Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.¹ Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the ¹³C NMR and 0.79 ppm for the ¹H NMR.²

1

Lodewyk and Tantillo³ examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen⁴ (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the ¹³C and ¹H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for ¹³C and 0.31 for ¹H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for ¹³C and 0.21 ppm for ¹H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.

2

They next employed the DP4 analysis developed by Smith and Goodman⁵ for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.⁶ Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis,"Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI:10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(4) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem., 2009, DOI:10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc., 2010, 132, 12946-12959, DOI:10.1021/ja105035r

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899

1-Adamantyl cation – Predicting its NMR spectra

1-Adamantyl cation – Predicting its NMR spectra

What is required in order to compute very accurate NMR chemical shifts? Harding, Gauss and Schleyer take on the interesting spectrum of 1-adamantyl cation to try to discern the important factors in computing its ¹³C and ¹H chemical shifts.¹

1

To start, the chemical shifts of 1-adamtyl cation were computed at B3LYP/def2-QZVPP and
MP2/qz2p//MP2/cc-pVTZ. The root means square error (compared to experiment) for the carbon chemical shifts is large: 12.76 for B3LYP and 6.69 for MP2. The proton shifts are predicted much more accurately with an RMS error of 0.27 and 0.19 ppm, respectively.

The authors speculate that the underlying cause of the poor prediction is the geometry of the molecule. The structure of 1 was optimized at HF/cc-pVTZ, MP2/cc-pVTZ and CCSD(T)/pVTZ and then the chemical shifts were computed using MP2/tzp with each optimized geometry. The RMS error of the ¹²C chemical shifts are HF/cc-pVTZ: 9.55, MP2/cc-pVTZ: 5.62, and CCSD(T)/pVTZ: 5.06. Similar relationship is seen in the proton chemical shifts. Thus, a better geometry does seem to matter. The CCSD(T)/pVTZ optimized structure of 1 is shown in Figure 1.

1

Figure 1. CCSD(T)/pVTZ optimized structure of 1.

Unfortunately, the computed chemical shifts at CCSD(T)/qz2p//CCSD(T)/cc-pVTZ are still in error; the RMS is 4.78ppm for the carbon shifts and 0.26ppm for the proton shifts. Including a correction for the zero-point vibrational effects and adjusting to a temperature of 193 K to match the experiment does reduce the error; now the RMS for the carbon shifts is 3.85 ppm, with the maximum error of 6 ppm for C3. The RMS for the proton chemical shifts is 0.21ppm.

The remaining error they attribute to basis set incompleteness in the NMR computation, a low level treatment of the zero-point vibrational effects (which were computed at HF/tz2p), neglect of the solvent, and use of a reference in the experiment that was not dissolved in the same media as the adamantyl cation.

So, to answer our opening question – it appears that a very good geometry and treatment of vibrational effects is critical to accurate NMR shift computation of this intriguing molecule. Let the
computational chemist beware!

References

(1) Harding, M. E.; Gauss, J.; Schleyer, P. v. R., "Why Benchmark-Quality Computations Are Needed To Reproduce 1-Adamantyl Cation NMR Chemical Shifts Accurately," J. Phys. Chem. A, 2011, 115, 2340-2344, DOI: 10.1021/jp1103356

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DOXOFYLLINE SPECTRAL DATA

DOXOFYLLINE

69975-86-6  CAS NO

7-(1,3-dioxolan-2-ylmethyl)-1,3-dimethylpurine-2,6-dione

Formula	C11H14N4O4
Mol. mass	266.25 g/mol

Doxofylline (INN), (also known as doxophylline) is a xanthine derivative drug used in the treatment of asthma.^[1]

It has antitussive and bronchodilator^[2] effects, and acts as aphosphodiesterase inhibitor.^[3]

In animal and human studies, it has shown similar efficacy to theophylline but with significantly fewer side effects.^[4]

Unlike other xanthines, doxofylline lacks any significant affinity for adenosine receptorsand does not produce stimulant effects. This suggests that its antiasthmatic effects are mediated by another mechanism, perhaps its actions on phosphodiesterase.^[1]

Doxofylline, [7-(1, 3-dioxolan-2-ylmethyl)-3, 7-dihydro-1, 3-dimethyl-1H-purine-2, 6-dione] is a new bronchodilator xanthine based drug which differs from theophylline by the presence of dioxalane group at position 7. It is used in the treatment of bronchial asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis . The mechanism of action is similar to that of theophylline in that it inhibits phosphodiesterase (PDE-IV), thereby preventing breakdown of cyclic adenosine monophosphate (cAMP). Increase in cAMP inhibits activation of inflammatory cells resulting in bronchodilating effect [52]. In contrast to theophylline, doxofylline has very low affinity towards adenosine A1 and A2 receptors which explain its better safety profile

Doxofylline (7-(l,3-dioxalan-2-ylmethyl)-theophylline) is a drug derived from theophylline which is used in therapy as a bronchodilator, with anti-inflammatory action, in reversible airway obstruction. It is commonly administered in doses ranging from 800 to 1200 mg per day, orally, according to a dosage which provides for the intake of two to three dosage units per day in order to maintain therapeutically effective haematic levels. The doxofylline tablets commercially available generally contain 400 mg of active ingredient and release almost all the drug within one hour from intake. The half- life of the drug is around 6-7 hours and for this reason several administrations are required during the 24-hour period.

Obviously a drop in haematic concentration of the drug in an asthmatic patient or patient suffering from COPD (chronic obstructive pulmonary disease) can result in serious consequences, in which case the patient must have recourse to rescue medication, such as salbutamol inhalers.

Pharmaceutical techniques for obtaining the modified release of drugs have been known for some time, but no modified release formulation of doxofylline is known. In fact the present inventors have observed that there are significant difficulties in the production of a doxofylline formula that can be administered only once a day and in particular have encountered problems correlated with bioequivalence.

Various attempts to formulate doxofylline in modified release systems, with different known polymers, have not provided the desired results, i.e. a composition that can be administered once a day, bio equivalent to the plasmatic concentration obtained with the traditional compositions currently on sale. In fact currently, dosage units containing 400 mg of active ingredient are currently administered two/three times a day for a daily average of approximately 1000 mg of active ingredient, a dosage considered necessary to maintain the therapeutic haematic levels of doxofylline.

Such a dosage unit is currently marketed by Dr. Reddy's Laboratories Ltd as DOXOBID and has the following quali-quantitative composition: doxofylline (400 mg), colloidal silicon dioxide (13 mg), corn starch (63 mg), mannitol (40 mg), povidone (7 mg), microcrystalline cellulose (64 mg), talc (30 mg), magnesium stearate (3 mg) and water (0.08 ml).

1.  Cirillo R, Barone D, Franzone JS (1988). "Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors". Arch Int Pharmacodyn Ther 295: 221–37.PMID 3245738.
2. Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A (October 1989). "Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure". Chest 96 (4): 772–8.doi:10.1378/chest.96.4.772. PMID 2791671.
3.  Dini FL, Cogo R (2001). "Doxofylline: a new generation xanthine bronchodilator devoid of major cardiovascular adverse effects". Curr Med Res Opin 16 (4): 258–68.doi:10.1185/030079901750120196. PMID 11268710.
4. Sankar J, Lodha R, Kabra SK (March 2008). "Doxofylline: The next generation methylxanthine". Indian J Pediatr 75 (3): 251–4. doi:10.1007/s12098-008-0054-1.PMID 18376093.

• Dali Shukla, Subhashis Chakraborty, Sanjay Singh & Brahmeshwar Mishra. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opinion on Pharmacotherapy. 2009; 10(14): 2343-2356, DOI 10.1517/14656560903200667, PMID 19678793

At present, domestic synthetic Doxofylline composed of two main methods: one is by the condensation of theophylline prepared from acetaldehyde and ethylene glycol, but this method is more complex synthesis of acetaldehyde theophylline, require high periodate oxidation operation. Another is a halogenated acetaldehyde theophylline and ethylene glycol is prepared by reaction of an organic solvent, the method were carried out in an organic solvent, whereby the product Theophylline caused some pollution, conducive to patients taking.

current domestic Doxofylline synthetic methods reported in the literature are: 1, CN Application No. 94113971.9, the name "synthetic drugs Doxofyllinemethod" patents, the patent is determined by theophylline with a 2 - (halomethyl) -1,3 - dimethoxy-dioxolane in a polar solvent, with a base made acid absorbent,Doxofylline reaction step. 2,  CN Application No. 97100911.2, entitled "Synthesis of Theophylline," the patent, the patent is obtained from 7 - (2,2 - dialkoxy-ethyl) theophylline with ethylene glycol in N, N-dimethylformamide solvent with an alkali metal carbonate to make the condensing agent, p-toluenesulfonic acid catalyst in the condensation Doxofylline.

Doxofylline of xanthine asthma drugs, and its scientific name is 7 - (1,3 - dioxolan - ethyl methyl) -3,7 - dihydro-1,3 - dimethyl-1H - purine-2 ,6 - dione. The drug developed by the Italian Roberts & Co. in 1988, listed its tablet tradename Ansimar. This product is compared with similar asthma drugs, high efficacy, low toxicity, oral LD50 in mice is 1.5 times aminophylline, non-addictive. Adenosine and its non-blocking agents, it does not produce bronchial pulmonary side effects, no aminophylline like central and cardiovascular system. U.S. patent (US4187308) reported the synthesis of doxofylline, theophylline and acetaldehyde from ethylene glycol p-toluenesulfonic acid catalyst in the reaction of benzene as a solvent Doxofylline. Theophylline acetaldehyde by the method dyphylline derived reaction with a peroxy periodate or 7 - (2,2 - dialkoxy-ethyl) ammonium chloride aqueous solution in the decomposition of theophylline converted to acetaldehyde theophylline . Former method is relatively complex, and the high cost of using periodic acid peroxide, low yield after France. And theophylline acetaldehyde and ethylene glycol solvent used in the reaction of benzene toxicity, harm to health, and the yield is low, with an average around 70%, not suitable for industrial production.

Theophylline-7-acetaldehyde (I) could react with ethylene glycol (II) in the presence of p-toluenesulfonic acid in refluxing benzene to produce Doxofylline.

.........................

CN102936248A

https://www.google.co.in/patents/CN102936248A?cl=en&dq=doxofylline&hl=en&sa=X&ei=prmeUp_yKMqClQXlj4DYDw&ved=0CIABEOgBMAg

the reaction is:

a, anhydrous theophylline and bromoacetaldehyde ethylene glycol as the basic raw material, purified water as a solvent with anhydrous sodium carbonate as acid-binding agent;

NMR

UV (95% C2H5OH, nm) λmax273 (ε9230); λmin244 (ε2190)

IR (KBr, cm-1) 1134 (CO); 1233 (CN) ; 1547 (C = N); 1656 (C = C); 1700 (C = O); 2993 (CH)

1H-NMR [CDCl3, δ (ppm)] 3.399 (s, 3H, N-CH3); 3.586 (S, 3H, N-CH3); 3.815-3.885 (m, 4H, OCH2 × 2); 4.581 (d, 2H, CH2); 5.211 (t, 1H, CH ); 7.652 (S, 1H, CH = N)

13C-NMR [CDCL3, δ (ppm)] 27.88 (CH3); 29.69 (CH3); 47.87 (CH2); 65.37 ( OCH2); 100.76 (CH); 107.26 (C = C); 142.16 (CH = N); 148.22 (C = C); 151.59 (C = O); 155.25 ( C

.........................

Spectral data of doxofylline
The ESI mass spectrum exhibited a protonated molecular ion peak at m/z 267 in positive ion mode indicating the molecular weight of 266. The tandem mass spectrum showed the fragment ions m/z 223, 181.2, 166.2, 138.1, 124.1 and 87.1.

The FT-IR spectrum, two strong peaks at 1697cm-1 and 1658cm-1 indicated presence of two carbonyl groups. A strong peak at frequency 1546cm-1 indicated presence of C=N stretch. A medium peak at 1232cm-1 was due to C-O stretch

FT IR

1H and 13C-NMR spectra of doxofylline and its degradation products were recorded by using Bruker NMR 300MHz instrument with a dual broad band probe and z-axis gradients. Spectra were recorded using DMSO-d6 as a solvent and tetramethylsilane as an internal standard.

1H NMR

13 C NMR

COMPARISONS

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'via Blog this'
locate spectral data

(R)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione

Equimolar ratios of both heated at 145 deg c for 4 hrs and then the oil  titurated in DCM , Dried over sodium sulphate , evapn gives oil , used as such for next step. is a method of protection of amino gp

 2-[(1R)-2-Hydroxy-1-phenylethyl]-1H-isoindole-1,3(2H)-dione

205380-30-9  cas no

SpectralData

¹H NMR (400 MHz, 298 K, CDCl₃) δ_H 7.83 – 7.74 (2H, m, Pht), 7.70 – 7.60 (2H, m, Pht), 7.49 (2H, d, ³J_HH = 7.4 Hz, Ph), 7.41 – 7.23 (3H, m, Ph), 

5.51 (1H, dd, ³J_HH = 8.9 Hz, ³J_HH = 5.0 Hz, CH), 

4.76 – 4.66 (1H, m, CH₂), 

4.24 (1H, dd, ³J_HH = 11.4 Hz, ⁴J_HH = 4.9 Hz, CH₂), 

3.47 (1H, s, OH).

¹³C NMR (100 MHz, 298 K, CDCl₃) δ_C 168.89 (C=O), 

136.88, 134.08 (Pht), 131.72, 128.70, 128.13, 127.97 (Ph), 123.31 (Pht), 

61.98 (CH₂), 57.46 (CH).

MS (ESI⁺) m/z 290.1 ([M+Na]⁺)

IR (cm^-1) ν 3457, 1772, 1700, 1611, 1585, 1495, 1467, 1388, 1358, 1332, 1288, 1266, 1185, 1172, 1120, 1065, 1040, 1013, 999, 962, 919, 877, 838, 793, 765, 719, 698.

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M. D. Chen, M. Z. He, X. Zhou, L. Q. Huang, Y. P. Ruan and P. Q. Huang, Tetrahedron, 2005, 61, 1335-1344http://dx.doi.org/10.1016/j.tet.2004.10.109

 http://www.sciencedirect.com/science/article/pii/S0040402004019143

Aguilar, Nuria; Moyano, Albert; Pericas, Miquel A.; Riera, Antoni 
Synthesis, 1998 ,  3,   p. 313 - 316

Cinacalcet Hydrochloride spectral data

 


IR (KBr) (cm^–1): 3447, 2964, 1587, 800, 776. 


MS: m/z = 358.3 [M + H] ⁺.




¹H NMR (CDCl₃): δ 1.98 (d, J = 6.7 Hz, 3H), 2.2–2.35 (m, 2H), 2.46–2.60 (m, 2H), 2.55–2.85 (m, 2H), 5.10–5.25 (m, 1H), 7.16–7.26 (m, 3H), 7.31–7.33 (d, J = 7.4 Hz 1H), 7.54–7.65 (m, 3H), 7.88–7.97 (m, 3H), 8.23 (d, J = 7.2 Hz,1H). 

  
¹³C NMR (DMSO-d₆): δ 19.99 (CH₃), 27.01 (CH₂), 31.50 (CH₂), 44.65 (CH₂), 52.05 (CH), 122.58, 122.69, 122.73, 124.42, 124.74, 124.67, 125.50, 126.10, 126.88, 128.83, 128.89, 129.32, 130.28, 132.39, 133.32, 134.10, 142.25.
 http://pubs.acs.org/doi/full/10.1021/op300164y


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next set
  IR (KBr): 3427 (broad, –NH–), 2951, 2797, 2750, 2712, 1587, 1450, 1327, 1165, 1128, 1072, 798, 775 cm⁻¹;  

¹H NMR (DMSO-d₆/TMS) δ 1.67 (d, J = 6.6, 3H, –CH₃), 1.99 (quintet, 2H, –CH₂), 2.70 (m, 2H, –CH₂), 2.93 (m, 2H, –CH₂), 5.30 (q, 1H, –CH), 7.46–7.61 (m, 7H, ArH), 7.95–8.03 (m, 3H, ArH), 8.23 (d, J = 8.0, 1H, ArH), 9.36 (s, 1H, –NH) and 10.04 (s, 1H, HCl); 

 ¹³C NMR (DMSO-d₆/TMS) δ 142.61, 134.48, 133.70, 132.80, 130.64, 129.74, 129.58,129.28, 127.29, 126.54, 125.90, 125.08, 124.67, 123.16, 122.98, 52.37, 45.04, 31.84, 27.44, 20.30; 

MS m/z: 358 [M + 1]⁺.
http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-8-158

...........................
 IR (KBr) cm⁻¹: 3436, 2962, 2797, 1587, 1450, 1379, 1327, 1166, 1129, 797, 774, 746; 
MS: m/z = 358.79 [M + H] ⁺;  
¹H NMR (400 MHz, DMSO-d₆): δ = 1.67−1.69 (d, 3H), 1.97−2.02 (m, 2H), 2.67−2.69 (t, 4H), 5.27 (q, 1H), 7.44−7.46 (m, 4H), 7.54−7.61 (m, 3H), 7.93−7.99 (m, 2H), 8.026−8.08 (d, J = 7.2 Hz, 1H), 8.20−8.23 (d, J = 7.2 Hz, 1H), 9.46 (s, 1H), 10.17 (s, 1H);  
¹³C NMR (100 MHz, DMSO-d₆): δ = 20.49 (CH₃), 27.50 (CH₂), 32.02 (CH₂), 45.18 (CH₂), 52.60 (CH), 123.06, 123..23, 123.26, 124.94, 125.17, 125.21 (CF₃), 126.0, 126.60, 127.39, 129.35, 129.39, 129.82, 130.79, 132.88, 133.83, 134.58, 142.75; 
Anal. Calcd for C₂₂H₂₃NF₃Cl: C, 67.09; H, 5.84; N, 3.55; Found: C, 66.92; H, 5.68; N, 3.58.
 http://pubs.acs.org/doi/full/10.1021/op200016a