Catalytic atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes via dynamic kinetic resolution

Tian-Jiao Han; Chun-Yan Guan; Na Li; Rui Dong; Li-Ping Xu; Xiao Xiao; Min-Can Wang; Guang-Jian Mei

doi:10.1016/j.isci.2023.107978

. 2023 Sep 20;26(10):107978. doi: 10.1016/j.isci.2023.107978

Catalytic atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes via dynamic kinetic resolution

Tian-Jiao Han ^1,⁴, Chun-Yan Guan ^1,⁴, Na Li ², Rui Dong ¹, Li-Ping Xu ², Xiao Xiao ³, Min-Can Wang ^1,^∗, Guang-Jian Mei ^1,^5,^∗∗

PMCID: PMC10562788 PMID: 37822512

Summary

Reported herein is a highly efficient dynamic kinetic resolution protocol for the atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes. Atropisomers bearing vicinal diaxes mainly exist in o-triaryls, while that of biaryls is highly challenging in terms of the concerted rotation and deplanarization effects. The combination of C−C biaryl with N−N nonbiaryl delivers a novel class of vicinal-diaxis heterobiaryls. For their atroposelective synthesis, the dynamic kinetic resolution enabled by either quinine-catalyzed allylation or isothiourea-catalyzed acylation has been developed, allowing the preparation of a wide range of vicinal-axis heterobiaryls in good yields with excellent enantioselectivities. Atropisomerization experiments revealed that the C−C bond rotation led to diastereomers, and the N−N bond rotation offered enantiomers. Besides, this protocol could be extended to kinetic resolution by employing substrates with a more hindered axis.

Subject areas: Chemistry, Chemical reaction engineering, Catalysis, Organic chemistry

Graphical abstract

Highlights

•
Heterobiaryls with vicinal C−C and N−N diaxes
•
Dynamic kinetic resolution
•
Wide range of substrates, good yields and excellent enantioselectivities

Chemistry; Chemical reaction engineering; Catalysis; Organic chemistry

Introduction

Atropisomeric biaryls arising from axially restricted aryl−aryl bond rotation are known for their wide prevalence in natural products, organocatalysts, chiral ligands, pharmaceuticals, and functional materials.¹^,²^,³^,⁴^,⁵ The past decades have witnessed significant progress in the preparation of atropisomeric biaryls with a single stereogenic axis.⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹ Atropisomers bearing vicinal diaxes are particularly intriguing for materials sciences, as they mainly exist in o-triaryls (Figure 1A).¹² Nevertheless, the concerted rotation of 1,2-diaxes poses a daunting challenge to enantiocontrol.¹³ To date, only a few successful catalytic asymmetric methods have been reported to access o-triaryls, which include the de novo construction of (hetero)arenes,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰ the central-to-axial chirality conversion,²¹ and the atroposelective C−H activation.²²^,²³^,²⁴ Although one can certainly design an o-triaryl atropisomer by merging two readily available biaryls, it is hard to imagine an atropisomeric biaryl with vicinal diaxes. To make that possible, the key is to find a suitable nonbiaryl system that can be merged. However, under equal conditions, the lower rotation barrier induced by the deplanarization renders a less stable conformer of nonbiaryls.²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰ This is the case in the pioneering contributions of the groups of Hsung building chiral ortho-disubstituted N,O-biaryls by combining the C−C and C−N axial chirality.³¹ Later, the preparation of 1,2-diaxially chiral biaryl benzamides had been achieved by Tanaka.³² More recently, the He group accomplished the synthesis of diaxially chiral B,N-heterobiaryls bearing vicinal C−B and C−N axes via a stepwise asymmetric allylic substitution-isomerization strategy.³³ Although these creative studies showcased the concept of biaryl atropisomers with vicinal diaxes, the catalytic atroposelective synthesis is still in its infancy and developing new structural types is highly desirable yet challenging.

Enantioselective synthesis of atropisomers with vicinal diaxes

(A–C) (A) Vicinal-diaxis systems; (B) N-N Axial chirality in nonbiaryls; (C) This work.

The N−N bond is ubiquitous in natural products and bioactive compounds,³³^,³⁴^,³⁵ while its atropisomerism has been largely overlooked. Although the first consideration of N−N atropisomers can be traced back to 1931,³⁶ catalytic asymmetric synthesis has not been reported until recently.³⁷^,³⁸ With the appropriate bulkiness and electronic properties, N−N heterobiaryls can be atropisomeric in analogy to C−C biaryls (Figure 1B). In this context, enantioselective synthetic approaches to access structurally diverse indole-pyrrole, indole-carbazole, bispyrrole, and bisindole atropisomers with an N−N axis has been reported by Liu, Shi and others.³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹ More importantly, nitrogen atom can assume a stable planar geometry beyond the aromatic ring since the unpaired electrons could conjugate with a carbonyl group. As a result, N−N axial chirality can be found in nonbiaryl systems. The seminal work came from the Lu group, in which they accomplished the asymmetric synthesis of N−N atropisomeric 1-aminopyrroles and 3-aminoquinazolinones.⁵⁰^,⁵¹^,⁵² Furthermore, Bencivenni et al. described the catalytic stereoselective synthesis of hydrazides containing a rotationally stable N–N axis by a sequential catalysis protocol.⁵³ Inspired by these impressive achievements, we envision that a biaryl atropisomer bearing vicinal C−C and N−N diaxes is feasible and with a suitable synthetic strategy its asymmetric synthesis can be achieved.

Dynamic kinetic resolution (DKR) represents a particularly appealing strategy for the synthesis of atropisomers from preformed racemic biaryls.⁷^,⁵⁴ The dynamics of atropisomers well conform to the requirement of DKR for the racemization of starting materials during reaction process. Consequently, DKR has been exploited with success in preparing various biaryls with a single stereogenic axis.⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴ However, when it comes to multi-axis systems, especially the vicinal-axis system, the stereocontrol is problematic. To our knowledge, the Miller group has successfully achieved the DKR of configurationally labile axes for atropisomerically enriched two-axis systems.¹³^,⁶⁵^,⁶⁶ DKR of racemic biaryls with a configurationally stable axis remains challenging and elusive. Our group has a continuous interest in developing effective methods to access structurally important axially chiral compounds.²⁸^,⁵²^,⁶⁷ Along this line, we envision that the enantioselective synthesis of vicinal-axis atropisomers could be enabled by DKR (Figure 1C). However, an effective DKR should fit the following criterions: (1) the catalyst must precisely discriminate the two enantiomers of starting material (v₂>v₃); (2) the enantioselective transformation must be slower than the racemization of the starting materials but faster than the racemization of the products (v₁>v₂>v₄/v₆ or v₅/v₇).

To address these issues, herein, we report in detail the catalytic atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes via DKR (Figure 1C). Notably, this DKR reaction can be enabled by either quinine-catalyzed allylation or isothiourea-catalyzed acylation, allowing the formation of vicinal-axis biaryls 3 and 5 in good yields and with excellent enantioselectivities. Not only are the products a new addition to atropisomeric biaryls with vicinal diaxes, but the protocol enriches the DKR strategy in atroposelective synthesis.

Results

The rational design of starting materials is crucial for an effective DKR. In our recent work on atroposelective synthesis of axially chiral C2-arylpyrrole-derived amino alcohols,⁶⁷ we found that heterobiaryl 1a possesses an atropoisomeric C–C bond which can rotate dynamically at room temperature (see the supplemental information for HPLC analysis on a chiral stationary phase). Considering that the N-functionalization could introduce sufficient rotation constraint for C–C and N–N bonds, 1a was chosen as our model substrate for our development of DKR. Asymmetric allylation of 1a with the Morita–Baylis–Hillman (MBH) adduct 2a in the presence of various quinolines was examined (Scheme 1) and the results are summarized in Table 1. To our delight, the DKR of 1a occurred under the catalysis of C1 in CH₂Cl₂ at room temperature, delivering the desired vicinal-axis product 3a as diastereoisomers in a moderate yield (entry 1). The screening of catalysts indicated that C4 was the best choice in terms of yield and stereoselectivity (entry 4). The solvent effect was then examined. Although toluene could increase the ee value, the yield decreased significantly (entry 7). Acetonitrile and tetrahydrofuran failed to afford enhancements (entries 8 & 9). At −20°C, the product 3a was obtained in a good enantioselectivity, however, the yield and the diastereoselectivity declined (entry 10).

Table 1.

Reaction optimization

Entry	Cat.	Solvent	Yield (%)	dr	ee (%)
1	C1	CH₂Cl₂	53	1.7:1	85/84
2	C2	CH₂Cl₂	32	2.5:1	86/83
3	C3	CH₂Cl₂	96	2.6:1	74/74
4	C4	CH₂Cl₂	94	3.2:1	86/80
5	C5	CH₂Cl₂	33	2.8:1	78/75
6	C6	CH₂Cl₂	67	2.7:1	75/75
7	C4	toluene	10	1.3:1	90/86
8	C4	CH₃CN	84	2.4:1	72/66
9	C4	THF	77	2.4:1	69/66
10^a	C4	CH₂Cl₂	50	1.6:1	90/89

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Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), and Cat. (10 mol %) in the solvent specified (1 mL) at RT for 12 h; Yields refer to isolated yields; The ee values were determined by HPLC analysis on a chiral stationary phase; The dr ratios were determined by ¹H NMR.

Performed at −20°C.

Further improvements were achieved by utilizing various MBH carbonates with different ester moieties (Scheme 2). The results implied that the steric effect had some influence on the enantio-control (Table 2). Changing the small methyl group (2a) to the sterically bulky groups such as ethyl (2b), benzyl (2c), and n-butyl (2d) resulted in enhanced enantioselectivities (entries 2−4). Notably, with the employment of t-butyl MBH carbonate (2e), the allylation product 3e was obtained in 96% yield with 2.8:1 dr and 95%/93% ee (entry 5).

Table 2.

Further optimization by screening MBH carbonates

Entry	R/2	3	Yield (%)	dr	ee (%)
1	Me (2a)	3a	94	3.2:1	86/80
2	Et (2b)	3b	95	3.2:1	93/91
3	Bn (2c)	3c	93	3:1	93/91
4	ⁿBu (2d)	3d	94	2.8:1	94/92
5	^tBu (2e)	3e	96	2.8:1	95/93

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Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), and C4 (10 mol %) in CH₂Cl₂ (1 mL) at RT for 12 h; Yields refer to isolated yields; The ee values were determined by HPLC analysis on a chiral stationary phase; The dr ratios were determined by ¹H NMR.

With the best conditions established, the generality of the substrate was studied. As shown in Figure 2, this N-alkylation enabled DKR protocol was applicable to a broad range of racemic heterobiaryls 1. Firstly, the N-protecting group (−CO₂R⁴) could be varied, giving the consistently good yields and excellent enantioselectivities (3f−i). Among them, the bulky fluorenylmethyl ester group led to a higher diastereoselectivity (3h). The tolerance of the ester group far from the central axis (−CO₂R²) was also investigated, while almost no influence on the reaction was observed (3j−m). The ester group −CO₂R¹ was supposed to have an impact on the C–C bond rotation. However, the small methyl group (3n) and sterically bulky propyl groups (3o and 3p) gave the similar good results. Different R³ group (3q−t) at the pyrrole ring were also well tolerated. In addition to the excellent yields and ee values, n-propyl (3r) and benzyl (3t) afforded the increased diastereoselectivities. Next, a variety of heterobiaryls 1 bearing different substituents at the naphthyl ring were employed. From the excellent yields and ee values of the products 3u−3b′, it seems that both the electronic nature and the patterns of the substituents have little effect on the reaction efficiency and stereoselectivity. Remarkably, substrates with 5,7-dimethyl naphthyl group (3c′) or anthranyl group (3d′) were also compatible with this reaction.

Substrate scope for allylation

Reaction conditions: 1a (0.1 mmol), 2e (0.15 mmol), and C4 (10 mol %) in CH₂Cl₂ (1 mL) at RT for 12 h; Yields refer to isolated yields; The ee values were determined by HPLC analysis on a chiral stationary phase; The dr ratios were determined by ¹H NMR.

Encouraged by the success of N-allylation, we preliminarily attempted other asymmetric N-functionalization reactions for this DKR protocol (see the supplemental information for details). We were pleased to discover that the DKR of heterobiaryls 1 could also be achieved by the isothiourea-catalyzed acylation. As shown in Figure 3, under the catalysis of chiral isothiourea C7 in CH₂Cl₂ at room temperature, racemic 1e reacted with cinnamic anhydride 4a in a DKR manner, delivering the corresponding vicinal-diaxis product 5a in moderate enantioselectivity. The subsequent reaction optimization revealed that the chiral isothiourea C9 was the best catalyst, affording the correspond product in 95% yield with 1.3:1 dr and 90%/90% ee values. With the best conditions in hand, the substrate scope of this catalytic asymmetric acylation had been investigated (Figure 4). Remarkably, in all the substrates tested, the asymmetric DKR reaction took place smoothly, affording the corresponding vicinal-diaxis heterobiaryls 5a−5l in good yields with excellent enantioselectivities.

DKR via acylation

Reaction conditions: 1e (0.1 mmol), 4a (0.15 mmol), and the **Cat.** (0.01 mmol) in CH₂Cl₂ (1 mL) at 0°C for 12 h. Isolated yields. The dr and ee values were determined by HPLC analysis on a chiral stationary phase.

Substrate scope for acylation

Reaction conditions: 1 (0.1 mmol), 4a (0.15 mmol), and the C9 (0.01 mmol) in CH₂Cl₂ (1 mL) at 0°C for 12 h. Isolated yields. The dr and ee values were determined by HPLC analysis on a chiral stationary phase.

Furthermore, the atropisomerization of 3b′ was conducted to investigate the configurational stability, which showed that the C–C and N–N axes are of different rotational barriers (Figure 5A). Rotation over the lower-barrier axis determines the dr value and that of the higher-barrier axis determines the ee value. The two diastereomers (R,S)-3b′ and (S,S)-3b′ are separable, and their interconversion over the C–C bond could be readily observed at the ambient temperature. Given the difference of the two diastereomers in structural stability, their energy barriers for interconversion should be slightly different. This analysis is consistent with experiments that complete erosion of dr values of the major isomer (R,S)-3b′ to equilibrium, requiring 24.0 kcal/mol, while that of the minor isomer (S,S)-3b′ only needs 23.5 kcal/mol. On the other hand, the racemization over the both axes occurs at about 130°C. The rotation barrier is determined to be 31.8 kcal/mol, which is similar to that 31.2 kcal/mol of compound 6 with a single N–N axis (Figure 5B). Thus, the rotation over the N–N axis dominates the atropisomerization of 3b′. In addition, the rotational barrier on the C-C bond of substrate 1f was calculated to be 22.9 kcal/mol, so, there was a slight increase in the energy of the C-C bond after reaction. Substrate 7 with a Bn-protected naphthol motif caused a higher rotation barrier (32.8 kcal/mol). The rotational energy barrier of 7 was so high that it does not racemate at room temperature and results in a kinetic resolution. To verify this hypothesis, hereobiaryl 7 was employed (Figure 5C). Under similar conditions, the catalytic asymmetric allylation occurred smoothly in a kinetic resolution manner. The corresponding vicinal-diaxis compound 8 was obtained in 46% yield with 7.7:1 dr and 92%/94% ee values, and the compound 7 was recovered in 43% yield and with 90% ee. In terms of the high s-factor (s = 95) achieved, this kinetic resolution is synthetically useful and will be fully investigated in the future. Finally, kinetic experiments were performed to shed light on the mechanism. As shown in Figure 5D, the dr value of the product underwent a reversal over time, and the ee value of the substrate 1b′ always remained at a low level. At the beginning, the dr and ee values of the product were very high, indicating that the enantioselectivity was set under kinetic control. However, the dr value decreased over reaction time, and even reversed finally (from 1:10 to 1.9:1). So, the final dr was set under thermodynamic control.

Atropisomerization and kinetic resolution

(A–D) (A) Racemization experiments; (B) Rotational energy barriers; (C) Kinetic resolution; (D) Mechanism considerations. After 4.5 h, **1b′** was fully consumed, the de value was determined by HPLC.

Discussion

In conclusion, we have established a highly efficient DKR protocol for the atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes. Atropisomers bearing vicinal diaxes mainly exist in o-triaryls, vicinal-diaxis biaryls has traditionally been regarded as challenging structural motifs. By using this protocol, a wide range of vicinal-axis heterobiaryls were readily prepared in good yields with excellent enantioselectivities under mild conditions. Notably, this dynamic kinetic resolution reaction can be enabled by either quinine-catalyzed allylation or isothiourea-catalyzed acylation. Atropisomerization experiments revealed that the C−C bond rotation led to diastereomers, while that of N−N bond of enantiomers. Besides, this protocol could be extended to kinetic resolution by employing substrates with a more hindered axis. Further investigation along this line is ongoing, and will be reported in due course.

Limitations of the study

The diastereoselectivities are relatively low, which can be attributed to the low rotational barrier at the C-C stereogenic axis in the products. The limited configurational stability at the C-C axes may hinder the practical application of the obtained products.

STAR★Methods

Key resources table

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Deposited data

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Resource availability

Lead contact

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Guang-Jian Mei (meigj@zzu.edu.cn).

Materials availability

All other data supporting the findings of this study are available within the article and the supplemental information or from the lead contact upon reasonable request.

Methods details

General procedures for asymmetric allylation

Racemic axial chiral compound 1 (0.10 mmol), MBH carbonic ester 2e (0.15 mmol) were dissolved in CH₂Cl₂ (1 mL), and C4 (10 mol %) were added. The reaction mixture was stirred for 12 h at room temperature. The solvent was removed in vacuo and the crude product was separated by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1–2:1) to afford the product 3.

(R,S)-Diethyl 1-((ethoxycarbonyl)(2-(methoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3a

A colorless oil; 50.4 mg; isolated yield = 94%; dr = 3.2:1. [α]^31.0_D = +7.00 (c 0.20, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 14.65 min (major), t₂ = 40.56 min (minor), ee = 86%; minor product: t₁ = 18.11 min (major), t₂ = 34.12 min (minor), ee = 80%; ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.59 (m, 3H), 7.60–7.30 (m, 4H), 6.27–5.62 (m, 1H), 5.36–5.16 (m, 1H), 4.46–4.22 (m, 4H), 4.22–3.67 (m, 4H), 3.66–3.49 (m, 3H), 2.30–2.20 (m, 3H), 1.42–1.20 (m, 6H), 0.74–0.56 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 164.5, 164.3, 154.8, 136.4, 133.8, 133.5, 133.3, 132.9, 131.9, 130.9, 130.2, 129.7, 128.4, 128.3, 127.0, 126.7, 126.1, 126.1, 125.4, 125.0, 115.7, 110.7, 63.4, 60.4, 60.2, 52.0, 51.0, 14.7, 14.3, 13.3, 10.5. HRMS (ESI) m/z calcd for C₂₉H₃₂N₂O₈Na⁺ [M + Na]⁺ = 559.2051, found = 559.2053.

(R,S)-Diethyl 1-((ethoxycarbonyl)(2-(ethoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3b

A colorless oil; 52.3 mg; isolated yield = 95%; dr = 3.2:1. [α]^31.4_D = −19.33 (c 0.30, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 13.07 min (major), t₂ = 33.40 min (minor), ee = 93%; minor product: t₁ = 15.20 min (major), t₂ = 25.06 min (minor), ee = 91%; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.62 (m, 3H), 7.61–7.32 (m, 4H), 6.20–5.72 (m, 1H), 5.39–5.17 (m, 1H), 4.43–4.23 (m, 4H), 4.20–3.96 (m, 3H), 3.96–3.40 (m, 3H), 2.31–2.20 (m, 3H), 1.42–1.08 (m, 9H), 0.78–0.44 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 164.5, 164.3, 154.8, 136.5, 134.1, 133.7, 133.5, 132.9, 131.9, 130.7, 130.6, 130.2, 129.7, 128.4, 128.3, 127.0, 126.7, 126.2, 126.1, 125.4, 125.1, 115.7, 110.6, 63.3, 61.0, 60.4, 60.2, 51.0, 14.7, 14.3, 14.0, 13.3, 10.6. HRMS (ESI) m/z calcd for C₃₀H₃₄N₂O₈Na⁺ [M + Na]⁺ = 573.2207, found = 573.2210.

(R,S)-Diethyl 1-((2-((benzyloxy)carbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3c

A colorless oil; 56.9 mg; isolated yield = 93%; dr = 3.0:1. [α]^31.5_D = −59.20 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.28 min (major), t₂ = 27.54 min (minor), ee = 93%; minor product: t₁ = 13.07 min (major), t₂ = 20.61 min (minor), ee = 91%; ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.82 (m, 2H), 7.74–7.56 (m, 1H), 7.56–7.25 (m, 9H), 6.23–5.98 (m, 1H), 5.43–4.85 (m, 3H), 4.48–4.21 (m, 4H), 4.17–3.33 (m, 4H), 2.36–2.07 (m, 3H), 1.43–1.05 (m, 6H), 0.78–0.48 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.0, 164.5, 164.3, 154.8, 136.5, 135.4, 133.5, 133.4, 132.9, 131.9, 131.3, 130.2, 129.7, 128.6, 128.6, 128.4, 128.3, 127.0, 126.7, 126.1, 126.1, 125.4, 125.0, 124.7, 115.7, 110.7, 66.8, 63.4, 60.4, 60.2, 51.0, 14.7, 14.3, 13.3, 10.5. HRMS (ESI) m/z calcd for C₃₅H₃₆N₂O₈Na⁺ [M + Na]⁺ = 635.2364, found = 635.2369.

(R,S)-Diethyl 1-((2-(butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3d

A colorless oil; 54.3 mg; isolated yield = 94%; dr = 2.8:1. [α]²⁵_D = −41.75 (c 0.40, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.60 min (major), t₂ = 27.15 min (minor), ee = 94%; minor product: t₁ = 12.93 min (major), t₂ = 19.85 min (minor), ee = 92%; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.62 (m, 3H), 7.59–7.32 (m, 4H), 6.25–5.68 (m, 1H), 5.37–5.15 (m, 1H), 4.45–4.25 (m, 4H), 4.19–3.36 (m, 6H), 2.31–2.20 (m, 3H), 1.65–1.44 (m, 2H), 1.40–1.15 (m, 8H), 0.95–0.90 (m, 3H), 0.78–0.48 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 164.5, 164.3, 154.8, 136.6, 134.1, 133.6, 133.5, 132.9, 131.8, 130.7, 130.2, 129.7, 128.4, 128.3, 127.0, 126.7, 126.2, 125.4, 125.1, 115.7, 110.6, 64.9, 63.3, 60.4, 60.2, 51.0, 30.4, 19.1, 14.7, 14.3, 13.7, 13.3, 10.6. HRMS (ESI) m/z calcd for C₃₂H₃₈N₂O₈Na⁺ [M + Na]⁺ = 601.2520, found = 601.2522.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3e

A colorless oil; 55.5 mg; isolated yield = 96%; dr = 2.8:1. [α]^31.1_D = −49.71 (c 0.35, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 21.74 min (major), t₂ = 32.15 min (minor), ee = 95%; minor product: t₁ = 16.05 min (major), t₂ = 17.42 min (minor), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.61 (m, 3H), 7.59–7.32 (m, 4H), 6.27–5.61 (m, 1H), 5.42–5.09 (m, 1H), 4.54–4.26 (m, 4H), 4.18–3.08 (m, 4H), 2.44–2.14 (m, 3H), 1.47–1.39 (m, 9H), 1.38–1.20 (m, 6H), 0.85–0.44 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.5, 164.3, 154.7, 137.0, 135.5, 134.9, 133.5, 132.9, 131.7, 130.2, 130.1, 129.8, 128.4, 128.3, 127.1, 126.7, 126.2, 125.4, 125.1, 115.7, 110.4, 81.4, 63.3, 60.4, 60.2, 50.9, 27.9, 14.8, 14.3, 13.3, 10.7. HRMS (ESI) m/z calcd for C₃₂H₃₈N₂O₈Na⁺ [M + Na]⁺ = 601.2520, found = 601.2530.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(methoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3f

A colorless oil; 50.1 mg; isolated yield = 89%; dr = 2.7:1. [α]^31.4_D = −42.67 (c 0.45, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 21.74 min (major), t₂ = 32.15 min (minor), ee = 95%; minor product: t₁ = 16.05 min (major), t₂ = 17.42 min (minor), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.59 (m, 3H), 7.58–7.28 (m, 4H), 6.18–5.92 (m, 1H), 5.46–5.10 (m, 1H), 4.59–4.18 (m, 3H), 4.11–3.11 (m, 6H), 2.36–2.16 (m, 3H), 1.48–1.38 (m, 9H), 1.37–1.33 (m, 3H), 0.74–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.5, 164.3, 155.3, 136.9, 134.9, 133.5, 133.4, 132.9, 131.6, 130.3, 130.1, 129.8, 128.4, 128.2, 127.0, 126.7, 126.2, 126.0, 125.4, 125.2, 124.6, 115.8, 110.5, 81.5, 60.4, 60.2, 54.1, 51.0, 27.9, 14.3, 13.3, 10.7. HRMS (ESI) m/z calcd for C₃₁H₃₆N₂O₈Na⁺ [M + Na]⁺ = 587.2364, found = 587.2369.

(R,S)-Diethyl 1-(((benzyloxy)carbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3g

A colorless oil; 55.5 mg; isolated yield = 91%; dr = 3.0:1. [α]^31.6_D = −38.25 (c 0.40 CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 12.87 min (major), t₂ = 16.93 min (minor), ee = 94%; minor product: t₁ = 9.29 min (major), t₂ = 10.97 min (minor), ee = 94%; ¹H NMR (400 MHz, CDCl₃) δ 8.00–7.56 (m, 3H), 7.52–6.85 (m, 9H), 6.15–5.89 (m, 1H), 5.49–4.64 (m, 3H), 4.53–3.04 (m, 6H), 2.32–2.23 (m, 3H), 1.55–1.29 (m, 12H), 0.72–0.56 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.4, 164.2, 154.6, 136.9, 135.3, 134.9, 133.4, 132.8, 131.9, 130.2, 130.0, 129.6, 129.1, 128.8, 128.7, 128.9, 128.6, 128.5, 128.5, 128.4, 128.0, 126.8, 126.6, 126.1, 125.4, 125.1, 124.6, 115.7, 110.6, 81.4, 68.7, 60.4, 60.1, 51.0, 27.8, 14.3, 13.3, 10.7. HRMS (ESI) m/z calcd for C₃₇H₄₀N₂O₈Na⁺ [M + Na]⁺ = 633.2677, found = 633.2672.

(R,S)-Diethyl 1-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3h

A colorless oil; 69.2 mg; isolated yield = 95%; dr = 4.5:1. [α]^31.8_D = +30.71 (c 0.28, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 23.83 min (major), t₂ = 31.33 min (minor), ee = 92%; minor product: t₁ = 18.75 min (major), t₂ = 22.28 min (minor), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 7.93–7.62 (m, 5H), 7.58–7.26 (m, 9H), 7.22–6.55 (m, 1H), 6.20–5.73 (m, 1H), 5.53–4.84 (m, 1H), 4.78–4.06 (m, 6H), 3.97–3.01 (m, 3H), 2.33–1.91 (m, 3H), 1.50–1.29 (m, 12H), 0.77–0.54 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.4, 164.2, 164.2, 154.4, 143.2, 143.0, 141.6, 141.4, 136.8, 134.7, 133.3, 132.8, 131.3, 130.2, 129.5, 128.5, 128.4, 128.1, 127.9, 127.2, 127.1, 126.8, 126.6, 126.0, 125.2, 125.2, 124.5, 124.2, 120.5, 120.3, 115.8, 110.2, 81.4, 68.8, 60.2, 60.0, 50.6, 46.7, 27.9, 14.4, 13.4, 10.3. HRMS (ESI) m/z calcd for C₄₄H₄₄N₂O₈Na⁺ [M + Na]⁺ = 751.2990, found = 751.2982.

(R,S)-Diethyl 1-((tert-butoxycarbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3i

A colorless oil; 57.6 mg; isolated yield = 95%; dr = 2.6:1. [α]^31.6_D = −16.18 (c 0.34, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 20.67 min (major), t₂ = 22.65 min (minor), ee = 96%; minor product: t₁ = 12.94 min (major), t₂ = 13.56 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.66 (m, 3H), 7.61–7.34 (m, 4H), 6.27–5.72 (m, 1H), 5.42–4.94 (m, 1H), 4.48–3.10 (m, 6H), 2.32 (s, 3H), 1.55–1.43 (m, 9H), 1.42–1.29 (m, 12H), 0.67–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 164.3, 153.3, 137.2, 136.8, 135.5, 135.1, 133.5, 133.4, 133.0, 132.0, 129.8, 129.7, 129.6, 128.9, 128.5, 128.4, 127.4, 126.6, 126.1, 126.0, 125.5, 125.0, 124.9, 115.4, 110.2, 82.8, 81.3, 60.3, 60.1, 50.3, 28.2, 27.9, 14.3, 13.3, 10.7. HRMS (ESI) m/z calcd for C₃₄H₄₂N₂O₈Na⁺ [M + Na]⁺ = 629.2833, found = 629.2837.

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-2-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3j

A colorless oil; 53.6 mg; isolated yield = 95%; dr = 2.7:1. [α]^30.8_D = −32.00 (c 0.50 CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 15.13 min (major), t₂ = 26.82 min (minor), ee = 96%; minor product: t₁ = 11.29 min (major), t₂ = 13.48 min (minor), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.60 (m, 3H), 7.57–7.32 (m, 4H), 6.16–5.90 (m, 1H), 5.43–5.09 (m, 1H), 4.60–4.00 (m, 3H), 4.00–3.11 (m, 6H), 2.38–2.20 (m, 3H), 1.45–1.41 (m, 9H), 1.35–1.19 (m, 3H), 0.72–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 164.5, 164.2, 154.7, 137.1, 135.5, 134.9, 133.5, 132.9, 132.0, 130.2, 130.1, 129.8, 128.5, 128.3, 127.1, 126.7, 126.2, 125.4, 125.1, 115.5, 110.2, 81.4, 63.3, 60.2, 51.5, 50.8, 27.9, 14.7, 13.3, 10.7. HRMS (ESI) m/z calcd for C₃₁H₃₆N₂O₈Na⁺ [M + Na]⁺ = 587.2364, found = 587.2363.

(R,S)-3-benzyl 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3k

A colorless oil; 56.3 mg; isolated yield = 88%; dr = 2.8:1. [α]^31.9_D = +17.00 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 10.21 min (major), t₂ = 34.60 min (minor), ee = 98%; minor product: t₁ = 8.99 min (major), t₂ = 14.28 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.61 (m, 3H), 7.59–7.27 (m, 9H), 6.15–5.90 (m, 1H), 5.47–5.05 (m, 3H), 4.50–3.13 (m, 6H), 2.32–2.31 (m, 3H), 1.44–1.37 (m, 9H), 1.35–1.18 (m, 3H), 0.63–0.49 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.4, 164.3, 154.7, 137.5, 136.2, 135.5, 134.9, 133.5, 132.8, 131.6, 130.2, 130.2, 129.8, 128.4, 128.4, 128.0, 126.9, 126.7, 126.2, 125.4, 125.1, 116.0, 110.0, 81.4, 66.4, 63.3, 60.2, 50.9, 27.9, 14.8, 13.2, 10.8. HRMS (ESI) m/z calcd for C₃₇H₄₀N₂O₈Na⁺ [M + Na]⁺ = 663.2677, found = 663.2672.

(R,S)-3-allyl 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3l

A colorless oil; 55.5 mg; isolated yield = 94%; dr = 4.0:1. [α]^30.8_D = +25.88 (c 0.34 CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 23.83 min (major), t₂ = 34.54 min (minor), ee = 97%; minor product: t₁ = 16.41 min (major), t₂ = 17.77 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.61 (m, 3H), 7.59–7.30 (m, 4H), 6.23–5.73 (m, 2H), 5.53–4.98 (m, 3H), 4.79–4.78 (m, 2H), 4.48–3.16 (m, 6H), 2.33–2.32 (m, 3H), 1.45–1.41 (m, 9H), 1.36–1.19 (m, 3H), 0.73–0.58 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.3, 164.2, 154.7, 137.3, 135.5, 134.9, 133.5, 132.9, 132.5, 131.8, 130.2, 130.1, 129.8, 128.5, 128.3, 127.0, 126.7, 126.2, 125.4, 125.1, 118.0, 115.8, 110.0, 81.4, 65.2, 63.3, 60.3, 50.8, 27.9, 14.8, 13.3, 10.8. HRMS (ESI) m/z calcd for C₃₃H₃₈N₂O₈Na⁺ [M + Na]⁺ = 613.2520, found = 613.2522.

(R,S)-3-(tert-butyl) 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3m

A colorless oil; 54.5 mg; isolated yield = 90%; dr = 2.3:1. [α]^31.6_D = −46.67 (c 0.48 CH₂Cl₂; HPLC (IE column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.77 min (major), t₂ = 28.54 min (minor), ee = 95%; minor product: t₁ = 10.11 min (major), t₂ = 10.86 min (minor), ee = 91%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.62 (m, 3H), 7.62–7.30 (m, 4H), 6.16–5.89 (m, 1H), 5.41–5.08 (m, 1H), 4.46–3.83 (m, 4H), 3.81–3.25 (m, 2H), 2.31–2.30 (m, 3H), 1.60–1.54 (m, 9H), 1.45–1.41 (m, 9H), 1.37–1.19 (m, 3H), 0.72–0.47 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.5, 163.7, 154.8, 136.5, 135.6, 134.9, 133.5, 133.4, 132.9, 131.2, 130.1, 129.9, 129.6, 128.4, 128.3, 127.2, 126.6, 126.1, 126.0, 125.9, 125.5, 125.1, 124.6, 116.0, 111.7, 81.4, 80.7, 63.2, 60.1, 50.9, 28.2, 27.9, 14.8, 13.3, 10.6. HRMS (ESI) m/z calcd for C₃₄H₄₂N₂O₈Na⁺ [M + Na]⁺ = 629.2833, found = 629.2835.

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3n

A colorless oil; 54.1 mg; isolated yield = 96%; dr = 2.6:1. [α]^31.7_D = −33.78 (c 0.45, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 15.78 min (major), t₂ = 28.43 min (minor), ee = 99%; minor product: t₁ = 11.03 min (major), t₂ = 18.67 min (minor), ee = 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.61 (m, 3H), 7.59–7.32 (m, 4H), 6.14–5.89 (m, 1H), 5.40–5.06 (m, 1H), 4.47–4.24 (m, 4H), 4.23–3.18 (m, 5H), 2.33–2.31 (m, 3H), 1.44–1.41 (m, 9H), 1.38–1.19 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 164.5, 164.4, 154.7, 137.1, 135.5, 134.9, 133.5, 133.5, 132.7, 131.6, 130.1, 129.9, 128.5, 128.4, 126.7, 126.2, 125.2, 125.1, 115.5, 110.2, 81.4, 63.3, 63.0, 60.3, 51.6, 27.9, 14.7, 14.3, 10.7. HRMS (ESI) m/z calcd for C₃₁H₃₆N₂O₈Na⁺ [M + Na]⁺ = 587.2364, found = 587.2368.

(R,S)-3-ethyl 4-propyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3o

A colorless oil; 57.2 mg; isolated yield = 97%; dr = 2.6:1. [α]^31.7_D = −38.37 (c 0.43, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 13.06 min (major), t₂ = 18.69 min (minor), ee = 95%; minor product: t₁ = 10.11 min (major), t₂ = 10.74 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.63 (m, 3H), 7.58–7.33 (m, 4H), 6.24–5.84 (m, 1H), 5.42–5.07 (m, 1H), 4.46–4.25 (m, 4H), 4.24–3.20 (m, 4H), 2.32–2.31 (m, 3H), 1.45–1.41 (m, 9H), 1.37–1.32 (m, 5H), 1.23–1.19 (m, 3H), 0.45–0.32 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 164.4, 154.7, 136.8, 135.6, 134.9, 133.5, 132.9, 131.6, 130.1, 130.0, 129.8, 128.4, 128.3, 127.1, 126.7, 126.2, 125.4, 125.1, 115.7, 110.6, 81.4, 66.0, 63.2, 60.4, 50.9, 27.9, 21.3, 14.8, 14.3, 10.7, 10.0. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2684.

(R,S)-3-ethyl 4-isopropyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3p

A colorless oil; 54.5 mg; isolated yield = 92%; dr = 2.8:1. [α]^31.6_D = −35.31 (c 0.32, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 14.22 min (major), t₂ = 20.54 min (minor), ee = 97%; minor product: t₁ = 11.03 min (major), t₂ = 18.67 min (minor), ee = 97%; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.62 (m, 3H), 7.60–7.31 (m, 4H), 6.17–5.91 (m, 1H), 5.43–5.10 (m, 1H), 4.77–4.64 (m, 1H), 4.53–3.21 (m, 6H), 2.32–2.31 (m, 3H), 1.45–1.41 (m, 9H), 1.39–1.17 (m, 6H), 0.81–0.36 (m, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 163.7, 154.7, 136.9, 135.6, 135.0, 133.5, 133.0, 131.6, 130.1, 129.9, 129.6, 128.8, 128.3, 127.3, 126.1, 125.6, 125.0, 116.1, 110.4, 81.4, 67.5, 63.2, 60.4, 50.9, 27.9, 21.3, 20.7, 14.8, 14.2, 10.7. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2676.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-ethyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3q

A colorless oil; 56.8 mg; isolated yield = 96%; dr = 2.7:1. [α]^31.2_D = −17.81 (c 0.32, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.14 min (major), t₂ = 14.10 min (minor), ee = 97%; minor product: t₁ = 9.09 min (major), t₂ = 9.54 min (minor), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 8.00–7.64 (m, 3H), 7.63–7.30 (m, 4H), 6.13–5.84 (m, 1H), 5.33–5.00 (m, 1H), 4.55–4.26 (m, 4H), 4.22–3.26 (m, 4H), 2.93–2.45 (m, 2H), 1.49–1.38 (m, 9H), 1.39–1.14 (m, 9H), 0.69–0.58 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.4, 164.4, 164.3, 155.1, 142.0, 134.9, 133.5, 133.1, 132.6, 131.5, 130.1, 129.8, 129.5, 129.2, 128.4, 128.4, 127.2, 126.7, 126.2, 125.8, 125.4, 125.0, 116.0, 110.2, 81.3, 63.3, 60.4, 60.2, 51.4, 27.9, 18.3, 14.6, 14.2, 13.4, 13.3. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2680.

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(naphthalen-1-yl)-5-propyl-1H-pyrrole-3,4-dicarboxylate: 3r

A colorless oil; 55.1 mg; isolated yield = 93%; dr = 4:1. [α]^31.1_D = −49.00 (c 0.30, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 21.99 min (major), t₂ = 41.20 min (minor), ee = 92%; minor product: t₁ = 19.64 min (minor), t₂ = 24.37 min (major), ee = 92%; ¹H NMR (400 MHz, CDCl₃) δ7.92–7.83 (m, 2H), 7.75–7.66 (m, 1H), 7.65–7.33 (m, 4H), 6.26–5.72 (m, 1H), 5.28–4.97 (m, 1H), 4.59–4.08 (m, 3H), 3.96–3.75 (m, 5H), 3.72–3.33 (m, 1H), 2.92–2.30 (m, 2H), 1.66–1.59 (m, 2H), 1.47–1.40 (m, 9H), 1.37–1.12 (m, 3H), 0.99–0.95 (m, 3H), 0.67–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 164.4, 164.3, 155.1, 140.7, 134.8, 133.4, 133.1, 132.0, 130.0, 129.8, 129.1, 128.9, 128.4, 128.3, 127.2, 126.8, 126.2, 125.3, 125.0, 115.6, 110.4, 81.3, 63.3, 60.2, 51.6, 27.9, 26.9, 22.4, 14.6, 14.4, 13.3. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2685.

(R,S)-4-ethyl 3-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-butyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3s

A colorless oil; 52.1 mg; isolated yield = 86%; dr = 2.8:1. [α]^31.7_D = −27.33 (c 0.30, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 20.38 min (major), t₂ = 35.83 min (minor), ee = 97%; minor product: t₁ = 17.76 min (minor), t₂ = 22.78 min (major), ee = 98%; ¹H NMR (400 MHz, CDCl₃) δ 7.99–7.64 (m, 3H), 7.60–7.31 (m, 4H), 6.12–5.80 (m, 1H), 5.28–4.94 (m, 1H), 4.50–3.96 (m, 3H), 3.93–3.74 (m, 5H), 3.67–3.33 (m, 1H), 3.03–2.34 (m, 2H), 1.67–1.53 (m, 2H), 1.49–1.33 (m, 12H), 1.17–0.81 (m, 5H), 0.67–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 164.4, 164.3, 155.1, 140.9, 135.4, 134.8, 133.4, 133.2, 133.0, 132.0, 130.1, 129.8, 129.0, 128.4, 128.4, 127.2, 126.7, 126.1, 125.3, 125.0, 115.7, 110.3, 81.3, 63.3, 60.2, 51.7, 51.5, 31.1, 27.9, 24.8, 22.9, 14.6, 13.8, 13.3. HRMS (ESI) m/z calcd for C₃₄H₄₂N₂O₈Na⁺ [M + Na]⁺ = 629.2833, found = 629.2841.

(R,S)-4-ethyl 3-methyl 2-benzyl-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3t

A colorless oil; 61.4 mg; isolated yield = 96%; dr = 4:1. [α]^31.6_D = −24.32 (c 0.37, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.22 min (major), t₂ = 17.52 min (minor), ee = 95%; minor product: t₁ = 10.38 min (major), t₂ = 12.28 min (minor), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.62 (m, 3H), 7.59–7.32 (m, 4H), 7.31–7.13 (m, 5H), 6.15–5.56 (m, 1H), 5.36–4.58 (m, 1H), 4.47–4.11 (m, 2H), 4.06–3.65 (m, 7H), 3.57–3.23 (m, 2H), 1.48–1.31 (m, 9H), 1.05–0.77 (m, 3H), 0.68–0.49 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 164.5, 163.9, 154.7, 137.7, 137.4, 135.4, 134.8, 133.4, 133.2, 130.1, 129.9, 129.5, 128.4, 128.4, 128.3, 127.1, 126.8, 126.4, 126.2, 125.3, 124.9, 115.3, 112.1, 81.4, 63.0, 60.2, 51.7, 51.4, 30.6, 27.9, 14.2, 13.3. HRMS (ESI) m/z calcd for C₃₇H₄₀N₂O₈Na⁺ [M + Na]⁺ = 663.2677, found = 663.2675.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(4-fluoronaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3u

A colorless oil; 48.9 mg; isolated yield = 82%; dr = 2.3:1. [α]^31.2_D = −32.67 (c 0.30, CH₂Cl₂); HPLC (IE column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.51 min (major), t₂ = 19.94 min (minor), ee = 97%; minor product: t₁ = 9.02 min (major), t₂ = 9.95 min (minor), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 8.16–8.11 (m, 1H), 7.88–7.61 (m, 1H), 7.60–7.28 (m, 3H), 7.19–7.14 (m, 1H), 6.18–5.89 (m, 1H), 5.45–5.08 (m, 1H), 4.43–4.22 (m, 4H), 4.00–3.31 (m, 4H), 2.31 (s, 3H), 1.45–1.41 (m, 9H), 1.38–1.23 (m, 6H), 0.79–0.65 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.4, 164.4, 164.3, 160.7, 158.2 (J = 250 Hz), 154.7, 136.9, 135.6, 135.0, 134.5, 134.4, 131.0, 129.9, 128.5, 128.4, 127.6, 126.6, 125.6, 125.5, 123.1, 121.0, 120.9, 120.7 (J = 25 Hz), 115.9, 110.6, 109.1, 108.9, 81.5, 63.3, 60.4, 60.3, 51.0, 27.9, 14.8, 14.3, 13.4, 10.7. ¹⁹F NMR (376 MHz, CDCl₃) δ −119.93, −119.97, −120.39. HRMS (ESI) m/z calcd for C₃₂H₃₇N₂O₈FNa⁺ [M + Na]⁺ = 619.2426, found = 619.2430.

(R,S)-Diethyl 2-(4-bromonaphthalen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3v

A colorless oil; 60.4 mg; isolated yield = 92%; dr = 2.3:1. [α]^31.7_D = −9.72 (c 0.36, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 10.90 min (major), t₂ = 28.45 min (minor), ee = 96%; minor product: t₁ = 11.79 min (major), t₂ = 17.65 min (minor), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 8.31–8.26 (m, 1H), 7.84–7.80 (m, 2H), 7.70–7.15 (m, 3H), 6.61–5.89 (m, 1H), 5.44–5.09 (m, 1H), 4.48–4.25 (m, 4H), 4.20–3.15 (m, 4H), 2.31 (s, 3H), 1.45–1.41 (m, 9H), 1.37–1.29 (m, 6H), 0.86–0.53 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.4, 164.3, 164.1, 154.6, 137.0, 135.6, 135.0, 134.0, 132.0, 130.8, 130.3, 130.1, 129.3, 128.9, 128.5, 127.7, 127.5, 127.2, 126.1, 124.9, 115.9, 110.7, 81.5, 63.4, 60.3, 60.3, 51.0, 27.9, 14.8, 14.3, 13.4, 10.7. HRMS (ESI) m/z calcd for C₃₂H₃₇N₂O₈BrNa⁺ [M + Na]⁺ = 679.1625, found = 679.1628.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(4-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3w

A colorless oil; 57.4 mg; isolated yield = 97%; dr = 2.3:1. [α]^31.3_D = −39.50 (c 0.40, CH₂Cl₂); HPLC (ID column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 15.40 min (major), t₂ = 26.04 min (minor), ee = 94%; minor product: t₁ = 12.25 min (major), t₂ = 31.14 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ 8.04–7.98 (m, 1H), 7.86–7.59 (m, 1H), 7.57–7.21 (m, 4H), 6.16–5.92 (m, 1H), 5.44–5.12 (m, 1H), 4.57–4.22 (m, 4H), 4.20–3.05 (m, 4H), 2.73 (s, 3H), 2.46–2.16 (m, 3H), 1.45–1.42 (m, 9H), 1.38–1.19 (m, 6H), 0.79–0.62 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 164.5, 154.7, 136.9, 136.3, 135.6, 135.0, 132.8, 132.7, 132.0, 130.3, 129.8, 128.1, 126.2, 126.0, 126.0, 125.5, 125.2, 124.6, 124.2, 115.7, 110.2, 81.4, 63.2, 60.3, 60.2, 50.8, 27.9, 19.7, 14.8, 14.3, 13.4, 10.7. dr = 2.3:1. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2677.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(4-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3x

A colorless oil; 58.4 mg; isolated yield = 96%; dr = 2.7:1. [α]^31.6_D = −22.08 (c 0.48, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 12.16 min (major), t₂ = 24.36 min (minor), ee = 97%; minor product: t₁ = 15.18 min (major), t₂ = 17.40 min (minor), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 8.39–8.06 (m, 1H), 7.83–7.56 (m, 1H), 7.51–7.19 (m, 3H), 6.83–6.81 (m, 1H), 6.18–5.93 (m, 1H), 5.47–5.14 (m, 1H), 4.55–4.23 (m, 4H), 4.04 (s, 3H), 3.98–3.04 (m, 4H), 2.31–2.30 (m, 3H), 1.45–1.42 (m, 9H), 1.37–1.29 (m, 6H), 0.88–0.55 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 164.5, 156.4, 154.8, 136.8, 135.6, 135.0, 133.8, 132.7, 131.8, 130.5, 130.4, 128.8, 127.1, 126.3, 125.8, 125.5, 125.4, 125.3, 125.2, 122.4, 122.0, 118.8, 115.8, 110.1, 103.2, 81.4, 63.2, 60.3, 60.2, 55.6, 50.8, 27.9, 14.8, 14.3, 13.5, 10.7. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₉Na⁺ [M + Na]⁺ = 631.2626, found = 631.2629.

(R,S)-Diethyl 2-(5-bromonaphthalen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3y

A colorless oil; 59.0 mg; isolated yield = 90%; dr = 2.3:1. [α]^31.3_D = −21.88 (c 0.48, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 30.69 min (major), t₂ = 76.70 min (minor), ee = 93%; minor product: t₁ = 28.75 min (major), t₂ = 76.70 min (minor), ee = 87%; ¹H NMR (400 MHz, CDCl₃) δ 8.37–8.35 (m, 1H), 7.85–7.39 (m, 4H), 7.34–7.16 (m, 1H), 6.30–5.72 (m, 1H), 5.44–5.05 (m, 1H), 4.53–4.23 (m, 4H), 4.20–3.09 (m, 4H), 2.31 (s, 3H), 1.45–1.41 (m, 9H), 1.37–1.26 (m, 6H), 0.78–0.65 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.4, 164.3, 164.2, 154.6, 136.9, 135.0, 134.2, 132.0, 131.2, 131.1, 130.4, 129.9, 129.3, 129.0, 127.7, 126.5, 125.6, 123.3, 115.8, 110.6, 81.5, 63.4, 60.4, 60.3, 51.0, 27.9, 14.8, 14.3, 13.4, 10.7. HRMS (ESI) m/z calcd for C₃₂H₃₇N₂O₈BrNa⁺ [M + Na]⁺ = 679.1625, found = 679.1622.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(6-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3z

A colorless oil; 58.4 mg; isolated yield = 96%; dr = 2.6:1. [α]^31.4_D = −7.81 (c 0.32, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 23.66 min (major), t₂ = 57.86 min (minor), ee = 94%; minor product: t₁ = 20.25 min (major), t₂ = 30.16 min (minor), ee = 96%; ¹H NMR (400 MHz, CDCl₃) δ7.81–7.79 (m, 1H), 7.73–7.49 (m, 1H), 7.45–7.19 (m, 2H), 7.16–7.00 (m, 2H) 6.16–5.90 (m, 1H), 5.42–5.07 (m, 1H), 4.51–4.22 (m, 4H), 4.18–3.16 (m, 7H), 2.40–2.12 (m, 3H), 1.45–1.41 (m, 9H), 1.37–1.28 (m, 6H), 0.77–0.66 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.5, 164.5, 164.4, 157.7, 154.8, 136.9, 135.5, 134.9, 134.8, 131.8, 130.1, 128.6, 128.3, 127.8, 127.0, 126.9, 126.0, 125.8, 125.3, 119.5, 118.8, 115.6, 110.3, 106.1, 81.4, 63.2, 60.4, 60.2, 55.3, 50.9, 27.9, 14.8, 14.3, 13.4, 10.7. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₉Na⁺ [M + Na]⁺ = 631.2626, found = 631.2635.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(7-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3a′

A colorless oil; 54.5 mg; isolated yield = 92%; dr = 2.6:1. [α]^31.3_D = +63.75 (c 0.40, CH₂Cl₂); HPLC (IF column, i-propanol/n-hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 34.27 min (minor), t₂ = 49.31 min (major), ee = 93%; minor product: t₁ = 24.28 min (major), t₂ = 43.71 min (minor), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.93–7.54 (m, 4H), 7.46–7.32 (m, 2H), 6.07–6.06 (m, 1H), 5.36–5.27 (m, 1H), 4.59–4.24 (m, 5H), 4.16–4.06 (m, 2H), 3.69–3.35 (m, 1H), 2.53–2.52 (m, 3H), 2.32–2.30 (m, 3H), 1.40 (s, 9H), 1.39–1.29 (m, 6H), 1.17–0.98 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.4, 164.5, 164.3, 154.9, 137.2, 136.9, 136.8, 136.3, 135.0, 133.4, 132.7, 131.3, 131.2, 129.2, 129.1, 128.8, 128.1, 127.6, 126.8, 126.7, 125.6, 114.9, 110.0, 81.5, 63.3, 60.8, 60.2, 50.3, 27.8, 21.8, 14.9, 14.3, 14.0, 10.7. HRMS (ESI) m/z calcd for C₃₃H₄₀N₂O₈Na⁺ [M + Na]⁺ = 615.2677, found = 615.2672.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(7-chloronaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3b′

A colorless oil; 54.5 mg; isolated yield = 89%; dr = 2.3:1. [α]^31.0_D = −57.71 (c 0.35, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 10.80 min (major), t₂ = 25.94 min (minor), ee = 90%; minor product: t₁ = 8.47 min (major), t₂ = 14.80 min (minor), ee = 92%; ¹H NMR (400 MHz, CDCl₃) δ7.90–7.88 (m, 1H), 7.85–7.62 (m, 2H), 7.63–7.34 (m, 3H), 6.19–5.93 (m, 1H), 5.42–5.09 (m, 1H), 4.48–4.26 (m, 4H), 4.22–3.11 (m, 4H), 2.33–2.31 (m, 3H), 1.45–1.42 (m, 9H), 1.40–1.24 (m, 6H), 0.79–0.74 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.7, 164.4, 164.4, 154.7, 137.1, 135.5, 134.9, 133.6, 132.9, 132.3, 131.7, 131.3, 130.8, 130.4, 130.2, 130.1, 129.9, 129.8, 129.6, 129.5, 127.3, 127.2, 126.6, 125.4, 125.0, 124.4, 116.0, 110.5, 81.6, 63.3, 60.4, 60.3, 51.0, 27.9, 14.8, 14.3, 13.4, 10.7. HRMS (ESI) m/z calcd for C₃₂H₃₇N₂O₈ClNa⁺ [M + Na]⁺ = 635.2131, found = 635.2129.

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(3,7-dimethylnaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3c′

A colorless oil; 57.0 mg; isolated yield = 94%; dr = 4.0:1. [α]^31.0_D = −72.25 (c 0.40, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.99 min (major), t₂ = 27.75 min (minor), ee = 97%; minor product: t₁ = 10.85 min (major), t₂ = 16.64 min (minor), ee = 92%; ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.62 (m, 2H), 7.48 (s, 1H), 7.36–7.12 (m, 2H), 6.23–5.82 (m, 1H), 5.29–5.14 (m, 1H), 4.55–4.26 (m, 4H), 4.25–3.09 (m, 4H), 2.47–2.46 (m, 3H), 2.42–2.40 (m, 3H), 2.35–2.27 (m, 3H), 1.48–1.39 (m, 9H), 1.38–1.29 (m, 6H), 0.81–0.60 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.60, 164.5, 154.8, 137.3, 137.1, 135.5, 135.3, 135.1, 133.6, 133.6, 132.5, 132.1, 132.0, 131.8, 131.2, 130.9, 130.6, 130.3, 130.2, 129.7, 128.7, 128.6, 128.4, 127.7, 127.6, 127.3, 126.0, 124.0, 115.7, 110.1, 81.4, 63.2, 60.3, 60.2, 50.8, 27.9, 21.8, 21.5, 14.9, 14.3, 13.4, 10.7. HRMS (ESI) m/z calcd for C₃₄H₄₂N₂O₈Na⁺ [M + Na]⁺ = 629.2833, found = 629.2834.

(R,S)-Diethyl 2-(anthracen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3d′

A colorless oil; 60.3 mg; isolated yield = 96%; dr = 2.3:1. [α]^31.3_D = −86.22 (c 0.45, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 11.65 min (major), t₂ = 30.67 min (minor), ee = 95%; minor product: t₁ = 10.29 min (major), t₂ = 15.51 min (minor), ee = 94%; ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.16 (m, 2H), 8.16–7.80 (m, 3H), 7.65–7.34 (m, 4H), 6.16–5.85 (m, 1H), 5.41–5.07 (m, 1H), 4.50–4.24 (m, 4H), 4.24–3.09 (m, 4H), 2.37–2.36 (m, 3H), 1.46–1.44 (m, 3H), 1.42–1.11 (m, 12H), 0.79–0.42 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.6, 164.5, 164.4, 154.8, 137.1, 135.0, 132.0, 131.7, 131.5, 130.9, 130.1, 130.0, 128.4, 128.2, 128.0, 127.2, 127.0, 125.9, 125.9, 125.7, 124.5, 124.1, 116.0, 110.4, 81.4, 63.3, 60.4, 60.2, 50.9, 27.8, 14.8, 14.3, 13.4, 10.8. HRMS (ESI) m/z calcd for C₃₆H₄₀N₂O₈Na⁺ [M + Na]⁺ = 651.2677, found = 651.2684.

General procedures for asymmetric acylation

Racemic axial chiral compound 1 (0.10 mmol), cinnamic anhydride 4a (0.15 mmol) were dissolved in CH₂Cl₂ (1 mL), and C9 (10 mol %) was added. The reaction mixture was stirred for 12 h at 0°C. The solvent was removed in vacuo and the crude product was separated by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1–2:1) to afford the product 5.

(S)-Diethyl 1-(N-(tert-butoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5a

A colorless oil; 56.6 mg; isolated yield = 95%; dr = 1.3:1. [α]^20.0_D = −80.01 (c 0.55, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 31.00 min (minor), t₂ = 36.52 min (major), ee = 90%; minor product: t₁ = 10.87 min (major), t₂ = 22.25 min (minor), ee = 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.86–6.43 (m, 14H), 4.31–3.96 (m, 2H), 3.65–3.56 (m, 2H), 2.17–2.16 (m, 3H), 1.30 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 0.96 (s, 6H), 0.42–0.33 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.8, 164.6, 164.6, 164.3, 150.0, 147.0, 136.1, 134.3, 133.3, 133.1, 132.9, 130.9, 129.6, 128.9, 128.8, 128.7, 128.6, 128.3, 128.0, 126.7, 126.5, 126.1, 125.9, 125.0, 117.9, 115.5, 111.1, 86.0, 60.4, 60.1, 27.4, 14.3, 13.3, 10.3. HRMS (ESI) m/z calcd for C₃₅H₃₇N₂O₇⁺ [M + H]⁺ = 597.2595, found = 597.2587.

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5b

A colorless oil; 52.3 mg; isolated yield = 92%; dr = 2.3:1. [α]^20.0_D = −51.20 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 25.735 min (minor), t₂ = 28.659 min (major), ee = 84%; minor product: t₁ = 12.086 min (major), t₂ = 17.613 min (minor), ee = 91%; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.49 (m, 5H), 7.48–6.78 (m, 9H), 4.56–3.56 (m, 6H), 2.38–2.21 (m, 3H), 1.39–1.35 (m, 4H), 1.04–1.00 (m, 2H), 0.66–0.58 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 164.6, 164.3, 164.2, 151.7, 147.6, 136.0, 134.2, 133.4, 133.1, 132.9, 131.0, 129.7, 129.0, 128.6, 128.4, 128.1, 126.5, 126.1, 126.0, 125.0, 117.2, 115.7, 111.2, 64.5, 60.4, 60.1, 14.3, 13.7, 13.3, 10.3. HRMS (ESI) m/z calcd for C₃₃H₃₃N₂O₇⁺ [M + H]⁺ = 569.2282, found = 569.2277.

(S)-Diethyl 1-(N-((benzyloxy)carbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5c

A colorless oil; 59.2 mg; isolated yield = 94%; dr = 1.7:1. [α]^20.0_D = −73.10 (c 0.55, CH₂Cl₂); HPLC (ID column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 15.874 min (minor), t₂ = 25.353 min (major), ee = 68%; minor product: t₁ = 19.745 min (minor), t₂ = 69.702 min (major), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 8.07–7.51 (m, 4H), 7.50–6.71 (m, 15H), 5.36–4.61 (m, 2H), 4.50–4.20 (m, 2H), 4.08–3.59 (m, 2H), 2.30–2.28 (m, 3H), 1.39–1.35 (m, 3H), 0.63–0.57 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 164.5, 164.2, 164.1, 151.6, 147.8, 136.0, 134.1, 133.9, 133.6, 133.4, 132.9, 131.1, 129.8, 129.1, 128.9, 128.9, 128.8, 128.6, 128.5, 128.0, 127.7, 126.5, 126.3, 126.1, 126.0, 124.9, 117.1, 115.7, 111.5, 69.5, 60.4, 60.1, 14.3, 13.3, 10.3. HRMS (ESI) m/z calcd for C₃₈H₃₅N₂O₇⁺ [M + H]⁺ = 631.2439, found = 631.2440.

(S)-3-Benzyl 4-ethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5d

A colorless oil; 56.7 mg; isolated yield = 90%; dr = 2.3:1. [α]^20.0_D = −54.00 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 26.903 min (minor), t₂ = 37.429 min (major), ee = 95%; minor product: t₁ = 13.964 min (major), t₂ = 19.710 min (minor), ee = 84%; ¹H NMR (400 MHz, CDCl₃) δ 7.93–6.85 (m, 19H), 5.35 (s, 2H), 4.55–3.56 (m, 4H), 2.38–2.37 (m, 3H), 1.37–0.99 (m, 3H), 0.57–0.59 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 164.3, 164.3, 164.2, 151.7, 147.7, 136.5, 136.3, 134.2, 133.4, 133.1, 132.9, 131.1, 129.8, 129.0, 128.6, 128.5, 128.4, 128.0, 127.7, 126.5, 126.4, 126.1, 126.0, 125.0, 117.2, 115.9, 110.7, 66.4, 64.5, 60.1, 13.7, 13.3, 10.4. HRMS (ESI) m/z calcd for C₃₈H₃₅N₂O₇⁺ [M + H]⁺ = 631.2439, found = 631.2426.

(S)-3-Ethyl 4-methyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5e

A colorless oil; 54.3 mg; isolated yield = 98%; dr = 1.3:1. [α]^20.0_D = −85.61 (c 0.50, CH₂Cl₂); HPLC (IF column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 18.255 min (minor), t₂ = 33.880 min (major), ee = 97%; minor product: t₁ = 12.078 min (minor), t₂ = 13.395 min (major), ee = 93%; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.49 (m, 5H), 7.49–6.80 (m, 9H), 4.57–3.61 (m, 4H), 3.44–3.41 (m, 3H), 2.39–2.38 (m, 3H), 1.39–1.34 (m, 4H), 1.04–1.00 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 165.0, 164.5, 164.3, 151.6, 147.7, 136.2, 134.2, 133.4, 133.0, 132.7, 131.0, 129.9, 129.0, 128.8, 128.6, 128.4, 128.2, 127.8, 126.4, 126.2, 126.0, 125.9, 125.0, 117.2, 115.4, 111.1, 64.5, 60.4, 51.5, 14.3, 13.7, 10.3. HRMS (ESI) m/z calcd for C₃₂H₃₁N₂O₇⁺ [M + H]⁺ = 555.2126, found = 555.2119.

(S)-3-Ethyl 4-isopropyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5f

A colorless oil; 56.0 mg; isolated yield = 96%; dr = 1.5:1. [α]^20.0_D = −109.63 (c 0.53, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 10.810 min (major), t₂ = 14.810 min (minor), ee = 90%; minor product: t₁ = 16.521 min (major), t₂ = 27.272 min (minor), ee = 98%; ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.49 (m, 5H), 7.48–6.86 (m, 9H), 4.85–4.54 (m, 1H), 4.50–3.67 (m, 4H), 2.38–2.37 (m, 3H), 1.39–1.36 (m, 4H), 1.05–1.01 (m, 2H), 0.73–0.65 (m, 3H), 0.59–0.45 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 164.6, 164.3, 163.6, 151.7, 147.6, 135.9, 134.2, 133.3, 133.2, 133.0, 133.0, 131.0, 129.6, 128.9, 128.6, 128.4, 128.0, 126.7, 126.7, 126.3, 125.9, 124.9, 117.2, 116.1, 111.2, 67.3, 64.5, 60.4, 21.3, 20.7, 14.3, 13.7, 10.2. HRMS (ESI) m/z calcd for C₃₄H₃₅N₂O₇⁺ [M + H]⁺ = 583.2439, found = 583.2439.

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-ethyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5g

A colorless oil; 50.1 mg; isolated yield = 86%; dr = 1.2:1. [α]^20.0_D = −79.32 (c 0.50, CH₂Cl₂); HPLC (IF column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 9.443 min (minor), t₂ = 11.384 min (major), ee = 93%; minor product: t₁ = 12.997 min (minor), t₂ = 24.180 min (major), ee = 95%; ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.50 (m, 5H), 7.47–6.83 (m, 9H), 4.53–3.53 (m, 6H), 2.97–2.53 (m, 2H), 1.39–1.35 (m, 4H), 1.24–0.94 (m, 5H), 0.65–0.56 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 164.4, 164.3, 164.3, 151.9, 147.6, 141.1, 134.2, 133.4, 132.9, 132.9, 131.0, 129.7, 129.0, 128.8, 128.6, 128.4, 128.1, 127.6, 126.7, 126.5, 126.2, 125.9, 125.0, 117.3, 115.9, 110.9, 64.4, 60.4, 60.1, 18.4, 14.3, 13.6, 13.4, 13.3. HRMS (ESI) m/z calcd for C₃₄H₃₅N₂O₇⁺ [M + H]⁺ = 583.2439, found = 583.2429.

(S)-3-Ethyl 4-methyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-(naphthalen-1-yl)-5-propyl-1H-pyrrole-3,4-dicarboxylate: 5h

A colorless oil; 51.8 mg; isolated yield = 89%; dr = 1.4:1. [α]^20.0_D = −63.52 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 15.843 min (major), t₂ = 20.782 min (minor), ee = 96%; minor product: t₁ = 10.11 min (major), t₂ = 10.74 min (minor), ee = 94%; ¹H NMR (400 MHz, CDCl₃) δ 8.05–7.50 (m, 5H), 7.49–6.85 (m, 9H), 4.43–3.53 (m, 7H), 2.97–2.45 (m, 2H), 1.72–1.32 (m, 3H), 1.00–0.96 (m, 5H), 0.63–0.55 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 165.0, 164.3, 164.2, 151.8, 147.7, 139.8, 134.2, 133.4, 132.9, 131.0, 129.8, 129.0, 128.6, 128.4, 128.1, 126.6, 126.5, 126.2, 125.9, 125.0, 117.2, 115.6, 111.2, 64.4, 60.1, 51.6, 26.8, 22.2, 14.2, 13.6, 13.3. HRMS (ESI) m/z calcd for C₃₄H₃₅N₂O₇⁺ [M + H]⁺ = 583.2439, found = 583.2429.

(S)-4-Ethyl 3-methyl 2-benzyl-1-(N-(ethoxycarbonyl)cinnamamido)-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5i

A colorless oil; 52.9 mg; isolated yield = 84%; dr = 1.1:1. [α]^20.0_D = −79.10 (c 0.55, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 9.738 min (major), t₂ = 14.429 min (minor), ee = 91%; minor product: t₁ = 22.438 min (major), t₂ = 28.628 min (minor), ee = 98%; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.49 (m, 5H), 7.49–6.70 (m, 14H), 4.66–4.52 (m, 1H), 3.91 (s, 3H), 3.90–2.99 (m, 5H), 1.12–1.08 (m, 1H), 0.71–0.41 (m, 5H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 165.1, 164.3, 164.0, 151.3, 147.7, 137.4, 136.9, 134.3, 134.1, 133.3, 132.7, 131.0, 129.7, 129.0, 128.7, 128.5, 128.1, 126.6, 126.4, 126.2, 126.0, 125.9, 117.3, 115.5, 112.2, 64.2, 60.2, 51.8, 31.0, 13.2, 13.1. HRMS (ESI) m/z calcd for C₃₈H₃₅N₂O₇⁺ [M + H]⁺ = 631.2439, found = 631.2433.

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(4-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5j

A colorless oil; 57.0 mg; isolated yield = 98%; dr = 1.1:1. [α]^20.0_D = −111.01 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 13.074 min (major), t₂ = 26.493 min (minor), ee = 85%; minor product: t₁ = 21.433 min (minor), t₂ = 40.600 min (major), ee = 94%; ¹H NMR (400 MHz, CDCl₃) δ 8.04–7.49 (m, 4H), 7.49–6.85 (m, 9H), 4.60–3.66 (m, 6H), 2.66 (s, 3H), 2.38–2.37 (m, 3H), 1.39–1.35 (m, 4H), 1.05–1.01 (m, 2H), 0.71–0.63 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 165.1, 164.3, 164.0, 151.3, 147.7, 137.4, 136.9, 134.3, 134.1, 133.3, 132.7, 131.0, 129.7, 129.0, 128.7, 128.5, 128.1, 126.6, 126.4, 126.2, 126.0, 125.9, 124.9, 117.3, 115.5, 112.2, 64.2, 60.2, 51.8, 31.0, 13.9, 13.3, 13.2, 13.1. HRMS (ESI) m/z calcd for C₃₄H₃₅N₂O₇⁺ [M + H]⁺ = 583.2439, found = 583.2441.

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-(4-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 5k

A colorless oil; 55.0 mg; isolated yield = 92%; dr = 1.1:1. [α]^20.0_D = −83.81 (c 0.50, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 19.525 min (minor), t₂ = 40.537 min (major), ee = 97%; minor product: t₁ = 12.895 min (major), t₂ = 24.465 min (minor), ee = 91%; ¹H NMR (400 MHz, CDCl₃) δ 8.32–7.96 (m, 1H), 7.85–7.43 (m, 3H), 7.40–6.99 (m, 8H), 6.92–6.55 (m, 1H), 4.38–3.56 (m, 9H), 2.30–2.29 (m, 3H), 1.31–1.27 (m, 4H), 0.97–0.93 (m, 2H), 0.63–0.58 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 164.6, 164.4, 164.3, 156.4, 151.8, 147.5, 135.8, 134.2, 133.8, 133.3, 131.0, 129.3, 129.0, 128.6, 128.4, 126.7, 126.4, 125.9, 125.4, 125.2, 122.0, 118.3, 117.3, 115.8, 111.0, 103.0, 64.4, 60.4, 60.1, 55.5, 14.3, 13.7, 13.5, 10.3. HRMS (ESI) m/z calcd for C₃₄H₃₅N₂O₈⁺ [M + H]⁺ = 599.2388, found = 599.2388.

(S)-Diethyl 2-(3,7-dimethylnaphthalen-1-yl)-1-(N-(ethoxycarbonyl)cinnamamido)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 5l

A colorless oil; 55.4 mg; isolated yield = 93%; dr = 1.3:1. [α]^20.0_D = −95.41 (c 0.50, CH₂Cl₂); HPLC (IF column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 6.500 min (major), t₂ = 7.417 min (minor), ee = 86%; minor product: t₁ = 9.564 min (minor), t₂ = 26.629 min (minor), ee = 97%; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.49 (m, 4H), 7.49–6.74 (m, 8H), 4.61–3.57 (m, 6H), 2.45–2.39 (m, 6H), 2.31–2.30 (m, 3H), 1.39–1.32 (m, 4H), 1.00–0.97 (m, 2H), 0.71–0.65 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 164.7, 164.5, 164.3, 151.7, 147.4, 136.1, 134.6, 134.2, 133.4, 133.3, 132.0, 131.2, 131.0, 130.9, 129.0, 128.9, 128.6, 128.4, 128.2, 125.6, 125.1, 124.6, 117.4, 115.6, 111.1, 64.3, 60.4, 60.1, 21.8, 21.4, 14.3, 13.6, 13.4, 10.3. HRMS (ESI) m/z calcd for C₃₅H₃₇N₂O₇⁺ [M + H]⁺ = 597.2595, found = 597.2603.

General procedure for asymmetric synthesis of compound 6

Compound 1e' (0.10 mmol), MBH carbonic ester 2e (0.15 mmol) were dissolved in DCM (1 mL), and C3 (10 mol %) were added. The reaction mixture was stirred for 6 h at room temperature. The solvent was removed in vacuo and the crude product was separated by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1–2:1) to afford the product 6. A colorless solid; 52.0 mg; isolated yield = 90%; m.p. 72.2°C–72.8°C; [α]²⁰_D = +51.34 (c 0.025, THF); HPLC (IC column, i-propanol/n-hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), product: t₁ = 9.22 min (minor), t₂ = 11.05 min (major), ee = 97%; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.77 (m, 4H), 7.56–7.48 (m, 2H), 7.46–7.33 (m, 1H), 6.13–6.01 (m, 1H), 5.43–5.23 (m, 1H), 4.55–4.37 (m, 1H), 4.34–4.22 (m, 2H), 4.11–3.94 (m, 2H), 3.93–3.84 (m, 3H), 3.63–3.41 (m, 1H), 2.37–2.24 (m, 3H), 1.55–1.43 (m, 2H), 1.39 (s, 9H), 1.36–1.28 (m, 3H), 0.70–0.51 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.4, 164.4, 164.2, 155.9, 155.4, 137.1, 136.7, 135.0, 134.7, 133.2, 133.0, 132.5, 131.4, 129.5, 128.7, 128.6, 128.5, 128.3, 128.3, 128.1, 127.8, 127.2, 127.1, 126.9, 126.8, 126.6, 126.6, 126.5, 125.7, 115.2, 110.2, 81.6, 68.2, 66.5, 66.4, 62.9, 60.3, 60.2, 54.3, 54.1, 51.2, 50.5, 27.8, 21.8, 21.4, 20.9, 19.2, 18.9, 14.3, 14.0, 13.5, 10.7, 10.2, 9.9; HRMS (ESI) m/z calcd for C₃₂H₃₈N₂O₈Na⁺ [M+Na]⁺ = 601.2520, found = 601.2525.

General procedure for kinetic resolution of 7

Racemic axial chiral compound 7 (0.2 mmol), MBH carbonic ester 2e (0.1 mmol) were dissolved in DCM (10 mL), and C3 (10 mol %) was added. The reaction mixture was stirred for 24 h at room temperature. The solvent was removed in vacuo and the crude product was separated by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the product 8 and recover compound 7.

(S)-Diethyl 2-(2-(benzyloxy)naphthalen-1-yl)-1-((tert-butoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 7

A colorless oil; 49.2 mg; isolated yield = 43%; [α]^32.6_D = +187.36 (c 0.30, CH₂Cl₂); HPLC (IC column, i-propanol/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm), product: t₁ = 8.06 min (minor), t₂ = 14.24 min (major), ee = 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 9.0 Hz, 1H), 7.74 (s, 2H), 7.40–7.28 (m, 6H), 7.23–7.17 (m, 2H), 7.00–6.89 (m, 1H), 5.21–5.08 (m, 2H), 4.45–4.15 (m, 2H), 3.99–3.55 (m, 2H), 2.45 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 0.91 (s, 9H), 0.57 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 164.8, 164.4, 154.1, 153.9, 137.2, 136.5, 134.1, 131.2, 129.6, 128.7, 128.2, 127.4, 126.8, 124.5, 116.2, 115.1, 110.5, 82.0, 72.9, 60.2, 59.9, 27.3, 14.3, 13.3, 10.5; HRMS (ESI) m/z calcd for C₃₃H₃₇N₂O₇⁺ [M + H]⁺ = 573.2595, found = 573.2590.

(R,R)-Diethyl 2-(2-(benzyloxy)naphthalen-1-yl)-1-((tert-butoxycarbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 8

A colorless oil; 65.5 mg; isolated yield = 46%; dr = 7.7:1. [α]^20.0_D = −98.00 (c 0.30, CH₂Cl₂); HPLC (IC column, i-propanol/n-hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm), major product: t₁ = 6.26 min (minor), t₂ = 6.98 min (major), ee = 92%; minor product: t₁ = 5.74 min (major), t₂ = 7.84 min (minor), ee = 94%; ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.47 (m, 3H), 7.43–7.14 (m, 8H), 5.77–5.67 (m, 1H), 5.24–5.04 (m, 2H), 4.92–4.70 (m, 1H), 4.47–3.73 (m, 6H), 2.37–2.34 (m, 3H), 1.47–1.43 (m, 9H), 1.41–1.35 (m, 3H), 1.33–1.09 (m, 9H), 0.78–0.49 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.0, 164.8, 164.4, 155.6, 153.0, 136.9, 136.8, 134.9, 131.4, 130.0, 128.9, 128.5, 127.9, 127.6, 127.1, 126.6, 126.3, 124.0, 115.4, 114.7, 113.9, 110.5, 82.8, 81.1, 71.2, 60.2, 59.8, 50.8, 14.3, 13.4, 10.9. HRMS (ESI) m/z calcd for C₄₁H₄₉N₂O₉⁺ [M + H]⁺ = 713.3433, found = 713.3442.

Acknowledgments

Financial supports from National Natural Science Foundation of China (22371265 to G.-J. Mei, 22208302 to X. Xiao), Natural Science Foundation of Henan Province (222300420084 to G.-J. Mei), and Application Research Plan of Key Scientific Research Projects in Colleges and Universities of Henan Province (22A150056 to G.-J. Mei) are gratefully acknowledged.

Author contributions

T-J.H. and C-Y.G. performed and analyzed the experiments. R.D., X.X., and M-C.W. participated in the early development of the project. N.L. and L-P.X. performed the calculations. G-J.M. conceived and designed the project. G-J.M. overall supervised the project. All authors prepared this manuscript.

Declaration of interests

The authors declare no competing interests.

Published: September 20, 2023

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.isci.2023.107978.

Contributor Information

Min-Can Wang, Email: wangmincan@zzu.edu.cn.

Guang-Jian Mei, Email: meigj@zzu.edu.cn.

Supplemental information

Document S1. Figures S1–S3, Tables S1–S19, and Data S1–S6

mmc1.pdf^{(10.5MB, pdf)}

Data and code availability

•
All data reported in this paper will be shared by the lead contact upon request. The crystallographic, catalysts and catalysis are provided in supplemental information as referenced in the main text. All original crystal structures have been deposited at CCDC and are publicly available as of the date of publication. CCDC numbers are listed in the key resources table.
•
This paper does not report original code.
•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Figures S1–S3, Tables S1–S19, and Data S1–S6

mmc1.pdf^{(10.5MB, pdf)}

Data Availability Statement

•
All data reported in this paper will be shared by the lead contact upon request. The crystallographic, catalysts and catalysis are provided in supplemental information as referenced in the main text. All original crystal structures have been deposited at CCDC and are publicly available as of the date of publication. CCDC numbers are listed in the key resources table.
•
This paper does not report original code.
•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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PERMALINK

Catalytic atroposelective synthesis of heterobiaryls with vicinal C−C and N−N diaxes via dynamic kinetic resolution

Tian-Jiao Han

Chun-Yan Guan

Na Li

Rui Dong

Li-Ping Xu

Xiao Xiao

Min-Can Wang

Guang-Jian Mei

Summary

Graphical abstract

Highlights

Introduction

Figure 1.

Results

Scheme 1.

Table 1.

Scheme 2.

Table 2.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Discussion

Limitations of the study

STAR★Methods

Key resources table

Resource availability

Lead contact

Materials availability

Methods details

General procedures for asymmetric allylation

(R,S)-Diethyl 1-((ethoxycarbonyl)(2-(methoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3a

(R,S)-Diethyl 1-((ethoxycarbonyl)(2-(ethoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3b

(R,S)-Diethyl 1-((2-((benzyloxy)carbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3c

(R,S)-Diethyl 1-((2-(butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3d

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3e

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(methoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3f

(R,S)-Diethyl 1-(((benzyloxy)carbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3g

(R,S)-Diethyl 1-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3h

(R,S)-Diethyl 1-((tert-butoxycarbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3i

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-2-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3j

(R,S)-3-benzyl 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3k

(R,S)-3-allyl 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3l

(R,S)-3-(tert-butyl) 4-ethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3m

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3n

(R,S)-3-ethyl 4-propyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3o

(R,S)-3-ethyl 4-isopropyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3p

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-ethyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3q

(R,S)-3-ethyl 4-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(naphthalen-1-yl)-5-propyl-1H-pyrrole-3,4-dicarboxylate: 3r

(R,S)-4-ethyl 3-methyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-butyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3s

(R,S)-4-ethyl 3-methyl 2-benzyl-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3t

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(4-fluoronaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3u

(R,S)-Diethyl 2-(4-bromonaphthalen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3v

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(4-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3w

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(4-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3x

(R,S)-Diethyl 2-(5-bromonaphthalen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3y

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(6-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3z

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-methyl-5-(7-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 3a′

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(7-chloronaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3b′

(R,S)-Diethyl 1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-2-(3,7-dimethylnaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3c′

(R,S)-Diethyl 2-(anthracen-1-yl)-1-((2-(tert-butoxycarbonyl)allyl)(ethoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 3d′

General procedures for asymmetric acylation

(S)-Diethyl 1-(N-(tert-butoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5a

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5b

(S)-Diethyl 1-(N-((benzyloxy)carbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5c

(S)-3-Benzyl 4-ethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5d

(S)-3-Ethyl 4-methyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5e

(S)-3-Ethyl 4-isopropyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5f

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-ethyl-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5g

(S)-3-Ethyl 4-methyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-(naphthalen-1-yl)-5-propyl-1H-pyrrole-3,4-dicarboxylate: 5h

(S)-4-Ethyl 3-methyl 2-benzyl-1-(N-(ethoxycarbonyl)cinnamamido)-5-(naphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5i

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-methyl-5-(4-methylnaphthalen-1-yl)-1H-pyrrole-3,4-dicarboxylate: 5j

(S)-Diethyl 1-(N-(ethoxycarbonyl)cinnamamido)-2-(4-methoxynaphthalen-1-yl)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 5k

(S)-Diethyl 2-(3,7-dimethylnaphthalen-1-yl)-1-(N-(ethoxycarbonyl)cinnamamido)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 5l

General procedure for asymmetric synthesis of compound 6

General procedure for kinetic resolution of 7

(S)-Diethyl 2-(2-(benzyloxy)naphthalen-1-yl)-1-((tert-butoxycarbonyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 7

(R,R)-Diethyl 2-(2-(benzyloxy)naphthalen-1-yl)-1-((tert-butoxycarbonyl)(2-(tert-butoxycarbonyl)allyl)amino)-5-methyl-1H-pyrrole-3,4-dicarboxylate: 8