A Catalytic Asymmetric Chlorocyclization of Unsaturated Amides

Abstract

Stereodefined carbon-halogen bonds are ubiquitous in nature with several natural products exhibiting this motif.[1] While the biogenetic origins of this unique chiral functionality has been a subject of several investigations in the past, [2] attempts by organic chemists to forge the carbon-halogen bond stereoselectively have largely been unsuccessful. This problem has come into focus only recently. Several elegant reports of asymmetric halogenations of alkenes and alkynes followed by an intramolecular attack of a pendant nucleophile have appeared in the literature in the last decade. Kang et al. reported a cobalt-salen catalyzed iodoetherification reaction.[3a] An asymmetric fluorocyclization of allyl silanes mediated by a cinchona alkaloid dimer was reported by Gouverneur and co-workers.[3b] Tang and co-workers disclosed an asymmetric bromolactonization of enynes catalyzed by a cinchona alkaloid derived urea; other bromolactonizations have also appeared following the disclosure of their report.[3c-e] More recently, Veitch and Jacobsen reported an asymmetric iodolactonization reaction mediated by chiral thiourea catalysts.[3f] Polyene cyclizations induced by chiral halonium ions have also been realized as reported by the research groups of Ishihara and Snyder.[4a-c] However, given the fledgling nature of this research area, one may find it easy to highlight the many drawbacks and limitations even in the present state of the art-for example, the relatively large catalyst loadings (superstoichiometric quantities in some cases) to achieve meaningful levels of enantioselectivity or the lack of a robust catalytic system that can catalyze a number of diverse reactions rather than one specific reaction. Moreover, efficient asymmetric chlorocyclizations have remained underdeveloped. This situation is attributable, at least in part, to the highly reactive nature of chloronium ions, which are known to exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions, [5a-c] thus making the development of chlorocyclizations a formidable challenge.Our research group has recently reported the catalytic asymmetric chlorolactonization of alkenoic acids.[7] Herein, we disclose the efficient halocyclization of unsaturated amides to furnish chiral heterocycles. Furthermore, these heterocycles have been transformed into useful chiral building blocks such as amino alcohols.Chiral heterocycles such as oxazolines and dihydrooxazines are commonly encountered motifs in natural products, [8a] molecules of pharmaceutical interest, [8b] and in several chiral ligands.[8c] Their syntheses, however, usually employ stoichiometric quantities of chiral amino alcohols. With only one precedented method to access these molecules in a catalytic asymmetric fashion, [6] we were intrigued by the possibility of one-step access to these versatile chiral heterocycles by a catalytic asymmetric halocyclization of easily accessed unsaturated amides.We chose the conversion of benzamide 1 into oxazoline 2 as our init...

Desymmetrization of Bisallylic Amides through Catalytic Enantioselective Bromocyclization with BINAP Monoxide

“…Therefore, there is great interest in applying metal-ando rgano-catalyzed reactions to symmetric diene substrates, and some highly enantioselective transformations have been developed. [7,8] However,a pplicationst oa symmetric desymmetrization are still quite limited, even including stoichiometric variants with a chiral auxiliary, [3e, 9, 10] although we previously reported desymmetrization of 1,4-cyclohexadienea cids by asymmetricb romo-lactonizationw ithacommerciallya vailable cinchonaa lkaloid catalyst. [3c, 4] Simple unactivated dienes have also been employed in severalt ransition-metal-catalyzed reactions, [5] but organocatalytic versionsr emain largely unexplored, probably due to the limited availability of effective methods for activating simple alkenes.…”

4.07 Electrophilic Cyclization

“…Then they developed another highly stereoselective chlorocyclization of unsaturated amides to chiral heterocycles mediated by catalytic amounts (1-2 mol%) of commercially available (DHQD) 2 PHAL (Scheme 129). 138 The reaction is simply handled without strictly anhydrous or inert reaction conditions. The reaction scope is fairly general with regard to the substitution pattern of the olefin.…”

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

“…19 Highly enantioselective syntheses of these chiral heterocycles were accomplished by using 1,3-dichloro-5,5-diphenylhydantoin (DCDPH) as the chlorenium source with the help of a very small amount (2 mol%) of the dimeric cinchona alkaloid (DHQD) 2 PHAL, the same catalyst that was used for enantioselective chlorolactonization. 7p Very recently, the authors disclosed a solventdependent enantiodivergency in the oxazoline formation; 20 however, only moderate levels of enantioselectivity could be achieved in this case.…”