Enantioselective anti-Mannich reaction catalyzed by modularly designed organocatalysts

Abstract

A highly stereoselective method for achieving the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate was realized using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and (A)-pyrrolidien-3-carboxylic acid in the reaction media. The desired anti-Mannich products were obtained in good to excellent yields (up to 93%), excellent diastereoselectivities (up to 99:1 dr), and good to high enantioselectivities (up to 99% ee).

Graphical Abstract

1. Introduction

The Mannich reaction is a very important C-C bond forming reaction for the highly efficient synthesis of β-amino carbonyl compounds bearing two adjacent stereocenters.¹ The reaction can also be made diastereoselective and/or enantioselective readily by using appropriate catalysts.¹ Due to the versatility of the β-amino carbonyl compounds in organic synthesis and drug discovery, highly stereoselective methods for obtaining both the syn-and anti-Mannich products have been vigorously sought in recent decades.^1,2

Since List³ and Barbas⁴ introduced the first organocatalyzed asymmetric direct Mannich reaction using L-proline as the catalyst, many chiral amine derivatives, most of which are derived from amino acids, such as proline, have been successfully applied as the catalysts in the direct Mannich reactions, and high diastereoselectivities and/or enantioselectivities have been achieved in many cases.^1a,b,5 Nonetheless, while amine-catalyzed asymmetric syn-Mannich reactions via the enamine mechanism are very common,^1a,b,5examples of organocatalytic asymmetric anti-Mannich reactions are relatively limited.^6–22

In this regard, Barbas’ group reported the first anti-selective Mannich reaction using (S)-2-methoxymethylpyrrolidine (SMP) as the catalyst in 2002.⁶ The anti-selectivity was achieved through the steric interactions between the α-methoxymethyl group on the catalyst pyrrolidine ring and the imine substrates.⁶ Later, the same group discovered that pyrrolidine-3-carboxylic acid, which is a cyclic β-amino acid, and its derivatives are highly stereoselective catalysts for the anti-Mannich reactions.⁷ In this case, the anti-selectivity was interpreted as the result of a different preferred conformation of the enamine intermediate as compared with that in the proline catalysis.⁷ After these seminal reports, several different pyrrolidine derivatives were reported to produce the anti-Mannich products as the major stereoisomers with good to excellent stereoselectivities.^8–18 In principle, they are either the SMP-type catalysts that bearing a steric group at the α position of the pyrrolidine ring^8,9 or the pyrrolidine-3-carboxylic acid-type catalysts that bears a hydrogen bonding site at the β position of the pyrrolidine ring.^10–18 In contrast, acyclic amino acids and their derivatives have been rarely used in the anti-Mannich reactions.^19–21 Cordova’s group reported the use of an acyclic β-amino acid for catalyzing the anti-Mannich reaction of ketones. On the other hand, the groups of Moyano and Lu used acyclic a-amino acid derivatives as catalysts for the anti-Mannich reactions of hydroxyacetone²⁰ and O-benzyl^21a or O-TBS^21b hydroxyacetones, respectively. A totally different type of amine catalysts for the anti-Mannich reaction was reported by Maruoka’s group. They have demonstrated that binaphthalene-based axially chiral amino sulfonamides are excellent organocatalysts for the anti-Mannich reactions.²²

A few years back we introduced the modularly designed organocatalysts (MDOs),^23a which could self-assemble under the reaction conditions from carefully designed precatalyst modules²⁴ through ionic interactions, for catalyzing the direct nitro-Michael reaction.^23a Later, we²³ and others²⁵ have shown that these MDOs are highly efficient catalysts for many important C-C bond forming reactions, such as Michael, Mannich, hetero-Diels-Alder, Biginelli, and aldol reactions. Most recently, we also demonstrated that MDOs could be used as excellent catalysts for the asymmetric diastereodivergent reactions.²⁶ In 2013 we showed that MDOs self-assembled from L-proline and cinchona alkaloid thioureas were highly reactive and stereoselective catalysts for the syn-Mannich reactions between ethyl (4-methoxyphenylimino)acetate and aldehydes or ketones.^23f In terms of both the reactivity and the stereoselectivity, remarkable synergistic effects of combining the two precatalyst modules to form the MDO were clearly demonstrated by the control experiments.^23f Encouraged by these results, we wondered whether we could use similar effects to improve the anti-Mannich reactions, which, as summarized above, is more challenge to achieve than the syn-Mannich reaction. Herein we wish to disclose our detailed study of using novel MDOs self-assembled from (R)-pyrrolidine-3-carboxyhc acid and cinchona alkaloid thioureas for the highly stereoselective anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate.

2. Results and discussions

Using heptanal (3a) and ethyl (4-methoxyphenylamino)-acetate (4a) as the model substrates, we initially screened the MDOs formed in situ in the reaction media from the precatalyst modules of the cinchona alkaloid and amino acid derivatives (Figure 1) to identify the best MDO for the anti-Mannich reaction. Based on our previous findings,^23f the reaction was carried out under neat conditions at room temperature. The results are summarized in Table 1. It should be pointed out that, in order to facilitate the ee value determination, the initial Mannich product 5a was reduced to the corresponding γ-alcohol 6a. When the quinidine-derived thiourea 1a and (R)-pyrrolidine-3-carboxylic acid (2a, 5 mol % each) were used to form the MDO in situ, the desired anti-Mannich product 5a was obtained in 90% yield as an essentially pure enantiomer (99% ee) with a dr of 99:1 (entry 1). Similar to the syn-Mannich reaction previously realized by us using the MDO self-assembled from L-proline and the quinidine-derived thiourea (1a),^23f a high product yield was achieved in just 20 min without the need to use a large excess of the aldehyde. Control experiments conducted with the individual module (i.e., 1a or 2a individually) as the catalyst under identical conditions showed either no reactivity (for 1a, entry 2) or much worse reactivity and stereoselectivity (for 2a, entry 3). These results clearly demonstrate that MDO do form under the reaction conditions and are responsible for the observed synergistic effects. Similar to the MDO assembled from 1a and 2a, the MDO assembled from cinchonine thiourea (1b) and 2a also produced product 5a in a high dr (92:8) with an excellent ee value (99% ee), but the yield was slightly lower (78%, entry 4). Very similar results were also obtained for the MDOs self-assembled from quinine thiourea (1c) and 2a and cinchonidine thiourea (1d) and 2a (entries 5 and 6). Nonetheless, a slightly lower ee value (96% ee) was obtained from the MDO of the quinidine-derived urea (1e) and 2a (entry 7). Likewise, the MDO self-assembled from the quinidine-derived C₆’-thiourea (1f) and 2a also led to a product with lower dr (86:14) and ee value (96% ee, entry 8). Thus, this screen identified quinidine thiourea (1a) as the best stereocontrolling module^23a in terms of both the product yield and the stereoselectivities.

Figure 1.

Precatalyst modules screened in the anti-Mannich reaction [Ar = 3,5-(CF₃)₂C₆H_3⁻].

Table 1.

Catalyst screening for the anti-Mannich reaction^a

Entry	MDO		Yield (%)b	dr (anti/syn) c	ee (%)d
1	1a	2a	90	99:1	99
2	1a	--	0	--	--
3	--	2a	80	90:10	85
4	1b	2a	78	92:8	99
5	1c	2a	83	90:10	99
6	1d	2a	83	95:5	98
7	1e	2a	83	96:4	96
8	1f	2a	87	86:14	96
9	1a	2b	49	83:17	96
10	1a	2c	34	76:24	12e
11	1a	2d	0	--	--
12	1a	ent-2d	0	--	--
13	1a	2e	0	--	--

^aUnless noted otherwise, all reactions were carried out with 3a (0.24 mmol, 1.2 equiv), 4a (0.20 mmol) and the specified catalyst modules (0.010 mmol, 5 mol % each) under neat conditions at room temperature (25 °C) for 20 min.

^bYield of the isolated product 6a after column chromatography.

^cDetermined by ¹H NMR analysis of the crude reaction mixture of the direct Mannich reaction.

^dDetermined by HPLC analysis of the reduced product 6a on a ChiralPak IC column. The absolute stereochemistry of products 5a and 6a was determined by comparing the measured optical rotation of compound 5a with that reported in the literature (Ref. 7c).

^eThe opposite enantiomer was obtained as the major product.

Next, additional amino acid derivatives were screened as the reaction-center module^23a using 1a as the stereocontrolling module. Unsatisfactory diastereoselectivity (83:17 dr) was obtained from the MDO assembled from 1a and (R)-piperidine-3-carboxylic acid (2b), which is also a cyclic β-amino acid. Moreover, the product yield was also poor (49%, entry 9). Similarly, poor yield (34%), diastereoselectivity (76:24 dr), and ee value (12% ee) were also obtained when the MDO formed from 1a and azetidine-3-carboxylic acid (2c) was applied (entry10). In addition, the opposite enantiomer was obtained as the major product in this case. Although the enantioselectivity of this MDO is poor, it should be pointed out that this result actually unequivocally reveals that the stereocontrolling module (i.e., 1a) indeed contributes to the overall stereoselectivity of this reaction, since azetidine-3-carboxylic acid (2c) is in fact an achiral compound, which cannot impart any product ee value by itself. In contrast to cyclic β-amino acids, MDOs formed from 1a and acyclic β-amino acids, such as (R)-3-amino-3-phenylpropanoic acid (2d, entry 11) and (S)-3-amino-3-phenylpropanoic acid (ent-2d, entry 12), did not furnish any product. Similarly, the MDO of 1a and an α-amino acid, L-glutamine (2e), did not give any product, either (entry 13). Thus, this screening identified (R)-pyrrolidine-3-carboxylic acid (2a) as the best reaction-center module.

With the best MDO self-assembled from 1a and 2a, we further optimized the reaction conditions. The results are summarized in Table 2. First some common organic solvents were screened (entries 2–9). As the results in Table 2 show, in general, results obtained from organic solvents are inferior in terms of both product yield and stereoselectivities as compared to those obtained under neat conditions (entry 1). Among these organic solvents, the best results were obtained in toluene, in which exactly the same level of stereoselectivities as those obtained under neat conditions were obtained, except that the product yield was slightly lower (81% vs. 90%, entry 2). Thus, solvent-free conditions proved to be the optimal conditions for this MDO-catalyzed anti-Mannich reaction. When the reaction was carried out under neat conditions at 50 °C (entry 10) and 0 °C (entry 11), both the product dr and yield dropped.

Table 2.

Effects of solvent and temperature on the anti-Mannich reaction^a

Entry	Solvent	Yield (%)b	dr (anti/syn)c	ee (%)d
1	neat	90	99:1	99
2	toluene	81	99:1	99
3	benzene	62	88:12	99
4	xylene	81	91:9	99
5	hexane	72	95:5	92
6	THF	87	96:4	96
7	CH2Cl2	82	97:3	99
8	CH3CN	56	90:10	98
9	DMF	72	95:5	98
10e	neat	68	80:20	99
11f	neat	73	91:9	96

^aUnless noted otherwise, all reactions were carried out with 3a (0.24 mmol, 1.2 equiv.) and the imine 4a (0.20 mmol) in the presence of (R)-pyrrolidine-3-carboxylid acid (1a, 0.010 mmol, 5 mol %) and quinidine thiourea (2a, 0.010 mmol, 5 mol %) in the specified solvent (0.5 mL) at room temperature (ca. 25 °C).

^bYield of the isolated product 6a after column chromatography.

^cDetermined by ¹H NMR analysis of the crude reaction mixture of the direct

^dDetermined by HPLC analysis of the reduced product 6a on a ChiralPak IC column. The absolute stereochemistry of products 5a and 6a was determined by comparing the measured optical rotation of compound 5a with that reported in the literature (Ref. 7c).

^eThe reaction was carried out at 50 °C.

^fThe reaction was carried out at 0 °C.

Next, the reaction scope was established under the optimized reaction conditions. Again, to facilitate the ee value determination via the HPLC analysis, the Mannich products of aldehydes and 4a and 4b were further reduced to the corresponding γ-alcohols (6a-i). In contrast, the Mannich products of ketones and 4a (5j-m) were directly analyzed by HPLC. The results are summarized in Table 3. As the data in Table 3 show, besides the anti-Mannich product of heptanal (6a, entry 1), the desired anti-Mannich products of other straight chain aliphatic aldehydes, such as those of propanal (6b, entry 2), pentanal (6c, entry 3), nonanal (6d, entry 4), dodecanal (6e, entry 5), and hydrocinnamaldehyde (6f, entry 6), were all obtained in high yields, excellent diastereoselectivities, and good to high ee values. Similarly, the branched isovaleraldehyde also produced the corresponding anti-Mannich product 6g in a high yield with excellent stereoselectivities (entry 7). Nonetheless, while the sterically more hindered isobutyraldehyde also produced the corresponding Mannich product 6h in a good yield, the product ee value dropped dramatically to only 18% (entry 8). Similarly, the anti-Mannich product 6i, which is the reaction product of 3a and the N-tosyl imine 4b, was obtained in a good yield with a good diastereoselectivity but a poor ee value (entry 9). Comparing this result with that in entry 1, it is evident that the PMP protecting group on the imine is essential for maintaining the high ee values of the anti-Mannich products, most likely because of the hydrogen bonding between the imine nitrogen atom and the catalyst. When an acyclic ketone, 2-hexanone, was employed as the substrate, the desired anti-Mannich product 5j was obtained in a good yield with a moderate dr (80:20) and a good ee value (entry 10). As for cyclic ketones, cyclohexanone yielded the desired anti-Mannich product 5k in a high yield with a high dr and a good ee value (entry 11). However, the anti-Mannich product of tetrahydropyran-4H-one 5l was obtained in much poorer dr and ee values (entry 12). Also, the reaction with cycloheptanone gave the desired anti-Mannich product 5m in only moderate yield, dr, and ee values (entry 13). There has been no report on using cyclopentanone in anti-Mannich reaction till now. We tried this substrate with 4a under the MDO catalysis, and, as expected, no desired anti-Mannich product was obtained (entry 14).

Table 3.

Substrate Scope of the anti-Mannich Reaction^a

Entry	R1	R2	R3	R4	Time (min) Product		Yield (%)b	dr (anti:syn)c	ee (%)d
1	H	CH3(CH2)4−	H	PMP	20	6a	93	99:1	99
2	H	CH3−	H	PMP	20	6b	88	99:1	90
3	H	CH3(CH2)2−	H	PMP	20	6c	90	95:5	89
4	H	CH3(CH2)6−	H	PMP	20	6d	91	99:1	86
5	H	CH3(CH2)9−	H	PMP	20	6e	83	95:5	82
6	H	PhCH2	H	PMP	40	6f	86	94:6	92
7	H	(CH3)2CH-	H	PMP	20	6g	92	96:4	94
8	H	CH3−	CH3−	PMP	40	6h	81	---	18
9	H	CH3(CH2)4−	H	Ts	40	6i	89e	81:19	5
10	Me	CH3(CH2)2−	H	PMP	1800	5j	76e	80:20	84f
11		−(CH2)4−	H	PMP	120	5k	90e	92:8	86f
12		−(CH2)2OCH2−	H	PMP	60	5l	78e	70:30	44f
13		−(CH2)5−	H	PMP	1440	5m	85e	84:16	59f
14		−(CH2)3−	H	PMP	--	5n	0	--	--

^aUnless noted otherwise, all reactions were carried out with 3 (0.24 mmol, 1.2 equiv.), 4 (0.20 mmol) in the presence of (R)-pyrrolidine-3-carboxylid acid (1a, 0.010 mmol, 5 mol %) and quinidine thiourea (2a, 0.010 mmol, 5 mol %) under neat conditions at room temperature (25 °C).

^bUnless otherwise noted, yield refers to that of the isolated product 6 after column chromatography.

^cDetermined by ¹H NMR analysis of the crude reaction mixture of the direct Mannich reaction.

^dDetermined by HPLC analysis of the purified product on a ChiralPak IC column. Unless otherwise indicated, the absolute stereochemistry of products6 was similarly assigned based on that of product 6a according to the reaction mechanism.

^eYield of the isolate product 5 after column chromatography.

^fThe absolute stereochemistry of product 5k was determined by comparing the measured optical rotation with that reported in the literature (Ref. 7a). The absolute stereochemistry of the other ketone Mannich products was similarly assigned based on the reaction mechanism.

From the results of our current study and our earlier study with the MDOs self-assembled from L-proline,^23f it is clear that the stereochemistry outcome of the Mannich reactions is mainly controlled by the reaction-center modules used (i.e., the amino acids), since the same relative and absolute configuration of the Mannich products were obtained from the amino acids and the corresponding MDOs formed from those amino acids. On the other hand, the cinchona alkaloid thioureas (i.e., the stereocontrolling modules of the MDOs) help improve the reactivity of the reaction-center modules greatly, especially under such solvent-free conditions, and their stereoselectivities.

3. Conclusions

In summary, we have demonstrated that the MDO self-assembled from (R)-pyrrolidine-3-carboxylic acid and quinidine thiourea is a highly efficient catalyst for the anti-Mannich reaction of aldehydes and ketones with ethyl (4-methoxyphenylimino)acetate. Under solvent-free conditions, the desired anti-Mannich products may be obtained in good to high yields (up to 93%) and good to excellent diastereoselectivities (up to 99:1) and ee values (up to 99%) in short reaction times without the need of using large excesses of the aldehyde or ketone substrates. Combing the current method with the method we developed earlier for the syn-Mannich products,^23f we have achieved a facile diastereodivergent synthesis^26c of the desired Mannich products using the MDOs.

4. Experimental

4.1. General methods.

All reactions were carried out in oven-dried glassware. Solvents were dried using standard protocols. Aldehydes and ketones were freshly distilled before use. Ethyl (4-methoxyphenylimino)acetate (4a) was prepared following the known procedure.²⁷ Precatalyst modules 1a-1d,²⁸ 1e,²⁹ and If³⁰ were synthesized following the reported procedures. Precatalyst modules 2a-2e were commercially available. ¹H NMR (300 or 500 MHz) and ¹³C NMR (75 or 125 MHz, respectively) spectra were recorded at 25 °C using CDCl₃ as the solvent.

4.2. General Procedure for the anti-Mannich Reaction.

Quinidine-derived thiourea 1a (5.9 mg, 0.010 mmol, 5 mol %) and (R)-pyrrolidine-3-carboxylic acid (2a, 1.2 mg, 0.010 mmol, 5 mol %) were added to heptanal (3a, 27.4 mg, 0.24 mmol) while stirring at rt (Note: If the reaction was conducted in a solvent, precatalysts 1a and 2a were first taken in 0.5 mL of the corresponding solvent and the mixture was stirred for 15 min before the addition of aldehyde.). The mixture was further stirred at room temperature for 10 min, and then the imine 4a (41.4 mg, 0.20 mmol) was added. Upon the completion (monitored by TLC), the reaction was quenched by adding aqueous ammonium chloride (2.0 mL). The mixture was then extracted with ethyl acetate (2.0 mL x 2). The combined extracts were dried over anhydrous sodium sulfate and the solvent was evaporated. The crude reaction mixture was transferred to a column packed with silica gel and hexane and eluted with a 90:10 hexane/EtOAc mixture to yield product 5a (61.8 mg, 96%) as a colorless gummy liquid, which was further reduced using sodium borohydride (11.3 mg, 0.30 mmol) in dichloromethane (1.0 mL) and ethanol (0.25 mL) at −78 °C for 45 min. Upon the completion of the reaction (monitored by TLC), the mixture was quenched with aq. NaHCO₃ (2.0 mL) and extracted with dichloromethane (2.0 mL x 2). The extracts were washed with brine (2.0 mL) and dried over anhydrous sodium sulfate. After evaporation of the solvent, the the crude reaction mixture was transferred to a column packed with silica gel and hexane and eluted with 30% ethyl acetate in hexane to yield product 6a (60.4 mg, 93%) as a yellow oil.

4.2.1. Ethyl(2S,3R)-3-(hydroxymethyl)-2-[(4methoxyphenyl)amino]octanoate (6a)

Yellow oil; 60.4 mg, 93% yield; 99:1 dr, 99% ee, [α]²⁵ _D = -(c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.90 – 6.63 (m, 4H), 4.16 (qt, J = 7.1, 1.3 Hz, 2H), 4.04 (dd, J = 6.4, 1.1 Hz, 1H), 3.88 – 3.69 (m, 6H), 2.07 (q, J = 4.8, 4.0 Hz, 1H), 1.45 – 1.25 (m, 9H), 1.22 (td, J = 7.1, 1.1 Hz, 3H), 0.89 (td, J = 7.0, 1.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 202.19, 175.08, 156.51, 142.73, 115.67, 114.80, 61.44, 57.03, 55.60, 53.89, 31.60, 26.91, 31.60, 26.91, 25.62, 22.27, 14.09, 13.86. v_max (neat, cm⁻¹): 3268, 2927, 1726, 1618, 1510, 1411, 1368, 1236. HRMS (ESI) m/z calcd. for C₁₈H₃₀NO₄ ([M+H]⁺): 324.2169; Found: 324.2173. Enantiomeric excess of 6a was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (75:25 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 7.1 min; minor enantiomer: t_R = 6.2 min.1508, 1464, 1370, 1238. HRMS (ESI) m/z calcd. for C₂₃H₄₀NO₄ ([M+H]⁺): 394.2952; Found: 394.2958. Enantiomeric excess of 6e was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, X = 254 nm), major enantiomer: t_R = 12.6 min, minor enantiomer: t_R = 11.8 min.

4.2.2. Ethy l (2S,3R) -4-hydroxy -2-[ (4-methoxyphenyl )amino] -3-methylbutanoat e (6b)

Colorless oil; 47.2 mg, 88% yield; 99:1 dr, 90% ee, [α]²⁵_D = -26.2 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.83 – 6.74 (m, 2H), 6.75 – 6.68 (m, 2H), 4.24 – 4.09 (m, 2H), 3.95 (d, J = 7.4 Hz, 1H), 3.82 – 3.62 (m, 6H), 2.16 (pd, J = 7.1, 4.8 Hz, 1H), 1.31 – 1.15 (m, 4H), 1.03 – 0.88 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 173.28, 153.67, 140.12, 116.84, 114.77, 66.91, 63.06, 61.09, 55.62, 38.36, 14.25, 13.75. νmax (neat, cm⁻¹): 3366, 2849, 1733, 1596, 1378, 1233. HRMS (ESI) m/z calcd. For C₁₄H₂₂NO₄ ([M+H]⁺): 268.1543; Found: 268.1553. Enantiomeric excess of 6b was determined by chiral stationary phase HPLC analysis using a ChiralPak IB column (95:5 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 34.9 min; minor enantiomer t_R = 25.9 min.

4.2.3. Ethy l (2S,3R) -3-(hydroxymethyl ) -2-[ (4-methoxyphenyl )amino] hexanoate (6c )

Yellow oil; 53.4 mg, 90% yield; 95:5 dr, 89% ee, [α]²⁵_D = −34.4 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.85 – 6.58 (m, 4H), 4.17 (h, J = 5.4 Hz, 2H), 4.04 (t, J = 5.4 Hz, 1H), 3.89 – 3.56 (m, 6H), 2.07 (qt, J = 7.9, 3.9 Hz, 1H), 1.48 – 1.28 (m, 4H), 1.22 (q, J = 11.5, 9.3 Hz, 3H), 1.02 – 0.76 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 173.57, 153.66, 140.11, 116.765, 114.80, 63.87, 61.99, 61.12, 55.66, 30.43, 20.26, 14.21, 14.19. νmax (neat, cm⁻¹): 3386, 2953, 1723, 1465, 1377, 1200. HRMS (ESI) m/z calcd. for C₁₆H₂₆NO₄ ([M+H]⁺): 296.1856; Found: 296.1860. Enantiomeric excess of 6c was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (85:15 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 16.4 min; minor enantiomer: t_R = 15.7 min.

4.2.4. Ethy l (2S,3R) -3-(hydroxymethyl ) -2- [ (4-methoxyphenyl )amino] decanoate (6d)

Colorless oil; 70 mg, 91% yield; 99:1 dr, 86% ee, [α]²⁵_D = −39.8 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.76 (d, J = 0.7 Hz, 4H), 4.15 (qd, J = 7.1, 0.6 Hz, 2H), 4.03 (d, J = 6.5 Hz, 1H), 3.89 – 3.63 (m, 6H), 2.05 (d, J = 2.4 Hz, 1H), 1.36 – 1.25 (m, 10H), 1.24 – 1.17 (m, 5H), 0.93 – 0.79 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 172.80, 154.40, 121.89, 117.84, 114.74, 114.22, 63.62, 62.84, 61.27, 55.61, 42.81, 31.78, 29.69, 29.14, 28.23, 27.04, 22.63, 14.08, 14.09. νmax (neat, cm⁻¹): 3281, 2918, 1733, 1596, 1463, 1378, 1233. HRMS (ESI) m/z calcd. For C₂₀H₃₄NO₄ ([M+H]⁺): 352.2482; Found: 352.2489. Enantiomeric excess of 6d was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 28.3 min; minor enantiomer t_R = 26.4 min.

4.2.5. Ethy l (2S,3R) -3-(hydroxymethyl ) -2- [ (4-methoxyphenyl )amino] t r idecanoate (6e)

Yellow oil; 65.2 mg, 83% yield; 95:5 dr, 82% ee, [α]²⁵_D = − 42.6 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.82 – 6.72 (m, 2H), 6.71 – 6.64 (m, 2H), 4.24 – 4.11 (m, 2H), 4.03 (d, J = 6.4 Hz, 1H), 3.88 – 3.66 (m, 5H), 2.03 (d, J = 7.5 Hz, 1H), 1.44 – 1.07 (m, 22H), 1.01 – 0.76 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 173.95, 153.30, 140.81, 116.32, 114.77, 64.18, 61.78, 61.07, 55.67, 43.17, 31.90, 29.77, 29.60, 29.50, 29.33, 28.26, 27.09, 22.69, 14.25, 14.14. νmax (neat, cm⁻¹): 3358, 2923, 1731, 1508, 1464, 1370, 1238. HRMS (ESI) m/z calcd. for C₂₃H₄₀NO₄ ([M+H]⁺): 394.2952; Found: 394.2958. Enantiomeric excess of 6e was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 12.6 min, minor enantiomer: t_R = 11.8 min.

4.2.6. Ethy l (2S,3R) -3-benzyl -4-hydroxy -2- [ (4-methoxyphenyl )amino] butanoate (6f )

Colorless oil; 63.6 mg, 86% yield; 94:6 dr, 92% ee, [α]²⁵_D = − 28.3 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 7.34 – 7.16 (m, 5H), 6.81 – 6.71 (m, 2H), 6.68 – 6.59 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.08 (d, J = 5.6 Hz, 1H), 3.84 – 3.60 (m, 4H), 2.91 – 2.61 (m, 2H), 2.39 (dqd, J = 9.9, 6.3, 3.6 Hz, 1H), 1.33 – 1.16 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 173.99, 153.09, 140.93, 139.32, 129.14, 128.52, 126.37, 115.97, 114.77, 62.97, 61.18, 60.57, 55.68, 55.65, 44.75, 34.66, 14.26. νmax (neat, cm⁻¹): 3292, 2932, 2838, 1731, 1508, 1453, 1332, 1256. HRMS (ESI) m/z calcd. for C₂₀H₂₆NO₄ ([M+H]⁺) 344.1856; Found: 344.1865. Enantiomeric excess of 6f was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 16.6 min; minor enantiomer: t_R = 19.2 min.

4.2.7. Ethy l (2S,3R) -3- (hydroxymethyl ) -2- [ (4-methoxyphenyl )amino] -4-methylpentanoate (6g)

Yellow oil; 54.4 mg, 92% yield; 96:4 dr, 94% ee, [α]²⁵_D = − 34.4 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.75 (qd, J = 9.2, 3.0 Hz, 4H), 4.24 – 4.01 (m, 3H), 3.85 (t, J = 4.0 Hz, 2H), 3.74 (d, J = 4.0 Hz, 3H), 1.85 (q, J = 5.7 Hz, 2H), 1.30 – 1.12 (m, 4H), 1.00 (ddd, J = 21.6, 6.8, 3.8 Hz, 7H); ¹³C NMR (125 MHz, CDCl₃): δ 173.91, 153.72, 140.09, 116.91, 114.76, 62.05, 61.91, 61.08, 55.64, 48.66, 21.40, 18.74, 14.19. νmax (neat, cm⁻¹): 3373, 2953, 1727, 1512, 1369, 1237. HRMS (ESI) m/z calcd. For C₁₆H₂₆NO₄ ([M+H]⁺): 296.1856; Found: 296.1863. Enantiomeric excess of 6g was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (92.5:7.5 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 35.6 min; minor enantiomer: t_R = 39.6 min.

4.2.8. Ethy l (S) -4-hydrox y -2- [ (4-methoxyphenyl )amino] -3,3-dimethylbutanoat e (6h)

Yellow oil; 46.0 mg, 81% yield; 18% ee, [α]²⁵_D = −42.6 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.82 – 6.74 (m, 2H), 6.74 – 6.68 (m, 2H), 4.28 – 4.05 (m, 2H), 3.93 (s, 1H), 3.74 (s, 3H), 3.62 – 3.48 (m, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.04 (d, J = 24.5 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 173.20, 153.61, 140.77, 116.96, 114.75, 71.75, 65.82, 65.79, 60.96, 55.65, 55.61, 38.38, 22.63, 20.16, 14.27. νmax (neat, cm⁻¹): 3375, 2932, 1723, 1511, 1465, 1368, 1235. HRMS (ESI) m/z calcd. for C₁₅H₂₄NO₄ ([M+H]⁺): 282.1700, Found: 281.1704. Enantiomeric excess of 6h was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 14.6 min; minorenantiomer t_R = 11.8 min.

4.2.9. Ethy l (2S,3R) -3- (hydroxymethyl ) -2- [ (4-methylphenyl ) sul fonamido] octanoate (6i )

Colorless oil; 54 mg, 89% yield; 81:19 dr, 5% ee, [α]²⁵_D = 33.7 (c = 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 7.76 (dq, J = 8.6, 2.1 Hz, 2H), 7.38 – 7.17 (m, 2H), 3.89 (dd, J = 11.2, 2.9 6 Tetrahedron Hz, 1H), 3.66 – 3.45 (m, 1H), 3.29 (t, J = 6.5 Hz, 1H), 2.42 (d, J = 2.8 Hz, 2H), 1.54 – 1.35 (m, 3H), 1.30 – 0.95 (m, 12H), 1.00 – 0.70 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 142.99, 138.52, 129.48, 127.01, 61.08, 56.06, 42.64, 33.62, 32.02, 31.65, 29.05, 28.08, 27.10, 25.58, 22.55, 22.49, 14.08. νmax (neat, cm⁻¹): 3390, 2953, 2856, 1723, 1465, 1377, 1330. HRMS (ESI) m/z calcd. For C18H30NO5S [M+H]⁺): 372.1829; Found: 372.1834. Enantiomeric excess of 6i was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (90:10 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 34.1 min; minor enantiomer: t_R = 29.6 min.

4.2.10. Ethy l (2S,3R) -3-acet yl -2- [ (4-methoxyphenyl )amino] hexanoate (5j)^7b

Colorless oil; 47.8 mg, 76% yield; 80:20 dr, 84% ee, [α]²⁵_D = −36.5 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.78 (ddd, J = 9.4, 4.9, 2.1 Hz, 2H), 6.73 – 6.60 (m, 2H), 4.21 – 4.10 (m, 3H), 3.76 (t, J = 1.9 Hz, 3H), 3.10 – 2.97 (m, 1H), 2.53 (ddd, J = 7.5, 5.4, 2.0 Hz, 2H), 1.63 – 1.50 (m, 3H), 1.27 – 1.16 (m, 5H), 0.92 (td, J = 7.4, 5.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 214.19, 172.59, 152.74, 140.99, 115.24, 114.89, 77.29, 77.03, 76.78, 61.31, 60.71, 55.74, 54.39, 43.90, 30.94, 29.93, 29.04, 27.21, 24.26, 14.18. νmax (neat, cm⁻¹): 3335, 2957, 1727, 1699, 1510, 1464, 1362, 1286. HRMS (ESI) m/z calcd. for C₁₇H₂₆NO₄ ([M+H]⁺): 308.1856; Found: 308.1861. Enantiomeric excess of 5j was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 8.8 min; minor enantiomer: t_R = 11.3 min.

4.2.11. Ethy l (S) -2- [ (4-methoxyphenyl )amino] -2- [ (R) -2-oxoc yc lohex yl] acetate (5k):^7b

Colorless oil; 59.4 mg, 90% yield; 92:8 dr, 86% ee, [α]²⁵_D = +32.8 (c = 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.93 – 6.69 (m, 2H), 6.70 – 6.54 (m, 2H), 4.28 – 4.04 (m, 2H), 3.98 (d, J = 4.1 Hz, 1H), 3.74 (d, J = 2.4 Hz, 3H), 3.21 – 3.03 (m, 1H), 2.60 – 2.23 (m, 2H), 2.23 – 2.01 (m, 2H), 2.02 – 1.83 (m, 2H), 1.88 – 1.56 (m, 3H), 1.36 – 1.15 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 211.00, 173.10, 152.74, 142.15, 115.64, 115.61, 114.74, 61.22, 59.18, 59.01, 55.79, 55.62, 53.62, 41.85, 30.56, 26.87, 24.57, 14.25, 14.18, 14.10. Enantiomeric excess of 5k was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 17.5 min; minor enantiomer: t_R = 16.3 min.

4.2.12. Ethy l (S) -2- [ (4-methoxyphenyl )amino] -2- [ (S) -4-oxot et rahydro-2H-pyran-3-y l] acetate (5l):^7b

Colorless oil; 54 mg, 78% yield; 70:30 dr, 44% ee, [α]²⁵_D = +46.3 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.82 – 6.74 (m, 2H), 6.74 – 6.58 (m, 2H), 4.34 – 3.97 (m, 6H), 3.97 – 3.85 (m, 1H), 3.86 – 3.77 (m, 1H), 3.74 (d, J = 2.2 Hz, 3H), 3.25 (dt, J = 9.5, 5.2 Hz, 1H), 2.67 – 2.54 (m, 1H), 2.48 (dt, J = 14.9, 3.9 Hz, 1H), 1.30 – 1.16 (m, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 208.19, 172.15, 153.19, 141.27, 116.22, 115.91, 114.82, 70.07, 69.58, 68.07, 67.84, 61.54, 61.49, 56.64, 55.68, 54.45, 53.84, 42.09, 42.03. Enantiomeric excess of 5l was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 19.2 min; minor enantiomer: t_R = 17.9 min.

4.2.13. Ethy l (S) -2- [ (4-methoxyphenyl )amino] -2- [ (R) -2-oxoc yc lohept yl] acetat e (5m)^7b

Yellow oil; 54.4 mg, 85% yield; 84:16 dr, 59% ee, [α]²⁵_D = +35.8 (c = 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 6.79 (d, J = 8.9 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 4.18 (t, J = 7.1 Hz, 2H), 3.76 (d, J = 1.5 Hz, 3H), 3.11 – 3.00 (m, 1H), 2.56 (d, J = 3.7 Hz, 2H), 2.19 (s, 1H), 2.10 – 1.86 (m, 4H), 1.57 (dd, J = 11.3, 2.6 Hz, 2H), 1.48 – 1.33 (m, 2H), 1.28 – 1.20 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 214.20, 172.60, 152.74, 140.99, 115.24, 114.89, 77.29, 77.03, 76.78, 61.31, 60.71, 55.74, 54.39, 43.90, 30.94, 29.93, 29.04, 27.21, 24.26, 14.18, 14.15. Enantiomeric excess of 5m was determined by chiral stationary phase HPLC analysis using a ChiralPak IC column (80:20 hexanes/i-PrOH at 1.0 mL/min, λ = 254 nm), major enantiomer: t_R = 17.7 min; minor enantiomer: t_R = 15.2 min.