A Diastereoselective Multicomponent Reaction for Construction of

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A Diastereoselective Multicomponent Reaction for Construction of Alkynylamide-substituted #,#-Diamino Acid Derivatives to Hunt Hits Ruirui Lei, Yong Wu, Suzhen Dong, Kaili Jia, Shunying Liu, and Wenhao Hu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02761 • Publication Date (Web): 22 Feb 2017 Downloaded from http://pubs.acs.org on February 23, 2017

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The Journal of Organic Chemistry

A Diastereoselective Multicomponent Reaction for Construction

of

α,β-

Alkynylamide-substituted

Diamino Acid Derivatives to Hunt Hits Ruirui Lei, Yong Wu, Suzhen Dong, Kaili Jia, Shunying Liu* and Wenhao Hu* Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

TOC:

Abstract: Highly diasetereoselective Mannich-type multi-component reaction was developed to rapidly construct alkynylamide-substituted α,β-diamino acid derivatives from simple starting materials under mild conditions in moderate to good yields for hit hunting. Most of the resulting products 4 exhibited good anticancer activity in HCT116, BEL7402 and SMMC7721 cells.

Introduction Alkyne moieties widely exist in natural products isolated from plants and marine organisms

1

2

and pharmaceuticals as important pharmacophores

(Scheme 1). For

instance, alkynylamide groups can covalently interact with the cysteine residue of protein targets via addition reaction. 3 Introducing alkyne moieties for the structureactivity relationship study is a common strategy in medicinal chemistry. 4 Moreover, alkynes are also used as versatile intermediates 6

owing to their good reactivity to amino,

5

for the synthetic transformations

hydroxyl,

7

imine,

8

diazo

9

and other

functional groups. 10 Hence, many elegant methods including Sonogashira reaction, 11 1

ACS Paragon Plus Environment


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Corey-Fuchs reaction

12

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and Seyferth-Gillbert homologation,

13

intramolecular

elimination reaction of halogenated hydrocarbon 14 have been successfully established for the construction of complex molecules containing alkyne moieties in synthetic community. The unsaturated and high energy structure makes alkynes very active in reactions, which initiates a great challenge to directly introduce an alkynyl group especially a terminal one into a complex molecule with poly functional groups and multiple stereogenic centres. As a result, developing straightforward and convenient approaches to rapid access to novel complex molecules containing alkynes is still in increasing demand.

Scheme 1. Examples of naturally- and pharmaceutical-occurring alkynes. Multi-component reactions (MCRs) 15 are more fascinating owning atom- and stepeconomy, flexibility and simplicity from simple starting materials than traditional twocomponent chemical synthesis. In recent studies, our group has been concentrating on the development of MCRs via trapping metal-carbene-induced active oxonium ammonium ylide intermediates 17 or zwitterionic intermediates

18

16

or

using an appropiate

electrophile to afford desirable complex compounds. One of the most intriguing work is trapping carbamate ammonium ylide with imines in the presence of Rh(II)/chiral phosphoric acids (CPAs) co-catalysts to obtain access to both syn- and anti-α,β-diamino acid derivatives with excellent diastereoselectivity and enantioselectivity (Scheme 2A).17c

2


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Scheme 2. MCRs of trapping ammonium ylides to construct α,β-diamino acid derivatives. As a continuation of our on-going effort to rapidly construct complex molecules through the trapping strategy for drug discovery, we presumed a [Rh]-catalyzed three-component reaction of phenyldiazoacetate 1, propiolamide 2 and N-arylaldimines 3 to furnish complex molecules containing terminal alkynylamide moieties via trapping metal-carbene-induced acyl ammonium ylide (Scheme 2B). N-Arylaldimines 3 containing hydroxyl group at 2-position for a further potential functionalization were employed in this investigation. 19

Results and Discussion The initial exploration was carried out by reacting methyl phenyldiazoacetate 1a, propiolamide 2a and N-arylaldimine 3a in CHCl3 with Rh2(OAc)4 (1 mol%) as a catalyst and 4Å molecular sieves (MS) as an additive. Encouragingly, the reaction was finished in 6 hrs and the desired three-component product 4a was obtained in 51% yield and with good dr (syn:anti = 93:7, Table 1, entry 1). Subsequent attempts at an asymmetric multi-component reaction failed to give the desired product 4a (Scheme 3a), and phenyldiazoacetate 1a cann’t be decomposed with our previousely reported methods.

17c

Interestingly, phenyldiazoacetate 1a was smoothly decomposed in the

absence of propiolamide 2a under the same conditions (see Supporting Information, Scheme S1), which indicates the reaction is strongly substrate-dependent. Additionally, a very poor enantiomeric excess (e.e.) and yield were obtained by using CPAs (10 3



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mol%) as co-catalysts without the additive acids (Scheme 3b, and see Supporting Information, Table S1). According to our previous research,

17c, 18a

CPAs, the co-

catalysts, not only control the stereoselectivity, but also activate the trapping reagent imines in multi-component reactions, which was not been revealed in this reaction. This result further illustrates the reaction is substrate-dependent. Thus, the optimization of the reaction conditions was commenced without CPAs or additive acids and the results were tabulated in Table 1. Comparably, other commonly used transition metal catalysts for the decomposition of diazo compounds, such as [PdCl(η3-C3H5)]2 20 and Cu(OTf)2 21

were much less effective to promote this reaction (entries 2-3). Solvent screening

showed that the solvent had a notable impact on the yield and the diastereoselectivity (entries 4-7). Significant amounts of N-H insertion product (6a) derived from the reaction of 1a and 2a was identified as a major side product in THF and EA and threecomponent product was not observed (entries 4-5). Toluene provided a high diastereoselectivity of 89:11 and a similar yield (entry 6 vs 1). DCM successfully improved the yield to 93% and with a remaining dr value (syn:anti=95:5, entry 7). The reaction temperature was also found to have an obvious effect on the yield (entries 79), and the best temperature was set at 25 oC. Finally, the optimized condition was indentifed as 1 mol% Rh2(AcO)4 in DCM at 25 oC with 4Å MS to give the product 4a in 93% yield (entry 7). It was worthy of noting that we didn’t observe any side product involved the alkynyl group in propiolamide 2a, which elucidates that the terminal alkynyl group is very stable in this reaction. It may attribute to the rapid trapping process under the mild condition.

4


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Scheme 3.

The synthesis of Alkynylamide-substituted α, β-diamino acid derivatives

under the conditions presented in Ref 17c. Table 1. Optimization for the three-component reaction of 1a, 2a and 3a. a

[M]

Solvent

Temp (oC)

Yield b (%)

Dr c (syn:anti)

Rh2(OAc)4

CHCl3

25

51

93:7

Cu(OTf)2

CHCl3

25

95:5

6


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16

p-MeO-Ph

acetylene

p-Br-Ph/ 2-OH

4o

91

90:10

17

Ph

vinyl

p-Br-Ph/ 2-OH

4p

65

85:15

18

Ph

methyl

p-Br-Ph/ 2-OH

4q

77

80:20

19

Ph

acetylene

p-Br-Ph/ 4-OMe

4r

75

>95:5

a

Reaction conditions: 1: 2: 3: Rh2(OAc)4=1.0/1.0/1.2/0.01 mmol, 1 and 2 in 1mL of CH2Cl2 was added in a solution of 3, Rh2(OAc)4 and 4 Å MS in 1mL

of CH2Cl2 at room temperature for 3h under nitrogen atmosphere. b Isolated yield of 4 based on 1. c Determined by 1H NMR analysis. d Not detected.

The possible reaction mechanism is outlined in Scheme 4. Rh2(OAc)4-catalyzed decomposition of phenyldiazoacetate 1 gives corresponding carbene I. Attack of the lone electron pair of nitrogen at amides 2 by the carbene I gives acyl ammonium ylide intermediate IIa/IIb. Rationally, the protic ammonium ylide IIa/IIb undergoes either 1,2-proton transfer to form N-H bond insertion product 6 or interception by an appropriate electrophiles 3, giving the protic ammonium ylide trapping product 4 via intermediate IIIa/ IIIb. The observed stereochemistry control of the MCRs could be rationalized by comparing the plausible transition states (TS) IIIa and IIIb. A less steric hindrance between the rhodium species and the the aryl ring in the imine leads to a relatively stable TS-IIIa rather than TS-IIIb. Comprehensive consideration of the reason

reveals

that

the

products

4

preferred

the

syn

selectivity.

Scheme 4. The plausible reaction mechanism. The synthetic application of the corresponding multi-component products 4 was illustrated by following the method of Yamamoto,

22

in which AgOTf

23

was used to

activate the triple C-C bond under an argon atmosphere. The reaction afforded benzooxazolopyrazinone derivative 7 in a good yield of 65% and with a good dr value (>95:5). 7



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Product 7 can be also obtained through a multi-component cascade reaction in one-pot reaction using Rh2(OAc)4 and AgOTf cooperative catalysis albeit a low yield of 17% (Scheme 5). The stereo-conformation of product 7 is determined by the single-crystal X-ray crystallography (Figure S1, see Supporting Information) as (3S*,4S*,10R*)-7. Consequently, the stereochemistry of product 4 is assigned as (2S*, 3S*) by comparing with 7 and the 2D NOESY NMR spectra of 4f (Figure S2, see Supporting Information). The mechanism of transformation from 4 into 7 is proposed in scheme 6. Intermediate IV 21 is formed through the AgOTf-coordinated product 4 with 4Å MS as an additive, and subsequent attack of the nitrogen atom at the electron-deficient triple bond leads to intermediate V. Intermediate V undergoes a nucleophilic addition to generate intermediate VI, which affords the desired product 7 via a proton transfer process.

Scheme 5. The one-pot multi-component cascade reaction.

Scheme 6. Plausible reaction mechanism of AgOTf catalyzed the cyclization of threecomponent product. Table 3. The vitro inhibitory activity of products 4 for HCT116, BEL7402 and 8


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SMMC7721 cells. a IC50/ μM b Entry

4 HCT116

BEL7402

SMMC7721

1

4a

1.748

1.874

6.460

2

4b

2.973

2.005

2.902

3

4c

5.938

6.820

6.374

3.660

4.119

c

4

4d

nd

5

4e

2.065

2.577

3.901

6

4f

3.295

4.175

3.464

7

4g

3.194

3.679

3.452

8

4h

1.580

1.540

3.191

9

4i

nd c

5.386

4.293

10

4j

3.282

3.688

4.412

11

4k

3.762

3.141

3.305

12

4l

2.046

2.453

2.591

13

4m

3.155

1.354

3.133

14

4n

3.409

2.724

3.072

15

4o

2.760

2.323

5.140

c

nd c

16

4p

nd

17

4q

nd c

nd c

nd c

18

4r

6.663

0.977

4.861

a

nd

c

The vitro assay produced by the tested compounds at 10 μM on HCT116, BEL7402 and SMMC7721 cells. b The IC50 of compounds were not determined

since the inhibition rate at 10 μM was lower than 50%. c The IC50 of compounds were not determined since the inhibition rate at 10 μg/mL was lower than 50%.

The value of our practically synthesized novel products for hit hunting has been demonstrated in exploring biological activity in HCT116, BEL7402 and SMMC7721 cells, and the results were shown in Table 3. Most of the preliminary resulting products 4 exhibited significant inhibitory activity with IC50 values in the low micromolar range (16 out of 18 examples, 0.98-6.82 μM). Interestingly, in the bioassay in vitro, although products 4d and 4i revealed no activity in HCT116 cells, the two products showed good anticancer activity in BEL7402 and SMMC7721 cells (entries 4 and 9). Prodcuts 4p and 4q bearing alkenyl and alkyl instead of terminal alkynyl were completely inactive, which indicated that alkynyl group is necessary for anticancer activity (entries 16-17).

Coclusions In summary, we have successfully developed an efficient one-pot route to rapidly construct alkynylamide-substituted α,β-diamino acid derivativesalkynylamide in 9



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moderate to good yields with excellent diastereoselectivity from simple starting materials. The established method provides a direct approach to introduce a terminal alkynyl moiety into complex molecules for hit hunting under mild reaction conditions. The synthetic application of the products was also demonstrated by AgOTf catalysis to afford the corresponding benzo-oxazolopyrazinone derivative 7. The biological assays reveal that the resulting products 4 may be a new potential class of anticancer drugs, which validates the promising application of the developed method in drug discovery.

EXPERIMENTAL SECTION General. All moisture sensitive reactions were carried out under an argon atmosphere in a well-dried glassware. Dichloromethane (DCM) and aceticether (EA) were freshly distilled over calcium hydride, toluene from sodium benzophenone ketyl, tetrahydrofuran (THF) from sodium, respectively, prior to use. All commercially available reagents were directly used as received. All 1H NMR and 13C NMR and 19F NMR (376 MHz) spectra were recorded on a 400 MHz spectrometer in CDCl3, DMSOd6 or CD3OD. Chemical shifts are reported in ppm with the solvent signals as reference, and coupling constants (J) are given in Hz. The abbreviations about peak information are described as: s= singlet, d= doublet, t= triplet, q= quartet, m= multiplet. Highresolution mass spectrometry (HRMS) was performed on Q-TOF micro Synapt High Definition Mass Spectrometer. Single crystal X-ray diffraction data were recorded on Bruker-AXS SMART APEX II single crystal X-ray diffractometer. Substrates 1 was synthesized following literature procedure.24 Imine 3 were prepared from condensation of the corresponding aldehydes with amines according to the literature method.25 4 Å MS were dried in a Muffle furnace at 250 oC over 5 hrs. General Experimental Procedure for the Synthesis of Products 4. A mixture of Rh2(OAc)4 (0.0024 mmol), N-arylaldimines 3 (0.24 mmol) and 4 Å MS (0.1 g) in DCM (1 mL) under an argon atmosphere were strirred at room temperature. Phenyldiazoacetate compound 1 (0.2 mmol) and propiolamide 2 (0.2 mmol) in DCM (1 mL) were then added over 1 h via a syringe pump at room temperature. After completion of the addition, the reaction mixture was stirred for another 5 h under 25 oC. 10


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After the completion of the reaction (monitored by TLC, until diazo compounds 1 disappeared), the reaction mixture was filtrated and evaporated in vacuo to give the crude products 4. The crude products 4 were purified by flash chromatography on silica gel (EtOAc/ light petroleum ether = 1:20~1:5) and stirred in light methyl tert-butyl ether to give the pure products 4 as a white solid. Diastereoselectivity was determined by 1H NMR spectroscopy of the crude reaction mixture. General Experimental Procedure for the Synthesis of Products 7. The three component products 4 (0.2mmol) and 4Å MS (0.1 g) in DCM (2 mL) was agitated at 0℃ between 5 min. AgOTf (0.04mmol) was then added, keeping the low temperature to stir for another 1h. When becoming green, the reaction mixture continued to stir for 1h until substrates 4 disappeared in TLC. The reaction mixture was filtrated and evaporated in vacuo to give the crude products 7. The crude products 7 were purified by flash chromatography on silica gel (EtOAc/ light petroleum ether = 1:10~1:5) to give the pure products 7. Diastereoselectivity was determined by 1H NMR spectroscopy of the crude reaction mixture. Methyl-3-(4-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamidopropanoate (syn-4a). 91.5mg, 93% yield. 1H NMR (400 MHz, MeOD) δ 7.34-2.28 (m, 4H), 7.21-7.19 (d, J = 6.4 Hz, 3H), 7.09 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 6.19 (d, J = 7.5 Hz, 1H), 5.48 (s, 1H), 3.60 (s, 1H), 3.59 (s, 1H). 13C NMR (100 MHz, MeOD) δ 171.6, 154.4, 145.9, 139.6, 137.1 (J = 2.6 Hz), 132.4, 131.6, 129.4, 129.2, 128.3, 122.9, 121.0, 118.1, 114.6, 111.9, 77.9, 77.3, 72.2, 63.1, 53.9. HRMS (ESI): calcd for C25H22BrN2O4 ([M+H]+): 493.0785, found 493.0793. Methyl-3-(4-fluorophenyl)-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamidopropanoate (syn-4b). 80.4mg, 93% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.23 (s, 1H), 7.40-7.25 (m, 5H), 7.12 (m, 2H), 7.04 (m, 2H), 6.58 (dd, J = 7.5, 1.28 Hz, 1H), 6.45 (t, J = 7.1 Hz, 1H), 6.38-6.30 (t, J =7.5, 1H), 6.23 (d, J = 7.1 Hz, 1H), 5.80 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 8.0 Hz, 1H), 4.34 (s, 1H), 3.59 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.6, 161.5 (d, J = 243.6 Hz), 151.7, 144.3, 136.5, 135.4, 134.5, 130.3 (d, J = 8.3 Hz), 127.7 (d, J = 7.5 Hz), 127.1, 119.3, 116.3, 114.5 (d, J = 21.2 Hz), 113. 3, 110.5, 77.7, 77.5, 69.3, 61.2, 52.7. 19F NMR (376 MHz, DMSO-d6) δ -115.08. HRMS(ESI): Calcd. for C25H21FN2O4Na ([M+ Na]+): 455.1383 , Found: 455.1369. Methyl-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamido-3-(4-(trifluoromethyl)phenyl)propanoate (syn-4c). 67.5mg, 70% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.27 (s, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.34 (m, 11



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7H), 6.58 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.35 (t, J = 7.5 Hz, 1H), 6.23 (d, J = 7.7 Hz, 1H), 5.83 (d, J = 7.9 Hz, 1H), 5.51 (d, J = 7.9 Hz, 1H), 4.36 (s, 1H), 3.59 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.5, 151.9, 144.3, 143.6, 136.3, 135.2, 129.3, 127.9 (d, J = 6.7 Hz), 127.0, 124.5, 119.4, 116.5, 113.4, 110.4, 77.7, 77.6, 69.2, 61.3, 52.8.

19F

NMR (376 MHz, DMSO-d6) δ -60.81. HRMS(ESI): Calcd. for C26H21F3N2O4Na ([M+ Na]+):

505.1351, Found: 505.1331. Methyl-3-((2-hydroxyphenyl)amino)-3-(4-methoxyphenyl)-2-phenyl-2-propiolamidopropanoate (syn-4d). 69.3 mg, 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.25 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 20.0, 8.7 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.89 (t, J = 10.8 Hz, 2H), 6.58 (d, J = 7.0 Hz, 1H), 6.45 (t, J = 7.4 Hz, 1H), 6.34 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.78 (m, 2H), 5.33 (d, J = 7.7 Hz, 1H), 4.34 (s, 1H), 3.74 (s, 3H), 3.59 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.7, 158.6, 151.7, 144.2, 138.1, 135.3, 130.6, 128.4, 128.1, 120.7, 119.3, 116.3, 113.3, 113.2, 77.7, 77.5, 68.7, 61.1, 55.0, 54. 9, 52.7. HRMS (ESI): calcd for C26H25N2O5 ([M+H]+): 445.1763, found 445.1744. Methyl-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamido-3-(p-tolyl)propanoate (syn-4e). 66.8mg, 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.09 (s, 1H), 7.44-7.21 (m, 5H), 7.01 (d, J = 7.7 Hz, 2H), 6.94 (d, J = 7.7 Hz, 2H), 6.58 (d, J = 7.4 Hz, 1H), 6.44 (t, J = 7.6 Hz, 1H), 6.33 (t, J = 7.4 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.90 (d, J = 7.8 Hz, 1H), 5.29 (d, J = 7.8 Hz, 1H), 4.34 (s, 1H), 3.61 (s, 3H), 2.22 (s, 3H).13C NMR (100 MHz, DMSO-d6) δ 169.7, 151.7, 144.2, 136.6, 136. 5, 135.6, 135.2, 128.4, 128.2, 127.70, 127.65, 127.3, 119.3, 116.1, 113.3, 110.4, 77.7, 77.5, 69.4, 61.6, 52.8, 20.6. HRMS(ESI) :Calcd. for C26H24N2O4Na ([M+Na]+): 451.1634, Found: 451.1640. Methyl-3-(3-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamidopropanoate (syn-4f). 68.9mg, 70% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.28 (s, 1H), 7.51-7.23 (m, 7H), 7.17 (2, 2H), 6.59 (d, J = 6.9 Hz, 1H), 6.46 (t, 1H), 6.37 (t, 1H), 6.27 (d, J = 6.9 Hz, 1H), 5.74 (d, J = 6.5 Hz, 1H), 5.39 (d, J = 6.5 Hz, 1H), 4.37 (s, 1H), 3.57 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.5, 151.8, 151.7, 144.2, 144.1, 141.5, 136.3, 135.2, 131.1, 130.4, 129.7, 127.8, 127.6, 127.0, 121.1, 119.4, 116.5, 113.4, 110.5, 77.6, 69.3, 61.3, 52. 7. HRMS(ESI) :Calcd. for C25H21BrN2O4Na ([M+Na]+): 515.0582 , Found:515.0582. Methyl-3-(2-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamidopropanoate (syn-4g). 53.1mg, 54% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.40 (s, 1H), 7.43-7.11 (m, 9H), 6.61 (d, J = 7.5 Hz, 1H), 6.44 (t, J = 7.4 Hz, 1H), 6.34 (t, J = 7.3 Hz, 1H), 6.20 (dd, J = 12.6, 8.3 Hz, 2H), 5.29 (d, J = 8.5 Hz, 1H), 4.40 (s, 1H), 3.67 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 168.9, 151.59, 144.3, 136.9, 136.1, 135.0, 131.9, 129.8,

12


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129.3, 128.1, 127.6, 127.4, 127.1, 126.9, 119.3, 116.5, 113.4, 110.6, 77.8, 77.6, 67.8, 61.0, 52.6. HRMS(ESI): Calcd. for C25H21BrN2O4Na ([M+Na]+): 515.0582 , Found: 515.0608. Methyl-3-((2-hydroxyphenyl)amino)-2,3-diphenyl-2-propiolamidopropanoate (syn-4h). 62.1mg, 75% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, J = 17.2 Hz, 2H), 7.28 (dd, J = 29.1, 25.1 Hz, 8H), 7.08 (s, 2H), 6.58 (d, J = 7.3 Hz, 1H), 6.35 (dd, J = 44.7, 26.0, 7.3 Hz, 3H), 5.92 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.33 (d, J = 7.7 Hz, 1H), 4.35 (s, 1H), 3.61 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.7, 151.7, 144.2, 138.3, 136.5, 135.6, 128.3, 127.7, 127. 6, 127.3, 119.3, 116.2, 113.3, 110.4, 77.7, 77.5, 75.4, 69.3, 62.0, 54.9, 52.8. HRMS (ESI): calcd for C25H23N2O4 ([M+H]+): 415.1677, found 415.1658. Methyl-3-((2-hydroxyphenyl)amino)-3-(naphthalen-2-yl)-2-phenyl-2-propiolamidopropanoate (syn-4i). 82.6mg, 89% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.37 (s, 1H), 7.83 (dd, J = 13.7, 7.7 Hz, 2H), 7.58 (s, 1H), 7.51-7.33 (m, 3H), 7.29-7.15 (m, 3H), 7.06 (dd, J = 19.9, 6.8 Hz, 3H), 6.60 (d, J = 6.3 Hz, 1H), 6.27 (d, J = 6.4 Hz, 3H), 6.00 (d, 7.15 (m, 3H), 7.06 (dd, J = 19.9, 6.8 Hz, 3H), 6.60 (d, J = 6.3 Hz, 1H), 6.27 (d, J = 6.4 Hz, 3H), 6.00 (d, J = 6.1 Hz, 1H), 5.85 (d, J = 6.8 Hz, 1H), 4.38 (s, 1H), 3.52 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.2, 151.6, 144.3, 136.5, 135.6, 134.2, 132.5, 132.4, 128.5, 128.3, 127.9, 127.3, 127.1, 125.9, 125.0, 119.2, 116.2, 113.3, 110.2, 77.8, 77.5, 68.5, 52.5. HRMS (ESI): calcd for C29H25N2O4 ( [M+H]+): 465.1799, found 465.1814. Methyl-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiolamido-3-(thiophen-2-yl)propanoate (syn-4j). 48.7mg, 58% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.21 (s, 1H), 7.33 (m, 6H), 6.93-6.88 (m, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.52 (t, J = 7.2 Hz, 1H), 6.39 (dd, J = 11.8, 7.6 Hz, 2H), 5.73 (s, 2H), 4.36 (s, 1H), 3.62 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.7, 151.8, 144.3, 143.3, 135.7, 135.5, 127.9, 127.0, 126.4, 126.3, 125.8, 119.4, 116.7, 113.4, 110.4, 77.7, 77.6, 69.8, 58.1, 52.9. HRMS(ESI): Calcd. for C23H20SN2O4Na ([M+ Na]+): 443.1041, Found: 443.1052. Methyl-3-(furan-2-yl)-3-((2-hydroxyphenyl)amino)-2-phenyl-2-propiol-amidopropanoate (syn-4k). 48.5mg, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.33 (s, 1H), 7.52 (s, 1H), 7.41-7.31 (m, 5H), 6.67 (d, J = 7.5 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.53-6.42 (m, 2H), 6.36 (m, 1H), 6.25 (d, J = 3.0 Hz, 1H), 5.48 (d, J = 9.7 Hz, 1H), 5.40 (d, J = 9.7 Hz, 1H), 4.39 (s, 1H), 3.67 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.6, 151.7, 151.5, 144.4, 142.4, 135.8, 135.4, 127.6, 127.6, 127.1, 119.4, 116.9, 113.6, 110.8, 110.2, 109.1, 77.8, 77.3, 68.4, 56.7, 52.6. HRMS(ESI): Calcd. for C23H20N2O5Na ([M+ Na]+): 427.1270, Found: 427.1258. Methyl-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-((2-hydroxyphenyl)amino)-2-propiolamidopropanoate (syn-4l). 84.8mg, 88% yield. 1H NMR (400 MHz, MeOD) δ 7.31-7.15 (m, 6H), 7.09 (d, J = 8.5 Hz, 2H), 6.56-6.49 (d, J = 7.1 Hz, 1H), 6.43 (t, J = 7.6 Hz, 1H), 6.34 (t, J = 7.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.38 (s, 1H), 3.64 (s, 3H).13C 13



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NMR (100 MHz, MeOD) δ 171.0, 154.4, 146.0, 139.7, 138.5, 136.9, 135.2, 134.9, 131.2, 130.7, 129.3, 129.2, 128. 8, 126.9, 121.0, 118.4, 114.7, 112.3, 71.6, 63.7, 54.0. HRMS(ESI) :Calcd. for C25H21Cl2N2O4 ([M+H]+): 483.0878, Found: 483.0879. Methyl-2,3-bis(4-chlorophenyl)-3-((2-hydr-oxyphenyl)amino)-2-propiolamidopropanoate (syn-4m). 68.5mg, 71% yield. 1H NMR (400 MHz, MeOD) δ 7.28 (d, J = 8.8 Hz, 2H), 7.24-7.16 (m, 4H), 7.12 (d, J = 8.5 Hz, 2H), 6.556.49 (m, 1H), 6.43 (dd, J = 7.6, 6.6 Hz, 1H), 6.33 (t, J = 7.5, 6.5 Hz, 1H), 6.19 (d, J = 7.1 Hz, 1H), 5.40 (3, 1H), 3.63 (s, 3H). 13C NMR (100 MHz, MeOD) δ 171.2, 154.4, 145.9, 138.7, 137.0, 136.2, 135.1, 134.9, 131.2, 130.2, 129.39, 129.36, 121.0, 118.3, 114.7, 112.1, 71.8, 63.5, 54.0. HRMS(ESI): Calcd. for C25H20Cl2N2O4Na ([M+ Na]+): 505.0698, Found: 505.0679. Methyl-3-(4-bromophenyl)-2-(4-chlorophenyl)-3-((2-hydroxyphenyl)amino)-2-propiolamidopropanoate

(syn-

4n). 73.6mg, 70% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.30 (s, 1H), 7.56-7.32 (m, 6H), 7.06 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 7.4 Hz, 1H), 6.45 (t, J = 7.4 Hz, 1H), 6.36 (t, J = 7.3 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 8.2 Hz, 1H), 5.29 (d, J = 8.2 Hz, 1H), 4.37 (s, 1H), 3.60 (s, 3H).

13C

NMR (100 MHz, DMSO-d6) δ

169.1, 151.8, 144.3, 137.6, 135.8, 135.1, 132.5, 130.7, 130.6, 129.1, 127.7, 120.9, 119.3, 116.6, 113.4, 110.7, 77.8, 77.6, 68.7, 61.6, 52.8. HRMS(ESI): Calcd. for C25H20ClBrN2O4Na ([M+Na]+): 549.0193, Found: 549.0211. Methyl-3-(4-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-(4-methoxy-phenyl)-2-propiolamidopropanoate (syn4o). 95mg, 91% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.25 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 7.0 Hz, 1H), 6.45 (t, J = 7.4 Hz, 1H), 6.34 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.89-5.62 (m, 2H), 5.33 (d, J = 7.7 Hz, 1H), 4.34 (s, 1H), 3.74 (s, 3H), 3.59 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.7, 158.6, 151.7, 144.2, 138.1, 135.3, 130.6, 128.4, 128.1, 120.7, 119.3, 116.3, 113.3, 113.2, 110.3, 77.7, 77.5, 68.7, 61.1, 55.0, 52.7.HRMS (ESI): calcd for C26H24BrN2O5 ([M+H]+): 523.0890, found 523.0869. Methyl-2-acrylamido-3-(4-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-phenylpropanoate (syn-4p). 64.2mg, 65% yield.

1H

NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.43 (s, 1H), 7.41 (d, J = 15.1 Hz, 2H), 7.30 (m, 5H), 7.08

(d, J = 8.1 Hz, 2H), 6.67 (dd, J = 16.9, 10.2 Hz, 1H),6.57 (d, J = 7.4 Hz, 1H), 6.46 (t, J = 7.4 Hz, 1H), 6.34 (t, J = 7.1 Hz, 2H), 6.23 (d, J = 7.7 Hz, 1H), 6.11 (d, J = 16.9 Hz, 1H), 5.68 (d, J = 10.5 Hz, 1H), 5.57 (d, J = 7.0 Hz, 1H), 3.61 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.4, 165.2, 144.2, 138.7, 136.6, 135.7, 131.2, 130.7, 130.5, 128.0, 127.7, 126.9, 120.7, 119.3, 116.0, 113.3, 109.8, 69.4, 60.6, 53.0. HRMS(ESI): Calcd. for C25H23BrN2O4 ([M+Na]+): 517.0739, Found: 517.0717.

14


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Methyl-2-acetamido-3-(4-bromophenyl)-3-((2-hydroxyphenyl)amino)-2-phenylpropanoate (syn-4q). 74.2mg, 77% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.18 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.35-7.25 (m, 5H), 7.11 (d, J = 8.4 Hz, 2H), 6.56 (dd, J = 7.6, 1.2 Hz, 1H), 6.45 (m, 1H), 6.37-6.28 (m, 1H), 6.22 (m, 2H), 5.52 (d, J = 7.4 Hz, 1H), 3.59 (s, 3H), 1.99 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ 170.6, 170.4, 144.2, 138.9, 136.8, 135.7, 130. 7, 130. 6, 127.9, 127.6, 127.0, 120.6, 119.3, 115.9, 113.3, 109.8, 69.2, 60.5, 52.8, 22.9. HRMS(ESI): Calcd. for C24H23BrN2O4Na ([M+Na]+): 505.0739, Found: 505.0716. Methyl-3-(4-bromophenyl)-3-((4-methoxy-phenyl)amino)-2-phenyl-2-propiolamidopropanoate (syn-4r). 75.9mg, 75% yield. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.9 Hz, 2H), 7.34-7.18 (m, 5H), 7.16 (t, J = 7.5 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 8.4 Hz, 2H), 6.20 (d, J = 4.1 Hz, 1H), 5.47 (d, J = 4.1 Hz, 1H), 3.63 (s, 3H), 3.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.6, 151.2, 150. 7, 139.7, 137. 8, 133. 7, 130.9, 128.6, 127.8, 127.5, 125.8, 121.3, 113. 8, 112.5, 74.0, 70.7, 61.2, 54.7, 53.0. HRMS(ESI): Calcd. for C26H23BrN2O4Na ([M+Na]+): 529.0739, Found: 529.0718. (3S*,4S*,10*R)-10a-methyl-1-oxo-3-phenyl-4-(4-(trifluoromethyl)phenyl)-1,3,4,10a-tetrahydro-2H-benzo [4,5]oxazolo[3,2-a]pyrazine-3-carboxylate (7). 62.7mg, 65% yield. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.3 Hz, 2H), 7.43 (m, 4H), 7.32 (d, J = 8.1 Hz, 2H), 6.72 (dd, J = 18.1, 7.5 Hz, 2H), 6.63 (m, 2H), 5.91 (s, 1H), 3.54 (s, 3H), 1.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.4, 145.0, 135.5(J = 250.1 Hz), 129.4, 129.2, 129.1, 128.6 (J = 27.0 Hz), 126.5, 126.2, 125.2(J = 3.7 Hz), 123.6, 121.5, 114.6, 109.8, 95.9, 67.2, 63.5, 53.6, 24.9. 19 F NMR (376 MHz, CDCl3) δ -62.78. HRMS (ESI): calcd for C26H21F3N2O4 ([M+Na]+): 505.1353, found 505.1351.

ASSOCIATED CONTENT Supporting Information 1

H NMR, 13C NMR and 19 F NMR spectra data and HR-MS data for products 4 and 7,

X-ray crystal data for compound 7. The supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *E-mail:[email protected]; [email protected], Fax: 86-21-62221237. Notes 15



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The authors declare no competing financial interest.

ACKNOWLEDGEMENT We greatly thank the National Science Foundation of China (No. 21332003 and No. 21672066) and Science and Technology Commission of Shanghai Municipality (No. 15ZR1411000) for financial support and thank for Mrs Yun Zhao for the help on analysis of the 2D NOESY NMR spectra.

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A Diastereoselective Multicomponent Reaction for Construction of

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