Carotenoids total synthesis

Carotenoid oxidation products were not only formed from the parent molecules in order to elucidate structure, they were also obtained by partial or total synthesis or by direct oxidation of carotenoid precursors. Thus, apo-8 -lycopenal was synthesized in 1966 more recently, the ozonide of canthaxanthin was obtained by chemical oxidation of canthaxanthin. ... 

Katsumura and collaborators [137-139] reported the total synthesis of a polyfimctional carotenoid, Peridinin 314 (Scheme 101). Diene-allenyl sulfone 312 was combined with unsaturated aldehyde 313 using NaHMDS in THF. The product was obtained in 50% yield as a mixture of isomers EjZ 25/75. 

Two key chiral building blocks used in the total synthesis of a-tocopherol were prepared via microbial reduction of unsaturated carbonyl compounds with baker s yeast and with Geotrichum candidum Similarly, a key intermediate in the total synthesis of optically active natural carotenoids was prepared by microbial reduction of oxoisophorone with baker s yeast. An alternative approach to the synthesis of a-tocopherol employs a chiral building block that was obtained by baker s yeast reduction of 2-methyl-5-phenylpentadienal. ... 

Method of manufacture all industrial processes for preparing carotenoids are based on P-ionone. This material can be obtained by total synthesis from acetone and acetylene via dehydrolinalol. The commercially available material is usually extended on a matrix such as acacia or maltodex-trin. These extended forms of beta-carotene are dispersible in aqueous systems. Beta-carotene is also available as micronized crystals suspended in an edible oil such as peanut oil. 

Proposed structures and exhaustive references to some 560 naturally occurring carotenoids studied until 1986, including trivial and semisystematic IUPAC names [2] have been compiled [7], as well as more recent additions [12]. A critical, selective treatment with key references will soon appear [13]. Extensive books on isolation and analysis including worked examples [1], applied spectroscopy [14], total synthesis [15] and biosynthesis and metabolism [16] have been published. 

The continuous development of carotenoid research is reflected in various monographs and reviews published over the years and three generations of books under the title Carotenoids have been published by Birkhauser. The first one, by Karrer and Jucker, published in 1948 [1] and the second, edited by Isler and published in 1971 [2], became classics which are still widely used as valuable sources of information. The book by Isler contains a major chapter of 250 pages on total synthesis and this comprehensive and authoritative review describes systematically the construction of many synthons and... 

Although only three carotenoids are commercially synthsised for use as permitted food colourants, namely p-carotene, apocarotenal and canthaxanthin, the availability of nature-identical counterparts of the natural products has always attracted interest. For the study of biological properties and for chromatographic studies access to synthetic versions is highly desirable. In the course of the isolation of the natural product its total synthesis finally always remained historically as a target. Such chemical work had invariably been carried out well before the introduction of the permitted range concept focussed attention on certain natural products... 

The classic sequence of experiments with natural compounds in the twentieth century has been as follows isolation from biological sources, purification, elucidation of molecular structure, and finally total synthesis. These tasks of organic chemistry were fulfilled by the end of the century as far as the major components of higher organisms are concerned. Only compounds that are central to the growth of their tissues are the subject of this book. Many individual compounds of this kind of natural product, namely lipids, steroids, carbohydrates, carotenoids, porphyrins, vitamins, nucleic acids, and proteins, are today commercially available, and their structural and dynamic analysis has reached an accuracy and diversity that leaves little to be desired (Karrer, 1954 Fieser and Feiser, 1960 Tedder et al., 1972 Nuhn, 1981 Fuhrhop, 1982 Beyer and Walter 1988 Fuhrhop and Penzlin, 1994 Mann et al., 1994). 

Total synthesis is applied for carotenoids on a lO t scale per year. One usually starts with the cheapest carbonyl components (formaldehyde, acetone) and carbanions (acetylide, acetoacetate, cyanide, Wittig ylides) available. A typical industrial synthesis of retinol acetate (vitamin A) is outlined in Scheme 5.3,1. 

At the 4th International Symposium on Carotenoids in Berne in 1975, the total synthesis of (3/, 3 / )-zeaxanthin (119) was reported by the Roche group. The 3-hydroxy-p end group is the most abundant chiral end group of the naturally occurring carotenoids almost 100... 

The Roche group extended this work and in 1981, at the 6th International Symposium on Carotenoids in Liverpool, reported the total synthesis of several of the ten optical isomers of e,8-carotene-3,3 -diol (tunaxanthin, 149) and of four diastereoisomers of p,e-carotene-3,3-diol, including the most common (3R,3 / ,6 / )-isomer, lutein (133). The starting material for these syntheses was 6-oxoisophorone, which the Roche scientists went on to use to synthesize a large number of dicyclic carotenoids in optically inactive and active form, as reported at the 7th International Symposium on Carotenoids in Munich in 1984. 

Today the total synthesis of a carotenoid for structure elucidation is often no longer necessary because of advances in high resolution spectroscopic methods but, when only small amounts of a new natural carotenoid, metabolite or degradation product are available, full spectroscopic characterization may not be possible, and total synthesis of the proposed structure then becomes indispensable, especially to establish its stereochemistry. 

In this Chapter, attention will be focused exclusively on total synthesis. In the ultimate step which leads to the target carotenoid there are theoretically two approaches, A and B, which could be used (Fig. 1). 

An essential requirement for all synthetic work is the rigorous characterization of all intermediates and products. In this Chapter, the application of various spectroscopic methods for the unequivocal identification of structure and stereochemistry of carotenoid products and intermediates in their total synthesis will be discussed. The examples covered are listed in Table 1. 

Since research on the total synthesis of carotenoids began, the enol ether and the aldol condensations have been frequently used for the formation of carbon-carbon double bonds. In general, the enol ether reaction has been employed successfully for the condensation of a wide range of acetals and sometimes of ketals with enol ethers and dienol ethers. 

The 3-hydroxy-p end group is the most abundant chiral end group in carotenoids and is often called the zeaxanthin end group. Zeaxanthin (119-121) possesses two chiral centres at C(3) and C(3 ), making possible three optical isomers, namely the (3/ ,3 / )-isomer (119, most abundant in Nature) and the (35,3 5)-isomer (121) as well as the (3/ ,3 5)-isomer (120) which constitutes a meso-form. It is this optically inactive mixture of isomers which is usually obtained by synthesis of the so-called racemate. For the first total synthesis of racemic zeaxanthin (119-121) the strategy Ci9 + C2 + Ci9 = C4o was applied [15]. The Ci9-synthon 50 was synthesized starting from isophorone (51) which was converted into p-isophorone (52) (Scheme 12). 

A representative allenic carotenoid is mimulaxanthin (202), a symmetrical structure with allenic end groups. For the total synthesis of mimulaxanthin (202), the most suitable candidate starting compound is the grasshopper ketone (11a) which has been synthesized by several groups [7-13]. 

The phenomenon of (E/Z)-isomerization (or cisitrans isomerization) in carotenoids has long been recognized. Interconversion of the (all- )- and various (mono-Z)- and (di-Z)-isomers occurs readily in solution, a process known to be catalysed by iodine in the presence of light [1]. Pure fZ)-isomers may be isolated by chromatography from such isomerization mixtures. The interest in pure (Z)-isomers of carotenoids has recently increased considerably [2,3], and the alternative preparation of (Z)-isomers by total synthesis has received growing attention. 

This Chapter deals with the total synthesis of specific (Z)-isomers of carotenoids by stereo-chemically controlled reactions. The preparation of fZj-isomers by (E/Zj-isomerization is not covered here. 

When a total synthesis of a particular fZj-isomer of a carotenoid is being planned the thermodynamic stability of that isomer relative to the (all- )- and other (Zj-isomers must be considered in mind, because isomerization in solution inevitably occurs as a secondary event. 

The (9Z)> and (9Z,9 Z)-isomers of acetylenic carotenoids have been prepared by synthesis. The total synthesis of the (9Z,9 Z)-isomer of optically inactive alloxanthin (117) [12,13] has been treated in detail in Chapter 3 Part IV, as has the synthesis of (9Z)-mytiloxanthin (353) [33,34]. The (9Z)- and (9Z,9 Z)-isomers, respectively, of 402 and 400, the mono- and diacetylenic analogues of (3.5,3 5)-astaxanthin, have been synthesized [14], and recently also the (9Z)-isomers of (3/ ,3 / )-diatoxanthin (118) and (3/ )-7,8-didehydro-p,p-caroten-3-ol [35]. All these syntheses are based on an acetylenic C 5-phosphonium salt, as discussed in Section C.4, where the Wittig condensation with an appropriate aldehyde leads to stereoselective formation of the thermodynamically stable (9Z)-isomer. 

Caroten-20-als with chiral end groups were also synthesized, including a Cso-carotenoid [16]. The naturally occurring lycopen-20-al (273) and rhodopin-20-al (277) have been obtained by the same strategy [42]. By application of the Shapiro reaction various caroten-19-ol and caroten-19-al type compounds have been prepared as (9 /9Z)-mixtures by total synthesis and characterized [17]. 

Several syntheses of carotenoids isotopically labelled with deuterium have been reported [65-68]. The total synthesis of spheroidenes (97) specifically labelled with deuterium in the central part is based on the synthetic scheme discussed above for the C-labelled spheroidenes [68]. When deuterium-enriched compounds are used, a few modifications are necessary to avoid scrambling and isotope dilution (Scheme 28). 

List of Naturally Occurring Carotenoids Prepared by Total Synthesis... 

In the Key to Carotenoids [1], where 563 naturally occurring carotenoids are listed, literature references for the total synthesis of 148 carotenoids are given. Since 1986, 54 new carotenoids have been isolated from natural sources [2] and some of these have been synthesized. 

The Key to Carotenoids includes some carotenoids which may not be natural products, such as the 5,8-epoxides which are generally considered to be artifacts but which are commonly found in natural extracts. Syntheses of such compounds are included in this Appendix. The total synthesis of Z-isomers, however, is treated in Chapter 3.4. and therefore not included here. 

This book, Volume 2 in the series Carotenoids, is the first book to be published that is devoted entirely to the total synthesis of carotenoids, but it is timely in view of the rapid development and the growing diversification of the carotenoid field. 

The 1971 Carotenoids book contained a major chapter of 250 pages on total synthesis by... 

Finally, two appendices provide tables of useful synthons and a list of natural carotenoids that have been prepared by total synthesis. 

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