CA2285175A1 - Rink-chloride linker for solid phase organic synthesis of organic molecules - Google Patents
Rink-chloride linker for solid phase organic synthesis of organic molecules Download PDFInfo
- Publication number
- CA2285175A1 CA2285175A1 CA002285175A CA2285175A CA2285175A1 CA 2285175 A1 CA2285175 A1 CA 2285175A1 CA 002285175 A CA002285175 A CA 002285175A CA 2285175 A CA2285175 A CA 2285175A CA 2285175 A1 CA2285175 A1 CA 2285175A1
- Authority
- CA
- Canada
- Prior art keywords
- resin
- bound
- rink
- chloride
- linker
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/045—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers using devices to improve synthesis, e.g. reactors, special vessels
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
Description
RINK-CHLORIDE LINKER FOR SOLID PHASE ORGANIC
SYNTHESIS OF ORGANIC MOLECULES
FIELD OF THE INVENTION
This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
BACKGROUND OF THE INVENTION
In the continuing search for new chemical moieties that can effectively modulate a variety of biological processes, the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks.
The biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
In an effort to reduce the time and expense involved in screening a large number of randomly chosen compounds for biological activity, several developments have been made to provide libraries of compounds for the discovery of lead compounds. The chemical generation of molecular diversity has become a major tool in the search for novel lead structures. Currently, the known methods for chemically generating large numbers of molecularly diverse compounds generally involve the use of solid phase synthesis, in particular to synthesize and identify peptides and peptide libraries. See, for example. Lebl et al., Int. J. Pept.
Prot. Res., ?5 41, p. 201 ( 1993) which discloses methodologies providing selectively cleavable linkers between peptide and resin such that a certain amount of peptide can be liberated from the resin and assayed in soluble form while some of the peptide still remains attached to the resin, where it can be sequenced: Lam et al., Nature, 354, p.
82 ( 1991 ) and (WO 92/00091 ) which disclose a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin;
Geysen et al., J. Lremunol. Meth., 102, p. 259 ( 1987) which discloses the synthesis of peptides on derivatized polystyrene pins which are arranged on a block in such a way that they correspond to the arrangement of wells in a 96-well microtiter plate: and Houghten et al., Nature, 354, p. 84 ( 1991 ) and WO 92/09300 which disclose an approach to de novo determination of antibody or receptor binding sequences involving soluble peptide pools.
The major drawback, aside from technical considerations, with all of these methods for lead generation is the quality of the lead. Linear peptides historically SUBSTITUTE SHEET (RULE 26) have represented relatively poor leads for pharmaceutical design. In particular, there is no rational strategy for conversion of a linear peptide into a non-peptide lead. As noted above. one must resort to screening large databanks of compounds, with each compound being tested individually, in order to determine non-peptide leads for peptide receptors.
In this respect, there has been increasing interest in the application of solid phase synthesis to the preparation of organic compounds, especially in the context of combinatorial chemistry and multiple simultaneous synthesis, or parallel synthesis.
One of the limitations in the solid phase approach in general, involves the linker by IO which the organic molecule is attached to the solid support. The Rink linker (Rink, H., Tetrahedron Lea., 1987,28, 3787-3790) has been effectively applied to the synthesis of some chemical libraries (Gordeev, M. F.; Patel, D. V.; Gordon, E.
M. J.
Org. Chem. 1996, 61, 924-928; Norman, T. C.; Gray, N. S.; Koh. J. T.: Schultz, P.
G. J. Am. Chem. Soc. 1996, p. 118, 7430-7431; Ward, Y. D.; Farina, V.
Tetrahedron Lett., 1996, 37, 6993-6996), because of the ease of use and mild conditions for release of the library component. However the Rink linker is currently limited to use in the preparation of amides and carboxylic acids. Therefore, a need exists for a Rink linker useful for a broader range of solid phase chemistry. Herein, we describe the preparation of a Rink-chloride linker, which allows a very general and practical method for the attachment of, inter alia, amines, alcohols and thiols to a solid support.
SUMMARY OF THE INVENTION
This invention relates to a novel solid phase Rink linker of formula (I), ?5 hereinafter referred to as a resin-bound Rink-chloride linker or a Rink-chloride linker. This represents a significant improvement over the current use of the Rink-acid linker. At present the use of the known Rink-acid linker is limited to preparing amides and carboxylic acids. The use of the instant improved Rink-chloride linker of formula (I) makes Rink technology available to a broad number of functional group attachments. The use of the Rink-chloride linker allows a very general and practical method for the attachment of amines, alcohols and thiols, including phenols and thiophenols to a solid support. Therefore, another aspect of the instant invention is in a method for making compounds by resin-bound synthesis using the Rink-chloride linker in solid phase synthesis. This method is applicable to mailing combinatorial libraries of compounds designed around a core molecular structure using known methods of solid phase combinatorial chemistry or multiple simultaneous synthesis ("parallel synthesis"). The compounds or libraries of SUBSTtTUTE SHEET (RULE 26) compounds made using this linker may be tested in biologically assays designed to test for a particular physical characteristic potentially useful in drug therapy.
DETAILED DESCRIPTION OF THE INVENTION
The terms "resin." "solid support." "inert resin." polymeric resin" or "polymeric resin support" are used herein at all occurrences to mean a bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, grafted co-poly beads, poiy-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N =bis-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface. The solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol-polystyrene resin, and any other substance which may be used as such and which would be known or obvious to one of ordinary skill in the art.
I S The term "substituted resin-bound Rink-chloride intermediate" is used herein at all occurrences to mean the intermediate produced by coupling a resin-bound Rink-chloride linker with a suitable nucleophile (with displacement of the chloride of the Rink linker) such that to the nucleophile is linked to the resin through the Rink linker.
The term "additional synthetic chemistry" is used herein at all occurrences to mean chemical reactions which are performed on the substituted resin-bound Rink-chloride intermediate prior to cleavage of the nucleophile from the polymeric resin, wherein said chemical reactions are compatible with and non-reactive with the Rink-chloride linker and may be used to prepare derivatives of the nucleophile. It will be ?5 understood by the skilled artisan that the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate, is done so prior to cleavage of the derivatized nucleophile. Chemical reactions which are incompatible with the nucleophile/Rink-chloride linkage, i.e., they cause cleavage of the nucleophile from the Rink-chloride linker, are not among the additional synthetic chemistry that may be used in the methods of this invention.
The terms "resin-bound synthesis" and "solid phase synthesis" are used herein interchangeably to mean a series of chemical reactions used to prepare either a single molecule/compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound which is bound to a polymer resin through a linkage, in particular, a Rink-chloride linkage.
Chemical synthesis on solid supports has become a cornerstone in the generation of small organic molecule combinatorial libraries. Paramount to the success of any solid-SUBSTITUTE SHEET (RULE 26) phase synthetic strategy is a reliable and general method for coupling the initial starting materials onto the solid support, namely through linker technology. Such linker technology should also be amenable to ready cleavage of the reaction products under relatively mild conditions, and without compromising the structure of the reaction products. The Rink linker has been effectively applied to the synthesis of some chemical libraries because of its ease of use and the mild conditions for release of library components from the solid support. However the Rink technology is currently limited to the preparation of amides and carboxylic acids. Herein, we describe the preparation and-utility of a Rink-chloride linker, which allows a very general and practical method for the attachment of amines, alcohols and thiols to a solid support, derivatization of these resin bound compounds, and their eventual release from the resin with trifluoroacetic acid.
The resin-bound Rink-acid linker 1-Scheme 1 can be converted to the resin-bound Rink-chloride resin of this invention, 2-Scheme 1, by treatment of the resin-bound Rink-acid linker with triphenyl phosphine and hexachloroethane. 2-Scheme 1 so obtained is 1 S stable at room temperature for several days and can be used without any loss of activity.
Scheme 1 2-Scheme 1 can be reacted cleanly with a variety of nucleophiles ("Nu") under mild reaction conditions (see, Scheme 2 and Table I below). The nucleophiles depicted herein are either commercially available or can be made using known procedures.
SUBSTITUTE SHEET (RULE 26~
Scheme 2 Nucleophiie y Hunig-s base --' ~O Nu / \ dichloroethane / \
- resin resin / ~ \ /
2-Scheme 1 j 2.Scheme 2 Table I
Nucleo hile Yield Puritv Nucleo hile Yield Puritv ;N / \ 0 95 93 °.H 90 - 95 ° H 94 90 ° ° 85 80 "H ~ ~H
H 95 96 ~ 96 91 i ". o \ / v 90 94 / S ~ ~ 84 90 H," ~ ~ ~
F
H CH2Ph g 'n, / \ 0 95 95 i I vH 92 95 H
°'H 85 95 ° 96 95 °~H
H~"'FMOC
Rink-chloride efficiently reacts with primary and secondary amines, anilines, alcohols, phenols, thiols, thiophenols, and carboxylic acids. The coupling is usually carried out in dichloroethane in the presence of Hiinig's base, under inert atmosphere for 18-26 hours at room temperature. The extent of coupling efficiency is monitored by MASNMR and then by cleaving the product from the resin with about 3-5% TFA in s SUBSTITUTE SHEET (RULE 26) CH~CI~. Release of the ligands from the resin is complete within 30 minutes as evidenced by MASNMR of the residual resin. As is apparent from Table I, the coupling is general and highly efficient. While cleavage from the resin is facile, it is sufficiently stable enough to carry out a wide range of chemistry commonly used in small molecule ~ library construction. Some illustrative examples are shown in Scheme 3.
Scheme 3 1. FMOC-glyine / \
p-naphthyl acid chloride/ / \ 5%TFA ~N /
a~ ~ / \ Hunig's base.._> ~ _in CH2C1 Cl / 2.20%piperidine N / v R«in~bound ~ in DMF O
Rink-chloride 75%
Linker H O
H~N~H
H~N~H
maieic O
furfuryl O ~ PhH/RT a 05%TFq Product alcohol ------> ~ in CH2CI decomposed _ ._ 2> upon CI p O ~ O cleavage.
Resio-bound Rink~Chloride Linker 3-bromo benzyi Br amine ~N ~ _... i I _ > N / .. _...
CI H ~ Pd(O) I ~ 5%TFA
R«in-donna 4-formylboronic acid H ~ in CH2CI2 Rink-Chloride aq. K2CO3 Linker EtOH/xylene NH
60%
It will be understood that after making the substituted resin-bound Rink-chloride intermediate, and prior to cleavage with TFA. additional syntheic chemistry may be performed on the intermediate in order to derivatize the nucleophile core.
Therefore, another aspect of the invention is in a method for synthesizing a 1 S compound by resin-bound synthesis comprising the steps of: (a) converting a resin bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) SUBSTITUTE SHEET (RULE 28) \ / O / \ CI
resin O \ /
/
O
/
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
and (c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile. The resin-bound derivatized nucleophile can remain bound to the resin for storage and/or further derivatization, or it may be cleaved from the resin with between about 3 and S% TFA.
In yet another aspect, this invention is in a method for synthesizing a library of molecularly diverse compounds by resin-bound synthesis, comprising the steps of: (a) convening a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) \ / o / \ cl resin O \ /
/
O
/
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate: (c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions; (d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile;
and (e) optionally recombining the portions.
Based upo the disclosure herein, it will be clear to one of ordinary skill in the art that there are many possible synthetic approaches to creating the libraries of this invention. For example the libraries may be prepared using the split and mix technique or parallel synthesis techniques. The libraries generated from either of the the synthetic methods are molecularly diverse and are prepared simultaneously.
The libraries are prepared on the polymer resins using the Rink-chloride linker described herein. For example, the compound to be derivatized (suitable nucleophile), is SUBSTITUTE SHEET (RULE 26) attached to the polymer resin through the Rink-chloride linker to give a substituted resin-bound Rink-chloride intermediate. In one embodiment, the substituent(s) are modified by reacting the resin-bound Rink-chloride intermediate, with a mixture of reagents. In an alternative embodiment, aliquots of the resin-bound Rink-chloride intermediate are reacted with individual reagents each one of which will modify a position on the core of the resin-bound nucleophile, and then the resultant products are mixed together to form the library of derivatized resin-bound intermediates. This library may then be further derivatized by repeating the process of dividing and recombining the intermediates formed by the additional synthetic chemistry. It will be clear to one of ordinary skill in the art that when the libraries of the invention are prepared according to the instant disclosure, each polymer support bears a single species created by the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate.
It will be obvious to one of skill in the art that the steps of optionally dividing and recombining the resin-bound aryl silane intermediate into portions are for purposes of varying the derivatization on the resin-bound nucleophiles which are generated by the combinatorial synthesis. Of course, it will be obvious to the skilled artisan that the resin-bound nucleophile intermediates may be divided into portions at any point during the synthetic sequence. The portions may be recombined at any point during the sequence or, further iterations may be applied if more derivatization is required. Therefore, it will be obvious to the skilled artisan that the steps of dividing the portions, performing additional synthetic chemistry and recombining the portions, may each be carried out more than once, depending upon the type of diversity required for the library of end-product compounds being prepared.
According to this invention, after the additional synthetic chemistry has been performed on the resin-bound aryl silane intermediate so that a library of molecularly diverse compounds has been prepared, the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry. The compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed. In addition, a partial array of compound members of the library may be cleaved from the resin, characterized and analyzed, while leaving a partial array of the compound members of the library bound to the resin.
s SUBSTITUTE SHEET (RULE 26~
EXAMPLES
Preparation of Rink-chloride (2-Scheme 1) To a suspension of resin-bound Rink-acid, 1-Scheme 1, ( I .Og, l.6mmol.) in - THF (25mL) was added triphenylphosphine (2.328, 8.8mmol.) and hexachloroethane (2.13g, 8.8mmol.). The reaction mixture was agitated with a constant flow of argon for 6h. The resin-bound Rink-chloride, 2-Scheme 1, was filtered and washed with THF and acetone. Completion of the reaction was affirmed by chlorine analysis and MASNMR (the signal for CH(OH)at 8 5.85 disappears completly). Chlorine analysis indicated a stoichometric amount of chlorine.
Reaction of rink-chloride with various nucleophiles To a suspension of 2-Scheme 1 (0.96g, l.6mMol.) in dichloroethane (25mL) was added Hiinig's base ( 1mL) and the requisite nucleophile ( lOmMol.). The reaction mixture was agitated with a constant flow of argon for 6-12h. The resin was filtered and washed with dichloromethane, MeOH, H20, EtOH, CH2Cl2 and MeOH.
Completion of the reaction was confirmed by MASNMR, IR or elemental analysis. Elemental analysis indicates no chlorine and a stoichometric amount of nitrogen or sulfur for the appropriate compounds.
Cleavage from Rink-linked lisands 3% TFA/CH2Cl2 was added to the substituted resin-bound Rink chloride moieties, either as individual beads or in bulk quantity. The cleavage was carried out for 30 min., and the product was isolated by extraction with 1:1/
MeOH:MeCN.
All the cleaved products from Table I were identified by comparing them with an authentic sample of the starting material (nucleophile).
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows.
SUBSTITUTE SHEET (RULE 26)
SYNTHESIS OF ORGANIC MOLECULES
FIELD OF THE INVENTION
This invention relates to a novel linker for use in solid phase chemistry, its preparation and methods of use of the linker.
BACKGROUND OF THE INVENTION
In the continuing search for new chemical moieties that can effectively modulate a variety of biological processes, the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks.
The biological activity of the pre-existing chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
In an effort to reduce the time and expense involved in screening a large number of randomly chosen compounds for biological activity, several developments have been made to provide libraries of compounds for the discovery of lead compounds. The chemical generation of molecular diversity has become a major tool in the search for novel lead structures. Currently, the known methods for chemically generating large numbers of molecularly diverse compounds generally involve the use of solid phase synthesis, in particular to synthesize and identify peptides and peptide libraries. See, for example. Lebl et al., Int. J. Pept.
Prot. Res., ?5 41, p. 201 ( 1993) which discloses methodologies providing selectively cleavable linkers between peptide and resin such that a certain amount of peptide can be liberated from the resin and assayed in soluble form while some of the peptide still remains attached to the resin, where it can be sequenced: Lam et al., Nature, 354, p.
82 ( 1991 ) and (WO 92/00091 ) which disclose a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin;
Geysen et al., J. Lremunol. Meth., 102, p. 259 ( 1987) which discloses the synthesis of peptides on derivatized polystyrene pins which are arranged on a block in such a way that they correspond to the arrangement of wells in a 96-well microtiter plate: and Houghten et al., Nature, 354, p. 84 ( 1991 ) and WO 92/09300 which disclose an approach to de novo determination of antibody or receptor binding sequences involving soluble peptide pools.
The major drawback, aside from technical considerations, with all of these methods for lead generation is the quality of the lead. Linear peptides historically SUBSTITUTE SHEET (RULE 26) have represented relatively poor leads for pharmaceutical design. In particular, there is no rational strategy for conversion of a linear peptide into a non-peptide lead. As noted above. one must resort to screening large databanks of compounds, with each compound being tested individually, in order to determine non-peptide leads for peptide receptors.
In this respect, there has been increasing interest in the application of solid phase synthesis to the preparation of organic compounds, especially in the context of combinatorial chemistry and multiple simultaneous synthesis, or parallel synthesis.
One of the limitations in the solid phase approach in general, involves the linker by IO which the organic molecule is attached to the solid support. The Rink linker (Rink, H., Tetrahedron Lea., 1987,28, 3787-3790) has been effectively applied to the synthesis of some chemical libraries (Gordeev, M. F.; Patel, D. V.; Gordon, E.
M. J.
Org. Chem. 1996, 61, 924-928; Norman, T. C.; Gray, N. S.; Koh. J. T.: Schultz, P.
G. J. Am. Chem. Soc. 1996, p. 118, 7430-7431; Ward, Y. D.; Farina, V.
Tetrahedron Lett., 1996, 37, 6993-6996), because of the ease of use and mild conditions for release of the library component. However the Rink linker is currently limited to use in the preparation of amides and carboxylic acids. Therefore, a need exists for a Rink linker useful for a broader range of solid phase chemistry. Herein, we describe the preparation of a Rink-chloride linker, which allows a very general and practical method for the attachment of, inter alia, amines, alcohols and thiols to a solid support.
SUMMARY OF THE INVENTION
This invention relates to a novel solid phase Rink linker of formula (I), ?5 hereinafter referred to as a resin-bound Rink-chloride linker or a Rink-chloride linker. This represents a significant improvement over the current use of the Rink-acid linker. At present the use of the known Rink-acid linker is limited to preparing amides and carboxylic acids. The use of the instant improved Rink-chloride linker of formula (I) makes Rink technology available to a broad number of functional group attachments. The use of the Rink-chloride linker allows a very general and practical method for the attachment of amines, alcohols and thiols, including phenols and thiophenols to a solid support. Therefore, another aspect of the instant invention is in a method for making compounds by resin-bound synthesis using the Rink-chloride linker in solid phase synthesis. This method is applicable to mailing combinatorial libraries of compounds designed around a core molecular structure using known methods of solid phase combinatorial chemistry or multiple simultaneous synthesis ("parallel synthesis"). The compounds or libraries of SUBSTtTUTE SHEET (RULE 26) compounds made using this linker may be tested in biologically assays designed to test for a particular physical characteristic potentially useful in drug therapy.
DETAILED DESCRIPTION OF THE INVENTION
The terms "resin." "solid support." "inert resin." polymeric resin" or "polymeric resin support" are used herein at all occurrences to mean a bead or other solid support such as beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, grafted co-poly beads, poiy-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N =bis-acryloyl ethylene diamine, glass particles coated with a hydrophobic polymer, etc., i.e., a material having a rigid or semi-rigid surface. The solid support is suitably made of, for example, cross linked polystyrene resin, polyethylene glycol-polystyrene resin, and any other substance which may be used as such and which would be known or obvious to one of ordinary skill in the art.
I S The term "substituted resin-bound Rink-chloride intermediate" is used herein at all occurrences to mean the intermediate produced by coupling a resin-bound Rink-chloride linker with a suitable nucleophile (with displacement of the chloride of the Rink linker) such that to the nucleophile is linked to the resin through the Rink linker.
The term "additional synthetic chemistry" is used herein at all occurrences to mean chemical reactions which are performed on the substituted resin-bound Rink-chloride intermediate prior to cleavage of the nucleophile from the polymeric resin, wherein said chemical reactions are compatible with and non-reactive with the Rink-chloride linker and may be used to prepare derivatives of the nucleophile. It will be ?5 understood by the skilled artisan that the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate, is done so prior to cleavage of the derivatized nucleophile. Chemical reactions which are incompatible with the nucleophile/Rink-chloride linkage, i.e., they cause cleavage of the nucleophile from the Rink-chloride linker, are not among the additional synthetic chemistry that may be used in the methods of this invention.
The terms "resin-bound synthesis" and "solid phase synthesis" are used herein interchangeably to mean a series of chemical reactions used to prepare either a single molecule/compound or a library of molecularly diverse compounds, wherein the chemical reactions are performed on a compound which is bound to a polymer resin through a linkage, in particular, a Rink-chloride linkage.
Chemical synthesis on solid supports has become a cornerstone in the generation of small organic molecule combinatorial libraries. Paramount to the success of any solid-SUBSTITUTE SHEET (RULE 26) phase synthetic strategy is a reliable and general method for coupling the initial starting materials onto the solid support, namely through linker technology. Such linker technology should also be amenable to ready cleavage of the reaction products under relatively mild conditions, and without compromising the structure of the reaction products. The Rink linker has been effectively applied to the synthesis of some chemical libraries because of its ease of use and the mild conditions for release of library components from the solid support. However the Rink technology is currently limited to the preparation of amides and carboxylic acids. Herein, we describe the preparation and-utility of a Rink-chloride linker, which allows a very general and practical method for the attachment of amines, alcohols and thiols to a solid support, derivatization of these resin bound compounds, and their eventual release from the resin with trifluoroacetic acid.
The resin-bound Rink-acid linker 1-Scheme 1 can be converted to the resin-bound Rink-chloride resin of this invention, 2-Scheme 1, by treatment of the resin-bound Rink-acid linker with triphenyl phosphine and hexachloroethane. 2-Scheme 1 so obtained is 1 S stable at room temperature for several days and can be used without any loss of activity.
Scheme 1 2-Scheme 1 can be reacted cleanly with a variety of nucleophiles ("Nu") under mild reaction conditions (see, Scheme 2 and Table I below). The nucleophiles depicted herein are either commercially available or can be made using known procedures.
SUBSTITUTE SHEET (RULE 26~
Scheme 2 Nucleophiie y Hunig-s base --' ~O Nu / \ dichloroethane / \
- resin resin / ~ \ /
2-Scheme 1 j 2.Scheme 2 Table I
Nucleo hile Yield Puritv Nucleo hile Yield Puritv ;N / \ 0 95 93 °.H 90 - 95 ° H 94 90 ° ° 85 80 "H ~ ~H
H 95 96 ~ 96 91 i ". o \ / v 90 94 / S ~ ~ 84 90 H," ~ ~ ~
F
H CH2Ph g 'n, / \ 0 95 95 i I vH 92 95 H
°'H 85 95 ° 96 95 °~H
H~"'FMOC
Rink-chloride efficiently reacts with primary and secondary amines, anilines, alcohols, phenols, thiols, thiophenols, and carboxylic acids. The coupling is usually carried out in dichloroethane in the presence of Hiinig's base, under inert atmosphere for 18-26 hours at room temperature. The extent of coupling efficiency is monitored by MASNMR and then by cleaving the product from the resin with about 3-5% TFA in s SUBSTITUTE SHEET (RULE 26) CH~CI~. Release of the ligands from the resin is complete within 30 minutes as evidenced by MASNMR of the residual resin. As is apparent from Table I, the coupling is general and highly efficient. While cleavage from the resin is facile, it is sufficiently stable enough to carry out a wide range of chemistry commonly used in small molecule ~ library construction. Some illustrative examples are shown in Scheme 3.
Scheme 3 1. FMOC-glyine / \
p-naphthyl acid chloride/ / \ 5%TFA ~N /
a~ ~ / \ Hunig's base.._> ~ _in CH2C1 Cl / 2.20%piperidine N / v R«in~bound ~ in DMF O
Rink-chloride 75%
Linker H O
H~N~H
H~N~H
maieic O
furfuryl O ~ PhH/RT a 05%TFq Product alcohol ------> ~ in CH2CI decomposed _ ._ 2> upon CI p O ~ O cleavage.
Resio-bound Rink~Chloride Linker 3-bromo benzyi Br amine ~N ~ _... i I _ > N / .. _...
CI H ~ Pd(O) I ~ 5%TFA
R«in-donna 4-formylboronic acid H ~ in CH2CI2 Rink-Chloride aq. K2CO3 Linker EtOH/xylene NH
60%
It will be understood that after making the substituted resin-bound Rink-chloride intermediate, and prior to cleavage with TFA. additional syntheic chemistry may be performed on the intermediate in order to derivatize the nucleophile core.
Therefore, another aspect of the invention is in a method for synthesizing a 1 S compound by resin-bound synthesis comprising the steps of: (a) converting a resin bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) SUBSTITUTE SHEET (RULE 28) \ / O / \ CI
resin O \ /
/
O
/
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
and (c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile. The resin-bound derivatized nucleophile can remain bound to the resin for storage and/or further derivatization, or it may be cleaved from the resin with between about 3 and S% TFA.
In yet another aspect, this invention is in a method for synthesizing a library of molecularly diverse compounds by resin-bound synthesis, comprising the steps of: (a) convening a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) \ / o / \ cl resin O \ /
/
O
/
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate: (c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions; (d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile;
and (e) optionally recombining the portions.
Based upo the disclosure herein, it will be clear to one of ordinary skill in the art that there are many possible synthetic approaches to creating the libraries of this invention. For example the libraries may be prepared using the split and mix technique or parallel synthesis techniques. The libraries generated from either of the the synthetic methods are molecularly diverse and are prepared simultaneously.
The libraries are prepared on the polymer resins using the Rink-chloride linker described herein. For example, the compound to be derivatized (suitable nucleophile), is SUBSTITUTE SHEET (RULE 26) attached to the polymer resin through the Rink-chloride linker to give a substituted resin-bound Rink-chloride intermediate. In one embodiment, the substituent(s) are modified by reacting the resin-bound Rink-chloride intermediate, with a mixture of reagents. In an alternative embodiment, aliquots of the resin-bound Rink-chloride intermediate are reacted with individual reagents each one of which will modify a position on the core of the resin-bound nucleophile, and then the resultant products are mixed together to form the library of derivatized resin-bound intermediates. This library may then be further derivatized by repeating the process of dividing and recombining the intermediates formed by the additional synthetic chemistry. It will be clear to one of ordinary skill in the art that when the libraries of the invention are prepared according to the instant disclosure, each polymer support bears a single species created by the additional synthetic chemistry performed on the substituted resin-bound Rink-chloride intermediate.
It will be obvious to one of skill in the art that the steps of optionally dividing and recombining the resin-bound aryl silane intermediate into portions are for purposes of varying the derivatization on the resin-bound nucleophiles which are generated by the combinatorial synthesis. Of course, it will be obvious to the skilled artisan that the resin-bound nucleophile intermediates may be divided into portions at any point during the synthetic sequence. The portions may be recombined at any point during the sequence or, further iterations may be applied if more derivatization is required. Therefore, it will be obvious to the skilled artisan that the steps of dividing the portions, performing additional synthetic chemistry and recombining the portions, may each be carried out more than once, depending upon the type of diversity required for the library of end-product compounds being prepared.
According to this invention, after the additional synthetic chemistry has been performed on the resin-bound aryl silane intermediate so that a library of molecularly diverse compounds has been prepared, the compounds can be separated and characterized by conventional analytical techniques known to the skilled artisan, for example infrared spectrometry or mass spectrometry. The compounds may be characterized while remaining resin-bound or they can be cleaved from the resin using the conditions described above, and then analyzed. In addition, a partial array of compound members of the library may be cleaved from the resin, characterized and analyzed, while leaving a partial array of the compound members of the library bound to the resin.
s SUBSTITUTE SHEET (RULE 26~
EXAMPLES
Preparation of Rink-chloride (2-Scheme 1) To a suspension of resin-bound Rink-acid, 1-Scheme 1, ( I .Og, l.6mmol.) in - THF (25mL) was added triphenylphosphine (2.328, 8.8mmol.) and hexachloroethane (2.13g, 8.8mmol.). The reaction mixture was agitated with a constant flow of argon for 6h. The resin-bound Rink-chloride, 2-Scheme 1, was filtered and washed with THF and acetone. Completion of the reaction was affirmed by chlorine analysis and MASNMR (the signal for CH(OH)at 8 5.85 disappears completly). Chlorine analysis indicated a stoichometric amount of chlorine.
Reaction of rink-chloride with various nucleophiles To a suspension of 2-Scheme 1 (0.96g, l.6mMol.) in dichloroethane (25mL) was added Hiinig's base ( 1mL) and the requisite nucleophile ( lOmMol.). The reaction mixture was agitated with a constant flow of argon for 6-12h. The resin was filtered and washed with dichloromethane, MeOH, H20, EtOH, CH2Cl2 and MeOH.
Completion of the reaction was confirmed by MASNMR, IR or elemental analysis. Elemental analysis indicates no chlorine and a stoichometric amount of nitrogen or sulfur for the appropriate compounds.
Cleavage from Rink-linked lisands 3% TFA/CH2Cl2 was added to the substituted resin-bound Rink chloride moieties, either as individual beads or in bulk quantity. The cleavage was carried out for 30 min., and the product was isolated by extraction with 1:1/
MeOH:MeCN.
All the cleaved products from Table I were identified by comparing them with an authentic sample of the starting material (nucleophile).
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows.
SUBSTITUTE SHEET (RULE 26)
Claims (8)
1. A resin-bound compound of formula (I) .
2. The resin-bound compound of formula (I) as claimed in claim 1, made by a method comprising reacting a resin-bound Rink-acid linker with triphenyl phosphine and hexachloroethane.
3. A method for synthesizing a compound by resin-bound synthesis comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) ;
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate; and (c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile.
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) ;
(b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate; and (c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile.
4. The method as claimed in claim 3, further comprising the step of cleaving the derivatized nucleophile from the substituted resin-bound Rink-chloride intermediate.
5. A method for synthesizing a compound by resin-bound synthesis comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) (b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile:
and (d) cleaving the resin-bound derivatized nucleophile.
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) (b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile:
and (d) cleaving the resin-bound derivatized nucleophile.
6. A method for preparing a library of diverse compounds by resin-bound synthesis, comprising the steps of:
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) (b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions;
(d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile;
and (e) optionally recombining the portions.
(a) converting a resin-bound Rink-acid linker into a resin-bound Rink-chloride linker of formula (I) (b) coupling the resin-bound Rink-chloride linker with a suitable nucleophile under appropriate conditions to provide a substituted resin-bound Rink-chloride intermediate;
(c) optionally dividing said substituted resin-bound Rink-chloride intermediate into a plurality of portions;
(d) performing additional synthetic chemistry on the substituted resin-bound Rink-chloride intermediate to provide a resin-bound derivatized nucleophile;
and (e) optionally recombining the portions.
7. The method of claim 6 wherein the steps of (c) dividing the portions, (d) performing additional synthetic chemistry, and (e) recombining the portions, are carried out more than once.
8. The method of claim 5 wherein the derivatized nucleophile is cleaved from the resin-bound Rink-chloride intermediate by reaction with between about to 5% TFA.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4469697P | 1997-03-28 | 1997-03-28 | |
| US60/044,696 | 1997-03-28 | ||
| PCT/US1998/005860 WO1998044329A2 (en) | 1997-03-28 | 1998-03-26 | Rink-chloride linker for solid phase organic synthesis of organic molecules |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2285175A1 true CA2285175A1 (en) | 1998-10-08 |
Family
ID=21933821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002285175A Abandoned CA2285175A1 (en) | 1997-03-28 | 1998-03-26 | Rink-chloride linker for solid phase organic synthesis of organic molecules |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0971947A4 (en) |
| JP (1) | JP2001518946A (en) |
| CA (1) | CA2285175A1 (en) |
| WO (1) | WO1998044329A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ20031921A3 (en) | 2001-01-12 | 2004-02-18 | Amersham Plc | Perfluorosulfonyl halides and related compounds as modifiers of a polymeric carrier |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69120821T2 (en) * | 1990-08-31 | 1997-01-23 | Univ Minnesota | Polyethylene glycol derivatives for solid phase applications |
| US5268423A (en) * | 1992-02-28 | 1993-12-07 | New York University | Method for preparation of peptide synthesis resins and peptide synthesis resins |
| JPH05271332A (en) * | 1992-03-30 | 1993-10-19 | Nippon Steel Chem Co Ltd | Production of amino group-bearing styrene-based polymer |
| AU4779493A (en) * | 1992-07-21 | 1994-02-14 | Bunsen Rush Laboratories Inc. | Oligomer library formats and methods relating thereto |
| GB9502225D0 (en) * | 1995-02-04 | 1995-03-22 | Zeneca Ltd | Method |
| US5684130A (en) * | 1995-06-05 | 1997-11-04 | Solid Phase Sciences Corporation | Process for synthesis of organic compounds using magnetic particles |
-
1998
- 1998-03-26 JP JP54176998A patent/JP2001518946A/en active Pending
- 1998-03-26 WO PCT/US1998/005860 patent/WO1998044329A2/en not_active Application Discontinuation
- 1998-03-26 CA CA002285175A patent/CA2285175A1/en not_active Abandoned
- 1998-03-26 EP EP98913115A patent/EP0971947A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998044329A2 (en) | 1998-10-08 |
| JP2001518946A (en) | 2001-10-16 |
| EP0971947A2 (en) | 2000-01-19 |
| EP0971947A4 (en) | 2005-01-26 |
| WO1998044329A3 (en) | 1998-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Früchtel et al. | Organic chemistry on solid supports | |
| US6368874B1 (en) | Methods for hard-tagging an encoded synthetic library | |
| US6265228B1 (en) | Process for preparing combinatorial amide alcohol libraries | |
| WO1995032425A1 (en) | Encoded combinatorial libraries | |
| US6218551B1 (en) | Combinatorial hydroxy-amino acid amide libraries | |
| Czarnik | Peer Reviewed: Combinatorial Chemistry | |
| EP0734398A1 (en) | Compounds and methods | |
| US6503759B1 (en) | Complex combinatorial chemical libraries encoded with tags | |
| US6210900B1 (en) | Method of encoding a series of combinatorial libraries and developing structure activity relationships | |
| CA2305771A1 (en) | Coding combinatorial libraries with fluorine tags | |
| CA2285175A1 (en) | Rink-chloride linker for solid phase organic synthesis of organic molecules | |
| EP0900241B1 (en) | Silyl linker for solid phase organic synthesis of aryl-containing molecules | |
| Cano et al. | From the combinatorial chemistry boom to polymer-supported parallel chemistry: established technologies for drug discovery | |
| US5773512A (en) | Compounds and methods | |
| CA2289719A1 (en) | Chloride linker for solid phase organic synthesis | |
| AU1907401A (en) | New functionalized polymeric reagents | |
| Dholi et al. | Combinatorial chemistry: a new approach of drug discovery | |
| Karskela | Solid-Phase Organic Synthesis: Bicyclic Peptides and Purine-Derived Small Molecules | |
| WO1998017695A1 (en) | Compounds and methods | |
| Krämer et al. | Encoding technologies | |
| EP1109816A1 (en) | Vinyl substituted cyclic products of the ene-yne reaction | |
| Freeman | Approaches to the analysis of single beads for Combinatorial chemistry | |
| US6004823A (en) | Compounds | |
| Li | How to Optimize Reactions for Solid-Phase Synthesis of Combinatorial Libraries Using RF-Tagged Microreactors | |
| EP0934345A1 (en) | Compounds and methods |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |