Enantiodivergence by minimal modification of an acyclic chiral secondary aminocatalyst.

The development of enantiodivergent catalysis for the preparation of both enantiomers of a chiral compound is of importance in pharmaceutical and bioorganic chemistry. With the design of a class of reactive and stereoselective organocatalysts, acyclic chiral secondary amines, a method for achieving the enantiodivergence is developed simply by changing the secondary N-i-Bu- to N-Me-group within the catalyst architecture while maintaining the same absolute configuration of the catalysts, which modulates the catalyst conformation. This catalyst-controlled enantiodivergent method not only enables challenging asymmetric transformations to occur in an enantiodivergent manner but also features a high level of stereocontrol and broad scope that is demonstrated in eight different reactions (90 examples), all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible, yet important, compounds in good yields with high stereoselectivities.

Introduction

Different enantiomers of a biologically active molecule generally have different or even opposite biological activities[1]. For example, (2S,3S)-paclobutrazol is a plant growth regulator while (2R,3R)-paclobutrazol is a fungicide[2]. Enantiodivergent syntheses through catalytic asymmetric transformations are one of the most powerful and economical approaches for the stereoselective synthesis of both enantiomeric products[3-24]. Although impressive advances have been made, existing catalytic enantiodivergent methods are still limited in scope and may not be suitable for all desired transformations. Meanwhile, there appears a growing number of challenging transformations that cannot be catalyzed effectively by existing chiral catalysts. Thus the development of chiral catalysts and methods enabling challenging asymmetric transformations to occur in an enantiodivergent manner remains significant challenges.

In asymmetric aminocatalysis, chiral secondary amines employed are usually cyclic[25-34]. The rationale is that the cyclic strain increases the nucleophilicity of the amine and the cyclic structure limits bond rotation, providing a well-organized chiral environment. In contrast, acyclic chiral secondary aminocatalysts with both reactivity and stereochemical control comparable to cyclic chiral secondary aminocatalysts remain elusive[35]. Meanwhile, the application of acyclic chiral secondary aminocatalysts in enantiodivergent transformations is not reported.

Herein we describe our studies on designing and engineering acyclic chiral secondary aminocatalysts for enantiodivergent, asymmetric reactions. By strategically changing the (achiral) secondary N-i-Bu- to N-Me-group (within the catalyst architecture) for modification of secondary amine while maintaining the same absolute configuration of the catalysts, a reversal of the enantioselectivity is achieved. This enantiodivergent strategy not only enables asymmetric transformations to occur in an enantiodivergent manner but also features broad scope and high levels of stereocontrol, as demonstrated by its application to 8 different reactions (90 examples), including 7 reactions generating 2 stereocenters, all delivering both enantiomers of structurally diverse products in good yields with good enantioselectivity and diastereoselectivity.

Results

Mannich reaction of β,γ-alkynyl-α-imino esters

Acyclic chiral secondary amines I, which we designed, were easily prepared from acyclic α-amino acids (for details, see Supplementary Note 2). First, they were tested to catalyze enantiodivergent Mannich reactions between aldehydes and C-alkynyl ketimines. The resulting products, chiral propargylamines[36] bearing quaternary stereocenters[37-39], are of synthetic and biological importance[40-46]. Although the catalytic asymmetric direct Mannich reactions of aldehydes with C-alkynyl aldimines have recently emerged[47-50], the corresponding catalytic asymmetric direct Mannich reactions of aldehydes with C-alkynyl ketimines providing quaternary propargylamines have not yet been realized.

Treatment of 1a and 2a with the acyclic chiral secondary amine catalyst Ia/0.5TfOH in MeCN at −40 °C afforded the corresponding Mannich product 3a in good yield; the major isomer, anti-3a with the (3S,4R) configuration, was obtained with >20:1 dr (anti/syn) and 98:2 er (Table 1, entry 1). The potential 1,4-addition onto the alkynyl ketimines was not observed. When secondary N-i-Bu was changed to N-Me within the catalyst architecture, a reversal of enantioselectivity was observed, and the enantiomeric Mannich product (R,S)-3a was obtained with 7:1 dr and 39.5:60.5 er (entry 2). Optimization of R1 and R3/R3’ substituents of I (keeping R2 = Me) led us to identify Id/0.5TfOH as the optimal catalyst for obtaining the enantiomeric Mannich product (R,S)-3a with good enantioselectivity and diastereoselectivity (entry 4). When dichloroethane (DCE) was used as the solvent, the diastereoselectivity and enantioselectivity of (R,S)-3a was further improved to >20:1 dr and 3.5:96.5 er, respectively (entry 6). In order to further evaluate the efficiency of our acyclic chiral secondary amine organocatalysts, we compared the performance of Ia with the commercially available cyclic chiral secondary amine catalysts III and IV as well as the chiral primary amine catalyst II. We found that II, III, and IV could not promote the asymmetric Mannich reaction of 1a and 2a under the same conditions (Table 1, entries 8–10. For details, see Supplementary Table 1).

Table 1

Optimization of the enantiodivergent Mannich reactiona

Entry	Catalyst	t [h]	Yield [%]b	dr [anti/syn]c	erd
1	Ia/0.5 TfOH	10	82	>20:1	98:2
2	Ib/0.5 TfOH	10	65	7:1	39.5:60.5
3	Ic/0.5 TfOH	14	83	14:1	17:83
4	Id/0.5 TfOH	14	87	8:1	8:92
5	Ie/0.5 TfOH	14	67	5:1	14:86
6e	Id/0.5 TfOH	10	78	>20:1	3.5:96.5
7	Id	72	Trace	—	—
8	II/0.5 TfOH	48	Trace	—	—
9	III	48	Trace	—	—
10	IV	48	Trace	—	—

Tf trifluoromethanesulfonyl

aUnless otherwise specified, the asymmetric direct Mannich reaction of β,γ-alkynyl-α-imino ester 1a (0.1 mmol) and propylaldehyde 2a (0.3 mmol) was conducted in the presence of catalyst (20 mol %) and p-NO2-C6H4CO2H (20 mol %) in MeCN (0.8 mL) at −40 °C

bYield of isolated product

cDetermined by 1H-NMR or HPLC

dDetermined by chiral HPLC

eDichloroethane was used as the solvent

We then investigated the Mannich reactions between various β,γ-alkynyl-α-imino esters and aldehydes in the presence of enantiodivergent catalysts, Ia/0.5TfOH and Id/0.5TfOH, respectively (Fig. 1). Here the use of catalyst Ia/0.5TfOH afforded functionalized quaternary propargylamines (S,R)-3a-l in good yields with both high diastereoselectivity and enantioselectivity, while the use of catalyst Id/0.5TfOH gave anti-Mannich adducts (R,S)-3a-l with the opposite absolute configuration in good yields with both high diastereoselectivity and enantioselectivity. It is mentioned that catalytic asymmetric direct Mannich reactions of aldehydes with acyclic ketimines have not previously been realized.

Fig. 1

Enantiodivergent Mannich reaction of β,γ-alkynyl-α-imino esters. Reaction conditions for the formation of (S,R)-3: 1 (0.1 mmol), PNBA (0.02 mmol, 20 mol %), Ia/0.5TfOH (0.02 mmol, 20 mol %), 2 (0.3 mmol), MeCN (0.8 mL), −40 °C. Reaction conditions for the formation of (R,S)-3: 1 (0.1 mmol), PNBA (0.02 mmol, 20 mol %), Id/0.5TfOH (0.02 mmol, 20 mol %), 2 (0.3 mmol), DCE (0.8 mL), −40 °C

Origin of the reversal of enantioselectivity

Based on the above observations and combined with density functional theory (DFT) calculations (for the details, see Supplementary Note 12), we propose the following possible transition state models (Fig. 2) to account for the observed absolute configuration of both Mannich products. In the case of Ia (N-i-Bu), the enamine Ia-int-I with s-syn C-N skeleton is energetically favored over the enamine Ia-int-II with s-anti C-N skeleton. The dominant s-syn enamine Ia-int-I is used for the C−C bond forming step via transition state TS-I (with the tertiary ammonium H-bonded to the imine N)[51]; the Si face of the enamine reacts with the Re face of the imine. TS-II involving s-anti-enamine Ia-int-II is disfavored compared to TS-I due to unfavorable steric repulsion. In contrast, in the case of Id (N-i-Me), the enamine Id-int-II with s-anti C-N skeleton is energetically favored over the enamine Id-int-I with s-syn C-N skeleton. The Re face of the s-anti enamine reacts with the Si face of the imine via the favorable TS-IV, which gives the R,S isomer predominantly.

Fig. 2

Origin of the reversal of enantioselectivity. a Enamine intermediate conformations. b Transition-state models for the asymmetric Mannich reaction of ketimine 1a and aldehyde 2a catalyzed by Ia/0.5TfOH and Id/0.5TfOH

Mannich reaction of trifluoromethyl alkynyl ketimines

Our developed enantiodivergent catalysts, Ia/0.5TfOH and Id/0.5TfOH, could also efficiently catalyze the asymmetric direct Mannich reactions between aldehydes and trifluoromethylated alkynyl ketimines (Fig. 3). These reactions provide an enantiodivergent catalytic asymmetric synthesis of quaternary propargylamines bearing trifluoromethyl group. Installing the trifluoromethyl (CF3) functionality into molecular architectures is an important objective in the pharmaceutical industry[52]. In order to further evaluate the efficiency of our acyclic chiral secondary amine organocatalysts, we compared the performance of Ia and Id with cyclic chiral secondary amine catalysts III and IV as well as chiral primary amine catalyst II. We found that II could not promote this reaction, while III and IV afforded poor enantioselectivity and diastereoselectivity with complementary relative configuration (for details, see Supplementary Table 2).

Fig. 3

Mannich reaction of trifluoromethyl alkynyl ketimines. Reaction conditions for the formation of (S,R)-5: 4 (0.1 mmol), PNBA (0.02 mmol, 20 mol %), Ia/0.5TfOH (20 mol %), 2 (0.3 mmol), MeCN (0.8 mL), −20 °C. Reaction conditions for the formation of (R,S)-5: 4 (0.1 mmol), PNBA (0.02 mmol, 20 mol %), Id/0.5TfOH (20 mol %), 2 (0.3 mmol), MeOH (0.8 mL), −20 °C. Single asterisk (*): Without PNBA as the additive. Double asterisks (**): Without PNBA as the additive. MeCN as the solvent (The absolute and relative configuration of 5k was determined by comparison with the reported ref. [50].)

Mannich reactions of cyclic ketimines

Next, designed enantiodivergent catalysis was explored in the asymmetric direct Mannich reactions of aldehydes with cyclic ketimines. When the reactions of isatin-derived ketimines 6 with aldehydes 2 were carried out in the presence of Ia/0.5TfOH and Id/0.5TfOH, respectively, both enantiomers of the desired Mannich products, anti-7, were obtained in good yields with both high diastereoselectivity and enantioselectivity (Fig. 4). Thus these reactions provide a highly stereoselective method for the catalytic asymmetric enantiodivergent synthesis of 3-substituted 3-amino-2-oxindoles[53].

Fig. 4

Enantiodivergent Mannich reaction of isatin ketimines. Reaction conditions for the formation of (S,R)-7: 6 (0.1 mmol), Ia/0.5TfOH (5 mol %), 2 (0.2 mmol), PhMe (0.8 mL), rt. Reaction conditions for the formation of (R,S)-7: 6 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Id/0.5TfOH (20 mol %), 2 (0.3 mmol), CHCl3 (0.8 mL), −20 °C. Single asterisk (*): PhMe was used as the solvent. MNBA m-NO2-C6H4CO2H, Cbz benzyloxycarbonyl

Designed enantiodivergent catalysis was also applicable to the unknown Mannich reaction between a monocyclic ketimine, 8, and 2a (Fig. 5). Both enantiomers of the functionalized chiral pyrazolone 9 were obtained in good yields with both high diastereoselectivity and enantioselectivity, in the presence of catalyst Ia/0.5TfOH (N-i-Bu) and Ie/0.5TfOH (N-Me), respectively[54].

Fig. 5

Enantiodivergent Mannich reaction of monocyclic ketimines. Reaction conditions for the formation of (S,R)-9: 8 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ia/0.5TfOH (20 mol %), 2a (0.3 mmol), MeCN (0.8 mL), −40 °C. Reaction conditions for the formation of (R,S)-9: 8 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ie/0.5TfOH (20 mol %), 2a (0.3 mmol), MeCN (0.8 mL), −40 °C

The above Mannich reactions are notable in that catalytic asymmetric enantiodivergent Mannich reactions between aldehydes and ketimines have not previously been reported[55-59].

Cross-aldol reaction of aldehydes with isatins

Next, we sought to further establish the generality of designed enantiodivergent catalysis to test other classes of reactions. First, we targeted the catalytic asymmetric aldol reactions. Among them, the catalytic asymmetric direct cross-aldol reaction of aldehydes with isatins, which is a potentially useful method for the synthesis of chiral 3-substituted 3-hydroxy-2-oxindoles[60], was first tested. Only few chiral catalysts have been reported for this reaction, and only 4-halogen-substituted isatin substrates can furnish acceptable levels of diastereoselectivities[61,62]. When other isatins were used as substrates, poor diastereoselectivities (1.4:1–1.6:1 dr) were observed[61-63]. Pleasingly, we found that, in the presence of our acyclic chiral secondary amine If (N-i-Bu), various isatins can react smoothly to give the anti-aldol products (R,R)-11 with both good diastereoselectivity and enantioselectivity (Fig. 6). The switch to Ig (N-Me) resulted in a reversal in enantioselectivity, thus giving (S,S)-11 with both good diastereoselectivity and enantioselectivity. These reactions provide a highly stereoselective method for the catalytic asymmetric enantiodivergent synthesis of 3-substituted 3-hydroxy-2-oxindoles[60].

Fig. 6

Enantiodivergent cross-aldol reaction of isatins. Reaction conditions for the formation of (R,R)-11: 10 (0.1 mmol), If/0.5TfOH (20 mol %), 2 (0.3 mmol), THF (0.8 mL), −40 °C. Reaction conditions for the formation of (S,S)-11: 10 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ig/TfOH (20 mol %), 2 (0.3 mmol), i-PrOH (0.8 mL), −20 °C. Single asterisk (*): Run at −20 °C. Double asterisks (**): Run at 0 °C in DMF (N,N-dimethylformamide)

Aldehyde–aldehyde cross-aldol reaction

The designed enantiodivergent catalysis methodology was also applicable to the direct aldehyde–aldehyde cross-aldol reaction[64,65]. Ia (N-i-Bu) gave the anti-aldol products (S,S)-13, while Ih (N-Me) afforded the enantiomer products (R,R)-13 (Fig. 7). It should be noted that the chiral primary amine II was previously reported by Luo and co-workers[66] for this reaction to give the complementary syn-selective aldol product (S,R)-13. Taken together, these reactions constitute a rare example where both enantiodivergence and diastereodivergence is achieved simply by a modest change within the catalyst architecture while maintaining the same absolute configuration.

Fig. 7

Enantiodivergent aldehyde–aldehyde cross-aldol reaction. Reaction conditions for the formation of (S,S)-13: 12 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ia/0.5TfOH (20 mol %), 2a (0.3 mmol), THF (0.8 mL), −40 °C. Reaction conditions for the formation of (R,R)-13: 12 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ih/0.5TfOH (20 mol %), 2a (0.3 mmol), THF (0.8 mL), −40 °C. Single asterisk (*): Im/0.5 TfOH (20 mol %) was used as the catalyst. The absolute and relative configuration of 13 was determined by comparison with the reported ref. [65]

α-Amination reaction of aldehydes

Finally, we explored the possibility of the designed enantiodivergent catalysis for the formation of single stereocenters and tested the α-amination reaction of aldehydes[67-69]. Ii (N-i-Bu) gave the (S)-configured aminated products, and the switch to Ie (N-Me) resulted in a reversal in enantioselectivity (Fig. 8).

Fig. 8

Enantiodivergent α-amination of aldehydes. Reaction conditions for the formation of (S)-15: 14 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ii/0.5TfOH (5 mol %), 2 (0.3 mmol), MeCN (0.8 mL), −20 °C. Reaction conditions for the formation of (R)-15: 14 (0.1 mmol), MNBA (0.02 mmol, 20 mol %), Ie/0.5TfOH (10 mol %), 2 (0.3 mmol), MeCN (0.8 mL), −20 °C. The absolute configuration of 15 was determined by comparison with the reported ref. [69]

Discussion

In summary, by designing a class of reactive and stereoselective acyclic chiral secondary amines as organocatalysts that are easily available and highly modular, we have developed a method for achieving the enantiodivergence, especially in challenging asymmetric transformations. Simple yet strategic modification of the secondary N-substituent (specifically, from N-i-Bu- to N-Me- group) of secondary amine while maintaining the same absolute configuration of the catalysts led to a reversal of the enantioselectivity through conformation modulation of the catalyst. Besides the high level of stereocontrol achieved, this designed approach to enantiodivergent catalysis displays broad scope that is demonstrated in eight different transformations including seven reactions involving two prochiral reactants with simultaneous control of diastereoselectivity, all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible yet important compounds in good yields with good stereoselectivities. The present study has made an advance in enantiodivergent organocatalysis. Also it showcases the potential of acyclic chiral secondary aminocatalysts in enantiodivergent catalysis as well as the unusual reactivity and stereoselectivity of acyclic chiral secondary aminocatalysts, which are not observable with existing chiral amine catalysts.

Methods

Mannich reaction of β,γ-alkynyl-α-imino esters by Ia

To a solution of β,γ-alkynyl-α-imino ester 1 (0.1 mmol), 4-nitrobenzoic acid (3.3 mg, 0.02 mmol), and catalyst Ia/0.5TfOH (6.7 mg, 20 mol%) in anhydrous MeCN (0.8 mL) was added aldehyde 2 (0.3 mmol) at −40 °C. The reaction mixture was stirred at this temperature until 1 disappeared via thin-layer chromatography (TLC) detection. Then NaBH4 (19.2 mg, 0.5 mmol) and MeOH (0.5 mL) were added at −20 °C. The resulting mixture was stirred for 0.5 h, then recovered to room temperature and kept stirring for 1 h. Finally, the resulting mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/10–1/5) to afford the Mannich product (S,R)-3.

Mannich reaction of β,γ-alkynyl-α-imino esters by Id

To a solution of β,γ-alkynyl-α-imino ester 1 (0.1 mmol), 4-nitrobenzoic acid (3.3 mg, 0.02 mmol), and catalyst Id/0.5TfOH (5.6 mg, 20 mol%) in anhydrous DCE (0.8 mL) was added aldehyde 2 (0.3 mmol) at −40 °C. The reaction mixture was stirred at this temperature until 1 disappeared via TLC detection. Then NaBH4 (19.2 mg, 0.5 mmol) and MeOH (0.5 mL) were added at −20 °C. The resulting mixture was stirred for 0.5 h, then recovered to room temperature and kept stirring for 1 h. Finally, the resulting mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/10–1/5) to afford the Mannich product (R,S)-3.

Aldol reaction of isatins by If

To a solution of isatin 10 (0.1 mmol) and catalyst If/0.5TfOH (7.9 mg, 20 mol%) in anhydrous THF (0.8 mL) was added aldehyde 2 (0.3 mmol) at −40 °C. The reaction mixture was stirred at this temperature until 10 disappeared via TLC detection. Then NaBH4 (19.2 mg, 0.5 mmol) and MeOH (0.4 mL) were added at −20 °C, and the resulting mixture was stirred for 0.5 h. Finally, the resulting mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/5–1/1) to afford the Mannich product (R,R)-11.

Aldol reaction of isatins by Ig

To a solution of isatin 10 (0.1 mmol), 3-nitrobenzoic acid (3.3 mg, 0.02 mmol), and catalyst Ig/TfOH (6.7 mg, 20 mol%) in anhydrous i-PrOH (0.8 mL) was added aldehyde 2 (0.3 mmol) at −20 °C. The reaction mixture was stirred at this temperature until 10 disappeared via TLC detection. Then NaBH4 (19.2 mg, 0.5 mmol) and MeOH (0.4 mL) were added at −20 °C, and the resulting mixture was stirred for 0.5 h. Finally, the resulting mixture was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/5–1/1) to afford the Mannich product (S,S)-11.

Peer Review File

Description of Additional Supplementary Files

Supplementary Data 1

Supplementary Data 2

Supplementary Data 3

Supplementary Data 4