A new route to Vitamin E key-intermediates by olefin cross-metathesis

Total Synthesis of (R,R,R)‐γ‐Tocopherol through Cu‐Catalyzed Asymmetric 1,2‐Addition

“…Although formally vitamin E comprises a family of tocopherols and tocotrienols with a chroman core (Figure 1), in practice the term is synonymous with α‐tocopherol or its acetate as it is by far the most dominant member 2a. 3 All ‐ rac ‐α‐tocopherol is produced on a scale of more than 30 000 ton per year 4. To meet this huge demand for vitamin E, the industrial synthesis is accomplished by the condensation of trimethylhydroquinone ( 9 ) and chemically produced isophytol 10 (Scheme ) 5…”

“…The naturally occurring ( R,R,R )‐tocopherols are biologically the most active,3, 6 and in particular the stereochemistry at C2 is important 7. Consequently, the asymmetric synthesis of 1 , and especially the stereoselective synthesis of the chroman core,8 has been the topic of intense research, which has been discussed in several reviews 9.…”

“…[4] To meet this huge demand for vitamin E, the industrial synthesis is accomplished by the condensation of trimethylhydroquinone (9) and chemically produced isophytol 10 (Scheme 1). [5] The naturally occurring (R,R,R)-tocopherols are biologically the most active, [3,6] and in particular the stereochemistry at C2 is important. [7] Consequently, the asymmetric synthesis of 1, and especially the stereoselective synthesis of the chroman core, [8] has been the topic of intense research, which has been discussed in several reviews.…”

Synthetic attempts toward α‐tocopherol—An overview

“…[20,107] 2.12 | Colobert chiral sulfoxide approach Colobert group revealed that synthesis of (2R,4 0 RS,8 0 RS)-α-tocopherol could be achieved through chiral sulfoxide [109] directed allylation and rutheniumcatalyzed cross-metathesis. [110][111][112] The synthesis started with tert-butylchlorodimethylsilyl (TBS) group protected 3,4-dihydrocoumarin 16a (which was prepared following Oku and co-workers reported procedure [113] ) and lithium diisopropyl amide (LDA) generated lithium ion of (S)-methyl-p-tolyl sulfoxide to afford chromanol 16b formation (yield 73%). Diastereomeric 2-methoxy-3,4-dihydro-benzopyran 16c formation was achieved through ketal formation of compound 16b in presence of p-toluene sulfonic acid (PTSA) in 87% yield.…”

Diastereoselective Synthesis of α-Tocopherol: A New Concept for the Formation of Chromanols

“…Selective protection of 10 at the less hindered phenol, followed by coupling of phytyl bromide, gave 12 in excellent yields. Lewis acid mediated double Claisen-rearrangement, and protection of the resulting phenol, afforded olefin 5i (>98:2, E / Z ), subsequently oxidized according to Shi, to yield 6i in 81% yield, and 97% de. Removal of the DPS protecting group of 6i under usual conditions (TBAF, THF) gave only the 5-membered ring product.…”