Helical Chiral Pyridine N‐Oxides: A New Family of Asymmetric Catalysts

Abstract

The design, synthesis, and study of new catalyst structures have had an enormous impact on chemical synthesis, and continue to be a central challenge in asymmetric catalysis.[1]We recently described that a 2-aminopyridinium ion might be a promising catalaphore [2] for the design of new asymmetric hydrogen-bond donor catalysts. [3] In that connection, we became interested in 1-aza [6]helicene [4] 1 as a chiraphore [2] because a first-order analysis of the crystal structure of an analogous 1,16-diaza[6]helicene [5] suggests that its pyridine ring is well-desymmetrized in terms of both top-from-bottom and left-from-right differentiations. To our knowledge, the application of 1 and analogous helical chiral pyridines [5][6][7] in asymmetric catalysis has not been studied, even though 1 has been known in the literature since 1975.[4d] In this context, we were prompted to develop an efficient synthesis of 1-azahelicenes, which allows systematic structural variation-important for the elucidation of the relationship between catalyst structure, reactivity, and selectivity-and to exploit them as chiraphores. In view of the utility of helical chiral pyridines such as 1, it occurred to us that the corresponding pyridine N-oxides might prove to be effective asymmetric catalysts.[8] Herein, we describe the scalable synthesis of 1-azahelicenes and the structural characterization of the corresponding N-oxides, and we apply this new family of compounds to the catalytic enantioselective desymmetrization of meso epoxides (see Table 1). This study provides the first report of the application of azahelicenes in asymmetric catalysis. [9] An examination of the structure of 1 suggests that the chiral environment in the vicinity of the nitrogen atom can be tuned by structural modification at cabon atoms 11-16. Therefore, we devised a convergent synthetic route to 1 in which benzoquinoline unit 2 and C11-C16 unit 3 could be expeditiously united (Scheme 1). This strategy would allow ready access to the necessary 1-azahelicene derivatives by simply replacing 3 with its readily available structural analogues, such as 9 and 12 (Scheme 2). Preparation of key unit 8 starts from commercially available pyridine 4 and phosphonium salt 5, which was readily synthesized in three steps from commercially available 2-bromo-4-methyl benzaldehyde. The highly Z-selective Wittig reaction [6b, 10] of 4 and 5 and subsequent Stille-Kelly reaction [5,11] provided benzoquinoline 6. The catalytic C À H functionalization method developed by Sanford and co-workers [12] readily converted 6 into 7 from which 8 was obtained in an ordinary way. The second sequence of the highly Z-selective Wittig reaction and the Stille-Kelly reaction of 8 with 9, 11, or 12 provided 1-azahelicenes 10, 1, or 13, respectively. The scalability of this Scheme 1. Synthesis design.Scheme 2. Syntheses of 1-azahelicenes: a) NaHMDS, DMF, 78 %; b) [PdCl 2 (Ph 3 P) 2 ], (Me 3 Sn-) 2 , PhMe, 77 %; c) Pd(II) catalyst, [12] NBS, CH 3 CN, 84 %; d) benzoyl peroxide, NBS, PhH, 71 %; e) 2-nitropropane,...

Helicene-Based Chiral Auxiliaries and Chirogenesis

“…For example, 1-aza [6]helicene-N-oxide derivatives 91-93 (Schemes 15 and 16) [67] were prepared in the racemic form using a general three-step synthetic methodology, and their enantiomers were resolved over chiral HPLC [67]. The representative synthesis of 93 starts from the benzoquinoline aldehyde unit 94 and corresponding bromo-substituted phosphonium salt 95 in three steps, where the initial step involves the Z-selective Wittig condensation followed by the palladium-catalyzed Stille-Kelly coupling reaction to result in azahelicene 96.…”

“…Finally, oxidation with meta-chloroperbenzoic acid gave the desired helicene-N-oxide 93 with 32-49% yield (Scheme 15). Then, the enantiopure (P)-helical ligands 91-93 were screened for the desymmetrization of meso epoxide 97 with chloride as a nucleophile to obtain 98 with satisfactory yields and ee (Scheme 16) [67].…”

“…Further, the catalyst 99 can be recovered (~80%) without any loss of activity and selectivity after the reaction, making it highly attractive for industrial application. Then, the enantiopure (P)-helical ligands 91-93 were screened for the desymmetrization of meso epoxide 97 with chloride as a nucleophile to obtain 98 with satisfactory yields and ee (Scheme 16) [67].…”

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

“…This counter-intuitive cooperative effect was strong enough to be preparatively useful (Z/E up to 95:5) and the resulting Z-2,2'-disubstituted stilbenes have been used to good effect in synthesis by others. 81,82 At the time, we rationalized the results within the cycloaddition mechanism by proposing that the increased Z-selectivity arose from the induction by the ortho-heteroatom of a lowered energy transition state (TS) in the kinetically controlled cycloaddition step leading to a lo wered energy cis-OPA. However, the experimental conditions employed (aqueous, room temperature, presence of sodium salts in solution, use of triphenylphosphine derived ylides), while very convenient, were not such that kinetic control in the Wittig reaction could be assumed and rendered the analysis provisional at best.…”

Intense redox-driven chiroptical switching with a 580 mV hysteresis actuated through reversible dimerization of an azoniahelicene

“…1C and 2). We have previously found 1-aza [6]helicene [36][37][38] (1) to be a highly useful scaffold for chiroptical applications, especially in the context of organic electronic devices. 12,13,17 Based on the electrochemical behaviour of related non-chiral systems, 39,40 we anticipated that quarternisation of the nitrogen atom would afford a system (2 + ) that could provide a new intermolecular pathway to strong chiroptical switching 21,41,42 with a large redox hysteresis.…”