Catalytic Enantioselective Halocyclizations beyond Lactones: Emerging Routes to Enantioenriched Nitrogenous Heterocycles

Abstract

Electrophilic halogen-induced reactions of unactivated olefins are an important class of transformations, whose catalytic enantioselective variants have surfaced during the past few years as effective means of olefin heterodifunctionalization. This article covers important developments in the area of enantioselective halocyclizations, specifically in the context of the synthesis of nitrogenous heterocycles.Stereoselective functionalization of unactivated olefins is possibly the most sought-after strategy for generating diversity from easily accessible starting materials. In this regard, the catalytic asymmetric homofunctionalization of unactivated olefins might be considered as a successful and rather mature area of research, thanks to the discovery of methods for epoxidation, dihydroxylation, aziridination, and, to some extent, diamination. Heterodifunctionalization, on the other hand, remained a relatively less well explored territory. Electrophilic halogen-induced activation of olefins followed by nucleophilic addition is a remarkably general strategy for stereoselective olefin heterodifunctionalization (Scheme 1). 1 Halolactonization [Scheme 1 (B); Nu = CO 2 H] is the most prominent example in this category. Even though halolactonization was discovered more than a century ago 2 and has been applied to the synthesis of numerous natural and nonnatural targets, 3 the development of catalytic enantioselective halolactonization and related halocyclization reactions has proved notoriously difficult. Because proven approaches to asymmetric catalysis failed when applied to halocyclization reactions, the field of asymmetric halocyclization was, until recently, virtually unexplored, except for some sporadic examples involving chiral phase-transfer catalysts and chiral Lewis acids. 4 The past few years have witnessed a renaissance in the area of enantioselective olefin halofunctionalization. 5,6 As expected, halolactonization was the first such reaction to catch the attention of researchers, and a number of methods for highly enantioselective chloro-, bromo-, and iodolactonization reactions were developed with the help of a range of structurally dissimilar catalysts. 7 These reactions were not restricted to olefins, as conjugated enynes 8 and alkynes 9 were also subjected to enantioselective halolactonizations. From these reports, the mechanistic pictures associated with these reactions became clearer and a foundation was laid for further developments. Subsequently, several other halocyclization reactions joined the Chandra Bhushan Tripathi (left) received his B.Sc.Scheme 1 Electrophilic halogen-induced stereoselective olefin functionalization (A) and its intramolecular variant, halocyclization (B) SYNLETT 2014, 25, 0163-0169 Advanced online publication: 03.12.20130 9 3 6 -5 2 1 4 1 4 3 7 -2 0 9 6

Chiral non Aromatic Nitrogen-Heterocycles by Asymmetric Intramolecular Haloamination and Haloamidation

“…The first intramolecular haloamination reactions of amino alkenes were carried out more than a century ago [18][19][20] and this methodology allowed to increase the molecular complexity of the starting material since a ring is created together with a halide functionality suitable for further derivatizations. In addition, when the nitrogen atom is tethered on a chiral center, two additional chiral centers can be introduced on the framework with definite configuration so that a lot of highly enantioenriched amino alkenes were easily converted into chiral polysubstituted non aromatic heterocycles generally using a source of halenium ions in a basic medium, the stereoselectivity being directed by internal asymmetric induction arising from in-tether chiral centers [21][22][23][24][25][26][27].…”