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[ CAS No. 565-63-9 ] {[proInfo.proName]}

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Chemical Structure| 565-63-9
Chemical Structure| 565-63-9
Structure of 565-63-9 * Storage: {[proInfo.prStorage]}
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Product Details of [ 565-63-9 ]

CAS No. :565-63-9 MDL No. :MFCD00002654
Formula : C5H8O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UIERETOOQGIECD-ARJAWSKDSA-N
M.W : 100.12 Pubchem ID :643915
Synonyms :
(Z)-2-Methylbut-2-enoic acid

Calculated chemistry of [ 565-63-9 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.4
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 27.45
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.21
Log Po/w (XLOGP3) : 0.99
Log Po/w (WLOGP) : 1.04
Log Po/w (MLOGP) : 0.79
Log Po/w (SILICOS-IT) : 0.19
Consensus Log Po/w : 0.84

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.02
Solubility : 9.6 mg/ml ; 0.0958 mol/l
Class : Very soluble
Log S (Ali) : -1.36
Solubility : 4.35 mg/ml ; 0.0435 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.04
Solubility : 91.5 mg/ml ; 0.914 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.42

Safety of [ 565-63-9 ]

Signal Word:Danger Class:8
Precautionary Statements:P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405 UN#:3261
Hazard Statements:H314-H290 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 565-63-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 565-63-9 ]

[ 565-63-9 ] Synthesis Path-Downstream   1~84

  • 1
  • [ 565-63-9 ]
  • [ 19319-26-7 ]
YieldReaction ConditionsOperation in experiment
66% With lithium aluminium tetrahydride In diethyl ether at 20℃; for 2h;
55% With lithium aluminium tetrahydride In diethyl ether for 5h; Heating;
With lithium aluminium tetrahydride; diethyl ether
With lithium aluminium tetrahydride
With lithium aluminium tetrahydride In diethyl ether Heating;
Multi-step reaction with 3 steps 1: 1.) (C2H5)3N, ClCOOEt, 2.) NH3 / 1.) toluene, 0 deg C, 2 h, 2.) toluene, ca. 1 h 2: LiAlH4 / diethyl ether / Heating 3: 25.3 percent Chromat. / NaNO2, HClO4

  • 2
  • [ 565-63-9 ]
  • [ 600-07-7 ]
YieldReaction ConditionsOperation in experiment
With phosphorus; hydrogen iodide
With hydrogen In methanol at 25℃; for 132h; Yield given;
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap 2: NADPH; enoyl reductase / 24 h / Enzymatic reaction
  • 3
  • [ 565-63-9 ]
  • [ 14868-24-7 ]
YieldReaction ConditionsOperation in experiment
With potassium permanganate; water; potassium carbonate at 0℃; aneglyceric acid;
  • 4
  • [ 565-63-9 ]
  • [ 5953-75-3 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: Angelic acid With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With 1-hydroxy-pyrrolidine-2,5-dione In tetrahydrofuran at 20℃; for 0.0833333h; Stage #3: With ammonium hydroxide In water; ethyl acetate at 20℃; for 0.5h;
(i) SOCl2, (ii) aq. NH3; Multistep reaction;
With ammonia; chloroformic acid ethyl ester; triethylamine 1.) toluene, 0 deg C, 2 h, 2.) toluene, ca. 1 h; Yield given. Multistep reaction;
  • 5
  • [ 565-63-9 ]
  • [ 94487-74-8 ]
YieldReaction ConditionsOperation in experiment
94% With dicyclohexyl-carbodiimide In dichloromethane; xylene at 20℃; for 1h; 5 Example 5; Preparation of angelic anhydride; To a solution of angelic acid (5 g, 50 mmol) in dichloromethane (100 mL) was added Λ,/V'-dicyclohexylcarbodiimide (8.6 mL, 60 % in xylene, 25 mmol) at room temperature. The reaction mixture was stirred at this temperature for 1 h. The precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 10: 1), giving 4.3 g of the title compound as an oil (94 %).*H NMR (300 MHz, CDCI3) δ 6.37 - 6.25 (m, 2H), 2.06 (dq, J = 7.4, 1.5 Hz, 6H), 1.97 - 1.93 (m, 6H).
94% With dicyclohexyl-carbodiimide In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane at 20℃; for 1h;
With 1-ethoxyacetylene; mercury(II) oxide
  • 6
  • [ 565-63-9 ]
  • [ 4136-95-2 ]
  • [ 137601-32-2 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In toluene at 20℃;
48% With triethylamine In toluene at 20℃; for 3.66667h;
48% With triethylamine In toluene at 20℃; for 3.66667h;
33% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 6℃; for 0.816667h; Inert atmosphere; 4 Example 4; Preparation of [(Z)-2-methylbut-2-enoyl] 2,4,6-trichlorobenzoate; Angelic acid (601 mg, 6.0 mmol) was dissolved in dichloromethane (3.0 mL) under argon. Diisopropylethylamine (1.23 mL, 7.20 mmol) was added at 5-10 °C in a period of 1 min. To this solution was added 2,4,6-trichlorobenzoyl chloride (1.12 mL, 7.20 mmol) at 3-6 °C in a period of 4 min. After the reaction solution had been stirred at 2 °C for 45 min, petroleum ether (9.0 mL) was added. The obtained suspension was purified by flash chromatography(petroleum ether/dichloromethane 3 : 1), giving the title compound as a white solid (605 mg, 33 %).H NMR (300 MHz, CDCI3) δ 7.40 (s, 2H), 6.42 (qq, J = 7.4, 1.5 Hz, 1H), 2.09 (dq, J = 7.4, 1.5 Hz, 3H), 1.97 (p, J = 1.5 Hz, 3H (XH NMR data : see alsoMatthew, B et al. ; Org Lett 2007, 9, 663-666).
33% With N-ethyl-N,N-diisopropylamine In dichloromethane at 2 - 10℃; for 0.75h; Inert atmosphere;
With triethylamine In toluene at 20℃; for 3h;
With triethylamine In toluene for 2h; Ambient temperature;
In toluene for 2h; Ambient temperature;
With triethylamine In toluene for 2h; Ambient temperature;
With triethylamine In dichloromethane; toluene at 20℃; for 2h;
With triethylamine In dichloromethane at 20℃; for 2h;
With triethylamine In toluene at 20℃; for 3h;
With triethylamine In toluene for 2h;
With triethylamine In toluene
With triethylamine In toluene
With triethylamine In toluene at 0 - 20℃; Inert atmosphere;
With triethylamine In toluene at 20℃; for 2h; Inert atmosphere;

Reference: [1]Merten, Joern; Froehlich, Roland; Metz, Peter [Angewandte Chemie - International Edition, 2004, vol. 43, # 44, p. 5991 - 5994]
[2]Ball, Matthew; Andrews, Stephen P.; Wierschem, Frank; Cleator, Ed; Smith, Martin D.; Ley, Steven V. [Organic Letters, 2007, vol. 9, # 4, p. 663 - 666]
[3]Andrews, Stephen P.; Ball, Matthew; Wierschem, Frank; Cleator, Ed; Oliver, Steven; Hoegenauer, Klemens; Simic, Oliver; Antonello, Alessandra; Huenger, Udo; Smith, Martin D.; Ley, Steven V. [Chemistry - A European Journal, 2007, vol. 13, # 20, p. 5688 - 5712]
[4]Current Patent Assignee: LEO FONDET - WO2012/10172, 2012, A1 Location in patent: Page/Page column 36
[5]Liang, Xifu; Grue-Sorensen, Gunnar; Petersen, Anders Klarskov; Högberg, Thomas [Synlett, 2012, vol. 23, # 18, p. 2647 - 2652]
[6]Hartmann, Benoit; Kanazawa, Alice M.; Depres, Jean-Pierre; Greene, Andrew E. [Tetrahedron Letters, 1991, vol. 32, # 38, p. 5077 - 5080]
[7]Witschel, Matthias Christian; Bestmann, Hans Juergen [Tetrahedron Letters, 1995, vol. 36, # 19, p. 3325 - 3328]
[8]Mori; Matsushima [Synthesis, 1995, # 7, p. 845 - 850]
[9]Witschel, Matthias C.; Bestmann, Hans Jürgen [Synthesis, 1997, # 1, p. 107 - 112]
[10]MacÍas, Francisco A.; Aguilar, José María; Molinillo, José María G.; Rodríguez-Luís, Francisco; Collado, Isidro G.; Massanet, Guillermo M.; Fronczek, Frank R. [Tetrahedron, 2000, vol. 56, # 21, p. 3409 - 3414]
[11]Aladro, F.Javier; Guerra, Francisco M; Moreno-Dorado, F.Javier; Bustamante, Jesús M; Jorge, Zacarías D; Massanet, Guillermo M [Tetrahedron, 2001, vol. 57, # 11, p. 2171 - 2178]
[12]Muri, Estela; Kanazawa, Alice; Barreiro, Eliezer; Greene, Andrew E. [Journal of the Chemical Society. Perkin Transactions 1 (2001), 2000, # 5, p. 731 - 735]
[13]Brocksom, Timothy J.; Coelho, Fernando; Depres, Jean-Pierre; Greene, Andrew E.; Freire de Lima, Marco E.; Hamelin, Olivier; Hartmann, Benoit; Kanazawa, Alice M.; Wang, Yanyun [Journal of the American Chemical Society, 2002, vol. 124, # 51, p. 15313 - 15325]
[14]Kuwabara, Nagako; Hayashi, Hiroyuki; Hiramatsu, Noriko; Choshi, Tominari; Kumemura, Teppei; Nobuhiro, Junko; Hibino, Satoshi [Tetrahedron, 2004, vol. 60, # 13, p. 2943 - 2952]
[15]Location in patent: experimental part Wright, Benjamin J. D.; Chan, Collin; Danishefsky, Samuel J. [Journal of Natural Products, 2008, vol. 71, # 3, p. 409 - 414]
[16]Wu, Yan-Chao; Zhu, Jieping [Organic Letters, 2009, vol. 11, # 23, p. 5558 - 5561]
[17]Location in patent: experimental part Marcos; Benéitez; Moro; Basabe; Díez; Urones [Tetrahedron, 2010, vol. 66, # 45, p. 8605 - 8614]
  • 7
  • [ 565-63-9 ]
  • (Z)-2-methylbut-2-enoyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With thionyl chloride Heating / reflux; A.II Tiglic acid (32) (100.0 g, 1.00 mol) and thionyl chloride (178.4 g, 1.5 mol) were placed in a 500 ml round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser. The mixture was refluxed until the development of HCl gas was completed. Then the reflux condenser was replaced by a distillation head. Excess of thionyl chloride was removed at 100-130 °C at ambient pressure, followed by tigloyl chloride (33) (106.32 g, 1.06 mol, 89 %) as a colorless liquid at 140-145 °C. The 1H NMR spectrum was identical with the literature (T. E. Ready, J. C. W. Chien, M. D. Rausch, J. Org. Chem. 1999 583, 11-27; B. B. Snider, Q. Che, Org. Lett. 2004, 6, 17, 2877-2880). 1H NMR (200 MHz, CDCl3): δ [ppm] 7.33 (q, 3J = 6.3 Hz, 1H, CH), 1.93 (d, 3J = 9.7 Hz, 3H, CH3 CH), 1.91 (s, 3H, CH3).
With n-butyllithium; oxalyl dichloride In tetrahydrofuran at -78 - 0℃; for 1.5h;
With potassium hydroxide; oxalyl dichloride In N,N-dimethyl-formamide
With potassium hydroxide; oxalyl dichloride 1.) MeOH, 2.) Et2O; Multistep reaction;
With potassium hydroxide; oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether for 2h;
Stage #1: Angelic acid With potassium hydroxide In methanol at 0℃; for 0.5h; Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 0℃; for 4h;
With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 20℃; for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 25℃; for 2.08333h; Cooling with ice; 3.2.1. (6S*,9R*,15R*)-(1,5,6,7,9,10,13,15-Octahydro-2,11-dimethoxy-3,12,16-trimethyl-1,4,7,10,13-pentaoxo-6,15-imino-4H-isoquino[3,2-b][3]-benzazocin-9-yl)methyl (2Z)-methyl-2-butenoate (15) A solution of angelic acid (60.1 mg, 0.60 mmol) in ether (3.0 mL) was cooled with iced water and a solution of oxalyl chloride (50.6 μL, 0.59 mmol) in DMF (4.6 μL, 59.2 mmol) was added dropwise over 5 min. The resulting solution was stirred at 25 °C for 2 h and then a solution of 9 (14.2 mg, 0.030 mmol) in CH2Cl2 (1.5 mL) was added over 5 min. The reaction mixture was concentrated to approximately 0.3 mL with a stream of argon and CH2Cl2 (0.8 mL) was then added. The resulting mixture was stirred at 25 °C for 21 h. The reaction mixture was purified by silica gel chromatography with hexane-ethyl acetate=1:2 to afford 15 (13.9 mg, 84%) as a dark purple film.
With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 0 - 25℃; for 2h; 2.8. Preparation of angelate 33 from 31 Oxalyl chloride (17.0 μL, 0.20 mmol) and DMF (1.5 μL, 19.8 μmol) were added to a stirred solution of commercially available angelic acid (20.2 mg, 0.20 mmol) in ether (1.0 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. A dichloromethane (0.5 mL) solution of 31 (5.0 mg, 9.7 μmol) was added to the above mixture over 5 min, the resulting mixture was concentrated in vacuo with a stream of argon gas to give a residue. Dichloroethane (1.0 mL) was added to the residue and the resulting mixture was heated at 80 °C for 3 h. After being concentrated, the crude product was subjected to chromatography [silica gel 4 g; elution with chloroform-methanol (30/1)] to give 33 (5.4 mg, 93%) as a colorless amorphous powder.
With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 25℃; for 2h; 3.23 (Z)-(4R FontWeight="Bold" FontSize="10" ,6R FontWeight="Bold" FontSize="10" ,11aS FontWeight="Bold" FontSize="10" )-(4-Cyano-8-methoxy-2,9-dimethyl-7,10-dioxo-1,3,4,6,7,10,11,11a-octahydro-2H-pyrazino[1,2-b]isoquinolin-6-yl)methyl 2-methylbut-2-enoate (12a) Oxalyl chloride (103.0μL, 1.22mmol) in DMF (9.0μL, 0.1mmol) was added dropwise to a stirred solution of angelic acid (122.2mg, 1.02mmol) in ether (4.60mL) at 0°C over 10min, and the reaction mixture was stirred at 25°C for 2h. A CH2Cl2 (2mL) solution of 9a (19.9mg, 0.06mmol) was added to the acid chloride, and the reaction mixture was stirred at 25°C for 17h. The reaction mixture was diluted with saturated aqueous NaHCO3 (20mL), and then extracted with CH2Cl2 (3×20mL). The combined extracts were washed with brine (20mL), dried, and concentrated in vacuo. The residue (36.5mg) was subjected to chromatography on a silica gel (5g) column with hexane/ethyl acetate (3:2) as the eluent to give 12a (20.1mg, 81%) as a pale yellow amorphous powder. IR (KBr) 2948, 2849, 2805, 2228, 1717, 1659, 1620, 1460, 1375, 1352, 1300, 1279, 1252, 1231, 1152, 1080, 1043, 964cm-1; 1H NMR (CDCl3, 400MHz) δ 1.79 (3H, quint, J=1.6Hz, 4′-H3), 1.81 (1H, t, J=11.6Hz, 1-H), 1.86 (1H, ddd, J=19.4, 13.3, 2.5Hz, 11-H), 1.91 (3H, dq, J=7.4, 1.5Hz, 2′-CH3), 1.96 (3H, s, 9-CH3), 2.33 (3H, s, NCH3), 2.34 (1H, dd, J=11.0, 4.0Hz, 3-H), 2.75 (1H, ddd, J=19.4, 2.5, 1.0Hz, 11-H), 2.78 (1H, ddt, J=13.3, 11.6, 2.5Hz, 11a-H), 2.92 (1H, dd, J=11.6, 2.5Hz, 1-H), 3.04 (1H, dd, J=11.3, 2.2Hz, 3-H), 4.03 (3H, s, 8-OCH3), 4.05 (1H, dd, J=2.9, 2.5Hz, 6-H), 4.22 (1H, dd, J=11.7, 2.9Hz, 6-CH), 4.23 (1H, t, J=2.2Hz, 4-H), 4.63 (1H, dd, J=11.7, 2.9Hz, 6-CH), 6.05 (1H, qq, J=7.4, 1.5Hz, 3′-H); 13C NMR (CDCl3, 100MHz) δ 8.7 (9-CH3), 15.8 (C4′), 20.6 (2′-CH3), 26.3 (C11), 45.5 (NCH3), 50.2 (C11a), 51.4 (C4), 56.1 (C6), 56.5 (C3), 60.7 (C1), 61.1 (8-OCH3), 62.3 (6-CH2), 117.1 (4-CN), 127.2 (C2′), 128.2 (C9), 136.6 (C6a), 138.9 (C3′), 141.2 (C10a), 155.9 (C8), 167.4 (CO), 181.3 (C7), 186.0 (C10); EIMS m/z 413 (M+, 10), 386 (8), 302 (38), 301 (21), 300 (100), 275 (15), 273 (20), 257 (8); HREIMS m/z 413.1947 (M+, calcd for C22H27N3O5, 413.1951).
With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Inert atmosphere;
With oxalyl dichloride In diethyl ether; N,N-dimethyl-formamide at 25℃; for 2h; 3.12. ((6S*,9R*,15R*)-2,11-dimethoxy-3,12,16-trimethyl-1,4,7,10,13-pentaoxo-1,5,6,7,9,10,13,15-octa-hydro-4H-6,15-epiminobenzo(4,5)azocino(1,2-b)isoquinolin-9-yl)methyl (Z)-2-methylbut-2-enoate (23) A solution of angelic acid (601.0 mg, 6.0 mmol) in ether (30 mL) was cooled with ice water, and asolution of oxalyl chloride (0.5 mL, 5.9 mmol) in DMF (46.0 μL, 592 mmol) was added dropwise over5 min. The resulting solution was stirred at 25 °C for 2 h. Then, a solution of 22 (142.0 mg, 0.3 mmol) in CH2Cl2 (15 mL) was added over 5 min. The reaction mixture was concentrated to approximately3.0 mL with a stream of argon, and CH2Cl2 (8.0 mL) was added. The resulting mixture was stirred at25 °C for 21 h. The reaction mixture was directly purified by silica gel chromatography with ethylacetate-hexane (2:1) to afford 23 (139.0 mg, 84%) as a dark purple film.
With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 25℃; for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h;
Stage #1: Angelic acid With potassium hydroxide In methanol at 0℃; Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether at 0℃; for 4h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Molecular sieve;

Reference: [1]Current Patent Assignee: UMICORE - EP1894938, 2008, A1 Location in patent: Page/Page column 26
[2]Niwa, Haruki; Ishiwata, Hiroyuki; Kuroda, Akio; Yamada, Kiyoyuki [Chemistry Letters, 1983, p. 789 - 790]
[3]Ashimori, Atsuyuki; Bachand, Benoit; Calter, Michael A.; Govek, Steven P.; Overman, Larry E.; Poon, Daniel J. [Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6488 - 6499]
[4]Torres-Valencia, J. Martin; Cerda-Garcia-Rojas, Carlos M.; Joseph-Nathan, Pedro [Tetrahedron Asymmetry, 1998, vol. 9, # 5, p. 757 - 764]
[5]Nicolaou; Nevalainen, Marta; Zak, Mark; Bulat, Stephan; Bella, Marco; Safina, Brian S. [Angewandte Chemie - International Edition, 2003, vol. 42, # 29, p. 3418 - 3424]
[6]Nicolaou; Safina, Brian S.; Zak, Mark; Lee, Sang Hyup; Nevalainen, Marta; Bella, Marco; Estrada, Anthony A.; Funke, Christian; Zecri, Frederic J.; Bulat, Stephan [Journal of the American Chemical Society, 2005, vol. 127, # 31, p. 11159 - 11175]
[7]Vincent, Guillaume; Williams, Robert M. [Angewandte Chemie - International Edition, 2007, vol. 46, # 9, p. 1517 - 1520]
[8]Location in patent: experimental part Yokoya, Masashi; Ito, Hiroshi; Saito, Naoki [Tetrahedron, 2011, vol. 67, # 47, p. 9185 - 9192]
[9]Location in patent: experimental part Yokoya, Masashi; Shinada-Fujino, Kimiko; Yoshida, Saiko; Mimura, Masahiro; Takada, Hiroki; Saito, Naoki [Tetrahedron, 2012, vol. 68, # 22, p. 4166 - 4181]
[10]Nakai, Keiyo; Kubo, Keiji; Yokoya, Masashi; Saito, Naoki [Tetrahedron, 2014, vol. 70, # 37, p. 6529 - 6545]
[11]Doan, Nhu Thi Quynh; Crestey, François; Olsen, Carl Erik; Christensen, Søren Brøgger [Journal of Natural Products, 2015, vol. 78, # 6, p. 1406 - 1414]
[12]Yokoya, Masashi; Kobayashi, Keiichiro; Sato, Mitsuhiro; Saito, Naoki [Marine Drugs, 2015, vol. 13, # 8, p. 4915 - 4933]
[13]Yokoya, Masashi; Toyoshima, Ryoko; Suzuki, Toshihiro; Le, Vy H.; Williams, Robert M.; Saito, Naoki [Journal of Organic Chemistry, 2016, vol. 81, # 10, p. 4039 - 4047]
[14]Wang, Huai-Wei; Qiao, Yu-Han; Wu, Jia-Xue; Wang, Qiu-Ping; Tian, Meng-Xin; Li, Yong-Fei; Yao, Qing-Xia; Li, Da-Cheng; Dou, Jian-Min; Lu, Yi [Organic Letters, 2021, vol. 23, # 3, p. 656 - 662]
[15]Shimura, Jun; Ando, Yoshio; Ohmori, Ken; Suzuki, Keisuke [Organic Letters, 2022, vol. 24, # 7, p. 1439 - 1443]
[16]Hamilton, David J.; Beemsterboer, Marieke; Carter, Caroline M.; Elsayed, Jasmina; Huiberts, Rilana E. M.; Klein, Hanna F.; O'Brien, Peter; de Esch, Iwan J. P.; Wijtmans, Maikel [ChemMedChem, 2022, vol. 17, # 9]
  • 8
  • isohelmanticine [ No CAS ]
  • [ 565-63-9 ]
  • [ 14868-24-7 ]
  • [ 98757-06-3 ]
YieldReaction ConditionsOperation in experiment
With Alkaline
  • 9
  • epoxyhelmanticine angelate [ No CAS ]
  • [ 565-63-9 ]
  • [ 14868-24-7 ]
  • [ 98757-06-3 ]
YieldReaction ConditionsOperation in experiment
With Alkaline
  • 10
  • decursinol [ No CAS ]
  • [ 565-63-9 ]
  • (S)-(+)-decursinol angelate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;
56.3% With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;
  • 11
  • [ 565-63-9 ]
  • C6H8C2OC2H6C3H4C5H7OCOCH3H2CH2 [ No CAS ]
  • (+/-)-methyl gummiferolate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 80℃; for 48h;
55% With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 80℃;
  • 12
  • [ 565-63-9 ]
  • [ 663606-14-2 ]
  • [ 663606-06-2 ]
YieldReaction ConditionsOperation in experiment
76% With 2,4,6-trichlorobenzoyl chloride In toluene at 80℃;
  • 14
  • kadsuphilin B [ No CAS ]
  • [ 565-63-9 ]
  • angeloylgomisin R [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; for 10h;
51% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; for 10h;
  • 15
  • [ 565-63-9 ]
  • [ 67667-64-5 ]
  • (Z)-2-Methyl-but-2-enoic acid (3aS,6aR,8R,9aR,9bS)-3,6,9-trimethylene-2-oxo-dodecahydro-azuleno[4,5-b]furan-8-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Stage #2: 3α-hydroxyguaia-4(15),10(14),11(13)-trien-12,6-olide In toluene at 20℃; for 96h;
  • 16
  • [ 565-63-9 ]
  • [ 142808-75-1 ]
  • (Z)-2-Methyl-but-2-enoic acid (3aS,6aS,8R,9aS,9bS)-9a-hydroxy-3,6,9-trimethylene-2-oxo-dodecahydro-azuleno[4,5-b]furan-8-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Stage #2: 3α,5α-dihydroxyguaia-4(15),10(14),11(13)-trien-12,6-olide In toluene at 20℃; for 96h;
  • 17
  • [ 565-63-9 ]
  • [ 109-89-7 ]
  • [ 133217-98-8 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: Angelic acid With trichloroisocyanuric acid; triphenylphosphine In dichloromethane at 0℃; for 0.75h; Stage #2: diethylamine With triethylamine In dichloromethane at 20℃; for 1h;
  • 18
  • [ 565-63-9 ]
  • [ 2038-57-5 ]
  • (Z)-2-Methyl-but-2-enoic acid (3-phenyl-propyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With tetrakis(pyridin-2-yloxy)silane In tetrahydrofuran at 20℃; for 24h;
  • 19
  • [ 565-63-9 ]
  • [ 828915-96-4 ]
  • [ 828915-98-6 ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 3.5h; Stage #2: (3aS,4S,7aR)-4-Hydroxy-3-methylene-5-((S)-1-methyl-4-trityloxy-butyl)-6-trityloxymethyl-3a,4,7,7a-tetrahydro-3H-benzofuran-2-one In toluene at 100℃; for 8h;
  • 20
  • [ 565-63-9 ]
  • [ 42221-49-8 ]
  • C12H9Cl3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In toluene at 20℃; for 2h;
  • 21
  • [ 565-63-9 ]
  • [ 5680-79-5 ]
  • [(Z)-2-methyl-but-2-enoylamino]-acetic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% Stage #1: Angelic acid With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -15℃; for 0.25h; Stage #2: glycine ethyl ester hydrochloride With 4-methyl-morpholine In dichloromethane at -15 - 24℃;
  • 22
  • [ 565-63-9 ]
  • [ 2916-68-9 ]
  • [ 920756-89-4 ]
YieldReaction ConditionsOperation in experiment
40% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Stage #2: 2-(Trimethylsilyl)ethanol In toluene at 75℃; for 18h;
  • 23
  • [ 565-63-9 ]
  • [ 930280-13-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 48 percent / triethylamine / toluene / 3.67 h / 20 °C 2: 52 percent / sodium hydrogen carbonate / toluene / 65 h / 80 °C 3: 84 percent / n-butanethiol; magnesium bromide diethyl etherate; potassium carbonate / diethyl ether / 0.5 h / 20 °C 4: 86 percent / DMAP / CH2Cl2 / 2 h / 20 °C
Multi-step reaction with 4 steps 1: triethylamine / toluene / 3.67 h / 20 °C 2: sodium hydrogencarbonate / toluene / 42 h / 80 °C 3: n-butanethiol; potassium carbonate; magnesium bromide / diethyl ether / 0.5 h / 20 °C 4: dmap / dichloromethane / 1 h / 20 °C
  • 24
  • [ 565-63-9 ]
  • thiapsigargin [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: 48 percent / triethylamine / toluene / 3.67 h / 20 °C 2: 52 percent / sodium hydrogen carbonate / toluene / 65 h / 80 °C 3: 84 percent / n-butanethiol; magnesium bromide diethyl etherate; potassium carbonate / diethyl ether / 0.5 h / 20 °C 4: 86 percent / DMAP / CH2Cl2 / 2 h / 20 °C 5: 100 percent / p-toluenesulfonic acid monohydrate / 1.75 h / 20 °C 6: 83 percent / aq. HCl; methanol / 0.75 h / 45 °C 7: 91 percent / CH2Cl2 / 1.25 h / 20 °C
Multi-step reaction with 7 steps 1: triethylamine / toluene / 3.67 h / 20 °C 2: sodium hydrogencarbonate / toluene / 42 h / 80 °C 3: n-butanethiol; potassium carbonate; magnesium bromide / diethyl ether / 0.5 h / 20 °C 4: dmap / dichloromethane / 1 h / 20 °C 5: toluene-4-sulfonic acid / 1.75 h / 20 °C 6: hydrogenchloride / methanol / 0.75 h / 45 °C 7: dichloromethane / 1.25 h / 20 °C
  • 25
  • [ 565-63-9 ]
  • [ 105662-35-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 48 percent / triethylamine / toluene / 3.67 h / 20 °C 2: 52 percent / sodium hydrogen carbonate / toluene / 65 h / 80 °C 3: 84 percent / n-butanethiol; magnesium bromide diethyl etherate; potassium carbonate / diethyl ether / 0.5 h / 20 °C 4: 86 percent / DMAP / CH2Cl2 / 2 h / 20 °C 5: 100 percent / p-toluenesulfonic acid monohydrate / 1.75 h / 20 °C 6: 83 percent / aq. HCl; methanol / 0.75 h / 45 °C
Multi-step reaction with 6 steps 1: triethylamine / toluene / 3.67 h / 20 °C 2: sodium hydrogencarbonate / toluene / 42 h / 80 °C 3: n-butanethiol; potassium carbonate; magnesium bromide / diethyl ether / 0.5 h / 20 °C 4: dmap / dichloromethane / 1 h / 20 °C 5: toluene-4-sulfonic acid / 1.75 h / 20 °C 6: hydrogenchloride / methanol / 0.75 h / 45 °C
  • 26
  • [ 565-63-9 ]
  • [ 123269-04-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 48 percent / triethylamine / toluene / 3.67 h / 20 °C 2: 52 percent / sodium hydrogen carbonate / toluene / 65 h / 80 °C 3: 84 percent / n-butanethiol; magnesium bromide diethyl etherate; potassium carbonate / diethyl ether / 0.5 h / 20 °C 4: 86 percent / DMAP / CH2Cl2 / 2 h / 20 °C 5: 100 percent / p-toluenesulfonic acid monohydrate / 1.75 h / 20 °C
Multi-step reaction with 5 steps 1: triethylamine / toluene / 3.67 h / 20 °C 2: sodium hydrogencarbonate / toluene / 42 h / 80 °C 3: n-butanethiol; potassium carbonate; magnesium bromide / diethyl ether / 0.5 h / 20 °C 4: dmap / dichloromethane / 1 h / 20 °C 5: toluene-4-sulfonic acid / 1.75 h / 20 °C
  • 27
  • [ 565-63-9 ]
  • (-)-renieramycin G [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine / toluene / 2 h / 20 °C 2: 8.0 mg / toluene / 84 h / 90 °C 3: 63 percent / aq. DDQ / acetone / 2 h
Multi-step reaction with 2 steps 1: triethylamine / toluene / 3 h / 20 °C 2: toluene / 6 h / 70 - 80 °C
  • 28
  • [ 565-63-9 ]
  • (-)-eriolangin [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 2,4,6-trichlorobenzoyl chloride; Et3N / toluene / 3.5 h / 20 °C 1.2: 60 percent / toluene / 8 h / 100 °C 2.1: 85 percent / pTsOH*H2O / methanol / 24 h / 20 °C
Multi-step reaction with 3 steps 1: 85 percent / Et3N / toluene / 20 °C 2: 100 °C 3: 85 percent / TsOH / methanol / 20 °C
  • 29
  • [ 565-63-9 ]
  • (S)-Benzylamino-((4S,5R)-2,2,4,5-tetramethyl-[1,3]dioxolan-4-yl)-acetonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C 4.1: 90 percent / p-toluenesulfonic acid / 1 h / 25 °C 5.1: 90 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 5 h / 0 - 25 °C 7.1: 4A molecular sieves; Yb(OTf)3 / CH2Cl2 / 3 h / 25 °C 7.2: CH2Cl2 / 2 h / 25 °C
  • 30
  • [ 565-63-9 ]
  • 2,3-Dihydroxy-2-methyl-butyric acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C
  • 31
  • [ 565-63-9 ]
  • [ 111319-75-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C 4.1: 90 percent / p-toluenesulfonic acid / 1 h / 25 °C 5.1: 90 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C
Multi-step reaction with 5 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C 5: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C
Multi-step reaction with 5 steps 1.1: potassium hydroxide / methanol / 0 °C 1.2: 4 h / 0 °C 2.1: dichloromethane / 62 h / 20 °C 3.1: (9S,9"S)-9,9"-[phthalazine-1,4-diylbis-(oxy)]bis[10,11-dihydro-6'-methoxycinchonane]; potassium carbonate; potassium osmate monohydrate; potassium hexacyanoferrate(III); methanesulfonamide / <i>tert</i>-butyl alcohol; water / 25 h / 0 °C 4.1: toluene-4-sulfonic acid / 16.5 h / 20 °C 5.1: diisobutylaluminium hydride / dichloromethane / 2.5 h / -78 - 0 °C
  • 32
  • [ 565-63-9 ]
  • [ 97672-26-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C
Multi-step reaction with 2 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C
Multi-step reaction with 2 steps 1: 1.) KOH, 2.) oxalyl chloride / 1.) MeOH, 2.) Et2O 2: CH2Cl2 / 48 h / Ambient temperature
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / dichloromethane; 5,5-dimethyl-1,3-cyclohexadiene / 1 h / 20 °C 2: caesium carbonate / acetonitrile / 0.17 h / 20 °C
Multi-step reaction with 2 steps 1.1: potassium hydroxide / methanol / 0 °C 1.2: 4 h / 0 °C 2.1: dichloromethane / 62 h / 20 °C

  • 33
  • [ 565-63-9 ]
  • (4R,5R)-2,2,4,5-Tetramethyl-[1,3]dioxolane-4-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C 4.1: 90 percent / p-toluenesulfonic acid / 1 h / 25 °C 5.1: 90 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 5 h / 0 - 25 °C
Multi-step reaction with 6 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C 5: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C
Multi-step reaction with 6 steps 1.1: potassium hydroxide / methanol / 0 °C 1.2: 4 h / 0 °C 2.1: dichloromethane / 62 h / 20 °C 3.1: (9S,9"S)-9,9"-[phthalazine-1,4-diylbis-(oxy)]bis[10,11-dihydro-6'-methoxycinchonane]; potassium carbonate; potassium osmate monohydrate; potassium hexacyanoferrate(III); methanesulfonamide / <i>tert</i>-butyl alcohol; water / 25 h / 0 °C 4.1: toluene-4-sulfonic acid / 16.5 h / 20 °C 5.1: diisobutylaluminium hydride / dichloromethane / 2.5 h / -78 - 0 °C 6.1: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 2 h / -78 - 0 °C
  • 34
  • [ 565-63-9 ]
  • [ 609358-97-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C 4.1: 90 percent / p-toluenesulfonic acid / 1 h / 25 °C 5.1: 90 percent / DIBAL-H / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 5 h / 0 - 25 °C 7.1: 4A molecular sieves; Yb(OTf)3 / CH2Cl2 / 3 h / 25 °C 7.2: CH2Cl2 / 2 h / 25 °C
Multi-step reaction with 8 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C 5: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8: CH2Cl2 / 3 h / 25 °C
  • 35
  • [ 565-63-9 ]
  • [ 609358-96-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: KOH / methanol / 0.5 h / 0 °C 1.2: oxalyl chloride; DMF / diethyl ether / 4 h / 0 °C 2.1: 24.8 g / CH2Cl2 / 48 h / 25 °C 3.1: 90 percent / K3Fe(CN)6; aq. K2OsO4; (DHQD)2PHAL / K2CO3; MeSO2NH2 / 2-methyl-propan-2-ol / 24 h / 0 °C 4.1: 90 percent / p-toluenesulfonic acid / 1 h / 25 °C
Multi-step reaction with 4 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C
Multi-step reaction with 4 steps 1.1: potassium hydroxide / methanol / 0 °C 1.2: 4 h / 0 °C 2.1: dichloromethane / 62 h / 20 °C 3.1: (9S,9"S)-9,9"-[phthalazine-1,4-diylbis-(oxy)]bis[10,11-dihydro-6'-methoxycinchonane]; potassium carbonate; potassium osmate monohydrate; potassium hexacyanoferrate(III); methanesulfonamide / <i>tert</i>-butyl alcohol; water / 25 h / 0 °C 4.1: toluene-4-sulfonic acid / 16.5 h / 20 °C
  • 36
  • [ 565-63-9 ]
  • [ 609358-98-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C 5: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8: CH2Cl2 / 3 h / 25 °C 9: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C
  • 37
  • [ 565-63-9 ]
  • [ 609359-02-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 13 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C
  • 38
  • [ 565-63-9 ]
  • [ 609358-99-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2: diethyl ether / 48 h / 25 °C 3: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4: TsOH / 1 h / 25 °C 5: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8: CH2Cl2 / 3 h / 25 °C 9: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C
  • 39
  • [ 565-63-9 ]
  • [ 609359-03-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 14 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C
  • 40
  • [ 565-63-9 ]
  • [ 609358-91-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 16 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C
  • 41
  • [ 565-63-9 ]
  • [ 609359-04-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 15 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C
  • 42
  • [ 565-63-9 ]
  • [ 609359-01-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 12 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C
  • 43
  • [ 565-63-9 ]
  • [ 609359-00-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C
  • 44
  • [ 565-63-9 ]
  • [ 609359-39-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 19 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C 18.1: LiOH / tetrahydrofuran; ethanol; H2O / 0 °C 19.1: methanol / 0 °C
  • 45
  • [ 565-63-9 ]
  • [ 609359-20-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 19 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 12 h / 25 °C 18.1: 52 percent / LiOH / tetrahydrofuran; ethanol; H2O / 1.5 h / 0 °C 19.1: 90 percent / methanol / 1 h / 0 °C
  • 46
  • [ 565-63-9 ]
  • [ 609359-37-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 18 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C 18.1: LiOH / tetrahydrofuran; ethanol; H2O / 0 °C
  • 47
  • [ 565-63-9 ]
  • [ 609359-19-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 18 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 12 h / 25 °C 18.1: 52 percent / LiOH / tetrahydrofuran; ethanol; H2O / 1.5 h / 0 °C
  • 48
  • [ 565-63-9 ]
  • [ 609359-35-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 17 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C
  • 49
  • [ 565-63-9 ]
  • [ 609359-18-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 17 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 12 h / 25 °C
  • 50
  • [ 565-63-9 ]
  • [ 609359-40-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 20 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C 18.1: LiOH / tetrahydrofuran; ethanol; H2O / 0 °C 19.1: methanol / 0 °C 20.1: 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C
  • 51
  • [ 565-63-9 ]
  • [ 609359-21-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 20 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 12 h / 25 °C 18.1: 52 percent / LiOH / tetrahydrofuran; ethanol; H2O / 1.5 h / 0 °C 19.1: 90 percent / methanol / 1 h / 0 °C 20.1: 83 percent / 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 5 h / 25 °C
  • 52
  • [ 565-63-9 ]
  • [ 609359-41-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 21 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C 18.1: LiOH / tetrahydrofuran; ethanol; H2O / 0 °C 19.1: methanol / 0 °C 20.1: 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 25 °C 21.1: Me3SnOH / 1,2-dichloro-ethane / Heating
  • 53
  • [ 565-63-9 ]
  • [ 609359-22-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 21 steps 1.1: (COCl)2; DMF; KOH / diethyl ether / 2 h 2.1: diethyl ether / 48 h / 25 °C 3.1: 90 percent / AD-mix-β; MeSO2NH2 / 2-methyl-propan-2-ol; H2O / 24 h / 0 °C 4.1: TsOH / 1 h / 25 °C 5.1: 90 percent / diisobutylaluminium hydride / CH2Cl2 / 2 h / -78 °C 6.1: Dess-Martin reagent; NaHCO3 / CH2Cl2 / 3 h / 25 °C 7.1: Yb(OTf)3 / CH2Cl2 / 2 h / 25 °C 8.1: CH2Cl2 / 3 h / 25 °C 9.1: 75 percent / H2 / Pd/Pd(OH)2 / ethyl acetate / 12 h / 25 °C 10.1: 90 percent / H2S; Et3N / ethanol; pyridine / 12 h / 25 °C 11.1: NaHCO3 / 1,2-dimethoxy-ethane / 24 h / 25 °C 11.2: 82 percent / pyridine / 1 h / 0 °C 12.1: 100 percent / NaOEt / ethanol / 1 h / 0 °C 13.1: CF3CO2H / ethanol; CH2Cl2 / 4 h / 0 - 25 °C 14.1: Et3N / CH2Cl2 / 12 h / 0 - 25 °C 15.1: 82 percent / TfN3; Et3N; CuSO4 / methanol; H2O; CH2Cl2 / 12 h / 25 °C 16.1: 95 percent / LiOH / tetrahydrofuran; H2O / 2 h / 0 °C 17.1: (i-Pr)2NEt; 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 12 h / 25 °C 18.1: 52 percent / LiOH / tetrahydrofuran; ethanol; H2O / 1.5 h / 0 °C 19.1: 90 percent / methanol / 1 h / 0 °C 20.1: 83 percent / 7-azabenzotriazol-1-ol; HATU / dimethylformamide / 5 h / 25 °C 21.1: 85 percent / Me3SnOH / 1,2-dichloro-ethane / 4 h / Heating
  • 54
  • [ 565-63-9 ]
  • (-)-homogynolide-A [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / toluene / 2 h 2: toluene / 16 h / 70 °C
Multi-step reaction with 2 steps 1: triethylamine / toluene / 3 h / 20 °C 2: 97 percent / toluene / 16 h / 70 °C
  • 55
  • [ 565-63-9 ]
  • (R)-1,3-Dimethyl-3-vinyl-1,3-dihydro-indol-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: KOH, (COCl)2 / dimethylformamide 2: 1,2,2,6,6-pentamethylpiperidine 3: 1.) NaH 4: Pd(dba)3*CHCl3, (R)-BINAP, 1,2,2,6,6-pentamethylpiperidine, Bu4NCl*H2O / N,N-dimethyl-acetamide / 23 h / 100 °C
Multi-step reaction with 4 steps 1.1: potassium hydroxide / ethanol / 0.5 h / 20 °C 2.1: oxalyl dichloride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 3 h / 20 °C 3.1: sodium hydride / tetrahydrofuran / 0.25 h / 0 °C 3.2: 20 °C 4.1: NiCl2(R,R-QuinoxP*); sodium carbonate; manganese; lithium iodide / N,N-dimethyl-formamide / 21 h / 20 - 60 °C / Inert atmosphere; Glovebox; Sealed tube
  • 56
  • [ 565-63-9 ]
  • (E)-3,5-dimethoxy-4-(S-2-methylbutyryloxy)phenylpropenol [ No CAS ]
  • (E)-3,5-dimethoxy-4-(S-2-methylbutyryloxy)phenylpropenyl angelate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.4% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 12h;
  • 57
  • [ 40000-20-2 ]
  • [ 565-63-9 ]
  • [ 1350890-16-2 ]
  • 58
  • [ 565-63-9 ]
  • [ 14162-95-9 ]
  • [ 1310048-26-0 ]
  • 59
  • [ 565-63-9 ]
  • [ 18107-18-1 ]
  • [ 5953-76-4 ]
YieldReaction ConditionsOperation in experiment
In diethyl ether at 20℃; for 2.91667h; 22 Example 22; The procedure described in Example 8 for angelic anhydride was employed for the reaction between methyl angelate and ingenol-5,20-acetonide using lithium hexamethyldisilazide in tetrahydrofuran. The experiment was conducted on a scale of 25 mg ingenol-5,20-acetonide.Table 10Svnthesis of inqenol-5,20-acetonide-3-anaelate usina Methvl anaelate(AngOMe)c Reagent Solvent Product formed (crude yield)3 {E /{Z)b HMDS THF I-5,20-A-3-Ang (7 %) 1 : 99 a,b The yield and ( )/(Z) ratio were estimated from H NMR and TLC data.b (E)/(Z) = 1 : 99 due to a content of 0.5-1 % TigOMe in AngOMe. The (E)/(Z) ratio is the I-5,20-A-3-Tig/I-5,20-A-3-Ang ratioc Prepared by dropwise addition of a solution of (trimethylsilyl)diazomethane in ethyl ether (2.0 M, 18.8 mL, 38 mmol) over a period of 175 minutes at 20 °C to a stirred solution of angelic acid (3.0 g, 30.0 mmol) indichloromethane/methanol = 3 :2 (30 mL). The reaction mixture wasconcentrated, and methyl angelate was purified by vacuum distillation. Also see J. Org. Chem. 1950, 15, 680-684.XH NMR (300 MHz, CDCI3) δ 6.06 (qq, 1H), 3.74 (s, 3H), 1.98 (dq, 3H), 1.89 (quintet, 3H).
  • 60
  • [ 565-63-9 ]
  • [ 77573-43-4 ]
  • [ 94487-74-8 ]
  • [ 14316-68-8 ]
  • [ 1356334-21-8 ]
  • [ 1356490-35-1 ]
  • 3-O-angeloyl-5,20-O-isopropylideneingenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tributyl-amine; 2-chloro-1-methyl-pyridinium iodide In toluene at 60℃; for 18h; 19.B Example 19B; Ingenol-5,20-acetonide (25.0 mg, 64 pmol), angelic acid (6.4 mg, 64 pmol) and 2-chloro-l-methyl-pyridinium iodide (19.7 mg, 77 pmol) (Mukaiyama's reagent) were suspended in toluene (108 pL). Tributylamine (37 pL, 29 mg, 155 pmol) was added, and the mixture was stirred at 60 °C for 18 hours. The progress of the reaction was monitored by TLC and XH NMR spectroscopy.Product distribution and reaction conditions for examples 19A and 19B are shown in table 7AProducts are shown in table 7BThe (E)/(Z) ratio is the Tiglate/Angelate ratio.
  • 61
  • [ 565-63-9 ]
  • [ 77573-43-4 ]
  • [ 94487-74-8 ]
  • [ 14316-68-8 ]
  • [ 1356334-21-8 ]
  • [ 1356490-35-1 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 19.A Synthesis of ingenol-5.20-acetonide-3-angelate using Angelic acid ( AngQH); Example 19A (general procedure); Ingenol-5,20-acetonide (10.0 mg, 26 pmol) and angelic acid (2.6 mg, 26 pmol) were dissolved in the solvent (175 pL) at 20 °C with stirring. For reactions conducted in the presence of base, either 4-(dimethylamino)pyridine (6.3 mg, 52 pmol) or A/,/V-diisopropylethylamine (9 pL, 6.7 mg, 52 pmol) was added before the dropwise addition of a solution/suspension of the coupling reagent (26-52 pmol) in the solvent (75 pL). The progress of the reaction was monitored by TLC and H NMR spectroscopy.
  • 62
  • [ 565-63-9 ]
  • [ 77573-43-4 ]
  • [ 1356490-35-1 ]
  • 3-O-angeloyl-5,20-O-isopropylideneingenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In chloroform-d1 at 20℃; 19.A Example 19A (general procedure); Ingenol-5,20-acetonide (10.0 mg, 26 pmol) and angelic acid (2.6 mg, 26 pmol) were dissolved in the solvent (175 pL) at 20 °C with stirring. For reactions conducted in the presence of base, either 4-(dimethylamino)pyridine (6.3 mg, 52 pmol) or A/,/V-diisopropylethylamine (9 pL, 6.7 mg, 52 pmol) was added before the dropwise addition of a solution/suspension of the coupling reagent (26-52 pmol) in the solvent (75 pL). The progress of the reaction was monitored by TLC and H NMR spectroscopy.
With dmap; dicyclohexyl-carbodiimide In chloroform-d1 for 48h;
  • 63
  • [ 565-63-9 ]
  • [ 77573-43-4 ]
  • [ 1356187-27-3 ]
  • [ 75567-37-2 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogenchloride; water In methanol at 20℃; for 1h;
  • 64
  • [ 3017-68-3 ]
  • [ 18414-58-9 ]
  • [ 565-63-9 ]
YieldReaction ConditionsOperation in experiment
97% With lithium trimethylsilanolate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 80℃; for 16h; Glovebox;
  • 65
  • [ 565-63-9 ]
  • (6R*,11aS*)-6-hydroxymethyl-8-methoxy-2,9-dimethyl-2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4,7,10(6H)-tetraone [ No CAS ]
  • (Z)-((6R*,11aS*)-8-methoxy-2,9-dimethyl-1,4,7,10-tetraoxo-2,3,4,6,7,10,11,11a-octahydro-1H-pyrazino[1,2-b]isoquinolin-6-yl)methyl 2-methylbut-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: Angelic acid With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether; toluene at 25℃; for 2h; Cooling with ice; Stage #2: (6R*,11aS*)-6-hydroxymethyl-8-methoxy-2,9-dimethyl-2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4,7,10(6H)-tetraone In diethyl ether; dichloromethane; toluene at 25℃; for 3.5h;
  • 66
  • [ 565-63-9 ]
  • (6S*,11aS*)-6-hydroxymethyl-8-methoxy-2,9-dimethyl-2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4,7,10(6H)-tetraone [ No CAS ]
  • (Z)-((6S*,11aS*)-8-methoxy-2,9-dimethyl-1,4,7,10-tetraoxo-2,3,4,6,7,10,11,11a-octahydro-1H-pyrazino[1,2-b]isoquinolin-6-yl)methyl 2-methylbut-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72.1% Stage #1: Angelic acid With oxalyl dichloride; N,N-dimethyl-formamide In diethyl ether; toluene at 25℃; for 2h; Cooling with ice; Stage #2: (6S*,11aS*)-6-hydroxymethyl-8-methoxy-2,9-dimethyl-2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4,7,10(6H)-tetraone In diethyl ether; dichloromethane; toluene at 25℃; for 3.5h;
  • 67
  • (3S,11S)-dihydroxytetradecanoic acid 11-O-(4-O-angeloyl)-α-L-rhamnopyranosyl-(1→2)-O-β-D-glucopyranosyl-(1→2)-β-D-quinovopyranoside methyl ester [ No CAS ]
  • [ 565-63-9 ]
  • (3S,11S)-dihydroxytetradecanoic acid 11-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-glucopyranosyl-(1→2)-β-D-quinovopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
15 mg Stage #1: (3S,11S)-dihydroxytetradecanoic acid 11-O-(4-O-angeloyl)-α-L-rhamnopyranosyl-(1→2)-O-β-D-glucopyranosyl-(1→2)-β-D-quinovopyranoside methyl ester With potassium hydroxide at 85℃; for 4h; Stage #2: Acidic conditions; Alkaline hydrolysis of 3 Compound 3 (20mg) was treated with 5%KOH (3ml) at 85°C for 4 h. The reactionmixture was acidified to pH 4.0 and extracted with Et2O (3 £ 10ml). The Et2O layer was dried (anhydr. MgSO4) and concentrated to a small volume (about0.2ml) to afford a short chain organic acid fraction. The aqueous layer was further extracted with n-BuOH (3 £ 20 ml). The n-BuOH solution was concentrated in vacuo to yield a residue which was subjected to Sephadex LH-20 CC using MeOH to afford a glycosidic acid 2 (15mg). The short chain organic acid fraction obtained from 3(1.0mg) was examined by GC-MS usinga ShimadzuGCMS-QP2000 Plus apparatus,equipped with Rxiw-5 ms fused silicacapillary column (30m £ 0.25 mm,0.25mm). The carrier gas was helium. Column temperature was initially 50°C and increased to 160°C at 20°C/min and to 220°C at 5°C/min, to give one predominant peak which was identified to be angelicacid (tR 3.7min): EI-MS: m/z 100 [M](100), 85 (29), 72 (0.8), 55 (86), 53(16), and 39 (25).
  • 68
  • [ 565-63-9 ]
  • [ 77573-43-4 ]
  • [ 75567-37-2 ]
YieldReaction ConditionsOperation in experiment
80 mg With dmap In toluene at 20℃; for 2h; 4 EXAMPLE 4 Producing Ingenol Tigliate (Formula II) [0038] A solution of ingenol-5,20-acetonide (100 mg, 0.26 mmol), angelic acid (39 mg, 0,39 mmol, 1.5 mol. equiv.) and DMAP (48 mg, 0.39 mmol, 1.5 mol. equiv.) in toluene (4 ml), was stirred at room temperature for 2 hours and was then filtered through a bed of celite and evaporated. The resulting material was filtered in silica gel (ca. 5 g) and evaporated. The residue was purified by means of silica gel gravity column chromatography (5 g, petroleum ether:EtOAc 85:15) until obtaining over 80 mg of ingenol-3-angelate with a purity >99%. For physical and spectroscopic data, see Hohmann J et al. Planta Medica 2000, 66, 291-294.
  • 69
  • [ 137-32-6 ]
  • [ 565-63-9 ]
  • [ 61692-77-1 ]
YieldReaction ConditionsOperation in experiment
54% With pyridine; dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 3.5h;
With dmap; dicyclohexyl-carbodiimide In dichloromethane
  • 70
  • [ 565-63-9 ]
  • [ 824-94-2 ]
  • 4-methoxybenzyl (Z)-2-methylbut-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;
  • 71
  • [ 7779-81-9 ]
  • [ 565-63-9 ]
YieldReaction ConditionsOperation in experiment
88% With lithium hydroxide monohydrate In methanol; water for 4h; Inert atmosphere; Reflux;
39% With lithium hydroxide monohydrate In methanol; water for 4h; Reflux;
  • 72
  • [ 565-63-9 ]
  • C25H30N2O6 [ No CAS ]
  • C30H36N2O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.4% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: C25H30N2O6 In toluene at 90℃; for 48h; Inert atmosphere; 4.15 (1S,3R,11R,13S)-(+)-10a To a solution of angelica acid (16.5mg, 0.165mmol) in anhydrous toluene (1mL) at 0°C were added 2,4,6-trichlorobenzoyl chloride (25.8μL, 0.165mmol) and Et3N (22.9μL, 0.165mmol) under argon. After stirring for 2h at room temperature, the solution of (1S,3R,11R,13S)-(+)-8a (30mg, 0.066mmol) in anhydrous toluene (4mL) was added to the reaction mixture and then the reaction mixture was stirred for 48h at 90°C. After cooled to room temperature, the reaction mixture was quenched with saturated aqNH4Cl, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford (1S,3R,11R,13S)-(+)-10a (26mg, 73.4%) as a white solid. [α]D20 +118.5 (c 2.0, CH2Cl2); HRMS calcd for C30H37N2O7 [M+H]+ 537.2595, found 537.2609; 1H NMR (300MHz, CDCl3): δ 6.49 (s, 1H), 6.46 (s, 1H), 5.94-5.89 (m, 1H), 5.89 (s, 1H), 5.71 (s, 1H), 5.51 (s, 1H), 5.04 (d, J=11.7Hz, 1H), 4.57 (d, J=10.8Hz, 1H), 4.17 (s, 1H), 3.76-3.73 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.32 (t, J=12.9Hz, 1H), 3.20 (d, J=12.0Hz, 1H), 3.10 (dd, J=17.1, 6.6Hz, 1H), 2.88-2.79 (m, 2H), 2.55 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.79 (d, J=7.5Hz, 3H), 1.72 (s, 3H); 13C NMR (125MHz, CDCl3): δ 167.4, 145.5, 145.3, 143.7, 143.3, 137.4, 135.2, 128.6, 127.9, 122.0, 121.0, 118.2, 62.8, 62.3, 60.7 (2C), 59.9, 55.9, 52.2, 40.2, 37.3, 30.9, 29.7, 25.1, 20.4, 15.7, 15.4.
  • 73
  • [ 565-63-9 ]
  • C25H30N2O6 [ No CAS ]
  • C30H36N2O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
57.6% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: C25H30N2O6 In toluene at 90℃; for 48h; Inert atmosphere; 4.15 (1S,3R,11R,13S)-(+)-10a General procedure: To a solution of angelica acid (16.5mg, 0.165mmol) in anhydrous toluene (1mL) at 0°C were added 2,4,6-trichlorobenzoyl chloride (25.8μL, 0.165mmol) and Et3N (22.9μL, 0.165mmol) under argon. After stirring for 2h at room temperature, the solution of (1S,3R,11R,13S)-(+)-8a (30mg, 0.066mmol) in anhydrous toluene (4mL) was added to the reaction mixture and then the reaction mixture was stirred for 48h at 90°C. After cooled to room temperature, the reaction mixture was quenched with saturated aqNH4Cl, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford (1S,3R,11R,13S)-(+)-10a (26mg, 73.4%) as a white solid. _4.16 (1S,3R,11S,13R)-(+)-10b (0036) Following the general reaction protocol, angelica acid (8.3mg, 0.083mmol) was activated by 2,4,6-trichloro-benzoyl chloride (13.0μL, 0.083mmol) and Et3N (12.0μL, 0.087mmol) in anhydrous toluene (4mL) and then reacted with (1S, 3R, 11S, 13R)-(+)-8b (15mg, 0.033mmol), which provided (1S,3R,11S,13R)-(+)-10b (10.2mg, 57.6%) as a white solid. [α]D20 +100.5 (c 4.0, CH2Cl2); HRMS calcd for C30H37N2O7 [M+H]+ 537.2595, found 537.2593; 1H NMR (300MHz, CDCl3): δ 6.56-6.44 (m, 2H), 5.94-5.70 (m, 4H), 4.33-4.21 (m, 3H), 4.00 (d, J=12.3Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.66 (d, J=6.9Hz, 1H), 3.17 (dd, J=17.4, 7.2Hz, 1H), 2.98 (m, 1H), 2.85 (m, 1H), 2.51 (m, 1H), 2.44 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 1.64 (d, J=7.2Hz, 3H), 1.38 (s, 3H); 13C NMR (125MHz, CDCl3): δ 167.1, 146.3, 145.6, 143.8, 143.1, 133.4, 129.1, 127.5, 122.2, 122.1, 120.7 (2C), 117.5, 64.1, 60.6 (2C), 59.9, 58.2, 55.2, 49.1, 40.2, 32.0, 28.4, 20.0, 15.7 (2C), 15.3.
  • 74
  • [ 565-63-9 ]
  • C25H26N2O8 [ No CAS ]
  • 11,13-epi-(-)-renieramycin G [ No CAS ]
YieldReaction ConditionsOperation in experiment
59.3% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: C25H26N2O8 In toluene at 90℃; for 48h; Inert atmosphere; 4.14 11,13-epi-(-)-Renieramycin G To a solution of angelica acid (6.6mg, 0.066mmol) in anhydrous toluene (1mL) at 0°C were added 2,4,6-trichlorobenzoyl chloride (11μL, 0.07mmol) and Et3N (10μL, 0.07mmol) under argon. After stirring for 2h at room temperature, the solution of (1R,3S,11S,13R)-(-)-9 (15mg, 0.031mmol) in anhydrous toluene (4mL) was added to the reaction mixture and then the reaction mixture was stirred for 48h at 90°C. After cooled to room temperature, the reaction mixture was quenched with saturated aqNH4Cl, extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel to afford 11,13-epi-(-)-renieramycin G (10.4mg, 59.3%) as a yellow solid. [α]D20 -123.3 (c 0.6, CH2Cl2); HRMS calcd for C30H33N2O9 [M+H]+ 565.2181, found 565.2185; 1H NMR (400MHz, CDCl3): δ 6.03 (dq, J=7.2, 1.2Hz, 1H), 5.22 (s, 1H), 5.13 (dd, J=12.0, 2.4Hz, 1H), 4.61 (dd, J=12.0, 2.4Hz, 1H), 4.06 (s, 3H), 4.00 (m, 1H), 3.98 (s, 3H), 3.84 (s, 1H), 3.13 (d, J=16.8Hz, 1H), 2.95 (d, J=10.4Hz, 1H), 2.85 (s, 2H), 2.71 (m, 1H), 2.56 (s, 3H), 1.94 (s, 6H), 1.84 (dq, J=7.2, 1.6Hz, 3H), 1.74 (t, J=1.2Hz, 3H); 13C NMR (125MHz, CDCl3): δ 186.3, 185.4, 182.2, 180.6, 167.2, 156.4, 155.3, 142.9, 139.8, 139.2, 137.6, 137.0, 129.5, 127.9, 126.8, 61.0, 60.7, 58.8, 58.4, 53.9, 53.2, 39.8, 29.4, 21.6, 20.5, 15.5, 8.7 (2C).
  • 75
  • [ 565-63-9 ]
  • [ 157160-53-7 ]
  • thiapsigargin [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: Angelic acid With benzoyl chloride; triethylamine In toluene at 40℃; for 2h; Inert atmosphere; Stage #2: Octanoic acid (3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetoxy-4-butyryloxy-3,3a,8-trihydroxy-3,6,9-trimethyl-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydro-azuleno[4,5-b]furan-7-yl ester In toluene at 90℃; for 72h; Inert atmosphere; Thapsigargin (1)3 To a solution of angelic acid (11.1 mg, 0.11 mmol) in dry toluene (100 L) at room temperature under nitrogen were successively added benzoyl chloride (15.6 mg, 0.11 mmol) and TEA (15.4 L,0.11 mmol). The reaction mixture was heated at 40 °C for 2 h then a solution of alcohol 6S (17.9mg, 0.03 mmol) in dry toluene (300 L) was added and the reaction mixture was heated at 90 °C for 72 h then cooled to room temperature. Volatiles were removed under reduced pressure and the resulting crude material was purified by flash column chromatography on silica gel using a gradient elution (EtOAc-heptane, 1:2 to 2:3) to lead to thapsigargin (1) as a white solid (13.4 mg, 65 %). Rf= 0.23 (EtOAc-heptane, 1:2); 1H NMR (400 MHz) δ 6.10 (qq, J = 7.0 and 1.4 Hz, 1H), 5.68 (br s,1H), 5.65 (br s, 1H), 5.62 (t, J = 3.6 Hz, 1H), 5.47-5.50 (m, 1H), 4.26-4.29 (m, 1H), 3.36 (br s,1H), 3.02 (dd, J = 14.8 and 3.4 Hz, 1H), 2.77 (br s, 1H), 2.23-2.38 (m, 5H), 1.99 (dq, J = 7.0 and1.4 Hz, 3H), 1.91-1.93 (m, 3H) 1.89 (s, 3H), 1.86 (s, 3H), 1.55-1.67 (m, 4H), 1.48 (s, 3H), 1.40 (s,3H), 1.24-1.34 (m, 8H), 0.93 (t, J = 7.2 Hz, 3H), 0.84-0.89 (m, 3H). The other analytical dataperfectly matched those reported in the literature.2,3 Starting material 6S (2.1 mg, 12 %) was alsorecovered.
59% Stage #1: Angelic acid With benzoyl chloride; triethylamine In toluene at 40℃; for 2h; Stage #2: Octanoic acid (3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetoxy-4-butyryloxy-3,3a,8-trihydroxy-3,6,9-trimethyl-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydro-azuleno[4,5-b]furan-7-yl ester In toluene at 90℃; for 72h; Thapsigargin (1) To lactone 17 (33 mg, 0.0582 mmol) in Et20 (2 mL) was added Zn(BH4)2 (0.5 M Et20 solution, 1.33 mL, 0.68 mmol) dropwise at - 20 °C. The resulting solution was stirred at that temperature for 4 hours. The reaction mixture was then diluted with EtOAc (3 mL) and ice water was added dropwise. The aqueous layer was extracted EtOAc (2 x 5 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (1:2 (0198) EtOAc: Hexanes) to afford intermediate alcohol 18 (29 mg, 88%) as an amorphous solid. The characterization data of 18 is in agreement with that reported in the Iiterature4. To a solution of angelic acid (11.1 mg, 0.11 mmol, ca.3 equiv.) in toluene (0.1 mL) at room temperature was sequentially added benzoyl chloride (15.6 mg, 0.11 mmol) and Et3N (15.4 μ, 0.11 mmol). The resulting white suspension was heated at 40 °C for 2 h. A solution of alcohol 18 (17.9 mg, 0.03 mmol) in toluene (300 μ) was added. The reaction mixture was then heated at 90 °C for 72 h before cooling to room temperature. The reaction mixture was passed through a short plug of Si02 before diluting with a 1:1 mixture of Et20 and hexanes (ca.5 mL). The solution was washed with NaHC03 (2 x 5 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (1:2 EtOAc: Hexanes) to afford (-)-thapsigargin 1 (12 mg, 59 %) as a white film.2 (0199) Physical State: white film (0200) 1H NMR (600 MHz, chloroform-d): 1H NMR (600 MHz, Chloroform-d) δ 6.10 (qq, J = 7.1 Hz, 1.4 Hz, 1H), 5.69 (br s, 1H), 5.65 (br s, 1H), 5.62 (t, J = 3.8 Hz, 1H), 5.49 (dd, J = (0201) 3.3, 3.2 Hz, 1H), 4.24 (br m, 1H), 3.05 (br s, 1H), 2.99 (dd, J = 14.9, 3.5 Hz, 1H), 2.58 (0202) (br s, 1H), 2.38 - 2.16 (m, 5H), 1.99 (m, 3H), 1.92 - 1.91 (m, 3H), 1.89 (s, 3H), 1.87 (0203) (s, 3H), 1.66 - 1.56 (m, 4H), 1.49 (s, 3H), 1.40 (s, 3H), 1.33 - 1.20 (m, 8H), 0.94 (t, J (0204) = 7.4 Hz, 3H), 0.87 (t, J = 6.7 Hz, 3H). (0205) 13C NMR (151 MHz, chloroform-d): δ 175.3, 172.7, 172.6, 170.8, 167.2, 142.2, 138.9, (0206) 130.1, 127.6, 84.5, 84.2, 78.8, 78.7, 77.9, 76.8, 66.3, 57.8, 38.4, 36.7, 34.4, 31.8, (0207) 29.2, 29.1, 25.0, 23.0, 22.8, 22.7, 20.7, 18.1, 16.4, 16.0, 14.2, 13.8, 13.1. (0208) HRMS (ESI) m/z: calculated for C34H50O12Na: 673.3200; found: 673.3188 [M + Na] + (0209) [a]D20: (c = 1, CHCI3) -31.6° (0210) Rf: 0.24 (1:2 EtOAc: Hexanes) Anisaldehyde: brown.
  • 76
  • [ 565-63-9 ]
  • [ 4136-95-2 ]
  • C12H18O3 [ No CAS ]
  • C17H24O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: Angelic acid; 2,4,6-trichlorobenzoyl chloride With triethylamine In toluene at 20℃; for 2h; Stage #2: C12H18O3 In toluene at 70℃; for 6h;
  • 77
  • [ 565-63-9 ]
  • C24H34O11 [ No CAS ]
  • 2-acetoxytrilobolide [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Inert atmosphere; Stage #2: C24H34O11 In toluene at 75℃; for 48h; 2-Acetoxytrilobolide 8 2-Acetoxytrilobolide 82,4,6-Trichlorobenzoyl chloride (9.4 μ, 0.06 mmol) and triethyl- amine (8.4 μ, 0.06 mmol) were successively added to a solution of angelic acid (6 mg, 0.06 mmol) in dry toluene (100 μ) at room temperature under an argon atmosphere. The resulting mixture was stirred at this temperature for 2 h and was subsequently treated with a solution of 3-(S)-alcohol 7 (15 mg, 0.03 mmol) in dry toluene (100 μ). The reaction mixture was stirred at 75 °C for 2 days. The resulting mixture was cooled to room temperature and quenched by the addition of an aqueous saturated ammonium chloride solution (3 mL). The separated aqueous phase was extracted with EtOAc (2 x 5 mL) and the combined organic phases were dried over MgS04, filtered and con- centrated under reduced pressure. The crude product was purified by dry vacuum column chromatography (silica gel, toluene-EtOAc 3:1 ) to provide the target 2- acetoxytrilobolide 8 (8.5 mg, 49%) as a colorless oil.
  • 78
  • [ 565-63-9 ]
  • [ 157160-53-7 ]
  • thapsigargin [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: Angelic acid With benzoyl chloride; triethylamine In toluene at 40℃; for 2h; Inert atmosphere; Stage #2: Octanoic acid (3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetoxy-4-butyryloxy-3,3a,8-trihydroxy-3,6,9-trimethyl-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydro-azuleno[4,5-b]furan-7-yl ester In toluene at 90℃; for 72h; Thapsigargin (1) Thapsigargin (1)To a solution of angelic acid (1 1 .1 mg, 0.1 1 mmol) in dry toluene (100 mL) at room temperature under nitrogen were successively added benzoyl chloride (15.6 mg, 0.1 1 mmol) and TEA (15.4 mL, 0.1 1 mmol). The reaction mixture was heated at 40 °C for 2 h then a solution of alcohol 6S (17.9 mg, 0.03 mmol) in dry toluene (300 mL) was add- ed and the reaction mixture was heated at 90 °C for 72 h then cooled to room temperature. Volatiles were removed under reduced pressure and the resulting crude material was purified by flash column chromatography on silica gel using a gradient elution (EtO Ac-heptane, 1 :2 to 2:3) to lead to thapsigargin (1 ) as a white solid (13.4 mg, 65 %). Rf = 0.23 (EtOAc-heptane, 1 :2); 1 H NMR (400 MHz) δ 6.10 (qq, J = 7.0 and 1 .4 Hz, 1 H), 5.68 (br s, 1 H), 5.65 (br s, 1 H), 5.62 (t, J = 3.6 Hz, 1 H), 5.47-5.50 (m, 1 H), 4.26- 4.29 (m, 1 H), 3.36 (br s, 1 H), 3.02 (dd, J = 14.8 and 3.4 Hz, 1 H), 2.77 (br s, 1 H), 2.23- 2.38 (m, 5H), 1 .99 (dq, J = 7.0 and 1 .4 Hz, 3H), 1 .91-1 .93 (m, 3H) 1 .89 (s, 3H), 1 .86 (s, 3H), 1 .55-1 .67 (m, 4H), 1 .48 (s, 3H), 1 .40 (s, 3H), 1 .24-1 .34 (m, 8H), 0.93 (t, J = 7.2 Hz, 3H), 0.84-0.89 (m, 3H). The other analytical data perfectly matched those re- ported in the literature. Starting material 6S (2.1 mg, 12 %) was also recovered.
  • 79
  • [ 565-63-9 ]
  • C16H28O3Si [ No CAS ]
  • C21H34O4Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With dmap; 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 20℃; for 2h; Inert atmosphere; Synthesis of (R,Z)-2-hydroxyl-2-(4-methyl-2-tert-butyldimethylsiloxylphenyl) propanyl angelate (9) 2,4,6-Trichlorobenzoylchloride (237 mg, 0.54 mmol) was added to a solution of angelic acid (108 mg, 1.08 mmol) and Et3N (109 mg, 1.08 mmol) in toluene (anhydrous, 2 mL) under N2. The mixture was stirred at r.t. for 2 hrs. When TLC showed the completion of the reaction, sat. NH4Cl (2 mL) was added to quench it. The mixture was diluted with EtOAc (50 mL) and washed with H2O (20 mLx3) and brine (20 mL). After dried over anhydrous Na2SO4, the organic phase was concentrated by rotary evaporator under reduced pressure to give a residue, which was purified by chromatography (1:30 EtOAc/PE) on silica gel to afford ester 9 as a colorless oil (51 mg, 0.12 mmol, 22%). [a]D26 +1.26 (c 0.80, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.65 (s, 1H), 5.99 (qq, J = 7.0, 1.5 Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 4.39 (d, J = 10.9 Hz, 1H), 2.28 (s, 3H), 1.86 (dq, J = 7.2, 1.5 Hz, 3H), 1.81 (qd, J = 1.5, 1.6 Hz, 3H), 1.62 (s, 3H), 1.04 (s, 9H), 0.37 (s, 3H), 0.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.0, 152.9, 138.4, 137.7, 130.0, 127.8, 127.6, 121.8, 119.1, 73.9, 70.2, 26.0, 24.7, 21.1, 20.5, 18.4, 15.6, -3.6, -3.8. FT-IR (film) nmax 3527 (br), 2956, 2931, 1718, 1257, 1155, 839, 783 cm-1. ESI-MS m/z 401.4 ([M+Na]+). ESI-HRMS: calcd. for C21H34O4NaSi ([M+Na]+) 401.2119, found 401.2118.
  • 80
  • [ 565-63-9 ]
  • (6aS,7R,13S,14R,16R)-5,8-dihydroxy-16-(hydroxymethyl)-9-methoxy-4,10,17-trimethyl-6,6a,7,13,14,16-hexahydro-12H-7,13-epiminobenzo[4,5]azocino[1,2-b][1,3]dioxolo[4,5-h]isoquinoline-14-carbonitrile [ No CAS ]
  • C31H35N3O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
  • 81
  • [ 565-63-9 ]
  • C28H29N3O8 [ No CAS ]
  • [ 1175596-29-8 ]
YieldReaction ConditionsOperation in experiment
66% With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 90℃;
  • 82
  • [ 565-63-9 ]
  • C28H28ClN3O8 [ No CAS ]
  • C33H34ClN3O9 [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: Angelic acid With 2,4,6-trichlorobenzoyl chloride; triethylamine In toluene at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: C28H28ClN3O8 In toluene at 90℃; for 36h; Inert atmosphere;
  • 83
  • [ 565-63-9 ]
  • [ 150-76-5 ]
  • 4-methoxyphenyl (Z)-2-methylbut-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;
  • 84
  • [ 67560-68-3 ]
  • [ 565-63-9 ]
  • (Z)-((2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4- dimethoxyphenyl)tetrahydrofuran -3-yl)methyl-2-methylbut-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; Schlenk technique; Darkness; B.17 (Z)-((2S,3R,4R)-4-(3,4-Dimethoxybenzyl)-2-(3,4- dimethoxyphenyl) tetrahydrofuran-3-yl)methyl 2-methylbut-2-enoate (leoligin, 29) A reaction vessel was charged with a stirring bar, starting material 21 (989 mg, 2.55 mmol,1.0 equiv.), angelic acid (383 mg, 3.83 mmol, 1.5 equiv.) and PPh3 (2.34 g, 8.93 mmol, 3.5equiv.), and then evacuated and back-filled with argon using standard Schlenk technique.Dry THF (20 mL) was then added and the solution cooled to 0 °C in an ice bath. To the stirredmixture was then added DEAD (1.40 mL, 8.93 mmol, 3.5 equiv.) dropwise via syringe, andthe reaction stirred for 12 h while being kept away from light and allowed to warm slowly toroom temperature. The solvent was evaporated, which was followed by the addition of CHCl3(15 mL), LP (300 mL) and water (200 mL). The layers were separated and the aqueous phasewas re-extracted with LP (4 x 50 ml). The solvents were evaporated from the combinedorganic phases and then flash column chromatography was performed (180 g silica, flow rate40 mL / min, EtOAc / LP, 25 : 75 to 50 : 50 in 60 min) to afford the title compound 29. Ananalytical sample could be crystallized from a saturated solution of heptane and cooling it to-20 °C for several days.
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;
With triphenylphosphine; diethylazodicarboxylate
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