Highly Diastereo- and Enantioselective Synthesis of Spiro

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Cite This: J. Org. Chem. 2018, 83, 8645−8654

Highly Diastereo- and Enantioselective Synthesis of Spirotetrahydrofuran-pyrazolones via Organocatalytic Cascade Reaction between γ‑Hydroxyenones and Unsaturated Pyrazolones Buddhadeb Mondal, Rajendra Maity, and Subhas Chandra Pan* Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India

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S Supporting Information *

ABSTRACT: The first diastereo- and enantioselective synthesis of spiro-tetrahydrofuran-pyrazolones is reported via organocatalytic asymmetric cascade oxa-Michael/Michael reaction between γ-hydroxyenones and unsaturated pyrazolones. Bifunctional squaramide catalyst was found to be effective for this reaction. With 10 mol % of catalyst, excellent results were attained for a variety of spiropyrazolones under mild reaction conditions.

O

Scheme 1. Organocatalytic Asymmetric Synthesis of Spiropyrazolones from Unsaturated Pyrazolones

ver the past decade, pyrazole and pyrazolone derivatives have been extensively studied due to their diverse applications as potential pharmaceutical agents, synthetic scaffolds, photographic couplers, and chelating agents etc.1 In particular, spiropyrazolones combining stereogenic cycloalkane/cycloalkane heterocycle and pyrazolone motifs have attracted attention because of their potent bioactivities in medicinal chemistry.2 For instance, pyrazolone-related spirocyclic derivatives A−D (Figure 1) can act as an antibacterial agent2a and also as a type-4-phosphodiesterase inhibitor.2b,c

Figure 1. Biologically active spiropyrazolone derivatives.

binucleophilic reactants to provide spiropyrazolones via both aminocatalysis and oxidative NHC catalysis.7 Ramon and coworkers first reported organocatalytic asymmetric synthesis of spiropyrazolones from unsaturated pyrazolones via a threecomponent reaction with aldehydes and unsaturated aldehydes.5a Wang and X. W. Wang have independently developed cinchona-derived primary amine catalyzed domino Michael/ Michael reaction of enones with unsaturated pyrazolones to afford spirocyclohexanonepyrazolones with three consecutive stereogenic centers.5b,c,e Enders et al. also showed the synthesis of a variety of spirocyclohexanepyrazolone derivatives bearing

Thus, the development of highly efficient methods to prepare optically active spiro-pyrazolones, in particular, unprecedented O-heterocycle embedded spiropyrazolones, would be of great utility for the discovery of new chiral drugs (Scheme 1).3 However, there is an inherent challenge for the preparation of spiro-motifs, including incorporating heterocycles and attaining high enantioselectivity.4 In the past few years, unsaturated pyrazolones, as electrophilic synthons, have been applied for the synthesis of a range of spiropyrazolones via organocatalysis (Scheme 1).5 In a parallel way, pyrazolones have been established as suitable nucleophile in a few asymmetric preparations of spiropyrazolones.6 In addition, unsaturated pyrazolones have recently been exploited as © 2018 American Chemical Society

Received: March 28, 2018 Published: May 29, 2018 8645

DOI: 10.1021/acs.joc.8b00781 J. Org. Chem. 2018, 83, 8645−8654

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The Journal of Organic Chemistry six stereocenters via sequential organocatalytic reactions.5d Recently, the synthesis of spiropyrazolones bearing Nheterocyclic ring was disclosed from the reaction of Ntosylaminomethyl enones with unsaturated pyrazolones.5f Interestingly, there is only a single report of organocatalytic oxa-Michael−Michael reaction by Miao and co-workers.5g Realizing the potential of heterocycle incorporated spiropyrazolones for medicinal chemistry, we embarked in a highly diastereo- and enantioselective double-Michael reaction between unsaturated pyrazolones and γ-hydroxyenones. We began our investigation by performing a model reaction between alkylidene pyrazolone 1a and (E)-4-hydroxy-1-phenylbut-2-en-1-one (2a)8 with quinine-derived bifunctional thiourea catalyst I in toluene solvent at room temperature (Table 1).

were detected. Other solvents were also examined but could not provide better results (see the Supporting Information for details). With the best optimized conditions established, the scope and generality of the cascade reaction was studied. At the beginning, a variety of γ-hydroxyenones 2 having different keto substitutents were investigated (Table 2). Interestingly, catalyst Table 2. Scope of γ-Hydroxyenonesa−d

Table 1. Catalyst Screening and Optimization of Reaction Conditions

entrya

catalyst

yieldb (%)

d.rc

eed (%)

1 2 3 4 5 6

I II III IV V VI

62 56 60 52 70 69

18:1 18:1 14:1 15:1 >20:1 >20:1

28 36 40 32 96 96

a

Reactions were carried out with 0.24 mmol of 1a with 0.2 mmol of 2 in 0.8 mL of toluene using 10% VI at rt for 5 days. bYields correspond to isolated yields after silica gel column chromatography. cDiastereoselectivity was determined by 1H NMR. dThe ee’s were determined by chiral HPLC.

a

Reaction conditions: 0.12 mmol of 1a with 0.1 mmol of 2a in 0.4 mL of solvent using 10 mol % of catalyst. bIsolated yield after silica gel column chromatography. cDetermined by 1H NMR. dDetermined by chiral HPLC.

VI was the best catalyst for γ-hydroxyenones. As can be seen in Table 2, a wide range of aryl group containing γ-hydroxyenones could be engaged in the reaction, and excellent results were achieved. Also, pleasingly, in most of the cases, only a single diastereomer was detected. Initially, different para-substitutions on the phenyl group were tested, and delightfully, excellent enantioselectivities were obtained. For example, p-tolylcontaining enone 2b delivered product 3b in 71% yield with 94% ee. A smooth conversion was also detected with enone 2d having a 4-anisyl motif. Enone 2e with a 4-bromoaryl group also took part in the reaction, and high enantioselectivity was attained for 3e. Then different m-substituted aryl enones were employed in the reaction, and excellent results were detected.

Pleasingly, after 5 days of stirring, the desired spiropyrazolone 3a having a tetrahydrofuran motif was isolated in 62% yield with 18:1 dr; however, the enantiomeric excess was low (28% ee, entry 1). Hydroquinine-derived thiourea II also could not improve the enantioselectivity of the reaction (entry 2). Then Takemoto catalyst III and proline-derived bifunctional thiourea IV were employed in the reaction (entries 3 and 4). The yields and diastereomeric ratios of 3a with these catalysts were good, but the enantiomeric excess was low. We then turned our attention to screen squaramide catalysts9 V and VI, and the results were promising for us (entries 5 and 6). Gratifyingly, an excellent enantioselectivity of 96% and diastereoselectivity of >20:1 were achieved with both catalysts, and acceptable yields 8646


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The Journal of Organic Chemistry An o-substituted aryl enone 2i also underwent smooth reaction with pyrazolone 1a to deliver product 3i in excellent enantioselectivity. The reaction outcome was not much different with 1-naphthyl-substituted enone 2j. A heteroaromatic group was also tolerated in the reaction; though acceptable yield was obtained for 3k, slightly lower enantioselectivity was observed. Then an aliphatic enone 2l was prepared and engaged in the reaction. To our delight, the desired product 3l was obtained in high 10:1 dr with 90% ee. Interestingly, an ester 2m can also participate in the reaction to provide 3m; though the obtained diastereoselectivity was high, enantioselectivity was moderate. In the next phase, screening of a variety of pyrazolones 1 having different benzylidene substitutents was performed, and catalyst V was found to be the best catalyst (Table 3). It turned out that a range of electron-withdrawing and electron-donating groups can be incorporated in the ortho-, meta-, and paraposition of the aryl group without having a pronounced effect on the yields and enantioselectivities. Here also, excellent diastereoselectivity was maintained. For example, pyrazolone 1n having a p-tolyl group provided the single diastereomeric product 3n in 96% ee. The reaction outcome was also not changed with other 4-alkylphenyl substituents. Product 3q having a 4-anisyl group was isolated in slightly higher yield of 73% and in 96% ee. Then 4-halosubstituted pyrazolones 1r−t were screened in the reaction, and excellent results were achieved. In particular, high yield was obtained for product 3t having a 4-bromophenyl group. Pyrazolone 1u having a 4trifluoromethyl substituent also participated in the reaction, delivering product 3u in 66% yields with 94% ee. A biphenyl motif was also tolerated in the reaction, although slightly lower diastereoselectivity was attained. Smooth conversions were also observed with meta-substituted pyrazolones 1w−y, and the corresponding products 3w−y were obtained in acceptable yields with excellent diastereo- and enantioselectivities. The reaction also progressed well with ortho-substituted pyrazolone 1z, and acceptable enantioslectivity was detected. A disubstituted aryl group containing pyrazolone 1z1 also took part in the reaction, and product 3z 1 was obtained in high enantioselectivity. Then a heteroaryl 2-thienyl group was incorporated in the pyrazolone motif, and gratifyingly, the corresponding product 3z2 was isolated in an acceptable yield with high enantioselectivity although the diastereoselectivity was reduced slightly. Finally, an aliphatic cyclohexyl-substituted pyrazolone 1z3 was employed in the reaction, and pleasingly, it also exhibited similar reactivities. The generality of the reaction was further extended by incorporating pyrazolones 1 with varied N-substitutions and hydrazone carbon substitutions (Table 4). Accordingly, a variety pyrazolones 1z4−z6 with different N-substitutions and 1z7−z8 with different hydrazone carbon substitutions were prepared and employed in the reaction. To our delight, the reactions progressed well, and the products 3z4−z8 were attained in moderate to excellent enantioselectivities. Then pyrazolones with N-aliphatic substitutions were employed in the reaction, but unfortunately, no product formation was observed. To exhibit the synthetic utility of our method, few derivatives were prepared from 3d (Scheme 2). Bayer−Villiger oxidation of 3d selectively provided ester 4 in 80% yield, and the enantioselectivity was retained. Then a substitution reaction of 4 with benzylamine was performed. This resulted in the

Table 3. Scope of Pyrazolones with Varied Benzylidene Substituentsa−d

a Reactions were carried out with 0.24 mmol of 1 with 0.2 mmol of 2a in 0.8 mL of toluene using 10% V at rt for 5 days. bYields correspond to isolated yields after silica gel column chromatography. cDiastereoselectivity was determined by 1H NMR. dThe ee’s were determined by chiral HPLC.

formation of amide 5 with moderate yield and here also the enantioselectivity was nearly preserved. The absolute structure of the product 3s was determined to be (2R,3S,4S) by single-crystal X-ray crystallography.10 By analogy, it is predicted that other products will also have similar absolute configurations. On the basis of the absolute configuration, a proposed TS has been drawn in Figure 2. It 8647


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spiropyrazolones in good yields and with excellent diasteroand enantioselectivities.

Table 4. Scope of Pyrazolones with Varied N-Substituents and Hydrazone C- Substituentsa−c

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EXPERIMENTAL SECTION

General Information. Chemicals and solvents were purchased from commercial suppliers and used as received. 1H NMR spectra were recorded on 400, 500, and 600 MHz spectrometers. 13C NMR spectra were recorded at 100, 126, and 150 MHz. Chemical shifts are reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: proton (chloroform δ 7.260), carbon (chloroform δ 77.23). Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), brs (broad singlet). Coupling constants are reported in hertz (Hz). High-resolution mass spectra (HRMS) were recorded in QTOF electron spray ionization (ESI). Enantiomeric ratios were determined by HPLC analysis using a Dionex (Ultimate 3000) instrument with chiral columns using a Daicel Chiralpak IA column, Daicel Chiralpak IB column, Daicel Chiralpak IC Column, Daicel Chiralpak ID Column. To visualize the products, UV light and I2 were used. Melting points were measured using a Büchi melting point B-540 apparatus. All melting points were measured in open glass capillary tubes, and values are uncorrected. Polarimetry: Rudolph research analytical auto plo II. Toluene was distilled over CaH2 under argon and stored over 4 Å molecular sieves. DCM was distilled over CaH2 under argon and stored over 4 Å molecular sieves. Silica gel (60−120 mesh size) was used for column chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25 mm). General Procedure for the Synthesis of trans-γ-Hydroxyenones. trans-γ-Hydroxyenones were prepared according to the reported procedure.11 General Procedure for the Synthesis of Unsaturated Pyrazolones. Unsaturated pyrazolones were prepared according to reported procedures.12 General Procedure for the Synthesis of Catalyst. Catalysts I, II, III, and VII were prepared according to reported procedures.13 Catalyst IV was prepared according to reported procedures.14 Catalysts V and VI were prepared according to reported procedures.15 Catalyst VIII was prepared according to reported procedures.16 General Procedure for the Synthesis of Compound 3. In an ovendried round-bottom flask, 1 (0.24 mmol), 2 (0.2 mmol), 10 mol % of catalyst V or VI were taken. Toluene (0.8 mL) was added to the reaction mixture and stirred at rt for 5 days. Completion of the reaction was checked by TLC. After the completion of reaction, solvent was concentrated, and reaction mixture was directly purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10−15%) to afford desired products 3a−3z8. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-2,6-diphenyl-7-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3a). Compound 3a was obtained as a light yellow sticky solid in 70% yield (59.4 mg) after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.84−7.90 (m, 4H), 7.55 (t, J = 7.4 Hz, 1H), 7.40−7.44 (m, 4H), 7.26−7.21 (m, 6H), 5.41 (s, 1H), 4.88 (t, J = 9.2 Hz, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.85−3.74 (m, 1H), 3.17 (dd, J = 17.7, 4.8 Hz, 1H), 3.01 (dd, J = 17.7, 10.0 Hz, 1H), 2.03 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.7, 171.8, 159.2, 137.9, 136.0, 135.9, 133.7, 129.0, 128.9, 128.6, 128.2, 128.1, 125.5, 124.4, 119.2, 86.3, 72.6, 68.1, 45.1, 38.2, 17.6. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 21.2 min, tminor = 18.2 min). The optical rotation of 3a was found to be [α]D24 = −60.0 (c 0.35, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H25N2O3 [M + H]+ 425.1865, found 425.1861. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-(p-tolyl)ethyl)-2,6-diphenyl-7oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3b). Compound 3b was obtained as an off-white solid in 71% (62.3 mg) yield after column chromatography. Mp = 135−138 °C. 1H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.26−7.20 (m, 8H), 5.39 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.82−3.72 (m, 1H), 3.14 (dd, J = 17.5, 4.7 Hz, 1H), 2.96 (dd, J = 17.5, 10.1 Hz, 1H), 2.39 (s, 3H), 2.02 (s, 3H). 13C

a

Reactions were carried out with 0.24 mmol of 1 with 0.2 mmol of 2a in 0.8 mL toluene using 10% VI at rt for 5 days. bYields correspond to isolated yields after silica gel column chromatography. cDiastereoselectivity was determined by 1H NMR. The dee’s were determined by chiral HPLC.

Scheme 2. Synthetic Transformations of 3d

Figure 2. Proposed TS.

seems a bifunctional mode of catalysis operates and pyrazolone 1a is activated by the squramide motif of the catalyst from the Si face. Thus, the Michael addition takes place form the Re face to generate intermediate 6. A second Michael cyclization from the Re face of the enone then provides 3a. In summary, we have developed the first diastereo- and enantioselective synthesis of spiro-tetrahydrofuran-pyrazolones via a mild and operationally simple oxa-Michael/Michael reaction between unsaturated pyrazolones and γ-hydroxyenones. This reaction furnished diverse multisubstituted 8648


Note

The Journal of Organic Chemistry NMR (150 MHz, CDCl3): δ 196.4, 171.9, 159.3, 144.7, 138.0, 136.0, 133.6, 129.6, 129.1, 128.6, 128.3, 128.2, 125.5, 124.4, 119.2, 86.3, 72.7, 68.1, 45.2, 38.1, 21.8, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (tmajor = 29.9 min, tminor = 20.1 min). The optical rotation of 3b was found to be [α]D26 = −36.9 (c 0.13, CHCl3). HRMS (+ESI-TOF) m/ z: calcd for C28H27N2O3 [M + H]+ 439.2022, found 439.2023. (5R,6R,9S)-9-(2-(4-tert-Butylphenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3c). Compound 3c was obtained as a brown sticky solid in 72% (69.3 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.47−7.38 (m, 4H), 7.23 (d, J = 7.3 Hz, 6H), 5.40 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.84−3.73 (m, 1H), 3.15 (dd, J = 17.5, 4.8 Hz, 1H), 2.97 (dd, J = 17.5, 10.1 Hz, 1H), 2.02 (s, 3H), 1.31 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 196.4, 171.9, 157.7, 138.0, 136.1, 133.5, 129.2, 129.0, 128.2, 128.0, 126.0, 125.7, 124.6, 119.4, 119.2, 86.5, 86.3, 68.2, 45.4, 45.1, 35.3, 31.3, 31.1, 17.8. HPLC analysis: ee = 86%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 18.4 min, tminor = 13.6 min). The optical rotation of 3c was found to be [α]D25 = −60.0 (c 0.170, CHCl3). HRMS (+ESI-TOF) m/ z: calcd for C31H33N2O3 [M + H]+ 481.2491, found 481.2487. (5R,6R,9S)-9-(2-(4-Methoxyphenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3d). Compound 3d was obtained as a brown sticky solid in 69% (62.7 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.26− 7.18 (m, 6H), 6.88 (d, J = 8.8 Hz, 2H), 5.39 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.78 (dd, J = 9.3, 4.8 Hz, 1H), 3.12 (dd, J = 17.3, 4.7 Hz, 1H), 2.93 (dd, J = 17.1, 10.1 Hz, 1H), 2.02 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 195.2, 171.9, 164.0, 159.4, 138.0, 136.0, 130.5, 129.1, 129.0, 128.6, 128.2, 125.5, 124.4, 119.2, 114.0, 86.3, 72.7, 68.2, 55.6, 45.3, 37.8, 17.7. HPLC analysis: ee = 90%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (tmajor = 38.5 min, tminor = 31.8 min). The optical rotation of 3d was found to be [α]D25 = −48.8 (c 0.40, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O4 [M + H]+ 455.1971, found 455.1969. (5R,6R,9S)-9-(2-(4-Bromophenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3e). Compound 3e was obtained as a brown sticky solid in 66% (66.3 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.26−7.20 (m, 6H), 5.39 (s, 1H), 4.85 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.77 (qd, J = 9.3, 5.0 Hz, 1H), 3.12 (dd, J = 17.7, 4.9 Hz, 1H), 2.96 (dd, J = 17.7, 9.9 Hz, 1H), 2.01 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 195.8, 171.8, 159.2, 138.0, 135.9, 134.8, 132.3, 129.7, 129.1, 128.6, 128.3, 125.6, 124.5, 119.2, 86.5, 72.6, 68.1, 45.1, 38.2, 17.7. HPLC analysis: ee = 92%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 26.6 min, tminor = 24.1 min). The optical rotation of 3e was found to be [α]D23 = −34.6 (c 0.455, CHCl3). HRMS (+ESI-TOF) m/ z: calcd for C27H24BrN2O3 [M + H]+ 503.0970, found 503.0972. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-m-tolylethyl)-2,6-diphenyl-7-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3f). Compound 3f was obtained as a brown sticky solid in 62% (54.4 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.91 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.29−7.23 (m, 6H), 5.42 (s, 1H), 4.90 (t, J = 9.2 Hz, 1H), 4.04 (t, J = 9.0 Hz, 1H), 3.87−3.77 (m, 1H), 3.17 (dd, J = 17.6, 4.8 Hz, 1H), 3.01 (dd, J = 17.6, 10.1 Hz, 1H), 2.40 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.0, 171.8, 159.3, 138.8, 138.0, 136.1, 136.0, 134.5, 129.1, 128.8, 128.6, 128.2, 125.5, 125.4, 124.4, 119.2, 86.4, 72.7, 68.1, 45.2, 38.3, 21.4, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (tmajor = 16.0 min, tminor = 15.1 min). The optical rotation of 3f was found to be [α]D28 = −72.8 (c 0.390, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O3 [M + H]+ 439.2022, found 439.2022.

(5R,6R,9S)-9-(2-(3-Methoxyphenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3g). Compound 3g was obtained as a light yellow sticky solid in 68% (62.0 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 7.9 Hz, 2H), 7.41 (t, J = 7.9 Hz, 3H), 7.37 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.26−7.21 (m, 6H), 7.10 (m, 1H), 5.40 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.78 (dd, J = 9.7, 4.2 Hz, 1H), 3.14 (dd, J = 17.6, 4.9 Hz, 1H), 2.99 (dd, J = 17.6, 9.9 Hz, 1H), 2.02 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 196.7, 171.9, 160.1, 159.2, 138.1, 137.5, 136.0, 129.9, 129.1, 128.9, 128.6, 128.3, 125.5, 124.5, 120.8, 120.2, 119.6, 119.3, 112.5, 86.5, 72.7, 68.1, 55.6, 45.3, 38.4, 17.7. HPLC analysis: ee = 92%, Chiralpak IB column, nhexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 15.7 min, tminor = 12.2 min). The optical rotation of 3g was found to be [α]D24 = −42.4 (c 0.50, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O4 [M + H]+ 455.1971, found 455.1962. (5R,6R,9S)-9-(2-(3-Chlorophenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3h). Compound 3h was obtained as a brown sticky solid in 61% (58.8 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.80 (d, J = 7.7 Hz, 2H), 7.74 (t, J = 1.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.33 (m, 4H), 7.19−7.14 (m, 5H), 5.32 (s, 1H), 4.79 (t, J = 9.2 Hz, 1H), 3.93 (t, J = 9.0 Hz, 1H), 3.71 (dt, J = 14.1, 6.8 Hz, 1H), 3.05 (dd, J = 17.8, 5.0 Hz, 1H), 2.91 (dd, J = 17.8, 9.9 Hz, 1H), 1.95 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 195.6, 171.8, 159.1, 138.0, 137.6, 135.9, 135.40, 133.7, 130.3, 129.1, 128.6, 128.3, 128.3, 126.3, 125.6, 124.5, 119.3, 86.5, 72.6, 68.1, 45.1, 38.4, 17.7. HPLC analysis: ee = 99%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 19.0 min, tminor = 14.2 min). The optical rotation of 3h was found to be [α]D23 = −25.3 (c 0.205, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24ClN2O3 [M + H]+ 459.1475, found 459.1472. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-o-tolylethyl)-2,6-diphenyl-7-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3i). Compound 3i was obtained as a light brown sticky solid in 59% (51.7 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.31 (m, 3H), 7.18−7.11 (m, 8H), 5.32 (s, 1H), 4.77 (t, J = 9.1 Hz, 1H), 3.95 (t, J = 9.0 Hz, 1H), 3.75−3.62 (m, 1H), 2.96 (td, J = 17.6, 10.2 Hz, 2H), 2.34 (s, 3H), 1.92 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 200.2, 172.0, 159.2, 139.0, 138.0, 136.4, 136.0, 132.5, 132.2, 129.0, 128.8, 128.6, 128.3, 126.0, 125.5, 124.5, 119.2, 86.50, 72.7, 68.1, 45.4, 40.8, 21.7, 17.7. HPLC analysis: ee = 98%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 65.8 min, tminor = 18.7 min). The optical rotation of 3i was found to be [α]D26 = −7.7 (c 0.08, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O3 [M + H]+ 439.2022, found 439.2021. (5R,6R,9S)-4-Methyl-9-(2-(naphthalen-1-yl)-2-oxoethyl)-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3j). Compound 3j was obtained as a brown sticky solid in 75% (70.8 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.54−7.39 (m, 5H), 7.23 (m, 6H), 5.43 (s, 1H), 4.90 (t, J = 9.0 Hz, 1H), 4.10 (t, J = 9.0 Hz, 1H), 3.88 (dt, J = 9.7, 6.6 Hz, 1H), 3.19 (ddd, J = 24.0, 17.6, 10.1 Hz, 2H), 2.01 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 200.5, 172.0, 159.2, 138.1, 136.0, 134.4, 134.1, 133.72, 130.2, 129.1, 128.6, 128.5, 128.3, 128.2, 126.8, 125.8, 125.5, 124.5, 124.4, 119.2, 86.6, 72.7, 68.1, 45.6, 41.4, 29.9, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 30.2 min, tminor = 25.7 min). The optical rotation of 3j was found to be [α]D26 = −2.4 (c 0.075, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C31H27N2O3 [M + H]+ 475.2022, found 475.2022. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-(thiophene-2-yl)ethyl)-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3k). Compound 3k was obtained as an off semisolid in 76% (73.2 mg) yield after column chromatography. The dr value was found to be 15:1 by 1H NMR analysis. 1H NMR (600 MHz, CDCl3): δ 7.86 (d, J = 7.8 Hz, 2H), 7.63 (m, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.26−7.20 (m, 6H), 7.12−7.08 (m, 1H), 5.39 (s, 1H), 4.83 (t, J = 9.2 Hz, 1H), 4.05 (t, J = 8649


Note


n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 21.4 min, tminor = 17.2 min). The optical rotation of 3o was found to be [α]D28 = −66.2 (c 0.160, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C30H31N2O3 [M + H] + 467.2335, found 467.2336. (5R,6R,9S)-6-(4-tert-Butylphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3p). Compound 3p was obtained as a brown sticky solid in 70% (67.3 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.78−7.82 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.33−7.37 (m, 4H), 7.15−7.19 (m, 3H), 7.07 (d, J = 8.2 Hz, 2H), 5.30 (s, 1H), 4.79 (t, J = 9.2 Hz, 1H), 3.93 (t, J = 9.0 Hz, 1H), 3.70 (dd, J = 9.6, 4.7 Hz, 1H), 3.09 (dd, J = 17.6, 4.6 Hz, 1H), 2.92 (dd, J = 17.7, 10.1 Hz, 1H), 1.96 (s, 3H), 1.18 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 196.8, 172.0, 159.6, 151.1, 138.1, 136.1, 133.8, 132.9, 129.1, 128.9, 128.2, 128.2, 125.5, 125.5, 124.4, 124.2, 119.3, 86.3, 72.6, 68.0, 45.3, 38.3, 31.4, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 19.4 min, tminor = 13.7 min). The optical rotation of 3p was found to be [α]D27 = −83.6 (c 0.495, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C31H33N2O3 [M + H] + 481.2491, found 481.2491. (5R,6R,9S)-6-(4-Methoxyphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3q). Compound 3q was obtained as an off white solid in 73% (66.3 mg) yield after column chromatography. Mp = 159−162 °C. 1H NMR (400 MHz, CDCl3): δ 7.83−7.89 (m, 4H), 7.55 (d, J = 7.0 Hz, 1H), 7.39− 7.44 (m, 4H), 7.21 (t, J = 7.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 2H), 5.35 (s, 1H), 4.86 (t, J = 9.1 Hz, 1H), 4.00 (t, J = 8.9 Hz, 1H), 3.75 (s, 4H), 3.16 (dd, J = 17.6, 4.3 Hz, 1H), 3.00 (dd, J = 17.6, 10.0 Hz, 1H), 2.04 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.8, 171.9, 159.5, 138.1, 133.8, 129.1, 128.9, 128.2, 125.7, 125.5, 119.2, 114.0, 86.4, 72.6, 68.3, 55.3, 45.1, 38.3, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 29.3 min, tminor = 22.3 min). The optical rotation of 3q was found to be [α]D28 = −37.0 (c 0.60, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O4 [M + H]+ 455.1971, found 455.1979. (5R,6R,9S)-6-(4-Fluorophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3r). Compound 3r was obtained as a light yellow solid in 68% (60.2 mg) yield after column chromatography. Mp = 124−127 °C. 1H NMR (400 MHz, CDCl3): δ 7.83−7.88 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.39−7.47 (m, 4H), 7.19−7.26 (m, 3H), 6.94 (t, J = 8.6 Hz, 2H), 5.35 (s, 1H), 4.87 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.87−3.72 (m, 1H), 3.16 (dd, J = 17.8, 5.0 Hz, 1H), 3.01 (dd, J = 17.6, 9.8 Hz, 1H), 2.02 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.7, 171.7, 162.5 (d, JC−F = 246.6 Hz), 159.1, 137.9, 136.0, 133.9, 129.1, 128.9, 128.1, 126.2, (d, JC−F = 8.1 Hz), 125.6, 119.2, 115.6 (d, JC−F = 21.6 Hz), 85.9, 72.7, 68.1, 45.0, 38.2, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 22.7 min, tminor = 15.4 min). The optical rotation of 3r was found to be [α]D25 = −43.2 (c 0.685, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24FN2O3 [M + H]+ 443.1771, found 443.1774. (5R,6R,9S)-6-(4-Chlorophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3s). Compound 3s was obtained as a colorless sticky solid in 72% (66.0 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.83−7.88 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.40−7.44 (m, 4H), 7.23 (d, J = 8.6 Hz, 3H), 7.17 (d, J = 8.4 Hz, 2H), 5.34 (s, 1H), 4.87 (t, J = 9.1 Hz, 1H), 4.01 (t, J = 9.1 Hz, 1H), 3.78 (dd, J = 9.4, 4.7 Hz, 1H), 3.16 (dd, J = 17.7, 4.9 Hz, 1H), 3.00 (dd, J = 17.7, 9.9 Hz, 1H), 2.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.7, 171.6, 159.0, 137.9, 136.0, 134.6, 134.1, 133.8, 129.1, 128.9, 128.9, 128.2, 125.9, 125.7, 119.2, 85.8, 72.7, 68.0, 45.1, 38.2, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 24.1 min, tminor = 15.8 min). The optical rotation of 3s was found to be [α]D29 = −86.8 (c 0.70, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24ClN2O3 [M + H]+ 459.1475, found 459.1475. (5R,6R,9S)-6-(4-Bromophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3t). Compound 3t was obtained as a light yellow solid in 75% (75.4 mg) yield after

9.1 Hz, 1H), 3.77 (td, J = 14.0, 9.3 Hz, 1H), 3.09 (dd, J = 17.0, 4.7 Hz, 1H), 2.92 (dd, J = 17.0, 10.3 Hz, 1H), 2.03 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 189.6, 171.7, 143.1, 138.0, 135.9, 134.5, 132.5, 129.1, 128.6, 128.4, 128.3, 125.6, 124.5, 119.3, 86.4, 72.5, 68.1, 45.2, 38.7, 17.7. HPLC analysis: ee = 84%, Chiralpak IB column, n-hexane/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 15.5 min, tminor = 13.5 min). The optical rotation of 3k was found to be [α]D24 = −60.3 (c 0.58, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C25H23N2O3S [M + H]+ 431.1429, found 431.1425. (5R,6R,9S)-4-Methyl-9-(2-oxo-4-phenylbutyl)-2,6-diphenyl-7-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3l). Compound 3l was obtained as a brown sticky solid in 63% (65.2 mg) yield after column chromatography. The dr value was found to be 10:1 by 1H NMR analysis. 1H NMR (600 MHz, CDCl3): δ 7.90 (d, J = 7.7 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.26−7.29 (m, 6H), 7.21 (m, 3H), 7.14 (d, J = 7.5 Hz, 2H), 5.36 (s, 1H), 4.75 (t, J = 9.2 Hz, 1H), 3.86 (t, J = 9.1 Hz, 1H), 3.60 (qd, J = 9.4, 5.0 Hz, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.70 (dt, J = 12.6, 6.2 Hz, 2H), 2.51 (dd, J = 17.9, 4.9 Hz, 1H), 2.43−2.34 (m, 2H), 1.93 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 206.8, 171.7, 159.2, 140.5, 137.9, 135.9, 129.1, 128.7, 128.6, 128.4, 128.2, 126.4, 125.5, 124.4, 119.1, 86.2, 72.4, 67.9, 44.7, 44.2, 42.5, 30.0, 17.5. HPLC analysis: ee = 90%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (tmajor = 17.9 min, tminor = 20.5 min). The optical rotation of 3l was found to be [α]D24 = −82.6 (c 0.230, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C29H29N2O3 [M + H]+ 453.2173, found 453.2170. Ethyl 2-((5R,6R,9S)-1-Methyl-4-oxo-3,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-1-en-9-yl)acetate (3m). Compound 3m was obtained as a colorless sticky solid in 65% (51.0 mg) yield after column chromatography. The dr value was found to be 15:1 by 1H NMR analysis. 1H NMR (600 MHz, CDCl3): δ 7.85 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.22−7.24 (m, 3H), 7.20 (d, J = 7.8 Hz, 3H), 5.36 (s, 1H), 4.70 (t, J = 9.2 Hz, 1H), 4.08−4.00 (m, 3H), 3.62 (dd, J = 9.1, 6.8 Hz, 1H), 2.41 (dd, J = 7.8, 4.3 Hz, 2H), 1.98 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 171.7, 170.6, 158.9, 138.0, 135.9, 129.1, 128.6, 128.3, 125.5, 124.4, 119.2, 86.7, 72.4, 68.0, 61.3, 45.5, 34.0, 17.6, 14.2. HPLC analysis: ee = 60%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 20.5 min, tminor = 14.5 min). The optical rotation of 3m was found to be [α]D24 = −40.5 (c 0.218, CHCl3). HRMS (+ESITOF) m/z: calcd for C23H25N2O4 [M + H]+ 393.1814, found 393.1812. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-6-p-tolyl7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3n). Compound 3n was obtained as an off white solid in 69% (60.5 mg) yield after column chromatography. Mp = 151−154 °C. 1H NMR (400 MHz, CDCl3): δ 7.84−7.89 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.39−7.44 (m, 4H), 7.22 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.37 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.79 (td, J = 9.6, 4.7 Hz, 1H), 3.16 (dd, J = 17.7, 4.7 Hz, 1H), 3.00 (dd, J = 17.6, 10.1 Hz, 1H), 2.28 (s, 3H), 2.04 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.8, 171.9, 159.4, 138.0, 137.9, 136.1, 133.8, 132.9, 129.3, 129.1, 128.9, 128.1, 125.5, 124.3, 119.2, 86.5, 72.6, 68.2, 45.1, 38.3, 21.3, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/ i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 22.8 min, tminor = 15.7 min). The optical rotation of 3n was found to be [α]D28 = −71.8 (c 0.805, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O3 [M + H] + 439.2022, found 439.2020. (5R,6R,9S)-6-(4-Isopropylphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3o). Compound 3o was obtained as a brown sticky solid in 65% (60.6 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.84−7.89 (m, 4H), 7.56 (t, J = 7.2 Hz, 1H), 7.41−7.44 (m, 4H), 7.20−7.26 (m, 1H), 7.08−7.15(m, 4H), 5.38 (s, 1H), 4.86 (t, J = 9.1 Hz, 1H), 4.00 (t, J = 8.9 Hz, 1H), 3.78 (td, J = 13.7, 9.2 Hz, 1H), 3.16 (dd, J = 17.6, 4.4 Hz, 1H), 3.00 (dd, J = 17.7, 10.2 Hz, 1H), 2.88−2.76 (m, 1H), 2.04 (s, 3H), 1.19 (d, J = 6.6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 196.8, 172.0, 159.5, 148.8, 138.1, 136.1, 133.8, 133.3, 129.1, 128.9, 128.2, 126.6, 125.5, 124.5, 119.3, 86.4, 72.6, 68.1, 45.3, 38.3, 33.9, 24.0, 24.0, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column, 8650


Note

The Journal of Organic Chemistry column chromatography. Mp = 172−175 °C. 1H NMR (400 MHz, CDCl3): δ 7.83−7.89 (m, 4H), 7.56 (t, J = 7.1 Hz, 1H), 7.47−7.36 (m, 6H), 7.23 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 5.32 (s, 1H), 4.87 (t, J = 9.1 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.83−3.71 (m, 1H), 3.16 (dd, J = 17.7, 4.5 Hz, 1H), 3.00 (dd, J = 17.7, 9.9 Hz, 1H), 2.01 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.7, 171.6, 158.9, 137.9, 136.0, 135.1, 133.8, 131.8, 129.1, 128.9, 128.2, 126.3, 125.7, 122.2, 119.2, 85.8, 72.7, 68.0, 45.2, 38.2, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/ min, λ = 254 nm (tmajor = 26.7 min, tminor = 16.7 min). The optical rotation of 3t was found to be [α]D28 = −79.6 (c 0.60, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24BrN2O3 [M + H]+ 503.0970, found 503.0968. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-6-(4(trifluoromethyl)phenyl)-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3u). Compound 3u was obtained as a red semisolid in 66% (65.0 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.75−7.81 (m, 4H), 7.43−7.50 (m, 3H), 7.35 (t, J = 8.1 Hz, 4H), 7.28 (d, J = 8.2 Hz, 2H), 7.19−7.13 (m, 1H), 5.33 (s, 1H), 4.81 (t, J = 9.2 Hz, 1H), 3.96 (t, J = 9.1 Hz, 1H), 3.73 (qd, J = 9.3, 5.0 Hz, 1H), 3.09 (dd, J = 17.7, 4.9 Hz, 1H), 2.93 (dd, J = 17.7, 9.9 Hz, 1H), 1.92 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.6, 171.5, 158.8, 140.1, 137.8, 135.9, 133.9, 130.4 (q, JC−F = 31.5 Hz), 129.2, 128.9, 128.1, 125.80, 125.6 (q, JC−F = 3.0 Hz), 124.97, 124.1 (q, JC−F = 286.5 Hz), 119.1, 85.6, 72.8, 67.9, 45.2, 38.1, 17.6. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/ min, λ = 254 nm (tmajor = 22.8 min, tminor = 15.0 min). The optical rotation of 3o was found to be [α]D24 = −67.0 (c 0.480, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H24F3N2O3 [M + H]+ 493.1739, found 493.1745. (5R,6R,9S)-6-([1,1′-Biphenyl]-4-yl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3v). Compound 3v was obtained as a light yellow semisolid in 68% (68.2 mg) yield after column chromatography. The dr value was found to be 8:1 by 1H NMR analysis. 1H NMR (400 MHz, CDCl3): δ 7.76− 7.85 (m, 4H), 7.45 (d, J = 7.0 Hz, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.29− 7.36 (m, 6H), 7.23 (t, J = 8.1 Hz, 3H), 7.12−7.16 (m, 1H), 5.36 (s, 1H), 4.81 (t, J = 9.1 Hz, 1H), 3.96 (t, J = 8.9 Hz, 1H), 3.73 (dd, J = 9.0, 4.4 Hz, 1H), 3.08 (dd, J = 16.2, 11.7 Hz, 1H), 2.94 (dd, J = 17.6, 10.0 Hz, 1H), 1.98 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.8, 171.9, 159.3, 141.0, 140.6, 138.0, 136.1, 135.0, 133.8, 129.1, 129.0, 128.9, 128.2, 128.2, 127.6, 127.3, 127.2, 125.6, 125.0, 119.3, 86.3, 72.7, 68.2, 45.2, 38.3, 17.7. HPLC analysis: ee = 92%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 25.7 min, tminor = 21.4 min). The optical rotation of 3v was found to be [α]D29 = −86.4 (c 0.90, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C33H29N2O3 [M + H]+ 501.2178, found 501.2178. (5R,6R,9S)-6-(3-Methoxyphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3w). Compound 3w was obtained as a light brown semisolid in 58% (52.7 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.83−7.90 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.39−7.44 (m, 4H), 7.13−7.22 (m, 2H), 6.75−6.80 (m, 3H), 5.37 (s, 1H), 4.87 (t, J = 9.1 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.74−3.82 (m, 1H), 3.60 (s, 3H), 3.17 (dd, J = 17.7, 4.7 Hz, 1H), 3.00 (dd, J = 17.7, 10.0 Hz, 1H), 2.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 171.9, 159.8, 159.3, 138.0, 137.6, 136.1, 133.8, 129.7, 129.1, 128.9, 128.2, 128.2, 125.5, 119.1, 116.7, 114.5, 109.4, 86.3, 72.7, 68.1, 55.2, 45.1, 38.2, 17.7. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 26.8 min, tminor = 22.4 min). The optical rotation of 3w was found to be [α]D24 = −51.3 (c 0.755, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O4 [M + H]+ 455.1971, found 455.1963. (5R,6R,9S)-6-(3-Bromophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3x). compound 3x was obtained as a light yellow sticky solid in 55% (55.3 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.82− 7.88 (m, 4H), 7.55 (dd, J = 15.6, 8.3 Hz, 2H), 7.36−7.45 (m, 4H), 7.37 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.34 (s, 1H), 4.87 (t, J = 9.2 Hz, 1H),

4.01 (t, J = 9.0 Hz, 1H), 3.78 (tt, J = 13.9, 7.0 Hz, 1H), 3.17 (dd, J = 17.8, 4.9 Hz, 1H), 3.01 (dd, J = 17.7, 9.8 Hz, 1H), 2.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.7, 171.6, 158.9, 138.4, 137.9, 136.1, 133.8, 131.4, 130.3, 129.1, 128.9, 128.2, 127.8, 125.8, 123.1, 122.96, 119.5, 85.6, 72.8, 68.0, 45.1, 38.1, 17.7. HPLC analysis: ee = 94%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/ min, λ = 254 nm (tmajor = 24.7 min, tminor = 18.9 min). The optical rotation of 3x was found to be [α]D27 = −58.7 (c 0.695, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24BrN2O3 [M + H]+ 503.0970, found 503.0974. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-6-(3(trifluoromethyl)phenyl)-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3y). Compound 3y was obtained as a brown sticky solid in 57% (56.2 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.7 Hz, 4H), 7.57 (s, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.33−7.38 (m, 4H), 7.29 (t, J = 7.7 Hz, 1H), 7.14−7.22 (m, 2H), 5.34 (s, 1H), 4.83 (t, J = 9.2 Hz, 1H), 3.98 (t, J = 9.0 Hz, 1H), 3.74 (td, J = 14.1, 9.2 Hz, 1H), 3.11 (dd, J = 17.7, 4.7 Hz, 1H), 2.95 (dd, J = 17.7, 9.8 Hz, 1H), 1.92 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.67, 171.52, 158.78, 137.75, 137.18, 135.96, 133.94, 131.0 (q, JC−F = 33.0 Hz), 129.23, 129.17, 128.98, 128.20, 127.86, 125.85, 125.2 (q, JC−F = 4.5 Hz), 123.7 (q, JC−F = 270.0 Hz), 121.6 (q, JC−F = 3.0 Hz), 119.3, 85.8, 72.8, 68.0, 45.0, 38.1, 17.6. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 21.9 min, tminor = 17.5 min). The optical rotation of 3y was found to be [α]D25 = −53.2 (c 0.50, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H24F3N2O3 [M + H]+ 493.1739, found 493.1735. (5R,6R,9S)-6-(2-Methoxyphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z). Compound 3z was obtained as a light yellow semisolid in 62% (56.3 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.7 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.59−7.53 (m, 1H), 7.38−7.44 (m, 4H), 7.25−7.13 (m, 2H), 6.96 (s, 1H), 6.69 (d, J = 8.2 Hz, 1H), 5.50 (s, 1H), 4.83 (t, J = 8.7 Hz, 1H), 3.97 (t, J = 9.2 Hz, 1H), 3.79−3.65 (m, 1H), 3.36 (s, 3H), 3.09 (dd, J = 17.6, 3.6 Hz, 1H), 2.98−2.82 (m, 1H), 1.80 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 196.9, 173.2, 159.2, 156.1, 138.7, 136.2, 133.7, 129.1, 129.0, 128.9, 128.2, 128.2, 126.7, 124.7, 120.3, 118.2, 109.7, 82.7, 72.8, 67.0, 54.8, 46.9, 37.5, 17.7. HPLC analysis: ee = 88%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 19.7 min, tminor = 17.2 min). The optical rotation of 3z was found to be [α]D26 = +6.4 (c 0.340, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O4 [M + H]+ 455.1971, found 455.1978. (5R,6R,9S)-6-(2,4-Dimethylphenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z1). Compound 3z1 was obtained as a light yellow sticky solid in 64% (57.9 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.83−7.88 (m, 4H), 7.59−7.48 (m, 2H), 7.45−7.36 (m, 4H), 7.19 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 5.57 (s, 1H), 4.82 (t, J = 8.8 Hz, 1H), 4.04 (t, J = 9.0 Hz, 1H), 3.78 (dt, J = 13.5, 9.2 Hz, 1H), 3.12 (dd, J = 17.5, 4.5 Hz, 1H), 2.99 (dd, J = 17.5, 10.2 Hz, 1H), 2.25 (s, 3H), 2.07 (d, J = 5.1 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 196.8, 172.3, 159.7, 138.1, 137.9, 136.1, 135.3, 133.8, 132.0, 131.5, 129.1, 128.9, 128.2, 126.3, 126.2, 125.4, 118.9, 84.9, 72.7, 67.8, 46.6, 37.9, 21.1, 19.3, 18.4. HPLC analysis: ee = 96%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/ min, λ = 254 nm (tmajor = 21.4 min, tminor = 16.6 min). The optical rotation of 3z1 was found to be [α]D26 = −68.9 (c 0.925, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C29H29N2O3 [M + H]+ 453.2178, found 453.2174. (5R,6S,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-6-(thiophene-2-yl)-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z2). Compound 3z2 was obtained as a brown sticky solid in 57% (49.0 mg) yield after column chromatography. The dr value was found to be 9:1 by 1H NMR analysis. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.42−7.47 (m, 5H), 7.19 (d, J = 5.0 Hz, 1H), 6.93−6.87 (m, 1H), 6.80 (s, 1H), 5.54 (s, 1H), 4.86 (t, J = 9.1 Hz, 1H), 4.01 (t, J = 9.1 Hz, 1H), 3.74 8651


Note


i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 43.8 min, tminor = 26.3 min). The optical rotation of 3z6 was found to be [α]D28 = −43.4 (c 0.290, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24BrN2O3 [M + H]+ 503.0970, found 503.0977. (5R,6R,9S)-9-(2-Oxo-2-phenylethyl)-2,4,6-triphenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3z7). Compound 3z7 was obtained as a colorless sticky solid in 60% (58.4 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.6 Hz, 2H), 7.94−7.92 (m, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 8.0 Hz, 3H), 7.38−7.27 (m, 6H), 7.17−7.19 (m, 2H), 7.13−7.08 (m, 3H), 5.54 (s, 1H), 4.85 (t, J = 9.5 Hz, 1H), 4.17 (dd, J = 9.0, 7.6 Hz, 1H), 3.88 (dd, J = 9.6, 7.8 Hz, 1H), 3.08 (dd, J = 18.2, 7.4 Hz, 1H), 2.93 (dd, J = 18.2, 8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 197.2, 173.3, 158.1, 138.2, 136.2, 135.5, 133.5, 132.3, 130.2, 129.1, 128.7, 128.7, 128.4, 128.1, 127.9, 127.8, 125.8, 124.7, 119.8, 89.1, 72.7, 68.3, 45.6, 39.2. HPLC analysis: ee = 76%, Chiralpak IA column, n-hexane/ i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 31.9 min, tminor = 27.4 min). The optical rotation of 3z7 was found to be [α]D24 = −55.8 (c 0.265, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C32H27N2O3 [M + H]+ 487.2022, found 487.2030. (5R,6R,9S)-9-(2-Oxo-2-phenylethyl)-2,6-diphenyl-4-propyl-7-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3z8). Compound 3z8 was obtained as a colorless sticky solid in 69% (62.4 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.95−7.90 (m, 2H), 7.87−7.82 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.41−7.45 (m, 4H), 7.25−7.18 (m, 6H), 5.40 (s, 1H), 4.86 (t, J = 9.1 Hz, 1H), 3.99 (t, J = 9.0 Hz, 1H), 3.77 (qd, J = 9.3, 4.6 Hz, 1H), 3.15 (dd, J = 17.6, 4.6 Hz, 1H), 2.98 (dd, J = 17.6, 10.1 Hz, 1H), 2.37−2.18 (m, 2H), 1.35−1.24 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 171.9, 162.3, 138.2, 136.2, 136.1, 133.8, 129.0, 128.9, 128.6, 128.1, 125.4, 124.4, 119.2, 86.3, 72.8, 68.1, 45.4, 38.3, 33.1, 17.9, 13.8. HPLC analysis: ee = 56%, Chiralpak IA column, n-hexane/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 15.7 min, tminor = 14.8 min). The optical rotation of 3z8 was found to be [α]D29 = +5.3 (c 0.150, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C29H29N2O3 [M + H]+ 453.2178, found 453.2186. General Procedure for the Preparation of Derivatives 4.17 In an oven-dried round-bottom flask was added compound 3d (45.2 mg, 0.1 mmol) in DCM (3.3 mL). Then m-CPBA (56.0 mg, 0.25 mmol) and Na2HPO4 (36.0 mg, 0.25 mmol) were added, and the solution was stirred at room temperature overnight. The mixture was poured into water (2 mL) and saturated aq NaHCO3 (2 mL), the organic layer was separated, and the aqueous phase was extracted with DCM (3 × 2 mL). The combined organic layers were washed with water (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography EtOAc−hexane (15−20%) as eluent to afford the compound 4. 4-Methoxyphenyl 2-((5R,6R,9S)-1-Methyl-4-oxo-3,6-diphenyl-7oxa-2,3-diazaspiro[4.4]non-1-en-9-yl)acetate (4). Compound 4 was obtained as a colorless sticky solid in 80% (37.6 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.75 (d, J = 7.6 Hz, 2H), 7.34−7.30 (m, 2H), 7.19−7.12 (m, 6H), 6.83 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 9.1 Hz, 2H), 5.32 (s, 1H), 4.69 (t, J = 9.2 Hz, 1H), 4.59−4.55 (m, 1H), 4.04 (t, J = 9.0 Hz, 1H), 3.69 (s, 3H), 3.67 (dd, J = 9.5, 6.6 Hz, 1H), 2.60−2.55 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 171.6, 169.6, 158.8, 157.5, 143.8, 137.9, 135.7, 129.0, 128.7, 128.4, 125.6, 124.4, 122.2, 119.3, 114.6, 86.80, 72.3, 68.0, 55.7, 45.5, 34.0, 17.6. HPLC analysis: ee = 90%, Chiralpak IA column, n-hexane/ i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 22.1 min, tminor = 37.9 min). The optical rotation of 4 was found to be [α]D28 = −38.9 (c 0.320, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O5 [M + H]+ 471.1920, found 471.1926. General Procedure for the Preparation of Derivatives 5.18 To a solution of compound 4 (47.0 mg, 0.1 mmol) in THF (1 mL) was added benzylamine (23 μL, 0.2 mmol), and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (3 mL), and the organic layer was washed with 1 N HCl (2 × 2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained

(m, 1H), 3.34 (t, J = 6.2 Hz, 1H), 3.23−3.13 (m, 1H), 3.02 (dd, J = 17.7, 10.0 Hz, 1H), 2.16 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.7, 171.0, 159.1, 138.1, 136.1, 133.8, 129.1, 128.9, 128.2, 128.2, 127.2, 125.6, 124.8, 123.4, 119.2, 84.2, 72.9, 68.1, 44.9, 38.1, 17.9. HPLC analysis: ee = 90%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 20.7 min, tminor = 23.3 min). The optical rotation of 3z2 was found to be [α]D28 = −21.4 (c 0.215, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C25H23N2O3S [M + H]+ 431.1429, found 431.1427. (5R,6R,9S)-6-Cyclohexyl-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z3). Compound 3z3 was obtained as a brown sticky solid in 50% (43.0 mg) yield after column chromatography. The dr value was found to be 9:1 by 1H NMR analysis. 1H NMR (600 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 4H), 7.30−7.26 (m, 1H), 4.66 (t, J = 9.2 Hz, 1H), 3.94 (d, J = 10.1 Hz, 1H), 3.76 (t, J = 9.0 Hz, 1H), 3.62−3.54 (m, 1H), 3.08 (dd, J = 17.5, 4.0 Hz, 1H), 2.88 (dd, J = 17.5, 10.6 Hz, 1H), 2.41−2.31 (m, 4H), 1.74 (d, J = 12.6 Hz, 2H), 1.63−1.54 (m, 3H), 1.09 (dd, J = 37.5, 9.8 Hz, 4H), 0.93−0.85 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 196.9, 172.2, 160.12, 138.2, 136.1, 133.7, 129.1, 128.9, 128.1, 125.4, 119.1, 90.1, 71.7, 65.4, 46.4, 39.9, 37.8, 31.36, 27.9, 26.1, 25.8, 25.5, 17.9. HPLC analysis: ee = 90%, Chiralpak IA column, n-hexane/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 20.6 min, tminor = 10.6 min). The optical rotation of 3z3 was found to be [α]D28 = +39.2 (c 0.530, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H31N2O3 [M + NH4]+ 431.2335, found 431.2339. (5R,6R,9S)-4-Methyl-9-(2-oxo-2-phenylethyl)-6-phenyl-2-p-tolyl7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z4). Compound 3z4 was obtained as a colorless sticky solid in 62% (54.0 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.85 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.21−7.24 (m, 7H), 5.39 (s, 1H), 4.87 (t, J = 9.2 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.82−3.74 (m, 1H), 3.16 (dd, J = 17.6, 4.6 Hz, 1H), 2.99 (dd, J = 17.7, 10.2 Hz, 1H), 2.36 (s, 3H), 2.01 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 196.8, 171.6, 159.2, 136.0, 136.0, 135.5, 135.3, 133.8, 129.6, 128.9, 128.6, 128.2, 128.2, 124.4, 119.3, 86.3, 72.7, 68.0, 45.1, 38.2, 21.2, 17.7. HPLC analysis: ee = 92%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/ min, λ = 254 nm (tmajor = 43.6 min, tminor = 28.3 min). The optical rotation of 3z4 was found to be [α]D28 = −41.8 (c 0.530, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C28H27N2O3 [M + H]+ 439.2022, found 439.2026. (5R,6R,9S)-2-(4-Chlorophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)6-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z5). Compound 3z5 was obtained as a colorless sticky solid in 55% (50.5 mg) yield after column chromatography. 1H NMR (600 MHz, CDCl3): δ 7.89−7.83 (m, 4H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.26−7.22 (m, 3H), 7.22−7.19 (m, 2H), 5.38 (s, 1H), 4.86 (t, J = 9.2 Hz, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.78 (qd, J = 9.3, 5.4 Hz, 1H), 3.15 (dd, J = 17.7, 5.3 Hz, 1H), 3.03 (dd, J = 17.7, 9.6 Hz, 1H), 2.01 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 196.7, 171.9, 159.5, 136.5, 136.0, 135.8, 133.9, 130.6, 129.1, 128.9, 128.6, 128.4, 128.1, 124.4, 120.2, 86.6, 72.7, 68.1, 45.0, 38.3, 17.7. HPLC analysis: ee = 80%, Chiralpak IA column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 36.3 min, tminor = 23.2 min). The optical rotation of 3z5 was found to be [α]D28 = −37.8 (c 0.465, CHCl3). HRMS (+ESI-TOF) m/z: calcd for C27H24ClN2O3 [M + H]+ 459.1475, found 459.1476. (5R,6R,9S)-2-(4-Bromophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)6-phenyl-7-oxa-2,3-diazaspiro[4.4]non-3-en-1-one (3z6). Compound 3z6 was obtained as a colorless sticky solid in 57% (57.4 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.79−7.84 (m, 4H), 7.58−7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 7.25−7.18 (m, 5H), 5.38 (s, 1H), 4.85 (t, J = 9.2 Hz, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.78 (td, J = 14.6, 9.1 Hz, 1H), 3.14 (dd, J = 17.6, 5.4 Hz, 1H), 3.02 (dd, J = 17.7, 9.5 Hz, 1H), 2.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.7, 172.0, 159.5, 137.1, 136.0, 135.8, 133.9, 132.1, 128.9, 128.6, 128.4, 128.1, 124.4, 120.5, 118.4, 86.6, 72.7, 68.2, 45.1, 38.3, 17.7. HPLC analysis: ee = 92%, Chiralpak IA column, n-hexane/ 8652


Note


Reactivity of Pyrazolin-5-one Derivatives. Chem. Commun. 2015, 51, 12890−12907. (4) For reviews on asymmetric synthesis of spiro compounds, see: (a) Franz, A. K.; Hanhan, N. V.; Ball-Jones, N. R. Asymmetric Catalysis for the Synthesis of Spirocyclic Compounds. ACS Catal. 2013, 3, 540−553. (b) Rios, R. Enantioselective Methodologies for the Synthesis of Spiro Compounds. Chem. Soc. Rev. 2012, 41, 1060−1074. (c) Nakazaki, A.; Kobayashi, S. Stereocontrolled Synthesis of Functionalized Spirocyclic Compounds Based on Claisen Rearrangement and its Application to the Synthesis of Spirocyclic Sesquiterpenes and Pyrrolidinoindoline Alkaloids. Synlett 2012, 23, 1427−1445. (d) Xie, X.; Huang, W.; Peng, C.; Han, B. Organocatalytic Asymmetric Synthesis of Six-Membered Carbocycle-Based Spiro Compounds. Adv. Synth. Catal. 2018, 360, 194−228. (5) (a) Zea, A.; Alba, A. N. P.; Mazzanti, A.; Moyano, A.; Rios, R. Highly Enantioselective Cascade Synthesis of Spiropyrazolones. Org. Biomol. Chem. 2011, 9, 6519−6523. (b) Zhang, J.-X.; Li, N.-K.; Liu, Z.M.; Huang, X.-F.; Geng, Z.-C.; Wang, X.-W. Enantioselective Synthesis of Unsymmetrical Diaryl-Substituted Spirocyclohexanonepyrazolones through a Cascade [4+ 2] Double Michael Addition. Adv. Synth. Catal. 2013, 355, 797−808. (c) Liang, J.; Chen, Q.; Liu, L.; Jiang, X.; Wang, R. An Organocatalytic Asymmetric Double Michael Cascade Reaction of Unsaturated Ketones and Unsaturated Pyrazolones: Highly Efficient Synthesis of Spiropyrazolone Derivatives. Org. Biomol. Chem. 2013, 11, 1441−1445. (d) Chauhan, P.; Mahajan, S.; Loh, C. C. J.; Raabe, G.; Enders, D. Streocontrolled Construction of Six Vicinal Stereogenic Centers on Spiropyrazolones via Organocascade Michael/Michael/ 1,2-Addition Reactions. Org. Lett. 2014, 16, 2954−2957. (e) Li, J.-H.; Feng, T.-F.; Du, D.-M. Construction of Spirocyclopropane-Linked Heterocycles Containing Both Pyrazolones and Oxindoles through Michael/Alkylation Cascade Reactions. J. Org. Chem. 2015, 80, 11369−11377. (f) Li, J.-H.; Wen, H.; Liu, L.; Du, D.-M. Diastereoand Enantioselective Synthesis of Spiro-Pyrrolidine-Pyrazolones by Squaramide-Catalyzed Cascade Aza-Michael/Michael Reactions. Eur. J. Org. Chem. 2016, 2016, 2492−2499. (g) Zheng, W.; Zhang, J.; Liu, S.; Miao, Z. Asymmetric Synthesis of Spiro[chroman-3,3′-pyrazol] Scaffolds with an All-carbon Quaternary Stereocenter via a oxaMichael-Michael Cascade Strategy with Bifunctional Amine-thiourea Organocatalysts. RSC Adv. 2015, 5, 91108−91113. (6) (a) Alba, A.-N. R.; Zea, L.; Valero, G.; Calbet, T.; Font-Bardía, M.; Mazzanti, A.; Moyano, A.; Rios, R. Highly Stereoselective Synthesis of Spiropyrazolones. Eur. J. Org. Chem. 2011, 2011, 1318− 1325. (b) Wu, B.; Chen, J.; Li, M.-Q.; Zhang, J.-X.; Xu, X.-P.; Ji, S.-J.; Wang, X.-W. Highly Enantioselective Synthesis of Spiro[cyclohexanone-oxindoles] and Spiro[cyclohexanone-pyrazolones] by Asymmetric Cascade [5 + 1] Double Michael Reactions. Eur. J. Org. Chem. 2012, 2012, 1318−1327. (c) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y. Asymmetric Synthesis of Spiropyrazolones Through Phosphine-Catalyzed [4 + 1] Annulation. Angew. Chem., Int. Ed. 2014, 53, 5643−5647. (d) Hack, D.; Dürr, A. B.; Deckers, K.; Chauhan, P.; Seling, N.; R̈ ubenach, L.; Mertens, L.; Raabe, G.; Schoenebeck, F.; Enders, D. Asymmetric Synthesis of Spiropyrazolones by Sequential Organo-and Silver Catalysis. Angew. Chem., Int. Ed. 2016, 55, 1797−1800. (e) Amireddy, M.; Chen, K. Organocatalytic one-pot Asymmetric Synthesis of Functionalized Spiropyrazolones via a Michael-Aldol Sequential Reaction. RSC Adv. 2016, 6, 77474−77480. (7) (a) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. EnantioselectiveSynthesis of Spirocyclohexadienones by NHCCatalyzed Formal [3 + 3] Annulation Reaction of Enals. Angew. Chem., Int. Ed. 2016, 55, 268−272. (b) Liu, J.-Y.; Zhao, J.; Zhang, J.-L.; Xu, P.F. Quaternary Carbon Center Forming Formal [3 + 3] Cycloaddition Reaction via Bifunctional Catalysis: Asymmetric Synthesis of Spirocyclohexene Pyrazolones. Org. Lett. 2017, 19, 1846−1849. (c) Mondal, S.; Mukherjee, S.; Yetra, S. R.; Gonnade, R. G.; Biju, A. T. Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds. Org. Lett. 2017, 19, 4367−4370. (d) Yang, W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.; Guo, H. Lewis-Base-Catalyzed Asymmetric [3 + 3]

residue was purified by silica gel column chromatography using EtOAc−hexane (30−50%) as eluent to afford the amide 5. N-Benzyl-2-((5R,6R,9S)-1-methyl-4-oxo-3,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-1-en-9-yl)acetamide (5). Compound 5 was obtained as a brown oil in 75% (34.2 mg) yield after column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.27−7.31 (m, 3H), 7.18−7.24 (m, 8H), 5.68 (s, 1H), 5.36 (s, 1H), 4.75 (t, J = 9.2 Hz, 1H), 4.31 (ddd, J = 43.5, 14.5, 5.6 Hz, 2H), 4.15−4.11 (m, 1H), 3.62 (m, 1H), 2.32 (dd, J = 15.0, 10.3 Hz, 1H), 2.21 (dd, J = 15.0, 5.3 Hz, 1H), 1.97 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 171.7, 169.2, 159.3, 137.9, 137.8, 136.0, 129.1, 128.9, 128.6, 128.3, 128.1, 127.9, 125.6, 124.4, 119.1, 86.2, 72.5, 68.2, 46.4, 44.0, 35.6, 17.6. HPLC analysis: ee = 88%, Chiralpak ID column, n-hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 86.4 min, tminor = 65.3 min). The optical rotation of 5 was found to be [α]D28 = −25.5 (c 0.395, CHCl3). HRMS (+ESI-TOF) m/ z: calcd for C28H28N3O3 [M + H]+ 454.2131, found 454.2122.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00781. Optimization, X-ray crystal data, NMR spectra, and HPLC chromatograms (PDF) Crystal data for compound 3s (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Subhas Chandra Pan: 0000-0002-7581-1831 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by DST-SERB (file no. EMR/2015/ 001034). We thank CIF, Indian Institute of Technology Guwahati, for the instrumental facility.

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REFERENCES

(1) For selected reviews, see: (a) Sondhi, S. M.; Dinodia, M.; Singh, J.; Rani, R. Heterocyclic Compounds as Anti-Inflammatory Agents. Curr. Bioact. Compd. 2007, 3, 91−108. (b) Varvounis, G. Pyrazol-3ones. Part IV: Synthesis and Applications. Adv. Heterocycl. Chem. 2009, 98, 143−224. (c) Schmidt, A.; Dreger, A. Recent Advances in the Chemistry of Pyrazoles. Properties, Biological Activities, and Syntheses. Curr. Org. Chem. 2011, 15, 1423−1463. (d) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. From 2000 to Mid2010: A Fruitful Decade for the Synthesis of Pyrazoles. Chem. Rev. 2011, 111, 6984−7034. (2) (a) Chande, M. S.; Barve, P. A.; Suryanarayan, V. Synthesis and Antimicrobial Activity of Novel Spirocompounds with Pyrazolone and Pyrazolthione Moiety. J. Heterocycl. Chem. 2007, 44, 49−53. (b) Schlemminger, I.; Schmidt, B.; Flockerzi, D.; Tenor, H.; Zitt, C.; Hatzelmann, A.; Marx, D.; Braun, C.; Kuelzer, R.; Heuser, A.; Kley, H.P.; Sterk, G. J. Novel Pyrazolone-Derivatives and Their Use as PD4 Inhibitors. Germany Patent WO2010055083, 2008. (c) Schmidt, B.; Scheufler, C.; Volz, J.; Feth, M. P.; Hummel, R.-P.; Hatzelmann, A.; Zitt, C.; Wohlsen, A.; Marx, D.; Kley, H.-P.; Ockert, D.; Heuser, A.; Christiaans, J. A. M.; Sterk, G. J.; Menge, W. M. P. B. Pyrazolone Derivatives as PDE4 Inhibitors. Germany Patent WO2008138939, 2010. (3) For a review, see: Chauhan, P.; Mahajan, S.; Enders, D. Asymmetric Synthesis of Pyrazoles and Pyrazolones Employing the 8653


Note


Enones: Asymmetric Synthesis of Quaternary α-Aminophosphonates. J. Org. Chem. 2015, 80, 1402−1413.

Annulation Reaction of Morita-Baylis-Hillman Carbonates: Enantioselective Synthesis of Spirocyclohexenes. ACS Catal. 2017, 7, 3142− 3146. (e) Leng, H.-J.; Li, Q.-Z.; Zeng, R.; Dai, Q.-S.; Zhu, H.-P.; Liu, Y.; Huang, W.; Han, B.; Li, J.-L. Asymmetric Construction of Spiropyrazolone Skeletons via Amine-Catalyzed [3+ 3] Annulation. Adv. Synth. Catal. 2018, 360, 229−234. (8) For selected reactions with 2a, see: (a) Li, D. R.; Murugan, A.; Falck, J. R. Enantioselective, Organocatalytic Oxy-Michael Addition to γ/δ-Hydroxy-α,β-enones: Boronate-Amine Complexes as Chiral Hydroxide Synthons. J. Am. Chem. Soc. 2008, 130, 46−48. (b) Asano, K.; Matsubara, S. Asymmetric Catalytic Cycloetherification Mediated by Bifunctional Organocatalysts. J. Am. Chem. Soc. 2011, 133, 16711−16713. (c) Asano, K.; Matsubara, S. Asymmetric Synthesis of 1,3-Dioxolanes by Organocatalytic Formal [3 + 2] Cycloaddition via Hemiacetal Intermediates. Org. Lett. 2012, 14, 1620−1623. (d) Liu, Y.; Ao, J.; Paladhi, S.; Song, C.-E.; Yan, H. Organocatalytic Asymmetric Synthesis of Chiral Dioxazinanes and Dioxazepanes with in Situ Generated Nitrones via a Tandem Reaction Pathway Using a Cooperative Cation Binding Catalyst. J. Am. Chem. Soc. 2016, 138, 16486−16492. (e) Mondal, K.; Pan, S. C. Synthesis of 2,5-Disubstituted Furans from Sc(OTf)3 Catalyzed Reaction of Aryl Oxiranediesters with γ-Hydroxyenones. J. Org. Chem. 2017, 82, 4415− 4421. (9) For reviews on squaramide catalysts, see: (a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. - Eur. J. 2011, 17, 6890−6899. (b) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253−281. (10) CCDC 1824042 contains the crystallographic data for 3s. (11) Sada, M.; Ueno, S.; Asano, K.; Nomura, K.; Matsubara, S. Stereoselective Preparation of 3-Alkanoylprop-2-en-1-ol Derivatives. Synlett 2009, 2009, 724. (12) Maity, R.; Gharui, C.; Sil, A. K.; Pan, S. C. Organocatalytic Asymmetric Michael/Hemiketalization/Retro-aldol Reaction of αNitroketones with Unsaturated Pyrazolones: Synthesis of 3-Acyloxy Pyrazoles. Org. Lett. 2017, 19, 662−665. (13) (a) Berkessel, A.; Mukherjee, S.; Muller, T. N.; Cleemann, F.; Roland, K.; Brandenburg, M.; Neudorfl, J.- M.; Lex, J. Structural Optimization of Thiourea-Based Bifunctional Organocatalysts for the Highly Enantioselective Dynamic Kinetic Resolution of Azlactones. Org. Biomol. Chem. 2006, 4, 4319−4330. (b) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly Enantioselective Conjugate Addition of Nitromethane to Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett. 2005, 7, 1967−1969. (c) Manna, M. S.; Kumar, V.; Mukherjee, S. Catalytic Enantioselective Construction of Quaternary Stereocenters by Direct Vinylogous Michael Addition of Deconjugated Butenolides to Nitroolefins. Chem. Commun. 2012, 48, 5193−5195. (d) Tripathi, C. B.; Kayal, S.; Mukherjee, S. Catalytic Asymmetric Synthesis of α,β-Disubstituted α,γ-Diaminophosphonic Acid Precursors by Michael Addition of α-Substituted Nitrophosphonates to Nitroolefins. Org. Lett. 2012, 14, 3296−3299. (14) Jin, H.; Kim, S. T.; Hwang, G. S.; Ryu, D. H. L-Proline Derived Bifunctional Organocatalysts: Enantioselective Michael Addition of Dithiomalonates to trans-β-Nitroolefins. J. Org. Chem. 2016, 81, 3263−3274. (15) Yang, W.; Du, Da. − M. Highly Enantioselective Michael Addition of Nitroalkanes to Chalcones Using Chiral Squaramides as Hydrogen Bonding Organocatalysts. Org. Lett. 2010, 12, 5450−5453. (16) Kumarswamyreddy, N.; Kesavan, V. Enantioselective Synthesis of Dihydrospiro[indoline-3,4′-pyrano[2,3-c]pyrazole] Derivatives via Michael/Hemiketalization Reaction. Org. Lett. 2016, 18, 1354−1357. (17) Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones with Isatins: Divergent Synthesis of 3 Hydroxy-2-Oxindole Derivatives. Angew. Chem., Int. Ed. 2013, 52, 6666−6670. (18) Bera, K.; Namboothiri, I. N. N. Quinine-Derived Thiourea and Squaramide Catalyzed Conjugate Addition of α-Nitrophosphonates to 8654


Highly Diastereo- and Enantioselective Synthesis of Spiro

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