Cyclic ethers, synthesis with

At the same time, Dale and Kristiansen reported a successful synthesis of 18-crown-6 from the diol and ditosylate just as shown in Eq. (3.2), but using benzene as solvent. They obtained the product as its potassium tosylate complex (mp 164°) in 33% yield. The free macrocycle was liberated by chromatography over a column of alumina, eluting with a benzene-cliloroform mixture. Dale and Kristiansen note that the cyclic ether cannot be liberated from its complex by simple heating . ... 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

The conversion of a thiolactone to a cyclic ether can also be used as a key step in the synthesis of functionalized, stereochemically complex oxacycles (see 64—>66, Scheme 13). Nucleophilic addition of the indicated higher order cuprate reagent to the C-S double bond in thiolactone 64 furnishes a tetrahedral thiolate ion which undergoes smooth conversion to didehydrooxepane 65 upon treatment with 1,4-diiodobutane and the non-nucleophilic base 1,2,2,6,6-pentamethylpiperidine (pempidine).27 Regio- and diastereoselective hydroboration of 65 then gives alcohol 66 in 89 % yield after oxidative workup. Versatile vinylstannanes can also be accessed from thiolactones.28 For example, treatment of bis(thiolactone) 67 with... 

Scheme 16 Construction of a nine-membered cyclic ether with a (Z,Z)-1,3-diene unit by sequential RCM and silicon-assisted intramolecular cross coupling in Denmark s synthesis of brasilenyne (85) [65]...

These reductions of lactols with Et3SiH 84b in combination of BE3 -OEt2, TfOH, or TMSOTf 20 have become standard reactions for synthesis of cyclic ethers [62-69]. Thus even co-hydroxyketones such as 1837 cyclize readily with excess EtsSiH 84b in the presence of TMSOTf 20, in high yields, via the lactols 1838, to give cyclic ethers such as the substituted oxepane 1839 in 90% yield [65] (Scheme 12.18). 

Condensations Highly atom economical since small molecules of water or alcohol are liberated Atom economy increases as the molecular weights of the combining fragments increases For cyclization reactions such as the Dieckmann condensation and the synthesis of cyclic ethers from straight chain diols the atom economy increases with increasing ring size... 

Redox-sensitive resin 24 designed for solid-phase peptide synthesis (SPPS) [29] was prepared from commercially available 2,5-dimethylben-zoquinone in seven steps [30] and loaded to a support via a Wittig reaction. Release of the peptide occurs using two sequential mild conditions, reduction with NaBH4 followed by TBAF-catalyzed cyclic ether formation (Scheme 8) which provide orthogonality to acid sensitive reactions. 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

Addition to thionolactones cyclic ethers. A wide variety of alkyliithium reagents add to the C=S group of thionolactones. The adducts, after reaction with CH,I, can be isolated in high yield as mixed methyl thioketals. The methylthio group can be removed by reduction with triphenyltin hydride (AIBN) to give cyclic ethers. The reaction is not dependent on the ring size and can be stereoselective, as shown by the synthesis of the ether lauthisan (2) from a thionolactone (1). 

Different strategies all including nucleophilic addition to acceptor-substituted allenes have been used for the synthesis of cyclic compounds, mostly heterocycles. Thus, it is obvious to release a nucleophile already existing within the allenic compound in a protected form. For example, treatment of silyl ethers 197 with tetrabu-tylammonium fluoride (TBAF) leads to the intermediates 198, which yield the dihy-drofurans 199 by nucleophilic addition (Scheme 7.32) [251]. 

Erlenmeyer synthesis org chem Preparation of cyclic ethers by the condensation of an aldehyde with an a-acylamino acid in the presence of acetic anhydride and sodium acetate. 3r-l3n,mT-3r sin-th3-s3s erucic acid org chem C22H42O2 A monoethenoid acid that is the cis isomer of bras-sidic acid and makes up 40 to 50% of the total fatty acid in rapeseed, wallflower seed, and mustard seed crystallizes as needles from alcohol solution, insoluble in water, soluble in ethanol and methanol. o rus ik as ad erythrite See erythritol. er o.thrTt ... 

The acetal [1,2]-Wittig rearrangement protocol is also applicable to the synthesis of medium-sized cyclic ethers. For example, a reaction of the 9-membered cyclic acetal 37 with lithium piperidide provides the 8-membered ring ether 38 in good yield along with high diastereoselectivity (equation 20) . 

The pioneering work on enantioselective [2,3]-Wittig rearrangement was carried out by Marshall and Lebreton in the ring-contracting rearrangement of a 13-membered cyclic ether using lithium bis(l-phenylethyl) amide (63) as a chiral base (equation 34). Upon treatment with a (S,S)-63 (3 equivalents) in THF at —70 to —15 °C, ether 64 afforded the enantioenriched [2,3]-product 65 in 82% yield with 69% ee. The reaction was applied in the synthesis of (+)-aristolactone (66). 

The sequential addition method also allows the synthesis of many different block copolymers in which the two monomers have different functional groups, such as epoxide with lactone, lactide or cyclic anhydride, cyclic ether with 2-methyl-2-oxazoline, imine or episul-Hde, lactone with lactide or cyclic carbonate, cycloalkene with acetylene, and ferrocenophane with cyclosiloxane [Aida et al., 1985 Barakat et al., 2001 Dreyfuss and Dreyfuss, 1989 Farren et al., 1989 Inoue and Aida, 1989 Keul et al., 1988 Kobayashi et al., 1990a,b,c Massey et al., 1998 Yasuda et al., 1984]. 

Scheme 5.40 The reaction of alkynyltungsten with aldehydes synthesis of cyclic ethers.

While N-heterocycles have dominated pharmaceutical synthesis from its inception, the increasing facility with which complex cyclic ethers can be assembled suggests that such cyclic ethers could also be suitable pharmaceutical platforms. 

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