Sulfonic transamination

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

DNA and RNA may be modified with hydrazide-reactive probes by reacting their cytosine residues with bisulfite to form reactive sulfone intermediates. These derivatives undergo transamination to couple hydrazide- or amine-containing probes (Draper and Gold, 1980) (Chapter 27, Section 2.1). 

Addition of a nucleophile to the C-6 position of cytosine often results in fascile displacement reactions occurring at the N4 location. With hydroxylamine attack, nucleophilic displacement causes the formation of an N4-hydroxy derivative. A particularly important reaction for bioconjugate chemistry, however, is that of nucleophilic bisulfite addition to the C-6 position. Sulfonation of cytosine can lead to two distinct reaction products. At acid pH wherein the N-3 nitrogen is protonated, bisulfite reaction results in the 6-sulfonate product followed by spontaneous hydrolysis. Raising the pH to alkaline conditions causes effective formation of uracil. If bisulfite addition is done in the presence of a nucleophile, such as a primary amine or hydrazide compound, then transamination at the N4 position can take place instead of hydrolysis (Fig. 38). This is an important mechanism for adding spacer arm functionalities and other small molecules to cytosine-containing oligonucleotides (see Chapter 17, Section 2.1). 

H(55)1759>. N-Unsubstituted l,2-benzisothiazolin-3-ones 344 (R = H R = H, Cl, OMe R = H, Cl, OMe) can be prepared in a chlorine-free synthesis by cyclization of 2-sulfenamoylbenzoates 342 (R = OR, R = NH2) which are prepared by amination of thiosalicylates with hydroxylamine-O-sulfonic acid. N-Substituted sulfenamoylbenzoates, prepared by transamination with different amines, can be cyclized to N-substituted 1,2-benzisothiazolin-3-one 344 (R = PhCH2,/ -MeOC6H4CH2,/>-ClC6H4CH2) <2003H(60)1855>. 

They introduced chirality on the a-methylpiperidine core in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by the development of a camphor sulfonic acid salt formatioa A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield. 

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