Asymmetric Synthesis of β‐Amino Nitriles through a Sc^III‐Catalyzed Three‐Component Mannich Reaction of Silyl Ketene Imines

Abstract

Chiral b-amino nitriles are versatile synthetic intermediates that are readily transformed into optically active compounds such as b-amino acids, and 1,3-diamines. [1] The asymmetric addition of alkyl nitriles to imines provides a straightforward route to such compounds. [2] Although many methods for the asymmetric Mannich reaction have been described, [3] the use of less nucleophilic alkyl nitriles as the nitrile species is a continuing challenge; [4][5][6] one reason for this issue is the poor acidity of the a protons of alkyl nitriles. [5,6] One strategy to solve this problem is the use of an N-metalloketene imine, generated from cyanocarboxylic acid or benzyl nitrile, as an active intermediate; two catalytic asymmetric systems have been reported for such Mannich reactions. [4b,d] As an alkyl nitrile equivalent, silyl ketene imines [7] (SKIs) are competent nucleophiles that can react to form C-substituted nitriles (Scheme 1). Moreover, owing to their unique structure and ready racemization, SKIs are attractive substrates for the construction of vicinal tertiary and quaternary stereogenic carbon centers, [8] which are difficult to synthesize. [9] Since Fu and co-workers reported the first asymmetric acylation of SKIs, [10a] they have become attractive nucleophiles for asymmetric catalytic reactions. [10] The asymmetric aldol-type reaction of SKIs has been reported. [10b,c,e] However, there is only a limited number of examples of the asymmetric addition of SKIs to aldimines and the addition of SKIs to similar substrates has proven somewhat more difficult to achieve and is generally characterized by a narrow substrate scope; the only asymmetric system, which uses stoichiometric quantities of a chiral silicon Lewis acid as the promoter, was reported by Leighton and co-workers. [11] Therefore, the development of a general and efficient asymmetric Mannich reaction of SKIs is particularly desirable. We have recently developed chiral N,N'-dioxide/metal catalysts, which we used for a variety of asymmetric transformations, [12] one of which is the three-component, [13] one-pot addition of N-aryl imines. [14] Herein, we describe a practical and highly efficient Mannich reaction of SKIs to address the challenges mentioned above. A three-component, one-pot method involving the use of a chiral N,N'-dioxide scandium(III) catalyst under mild reaction conditions was developed for the synthesis of bamino nitriles. The desired products, which contain a quaternary stereogenic center, were generated in excellent yield and stereoselectivity (up to 95 % yield, > 95:5 d.r., 97 % ee). The procedure is convenient as no exclusion of air and moisture is required.In the initial study, the reaction between aldimine 1 a [15] and SKI 2 a was performed in EtOAc at À20 8C with 10 mol % of a Lewis acid catalyst, which was prepared in situ from Sc(OTf) 3 and chiral N,N'-dioxide ligand L1. The desired bamino nitrile 3 a was obtained in moderate yield and enantioselectivity and extremely low diastereoselectivity (56:44 d.r.; Table 1, entry ...

Kinetic Resolution of Racemic Mandelic Acid Esters by N,N′‐Dioxide–Scandium‐Complex‐Catalyzed Enantiomer‐Selective Acylation

“…In our previous work, privileged N,N'-dioxide ligands (Figure 1) frequently show wide substrate generality and ex-ceptional levels of stereocontrol for a number of asymmetric reactions. [10,11] For example, KR of racemic 2-arylcyclohexanones through chiral N,N'-dioxide-scandium(III)-complex-catalyzed asymmetric Baeyer-Villiger oxidation was accomplished in high efficiency with an abnormal migratory aptitude. [11a] Furthermore, we found that chiral N,N'-dioxide-metal complexes were capable of acting as chemo-and enantioselective sensors [12] for fluorescent recognition of racemic a-hydroxycarboxylic acids, [12a] amino alcohols, [12b] and so forth.…”

The Future of Catalysis by Chiral Lewis Acids

“…Low catalyst loadings (10 mol%) are common, but a broad spectrum of Lewis acid catalysts are effective, especially those with N,N 0 -dioxide [157][158][159], Schiff base [160][161][162], and phosphine ligands [163][164][165][166][167][168]. The use of ortho-hydroxyaniline has been developed as an effective template for in situ imine formation that, following asymmetric condensation, can be easily removed (Scheme 35) [159]. Analogous to the asymmetric tandem aldolMichael reactions (Scheme 34) are the asymmetric tandem vinylogous MannichMichael reactions of α,β-unsaturated-γ-butyrolactams with nitrovinyl compounds using a novel dinuclear nickel catalyst (Scheme 36) [161].…”

Generation of Stereochemically Defined Tetrasubstituted Enolborinates by 1,4‐Hydroboration of α,β‐Unsaturated Morpholine Carboxamides with (Diisopinocampheyl)borane

“…Thus, alternative methods for generation of acyclic tetrasubstituted enolates or their synthetic equivalents have been developed. [5–8] Noteworthy among these, a highly stereoselective carbocupration of chiral ynamides followed by oxidation of the resultant vinylcuprate has been developed by Marek and co-workers.. [8] Nevertheless, the development of a simple, highly stereocontrolled method for synthesis of stereochemically defined tetrasubstituted enolates from readily available achiral starting materials remains an important objective. Toward this end, we report herein a simple procedure by which stereodefined tetrasubstituted enolborinates are generated with exceptional stereoselectivity via 1,4-hydroboration reactions [9,10] of unsaturated morpholine carboxamides with (diisopinocampheyl)borane ((Ipc) 2 BH), and demonstrate that the tetrasubstituted enolborinates undergo highly enantio- and diastereoselective aldol reactions with representative achiral aldehydes.…”

“…[2] To the best of our knowledge, stereodefined tetrasubstituted enolates have not been successfully generated with high stereochemical control by using alternative reductive aldol procedures, [9,10,12,13] but several have been generated by 1,4-addition of organometallic reagents to unsaturated carbonyl derivatives. [5m,q,r,14] …”

“…As such, the results presented here demonstate a simple solution to the stereoselective synthesis of tetrasubstituted enolates, which are not accessible with synthetically useful stereoselectivity by using conventional enolate forming reactions. [5] …”