Highly enantioselective synthesis of functionalized glutarimide using

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Highly enantioselective synthesis of functionalized glutarimide using oxidative N-heterocyclic carbene catalysis: a formal synthesis of (-)-paroxetine Arka Porey, Surojit Santra, and Joyram Guin J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00320 • Publication Date (Web): 18 Mar 2019 Downloaded from http://pubs.acs.org on March 18, 2019

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The Journal of Organic Chemistry

Highly enantioselective synthesis of functionalized glutarimide using oxidative N-heterocyclic carbene catalysis: a formal synthesis of (-)-paroxetine Arka Porey, Surojit Santra and Joyram Guin* School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032 (India) Supporting Information Placeholder R

O NHPG O

O H +

*

*

N O O PG up to 94% yield, 99% ee, 99:1 dr

O NHPG

R

PGHN

* NHC, [O]

R PG

X

*

* N PG

simple substrates operational simplicity scalability valuable products > 25 examples

ABSTRACT: A simple yet highly effective approach towards enantioselective synthesis of trans-3,4-disubstituted glutarimides from readily available starting materials is developed using oxidative NHC-catalysis. The catalytic reaction involves a formal [3+3] annulation between enals and substituted malonamides enabling the production of glutarimide derivatives in single chemical operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a board range of functionalized glutarimides in excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal synthesis of (-)-paroxetine and other bioactive molecules.

INTRODUCTION Cyclic imides particularly glutarimide derivatives are extremely valuable nitrogen heterocycles. These structural units occur frequently in various natural products1 and pharmaceuticals (Fig. 1).2 Furthermore, substituted glutarimides serve as key precursors of functionalized piperidines of biological relevance.3 Notably, enantioenriched piperidine rings possessing trans related substituents at C3 and C4 position are found in different synthetic drugs like (-)paroxetine and (+)-femoxetine (Fig. 1).4 In view of great significance of enantioenriched glutarimides in organic synthesis and medicinal chemistry, the development of a catalytic and enantioselective synthesis of these molecules would be highly desirable.

Enantioselective N-heterocyclic carbene (NHC) catalysis emerges as a reliable synthetic tool for efficient and selective conversion of simple substrates to complex molecules. In particular, NHC catalyzed annulation reaction has recognized as a powerful synthetic strategy for the construction of different class of functionalized heterocycles.5 Accordingly, biologically relevant six-membered heterocycles like dihydropyranone, dihydropyridinone and dihydropyridazin-3one derivatives have been synthesized using stereoselective [3+3] annulation between α,β-unsaturated acylazolium ion and 1,3-bis-nucleophiles such as 1,3-diones, β-ketoesters, βketoamides.6 However, the synthesis of enantioenriched glutarimide derivatives using NHC-catalyzed [3+3] annulation reaction is relatively unknown and the synthesis of spiro-

Figure 1. Some selected examples of biologically active glutarimides and piperidine derivatives

Scheme 1. Enantioselective synthesis of trans-3,4disubstituted glutarimide via oxidative NHC-catalysis

O

O

MeO

O

O

H

O Ph

N O

O

O

Me N H

()-Thalidomide

O

NHC, [O]

F O

R

Ph O

N H

O

()-Glutethimide

HN (-)-Paroxetine

N

N N Ar

NHAr O +

O R acylazolium ion

O NHAr

R

O ArHN

*

*

N O Ar up to 94% yield, 99% ee O

MeN

glutarimide has been reported very recently.7 Continuing our current research activity towards NHC catalysis,8 herein, we report a general strategy for highly enantioselective synthesis

(+)-Femoxetine

1 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

of functionalized glutarimides using oxidative NHC-catalysis. The reaction proceeds through formal [3+3] annulation between readily available enals and malonamide derivatives to afford highly enantioselective trans-3,4-disubstituted glutarimides in single chemical operation (Scheme 1).

precatalyst 3e could not improve the reaction outcome and structurally different azolium salts 3f gave inferior result (entries 5 and 6). Slight improvement on the yield of 4 was realized using 15 mol% of the precatalyst 3d (entry 7). By carrying out the reaction at 0 °C, the reaction afforded the product 4 in 97% ee albeit with moderate yield (entry 8). This reactivity issue at 0 °C was resolved by adding 3Å MS into the reaction mixture (entry 9). Presumably, 3Å MS inhibits the hydrolysis of the in situ formed acyl donor intermediate. Further lowering of reaction temperature was detrimental to the reaction (entry 10). Importantly, the reaction could be scalable, working well with 0.85 g of malonamide 2c to afford 0.9 g of 4 in 72% yield with 91% ee and 4:1 dr (entry 11). Having identified the optimized reaction condition, different functionalized aromatic as well as aliphatic enals were subjected to the catalytic annulation reaction with amide 2c (Table 2). The enals bearing alkyl/aryl substituents at o/p position of the aromatic ring were effectively converted to the products 5-8. Mesityl substituted enal gave moderate yield of the product 9 with 99% ee and dr = 13:1. The reaction also worked well with the substrates having halides, delivering the products 10-15 with good yield and stereoselectivity. Enantioenriched glutarimides 16-22 having synthetically important functional groups such as electron rich: OMe, OiPr and OAc and electron deficient: azide, nitro and trifluoromethyl were obtained in yields ranging 48-90%, ee = 88-99% and dr = 3:1-7:1, irrespective of their position. The reaction furnished products 23 Scheme 2. Formal synthesis of (-) Paroxetine and other important molecules

Table 1. Reaction developmenta

+ 1a Ph

ArHN Ar = m-tolyl

Ph

O

ArHN

O

O

cat. 3a-f , DBU

O

oxidant, THF, temp.

ArHN

* * O

2c

4

O

N Ar

N Ph

N N Z

N N BF4 Ar

N Ph

O

N

O N N BF4 3e Mes

TMSO Ph Ph t

3a, Z = H, Ar = mesityl 3b, Z = NO2, Ar = mesityl 3c, Z = H, Ar = 2,4,6 triphenylbenzene 3d, Z = H, Ar = 2,4,6 triisopropylbenzene

BF4 3f

Bu

t

Bu

t

O t

Bu O

oxidant

Bu

entry

cat. (mol%)

temp. (°C)

ee (%)

yield (%)

1

3a (10%)

20

91

56

2

3b (10%)

20

85

55

3

3c (10%)

20

87

51

4

3d (10%)

20

94

58

5

3e (10%)

20

87

48

6

3f (10%)

20

-

trace

7

3d (15%)

20

94

73

8

3d (15%)

0

97

58

9b

3d (15%)

0

95

81

10b 11b,c

3d (15%) 3d (15%)

-10 0

91

Page 2 of 18

O

Ref. 12

F

O

O

HN

* *

(-)-paroxetine

X

X PMP

trace

N

HO Boc

iv

* *

72

Ar = m-tolyl

PMP 34, X = H, 72%, 96% ee 35, X = F, 68%, 95% ee

O

i

PMPHN

O

O 4, X = H; 10, X = F

complete reduction

v

* * O PMPN

ArN

We began the catalytic reaction using cinnamaldehyde 1a and different malonamides 2 under various reaction conditions with 10 mol% of mesityl substituted NHC 3a (see, Supporting Information). Initial optimization studies revealed that the product 4 could be obtained in good stereoselectivity (91% ee, dr = 4:1) with 56% yield using DBU, oxidant, substituted malonamide 2c9 and THF (Table 1, entry 1). Further reaction optimization studies were then carried out employing different chiral NHCs. Accordingly, 1-amino-2-indanol derived azolium salts 3a-d were first examined in this reaction (entries 1-4). Both the azolium salts 3a and 3d afforded the product 4 in nearly identical yield. However, slight improvement on ee value of the product 4 was obtained with the salt 3d having triisopropyl benzene substituent. The morpholino-based

partial ii reduction

O

* *

O

PMP 32, X = H, 53%, 96% ee 33, X = F, 55%, 95% ee X

X

ArHN

RESULTS AND DISCUSSION

* * N

N

PMP 36, X = H, 64%, 95% ee 37, X = F, 62%, 95% ee

conditions: 1a (2.0 equiv), 2c (1.0 equiv), 3 (10-15 mol%), DBU (15-20 mol%), oxidant (1.5 equiv) in THF; isolated yield; dr = 4:1 determined by 1H NMR analysis; ee determined by HPLC analysis on a chiral stationary phase. bReaction performed using 3Å MS. cPreparative scale experiment.

O

iii

* *

N

aReaction

X PMP HN

O

30, X = H, 63%, 97% ee 31, X = F, 51%, 96% ee

PMP HN * *

vi

N PMP

ArHNOC CONHAr Ph

*

vii

CO2Et

39, 79%, 97% ee

CONHAr ArHN

*

38, 63%, 97% ee OH viii

Ph O 40, 82%, 97% ee

NHAr O CONHAr

CCDC 1878494

=

Ph

*

OMs 41, 87%, 97% ee Reaction conditions: i) PMP-NH2, LiCl cat., THF, 160 C, 72 h; ii) LAH, THF, 25 C, 12 h; iii) (Boc)2O, DMAP, THF, 25 C, 6 h; iv) DIBALH, THF, 3-4 h; v) LAH, THF, reflux, 12 h; vi) EtOH, HCl (1 M), 80 C, 12 h; vii) LAH, THF, 25 C, 6 h; viii) MsCl, pyridine, 25 C, 2 h.


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Table 2. Substrate scopea

R

cat. 3d (15 mol%), DBU (20 mol%

NHAr

ArHN

+

O 1b-z

* * N O 5-29 Ar

N N

N

ArHN

THF, 48 h, 4Å MS, 0 C

O O 2c Ar = m-tolyl

O

R

O

BF4

O 3d

i

i

Pr

Pr i

O

O

O

O

ArN

NHAr

O NHAr

O 5

Me 66%, 96% ee, dr = 6:1 O

O

ArN

12

O

O

ArN

NHAr

O

O

ArN

O NHAr

ArN

O

O 18

OMe

90%, 90% ee, dr = 3:1 O ArN O

O NHAr

OAc OMe 68%, 97% ee, dr = 3:1 O

25

ArN O

O

O

ArN

71%, 92% ee, dr = 4:1 O ArN

c

61%, 99% ee, dr = 3:1

NHAr O

O ArN

CF3 48%, 91% ee, dr = 3:1

67%, 94% ee, dr = 5:1

O

O NHAr

ArN

O NH2

O

ArN

NHAr

O 23

24

O

70%, 95% ee, dr = 3:1

O

=

S

72%, 97% ee, dr = 3:1 O NHAr

ArN O 29

56%, 82% ee, dr = 3:1

56%, 98% ee, dr = 4:1 63%, 98% ee, dr = 6:1

O

O

ArN

NHAr 28

Cl

67%, 98% ee, dr = 3:1

O

O

27

c

O

O 22

O2N

O 26

NHAr

ArN

NHAr

O 21

N3

NHAr

11

17 i PrO MeO 81%, 97% ee, dr = 5:1 81%, 88% ee, dr = 7:1

CCDC 1878492 O O

O

O NHAr

ArN O 16

O

ArN

NHAr 20

9

15

O

19

O NHAr

O

NHAr

O

=

I c 71%, 97% ee, dr = 3:1

O

ArN

O

NHAr

O

14 13 Br Br c c 76%, 98% ee, dr = 3:1 63%, 96% ee, dr = 5:1 57%, 96% ee, dr = 5:1

O NHAr

c

O

ArN Br

O

O

ArN

O

10 F 72%, 97% ee, dr = 4:1 57%, 99% ee, dr = 13:1 b,c 58% (1 g), 87% ee O O

Ph

78%, 95% ee, dr = 4:1

78%, 99% ee, dr = 6:1 O

NHAr

ArN O

8

Ph

O

NHAr

O NHAr

O

O

O

O

ArN

NHAr

7

Me 94%, 97% ee, dr = 4:1 O

NHAr

O

O

ArN O

6

O

ArN

c

O

ArN

Pr

CCDC 1878493

53%, 98% ee, dr > 99:1

aReaction conditions: aldehydes (0.2 mmol), 2c (0.1 mmol), 3d (15 mol%), DBU (20 mol%), 3Å MS (50 mg) in THF (1.0 mL); isolated yields; diastereomeric ratio (dr) determined by 1H NMR analysis; ee determined by HPLC analysis on a chiral stationary phase. bReaction performed with 1 g of aldehyde. cReaction performed using aldehyde (0.1 mmol) and amide 2c (0.15 mmol).

and 24 in equal efficiency, when phenyl ring of the substrate was replaced with aromatic heterocycle. Naphthyl substituted enals were found to be suitable substrates for the reaction (products 25 and 26). Importantly, the reaction afforded the product 27 in a single diastereoisomer with 98% ee with 9anthranyl substituted enal. Substrate scope of the reaction was also evaluated with aliphatic enals. Notably, the aliphatic enals are challenging substrates for the oxidative NHC-catalysis. With this catalytic process, the aliphatic enals having cyclohexyl and cyclopropyl structural scaffold were transformed to the corresponding products 28 and 29 in good stereoselectivity albeit with moderate isolated yield of 56%. Absolute stereochemistry determined to be 3R, 4R for the compound 15 via single-crystal X-ray analysis.10 Synthetic utility of the method was demonstrated by the preparation of different valuable enantioenriched materials (Scheme 2). Accordingly, enantioenriched synthesis of medicinally potent piperidine derivatives 36 and 37 were accomplished using the enantioenriched glutarimides 4 and 10. The synthesis involved four simple transformations: transamidation with p-methoxy aniline to install easily

removable PMP-group,11 LiAlH4 mediated imide reduction, Boc-protection and finally DIBAL-H reduction, delivering the alcohols 36 and 37 in single diastereoisomer with excellent ee value. Absolute configuration 3S, 4R of the alcohol 37 was confirmed by analogy with the reported sign of optical rotation data (see, Supporting Information).12 The enantioenriched alcohol 37 could be transformed to the marketed drug (-)paroxetine13 via etherification with sesamol followed by PMP deprotection.12 Furthermore, complete reduction of the glutarimide 30 gave access to the enantioenriched amino piperidine derivative 38. The product 4 was also converted to an open chain ester 39 upon treatment with ethanol. The ethyl ester 39 was reduced with LiAlH4 to afford the enantioenriched alcohol 40. Single crystal X-ray analysis of the mesyl protected alcohol 41 resulted in R absolute stereochemistry (Scheme 2). A possible catalytic cycle is depicted in Scheme 3, in which free carbene is formed via deprotonation of azolium salt with a catalytic amount of DBU. The in-situ generated carbene then undergoes nucleophilic addition to carbonyl group of enal to form the Breslow intermediate I, which provides the α,β-



= triplet, dt = doublet of triplet, m = multiplet, br. = broad), coupling constants (Hz) and integration. 13C chemical shifts are reported in ppm (δ) from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 δ 77.0 ppm). High resolution mass spectra were measured on Q-Tof micro MS system by electron spray ionization (ESI) technique. IR spectra were recorded on PerkinElmer FT-IR spectrometer (model: Spectrum Two) as Neat. The wave numbers (n) are reported in cm−1. Optical rotations were measured on an Anton Paar automatic polarimeter and are reported as follows: concentration (c = g/dL), and solvent. The enantiomeric excesss were determined by HPLC (Shimadzu) analysis employing a chiral stationary phase column specified in the individual experiment, by comparing the samples with the appropriate racemic mixtures. Enals 1a, 1g, 1h, 1i, 1o, 1p, 1q, 1r, 1t, 1x are commercially available and the rest of the enals were synthesized following the similar reported procedure15 that is briefly described in GP-1. See also Supporting Information for synthetic scheme of those enals. General procedure for synthesis of enals (GP-1): Step-1: Ethyl (triphenylphosphoranylidene)acetate (1.2 equiv.) was added to a solution of aldehyde (1.0 equiv) in anhydrous dichloromethane (10 mL/g) under an inert atmosphere. The solution was stirred for 16 h at 25 °C. Volatiles were removed in vacuo and the resulting solid purified by flash chromatography to give the desired α,βunsaturated ester. Step-2: To a solution of the above obtained α,β-unsaturated ester (1.0 equiv) in dichloromethane (0.2 M) at -78 °C was added dropwise DIBAL-H in THF (2.1 equiv) and the reaction mixture was stirred until complete consumption of the α,βunsaturated ester was realized (usually 4 h). The reaction was quenched by slow addition of 10% aqueous NaOH. Finally, the reaction mixture was extracted with DCM and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to give the desired α,β-unsaturated alcohol. Step-3: To a solution of α,β-unsaturated alcohol (1.0 equiv) in anhydrous DCM was added PDC (1.5 equiv). After stirring for 24 hours at 25 °C, the solution was diluted with diethyl ether and hexane (1:1) and filtered through celite pad and washed with ether. The combined filtrate was concentrated in vacuo and purified by column chromatography to give the desired enal. 3-(2-Methylphenyl)-2-propenal (1b): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (320.0 mg) to afford 1b (246.0 mg) as white solid in 78% yield (step-3). Spectroscopic data are in good agreement with reported values.16 3-(4-Methylphenyl)-2-propenal (1c): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (500.0 mg) to afford 1c (440.0 mg) as white solid in 88% yield (step-3). Spectroscopic data are in good agreement with reported values.16 3-[1,1'-Biphenyl]-4-yl-2-propenal (1d): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (430.0 mg) to afford 1d (304.0 mg) as white solid in

unsaturated azolium ion II upon oxidation.14 Conjugate addition of the enolizable diamide to the azolium ion II results in the formation of enolether III. The intermediate IV is most likely formed through an internal proton transfer from the intermediate III. Finally, the intermediate IV delivers the desired product via imide formation along with the regeneration of carbene. Scheme 3. Probable catalytic cycle for the reaction

ArHN

*

*

N Ar1

O

N e on id ti i m r ma fo

N

R

ad c l e d i oph tio il n i

NHC

c

* N

O IV

H

R

O

Ar1

N Ar

III

N NAr1 R

HO

I

on

N N N

BF4

N N Ar1 n u

N Ar

O H *

N NAr1

N

H

O

H

*

l inter na pr ot on tr ansf er

O Ar N N

*

N Ar

O

*

DBU

R

O

ox id ati

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

O

H R

H N Ar

O

O H

conjugate addition

ArHN

R NHAr

O

H

O

N

*

N N II Ar1 ArHN

NHAr O

Page 4 of 18

O

CONCLUSIONS In conclusion, we have demonstrated an efficient NHCcatalytic approach to highly enantioselective and biologically active trans-3,4-disubstituted glutarimides via annulation between enals and 1,3-diamides under oxidative conditions. Notable aspects of this catalytic enantioselective reaction include: simple substrates, excellent enantioselectivity, scalability and operational ease. Starting from the product 10, a formal synthesis of the marketed drug (-)-paroxetine is completed with excellent stereoselectivity (ee and dr).

EXPERIMENTAL SECTION General Information: Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. THF was freshly dried prior to the reaction over Na. 3Å MS was activated by heating at elevated temperature (> 150 ºC) under vacuum for 12 h. All reactions were performed in flame-dried schlenk tubes (inner diameter = 18 mm, length = 105 mm) with glass stoppers/silicon septum and Teflon coated magnetic stirring bar. Reactions were monitored by thin layer chromatography (TLC) analysis on silica gel 60 F254 and visualization was accomplished with short wave UV light at 254 nm or KMnO4 staining solutions followed by heating, crude product was purified by column chromatography on Merck silica gel (100200 mesh). 1H and 13C NMR spectra were recorded on Bruker AVANCE III 500, 400 and 300 MHz spectrometers in deuterated solvents. Proton chemical shifts are reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 δ 7.26 ppm). 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublet, t


Page 5 of 18 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


(step-3). Spectroscopic data are in good agreement with reported values.17 3-(1-Naphthalenyl)-2-propenal (1w): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (300.0 mg) to afford 1w (210.0 mg) as white solid in 71% yield (step-3). Spectroscopic data are in good agreement with reported values.16 3-Cyclohexyl-2-propenal (1y): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (300.0 mg) to afford 1y (190.0 mg) as colorless liquid in 64% yield (step-3). Spectroscopic data are in good agreement with reported values.21 3-Cyclopropyl-2-propenal (1z): Prepared according to GPI from the corresponding α,β-unsaturated alcohol (320.0 mg) to afford 1z (200.0 mg) as white solid in 64% yield (step-3). Spectroscopic data are in good agreement with reported values.22 Diamides 2a-f were synthesized following the similar reported procedure 23 that is briefly described in GP-2. See also Supporting Information for synthetic scheme of diamides 2a-f. General procedure for the synthesis of diamides (GP-2): A pressure tube (30 mL) equipped with a magnetic stirrer was charged with diethyl malonate (1.0 equiv) and appropriate aniline derivative (2.0 equiv.). The pressure tube was capped and heated at 160 °C for 12 h. After completion the reaction mixture was diluted with hexane and the precipitate formed was filtered, washed with (1:1) DCM:Hexane and dried to afford the desired diamides. Malonamide 2a: Prepared according to GP-2, combining diethylmalonate (1.0 g) and aniline (1.16 g) to afford 2a (1.03 g) as white solid in 65% yield. Spectroscopic data are in good agreement with reported values.24 Malonamide 2b: Prepared according to GP-2 combining diethylmalonate (1.0 g) and 2-methylaniline (1.34 g) to afford 2b (916.0 mg) as white solid in 52% yield. Spectroscopic data are in good agreement with reported values.24 Malonamide 2c: Prepared according to GP-2 combining diethylmalonate (3.0 g) and 3-methylaniline (4.01 g) to afford 2c (3.17 g) as off-white solid in 60% yield. Spectroscopic data are in good agreement with reported values.24 Malonamide 2d: Prepared according to GP-2 combining diethylmalonate (1.0 g) and 3-phenylaniline (2.11 g) to afford 2d (964.0 mg) as white solid in 38% yield. 1H NMR (400 MHz, CDCl3) δ = 9.64 (s, 1H), 7.87 (m, 1H), 7.61-7.58 (m, 6H), 7.41-7.37 (m, 10H), 3.72(s, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 165.8, 142.1, 140.4, 137.7, 129.3, 128.7, 127.5, 127.1, 123.7, 119.1, 119.0, 44.8 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C27H22N2O2 407.1754; found 407.1755. IR (Neat) ѵmax = 3282, 3060, 1649, 1608, 1544, 1478, 1235, 886, 794, 752, 696 cm-1. Malonamide 2e: Prepared according to GP-2 to combining diethylmalonate (1.0 g) and aniline (1.53 g) to afford 2e (1.07 g) as white solid in 55% yield. Spectroscopic data are in good agreement with reported values.24 Malonamide 2f: Prepared according to GP-2 combining diethylmalonate (1.0 g) and aniline (1.33 g) to afford 2a (1.26

71% yield (step-3). 1H NMR (400 MHz, CDCl3) δ = 9.46 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.47-7.24 (m, 9H), 6.61 (q, J = 8.0 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 193.8, 151.7, 143.3, 139.5, 131.9, 130.7, 130.6, 129.7, 129.3, 128.3, 127.8, 127.7, 126.9 ppm. HRMS (ESITOF) m/z : [M+H]+ calcd for C15H12O 209.0961; found 209.0963. IR (Neat) ѵmax = 3059, 2737, 1675, 1620, 1596, 1474, 1127, 1098, 1008 cm-1. 3-(2,4,6-Trimethylphenyl)-2-propenal (1f): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (500.0 mg) to afford 1f (330.0 mg) as white solid in 67% yield (step-3). Spectroscopic data are in good agreement with reported values. 17 3-(2-Bromophenyl)-2-propenal (1j): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (300.0 mg) to afford 1j (190.0 mg) as white solid in 64% yield (step3). Spectroscopic data are in good agreement with reported values. 17 3-(3-Bromophenyl)-2-propenal (1k): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (450.0 mg) to afford 1k (336.0 mg) as white solid in 75% yield (step-3). Spectroscopic data are in good agreement with reported values.18 3-(4-Iodophenyl)-2-propenal (1l): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (500.0 mg) to afford 1l (410.0 mg) as white solid in 83% yield (step3). Spectroscopic data are in good agreement with reported values.19 3-(2-Methoxyphenyl)propenal (1m): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (300.0 mg) to afford 1m (210.0 mg) as pale yellow solid in 71% yield (step-3). Spectroscopic data are in good agreement with reported values.20 3-[2-(1-methylethoxy)phenyl]-propenal (1n): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (440.0 mg) to afford 1n (270.0 mg) as white solid in 62% yield (step-3). 1H NMR (400 MHz, CDCl3) δ =9.69 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.37 (t, J = 6.8 Hz, 1H), 6.97-6.93 (m, 2H), 6.78 (dd, J = 16.0, 8.0 Hz, 1H), 4.69-4.62 (m, 1H), 1.40-1.38 (d, J = 6.02 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 194.5, 156.7, 148.6, 132.5, 128.9, 128.7, 123.7, 120.5, 113.6, 70.8, 22.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H14O2 191.1067; found 191.1069. IR (Neat) ѵmax = 2978, 1673, 1597, 1482, 1247, 1129, 1093, 952, 751 cm-1. 3-(4-Trifluoromethylphenyl)propenal (1s): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (400.0 mg) to afford 1s (260.0 mg) as white solid in 66% yield (step-3). Spectroscopic data are in good agreement with reported values. 16 3-(2-Thienyl)-2-propenal (1u): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (200.0 mg) to afford 1u (104.0 mg) as white solid in 53% yield (step-3). Spectroscopic data are in good agreement with reported values. 16 3-(2-Naphthalenyl)-2-propenal (1v): Prepared according to GP-I from the corresponding α,β-unsaturated alcohol (450.0 mg) to afford 1v (335.0 mg) as white solid in 75% yield



Page 6 of 18

1H), 3.16 (dd, J = 17.4, 4.2 Hz, 1H), 3.03 (d, J = 17.1 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ =148.5, 144.8, 144.5, 140.3, 139.2, 138.7, 136.3, 134.8, 129.3, 129.3, 129.1, 129.0, 128.7, 128.5, 128.5, 127.7, 127.4, 125.1, 123.6, 77.4, 61.9, 59.7, 37.0 ppm. HRMS (ESI-TOF) m/z: [M-BF4]+ calcd for C36H29N3O 518.2234; found 518.2233. IR (Neat) ѵmax = 3045, 2928, 1591, 1210, 1106, 1064, 973, 892 cm-1. [α]D 25 = -4.81 (c = 0.81, CHCl3). General procedure (GP-3): NHC-catalyzed 1,4conjugate addition reaction: To a flame dried Schlenk tube equipped with a magnetic stir bar, carbene precursor 3d (7.6 mg, 0.015 mmol, 0.15 equiv), activated 3Å MS (50.0 mg) and THF (1.0 mL) were placed under argon. To the resulting mixture, DBU (3.0 µL, 0.020 mmol) was added at 25 °C and the mixture was stirred for another 5 min. To the mixture, 1,3diamide 2c (0.1-0.11 mmol, 1-1.1 equiv) and oxidant (0.15 mmol, 1.5 equiv) were added successively. The reaction tube was cooled to 0 ºC. To the cold solution, an appropriate enal (0.1-0.2 mmol, 1.0-2.0 equiv) was added and the reaction was continued for 48 h while maintaining the reaction temperature at 0 ºC. The progress of the reaction was monitored by TLC analysis. The crude reaction mixture was concentrated under reduced pressure and purified by gradient column chromatography from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to afford the desired compound. Compound 4: The GP-3, combining 2c and enal 1a gave compound 4 along with minor diastereomer (34.0 mg, 81%, combined yield) as off-white solid. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.10 (s, 1Hmajor), 7.34-7.21 (m, 14Hmajor+minor), 7.18-7.04 (m, 6Hmajor+minor), 6.93-6.77 (m, 6Hmajor+minor), 4.13 (d, J = 4.5 Hz, 1Hmajor), 4.07-4.05 (m, 1Hminor), 3.96 (d, J = 4.0 Hz, 1Hmajor), 3.86 (d, J = 4.5 Hz, 1Hminor), 3.61 (dd, J = 17.5, 9.5 Hz, 1Hminor), 3.38 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.10 (d, J = 5.0 Hz, 1Hminor), 3.05 (dd, J = 17.0, 5.5 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.28 (s, 3Hmajor), 2.46 (s, 3H major), 2.21 (s, 3Hminor), ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 171.0, 170.9, 170.9, 163.9, 163.1, 140.2, 139.5, 139.5, 139.1, 138.9, 137.8, 137.0, 136.6, 134.7, 134.3, 129.8, 129.3, 129.2, 128.9, 128.8, 128.7, 128.7, 128.1, 127.8, 127.1, 126.8, 125.8, 125.8, 125.1, 125.0, 121.1, 120.7, 117.5, 117.1, 55.9, 54.9, 37.2, 36.6, 36.3, 35.3, 21.4, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C26H25N2O3 413.1860; found 413.1861. IR (Neat) ѵmax = 3331, 3031, 2920, 1736, 1667, 1552, 1489, 1245, 1191, 765, 695 cm1. HPLC: The enantiomeric excess (% of ee = 96, minor diastereoisomer and 95, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 15.27 min, τminor = 21.85 min for minor diastereoisomer and τminor = 24.63 min, τmajor = 30.99 min for major diastereoisomer. Compound 5: The GP-3, combining 2c and enal 1b gave 5 along with minor diastereomer (28.0 mg, 66%, combined yield) as off-white solid. The diastereomeric ratio (dr) determined to be 6:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.15 (s, 1Hmajor), 7.72 (s, 1Hminor), 7.33-7.23 (m, 4Hmajor+minor), 7.21-7.03 (m, 14Hmajor+minor), 7.03-7.01 (m, 1Hminor), 6.96-6.90 (m, 2Hminor), 6.89-6.80 (m, 3Hmajor), 4.33 (dd, J = 10.0, 5.5 Hz, 1Hmajor), 4.19-4.14 (m, 1Hminor), 3.91 (d,

g) as white solid in 71% yield. Spectroscopic data are in good agreement with reported values.24 Azolium salts 3a-f were synthesized according to the literature procedure.25 2,4,6 triphenylbromobenzene was synthesized according to the reported procedure.26 Synthesis of 1,3,5-(triphenyl)phenylhydrazine hydrochloride (B), see also Supporting Information: Step I: An oven dried 250 mL two necked flask fitted with Ar-inlet, magnetic stirring bar, reflux condenser and septum was charged with Mg (234.0 mg, 9.76 mmol, 1.5 equiv, activated with a spatula tip of iodine). The Mg was covered with THF (2 ml), subsequently 2-bromo-1,3,5triphenylbenzene (2.5 g, 6.51 mmol, 1.0 equiv), the rest of the THF (8 ml) and 0.1 ml 1,2-dibromoethane (as activator) were added via different syringes maintaining the exothermic Grignard-reaction active. After complete addition of all the components, the resulting grey solution was placed in a preheated oil bath and the solution was heated under refluxed for 24 h. Step II: To a stirred solution of di-tert-butyl azodicarboxylate (1.16 g, 5.00 mmol) in THF (4 mL) at -78 °C, was added the pre-formed Grignard reagent. The resulting solution was stirred at -78 °C for 5 h before the reaction was quenched with acetic acid (0.5 mL). The mixture was allowed to warm to room temperature and diluted with H2O (10 mL). The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford the product A (2.3 g, 86%). Step II: The obtained product A (2.3 g, 4.28 mmol) was dissolved in i-PrOH (5.4 mL). To the solution, HCl (4 M in dioxane, 5.4 mL) was added. The resulting mixture was stirred at room temperature for 24 h. Upon dilution with cooled Et2O, the desired hydrazine hydrochloride was precipitated. The precipitate was collected by cannula filtration, washed with Et2O and dried under vacuum to give the 1,3,5(triphenyl)phenylhydrazine hydrochloride (B) as white solid (1.59 g, 75%). Synthesis of the azolium salt 3c: To a solution of (1R,2S) morpholinone (265 mg, 1.40 mmol) in CH2Cl2 (7.0 mL) was added trimethyloxonium tetrafluoroborate (155.0 mg, 1.47 mmol). The mixture was stirred for 12 h at 25 °C before a solution of 1,3,5(triphenyl)phenylhydrazine (518 mg, 1.54 mmol (synthesized from the hydrazine hydrochloride B) was added. The mixture was stirred for another 12 h. The solvent was evaporated under vacuum and chlorobenzene (7 mL) was added, followed by triethyl orthoformate (2.32 mL, 14 mmol). The flask was fitted with a reflux condenser and heated at 110 °C (oil bath temperature) for 12 h. All the low boiling materials were removed under reduced pressure and the crude mass was purified by FC using EtOAc:Hexane (1:1) to afford the azolium salt 3c (513 mg, 60%) as white solid. 1H NMR (300 MHz, CDCl3) δ = 10.05 (s, 1H), 7.69-7.64 (m, 4H), 7.53-7.45 (m, 3H), 7.39-7.31 (m, 5H), 7.28-7.23 (m, 6H), 7.19-7.17 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.08 (d, J = 7.8 Hz, 1H), 5.98 (d, J = 3.6 Hz, 1H), 4.88-4.79 (m, 2H), 4.59 (d, J = 15.9 Hz,


Page 7 of 18 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


55.5, 53.7, 36.3, 35.5, 33.5, 32.9, 21.4, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C32H29N2O3 489.2173; found 489.2175. IR (Neat) ѵmax = 3313, 3023, 2919, 1735, 1681, 1489, 1364, 1188, 751, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 91, minor diastereoisomer and 99, major diastereoisomer) and diastereomeric ratio (dr = 88:12) were determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 5.05 min, τminor = 5.86 min for minor diastereoisomer and τminor = 15.27 min, τmajor = 8.31 min for major diastereoisomer. Compound 8: The GP-3, combining 2c and enal 1e gave compound 8 along with minor diastereomer (38.0 mg, 78%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.13 (s, 1Hmajor), 7.54-7.47 (m, 8Hmajor+minor), 7.39-7.35 (m, 4Hmajor+minor), 7.30-7.25 (m, 8H5H-major+3H-minor), 7.19-7.10 (m, 6Hmajor+minor), 7.06-7.03 (m, 2Hminor), 6.97-6.95 (m, 1Hminor), 6.90-6.77 (m, 5H3H-major+2H-minor), 4.16 (d, J = 4.5 Hz, 1Hmajor), 4.11-4.07 (m, 1Hminor), 4.00 (d, J = 4.0 Hz, 1Hmajor), 3.89 (d, J = 5.0 Hz, 1H minor), 3.63 (dd, J = 17.5, 9.5 Hz, 1Hminor), 3.41 (dd, J = 17.5, 5.0 Hz, 1Hmajor), 3.13-3.06 (m, 2Hmajor+minor), 2.31 (s, 3H minor), 2.85 (s, 3Hmajor), 2.24 (s, 3H 13 1 major), 2.18 (s, 3Hminor) ppm. C{ H} NMR (125 MHz, CDCl3) δ = 171.3, 170.9, 170.9, 163.9, 163.1, 141.1, 140.8, 140.8, 140.3, 140.2, 139.4, 139.3, 139.1, 138.9, 137.1, 136.9, 136.8, 134.8, 134.5, 129.8, 129.2, 128.9, 128.9, 128.8, 127.9, 127.9, 127.6, 127.6, 127.6, 127.3, 127.1, 127.0, 125.8, 125.2, 125.1, 121.1, 120.8, 117.6, 117.3, 55.9, 54.9, 37.1, 36.7, 36.6, 35.1, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C32H28N2O3Na 511.1998; found 511.1996. IR (Neat) ѵmax = 3332, 3029, 2921, 1735, 1666, 1488, 1372, 1190, 764, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 97, minor diastereoisomer and 95, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 16.32 min, τminor = 23.12 min for minor diastereoisomer and τminor = 25.41 min, τmajor = 33.65 min for major diastereoisomer. Compound 9: The GP-3, combining 2c and enal 1f gave compound 9 along with minor diastereomer (26.0 mg, 57%, combined yield) as white solid with excellent diastereomeric ratio. 1H NMR (300 MHz, CDCl3) δ = 7.67 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.18-7.15 (m, 1H), 6.98-6.90 (m, 5H), 6.806.75 (m, 3H), 4.53-4.43 (m, 1H), 4.18 (d, J = 12.0 Hz, 1H), 3.23-3.12 (m, 1H), 2.91 (dd, J = 17.1, 4.8 Hz, 1H), 2.36 (s, 6H), 2.31 (s, 3H), 2.14-2.13 (m, 6H), ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.3, 164.7, 139.5, 138.6, 137.0, 134.7, 131.8, 130.9, 130.9, 129.8, 129.2, 128.8, 128.5, 125.4, 125.2, 120.9, 117.3, 54.8, 35.9, 32.0, 21.6, 21.3, 20.6 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C29H31N2O3 455.2329; found 455.2327. IR (Neat) ѵmax = 3329, 3029, 2921, 1735, 1667, 1613, 1489, 1355, 1189, 1046, 756, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 99 of both the diastereomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 10.36 min, τminor = 20.34 min for minor diastereoisomer and τminor = 13.15 min, τmajor = 16.98 min for major diastereoisomer.

J = 3.0 Hz, 1Hmajor), 3.81 (d, J = 5.0 Hz, 1Hminor), 3.63 (dd, J = 17.5, 6.0 Hz, 1Hminor), 3.33 (dd, J = 17.5, 6.0 Hz, 1Hmajor), 2.99-2.90 (m, 2Hmajor+minor), 2.38 (s, 3H minor), 2.35 (s, 3Hmajor), 2.32 (s, 3H minor), 2.30 (s, 3Hmajor), 2.24 (s, 3Hmajor), 2.20 (s, 3H 13 1 minor) ppm. C{ H} NMR (125 MHz, CDCl3) δ = 171.4, 171.3, 171.1, 170.9, 164.0, 163.1, 139.5, 139.1, 138.8, 137.1, 136.6, 136.3, 135.9, 135.7, 134.9, 134.5, 131.6, 131.5, 129.8, 129.7, 129.2, 128.9, 128.8, 128.7, 127.9, 127.7, 126.8, 126.7, 125.9, 125.8, 125.3, 125.1, 124.8, 121.3, 120.8, 117.7, 117.2, 55.1, 53.9, 36.2, 35.7, 33.8, 33.1, 31.8, 21.3, 21.2, 19.4 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H27N2O3 427.2016; found 427.2015. IR (Neat) ѵmax = 3322, 3022, 2922, 1736, 1682, 1554, 1490, 1372, 1241, 1197, 763, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 98, minor diastereoisomer and 96, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 12.53min, τminor = 16.76 min for minor diastereoisomer and τminor = 13.32 min, τmajor = 15.23 min for major diastereoisomer. Compound 6: The GP-3, combining 2c and enal 1c gave compound 6 along with minor diastereomer (40.0 mg, 94%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (300 MHz, CDCl3) δ = 8.11 (s, 1Hmajor), 7.32-7.23 (m, 4Hmajor+minor), 7.18-7.04 (m, 14Hmajor+minor), 6.96-6.93 (m, 1Hminor), 6.88-6.82 (m, 3H1H-major+2H-minor), 6.79-6.76 (m, 2Hmajor), 4.09-3.98 (m, 1Hmajor+minor), 3.93 (d, J = 3.9 Hz, 1Hmajor), 3.84 (d, J = 4.5 Hz, 1Hminor), 3.57 (dd, J = 17.4, 9.6 Hz, 1Hminor), 3.35 (dd, J = 11.7, 5.4 Hz, 1Hmajor), 3.03 (m, 2Hmajor+minor), 2.26 (m, 18Hmajor+minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.6, 171.2, 171.1, 171.0, 164.0, 163.2, 139.5, 139.4, 139.0, 138.8, 137.8, 137.5, 137.1, 137.0, 136.6, 134.7, 134.3, 129.9, 129.8, 129.2, 129.2, 128.8, 128.7, 128.7, 126.9, 126.7, 125.7, 125.7, 125.1, 125.0, 121.1, 120.6, 117.5, 117.1, 55.9, 54.9, 36.9, 36.7, 36.4, 34.9, 21.4, 21.3, 20.9 ppm. HRMS (ESITOF) m/z : [M+Na]+ calcd for C27H26N2O3 Na 449.1841; found 449.1842. IR (Neat) ѵmax = 3332, 3023, 2921, 1736, 1667, 1489, 1243, 1191, 754, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 96, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 16.48 min, τminor = 23.69 min for minor diastereoisomer and τminor = 26.36 min, τmajor = 33.35 min for major diastereoisomer. Compound 7: The GP-3, combining 2c and enal 1d gave compound 7 along with minor diastereomer (38.0 mg, 78%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 6:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 7.45-7.20 (m, 18Hmajor+minor), 7.13-7.05 (m, 8Hmajor+minor), 6.99-6.97 (m, 2Hmajor+minor), 6.86-6.78(m, 6Hmajor+minor), 4.29-4.24 (m, 2Hmajor+minor), 3.72 (d, J = 3.0 Hz, 1Hmajor), 3.55 (d, J = 5.0 Hz, 1H minor), 3.47 (dd, J = 17.0, 9.5 Hz, 1Hminor), 3.22 (dd, J = 18.0, 6.0 Hz, 1Hmajor), 2.94 (dd, J = 18.0, 4.0 Hz, 1Hmajor), 2.79 (dd, J = 17.5, 5.0 Hz, 1H minor), 2.28 (s, 3H minor), 2.27 (s, 3Hmajor), 2.23 (s, 3H minor), 2.22 (s, 3Hmajor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.3, 169.9, 164.1, 163.9, 142.5, 142.3, 140.8, 140.7, 139.3, 138.9, 137.7, 136.9, 136.7, 135.4, 134.8, 134.6, 131.4, 131.3, 129.7, 129.3, 129.1, 128.9, 128.9, 128.8, 128.3, 128.0, 127.8, 127.7, 125.9, 125.7, 125.2, 125.1, 125.0, 121.3, 120.7, 117.7, 117.2,



Compound 10: The GP-3, combining 2c and enal 1g compound 10 along with minor diastereomer (31.0 mg, 72%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.33 (s, 1Hminor), 8.08 (s, 1Hmajor), 7.33-7.25 (m, 2Hmajor+minor), 7.24-7.06 (m, 12Hmajor+minor), 7.04-6.95 (m, 4Hmajor+minor), 6.91-6.73 (m, 6Hmajor+minor), 4.15-4.09 (m, 1Hmajor), 4.08-4.02 (m, 1Hminor), 3.91 (d, J = 4.5 Hz, 1Hmajor), 3.84 (d, J = 4.5 Hz, 1Hminor), 3.62 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.36 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.08 (dd, J = 17.5, 5.5 Hz, 1Hminor), 3.01 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.32 (s, 3Hminor), 2.29 (s, 3Hmajor), 2.25 (s, 3Hmajor), 2.22 (s, 3Hminor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.2, 170.8, 170.7, 163.7 (d, J = 245.2 Hz), 163.6, 162.9, 160.4, 139.5, 139.5, 139.0, 138.9, 136.8, 136.5, 135.8, 135.8, 134.5, 134.1, 133.5, 133.5, 129.9, 129.2, 129.2, 128.8, 128.8, 128.7, 128.7, 128.6, 128.5 (d, J = 7.5 Hz), 128.5, 128.4, 125.9, 125.8, 125.0, 124.9, 121.0, 120.6, 117.4, 117.1, 116.3 (d, J = 21.0 Hz, major), 116.2 (d, J = 21.0 Hz), 116.0, 115.9, 56.0, 54.5, 36.8, 36.5, 34.7, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24FN2O3 431.1772; found 431.1771. IR (Neat) ѵmax = 3334, 2925, 1736, 1670, 1512, 1240, 1206, 836, 781, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 98, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 11.74 min, τminor = 14.31 min for minor diastereoisomer and τminor = 18.78 min, τmajor = 24.36 min for major diastereoisomer. Compound 11: The GP-3, combining 2c and enal 1h gave compound 11 along with minor diastereomer (30.0 mg, 67%, combined yield) as white solid The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.40 (s, 1Hminor), 8.09 (s, 1Hmajor), 7.32-7.23 (m, 7H4H-major+3H-minor), 7.18-7.07 (m, 9H6H-major+3H-minor), 7.027.00 (m, 1Hminor), 6.89-6.84 (m, 4H1H-major+3H-minor), 6.78-6.76 (m, 3H1H-major+2H-minor), 4.13-4.09 (m, 1Hmajor), 4.07-4.04 (m, 1Hminor), 3.91 (d, J = 4.0 Hz, 1H major), 3.84 (d, J = 5.0 Hz, 1H minor), 3.60 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.35 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.08 (dd, J = 17.5, 5.0 Hz, 1Hminor), 3.01 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.32 (s, 3H minor), 2.29 (s, 3Hmajor), 2.25 (s, 3H major), 2.23 (s, 3H minor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 170.9, 170.8, 170.7, 170.6, 163.6, 162.8, 139.5, 139.5, 139.1, 138.9, 138.8, 136.9, 136.7, 136.5, 134.6, 134.3, 134.1, 133.8, 129.9, 129.5, 129.4, 129.2, 128.9, 128.8, 128.7, 128.7, 128.6, 128.3, 125.9, 125.9, 125.1, 125.1, 121.1, 120.8, 117.6, 117.2, 55.9, 54.4, 54.3, 36.7, 36.7, 34.9, 21.4, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24ClN2O3 447.1470; found 447.1472. IR (Neat) ѵmax = 3333, 3025, 2922, 1735, 1665, 1490, 1373, 1207, 1190, 1093, 755, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 92, minor diastereoisomer and 98, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 11.10 min, τminor = 13.28 min for minor diastereoisomer and τminor = 16.15 min, τmajor = 20.28 min for major diastereoisomer. Compound 12: The GP-3, combining 2c and enal 1i gave 12 along with minor diastereomer (39.0 mg, 76%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ

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= 8.47 (s, 1Hminor), 8.18 (s, 1Hmajor), 7.52 (d, J = 8.0 Hz, 2Hmajor), 7.49 (d, J = 8.0 Hz, 2Hminor), 7.40-7.28 (m, 4Hmajor+minor), 7.25-7.06 (m, 10Hmajor+minor), 6.98-6.80 (m, 6Hmajor+minor), 4.19-4.13 (m, 1Hmajor), 4.12-4.07 (m, 1Hminor), 3.97 (d, J = 4.5 Hz, 1Hmajor), 3.92 (d, J = 4.5 Hz, 1Hminor), 3.68 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.42 (dd, J = 17.5, 5.0 Hz, 1Hmajor), 3.15 (dd, J = 17.5, 5.0 Hz, 1Hminor), 3.07 (dd, J = 17.5, 6.0 Hz, 1Hmajor), 2.39 (s, 3Hminor), 2.37 (s, 3Hmajor), 2.32 (s, 3Hmajor), 2.30 (s, 3Hminor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.0, 170.7, 170.6, 163.5, 162.7, 139.6, 139.5, 139.1, 139.0, 138.9, 136.8, 136.5, 134.4, 134.1, 132.3, 132.3, 129.9, 129.2, 129.2, 128.8, 128.8, 128.6, 128.5, 125.9, 125.8, 125.0, 124.9, 122.0, 121.7, 121.0, 120.6, 117.4, 117.1, 55.6, 54.1, 36.6, 36.5, 36.4, 34.9, 21.4, 21.2 ppm. HRMS (ESITOF) m/z: [M+H]+ calcd for C26H24BrN2O3 491.0965 and 493.0948; found 491.0967 and 493.0767. IR (Neat) ѵmax = 3333, 3029, 2921, 1668, 1552, 1489, 1373, 1244, 823, 756, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 92, minor diastereoisomer and 98, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 11.10 min, τminor = 13.28 min for minor diastereoisomer and τminor = 16.15 min, τmajor = 20.28 min for major diastereoisomer. Compound 13: The GP-3, combining 2c and enal 1j gave compound 13 (31.0 mg, 63%, combined yield) as white solid, along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 5:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.16 (s, 1Hmajor), 7.61-7.58 (m, 2Hmajor+minor), 7.33-7.10 (m, 15H8H-major+7H-minor), 7.06-7.01 (m, 2Hminor), 6.93-6.86 (m, 3H1H-major+2H-minor), 6.846.78 (m, 2Hmajor), 4.45 (m, 1Hmajor), 4.32-4.27 (m, 1Hminor), 4.09-4.08 (m, 2Hmajor+minor), 3.90 (dd, J = 16.5, 12.0 Hz, 1Hminor), 3.51 (dd, J = 17.5, 6.0 Hz, 1Hmajor), 3.13-3.08 (m, 1Hmajor), 2.97-2.93 (m, 1Hminor), 2.32 (s, 3H minor), 2.29 (s, 3Hmajor), 2.27 (s, 3H major), 2.20 (s, 3H minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.3, 171.3, 170.6, 170.1, 163.7, 162.6, 139.6, 139.5, 139.3, 139.1, 138.9, 136.9, 136.5, 136.4, 134.6, 134.2, 133.7, 129.9, 129.8, 129.6, 129.5, 129.2, 129.2, 128.9, 128.8, 128.7, 128.6, 128.2, 128.2, 127.9, 126.9, 125.9, 125.8, 125.2, 124.9, 124.7, 124.3, 121.1, 120.5, 117.5, 116.9, 53.9, 53.0, 36.7, 35.0, 34.5, 21.4, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24BrN2O3 491.0965 and 493.0948; found 491.0962 and 493.0763. IR (Neat) ѵmax = 3317, 3032, 2919, 1737, 1683, 1615, 1489, 1370, 1209, 1192, 755, 693 cm-1. HPLC: The enantiomeric excess (% of ee = 96 of both the diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.17 min, τminor = 17.41 min for minor diastereoisomer and τminor = 20.36 min, τmajor = 22.15 min for major diastereoisomer. Compound 14: The GP-3, combining 2c and enal 1k gave 14 along with minor diastereomer (28.0 mg, 57%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 5:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.19 (s, 1Hmajor), 7.50-7.44 (m, 4Hmajor+minor), 7.41-7.35 (m, 2Hmajor+minor), 7.35-7.27 (m, 4Hmajor+minor), 7.26-7.06 (m, 8Hmajor+minor), 6.98-6.83 (m, 6Hmajor+minor), 4.22-4.16 (m, 1Hmajor), 4.15-4.11 (m, 1Hminor), 4.00 (d, J = 3.5 Hz, 1Hmajor), 3.92 (d, J = 5.0 Hz, 1Hminor), 3.67 (dd, J = 17.5, 8.5 Hz,

ACS Paragon Plus Environment

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1Hminor), 3.43 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.17 (dd, J = 17.5, 5.5 Hz, 1Hminor), 3.09 (dd, J = 17.5, 5.0 Hz, 1Hmajor), 2.39 (s, 3Hminor), 2.37 (s, 3Hmajor), 2.33 (s, 3Hmajor), 2.30 (s, 3Hminor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 170.9, 170.6, 170.6, 170.5, 163.4, 162.5, 142.5, 140.1, 139.6, 139.5, 139.0, 138.9, 136.8, 136.4, 134.4, 134.1, 131.2, 131.0, 130.8, 130.7, 130.4, 130.0, 129.9, 129.2, 129.2, 128.9, 128.7, 128.6, 128.5, 126.0, 125.8, 125.7, 125.6, 125.0, 124.9, 123.3, 123.2, 121.3, 120.6, 117.7, 117.1, 55.4, 54.0, 36.8, 36.5, 35.0, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24BrN2O3 491.0965 and 493.0948; found 491.0963 and 493.0768. IR (Neat) ѵmax = 3320, 2922, 1736, 1681, 1614, 1489, 1553, 780, 692 cm-1. HPLC: The enantiomeric excess (% of ee = 85, minor diastereoisomer and 96, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.35 min, τminor = 23.64 min for minor diastereoisomer and τminor = 18.47 min, τmajor = 26.67 min for major diastereoisomer. Compound 15: The GP-3, combining 2c and enal 1l gave compound 15 along with minor diastereomer (38.0 mg, 71%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. Compound 15 was crystallized by slow evaporation from a mixture of EtOAc:iPrOH (1:6). Absolute configuration of the compound 15 was unambiguously determined by the single-crystal X-ray analysis. 1H NMR (500 MHz, CDCl3) δ = 8.35 (s, 1Hminor), 8.10 (s, 1Hmajor), 7.64-7.59 (m, 4Hmajor+minor), 7.31-7.05 (m, 10Hmajor+minor), 7.01-6.95 (m, 4Hmajor+minor), 6.88-6.75 (m, 6Hmajor+minor), 4.06 (d, J = 5.5 Hz, 1Hmajor), 3.99-3.98 (m, 1Hminor), 3.88 (d, J = 4.5 Hz, 1Hmajor), 3.83 (d, J = 4.5 Hz, 1H minor), 3.58 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.32 (dd, J = 17.0, 5.0 Hz, 1Hmajor), 3.05 (dd, J = 17.0, 4.5 Hz, 1Hminor), 2.98 (dd, J = 17.5, 6.0 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.29 (s, 3Hmajor), 2.24 (s, 3H major), 2.22 (s, 3H minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.1, 170.8, 170.6, 163.6, 162.8, 139.9, 139.5, 139.06, 138.9, 138.5, 138.4, 138.2, 138.1, 137.6, 136.9, 136.6, 134.5, 134.2, 129.9, 129.3, 129.2, 129.1, 129.1, 128.9, 128.9, 128.8, 128.8, 128.5, 125.9, 125.8, 125.1, 124.9, 124.8, 121.0, 120.8, 120.7, 117.5, 117.2, 93.6, 93.2, 55.9, 55.5, 36.7, 36.6, 36.4, 35.3, 34.9, 21.5, 21.3, 21.2 ppm. HRMS (ESITOF) m/z : [M+H]+ calcd for C26H24IN2O3 539.0826; found 539.0825. IR (Neat) ѵmax = 3332, 3022, 2920, 1734, 1664, 1487, 1371, 1206, 1005, 753, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 98, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 12.78 min, τminor = 15.16 min for minor diastereoisomer and τminor = 18.30 min, τmajor = 22.78 min for major diastereoisomer. Compound 16: The GP-3, combining 2c and enal 1m gave desired compound 16 along with minor diastereomer (36.1 mg, 81%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 5:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.10 (s, 1Hmajor), 7.32-7.28 (m, 1Hmajor), 7.28-7.21 (m, 4Hmajor+minor), 7.21-7.18 (m, 2Hmajor+minor), 7.167.08 (m, 6Hmajor+minor), 7.03-7.00 (m, 1Hminor), 6.94-6.84 (m, 6Hmajor+minor), 6.84-6.75 (m, 4Hmajor+minor), 4.32-4.23 (m, 2Hmajor+minor), 4.14-4.10 (m, 1Hmajor), 4.07 (d, J = 4.64 Hz, 1Hminor), 3.81 (s, 3Hminor), 3.80 (s, 3Hmajor), 3.74-3.68 (m, 1Hminor), 3.39 (dd, J = 17.67, 5.94 Hz, 1Hmajor), 3.12 (dd, J =

17.04, 3.30 Hz, 1Hmajor), 2.92 (dd, J = 17.08, 4.26 Hz, 1Hminor), 2.31 (s, 3Hminor), 2.28 (s, 3Hmajor), 2.26 (s, 3Hmajor), 2.19 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.8, 171.3, 171.0, 164.4, 163.7, 157.0, 156.7, 139.3, 139.0, 138.8, 137.2, 136.6, 135.0, 134.6, 129.6, 129.6, 129.0, 129.0, 128.9, 128.8, 128.8, 128.6, 128.3, 127.2, 127.0, 125.6, 125.5, 125.3, 125.1, 121.1, 121.0, 120.6, 117.5, 117.0, 111.1, 110.8, 55.4, 54.0, 53.3, 34.8, 31.6, 31.0, 21.3, 21.2, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C27H27N2O4 443.1965; found 443.1967. IR (Neat) ѵmax = 3322, 3018, 2922, 2841, 1734, 1666, 1491, 1357, 1243, 1204, 753, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 97 of both the diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 20.20 min, τminor = 28.36 min for minor diastereoisomer and τminor = 25.53 min, τmajor = 35.52 min for major diastereoisomer. Compound 17: The GP-3, combining 2c and enal 1n gave desired compound 17 along with minor diastereomer (38.2 mg, 81%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 7:1 by 1H NMR analysis.1H NMR (500 MHz, CDCl3) δ = 8.06 (s, 1Hmajor), 7.50 (s, 1Hminor), 7.327.28 (m, 2Hmajor+minor), 7.28-7.23 (m, 2Hmajor+minor), 7.22-7.15 (m, 4Hmajor+minor), 7.15-6.99 (m, 6Hmajor+minor), 6.98-6.83 (m, 6Hmajor+minor), 6.83-6.73 (m, 4Hmajor+minor), 4.63-4.54 (m, 2Hmajor+minor), 4.30-4.21 (m, 2Hmajor+minor), 4.15-4.09 (m, 1Hmajor), 4.06 (d, J = 4.5 Hz, 1Hminor), 3.69 (dd, J = 17.5, 12.0 Hz, 1Hminor), 3.39 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.13 (dd, J = 17.5, 2.5 Hz, 1Hmajor), 2.90 (dd, J = 17.5, 4.5 Hz, 1Hminor), 2.31 (s, 3Hminor), 2.28 (s, 3Hmajor), 2.26 (s, 3Hmajor), 2.19 (s, 3Hminor), 1.38 (d, J = 6.0 Hz, 3Hminor), 1.33 (d, J = 6.0 Hz, 3Hmajor), 1.32-1.26 (m, 6Hmajor+minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 172.0, 172.0, 171.2, 170.9, 164.4, 163.8, 155.0, 154.9, 139.3, 139.0, 138.7, 137.1, 136.4, 134.8, 134.4, 129.7, 129.6, 129.1, 128.8, 128.7, 128.7, 128.5, 126.9, 126.7, 126.3, 125.6, 125.5, 125.2, 125.0, 121.1, 120.6, 120.5, 120.4, 117.5, 116.9, 112.7, 112.6, 70.2, 69.8, 53.9, 53.2, 34.5, 34.3, 31.3, 30.8, 22.3, 22.3, 22.0, 21.9, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C29H31N2O4 471.2278; found 471.2276. IR (Neat) ѵmax = 3314, 2976, 2920, 1735, 1673, 1596, 1371, 1239, 956, 752, 692 cm-1. HPLC: The enantiomeric excess (% of ee = 78, minor diastereoisomer and 88, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak ID-3 column: n-hexane:i-PrOH = 83:17, flow rate 0.6 mL/min, λ = 254 nm: τmajor = 23.33 min, τminor = 20.72 min for minor diastereoisomer and τminor = 21.72 min, τmajor = 26.29 min for major diastereoisomer. Compound 18: The GP-3, combining 2c and enal 1o gave 18 along with minor diastereomer (40.0 mg, 90%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.06 (s, 1Hmajor), 7.31-7.24 (m, 3H2Hmajor+1Hminor), 7.18-7.05 (m, 10Hmajor+minor), 6.97 (d, J = 7.5 Hz, 1Hminor), 6.87-6.77 (m, 10Hmajor+minor), 4.06-4.00 (m, 2Hmajor+minor), 3.91 (d, J = 4.0 Hz, 1Hmajor), 3.81 (d, J = 4.5 Hz, 1Hminor), 3.73 (s, 3Hmajor), 3.71 (s, 3H minor), 3.56 (dd, J = 17.0, 9.0Hz, 1Hminor), 3.35 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.07 (d, J = 5.0 Hz, 1H minor), 3.01 (dd, J = 17.0, 5.0 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.29 (s, 3Hmajor), 2.24 (s, 3H major), 2.21 (s, 3H minor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.5, 171.1, 171.0, 164.1, 163.3, 159.4, 159.1, 139.4, 139.4, 139.0, 138.9, 137.1, 136.8, 134.8, 134.5,

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rate 1.0 mL/min, λ = 254 nm: τmajor = 14.07min, τminor = 19.22 min for minor diastereoisomer and τminor = 23.25 min, τmajor = 29.78 min for major diastereoisomer. Compound 21: The GP-3, combining 2c and enal 1r gave compound 21 along with minor diastereomer (28.0 mg, 61%, combined yield) as green solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.12 (s, 1Hmajor), 7.97 (d, J = 7.0 Hz, 2Hmajor+minor), 7.86 (d, J = 8.0 Hz, 1Hminor), 7.61 (t, J = 7.5 Hz, 1Hmajor), 7.55-7.49 (m, 2Hminor), 7.45 (t, J = 7.5 Hz, 1Hmajor), 7.41-7.36 (m, 2Hmajor+minor), 7.31-7.27 (m, 2Hmajor+minor), 7.227.10 (m, 6H4Hmajor+2Hminor), 7.05-7.00 (m, 2Hminor), 6.92-6.80 (m, 6Hmajor+minor), 4.64-4.58 (m, 1Hmajor), 4.44-4.38 (m, 1Hminor), 4.24 (d, J = 5.0 Hz, 1H minor), 4.09-4.02 (m, 2Hmajor+minor), 3.54 (dd, J = 18.0, 6.5 Hz, 1Hmajor), 3.04 (dd, J = 18.0, 4.0 Hz, 1Hmajor), 2.92 (dd, J = 17.0, 4.0 Hz, 1H minor), 2.30 (s, 6Hmajor+minor), 2.25 (s, 3Hmajor), 2.19 (s, 3H minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 170.9, 170.8, 169.8, 169.8, 163.8, 162.9, 149.6, 149.3, 139.6, 139.4, 139.0, 138.8, 136.9, 136.4, 135.6, 134.4, 134.1, 133.9, 133.4, 132.1, 129.9, 129.8, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.6, 127.4, 126.1, 125.9, 125.7, 125.2, 125.1, 124.9, 120.9, 120.6, 117.3, 117.0, 55.2, 54.3, 35.5, 34.9, 32.8, 32.1, 21.4, 21.3, 21.2, 21.2 ppm. IR (Neat) ѵmax = 3317, 2925, 1738. 1615, 1686, 1526, 1492, 1356, 1244, 1190, 782,694 cm-1. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24N3O5 458.1716; found 458.1717. IR (Neat) ѵmax = 3317, 2925, 1738, 1685, 1615, 1526, 1429, 1356, 1244, 782, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 96, minor diastereoisomer and 99, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE3 column: n-MTBE :i-PrOH = 95:5, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 5.95 min, τminor = 7.14 min for minor diastereoisomer and τminor = 10.69 min, τmajor = 9.14 min for major diastereoisomer. Compound 22: The GP-3, combining 2c and enal 1s gave compound 22 (23.0 mg, 48%, combined yield) as white solid along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.21 (s, 1Hmajor), 7.68-7.63 (m, 4Hmajor+minor), 7.46-7.40 (m, 4Hmajor+minor), 7.397.34 (m, 2Hmajor+minor), 7.30-7.13 (m, 8Hmajor+minor), 7.09-7.08 (m, 1Hminor), 6.97-6.84 (m, 5H3H-major+ 2H-minor), 4.31-4.27 (m, 1Hmajor), 4.24-4.20 (m, 1Hminor), 4.04 (d, J = 4.0 Hz, 1Hmajor), 3.98 (d, J = 4.5 Hz, 1H minor), 3.78-3.72 (m, 1Hminor), 3.45 (dd, J = 17.0, 5.0 Hz, 1Hmajor), 3.21 (dd, J = 17.5, 5.00 Hz, 1H minor), 3.12 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.39 (s, 3H minor), 2.37 (s, 3Hmajor), 2.33 (s, 3H major), 2.29 (s, 3H minor) ppm. 13C{1H} NMR (75 MHz, CDCl ) δ = 170.9, 170.7, 170.6, 3 170.5, 163.2, 162.5, 144.3, 142.0, 139.6, 139.1, 139.0, 136.8, 136.5, 134.4, 134.0, 130.4, 130.0, 129.3, 128.9, 128.8, 128.6, 127.6, 127.4, 126.3, 126.2, 126.2, 126.1, 126.0, 125.9, 125.6, 124.9, 124.9, 122.0, 120.9, 120.7, 117.4, 117.1, 55.4, 53.9, 36.9, 36.5, 36.4, 35.2, 29.7, 21.4, 21.3 ppm. HRMS (ESITOF) m/z : [M+Na]+ calcd for C27H23F3N2O3Na 503.1559; found 503.1556. IR (Neat) ѵmax = 3332, 2925, 1737, 1673, 1617, 1490, 1553, 1325, 1167, 1070, 780 cm-1. HPLC: The enantiomeric excess (% of ee = 90, minor diastereoisomer and 91, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 7.86 min,

132.2, 129.8, 129.2, 129.1, 128.9, 128.8, 128.7, 128.2, 127.9, 125.8, 125.8, 125.2, 125.1, 121.2, 120.8, 117.6, 117.2, 114.7, 114.7, 56.3, 55.3, 55.2, 46.2, 36.9, 36.7, 34.7, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C27H26N2O4 Na 465.1790; found 465.1792. IR (Neat) ѵmax = 3332, 2920, 2834, 1735, 1667, 1613, 1514, 1374, 1249, 1188, 1033, 753, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 90 of both the diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 75:25, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.99 min, τminor = 19.95 min for minor diastereoisomer and τminor = 21.65 min, τmajor = 27.23 min for major diastereoisomer. Compound 19: The GP-3, combining 2c and enal 1p gave 19 (34.0 mg, 68%, combined yield) as white solid along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.81 (s, 1Hminor), 8.15 (s, 1Hmajor), 7.32-7.24 (m, 2Hmajor+minor), 7.19-7.04 (m, 8Hmajor+minor), 6.98-6.93 (m, 2Hmajor+minor), 6.91-6.74 (m, 10Hmajor+minor), 4.11-4.04 (m, 1Hmajor), 3.99-3.93 (m, 1Hminor), 3.91 (d, J = 4.5 Hz, 1Hmajor), 3.82 (d, J = 4.5 Hz, 1Hminor), 3.72 (s, 3Hmajor), 3.60 (dd, J = 17.5, 10.5 Hz, 1Hminor), 3.55 (s, 3Hminor), 3.34 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.08-2.97 (m, 2Hmajor+minor), 2.31 (s, 3Hminor), 2.28 (s, 3Hmajor), 2.24 (s, 6Hmajor), 2.23 (s, 3Hminor), 2.21 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.3, 170.8, 170.6, 170.4, 168.7, 168.6, 164.2, 163.4, 151.7, 139.7, 139.4, 139.2, 139.0, 138.8, 137.0, 136.6, 136.5, 134.7, 134.3, 129.7, 129.7, 129.1, 128.8, 128.8, 128.7, 128.6, 125.8, 125.8, 125.6, 125.1, 125.0, 123.4, 123.3, 121.1, 120.9, 120.8, 119.1, 118.3, 117.6, 117.4, 117.2, 111.8, 111.6, 56.3, 56.0, 55.7, 55.5, 37.5, 36.6, 35.9, 35.6, 21.3, 21.1, 20.5 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C29H28N2O6Na 523.1845; found 523.1844. IR (Neat) ѵmax = 3332, 3029, 2928, 1764, 1737, 1678, 1553, 1370, 1200, 1032, 781, 696 cm-1. HPLC: The enantiomeric excess (% of ee = 98, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 75:25, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 14.19 min, τminor = 19.04 min for minor diastereoisomer and τminor = 21.18 min, τmajor = 27.94 min for major diastereoisomer. Compound 20: The GP-3, combining 2c and enal 1q gave 20 along with minor diastereomer (32.3 mg, 71%, combined yield) as yellow solid. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (300 MHz, CDCl3) δ = 8.44 (s, 1H), 8.12 (s, 1H), 7.36-7.04 (m, 14H), 7.03-6.91 (m, 4H), 6.91-6.73 (m, 6H), 4.15-4.01 (m, 2H), 3.91 (d, J = 4.5 Hz, 1H), 3.85 (d, J = 4.5 Hz, 1H), 3.62 (dd, J = 17.4, 8.7 Hz, 1H), 3.35 (dd, J = 17.4, 5.1 Hz, 1H), 3.14-2.93 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.1, 170.9, 170.7, 163.6, 162.9, 139.9, 139.7, 139.5, 139.5, 139.2, 139.0, 138.9, 136.9, 136.7, 136.6, 134.5, 134.4, 134.2, 129.8, 129.2, 129.2, 128.8, 128.7, 128.6, 128.6, 128.5, 128.3, 125.9, 125.8, 125.0, 125.0, 121.0, 120.7, 119.8, 119.7, 117.4, 117.1, 55.9, 54.3, 36.8, 36.6, 34.9, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C26H23N5O3Na 476.1699; found 476.1698. IR (Neat) ѵmax = 3331, 3032, 2921, 2416, 2257, 2120, 1736, 1670, 1503, 1191, 756, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 92 of both the diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow


Page 11 of 18 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


minor),

τminor = 8.70 min for minor diastereoisomer and τminor = 11.82 min, τmajor = 15.23 min for major diastereoisomer. Compound 23: The GP-3, combining 2c and enal 1t gave compound 23 along with minor diastereomer (28.1 mg, 70%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.26 (s, 1Hmajor), 7.34 (d, J = 1.5 Hz, 1Hmajor), 7.32-7.22 (m, 7H3Hmajor+4Hminor), 7.19-7.08 (m, 6H3Hmajor+3Hminor), 6.92-6.84 (m, 2Hmajor+minor), 6.83-6.73 (m, 2Hmajor+minor), 6.32-6.26 (m, 2Hmajor+minor), 6.24-6.17 (m, 2Hmajor+minor), 4.35-4.30 (m, 1Hminor), 4.20-4.16 (m, 1Hmajor), 4.12-4.10 (m, 1Hmajor), 3.86 (d, J = 4.5 Hz, 1Hminor), 3.43-3.36 (m, 1Hmajor+minor), 3.15-3.05 (m, 1Hmajor+minor), 2.32 (s, 3Hminor), 2.29 (s, 3Hmajor), 2.28 (s, 3Hmajor), 2.24 (s, 3Hminor) ppm. 13C{1H} NMR (100 MHz, CDCl ) δ = 170.8, 170.5, 163.3, 3 162.1, 153.4, 151.7, 142.6, 142.4, 139.5, 139.4, 139.1, 138.9, 137.0, 136.9, 134.6, 134.3, 129.9, 129.8, 129.2, 129.1, 128.9, 128.7, 128.6, 125.8, 125.6, 125.0, 121.1, 120.5, 117.5, 117.0, 110.8, 110.6, 107.6, 106.5, 53.0, 51.1, 36.8, 34.2, 32.0, 29.9, 21.4, 21.3, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C24H22N2O4Na 425.1477; found 425.1443. IR (Neat) ѵmax = 3332, 2925, 1736, 1673, 1554, 1489, 1369, 1248, 780, 696 cm-1. HPLC: The enantiomeric excess (% of ee = 95 of both the diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 16.83 min, τminor = 24.28 min for minor diastereoisomer and τminor = 20.75 min, τmajor = 35.64 min for major diastereoisomer. Compound 24: The GP-3, combining 2c and enal 1u gave compound 24 along with minor diastereomer (30.0 mg, 72%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 9.18 (s, 1Hminor), 8.19 (s, 1Hmajor), 7.31-7.08 (m, 11H7Hmajor+4Hminor), 6.94-6.89 (m, 4H3Hmajor+1Hminor), 6.876.83 (m, 3Hminor), 6.79-6.77 (m, 4H1H-major+3H-minor), 4.51-4.48 (m, 1Hminor), 4.41-4.38 (m, 1Hmajor), 4.05-4.04 (m, 1Hmajor), 3.87 (d, J = 4.5 Hz, 1H minor), 3.53-3.46 (m, 2Hmajor+minor), 3.21 (dd, J = 18.0, 5.5 Hz, 1H minor), 3.14-3.09 (m, 1Hminor), 2.32 (s, 3H minor), 2.29 (s, 3Hmajor), 2.27 (s, 3H major), 2.34 (s, 3H minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.1, 170.7, 170.6, 170.5, 163.4, 162.3, 143.6, 140.6, 139.6, 139.5, 139.1, 138.9, 136.9, 134.4, 134.1, 129.9, 129.9, 129.3, 129.2, 128.9, 128.8, 128.6, 127.3, 127.2, 125.8, 125.8, 125.6, 125.3, 124.9, 124.9, 124.8, 121.1, 120.6, 117.5, 117.0, 56.3, 53.7, 38.9, 37.2, 33.5, 31.5, 29.7, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C24H23N2O3S 419.1424; found 419.1422. IR (Neat) ѵmax = 3332, 3027, 2922, 1736, 1667, 1614, 1553, 1361, 1196, 754, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 99, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.69 min, τminor = 22.12 min for minor diastereoisomer and τminor = 19.54 min, τmajor = 24.49 min for major diastereoisomer. Compound 25: The GP-3, combining 2c and enal 1v gave compound 25 along with minor diastereomer (31.0 mg, 67%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 5:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.16 (s, 1Hmajor), 7.79-7.72 (m, 5H3H-major+2Hminor), 7.68-7.62 (m, 3H1H-major+2H-minor), 7.45-7.40 (m, 4Hmajor+-

11

7.33-7.22 (m, 6Hmajor+minor), 7.17-7.07 (m, 6Hmajor+minor), 6.99-6.96 (m, 1Hminor), 6.90-6.76 (m, 5H3H-major+2H-minor), 4.274.24 (m, 1Hmajor), 4.19-4.16 (m, 1Hminor), 4.08 (d, J = 3.5 Hz, 1Hmajor), 3.93 (d, J = 4.5 Hz, 1H minor), 3.71 (dd, J = 17.5, 10.0 Hz, 1Hminor), 3.44 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.17-3.13 (m, 2Hmajor+minor), 2.29 (s, 3Hminor), 2.26 (s, 3Hmajor), 2.22 (s, 3Hmajor), 2.11 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 170.9, 170.9, 164.0, 163.2, 139.4, 139.1, 138.8, 137.7, 137.1, 136.5, 135.3, 134.8, 134.5, 133.5, 133.5, 132.9, 132.7, 129.8, 129.3, 129.2, 128.9, 128.8, 128.8, 128.7, 127.9, 127.8, 127.7, 127.7, 126.7, 126.5, 126.4, 125.9, 125.8, 125.3, 125.2, 125.1, 121.3, 120.8, 117.8, 117.2, 55.9, 54.9, 37.5, 36.6, 36.5, 35.6, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C30H26N2O3Na 485.1841; found 485.1842. IR (Neat) ѵmax = 3331, 3021, 2920, 1735, 1666, 1363, 1242, 1195, 749, 695, 476 cm-1. HPLC: The enantiomeric excess (% of ee = 97, minor diastereoisomer and 94, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 17.21 min, τminor = 23.02 min for minor diastereoisomer and τminor = 24.72 min, τmajor = 32.24 min for major diastereoisomer. Compound 26: The GP-3, combining 2c and enal 1w gave compound 26 along with minor diastereomer (29.0 mg, 63%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 6:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.19 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H minor), 8.02 (d, J = 8.5Hz, 1Hmajor), 7.97-7.93 (m, 2Hmajor+minor), 7.877.84 (m, 2Hmajor+minor), 7.66-7.55 (m, 4H2H-major+2H-minor), 7.517.48 (m, 1Hmajor), 7.45-7.39 (m, 8H4H-major+4H-minor), 7.27-7.23 (m, 4H2H-major+2H-minor), 7.09-7.03 (m, 3Hminor), 6.99 (d, J = 7.5 Hz, 1H major), 6.88-6.86 (m, 2Hmajor), 6.78 (d, J = 8.0 Hz, 1H minor), 5.08-5.07 (m, 1Hmajor), 4.87 (m, 1Hminor), 4.24 (t, J = 2.0 Hz, 1H), 4.19-4.18 (m, 1Hminor), 3.96 (dd, J = 17.0, 10.5 Hz, 1Hminor), 3.67 (dd, J = 17.5, 6.0 Hz, 1H major), 3.31 (td, J = 17.5, 2.5 Hz, 1H major), 3.18 (dd, J = 17.0, 4.0 Hz, 1Hminor), 2.41 (s, 3Hminor), 2.38 (s, 3H major), 2.37 (s, 3H major), 2.25 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 171.3, 163.9, 162.6, 139.4, 139.1, 138.8, 137.1, 136.4, 134.9, 134.4, 134.3, 133.2, 130.7, 130.6, 129.8, 129.7, 129.6, 129.5, 129.1, 128.9, 128.8, 128.7, 128.6, 127.2, 126.2, 125.8, 125.4, 125.3, 125.1, 125.0, 123.7, 122.8, 122.4, 122.0, 121.2, 120.6, 54.9, 54.3, 35.6, 35.3, 33.0, 30.7, 21.4, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C30H27N2O3 463.2016; found 463.2014. IR (Neat) ѵmax = 3340, 3059, 2922, 2846, 1735, 1670, 1614, 1363, 1046, 776, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 97, minor diastereoisomer and 98, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 17.56 min, τminor = 22.55 min for minor diastereoisomer and τminor = 16.16 min, τmajor = 26.21 min for major diastereoisomer. Compound 27: The GP-3, combining 2c and enal 1x gave compound 27 (27.0 mg, 53%) as white solid with excellent diastereoselectivity. 1H NMR (300 MHz, CDCl3) δ = 8.39 (s, 2H), 7.98 (d, J = 8.1 Hz, 2H), 7.59-7.46 (m, 2H), 7.45-7.29 (m, 4H), 7.22-7.14 (m, 2H), 7.07-6.98 (m, 2H), 6.86 (t, J = 7.8 Hz, 1H), 6.79-6.61 (m, 3H), 5.80-5.59 (m, 1H), 4.82 (d, J = 11.1 Hz, 1H), 3.82 (dd, J = 17.1, 14.4 Hz, 1H), 3.17 (dd, J = 17.1, 5.4 Hz, 1H), 2.34 (s, 3H), 2.03 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.0, 170.9, 164.6, 139.5,



138.5, 136.6, 134.9, 131.9, 129.8, 129.7, 129.2, 129.2, 128.9, 128.4, 125.5, 125.3, 123.6, 120.9, 117.4, 55.8, 37.1, 30.4, 21.3, 21.1 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C34H28N2O3Na 535.1998; found 535.1996. IR (Neat) ѵmax = 3346, 3048, 2925, 1734, 1678, 1357, 1236, 1193, 1045, 730, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 98) was determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 27.61 min, τminor = 15.01min. [α]D 25 = -3.43 (c = 0.60, CHCl3). Compound 28: The GP-3, combining 2c and enal 1y compound 28 along with minor diastereomer (24.0 mg, 56%, combined yield) as white solid. Compound 28 was crystallized by slow evaporation from iPrOH. Absolute configuration of the compound 28 was unambiguously determined by the single-crystal X-ray analysis. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.19 (s, 1Hmajor), 7.30-7.26 (m, 4Hmajor+minor), 7.22-7.20 (m, 2Hmajor+minor), 7.16-7.12 (m, 4Hmajor+minor), 6.896.87 (m, 2Hmajor+minor), 6.83-6.79 (m, 4Hmajor+minor), 3.78-3.74 (m, 2Hmajor+minor), 3.30 (dd, J = 18.0, 11.0 Hz, 1H minor), 3.09 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.89 (dd, J = 17.5, 4.5 Hz, 1H minor), 2.80-2.76 (m, 1Hmajor), 2.63-2.62 (m, 2Hmajor+minor), 2.30 (s, 6H major+minor), 2.26 (s, 6H major+minor), 1.76-1.62 (m, 10Hmajor+minor), 1.47-1.41 (m, 2Hmajor+minor), 1.22-0.91 (m, 10Hmajor+minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 172.5, 171.9, 171.5, 164.1, 163.6, 139.4, 139.0, 137.1, 137.0, 134.7, 134.4, 129.8, 129.7, 129.2, 128.9, 128.7, 128.6, 125.7, 125.6, 125.0, 124.9, 120.8, 120.5, 117.2, 116.9, 52.6, 51.7, 40.3, 38.2, 37.8, 35.3, 33.0, 31.0, 30.9, 30.5, 29.8, 26.2, 26.201, 26.1, 25.9, 25.9, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H31N2O3 419.2329; found 419.2328. IR (Neat) ѵmax = 3329, 2925, 2853, 1734, 1666, 1552, 1489, 1372, 1254, 1197, 756, 693 cm-1.HPLC: The enantiomeric excess (% of ee = 97, minor diastereoisomer and 98, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 10.70 min, τminor = 14.59 min for minor diastereoisomer and τminor = 16.48 min, τmajor = 20.02 min for major diastereoisomer. Compound 29: The GP-3, combining 2c and enal 1z gave compound 29 along with minor diastereomer (21.0 mg, 56%, combined yield) as white solid. The diastereomeric ratio (dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (400 MHz, CDCl3) δ = 8.93 (s, 1Hminor), 8.22 (s, 1Hmajor), 7.31-7.27 (m, 4Hmajor+minor), 7.21-7.11 (m, 6Hmajor+minor), 6.89-6.82 (m, 6Hmajor+minor), 3.78 (d, J = 0.8 Hz, 1Hmajor), 3.68 (d, J = 4.4 Hz, 1H minor), 3.27-3.23 (m, 1Hminor), 3.18 (dd, J = 17.2, 5.2 Hz, 1Hmajor), 2.91 (dd, J = 18.0, 5.2 Hz, 1H minor), 2.80 (dd, J = 17.2, 2.4 Hz, 1Hmajor), 2.30 (s, 6Hmajor+minor), 2.26 (s, 6Hmajor+minor), 1.99-1.88 (m, 2Hmajor+minor), 0.87-0.78 (m, 2Hmajor+minor), 0.63-0.47 (m, 4Hmajor+minor), 0.34-0.14 (m, 4Hmajor+minor) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 171.7, 171.6, 171.4, 171.4, 164.3, 163.3, 139.4, 139.0, 137.1, 134.7, 134.4, 129.7, 129.1, 128.8, 128.7, 125.6, 125.1, 120.9, 120.5, 117.3, 116.9, 55.2, 53.4, 38.1, 37.2, 35.9, 35.8, 29.6, 21.4, 21.2, 14.8, 12.1, 4.7, 4.7, 4.0, 3.8 ppm. HRMS (ESITOF) m/z : [M+H]+ calcd for C23H25N2O3 377.1860; found 377.1862. IR (Neat) ѵmax = 3629, 3382, 2955, 1688, 1583, 1511, 1439, 1178, 756, 701 cm-1. HPLC: The enantiomeric excess (% of ee = 84, minor diastereoisomer and 82, major

Page 12 of 18

diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 90:10, flow rate 0.6 mL/min, λ = 254 nm: τmajor = 18.22 min, τminor = 17.19 min for minor diastereoisomer and τminor = 25.41 min, τmajor = 22.16 min for major diastereoisomer. Synthetic application-I: General procedure (GP-4) for the synthesis of piperidine rings (36 and 37): Step 1: Gram scale experiment: To a flame dried Schlenk round bottom flask equipped with a magnetic stir bar, carbene precursor 3d (0.15 equiv), activated 3Å MS (50.0 mg / mmol) and THF (0.1 M) were placed under argon atmosphere. To the resulting heterogeneous mixture, DBU (0.2 equiv) was added. The mixture was stirred at 25 °C for 5 minutes before 1,3diamide 2c (1.1 equiv) and oxidant (1.5 equiv) were added successively to the reaction mixture. The resulting mixture was cooled to 0 ºC. To the cold reaction mixture, enal (1.5 equiv or 1.0 equiv) was added. The reaction was continued for 48 h, while maintaining the reaction temperature -2 ºC. The progress of the reaction was monitored by TLC analysis. The crude reaction mixture was concentrated under reduced pressure and purified by gradient column chromatography from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to afford the desired compound. Step-2: Trans amidation: To a 100 ml screw cap pressure tube equipped with a magnetic stirr bar, was added glutarimide (1.0 equiv), p-anisidine (8.0 eq.) and LiCl (10 mol%). The pressure tube was evacuated and refilled with argon before anhydrous THF (0.1 M) was added into it. The reaction mixture was heated at 160 °C and the progress of the reaction was monitored by TLC. The reaction was quenched by the addition of 2(M) HCl. Aqueous layer was extracted with EtOAc. The combined organic layer was washed with a brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography. Step-3: LAH reduction: To an oven-dried schlenk tube equipped with a magnetic stirring bar, amide (4 or 10) (1.0 equiv) and anhydrous THF (0.1 M) were added under argon atmosphere. The solution was cooled to 0 °C and LAH (8.0 equiv) was added portion wise to the reaction mixture maintaining the continuous flow of argon. The mixture was stirred at 25 °C for 12 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography Step-4: Boc-protection: To a solution of amide 32 or 33 (1.0 equiv) in dry THF (0.1M) was added DMAP (0.5 equiv) and Boc2O (2.0 equiv). The resultant mixture was allowed to stir at room temperature until the complete consumption of amide (generally 6 h) was realized by TLC analysis. After removal of the volatile materials under vacuum, the crude mixture was purified directly by flash column chromatography to deliver the corresponding product as off-white solid. Step-5: DIBALH reduction: To a stirred solution of imide 34 or 35 (1.0 equiv) in anhydrous THF (0.1 M) at -78 °C, was added DIBAL-H (5.0 equiv) slowly. The reaction mixture was allowed to warm to 0 °C and stirred until no starting material

12


Page 13 of 18 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


diastereoisomer and τminor = 26.75 min, τmajor = 22.40 min for major diastereoisomer. Compound 32: Prepared according to GP-4 (step-3), combining glutarimide 30 (220 mg, 0.49 mmol, 1.0 equiv), LiAlH4 (150 mg, 3.95 mmol, 8.0 equiv) in THF (0.01 M, 4.9 mL) for 12 h. The reaction was quenched with water and extracted with ethyl acetate and the crude product was purified by column chromatography from EtOAc:Hexane (25:75) to afford the desired compound 32 (110 mg, 53%) as brown solid with excellent diastereomeric ratio. 1H NMR (500 MHz, CDCl3) δ = 7.32-7.29 (m, 3H), 7.25-7.22 (m, 2H), 7.00-6.95 (m, 3H), 6.88-6.85 (m, 2H), 6.75-6.72 (m, 2H), 6.61-6.57 (m, 1H), 3.83-3.80 (m, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.66-3.63 (m, 1H), 3.18-3.12 (m, 1H), 3.00 (dt, J = 12.0, 4.4 Hz, 1H), 2.88 (dt, J = 12.00, 2.8 Hz, 1H), 2.72 (dt, J = 10.8, 3.6 Hz, 1H), 2.18-2.08 (m, 1H), 2.04-1.98 (m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 170.7, 156.5, 154.1, 145.6, 143.4, 130.1, 129.0, 128.9, 128.1, 127.3, 127.0, 122.2, 121.4, 119.2, 114.6, 114.5, 113.9, 55.5, 55.4, 53.8, 52.0, 51.8, 45.4, 32.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C26H29N2O3 417.2173; found 417.2171. IR (Neat) ѵmax = 3294, 2926, 2841, 1650, 1509, 1243, 827 cm-1. HPLC: The enantiomeric excess (% of ee = 96, major diastereoisomer) and diastereomeric ratio (dr = 99:1) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 15.77 min, τminor = 15.59 min for minor diastereoisomer and τminor = 45.15 min, τmajor = 32.34 min for major diastereoisomer. Compound 34: Prepared according to GP-4 (step-4), combining 32 (90.0 mg, 0.22 mmol, 1.0 equiv), di-tertbutyldicarbonate (94.32 mg, 0.43 mmol, 2.0 equiv) and DMAP (13.2 mg, 0.015 mmol, 0.5 eq.). The crude reaction mixture was purified by column chromatography from EtOAc:Hexane (10:90) to afford the desired compound 35 (80 mg, 72%) as white solid with excellent diastereomeric ratio. 1H NMR (500 MHz, CDCl ) δ = 7.35-7.32 (m, 2H), 7.30-7.25 3 (m, 3H), 6.99 (d, J = 8.5 Hz, 2H), 6.86-6.85 (m, 2H), 6.72 (d, J = 9.0 Hz, 2H), 6.28 (d, J = 8.5 Hz, 2H), 4.04-4.00 (m, 1H), 3.96-3.93 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.67-3.64 (m, 1H), 3.05 (dt, J = 12.0, 4.0 Hz, 1H), 2.98 (t, J = 11.0 Hz, 1H), 2.90-2.86 (m, 1H), 1.99 (dt, J = 12.0, 3.5 Hz, 1H), 1.94-1.91 (m, 1H), 1.36 (s, 9H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 176.3, 158.8, 153.8, 152.8, 145.7, 143.5, 131.3, 128.9, 128.51, 127.9, 126.7, 119.1, 114.4, 114.0, 82.9, 55.5, 55.3, 53.8, 51.9, 49.7, 46.7, 32.9, 27.79 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C31H37N2O5 517.2697; found 517.2695. IR (Neat) ѵmax = 2934, 2834, 1727, 1508, 1243, 1149, 1035, 758 cm-1. HPLC: The enantiomeric excess (% of ee = 96, major diastereoisomer) and diastereomeric ratio (dr = >99:1) were determined by HPLC analysis using Daicel Chiralpak IE3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 14.37 min, τminor = 17.01 min for minor diastereoisomer and τminor = 23.17 min, τmajor = 12.83 min for major diastereoisomer. Compound 36: Prepared according to GP-4 (step-5), combining 34 (60.0 mg, 0.12 mmol, 1.0 equiv) and DIBALH (0.58 mL, 1(M) in THF) in THF (0.1 M, 1.2 mL) at -78°C to rt for 3h. The reaction mixture was quenched and extracted with EtOAc. The crude reaction mixture was purified by column

remained (monitored by TLC analysis, generally 4 h). The reaction was quenched by sequential addition of MeOH, saturated Rochelle Salt solution and ethyl acetate at -78 °C The reaction was allowed to warm to room temperature and the resulting slurry was vigorously stirred for additional 4 h until both layers became homogeneous. The aqueous phase was extracted with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residual oil was purified by flash column chromatography on silica gel to provide the desired product as white solid. Compound 4: Prepared according to GP-4 (Step-1), combining 1,3-diamide 2c (846.4 mg, 3.0 mmol, 1.0 equiv), enal 1a (0.56 mL, 4.5 mmol, 1.5 equiv), 3d (226.5 mg, 0.45 mmol, 15.0 mol%), DBU (90 µL, 0.6 mmol, 20.0 mol%), oxidant (1.84 g, 4.5 mmol, 1.5 equiv) and 3Å MS (1 g) in THF (0.1 M, 30 mL) at -2 °C for 48 h. 3Å MS was filtered through a pad of celite and the crude reaction mixture was concentrated and purified by gradient column chromatography from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to afford the desired compound 4 (900 mg, 72%) as white solid along with the non separable minor diastereoisomer with diastereomeric ratio 4:1, determined by 1HNMR analysis. HPLC: The enantiomeric excess (% of ee = 91 of both the diastereoisomer) was determined by HPLC analysis. The enantioselectivity of the product was further improved by crystallization from EtOAc and hexane to afford (458 mg, crystallization yield 51%) of 4 with enantiomeric excess (% of ee = 97 of both the diastereoisomer). Compound 30: Prepared according to GP-4 (step-2), combining glutarimide 4 (400 mg, 0.97 mmol, 1.0 equiv), panisidine (716 mg, 5.81 mmol, 6.0 equiv), and LiCl (4.1 mg, 0.097 mmol, 0.1 eq.) in THF (0.1 M, 9.7 mL) at 160 °C for 72 h. 2(M) HCl was added to it and the reaction mixture was extracted with EtOAc. The crude reaction mixture was purified by column chromatography from EtOAc:Hexane (35:65) to afford the desired compound 30 (270 mg, 63%, combined yield) as off-white solid along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ = 8.13 (s, 1H), 7.40-7.29 (m, 14H7H-major+7Hminor), 7.13 (d, J = 9.0 Hz, 2H minor), 7.06 (d, J = 9.0 Hz, 1H minor), 7.00-6.95 (m, 5H4H-major+1H-minor), 6.84-6.77 (m, 4H2Hmajor+2H-minor), 4.17 (dd, J = 11.0, 5.5 Hz, 1H major), 4.11 (dd, J = 10.0, 5.0 Hz, 1H minor), 4.02 (dd, J = 5.0, 1.0 Hz, 1H major), 3.91 (d, J = 4.5 Hz, 1H), 3.83 (s, 3H minor), 3.81 (s, 3H major), 3.78 (s, 3H major), 3.76 (s, 3H minor), 3.71-3.66 (m,1H minor), 3.43 (dd, J = 17.5, 5.5 Hz, 1H major), 3.16-3.08 (m, 2H1H-major+1H-minor) ppm. 13C{1H} NMR (100 MHz, CDCl ) δ = 171.7, 171.2, 171.2, 3 171.0, 163.9, 163.1, 159.7, 157.0, 156.9, 140.2, 137.9, 130.2, 129.7, 129.3, 129.2, 129.1, 129.1, 128.1, 127.8, 127.2, 127.1, 126.8, 122.36, 121.9, 114.8, 114.7, 114.2, 114.1, 55.9, 55.5, 55.4, 55.0, 37.3, 36.7, 36.2, 35.5 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H25N2O5 445.1758; found 445.1757. IR (Neat) ѵmax = 2834, 1735, 1677, 1510, 1247, 828, 773 cm-1. HPLC: The enantiomeric excess (% of ee = 92, minor diastereoisomer and 97, major diastereoisomer) was determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 70:30, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 18.73 min, τminor = 12.88 min for minor



Page 14 of 18

3.06 (dd, J = 17.5, 6.5 Hz, 1H major) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 170.9, 170.9, 163.7, 163.3, 163.1(d, J = 246.5 Hz), 163.0, 161.1, 159.8, 157.0, 157.0, 135.9, 130.2, 129.7, 129.2, 129.1, 128.9 (d, J = 7.5 Hz, minor), 128.8, 128.5 (d, J = 7.5 Hz, major), 128.4, 127.1, 126.8, 122.2, 122.0, 116.3 (d, J = 21.3 Hz, major), 116.2, 116.1 (d, J = 20.5 Hz, minor), 116.0, 114.8, 114.7, 114.2, 114.2, 56.1, 55.4, 55.4, 37.0, 36.6, 36.5, 34.9 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H24FN2O5 463.1664; found 463.1663. IR (Neat) ѵmax = 3302, 2941, 2841, 1668, 1510, 1247, 829 cm-1. HPLC: The enantiomeric excess (% of ee = 90, minor diastereoisomer and 96, major diastereoisomer) and diastereomeric ratio (dr = 92:8) were determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 70:30, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 20.86 min, τminor = 12.27 min for minor diastereoisomer and τminor = 29.7 min, τmajor = 24.14 min for major diastereoisomer. Compound 33: Prepared according to GP-4 (step-3), combining 31 (173 mg, 0.38 mmol, 1.0 equiv), LiAlH4 (116 mg, 3.1 mmol, 8.0 equiv) in THF (0. 1 M, 3.8 mL) for 12 h. The reaction was quenched with water and extracted with ethyl acetate and the crude product was purified by column chromatography from EtOAc:Hexane (25:75) to afford the desired compound 33 (91 mg, 55%) as brown solid with excellent diastereomeric ratio. 1H NMR (400 MHz, CDCl3) δ = 7.26-7.23 (m, 4H2Hmajor+2Hminor), 7.06-7.03 (m, 4H 2Hmajor+2Hminor), 7.00-6.96 (m, 6H3H-major+3H-minor), 6.88-6.84 (m, 6H 3H-major+3H-minor), 6.76-6.74 (m, 4H 2H-major+2H-minor), 3.82-3.79 (m, 2H major+minor), 3.78 (s, 6H3H-major+3H-minor), 3.74 (s, 6H3Hmajor+3H-minor), 3.64-3.61 (m, 2H major+minor), 3.11 (t, J = 11.2 Hz, 2H major+minor), 3.03 (dt, J = 12.0, 4.0 Hz, 2H major+minor), 2.892.82 (m, 2H major+minor), 2.68 (dt, J = 10.8, 3.6 Hz, 2H major+minor), 2.11-1.95 (m, 4H2H-major+2H-minor) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 170.6, 166.0, 162.9(d, J = 244.5 Hz), 160.4, 156.6, 155.9, 154.2, 145.5, 140.9, 139.5, 139.1, 139.1, 130.1, 129.6, 129.5, 128.8 (d, J = 8.0 Hz), 128.7, 127.3, 127.0, 122.2, 121.6, 119.3, 119.2, 115.7, 115.6 (d, J = 21.0 Hz), 115.4, 114.8, 114.6, 114.5, 114.2, 114.0, 113.9, 55.5, 55.4, 54.0, 52.2, 52.1, 45.3, 44.4, 42.0, 36.2, 32.3, 30.5, 29.6 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H28 FN2O3 435.2079; found 435.2077. IR (Neat) ѵmax = 3290, 2925, 2835, 1650, 1508, 1241, 827 cm-1. HPLC: The enantiomeric excess (% of ee = 95, major diastereoisomer) and diastereomeric ratio (dr = 97:3) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 31.49 min, τminor = 43.70 min for minor diastereoisomer and τminor = 27.37min, τmajor = 23.01 min for major diastereoisomer. Compound 35: Prepared according to GP-4 (step-4), combining 33 (50.0 mg, 0.12 mmol, 1.0 equiv), di-tert-butyl dicarbonate (51.1 mg, 0.23 mmol, 2.0 equiv) and DMAP (7.1mg, 0.06 mmol, 0.5 eq.). The crude reaction mixture was purified by column chromatography from EtOAc:Hexane (10:90) to afford the desired compound 35 (42 mg, 68%) as white solid with excellent diastereomeric ratio. 1H NMR (500 MHz, CDCl ) δ = 7.24-7.21 (m, 2H), 7.04-6.98 3 (m, 4H), 6.85 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 6.37 (d, J = 9.0 Hz, 2H), 3.99-3.93 (m, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.65-3.63 (m, 1H), 3.06 (dt, J = 12.0, 4.5 Hz, 1H), 2.96 (t, J = 10.5 Hz, 1H), 2.87 (t, J = 12.0 Hz, 1H), 2.01-1.88

chromatography from EtOAc:Hexane (20:80) to afford the desired compound 36 (22 mg, 64%) as off-white solid with excellent diastereomeric ratio. 1H NMR (500 MHz, CDCl3) δ = 7.34-7.31 (m, 2H), 7.25-7.22 (m, 3H), 7.01 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.5 Hz, 2H), 3.85-3.81 (m, 1H), 3.78 (s, 3H), 3.63-3.60 (m, 1H), 3.48 (dd, J = 11.0, 3.5 Hz, 1H), 3.34-3.30 (m, 1H), 2.74 (dt, J = 12.0, 3.0Hz, 1H), 2.62 (t, J = 11.5 Hz, 1H), 2.44 (dt, J = 11.5, 4.0 Hz, 1H), 2.24-2.17 (m, 1H), 2.03 (ddd, J = 25.0, 12.5, 4.0 Hz, 1H), 1.94-1.90 (m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl ) δ = 154.0, 145.9, 144.1, 3 128.7, 127.4, 126.6, 119.0, 114.4, 64.0, 55.5, 55.3, 52.2, 45.0, 44.0, 34.3 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C19H24NO2 298.1801; found 298.1800. IR (Neat) ѵmax = 3319, 2930, 2832, 1659, 1508, 1241, 1034, 700 cm-1. HPLC: The enantiomeric excess (% of ee = 95, major diastereoisomer) and diastereomeric ratio (dr = >99:1) was determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 17.47 min, τminor = 7.67 min for minor diastereoisomer and τminor = 9.27 min, τmajor = 10.37 min for major diastereoisomer. [α]D 25 = -1.95 (c = 0.1, CHCl3). Compound 10: Prepared according to GP-4 (step-1), combining 1,3-diamide 2c (1.13 g, 4.0 mmol, 1.0 equiv), enal 1g (600 mg, 4.0 mmol, 1.0 equiv), 3d (302 mg, 0.6 mmol, 15.0 mol%), DBU (116 µL, 0.8 mmol, 20.0 mol%), oxidant (2.45 g, 6.0 mmol, 1.5 equiv) and 3Å MS (1.5 g ) in THF (0.1 M, 40 mL) at -2 °C for 48 h. 3Å MS was filtered through a pad of celite and the crude reaction mixture was concentrated and purified by gradient column chromatography from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to afford the desired compound 10 (1.0 g, 58%) as white solid , along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis. HPLC: The enantiomeric excess (% of ee = 87 of both the diastereoisomer) was determined by HPLC analysis. The enantioselectivity of the product was further improved by crystallization from EtOAc and hexane to afford (550 mg, crystallization yield 55%) of 10 with enantiomeric excess (% of ee = 96 of both the diastereoisomer). Compound 31: Prepared according to GP-4 (step-2), combining glutarimide 10 (545 mg, 1.27 mmol, 1.0 equiv), panisidine (935 mg, 7.60 mmol, 6.0 equiv), and LiCl (5.3 mg, 0.13 mmol, 0.1 eq.) in THF (0.1 M, 12.6 mL) at 160 °C for 72 h. 2(M) HCl was added to it and the reaction mixture was extracted with EtOAc. The crude reaction mixture was purified by column chromatography from EtOAc:Hexane (35:65) to afford the desired compound 31 (300 mg, 51%, combined yield ) as off-white solid along with the non separable minor diastereoisomer. The diastereomeric ratio (dr) determined to be 4:1 by 1H NMR analysis.1H NMR (500 MHz, CDCl3) δ = 8.29 (s, 1H minor), 8.13 (s, 1H major), 7.32 (d, J = 9.0 Hz, 1H major), 7.27-7.25 (m, 3H2H-major+1H-minor), 7.17 (d, J = 8.5 Hz, 1H minor), 7.08-7.05 (m, 4H2H-major+2H-minor), 7.08-7.03 (m, 6H2Hmajor+4H-minor), 7.00-6.94 (m, 6H4H-major+2H-minor), 6.83-6.79 (m, 3H2H-major+1H-minor), 4.15 (dd, J = 11.5, 6.0 Hz, 1H major), 4.094.06 (m, 1Hminor), 3.94 (d, J = 5.0 Hz, 1H major), 3.89 (d, J = 5.0 Hz, 1H minor), 3.83 (s, 3H minor), 3.81 (s, 3H major), 3.77 (s, 3H major), 3.76 (s, 3H minor), 3.72-3.66 (m, 1H minor), 3.39 (dd, J = 17.5, 5.5 Hz, 1H major), 3.12 (dd, J = 17.5, 5.5 Hz, 1H minor),


Page 15 of 18 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


11.5 Hz, 1H), 2.29 (dt, J = 11.5, 4.0 Hz, 1H), 2.23-2.16 (m, 1H), 1.93 (ddd, J = 16.5, 11.5, 3.0 Hz, 1H), 1.86-1.83 (m, 1H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 154.0, 152.1, 146.2, 144.3, 142.4, 128.7, 127.5, 126.7, 119.0, 114.9, 114.5, 114.1, 56.5, 55.8, 55.6, 52.2, 47.4, 47.3, 41.6, 34.6 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H31N2O2 403.2386; found 403.2385. IR (Neat) ѵmax = 3400, 3027, 2928, 2831, 1508, 1463, 1236, 1036, 702, 530 cm-1. HPLC: The enantiomeric excess (% of ee = 97) was determined by HPLC analysis using Daicel Chiralpak IA-3 column: n-hexane:iPrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 19.55 min, τminor = 17.72 min. Synthetic application-ll: Compound 39: To a 30 ml pressure tube equipped with a magnetic stir bar, was added glutarimide 4 (400 mg, 0.48 mmol, 1.0 equiv), ethanol (2.4 mL, 0.2 M) and 1(M) HCl (2.4 mL). The reaction mixture was allowed to heat at 80 °C for 12 h. After complete consumption of the glutarimide 4 (determined by TLC analysis), excess ethanol was removed under reduced pressure and the reaction mixture was extracted with EtOAc. The combined organic layer was washed with a brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Hexane/EtOAc = 4:1) to afford the title compound 39 (350 mg, 79%) as white solid. 1H NMR (500 MHz, CDCl3) δ = 9.39 (s, 1H), 8.84 (s, 1H), 7.417.39 (m, 2H), 7.26-7.17 (m, 5H), 7.14-7.09 (m, 2H), 7.04-7.03 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 3.98-3.90 (m, 3H), 3.74 (d, J = 9.5 Hz, 1H), 2.99 (dd, J = 16.0, 6.0 Hz, 1H), 2.84 (dd, J = 15.5, 9.0 Hz, 1H), 2.34 (s, 3H), 2.56 (s, 3H), 1.04 (t, J = 7.5 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 171.4, 167.8, 167.5, 139.1, 138.9, 138.6, 137.2, 136.8, 128.8, 128.5, 127.9, 127.5, 125.6, 121.2, 120.9, 117.7, 117.4, 61.2, 60.6, 45.5, 38.2, 21.4, 21.3, 13.9 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C28H31N2O4 459.2284; found 459.2285. IR (Neat) ѵmax = 3283, 2990, 2918, 1673, 1736, 1550, 1259, 1169, 780 cm-1. HPLC: The enantiomeric excess (% of ee = 97) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 9.21 min, τminor = 8.15 min. Compound 40: To an oven-dried 25.0 mL schlenk tube equipped with a magnetic stirring bar, 39 (200 mg, 0.22 mmol, 1.0 equiv) and anhydrous THF (2.1 mL, 0.1 M) were added under argon atmosphere. The solution was allowed to cool to 0 °C. To the cold solution, LAH (16.6 mg, 0.44 mmol, 2.0 equiv) was added maintaining a continuous flow of argon. The mixture was stirred at 25 oC for 6 h. The reaction was quenched with water and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Hexane/EtOAc = 3:2, Rf = 0.8) to afford the title compound 40 (150 mg, 82%) as white solid. 1H NMR (500 MHz, CDCl ) δ = 9.60 (s, 1H), 8.86 (s, 1H), 3 7.42-7.40 (m, 2H), 7.26-7.17 (m, 5H), 7.14-7.08 (m, 3H), 7.03-7.02 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 10.5 Hz, 1H), 3.65-3.58 (m, 2H), 3.513.46 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.10-2.03 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 168.4, 168.2,

(m, 2H), 1.35 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 175.9, 162.7, 160.8 (d, J = 243.5 Hz) , 158.9, 153.9, 152.7, 145.6, 139.3, 131.3, 129.4, 129.3 (d, J = 7.3 Hz), 128.8, 128.5, 127.9, 119.1, 115.2, 115.1 (d, J = 21.3 Hz), 114.5, 114.1, 83.1, 55.6, 55.3, 54.0, 51.8, 49.8, 45.7, 32.9, 27.8 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C31H36 FN2O5 535.2603; found 535.2604. IR (Neat) ѵmax = 2935, 2844, 1729, 1699, 1509, 1289, 1247, 1151, 777 cm-1. HPLC: The enantiomeric excess (% of ee = 95, major diastereoisomer) and diastereomeric ratio (dr = 97:3) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 12.93 min, τminor = 23.26 min for minor diastereoisomer and τminor = 17.14 min, τmajor = 10.66 min for major diastereoisomer. Compound 37: Prepared according to GP-4 (step-5), combining 35 (35.0 mg, 0.066 mmol, 1.0 equiv) and DIBALH (0.33 mL, 1(M) in THF) in THF (0.1 M, 0.7 mL) at 0 °C to rt for 3h. The reaction mixture was quenched and extracted with EtOAc. The crude reaction mixture was purified by column chromatography from EtOAc:Hexane (20:80) to afford the desired compound 37 (13 mg, 62%) as off-white solid with excellent diastereomeric ratio. 1H NMR (500 MHz, CDCl3) δ = 7.21-7.18 (m, 2H), 7.02-6.98 (m, 4H), 6.87-6.85 (m, 2H), 3.84-3.80 (m, 1H), 3.78 (s, 3H), 3.62-3.58 (m, 1H), 3.47 (dd, J = 11.0, 3.5 Hz, 1H), 3.31 (dd, J = 10.5, 7.0 Hz, 1H), 2.72 (dt, J = 11.5, 2.5 Hz, 1H), 2.61 (t, J = 11.0 Hz, 1H), 2.44 (dt, J = 11.5, 4.0 Hz, 1H), 2.16-2.09 (m, 1H), 2.01-1.87 (m, 2H) ppm. 13C{1H} NMR (125 MHz, CDCl ) δ = 162.6, 160.6 (d, J = 3 243.6 Hz), 154.0, 146.2, 139.9, 128.8, 128.7 (d, J = 7.5 Hz), 118.9, 115.5, 115.3 (d, J = 20.2 Hz), 114.5, 63.8, 55.6, 55.2, 52.1, 44.3, 34.5 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C19H23FNO2 316.1707; found 316.1706. IR (Neat) ѵmax = 2925, 2834, 1667, 1609, 1509, 1243, 826 cm-1. HPLC: The enantiomeric excess (% of ee = 95, major diastereoisomer) and diastereomeric ratio (dr = 97:3) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:iPrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 11.92 min, τminor = 11.52 min for minor diastereoisomer and τminor = 8.40 min, τmajor = 10.04 min for major diastereoisomer. [α]D 25 = -2.84 (c = 0.5, CHCl3). Synthesis of amino piperidine 38: To an oven-dried 25.0 mL schlenk tube equipped with a magnetic stirring bar, 30 (100 mg, 0.22 mmol, 1.0 equiv) and super dry THF (2.2 mL, 0.1 M) were added under argon .The solution was cooled to 0 °C and LAH (85 mg, 2.24 mmol, 1.0 equiv) was added to the reaction mixture maintaining the continuous flow of argon. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with a brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Hexane/EtOAc = 3:2, Rf = 0.8) to afford the title compound 39 (52mg , 62%) as white solid. 1H NMR (500 MHz, CDCl3) δ = 7.28-7.25 (m, 2H), 7.18 (d, J = 8.0 Hz, 3H), 6.88 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 9.0 Hz, 2H), 6.25 (d, J = 9.0 Hz, 2H), 3.763.73 (m, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.54-3.52 (m, 1H), 3.04 (brs, 1H), 2.86 (dd, J = 13.0, 3.5 Hz, 1H), 2.73 (dd, J = 12.0, 8.0 Hz, 1H), 2.65 (dt, J = 12.0, 2.5 Hz, 1H), 2.42 (t, J =



Page 16 of 18

with the formal synthesis of (±)-paroxetine. We are grateful for the help of all analytical departments of IACS.

139.7, 138.9, 138.6, 137.3, 136.9, 128.8, 128.6, 128.5, 128.1, 127.4, 125.6, 125.5, 121.2, 120.9, 117.7, 117.4, 62.0, 60.4, 46.7, 35.8, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C26H28N2O3Na 439.1998; found 439.1996. IR (Neat) ѵmax = 3285, 2935, 1675, 1614, 1546, 1490, 1453, 1194, 779, 700 cm-1. HPLC: The enantiomeric excess (% of ee = 97) were determined by HPLC analysis using Daicel Chiralpak IE3 column: n-hexane:i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 15.33 min, τminor = 14.40min. Compound 41: Methanesulfonyl chloride (MsCl) (48.0 μL, 0.62 mmol, 2.0 equiv) was added to a stirred solution of compound 40 (130.0 mg, 0.31 mmol, 1.0 equiv) in pyridine (0.7 M, 0.44 mL) under argon atmosphere at 0 °C. The resulting heterogeneous mixture was stirred for 2 h and slowly warmed up to room temperature. After complete consumption of the starting material, pyridine was removed under reduced pressure. To the mixture, 5.0 mL water and 25.0 mL EtOAc were added successively. The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The solid residue was purified by column chromatography (SiO2, 30% EtOAcHexane, Rf = 0.52 for the product) to afford the title compound 41 (134.0 mg, 87%) as white solid. Compound 41 was crystallized from the slow evaporation of its EtOAc solution. Absolute configuration of compound 41 was unambiguously determined by the single crystal X-ray analysis. 1H NMR (300 MHz, CDCl3) δ = 9.52 (s, 1H), 8.83 (s, 1H), 7.52-7.39 (m, 2H), 7.31-7.08 (m, 7H), 7.03-6.97 (m, 3H), 6.91-6.89 (m, 1H), 4.12-4.05 (m, 1H), 3.92-3.84 (m, 1H), 3.73 (d, J = 10.5 Hz, 1H), 3.57 (dt, J = 10.8, 3.9 Hz, 1H), 2.79 (s, 3H), 2.49-2.39 (m, 1H), 2.36 (s, 3H), 2.25 (s, 3H), 2.18-2.12 (m, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 167.8, 167.5, 139.0, 138.6, 138.3, 137.2, 136.7, 128.9, 128.9, 128.6, 127.9, 127.8, 125.8, 125.7, 121.2, 120.9, 117.6, 117.4, 67.3, 62.3, 45.8, 37.1, 32.5, 21.4, 21.3, ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for C27H31N2O5S 495.1954; found 495.1951. IR (Neat) ѵmax = 3289, 3035, 2918, 1596, 1456, 1680, 1555, 1490, 1354, 1175, 961, 780 cm-1. HPLC: The enantiomeric excess (% of ee = 97) were determined by HPLC analysis using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.63 min, τminor = 14.44 min.

REFERENCES (1) (a) Li, W.; Georg, G. I. A concise formal total synthesis of lactimidomycin. Chem. Commun. 2015, 51, 8634; (b) Sun, D.; Sun, W.; Yu, Y.; Li, Z.; Deng, Z.; Lin, S. A new glutarimide derivative from marine sponge-derived Streptomyces anulatus S71. Nat. Prod. Res. 2014, 28, 1602; (c) Rajski, S. R.; Shen, B. Multifaceted modes of action for the glutarimide-containing polyketides revealed. ChemBioChem 2010, 11, 1951. (2) (a) Guo, H.-f.; Li, Y.-h.; Yi, H.; Zhang, T.; Wang, S.-q.; Tao, P.-z.; Li, Z.-r. Synthesis, structures and anti-HBV activities of derivatives of the glutarimide antibiotic cycloheximide. J. Antibiot. 2009, 62, 639; (b) Bartlett, J. B.; Dredge, K.; Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 2004, 4, 314; (c) Popa, D.; Loghin, F.; Imre, S.; Curea, E. The study of codeine–gluthetimide pharmacokinetic interaction in rats. J. Pharm. Biomed. Anal. 2003, 32, 867; (d) Kiyota, H.; Shimizu, Y.; Oritani, T. Synthesis of actiketal, a glutarimide antibiotic. Tetrahedron Lett. 2000, 41, 5887; (e) ElZanfally, S.; Khalifa, M.; Abou-Zeid, Y. M. Derivatives of glutarimide likely to possess therapeutic activity. J. Pharm. Sci. 1965, 54, 467. (3) (a) Zhang, Y.; Liao, Y.; Liu, X.; Yao, Q.; Zhou, Y.; Lin, L.; Feng, X. Catalytic Michael/Ring-Closure Reaction of α,βUnsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (−)-Paroxetine. Chem. Eur. J. 2016, 22, 15119; (b) Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. Chemoselective Hydrogenation of Imides Catalyzed by Cp*Ru(PN) Complexes and Its Application to the Asymmetric Synthesis of Paroxetine. J. Am. Chem. Soc. 2007, 129, 290; (c) de Gonzalo, G.; Brieva, R.; Sánchez, V. M.; Bayod, M.; Gotor, V. Enzymatic Resolution of trans-4-(4‘Fluorophenyl)-3-hydroxymethylpiperidines, Key Intermediates in the Synthesis of (−)-Paroxetine. J. Org. Chem. 2001, 66, 8947. (4) (a) Bursavich, M. G.; Rich, D. H. Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles. J. Med. Chem. 2002, 45, 541; (b) Bourin, M.; Chue, P.; Guillon, Y. Paroxetine: A Review. CNS Drug Rev. 2001, 7, 25; (c) Gunasekara, N. S.; Noble, S.; Benfield, P. Paroxetine. Drugs 1998, 55, 85. (5) Some selected reviews on NHC-catalysis: (a) Murauski, K. J. R.; Jaworski, A. A.; Scheidt, K. A. A continuing challenge: Nheterocyclic carbene-catalyzed syntheses of γ-butyrolactones. Chem. Soc. Rev. 2018, 47, 1773; (b) Zhang, C.; Hooper, J. F.; Lupton, D. W. N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl Azolium. ACS Catal. 2017, 7, 2583; (c) Yetra, S. R.; Patra, A.; Biju, A. T. Recent Advances in the N-Heterocyclic Carbene (NHC)Organocatalyzed Stetter Reaction and Related Chemistry. Synthesis 2015, 47, 1357; (d) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic Reactions Enabled by NHeterocyclic Carbenes. Chem. Rev. 2015, 115, 9307; (e) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. An overview of Nheterocyclic carbenes. Nature 2014, 510, 485; (f) Grossmann, A.; Enders, D. N-Heterocyclic Carbene Catalyzed Domino Reactions. Angew. Chem. Int. Ed. 2012, 51, 314; (g) Douglas, J.; Churchill, G.; Smith, A. D. NHCs in Asymmetric Organocatalysis: Recent Advances in Azolium Enolate Generation and Reactivity. Synthesis 2012, 44, 2295; (h) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Employing homoenolates generated by NHC catalysis in carbon–carbon bond-forming reactions: state of the art. Chem. Soc. Rev. 2011, 40, 5336. (6) Some selected examples of NHC-catalyzed enantioselective synthesis of six-membered heterocycles via [3+3] annulation: (a) Zhao, C.; Guo, D.; Munkerup, K.; Huang, K.-W.; Li, F.; Wang, J. Enantioselective [3+3] atroposelective annulation catalyzed by Nheterocyclic carbenes. Nat. Commun. 2018, 9, 611; (b) Yi, L.; Zhang, Y.; Zhang, Z.-F.; Sun, D.; Ye, S. Synthesis of Dihydropyridinone-

ASSOCIATED CONTENT Supporting Information Supporting Information: 1H and 13C spectra and HPLC traces of compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Corresponding Author * E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We acknowledge the generous financial support from Science and Engineering Research Board, India (EMR/2016/006344) and CSIR for fellowship to AP and SS. We thank Mr. Partha Mitra and Mr. Manish Jana for helping with single crystal X-ray analysis. Mr. Bhaskar Deb Mondal is acknowledged for helping


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Fused Indoles and α-Carbolines via N-Heterocyclic CarbeneCatalyzed [3 + 3] Annulation of Indolin-2-imines and Bromoenals. Org. Lett. 2017, 19, 2286; (c) Li, G.-T.; Li, Z.-K.; Gu, Q.; You, S.-L. Asymmetric Synthesis of 4-Aryl-3,4-dihydrocoumarins by NHeterocyclic Carbene Catalyzed Annulation of Phenols with Enals. Org. Lett. 2017, 19, 1318; (d) Xie, D.; Yang, L.; Lin, Y.; Zhang, Z.; Chen, D.; Zeng, X.; Zhong, G. Rapid Access to Spirocylic Oxindoles: Application of Asymmetric N-Heterocyclic Carbene-Catalyzed [3 + 3] Cycloaddition of Imines to Oxindole-Derived Enals. Org. Lett. 2015, 17, 2318; (e) Gao, Z.-H.; Chen, X.-Y.; Zhang, H.-M.; Ye, S. NHeterocyclic carbene-catalyzed [3+3] cyclocondensation of bromoenals with aldimines: highly enantioselective synthesis of dihydropyridinones. Chem. Commun. 2015, 51, 12040; (f) Cheng, J.; Huang, Z.; Chi, Y. R. NHC Organocatalytic Formal LUMO Activation of α,β-Unsaturated Esters for Reaction with Enamides. Angew. Chem. Int. Ed. 2013, 52, 8592; (g) Zhu, Z.-Q.; Zheng, X.-L.; Jiang, N.-F.; Wan, X.; Xiao, J.-C. Chiral N-heterocyclic carbene catalyzed annulation of α,β-unsaturated aldehydes with 1,3dicarbonyls. Chem. Commun. 2011, 47, 8670; (h) Wanner, B.; Mahatthananchai, J.; Bode, J. W. Enantioselective Synthesis of Dihydropyridinones via NHC-Catalyzed Aza-Claisen Reaction. Org. Lett. 2011, 13, 5378; (i) Sun, F.-G.; Sun, L.-H.; Ye, S. N-Heterocyclic Carbene-Catalyzed Enantioselective Annulation of Bromoenal and 1,3-Dicarbonyl Compounds. Adv. Synth. Catal. 2011, 353, 3134; (j) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Enantioselective N-Heterocyclic Carbene-Catalyzed Michael Addition to α,β-Unsaturated Aldehydes by Redox Oxidation. Org. Lett. 2011, 13, 4080; (k) De Sarkar, S.; Studer, A. NHC-Catalyzed Michael Addition to α,β-Unsaturated Aldehydes by Redox Activation. Angew. Chem. Int. Ed. 2010, 49, 9266; (l) Ryan, S. J.; Candish, L.; Lupton, D. W. N-Heterocyclic Carbene-Catalyzed Generation of α,β-Unsaturated Acyl Imidazoliums: Synthesis of Dihydropyranones by their Reaction with Enolates. J. Am. Chem. Soc. 2009, 131, 14176. (7) Mondal, S.; Ghosh, A.; Mukherjee, S.; Biju, A. T. NHeterocyclic Carbene-Catalyzed Enantioselective Synthesis of Spiroglutarimides via α,β-Unsaturated Acylazoliums. Org. Lett. 2018, 20, 4499. (8) (a) Santra, S.; Porey, A.; Jana, B.; Guin, J. N-Heterocyclic carbenes as chiral Brønsted base catalysts: a highly diastereo- and enantioselective 1,6-addition reaction. Chem. Sci. 2018, 9, 6446; (b) Santra, S.; Porey, A.; Guin, J. 1,6-Conjugate Addition of 1,3Dicarbonyl Compounds to para-Quinone Methides Enabled by Noncovalent N-Heterocyclic Carbene Catalysis. Asian J. Org. Chem. 2018, 7, 477; (c) Porey, A.; Santra, S.; Guin, J. Direct N-Acylation of Sulfoximines with Aldehydes by N-Heterocyclic Carbene Catalysis under Oxidative Conditions. Asian J. Org. Chem. 2016, 5, 870. (9) While different malonamide derivatives were examined in this reaction (see`, Supporting Information), the m-tolyl aniline derived malonamide 2c afforded the desired product in good isolated yield and stereoselectivity. This is may be due to better solubility of 2c in the reaction medium than the other amides tested in this reaction. (10) CCDC 1878492, 1878493 and 1878494 contain the supplementary crystallographic data for 15 and 28 and 41 respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre (see also Supporting Information). (11) Very low solubility of malonamide derived from p-methoxy aniline in the reaction medium resulted in unsatisfactory outcome of the reaction. Thus, transamidation with p-methoxy aniline was performed at the beginning of paroxetine synthesis. (12) Hughes, G.; Kimura, M.; Buchwald, S. L. Catalytic Enantioselective Conjugate Reduction of Lactones and Lactams. J. Am. Chem. Soc. 2003, 125, 11253; we could not obtained the reported optical rotation value; however, sign of the optical rotation is in good agreement with the reported data. (13) White, N. A.; Ozboya, K. E.; Flanigan, D. M.; Rovis, T. Rapid Construction of (−)-Paroxetine and (−)-Femoxetine via an N-

Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes. Asian J. Org. Chem. 2014, 3, 442. (14) Selected reviews on oxidative NHC-catalysis: (a) Mahatthananchai, J.; Bode, J. W. On the Mechanism of NHeterocyclic Carbene-Catalyzed Reactions Involving Acyl Azoliums. Acc. Chem. Res. 2014, 47, 696; (b) De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Catalysis with N-Heterocyclic Carbenes under Oxidative Conditions. Chem. Eur. J. 2013, 19, 4664. (15) Avery, T. D.; Caiazza, D.; Culbert, J. A.; Taylor, D. K.; Tiekink, E. R. T. 1,2-Dioxines Containing Tethered Hydroxyl Functionality as Convenient Precursors for Pyran Syntheses. J. Org. Chem. 2005, 70, 8344. (16) Li, C.; Chen, H.; Li, J.; Li, M.; Liao, J.; Wu, W.; Jiang, H. Palladium-Catalyzed Regioselective Aerobic Allylic C−H Oxygenation: Direct Synthesis of α,β-Unsaturated Aldehydes and Allylic Alcohols. Adv. Synth. Catal. 2018, 360, 1600. (17) Killoran, P. M.; Rossington, S. B.; Wilkinson, J. A.; Hadfield, J. A. Expanding the scope of the Babler–Dauben oxidation: 1,3oxidative transposition of secondary allylic alcohols. Tetrahedron Lett. 2016, 57, 3954. (18) Kim, E.; Koh, M.; Lim, B. J.; Park, S. B. Emission Wavelength Prediction of a Full-Color-Tunable Fluorescent Core Skeleton, 9-Aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one. J. Am. Chem. Soc. 2011, 133, 6642. (19) Watanabe, H.; Ariyoshi, T.; Ozaki, A.; Ihara, M.; Ono, M.; Saji, H. Synthesis and biological evaluation of novel radioiodinated benzimidazole derivatives for imaging α-synuclein aggregates. Bioorg. Med. Chem. 2017, 25, 6398. (20) Liu, J.; Zhu, J.; Jiang, H.; Wang, W.; Li, J. Direct Oxidation of β-Aryl Substituted Aldehydes to α,β-Unsaturated Aldehydes Promoted by an o-Anisidine–Pd(OAc)2 Co-catalyst. Chem. Asian J. 2009, 4, 1712. (21) Bouisseau, A.; Gao, M.; Willis, M. C. Traceless RhodiumCatalyzed Hydroacylation Using Alkyl Aldehydes: The Enantioselective Synthesis of β-Aryl Ketones. Chem. Eur. J. 2016, 22, 15624. (22) Olah, G. A.; Spear, R. J. Stable carbocations. CLXXX. Carbon-13 and proton nuclear magnetic resonance spectroscopic study of phenyl-, methyl-, and cyclopropyl-substituted alkenyl (allyl) cations. Further studies of the trend of charge distribution and the relative delocalization afforded by phenyl, methyl, and cyclopropyl. J. Am. Chem. Soc. 1975, 97, 1539. (23) Bouckaert, C.; Serra, S.; Rondelet, G.; Dolušić, E.; Wouters, J.; Dogné, J.-M.; Frédérick, R.; Pochet, L. Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors. E. J. Med. Chem. 2016, 110, 181. (24) Habash, M.; Taha, M. O. Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads. Bioorg. Med. Chem. 2011, 19, 4746. (25) (a) Zhao, C.; Li, F.; Wang, J. N-Heterocyclic Carbene Catalyzed Dynamic Kinetic Resolution of Pyranones. Angew. Chem. Int. Ed. 2016, 55, 1820; (b) Candish, L.; Forsyth, C. M.; Lupton, D. W. N-tert-Butyl Triazolylidenes: Catalysts for the Enantioselective (3+2) Annulation of α,β-Unsaturated Acyl Azoliums. Angew. Chem. Int. Ed. 2013, 52, 9149; (c) Piel, I.; Steinmetz, M.; Hirano, K.; Fröhlich, R.; Grimme, S.; Glorius, F. Highly Asymmetric NHCCatalyzed Hydroacylation of Unactivated Alkenes. Angew. Chem. Int. Ed. 2011, 50, 4983; (d) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Organocatalytic Enantioselective Synthesis of Nitrogen-Substituted Dihydropyran-2-ones, a Key Synthetic Intermediate of 1β-Methylcarbapenems. Org. Lett. 2009, 11, 3934; (e) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Chiral Bifunctional NHeterocyclic Carbenes: Synthesis and Application in the Aza-MoritaBaylis-Hillman Reaction. Synthesis 2008, 2008, 2825; (f) Herrmann, W. A.; Goossen, L. J.; Köcher, C.; Artus, G. R. J. Chiral Heterocylic Carbenes in Asymmetric Homogeneous Catalysis. Angew. Chem. Int. Ed. 1996, 35, 2805.



(26) Hintermann, L.; Dang, T. T.; Labonne, A.; Kribber, T.; Xiao, L.; Naumov, P. The AZARYPHOS Family of Ligands for Ambifunctional Catalysis: Syntheses and Use in Ruthenium-Catalyzed

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anti-Markovnikov Hydration of Terminal Alkynes. Chem. Eur. J. 2009, 15, 7167.


Highly enantioselective synthesis of functionalized glutarimide using

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