The First Enantioenriched Metalated Nitrile Possessing Macroscopic Configurational Stability

Magnesium−bromine exchange on enantiopure cyclopropyl bromonitrile 5 at −100 °C for 1 min followed by a D2O quench gives the deuterionitrile in 81% ee (retention); additional trapping experiments establish t1/2(rac) = 11.4 h at −100 °C. These experiments provide the first glimpse into the stereochemical aspects of Mg−Br exchange. The intermediate formed is the first metalated nitrile demonstrated to possess macroscopic configurational stability

Computational Studies of Ion-Pair Separation of Benzylic Organolithium Compounds in THF: Importance of Explicit and Implicit Solvation

Ion-pair separation (IPS) of THF-solvated fluorenyl (1C), diphenylmethyl (2C), and trityl (3C) lithium was studied computationally. Minimum energy equilibrium geometries of explicit bis- and tris-solvated contact ion pairs (CIPs) and tetrakis-solvated separated ion pairs (SIPs) were located at B3LYP/6-31G*. Associative transition structures linking the tris-solvated CIPs and tetrakis-solvated SIPs were also located. Based on MP2/6-31G*//B3LYP/6-31G* energies, the resting states of the CIPs are predicted to be trisolvates. Calculated enthalpies of IPS (ΔHIPS) at 298 K were compared to experimental (UV−vis spectroscopy) solution values reported in the literature. In vacuum, B3LYP/6-31G* ΔHIPS values for 1C·(THF)3−3C·(THF)3 are 6−8 kcal/mol less exothermic than the experimentally determined values in THF solution. Closer examination of the individual steps of ion-pair separation (ionization, solvation, ion-pair recombination), as well as comparison of calculated structures with the published X-ray structures of 1C·(THF)3 and 3S·(THF)4, suggested that in vacuo modeling of the SSIPs was problematic. Incorporation of secondary solvation in the form of Onsager and PCM single-point calculations showed an increase in exothermicity of IPS. Application of a continuum solvation model (Onsager) during optimization at the B3LYP/6-31G* level of theory produced significant changes in the Cα−Li contact distances in the SSIPs, and B3LYP/6-31G* (PCM)//B3LYP/6-31G* (Onsager) energies bring ΔHIPS within 5−6 kcal/mol of experiment. Possible strategies to achieve closer agreement with experiment are discussed

Regioselective Synthesis of Aniline-Derived 1,3- and <i>C</i>_i-Symmetric 1,4-Diols from <i>trans</i>-1,4-Cyclohexadiene Dioxide

trans-Diepoxide 1 is well-known to react with aliphatic amines and the azide ion to give exclusively the 1,3-diol products. However, we observed that by judicious choice of conditions, reaction with anilines can give predominantly the 1,3-diol (3) or the heretofore rarely seen Ci-symmetric 1,4-diol (4). Synthesis of an unsymmetrical 1,4-diol from two different anilines is also demonstrated. These studies demonstrate that an intramolecular anilino−NH hydrogen bond donor can direct Fürst−Plattner epoxide opening

Highly Enantioselective Synthesis of Rigid, Quaternary 1,4-Benzodiazepine-2,5-diones Derived from Proline

Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality

Effective Computational Modeling of Constitutional Isomerism and Aggregation States of Explicit Solvates of Lithiated Phenylacetonitrile

We present the first calculations which accurately account for the position of metalation and aggregation state of lithiated nitriles. Solvation is found to be a key determinant of structure. Five known solvates of lithiated phenylacetonitrile were examined computationally to determine the minimum level of theory required to reproduce the observed X-ray and multinuclear NMR structures. In all cases Hartree−Fock 3-21G energies of explicit solvates calculated at PM3 geometries correctly predict the observed N-lithiated constitutional isomer. Selected density functional theory (B3LYP/6-31+G*//PM3) energy calculations reproduce this trend. We also show that 3-21G//PM3 calculations which do not include explicit solvent molecules, or which include water as a model for diethyl ether, may lead to incorrect predictions of the preferred constitutional isomer. 3-21G//PM3 energies also adequately account for observed aggregation states of the TMEDA, diethyl ether, and THF solvates. Finally, calculations of THF-solvated monomers up to the B3LYP/6-31+G*//B3LYP/6-31+G* level indicate a significant (6.8 kcal/mol) preference for N-lithiation

⁷Li/³¹P NMR Studies of Lithiated Arylacetonitriles in THF−HMPA Solution: Characterization of HMPA-Solvated Monomers, Dimers, and Separated Ion Pairs

The structures of lithiated phenylacetonitrile and 1-naphthylacetonitrile were studied in THF and HMPA−THF solution. In pure THF, 7Li NMR line width studies suggest that these species exist as contact ion pairs; HMPA titration studies confirm this conclusion. In the presence of 0.25−2 equiv of HMPA, HMPA-solvated monomeric and dimeric contact ion pairs are detected by 31P and 7Li NMR spectroscopy. Finally, at 4−6 equiv of added HMPA, 7Li NMR spectra provide direct evidence for the formation of HMPA-solvated separated ion pairs

Experimental and Computational Studies of Ring Inversion of 1,4-Benzodiazepin-2-ones: Implications for Memory of Chirality Transformations

We recently reported the enantioselective syntheses of quaternary 1,4-benzodiazepin-2-ones via memory of chirality. The success of this method depends on formation of conformationally chiral enolates that racemize very slowly under the reaction conditions. As a prelude to undertaking experimental and computational studies on the racemization of these enolates, we have studied the ring-inversion process of the parent 1,4-benzodiazepin-2-ones. In this paper, we use dynamic and 2D-EXSY NMR to characterize inversion barriers. Using DFT calculations, we reproduce the experimental results with high accuracy (within 1−2 kcal/mol). Structural parameters obtained from DFT calculations provide valuable insights into the important effect of the N1 substituent on the ring-inversion barrier and shed light on the mechanism of the memory of chirality method. These measurements and calculations provide a foundation for future studies of benzodiazepine enolates and will be valuable in the design of new memory of chirality reactions

Protonated 2-Methyl-1,2-epoxypropane: A Challenging Problem for Density Functional Theory

Protonated epoxides feature prominently in organic chemistry as reactive intermediates. Herein, we describe 10 protonated epoxides using B3LYP, MP2, and CCSD/6-311++G** calculations. Relative to CCSD, B3LYP consistently overestimates the C2−O bond length. Protonated 2-methyl-1,2-epoxypropane is the most problematic species studied, where B3LYP overestimates the C2−O bond length by 0.191 Å. Seventeen other density functional methods were applied to this protonated epoxide; on average, they overestimated the CCSD bond length by 0.2 Å. We present a range of data that suggest the difficulty for DFT methods in modeling the structure of the titled protonated epoxide lies in the extremely weak C2−O bond, which is reflected in the highly asymmetric charge distribution between the two ring carbons. Protonated epoxides featuring more symmetrical charge distribution and cyclic homologues featuring less ring strain are treated with greater accuracy by B3LYP. Finally, MP2 performed very well against CCSD, deviating in the C2−O bond length at most by 0.009 Å; it is, therefore, recommended when computational resources prove insufficient for coupled cluster methods

Stereochemical Inversion of a Cyano-Stabilized Grignard Reagent: Remarkable Effects of the Ethereal Solvent Structure and Concentration

Chiral organometallic reagents are useful in asymmetric synthesis, and configurational stability of these species is critical to success. In this study we followed the epimerization of a chiral Grignard reagent, prepared by Mg/Br exchange of bromonitrile <i>trans</i>-<b>2b</b>. This compound underwent highly retentive Mg/Br exchange in Et₂O; less retention was observed in 2-MeTHF and THF. Epimerization rate constants <i>k</i>_tc were determined at 195 K by measuring the diastereomer ratio of deuteration product <i>d</i>₁-<b>3b</b> as a function of the delay time before quench. Studies were also performed at varying concentrations of Et₂O in toluene. Remarkable dynamic range in <i>k</i>_tc was seen: relative to reaction at 0.12 M Et₂O in toluene, epimerization was 26-, 800-, and 1300-fold faster in Et₂O, 2-MeTHF, and THF, respectively. Thus, the identity and concentration of an ethereal solvent can dramatically affect configurational stability. Reaction stoichiometry experiments suggested that, in Et₂O, the Grignard reagent derived from <i>trans</i>-<b>2b</b> exists as an <i>i</i>-PrMgCl heterodimer; the invariance of <i>k</i>_tc over a 20-fold range in [Mg]_total ruled out mandatory deaggregation (or aggregation) on the epimerization path. Analysis of the dependency of <i>k</i>_tc on [Et₂O] and temperature in Et₂O/toluene solution at 195, 212, and 231 K indicated fast incremental solvation before rate-limiting ion-pair separation and provided an estimate of the entropic cost of capturing a solvent ligand (−13 ± 3 eu). Calculations at the MP2/6-31G*­(PCM)//B3LYP/6-31G* level provide support for these conclusions and map out a possible “ionogenic conducted tour” pathway for epimerization

Catalytic Asymmetric Synthesis of Protected Tryptophan Regioisomers

Tryptophan 1 (Trp) is superior to all other naturally occurring peptide residues in its ability to bind cations (the cation−π interaction). In an effort to expand the toolbox of Trp-like amino acids, in this note we report catalytic asymmetric syntheses of Trp regioisomers 2a−e, where the alanine unit is attached not to C-3 of indole but to C-2, C-4, C-5, C-6, or C-7. Excellent asymmetric induction is obtained in each case (generally >97% ee). Ab initio calculations suggest that the indole nuclei of 2a−e will bind Na+ with the same affinity as that of Trp