Enzyme cleavable linker bound to solid phase for organic compound synthesis

An enzyme cleavable linker is prepared on which organic compounds are synthesized when the linker is bound to a solid phase. The linker contains a functional group on which a synthesized organic compound is bound when synthesis takes place, and a recognition site for a hydrolytic enzyme. Reacting the linker with the enzyme causes the linker to fragment at a site different from the recognition site to liberate the synthesized organic compound. The solid phase may be a crosslinked polyacrylamide containing an amino group for attaching the linker, and the linker is bound to the solid phase via a spacer. The spacer is attached to the solid phase by an ester, ether, amide or amine linkage, or a sulfide or phosphate linkage. In a specific reaction of forming a solid phase containing the linker, 2-acetoxy-5-hydroxymethylbenzoic acid is attached to an amino group-containing polymer via a spacer followed by conversion to a chloroformic ester.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The invention relates to enzymatically cleavable linkers for solid-phase
 syntheses, to a process for their preparation and to their use.
 2. Description of the Related Art
 A large number of molecular assay systems are being developed for modern
 research looking for active substances, such as receptor binding assays,
 enzyme assays and cell-cell interaction assays. Automation and
 miniaturization of these assay systems makes it possible to assay an
 increasingly large number of chemicals for their biological effect in
 random screening and thus form a possible use as lead structure for an
 active substance in medicine, veterinary medicine or crop protection.
 This development has led to classical synthetic chemistry becoming the
 limiting factor in research looking for active substances.
 If the efficiency of the developed assay systems is to be fully exploited
 there must be a considerable increase in the efficiency of chemical
 synthesis of active substances.
 Combinatorial chemistry can contribute to this required increase in
 efficiency, especially when it makes use of automated solid-phase
 synthetic methods (see, for example, review articles in J. Med. Chem. 37
 (1994), 1233 and 1385).
 The principle of these combinatorial syntheses is based on reaction at
 every stage of the synthesis not just with one building block in the
 synthesis but with several, either in parallel or in a mixture. All
 possible combinations are formed at every stage, so that a large number of
 products, called a substance library, results after only a few stages with
 relatively few building blocks.
 Solid-phase synthesis has the advantage that byproducts and excess
 reactants can easily be removed, so that elaborate purification of the
 products is unnecessary. Reaction rates can be increased, and conversions
 optimized, by large excesses of the dissolved reactant. The finished
 synthetic products can be passed directly, i.e. bound to the support, or
 after elimination from the solid phase to mass screening. Intermediates
 can also be tested in the mass screening.
 Applications described hitherto are confined mainly to the peptide and
 nucleotide sectors (Lebl et al., Int. J. Pept. Prot. Res. 41, 1993: 203
 and WO 92/00091) or their derivatives (WO 96/00391). Since peptides and
 nucleotides have only limited uses as drugs because of their unfavorable
 pharmacological properties, it is desirable to utilize the solid-phase
 synthetic methods known and proven in peptide and nucleotide chemistry for
 synthetic organic chemistry.
 U.S. Pat. No. 5,288,514 reports one of the first combinatorial solid-phase
 syntheses in organic chemistry outside peptide and nucleotide chemistry.
 U.S. Pat. No. 5,288,514 describes the sequential solid-phase synthesis of
 1,4-benzodiazepines.
 WO 95/16712, WO 95/30642 and WO 96/00148 describe other solid-phase
 syntheses of potential active substances in combinatorial chemistry.
 However, in order fully to utilize the possibilities of modern assay
 systems in mass screening, it is necessary continually to feed novel
 compounds with a maximum degree of structural diversity into the mass
 screening. This procedure makes it possible to reduce considerably the
 time taken to identify and optimize a novel lead structure for active
 substances.
 It is therefore necessary continually to develop novel and diverse
 combinatorial solid-phase syntheses.
 It is important for these novel syntheses that the individual building
 blocks in the solid-phase synthesis are optimally matched with one
 another. The choice of the solid phase, such as glass, ceramic or resins,
 and of the linker crucially influences the subsequent chemistry on the
 support.
 In order to be able to carry out the widest possible range of organic
 syntheses on solid phases there is a considerable need for novel solid
 phases, and novel linker and anchor groups, to be developed.
 Linker groups used hitherto are labile to bases or acids, and their
 elimination conditions are too drastic for many substances synthesized on
 the support. Great efforts are therefore being made to construct linkers
 which can be eliminated from the solid phase under milder conditions.
 It would be desirable in this connection to be able to use enzymes for
 cleavage of the linkers under mild conditions, as is already possible in a
 few cases for protective groups. An example of an enzymatically cleavable
 protective group is described by Waldmann et al. in Angew. Chem. 107
 (1995) 2425-2428.
 Elmore et al. describe a first enzymatically cleavable linker for
 solid-phase peptide synthesis (J. Chem. Soc., Chem. Commun. 14 (1992)
 1033-1034) which can be cleaved off the support under mild conditions.
 Schuster et al. describe another enzymatically cleavable linker for
 solid-phase syntheses of sugars (J. Am. Chem. Soc. 116 (1994) 1135-1136
 and U.S. Pat. No. 5,369,017).
 The disadvantage of both methods is that parts of the linker always remain
 in the product after the enzymatic cleavage. In addition, both methods are
 greatly restricted with regard to the linker-cleaving enzymes; thus Elmore
 uses calf spleen phosphodiesterase for the cleavage, and Schuster et al.
 describe serine proteases for the cleavage.
 SUMMARY OF THE INVENTION
 It is an object of the present invention to develop a linker which can be
 cleaved under mild conditions and, does not have the abovementioned
 disadvantages and makes possible a wide range of solid-phase organic
 syntheses.
 We have found that this object is achieved by an enzymatically cleavable
 linker which is bound to a solid phase and on which organic compounds are
 synthesized via a functional group, wherein the linker contains a
 recognition site for a hydrolytic enzyme and is fragmented by reaction
 with the enzyme in such a way that no parts of the linker molecule remain
 in the synthesized product, and wherein the recognition site for the
 enzyme and the site at which the synthetic product is liberated by
 fragmentation of the linker are different.
 The invention additionally relates to the preparation of the linkers and to
 their use.
 DETAILED DESCRIPTION OF THE INVENTION
 A preferred linker has the formula I
 ##STR1##
 in which the variables and substituents have the following meanings:
 (P) a solid phase
 (S) a spacer with a length equivalent to 1 to 30 methylene groups
 R hydrogen or a radical which is inert under the reaction conditions or two
 adjacent inert radicals R which together form an aromatic, heteroaromatic
 or aliphatic ring
 R.sup.1 substituted or unsubstituted C.sub.1 -C.sub.20 -alkyl, C.sub.3
 -C.sub.20 -alkenyl, C.sub.3 -C.sub.6 -alkynyl, C.sub.l -C.sub.20
 -alkylcarbonyl, C.sub.1 -C.sub.20 -alkylphosphoryl, C.sub.3 -C.sub.20
 -alkenylcarbonyl, C.sub.3 -C.sub.6 -alkynylcarbonyl, C.sub.3 -C.sub.20
 -alkenylphosphoryl, C.sub.3 -C.sub.6 -alkynylphosphoryl, C.sub.3 -C.sub.20
 -cycloalkyl, C.sub.3 -C.sub.20 -cycloalkylcarbonyl, C.sub.3 -C.sub.20
 -cycloalkylphosphoryl, aryl, arylcarbonyl, arylphosphoryl, hetaryl,
 hetarylcarbonyl, hetarylphosphoryl, glycosyl, substituted or unsubstituted
 amino acids or peptides
 R.sup.2 a nucleofugic group
 n 1 or 2.
 Linkers according to the invention are linkers which contain a recognition
 site for a hydrolytic enzyme and are fragmented by reaction with the
 enzyme in such a way that the linker is completely eliminated from a
 synthesized product which is bound via the linker to the solid phase, i.e.
 no parts of the linker molecule remain in the synthesized product.
 The linker is preferably eliminated from the product synthesized on the
 solid phase with elimination of CO.sub.2.
 A recognition site for an enzyme means a linkage which can be cleaved by a
 hydrolytic enzyme. Examples of linkages which can be cleaved by hydrolytic
 enzymes are ester, amide, ether, phosphoric ester or glycoside linkages.
 Suitable enzymes for cleaving the linker according to the invention under
 mild conditions are hydrolytic enzymes such as lipases, esterases,
 amidases, proteases, peptidases, phosphatases, phospholipases, peroxidases
 or glycosidases. Preferred enzymes are selected from the group of lipases,
 esterases, amidases, proteases or glycosidases, particularly preferably
 lipases, esterases or glycosidases.
 Linkers according to the invention are depicted by way of example in
 formula IV (Scheme A).
 ##STR2##
 where the substituents and variables have the following meanings:
 (P) a solid phase
 (S) a spacer with a length equivalent to 1 to 30 methylene groups
 (E) recognition site for a hydrolytic enzyme
 (K) central linker structure
 (Z) functional group on which the product is liberated
 R.sup.2 nucleofugic group via which synthesis of the products on the linker
 takes place.
 There is connection via the central linker structure of the enzyme
 recognition site (E), the solid phase (P) via the spacer (C) and the site
 (Z) at which the product is liberated.
 To construct the linker it is necessary for at least three functionalities
 to be present in the molecule or to be introducable into the central
 molecule. The enzyme recognition site, the solid phase and the functional
 group on which the product is linked to the linker are connected via the
 functionalities. Beyond this, there are no restrictions on the chemical
 structure of the central linker.
 The central linker structure may consist of unsubstituted or substituted
 aliphatic, aromatic or heteroaromatic structures or combinations thereof.
 The central linker structure preferably contains aromatic structures, for
 example a phenyl or naphthyl ring.
 Besides the solid phase, the spacer, the enzyme recognition site and the
 functional group at which the product is liberated (=core of the linker),
 the linker contains a nucleofugic group (R.sup.2) via which the synthetic
 products are attached.
 Mild and selective elimination of the synthetic products from the support
 material is made possible by the linker without the synthetic products
 being destroyed or altered.
 Advantageous for the enzymatic elimination of the product from the linker
 are pH ranges of pH 2.0 to 10.0, preferably of pH 4.0 to 8.0, and
 temperature ranges of -10.degree. C. to 100.degree. C., preferably of
 15.degree. C. to 500.degree. C. The elimination can take place in aqueous
 solution or in up to almost pure solvent with traces of water. Elimination
 with a solvent content of from 10 to 50% by weight is preferred.
 To assemble the linker on a solid phase, the latter must if necessary be
 modified in a manner known to the skilled worker.
 The linker is linked to the solid phase via an ester, ether, amide, amine,
 sulfide or phosphate linkage, depending on which solid phase is to be
 used.
 Linkage to the solid phase moreover takes place in a conventional way.
 Thus, for example, attachment to Merrifield resin or to
 2-chlorotrityl-resin of compounds with free hydroxyl groups is described
 in P.M. Worster et al. (Angew. Chem. Int. Ed. Engl. 18 (1979) 221) and in
 C. Chen et al. (J. Am. Chem. Soc. 116 (1994) 2661-2662).
 Attachment via an amino linkage is described, for example in M. Cardno et
 al. (J. Chem. Soc., Chem. Commun. 1995, 2163 ff) for 2-chlorotrityl-resin,
 in E. Bayer (Angew. Chem. 103 (1991) 117) for Nova Syn.RTM. TG
 carboxyl-resin, in J. R. Hanske et al. (Tetrahedron Lett., 36 (1995),
 1589-1592) for Wang or Tentagel.RTM. S PHB resin.
 Attachment to the support via thiol groups is described, for example, for
 Merrifield resin in Reynolds et al. (U.S. Pat. No. 5,324,483).
 The examples of attachment which are mentioned here and are well known to
 the skilled worker are given here only as examples of reactions, and other
 possibilities for attachment are known to the skilled worker (Lit.
 Calbiochem-Novabiochem--The Combinatorial Chemistry Catalog Feb. 1996,
 1-26 and S1-S24).
 In the preferred linker of the formula I, fragmentation of the linker is
 induced by cleavage of the enzyme recognition site by, for example,
 enzymes such as lipases, esterases, amidases, proteases or glycosidases.
 The enzymatic cleavage of the linker initially results in a phenolate
 which spontaneously decomposes into a quinone methide which is linked to
 the solid phase and CO.sub.2. This liberates the product containing no
 linker residues.
 The preferred linker of the formula I is a phenylogous acetal. Other
 linkers according to the invention may also contain vinylogous or normal
 acetals derived therefrom (see reaction 2).
 Advantageous linkers according to the invention fragment after enzymatic
 cleavage to form, for example, a lactam or lactone and thus liberate the
 product without linker residues. The following reactions 1 and 2 are
 intended to illustrate these general principles of fragmentation by way of
 example:
 ##STR3##
 ##STR4##
 These principles of fragmentation illustrated in reactions 1 and 2 are not
 restricted to the enzyme recognition sites shown therein, such as lipases
 or amidases.
 Linkers according to the invention are distinguished by a spatial distance
 between the enzyme recognition site and the site at which the product is
 liberated by fragmentation of the linker, i.e. enzyme recognition site and
 the site at which the product is liberated are different. This very
 substantially precludes steric impairment of the enzymatic reaction by the
 substrate. The distance between the enzyme recognition site and the site
 at which the product is liberated is, expressed in methylene group units,
 advantageously from 2 to 8 methylene units, preferably 4 to 8 methylene
 units.
 The linkers according to the invention are completely eliminated from the
 product by a large number of enzymes under mild conditions, and remain on
 the solid phase.
 It is possible in principle to use as solid phase (P) for the linkers
 according to the invention all the supports as are known, for example,
 from solid-phase peptide synthesis or nucleic acid synthesis.
 Supports which can be used may consist of a large number of materials as
 long as they are compatible with the synthetic combinatorial chemistry
 used and with the attachment of the linker to the solid phase. The size of
 the supports can vary within wide limits depending on the material.
 Particles in the range from 1 .mu.m to 1.5 cm are preferably used as
 support, and particles in the range from 1 .mu.m to 150 .mu.m are
 particularly preferred in the case of polymeric supports. However, gels
 are also suitable.
 The shape of the supports is as desired, and spherical particles are
 preferred. The supports may have a homogeneous or heterogeneous size
 distribution, but homogeneous particle sizes are preferred.
 It is also possible, where appropriate, for mixtures of different particles
 to be used.
 Support materials of little or no compressibility are preferred to
 compressible materials if, for example, the product bound to the support
 is to be removed, for example, by centrifugation, or a product is to be
 synthesized in flow reactors, i.e. the supports should advantageously have
 a certain stability to pressure and favorable sedimentation
 characteristics.
 It is also advantageous when mechanical stress is prolonged for the
 supports to have favorable resistance to abrasion.
 Advantageous supports should be porous materials such as sintered glass,
 sintered metals, porous ceramics or resins with a large internal surface
 area in a range from 5 to 2000 m.sup.2 /g of support material, preferably
 40 to 800 m.sup.2 /g, particularly preferably 50 to 500 m.sup.2 /g. The
 pore diameter of the materials should advantageously be chosen so that
 there are no limitations on mass transfer through diffusion or through
 active mass flow. The pore diameter is expediently from 10 nm to 500 nm,
 preferably from 30 nm to 200 nm.
 The support materials should advantageously have a pore volume which is as
 large as possible (&gt;1 ml/g of support material).
 It is possible to use natural, inorganic or organic materials.
 Examples of suitable solid phases (P) are functionalized particles selected
 from the group of ceramics, glass, latex, crosslinked polystyrenes,
 crosslinked polyacrylamides or other resins, natural polymers, gold,
 colloidal metal particles, silica gels, aerogels or hydrogels.
 The linkers can be linked on the surface of the solid phase or in the
 interior of the solid phase or to both.
 Latices mean colloidal dispersions of polymers in aqueous media.
 These may be natural or synthetic latices or microlatices which have been
 prepared, for example, by emulsion polymerization of suitable monomers or
 by dispersing polymers in suitable solvents.
 Crosslinked polystyrenes, crosslinked polyacrylamides and other resins
 mean, for example, polyacrylamide, polymethacrylamide, poly(hydroxyethyl
 methacrylate), polyamide, polystyrene, (meth)acrylate copolymers of, for
 example, (meth)acrylic acid, (meth)acrylic esters and/or itaconic acid,
 crotonic acid, maleic acid, PU foams, epoxy resins or other copolymers.
 Examples of natural polymers or supports which may be mentioned are
 agarose, cellulose, alginate, chitosan, dextran, levan, xanthan, collagen,
 gellan, X-carrageenan, agar, pectin, ramanian, wood chips,
 microcrystalline cellulose, hexosamines or gelatin.
 Supports which are likewise suitable are diatomaceous earth, kieselguhr,
 metal oxides or expanded clay.
 Selection of the suitable support depends on the chemistry for attaching
 the linker to the solid phase and on the synthetic chemistry carried out
 subsequently. Groups incompatible with this chemistry are protected in a
 manner known to the skilled worker.
 A part is also played in the selection of the suitable support by the fact
 that the support advantageously contains no groups or ions or other
 molecules which damage the enzyme used for eliminating the linker, and,
 where appropriate, these groups should be removed, protected, washed out
 or inactivated before or after the synthesis.
 If this is impossible, use of a larger amount of enzyme may, where
 appropriate, overcome this problem.
 In order to make it possible to attach the linker to the solid phase, a
 support which is suitably functionalized or can be functionalized in a
 manner known to the skilled worker will be selected.
 Examples of suitable and preferred supports are chlorobenzyl-resin
 (Merrifield resin), Rink resin (Novabiochem), Sieber resin (Novabiochem),
 Wang resin (Bachem) Tentagel resins (Rapp-Polymere), Pega resin (Polymer
 Laboratories) or polyacrylamides. 9-Fmoc-amino-3-xanthenyloxy-Merrifield
 resin, phenylalaninol-2-chlorotrityl-resin, prolinol-2-chlorotrityl-resin,
 5-nitroanthranilic acid-2-chlorotrityl-resin or
 hydrazine-2-chlorotrityl-resin.
 Suitable and particularly preferred supports are supports with an amino
 group for attachment of the linker, such as polyacryl-amides, Pega resins,
 Tentagel.RTM. S-NH.sub.2, aminomethyl-polystyrene,
 4-methylbenzhydrylamine-resin (=MBHA); Novasyn.RTM. TG amino-resin,
 4-(2'4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidonor-leucylaminome
 thyl-resin [sic],
 4-(2'4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidonorleucyl-MBHA-re
 sin [sic], 4-(2'4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy-resin [sic],
 9-Fmoc-amino-3-xanthenyloxy-Merrifield resin,
 phenylalaninol-2-chlorotrityl-resin, prolinol-2-chlorotrityl-resin,
 5-nitro-anthranilic acid-2-chlorotrityl-resin or
 hydrazine-2-chloro-trityl-resin.
 The spacer (S) in the compounds of the general formulae I and II means a
 spacer with a length equivalent to 1 to 30 methylene groups. The spacer
 can have any desired structure. The distance between the central linker
 structure and the solid phase is advantageously adjusted by the length of
 the spacer so that the linker can be optimally cleaved by the enzymes
 used.
 If the reactive group via which the spacer is linked to the solid phase is
 already at a spatial distance from the solid phase, as is the case, for
 example, with Nova Syn.RTM. TG bromo-resin (=slightly crosslinked
 polystyrene resin with polyethylene glycol tails of 3000-4000 MW
 terminally functionalized with bromine) via polyethylene glycol chains or
 with Rink amides MBHA-resin
 [=4(2'4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamidonorleucyl-4-met
 hylbenzhydrylamine-resin] [sic], the spacer can advantageously be chosen to
 be correspondingly shorter. If this reactive group is directly on the
 support, the spacer should advantageously be chosen to be correspondingly
 longer. The spacer can have any desired structure, which is of minor
 importance. The groups present in the structure and in the substituents
 which are present where appropriate should, however, expediently not
 interfere with the synthetic chemistry which is carried out.
 The basic framework or backbone of the spacer can consist, for example, of
 an unsubstituted or substituted polymethylene chain which, in place of one
 or more methylene groups, contains radicals such as heteroatoms such as N,
 O, S, P, Sn or Si or unsubstituted or substituted aliphatic or aromatic
 rings or ring systems, which may, where appropriate, contain further
 heteroatoms such as N, S or O.
 Combinations of said radicals can also be present in the basic framework of
 the spacer.
 The spacer is linked to the solid phase by at least one linkage selected
 from the group of ester, ether, amide, amine, sulfide or phosphate
 linkages.
 Meanings which may be mentioned for radical R in the compounds of the
 formula I and II are hydrogen or a radical which is inert under the
 reaction conditions, or two adjacent inert radicals R which may together
 form an aromatic, heteroaromatic or aliphatic ring. Inert radicals mean
 any suitable aliphatic, aromatic or heteroaromatic radicals or mixtures of
 these radicals.
 Examples of aliphatic radicals which may be mentioned are unsubstituted or
 substituted C.sub.1 -C.sub.8 -alkyl, C.sub.2 -C.sub.8 -alkynyl, C.sub.3
 -C.sub.6 -alkynyl or cycloalkyl.
 Alkyl radicals which may be mentioned are branched or unbranched C.sub.1
 -C.sub.8 -alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl,
 n-butyl, 1-methylpropyl, 2-methylpropyl, 1,-dimethylethyl, n-pentyl,
 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1
 -ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,
 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl.
 Alkenyl radicals which may be mentioned are branched or unbranched C.sub.3
 -C.sub.8 -alkenyl chains such as propenyl, 1-butenyl, 2-butenyl,
 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,
 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl,
 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,
 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl,
 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,
 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,
 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,
 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,
 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,
 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,
 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,
 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,
 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,
 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,
 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,
 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,
 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,
 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,
 1-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl,
 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl,
 4-octenyl, 5-octenyl, 6-octenyl or 7-octenyl.
 Alkynyl means C.sub.3 -C.sub.6 -alkynyl radicals such as prop-1-yn-1-yl,
 prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl,
 n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl,
 n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl,
 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1-yn-1-yl,
 n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl,
 n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl,
 n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methyl-pent-1-yn-1-yl,
 3-methyl-pent-1-yn-3-yl, 3-methyl-pent-1-yn-4-yl, 3-methyl-pent-1-yn-5-yl,
 4-methyl-pent-1-yn-1-yl, 4-methyl-pent-2-yn-4-yl or
 4-methyl-pent-2-yn-5-yl.
 Cycloalkyl radicals which may be mentioned are branched or unbranched
 C.sub.3 -C.sub.10 -cycloalkyl chains with 3 to 7 carbon atoms in the ring,
 which may contain heteroatoms such as S, N or O or ring system such as
 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl,
 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl,
 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl, cyclooctyl,
 cyclononyl oder cyclodecyl.
 Suitable substituents are one or more inert substituents such as halogen,
 alkyl, aryl, alkoxy, benzyloxy or benzyl.
 Aromatic radicals mean single or fused ring systems. Phenyl and naphthyl
 are the preferred radicals.
 Heteroaromatic radicals are advantageously single or fused aromatic ring
 systems with one or more heteroaromatic 3- to 7-membered rings. The
 heteroatoms which may be present are one or more nitrogen, sulfur and/or
 oxygen atoms in the ring or ring system.
 Suitable substituents on the aromatic or heteroaromatic radicals are one or
 more substituents such as halogen, alkyl, aryl, alkoxy, benzyloxy or
 benzyl.
 Two adjacent radicals R may together form an aromatic, heteroaromatic or
 aliphatic, unsubstituted or substituted, 4- to 8-membered ring.
 The variable n in the compounds of the formulae I and II has the meaning of
 one or two.
 Radicals which may be mentioned for R.sup.1 in the compounds of the
 formulae I and II are substituted or unsubstituted C.sub.1 -C.sub.20
 -alkyl, C.sub.3 -C.sub.20 -alkenyl, C.sub.3 -C.sub.6 -alkynyl, C.sub.1
 -C.sub.20 -alkylcarbonyl, C.sub.1 -C.sub.20 -alkylphosphoryl, C.sub.3
 -C.sub.20 -alkenylcarbonyl, C.sub.3 -C.sub.6 -alkynylcarbonyl, C.sub.3
 -C.sub.20 -alkenylphosphoryl, C.sub.3 -C.sub.6 -alkynylphosphoryl, C.sub.3
 -C.sub.20 -cycloalkyl, C.sub.3 -C20-cycloalkylcarbonyl, C.sub.3 -C.sub.30
 -cycloalkylphosphoryl, aryl, arylcarbonyl, arylphosphoryl, hetaryl,
 hetarylcarbonyl, hetarylphosphoryl, glycosyl, substituted or unsubstituted
 amino acids or peptides, where
 alkyl is branched or unbranched C.sub.1 -C.sub.20 -alkyl such as methyl,
 ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,
 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl,
 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,
 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl,
 n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl,
 n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl or
 n-eicosenyl [sic];
 alkenyl is branched or unbranched C.sub.3- C.sub.20 -alkenyl such as
 propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl,
 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,
 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,
 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,
 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,
 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,
 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
 1methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,
 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,
 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,
 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,
 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,
 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,
 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,
 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,
 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,
 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,
 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,
 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,
 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,
 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-heptenyl,
 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl,
 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, nonenyl,
 decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl,
 hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl or eicosenyl;
 alkynyl is branched or unbranched C.sub.2 -C.sub.6 -alkynyl such as
 ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl,
 n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl,
 n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl,
 n-pent-2-yn-5-yl, 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl,
 n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl,
 n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl,
 n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl,
 3-methyl-pent-1-yn-1-yl, 3-methyl-pent-1-yn-3-yl, 3-methyl-pent-1-yn-4-yl,
 3-methyl-pent-1-yn-5-yl, 4-methyl-pent-1-yn-1-yl, 4-methyl-pent-2-yn-4-yl
 or 4-methyl-pent-2-yn-5-yl;
 alkylcarbonyl is branched or unbranched C.sub.1 -C.sub.20 -alkylcarbonyl
 with alkyl groups as defined above for R.sup.1, which are linked to the
 framework via a carbonyl group [--(C.dbd.O)--];
 alkylphosphoryl is branched or unbranched C.sub.1 -C.sub.20
 -alkylphosphoryl with alkyl groups as defined above for R.sub.1, which are
 linked to the framework via a phosphoryl group [--O--P(O)(OH)--];
 alkenylcarbonyl is branched or unbranched C.sub.3 -C.sub.20
 -alkenylcarbonyl with alkenyl groups as defined above for R.sup.1, which
 are linked to the framework via a carbonyl group [--(C.dbd.O)--];
 alkenylphosphoryl is branched or unbranched C.sub.3 -C.sub.20
 -alkenylphosphoryl with alkenyl groups as defined above for R.sup.1, which
 are linked to the framework via a phosphoryl group [--O--P(O)(OH)--);
 alkynylcarbonyl is branched or unbranched C.sub.3 -C.sub.6 -alkynylcarbonyl
 with alkynyl groups as defined above for R.sup.1, which are linked to the
 framework via a carbonyl group [--(C.dbd.O)--];
 alkynylphosphoryl is branched or unbranched C.sub.3 -C.sub.6
 -alkynylphosphoryl with alkynyl groups as defined above for R.sup.1, which
 are linked to the framework via a phosphoryl group (--O--P(O)OH--];
 cycloalkyl is branched or unbranched C.sub.3 -C.sub.20 -cycloalkyl chains
 with 3 to 7 carbon atoms in the ring, which may contain heteroatoms such
 as S, N or O or ring systems such as cyclopropyl, cyclobutyl, cyclopentyl,
 cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl,
 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl,
 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl,
 1-methyl-2-ethylcyclopropyl, cyclooctyl, cyclononyl or cyclodecyl;
 cycloalkylcarbonyl is branched or unbranched C.sub.3 -C.sub.2
 -cycloalkylcarbonyl chains with 3 to 7 carbon atoms in the ring, which may
 contain heteroatoms such as S, N or O or ring systems such as
 cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,
 cyclohexylcarbonyl, cycloheptylcarbonyl, 1-methylcyclopropylcarbonyl,
 1-ethylcyclopropylcarbonyl, 1-propylcyclopropylcarbonyl,
 1-butylcyclopropylcarbonyl, 1-pentylcyclopropylcarbonyl,
 1-methyl-1-butylcyclopropylcarbonyl, 1,2-dimethylcyclopropylcarbonyl,
 1-methyl-2-ethylcyclopropylcarbonyl, cyclooctylcarbonyl,
 cyclononylcarbonyl or cyclodecylcarbonyl;
 cycloalkylphosphoryl is branched or unbranched C.sub.3 -C.sub.20
 -cycloalkylphosphoryl chains with 3 to 7 carbon atoms in the ring, which
 may contain heteroatoms such as S, N or O or ring systems such as
 cyclopropylphosphoryl, cyclobutylphosphoryl, cyclopentylphosphoryl,
 cyclohexylphosphoryl, cycloheptylphosphoryl,
 1-methylcyclopropylphosphoryl, 1-ethylcyclopropylphosphoryl,
 1-propylcyclopropylphosphoryl, 1-butylcyclopropylphosphoryl,
 1-pentylcyclopropylphosphoryl, 1-methyl-1-butylcyclopropylphosphoryl,
 1,2-dimethylcyclopropylphosphoryl, 1-methyl-2-ethylcyclopropylphosphoryl,
 cyclooctylphosphoryl, cyclononylphosphoryl or cyclodecylphosphoryl;
 aryl such as phenyl or naphthyl;
 arylcarbonyl such as phenylcarbonyl or naphthylcarbonyl;
 arylphosphoryl such as phenylphosphoryl or naphthylphosphoryl;
 hetaryl, hetarylcarbonyl or hetarylphosphoryl which [lacuna] in their
 hetaryl moiety aromatic mono- or polycyclic radicals which, besides carbon
 ring members, may additionally contain one to four nitrogen atoms or one
 to three nitrogen atoms and one oxygen or one sulfur atom or one oxygen or
 one sulfur atom;
 glycosyl, mono-, di- or oligosaccharides such as glucose, galactose,
 mannose, fructose, fucose, N-acetyl-D-glucosamine, maltose, lactose,
 chitobiose, cellobiose or oligosaccharides in all their stereoisomeric
 forms (.alpha.- or .beta.-configuration) and all their possible linkage
 types [.alpha.-(1,3)-, .alpha.-(1,4)-, .alpha.-(1,6)-, .beta.-(1,2)-,
 .beta.-(1,3)-, .beta.-(1,4)-, .beta.-(1,6)] as homo- or heteromers, it
 being necessary that the sugar linking to the framework be recognized by
 an endo- or exoglycosidase or mixtures thereof, and the glycosidic linkage
 be cleavable.
 Substituted or unsubstituted amino acids or peptides mean natural or
 unnatural amino acids or peptides which contain the latter. The amino
 acids and peptides attached to the framework must be chosen so that they
 can be eliminated by an exo- or endopeptidase or an exo- or endoprotease
 or mixtures of these.
 All said radicals R.sup.1 may, where appropriate, carry other substituents
 as long as they do not block the recognition site for the enzyme.
 R.sup.2 in the compounds of the formulae I and III is a nucleofugic group
 which permits attachment of other suitable radicals via a nucleophilic
 group to the linker according to the invention and thus makes subsequent
 combinatorial chemistry on the solid phase possible.
 Nucleofugic groups which may be mentioned are leaving groups such as
 halogen such as Br, Cl or F or groups such as
 ##STR5##
 Y in the compounds of the formula III has the meaning specified for R.sup.2
 and can be identical to or different from R.sup.2.
 X in the compounds of the formula II is one of the following groups
 --(C.dbd.O)--O--, --O--, -NR.sup.3 --, --S--, --OPO(OR.sup.4)--O--, where
 R.sup.3 and R.sup.4 are, independently of one another, hydrogen or C.sub.1
 -C.sub.8 -alkyl such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl,
 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,
 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,
 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl.
 The linker is linked via the group XH to the solid phase (P). All groups
 which make this linkage possible are suitable for the synthesis.
 The linker which is linked according to the invention to the solid phase is
 advantageously assembled in a reaction sequence which is depicted
 hereinafter by way of example for Tentagel.RTM. S-NH.sub.2 as suppport and
 two different linker structures (Scheme I and II).
 ##STR6##
 The attachment reactions a) between the support and compounds of the
 formula II are carried out, for example when XH is a carboxyl radical, in
 solvent with the aid of, for example, diisopropylcarbodiimide (=DIC).
 Other coupling reagents suitable for forming this amide linkage are, for
 example, TBTU, HBTS, BOP or PYBOP (Lit.: Int. J. Peptide Prot. Rev. 35,
 1990: 161-214). Suitable solvents are aprotic, nonpolar or polar solvents,
 for example dimethylformamide (DMF), methylene chloride (CH.sub.2
 Cl.sub.2), dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF). It is
 possible to use single solvents or mixtures. The hydroxymethylene group in
 the formula II must be protected where appropriate for the attachment to
 the linker.
 Reaction b) is carried out to introduce the nucleofugic group which makes
 it possible to attach other molecules, which are then subsequently
 derivatized combinatorially, into the linker.
 Reaction b) is advantageously carried out with phosgene or phosgene
 equivalents in an aprotic, polar or nonpolar solvent such as CH.sub.2
 Cl.sub.2, DMF, DMSO, THF, toluene, acetonitrile or mixtures thereof.
 Y and R.sup.2, and the other radicals mentioned in the formulae I to III in
 Scheme I have the abovementioned meanings.
 Both reactions are carried out at a temperature in the range from
 -20.degree. C. to +120.degree. C., preferably from 0.degree. C. to
 +60.degree. C., and reaction b) can, where appropriate, be carried out in
 the presence of catalytic amounts of DMAP (=4-dimethylaminopyridine).
 ##STR7##
 To attach the linker to the solid phase or the support (see Scheme II), the
 latter is initially functionalized. To do this, the support is reacted
 with a compound of the formula III (see reaction c) where the radicals
 R.sup.2 and Y have the abovementioned meanings. All phosgene equivalents
 are suitable for functionalizing the support. They result in introduction
 of a nucleofugic group, via which the linker is linked to the support.
 Reaction c) is carried out in aprotic, polar or nonpolar solvents such as
 CH.sub.2 Cl.sub.2, DMF, DMSO, THF, toluene, acetonitrile or mixtures
 thereof.
 The reaction is carried out at a temperature in the range from -20.degree.
 C. to +120.degree. C., preferably from 0.degree. C. to +60.degree. C., and
 the reaction can, where appropriate, be carried out in the presence of
 catalytic amounts of DMAP. The linker is finally linked to the support via
 the nucleofugic group R.sup.2 (reaction d).
 Reaction d) is carried out in aprotic, polar or nonpolar solvents such as
 CH.sub.2 C.sub.2, DMF, DMSO, THF, toluene, acetonitrile or mixtures
 thereof.
 The reaction is carried out in the presence of a tertiary amine base such
 as triethylamine- [sic] or diisopropylethylamine and catalytic amounts of
 DMAP. Reaction d) is carried out at a temperature in the range from
 0.degree. C. to +120.degree. C., preferably from 20.degree. C. to
 80.degree. C.
 The radicals R.sup.5, R.sup.6 and Q have the following meanings:
 R.sup.5 hydrogen, OH, NO.sub.2, unsubstituted or substituted C.sub.l-
 C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, C.sub.3 -C.sub.10 -cycloalkyl,
 C.sub.3 -C.sub.10 -cycloalkyloxy,
 R.sup.6 substituted or unsubstituted C.sub.1 -C.sub.20 -alkyl, C.sub.3
 -C.sub.20 -alkenyl, C.sub.3 -C.sub.6 -alkynyl, C.sub.1 -C.sub.20
 -alkylcarbonyl, C.sub.1 -C.sub.20 -alkylphosphoryl, C.sub.3 -C.sub.20
 -alkenylcarbonyl- [sic], C.sub.3 -C.sub.6 -alkynylcarbonyl- [sic], C.sub.3
 -C.sub.20 -alkenylphosphoryl- [sic], C.sub.3 -C.sub.6
 -alkynylphosphoryl-[sic], C.sub.3 -C.sub.20 -cycloalkyl- [sic], C.sub.3
 -C.sub.20 -cycloalkylcarbonyl-[sic], C.sub.3 -C.sub.20
 -cycloalkylphosphoryl-[sic], aryl-[sic], arylcarbonyl- [sic],
 arylphosphoryl-[sic], hetaryl-[sic], hetarylcarbonyl-[sic],
 hetarylphosphoryl-[sic], glycosyl-[sic], substituted or unsubstituted
 amino acids or peptides
 Q NH or O.
 The radical R.sup.6 must be selected so that recognition sites which can be
 recognized and cleaved by enzymes are produced. Linkages produced by
 suitable choice of the radical R.sup.6, and meeting the abovementioned
 criterion are, for example, ester, ether, amide, phosphoric ester and
 glycoside linkages. Enzymes which cleave these linkages are, for example,
 hydrolytic enzymes such as lipases, esterases, amidases, proteases,
 peptidases, phosphatases, phospholiphases [sic], peroxidases or
 glycosidases.
 The advantage of the linker according to the invention and of the process
 according to the invention is that the linker is eliminated simply and
 completely from the product.
 The linker according to the invention makes a wide range of subsequent
 synthetic chemistry possible, e.g. construction of a substance library in
 combinatorial chemistry, which can, where appropriate, be automated. The
 linker according to the invention can be used advantageously for
 solid-phase syntheses.
 The following examples serve to illustrate the invention further without
 restricting it in any way.

EXAMPLE 1
 Preparation of 2-acetoxy-5-methylbenzoic acid
 ##STR8##
 1 g of 5-methylsalicylic acid (6.58 mmol) and 1.83 ml of tri-ethylamine (2
 equivalents) were dissolved in 80 ml of ethyl acetate. At 0.degree. C.,
 0.94 ml of acetyl chloride (2 equivalents) was added dropwise, and the
 mixture was then stirred at 23.degree. C. for 1 h. The precipitated salts
 are [sic] filtered off. 100 ml of 1M HCl were added to the filtrate, which
 was then stirred overnight. A homogeneous solution formed, and it was
 adjusted to about pH 4 with saturated NaHCO.sub.3 solution. It was then
 extracted with chloroform, and the organic phase was washed with a little
 water and dried over MgSO.sub.4. The solvent was substantially removed,
 and the crude product was recrystallized from hexane/ethyl acetate.
 Yield: 1.21 g (95%) .sup.1 H-NMR (CDCl.sub.3): 7.89 (d,J=2 Hz); 7.39
 (dd,J=8 Hz, J'=2 HZ [sic]); 6.99 (d,J=8 Hz); 2.40 (s,3 H, --CH.sub.3);
 2.31 (s,3 H, --OAc).
 EXAMPLE 2
 Preparation of 2-acetoxy-5-bromomethylbenzoic acid
 ##STR9##
 1 g of 2-acetoxy-5-methylbenzoic acid (5.16 mmol), 1.16 g of
 N-bromosuccinimide (1.25 equivalents) and 33 mg of azodiisobutyronitrile
 in 20 ml of absolute tetrachloromethane were cautiously heated while
 stirring under an argon atmosphere and refluxed while exposing to a sun
 lamp for 2.5 h. The mixture was then left to cool in an ice bath and
 filtered, and the filter cake was washed with n-pentane. The mass of
 crystals was taken up in CHCl.sub.3 and washed with cold water. The
 organic phase was dried over MgSO.sub.4 and concentrated. The crude
 product was further reacted immediately.
 Yield: 1 g, 58% of title compound in addition to about 10% of
 2-acetoxy-5-dibromomethylbenzoic acid (estimated from the .sup.1
 H-NMR-spectrum) .sup.1 H-NMR (CDCl.sub.3): 8.11 (d,J=2 Hz); 7.62 (dd,J=8
 Hz, J'=2 Hz); 7.11 (d,J=8 Hz); 4.48 (s,2 H, --CH.sub.2 --); 2.33 (s,3 H,
 --OAc).
 EXAMPLE 3
 Preparation of 2-acetoxy-5-hydroxymethylbenzoic acid
 ##STR10##
 1 g of the crude product (2.99 mmol of 4) from Example 2 were mixed with
 25.5 ml of dioxane and 30 ml of 0.1 N AgNO.sub.3 solution and stirred at
 room temperature overnight. The mixture was then extracted several times
 with ethyl acetate, and the combined organic phases were dried over
 MgSO.sub.4 and evaporated to dryness. Column chromatography with
 CHCl.sub.3 /methanol (5:1) afforded a yield of 389 mg (62%).
 .sup.1 H-NMR (CDCl.sub.3): 8.07 (d.J=2 Hz); 7.61 (dd,J=8 Hz, J'2 Hz); 7.12
 (d,J=8 Hz); 4.73 (s,2 H, -CH.sub.2); 2.32 (s,3 H, -OAc).
 EXAMPLE 4
 Attachment of the anchor building block 2-acetoxy5-hydroxy-methylbenzoic
 acid to Tentagel.RTM. S-NH.sub.2
 ##STR11##
 36.5 mg of 2-acetoxy-5-hydroxymethylbenzoic acid (1.2 equivalents) and 21.5
 .mu.l of diisopropylcarbodiimide (1.44 equivalents) were added to 500 mg
 of Tentagel.RTM. S-NH.sub.2 (0.29 mmol of NH.sub.2 groups/g) in 6 ml of
 absolute CH.sub.2 Cl.sub.2. The reaction mixture was stirred at room
 temperature, and the resin was filtered off with suction. It was then
 washed successively on the filter three times each with absolute DMF,
 methanol and CH.sub.2 Cl.sub.2, mixing by passing nitrogen through. The
 resin was dried under oil pump vacuum and the attachment protocol was
 repeated once, until the Kaiser test for free NH.sub.2 groups was negative
 (E. Kaiser et al. Anal. Biochem. 1979, 34, 595).
 FT-IR: 1766 cm-.sup.-1 (--OAc), 1666 cm.sup.-1 (--CONH--), 1540 cm.sup.-1
 (--NH--), 3100-3500 cm.sup.31 1 (--OH).
 EXAMPLE 5
 Conversion to the chloroformic ester
 ##STR12##
 210 mg of the product obtained in Example 4 were introduced into 3.5 ml of
 absolute THF under argon, and 400 .mu.l (about 12 equivalents) of a
 solution of phosgene in toluene (1.93 M) were added dropwise at 23.degree.
 C. The suspension was stirred for 2 h and, after dropwise addition of a
 further 200 .mu.l of the phosgene solution, stirred for a further 2 h. It
 was subsequently washed successively twice each with absolute THF, ethyl
 ether, THF and ethyl ether again, and the resin was dried under reduced
 pressure.
 FT-IR: 1770,5 cm.sup.-1 (--OAc and --COCl), 1666 cm.sup.-1 (--CONH--), 1540
 cm.sup.-1 (--NH--).
 EXAMPLE 6
 Preparation of
 ##STR13##
 by coupling to leucine tert-butyl ester hydrochloride.
 A solution, cooled in an ice-water bath, of 29 mg of leucine tert-butyl
 ester hydrochloride (4 equivalents) and 20 .mu.l of triethylamine (about 5
 equivalents) in 4 ml of absolute CH.sub.2 Cl.sub.2 was slowly added at
 0.degree. C., under argon, to a suspension of 110 mg of the compound
 obtained in Example 5 in 2 ml of CH.sub.2 Cl.sub.2. The suspension was
 stirred at 0.degree. C. for 0.5 h and at 23.degree. C. for 3 h. It was
 then washed successively in each case with absolute methanol, CH.sub.2
 Cl.sub.2, methanol and ethyl ether, and the resin was dried under reduced
 pressure.
 FT-IR: 1776 cm.sup.-1 (--OAc), 1724 cm.sup.-1 (--OCONH--), 1666 cm.sup.-1
 (-CONH-), 1540 cm.sup.-1 (--NH--).
 EXAMPLE 7
 Basic elimination of the leucine tert-butyl ester to determine the
 occupation density
 6 mg of the coupling product from Example 6 were suspended in a solution of
 200 .mu.l of THF and 200 .mu.l of saturated NaHCO.sub.3 solution, pH 10.5,
 and the reaction mixture was shaken at 23.degree. C. for about 30 min. It
 was then extracted with 200 .mu.l of CHl.sub.3, and the organic phase was
 quantified by GC-MS using a calibration plot. The proportion of leucine
 tert-butyl ester attached via the anchor building block to the polymeric
 support was 51% based on available NH.sub.2 groups.
 EXAMPLE 8
 Enzymatic elimination of the leucine tert-butyl ester
 27 mg of the coupling product from Example 6 were suspended in 1066 .mu.l
 of phosphate buffer (0,1 M Na.sub.2 HPO.sub.4, 0,2 M KI, pH 5) and 500
 .mu.l of methanol; 3 U of Mucor miehei lipase dissolved in 100 .mu.l of
 the same buffer were added, and the mixture was incubated at 30.degree. C.
 with shaking. The quinone methine [sic] produced as intermediate was
 trapped owing to the presence of iodide in the buffer solution. A further
 100 .mu.l of the lipase solution was added after 6 h and after 32 h. The
 incubation was stopped after 58 h. The reaction mixture was extracted with
 CHCl.sub.3. The combined and dried organic phases were concentrated to 1
 ml and quantified by GC-MS.
 Yield: 42%