Chemo- and Diastereoselective Synthesis of N-Propargyl

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Chemo- and Diastereoselective Synthesis of N-Propargyl Oxazolidines through a Copper-Catalyzed Domino A3 Reaction Yazhen Zhang, Liliang Huang, Xiaoyang Li, Le Wang, and Huangdi Feng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03244 • Publication Date (Web): 22 Mar 2019 Downloaded from http://pubs.acs.org on March 22, 2019

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

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The Journal of Organic Chemistry

Chemo- and Diastereoselective Synthesis of N-Propargyl Oxazolidines through a Copper-Catalyzed Domino A3 Reaction Yazhen Zhang,† Liliang Huang,† Xiaoyang Li, Le Wang, and Huangdi Feng* College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, 201620, China; *E-mail: [email protected]; †These authors contributed equally

Graphical Abstract O R1 OH R1 NH2

HCHO, R

2

R

CHO

major

3

20 mol% CuCl2, DCE

N

R2

O R3

O R1

N minor

highly chemoselective: up 84% yield

N

Y X

X = I, Br Y = C, N R3

Low diastereomeric ratio

excellent diastereoselective: dr > 20:1

broad substrate scope: 42 examples

ABSTRACT Herein we describe a highly chemoselective A3-coupling/annulation of amino alcohols, formaldehyde, two kinds of aldehydes and alkynes, catalyzed by a copper(II). This cascade reaction, employing readily available materials, provides a new and highly effective access to chiral N-propargyl oxazolidines with good diastereoselectivity (up to >20:1). In the case of ortho-substituted aromatic aldehydes, an intriguing steric effect is observed: a bulky group exhibits a remarkably adverse effect on the diastereoselectivity for the formation of the title molecule.

INTRODUCTION Chiral oxazolidine derivatives have gained considerable attention due to their broad biological profiles in medicinal chemistry1, and wide utilities in chemical and material research.2 Among them, the study of 1,3-oxazolidine compounds as a synthetic antibiotic3 or Ƙ opioid receptor agonist4 is of growing interest, such as Quinocarcin, Malbracheamide B unit and SKY-146 (Fig 1).5 Meanwhile, these structural motifs are diffusely explored as chiral ligands,6 catalysts,7 and chiral building blocks,8 exhibiting high enantioselectivity in asymmetric synthesis. Additionally, some reactivity features of oxazolidine species have been reported in the literature, including nucleophilic additions, ring-opening reactions, and ring expansions.9

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

CO2H H

Me

N N OMe

O

H

Quinocarcin

MeO O

N

N

H Ph

Me Me

Page 2 of 24

O

BOM N

Me

N O

Cl

O Me

O

Malbracheamide B unit

OH

OH SYK-146

Figure 1. Several Pharmacologically Active Molecules with Oxazolidine Unit

Notwithstanding the impressive scope of the oxazolidines, it does not fully exploit the synthetic method for the construction of triple-bond-containing oxazolidines, e.g. N-propargyl oxazolidines. Whereas the reactivity of C≡C triple bonds has gained tremendous popularity, the corresponding N-propargyl oxazolidines should occupy an important position in synthetic chemistry.10 Over the years, chiral amino alcohols have emerged as versatile substrates for the synthesis of a wide range of chiral 1,3-oxazolidines involving the formation of the C-N and the C-O bond.11 In addition, a few reports appeared on the generation of chiral propargylamines while amino alcohols were used as chiral sources (Scheme 1a).12 Among these reports, most synthetic strategies were based on chiral prolinols or 1,3-oxazolidines. However, the use of chain 1,2-amino alcohols has scarcely been introduced, and chemo- and diastereocontrol remains a challenging task. Recently, we have established a metal-free decarboxylation method for the formation of N-propargyl oxazolidines via A3-coupling of formaldehyde, alkynes with in situ generated 1,3-oxazolidines (Scheme 1b).13 Due to their important biological activities and synthetic applications, we next sought to extend this system to the diastereodivergent synthesis of chiral N-propargyl oxazolidines (Scheme 1c). To the best of our knowledge, the one step coupling of amino alcohols with two different aldehydes and alkynes remains elusive in the literature. In particular, two key challenges need to be addressed to achieve the efficient access to target product 5. First, the diastereocontrolled generation of 2,4- or 2,5-disubstituted oxazolidines is typically depending on the structure of the starting 1,2-amino alcohol, N-unsubstituted

substrates

are

relatively

rarely

reported

and

not

amenable

for

diastereoselectivity.14 Moreover, chemoselective methods for the preparation of the desired product 5 are extremely difficult to perform, especially when two different aldehydes are introduced.


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a) Classical approach OH R1

R

1

O R

2

R1

R3

R2Al

HO

N R

NH R OH N H

O

+ R

+

2

R N

R3

R2 cat. Cu, Au, Sn

R3

N

HO

H

R3

R2

b) Our previous work OH R1

+

+

HCHO

R2

COOH

CH2Cl2, 60 oC 11 h

NH2 c) This work (chemo-, diastereoselectivity)

OH R1

HCHO, R

2

R

O 5 2 R1 4 N

CHO

major

R2

R3

N R2

R2

R1 R3

[5-1]

N

undesired O

O R1

N

O R1

[5]

3

NH2 20 mol% CuCl2, DCE

O R1

N

R3

R2 R3

R2

Scheme 1. Diastereoselective Access to Propargylamines and Oxazolidines from Amino Alcohols

RESULTS AND DISCUSSION We launched our studies by examining the coupling of (R)-plenylglycinol 1a, formaldehyde solution 2a, benzaldehyde 3a, and phenylacetylene 4a. To our delight, in the presence of 10 mol% CuBr2 at 80 oC for 10 h, the target oxazolidine 5a was obtained in 52% yield with more than 20:1 diastereomeric ratio (Table 1, entry 1). The structure and stereochemistry of 5a (R) were confirmed by X-ray crystallographic analysis.15 Further optimization of the reaction conditions, such as the ratio of the starting materials, the amount of catalysts, the kind of solvent, and the temperature was performed (Table 1). Owing to homo-coupling 1,3-diyne was detected as a byproduct. The amount of phenylacetylene 4a was tested to inhibit its formation, and the title compound was delivered in 64% and 72% yield, respectively (entries 2 and 3). In the investigation of the solvent effect, we found that 1,4-dioxane, toluene, and acetonitrile, as well as solvent-free conditions, led to a negative effect on the yield, resulting in the generation of byproduct 5-1 (entries 4-7). Next, various copper catalysts were evaluated. The lowest yield of the product (34%) was observed when Cu(OAc)2 was introduced (entry 8). In addition, both CuSO4 and CuI showed moderate efficiency while excellent stereoselectivity was obtained (dr > 20/1, entries 9 and 10). In the case of CuBr, CuCl, and CuCl2, there was an upward trend of the yield (up to 82%), together with an excellent diastereoselectivity (entries 11-13). Notably, reducing the amount of CuCl2 resulted in a decreased yield of the target product (entry 14). Moreover, a slightly increased yield and excellent diastereoselectivity were achieved (84%, dr >



Page 4 of 24

20/1, entry 15) when using 20 mol% CuCl2. The reaction was also sensitive to the reaction temperature, and a lower yield of the expected product was obtained at 100 oC resulting in an increased amount of byproducts (entry 16). Although the reaction temperature at 60 °C still held good diastereoselectivity, only a moderate yield was observed (entry 17). When the reaction was carried out under microwave-irradiation for 30 min, a significantly lower yield of the desired product was observed (entry 18). Table 1: Optimization of Reaction Conditionsa OH Ph 1a

O

O +

NH2

H

H

+

2a

Ph

H 3a

Ph

+

O

catal., solvent temp., 10 h

4a

Ph

Ph

N 5a

Ph

entry

catalyst (mol%)

solvent

temp.(oC)

yieldb (%)

drc

1d

CuBr2 (10)

DCE

80

52%

>20:1

2e

CuBr2 (10)

DCE

80

64%

>20:1

3

CuBr2 (10)

DCE

80

72%

>20:1

4

CuBr2 (10)

1,4-dioxane

80

46%

>20:1

5

CuBr2 (10)

toluence

80

51%

>20:1

6

CuBr2 (10)

CH3CN

80

33%

>20:1

7

CuBr2 (10)

--

80

45%

>20:1

8

Cu(OAC)2 (10)

DCE

80

34%

>20:1

9

CuSO4 (10)

DCE

80

60%

>20:1

10

CuI (10)

DCE

80

57%

>20:1

11

CuBr (10)

DCE

80

66%

>20:1

12

CuCl (10)

DCE

80

80%

>20:1

13

CuCl2 (10)

DCE

80

82%

>20:1

14

CuCl2 (5)

DCE

80

60%

>20:1

15

CuCl2 (20)

DCE

80

84%

>20:1

16

CuCl2 (20)

DCE

100

66%

>20:1

17

CuCl2 (20)

DCE

60

49%

>20:1

18f

CuCl2 (20)

DCE

80

36%

>20:1

aReaction

solvent;

conditions: 1a (0.55 mmol), 2a (0.50 mmol), 3a (0.55 mmol) and 4a (0.40 mmol) in 1 mL of

bIsolated

yield; cDiastereomeric ratios were determined by 1H NMR spectroscopy of the crude

reaction mixture; d0.7mmol 4a was used. e0.55 mmol 4a was used. fmicrowave irradiation for 30 min.

Having identified the optimal reaction conditions, we first examined the scope of his one-pot transformation of amino alcohol 1 and alkyne 4 (Table 2). In general, various substituents seemed to be well-tolerated, giving a variety of oxazolidines with a high diastereomeric ratio and moderate to good yield. All chiral amino alcohols substituted with aryl, alkyl and diphenyl worked well, and provided the corresponding products (5a-5f) with 53−84% yields and with complete diastereoselectivity (diastereometric ratio >20/1) except for 5b (95/5 dr). Additionally,


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a range of phenylacetylenes with various functional groups, including electron-donating groups (methoxyl, methyl, ethyl, t-butyl, phenyl) and electron-withdrawing groups (fluoro, trifluoromethyl), could be readily converted into the oxazolidine-propargylamines 5g-5r in good yields. Furthermore, alkyl substituted alkynes were suitable coupling partners for this domino

reaction,

effectively

leading

to

target

products

5s-5u

with

excellent

diastereoselectivities. It was noteworthy that 3-chloropropyne also could be employed, and the resulting product 5v was obtained in 42% yield with 90/10 dr. Table 2: Scope of the Amino Alcohols 1 and Alkynes 4a OH R1

O +

NH2

1

O

+ H

H

2a

20 mol% CuCl2

R3

3a

DCE 80 oC, 10-11h

N

O

N

Me

5c, 68%, >20/1 dr

5d, 53%, >20/1 dr

O

O

N

Ph

N

Ph

O

N

Ph

O

N

R3

O

Ph

5b, 65%, 95/5 dr

5a, 84%, >20/1 dr

N

5

N

Bn

O R1

4

O

O Ph

+

Me

N

Ph MeO

5e, 69%, >20/1 dr

5f, 81%, >20/1 dr

O Ph

N

Me Ph

5i, 70%, >20/1 dr

Ph 5m, 60%, >20/1 dr

Ph

CF3 Ph

5q, 69%, >20/1 dr

OMe

O

F Ph

5o, 80%, >20/1 dr

N F 5p, 74%, >20/1 dr

O

F

N Ph F

N

5l, 62 %, >20/1 dr

N

Ph

5r, 73%, >20/1 dr

O Ph

O

N

O

N

t-Bu Ph

5k, 74%,>20/1 dr

F 5n, 76%, >20/1 dr

O Ph

Et Ph

O

N

O

N

5j, 71%, >20/1 dr

O Ph

O

O

N

5h, 79%, >20/1 dr

5g, 65%, >20/1 dr

N

5s, 71%, >20/1 dr

O Ph

N

5t, 69%, >20/1 dr

O

N

Ph

N Cl

5u, 50%, >20/1 dr aReaction

5v, 42%, 90/10 dr

conditions: CuCl2 (20 mol%), 1 (0.55 mmol), 2a (0.50 mmol), 3a (0.55 mmol) and 4 (0.40

mmol), in 1,2-dichloroethane (1.0 mL) at 80 oC for 10-11 hours under oil bath; Isolated yield based on alkyne. Diastereomeric ratios were determined by 1H NMR spectroscopy of the crude reaction mixture.



Page 6 of 24

We then evaluated the scope of aldehyde 3 to enhance the applicability of the reaction (Table 3). The reaction performed well for a diverse range of aryl-substituted substrates to afford the desired products 5w-5ze with excellent diastereoselectivities and good yields. The electronic variation of the aryl group was well-tolerated, ranging from electron-donating groups (methyl, dimethyl) to electron-withdrawing groups (bromo, trifluoromethyl, fluoro, nitro). However, the size of the substituent group on the ortho-position of the benzene ring showed a strong influence on the diastereoselectivity. Attaching a bulky substituent (such as bromo) reduced the diastereometric ratio dramatically. In addition, several heterocyclic aldehydes were found suitable for this reaction. In these cases, the desired products 5zf-5zi were obtained in 59−66% yields with high diastereomeric ratios. The effect of alkyl substituents (isobutyl, cyclohexyl, and 2-ethylbutyl) on the reactivity was investigated, but only 5zj was isolated in a yield of 75 %. In other cases, the 4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine was obtained as the main byproduct. Table 3: Substrate Scope of the Aldehydes 3a OH

O

+ Ph

NH2

1a

H

H

2a

+

R2

3

4a

O N

Ph

N

Ph

5x, 65%, >20/1 dr

Br

N Ph

N

O N

Ph

5z, 67%, >20/1 dr

N

Ph

Ph

5zi, 61%, >20/1 dr

Ph

N

Ph

5zd, 71%, >20/1 dr O

N

5zg, 66%, >20/1 dr

O O

N

Ph

Ph

5zj, 75%, >20/1 dr

N

5zk, trace


N

N

5zh, 59%, >20/1 dr O

O

N

F

O

O N

5zf, 63%, >20/1 dr

O

N

5zc,69%, >20/1 dr

O Ph

5ze, 68%, >20/1 dr

N

N

CF3

O

5zb,73%, >20/1 dr NO2

O

N

Me

5y, 70%, >20/1 dr

O

5za, 79%, 89/11 dr

Ph

5

CF3

O

Ph

N

Ph

O

O

5w, 72%, >20/1 dr

Ph

DCE 80 oC, 10-11h

R2

Me

Me

Ph

O

20 mol% CuCl2

+

O

Ph

N

5zl, trace

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aReaction

conditions: CuCl2 (20 mol%), 1a (0.55 mmol), 2a (0.50 mmol), 3 (0.55 mmol) and 4a (0.40

mmol), in 1,2-dichloroethane (1.0 mL) at 80 oC for 10-11h under oil bath; Isolated yield based on alkyne. Diastereomeric ratios were determined by 1H NMR spectroscopy of the crude reaction mixture.

To clearly illustrate steric effect of the ortho-substituents on the diastereoselectivity, a series of ortho-substituted benzaldehydes were examined (Table 4). Increasing the steric bulk of the halogen substituents (chloro, bromo, indo) resulted in reduced diastereoselectivity of the chiral oxazolidine-propargylamine products 5za, 5zm-5zo. Meanwhile, the yield of products 5zn and 5zo was also decreased to 54% and 42% respectively. Notably, good yield and diastereoselectivity of product 5zp were obtained, when 2,6-dichlorobenzaldehyde was treated to amplify the steric hindrance. These results indicated that the atomic radius was part of the key factors to affect the diastereomeric ratio in the process. Here, some substituents of o-benzaldehyde, such as methyl, trifluoromethyl, and nitro were well tolerated to give the target products with a satisfactory diastereomeric ratio, albeit with slightly reduced yield (5w, 5zq, 5zr, 5z). In addition, 2,4,6-trimethoxybenzaldehyde did not lead to the formation of product (5zs) mainly giving the byproduct 4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine. Table 4: Steric hindrance effect of the o-substituted aromatic aldehydesa OH

+ Ph

O

O H

NH2

1a

2a

3

Cl

Ph

Cl

N

Ph

5zp, 72%, >20/1 dr MeO O Ph

O

N MeO

5zs, n.d. aReaction

N

Br

Ph

N

N

Ph

Br

O Ph

Ph

5w, 72%, >20/1 dr

N F3C

5zq, 46%, >20/1 dr

N

I

5zo, 42%, 81/19 dr Cl

O

N H 3C

R

5

N

5zn, 54%, 56/44 dr

O

Cl

DCE 80 oC, 10-11h

4a

5za, 79%, 89/11 dr

5zm, 75%, >20/1 dr

Ph

Ph

O

N

O

+

R

O Ph

O

+ H

20 mol% CuCl2

O Ph

N O 2N

5zr, 50%, >20/1 dr

CH3 OMe

O Ph

N H 3C 5z, 67%, >20/1 dr

conditions: CuCl2 (20 mol%), 1a (0.55 mmol), 2a (0.5 mmol), 3 (0.55 mmol) and 4a (0.40 mmol),

in 1,2-dichloroethane (1.0 mL) at 80 oC for 10-11h under oil bath; Isolated yield based on alkyne. Diastereomeric ratios were determined by 1H NMR spectroscopy of the crude reaction mixture; n.d. = not detected.



In order to better understand the process of the reaction, control experiments were performed. (R)-3-benzyl-4-phenyloxazolidine A-1 and (R)-4-phenyloxazolidine A were prepared firstly,16 and both of them was subjected to the standard conditions. Not surprisingly, the desired product 5zt was obtained, which indicated that the C-O bond of oxazolidine ring could be cleaved by copper-alkyne complex (Scheme 2a). However, no desired product 5zu was detected with 46% recycling of starting material A (Scheme 2b). Interestingly, C-O bond of oxazolidine was activated when benzaldehyde was introduced, and desired product 5a was observed (Scheme 2c). Based on control experiments and previous reports,12,14,17 a tentative mechanism is proposed (Scheme 2d). Initially, oxazolidine A was in situ generated from the condensation of amino alcohol 1 and formaldehyde. Then the intermediate A reacted with aldehyde 3, resulting in the formation of a N-substituted oxazolidine B. Subsequently, treatment with copper-alkyne complex, which could be obtained upon terminal alkyne activation by the copper(II) catalyst, afforded the corresponding propargylamine species C with concomitant regeneration of the copper catalyst. Finally, the intramolecular cyclization of intermediate C occurred to afford the titled product 5 through intermediate D. Control Experiments: O a) + Ph N Ph Bn A-1 4a (0.4 mmol) (0.5 mmol)

Ph

A (0.5 mmol)

N H A (0.5 mmol) Ph

O

+ Ph

OH

standard conditions

Ph NH Ph

4a (0.4 mmol)

O

c)

Bn

5zt, 53%, >20/1 dr

+ Ph

N H

Ph

Ph N

O

b)

OH

standard conditions

5zu, n.d. O

standard conditions

+ Ph

Ph

N

Ph

Ph 5a, 48%, >20/1 dr

3a 4a (0.5 mmol) (0.4 mmol)

d) Proposed Mechanism:

R1

R3 N

D

R2

1 H 2O R

R3

N R2

OH

C

R1 B N R2 CuII

O R1

R

2

N

OH

O R2

H 3

R1 A N H

H 2O R3 HCHO + NH2

CuII R3

R3 5

O

O

OH

O

4

HO 1

R1

Scheme 2. Control Experiments and Proposed Mechanism


Page 8 of 24

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CONCLUSIONS In summary, we have developed a copper catalyzed A3-coupling/annulation of readily available amino alcohols, formaldehyde, aldehydes and alkynes to form oxazolidine-propargylamines in reasonable yields with good diastereoselectivities. Moreover, the steric effect on diastereoselectivity was illustrated via evaluating the bulkiness of the ortho-substituent on the aromatic aldehydes. This new activation method endures the dual challenge of chemoselectivity and stereoselectivity, and has a wide range of substrate universality.

EXPERIMENTAL SECTION General Information. Unless otherwise noted, all commercial reagents were used directly as purchased. All work-up and purification procedures were carried out with reagent-grade solvents that had not been pre-dried under ambient atmosphere. Thin-layer chromatography (TLC) was performed and Visualization of the compounds was accomplished with UV light (254 nm) or iodine. Flash column chromatography was performed on silica gel (200–300 mesh). All 1H and 13C NMR spectra were recorded on a Bruker Avance III instrument (400 MHz and 100 MHz, respectively). Chemical shifts (δ) are reported in ppm relative to the tetramethylsilane (TMS) signal or residual protio solvent signal. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br = broad singlet, coupling constant(s) in Hz, integration). Data for

13C

NMR is

reported in terms of chemical shift (δ, ppm). High resolution mass spectra were obtained on a Waters GC-TOFMS mass spectrometer with an electron impact ionization (EI) probe. Optical rotations were recorded on an Anton Paar MCP 5500 polarimeter. X-ray crystallographic analyses were performed on an Bruker APEX-II CCD diffractometer. Melting Point: heating rate: 2°C/min, the thermometer was corrected. General Procedure for the Synthesis of N-Propargyl Oxazolidines. To a test tube equipped with a magnetically stirred chip was added chiral hydroxylamine 1 (0.55 mmol), formaldehyde solution 2a (0.50 mmol), another aldehyde 3 (0.55 mmol) and alkyne 4 (0.40 mmol) in 1,2-dichloroethane (1.0 mL). The catalyst CuCl2 (20% mmol) was added successively, and then the tube was sealed. Finally, the reaction vessel was placed at 80 oC in oil bath for 10-11 hours. After the reaction was completed, the resulting reaction suspension was directly loaded onto a silicon gel column and flashed within 2-10% ethyl acetate in petroleum ether to afford the desired product 5a–5zr as the oil or solid. (2R,4R)-2,4-diphenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5a) The product 5a (113.9 mg, 84% yield, >20/1 dr) was obtained following the general procedure as a white solid; [α]D25 =



−65.2 (c 0.6, CHCl3); MP: 103–105 oC; 1H NMR (400 MHz, CDCl3) δ 7.67–7.63 (m, 2H), 7.56– 7.50 (m, 2H), 7.48–7.42 (m, 3H), 7.41–7.35 (m, 4H), 7.35–7.28 (m, 4H), 5.43 (s, 1H), 4.43– 4.32 (m, 2H), 4.04–3.94 (m, 1H), 3.52 (d, J = 18.0 Hz, 1H), 3.40 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 138.5, 131.9, 129.3, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.1, 123.0, 94.7, 86.2, 83.0, 74.0, 64.4, 36.3; HRMS (EI) m/z calcd for C24H21NO[M]+ 339.1603, found 339.1602. (2R,4R)-4-benzyl-2-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5b) The product 5b (91.8 mg, 65% yield, 95/5 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.57–7.51 (m, 2H), 7.46–7.42 (m, 2H), 7.41–7.36 (m, 3H), 7.34– 7.29 (m, 5H), 7.28–7.20 (m, 3H), 5.27 (s, 1H), 4.01 (t, J = 7.5 Hz, 1H), 3.95–3.87 (m, 1H), 3.71 (d, J = 18.0 Hz, 1H), 3.67–3.57 (m, 1H), 3.45 (d, J = 18.0 Hz, 1H), 3.14–3.07 (m, 1H), 2.80– 2.72 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 139.0, 138.6, 131.7, 131.6, 129.1, 129.1,

128.5, 128.4, 128.3, 128.2, 128.0, 126.4, 123.0, 95.4, 85.8, 83.6, 71.5, 61.2, 39.3, 37.8, 29.7; HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780, found 353.1785. (2S,4S,5S)-2,4,5-triphenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5c) The product 5c (112.9 mg, 68% yield, >20/1 dr) was obtained following the general procedure as a light yellow solid; MP: 94–96 oC; 1H NMR (400 MHz, CDCl3) δ 7.88–7.81 (m, 2H), 7.53–7.43 (m, 5H), 7.3–7.36 (m, 3H), 7.13–7.01 (m, 10H), 5.59 (s, 1H), 5.48 (d, J = 8.7 Hz, 1H), 4.78 (d, J = 8.7 Hz, 1H), 3.62–3.49 (m, 2H);

13C{1H}

NMR (100 MHz, CDCl3) δ 139.1, 137.6, 137.4, 131.8, 129.6,

128.9, 128.7, 128.4, 128.3, 127.7, 127.3, 127.3, 127.2, 127.0, 123.0, 94.2, 86.5, 82.9, 82.8, 68.8, 36.9; HRMS (EI) m/z calcd for C30H25NO[M]+ 415.1936, found 415.1938. (2S,4S)-4-methyl-2-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5d) The product 5d (58.8 mg, 53% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 2H), 7.48–7.41 (m, 2H), 7.41–7.34 (m, 3H), 7.33–7.26 (m, 3H), 5.22 (s, 1H), 4.17 (t, J = 7.1 Hz, 1H), 3.79–3.70 (m, 2H), 3.49–3.36 (m, 2H), 1.23 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.2, 131.8, 129.1, 128.4, 128.3, 128.2, 128.0, 123.0, 94.9, 85.8, 83.1, 73.1, 55.0, 36.2, 15.8; HRMS (EI) m/z calcd for C19H19NO[M]+ 277.1467, found 277.1471. (2S,4S)-4-isopropyl-2-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5e) The product 5e (84.2 mg, 69% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.58–7.51 (m, 2H), 7.46–7.41 (m, 2H), 7.40–7.34 (m, 3H), 7.34–7.27 (m, 3H), 5.30 (s, 1H), 4.01 (t, J = 7.9 Hz, 1H), 3.95 (m, 1H), 3.73 (d, J = 17.9 Hz, 1H), 3.46 (d, J = 17.9 Hz, 1H), 3.26–3.17 (m, 1H), 1.91 (m, 1H), 1.03–0.96 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.3, 131.7, 128.9, 128.3, 128.1, 128.0, 123.1, 95.4, 85.5, 84.3, 68.0, 65.1, 38.8, 29.7, 19.7, 17.0, 1.0; HRMS (EI) m/z calcd for C21H23NO[M]+ 305.1780, found 305.1783.


Page 10 of 24

Page 11 of 24 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


(2S,4S)-2,4-diphenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5f) The product 5f (109.9 mg, 81% yield, >20/1 dr) was obtained following the general procedure as a white solid; [α]D25 = 68.4 (c 0.6, CHCl3); MP: 104–106 oC; 1H NMR (400 MHz, CDCl3) δ 7.68–7.62 (m, 2H), 7.56– 7.50 (m, 2H), 7.47–7.41 (m, 3H), 7.41–7.35 (m, 4H), 7.34–7.28 (m, 4H), 5.43 (s, 1H), 4.45– 4.30 (m, 2H), 4.03–3.95 (m, 1H), 3.52 (d, J = 18.0 Hz, 1H), 3.40 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 138.5, 131.9, 129.3, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.1, 123.0, 94.7, 86.2, 83.0, 74.0, 36.3; HRMS (EI) m/z calcd for C24H21NO[M]+ 339.1603, found 339.1604. (2R,4R)-3-(3-(2-methoxyphenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5g) The product 5g (95.9 mg, 65% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H

NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.46–7.35 (m,

6H), 7.33–7.25 (m, 2H), 6.95–6.87 (m, 2H), 5.48 (s, 1H), 4.48 (t, J = 8.0 Hz, 1H), 4.35 (t, J = 7.5 Hz, 1H), 4.00 (t, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.55 (d, J = 18.0 Hz, 1H), 3.43 (d, J = 18.0 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 160.3, 139.0, 138.7, 133.6, 129.6, 129.2, 128.7,

128.4, 128.2, 128.1, 128.0, 120.4, 110.7, 94.5, 87.2, 82.4, 73.9, 64.1, 55.8, 36.4, 29.7; HRMS (EI) m/z calcd for C25H23NO2[M]+ 369.1729, found 369.1734. (2R,4R)-2,4-diphenyl-3-(3-(m-tolyl)prop-2-yn-1-yl)oxazolidine (5h) The product 5h (111.6 mg, 79% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.74–7.69 (m, 2H), 7.60 (d, J = 7.1 Hz, 2H), 7.52–7.41 (m, 5H), 7.38 (t, J = 7.3 Hz, 1H), 7.34–7.24 (m, 3H), 7.20 (d, J = 7.3 Hz, 1H), 5.49 (s, 1H), 4.50–4.39 (m, 2H), 4.06 (t, J = 7.7 Hz, 1H), 3.57 (d, J = 18.0 Hz, 1H), 3.46 (d, J = 18.0 Hz, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 138.5, 138.1, 134.5, 132.4, 129.8, 129.3, 129.1, 128.9, 128.8, 128.5, 128.3, 128.2, 128.1, 122.8, 94.7, 86.4, 82.5, 74.0, 64.4, 36.2, 21.3;HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780, found 353.1768. (2R,4R)-2,4-diphenyl-3-(3-(p-tolyl)prop-2-yn-1-yl)oxazolidine (5i) The product 5i (101.7 mg, 70% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.67–7.63 (m, 2H), 7.57–7.50 (m, 2H), 7.45–7.37 (m, 5H), 7.35– 7.29 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H), 5.42 (s, 1H), 4.43–4.32 (m, 2H), 4.03–3.95 (m, 1H), 3.51 (d, J = 17.9 Hz, 1H), 3.39 (d, J = 17.9 Hz, 1H) , 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 138.5, 138.3, 131.7, 129.7, 129.2, 129.1, 129.0, 128.7, 128.5, 128.2, 128.1, 119.9, 94.7, 86.2, 82.1, 73.9, 64.3, 36.2, 21.4; HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780, found 353.1781. (2R,4R)-3-(3-(4-ethylphenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5j) The product 5j (104.3 mg, 71% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H

NMR (400 MHz, CDCl3) δ 7.67–7.62 (m, 2H), 7.55–7.50 (m, 2H), 7.44–7.34 (m, 7H), 7.33–

7.28 (m, 1H), 7.15 (d, J = 8.1 Hz, 2H), 5.42 (s, 1H), 4.41 (t, J = 7.9 Hz, 1H), 4.34 (t, J = 7.4 Hz, 1H), 4.02–3.95 (m, 1H), 3.51 (d, J = 17.9 Hz, 1H), 3.39 (d, J = 17.9 Hz, 1H), 2.68–2.60 (m,



Page 12 of 24

2H), 1.23 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 139.1, 138.6, 131.8, 129.3, 128.8, 128.5, 128.2, 128.1, 127.9, 127.8, 120.2, 94.7, 86.3, 82.2, 74.0, 64.4, 36.3, 28.9, 15.4; HRMS (EI) m/z calcd for C26H25NO[M]+ 367.1936, found 367.1939. (2R,4R)-3-(3-(4-(tert-butyl)phenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine

(5k)

The

product 5k (116.9 mg, 74% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.68–7.62 (m, 2H), 7.56–7.49 (m, 2H), 7.44–7.37 (m, 6H), 7.36 (s, 2H), 7.34–7.26 (m, 2H), 5.42 (s, 1H), 4.41 (t, J = 7.9 Hz, 1H), 4.34 (t, J = 7.4 Hz, 1H), 4.03–3.94 (m, 1H), 3.51 (d, J = 18.0 Hz, 1H), 3.39 (d, J = 18.0 Hz, 1H), 1.32 (s, 9H); 13C{1H}

NMR (100 MHz, CDCl3) δ 151.6, 139.1, 138.6, 134.4, 131.6, 129.8, 129.3, 128.8,

128.5, 128.2, 128.1, 125.4, 120.1, 94.7, 86.3, 82.2, 64.4, 36.3, 34.8, 31.2; HRMS (EI) m/z calcd for C28H29NO[M]+ 395.2249, found 395.2251. (2R,4R)-3-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5l) The product 5l (96.0 mg, 62% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H


7.29 (m, 1H), 6.88–6.83 (m, 2H), 5.42 (s, 1H), 4.43–4.32 (m, 2H), 4.02–3.95 (m, 1H), 3.82 (s, 3H), 3.50 (d, J = 17.9 Hz, 1H), 3.39 (d, J = 17.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 139.1, 138.6, 133.2, 129.2, 128.7, 128.4, 128.1, 128.0, 115.2, 114.0, 94.7, 86.0, 81.4, 73.9, 64.3, 55.3, 36.3; HRMS (EI) m/z calcd for C25H23NO2[M]+ 369.1729, found 369.1730. (2R,4R)-3-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine

(5m)

The

product 5m (99.6 mg, 60% yield, >20/1 dr) was obtained following the general procedure as a light yellow solid; MP: 92–94 oC; 1H NMR (400 MHz, CDCl3) δ 7.70–7.65 (m, 2H), 7.64–7.50 (m, 8H), 7.49–7.30 (m, 9H), 5.45 (s, 1H), 4.46–4.34 (m, 2H), 4.05–3.95 (m, 1H), 3.55 (d, J = 18.0 Hz, 1H), 3.44 (d, J = 18.0 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 141.1 140.4,

139.0, 138.5, 132.2, 129.3, 128.9, 128.7, 128.5, 128.2, 128.1, 127.7, 127.0, 121.9, 94.8, 86.0, 83.6, 74.0, 64.4, 36.4; HRMS (EI) m/z calcd for C30H25NO[M]+ 415.1936, found 415.1930. (2R,4R)-3-(3-(2-fluorophenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5n) The product 5n (108.6 mg, 76% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H

NMR (400 MHz, CDCl3) δ 7.68–7.62 (m, 2H), 7.54 (d, J = 7.1 Hz, 2H), 7.46–7.35 (m, 6H),

7.34–7.26 (m, 2H), 7.13–7.05 (m, 2H), 5.43 (s, 1H), 4.43 (t, J = 7.9 Hz, 1H), 4.36 (t, J = 7.4 Hz, 1H), 4.00 (t, J = 7.9 Hz, 1H), 3.54 (d, J = 18.1 Hz, 1H), 3.42 (d, J = 18.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 161.8, 138.9, 138.5, 133.6, 130.0, 129.9, 129.3, 128.8, 128.5, 128.2, 128.1, 123.9, 115.6, 115.4, 111.7, 111.5, 94.6, 88.5, 79.5, 73.9, 64.3, 36.3; HRMS (EI) m/z calcd for C24H20FNO[M]+ 357.1529, found 357.1523. (2R,4R)-3-(3-(3-fluorophenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5o) The product 5o (114.3 mg, 80% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.72–7.61 (m, 2H), 7.52–7.49 (m, 2H), 7.45–7.36 (m, 5H),


Page 13 of 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.35–7.29 (m, 1H), 7.28–7.23 (m, 1H), 7.22–7.17 (m, 1H), 7.14–7.08 (m, 1H), 7.05–6.97 (m, 1H), 5.39 (s, 1H), 4.40–4.31 (m, 2H), 4.08–3.90 (m, 1H), 3.51 (d, J = 18.0 Hz, 1H), 3.39 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.7, 161.2, 138.9, 138.4, 130.0, 129.9, 129.4, 128.8, 128.5, 128.2, 128.1, 127.7, 124.9, 124.8, 118.8, 118.5, 115.7, 115.5, 94.8, 85.0, 84.2, 74.0, 64.6, 36.3; HRMS (EI) m/z calcd for C24H20FNO[M]+ 357.1529, found 357.1536. (2R,4R)-3-(3-(4-fluorophenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5p) The product 5p (105.7 mg, 74% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.75–7.68 (m, 2H), 7.65–7.56 (m, 2H), 7.52–7.43 (m, 7H), 7.42–7.36 (m, 1H), 7.11–7.04 (t, J = 8.7 Hz, 2H), 5.47 (s, 1H), 4.49–4.37 (m, 2H), 4.06 (t, J = 6.4 Hz, 1H), 3.58 (d, J = 17.9 Hz, 1H), 3.46 (d, J = 17.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.8, 161.3, 139.0, 138.5, 133.7, 133.7, 129.3, 128.8, 128.5, 128.2, 128.0, 119.1, 115.7, 115.5, 94.8, 85.1, 82.8, 74.0, 64.6, 36.3; HRMS (EI) m/z calcd for C24H20FNO[M]+ 357.1529, found 357.1532. (2R,4R)-2,4-diphenyl-3-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxazolidine (5q) The product 5q (115.6 mg, 69% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.74–7.68 (m, 2H), 7.65–7.54 (m, 6H), 7.52–7.42 (m, 5H), 7.41–7.35 (t, J = 7.2 Hz, 1H), 5.45 (s, 1H), 4.46–4.36 (m, 2H), 4.05 (t, J = 11.1 Hz, 1H), 3.60 (d, J = 18.0 Hz, 1H), 3.48 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.9, 138.3, 134.4, 132.0, 129.4, 128.8, 128.5, 128.2, 128.1, 128.0, 126.8, 125.3, 125.2, 94.9, 85.9, 84.9, 74.0, 36.4. HRMS (EI) m/z calcd for C25H20F3NO[M]+ 407.1497, found 407.1490. (2R,4R)-3-(3-(3,5-difluorophenyl)prop-2-yn-1-yl)-2,4-diphenyloxazolidine (5r) The product 5r (109.5 mg, 73% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.72–7.66 (m, 2H), 7.62–7.54 (m, 2H), 7.51–7.42 (m, 5H), 7.41–7.33 (m, 1H), 7.01–6.91 (m, 2H), 6.87–6.80 (m, 1H), 5.40 (s, 1H), 4.45–4.33 (m, 2H), 4.04 (t, J = 6.5 Hz, 1H), 3.57 (d, J = 18.0 Hz, 1H), 3.45 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.0, 163.9, 161.5, 161.4, 138.8, 138.3, 129.4, 128.8, 128.5, 128.2, 128.1, 128.1, 128.0, 125.6, 114.9, 114.6, 104.7, 104.4, 104.2, 94.9, 85.5, 84.0, 74.0, 64.7, 36.4; HRMS (EI) m/z calcd for C24H19F2NO[M]+ 375.1435, found 375.1437. (2R,4R)-3-(3-cyclopropylprop-2-yn-1-yl)-2,4-diphenyloxazolidine (5s) The product 5s (86.1 mg, 71% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.69–7.61 (m, 2H), 7.59–7.50 (m, 2H), 7.49–7.38 (m, 5H), 7.38– 7.30 (m, 1H), 5.35 (s, 1H), 4.43–4.28 (m, 2H), 4.04–3.95 (m, 1H), 3.29 (d, J = 17.7, 1.8 Hz, 1H), 3.17 (d, J = 17.7, 1.7 Hz, 1H), 1.31–1.27 (m, 1H), 0.87–0.78 (m, 2H), 0.74–0.63 (m, 2H); 13C{1H}

NMR (100 MHz, CDCl3) δ 139.3, 138.7, 129.1, 128.7, 128.4, 128.1, 128.0, 94.6, 89.6,

73.9, 68.4, 64.2, 35.9, 8.4, 1.1, -0.5; HRMS (EI) m/z calcd for C21H21NO[M]+ 303.1623, found 303.1620.



Page 14 of 24

(2R,4R)-3-(4,4-dimethylpent-2-yn-1-yl)-2,4-diphenyloxazolidine (5t) The product 5t (88.1 mg, 69% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 2H), 7.56–7.50 (m, 2H), 7.48–7.39 (m, 5H), 7.37– 7.32 (m, 1H), 5.34 (s, 1H), 4.38–4.28 (m, 2H), 4.04–3.95 (m, 1H), 3.30 (d, J = 17.6 Hz, 1H), 3.18 (d, J = 17.6 Hz, 1H), 1.30 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.2, 138.7, 129.1, 128.6, 128.4, 128.1, 128.0, 127.9, 95.1, 94.5, 73.9, 71.3, 64.1, 35.7, 31.3, 27.6; HRMS (EI) m/z calcd for C22H25NO[M]+ 319.1933, found 319.1929. (2R,4R)-3-(hept-2-yn-1-yl)-2,4-diphenyloxazolidine (5u) The product 5u (63.8 mg, 50% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 2H), 7.56–7.50 (m, 2H), 7.47–7.38 (m, 5H), 7.36–7.31 (m, 1H), 5.36 (s, 1H), 4.40–4.31 (m, 2H), 4.03–3.95 (m, 1H), 3.34–3.26 (m, 1H), 3.22–3.14 (m, 1H), 2.31–2.19 (m, 2H), 1.61–1.45 (m, 4H), 0.99 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 139.2, 138.6, 129.2, 128.7, 128.4, 128.1, 128.1, 128.0, 127.7, 94.5, 86.4, 85.9, 73.9, 72.9, 64.0, 35.6, 31.1, 22.0, 18.4, 13.7; HRMS (EI) m/z calcd for C22H25NO[M]+ 319.1936, found 319.1936. (2R,4R)-3-(4-chlorobut-2-yn-1-yl)-2,4-diphenyloxazolidine (5v) The product 5v (52.3 mg, 42% yield, 90/10 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.72–7.62 (m, 2H), 7.58–7.51 (m, 2H), 7.49–7.39 (m, 5H), 7.39–7.32 (m, 1H), 5.34 (s, 1H), 4.41–4.30 (m, 2H), 4.22 (s, 2H), 4.01 (t, J = 7.6 Hz, 1H), 3.39 (d, J = 18.0 Hz, 1H), 3.26 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.9, 138.3, 129.3, 128.8, 128.5, 128.2, 128.1, 128.0, 126.8, 94.6, 79.0, 76.7, 73.9, 64.3, 35.7, 31.5; HRMS (EI) m/z calcd for C19H18ClNO[M]+ 311.1077, found 311.1079. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(o-tolyl)oxazolidine (5w) The product 5w (101.7 mg, 72% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.64–7.54 (m, 2H), 7.52–7.46 (m, 4H), 7.45–7.40 (m, 2H), 7.39–7.31 (m, 5H), 7.26–7.22 (m, 1H), 5.42 (s, 1H), 4.47–4.36 (m, 2H), 4.07–3.99 (m, 1H), 3.56 (d, J = 18.0 Hz, 1H), 3.45 (d, J = 17.9 Hz, 1H), 2.45 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 138.8, 138.5, 138.2, 131.8, 130.1, 128.7, 128.7, 128.4, 128.3, 128.2, 128.1, 125.3, 123.0, 94.7, 86.2, 82.9, 73.9, 64.3, 36.2, 21.5; HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780, found 353.1773. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(m-tolyl)oxazolidine (5x) The product 5x (91.8 mg, 65% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.64–7.56 (m, 2H), 7.54–7.47 (m, 4H), 7.47–7.42 (m, 2H), 7.41–7.34 (m, 5H), 7.30–7.22 (m, 1H), 5.44 (s, 1H), 4.48–4.37 (m, 2H), 4.08–3.99 (m, 1H), 3.57 (d, J = 18.0 Hz, 1H), 3.47 (d, J = 18.0 Hz, 1H), 2.46 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 138.9, 138.5, 138.2, 131.8, 130.1, 128.7, 128.7, 128.3, 128.2, 128.1, 125.3, 123.1, 94.8, 86.2, 83.0, 73.9, 64.4, 36.3, 21.5;HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780,


Page 15 of 24 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


found 353.1782. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(p-tolyl)oxazolidine (5y) The product 5y (98.8 mg, 70% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H


7.34 (m, 4H), 7.27 (d, J = 8.5 Hz, 2H), 5.43 (s, 1H), 4.46–4.35 (m, 2H), 4.02 (t, J = 7.6 Hz, 1H), 3.55 (d, J = 17.9 Hz, 1H), 3.44 (d, J = 17.9 Hz, 1H), 2.42 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 139.1, 138.6, 136.0, 131.8, 129.2, 128.7, 128.3, 128.2, 128.1, 128.1, 123.1, 94.6, 86.1, 83.0, 73.9, 64.4, 36.3, 21.3; HRMS (EI) m/z calcd for C25H23NO[M]+ 353.1780, found 353.1780. (2R,4R)-2-(2,5-dimethylphenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5z) The product 5z (98.4 mg, 67% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.63–7.57 (m, 3H), 7.52–7.43 (m, 4H), 7.41–7.35 (m, 4H), 7.13 (d, J = 1.0 Hz, 2H), 5.71 (s, 1H), 4.48–4.37 (m, 2H), 4.08–3.97 (m, 1H), 3.58 (d, J = 17.9 Hz, 1H), 3.46 (d, J = 17.9 Hz, 1H), 2.59 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.5, 135.6, 135.5, 134.9, 131.8, 130.7, 129.6, 129.0, 128.8, 128.4, 128.2, 128.1, 128.1, 123.1, 92.2, 86.2, 83.1, 73.6, 64.4, 36.2, 21.2, 18.7; HRMS (EI) m/z calcd for C26H25NO[M]+ 367.1936, found 367.1938. (2R,4R)-2-(2-bromophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5za)

The

product 5za (131.8 mg, 79% yield, 89/11 dr) was obtained following the general procedure as a white solid; MP: 117–119 oC; 1H NMR (400 MHz, CDCl3) δ 7.96–7.91 (m, 1H), 7.66–7.56 (m, 3H), 7.51–7.41 (m, 5H), 7.41–7.33 (m, 4H), 7.30–7.24 (m, 1H), 5.98 (s, 1H), 4.55–4.45 (m, 1H), 4.40 (t, J = 7.4 Hz, 1H), 4.05–3.98 (m, 1H), 3.59 (d, J = 17.9 Hz, 1H), 3.49 (d, J = 17.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.1, 137.8, 133.0, 131.8, 130.5, 130.1, 128.8, 128.3, 128.2, 128.2, 128.1, 127.7, 124.8, 123.0, 93.0, 86.2, 83.1, 73.9, 64.6, 36.6; HRMS (EI) m/z calcd for C24H20BrNO[M]+ 417.0728, found 417.0734. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(3-(trifluoromethyl)phenyl)oxazolidine (5zb) The product 5zb (118.9 mg, 73% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61–7.55 (m, 3H), 7.51–7.42 (m, 4H), 7.40–7.33 (m, 4H), 5.52 (s, 1H), 4.49–4.38 (m, 2H), 4.08–4.00 (m, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.43 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.4, 137.9, 131.8, 131.6, 128.9, 128.8, 128.4, 128.3, 128.0, 126.1, 126.1, 125.0, 124.9, 122.8, 94.0, 86.4, 82.5, 74.0, 64.6, 36.4; HRMS (EI) m/z calcd for C25H20F3NO[M]+ 407.1497, found 407.1498. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(4-(trifluoromethyl)phenyl)oxazolidine (5zc) The product 5zc (112.4 mg, 69% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.1 Hz, 2H), 7.73 (d, J



Page 16 of 24

= 8.1 Hz, 2H), 7.57 (d, J = 7.0 Hz, 2H), 7.50–7.41 (m, 4H), 7.41–7.34 (m, 4H), 5.52 (s, 1H), 4.50–4.39 (m, 2H), 4.04 (t, J = 7.2 Hz, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.43 (d, J = 18.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 143.3, 138.0, 131.8, 128.8, 128.5, 128.4, 128.3, 128.0,

125.5, 125.4, 122.8, 94.0, 86.4, 82.6, 74.1, 64.7, 36.5; HRMS (EI) m/z calcd for C25H20F3NO[M]+ 407.1497, found 407.1497. (2R,4R)-2-(4-fluorophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5zd)

The

product 5zd (101.4 mg, 71% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.74–7.67 (m, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.57– 7.50 (m, 2H), 7.46 (t, J = 7.3 Hz, 2H), 7.42–7.36 (m, 4H), 7.18 (t, J = 8.7 Hz, 2H), 5.48 (s, 1H), 4.51–4.39 (m, 2H), 4.05 (t, J = 7.7 Hz, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.44 (d, J = 18.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 164.7, 162.3, 138.4, 134.9, 131.8, 130.1, 130.0, 128.8,

128.4, 128.2, 128.1, 123.0, 115.6, 115.3, 94.1, 86.3, 82.8, 73.9, 64.4, 36.2; HRMS (EI) m/z calcd for C24H20FNO[M]+ 357.1529, found 357.1531. (2R,4R)-2-(4-nitrophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5ze)

The

product 5ze (104.5 mg, 68% yield, >20/1 dr) was obtained following the general procedure as a light yellow solid; MP: 114–116 oC; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.3 Hz, 2H), 7.48–7.41 (m, 4H), 7.37 (s, 4H), 5.54 (s, 1H), 4.53–4.35 (m, 2H), 4.08–3.99 (m, 1H), 3.59 (d, J = 18.1 Hz, 1H), 3.41 (d, J = 18.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 148.6, 146.5, 137.5, 131.7, 129.0, 128.8, 128.4, 128.4,

127.9, 123.7, 122.6, 93.4, 86.5, 82.2, 74.1, 64.7, 36.5; HRMS (EI) m/z calcd for C24H20N2O3[M]+ 384.1474, found 384.1478. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(pyridin-2-yl)oxazolidine (5zf) The product 5zf (85.7 mg, 63% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.68–8.64 (m, 1H), 7.85–7.80 (m, 2H), 7.60–7.51 (m, 2H), 7.48–7.38 (m, 4H), 7.38–7.29 (m, 5H), 5.59 (s, 1H), 4.55–4.47 (m, 1H), 4.44 (t, J = 7.3 Hz, 1H), 4.10–4.01 (m, 1H), 3.70 (d, J = 17.8 Hz, 1H), 3.61 (d, J = 17.8 Hz, 1H);

13C{1H}

NMR (100

MHz, CDCl3) δ 159.7, 149.0, 138.2, 138.2, 136.9, 131.9, 128.7, 128.2, 128.1, 128.1, 128.0, 123.6, 123.0, 121.5, 95.0, 86.1, 83.2, 74.3, 64.9, 37.1; HRMS (EI) m/z calcd for C23H20N2O[M]+ 340.1576, found 340.1574. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(pyridin-3-yl)oxazolidine (5zg) The product 5zg (89.8 mg, 66% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 1.6 Hz, 1H), 8.70–8.65 (m, 1H), 8.04– 7.98 (m, 1H), 7.61–7.52 (m, 2H), 7.50–7.34 (m, 9H), 5.50 (s, 1H), 4.47–4.36 (m, 2H), 4.06– 3.98 (m, 1H), 3.58 (d, J = 18.0 Hz, 1H), 3.41 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.6, 149.9, 137.9, 135.8, 134.7, 131.8, 128.8, 128.3, 128.3, 127.9, 123.6, 122.7, 92.8, 86.5, 82.4, 74.0, 64.6, 36.4; HRMS (EI) m/z calcd for C23H20N2O[M]+ 340.1576, found 340.1573.


Page 17 of 24 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


(2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(pyridin-4-yl)oxazolidine (5zh) The product 5zh (80.3 mg, 59% yield, >20/1 dr) was obtained following the general procedure as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.9 Hz, 2H), 7.62–7.57 (m, 2H), 7.56–7.50 (m, 2H), 7.49–7.34 (m, 8H), 5.46 (s, 1H), 4.50–4.37 (m, 2H), 4.03–3.96 (m, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.45 (d, J = 18.0 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 161.6, 150.1, 148.2,

137.7, 131.8, 128.8, 128.4, 128.3, 127.9, 122.8, 93.2, 86.5, 82.4, 74.2, 64.8, 36.7; HRMS (EI) m/z calcd for C23H20N2O[M]+ 340.1576, found 340.1576. (2R,4R)-2-(furan-2-yl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5zi) The product 5zi (80.3 mg, 61% yield, >20/1 dr) was obtained following the general procedure as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.61–7.53 (m, 3H), 7.50–7.46 (m, 2H), 7.45–7.40 (m, 2H), 7.38–7.34 (m, 4H), 6.65 (d, J = 3.1 Hz, 1H), 6.46–6.42 (m, 1H), 5.63 (s, 1H), 4.44–4.38 (m, 1H), 4.33 (t, J = 7.2 Hz, 1H), 4.01–3.95 (m, 1H), 3.64 (s, 2H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 152.5, 143.4, 137.9, 131.8, 128.7, 128.3, 128.3, 128.1, 128.0, 122.9, 110.2, 109.3, 88.1, 86.2, 82.9, 7, 73.6, 64.5, 37.2; HRMS (EI) m/z calcd for C22H19NO2[M]+ 329.1416, found 329.1410. (2R,4R)-2-isopropyl-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5zj) The product 5zj (95.2 mg, 75% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.54–7.46 (m, 4H), 7.44–7.31 (m, 6H), 4.56 (s, 1H), 4.37– 4.28 (m, 1H), 4.25 (t, J = 7.2 Hz, 1H), 3.78–3.70 (m, 1H), 3.63 (t, J = 14.3 Hz, 2H), 2.10–1.91 (m, 1H), 1.17–1.09 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 131.8, 128.6, 128.3, 128.2, 127.9, 123.1, 97.4, 85.7, 83.6, 73.7, 65.2, 37.8, 31.1, 29.7, 18.8, 15.3; HRMS (EI) m/z calcd for C21H23NO[M]+ 305.1780, found 305.1776. (2R,4R)-2-(2-chlorophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5zm)

The

product 5zm (111.9 mg, 75% yield, >20/1 dr) was obtained following the general procedure as a white solid; MP: 119–121 oC; 1H NMR (400 MHz, CDCl3) δ 7.96–7.91 (m, 1H), 7.64–7.54 (m, 2H), 7.48–7.41 (m, 5H), 7.41–7.31 (m, 6H), 6.03 (s, 1H), 4.52–4.44 (m, 1H), 4.40 (t, J = 7.4 Hz, 1H), 4.06–3.96 (m, 1H), 3.59 (d, J = 17.9 Hz, 1H), 3.50 (d, J = 17.9 Hz, 1H);

13C{1H}

NMR

(100 MHz, CDCl3) δ 138.1, 136.3, 135.0, 131.8, 130.1, 129.8, 129.7, 128.8, 128.3, 128.2, 128.2, 128.1, 127.1, 123.0, 90.8, 86.2, 83.0, 73.9, 64.6, 36.6; HRMS (EI) m/z calcd for C24H20ClNO[M]+ 373.1233, found 373.1234. (2R,4R)-2-(2-bromopyridin-3-yl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5zn)

The product 5zn (90.3 mg, 54% yield, 56/44 dr) was obtained following the general procedure as a white solid; MP: 111–113 oC; 1H NMR (400 MHz, CDCl3) δ 8.46–8.40 (m, 1H), 8.29–8.20 (m, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.48–7.42 (m, 4H), 7.41–7.32 (m, 5H), 5.92 (s, 1H), 4.53– 4.44 (m, 1H), 4.41 (t, J = 7.4 Hz, 1H), 4.00 (t, J = 8.1 Hz, 1H), 3.59 (d, J = 17.8 Hz, 1H), 3.49 (d, J = 17.8 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 151.7, 150.6, 150.0, 144.1, 138.9,

138.7, 137.7, 135.7, 133.5, 131.8, 128.9, 128.4, 128.0, 123.3, 123.0, 122.8, 92.5, 90.7, 86.5,



Page 18 of 24

82.7, 74.0, 64.8, 36.9; HRMS (EI) m/z calcd for C23H19BrN2O[M]+ 418.0681, found 418.0682. (2R,4R)-2-(2-iodophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine

(5zo)

The

product 5zo (78.1 mg, 42% yield, 81/19 dr) was obtained following the general procedure as a white solid; MP: 98–100 oC; 1H NMR (400 MHz, CDCl3) δ 7.94–7.86 (m, 2H), 7.65–7.55 (m, 2H), 7.52–7.41 (m, 5H), 7.40–7.32 (m, 4H), 7.15–7.08 (m, 1H), 5.78 (s, 1H), 4.54–4.45 (m, 1H), 4.39 (t, J = 7.4 Hz, 1H), 4.05–3.96 (m, 1H), 3.58 (d, J = 17.9 Hz, 1H), 3.47 (d, J = 17.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.2, 139.7, 138.0, 131.8, 130.9, 129.9, 128.7, 128.5, 128.2, 128.2, 128.2, 128.0, 123.0, 99.7, 97.3, 90.7, 86.3, 83.0, 73.8, 64.4, 36.5; HRMS (EI) m/z calcd for C24H20INO[M]+ 465.0590, found 465.0590. (2R,4R)-2-(2,6-dichlorophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazolidine (5zp) The product 5zp (117.2 mg, 72% yield, >20/1 dr) was obtained following the general procedure as a white solid; MP: 99–101 oC; 1H NMR (400 MHz, CDCl3) δ 7.67–7.59 (m, 2H), 7.51–7.44 (m, 2H), 7.42–7.39 (m, 3H), 7.38–7.34 (m, 5H), 7.29–7.21 (m, 1H), 6.37 (s, 1H), 4.49–4.38 (m, 2H), 4.24–4.19 (m, 1H), 3.52 (d, J = 17.9 Hz, 1H), 3.41 (d, J = 17.9 Hz, 1H);

13C{1H}

NMR

(100 MHz, CDCl3) δ 137.2, 136.8, 133.5, 132.3, 131.8, 130.2, 129.7, 129.6, 128.7, 128.3, 128.2, 128.2, 123.0, 91.1, 86.2, 82.9, 74.0, 65.1, 36.2; HRMS (EI) m/z calcd for C24H19Cl2NO[M]+ 407.0844, found 407.0848. (2R,4R)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)-2-(2-(trifluoromethyl)phenyl)oxazolidine (5zq) The product 5zq (74.9 mg, 46% yield, >20/1 dr) was obtained following the general procedure as a white solid; MP: 104–106 oC; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.77–7.69 (m, 2H), 7.62 (d, J = 7.1 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.49–7.43 (m, 4H), 7.43–7.33 (m, 4H), 5.94 (s, 1H), 4.55–4.46 (m, 1H), 4.41 (t, J = 7.5 Hz, 1H), 4.08–4.00 (m, 1H), 3.58 (d, J = 17.9 Hz, 1H), 3.43 (d, J = 17.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.1, 138.0, 132.3, 131.8, 130.0, 129.1, 128.8, 128.2, 128.2, 128.0, 125.5, 125.4, 122.9, 89.4, 89.3, 86.1, 82.4, 74.0, 64.3, 36.3; HRMS (EI) m/z calcd for C25H20F3NO[M]+ 407.1497, found 407.1499. ((2R,4R)-2-(5-chloro-2-nitrophenyl)-4-phenyl-3-(3-phenylprop-2-yn-1-yl)oxazoledine (5zr) The product 5zr (88.6 mg, 50% yield, >20/1 dr) was obtained following the general procedure as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.56–7.51 (m, 2H), 7.51–7.37 (m, 6H), 7.36–7.30 (m, 3H), 6.10 (s, 1H), 4.52–4.42 (m, 1H), 4.37 (t, J = 7.4 Hz, 1H), 3.96–3.88 (m, 1H), 3.64 (d, J = 17.8 Hz, 1H), 3.56 (d, J = 17.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.7, 139.2, 137.3, 136.4, 131.9, 130.2, 129.8, 128.9, 128.4, 128.3, 127.9, 125.8, 122.6, 89.3, 86.6, 82.5, 73.7, 65.3, 37.9; HRMS (EI) m/z calcd for C24H19ClN2O3[M]+ 418.1084, found 418.1089. (R)-2-(benzyl(3-phenylprop-2-yn-1-yl)amino)-2-phenylethan-1-ol (5zt) The product 5zt (72.2 mg, 53% yield, >20/1 dr) was obtained following the general procedure as a light yellow


Page 19 of 24 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


oil; 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.29 (m, 15H), 4.19 – 4.07 (m, 2H), 4.01 – 3.90 (m, 2H), 3.69 (d, J = 17.5 Hz, 1H), 3.55 (d, J = 13.3 Hz, 1H), 3.45 (d, J = 17.5 Hz, 1H), 2.51 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.7, 138.2, 131.8, 129.0, 128.9, 128.6, 128.5, 128.3, 128.1, 128.0, 127.3, 123.2, 85.7, 84.9, 66.6, 62.7, 54.4, 39.9.; HRMS (EI) m/z calcd for C24H23NO[M]+ 341.1776, found 341.1779.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR spectra for compounds 5a−5zj, 5zm−5zr (PDF)

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. ORCID Huangdi Feng: 0000-0002-5500-8283 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS The authors thank Prof. Dr Erik Van der Eycken at the University of Leuven (KU Leuven) for revising the English. This work was supported by Shanghai University of Engineering Science and the Innovation Research Projects (nhrc-2015-15, 201810856017, cs1704006). We are grateful to the China Postdoctoral Science Foundation (2016M601681), and the Opening Project of Shanghai Key Laboratory of Chemical Biology for financial support.

NOTES AND REFERENCES (1) (a) Eustice, D. C.; Brittelli, D. R.; Feldman, P. A.; Brown, L. J.; Borkowshi, J. J.; Slee, A. M. An automated pulse labelling method for structure-activity relationship studies with antibacterial oxazolidinones. Drugs Exp. Chim. Res. 1990, 16, 149–155. (b) Williams, R. M.; Cox, R. J. Paraherquamides, Brevianamides, and Asperparalines: Laboratory synthesis and biosynthesis. An interim report. Acc. Chem. Res. 2003, 36, 127–139. (c) Williams, R. M. Total



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synthesis and biosynthesis of the paraherquamides: an intriguing story of the biological Diels– Alder construction. Chem. Pharm. Bull. 2002, 50, 711–740. (d) Qian-Cutrone, J. F.; Huang, S.; Shu, Y. Z.; Vyas, D.; Fairchild, C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao, Q.

Stephacidin

A

and

B:

Two

structurally

novel,

selective

inhibitors

of

the

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Chemo- and Diastereoselective Synthesis of N-Propargyl

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