Convergent Synthesis of Menaquinone‐7 (MK-7)

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. ■ INTRODUCTION Vitamin K is the family of fat-soluble compounds that contain a 2-methyl-1,4-naphthoquinone moiety and differ in an alkenyl substituent at the 3-position. There are two natural forms of vitamin K: vitamin K1 (phylloquinone or phytonadione) bearing a long phytyl side chain and vitamin K2 (menaquinones) with a polyprenyl side chain (Figure 1). Vitamin K3 (menadione) is a synthetic form of vitamin K which acts as a provitamin. However, it is not recommended for humans as a dietary supplement. According to some reports, menadione might be toxic to the liver and in addition may lead to hemolytic anemia and allergic reactions. The major dietary source of vitamin K is phylloquinone, which is synthesized by plants and algae. A high concentration of vitamin K1 is present in green leafy vegetables (e.g., broccoli, iceberg lettuce, spinach) and some plant oils (e.g., soybean oil, olive oil). Vitamin K2 is a group of related compounds described as MK-n, where n is the number of unsaturated isoprenoid units in the side chain (from 4 to 13). The chain length and number of double bonds have an influence on the activity and bioavailability. The main dietary source of vitamin K2 are animal products, e.g., eggs, meat, and fermented foods such as natto, cheese, curd, and sauerkraut. A high concentration of MK-7 (Figure 2) is present in traditional Japanese “natto” (900−1200 μg/100 g, when the content of vitamin K1 in spinach is 380 μg/100 g ). Menaquinones are synthesized by bacteria, except for MK-4 (menatetrenone), which can be formed in direct conversion of dietary phylloquinone or by alkenylation of menadione. In humans, deficiency of vitamin K2 may occur after prolonged treatment with sulfonamide antibacterials when bacterial flora may be partially or completely destroyed. It is commonly known that vitamin K is required for proper blood clotting. In the liver it catalyzes the synthesis of prothrombin, the inactive precursor of thrombin, which converts fibrinogen of blood plasma into fibrin. Vitamin K is an essential cofactor in the γ-glutamyl carboxylation pathway. γGlutamyl carboxylase is responsible for post-translational conversion of some glutamate residues to γ-carboxyglutamic acid residues in osteocalcin. Recent studies have shown that vitamin K plays an important role in bone health, reduction of vascular calcification, and cardiovascular risk processes. Some data suggest that Received: February 8, 2016 Published: May 6, 2016 Figure 1. Chemical structure of vitamins K. Figure 2. Chemical structure of menaquinone-7 (MK-7). Article