Polymer-bound dienes

Chemistry on solid support has gained tremendous importance during the last few years, mainly driven by the needs of the pharmaceutical sciences. Due to the robust and tolerable nature of the available catalysts, metathesis was soon recognized as a useful technique in this context. Three conceptually different, RCM-based strategies are outlined in Fig. 11. In the approach delineated in Fig. 1 la, a polymer-bound diene 353 is subjected to RCM. The desired product 354 is formed with concomitant traceless release from the resin. This strategy is very favorable, since only compounds with the correct functionality will be liberated, while unwanted by-products remain attached to the polymer. However, as the catalyst is captured in this process by the matrix (355), a higher catalyst loading will be required, or ancillary alkenes have to be added to liberate the catalyst. 

With polymer-bound diene 356, two different strategies are possible. Following path A, RCM results in the formation of a (volatile) alkene 357a and a... 

The first approach involves RCM of a polymer bound diene 77 and results in the formation of a cyclic product 78 which remains attached to the polymer support. This product can undergo further manipulation, with cleavage from the resin occurring at a later stage. In a second, complementary approach, RCM proceeds with concomitant cleavage of the substrate from the resin (80 81). The latter protocol is highly attractive since only compounds possessing the correct... 

Only recently a selective crossed metathesis between terminal alkenes and terminal alkynes has been described using the same catalyst.6 Allyltrimethylsilane proved to be a suitable alkene component for this reaction. Therefore, the concept of immobilizing terminal olefins onto polymer-supported allylsilane was extended to the binding of terminal alkynes. A series of structurally diverse terminal alkynes was reacted with 1 in the presence of catalytic amounts of Ru.7 The resulting polymer-bound dienes 3 are subject to protodesilylation (1.5% TFA) via a conjugate mechanism resulting in the formation of products of type 6 (Table 13.3). Mixtures of E- and Z-isomers (E/Z = 8 1 -1 1) are formed. The identity of the dominating E-isomer was established by NOE analysis. 

Generation of polymer-bound dienes upon oxidation of a hydroquinone... 

Polymer-bound diene 25 was subjected to a Diels-Alder reaction with tiglic aldehyde 26 in the presence of tetrame-thylsilane (TMS)-triflate for the construction of the bicyclic core structure (Scheme 16.4). Cycloadduct 27 was obtained as a mixture of four isomers that were formed in a ratio of 67 16 16 1 endolendo lexolexo ) with the desired endo isomer predominating. To improve the stereoselectivity, tiglic aldehyde was converted into the quasi-Ca-symmetric chiral acetal 28 derived with (R,R)-2,4-pentanediol. This chiral dienophile underwent an asymmetric Diels-Alder reaction at -78°C. Removal of the chiral auxiliary from the acetal 29 resulted in the cycloadduct 27 as a mixmre of the four isomers in a ratio of 87 4 9 0.1 endolendo lexolexo ), demonstrating that the stereoselectivity of the main isomer increased from 67% to 87%. ... 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a, S-unsaturated aldehydes with several dienes. It has been prepared from (ri -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels-Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

Asymmetric Diels-Alder reactions have also been achieved in the presence of poly(ethylene glycol)-supported chiral imidazohdin-4-one [113] and copper-loaded silica-grafted bis(oxazolines) [114]. Polymer-bound, camphor-based polysiloxane-fixed metal 1,3-diketonates (chirasil-metals) (37) have proven to catalyze the hetero Diels-Alder reaction of benzaldehyde and Danishefsky s diene. Best catalysts were obtained when oxovanadium(lV) and europium(III) where employed as coordinating metals. Despite excellent chemical yields the resulting pyran-4-ones were reported to be formed with only moderate stereoselectivity (Scheme 4.22). The polymeric catalysts are soluble in hexane and could be precipitated by addition of methanol. Interestingly, the polymeric oxovanadium(III)-catalysts invoke opposite enantioselectivities compared with their monomeric counterparts [115]. 

The polymer-bound Mn and Cr complexes were used as catalysts for epoxidations of six phenyl-substituted olefins with m-CPBA/NMO and for dihydropyranone formation from the Danishefsky diene and aldehydes. There are several remarkable features of the novel immobilized salens ... 

Cleavage of polymer-bound allyl esters with palladium catalysts provides general access to 7i-allyl complexes, which can react with a variety of nucleophiles. This has been used in the development of re-allyl-based linkers. Ene-yne cross metathesis and subsequent cleavage in the presence of different nucleophiles yields the corresponding functionalized dienes 93 [93] (Scheme 6.1.19). 

Reactivity With Nitroso Compounds. Functionalization of diene based rubbers with aromatic nitroso compounds bearing aminic or phenolic moieties 174, like with iV,A-diethyl-4-nitrosoaniline, 4-nitrosodiphenylamine, 4-nitrosodiphenylhy-droxylamine or 4-nitrosophenol represents an effective way for the synthesis of polymer-bound antioxidants [233], The respective nitroso compound can be mixed with rubbers during compounding or with concentrated rubber latexes. The chemical attachement of stabilizing active moieties takes place during subsequent... 

Phosphonates have also been prepared from alcohols and (Ar0)2P(=0)Cl, NEts and a TiCl4 catalyst. ° The reaction of (R0)2P(=0)H and aryl iodides with a Cul catalyst leads to aryl phosphonates. " Polymer-bound phosphonate esters have been used for olefination. Dienes are produced when allylic phosphonate esters react with aldehydes. 

Wang, Y., Wilson, S. R. Solid phase synthesis of 2,3-dihydro-4-pyridones reaction of Danishefsky s diene with polymer-bound imines. Tetrahedron Lett. 1997, 38,4021-4024. 

Osmium tetroxide. 13,222-225 236-240 18,265-267 19, 241-2-Chemoselective dihydroxyletm allylic alcohols are preferentially d nonconjugated dienes is favored.-Asymmetric dihydroxylaiiomt. both ends, producing major product Another type of polymer-bound Dl... 

Asymmetric dihydroxylations. a,(0-Dienes undergo asymmetric dihydroxylation at both ends, producing major products which are homochiral at the secondary alcohol sites " Another type of polymer-bound DHQ and DHQD ligands has been developed. ... 

Cycloadditions. Both hetero-Diels-Alder reactions of polymer-bound aldimines with Danishefsky s diene to afford 2-aryl-2,3-dihydro-4-pyridones and 1,3-dipolar cycloadditions of nitrones with a, 3-unsaturated amides are catalyzed by YbfOTflj. Remarkable switch in diastereoselectivity by solvent is observed in the latter reactions. 

I, was oxidized with lead tetraacetate (LTA), the characteristic Diels-Alder adduct with tetracyclone (TC) could be obtained even when the diene was added following completion of N2 evolution, indicating that the polymer-bound intermediate had survived for tens of seconds. Secondly, while LTA oxidation of the monomeric aminotriazole I-a, affords the corresponding biphenylenes in high yield, the only products formed by I-b, in the absence of TC, were the aryl acetates II and III (combined yield of 80%). Monomeric o-benzyne is known to dimerize at the diffusion limited rate in the gas phase, therefore, formation of the Diels-Alder product following delayed addition of diene requires a substantially slower encounter process for the polymer-bound analog. 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

Cheng et al. [316] synthesized the polymer-bound 2-sulfony-l, 3-dienes from the corresponding support-bound suhblene, which upon thermal S02-extrusion gave the highly reactive diene (345), which could be trapped with dienophiles. The synthesis on a polystyrene support begins with polymer-bound lithium phenyl-sulfinate. S-Alkylation with trans-3, 4-dibromosulfolane (343) in the presence of pyridine gave the resin-bound 3-(phenylsulfonyl)-3-sulfolene. Thermal SO2 extrusion had to be performed in xylene under reflux, which restricts the use of this reaction to PS/DVB-resins. Neither the IRORY-Kans [317] nor the Synphase Crowns [199], which are made of polypropylene, are compatible with these reaction conditions, in which polypropylene is dissolved (Scheme 72) ... 

Acetylation-elimination to the support-hound diene (338) (Scheme 70) [314] Polymer-bound sulfonylated allylic alcohol (336) (3.1g) was allowed to swell in THF (35 mL) at 0 °C, and acetic anhydride (1.1 g, 1 mL, 11 mmol) and DBU (2.5 mL, 16.1 mmol) were added. The reaction was stirred at r. t. for one day, after which time the resin was collected by filtration using a medium sin-tered-glass fritted Buchner funnel and washed as follows ... 

The polymer-bound l-sulfonyl-2,3-diene (338) was obtained as yellow beads and dried in vacuo. 

Generation of a diene from a polymer-bound benzocyclobutane [320] The polymer-bound benzocyclobutene (358) can be converted into a very reactive diene upon thermal 47r-conrotatory ring opening. The resulting diene (359) can react with a series of dienophiles containing heteroatoms to afford a series of heterocycles (Scheme 75). Lewis acid-catalyzed reductive alkylation concluded the synthesis to give 363. 

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