CA2356455A1 - Preparation and uses of conjugated solid supports for boronic acids - Google Patents

Abstract

The invention provides novel solid supports comprising dihydroxyalkyl aminoalkyl and dihydroxyalkylaminobenzyl groups, and methods for making and using them. The supports are particularly useful for immobilizing and derivatizing functionalized boronic acids for use in solid phase synthesis, such as those used in combinatorial chemistries. The compositions and methods of the invention are also useful as scavenger solid supports, e.g., in solution-phase parallel synthesis of small molecule libraries, and for use in resin-to-resin transfer reactions via phase transfer of solid supported boronic acids under both aqueous and anhydrous conditions. The methods of the invention provide convergent solid-phase synthesis of symmetrically or unsymmetrically functionalized compounds, such as biphenyl compounds. Also provided are synthesizer devices, e.g., semiautomated parallel synthesizers.

Description

PREPARATION AND USES OF CONJU(~:ATED SOLID SUPPORTS
FOR BORONIC' ACIDS
TECHNICAL FIELD
This invention generally relates the 'elds of chemistry and pharmaceutical drug preparation. In particular, the invention is directed to dihydroxyalkylaminoalkyl- and dihydroxyall<ylaminobenzyl-conjugated solid supports and methods for making and using them, particularly, for the immobilization, purification and derivatization of boronic acids.
BACKGROUND
Boronic acid containing molecules, such as arylboronic acids, are employed in a broad range of~
biological, medicinal and synthetic applications, including pharmaceutical compositions.
They are employed in applications such as carbohydrate rE;cognition (for recent reviews see, e.g., Wulff, Pure Appl. Cheat. 1982, 2093-2102; .lames et al., Augmv. C'hern. Irtt.
Fd. Ertgl. 1996, 3.5, 191 ()-1922). Also, arylboronic acids can be crucial synthetic intermediates or potential inhibitors of therapeutically relevant serine protease enzymes (For recent examples see, e.g., Kettner et al., J. l3iol. Cheat. 1984, ?59, 15106; Martichonok et al., J. Aru. C'heru. Soc. I
996, 118, 950-958;
'Tian et al.; J. Org. Chem. 1997, G2, 514-522; Zhong et al., J. :lrrt. C'hcnr.
Soc. 1995, 117, 7048;
Priestley et al., Org. l.ett. 2000, ?, 3095-3097). Boronic acids have also been applied in neutron capture therapy for cancer (for reviews see, e.g., Barth et al., Sci. .9m.
1990, ?63, 68-73;
Hawthorne, Artgew. C'herrt. Irtt. Ecl. Errgl. 1993, 3?, 950-984; Mehta et al., Phcrrru. Rcs. I 996, l3, 344-351; Soloway et al., Cheat. Rev. 1998, 1515-1562), and as transmembrane transport agents (for a recent review, see, e.g., Smith et al., Aclv. S'u prcrntol. C'hern.
1999, ~, 157-202 and references cited therein).

In recent years, boronic acids have also gained tremendous popularity as substrates and building blocks in organic synthesis and combinatorial chemistry. They have found widespread use in Suzuki cross-coupling reactions (see, e.g., Suzuki, Orgcrnr~ryretal. Chem.
1999, ~ 76, 147-168;
Suzuki, A., in "Metal-catalyzed Cross-coupling Reactions". 1?ds. Diedcrich, F., et al., Wiley-VCH, 1997, Chapt. 2). Suzuki cross-coupling reactions (see, e.g., Suzuki (1999) Organometal.
Chem. 576:147-168; Suzuki, A., in Metal-catalyzed cross-coupling reactions, Eds. Diederich., F., et al., Wiley-VCH, 1997, Chapt. 2) are commonly used in industrial and pharmaceutical chemistries. They can also provide novel biphenyl units, such as those represented in several biologically active molecules (see, e.g., Duncia (1992) Medical Research Reviews 12:149).
Many new types of synthetic transformations that use boronic acids have created a demand for the commercial availability of a larger number of functionalized boronic acids.
However, in spite of the demand for boronic acids, particularly arylboronic acids, and conjugated forms of these compounds, there remains a shortage of commercially available supplies. The paucity of boronic acids can be explained by the non-existence of natural ones, and in large part by difficulties associated with the synthesis and derivatization of even the simplest functionalized ones by solution-phase methods.
The isolation of compounds containing a boronic acid functionality can prove notoriously troublesome due to their amphiphilic character. These problems are amplified when the desired boronic acid-containing compound comprises other sites with basic or acidic lunctionalities.
Boronic acids are also typically slow moving on silica gel, and consequently must often be purified by recrystallization. In addition, boronic acids can be sensitive to oxidation (see, e.g.., Snyder et al., J. Arrt. Chern. Soc. 1938, 60, 105-111; Matteson,.l. Anr.
C'herrr. Soc. 1960, S?, 4228-4233). Some of these problems can be alleviated by protection ol~ the boronic group as an ester (see, e.g., Matteson, D.S. Ster-eoclirected Svrathesis with Or~ganofior°unes, Springer:1995, Berlin, Heidelberg, p. 17 (section 1.4.2). However, these approaches require additional synthetic operations.

Solid-phase methods circumvent the need for aqueous work-~up and other time-consuming operations required to isolate the desired boronic acid from excess reagents and by-products.
Solid-phase Suzuki reactions in ''one resin-bound substrate" schemes have been described, e.g., by Frenette ( 1994) Tetrahedron Lett. 35:9177-9180; Eluwe ( 1999) Tetrahedron Lett. 40:683-686;
Chamoin (1998) Tetrahedron Lett. 39:4179-4182. Two resin systems, also called resin-to-resin transfer reactions (RRTR), constitutes a significant simplification of solid-phase organic synthesis (SPOS). RRTR can be extremely valuable as a tinne saving strategy in combinatorial chemistry (see, e.g., Hamuro (1999) J. Am. Chem. Soc. 121:1636-1644). In RRTR, one resin-bound substrate is transferred to solution-phase by action of a phase-transfer agent or chaperone, and coupled in situ to another resin-bound substrate.
In view of all the above mentioned impediments in handling boronic acid containing molecules by solution-phase methods, it is clear that simple and general solid-phase approaches for their use, immobilization and derivatization would be of tremendous usefulness SUMMARY
The invention provides novel solid supports comprising dihydroxyalkylaminoalkyl and dihydroxyalkylaminobenzyl groups and methods for making and using them. These compositions are particularly useful for immobilizing boronic acids for use in solid phase chemical reactions, e.g., solid-phase synthesis, such as those used in combinatorial chemistries.
For example, the compositions and methods of the invention are also useful as "scavenger" or "fishin g out" solid supports, e.g., in solution-phase parallel synthesis of small molecule libraries.
The invention provides a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyalkylaminobenzyl group, wherein the dihydroxyalkylamino moiety comprises a tertiary amine having two hydroxyalkyl substituents having a formula HO
(CHZ),~ hl (CH~),: C1H, wherein x and y are integers between 1 to about 20. In one preferred embodiment, the dihydroxyalkylaminoalkyl is a dihydroxyalkylaminomethyl group or a dihydroxyalkylaminobenzyl group. In one embodiment, the dihydroxyalkylaminoalkyl group can be a dihydroxyalkylaminoethyl, a dihydroxyalkylaminopropyl, a dihydroxyalkylaminobutyl group. In one prefen-ed embodiment, the dihydroxyalkylamino moiety c:an be a diethanolamivne In another embodiment, the solid-supported group is a dil~ydroxyalkylaminobenzyl group.
In one embodiment, the solid support comprises a polystyrene or an equivalent composition.
The polystyrene can be a polystyrene-divinylbenzene) (PS-DVB) or an equivalent composition.
In one preferred embodiment, the polystyrene is cross-linked with about 1 % to 2%
divinylbenzene.
In alternative embodiments, the solid support comprises a plastic or a plastic co-polymer or an equivalent thereof. The solid support can comprise a silica or a silica gel or an equivalent thereof. The solid support can comprise a cellulose or a cellulose acetate or an equivalent thereof. The solid support can comprise a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or an equivalent thereof, or a. co-polymeric mixture thereof. The solid support can comprise a polyvinyl alcohol) (PVA) hydrogel, or an equivalent composition. 1 °ro PS-DV6 is an example of this type of support. (n one preferred embodiment, the solid support may comprise a polystyrene-polethylene glycol copolymer, e.g. TantagelOO or Argogel O.
In one embodiment, the solid supports of the present invention can comprise a POEPOP
(polyoxyethylene/polyoxypropylene copolymer) or a SPOCC (superpermeable organic combinatorial chemistry resin).
In one embodiment, the solid support eau comprise a polyacrylamide or an equivalent polymer composition. The polyacrylamide can comprise a polymethacrylamide. a methyl methacrylate, a glycidyl methacrylatc, a dialkylaminoalkyl-(meth)acrylate, or an N,N-dialkyl-aminoalkyl(meth)acrylate, or an equivalent composition.

Alternatively, the solid support can comprise an inorganic; composition selected from the groi_~p consisting of sand, silica, silica gel, glass, glass fibers, gold, alumina, zirconia, titania, and nickel oxide and combinations thereof and equivalents thereof.
In one embodiment, the solid supports of the invention further comprise a boronic acid attached as a boronic ester-dioxyalkylaminoalkyl- or -dihydroxyalkylaminobenr:yl-conjugated support.
The boronic acid can be an arylboronic acid. In one preferred embodiment, the boronic acid is a functionalized boronic acid, e.g., carboxy-functionalized-boronic acid, bromomethyl functionalized boronic acid, formyl-functionalized boronic acid, aniline-funetionalized boronic acid.
In one preferred embodiment, the solid support comprises N,N-diethanolaminomeChyl-conjugated polystyrene (DEAM-PS). In one preferred embodiment, the cross-linking is about 1 °,a to 2%.
The invention also provides a solid support derivatized with a dihydroxyalkylamine moiety made by the process comprising mixing an aminoalkylated or aminobenzylatcd solid support comprising a primary amino group, with an excess of an epoxide, and a solvent, thereby derivatizing the solid support with a dihydroxylakylamine moiety comprising a tertiary amine having two hydroxyethyl substituents.
In one embodiment, the solid support is made by a process comprising mixing an aminoalkylated solid support comprising a primary amino group with an excess ethylene oxide at about SO"C in a solvent comprising a tetrahydrofuran/water mixture, or equivalent, or dioxane, or equivalent, in a sealed, pressure resistant container, thereby derivatizing the solid support with a diethanolaminoalkyl group comprising a tertiary amine having two hydroxyethyl substituents and a formula HO (CHz)Z N (CHZ)~ OH. In one embodiment, the aminoalkylated solid support is an aminomethylated solid support. The ethylene oxide can be in the sealed, pressure resistant container as a gas; the pressure of the ethylene oxide gas c:an be at about I
to about 20 atmospheres. In one embodiment, the dihydroxyalkylamino moiety can be a diethanolamine or a dipropanolamine. In one embodiment, the solvent is at a concentration of about 0.1 to about 1 M. The mixing can last for about 12 hours to about 72 hours. The solid support can be a polystyrene or an equivalent composition.
In other embodiments, the epoxide comprises isobutylene oxide and the reaction takes place at 80°C. In yet other embodiments, the epoxide comprises an aryl-substituted epoxide. In yet another embodiment, the epoxide comprises styrene oxide.
In one embodiment, the invention provides a boronic ester-dioxyalkylaminoalkyl-or boronic~-ester-dioxyalkylaminobenzyl-conjugated solid support with a formula (CH2)X\
g\ 'N-R-solid support \O(CH2)y wherein x and y are integers between I to about 20, and R is an alkyl, substituted alkyl, or benzyl group. The boronic ester can be an aryl boronic ester, a vinylboronic ester or an alkylboronic ester.
The invention provides a solid support derivatized with a boronic ester-dialkylaminoalkyl or-dialkylaminobenzylgroup made by a process comprising the following steps: (a) mixing an aminoalkylated or aminobenzylated solid support comprising a primary amino group with excess ethylene oxide at about 50"C in a solvent comprising a tctrahydrofuran/water mixture, or equivalent, or dioxane, or equivalent, in a sealed, pressure resistant coni.ainer, thereby derivatizing the solid support with a boronic ester-oxyethylaminoalkyl group or boronic cster-oxyethylaminobenzyl group; and, (b) mixing the boronic c;ster-dioxycthylaminoalkyl or -dioxyethylaminobenzyl-derivatized solid support with a boronic acid, in an anhydrous solvent, thereby derivatizing the solid support with a boronic ester-ethylatninoalkyl or -ethylaminobenzyl group having the formula (CHz)2\
g \ 'N-R solid support O(CH2)2 /
wherein R is an alkyl, substituted alkyl, or benzyl group.
In alternative embodiments, for the processes for making the dihydroxyalkylaminoalkyl derivatized solid support or the dihydroxyalkylaminoben~.yl-derivatized solid supports, the supports can be mixed with the boronic acid in dry tetrahy drofuran. Tlae mixing of step (b) c;an last from about one to about 60 minutes.
The invention provides a method for making a solid support derivatized with a dihydroxyalkylaminoalkyl of dihydroxyalkylaminobenzyi group comprising mixing an aminoalkylated solid support or aminobenzylated solid support comprising a primary amino group with excess ethylene oxide at about 50°C in a solvent comprising a tetrahydrofiu-an/water mixture, or equivalent, or dioxane, or equivalent, in a sealed, pressure resistant container, thcrebv derivatizing the solid support with a dihydroxyethylamino moiety comprising a tertiary amine having two hydroxyethyl substituents and a formula HO (CH~)~ N (CH~)2 OH.
The invention provides a method for immobilizing a boronic acid comprising the following steps: (a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyaminobenzyl group, wherein the dihydroxyalkylamino moiety has a fotznula HO
(CR'~)~ CH2N CHz(C"R'Z)y OH, wherein R" is independently selected from the group consisting consisting of H, C,-CZ~ alkyl radical, and Ci-Cz~ substitutf;d alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid; and (c) mixing the solid support of step (a) with the sample of step (b) in an anhydrous solvent, thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl-conjugated group having the formula (CR'2)xCH2 -B \N-R solid support O(CR'2)yCHz wherein R comprises an alkyl or a benzyl, R' comprises at least one of H and C,-C~« radical, and x and y are integers between 1 to about 20. In a preferred embodiment x and y are one.
In other preferred embodiments, the alkyl comprises a substituted alkyl group.
The invention provides a method for purifying a boronic acid comprising the following steps:
(a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyaminobenzyl group, wherein the dihydroxyalkylamino moiety has a formula HO
(CR'~)x CHIN CHZ(C'R'~)y OH, wherein R' is independently selected from the group consistin~~
consisting of H, C,-C'~~ alkyl radical, and C',-C~« substituted alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid; (c) mixing the solid support of step (a) with the sample of step (b) in an anhydrous solvent, thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl-or dioxyalkylaminobenzyl-conjugated group having the formula (CR'2)xCH2 -B \N-R solid support O(CR'2)yCH2 wherein R comprises an alkyl or a benzyl, R' comprises at least one of I1 and C~-C~« radical, and x and y are integers between 1 to about 20; and (d) hydrolyzing the boronic ester linkage, thereby releasing from the support a purified boronic acid. In a prefec~red embodiment x and y are one.

In one embodiment, the hydrolyzing step is in a solution comprising tetrahydrofuran, water and acetic acid. In one embodiment, the tetrahydrofuran, water and acetic acid ratio is about 90:5:5, respectively. The hydrolyzing step can last about one to about ten minutes.
The hydrolyzing, step can be in a solution comprising tetrahydrofuran and water. The tetrahydrofuran:water ratio can be about 9:1, respectively. The hydrolysis step can last between about one to about sixty minutes.
In one embodiment, the method further comprises washing the solid support at least once with an anhydrous solvent after the mixing step and before the hydrc>lysis step. In alternative embodiments, the method is performed in a batch or a column. The method can be perfoni~e~d in an automated or semiautomated synthesizer.
The invention also provides a method for scavenging a boronic acid from a multiple component solution to generate a boronic acid-free solution comprising the following steps: (a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyalkylaminobenzyl group, wherein the dihydroxyalkylamino moiety has a formula HO
(CR'Z)x CHzN CHz(C'R',)y OH, wherein R' is independently selected from the group consisting consisting of H, C,-C~« alkyl radical, and C',-C~~ substituted alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid; (c) mixing the solid support of step (a) with the sample of step (b), thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl-conjugated group having the formula (CR'2)xCH2 --B \N-R solid support O(CR'2)yCH2 wherein R comprises an alkyl or a benzyl. R' comprises at least one of I I and C,-C2~ radical, and x and y are integers between 1 to about 20; and (d) washing the solid support after the mixing of c) step (c) to remove non-boronic acid components; thereby scavenging the boronic acid from the multiple component sample to generate a boronic acid-free solution. Izn a preferred embodinnent x and y are one.
In one embodiment, a molar excess of the support (i.e., boronic ester-dioxyalkylaminoalkyl-conjugated groups) compared to an estimated (or theoretical) amount of boronic acid in the multiple component sample is used.
In yet another embodiment, the invention provides novel compositions and methods for resin-to-resin transfer reactions, e.g., Suzuki coupling reactions, via phase transfer of solid supported boronic acids under both aqueous and anhydrous conditions.
In one embodiment, the invention provides a method for the solid phase synthesis of functionalized compounds, such as functionalized biphenyl compounds.
comprising the following steps: (a) providing a boronic ester-dioxyalkylaminoalkyl-conjugated solid support or a boronic ester-dioxyalkylaminobenzyl -conjugated solid support, (b) providing a substituted haloarene-conjugated solid support; (c) reacting the conjugated support of step (a) with the conjugated support of step (b) under conditions comprising a catalyst, a base and a solvent, thereby producing a solid supported, functionalized reaction product conjugated to a solid support; and, (d) reacting the reaction product of step (c) with a solvent comprising an acid, such as trifluoroacetic acid, or equivalent, and a non-protic, non-polar solvent, such as methylene chloride, or equivalent, thereby liberating a functionalized compound, such as a biphenyl compound, from the solid support.
In alternative embodiments of the methods of the invention, the solid-supported boronic ester derivative originates li-om a polyfunctionaliced arylboronic acid containing at least one of the following substituents at either ortho-, meta- and/or para- positions: (a) a carboxamide or equivalent; (b) a carboxilic ester or equivalent; (c) a methylamino group or equivalent; (d) an anilide group, or equivalent, comprising an acyl group; (e1 a urea, or equivalent, comprising an acylamino group; (t~ a sulfonamide, or equivalent, comprising a sulfonyl group; or (g) an aryl alkyl ether or equivalent. The carboxamide or equivalent of step (a) can be made from either a primary or a secondary amine and a corresponding carboxylic acid via couplin g methods for amide formation. The carboxi(ie ester or equivalent of step (b) can be made from an alcohol and a corresponding carboxylate. The amine of the methylan nino group of step (c) can be a secondary or a tertiary amine made by reactions of a primary or secondary amine on a corresponding halomethyl substitute. The acyl group of step (d) can be an alkanoyl or a benzoyl group reacted with a corresponding aniline. The acylamino group of step (e) can be derived from an alkanoyl or a benzoyl group of an isocyanate reacted from a corresponding aniline. 'The sulfonyl group of step (f) can be derived from a sulfonyl chloride react~.d onto the corresponding aniline. The alkyl group of step (g) can be derived f i-om a primary or secondary alcohol reacted on the corresponding phenol via a Mitsunobu-like reaction.
In one embodiment, the a solid-supported boronic ester of substituent (a) is an amide derivative of p-carboxybenzeneboronic acid or equivalent. The amide can comprise NH(CH,)3Ph or equivalent. The functionalized compound produced in step (d) can be a 4,4"-biphenyl dicarboxylic acid monoamide or equivalent.
In one embodiment, the solid-supported boronic ester of step (a) comprises a benzylamine or equivalent. The functionalized compound produced in step (d) can be a monoalkylated biphenyl dibenzylamine or equivalent. The solid-supported boronic ester of step (a) can comprise a NHCOPh group or equivalent. The functionalized compound produced in step (d) can be a monoacylated biphenyl dianiline or equivalent.
In one embodiment, the molar equivalent ratio of solid supported boronic ester to haloarene-conjugated solid support is about 3 to about 4 In one embodiment, the solid-supported boronic ester of step (a) is originating from an arylboronic acid or a vinyl boronic acid. The arylboronic acid can be a ~-tolueneboronic acid or an equivalent thereof.
In one embodiment, the solid support is a resin, such as a polystyrene resin or an equivalent thereof. The solid support also can be a polystyrene-polyethylene glycol resin or an cduivalent thereof. The solid-supported haloarene of step (b) can be a solid-supported polysubstituted halobenzoic acid, a solid-supported amino-substituted haloarene, a solid-supported aminoalkyl-substituted haloarene, or an equivalent thereof. The halobenzoic acid c;arboxy group can be conjugated to a hydroxymethylphenoxy-polystyrene resin or an equivalent thereof. The halobenzoic acid carboxy group can be conjugated to a hydroxymethylphenoxy-polystyrene-polyethylene glycol resin or an equivalent thereof. The amino group can be attached to a triphenyhnethylpolystyrene resin or an equivalent thereof.
In alternative embodiments, the haloarene of step (b) of the method is an iodoarene, a chloroarene, a bromoarene or an equivalent thereof. The iodoarene can be a p-iodobenzoic acid group or an equivalent thereof.
In one embodiment, the conditions of step (c) of the method further comprise use of a Pd(0) catalyst or an equivalent thereof. The Pd(0) catalyst can comprises a Pd(PPh~).~ or a Pd,(dba)3.
In one embodiment, the basic solvent of step (c) of the method is an aqueous solvent. The basic solvent of step (c) of the method can comprise a sodium carbonate, a potassium carbonate or an equivalent thereof. The basic solvent of step (c) can comprise a trialkylamine, a potassium fluoride, a sodium fluoride, a cesium fluoride or an equivalent thereof.
In alternative embodiments of the method, wherein the reaction conditions of step (c) comprise a temperature of between about 25°C to about 120"C; of between about 50°C to about 100°C; and, of between about 80"C to about 90°C.

In alternative embodiments of the method, the reaction conditions of step (c) comprise a reaction time of between about 1 hours to about 72 hours; of between about 10 hours to about 50 hours;
and, of between about 15 hours to about 25 hours In alternative embodiments of the method, the aqueous solvent comprises a PhMe/EtOH, a DME/water and a DMF/water solvent. The PhMe/EtOH molar ratio can be about 4:1;
about 3 or about 2:1. The DME/water and DMF/water molar ratios can be abo~.it 12:1;
about 9:1; about 6:1; or about 3:1.
In one embodiment, the Pd(0) catalyst comprises a Pd(PPh3):~ and the solvent is PhMe/EtOH at about a 3:1 molar ratio and the reaction conditions of step (b) comprise a reaction time of about 20 hours and a temperature of about 80°C to about 1 10"C
In one embodiment, the basic solvent of step (c) is an anhydrous basic solvent. The basic solvent can further comprise ethylene glycol or equivalent as a co-solvent. The basic solvent can comprise at least one tertiary amine base. The tertiary amine base can comprise diisopropylethylamine, Et3N (triethylamine), N(CH?CH~OH) ~ or an equivalent thereof. The basic solvent can comprise Et3N (triethylamine) or equiv<~lent and ethylene glycol or equivalent at a molar ratio of about 1:1.
In alternative embodiments, the reaction conditions of step (c) comprise a temperature of between about 25°C to about 120"C; of between about 50"C to about 1 1 S"C; or, of between about 80°C to about 110"C. The reaction conditions can comprise a reaction time of between about l hours to about 25 hours.
In alternative embodiments, the anhydrous solvent comprises a DMF solvent, a PhMe solvent or a dioxane solvent, or an equivalent thereof.

In one embodiment of the method, the reaction conditions of step (c) comprise a Pd(0) catalyst comprising a Pd,(dba)3 , and a solvent comprising UMF and Et~N (tricthylamine) or equivalent and ethylene glycol or equivalent at a molar ratio of about 1:1 at about 105"C
for at least about 20 hours.
In one embodiment, the aminoalkyl moiety is an aminomethyl group In yet another embodiment of the invention, there is provided a method for the solid phase synthesis of functionalized compounds comprising the following steps: (a) providing a first reactant comprising a boronic ester-dioxyalkylaminoalkyl- or-dioxyalkylaminobenzyl-conjugated solid support, (b) providing a second reactant conjugated to a solid support; (c) providing a transfer agent; (d) providing a solvent; (e) reacting the boronic ester-dioxyalkylaminoalkyl- or-dioxyalkylaminobenzyl- conjugated solid support of step (a) with the second reactant of step (b) and the transfer agent of step (c) in the solvent of step (d), thereby producing a solid supported, functionalized reaction product; and (f) lilnerating the functionalized compound from the solid support.
In yet another embodiment of the invention, there is provided a method for the solid phase synthesis of functionalized glycine compounds comprising the following steps:
(a) providing a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl conjugated solid support, (b) providing a solid-supported iminium compound; (c) providing a transfer agent;
(d) reacting t:he boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl conjugated solid support of step (a) with the transfer agent of step (c) and the solid-supported iminium of step (b) in a solvent, thereby producing a solid supported, functionalized glycine reaction product;
and, (e) liberating the functionalized compound from the solid support.
In yet another embodiment of the invention, there is provided a method for the solid-phase derivatization of a functionalized boronic acid comprisin" the following steps: (a) providing .a dihydroxyalkylaminoalkyl or dihydroxyalkylaminobenzyl- conjugated solid support; (b) providing a sample comprising a functionalized boronic ;acid; (c) mixing the solid support with the sample in an anhydrous solvent, thereby immobilizing the functionalized boronic acid by generating a functionalized boronic ester-dioxyalkylaminoalkyl- or boronic dioxyalkylaminobenzyl-conjugated group; (d) providing at least one derivatizing agent capable of reacting with the functional group of the functionalize~l boronic acid; and (e) contacting tL~e derivatizing agent of step (d) with the fimctionalized boronic ester-dioxyalkylaminoalkyl- or functionalized boronic dioxyalkylaminobenzyl-conjugated group in a solvent, thereby producing a solid supported, derivatized boronic acid product.
In one embodiment, the reaction takes place in a device, such as a synthesizer, such as a semiautomated synthesizer, e.g., a parallel synthesizer.
The invention also provides a device, such as a "synthesizer.'' comprising (aj a boronic ester-dioxyalkylaminoalkyl-conjugated solid support or a boronic ester-dioxyalkylaminobenzyl -conjugated solid support, and, (b) a haloarene-conjugated solid support. The synthesizer can be a semiautomated synthesizer, such as a parallel semiautornated synthesizer, or a fully automated synthesizer.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is a schematic summarizing the synthesis of DEAM-PS resin, and the immobilization of a boronic acid as discussed in detail in Example 1, below.
Figure 2 is a schematic summarizing the structure of boronic acid compounds, as set forth in Table 1, and discussed in detail in Example l, below.

Figure 3 is a schematic summarizing the immobilization and solid-phase transformations of resin-bound arylboronic acids, as discussed in detail in Example l, below.
Figure 4 is a schematic summarizing resin capture purification of dienylboronic acid, as described in detail in Example l, below.
Figure 5 is a schematic summarizing a borono-Mannich resin-to-resin transfer reaction between boronic acids supported onto N,N-diethanolaminomethyl polystyrene and the iminium intermediate formed from dialkylamino resin 3 and glyox.ylic acid, as described in detail in Example 2, below.
Figure 6 is a schematic summarizing a RRTR with different DEAM-PS-boronates and cleavage of the final resin mixture to provide arylglycine derivatives, as described in detail in Example: ?, below.
Figure 7, Scheme 1 is a schematic summarizing a RRTR with an arylboronic acid as described in detail below in Example 3; Scheme 2 is a schematic stnnmarizing the transfer of resin-bound p-tolueneboronic acid to Wang resin-bound p-iodobenzoic acid as described in detail below in Example 3.
Figure 8 is a schematic for "Method A'' and "Method B," as described in detail in Example 3, below.
Figure 9 is a schematic of a library of biphenyl compounds synthesized using the methods of the invention with a commercial, semi-automated parallel synthesizer as described in detail in Example 3, below.

Figure 10 is a Gel-phase ~H NMR spectra (500 MHz) oC DEAM-PS (A) and REAM-PS
supportedp-tolylboronic acid (B) using a Varian magic angle spinning nanoprobe. Solvent is CDzCIz (peak identified by a dot) as described in detail in Example 4 .
Figure 11 is an eduation relating to the. boronate exchange process as described in detail in Example 5;
Figure 12 is a graph relating the percentage of hydrolytic cleavage of REAM-PS
supported p-tolylboronic acid followed by UV spectroscopy (225 nm) as a function of water stoichiomet,ry as described in detail in Example 5.
Figure 13 is a schematic summarizing DEAM-PS resin immobilization and cleavage.
Figure 14 is a schematic summarizing the production of diisobutanolanainomethyl substituted polystyrene substituted resin from isobutylene oxide as described in detail in Example (i.
Figure 15 is a schematic summarizing the substitution reactions of bromomethyl derivatized benzeneboronic acids with primary and secondary amines as describes in detail in Example T.
Figure 16 is a schematic summarizing the reductive amination of supported fonnyl-substituted benzeneboronic acids with various primary and secondary amines as described in detail in Example 8.
Figure 17 is a schematic summarizing the formation of amide derivatives from REAM-PS
supported carboxy-functionalized arylboronic acids as described in detail in Example 9.
Figure 18 is a schematic summarizing the. reaction of carboxylic acids with DEAM-PS supported anilines as described in detail in Example 10.

Figure 19 is a schematic of the reaction of DEAM-PS supported anilines for the formation of areas as described in detail in Example 11.
Figure 20 is a schematic of the reaction of DEAM-PS supported p-substituted bromomethyl derivatized benzeneboronic acid with sodium phenoxide s as described in detail in Example 7 Figure 21 is a schematic of the possible forms of ortho-ac;ylaminobenzf;neboronic acids (compound 23) in hydroxylic solvents (e.g. water or methanol) as described in detail in Example 10. B is the naphtalene-like form originating from dehydrative cyclization ofA. C is the putative ate form arising from 1,4-addition of water or methanol.
Figure 22 is a schematic of a Ugi multicomponent reaction using a DEA1VI-PS
supported aniline as described in detail in Example 12.
Figure 23 is a schematic of three equations showing the derivatiziation and sequential trasnformation of multifunctional boronic acids as describedin detail in Example l 3.
Figure 24 is a schematic of the immobilization and derivatization of functionalized boronic acids using N,N-diethanolaminomethyl polystyrene (DEAM-PS
DETAILED DESCRIPTION
The invention provides solid supports for the immobilization of boronic acids, particularly, functionalized boronic acids, such as aryl boronic acids. As noted above, the compositions and methods of the invention are particularly useful in solid-phase syntheses, such as those used in combinatorial chemistries.
The invention provides solid supports derivatized with dihydroxyalkylaminoalkyl and dihydroxyalkylaminobenzyl groups. For example, in one embodiment, the solid support derivatized with a dihydroxyalkylaminoalkyl group is an .N, ,~V-diethanolaminomethyl. (n another embodiment, the solid support is derivatized with a dihydroxy-alkylamino-benzyl group. The solid supports can be of any material that can be derivatized with or coupled to dihydroxyalkylaminoalkyl groups. For example, in one embodiment, the solid support is a polystyrene, e.g., a dihydroxyalkylaminoalkyl-conjugated resin, such a;;
diethanolamine derivatized polystyrene (''DEAM-PS"j. The solid support can be in any form, e.g., as a bead, a filament, a porous material, and the like.
The invention also provides novel methods for making and using the solid supports of the invention. Solid supports of the invention, e.g., DEAM-fS, can be employed to efficiently immobilize and transform fimctionalized boronic acids (e.g., arylboronic acids, vinyl boronic:
acids, and the like). Solid supports of the invention can he used to immobilize boronic acids for use in any reaction involving boronic acids or derivatives thereof, such as for amide coupling, acylation or reductive amination methods. Solid supports of the inveni.ion can be used to ''scavenge'' or "fish out" a boronic acid from a sample, particularly a sample comprising a complex mixture of chemicals. "Scavenging" is a reaction in solution-phase with a molar excess of a boronic acid as reagent (e.g., a solid support of the invention comprising a dihydroxyalkylaminoalkyl group), as compared to the amount of boronic acid in the sample. The reaction generates a boronic acid-free solution.
In alternative embodiments, solid supports of the invention also facilitate the synthesis of new functionalized boronic acids, such as new arylboronic acids, vinyl boronic acids, alkyl boronic acids, and the like. Solid supports of the invention can be; used in the large-scale synthesis and/or purification of boronic acids, e.g., arylboronic acids. Solid supports of the invention arc useful in resin to resin transfer reactions, such as in Suzuki cross-coupling reactions. 7~he resultant biphenyl products can be used to produce a variety of chemicals and products, e.g., pharmaceutical reagents.

The dihydroxyalkylaminoalkyl- and dihydroxyalkylaminobenzyl-derivatized solid supports of the invention are particularly useful in combinatorial chemistries and various devices (automated and semiautomated) used in such solid-phase chemistries.
The compositions of the invention are also useful for stabilizing boronic acids from oxidation by air. Accordingly, the compositions of the invention can be used to store boronic acids, particularly, those sensitive to oxidation. For example, use of a resin-to-resin transfer reactions (RRTR) strategy using the derivatized solid supports of the invention (c:.g., DEAM-PS resin) is advantageous for handling and storage of boronic acids; otherwise air-sensitive boronic acids (e.g., alkenylboronic acid) are stabilized through immobilization as diethanolamine adducts.
In one embodiment, as described in Example 1, below, polystyrene resin was derivatized with a diethanolamine anchor. This was achieved through the reaction of 1%
divinylbenzene cross-linked aminomethylated polystyrene (AM-PS) with excess ethylene oxide at ~0 °C in a tetrahydrofuran (THF)/water solvent mixture using a sealed, pressure-resistant tube (see Figure 1 ). Under these conditions, quaternization to give the trie;thanolalkylannnonium hydroxide salt and oxirane alcoholysis are known to be minimal (see, e.g., Sundaram ( 1969) Bull. Chem. Soc.
Jpn. 42:3141-3147). The resulting diethanolamine-derivatized resin possessed characteristics and a loading level that demonstrated the clean and complete bis-alkylation of amino-methylated polystyrene (AM-PS) to give DEAM-PS. In another embodiment, polystyrene resin was derivatized with a diisobutanolamine anchor using isobutylene oxide (see Example 6). In other preferred embodiments, other oxiranes, e.g., styrene oxide, substituted styrene oxide, aryl substituted oxiranes, can be used to foam the corresponding dihydroxyalkylamine-derivatized resin.
The invention also provides novel strategies for resin-to-resin transfer reactions. via phase transfer of solid supported boronic acids under both aqueous and anhydrous conditions. Resin-to-resin transfer reactions represent an advance in solid-phase synthesis. In addition to further simplifying solid-phase synthesis, they allow the use of convergent strategies and their associated advantages. The invention's novel RRTR process can be applied to the synthesis of many classes of compounds, e.g., biologically relevant biphenyl and arylglycine compounds.
Biphenyl and arylglycine compounds are commonly used as, or the synthesis of;
therapeutic agents, and in the generation of combinatorial libraries.
For example, the methods of the invention provide convergent solid-phase synthesis of symmetrically or unsymmetrically functionalized compounds, such as biphenyl compounds.
Biphenyl units, whether spnmetrical or not, are popular pharmacophore,s in drug discovery.
Also, other advantages of RRTR over the traditional approaches also relate to the advantages of using dihydroxyalkylamino-derivatized resins, e.g., it is not necessary to cleave and handle the boronic acid in solution and saves time. Also, it allows the use of convc;rgent synthetic strategies which can potentially allow access to compounds that arc inaccessible othec-wise.
Examples 2 and 3, below, describes prefen-ed embodiments of uses of the present invention for resin-to-resin transfer reactions (RRTR). As described in Example 3, below, the invention provides the first resin-to-resin transfer reaction for the formation of carbon-carbon bonds via Suzuki cross-coupling reactions between resin-bound aryl iodides and arylboronic acids supported onto N,N-diethanolaminomethyl polystyrene (f)EAM-PS). These solid supports facilitate the synthesis of functionalized arylboronic acids which can otherwise be difficult to handle in solution. As described in detail in Figure 8, below. p-carboxy-, p-(bromomethyl)-, .and ~n-aminobenzeneboronic acids were bound to N,N-diethanolaminomethyl polystyrene (DEAM-PS) and transformed on solid supports using amide formation, alkylation by a secondary amine, and acylation, respectively. Under conditions for Suzuki coupling, the new resin-bound boronic acids were transferred to solution phase by transesterification and coupled in sitTi with a haloarene resin. Using the methods of the invention, there is no need fur cleaving and therefore handling boronic acids derivatized on the solid support prior to the Suzuki coupling.
The potential of the invention was demonstrated with a convergent solid-phase synthesis of unsymmetrically functionalized biphenyl compounds (see Figure 9) that would be difficult to ?1 access using a linear solid-phase synthesis. The invention's novel resin-to-resin transfer system for carbon-carbon bond formation simplifies solid-phase Suzuki couplings considerably and is very valuable for use in high-throughput combinatorial library synthesis.
Another preferred embodiment is the optimization of a resin-to-resin borono-Mannich reaction between secondary amines and arylboronic acids to make arylglycine derivatives describedin Example 2. Compounds of this nature are of particular interest for their biological activity (see, e.g., Bedingfield (1995) J. Pharmacol. 116:3323-3330). Irnlnltrm intermediates, formed from the condensation of glyoxylic acid and resins fiu~ctionalized with a secondary amine, were coupled to resin-derivatized boronic acids. The iminium intermediates were then transferred to solution from the corresponding N,N-diethanolaminomethyl-polystyryl boronates by ija situ transesterification with the ethanol co-solvent to provide arylglycine derivatives.
Any reaction involving a boronic acid is adaptable to the methods of the invention, including, e.g., Chan ( 1998) Tetrahedron Lett. 39:29 33-2936; Petasis ( 1998) .1. Am.
Chem. Soc. 120: I 1798-11799.
The invention also provides synthesizer devices, e.g., synthesizers, such as parallel synthesizers, comprising solid supports derivatized with haloarenes and various boronic acids.
Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As used herein, the following terns have the meanings ascribed to them unless specified otherwise.
As used herein, the term "alkyl" is used to refer to a branched or unbranched, saturated or unsaturated, open chain or cyclic, hydrocarbon radical having from 1 to about 20 carbons, or, from about 4 to about 20 carbons, or, from about 6 to about 18 carbons. When the alkyl group has from I to about 6 carbon atoms, it can be referred to as a "lower alkyl."
Suitable alkyl radicals include, for example, structures containing one or more methylene, methine and/or methyne groups. The term also includes branched structures have a branching motif similar to i-propyl, t-butyl, i-butyl, 2-ethylpropyl, etc. As used herein, the term encompasses "substituted alkyls." "Substituted alkyl" refers to an alkyl as just described including one or more functional groups such as lower alkyl, aryl, acyl, halogen (i.e., alkylhalos), hydroxy, amino, alkoxy, alkylamino, acylamino, thioamido, acyloxy, aryloxy, aryloxyalkyl, mercapto, thia, aza, oxo, both saturated and unsaturated cyclic hydrocarbons, heterocycles and the like.
These groups may be attached to any carbon of the alkyl moiety. Additionally, these groups may be pendent from, or integral to, the alkyl chain.
As used herein, the term "arene" refers to any substituted or unsubstituted mono- or polycyclic aromatic hydrocarbon compound as well as any mono- or polycylic heteroaromatic compounds, and can include fused or bridged ring systems.
The term "boronie acid" includes any form of boronic acid or equivalent.
including, e.g., aryl boronic acids, such as such as phenylboronic acids; see also, U.S. Patent Nos.
6,IJ83,903;
6,075,126; 6,037,490; 6,031,117; 6,013,783; 5,840,677; 5,780,454; 5,739,318.
Boronic acid reagents and boronic acid complexing reagents are described in, e.g., U.S.
Patent Nos. 5,594,1 I 1, 5,623,055, 5,668,258, 5,648,470, 5,594,1 _S 1, 5,668,257, 5.67'7,431, 5,688,928, 5,744,627, 5,777,148, 5,831,045 and 5,831,046.
As used herein, the term "Mitsunobu-like reaction" means any reaction based on a Mitsunobu reaction (the nucleophilic substitution of an alcoholic hydroxyl group mediated by the redox system trialkylphosphine/dialkyl azodicarobxylate), which is well known in the art, see, e.g., Barren (2000) Org. Lett. 2:2999-3001; Stachel (2000) Org. Lett. 2:1637-1639;
Falkiewicz (1999) Nucleic Acids Symp. Ser. 42:9-10; Wisniewski (1998) ,l. f'ept. Sci. 4:1-14.

As used herein, the term "trmsfer agent'' or "chaperone" refers to any neutral chemical agent. In RRTR, transfer of one resin-bound substrate to solution phase is necessary in order to effect its coupling to other resin-bound substrates. A neutral chemical agent, or chaperone, is required to promote this event under conditions compatible with the desired reaction.
As used herein, the term "resin" refers to any insoluble polymeric material which allows ready separation from liquid phase materials by filtration and which can be used to carry library members or reagents, or to trap excess reagents or reaction by-products (i.e.
scavenger resin).
As used herein the term "solid support" refers to insoluble, funetionalized, polymeric material to which library members or reagents may be attached (often via a linker) allowing them to be readily separated (e.g. by f ltration, centrifugation, ete.) from excess reagents, soluble reaction by-products or solvents.
The terms ''dioxyalkylaminoalkyl" and "bis(oxyalkyl)aminoalkyl'" described the same structure, as schematically shown, above.
As used herein, the terms "mixing or "contacting" refer to the act of bringing components of~a reaction into adequate proximity such that the reaction can occur. Mor<:
particularly, as used herein, the terms "mixing" and "contacting" can be used interchangeably with the following:
combined with, added to, mixed with, passed over, flowed over, etc.
General Methods The present invention provides novel solid supports derivatized with a dihydroxyalkylaminoalkyl (e.g., a diethanolaminoalkyl) or dihydroxyalkylaminobenzyl group. The invention also provides novel means of making and using these solid supports, including the resin-to-resin transfer reactions via phase transfer of soid supported boronic acids under both aqueous acid anhydrous conditions. Figure 24 is a schematic of the immobilization and derivatization of functionalized boronic acids using N,N-diethanolaminomethyl polystyrene (DEAM-PS).
The skilled artisan will recognize that the methods of the invention can be practiced using a variety of ancillary and equivalent procedures and methodologies, which are well described in the scientific and patent literature., e.g., Organic Syntheses C.'ollective Volumes, Gilman et cc.!.
(Eds) John Wiley & Sons, hic., NY; Venuti ( 1989) Phcarrn IZes. 6:867-873. The invention can be practiced in conjunction with any method or protocol lznown in the art, which are well described in the scientific and patent literature. Therefore:, only a few general techniques will be described prior to discussing specific methodologies and examples relative to the novel metlnoc(s of the invention.
Solid Support Sacrfaees The solid supports can be of any material that can be used in solid phase synthesis and that can be coupled to (or "derivatized with"), directly or indirectly, covalently or non-covalently, a dihydroxyalkylaminoalkyl group, or a dihydroxyalkylaminobenzyl group, or mixtures thereof:
Any solid or semisolid surface that can be derivatized with a dihydroxyalkylaminoalkyl (e.g., a diethanolaminoalkyl) group or a dihydroxyalkylaminobenzyl group can be used to practice the invention. In one embodiment, the invention uses an aminoalkylated sc>lid support. Any solid support with can be directly or indirectly aminoalkyl-derivatized can be used.
The solid support need only be substantially insoluble under conditions for practicing the methods of the invention. The solid support can be of a rigid' semi-rigid or flexible material.
The solid support can be flat or planar, be shaped as wells. raised regions, etched trenches, pores, beads, filaments, or the like.
Any solid suppou upon which a dihydroxyalkylaminoalkyl (e.g., a diethanolaminoalkyl) or a dihydroxyalkylaminobenzyl group can be bound can be used to practice the invention. For ?~

example solid supports can be of any material, or mixture of material, upon which an alkyl halide or a substituted alkyl halide, or an aminoalkyl group, carp be directly or indirectly bound. For example, suitable materials can include, e.g., resins, such as polystyrenes or equivalent compositions (see, e.g., U.S. Patent No. 5,290,819; 5,52'~,637; 5,591,7'78;
5,880,166; 5,90(),146).
The polystyrene can comprise a polystyrene-divinylbermenc) (PS-DVB) or an equivalent composition. The solid support can comprise a plastic or a plastic co-polymer (NylonT"'.
TellonTM) or an equivalent thereof. The solid support can comprise a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or an equivalent thereof, or a mixture thereof. For example, an equivalent of glycol is a polyethylene glycol copolymer, e.g., ffentagel RT"' parlous TentaGel resins are sold by Rapp Polymere GmbH, Tiibingen, Germany). The solid support can comprise a polyvinyl alcohol) (PVA) hydrogel. The solid support can comprise a polyacrylamide or an equivalent polymer composition. The polyacrylamide can comprise a polymcahacylamide> a methyl methacrylate, a glycidyl methacrylate, a dialkylaminoalkyl-(meth)acrylate, or a N,N-dialkylaminoalkyl(meth)acrylate, or an equivalent composition. The solid support can comprise an inorganic composition selected from the group consisting of sand, silica (e.g., silica porous microbeads, see, e.g., U.S. Patent Nos. 5,128,114, 5,032,2.66, or silica gels, see, e.g., U.S. Patent No. 6,071,838, such as a silica hydrogel, see, e.g., U.S. Patent No.
6,074,983), glass (see, e.g., U.S. Patent No. 5,843,767; 5,604,163), glass fibers (see, e.g., U.S. Patent No. 6,053,012), quartz glass (see, e.g., U.S. Patent No. 6,071,838), metals (e.g., g;old, alumina (see, e.g., U.S. Patent No.
6,048,577), zirconia, titania, and nickel oxide). Other solid support alternatives include ceramics, quartz (see quartz glass, above) or other crystalline substrates (e.g. gallium arsenide), metalloids, polacryloylmorpholide, poly(4-methylbutene), poly(ethylenc icrephthalate), rayon (see, e.g., U.S. Patent No. 5,609,957), nylon, polyvinyl butyrate), polyvinylidene difluoride (PVDF) (see, e.g., U.S. Patent No. 6,024,872), silicones (see, e.g., U.S.
Patent No. 6,096,817), polyformaldehyde (see, e.g., U.S. Patent Nos. 4,355,153; 4,652,613), cellulose (see, e.g., U.S.
Patent No. 6,103,885), cellulose acetate (see, e.g., U.S. Patent No.
5,929,229), nitrocellulose, various membranes and gels (e.g., silica aerogels, see, e.g.., U.S. Patent No.
5,795,557), paramagnetic or superparamagnetic microparticles (see, e. ., U.S. Patent No.
5,939,261 ) and the like. The surface can be derivatized for application of the alkyl halide or a substituted alkyl halide or equivalents. Reactive functional groups can be, e.g., hydroxyl, carboxyl, amino groups or the like.
In one preferred embodiment, the polystyrene has a low degree of divinylbenzene cross-linking.
In solid-phase chemistry, both for immobilization and derivatization p~~rposes, about 1 %-2%
cross-linking is preferred in one embodiment to optimize resin swelling and reagent diffusion.
Higher degrees of cross-linking found in macroreticular resins (8'%-20°,%) generally provide materials of much lower efficiency for use in solid-phase chemistries. It has been shown that tl~e degree of cross-linking is important to solid-phase applications, and hi' her degrees of cross-linking have been shown to be unsuitable for solid-phase reactions (sec Rana et al., .l. C'omh.
Chem. 2001, 3, 9-15).
In one embodiment, the solid support is a plurality of conjugated beads or bundles of conjugated fibers, e.g., a column of conjugated resin beads.
Synthesizers The invention also provides synthesizers, such as semiautomated or fully automated synthesizers, e.g., parallel synthesizers, comprising solid supports derivatized with haloarenes and various boronic acids. A variety of semi-automated and automated synthesizers are available for chemical synthesis, particularly for use in combinatorial chemistries. For example;., the TridentT~' library synthesizer of Argonaut Technologies, San Carlos, C'A;
synthesizers o1' ArQule of Medford, Mass; Accelab Laboratory Automation or RAPP Polymere GmbH, of Tuebingen, Germany; and the like. See also Bhattacharyya (2000) Comb. Chem.
High Throughput Screen. 3:1 17-124; South (2000) Comb. Chem. High Throughput Screen. 3:169-151;
South (2000) Biotechnol. Bioeng. 7:51-57; Davis (2000) Biotechnol. Bioeng.
71:19-27). Other devices that are suited for, are can be adapted to be suited for, making and using the instant invention are described in, e.g., U.S. Patent Nos. 6,086,74(1; 6,025,371.

Cozzzbinatorial Chemistries The dihydroxyalkylaminoalkyl- and dihydroxyalkylaminobenzyl-derivatized solid supports are particularly useful in combinatorial chemistries. For example, the solid supports of the invention can be used to immobilize boronic acids, e.g., aryl boronic acids. The solid supports of the invention can be used to immobilize aryl, alkenyl, and alkyl boronic acids near quantitatively in a wide range of organic solvents.
The invention's novel methods, including its strategies far resin-to-resin Suzuki coupling reactions and borono-Mannich reactions via phase transfc;r of solid supported boronic acids under both aqueous and anhydrous conditions, are particularly useful in combinatorial chemistries. For example, the methods of the invention, incorporating a Suzuki RRTR system, allow for the convergent solid-phase synthesis of symmetrically or unsymmetrically functionalized compounds, including symmetrically or unsymmetrically functionalized biphenyl compounds.
Methods, reagents and apparatus for practicing combinatorial chemistries are well known in the art, see, e.g., U.S. Patent Nos. 6,096,496; 6,075,166; 6,054,047; 5,980,839;
5,917,185;
5,767,238.
It is understood that the examples and embodiments described herein arc for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of Ibis application and scope of the appended claims.

EXAMPLES
The following examples are offered to illustrate, but riot to limit the claimed invention.
Example 1: Preparation and use of N, N diethanolaminomethyl polystyrene The following example describes an exemplary protocol for practicing the methods of the rnvenhon to prepare and use a stable, resin-bound boronic; ester in the Ior-m of an N. N-diethanolaminomethyl polystyrene (DEAM-PS).
Preparcatio'a of'DEAM-PS resin. Referring now to Figure 1, reaction a.
polystyrene resin wa s derivatized with a diethanolamine anchor through the reaction of aminomethylated polystyrene (AM-PS) with excess ethylene oxide at S0 °C in a tetrahydrohrran ('THF)/water solvent mixture using a sealed, pressure-resistant tube.
1% Divinylbenzene (DVB) cross-linked aminomethylated polystyrene (3.0 g, 1.00 mmol g-~
substitution) was weighed out in a large thick-walled pressure tube equipped with a stirring bar.
A 9:1 THF/water solvent mixture (2S mL) was added; followed by excess ethylene oxide (approximately 2 mL). The tube was quickly closed through its Teflon'"'' screw cap equipped with a seal and immersed into a SO to SS°C oil bath. The tube was hand shaken periodically when magnetic stirring becomes inefficient. After about 12 to 24 hours.. the tube was allowed to cool to RT and uncapped. The tube contents were passed through a medium-porosity fritted glass filter and the resin was rinsed with T HF (Sx), CHZCI~/Et3N 3:1 (3r:), then CH~C1, (Sx j, ;end dried under high vacuum for a few days (the resin was pulverized to powder after a few hours of drying), affording 3.35 g of a white colored resin (theoretical: 3.26 g, 0.92 mmol g~~).
The resulting diethanolamine-derivatized resin possessed characteristics and a loading level that demonstrated the clean and complete bis-alkylation of aminomethylated polystyrene (AM-PS;I to give DEAM-PS. The resulting resin gave a negative outcome on Kaiser's ninhydrin assay (see.
e.g., Kaiser (1970) Anal. Biochem. 34:S9S-S98), indicating the absence of any primary and 2 c) secondary amines originating from incomplete alkylation. The presence of a basic tertiary amine site, however, is shown through a positive reaction with bromophenol blue. The absence of over-alkylation to give a triethanolalkylarmnonium hydroxide resin was indirectly confirmed by exhaustive acylation with FmocGlyOH (HOBT, DIC, DMAP; DMF, RT, 6 h) followed by LTV
quantitation of tile resulting fulvene-piperidine adduct. The loading level obtained therein was in agreement with the formation of two ethanolamine arms per aminomethyl site according to tlhe initial loading of commercial AM-PS.
A slightly high O/N ratio from combustion analysis of the resin (theoretical =
2.3, experimental = 2.6) was found in one embodiment, possibly indicating the presence of residual water, or of a few hydroxyethoxyethyl arms (HOCH~CHzOCH2C1-IZN-) formed by ethylene oxide solvolvsis in one embodiment. These trace inhomogeneities did not affect the resin's efficiency.
Inif~robilization urnl subseduent release of horonic acids,fi-onr DEAM-PS
resin. Referring now to Figure 1, reactions b and c, a schematic of a typical immobilization and subsequent release of a boronic acid is shown. In one preferred embodiment of reaction "b" conditions comprised a boronic acid (compound 2), solvent, RT, 15 min. In other embodiments, boronic acid b comprised any of the boronic acids of Figure 2 and Table 1. In one prefi~rred embodiment of reaction '' c", conditions comprised rfFIF/HZO/AcOH 90:5:5, RT, 1 h; or THF'/H~O 9:1, RT, 2 h.
Preliminary experiments showed that DEAM-PS resin could couple almost quantitatively to equimolar amounts of arylboronic acids in dry THF or other suitable solvents after a few minutes. The formation of a stable resin-bound boronic ester adduct (compound 3) was highly favored; there was no need to remove the produced water, unlike with other types of diols, whether solid-supported or not, which usually require azeotropic removal of water. The use of a glycerol-PS resin (purchased from Advanced Chemicals, Inc.) led to less than 50~% couplin~~
under the same conditions (data not shown). These results clearly underlined the benefit of nitrogen coordination allowed by dihydroxyalkylamine-conjugated resins, such as DEAM-PS.
Another control experiment ruled out the possibility that a tertiary amine site alone could be sufficient by forming a tight acid-base complex. Diisopropylaminomethyl polystyrene (Argonaut Technologies, San Carlos, CA) failed to couple with compound 2a (see Figure ?) under usual conditions (data not shown).
Immobilization card solid phase tr~a~zs~ornmtions of resin--boujrd cuwlbor-ouic acid corraPourrds, arnl svrtthesis of neu~ boronic uucid derivatives cornpourzds using DF,AM-PS
resin. Of particular interest to combinatorial chemistry was the use of solid supports arid methods of the invention to immobilize functionalized boronic acid templates and plan different solid-phase transformations.
For example, this would allow the elaboration of diverse libraries of new arylboronic acids with potential use as inhibitors of serine protease enzymes (for example, benzeneboronic acid is ar.~
effective competitive inhibitor of a-chymotrypsin and subtilisin; see, e.g., Philipp (1971 ) Proc.
Nat. Acad. Sci. USA 68:478-480). In addition, whereas L~oronic acids arc important building blocks for solid-phase Suzuki reactions in combinatorial chemistry (see, e.g., Wendeborn ( 1998) Synlett pg 671-675), few are commercially available.
Referring now to Figure 3, the immobilization and solid-phase transformations of the rcsin-bound arylboronic acids compound 3e, compound 3f , and compound 3g, and synthesis of new boronic acid derivatives compounds 7 through compound l0 are described. In one preferred embodiment, reaction "a" represents RNH~ (2.5 equivj, N-hydroxybenzotriazole~H20 (2.5 equiv), N,N'-diisopropylcarbodiimide (2.5 equiv), DMF, rt, 6 h; reaction "b"
represents THF/H20/AcOH 90:5:5, RT, I h; "reaction c" represents PhC'OC1 (10 equiv), i-PrzEtN ( 11 equiv), THF, rt, 24 h; "reaction d" represents PhCH~NH~ (2.0 equiv), NaBH(OAc)~ (2 equiv), (C 1CHZ)2, rt, 2 h.
The DEAM-PS boronate linkage was found resistant to standard carbodiimide methods for amide bond formation. Benzylamine and butylamine were coupled with high efficiency to res,in-bound p-carboxyphenylboronic acid (compound 3e), affording the corresponding amides compound 7 and compound 8 in high yields after cleavage (non-optimized yields of crude isolated compounds of satisfying purity, all characterized by NMR and MS).

Similarly, resin-bound m-aminophenylboronic acid (conupound 3f) was transformed into anilide 9 upon treatment with benzoyl chloride (reaction b) and reductive amination of compound 3g (Figure 3) with benzylamine afforded compound 10 ((Figure 3, reaction "c") (non-optimized yields of crude isolated compounds of satisfying purity, all characterized by NMR and MS).
Tvpiccrl protocol of one embodiment of tire invention for the immobilization of compound 3e, followed by amide coupling with butvkrmine urrd clcuvuge to give cornporrnd 8:
Referring now to Figure 3, a slight excess of p-carboxyphenylboronic acid (45 mg, 0.?7 mmol) was added to a polypropylene filter vessel containing a suspension of resin 1 as depictf:d in Figure 1 (200 m g, 0.18 mmol) in dry THF (2 mL). The vessel was shaken for 2 hours after which the resin was rinsed with dry THF (Sx) and dry dimethylformamide (DMF) (2x). Unbound boronic acid (a quantity of 13 mg of unreacted boronic acid) was recovered from the first three THF rinses, corresponding almost exactly to the theoretical unbound excess. Dry DMF (2 mL) was then added to resin 3e and a DMF solution ( I mL) containing N-hydroxybenzotriazole (70 mg, 0,46 mmol) and butylamine (50 pL, 0.46 mmol) was added to the suspension. The latter was homogenized by gentle vortexing followed by the addition oi~diisoprop;yl-carbodiimide (72 yL.
0.46 mmol). The vessel was shaken for 5 hours then rinsed with dry DMF (3x) and drv THF
(Sx). The resulting resin was treated with a 90:5:5 THF/water/acetic acid mixture (2 mL) for I
hour. The liquid phase was drained and the resin rinsed with the above cleavage mixture (1 x j and THF (3x). The combined filtrates were concentrated and dried under high vacuum (>12 hours) to afford arylboronic acid 8 as a white powder (41 mg, 90°/~). ~
H NMR (300 MHz, 5°/>
D~O/CD30D, 25 °C): b = 7.7-8.0 (m, 4H; Ar), 3.37 (t, ~.1(H,H) = 7 Hz, '?H; NCH), 1.59 (m, 2H;
CHZCH~CH3), 1.40 (m, 2H; CHZCH3), 0.96 (t, 3.1(H,H) = 7 Hz, 3H; CH_~); ~3C NMR
(75 MHz, 5% D20/CD~OD, 25 °C): b = 170.4 (CONH), 134.9 and 134.8 and 129.ti and 127.1 (4s, Ar), 40.7 (NCH), 32.6 (CHZCH~CH3), 21.1 (CH~CH3), 14.1 (CH3); MS (+ES): m/z (%): 244 (45) [M
++Na], 222 (100) [M ~]; HRMS (+ES): m/z calculated for C" H,~N03B [M +]:
222.1303; found 222.1301.

Example of the rrse of DEAM PS resin_for scaverzgirrglc apturing hororric acids n~ith THFlwaterlcrcetic acid cleavage. The boronic ester linkage of the DEAM-PS
boronate ester can be quickly hydrolyzed using a 90:5:5 'THF/water/acetic acid cleavage cocktail to release free boronic acids such as those in Figure ?. For acid-sensitive boronic acids, the resin can also be cleaved under neutral conditions with prolonged exposure to 9:1 THF/water.
Referring now to Table 1 and Figure 2, a solvent profile study usingp-tolylboronic acid (compound 2a, Figure 2) as a model compound anti a slight excess of REAM-PS
resin showed that a broad range of organic solvents is suitable for scavenging/immobilizing applications (see entries 1-6).
Table 1. Coupling of different boronic acids (2) with DEAM-PS resin l.~a~
Entry Boronic Acid Solvent Yield ~ Purity C%~(bl ~%l[cj 1 2a C'H,CI~ > 9S > 9S
_ __- ___ __ i_ _ 2 ?a DMF 87 j > 95 -- 2a __-_ ~, ___-_-_._ _-__ -_ _ ___ ' oluene - > )S ~ > 95 j 4 2a CH30H S3 > 9S
S 2a Et20 _ ~ _ 90 _. - > 95 ~ ?<< THF ~~ > 9S > 9S
I 7 2b 'fHF > 9S -__ ; 9S -_ - --___ --,_-__- _-.__ _ ___ 8 2c THF
>9S >9S
_--___ _i_-._ _-___ __- _-___ 2d THF ' > 9S > 9S
10-~ 2c THF _- _ > 9S _ -____. ______-_-____ __._ _-_ _ _~ _ Entry Boronic Acid Solvent Yield Purity j 1 l '2f THF > 95 > 90 2 2g THF 90 > )5 -_--____ 13 'h _____ ._____ __ _-_-_ __-THF 91 > 90 -__ 14 T H F __.-__ ____ 5 0 _ > () ~
_--_____-_ __ _ __ _ _ _-_ _- I

[a] Coupling reactions were conducted by shaking a slight excess of resin 1 (200 mg, 0.92 mmol/g substitution) with the boronic acid (0.8 equiv.) in the indicated solvent (2 mL) at room temperature for 1 S min in a polypropylene vessel equipped with a fritted filter. [b] Based on the amount of boronic acid recovered after cleavage of the resin for 1 h in ;r 90:5:5 THF/H~O/Ac~OH
mixture. Similar results were observed using a,water/THF 5:95 mixture. A
slight imprecision must be ascribed to these values as a result of exhaustive drying that may lead to partial dehydration to give boronic acid anhydrides. [c] Estimated through ~H NMR
analysis of the recovered boronic acids compared to commercial starting material.
All boronic acids used in Table 1 were obtained li-om commercial sources except compound 2h, which was synthesized according to Brown (1972) ,I. Am. Chem.
Soc.
94:4370-4371.
The DEAM-PS resin was also found to be very efficient for immobilizing a wide variety of electron-rich and electron-poor arylboronic acids in near quantitative yields in THF (Table 1, entries 6-12). These values were determined from the amounts of boronic acids recovered after subsequent hydrolytic release from the support. Concentration of the filtrate from exhaustive rinsing of the resin after immobilization revealed none or very little unbound (unreacted) boronic acid. DEAM-PS resin also coupled efFciently with alkenylboronic acids (entry 13) and with air-sensitive alkylboronic acids (entry 14). The boronic acids 2a-2i of Figure 2 were recovered intact after cleavage from the solid support.

The DEAM-PS resin was recycled with no apparent loss of efficiency after neutralization with base washings (e.g., 3:1 CH~CIz/Et~N).
Use of DEAM PS resizz as cz resin for scavengizzglcapturiug horozzic acids with THFhvuter.~
cleavage. Referring now to Table 5 and Figure 13, a series of boronic acids similar to those of Table 1 presenting different steric and electronic characteristics were tested by shaking with DEAM-PS at room temperature for 1 hour, followed by cleavage with 7'% Hz0/THF.
A slight excess of the boronie acid (ca. 1.3 equiv), pre-dried in vacuo a:~
the monoanhydride form, was shaken with DEAM-PS at room temperature for 1 hour. Percentages of recovery v.vere based on the amount of boronic acid isolated after cleavage of 2 with water/THF (5:95 ). A
solvent profile study usingp-tolylboronic acid revealed that a wide range of anhydrous solvents could be employed (entries 1-6). In a prei-erred embodimf:nt, THF was found to be a general solvent to solubilize and immobilize boronic acids efficiecitly. In another preferred embodiment, dichloromethane provided higher yields of immobilization (entries 5 vs 6). The limited solubility of water in dichloromethane may minimize the hack reaction (hydrolysis).
When using THF as solvent, a wide variety of functionaliced arylboronic acids presenting different steric and electronic characteristics were found to immobilize efficiently onto DEAM-PS (entries 6-18).
Hydroxylic solvents such as methanol and ethanol allowed for a dynamic transesterification process to take place, leading to non-quantitative immobilization (Table 5, entry 1 ). A control experiment was devised to measure the extent of transesterification of REAM-PS
supported p-tolylboronic acid (R =p-Tolyl) in 7:1 THF/ethanol. Equilibrium was reached within 15 minutes of exposure of the supported p-tolylboronic acid to the 7:1 THF/ethanol solvent. Successive incubations of the resin under constant resin:solvent proportions, followed by rinses with dry THF, revealed that approximately 40% p-tolylboronic acid was released from the resin under these conditions. The reverse reaction (resin +p-tolylboronic acid) gave a similar outcome under the same conditions, showing that the transesteriiic:ation process was under equilibrium.
In one preferred embodiment, it was preferable to employ a cleavage solution prepared from air-and peroxide-free, freshly distilled THF. The 2,6-di-t-butyl p-cresol used as stabilizer in non-distilled THF could accumulate in the polymer matrix of DEAM-PS and contaminate products upon cleavage. This could be prevented by the use of distilled THF for resin washing and for the cleavage solution. In a preferred embodiment, in the absence of the stabilizer, freshly distilled 'fHF was used in order to avoid a presumed build-up of peroxides, which have caused oxidation of the boronic acids into the corresponding phenols.
Table 5. Immobilization of various boronic acids onto l.'' Entry R Saivent Yield Purity',' %)b.

12 2-CHO-C~,H~ THF 98'' > 95 - __-_. _ -._______ ___ ___-_ _.______-_ 13 4-Ph0-C~,H~ THF 93 > 95 14 4-BrCH2-C~,H4 i THF 85 > 95 15 2,6-di-Me-C~H3 THF 46 > 95 16 2,4-di-F-C~H3 THF 46 > 95 17 2-naph THF 8cy, I -> 9> -__ 18 (E)-PhCH=CH ~ THF 81 -~

__ __ _-_--_-__ - ____ _-_~ -_ ° Coupling reactions were conducted by shaking resin 1 (1 ecluiv, 120 mg, 1.15 mmol/g) with the boronic acid (1.3 equiv) in the indicated solvent ( 1.5 mL) at room temperarurc for 1 hour in a polypropylene fritted vessel. h Yields of boronic acid recovered atter cleavage from the resin with 5% H~O/THF for 1 min at rt and washed with S% H~O/'THF (3x). The resin was rinsed with the reaction solvent (3x) prior to cleavage. For entries 4 and 5, additional THF rinses were carried out (3x). The reported yields are an average of mass balance and internal standardization based on the loading of resin 1 measured by elemental analysis. ' Estimated by comparison of 'H NMR spectra of starting and recovered boronic acids. '~ Calculated only from mass balance, tendency of this boronic acid to form anhydrides made NMR quantitation difficult.
Purification of crude dienylbororric acid. Referring now to Figure 4, solid support resin 1 was employed in the purification of crude dienylboronic acid 6 (see, e.g., Vaultier ( 1987) Tetrahedron Lett. 28:4169-4172).
Dienylboronic acid was produced by treating 2-methyl-1-buten-3-yne (compound 4) with dicyclohexylborane followed by oxidative workup. The purification of alkenvlboronic acids such as compound 6 can be considerably troublesome.

The use of resin 1 to capture dienylboronic acid (compound 6) and eliminate excess reagents and cyclohexanol oxidation by-product facilitated its purification through simple rinsing of its resin-bound form depicted as conjugated compound 5.
Figure 4 is a schematic summarizing resin capture purific;anon of dienylboronic acid with resin 1 following dicyclohexylboration/oxidation of compound 4. In one preferred embodiment, reaction "a'', the addition of compound 4 to (Cc,H" )~BH (1.0 equiv) was conducted in THF, 0 °C. 0.5 h; RT, 0.5 h: then (CH3)3N0~2H~0 (2.0 equiv), 0 °C" to R~,, 12 h; in one preferred embodiment, reaction "b" represents DEAM-PS resin 1 (0.5 equiv), CI-IZCI,, 1.5 h; and reaction ''c" represents THF/H20 9:1, RT, 1.5 h, 95% (overall yield based on compound 1 ).
Example 2: Resin-to-resin borono-Mannich transfer reactions using solid supported boronic acids Examples 2 and 3 describe preferred embodiments for practicing the methods of the invention.
The concept of resin-to-resin transfer reactions (RRTR), also called two resin systems, constitutes a significant simplification of solid-phase organic synthesis (SPOS) which can be extremely valuable as a time saving strategy in combinatorial chemistry. RRTR
systems allow for the convergent solid-phase synthesis and eventual coupling of fragments for which a linear SPOS strategy would involve incompatible reaction conditions.
In RRTR, transfer of one resin-bound substrate to solution-phase is necessary in order to efiec;t its coupling to the other resin-bound substrate. A neutral chemical agent, or chaperone, is required to promote this event under conditions compatible with the desired reaction (in the resin-to-resin acyl transfer system reported by Hamuro (1999) J. Am. Chem.
Soc. 121:1636-1644, the transfer agents employed therein were termed chaperones because they also act as solution-phase activators).

In particular, in Example 2, a resin-to-resin borono-Mamich reaction between dialkylamino resins and solid supported boronic acids of the invention is described. 'This embodiment is one optimization of a resin-to-resin transfer reaction between secondary amines and arylboronic acids to make arylglycine derivatives.
N,N-diethanolaminomethylpolystyrene (DEAM-PS) was made as described above (see Example I). All boronic acids were purchased from commercial sources (Sigma-Aldrich, Lancaster Synthesis, Windham, NH, or Combi-Blocks, San Diego, ~~A) and were loaded onto DEAM-E'S
as described above. The dialkylaminotrityl resins were made by the condensation of excess diamine (20 equiv.) onto commercial chlorotrityl polystyrene (Rapp Polymere, T
ubingcn, Germany) swelled in N-methyl-2-pyrrolidone (NMF'). Loading measurements were carried out by analysis of nitrogen content. For RRTR's, runs were done in 10 mL_.
TeflcmTM fritted vessels on a Quest 21 OTM instrument with solvent wash unit (Argonaut Technologies, San Carlos, (~P,).
Cleavage was effected on-line and crude products were obtained after evaporation of solvents.
Yields and purity were estimated by comparison with an inteunal NMR standard (EtOAc, I ~ sees relaxation delay).
Typical procedure for the borono-Mannich RRTR involved preparation of compound Sc of Figure 6. Figure 6 is a schematic summarizing a borono-Mannich resin-to-resin transfer reaction between boronic acids supported onto N,N-diethanolaminomethyl polystyrene and the iminium intermediate formed from dialkylamino resin 3 and glyoxvlic acid.
Referring now to Figures 5 and 6, in one preferred embodiment, to piperazinetrityl resin 3 (32 mg, 0.030 mmol, theoretical (theor.) loading: 0.95 mmol/g;) weighed out in a reaction vessel was added a solution of glyoxylic acid monohydrate (0.032 mmol) in dry THF (2 mL).
The suspension was allowed to mix at room temperature (rt) under a nitrogen atmosphere for 2 hours.
An excess of DEAM-PS boronic ester 2c ( I 27 mg, 0.120 mmol, theor. loading:
0.95 mm/g) was then added followed by 1.5 ml of 8:3 THF/EtOH. The suspension was mixed at G5°C for 48 hours (h) under a nitrogen atmosphere and then cooled to rt. The resin mixture was filtered and rinsed with 8:3 THF/EtOH (3x), 2:1 THF/H20 (3x) and CH~CI~ (Sx), mixed with 3 ml of S~o TFA/ CHZC1Z in the same vessel at rt for one hour, then filtered and rinsed with CHZCI~ (3x) and MeOH (2x). The combined filtrates were concentrated and dried under high vacuum for 12h to afford crude compound Sc as a clear oil ( 14 mg, 90 '% conversion). An analytically pyre sample was obtained by dissolving the oil in a small amount of methanol followed by addition of ether, filtration of the precipitate, and concentration of the resulting solution.
The boronic acid Mannich reaction was compatible with a wide range of solvents, including hydroxylic ones. In one embodiment of the invention, an alcohol was employed as co-solvent to act as neutral phase transfer agent to cleave a solid support-derivatized boronic acid of the invention (e.g., DEAM-PS) under mild conditions appropriate toward a RRTR
system. The boronic acid liberated in sitzz as an ester was then add to the imine formed between an amino functionalized resin and an activated aldehyde such as glyoxylic acid. The resulting arylglycinc products obtained after cleavage of the resin mixture were compounds of particuar interest for their biological activity.
Referring now to Table 13, in one preferred embodiment, conditions using DEAM-PS supported p-tolylboronic acid (compound 2, R = 4-Me-C~H4- in Figure 5), piperazinetrityl resin, and glyoxylic acid in a semi-automated synthesizer, as descriL~ed, above were explored. The rate of reaction was found to be dependent on the nature of the solvent system;
THF/EtOH (7:1 ) and DMF/n-BuOH (7:1 ) being first and second best respcctivE;ly of those tried for the system as described in Table 13.
Table 13 Optimization of solvent system, at 65 °C for 24 h, for the borono-Mannich RR'TR
of compound 3, Figure 6 and compound 2, Figure 7, to give compound 5, Figure 6.~
Entry ''Solvent Conversion (%)' 1 7:1 DMF/EtOH (>5 -______ --_-_ i Entry Solvent Canversian {p~0)~

2 7:1 DMF/rt-BuOH 54 3 7:1 dioxane/n-BuOH 23 4 7:1 THF/(HOCH~)~ 37 7:1 THF/EtOH 79 '~ Preparation of resin substrates, RRTR trials, and subsequent cleavage of the resin mixture were carried out as indicated above. ~' Based on the relative amounts of product and bis(trifluoroacetate) salt 6, Figure 6, calculated by integration of relevant signals by'H NMR
after 24 h reaction time.
In one preferred embodiment, one set of experimental conditions first involved incubating thc~
dialkylamino resin with glyoxylic acid monohydrate (l.l equivalent) Ior two hours in dry THF at room temperature. Then, four equivalents of DEAM-PS bound boronic acid were added along with the appropriate volume of 8:3 THF/1a01-1. ~l'he suspension was shaken at 6~°C for up to 48 hours. Conversion levels superior to 75°/~ were observed ~n the case ofp-tolylboronic acid as seen after cleavage of the final resin mixture 1 and 4 (Figure 5) with 5°,~ trifluroacetic acid/dichloromethane to give the corresponding amino acid product Sa as a bis(trifluroroacet<~te) salt (Table 2, below). The rest of unreacted starting resin 3 was cleaved into the bis(trifluoroacetate) salt of piperazine (compound 6) which can be eventually removed by precipitation. There were no other by-products observed, as the leftover DEAM-PS resin (compound 1) did not give any artifacts upon treatment with trifluoroacetie acid in the produca release step.
RR TR of cornpoztnd 3, compound 7, arid compound I I with different Dl:AM-YS-borof-icttes ctrrcl cleavage to provide arylglycine dE~rivatives compounds S, 9, artd 12.
Referring now to Figure 6 and Table 2, different substrates for use in the RRTR systems of the present invention were explored.

Figure 6 illustrates preferred embodiments of the RRTR of compound 3, compound 7, and compound 11 with different DEAM-PS-boronates and cleavage of the final resin mixture to provide arylglycine derivatives compounds 5, 9, and 12, respectively. t~s shown in Table 2, conversion values and product yields were generally good. Conversion values for the RRTR of electron-poor arylboronic acids were found to be lower.
A typical procedure for the preparation of 3 comprised the following. Trityl chloride resin (500 mg, 0.535 mmol, theor. loading: 1.07 mmol g-~) was weighed into a 70 ml pp vessel and a solution of piperazine (920 mg, 10.7 mmol) in NMP (20 mL) was added. The reaction was shaken at rt overnight. The suspension was drained, and the resin was rinsed with Me01-1 (3x), and CHZC12 (6x). The resin was dried under high vacuum for > 24 h to afford a yellow resin (460 mg, theor. 515 mg, 1.02 mmol g-~ ).
A typical procedure for the borono-Mannich RRTR for the preparation of 5c comprised the following. To piperazinetrityl resin 3 (32 mg, 0.030 mmol, theor. loading:
0.95 mmol g ~) weighed out in a 10 ml teflon fritted reaction vessel was added a solution of glyoxylic acid monohydrate (0.032 mmol) in dry'fHF (2 mL). The suspension was allowed to mix at rt under a nitrogen atmosphere for 2 h. An excess of DEAM-YS boronic ester 2c (127 mg, 0.120 mmol, theor. loading: 0.95 mm g-~) was then added, followed by a 8:3 THF/EtOH
solution (1.5 mL).
The suspension was mixed at 65°C for 48 h under a nitrogen atmosphere and then cooled to rt.
The resin mixture was filtered and rinsed with 8:3 THF/EtOH (3x), 2:1 THF!H~O
(3x) and CHZC12 (5x), mixed with 3 ml of 5% TFA/CHzCIz in the same vessel at rt for 1 h, then filtered and rinsed with CHzCI~ (3x) and MeOH (2x). The combined filtrates were concentrated and dried under high vacuum for 12 h to afford crude Sc as a dear oil ( 14 mg, 90 % conversion). An analytically pure sample was obtained by dissolving the oil in a small amount of methanol followed by addition of ether, filtration of the precipitate, and concentration of the resulting solution.

Selected data for all products: 5a: 'H NMR (300 MHz, CD3OD) b 7.30 (d, J=8.0 Hz, 2H), 7.20 (d, J =8 Hz, 2H), 4.17 (s, 1 H), 3.23-3.20 (m, 4H), 2.77-2.74 I;m, 4H), 2.:33 (s, 3H); ' jC NMR (75 MHz, CD30D) 8 173.5, 140.5, 132.0, 130.7, 130.1, 73.3, 48.1, 44.3, 21 .2; ESMS
235.1 (M+HT).
5b: ~ H NMR (300 MHz, CD;OD) d 7.40 (d, J=6.0 Hz, 1 H ), 7.24-7.18 (m, 3H), 4.50 (s, 1H), 3.20-3.16 (m, 4H), 2.85-2.82 (m, 4H), 2.45 (s, 3H);'3C NMR (75 MHz, CD~OD) 8 174.2, 138.9, 134.7, 131.8, 129.3, 129.1, 127.1, 69.3, 47.7, 44.9, 19.4; I-,SMS 235.3 (M+H~). 5c: 'H NMR
(300MHz, CD30D) h 7.34 (d, J=8.6 Hz, 2H), 6.93 (d, J==8.9 Hz, 2H), 4.13 (s, 1 H), 3.79 (s, 3H), 3.23-3.19 (m, 4H), 2.75-2.72 (m, 4H);'3C NMR (100 MHz, CD~OD) b 174.3, 161.7, 1 31.2, 127.9, 115.2, 73.1, 55.7, 48.3, 44.7; ESMS 251.1 (M+H'). 5d:'H NMR (300 MHz, CD;OD) b 7.55 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 4.22 (s, 1 H), 3.25-3.19 (m, 4H), 2.77-2.73 (m, 4H); ESMS 301.1 (M+H+). 5e: 'H NMR (300 MHz, CDzOD) b 8.43 (d, J=7.9 Hz, 1H) 7.91-7.88 (m, 2H), 7.60-7.45 (m, 4H), 5.06 (s, 1H) 3.16-3.12 (m, 4H), 2.93-2.90 (m, 4H);'3C NMR (75 MHz, CD30D) cS 174.3, 135.7, 133.4, 132.4, 130.5, 129.8, 128.4, 127.6, 127.1, 126.2, 125.2, 70.1, 47.9, 45.2; ESMS 271.1 (M+H+). 5f: 'H NMR (300 MHz, CD~OD) 8 5.89 (dt, J,=15.0 Hz, JZ=7.0 Hz, 1 H) 5.48 (dd, J,=15.0 Hz, J~=8.0 Hz, 1 H) 3.70 (d, J=8.0 Hz.. 1 H) 3.26-3.23 (m, 4H), 2.95-2.87 (m, 2H), 2.84-2.76 (m, 2H), 2.12 (app q, J=7.0 Hz, 2H) 1.44--1.29 (m, 4H) 0.92 (t, J=7.0 Hz, 3H); IBC NMR (100 MHz, CDzOD) b 173.9, 140.5, 124.3, 71.8, 48.1, 44.6, 33.2, 32.2, 23.2, 14.2; ESMS 227.2 (M+H+). 9c: ~ H NMR (300 MHz, C'D~OD) b 7.38 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 4.65 (s, 1H), 3.80 (s, 3H), 3.34-3.21 (m, 2H) 3. 21-3.10 (m, 4H), 3.01-2.97 (m, 2H), 2.07-2.04 (m, 2H);'3C NMR (75 MHz, CD30D) 8 174.4. 161.8, 131.5, 128.0, 115.4, 73.1, 55.8, 53.3, 49.2, 46.7, 45.9, 26.1; ESMS 265.1 (M+H'). 12c: 'H
NMR (300 MH:z, CD;OD) b 7.48 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.96(s, I H), 3.83 (s, 3H), 3.13-3.01 (m, 8H), 2.18-2.03 (m, 2H), 1.33-1.25 (m, 3H); ESMS 295.4 (M-+-H+).

Table 2: Preparation of arylglycine derivatives by borono-Mannich RRTR as shown in Figure 6 a Entry Amino DEAM-PS- Product ConversionYield Resin Boronate 2 !b ' (f)' 1 3 R=4-Me-C~,H4 Sa 79 90 2 3 R=2-Me-C~,H.~ Sb 81 73 3 3 R=4-Me0-C~,H~ Sc 90 -~ 9~

--___ -_ __ ____ 4 3 R=4-B r-C~ H,~ S d 21 10 I
3 R=1-Naph Se 78 90 6 3 R=E-HC=CH(Bu) Sf 89 > 95 __-___ _____- __-__.__ __ __ 7 7 R=4-Me0-C~,H4 9c 95 91 __- _____ _ ._ _.
_ 8 11 R= 4-Me0-C'.~,H4 12c 76 82 a Preparation of resin substrates, RRTR trials, and subsequent cleavage of the resin mixture were carried ovt as indicated herein. n Based on the relative amounts of product and respective bis(trilluoroacetate) salt 6, 10, or 13 calculated by integration of relevant peaks by ~H NMR after 24-48h reaction time. ' Yields of crude product based Otl ~ H NMR analysis with an internal standard.
Observed conversion values for the reactions conditions of Table 2 were highest for DEAM-:PS
supportedp-methoxybenzene boronic acid (entries 3, 7, 8;), and lowest fore-bromophenyl boronic acid (entry 4). DEAM-PS-supported alkenylboronic acids were also appropriate substrates (entry 6). In this case the use of a RRTR strategy using DEAM-PS
resin was even more advantageous for handling and storage purposes since the otherwise air-sensitive alkenylboronic acids were stabilized through immobilization as diethanolamine adducls. Use of an acyclic amine (compound 11 ) was equally successful (entry 8), demonstrating that a variety of secondary amines such as terminal N-alkylamino acids can be employed in the methods of the invention. Analytically pure samples of most reported compounds could be obtained following precipitation with methanol/ether and filtration of the unreacted dialkylamine as a bis(trifluoroacetate) diammonium salt.
The borono-Mannich RRTR incorporating the derivatized solid supports of the present invention was also useful for the convergent solid-phase synthesis of libraries of arylglycine derivatives.
This could be achieved by combining libraries of dialkylamino resins with libraries of supported arylboronic acids made by derivatizing fimctionalized ones immobilized onto DEAM-PS.
Example 3: Resin-to-resin Suzuki Coupling of Solid Supported Arylboronic Acids Example 3 describes one embodiment of the present invention for resin-to-resin Suzuki coupling reactions via phase transfer of solid supported arylboronic: acids under both adueous and anhydrous conditions. The potential of these methods is illustrated with the convergent solid-phase synthesis of unsymmetrically functionalized biphenyl compounds.
In one preferred embodiment, aqueous conditions were optimized for Suzuki cross-coupling in which water or a hydroxylic co-solvent acts as phase transfer agent. As shown conceptually in scheme 1, Figure 7, hydrolysis or transesterifieation on the REAM-PS boronate linkage is expected to liberate the free boronic acid (or ester) which will be transferred in situ to a haloarene resin under palladium(0) catalysis and added base.
Typical synthesis of 4-lodobenzoute Wung-PS resirt (3, li'i,gure 7). To a suspension of Wang resin (1.00 g, 0.63 mmol, theor. loading: 0.~3 mmol g ~) in 10 mL of CHZCIz in a pp vessel were added successively 4-iodobenzoic acid (240 mg, 0.95 mmol), triethylamine ( 135 pL, 0.98 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCl) (180 mg, 0.94 mmol), and HOBYH~O (l5 mg, 0.098 mmol), vortexing after each addition. The suspension was shaken at rt for 24 h, after which the resin was rinsed with DMF (Sx), CHZCI~ (Sx), and dried under high vacuum for > 24 h, affording 1.18 g of a white resin (theor.: 1.14 g, O..SS
mmol g ~).
Typical procedure for the Suzuki RRTR using 4-iodobenzoute Wung-PS resih:
Prepurution of 4, Figure 7. To a mixture of DEAM-PS supported p-tolylboronic acid 2 (77 mg, 0.075 mmol, theor. loading: 0.97 mmol g ~) and 4-iodobenzoate Wang-PS resin 3 (49 mg, 0.050 mmol, the:or.
loading: 1.02 mmol g-~) in a 10-mI. round-bottom flask were added successively 2.5 ml. of DMF, 0.25 mL of ethylene glycol, 0.25 mL of triethylamine. and the dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (PdC:-l~(-dppf)~CH~CI~) (4 mg, 0.005 mmol). The flask was equipped with a reflex condenser. The suspension was stirred gently at 105 °C for 8 h under a nitrogen flow, then the second portion of PdClz(dppf)~CH~C12 (4 mg, 0.005 mmol) was added. The heating was resumed for 12 h, after which the reaction mixture was cooled down to rt. The mixture was transferred to a pp vessel, then rinsed with DMF (1 x), 1:1 DMF/H~O (3x), MeOH ( 3x), CH~CI~ (6x). 'fhe resulting brown resin was swollen in CHzCl2 (1 mL) and trilluoroacetic acid (1 mL), and the resulting suspension was stirred for 2 h. The resin was filtered and rinsed with a l :l CHzCI~/TFA
solution (2x). The combined filtrates were concentrated and dried under high vacuum, affording a pale brown solid.
(105% yield by mass; 64% yield by ~H NMR with EtOAc: int. std.): ~H NMR (500 MHz, CD30D) 8 8.06 (d, J= 8 Hz, 2H), 7.69 (d, J= 8 Hz. 2H), 7.55 (d, J= 8 Hz, 2H), 7.27 (d, .J= 8 Hz, 2H), 2.37 (s, 3H); ~3C NMR (75 MHz, 5% D20 in CI>~OD) b 164.9, 147.0, 139.3, 138.3, 131.3, 130.7, 128.0, 127.7, 21.1; IR (microscope) 3:300-2500, 3028, 2916, 1678, 1607, 1358 cm-l; HRMS (EI, rnlz) calcd for Ci4H,z0~ 212.0837, found 212.0838.
Sa~zuki RRTR under uqueous coyiditioyis. Referring now to Figure 7, Seheme 2, and Table 3, the transfer of DEAM-PS resin-bound p-tolueneboronic acid (compound 2) to Wang resin-bound p-iodobenzoic acid (compound 3) was tested with different stoiehiometries under various solvent, base and temperature conditions. The resulting resin mixaure was then treated with 1:1 trifluoroaeetic acid/dichloromethane to liberate the biphenyl product (compound 4) and, if any, unreacted p-iodobenzoic acid. In all cases, no boronic acid was recovered. It was, therefore, completely released to solution under the reaction and resin washing conditions used. Leftover DEAM-PS resin did not liberate any by-products upon treatment with T'FA. In a preferred embodiment, ''Method A" was DEAM-PS-boronic ester (4 equiv.), iodoarene resin (1 eduiv.), Na2C03 (5 equiv., 2M/Hz0), 20% Pd(PPh3)a, toluene/MeOH 3:1, 85 °(', 24 h.; and, "Method B"
was DEAM-PS-boronic ester (4 equiv.), iodoarene resin (1 equiv.), 20°,~o Pd2(dba)3, DMF/Et3N/(HOCHZ)~ 8:1:1, 105 °C, 24 h.
Conversion results are summarized in Table 3:
Table 3. Suzuki RRTR of compound 2 and compound 3 under aqueous conditions.'' Entry Solvent Base' Equiv.'Temp. Time Conversion Of 2 (C) 1 PhMe/EtOH 3:1 Na2C03 4 85 20 100 2 PhMe/EtOH 3:1 KZCO~ 4 85 20 1 ()0 3 PhMe/EtOH 3:1 Na2C03 3 85 l6 70 i 4 DME/H20 9:1 Na2C0~ 4 85 20 60 DMF/H,O 9:1 Na~CO~ 3 85 20 ~5 ____-_-__.__ _..__ _ Typical trials were carried out with 40 mg of compound 3 (0.55 mmol/g) and the according amount of compound 2 in 2 mL degassed solvent, and 10-20'% Pd(PPhz):~ as catalyst. ~' An additional equiv. relative to compound 2 was employed (horn a 2M aqueous solution).
Measured by ~H NMR integration on crude reaction products.
With 10-20% Pd(0) catalyst loading and either sodium or potassium carbonate as base, the original Suzuki conditions (Suzuki, A., in Metal-catalyzed cross-coupling reactions, Eds.
Diederich, F., et al., Wiley-VCH, 1997, C'hapt. 2) using toluene/ethanol (3:1 ) as solvent gave the highest conversions (entries 1 to 2). Using the optimal conditions of entry 1, designated Method A (Scheme 2, Figure 7), a larger scale reaction (~0.1 mmol) afforded a 91 %
yield of essentially pure compound 4.
Suzuki RRTR under icnhyd~ous conditions. Referring now to Figure 7, scheme 2 and Table 4, anhydrous conditions employing a tertiary amine as base were also optimized for RRTR
processes that use water-sensitive substrates.
Table 4. Suzuki RRTR of 2 and 3 under anhydrous conditions.
Entry SolventBaseb Transfer Temp. Time Conversio ' ' -Agent (~) (h) n 1 DMF Et3N~' (HOCH~)< <' 1 OS 20 100 ! _ _-_ _-_ --__-2 DMF -_ (HOCH~)~ ' ~ 20 100 Et3N' 105 3 DMF Et3Nb (HOCH~)2 h 85 20 100 4 DMF Et3N' (HOCHZ)~ ' 85 20 85 DMF N(CHZCHzOH)3h N(CHZCHZOH)~h 105 20 40 G PhMe N(CH~CHZOH)3 N(CHzCHZOH), 105 20 45 ~' ~' 7 dioxaneNH(CHZCHZOH)2 NH(CH2CHZOH)Z 85 ~' ~' 20 45 '~ Typical trial same as in Table 3 except for the constant use of 4 equiv. of compound 2 ( 107 mg, 0.82 mmol/g). b A large excess is used, ca. 10% v/v. ' 20 equiv.'s Measured by'H NMR
integration on crude reaction products.
The use of diethanola~nine and triethanolamine as phase transfer agents that could also function as required base was examined. As shown from entries S to 7 (Table 4), diethanolamine and triethanolamine showed lower conversion percentages (this may be because the transmctallation of the corresponding diethanolamine boronic esters with the PS-Ar-Pd-I
intermediate is significantly slower than with the ethylene glycol esters). The use of ethylene glycol as transfer agent (Scheme 1, Figure 7) with triethylamine as base in DMF
(dimethylforniamide) was found to be a preferred embodiment (entries 1 to 4, Table 4). When triethylannine and ethylene glycol (1:1) were used in large excess, full conversion was achieved at 85 °C
for 20h (entry 3, Table 4).
Furthermore, in one preferred embodiment, substitution of Pd(PPh3)4 for Pd~(dba)3 appeared to result in crude reaction products of apparently higher purity. These latter conditions were designated "Method B," with a temperature of 105 °C to ensure completion of more demanding substrates. On a larger scale, Method B afforded a 80% yield of compound 4 Referring now to Table 11, and Figure 7, Scheme 2, the effect of the nature of the bast: on conversion using 50 mol% Pd~(dba)3 at 60 °C' was explored. In one preferred embodinnent, fluoride and triethylamine were found to be satisfactory, and provided some biphenyl product at room temperature (entries 7 and 10).
Table 11. Anhydrous Suzuki RRTR of 2 and 3. Effect of base and temperature under Pd~(dba)3 catalysis (50 mol%).~
b ' Entry Base Temp. (G) Conversion Yield (%) (%) 1 N aOH 60 -'i 0'j 2 Ba(OH)Z fi0 -'i 0'' 3 KZC03 GO -'' 0'' 4 Cs2C03 60 -'i 0'~

S K3PO4 60 -'i 0d G KF b0 > 98 - ~ -- > 98 _-_ -_ >98 >98 Entry Base Temp. (C) Conversion Yield (%)~
(%)b 9 Et3N 60 > 98 > 98 Et3N 25 72 71 a Typical trials were carried out with 20 tng of 3 (0.55 mmol,'g) and 2 (3.2 equiv, 45 mg, 0.79 mmol/g) with the indicated base ( 10 equiv) and 50 mol% Pd~(dba)~ as catalyst in DMF-ethylene glycol 10:1 (2.5 mL) for 18 h. 'Measured by'H NMR integration of representative signals on crude reaction products. ~~ Non optimized yields of crude products after cleavage from the resin and drying in vacuo for > 12 hours. The reported values are usually an average of mass balance and internal standardization. '~ Premature cleavage.
Referring now to Table 12 and Figure 7, Scheme 2, in one preferred embodiment, conditions were explored that were mild enough to minimize alcoholysis of the Wang ester linker while still providing complete coupling within 20 hours at 105 °C, with only 1.5 equivalents of DFAM-~PS
supported boronic acid, and with a lower catalyst loading. In one embodiment, triethylamine, essentially as a co-solvent (entries 7-8), was an effective base in combination with 20°/~
PdClz(dppf) as catalyst. In one preferred embodiment, PdCI.~(dppf) was added in 2-3 portions at a few hours interval in order to minimize the effects of catalyst inactivation. The use of cesium fluoride and TBAF as bases led to full conversion (entries 2-3).
Table 12. Anhydrous Suzuki RRTR of 2 and 3. Effect of base and catalyst at high temperature (105 °C).a ~ Entry Base Catalyst ' Conversion Yield (%)' ' (%)b ' I NaF Pd~(dba); 29 33 2 TBAF Pd~(dba)3 > 98 < 2 3 CsF Pd?(dba)3 > 98 3 ' Entry Base Catalyst ' Conversion 'Field (%)' (%)~ ' 4 KF Pd~(dba)3 93 65 KF - PdCI~(dppf) -__-_-> 98 - 48 _.--_ i 6 Et3N'j Pd~(dba)3 42 58 7 Et3N~ PdCh(dpp f) 81 63 i 8 fa3N'~ PdClz(dppf)' > 98 i 64 i '' Typical trials were carried out with 40 mg of 3 (0.98 mmol/g) and ?. (1.5 equiv, 58 mg, 1.07 mmol/g) with the indicated base ( 10 equiv) and catalyst ( I 0 mol'~,~
Pd2(dba)~ or 20 mol°
PdClz(dppf)) in DMF-ethylene glycol 10:1 (2.5 mL) at 105 °C' for 20 h.
'Measured by ~H NMR
integration of representative signals on crude reaction products. ~ Non optimized yields of crude products after cleavage from the resin and drying in vacuo for > 12 hours. The reported values are based on internal standardization. '~ A large excess was used (0.25 mL). ' The catalyst was added in two portions, one at the start, one after 8 h.
Control experiments were devised to cor f rm the role carad efficierrcv of ethylene glycol phase trurrsfer agent. Referring to Scheme 2, Figure 7, control experiments were devised to confirm the role and efficiency of ethylene glycol as phase transfer agent under anhydrous Method E3.
Resin-to-resin cross coupling of model substrates compound 2 and compound 3 in the absence of ethylene glycol gave largely incomplete transfer, as shown by a lower than 50%
conversion to product 4 (treatment of resin 2 alone in hot anhydrous DMF/Et3N (9:1, 105 °C, 24h) led to less than 25% leaching of the boronic acid). This confirmed the advantage of using the phase transfer agent. Ethylene glycol trans-esterified the resin-bound boronic acid within a time scale that minimized any rate-lowering of the cross-coupling. When resin 2 was treated for 0.5 h i n a 8:1: I mixture of DMF/ triethylamine/ethylene glycol at 105 "C, less than 10%
of the boronic acid remained bound to DEAM-PS support.

Resin-to-resin Suzaski coupling strcltegy~ to synthesize raew an~lhoronic acids. Referring to Figure 8, the usefulness of solid supports derivatized with dihydroxyalkylaminoall<yl groups (e.g.
DEAM-PS) to synthesize new arylboronic acids and the potential of the methods of the invention incorporating resin-to-resin Suzuki coupling strategy was demonstrated by the convergent synthesis of unsymmetrically funetionalized biphenyl compounds (schemes 1 to 3).
Figure 8 is a schematic for "Method A" and ''Method B"': "reaction (a)" was Ph(CHZ)~NH~, DIC, HOBT, DMF, rt, 6 h; "reaction (b)'" was morpholine (10 equiv.), DMF, rt, 17 h; "reaction (c)" was a modified ''Method B" using 6 equiv. compound 10 or compound 15, and KzCOz (8 equiv.) in place of Et3N, 115 °C, 60 h; "reaction (d)~' is fhCOCI ( 10 equiv.), (i-Pr)ZEtN (11 equiv.), THF, rt, 8 h.
Referring to Scheme l , Figure 8, amide derivative compound 6 was made from resin-bound p-carboxybenzeneboronic acid (compound 5) under standard carbodiimide methods, as described in, e.g., Hall (1999) Angew. Chem. Int. Ed. 38:3064-3067. rl'he efficiency of this step was validated via cleavage of a resin sample (T'HF/AcOH/HaO 90:5:5, 1 h), followed by characterization of the resulting boronic acid. Following washing and drying operations, resin 6 was reacted with compound 3 of Figure 7 using method A (Scheme 1, Figure 8), affording 4,4'-biphenyl dicarboxylic acid monoamide (compound 8, Scheme 1, Figure 8) after cleavage from the resin mixture (resin 7, Scheme l, Figure 8, and resin 1, F'igme 7). 'these results demonstrate the effectiveness of a convergent RRTR strategy in solid-phase synthesis using solid supports derivatized with dihydroxyalkylaminoalkyl groups. Indeed, as p-carboxybenzeneboronic acid was inept as a substrate in Suzuki reactions; attempts to couplep-carboxybenzeneboronic acid to resin 3 (Scheme 2, Figure 7) failed (similar results reported in Wendeborn ( 1998) Synlett 671-675). A linear solid-phase strategy involvingp-carboxybenzeneboronic acid coupling to resin 3 of Figure 7 followed by amide formation would be impracticable.
Referring to Scheme 2, Figure 8, the methods of the invention (a Suzuki RRTR-based strategy) were also useful to afford monoalkylated biphenyl diben zylamines. For example, DEAM-PS
.S 2 boundp-(bromomethyl)benzeneboronic acid (compound 9) was alkylated with morpholine to give compound 10 (the efficiency of this step was validated via cleavage of a resin sample (THF/AcOH/H20 90:5:5, 1 h), followed by characterization of the resulting boronic acid).
Compound 10 was treated with trityl-PS bound ni-iodobenzylamine (compound 11 ) under modified RRTR Method B (Scheme 2) (KZC03 as base), and after cleavage of the resin mixture, afforded crude diamine compound 13 in 84% yield and high purity (> 90'% by HPLC). Again, with this example, a linear synthesis based on the cross-coupling of compound I 1 withp-(bromomethyl)benzeneboronic acid would be hampered by incompatible reaction conditions.
The basic conditions required in the Suzuki coupling could promote nuc;leophilic displacement on the benzylic bromide which in addition can react with palladium(0) by oxidative addition (see, a g., Tsuji, J. Pcallczdium Reagerats and Catcclvsts; Wiley: Chichester, UK, 1995).
Referring to Scheme 3, Figure 8, monoacylated biphenyl dianilines were also synthesized efficiently. Cleavage and handling of the boronic acid prior to the Suzuki coupling was eliminated and there was no need for transferring the resin to a new reaction vessel after washing and drying operations. In addition, solid-phase immobilization circumvented the tendency of free boronic acids to dehydrate by forming anhydrides that are diff cult to characterize and weight accurately. These advantages were very appealing toward combinatorial chemistry applications. For example, libraries of new solid suppouts derivatized with dihydroxyalkylaminoalkyl groups (e.g., DEAM-PS bound arylboronic acids) could be made and combined with libraries of supported haloarenes.
l '-(3-Phenyl propylcc~rbarnoyl)-biphenyl-4-carboxylic caci~l ~8). Pale brown solid (96% yield by mass; 78% yield by ~H NMR with EtOAc int. std.): ~ H NMR (300 MHz, CD~OD) 8 8.10 (d, J
8 Hz, 2H), 7.90 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.77 (d, J -- 8 Hz, 2H), 7.29-7.13 (m, SH), 3.44 (t, J= 7 Hz, 2H), 2.71 (t, J = 8 Hz, 2H), 1.96 I,qn, .7= 8 Hz, 2H);
'3C NMR (75 MHz, CD30D) b 170.6, 169.9, 145.3, 144.4, 143.1, 135.2, 131.4, 129.5, 129.0, 128.3, 128.1, 126.9, 40.8, 34.4, 32.3 (the resolution of this ~3C NMR was poor because of tine limited solubility of the product in most commercial deuterated solvents); 1R (mic;roscope) 3400-2400, 3343, 3298, 3031, 2928, 1679, 1626 cm-~; HRMS (ES, rralz) calcd for C'23H~,NNa03 (M+Na)~
382.1419, found 382.1418.
3-lodobenzylamino trityl-PS resin (l l). A solution of 3-iodobenzylamine (213 ESL, 1.6 mmol) in 8 mL of CH~C12 was added to trityl chloride resin (500 mg, 0.40 mmol, theor.
loading: 0.80 mmol g-~) in a pp vessel. The resulting suspension was shaken for 3 h, after which the resin was rinsed with CHZCIZ (3x), 19:1 DMF/Et3N (3x), MeOH (I:~ 15 min.), CH~C12 (5x), and dried under high vacuum for > 24 h, affording 545 mg of a white resin (theor.: 557 mg, 0.72 nnnol g ).
C-(~'-Morpholin-4-~-hnethyl-biphenvl-3 yl)-methylcmaine (13). Brown oil (144%
yield by nuass;
82% yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, CD,OD) 8 7.80-7.40 (m, 8H), 4.40 (s, 2H), 4.19 (s, 2H), 4.01 (br s, 2H), 3.76 (br s, 2H), 3.37 (br s, 2H), 3.23 (br s, 2H); ~~C
NMR (75 MHz, CD30D) d 143.5, 142.1, 135.3, 133.1, 130.9, 129.5, 129.3, 128.9, 128.8, 128.7, 65.0, 61.6, 52.9, 44.3; IR (MeOH cast) 3300-2400, 2996, 1675, 1203, 1132 cm ~;
HRMS (ES, m/z) calcd for C,HH~~NZO (M+H)1 283.1805, found 283.1820.
4-lodoanilino trityl-PS r-esirt (16). A solution of 4-iodoaniline (360 nug, I
.6 mmol) in 8 mL of pyridine was added to trityl chloride resin (1.03 g, 0.82 mmol, theor.
loading: 0.80 mmol g-~) in a pp vessel. The resulting suspension was shaken for 3 days, after which the resin was rinsed with pyridine (4x), diethyl ether (5x), and dried under high vacuum for > 24 h, affording 1.16 g of a white resin (theor.: 1. I 8 g, 0.70 mmol g ~ ).
N-(~t'-Amino-biphenyl-3-yl)-benzczmicle (18). Brown solid (81% yield by mass;
55% yield by ~H
NMR with EtOAc int. std.): ~H NMR (300 MHz, CD30D) b 8.07 (s, l H), 7.95 (d, J= 7 Hz, 2H), 7.77 (d, J= 8 Hz, 2H), 7.68-7.34 (m, 8H); ~~C NMR (75 MHz, CD~OD) b 169.0, 141.9, 140.5, 136.2, 135.5, 133.0, 130.4, 129.7, 129.5, 128.6, 124.0, 122.7, 121.4, 120.7;
IR (MeOH cast) 3500-2400, 2917, 2624, 1673, 1202 cm-~; HRMS (ES, rnlz) calcd for C,~~H,~N20 (M-~-H)+
289.1335, found 289.1338.

Libraries of new solid supports derivatized with clihyclro_xvull~yla~ninoullcyl groups. Referring now to Figure 9, a model library of biphenyl compounds was made using the methods of the invention with a commercial, semi-automated parallel synthesizer. A Quest 210Th'' instrument with solvent wash unit was employed (Argonaut Technologies, San Carlos, CA).
Cleavage was effected on-line and crude products were obtained after evaporation of solvents. Yields anti purity were estimated by comparison with an internal NMR standard.
Supported boronic acids compound 20 { 1 } , compound 20 ; 2 } and compound 20 { 3 } were synthesized from compound 14 and acid chlorides, compound 19{ 1 }, compound 19}2; and compound 19{3}. After resin rinsing, these acid chlorides were immediately reacted with iodoarene resins compound 11 and compound 16 using the same conditions used for the synthesis of compound 18 (Figure 8). After on-line cleavage, all six biphenyl products compound 21 { 1 }, compound 21 }2} and compound 21 {3; and compound 22{ 1 ~, compound 22{2} and compound 22{3 ~ were obtained in excellent yields (75-100'io) and high purity (=> 90'%
by NMR). In one embodiment, reactions performed with the synthesizc;r were significantly more efficient and cleaner compared to the manual protocol using glass vessels.
This was shown by comparing spectra of reference library member 22 { 1 } with another sample made previously via manual synthesis.
Example 4 - Examination of the role of the nitrogen in dihydroxyalkylaminoalkyl-coniu~ated resins.
Referring now to Figure 10, Figure 1 OA shows the Gel-phase ~ H NMR spectra (500 MHz) of the free form of DEAM-PS, while Figure 10 B shows the NMR spectra of the p-tolylboronic acid conjugated form using a Varian magic angle spinning nanoprobe. Solvent was CDZCI~ (peak identified by a dot). Conditions: A; at = 3, pw = 2.5, dl --= 0, spinning (c-r~ 2119 Hz. B; at = 3, pw = 2.0, dl = 0, spinning @. 2300 Hz (Note: signal at 3.7 ppm is residual 'THF).
PS: polystyrene resonances.

By making abstraction of peaks from the polystyrene matrix, two broad singlets showed up at 2.6 and 3.5 ppm in the spectrum of free DEAM-PS (A). The largest most unshielded peak contained resonances from both benzylamino and hydroxymethyl methylenes. Upon formation of a cis ft~sed bicyclic diethanolamine boronate adduct whose two faces are non-equivalent, the ring hydrogens became diastereotopic. As expected, the resulting spectrum (B) showed extensive degeneration of the methylenic protons in the hydroxyethyl arms. As many as four peaks were seen between 2.2 and 3.6 ppm, thereby lending support to a tetrahedral, nitrogen-coordinated boronic ester.
Example 5 - UV spectroscopic studies conducted on the cleavage of p-tolylboronic acid from DEAM-PS (1).
To investigate the extent to which the diethanolamine boronate linkage was sensitive to water, UV spectroscopic assay were carried out, whereby the hydrolysis of DL;AM-PS-supportedp-tolylboronic acid (compound 2) was monitored quantitatively both in a time related fashion, and with respect to the amount of water used. In principle, a minimum of rivo molar equivalents ~of~
water was required to effect quantitative cleavage of the compound. This type of boronate exchange process involving water and a competing diol like DEAM-PS (compound 1), however, is usually under equilibrium as detailed in Figure 1 1.
Referring now to Figure 12, a time profile of boronic acid release with variable amounts of water showed that the extent of boronic acid release rapidly reached a plateau within less than one minute (data not shown). A comparison of the percentage of boronic acid release with different number of equivalents of water is shown.
A calibration graph (absorbance at 225 nm vs concentation (M)) was made usingp-tolylboronic acid. DEAM-PS supportedp-tolylboronic acid (2a) (330 mg, 0.278 mmol, obs.
loading: 0.842 mmol g ~) was weighed into a 20 mL pp reaction vessel and swollen in dry THF
(5 mL). A '_~0 pL aliquot was diluted to 25 mL with dry THF for UV analysis. Then resin 2a was cleaved with _56 a sequential addition of water. First, H20 (10 pL, 2 equiv) v~-~as added and the pp vessel was shaken for I min and a 50 ~L aliquot was diluted to 25 mL with dry THF for UV
analysis. Next, the previous sequence was repeated for 4 (20 ~L total), 8 (40 pL total). 16 (80 qL total), 32 (160 ~uL total), 64 (320 l~L total) and 128 (640 hL total) equivalents of water.
Overall, the resulting data confirmed that hydrolysis was under equilibrium and that a large excess of water (>32 equivalents) was required in order to provide a practically quantitative hydrolysis.
In one preferred embodiment, such a quantity of water corresponded roughly to the use of l0 mL
of cleavage solution (5% water/THF) per gram of resin at a C1.8 mmol/g resin loading. This relationship, however, may not be generalized to all types of functionalized boronic acids. In particular, some ortho-substituted arylboronic acids may behave differently and prove more difficult to liberate from DEAM-PS. In one preferred embodiment, a larger proportion of water or the use of acidic conditions (THF/H~O/AcOH 90:5:5 ) may be used.
The above hydrolysis study also suggested that the reverse process - boronic acid immobilization from DEAM-PS - by releasing 2 molar equivalents of water cannot be quantitative in THF
unless a large excess of boronic acid is employed to shift the equilibrium.
Otherwise, according to Figure 12, the approximate maximum yield of immobilization for equimolar amounts of DEAM-PS and boronic acid was 80%. Thus, in one preferred embodiment, in order to optin-size the yield of immobilization, the latter must be largely monodehydrated before.
use (although commercial boronic acids tend to come as largely dehydrated anhydride: forms, in a preferred.
embodiment, they may be further dried in vacuo prior to immobilization with DEAM-PS; for a pertinent review, see: Lappert, M.F. C'herrt. Rev. 1956, 5G, 959).
Example 6 - Preparation and use of diisobutanolaminomethyl polystyrene substituted resin Referring now to Figure 14, diisobutanolaminomethyl polystyrene substituted resin (compound 3) was made from isobutylene oxide by a procedure similar to that in Example 1 for the production of DEAM-PS. 1% Divinylbenzene (DV13) crass-linked aminomethylated polystyrene (AM-PS) was derivatized with a diisobutanolamine anchor through the reaction of aminomethylated polystyrene (AM-PS) with excess isobutylene oxide at ~0 °C in a 9:1 tetrahydrofuran (THF)/water solvent mixture using a sealed, pressure-resistant tube. Reaction time was 24-48 hours. In another embodiment, reaction time was 72 hours.
Immobilization and cleavage ofp-tolylboronic acid from resin 3, showed similar results to that for DEAM-PS when carried out under similar conditions.
Examples 7 - 11 : Solid-phase derivatization of functionalized boronic acids Referring now to Figures 15-23 and Tables 6-10 in Example 7-1 l, a series of solid-phase reaction protocols to derivatize functionalized, DEAM-PS-supported boronic acids are described In principle, the use of dihydroalkylamino-conjugated resins of the present itwention, including DEAM-PS, are not limited to the procedures described herein and many other types of transformations could be envisaged. These examples clearly demonstrate that multistep transformations can be carried out with high efficiency. Synthetic schemes such as these ones could be employed to rapidly assemble two-dimensional combinatorial libraries of new boronic acids for biological screening or as building blocks for subsequent reactions.
Obviously, several other types of transformations could be envisaged. All these reactions could be performed easily on gram scale or larger especially with the use of the high loading resins of the present invention, e.g., DEAM-PS. The use of use of dihydroalkylamino- and dihydroxyalkylaminobenzyl-conjugated resins of the present invention, including DEAM-PS, for solid-phase derivatization of functionalized boronic acids is also advantageous for handling and storage purposes. Indeed, boronic acids can be protected against slow air oxidation through immobilization as solid support adducts.
In the following examples, all supported substrates were easily prepared in high yield froth DEAM-PS as described in protocols in the previous examples. Most boronic acid products obtained after cleavage with 5% water/THF were not further purified and were characterized by mass spectrometry, I R, and ' H and ~ 3C NMR spectroscopy. 'The reported yields of products were inclusive of the boronic acid immobilization step may not be quantitative (Woods, W.G.;
Bengelsdorf, LS.; 1-Iunter, D.L. J. Org. Che~n. 1966, 3l, 2766-2768).
Percentage yields were calculated as an average value of mass balance and internal standardization with ethyl acetate as compared with the theoretical loading of free DEAM-PS resin. These two methods were almost always found to be within a 5% range using optimized analytical methods. The indicated purity values for the products was a conservative estimate based on inspection of NMR
spectra and quantitation of peaks from the expected product relative to unknown signals from possible by-products and starting material. In general, all compounds were obtained with a minimum of 90%
purity, and in a majority of cases there were no detectable by-products by NMR
analysis.
Example 7 - Substitution of bromomethyl derivatized benzeneboronic acids with representative primary and secondary amines Table 6 summarizes the results for the substitution of bromomethyl derivatized benzeneboronic acids with representative primary and secondary amines shown in Figure 15. In this example involving amphoteric aminomethyl-substituted products, the advantages of a solid-phase approach towards product isolation were optimal vis-a-vis solution-phase methods. In one preferred embodiment, suitable conditions found from alkylations of meta and parca substrates 5 and 6 involved simple stirring of DEAM-PS supported bromomethylbenzeneboronic acid with the amine in NMP for approximately S hours at room temperature. In one preferred embodiment, as much as 10 equivalents of secondary amines were employed to ensure reaction completion under these conditions. In order to suppress cross-linking by double alkylation with primary amines, in one embodiment it was found preferable to use a low loading DEAM-PS
resin (< 0.60 mmol/g) with a larger excess of the amine (50 equiv). Due to the large excess of primary amine reactant, the yields of the secondary aminf: products could be diminished from premature cleavage of the supported boronic acid. Nonetheless, these protocols provided good to excellent yields of isolated secondary and tertiary amine products 8 and 9.

Referring now to Figure 20, Sodium phenoxide was used as an example of an oxygen-based nucleophile. Treatment of 6 (Figure 15) with PhONa in the presence of iodide ion in NMP for 24 hours provided ether 10 of Figure 20 in moderate yield after cleavage from the resin followed by rapid filtration through silica gel.
Table 6. Substitution reactions on 5 and 6 (Figure 15).
Entry SubstrateConditionsaProduct Yieldb Purity ~Rt~Ra~ ~%) ~%) 1 5 A 8a {H, CHZPh} 69 95 2 5 A 8b {H, C'HZCI-((CH3)2',50 > 90 3 5 B 8c {(CHZ)20(Cl-~z)Zt85 95 4 5 B 8d { Me, CHZPh } 75 > 95 6 A 9a {H, C'1-hPh} 69 =~ 90 6 6 A 9b { H, CHZCH(C'H3)253 95 }

7 6 B 9c { (CH2)~OI,CH~)?98 > 90 i _ } __ -____ 6 -_ __-_-__ 8 ~ B 94 95 i 9d ; Me, C HZPh }

a Reactions were carried out by shaking the supported benzyl bromide with the amine in NMl? at rt for approx. 5 hours (typical scale 0.12 mmol 5-6) . Conditions: A: 50 eduiv of primary amine, use of low loading DEAM-PS resin (0.60 mmol/g). B: 10 equiv of secondary amine, use of either low loading (0.60 mmol/g) or high loading (1.14 mmol/g) DEAM-PS resin.
h Non optimized yields of crude products after cleavage from the resin with 5~'~o H20/THF and drying in vacuo for > 12 hours. The reported values are an average of mass balance and internal standardization. ' Estimated from ~ H and ~ 'C NMR data.

Tvpical procedure for substitutiorz of a DEAM-PS supported bronzomethyl-substitt-zted ar~~lboronic acid: Preparation of 3-(benzylanainomethyl)pheroylboronic r_cc~id (8a). Tlve DEAM-PS resin (200 mg, 0.120 mmol, theor. loading: 0.60 mmol g'), and 3-bromomethylphenyl boronic acid (34 mg, 0.16 mmol) were weighed into a lU mL polypropylene (pp) reaction vessel.
Dry CH~CIz (2 mL) was added and the reaction suspension was shaken for 1 h and 40 rain at rt.
The pp vessel was drained, and the resin was washed with dry CH~CI~ (:3x, 2rnL). The resin was then swollen in dry NMP (2 mL), and benzylamine (0.655 mL, 6.0 mmol) was added. The reaction vessel was shaken for 5 h, then drained and the resin was washed successively with dry DMF (3x), dry CHzCh (5x), and dry THF (5x). The product was then cleaved from the resin by vortexing the resin using the typical procedure described ;above (5'% H20/THF
for 20 min). 7,he product containing solution was drained and the resin was washed with 5%
H~O'THF (3x). The product filtrates were combined, concentrated under reduced pressure and dried under high vacuum overnight to afford a white solid (19 mg, 70% yic;ld by mass; G'7%
yield by'H NMR
with EtOAc int. std.):'H NMR (300 MHz, 5'% DSO in CI);OD) b 7.66 (m, 2H), 7.36-7.30 (m, 7H), 3.84 (s, 2H), 3.83 (s, 2H); '~C NMR (75 MHz, 5~% DSO in CD~OD) ii 135.6, 135.2, 134.2, 131.0, 129.9, 129.7, 129.2, 128.8, 128.7, 53.5, 53.1; IR (C'.H~CI~ cast) 3360, 3029, 2925, 2852, 1652, 1602 crri'; HRMS (ES, zn/z) calcd for C,:~H,~BNO~ (M+H)i 242.1347, found 242.1350.
3-(iso-Butylaminomothyl)plaenylboroyaic acid (86). White solid (52% yield by mass; 48% yield by' H NMR with EtOAc int. std.): ' H NMR (300 MHz, 5~~° D20 in CD;,OD) ~i 7.62-7.61 (m, 2H), 7.29-7.28 (m, 2H), 3.94 (s, 2H), 2.62 (d, J= 6 Hz, 21-I), 1.91 (nonet, J=
6 Hz, 7 Hz, I H), 0.95 (d, J= 7 Hz, 6H);'3C NMR (75 MHz, 5% DSO in CD30D) cS 135.7, 135.3, 134.6, 130.3, 128.6, 56.6, 54.1, 28.1, 20.7; IR (C~HZC1~ cast) 3259, 3046, 2956, 2871, 1665, 1602 cm-~; HRMS
(ES mlz) calcd for C, ~H,yBN02 (M+H)+ 208.1503, found 208.1501.
3-(Morpholinornethy°l)pheyzylboronic acid (8c). White solid (81% yield by mass; 90% yield by 'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5°/~ D 20 in CD~OD) b 7.69-7.64 (m, 2H), 7.39-7.36 (m, 1H), 7.32-7.27 (m, IH), 3.68 (m, 4H), 3.53 (s, 2H), 2.47 (m, 4H);'3C NMR (7.5 MHz, 5% DSO in CD30D) 8 141.1, 136.7, 136.4, 134.1, 132.8, 128.6, (~7.5, 64.4, 54.5; IR

(CHzCl2 cast) 3405, 3047, 2957, 2857, 2808, 1652, 1602 cm-~; HRMS (ES, rtt~'z) calcd for C"H,~BNO~ (M+H)+ 222.1296, found 222.1297.
N Methyl-3-(bertzylaminomethyl)phenylboronic acid (8cl). White solid (73%
yield by mass; 77°ro yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5% DZO in CD.30D) 8 7.69-7.64 (m; 2H), 7.36-7.27 (m, 7H), 3.56 (s, 4H), 2.18 (s, 3H); ~~C'. NMR (75 MHz, 5%
Dz0 in CD,OD) b 138.7, 137.6, 136.2, 134.1, 132.4, 130.7, 129.4, 128.6, 128.5, 62.7, 62.5, 42.1; IR (CHzCl2 cast) 3405, 3028, 2942, 2835, 2785, 1601 cm-'; HRMS (ES, rn~'z) calcd for C,SH,oBNOz (M+H) 256.1503, found 256.1506.
4-(Bertzvlaminorrtethvl)phenylborortic acid (9a). White solid (69% yield by mass; 69°/~ yield by ' H NMR with EtOAc int. std.): ' H NMR (300 MHz, 5°/~ I)~O in CD~OD) b 7.72 (d, J= 8 Hz, 2H), 7.36-7.30 (m, 7H), 3.84 (s, 4H); '~C NMR (75 MHz. 5% DSO in CD30D) b 138.3, 1 35.2., 131.7, 130.0, 129.7, 129.0, 128.9, 53.1; IR (CHzCh cast) 3396, 3028, 2925, 2819, 1608 cm-';
HRMS (ES, mlz) calcd for C~4H,~BN02 (M+H)+ 242.1347, found 242. I 344.
4-(iso-Butylaminomethyl)phenylborortic acid (9b). White solid (52% yield by mass; 53°/~ yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5~% DSO in CD~OD) G 7.70 (d, J= 8 Hz, 2H), 7.32 (d, J= 8 Hz, 2H), 3.93 (s, 2H), 2.60 (d, J = 7 Hz, 2H), 1.90 (nonet, J=- 6 Hz, 7 Hz, 1H), 0.95 (d, J= 7 Hz, 6H);'3C NMR (75 MHz, 5°/~ DSO in CD30D) G 135.2, 134.9, 134.7, 129.1, 56.6, 53.7, 28.0, 20.7; TR (CHZC1~ cast) 3432, 2957, 2872, 2823, 1660, 1610 cm-'; HRMS
(ES, m/z) calcd for C,~H~aBNOZ (M+H)+ 208.1503, found 208.1506.
4-(Morpholirtomethvl)phenylboronic acid (9c). White solid (88% yield by mass):
' H NMR (300 MHz, 5% D20 in CD~OD) b 7.72 (d, J= 8 Hz, 2H), 7.32 (d, J= 8 Hz, 2I-1), 3.70 (m, 4H), 3.34 (s, 2H), 2.55 (t, J= 5 Hz, 4H);'3C NMR (75 MHz, 5% Dz0 in CD30D) b 138.8, 135.1, 130.1, C>7.3, 64.0, 54.3; IR (CHZCIz cast) 3406, 2957, 2859, 281 l, 1657, 1609 cm-'; HRMS
(ES, ntlz) calcd for C"H,~BN03 (M-+H)' 222.1296, found 222.1294.

4-(l3e~zylarninomethvl)pheravlbororric crcicl (9d). White solid (89% yield by mass; 99% yield by ~H NMR with 2,5-dimethylfuran int. std.): ~H NMR (300 MHz, 5% DZO in CD~OD) 8 7.73 (d, J
= 8 Hz, 2H), 7.35-7.31 (m, 7H), 3.64 (s, 4H), 2.24 (s, 3H); ~ ;C NMR ( 100 MHz, S% DSO in CD30D) 8 137.9, 135.1, 134.8, 130.8, 129.9, 129.5, 128.9, 62.3, 62.3, 41.9; IR
(CH~CI, cast) 3408, 3027, 2927, 2838, 2787, 1609 cW ~; HRMS (ES, nZlz) calcd for C,SH,<~BNOZ
(M+H)1 256.1503, found 256.1504.
Preparation of 4-(Phertoxyrr-iethyl~pherzylboro~~ic acid (10~. Phenol (41 mg, 0.437 tnmol) was weighed into a round bottom flask and dissolved in dry NMP (1.5 mL)_ NaH (18 mg, 0.728 mmol) was added at 0 °C and the suspension was stirred for 30 min.
Resin 6 (325 mg, 0.291 mmol, theor. loading 0.895 mmol g-~) was weighed into a 20 mL. pp vessel and swollen in NMP
(4 mL). The PhONa suspension was added to the resin followed by nBu:,NI (54 mg, 0.146 mmol) and the reaction was shaken for 24 h at rt. The reaction suspension was drained and the resin was rinsed with DMF (3x, 4 mL), THF (3x, 4 mL) and CHaCIz (3x, 4 mL).
The product was cleaved from the resin using standard conditions and the combined filtrates were concentrated. Filtration of the product through a pad of silica gel using 10%
MeOH/CHzCI~
followed by concentration yielded a white solid (37 mg, 61 °ia yield by mass; 42°% yield by ~ H
NMR with EtOAc int. std.): ~H NMR (300 MHz, 5°a> DEC) in CD30D) t~;
7.73 (br d, J = 8 Hz, 2H), 7.40-7.37 (d, J= 8.0 Hz, 2H), 7.27-7.21 (gin, 2H), 6.98-6.88 (m, 31-i), 5.06 (s, 2H); ~3C NMR
(75 MHz, 5% D20 in CD30D) b 164.9, 145.5, 139.8, 135.3, 132.4, 126.8, 120.7, 75.7; IR
(microscope) 3427, 3039, 2920, 2869, 1612, 1598 cm-~; L.RMS (ES, rrr,~z, negative mode with NH4F postcolumn) 249 (M+F)-.
Example 8 - Reductive amination of supported formyl-substituted benzeneboronic acids with various primary and secondary amines Referring now to Table 7, the results for the reductive amination of supported formyl-substituted benzeneboronic acids with various primary and secondary amines shown in Figure 16 are described.

In one preferred embodiment, conditions involved pre-formation of the imine in THF, followed by addition of sodium borohydride as hydride source. In on embodiment, NaBHOAc3, and NaBH3CN led to premature cleavage of the supported boronic acid under these conditions. The ortho substrate 11 was observed to give the most satisfactory yields of products 7 with a good purity. This chemistry thus complements the bromomcthyl substitution method described above.
In one embodiment, the less hindered mcta and parcr substrates 12 and 13 gave the respective amine products 8 and 9 in lower parities. There was no evidence for double alkylation in the case of primary amines.
Table 7. Reductive amination on aldehyde 11 (Figure 16).
Entry SubstrateConditionsaProduct Yieldb Purity' ' fRr~R2} (%) (%) 1 1 1 A 7a {H, CHZPh } 66 ~ 90 2 11 A 7b {H, C.'HZCI-i(C'H~)Z}55 > 90 3 11 A 7c {H, (CH~)jPh} 62 95 4 11 A 7d {H, (CH~~)3('H3 73 > 95 ~

a Typical scale 0.1 mmol. A: Reactions were carried out by preforming the imine from supported aldehyde and the amine (2 equiv) in 'fHF at rt for approx. 2.~~
hours. Sodium borohydride was added and the suspension was shaken for approx. 4 hours. ~' Non optimized yields of crude products after cleavage from the resin with 5'% Hz0/THF and drying in vacuo for > 12 hours. The reported values are an average of mass balance and inteunal standardization.
Estimated from ~ H and ~ ~C NMR data.
Typical pr°ocedure for reductive amination of a DE~tM-P,f sz~pported for~rayl-substituted ar~~l6ororaic acid: Preparcatioir of 2-(benzylanainometlyl~yhe~rylboronic acid (7rx). REAM-PS
resin (100 mg, 0.1 14 mmol, theor. loading: 1.14 mmol g ~) and 2-formylphenylboronic acid (23 mg, 0.15 mmol), were weighed into a pp reaction vessel. Dry CH~C1~ (~? mL) was added, and the reaction suspension was shaken for 1 h and 45 min. The pp vessel was then drained, and the resin washed with dry CHZC12 (3x). The resin was swollen in dry THF (2 mL), and benzylamine (25 ~LI_, 0.23 mmol) was added. The reaction vessel was shaken for 2.5 h, then NaBHa ( 18 mg, 0.46 mmol) was added, and the vessel was shaken for an additional 3 h and 45 min. The pp vessel was drained, and the resin was washed successively with dry DMF (3x), dry CH~C1~ (5x), and dry THF (Sx). The product was then cleaved from the resin using tl~e typical procedure described above (5% H20/THF, 2 mL for 20 min). The product-containing solution was drained and the resin was washed with 5% Hz0/THF (3x, 2 mL). The product filtrates were combined, concentrated under reduced pressure and dried under high vacuum overnight to afford a white.
solid (71 % yield by mass; 60% yield by ~ H NMR with 2,5-dimethylfuran int.
std.): ~H NMR
(300 MHz, 5% Dz0 in CD~OD) ~ 7.47-7.31 (m, 6H), 7.21-7.14 (m, 2H), 7.08-7.05 (m, 1 H), 3.98 (s, 2H), 3.85 (s, 2H); ~3C NMR (125 MHz, 5% Dz0 in CL)~OD) b 142.4, 136.2, 131.6, 130.8, 129.9, 129.6, 129.5, 128.3, 127.7, 124.2, 54.1, 51.1; 1R (C'H~CIZ cast) 3300, 3060, 3028, 3004, 2923, 2870, 1454 cm-~; HRMS (ES, ~yil~) calcd for C',4H,~BN02 (M+Hl~ 242.1347, found 242.1344.
?-(iso-Butylaminornetlayl)pheraylboronic acid (76). White solid (57% yield by mass); ~ H NMR
(300 MHz, 5% DZO in CD30D) 8 7.47-7.44 (m, 1H), 7.21-7.12 (m, 3~I), 4.02 (s, 2H), 2.70 (d, J
= 7 Hz, 2H), 2.10 (tq, J= 6 Hz, 7 Hz, 1 H), I .02 (d, J= 7 Hz, 6H); ~3C NMR ( 125 MHz, 5°/~ DSO
in CD30D) 8 132.0, 128.2, 127.7, 124.0, 56.5, 55.4, 26.9, 20.9; IR (CH;~Cl2 cast) 3301, 3090, 2956, 2926, 2869, 1443 cm-~; HRMS (ES, m/z) calcd for c.""H,~BNO~ (M+H)i 208.1503, found 208.1503.
2-((3'-Phenyl propylarnino)methyl)pher-avlboronic acid (7c). White solid (62%
yield by mass;
62% yield by'H NMR with 2,S-dimethylfuran int. std.): ~ H NMR (300 MHz S°/, DZO in CD30D) d 7.43-7.41 (m, 1H), 7.30-7.13 (m, 8H), 3.98 (s, 2H), 2.88 (m, 2H), 2.70 (t, J = <y Hz, 2H), 2.05 (qn, J = 8 Hz, 2H); ~3C NMR (75 MHz, S'% Dz0 in CD30D): b 142.5, 131.5, 129.5, 129.4, 128. 3, 127.7, 127.1, 124.0, 54.9, 34.4, 29.7; IR (C1-IZCh cast) 3230, 3058, 3026, 2917, 2849, 1495 cm-~; HRMS (ES, rrrlz) calcd for C,~,HZ,BNOZ (M+H)+ 270.1660, found 270.1656.
2-(n-Butylarrainomethyl)pherylboronic acid (7d). White solid (75'%~ yield by mass; 71 % yield by ~H NMR with EtOAc int. std.): ~H NMR (300 MHz, 5% DSO in CD;OD) b 7.45-7.42 (m, 1 H), 7.20-7.14 (m, 3H), 4.00 (s, 2H), 2.86 (t, J-- 8 Hz, 2H), 1.71 (qn, .l= 8 Hz, 2H), 1.41 (sx, J= 8 Hz, 2H), 0.99 (t, J= 8 Hz, 3H); ~3C NMR (75 MHz, 5% hz0 in CD~OD) b 142.5, 131.5, 128.2, 127.7, 124.1, 54.9, 30.1, 21.4, 14.1; IR (CH~C12 cast) 3310, 3233, 3057, 3005, 2958, 2930, 2872, 1598 cm-~; HRMS (ES, rnlz) calcd for C, ~ H,~,BNO~ (M+H )+ 208.1503, found 208.1508.
Example 9 - Amide derivatives from DEAM-PS supported carboxy-functionalized arylboronic acids Referring now to Table 8 and Figure 17, the formation of amide derivatives from DEAM-PS
supported carboxy-functionalized arylboronic acids was explored. In the schematic shown in Figure 17, the reaction proved to be very general with respect to reaction conditions.
The rrreta- andparcr-carboxy substituted substrates 15 and 16 provided good yields of amide products. The use of carbodiimide/HOBT protocols were satisfactory for the coupling of both primary and secondary amines and even aromatic amines (entries 4 and I 1 ). In other embodiments, it was found preferable to employ coupling reagents suclo as PyBOP or HBTU, for example case of isopropylamine (entry 9). In one preferred embodiment, conditions using these coupling reagents induce less premature cleavage as compared to the use of carbodiimide reagents.
One example of amide formation with supported boronic acids is that of entry I
5 involving 16 and N,N-diethylethylenediamine. The resulting amphoteric p-boronobenzamide product 19h, a known melanoma-seeking agent with potential use in boron neutron capture therapy, was obtained pure in a 75% yield after cleavage from the resin. Previously reported syntheses of 19h involve protection of the boronic acid and extensive manipulations such as successive recrystallizations.
Table 8. Amide synthesis from IS and 16 (Figure 17).
Entry Substrate~olldlt1o11SaProduct Yieldb Purity ~RI'Rr} (/) (/) 1 1 S A 18a { H, (CH~)~Ph 57 95 J

2 15 A 18b { H, CH(CH3)2 60 -' 90 j 3 15 A 18c {H, (CHZ)~CH~ 56 ~ 90 4 15 B 18d { H, Ph; 82 > 95 15 A 18e {Et, Et; 77 90 6 15 ~ A-._ {Bu gu} _ _79 ____()0 -18 f -_ , 7 15 A__.' 18g _ 6~____~' 90 {CHZPh,-Cl-l2Phf__ -8 16 I B , 19a 65 95 {Fi, (CHZ)3Ph __-~
~_-.__-.
_ _ 9 16 j B 81 =y 95 ~ 19b ____ -~
{ H, C',H(CH~)z {
~____.__-_ , i 16 i A 95 ~ 19c {H, (CH
~)~CH~
{

11 16 A 19d { 67 > 95 H, -Ph 19e { Et, ~ 59 => 90 13 16 Et J __ __ A i 53 90 ______ A 19f Bu, Bu ~
{ {

14 16 B 19g {CH~Ph, 70 95 CHZPh{

16 A 19h {H, 70 => 95 CH~C'H~NEt~
{

Typical scale 0.1 mmol. A: Reactions were carried out by shaking the supported carboxylic acid with the amine (4 equiv), DIC (4 equiv) and HOBT-HzO (4 equiv) in NMP or DMF at rt for 18 h. B: Reactions were carried out by shaking the supported carboxylic acid with the amine (2 equiv), DIPEA (4 equiv), and PyBOP (2 cquiv) in DMF at rt for 20 h. ' Non optimized yields of crude products after cleavage from the resin with 5°/~ HZO~THF and drying in vacuo for > 12 hours. The reported values are an average of mass balance and internal standardization.
Estimated from ~ H and ~ 3C NMR data.
Typical procedure for the formation of secondary cernides with DIC%HOBT:
Preparation of 4-Benzvlaminocarbonylplrenylboronic ucid (I ~csJ. In a 10 n uL pp vessel, resin 16 (100 mg, 0.10 mmol) was swollen in NMP (3.5 ml~). Benzylamine (44 ~rL, 0.40 mmol), HOBt~H20 (61 mg, 0.40 mmol), and 1,3-diisopropylcarbodiimide (63 ltl_, 0.40 mmol) were successively added and the vessel was shaken for 20 h at rt. The suspension was drained, and the resin was rinsed with NMP (3x), THF (Sx), and CH~CI~ (-Sx). Cleavage of the resin-bound boronic acid using the standard conditions described above, followed by concentration of the filtrates afforded 19a as a white solid (15 mg, 63% yield by mass; 73°,% yield by ~H NMR with EtOAc int. std.).
Typical procedzzr°e for the fonnution of ter°tiarv amides using PyBroP: f'repczration of~~l-('di-n-bretykzmino)-carboraylphenylboronic acid (l9f): In a 10 mL pp vessel, resin 16 (150 mg, 0.15 mmol) was swollen in DMF (4 mL). Dibutylamine (101 lAL, 0.60 mmol), PyBroP
(140 mg, 0. 31) mmol), and N,N-diisopropylethylamine (105 lrL, 0.60 mmol) were added and the vessel was shaken for 20 h at rt. The suspension was drained, and the resin was rinsed with DMF (3x), 'THF
(Sx), and CH2C12 (Sx). Cleavage of the resin-bound boronic acid using the standard conditions described above, followed by concentration of the filtrates afforded 19f as a white solid (22 rng, 57% yield by mass; 50% yield by ~ H NMR with EtOAc- int. std.).
Typicul pr°ocednre for the forrrration of secorzdury urrcidos using POBoP: Preparation of 19b. In a mL pp vessel, resin 16 (80 mg, 0.08 mmol) was swoll~;n in DMF (2 mL). Iso-propylamine ( 14 frL, 0.16 mmol). and PyBOP (84 mg, 0.16 mmol) were added and the vessel was shaken for 20 h at rt. The suspension was drained, and the resin was rinsed with DMF
(3x), THF (5x), and CHZCIz (6x). Cleavage of the resin-bound boronic acid using the standard conditions described above, followed by concentration of the filtrates afforded 19b as a white solid (13 mg, $2% yield by mass; 80% yield by'H NMR with EtOAc int. std.).
3-(3 '-Phenylpropyl-l '-amino)cccrbonylphenylboronic acid (18a~. Off white solid (60% yield by mass): 'H NMR (300 MHz, 5% DSO in CD~OD) ?~ 8.16 (s, 1 H), 7.88 (d, J= 7 Hz, 1 H), 7.80 (d, J= 8 Hz, 1 H), 7.41 (t, J= 8 Hz, l 1=1), 7.2$-7.11 (m, 5 H), 3.40 (t, J= 7 Hz, 2 H), 2.69 (t, J= 7 Hz, 2 H), 1.93 (qn, J= 7 Hz, 2 H);'3C NMR (75 MHz, 5'~~o D20 in CDaOD) 6 170.9, 143.1, 137.9, 135.0, 133.6, 129.9, 129.4, 129.4 128.7, 126.9, 40.$, 34.4, 32.3; IR
(microscope) 331)3, 3026, 2925, 1633, 1537 cm-'; HRMS (ES, rnlz) calcd for C»H,aBNO~
(M+H)~284.1452, found 284.1452.
3-iso-Propylaminocarbonylphehvlborortic cacid (18b). Ofl=white solid (56%
yield by mass; 63%
yield by'H NMR with 2,5-dimethylfuran int std): 'H NMR (300 MHz, 5'% D~O in CD~OD) <i 8.15 (s, 1 H), 7.87 (d, J= 7 Hz, 1 H), 7.80 (d, J= 8 Hz, 1 H), 7.41 (t, J = 8 Hz, 1 H), 4.20 (sp, J =
7 Hz, 1 H), 1.25 (d, J= 7 Hz, 6 H); ~~C NMR (75 MHz, 5'% Dz0 in CD30D) c~
170.1, 137.$, 135.3, 133.6, 130.0, 128.7, 43.1, 22.6; IR (microscope) 3335, 2976, 1621, 1536 cm-'; HRMS
(ES, rnlz) calcd for f,oH,5BN03 (M+H)+208.1139, found 208.1 143 3-n-Btetvlan-zinocarbonylphertylboronic acid (18c~. White solid (56% yield by mass; 55% yield by ' H NMR with EtOAc int. std.): ' H NMR (300 MHz, 5% DSO in CD SOD) c~ 8.16 (s, I H), '7.88 (d, J = 7 Hz, 1 H), 7.80 (d, J = 8 Hz, 1 H), 7.41 (t, J = 8 I-lz, 1 H), 3.37 (t, J = 7 Hz, 2 H ), 1.6:>-1-55 (m, 2 H), 1.47-1.35 (m, 2 H), 0.96 (t, J= 7 Hz, 3 H); ' 3C NMR (75 MHz, 5%
D20 in CD30D) 8 170.8, 137.9, 135.1, 133.5, 129.9, 128.7, 40.7, 32.6, 21.'2, 14.1; IR
(microscope) 3310, 2954, 1637, 1536 cm-'; HRMS (ES, m/z) calcd for C"H,~BNO; (M+H)t 222.1296, found 122.1297.
3-Phenylarninocarbonylphenylbororaic acid (l8cl). White solid ($1% yield by mass; 83'% yield by 'H NMR with EtOAc int. std.):'H NMR (300 MHz, 5°/a, Dz0 in CD30D) c~
8.29 (s, 1 H), 7.95-7.92 (m, 2 H), 7.69-7.65 (m, 2 H), 7.47 (t, .I = 8 Hz, 1 H), 7.39-7.32 (m, 2 H), 7.17-7.11 (m, 1 H); ~ jC NMR (75 MHz, 5% DSO in CD30D) b 169.5, 139.8, 138.3, 135.5, 134.0, 130.3, 129.8, 128.8, 125.7, 122.3; IR (microscope) 3309, 3057, 1644, 1538 cni ~; HRMS (ES, nu/z) calcd fon-C,3H~3BN03 (M+H)' 242.0983, found 242.0980 3-(Diethylamirzo)carhonylphenylboronic cecid (l8e). White solid (77% yield by mass; 77% yield by ~H NMR with EtOAc int. std.): ~ H NMR (300 MHz, 5°,~~ Dz0 in CD,OD) d 7.81 (d, J= (~.6 Hz, 1 H), 7.71 (s, 1 H), 7.44-7.36 (tn, 2 H), 3.57-3.51 (m, 2 H), 3.31-3.25 (m, 2 H), 1.27-1.22 (m, 3 H), 1.12-1.07 (m, 3 H); ~~C NMR (75 MHz, 5°/, D~O in CD30D) b 174.1, 137.2, 136.0, 132.4, 128.8, 128.8, 45.0, 40.8, 14.3, 13.1; IR (microscope) 3314. 3065, 2979, 2475, 1587 cm~~HRMS
(ES, m/z) calcd for C"H,~BN03 (M+H)+222.1296, found 222.1298.
3-(Di-n-butylccrnino)curborrylphenvlborortic acid (18f). Clear, colorless ~;um (77% yield by mass;
81% yield by ~H NMR with EtOAc int. std.): ~H NMR (300 MHz, 5% Dz0 in CD30D) a 7.82 (d, J= 7 Hz, I H), 7.71 (s, 1 H), 7.44-7.35 (m, 2 H), 3.50 (t, J= 7 Hz, 2 H), 3.23 (t, J= 7 Hz, 2 H), 1.71-1.62 (m, 2 H), 1.55-1.36 (m, 4 H), 1.17-1.05 (m, 2 H), 0.99 (t, J = 7 Hz, 3 H), 0.75 (t, J= 7 Hz, 3 H); ~3C NMR (75 MHz, 5% D20 in C'D30D) b 174.:x, 137.2, 135.9, 132.6, 129.1, 128.8.
50.3, 46.0, 31.7, 30.7, 21.2, 20.6, 14.2, 13.8; IR (microscope) 3362, 2961, 1610, 1416, 1344 cm-~; HRMS (ES, m/z) calcd for C,SHz5BN0; (M+H)' 278.1922, found 278.1930.
3-(Dibenzvlacnirro)carbonylphenylbororcic cacid (18g~. White solid (61 °/. yield by mass; 59°/, yield by ~H NMR with EtOAc int std): 'H NMR (300 MHz, 5% DSO in CD~OD) d 7.86-7.84 (m, 2 H), 7.50-7.47 (m, 1 H), 7.41-7.30 (m, 9 H), 7.11-7.09 (m, 2 H), 4.66 (s, 2 H), 4.41 (s, 2 Hj; ~'C
NMR (125 MHz, 5% DSO in CD30D) fi 175.1, 137.9, 137.4, 136.4, 136.3, 132.9, 129.9. 129.8, 129.2, 128.9, 128.8, 128.7, 128.3, 53.3; 1R (microscope) 3364, 3030, 2926, 1606 cm~~; HRMS
(ES, m/z) calcd for C~iH2~BN03 (M+H)+346.1609, found 34f~.1599.
4-(3 '-Pheraylpropvl-l '-amino)cccrbonylpheraylbororcic acid (IOa). White solid (64% yield by mass; 65% yield by ~H NMR with EtOAc int std):'H NMR (300 MHz, .5% D20 in CD~OD) a 7.80 (d, J= 8 Hz, 2 H), 7.72 (d, J= 8 Hz, 2 H), 7.28-7.10 (m. 5 H), 3.3~) (t, J= 7 Hz, 2 f-I), 2.'72-2.64 (m, 2 H), 1.92 (qn, J=7 Hz, 2 H);'3C NMR (125 MHz, 5% DSO in CD30D) c~
170.5, 143.0, 137.1, 134.9, 129.4, 127.2, 126.9, 40.9, 34.5, 32.4; IR (microscope) 3310, 2924, 1633, 1545 c;m-'; HRMS (ES, nalz) calcd for C,6H,aBNO~ (M+H)+284.1458, found 284.1456.
4-iso-Propylaminoccrrbonylphenylborouic acid (19b). Off-white solid (82% yield by mass; 80°r~
yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5% D~O in CD30D) 8 7.81-7.7:?
(m, 4 H), 31.8 (h, J= 7 Hz, 1 H), 1.24 (d, J= 7 Hz, 6 H); '3C NMR ( 125 MHz, 5% D20 in CD30D) 8 169.7, 137.3, 134.8, 127.2, 43.3, 22.7; IR (microscope) 323'), 2972, 1633, 1548 crn-';
HRMS (ES, m/z) calcd for C,~H,~BNO~ (M+H)+208.113'), found 208.1 140.
4-n-Butvlaminocarbonylphenylborortic acid (~9c). White solid (63% yield by mass): 'I-1 NMR
(300 MHz, 5% DZO in CD30D) b 7.81 (d, J= 8 Hz, 2 H), 7.74 (d, J= 8 Hz, 2 H), 3.37 (t, J= 7 Hz, 2 H), 1.65-1.55 (m, 2 H), 1.47-1.34 (m, 2 H), 0.96 (t, .I== 7 Hz, 3 H;1;
'3C NMR (75 MHz, 5°,%
Dz0 in CD~OD) b 170.5, 137.1, 134.9, 127.2, 40.8, 32.6, 21.2, 14.1; IR
(microscope) 3257, 2958, 1634, 1546 cm-' ; HRMS (ES, m/z) calcd for C', i H i ~BN03 (M+H ) ~
222.1296, found 222.1303.
4-Phenylaminocurbonylphenylboronic acid (19d). White solid (67% yield by mass): 'H NMR
(300 MHz, 5% DZO in CD30D) 8 7.87 (s, 4 H), 7.69-7.65 (m, 2 H), 7.39-7.32 (m, 2 H), 7.14 (m, 1 H); 13C NMR (100 MHz, 5% DZO in CD~OD) 8 169.1, 139.7, 1 37.6, 135.0, 129.8, 127.6, 125.7, 122.4; IR (microscope) 3301, 3042, 1643, 1537 cm-~; HRMS (ES, ml~) calcd for C,~H,3BN03 (M+H)+242.0983, found 242.0984.
4-(Diethylamino)carbonylphenylborosaic acid (l9e). Yellow gum (59°/.
yield by mass): 'H NMR
(300 MHz, 5% Dz0 in CD30D) 8 7.81 (d, J= 7 Hz, 2 H), 7.31 (d, J= 8 Hz, 2 H), 3.53 (q, J= 7 Hz, 2 H), 3.27 (q, J= 7 Hz, 2 H), 1.24 (t, .l= 7 Hz, 3 H), 1.10 (t, J= 7 Iiz, 3 H); '3C NMR (75 MHz, 5% DZO in CD30D) 8 173.8, 139.5, 135.1, 126.2, 44.9, 40.8, 14.4, 13.1; IR
(microscope) 3380, 2974, 1598, 1549 crri'; HRMS (ES, mlz) calcd for (_'"Hi~BN03 (:VI+H)' 222.1296, found 222.1298 4-(Di-rz-bzctylarnino)cczrborzylphenylbor-orzic acid (19~. White solid (57°,% yield by mass; 50%
yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5°/~ D20 in CD30D) b 7.80 (d, ~l=
8 Hz, 2 H), 7.29 (d, J= 8 Hz, 2 H), 3.49 (t, J= 8 Hz, 2 H), 3.22 (t, J = 8 Hz, 2 H), 1.71-1.61 (m, 2 H), 1.54-I .34 (m, 4 H), I .17-1.05 (m, 2 1-I), 0.99 (t, J== 7 Hz, 3 H), 0.75 (t, ,l= 7 Hz, 3 H); '3C
NMR (75 MHz, 5% DSO in CD30D) 8 174.2, 139.6, 135.1, 126.4, 50.2. 45.9, 31.7, 30.7, 21.2, 20.7, 14.2, 13.8; IR (microscope) 3276, 2958, 1603, 1514 cm-'; HRMS (ES, zzclz) calcd for C,SH~SBNOj (M+H)' 278.1922, found 278.1928.
4-(Dibenzylamirao)cczrbonylphenvlboronic cecid (19g). White solid (69' o yield by mass; 70%
yield by'H NMR with EtOAc int. std): 'H NMR (300 M1-Iz, 5% D20 in CD~OD) 8 7.79 (d, J'= 8 Hz, 2 H), 7.42 (d, J= 8 Hz, 2 H), 7.34-7.30 (m, 8 1-I), 7.13-7.11 (m, 2 H), 4.67 (s, 2 H), 4.42 (s, 2 H); ' ~C NMR (75 MHz, CD30D) b 174.8, 138.0, 137.5, 135.1, 129.9, 129.2, 128.8, 128.2, 126.6, 53.1; IR (microscope) 3357, 2918, 1605, 1341 cm-'; HRMS IES, nz/z) calcd for CZ,HZ,BN03 (M+H)' 346.1609, found 346.1608.
4-~? '-(Diethylamino)ethylaznirzoJcczr~borcylphenvlbor~onic° acid (l9lz). White solid (71 % yield by mass; 70% yield by ~H NMR with EtOAc int. std): 'H NMR (300 MHz, 5°/«
DSO in CD30D) 8 7.80-7.70 (m, 4 H), 3.56 (t, J= 7 Hz, 2 H), 2.89 (t, J= 7 Hz, 2 H), 2.82 (q, J= 7 Hz, 4 H), 1.115 (t, J= 7 Hz, 6 H); '3C NMR (125 MHz, 5% DZO in CD~OD) b 171.0, 134.9, 127.0, 52.6, 48.4, 37.8, 11.0; IR (microscope) 3326, 2970, 2820, 1638, 154:3, 1432 ctn-'; HRMS
(ES, m/z) calcd for C~3HZZBN~03 (M+H)+265.1718, found 265.1718.
Example 10 - Reaction of carboxylic acids with supported anilines Example 3 detailed that anilide-derivatized boronic acids can be obtained from the reaction of DEAM-PS supported aminobenzeneboronic acids with acid chlorides. Referring now to Figure 18 and Table 9, anilide-derivatized boronic acids of this were isolated in a variable range of yields (ca. 50-80%) by reaction of carboxylic acids with supported anilines 20-22. All three substitution patterns were explored with this type of chemistry.
In one preferred embodiment, the use of PyBOP as a coupling agent in NMP or DMF for 20 hours at room temperature was preferred. In one preferred embodiment for entries 3-6, PyBOP
was preferred over use of carbodiimide. A wide variety ol~carboxylic acids were tested, including Fmoc-protected alanine (entry 9), which provided a 51 % yield of the expected amide product 24e. All rnetca- andpara-substituted substrates provided the expected anilide products.
Referring now to Figure 21, ES-MS analysis, suggested that the ortho-substituted anilides 23 existed in a cyclic monodehydrated form B. This may be the case in aqueous or alcohol solutions as well owing to the partial aromatic character of these boron-containing heterocycles. It may be that these and similar compounds like ureas can add one molecule of water or alcohol by 1,4-addition and thus exist in equilibrium with form C of Figure 21. ortho-.~cylamino-substituted benzeneboronic acids 23 were found to have limited solubility in all solvents, thus they were also characterized as their pinacol ester (form A) in order to unambiguously demonstrate their identity by ~ H and ~ ~C NMR.
Table 9. Anilide synthesis from anilines 20-22 (Figure 19).~
Entry' SubstrateConditionsaProduct Yieldh Purity' {R~ (%) (%) 1 20 B 23a ~CH~C.'H;} 61 =~ 95 _-_.___ _ .

2 20 B 23b {Ph} 60 > 90 3 21 A 24a ; CHZC'H 3 } 42 > 90 4 21 A 24b { Ph } 52 > 95 Entry SubstrateConditions&Product Yields Purity' ~R} (%) (%) 21 B 24a {CH~C'H;} 72 95 _ ______ . ___ 6 21 B 24b {Ph} , 82 95 I

7 21 B 24c {CH2CH~C'.H=(,H~}70 > 95 8 21 B 24d {CCf'h', 75 > 95 - _ --____ __ 9 21 B 24e {(S)CH(MejNHFmoc}~ 51 95 -___-_ _-_ ~ _ ___--.

22 B ; ~~ 61 =' 95 _.__ 25a ~CH~C'H~}

_- _________.. ___- ;-._ i 11 22 B 25b { Pla } ~ 46 95 a Typical scale 0.1 mmol. A: Reactions were carried out by shaking the supported aniline with the carboxylic acid (2 equiv), D1C (2 equiv) and HOBT-HZO (2 equiv) in DMF at rt for 20 h. B:
Reactions were carried out by shaking the supported aniline with the carboxylic acid (2 equiv), PyBOP (2 equiv), DIPEA (4 equiv) in NMP at rt for 20 h. ~' Non optimized yields of crude products after cleavage from the resin with 5% H20/THF and drying in vacuo for > 12 hours.
The reported values are usually an average of mass balance and internal standardization.
Estimated from ~H and ~3C NMR data.
Typical procedure for the formation of urtilides using DI(:'lHOBT:
Pre~~aratiorz of 24a. In a :l0 mLpp reaction vessel, resin 21 (155 mg, 0.150 mmol, theor. loading: 0.966 mmol g ~) was swollen in DMF (4.0 mL). Propionic acid (22 ~rL, 0.30 mmol), HOBt~H~O (46 mg, 0.30 mmol), and 1,3-diisopropylcarbodiimide (47 pL, 0.30 mmol) were added successively and the reaction vessel was shaken for 19 h at rt. The suspension was drained, and the resin was rinsed with DMF (3x), THF (5x), and CH~CIZ (5x). Cleavage of the resin-bound boronic acid under standard conditions, followed by concentration of the filtrates afforded 24a as a brown solid (11 mg, 42~%>
yield by mass; 41% yield by ~ H NMR with 2,5-dimethylfuran int. std. ).

Typical procedure for the formation of cznilides using PyBOf': Preparation of 24a. Resin 21 ( 102 mg, 0.0965 mmol, theor. loading: 0.946 mmol g-') was added to a 10 mL
polypropylene vessel and swollen in NMP (I.5 mL). PyBoP (100 mg, 0.193 mmol), DIPEA (67 ErL, 0.386 mmol), and propionic acid (14 pL, 0.193 mmol) were added in the given order and the reaction vessel was shaken for 19 h at rt. The suspension was drained, and the resin was rinsed with NMP (3x), CHZC12 (Sx), and THF (3x). The product was then cleaved from the resin using the standard conditions described above. The product rinses were combined, concentrated under reduced pressure and dried under high vacuum overnight to afford a yellow solid (13 mg, 76°i°
yield by mass; 68% yield by'H NMR with EtOAc int. std.).
N-(Propionyl)-2-amirzophenylbororric acid (23~). White solid (61 °/«
yield by mass): 'H NMR
(300 MHz, CD30D) b7.46-7.43 (m, 1 H), 7.31-7.20 (m, 2H), 7.03-7.00 (m, I H), 2.66 (q, J = 8 Hz, 2H), 1.33 (t, J - 8 Hz, 3H); IR (microscope) 3100-2400, 3000, 2979, 1640, 1601 cm-';
HRMS (ES, rnlz) calcd for C~H,ZBNO;Na (M+Na)+216.0802, found 216.0806. A "C
NMR
spectnrm of 23a could not be obtained due to low solubility. Therefore, compound 23a was derivatized as its pinacol ester 23a' in order to obtain a ~3~;~ NMR spectrum.
C.'ompound 23a was cleaved from resin 20 with 10% pinacol/THF and purified by flash chromatography on silica gel using 1/I ethyl acetate/CHZCIz as eluent giving a white solid. ' H NMR (500 MHz, CD~OD) ~i 8.16 (br d, J = 6 Hz, 1 H), 7.71-7.70 (m, I H), 7.35 (t, J = 8 Hz, 1 H), 7.05 (t, J = 7 Hz, 1 H), 2.:? 9 (q, _,l= 8 Hz, 2H), 1.35 (s, 12H), 1.18 (t, J== 8 Hz, 3H); ~3C NMR ( 125 MHz, CDC13) c~ 172.2, 143.4, 135.6, 131.9, 123.4, 118.6, 83.7, 30.6, 25.1, 9.4.
N-(Bertzovl)-2-amirzophenylboronic acid (23b). White solid (60'% yield by mass): ' H NMR (500 MHz, CD30D) cS 8.18-8.16 (m, 2H), 7.76-7.73 (m, 1 H), 7.65-7.62 (m, 2H), 7.53-7.51 (m, 1 H), 7.37-7.28 (m, 3H); IR (microscope) 3203, 3063, 298, 1624, 1602 cm-~; HRMS (ES, rnlz) calcd for Ci3H,zBNO~Na (M+Na)+ 264.0802, found 264.0798. A'3C NMR spectrum of 23b could not be obtained due to low solubility. Therefore, compound 23b was derivatized as its pinacol ester 23b' in order to obtain a' ~C NMR spectrum. Compound 23b was cleaved from resin 20 with 10% pinacol/THF and purified by flash chromatography on silica gel using ethyl acetate as eluent to give a white solid. 'H NMR (500 MHz, CD30D) 8 8.70 (d, J== 8 Hz, 1H), 8.02 (m, :?
H), 7.80 (m, 1 H), 7.54-7.45 (m, 4 H), 7.08 (m, 1H), 1.39 (s, 12H);'3C NMR
(125 MHz, CD(~'13) 8 165.2, 144.9, 136.2, 135.3, 133.0, 131.6, 128.5, 127.2, 123.0, 119.1, 84.5, 24.9 N-(Propionvl,)-3-aminophenylboronic acid (24a). Yellow solid (76% yield by mass; 68% yield by'H NMR with EtOAc int. std.):'H NMR (300 MHz, 5% DSO in CD30D) a 7.77 (s, 1 H), 7.60 (d, J= 8 Hz, 1 H), 7.45 (d, J= 7 Hz, 1 H), 7.26 (t, J=== 8 Hz, 1 H), 2.38 (q, J= 8 Hz, 2 H), 1.19 (t, J= 8 Hz, 3 H);'3C NMR (75 MHz, 5% D20 in CD3OD) 8 175.6, 139.0, 130.7, 129.0, 126.9, 123.5, 31.0, 10.3; IR (microscope) 3303, 3057, 2980, 1665, 161: cm-';
HRMS (ES, sfz%) calcd for C.>H,ZBN03 (M+H)~ 194.0983, found 194.0981.
N-(Benzovl)-3-caminophenylboronic acid (24b). Beige solid ( 86% yield by mass;
77% yield by 'H NMRwith EtOAc int. std.):'H NMR (300 MHz, 5°/, D ZO in C:D30D) S
7.93-7.90 (m, 3 FI), 7.73 (d, J= 8 Hz, 1 H), 7.60-7.47 (m, 4 H), 7.34 (t, J= 8 E~z, 1 H); '3C NMR
(75 MHz, 5°/. DSO
in CD30D) ~ 169.0, 142.1 (broad), 138.9, 136.2, 132.9, 131.3, 129.7, 1'29.1, 128.6, 128.0, 124.7;
IR (microscope) 3317, 3066, 3045, 1645, 1603, 1580 cm-'; HRMS (ES, m/z) calcd for C,3H,3BN03 (M+H)~242.0983, found 242.0984.
N-(3 '-Bacteftylcarbonyl)-3-aminophenylboronic cacid (24c,). White solid (74%
yield by mass, 66% yield by'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5% D20 in CD~OD) b 7.76 (s, 1 H), 7.59 (d, .I= 8 Hz, 1 H), 7.46 (d, J= 7 Hz, I H), 7.27 (t, J = 8 Hz, 1 H), 5.94-5.81 (m, 1 H), 5.12-4.97 (m, 2H), 2.47-2.41 (m, 4H);'3C NMR (75 MHz, 5% DSO in CD~OD) b 174.0, 1 38.9, 138.2, 135.3 (broad), 130.8, 129.0, 126.9, 123.6, 1 16.0, 37.2, 30.8; IR
(microscope) 3319, 3079, 2978, 1660, 1644, 1606, 1532 em-'; HRMS (ES, nZ/z) calcd for C, iH,;BN03 (M+H)+220.1 145, found 220.1146.
N-(2'-Pherrylethynylcarbonyl)-3-arninophenvlboronic acid (?4d). Yellow solid (76% yield by mass, 73% yield by ~H NMR with EtOAc int. std.):'H NMR (300 MHz, 5'% DSO in CD~OD) c~
7.84 (br s, 1H), 7.69-7.67 (m, 1H), 7.63-7.60 (m, 2H); 7.54-7.50 (yo, IH), 7.48-7.39 (m, 3H), 7.36-7.30 (m, 1H);'zC NMR (75 MHz, 5'% D20 in C'D30D) 6 153.5, 143.9 (broad), 138.4, 133.6, 131.6, 131.5, 129.8, 129.3, 126.7, 123.7, 121.2, 87.0, 84.0; IR
(microscope) 3263, 3056, 221 l, 1642, 1583 cm-'; HRMS (ES, m/z) calcd for C,SHizE3N03Na (M+Na)' 288.0808, found 288.0806.
N-~N'-(9-Fluorenylmethoxvcarboyyl)-L-alcrninylJ-3-umiraopheraylboronic acid (24e). Yellow solid (53% yield by mass, 48'% yield by'H NMR with EtOAc int. std.): 'H NMR
(300 MHz, 5°,a>
Dz0 in THF-d~) 8 7.82 (m, 2H), 7.73 (d, J= 7 Hz, 2H), 7.63 (t, J= 7 Hz, 2H), 7.47 (d, ,I = 7 Hz, 1H), 7.32-7,14 (m, 5H), 4.35 (q, J= 7 Hz, 1H), 4.29-4.14 (m, 3H), 1.45 (d, J=
7 Hz, 3H); "C
NMR (75 MHz, 5% Dz0 in THF-dH) 8 172.1, 157.2, 145. ~, 145.1, 142.2, 139.2, 141.4 (broad), 130.4, 128.4, 127.9. 126.2, 126.1, 122.3, 120.6, 51.9, 48.2, 19. I ; IR
(microscope) 3307, 3065, 2977, 1673, 1610 cm-'; HRMS (ES, rrzl~) calcd for C~4Hz3~3N-~OSNa (M-i-Na)+453.1598, found.
453.1598.
N-(Propiorayl)-4-amiraophenvlbororric acid (25a). Cream-colored solid (61%
yield by'H NMR
with EtOAc int. std.): ' H NMR (300 MHz, 5% D-z0 in CD30D) cS 7.73-7.66 (m, 2H), 7.54-7.49 (m, 2H), 2.38 (q, J= 8 Hz, 2H), 1.18 (t, .l= 8 Hz, 3H); ' ~C' NMR (75 MHz, 5'io Dz0 in CD30:D) d 175.9, 141.6, 135.6, 130.0 (broad), 120.1, 31.1, 10.3; IR (microscope) 3306, 3044, 2979, 1660, 1594 cm-'; HRMS (ES, m/z) calcd for CoH,3BN03 (M+H)~ 194.0983, found 194.0985.
N-(Benzovl)-4-aminophenylboronic ucid (256). White solid (47% yield by mass, 45% yield by 'H NMR with EtOAc int. std.): 'H NMR (300 MHz, 5% Gz0 in CD~OD) b 7.92-7.89 (rn, 2H), 7.76-7.73 (m, 2H), 7.69-7.64 (m, 2H), 7.60-7.47 (m, 3H); ~'C NMR (75 MHz, 5%
Dz0 in CDzOD) b 169.1, 136.1, 135.6, 133.0, 129.7, 128.6, 121.1; IR (microscope) 3313, 3040, 1650, 1601, 1588 cm-'; HRMS (ES, m/z) calcd for C,3H~zBN03Na (M+Na)+264.0808, found 264.0803.

Example 11 - Synthesis of Ureas and Thioureas:
Referring now to Figure 19 and Table 10, areas of type 27 and 28 were isolated from the reaction of the respective rnet~c- andpara-substituted anilines 21 and 22 with various isocyanates of different electronic nature, in dichloromethane for 5-G hours at room temperature. An example of thiourea was also made with ease (27e, entry 5). Yields of products were excellent for all reported examples regardless of the electronic characteristics of the isocyanate reagent. Using conditions as outlined in Table 10, the or~tho-substituted substrate 20 provided products 26 accompanied with varying amounts of double addition products.
Table 10. Synthesis of areas from anilines 21 and 22 (Figure 19).
Entry SubstrateConditionsaProduct'' Yieldb Purity' ~R~ ' (~~
(~~
) 1 21 B 27a { CH(CH3 j~ ; 66 95 2 21 A 27b { Ph f 79 > 9~

3 21 A 27c {4-Me0-C~,Ha~ 82 > 95 4 21 A 27d {4-NOz-C~,H~ f 80 > 95 21 A 27e~~Ph{ 85 95 ',I 6 22 B - 28a {CH(CH~)z~ -_ _~5_ /~ ()J
~ _.

~', 7 - __ 28b { Ph p 85 ~. 95 22 '~I A

', 8 ~2 ~ A _- ~8c {4-Me0-C~;Ha~-_._ ,~ ~5 ~ ____-_ gg- -.
_.___ 9 22 A 28d {4-NO~-Cc,H4{ 9 ' 92 Typical scale 0.1 mmol. A: Reactions were carried out by shaking the supported aniline with the isocyanate (2 equiv), in CHZCh at rt for 5-6 h. B: longer reaction time (20-45 h). ~' Non optimized yields of cn,ide products after cleavage from th~:. resin with 5°% H20/THF and drying in vacuo for > 12 hours. The reported values are usually an average of mass balance and internal standardization. ' Estimated from I H and ~ 3C NMR data.
Typiccal procedure for the forrraation of areas: Prepuratiofr c~,f 27ca. W a 10 mI. pp reaction vessel, resin 21 (104 mg, 0.10 mmol, theor. loading: 0.96 mmol g ~) was swollen in CH~C1~ (2 mL.). Isopropylisocyanate (20 yL, 0.20 mmol) was added and the vessel was shaken for 7 h at rt.
The suspension was drained, and the resin was rinsed with CHZCIZ (8x 1. The product was then cleaved from the resin using the standard conditions described above. The combined 'rltrate:;
were concentrated under reduced pressure and dried under high vacuum overnight to afford a brown solid (16 mg, 76% yield by mass; 66% yield by ~ H NMR with EtOAc int.
std.).
N-(iso-Propylan-iiraocarbonyl)-3-amirropheftylboronic caci':l (?7a). Brown solid (76% yield by mass; 66% yield by ~H NMR with EtOAc int std): ~H NIVIR (300 MHz, 5% DSO in CD~OD) b 7.58 (s, 1 H), 7.43 (d, J = 8 Hz, 1 H), 7.35 (d, J = 7 l-Iz, 1 H), 7.22 (t, .I
= 8 Hz, 1 H), 3.87 (heptet, J = 7 Hz, 1 H), 1.16 (d, J = 7 Hz, 6 H); ~3C NMR (75 MHz, 5°~o DSO in CD30D) b 157.9, 140.1, 129.1, 129.0, 125.8, 122.6, 42.9, 23.4 (the resolution of this ~3C NMR was poor because of the limited solubility of the product in most commercial deuterated solvents); IR
(microscope) 3347, 3036, 2985, 1639, 1568, 1343 cm-~; HRMS (ES, m/z) calcd for HRMS (ES, m/z) calcd for C,«H»BN20~ (M+H)~223.1248, found 223.1250.
N-(Phenylarninocczrbonyl)-3-arrrinopherrylborortic acid (27b). Beige solid (79% yield by ~H
NMR with EtOAc int std): ~H NMR (300 MHz, 5% Dz0 in CD~OD) d 7.67 (s, 1 H), 7.52 (d, J=
8 Hz, 1 H), 7.42-7.38 (m, 3 H), 7.30-7.23 (m, 3 H), 7.03-6.97 (m, 1 H); ~ 'C
NMR (75 MHz, 5°a DSO in CD30D) 8 155.7, 140.5, 139.6, 129.9, 129.5, 129.1, 126.1, 123.9, 122.8, 120.5; IR
(microscope) 3317, 1639, 1567, 1343 cm-~; HRMS (ES, nalz) calcd for C, 3H,aBN203 (M+H)+
257.1092, found 257.1093.

N-(=l'-Metlroxyphertvlanzinocczrborryl)-3-zznainopherylbororzic ucicl (27c).
Beige solid (85°io ~rield by mass; 78% yield by ~H NMR with EtOAc int std): rH NMR (300 MHz, 5°,%
Dz0 in CD;GD) <~
7.65 (s, 1 H), 7.50 (d, J= 8 Hz, 1 H), 7.40-7.38 (m, 1 H), 7.32-7.22 (m, 3H), 6.89-6.84 (m, 2H), 3.76 (s, 3H); ~ ~C NMR (75 MHz, 5% DSO in CD30D) ~i 157.3, 156.1, I 39.7, 133.3, 129.4, 129.1, 126.0, 122.9, 122.7, 115.2, 56.0; IR (microscope) 3317, 3046, 2960, 1643, 1572, 1346 cm-~; HRMS (ES, rnlz) calcd for C,aH,r,BN~O,~ (M+H)+287.1 198, found 287.1 197.
N-(=l '-Nitrophenylanrinoeczrbonyl)-3-cznzirropherrvlbor°orrie aeicl (27c1). E3right yellow solid (8:S°,%
yield by mass; 74% yield by ~H NMR with EtOAc int std): ~H NMR (300 MHz, 5%
D~O in CD30D) 8 8.20-8.15 (m, 2H), 7.68-7.63 (m, 3H), 7.55 (d. J=== 8 Hz, 1 H I, 7.45-7.42 (m, 1 H), '7.28 (t, J= 8 Hz, 1H); ~3C NMR (75 MHz, 5% DSO in CD30D) 8 154.6, 147.4, 143.4, 139.1, 130.0, 129.2, 126.2, 126.0, 122.9, 119.0; IR (microscope) 3365, 1705, 1552, 1329 cm-~; HRMS (ES, rnlz) calcd for C, ~H, ,BN305 (M+H)+ 302.0943, found 30'2.0943.
N-(Pherzylanrirrothiocarbonyl)-3-clrnirroplaerrylbororric czci~:l (27e). Resin 21 (100 mg, 0.0946 mmol, theor. loading: 0.946 mmol g-~) was added to a 10 wL: pp vessel and swollen in CH~CI~ (2 mL). A solution of phenyl isothiocyanate (10% (v/v) in CH3CN, 226 ~I_,, 0.189 mmol) was added and the vessel was shaken for 20 h at rt. The suspension was drained, and the resin was rinsed with CHzCIz (Sx). The product was then cleaved from the resin using the standard conditions described above. The combined Filtrates were concentrated under reduced pressure and dried under high vacuum overnight to afford a cream colored solid (21 mg, 88% yield by mass; 82% yield by'H NMR with EtOAc int. std.): ~H NMR (300 MHz, 5% D20 in CD30D) h 7.66 (s, 1H), 7.59 (d, J= 7 Hz, 1 H), 7.47 (br d, J= 8 Hz, 1 H), 7.41-7.32 (m, 5H), 7.23-7.17 (nn, 1H); '3C NMR (75 MHz, 5% Dz0 in CD3OD) 8 181.9, 139.9, 139.2, 13 2.6, 131.5, 130.0, 129.3, 128.4, 127.1, 126.2; 1R (microscope) 3214, 3054, 1597, 1530, 1497, 14:?.9, 1344 cm-~; HRMS
(ES, rnlz) calcd for C,3HIaBN20~S (M+1 )-'- 273.0869, found 273.0871.
N-(iso-Propylarninocczrbonyl)-4-czrrzinophenylboronic acid (2aa). Creann solid (65 % yield by mass): 1H NMR (300 MHz, 5% DSO in CD30D) b 7.68-7.61 (m, 2H), 7.33-7.28 (m, 2H), 3.86 (sp, J= 7 Hz, 1H), 1.15 (d, J= 7 Hz, 6H); ~3C NMR (75 MHz, 5% D~O in CD30D) b 157.4, 143.0, 135.7, 127.7 (broad), 118.7, 42.8, 23.3; IR (microscope) 3327, 3045, 2973, 1650, 1595 cm-'; HRMS (ES, ntlz) calcd C,oH,sBNZO~Na (M+Na)-' 245.1068, found 245.1075.
N-(Pherayluminoccxrborayl~-4-umir2opheny~lboronic acid ('BbJ. White solid (85°/> yield by mass):
~H NMR (300 MHz, 5% DZO in CD30D) 8 7.73-7.66 (m, 2H), 7.42-7.37 (m, 4H), 7.31-7.25 (m, 2H), 7.04-6.99 (m, 1 H); ~ 3C NMR (75 MHz, 5% D20 in ~'D30D) a 155.3, 142.4, 140.3, 1 35.8, 129.9, 128.1 (broad), 124.0, 120..5, 119.0; 1R (microscope) 3391, 3313, 3057, 1671, 1591, 1531, 1499 cm~~; HRMS (ES, ml~) calcd for C"1-1,4BNzOz (M+H)' 257.1092, found 257.1092.
N-(-I '-Metlzoxyphenylccrrainocurboxryl)-4-uminoplze~rvlboroyair~ acid (28c-).
Cream solid (91 yield by mass; 84% yield by 1H NMR with EtOAc int std): ~ H NMR (300 MHz, 5%
D~O in CD30D) 8 7.68-7.65 (m, 2H), 7.38-7.36 (m, 2H), 7.29 (d, J-= 9 Hz, 2H1, 6.86 (d, J= 9 Hz, 2H), 3.75 (s, 3H)'3C NMR (75 MHz, 5% DZO in THF-d~) 8 156.0, 153.6, 143.1, 135.8, 134.2, 12 7.4 (broad), 120.8, 1 17.7, 114.6, 55.7; IR (microscope) 3390, 33()5, 3051, a?961, 1662, 1589 cm-~;
HRMS (ES, m/z) calcd for C,~H,~,BN204 (M+H)+287.1 198, found 287.1201.
N (-I '-Nitrophenylczminocurbory~l)-4-umirtopheraylbor-onic acid (28d).
E3right yellow solid (92%
yield by mass): ~ H NMR (300 MHz, 5% DSO in CDzOD) ~ 8.16 (d, J= 9 Hz, 2H) 7.75-7.62 (m, 4H), 7.41 (d, J= 8 Hz, 2H); ~3C NMR (300 MHz, 5°% D~() in CD30D) ~i 154.1, 147.2, 143.5, 141.9 (broad), 141.4(broad), 135.7, 125.9, l 19.3, 1 18.9; IlZ (microscope) 3439, 3354, 3 303, 3109, 1724, 1621, 1598, 1574, 1546, 1521, 1498 cm-'; HRMS (ES, m/.) calcd for C,~H,~BN30;
(M+H)+302.0943, found 302.0940.
Example 12 - U~i multicomponent reaction Referring now to Figure 22, a Ugi multicomponent reaction (IJgi, L; Domling, A.; Horl, W.
Endeavour 1994, J8, I 15-122), was carried out on DEAM-PS supported aniline 21 of Figure 18 and provided dipeptide derivative 30 in high purity after cleavage from resin 29.

N-(Acetyl)-N-(1 '-cvclohexylaminocczrbozyl-2 '-znetlzylproparze)-3-czminophezzvl boronic cicicl (30).
Resin 21 (122 mg, 0.115 mmol, theor. loading: 0.946 mmol g-~) was added to a 10 mL pp vessel and swollen in NMP (1 mL). Isobutyraldehyde (105 ~L, 1.150 mmol), glacial acetic acid (66 ~L, 1.150 mmol), and cyclohexylisonitrile (120 lzL, 1.150 mmol) were added in the given order and the vessel was shaken for 50 h at rt. 'T'he suspension was drained, and the resin was rinsed with THF (5x), CH~C12 (Sx), and THF (5x). The product was then cleaved from the resin using the standard conditions described above. The product rinses were combined, concentrated ~mder reduced pressure and dried under high vacuum overnight to afford a cream solid (26 mg, 67%
yield by mass): ~H NMR (300 MHz, 5% DSO in CD30D)' b 7.77 (d, J == 7 Hz, 1H), 7.59 (s, 1H), 7.41 (t, J= 8 Hz, 1 H), 7.30 (d, J = 8 Hz, 1 H), 4.63 (d, J == 1 1 Hz, 1 H).
3.62-3.54 (m, I H), 2.17-2.04 (m, 1H), 1.90-1.83 (m, 1H), 1.78 (s, 3H); 1.78-169 (m, 3H), 1.63-1.51 (m, 1H), 1.41-1.13 (m, 5H); 1.04 (d, J = 7 Hz, 3H), 0.87 (d, .l = 7 Hz, 3H); jC NMR (125 MHz, 5%
Dz0 in CD30D) b 174.3, 170.8, 140.9, 136.5 (broad), 135.8 (broad), 135.1, 132.0 (broad), 129.7, 68.4, 49.8, 33.5, 28.6, 26.6, 26.0, 23.5, 20.3, 19.9; IR (microscope) 3240, 30C>7, 2963, 2931, 1632, 1558 cm-~; HRMS (ES, m/z) calcd for C,<rHZ~BN~04Na (M+Na)~ 383.2118, found 383.211 I.
Example 13 - Derivatization and sequential transformations of multifunctional boronic acids Referring now to Figure 23, derivatization of multifunctional boronic acids and sequential transformations were also examined. As shown in scheme ( 1 ) of Figure; 23, the pczru-bromomethyl substituted substrate 6 was first treated with benzylamine as described above (Table 6). Following resin washes, the resulting substitution product was reacted withp-methoxyphenylisocyanate to give 31. The expected boronic acid product 32 was obtained in 64% yield and high purity after cleavage from the support.
As shown in scheme (2) of Figure 23, in a similar fashion, supported 3-amino-5-carboxyphenylboronic acid (33) was treated withp-methoxyphenyl isocyanate. The carboxyl functionality was then coupled with isopropylamine to give after treatment of resin 34 with wet THF, the final product 35 in 73% yield.
Referring now to scheme (3) of Figure 23, amide formation could also be effected as first step on the same substrate, which can then tmdergo a Ugi reaction involving the aniline functionality, ultimately providing boronic acid 37.
N-(Benzyl)-N-(~l '-methoxypherzyluznirzoccrrborzyl)-4-aznizzornethylphezzvlborozzic acid (3?~. The general procedure for substitution of a bromomethyl-substituted arylboronic acid using benzylamine (vide szzprcz) was carried out on resin 6 and was followed directly by the general procedure for the formation of areas using 4-methoxyphenyl isocyanaW (vide supra) to yield a yellow solid (67% yield by mass; 60% yield by ~H NMR with EtOAc int. std.): ~H
NMR (300 MHz, 5% DSO in CD30D) 8 7.72 (d, J= 8 Hz, 2H), 7.36-7.28 (m, 3H), 7.26-7.16 (m, 6H), 6.8 3 (d, J= 9 Hz, 2H), 4.56 (s, 4H), 3.74 (s, 3H;); ~3C NMR (75 MHz, 5% DSO in CD30D) ~i 159.1, 157.7, 140.9, 138.8, 135.3, 133.3, 129.8, 128.5, 128.5, 127.6, 125.1, 114.9, 55.9, 50.7, 50.6; 1R
(microscope) 3327, 3030, 2932, 1638, 1610, 1512 cm-~; HRMS (ES, zrz,'z) calcd for Cz~Hz3BN~04Na (M+Na)+413.1643, found 413.1631.
5-(iso-Propylczzrtizzoeczrbonyl~-N-(-t '-znethoxvphejzylcrrnirrot~cxz-bonyl~-3-czzninoplzejzylboroz~ie acid (35). The general procedure for the formation of areas using 4-methoxyphenyl isocyanate (vide sc~pz~a) was carried out on resin 33 followed directly by the: general procedure for the formation of amides using iso-propyl amine, PyBoP and DIPEA (vide supra) to yield a yellow solid (77'%
yield by mass; 65% yield by ~H NMR with EtOAc int. std.): 'H NMR (:300 MHz, 5%
D~O in CD30D, the sample was made up >16 h prior to running in order to obtain full exchange of the secondary amide proton with deuterated solvents) t~ 7.89 (br s, 1 H), 7.80 (br s, 2H), 7.31 (d, J= 9 Hz, 2H), 6.88 (d, J= 9 Hz, 2H) 4.17 (h, J == 7 Hz, 1H), 3.76 (s, 3H), 1.24 (d, J= 7 Hz, 6H); '3C
NMR (75 MHz, 5°/> D20 in CD30D) ~ 170.1, 157.3, 156.0, 140.0, 136.2, 133.0, 128.9, 128.0, 123.0, 121.2, 1 15.2, 56.1, 43.2, 22.6; IR (microscope) 3399, ,310, 2970, 1664, 1626, 1599, 1547, 1514 cm-'; HRMS (ES, nzlz) calcd for C,sHZZBN30.~Na (M+Na)+ 394.1550, found 394.1549.
N-(Acetyl)-N-(1 '-cyclohexylczminocarbon' 'l-2 '-methylproparze)-3-amino--5-(isopropylazninocczrbonyl)phezzylboronic acid (37). The general procedure for the formation of secondary amides using iso-propylamine, PyBoP and DIPEA (vide supz-cz) was carried out on resin 33 and was followed directly by the general procedure for the formation of 30 using iso-butyraldehyde, glacial acetic acid and cyclohexylisonitrile (vide supra) to yield a white solid (53% yield by mass; 42% yield by ~ H NMR with EtOAc int. std.): ~ H N MR (500 MHz, 5'% DSO
in CD,30D, the sample was made up >16 h prior to running in order to obtain full exchange of the secondary amide proton with deuterated solvents) b 8.17 (s, 1 H), 7.74 (s, 1 H) 7.68 (s, 1 H), 4. ~'2 (d, J= 11 Hz, 1H), 4.19 (heptet, J= 7 Hz, 1 H), 3.62-3.48 (m, 1 H), 2.1 l -2.06 (rn, 1 H), 1.88-1.85 (m, 1H), 1.80 (s, 3H), 1.78-1.70 (m, 3H), 1.62-160 (m, 1H), l .38-1.15 (on, 1 1H), 1.06 (d, J== 7 Hz, 3H) 0.88 (d, J= 7 Hz, 3H); ~;C NMR (75 MHz, 5% DSO in CD30D) b 174.1, 170.6, 169.0, 143.5, 141.0 (broad), 136.8, 133.6, 131.1 (broad), 68.9, 6 7.9, 43.3, 33.5, 33.5, 28.7, 26.5, 26.4, 26.0, 26.0, 23.6, 22.5. 20.2, 19.8; IR (microscope) 3308, 2969, 2932, 2856, 1640, 1586, 1537, 1428 cm-'; HRMS (ES, m/z) calcd for Cz~H~~BN305 (M+li)+ 446.2821, found 446.2816.
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (83)

1. A dihydroxyalkylaminoalkyl- or dihydroxyalkylaminobenzyl- conjugated solid support, wherein the dihydroxyalkylamino moiety comprises the formula HO(CH2)2 N(CH2)2 OH.

2. The solid support of claim 1, wherein the dihydroxyalkylaminoalkyl group or dihydroxyalkylaminobenzyl group is a diethanolaminoethyl, a diethanolaminopropyl, a diethanolaminobutyl group or a diethanolaminobenzyl group.

3. The solid support of claim 1, wherein the solid support comprises a polystyrene.

4. The solid support of claim 3, wherein the polystyrene is a cross-linked poly(styrene-divinylbenzene) (PS-DVB) copolymer.

5. The solid support of claim 4, wherein the cross-linked poly(styrene-divinylbenzene) (PS-DVB) copolymer is 1 % to 2% cross-linked.

6. The solid support of claim 1, wherein the solid support comprises a plastic or a plastic co-polymer.

7. The solid support of claim 1, wherein the solid support comprises a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or a co-polymeric mixture thereof.

8. The solid support of claim 1, wherein the solid support comprises a polystyrene-polyethylene glycol copolymer.

9. The solid support of claim 1, wherein the solid support comprises a poly(vinyl alcohol) (PVA) hydrogel.

10. The solid support of claim 1, wherein the solid support comprises a polyacrylamide.

11. The solid support of claim 10, wherein the polyacrylamide comprises a polymethacrylamide, a methyl methacrylate, a glycidyl methacrylate, a dialkylaminoalkyl-(meth)acrylate, or an N,N-dialkyl-aminoalkyl(meth)acrylate.

12. The solid support of claim 1, wherein the solid support comprises a cellulose or cellulose acetate.

13. The method of claim 1, wherein the solid support of step (a) comprises an inorganic composition selected from the group consisting of sand, silica, silica gel, glass, glass fibers, gold, alumina, zirconia, titania, and nickel oxide and combinations thereof and equivalents thereof.

14. The method of claim 1, wherein the diethanolaminoalkyl- or diethanolaminobenzyl-conjugated group is covalently bonded to the solid support through a spacer group.

15. The method of claim 14, wherein the solid support comprises silica gel and the spacer group comprises an aryl-silane linker group.

16. A method for making a solid support derivatized with a dihydroxyalkylamine group comprising mixing an aminoalkylated or aminobenzylated solid support comprising a primary amino group, with an excess of an epoxide, and a solvent, thereby derivatizing the solid support with a dihydroxylalkylamine group comprising a tertiary amine having two hydroxyalkyl substituents or two substituted hydroxyalkyl substituents.

17. The method of claim 16, wherein the dihydroxyalkylamine group has the formula HO
(CH2)2N (CH2)2 OH.

18. The method of claim 16, wherein the dihydroxyalkylamine group has the formula HOCR2 CH2NCH2 CR2OH, and R is independently selected from the group consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical.

19. The method of claim 16, wherein the mixing takes place under pressurized conditions in a sealed, pressure resistant container.

20. The method of claim 16, wherein the epoxide comprises ethylene oxide, and the dihydroxyalkylamine group comprises a N,N-diethanolamine group.

21. The method of claim 20, wherein the ethylene oxide in the sealed, pressure resistant container is a gas at about 1 to about 20 atmospheres.

22. The method of claim 20, wherein the reaction takes place at about 50ÀC.

23. The method of claim 16, wherein the epoxide comprises isobutylene oxide and the dihydroxyalkylamine group comprises a diisobutanolamine group.

24. The method of claim 16, wherein the epoxide comprises an aryl-substituted oxirane.

25. The method of claim 16, wherein the solvent comprises a tetrahydrofuran/water mixture or dioxane.

26. The method of claim 16, wherein the mixing lasts for about 12 to 72 hours.

27. A boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support, wherein the boronic ester-dioxyalkylamino group has a formula wherein R comprises an alkyl or a benzyl group, and R' is selected from the group consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical.

28. The boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 27, wherein the boronic ester is an aryl boronic ester, a vinylboronic ester or an alkylboronic ester.

29. The boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 27, wherein the solid support is selected from the group consisting of:
i. a polystyrene or an equivalent composition;
ii. a plastic or a plastic co-polymer;
iii. a silica or a silica gel;
iv. cellulose or cellulose acetate;
v. a polyphenol, a polyvinyl, a polypropylene, a polyester, a polyethylene, a polyethylene glycol, a polystyrene-copolymer, or a co-polymeric mixture thereof;
vi. a poly(vinyl alcohol) (PVA) hydrogel;
vii. a polyacrylamide.

30. The boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 29, wherein the polystyrene is a cross-linked poly(styrene-divinylbenzene) (PS-DVB) copolymer.

31. The boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 30, wherein the cross-linked poly(styrene-divinylbenzene) (PS-DVB) copolymer is about 1% to 2% cross-linked.

32. The boronic ester-dioxyalkylaminoalkyl or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 27, wherein the boronic ester-dioxyalkylamino group has the formula wherein R comprises an alkyl or a benzyl group.

33. The boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support of claim 27, wherein the boronic ester-dioxyalkylamino group has the formula wherein R comprises an alkyl or a benzyl group.

34. A method for making a boronic ester-dioxyalkylaminoalkyl- or boronic ester-dioxyalkylaminobenzyl-conjugated solid support comprising the following steps:
(a) mixing an aminoalkylated or aminobenzylated solid support comprising a primary amino group, with an excess of an epoxide, and a solvent, thereby derivatizing the solid support with a dihydroxylakylamine group comprising a tertiary amine having two hydroxyalkyl or two substituted hydroxyalkyl substituents;
(b) mixing the dihydroxyalkylamine-derivatized solid support of step (a) with a boronic acid, in an anhydrous solvent, thereby derivatizing the solid support with a boronic ester-dioxyalkylaminoalkyl or dioxyalkylaminobenzyl group having the formula wherein R comprises an alkyl or a benzyl group, and R' is selected from the group consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical.

35. A method for immobilizing a boronic acid comprising the following steps:
(a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyaminobenzyl group, wherein the dihydroxyalkylamino moiety has a formula HO (CR'2)x CH2N
CH2(CR'2)y OH, wherein R' is independently selected from the group consisting consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid; and (c) mixing the solid support of step (a) with the sample of step (b) in an anhydrous solvent, thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl-conjugated group having the formula wherein R comprises an alkyl or a benzyl, R' comprises at least one of H
and C1-C20 radical, and x and y are integers between 1 to about 20.

36. A method for purifying a boronic acid comprising the following steps:
(a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyaminobenzyl group, wherein the dihydroxyalkylamino moiety has a formula HO (CR'2)x CH2N CH2(CR'2)y OH, wherein R' is independently selected from the group consisting consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid;
(c) mixing the solid support of step (a) with the sample of step (b) in an anhydrous solvent, thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl-conjugated group having the formula wherein R comprises an alkyl or a benzyl, R' comprises at least one of H
and C1-C20 radical, and x and y are integers between 1 to about 20; and (d) hydrolyzing the boronic ester linkage, thereby releasing from the support a purified boronic acid.

37. The method of claim 36, wherein the hydrolyzing of step (d) is in a solution comprising tetrahydrofuran, water and acetic acid.

38. The method of claim 36, wherein the hydrolyzing of step (d) is in a solution comprising tetrahydrofuran and water.

39. The method of claim 36, further comprising washing the solid support at least once with an anhydrous solvent after the mixing of step (c) and before the hydrolysis of step (d).

40. The method of claim 36, performed in a batch or a column.

41. The method of claim 36, performed in an automated or semiautomated synthesizer.

42. A method for scavenging a boronic acid from a multiple component solution to generate a boronic acid-free solution comprising the following steps:
(a) providing a solid support derivatized with a dihydroxyalkylaminoalkyl group or a dihydroxyaminobenzyl group, wherein the dihydroxyalkylamino moiety has a formula HO (CR'2)x CH2N CH2(CR'2)y OH, wherein R' is independently selected from the group consisting consisting of H, C1-C20 alkyl radical, and C1-C20 substituted alkyl radical, and x and y are integers between 1 to about 20, (b) providing a sample comprising at least one boronic acid;
(c) mixing the solid support of step (a) with the sample of step (b), thereby immobilizing a boronic acid by generating a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl-conjugated group having the formula wherein R comprises an alkyl or a benzyl, R' comprises at least one of H and C1-C20 radical, and x and y are integers between 1 to about 20; and (d) washing the solid support after the mixing of step (c) to remove non-boronic acid components; thereby scavenging the boronic acid from the multiple component sample to generate a boronic acid-free solution.

43. The method of claim 42, wherein a molar excess of the support versus an estimated amount of boronic acid in the multiple component sample is used.

44. A method for the solid phase synthesis of functionalized compounds comprising the following steps:
(a) providing a boronic ester-dioxyalkylaminoalkyl or -dioxyalkylaminobenzyl-conjugated solid support, (b) providing a vinyl halide- or aryl halide- conjugated solid support;
(c) providing a transfer agent;
(d) combining the conjugated support of step (a) with the conjugated support of step (b) and the transfer agent of step (c) under conditions comprising a catalyst, a base and a solvent, thereby effecting coupling of the aryl or vinyl group of the conjugated support of step (a) with the vinyl or aryl group of step (e) to produce a solid supported, functionalized reaction product;
(f) liberating the functionalized compound from the solid support.

45. The method of claim 44, wherein the boronic ester-dioxyalkylaminoalkyl or -dioxyalkylaminobenzyl-conjugated solid support comprises the formula wherein R comprises an alkyl or a benzyl, R' comprises at least one of H and C1-C20 radical, and x and y are integers between 1 to about 20; and

46. The method of claim 44, wherein the functionalized compound of step (e) is liberated from the solid support by reacting the solid supported reaction product of step (d) with a solvent comprising an acid and a non-protic, non-polar solvent.

47. The method of claim 44, wherein the synthesized functionalized compound liberated from the solid support in step (e) comprises a functionalized biphenyl compound.

48. The method of claim 44, wherein the solid-supported boronic ester derivative originates from a poly-functionalized arylboronic acid containing at least one of the following substituents at at least one of the ortho-, meta- and para- positions:
(a) a carboxamide;
(b) a carboxylic ester;
(c) a methylamino group;
(d) an anilide group comprising an acyl group;
(e) a urea comprising an acylamino group;
(f) a sulfonamide comprising a sulfonyl group; or (g) an aryl alkyl ether.

49. The method of claim 44, wherein the molar equivalent ratio of solid supported boronic ester of step (a) to the conjugated solid support of step (b) is about 3 to about 4.

50. The method of claim 44, wherein the solid support comprises a polystyrene resin.

51. The method of claim 44, wherein the solid-supported aryl halide of step (b) is a solid-supported polysubstituted halobenzoic acid, a solid-supported amino-substituted haloarene or a solid-supported aminoalkyl-substituted haloarene.

52. The method of claim 44, wherein the catalyst of step (d) comprises a Pd(0) catalyst or a Pd(II) pre-catalyst.

53. The method of claim 44, wherein the Pd(0) catalyst comprises a Pd(PPh3)4 or a Pd2(dba)3.

54. The method of claim 44, wherein the solvent of step (d) comprises an aqueous solvent.

55. The method of claim 44, wherein the transfer agent of step (c) comprises an aqueous solvent.

56. The method of claim 44, wherein the base of step (d) comprises sodium carbonate, a trialkylamine, potassium fluoride, sodium fluoride or cesium fluoride.

57. The method of claim 44, wherein the reaction conditions of step (d) comprise a temperature of between about 25ÀC to about 120ÀC.

58. The method of claim 44, wherein the reaction conditions of step (c) comprise a reaction time of between about 1 hours to about 72 hours.

59. The method of claim 44, wherein the solvent of step (d) comprises an anhydrous basic solvent.

60. The method of claim 59, wherein the solvent of step (d) further comprises ethylene glycol as a co-solvent.

61. The method of claim 59, wherein the solvent of step (d) comprises at least one tertiary amine base.

62. The method of claim 59, wherein the reaction conditions of step (d) comprise a temperature of between about 25ÀC to about 120ÀC.

63. The method of claim 44, wherein the reaction takes place in semiautomated parallel synthesizer.

64. A semiautomated parallel synthesizer comprising (a) a boronic ester-dioxyalkylaminoalkyl or -dioxyalkylaminobenzyl-conjugated solid support, and (b) a vinyl halide- or aryl halide-conjugated solid support.

65. A method for the solid phase synthesis of functionalized compounds comprising the following steps:
(a) providing a first reactant comprising a boronic ester-dioxyalkylaminoalkyl-or -dioxyalkylaminobenzyl- conjugated solid support, (b) providing a second reactant conjugated to a solid support;
(c) providing a transfer agent;
(d) providing a solvent (e) reacting the boronic ester-dioxyalkylaminoalkyl- or -dioxyalkylaminobenzyl-conjugated solid support of step (a) with the second reactant of step (b) and the transfer agent of step (c) in the solvent of step (d), thereby producing a solid supported, functionalized reaction product;
(f) liberating the functionalized compound from the solid support.

66. The method of claim 65, wherein the solvent of step (d) comprises an anhydrous solvent.

67. The method of claim 65, wherein the solvent of step (d) comprises an aqueous solvent.

68. The method of claim 67, wherein the the transfer agent of step (c) comprises the solvent of step (d).

69. The method of step 67, wherein the transfer agent of step (c) comprises water.

70. The method of step 67, wherein the transfer agent of step (c) comprises an alcohol.

71. A method for the solid phase synthesis of functionalized glycine compounds comprising the following steps:
(a) providing a boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl conjugated solid support, (b) providing a solid-supported iminium compound;
(c) providing a transfer agent;
(d) reacting the boronic ester-dioxyalkylaminoalkyl- or dioxyalkylaminobenzyl conjugated solid support of step (a) with the transfer agent of step (c) and the solid-supported iminium of step (b) in a solvent, thereby producing a solid supported, functionalized glycine reaction product; and, (e) liberating the functionalized compound from the solid support.

72. The method of claim 71, wherein the solvent of step (d) comprises a hydroxylic solvent.

73. The method of claim 71, wherein the hydroxylic solvent acts as the transfer agent of step (c).

74. The method of claim 71, wherein reacting step (e) lasts for about 12 hours to about 48 hours.

75. The method of claim 71, wherein the functionalized compound of step (e) is liberated from the solid support by reacting the solid supported reaction product of step (d) with a solvent comprising an acid and a non-protic, non-polar solvent.

76. The method of claim 71, wherein step (d) further comprises the step of washing the solid supported, functionalized reaction product at least once with a solvent prior to liberating of the compound of step (e).

77. A method for the solid-phase derivatization of a functionalized boronic acid comprising the following steps:
(a) providing a dihydroxyalkylaminoalkyl or dihydroxyalkylaminobenzyl-conjugated solid support;
(b) providing a sample comprising a functionalized boronic acid;
(c) mixing the solid support with the sample in an anhydrous solvent, thereby immobilizing the functionalized boronic acid by generating a functionalized boronic ester-dioxyalkylaminoalkyl- or boronic dioxyalkylaminobenzyl-conjugated group;
(d) providing at least one derivatizing agent capable of reacting with the functional group of the functionalized boronic acid; and (e) contacting the derivatizing agent of step (d) with the functionalized boronic ester-dioxyalkylaminoalkyl- or functionalized boronic ester dioxyalkylaminobenzyl-conjugated group in a solvent, thereby producing a solid supported, derivatized boronic acid product.

78. The method of claim 77, further comprising reacting the solid supported, derivatized boronic acid with a solvent, thereby liberating the derivatized boronic acid from the solid support.

79. The method of claim 77, wherein the functionalized boronic acid of step (b) comprises a formyl-functionalized benzeneboronic acid, and the derivatizing agent of step (d) comprises a primary or secondary amine, along with sodium borohydride.

80. The method of claim 77, wherein the functionalized boronic acid of step (b) comprises a bromomethyl-functionalized benzeneboronic acid, and the derivatizing agent of step (d) comprises a primary or secondary amine.

81. The method of claim 77, further comprising a coupling agent, and wherein the functionalized boronic acid of step (b) comprises a carboxy-functionalized arylboronic acid, and the derivatizing agent of step (d) comprises an amine.

82. The method of claim 77, wherein the functionalized boronic acid of step (b) comprises an amino-functionalized boronic acid, and the derivatizing agent of step (d) comprises a isocyanate.

83. The method of claim 78, wherein step (e) further comprises the step of washing the solid supported, derivatized reaction product at least once with a solvent prior to liberating of the compound.