Structure of 709-63-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Dehaloperoxidase Catalyzed Stereoselective Synthesis of Cyclopropanol Esters
Siriboe, Mary G ; Vargas, David A ; Fasan, Rudi ;
Abstract: Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N−H/S−H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.
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CAS No. : | 709-63-7 |
Formula : | C9H7F3O |
M.W : | 188.15 |
SMILES Code : | C1=C(C=CC(=C1)C(C)=O)C(F)(F)F |
MDL No. : | MFCD00000401 |
InChI Key : | HHAISVSEJFEWBZ-UHFFFAOYSA-N |
Pubchem ID : | 69731 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.64 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.9 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.62 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.06 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.82 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.87 |
Solubility | 0.256 mg/ml ; 0.00136 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.63 |
Solubility | 0.443 mg/ml ; 0.00235 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.62 |
Solubility | 0.045 mg/ml ; 0.000239 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.59 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.09 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Ti(OiPr)4 (31.5 mL, 106 mmol) was added to (p-trifluoromethyl)acetophenone 108 (10.0 g, 53.1 mmol) in NH3 (2.0 M in EtOH, 133 mL) and the resultant mixture was stirred at rt for 6 h. NaBH4 (3.01 g, 79.7 mmol) was added at 0 C, and the resultant suspension was stirred at rt for 3 h, then poured into 2.0 M aq NH4OH (200 mL). The resultant suspension was filtered (eluent EtOAc) and the aqueous layer was extracted with EtOAc (2*80 mL). The combined organic extracts were extracted with 1.0 M aq HCl (3*50 mL) and the combined aqueous extracts were washed with EtOAc (3*30 mL), treated with 2.0 M aq NaOH until pH>8 was observed, then extracted with EtOAc (4*50 mL). The combined organic extracts were washed with brine (200 mL), then dried and concentrated in vacuo to give (RS)-117 as a pale yellow oil (6.84 g, 68%);43 δH (400 MHz, CDCl3) 1.40 (3H, d, J 6.6, C(α)Me), 1.59 (2H, br s, NH2), 4.20 (1H, q, J 6.6, C(α)H), 7.48 (2H, d, J 7.8, C(2)H, C(6)H), 7.59 (2H, d, J 7.8, C(3)H, C(5)H). | |
52% | A mixture of 1-(4-(trifluoromethyl)phenyl)ethanone (400 mg, 2.13 mmol), Ti(O-i-Pr)4 (1.25 mL, ∼4.25 mmol) and ammonia in EtOH (2 M, 5.30 mL, ∼10.6 mmol) was stirred under argon at room temperature for 24 h NaBH4 (120 mg, 3.19 mmol) was then added, and the resulting mixture was stirred for another 24 h. The pH of the reaction mixture was adjusted to pH 2 using HCl (6 M), and washed with tert-butyl methyl ether (TBME) (3 × 20 mL). Using NaOH (pellets) the pH was adjusted to ca 10, and the mixture was extracted with TBME (6 × 30 mL). The combined organic phase was dried over MgSO4, and the solvent was removed under reduced pressure to give 210 mg (1.11 mmol, 52%) of a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.58 (m, 2H), 7.46 (m, 2H), 4.19 (q, J = 6.7, 1H), 1.38 (d, J = 6.7, 3H), 1.51 (s, 2H, NH2). 13C NMR (100 MHz, CDCl3) δ: 152.1 (q, J = 1.1), 129.4 (q, J = 31.5), 126.5 (2C), 125.8 (q, J = 3.8, 2C), 124.6 (q, J = 270.9), 51.4, 25.1. | |
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; ammonium formate; In methanol; at 70℃; for 7h;Inert atmosphere; | General procedure: The corresponding ketone (20 mmol, 1.0 eq) and CH3OH (20 mL) were added to a 250 mL Schlenk tube containing [RhCp*Cl2]2 (61.8 mg, 100 μmol, 0.005 equiv) and HCOONH4 (6.36 g, 100 mmol, 5.0eq). The brown mixture was frozen, and the whole system was evacuated. The system was closed and then stirred at 70 C for 7 h. After the dark green resulting solution was cooled to room temperature, 1M aqueous HCl solution (38.4 mL) was added, and the mixture was washed twice with CH2Cl2 (5 mL) to remove the neutral compounds. After addition of a cold 12 M aqueous NaOH solution (3.6 mL) to the aqueous layer, the mixture was extracted six times with CH2Cl2 (12 mL). The combined organic layers were dried over anhydrous Na2SO4. Filtration and evaporation under reduced pressure gave crude amine,which was used without purification. All the crude corresponding amine was dissolved in dichloromethane (50 mL), and TCCA (trichloroisocyanuric acid) (3.2 g, 14 mmol) was added in a250 ml round-bottom flask at 0 C. Then, the mixture was stirred at ambient temperature during 1 h. Triethylamine (6.0 g, 6 mol) dissolved in dichloromethane (50 mL) was added, and the resulting mixture was washed with water (200 mL) and hydrochloric acid (1 M, 200 mL)successively. The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, purification by column chromatography on silica gel (n-hexane/EtOAc:40/1) afforded pure product. |