Dihydropyran resin

In planning fhe solid-supported total synfhesis of 6-epi-dysidiohde and other related phosphatase inhibitors, Brohm and co-workers [226] developed a robust linker, which provided the terminal alkene by means of a traceless RCM release from the resin. Thus, suitable precursor (112) was prepared, after intensive investigations, on Ellman s dihydropyran resin [227]. Subsequent RCM with the Grubbs catalyst afforded the expected triene (113) in 82% isolated yield along with the solid-supported cyclopentene derivative (114) (Scheme 26). The tetrahydro-pyran link has a great impact on the yield of the RCM a direct benzylic resin attachment resulted in much lower yields. 

Nucleoside chemistry is traditionally labor intensive and the output of compoxmds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the piupose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine diehloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two ehloro atoms by various amines. The purine heterocyclic bases were then condensed with Dd.-ribofuranosides following a classical Vorbruggen method to yield nucleosides of general formula 171. 

Reillex 425-HCl, dihydropyran, 86°, 1.5 h, 84-98% yield. The Reillex resin is a macroreticular polyvinylpyridine resin and is thus an insoluble form of the PPTS catalyst. 

Amberlyst H-15 (SO3H ion-exchange resin), dihydropyran, hexane, 1-2 h, 95% yield. ... 

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

A number of efforts have been devoted to the simplified, acid catalyzed reaction between dihydropyran and alcohols to form THP-ethers. Thus, employing the hydrochloride salt of Reillex 425 (34) [a cross-linked macroreticular poly(4-vinylpyri-dine) resin] the tetrahydropyranylation even of hindered alcohols proceeds under mild conditions in high yields without side-reactions (Scheme 4.20) [107]. 

A reaction flask was charged with 2,5-dichloro-2, 4 -dihydroxybenzophenone (100 mmol), 2H-dihydropyrane (2400 mmol), and 100 ml of toluene. While the mixture was stirring, it was treated with cation exchange resin Amberlist 15 (3.0 g) and then stirred an additional 5 hours at ambient temperature. At this point the cation exchange resin was removed and the filtrate washed with aqueous solutions of sodium hydroxide and brine The mixture was dried using MgSOzt, concentrated, the residue recrystallized from toluene, and 21.2 g of product isolated. 

The acid-catalyzed cyclization of the diol (209), available from penta-1,3-diene and bromomesityl oxide via the hydroxyketone, gives a mixture of the fused dihydropyrans (210) and (211), edulan I and II, respectively (Scheme 40) <75JCS(P1)1736). The former compound predominates when an ion exchange resin is used as the catalyst, but the latter... 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Some heterocycles can be linked to supports as tetrahydropyranyl derivatives. Attachment of indoles, purines, or tetrazoles (Table 3.29) has been achieved by treatment of a support-bound dihydropyran with the heterocycle in the presence of catalytic amounts of pyridinium tosylate [487], camphorsulfonic acid [539], or TFA [540] in DCE at 60-80 °C for 16-24 h. Indole-derived orthoesters, such as that in Entry 7 (Table 3.29), can be prepared by heating the indole with triethyl orthoformate (160 °C, 24 h) followed by acid-catalyzed reaction of the resulting orthoester with a resin-bound diol [541,542], As illustrated by Entry 8 (Table 3.29), indoles can also be linked to the Wang resin or related supports as carbamates. Cleavage by TFA is, how-... 

Tetrahydropyranyl ethers, THP-ethers, are formed by reaction of an alcohol with 2,3-dihydropyran in the presence of an acid catalyst. The procedures below illustrate the use of concentrated hydrochloric acid or pyridinium toluene-p-sulphonate. Amberlyst H-15 resin has also been used as a reaction catalyst.81... 

Solid-phase three-component domino-Knoevenagel-hetero-Diels-Alder reaction can also be performed using a resin-linked 1,3-dicarbonyl compound such as 100 with aldehydes and an enol ether to give dihydropyrans 102 via the intermediately formed 1-oxa-l,3-butadiene 101 (Scheme 5.18) [30], The resin can be deaved off after the reaction by solvolysis, for instance using sodium methanolate to give the corresponding methyl ester 103 as a mixture of diastereomers. The overall yield varies from 12 to 37% and the selectivity from 1 1 to 1 5 in favor of the tis-product depending on the applied aldehyde. The crude dihydropyrans thus obtained are reasonably pure (> 90% HPLC). 

The THP group is a widely used protecting group it is readily introduced by reaction of the enol ether dihydropyran with an alcohol in the presence of an acid catalyst, such as TsOH, BF3 OEt2, or POCI3. For sensitive alcohols such as allylic alcohols, PPTS (pyridinium p-toluenesulfonate) is used as a catalyst for tetrahydropy-ranylation. As an acetal, the THP group is readily hydrolyzed under aqueous acidic conditions with AcOH-THF, TsOH, PPTS-EtOH, or Dowex-H (cation exchange resin). 

Before all these acetal-based protecting groups were introduced, the tetrahydropyranyl (THP) ether had found extensive use in organic synthesis. It can easily be synthesized from a variety of hydroxy-containing compounds like carbohydrates, amino acids, steroids and nucleotides by the acid-catalyzed reaction with dihydropyran. It is stable to bases, but the protection is removed through acidic hydrolysis with hydrochloric acid, toluenesulfonic acid or acidic ion-exchange resin (Scheme 27). In the case of acid sensitive substrates, e.g. containing an epoxide or a further acetal, pyridinium p-toluenesulfonate should be applied for particularly mild deprotection conditions. ... 

Hydroxymethyl dihydropyran was coupled to chloromethyl resin via an ether linkage to yield 41 (Scheme 21) [45]. The alcohol was then attached as a THP ether (42). After combinatorial synthesis, the alcohol was released under acidic conditions. 

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. 

Chaturvedula et al. identified other derivatives of nemorosone named ochrocarpinones A-C (85-87) which constitute the first PBDs isolated from genus Ochrocarpus [14]. The structures of ochrocarpinones B-C showed NMR data very similar to those observed in hyperibones A-G. The presence of a 2,2-dimethyl-3-hydroperoxy-2-H-dihydropyran ring in ochrocarpinone A was indicate by a positive peroxide test with FeSCN. Ochrocarpinone A was a derivative of plukenetione G, but, the l3C chemical shifts were most similar to scrobiculatone A (C-7 epimer of plukenetione G) a derivative of nemorosone isolated from floral resins of Clusia sp. Ochrocarpinone C (87) seems to have the same structure of hyperibones A or B, two epimers isolated from H. scabrum, stereochemistry of ochrocarpinones was not reported. 

DIHYDROPYRAN, CARBOXYLATE, AND SULFONATE RESINS AND THEIR DERIVATIVES... 

Procedure [149]. Dihydropyran (DHP)-resin 4a (6.0 g) in dichloro-ethane (70 mL) was treated with A-etiioxycarbonyl-rran5-4-hydroxy-L-pro-line methyl ester (21 mmol) and PPTS (6.7 mmol) and the suspension heated to 80°C for 48 h, filtered, washed with CH2CI2 (8 X 50 mL), and dried. The resin-bound methyl ester (1.0 g, 0.43 mmol) in tetrahydrofuran (THF) (25 mL) was treated with phenylmagnesium bromide in THF (50 equiv.) at 0 C and the mixture allowed to warm to ambient temperature and stirred for 12... 

Glycerides, MA ene adduct uses, 175 4-Glycidoxychalcone, SMA resin coupled, 445 2-Glycidoxy-2,3-dihydropyran, MA copolymerization, 322... 

Protocols have been developed which utilize an insoluble solid catalyst in combination with dihydropyran to effect the protection of alcohols as their corresponding THP ethers. These procedures are advantageous in that the catalyst may be recovered by simple filtration and the products isolated by evaporation of volatiles. In many cases the catalyst can be reused without regeneration. Reaction of alcohols with dihydropyran in the presence of Amberlyst H-15 (25 °C, 1 h, 90-98%) yields THP derivatives. Alternatively, a solution of dihydropyran and the alcohol may be passed slowly through a column of silica overlaid with Amberlyst H-15 to yield the THP ethers directly (73-97%). The acidic clay Montmorillonite KIO (25 °C, 15-30 min, 63-95%) is similarly applicable, Reillex 425 resin (86 °C, 1,5 h, 84-98%) is applicable with the advantage that it does not promote the sometimes troublesome polymerization of dihydropyran. Polymeric derivatives of pyridinium p-toluenesulfonate are also effective. Poly(4-vinylpyridinium p-toluenesulfonate) and poly(2-vinylpyridinium p-toluenesulfonate) catalysts yield tetrahydropyranyl derivatives of primary, secondary, and tertiary alcohols (24 °C, 3-8 h, 72-95%). ... 

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