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BOCN NHBOC _______8_________^
16 (ii) TFA, CH2CI2 2
99 % yield
1.4. SOLID-PHASE SYNTHESES INVOLVING ELECTROPHILES IN SOLUTION 15
O r^l B X
/-× II BOCN^NHBOC ^ 4
ñÞÍçÑÍçÎ² - mP,X,M <3>
17 (ii) TFA, CH2CI2
reacted with a carbodiimide-activated thiourea, or an N,N'-bis(tert-butoxy-carbonyl)-1-guanylpyrazole 8. The aromatic amines gave less product, or none at all (Scheme 17), on the solid phase but were guanylated in solution.
Shey and Sun reported syntheses of guanidines that almost exactly parallel those shown in reactions 1-3, except that polyethylene glycol was used for the support.42 All the reaction steps were therefore carried out in solution, but some of the purifications relied on precipitation.
Î í ¥ BOCN\^NHBOC
'o^ 'Y'NY 'NHBOC
. Î Ph
16 SOLID-PHASE SYNTHESES OF GUANIDINES
Reagent 8 has also been used to add guanidine groups to a supported dipeptide intermediate to a diketopiperazine43 that is reported to be a catalyst for enantioselective Strecker reactions.44 The key step is shown in Scheme 19.
An impressive solid-phase synthesis of bicyclic guanidines has been communicated, and the approach is outlined in Scheme 20 45,46 A'-acyiatecl dipeptides 18 were reduced to triamines by exhaustive borane reduction, then reacted with thiocarbonyldiimidazole. An intermediate thiocarbonyl was cyclized to the guanidine product in this process.
Antisense oligonucleotides with guanidine groups substituted for phosphates bind to natural DNA with particularly high melting temperatures. This is because the positive charge of an oligoguanidine strand complements that of a natural oligophosphate. Solid-phase syntheses of antisense DNA strands wherein guanidine replaces phosphate has been achieved via reactions of a nucleoside-carbodiimide with a resin-bound strand with a free 3'-amino group (Scheme 21) 47 48 The 5'-thiourea 19 starting material was prepared from a Ç'-protected 5',3'-diaminothymidine and trichlo-roethoxycarbonylisothiocyanate (TROC-NCS). Mercuric chloride was then used to convert this to the corresponding carbodiimide in situ. Thus a trityl-based resin with an amino terminus was coupled with 19; then further cycles of FMOC removal and coupling were used to build the antisense strand. Finally, cleavage from the resin and removal of the TROC groups gave the desired heptamer product.
0) f 4
n^nAn^n r""\ W W N
1.4. SOLID-PHASE SYNTHESES INVOLVING ELECTROPHILES IN SOLUTION Ph Ph _
^ ' ^NH2
A ° N
NTROC J (i) piperidine
(ii) 19, HgCI2 NEt3
(ii) remove TROC
18 SOLID-PHASE SYNTHESES OF GUANIDINES
1.5. OTHER SUPPORTED GUANIDINES
Guanidines have been used as a point of attachment for solid-phase syntheses in transformations that do not involve construction of a guanidine. In one case (Scheme 22) the modified Merrifield resin 20 was reacted with Na-BOC-Arg to give a side-chain-anchored amino acid.49 This was then used in peptide syntheses. The resin-linker system was shown to be compatible with both BOC and FMOC coupling strategies. Several cleavage conditions were investigated, but only anhydrous HF gave clean formation of the desired products; other conditions resulted in unwanted fission of the resin-linker bond.
BOC-Arg-OH, 4M KOH dioxane, 75 °Ñ, 2 d
Another approach to coupling guanidines to solid supports was key to solid-phase syntheses of parallel peptide strands, “tweezer receptors” (Scheme 23).50 Combination of the sulfonamide 21 with the thiouronium salt 22 followed by hydrolysis of the ester group gave the linker required for this work. It was then coupled to aminomethylpolystyrene resin and used as a foundation for syntheses of two symmetrical peptide strands. Cleavage from the resin was achieved using triflic acid in the presence of a peptide scavenger. The resin-linker system is not benzylic and hence is more stable to acids than the linkage shown in Scheme 21 and less vulnerable to unwanted fission at the linker position.