Solid-phase synthesis aldehydes

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Fivush AM, Willson TM. AMEBA An acid sensitive aldehyde resin for solid phase synthesis. Tetrahedron Lett 1997 38 7151-7154. 

Ede NJ, Bray AM. A simple linker for the attachment of aldehydes to the solid phase. Application to solid phase synthesis by the Multipin method. Tetrahedron Lett 1997 38 7119-7122. 

Cheng et al. describes an efficient solution phase and solid phase synthesis of 2-oxopiperazines [29]. These reactions involve a novel Ugi condensation-A-acylimi-nium condensation reaction (Scheme 9). A carboxylic acid 50, an aldehyde 51,... 

Ede, N. J. Bray, A. M. A Simple Linker for the Attachment of Aldehydes to the Solid Phase. Application to Solid Phase Synthesis by the Multipin Method, Tetrahedron Lett. 1997, 38, 7119. 

Scheme 9 Solid-Phase Synthesis of an a-Amino or Peptide Aldehyde by Reduction of the Corresponding Weinreb Amide LinkerN...

A reduced peptide bond can be obtained either in soln or by solid-phase synthesis. The aldehyde of the N -protected a-amino acid reacts with the a-amino function of the C-protected a-amino acid or peptide, to yield a Schiff base 17 which is reduced to give the pseudopeptide 18 (Scheme 10). 

One problem that may be encountered with this type of reaction is related to the fact that in solid-phase synthesis reagents generally have to be used in excess. This can occasionally lead to side reactions, ff, for instance, a resin-bound aldehyde is condensed under basic conditions with excess ketone, the resulting enone might undergo Michael addition with an additional equivalent of ketone (Figure 5.10). For some of these enones, the Wittig reaction may represent a superior synthetic method [75]. 

Nitro- or 2,4-dinitrobenzenesulfonamides of primary or secondary amines can be hydrolyzed under mildly basic conditions, and are increasingly being used for amine protection (see Section 10.1.10.7 [123,139,140]). /V-(2-Nitrobenzenesulfonyl)amino acids can be used as an alternative to TV-Fmoc amino acids for the solid-phase synthesis of peptides [141]. Deprotection is achieved by treatment of the polystyrene-bound sulfonamide with a solution of PhSH (0.5 mol/L) and K2C03 (2 mol/L) in DMF for 10 min at room temperature [141], conditions that do not lead to cleavage of esters (e.g. of the Wang linker) or to racemization. The condensation of polystyrene-bound sulfinamides H2N-SO-Pol with aldehydes yields /V-sulfinylimines, which add... 

Solid-phase schemes have also been used for the synthesis of the K2K and di-K2K dendrons.1 L2X These dendrons can be further modified with electrophiles and nucleophiles. N-Terminal Ser, which can be readily converted into an aldehyde at neutral pH in an aqueous condition, has been used by Spetzler and Tam[89l as a convenient masked aldehyde precursor. The solid-phase synthesis of aldehyde K2K dendrons by Fmoc chemistry is illustrated in Scheme 7. 

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

Linhardt employed Reformatsky-type additions to carbon electrophiles (see Chapter 5, Section 5.5) in a solid-phase synthesis of C-sialosides.43 Immobilised sialyl donor 9 was treated with Sml2 in the presence of ketone and aldehyde... 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

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