Chemo- and Regioselective Asymmetric Synthesis of Cyclic Enamides

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Chemo- and Regioselective Asymmetric Synthesis of Cyclic Enamides Through the Catalytic Umpolung Organocascade Reaction of #-Imino Amides Yasushi Yoshida, Tomohiko Hiroshige, Kazuki Omori, Takashi Mino, and Masami Sakamoto J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01036 • Publication Date (Web): 10 May 2019 Downloaded from http://pubs.acs.org on May 11, 2019

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The Journal of Organic Chemistry

Chemo- and Regioselective Asymmetric Synthesis of Cyclic Enamides Through the Catalytic Umpolung Organocascade Reaction of α-Imino Amides Yasushi Yoshida*, Tomohiko Hiroshige, Kazuki Omori, Takashi Mino, and Masami Sakamoto Soft Molecular Activation Research Center (SMARC), Molecular Chirality Research Center (MCRC), and Graduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522, Japan. ABSTRACT: The efficient chemo- and regioselective catalytic asymmetric syntheses of enamides, which are important core structures of bioactive natural products, have been achieved through the first umpolung organocascade reaction of α-imino amides. A variety of enamides have been synthesized enantioselectively in high yields with up to 99% ee. Notably, both enantiomers of the products can be selectively prepared by the simple pretreatment of the substrate. Mechanistic studies reveal that E/Z-geometry information from the substrate is transferred to the product. The present method can be applied to a wide range of α-imino amides, irrespective of the electronic nature of the substituents. Keywords: asymmetric organocatalysis, enamide, imine, regioselective synthesis, umpolung

INTRODUCTION The catalytic asymmetric umpolung reaction of imines has been extensively researched because it provides chiral amine derivatives in high enantiopurity and with high efficiency.1 In 2015, Deng and co-workers first applied this methodology with a chiral ammonium salt catalyst2 for the reaction of aldimines and trifluoromethyl ketimines with enals to form the corresponding chiral γamino alcohols and carbonyls in up to 99% ee.1a Subsequently, this process has been successfully applied to several important chemical transformations and excellent enantioselectivities have been achieved.1b–h In 2018, Xiao and co-workers reported the first catalytic umpolung [3 + 2] cycloaddition reaction of imines with nitroolefins, which provided chiral pyrrolidines in up to 99% ee.1e We have previously developed an ammonium-salt-catalyzed asymmetric umpolung reaction of α-imino esters with α,β-unsaturated carbonyl compounds to give α-tetrasubstituted unnatural amino acid derivatives in up to 98% ee (Figure 1a).3 Although, the several important research areas have been disclosed by umpolung reaction of imines so far, this concept has considerable potential for the development of more complex molecular transformations such as organocascade reactions.4 In particular, we thought that it would be possible to prepare chiral hemiaminals and cyclic enamides in a highly enantioselective manner by utilizing our previously developed methodology. The chiral hemiaminal skeleton is known to be crucial for the high bioactivity of various pharmaceutical natural products (Figure 2a).5 This skeleton is also recognized as not only an important endpoint, but is also found in useful key intermediates in Mannich, Strecker, and Betti

reactions because it undergoes easy dehydrative decomposition to form a highly reactive iminium salt.6 Therefore, the development of efficient asymmetric synthetic methods for this skeleton is important. However, the catalytic asymmetric synthesis of hemiaminals has rarely been achieved by chiral Brønsted acid catalysis or palladium catalysis.7 Chiral enamides are synthetically challenging but essential structures that are found in many natural products and pharmaceuticals (Figure 2b).8 Owing to their wide applicability in the stereoselective addition of nitrogen functionalities to complex molecules by hydrogenation, cycloaddition, or metal-catalyzed transformations, the asymmetric preparation of these compounds is of great importance.9 Despite their wide applicability in organic synthesis, the efficient catalytic asymmetric preparation of enamides has not been accomplished to date. In this paper, we describe the highly chemo-, regio-, and enantioselective syntheses of chiral enamides by the first catalytic asymmetric umpolung cascade reaction of α-imino amides through a chiral hemiaminal key intermediate (Figure 1b). a) Previous work: Catalytic Asymmetric Umpolung Reaction of Imines X N Ph

Ph N O N

NO2

N

NO2

R3

Br

OTBS R3 2 + R

N R1

Cat. 3 Base CHO

EWG

Ketimine EWG = CF3, Deng, 2015 EWG = COOR, Our Group, 2017

ACS Paragon Plus Environment

NaBH4

R2 NH *

OH

R1 * CF3

High Yields Excellent Enantioselectivities

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

b) This work: Chemoselective Asymmetric Synthesis of Enamides Through Catalytic Umpolung Reaction of α-Imino amide

Cl N Ph O

NO2

N

NO2

R1

R2

N

CHO

R1

Umpolung Organocascade Reaction

2

O

H N

Br

NO2

H

Chiral Catalyst 3 +

OTBS Ph

* OH

NaBH4

HN

R2

R1

O

α-Imino amide 1

N

R2

3a (2 mol%) K2CO3 aq. (200 mol%) CHO toluene (0.05 M) -20 to 0 °C

+

O

N

5 Hemiaminal

H N

Ph

HN R1

N

➢ Preparations of Both Enantiomers

Bn

H

O

H N

N Ph

NaBH4

OH HN Ph

Bn

Bn

O

O

5a Major: 42% (90% ee) Minor: 22% (90% ee)

4a

2

N

Scheme 1. Catalytic asymmetric umpolung synthesis of hemiaminal 5.

R2

➢ Mechanistic Study

O

NO2 O2N

O

1a

O2N

Chemoselective Transformation

Ph

N

O

H N

Ph N

NO2

N

Page 2 of 14

Enamide 6 High yields (up to 85%) High enantioselectivities (up to 99% ee)

Figure 1. Catalytic asymmetric umpolung reactions of imines in (a) previous work and (b) this work.

Table 1. Chemoselective transformation of hemiaminal 5a into enamide 6a.[a]

O O

S

O N H

O H N

NH O

N

N H H N

O

H N

b)

OH

O MeN

OH O

O

(-)-Apicularen A Anticancer Drug

O

O

NH O O

N

Bn

+

Solvent (0.01 M) Temp., Time

N

N H H N

O MeN

H O

Micropeptin T-20

H N

OH O

O

H

Br

O N

H

RESULTS AND DISCUSSION 10

We first examined the reaction of α-imino amide 1a with acrolein in the presence of aqueous K2CO3 and chiral phase-transfer catalyst 3a in toluene at 0 °C, which fortunately produced chiral hemiaminal 5a in moderate yield with high enantioselectivity (Scheme 1). With good conditions for the enantioselective preparation of hemiaminal 5a in hand, chemoselective derivatizations were conducted to show the high potential of this approach for the synthesis of complex molecules (Table 1).11 When hemiaminal 5a was treated with benzoic acid in DMSO at 100 °C, dehydrative formation of both enamide 6a and aminal 7a was observed in a poor ratio (Table 1, entry 1). Screening of acidic additives and solvents revealed that although benzoic acid derivatives and pyridinium p-toluenesulfonate (PPTS) produced enamide 6a in low chemoselectivities, the treatment of 5a with SOCl2 in THF exclusively generated enamide 6a in a quantitative yield at room temperature (Table 1, entries 1–7). The use of DMF as a solvent in the present reaction gave a complex mixture and the desired product was obtained in low yield, probably because DMF was decomposed under the acidic conditions, which accelerated the decomposition of the products (Table 1, entry 4).

N O

5a 90% ee

6a

N Bn

N

Ph

Bn

O

7a

Temp. Time Yield of Yield of (°C) (h) 6a (%)[b] 7a (%)[b]

Entry

Additive

Solvent

1

Benzoic acid

DMSO

100

2

13

72

2

p-Anisic acid

DMSO

100

2

69

10

3

p-Nitrobenzoic acid

DMSO

100

2

65

16

4

Benzoic acid

DMF

100

17

14

0

5

Benzoic acid

DMA

100

22

23

27

6

PPTS

Toluene

100

0.5

70

8

7[c]

Thionyl chloride

THF

r.t.

15

Quant.

Trace

Repellent

Figure 2. Bioactive natural products or pharmaceuticals containing (a) chiral hemiaminal and (b) chiral enamide skeletons.

HN Ph

O

OH

O

H N

HN Ph OH

Somamide A

O NaO P O ONa

* OH

OH O

O

Additive (3 equiv) O

O O

NO2

NO2

NO2 a)

[a] Conditions: 5a (1.0 equiv), additive (3.0 equiv), solvent (0.01 M). [b] All yields were determined by NMR using 1,3,5-trimethoxybenzene as an internal standard. [c] With a catalytic amount of DMF.

With the best conditions for the chemo-, regio-, and enantioselective synthesis of chiral enamides in hand, the reaction conditions for their direct synthesis from α-imino amides were optimized (Table 2). Screening of bases in toluene at 0 °C revealed that a strong base, KOH, catalyzed the present reaction efficiently to produce the enamide product in 60% yield with 90% ee (Table 2, entry 2). When the reaction temperature was reduced to -10 °C, the enantioselectivity was increased to 91% ee and the good yield was maintained, but further reduction of the temperature caused the conversion of 1a to decrease (Table 2, entries 1, 4, and 5). In addition, increasing the amount of base had a negative effect on the reaction outcome (Table 2, entry 6). Catalyst screening was performed using the 3b–3c (Table 2, entries 5, 7, and 8). 4Biphenyl-substituted 3b produced the chiral enamide in 64% yield with 91% ee. However, when 3c bearing a NMe2 group on the pyrimidine ring was used for the


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present reaction (using 0.0125 M 1a in toluene), the enantioselectivity increased to 95% ee with an isolated product yield of 74%.12

NO2 N N Ph

Ph N

N

H N

O N

Table 2. Optimization for the direct asymmetric synthesis of enamides.[a] 1)

NO2

CHO

NO2

3 (2 mol%) SOCl2 (5 equiv) Base (X mol%) DMF cat. toluene (0.05 M),Temp. N

H N

Ph O

THF r.t., 15 h

2) NaBH4 (5 equiv) ethanol/CH2Cl2 Bn -20 °C

HN Ph

N

Bn

O

6a

1a

Temp. Time (h) (°C)

Yield (%)[b]

ee (%)[c]

15

51

89

0

15

60

90

0

15

25

90

3a

-10

15

60

91

3a

-20

15

46

92

50

3a

-20

15

40

92

20

3b

-20

2

64

91

Entry

Base

X

3

1

K2CO3 aq.

200

3a

0

2

KOH aq.

20

3a

3

CsOH aq.

20

3a

4

KOH aq.

20

5

KOH aq.

20

6

KOH aq.

7

KOH aq.

8

[d]

KOH aq.

20

3c

-10

2

74

[e]

N

OTBS 4-Biphenyl

Figure 3. Plausible transition state model for the asymmetric umpolung sequence. Next, the scope for the R1 group was investigated. A phenyl group and aromatic groups with electron-donating substituents were successfully applied for the present umpolung reaction, forming the corresponding enamides in high yields with 91–98% ee (6j–6m). o-Tolyl-substituted 6l was obtained in only 36% yield but 91% ee owing to a low conversion caused by steric hindrance. Electronwithdrawing substituents were also tolerated, with the pCF3C6H4-substituted substrate providing 6n in a high yield with 88% ee. Interestingly, in every case, the enamide was regio- and chemoselectively synthesized in a >20:1 ratio.13

95

[a] Conditions: 1a (1.0 equiv), acrolein (2.0 equiv), 3 (2 mol%), base (33% K2CO3 aq., 50% CsOH aq., or 50% KOH aq.; X mol%), toluene (0.05 M). [b] All yields were determined by NMR using 1,3,5-trimethoxybenzene as an internal standard, unless otherwise stated. [c] The ees were determined by chiral HPLC analysis. [d] 0.0125 M in toluene. [e] Yield of isolated product. Cl

3b: R =

R

N Ph

Ph N

O N 4-Biphenyl

N Br

OTBS 4-Biphenyl

N

3c: R =

N Ph

Bn

O

4-Biphenyl

Ph N

3b-c

With the optimized reaction conditions in hand, the substrate scope for the present catalytic asymmetric enamide formation reaction was examined (Table 3). First, the effect of substituents on the benzylic imine moiety was investigated. When 4-NO2-substituted 1a was applied, 6a was obtained in high yield with 95% ee, but nonsubstituted 6b and 4-CF3-substituted 6c were not obtained and obtained in low yield, respectively. These observations indicate that the 4-NO2C6H4CH2 group on the imine moiety is essential for both high reactivity and enantioselectivity by formation of π-stacking complex between an electron-deficient aromatic ring with 3c (Figure 3). Variation of the R2 moiety revealed that benzyl groups with both electron-donating and withdrawing substituents were well tolerated, irrespective of the steric bulkiness, giving corresponding 6a and 6d–6i in high yields with 94–99% ee. Interestingly, the highest enantioselectivity was observed for p-bromobenzyl-substituted 6g (99% ee). In addition to substituted benzyl groups, a butyl group was successfully applied, giving 6i in high yield with 93% ee.



To gain mechanistic insight, several reactions were conducted (Scheme 2). When an E,Z-mixture of 1k was applied to the present asymmetric umpolung sequence, the corresponding enamide was isolated in almost the same yield but with only 60% ee. This result suggested that the E,Z-ratio of the substrate strongly affected the enantiopurity of the product.14 The drastic decrease of enantioselectivity clearly showed that the nucleophile in the enantioselectivity-determining step retains the double bond configuration of the substrate. Additionally, when 1k was isomerized to aldimine rac1k′, which was expected to form the same 2-azaallyl anion intermediate as α-imino amide 1k, and then subjected to the optimized reaction conditions for the asymmetric synthesis of enamides, product 6k was isolated in almost the same yield but the completely opposite enantioselectivity (90% ee for the (R)-isomer). This result indicated that although the carbon–nitrogen single bond of 1k′ could easily rotate, the more conformationally stable isomer existed exclusively at the reaction temperature. Subsequent reaction of 1k′ with base and a chiral ammonium salt catalyst formed ion pair B, which was the same as that derived from E-1k. Thus, our present reaction provides a complementary method to the asymmetric α-alkylation of aldimine for the selective preparation of both enantiomers.15 To the best of our knowledge, this is the first example to reveal that the E,Z-information of the nucleophilic imine moiety affects the stereoselectivity of the product. NO2

1)

Table 3. Direct catalytic asymmetric synthesis of various enamides from α-imino amides.[a]

H N O

X

N

H N

R1

O

HN R1

THF r.t., 15 h

2) NaBH4 (5 equiv) ethanol/CH2Cl2 -20 °C

R2

N

R2

O

6

1 NO2

CF3

HN

HN

HN

N

N

N

O

O

O

6b No Reaction

6a 74%, 95% ee NO2

6c 28%, 7% ee

NO2

NO2

OMe HN

HN

HN

N

N

O

N

O

O

6e 84%, 96% ee

6d 70%, 95% ee NO2

6f 64%, 94% ee

NO2

NO2

Br HN

CF3

HN N

HN

N

O

N

O

Bu

O

6g 84%, 99% ee

6h 84%, 95% ee

NO2

NO2

HN

HN

6i 66%, 93% ee NO2

HN

N

HN

THF r.t., 15 h

N

Bn

O

(S)-6k 64%, 60% ee

1k E : Z = 1 : 5.1

N

NO2

O

O

6j 77%, 98% ee

6k 70%, 96% ee NO2

NR*3

N

Bn

O

rac-1k’

H N O

B

Scheme 2. Control experiments.

N

N HN

Bn

HN

HN

As above H N

6l 36%, 91% ee

NO2

DBU (20 mol%) N

N

O

NO2 NO2

toluene r.t., 30 min.

CHO

3c (2 mol%) SOCl2 (5 equiv) KOH aq. (20 mol%) DMF cat. toluene (0.0125 M), -10 °C

NO2

CHO

2) NaBH4 (5 equiv) ethanol/CH2Cl2 Bn -20 °C

1k

1)

X

3c (2 mol%) SOCl2 (5 equiv) KOH aq. (20 mol%) DMF cat. toluene (0.0125 M), -10 °C N

Page 4 of 14

N

Bn

O

(R)-6k 49%, 90% ee

MeO

O

6m 64%, 97% ee

F3C

O

6n 56%, 88% ee

[a] Conditions: 1 (1.0 equiv), acrolein (2.0 equiv), 3c (2 mol%), 50% KOH aq. (20 mol%), toluene (0.0125 M), -10 °C. All yields are for isolated products. The ees were determined by chiral HPLC analysis. Every product was obtained in a 6:7 ratio of >20:1, except for 6b.


Page 5 of 14

The Journal of Organic Chemistry Ar

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

OH N

N

R1

O

R2

8

N

KHCO3

Q

KBr

O

3

R2

1

N

EXPERIMENTAL SECTION

R2

O

Q

1

B

E

N R1

N

Q

Ar

Q

O

D Ar

O N

Cl

O S

Ar H

Cl

H

HN

R2

HCl

O

Hemiaminal 5

R1

O N

H N

N R1

Proton transfer

R2

R

O

S 2O

Q

H

O

H

O Ar

CHO

Michael addition

Cyclization

R1

R2

O

N

O

HN

H N

R1

KOH

A

R1

N

R1

R2 Ar

Cation exchange

O Q N

Ar N

H N

R1

K

Br

Protonation

Ar

H 2O

Ar

K2CO3

H

O

Ar H N

N R1

R2

O

O

C

C’

R2

Ar

Cl HN

N

R1 SO2 HCl

R2

O

Enamide 6

BzOH

Ar HN

R1

BzO H O H N 2 R O

Ar

Ar HN

R1 H 2O

N

N R2

O BzO

Mechanistic studies suggested that the reaction intermediate maintained the E/Z-geometry information from the substrate. Both enantiomers of the products could be successfully synthesized by simple pretreatment of the substrate with DBU. Further investigations on the bioactivity of optically active enamides and the detailed chemical structure of the 2-azaallyl anion are ongoing.

R1

N

R2

O

Aminal 7

Figure 4. Plausible reaction mechanism for the asymmetric umpolung sequence.16

From the observed substrate scope and the control experiments, a plausible reaction mechanism for the present catalytic asymmetric umpolung reaction was proposed (Figure 4). Irreversible deprotonation at the benzylic moiety occurred to form ion pair intermediate A, which underwent countercation exchange from potassium to chiral ammonium to provide chiral ion pair B. Michael addition of acrolein to B formed enol intermediate C, which underwent intramolecular proton transfer to afford nitrogen anion intermediate D. Cyclization of D via addition of a nitrogen anion to the formyl group, followed by protonation provided hemiaminal intermediate 8 enantioselectively with regeneration of chiral ammonium catalyst 3. Under the optimized reaction conditions, interconversion between A and B derived from E- or Z-substrates does not proceed, and the E-substrate seems to form the opposite enantiomer to the Z-substrate as the major product. CONCLUSION In summary, the highly enantioselective syntheses of chiral enamides were demonstrated via a catalytic asymmetric umpolung organocascade reaction of α-imino amides. This sequence provides attractive enamides in high yields with excellent chemo-, regio-, and enantioselectivities.

H-, 13C-NMR spectra were recorded with JEOL JMN ECS400 FT NMR, JNM ECA500 FT NMR or Bruker AVANCEIII-400M, DPR-300 (1H-NMR 300, 400, 500 MHz, 13C-NMR 75, 100 or 125 MHz, 19F-NMR 376 MHz). 1 H-NMR spectra are reported as follows: chemical shift in ppm (δ) relative to the chemical shift of CHCl3 at 7.26 ppm, integration, multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants (Hz). 13CNMR spectra reported in ppm (δ) relative to the central line of triplet for CDCl3 at 77 ppm. CF3CO2H used as external standards for 19F-. ESI-MS spectra were obtained with Thermo Fisher, Exactive. Optical rotations were measured with JASCO P-2100 polarimeter. HPLC analyses were performed on a JASCO HPLC system (JASCO PU 980 pump and UV-975 UV/Vis detector). FT-IR spectra were recorded on a JASCO FT-IR system (FT/IR-460 Plus). Mp was measured with AS ONE ATM-02. Column chromatography on SiO2 and neutral SiO2 was performed with Kanto Silica Gel 60 (40-50 µm). All reactions were carried out under Ar atmosphere unless otherwise noted. Commercially available organic and inorganic compounds were used without further purification. All dehydrated solvents were purchased from Wako Pure Chemical Industries, Ltd, and were used without further purification. Catalysts 3 were prepared according to the reported procedure.1a,3 Synthesis of α-Keto amides All known α-keto amides were synthesized according the reported procedure, and the spectroscopic data were matched with the reported value.17 Other new compounds were prepared by the same procedure.17d N-(2-methylbenzyl)-2-oxo-2-phenylacetamide yellow solid, m.p. 88-90 ℃, 1.25 g, 4.95 mmol, 74%; 1HNMR (400 MHz, CDCl3) δ 8.35-8.37 (m, 2H), 7.62-7.66 (m, 1H), 7.47-7.51 (m, 2H), 7.20-7.30 (m, 4H), 4.57 (d, J = 5.9 Hz, 2H), 2.37 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 187.5, 161.3, 136.5, 134.7, 134.5, 133.2, 131.2, 130.6, 128.6, 128.5, 128.1, 126.3, 41.6, 19.1; HRMS (ESI− in MeCN) calcd for C16H14NO2 [M–H]– 252.1030 found 252.1038; IR (NaCl) n 3256, 3058, 1682, 1631, 1550, 1449, 1214, 766, 712, 672 cm-1 N-(4-bromobenzyl)-2-oxo-2-phenylacetamide yellow solid, m.p. 102-103 ℃, 1.50 g, 4.75 mmol, 71%; 1HNMR (400 MHz, CDCl3) δ 8.35-8.37 (m, 2H), 7.62-7.66 (m, 1H), 7.47-7.51 (m, 4H), 7.43-7.43 (m, 1H), 7.20-7.23 (m, 2H), 4.53 (d, J = 6.3 Hz, 2H); 13C{1H}-NMR (101 MHz,



CDCl3) δ 187.3, 161.5, 136.15, 134.6, 133.2, 132.0, 131.3, 129.5, 128.5, 121.8, 42.8; HRMS (ESI− in MeCN) calcd for C15H11BrNO2 [M–H]– 315.9979 found 315.9991; IR (NaCl) n 3210, 3060, 1678, 1636, 1550, 1218, 1067, 1010, 819, 676 cm-1 2-oxo-2-phenyl-N-(4-(trifluoromethyl)benzyl)acetamide yellow solid, m.p. 110-111 ℃, 1.46 g, 4.77 mmol, 72%; 1HNMR (400 MHz, CDCl3) δ 8.35-8.38 (m, 2H), 7.61-7.67 (m, 3H), 7.55-7.55 (m, 1H), 7.44-7.52 (m, 4H), 4.64 (d, J = 6.3 Hz, 2H); 13C{1H}-NMR (101 MHz, CDCl3) δ 187.2, 161.6, 141.2, 134.6, 133.1, 131.2, 130.1 (q, J = 32.3 Hz), 128.6, 128.0, 125.8 (q, J = 3.7 Hz), 124.0 (q, J = 273.2 Hz), 42.9; 19 F-NMR (377 MHz, CDCl3) δ –62.6; HRMS (ESI− in MeCN) calcd for C16H11F3NO2 [M–H]– 306.0747 found 306.0758; IR (NaCl) n 3252, 3080, 1688, 1631, 1319, 1220, 1108, 1065, 701, 633 cm-1 General procedure for the synthesis of α-imino amides 1 4-Nitro benzylamine (3.0 equiv) in CH2Cl2 (0.05 M) was cooled to –40 ºC, corresponding α-keto amides (1.0 equiv) in CH2Cl2 (0.05 M) were added to the pre-cooled flask and stirred for 5 min. TiCl4 (1.0 M in CH2Cl2, 0.6 equiv.) was added to the reaction mixture and it was gradually warmed to –10 ºC. After that it was poured into pre-cooled (–50 ºC) ether (10 times larger volume to total reaction solution) and stirred for 30 min. at the same temperature. Then reaction solution was filtered by Celite and solvents were removed under vacuum to give crude material. The crude product was purified by column chromatography (neutral Silica-gel, ethyl acetate/hexane), followed by re-crystallization (CHCl3/hexane) to give the corresponding α-imino amides. 1b was prepared according to the reported procedure.[18] (Z)-N-benzyl-2-((4-nitrobenzyl)imino)-2-phenylacetamide (1a) colorless solid, m.p. 125-128 ℃, 575 mg, 1.54 mmol, 26% (6.0 mmol scale reaction); 1H-NMR (400 MHz, Acetone-d6) δ 8.42 (brs, 1H), 8.20-8.23 (m, 2H), 7.84-7.87 (m, 2H), 7.657.69 (m, 2H), 7.28-7.51 (m, 8H), 4.88 (s, 2H), 4.66 (d, J = 6.0 Hz, 2H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 166.4, 166.2, 148.6, 147.8, 139.7, 136.0, 131.8, 129.6, 129.4, 129.3, 128.9, 128.4, 128.2, 124.2, 57.3, 43.3; HRMS (ESI+ in MeCN) calcd for C22H20N3O3 [M+H]+ 374.1499 found 374.1498; IR (NaCl) n 3388, 3238, 3058, 1640, 1516, 1449, 1342, 1108, 847, 696 cm-1 (Z)-N-benzyl-2-phenyl-2-((4-(trifluoromethyl)benzyl)imino)acetamide (1c) colorless solid, m.p. 107-109 ℃, 95 mg, 0.24 mmol, 32% (0.75 mmol scale reaction);1H-NMR (400 MHz, Acetoned6) δ 8.42 (brs, 1H), 7.83-7.85 (m, 2H), 7.66-7.68 (m, 2H), 7.60-7.62 (m, 2H), 7.27-7.49 (m, 8H), 4.84 (s, 2H), 4.66 (d, J = 6.0 Hz, 2H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 166.5, 165.9, 145.5, 139.8, 136.2, 131.7, 129.38, 129.35, 129.30, 129.2 (q, J = 32.3 Hz), 128.9, 128.3, 128.2, 125.9 (q,

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J = 4.3 Hz), 125.5 (q, J = 271.7 Hz), 57.6, 43.4 (One carbon peak is overlapped with other peak.); 19F-NMR (377 MHz, Acetone-d6) δ –62.8; HRMS (ESI+ in MeCN) calcd for C23H20F3N2O (M+H) 397.1522 found 397.1518; IR (NaCl) n 3222, 3054, 2938, 1640, 1325, 1172, 1107, 1062, 757, 688 cm-1 (Z)-N-(4-methylbenzyl)-2-((4-nitrobenzyl)imino)-2-phenylacetamide (1d) colorless solid, m.p. 119-120 ℃, 218 mg, 0.56 mmol, 35% (1.58 mmol scale reaction); 1H-NMR (400 MHz, Acetoned6) δ 8.35 (brs, 1H), 8.20-8.23 (m, 2H), 7.84-7.86 (m, 2H), 7.65-7.69 (m, 2H), 7.42-7.51 (m, 3H), 7.31-7.33 (m, 2H), 7.16-7.18 (m, 2H), 4.88 (s, 2H), 4.61 (d, J = 6.0 Hz, 2H), 2.31 (s, 3H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ166.3, 148.7, 147.8, 137.7, 136.7, 136.1, 131.8, 130.0, 129.6, 129.3, 128.9, 128.4, 124.2, 57.3, 43.1, 21.1 (One carbon peak is overlapped with other peak.); HRMS (ESI+ in MeCN) calcd for C23H22N3O3 [M+H]+ 388.1656 found 388.1654; IR (NaCl) n 3232, 3060, 1644, 1519, 1441, 1342, 1056, 813, 740, 690 cm-1 (Z)-N-(2-methylbenzyl)-2-((4-nitrobenzyl)imino)-2-phenylacetamide (1e) colorless solid, m.p. 120-121 ℃, 34 mg, 0.088 mmol, 11% (0.79 mmol scale reaction);1H-NMR (400 MHz, Acetoned6) δ 8.27 (brs, 1H), 8.20-8.23 (m, 2H), 7.84-7.87 (m, 2H), 7.66-7.69 (m, 2H), 7.38-7.51 (m, 4H), 7.16-7.21 (m, 3H), 4.89 (s, 2H), 4.67 (d, J = 5.8 Hz, 2H), 2.40 (s, 3H); 13C{1H}NMR (101 MHz, Acetone-d6) δ 166.3, 148.7, 147.8, 137.2, 137.0, 136.1, 131.8, 131.1, 129.7, 129.6, 129.3, 128.41, 128.36, 126.9, 124.2, 57.3, 41.2, 19.2 (One carbon peak is overlapped with other peak.); HRMS (ESI+ in MeCN) calcd for C23H22N3O3 [M+H]+ 388.1656 found 388.1647; IR (NaCl) n 3185, 3021, 1621, 1512, 1342, 1238, 1068, 851, 736, 690 cm-1 (Z)-N-(4-methoxybenzyl)-2-((4-nitrobenzyl)imino)-2phenylacetamide (1f) colorless solid, m.p. 100-103 ℃, 241 mg, 0.60 mmol, 23% (2.60 mmol scale reaction);1H-NMR (300 MHz, Acetoned6) δ 8.38 (brs, 1H), 8.19-8.23 (m, 2H), 7.77-7.81 (m, 2H), 7.65-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.29-7.39 (m, 3H), 6.97-7.00 (m, 2H), 4.83 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H); 13C{1H}-NMR (76 MHz, Acetone-d6) δ 166.6, 165.6, 162.9, 149.0, 147.7, 139.8, 130.0, 129.6, 129.4, 128.9, 128.6, 128.1, 124.1, 114.6, 57.1, 55.8, 43.3; HRMS (ESI+ in MeCN) calcd for C23H22N3O4 [M+H]+ 404.1605 found 404.1602; IR (NaCl) n 3234, 3062, 1642, 1513, 1445, 1341, 1244, 1059, 807, 691 cm-1 (Z)-N-(4-bromobenzyl)-2-((4-nitrobenzyl)imino)-2-phenylacetamide (1g) colorless solid, m.p. 134-136 ℃, 584 mg, 1.29 mmol, 59% (2.20 mmol scale reaction);1H-NMR (400 MHz, Acetoned6) δ 8.45 (brs, 1H), 8.21-8.24 (m, 2H), 7.83-7.86 (m, 2H), 7.67-7.70 (m, 2H), 7.40-7.57 (m, 7H), 4.89 (s, 2H), 4.64 (d,


Page 7 of 14 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


J = 6.0 Hz, 2H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 166.5, 166.1, 148.6, 147.9, 139.2, 136.0, 132.4, 131.9, 131.0, 129.6, 129.4, 128.4, 124.2, 121.6, 57.3, 42.7; HRMS (ESI+ in MeCN) calcd for C22H19BrN3O3 [M+H]+ 452.0604 found 452.0603; IR (NaCl) n 3232, 3058, 1644, 1517, 1342, 1244, 1040, 823, 695, 651 cm-1 (Z)-2-((4-nitrobenzyl)imino)-2-phenyl-N-(4-(trifluoromethyl)benzyl)acetamide (1h) colorless solid, m.p. 139-140 ℃, 17 mg, 0.039 mmol, 3% (1.30 mmol scale reaction);1H-NMR (400 MHz, Acetoned6) δ 8.54 (brs, 1H), 8.20-8.23 (m, 2H), 7.84-7.87 (m, 2H), 7.67-7.74 (m, 6H), 7.43-7.51 (m, 3H), 4.91 (s, 2H), 4.77 (d, J = 6.0 Hz, 2H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 166.7, 166.0, 148.5, 147.8, 144.3, 135.9, 131.9, 129.8 (q, J = 32.4 Hz), 129.5, 129.4, 129.4, 128.3, 126.3 (q, J = 3.7 Hz), 125.3 (q, J = 272.7 Hz), 124.2, 57.3, 42.9; 19F-NMR (377 MHz, Acetone-d6) δ –62.9; HRMS (ESI− in MeCN) calcd for C23H17F3N3O3 [M–H]– 440.1227 found 440.1234; IR (NaCl) n 3264, 3032, 1639, 1604, 1516, 1345, 1226, 1061, 729, 694 cm-1 (Z)-N-butyl-2-((4-nitrobenzyl)imino)-2-phenylacetamide (1i) colorless solid, m.p. 107-108 ℃, 234 mg, 0.69 mmol, 34% (2.0 mmol scale reaction);1H-NMR (400 MHz, Acetone-d6) δ 8.22-8.25 (m, 2H), 7.90-7.93 (m, 1H), 7.85-7.88 (m, 2H), 7.72-7.75 (m, 2H), 7.43-7.52 (m, 3H), 4.90 (s, 2H), 3.46 (td, J = 7.1, 5.7 Hz, 2H), 1.60-1.67 (m, 2H), 1.38-1.47 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H}-NMR (101 MHz, Acetoned6) δ 166.7, 166.3, 148.8, 147.8, 136.2, 131.8, 129.7, 129.3, 128.4, 124.2, 57.3, 39.2, 32.3, 20.8, 14.0; HRMS (ESI+ in MeCN) calcd for C19H22N3O3 [M+H]+ 340.1656 found 340.1653; IR (NaCl) n 3279, 2934, 2621, 1558, 1516, 1340, 849, 738, 703, 653 cm-1 (Z)-N-benzyl-2-((4-nitrobenzyl)imino)-2-(p-tolyl)acetamide (1j) colorless solid, m.p. 127-129 ℃, 294 mg, 0.76 mmol, 28% (2.76 mmol scale reaction);1H-NMR (400 MHz, Acetoned6) δ 8.35 (brs, 1H), 8.19-8.23 (m, 2H), 7.72-7.75 (m, 2H), 7.65-7.68 (m, 2H), 7.43-7.45 (m, 2H), 7.34-7.38 (m, 2H), 7.24-7.32 (m, 3H), 4.86 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 2.36 (s, 3H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 166.7, 166.4, 149.0, 148.0, 142.3, 140.0, 133.7, 130.2, 129.8, 129.6, 129.1, 128.6, 128.4, 124.4, 57.4, 43.5, 21.6; HRMS (ESI+ in MeCN) calcd for C23H22N3O3 [M+H]+ 388.1656 found 388.1648; IR (NaCl) n 3256, 3027, 1636, 1514, 1345, 1180, 1063, 852, 752, 694 cm-1 (Z)-N-benzyl-2-((4-nitrobenzyl)imino)-2-(m-tolyl)acetamide (1k) colorless solid, m.p. 105-107 ℃, 343 mg, 1.00 mmol, 45% (1.98 mmol scale reaction);1H-NMR (300 MHz, Acetoned6) δ 8.41 (brs, 1H), 8.20-8.23 (m, 2H), 7.62-7.69 (m, 4H), 7.27-7.47 (m, 7H), 4.87 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H); 13C{1H}-NMR (76 MHz, Acetone-d6) δ 166.5,

166.3, 148.7, 147.8, 139.9, 139.0, 136.0, 132.4, 129.6, 129.4, 129.2, 128.91, 128.87, 128.2, 125.5, 124.2, 57.3, 43.3, 21.3; HRMS (ESI+ in MeCN) calcd for C23H22N3O3 [M+H]+ 388.1656 found 388.1641; IR (NaCl) n 3234, 3058, 1630, 1514, 1342, 1253, 1070, 853, 760, 699 cm-1 (Z)-N-benzyl-2-((4-nitrobenzyl)imino)-2-(o-tolyl)acetamide (1l) colorless solid, m.p. 120-123 ℃, 389 mg, 0.89 mmol, 51% (1.97 mmol scale reaction); 1H-NMR (400 MHz, Acetoned6) δ 8.67 (brs, 1H), 8.17-8.20 (m, 2H), 7.63-7.66 (m, 2H), 7.22-7.37 (m, 8H), 7.11-7.14 (m, 1H), 4.54-4.64 (m, 4H), 2.16 (s, 3H); 13C{1H}-NMR (101 MHz, Acetone-d6) δ 167.6, 164.4, 147.93, 147.86, 140.5, 136.1, 135.1, 130.9, 129.8, 129.6, 129.2, 128.3, 127.9, 127.8, 126.5, 124.2, 56.9, 43.5, 19.6; HRMS (ESI+ in MeCN) calcd for C23H22N3O3 [M+H]+ 388.1656 found 388.1645; IR (NaCl) n 3342, 3070, 1636, 1513, 1343, 1071, 835, 759, 727, 702 cm-1 (Z)-N-benzyl-2-(4-methoxyphenyl)-2-((4-nitrobenzyl)imino)acetamide (1m) colorless solid, m.p. 112-115 ℃, 160 mg, 0.40 mmol, 25% (1.86 mmol scale reaction);1H-NMR (300 MHz, Acetoned6) δ 8.38 (brs, 1H), 8.19-8.23 (m, 2H), 7.77-7.82 (m, 2H), 7.65-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.29-7.39 (m, 3H), 6.96-7.00 (m, 2H), 4.83 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H); 13C{1H}-NMR (76 MHz, Acetone-d6) δ 166.6, 165.6, 162.9, 149.0, 147.8, 139.8, 130.0, 129.6, 129.4, 128.9, 128.6, 128.1, 124.1, 114.6, 57.1, 55.8, 43.3; HRMS (ESI+ in MeCN) calcd for C23H22N3O4 [M+H]+ 404.1605 found 404.1598; IR (NaCl) n 3226, 3056, 1595, 1510, 1341, 1260, 1170, 1031, 839, 699 cm-1 (Z)-N-benzyl-2-((4-nitrobenzyl)imino)-2-(4-(trifluoromethyl)phenyl)acetamide (1n) colorless solid, m.p. 136-137 ℃, 140 mg, 0.32 mmol, 16% (2.0 mmol scale reaction);1H-NMR (400 MHz, Acetone-d6) δ 8.55 (brs, 1H), 8.20-8.23 (m, 2H), 8.04-8.06 (m, 2H), 7.797.81 (m, 2H), 7.67-7.69 (m, 2H), 7.44-7.46 (m, 2H), 7.307.39 (m, 3H), 4.94 (s, 2H), 4.67 (d, J = 5.8 Hz, 2H); 13C{1H, 19 F}-NMR (99 MHz, Acetone-d6) δ 165.8, 165.1, 148.2, 147.9, 139.7, 139.5, 132.7, 129.7, 129.5, 129.0, 128.9, 128.3, 126.4, 124.3, 57.6, 43.5 (One carbon peak is overlapped with other peak.); 19F-NMR (377 MHz, Acetone-d6) δ –63.4; HRMS (ESI+ in MeCN) calcd for C23H19F3N3O3 [M+H]+ 442.1373 found 442.1372; IR (NaCl) n 3261, 3068, 1628, 1514, 1334, 1117, 1072, 1016, 850, 699 cm-1 Reaction condition optimizations Synthesis of hemiaminal 5a The solution of 1a (0.107 mmol, 1.0 equiv) and 3a (0.00214 mmol, 2.0 mol%) in toluene (0.05 M) was cooled to –20 ºC and stirred for 10 min. Acrolein (12.0 mg, 0.214 mmol, 2.0 equiv) and K2CO3 (33% aq., 72 µl, 0.214 mmol, 200 mol%) were added and the solution was warmed to 0 ºC. The reaction was stirred until consumption of substrate. After that,



reaction solution was passed short pad of deactivated neutral silica-gel (ethyl acetate) and solvent was evaporated to give crude imine intermediate. Suspension of NaBH4 (20.2 mg, 0.535 mmol, 5.0 equiv) in mixture of CH2Cl2/EtOH = 5/1 (0.1 M) was cooled to –20 ºC. After stirring for 10 min. at same temperature, –20 ºC pre-cooled CH2Cl2 (0.5 ml) solution of above imine intermediate was added and stirred for 1 h. Reaction was quenched by the addition of AcOH (excess, until the gas evolution eased) and stirred for 30 min. at room temperature. After neutralization by NaHCO3 aq., extracted by CH2Cl2, dried over Na2SO4, concentrated in vacuum to give crude product. Purification of hemiaminal was carried out by column chromatography (Silica-gel, hexane/ethyl acetate) to give 5a. (3S)-1-benzyl-6-hydroxy-3-((4-nitrobenzyl)amino)-3phenylpiperidin-2-one (5a major) colorless oil, 19.4 mg, 0.045 mmol, 42%, 90% ee (0.107 mmol scale reaction); 1H-NMR (300 MHz, CDCl3) δ 8.168.19 (m, 2H), 7.59-7.62 (m, 2H), 7.27-7.44 (m, 10H), 5.18 (d, J = 14.6 Hz, 1H), 5.04 (s, 1H), 4.58 (d, J = 14.6 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 3.85 (d, J = 14.1 Hz, 1H), 2.572.68 (m, 1H), 1.96-2.02 (m, 1H), 1.75-1.79 (m, 2H); 13 C{1H}-NMR (76 MHz, CDCl3) δ 173.4, 149.0, 146.9, 143.3, 137.4, 128.9, 128.7, 128.6, 128.3, 127.9, 127.8, 127.0, 123.5, 79.0, 66.9, 48.4, 47.9, 27.5, 27.0; HRMS (ESI+ in MeCN) calcd for C25H26N3O4 [M+H]+ 432.1918 found 432.1912; IR (NaCl) n 3352, 3062, 2949, 1635, 1518, 1348, 1068, 958, 851, 760 cm-1; [α]D20 = +16.15 ( c = 0.73, CHCl3 for 94% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IB, hexane/2-propanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 9.9 min, second peak: tR = 12.1 min. (3S)-1-benzyl-6-hydroxy-3-((4-nitrobenzyl)amino)-3phenylpiperidin-2-one (5a minor) colorless oil, 10.2 mg, 0.024 mmol, 22%, 90% ee (0.107 mmol scale reaction); 1H-NMR (300 MHz, CDCl3) δ 8.158.18 (m, 2H), 7.28-7.57 (m, 12H), 5.29 (d, J = 14.3 Hz, 1H), 4.90-4.90 (m, 1H), 4.56 (d, J = 14.3 Hz, 1H), 3.84 (d, J = 14.1 Hz, 1H), 3.78 (d, J = 14.1 Hz, 1H), 1.99-2.23 (m, 4H); 13 C{1H}-NMR (76 MHz, CDCl3) δ 172.8, 149.0, 147.0, 142.6, 137.4, 128.8, 128.7, 128.58, 128.56, 128.0, 127.7, 127.1, 123.6, 79.9, 66.2, 48.0, 46.3, 30.0, 28.9; HRMS (ESI+ in MeCN) calcd for C25H26N3O4 [M+H]+ 432.1918 found 432.1914; IR (NaCl) n 3356, 3058, 2942, 1634, 1522, 1348, 1074, 971, 853, 760 cm-1; [α]D20 = +124.24 ( c = 0.51, CHCl3 for 92% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IB, hexane/2-propanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 7.6 min, second peak: tR = 9.6 min. General procedure for catalytic asymmetric umpolung organocascade synthesis of enamide 6

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The solution of 1 (0.05 mmol, 1.0 equiv) and 3c (0.001 mmol, 2.0 mol%) in toluene (0.0125 M) was cooled to –10 ºC and stirred for 10 min. Acrolein (0.1 mmol, 2.0 equiv) and KOH (50% aq., 0.8 µl, 0.01 mmol, 20 mol%) were added and the solution was stirred until consumption of substrate at the same temperature. After that, reaction solvent was evaporated and CH2Cl2/EtOH = 5/1 (0.0125 M) was added at –20 ºC. Then, NaBH4 (0.25 mmol, 5.0 equiv) was added and stirred for 1 h at –20 ºC. Reaction was quenched by the addition of AcOH (excess, until the gas evolution eased) and stirred for 30 min. at room temperature. After neutralization by NaHCO3 aq., extracted by CH2Cl2, dried over Na2SO4, concentrated in vacuum to give crude product. The crude product obtained above in THF (0.05 M) was added SOCl2 (0.25 mmol, 5 equiv) and 1 drop of DMF at room temperature, and the reaction was stirred for 15 h at same temperature. The solvent was evaporated and neutralized by NaHCO3 aq., extracted by CH2Cl2, dried over Na2SO4, concentrated in vacuum to give crude product. Purification of enamide was carried out by column chromatography (Silica-gel, hexane/ethyl ether) to give 6. (S)-1-benzyl-3-((4-nitrobenzyl)amino)-3-phenyl-3,4-dihydropyridin-2(1H)-one (6a) yellow oil, 15.1 mg, 0.037 mmol, 74%, 95% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.12-8.16 (m, 2H), 7.47-7.50 (m, 2H), 7.42-7.45 (m, 2H), 7.25-7.37 (m, 6H), 7.14-7.16 (m, 2H), 5.96 (dd, J = 7.7, 2.4 Hz, 1H), 5.18 (ddd, J = 7.7, 5.2, 2.4 Hz, 1H), 4.78 (d, J = 14.9 Hz, 1H), 4.71 (d, J = 14.9 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.59 (d, J = 14.3 Hz, 1H), 2.86 (dd, J = 17.2, 5.2 Hz, 1H), 2.74 (ddd, J = 17.2, 5.2, 2.4 Hz, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ 170.8, 148.7, 146.9, 139.4, 136.8, 128.9, 128.66, 128.64, 128.3, 127.9, 127.60, 127.57, 126.9, 123.5, 104.9, 63.6, 49.8, 47.2, 32.4; HRMS (ESI+ in MeCN) calcd for C25H23N3O3 [M+H]+ 414.1812 found 414.1811; IR (NaCl) n 3223, 3064, 2927, 1661, 1519, 1345, 1258, 856, 756, 700 cm-1; [α]D20 = +108.09 ( c = 1.51, CHCl3 for 95% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA-3, hexane/2-propanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 13.6 min, second peak: tR = 78.6 min. (S)-1-benzyl-3-phenyl-3-((4-(trifluoromethyl)benzyl)amino)-3,4-dihydropyridin-2(1H)-one (6c) yellow oil, 6.1 mg, 0.014 mmol, 28%, 7% ee (0.05 mmol scale reaction); 1H-NMR (392 MHz, CDCl3) δ 7.52-7.55 (m, 2H), 7.41-7.46 (m, 4H), 7.27-7.37 (m, 5H), 7.25-7.25 (m, 1H), 7.14-7.16 (m, 2H), 5.95 (dd, J = 7.7, 2.4 Hz, 1H), 5.18 (ddd, J = 7.7, 5.6, 2.4 Hz, 1H), 4.79 (d, J = 15.0 Hz, 1H), 4.70 (d, J = 15.0 Hz, 1H), 3.63 (d, J = 13.5 Hz, 1H), 3.52 (d, J = 13.5 Hz, 1H), 2.87 (dd, J = 17.3, 5.6 Hz, 1H), 2.75 (ddd, J = 17.3, 5.6, 2.4 Hz, 1H); 13C{1H, 19F}-NMR (99 MHz, CDCl3) δ 170.7, 144.9, 139.7, 136.9, 129.1, 128.9, 128.7, 128.34, 128.29, 127.8, 127.60, 127.58, 127.0, 125.2, 104.9, 63.6, 49.8, 47.4, 32.5 (One carbon peak is overlapped with other peak.); 19F-NMR (377 MHz, CDCl3) δ –62.4; (ESI+ in


Page 9 of 14 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


MeCN) calcd for C26H24F3N2O [M+H]+ 437.1835 found 437.1829 ; IR (NaCl) n 3325, 3066, 2924, 1662, 1386, 1325, 1122, 1064, 825, 695 cm-1; [α]D20 = +3.88 ( c = 0.17, CHCl3 for 7% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK AD-3, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 10.5 min, second peak: tR = 25.1 min. (S)-1-(4-methylbenzyl)-3-((4-nitrobenzyl)amino)-3-phenyl-3,4-dihydropyridin-2(1H)-one (6d) yellow oil, 15.1 mg, 0.035 mmol, 70%, 95% ee (0.05 mmol scale reaction); 1H-NMR (300 MHz, CDCl3) δ 8.12-8.15 (m, 2H), 7.41-7.50 (m, 4H), 7.30-7.40 (m, 3H), 7.03-7.10 (m, 4H), 5.95 (dd, J = 7.7, 2.4 Hz, 1H), 5.17 (ddd, J = 7.7, 5.7, 2.4 Hz, 1H), 4.75 (d, J = 14.8 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 3.58 (d, J = 14.1 Hz, 1H), 2.85 (dd, J = 17.2, 5.7 Hz, 1H), 2.73 (ddd, J = 17.2, 5.7, 2.4 Hz, 1H), 2.31 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 170.8, 148.8, 147.0, 139.6, 137.3, 133.8, 129.3, 128.9, 128.7, 128.3, 127.9, 127.7, 127.0, 123.5, 104.8, 63.7, 49.6, 47.3, 32.5, 21.1; HRMS (ESI+ in MeCN) calcd for C26H26N3O3 [M+H]+ 428.1969 found 428.1957; IR (NaCl) n 3225, 3023, 2924, 1661, 1519, 1345, 1254, 1109, 856, 755 cm-1; [α]D20 = +99.92 ( c = 1.50, CHCl3 for 95% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 16.4 min, second peak: tR = 22.6 min. (S)-1-(2-methylbenzyl)-3-((4-nitrobenzyl)amino)-3-phenyl-3,4-dihydropyridin-2(1H)-one (6e) yellow oil, 18.1 mg, 0.042 mmol, 84%, 96% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.14-8.16 (m, 2H), 7.50-7.52 (m, 2H), 7.45-7.47 (m, 2H), 7.33-7.39 (m, 3H), 7.12-7.19 (m, 2H), 7.05-7.09 (m, 1H), 6.88-6.90 (m, 1H), 5.84 (dd, J = 7.8, 2.8 Hz, 1H), 5.20 (ddd, 7.8, 5.9, 2.8 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.61 (d, J = 14.3 Hz, 1H), 2.91 (dd, J = 17.2, 5.9 Hz, 1H), 2.80 (ddd, J = 17.2, 5.9, 2.8 Hz, 1H), 2.20 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 170.6, 148.6, 146.9, 139.1, 136.2, 134.2, 130.5, 128.7, 128.5, 128.4, 128.0, 127.6, 127.5, 127.0, 126.1, 123.5, 104.9, 63.6, 47.6, 47.2, 31.8, 19.0; HRMS (ESI+ in MeCN) calcd for C26H26N3O3 [M+H]+ 428.1969 found 428.1964; IR (NaCl) n 3327, 3062, 2925, 2851, 1659, 1517, 1345, 1265, 857, 741 cm-1; [α]D20 = +62.90 ( c = 0.16, CHCl3 for 96% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 9.7 min, second peak: tR = 15.9 min. (S)-1-(4-methoxybenzyl)-3-((4-nitrobenzyl)amino)-3phenyl-3,4-dihydropyridin-2(1H)-one (6f)

yellow oil, 14.0 mg, 0.032 mmol, 64%, 94% ee (0.05 mmol scale reaction); 1H-NMR (300 MHz, CDCl3) δ 8.12-8.15 (m, 2H), 7.30-7.49 (m, 7H), 7.09-7.12 (m, 2H), 6.79-6.83 (m, 2H), 5.95 (dd, J = 7.8, 2.3 Hz, 1H), 5.16 (ddd, J = 7.8, 5.1, 2.3 Hz, 1H), 4.72 (d, J = 14.8 Hz, 1H), 4.63 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 3.67 (d, J = 14.1 Hz, 1H), 3.58 (d, J = 14.1 Hz, 1H), 2.84 (dd, J = 17.2, 5.1 Hz, 1H), 2.71 (ddd, J = 17.2, 5.1, 2.3 Hz, 1H); 13C{1H}-NMR (76 MHz, CDCl3) δ 170.7, 159.2, 148.7, 146.9, 139.6, 129.1, 128.9, 128.8, 128.7, 128.3, 127.9, 126.9, 123.5, 114.0, 104.8, 63.6, 55.3, 49.3, 47.2, 32.4; HRMS (ESI+ in MeCN) calcd for C26H26N3O4 [M+H]+ 444.1918 found 444.1910; IR (NaCl) n 3323, 3066, 2929, 1661, 1515, 1345, 1248, 1034, 854, 701 cm-1; [α]D20 = +93.73 ( c = 0.69, CHCl3 for 89% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 19.3 min, second peak: tR = 24.1 min. (S)-1-(4-bromobenzyl)-3-((4-nitrobenzyl)amino)-3-phenyl-3,4-dihydropyridin-2(1H)-one (6g) yellow oil, 20.5 mg, 0.042 mmol, 84%, 99% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.13-8.15 (m, 2H), 7.30-7.48 (m, 9H), 6.98-7.00 (m, 2H), 5.91 (dd, J = 7.8, 2.5 Hz, 1H), 5.21 (ddd, J = 7.8, 6.0, 2.5 Hz, 1H), 4.69 (d, J = 15.1 Hz, 1H), 4.65 (d, J = 15.1 Hz, 1H), 3.64 (d, J = 14.1 Hz, 1H), 3.56 (d, J = 14.1 Hz, 1H), 2.87 (dd, J = 17.2, 6.0 Hz, 1H), 2.74 (ddd, J = 17.2, 6.0, 2.5 Hz, 1H); 13C{1H}NMR (101 MHz, CDCl3) δ 170.8, 148.6, 146.9, 139.1, 135.8, 131.7, 129.2, 128.70, 128.64, 128.4, 128.1, 126.9, 123.5, 121.5, 105.2, 63.4, 49.3, 47.1, 32.0; HRMS (ESI+ in MeCN) calcd for C25H23BrN3O3 [M+H]+ 492.0917 found 492.0910; IR (NaCl) n 3325, 3062, 2930, 1662, 1518, 1344, 1072, 855, 757, 701 cm-1; [α]D20 = +62.81 ( c = 1.58, CHCl3 for 99% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 14.9 min, second peak: tR = 22.9 min. (S)-3-((4-nitrobenzyl)amino)-3-phenyl-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyridin-2(1H)-one (6h) yellow oil, 20.0 mg, 0.042 mmol, 84%, 95% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.12-8.15 (m, 2H), 7.50-7.52 (m, 2H), 7.46-7.49 (m, 2H), 7.41-7.43 (m, 2H), 7.33-7.39 (m, 3H), 7.20-7.22 (m, 2H), 5.93 (dd, J = 7.8, 2.4 Hz, 1H), 5.25 (ddd, J = 7.8, 6.1, 2.4 Hz, 1H), 4.82 (d, J = 15.3 Hz, 1H), 4.73 (d, J = 15.3 Hz, 1H), 3.64 (d, J = 14.1 Hz, 1H), 3.56 (d, J = 14.1 Hz, 1H), 2.91 (dd, J = 17.4, 6.1 Hz, 1H), 2.77 (ddd, J = 17.4, 6.1, 2.4 Hz, 1H); 13C{1H}NMR (101 MHz, CDCl3) δ 170.9, 148.5, 147.0, 140.8, 138.9, 129.9 (q, J = 33.3 Hz), 128.73, 128.65, 128.4, 128.1, 127.6, 126.9, 125.6 (q, J = 3.9 Hz), 124.0 (q, J = 272.9 Hz), 123.5, 105.4, 63.4, 49.5, 47.1, 31.9; 19F-NMR (377 MHz, CDCl3) δ –62.6; HRMS (ESI+ in MeCN) calcd for C26H23F3N3O3 [M+H]+ 482.1686 found 482.1677; IR (NaCl) n 3325, 3062,



2924, 2853, 1659, 1518, 1345, 1066, 851, 701 cm-1; [α]D20 = +59.47 ( c = 0.19, CHCl3 for 95% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 12.7 min, second peak: tR = 19.7 min. (S)-1-butyl-3-((4-nitrobenzyl)amino)-3-phenyl-3,4-dihydropyridin-2(1H)-one (6i) yellow oil, 12.6 mg, 0.033 mmol, 66%, 93% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.12-8.16 (m, 2H), 7.50-7.52 (m, 2H), 7.40-7.43 (m, 2H), 7.28-7.36 (m, 3H), 5.91 (dd, J = 7.8, 2.5 Hz, 1H), 5.15 (ddd, J = 7.8, 5.9, 2.5 Hz, 1H), 3.66 (d, J = 14.3 Hz, 1H), 3.60(d, J = 14.3 Hz, 1H), 3.59 (dt, 13.2, 7.2 Hz, 1H), 3.45 (dt, 13.2, 7.2 Hz, 1H), 2.81 (dd, J = 17.2, 5.9 Hz, 1H), 2.71 (ddd, J = 17.2, 5.9, 2.5 Hz, 1H), 1.55 (quit, J = 7.2 Hz, 2H), 1.24-1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 170.6, 148.8, 147.0, 139.6, 129.4, 128.7, 128.3, 127.8, 126.8, 123.5, 104.4, 63.5, 47.3, 46.8, 32.0, 30.6, 19.9, 13.7; HRMS (ESI+ in MeCN) calcd for C22H26N3O3 [M+H]+ 380.1969 found 380.1964; IR (NaCl) n 3325, 2930, 2857, 1658, 1520, 1345, 1256, 1105, 855, 701 cm-1; [α]D20 = +72.52 ( c = 0.13, CHCl3 for 93% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 9.3 min, second peak: tR = 17.7 min. (S)-1-benzyl-3-((4-nitrobenzyl)amino)-3-(p-tolyl)-3,4-dihydropyridin-2(1H)-one (6j) yellow oil, 16.4 mg, 0.038 mmol, 77%, 98% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.12-8.15 (m, 2H), 7.47-7.50 (m, 2H), 7.25-7.32 (m, 5H), 7.14-7.16 (m, 4H), 5.94 (dd, J = 7.8, 2.4 Hz, 1H), 5.18 (ddd, J = 7.8, 5.9, 2.4 Hz, 1H), 4.79 (d, J = 15.1 Hz, 1H), 4.68 (d, J = 15.1 Hz, 1H), 3.66 (d, J = 14.3 Hz, 1H), 3.60 (d, J = 14.3 Hz, 1H), 2.84 (dd, J = 17.2, 5.9 Hz, 1H), 2.73 (ddd, J = 17.2, 5.9, 2.4 Hz, 1H), 2.35 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 171.0, 148.8, 146.9, 137.7, 136.8, 136.3, 129.1, 128.9, 128.7, 128.6, 127.6, 126.8, 123.5, 105.0, 63.3, 49.8, 47.2, 32.1, 21.1 (One carbon peak is overlapped with other peak.); HRMS (ESI+ in MeCN) calcd for C26H26N3O3 [M+H]+ 428.1969 found 428.1959; IR (NaCl) n 3325, 3027, 2923, 2849, 1659, 1517, 1344, 1255, 856, 700 cm-1; [α]D20 = +104.32 ( c = 1.38, CHCl3 for 98% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 13.6 min, second peak: tR = 21.0 min. (S)-1-benzyl-3-((4-nitrobenzyl)amino)-3-(m-tolyl)-3,4-dihydropyridin-2(1H)-one (6k) yellow oil, 14.9 mg, 0.035 mmol, 70%, 96% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.12-8.16 (m,

Page 10 of 14

2H), 7.48-7.50 (m, 2H), 7.11-7.31 (m, 9H), 5.95 (dd, J = 7.8, 2.5 Hz, 1H), 5.18 (ddd, J = 7.8, 5.9, 2.5 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 15.2 Hz, 1H), 3.68 (d, J = 14.1 Hz, 1H), 3.61 (d, J = 14.1 Hz, 1H), 2.85 (dd, J = 17.2, 5.9 Hz, 1H), 2.74 (ddd, J = 17.2, 5.9, 2.5 Hz, 1H), 2.32 (s, 3H); 13 C{1H}-NMR (101 MHz, CDCl3) δ 171.0, 148.8, 146.9, 139.3, 138.0, 136.8, 128.9, 128.71, 128.70, 128.6, 128.2, 127.64, 127.60, 127.5, 124.0, 123.5, 105.0, 63.6, 49.8, 47.3, 32.1, 21.6; HRMS (ESI+ in MeCN) calcd for C26H26N3O3 [M+H]+ 428.1969 found 428.1959; IR (NaCl) n 3325, 3030, 2924, 2851, 1664, 1517, 1345, 1257, 851, 701 cm-1; [α]D20 = +92.46 ( c = 1.49, CHCl3 for 96% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 70/30, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 9.5 min, second peak: tR = 11.0 min. (S)-1-benzyl-3-((4-nitrobenzyl)amino)-3-(o-tolyl)-3,4-dihydropyridin-2(1H)-one (6l) yellow oil, 7.5 mg, 0.018 mmol, 36%, 91% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.16-8.20 (m, 2H), 7.62-7.64 (m, 1H), 7.49-7.51 (m, 2H), 7.29-7.37 (m, 5H), 7.13-7.22 (m, 3H), 6.21 (dd, J = 8.0, 2.3 Hz, 1H), 5.07 (ddd, J = 8.0, 5.5, 2.3 Hz, 1H), 4.83 (d, J = 14.6 Hz, 1H), 4.73 (d, J = 14.6 Hz, 1H), 3.86 (d, J = 15.1 Hz, 1H), 3.55 (d, J = 15.1 Hz, 1H), 2.91 (ddd, J = 18.6, 5.5, 2.3 Hz, 1H), 2.49 (dd, J = 18.6, 5.5 Hz, 1H), 2.31 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3) δ 168.1, 148.2, 147.0, 139.3, 137.3, 136.0, 132.4, 128.72, 128.67, 128.4, 128.3, 127.8, 127.4, 125.9, 125.5, 123.6, 103.3, 63.7, 50.1, 47.2, 36.6, 21.4; HRMS (ESI+ in MeCN) calcd for C26H26N3O3 [M+H]+ 428.1969 found 428.1968; IR (NaCl) n 3315, 3025, 2925, 2851, 1664, 1517, 1345, 859, 757, 699 cm-1; [α]D20 = –123.61 ( c = 0.75, CHCl3 for 91% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA, hexane/ethanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 11.6 min, second peak: tR = 15.2 min. (S)-1-benzyl-3-(4-methoxyphenyl)-3-((4-nitrobenzyl)amino)-3,4-dihydropyridin-2(1H)-one (6m) yellow oil, 14.0 mg, 0.032 mmol, 64%, 97% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.13-8.16 (m, 2H), 7.47-7.51 (m, 2H), 7.33-7.37 (m, 2H), 7.26-7.31 (m, 3H), 7.14-7.16 (m, 2H), 6.86-6.90 (m, 2H), 5.95 (dd, J = 7.8, 2.5 Hz, 1H), 5.19 (ddd, J = 7.8, 5.9, 2.5 Hz, 1H), 4.78 (d, J = 14.8 Hz, 1H), 4.71 (d, J = 14.8 Hz, 1H), 3.82 (s, 3H), 3.66 (d, J = 14.1 Hz, 1H), 3.60 (d, J = 14.1 Hz, 1H), 2.83 (dd, J = 17.2, 5.9 Hz, 1H), 2.73 (ddd, J = 17.2, 5.9, 2.5 Hz, 1H); 13 C{1H}-NMR (101 MHz, CDCl3) δ 171.1, 159.2, 148.8, 146.9, 136.8, 131.3, 128.9, 128.7, 128.6, 128.2, 127.6, 127.5, 123.5, 113.6, 104.9, 63.0, 55.3, 49.8, 47.2, 32.1; HRMS (ESI+ in MeCN) calcd for C26H26N3O4 [M+H]+ 444.1918 found 444.1911; IR (NaCl) n 3325, 2930, 2839, 1662, 1516, 1345, 1253, 1034, 856, 701 cm-1; [α]D20 = +97.98 ( c = 1.40, CHCl3 for 97% ee sample).


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Enantiomeric excess was determined by HPLC (CHIRALPAK IA-3, hexane/ethanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 27.5 min, second peak: tR = 39.5 min.

give crude product, which was used without further purification.

(S)-1-benzyl-3-((4-nitrobenzyl)amino)-3-(4-(trifluoromethyl)phenyl)-3,4-dihydropyridin-2(1H)-one (6n)

ASSOCIATED CONTENT

yellow oil, 13.4 mg, 0.028 mmol, 56%, 88% ee (0.05 mmol scale reaction); 1H-NMR (400 MHz, CDCl3) δ 8.14-8.17 (m, 2H), 7.55-7.61 (m, 4H), 7.46-7.48 (m, 2H), 7.28-7.31 (m, 3H), 7.17-7.19 (m, 2H), 6.04 (dd, J = 7.8, 2.1 Hz, 1H), 5.18 (ddd, J = 7.8, 3.8, 2.1 Hz, 1H), 4.80 (d, J = 15.1 Hz, 1H), 4.71 (d, J = 15.1 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.57 (d, J = 14.3 Hz, 1H), 2.82 (dd, J = 17.4, 3.8 Hz, 1H), 2.75 (ddd, J = 17.4, 3.8, 2.1 Hz, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ 169.8, 148.1, 147.1, 144.0, 136.6, 130.0 (q, J = 32.4 Hz), 129.2, 128.8, 128.6, 127.8, 127.7, 127.4, 125.3 (q, J = 3.7 Hz), 123.9 (q, J = 260.9 Hz), 123.6, 104.4, 63.6, 50.1, 47.2, 33.4; 19F-NMR (377 MHz, CDCl3) δ –62.6; HRMS (ESI+ in MeCN) calcd for C26H23F3N3O3 [M+H]+ 482.1686 found 482.1678; IR (NaCl) n 3325, 2925, 2853, 1665, 1520, 1328, 1125, 1071, 858, 701 cm-1; [α]D20 = +72.66 ( c = 1.34, CHCl3 for 88% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IA-3, hexane/ethanol = 80/20, flow rate 1.0 mL/min, 25℃, 254 nm) first peak: tR = 33.4 min, second peak: tR = 38.1 min. (1R,4S)-2-benzyl-7-(4-nitrobenzyl)-4-phenyl-2,7-diazabicyclo[2.2.1]heptan-3-one (7a) colorless solid, m.p. 130-131 ℃; 1H-NMR (400 MHz, CDCl3) δ 8.04-8.06 (m, 2H), 7.97-8.00 (m, 2H), 7.35-7.47 (m, 8H), 6.95 (d, J = 8.5 Hz, 2H), 4.94 (d, J = 14.6 Hz, 1H), 4.16 (d, J = 2.2 Hz, 1H), 3.84 (d, J = 14.6 Hz, 1H), 3.39 (d, J = 13.5 Hz, 1H), 3.12 (d, J = 13.5 Hz, 1H), 2.25-2.31 (m, 1H), 1.98-2.07 (m, 2H), 1.69-1.76 (m, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ 173.2, 147.0, 146.2, 136.7, 134.7, 129.3, 129.01, 128.95, 128.6, 128.1, 127.7, 123.4, 74.1, 73.6, 48.1, 44.5, 34.6, 28.0; HRMS (ESI+ in MeCN) calcd. for C25H24N3O3 [M+H]+ 414.1812 found 414.1802; IR (KBr) ν 3001, 2961, 1698, 1519, 1493, 1399, 1337, 766, 742, 703 cm-1; [α]D20 = +86.25 (c = 0.6, CHCl3 for 95% ee sample). Enantiomeric excess was determined by HPLC (CHIRALPAK IB, hexane/2-propanol = 80/20, flow rate 1.0 mL/min, 25 ℃, 254 nm) first peak: tR = 8.4 min, second peak: tR = 10.1 min. Control experiments 1k (E: Z = 1 : 5.1) was prepared by passing Z-1k on the short pad of silica-gel (EtOAc). Rac-1k’ was prepared by the reaction of 1k in toluene (0.05 M) with DBU (20 mol%). The reaction was stirred for 2.5 h at room temperature, and quenched by adding saturated NH4Cl aq., dried over Na2SO4, concentrated in vacuum to

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. X-ray crystallography data, CIF file, reaction optimization, 1 H- and 13C-NMR spectra, HPLC chromatograms

AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful for financial support from the Toyo Gosei Memorial Foundation, the Meiji Seika Pharma Award in Synthetic Organic Chemistry, Japan, and Leading Research Promotion Program ‘Soft Molecular Activation’ of Chiba University, Japan.

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Heydt, H.; Gooßen, L. J. Late Transition Metal-Catalyzed Hydroamination and Hydroamidation. Chem. Rev. 2015, 115, 2596−2697; (f) Bai, X.-Y.; Wang, Z.X.; Li, B.-J. Iridium-Catalyzed Enantioselective Hydroalkynylation of Enamides for the Synthesis of Homopropargyl Amides. Angew. Chem., Int. Ed. 2016, 55, 9007−9011; (g) Trost, B. M.; Cregg, J. J.; Quach, N. Isomerization of N-Allyl Amides To Form Geometrically Defined Di-, Tri-, and Tetrasubstituted Enamides. J. Am. Chem. Soc. 2017, 139, 5133−5139. [10] We determined the structure of 1k as Z-1k by X-ray crystallographic analysis. CCDC 1893130 (for com pound Z-1k) contains the supplementary crystallographic data for this paper. These data can be obtained from The Cambridge Crystallographic Data Centre. See SI for more detail. The absolute configuration of compounds of type 6 is proposed by comparing their optical rotations to those of the umpolung adducts of αimino esters in reference 9. [11] (a) Boiteau, L.; Boivin, J.; Liard, A.; Quiclet–Sire, B.; Zard, S. Z. A Short Synthesis of (±)–Matrine. Angew. Chem. Int. Ed. 1998, 37, 1128–1131; (b) Yokokawa, F.; Inaizumi, A.; Shioiri, T. Synthetic studies of the cyclic depsipeptides bearing the 3-amino-6-hydroxy-2piperidone (Ahp) unit. Total synthesis of the proposed structure of micropeptin T-20. Tetrahedron, 2005, 61, 1459–1480; (c) Estiarte, M. A.; de Souza, M. V. N; del Rio, X.; Dodd, R. H.; Rubiralta, M.; Diez, A. Synthesis and synthetic applications of 3-amino-Δ5-piperidein-2ones: Synthesis of methionine-derived pseudopeptides. Tetrahedron, 1999, 55, 10173–10186. [12] More details for reaction condition optimization, see SI. [13] Alkyl and alkenyl substituted substrates for R1group could not be prepared in E or Z-pure form. [14] (a) Cogan, D. A.; Ellman, J. A. Asymmetric Synthesis of α,α-Dibranched Amines by the TrimethylaluminumMediated 1,2-Addition of Organolithiums to tert-Butanesulfinyl Ketimines. J. Am. Chem. Soc. 1999, 121, 268-269; (b) Cogan, D. A.; Liu, G.; Ellman, J. A. Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines. Tetrahedron 1999, 55, 8883-8904; (c) Kano, T.; Aota, Y.; Maruoka, K. Asymmetric Synthesis of Less Accessible α-Tertiary Amines from Alkynyl Z-Ketimines. Angew. Chem. Int. Ed. 2017, 56, 16293-16296.

[15] (a) Ooi, T.; Kameda, M.; Maruoka, K. Molecular Design of a C2-Symmetric Chiral Phase-Transfer Catalyst for Practical Asymmetric Synthesis of α-Amino Acids. J. Am. Chem. Soc. 1999, 121, 6519-6520; (b) Hashimoto, T.; Maruoka, K. Recent Development and Application of Chiral Phase-Transfer Catalysts. Chem. Rev. 2007, 107, 5656-5682; (c) Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.-W.; Tan, C.-H. Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions. J. Am. Chem. Soc. 2011, 133, 2828-2831; (d) Shirakawa, S.; Maruoka, K. Recent Developments in Asymmetric Phase-Transfer Reactions. Angew. Chem., Int. Ed. 2013, 52, 4312-4348. [16] For the use of SOCl2-DMF, see: Arrieta, A.; Aizpurua, J. M.; Palomo, C. N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) a versatile dehydrating reagent. Tetrahedron Lett. 1984, 25, 3365-3368. [17] (a) Zhang, Z.; Su, J.; Zha, Z.; Wang, Z. A novel approach for the one-pot preparation of α-ketoamides by anodic oxidation. Chem. Commun., 2013, 49, 89828984; (b) Gu, G.; Yang, T.; Yu, O.; Qian, H.; Wang, J.; Wen, J.; Dang, L.; Zhang, X. Enantioselective IridiumCatalyzed Hydrogenation of α-Keto Amides to α-Hydroxy Amides. Org. Lett., 2017, 19, 5920-5923; (c) Salunke, S. B.; Babu, N. S.; Chen, C.-T. Asymmetric Aerobic Oxidation of α-Hydroxy Acid Derivatives Catalyzed by Reusable, Polystyrene-Supported Chiral NSalicylidene Oxidovanadium tert-Leucinates. Adv. Synth. Catal., 2011, 353, 1234-1240; (d) Kumar, G.; Muthukumar, A.; Sekar, G. A Mild and Chemoselective Hydrosilylation of α-Keto Amides by Using a Cs2CO3/PMHS/2-MeTHF System. Eur. J. Org. Chem., 2017, 4883-4890; (e) Bouma, M.; Masson, G.; Zhu, J. Zinc Chloride Promoted Formal Oxidative Coupling of Aromatic Aldehydes and Isocyanides to α-Ketoamides. J. Org. Chem. 2010, 75, 2748-2751; (f) Zhang, C.; Jiao, N. Dioxygen Activation under Ambient Conditions: Cu-Catalyzed Oxidative Amidation-Diketonization of Terminal Alkynes Leading to α-Ketoamides. J. Am. Chem. Soc. 2010, 132, 28-29. [18] Lin, Y.-S.; Alper, H. A Novel Approach for the OnePot Preparation of α-Amino Amides by Pd-Catalyzed Double Carbohydroamination. Angew. Chem. Int. Ed., 2001, 40, 779-781.



1) Ammonium salt cat. KOH aq. 2) NaBH4

Ar N

H N

R1

+ R2

CHO

O

Umpolung organocascade reaction

α-Imino amide

SOCl2

Ar HN R1

N O

R2

Page 14 of 14

Ar HN R1

OH N

O

R2

Hemiaminal

➢ Facile Preparations of Both Enantiomers ➢ Mechanistic Study

Enamide High yield Up to 99% ee


14

Chemo- and Regioselective Asymmetric Synthesis of Cyclic Enamides

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