Catalytic Asymmetric Synthesis of Diketopiperazines by Intramolecular Tsuji–Trost Allylation

Abstract

We report the intramolecular Tsuji–Trost reaction of Ugi adducts to give spiro-diketopiperazines in high yield and with high enantioselectivity. This approach allows the catalytic asymmetric construction of a broad range of these medicinally important heterocycles under mild conditions, in two steps from cheap, commercially available starting materials.

Introduction

Heterocyclic small molecules are of immense importance in drug discovery. In recent years, the focus has shifted from purely aromatic heterocycles to scaffolds with a higher fraction of sp³-hybridized atoms.¹ Evidently, this is accompanied by a higher number of stereogenic centers. Consequently, new strategies that allow straightforward access to such scaffolds with full stereochemical control are of high and continuous interest. In this context, intramolecular transition metal-catalyzed allylation reactions such as the Tsuji–Trost reaction offer great opportunities, given the high level of stereocontrol and typically mild reaction conditions.² While considerable progress has been made in applying this strategy to the synthesis of (hetero)cyclic molecules, we aim to expand the current state of the art to more challenging systems, such as precursors bearing diverse functionalities and/or not naturally predisposed to adopt a favorable conformation for cyclization.

As an example, spiro-2,5-diketopiperazines³ (DKPs) display diverse biological activities (Figure 1), including neuroprotective properties,⁴ anti-inflammatory activity,⁵ and antiproliferative effects against drug-resistant human cancer cell lines.⁶ Despite these diverse medicinal properties, only few synthetic approaches to spiro-DKPs have been reported. Recent examples include Diels–Alder type reactions,⁷ intramolecular aminolysis,⁸ and post-Ugi cyclizations^9,10 (Scheme 1A). Importantly, these methods invariably rely on chiral pool starting materials (mostly amino acids) as the source of chirality.³ Obviously, this leads to limited substituent variation, while the D-configured antipodes are often only available at considerably higher cost. Catalytic asymmetric methods that allow full stereochemical control in a late stage of the synthesis would greatly expand the range of accessible spiro-DKPs and thus their application in drug discovery.

Figure 1.

Bioactive compounds and natural products based on DKP scaffold.

Scheme 1. Synthesis of 2,5 DKPs by Post-Ugi Cyclization.

However, to the best of our knowledge, no catalytic asymmetric methods to prepare DKPs have been reported to date. In light of our interest in multicomponent reactions, palladium catalysis, and asymmetric synthesis, we envisioned the use of the versatile Ugi reaction to construct compounds 2 as substrates for an enantioselective intramolecular Tsuji–Trost reaction (Scheme 1B). Ugi adducts 2 can be regarded as challenging substrates for Tsuji–Trost cyclization, given their high degree of substitution, potentially unfavorable minimum energy conformation, and electron-deficient allylic system.¹¹

On the other hand, strong bases such as LiHMDS, nBuLi, or NaH are usually required for the allylation of amides as a result of their low nucleophilicity in their neutral form.¹² However, even a small excess of base could lead to racemization of the newly formed stereocenter (or isomerization of the alkene), while a substoichiometric amount of base would result in incomplete conversion. Thus, we decided to employ the ethyl carbonate as the leaving group in order to generate the base in situ in precisely stoichiometric amount.

Results and Discussion

We began our investigation by treating the Ugi adduct 2aa with Pd₂dba₃ and dppe as the ligand in tetrahydrofuran (THF) at 50 °C. To our delight, the desired product 3a could be obtained in 86% yield after only 30 min (Table 1, entry 1). After screening various other palladium sources (Pd(PPh₃)₄, Pd(OAc)₂, and [PdClallyl]₂), it became evident that none could match the efficiency of Pd₂dba₃, which was thus selected for the screening of chiral ligands (Figure 2). Interestingly, reaction with the Trost ligand (L1) gave no conversion. Ligands L2, L5, and L7–9 showed poor enantioselectivity, despite the reasonable conversion (in case of L5 and L7–9). Higher stereoselectivity was observed with L3, L4, and L6, albeit with modest conversion. Remarkably, the enantioselectivity achieved with L2 was considerably lower than with L3 and L6, despite their similarity in terms of steric and electronic properties. Ligand L4(13) was selected for further optimization, combining the highest enantioselectivity with reasonable conversion. Having selected L4 as the best ligand, we performed the reaction at room temperature (entry 9), which led to a higher ee, although the reaction needed 24 h to reach completion and the yield dropped slightly. Switching the solvent to CH₂Cl₂ or toluene (entries 12 and 13) led to a decrease in enantioselectivity, whereas no reaction took place in dimethylformamide (DMF) (entry 14). On the other hand, using dioxane as the solvent gave the desired product in slightly better yield and enantioselectivity. Finally, we observed that the concentration plays a crucial role: running the reaction at higher dilution dramatically improved the yield as well as (to a minor degree) the enantioselectivity (entries 15–18), possibly as a result of the increased solubility of the palladium complex.¹⁴ Under the optimized conditions, we screened some additional ligands and conditions in an attempt to further improve the reaction outcome.

Table 1. Optimization of Reaction Conditions.

entrya	ligand	solvent	T (°C)	yieldb (%)	erc
1	dpped	THF	50	86
2	L1d	THF	50
3	L2d	THF	50	35	58/42
4	L3d	THF	50	12	80/20
5	L4e	THF	50	46	88/12
6	L5d	THF	50	62	58/42
7	L6d	THF	50	17	82/18
8	L7d	THF	50	75	63/27
9	L8d	THF	50	72	60/40
10	L9d	THF	50	74	51/49
11	L4e	THF	rt	31	93/7
12	L4e	CH2Cl2	rt	75	89/11
13	L4e	PhMe	rt	12	89/11
14	L4e	DMF	rt
15	L4e	Diox	rt	41	94/6
16f	L4e	Diox	rt	53	95/5
17g	L4e	Diox	rt	86	97/3
18h	L4e	Diox	rt	58	97/3
19g	L10e	Diox	rt
20g	L11e	Diox	rt
21g	L12e	Diox	rt	46	96/4
22g	L13e	Diox	rt	49	71/29
23g	L14e	Diox	rt	81	70/30
24g	L15e	Diox	rt	88	95/5

^aReaction conditions: 2aa (0.20 mmol), Pd₂(dba)₃ (0.01 mmol) in the indicated solvent (1 mL).

^bIsolated yield.

^cDetermined by chiral HPLC.

^d0.02 mmol ligand.

^e0.04 mmol ligand.

^f0.05 M substrate concentration.

^g0.025 M substrate concentration.

^h0.01 M substrate concentration. Diox = 1,4-dioxane.

Figure 2.

Chiral ligands screened.

Bisoxazole ligands L10 and L11 did not promote the reaction. With ligand L12, which is highly similar to L4, the product was obtained in good stereoselectivity but with only moderate conversion. Ligand L15 performed similarly as L4, but gave slightly lower enantioselectivity. Substitution of the tBu group by an iPr group led to significant erosion of the stereoselectivity (entries 22 and 23). Finally, the use of Me and tBu carbonates proved less efficient, and the addition of commonly used halide additives (LiCl, nBu₄NCl, nBu₄NF) was found to completely inhibit the reaction (for details, see the Supporting Information).

We then examined the scope of the reaction by subjecting various Ugi adducts 2 to the optimized reaction conditions (Scheme 2). We were delighted to observe that the reaction tolerates various spiro ring sizes, affording the desired DKPs smoothly for spiro-fused cyclohexanes and cyclopentanes (3a, 3d, 3g, 3i, 3j, 3l, 3n, 3o, and 3p) with generally high yield and enantioselectivity. In the case of spiro-cycloheptanes (3b–c), the yields are generally lower, possibly because of the increased flexibility of the system. To our delight, cyclobutane-containing substrates gave the corresponding DKP in excellent yield and enantioselectivity with a primary R³ substituent (3h), while the yield dropped with a sterically demanding R³ substituent (3k). The non-spiro products 3e,f were obtained in the lowest yields and selectivity, likely because of the reduced Thorpe–Ingold effect. Substrate 2q with a basic nitrogen atom in the spiro ring did not undergo the enantioselective cyclization, although the product 3q could be obtained as a racemate with the achiral catalyst (Scheme 3).

Scheme 2. Scope of the Reaction^,

Reaction conditions: 2aa–o (0.20 mmol), Pd₂(dba)₃ (0.01 mmol). L4 (0.04 mmol) in dioxane (8 mL; 0.025 M) at rt.

Determined by chiral SFC analysis.

1.0 mmol scale reaction.

Scheme 3. Scope of the Racemic Tsuji–Trost Cyclization.

Reaction conditions: 2q–s (0.20 mmol), Pd₂(dba)₃ (0.01 mmol). dppe (0.04 mmol) in THF (2 mL) at 50 °C.

A wide variety of R³ substituents is tolerated in the reaction. In particular, aromatic and other electron-withdrawing substituents gave the highest yield and enantioselectivity (3g, 3h, 3j, 3l, 3m, 3n, and 3o). On the other hand, bulky electron-rich alkyl substituents led to lower yield, probably by increasing the pK_a of the corresponding amide (3f). Primary alkyl substituents present an intermediate scenario, giving the products (3c, 3d, 3e, and 3f) in moderate yield. Reaction of tert-butyl amide 2r afforded the product only under the racemic conditions (Scheme 3, 3r). The lowest enantioselectivity was observed for 3o, bearing a pyridyl R³ substituent, probably because of the competing coordination of the Pd complex to the pyridine substituent, (partially) displacing the chiral oxazoline of L4. Aromatic R¹ substituents are not tolerated; product 3s was only formed under the racemic conditions (Scheme 3). On the other hand, a broad range of (primary) aliphatic R¹ substituents containing diverse functionalities (esters, amides, acetals, ethers, alkenes, alkynes, carbamates, and aromatic bromides) were shown to be compatible with the reaction, regardless of their steric and electronic properties.

To further demonstrate the synthetic utility of our method, we isomerized the terminal vinyl group of 3a to give trisubstituted alkene 4 as a 1:1 mixture of E/Z isomers (Scheme 4). Catalytic hydrogenation of 3a afforded 5 bearing an ethyl side chain, leaving the two benzylic amides untouched. Furthermore, Heck coupling with the relatively challenging 4-iodophenol under harsh conditions afforded the corresponding alcohol 6 without loss of stereochemical information. Finally, we were able to selectively remove the PMB group of 3a by treatment with cerium ammonium nitrate (CAN) in H₂O/MeCN to give the secondary amide 7. X-ray crystallographic analysis of 7 allowed us to unequivocally confirm the absolute configuration of the new stereocenter (R).

Scheme 4. Further Transformations of Spiro-DKP 3a.

The mechanism of DKP formation is proposed to proceed via the commonly accepted pathway for the Tsuji–Trost reaction, that is, via a π-allylpalladium intermediate and subsequent cross-coupling with the deprotonated secondary amide. As the pK_a of such amides is considerably lower than the generally accepted cutoff value of 25, C–N bond formation likely proceeds via S_N2-type substitution of the π-allylpalladium intermediate (“soft nucleophile mechanism”).¹⁵ The consistent performance of our reaction over various R³ substituents suggests that all reactions proceed via the same pathway. The regioselectivity is fully governed by the explicit E-geometry of the π-allylpalladium intermediate, considering that cyclization can be expected to outcompete allyl isomerization.^15,16

Conclusions

In conclusion, we successfully developed the first method for the synthesis of enantioenriched DKPs based on asymmetric catalysis rather than chiral pool starting materials. This two-step method provides access to a wide range of highly functionalized (spiro-)DKPs with good to excellent enantioselectivity. Moreover, the mild reaction conditions tolerate the presence of a wide range of functional groups. Finally, various further transformations to extend the range of accessible products were demonstrated.

Experimental Section

General Information

Commercially available reagents were purchased from Sigma-Aldrich, Fischer, Strem Chemicals or Fluorochem and were used as purchased unless mentioned otherwise. Solvents were purchased from VWR Chemicals or Sigma-Aldrich and used without purification, unless stated otherwise. Anhydrous, air-free solvents were obtained from a PureSolv MD 5 solvent purification system. Infrared (IR) spectra were recorded neat using a Shimadzu FTIR-8400s spectrophotometer and wavelengths are reported in cm^–1. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVANCE 600 (150.90 MHz for ¹³C), Bruker AVANCE 500 (125.78 MHz for ¹³C), Bruker AVANCE 400 (376.50 MHz for ¹⁹F), or Bruker AVANCE 300 using the residual CHCl₃ as internal standard (¹H: δ 7.26 ppm, ¹³C{¹H}: δ 77.16 ppm). Chemical shifts (δ) are given in ppm and coupling constants (J) are quoted in hertz (Hz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), br (broad singlet), and m (multiplet) or combinations thereof. Electrospray ionization (ESI) high-resolution mass spectrometry was carried out using a Bruker micrOTOF-Q instrument in positive ion mode (capillary potential of 4500 V). Flash chromatography was performed on Silicycle Silica-P Flash Silica Gel (particle size 40–63 μm, pore diameter 60 Å) using the indicated eluent. Thin layer chromatography (TLC) was performed using TLC plates from Merck (SiO₂, Kieselgel 60 F254 neutral, on aluminium with fluorescence indicator), and compounds were visualized by UV detection (254 nm) and/or KMnO₄ stain. SFC-MS analysis was conducted using a Shimadzu Nexera SFC-MS equipped with a Nexera X2 SIL-30AC autosampler, Nexera UC LC-30AD SF CO₂ pump, Nexera X2 LC-30AD liquid chromatograph, Nexera UC SFC-30A back pressure regulator, prominence SPD-M20A diode array detector, prominence CTO-20AC column oven, and CBM-20A system controller. Enantiomeric excess was determined by SFC-MS analysis using: Lux 3 μm Cellulose-1 column (cellulose tris(3,5-dimethylphenylcarbamate)) (column 1), Lux 3 μm Cellulose-2 column (cellulose tris(3-chloro-4-methylphenylcarbamate)) (column 2), Lux 3 μm Cellulose-3 column (cellulose tris(4-methylbenzoate), 150 × 4.6 mm) (column 3), and Lux 3 μm Cellulose-4 column (cellulose tris(4-chloro-3-methylphenyl-carbamate)) (column 4). A gradient of supercritical CO₂ (A) and methanol (B) was used. Method 1 (column 1): 2% B/98% A to 30% B/70% A over the course of 4 min and was maintained at 30% B/70% A for 2 min (flow: 1.5 mL/min). Method 2 (column 1): 2% B/98% A to 25% B/75% A over the course of 6 min and was maintained at 25% B/75% A for 1 min (flow: 2 mL/min). Method 3 (column 2): 2% B/98% A to 30% B/70% A over the course of 4 min and was maintained at 30% B/70% A for 2 min (flow: 2 mL/min). Method 4 (column 3): 2% B/98% A to 25% B/75% A over the course of 5 min and was maintained at 25% B/75% A for 1 min (flow: 1 mL/min). Method 5 (column 3): 2% B/98% A to 30% B/70% A over the course of 4 min and was maintained at 30% B/70% A for 2 min (flow: 2 mL/min). Method 6 (column 3): 2% B/98% A to 30% B/70% A over the course of 15 min and was maintained at 30% B/70% A for 1 min (flow: 2 mL/min). Method 7 (column 4): 2% B/98% A to 25% B/75% A over the course of 5 min and was maintained at 25% B/75% A for 1 min (flow: 2 mL/min). The sample injection volume was 5 μL. Mass spectrometry analyses were performed using a Shimadzu LCMS-2020 mass spectrometer. The data were acquired in full-scan APCI mode (MS) from m/z 100 to 800 in positive ionization mode. Data were processed using Shimadzu Labsolutions 5.82. Specific rotations were measured with an automatic AA-10 polarimeter.

Procedure A: Synthesis of the Ugi Precursors (GP-A)

A solution of the corresponding aldehyde (5 mmol, 1 equiv) and amine (5 mmol, 1 equiv) in MeOH (1 M, 5 mL) was stirred for 30 min, then, the carboxylic acid 1 (871 mg, 5 mmol, 1 equiv) was added and, after 5 min, the corresponding isocyanide (5 mmol, 1 equiv) was added. The reaction mixture was stirred for 24 h, concentrated, and purified by silica gel column chromatography as described in the corresponding synthetic procedure.

Procedure B: Enantioselective Tsuji–Trost Cyclization (GP-B)

A solution of Pd₂(dba)₃ (9 mg, 0.01 mmol, 0.05 equiv) and L4 (16 mg, 0.04 mmol, 0.2 equiv) in dioxane (4 mL) was stirred at rt for 30 min, then, a solution of the corresponding Ugi precursor (0.2 mmol, 1 equiv) in dioxane (0.05 M, 4 mL) was added dropwise and stirred overnight. The reaction mixture was filtrated, concentrated, and purified by silica gel column chromatography as described in the corresponding synthetic procedure.

Procedure C: Racemic Tsuji–Trost Cyclization (GP-C)

A solution of Pd₂(dba)₃ (9 mg, 0.01 mmol, 0.05 equiv), dppe (8 mg, 0.02 mmol, 0.1 equiv), and the corresponding Ugi precursor (0.2 mmol, 1 equiv) in dioxane (0.2 M, 2 mL) was stirred at 50 °C in an oil bath until full conversion of the starting material (monitored by TLC). The reaction mixture was filtrated, concentrated, and purified by silica gel column chromatography as described in the corresponding synthetic procedure.

Procedure D: Synthesis of Carboxylic Acid (GP-D)

To a solution of the corresponding alcohol (18.303 g, 113.2 mmol, 1.00 equiv) in MeCN (1 M, 113.2 mL) were subsequently added CuBr (812 mg, 5.66 mmol, 0.05 equiv), 2,2′-bipyridine (884 mg, 5.66 mmol, 0.05 equiv), 6-tetramethylpiperidine-1-oxyl (884 mg, 5.66 mmol, 0.05 equiv), and 4-(dimethylamino)pyridine (2.074 g, 16.98 mmol, 0.15 equiv). An O₂-balloon was fit to the flask, then the reaction mixture was degassed under vacuum, and the flask was backfilled with oxygen. This procedure was repeated three times, and the solution was stirred overnight. When the oxidation was complete (checked by TLC), the mixture was cooled to 0 °C and H₂O₂ (35%, 12.170 mL, 1.25 equiv), and a solution of KH₂PO₄ (6.932 g, 50.94 mmol, 0.45 equiv) and NaClO₂ (20.476 g, 226.4 mmol, 2.00 equiv) in water (240 mL) was added dropwise. Stirring was continued for 24 h at room temperature.

After complete consumption of the aldehyde (checked by TLC), 1 M HCl was added, and the aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried over Na₂SO₄ and filtered, and the solvent removed under vacuum.

E-4-((Ethoxycarbonyl)oxy)but-2-enoic Acid (1a)

It was prepared according to GP-D. Obtained as a pale oil that solidified when cooled to −20 °C (yield: 98%, 19.320 g, 110.936 mmol) and was used without further purification. ¹H NMR (600 MHz, CDCl₃): δ 12.30–10.95 (br, 1H), 7.04 (dt, J = 15.8, 4.3 Hz, 1H), 6.08 (dd, J = 15.8, 1.9 Hz, 1H), 4.82 (dd, J = 4.3, 1.9 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.1, 154.6, 143.4, 121.4, 65.4, 64.6, 14.2. IR (neat) ν_max (cm^–1): 3074, 2922, 1745, 1725, 1664, 1366, 1079, 1047. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₇H₁₁O₅, 175.0601; found, 175.0612.

E-4-((Methoxycarbonyl)oxy)but-2-enoic Acid (1b)

It was prepared according to GP-D on 5 mmol scale, obtained as a pale oil (yield: 97%, 777 mg, 4.85 mmol) and was used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 10.29–9.10 (br, 1H), 7.03 (dt, J = 15.8, 4.3 Hz, 1H), 6.06 (d, J = 15.8 Hz, 1H), 4.82 (dd, J = 4.4, 2.0 Hz, 2H), 3.81 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 171.1, 155.4, 143.4, 121.6, 65.8, 55.3. IR (neat) ν_max (cm^–1): 2964, 1745, 1682, 1655, 1437, 1252, 1205, 932, 908, 787. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₆H₉O₅, 161.0444; found, 161.0448.

E-4-((tert-Butoxycarbonyl)oxy)but-2-enoic Acid (1c)

It was prepared according to GP-D on 5 mmol scale, obtained as a pale oil that solidified when cooled to −20 °C (yield: 95%, 960 mg, 4.75 mmol), and was used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 10.61–8.43 (br, 1H), 7.04 (dt, J = 15.7, 4.3 Hz, 1H), 6.06 (dt, J = 15.8, 2.0 Hz, 1H), 4.75 (dd, J = 4.4, 2.0 Hz, 2H), 1.49 (s, 9H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ 171.2, 153.0, 143.9, 121.4, 83.1, 64.8, 27.8 (3C). IR (neat) ν_max (cm^–1): 2982, 1742, 1701, 1369, 1273, 1252, 1155, 1121, 851, 756. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₉H₁₅O₅, 203.0914; found, 203.0910.

(E)-4-((1-(Benzylcarbamoyl)cyclohexyl)(4-methoxybenzyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2aa)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as a pale oil in 82% yield (2.085 g, 4.1 mmol). R_f = 0.31 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.35–7.22 (m, 5H), 7.15 (d, J = 8.3 Hz, 2H), 6.86 (dt, J = 15.1, 5.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 3H), 6.36 (d, J = 15.1 Hz, 1H), 4.71 (d, J = 5.0 Hz, 2H), 4.62 (s, 2H), 4.40 (d, J = 5.5 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.44 (d, J = 12.5 Hz, 2H), 1.71 (td, J = 10.6, 5.4 Hz, 2H), 1.63–1.50 (m, 6H), 1.25 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 173.3, 168.4, 159.0, 154.7, 139.0, 138.7, 130.5, 128.7 (2C), 127.9 (2C), 127.6 (2C), 127.3 (2C), 124.7, 114.4, 66.5, 66.3, 64.4, 55.4, 47.9, 43.9, 33.1, 25.4 (2C), 23.0 (2C), 14.30. IR (neat) ν_max (cm^–1): 2366, 1745, 1670, 1510, 1355, 978, 704. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₆N₂O₆, 509.2646; found, 509.2624.

(E)-4-((1-(Benzylcarbamoyl)cyclohexyl)(4-methoxybenzyl)amino)-4-oxobut-2-en-1-yl Methyl Carbonate (2ab)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as a pale oil in 88% yield (2.176 g, 4.4 mmol). R_f = 0.30 (50% EtOAc/cHex). ¹H NMR (500 MHz, CDCl₃): δ 7.31–7.28 (m, 2H), 7.27–7.24 (m, 3H), 7.15 (d, J = 8.7 Hz, 2H), 6.86 (dt, J = 15.1, 5.0 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6.78–6.75 (m, 1H), 6.36 (dt, J = 15.1, 1.8 Hz, 1H), 4.71 (dd, J = 5.0, 1.8 Hz, 2H), 4.62 (s, 2H), 4.40 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 2.43 (d, J = 13.2 Hz, 2H), 1.70 (ddd, J = 13.4, 10.7, 3.9 Hz, 2H), 1.64–1.48 (m, 6H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ 173.3, 168.3, 158.9, 155.3, 138.8, 138.6, 130.4, 128.7 (2C), 127.9 (2C), 127.6 (2C), 127.3, 124.7, 114.3 (2C), 66.5 (2C), 55.4, 55.1, 47.8, 43.9, 33.1 (2C), 25.4, 22.9 (2C). IR (neat) ν_max (cm^–1): 2932, 1749, 1663, 1610, 1512, 1445, 1244, 1173, 1030, 918, 727, 698. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₈H₃₅N₂O₆, 495.2490; found, 495.2486.

(E)-4-((1-(Benzylcarbamoyl)cyclohexyl)(4-methoxybenzyl)amino)-4-oxobut-2-en-1-yl tert-Butyl Carbonate (2ac)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as a pale oil in 78% yield (2.093 g, 3.9 mmol). R_f = 0.35 (50% EtOAc/cHex). ¹H NMR (500 MHz, CDCl₃): δ 7.33–7.28 (m, 2H), 7.27–7.24 (m, 3H), 7.15 (d, J = 8.7 Hz, 2H), 6.87 (dt, J = 15.1, 4.9 Hz, 1H), 6.83–6.79 (m, 3H), 6.34 (dt, J = 15.1, 1.8 Hz, 1H), 4.65 (dd, J = 4.9, 1.8 Hz, 2H), 4.61 (s, 2H), 4.39 (d, J = 5.5 Hz, 2H), 3.77 (s, 3H), 2.46–2.40 (m, 2H), 1.74–1.67 (m, 2H), 1.62–1.51 (m, 6H), 1.41 (s, 9H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ 173.3, 168.5, 158.9, 153.0, 139.6, 138.7, 130.4, 128.7 (2C), 127.9 (2C), 127.6 (2C), 127.3, 124.3, 114.3 (2C), 82.7, 66.4, 65.5, 55.3, 47.9, 43.9, 33.1 (2C), 27.7 (3C), 25.4, 23.0 (2C). IR (neat) ν_max (cm^–1): 2934, 1742, 1661, 1512, 1275, 1246, 1157, 1119, 727, 698. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₁H₄₁N₂O₆, 537.2959; found, 537.2961.

Benzyl (E)-3-(2-(1-(N-(2,2-Dimethoxyethyl)-4-((ethoxy carbonyl)oxy)but-2-enamido)cycloheptane-1-carboxamido)ethyl)-1H-indole-1-carboxylate (2b)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (25% EtOAc/cHex) provided the title compound as a pale oil in 74% yield (2.508 g, 3.7 mmol). R_f = 0.33 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.20–8.05 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.50–7.44 (m, 2H), 7.42–7.31 (m, 5H), 7.29 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.76 (dt, J = 15.3, 4.8 Hz, 1H), 6.39 (d, J = 15.3 Hz, 1H), 5.42 (s, 2H), 4.69 (d, J = 4.8 Hz, 2H), 4.62–4.48 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.62–3.54 (m, 2H), 3.51 (q, J = 6.7 Hz, 2H), 3.22 (s, 6H), 2.85 (t, J = 6.9 Hz, 2H), 2.44–2.26 (m, 2H), 1.95–1.79 (m, 2H), 1.73–1.63 (m, 2H), 1.56–1.40 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 154.7, 150.8, 138.2, 136.5, 135.7, 135.2, 130.4, 128.8 (2C), 128.7, 128.5 (2C), 127.3, 124.8, 123.8, 123.0, 122.8, 119.1, 119.0, 115.3, 69.2, 68.7, 66.4, 66.2, 64.4, 55.3 (2C), 46.3 (2C), 39.3, 30.4 (2C), 25.2 (2C), 24.1 (2C), 14.3. IR (neat) ν_max (cm^–1): 2925, 1736, 1666, 1454, 1396, 1354, 1244, 1180, 1122, 1088, 1049, 1016, 731, 698. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₇H₄₈N₃O₉, 678.3385; found, 678.3357.

(E)-4-((1-(Benzylcarbamoyl)cycloheptyl)(butyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2c)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (25% EtOAc/cHex) provided the title compound as a white solid in 78% yield (1.789 g, 3.9 mmol). R_f = 0.27 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.41–7.14 (m, 5H), 6.85 (dt, J = 15.1, 4.8 Hz, 1H), 6.44 (dt, J = 15.1, 1.9 Hz, 1H), 6.16 (t, J = 5.6 Hz, 1H), 4.78 (dd, J = 4.8, 1.9 Hz, 2H), 4.43 (d, J = 5.6 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.51–3.28 (m, 2H), 2.43 (ddd, J = 15.2, 9.4, 1.6 Hz, 2H), 2.09–1.89 (m, 2H), 1.76–1.68 (m, 2H), 1.67–1.47 (m, 8H), 1.38–1.25 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃) 175.1, 166.9, 154.8, 138.9, 138.4, 128.6 (2C), 127.9 (2C), 127.3, 123.6, 69.4, 66.3, 64.4, 44.8, 43.9 (2C), 35.7, 34.1, 30.2 (2C), 23.8 (2C), 20.3, 14.4, 13.7. IR (neat) ν_max (cm^–1): 3321, 2930, 1744, 1670, 1603, 1526, 1423, 1250, 1217, 1188, 997, 957, 793, 716, 644. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₆H₃₈N₂NaO₅, 481.2673; found, 481.2660.

(E)-4-((3,5-Bis(trifluoromethyl)benzyl)(1-((3-methoxy propyl)carbamoyl)cyclohexyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2d)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (50% EtOAc/cHex) provided the title compound as a white solid in 67% yield (2.063 g, 3.8 mmol). R_f = 0.13 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.84 (s, 2H), 7.78 (s, 1H), 6.93 (t, 1H), 6.85 (dt, J = 15.1, 4.8 Hz, 1H), 6.17 (d, J = 15.1 Hz, 1H), 4.80 (s, 2H), 4.66 (d, J = 4.8 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 5.7 Hz, 2H), 3.41–3.33 (m, 2H), 3.29 (s, 3H), 2.43–2.35 (m, 2H), 1.82–1.73 (m, 2H), 1.62–1.53 (m, 8H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 172.8, 168.2, 154.5, 142.0, 139.6, 132.1 (q, J = 33.4 Hz, 2C), 126.6, 123.7 (2C), 123.2 (q, J = 274.8, 2C), 121.4, 72.1, 66.3, 65.9, 64.3, 58.8, 47.7, 38.6, 33.2, 28.8 (2C), 25.3, 22.8 (2C), 14.1. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −62.9. IR (neat) ν_max (cm^–1): 2932, 1749, 1663, 1653, 1620, 1377, 1348, 1277, 1254, 1169, 1128, 1003, 995, 906, 791, 733, 706, 681, 409. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₇H₃₄F₆N₂NaO₆, 619.2213, found, 619.2189.

(E)-4-((1-(Butylamino)-2-methyl-1-oxopropan-2-yl)(2,4-dimethoxybenzyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2e)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (60% EtOAc/cHex) provided the title compound as a white solid in 54% yield (1.254 g, 2.7 mmol). R_f = 0.13 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.50 (d, J = 8.4 Hz, 1H), 6.84 (dt, J = 15.2, 5.2 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.23 (dt, J = 15.2, 1.7 Hz, 1H), 5.77 (t, J = 5.7 Hz, 1H), 4.64 (dd, J = 5.2, 1.8 Hz, 2H), 4.51 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.23 (td, J = 7.3, 5.6 Hz, 2H), 1.50–1.42 (m, 2H), 1.39 (s, 6H), 1.33–1.26 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 174.8, 167.0, 160.2, 156.9, 154.6, 138.5, 128.4, 123.8, 118.9, 104.2, 98.4, 66.3, 64.2, 62.5, 55.4, 55.2, 42.5, 39.6, 31.5, 24.1 (2C), 20.2, 14.2, 13.8. IR (neat) ν_max (cm^–1): 3283, 2962, 2934, 1744, 1643, 1616, 1508, 1412, 1373, 1248, 1209, 1198, 1175, 1159, 1115, 1045, 1036, 1007, 989, 960, 928, 791. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₄H₃₆N₂NaO₇, 487.2415; found, 487.2396.

(E)-Ethyl (4-((4-Fluorobenzyl)(1-(isopropylamino)-2-methyl-1-oxopropan-2-yl)amino)-4-oxobut-2-en-1-yl)carbonate (2f)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (60% EtOAc/cHex) provided the title compound as a white solid in 47% yield (0.960 g, 2.35 mmol). R_f = 0.10 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.44–7.39 (m, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.88 (dt, J = 15.2 Hz, J = 4.7, 1H), 6.24 (d, J = 15.2 Hz, 1H), 5.49 (d, J = 7.8 Hz, 1H), 4.68 (d, J = 4.7 Hz, 2H), 4.64 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.05 (m, 1H), 1.42 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 7.8 Hz, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 173.8, 167.6, 167.0, 162.2 (d, J = 245.8 Hz), 154.7, 139.2, 134.4, 128.0, 123.3 (2C), 115.9 (d, J = 21.5 Hz, 2C), 66.2, 64.4, 62.6, 47.0, 41.7 (2C), 22.7 (2C), 14.3. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −115.3. IR (neat) ν_max (cm^–1): 3323, 2974, 1749, 1651, 1599, 1526, 1508, 1383, 1364, 1252, 1227, 1186, 1173, 1155, 1097, 1057, 1034, 827, 791, 500. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₃₀FN₂O₅, 409.2133; found, 409.2125.

Methyl (E)-(1-(4-((Ethoxycarbonyl)oxy)-N-(4-methoxybenzyl)but-2-enamido)cyclohexane-1-carbonyl)glycinate (2g)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (60% EtOAc/cHex) provided the title compound as an orange oil in 79% yield (1.937 g, 3.95 mmol). R_f = 0.11 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.22 (d, J = 8.6 Hz, 2H), 6.95–6.83 (m, 4H), 6.35 (d, J = 15.1 Hz, 1H), 4.70 (dd, J = 4.9, 1.5 Hz, 2H), 4.60 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.00 (d, J = 5.0 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 2.43–2.36 (m, 2H), 1.69–1.50 (m, 8H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 173.7, 170.7, 168.4, 159.0, 154.7, 139.1, 130.4 (2C), 127.5, 124.5, 114.4 (2C), 66.3, 66.2, 64.4, 55.4, 52.3, 47.8, 41.6 (2C), 32.9, 25.4, 22.8 (2C), 14.3. IR (neat) ν_max (cm^–1): 2932, 1744, 1664, 1612, 1512, 1401, 1364, 1244, 1202, 1173, 1028, 1007, 991, 789. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₄N₂O₈, 491.2388; found, 491.2390.

Methyl (E)-(1-(4-((Ethoxycarbonyl)oxy)-N-phenethylbut-2-enamido)cyclobutane-1-carbonyl)glycinate (2h)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (25% EtOAc/cHex) provided the title compound as a yellow oil in 84% yield (1.875 g, 4.2 mmol). R_f = 0.28 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.04 (t, J = 5.8 Hz, 1H), 7.34–7.22 (m, 2H), 7.22–7.16 (m, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.88 (dt, J = 15.1, 4.7 Hz, 1H), 6.49 (d, J = 15.1 Hz, 1H), 4.78 (dd, J = 4.7, 2.0 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.00 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H), 3.45 (t, J = 8.4 Hz, 2H), 2.88–2.63 (m, 4H), 2.28–2.21 (m, 2H), 1.82–1.66 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 174.3, 170.1, 166.7, 154.7, 138.9, 138.0, 128.7 (2C), 128.6 (2C), 126.7, 121.9, 66.0, 65.3, 64.4, 52.1, 47.2, 41.3 (2C), 36.7, 31.8, 14.7, 14.3. IR (neat) ν_max (cm^–1): 3321, 2930, 1744, 1670, 1655, 1597, 1528, 1508, 1423, 1377, 1252, 1190, 999, 793, 717, 644, 451, 407. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₃H₃₀N₂NaO₇, 469.1945; found, 469.1941.

(E)-4-((4-Chlorobenzyl)(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamoyl)cyclopentyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2i)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (35% EtOAc/cHex) provided the title compound as a pale oil in 76% yield (2.063 g, 3.8 mmol). R_f = 0.41 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 9.37 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.95 (dt, J = 15.1, 4.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.19 (d, J = 15.0 Hz, 1H), 4.68 (dd, J = 4.7, 1.9 Hz, 2H), 4.62 (s, 2H), 4.20–4.17 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 2.81–2.75 (m, 2H), 1.86–1.80 (m, 2H), 1.69–1.62 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.8, 169.2, 154.5, 143.4, 140.4, 140.1, 136.7, 133.2, 132.1, 129.1 (2C), 127.3 (2C), 123.0, 117.0, 113.4, 109.5, 74.6, 65.9, 64.4, 64.3, 64.3, 50.5, 36.0 (2C), 22.8 (2C), 14.1. IR (neat) ν_max (cm^–1): 2328, 1659, 1502, 1414, 1256, 1244, 1203, 1190, 1067, 1014, 982, 812, 783, 608, 482, 451, 411. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₈H₃₁ClN₂NaO₇, 565.1712; found, 565.1687.

(E)-4-((1-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)carbamoyl)cyclohexyl)(prop-2-yn-1-yl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2j)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as a pale solid in 77% yield (1.812 g, 3.85 mmol). R_f = 0.51 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.48 (s, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.91–6.80 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 15.2 Hz, 1H), 4.76 (dd, J = 4.8, 1.9 Hz, 2H), 4.31–4.02 (m, 8H), 2.43 (t, J = 2.4 Hz, 1H), 2.38–2.24 (m, 2H), 2.17–2.06 (m, 2H), 1.74–1.64 (m, 2H), 1.59–1.37 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.5, 168.5, 154.7, 143.4, 140.2, 139.6, 132.0, 123.6, 117.0, 113.7, 109.8, 80.0, 73.8, 66.9, 66.1, 64.4, 64.4, 64.3, 35.0, 32.9 (2C), 25.3, 22.7 (2C), 14.3. IR (neat) ν_max (cm^–1): 3288, 2934, 1744, 1664, 1504, 1406, 1379, 1300, 1254, 1240, 1202, 1173, 1067, 885, 802, 791, 737. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₃₀N₂NaO₇, 493.1945; found, 493.1935.

(E)-4-((4-Bromobenzyl)(1-((2,6-dimethylphenyl)carbamoyl)cyclobutyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2k)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as a white solid in 62% yield (1.685 g, 3.1 mmol). R_f = 0.53 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.94 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.06–6.98 (m, 3H), 6.94 (dt, J = 15.1, 4.5 Hz, 1H), 6.16 (d, J = 15.1 Hz, 1H), 4.66 (d, J = 4.5 Hz, 2H), 4.46 (s, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.83 (s, 2H), 2.31 (s, 2H), 2.12 (s, 6H), 1.85–1.68 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.9, 167.1, 154.2, 140.4, 136.7, 134.7 (2C), 134.0, 131.8 (2C), 127.9 (2C), 127.5 (2C), 126.7, 121.6, 121.2, 66.1, 65.6, 64.1, 48.3, 18.1 (2C), 14.7, 14.0. Two secondary carbons of the cyclobutane are not visible. IR (neat) ν_max (cm^–1): 2957, 2336, 1745, 1664, 1489, 1462, 1396, 1379, 1248, 11 981, 1009, 787, 770, 480. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₇H₃₂BrN₂O₅, 543.1489; found, 543.1462.

(E)-4-(Allyl(1-((4-methoxyphenyl)carbamoyl)cyclopentyl)amino)-4-oxobut-1-en-1-yl Ethyl Carbonate (2l)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a pale solid in 66% yield (1.421 g, 3.3 mmol). R_f = 0.43 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 9.47 (s, 1H), 7.41 (d, J = 9.0 Hz, 2H), 6.92 (dt, J = 15.1, 4.8 Hz, 1H), 6.83 (d, J = 9.0 Hz, 2H), 6.38 (dt, J = 15.1, 1.8 Hz, 1H), 5.91 (ddt, J = 17.1, 10.4, 4.4 Hz, 1H), 5.29 (d, J = 10.4 Hz, 1H), 5.25 (d, J = 17.1 Hz, 1H), 4.76 (dd, J = 4.8, 1.9 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.06–3.96 (m, 2H), 3.77 (s, 3H), 2.94–2.76 (m, 2H), 1.99–1.90 (m, 2H), 1.77–1.65 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.3, 169.3, 156.2, 154.8, 139.5, 134.9, 131.8, 123.9, 121.6 (2C), 117.4, 114.2 (2C), 74.6, 66.2, 64.5, 55.6, 50.0, 36.0 (2C), 23.0 (2C), 14.4. IR (neat) ν_max (cm^–1): 3340, 2957, 1742, 1663, 1624, 1510, 1408, 1396, 1257, 1244, 1227, 1202, 1169, 1034, 993, 976, 959, 920, 829, 789, 523, 419. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₃H₃₀N₂NaO₆, 453.1996; found, 453.1989.

(E)-4-((3,3-Diethoxypropyl)(8-((2,6-dimethylphenyl)carbamoyl)-1,4-dioxaspiro[4.5]decan-8-yl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2m)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (50% EtOAc/cHex) provided the title compound as a pale solid in 58% yield (1.713 g, 2.9 mmol). R_f = 0.17 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.47 (s, 1H), 7.02–6.84 (m, 3H), 6.77 (dt, J = 15.1, 4.4 Hz, 1H), 6.59 (dt, J = 15.1, 2.2 Hz, 1H), 4.69 (t, J = 4.4, 2.2 Hz, 2H), 4.41 (t, J = 4.7 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.84 (s, 4H), 3.62–3.49 (m, 4H), 3.44–3.30 (m, 2H), 2.52–2.38 (m, 2H), 2.31 (t, J = 11.0 Hz, 2H), 2.09 (s, 6H), 1.96–1.80 (m, 4H), 1.62–1.52 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.4, 168.6, 154.4, 138.4, 134.9 (2C), 134.1, 127.9 (2C), 126.4, 124.0, 107.5, 100.7, 65.9, 65.1, 64.1, 64.0 (2C), 61.9 (2C), 41.1, 35.2 (2C), 31.3 (2C), 30.3, 18.6 (2C), 15.0 (2C), 14.0. IR (neat) ν_max (cm^–1): 3339, 2976, 2935, 1744, 1684, 1621, 1516, 1366, 1248, 1230, 1198, 1171, 1144, 1109, 1094, 1070, 1038, 991, 959, 947, 926, 899, 889, 866, 852, 793, 775. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₃₁H₄₆N₂NaO₉, 613.3096; found, 613.3074.

(E)-Ethyl (4-((1-((4-Methoxyphenyl)carbamoyl)cyclopentyl)(propyl)amino)-4-oxobut-2-en-1-yl)carbonate (2n)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a white solid in 63% yield (1.362 g, 3.15 mmol). R_f = 0.44 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 9.60 (s, 1H), 7.41 (d, J = 9.0 Hz, 2H), 6.91 (dd, J = 13.5, 4.7 Hz, 1H), 6.83 (d, J = 9.0 Hz, 2H), 6.47 (d, J = 13.5 Hz, 1H), 4.80 (d, J = 4.7 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.38 (m, 2H), 2.88–2.75 (m, 2H), 1.95–1.82 (m, 2H), 1.80–1.68 (m, 4H), 1.68–1.55 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 172.2, 169.2, 156.3, 154.9, 139.0, 132.0, 124.0, 121.7 (2C), 114.3 (2C), 74.2, 66.3, 64.6, 55.7, 49.6, 36.5, 24.4 (2C), 23.0 (2C), 14.5, 11.4. IR (neat) ν_max (cm^–1): 2935, 1745, 1664, 1620, 1514, 1448, 1418, 1252, 1234, 1198, 1155, 1140, 1026, 789, 700. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₃N₂O₆, 433.2333; found, 433.2345.

(E)-4-((4-Chlorobenzyl)(1-(naphthalen-2-ylcarbamoyl)cyclopentyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2o)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (40% EtOAc/cHex) provided the title compound as an orange solid in 68% yield (1.819 g, 3.4 mmol). R_f = 0.55 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 9.86 (s, 1H), 8.19 (s, 1H), 7.88–7.72 (m, 3H), 7.48–7.36 (m, 3H), 7.33 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.04 (dt, J = 15.1, 4.7 Hz, 1H), 6.25 (dt, J = 15.1, 1.8 Hz, 1H), 4.73 (dd, J = 4.7, 1.9 Hz, 2H), 4.67 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.90 (d, J = 13.3 Hz, 2H), 1.97–1.86 (m, 2H), 1.76–1.67 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.4, 169.6, 154.6, 140.8, 136.7, 135.9, 134.0, 133.5, 130.6, 129.3 (2C), 128.7, 127.7 (2C), 127.6, 127.5, 126.5, 124.9, 123.2, 120.2, 116.5, 75.0, 66.0, 64.5, 50.8, 36.1 (2C), 22.9 (2C), 14.2. IR (neat) ν_max (cm^–1): 3244, 2957, 2326, 1744, 1663, 1524, 1491, 1429, 1400, 1354, 1256, 1236, 1215, 1194, 1094, 814, 787, 731, 474. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₃₀H₃₁ClN₂NaO₅, 557.1814; found, 557.1788.

(E)-4-((1-((5-Bromopyridin-2-yl)carbamoyl)cyclohexyl)(4-fluorobenzyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2p)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a pale solid in 46% yield (1.294 g, 2.3 mmol). R_f = 0.36 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.96 (s, 1H), 8.26 (d, J = 2.5 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.8, 2.5 Hz, 1H), 7.24 (dd, J = 8.5, 5.3 Hz, 2H), 6.99 (t, J = 8.6 Hz, 2H), 6.94 (dt, J = 15.1, 4.6 Hz, 1H), 6.37 (dt, J = 15.1, 1.9 Hz, 1H), 4.70 (dd, J = 4.7, 1.9 Hz, 2H), 4.66 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.43–2.32 (m, 2H), 1.84–1.75 (m, 2H), 1.70–1.51 (m, 6H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.7, 168.6, 162.1 (d, J = 246.7 Hz), 154.5, 148.7, 140.4, 140.4, 133.5 (d, J = 3.1 Hz), 128.2 (d, J = 8.0 Hz, 2C), 123.2, 115.9 (d, J = 21.6 Hz, 2C), 115.1, 114.2, 66.7, 66.0, 64.4, 47.8, 32.6 (2C), 25.3, 22.6 (2C), 14.2. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −114.5. IR (neat) ν_max (cm^–1): 2934, 2330, 1745, 1502, 1452, 1369, 1288, 1256, 1223, 1190, 1157, 1128, 1092, 1001, 824, 791, 737, 631, 515. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₀BrFN₃O₅, 562.1347; found, 562.1326.

(E)-4-((1-Benzyl-4-((3,4-dimethoxyphenethyl)carbamoyl)piperidin-4-yl)(4-(trifluoromethyl)benzyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2q)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (80% EtOAc/cHex) provided the title compound as a pale oil in 49% yield (1.743 g, 2.45 mmol). R_f = 0.10 (90% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.58 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.31–7.16 (m, 5H), 6.87–6.81 (m, 2H), 6.78 (m, 2H), 6.74 (d, J = 7.81 Hz, 1H), 6.10 (d, J = 15.1 Hz, 1H), 4.68 (d, J = 4.7, 2H), 4.58 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.56 (q, J = 6.8 Hz, 2H), 3.31 (s, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.62–2.58 (m, 2H), 2.56–2.50 (m, 2H), 2.06 (t, J = 11.6 Hz, 2H), 1.75 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.7, 168.7, 154.5, 149.1, 147.7, 142.6, 140.0, 138.0, 131.4, 129.7 (q, J = 32.5 Hz), 129.1 (2C), 128.2 (2C), 127.1, 126.3 (2C), 125.9 (d, J = 3.7 Hz, 2C), 124.0 (d, J = 272.0 Hz), 123.6, 120.8, 111.9, 111.2, 65.9, 64.9, 64.3, 62.7, 55.8, 55.8, 50.3 (2C), 48.3, 40.4, 35.0, 32.8 (2C), 14.1. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −62.4. IR (neat) ν_max (cm^–1): 2915, 1649, 1323, 1279, 1261, 1238, 1159, 1119, 1067, 1028, 1016, 737, 700. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₈H₄₅F₃N₃O₇, 712.3204; found, 712.3232.

(E)-4-((8-(tert-Butylcarbamoyl)-1,4-dioxaspiro[4.5]decan-8-yl)(4-fluorobenzyl)amino)-4-oxobut-2-en-1-yl Ethyl Carbonate (2r)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (50% EtOAc/cHex) provided the title compound as a white solid in 74% yield (1.926 g, 3.7 mmol). R_f = 0.25 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.19 (dd, J = 8.1, 5.3 Hz, 2H), 6.96 (t, J = 8.3 Hz, 2H), 6.80 (dt, J = 15.1, 4.7 Hz, 1H), 6.40–6.30 (br, 1H), 6.26 (d, J = 15.1 Hz, 1H), 4.63 (d, J = 4.7 Hz, 2H), 4.55 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.80 (s, 4H), 2.35–2.24 (m, 2H), 1.96–1.83 (m, 2H), 1.82–1.69 (m, 2H), 1.56–1.46 (m, 2H), 1.19 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.1, 168.2, 161.7 (d, J = 246.0 Hz), 154.3, 138.9, 134.1, 127.8 (d, J = 7.7 Hz, 2C), 123.9, 115.5 (d, J = 21.5 Hz, 2C), 107.3, 65.7 (2C), 65.6, 64.0, 63.9, 50.7 (2C), 47.3, 31.3 (2C), 30.3, 28.2 (3C), 13.9. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −116.0. IR (neat) ν_max (cm^–1): 3357, 2296, 1753, 1664, 1616, 1508, 1410, 1367, 1246, 1219, 1190, 1105, 1095, 1040, 951, 895, 862, 814, 791. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₇H₃₈FN₂O₇, 521.2658; found, 521.2641.

(E)-Ethyl (4-((1-(Isopropylcarbamoyl)cyclopentyl)(p-tolyl)amino)-4-oxobut-2-en-1-yl)carbonate (2s)

It was prepared according to GP-A. Purification of the crude material by silica gel column chromatography (50% EtOAc/cHex) provided the title compound as a pale solid in 67% yield (1.395 g, 3.35 mmol). R_f = 0.27 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.14 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.72 (dt, J = 15.3, 5.1 Hz, 1H), 6.43 (d, J = 7.5 Hz, 1H), 5.68 (d, J = 15.3 Hz, 1H), 4.52 (d, J = 5.1 Hz, 2H), 4.05 (m, 3H), 2.33 (s, 3H), 2.30–2.20 (m, 2H), 1.77–1.66 (m, 2H), 1.58–1.50 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H), 1.13 (d, J = 7.5 Hz, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 173.0, 166.1, 154.5, 138.4, 137.4, 137.1, 129.9 (2C), 129.8 (2C), 124.4, 74.0, 66.1, 64.1, 41.5, 36.8 (2C), 23.2 (2C), 22.3 (2C), 21.1, 14.2. IR (neat) ν_max (cm^–1): 3346, 2943, 1744, 1655, 1510, 1375, 1244, 1227, 1169, 1036, 966, 829, 791, 685, 525. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₃N₂O₅, 417.2384; found, 417.2381.

(R)-4-Benzyl-1-(4-methoxybenzyl)-3-vinyl-1,4-diazaspiro[5.5]undecane-2,5-dione (3a)

It was prepared according to GP-B using 2a. The crude material was purified by silica gel column chromatography (20% EtOAc/cHex) provided the title compound as a colorless oil in 86% yield (71.9 mg, 0.17 mmol). R_f = 0.36 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.34 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.25–7.21 (m, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 5.98 (ddd, J = 16.9, 10.3, 5.5 Hz, 1H), 5.50–5.42 (m, 2H), 5.36 (d, J = 16.9 Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 4.57 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 15.8 Hz, 1H), 3.84 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 2.42 (dddd, J = 17.5, 13.1, 8.7, 4.3 Hz, 1H), 2.05–1.99 (m, 1H), 1.96–1.92 (m, 1H), 1.80 (td, J = 12.9, 5.2 Hz, 1H), 1.74–1.53 (m, 5H), 1.10 (tdd, J = 12.9, 9.0, 3.3 Hz, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.7, 167.2, 158.7, 136.1, 133.2, 130.4, 129.0 (2C), 128.2 (2C), 128.0 (3C), 119.0, 114.0 (2C), 63.1, 61.8, 55.4, 47.6, 45.0, 36.0, 33.3, 24.6, 23.5, 22.3. IR (neat) ν_max (cm^–1): 2926, 2851, 1649, 1512, 1452, 1410, 1354, 1300, 1242, 1175, 1032, 802, 731, 698, 625, 419. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₁N₂O₃, 419.2329; found, 419.2343. [α]_D²⁰ +100.0 (c = 0.2, CHCl₃). SFC-MS (method 5) er: 97:3; tret (major) = 3.875 min (96.9%), tret (minor) = 4.067 min (3.1%).

Benzyl-(R)-3-(2-(1-(2,2-dimethoxyethyl)-2,5-dioxo-3-vinyl-1,4-diazaspiro[5.6]dodecan-4-yl)ethyl)-1H-indole-1-carboxylate (3b)

It was prepared according to GP-B using 2b. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a pale oil in 33% yield (37.8 mg, 0.07 mmol). R_f = 0.22 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.16 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.45–7.36 (m, 4H), 7.32 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 5.84 (ddd, J = 16.8, 10.2, 6.2 Hz, 1H), 5.42 (s, 2H), 5.35 (d, J = 10.8 Hz, 1H), 5.25 (d, J = 17.1 Hz, 1H), 4.67 (t, J = 5.0 Hz, 1H), 4.41 (d, J = 6.1 Hz, 1H), 4.09 (dt, J = 14.6, 7.4 Hz, 1H), 3.54 (dd, J = 13.9, 4.6 Hz, 1H), 3.42 (s, 3H), 3.40–3.35 (m, 4H), 3.17 (dt, J = 13.5, 7.8 Hz, 1H), 2.98 (t, J = 7.7 Hz, 2H), 2.67 (dd, J = 15.7, 11.1 Hz, 1H), 2.18 (dd, J = 15.9, 7.8 Hz, 1H), 2.05–1.99 (m, 2H), 1.88 (q, J = 7.2 Hz, 1H), 1.74–1.61 (m, 4H), 1.55–1.49 (m, 2H), 1.37–1.31 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃) 169.6, 166.2, 150.8, 135.1, 133.4, 133.3, 130.4, 128.9 (2C), 128.8, 128.6 (2C), 124.9, 123.1, 119.5, 119.1, 118.3, 115.5, 103.0, 76.9, 68.7, 67.9, 63.8, 56.0, 55.9, 47.3, 46.4, 39.7, 36.5, 31.5, 31.3, 25.7, 23.6, 22.9. IR (neat) ν_max (cm^–1): 2934, 1736, 1666, 1454, 1396, 1354, 1244, 1180, 1122, 1088, 1049, 1016, 731, 698. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₄H₄₂N₃O₆, 588.3068; found, 588.3048. [α]_D²⁰ +40.0 (c = 0.3, CHCl₃). SFC-MS (method 1) er: 90:10; tret (major) = 5.446 min (89.7%), tret (minor) = 6.092 min (10.3%).

(R)-4-Benzyl-1-butyl-3-vinyl-1,4-diazaspiro[5.6]dodecane-2,5-dione (3c)

It was prepared according to GP-B using 2c. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a colorless oil in 56% yield (41.3 mg, 0.11 mmol). R_f = 0.31 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.41–7.26 (m, 3H), 7.25–7.11 (m, 2H), 5.89 (ddd, J = 17.1, 10.3, 6.0 Hz, 1H), 5.46 (d, J = 14.7 Hz, 1H), 5.42 (dd, J = 10.2, 1.5 Hz, 1H), 5.33 (dd, J = 17.1, 1.5 Hz, 1H), 4.43 (d, J = 6.0 Hz, 1H), 3.83 (d, J = 14.7 Hz, 1H), 3.51 (ddd, J = 13.5, 11.1, 5.1 Hz, 1H), 3.25 (ddd, J = 13.5, 11.2, 4.9 Hz, 1H), 2.89–2.72 (m, 1H), 2.12 (dd, J = 14.7, 9.0 Hz, 1H), 2.08–1.88 (m, 3H), 1.77 (q, J = 7.6 Hz, 2H), 1.71–1.53 (m, 6H), 1.48–1.23 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.0, 165.0, 136.0, 133.3, 128.9 (2C), 128.3 (2C), 127.9, 119.4, 67.6, 61.8, 47.9, 44.2, 40.10, 37.2, 31.6, 31.5, 31.4, 25.9, 23.7, 20.7, 13.8. IR (neat) ν_max (cm^–1): 2926, 1649, 1452, 1416, 1400, 1393, 1358, 1302, 1250, 1205, 727, 698, 419. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₃N₂O₂, 369.2537; found, 369.2542. [α]_D²⁰ +62.0 (c = 1.0, CHCl₃). SFC-MS (method 4) er: 97:3; tret (major) = 2.451 min (96.6%), tret (minor) = 2.586 min (3.4%).

(R)-1-(3,5-Bis(trifluoromethyl)benzyl)-4-(3-methoxypropyl)-3-vinyl-1,4-diazaspiro[5.5]undecane-2,5-dione (3d)

It was prepared according to GP-B using 2d. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a colorless oil in 44% yield (35.3 mg, 0.09 mmol). R_f = 0.39 (40% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.75 (s, 1H), 7.62 (s, 2H), 5.98 (ddd, J = 17.2, 10.4, 4.9 Hz, 1H), 5.41 (dd, J = 10.4, 1.9 Hz, 1H), 5.31 (dd, J = 17.2, 1.9 Hz, 1H), 5.15 (d, J = 16.6 Hz, 1H), 4.75 (dt, J = 5.0, 1.9 Hz, 1H), 4.43 (d, J = 16.6 Hz, 1H), 4.09–3.98 (m, 1H), 3.48–3.37 (m, 2H), 3.30 (s, 3H), 2.93 (dt, J = 13.6, 7.4 Hz, 1H), 2.49–2.32 (m, 1H), 2.06–1.91 (m, 2H), 1.90–1.80 (m, 2H), 1.75–1.66 (m, 2H), 1.64–1.47 (m, 4H), 1.10 (qt, J = 13.8, 4.4 Hz, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.0, 167.6, 141.1, 133.6, 132.0 (q, J = 33.3 Hz, 2C), 126.6 (q, J = 3 Hz, 2C), 123.3 (d, J = 272.8 Hz, 2C), 121.3 (h, J = 3.7 Hz) 118.6, 69.9, 63.3, 63.1, 58.7, 45.1, 43.9, 35.3, 33.7, 27.3, 24.5, 23.4, 22.0. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −62.9. IR (neat) ν_max (cm^–1): 2932, 1745, 1649, 1281, 1240, 1175, 1165, 1121, 1101, 878, 702, 681, 413. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₉F₆N₂O₃, 507.2077; found, 507.2092. [α]_D²⁰ +48.0 (c = 1.0, CHCl₃). SFC-MS (method 7) er: 93:7; tret (minor) = 3.926 min (6.9%), tret (major) = 4.063 min (93.1%).

(R)-1-Butyl-4-(2,4-dimethoxybenzyl)-3,3-dimethyl-6-vinyl Piperazine-2,5-dione (3e)

It was prepared according to GP-B using 2e. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a pale solid in 24% yield (18.0 mg, 0.05 mmol). R_f = 0.37 (40% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.00 (d, J = 8.6 Hz, 1H), 6.49–6.35 (m, 2H), 5.97 (ddd, J = 17.2, 10.3, 5.3 Hz, 1H), 5.40 (dd, J = 10.4, 1.7 Hz, 1H), 5.32 (dd, J = 17.2, 1.7 Hz, 1H), 4.69 (d, J = 16.1 Hz, 1H), 4.65 (dt, J = 5.4, 1.8 Hz, 1H), 4.54 (d, J = 16.1 Hz, 1H), 4.02 (ddd, J = 13.5, 8.9, 6.7 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.77 (ddd, J = 13.5, 8.7, 5.9 Hz, 1H), 1.61–1.52 (m, 2H), 1.48 (s, 3H), 1.37 (s, 3H), 1.36–1.31 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.0, 165.7, 160.0, 157.2, 133.7, 128.4, 118.6, 118.6, 104.4, 98.4, 62.9, 61.9, 55.5, 55.4, 45.3, 39.9, 29.4, 27.1, 25.6, 20.2, 13.9. IR (neat) ν_max (cm^–1): 2934, 1651, 1612, 1512, 1412, 1244, 1175, 1034, 733, 700. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₃₁N₂O₄, 375.2278; found, 375.2283. [α]_D²⁰ +90.0 (c = 0.2, CHCl₃). SFC-MS (method 1) er: 12:88; tret (minor) = 5.687 min (11.8%), tret (major) = 6.215 min (88.2%).

(R)-4-(4-Fluorobenzyl)-1-isopropyl-3,3-dimethyl-6-vinyl Piperazine-2,5-dione (3f)

It was prepared according to GP-B using 2f. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a colorless oil in 32% yield (20.4 mg, 0.06 mmol). R_f = 0.22 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.18 (dd, J = 8.6, 5.4 Hz, 2H), 6.95 (t, J = 8.7 Hz, 2H), 5.91 (ddd, J = 17.1, 10.3, 6.1 Hz, 1H), 5.49 (dd, J = 17.1, 1.5 Hz, 1H), 5.38 (dd, J = 10.4, 1.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.67 (dt, J = 6.1, 1.6 Hz, 1H), 4.51 (d, J = 15.6 Hz, 1H), 4.37 (hept, J = 6.9 Hz, 1H), 1.48 (s, 3H), 1.34 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.2, 166.3, 161.7 (d, J = 245.5 Hz), 135.6, 134.0 (d, J = 3.2 Hz), 128.9 (d, J = 8.1 Hz), 119.5, 115.5 (d, J = 21.5 Hz), 62.0, 60.3, 48.5, 45.3, 27.6, 26.2, 20.4, 20.0. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −115.5. IR (neat) ν_max (cm^–1): 2926, 2851, 1652, 1508, 1412, 1354, 1221, 1194, 1157, 829, 698, 419. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₄FN₂O₂, 319.1816; found, 319.1832. [α]_D²⁰ +16.0 (c = 0.5, CHCl₃). SFC-MS (method 3) er: 88:12; tret (major) = 3.419 min (87.8%), tret (minor) = 3.545 min (12.2%).

Methyl (R)-2-(1-(4-Methoxybenzyl)-2,5-dioxo-3-vinyl-1,4-diazaspiro[5.5]undecan-4-yl)acetate (3g)

It was prepared according to GP-B using 2g. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a pale oil in 77% yield (62.78 mg, 0.15 mmol). R_f = 0.16 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.15 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.02 (m, 1H), 5.43 (d, J = 10.3 Hz, 1H), 5.39 (d, J = 17.1 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.69 (d, J = 6.1 Hz, 1H), 4.49 (d, J = 15.8 Hz, 1H), 4.42 (d, J = 17.1 Hz, 1H), 3.78 (s, 3H), 3.77–3.74 (m, 4H), 2.24–2.14 (m, 1H), 1.99–1.92 (m, 2H), 1.76–1.53 (m, 6H), 1.10–1.01 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.3, 169.2, 167.1, 158.9, 133.2, 130.6, 128.2 (2), 119.9, 114.3 (2), 64.6, 63.1, 55.6, 52.8, 47.0, 45.3, 36.2, 33.0, 24.8, 23.4, 22.6. IR (neat) ν_max (cm^–1): 2929, 1747, 1649, 1512, 1427, 1412, 1400, 1263, 1244, 1209, 1176, 1032, 1014, 804. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₉N₂O₅, 401.2071; found, 401.2084. [α]_D²⁰ +30.0 (c = 1.0, CHCl₃). SFC-MS (method 4) er: 92:8; tret (major) = 3.718 min (92.0%), tret (minor) = 3.971 min (8.0%).

Methyl (R)-2-(6,9-Dioxo-5-phenethyl-7-vinyl-5,8-diazaspiro[3.5]nonan-8-yl)acetate (3h)

It was prepared according to GP-B using 2h. The crude material was purified by silica gel column chromatography (50% EtOAc/cHex) provided the title compound as a pale oil in 95% yield (67.7 mg, 0.19 mmol). R_f = 0.05 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.35–7.27 (m, 2H), 7.25–7.19 (m, 3H), 5.82 (ddd, J = 16.9, 10.2, 6.6 Hz, 1H), 5.40–5.25 (m, 2H), 4.58–4.46 (m, 2H), 3.98 (ddd, J = 13.7, 10.4, 5.4 Hz, 1H), 3.82–3.71 (m, 4H), 3.56 (ddd, J = 13.7, 10.2, 5.8 Hz, 1H), 2.97 (ddd, J = 13.2, 10.2, 5.4 Hz, 1H), 2.87–2.75 (m, 2H), 2.52–2.43 (m, 2H), 2.36–2.27 (m, 1H), 2.13–2.00 (m, 1H), 1.89–1.78 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃) 169.4, 168.8, 164.9, 138.5, 132.4, 128.9 (2C), 128.7 (2C), 126.7, 119.9, 64.3, 62.3, 52.5, 46.4, 45.3, 35.6, 34.4, 30.5, 14.5. IR (neat) ν_max (cm^–1): 2953, 1749, 1655, 1454, 1412, 1402, 1283, 1257, 1207, 1178, 1148, 748, 700, 505. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₅N₂O₄, 357.1809; found, 357.1815. [α]_D²⁰ +12.0 (c = 1.0, CHCl₃). SFC-MS (method 1) er: 88:12; tret (minor) = 5.673 min (12.3%), tret (major) = 6.190 min (87.7%).

(R)-6-(4-Chlorobenzyl)-9-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8-vinyl-6,9-diazaspiro[4.5]decane-7,10-dione (3i)

It was prepared according to GP-B using 2i. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) provided the title compound as a brown oil in 97% yield (87.9 mg, 0.19 mmol). R_f = 0.18 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.29 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 5.95 (ddd, J = 16.9, 10.3, 6.3 Hz, 1H), 5.42–5.34 (m, 2H), 4.98 (d, J = 16.0 Hz, 1H), 4.92 (dt, J = 6.3, 1.5 Hz, 1H), 4.25 (d, J = 16.0 Hz, 1H), 4.23 (s, 4H), 2.57–2.51 (m, 1H), 2.34 (ddd, J = 12.8, 7.2, 4.7 Hz, 1H), 1.97–1.71 (m, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.7, 166.4, 143.7, 143.0, 136.5, 133.3, 132.9 (2C), 128.9 (2C), 127.8 (2C), 120.4, 120.0, 117.6, 116.2, 71.0, 66.3, 64.3, 64.3, 46.5, 41.5, 35.8, 27.0, 26.4. IR (neat) ν_max (cm^–1): 3292, 2932, 1744, 1664, 1504, 1402, 1302, 1254, 1240, 1202, 1175, 1067, 885, 800, 791, 734, 652, 420. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₅H₂₅ClN₂NaO₄, 475.1395; found, 475.1387. [α]_D²⁰ +22.0 (c = 1.0, CHCl₃). SFC-MS (method 2): er: 95:5; tret (major) = 6.118 min (95.1%), tret (minor) = 6.417 min (4.9%).

It was also prepared according to GP-B from 430.5 mg (1.00 mmol) of 2i, providing the title compound in 89% yield (303.0 mg, 0.89 mmol).

(R)-4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-(prop-2-yn-1-yl)-3-vinyl-1,4-diazaspiro[5.5]undecane-2,5-dione (3j)

It was prepared according to GP-B using 2j. The crude material was purified by silica gel column chromatography (40% EtOAc/cHex), providing the title compound as a pale oil in 73% yield (55.5 mg, 0.15 mmol). R_f = 0.16 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 6.87 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.6, 2.5 Hz, 1H), 5.91 (ddd, J = 16.7, 10.3, 5.9 Hz, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.32 (dd, J = 10.4, 1.6 Hz, 1H), 4.90 (d, J = 5.9 Hz, 1H), 4.41 (dd, J = 17.6, 2.4 Hz, 1H), 4.30–4.22 (m, 5H), 2.41 (tdd, J = 13.0, 8.8, 4.6 Hz, 1H), 2.26 (t, J = 2.5 Hz, 1H), 2.23–2.19 (m, 1H), 2.14–2.10 (m, 1H), 2.01 (td, J = 12.8, 5.0 Hz, 1H), 1.91 (td, J = 12.9, 4.8 Hz, 1H), 1.76–1.68 (m, 4H), 1.22 (dd, J = 10.6, 6.4 Hz, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.0, 166.5, 143.9, 143.1, 133.1, 133.1, 120.5, 120.2, 117.9, 116.7, 80.0, 71.8, 65.9, 64.4, 64.4, 63.1, 35.8, 32.8, 31.5, 24.6, 23.2, 22.3. IR (neat) ν_max (cm^–1): 2932, 1647, 1504, 1404, 1308, 1292, 1279, 1261, 1242, 1213, 1065, 887, 746, 663, 621, 409. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₅N₂O₄, 381.1809; found, 381.1813. [α]_D²⁰ +10.0 (c = 1.0, CHCl₃). SFC-MS (method 2) er: 94:6; tret (minor) = 4.943 min (5.8%), tret (major) = 5.505 min (94.2%).

(R)-5-(4-Bromobenzyl)-8-(2,6-dimethylphenyl)-7-vinyl-5,8-diazaspiro[3.5]nonane-6,9-dione (3k)

It was prepared according to GP-B using 2k. The crude material was purified by silica gel column chromatography (20% EtOAc/cHex), providing the title compound as a pale oil in 46% yield (41.7 mg, 0.09 mmol). R_f = 0.19 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.46 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.14–7.05 (m, 4H), 5.82 (ddd, J = 17.0, 9.9, 8.4 Hz, 1H), 5.32–5.20 (m, 2H), 5.09 (d, J = 16.0 Hz, 1H), 4.74 (d, J = 16.0 Hz, 1H), 4.59 (d, J = 8.4 Hz, 1H), 2.87–2.78 (m, 1H), 2.69 (ddt, J = 12.3, 8.0, 3.7 Hz, 1H), 2.51–2.42 (m, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.09–2.00 (m, 1H), 1.85–1.78 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 167.3, 167.1, 137.1, 136.9, 134.9, 132.0 (2C), 131.1, 129.2, 128.8, 128.5 (2C), 128.4, 121.9 (2C), 121.3, 66.3, 63.1, 45.8, 33.9, 30.4, 18.7, 18.1, 14.8. IR (neat) ν_max (cm^–1): 2957, 1663, 1487, 1398, 1306, 1284, 1221, 1161, 1009, 924, 771, 731, 473. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₆BrN₂O₂, 453.1172; found, 453.1162. [α]_D²⁰ −38.0 (c = 2.0, CHCl₃). SFC-MS (method 2) er: 91:9; tret (major) = 4.955 min (91.1%), tret (minor) = 5.126 min (8.9%).

(R)-6-Allyl-9-(4-methoxyphenyl)-8-vinyl-6,9-diazaspiro[4.5]decane-7,10-dione (3l)

It was prepared according to GP-B using 2l. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex), providing the title compound as a yellow oil in 96% yield (65.4 mg, 0.19 mmol). R_f = 0.17 (30% EtOAc/cHex). 1 mmol scale: prepared according to GP-B using 2l. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex) providing the title compound as a yellow oil in 89% yield (303.0 mg, 0.89 mmol). ¹H NMR (600 MHz, CDCl₃): δ 7.17 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 6.02–5.83 (m, 2H), 5.37–5.29 (m, 2H), 5.25–5.09 (m, 2H), 4.83 (d, J = 6.5 Hz, 1H), 4.35–4.24 (m, 1H), 3.79 (s, 3H), 3.77–3.65 (m, 1H), 2.61 (ddd, J = 14.3, 8.4, 7.2 Hz, 1H), 2.36–2.30 (m, 1H), 2.13–2.07 (m, 1H), 2.01–1.95 (m, 1H), 1.94–1.68 (m, 4H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.0, 165.4, 158.6, 134.0, 133.6, 132.5, 128.2 (2C), 120.2, 116.6, 114.5 (2C), 70.8, 66.4, 55.5, 46.4, 41.6, 36.0, 27.2, 26.6. IR (neat) ν_max (cm^–1): 2957, 1655, 1508, 1425, 1404, 1298, 1279, 1238, 1180, 1134, 1030, 926, 827, 532. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₅N₂O₃, 341.1860; found, 341.1864. [α]_D²⁰ −14.0 (c = 1.0, CHCl₃). SFC-MS (method 4) er: 93:7; tret (minor) = 4.244 min (7.3%), tret (major) = 4.479 min (92.7%).

(R)-9-(3,3-Diethoxypropyl)-12-(2,6-dimethylphenyl)-11-vinyl-1,4-dioxa-9,12-diazadispiro[4.2.58.25]pentadecane-10,13-dione (3m)

It was prepared according to GP-B using 2m. The crude material was purified by silica gel column chromatography (50% EtOAc/cHex), providing the title compound as a colorless oil in 91% yield (91.1 mg, 0.18 mmol). R_f = 0.14 (40% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.11 (t, J = 7.5 Hz, 1H), 7.08–6.98 (m, 2H), 5.79 (ddd, J = 16.8, 10.0, 8.3 Hz, 1H), 5.19 (d, J = 9.9 Hz, 1H), 5.11 (d, J = 16.8 Hz, 1H), 4.60 (t, J = 5.6 Hz, 1H), 4.53 (d, J = 8.3 Hz, 1H), 3.93–3.87 (m, 4H), 3.77–3.64 (m, 3H), 3.55–3.48 (m, 2H), 3.42 (ddd, J = 13.8, 10.8, 4.9 Hz, 1H), 2.54 (td, J = 13.2, 4.9 Hz, 1H), 2.33–2.24 (m, 2H), 2.18 (td, J = 13.4, 4.1 Hz, 1H), 2.13 (s, 3H) 2.12 (s, 3H), 2.10–2.04 (m, 3H), 1.88 (dtd, J = 13.2, 6.0, 3.0 Hz, 1H), 1.71–1.65 (m, 2H), 1.20 (q, J = 7.1 Hz, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 167.6, 166.2, 136.6 (2C), 134.3, 129.1, 128.7, 128.3, 121.8, 107.6, 101.0, 65.1, 64.5, 64.2, 61.8, 61.7, 61.1, 39.4, 33.9, 32.7, 31.8, 31.2, 30.7, 26.9, 18.5, 17.7, 15.3 (2C). IR (neat) ν_max (cm^–1): 2934, 2874, 1655, 1416, 1371, 1277, 1167, 1121, 1103, 1090, 1051, 1036, 930, 903, 783. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₈H₄₀N₂NaO₆, 523.2779; found, 523.2748. [α]_D²⁰ −124.0 (c = 1.0, CHCl₃). SFC-MS (method 1) er: 90:10; tret (minor) = 5.059 min (9.6%), tret (major) = 6.027 min (90.4%).

(R)-9-(4-Methoxyphenyl)-6-propyl-8-vinyl-6,9-diazaspiro[4.5]decane-7,10-dione (3n)

It was prepared according to GP-B using 2n. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex), providing the title compound as a colorless oil in 98% yield (67.1 mg, 0.20 mmol). R_f = 0.23 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.17 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 5.90 (ddd, J = 16.9, 10.3, 6.5 Hz, 1H), 5.38–5.27 (m, 2H), 4.80 (d, J = 6.5 Hz, 1H), 3.80 (s, 3H), 3.53 (ddd, J = 13.4, 11.2, 5.2 Hz, 1H), 3.00 (ddd, J = 13.4, 11.3, 4.9 Hz, 1H), 2.64 (tt, J = 9.8, 4.8 Hz, 1H), 2.35–2.29 (m, 1H), 2.06–1.97 (m, 2H), 1.93–1.77 (m, 5H), 1.67–1.56 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.1, 165.6, 158.7, 133.7, 132.6, 128.2 (2C), 120.1, 114.5 (2C), 70.7, 66.5, 55.6, 46.4, 41.6, 36.1, 27.2, 26.5, 22.8, 11.7. IR (neat) ν_max (cm^–1): 2959, 2934, 1647, 1512, 1420, 1300, 1240, 1034, 928, 831, 808, 563, 527. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₇N₂O₃, 343.2016; found, 343.2033. [α]_D²⁰ −34.0 (c = 1.0, CHCl₃). SFC-MS (method 5) er: 95:5; tret (major) = 3.701 min (95.1%), tret (minor) = 3.945 min (4.9%).

(R)-6-(4-Chlorobenzyl)-9-(naphthalen-2-yl)-8-vinyl-6,9-diazaspiro[4.5]decane-7,10-dione (3o)

It was prepared according to GP-B using 2o. The crude material was purified by silica gel column chromatography (20% EtOAc/cHex), providing the title compound as a pale oil in 94% yield (83.7 mg, 0.19 mmol). R_f = 0.36 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.89 (d, J = 8.8 Hz, 1H), 7.86–7.81 (m, 2H), 7.79 (d, J = 2.1 Hz, 1H), 7.54–7.49 (m, 2H), 7.45 (dd, J = 8.7, 2.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.07 (ddd, J = 17.1, 10.3, 6.1 Hz, 1H), 5.43 (dd, J = 17.1, 1.5 Hz, 1H), 5.39 (dd, J = 10.3, 1.5 Hz, 1H), 5.18 (dt, J = 6.1, 1.6 Hz, 1H), 5.05 (d, J = 15.8 Hz, 1H), 4.29 (d, J = 15.9 Hz, 1H), 2.66–2.59 (m, 1H), 2.46 (ddd, J = 13.4, 7.3, 4.7 Hz, 1H), 2.06–1.92 (m, 3H), 1.92–1.86 (m, 1H), 1.85–1.76 (m, 2H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 171.0, 166.4, 137.3, 136.5, 133.5, 133.4, 133.0, 132.3, 129.1, 128.9 (2C), 128.0, 127.9 (2C), 127.7, 126.6, 126.6, 125.1, 124.7, 120.4, 71.2, 66.3, 46.6, 41.6, 36.0, 27.1, 26.5. IR (neat) ν_max (cm^–1): 2957, 1649, 1491, 1398, 1308, 1296, 1273, 1227, 1092, 1014, 808, 793, 748, 733, 476. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₇H₂₆ClN₂O₂, 445.1677; found, 445.1680. [α]_D²⁰ +33.0 (c = 2.0, CHCl₃). SFC-MS (method 6) er: 95:5; tret (major) = 11.817 min (95.2%), tret (minor) = 13.022 min (4.8%).

(R)-4-(5-Bromopyridin-2-yl)-1-(4-fluorobenzyl)-3-vinyl-1,4-diazaspiro[5.5]undecane-2,5-dione (3p)

It was prepared according to GP-B using 2p. The crude material was purified by silica gel column chromatography (20% EtOAc/cHex), providing the title compound as a pale oil in 93% yield (87.9 mg, 0.19 mmol). R_f = 0.39 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 8.46 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.8, 2.5 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 8.6, 5.4 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 6.23 (dt, J = 4.4, 2.4 Hz, 1H), 6.08 (ddd, J = 17.3, 10.6, 4.2 Hz, 1H), 5.23 (dd, J = 10.6, 2.4 Hz, 1H), 5.15 (dd, J = 17.3, 2.4 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.47 (d, J = 16.0 Hz, 1H), 2.41–2.30 (m, 1H), 2.26–2.19 (m, 1H), 1.96–1.91 (m, 1H), 1.77 (dt, J = 13.0, 6.5 Hz, 1H), 1.73–1.49 (m, 5H), 1.13–1.04 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.6, 167.5, 161.9 (d, J = 245.4 Hz), 150.2, 148.9, 140.0, 134.1, 134.0 (d, J = 3.2 Hz), 128.6 (d, J = 8.0 Hz, 2C), 121.9, 117.5, 117.1, 115.5 (d, J = 21.5 Hz, 2C), 63.9, 60.4, 44.9, 35.7, 33.0, 24.5, 23.3, 22.2. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −115.5. IR (neat) ν_max (cm^–1): 2934, 1680, 1643, 1508, 1454, 1394, 1366, 1263, 1221, 1140, 1095, 814, 731, 411. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₄BrFN₃O₂, 472.1030; found, 472.1040. [α]_D²⁰ +40.0 (c = 2.0, CHCl₃). SFC-MS (method 2) er: 84:16; tret (major) = 4.565 min (84.2%), tret (minor) = 4.796 min (15.8%).

9-Benzyl-4-(3,4-dimethoxyphenethyl)-1-(4-(trifluoromethyl)benzyl)-3-vinyl-1,4,9-triazaspiro[5.5]undecane-2,5-dione (3q)

It was prepared according to GP-C using 2q. The crude material was purified by silica gel column chromatography (80% EtOAc/cHex), providing the title compound as pale solid in 47% yield (58.4 mg, 0.09 mmol). R_f = 0.16 (80% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.57 (d, J = 8.1 Hz, 2H), 7.35–7.17 (m, 7H), 6.83–6.66 (m, 3H), 5.92 (ddd, J = 17.2, 10.3, 5.1 Hz, 1H), 5.39 (dd, J = 10.4, 1.9 Hz, 1H), 5.27 (dd, J = 17.2, 1.8 Hz, 1H), 5.13 (d, J = 16.5 Hz, 1H), 4.52–4.49 (m, 1H), 4.40 (d, J = 16.6 Hz, 1H), 4.31–4.23 (m, 1H), 3.92–3.79 (m, 7H), 3.51 (t, J = 12.2 Hz, 2H), 3.07–2.96 (m, 2H), 2.91–2.85 (m, 2H), 2.74–2.70 (m, 2H), 2.47–2.38 (m, 1H), 2.02–1.91 (m, 2H), 1.65 (d, J = 13.5 Hz, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.1, 166.8, 149.2, 148.0, 142.2, 130.5, 133.3, 129.5 (q J = 32.4 Hz), 129.3 (2C) 129.3, 128.4 (2C), 126.7 (2C), 125.7 (q, J = 3.6 Hz 2C), 124.2 (q, J = 272.0 Hz), 120.9, 118.7, 112.2, 111.4, 70.0, 63.0, 62.8, 61.0, 56.0, 56.0, 51.1, 49.0, 47.0, 45.3, 33.0, 29.8; 1 quaternary aromatic C is not visible. ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −62.0. IR (neat) ν_max (cm^–1): 2932, 1649, 1323, 1279, 1261, 1238, 1159, 1119, 1067, 1028, 1016, 737, 700. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₅H₃₉F₃N₃O₄, 622.2814; found, 622.2827.

12-(tert-Butyl)-9-(4-fluorobenzyl)-11-vinyl-1,4-dioxa-9,12-diazadispiro[4.2.58.25]pentadecane-10,13-dione (3r)

It was prepared according to GP-C using 2r. The crude material was purified by silica gel column chromatography (30% EtOAc/cHex), providing the title compound as a white solid in 92% yield (72.2 mg, 0.18 mmol). R_f = 0.30 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.17 (dd, J = 8.5, 5.4 Hz, 2H), 6.97 (t, J = 8.7 Hz, 2H), 5.97 (ddd, J = 17.2, 10.4, 5.4 Hz, 1H), 5.49 (dd, J = 17.2, 1.7 Hz, 1H), 5.37 (dd, J = 10.5, 1.8 Hz, 1H), 4.98–4.84 (m, 2H), 4.31 (d, J = 16.0 Hz, 1H), 3.96–3.84 (m, 4H), 2.66 (td, J = 13.1, 5.4 Hz, 1H), 2.09–1.96 (m, 4H), 1.81–1.73 (m, 1H), 1.58 (dq, J = 10.5, 2.7 Hz, 2H), 1.48 (s, 9H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.1, 167.7, 161.9 (d, J = 245.0 Hz), 137.2, 134.0 (d, J = 3.1 Hz), 128.3 (d, J = 7.6 Hz, 2C), 118.8, 115.4 (d, J = 21.5 Hz, 2C), 107.9, 64.5, 64.2, 62.3, 60.8, 58.7, 45.3, 32.2, 32.2, 32.0, 30.8, 28.4 (3C). ¹⁹F NMR{¹H} (376 MHz, CDCl₃): δ −116.0. IR (neat) ν_max (cm^–1): 2939, 1651, 1508, 1400, 1221, 1196, 1178, 1157, 1097, 1034, 928, 808, 486, 465, 413. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₂FN₂O₄, 431.2341; found, 431.2341.

9-Isopropyl-6-(p-tolyl)-8-vinyl-6,9-diazaspiro[4.5]decane-7,10-dione (3s)

It was prepared according to GP-C using 2s. The crude material was purified by silica gel column chromatography (20% EtOAc/cHex), providing the title compound as a pale solid in 85% yield (55.52 mg, 0.17 mmol). R_f = 0.25 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.21 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.02 (ddd, J = 17.2, 10.4, 5.6 Hz, 1H), 5.53 (dd, J = 17.2, 1.6 Hz, 1H), 5.39 (dd, J = 10.4, 1.7 Hz, 1H), 4.71 (dt, J = 5.7, 1.8 Hz, 1H), 4.55 (hept, J = 6.9 Hz, 1H), 2.50–2.42 (m, 1H), 2.36 (s, 3H), 2.27 (ddd, J = 14.3, 8.0, 6.6 Hz, 1H), 2.15 (ddd, J = 13.9, 8.2, 6.1 Hz, 1H), 1.76–1.64 (m, 3H), 1.56 (dt, J = 8.6, 6.2 Hz, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H), 1.23–1.12 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.6, 167.2, 138.4, 135.9, 135.6, 130.2 (4C), 119.2, 71.2, 60.4, 47.8, 42.6, 36.1, 26.4, 26.0, 21.3, 20.6, 20.1. IR (neat) ν_max (cm^–1): 2942, 1649, 1510, 1393, 1362, 1215, 1188, 949, 802. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₇N₂O₂, 327.2067; found, 327.2065.

Synthesis of (E/Z)-4-Benzyl-3-ethylidene-1-(4-methoxybenzyl)-1,4-diazaspiro[5.5]undecane-2,5-dione (4a/4b)

To a solution of 3a (84 mg, 0.2 mmol, 1 equiv) in THF (0.033 M, 6.66 mL) at 0 °C was added NaH (0.22 mmol, 1.1 equiv), which then was allowed to reach rt and stirred for 30 min. The reaction mixture was quenched with a saturated solution of NH₄Cl (2 mL) and extracted with ethyl acetate (2 × 5 mL), the combined organic layers were dried with Na₂SO₄, and the solvent was removed under reduced pressure. The reaction mixture was purified by silica gel column chromatography (25% EtOAc/cHex), affording the product as a colorless solid, as a 1/1 mixture of isomers in 98% yield. The absolute configurations of the two isomers have been assigned with NOESY experiments.

(E)-4-Benzyl-3-ethylidene-1-(4-methoxybenzyl)-1,4-diaza Spiro[5.5]undecane-2,5-dione (4a)

R_f = 0.45 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.33 (dd, J = 8.2, 7.0 Hz, 2H), 7.29–7.22 (m, 1H), 7.21–7.13 (m, 4H), 6.83 (d, J = 8.6 Hz, 2H), 5.72 (q, J = 7.4 Hz, 1H), 4.91 (s, 2H), 4.76 (s, 2H), 3.79 (s, 3H), 2.21–2.15 (m, 2H), 2.12 (d, J = 7.4 Hz, 3H), 1.81 (qt, J = 11.8, 3.2 Hz, 2H), 1.71–1.50 (m, 5H), 1.11–1.02 (m, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 168.6, 163.5, 158.7, 137.4, 132.8, 130.9, 128.9 (2C), 128.5 (2C), 127.4, 126.3 (2C), 121.0, 114.1 (2C), 62.7, 55.4, 49.4, 43.9, 33.7 (2C), 25.1, 23.3 (2C), 14.1. IR (neat) ν_max (cm^–1) (1/1 mixture of isomers): 2934, 1672, 1630, 1612, 1387, 1356, 1304, 1242, 810, 727, 700, 407. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₃N₂O₂, 299.1754; found, 299.1759.

(Z)-4-Benzyl-3-ethylidene-1-(4-methoxybenzyl)-1,4-diaza Spiro[5.5]undecane-2,5-dione (4b)

R_f = 0.30 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.31 (dd, J = 8.1, 6.7 Hz, 2H), 7.26 (d, J = 3.5 Hz, 1H), 7.21–7.17 (m, 2H), 7.06 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.36 (q, J = 7.7 Hz, 1H), 4.88 (s, 2H), 4.71 (s, 2H), 3.78 (s, 3H), 2.18–2.08 (m, 2H), 1.84 (d, J = 7.7 Hz, 3H), 1.81–1.71 (m, 2H), 1.70–1.50 (m, 6H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 170.1, 165.4, 158.7, 137.2, 134.8, 131.0, 128.7 (2C), 128.4 (2C), 127.5, 126.8 (2C), 120.4, 114.0 (2C), 63.1, 55.4, 50.1, 44.1, 33.5 (2C), 25.1, 23.6 (2C), 14.2.

Synthesis of (R)-4-Benzyl-3-ethyl-1-(4-methoxybenzyl)-1,4-diazaspiro[5.5]undecane-2,5-dione (5)

To a solution of 3a (84 mg, 0.2 mmol, 1 equiv) in EtOAc (4 mL), 10% Pd/C was added (21 mg). The reaction flask was filled with H₂ and then was degassed under vacuum, and the flask was backfilled with H₂. The procedure was repeated three times, and then the reaction mixture was stirred overnight. The crude was filtrated through a Celite pad, and the solvent was removed under reduced pressure, affording the product without further purification as a white solid in 99% yield (83 mg). R_f = 0.36 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.39–7.31 (m, 2H), 7.31–7.28 (m, 1H), 7.25–7.20 (m, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.39 (d, J = 14.9 Hz, 1H), 4.76 (d, J = 15.7 Hz, 1H), 4.56 (d, J = 15.7 Hz, 1H), 3.97 (d, J = 14.9 Hz, 1H), 3.92 (dd, J = 6.6, 3.5 Hz, 1H), 3.78 (s, 3H), 2.24 (qt, J = 13.0, 4.3 Hz, 1H), 2.12–1.90 (m, 4H), 1.89–1.84 (m, 1H), 1.81–1.72 (m, 3H), 1.69–1.57 (m, 2H), 1.12 (qt, J = 13.2, 4.0 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.8, 168.1, 158.6, 136.3, 130.6, 129.0 (2C), 128.0 (2C), 127.9, 127.9 (2C), 114.0 (2C), 62.7, 59.2, 55.4, 46.9, 45.3, 35.2, 34.4, 25.6, 24.5, 23.1, 22.7, 9.9. IR (neat) ν_max (cm^–1): 2934, 1636, 1614, 1514, 1456, 1427, 1418, 1273, 1250, 1175, 1129, 1040, 797, 739, 702, 600, 492. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₃N₂O₃, 421.2486; found, 421.2495. [α]_D²⁰ +72.0 (c = 1.0, CHCl₃). SFC-MS (method 5) er: 91:9; tret (major) = 4.161 min (90.6%), tret (minor) = 4.490 min (9.4%).

Synthesis of (R,E)-4-Benzyl-3-(4-hydroxystyryl)-1-(4-methoxy benzyl)-1,4-diazaspiro[5.5]undecane-2,5-dione (6)

To a solution of 3a (84 mg, 0.2 mmol, 1.0 equiv), 4-iodophenol (88 mg, 0.4 mmol, 2.0 equiv), palladium(II) acetate (9 mg, 0.04 mmol, 0.2 equiv), and triethyl phosphite (7 μL, 0.04 mmol, 0.20 equiv) in 1,4-dioxane (3.6 mL) was added N,N-diisopropylethylamine (70 μL, 0.4 mmol, 2.0 equiv) and refluxed overnight. The reaction mixture was diluted with DCM (8 mL), washed with 1 M HCl (4 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (30% EtOAc/cHex), affording the product as a pale solid, in 64% yield (65 mg).

R_f = 0.22 (30% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.52–7.44 (m, 1H), 7.37–7.33 (m, 2H), 7.33–7.28 (m, 1H), 7.27–7.23 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 15.8 Hz, 1H), 5.95 (dd, J = 15.8, 6.7 Hz, 1H), 5.43 (d, J = 14.8 Hz, 1H), 4.97 (d, J = 15.9 Hz, 1H), 4.69 (d, J = 6.7 Hz, 1H), 4.48 (d, J = 15.9 Hz, 1H), 3.96 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 2.41 (qt, J = 12.8, 4.2 Hz, 1H), 2.10–2.04 (m, 1H), 2.02–1.95 (m, 1H), 1.87–1.60 (m, 6H), 1.13 (qt, J = 12.4, 3.2 Hz, 1H). ¹³C NMR{¹H} (151 MHz, CDCl₃): δ 169.5, 168.1, 158.8, 157.1, 136.1, 134.9, 130.0, 129.1 (2C), 128.3 (2C), 128.2 (2C), 128.0, 127.9 (2C), 127.5, 120.4, 116.0 (2C), 114.2 (2C), 63.3, 61.7, 55.4, 47.6, 45.5, 36.2, 33.4, 24.6, 23.4, 22.4. IR (neat) ν_max (cm^–1): 2934, 1657, 1632, 1609, 1510, 1414, 1261, 1244, 1171, 908, 802, 725, 698, 519, 444, 434. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₂H₃₅N₂O₄, 511.2591; found, 511.2573. [α]_D²⁰ +20.0 (c = 0.3, CHCl₃). SFC-MS (method 5) er: 96:4; tret (major) = 5.514 min (95.7%), tret (minor) = 5.806 min (4.3%).

Synthesis of (R)-4-Benzyl-3-vinyl-1,4-diazaspiro[5.5]undecane-2,5-dione (7)

To a solution of 3a (84 mg, 0.2 mmol, 1 equiv) in MeCN (0.2 mL) was added a solution of CAN (329 mg, 0.6 mmol, 3 equiv) in H₂O (0.2 mL), and it was stirred at room temperature for 3 h. The reaction mixture was extracted with DMC (3 × 2 mL), the combined organic layers were dried with Na₂SO₄, and the solvent was removed under reduced pressure. The crude was purified by silica gel column chromatography (40% EtOAc/cHex), affording the product as a white solid, in 95% yield (57 mg).

mp 138.9 °C. R_f = 0.23 (50% EtOAc/cHex). ¹H NMR (600 MHz, CDCl₃): δ 7.36–7.27 (m, 3H), 7.21–7.14 (m, 2H), 6.79 (s, 1H), 5.87 (ddd, J = 17.1, 10.2, 6.0 Hz, 1H), 5.51 (d, J = 14.8 Hz, 1H), 5.44 (dd, J = 10.3, 1.5 Hz, 1H), 5.35 (dd, J = 17.1, 1.5 Hz, 1H), 4.36 (d, J = 6.1 Hz, 1H), 3.75 (d, J = 14.8 Hz, 1H), 2.31 (td, J = 13.6, 4.4 Hz, 1H), 1.91 (td, J = 13.1, 3.9 Hz, 1H), 1.83–1.74 (m, 2H), 1.72–1.64 (m, 3H), 1.46–1.30 (m, 3H). ¹³C NMR {¹H} (151 MHz, CDCl₃): δ 170.0, 165.9, 135.8, 132.6, 129.0 (2C), 128.3 (2C), 128.1, 119.8, 61.8, 58.3, 47.5, 36.9, 34.5, 24.6, 20.6, 20.6. IR (neat) ν_max (cm^–1): 2930, 1659, 1649, 1427, 1290, 1269, 1240, 1167, 939, 824, 816, 750, 731, 700, 434. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₃N₂O₂, 299.1754; found, 299.1759. [α]_D²⁰ +44.0 (c = 0.5, CHCl₃). SFC-MS (method 1) er: 96:4; tret (major) = 5.754 min (96.1%), tret (minor) = 6.266 min (3.9%).

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01994.

• Additional optimization studies, X-ray crystallography data, and copies of ¹H and ¹³C NMR spectra (PDF)

• Data for 7 (CIF)

Accession Codes

CCDC 1902629 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.