P-Carotene synthesis

By this route, the C10 dialdehyde, 2,7 dimethyl-2,4,6-octatriene-l,8-dial (22), is readily obtainable 26a) from 2-butene-l,4-bis(dimethylphosphonate) (19, n = 1) and methylglyoxaldimethylacetal (21). It is employed as the C10 building block in an industrially used P-carotene synthesis (see page 16). 

A great part of carotenoids in the market are from synthetic processes, as, for example, p-carotene synthesis by Wittig condensation using p-ionone as precursor, but the natural carotenoid market is growing. Both synthetic and natural carotenoids have the same molecular polyenic structure the natural compound contains several other carotenoids in low concentrations, which provides further health benefits and can be consumed in larger quantities. 

Precursor balancing and alteration of metabolic fluxes in the central pathways play major roles in the high-level production of metabolites. Redirection of carbon flux from pyruvate to G3P by overexpression of phosphoenolpyruvate synthase and inactivation of competing pathways resulted in improved lycopene production in E. coli [107]. In one study, P-carotene synthetic genes of Pantoea agglomerans were first integrated into the E. coli chromosome. P-Carotene synthetic pathway in recombinant E. coli was then divided into five modules P-carotene synthesis, MEP, and three central metabolic modules. Expression... 

In view of the synthetic importance of dicarbonvl compounds surprisingly little has been done, apart from carotene synthesis, on dialkenylation with Wittig reagents. However, from the few examples reported one may conclude, that no special problems are involved. Benzocyclobutanedione was converted by two equivalents of methoxycarbonylmethylidenetri-phenylphosphorane to the corresponding diene in 85% yield (M. P. Cava, 1960). 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

The Wittig reaction has proved very useful in the synthesis of natural products, some of which are quite difficult to prepare in other ways. One example out of many is the synthesis of P-carotene ... 

It is interesting that the retention behavior of lycopene varies dramatically depending on the stationary phase synthesis lycopene usually elutes before a- and P-carotene in monomeric columns, whereas with polymeric C30 columns, lycopene elutes after these carotenes. ... 

Design and Synthesis of Enzyme Mimics of P-Carotene 15,15 -monooxygenase 35... 

The synthesis of the bis-P-cyclodextrin 35 is outlined in Fig. 14. Interestingly, however, the X-ray structure of 36, the de-tosylated 35, revealed that P-carotene would not be incorporated into both CD units due to the unfavorable orientation of the diamide linker which blocks the entrance to the second P-CD. In agreement with this result are experiments with the target Ru complex 37 which displayed central cleavage on P-carotene 1 5delding retinal 2 as the major product (Fig. 15) (19). 

Other molecules in which the presence of a C2 axis of symmetry also simplifies the syntheses are squalene (5) rmd P-carotene (6). Notice that in such cases the simplification derives from the fact that the syntheses are convergent and reflexive i.e., syntheses which start from identical precursors [5]. In practice, the synthesis of these two substances may be carried out not only by dimerisation of two identical moieties [10] [11] -which may lead to a mixture of isomers-, but preferentially by addition of two identical fragments to a central bifunctional unit according to the scheme -1- + C. = Cjj (squalene Cji -t-Cg + Cj] = 30 [12] p-carotene ... 

Figure 9.2. The inherent metabolic flexibility of the isoprenoid pathway leading to the synthesis of some carotenoid pigments. Genes coding for two enzymes capable of acting on carotenoid structures were introduced into Escherichia coli which had already been transformed to give it the capacity to make p,p-carotene. Both of the two introduced new enzymes (one shown with red arrows and the other with blue arrows) acted on multiple substrates because of their lack of specificity. The resulting matrix of transformations means that nine different products can be made by just two tailoring enzymes. (Adapted from Umeno et al. ° who used data from Misawa et al. °)...

Babler and Schlidt [86] described a route to a versatile C15 phosphonate, used for a stereoselective synthesis of all E retinoic acid and p-carotene. Base-catalyzed isomerization of the vinyl-phosphonate afforded the corresponding allyl-phosphonate as the sole product. Homer-Emmons olefination with ethyl 3-methyl-4-oxo-2-butenoate concluded the facile synthesis of all E ethyl retinoate. The C15 phosphonate was synthesized starting from the epoxide of P-ionone. Subsequent isomerization with MgBr2, afforded the C14 aldehyde in 93%... 

A genetic engineering success is the transfer of genes for synthesis of P-carotene into rice. The resulting "golden rice" contains enough carotene in its endosperm to make a significant contribution to the vitamin A needs of people for whom... 

Citranaxanthene 543 is found in citrus fruits and is used as a food dye like P-carotene. The same phosphonium salt synthon 505 as used for the vitamin A synthesis is monoolefinated with the polyene dialdehyde 539. The Wittig reaction of the resulting 540 with phosphorane 541 followed by aldol condensation of the obtained 542 with acetone gives citranaxanthene 54 3 255,263) (Scheme 92). In the preparation of the polyenedial 539 l,4-dibromo-2-butene 544 is reacted with trimethyl... 

The first synthesis of a carotenoid, which was identical in structure to the dihydro-P-carotene obtainable from p-carotene (1), was successfully carried out by... 

An industrial synthesis for p-carotene (1), the orange-red colorant of carrots and the important provitamin A, is based on the linking of two C15 phosphonium salts (13) with a C10 dialdehyde (22), in a double Wittig reaction 40) ... 

Several of the carotenoids are now commercially synthesized and used as food colors. A possible method of synthesis is described by Borenstein and Bunnell (1967). Beta-ionone is obtained from lemon grass oil and converted into a C14 aldehyde. The C14 aldehyde is changed to a C16 aldehyde, then to a C19 aldehyde. Two moles of the C19 aldehyde are condensed with acetylene dimagnesium bromide and, after a series of reactions, yield p-carotene. 

Hof mann-La Roche has produced P-carotene since the 1950s and has reUed on cote knowledge of vitamin A chemistry for the synthesis of this target. In this approach, a five-carbon homologation of vitamin A aldehyde (19) is accomplished by successive acetahzations and enol ether condensations to prepare the Cjg aldehyde (46). Metal acetyhde coupling with two molecules of aldehyde (46) completes constmction of the carbon framework. Selective reduction of the internal triple bond of (47) is followed by dehydration and thermal isomerization to yield P-carotene (21) (Fig. 10). 

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