Conjugated trienes, synthesis

Leukotriene B4, formed by enzymic hydrolysis of LTA4, is chemotactic for macrophages and neutrophils at concentrations as low as 1 ng/ml. The stereochemistry of the conjugated triene subunit was established by synthesis which also made LTB4 available in quantity for biological research. 

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

The first example of successful diene-diene RCM to construct a macrocyclic conjugated triene was disclosed by Wang and Porco in the first total synthesis of oximidine II (258) [121]. Oximidine II belongs to the family of salicylate en-... 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

Cross-conjugated trienes have attracted interest in polymer chemistry and theoretical chemistry as well as in synthetic chemistry.11 Although a palladium complex catalyzed 1,2-propadiene dimerization in the presence of water or an amine produced hydroxylated or aminated 2,3-dimethyl-2,3-butadiene,12 the method was not applied to the synthesis of cross-conjugated trienes. Another interesting feature... 

The synthesis of dihydrocostunolide (11) involves a light-induced rearrangement of the conjugated cyclohexadiene (9) to its isomer, the conjugated triene (10). ... 

In the course of their synthesis of Vitamin B12, R. B. Woodward and co-workers were puzzled by the failure of certain cyclic products to form from apparently appropriate starting materials—in particular, the stereochemistry of interconversions of cyclohexadienes with conjugated trienes in thermal and photochemical reactions. Woodward, in collaboration with Roald Hoffmann (ca. 1965), discovered that the course of such reactions depended on identifiable symmetries of the participating molecular orbitals. The principle of conservation of orbital symmetry can be stated thus ... 

Hydroboration of enynes provides 1,3-alkadienylboron derivatives. The coupling of dienylboron compounds with haloalkenes allows a short-step synthesis of conjugated trienes such as the synthesis of leukotriene B4 shown in Scheme 2-31 [88, 89]. 

Tricarbonyliron complexes of conjugated trienes react with diazoalkanes at the free (uncom-plexed) double bond. In the synthesis of dimethyl 2-formylcyclopropane-l, 1-dicarboxylate (48), the ceric ion served the double function of catalyzing the deazetization and removing the tricarbonyl iron protecting group. When the optically active iron carbonyl complex was used, the addition of diazomethane gave selectively one diastereomer and this was used to make optically active dimethyl 2-formylcyclopropane-l,1-dicarboxylate (>90% ee). A similar route was employed to make the optically active formyl cyclopropanes 49, precursors to optically active cis- and tran.v-chrysanthemic acids. 

For obtaining rearranged conjugated trienes 52a-e and 53a-e on a preparative scale, the reaction mixture from the synthesis in 1 -(2, 6, 6 -trimelhyl-1 -cyclohexen-l -yl)-3-(phenylsulfinyl)-1,2-alkadienes 51a-c (200-300 mg) (both diastereomers of the vinylallene sulfoxides) after Et20 workup is allowed to stand in Et20 (15-20 mL) at r.t. for > lOh. The residue after removal of solvent is subjected to 1IPLC purification (Whatman Partisil M 9 10/50 column, 10-20% ElOAc/Skellysolve B) to afford the two conjugated trienes. From 51a yield 63% ratio (53a/52a) 81 19 from 51 b yield 91 % ratio (53b/52b) 92 8 from 51c yield 75% ratio (53c/52c) 92 8 from 51 d yield 80% ratio (53d/52d) 94 6 from 51e yield 58% ratio (53d/52d) >98 2,... 

Oxidation of primary allylic alcohols. In the synthesis of several isomeric phytoenes (C40-conjugated trienes), Weedon et al. used Fetizon s reagent for oxidation of primary allylic alcohols to allylic aldehydes. Yields of >85% were reported. Use of manganese dioxide led to much lower yields (40-50%). 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone also gave high yields, but mixtures of stereoisomers were obtained. 

Wise ML, Soderstrom K, Murray TF, and Gerwick WH (1996) Synthesis and cannabinoid receptor binding activity of conjugated triene anandamide, a novel eicosanoid. Experientia 52 88-92. 

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