Natural product synthesis Tocopherol

Structure (Scheme 3.9). A mechanism that has been proposed is shown in Scheme 3.10. Intermediate 60 was formed upon activation of phytal 56 by dien-amine catalysis. Subsequently, an intermolecular aldol reaction between phytal 56 and aldehyde 55 occurred in the presence of catalyst 57. Finally, the tricyclic core structure 58 was built after the adjacent phenol group captured the newly formed iminium ion 61 via an oxa-Michael reaction. The cascade product desired was obtained in 58% yield with 97% diastereomeric excess. The total synthesis of natural product a-tocopherol was achieved through a four-step chemical synthesis. 

The domino Wacker carbopalladation can be extended to intermolecular cases (Scheme 5-208, Experimental Procedure below). In this case, a 1,1-ethenyl relay was used to generate are neopentyl-type palladium intermediate that in turn react with an external alkene (Scheme 5-208). The Tietze group used this strategy very efficiently for the total synthesis of natural products such tocopherol. "" Besides carbocycles, also oxygen carbocycles can be formed (Experimental Procedure below). 

S )-3-nydroxy-2-mcthylpropanoic acid, 13-A, can be obtained in enantiomeri-cally pure form from isobutyric acid by a microbiological oxidation. The aldehyde 13-B is available from a natural product, pulegone, also in enantiomerically pure form. Devise a synthesis of enantiomerically pure 13-C, a compound of interest as a starting material for the synthesis of a-tocopherol (vitamin E). 

Synthesis of Heterocyclic Natural Products (-)-Ephedradine A, (-)-a-Tocopherol, (-)-Lepadin D, and (-)-Phenserine... 

The chroman moiety is a constituent of some important natural products, e.g. the tocopherols and canabinoids. a-Tocopherol 12 (vitamine E) occurs in wheatgerm oil. It contains three asymmetric centres (C-2, C-4 and C-8 ) which each have an (/ )-configuration. a-Tocopherol was prepared by a stereoselective synthesis [44]. 

In the course of their total synthesis of a-tocopherol, Woggon and co-workers [56] reported a domino aldol/oxa-Michael/hemiacetalization sequence as the key step of their approach affording the chromenol core of the natural product (Scheme 16.28). 

Another impressive example of dienamine-iminium cascade catalysis was developed during the total synthesis of a-tocopherol 59 by Liu et al. [31]. This natural product is a member of the vitamin E family and possesses remarkable biological activity. The key step in the total synthesis of this natural product involved an organocatalytic aldol/oxa-Michael cascade reaction for construction of the core... 

Roche ester, (R)-3-hydroxy-2-methylpropionic acid methyl ester (16b), is a chiral building block for the synthesis of vitamins (a-tocopherol), natural products (spiculoic acid A), antibiotics (calcimycin), and fragrance components (muscone) and therefore of high interest for industry. Faber and coworkers employed ERs for the asymmetric synthesis of methyl 2-hydroxymethylacrylate derivatives... 

With the exception of the diol 9, that was obtained from the corresponding aldehyde in up to 35% yield, most of the chiral diols mentioned above were isolated in yields of only 20-25%. The formation of the acyloin-type condensation products is in competition with the much more efficient reduction of the carbonyl carbon and saturation of the double bond of the unsaturated aldehydes that were used as substrates. We became interested in the mode of reduction of particular aldehydes such as 54-56 (Scheme 8) in a study of the total synthesis of natural a-tocopherol (vitamin E) (23). We expected to obtain chiral alcohols that would be useful for conversion into natural isoprenoids from the reduction of the a-double bond of the above aldehydes. Indeed, 54-56 afforded up to 75% yield of the saturated carbinols 57-59 by treatment with yeast. Whereas the ee of 57 and 58 was ca 85%-90%, that of 59 is 99%, as shown by NMR experiments on the (-)-MTPA derivative (24). The synthetic significance of carbinol 59 was based on the structural unit present in natural isoprenoids (see brackets in structural formulas). This protected synthon can be unmasked by ozonolysis, as indicated by the high yield conversion of 59 into (S)-(-) -3-methyl-y-butyrolactone 60 (Scheme 9). Product 59 is a bifunctional chiral intermediate which does not need protective manipulation in that... 

Tocopherols and tocotrienols used for supplementation of foods and feeds or production of nutraceuticals, e.g., pills and powders, are obtained either by extraction from natural sources or by chemical synthesis (Schuler, 1990 O Leary, 1993). Extraction of tocopherols and tocotrienols from natural sources is economically feasible only if tocopherol/tocotrienol-rich raw materials are available at large quantities and are of high quality. In production of both natural and synthetic compounds, there are several extraction and purification processes that have to be optimized and controlled. Moreover, the environmental impacts of these processes should be acknowledged. Technological innovations in these areas are constantly needed. 

Optically active products formed by such reductions may serve as useful intermediates in organic syntheses. A concept for a new total synthesis of natural a-tocopherol has been proposed27 where the optically active C5 units, (5)-3-methyl-y-butyrolactone or (5)-2-methyl-y-butyrolac-tone, were used to build up the side chain. Both compounds are broadly applicable optically active building blocks for the syntheses of chiral compounds and have been prepared by stereospecific reduction of suitable unsaturated precursors. 

The same authors31 prepared (S)-3-(2-furyl)-2-methylpropan-l-ol by hydrogenation of a-methyl-/ -(2-furyl)acrolein with baker s yeast. This product can also be converted into optically pure (.S)-3-methyl--. -butyrolactone (see above). It has been used, not only for the total synthesis of natural a-tocopherol but also for the preparation of (4/5,87 )-4,8-dimethyldecanal, a pheromone component of the red flour beetle Tribolium castaneum. 

A variety of methods is now available for the synthesis (artificial production) of the tocopherols. In the most commonly used procedure, 2,3,5-trimethylhydroquinone is reacted with isophytol over one of many possible catalysts. A small amount of the vitamin is still obtained from natural sources, usually as the by-product in the treatment of one of its natural sources. 

I would now like to discuss briefly these results. The most important point is, in my opinion, the conclusion that the synthesis of E2(so) is obviously not a random process, but on the contrary a determinant one. The high yield of E2(W) observed upon administration of tocopherol, especially when vitamin E-deficient animals are used, is in itself strong evidence for this deduction. The second point is the nature of the isolated compound. It must be considered as highly significant that the product of the biosynthesis is a quinone rather than a chromanol, in spite of the fact that chromanols also may occur as by-products. The biological activity of tocopherol has so far been attributed mainly to its antioxidative properties. 

---