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Helvetica Chimica Acta Vol. 87 (2004)
Electrophilic Bromination of N-Acylated Cyclohex-3-en-1-amines:
Synthesis of 7-Azanorbornanes
by Peter Kapferer and Andrea Vasella*
Laboratorium f¸r Organische Chemie, ETH-Hˆnggerberg, HCI, CH-8093Z¸rich
The intramolecular bromo-amidation and the dibromination-cyclisation of the N-acylcyclohex-3-en-1-
amines 4, 8, 9, 11, 13, 14, and 16 was studied in view of the synthesis of bicyclic amines that are of interest as
building blocks and potential glycosidase inhibitors. The trifluoroacetamides 4, 9, and 14 reacted with N-
bromosuccinimide (NBS) in AcOH to give dihydro-1,3-oxazines in good yields. The stereoselectivity of the
dibromination of the alkenes 8 and 9 depends on the nature of the protecting group, the reagent, and the
reaction conditions. Br2 in CH2Cl2 transformed the alkenes 8 and 9 predominantly into diaxial trans,trans-
dibromides. Bromination of 9 with PhMe3NBr3 or with Br2 in the presence of Et4NBr gave predominantly the
diequatorial trans,cis-27 besides some trans,trans-28. A similar bromination of the C(5)-substituted N-acyl-4-
aminocyclohexenes 11, 13, 14, and 16 with PhMe3NBr3 was accompanied by intramolecular side reactions that
were suppressed by the addition of excess Et4NBr. Under these conditions, 11 gave diastereoselectively trans-
dibromides, while its reaction with Br2 gave trans-dibromides along with the dihydrooxazinone 31. Also the
carbamate 13 reacted with PhMe3NBr3/Et4NBr selectively to the trans-dibromide 32 and with Br2 to the trans-
dibromides 32 and 33, the dihydrooxazinone 34, and the bicyclic ether 35. Similarly, the trifluoroacetamide 14
provided the dibromide 36 (89%), while its reaction with Br2 led to the dihydrooxazine 22, and the dibromides
36 and 37. The N-benzyl-N-Boc derivative 16 did not yield any dibromide; it reacted with PhMe3NBr3/Et4NBr to
the dihydrooxazinone 38, and with Br2 to the oxazinone 38 and the bicyclic ether 39. The high stereoselectivity of
the bromination with PhMe3NBr3/Et4NBr suggests an anchimeric assistance of the NHR substituent.
Deprotection, cyclisation, and carbamoylation transformed the dibromides 27, 29, and 32 into the 7-
azanorbornanes 42, 49, and 53. The diols 45 and 57 were obtained from 42 and 53 via HBr elimination and
stereoselective dihydroxylation; they proved weak inhibitors of several glycosidases. In no case could the
formation of a bicyclic azetidine (6-azabicyclo[3.1.1]heptane) from the dibromides 26 and 30 be observed.
Introduction. According to the principle of stereoelectronic control, hydrolysis of
glycopyranosides with an equatorial aglycon requires an anti- or syn-periplanar
arrangement of a C(5)O lone pair and the scissile bond and, thus, a distortion of the
ground-state chair conformation [1][2]. Substrates or inhibitors adopting such a
conformation have been observed in the crystal structure of their complexes with
several b-glycosidases (see [3] and refs. cit. therein), and Varrot et al. have postulated
that all conformations satisfying this stereoelectronic requirement are harnessed by one
or the other glycosidase [4]. Mimics of the corresponding conformers are of interest as
potential glycosidase inhibitors. The calystegines, hydroxylated 8-azabicyclo[3.2.1]oc-
tanes isolated from Calystegia sepium and other species, are competitive inhibitors of
several a- and b-glycosidases (Ki values ranging from 0.8 to 200 mm [5]). The binding
mode of the calystegines has not yet been determined. They may bind as mimics of
4
isofagomine that adopts a C1 conformation, but they may as well adopt a distorted
chair conformation. The isoquinuclidine 1, a 2-azabicyclo[2.2.2]octane (Scheme 1),
mimicking a slightly distorted 1,4B conformer of a b-d-mannopyranoside inhibits
selectively snail b-mannosidase (Ki 1.0 mm at pH 4.5, mixed type inhibition) [3],
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich