Horner-Emmons coupling

In each of the coupling reactions, a mixture of ( /Z)-isomers is formed. The product of every step is predominantly the (all- )-form, but with about 20% of the (Z)-isomer. Mixtures of (E/Z)-isomers of the nitriles cannot easily be separated but are reduced with DIBAH and the isomers of the resultant aldehyde separated. The fZ)-isomers can be effectively converted into the f j-isomers by irradiation with visible light in hexane in the presence of a trace of iodine. This procedure is repeated after each Horner-Emmons coupling / DIBAH reduction step. In this way, the product consists mainly (>85%) of the f /Z)-isomer. Repeated crystallization from petroleum ether affords the pure (all- )-spheroidene (97). 

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37], The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Horner-Emmons reaction or a bioisosteric analog of a carboxylic acid [38]. The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RaSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22]. Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23], Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Horner-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

Sulfanylalkanoyl amino acids and peptides are prepared by reaction of the (acetyl-sulfanyl)- or (benzoylsulfanyl)alkanoic acids or acid chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 101114 16 27 29 For example, the 3-(acetylsulfanyl)alkanoic acids 7 are prepared from the condensation of ethyl (diethoxyphosphoryl) acetate 5 with various aldehydes according to the Horner-Emmons reaction, providing the a, 3-unsaturated ethyl esters 6 (a mixture of Z- and E-isomers, 50 50), followed by saponification of the ethyl esters and Michael addition of thiolacetic acid. The 3-(acetylsulfanyl)alkanoic acids 7 can be coupled with a-amino esters or peptide esters and subsequent hydrolysis of the 3-(acetylsulfanyl) derivatives provides the desired products 8 (Scheme 2). 14 ... 

Horner-Emmons reaction of N-terminal blocked aldehyde 1 with sulfonylphosphonates in the presence of sodium hydride gives the amino acid vinyl sulfone 2, which is deprotected with acid and converted into its chloride or tosylate salt 3 and coupled by the mixed anhydride method with an N-terminal protected peptide or amino acid to give the desired peptide vinyl sulfones 4 (Scheme 2). 4 5 N-Terminal protected aldehydes 1 are obtained from reduction of Boc amino acid V-methoxy-A-methylamides (Weinreb amides, see Section 15.1.1) by lithium aluminum hydride. 9 The V-methoxy-V-methylamide derivatives are prepared by reaction of Boc amino acids with N,O-dimethylhydroxylamine hydrochloride in... 

In the Horner-Emmons reaction (Scheme 3), the sulfonylphosphonate carbanion 5 is formed in the presence of NaH and then reacts with an aldehyde to produce the intermediate 6 that undergoes in situ elimination to yield the vinyl sulfones and phosphonate anion. The sulfonyl group can stabilize the anion in the sulfonylphosphonate 5. The vinyl sulfones that are produced by this method using aldehydes as starting materials are exclusively the E (trans) isomers. The E-isomers of the vinyl sulfones are shown in the NMR spectra based on the coupling constants of the vinylic protons. Although strongly basic conditions are used in the Horner-Emmons reaction and a-amino aldehydes are easily racemized, the amino acid vinyl sulfones prepared by this method still show substantial optical activity. However, the enantiomeric purity of these compounds has not been determined. 5 ... 

Numerous synthetic routes have been utilized to prepare isoprenoid analogs. The classical synthetic route to isoprenoids and isoprenoid analogs utilized iterative Horner-Emmons-Witting coupling reactions to generate the trisubstituted double bonds characteristic of linear isoprenoids... 

Jarosz, S. Synthesis of higher carbon sugars via coupling of simple monosaccharides-Wittig, Horner-Emmons, and related methods. Journai of Carbohydrate Chemistry 200, 20, 93-107. 

In another approach to the technical synthesis of the apocarotenoids 286, 287 and 292 [118] the C25-aldehyde 12 -apo-p-caroten-12 -al (293) is the key intermediate. Several ways to synthesize this compound have been developed, applying the Wittig reaction to couple the building blocks. By the reaction of the Cas-aldehyde 293 with the protected Cs-phosphonium salt 294 the Cao-aldehyde is obtained [119,120], and this can be transformed by a base-catalysed aldol condensation with acetone (295) to give the Css-ketone citranaxanthin (292) [121]. Alternatively the C2s-aldehyde 293 can be reacted in a Horner-Emmons reaction with the Cs-phosphonate 296 to give 292 [122] Scheme 61). 

Nicolaou s carbonolide synthesis is also based on the coupling of the C -Cio (172) and C11-C15 (174) segments, and the macrolactonization by the intramolecular Horner-Emmons reaction (Nicolaou method). 

The Cs-phosphonate 39 is prepared by an Horner-Emmons reaction of triethyl-phosphonoacetate (11) with chloroacetone (40) in THE, with NaH or LDA as a base (yield 58%). The chloro product 47 is reacted with triethyl phosphite in an Arbusov reaction which gives, after distillation in vacuo, pure 39 in a yield of 81% [50] (Scheme 13). Similarly, diethyl cyanomethylphosphonate (3) is coupled to chloroacetone (40) in 72% yield and the coupling product 42 is converted into the C5-phosphonate 43 by reaction with triethyl phosphite. The yield after distillation is 89% [50]. 

For the preparation of the phosphonate 44 (Scheme 14), propionitrile is reacted with two equivalents of LDA and one equivalent of diethyl chlorophosphate to give the C3-phosphonate 18 as described in Scheme 6. In an Horner-Emmons reaction, 18 is coupled to chloroacetaldehyde (45) in a yield of 63%. Chloroacetaldehyde (45) is commercially available as a 50% solution in water and has to be isolated by an ether extraction, dried with MgS04 and concentrated before addition in THF to the anion of the phosphonate 18. The C5-chloronitrile 46 is subsequently converted by an Arbusov reaction into the Cs-phosphonate 44, in 95% yield after distillation in vacuo [20]. 

Many syntheses of the Cio-dialdehyde 28 in unlabelled form have been published [48, 52-55]. One of the most useful routes for the preparation of this synthon on a small scale (Scheme 16) is that in which commercially available f )-l,4-dichlorobut-2-ene (48) is converted into the double phosphonate 49 in 81% yield by reacting it in an Arbusov reaction with two equivalents of triethyl phosphite [55]. The dianion of the phosphonate 49 is formed by deprotonation with LDA and is coupled in an Horner-Emmons reaction to pyruvaldehyde dimethylacetal (30). Addition of HMPA almost doubles the yield of this reaction to 46%. Deprotection of the diacetal 50 in acetone yields the Cio-dialdehyde 28 in 99% yield. 

For the linear synthesis of spheroidene (97) [20] that is described in Section B.4, the Cig-ketone 51 is used as starting material. This is prepared (Scheme 17) from commercially available (5jF)-6,10-dimethylundeca-5,9-dien-2-one (geranylacetone) (52). This ketone 52 is coupled in an Horner-Emmons reaction with the commercially available triethyl phosphonocrotonate (53), in the presence of BuLi as base. Yields for this reaction are almost doubled (from 45 to 85%) when HMPA is added. The ester 54 is converted in one step into the Ci8-ketone 51 by addition of an excess of MeLi (55) in the presence of five equivalents of trimethylsilyl chloride at -100°C, giving, after acidic work-up, the all-E" Cig-ketone 51 in 69% yield [20]. 

The reaction of the ester 51 with MeLi (55) in the presence of trimethylsilyl chloride cannot be performed on a large scale in a reproducibly high yield. For the synthesis of the Ci8-ketone 51 on a large scale, an alternative, a three-step route is used (Scheme 18). First the geranylacetone (52J is coupled in an Horner-Emmons reaction with diethyl cyano-methylphosphonate (4) with NaH as a base. Reduction of the nitrile by DEB AH then gives the aldehyde 56 in 73% yield. Aldol condensation of 56 with acetone (57) in the presence of a... 

This C25-aldehyde 82 is elongated to spheroidene (97) by coupling in an Horner-Emmons reaction with the anion of C -phosphonate 44 and subsequent reduction with DIBAH to the Cio-aldehyde 83. This aldehyde can be converted in one step into spheroidene (97) by a Wittig reaction with the Cio-phosphonium salt 58 and BuLi as base. The overall yield, based on acetonitrile in the first coupling reaction, is 32%. 

As has been shown in previous Chapters the Wittig and the Horner-Emmons reactions are of utmost importance for the coupling of carotenoid end groups with the polyene chain. In the following example, the synthesis of the naturally occurring C25-apocarotenal 507 (12 -apo-P-caroten-12 -al, (3-apo-12 -carotenal) and also ethyl 8 -apo-P-caroten-8 -oate (1) (P-apo-8-carotenoic acid ethyl ester), which is produced industrially by means of these reactions, is described. 

The coupling of 77 and 84 was performed via the Julia-Julia olefination [50] to construct the ( )-olefin 85 EjZ => 20) at the C14-C15 bond. This approach is slightly more efficient than that of the Kocienski-Julia protocol in the case of Lee s synthesis. As a macrocyclization, the intramolecular Horner-Emmons reaction was adopted, because macrolactonization of the hydroxy (E, )-dienylcarboxylic acid was difficult. The phosphonate 86, derived from 85, was exposed to K2CO3 and 18-crown-6 [51-53] to provide the macrolactone 87 in good yield. Finally, the side chain was introduced via the Wittig reaction like Lee s method, and the second total synthesis was accomplished. 

---