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Remote substituent effects on the regioselectivity and stereoselectivity in the boron trifluoride mediated addition of nucleophiles (iodide and bromide) to endo- and exo-2-substituted norbornene derivatives have been investigated. The main products of the reactions resulted from the regioselective addition of nucleophiles to the double bond of norbornene derivatives. Products resulting from the Wagner-Meerwein type rearrangement were also isolated in considerable amounts. All of the reactions gave the addition products in reasonably good yields with high regioselectivity. The endo/exo selectivity, on the other hand, changed depending on the nucleophile and the substrate.

A new preparative route to Oppolzer's glycylsultam, the 'NC' component in the asymmetric [C+NC+CC] coupling reaction leading to functionalized pyrrolidines, is described. The synthesis features a novel application of the Delépine reaction, providing a safe, efficient, and environmentally benign route to this useful chiral reagent for pyrrolidine synthesis.We recently described a set of stereocomplementary multicomponent [C+NC+CC] coupling reactions that provide direct access to functionalized pyrrolidines (Scheme 1, 'C' can be a complex aldehyde). 1,2 Since the pyrrolidine ring is an important structural motif found in many bioactive molecules, the asymmetric [C+NC+CC] coupling reaction is expected to find widespread application in synthesis. 3 During the course of these studies, we required a supply of both the L-and D-versions of Oppolzer's glycylsultam 4,5 (H 2 NCH 2 COX*, where X* = camphorsultam), which serves as the 'NC' component in the [C+NC+CC] coupling reaction. Prior syntheses of this glycylsultam were deemed unsuitable for our purposes. We now report an efficient, scalable, and environmentally friendly synthesis of Oppolzer's glycylsultam 6 (see Scheme 2) based on the Delépine reaction. Scheme 1 Asymmetric [C+NC+CC] synthesis of pyrrolidines (X L and X D = antipodes of Oppolzer's camphorsultam)Initially, we employed a variation of Oppolzer's synthesis of a-amino acids to prepare the glycylsultam. 6 This synthesis involved trimethylaluminum-mediated acylation of the parent sultam using methyl N-[bis(methylsulfanyl)methylene]glycinate [(MeS) 2 C=NCH 2 CO 2 Me] 7 to give (MeS) 2 C=NCH 2 COX*, which was hydrolyzed to provide the amine. Chassaing and co-workers 8 synthesized the 15 N-labeled hydrochloride salt of the glycylsultam via alkylation of labeled potassium phthalimide with BrCH 2 COX* followed by N-deprotection. The sodiosultam could also be acylated with the mixed anhydride of labeled N-Boc-protected glycine, followed by Ndeprotection. Dogan and co-workers reported acylation of the sodiosultam with azidoacetyl chloride to give the N 3 CH 2 COX*, which was then subjected to a Staudinger reaction. 9 Our group subsequently developed an alternative route to H 2 NCH 2 COX* via S N 2 displacement of BrCH 2 COX* with azide followed by hydrogenolysis. 10 Since this last sequence involved potentially explosive and/or toxic azides, 11 as well as flammable hydrogen gas, a safer and environmentally benign process was clearly desirable.It was in this context that we began investigating a new route to the glycylsultam based on the Delépine reaction. Though often overlooked, this classical transformation 12 can provide an excellent route to primary amines on a preparative scale. 13 The mechanism of this two-step process involves (a) nucleophilic displacement of an activated halide by the inexpensive and relatively nontoxic hexamethylenetetramine (HMTA), followed by (b) decomposition of the intermediate quaternary hexamethylenetetramine salt with ethanolic hydrogen chloride. This reaction sequence results in...

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