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.

Pyrrolidine 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]

Figure 1

Selection of biologically active natural products containing pyrrolidine motifs.

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.

Scheme 1

Concept of an Enantioselective Pyrrolidine Synthesis Using a Nitro-Mannich/Hydroamination Cascade

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 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-Cbz-protected 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).

Figure 2

Organocatalysts used in preliminary enantioinduction screen in the nitro-Mannich reaction of N-Cbz imine 1a and nitroallene 2.

Table 1

Optimization of the Diastereo- and Enantioselectivity in the Organocatalytic Nitro-Mannich Reaction of N-Cbz Imine 1a and Nitroallene 2

entrya	cat.	temp (°C)	time (h)	yield (%)b	drc3:3′	ee (%)c3/3′
1	A	RT	20	59	65:35	55/33d
2	C	RT	15	77	75:25	86/75
3	A	–15	72	57	79:21	51/37d
4	B	–15	72	59	82:18	58/55
5	C	–15	44	77	87:13	91/77

All reactions were conducted on a 0.10 mmol scale.

Isolated yield after purification by flash column chromatography.

Determined by HPLC analysis of the purified product.

Opposite enantiomers obtained.

With these results in hand, studies into the hydroamination reaction of the enantioenriched β-nitroamines 3 and 3′ were then conducted (Table 2). Pleasingly, β-nitroamines 3 and 3′ (dr 87:13, 91% ee for the major diastereomer 3) were successfully cyclized using a catalyst combination of Au(PPh3)Cl (10 mol %) and AgSbF6 (20 mol %),[10] affording pyrrolidine 4a in 61% yield and 81:19 crude dr without erosion of the enantioselectivity observed in β-nitroamine 3 (91% ee; Table 2, entry 1).[11] Changing the silver salt to AgOTf or AgNTf2 gave minor increases in the diastereoselectivity of the hydroamination reaction while maintaining good yields of pyrrolidine 4a (Table 2, entries 2, 3).

Table 2

Cyclization Optimization of β-Nitroamines 3 and 3′

entrya	Au complex (10 mol %)	Ag salt (20 mol %)	time (h)	yield (%)b	drc4a:4a′	ee (%)d
1	Au(PPh3)Cl	AgSbF6	2	61	81:19	91
2	Au(PPh3)Cl	AgOTf	2	58	83:17	91
3	Au(PPh3)Cl	AgNTf2	2	65	82:18	91
4	Au(PPh3)Cl	AgBF4	2	69	89:11	91
5	Au[(PhO)3P]Cl	AgBF4	4	54	80:20	91
6	Au(PtBu3)Cl	AgBF4	3	50	83:17	91

All reactions were conducted on a 0.10 mmol scale.

Isolated yield of single diastereomer 3 after purification by flash column chromatography on silica gel.

Determined by 1H NMR analysis of the crude reaction mixture.

Determined by HPLC analysis of the purified product; ee of the major diastereomer 4a is shown, ee of the minor diastereomer 4a′ was not determined. DPP = diphenylphosphate

Not only did the employment of AgBF4 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]

Scheme 2

One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascade Reaction to Pyrrolidine 4a

DPP = diphenylphosphate.

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).

Table 3

Scope of the Enantioselective Nitro-Mannich/Hydroamination Cascade for the Enantioselective Synthesis of Pyrrolidines 4 and 4′

entrya (4:4′)	R1	(i) time (h)	(ii) time (h)	crude drb4:4′	yield (%)c	drd4:4′	ee (%)e
1 (a)	Ph	40	3	84:16	60	92:8	90
2 (b)	o-ClC6H4	48	3	85:15	52	>98:2	90
3f (c)	p-ClC6H4	24	2	79:21	36	>98:2	93
4 (d)	m-FC6H4	48	4	78:22	58	>98:2	95
5f (e)	p-FC6H4	40	2	84:16	50	>98:2	94
6f (f)	m-BrC6H4	40	3	84:16	54	>98:2	96
7 (g)	o-MeC6H4	40	2	82:18	66	>98:2	91
8f (h)	p-MeC6H4	40	3	81:19	53	>98:2	91
9 (i)	o-MeOC6H4	54	3	76:24	39	>98:2	85
10f (j)	m-MeOC6H4	40	2	84:16	64	>98:2	92
11 (k)	m,p-(MeO)2C6H3	40	2	85:15g	67	93:7h	92
12f (l)	m,p-(OCH2O)C6H3	40	2	86:14	67	96:4	91
13 (m)	2-thienyl	48	14	87:13	32	88:12	85

All reactions were conducted on a 0.20 mmol scale.

Determined by 1H NMR analysis of the crude reaction mixture.

Yield after purification by flash column chromatography on silica gel.

Determined by 1H NMR analysis of the purified product; dr >98:2 minor isomer 4′ was not visible by 1H NMR analysis.

Determined by HPLC analysis of the purified product.

Minor diastereomer 4′ isolated in this example; see the Supporting Information for details.

Approximately 8% of a third diastereomer of unknown configuration was visible in the crude 1H NMR spectrum.

The minor diastereomer refers to that of unknown configuration; see footnote g. DPP = Diphenylphosphate.

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-thienyl-substituted 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 CH2Cl2. 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.

Figure 3

X-ray crystal structure representation of pyrrolidine 4k.

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 Et3N to afford pyrrolidine 5 in excellent enantioselectivity (dr 98:2, 95% ee).

Scheme 3

Nitro Group Reduction of Pyrrolidine 4f

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.