Somatostatin Mimics Design and Synthesis of g-Dipeptide Derivatives with Submicromolar Affinities for Human Somatostatin Receptors Dieter Seebach,* Laurent Schaeffer, Meinrad Brenner, and Daniel Hoyer In a previous paper we have shown that simple N-acyl-g- dipeptide amides that resemble a bII’ turn of an a-peptide can be designed to form a turn structure in solution (NMR) and in the solid state (X-ray). [1,2] To see whether such a turn could also be used to mimic a peptide, the biological activity of which rests upon a turn structure carrying functionalized side chains, we have now synthesized compounds 1a–g (Scheme 1), with the side chain of tryptophan in the g 2 position of the first and of lysine in the g 4 position of the second g-amino acid, and have tested their affinities for the human somatostatin receptors hsst 1–5 . [3–6] The synthesis of g-dipeptide derivatives 1 commenced with the N-Boc-g-lactams 2 and 3 (Boc = tert-butoxycarbon- yl), readily available from the corresponding commercial (R)- Ala and (S)-Lys acids by known procedures. [1,7] Ring opening (with the Lys derivative after change of side-chain protection, !4), and esterification with Me 3 Si(CH 2 ) 2 OH provided the (R)-Boc-g 4 -hhAla and Boc-g 4 -hhLys(Bn 2 ) esters, which were doubly deprotonated and alkylated with 1-mesitylenesulfon- yl-3-bromomethylindole and MeI to give the unlike g 2,4 -amino acid derivatives 5 and 7, respectively. The ester group in compound 5 with Trp side chain was cleaved (Bu 4 NF, !6), and the lysine-derived esters were converted to the methyl- amides 8 and 9 without and with 2-methyl substitution, respectively (1. Bu 4 NF, 2. MeNH 2 ,3.F 3 CCO 2 H). Coupling of the two g-amino acid derivatives (6 + 8 and 6 + 9), removal of the Boc groups, and acylation with 2-naphthylacetic acid [8] (4-methylmorpholine, 1-hydroxy-1H-benzotriazole, 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide) produced the side- chain-protected N-acyl-dipeptide amides 1a and 1b. Depro- tection procedures (MeSO 3 H,F 3 CCO 2 H, and Pd/C, H 2 )ledto the various partially or fully deprotected g-dipeptide deriv- atives 1c–1g. All compounds were purified and fully charac- terized by elemental analyses, specific optical rotations, circular dichroism (CD), IR, and NMR spectroscopy, and mass spectrometry. Scheme 1. Structuralformulaeofthe g-peptides 1.Intheexpectedcon- formationof 1 theredarrowpointstoaCH 2 groupoftheH 2 N(CH 2 ) 4 unit,whichisplacedinsidetheshieldingconeofthearomaticindole ring.Mes = mesitylenesulfonyl,Bn = benzyl,Nap = naphthyl. BocN O R BocHN OR O N Mes N H R 1 X O R 2 NBn 2 (R)-2, R = Me (S)-3, R = (CH 2 ) 4 NH(2-Cl-Z) (S)-4, R = (CH 2 ) 4 NBn 2 5, R = (CH 2 ) 2 SiMe 3 6, R = H 7, R 1 = Boc, R 2 = Me, X = O(CH 2 ) 2 SiMe 3 8, R 1 = R 2 = H, X = NHMe 9, R 1 = H, R 2 = Me, X = NHMe [*] Prof.Dr.D.Seebach,Dr.L.Schaeffer,Dr.M.Brenner LaboratoriumfürOrganischeChemie EidgenössischeTechnischeHochschule ETHHönggerberg,8093Zürich(Switzerland) Fax:(+ 41)1-632-11-44 E-mail:seebach@org.chem.ethz.ch Dr.D.Hoyer NovartisPharmaAG NervousSystemResearch S-386-745,4002Basel(Switzerland) Zuschriften 800 # 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 0044-8249/03/11507-0800 $ 20.00+.50/0 Angew. Chem. 2003, 115, Nr. 7