Asymmetric Synthesis of 3,4-Diaminocyclohexanol and endo-7-Azabicyclo[2.2.1]heptan-2-amine Diego Savoia,* Stefano Grilli, and Andrea Gualandi Dipartimento di Chimica “G. Ciamician”, UniVersita ` di Bologna, Via Selmi 2, 40126 Bologna, Italy diego.saVoia@unibo.it Received September 3, 2010 ABSTRACT Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures of the 3,4-diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration of the newly formed stereocenter under Mitsunobu conditions, followed by reductive removal of the N-substituents, gave the optically pure endo-7-azabicyclo[2.2.1]heptane-2-amine. The 7-azabicyclo[2.2.1]heptane skeleton is present in a variety of biologically and pharmacologically active com- pounds. 1 Chiral 7-azabicyclo[2.2.1]heptan-2-amines, endo-1 and exo-1 (Figure 1), are relatively unexplored compounds despite their usefulness as structural fragments of more complex, biologically and pharmacologically active mol- ecules. Racemic endo-1 was prepared in five steps starting from N-Boc-pyrrole exploiting a cycloaddition reaction with a 3-bromopropargylic ester to construct the bicyclic skeleton and Curtius rearrangement to form the 2-amino substituent. Then, introduction of the endo-7-azabicyclo[2.2.1]heptan- 2-yl substituent at N 6 of adenosine under S N Ar conditions afforded a reasonably potent A 1 agonist 2a, while the corresponding N 7 -Boc-derivative 2b was a highly potent A 1 AR agonist. 2 The racemic compound 3, prepared through the cycloaddition of N-Boc-pyrrole with an acetylenic sulfone followed by Michael addition of a benzylic amine, displayed potent activity against PM I, II, and IV. Further, the two enantiomers were resolved by preparative chiral HPLC, and the IC 50 values of the (-)-enantiomer were 2-fold better than (1) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179–1193. (2) Ashton, T. D.; Aumann, K. M.; Baker, S. P.; Schiesser, C. H.; Scammels, P. J. Bioorg. Med. Chem. Lett. 2007, 17, 6779–6784. Figure 1. Endo- and exo-7-azabicyclo[2.2.1]heptan-2-amines and compounds containing these motifs. ORGANIC LETTERS 2010 Vol. 12, No. 21 4964-4967 10.1021/ol102103y  2010 American Chemical Society Published on Web 10/08/2010