Linkers for Aldehydes and Ketones

Entry Loaded resin Cleavage conditions Product, yield (purity) Ref. 

Acetals are usually easy to cleave by acid-catalyzed transacetalization or hydrolysis (Table 3.40). Dithioacetals, on the other hand, tend to be more resistant to hydrolysis, but cleavage can be achieved by treatment with mercury(II) salts or by oxidation with either [bis(trifluoroacetoxy)iodo]benzene [723] or periodic acid [724]. Use of the latter reagent can, however, also lead to the conversion of methyl ketones into iodo-methyl ketones [721], 

Aldehydes and ketones have also been prepared by nucleophilic cleavage of resin-bound O-alkyl hydroxamic acids (Weinreb amides [744]) with lithium aluminum hydride [745] or Grignard reagents (Entries 1 and 2, Table 3.41). Similarly, support-bound thiol esters can be cleaved with Grignard reagents to yield ketones [272], or with reducing agents to yield aldehydes (Entry 3, Table 3.41). Polystyrene-bound sele-nol esters (RCO-Se-Pol) react with alkynyl cuprates to yield alkynyl ketones [746]. 

Intramolecular Dieckmann cyclization of polystyrene-bound pimelates has been used to prepare (l-keto esters (Entry 4, Table 3.41). Oxidative cleavage reactions leading to the formation of aldehydes include the ozonolysis of resin-bound alkenes, the periodate-mediated cleavage of 1,2-diols, and the oxidation of Wang resin derived ethers (Entries 5-7, Table 3.41). 

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Resin-bound aldehydes and ketones have been used as linkers for 1,2- and 1,3-diols (Entries 4-6, Table 3.33). Cleavage of acetal-based linkers is usually effected by acid-catalyzed transacetalization or by hydrolysis. 

Resin-bound diols, amino alcohols, and dithiols, which reversibly form cyclic acetals with aldehydes and ketones, have been successfully used as linkers for carbonyl compounds (Entries 5-11, Table 3.40). Acetal formation on insoluble supports can be achieved by azeotropic removal of water (C6H6, TsOH, reflux [720]), whereas dithio-acetals can be prepared by acid-catalysis alone (BF3 OEt2 or TMSC1 CHCI3,0 °C, 2 h [721]). /V-Acylaminals such as R-CFI(OMe)NFI-CO-Pol have been prepared by treatment of resin-bound amides H2NCO-Pol with aldehydes in the presence of HC(OMe)3 and TFA [722],... 

For the solid phase synthesis of aldehydes and ketones, various linkers based on diols 48 have been used (Figure 14.16) [110-112]. Loading of this type linker with carbonyl compound is generally achieved by treatment of the resin with pTsOH in benzene with azeotropic removal of water. Products are released upon treatment with HC1 or pTsOH in aqueous dioxane. 

A recent and important example for a N-containing linker system is the hydrazone linker developed by the group of Lazny [253]. This system is useful for the immobilization of aldehydes and ketones via hydrazone bonding. The linker was synthesized starting from commercially available 2-(AT-methylamino)ethanol (or corresponding aminoalcohols) which is nitrosated with t-butylnitrite and subsequently reduced with lithium aluminum hydride... 

Interest in linkers for carbonyl compounds has only slowly emerged in recent years. The main driving force for the development of such linkers was the need for methods to prepare peptide aldehydes and related compounds (e.g. peptide trifluoromethyl ketones), which can be highly specific and valuable enzyme inhibitors [700,701], and are potentially useful for the treatment of various diseases. 

Sulfur analogs of some of the described hydroxy linkers and resins (Figure 15.2) have been employed to synthesize resin-bound thioesters that can then be cleaved with alcohols, amines and organometallic reagents to furnish esters, amides, ketones, aldehydes and alcohols [50]. Secondary amines react sluggishly with linker 9 and, therefore, more reactive thioester-linker derivatives were developed, such as 17 and 18. Yields for a hindered amine such as Pro-OMe were in the order of 60-70%. Thiol-containing PS-DVB resin 7 has been used for the obtention of P-hydroxyacids by hydrolysis with 0.2 M NaOH in aqueous dioxane [51],... 

More recently, several papers reporting the solid phase synthesis of peptide aldehydes have been published. Dinh and Amstrong (61) outline the use of Weinreb-type amides on solid support for the synthesis of ketones and aldehydes Ede and Bray (62) report a new linker based on the oxazolidine moiety and use this method with Multipin technology Galeotti et oL (63) apply their thiazolidinyl linker to a solid support. The great interest in these aldehydic compounds has also been demonstrated by the fact that the Weinreb amide resin is now commercially available from Bachem and Novabiochem. 

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