Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via

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Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via Chiral Squaramide Catalyzed [4+2] Cyclization of Azadienes with Azlactones Xiaoping Li, Juzhang Yan, Jialiang Qin, Shilin Lin, Weiwen Chen, Ruoting Zhan, and Huicai Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00911 • Publication Date (Web): 03 Jun 2019 Downloaded from http://pubs.acs.org on June 4, 2019

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The Journal of Organic Chemistry

Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via Chiral Squaramide Catalyzed [4+2] Cyclization of Azadienes with Azlactones

Xiaoping Li, Juzhang Yan, Jialiang Qin, Shilin Lin, Weiwen Chen, Ruoting Zhan, and Huicai Huang*

Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education. Guangzhou, 510006, China

F3C O

NR2 R3

+ O

R1

O R5

R4 N

10 mol% 4c

R

R2 N

3

O

O R4 NHCOR5

R1 32 examples, up to 92% yield up to > 20:1 dr, up to 99% ee

F3C

O

O

N H

NH N

N 4c

OMe

ABSTRACT An asymmetric cyclization reaction of azadienes and azlactones was investigated by employing a cinchona-squaramide catalyst, which could afford a series of benzofuran-fused six-membered heterocycles containing α,α-disubstituted amino acids unit in a highly diastereo- (>20:1 dr) and enantioselective (up to 99% ee) manner with good to excellent yields (up to 92%). A plausible pathway was proposed to explain the reaction process.

INTRODUCTION The efficient generation of structural diversity in organic compounds is an important goal in chemistry and chemical biology.1 Among the biologically relevant molecules benzofurans2 and their nitrogenous heterocycles3 represent privileged structural motifs,

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which are present in numerous natural products and pharmacologically active molecules. Recent efforts from Zhao group have identified azadiene as an effective four-atom synthon in cycloaddition reactions to produce benzofuran-fused N-heterocyclic compounds. For example, they have applied the complementarity of chiral amine and NHC catalysts to access either diastereomeric series of the benzofuran-fused lactams and tetrahydropyridines (Scheme 1A).4 Recently, the NHC catalyzed annulation of aurone-derived azadienes with enals was also illustrated by Ye et al, and benzofuran-fused seven-membered N-heterocycles were obtained in high enantioselectivities (Scheme 1B).5 In addition, Ullah and Lu et al. realized high enantioselective phosphine-catalyzed reaction of azadienes with allene ketones to structure benzofuran-fused eight-membered N-heterocycles (Scheme 1C).6 Zhao group obtained two kinds of enantioenriched benzofuran-fused N-heterocycles through palladium catalysis, which were synthesized by [4+5] cycloaddition of azadienes to vinylethylene carbonates and by [4+6] cycloaddition of azadienes to vinyl oxetanes, respectively (Scheme 1D).7 Very recently, Shi group developed a chiral guanidine catalyst-enabled asymmetric [4+1] cyclization between benzofuran-derived azadienes and 3-chlorooxindoles to access spirooxindole skeletons in high diastereoselectivities and good enantioselectivities (Scheme 1E).8 Despite these exquisite advancements, organocatalytic asymmetric cyclizations of benzofuran-derived azadienes9 are still far from well-developed. Furthermore, it is reported that α,α-disubstituted amino acids constitute another group of compounds with widespread applications in bioscience owing to the presence of the quaternary stereogenic center.10 Given the relevance of azadienes and α,α-disubstituted amino acids, it was anticipated that incorporation of both structural motifs into one molecule might lead to the creation of a new group of azadienes derivatives with potentially interesting biological properties, or it may be possible to construct a benzofuran N-heterocyclic skeleton. Herein, we disclose a stereoselective [4+2] cyclization of azadienes to azlactones11, acquiring the benzofuran-fused six-membered N-heterocycles in good yields with excellent diastereoselectivities and good to excellent enantioselectives (Scheme 1F). Scheme 1. Reports on the Asymmetric Cyclizations of Azadienes.


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A. Complementary catalyses with chiral amine and NHC, 2016, Zhao et al. Ts N

O R

Reduction

O

Ts N

O Cl

H 1 mol% chiral amine

R

R

NTs

H

Ar 1 mol% NHC

O

O

NTs + O

O

R' R

Ar

O

10 mol% NHC H

N

R' R

R

Ar

Ar B. By NHC-catalysis, 2018, 2019, Ye et al.

O

Ts

O

Ar

C. By Phosphine-catalysis, 2017, Ullah & Lu et al.

O

+ O

Ts N

R

NTs

5 mol% amide-phosphine

Ar

D. By Pd-catalysis, 2017, 2018, Zhao et al. R' TsN

O

O

R' 5 mol% [Pd] Chiraphos

O

R E. By guanidine-catalysis, 2019, Shi et al. Cl

NTs

O

R

5 mol% [Pd]/SIPHOX

Ts O N O

F. This work: O

O

R

1

R

5

R4 N

2

N

10 mol% chiral squaramide R3

NH

R R

O +

O

O R

N H

NR2

R'

N

R'

R' 10 mol% chiral guanidine

+ R

O

Ts

O

NTs

O

O

R3

R

O

Ar

O

O

O

R' O R4 NHCOR5 R1

RESULTS AND DISCUSSION

At the outset, we started our research with azadiene 1a and azlactone 2a as the model substrates. The model reaction was initially carried out with the thiourea catalyst 4a and resulted in the formation of a single diastereomer of the desired benzofuropyridinone 3aa through a cyclization reaction in 40% yield and 99% ee (Table 1, entry 1). Takemoto’s thiourea catalyst 4b provided the product 3aa with slightly increased yield with a decreased in the ee value to 92% (entry 2). We then extended the catalyst screening by using more acidic squaramide catalysts 4c-4d (entries 3-4). In the corresponding reactions, excellent enantioselectivity was maintained and yield improved slightly. To improve the yield of this reaction, we next tested catalysts 4e-4f (entries 5-6), the results



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showed that catalyst 4e gave a higher yield than catalyst 4c, but the enantioselectivity was lower (entry 5), and catalyst 4f have a lower yield despite an excellent enantioselectivity (entry 6). Among all the chiral organocatalysts, catalyst 4c proved to be the most favorable catalyst in terms of product yields and enantioselectivities (Table 1, entries 1-6). The catalyst 4c was then chosen for further optimization studies for the [4+2] cyclization reaction. A survey of the solvents (entries 7-17) indicated that halogenated solvents PhCF3 and PhCl could afford the [4+2] cyclization in better yields than other solvents. To further optimize the reaction conditions, the reaction temperature was investigated. The results showed that the yield would decline to 77% and 81%, respectively, when the reaction temperature was lowered to 0 C (entries 18-19). Finally, the best result was achieved when the reaction was conducted in 1.0 mL of PhCl at 0 C for 24 h, then warmed to room temperature for 48 h, the desired product 3aa was obtained in 81% yield with 99% ee (entry 19). Table 1. Screening of the Reaction Conditionsa F3C

F3C S NH

S N

N

N

4a

F3C

N H

N H

CF3

N

NH

CF3 N

S

CF3

4d

N

NH

HN

OMe

OMe

N

O

N

4c

OMe

N H

N H N

4b

OMe

O

O

CF3

N H

F3C

O

NH

N

O 4f

CF3

4e

CF3

NH NH

CF3

O

F3C

1a

Ph

Cat. 4 (10 mol%)

O

+ O

Ts N

O

N Ts

Ph

N

Ph

Solvent, RT, 0.1 M

Ph

NHCOPh

O

2a

O

3aa

Ph

entry

cat.

solvent

t (h)

yield %b

drc

ee %d

1

4a

Toluene

24

40

>20:1

99

2

4b

Toluene

24

46

>20:1

92

3

4c

Toluene

24

45

>20:1

99


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4

4d

Toluene

24

26

>20:1

99

5

4e

Toluene

24

54

>20:1

-92

6

4f

Toluene

24

20

>20:1

-99

7

4c

MeOH

24

14

>20:1

79

8

4c

EtOAc

24

17

>20:1

70

9

4c

MTBE

24

37

>20:1

99

10

4c

DCM

24

88

>20:1

87

11

4c

CHCl3

24

67

>20:1

96

12

4c

CCl4

24

61

>20:1

98

13

4c

PhCF3

24

86

>20:1

96

14

4c

PhCl

24

83

>20:1

98

15

4c

PhF

24

44

>20:1

99

16

4c

PhBr

24

45

>20:1

98

17

4c

PhF6

24

18

>20:1

87

18 19

4c e

PhCF3 PhCl

72 72

77 81

>20:1 >20:1

99 99

aUnless

4c e

otherwise noticed, all reactions were carried out using 1.0 equiv of 1a (0.05 mmol), 1.1 equiv of 2a (0.055

mmol), 0.1 equiv of catalyst 4 (0.005 mmol), 0.5 mL solvent. bIsolated yield of two diastereoisomers. cDetermined by crude 1H NMR analysis. dDetermined by HPLC analysis. eReactions were carried out using 1.0 equiv of 1a (0.10 mmol), 1.1 equiv of 2a (0.11 mmol), 0.1 equiv of catalyst 4c (0.01 mmol), 1.0 mL solvent at 0 C for 24 h, then warmed to room temperature and stirred for 48 h.

With the optimized conditions in hand, the substrate scope was investigated, and the results are shown in Table 2. For azadienes 1, bearing either electron-rich or electron-deficent groups on metaor para- positions of the phenyl ring are tolerable, giving corresponding products 3aa-3pa in good yields and excellent stereoselectivities (62-92% yields with >20:1 dr and 90-99% ee). However, ortho-position substituents on the phenyl ring group had a significant negative effect on stereochemistry of the reaction, in which the desired products 3qa-3sa were afforded in moderate enantioselectivities (62-80% ee), probably owing to the steric effect of the ortho-substituent. In addition, when substituent R2 was para-toluenesulfonyl group, 3,5-dichloro- substituent on the phenyl ring gave the desired product 3ta in 73% yield with 94:6 dr and 92% ee. Gratifyingly, azadienes containing 1-naphthyl, 2-naphthyl and thiophene groups (R1) were also found to be suitable substrates, the reactions proceeded smoothly to get corresponding products 3ua3xa under the optimal conditions. Moreover, the bromobenzofuran core of substrate can also



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be cyclized to deliver corresponding adduct 3ya with excellent stereoselectivity (98% ee). The absolute configuration of this series of compounds was confirmed by single-crystal Xray diffraction analysis of 3ba.12 Table 2. Substrate Scope of the Azadienesa,b,c,d,,e,f 2 N R

O O

+

R3

R1

O

Ph

1 Ts N O

Ts N

N

Ph

R3

PhCl, 0 oC to RT

O

Ts N O

O

O

Ph

Ph

NHCOPh

O

O

NHCOPh

Ms N

NHCOPh

O

Ph

NHCOPh

O

O

Ph

R

3qa (R = Cl): 86%, 62% ee, 72he 3ra (R = Me): 74%, 67% ee, 72he Ts N

O

3ja (R = H): 92%, 95% ee, 48h 3ka (R = F): 90%, 90% ee, 72h 3la (R = Me): 84%, 95% ee, 72h

R

Ts N

R

O

R 3ma (R = Br): 88%, 94% ee, 48h 3na (R = Cl): 87%, 93% ee, 48h 3oa (R = F): 81%, 98% ee, 48h 3pa (R = Me): 69%, 98% ee, 72h

NHCOPh 1

Ms N

Ph

Ph

Ph

3

3aa(R = H): 81%, 99% ee, 72h 3ba (R = Br): 81%, 99% ee, 48h 3ca (R = Cl): 85%, 96% ee, 72h NHCOPh 3da (R = F): 83%, 97% ee, 72h 3ea (R = Me): 64%, 99% ee, 72he 3fa (R = OMe): 62%, 97% ee, 72h 3ga (R = CF3): 83%, 99% ee, 72h R 3ha (R = NO2): 74%, 93% ee, 48h 3ia (R = COOMe): 86%, 97% ee, 48h

O

O

O

2a

NHCOPh

O

4c (10 mol%)

R2 N

3sa: 58%, 80% ee, 72h Ts N

Ph

NHCOPh

O

Ph

NHCOPh

O

Cl Cl 3ta: 73%, 94:6 dr, 92% ee, 48h Ts N O

O

Ph

NHCOPh S

3wa: 82%, 90% ee, 48h aUnless

3va: 75%, 99% ee, 72he

3ua: 74%, 95% ee, 48h Ms N O

O

Ts N

Ph

NHCOPh

Br O

O

Ph

NHCOPh

S 3xa: 86%, 84% ee, 48h

3ya: 25%, 98% ee, 48hf

otherwise noticed, all reactions were carried out using 1.0 equiv of 1 (0.10 mmol), 1.1 equiv of 2a

(0.11 mmol), 0.1 equiv of 4c (0.01 mmol), 1.0 mL PhCl at 0 C for 24 h, then warmed to room temperature and stirred for 24 h or 48 h. bIsolated yield. cThe dr values were determined by crude 1H NMR analysis. dThe

ee values were determined by HPLC analysis. ePhCF3 as solvent. fThe reactions was carried out using


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1.0 equiv of 1 (0.05 mmol), 1.1 equiv of 2a (0.055 mmol), 0.1 equiv of 4c (0.005 mmol), 0.5 mL PhCl at 0 C for 24 h, then warmed to room temperature and stirred for 24 h.

Encouraged by above-mentioned results, we continued to investigate into the variation of the azlactones, and the results are collected in Table 3. When other azlactone substrates were investigated under the optimized conditions, the reactions proceeded very slowly and only trace amounts of the desired products were formed after several days, except for the benzofuran-fused heterocycle 3ab and 3ac, which were produced in 87% and 91% yield and with 91% and 88% ee, respectively. Subsequently, inspired by the solvent effect as mentioned above (Table 1, entries 13-14), the reaction was conducted in PhCF3 at room temperature to improve the conversions. Fortunately, these new conditions led to the formation of the desired products 3ad-3ag in moderate to good yields (35-85%) and excellent enantioselectivities (93-99% ee). It is noteworthy that the propyl-substituted azlactone 2h is also tolerated, and the desired product 3ah was formed in 12% yield with >20:1 dr and 97% ee. To demonstrate the potential applicability of this method, a larger-scale reaction of azadiene 1j and azlactone 2a was performed at standard conditions. The desired product 3ja was obtained in 80% yield and 95% ee with >20:1 dr (Table 4). Furthermore, a transformation of adduct was conducted to show the synthetic potential of this work (Table 4). Treated 3aa with 0.2 mL of HMPA and 4.0 mL of SmI2 at -78 C in THF for 0.5 h under nitrogen, the tosyl group removal product 5 was obtained in 91% yield and with complete retention of the stereochemistry.13 Table 3. Substrate Scope of the Azlactonesa,b,c,d,e



O

N Ts

O 1a Ts N

PhCl, RT

F

Ts N

O

O

R NHCOPh

O

Ts N

O O

3ae: 35%, 99% ee, 72he

Br

Ts N

O

O

O N H

O

N H

NHCOPh

O

3ad: 82%, 93% ee, 72he

NHCOPh

O O

O 3af: 41%, 97% ee, 72he aUnless

R1 NHCOR2 Ph

Cl

Ts N

Cl

O

O

3

3ab (R = Br): 87%,91% ee, 48h 3ac (R = Cl): 91%, 88% ee, 72h

Ts N

O

2

O O Bn N H

O

R1 N

R2

Ph

Ts N

4c (10 mol%)

O

+

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3ah: 12%, 97% ee, 72he

3ag: 85%, 99% ee, 72he

otherwise noticed, all reactions were carried out using 1.0 equiv of 1a (0.10 mmol), 1.1 equiv of a (0.11

mmol), 0.1 equiv of 4c (0.01 mmol), 1.0 mL PhCl at rt for 48 h or 72 h. bIsolated yield. cThe dr values were determined by crude 1H NMR analysis. dThe ee values were determined by HPLC analysis. ePhCF3 as solvent.

Table 4. Larger-Scale Synthesis of Compound 3ja and Transformation of Compound 3aa

Ph

4c (10 mol% )

O

+ O

Ms N

O

NMs

N

Ph

1j

Ph

PhCl, 0 oC to rt, 72 h

2.0 mmol

3ja

Ts N O

2.2 mmol O

3aa >20:1 dr, 99% ee

Ph

0.89 g, 80% yield, 95% ee H N

Ph

NHCOPh

NHCOPh Ph

O

2a

O

SmI2 HMPA/THF

O

O

Ph

NHCOPh

5 91% yield, >20:1 dr, 99% ee

Actually, Michael adduct A mixture can be isolated quantitatively at the beginning of the reaction. This result indicates that the reaction maybe goes through three consecutive steps11b


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involving Michael addition, cyclization, and finally a ring opening process. The plausible reaction pathway was illustrated in scheme 2, a catalyzed Michael addition as the stereocontrol step, followed by intramolecular N-acylation of enamine and opening of the oxazolone ring. Scheme 2. Plausible Reaction Pathway. F3C Ts N O

O

R

Ph

4c

Bn

F3C

N H

N H

O Tol O S N

N 2a

1

O OMe

O +

O

O

H N H O

O Ph

N

Bn R

Michael addition

Ts N O R

O N BnH

N-acylation ring opening

O Ph

Ts

N O

O N Bn

O

Ts NO Ph

R

O R

O

N Bn

Ph

A

CONCLUSION In summary, an efficient and highly stereoselectivity asymmetric cyclization reaction of azadienes and azlactones has been developed through a chiral squaramide catalysis strategy. With the developed protocol, a series of benzofuran-fused six-membered heterocycles were synthesized in good yields (up to 92%) and excellent diastereoselsectivities (up to >20:1) and enantioselectivities (up to 99%). The synthetic method showed the practicality by largerscale reaction. Moreover, the tosyl group removal of a benzofuran-fused six-membered heterocyclic derivative was successfully carried out, and the desired product was obtained in a high yield (91%) and with complete retention of the stereochemistry.

EXPERIMENTAL SECTION



General Information. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker AV-400 spectrometer (400 MHz and 100 MHz). Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CDCl3: 7.26) Chemical shifts for carbon are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3: 77.16). Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz). High resolution mass spectra (EI) were measured on a Waters Micromass GCT spectrometer. High resolution mass spectrometry (ESI) were carried out using a Waters Quatro Macro triple quadrupole mass spectrometer. Optical rotations were measured on an Autopol III automatic polarimeter (Rudolph Research analytical). Melting points were measured on a XT3A apparatus. High performance liquid chromatography (HPLC) was performed on an Agilent 1200 Series chromatographs using chiral columns (DAICEL CHIRALPAK IA) as noted. All solvents and reagents were from commercial sources (Adamasbeta®) and used without purification unless otherwise noted. The azadienes 1a-1y were synthesized following the literature procedure.4-9 The azlactones 2a−2h were prepared according to the reported literature procedures. 11 General procedure for the enantioselective synthesis of 3. To a stirred solution of azadienes 1 (0.10 mmol) and catalyst 4c (0.01 mmol) in PhCl (1.0 mL) at 0 C was added azlactones 2 (0.11 mmol) and this reaction was stirred at 0 C for 24 h, then warmed to room temperature for 24 h or 48 h. The solvent was removed under vacuum, the residue was purified through column chromatography on silica gel with Hex/EtOAc (10:1) to yield the target product 3. N-((3S,4R)-3-benzyl-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (3aa). The product was obtained as a white solid (50.8 mg, 81% yield), m.p. 112114 C; [α]25D -72.0 (c 0.476, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.29-8.27 (m, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.42-7.40 (m, 1H), 7.34-7.19 (m, 7H), 7.15-7.10 (m, 2H), 6.99-6.95 (m, 2H), 6.93-6.83 (m, 6H), 6.79 (d, J = 7.2 Hz, 2H), 6.61 (s, 1H), 5.32 (s, 1H), 3.94 (d, J = 13.6 Hz, 1H), 2.70 (d, J = 14.0 Hz, 1H), 2.38 (s, 3H);

13C{1H}

NMR (100 MHz, Chloroform-d) δ 169.7,

167.5, 154.7, 146.7, 146.1, 135.1, 134.7, 134.3, 134.2, 131.5, 130.2, 129.9, 129.6, 128.6, 128.5,


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128.3, 128.2, 127.9, 127.3, 125.6, 123.8, 123.1, 122.0, 117.8, 112.0, 67.0, 46.3, 38.5, 21.8; IR (KBr): 3401, 2925, 1718, 1663, 1507, 1176, 667 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H31N2O5S 627.1948, found 627.1958; The enantiomeric excess was determined by HPLC. [ADH column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 17.7 min (major), 33.6 min (minor), ee 99%. N-((3S,4R)-3-benzyl-4-(4-bromophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ba). The product was obtained as a white solid (57.2 mg, 81% yield), m.p. 111-113 C; [α]25D -73.2 (c 0.528, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.31-8.27 (m, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.47-7.43 (m, 1H), 7.38-7.27 (m, 7H), 7.24-7.20 (m, 2H), 7.036.99 (m, 3H), 6.95-6.92 (m, 2H), 6.78-6.74 (m, 4H), 6.67 (s, 1H), 5.32 (s, 1H), 3.90 (d, J = 13.6 Hz, 1H), 2.68 (d, J = 13.6 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 169.5, 167.4, 154.7, 146.2, 146.0, 134.7, 134.1, 133.6, 131.7, 131.6, 130.1, 129.9, 129.6, 128.6, 128.2, 127.3, 126.6, 125.7, 123.9, 123.1, 122.0, 121.9, 118.0, 112.0, 66.8, 45.6, 38.4, 21.8; IR (KBr): 3401, 2927, 1716, 1663, 1486, 1177, 666, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30BrN2O5S 705.1053, found 705.1064; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 18.5 min (major), 43.2 min (minor), ee 99%. N-((3S,4R)-3-benzyl-4-(4-chlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ca). The product was obtained as a white solid (56.1 mg, 85% yield), m.p. 80-82 C; [α]25D -68.8 (c 0.546, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.30-8.27 (m, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.46-7.44 (m, 1H), 7.35-7.26 (m, 7H), 7.23-7.19 (m, 2H), 7.02-6.99 (m, 1H), 6.93 (t, J = 7.2 Hz, 2H), 6.84 (t, J=9.2 Hz, 4H), 6.77 (d, J = 7.6 Hz, 2H), 6.66 (s, 1H), 5.33 (s, 1H), 3.90 (d, J = 14.0 Hz, 1H), 2.68 (d, J = 14.0 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.8, 167.6, 155.0, 146.4, 135.0, 134.4, 134.0, 133.4, 131.9, 130.4, 130.1, 129.8, 129.6, 128.9, 128.8, 128.4, 127.6, 126.8, 126.0, 124.1, 123.3, 122.1, 118.2, 112.2, 67.1, 45.8, 38.7, 22.0; IR (KBr): 3396, 2925, 1716, 1666, 1484, 1177, 1080, 671, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30ClN2O5S 661.1558, found 661.1568; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 16.5 min (major), 35.9 min (minor), ee 96%. N-((3S,4R)-3-benzyl-4-(4-fluorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3da). The product was obtained as a white solid (53.5 mg, 83% yield),



m.p. 102-104 C; [α]25D -65.0 (c 0.480, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.29-8.28 (m, 1H), 8.00 (d, J = 7.6 Hz, 2H), 7.46-7.44 (m, 1H), 7.36-7.19 (m, 9H), 7.02-6.99 (m, 1H), 6.946.86 (m, 4H), 6.77 (d, J = 7.2 Hz, 2H), 6.65 (s, 1H), 6.58 (t, J = 8.0 Hz, 2H), 5.33 (s, 1H), 3.91 (d, J = 13.6 Hz, 1H), 2.69 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.6, 167.4, 162.2 (JCF = 245.7 Hz), 154.7, 146.4, 146.1, 134.8, 134.2, 131.6, 130.5, 130.4, 130.1, 130.0, 129.9, 129.6, 128.6, 128.2, 127.3, 126.6, 125.7, 123.8, 123.1, 121.9, 117.7, 115.4 (JCF = 21.4 Hz), 111.9, 67.0, 45.4, 38.4, 21.8; IR (KBr): 3401, 2925, 1666, 1509, 1389, 1180, 676, 661, 569 cm-1;

19F

NMR (376 MHz, CDCl3) δ -113.7 (Ar-F). HRMS (ESI-TOF) m/z: [M+H]+ calcd for

C38H30FN2O5S 645.1854, found 645.1849; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 14.1 min (major), 20.7 min (minor), ee 97%. N-((3S,4R)-3-benzyl-2-oxo-4-(p-tolyl)-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (3ea). The product was obtained as a white solid (41.2 mg, 64% yield), m.p. 115-117 C; [α]25D -68.4 (c 0.401, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.30-8.28 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.45-7.43 (m, 1H), 7.37-7.25 (m, 7H), 7.22-7.18 (m, 2H), 7.03-6.99 (m, 1H), 6.96-6.92 (m, 2H), 6.80-6.75 (m, 4H), 6.69 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 5.30 (s, 1H), 3.94 (d, J = 13.6 Hz, 1H), 2.70 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H), 2.08 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.7, 167.4, 154.6, 146.9, 145.9, 137.5, 135.1, 134.3, 134.2, 131.4, 130.1, 129.9, 129.5, 129.2, 128.4, 128.1, 128.0, 127.2, 126.6, 123.7, 123.0, 122.0, 117.6, 111.9, 67.1, 45.8, 38.4, 21.8, 21.0; IR (KBr): 3404, 2922, 1666, 1479, 1392, 1172, 701, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H33N2O5S 641.2104, found 641.2096; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 15.2 min (major), 42.9 min (minor), ee 99%. N-((3S,4R)-3-benzyl-4-(4-methoxyphenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3fa). The product was obtained as a white solid (40.6 mg, 62% yield), m.p. 165-167 C; [α]25D -53.3 (c 0.392, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.30-8.28 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.45-7.43 (m, 1H), 7.37-7.26 (m, 7H), 7.22-7.18 (m, 2H), 7.026.99 (m, 1H), 6.95-6.91 (m, 2H), 6.81-6.78 (m, 4H), 6.64 (s, 1H), 6.41 (d, J = 8.8 Hz, 2H), 5.28 (s, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.57 (s, 3H), 2.69 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.8, 167.4, 159.0, 154.6, 147.0, 145.9, 135.1, 134.4, 134.2, 131.5,


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130.1, 129.9, 129.5, 129.3, 128.5, 128.1, 127.2, 126.6, 126.5, 125.5, 123.7, 123.0, 122.0, 117.6, 113.8, 111.9, 67.2, 55.0, 45.4, 38.4, 21.8; IR (KBr): 3401, 2932, 1659, 1514, 1382, 1180, 1030, 664, 572 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H33N2O6S 657.2053, found 657.2070; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 10.4 min (minor), 11.8 min (major), ee 97%. N-((3S,4R)-3-benzyl-2-oxo-1-tosyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,4tetrahydrobenzofuro[3,2-b]pyridin-3-yl)benzamide (3ga). The product was obtained as a white solid (57.5 mg, 83% yield), m.p. 187-189 C; [α]25D -77.4 (c 0.562, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.30-8.28 (m, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.44-7.42 (m, 1H), 7.36-7.23 (m, 7H), 7.19-7.16 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.00-6.98 (m, 3H), 6.93-6.90 (m, 2H), 6.77 (d, J = 7.2 Hz, 2H), 6.67 (s, 1H), 5.42 (s, 1H), 3.90 (d, J = 13.6 Hz, 1H), 2.69 (d, J = 13.6 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.5, 167.5, 154.8, 146.3, 145.7, 138.8, 134.7, 134.1, 134.0, 131.8, 130.2, 130.0, 129.9, 129.7, 128.7, 128.3, 127.4, 126.6, 125.9, 125.5 (JCF =3.6 Hz), 124.0, 123.8 (JCF =270.4 Hz), 123.2, 121.9, 118.2, 112.0, 66.8, 45.9, 38.5, 21.7; 19F NMR (376 MHz, CDCl3) δ -62.7 (Ar-CF3). IR (KBr): 3401, 2935, 1656, 1509, 1319, 1177, 754, 666, 544 cm1;

HRMS (ESI-TOF) m/z: [M-H]- calcd for C39H28F3N2O5S 693.1676, found 693.1674; The

enantiomefric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 15.2 min (major), 68.5 min (minor), ee 99%. N-((3S,4R)-3-benzyl-4-(4-nitrophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ha). The product was obtained as a white solid (49.8 mg, 74% yield), m.p. 107-108 C; [α]25D -70.1 (c 0.470, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.32-8.30 (m, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.48-7.45 (m, 1H), 7.41-7.34 (m, 5H), 7.30-7.22 (m, 4H), 7.06-7.03 (m, 3H), 6.98-6.94 (m, 2H), 6.79 (d, J = 7.2 Hz, 2H), 6.71 (s, 1H), 5.50 (s, 1H), 3.90 (d, J = 13.6 Hz, 1H), 2.73 (d, J = 13.6 Hz, 1H), 2.49 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.3 , 167.3 , 154.8 , 147.3 , 146.6 , 142.0 , 134.3 , 133.9 , 133.7 , 131.9 , 130.1 , 129.8 , 129.7 , 129.2 , 128.7 , 128.2 , 127.5 , 126.5 , 126.0 , 124.0 , 123.5 , 123.2 , 121.7 , 118.4 , 112.0 , 66.6 , 45.8 , 38.5 , 21.8 ; IR (KBr): 3394, 2962, 1663, 1526, 1347, 1177, 1083, 808, 666, 544 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30N3O7S 672.1799, found 672.1795; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 29.0 min (major), 57.8 min (minor), ee 93%.



methyl4-((3S,4R)-3-benzamido-3-benzyl-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-4-yl)benzoate (3ia). The product was obtained as a white solid (59.0 mg, 86% yield), m.p. 100-101 C; [α]25D -66.9 (c 0.546, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.33-8.30 (m, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.47-7.44 (m, 1H), 7.38-7.30 (m, 5H), 7.26-7.18 (m, 4H), 7.05-7.02 (m, 1H), 6.99-6.95 (m, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 7.2 Hz, 2H), 6.65 (s, 1H), 5.41 (s, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.74 (s, 3H), 2.72 (d, J = 13.6 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.5 , 167.4 , 166.4 , 154.7 , 146.4 , 145.8 , 139.7 , 134.7 , 134.0 , 133.8 , 131.6 , 130.2 , 129.9 , 129.7 , 129.6, 129.5, 127.4, 126.5, 125.8, 123.9, 123.2, 121.9, 118.2, 111.9, 66.7, 52.1, 46.0, 38.5, 21.7; IR (KBr): 3411, 2952, 1721, 1659, 1481, 1282, 1180, 701, 549 cm-1; HRMS (ESI-TOF) m/z: [M-H]- calcd for C40H31N2O7S 683.1857, found 683.1853; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 26.3 min (major), 47.2 min (minor), ee 97%. N-((3S,4R)-3-benzyl-1-(methylsulfonyl)-2-oxo-4-phenyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ja). The product was obtained as a white solid (50.4 mg, 92% yield), m.p. 119-121 C; [α]25D -103.1 (c 0.492, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.06-8.04 (m, 1H), 7.58-7.56 (m, 1H), 7.53-7.47 (m, 3H), 7.44-7.36 (m, 6H), 7.31-7.25 (m, 3H), 7.21-7.20 (m, 3H), 7.01-6.97 (m, 3H), 5.57 (s, 1H), 4.24 (d, J = 13.6 Hz, 1H), 3.57 (s, 3H), 2.81 (d, J = 14.0 Hz, 1H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 171.1, 167.6, 154.6, 146.8, 134.9, 134.6 , 134.3 , 131.7 , 129.8 , 128.9 , 128.6 , 128.3 , 127.6 , 126.7 , 125.6 , 123.8 , 122.2 , 121.6 , 117.0 , 112.1 , 68.0 , 45.8 , 43.2 , 38.5 ; IR (KBr): 3389, 2930, 1716, 1656, 1511, 1372, 1117, 965, 701, 514 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C32H27N2O5S 551.1635, found 551.1644; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 20.3 min (major), 25.7 min (minor), ee 95%. N-((3S,4R)-3-benzyl-4-(4-fluorophenyl)-1-(methylsulfonyl)-2-oxo-1,2,3,4tetrahydrobenzofuro[3,2-b]pyridin-3-yl)benzamide (3ka). The product was obtained as a white solid (51.0 mg, 90% yield), m.p. 169-170 C; [α]25D -103.4 (c 0.488, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 7.2 Hz, 1H), 7.53-7.41 m, 4H), 7.35-7.33 (m, 4H), 7.18-7.10 (m, 5H), 6.97-6.80 (m, 5H), 5.83 (s, 1H), 3.97 (d, J = 13.6 Hz, 1H), 3.43 (s, 3H), 2.65 (d, J = 14.0 Hz, 1H); 13C{1H}

NMR (100 MHz, Chloroform-d) δ 171.0, 162.5 (JCF = 246.2 Hz), 154.6, 146.6, 134.6,

134.5, 131.9, 130.2, 130.1, 129.8, 128.7, 128.3, 127.6, 126.6, 125.7, 123.8, 122.1, 121.5, 116.8,


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115.9 (JCF = 21.3 Hz), 112.1, 68.0, 45.1, 43.4, 38.4; 19F NMR (376 MHz, CDCl3) δ -113.3 (Ar-F). IR (KBr): 3396, 3022, 2945, 1716, 1663, 1511, 1369, 1110, 965, 754, 542 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C32H26FN2O5S 569.1541, found 569.1544; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: IPA = 65:35, 0.7 mL/min]: 16.7 min (minor), 21.0 min (major), ee 90%. N-((3S,4R)-3-benzyl-1-(methylsulfonyl)-2-oxo-4-(p-tolyl)-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3la). The product was obtained as a white solid (47.7 mg, 84% yield), m.p. 110-111 C; [α]25D -99.0 (c 0.468, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 7.93-7.91 (m, 1H), 7.45-7.36 (m, 4H), 7.31-7.25 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 7.08-7.07 (m, 3H), 6.96 (d, J = 7.6 Hz, 2H), 6.88-6.84 (m, 3H), 5.40 (s, 1H), 4.09 (d, J = 13.6 Hz, 1H), 3.43 (s, 3H), 2.65 (d, J = 14.0 Hz, 1H), 2.14 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 171.1, 167.5, 154.6, 147.0, 138.1, 135.0, 134.6, 131.7, 131.1, 129.8, 129.6, 128.6, 128.3, 128.2, 127.5, 126.7, 125.5, 123.7, 122.1, 121.7, 117.0, 112.0, 68.0, 45.3, 43.2, 38.3, 21.0; IR (KBr): 3401, 2930, 1661, 1514, 1367, 1172, 965, 756, 512 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C33H29N2O5S 565.1791, found 565.1797; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, nHexane: EtOH = 65:35, 0.7 mL/min]: 16.0 min (major), 21.0 min (minor), ee 95%. N-((3S,4R)-3-benzyl-4-(3-bromophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ma). The product was obtained as a white solid (61.8 mg, 88% yield), m.p. 88-89 C; [α]25D -78.5 (c 0.584, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.29-8.27 (m, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.47-7.45 (m, 1H), 7.41 (s, 1H), 7.36-7.29 (m, 7H), 7.22 (t, J = 7.6 Hz, 2H), 7.17-7.14 (m, 1H), 7.03-6.99 (m, 1H), 6.92 (t, J= 7.6 Hz, 2H), 6.76 (d, J = 7.2 Hz, 2H), 6.71 (d, J = 4.8 Hz, 2H), 6.64 (s, 1H), 5.33 (s, 1H), 3.92 (d, J = 14.0 Hz, 1H), 2.69 (d, J = 13.6 Hz, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.3, 167.7 , 154.7 , 146.0 , 145.6 , 136.8 , 134.9 , 134.4 , 134.0 , 131.9 , 131.6 , 131.2 , 130.0 , 129.9 , 129.6 , 128.5 , 128.1 , 127.3 , 126.6 , 126.2 , 125.7 , 123.8 , 123.0 , 122.8 , 121.8 , 118.1 , 112.0 , 66.9 , 45.6 , 38.5 , 21.8; IR (KBr): 3394, 2922, 1713, 1661, 1479, 1389, 1175, 926, 694, 572 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30BrN2O5S 705.1053, found 705.1061; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 28.6 min (major), 38.6 min (minor), ee 94%. N-((3S,4R)-3-benzyl-4-(3-chlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-



b]pyridin-3-yl)benzamide (3na). The product was obtained as a white solid (57.7 mg, 87% yield), m.p. 91-93 C; [α]25D -77.7 (c 0.553, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.45 (s, 1H), 7.34-7.27 (m, 7H), 7.21-7.17 (m, 3H), 6.99 (d, J = 6.8 Hz, 2H), 6.93-6.90 (m, 2H), 6.77-6.69 (m, 4H), 6.63 (s, 1H), 5.33 (s, 1H), 3.92 (d, J = 13.6 Hz, 1H), 2.69 (d, J = 13.6 Hz, 1H), 2.39 (s, 3H);

13C{1H}


167.7, 154.7, 146.1, 145.6, 136.6, 134.9, 134.5, 134.3, 134.0, 131.6, 130.0, 129.9, 129.7, 128.8, 128.5, 128.1, 127.3, 126.6, 125.9, 125.7, 123.8, 123.0, 121.8, 118.0, 112.0, 66.8, 45.7, 38.6, 21.8; IR (KBr): 3399, 2925, 1713, 1663, 1481, 1389, 1180, 926, 664, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30ClN2O5S 661.1558, found 661.1564; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 20.9 min (major), 28.5 min (minor), ee 93%. N-((3S,4R)-3-benzyl-4-(3-fluorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3oa). The product was obtained as a white solid (52.4 mg, 81% yield), m.p. 85-86 C; [α]25D -58.1 (c 0.471, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.32-8.30 (m, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.47-7.45 (m, 1H), 7.37-7.35 (m, 2H), 7.31-7.26 (m, 5H), 7.22 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.98-6.95 (m, 2H), 6.90-6.84 (m, 1H), 6.81 (d, J = 7.2 Hz, 2H), 6.73-6.69 (m, 2H), 6.66 (s, 1H), 6.60 (d, J = 9.6 Hz, 1H), 5.35 (s, 1H), 3.93 (d, J = 13.6 Hz, 1H), 2.72 (d, J = 13.6 Hz, 1H), 2.42 (s, 3H);

13C{1H}


167.5, 162.6 (JCF = 245.6 Hz), 154.7, 146.3, 145.8, 137.2 (JCF = 6.9 Hz),134.9, 134.1, 134.0, 131.6, 130.1, 130.0, 129.9, 129.6, 128.6, 128.2, 127.3, 126.5, 125.7, 123.9 (JCF = 2.7 Hz), 123.8, 123.2, 121.8, 118.0, 115.2 (JCF = 22.1 Hz), 111.9, 66.7, 45.9, 38.6, 21.8; 19F NMR (376 MHz, CDCl3) δ 111.6 (Ar-F). IR (KBr): 3401, 2962, 1716, 1661, 1484, 1177, 926, 666, 567 cm-1; HRMS (ESITOF) m/z: [M+H]+ calcd for C38H30FN2O5S 645.1854, found 645.1851; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 14.1 min (major), 17.2 min (minor), ee 98%. N-((3S,4R)-3-benzyl-2-oxo-4-(m-tolyl)-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (3pa). The product was obtained as a white solid (44.2 mg, 69% yield), m.p. 92-93 C; [α]25D -83.2 (c 0.521, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.46-7.44 (m, 1H), 7.36-7.30 (m, 5H), 7.27-7.16 (m, 4H), 7.00 (t, J = 9.6 Hz, 2H), 6.92-6.88 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.77-6.71 (m, 3H), 6.60-6.55 (m, 2H), 5.29


Page 16 of 29

Page 17 of 29 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


(s, 1H), 3.97 (d, J = 14.0 Hz, 1H), 2.70 (d, J = 13.6 Hz, 1H), 2.42 (s, 3H), 2.06 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.7, 167.6, 154.6, 146.7, 145.9, 138.5, 135.2, 134.5, 134.4, 134.3, 131.4, 130.0, 129.9, 129.5, 129.4, 128.7, 128.4, 128.3, 128.0, 127.1, 126.5, 125.4, 124.7, 123.7, 122.8, 121.9, 117.6, 112.0, 67.1, 46.0, 38.4, 21.8, 21.2; IR (KBr): 3401, 2920, 1716, 1663, 1484, 1392, 1175, 699, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H33N2O5S 641.2104, found 641.2099; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, nHexane: EtOH = 65:35, 0.7 mL/min]: 13.2 min (major), 22.1 min (minor), ee 98%. N-((3S,4R)-3-benzyl-4-(2-chlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3qa). The product was obtained as a white solid (57.0 mg, 86% yield), m.p. 87-88 C; [α]25D -19.7 (c 0.549, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.21-8.18 (m, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.50-7.46 (m, 1H), 7.34-7.28 (m, 5H), 7.24-7.16 (m, 5H), 7.04 (t, J = 7.2 Hz, 1H), 6.99-6.92 (m, 3H), 6.81 (d, J = 7.2 Hz, 2H), 6.75 (s, 1H), 6.57-6.53 (m, 1H), 6.17 (d, J = 6.8 Hz, 1H), 6.04 (s, 1H), 3.92 (d, J = 13.6 Hz, 1H), 2.79 (d, J = 13.6 Hz, 1H), 2.45 (s, 3H); 13C{1H}

NMR (100 MHz, Chloroform-d) δ 170.1, 166.4, 154.6, 146.1, 145.9, 134.8, 134.7, 134.0,

133.8, 133.3, 131.4, 130.3, 130.1, 130.0, 129.5, 128.6, 128.4, 128.2, 128.1, 127.3, 125.5, 123.6, 122.9, 121.9, 116.7, 112.0, 65.2, 43.0, 39.3, 21.8; IR (KBr): 3404, 2927, 1668, 1484, 1175, 928, 704, 542 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30ClN2O5S 661.1558, found 661.1562; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 80:20, 0.5 mL/min]: 14.2 min (major), 29.6 min (minor), ee 62%. N-((3S,4R)-3-benzyl-2-oxo-4-(o-tolyl)-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (3ra). The product was obtained as a white solid (47.7 mg, 74% yield), m.p. 95-96 C; [α]25D -14.8 (c 0.304, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.23-8.20 (m, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.43-7.41 (m, 1H), 7.32-7.24 (m, 5H), 7.15-7.12 (m, 4H), 7.06-6.98 (m, 4H), 6.876.84 (m, 3H), 6.71 (s, 1H), 6.40-6.37 (m, 1H), 5.91 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 3.92 (d, J = 13.6 Hz, 1H), 2.79 (d, J = 13.6 Hz, 1H), 2.63 (s, 3H), 2.42 (s, 3H);

13C{1H}

NMR (100 MHz,

Chloroform-d) δ 170.2, 166.9, 154.4, 147.4, 145.9, 137.6, 134.9, 134.0, 133.9, 131.3, 131.1, 130.2, 130.0, 129.5, 128.4, 128.2, 127.4, 127.2, 126.5, 126.2, 125.8, 125.3, 123.6, 123.1, 122.1, 116.3, 111.7, 65.4, 42.7, 39.3, 21.8, 20.0; IR (KBr): 3046, 2925, 1713, 1663, 1481, 1387, 1177, 926, 701, 572 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H33N2O5S 641.2104, found 641.2097; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 80:20, 0.5



mL/min]: 11.2 min (major), 19.2 min (minor), ee 67%. N-((3S,4R)-3-benzyl-1-(methylsulfonyl)-2-oxo-4-(o-tolyl)-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3sa). The product was obtained as a white solid (32.9 mg, 58% yield), m.p. 114-116 C; [α]25D -36.3 (c 0.313, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 7.82-7.80 (m, 1H), 7.41-7.39 (m, 1H), 7.32-7.29 (m, 3H), 7.25-7.18 (m, 4H), 7.08-7.05 (m, 4H), 7.01-6.94 (m, 4H), 6.88-6.86 (m, 2H), 5.71 (s, 1H), 4.06 (d, J = 14.0 Hz, 1H), 3.47 (s, 3H), 2.78 (d, J = 13.6 Hz, 1H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 172.1 , 166.9 , 154.3 , 147.6 , 137.6 , 134.8 , 134.3 , 134.0 , 131.6 , 131.4 , 129.9 , 128.6 , 128.3 , 127.7 , 127.6 , 126.6 , 126.5 , 125.3 , 123.5 , 122.1 , 121.6 , 115.1 , 111.9 , 66.4 , 43.2 , 42.7 , 39.4 , 20.0 ; IR (KBr): 3414, 2932, 1701, 1668, 1481, 1367, 1175, 960, 736, 504 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C33H29N2O5S 565.1791, found 565.1796; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 7.8 min (major), 10.9 min (minor), ee 80%. N-((3S,4R)-3-benzyl-4-(3,5-dichlorophenyl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ta). The product was obtained as a white solid (51.0 mg, 73% yield), m.p. 89-90 C; [α]25D -85.4 (c 0.502, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.29-8.27 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.48-7.46 (m, 1H), 7.40-7.29 (m, 7H), 7.26-7.23 (m, 2H), 7.06-7.00 (m, 4H), 6.92 (t, J = 7.6 Hz, 2H), 6.75 (d, J = 7.2 Hz, 2H), 6.67 (s, 1H), 5.35 (s, 1H), 3.92 (d, J = 14.0 Hz, 1H), 2.70 (d, J = 14.0 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 168.8, 167.9, 154.8, 146.2, 144.6, 138.0, 135.2, 134.7, 134.5, 133.8, 131.7 , 129.9 , 129.7 , 128.6 , 128.5 , 128.1, 127.3, 126.9, 126.6, 125.9, 123.9, 123.0, 121.6, 118.3, 112.1, 66.7, 45.4, 38.7, 21.9; IR (KBr): 3399, 2925, 1716, 1663, 1571, 1481, 1175, 803, 669, 567 cm-1; HRMS (ESI-TOF) m/z: [M-H]- calcd for C38H27Cl2N2O5S 693.1023, found 693.1019; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 16.5 min (minor), 19.4 min (major), ee 92%. N-((3S,4R)-3-benzyl-4-(naphthalen-1-yl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ua). The product was obtained as a white solid (50.1 mg, 74% yield), m.p. 130-132 C; [α]25D -17.2 (c 0.496, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.64-7.56 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.43-7.25 (m, 2H), 7.32-7.24 (m, 4H), 7.18-7.15 (m, 1H), 7.05-6.98 (m, 7H), 6.88 (d, J =


Page 18 of 29

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6.8 Hz, 2H), 6.68 (s, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.30-6.26 (m, 2H), 4.10 (d, J = 13.6 Hz, 1H), 2.86 (d, J = 13.6 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 170.3, 167.0, 154.5, 147.5, 145.9, 134.8, 134.2, 134.1, 133.9, 131.7, 131.6, 131.2, 130.2, 130.1, 129.6, 128.6, 128.3, 128.2, 127.4, 126.6, 126.4, 126.0, 125.5, 124.6, 124.2, 123.7, 123.0, 122.2, 117.0, 111.9, 66.0, 41.5, 39.0, 21.8; IR (KBr): 3406, 2922, 1713, 1668, 1481, 1389, 1182, 783, 572 cm-1; HRMS (ESITOF) m/z: [M+H]+ calcd for C42H33N2O5S 677.2104, found 677.2102; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 10.9 min (major), 18.8 min (minor), ee 95%. N-((3S,4R)-3-benzyl-4-(naphthalen-2-yl)-2-oxo-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3va). The product was obtained as a white solid (50.7 mg, 75% yield), m.p. 179-181 C; [α]25D -96.1(c 0.485, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.57-7.51 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.37-7.26 (m, 7H), 7.24-7.21 (m, 3H), 7.15-7.10 (m, 2H), 7.01-6.97 (m, 2H), 6.91-6.88 (m, 2H), 6.77 (d, J = 7.2 Hz, 2H), 6.64 (s, 1H), 5.53 (s, 1H), 4.02 (d, J = 14.0 Hz, 1H), 2.76 (d, J = 13.6 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.7, 167.6, 154.7, 146.7, 146.0, 134.9, 134.6, 134.3, 133.2, 132.7, 132.0, 131.4, 130.0, 129.9, 129.6, 128.4, 128.3, 128.1, 127.8, 127.4, 127.2, 126.6, 126.2, 126.1, 125.6, 123.8, 122.9, 121.9, 117.8, 112.0, 67.2, 46.2, 38.5, 21.8; IR (KBr): 3399, 2925, 1716, 1659, 1477, 1307, 1115, 754, 584 cm-1; HRMS (ESI-TOF) m/z: [MH]- calcd for C42H31N2O5S 675.1959, found 675.1957; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 19.7 min (major), 63.0 min (minor), ee 99%. N-((3S,4R)-3-benzyl-2-oxo-4-(thiophen-2-yl)-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3wa). The product was obtained as a white solid (52.2 mg, 82% yield), m.p. 90-92 C; [α]25D -69.7 (c 0.521, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 8.28-8.26 (m, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.49-7.46 (m, 1H), 7.40-7.33 (m, 5H), 7.26-7.22 (m, 4H), 7.02-6.99 (m, 1H), 6.93-6.90 (m, 3H), 6.74 (d, J = 7.2 Hz, 3H), 6.59-6.56 (m, 1H), 6.55 (d, J = 3.2 Hz, 1H), 5.70 (s, 1H), 3.85 (d, J = 14.0 Hz, 1H), 2.63 (d, J = 14.0 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.3, 167.5, 154.6, 146.3, 145.9, 136.6, 134.9, 134.3, 134.2, 131.7, 130.0, 129.8, 129.5, 128.6, 128.1, 127.3, 127.06, 126.8, 126.7, 125.8, 125.7, 123.9, 123.0, 122.0, 117.4, 112.1, 67.4, 40.8, 38.1, 21.8; IR (KBr): 3396, 3030, 2940, 1708, 1659, 1484, 1372, 921, 811, 666



Page 20 of 29

cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C36H29N2O5S2 633.1506, found 633.1507; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 16.3 min (major), 28.8 min (minor), ee 90%. N-((3S,4R)-3-benzyl-1-(methylsulfonyl)-2-oxo-4-(thiophen-2-yl)-1,2,3,4tetrahydrobenzofuro[3,2-b]pyridin-3-yl)benzamide (3xa). The product was obtained as a white solid (48.0 mg, 86% yield), m.p. 160-162 C; [α]25D -73.2 (c 0.404, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 7.2 Hz, 1H), 7.53-7.41 (m, 4H), 7.34 (d, J = 7.2 Hz, 4H), 7.11 (s, 4H), 6.97-6.80 (m, 5H), 5.83 (s, 1H), 3.97 (d, J = 13.6 Hz, 1H), 3.43 (s, 3H), 2.65 (d, J = 14.0 Hz, 1H); 13C{1H}

NMR (100 MHz, Chloroform-d) δ 170.5 , 167.5 , 154.6 , 146.1 , 136.5 , 134.8 , 134.3 ,

131.9 , 129.8 , 128.7 , 128.3 , 127.7 , 127.6 , 127.3 , 126.8 , 126.1 , 125.8 , 123.9 , 122.5 , 121.7 , 116.9 , 112.1 , 68.0 , 42.8 , 40.8 , 38.2 ; IR (KBr): 3396, 3030, 2935, 1713, 1654, 1489, 1374, 1177, 963, 721, 549 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C30H25N2O5S2 557.1199, found 557.1206; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: IPA = 70:30, 0.7 mL/min]: 24.7 min (minor), 58.3 min (major), ee 84%. N-((3S,4R)-3-benzyl-7-bromo-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ya). The product was obtained as a white solid (17.4 mg, 25% yield), m.p. 105-107 C; [α]25D 12.3 (c 0.077, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 7.347.30 (m, 3H), 7.23–7.18 (m, 5H), 7.06–6.96 (m, 4H), 6.89–6.81 (m, 5H), 6.61 (s, 1H), 5.31 (s, 1H), 3.95 (d, J = 13.6 Hz, 1H), 2.72 (d, J = 13.6 Hz, 1H), 2.45 (s, 3H);

13C{1H}

NMR (100 MHz,

Chloroform-d) δ 169.5, 167.4, 154.8, 147.1, 146.2, 134.9, 134.3, 134.1, 133.9, 131.5, 130.1, 129.8, 129.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.3, 127.2, 126.5, 124.2, 121.0, 118.9, 117.7, 115.2, 66.8, 46.2, 38.6, 21.8. IR (KBr): 3404, 2922, 1716, 1663, 1601, 1484, 1382, 1177, 813, 699, 579 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30BrN2O5S 705.1053, found 705.1060; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 16.3 min (minor), 18.2 min (major), ee 98%. N-((3S,4R)-3-benzyl-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3-yl)4-bromobenzamide (3ab). The product was obtained as a white solid (61.6 mg, 87% yield), m.p. 123-124 C; [α]25D -67.1 (c 0.601, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.31-8.29 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.46-7.43 (m, 1H), 7.36-7.31 (m, 6H), 7.09 (d, J = 8.0 Hz, 2H), 7.03-


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7.00 (m, 2H), 6.94 (t, J = 7.6 Hz, 2H), 6.90-6.84 (m, 4H), 6.78 (d, J = 7.6 Hz, 2H), 6.58 (s, 1H), 5.29 (s, 1H), 3.91 (d, J = 13.6 Hz, 1H), 2.73 (d, J = 13.6 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.6, 166.3, 154.6, 146.5, 146.0, 134.5, 134.2, 134.1, 133.7, 131.7, 130.1, 129.8, 129.5, 128.5, 128.2, 128.1, 127.9, 127.3, 126.2, 125.5, 123.7, 123.0, 121.9, 117.7, 111.9, 66.9, 46.2, 38.5, 21.8; IR (KBr): 3397, 2927, 1671, 1474, 1397, 1180, 669, 567 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30BrN2O5S 705.1053, found 705.1070; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: IPA = 70:30, 0.7 mL/min]: 30.9 min (major), 49.2 min (minor), ee 91%. N-((3S,4R)-3-benzyl-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3-yl)4-chlorobenzamide (3ac). The product was obtained as a white solid (59.9 mg, 91% yield), m.p. 100-101 C; [α]25D -75.9 (c 0.583, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.44-8.42 (m, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.58-7.56 (m, 1H), 7.50-7.43 (m, 4H), 7.29 (t, J = 9.2 Hz, 4H), 7.167.13 (m, 2H), 7.09-7.04 (m, 2H), 7.00 (t, J = 7.2 Hz, 3H), 6.91 (d, J = 7.2 Hz, 2H), 6.72 (s, 1H), 5.43 (s, 1H), 4.05 (d, J = 13.6 Hz, 1H), 2.86 (d, J = 13.6 Hz, 1H), 2.56 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.7, 166.3, 154.7, 146.5, 146.1, 137.7, 134.6, 134.2, 134.1, 133.3, 130.2, 129.8, 129.6, 128.7, 128.5, 128.2, 128.1, 128.0, 128.0, 127.3, 125.6, 123.8, 123.1, 121.9, 117.8, 111.9, 67.0, 46.3, 38.5, 21.8; IR (KBr): 3396, 3032, 2927, 1708, 1666, 1477, 1389, 1177, 749, 666, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30ClN2O5S 661.1558, found 661.1564; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 65:35, 0.7 mL/min]: 16.5 min (major), 27.9 min (minor), ee 88%. N-((3S,4R)-3-(4-chlorobenzyl)-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ad). The product was obtained as a white solid (54.4 mg, 82% yield), m.p. 93-95 C; [α]25D -83.5 (c 0.517, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.36-7.29 (m, 5H), 7.25-7.17 (m, 4H), 7.00 (s, 1H), 6.91-6.86 (m, 6H), 6.70 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 5.29 (s, 1H), 3.94 (d, J = 13.6 Hz, 1H), 2.66 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.5 , 167.4 , 154.7 , 146.5 , 146.2 , 134.8 , 134.4 , 134.1 , 133.72 , 132.8 , 131.6 , 131.1 , 130.1 , 129.6 , 128.6 , 128.3 , 128.1 , 128.0 , 126.5 , 125.6 , 123.8 , 123.0 , 121.8 , 117.7 , 112.0 , 66.9 , 46.1 , 37.8 , 21.8 ; IR (KBr): 3404, 3027, 2922, 1713, 1659, 1486, 1374, 1172, 1088, 661, 572 cm1;

HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30ClN2O5S 661.1558, found 661.1568; The



enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: EtOH = 65:35, 0.6 mL/min]: 32.9 min (major), 48.8 min (minor), ee 93%. N-((3S,4R)-3-(4-fluorobenzyl)-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)benzamide (3ae). The product was obtained as a white solid (22.7 mg, 35% yield), m.p. 81-82 C; [α]25D -28.6 (c 0.212, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.31-8.29 (m, 1H), 8.05-7.99 (m, 2H), 7.47-7.44 (m, 1H), 7.40-7.32 (m, 5H), 7.26-7.21 (m, 3H), 7.18 (s, 1H), 7.04-7.00 (m, 1H), 6.91-6.85 (m, 4H), 6.79-6.76 (m, 2H), 6.66-6.62 (m, 3H), 5.30 (s, 1H), 3.95 (d, J = 14.0 Hz, 1H), 2.70 (d, J = 14.0 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.6, 167.4, 162.0 (JCF = 244.7 Hz), 154.6, 146.5, 146.1, 134.8, 134.5, 134.1, 133.6, 131.6, 131.4 (JCF = 8.4 Hz), 130.1, 129.5, 128.5, 128.4, 128.1, 127.9, 126.5, 125.6, 123.8, 123.0, 121.8, 117.7, 115.1 (JCF = 21.2 Hz), 111.9, 66.9, 46.1, 37.6, 21.8; 19F NMR (376 MHz, CDCl3) δ -114.9 (Ar-F). IR (KBr): 3396, 2823, 1601, 1509, 1387, 1175, 669, 572 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C38H30FN2O5S 645.1854, found 645.1872; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: EtOH = 65:35, 0.6 mL/min]: 21.8 min (major), 41.7 min (minor), ee 99%. N-((3S,4R)-3-(4-chlorobenzyl)-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)-4-methoxy-benzamide (3af). The product was obtained as a white solid (28.2 mg, 41% yield), m.p. 179-181 C; [α]25D -23.2 (c 0.268, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.29-8.27 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.46-7.43 (m, 1H), 7.37-7.31 (m, 4H), 7.26 (d, J = 8.4 Hz, 2H), 7.04-6.99 (m, 1H), 6.92-6.86 (m, 6H), 6.70 (dd, J = 8.4, 4.8 Hz, 4H), 6.57 (s, 1H), 5.30 (s, 1H), 3.95 (d, J = 14.0 Hz, 1H), 3.71 (s, 3H), 2.65 (d, J = 13.6 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 169.6, 166.8, 162.3, 154.6, 146.6, 146.2, 134.5, 134.1, 133.1, 132.9, 131.1, 130.1, 129.6, 128.5, 128.4, 128.3, 128.1, 127.9, 126.9, 125.6, 123.8, 122.9, 121.8, 117.7, 113.7, 112.0, 76.7, 66.8, 55.4, 46.1, 37.7, 21.8; IR (KBr): 3436, 2960, 1609, 1382, 1170, 669, 569 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H32ClN2O6S 691.1664, found 691.1672; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: IPA = 70:30, 0.7 mL/min]: 31.2 min (major), 78.4 min (minor), ee 97%. N-((3S,4R)-3-(3-bromobenzyl)-2-oxo-4-phenyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2b]pyridin-3-yl)-4 methoxy-benzamide (3ag). The product was obtained as a white solid (62.2 mg, 85% yield), m.p. 100-102 C; [α]25D -62.0 (c 0.603, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ


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8.28-8.26 (m, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.45-7.43 (m, 1H), 7.36-7.32 (m, 4H), 7.25 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.03-7.00 (m, 1H), 6.97 (s, 1H), 6.92-6.88 (m, 4H), 6.83-6.80 (m, 1H), 6.74-6.70 (m, 3H), 6.55 (s, 1H), 5.31 (s, 1H), 3.91 (d, J = 14.0 Hz, 1H), 3.71 (s, 3H), 2.70 (d, J = 13.6 Hz, 1H), 2.43 (s, 3H);

13C{1H}

NMR (100 MHz, Chloroform-d) δ 169.6, 167.1, 162.2,

154.6, 146.5, 146.1, 136.6, 134.5, 134.2, 133.0, 130.4, 130.0, 129.7, 129.6, 128.5, 128.4, 128.2, 127.9, 127.1, 125.5, 123.7, 123.0, 122.2, 121.9, 117.7, 113.7, 111.9, 66.7, 55.4, 46.2, 38.3, 21.8; IR (KBr): 3404, 2937, 1713, 1656, 1484, 1175, 1025, 669, 567 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C39H32BrN2O6S 735.1159, found 735.1172; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: EtOH = 70:30, 0.6 mL/min]: 35.0 min (major), 48.8 min (minor), ee 99%. N-((3S,4R)-2-oxo-4-phenyl-3-propyl-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (3ah). The product was obtained as a white solid (6.7 mg, 12% yield), m.p. 181-183 C; [α]25D -11.8 (c 0.054, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 8.25-8.22 (m, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.41-7.38 (m, 1H), 7.35-7.28 (m, 7H), 7.20 (t, J = 7.6 Hz, 2H), 6.96 (t, J = 7.2 Hz, 1H), 6.88 (s, 1H), 6.82-6.78 (m, 2H), 6.73 (d, J = 8.0 Hz, 2H), 5.12 (s, 1H), 2.71-2.64 (m, 1H), 2.41 (s, 3H), 1.44-1.37 (m, 1H), 1.28-1.17 (m, 1H), 1.08-0.99 (m, 1H), 0.66 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (100 MHz, Chloroform-d) δ 171.0, 166.6, 154.5, 146.5, 146.0, 134.9, 134.7, 134.1,

131.5 , 130.0, 129.6, 128.5, 128.4, 128.0, 127.7, 126.6, 125.4, 123.6, 123.4, 121.9, 117.7, 111.8, 66.0, 46.5, 34.9, 21.8, 17.7, 13.8; IR (KBr): 3416, 2957, 1673, 1516, 1170, 928, 666, 574 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C34H31N2O5S 579.1948, found 579.1956; The enantiomeric excess was determined by HPLC. [AD-H column, 254 nm, n-Hexane: EtOH = 65:35, 0.6 mL/min]: 10.9 min (major), 21.1 min (minor), ee 97%. Larger-Scale Reaction of Asymmetric Synthesis of 3ja. Azlactone 2a (552.8 mg, 2.2 mmol, 1.1 equiv) was added to a mixture of catalyst 4c (126.1 mg, 0.2 mmol, 0.10 equiv) and azadiene 1j (598.7 mg, 2.0 mmol, 1.0 equiv) in PhCl (20 mL) at 0 C for 24 h, then warmed to room temperature and stirred for 48 h. The reaction solution was concentrated in vacuo and the crude products were purified through column chromatograghy on silica gel (hexane/AcOEt =10:1 to 4:1) to afford the desired products 3ja as white solid (886.2 mg, 80% yield, >20:1 dr, 95% ee). Synthesis of 5. To a mixture of the compound 3aa (62.7 mg, 0.10 mmol) and HMPA (0.2 mL) in THF (2.0 mL) under nitrogen at -78 C was added SmI2 (4.0 mL, 0.10 M solution in THF, 0.40



mmol). The mixture was then stirred at -78 C for 0.5 h. Then the reaction mixture was then quenched by adding aq. NaHCO3 solution (10 mL) and extracted with AcOEt (2 × 10 mL). The combined organic phase was dried over Na2SO4 and the solvent was then removed under reduced pressure. The resulting crude mixture was purified by column chromatography (5:1 hexane/AcOEt) to afford the product 5 as as a white solid. N-((3S,4R)-3-benzyl-2-oxo-4-phenyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridin-3yl)benzamide (5). The product was obtained as a white solid (42.8 mg, 91% yield), m.p. 182-184 C; [α]D 25 -102.7 (c 0.410, CH2Cl2); 1H NMR (400 MHz, Chloroform-d) δ 9.34-9.26 (m, 1H), 7.38-7.32 (m, 4H), 7.24 (t, J = 7.2 Hz, 3H), 7.20-7.16 (m, 3H), 7.14-7.07 (m, 5H), 7.04-6.99 (m, 5H), 5.46 (s, 1H), 4.28 (d, J = 13.6 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 170.6, 167.8, 154.4, 142.8, 136.7, 135.5, 131.4, 130.2, 128.7, 128.5, 128.1, 128.0, 127.8, 127.5, 126.6, 124.9, 123.0, 120.1, 117.7, 116.5, 112.1, 66.5, 47.9, 39.4; IR (KBr): 3354, 3179, 2962, 1641, 1516, 1260, 1105, 741, 696, 569 cm-1; HRMS (ESI-TOF) m/z: [M-H]- calcd for C31H23N2O3 471.1714, found 471.1706; The enantiomeric excess was determined by HPLC. [IA column, 254 nm, n-Hexane: EtOH = 50:50, 0.5 mL/min]: 11.2 min (major), 14.1 min (minor), ee 99%. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI:10.1021/acs.joc.XXX. Copies of 1H,

13C, 19F

NMR and HPLC spectra for new products, X-ray single-crystal data for

product 3ba (PDF) X-ray crystallographic data of product 3ba (CIF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Huicai Huang: 0000-0002-8813-1499 Notes The authors declare no competing financial interest.


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Acknowledgements We are grateful for financial support of the start-up fund of Guangzhou University of Chinese Medicine, Guangdong Province “Pearl River Talents Recruitment Program” (2017GC010361), and Department of Education of Guangdong Province (2014KTSPT016).

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Feng, X.; Liu, X. Asymmetric Synthesis of 3-Aminodihydrocoumarins via Chiral Guanidine Catalyzed Cascade Reaction of Azlactones. Org. Chem. Front. 2018, 5, 32-35. (n) Zhang, Z.-P.; Xie, K.-X.; Yang, C.; Li, M.; Li, X. Asymmetric Synthesis of Dihydrocoumarins through Chiral Phosphoric Acid-Catalyzed Cycloannulation of para-Quinone Methides and Azlactones. J. Org. Chem. 2018, 83, 364-373. (o) Wang, Y.; Chen, Y.; Li, X.; Mao, Y.; Chen, W.; Zhan, R.; Huang, H. Enantioselective Synthesis of Pyrano[2,3-c]pyrrole via Organocatalytic [4+2] Cyclization Reaction of Dioxopyrrolidines and Azlactones. Org. Biomol. Chem. 2019, 17, 3945-3950. (12) CCDC 1901589 (3ba) contains the supplementary crystallographic data for this paper. (13) Guang, J.; Rout, S.; Bihani, M.; Larson, A. J.; Arman, H. D.; Zhao, J. C. G. Organocatalyzed Enantioselective Direct Mannich Reaction of α-Styrylacetates. Org. Lett. 2016, 18, 2648-2651.


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