A practical synthesis of menaquinone-7 (MK-7, vitamin K2) in the all-trans form was designed. Stereoselective synthesis of MK-7 was achieved through a “1 + 6” convergent strategy by condensation of two building blocks, menadione monoprenyl derivative (fragment “1”) with hexaprenyl bromide (fragment “6”, 82%). Pd-catalyzed desulfonation with LiEt3BH (78%) was followed by oxidation of the hydroquinone moiety using ammonium cerium­(IV) nitrate (72%). The major challenge in our methodology was the preparation of all-trans hexaprenyl bromide by coupling of two triprenyl units derived from trans,trans-farnesol. Manufacturing on a pilot scale was accomplished through our approach. The scalable method was designed especially for a large, kilogram-scale production from easily available intermediates. Furthermore, the proposed methodology avoids many chromatographic purifications and allows for a relatively cost-effective manufacturing. Moreover, our synthesis yielded high-purity (99.9%) final product MK-7, which can be used as a dietary supplement as well as an active pharmaceutical ingredient.

Overall conformations of both anomeric per-O-acetylated glucosyl derivatives of 2,2,5,7,8-pentamethylchroman-6-ol were studied in the context of their high flexibility, on the basis of NMR spectra in CDCl3 solution and related DFT calculation results. A few computational protocols were used, including diverse density functional/basis set combinations with a special emphasis on accounting (at various steps of the study) for the impact of intramolecular London-dispersion (LD) effects on geometries and relative Gibbs free energies (ΔGs) of different conformers coexisting in solution. The solvent effect was simulated by an IEF-PCM approach with the UFF radii; its other variants, including the use of the recently introduced IDSCRF radii, were employed for a few compact B3LYP-GD3BJ optimized structures showing one small imaginary vibrational frequency. The advantage of using IDSCRF radii for such purposes was shown. Of the four tested DFT methods, only the application of the B3LYP/6-31+G(d,p) approximation afforded ensembles of 7-8 single forms for which population-average values of computed NMR parameters (δH, δC and some (n)JHH data) were in close agreement with those measured experimentally; binuclear (δH,C 1 : 1) correlations, rH,C(2) = 0.9998. The associated individual ΔG values, corrected for LD interactions by applying Grimme's DFT-D3 terms, afforded relative contents of different contributors to the analyzed conformational families in much better agreement with pertinent DFT/NMR-derived populations (i.e., both data sets were found to be practically equal within the limits of estimated errors) than those calculated from dispersion uncorrected ΔGs. All these main findings were confirmed by additional results obtained at the MP2 level of theory. Various other aspects of the study such as the crystal vs. solution structure, gg/gt rotamer ratio, diagnostic (de)shielding effects, dihydrogen C-H···H-C contacts, and doubtful applicability of some specialized DFT functionals (M06-2X, ωB97X-D and B3LYP-GD3BJ) for the description of highly flexible molecules are also discussed in detail.

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Condensation of α-tocopherol and 2,2,5,7,8-pentamethyl-6-hydroxychroman (the model compound) with peracetylated glucose, mannose and galactose was carried out. The influence of various acidic catalysts on the chemical yield and the stereochemical outcome of the glycosylation was investigated.