Synthesis of All Four Stereoisomers of (E)‐Vitamin KT (Phylloquinone), Analysis of Their Diastereoisomeric and Enantiomeric Purities and Determination of Their Biopotencies

Abstract

All four stereoisomers of@)-vitamin K,, i.e. (2'E,7'R,1 l'R)-l ( = la), (2'E,7'R,ll'S)-l( = lb), (2'E,7'S,lI'S)-1 ( = Ic), and (2'E,7'S,1 l'R)-l ( = Id), have been synthesized in a state of high chemical and stereoisomeric purity. The synthesis of stereoisomers 1 M relied on the use of the optically active CT-and Cy,,-building blocks ( R ) -or (S)-4-(benzyloxy)-3-methylbutanal ( ( R ) -or (9-2) and ( R ) -or (S)-citronella1 ((R)-or (S)-3) which had been secured by the Rh'-catalyzed allylamine-to-enamine isomerization technology. For the synthesis of the natural (E)-vitamin-K, stereoisomer la, a new route starting from natural phytol was developed, based on an 0-alkylation/rearrangement procedure. A HPLC method was developed which separates with remarkable efficiency all four stereoisomers of ( E ) -as well as three out of the four stereoisomers of (2)-vitamin K, on optically active poly(trity1 methacrylate) as the chiral stationary phase supported on Nucleosil. By this method, the stereoisomeric content of the stereoisomers 1 M synthesized was shown to be in the range of 96-98 %, while the natural isomer l a was configurationally uniform. The biological activity of the four (E)-vitamin-K, stereoisomers was determined by means of the curative prothrombin time test with vitamin-K-depleted chicks. A high precision of the results was obtained with the recently introduced up-and-down organization of the test and the statistical evaluation according to an estimation procedure. With the natural (E)-vitamin-K, stereoisomer l a as standard (set at l.O), activities of 0.93, 1.19, and 0.99 were found for stereoisomers lb, lc, and Id, respectively. Within the confidence limits, these activity ratios can be regarded as identical. A very similar efficacy was obtained by comparison of (E, all-rac)-vitamin K, ((2E,7'RS,1 l'RS)-l; equimolar mixture of the four stereoisomers la-d) with the natural (E)-vitamin-K, stereoisomer la). A synergistic effect was not detectable, as was the case with the eight a -tocopheryl-acetate stereoisomers.

Enantio‐ and Diastereoselective Hydrogenation of Farnesol and O‐Protected Derivatives: Stereocontrol by Changing the CC Bond Configuration

“…This class of substrates was chosen because efficient routes to all four cis/trans isomers were available, [5] and we were interested in comparing the reactivity of the two trialkyl-substituted C=C bonds with the allylic alcohol unit in its free and protected form. Furthermore, hexahydrofarnesol, which can be readily prepared by this route in any of the four possible stereoisomeric forms, [6] is an important building block for the syntheses of vitamins E and K [7] or related antioxidants, [8] and insect pheromones. [9] It also has an important function as a constituent of ether lipids in archea [10] and was identified as a precursor of many terpenoid compounds in plants [11] and geological sediments.…”

The Synthesis of Naturally Occurring Vitamin K and Vitamin K Analogues

“…A related route to vitamin K based on a photochemicalmediated radical coupling of a geranyl organotellurium species to 3 was reported in 2002 (Scheme 8) [23b]. Thus, geranyl tolyl telluride 26 (73:27 mixture of E and Z isomers, prepared from the corresponding bromide on treatment with SmI 2 and ditolyl ditelluride) was coupled to 3 to give MK-2 (27) in 73% yield (7:3 E to Z).…”

“…An alternative approach to the K vitamins involves the stepwise elongation of a suitable short side chain analogue. This methodology has been used to prepare natural phylloquinone (Vitamin K 1 ) as a mixture of stereoisomers [27]. The addition of the Grignard reagent derived from 2-bromo-3-methyl-1,4-dimethoxynaphthalene 31, to isoprene epoxide 32, gave the short chain alcohol derivative 33.…”

“…In another isolated report, natural phylloquinone 1 has been synthesised by an O-alkylation of the menadiol monoactetate 40 giving ether 41 which is followed by a Lewis acid catalysed rearrangement [27]. The intramolecular rearrangement of 41 occurs under mild reaction conditions and low catalyst loading to give a high (E)-selectivity in the double bond formation (Scheme 13).…”

Highly Enantioselective Rhodium‐Catalyzed Hydrogenation of 2‐(2‐Methoxy‐2‐oxoethyl)acrylic Acid − A Convenient Access of Enantiomerically Pure Isoprenoid Building Blocks

“…Most often the lactones (S)-A1 and (S)-A2 were used, for example for syntheses of α-tocopherol, [1b,1c] vitamin K 1 , [2] mammalian dolichols, [3] Archaea membrane lipids, [4] (S)-26-hydroxycholesterol [5] and (ϩ)-invictolide. [6] Widely differing methods were employed for syntheses of these synthons.…”