Acetylenic carotenoids synthesis

Other Degraded Carotenoids. Several syntheses of ionones and related compounds have been described. Some of these may prove useful for end-group construction in carotenoid synthesis. Thus 4-keto-j8-ionone (126) and 3,4-dehydro-jS-ionone (127) have been prepared by condensation of the sulphone (128) with propylene oxide, followed by elimination of phenylsulphinic acid and either oxidation or dehydration. A novel method utilizes a thermal acetylenic oxy-Cope rearrangement process to prepare the ionone compounds (129—131 R = Me) and analogues (R = Et or Pr ) from cyclohex-2-enylprop-2rynols (132). 

Most of the natural acetylenic carotenoids have an acetylenic group in the 7-and/or the 7 -position. An appropriate synthon to construct acetylenic carotenoids is ( )-3-methyipent-2-en-4-yn-1-ol (93) which is a commercially available Ce-unit containing an acetylenic bond. Recently the synthesis of diatoxanthin (94) and its (9Z)-isomer have been reported [58,59],... 

Oxidation of 5 with Mn02 in acetone led to the acetylenic Cio-dialdehyde 6. Partial hydrogenation over Lindlar catalyst [3,4] provided (2 ,4Z,6 )-2,7-dimethylocta-2,4,6-triene-1,8-dialdehyde (7), which was isomerized to the (all- )-Cio-dialdehyde 8. This Cio-building block 8 (Cio-dialdehyde) is by far the most important unit in carotenoid synthesis. 

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. 

Starting from their experience in manufacturing /3-ionone, Hoffmann-La Roche initially favoured acetylene as the universal building block for further syntheses. The reaction of methyl vinyl ketone with lithium acetylide in ammonia gives a tertiary alcohol, which is isomerised with sulfuric acid into a mixture of the (Eland (Z)-isomers of 3-methylpent-2-en-4-ynol. The isomers can be separated by distillation. Whereas the main component, the (Z)-isomer, is used for the production of Vitamin A, the (E)-isomer finds application in carotenoid synthesis. 

Haugan, J.A. and liaaen-Jensen, S. (1994a) Total synthesis of acetylenic carotenoids. 2. Synthesis of (aH- )-(3R,3 R)-diatoxanthin and (all- )-(3R)-7,8-dihydrocryptoxanthinn. Acta Chem. Scatid., 48,899-904. 

The transformations of compounds which are precursors for vitamin A and carotenoids have a special position among the rearrangements of the conjugated polyenes. Numerous isomerizations such as cw-fraws-isomerization, the dehydration of polyunsaturated acetylenic carbinols etc. were utilized to prepare the various carotenoides (e.g. /1-carotene, lycopene, cryptoxanthin, zeaxanthin) (for reviews, see References 146 and 147). However, one of these rearrangements turned out to be a considerable hindrance for the synthesis of target products. 

The special potential for constructing double bonds stereoselectively, often necessary in natural material syntheses, makes the Wittig reaction a valuable alternative compared to partial hydrogenation of acetylenes. It is used in the synthesis of carotenoids, fragrance and aroma compounds, terpenes, steroides, hormones, prostaglandins, pheromones, fatty acid derivatives, plant substances, and a variety of other olefinic naturally occurring compounds. Because of the considerable volume of this topic we would like to consider only selected paths of the synthesis of natural compounds in the following sections and to restrict it to reactions of phosphoranes (ylides) only. 

The work is based on the idea of W. Reppe of applying the acetylene chemistry developed by him to the synthesis of terpenes. The 2-methylbutyn-2-ol (40, see page 14) formed by the addition of acetylene to acetone (39) was intended, as the C5 building block, as the starting point for terpene syntheses. A C5 building block appeared to be small enough to ensure the required flexibility for terpenoid vitamins and carotenoids and the extensive area of terpenoid flavors and fragrances. 

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. 

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. 

The key step of the synthesis is the rearrangement of the a-acetylenic alcohol 97 into the unsaturated carbonyl compound 124. This rearrangement was carried out with tris(triphenylsilyl)vanadate, triphenylsilanol and benzoic acid to give a mixture of the isomers 124 and 125. The latter was converted by iodine catalysis into the desired isomer 124. This key intermediate was afterwards transformed into the Cis-phosphonium salt 123 by standard procedures. The Wittig olefination of the Cio-dial 45 first with the fucoxanthin end group 123 and then with the peridinin end group 122 gave, in five steps, the C4o-carotenoid 126. Finally the epoxidation of this compound resulted in optically active fucoxanthin (121) and its (5S,6R)-isomer (Scheme 28). 

The C 10-dialdehyde is chosen as the middle part because its synthesis has already been evaluated extensively (see Chapter 3 Part I) and the compound is available on an industrial scale. The corresponding C 15-end groups have been synthesized in high yield from the C9-cyclic compound and the acetylenic C6-buiIding block. These procedures were developed in the early 1960s and became the basis of the present day industrial syntheses of such carotenoids as astaxanthin (403) (Scheme 2) and zeaxanthin (119) [1,2]. 

Because of their ready accessibility and their ease of reduction to give alkenes of predictable geometry, acetylenes have featured prominently in the synthesis of vitamin h (1) and carotenoids, principally by nucleophilic addition of metal acetylides RC=CM (M = Li, Na, K, MgX, X = halogen) to aldehydes and ketones to produce the corresponding a-hydroxyalkynes [2]. 

The acetylenic diol 1 has been used for the preparation of the phosphonium salts 9 (route 7 —and 10 (route 7 7772 70) which have been applied to the synthesis of p,p-carotene (3) [6]. The phosphonium salts 9 and 70 also proved their utility in the syntheses of 7,8-didehydroastaxanthin (402) and 7,8,7 ,8 -tetradehydroastaxanthin (400) [7] and of optically active carotenoids with 3,5,6-trihydroxy-5,6-dihydro-p-end groups [8]. Despite these interesting examples it is noteworthy that, in general, the diphosphonates are much better reagents for double olefination than the corresponding diphosphonium salts [9]. 

The acetylenic diphosphonate 73 is easily obtained by reaction of dibromide 4 with two equivalents of triethylphosphite under Arbusov conditions [5]. The specific advantages of the diphosphonate 13 have been demonstrated in the field of the synthesis of allenic carotenoids [10]. 

Part IV Synthesis of Acetylenic, Allenic and In-chain Substituted Carotenoids... 

In some important examples of naturally occurring carotenoids, the polyene chain is modified by the presence of one or two acetylenic or allenic groups. These and other interesting features are illustrated by peridinin (558) and pyrrhoxanthin (556) which contain allenic and acetylenic groups, respectively, as well as unusual modifications such as a C37-skeleton with an abnormal arrangement of side-chain methyl groups, and the presence of a butenolide structure. The synthesis of such carotenoids, particularly in the natural optically active form, provides a major challenge and the syntheses that have been developed are described in this Chapter. 

The units 49 and 50 used in the synthesis of vitamin A are also used in many ways in carotenoid syntheses and are produced industrially in large scale. p-Ionone (17) can be converted into vinyl-p-ionol (51) by ethynylation to 52 and partial hydrogenation [42]. This conversion is also achieved in one step by 1,2-addition of vinylmagnesium chloride 55[43]. The two routes are, in principle, equivalent, and which one is used in practice is decided by conditions on site. In this example, the main considerations are the availability of acetylene (4) and vinyl chloride, operating experience, and permits for handling these materials. The Ci5-phosphonium salt 49 is formed directly from 51 by the action of triphenylphosphine and acid [44,45]. A step involving labile P-ionylidene-ethyl halide is thus avoided. Crystalline (lE,9E)-49 is obtained in excellent yield by reaction of 51 with triphenylphosphine and sulphuric acid in isopropanol/heptane [46]. 

Acetylenic retinoids (439) with a cyclogeranyl ring containing a functional group were prepared and used as building blocks in the synthesis of the carotenoid canthaxanthin (Rosenberger et al., 1979). 

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