Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent Kenichi Akaji p and Saburou Aimoto Institute for Protein Research, Osaka University, Suita, 3-2 Yamadaoka, Osaka 565-0871, Japan Received 13 November 2000; accepted 15 December 2000 Abstract —The synthesis of MEN11420, a potent tachykinin receptor antagonist, has been achieved. The bicyclic glycosylated structure of MEN11420 was constructed via intramolecular double cyclization using CIP-mediated activation. The head to tail cyclization of the linear precursor, which contained an a-amino acid at its C-terminus, proceeded so rapidly that no serious racemization was apparent at the activated carboxyl function. The desired product was obtained without the need for purification of the intermediates throughout the synthesis. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction Tachykinins (TKs) comprise a family of peptides that are widely distributed in the central and peripheral nervous system and play a key role in neuronal stimulation. 1 Of the three mammalian’s TKs (Substance P, Neurokinin A, and Neurokinin B), Neurokinin A (NKA) is known to play a role in bronchoconstriction, smooth muscle contrac- tion and inflammation. Thus, antagonists of the Tachykinin NK 2 receptor which recognize Neurokinin A have a wide range of potential therapeutic applications. 2 MEN11420, which is derived from the bicyclic Tachykinin analogue MEN10627, is a potent and selective tachykinin NK 2 recep- tor antagonist as has been reported by Renzetti et al. 3 in 1998. Structurally, MEN11420, cyclo{[Asn(b-d-GlcNAc)- Asp-Trp-Phe-Dap-Leu]cyclo(2b –5b)} (Fig. 1), is a bicyclic peptide with a (2-acetylamino-2-desoxy-b-d-glucopyrano- syl)-l-asparaginyl residue in the place of the Met residue, which is normally present in MEN10627. In spite of its unique structure and specific activity for the NK 2 receptor, no detailed procedure for the synthesis of MEN11420 has, to date, been reported, although, a Boc-based classical synthesis of bicyclic MEN10627 was reported by Pavone et al. 4 in 1995. Recently, we have developed a new coupling reagent, 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophos- phate (CIP), 5 which in the presence of an additive (HOAt 6 or DMAP 7 ) permits the effective coupling of sterically hindered a-dialkylamino acids or N-methylamino acids (Fig. 2). Using this coupling reagent, we were able to Tetrahedron 57 (2001) 1749–1755 Pergamon TETRAHEDRON 0040–4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(01)00011-4 Figure 1. Structure of MEN11420. Figure 2. Structures of CIP, HOAt and DMAP. Keywords: CIP; coupling reagent; intramolecular cyclization; MEN11420; tachykinin antagonist. Abbreviations: Boctert-butoxycarbonyl; Bu t tert-butyl; CIP2-chloro- 1,3-dimethyl-2-imidazolium hexafluorophosphate; Dap2,3-diaminopro- pionic acid; DIEAN,N-diisopropylethylamine; DIPCDIN,N 0 -diisopro- pylcarbodiimide; DMAP4-dimethylaminopyridine; Fmocfluoren-9- ylmethyloxycarbonyl; HOAt1-hydroxy-7-azabenzotriazole; HOBtN- hydroxybenzotriazole; MALDI-TOFmatrix-assisted laser desorption ionization time-of-flight; SPPSsolid phase peptide synthesis; TFAtri- fluoroacetic acid; TFE2,2,2-trifluoroethanol. p Corresponding author. Tel.: 181-06-6879-8608; fax: 181-06-6879- 8609; e-mail: akaji@protein.osaka-u.ac.jp