Unprecedented Migration of N-Alkoxycarbonyl Groups in Protected Pyroglutaminol Lennart Bunch, Per-Ola Norrby, Karla Frydenvang, Povl Krogsgaard-Larsen, and Ulf Madsen* Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, UniVersitetsparken 2, DK-2100 Copenhagen, Denmark um@dfh.dk Received November 30, 2000 ABSTRACT Cleavage of an O-silyl ether in an N-BOC-protected pyroglutaminol using TBAF led to an unprecedented migration of the BOC group. An investigation of the mechanism, based on experimental data and quantum mechanical calculations, is presented. Similar migration was observed for N-Cbz and N-methoxycarbonyl groups. (S)-Pyroglutaminol (1), derived from (S)-glutamic acid in two steps, serves as an important building block in synthetic organic chemistry. 1 In an approach to synthesize a novel potentially CNS active glutamic acid analogue, selective cleavage of the TBDMS ether in 2a with TBAF was expected to proceed in high yield on the basis of a previously reported synthesis. 2 However, instead of obtaining the expected free hydroxyl functionality in compound 3a, migration of the BOC group led to the lactam-carbonate derivative 4a as the only product observed (Scheme 1). An X-ray diffraction study of 4a confirmed the structure (Figure 1). In general, migration of the oxycarbonyl moiety in N-carbamates is a known but rarely observed rearrangement reaction and only favorable if an additional anion stabilizing group is present (1) For an extensive review, see: Na ´jera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-2303. (2) Ikota, N. Chem. Pharm. Bull. 1992, 40, 1925-1927 (3) Valentekovich, R. J.; Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 9069-9070 (4) Johnson, C. K. ORTEPII. Report ORNL-5138; Oak Ridge Laboratory, Tennessee, 1976. (5) Experimental procedure: To 0.30 mmol of 2a-d in dry THF (0.5 mL) was added 0.9-1.6 equiv of a 1 M solution of TBAF‚3H 2O in THF (Aldrich). The reaction mixture was stirred for 5 or 30 min at rt and then diluted with EtOAc and quenched by addition of H2O. The organic layer was separated and washed with brine, dried over Na2SO4, and evaporated. Ratios of products determined from 1 H NMR. Scheme 1. Reaction Pathway to 3 and 4 ORGANIC LETTERS 2001 Vol. 3, No. 3 433-435 10.1021/ol0069397 CCC: $20.00 © 2001 American Chemical Society Published on Web 01/06/2001