One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascades for the Synthesis of Pyrrolidine Derivatives: Combining Organocatalysis and Gold Catalysis

The highly enantioselective preparation of trisubstituted pyrrolidine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This cascade approach utilizes an asymmetric bifunctional organocatalytic nitro-Mannich reaction followed by a gold-catalyzed allene hydroamination reaction. The products are afforded in good yields and excellent diastereo- and enantioselectivities.

P yrrolidine heterocycles are prevalent structures found in a myriad of biologically active molecules and natural products ( Figure 1). 1 Because of the abundance of the pyrrolidine motif, research into the synthesis of such an important structural unit continues to be an attractive challenge for the reaction designer. 2 Recently, cascade reactions have emerged as a powerful tool for the preparation of single and polycyclic systems. 3 Cascade reactions are typically resource-efficient and can rapidly build up molecular complexity without the need for isolation of the intermediate compounds. As part of our ongoing research program into cascade reactions using nitro-Mannich 4 and hydroamination 5 reactions, we envisaged that a nitro-Mannich/ hydroamination cascade 6 could provide an efficient method to access trisubstituted pyrrolidine derivatives in an enantioselective fashion. Building on our previous diastereoselective pyrrolidine synthesis employing a nitro-Mannich/hydroamination cascade with N-p-toluenesulfonyl-protected imines, 6c we postulated that the effective combination of an imine protecting group and an organocatalyst would allow this cascade reaction to be conducted in an asymmetric fashion, resulting in a new methodology to produce enantioenriched pyrrolidine heterocycles. Herein, we report our findings.
In our proposed concept (Scheme 1), nitroallene II would react with a protected imine I using an appropriate organocatalyst. 7 The resulting enantioenriched β-nitroamine III would then be poised to cyclize via a diastereoselective gold-catalyzed 5-exo-trig allene hydroamination reaction. 8 Protodemetalation would then afford the desired enantioenriched pyrrolidine V and allow the catalytic cycle to continue.
Our previous investigation 6c had utilized N-p-toluenesulfonyl-protected imines for the nitro-Mannich/hydroamination cascade reaction; however, this protecting group is known to Scheme 1. Concept of an Enantioselective Pyrrolidine Synthesis Using a Nitro-Mannich/Hydroamination Cascade give low enantioselectivities in bifunctional organocatalyzed nitro-Mannich reactions, 4a making it unsuitable for this study. In addition, N-Boc-and N-phosphinoyl-protected substrates did not undergo the allene hydroamination reaction in our previous study. 6c Therefore, we decided to investigate N-Cbzprotected imines as a possible solution to our reactivity and stereoselectivity issues. Accordingly, we studied the level of enantioinduction obtained in the nitro-Mannich reaction between N-Cbz imine 1a and nitroallene 2 using organocatalysts A, B, and C ( Figure  2). 9 After a concise optimization study (Table 1), we found that with the use of catalyst C (5 mol %) at −15°C, a concentration of 0.5 M resulted in the best diastereo-and enantioselectivity in the formation of β-nitroamine 3 (dr 87:13, 91% ee for the major isomer 3) as well as the best isolated yield (77%; Table 1, entry 5).
Not only did the employment of AgBF 4 give an improved yield of pyrrolidine 4a (69%), but also the diastereoselectivity of the crude reaction mixture was improved (dr 89:11; Table 2, entry 4). Changing the ligand of the gold complex to a phosphite led to a reduced yield of pyrrolidine 4a and erosion of the diastereoselectivity (Table 2, entry 5). 12 With both the nitro-Mannich and hydroamination reactions independently optimized, we were confident that combining these two reactions in a sequential cascade procedure would allow for a highly enantioselective pyrrolidine synthesis. 13 Pleasingly, the sequential procedure was successful, affording pyrrolidine 4a in 60% yield and 91% ee as a single diastereomer after separation of the minor diastereomer by column chromatography (Scheme 2). 14 To examine the scope of the developed reaction cascade, a series of substituted N-Cbz imines 1 were subjected to our optimized nitro-Mannich/hydroamination conditions (Table  3). Pleasingly, the cascade reaction was shown to tolerate variations in the substituents present on the aromatic ring of the N-Cbz imines. The electron-poor halogen (fluoro, chloro, bromo)-substituted imines all afforded the desired enantioenriched pyrrolidines 4b−4f in moderate to good yields (36− 58%). The diastereoselectivity observed in the crude reaction mixtures were generally good (dr 78:22−85:15), with the major isomer being isolated as a single diastereomer after purification with excellent enantioselectivities in all cases (90−96% ee).
In the preparation of compounds 4c, 4e, and 4f, the minor isomers were also isolated after purification by column chromatography on silica gel with excellent enantioselectivities (93−94% ee). Methoxy-substituted aryl groups were also found to be suitable substrates for the cascade reaction. The ortho-   methoxy-substituted aryl pyrrolidine 4i did suffer from a diminished yield and enantioenrichment (39% yield, 85% ee), but all of the other pyrrolidines bearing methoxy groups were afforded with good yields (64−67%) and enantioselectivities (91−92% ee). The minor diastereomers 4j′ and 4l′ were also isolated from these reactions. The electron-rich 2-thienylsubstituted pyrrolidine 4m was pleasingly furnished by the cascade reaction, although it was obtained in only 32% yield and 85% ee.
To prove the absolute configuration of the prepared pyrrolidines 4, we obtained a single crystal of pyrrolidine 4k for X-ray diffraction analysis by crystallization from CH 2 Cl 2 . The X-ray diffraction data showed that pyrrolidine 4k contained a 2S,3R,5R configuration ( Figure 3). 15 All other major pyrrolidine diastereomers of 4 were assigned by analogy.
The relative configuration of the minor pyrrolidines 4′ was determined using NOESY analysis of pyrrolidine 4h′. 16 In this experiment, the cis relationship of the protons at the C2 and C5 positions was confirmed (see the Supporting Information for details). All other minor pyrrolidine diastereomers of 4′ were assigned by analogy.
To demonstrate that the enantioenrichment of the synthesized products was retained in subsequent reactions, pyrrolidine 4f was transformed into the sulfonamide-containing pyrrolidine 5 using a two-step procedure (Scheme 3). First, reduction of the nitro group using zinc powder and acetic acid in THF at RT proceeded smoothly to furnish the primary amine, which was then reacted with p-TsCl in the presence of Et 3 N to afford pyrrolidine 5 in excellent enantioselectivity (dr 98:2, 95% ee).
In summary, we have developed an enantioselective synthesis of substituted pyrrolidines using a nitro-Mannich/hydroamination cascade methodology. The combination of bifunctional organocatalysis and gold catalysis used in conjunction with N-Cbz imines afforded pyrrolidines 4 in moderate to good yields (32−67%) with excellent enantioselectivities (85−96% ee). This methodology will allow new, highly substituted pyrrolidine-based architectures to be prepared for library generation and target synthesis.   Author Contributions §