Tetrahydropyrans formation

Tetrahydropyrans, formation from 1,5-diketones in conditions of their catalytic reduction 90KGS1011. 

Replacing the (3,y-unsaturated carbonyl group by an alkoxy group offers a different cyclization process for tetrahydropyran formation, namely simple acetalizations as shown in Equation 1.46 [44],... 

In studies using tetrahydropyran formation as part of a synthesis of frenolicin and other naphthoquinone antibiotics50 53, this reaction proceeds with high stereoselectivity. Thus, palladium-catalyzed intramolecular alkoxycarbonylation of various 6-hydroxyaIkenes (e.g., 1) leads to 2,6-disubstituted tetrahydropyrans 2 with up Lo 97 % diastereoselectivity. The configuration of the exocyclic stereocenter depends on the E or Z geometry of the substrate double bond34... 

Tetrahydropyran Formation. The use of an appropriately substituted allylsilane with a variety of electrophiles with 10% TMSNTfa gave the cyclized tetrahydropyran compounds (eq 9). For this reaction, TMSNTf2 outperformed, variety of Lewis acids including TMSOTf, TiCU, TiCl2(Of-Pr)2, SnCLj, BF3-OEt2, and EtAlCh. ... 

Wacker-type chemistry can be combined with other aspects of palladium chemistry to create tandem reactions. For instance, the -intermediate can be intercepted by carbon monoxide giving ester products. This chemistry has been found to be useful in the formation of tetrahydrofurans and tetrahydropyrans as the stereochemistry of the newly formed ring is usually eontroUed quite well (Scheme 6.21 For tetrahydrofuran formation, the substituent in the allylic position seems to have the most stereochemical-directing effect (Scheme 6.22). For tetrahydropyran formation, the 2,6-cis isomer, with both a-substituents equatorial, is favoured. If a disubstituted alkene is used, an additional ehiral eentre is created, and the two geometrical isomers of the alkene starting material give different diastereoisomers of the product (Scheme 6.23). The stereochemistry is consistent with nucleophilic attack trans to palladium, followed by CO insertion with retention. For most substrates, eyehzation is found to be exo, but there are exceptions (Scheme 6.24). 

SCHEME 4.9 Oxepane and tetrahydropyran formation through epoxonium ion intermediates. 

Hoye applied a bidirectional acid-mediated epoxide-opening sequence to the total synthesis of the annonaceous aceto-genin parviflorin (136 Scheme 4.27) [61]. This reaction employed a Sharpless asymmetric dihydroxylation (ADH) reaction of 137, in which the epoxides were introduced by a double Sharpless epoxidation to yield a diol intermediate that was immediately treated with CEjCO H to yield 138 in 85% yield. No competition from 6-cxo-pathways was reported, showing the kinetic preference for tetrahydrofuran formation over tetrahydropyran formation. The natural product was accessed through a multistep route from 138 that inverted the configurations of the two alcohol centers. 

The use of 2-cyanopyrans 87 as key intermediates for tetrahydropyran formation has received increased attention in recent years. Rychnovsky and co-workers used the cyano group as a versatile functionality through reductive decya-nation process to construct strucmrally complex fragments of natural products. We have found that amides 88 are generated from a one-pot hydration and epimerization in wet t-BuOH/t-BuOK. In addition, the exposure of 2-cyanopyrans to basic methanolysis affords methyl esters 89 in moderate yield (Scheme 37.21). ... 

In the NTC region, back-bitiag reactioas appear to be respoasible for the formation of cycHc ethers (60,165—170). la additioa to oxetanes and tetrahydrofurans, tetrahydropyrans, oxiranes, and others are also observed (60,96,169) the tetrahydrofurans are favored. 0-Heterocycle yields of 25 to 30% have been reported for / -pentane (165,171). Conjugate and other olefins are also prominent products ia this regioa (60,169—172). 

The reactions of diazomethane with heterocycles containing a ketonic grouping in the ring do not differ, in principle, from those of alicyclic ketones (see footnotes 3 and 177) ring expansion and the formation of epoxides compete. In general, ring expansion is the more important reaction for example, tetrahydropyran-4-one (99) is converted to l-oxacycloheptan-4-one (100) (60%) and 4,4 -epoxy-4-methyltetrahydropyran (101) (23%). ... 

Retrosynthetic disassembly of the tetrahydropyran ring in 14, a mixed cyclic ketal, provides ketone 15 as a plausible precursor. In the synthetic direction, the solvolytic cleavage of the ester functions in 15 would likely be attended by the formation of a cyclic hemi-ketal. On treatment with acidic methanol, this substance could then be converted to mixed ketal 14. 

There are two possible ways for the ring opening of 35 in the polymerization The C1—O7 bond cleavage leads to the formation of a substituted tetrahydropyran ring 36 in the polymer chain, while the C1—O2 bond cleavage produces a substituted tetrahydrofuran ring 37. Product analysis of the acid-catalyzed hydrolysis of the... 

Scheme 2.68. Diastereoselective formation of substituted tetrahydropyran-4-ones.

Interesting intramolecular cyclization of 1-nitroalkyl radicals generated by one-electron oxidation of aci-nitro anions with CAN is reported. As shown in Eq. 5.44, stereoselective formation of 3,4-functionalized tetrahydrofurans is observed.62 l-Nitro-6-heptenyl radicals generated by one electron oxidation of aci-nitroanions with CAN afford 2,3,4-trisubstituted tetrahydropyrans.63 The requisite nitro compounds are prepared by the Michael addition of 3-buten-l-al to nitroalkenes. 

The formation of unsymmetrical ethers from the reduction of aldehydes in the presence of tetrahydropyran (THP) ethers is reported (Eq. 182).340... 

If the side chain with the nucleophile is situated in the 1-position of the conjugated diene, a palladium-catalyzed spirocyclization occurs. In this case stereoselective oxa-spirocyclizations were obtained from the diene alcohols 59 and 60 (equation 23 -25)58. The reaction worked well for the formation of a tetrahydrofuran and tetrahydropyran in the spirocyclization. In the absence of chloride ions 59 gave high yields of the acetoxy oxaspirocyclic compound 61 via a 1,4-anti addition across the diene (equation 23). In the presence of stoichiometric amounts of LiCl a 1,4-syn oxychlorination took place and allylic chloride 62 was obtained (equation 24). Under chloride-free conditions, cyclohep-tadiene alcohol 60 afforded oxaspirocyclic acetate 63 (equation 25). 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Rychnovsky et al. considered the formation of achiral conformers from chiral molecules and trapping the prochiral radical with a hydrogen atom donor based on memory of chirality (Scheme 12) [41], The photo-decarboxylation of optically active tetrahydropyran 40 leads to an intermediate 43, which now does not contain a stereocenter. If the intermediate 43 can be trapped by some hydrogen atom source before ring inversion takes place, then an optically active product 41 will be formed. This is an example of conformational memory effect in a radical reaction. It was reported that the radical inversion barrier is low (< 0.5 kcal/mol) while the energy for chair flip 43 44 is higher (5 to... 

Scheme 10 Formation of tetrahydropyran or tetrahydrofuran rings in the alkoxycarbony-lation of alkenols...

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

The acid-catalysed hydrolysis of the acylal, 1-phenoxyethyl propionate (13), has been studied using the PM3 method in the gas phase. The kinetics and mechanism of the hydrolysis of tetrahydro-2-furyl and tetrahydropyran-2-yl alkanoates (14) in water and water-20% ethanol have been reported. In acidic and neutral media, kinetics, activation parameters, isotope-exchange studies, substituent effects, solvent effects and the lack of buffer catalysis pointed clearly to an Aai-1 mechanism with formation of the tetrahydro-2-furyl or tetrahydropyran-2-yl carbocation as the rate-limiting step (Scheme 1). There is no evidence of a base-promoted Bac2 mechanism up to pH 12. ... 

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