Catalytic Asymmetric Additions of Enol Silanes to In Situ Generated Cyclic, AliphaticN‐Acyliminium Ions

Abstract

Strong and confined imidodiphosphorimidate (IDPi) catalysts enable highly enantioselective substitutions of cyclic, aliphatic hemiaminal ethers with enol silanes. 2-Substituted pyrrolidines, piperidines, and azepanes are obtained with high enantioselectivities, and the method displays a broad tolerance of various enol silane nucleophiles. Several natural products can be accessed using this methodology. Mechanistic studies support the intermediacy of non-stabilized, cyclic N-(exo-acyl)iminium ions, paired with the confined chiral counteranion. Computational studies suggest transition states that explain the observed enantioselectivity.

Enamine-mediated Mannich reaction of cyclicN,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors

“…37 In contrast, in both cases, six- and seven-membered cycles exhibit excellent stereoselectivity under the same conditions. Indeed, the only example of the successful stereoselective Mannich-type reaction of the 1-pyrrolinium cation is the abovementioned paper by List et al 15 One can conclude that this is due to some properties inherent to the pyrrolidine ring itself. This phenomenon needs separate studies, which, however, fall outside the scope of the current paper.…”

“…10,12 A very similar TMSOTf catalysed reaction of N , O -acetal derived from l -malic acid was reported earlier by Specamp. 14 Recently, an interesting paper by List and coworkers appeared, describing the highly enantioselective addition of silyl enol ethers to the 1-pyrrolinium ion using a BINOL-based imidodiphosphorimidate catalyst 15 (Scheme 1).…”

“…10,12 A very similar TMSOTf catalysed reaction of N,O-acetal derived from L-malic acid was reported earlier by Specamp. 14 Recently, an interesting paper by List and coworkers appeared, describing the highly enantioselective addition of silyl enol ethers to the 1-pyrrolinium ion using a BINOL-based imidodiphosphorimidate catalyst 15 (Scheme 1). Many similar reactions have been reported, such as Ti(IV) catalyzed coupling between 1-methoxycarboyl-2-methoxypyrrolidine and silyl enol ethers, 16,17 and addition of silyl enol ethers to 1-pyrrolinum ions in an N-methyl-N′-butylimidazolium based organoindate(III) ionic liquid.…”

“…In the course of our ongoing research, we were faced with the need for synthesizing a series of N-substituted 2-(acylmethylene)pyrrolidine derivatives on a multi-gram scale. However, the usage of hardly available and expensive catalysts, 6,15,24 as well as the small reaction scale, rendered the abovementioned methods less suitable for our purposes. Additionally, the reported syntheses of starting 2-hydroxy/alkoxy pyrrolidines suffer from cumbersome multistep synthetic procedures involving either moisture-sensitive reagents or harsh reaction conditions and an inert atmosphere.…”

Cyclization Strategies Using Imide Derivatives for the Synthesis of Polycyclic Nitrogen‐Containing Compounds

“…In addition to the generation of NAI intermediates from imides, there are numerous other methods allowing access to these highly reactive intermediates starting from different precursors, therefore making them outside the scope of this review. In order to briefly illustrate this possible diversity of precursors, we can mention here a few representative examples: Sharada and co‐workers generated functionalized oxazoles from a multicomponent reaction using 2‐oxo‐2‐arylacetaldehydes, carbamates (or lactams) and nitriles, in the presence of an excess of TfOH and heating at 130 °C in DCE; [44] Takemoto and co‐workers described a Petasis‐ like reaction between quinolines and boronic acids promoted by a chiral thiourea catalyst, and applied this method for the enantioselective synthesis of (+)‐galipinine; [45] Shibasaki and co‐workers employed a chiral Al‐based Lewis acid to perform a combination of N‐ acylation and enantioselective addition of a cyanide ion at C2 of quinoline derivatives, and explored this method for the highly enantioselective synthesis of MK801, an active pharmaceutical ingredient (API) of a potent anticonvulsant; [46] and List reported the addition of silyl enol ethers onto cyclic hemiaminal ethers employing a confined imidodiphosphorimidate (IDPi) catalyst to afford the corresponding highly enantioenriched C2‐functionalized pyrrolidines [47] . From the synthesis of benzyl ( S )‐2‐(2‐oxopropyl)pyrrolidine‐1‐carboxylate, the authors claimed the formal syntheses of small alkaloids (−)‐hygrine and (−)‐norhygrine, [48] (+)‐ipalbidine, [49] and (−)‐hygroline and (−)‐pseudohygroline, [50] among others.…”