Enol Ether Condensations

Hoffmaim-La Roche has produced -carotene since the 1950s and has rehed on core knowledge of vitamin A chemistry for the synthesis of this target. In this approach, a five-carbon homologation of vitamin A aldehyde (19) is accompHshed by successive acetalizations and enol ether condensations to prepare the aldehyde (46). Metal acetyUde coupling with two molecules of aldehyde (46) completes constmction of the C q carbon framework. Selective reduction of the internal triple bond of (47) is followed by dehydration and thermal isomerization to yield -carotene (21) (Fig. 10). 

Allylation andaldol reaction. Diallylstannane and silyl enol ethers condense with carbonyl compounds to furnish homoallylic alcohols and p-hydroxy ketones, respectively. A mixture of HjO, EtOH, and toluene is a suitable reaction medium as CufOTflj is stable in water. 

Preparation of enol ethers. Condensation of a 3-keto-5o -steroid (1) with triethyl orthoformate in ethanol containing a trace of hydrogen chloride affords the diethyl ketal (2) in good yield when refluxed in xylene the ketal loses a molecule of ethanol and affords the A -enol ether (3). A A -3-ketosteroid (4) when condensed with... 

Since carotenoid synthesis began, the enol ether condensation has frequently been used for the formation of carbon-carbon double bonds and this reaction was also applied for large-scale industrial production of carotenoids. The reaction is an addition of an enol ether 12 to an acetal 13, promoted by a Lewis acid, especially BFa-etherate or ZnCl2, and involves a chain lengthening of two or more carbon atoms to yield an intermediary 3-alkoxyacetal 14 which subsequently is converted into an unsaturated aldehyde 15 (Scheme 3). 

The reaction mechanism and the application of the enol ether condensation in the synthesis of carotenoids have recently been reviewed [38]. The main advantage of the enol ether condensation, compared with the aldol condensation, is that the enol ether reacts exclusively as the nucleophilic reaction partner and the acetal exclusively as the electrophilic one and this leads unequivocally to the desired, uniform, reaction product. As the alkoxy group of the starting acetal takes part in the formation of the new acetal grouping that results from the enol ether moiety, it is preferable for all the alkoxy groups of both reactant to be identical. Most of the examples published have been carried out with vinyl methyl ether (16) and vinyl ethyl ether (17), used to extend the carbon skeleton by two carbon atoms, or propenyl ethyl ether (18) and 1-methoxy-1-methylethene (19) for the extension by three carbon atoms (Figure 5). 

A modification of the enol ether condensation is based on the observation that trimethylsilyl enol ethers 20 react readily with acetals 21 at very low temperatures in the presence of Lewis acids to give alkoxyaldehydes 22 with much higher reaction rates compared to the alkyl enol ethers Scheme 4). 

The commercial apo-p-carotenoids ethyl 8 -apo-p-caroten-8 -oate (286) and 8 -apo-p-caroten-8 -al (287) may be prepared from the Cig-aldehyde 53, used in the synthesis of p,p-carotene (2). By reaction of 53 with the Cg-acetal 288 the C25-aldehyde 15,15 -didehydro-12 -apo-p-caroten-12 -al (289) is obtained [115], This compound can be transformed into the Cso-aldehyde 287 by consecutive enol ether condensations first with vinyl ethyl ether (17), to give the C2/-aldehyde 290, and then with prop-1-enyl ether (18), followed by partial hydrogenation and isomerization [116] Scheme 59... 

The importance of the enol ether condensation for the synthesis of polyenes and carotenoids is evident from the variety of reactions shown in Tables 1 (examples 13 to 15 and 19 and Table 2 examples 12 and 21). This reaction has also found use in large-scale production, for example in the technical synthesis of p,p-carotene (3) and 8 -apo-p-caroten-8 -al (482) (see Chapter 3 Part VII). 

In the past two decades, investigations of the enol ether condensation have concentrated almost exclusively upon this alternative, the history and development of which were rather different from those of the alkyl enol ether method. Whereas the work in the field of alkyl enol ethers concentrated mostly on the C2- and Ca-building blocks 77-75, with which significant results were achieved particularly in the chemistry of polyenes and carotenoids, the C.<5-reagents 75 and 16 were applied less frequently, because of the problem of side... 

The conversion of 6-alkoxy-a,p-unsaturated aldehydes into polyenes is performed under acidic conditions identical to those used for the elimination and hydrolysis reactions of alkoxy acetals prepared by alkyl enol ether condensations the yields and diverse reaction conditions have been compared [45]. Elimination under basic conditions, in the presence of DBU or DBN (l,5-diazabicyclo[4.3.0]non-5-ene) and a molecular sieve, was found to be superior to the above methods [45]. 

Examples of carbon chain lengthening by enol ether condensation are summarized in Tables 1 to 4. As interesting and useful results have also been achieved in another connection, the choice of reactions listed has not been limited strictly to the chemistry of polyenes and carotenoids. The reactions in the Tables are listed according to the increasing number of carbon atoms of the target compound. 

The aldol condensation is a very attractive route to a,p-unsaturated carbonyl compounds. The application of this reaction is nevertheless rather limited, since numerous side reactions usually occur amongst these are self-condensation of the ketone, Michael-type addition to the newly formed product, or Cannizzaro reactions. As a consequence, poor yields are obtained in most cases [90]. In the enol ether condensation, described earlier, these side reactions are less troublesome. A disadvantage of the enol ether condensation compared to the aldol condensation is that strongly acidic conditions have to be used to cleave the intermediate in the enol ether synthesis. 

Table 1. Alkyl enol ether condensation (chain lengthening by C2, products as mixed f /Z)-isomers)... 

An alternative route starts from furan (19). Reaction with bromine in methanol leads to 2,5-dimethoxy-2,5-dihydrofuran (20) which is transformed to but-2-ene-1,4-dial bisdimethyl-acetal (21). Double enol ether condensation with 1-propenyl methyl ether (22), followed by acetal hydrolysis and elimination, provides crystalline (all- -Cio-dialdehyde 8 in an overall yield >50% [13]. 

The first industrial synthesis of P,P-carotene (3) by Roche [1] followed the C19 + C2 + C19 synthesis principle [1,20]. As in the vitamin A process, the polyene chain was produced by Grignard coupling, elimination and partial hydrogenation. In addition, a new effective synthesis for polyene aldehydes has now been developed in the form of the enol ether condensation and employed industrially for the first time in the production of the C19-aldehyde 27 (Scheme 6). The enol ether condensation permits specific stepwise lengthening of conjugated aldehydes by two carbon atoms each time. Use of prop-l-enyl ethyl ether (28) (Scheme 9) gives a-methyl-branched polyene aldehydes. Chemically, the chain lengthening proceeds in three steps as follows ... 

Scheme 5 shows the enol ether condensation as exemplified by the reaction of 23 to give the C 16-aldehyde 29. Acetylation of 23 gives 30, which reacts with vinyl ethyl ether 31 to 32, and after hydrolysis and elimination 29 is obtained. Similarly, 29 and prop-l-enyl ethyl ether (28) give the C 19-aldehyde 27 (see Chapter 2 Part I). 

The commercial apo-(i-carotenoids 1 and 482 may also be prepared from the C 19-aldehyde 27. A particularly important intermediate in this synthesis is 15,15 -didehydro-12 -apo- 3-caroten-12 -al (36)[2 ]. As 1,6-branched polyene chains cannot be synthesized by the enol ether condensation, the Ce-acetal 37 is prepared for the chain lengthening from 27 to 36. 

The methylmalondialdehyde acetal (38) obtained by enol ether condensation of prop-l-enyl ethyl ether (28) and triethyl orthoformate (39) is partially hydrolysed to form 2-methyl-3-ethoxypropenal (40). Reaction of 40 with sodium acetylide (41) gives 42 and acetal formation with triethyl orthoformate (39) gives 37 in an overall yield of approximately 50% (Scheme 7). 

The three-step enol ether condensation is again used in the chain lengthening of 36 (Scheme 9) [22]. Coupling to vinyl ethyl ether (31) leads to the C27-aldehyde 44. Repetition of the reaction sequence with prop-l-enyl ethyl ether (28) yields the corresponding C30-aldehyde. After partial hydrogenation and thermal isomerization in petroleum ether, 8 -apo-P-caroten-8 -al (482) is obtained in a yield of approximately 50% based on 27. The conversion of 44 into ethyl 8 -apo-p-caroten-8 -oate (7) is described in Section C. 

The synthesis of 1 from the C 14-aldehyde 23 requires twenty reaction steps, including the preparation of the C6-acetal 37, and the formation of seven C-C bonds. Nevertheless, the process is economic because of the chemical and technological integration of the manufacturing process. Construction of the polyene chain, for example, only requires the simple chemicals acetylene, triethyl orthoformate, propenyl ethyl ether and vinyl ethyl ether. Five C-C bonds are formed with the aid of the enol ether condensation. This repetition of simple operations simplifies the process and allows even multistep syntheses to be carried out cost-effectively. 

As an example to the enol ether condensation, the synthesis of Cio-dialdehyde (12,12-diapocarotene-12,12 -dial) (4) was chosen because this compound is not available commercially, but is a building block of major importance in carotenoid synthesis (Chapter 3 Part I). The procedure described is based on previously published work [1-3] (Scheme 1). 

Universal methods for coupling of the synthetic building blocks are the Wittig reaction, the Horner-Wadsworth-Emmons reaction, the sulfone coupling by Julia s procedure, the enol ether condensation (Miiller-Cunradi-Pieroh reaction), and the Saucy-Marbet rearrangement. Since in very many cases mixtures... 

Alternatively, furan may also be brominated and then subjected to an exhaustive methanolysis. A zinc chloride-catalysed double enol ether condensation with 1-propenyl methyl ether (Miiller-Cunradi-Pieroh reaction) gives finally the crystaUine (aU )-Cio-dialdehyde in an overall yield of >50 %. 

Self-condensation of glyceraldehyde has been observed at 40°C in the presence of sodium-exchanged montmorillonite to give a mixture of C5 and Ce monosaccharides in yields of up to 90% [86]. Acetals and enol ethers condense under mild conditions in the presence of KIO clay and this is a useful approach to unsaturated carbonyl compounds (e.g. equation 4.15) [87]. 

Silyl enol esters result from silyl-substituted ally alcohols (using RLi derivatives), from a-haloketones, enolizable aldehydes or ketones (using Nal/Mes-SiCl), from dialdehydes and (MesSi)2NH, and from anions of thioesters e.g.y Bu C=C(OSiMe3)SPh]. /3-Seleno- and /S-thiosilyl enol ethers are formed from the enone on reaction with RSH-MeaSiCl-CgHsN. On storing for long periods, silyl enol ethers condense to symmetric ketones, so should be redistilled before use. ... 

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