Direct, Enantioselective Synthesis of Pyrroloindolines and Indolines From Simple Indole Derivatives

Abstract

The (R)-BINOL•SnCl₄-catalyzed formal (3 + 2) cycloaddition between 3-substituted indoles and benzyl 2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,3'-dichloro-BINOL•SnCl₄ provides the corresponding pyrroloindolines with improved diastereoselectivity (typically ≥10:1). Guided by mechanistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent iminium ion is also described.

1. Introduction

Nitrogen-containing heterocycles, such as indolines¹ and pyrroloindolines,² are prevalent in a variety of natural products that exhibit an array of promising biological activities (see Figure 1 for representative examples).³ Many of these compounds possess all-carbon quaternary stereocenters at C3 of the indoline or pyrroloindoline, and the synthetic challenge presented by this structural feature has driven innovative research aimed at the discovery of new methods to stereoselectively prepare such heterocycles. These methods include several stereoselective transformations starting from tryptophan,⁴ as well as catalytic asymmetric reactions using both organo-⁵ and transition metal catalysts.⁶

Figure 1.

Indoline and pyrroloindoline containing natural products.

In 2010, our group reported an enantioselective synthesis of pyrroloindolines (8) via an (R)-BINOL•SnCl₄-catalyzed formal (3 + 2) cycloaddition between 3-substituted indoles (5) and benzyl 2-trifluoroacetamidoacrylate (6) (Scheme 1).⁷ Good yields, moderate exo/endo diastereoselectivity, and high enantioselectivities were obtained for a variety of indole substrates. Unexpectedly, studies aimed at epimerizing C2 revealed that exo-8 and endo-8 possess the opposite absolute configurations at the bridgehead carbons.

Scheme 1.

(R)-BINOL•SnCl₄-catalyzed pyrroloindoline formation.

Although further mechanistic studies are required, this observation led us to propose a cooperative Lewis acid/Lewis acid-assisted Brønsted acid (LBA) mechanism, shown in Scheme 2. Activation of acrylate 6 by coordination to SnCl₄ would result in reversible conjugate addition by the indole to generate a racemic mixture of Sn-enolates 9 and ent-9. Highly face-selective protonation of 9/ent-9 by an (R)-BINOL•SnCl₄ complex (11) would serve to resolve the two enantiomers into diastereomers in a rate- and stereoselectivity-determining step. In this scenario, the ee of the two pyrroloindoline products would reflect the facial selectivity of the protonation step, while the dr would reflect the difference in protonation rates for the two chiral enolates 9 and ent-9, due to matching and mismatching effects with chiral complex 11.⁸ The stoichiometric proton source required to turn over complex 12 could potentially be the N-H of trifluoroacetamide exo-13/ent-endo-13, which upon coordination to SnCl₄ would be rendered sufficiently acidic.

Scheme 2.

Proposed mechanism for pyrroloindoline formation.

The proposed mechanism is consistent with Yamamoto's prior reports that (R)-BINOL•SnCl₄(11) behaves as a Lewis acid-assisted Brønsted acid (LBA), which is capable of catalyzing the enantioselective protonation of silyl enolates.⁹ However, the pyrroloindoline formation described above constitutes the first example of a tandem conjugate addition/asymmetric protonation process catalyzed by 11. Based on our mechanistic proposal for pyrroloindoline formation, we recently identified similar conditions for the synthesis of unnatural tryptophan derivatives (18) from 2-substituted indoles (15) and methyl 2-acetamidoacrylate (16), in which the sole stereogenic center is set during an asymmetric protonation step (Scheme 3).¹⁰ This tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction provides direct access to a variety of tryptophan derivatives (18) without the need for pre-functionalization of the indole substrate.

Scheme 3.

17•SnCl₄-catalyzed conjugate addition/asymmetric protonation.

Returning to the enantioselective pyrroloindoline synthesis shown in Scheme 1, the fact that exo-8 and ent-endo-8 are of opposite enantiomeric series presents a practical challenge for synthetic applications. Specifically, in order to preclude erosion of ee during subsequent synthetic steps, it is imperative to separate the two diastereomers. Unfortunately, depending on the indole substitution pattern, separation of the diastereomers can be tedious using standard silica gel chromatography. In addition, the modest diastereoselectivity results in lower isolated yields of the pure exo-diastereomer. In an effort to identify conditions more amenable to application in total synthesis endeavors, we sought to re-optimize the reaction parameters for the formal (3 + 2) cycloaddition with the objective of improving the diastereoselectivity while maintaining synthetically useful enantioselectivity. Herein, we report the successful realization of this objective, as well as mechanism-guided studies that resulted in the development of a one-flask reduction process for the direct synthesis of related indoline derivatives.

2. Results and Discussion

The optimization studies disclosed in our original report determined that the enantio- and diastereoselectivity of pyrroloindoline formation was highly dependent on the substitution of the 2-amidoacrylate: the highest enantioselectivity was obtained using benzyl 2-trifluoroacetamidoacrylate (6), while the highest diastereoselectivity was attained using methyl 2-trifluoroacetamidoacrylate (20) (Scheme 4). In the latter case, the ee's of the two diastereomers were only modestly reduced. Thus, we returned to the use of acrylate 20 in the cycloaddition, and sought to improve the ee and dr by optimizing the catalyst structure.

Scheme 4.

Dependence of diastereoselectivity on acrylate substitution.

A screen of (R)-BINOL derivatives revealed that several catalysts containing substitution at the 3- and 3'-positions provided an improvement in both dr and ee. Hypothesizing that catalyst selectivity might correlate to the pK_a of the BINOL O-H protons, several 6,6'-derivatives were also prepared in order to isolate the electronic and steric effects; however, no linear correlation was observed. Ultimately, (R)-3,3'-Cl₂-BINOL (25) was identified as the catalyst that provided the optimal combination of ee, dr, and overall yield.

With these newly optimized conditions in hand, a survey of indole substrates was conducted (Table 2). As previously observed, indoles bearing electron-donating substituents on the aryl backbone provide the highest yields; however, both electron-rich and electron-poor substrates provide high ee's. More sterically-hindered indoles are less reactive and require 1.6 equivalents of SnCl₄, but nevertheless furnish the desired pyrroloindoline in good yield with high selectivity.

Table 2.

Substrate scope of pyrroloindoline formation.

^aDetermined by ¹H NMR analysis of crude reaction mixture. Values in parentheses are dr obtained using acrylate 6 and catalyst 7.

^bDetermined by SFC using chiral stationary phase. Values in parentheses are ee obtained using acrylate 6 and catalyst 7.

^cIsolated yield of exo-diastereomer.

^d1.6 equiv SnCl₄ was employed.

Having identified conditions that provide the pyrroloindoline products with improved diastereoselectivity, we sought to obtain further mechanistic insight by monitoring the reaction using in situ ¹H NMR spectroscopy. For this purpose, we returned to the reaction between 1,3-dimethylindole (5a) and benzyl 2-trifluoroacetamidoacrylate (6) because it is homogeneous over the course of the reaction. Figure 2 shows a sample of ¹H NMR spectra taken over the first 9 hours of the reaction, and reveals several interesting aspects of this transformation. Notably, upon addition of SnCl₄ and (R)-BINOL (7) to a mixture of 5a and 6, the indole proton resonances broaden significantly (Figure 2, t = 0). This broadening is also observed in the absence of acrylate 6; however, SnCl₄ alone does not alter the ¹H NMR spectrum of 5a. It is possible that this broadening is due to a rapid, dynamic proton exchange process promoted by 7•SnCl₄, which is consistent with the finding that deuteurated 5a undergoes rapid D-H exchange under the reaction conditions. Interestingly, the chemical shifts of the acrylate remain unchanged, indicating that there is no significant accumulation of an acrylate–SnCl₄ complex. Over the course of the reaction, resonances corresponding to an indole–acrylate adduct grow in; however, these peaks do not correspond to the pyrroloindoline product.

Figure 2.

In situ monitoring of the formal (3 + 2) cycloaddition using ¹H NMR.

We hypothesized that in the presence of a strong Lewis acid, such as SnCl₄, coordination of the amide might favor the ring-opened iminium ions exo-14/ent-endo-14. To test this hypothesis, we resubjected diastereomerically pure exo-8a to SnCl₄ (1.2 equiv) and varying equivalents of (R)-BINOL (7) (Figure 3). The NMR spectra of the mixtures were dependent on the concentration of 7. In the presence of 20 mol % 7, the ¹H NMR spectrum closely resembles that of the indole-acrylate adduct observed in the ¹H NMR experiment. Notably, this species exhibits a resonance between 9 and 10 ppm (depending on concentration of 7, Figure 3, a and b), which we assign to the indolinium proton (H_b). In addition, the N-methyl group (H_a) in this species is shifted downfield relative to the pyrroloindoline (4.0 ppm versus 3.1 and 2.9 ppm for the two rotamers of the exo diastereomer), and is consistent with literature data for other iminium ions.¹¹ This structural assignment is further supported by 2D ¹H–¹³C NMR correlation data. In the presence of SnCl₄ alone, the pyrroloindoline peaks broaden, likely due to dynamic interconversion between the ring-opened and -closed forms (Figure 3, c). The fact that addition of 1.2 equivalents of 7 resolves this mixture into one species suggests that 7•SnCl₄, an LBA,^9a might preferentially stabilize the open structure. Importantly, following aqueous work-up, pyrroloindoline exo-8a is cleanly reisolated with no indication of epimerization or racemization.

Figure 3.

NMR spectra of (a) pyrroloindoline exo-8a, SnCl₄ (1.2 equiv), (R)-BINOL (7) (1.2 equiv) (b) pyrroloindoline exo-8a, SnCl₄ (1.2 equiv), (R)-BINOL (7) (0.2 equiv) (c) pyrroloindoine exo-8a, SnCl₄ (1.2 equiv) (d) pyrroloindoline exo-8a.

The progress of the reaction can be quantified by integrating the vinyl protons of the acrylate relative to 1,4-diethylbenzene as an internal standard. However, further kinetic analysis of the (R)-BINOL-catalyzed reaction has been complicated by several factors, including the racemic background reaction (particularly at higher SnCl₄:(R)-BINOL ratios) and product inhibition.

Given that iminium ions exo-14/ent-endo-14 are observed under the reaction conditions, we wondered if it would be possible to trap these intermediates with an external hydride source. The resulting product would be an indoline-containing amino acid derivative bearing an all-carbon quaternary stereocenter at the C3-position (Scheme 5). Commonly employed strategies for the enantioselective generation of indolines include asymmetric hydrogenation of prochiral indoles,¹² reduction of oxindoles,¹³ C-H activation of substituted anilines,¹⁴ and kinetic resolution of racemic mixtures of indolines.¹⁵ However, these methods are often limited in scope or require multiple steps.

Scheme 5.

Intercepting an iminium ion intermediate to yield indolines.

To assess the feasibility of our proposed transformation, the formal (3 + 2) cycloaddition was performed under the previously optimized conditions, but in the presence of a reductant (Table 3). Whereas weaker reductants such as triethylsilane and sodium triacetoxyborohydride proved ineffective, we were pleased to find that use of Hantzsch ester 29 did provide the indoline product, albeit in low yield (entry 3). Alternatively, use of sodium borohydride furnishes 28a in good yield, 15:1 dr, and 92% ee (entry 5). The more soluble reducing agent lithium borohydride provided a lower yield of the desired product along with a greater amount of byproducts. The limited solubility of NaBH₄ and LiBH₄ in methylene chloride likely contributes to the compatibility of all the reagents, allowing the reaction to be carried out in one pot.

Table 3.

Screen of reducing agents.

entry	Reductant	yield (%)
1	Et3SiH	0
2	NaBH(OAc)3	0
3	Hantzsch ester 29	3
4	LiBH4	85
5	NaBH4	93a

^aproduct isolated in 15:1 dr and 92% ee.

Having identified an optimal reducing agent, a survey of indole substrates was conducted (Table 4). Indoles with either electron-donating or -withdrawing substituents are good substrates for the reaction. At the 3-position, n-butyl and phenylethyl groups are tolerated, but reactivity decreases with increasing steric bulk, and 1.6 equivalents of SnCl₄ are required to achieve good reactivity. Whereas cleavage of the protecting group was observed when TBS-protected tryptophol was employed, use of the TIPS-protected trpytophol furnished 28k in good yield. The indole nitrogen can also be protected with an allyl group, making this method more useful when an N-Me functionality is not desired in the product.

Table 4.

In situ reduction for the synthesis of indolines.

^aDetermined by ¹H NMR analysis of crude reaction mixture.

^bDetermined by SFC using chiral stationary phase.

^cIsolated yield of exo-diastereomer.

^d1.6 equiv SnCl₄ was employed.

The reduced products 28 are formed with the same diastereomeric and enantiomeric ratios as the corresponding pyrroloindolines, suggesting that the reduction does not affect the selectivities of the other steps. If a methylene chloride solution of pyrroloindoline exo-8a and SnCl₄ is re-exposed to sodium borohydride, the pyrroloindoline is reduced to indoline 28a in quantitative yield.

3. Conclusion

Building on our initial report of a formal (3 + 2) cycloaddition between 3-substituted indoles and 2-amidoacrylates to yield enantioenriched pyrroloindolines, we have further optimized the catalyst structure to significantly improve the diastereoselectivity of this reaction while maintaining comparable yields and ee's. Subsequent NMR studies have provided a more thorough understanding of this reaction, revealing that the initial product of the reaction is an indolinium ion. Based on these findings, a method has been developed to trap this intermediate with sodium borohydride to yield enantioenriched indoline products with a quaternary stereocenter at C3. The study and development of additional transformations that proceed by cooperative Lewis acid–LBA mechanisms are the subject of ongoing research in our laboratory.

4. Experimental Section

4.1. General

Unless otherwise stated, reactions were performed under a nitrogen atmosphere using freshly dried solvents. Tetrahydrofuran (THF), methylene chloride (CH₂Cl₂), and toluene were dried by passing through activated alumina columns. Deuterated methylene chloride (CD₂Cl₂) was dried by passing through a plug of activated alumina in a glovebox. Dimethylformamide (DMF) was dried over activated molecular sieves, dichloroethane (DCE) was distilled over calcium hydride. All other commercially obtained reagents were used as received unless specifically indicated. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm). Flash column chromatography was performed either as described by Still et al. (Still, W. C., Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.) using silica gel (partical size 0.032–0.063) purchased from Silicycle or using pre-packaged RediSep®Rf columns on a CombiFlash Rf system (Teledyne ISCO Inc.). Diastereomeric ratios were determined by integration of crude NMR spectra. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. ¹H and ¹³C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), a Varian 400 (at 400 MHz and 100 MHz respectively) or a Varian Inova 500 (at 500 MHz and 125 MHz respectively), and are reported relative to internal chloroform (¹H, δ = 7.26, ¹³C, δ = 77.0). Data for ¹H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm⁻¹). Preparatory HPLC was performed with either an Agilent 1100 or 1200 Series HPLC utilizing an Agilent Zorbax RX-SIL 5mm column (9.4 × 250 mm). Analytical SFC was performed with a Mettler SFC supercritical CO₂ analytical chromatography system with Chiralcel AD-H, OJ-H columns (4.6 mm × 25 cm). Melting points were determined using a Büchi B-545 capillary melting point apparatus and the values reported are uncorrected. HRMS were acquired using either an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) or mixed (MM) ionization mode, or obtained from the Caltech Mass Spectral Facility.

4.2 Preparation of indole substrates

4.2.1 1,3,4-trimethyl-1H-indole

Procedure for Vilsmeier-Haack reaction followed by LiAlH₄ reduction was adapted from Petit et al.¹⁶ In a flame-dried flask under nitrogen, POCl₃ (0.42 mL, 4.6 mmol) was added at 0 °C to 4-methyl-1H-indole (0.5 g, 3.8 mmol) in DMF (7.6 mL). The reaction was stirred at room temperature overnight. 2N NaOH_(aq) was then added, the solution was stirred for 2 h, then poured into EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated. The crude aldehyde was carried forward without further purification.

In a flame-dried flask under nitrogen, a solution of the Vilsmeier-Haack product (0.39 g, 2.5 mmol) in THF (5 mL) was added dropwise to a suspension of LiAlH₄ (0.19 g, 5 mmol) in THF (1.6 mL). The reaction was heated to reflux for 4 h, then cooled to room temperature and stirred overnight. The reaction was diluted with Et₂O and cooled to 0 °C. Water (0.19 mL) was added slowly, then 15% NaOH_(aq) (0.19 mL), then water (0.6 mL) were added. The mixture was warmed to room temperature and stirred for 15 minutes. Some MgSO₄ was added, the mixture was stirred for 15 minutes, filtered and concentrated. The crude indole was carried forward without further purification.

In a flame-dried flask, the indole (0.3 g, 2.1 mmol) was dissolved in THF (13 mL). Sodium hydride (60% w/w, 124 mg, 3.1 mmol) was added in one portion, then methyl iodide (0.26 mL, 4.1 mmol) was added dropwise. The reaction was stirred at room temperature until consumption of starting material was observed by TLC. The reaction was diluted with ethyl acetate and the excess NaH was quenched with water. The organic layer was separated, and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography. 44% yield over three steps.

¹H NMR (500 MHz, CDCl₃) δ 7.12-7.05 (m, 2H), 6.81 (ddd, J = 6.6, 1.4, 0.8 Hz, 1H), 6.76 (d, J = 0.9 Hz, 1H), 3.69 (s, 3H), 2.72 (s, 3H), 2.51 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 137.5, 131.4, 126.9, 126.7, 121.5, 120.0, 110.9, 107.0, 32.5, 20.0, 12.8; IR (NaCl/thin film): 2918, 1608, 1573, 1551, 1497, 1453, 1417, 1313, 1250, 1205, 1157, 1057, 767, 739 cm⁻¹.

4.2.2 1,3,7-trimethyl-1H-indole

Prepared according to the procedure for 1,3,4-trimethyl-1H-indole. Spectral data matches that reported in the literature.¹⁷

4.2.3 1,3-dimethyl-5-reverse prenyl-1H-indole

In a glovebox, Pd₂(dba)₃ (51 mg, 6 mmol) and SPhos (91 mg, 22 mmol) in THF (3 mL) were stirred at room temperature for 1h until a dark yellow homogeneous solution was formed. The solution was then transferred to a Schlenk tube, and 5-iodo-1,3-dimethyl-1H-indole (300 mg, 1.11 mmol), trifluorosilane¹⁸ (256 mg in 2.1 mL THF, 1.66 mmol), TBAF (1 M solution in THF, 1.66 mL) and THF (7 mL) were added. The reaction mixture was heated to 60°C for 36 hours. Additional portions of TBAF (1M solution in THF, 0.55 mL) were added at 12-hour intervals. 5% EtOAc in hexanes was then added to the reaction, and the mixture was filtered through a silica gel plug. The solution was concentrated, and the crude orange oil was purified by flash chromatography (5% to 9% EtOAc in hexanes) to give the reverse prenylated indole as a light yellow oil (177 mg, 0.84 mmol, 76% yield). ¹H NMR (500 MHz, CDCl₃) 7.51 (t, J = 0.9 Hz, 1H), 7.24 (dd, J = 8.7, 1.83 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 1.0 Hz, 1H), 6.13 (dd, J = 17.5, 10.6 Hz, 1H), 5.09 (dd, J = 17.6, 1.5 Hz, 1H), 5.04 (dd, J = 10.5, 1.5 Hz, 1H), 3.71 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H), 1.49 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) 149.1, 138.8, 135.4, 128.3, 126.7, 120.6, 115.5, 110.1, 109.9, 108.5, 41.1, 32.5, 28.8, 9.5; IR (NaCl/thin film): 3080, 2964, 2920, 1634, 1489, 1455, 1425, 1387, 1376, 1365, 1292, 1256, 1201, 1152, 1053, 1004, 909, 874, 788; HRMS (MM) calc'd for C₁₅H₁₉N [M+H]⁺ 214.1590, found 214.1592.

4.3 General procedure for the formal (3 + 2) cycloaddition of indoles and acrylates

To a flame-dried flask was added indole (0.20 mmol, 1.00 equiv), acrylate (0.20 mmol, 1.00 equiv), and (R)-3,3'-dichloro-BINOL (0.04 mmol, 0.20 equiv). The flask was charged with CH₂Cl₂ (1.5 mL), followed by addition of SnCl₄ (0.24 mmol, 1.20 equiv unless specifically indicated, 1 M in CH₂Cl₂), then stirred at room temperature. The reaction was quenched by diluting with 1 mL MeCN and 1 mL 1 M HCl, followed by addition of 5 mL H₂O. The aqueous layer was extracted with diethyl ether (3 × 15 mL) and the combined organic layers were washed with 3 N NaOH_(aq) (10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated. The crude residue was purified by flash chromatography.

4.3.1 Pyrroloindoline 21a

The dr was determined to be 14:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→10% ethyl acetate/hexanes) to yield 49.4 mg (73% yield) of 21a. The enantiomeric excess was determined to be 91% by chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO₂, λ = 254 nm): t_R(major) = 2.9 min t_R(minor) = 2.4 min. Spectral data matches that reported in the literature.⁷

4.3.2 Pyrroloindoline 21b

The dr was determined to be 7:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to yield 49.1 mg (69% yield) of 21b. The enantiomeric excess was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO₂, λ = 254 nm): t_R(major) = 3.1 min t_R(minor) = 2.3 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 3.7:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by^§) δ 7.08 (t, J = 7.8 Hz, 1H*, 1H^§), 6.65-6.57 (m, 1H^§), 6.55 (d, J = 7.6 Hz, 1H*), 6.45-6.40 (m, 1H^§), 6.38 (d, J = 7.8 Hz, 1H*), 5.49 (s, 1H*), 5.29 (s, 1H^§), 4.74 (d, J = 9.3 Hz, 1H*), 4.45 (m, 1H^§), 3.83 (s, 3H*), 3.78 (s, 3H^§), 3.12 (s, 3H*), 2.85 (s, 3H^§), 2.68 (dd, J = 13.3, 9.7 Hz, 1H*), 2.64-2.59 (m, 1H^§), 2.53 (dd, J = 13.3, 1.6 Hz, 1H*), 2.33 (s, 3H^§), 2.31 (s, 3H*), 2.20-2.10 (m, 1H^§), 1.60 (s, 3H^§), 1.47 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 3.7:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.7*, 170.5^§, 159.0^§ (q, J_C-F = 37.2 Hz), 150.6*, 149.7^§, 133.1^§, 132.7*, 131.6*, 130.9^§, 128.8*^§, 122.6^§, 121.5*, 116.1* (q, J_C-F = 288.3 Hz), 107.3^§, 106.2*, 94.0*, 92.0^§, 61.3^§, 60.0*, 53.1*, 52.6^§, 50.0*, 42.7*, 39.4^§, 37.4*, 34.6^§, 24.1*, 23.3^§, 18.5*^§; IR (NaCl/thin film): 3047, 2957, 2930, 2880, 2825, 1752, 1701, 1596, 1477, 1434, 1385, 1356, 1338, 1293, 1263, 1254, 1216, 1204, 1155, 1097, 1064, 1020, 989, 854, 772, 744, 727 cm⁻¹;[a]_D²⁵ = −158.8 (c = 1.01, CHCl₃). HRMS (APCI) calc'd for C₁₇H₁₉F₃N₂O₃ [M+H]⁺ 357.1421, found 357.1426.

4.3.3 Pyrroloindoline 21c

The dr was determined to be 13:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to yield 51.3 mg (72% yield) of 21c. The enantiomeric excess was determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 4.4 min t_R(minor) = 2.7 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 1.9:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 6.98 (d, J = 7.4 Hz, 1H*, 1H^§), 6.87 (s, 1H^§), 6.84 (s, 1H*), 6.50 (d, J = 7.8 Hz, 1H^§), 6.43 (d, J = 8.0 Hz, 1H*), 5.57 (s, 1H*), 5.27 (s, 1H^§), 4.73 (d, J = 9.3 Hz, 1H*), 4.41 (t, J = 7.6 Hz, 1H^§), 3.82 (s, 3H*), 3.76 (s, 3H^§), 3.05 (s, 3H*), 2.86 (s, 3H^§), 2.59 (dd, J = 13.3, 9.7 Hz, 1H*), 2.55-2.48 (m, 1H^§), 2.35 (dd, J = 13.5, 2.2 Hz, 1H*), 2.28 (br s, 3H^§), 2.20-2.10 (m, 1H^§), 1.49 (s, 3H^§), 1.38 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 1.9:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.6*, 170.7^§, 159.1^§ (q, J_C-F = 37.0 Hz), 147.3*, 147.2^§, 134.4*^§, 129.7^§, 129.2^§, 129.1*, 128.2*, 122.3*^§, 116.1* (q, J_C-F = 288.2 Hz), 109.9^§, 108.2*, 93.8*, 92.1^§, 61.2^§, 60.3*, 53.2^§, 53.0*, 52.5^§, 49.2*, 44.0*, 40.3^§, 37.4*, 35.5^§, 23.5*, 23.2^§, 20.8*^§; IR (NaCl/thin film): 2958, 2924, 2873, 2822, 1750, 1699, 1618, 1500, 1435, 1384, 1356, 1339, 1288, 1257, 1201, 1152, 1117, 1094, 1057, 1035, 986, 874, 844, 807, 761, 728 cm⁻¹; [a]_D²⁵ = −128.4 (c = 1.08, CHCl₃). HRMS (APCI) calc'd for C₁₇H₁₉F₃N₂O₃ [M+H]⁺ 357.1421, found 357.1407.

4.3.4 Pyrroloindoline 21d

The dr was determined to be 14:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to yield 56.3 mg (79% yield) of 21d. The enantiomeric excess was determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 3.4 min t_R(minor) = 2.8 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 2.4:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 6.99-6.93 (m, 1H^§), 6.91 (d, J = 7.4 Hz, 1H*), 6.65 (d, J = 6.7 Hz, 1H^§), 6.58 (d, J = 7.3 Hz, 1H*), 6.41 (s, 1H^§), 6.34 (s, 1H*), 5.60 (s, 1H*), 5.31 (s, 1H^§), 4.72 (d, J = 9.0 Hz, 1H*), 4.48-4.39 (m, 1H^§), 3.82 (s, 3H*), 3.77 (s, 3H^§), 3.06 (s, 3H*), 2.86 (s, 3H^§), 2.58 (dd, J = 13.2, 9.2 Hz, 1H*), 2.52-2.45 (m, 1H^§), 2.39-2.33 (m, 1H*), 2.32 (br s, 3H*, 3H^§), 2.10-2.00 (m, 1H^§), 1.49 (s, 3H^§), 1.38 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 2.4:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.6*, 170.6^§, 159.1^§ (q, J_C-F = 37.9 Hz), 149.6*, 149.4^§, 139.0^§, 138.9*, 131.5*, 131.4^§, 121.2*^§, 120.6^§, 119.3*, 116.1* (q, J_C-F = 288.4 Hz), 110.4^§, 108.9*, 93.5*, 91.9^§, 61.3^§, 60.3*, 53.0*, 52.9^§, 52.5^§, 49.0*, 44.0*, 40.5^§, 36.7*, 34.6^§, 23.6*, 23.0^§, 21.7*; IR (NaCl/thin film): 2958, 2929, 2875, 2813, 1750, 1697, 1617, 1594, 1499, 1435, 1382, 1356, 1341, 1294, 1257, 1203, 1190, 1148, 1111, 1094, 1059, 1034, 1006, 985, 877, 852, 803, 763, 729 cm⁻¹; [a]_D²⁵ = −115.4 (c = 1.54, CHCl₃). HRMS (MM) calc'd for C₁₇H₁₉F₃N₂O₃ [M+H]⁺ 357.1421, found 357.1434.

4.3.5 Pyrroloindoline 21e

The dr was determined to be 15:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→25% ethyl acetate/hexanes) to yield 48.1 mg (68% yield) of 21e (major diastereomer only). The enantiomeric excess was determined to be 93% by chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO₂, λ = 254 nm): t_R(major) = 3.6 min t_R(minor) = 2.5 min. ¹H NMR (500 MHz, CDCl₃; compound exists as a 6.1:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 7.05-7.00 (m, 1H*), 7.00-6.93 (m, 2H*, 1H^§), 6.91 (d, J = 7.2 Hz, 1H^§), 6.82 (t, J = 7.4 Hz, 1H^§), 5.27 (s, 1H^§), 5.14 (d, J = 1.6 Hz, 1H*), 4.59 (dd, J = 9.1, 2.3 Hz, 1H^§), 4.06 (dd, J = 11.2, 6.6 Hz, 1H*), 3.80 (s, 3H^§), 3.72 (s, 3H*), 3.26 (s, 3H^§), 2.99 (s, 3H*), 2.67 (dd, J = 12.6, 6.6 Hz, 1H*), 2.57 (dd, J = 13.4, 9.2 Hz, 1H^§), 2.30 (s, 3H^§), 2.22 (s, 3H*), 2.13-2.03 (m, 1H*, 1H^§), 1.47 (s, 3H*), 1.42 (s, 3H^§); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 6.1:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.6^§, 171.1*, 158.7*, 149.9*, 148.8^§, 136.6*^§, 131.4^§, 131.0*, 126.6*, 124.01*, 122.6^§, 121.2^§, 119.6*, 119.4^§, 116.0* (q, J_C-F = 285.8 Hz), 95.6^§, 92.5*, 60.3*, 59.2^§, 55.1*, 52.9^§, 52.4*, 49.7^§, 44.0^§, 41.9^§, 41.0*, 38.6*, 26.3*, 26.0^§, 18.9^§, 17.5*; IR (NaCl/thin film): 2963, 1753, 1684, 1437, 1359, 1269, 1162, 1120, 1103, 1086, 1067, 977 cm⁻¹; [a]_D²⁵ = −27.0 (c = 0.91, CH₂Cl₂). HRMS (MM) calc'd for C₁₇H₁₉F₃N₂O₃ [M+H]⁺ 357.1421, found 357.1434.

4.3.6 Pyrroloindoline 21f

The dr was determined to be 10:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→25% ethyl acetate/hexanes) to yield 41.4 mg (58% yield) of 21f. The enantiomeric excess was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 3.7 min t_R(minor) = 2.3 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 2.0:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 6.92-6.82 (m, 1H*, 1H^§), 6.81-6.76 (m, 1H^§), 6.74 (dd, J = 8.0, 2.7 Hz, 1H*), 6.50 (dd, J = 8.6, 4.1 Hz, 1H^§), 6.40 (dd, J = 8.6, 4.1 Hz, 1H*), 5.60 (s, 1H*), 5.31 (s, 1H^§), 4.74 (d, J = 9.3 Hz, 1H*), 4.43 (t, J = 7.8 Hz, 1H^§), 3.82 (s, 3H*), 3.77 (s, 3H^§), 3.04 (s, 3H*), 2.85 (s, 3H^§), 2.58 (dd, J = 13.5, 9.6 Hz, 1H*), 2.53-2.45 (m, 1H^§), 2.40-2.32 (m, 1H*), 2.06 (dd, J = 13.3, 6.6 Hz, 1H^§), 1.49 (s, 3H^§), 1.38 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 2.0:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.4*, 170.5^§, 159.0^§ (q, J_C-F = 35.8 Hz), 157.9*, 156.7^§, 156.0*, 145.6*, 145.4^§, 135.8^§ (d, J_C-F = 8.7 Hz), 135.6* (d, J_C-F = 7.5 Hz), 116.0* (q, J_C-F = 289.2 Hz), 115.1^§, 114.8* (d, J_C-F = 23.2 Hz), 110.5^§ (d, J_C-F = 7.3 Hz), 110.2^§ (d, J_C-F = 24.3 Hz), 109.4^§ (d, J_C-F = 24.1 Hz), 109.3* (d, J_C-F = 24.4 Hz), 108.6* (d, J_C-F = 8.1 Hz), 105.9^§ (d, J_C-F = 8.0 Hz), 93.8*, 92.1^§, 61.1^§, 60.2*, 53.2^§, 53.1*, 52.6^§, 49.2^§, 43.8*, 40.1^§, 37.6*, 35.5^§, 23.4*, 22.9^§; IR (NaCl/thin film): 2959, 2880, 2825, 1750, 1699, 1611, 1495, 1436, 1386, 1356, 1339, 1270, 1229, 1202, 1178, 1152, 1118, 1091, 1052, 1034, 986, 872, 845, 808, 756, 728 cm⁻¹; [a]_D²⁵ = −108.5 (c = 1.08, CHCl₃). HRMS (APCI) calc'd for C₁₆H₁₆F₄N₂O₃ [M+H]⁺ 361.1170, found 361.1187.

4.3.7 Pyrroloindoline 21g

The dr was determined to be 10:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to yield 44.8 mg (61% yield) of 21g. The enantiomeric excess was determined to be 90% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 3.8 min t_R(minor) = 2.5 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 1.8:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 6.75-6.70 (m, 1H*, 1H^§), 6.67-6.65 (m, 1H^§), 6.64 (d, J = 2.4 Hz, 1H*), 6.55 (d, J = 8.5 Hz, 1H^§), 6.45 (d, J = 8.5 Hz, 1H*), 5.55 (s, 1H*), 5.24 (s, 1H^§), 4.74 (d, J = 9.4 Hz, 1H*), 4.38 (t, J = 8.0 Hz, 1H^§), 3.81 (s, 3H*), 3.77 (s, 3H^§), 3.76 (s, 3H*, 3H^§), 3.04 (s, 3H*), 2.86 (s, 3H^§), 2.59 (dd, J = 13.5, 9.6 Hz, 1H*), 2.52 (dd, J = 13.0, 8.7 Hz, 1H^§), 2.35 (dd, J = 13.5, 2.5 Hz, 1H*), 2.09-2.00 (m, 1H^§), 1.48 (s, 3H^§), 1.38 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 1.8:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.5*, 170.7^§, 159.0^§ (q, J_C-F = 37.1, 36.6 Hz), 154.6^§, 153.6*, 143.7*, 143.6^§, 135.9^§, 135.7*, 116.1* (q, J_C-F = 288.3 Hz), 113.3^§, 113.0*, 111.4^§, 109.02*, 108.98*, 108.8^§, 94.1*, 92.3^§, 61.0^§, 60.3*, 56.0*, 55.9^§, 53.6^§, 53.1*, 52.6^§, 49.3*, 43.9*, 39.9^§, 38.1*, 36.8^§, 23.5*^§; IR (NaCl/thin film): 2958, 2833, 1750, 1691, 1598, 1497, 1434, 1384, 1356, 1341, 1281, 1259, 1231, 1203, 1154, 1093, 1062, 1031, 986, 870, 844, 808, 756, 728 cm⁻¹; [a]_D²⁵ = −103.2 (c = 0.82, CHCl₃). HRMS (APCI) calc'd for C₁₇H₁₉F₃N₂O₄ [M+H]⁺ 373.1370, found 373.1383.

4.3.8 Pyrroloindoline 21h

The dr was determined to be 13:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to yield 74.1 mg (86% yield) of 21h. The enantiomeric excess was determined to be 87% by chiral SFC analysis (AD-H, 2.5 mL/min, 8% IPA in CO₂, λ = 254 nm): t_R(major) = 5.3 min t_R(minor) = 8.1 min. The major diastereomer was separated by flash chromatography (5% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 2.6:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 7.32-7.15 (m, 4H*, 4H^§), 7.08 (br t, J = 7.7 Hz, 3H*, 3H^§), 6.95-6.75 (m, 1H*, 1H^§), 6.65-6.50 (m, 1H*, 1H^§), 5.72 (br s, 1H*), 5.46 (br s, 1H^§), 4.65 (br d, J = 6.3 Hz, 1H*), 4.33 (br s, 1H^§), 3.78 (br s, 3H*, 3H^§), 3.13 (br s, 3H*), 2.90 (br s, 3H^§), 2.76-1.87 (m, 6H*, 6H^§); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 2.6:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.6*, 170.6^§, 159.0* (q, J_C-F = 37.5 Hz), 150.3*^§, 141.1*^§, 131.9*, 131.7^§, 129.0*^§, 128.5*^§, 128.2*^§, 126.1*^§, 122.0*, 121.2* (q, J_C-F = 278.2 Hz), 119.0*, 117.2^§, 114.9^§, 109.8^§, 108.3*, 90.5*, 89.2^§; IR (NaCl/thin film): 3026, 2952, 1751, 1701, 1607, 1491, 1437, 1355, 1204, 1151, 985, 749 cm⁻¹; [a]_D²⁵ = −128.3 (c = 1.22, CH₂Cl₂). HRMS (MM) calc'd for C₂₃H₂₃F₃N₂O₃ [M+H]⁺ 433.1734, found 433.1750.

4.3.9 Pyrroloindoline 21i

The dr was determined to be 5:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→15% ethyl acetate/hexanes) to yield 61.1 mg of white needles 21i (84% yield). The enantiomeric excess was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 7.8 min t_R(minor) = 3.5 min. The major and minor diastereomers were separated by reverse phase preparatory HPLC (50→95% acetonitrile/water, 0.05% trifluoroacetic acid). ¹H NMR (500 MHz, CDCl₃; compound exists as a 4.9:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 7.14 (td, J = 7.7, 1.3 Hz, 1H*, 1H^§), 7.03 (br d, J = 7.3 Hz, 1H*, 1H^§), 6.90-6.80 (br s, 1H^§), 6.76 (t, J = 7.4 Hz, 1H*), 6.67-6.58 (br s, 1H^§), 6.54 (d, J = 7.9 Hz, 1H*), 5.81 (dtd, J = 16.5, 11.6, 11.1, 6.2 Hz, 1H*, 1H^§), 5.74 (s, 1H*), 5.51 (br s, 1H^§), 5.27 (br d, J = 17.1 Hz, 1H*, 1H^§), 5.14 (br d, J = 10.2 Hz, 1H*, 1H^§), 4.72 (d, J = 9.1 Hz, 1H*), 4.34 (br s, 1H^§), 4.25 (dd, J = 16.5, 3.6 Hz, 1H*), 4.04 (dd, J = 16.5, 6.2 Hz, 1H*), 4.00-3.94 (m, 1H^§), 3.82 (s, 3H*), 3.76 (s, 3H^§), 2.62 (dd, J = 13.3, 9.7 Hz, 1H*), 2.58-2.49 (m, 1H^§), 2.40 (dd, J = 13.5, 2.6 Hz, 1H*), 2.11 (br s, 1H^§), 1.48 (s, 3H^§), 1.39 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 4.9:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 172.6*, 170.6^§, 158.9^§ (q, J_C-F = 36.9 Hz), 148.4*, 134.7*, 133.8*, 133.3^§, 128.7*, 121.7^§, 121.5*, 120.3^§, 118.8*, 117.8^§, 116.8*, 116.0* (q, J_C-F = 288.4 Hz), 110.8^§, 108.5*, 91.3*, 89.6^§, 60.9^§, 59.9*, 53.0*, 52.5^§, 51.8*, 50.4^§, 49.4*, 44.3*, 40.8^§, 23.7*, 23.4^§; IR (NaCl/thin film): 3053, 2958, 2877, 1751, 1700, 1691, 1685, 1642, 1608, 1487, 1437, 1384, 1356, 1340, 1309, 1257, 1205, 1151, 1106, 1093, 1027, 991, 925, 841, 817, 792, 744 cm⁻¹; [a]_D²⁵ = −146.2 (c = 1.60, CHCl₃). HRMS (APCI) calc'd for C₁₈H₁₉F₃N₂O₃ [M+H]⁺ 369.1421, found 369.1416.

4.3.10 Pyrroloindoline ent-endo-21i

¹H NMR (500 MHz, CDCl₃; compound exists as a 15.0:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 7.11-7.07 (m, 1H^§), 7.06 (td, J = 7.6, 1.3 Hz, 1H*), 7.06-7.03 (m, 1H^§), 6.98 (dd, J = 7.3, 0.7 Hz, 1H*), 6.73 (td, J = 7.4, 1.0 Hz, 1H ^§), 6.66 (td, J = 7.4, 1.0 Hz, 1H*), 6.46-6.44 (m, 1H^§), 6.44 (d, J = 7.9 Hz, 1H*), 5.87 (dddd, J = 17.1, 10.3, 5.9, 5.1 Hz, 1H*), 5.82-5.75 (m, 1H^§), 5.57 (s, 1H*), 5.53 (d, J = 1.4 Hz, 1H^§), 5.30 (dq, J = 17.2, 1.7 Hz, 1H*), 5.22-5.19 (m, 1H^§), 5.16 (dq, J = 10.2, 1.5 Hz, 1H*), 5.10 (dd, J = 9.5, 4.5 Hz, 1H^§), 4.75 (dt, J = 8.4, 1.3 Hz, 1H*), 4.24-4.13 (m, 2H*), 3.85 (ddd, J = 49.3, 17.2, 5.1 Hz, 2H^§), 3.53 (s, 3H^§), 3.17 (s, 3H*), 2.85 (d, J = 13.0 Hz, 1H*), 2.50 (dd, J = 13.2, 4.5 Hz, 1H^§), 2.39 (dd, J = 13.0, 8.4 Hz, 1H*), 2.25 (dd, J = 13.3, 9.6 Hz, 1H^§), 1.44 (s, 3H^§), 1.42 (s, 3H*); ¹³C NMR (125 MHz, CDCl₃; compound exists as a 15.0:1 mixture of rotamers, the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 170.0*, 156.8^§ (q, J_C-F = 36.8 Hz), 149.3*, 147.8^§, 134.2*, 133.2^§, 132.6^§, 132.0*, 128.9*, 128.6^§, 122.5*, 121.7^§, 118.7^§, 118.0*, 117.1^§, 116.3*, 116.1* (q, J_C-F = 288.6 Hz), 108.0^§, 106.8*, 88.7^§, 88.1*, 60.3^§, 60.1* (q, J_C-F = 3.1 Hz), 52.6^§, 52.5^§, 52.4*, 50.6*, 49.0*, 46.6^§, 42.5*, 41.4^§, 25.7*, 22.9^§; IR (NaCl/thin film): 3055, 2954, 2869, 1760, 1742, 1699, 1607, 1490, 1447, 1436, 1338, 1317, 1274, 1254, 1208, 1183, 1144, 1105, 1093, 1032, 999, 942, 922, 887, 842, 859, 742 cm⁻¹; [a]_D²⁵ = +188.1 (c = 0.275, CHCl₃). HRMS (APCI) calc'd for C₁₈H₁₉F₃N₂O₃ [M+H]⁺ 369.1421, found 369.1429.

4.3.11 Pyrroloindoline 21j

The dr was determined to be 18:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to yield 68.6 mg (84% yield) of 21j. The enantiomeric excess was determined to be 92% by chiral SFC analysis (OD, 2.5 mL/min, 3% IPA in CO₂, λ = 254 nm): t_R(major) = 6.5 min t_R(minor) = 5.6 min. The major diastereomer was separated by flash chromatography (0→10% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃; compound exists as a 2.1:1 mixture of rotamers the major rotamer is denoted by *, minor rotamer denoted by ^§) δ 7.16 (d, J = 8.1 Hz, 1H*, 1H^§), 7.02 (s, 1H^§), 6.99 (s, 1H*), 6.52 (d, J = 7.7 Hz, 1H^§), 6.45 (d, J = 8.2 Hz, 1H*), 6.00 (dd, J = 17.3, 10.5 Hz, 1H*, 1H^§), 5.60 (s, 1H*), 5.31 (s, 1H^§), 5.07 – 4.96 (m, 2H*, 2H^§), 4.73 (d, J = 9.3 Hz, 1H*), 4.47 – 4.41 (m, 1H^§), 3.82 (s, 1H*), 3.77 (s, 1H^§), 3.06 (s, 1H*), 2.86 (s, 1H^§), 2.60 (dd, J = 13.1, 9.9 Hz, 1H*), 2.52 (t, J = 10.7 Hz, 1H^§), 2.38 (d, J = 12.5 Hz, 1H*), 2.14 – 1.98 (m, 1H^§), 1.57 – 1.31 (m, 9H*, 9H^§); ¹³C NMR (126 MHz, CDCl₃) ; IR (NaCl/thin film): 3081, 2965, 2874, 2822, 1753, 1698, 1618, 1496, 1434, 1359, 1283, 1257, 1204, 1156, 1117, 1054, 995, 912, 844, 813; [a]_D²⁵ = −115 (c = 0.450, CHCl₃). HRMS (ESI) calc'd for C₂₁H₂₅F₃N₂O₃ [M+H]⁺ 3 411.1890, found 411.1901.

4.4 General procedure for the formal (3 + 2) cycloaddition/in situ reduction

To a flame-dried flask was added indole (0.20 mmol, 1.00 equiv), acrylate (0.20 mmol, 1.00 equiv), and (R)-3,3'-dichloro-BINOL (0.04 mmol, 0.20 equiv). The flask was charged with CH₂Cl₂ (1.5 mL), followed by addition of SnCl₄ (0.24 mmol, 1.20 equiv unless specifically indicated, 1 M in CH₂Cl₂). NaBH₄ (0.30 mmol, 1.50 equiv) was then added, and the reaction was stirred at room temperature for 24 h (unless specifically indicated). The reaction was quenched by diluting with 1 mL MeCN and 1 mL 1 M HCl, followed by addition of 5 mL H₂O. The aqueous layer was extracted with ethyl acetate (3 × 15 mL) and the combined organic layers were washed with saturated NaHCO3_(aq) (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated. The crude residue was purified by flash chromatography.

4.4.1 Indoline 28a

Prepared from 1,3-dimethyl-1H-indole ¹⁹ and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 15:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→25% ethyl acetate/hexanes) to yield 64.1 mg (93% yield) of 28a, a pale yellow oil. The enantiomeric excess of the major diastereomer was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 9.9 min t_R(minor) = 5.9 min. The major diastereomer was separated by flash chromatography (5% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.23 (br d, J = 5.9 Hz, 1H), 7.14 (td, J = 7.7, 1.2 Hz, 1H), 6.99 (dd, J = 7.3, 0.8 Hz, 1H), 6.76 (td, J = 7.4, 0.8 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.27 (br td, J = 7.7, 4.7 Hz, 1H), 3.65 (s, 3H), 3.31 (d, J = 9.1 Hz, 1H), 2.98 (d, J = 9.1 Hz, 1H), 2.74 (s, 3H), 2.21 (dd, J = 14.7, 4.7 Hz, 1H), 2.15 (dd, J = 14.7, 8.2 Hz, 1H), 1.40 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.1, 156.6 (q, J_C-F = 37.5 Hz), 152.1, 153.3, 128.5, 122.4, 119.0, 115.6 (q, J_C-F = 287.9 Hz), 108.4, 68.3, 52.7, 51.2, 42.8, 42.1, 35.8, 26.1; IR (NaCl/thin film): 3319, 2956, 2858, 2811, 1751, 1718, 1607, 1559, 1491, 1452, 1209, 1179, 744 cm⁻¹; [a]_D²⁵ = +79.6 (c = 1.32, CH₂Cl₂). HRMS (MM) calc'd for [M+H]⁺ C₁₆H₁₉F₃N₂O₃ 345.1421, found 345.1423.

4.4.2 Indoline 28b

Prepared from 1,3,4-trimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 11:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→25% ethyl acetate/hexanes) to yield 56.8 mg (79% yield, yellow oil) of 28b as a single diastereomer. The enantiomeric excess of the major diastereomer was determined to be 93% by chiral SFC analysis (AD-H, 2.5 mL/min, 6% IPA in CO₂, λ = 254 nm): t_R(major) = 3.9 min t_R(minor) = 3.5 min. ¹H NMR (500 MHz, CDCl₃) δ 7.64 (br d, J = 4.9 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 7.9 Hz), 4.10 (ddd, J = 9.0, 6.5, 4.2 Hz, 1H), 3.65 (s, 3H), 3.32 (d, J = 9.3 Hz, 1H), 2.95 (d, J = 9.2 Hz, 1H), 2.71 (s, 3H), 2.45 (dd, J = 15.0, 4.0 Hz, 1H), 2.30 (s, 3H), 2.13 (dd, J = 14.8, 8.9 Hz, 1H), 1.50 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.0, 156.7 (q, J_C-F = 37.5 Hz), 152.8, 134.5, 131.5, 128.8, 122.4, 115.6 (q, J_C-F = 287.9 Hz), 106.7, 68.6, 52.7, 51.7, 43.7, 40.9, 35.9, 26.6, 18.7; IR (NaCl/thin film): 3315, 2956, 2812, 1750, 1710, 1593, 1559, 1484, 1457, 1209, 1179, 774 cm⁻¹; [a]_D²⁵ = +66.0 (c = 1.04, CH₂Cl₂). HRMS (MM) calc'd for C₁₇H₂₁F₃N₂O₃ [M+H]⁺ 359.1577, found 359.1591.

4.4.3 Indoline 28c

Prepared from 1,3,5-trimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 17:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (10→25% ethyl acetate/hexanes) to yield 52.6 mg (73% yield) of 28c, a yellow oil. The enantiomeric excess of the major diastereomer was determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 6% IPA in CO₂, λ = 254 nm): t_R(major) = 4.8 min t_R(minor) = 3.4 min. The major diastereomer was separated by flash chromatography (7% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.43 (br d, J = 4.8 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.81 (s, 1H), 6.47 (d, J = 7.9 Hz, 1H), 4.16 (q, J = 6.5 Hz, 1H), 3.67 (s, 3H), 3.27 (d, J = 9.1 Hz, 1H), 2.91 (d, J = 9.1 Hz, 1H), 2.70 (s, 3H), 2.25 (s, 3H), 2.17 (d, J = 6.5 Hz, 2H), 1.39 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.0, 156.7 (q, J_C-F = 37.5 Hz), 150.0, 135.5, 128.9, 128.8, 123.3, 115.6 (q, J_C-F = 287.9 Hz), 108.7, 69.0, 52.7, 51.5, 42.7, 42.1, 36.4, 26.07, 20.7; IR (NaCl/thin film): 3326, 2955, 2922, 2863, 2806, 1752, 1719, 1555, 1499, 1452, 1209, 1163, 806 cm⁻¹; [a]_D²⁵ = +42.3 (c = 0.87, CH₂Cl₂). HRMS (MM) calc'd for C₁₇H₂₁F₃N₂O₃ [M+H]⁺ 359.1577, found 359.1565.

4.4.4 Indoline 28d

Prepared from 1,3,6-trimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 17:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→30% ethyl acetate/hexanes) to yield 65.0 mg (91% yield) of 28d, a yellow oil. The enantiomeric excess of the major diastereomer was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 11.1 min t_R(minor) = 5.0 min. The major diastereomer was separated by flash chromatography (5% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.29 (d, J = 5.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1H), 6.37 (s, 1H), 4.22 (td, J = 7.5, 4.9 Hz), 3.66 (s, 3H), 3.29 (d, J = 9.1 Hz, 1H), 2.96 (d, J = 9.1 Hz, 1H), 2.72 (s, 3H), 2.30 (s, 3H), 2.20-2.11 (m, 2H), 1.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.1, 156.6 (q, J_C-F = 37.5 Hz), 152.3, 138.6, 132.5, 122.2, 119.8, 115.6 (q, J_C-F = 287.8 Hz), 109.3, 68.6, 52.7, 51.4, 42.5, 42.2, 35.8, 26.2, 21.6; IR (NaCl/thin film): 3321, 2956, 2923, 2870, 2804, 1750, 1716, 1615, 1557, 1497, 1455, 1208, 1179, 802 cm⁻¹; [a]_D²⁵ = +76.0 (c = 1.56, CH₂Cl₂). HRMS (MM) calc'd for C₁₇H₂₁F₃N₂O₃ [M+H]⁺ 359.1577, found 359.1577.

4.4.5 Indoline 28e

Prepared from 1,3,7-trimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 17:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→30% ethyl acetate/hexanes) to yield 58 mg (81% yield) of 28e, a pale yellow oil. The enantiomeric excess of the major diastereomer was determined to be 94% by chiral SFC analysis (AD-H, 2.5 mL/min, 6% IPA in CO₂, λ = 254 nm): t_R(major) = 4.3 min t_R(minor) = 3.3 min. The major diastereomer was separated by flash chromatography (5% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J = 4.7 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 4.14-4.08 (m, 1H), 3.66 (s, 3H), 3.29 (d, J = 9.6 Hz, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.17-2.06 (m, 2H), 1.40 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.1, 156.7 (q, J_C-F = 37.5 Hz), 149.9, 136.1, 131.8, 121.2, 120.4, 120.3, 115.6 (q, J_C-F = 287.8 Hz), 69.7, 52.7, 51.3, 42.8, 42.3, 39.5, 26.6, 19.5; IR (NaCl/thin film): 3322, 2959, 2924, 1750, 1713, 1557, 1480, 1456, 1412, 1208, 1180, 1071, 750 cm⁻¹; [a]_D²⁵ = +84.9 (c = 1.20, CH₂Cl₂). HRMS (APCI) calc'd for C₁₇H₂₁F₃N₂O₃ [M+H]⁺ 359.1577, found 359.1595.

4.4.6 Indoline 28f

Prepared from 5-fluoro-1,3-dimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be 13:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (10→30% ethyl acetate/hexanes) to yield 57.0 mg (79% yield) of 28f, a pale yellow oil. The enantiomeric excess of the major diastereomer was determined to be 90% by chiral SFC analysis (AD-H, 2.5 mL/min, 6% IPA in CO₂, λ = 254 nm): t_R(major) = 3.9 min t_R(minor) = 2.9 min. The major diastereomer was separated by preparatory TLC (40% CH₂Cl₂/hexanes then 50% CH₂Cl₂/hexanes). ¹H NMR (300 MHz, CDCl₃) δ 7.31 (br d, J_C-H = 5.8 Hz, 1H), 6.83 (td, J_C-H = 8.8, 2.6 Hz, 1H), 6.72 (dd, J_C-H = 8.2, 2.6 Hz, 1H), 6.44 (dd, J_C-H = 8.5, 4.1 Hz, 1H), 4.25 (td, J_C-H = 7.7, 4.8 Hz, 1H), 3.68 (s, 3H), 3.31 (d, J_C-H = 9.2 Hz, 1H), 2.97 (d, J_C-H = 9.2 Hz, 1H), 2.70 (s, 3H), 2.21 (dd, J_C-H = 14.7, 4.8 Hz, 1H), 2.12 (dd, J_C-H = 14.7, 8.1 Hz, 1H), 1.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.0, 157.2 (d, J_C-F = 237.2 Hz), 156.6 (q, J_C-F = 37.8 Hz), 148.4, 137.1 (d, J_C-F = 7.1 Hz), 116.7, 114.5 (d, J_C-F = 23.3 Hz), 110.1 (d, J_C-F = 24.0 Hz), 108.8 (d, J_C-F = 8.1 Hz), 68.6, 52.8, 51.1, 42.8, 42.0, 36.4, 26.1; IR (NaCl/thin film): 3319, 2958, 2866, 2811, 1745, 1711, 1552, 1494, 1468, 1267, 1210, 1179, 808 cm⁻¹; [a]_D²⁵ = +63.7 (c = 0.62, CH₂Cl₂). HRMS (ESI) calc'd for C₁₆H₁₈F₄N₂O₃ [M+H]⁺ 363.1326, found 363.1334.

4.4.7 Indoline 28g

Prepared from 5-methoxy-1,3-dimethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The reaction was allowed to run for 18.5 h. The dr was determined to be 14:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (10→30% ethyl acetate/hexanes) to yield 68.5 mg (91% yield) of 28g, a yellow oil. The enantiomeric excess of the major diastereomer was determined to be 88% by chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO₂, λ = 254 nm): t_R(major) = 7.1 min t_R(minor) = 3.6 min. ¹H NMR (500 MHz, CDCl₃) δ 7.81 (br d, J_C-H = 5.0 Hz, 1H), 6.70 (dd, J_C-H = 8.4, 1.9 Hz, 1H), 6.62 (d, J_C-H = 1.8 Hz, 1H), 6.50 (d, J_C-H = 8.3 Hz, 1H), 4.01 (dd, J_C-H = 13.1, 6.3 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.28 (d, J_C-H = 8.6 Hz, 1H), 2.89 (d, J_C-H = 9.1 Hz, 1H), 2.68 (s, 3H), 2.23-2.08 (m, 2H), 1.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.0, 156.8 (q, J_C-F = 37.5 Hz), 154.1, 146.1, 137.0, 115.6 (q, J_C-F = 287.8 Hz), 113.1, 110.8, 109.6, 69.0, 55.8, 52.7, 51.5, 43.0, 42.0, 36.9, 26.2; IR (NaCl/thin film): 3319, 2955, 2804, 1751, 1718, 1555, 1496, 1468, 1214, 1179, 1031 cm⁻¹; [a]_D²⁵ = +26.3 (c = 1.24, CH₂Cl₂). HRMS (APCI) calc'd for C₁₇H₂₁F₃N₂O₄ [M+H]⁺ 375.1526, found 375.1542.

4.4.8 Indoline 28h

Prepared from 1-allyl-3-methyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure, except the formal (3 + 2) cycloaddition was allowed to run for 24 h before adding NaBH₄. After adding NaBH₄, the reaction was allowed to run for another 24 h. The dr was determined to be 5:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to yield 60.0 mg (81% yield) of 28h, a yellow oil. The enantiomeric excess of the major diastereomer was determined to be 90% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 7.2 min t_R(minor) = 6.2 min. Isolated as a 5:1 mixture of diastereomers; the major diastereomer is denoted by *, minor diastereomer denoted by ^§. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (br d, J = 8.5 Hz, 1H^§), 7.16-7.05 (m, 2H*, 1H^§), 6.98 (ddd, J = 7.4, 1.2, 0.5 Hz, 1H*, 1H^§), 6.78 (td, J = 7.4, 1.0 Hz, 1H^§), 6.72 (td, J = 7.4, 1.0 Hz, 1H*), 6.64 (d, J = 7.9 Hz, 1H^§), 6.56 (d, J = 7.9 Hz, 1H*), 5.93-5.83 (m, 1H*, 1H^§), 5.32-5.20 (m, 1H*, 1H^§), 4.81-4.75 (m, 1H^§), 4.40 (td, J = 7.6, 5.0, 1H*), 3.79 (ddt, J = 15.0, 5.9, 1.4 Hz, 1H*, 1H^§), 3.73-3.70 (m, 1H^§), 3.65-3.59 (m, 1H*), 3.63 (s, 3H*), 3.42 (s, 3H^§), 3.31 (d, J = 9.3 Hz, 1H*), 3.28 (d, J = 9.6 Hz, 1H^§), 3.07 (d, J = 9.6 Hz, 1H^§), 3.05 (d, J = 9.3 Hz, 1H*), 2.35 (ddd, J = 14.8, 5.9, 0.6 Hz, 1H^§), 2.23 (dd, J = 14.6, 4.9 Hz, 1H*), 2.18 (dd, J = 14.9, 4.6 Hz, 1H^§), 2.13 (dd, J = 14.7, 7.8 Hz, 1H*), 1.41 (s, 3H^§), 1.38 (s, 3H*); ¹³C NMR (100 MHz, CDCl₃) δ 171.2*, 170.1^§, 156.6* (q, J_C-F = 37.6 Hz), 150.8*, 135.4*, 133.3*, 132.4^§, 128.6^§, 128.4*, 123.3^§, 122.5*, 119.4^§, 118.9^§, 118.7*, 118.1*, 115.5* (q, J_C-F = 287.9 Hz), 109.9^§, 108.4*, 65.2^§, 65.1*, 52.7*, 52.5^§, 52.1^§, 51.8*, 50.9*, 50.5^§, 42.7^§, 42.6*, 42.5^§, 42.1*, 27.8^§, 26.1*; IR (NaCl/thin film): 3316, 2957, 2923, 1750, 1718, 1605, 1554, 1487, 1460, 1437, 1209, 1165, 744 cm⁻¹; [a]_D²⁵ = +33.412 (c = 1.62, CH₂Cl₂). HRMS (MM) calc'd for C₁₈H₂₁F₃N₂O₃ [M+H]⁺ 371.1577, found 371.1582.

4.4.9 Indoline 28i

Prepared from 3-butyl-1-methyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure. The dr was determined to be >20:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to yield 63.4 mg (82% yield) of 28i, a pale yellow oil. The enantiomeric excess of the major diastereomer was determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 7.2 min t_R(minor) = 5.3 min. The major diastereomer was separated by flash chromatography (5% ethyl acetate/hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.30 (br d, J_C-H = 5.5 Hz, 1H), 7.13 (td, J_C-H = 7.7, 1.2 Hz, 1H), 6.96 (dd, J_C-H = 7.3, 0.7 Hz, 1H), 6.75 (t, J_C-H = 7.3 Hz, 1H), 6.53 (d, J_C-H = 7.8 Hz, 1H), 4.22-4.15 (m, 1H), 3.64 (s, 3H), 3.24 (d, J_C-H = 9.3 Hz, 1H), 3.08 (d, J_C-H = 9.3 Hz, 1H), 2.74 (s, 3H), 2.23 (dd, J_C-H = 14.7, 8.4 Hz, 1H), 2.17 (dd, J_C-H = 14.7, 4.7 Hz, 1H), 1.86-1.77 (m, 1H), 1.69-1.57 (m, 1H), 1.40-1.24 (m, 3H), 1.19-1.08 (m, 1H), 0.89 (t, J_C-H = 7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.2, 156.6 (q, J_C-F = 37.5 Hz), 152.3, 134.3, 128.6, 123.0, 119.0, 115.5 (q, J_C-F = 287.8 Hz), 108.4, 66.4, 52.7, 51.2, 46.2, 40.6, 39.3, 35.9, 26.5, 23.2, 14.0; IR (NaCl/thin film): 3319, 2956, 2932, 2860, 2809, 1751, 1718, 1606, 1559, 1491, 1465, 1207, 1178, 743 cm⁻¹; [a]_D²⁵ = +62.0 (c = 1.15, CH₂Cl₂). HRMS (ESI) calc'd for C₁₉H₂₅F₃N₂O₃ [M+H]⁺ 387.1890, found 387.1902.

4.4.10 Indoline 28j

Prepared from 1-methyl-3-phenethyl-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure, except the formal (3 + 2) cycloaddition was allowed to run for 24 h before adding NaBH₄. After adding NaBH₄, the reaction was allowed to run for another 24 h. The dr was determined to be 12:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to yield 77.6 mg (89% yield) of 28j. The enantiomeric excess of the major diastereomer was determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO₂, λ = 254 nm): t_R(major) = 9.5 min t_R(minor) = 8.1 min. The major diastereomer was separated by flash chromatography (10% ethyl acetate/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.22 (m, 3H), 7.21-7.11 (m, 4H), 6.99 (dd, J_C-H = 7.4, 1.0 Hz, 1H), 6.75 (td, J_C-H = 7.4, 0.7 Hz, 1H), 6.55 (d, J_C-H = 7.9 Hz, 1H), 4.27 (dt, J_C-H = 12.6, 6.4 Hz, 1H), 3.63 (s, 3H), 3.30 (d, J_C-H = 9.3 Hz, 1H), 3.17 (d, J_C-H = 9.3 Hz, 1H), 2.76 (s, 3H), 2.68 (td, J_C-H = 13.0, 5.0 Hz, 1H), 2.47 (td, J_C-H = 12.9, 4.7 Hz, 1H), 2.34-2.22 (m, 2H), 2.13 (ddd, J_C-H = 13.7, 12.3, 5.1 Hz, 1H), 1.97 (ddd, J_C-H = 13.8, 12.6, 4.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 171.1, 156.6 (q, J_C-F = 37.5 Hz), 152.4, 141.7, 133.5, 128.7, 128.5, 128.2, 126.0, 122.9, 119.0, 115.5 (q, J_C-F = 287.8 Hz), 108.4, 66.0, 52.7, 51.1, 46.3, 41.5, 40.7, 35.8, 30.8; IR (NaCl/thin film): 3317, 2951, 2858, 2812, 1749, 1716, 1606, 1555, 1494, 1453, 1208, 1178, 745 cm⁻¹; [a]_D²⁶ = +23.1 (c = 0.87, CH₂Cl₂). HRMS (MM) calc'd for C₂₃H₂₅F₃N₂O₃ [M+H]⁺ 435.1890, found 435.1882.

4.4.11 Indoline 28k

Prepared from 1-methyl-3-(2-((triisopropylsilyl)oxy)ethyl)-1H-indole and methyl 2-trifluoroacetamidoacrylate using the general procedure, except the formal (3 + 2) cycloaddition was allowed to run for 20.5 h before adding NaBH₄. After adding NaBH₄, the reaction was allowed to run for another 24 h. The dr was determined to be >20:1 by ¹H NMR analysis of the crude reaction mixture. The crude residue was purified by flash chromatography (5→30% ethyl acetate/hexanes) to yield 68.3 mg (64% yield) of 28k, a yellow oil. The enantiomeric excess of the major diastereomer was determined to be 85% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO₂, λ = 254 nm): t_R(major) = 8.7 min t_R(minor) = 7.5 min. ¹H NMR (500 MHz, CDCl₃) δ 7.51 (br s, 1H), 7.15 (t, J_C-H = 7.6 Hz, 1H), 7.00 (d, J_C-H = 7.2 Hz, 1H), 6.75 (t, J_C-H = 7.1 Hz, 1H), 6.54 (d, J_C-H = 7.3 Hz, 1H), 4.22-4.15 (m, 1H), 3.81 (dd, J_C-H = 6.96, 5.35 Hz, 2H), 3.64 (s, 3H), 3.34-3.26 (m, 1H), 3.26-3.18 (m, 1H), 2.74 (s, 3H), 2.46-2.36 (m, 1H), 2.24 (dd, J_C-H = 14.7, 3.7 Hz, 1H), 2.11-1.94 (m, 2H), 1.08-1.03 (m, 21H); ¹³C NMR (125 MHz, CDCl₃) δ 171.1, 156.7 (q, J_C-F = 37.6 Hz), 152.1, 134.3, 128.7, 123.0, 118.9, 115.6 (q, J_C-F = 287.8 Hz), 108.5, 67.6, 60.0, 52.6, 51.2, 45.3, 41.2, 39.5, 18.0, 18.0, 11.9; IR (NaCl/thin film): 3323, 2943, 2866, 1719, 1606, 1552, 1491, 1463, 1207, 1175, 1104, 882, 742 cm⁻¹; [a]_D²⁵ = +27.4 (c = 0.85, CH₂Cl₂). HRMS (APCI) calc'd for C₂₆H₄₁F₃N₂O₄Si [M+H]⁺ 531.2860, found 531.2883.

4.5 General procedure for in situ monitoring of the formal (3 + 2) cycloaddition by ¹H NMR

In the glovebox, a 1 M solution of 1,3-dimethylindole, a 1 M solution of benzyl trifluoroacetamidoacrylate (with 0.3 equiv 1,4-diethylbenzene as an internal standard), a 0.72 M solution of SnCl₄, and a 0.0675 M solution of (R)-BINOL in CD₂Cl₂ were made. To an oven-dried NMR tube equipped with a Teflon-lined cap were added 90 μL of the indole solution, 90 μL of the acrylate + internal standard solution, 267 μL of the (R)-BINOL solution, and 186 μL of CD₂Cl₂. A ¹H NMR spectrum was taken (1 scan) to determine the initial ratio of substrates, (R)-BINOL, and internal standard. Immediately before beginning the collection of kinetics data, SnCl₄ was added via a microsyringe through the Teflon cap of the NMR tube. The tube was inverted once, then quickly inserted into the instrument.

The concentration of acrylate over the course of the reaction was determined by integrating its resonance at 6.3 ppm, then normalizing by the internal standard's resonance at 2.74 ppm.

Scheme 6.

Re-exposure of pyrroloindoline exo-8a to SnCl₄ and NaBH₄

Table 1.

Catalyst screen.

entry	BINOL derivative	yield (%)a	d.r.b	ee (%)c
1	H (7)	88	10:1	90
2	6,6'-(OMe)2 (22)	63	6:1	82
3	6,6'-Br2 (23)	65	8:1	86
4	3,3'-Me2 (24)	63	8:1	90
5	3,3'-Br2 (17)	63	16:1	90
6	3,3'-Cl2 (25)	73	14:1	91

^aIsolated yield of exo:endo mixture.

^bDetermined by ¹H NMR analysis of crude reaction mixture.

^cDetermined by HPLC using chiral stationary phase.

Abbreviations used

BINOL

1,1'-Bi(2-naphthol)

IPA

isopropanol

dba

dibenzylidineacetone