2,3-Dihydrofuran derivatives, synthesis

Scheme 21 shows the synthesis of a dihydrofuran derivative 86. Synthesis of this compound was described by Nam et al. [68] utilizing a furanone compound 87 synthesized by Kim et al. [61] via a similar synthetic approach as described in Scheme 17. The lactone was reduced using lithium aluminum hydride to give the diol 88 and intramolecular etherification using the Mitsunobu reaction afforded the dihydrofuran 86 in moderate yield (47%).

Other examples of the iodonium ylide-based syntheses of furan derivatives involve cycloaddition reactions with alkenes or alkynes. Although the majority of these syntheses involve stable iodonium ylides (86JOC3453 94T11541) (e.g., Eqs. 16 and 17), in some cases the ylides are unstable and are generated in situ (92JOC2135) (e.g., Eq. 18). In the case of alkenes, dihydrofuran derivatives are obtained (Eqs. 16-18). This synthetic route is especially useful for the synthesis of dihydrobenzofuran derivatives that are related to the neolignan family of natural products (Eq. 18). 

Synthesis of dihydrofuran derivatives by cyclization of oxime derivatives has been described. Thus, reduction of 2-quinolineacetaldoxime (26) with H2/Pt02 afforded fura-noquinoline 27 as a single product (equation 1. 4-Formy l-3-hydroxy-5-hydroxymethyl-2-methylpyridine oxime (28) in the system NaN02/HCl/H20 cyclized to furopyridine 29 (equation 13). ... 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

The dihydrofuran derivative 35 was also employed for the synthesis of ethyl 3-amino-3-deoxy-/3-DL-arafiino-pentofuranoside (40b). The synthesis was accomplished27 in three stages. By the action of calcium hypochlorite on 35, a chlorohydrin intennediate was formed which, on treatment with a base, afforded a mixture of the epoxides 37, 38,... 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

Table 6. Synthesis of Dihydrofuran Derivatives Analogous to 177 (Scheme 7)...

An interesting example of triple electrophilic aromatic substitution between a dihydrofuran derivative and phloroglu-cinol was exploited for the total synthesis of the (Tj-symmetric xyloketal A, as shown in Equation (128) <20060L1427>. 

Enantiomerically enriched 2,5-dihydrofuran derivatives can be obtained from easily available enantiomerically enriched trisubstituted (acyloxy)butynols of type 30. These compounds were transformed into (acyloxy)dihydrofur-ans with complete stereospecificity by Ag(l)-mediated rearrangement to allenic intermediates 31, followed by Ag(l)-assisted cyclization (Scheme 36). This sequence was successfully applied to the formal synthesis of a differentiation-inducing antibiotic, (i)-(—)-ascofuranone <1999BCJ279>. 

A multicomponent reaction of a species generated from addition of dimethoxycarbene onto the triple bond in DMAD in the presence of aldehydes or quinones has been described, affording a facile synthesis of dihydrofuran derivatives (Equation 70) <2001TL2043>. 

S-Dimethoxy-2,5-dihydrofuran derivatives have been used extensively for the synthesis of aromatic and aliphatic ring systems, as shown in equations (42) and (43). ... 

Z)-2-butenylene dicarbonate with dimethyl malonate gives a low yield (20—40%) of 2-vinylcyclopropane-l,l-dicarboxylate with up to 70% ee (Scheme 2-38) [54], Reaction with methyl acetoacetate or acetylacetone takes place in a different manner to give a dihydrofuran derivative (59% ee), which results from nucleophilic attack of enolate oxygen at the cyclization step, (c) Asymmetric elimination of an acetyl-acetate ester gives (R)-4-rerr-butyl-l-vinylcyclohexene of up to 44% ee (Scheme 2-39) [55]. (d) Palladium-catalyzed allylic silylation is also applied to asymmetric synthesis... 

In contrast, tautens and coworkers recently focused on asymmetric hydroalumination using Ni-BINAP as catalyst [177]. The reaction involves ring-opening desymmetrization of several 1,4-dihydrofuran derivatives that produce important chiral building blocks for natural product synthesis high ee is usually obtained (Scheme 6.138) [178]. 

The reaction of o-lithio-a-methoxyallene with cyclopentanone gives an allenic carbinol. Treatment of this material with potassium r-butoxide in r-butyl alcohol containing 18-crown-6 heated at reflux for 15 h provides the dihydrofuran derivative, which, after acid hydrolysis, gives a spirodihydrofuranone. The method has been utilized as an iterative process for the synthesis of helical molecules (Scheme 16). ... 

Desulfurization. A synthesis of pyrroles from phenylthio dihydrofuran derivatives is mediated by HgCh-... 

The similar reaction is used for the synthesis of dihydrofuran derivatives. Photo-lytic cleavage of the Se-CF2 bond of 22 in the presence of 2,3-dihydrofuran, the phenylselenyl group transfer reaction proceeds quickly to provide 24, and further photolysis of 24 results in the formation of the compound 25. ... 

A concise enantioselective synthesis of (-l-)-muscarine from (R)-benzyloxymethyloxirane was recently reported by Takano et al. (36) (Scheme 10). The starting oxirane was coupled with lithium acetylide-ethylenediamine, forming the hydroxyalkyne, which was converted to the acid-sensitive 2,3-dihydrofuran by methylation and subsequent treatment with base. The dihydrofuran derivative was hydroborated and oxidized in... 

Liu, S., M.A. Haller, H. Ma, L.R. Dalton, S.H. Jang, and A.K.Y. Jen. 2003. Focused microwave-assisted synthesis of 2,5-dihydrofuran derivatives as electron acceptors for highly efficient nonlinear optical chromophores. Adv Mater 15 603-607. 

The acid-sensitive hydroxyl group was protected as an O-thiocarbamate, and treatment of the resulting vinyloxirane 49 with catalytic amounts of trifluoroacetic acid (TFA) afforded the substituted-dihydrofuran derivative 50 in high yield. Free-radical deoxygenation followed by the cleavage of the methyl ethers conpleted the synthesis. 

Following the general strategy depicted in Scheme 5.4, Nair and coworkers have described an easy route for the synthesis of highly substituted dihydrofuran derivatives 2-5 by the one-pot reaction of dimethoxycarbene I, generated in situ from oxadia-zole 1, DMAD, and different carbonyl compounds, such as aldehydes (a) [5,6], ketones (b) [7], a,p-unsaturated ketones (c) [5, 8], or quinones (d) [5,6] (Scheme 5.5). hi the specific case of enones (c), the addition of the zwitterion II took place in the carbonyl group regioselectively. 

SCHEME 5.5 Synthesis of substituted dihydrofuran derivatives by MCR of dimethoxycarbene I. 

V. Nair, S. Bindu, V. Sreekumar, L. Balagopal, Synthesis 2003, 1446-1456. Novel dipolar cycloaddition reactions of zwitterionic species generated from dimethoxycarbene and dimethyl acetylenedicarhoxylate with carhonyl compounds facile synthesis of dihydrofuran derivatives. 

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