Acyl Transfer Reaction

Subscriber access provided by UNIV OF DURHAM

Organocatalytic Asymmetric Domino Michael/Acyl Transfer Reaction between #/#-Hydroxyenones and #-Nitroketones Keshab Mondal, and Subhas Chandra Pan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00436 • Publication Date (Web): 10 Apr 2018 Downloaded from http://pubs.acs.org on April 10, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 35 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

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

ACS Paragon Plus Environment

The Journal of Organic Chemistry 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

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 spiropyrazolones, in particular unprecedented O-heterocycle embedded spiropyrazones, 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


Page 2 of 35

Page 3 of 35 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


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 spiropyrazolones6 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.5d,e Enders et al also shown the synthesis of a variety of spirocyclohexanepyrazolone derivatives bearing six stereocentres

via

sequential

organocatalytic

reactions.5g

Recently,

the

syntheses

of

spiropyrazolones bearing N-heterocyclic ring were disclosed by Wang, Yuan and Du groups utilizing isothiocyanato oxindoles/α-isothiocyanato imides/N-tosylaminomethyl enones and unsaturated

pyrazolones.5b,c,f,i

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 tetrhaydrofuran motif was isolated in 62% yield with 18:1



Page 4 of 35

dr but the enantioselectivity was less (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 catalysts9 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 CF3

OMe

OMe H

H

N

N NH

NH N

S I

S

N H

N

Ar

S

Ar

N H

N H

N NMe2H

CF3 III

II

Ar = 3,5-(CF3)2C6H3

R H

N

CF3 H Ph N Me

NH S

N H

N N H

O

CF3

R = H, V R = OMe, VI

IV

Ph N

N Ph 1a

O

+

NH O

CF3 F3C

catalyst (10 mol%)

O OH

Ph

O

Ph N

toluene, rt 5d 2a

O N Ph 3a

O

entrya

catalyst

yieldb

d.rc

eed

1

I

62

18:1

28

2

II

56

18:1

36


Ph

Page 5 of 35 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


a

3

III

60

14:1

40

4

IV

52

15:1

32

5

V

70

>20:1

96

6

VI

69

>20:1

96

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

catalyst. bIsolated yield after silica gel column chromatography.cDetermined by 1H NMR. d

Determined 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 wereemployed 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 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

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


Page 6 of 35

Page 7 of 35 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


chromatography. cDiastereoselectivity was determined by 1H NMR. dees were determined by chiral HPLC. In the next phase, screening of a variety of pyrazolones 1 having different benzylidene substitutents were investigated with catalyst V (Table 3). It turned out that a range of electronwithdrawing and Table 3. Scope of Pyrazolones with Varied Benzylidene Substituent R2 N

O

N Ph

catalyst V (10 mol%)

O +

OH

Ph

1

toluene, rt 5d

N

2a

O

O Ph

N Ph 3n 69%, d.r>20:1, 96% ee

Ph

O

N Ph

O

O O

O

3n-z3

O

N

O

R2

O Ph

N

N

O N Ph 3o 65%, d.r>20:1, 96% ee

Ph

O

N Ph 3p

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

F

MeO

Cl O

O

N

N

O

O

O

O

O N

Ph

N

O

Ph N

Ph 3r

Ph 3q 73%, d.r>20:1, 96% ee

68%, d.r>20:1, 94% ee

Br

F3C

Ph 3s 72%, d.r>20:1, 94% ee Ph

O

O O

N

O

O Ph

O N Ph 3t 75%, d.r>20:1, 96% ee

Ph

O

N

N

O Ph

O N Ph 3u 66%, d.r>20:1, 94% ee

N

N Ph

O

Ph

3v 68%, d.r = 8:1, 92% 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. cDiastereoselectivity was determined by 1H NMR. dees were determined by chiral HPLC. 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


Page 8 of 35

Page 9 of 35 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


the corresponding products 3w-3y were obtained in acceptable yields with excellent diastereoand 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 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. 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. cDiastereoselectivity was determined by 1H NMR. dees were determined by chiral HPLC. 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.


Page 10 of 35

Page 11 of 35 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


The absolute structure of the product 3s was determined to be (2R, 3S, 4S) by single crystal Xray crystallography10. By analaogy, it is predicted that other products will also have similar absolute 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 thiourea 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). Using ESI mode HRMS spectra were recorded. Enantiomeric ratios were determined by HPLC analysis performed on 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. 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-઻-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


Page 12 of 35

Page 13 of 35 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


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 (1015 %) to afford desired product 3a-3z8. Characterization of the products: (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).

13

C NMR (151 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). ESI HRMS: 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).

13

C NMR (151 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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 220 nm (tmajor = 29.9 min, tminor = 20.1 min). ESI HRMS: 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).

13

C NMR (151 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). ESI HRMS: 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-2,3diazaspiro[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),


Page 14 of 35

Page 15 of 35 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


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).

13

C

NMR (126 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). ESI HRMS: 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 7.80 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.18 – 7.15 (m, 5H), 7.10 (d, J = 7.1 Hz, 1H), 5.32 (s, 1H), 4.78 (t, J = 9.2 Hz, 1H), 3.93 (t, J = 9.0 Hz, 1H), 3.70 (qd, J = 9.3, 5.0 Hz, 1H), 3.04 (dd, J = 17.7, 4.9 Hz, 1H), 2.88 (dd, J = 17.7, 9.9 Hz, 1H), 1.94 (s, 3H).

13

C NMR (126 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). ESI HRMS: calcd. For C27H24BrN2O3 [M+H]+ 503.0970, found 503.0972. (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 (101 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). ESI HRMS: 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). 13

C NMR (126 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). ESI HRMS: 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-2,3diazaspiro[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,


Page 16 of 35

Page 17 of 35 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


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).

13

C

NMR (126 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). ESI HRMS: 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 (126 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). ESI HRMS: 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).

13

C

NMR (126 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). ESI HRMS: 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).

13

C NMR (126 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 (tmajor = 15.5 min, tminor = 13.5 min). ESI HRMS: 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 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).

13

C NMR (126 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,


Page 18 of 35

Page 19 of 35 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


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 (tmajor = 17.9 min, tminor = 20.5 min). ESI HRMS: 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).

13

C NMR (126

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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 20.5 min, tminor = 14.5 min). ESI HRMS: 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 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).

13

C NMR (151 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,



Page 20 of 35

flow rate 1.0 mL/min, λ = 254 nm (tmajor = 22.8 min, tminor = 15.7 min). ESI HRMS: 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 (126 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). ESI HRMS: calcd. For C30H31N2O3 [M+H] + 467.2335, found 467.2336. (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).

13

C NMR (126

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


Page 21 of 35 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


mL/min, λ = 254 nm (tmajor = 19.4 min, tminor = 13.7 min). ESI HRMS: 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). 13

C NMR (151 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). ESI HRMS: calcd. For C28H27N2O3 [M+H]+ 455.1971, found 455.1979. (5R,6R,9S)-6-(4-fluorophenyl)-4-methyl-9-(2-oxo-2-phenylethyl)-2-phenyl-7-oxa-2,3diazaspiro[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).

13

C NMR (126 MHz,

CDCl3) δ 196.7, 171.7, 159.1, 137.9, 136.0, 133.8, 129.1, 128.9, 128.1, 126.2 (d, J = 8.1 Hz), 125.6, 119.2, 115.7 (d, J = 21.5 Hz), 86.0, 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). ESI HRMS: calcd. For C27H27FN2O3 [M+H]+ 443.1771, found 443.1774.



Page 22 of 35

(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).

13

C NMR (101

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). ESI HRMS: 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-2,3diazaspiro[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).

13

C NMR (151

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). ESI HRMS: calcd. For C27H24BrN2O4 [M+H]+ 503.0970, found 503.0968.


Page 23 of 35 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)-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 (101 MHz, CDCl3) δ 196.6, 171.5, 158.8, 140.1, 137.8, 136.0, 133.9, 129.2, 128.9, 128.1, 125.8, 125.6 (q, J = 3.73 Hz), 119.2, 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). ESI HRMS: calcd. For C28H27F3N2O3 [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. 1

H 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 (151 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). ESI HRMS: 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 (101 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). ESI HRMS: 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-2,3diazaspiro[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).

13

C NMR (101 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/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 24.7 min, tminor = 18.9 min). ESI HRMS: calcd. For C27H24BrN2O3 [M+H]+ 503.0970, found 503.0974.


Page 24 of 35

Page 25 of 35 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)-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).

13

C NMR (151 MHz, CDCl3) δ 196.6, 171.5, 158.7, 137.8, 137.2, 136.0,

133.9, 129.2, 129.1, 128.9, 128.7, 128.2, 127.8, 125.8, 125.1, 121.6, 119.4, 85.8, 72.9, 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). ESI HRMS: calcd. For C28H24F3N2O3 [M+H]+ 493.1939, 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).

13

C NMR (126 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/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 19.7 min, tminor = 17.2 min). ESI HRMS: 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 (126 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). ESI HRMS: calcd. For C29H29N2 [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. 1

H 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 (151 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). ESI HRMS: calcd. For C25H23N2O3S [M+H]+ 431.1429, found 431.1427.


Page 26 of 35

Page 27 of 35 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-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. 1

H 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).

13

C NMR (151 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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 20.6 min, tminor = 10.6 min). ESI HRMS: 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 (151 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). ESI HRMS: 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). 13

C NMR (126 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). ESI HRMS: 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).

13

C 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/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 43.8 min, tminor = 26.3 min). ESI HRMS: 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


Page 28 of 35

Page 29 of 35 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


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). ESI HRMS: 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). 13

C NMR (101 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 (tmajor = 15.7 min, tminor = 14.8 min). ESI HRMS: 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. 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).

13

C NMR (151 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/iPrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 22.1 min, tminor = 37.9 min). ESI HRMS: 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.


Page 30 of 35

Page 31 of 35 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


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).

13

C NMR (151 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, nHexane/i-PrOH = 90/10, flow rate 1.0 mL/min, λ = 254 nm (tmajor = 86.4 min, tminor = 65.3 min). ESI HRMS: calcd. For C28H28N3O3 [M+H]+ 454.2131, found 454.2122. ASSOCIATED CONTENT Supporting Information Optimization and control experiments, X-ray crystal data, NMR spectra, and HPLC chromatograms. 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 1. For selected reviews, see: (a) Sondhi, S. M.; Dinodia, M.; Singh, J.; Rani, R. Curr. Bioact. Comp. 2007, 3, 91. (b) Varvounis, G. Adv. Heterocycl. Chem. 2009, 98, 143. (c) Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15, 1423. (d) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. Chem. Rev. 2011, 111, 6984. 2. (a) Chande, M. S.; Barve, P. A.; Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49. (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. 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. Germany Patent WO2008138939, 2010. 3. For a review, see: Chauhan, P.; Mahajan, S.; Enders, D. Chem. Commun. 2015, 51, 12890. 4. For reviews on asymmetric synthesis of spiro compounds, see: (a) Franz, A. K.; Hanhan, N. V.; Ball-Jones, N. R. ACS Catal. 2013, 3, 540. (b) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (c) Nakazaki, A.; Kobayashi, S. Synlett 2012, 23, 1427. (d) Xie, X.; Huang, W.; Peng, C.; Han, B. Adv. Synth. Catal. 2018, 360, 194. 5. (a) Zea, A.; Alba, A. N. P.; Mazzanti, A.; Moyano, A. Rios, R. Org. Biomol. Chem. 2011, 9, 6519. (b) Liu, L.; Zhong, Y.; Zhang, P.; Jiang, X.; Wang, R. J. Org. Chem. 2012, 77, 10228. (c)


Page 32 of 35

Page 33 of 35 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


Chen, Q.; Liang, J.; Wang, S.; Wang, D.; Wang, R. Chem. Commun. 2013, 49, 1657. (d) Zhang, J.-X.; Li, N.-K.; Liu, Z.-M.; Huang, X.-F.; Geng, Z.-C.; Wang X.-W. Adv. Synth. Catal. 2013, 355, 797. (e) Liang, J.; Chen, Q.; Liu, L.; Jiang, X.; Wang, R. Org. Biomol. Chem. 2013, 11, 1441. (f) Cui, B.-D.; Li, S.-W.; Zuo, J.; Wu, W.-J.; Zhang, X.-M.; Yuan. W.-C. Tetrahedron 2014, 70, 1895. (g) Chauhan, P.; Mahajan, S.; Loh, C. C. J.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 2954. (h) Li, J.-H.; Feng, T.-F.; Du, D.-M. J. Org. Chem. 2015, 80, 11369. (i) Li, J.-H.; Wen, H.; Liu, L.; Du, D.-M. Eur. J. Org. Chem. 2016, 2492. (j) Meninno, S.; Roselli, A.; Capobianco, A.; Overgaard, J.; Lattanzi, A. Org. Lett. 2017, 19, 5030. (k) Han, W.-Y.; Zhao, J.; Wang, J.-S.; Xiang, G.-Y.; Zhang, D.-L.; Bai, M.; Cui, B.-D.; Wan, N.-W.; Chen, Y.-Z. Org. Biomol. Chem. 2017, 15, 5571. (l) Han, W.-Y.; Zhao, J.; Wang, J.-S.; Cui, B.-D.; Wan, N.-W.; Chen, Y.-Z. Tetrahedron 2017, 73, 5806. 6. (a) Alba, A.-N. R.; Zea, L.; Valero, G.; Calbet, T.; Font-Bardía, M.; Mazzanti, A.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2011, 1318. (b) Wu, B.; Chen, J.; Li, M.-Q.; Zhang, J.-X.; Xu, X.-P.; Ji, S.-J.; Wang, X.-W. Eur. J. Org. Chem. 2012, 1318. (c) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiatkowski, J.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 5643. (d) Hack, D.; Dürr, A. B.; Deckers, K.; Chauhan, P.; Seling, N.; R¨ubenach, L.; Mertens, L.; Raabe, G.; Schoenebeck, F.; Enders, D. Angew. Chem. Int. Ed. 2016, 55, 1797. (e) Amireddy, M.; Chen, K. RSC Adv. 2016, 6, 77474. 7. (a) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A. T. Angew. Chem., Int. Ed. 2016, 55, 268. (b) Liu, J.-Y.; Zhao, J.; Zhang, J.-L.; Xu, P.-F. Org. Lett. 2017, 19, 1846. (c) Mondal, S.; Mukherjee, S.; Yetra, S. R.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2017, 19, 4367. (d) Yang, W.; Sun, W.; Zhang, C.; Wang, Q.; Guo, Z.; Mao, B.; Liao, J.; Guo, H. ACS Catal.



2017, 7, 3142. (e) Leng, H.-J.; Li, Q.-Z.; Zeng, R.; Dai, Q.-S.; Zhu, H.-P.; Liu, Y.; Huang, W.; Han, B.; Li, J.-L. Adv. Synth. Catal. 2017, DOI: 10.1002/adsc.201701035. 8. For selected reactions with 2a, see: (a) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130, 46. (b) Asano, K.; Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711. (c) Asano, K.; Matsubara, S. Org. Lett. 2012, 14, 1620. (d) Liu, Y.; A, Jun.; Paladhi, S.; Song, C.-E.; Yan, H. J. Am. Chem. Soc. 2016, 138, 16486. (e) Mondal, K.; Pan, S. C. J. Org. Chem. 2017, 82, 4415. 9. For reviews on squaramide catalysts, see: (a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890. (b) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. 10. CCDC 1824042 contains the crystallographic data for 3s. 11. Sada, M.; Ueno, S.; Asano, K.; Nomura, K.; Matsubara, S. Synlett. 2009, 724. 12. Maity, R.; Gharui, C.; Sil, A. K.; Pan, S. C. Org. Lett. 2017, 19, 662. 13. (a) Berkessel, A.; Mukherjee, S.; Muller, T. N.; Cleemann, F.; Roland, K.; Brandenburg, M.; Neudorfl, J.-

M.; Lex, J. Org. Biomol. Chem. 2006, 4, 4319. (b) Vakulya, B.; Varga, S.;

Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. (c) Manna, M. S.; Kumar, V.; Mukherjee, S. Chem. Commun. 2012, 48, 5193. (d) Tripathi, C. B.; Kayal, S.; Mukherjee, S. Org. Lett. 2012, 14, 3296. 14. Jin, H.; Kim, S. T.; Hwang, G. S.; Ryu, D. H. J. Org. Chem. 2016, 81, 3263. 15. Yang, W.; Du, Da. – M. Org. Lett. 2010, 12, 5450. 16. Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 1354.


Page 34 of 35

Page 35 of 35 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


17. Zhu, B.; Zhang, W.; Lee, R.; Han, Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Angew. Chem. Int. Ed. 2013, 52, 6666. 18. Bera, K.; Namboothiri, I. N. N. J. Org. Chem. 2015, 80, 1402.


Acyl Transfer Reaction

Recommend Documents