Solid-phase synthesis alcohols

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Wang SS. p-Alkoxybenzyl alcohol resin and p-alkoxybenzyloxycarbonylhy-drazide resin for solid-phase synthesis of protected peptide fragments. J Am Chem Soc 1973 95 1328-1333. 

Alsina J, Chiva C, Ortiz M, Rabanal F. Active carbonate resins for solid-phase synthesis through the anchoring of a hydroxyl function. Synthesis of cyclic and alcohol peptides. Tetrahedron Lett 1997 38 883-886 and references cited therein. 

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The R-alcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold . The achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, OOCC1835>. 

In 1983, Prasad et al.12 first reported the condensation of chloromethyl polystyrene with /V-hydroxyphthalimide to give the ester, hydrazinolysis of which yielded the desired resin-bound hydroxylamine. However, the sole purpose of this reagent was to react with, and hence extract ketones from, a complex steroidal mixture, and its use for the solid-phase synthesis of hydroxamic acids was not explored. Recently, the exploitation of the above solid-phase approach for the synthesis of hydroxamic acids was independently reported by three groups,7-9 all of which differ only in the method for the initial anchoring of TV-hydroxyphtha-limide to an 4-alkoxybenzyl alcohol functionalized polystyrene or trityl chloride polystyrene. Subsequent /V-deprotection was... 

Finally, single bead FT-IR has been further exploited in many applications, such as the study of the tetrapropylammonium perrutherate (TPAP)-catalyzed oxidation of supported alcohols [167], the ring opening of a supported oxazolidinone [173], and the solid-phase synthesis of a benzimidazole [174]. 

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

Wang, S.-S. p-Alkoxybenzyl Alcohol Resin and p-Alkoxybenzyloxycar-bonylhydrazide Resin for Solid Phase Synthesis of Protected Peptide Fragments, J. Am. Chem. Soc. 1973, 95, 1328-1333. 

Further materials that have been evaluated as supports for solid-phase synthesis include phenol-formaldehyde polymers [239,240], platinum electrodes coated with polythiophenes [241], proteins (bovine serum albumin) [242], polylysine [243], soluble poly (vinyl alcohol) [244], various copolymers of vinyl alcohol [4,245,246], and soluble dendrimers [14,247]. 

Esters of unsubstituted, polystyrene-bound trityl alcohol are too acid-sensitive to be useful for solid-phase synthesis [49]. Even treatment with alcohols or HOBt can lead to significant product release from the support. More stable towards solvolysis is... 

Silyl ethers of aliphatic alcohols are inert towards strong bases, oxidants (ozone [81], Dess-Martin periodinane [605], iodonium salts [610,611], sulfur trioxide-pyridine complex [398]), and weak acids (e.g., 1 mol/L HC02H in DCM [605]), but can be selectively cleaved by treatment with HF in pyridine or with TBAF (Table 3.32). Phenols can also be linked to insoluble supports as silyl ethers, but these are less stable than alkyl silyl ethers and can even be cleaved by treatment with acyl halides under basic reaction conditions [595], Silyl ether attachment has been successfully used for the solid-phase synthesis of oligosaccharides [600,601,612,613] and peptides [614]. 

For many years, most efforts directed towards the development of solid-phase preparations of alcohols had been limited to the synthesis of biopolymers, such as oligonucleotides and oligosaccharides. Interest in the preparation and chemical transformation of all types of alcohol on insoluble supports only began to grow rapidly in the early 1990s, when chemists realized the potential of parallel solid-phase synthesis for high-throughput compound production. 

The solid-phase synthesis of oligosaccharides is usually performed using acid-resistant linkers and protective groups, because of the slightly acidic reaction conditions required for glycosylations (Section 16.3). Hydroxyl group protection is conveniently achieved by conversion into carboxylic esters, such as acetates, benzoates, or nitro-benzoates. Support-bound esters of primary or secondary aliphatic alcohols can be cleaved by treatment with alcoholates [97-99] (Table 7.8), with DBU in methanol, with hydrazine in DMF [100] or dioxane [101], or with ethylenediamine [102], provided that a linker resistant towards nucleophiles has been chosen. 

Ethers are widely used in solid-phase synthesis, either as linkers for alcohols or as target compounds. Almost all reported solid-phase syntheses of ethers are O-alkyla-tions or O-arylations of alcohols, which differ only in the type of alkylating/arylating agent used and in the precise reaction conditions. This section covers mainly syntheses of acyclic ethers. Preparations of cyclic ethers are considered in Chapter 15. 

Trichloroacetimidates are the only type of imino ethers to have found some application in solid-phase synthesis. Trichloroacetimidates can readily be prepared from support-bound alcohols by treatment with trichloroacetonitrile and a base (Entry 6, Table 13.18). Because trichloroacetimidates are good alkylating agents, this reaction offers a convenient alternative for converting support-bound aliphatic alcohols into alkylating agents. Trichloroacetimidates prepared from Wang resin or from hydroxymethyl polystyrene are quite stable and can be stored for several months without decomposition [253],... 

Carbamates have mainly been used in solid-phase synthesis as linkers and protective groups for amines (see Sections 3.6.2 and 10.1.10.1). Carbamates are generally prepared by treating amines with aryl carbonates or chloroformates, which can be prepared from alcohols and phosgene or synthetic equivalents thereof. The alternative route, in which carbamates, isocyanates, or carbamoyl chlorides are reacted with alcohols, is less widely used, but can also lead to satisfactory results on insoluble supports (Tables 14.7 and 14.8). 

In early attempts directed towards the solid-phase synthesis of oligosaccharides, glycosidic bonds were formed by treating pyranosyl bromides with partially protected carbohydrates (Figure 16.16). These syntheses could be performed with either the pyranosyl bromide (glycosyl donor) [184,185] or the alcohol (glycosyl acceptor) [186— 188] linked to the support. 

Enantiomerically pure aminoalcohols, which are readily available by reduction of a-amino acids, can be converted into alkoxycarbonylating reagents suitable for the solid-phase synthesis of oligocarbamates (Figure 16.26). Particularly convenient alkoxycarbonylating reagents are 4-nitrophenyl carbonates, which can be prepared from alcohols and 4-nitrophenyl chloroformate, and which react smoothly with aliphatic primary or secondary amines to yield the corresponding carbamates. 

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