Diastereoselective Syntheses of N-Protected Derivatives of 1α,5α,6β-6-Amino-3-azabicyclo[3.1.0]hexane; A Route to Trovafloxacin 6β-Diastereomer

Abstract

N-Protected derivatives 12, 13 and 17 of 1a,5a,6b-6amino-3-azabicyclo[3.1.0]hexane 5 were synthesized via chloroenamines 6a or 6b. The specific N-protection was realized either by using a chloroenamine 6b with different protecting groups or by selective removal of identical protecting groups at the bicyclic target molecule 7. Dibenzylamino compound 13 allowed the preparation of naphthyridine derivative 25 which represents the 6bdiastereomer of trovafloxacin mesylate, a potent Gyrase inhibitor.

Complementary Ways to Diastereomers of Bridged Aminopiperidine Derivatives - A Stereochemical Challenge

“…Examples were the best suitable diastereomer did not exceed the activity of the aminopiperidine derivative include analogues of the analgesic fentanyl 12 (decahydroquinoline type [108], isoquinuclidine type [101,109], tropane type [110], granatane type [111] and norcamphidine type [94]), of the neuroleptic Pipamperone 1 (azabicyclohexane type [64]) or of the analgesic piritramide 2 (azabicyclohexane type [72]). A clear improvement of activity, however, was performed with the substances 102 (analogue of bamipine 6 and 15 times more active [76,83]), 103 (analogue of Clebopride 9 and 30 times more active [26]) and 104a (300 times more active than the analogous aminopiperidine derivative [27]) (Fig. 14).…”

“…Formation of a mixture of diastereomeric amines 56/57 was observed to a more or less extent from Nethoxycarbonyl substituted chloroenamines 59 with cyanide or borohydride [61,70]. Chloroenamines 59 with a diallylamino- [67 -69] or dibenzylamino moiety [65,67,68] served as starting materials for the synthesis of C(6)-N protected compounds; a benzyl, an ester or a methyl rest were used as protecting groups for N(3). Deprotection was realized by a Palladium catalyzed deallylation [67 -69], a hydrogenolytic [64, 65, 68, 71 -73] or a chloroformate initiated debenzylation [67,68], a urethane cleavage by trimethylsilyl iodide [64,67,68] or a demethylation via a Polonovsky reaction [74].…”

“…An additional example of complementary routes to 3-azabicyclohexane diastereomers was found in the substitution of the OMe moiety in an N,O-acetal 66c or 67c by a hydrogen atom. Lithium aluminum hydride as hydride reagent transformed 66c into 66b with exclusive retention of configuration [67,68]. Selective hydrogenolytic monodebenzylation of 66c to 67c and subsequent introduction of a hydrogen atom with DIBAH provided 6α-amine 67b in an acceptable diastereomer ratio but only in moderate yield [68,76] (Scheme 9).…”

“…Lithium aluminum hydride as hydride reagent transformed 66c into 66b with exclusive retention of configuration [67,68]. Selective hydrogenolytic monodebenzylation of 66c to 67c and subsequent introduction of a hydrogen atom with DIBAH provided 6α-amine 67b in an acceptable diastereomer ratio but only in moderate yield [68,76] (Scheme 9). Complexation of the DIBAH to the N(3)-atom combined with the fact of a missing second substituent at C(6)-N-atom could explain the preferred access to 67b.…”

“…A thermodynamically controlled isomerization of N,O-acetals or of semiaminals of type 68 (R 4 = Me, H) to 69 was realized by addition of acid [75,76] or simple An unexpected access to 6α-amino compounds 56a and 56b was found by the reaction of dichloroenamine 60 with cyanide in an aqueous medium to give 6α-nitriles 70a as primary products [61]. Very high diastereoselectivities were observed in some cases (e.g.…”