Amines secondary/differentially protected

Another example from the early years of polyamine solid phase chemistry comes from Byk et aL [165] (Scheme 6). After immobilization of 2-bromoacetic acid on a Barlos resin (120) they coupled spermine by Sn2-displacement of the bromine. The spermine is either completely protected with Boc-groups (128) or, according to Bycroft et al., the primary and secondary amines are differentiated by the use of Dde-/Boc-strategy [197]. 

There are basically two strategies for this. The first one is the attachment of whole and commercially available polyamines like spermine or their appropriate derivatives to solid phase. This mostly requires protection of the polyamine and at least one tedious chromatographic step before linking it to the solid support. All earlier examples in the literatme go back on this approach and they mostly adopt protection group strategies for tri- and tetra-aza-polyamines, which have already been established in solution phase. The differentiation between primary and secondary amines is a crucial factor. Depending on the type of resin (see Table 1) and the chosen substrate, the crosslinking reactions of symmetrical molecules must also be taken into account as these can decrease the overall yield and pmity of the final products. 

An adaptation of the protection strategies for polyamines from solution phase chemistry was first mentioned for solid phase synthesis of PhTX-343 (27) published by Bycroft et al. in 1996 [197] (Scheme 4). Therein, they attached unmodified spermine on a Barlos resin (120) and used the enamine of acetyldimedone-(Dde) (141) and the Boc-group (128) to differentiate between primary and secondary amines (Table 2). It is known that Dde-OH exclusively reacts with primary amines in the presence of secondary amines even if large excess of Dde-OH is used. Investigation of the crude product after Dde-protection showed no bis-Dde-protected spermine, indicating that only the primary amines reacted with the 2-chlorotrityl resin (120) in the initial step. 

---