Name: 517-89-5|(R)-5,8-Dihydroxy-2-(1-hydroxy-4-methylpent-3-en-1-yl)naphthalene-1,4-dione|97%
Brand: Ambeed
SKU: A706788
Price: 12.0 USD
Availability: InStock
Rating: 99 (25 reviews)

1
[ 517-89-5 ]
[ 43043-74-9 ]
metaboshikonin II [ No CAS ]
shikometabolin B [ No CAS ]
shikometabolin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 0.35% 2: 1% 3: 0.85% 4: 0.05%	In dimethyl sulfoxide at 37℃; for 72h; pH 7.3 (phosphate buffer); general anaerobic medium, Bacteroides fragilis subsp. thetaotus; Further byproducts given;

Reference： [1]Meselhy, Meselhy R.; Kadota, Shigetoshi; Tsubono, Koji; Hattori, Masao; Namba, Tsuneo [Tetrahedron, 1994, vol. 50, # 10, p. 3081 - 3098]

2
[ 13991-37-2 ]
[ 517-89-5 ]
(E)-Pent-2-enoic acid (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-4-methyl-pent-3-enyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 4h;

Reference： [1]Ahn; Baik; Kweon; Lim; Hwang [Journal of Medicinal Chemistry, 1995, vol. 38, # 6, p. 1044 - 1047]

3
[ 13419-69-7 ]
[ 517-89-5 ]
(E)-Hex-2-enoic acid (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-4-methyl-pent-3-enyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 4h;

Reference： [1]Ahn; Baik; Kweon; Lim; Hwang [Journal of Medicinal Chemistry, 1995, vol. 38, # 6, p. 1044 - 1047]

4
[ 517-89-5 ]
[ 74-88-4 ]
(R)-2-(1-hydroxy-4-methylpent-3-enyl)-5,8-dimethoxynaphthalene-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.3%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 6h;
76.6%	Stage #1: shikonin With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide for 5h;

Reference： [1]Han, Xuan-zhen; Liu, Xinhua; Shen, Xiao-bao; Sheng, Liang-quan; Wang, Yang; Wu, Fu-fang [Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, vol. 35, # 1, p. 773 - 785]
[2]Location in patent: experimental part Zhou, Wen; Peng, Ying; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2010, vol. 45, # 12, p. 6005 - 6011]

5
[ 517-89-5 ]
[ 107-30-2 ]
[ 1253934-34-7 ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With potassium carbonate In acetone at 20℃; for 3h;	5.5. General methods for the synthesis of 15a-15f K2CO3 (15 mmol) and methyl chloromethyl ether (10 mmol) was added to a solution of shikonin (5 mmol) in acetone (10 ml). The mixture was stirred at rt for 3 h. The resulting mixture was filtered. The organic phase was concentrated under vacuum and the residue was purified by flash column chromatography to give 13. Yield 84.5%, yellow oil. To a solution of heterocycle-bearing acid (4 mmol) and 13 (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 14. To a solution of 14 (2 mmol) in ethanol (5 ml) was added 5 drops of concentrated hydrochloric acid. The mixture was stirred at rt for 5 min. The reaction mixture was poured into saturated aqueous NaHCO3 (25 ml). The mixture was extracted with ethyl acetate (25 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give 15.microwave
77.1%	Stage #1: shikonin With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.5h; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 40℃; for 1h; Inert atmosphere;	5.2. 2-(1-hydroxy-4-methylpent-3-enyl)-5,8-bis-(methoxymethoxy)-naphthalene-1,4-dione (2) Shikonin 1 (2.88 g, 0.01 mol) and potassium carbonate(13.8 g, 0.1 mol) in dimethyl formamide (20 ml) were stirred for 30 min at 40 °C, and then newly distilled chloromethyl ether was added in batches. The reaction proceeded for 1 h under the monitoring of TLC. Ethyl acetate (30 ml) and distilled water (20 ml) were poured into the reaction mixture. The organic layer was washed by water and brine respectively, dried over anhydrous MgSO4 for 1 h and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel with ethyl acetate and petroleum ether (V:V = 1:2) to afford 2-(1-hydroxy-4-methylpent-3-enyl)-5,8-bis-(methoxymethoxy)- naphthalene-1,4-dione 2 (2.24 g, 77.1) as yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.47 (s, 2H, benzene ring H), 6.80 (s, 1H, quinone ring H), 5.30 (m, 5H), 4.76 (t, 1H, J = 6.3 Hz), 3.56 (s, 6H), 2.55 (m, 2H), 1.72 (s, 3H), 1.62 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 185.1, 184.8, 152.6, 152.1, 136.7, 134.4, 125.6, 125.0, 120.4, 119.1, 102.6, 96.3, 96.2, 68.9, 57.9, 56.9, 56.8, 35.7, 26.1, 18.3. ESI-MS: 399.39 (M + Na) +.

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]
[2]Location in patent: experimental part Zhou, Wen; Zhang, Xu; Xiao, Ling; Ding, Jing; Liu, Quan-Hua; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 8, p. 3420 - 3427]

6
[ 517-89-5 ]
[ 860407-29-0 ]
[ 1253934-33-6 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; Inert atmosphere;	5.2. 2-[1-(3-Hydroxypropionoxy)-4-methyl-3-pentenyl]naphthazarin (7a) 3-hydroxypropionitrile 8 (10 mmol) was added to saturated aqueous sodium hydroxide (20 ml), and the mixture was stirred under reflux for 8 h. After acidized by concentrated hydrochloric acid, the resulting mixture was extracted with ethyl acetate (50 ml × 3). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford 3-hydroxypropionic acid 9. Yield 92.1%, colourless oil. To a solution of 9 (5 mmol) and DIPEA (7.5 mmol) in CH2Cl2 (5 ml) was dropwise added a solution of TMSCl (6 mmol) in CH2Cl2 (5 ml) at 0 °C. Then the mixture was stirred at rt for 1 h. After diluted in ethyl acetate (50 ml), the organic phase was washed with saturated brine (50 ml × 3), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford crude product 3-trimehylsilylpropionic acid 10. Yield 95.0%, light yellow oil. To a solution of 10 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 11. Yield 87.5%, red oil. To a solution of 11 (2 mmol) in EtOH (5 ml) was added acetic acid (0.5 ml). The mixture was stirred for 15 min at rt. After dissolved in ethyl acetate (50 ml), the resulting mixture was washed with saturated NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give 7a. Yield 74.5%.

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]

7
[ 65371-45-1 ]
[ 517-89-5 ]
[ 1253934-14-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; Inert atmosphere;	5.4. General methods for the synthesis of 7b-7k, 7m and 7n General procedure: Under N2 atmosphere, benzyl bromoacetate (10 mmol) immediately followed by carbonyl compounds 3 (5 mmol) were added to freshly-etched zinc powder (8 mmol) in THF (8 ml) at rt and the mixture was stirred at 40 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give benzyl β-hydroxyalkanoate 4 as colourless oil. Under H2, Pd/C (15 mg) was added to a solution of 4 (150 mg) in ethyl acetate (4 ml). The mixture was stirred at rt for 1 h, followed by filteration. The filtrate was concentrated under vacuum to give β-hydroxyalkanoic acid 6 as colourless oil. To a solution of 6 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 7.

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]

8
3-hydroxyhexanoic acid [ No CAS ]
[ 517-89-5 ]
[ 1253934-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; Inert atmosphere;	5.4. General methods for the synthesis of 7b-7k, 7m and 7n General procedure: Under N2 atmosphere, benzyl bromoacetate (10 mmol) immediately followed by carbonyl compounds 3 (5 mmol) were added to freshly-etched zinc powder (8 mmol) in THF (8 ml) at rt and the mixture was stirred at 40 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give benzyl β-hydroxyalkanoate 4 as colourless oil. Under H2, Pd/C (15 mg) was added to a solution of 4 (150 mg) in ethyl acetate (4 ml). The mixture was stirred at rt for 1 h, followed by filteration. The filtrate was concentrated under vacuum to give β-hydroxyalkanoic acid 6 as colourless oil. To a solution of 6 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 7.

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]

9
[ 58888-77-0 ]
[ 517-89-5 ]
[ 1253934-13-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; Inert atmosphere;	5.4. General methods for the synthesis of 7b-7k, 7m and 7n General procedure: Under N2 atmosphere, benzyl bromoacetate (10 mmol) immediately followed by carbonyl compounds 3 (5 mmol) were added to freshly-etched zinc powder (8 mmol) in THF (8 ml) at rt and the mixture was stirred at 40 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give benzyl β-hydroxyalkanoate 4 as colourless oil. Under H2, Pd/C (15 mg) was added to a solution of 4 (150 mg) in ethyl acetate (4 ml). The mixture was stirred at rt for 1 h, followed by filteration. The filtrate was concentrated under vacuum to give β-hydroxyalkanoic acid 6 as colourless oil. To a solution of 6 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 7.

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]

10
[ 58888-76-9 ]
[ 517-89-5 ]
[ 1253934-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20.0℃; for 1.0h;Inert atmosphere;	General procedure: Under N2 atmosphere, benzyl bromoacetate (10 mmol) immediately followed by carbonyl compounds 3 (5 mmol) were added to freshly-etched zinc powder (8 mmol) in THF (8 ml) at rt and the mixture was stirred at 40 C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give benzyl beta-hydroxyalkanoate 4 as colourless oil. Under H2, Pd/C (15 mg) was added to a solution of 4 (150 mg) in ethyl acetate (4 ml). The mixture was stirred at rt for 1 h, followed by filteration. The filtrate was concentrated under vacuum to give beta-hydroxyalkanoic acid 6 as colourless oil. To a solution of 6 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 7.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3934 - 3941

11
[ 517-89-5 ]
[ 3480-87-3 ]
[ 1253934-08-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	General procedure: Under N2 atmosphere, benzyl bromoacetate (10 mmol) immediately followed by carbonyl compounds 3 (5 mmol) were added to freshly-etched zinc powder (8 mmol) in THF (8 ml) at rt and the mixture was stirred at 40 C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give benzyl beta-hydroxyalkanoate 4 as colourless oil. Under H2, Pd/C (15 mg) was added to a solution of 4 (150 mg) in ethyl acetate (4 ml). The mixture was stirred at rt for 1 h, followed by filteration. The filtrate was concentrated under vacuum to give beta-hydroxyalkanoic acid 6 as colourless oil. To a solution of 6 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 7.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3934 - 3941

12
[ 517-89-5 ]
[ 74-95-3 ]
[ 206996-08-9 ]

Yield	Reaction Conditions	Operation in experiment
72.6%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 130℃; for 0.333333h;	5.6. General methods for the synthesis of 20a-20i A mixture of shikonin (1 mmol), KI (2 mmol), K2CO3 (15 mmol) and CH2Br2 (20 mmol) in DMF (10 ml) was stirred at 130 °C for 20 min. The resulting mixture was filtered. The organic phase was concentrated under vacuum and the residue was purified by flash column chromatography to give 16. Yield 72.6%, colourless oil. Epoxyalkane (5 mmol) and NaH (2 mmol) were added to a solution of 16 (1 mmol) in DMF (5 ml). The mixture was stirred at 0°C for 24 h and then poured into saturated aqueous NH4Cl (25 ml). The aqueous phase was extracted with ethyl acetate (25 ml × 2). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give 17 as colourless oil. 20 was obtained from 17 by electrolysis according to a recently reported procedure [17].

Reference： [1]Location in patent: experimental part Rao, Zhen; Liu, Xin; Zhou, Wen; Yi, Jing; Li, Shao-Shun [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3934 - 3941]

13
[ 197573-96-9 ]
[ 517-89-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: (1R)-4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-en-1-ol With pyridine; dmap; acetic anhydride In dichloromethane at 0 - 20℃; for 0.333333h; Stage #2: With ammonium cerium (IV) nitrate In dichloromethane; water at 20℃; for 0.25h; Further stages;
	Multi-step reaction with 3 steps 1.1: dmap; triethylamine / dichloromethane / 0.33 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: dmap; triethylamine; zinc / 2 h / 20 °C 3.1: ammonium cerium (IV) nitrate / acetonitrile / 0.17 h / 20 °C 3.2: 6 h
	Multi-step reaction with 3 steps 1.1: dmap; triethylamine / dichloromethane / 0.33 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: dmap; triethylamine; zinc / 2 h / 20 °C 3.1: ammonium cerium (IV) nitrate / acetonitrile / 0.17 h / 20 °C 3.2: 6 h

Reference： [1]Wang, Rubing; Zhou, Shanshan; Jiang, Hudagula; Zheng, Xiaogang; Zhou, Wen; Li, Shaoshun [European Journal of Organic Chemistry, 2012, # 7, p. 1373 - 1379]
[2]Wang, Rubing; Guo, Hui; Cui, Jiahua; Li, Shaoshun [Tetrahedron Letters, 2012, vol. 53, # 31, p. 3977 - 3980]
[3]Wang, Rubing; Guo, Hui; Cui, Jiahua; Li, Shaoshun [Tetrahedron Letters, 2012, vol. 53, # 31, p. 3977 - 3980]

14
[ 373-96-6 ]
[ 517-89-5 ]
[ 1380298-12-3 ]

Reference： [1]Chirality,2013,vol. 25,p. 757 - 762

15
[ 756-09-2 ]
[ 517-89-5 ]
[ 1380298-14-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at -10 - 0℃; Inert atmosphere;

Reference： [1]Kong, Wen-Yao; Chen, Xiao-Feng; Shi, Jing; Baloch, Shahla Karim; Qi, Jin-Liang; Zhu, Hai-Liang; Wang, Xiao-Ming; Yang, Yong-Hua [Chirality, 2013, vol. 25, # 11, p. 757 - 762]

16
[ 517-89-5 ]
[ 99783-23-0 ]
[ 1380298-16-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at -10 - 0℃; Inert atmosphere;

Reference： [1]Kong, Wen-Yao; Chen, Xiao-Feng; Shi, Jing; Baloch, Shahla Karim; Qi, Jin-Liang; Zhu, Hai-Liang; Wang, Xiao-Ming; Yang, Yong-Hua [Chirality, 2013, vol. 25, # 11, p. 757 - 762]

17
[ 406-93-9 ]
[ 517-89-5 ]
[ 1380298-17-8 ]

Reference： [1]Chirality,2013,vol. 25,p. 757 - 762

18
[ 1912-43-2 ]
[ 517-89-5 ]
[ 1397292-76-0 ]

Reference： [1]Chemical Biology and Drug Design,2014,vol. 83,p. 334 - 343

19
[ 5928-51-8 ]
[ 517-89-5 ]
[ 1397292-83-9 ]

Reference： [1]Chemical Biology and Drug Design,2014,vol. 83,p. 334 - 343

20
[ 4653-11-6 ]
[ 517-89-5 ]
[ 1397292-84-0 ]

Reference： [1]Chemical Biology and Drug Design,2014,vol. 83,p. 334 - 343

21
[ 21010-06-0 ]
[ 517-89-5 ]
[ 1397292-85-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at -10 - 0℃; for 12h; Inert atmosphere;

Reference： [1]Wang, Xiao-Ming; Lin, Hong-Yan; Kong, Wen-Yao; Guo, Jing; Shi, Jing; Huang, Shou-Cheng; Qi, Jin-Liang; Yang, Rong-Wu; Gu, Hong-Wei; Yang, Yong-Hua [Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 334 - 343]

22
[ 517-89-5 ]
[ 1759-53-1 ]
(1R)-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl cyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: shikonin With dicyclohexyl-carbodiimide In dichloromethane for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: With dmap In dichloromethane for 0.25h; Cooling with ice; Inert atmosphere; Stage #3: cyclopropanecarboxylic acid In dichloromethane for 14h; Cooling with ice; Inert atmosphere;
20%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cyclopropanecarboxylic acid In dichloromethane for 22h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Baloch, Shahla Karim; Ling, Li-Jun; Qiu, Han-Yue; Ma, Lin; Lin, Hong-Yan; Huang, Shou-Cheng; Qi, Jin-Liang; Wang, Xiao-Ming; Lu, Gui-Hua; Yang, Yong-Hua [RSC Advances, 2014, vol. 4, # 67, p. 35588 - 35596]
[2]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

23
[ 588-32-9 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(3-chlorophenoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	Stage #1: shikonin With dicyclohexyl-carbodiimide In dichloromethane for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: With dmap In dichloromethane for 0.25h; Cooling with ice; Inert atmosphere; Stage #3: 3-chlorophenoxyacetic acid In dichloromethane for 14h; Cooling with ice; Inert atmosphere;

Reference： [1]Baloch, Shahla Karim; Ling, Li-Jun; Qiu, Han-Yue; Ma, Lin; Lin, Hong-Yan; Huang, Shou-Cheng; Qi, Jin-Liang; Wang, Xiao-Ming; Lu, Gui-Hua; Yang, Yong-Hua [RSC Advances, 2014, vol. 4, # 67, p. 35588 - 35596]

24
[ 517-89-5 ]
[ 1643-16-9 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(4-isopropylphenoxy)acetate [ No CAS ]

Reference： [1]RSC Advances,2014,vol. 4,p. 35588 - 35596

25
[ 517-89-5 ]
[ 32852-81-6 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(3-phenoxyphenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: shikonin With dicyclohexyl-carbodiimide In dichloromethane for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: With dmap In dichloromethane for 0.25h; Cooling with ice; Inert atmosphere; Stage #3: (3-phenoxyphenyl)acetic acid In dichloromethane for 14h; Cooling with ice; Inert atmosphere;

Reference： [1]Baloch, Shahla Karim; Ling, Li-Jun; Qiu, Han-Yue; Ma, Lin; Lin, Hong-Yan; Huang, Shou-Cheng; Qi, Jin-Liang; Wang, Xiao-Ming; Lu, Gui-Hua; Yang, Yong-Hua [RSC Advances, 2014, vol. 4, # 67, p. 35588 - 35596]

26
[ 517-89-5 ]
[ 5123-55-7 ]
(2S)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-3-yl)-4-methylpent-3-en-1-yl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: Nα-phthaloyl-L-phenylalanine With dicyclohexyl-carbodiimide In dichloromethane for 0.25h; Inert atmosphere; Cooling with ice; Stage #2: shikonin With dmap In dichloromethane for 12h; Cooling with ice;

Reference： [1]Baloch, Shahla Karim; Ma, Lin; Wang, Xue-Liang; Shi, Jing; Zhu, Yu; Wu, Feng-Yao; Pang, Yan-Jun; Lu, Gui-Hua; Qi, Jin-Liang; Wang, Xiao-Ming; Gu, Hong-Wei; Yang, Yong-Hua [RSC Advances, 2015, vol. 5, # 40, p. 31759 - 31767]

27
[ 517-89-5 ]
(4R)-2-phenyl-4,5-dihydro-1,3-thiazole-4-carboxylic acid [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-phenyl-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

28
[ 517-89-5 ]
C₁₁H₁₁NO₃S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(3-methoxyphenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

29
[ 517-89-5 ]
[ 1492891-14-1 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-methoxyphenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

30
C₁₂H₁₃NO₄S [ No CAS ]
[ 517-89-5 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(3,4-dimethoxyphenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

31
[ 517-89-5 ]
(R)-2-(3'-methylphenyl)-4-carboxy-4,5-dihydrothiazole [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(m-tolyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

32
[ 1196463-53-2 ]
[ 517-89-5 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(p-tolyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

33
[ 517-89-5 ]
C₁₁H₈F₃NO₃S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-(trifluoromethoxy)phenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

34
[ 517-89-5 ]
C₁₃H₁₅NO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-isopropylphenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

35
[ 517-89-5 ]
C₁₁H₁₀FNO₃S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2-fluoro-6-methoxyphenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

36
[ 1196463-54-3 ]
[ 517-89-5 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2-fluorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

37
[ 517-89-5 ]
C₁₀H₇ClFNO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2-chloro-4-fluorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

38
[ 517-89-5 ]
[ 62096-94-0 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

39
[ 517-89-5 ]
C₁₀H₇Cl₂NO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2,3-dichlorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

40
[ 517-89-5 ]
C₁₀H₇Cl₂NO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2,4-dichlorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

41
[ 517-89-5 ]
C₁₀H₇Cl₂NO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(2,5-dichlorophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

42
[ 1196463-67-8 ]
[ 517-89-5 ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-bromophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

43
[ 517-89-5 ]
C₁₀H₈INO₂S [ No CAS ]
(4R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 2-(4-iodophenyl)-4,5-dihydrothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; dicyclohexyl-carbodiimide In dichloromethane for 12h; Cooling with ice;	General procedure for the preparation of compounds C1-C17 General procedure: Aryl dihydrothiazol acids b1-b17, shikonin, 4-dimethyaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) were dissolved in dichloromethane and cooled and stirred for 12 h. Adding proper amount of silica gel and condensing solvent by vacuum concentration. Then, collecting target compounds by column chromatography. Chemical structures of the target compounds (C1-C17) were shown in Table 1 and the eluent composition and proportion was shown in Table 2.

Reference： [1]Lin, Hong-Yan; Li, Zi-Kang; Bai, Li-Fei; Baloch, Shahla Karim; Wang, Fang; Qiu, Han-Yue; Wang, Xue; Qi, Jin-Liang; Yang, Raong-Wu; Wang, Xiao-Ming; Yang, Yong-Hua [Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106]

44
[ 517-89-5 ]
[ 25021-04-9 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclobutylideneacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: 2-cyclobutylideneacetic acid In dichloromethane for 120h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

45
[ 1903-27-1 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopentylideneacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cyclopentylidene acetic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

46
[ 1552-91-6 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclohexylideneacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%		General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Molecules,2018,vol. 23

47
[ 517-89-5 ]
[ 1903-29-3 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cycloheptylideneacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cycloheptylideneacetic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

48
[ 517-89-5 ]
[ 6540-33-6 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclobutylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite® (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Molecules,2018,vol. 23

49
[ 517-89-5 ]
[ 5239-82-7 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopropylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cyclopropylacetic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

50
[ 1123-00-8 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopentylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Molecules,2018,vol. 23

51
[ 5292-21-7 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclohexylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite® (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Molecules,2018,vol. 23

52
[ 18294-87-6 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 1-cyclohexen-1-ylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%		General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Molecules,2018,vol. 23

53
[ 3721-95-7 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclobutanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: Cyclobutanecarboxylic acid In dichloromethane for 22h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

54
[ 3400-45-1 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopentanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cyclopentanecarboxylic acid In dichloromethane for 17h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

55
[ 517-89-5 ]
[ 98-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: Cyclohexanecarboxylic acid In dichloromethane for 120h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

56
[ 636-82-8 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclohex-1-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: cyclohexene-1-carboxylic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

57
[ 4771-80-6 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclohex-3-enecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: 1,2,5,6-tetrahydrobenzoic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

58
[ 517-89-5 ]
[ 29555-02-0 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl trans 2-methylcyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: 2-methyl-cyclopropanecarboxylic acid In dichloromethane for 15h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

59
[ 1007-01-8 ]
[ 517-89-5 ]
(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl bicyclo[2.2.1]heptane-2-ylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: 2-norbornyl acetic acid In dichloromethane for 16h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

60
[ 517-89-5 ]
exo-5-norbornene-2-carboxylic acid [ No CAS ]
exo-(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-3-yl)-4-methylpent-3-enyl bicyclo[2 .2.1]hept-5-ene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: exo-5-norbornene-2-carboxylic acid In dichloromethane for 120h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

61
[ 517-89-5 ]
C₈H₁₀O₂ [ No CAS ]
endo-(R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-3-yl)-4-methylpent-3-enyl bicyclo[2.2.1]hept-5-ene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: shikonin With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: C₈H₁₀O₂ In dichloromethane for 120h; Inert atmosphere;	3.1.3. General Procedure for the Acylation of Shikonin General procedure: A solution of shikonin in abs. CH2Cl2 (0.1 mmol/5 mL) was cooled to 0 C under argonatmosphere and DCC was added. DMAP was added after stirring for 15 min. After further stirring for15 min, the corresponding acid was added and stirring was continued for 14 h to 5 days with slowlywarming up to room temperature. After addition of 1 mL cyclohexane/0.1 mmol shikonin, the mixturewas concentrated under reduced pressure at room temperature to approx. 0.5 mL/0.1 mmol shikonin.The mixture was filtered over 3 mm silica and 2 mm celite (eluent: petroleum ether/CH2Cl2 = 1:0 to1:2). Product containing fractions were evaporated and submitted to flash CC and/or repeated PTLC(cyclohexane/CH2Cl2 mixtures). Due to the rapid decomposition of raw acylshikonin mixtures onevaporation to higher concentrations (c > approx. 0.2Macylshikonin) and degradation of acylshikoninson prolonged contact with silica, intermediate solutions were not to be concentrated to dryness and allisolation and purification steps had be performed at a good pace.

Reference： [1]Durchschein, Christin; Bauer, Rudolf; Kretschmer, Nadine; Hufner, Antje; Rinner, Beate; Stallinger, Alexander; Deutsch, Alexander; Lohberger, Birgit [Molecules, 2018, vol. 23, # 11]

62
[ 517-89-5 ]
[ 15254-22-5 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(2,5-dimethylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: (E)-4-(2,5-dimethylphenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

63
[ 517-89-5 ]
[ 20972-36-5 ]
(R,E)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 4-oxo-4-(4-methylphenyl)-2-butenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: (E)-4-oxo-4-(p-tolyl)but-2-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.
4%	Stage #1: shikonin With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: With dmap In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #3: (E)-4-oxo-4-(p-tolyl)but-2-enoic acid In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]
[2]Kretschmer, Nadine; Hufner, Antje; Durchschein, Christin; Popodi, Katrin; Rinner, Beate; Lohberger, Birgit; Bauer, Rudolf [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 25]

64
[ 517-89-5 ]
[ 129904-81-0 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(3,4-dimethylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: (E)-4-(3,4-dimethylphenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

65
(E)-4-(2-chloro-4-methylphenyl)-4-oxo-2-butenoic acid [ No CAS ]
[ 517-89-5 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(2-chloro-4-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (E)-4-(2-chloro-4-methylphenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

66
[ 517-89-5 ]
[ 29587-80-2 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(4-ethylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: (E)-4-(4-ethylphenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

67
[ 517-89-5 ]
[ 29582-39-6 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(4-chlorophenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: (E)-4-oxo-4-(4-chloro-phenyl)-but-2-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

68
[ 517-89-5 ]
[ 35504-85-9 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(4-fluorophenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: (E) 4-(4-fluorophenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

69
[ 517-89-5 ]
C₁₁H₉FO₃ [ No CAS ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(3-fluoro-4-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: C₁₁H₉FO₃ With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

70
[ 517-89-5 ]
[ 132972-06-6 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(2,4-dimethylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: trans-4-(2,4-dimethylphenyl)-4-oxo-2-butenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

71
[ 517-89-5 ]
[ 39270-18-3 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(3-bromo-4-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: C₁₁H₉BrO₃ With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

72
[ 517-89-5 ]
C₁₁H₉ClO₃ [ No CAS ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(5-chloro-2-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: C₁₁H₉ClO₃ With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

73
[ 517-89-5 ]
[ 17812-07-6 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-oxo-4-phenylbut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: Benzoylacrylic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

74
[ 517-89-5 ]
C₁₁H₉FO₃ [ No CAS ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(2-fluoro-4-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: C₁₁H₉FO₃ With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

75
[ 517-89-5 ]
C₁₁H₉FO₃ [ No CAS ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(5-fluoro-2-methylphenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: C₁₁H₉FO₃ With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

76
[ 517-89-5 ]
[ 20972-38-7 ]
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-4-(4-bromophenyl)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: (E)-4-(4-bromophenyl)-4-oxobut-2-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.333333h; Stage #2: shikonin In dichloromethane	3.3. General procedure for the synthesis of compounds PMMB-311-PMMB-325 General procedure: At room temperature, 50 mmol intermediate, benzoyl acrylic acidderivative (2a) was added to 30 mL anhydrous dichloromethane tomake it fully dissolved. The catalyst dicyclohexylcarbodiimide (DCC)and 4-dimethylaminopyridine (DMAP) are added into the solutionsystem by 0.1 times the amount of the intermediate, stirring 20 min.Add 25 mmol shikonin to the reaction solution and continue mixing3-4 h. Progress of the reaction was monitored by the TLC. Finally,target compounds were collected by column chromatography (Scheme1). Chemical structures of the target compounds (PMMB-311-PMMB-325) shown in Table 1 and the eluent composition and proportion areshown in Table S2 (SI Appendix). Theoretically, there may occur thegeometrical isomerism of the double bonds in the target compounds.Although structural characterization through X-ray single crystal diffractionwas difficult to be obtained, the TLC, HPLC detections and 1HNMR assay have been conducted. During the TLC detection and HPLCanalysis, there is only one new compound, which means only to beeither cis- or trans- conformation. In theory, the trans- conformation ismore reasonable due to its lower energy and more stablilty. Moreover,all 1H NMR spectrums of the target compounds are in accordance to thetrans- conformation. If they are cis- conformation, the carbonyl groupmust have an effect on the hydrogen displacement of side chain of shikonin. Apparently, all the 1H NMR spectrums showed no suchchange in hydrogen displacement of side chain of shikonin. Thus, thecombined results above indicated that the double bond exists in a morestable trans- conformation.

Reference： [1]Bao, Jia-Xin; Fu, Jiang-Yan; Han, Hong-Wei; Lin, Hong-Yan; Lu, Gui-Hua; Lu, Yun-Ting; Qi, Jin-Liang; Sun, Wen-Xue; Wang, Ming-Yue; Wang, Xiao-Ming; Wang, Yin-Song; Wen, Zhong-Ling; Yang, Min-Kai; Yang, Yong-Hua [Bioorganic and medicinal chemistry, 2019, vol. 27, # 23]

77
[ 496-41-3 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl benzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.7%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography. 4.1.3.1 (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl benzofuran-2-carboxylate (6a) Violet powder. Yield: 35.7%. m. p: 88.7-90.3°C. 1H NMR (600MHz, CDCl3): 12.62 (s, 1H, OH), 12.42 (s, 1H, OH), 7.72 (d, J=7.8Hz, 1H, ArH), 7.62 (d, J=6.2Hz, 2H, ArH), 7.49 (t, J=7.9Hz, 1H, ArH), 7.34 (t, J=7.3Hz, 1H, ArH), 7.19 (s, 2H, ArH), 7.15 (s, 1H, ArH), 6.32 (dd, J=6.7, 4.7Hz, 1H, CH-O), 5.22 (t, J=7.3Hz, 1H, CH=C), 2.81-2.76 (m, 1H, CH2), 2.65 (dt, J=14.9, 7.4Hz, 1H, CH2), 1.69 (s, 3H, CH3), 1.62 (s, 3H, CH3). 13C NMR (151MHz, CDCl3): 177.38, 175.85, 168.34, 167.81, 158.32, 155.97, 147.43, 144.86, 136.63, 133.25, 133.06, 131.51, 128.03, 126.85, 124.00, 122.96, 117.41, 114.70, 112.50, 111.88, 111.65, 70.54, 32.99, 25.84, 18.05. HRMS (ESI) m/z: 455.1102 [M+Na]+ (calcd for 455.1101, C25H20NaO7).

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

78
[ 50779-65-2 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 6-methylbenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.6%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

79
[ 50551-61-6 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 6-methoxybenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.6%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

80
[ 10242-11-2 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 5-bromobenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.1%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0℃; for 8h;	General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N?- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 190

81
[ 517-89-5 ]
4-Chloro-benzofuran-2-carboxylic acid [ No CAS ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 4-chlorobenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.2%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

82
[ 517-89-5 ]
4-bromobenzofuran-2-carboxylic acid [ No CAS ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 4-bromobenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.2%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

83
[ 517-89-5 ]
[ 89197-62-6 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 5-fluorobenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.1%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

84
[ 50635-20-6 ]
[ 517-89-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 5,7-dichlorobenzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.9%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

85
[ 517-89-5 ]
[ 1210226-99-5 ]
(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl 7-(tert-butyl)benzofuran-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.4%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 8h;	4.1.3 Synthesis of compounds 6a-6q General procedure: Shikonin (1mmol), benzofuran-2-carboxylic acid derivatives (4a-4q) (3mmol), 4-dimethyaminopyridine (0.5mmol), and N, N′- dicyclohexylcarbodiimide (0.5mmol) were suspended in the anhydrous DCM (10ml). The reaction mixture was stirred for 8h under 0°C. Afterwards, the targeted compounds 6a-6q were purified by column chromatography.

Reference： [1]Kong, Ling-Yi; Leng, Jia-Fu; Lian, Bao-Ping; Shao, Yu-Ying; Xia, Yuan-Zheng; Yin, Yong [European Journal of Medicinal Chemistry, 2020, vol. 190]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	517-89-5	MDL No. :	MFCD00075680
Formula :	C₁₆H₁₆O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NEZONWMXZKDMKF-SNVBAGLBSA-N
M.W :	288.30	Pubchem ID :	479503
Synonyms :	Isoarnebin 4;C.I. 75535;Tokyo Violet;NSC 252844	Chemical Name :	(R)-5,8-Dihydroxy-2-(1-hydroxy-4-methylpent-3-en-1-yl)naphthalene-1,4-dione

Num. heavy atoms :	21
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	77.82
TPSA :	94.83 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.96 cm/s

Log Po/w (iLOGP) :	2.56
Log Po/w (XLOGP3) :	2.96
Log Po/w (WLOGP) :	2.12
Log Po/w (MLOGP) :	0.42
Log Po/w (SILICOS-IT) :	2.48
Consensus Log Po/w :	2.11

[ CAS No. 517-89-5 ] {[proInfo.proName]}

Quality Control of [ 517-89-5 ]

Related Doc. of [ 517-89-5 ]

Product Details of [ 517-89-5 ]

Calculated chemistry of [ 517-89-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 517-89-5 ]

Application In Synthesis of [ 517-89-5 ]

[ 517-89-5 ] Synthesis Path-Downstream 1~85

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

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Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-3.51
Solubility :	0.09 mg/ml ; 0.000312 mol/l
Class :	Soluble
Log S (Ali) :	-4.61
Solubility :	0.00701 mg/ml ; 0.0000243 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-2.62
Solubility :	0.688 mg/ml ; 0.00239 mol/l
Class :	Soluble

PAINS :	2.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.55

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P270-P273-P301+P312+P330-P501	UN#:	N/A
Hazard Statements:	H302-H412	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
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P101	If medical advice is needed,have product container or label at hand.
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Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P231 + P232	Handle under inert gas. Protect from moisture.
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Response
Code	Phrase
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P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
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P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
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P361	Remove/Take off immediately all contaminated clothing.
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P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling