T-BUTYL CASCADE POLYMERS Technical Field
The present invention relates to the field of polymer chemistry and, more specifically with regard to the field of cascade or dendritic polymer chemistry. These polymers are based upon the application of mathematical progressions to organic synthesis and thereby possess well-defined molecular topologies.
BACKGROUND OF THE INVENTION
The field of cascade polymer chemistry is expanding the traditional synthetic limits into the meso-macro-molecular frontier. Such polymers possess well-defined molecular
topologies as they can be constructed in discrete layers rendering upon the molecule discrete, symmetric and consistent chemical
characteristics.
These polymeric structures provide specific micellar molecules.
The synthesis and spectral features of cascade polymers, also referred to as arborols possessing two-, three- and four-directional microenvironments /with functionalized polar outer
surfaces, have been recently reported(1-8).
Depending on their molecular shape, many of these macromolecules aggregate to form gels or show novel micellar characteristics in aqueous
solution (3,7,8). In view of an interest in generating a spherical hydrophilic surface with a compact lipophilic core, the present invention provides a cascade system which in one embodiment emanates from a central adamantane core. This core includes bridgehead positions which have suitable geometry to mimic a tetrahedral nucleus and can be envisioned as an extended methane core. Such a core is an ideal starting point toward four-directional cascade polymers.
In constructing such spherical polymers, several further problems were
uncovered. One such problem related to the generation of a tri-branched monomer which would not cyclize. More specifically, to provide tri-valent branching from a single branch of a polymer, at least two qualities are required. First, there must be directionality such that the monomer combines with the branch so as to expose three branch binding sites for further tiering of the macromolecule. The branches of the
macromolecule extending from a central core must
also extend sufficiently to be able to allow further reactions therewith for the additional tiering while not cyclizing onto themselves.
Cyclizing removes branches from being chemically reactive thereby causing a dead-end to the tiering process. For example, the following reaction sequence generated the polymeric product set forth below.
Attempted oxidation of compound 11 by a RuO2 procedure of Irngartinger, et al. (9)
resulted in limited success in that complete oxidation was not reproducible.
Applicant herein provides novel
monomers which are ideal in that they do not cyclize and further can be used in a cascade system for producing macromolecular monomers through tetradirectional polymers, particularly
on an adamantane, methane equivalent, or four-directional core.
Further, the present invention provides novel four-directional spherical dendritic macromolecules based on adamantane made in accordance with the novel method set forth herein.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is a method forming an amine monomer of the formula
by the steps of reacting nitromethane and
CH2=CHCO2-TBu by nucleophilic addition to form the triester nitrotrialkanoate of the formula
and reducing the nitrosubstituent to said amine monomer.
Further in accordance with the present invention the novel amine monomer can be used to create several novel one, two, three, or four- directional polymers based on the adamantane, or similar core.
DETAILED DESCRIPTION OF THE INVENTION
The present invention generally will provide a monomer of the formula
wherein R is selected from the group consisting essentially of NH2 and NO2. This novel compound is a building block for novel cascade polymers made in accordance with the inventive method set forth below. Products made in accordance with the present invention can be used in various fields, such as pharmaceutical chemistry, as micelles. However these compounds are used to make unimolecular micelles as opposed to multi-molecular micelles, previously known in the art.
These monomeric micelles generally have a core and branching which leads from the core. In accordance with the present invention, the branching can be tetra-directional extending from the four bridgehead positions of the core and can be tiered or layered such that a first layer of branching can be combined with the core and then subsequent layers can be added to provide a well-defined molecular topology.
More specifically, as discussed above, attempted oxidation of the arborol of the formula
by the RuO
2 procedure discussed above met with limited success in that complete oxidation was not reproducible. To circumvent this problem as well as to shorten the overall iterative
procedure, the novel building block di-tert-butyl 4-amino-[2-(tert-butoxvcarbonvlethyl]-heptanedioate was prepared by the following scheme.
A key factor was the bulky nature of the tert-butyl ester, so it was necessary to prevent lactam formation during reduction of the nitro functionality. That is, the following reaction did not occur under the condition conducted in accordance with the present invention.
An attempt to synthesize the nitro ester precursor by modification of the procedure reported by Bruson and Riener(10) using tert-butyl acrylate in place of the acrylonitrile resulted in a poor yield of about 5%. To
circumvent this sluggish nucleophilic addition, the reaction temperature was elevated during the initial addition phase and then maintained at about 70° to 80°C for one hour. This modification resulted in a 72% yield of the desired triester, which was confirmed by 13C NMR by the peaks for the quaternary and carbonyl carbons at 92.1 and 170.9 ppm, respectively. The 1H NMR spectrum showed a singlet at 1.45 ppm assigned to (CH3)3CO in a multiplet at 2.21 ppm for the methylene protons. Analysis of the crystal structure ultimately confirmed the analysis.
The prior art discusses diverse
reduction conditions for the conversion of nitroalkanols to aminoalkanols(II). The use of
platinum, palladium, or Raney nickel catalyst all resulted in very poor yields and gave mostly recovered nitrotrialkanoate compound. However, a reduction with specially generated T-1 Raney nickel by the process of Domingues, et al. (12) at elevated temperatures (ca. 60°C) gave an 88% yield of the aminoester after purification.
Successful reduction was confirmed by 13C NMR by an upfield shift for the quaternary carbon at 52.2 ppm. The 1H NMR spectrum of the
aminotrialkanoate showed a singlet at 1.44 ppm for the tert-butyl group, multiplets at 1.68 arid 2.26 ppm for the methylene protons and a broad singlet at 5.49 ppm for the amino moiety.
Since related alkyl esters of the aminotrialkanoate could not be prepared because of facile intramolecular lactam formation during the hydrogenation of the nitro moiety, the tert-butyl ester is ideal in that no cyclization was observed. The advantages of the tert-butyl ester are: a) reduced number of overall steps for cascade synthesis; b) easy preparation on a large scale; c) facile hydrolysis to the desired acids in nearly quantitative yield; and d) the poly tert-butyl esters were easily purifiable solids.
An example of the use of the tert-butyl ester in a cascade synthesis is as follows.
Treatment of adamantanecarbonyl chloride with the aminotrialkanoate as set forth above furnished 71% yield of the desired triester (amine monomer) of the formula
This structure was confirmed by 13C NMR by the peaks at 172.8 (ester), 177.4 (CONH), and 56.7 ppm (side-quaternary carbon). Hydrolysis of the ester to a triacid was accomplished with about 100% yield by treatment with formic acid. It was identical in all respects to a sample prepared by the above procedure. Application of peptide coupling procedures known in the art of the acid with the aminotrialkanoate in the presence of DCC and 1-hydroxybenzotriazole in dry dimethyl formamide (DMF) afforded a 61% yield of a
nonaester(13). The following scheme summarizes the reaction sequence
The presence of the structure was confirmed by 13C NMR showing two carbonyl peaks at 172.6 (ester) and 177.0 ppm (CONH) as well as the peaks for the side-chain quaternary carbons at 57.6 and 57.0 ppm thereby confirming the
transformation. The specific assignment of internal and external methylene signals was based on the intensity ratios as well as the fine shape, the internal methylenes being broader.
The final acid was obtained in a 95% yield by the treatment of the ester with formic acid. The absence of the tert-butyl groups in the NMR
spectra and the shift for the carbonyl, 172.6 ppm (ester) to 177.6 ppm (acid) supports the
conclusion that hydrolysis occurred. Experimental Section
General Comments. Melting point data were obtained in capillary tubes with a Gallenkamp melting point apparatus and are uncorrected. 1H and 13C NMR spectra were obtained in CHCl3, except where noted, with Me4Si as the internal standard (5 = 0 ppm), and recorded at either 80 or 360 MHz. Infrared spectral data were obtained on an IBM IR-38 spectrometer. Elemental analyses were performed by MicAnal Laboratories in Tucson, Arizona.
Di-tert-butyl 4-Nitro-4-[2-(tert-butoxycarbonyl)ethyl]heptanedioate. A stirred solution of MeNO2 (6.1 g, 100 mmol), Triton B (benzyltrimethylammonium hydroxide, 40% in MeOH; 1.0 mL) in dimethoxyethane (DME; 20 mL) was heated to 65° to 70°C. tert-Butyl aerylate (39.7 g, 310 mmol) was added portion wise to maintain the temperature at 70° to 80°C. Additional Triton B (2×1 mL) was added when the temperature started to decrease; when the addition was completed, the mixture was maintained at 70° to 75°C for one
hour. After concentration in vacuo, the residue was dissolved in CHCl3 (200 mL), washed with 10% aqueous HCl (50 mL) and brine (3×50 mL), and dried (MgSO4). Removal of solvent in vacuo gave a pale yellow solid, which was crystallized (95% EtOH) to afford a 72% yield of the triester, as white microcrystals: 33 g; mp 98-100°C; 1H NMR δ 1.45 (s, CH3, 27 H), 2.21 (m, CH2, 12 H); 13C NMR δ 27.9 (CH3), 29.7 (CH2CO), 30.2 (CCH2), 80.9 (CCH3), 92.1 (O2NC), 170.9 (CO); IR (KBr) 1542
(NO2), 1740 (CO) cm-1. Anal. Calcd for C22H39O8N: C, 59.35; H; 8.76; N, 3.14. Found: C, 59.27; H, 9.00; N, 3.14.
Di-tert-butyl 4-Amino-4-[2-(tert-butoxycarbonyl)ethyl]heptanedioate. A solution of the above synthesized nitro triester (4.46 g, 10 mmol) in absolute EtOH (100 mL) with T-1 Raney Ni12 (4.0 g) was hydrogenated at 50 psi and 60°C for 24 hours. The catalyst was cautiously filtered through Celite. The solvent was removed in vacuo, affording a viscous liquid, which was column chromatographed (SiO2), eluting with EtOAc to give a 88% yield of the amino triester as a white crystalline solid: 3.7 g; mp 51-52°C; 1H NMR δ 1.44 (s, CH3, 27 H), 1.78 (m, CH2, 12 H); 13C
NMR δ 27.8 (CH3), 29.8 (CH2CO), 34.2 (CCH2), 52.2
(H2NC), 80.0 (CCH3), 172.8 (CO); IR (KBr) 1745 (CO) cm-1. Anal. Calcd for C22H41O6N: C, 63.58; H, 9.95; N, 3.37. Found: C, 63.72; H, 10.05; N, 3.38.
1-[[N-[3-(tert-Butoxycarbonyl)-1,1-bis[2-tert-butoxycarbonyl)ethyl]propyl]amino]carbonyl]adamantane. A solution of 1-adamantanecarbonyl chloride (1 g, 5 mmol), amine monomer (2.1 g, 5 mmol), and Et3N (600 mg, 6 mmol) in dry benzene (25 mL) was stirred at 25°C for 20 hours. The mixture was washed
sequentially with aqueous NaHCO3 (10%), water, cold aqueous HCl (10%), and brine. The organic layer was dried (Na2SO4) and then concentrated in vacuo to give a residue which was chromatographed (SiO2), eluting first with CH2Cl2 to remove some by-products and then with EtOAc to give a 71% yield of the ester as a white solid: 2 g; mp 84-86°C; 1H NMR δ 1.46 (s, CH3, 27 H), 1.68-2.1 (m, CH, CH2 , 27 H), 4.98 (bs, NH, 1 H); 13C NMR δ 28.0 (CH3), 28.2 (γ-CH), 29.8, 30.1 (NHCCH2CH2CO), 36.4 (5-CH2), 39.2 (β-CH2), 41.2 (α-C), 56.7 (NHC), 80.5 (CCH3), 172.8 (COO), 177.4 (CONH); IR (KBr) 3350, 2934, 2846, 1740, 1638, 1255, 1038 cm-1, Anal. Calcd for C33H55O7N: C, 68.58; H, 9.60; N, 2.43. Found: C, 68.36; H, 9.66; N, 2.36.
1-[{N-[3-[[N-[3-(tert-Butoxycarbonyl)-1,1-bis[2-(tert-butoxycarbonyl)ethyl]propyl]-amino]carbonyl]-1,1-bis[2-[IN-[3-(tert-butoxycarbonyl)-1,1-bis[2-(tert-butoxycarbonyl)-ethyl]propyl]amino]carbonyl]ethyl]propyl]amino]carbonyl]adamantane. A mixture of the triacid 1-[[N-[3-carboxy-1,1-bis(2-carboxyethyl)propyl]-amino]carbonyl]adamantane (400 mg, 1 mmol) amine monomer (1.45 g, 3.5 mmol), DCC (620 mg, 3 mmol), and 1-hydroxybenzotriazole (400 mg, 3 mmol) in dry DMF (15 mL) was stirred at 25°C for 48 hours. After filtration of the dicyclohexylurea, the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and sequentially washed with cold aqueous HCl (10%), water, aqueous NaHCO3 (10%), and brine. The organic phase was dried (Na2SO4). Removal of solvent in vacuo gave a thick viscous residue, which was flash chromatographed (SiO2) eluting first with EtOAc/CH2Cl2 (1:1) then with 5% MeOH in EtOAc, furnished A 61% yield of the ester, as a white solid: 970 mg; mp 115-118°C; 1H NMR δ 1.42 (s, CH3, 81 H), 1.64-2.20 (m, CH, CH2 , 63 H), 5.88 (bs, NH, 4 H) 13C NMR δ 27.9 (CH3), 28.4 (γ-CH), 29.6, 30.0 (NHCCH2CH2COO), 31.6, 32.2
(NHCCH2CH2CONH), 36.6 (γ-CH2), 39.2 (β-CH2), 41.1
(α-C), 57.0 (NHCCH2CH2COO), 57.6 (NHCCH2CH2CONH), 80.3 (CCH3), 172.6 (COO), 177.0 (CONH); IR (KBr) 3348, 2936, 2850, 1740, 1665, 1260, 1040 cm-1.
Anal. Calcd for C87H148O22N4: C, 65.22; H, 9.31; N, 3.50. Found: C, 65.41; H, 9.30; N, 3.39.
1-[[N-[3-[[N-[3-Carboxy-1,1-bis(2-carboxyethyl)propyl]amino]carbonyl]-1,1-bis[2-[[N-[3-carboxy-1,1-bis(2-carboxyethyl)propyl]-amino]carbonyl]ethyl]propyl]amino]carbonyl]-adamantane. A solution of the above tert-butyl ester (800 mg, 500 μmol) in formic acid (96%, 5 mL) was stirred at 25°C for 12 hours. The
solvent was removed in vacuo to give a residue; toluene (5 mL) was added and the solution was again evaporated in vacuo to azeotropically remove residual traces of formic acid. The resulting white solid was extracted with warm acetone (5×50 mL). The combined extract was filtered (SiO2), eluting with acetone. The residue obtained after concentration was
dissolved in aqueous NaOH (10%) and acidified with concentrated HCl to give a 95% yield of the acid as a white solid: 520 mg, mp 346°C dec; 1H NMR (Me2SO-d6) δ 1.82-2.40 (m, CH, CH2 , 63 H), 4.45 (bs, OH, 9 H, exchanged with D2O), 6.28 (bs, NH, 4 H); 13C NMR (Me2SO-d6) δ 29.6 (γ-CH), 30.2
(NHCCH2CH2COOH), 31.0, 32.4 (NHCCH2CH2CONH), 37.8 (δ-CH2), 40.1 (β-CH2), 42.5 (α-C), 58.0
(NHCCH2CH2CONH), 58.4 (NHCCH2CH2COOH), 177.6 (COOH), 179.8 (CONH); IR (KBr) 3360, 3340-2600, 2900, 1744, 1690, 1245, 1090 cm-1. Anal. Calcd for C51H76O22N4: C, 55.83; H, 6.98; N, 5.11.
Found: C, 55.71; H, 7.04; N, 4.98.
The monomers of the present invention can be used for the design and synthesis of novel dendritic polymers which are one, two, three, or four-directional. In accordance with the present invention, the monomers can be used to synthesize four-directional spherical dendritic
macromolecules based on adamantane. The use of the aminotrialkanoate monomer offers several advantages. The t-butyl ester intermediates are easily purified solids. Further, only two steps are required to progress from generation to generation.
A specific example of a synthesis is as follows. An acid chloride of the following formula
is treated with the aminotrialkanoatee present invention to afford a dodecaester of the
following formula
wherein R=t-Bu.
The dodecaester was hydrolyzed in good yield with 96% formic acid to yield the
corresponding dodecaacid.
Addition of further tiers was easily obtained by the coupling of the dodecaacid and further layers of the aminotrialkanoate with DCC an 1-HBT to afford the ester wherein R=TBu. Upon hydrolysis, the ester quantitatively generated the corresponding next tiered polyacid.
A specific example of the method of forming the above-mentioned acid moiety is as follows.
1,3,5,7-Tetrakis{[N-[3-(tert-butoxycarbonyl)-1,1-bis[2-(tert-
butoxycarbonyl)ethyl]propyl]amino]carbonyl}-adamantane. A mixture of adamantanetetra-carboxylic acid (78 mg, 250 μmol) and freshly distilled SOCl2 (2 mL) was refluxed for 4 hours. Excess of S0Cl2 was removed in vacuo. benzene (5 mL) was added, and the solution was concentrated in vacuo to yield the corresponding tetraacyl chloride, as a white solid.
Crude 1,3,5,7-Tetrakis (chlorocarbonyl) adamantane, amine monomer (450 mg, 1.1 mmol), and Et3N (110 mg, 1.1 mmol) in dry benzene (10 mL) were stirred at 25°C for 20 hours. Additional benzene (40 mL) was added, and the mixture was sequentially washed with aqueous NaHCO3 (10%), water, cold aqueous HCl (10%), and brine. The organic phase was dried (Na2SO4) and then
concentrated in vacuo to furnish a viscous oil, which was chromatographed (SiO2), eluting with 5% MeOH in EtOAc to generate a 61% yield of the dodecaester, as a white solid: 290 mg; mp 105- 107°C; 1H NMR δ 1.40 (s, CH3, 108 H), 172 (s, CH2, 12 H), 2.24 (m, CH2, 48 H), 5.88 (bs, NH 4 H); 13C NMR δ 28.1 (CH3), 30.0, 30.4 (CCH2CH2COO), 39.0 (β-CH2), 42.8 (α-C), 57.1 (HNC), 80.2 (CCH3), 173.1 (COO), 177.6 (CONH); IR (KBr) 3348, 2930, 2845, 1740, 1645, 1260, 1038 cm-1. Anal. Calcd
for C102H172O28N4: C, 64.38; H, 9.12; N, 2.95.
Found: C, 64.52; H, 8.91; N, 2.86.
1,3,5,7-Tetrakis{[N-[3-carboxy-1,1-bis(2-carboxyethyl)propyl]amino]carbonyl}-adamantane. A solution of the dodecaester (190 mg, 100 μmol) in formic acid (96%, 2 mL) was stirred at 25°C for 20 hours. Excess solvent was removed in vacuo. and toluene (3×2 mL) was added. The solvents were removed in vacuo to give a 94% yield of the dodecaacid, as a white solid: 115 mg; mp 282-284°C dec; 1H NMR (D2O) -5 1.84 (s, CH2, 12H), 2.34 (m, CH2, 48H); 13C NMR (D2O) δ 30.1 (CCH2CH2COOH), 38.8 (β-CH2), 42.7 (α-C), 58.6 (HNC), 177.8 (COOH), 180.4 (CONH); (KBr) 3360, 3330-2600, 2903, 1745, 1690, 1245, 1090 cm-1.
Anal. Calcd for C54H76O28N4: C, 52.75; H, 6.23; N, 4.56. Found: C, 52.59; H, 6.22; N, 4.51.
1,3,5,7-Tetrakis{[N-[3-[[N-[3-(tert-butoxycarbonyl)-1,1-bis[2-(tert-butoxycarbonyl)-ethyl]propyl]amino]carbonyl]-1,1-bis[2-[[N-[3- (tert-butoxycarbonyl)-l,1-bis[2-(tert-butoxycarbonyl)ethyl]propyl]amino]carbonyl]-ethyl]propyl]amino]carbonyl}adamantane. A mixture of the dodecaacid (74 mg, 60 μmol), the amine monomer (330 mg, 790 μmol), dicyclohexyl-carbodiimide (DCC; 150 mg, 720 μmol), and 1-
hydroxybenzotriazole (100 mg, 740 μmol) in dry DMF (3 mL) was stirred at 25°C for 48 hours.
After filtration of dicyclohexylurea, the solvent was removed in vacuo to give a residue, which was dissolved in EtOAc (25 mL) and was sequentially washed with cold aqueous HCl (10%), water, aqueous NaHCO3 (10%), and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo, and the residue was chromatographed
(SiO2), eluting first with EtOAc/CH2Cl2 (1:1) to remove some impurities and then with 5% MeOH in EtOAc to furnish a 58% yield of the ester, as a white solid: 200 mg; mp 138°C; 1H NMR δ 1.40 (s, CH3); 13C NMR -5 28.1 (CH3), 30.0 (CCH2CH2CONH), 29.8, 30.2 (CCH2CH2COO), 38.9 (β-CH2), 42.4 (α-C), 57.2 (CCH2CH2COO), 57.6 (CCH2CH2CONH), 80.0
(CCH3), 172.8 (COO), 177.8 (CONH); IR (KBr) 3350, 2938, 2846, 1740, 1680, 1260, 1045 cm-1. Anal. Calcd for C318H544O88N16: C, 63.64; H, 9.14; N, 3.74. Found: C, 63.28; H, 8.96; N, 3.77.
1,3,5,7-Tetrakis{[N-[3-[[N-[3-carboxy-1,1-bis(2-carboxyethyl)propyl]amino]carbonyl]-1,1-bis[2-[IN-[3-carboxy-1,1-bis(2-carboxyethyl)-propyl]amino]carbonyl]ethyl]propyl]amino]-carbonyl}adamantane. A solution of the ester
(150 mg, 25 μmol) in formic acid (96%, 2 mL) was
stirred at 25°C for 20 hours. Workup and
purification, similar to that of the dodecaacid, gave (95%) the corresponding acid, as a very hygroscopic solid: mp 350-354°C dec; 1H NMR (D2O) δ 1.80 (S, CH2, 12 H), 2.18-2.41 (m, CH2, 192 H); 13C NMR (D2O) δ 30.2 (CCH2CH2COOH), 30.8, 31.6 (CCH2CH2CONH), 39.1 (β-CH2), 42.8 (α-C), 58.1 (CCH2CH2CONH), 58.5 (CCH2CH2COOH), 178.0 (COOH), 180.2 (CONH); IR (KBr) 3360, 3340-2600, 2920, 1745, 1685, 1240, 1060 cm-1.
The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of
description rather than of limitation.
Obviously many modifications and variations of the present invention are possible in light of the above teachings. It is,
therefore, to be understood that within the scope of the appended claims the invention may be practiced otherwise than as specifically
described.