Modeling of the Diels-Alder reaction enantioselectivity by quantum mechanics and molecular mechanics

Article abstract of DOI:10.1016/j.mencom.2015.07.012

The enantioselectivity of the Diels-Alder reaction between (E)-3-(4-nitrophenyl)-1-(pyridin-3-yl)prop-2-en-1-one and cyclopenta-1,3-diene in the chiral ionic liquids 3-butyl-1-methylimidazolium (S)-camphorsulfonate and (S)-1-methyl-3-(pyrrolidin-2-ylmethyl)- imidazolium tosylate or upon chiral promotion with chiral oxazaborolidine was modeled by molecular and quantum mechanics and then experimentally studied; computations were in good agreement with the experimental data, resulting in no stereoselectivity with a chiral ionic liquid used as a co-solvent and prominent stereoselectivity upon chiral promotion.

Full text of DOI:10.1016/j.mencom.2015.07.012

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 269–270
Modeling of the Diels–Alder reaction enantioselectivity
by quantum mechanics and molecular mechanics
Alexey A. Zeifman,*a Viktor S. Stroylov,a Ilya Yu. Titov,a Fedor N. Novikov,a
Oleg V. Stroganov,a Igor V. Svitankoa,b and Ghermes G. Chilova
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5313; e-mail: azeif@mail.ru
b Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2015.07.012
The enantioselectivity of the Diels–Alder reaction between (E)-3-(4-nitrophenyl)-1-(pyridin-3-yl)prop-2-en-1-one and cyclopenta-
1,3-diene in the chiral ionic liquids 3-butyl-1-methylimidazolium (S)-camphorsulfonate and (S)-1-methyl-3-(pyrrolidin-2-ylmethyl)-
imidazolium tosylate or upon chiral promotion with chiral oxazaborolidine was modeled by molecular and quantum mechanics and
then experimentally studied; computations were in good agreement with the experimental data, resulting in no stereoselectivity with
a chiral ionic liquid used as a co-solvent and prominent stereoselectivity upon chiral promotion.
Me
Various approaches to asymmetric synthesis have been widely
used in fine and industrial reactions, including chiral catalysts,1–3
N
N
N
chiral solvents,4,5 in particular, chiral ionic liquids,6–8 temporary
chiral auxiliaries9 and even spontaneous asymmetric synthesis.10
Computational chemistry potentially allows achieving desired
selectivity without testing all possible reaction conditions. Here,
we used molecular mechanics free energy perturbation and
quantum mechanics (QM) DFT calculations† to optimize Diels–
Alder reaction conditions for obtaining the best stereoselectivity.
We studied the Diels–Alder cycloaddition of (E)-3-(4-nitro-
phenyl)-1-(pyridin-3-yl)prop-2-en-1-one to cyclopenta-1,3-diene
(Scheme 1), which produces two enantiomeric products (R,R,R,S
and S,S,S,R). To assess the potential of chiral induction in this
reaction by a chiral solvent, we calculated the free energy of
solvation for each product in a mixture of ethanol with 0.5 mol dm–3
chiral ionic liquid 3-butyl-1-methylimidazolium (S)-camphorsul-
H
N
N
Me
Me
O
O
O
S
O
O
S
Me
O
O
Me
Me
Promim-TSA
Bmim-CSA
Figure 1 Chiral ionic liquids.
fonate (Bmim-CSA)‡ or (S)-1-methyl-3-(pyrrolidin-2-ylmethyl)-
imidazolium tosylate (Promim-TSA) (Figure 1) by molecular
dynamics free energy perturbation. Resulting solvation free
energies were essentially the same for both enantiomers in both
systems indicating that the media did not differentiate them, and
no chiral induction is expected (Table 1).
Alternatively, the influence of a chiral oxazaborolidine reagent
(Figure 2) was studied by QM DFT. Geometry optimization of
the guess-structure of the initial product–oxazaboralidine complex
resulted into dissociation of the complex (boron–oxygen distance
changed from 1.55 Å in the initial guess to 3.61 Å in the final
O
+
N
NO2
N
O
N
O
H
H
H
H
‡
+
Synthesis of Bmim-CSA. Freshly distilled thionyl chloride (22.0 ml,
0.3 mol) was added dropwise to a boiling solution of (1S)-(+)-10-camphor-
sulfonic acid (58.0 g, 0.25 mol) in 500 ml of dry chloroform. The reaction
mixture was refluxed for 15 h; the solvent was evaporated in a vacuum,
and the residue was dried in a vacuum desiccator with NaOH to constant
weight. The product was dissolved in 400 ml of dry dichloromethane, and
a mixture of 42.0 ml (~0.3 mol) of triethylamine and 32.0 ml (0.35 mol)
of butan-1-ol was added dropwise. The mixture was stirred at room tempe-
rature for 48 h and washed with 1 n aqueous HCl (2×200 ml), saturated
NaHCO3 solution (3×200 ml) and water to neutral pH. Organic phase
was dried over anhydrous Na2SO4, and the solvent was removed. 64.2 g
(89%) of butyl (S)-camphorsulfonate was obtained.
NO2
NO2
R,R,R,S
S,S,S,R
Scheme 1
†
Computational methods. Geometry optimization and Gibbs free energies
in a vacuum were calculated in Gaussian0912 with B3LYP DFT functional
and 6-31G(d) basis set. Molecular mechanics free energy perturbation
(MM-FEP) calculations were performed in Gromacs13 in OPLS-AA
force field.14 The solute molecule was positioned in a 70 Å cubic box of
solvent using the Gromacs utility ‘genbox’. Then, FEP was used to switch
off the solute–solvent interaction. FEP calculations were performed in
10l steps (separately for VdW and Coulomb interactions), each step
included 100 ps NVT equilibration, 500 ps NPT equilibration and 10 ns
NPT production dynamics.
N-Methylimidazole (17.2 g, 0.21 mol) was added to a solution of butyl
(S)-camphorsulfonate (60.0 g, 0.21 mol) in 300 ml of anhydrous toluene,
and the reaction mixture was refluxed for 30 h. Solvent was removed in a
vacuum, and 200 ml of toluene was added to the residue. Solvent was
again removed in a vacuum, and the residue was dried for 6 h in a vacuum
at 80°C and 0.2 Torr to give 70.0 g (99%) of the product.
Promim-TSA was synthesized as described elsewhere.15
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 269 –

Mendeleev Commun., 2015, 25, 269–270
Table 1 Solvation free energy of enantiomeric adducts of (E)-3-(4-nitro-
In summary, we have successfully applied state-of-the-art
computational chemistry methods to study factors affecting the
enantioselectivity of the Diels–Alder reaction. Our work supports
extensive application of molecular modeling techniques to the
optimization of organic reaction conditions.
phenyl)-1-(pyridin-3-yl)prop-2-en-1-one and cyclopenta-1,3-diene in ethanol
+ 0.5 m ionic liquid and 0.02 m CuCl2 calculated using an MM FEP approach.
Coulomb
VdW DG/
Total solvation
Product Ionic liquid
DG/kJ mol–1 kJ mol–1
DG/kJ mol–1
R,R,R,S Bmim-CSA
S,S,S,R Bmim-CSA
–24.34 0.99 –58.66 0.19 –83.00 1.00
–25.55 1.71 –58.28 0.22 –83.83 1.71
This work was supported by the Russian Foundation for Basic
Research (project nos. 12-03-33109 mol_a_ved and 15-03-08344a).
R,R,R,S Promim-TSA –25.31 0.62 –57.39 0.40 –82.70 0.74
S,S,S,R Promim-TSA –24.97 0.16 –57.07 0.46 –82.04 0.49
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The model reaction enantioselectivity was further experi-
mentally studied in a chiral ionic liquid or with chiral promotion.§
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led to the formation of racemic product (ee 0.04% for Promim-
TSA and 3.26% for Bmim-CSA). The addition of a chiral reagent
resulted in moderate but distinguishable enantioselectivity (ee
11% in Bmim-CSA and 16% in Promim-TSA), which corre-
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Received: 18th December 2014; Com. 14/4533
§
Diels-Alder reaction without chiral oxazaborolidine. (E)-3-(4-Nitro-
Diels–Alder reaction with chiral oxazaborolidine. (E)-3-(4-Nitrophenyl)-
1-(pyridin-3-yl)prop-2-en-1-one (10 mmol) was dissolved in 100 ml of a
0.5 mm ionic liquid solution in 70% (v/v) aqueous ethanol, and a solution
of copper(ii) chloride (1 mmol) in 5 ml of water and chiral oxazaborolidine
(61 mg, 0.1 mmol) were added. The reaction mixture was stirred for
10 min at room temperature, and freshly distilled cyclopentadiene (1.0 ml,
12 mmol) was added. The mixture was stirred at 30°C until complete
disappearance of the starting chalcone. The solution was filtered through
silica gel, ethanol was evaporated in a vacuum, the residue was dissolved
in 100 ml of dichloromethane and washed with water (4×50 ml), dried
with Na2SO4 and separated chromatographically (to remove 1,3-diaryl-
1,2-dihydropentalene) to give 83% of a white crystalline product.
phenyl)-1-(pyridin-3-yl)prop-2-en-1-one (10 mmol) was dissolved in
100 ml of a 0.5 mm ionic liquid solution in 70% (v/v) aqueous ethanol,
and a solution of copper(ii) chloride (1 mmol) in 5 ml of water was added.
The reaction mixture was stirred for 10 min at room temperature, and
freshly distilled cyclopentadiene (1.0 ml, 12 mmol) was added. The
resulting mixture was stirred at 30°C until complete disappearance of the
starting chalcone. The solution was filtered through silica gel; ethanol
was evaporated in a vacuum; the residue was dissolved in 100 ml of
dichloromethane and washed with water (4×50 ml), dried with Na2SO4
and separated chromatographically (to remove 1,3-diaryl-1,2-dihydro-
pentalene).A white crystalline product was obtained, yield 79%. 1H NMR
(CDCl3, 500 MHz) d: 1.71 (d, 1H), 1.98 (d, 1H), 3.15 (s, 1H), 3.43 (s,
1H), 3.61 (d, 1H), 3.82 (d, 1H), 5.85 (d, 1H), 6.45 (d, 1H), 7.41 (m, 3H),
8.12 (m, 2H), 8.18 (d, 1H), 8.76 (d, 1H), 9.13 (s, 1H).
Chiral chromatography. Chiral chromatography was performed on a Lux
Cellulose-3 column (4.6×150 mm) using isocratic elution with a hexane–
isopropanol (90:10) mixture. Analytes were detected by UV at l = 220 nm.
– 270 –