Teuahcdron Letters, Vo1.32. No.463 pp 6779-6782, 1991 Printed in Great Britain 0040~4039191 $3.00 + .oo Pcrgamon Press plc Retrosulfonamido Peptide Analogues. Synthesis and Crystal Conformation of Boc-Pro-Leu-v(NH-SO$Gly-NH2 Giampiero Pagani Zecchini,a Mario Paglialunga Paradisi,a Ines Tonima Gino Lucente,a** Enrico Gavuzzo,b Fernando Mazza,b and Giorgio Pochettib a Dipartimento di Studi Farmaceutici and Centro di Studio per la Chimica de1 Farmaco de1 CNR, Universita “La Sapienza”, 00185 Roma, Italy bIstituto di Strutturistica Chimica “G. Giacomello” CNR, Monterotondo Stazione, Roma, Italy zyxwvutsrqponm Abstract: Boc-Pro-Leu-y(NH-S02)-Gly-NH2 (3) has been synthesized as the first example of a pseudopeptide incorporating the NH-SO2 junction. The crystal structure of 3 indicates that the w(NH-SO2) induces a cisoidal (gauche-) conformation which induces a backbone folding and prevents the H-bonded pturn found in the parent peptide. In the context of the isosteric replacement of the peptide bond we introduced recently a new group of pseudopeptides characterized by the presence of the sulfonamido junction *. This modification offers a peptide bond surrogate which presents, in addition to significant changes in polarity, H-bonding capacity and acid-base character, metabolic stability and structural resemblance to the tetrahedral intermediate involved in the amide bond enzymatic hydrolysis. Whereas this latter property is clearly relevant to the synthesis of transition state analogue (T.S.A.) protease inhibitors, recent theoretical and experimental results suggest that S02-NH junction can alter, in a very specific way, the backbone conformation 1,2. Thus, several promising properties are stimulating further studies on this new group of pseudopeptides 3. As an extension of our research in this field we are now adopting the retro-inverso concepti and are examining the synthesis and properties of the retrosulfonamido v(NH-S02) peptide analogues. The hypothalamic MSH release-inhibiting factor Pro-Leu-Gly-NH2 (MIF-I) has been selected as a bioactive natural molecule suitable for introducing the new modification and studying the biochemical and conformational consequences. Due to its endocrine and neuropharmacological activities, this simple tripeptide has been in fact extensively studied and detailed information is available on the conformational preferences of both the native molecule and several of its analogues5.The peptidomimetic link has been inserted in correspondence of the Leu- Gly junction which is located at the central position of the characteristic R-bend structure present in MIF-I and analogues. The retrosulfonamido analogue Boc-Pro-Leu-v(NH-S02)-Gly-NH2 (3) has been synthesized according to Scheme 1. The two “false” termini used are the prochiral gem-diamino analogue of leucine and sulfoacetic acid. 6779