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

Welwitindolinones structure

A quick note here on the use of computed NMR to determine stereochemical structure. The Garg group synthesized two “oxidized welwitindolines”, compounds 1 and 2.¹ The relative stereochemistry at the C3 position (the carbon with the hydroxy group) was unknown.

1

2

Low energy gas-phase conformers of both epimers of 1 and 2 were optimized at B3LYP/6-31+G(d,p). (These computations were done by the Tantillo group.) See Figure 1 for the optimized lowest energy conformers. Using these geometries the NMR chemical shifts were computed at mPW1PW91/6-311+G(d,p) with implicit solvent (chloroform). The chemical shifts were Boltzmann-weighted and scaled according to the prescription (see this post) of Jain, Bally and Rablen.² The computed chemical shifts were then compared against the experimental NMR spectra. For both 1and 2, the ¹³C NMR shifts could not readily distinguish the two epimers. However, the computed ¹H chemical shifts for the S epimer of each compound was significantly in better agreement with the experimental values; the mean average deviation for the S epimer of 2 is 0.08 ppm but 0.36ppm for the R epimer. As a check of these results, DP4 analysis³ (see this post) of 2 indicated a 100% probability for the S epimer using only the proton chemical shifts or with the combination of proton and carbon data.

1

2

Figure 1. B3LYP/6-31+G(d,p) optimized geometries of the
lowest energy conformations of 1 and 2.

References

(1) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K., "Total Synthesis of Oxidized Welwitindolinones and (-)-N-Methylwelwitindolinone C Isonitrile," J. Am. Chem. Soc. 2011,134, 1396-1399, DOI: 10.1021/ja210837b

(2) 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, 74, 4017-4023, DOI: 10.1021/jo900482q.

(3) 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

Malleobactin Structure Elucidated

A team of scientists based in Germany have elucidated the structure and absolute configuration of malleobactin, which is the siderophore of the pathogenic Burkholderia mallei. Siderophores are strong iron-binding agents, and act as virulence factors for pathogenic bacteria.

The virulence factor malleobactin has been shown to contain an unprecedented nitro-bearing amino acid
Read more



http://www.chemistryviews.org/details/ezine/4997511/Malleobactin_Structure_Elucidated.html

Video tutorial on spectroscopy

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IB Chemistry Atomic Absorption Spectroscopy, Nuclear Magnetic Resonance Spectroscopy and NMR from Lawrence Kok

SPECTROSCOPY DATA of ASPIRIN

 Dear blog reader , this post is for brushing up our fundamentals of spectroscopy using simple molecules like aspirin
text may be less but graphs are educative. one can browse through this to brush up




Product Name: Acetylsalicylic acid CAS:50-78-2










1H NMR



 

    Assign.     Shift(ppm)

      A            11.
      B             8.125
      C             7.624
      D             7.356
      E             7.142
      F             2.352
  ABOVE IS PROTON NMR OF ASPIRIN AND ITS INTERPRETATION

abelled.



The peaks I have are:

2.30ppm (I this is a singlet and would be F)
7.07ppm (I think this is E)
7.29ppm (I think this is D)
7.53ppm (I think this is C)
8.05ppm (I think this is B)
11.44ppm (this is a singlet and would be A)


For B,C,D,E I need to say what kind of splitting pattern there would be and how many coupling constants are present and there approximate value. I think I know the assignments of them but I don't know the splitting pattern or coupling constants.

Would E and B be doublet of doublets because they couple with D and C so they would have ortho and meta coupling?

Would D and C be coupling with each other and B and E so would they be doublet of doublets of doublets, with two ortho and one meta coupling?

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 BELOW IS IR OF ASPIRIN KBR DISC









IR in nujol mull

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



MASS SPECTRUM







above is mass spectrum of aspirin

o-acetoxybenzoic acid
C9H8O4              (Mass of molecular ion:    180)

 Source Temperature: 170 °C
   Sample Temperature: 100 °C
   DIRECT, 75 eV

13 C NMR

 


above is 13 C NMR OF ASPIRIN

50.18 MHz
C9 H8 O4	0.039 g : 0.5 ml CDCl3

 ppm   Int.  Assign.

      170.20   450      1
      169.76   510      2
      151.28   560      3
      134.90   924      4
      132.51  1000      5
      126.17   986      6
      124.01   974      7
      122.26   397      8
       20.99   674      9

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below is Raman spectra of aspirin





NMR INTERPRETATIONS

H-NMR spectral analysis

CAS NO. 50-78-2, Acetylsalicylic acid H-NMR spectral analysis

C-NMR spectral analysis

CAS NO. 50-78-2, Acetylsalicylic acid C-NMR spectral analysis H, H-COSY spectrum In H, H-COSY spectrum are on both axes, the 1 H chemical shifts plotted; In principle, both the axes 1 to see H-NMR spectra. Thus, there is a symmetric to the diagonal diagram. 1 H-NMR spectrum of acetylsalicylic acid Fig.2 H, H-COSY spectrum of acetylsalicylic acid In the spectrum, only the range from 7.0 to 8.2 ppm is applied, because only here HH scalar couplings can be expected. Fig.3 There are two types of signals: Diagonal signals: join the coordinates δ a δ a (in core A), δ b δ b (in core B) ... on, but play no role in the evaluation of the couplings between different cores, since it is only the signal of a nucleus is. The diagonal with all its signals corresponding to the 1D H-NMR spectrum. EXAMPLE Acetylsalicylic acid 7.13 ppm / 7.13 ppm = δ 2 δ 2 (H atom 2) 7.34 ppm / 7.34 ppm = δ 4 δ 4 (H atom 4) 7.61 ppm / 7.61 ppm = δ 3 δ 3 (H atom 3) 8.11 ppm / 8.11 ppm = δ 5 δ 5 (H atom 5) Cross signals: These signals are based on the scalar spin-spin coupling and are suitable for the evaluation of spectra of enormous importance. EXAMPLE Acetylsalicylic acid 7.13 ppm / 7.61 ppm (δ 2 δ 3 ), and 7.61 ppm / 7.13 ppm (δ 3 δ 2 ) - vicinal coupling between the H-atoms 2 and 3 7.34 ppm / 7.61 ppm (δ 4 δ 3 ) and 7.61 ppm / 7.34 ppm (δ 3 δ 4 ) - vicinal coupling between the H-atoms 4 and 3 7.34 ppm / 8.11 ppm (δ 4 δ 5 ) and 8.11 ppm / 7.34 ppm (δ 5 δ 4 ) - vicinal coupling between the H-atoms 4 and 5 In general it can be seen in the COSY spectrum each scalar coupling between two nuclei at four signals (two cross and two diagonal peaks) resulting connected a square; in the following example, the vicinal coupling between the H atoms is highlighted 3 and 4. Fig.4 With good resolution of the COSY spectrum, the coupling constants can be determined from the fine structure of the cross and diagonal signals, but this is rarely done because of the 1-D H-NMR spectra is easily possible. DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE Join me on Linkedin Join me on Facebook FACEBOOK Join me on twitter      Join me on google plus Googleplus  amcrasto@gmail.com KHAJURAHO INDIA Location of Khajuraho Group of Monuments in India. Location in Madhya Pradesh Khajuraho Group of Monuments - Wikipedia, the free ... en.wikipedia.org/wiki/Khajuraho_Group_of_Monuments The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, ... Hotel Chandela - A Taj Leisure Hotel