Wittig coupling synthesis

Ley, S.V., Lygo, B., Organ, H.M., and Wonnacott, A., Wittig and Homer-Wittig coupling reactions of 2-substituted cyclic ethers and their application to spiroketal synthesis, Tetrahedron, 41, 3825, 1985. 

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

Cyclopropanone ethyl hemiketal (167) has also been used in the synthesis of cyclopropanespiro-2-bis-norpenicillanic acidsnovel analogs of the natural penicillins. In this case, the use of cyclopropanone in a Wittig coupling reaction was nicely illustrated. The intermediate (168) was generated in this process and then carried on to the )8-lactam derivative as illustrated in Scheme 62. 

Numerous monographs [4] and reviews [5] on the famous Wittig reaction have been written since its discovery in 1953. The BASF vitamin-A synthesis depends in the final step on a Wittig coupling between vinyl-)ff-ionol (C15) and y-formyl-crotyl acetate (C5). This application was developed by Pommer et al. [6] of BASF in the 1960s. 

Smith III and coworkers [123] have achieved the total synthesis of 141 through union of northern and southern hemispheres (A and B) via Horner-Wittig coupling followed by macrocyclic lactonisation to form the desired product. 

The first total synthesis of altohyrtin C (spongistatin 2 4b) was accomplished via diastereoselective aldol coupling of the C1-C15 AB and C16-C28 CD segments, Wittig coupling of the ABCD and the C29-C43 EF segments, addition of the C44-C51 side chain to the fully elaborated ABCDEF system, and the regiose-lective macrolactonization (Fig. 8). 

The first total synthesis of (+)-altohyrtin A (spongistatin T, 4a) by Kishi et al. was accomplished via Wittig coupling of the C1-C28 ABCD and C29-C51 EF... 

A novel two carbon analog of 8, namely the 7-methyl-6(Z)-octadecenoic acid was recently identified in the holothurian Holothuria mexicana [27]. However, both Z and E stereoisomers were later shown to originate from the bacterium Vibrio alginolyticus [27]. Therefore, the real source of 7-methyl-6-octadecenoic acid is also bacterial. Both Z and E isomers of 7-methyl-6-octadecenoic acid were synthesized as shown in Fig. (9). In this short synthesis (little more than one step) a Wittig coupling of (6-carboxyhexyl)triphenylphosphonium bromide with 2-tridecanone readily afforded a 1 1 mixture of 7-methyl-6(Z)-octadecenoic... 

The synthesis of (5Z,9Z)-24-methylpentacosa-5,9-dienoic acid (15) was also reported in the same communication [52], and it started with commercially available 10-bromodecan-l-ol that was oxidized with PCC to 10-bromodecanal, followed by Wittig coupling with 4-methyl-1-pentyltriphenylphosphonium bromide resulting in the (Z)- and ( )-l-bromo-14-methylpentadec-10-ene, as shown in Fig. (18). Catalytic... 

BASF is a major producer of vitamin A, a carotenoid which is found naturally in various foods and is important for vision and for tissue growth and differentiation. Carotenoid derivatives have also been used as pharmaceuticals and as colorants for a wide variety of foods. The synthesis of vitamin A by BASF involves the Wittig coupling of an ylide and aldehyde to form the desired vitamin A product (Scheme 6.3) [34], and BASF explored variations of the Semmelhack catalyst system for the oxidation of carotenoid precursors [35]. The high copper and TEMPO loading originally reported by Semmelhack (10 mol%) were lowered to make the process more suitable for industrial scale, while mild temperatures, bubbling O2, and the use of DMF as a solvent were maintained in the modified procedure... 

Synthesis of diaryl heteroarotinoids (11) and (12) [27,30,31] began with a Lewis acid-catalyzed cyclization of tertiary alcohol (34) to give dihydroben-zothiophene (36) as the sole isolated product. The chemistry of the ensuing steps was similar to that used to prepare (9) and (10) and other diaryl heteroarotinoids and involved (a) Friedel-Crafts acylation of a fused aromatic-heterocyclic system, (b) reduction of the resulting ketone to a benzylic carbinol, (c) phosponium salt formation, and finally (d), Wittig coupling to methyl 4-formylbenzoate. The free acids (13) and (14) were obtained by saponification. 

The 13-cw-analogue (56) of (6), was prepared from known [67] phosphonium salt (62) and 4-hydroxy-3-methylbut-3-enolide [77] as indicated in Scheme 1.5. The synthesis of (57), containing a terminal cyclopropyl ring, was effected by Wittig coupling of the ylide from salt (62) with ethyl ( )- 8-formylcyclopropylcarboxylate [78]. 

The strategy for the synthesis of functionalised epoxides involved the oxidation of ( )-olefinic precursors resulting from the Wittig coupling of aldehydes 287 with the appropriate phosphoranes [125]. The treatment of the phosphonium salt 295 [158], a synthetic equivalent of the p-propionate unit, with n-butyllith-ium gave the corresponding ylide which was reacted in situ with aldehydes 287 (Scheme 89). The Wittig reaction was stereoselective in favour of the desired trans olefin 296 (E Z = 9 1). A conventional two step procedure [158] allowed the formation of carboxylic acids 297 from trimethylsilylalkyne precursors. The oxidation step led to intractable mixtures. Apparently the epoxides 298 were unstable under these conditions. 

The total synthesis of 5(5)-hydroxy-12-oxo-20 3(6Z,8.E,14Z) involving Wittig coupling reactions of tailored intermediates was described (38). 10(5)-Hydroxy-20 4(5Z,8Z,11Z,14Z) was synthesized in eight steps starting from enantiomerically pure (7 )-glyceraldehyde acetonide (39). Chiral adducts from Grignard or allylsilane... 

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