S -Zearalenone

Coupling of aryl halides with alkenyl stannanes promoted through palladium metal catalysis, otherwise known as the Stille coupling, has many applications, including solid-phase variants (see Chapter 2). One of these is featured in Nicolaou and co-workers solid-phase synthesis of (5)-zearalenone wherein a resin-bound alkenylstannane undergoes a Stille cycli- 

The synthesis of (S)-zearalenone began with creation of the chlo-rodibutylstannyl polystyrene resin 32, which ultimately would serve as a Stille coupling partner. Oxidation of chloromethyl polystyrene resin fol- 

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An intramolecular palladium(o)-catalyzed cross-coupling of an aryl iodide with a trans vinylstannane is the penultimate maneuver in the Stille-Hegedus total synthesis of (S)-zearalenone (142) (see Scheme 38).59 In the event, exposure of compound 140 to Pd(PPh3)4 catalyst on a 20% cross-linked polystyrene support in refluxing toluene brings about the desired macrocyclization, affording the 14-membered macrolide 141 in 54% yield. Acid-induced hydrolysis of the two methoxyethoxymethyl (MEM) ethers completes the total synthesis of 142. 

Stannane based Hnkers (Tab. 3.8) are used for the StiUe reaction (see below, section 3.3.2.1) onsoHd supports [119]. Nicolaouetal. developed polymer-bound aUcenylstan-nanes to obtain the natural product (S)-zearalenone by an intramolecular StiUe reaction and a cyclative cleavage [120]. 

Grignard reaction and similar transformations allow C-C bond formation without a palladium catalyst. Grignard reagents and organolithium compounds are very versatile carbanion sources used in the synthesis of acyclic, heterocychc and carbo-cychc compounds. The esters, ketones and aldehydes are more stable when the reaction takes place on solid supports than in the hquid-phase, because this immo-bihzed components are not so sensitive towards water or oxygen. In the total synthesis of (S)-zearalenone (155) on solid supports the Grignard reaction is one of the key steps (Scheme 3.16) [120]. 

Scheme 3.16 Grignard key step for the synthesis of (S)-zearalenone (155) by Nicolaou et al. [120].

Nicolaou, K. C. Winssinger, N. Pastor, J. Murphy, F. Solid-Phase Synthesis of Macrocyclic Systems by a Cyclorelease Strategy Application of the Stille Coupling to a Synthesis of (.S )-Zearalenone, Angew. Chem. Int. Ed. Eng. 1998, 37, 2534. 

In the synthesis of (S)-zearalenone and of a chiral spiroac-etal, (2S,6/ )-2-methyl-l,7-dioxaspiro[5.6]dodecane, the starting product was a functionalized 3-keto sulfoxide resulting from the reaction of glutaric anhydride with lithiated (+)-(7 )-methyl p-tolyl sulfoxide (eq 6). 

Furstner, A., Thiel, O. R., Kindler, N., Bartkowska, B. Total Syntheses of (S)-(-)-Zearalenone and Lasiodiplodin Reveal Superior Metathesis Activity of Ruthenium Carbene Complexes with lmidazol-2-ylidene Ligands. J. Org. Chem. 2000, 65, 7990-7995. 

The solid-phase total synthesis of (S)-zearalenone by Nicolaou et al. (372) started with the preparation of the resins 488 and 489 from the Merrifield resin (486, Scheme 9.1). Oxidation, followed by olefination of the resulting aldehyde, gave a polystyrene vinyl resin (487), which was converted into dibutyltin chloride 488. In this process, the stannylation reagent n-Bu2SnHCl was formed in situ from -Bu2SnCl2 and n-Bu2SnH2. Reduction of 488 yielded the polymer supported tin hydride 489. 

In 2008, Barrett et al. reported on a biomimetic synthesis of (,S)-zearalenone involving a late-stage aromatization (373). They started with the synthesis of the two building blocks 505 and 509 (Scheme 9.4). The enantiopure alcohol 505 was prepared in five steps from ( )-5-hexanolide (502) by applying a Upase-mediated strategy. Dioxinone 509 was synthesized using a vinylogous Mukaiyama aldol reaction to link aldehyde 506 with olefin 507. 

Kalivretenos K, Stille JK, Hegedus LS (1991) Synthesis of p-Resorcylic Macrolides via Organopalladium Chemistry. Application to the Total Synthesis of (S)-Zearalenone. J Org... 

Franzen [56] has reviewed advances in the Suzuki, Heck, and Stille reactions in solid-state organic synthesis. There are basically two ways of adapting the Stille reaction to solid-state conditions. Either the organotin moiety or the organic residue can be attached to a solid support Nicolaou et al. [57] reported a very elegant intramolecular reaction of a polystyrene-supported vinyltin spedes bearing a terminal vinyl iodide moiety to give a 1,3-diene (Scheme 6.16) this reaction formed part of a synthesis of the natural product (S)-zearalenone. 

Scheme 6.42. Synthesis of (S)-zearalenone (177) via a solid-supported Stille cyclizative cieavage. NCS = A/-chiorosuccinimide MEM = methoxyethoxymethyl ether DEAD = diethyl azodicarboxyiate.

Barrett s group [59b] exploited the intramolecular ketene trapping-transaimular aromatization sequence firstly developed for (S)-zearalenone (Scheme 7.5) to prepare LL-Z1640-2 starting from 2-deoxy-D-ribose. Thomas and collaborators... 

Furstner A, Thiel OR, Kindler N et al (2000) Total syntheses of (s)-(-)-zearalenone and lasiodiplodin reveal superior metathesis activity of ruthenium carbene complexes with imidazol-2-ylidene ligands. J Org Chem 65 7990-7995... 

Solid Phase chemistry has also been used to help solving this problem by immobilizing one of the partners (organic electrophile or organostannane) on the solid support to help purification. An example of this approach is found in Nicolaou s total synthesis of (S)-zearalenone (43 — 44). 

S)-Zearalenone 281 Resin-bound chiral iodide 279 and Pd(PPh3)4 (0.10 equiv) were dissolved in toluene and heated at 100 C for 48 hours to promote cyclo-release and provide protected zearalenone 280 in 54% yield. Zearalenone 280 was then treated with 2 1 THF/HCl aq. (5%) at room temperature for 5 days to provide (5)-zearalenone 281, as a single isomer, in 80% yield. 

Another palladium-catalysed process that has proven utility for cyclic structures is the Stille coupling between organostannanes and aiyl or vinyl halides/triflates. Specifically for the macrocyclic framework, this chemistry was applied to the preparation of cyclic trienes (102) with defined geometry (Scheme 11.11) that were intermediates for transannular Diels-Alder reactions. The intramolecular Stille reaction also has been efficiently conducted on solid phase to form 104, an advanced intermediate in the synthesis of (S)-zearalenone, from 103 by a cyclization-release strategy. ... 

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