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Table 1. Overall yield of N β -Fmoc-N β -Me-aza-β 3 -aa 5entry N β -Fmoc-N β -Me-aza-β 3 -aa 5 R yield (%)a Fmoc-N β -Me-aza-β 3 -Gly-OH H 83b Fmoc-N β -Me-aza-β 3 -Ala-OH CH 3 28c Fmoc-N β -Me-aza-β 3 -Val-OH CH(CH 3 ) 2 47d Fmoc-N β -Me-aza-β 3 -Leu-OH CH 2 CH(CH 3 ) 2 37e Fmoc-N β -Me-aza-β 3 -Phe-OH CH 2 Ph 89f Fmoc-N β -Me-aza-β 3 -Orn(Boc)-OH (CH 2 ) 3 NHBoc 34g Fmoc-N β -Me-aza-β 3 -Arg(Boc) 2 -OH (CH 2 ) 3 NHC(NHBoc)NBoc 20h Fmoc-N β -Me-aza-β 3 -Asp(t-Bu)-OH CH 2 CO 2 tBu 61The analogue alanine was prepared in four step following the general procedure usingformaldehyde in solution in water, but it could be obtained in two step starting fromN,N'-dimethyl hydrazine 6 by nucleophilic substitution of fluorenyl chloroformate at -78°Cin the presence of one equivalent of triethylamine. This reaction affords themonosubstitution in 39% yield after purification. The reductive amination then leads to 5(R=CH 3 ).Similarly to the synthesis of N β -Fmoc-aza-β 3 -Arg(Boc)-OH [9], N β -Fmoc-N β -Methylaza-β3 -Arg(Boc)-OH 5 (R = (CH 2 ) 3 NHC(NHBoc)NBoc) was prepared from the N β -Fmoc-N β -Methyl-aza-β 3 -Orn(Boc)-OBn. Condensation of 3-t-butoxy carbonyl aminopropanalwith the N-Fmoc-N-Me hydrazine 2 and then reduction of the hydrazone with sodiumcyanoborohydride affords N,N'-trisubstituted hydrazine 4 (R 1 = (CH 2 ) 3 NHBoc). From thishydrazine the reductive amination of glyoxylic acid lead to the N β -Fmoc-N β -Methyl-aza-β 3 -Orn(Boc)-OH 5 (R = (CH 2 ) 3 NHBoc). In the other way, N β -Fmoc-N β -Methyl-aza-β 3 -Orn(Boc)-OBn (R = (CH 2 ) 3 NHBoc) was obtained by nucleophilic substitution of benzylbromoacetate with hydrazine 4 (R = (CH 2 ) 3 NHBoc). Selective deprotection withtrifluoroacetic acid (TFA) gave N β -Fmoc- N β -Methyl-aza-β 3 -Orn-OBn (R = (CH 2 ) 3 NH 2 ) in90% yield. The crude amine was guanidinylated with the Goodman reagent (BocNH) 2NTf[10], and the protected analogue of arginine was obtained in 66% yield. Finally,deprotection of the benzyl protecting group with Pd/C (10 %) in ethanol gave the N β -Fmoc-N β -Methyl-aza-β 3 -Arg(Boc) 2 -OH 5 (R = (CH 2 ) 3 NHC(NHBoc)NBoc) in 56% yield.New building blocks corresponding to N β -methylated-N β -Fmoc-aza-β 3 -aa-OH, can beconveniently prepared with various side chains. These new monomers, compatible withstandard protocols of Fmoc/tBu SPPS, will facilitate preparation of modified peptides onsolid-phase support. So, using these new monomers during the solid phase synthesis, fourpeptide analogs of RRASVA, known as the “minimal substrate” of the catalytic subunit ofthe cAMP-dependent protein kinase (PKA) have been prepared (H-R-N β -Meaza-β3 R-ASVA-OH, H-RR-N β -Me-aza-β 3 A-SVA-OH, H-RRAS-N β -Me-aza-β 3 V-A-OH,H-RRASV-N β -Me-aza-β 3 A-OH) and are under biological investigations.References1. Fairlie, D.P., Abbenante, G., March, D.R. Curr. Med. Chem. 2, 654-686 (1995).2. Cody, W.L., et al. J. Med. Chem. 40, 2228-2240 (1997).3. Barker, P.L., et al. J. Med. Chem. 35, 2040-2048 (1992).4. Chatterjee, J., Mierke, D, Kessler, H. J. Am. Chem. Soc. 128, 15164-15172 (2006).5. Holladay, M.W., et al. J. Med. Chem. 37, 630- 635 (1994).6. Rohrer, S.P., et al. Science 282, 737-740 (1998).7. Dali, H., Busnel, O., Hoebeke, J., Bi, L., Decker, P., Briand J.P., Baudy-Floc’h, M., Muller, S. Mol.Immunol. 44, 3024-3036 (2007).8. Busnel, O., Baudy-Floc’h, M. Tetrahedron Lett. 48, 5767-5770 (2007).9. Busnel, O., Bi, L., Dali, H., Cheguillaume, A., Chevance, S., Bondon, A., Muller, S., Baudy-Floc’h,M. J. Org. Chem. 70, 10701-10708 (2005).10. Planas, M., Bardaji, E., Jensen, K.J., Barany, G. J. Org. Chem. 64, 7281 (1999).105