Unimolecular micelles and method of making the same

In accordance with the present invention there is provided a method of making a cascade polymer including the steps of alkylating the branches of a multi-branch core alkyne building block including multiple ether side chains and simultaneously reducing the alkyne triple bonds and deprotecting to form a multi-hydroxyl terminated, multi-branched all alkyl polymer. The inventive method results in the formation of a unimolecular micelle consisting essentially of alkyl carbon.

TECHNICAL FIELD 
The present invention relates to highly branched molecules possessing a 
predetermined three dimensional morphology. More specifically, the present 
invention relates to micelles having uses in areas such as detergents, 
radioimaging, binding sites for drug delivery, polyfunctional bases and 
other areas of use. 
BACKGROUND ART 
The synthesis of high molecular weight, highly branched, multifunctional 
molecules possessing a predetermined three dimensional morphology has been 
the focus of a growing number of research groups throughout the world. (1) 
Synthetic strategies employed for the realization of such cascade polymers 
require consideration of diverse factors including the content of the 
initial core, building blocks (or repeat units), spacer molecules, 
branching numbers, dense packing limits, and desired porosity as well as 
other factors. The selection of an appropriate building block(s) is 
governed by the type branching desired, such as carbon versus heteroatom 
branching, as well as the technology used to attach each successive layer 
or tier of the cascade polymer. At this time, building block synthons have 
relied predominantly on heteroatom chemistry for either a center of 
branching or for attachment of individual building blocks. 
Applicants have participated in the design and application of cascade 
polymers (2). Through applicants, research, high molecular weight 
molecules were synthesized containing quaternary carbon branching points 
and a maximum number of terminal functional groups with a focus on the 
formation of the amide bond. Applicants developed a multiplicative 
approach utilizing two building blocks, a trialkyl methanetricarboxylate 
(3) and tris(hydroxymethyl)aminomethane (Tris). From this basic work, 
applicants have derived a novel method for making the first example of an 
all alkyl carbon unimolecular micelle. 
SUMMARY OF THE INVENTION 
In accordance with the present invention there is provided a method of 
making a cascade polymer including the steps of alkylating the branches of 
a multi-branch core alkyl compound with a terminal alkyne building block 
including multiple ethereal side chains and simultaneously reducing the 
alkyne triple bonds and deprotecting to form a multihydroxyl terminated, 
multi-branched all alkyl polymer. 
The present invention further provides a unimolecular micelle consisting 
essentially of alkyl carbon possessing terminal functionality.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides a method of making a cascade polymer which 
generally includes the steps of alkylating the branches of a 
multi-branched core alkyl compound with a terminal alkyne building block 
including multiple ether side chains and then simultaneously reducing the 
alkyne triple bonds and deprotecting to form a multihydroxyl terminated, 
multi-branched all alkyl polymer. This all alkyl polymer can be further 
modified by repetition of the alkylating, reducing and deprotecting steps 
in sequence to increase the size of the all alkyl polymer. 
More specifically, the first step of the method in its broadest sense 
includes the alkylation of a multi-branched core alkyl compound with a 
terminal alkyne building block. The two compounds are derived through a 
similar step reaction process. This process is derived from the previous 
work by inventors discussed above (3). 
By way of background, to circumvent the use of extraneous steps to 
incorporate a spacer moiety (4), due to the inertness of nucleophilic 
substitution at the terminal neopentyl carbons, bis-homotris was prepared 
(5). In general, pursuant to applicants, prior discoveries, it has been 
found the three carbon atoms are necessary to insure an appropriate 
distance to minimize the reaction retardation caused by an adjacent 
quaternary center. Therefore, C[(CH.sub.2).sub.3 Br].sub.4 and 
Y(CH.sub.2).sub.2 C[(CH.sub.2).sub.3 X].sub.3 were selected previously as 
the ideal alkyl core (6) and building blocks, respectively. 
Taking this prior discovery several steps further, and referring 
specifically to FIG. 1, nitrotriol (I) was pivotal to the preparation of 
bis-homotris, and was chosen as the starting point for the repetitive 
procedure to prepare unimolecular micelles in accordance with the present 
invention (7). Also, a procedure reported by Ono and coworkers (8) is well 
suited since it provides the 3-carbon homologating (9) methodology from a 
quaternary center by addition of tertiary radical to an electron deficient 
alkene, such as an acrylonitrile or methyl acrylate. Although the yield 
associated with this reaction has been found to vary (30-90%), applicant 
has prepared a novel series of tetra(bishomologated) analogs of 
pentaerythritol via this procedure. 
Again referring to FIG. 1, 4-nitro-4-[1-(hydroxypropyl)]-1,7-heptanediol(I) 
was treated (10) with benzyl chloride to give the tris-ether II with a 78% 
yield. The tris-ether was subsequently cyanoethylated (9) affording a 61% 
yield of cyanotri(benzylether) III. The characteristic .sup.13 C NMR 
chemical shifts for the 4.degree. carbon (36.5 ppm), cyano moiety (120 
ppm), and CH.sub.2 CN (11.6 ppm) and the loss of the peak at 94.0 ppm for 
the nitro substituted carbon support the assignment of III. 
Hydrolysis of the nitrile III was made by standard methods (11) and 
proceeded cleanly to derive a 92% yield of the carboxylic acid IV. This 
compound was indicated by the new appearance of a peak at 179.8 ppm 
(CO.sub.2 H) using .sup.13 C NMR spectroscopy. Conversion of acid IV to an 
alcohol V proceeded with a yield of greater than 95% when excess 1.0 M 
BH.sub.3 /THF solution was used. This reaction product was confirmed with 
13C NMR by the absorption at 63.3 ppm (CH.sub.2 OH). Transformation of V 
to a chloride VI was achieved at a 92% yield in CH.sub.2 Cl.sub.2 with 
excess thionyl chloride and a catalytic amount of pyridine (12). This 
conclusion with regard to the derived compound was supported (.sup.13 C 
NMR) by a new peak at 45.6 ppm (CH.sub.2 Cl). Reaction of lithium 
acetylide ethylenediamine complex (13) in Me.sub.2 SO with VI gave an 87% 
yield of the desired terminal alkyne VII. This terminal alkyne was used as 
the building block of the present invention and was characterized by 
.sup.13 C NMR by the appearance of new signals at 84.0 (CH.sub.2 C.tbd.CH) 
and 68.1 ppm (CH.sub.2 C.tbd.CH). 
Applicant synthesized the core tetrabromide (VIII) from the alcohol V by 
bromination with HBr/H.sub.2 SO.sub.4. Accordingly, applicants' method 
utilizes eight steps from nitromethane providing a 24% (overall) yield 
versus prior art methods including 17 steps from citric acid yielding a 
less than 2% overall yield (14) or 12 steps from tetrahydropyran-4-one 
providing a less than 5% overall yield (6). 
In view of the above, applicant synthesized the multi-branch core alkyl 
compound and the terminal alkyne building block from the same original 
starting material, the nitrotriol I. This reaction sequence provided an 
efficient route to the desired results and further provides an 
economically feasible method utilizing common reactions to synthesize the 
two necessary components of the present invention. 
As stated above, the progressive building of the tiers of the cascade 
polymer results from sequential alkylation, reduction/deprotection and the 
repetition of the two-step procedure. The specific steps are set forth as 
follows. 
Alkylation of the four-directional core VIII is accomplished with four or 
more equivalents of the terminal alkyne building block VII, as shown in 
FIG. 2. The alkylation is accomplished using hexamethylphosphoramide 
(HMPA), tetramethylethylenediamine (TMEDA) and lithium diisopropylamide 
(LDA) giving a 67% yield of the purified dodecabenzyl ether (IX) pursuant 
to methods previously disclosed (15). This conversion was evidenced by the 
disappearance of the terminal alkyne absorptions and the appearance of a 
peak at 80.9 ppm (C.tbd.C). The structure of IX via .sup.13 C NMR and 
.sup.1 H NMR analysis being shown in FIGS. 4 and 5). 
##STR1## 
1,25-Dibenzyloxy-8,17-diyne-13,13-bis[12-benzyloxy-9,9-bis(3-benzyloxypropy 
l)dodecyl-1-yne]-4,4,22,22-tetrakis(3-benzyloxypropyl)pentacosane(IX). 
.sup.13 C NMR (CDCl.sub.3) .delta. 19.8 (C-7, C-10), 23.1 (C-6, C-11), 23.3 
(C-2), 32.1 (C-3), 36.0 (C-5, C12), 36.8 (C-4), 37.1 (C-13), 71.0 (C-1), 
72.6 (OCH.sub.2 C.sub.6 C.sub.5), 80.1 (C-8, C-8, C-9), 127.3, 128.1, 
138.4 (C.sub.6 H.sub.5). .sup.1 H NMR (CDCl.sub.3) .delta. 1.10-1.65 (m, 
80 H), 2.00-2.21 (m, 16 H), 3.35 (br t, 24 H), 4.45 (S, 24 H), 7.28 (s, 60 
H). 
The alkylation step is followed by the simultaneous reduction of the triple 
bonds and the deprotection in accordance with the present invention. The 
simultaneous reduction and deprotection of IX are accomplished with Pd-C 
under hydrogen at 3 atmospheres. This procedure afforded a 91% yield of 
the dodecaalcohol X. As shown by the following data from .sup.13 C NMR and 
.sup.1 H NMR and as indicated by the structure set forth below, as well as 
the graphic spectographic data shown in FIG. 6, the results were indicated 
by the disappearance of absorptions assigned to alkyne carbons and the 
carbons alpha to the triple bonds (19.8 ppm as well as the appearance as a 
peak at 64.1 ppm) (CH.sub.2 OH). 
##STR2## 
1,25-Dihydroxy-13,13-bis[12-hydroxy-9,9-(3-hydroxypropyl)dodecyl]-4,4,22,22 
-tetrakis(3-hydroxypropyl)pentacosane (X). 
.sup.13 C NMR (CD.sub.3 OD) .delta. 23.9, 24.1 (C-6, C-11), 27.4 (C-2), 
30.8 (C-8, C-9, C-13), 31.7, 31.8 (C-10, C-7), 33.6 (C-3), 37.5 (C-4), 
37.8, 38.1 (C-5, C-12), 63.8 (C-1). .sup.1 H NMR (CD .sub.3 OD) .delta. 
1.08-1.32 (m, 112 H), 3.37 (t, 245 H, J=6.5 Hz). 
In order to add an additional tier to the polymer, the alcohol X was 
converted to the dodecabromide employing SOBr.sub.2 at 40.degree. C. for 
12 hours resulting in a 53% yield (34.8 ppm:CH.sub.2 Br). As shown in FIG. 
3, the second tier was readily obtained by alkylation of the dodecabromide 
resulting from the bromination of X with 12 or more equivalents of the 
alkyne building block VII to give a 49% yield of the 
hexatricontabenzylether XI, the structure of which being shown below as 
the spectographic data, the graphics of the spectroscopy being shown in 
FIGS. 7 & 8 . 
##STR3## 
.sup.13 C NMR (CDCl.sub.3) .delta. 19.3 (C-7, C-10), 22.8 (C-6, C-11, C-15, 
C-20), 23.2 (C-2), 29.4 (C-17, C-18, C-22), 31.9 (C-16, C-19), 32.3 (C-3), 
35.5 (C-14), C-21, C-12, C-5), 36.3 (C-4, C-13), 71.0 (C-1), 72.6 
(OCH.sub.2 C.sub.6 H.sub.5), 80.1 (C-8, C-9), 127.2, 127.3, 128.0, 138.3 
(C.sub.6 H.sub.5 ); .sup.1 H NMR (CDCl.sub.3) .delta. 1.05-1.70 (m, 300 
H), 2.00-2.22 (m, 48 H), 3.36 (br t, 72 H), 4.43 (s, 72 H), 7.27 (s, 180 
H). 
XI was similarly reduced and deprotected in one step providing an 89% yield 
of the hexatricontaalcohol XII. The structure as well as the .sup.13 C NMR 
and .sup.1 H NMR data are set forth below, the spectroscopy being in shown 
in FIG. 9. 
##STR4## 
1,43-Dihydroxy-4,4,40,40-tetrakis(3-hydroxyropyl)-13,13,31,31-tetrakis[12-h 
ydroxy 
9,9-bis(3-hydroxypropyl)-dodecyl]-22,22-bis[21-hydroxy-18,18-bis(3-hydroxy 
propyl); 
9,9-bis[12-hydroxy-9,9-bis(3-hydroxypropyl)-dodecyl]heneicosyl]tritetranco 
ntane (XII). 
.sup.12 C NMR (CD.sub.3 OD) .delta. 23.8 (C-15, C-20), 24.0 (C-6, C-11), 
27.4 (C-2), 29.5 (C-13, C-22), 30.7, 30.8 (C-8, C-9, C-17, C-18), 31.6 
(C-7, (C-10, C-16, C-19), 33.6 (C-3), 37.5 (C-4), 37.7 (C-5, C-12, C-14, 
C-21), 63.9 (C-1); .sup.1 H NMR (CD.sub.3 OD) .delta. 1.15-1.87 (m, 400 
H), 3.50 (t, 72 H, J=6.5 Hz). 
Both the polyether XI and the polyalcohol XII exhibited many of the same 
.sup.13 C NMR signals as their lower analogs, IX, X. 
Although the polyol XII is only marginally soluble in water, molecular 
inclusion of the micellar probe chlortetracycline (CTC) by methods 
previously reported (16) supports the guest-host relationship and micellar 
character of XII. CTC is a water soluble dye which is fluorescent only in 
lipophilic environments. 
In accordance with the present invention, the cascade polymer made acts as 
a micelle. To increase the aqueous solubility of the micelle, XII was 
oxidized by RuO.sub.4 pursuant to previously reported methods (17). The 
reaction afforded an 85% yield of the hexatricontacarboxylate salt XIII. 
The disappearance of the absorption for the hydroxymethyl moiety (64.0 
ppm) and the appearance of carboxylate signal (187.4 ppm) as well as the 
high water solubility of the sodium salt support this transformation (the 
spectographic results not being shown in the Figures). Again the micellar 
properties of XIII were confirmed by the uniform fluorescence when CTC was 
added to an aqueous solution of XIII. 
The above inventive method sets forth a unique sequence of reactions for 
deriving for the first time an all alkyl carbon unimolecular micelle 
having the formula 
##STR5## 
wherein R.sub.1 is an alkyl having C.sub.3 to C.sub.20, R.sub.2 is an 
alkyl having C.sub.3 to C.sub.20 and R.sub.3 is selected from the group 
including --CONH.sub.2, --COCl, --CHO, --CN, --CO.sub.2 R.sub.4, 
--COR.sub.4, and R.sub.4 being ammonium, sulfonium, phosphonium, --H, 
alkyl, alkaryl, or aryl group(s) or alkaline or alkaline earth metalions. 
These surface group functionalities can be easily modified by standard 
chemical processes. Further, other groups such as halogens, bipy, 
9,10-phen, amines, sulfur or phosphorus moieties, for example, can be 
added to/or substituted for the surface group functionalities. 
Of course, the unimolecular micelle in accordance with the present 
invention could have predefined branching, depending upon the number of 
sequential alkylations, reductions, and deprotections that are performed. 
The surface of the unimolecular micelle can be readily coated with metal 
ions. All mono-, di-, and tri-valent metals are possibly bonded directly 
(with bipy) or indirectly through --CO.sub.2 .sup.- bonds. 
The alkyl carbon surrounded by the branched arms of the micelle define a 
core therewithin. The incorporation of a single nitrogen, oxygen, sulfur, 
or phosphorus molecule into the molecular core, per arm or branch of the 
micelle, permits the inclusion of metals as well as organics into the 
micelle infrastructure. 
It is further possible to incorporate chirality into either the core region 
or surface thereby creating a chiral sphere with an objectively active 
surface for resolution of achiral mixtures. This can be accomplished by 
incorporating chiral moieties e.g. naturally occurring amino acids or 
resolved molecules of known chirality either at the core or in or on the 
branching arms. Polyacids upon treatment with protected amino acids in the 
presence of DCC afforded the protected polyamino acid, which is 
deprotected and subjected to the above iterative procedures. 
The micelle made in accordance with the present invention has a 
predetermined porosity created by the relationships of the branches, the 
core defined above, and each of the quaternary centers created by each 
additional tier layered thereon. The porosity of the inside core can be 
changed by increasing or decreasing the distances between the quaternary 
centers, that is by changing the branch arm lengths (R1, R2 . . . ). 
By changing the surface character of the micelles made in accordance with 
the present invention, various uses can be developed for the micelles. For 
example, a --CO.sub.2 .sup.- surface can be created thereby rendering the 
micelles useful for detergents (soaps) and surfactants. Iodine can be 
incorporated onto the surface of the micelles for use of the micelles in 
radioimaging. Hydroxyl groups can be incorporated onto the surface of the 
micelles for use of the micelles as detergents and for binding sights for 
drug delivery. Amine surface functionalization can be created on the 
micelles to provide a polyfunctional base (organic). A bipy surface can be 
created for metal ion sequestering. A bipy metal surface can be created 
for chemical catalysts. Further, --CONHR.sub.1 can be created for chiral 
recognition and molecular recognition. Of course, the surface of the all 
aliphatic four directional cascade polymer be modified for many other 
uses. 
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. 
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