Highly Diastereo and Enantioselective Synthesis of Spiro

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Highly Diastereo and Enantioselective Synthesis of SpiroTetrahydrofuran-Pyrazolones via Organocatalytic Cascade Reaction between #-hydroxyenones and Unsaturated Pyrazolones Buddhadeb Mondal, Rajendra Maity, and Subhas Chandra Pan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00781 • Publication Date (Web): 29 May 2018 Downloaded from http://pubs.acs.org on May 29, 2018

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The Journal of Organic Chemistry

Highly Diastereo and Enantioselective Synthesis of Spiro-TetrahydrofuranPyrazolones 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

ABSTRACT: The first diastereo and enantioselective synthesis of spiro-tetrahydrofuranpyrazolones 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 condition.

Over the last 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

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their potent bioactivities in medicinal chemistry. 2 For instance, pyrazolone related spirocyclic derivatives A−D (Figure 1) can be act as an antibacterial agent2a and also as a type-4phosphodiesterase inhibitor.2b,c

Figure 1. Biologically active spiropyrazolone derivatives 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 Scheme 1. Organocatalytic asymmetric synthesis of spiropyrazolones from unsaturated pyrazolones


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However, there is an inherent challenge for the preparation of spiro-motifs, including incorporating heterocycles and attaining high enantioselectivity. 4 In the last 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 preparation of spiropyrazolones 6 Also, unsaturated pyrazolones have recently been exploited as binucleophilic reactants to provide spiropyrazolones both via aminocatalysis and oxidative NHC catalysis.7 Ramon and co-workers first reported organocatalytic asymmetric synthesis of spiropyrazolones from unsaturated pyrazolones via a three component reaction with aldehydes and unsaturated aldehydes.5a R. 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 centres.5b,ec Enders et al also shown the synthesis of a variety of spirocyclohexanepyrazolone derivatives bearing six stereocentres via sequential organocatalytic reactions.5d Recently, the syntheses of spiropyrazolones bearing N-heterocyclic ring was disclosed from the reaction of N-tosylaminomethyl enones with unsaturated pyrazolones. 5f Interestingly, there is only a single report of organocatalytic oxa-Michael-Michael reaction by Miao and coworkers.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). Pleasingly, after stirring for 5 days, the desired spiropyrazolone 3a having tetrahydrofuran motif was isolated in 62% yield with 18:1 dr however



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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 3-4). Though the yields and diastereomeric ratios of 3a with these catalysts were good but the enantiomeric excess was low. Then we turned our attention to screen squaramide catalysts 9 V and VI and the results were promising for us (entries 5-6). Gratifyingly, an excellent enantioselectivity of 96% and diastereoselectivity of >20:1 were achieved with both catalysts and acceptable yields were detected. Other solvents were also examined but could not provide better results (see supporting information for details). Table 1. Catalyst Screening and Optimization of Reaction Condition

entrya

catalyst

yieldb

d.rc

eed

1

I

62

18:1

28

2

II

56

18:1

36


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3

III

60

14:1

40

4

IV

52

15:1

32

5

V

70

>20:1

96

6

VI

69

>20:1

96

a

Reaction condion: 0.12 mmol of 1a with 0.1 mmol of 2a in 0.4 ml solvent using 10 mol% catalyst.

b

Isolated yield after silica gel column chromatography.cDetermined by 1H NMR. dDetermined by

chiral HPLC. 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 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-tolyl containing enone 2b delivered product 3b in 71% yield with 94% ee. A smooth conversion was also detected with enone 2d having 4-anisyl motif. Enone 2e with 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. An o-substituted aryl enone 2i also underwent smooth reaction with pyrazolone 1a delivering product 3i in excellent enantioselectivity. The reaction outcome was not much different with 1-naphthyl substituted enone 2j. An heteroaromatic group was also tolerated in the reaction; though acceptable yield was



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obtained for 3k, slight less 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. Table 2. Scope of γ-hydroxyenones Ph N

+

O

N Ph

N

O

N

OMe

3d 69%, d.r>20:1, 90% ee O

Ph

3g 68%, d.r>20:1, 92% ee

N

N Ph

O

N Ph

N

N

O

3j 75%, d.r>20:1, 94% ee

N

O Br

Cl

O

N Ph

N

N Ph

N Ph

O

O

O O

3i 59%, d.r>20:1, 98% ee

N S

3k 76%, d.r = 15:1, 84% ee Ph

N

O

O

O O

O O

N Ph

Ph

Ph

O

O

3f 62%, d.r>20:1, 94% ee

O

3h 61%, d.r>20:1, 98% ee Ph

O

N Ph

O

N Ph

Ph

O

O

Ph OMe

O

3c 72%, d.r>20:1, 88% ee

3e 66%, d.r>20:1, 92% ee

O O

N Ph

Ph

O

O O

N Ph

N

3b 71%, d.r>20:1, 94% ee

N

O

O

Ph

O

Ph

R1

3a-m

O

N Ph

O O

N Ph

Ph

O

Ph

O

3a 70%, d.r>20:1, 96% ee

N

toluene, rt 5d

O

N Ph

N

N

2

1a

Ph

OH

R1

O

Ph

catalyst VI (10 mol%)

O

N Ph

O

3l 72%, d.r = 10:1, 90% ee

O O

OEt

3m 65%, d.r = 15:1, 60% ee

a

Reactions were carried out with 0.24 mmol of 1a with 0.2 mmol of 2 in 0.8 ml toluene using 10%

VI at RT for 5 days. bYields correspond to isolated yields after silica gel column chromatography. c

Diastereoselectivity was determined by 1H NMR. dees were determined by chiral HPLC.


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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 Table 3. Scope of Pyrazolones with Varied Benzylidene Substituent



OMe

Br

O

N

O

N Ph

CF3 O

O Ph

3w 58%, d.r>20:1, 96% ee

N

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Ph

O

N Ph

O

O N

N

N

55%, d.r>20:1, 94% ee

N

Ph

57%, d.r>20:1, 96% ee S O

O

Ph

Ph 3z 62%, d.r>20:1, 88% ee

N

N Ph

O

N Ph

O

Ph

3z 2

3z1

O

N Ph 3z3

N

Ph

64%, d.r> 20:1, 96% ee

N

O

O

O O

O

Ph 3y

3x

OMe O

O

57%, d.r 9:1, 90% ee

O O

Ph

50%, d.r 9:1, 90% ee

a

Reactions were carried out with 0.24 mmol of 1 with 0.2 mmol of 2a in 0.8 ml toluene using 10%

V at RT for 5 days. bYields correspond to isolated yields after silica gel column chromatography. c


electron-donating groups can be incorporated in the ortho-, meta- and para-position of the aryl group without having much pronounced effects on the yields and enantioselectivities. Here also, the excellent diastereoselectivity was maintained. For example, pyrazolone 1n having 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 3o having 4-anisyl group was isolated in slightly higher yield of 73% and in 96% ee. Then 4-halosubstituted pyrazolones 1r-1t were screened in the reaction and excellent results were achieved. In particular high yield was obtained for product 3t having 4-bromophenyl group. Pyrazolone 1u having 4-trifluromethyl substituent also participated in the reaction delivering product 3u in 66% yields with 94% ee. A biphenyl motif was also tolerated in the reaction albeit slight lower diastereoselectivity was attained. Smooth conversions were also observed with meta-substituted pyrazolones 1w-1y and the


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corresponding products 3w-3y were obtained in acceptable yields with excellent diastereo- and enantioselectivities. The reaction also progressed well with o-substituted pyrazolone 1z and acceptable enantioslectivity was detected. A disubstituted aryl group containing pyrazolone 1z1 also took part in the reaction and product 3z1 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 though the diastereoselectivity got 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 Nsubstitutions 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. Table 4. Scope of Pyrazolones with Varied N-Substituents and Hydrazone C- Substituents



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. c


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 formation of amide 5 with moderate yield and here also the enantioselectivity got almost preserved. Scheme 2. Synthetic Transformations of 3d.

The absolute structure of the product 3s was determined to be (2R, 3S, 4S) by single crystal X-ray crystallography10. By analaogy, it is predicted that other products will also have similar absolute


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configuration. Based on the absolute configuration a proposed TS has been drawn in Figure 2. It 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.

Figure 2. Proposed TS. In summary, we have developed the first diastereo- and enantioselective synthesis of spirotetrahydrofuran-pyrazolones via a mild and operationally simple oxa-Michael/Michael reaction between unsaturated pyrazolones and γ-hydroxyenones. This reaction furnished diverse multisubstituted spiropyrazolones in good yields and with excellent diastero- and enantioselectivities.

Experimental Section



General Information: Chemicals and solvents were purchased from commercial suppliers and used as received. 1H NMR spectra were recorded on 400 MHz, 500 MHz and 600 MHz spectrometer. 13C NMR spectra were recorded on 100 MHz , 126 MHz and 150 MHz. Chemical shifts were 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 were reported in Hertz (Hz). High-resolution mass spectra (HRMS) were recorded in Q-TOF electron spray ionization (ESI). Enantiomeric ratios were determined by HPLC analysis using 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. For visualizing the products UV light and I2 were used. Melting points were measured using BüCHI melting point B-540 apparatus. All melting points were measured in open glass capillary and values are uncorrected. Polarimetry: Rudolph research analytical auto plo II. Toluene was distilled over CaH2 under argon and stored over 4A° molecular sieves. DCM was distilled over CaH2 under argon and stored over 4A° molecular sieves. Silica gel (60-120 mesh size) was used for the 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 reported procedure. 11 General procedure for the synthesis of unsaturated pyrazolones Unsaturated pyrazolones were prepared according to reported procedures. 12


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General procedure for the synthesis of catalyst The catalyst (I, II, III and VII) was prepared according to reported procedures.13 The catalyst IV was prepared according to reported procedures.14 The catalyst (V and VI) was prepared according to reported procedures.15 The catalyst VIII was prepared according to reported procedures.16 General procedure for the synthesis of compound 3: In an oven dried round bottom flask, 1 (0.24 mmol), 2 (0.2 mmol), 10 mol% of catalyst V or VI were taken. 0.8 mL of toluene was added to the reaction mixture and stirred at rt for 5 days. Completion of 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-oxa-2,3-diazaspiro[4.4]non-3en-1-one (3a): 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-7-oxa-2,3-diazaspiro[4.4]non-3en-1-one (3b): 3b was obtained as an off white solid in 71% (62.3 mg) yield after column chromatography. M.P. = 135-138 oC. 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

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/iPrOH = 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-butyl)phenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3c): 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/iPrOH = 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.


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(5R,6R,9S)-9-(2-(4-methoxyphenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3d): 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 (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3e): 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/iPrOH = 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.



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(5R,6R,9S)-4-methyl-9-(2-oxo-2-(m-tolyl)ethyl)-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non3-en-1-one (3f): 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 (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3g): 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, n-Hexane/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.


Page 17 of 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(5R,6R,9S)-9-(2-(3-chlorophenyl)-2-oxoethyl)-4-methyl-2,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3h): 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 (t major = 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-tolyl)ethyl)-2,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non-3en-1-one (3i): 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). 13C 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-2,3diazaspiro[4.4]non-3-en-1-one (3j): 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-(thiophen-2-yl)ethyl)-2,6-diphenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3k): 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 = 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/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 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-oxa-2,3-diazaspiro[4.4]non-3en-1-one (3l): 3l was obtained as a brown sticky solid in 63% (65.2 mg) yield after column


Page 18 of 38

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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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (t major = 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-2,3-diazaspiro[4.4]non-1-en-9-

yl)acetate (3m): 3m was obtained as a colourless 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 (+ESI-TOF) 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-tolyl)-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3n): 3n was obtained as an off white solid in 69% (60.5 mg) yield



Page 20 of 38

after column chromatography. M.P. = 151-154 oC. 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-2,3diazaspiro[4.4]non-3-en-1-one (3o): 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, 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.


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(5R,6R,9S)-6-(4-(tert-butyl)phenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3p): 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 Column, n-Hexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3q): 3q was obtained as an off white solid in 73% (66.3 mg) yield after column chromatography. M.P. = 159-162 oC. 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 (t major = 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.



Page 22 of 38

(5R,6R,9S)-6-(4-fluorophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3r): 3r was obtained as a light yellow solid in 68% (60.2 mg) yield after column chromatography. M.P. = 124-127 oC. 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-2,3diazaspiro[4.4]non-3-en-1-one (3s): 3s was obtained as a colourless 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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 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.


Page 23 of 38 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(5R,6R,9S)-6-(4-bromophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3t): 3t was obtained as a light yellow solid in 75% (75.4 mg) yield after column chromatography. M.P. = 172-175 oC. 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 (t major = 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-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3u): 3u was obtained as a red semi solid 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, J C-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-2,3diazaspiro[4.4]non-3-en-1-one (3v): 3v was obtained as a light yellow semi solid 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 (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3w): 3w was obtained as a light brown semi solid 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 (t major = 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.


Page 24 of 38

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(5R,6R,9S)-6-(3-bromophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3x): 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-oxa2,3-diazaspiro[4.4]non-3-en-1-one (3y): 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, J C-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-2,3diazaspiro[4.4]non-3-en-1-one (3z): 3z was obtained as a light yellow semi solid 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). 13C 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-2,3diazaspiro[4.4]non-3-en-1-one (3z1): 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


Page 26 of 38

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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-(thiophen-2-yl)-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3z2): 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 (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/iPrOH = 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-2,3diazaspiro[4.4]non-3-en-1-one (3z3): 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,



Page 28 of 38

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/i-PrOH = 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-tolyl)-7-oxa-2,3diazaspiro[4.4]non-3-en-1-one (3z4): 3z4 was obtained as a colourless 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 (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3z5): 3z5 was obtained as a colourless 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,


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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 (t major = 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-2,3diazaspiro[4.4]non-3-en-1-one (3z6): 3z6 was obtained as a colourless 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/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-2,3-diazaspiro[4.4]non-3-en-1-one (3z7): 3z7 was obtained as a colourless 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 (t major = 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-oxa-2,3-diazaspiro[4.4]non-3en-1-one (3z8): 3z8 was obtained as a colourless 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/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (t major = 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 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) was 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.


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4-methoxyphenyl 2-((5R,6R,9S)-1-methyl-4-oxo-3,6-diphenyl-7-oxa-2,3-diazaspiro[4.4]non1-en-9-yl)acetate (4): 4 was obtained as a colourless 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, and the residue was dissolved in EtOAc (3 mL), the organic layer was washed with 1 N HCl (2 × 2 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained 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-2,3-diazaspiro[4.4]non-1-en-9yl)acetamide (5): 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/iPrOH = 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. ASSOCIATED CONTENT Supporting Information Optimization, X-ray crystal data, NMR spectra, and HPLC chromatograms (PDF), Crystal data for compound 3s (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Email: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by DST-SERB (file no. EMR/2015/001034). We thank CIF, Indian Institute of Technology Guwahati for the instrumental facility.

REFERENCES


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Highly Diastereo and Enantioselective Synthesis of Spiro

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