Short and sweet: A simple and practical route to α‐tocopherol is described (see scheme; TES=triethylsilyl). The key step is a remarkably diastereoselective domino aldol/oxa‐Michael reaction, which is promoted by proline derivative 1.

The diastereoselective formation of the chromanol ring is one of the most challenging reactions during the biosynthesis of tocopherols in photosynthetic organisms. We discovered the enzyme that catalyzes this transformation in the cyanobacteria Anabaena variabilis [1] and subsequently determined its substrate specificity [2] and recently cloned the tocopherol cyclase from the related Anabaena sp. into E. coli.[3] The enzymatic reaction mechanism was determined by isotopic labeling experiments, [4] which revealed that the reaction proceeds by si protonation of the double bond of 1 followed by re attack of the phenolic oxygen to yield g-tocopherol (2; Scheme 1).Two further observations suggest a concerted nonsynchronous cyclization, during which positive charge develops at the carbon atom that is trapped by the phenol (see 3, Scheme 2): 1) the tetrahydroisoquinolinium terpenoid 4 as a transition-state analogue is an excellent inhibitor (IC 50 = 1.4 nm) of tocopherol cyclase, [5] and 2) the epoxide of 1 cyclizes under acidic conditions yielding two compounds, the five-membered-ring "Baldwin" product and the six-membered ring analogue of the enzymatic product (4:6 ratio). [3,4]

A diastereoselective synthesis of α-tocopherol 1 (93% de) was achieved via two key steps, (i) a highly diastereoselective Shi epoxidation of a trisubstituted alkene and (ii) an acid supported, “anti-Baldwin” epoxide ring opening under inversion of configuration leading to the 6-membered chromanol ring.

Ganz einfach: Ein einfacher und praktischer Zugang zu α‐Tocopherol wird vorgestellt (siehe Schema; TES=Triethylsilyl). Schlüsselschritt ist eine durch das Prolinderivat 1 geförderte, bemerkenswert diastereoselektive Aldol‐Oxa‐Michael‐Dominoreaktion.

The diastereoselective formation of the chromanol ring is one of the most challenging reactions during the biosynthesis of tocopherols in photosynthetic organisms. We discovered the enzyme that catalyzes this transformation in the cyanobacteria Anabaena variabilis [1] and subsequently determined its substrate specificity [2] and recently cloned the tocopherol cyclase from the related Anabaena sp. into E. coli.[3] The enzymatic reaction mechanism was determined by isotopic labeling experiments, [4] which revealed that the reaction proceeds by si protonation of the double bond of 1 followed by re attack of the phenolic oxygen to yield g-tocopherol (2; Scheme 1).Two further observations suggest a concerted nonsynchronous cyclization, during which positive charge develops at the carbon atom that is trapped by the phenol (see 3, Scheme 2): 1) the tetrahydroisoquinolinium terpenoid 4 as a transition-state analogue is an excellent inhibitor (IC 50 = 1.4 nm) of tocopherol cyclase, [5] and 2) the epoxide of 1 cyclizes under acidic conditions yielding two compounds, the five-membered-ring "Baldwin" product and the six-membered ring analogue of the enzymatic product (4:6 ratio). [3,4]