Oxalyl linkage

In order to deprotect base-sensitive oligonucleotide derivatives efficiently, an oxalyl linkage, 41, was developed to allow expedited cleavage of newly synthesized oligonucleotides under mild conditions [110]. 

Oxalyl-CPG is obtained by reacting oxalyl chloride and 1,2,4-triazole with a 3 -hydroxyl nucleoside and LCAA-CPG. Cleavage of the oxalyl linker can be effected by a variety of mild reagents including triethylamine, propylamine-DCM, 5% ammonium hydroxide in methanol, or 0.5 M cesium fluoride in methanol for 15 min. Alternatively, 0.5 M DBU in either pyridine, dichloromethane, or dioxane was shown to effect full cleavage of the oxalyl linkage in less than 30 min at room temperature [111]. 

An oxalyl linkage has also been used to attach nucleosides to LC AA-CPG (41). In this method, oxalyl chloride replaces succinic anhydride as the linker that joins the nucleoside to the support (Fig, 8), This oxalyl linkage is quite labile and is cleaved in <5 min by 5% ammonium hydroxide in methanol. Other mildly basic reagents, such as wet triethylamine or 40% trimethylamine/methanol, also rapidly cleave the oxalyl linkage. However, it was quite resistant to normal conditions employed in either phosphoramidite or H-phosphonate synthesis and to anhydrous amines, such as pyridine, triethylamine, and diisopropylamine. This support is particularly well suited for use when synthesis is performed without base-protecting groups (38). 

Oxalic acid is another dicarboxylic acid with restricted occurrence as an acyl moiety of anthocyanins. In addition to some European orchids flowers (Section 10.5.10), cyanidin 3-dioxalylglucoside has been isolated from fruits of Rubus laciniatus. Altogether six different anthocyanins acylated with oxalic acid have been reported. With the exception of cyanidin 3-[6-(oxalyl)glucoside], evidences for proper determination of the linkage position of this acyl moiety are absent. 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

The group of antitumour agents related to pederin have a common structural feature 96 of a functionalised tetrahydropyran attached through an amide linkage to a variety of complex amines. In his successful syntheses of these compounds, Kocienski21 chose to disconnect next to the ring and use a reagent 99 for the d1 synthon 97 that would be acylated by the oxalyl derivative 98. 

An alternative to this route involves 4-vinylaniline or 4-vinylbenzoic acid, relatively easily coupled to various acid counterparts to produce amide linkages. A multitude of amide coupling protocols may in this case in principle be used, for example, by initial activation of the acid by thionyl- or oxalyl chloride and subsequent addition of the corresponding amine in the presence of base (pyridine, triethylamine, etc.) [5,6], or by use of coupling reagents such as dicyclohexylcarbodii-mide (DCC). 

Oligothiophenes end-capped with polybenzyl ether dendrons were prepared by Frechet s group (Scheme 1.70) [508]. Benzyl ester-substituted quinquethiophene 5.65 was deprotected in basic medium to the carboxylic acid and converted to the corresponding acid chloride using oxalyl chloride. This was then connected to a G5-hydroxyl-terminated Frdchet dendron by ester linkages. Stille-type coupling of the terminally brominated quinquethiophene and 2,5-bis(trimethylstannyl)thiophene afforded the highly... 

Triazoles are obtained via 1,3-dipolar cycloadditions between azides and al-kynes, and they are probably the most common nitrogen heterocycles prepared on solid supports via 1,3-dipolar cycloaddition. A wide variety of 1,2,3-triazoles have been prepared on solid supports, with an alkyne or azide attached to the resin. In addition, various linkers have been studied. Alkyne-functionalized alcohol was attached to the MeOPEG resin with an oxalyl chloride linkage (Scheme 11.23). Cycloaddition of alkynes with carbohydrate-derived azides gave resin-bound 1,2,3-triazoles, and reductive cleavage with sodium borohydride released the products as primary alcohols. 

Fig. 8. Easily cleavable nucleoside linkages. Fig 1 A disulfide linkage that yields 3 -phosphorylated products (39) Figs. 2. and 3. Linkages containing a 2-(2-nitrophenyl)ethyl linker, which can be cleaved by DBU, for the synthesis of oligonucleotides with either free or phosphorylated 3 -ends (40) Fig. 4. The oxalyl-CPG linkage (41), which is the most easily hydrolyzable linkage avmlable.

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