Preformed linkers

Preformed Two-Piece Metal Containers. Ink vehicles for letterset printing of two-piece aluminum or steel containers are mainly based on special polyester vehicles used in conjunction with melamine cross-linkers. Short cycle ovens which dry inks in 1—5 seconds are now used and operate at temperatures as high as 350 °C. The rheology of these inks must be adjusted to the unique geometry of the press. Desired rheological properties are achieved by the use of additives as weU as extender pigments. 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

The sulfoxide method has been applied to the concept [319,374] of intramolecular aglycone delivery for the formation of [1-mannosidcs by means of a silylene linker. In the original work, the acceptor and a thioglycoside donor were joined by means of a silylene group before the oxidation to the sulfoxide [141]. However, it was later found that the preformed sulfoxide was tolerated by the chemistry for the introduction of the linker [286,375]. The intramolecular aglycone delivery step was shown to function effectively for the transfer of the donor to the 2-, 3- and 6-position of glucopyr-anosides, as exemplified in Scheme 4.64. 

Figure 2.10. Schematic diagram of coupling of a thiolated antibody to a linker lipid (maleimide-PEG-phospholipid) which is part of a preformed liposome. The resulting thioether bond is meta-bolically stable. The strategy shown here was used to synthesize OX26-immunoliposomes [111].

During neutralization of dipeptides linked to alcohol resins as esters, diketopipera-zines can be formed by intramolecular nucleophilic cleavage (Section 15.22.1). Dike-topiperazine formation during peptide synthesis can be avoided by acylating the first support-bound amino acid with a preformed N-protected dipeptide, or by using the 2-chlorotrityl linker, which cannot be readily cleaved by nucleophiles. 

Preformed polymers can also be employed to prepare imprinted core-shell particles [143]. The group of Chang recently prepared a poly(amic acid) bearing oestrone as a template molecule covalently bound to the polymer through a urethane linker (see Fig. 2). A layer of this polymer was subsequently deposited on silica particles (10 pm diameter) prefunctionalised with amino groups at their surface. Thermal imidisation of the polymer yielded finally a polyimide shell (thickness about 100 nm) on the silica particles. Subsequent template removal yielded the imprinted cavities, which exhibited selective rebinding of oestrone in HPLC experiments. 

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

Sulfur has been used in linkers such as thioethers, sulfoxides, sulfones, sulfonic acids and their corresponding derivatives. A safety-catch linker for amines is based on 2-(thiobenzyl)ethylcarbamates [44]. Linkage is performed with preformed handles containing ethenyloxycarbonyl-protected amines 37. Attachment to thiomethyl-ated polystyrene 38 is performed under conditions involving radicals. Cleavage was performed with an oxidizing agent, which forms the retro Michael substrate (Scheme 6.1.11). 

Four recent examples of universal linkers/supports, in which the first nucleoside is anchored onto the preformed linker-support construct, are shown in Fig. 2.14. The disulfide linker 2.33 has been used to prepare terminal 3 -phosphate ONs (94, 95) through cleavage with a solution of ammonia in dithiothreitol. The photolabile linker 2.34 (96) is used to prepare 3 -alkyl carboxylic acids. The allyl-based linker 2.35 (97) is used to prepare free 3 -OH ONs by cleavage with Pd(0) and treatment with an aqueous buffer at pH 10. The linker 2.36 (98) differs from those discussed so far in... 

In the mid to late 1990s, Seitz and Kunzh described a new allylic linker called HYCRON in which a polyether chain is inserted between the allylic group and the carboxy group. The loading on the polymer is best achieved by the preformed handle approach, as outlined in Scheme 4. 

A chiral aldehyde, attached through a silyl linker to a hydroxymethyl Merrifield resin, was employed for expanding polyketide diversity. Aldol reaction with preformed (H)-enol borinate derived from a suitable chiral (R)-ketone afforded the anti-anti aldol product. Titanium-mediated enolization of the enantiomer (S)-ketone afforded the syn-syn product. 

Polymerised preformed [(N,N -dimethyl-l,2-diphenylethane diamine)2Rh] complex allows us to obtain enantioselective material. We have then shown that it is possible to imprint an optically pure template into the rhodium-organic matrix and to use the heterogeneous catalyst in asymmetric catalysis with an obvious template effect. The study of yield versus conversion graphs has shown that the mechanism occurs via two parallel reactions on the same site without any inter-conversion of the final products. Adjusting the cross-linker ratio at 50/50 allows us to find a compromise between activity and selectivity. Phenyl ethyl ketone (propiophenone) was reduced quantitatively in 2 days to (R)-l-phenyl propanol with 7tf% enantiomeric excess We have then shown that the imprinting effect is obvious for molecules related in structure to the template (propiophenone, 4 -trifluoromethyl acetophenone). It is not efficient if the structure of the substrate is too different to that of the template. 

XJ F NH2 R-SH 0 H Observations - The linker is immobilized through an anilide formation. N-Boc-cyslcine is coupled to the anchor by a nucleophilic substitution. Further reactions can be preformed either on the COOH or NH2 of cysteine. - Compatible with Boc/Bnz-SPPS strategy. ... 

Figu re 1.4 Optimized solid-phase strategy using a preformed linker/handle and IRaa. 

Photolabile carbonate supports 2j have been constructed by attachment of a preformed handle consisting of the reaction scaffold and an ortho-nitrobenzyl alcohol photolabile linker to PEG-PS [121]. Peptide sequences were constructed from the scaffold, and final products were liberated in a form suitable for direct biological screening by irradiation at 365 nm in an aqueous medium. 

The 4-acetyl-3,5-dioxo-l-methylcyclohexane carboxylic acid (ADCC) linker 2n [128] was developed to provide a support for anchoring primary amines via a preformed handle method. The anchor is stable toward acids and bases including piperidine and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and is thus compatible with Fmoc chemistry. The amine can be released by rapid hydrazinolysis on treatment with 2% hydrazine in DMF. A formamidine linker 2o has been obtained from Merrifield resin by reaction with the appropriate phenol. Secondary amines can be anchored to the support by an amidine exchange reaction and after further transformations cleaved by treatment with hydrazine [129]. 

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