Catalytic processes in vitamins synthesis and production

Applied Catalysis A: General 280 (2005) 55–73 www.elsevier.com/locate/apcata

Catalytic processes in vitamins synthesis and production Werner Bonrath*, Thomas Netscher Roche Vitamins Ltd., Research and Development, Grenzacherstr. 124, CH-4070 Basel, Switzerland Available online 30 November 2004

Abstract Water- and fat-soluble vitamins are essential for human and animal nutrition. Several of them are produced in amounts of well above 1000 t annually worldwide. In this highly competitive field, catalytic methods represent ideal tools to lower production costs, and consequently gain an economical advantage, by the application of environmentally benign processes. Examples of industrially important transformations given in this review are grouped by reaction types, e.g. hydrogenation, oxidation and various alkylation, rearrangement, cycloaddition, and esterification reactions. # 2004 Elsevier B.V. All rights reserved. Keywords: Catalysis; Environmentally benign processes; Fine chemicals; Organic synthesis; Selectivity

1. Introduction The development and application of catalytic reactions is one of the fundamental issues for fine chemical industry. The aim of these activities is to reduce waste and to achieve an economical and ecological benefit. In this review, the application of catalytic procedures in the synthesis and production of vitamins are covered. For an overview about new catalytic processes developed in Europe during the 1980s, see [1] where the production of fine chemicals is included. Vitamins are organic compounds, which are essential for animal and human organisms, because they are not synthesized or formed only in insufficient amounts in the body [2]. The classification of vitamins is based on their biological activity. The term ‘‘vitamins’’ originates from the searching for the causes of beriberi, a nervous disease, and was introduced to literature by Funk [3]. According to Sheldon’s classification [4], most vitamins are typical fine chemicals with prices above US$ 10 per kg and production volumes of about 1000–10,000 t per annum. A few vitamins can be placed in the class of bulk chemicals. * Corresponding author. E-mail address: [email protected] (W. Bonrath), [email protected] (T. Netscher). 0926-860X/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.apcata.2004.08.028

Many transformations in fine chemical industry are still based on stoichiometric reactions from the area of organic chemistry where often large amounts of waste are formed. In general, chemical processes can be classified by production volume as well as extent of atom economy, i.e. the number of atoms of all starting materials, which ends up in the product [5]. From an industrial and more chemical processes oriented point of view, an additional aspect has to be considered, which includes the loss of solvents, the type of waste, and the energy balance. The e-factor [6] introduced by Sheldon and defined as kilogram by-product per kilogram product, gives typical numbers, and is a first orientation to characterize a process or synthetic procedure (Table 1). The driving forces for the development of new processes are summarized in Table 2. In the following paragraphs industrially important catalytic processes for the application in the synthesis of vitamins or their building blocks are discussed. Sections are organized by reaction types. These are then exemplified by typical procedures concerned with the production of particular products or classes of compounds. It has, however, to be mentioned that the aim of this article is to show some trends in this area illustrated by selected examples, rather than giving a comprehensive overview.

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Table 1 The e-factor in various segments of industry [6] Industry segment

Product tonnage

Kilogram by-product/kilogram product

Oil refining Bulk chemicals Fine chemicals Pharmaceuticals

106 104 102 101

<0.1 1–5 5–50 25 to >100

to to to to

108 106 104 103

Table 2 Driving forces for new processes

Scheme 2. Industrial synthesis of (all-rac)-a-tocopherol.

Improved process economics New (improved) quality Competitive advantage through superior technology Health, safety, environment Pay-back

2. Hydrogenation Catalytic hydrogenation reactions belong to the most important transformations in chemical industry. This type of reaction can be carried out in a homogeneous or heterogeneous manner. In the following section, some new trends will be discussed. For an overview of the application of supercritical fluids, in particular scCO2, as process solvent, see [7]. With respect to production scale as well as number of individual process steps, hydrogenation procedures find wide applications in the production of Vitamin E. Substances with Vitamin E activity are all homologues of 6-chromanol. The eight naturally occurring compounds are divided in two groups, the tocopherols (RRR-1 to RRR-4), which have a saturated C16 isoprenoid side chain, and the tocotrienols (REE-5 to REE-8), which have a triply unsaturated C16 side chain (Scheme 1) [8,9]. The total synthesis of (all-rac)-a-tocopherol (1), the compound of highest commercial interest due to its biological and antioxidant properties, is based on the

Scheme 3. C2 and C3 chain extensions for isophytol synthesis.

reaction of trimethylhydroquinone (9) with isophytol (10) (Scheme 2, cf. Section 9). Isophytol (10), the building block for introduction of the isoprenoid side chain, is produced in a series of C2 and C3 chain extension steps (Scheme 3). Starting materials are acetone, ethyne, and hydrogen. The C2 extensions can be carried out by adding the vinyl-Grignard reagent or by ethynylation followed by Lindlar-type and total hydrogenation. For the C3 extension the Carroll reaction or the Saucy– Marbet reaction (cf. Section 5) are the preferred methods [10,11]. A procedure starting from cheap isobutene, carbon monoxide, and hydrogen to synthesize methylheptanone (11) is claimed by Krill [12]. The intermediate isobutyraldehyde is obtained by a hydroformylation reaction (Scheme 4). Subsequent aldol reaction and hydrogenation

Scheme 1. Compounds with Vitamin E activity.

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Scheme 4. Methylheptanone from isobutene.

Scheme 5. Hydrogenation reaction of unsaturated ketones.

yields the product. When starting from methylheptanone the established processes can be used for chain extension. The synthesis of geranylacetone from myrcene and methyl acetoacetate and following the conventional route is another possibility for isophytol production [13]. The reaction can be carried out Rh-catalyzed in two-phasesolvent systems. For myrcene synthesis see Section 4. For total hydrogenation and Lindlar-type hydrogenation of isophytol building blocks several industrial processes have been implemented [14]. During the last years several improvements could be achieved by catalyst development and process optimization. For example, the manufacture of alkenes by Lindlar-type hydrogenation using a solid catalyst (Pd on a solid carrier) is described in [15]. The hydrogenation of dehydrolinalool or dehydroisophytol to the corresponding vinyl alcohols using colloidal Pd in block polymer micelles can be carried out with high selectivity (>99.5%) in various solvents, e.g. methanol or toluene [16]. The hydrogenation reaction can also be performed in supercritical fluids, e.g. scCO2, and is based on the solubility of H2 in CO2 above 304 K [17]. Homogeneous hydrogenations in scCO2 could also be carried out. The solvent does not react under those conditions. The catalytic hydrogenation of unsaturated ketones in supercritical carbon dioxide with a supported palladium catalyst (Scheme 5) was described by Bertucco et al. [18]. Compared to industrial batch processes, which are run at low pressure and are mass transfer controlled, the continuous supercritical hydrogenation has the advantages of a tremendous acceleration of both reaction rate and productivity. First small-scale laboratory experiments indicated a productivity increase of approximately 500-fold. Continuous hydrogenation reactions with organic substances like cyclohexene derivatives in scCO2 using scC3H6 is described by Hinzler and Poliakoff [19], and is in the meantime commercialized by Thomas Swan Ltd. [20]. The

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advantages of sc-fluids for controlling the reaction conditions to achieve a better selectivity were illustrated, but these results were not compared to that under normal pressure conditions. The continuous Lindlar-type hydrogenation of propargylic alcohols, e.g. dehydroisophytol, over amorphous Pd81Si19 in dense carbon dioxide depending from a modifier was described in [21]. Another type of hydrogenation which is important for the industrial synthesis of tocopherol is the production of trimethylhydroquinone (14) from trimethylquinone (13, Scheme 6). For the synthesis of trimethylquinone from 2,3,6-trimethylphenol (12) see Section 3. The heterogeneous hydrogenation of trimethylquinone can be carried out using Pt/Al2O3 as catalyst [22]. Nobel metal catalysts on SiO2–Al2O3 yield the product with high conversion and selectivity (>99.5%) [23]. Raney-nickel [24], Pt-group elements on zeolites [25], and Pd/C [26] are very efficient hydrogenation catalysts. The hydroquinone product can be synthesized in >95% yield. Asymmetric catalysis, in particular enantioselective hydrogenation, is a powerful tool to achieve cost-efficient and environmentally benign selective syntheses in the area of vitamins and fine chemicals on industrial scale [27–29]. Processes can be operated in both a homogeneous and heterogeneous manner. For industrial production of (R)-pantothenic acid (R-16) and calcium (R)-pantothenate, racemic pantolactone (RS15), synthesized from isobutyraldehyde, formaldehyde, and hydrogen cyanide, followed by saponification under acidic conditions, is the key intermediate. Pantothenic acid (16) occurs in nature in bound form as a component of coenzyme A and is required for numerous biochemical processes. The commercial form is the calcium salt. Processes for the preparation of optically pure (R)-pantolactone are described [30]. Alternative procedures for (R)-pantolactone synthesis are based on the enantioselective hydrogenation of 2-oxopantolactone (17) [31]. For the synthesis of 2oxopantolactone see Section 3. The enantioselective hydrogenation can be carried out in a very efficient manner. Using Rh(mTolPOPPM)TFA as catalyst a TON (turn over number, moles product/moles catalyst) of 200,000, TOF (turn over frequencies) of 10 s
1 and an ee of 91% could be achieved (Scheme 7). This type of enantioselective hydrogenation could also be carried out in a continuous process using a heterogeneous catalyst in the presence of a chiral modifier, e.g. cinchonidine [32]. Biotin is a water-soluble B-vitamin playing an important role as a coenzyme. It has three asymmetric centers, and the

Scheme 6. Preparation of trimethylhydroquinone.

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Scheme 7. Synthesis of pantothenic acid.

isomer with the configuration (3aS,4S,6aR), D-(+)-biotin (18), has full biological activity [33]. Several approaches for the total synthesis of biotin are reviewed [34]. Industrial processes start e.g. from fumaric acid and use the separation and recycling of the biologically inactive isomer in an early stage in the synthesis, as first described by Gerecke [35]. This lactone–thiolactone approach (Scheme 8) was optimized by asymmetric induction using optically active amines or alcohols [36,37]. An alternative procedure for the synthesis of biotin starts from tetronic acid, easily prepared from diketene (Scheme 9). Key-step in this approach is a stereoselective hydrogenation. Originally, the heterogeneous (diastereoselective) hydrogenation of the bicyclic intermediate 20 with Rh metal on Al2O3 delivered a 70:30 mixture of diastereomers 21a/21b. An asymmetric hydrogenation process has been developed by Lonza in collaboration with the catalysis group of the former Ciba-Geigy. Ligand tuning for the Rh(I)-catalyzed asymmetric hydrogenation resulted in a >99:1 ratio when using the diphosphane josiphos2 (19)

[38]. Production had been operated on multi-ton scale before termination [29]. On the way to RRR-a-tocopherol (RRR-1) by total synthesis, the key-building block (RR)-hexahydrofarnesol is accessible via enantioselective hydrogenation of allylic alcohols. The fundamental findings of Takaya and Noyori et al. on this methodology, e.g. used in the transformation of geraniol/nerol (22/24) to (R)/(S)-citronellol (R/S-23, Scheme 10), homogeneously catalyzed by Ru(BINAP) complexes [39], represents a breakthrough for the largescale preparation of chiral terpenoid compounds. Ligands with superior performance have been developed by the Roche catalysis group. By using BIPHEP-type ligands, the Ru-catalyzed hydrogenation of C10-building block 22 and of C15-building block E-29 could be realized on pilot scale with extremely satisfying results. With substrate-to-catalyst ratios of up to 100,000, ee/de values of >98% for products R-23 and 31 could be achieved (Scheme 11). The E/Z isomer separation to obtain E-28 on a technical scale remains a challenge on this route. As an

Scheme 8. Lactone–thiolactone approach to D-(+)-biotin (Hoffmann–La Roche).

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Scheme 9. D-(+)-Biotin process using asymmetric hydrogenation (Lonza).

alternative to the preparation of C13-ketone 25 via (R)dihydrocitronellol 26, enantioselective hydrogenation of the unsaturated ketone 27 (obtained from cheap starting material 30) delivered 25, although with a considerably lower substrate-to-catalyst ratio (1000) and a somewhat lower ee (91%) [40,41].

3. Oxidations The application of catalytic oxidation reactions for several intermediates in vitamin syntheses is well established. An important field is the preparation of L-ascorbic acid (Vitamin C, 34), which is vital for stimulating enzymes, as water-soluble antioxidant, and as a co-factor in hydroxylation reactions [42]. In the production of 34 the oxidation of 2,3:4,6-di-O-isopropylidene-a-L-sorbofuranose (32) by hypochlorite in the presence of nickel salts at 323 K (the active oxidant is presumably nickel peroxide [42]) has

been replaced by air oxidation in presence of a palladium or platinum catalyst [43,44]. The resulting 2,3:4,6-di-Oisopropylidene-2-keto-L-gulonic (33) acid is transformed by base or acid-catalyzed rearrangement to Vitamin C (34) [45–48] (Scheme 12). Alternatively, the oxidation of L-sorbose (35) to 2-keto-Lgulonic acid (36) in presence of noble metal catalysts promoted with a modifier [49] is not efficient. Deactivation and low yield (selectivity) are the main disadvantages. The microbiological oxidation of sorbose can be carried out with microorganisms or enzymes [50]. The microbiological route to 2-keto-L-gulonic acid is a cheap and efficient modification of the traditional Reichstein process. The key intermediate for the production of pantothenic acid is (R)-pantolactone (R-15), which can be prepared from (RS)-pantolactone (RS-15), by optical resolution or by enantioselective hydrogenation of ketopantolactone (cf. Section 2, Scheme 7). The oxidation of RS-15 to

Scheme 10. Enantioselective hydrogenation of allylic alcohols by Takaya and Noyori et al.

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Scheme 11. Large-scale preparation of side-chain building blocks for RRR-a-tocopherol.

2-oxopantolactone (ketopantolactone, 17) can be carried out using RuCl2(PPh3)3 in benzene in the presence of tertBuOOH [51], or by air oxidation at 413–673 K using MoO3 and V2O5 supported on a-alumina [52]. An efficient method

for the Ru-catalyzed periodate oxidation of RS-15 under microwave irradiation is described in [53]. Aromatic oxidation is one of the key-reactions for the synthesis of vitamin building blocks. Menadione (38),

Scheme 12. Oxidation reactions in the synthesis of Vitamin C.

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Scheme 13. Oxidation of 2-methylnaphthaline.

a starting material in Vitamins K production, can be synthesized by chromium(VI) oxidation of 2-methylnaphthaline (37, Scheme 13). Alternative procedures use iron(III)-chloride/H2O2, or nitric acid [54]. The methyltrioxorhenium catalyzed oxidation of 37 [55] by-passes the problems of waste and low selectivity, which are drawbacks in chromium oxide treatment. Menadione (38) can further be hydrogenated to menadiol (39), which is used for the preparation of Vitamin K1 (cf. Section 9, Scheme 28). Another important oxidation reaction in the field of fatsoluble vitamins is the synthesis of trimethylquinone (13) from 2,3,6-trimethylphenol (12, Scheme 6). This oxidation is carried out on industrial scale using copper chloride, especially with diverse co-catalysts [56]. Air or oxygen or an oxygen-containing gas can be used at various temperatures, e.g. 332–380 K in various solvents, e.g. two-phase solvent systems, whereby high yields (>95%) and selectivities are obtained. The preparation of trimethylquinone (13) from phenol 12 by co-catalyzed oxidation in described in [57]. Another method for the direct oxidation of 12 used the mesoporous silica catalyzed, e.g. Ti- and V-MMM, in combination with hydrogen peroxide or tert-butylhydroperoxide. At total conversion selectivities of 86% could be achieved [58]. The heteropoly acid-catalyzed oxidation of 12 can be carried out in homogeneous phase [59] or in biphasic solvent systems [60]. The application of H7PMo8V4O40 as catalyst in the solvent system p-Cl2C6H4/HOAc/H2O yielded 13 in 84%. Another route to trimethylhydroquinone starts from aisophorone (40), which can be isomerized to b-isophorone (41). Allylic oxidation of 41 delivers ketoisophorone (42), a key intermediate in the synthesis of carotenoids [61], e.g. astaxanthin. 42 is acid catalyzed transferred to 69, which can be saponified to 9 (Scheme 14) [9]. For the oxidation of 41 several catalysts are described. Examples are Pb(OAc)2 in pyridine (yield 76% [62]), phospho- and silico-molybdic acid [63], Co-, Cr- or Pb-salts [64], Mn(II)-, or Co(II)complexes (85% yield [65]), Mn-bis(salicylideneiminato) complexes (>90% yield [66]), Cu-acetylacetonate [67], Mncomplexes [68], or Co-salen-complexes [69].

Scheme 14. Trimethylhydroquinone-1-monoacetate (87) as an intermediate to (all-rac)-a-tocopheryl acetate (72).

4. Gasphase reactions Gasphase reactions are useful tools for the synthesis of low-molecular-weight compounds. Pyrolyses of several organic compounds are well known since many years [70]. Industrial interesting compound could be synthesized in a very efficient manner using continuous processes often combined with fixed-bed catalysts. 2-Oxopantolactone (17), a key intermediate in the synthesis of (R)-pantolactone (R-15, Scheme 7), can be produced by air oxidation of racemic pantolactone in the presence of metal oxide catalysts, e.g. MoO3 or V2O5 on a-Al2O3, in the vapour phase (413–673 K) [71]. Advantages of this procedure are high conversion (>99%) and good selectivity (>86%). Oxidation reactions for the preparation of substituted benzaldehydes could also be carried out in the gasphase. Application of Mo-based catalysts at 463 K in the air oxidation of p-substituted benzaldehydes yields the corresponding toluenes in 58% conversion and 35% selectivity [72]. The dehydration reaction of amides to the corresponding nitriles, e.g. 4-alkyl-5-carbamoyloxazole (43), in the presence of SiO2-based catalysts at about 723 K results in the formation of the corresponding nitrile 44 (Scheme 15), in this case a key intermediate in an industrial Vitamin B6 process, in 95% yield [73]. A gasphase dehydrogenation of a primary aliphatic alcohol to the corresponding aldehyde was used in the synthesis of the Vitamin E side chain, cf. Scheme 11 (26 ! 25). An interesting method for the gasphase air oxidation of alcohols, especially aliphatic alcohols, using gold catalysts (1% Au on SiO2) with high selectivity (87–100%) and conversions of 25–100% at about 420–580 K is described in [74]. Another application of gasphase reactions is the methyl vinyl ketone (MVK, 45) synthesis (Scheme 16). Methyl vinyl ketone (45) is a starting material for Vitamin A syntheses. In the past MVK was produced by Hg-catalyzed addition of water to vinyl acetylene, see e.g. [75]. For example, 45 can be synthesized in the gasphase from ketobutanol over Cu-, Ag-, or Au-catalysts on Si/C at 780– 980 K by dehydration [76], from methanol and acetone at

Scheme 15. Synthesis of 4-methyl-5-cyano-oxazole in the gasphase.

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Scheme 16. Synthesis of MVK in the gasphase.

620–680 K on Ag2O [77], and in the liquid phase by dehydration with sulfuric acid at 393–525 K (96% conversion and 96% selectivity) [78]. The condensation reaction of acetone and formaldehyde in the gasphase over Zr/SiO2 at 573 K [79] yields 45 in 54%. The reaction can be carried out in a more efficient manner, if lanthanoide oxide catalysts are used (yield 67%, at 525 K) [80]. The manufacturing of myrcene (47) by pyrolysis of b-pinene (46) in a tube reactor at 670–825 K is carried out for several years [81]. By-product in this procedure is limonene (48, Scheme 17). The formation of these products can be explained by a diradical mechanism. The purification of myrcene from the pyrolysis mixture is performed by careful rectification [82]. For the synthesis of C13-compounds from myrcene, intermediates in Vitamins A and E syntheses, see Section 5. A study of product formation, reaction mechanism, and mass balance of the myrcene synthesis at various temperatures showed that limonene plays an important role in this system, and the results give a hint to a more complex reaction system than assumed for 50 years [83].

5. C–C-bond formation The formation of C–C-bonds is the main topic in organic chemistry. In the field of vitamin chemistry several classical types of C–C-bond formation are well established. Aldol condensation of isobutyraldehyde with formaldehyde to 3-hydroxy-2,2-dimethylpropanal, an intermediate for pantolactone synthesis, is one example. Another type of Aldol condensation is the C3-elongation of citral (49) to pseudoionone 50 (Scheme 18), a key intermediate in the synthesis of Vitamins A and E. The sodium or potassium

Scheme 17. Mechanism for the formation of myrcene from b-pinene.

hydroxide catalyzed reaction of citral (49) with acetone at 313 K yielded in 80–98% an E/Z-mixture of pseudoionone (50) [84]. The reaction can be carried out continuously under pressure. The application of lithium hydroxide is less efficient. 50 is obtained in 53% yield [85]. Application of strongly basic anion exchangers at about 330 K in methanol gave 50 in 80% yield [86]. The solid base catalyzed condensation of 49 with acetone is described in [87]. Another method using KF on alumina as catalyst at room temperature and 2 h reaction time yields 50 in 96% [88]. The application of modified hydrotalcite catalysts at 273 K shows a conversion of 60% and a selectivity of 90% when a low concentration of citral is applied [89]. Furthermore, the application of solid base catalysts, e.g. earth alkali oxides, in the synthesis of 50 is described [90]. This type of catalysts shows a selectivity of 93% at 83% conversion. Another important method of C3-elongation is the reaction of an unsaturated alcohol with an ether according to Scheme 19, to yield ketones 52. This reaction type is based on the pioneering work of Saucy and Marbet [91]. The homogeneous reaction is usually acid catalyzed at 370–420 K at a pressure of 8–15 bar. The use of heterogeneous catalysts, e.g. Deloxan ASP, in a continuous procedure is described in [92]. Processes using MeSO3H or phosphorous derivatives as catalyst for the preparation of ketones from propargyl alcohols and enol ethers, have the advantages of high yields and short reaction times [93]. The C3-extension of unsaturated alcohols 51 by transesterification-rearrangement with methyl acetonate (Carroll reaction, Scheme 19) is catalyzed by aluminum acetylacetonate [94]. The application of liquid aluminum alkoxy catalysts, e.g. aluminum alkoxides, is described in [95]. The reaction of isobutene and formaldehyde to isoprenol (Prins reaction) is of high commercial interest. Isoprenol can be isomerized to prenol or oxidized to isoprenal. Both compounds are building blocks in the synthesis of citral (49) by Cope rearrangement (Scheme 20). For the gasphase oxidation step at 773 K a special supported silver catalyst (Ag/SiO2) is used. Advantages of this procedure are high selectivity and yield (atom economy, low amount of waste) [1,96]. The application of SnCl4 anchored on MCM-41 yields isoprenol in 90% [97]. Isomerization and oxidation with Pd–Se–Ce/SiO2 and Ag or Ag/Al2O3 yields prenal in 48%. The reaction sequence isomerization/oxidation can be inverted [97].

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Scheme 18. Synthesis of pseudoionone from citral and acetone.

6. Allylic rearrangement The allylic rearrangement of tertiary allyl alcohols 54 is of considerable interest in the field of terpenoid compounds. Due to the easy access to tertiary ethynyl carbinols 53 (cf. Sections 7 and 8) and subsequent Lindlar hydrogenation (cf. Section 2), the basis for production of primary allyl alcohols 57 and 60 is given (Scheme 21). The latter compounds would serve as valuable starting materials on the way to optically active Vitamin E building blocks like 26 and 31, e.g. by Noyori-type enantioselective hydrogenation (cf. Section 2, Scheme 11), or for preparation of a,b-unsaturated carbonyl compounds E-56 by oxidation (cf. citral (49), see below). Two major problems, however, have to be solved for an economical application of such rearrangement reactions. First of all, the direct acid catalyzed or thermally induced allylic rearrangement leads to unwanted diene by-products (59 or isomers) formed under solvolytic conditions via stabilized carbocations. Therefore, much more efficient procedures in terms of selectivity and mildness of conditions use allyl carbinol derivatives 55, which, however, have the disadvantage of the additional protection and deprotection steps. The second general problem in using this methodology is, that always mixture of the three isomers 54, 57, and 60 (or their corresponding derivatives) are obtained, which are not so easy to separate on technical scale. Regarding the applicability of the allylic equilibrium, it has to be mentioned, that the ratio of the individual isomers is depending on what derivative is used. While (under thermodynamic control) the tertiary alcohol is by far the

Scheme 19. Saucy–Marbet and Carroll reaction.

major component (typically 60–80%), primary isomers are highly favoured when esters or other derivatives are applied. As an example, the ratio of (E + Z)-phytyl (primary) to isophytyl formiate (tertiary) obtained from treatment of isophytol with formic acid was found to be 98:2 [98]. As a result, [3.3]-sigmatropic rearrangement reactions catalyzed by metal (e.g. Hg(II)/Pd(II)) complexes [99] are generally more suitable for laboratory and commercial use. The development of transition metal (V, Mo, Re) oxo complexes as catalysts for the rearrangement of allylic alcohols, as also mechanistic investigations, are discussed in a short review [100]. The tungsten-catalyzed rearrangement of allylic alcohols is typically performed at 470 K. The catalyst must be stabilized by addition of an amine or phosphane base. Using this system nerol/geraniol can be isomerized to linalool [101]. A similar process for the isomerization of prenol in a continuous acid-catalyzed procedure is also described [102]. A highly practical procedure starts from tertiary allylic acetates using Pd2Cl2(CH3CN)2 as a catalyst [103]. Isomers E/Z-58 are obtained with high selectivities under neutral conditions. The concerted charge-induced mechanism via a cyclic transition state (Scheme 22 [99]) is generally accepted and delivers the best explanation for the selectivities observed in such reactions mediated by metal complexes. Also the suprafacial chirality transfer in optically active substrates [104,105] can be explained by this model. The similarity to other [2.3]- and [3.3]-sigmatropic reactions (Claisen-type rearrangements, oxy-Cope, Wittig, Pauling, Carroll rearrangements) has to be mentioned. In the preparation of citral (49) from myrcene (47), an allylic intermediate is involved. Myrcene is of interest as a building block for various syntheses, e.g. of Vitamins A, E, K, and flavours and fragrances. As an alternative to the

Scheme 20. Synthesis of citral from isobutene.

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Scheme 21. Rearrangement of terpenoid allylic alcohols and other substrates.

production of citral (49, Scheme 20), the direct Pd-catalyzed oxidation of myrcene (47) has been investigated [106]. By using a complex system of water and a water-immiscible solvent, a phase transfer agent, cupric chloride, and a metal oxoanionic salt in the presence of palladium chloride as catalyst, 49 was found to be selectively formed. Since allylic rearrangement can be considered as a special case of allylic substitution (i.e. nucleophile and leaving group being identical), a remark on the latter type of reaction may be added. The application of the p-allyl concept for the preparation of optically active intermediates by catalytic generation of chiral centers possesses a high potential for possible future use. As an example, we would like to mention the synthesis of the chiral chroman precursor 63 by Trost and Toste [107] sketched in Scheme 23. Key-step is the attack of phenol 61 at the intermediate p-allyl complex (originating from allylic carbonate 62), regio- and stereoselectively driven by the C2-symmetric diphosphane ‘‘Trost ligand’’ 64. Although the sequence is far away from a commercial process, it represents an interesting new strategy in the field of Vitamin E chemistry.

7. Rearrangement of a-alkinols From an economical point of view, the rearrangement of tertiary propargyl alcohols 53 to a,b-unsaturated aldehydes (56 and their Z-isomers, Scheme 24) is a shorter and very interesting alternative for the preparation of allyl alcohols 57. Similar to the case of allylic alcohols (cf. preceding

Scheme 22. General mechanism for rearrangement of allylic derivatives catalyzed by metal complexes [99].

section), acidic conditions are not suitable for obtaining pure products with high selectivity, due to the formation of unwanted side-products. An overview on acid-catalyzed (Rupe, Meyer–Schuster) rearrangement reactions is given in [108]. Again, the formation of carbocationic intermediates and, therefore, of unwanted by-products can be avoided by using appropriate catalytic systems. Oxometal catalysts like vanadates ((RO)3V = O, 65) are often-used catalysts [109–111], which first undergo a transesterification reaction with the tertiary alcohol 51 (Scheme 24). The subsequent [3.3]-sigmatropic reactions are analogous to the rearrangement of propargyl esters (e.g. acetate) catalyzed by silver ions which has been studied mechanistically in detail [112]. A similar process using the system titanate/cuprous chloride described by a Rhone–Poulenc group [113,114] is believed to follow this mechanism. A remarkable mechanistic difference between the rearrangement reaction of propargyl alcohols and the allylic rearrangement (which can both be induced by the same vanadate catalysts [111]) should be pointed out. According to Scheme 24, an allenyl ester 66a,b is formed as an intermediate. As a first result, the equilibrium between tertiary alcohol 53 and a,b-unsaturated carbonyl compound 56 is determined by the stereochemistry of this intermediate. In this case, the side of unsaturated aldehyde 56 is strongly favoured. In strong contrast, the tertiary form is predominant in the equilibrium of allyl alcohols (cf. preceding section, Scheme 21: 54 versus 57/60). As a second result, a chirality transfer is found in rearrangement reactions of optically active allylic starting materials (charge-induced mechanism, cf. Scheme 22), but not with propargyl esters: Complete racemization has been observed by a fast equilibrium between the allenyl esters 66a and 66b (Scheme 24) [112]. The development of siloxyvanadium oxide catalysts has led to the industrial application of this Pauling rearrangement [109,115] for the production of citral (49) at Givaudan (Roche group) in Vernier. A limitation of this type of transformation, however, has become apparent from various investigations. The main problem is still the relatively low

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Scheme 23. Preparation of an optically active chroman precursor by allylic substitution [107].

quality of products obtained, due to formation of difficult-toseparate isomeric by-products (e.g. b,g-unsaturated aldehydes) under the drastic reaction conditions (>120 8C) necessary. Such products are, therefore, not suitable for their use in routes e.g. involving enantioselective catalytic methods for the preparation of highly enantiomerically pure intermediates (cf. preceding section, Scheme 21). The rearrangement of a-alkinols under mild reaction conditions, e.g. room temperature, can be carried out in the presence of perrhenat-catalysts [116]. In some cases ketones are the reaction products (Rupe–Kambli rearrangement). The Mo-catalyzed rearrangement of a-alkinols, e.g. of dehydrolinalool, yields aldehydes in 90% (at total conversion), e.g. citral (E/Z-mixture of geranial/neral = 4/1). The reaction can be carried out in toluene at about 373 K [117].

8. Ethynylation a-Alkynols 68, e.g. dehydrolinalool (69, Scheme 25), are key intermediates in the production of isoprenoids. Therefore, their synthesis starting from the corresponding ketone 67 (Scheme 25) is of synthetic and industrial importance. As pointed out (cf. Section 2) the C2-extension can be carried out using a vinyl-Grignard reaction or ethynylation followed by partial hydrogenation [9]. The stoichiometric addition of organolithium or organomagnesium reagents, e.g. ethynyl lithium or ethynylmagnesium bromide, to carbonyl

compounds creates a large amount of waste. These methods are well described in literature [118]. In some cases, the method is used to synthesize interesting compounds from cheap starting materials. The addition of ethynylmagnesium chloride to esters for the synthesis of 3-hydroxy-3-methylpentadiine, a potential precursor for Vitamin A building blocks, is described in [119]. A general problem in ethynylation reactions is the formation of diols of type 70 as by-products (Scheme 25). Ethynylation reactions using ethine and equimolar amounts of potassium hydroxide are also well known [120]. Carrying out this reaction with catalytic amounts of potassium hydroxide [121] or cesium hydroxide [122] leads to the propargylic alcohol in >90%. For the application of potassium hydroxide several solvents can be used, e.g. ammonia, dimethylsulfoxide (DMSO), or N-methylpyrroidine (NMP). Reaction temperatures from 273 to 315 K and a pressure range from 10 to 30 bar are preferred. Another procedure describes the application of quarternary ammonium hydroxide as solid base catalyst for the ethynylation of ketones and aldehydes [123]. The ethynylation can be carried out in ammonia [124] or organic solvents [125], e.g. NMP or DMSO in a temperature range from 293 to 323 K at 25–30 bar. Useful catalysts are strong basic resins, which are commercially available, e.g. Amberlite IRA 400. Advantages of the described solid fixed-bed procedures are waste minimization and easy recovery of the catalyst.

Scheme 24. Rearrangement of tertiary propargyl alcohols catalyzed by vanadates.

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Scheme 25. Metal hydroxide catalyzed ethynylation of carbonyl compounds.

9. Friedel–Crafts alkylation Friedel–Crafts-type alkylation reactions play an important role in syntheses of fat-soluble Vitamins E and K1. As already mentioned (Section 2, Scheme 2), the final step in the total synthesis of (all-rac)-a-tocopherol (1) is the acidcatalyzed Friedel–Crafts alkylation reaction of trimethylhydroquinone (9) with (all-rac)-isophytol (10), or a C20 equivalent thereof, e.g. phytol or a phytyl halide, followed by a ring closure reaction (Scheme 26). An alternative route starts from trimethylhydroquinone diacetate 71 [126] (for its synthesis cf. Section 3). It is believed that (partial) hydrolysis of the ester groups precedes the condensation reaction with isophytol (10), which is effected, in principle, by the same Friedel–Crafts catalysts. Subsequent acetylation yields derivative 72, which is the major sales form. Original investigations of Vitamin E synthesis starting from trimethylhydroquinone (9) were published in parallel by Karrer et al. [127], Bergel et al. [128], and Smith et al. [129] in 1938. The pioneering work of Karrer and Isler [130] resulted in the first Vitamin E production at Roche in Basel in the early 1950s. Later on, a large number of catalytic systems have been developed. Since it would be beyond the scope of this review to completely cover all activities described in literature, only selected examples and, in

particular, new developments in the field of the economically most important transformation (Scheme 26) will be mentioned. Representative references are covered to a certain extent by general reviews [7,9,131–133]. Several classical Lewis and Brønsted acids, or combinations thereof, work well in this reaction. Typical examples are ZnCl2/HCl, BF3, AlCl3, or FeCl2/Fe/HCl, applied in various organic solvents. For large-scale production, however, corrosion problems and contamination of wastewater, in particular with zinc and halide ions, are major drawbacks of such procedures. Also the amounts of catalysts necessary for obtaining satisfying results are often substoichiometric rather than really catalytic. This may be due to the fact, that 1 mol of water is formed during this condensation reaction, which may contribute to the inactivation of the catalyst. In addition, the purity of the product depends strongly on the catalyst and conditions used. And, in many cases, an excess of (iso)phytol has to be used in order to obtain good yields, since allyl alcohols typically tend to dehydrate under strongly acidic reaction conditions (cf. Section 6). The majority of work in this area in recent years has, therefore, concentrated on the development of more efficient catalytic systems. Regarding an environmentally friendly recycling of catalyst and easy recovery of the product, supercritical

Scheme 26. Friedel–Crafts alkylation route to Vitamin E.

W. Bonrath, T. Netscher / Applied Catalysis A: General 280 (2005) 55–73

Scheme 27. Strongly acidic compounds used in Friedel–Crafts-type preparations of Vitamin E.

fluids [134,135] and multiple-phase-solvent systems were applied as alternative reaction media. The use of polar aprotic solvents and, in particular, two-phase-solvent systems (e.g. consisting of ethylene or propylene carbonate and a hydrocarbon like heptane) was found to yield excellent results, even with ‘‘traditional’’ catalysts like ZnCl2/HCl [136]. For going towards the same direction, also heterogeneous acids like zeolites [137], silica- or alumina-based systems [138], ion exchange resins [134,139], Nafion [140] or micro-encapsulated catalysts [141] were used as substitutes for mineral acids. New developments of modern catalysts include the work on the combined use of boric and oxalic (tartaric, citric) acid [142], and the application of various new types of efficient Friedel–Crafts mediators in truly catalytic amounts, i.e. below 1 mol%. Examples of such catalysts are rare earth metal triflates, e.g. Sc(OTf)3 [143,144], heteropolytungsten acids [145],

Scheme 28. First industrial synthesis of Vitamin K1.

67

polyfluorinated compounds of type 73 [146,147] and 74 [148], or their metal salts, and tris(oxalato)phosphorus acid 75 [149] (Scheme 27). Remarkable features of these systems are not only the high chemical yield, but in particular the extremely high selectivity of the overall condensation reaction of trimethylhydroquinone (9) with (all-rac)isophytol (10): The formation of isomeric products, e.g. benzofuran compounds [143], is considerably reduced, thus facilitating the purification of the final product. K-vitamins play an important role in control of blood clotting [150]. In the synthesis of the most important representative of this group, Vitamin K1 (80, Scheme 28), serious selectivity problems were encountered in the alkylation key-step: When starting from menadiol (39, prepared from 2-methylnaphthaline (37), cf. Section 3, Scheme 13), partial cyclization to phyllochromanol 76 occurred, in analogy to Vitamin E synthesis (cf. Scheme 26). In addition, the regioisomeric product 77 alkylated in 2position was obtained in considerable amounts. A practical solution to this problem was found by research groups at Roche and Merck by using monoacylated starting materials [151,152]. The monobenzoate 78 [152] could be alkylated with less than 1 mol equivalent of isophytol (10) in satisfactory yield to deliver the crystalline dihydro-Vitamin K1 derivative 79. BF3OEt2 was found to act as a good catalyst [153]. Based on these findings, an industrial process was implemented, and synthetic Vitamin K1 (80) was introduced by Roche in 1953 under the brandname Konakion1. For the preparation of semi-synthetic (RRR)-a-tocopherol (RRR-1) from natural sources, a procedure for catalytic aromatic methylation was developed. The application of RRR-1 is restricted to the pharmaceutical, food, and cosmetics industry. The most important natural sources of Vitamin E are plant oil and fats. Various processes for isolation/purification of tocopherols are described. The amount of a-tocopherol (compound with highest Vitamin E activity) in the mixture of tocopherols isolated from soybean oil is low [9,131]. Hence, there is a need for the synthesis of a-tocopherol (RRR-1) from non-a-tocopherols (RRR-2 to RRR-4). In existing processes for the synthesis of a-tocopherol from non-a-tocopherols, e.g. halo-, hydroxy-, and aminomethylation, and subsequent reductive cleavage, disadvantages are met due to the production of waste or handling of corrosive materials like HCl, ZnCl2, SnCl2, PCl5, POCl3, etc. The reduction step is usually performed by catalytic hydrogenation or with Zn-dust/HCl [133,154]. The per-methylation of non-a-tocopherols to a-tocopherol under sc- or near-sc conditions, at a pressure of 50–120 bar and a temperature of 513–623 K using methanol (or CO and H2, with or without containing H2O) and an unpolar organic co-solvent like hexane or toluene, has the advantages of high yield and reduced waste problems [155] (Scheme 29). The reaction is catalyzed by hydrotalcite catalysts, for example Mg6Al2(OH)16CO34H2O.

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Scheme 29. Methylation of non-a-tocopherols to a-tocopherol [155].

10. Cycloaddition Diels–Alder reactions are used in several industrial processes. One application concerns the preparation of Vitamin B6 (pyridoxine, 85), which is essential as a coenzyme in several enzymatic reactions, e.g. transamination and decarboxylation reactions [156]. For the production of Vitamin B6 (85) the reaction of an oxazole 81 with a dioxepin derivative 82 and reaction times of several hours at 388–453 K results, after aromatization and deprotection, in pyridoxine (85, Scheme 30) in a overall yield of >90% (recovery of the protecting reagent isobutyraldehyde). The aromatization reaction is acid catalyzed [157]. 4-Methyl-5cyano-oxazole (44) or 5-ethoxy-4-methyl-oxazole (82) has also been used as diene components [42,158]. Another precursor is 5-ethoxy-4-methyl-oxazole-2-carboxylic acid (83) [157], which is decarboxylated during the Diels–Alder reaction. The diene compounds can be synthesized from diketene or an acid, e.g. propionic acid, alanine or aspartic acid. The dienophile 84, e.g. an isopropylidenedioxepin derivative, can be produced from 2-butene-1,4-diol and isobutyraldehyde [42]. An alternative pathway to Vitamin B6, based on the cobalt-catalyzed [2 + 2 + 2]-cycloaddition reaction of acetonitrile with a,v-diine derivatives (especially ethers, Scheme 31) yielded Vitamin B6 in less than 10% [159,160]. Problems of this route are the transformation of a

Scheme 30. Diels–Alder reaction in the synthesis of pyridoxine.

trimethylsilyl ether group into an aromatic OH-group, and formation of carbocyles as by-products. A new approach for the synthesis of pyridoxine intermediates carried out under irradiation (300–800 nm) uses XCoL1,2 catalysts (X = phenylborino, indenyl, etc., L = ethene, CO, etc.) [161]. Advantages of this efficient method are the selectivity and high yield of heterocyclic product, and mild reaction conditions.

11. Esterification In general, esterification is one of the most important reactions in organic chemistry. The esterification of alcohols, used for the protection of hydroxyl groups, is usually carried out by treatment with acid anhydrides or chlorides in the presence of amines, Lewis acids, Brønsted acids or solid acids [162]. The development of protocols to perform this type of reaction in an efficient manner is an ongoing topic of actual research [163,164]. Recently, it was found that Bi(OTf)3 is a more powerful catalyst than Sc(OTf)3 for the esterification of alcohols [165]. Disadvantages of many procedures are the formation of waste (e.g. chloride, salts), the necessity to use the esterification agent in excess, and in some cases the handling with amines. In recent papers the acetylation of alcohols using Hf-catalysts, e.g. HfCl4, is described [166]. Under those conditions, acetylation of phenols, compared to alcohols, proceeds slowly (<1%, toluene, reflux, 6 h). Methide-salt based catalysts, e.g. Yb(C(SO2C8F17)3)3, or Sc(C(SO2C8F17)3)3, were used for the acetylation of cyclohexanol under fluorous-phases conditions (yield 95%) [167]. As outlined in Section 9, tocopheryl acetate (72) is the major sales form of Vitamin E. The acetylation of tocopherol can be carried out in presence of various types of acid or base catalysts (e.g. sulfuric acid, pyridine) [168,169]. Several processes based on these methods are carried out discontinuously or continuously [170]. A recently described method is based on a catalyst-free acetylation reaction under microwave irradiation [171]. The continuous reaction can be carried out in various reactor types, e.g. in a contercurrent

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69

Scheme 31. Co-catalyzed [2 + 2 + 2]-cycloaddition reaction.

column or a plug-flow reactor. An example for a continuous production set-up is shown in Scheme 32. Advantages of these procedures are the high efficiency (low waste formation) and easy work-up.

12. Enzymatic reactions Enzymes may be simply considered as a special group of catalysts for chemical transformations designed by nature. They are preferentially used for the preparation of stereochemically demanding products like high-value pharmaceuticals or natural products possessing complex structures [172]. There are, however, also cases in which enzymatic transformations exhibit competitive advantages over classical chemical procedures, even for the production of racemic or achiral low-cost fine chemicals like vitamins. High selectivity, avoidance of toxic reagents, and applic-

ability of a continuous mode under mild reaction conditions are key-factors for the development of such superior processes [173–176]. Lipases accepting a broad range of substrates are particularly useful for catalysis of transesterification reactions [177,178] on a technical scale. In the following paragraphs, selected examples for the application of isolated enzyme preparations will be given. (all-rac)-a-Tocopheryl acetate (72), the major application form of Vitamin E in feed and food industry, is obtained by acetylation of phenol 1 (Scheme 26). An attractive alternative route starts from diacetate 71, which is accessible from cheap a-isophorone (40, cf. Section 5, Scheme 33). In order to obtain acetate 72 by the direct condensation reaction with isophytol (10), trimethylhydroquinone-1-monoacetate 87 is needed. While the preparation of 87 is difficult to achieve by classical chemical methods, enzymatic hydrolysis was the method of choice. Mono-saponification of trimethylhydroquinone diacetate 71 with Thermomyces

Scheme 32. Continuous production of tocopheryl acetate.

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Scheme 33. Synthesis of ketoisophorone.

Scheme 34. Vitamin A acetate synthesis via enzymatically prepared monoester 89.

lanoginosus lipase, a particularly cheap enzyme used in laundry industry, proceeds with complete regioselectivity. Neither monoacetate isomer 86 nor hydroquinone 9 (the product of total hydrolysis) was detected [179,180]. Another considerably improvement of a current process is sketched in Scheme 34. Vitamin A is involved in vision (eye, as dialdehyde), and in the epithelium for cell differentiation [181]. In a Roche Vitamin A synthesis, (all-E)-retinyl acetate (90) [182] is obtained from intermediate diol 88 via partial acetylation (delivering generally mixtures of mono- and diacetylated compounds) and subsequent dehydration/isomerization. Yields in the last step are, however, considerably higher when pure monoacetate 89 is used. The highly regioselective monoacetylation of the primary–secondary diol 88 by immobilized Chirazyme L-2 delivered monoacetate 89 with >99% conversion rate and >97% selectivity for the primary hydroxy group. Continuous operation on miniplant-scale

Scheme 35. Lipase-catalyzed resolution of pantolactone.

using vinyl acetate and a fixed-bed reactor yielded 1.6 kg monoacetate 89 per day [183,184]. Stereoselective syntheses of (R)-pantolactone (R-15) were realized by enantioselective hydrogenation of 2oxopantolactone (17, cf. Scheme 7, Section 2), or oxynitrilase-catalyzed addition of HCN to b-substituted pivalaldehydes [185–187]. Another route uses the resolution of racemic starting material [30,185,188]. The lipasecatalyzed kinetic resolution of racemic pantolactone (RS-15, Scheme 7) works well, but suffers from the number of additional operations necessary for separation and recycling of the other enantiomer (extraction, saponification of acetate 91, and racemization) [179] (Scheme 35).

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