m, 6 H), 1.35 (s, 12 H).

13C NMR (100 MHz, DMSO-d 6): δ = 175.2, 68.3, 45.5, 45.1, 37.9, 37.4, 33.7, 33.5, 28.0, 20.7.

HRMS (ESI): m/z [M + H]+ calcd for C22H36NO6: 410.2537; found: 410.2545.


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Trimethyl 7-Aminoadamantane-1,3,5-tripropanoate (28)

Compound 9 (0.75 g, 1.85 mmol) was dissolved in anhyd MeOH (75 mL) and cooled to 0 °C. SOCl2 (1.3 mL, 11.1 mmol) was added slowly. Additionally anhyd DMF (5 drops) was added to the mixture. The mixture was stirred for 24 h at r.t. After concentration in vacuo the residue was dissolved in aq NaHCO3 and extracted with EtOAc (3 × 50 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give 28 (0.48 g, 1.17 mmol, 64%) as a colorless solid.

1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 9 H), 2.22 (t, 3 J = 8.0 Hz, 6 H), 1.50 (t, 3 J = 8.0 Hz, 6 H), 1.19 (s, 6 H), 1.04 (d, 2 J = 12.0 Hz, 3 H), 1.01 (d, 2 J = 12.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.6, 51.7, 49.6, 49.1, 45.1, 37.5, 35.3, 28.2.

MS (ESI): m/z [M + H]+ calcd for C22H36NO6: 410.2537; found: 410.2538.


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Trimethyl 7-(Propynoylamino)adamantane-1,3,5-tripropanoate (29)

Compound 28 (0.69 g, 1.58 mmol) and propiolic acid were dissolved in anhyd CH2Cl2 and cooled to 0 °C. After 5 min, DCC (0.42 g, 2.03 mmol) was added and the soln was stirred at r.t. for 24 h. The formed dicyclohexylurea was filtered off and the filtrate was concentrated. The resulting crude product was purified by flash chromatography (silica gel) to give 29 (0.63 g, 1.50 mmol, 95%) as a yellow oil.

IR (film): 3259, 2919–2851, 2104, 1732, 1651, 1535, 1453–1437, 1353–1199, 1087–1018 cm–1.

1H NMR (400 MHz, CDCl3): δ = 5.96 (s, 1 H), 3.58 (s, 9 H), 2.69 (s, 1 H), 2.18 (t, 3 J = 8.2 Hz, 6 H), 1.56 (s, 6 H), 1.46 (t, 3 J = 8.2 Hz, 6 H), 1.08 (d, 2 J = 12.0 Hz, 3 H), 0.98 (d, 2 J = 12.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.3, 151.1, 78.1, 71.7, 54.9, 51.6, 44.8, 44.3, 37.3, 34.8, 27.9.

HRMS (ESI): m/z [M + Na]+ calcd for C25H35NNaO7: 484.2306; found: 484.2308.


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7-{(3-(Benzyloxycarbonyl)propanoyl]amino}adamantane-1,3,5-tripropanoic Acid (31)

Compound 9 (0.314 g, 0.78 mmol) was dissolved in anhyd DMSO (5 mL). Et3N (0.225 mL, 1.6 mmol) and 30 (0.29 g, 0.95 mmol) were added. The mixture was stirred for 72 h at r.t. The solvent was removed in vacuo and the residue was dissolved in sat. aq NaHCO3 (20 mL) The soln was washed with EtOAc (2 × 20 mL), acidified with HCl, and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give 31 (0.29 g, 0.50 mmol, 67%) as a yellowish solid.

1H NMR (400 MHz, CD3OD): δ = 7.40–7.32 (m, 5 H), 5.12 (s, 2 H), 2.62 (t, 3 J = 6.5 Hz, 2 H), 2.44 (t, 3 J = 6.6 Hz, 2 H), 2.25 (t, 3 J = 8.0 Hz, 6 H), 1.58 (s, 6 H), 1.52–1.48 (m, 6 H), 1.15 (d, 2 J = 12.1 Hz, 3 H), 1.09 (d, 2 J = 12.1 Hz, 3 H).

13C NMR (100 MHz, CD3OD): δ = 178.2, 174.2, 173.5, 137.6, 129.6, 129.2, 129.1, 67.4, 54.8, 46.2, 45.5, 39.0, 35.8 32.2 30.6, 29.1.

HRMS (ESI): m/z [M + H]+ calcd for C30H40NO9: 558.2698; found: 558.2689.


#

7-{(6-(Benzyloxycarbonylamino)hexanoyl]amino}adamantane-1,3,5-tripropanoic Acid (33)

Compound 9 (1.26 g, 3.12 mmol) was dissolved in DMSO (20 mL). Et3N (1.70 mL, 12.5 mmol) and 32 (1.70 g, 4.68 mmol) were added. The mixture was stirred for 12 h at r.t. and concentrated. The residue was dissolved in EtOAc (20 mL) and washed with sat. aq KHSO4. The organic layer was concentrated and the residue dissolved in 1 M NaOH (20 mL). After washing with EtOAc, the alkaline soln was acidified with HCl and extracted with EtOAc (3 × 50 mL). The combined extracts were dried (Na2SO4) and filtered and the solvent was removed in vacuo to give 33 (1.37 g, 2.22 mmol, 72%) as a yellowish solid.

1H NMR (400 MHz, CD3OD): δ = 7.34–7.29 (m, 5 H), 5.06 (s, 2 H), 3.11 (t, 3 J = 7.0 Hz, 2 H), 2.27 (m, 6 H), 2.10 (t, 3 J = 7.5 Hz, 2 H), 1.66–1.45 (m, 16 H), 1.38–1.28 (m, 2 H), 1.17 (d, 2 J = 12.2 Hz, 3 H), 1.11 (d, 2 J = 12.2 Hz, 3 H).

13C NMR (100 MHz, CD3OD): δ = 178.1, 175.6, 129.5, 128.9, 128.7, 67.3, 54.8, 46.3, 45.6, 41.6, 39.0, 37.8, 35.9, 30.6, 29.0, 27.3, 26.7, 26.3.

HRMS (ESI): m/z [M + H]+ calcd for C33H47N2O9: 615.3276; found: 615.3273.


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Acknowledgment

We gratefully acknowledge support from the Deutsche Forschungsgemeinschaft.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


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Scheme 1 Mono-, di-, tri- and tetrabromoadamantanes 2–5 by selectively bromination of adamantane (1)
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Scheme 2
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Scheme 3 Synthesis of triscatecholate 10 via EDC/HOBt coupling
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Scheme 4 Synthesis of tetraamine 12 via Curtius degradation of tricarboxylic acid Cbz-9
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Scheme 5 Synthesis of trisamine 14 and triscatecholates 15 and 16
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Scheme 6 Preparation of spaced trisamines 17, 18, and trisalcohol 19
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Scheme 7 Synthesis of trisazides 20 and 22
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Scheme 8 Bromide 23 as a versatile precursor for the synthesis of (3 + 1) scaffolds 24, 26, and 27 and the tetrahedral scaffold 25 via radical chemistry
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Scheme 9 Synthesis of the alkyne-functionalized triester 29
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Scheme 10 Elongation of the effector conjugation site via NHS ester coupling to amino acid 33