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Synthesis of Diastereoenriched Oxazolo[5,4-b]indoles via Catalyst-Free Multicomponent Bicyclizations Lu Wang, Li-Xia Shi, Lu Liu, Zhuo-Xuan Li, Ting Xu, Wen-Juan Hao, Guigen Li, Shu-Jiang Tu, and Bo Jiang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00129 • Publication Date (Web): 15 Mar 2017 Downloaded from http://pubs.acs.org on March 16, 2017

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The Journal of Organic Chemistry

Synthesis of Diastereoenriched Oxazolo[5,4-b]indoles via CatalystFree Multicomponent Bicyclizations Lu Wang,a,1 Li-Xia Shi,a,1 Lu Liu,a,1 Zhuo-Xuan Li,a,1 Ting Xu,a,1 Wen-Juan Hao,*,a Guigen Li,b ShuJiang Tu,*,a and Bo Jiang*,a a

School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for

Functional Materials, Jiangsu Normal University, Xuzhou 221116, P. R. China; bDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA. 1These authors contributed equally E-mail [email protected] (WJH); [email protected](SJT); [email protected](BJ) RECEIVED DATE

ABSTRACT. A new and highly eco-friendly approach to diverse and functionalized oxazolo[5,4b]indoles with good yield and high diastereoselectivity (up to >99:1) has been disclosed from simple and readily available arylglyoxals with cyclic enaminones and amino acids. These microwave-assisted transformations in environmentally compatible ethanol resulted in continuous multiple bond-forming events including C−C, C-N and C−O bonds, enabling catalyst-free multicomponent bicyclizations to rapidly build up functional N,O-heterocycles.

ACS Paragon Plus Environment

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Introduction

Development of efficient and practical synthetic strategy toward valuable target compounds, along with minimum environmental impacts, is one of the most significant research goals in academia and industry.1 In this context, metal-free transformations are generally thought to be green and sustainable, especially in the preparation of some fine chemicals and pharmaceutically active ingredients,2 since these compounds are typically allowed in low level of the heavy metal content, which cause a critical and difficult problem in the removal of heavy metal-catalyst from the final products.3 Specifically, multicomponent bicyclization reactions (MBRs) have emerged as a very useful and sustainable platform for the collection of bioactive small-molecule heterocyclic libraries for their SAR studies4 due to their annulation efficiency, economic and environmental aspects, and ease of operation as well as diminished waste disposals.5 If such MBRs can be performed in environmentally benign solvents by using microwave irradiation as an alternatively saving energy source,6 it is feasible to furnish the reactions without percolating anything to the environment during the reaction process. In view of the great environmental awareness of the scientific community, designing environmentally compatible approaches without hazardous chemical ingredients to eliminate toxic waste and byproducts is highly desirable but challenging. As organic solvents are considered to be the highest contributors toward environmental waste, the use of environmentally compatible solvents such as ethanol or water is the utmost priority for organic transformations.7 As a result, the exploration of new MBRs to facilitate the preparation of heterocyclic libraries without the use of hazardous solvents continues to be of great interest in pharmaceutical sciences and drug discovery. Fused indoline heterocycles as key core components are prevalent in a large number of biologically significant alkaloids, natural products, and pharmaceuticals.8 As such, substantial effort has been paid to develop efficient and straightforward methods to synthesize those molecules for their diverse bioactivity profiles, which include anti-inflammatory, and analgesic,9 potent neuroleptic10 and antitumor.11 Most of the synthetic endeavors to construct this bioactive core involve the cascade annulation of indoles.12 To ACS Paragon Plus Environment

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the best of our knowledge, a catalyst-free multi-component bicyclization reaction for the green synthesis of tricyclic oxazolo[5,4-b]indoles from readily available arylglyoxals remains unexplored so far.13 In recent years, our group14 and others15 have been heavily involved in the development of various multicomponent bicyclization reactions (MBRs) for multiple heterocyclic ring formations using arylglyoxals as a reaction partner. To continue our efforts in this project, we found that when cyclic enaminones 2 endowed with C,N-nucleophilic sites were subjected to a reaction with arylglyoxals 1 and amino acids 3 in EtOH under microwave heating (Scheme 1), the reaction proceeded in a 1:2:1 mole ratio of substrates, undergoing an unexpected bicyclization direction to give richly decorated oxazolo[5,4b]indoles with high diastereoselectivity. Notably, single diastereoisomer products were obtained using

β-alanine as a reaction substrate whereas glycine gave a mixed diastereoisomer products with 5:1 to 20:1 diastereomeric ratio. Three stereogenetic centres including a quaternary amino functionality attached on the pyrrole ring have been completely controlled without any catalyst in a one-pot intermolecular manner. The reaction process is environmentally friendly in which water is the major byproduct. This protocol represents the first domino procedure for the eco-friendly synthesis of these new

diastereoenriched

oxazolo[5,4-b]indoles

through

a

microwave-assisted

four-component

bicyclization.

Scheme 1. Synthesis of Diastereoenriched Oxazolo[5,4-b]indoles Results and Discussion Our study commenced with the reaction of the preformed arylglyoxal 1a with cyclic enaminone 2a and β-alanine 3a in a 1:1:1 mole ratio to synthesize N-tetrahydroindol-3-yl β-alanine.16 Unexpectedly, the reaction worked readily in a 1:2:1 mole ratio, enabling a four-component bicyclization toward the clean formation of oxazolo[5,4-b]indoles 4a with three stereogenetic centres and outstanding


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diastereoselectivity. Based on these inspired results, we made our efforts to search the optimal conditions. The results are summarized in Table 1. The reaction of 1a with 2a and 3a in a 2:1:1 mole ratio was conducted in HOAc at 60 oC under microwave heating, and diastereoenriched product 4a was obtained in 45% yield (Table 1, entry 1). The inferior outcomes were observed when CH3CN, MeOH and N,N-dimethylformamide (DMF) as well as 1,4-dioxane were selected as reaction media (entries 25). The use of 1,2-dichloroethane (DCE) and dimethyl sulfoxide (DMSO) completely suppressed the reaction process (entries 6-7). In another case of EtOH, this reaction worked more efficiently, leading to a higher yield (65%) compared with HOAc (entry 8). Exchanging EtOH for H2O lowered the reaction efficiency and the obtainable yield (35%, entry 9). It was also found that the reaction temperature affected the reaction efficiency. Increasing reaction temperature to 80 oC facilitated this transformation, delivering the diastereoenriched product 4a in a higher 85% yield (entry 10). The yield levelled off when the reaction was carried out at 100 oC (entry 11) whereas the lower conversion was detected with reaction temperature being at 120 °C (entry 12). Table 1 Optimization of Reaction Condition for 4a under MWa

Entry

Solvent

Time (min)

T (oC)

Yieldb (%)

1

HOAc

20

60

45

2

CH3CN

26

60

33

3

MeOH

20

60

39

4

DMF

20

60

29

5

1,4-dioxane

20

60

37

6

DCE

25

60

trace


4

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a


7

DMSO

20

60

trace

8

EtOH

20

60

65

9

H2 O

20

60

35

10

EtOH

20

80

85

11

EtOH

20

100

84

12

EtOH

20

120

60

Reaction conditions: arylglyoxal 1a (2.0 mmol, 2.0 equiv.), cyclic enaminone 2a (1.0 mmol, 1.0 equiv), β-alanine

3a (1.0 mmol, 1.0 equiv), solvent (2.0 mL), air conditions, microwave heating. bIsolated yield.

With the above optimal conditions in hand, we then evaluated the scope of substrates. As shown in Scheme 2, a range of cyclic enaminones are applicable to the present catalyst-free bicyclization, in which 2,2-dihydroxy-1-(p-tolyl)ethan-1-one (1a) and β-alanine 3a were first subjected to the reaction with these enaminones of different electronic properties on their phenyl rings to give the desired oxazolo[5,4-b]indoles 4a-4e with 78%-89% yields and outstanding diastereoselectivity (dr > 99:1). It seems that the presence of electron-donating substituent (2e) at the para-position on the arene ring favors the reaction more than their electron-withdrawing counterparts (2a-2c). Similarly, on replacing the aryl group with a 4-methoxybenzyl (4-MeOBn) group on the enaminone unit, cyclic enaminone 2f proved to be a good component for this reaction, providing the expected product 4f in 74% yield. The substrates 1 with methoxy (p-methoxyphenyl, PMP) and bromo functionalities at para positions of arylglyoxal ring would be accommodated, confirming the reaction efficiency, as 4g-4j with high diastereopurity (dr > 99:1) were generated in 74%-88% yields. Alternatively, 4,4-dimethyl substituted cyclic enaminone 2h was successfully engaged in this multicompoent bicyclization, delivering the corresponding product 4k with 79% yield and > 99:1 dr. Next, glycine 3b as a replacement for β-alanine was explored, employing both arylglyoxals 1 and enaminones 2 with different functionalities on the aromatic ring including methyl, methoxy, fluoro, chloro and bromo groups. The results indicated that both electron-rich, neutral and electron-poor counterparts are suitable reaction partners, giving access to


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the corresponding oxazolo[5,4-b]indoles 4l-4y in overall good yields (77%-89%) with 5:1 to 20:1 diastereomeric ratio. We believe different diastereoselectivity observed in the bicyclization of 3a and 3b depends on their steric hindrance, which is consistent with the analysis of X-ray single-crystals of 4g and 4u, showing that the carboxyl group far from the new formed ring is beneficial to the diastereoselectivity (See Supporting Information). Scheme 2. The Scope of Multi-Component Bicyclizationa O

R2 OH R + R1 OH R1

O

R2

2

Ar

H2N

+ NH

R CO2H

O

O O N p-Tolyl R3 4a-4f

CO2H

O H N

H PMP

O O N PMP R3 4p-4q 4p, R3 = 3,4-Cl2Ph (83%) dr = 7:1, 24 min 4q, R3 = p-Tolyl (87%) dr = 5:1, 22 min CO2H

O N

H

4-ClPh

O O N 4-ClPh 4-BrPh 4s (78%), dr = 10:1, 20 min a

4g, R3 = 4-BrPh (83%) dr >99:1, 25 min 4h, R3 = p-Tolyl (88%) dr >99:1, 15 min CO2H

H N

4

H

4-BrPh

CO2H

O H

N

H p-Tolyl

H p-Tolyl

N

O O N p-Tolyl 3 R 4l-4o

O O p-Tolyl

N 4-BrPh 4k (79%), dr >99:1, 22 min CO2H H

Ar

O O N 4-BrPh 3 R 4i-4j 3 4i, R = 4-ClPh (74%) dr >99:1, 23 min 4j, R3 = p-Tolyl (84%) dr >99:1, 17 min

O

O

O Ar

CO2H

H PMP

N

O O N PMP R3 4g-4h

H

CO2H ( )n N H O

O

H

H p-Tolyl

4a, R3 = 4-FPh (85%) dr >99:1, 20 min 4b, R3 = 4-ClPh (80%) dr >99:1, 21 min 4c, R3 = 4-BrPh (84%) dr >99:1, 22 min 4d, R3 = 3,4-Cl2Ph (78%) dr >99:1, 25 min 4e, R3 = PMP (89%) dr >99:1, 18 min 4f, R3 = 4-MeOBn (74%) dr >99:1, 25 min

N

3

O H N

R1 R1

H

3

CO2H

H

MW, 80 oC

R3

2

1

EtOH

CO H ( )n 2

R2 O

H

N

4-FPh

O O N 4-FPh Ph 4r (79%), dr = 5:1, 28 min CO2H O H N H 4-BrPh

4l, R3 = 4-ClPh (81%) dr = 5:1, 26 min 4m, R3 = 4-BrPh (77%) dr = 5:1, 20 min 4n, R3 = 3,4-Cl2Ph (80%) dr = 8:1, 24 min 4o, R3 = Ph (84%) dr = 5:1, 17 min

4u, R3 = 4-ClPh (78%) dr = 20:1, 20 min 4v, R3 = 4-BrPh (82%) dr = 5:1, 25 min 4w, R3 = 4-FPh (80%) CO2H O dr = 7:1, 24 min H N H Ph 4x, R3 = 3,5-Cl2Ph (82%) dr = 10:1, 26 min O O N Ph 4y, R3 = PMP (89%) R3 4u-4y dr = 7:1, 20 min

O O N 4-BrPh 4-FPh 4t (85%), dr = 6:1, 18 min

Reaction conditions: arylglyoxals 1 (2.0 mmol, 2.0 equiv), cyclic enaminones 2 (1.0 mmol, 1.0 equiv) amino acids 3 (1.0 mmol, 1.0 equiv), EtOH (2.0

mL), 80 oC under air conditions, microwave heating. bIsolated yield in brackets.

Similar to our previous four-component domino process,17 the present bicyclization reaction also showed the following attractive features: (1) the high diastereoselectivity (up to dr > 99:1); (2) the use ACS Paragon Plus Environment

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of environmentally compatible solvent; (3) short reaction periods within 15-28 min; (4) convenient workup and easy purification since the products directly precipitate out after the reaction mixtures are diluted with cold water and were purified by simple filtration and recrystallization; (5) the formation of multiple chemical bonds that enables the direct construction of functional amino acid derivatives. On the basis of our own observations and literature survey,15,16 a tentative mechanism is proposed in Scheme 3. The first step is to form imines A, derived from the condensation of arylglyoxals 1 and amino acids 3, which react with another molecule of arylglyoxals 1 to give zwitterionic intermediates B. Then, the intermolecular nucleophilic addition of cyclic enaminones 2 onto intermediates B, followed by continuously intramolecular 5-exo-trig aza-cyclization/5-endo-trig oxo-cyclization (D to E) and subsequent H-transfer to afford the desired products 4. Scheme 3. Proposed Mechanism for Forming Products 4

In conclusion, we have established a highly sustainable and efficient multicomponent bicyclization reaction of readily available arylglyoxals with cyclic enaminones and amino acids, by which a wide range of richly decorated oxazolo[5,4-b]indoles with good yields and high diastereoselectivity (up to >99:1) can be synthesized in an eco-friendly manner. This catalyst-free reaction pathway involved an imine/zwitterion formation, nucleophilic addition and 5-exo-trig/5-endo-trig bicyclization sequence, allowing multiple σ-bond-forming process to access oxazolo[5,4-b]indoles of chemical and biomedical


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potential. The bond-forming/annulation efficiency, accessibility of starting materials, and environmental friendliness make this transformation a powerful synthetic tool with a great substrate scope. Further study on the scope extension of this reaction is currently underway in our laboratory. Experimental Section General Microwave irradiation was conducted with Initiator 2.5 Microwave Synthesizers from Biotage (Uppsala, Sweden). The reaction temperatures were measured with an infrared detector during MW heating. General Procedure for the Synthesis of Products 4 Example for the synthesis of 4a Microwave Heating: Typically, 2,2-dihydroxy-1-p-tolylethanone (1a, 2.0 mmol, 332 mg, 2.0 equiv) was introduced in a 10-mL InitiatorTM reaction vial, 3-(4-fluorophenylamino)-5,5-dimethylcyclohex-2enone (2a, 1.0 mmol, 233 mg, 1.0 equiv) and β-alanine (3a, 1.0 mmol, 89 mg, 1.0 equiv) as well as ethanol (2.0 mL) were then successively added. Subsequently, the reaction vial was capped and then pre-stirring for 10 second. The mixture was irradiated (Time: 20 min, Temperature: 80 oC; Absorption Level: High; Fixed Hold Time) until TLC (petroleum ether: acetone 3:1) revealed that conversion of the starting material 2a was complete. The reaction mixture was cooled to room temperature and diluted with cold water (20 ml). The solid product was collected by Büchner filtration and washed by petroleum ether/ethyl acetate (10:1 V/V). The final solid was purified by recrystallization with 95% ethanol to afford the desired oxazolo[5,4-b]indole 4a as a white solid. 3-(4-(4-Fluorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4a) White solid, 495 mg, 85% yield; mp 204-206 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.60-7.57 (m, 2H), 7.29-7.26 (m, 4H), 7.02-7.08 (m, 4H), 6.41 (s, 1H), 4.52 (s, 1H), 3.00-2.88 (m, 1H), 2.62-2.56 (m, 2H), 2.54-2.46 (m, 2H), 2.36 (s, 3H), 2.22 (s, 3H), 2.01 (d, J = 16.0 ACS Paragon Plus Environment

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Hz, 1H), 1.72 (d, J = 17.2 Hz, 1H), 1.66 (d, J = 16.0 Hz, 1H), 0.97 (s, 3H), 0.70 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 194.3, 190.0, 173.2, 165.9, 160.4 (JCF =242.6 Hz), 143.2, 137.2, 137.1, 133.7 (JCF =2.8 Hz), 132.2, 129.6 (JCF =8.3 Hz), 129.3, 128.9, 128.7, 125.4, 115.2 (JCF =22.4 Hz) 105.8, 104.3, 100.4, 76.3, 52.8, 50.2, 36.7, 34.1, 33.0, 29.3, 27.1, 21.2, 20.6; IR (KBr, ν, cm-1) 3037, 2946, 2871, 1748, 1688, 1607, 1568, 1511, 1442, 1408, 1219, 1153, 1116, 1090, 919, 849, 818; HRMS (TOF-ESI) m/z calcd for C35H35FN2NaO5, 605.2422 [M+Na]+, found: 605.2430. 3-(4-(4-Chlorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4b) White solid, 478 mg, 80% yield; mp 205-206 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.35-7.18 (m, 6H), 7.08 (d, J = 8.0 Hz, 2H), 6.37 (s, 1H), 4.52 (s, 1H), 3.39 (d, J = 7.6 Hz, 1H), 2.31-2.94 (m, 1H), 2.61-2.57 (m, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 2.03 (d, J = 16.0 Hz, 1H), 1.79 (d, J = 17.2 Hz, 1H), 1.67 (d, J = 16.0 Hz, 1H), 1.00 (s, 3H), 0.71 (s, 3H);

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C NMR (100 MHz, DMSO-d6) δ 194.1, 190.2, 173.2, 165.4, 143.3, 137.3, 137.1, 136.5, 132.2,

130.7, 129.3, 129.0, 128.8, 128.7, 128.4, 125.4, 106.4, 104.3, 100.4, 76.3, 52.8, 50.1, 36.8, 34.0, 33.1, 29.4, 27.0, 21.2, 20.6; IR (KBr, ν, cm-1) 3028, 2945, 2891, 1751, 1687, 1606, 1579, 1566, 1497, 1439, 1405, 1237, 1153, 1090, 984, 818; HRMS (TOF-ESI) m/z calcd for C35H35ClN2NaO5, 621.2127 [M+Na]+, found: 621.2134. 3-(4-(4-Bromophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4c) White solid, 538 mg, 84% yield; mp 191-192 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.51-7.44 (m, 4H), 7.29-7.26 (m, 4H), 7.09 (d, J = 7.6 Hz, 2H), 6.42 (s, 1H), 4.49 (s, 1H), 3.08-2.88 (m, 1H), 2.61-2.57 (m, 4H), 2.36 (s, 3H), 2.22 (s, 3H), 2.04 (d, J = 16.0 Hz, 1H), 1.77 (d, J = 17.2 Hz, 1H), 1.67 (d, J = 16.0 Hz, 1H), 0.99 (s, 3H), 0.68 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 194.1, 190.2, 173.2, 165.4, 143.3, 137.3, 137.1, 137.0, 132.1, 131.4, 129.3, 129.1, 129.0, 128.7, 125.4, 119.1, 106.4, 104.3, 100.5, 76.3, 52.8, 50.1, 36.9, 34.0, 33.1, 29.4, 26.9, 21.2, 20.6; IR (KBr, ν, cm-1)


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3057, 2945, 2869, 1751, 1686, 1606, 1578, 1561, 1493, 1440, 1408, 1285, 1236, 1179, 1115, 1070, 1011, 984, 917, 818; HRMS (TOF-ESI) m/z calcd for C35H35BrN2NaO5, 667.1608 [M+Na]+, found: 667.1614. 3-(4-(3,4-Dichlorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4d) White solid, 493 mg, 78% yield; mp 192-193 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.90 (d, J = 11.2 Hz, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.31-7.26 (m, 4H), 7.11 (d, J = 7.2 Hz, 2H), 6.48 (s, 1H), 4.48 (s, 1H), 3.10-2.87 (m, 1H), 2.89-2.45 (m, 4H), 2.36 (s, 3H), 2.22 (s, 3H), 2.06 (d, J = 16.0 Hz, 1H), 1.79 (d, J = 17.2 Hz, 1H), 1.69 (d, J = 16.0 Hz, 1H), 0.99 (s, 3H), 0.67 (s, 3H);

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C NMR (100 MHz, DMSO-d6) δ 194.2, 190.5, 173.2, 164.9, 143.4, 137.8, 137.5, 136.8, 132.1,

130.8, 130.2, 129.3, 129.1, 128.8, 128.6, 128.2, 127.4, 125.3, 107.0, 104.3, 100.6, 76.3, 52.9, 50.1, 36.7, 34.0, 33.1, 29.6, 26.7, 21.2, 20.6; IR (KBr, ν, cm-1) 3034, 2958, 2874, 1746, 1694, 1605, 1557, 1478, 1455, 1409, 1384, 1118, 1090, 986, 937, 810; HRMS (TOF-ESI) m/z calcd for C35H34Cl2N2NaO5, 655.1737 [M+Na]+, found: 655.1758. 3-(4-(4-Methoxyphenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4e) White solid, 527 mg, 89% yield; mp 194-195 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.28-7.24 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 9.2 Hz, 2H), 6.31 (s, 1H), 4.54 (s, 1H), 3.69 (s, 3H), 3.31 (d, J = 7.6 Hz, 1H), 2.99-2.92 (m, 1H), 2.602.56 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.09 (s, 1H), 1.98 (d, J = 16.0 Hz, 1H), 1.75 (d, J = 17.2 Hz, 1H), 1.67 (d, J = 16.0 Hz, 1H), 0.98 (s, 3H), 0.75 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.1,

192.8, 190.9, 190.2, 173.2, 167.0, 165.1, 162.9, 158.8, 157.7, 143.1, 137.4, 137.1, 137.0, 132.1, 131.5, 131.3, 130.9, 129.9, 129.6, 129.1, 129.0, 128.8, 128.6, 127.4, 127.2, 126.7, 125.3, 113.6, 113.4, 113.3, 106.9, 105.2, 104.3, 104.1, 100.5, 100.2, 76.1, 76.0, 55.3, 54.9, 54.9, 52.8, 52.7, 50.0, 36.8, 34.2, 34.0, 33.1, 33.0, 30.5, 29.3, 28.9, 27.5, 27.0, 21.2, 20.6; IR (KBr, ν, cm-1) 3071, 2956, 2864, 1731, 1673,


10

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1605, 1564, 1508, 1446, 1405, 1257, 1237, 1172, 1031, 1011, 950, 885, 811. HRMS (TOF-ESI) m/z calcd for C36H38N2NaO6, 617.2622 [M+Na]+, found: 617.2638. 3-(4-(4-methoxybenzyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-4,5,6,7,8,8b-hexahydro2H-oxazolo[5,4-b]indol-1(3aH)-yl)propanoic acid (4f) White solid, 450 mg, 74% yield; mp 195-196 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.32-7.25 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 6.19 (s, 1H), 4.50-4.45 (m, 2H), 4.38 (d, J = 16.4 Hz, 1H), 3.66 (s, 3H), 3.28-3.20 (m, 1H), 2.91-2.84 (m, 1H), 2.57-2.52 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.05-2.00 (m, 2H), 1.86-1.55 (m, 2H), 0.90 (s, 3H), 0.81 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.9, 189.5, 173.6, 168.7, 158.5, 143.6,

137.9, 137.8, 132.9, 130.0, 129.7, 129.3, 129.1, 128.9, 126.0, 113.8, 104.9, 103.8, 100.0, 75.9, 55.4, 52.7, 50.5, 46.4, 36.9, 34.5, 33.6, 29.0, 28.7, 21.7, 21.2; IR (KBr, ν, cm-1) 3420, 3122, 2959, 1731, 1674, 1653, 1599, 1405, 1293, 819; HRMS (TOF-ESI) m/z calcd for C37H40N2O6Na, 631.2784 [M+Na]+; found 631.2794. 3-(4-(4-Bromophenyl)-2-(4-methoxybenzoyl)-3a-(4-methoxyphenyl)-6,6-dimethyl-8-oxo2,3a,4,5,6,7,8,8b-octahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4g) White solid, 558mg, 83% yield; mp 208-209 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.27 (s, 1H), 4.54 (s, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.40 (d, J = 8.0 Hz, 1H), 3.04-2.98 (m, 1H), 2.63-2.60 (m, 2H), 2.47 (d, J = 17.2 Hz, 1H), 2.02 (d, J = 16.0 Hz, 1H), 1.81 (d, J = 17.2 Hz, 1H), 1.68 (d, J = 16.0 Hz, 1H), 1.01 (s, 3H), 0.72 (s, 3H);

13

C NMR (100

MHz, DMSO-d6) δ 192.9, 190.2, 173.2, 165.2, 162.9, 158.7, 137.0, 132.0, 131.6, 131.4, 129.2, 127.4, 126.8, 119.1, 113.6, 113.4, 106.4, 104.2, 100.4, 76.2, 55.4, 54.9, 52.8, 50.1, 36.9, 34.0, 33.1, 29.4, 26.9. IR (KBr, ν, cm-1) 3065, 2957, 2909, 2838, 1728, 1673, 1602, 1562, 1513, 1491, 1442, 1256, 1173, 1030, 985, 885; HRMS (TOF-ESI)

m/z calcd for C35H35BrN2NaO7, 699.1506 [M+Na]+, found:

699.1509.


11


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Page 12 of 22

3-(2-(4-Methoxybenzoyl)-3a-(4-methoxyphenyl)-6,6-dimethyl-8-oxo-4-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4h) White solid, 536 mg, 88% yield; mp 199-200 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.32 (s, 1H), 4.49 (s, 1H), 3.83 (s, 3H), 3.69 (s, 3H), 3.31 (d, J = 8.8 Hz, 1H), 2.99-2.92 (m, 1H), 2.60 (t, J = 8.0 Hz, 2H), 2.44 (s, 1H), 2.20 (s, 3H), 2.00 (d, J = 16.0 Hz, 1H), 1.72 (d, J = 17.2 Hz, 1H), 1.64 (d, J = 16.0 Hz, 1H), 0.97 (s, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 192.9, 189.8, 173.2, 166.0, 162.8, 158.6, 135.7, 134.8, 132.3, 131.5, 128.9, 127.6, 127.4, 126.8, 113.5, 113.4, 105.6, 104.2, 100.2, 76.2, 55.4, 54.9, 52.7, 50.2, 37.0, 34.1, 33.0, 29.3, 27.2, 20.5; IR (KBr, ν, cm-1) 3064, 2932, 2837, 1743, 1686, 1600, 1558, 1513, 1458, 1389, 1196, 1313, 1239, 1172, 1028, 983, 836; HRMS (TOF-ESI) m/z calcd for C36H38N2NaO7, 633.2571 [M+Na]+, found: 633.2589. 3-(2-(4-Bromobenzoyl)-3a-(4-bromophenyl)-4-(4-chlorophenyl)-6,6-dimethyl-8-oxo-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4i) White solid, 538 mg, 74% yield; mp 194-196 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 4H), 6.46 (s, 1H), 4.64 (s, 1H), 3.01-2.86 (m, 1H), 2.63-2.55 (m, 3H), 2.49-2.40 (m, 1H) 2.00 (d, J = 16.0 Hz, 1H), 1.74 (d, J = 17.6 Hz, 1H), 1.64 (d, J = 16.0 Hz, 1H), 0.98 (s, 3H), 0.66 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 193.9, 190.2, 173.2, 165.6, 139.1, 136.1, 133.6, 131.3, 131.2,

131.1, 128.9, 128.6, 127.9, 127.2, 121.5, 106.0, 103.7, 100.7, 76.1, 52.6, 50.1, 36.7, 33.9, 33.1, 29.1, 27.1; IR (KBr, ν, cm-1) 3057, 2929, 2872, 1731, 1687, 1583, 1556, 1494, 1460, 1407, 1089, 1072, 1010, 983, 917, 814, 743; HRMS (TOF-ESI) m/z calcd for C33H29Br2ClN2NaO5, 749.0029 [M+Na]+, found: 749.0042. 3-(2-(4-Bromobenzoyl)-3a-(4-bromophenyl)-6,6-dimethyl-8-oxo-4-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4j)


12

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White solid, 593 mg, 84% yield; mp 188-189 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.39-7.33 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 6.41 (s, 1H), 4.64 (s, 1H), 2.97-2.84 (m, 1H), 2.62-2.59 (m, 2H), 2.43 (d, J = 17.2 Hz, 2H), 2.21 (s, 3H), 1.97 (d, J = 16.0 Hz, 1H), 1.70 (d, J = 17.2 Hz, 1H), 1.63 (d, J = 16.0 Hz, 1H), 0.97 (s, 3H), 0.69 (s, 3H).

13

C NMR (100 MHz, DMSO-d6) δ 193.9, 189.8, 173.2, 166.3, 139.4, 136.1, 134.4,

133.8, 131.2, 129.1, 127.9, 127.4, 127.0, 121.3, 105.3, 103.7, 100.5, 76.2, 52.5, 50.2, 36.8, 33.9, 33.0, 28.9, 27.4, 20.5; IR (KBr, ν, cm-1) 3062, 2952, 2872, 1729, 1691, 1584, 1555, 1513, 1465, 1441, 1408, 1068, 1010, 983, 816, 735; HRMS (TOF-ESI) m/z calcd for C34H32Br2N2NaO5, 731.0553 [M+Na]+, found: 731.0552. 3-(4-(4-bromophenyl)-7,7-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8b-octahydro1H-oxazolo[5,4-b]indol-1-yl)propanoic acid (4k) White solid, 506 mg, 79% yield; mp 197-198 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.33 (s, 1H), 4.48 (s, 1H), 3.30 (d, J = 7.6 Hz, 1H), 2.93-2.87 (m, 1H), 2.73-2.67 (m, 1H), 2.62 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.85-1.81 (m, 1H), 1.571.54 (m, 1H), 1.33-1.25 (m, 1H), 0.97 (s, 3H), 0.48 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 196.0,

195.0, 173.7, 165.9, 143.5, 137.7, 137.6, 132.9, 131.7, 129.9, 129.4, 129.0, 128.9, 126.1, 119.0, 106.2, 103.9, 101.3, 77.4, 52.8, 35.7, 34.5, 25.1, 24.3, 21.6, 21.4, 21.1; IR (KBr, ν, cm-1) 3420, 3123, 2956, 1735, 1683, 1602, 1398, 1184, 1051, 818; HRMS (TOF-ESI) m/z calcd for C35H35BrN2O5Na, 665.1627 [M+Na]+; found 665.1628. 2-(4-(4-Chlorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4l) White solid, 472 mg, 81% yield; mp 174-175 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.34-7.26 (m, 6H), 7.10 (d, J = 8.0 Hz, 2H), 6.37 (s, 1H), 4.67 (s, 1H), 4.10 (d, J = 17.6 Hz, 1H), 3.47 (d, J = 17.6 Hz, 1H), 2.57 (d, J = 18.4 Hz, 1H), 2.36 (s, 3H),


13


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Page 14 of 22

2.23 (s, 3H), 2.08 (d, J = 16.4 Hz, 1H), 1.83 (d, J = 17.2 Hz, 1H), 1.72 (d, J = 15.6 Hz, 1H), 1.03 (s, 3H), 0.83 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.8, 191.7, 171.1, 166.8, 143.7, 137.7, 136.0,

135.9, 131.8, 131.3, 129.2, 129.0, 128.9, 128.8, 128.7, 125.6, 106.4, 105.0, 99.4, 75.8, 56.6, 49.3, 36.6, 33.5, 28.6, 27.6, 21.1, 20.6; IR (KBr, ν, cm-1) 3066, 2959, 2891, 1746, 1679, 1608, 1564, 1492, 1446, 1405, 1294, 1194, 1126, 983, 861, 758; HRMS (TOF-ESI) m/z calcd for C34H33ClN2NaO5, 607.1970 [M+Na]+, found: 607.1940. 2-(4-(4-Bromophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4m) White solid, 484 mg, 77% yield; mp 175-176 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.47-7.39 (m, 4H), 7.31-7.26 (m, 4H), 7.11 (d, J = 7.2 Hz, 2H), 6.36 (s, 1H), 4.67 (s, 1H), 4.10 (d, J = 17.6 Hz, 1H), 3.47 (d, J = 17.6 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.36 (s, 3H), 2.23 (s, 3H), 2.08 (d, J = 16.0 Hz, 1H), 1.84 (d, J = 17.2 Hz, 1H), 1.72 (d, J = 16.0 Hz, 1H), 1.03 (s, 3H), 0.83 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 193.8, 191.7, 171.1, 166.6, 143.7, 137.7, 136.4, 136.0, 131.8,

131.6, 129.2, 129.1, 129.0, 128.8, 125.6, 119.7, 106.5, 105.0, 99.3, 75.8, 56.5, 49.4, 36.7, 33.5, 28.8, 27.6, 21.2, 20.6; IR (KBr, ν, cm-1) 3024, 2955, 2884, 1748, 1665, 1607, 1566, 1491, 1439, 1409, 1287, 1193, 1126, 1010, 991, 851, 813; HRMS (TOF-ESI) m/z calcd for C34H33BrN2NaO5, 653.1451 [M+Na]+, found: 653.1458. 2-(4-(3,4-Dichlorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-8-oxo-3a-(p-tolyl)-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4n) White solid, 494 mg, 80% yield; mp 179-180 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.77 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.43-7.22 (m, 5H), 7.13 (d, J = 7.6 Hz, 2H), 6.43 (s, 1H), 4.66 (s, 1H), 4.08 (d, J = 17.6 Hz, 1H), 3.52 (d, J = 18.0 Hz, 1H), 2.66 (d, J = 17.2 Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 2.11 (d, J = 16.0 Hz, 1H), 1.87 (d, J = 16.8 Hz, 1H), 1.74 (d, J = 16.0 Hz, 1H), 1.04 (s, 3H), 0.82 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 193.9, 192.0, 171.1, 166.1,

143.8, 137.8, 137.2, 135.8, 131.8, 130.9, 130.5, 129.2, 129.2, 129.1, 128.9, 128.3, 127.4, 125.5, 107.0,


14

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104.9, 99.4, 75.9, 56.6, 49.4, 36.5, 34.0, 29.0, 27.3, 21.2, 20.6; IR (KBr, ν, cm-1) 3023, 2956, 2884, 1748, 1664, 1606, 1572, 1561, 1477, 1439, 1409, 1287, 1192, 1126, 990, 852; HRMS (TOF-ESI) m/z calcd for C34H32Cl2N2NaO5, 641.1580 [M+Na]+, found: 641.1584. 2-(6,6-Dimethyl-2-(4-methylbenzoyl)-8-oxo-4-phenyl-3a-(p-tolyl)-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4o) White solid, 461 mg, 84% yield; mp 167-168 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.31-7.23 (m, 7H), 7.09 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 4.67 (s, 1H), 4.13 (d, J = 18.0 Hz, 1H), 3.47 (d, J = 18.0 Hz, 1H), 2.56 (d, J = 17.2 Hz, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 2.08 (d, J = 16.0 Hz, 1H), 1.83 (d, J = 17.2 Hz, 1H), 1.73 (d, J = 16.0 Hz, 1H), 1.04 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 193.8, 191.5, 171.2, 167.2, 143.6, 137.5, 136.9, 136.2, 131.9, 129.2, 128.9, 128.8, 128.6, 127.3, 126.9, 125.6, 106.0, 105.0, 99.2, 75.8, 56.4, 49.3, 33.5, 28.7, 27.7, 21.2, 20.6; IR (KBr, ν, cm-1) 3059, 2938, 2875, 1752, 1676, 1600, 1589, 1544, 1496, 1459, 1448, 1406, 1290, 1209, 1176, 1126, 1012, 992, 869, 789; HRMS (TOF-ESI) m/z calcd for C34H34N2NaO5, 573.2359 [M+Na]+, found: 573.2329. 2-(4-(3,4-Dichlorophenyl)-2-(4-methoxybenzoyl)-3a-(4-methoxyphenyl)-6,6-dimethyl-8-oxo2,3a,4,5,6,7,8,8b-octahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4p) White solid, 539 mg, 83% yield; mp 197-199 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.44-7.33 (m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 6.40 (s, 1H), 4.66 (s, 1H), 4.10 (d, J = 17.6 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.52 (d, J = 17.6 Hz, 1H), 2.63 (d, J = 17.6 Hz, 1H), 2.10 (d, J = 16.0 Hz, 1H), 1.86 (d, J = 17.2 Hz, 1H), 1.72 (d, J = 16.0 Hz, 1H), 1.03 (s, 3H), 0.80 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 192.5,

191.9, 171.1, 166.1, 163.2, 159.1, 137.1, 131.6, 131.0, 130.6, 130.3, 129.4, 128.6, 127.5, 127., 127.0, 113.7, 113.4, 106.8, 104.8, 99.4, 75.8, 56.7, 55.4, 54.9, 49.4, 36.6, 33.5, 28.9, 27.5; IR (KBr, ν, cm-1) 3086, 2957, 2873, 1747, 1666, 1617, 1597, 1512, 1453, 1408, 1212, 1171, 1116, 987, 870, 837, 755. HRMS (TOF-ESI) m/z calcd for C34H32Cl2N2NaO7, 673.1479 [M+Na]+, found: 673.1502.


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Page 16 of 22

2-(2-(4-Methoxybenzoyl)-3a-(4-methoxyphenyl)-6,6-dimethyl-8-oxo-4-(p-tolyl)-2,3a,4, 5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4q) White solid, 517 mg, 87% yield; mp 174-175 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.35-7.27 (m, 4H), 7.04 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.28 (s, 1H), 4.65 (s, 1H), 4.15 (d, J = 18.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.45 (d, J = 18.0 Hz, 1H), 2.41 (d, J = 17.6 Hz, 1H), 2.23 (s, 3H), 2.04 (d, J = 16.0 Hz, 1H), 1.83 (d, J = 17.6 Hz, 1H), 1.72 (d, J = 16.0 Hz, 1H), 1.04 (s, 3H), 0.87 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 192.6,

191.2, 171.2, 167.3, 163.1, 158.9, 136.4, 134.2, 131.5, 131.1, 129.2, 127.4, 127.2, 127.0, 113.6, 113.4, 105.7, 104.9, 99.1, 75.6, 55.5, 55.0, 49.3, 36.7, 33.4, 28.6, 27.8, 20.5; IR (KBr, ν, cm-1) 3066, 3026, 2959, 2884, 1747, 1680, 1603, 1561, 1513, 1453, 1406, 1190, 1126, 983, 859, 761, 751, 728; HRMS (ESI) m/z calcd for C35H36N2NaO7, 619.2414 [M+Na]+, found: 619.2416. 2-(2-(4-Fluorobenzoyl)-3a-(4-fluorophenyl)-6,6-dimethyl-8-oxo-4-phenyl-2,3a,4,5,6,7,8,8b-octahydro1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4r) White solid, 440 mg, 79% yield; mp 167-168 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.188.14 (m, 2H), 7.48-7.44 (m, 2H), 7.41-7.39 (m, 2H), 7.33-7.25 (m, 5H), 7.14-7.09 (m, 2H), 6.34 (s, 1H), 4.79 (s, 1H), 4.04 (d, J = 18.0 Hz, 1H), 3.52 (d, J = 18.0 Hz, 1H), 2.47 (d, J = 17.6 Hz, 1H), 2.04 (d, J = 16.0 Hz, 1H), 1.82 (d, J = 17.6 Hz, 1H), 1.69 (d, J = 16.0 Hz, 1H), 1.03 (s, 3H), 0.84 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 192.9, 191.3, 171.1, 167.0, 164.9 (JCF = 250.9 Hz), 161.7 (JCF = 243.7 Hz), 136.6, 135.2 (JCF = 2.6 Hz), 132.2 (JCF = 9.3 Hz), 131.2 (JCF = 2.7 Hz), 128.7, 128.0 (JCF = 8.2 Hz), 127.4, 127.0, 115.2 (JCF = 21.7 Hz), 115.1 (JCF = 21.5 Hz), 105.8, 104.4, 99.2, 75.7, 56.1, 49.4, 36.7, 33.4, 28.4, 27.9; IR (KBr, ν, cm-1) 3071, 2960, 2873, 1748, 1682, 1600, 1542, 1498, 1459, 1407, 1127, 1012, 987, 924, 844, 705. HRMS (TOF-ESI) m/z calcd for C32H28F2N2NaO5, 581.1858 [M+Na]+, found: 581.1844. 2-(4-(4-Bromophenyl)-2-(4-chlorobenzoyl)-3a-(4-chlorophenyl)-6,6-dimethyl-8-oxo-2,3a,4,5,6,7,8,8boctahydro-1H-oxazolo[5,4-b]indol-1-yl)acetic acid (4s)


16

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White solid, 521 mg, 78% yield; mp 188-189 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.49-7.44 (m, 4H), 7.42-7.34 (m, 4H), 6.37 (s, 1H), 4.80 (s, 1H), 3.99 (d, J = 17.2 Hz, 1H), 3.54 (d, J = 17.2 Hz, 1H), 2.53 (d, J = 17.2 Hz, 1H), 2.05 (d, J = 16.0 Hz, 1H), 1.83 (d, J = 17.2 Hz, 1H), 1.69 (d, J = 16.0 Hz, 1H), 1.02 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 193.4, 191.9, 171.2, 166.9, 138.2, 137.6, 135.9, 133.1, 131.7, 131.1, 129.2, 128.7, 128.4, 128.3, 127.7, 120.1, 106.2, 104.2, 99.4, 75.8, 56.2, 49.3, 36.5, 33.4, 28.4, 27.6; IR (KBr, ν, cm-1) 3067, 2959, 2892, 1747, 1681, 1605, 1559, 1491, 1443, 1402, 1196, 1296, 1201, 1127, 1093, 1011, 983, 872, 747; HRMS (TOF-ESI) m/z calcd for C32H27BrCl2N2NaO5, 693.0352 [M+Na]+, found: 693.0336. 2-(2-(4-Bromobenzoyl)-3a-(4-bromophenyl)-4-(4-fluorophenyl)-6,6-dimethyl-8-oxo-4,5,6,7,8,8bhexahydro-2H-oxazolo[5,4-b]indol-1(3aH)-yl)acetic acid (4t) White solid, 590 mg, 85% yield; mp 168-170oC; 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.50-7.48 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.15-7.11 (m, 2H), 6.35 (s, 1H), 4.82 (s, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.51 (d, J = 17.6 Hz, 1H), 2.42 (d, J = 16.9 Hz, 1H), 2.02 (d, J = 15.9 Hz, 1H), 1.79 (d, J = 17.8 Hz, 1H), 1.68 (d, J = 16.3 Hz, 1H), 1.01 (s, 3H), 0.82 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 193.7, 191.4, 171.1, 167.3, 160.7 (JCF = 243.4 Hz),

138.2, 132.8 (JCF = 3.0 Hz), 131.3, 131.2, 131.2, 129.8 (JCF = 8.5 Hz), 128.1, 127.4, 121.7, 115.6 (JCF = 22.2 Hz), 105.6, 104.3, 99.4, 75.7, 56.3, 49.4, 36.5, 33.4, 28.4, 27.8; IR (KBr, ν, cm-1) 3059, 2951, 2867, 1749, 1679, 1673, 1583, 1557, 1509, 1456, 1408, 1218, 1123, 1009, 984, 813; HRMS (TOF-ESI) m/z calcd for C32H27Br2FN2NaO5, 721.0145 [M+Na]+, found: 721.0154. 2-(2-Benzoyl-4-(4-chlorophenyl)-6,6-dimethyl-8-oxo-3a-phenyl-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4u) White solid, 435 mg, 78% yield; mp 186-188 oC; 1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.39 (d, J = 6.9 Hz, 2H), 7.34 (s, 2H), 7.30-7.29 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 6.02 (s, 1H), 4.74 (s, 1H), 3.95 (d, J = 18.0 Hz, 1H), 3.73 (d, J = 16.4 Hz, 1H), 2.18 (d, J = 17.6 Hz, 1H), 2.07 (d, J = 16.8 Hz, 1H), 1.98 (d, J = 17.6 Hz, 1H),


17


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1.77 (d, J = 16.8 Hz, 1H), 1.08 (s, 3H), 0.94 (s, 3H);

13

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C NMR (100 MHz, DMSO-d6) δ 187.8, 187.7,

165.7, 163.8, 132.7, 129.6, 128.8, 128.6, 128.6, 124.3, 124.2, 124.1, 124.0, 123.9, 123.6, 123.5, 120.3, 100.4, 99.8, 96.4, 54.4, 43.7, 32.0, 28.4, 24.2, 22.9; IR (KBr, ν, cm-1) 3067, 2961, 2887, 1746, 1679, 1609, 1564, 1494 1446, 1405, 1195, 1127, 984, 846, 760; HRMS (TOF-ESI) m/z calcd for C32H29ClN2NaO5, 579.1663 [M+Na]+, found: 579.1640. 2-(2-Benzoyl-4-(4-bromophenyl)-6,6-dimethyl-8-oxo-3a-phenyl-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4v) White solid, 492 mg, 82% yield; mp 198-200 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.50-7.42 (m, 6H), 7.41-7.37 (m, 3H), 7.33-7.29 (m, 3H), 6.41 (s, 1H), 4.74 (s, 1H), 4.09 (d, J = 18.0 Hz, 1H), 3.51 (d, J = 18.0 Hz, 1H), 2.57 (d, J = 17.2 Hz, 1H), 2.07 (d, J = 16.0 Hz, 1H), 1.85 (d, J = 17.2 Hz, 1H), 1.71 (d, J = 16.0 Hz, 1H), 1.04 (s, 3H), 0.84 (s, 3H);

13

C NMR (100

MHz, DMSO-d6) δ 194.1, 191.6, 170.1, 166.6, 138.7, 136.0, 134.3, 133.1, 131.8, 131.5, 129.2, 129.0, 128.3, 128.1, 125.5, 120.0, 106.4, 104.8, 99.4, 75.9, 56.4, 49.3, 36.8, 33.5, 28.5, 27.9; IR (KBr, ν, cm-1) 3067, 2960, 2884, 1746, 1678, 1610, 1564, 1493, 1452, 1403, 1198, 1125, 984, 862, 758; HRMS (TOFESI) m/z calcd for C32H29BrN2NaO5, 625.1137 [M+Na]+, found: 625.1128. 2-(2-Benzoyl-4-(4-fluorophenyl)-6,6-dimethyl-8-oxo-3a-phenyl-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4w) White solid, 433 mg, 80% yield; mp 179-180 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.52-7.45 (m, 4H), 7.43 (d, J = 7.2 Hz, 2H), 7.32-7.25 (m, 4H), 7.13-7.09 (m, 2H), 6.41 (s, 1H), 4.77 (s, 1H), 4.10 (d, J = 17.6 Hz, 1H), 3.50 (d, J = 17.6 Hz, 1H), 2.48 (d, J = 17.6 Hz, 1H), 2.05 (d, J = 16.0 Hz, 1H), 1.82 (d, J = 17.6 Hz, 1H), 1.71 (d, J = 16.0 Hz, 1H), 1.03 (s, 3H), 0.86 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.5, 191.4, 171.1, 167.1, 160.7 (JCF = 243.6 Hz), 138.8,

134.5, 133.2, 133.0 (JCF = 3.0 Hz), 129.7 (JCF = 8.6 Hz), 129.1, 128.5, 128.4, 128.2, 125.6, 115.5 (JCF = 22.4 Hz), 105.9, 104.9, 99.3, 75.7, 56.4, 49.4, 36.5, 33.4, 28.5, 27.9; IR (KBr, ν, cm-1) 3067, 2959, 2892, 1745, 1679, 1609, 1564, 1508, 1448, 1406, 1196, 1128, 984, 850, 760. HRMS (ESI) m/z calcd for


18

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C32H29FN2NaO5, 563.1953 [M+Na]+, found: 563.1923. 2-(2-Benzoyl-4-(3,5-dichlorophenyl)-6,6-dimethyl-8-oxo-3a-phenyl-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4x) White solid, 484 mg, 82% yield; mp 165-167 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.63-7.59 (m, 1H), 7.48-7.46 (m, 6H), 7.35-7.31 (m, 3H), 7.28-7.25 (m, 1H), 6.47 (s, 1H), 4.72 (s, 1H), 4.07 (d, J = 17.6 Hz, 1H), 3.55 (d, J = 17.6 Hz, 1H), 2.67 (d, J = 17.2 Hz, 1H), 2.11 (d, J = 16.0 Hz, 1H), 1.91 (d, J = 17.2 Hz, 1H), 1.76 (d, J = 16.0 Hz, 1H), 1.07 (s, 3H), 0.86 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.5, 192.1, 171.1, 165.6, 139.5, 138.6, 134.5, 133.7, 133.3,

129.1, 128.5, 128.3, 126.3, 125.6, 125.5, 107.6, 104.9, 99.3, 75.9, 56.3, 49.6, 36.5, 33.7, 29.1, 27.2; IR (KBr, ν, cm-1) 3079, 2958, 2892, 1745, 1699, 1595, 1566, 1441, 1179, 1126, 1003, 892, 761. HRMS (ESI) m/z calcd for C32H27Cl2N2O5, 589.1292 [M-H]-, found: 589.1252. 2-(2-Benzoyl-4-(4-methoxyphenyl)-6,6-dimethyl-8-oxo-3a-phenyl-2,3a,4,5,6,7,8,8b-octahydro-1Hoxazolo[5,4-b]indol-1-yl)acetic acid (4y) White solid, 491 mg, 89% yield; mp 166-168 oC; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.63-7.60 (m, 1H), 7.50-7.46 (m, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.34-7.24 (m, 5H), 6.79 (d, J = 8.8 Hz, 2H), 6.37 (s, 1H), 4.74 (s, 1H), 4.11 (d, J = 17.6 Hz, 1H), 3.67 (s, 3H), 3.47 (d, J = 17.6 Hz, 1H), 2.40 (d, J = 17.6 Hz, 1H), 2.02 (d, J = 16.0 Hz, 1H), 1.80 (d, J = 17.6 Hz, 1H), 1.71 (d, J = 16.0 Hz, 1H), 1.02 (s, 3H), 0.87 (s, 3H);

13

C NMR (100 MHz, DMSO-d6) δ 194.4, 191.0, 171.1,

167.9, 158.1, 139.0, 129.0, 128.3, 128.1, 125.6, 113.7, 104.9, 99.2, 75.6, 56.4, 55.0, 36.6, 33.3, 28.3, 28.2; IR (KBr, ν, cm-1) 3067, 2960, 2839, 1736, 1699, 1609, 1571, 1513, 1445, 1408, 1296, 1249, 1196, 1151, 981, 845. HRMS (ESI) m/z calcd for C33H32N2NaO6, 575.2158 [M+Na]+, found: 575.2130 ASSOCIATED CONTENT Supporting Information 1

H and 13C NMR spectra for all pure products, and X-ray crystal data (CIF) for 4g and 4u. This material


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is available free of charge via the Internet at http//pubs.acs.org. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for financial support from the NSFC (Nos. 21232004, 21472071 and 21602087), TAPP, PAPD of Jiangsu Higher Education Institutions, the Outstanding Youth Fund of JSNU (YQ2015003), NSF of Jiangsu Province (BK20151163 and BK20160212), the Qing Lan and NSF of Jiangsu Education Committee (15KJB150006). Thanks for Mr Peng Zhou’s generous help. REFERENCES [1]

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Synthesis of Diastereoenriched Oxazolo[5,4-b ... - ACS Publications

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