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Chapter III
A new synthetic approach for the synthesis of 2,5-disubstituted-2,5-dihydrofurans
3.1 Introduction
2,5-Dihydrofuran structure can be considered an important scaffold in medicinal chemistry, because of the antibacterial, antiviral and cytotoxic activity of some natural and synthetic derivatives.30,31 They are also important intermediates in organic synthesis due to the presence of the C=C bond as well as the five-membered ring. Consequently, much attention has been paid to the development of efficient and synthetic methods for construction of this five-membered system.
The most representative molecule of this class is stavudine (Scheme 3.1). It is a nucleoside analog reverse transcriptase inhibitor, active against HIV. Its structure mimics thymidine and it is phosphorylated by cellular kinases, in order to obtain the active triphosphate form. The inhibition of reverse transcriptase of HIV occurs for competition with the natural substrate, also causing the interruption of DNA replication if incorporated in the DNA growing chain.
Scheme 3.1 Stavudine
Varitriol, furanomycin and incrustoporin are natural derivatives with evident cytotoxic, antibacterial and antifungal activity, respectively (Scheme 3.2).
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(+)-Varitriol is a natural product isolated from the marine fungus Emericella variecolor. It has shown increased potency in vitro against renal, breast and CNS cancer cell lines.32 The major challenge in this field seems to be finding an efficient stereoselective synthetic approach, in order to obtain the (+)-eutomer.
(+)-Furanomycin is a natural α-amino acid isolated from Streptomyces threomyceticus. It has turned out to be effective as antibiotic against several bacterial species, nevertheless acts as isoleucyl aminoacyl t-RNA synthetase inhibitor of E. Coli, incorporated in proteins instead of isoleucine.33
(-)-Incrustoporin is a γ-butenolide derivative from the Basidyomycete Incrustoporia carneola. It shows antifungal activity, with prominent cytotoxicity against Absidia glauca, Botrytis cinerea, Mucor miehei, and Rhodotorula glutinis. Recently there is an increasing interest towards these kind of derivatives, as γ-butenolides have potential antitumor, antibiotic, antifungal, and neurotoxic properties.34 The goal is to synthetize and study new analogues with better pharmacological profile.
3.2 Synthetic approach to synthesis of 2,5-dihydrofuran moieties
Synthesis of several 2,5-dihydrofurans has been widely treated in literature,35-43 for the obtainment of compounds with a certain pharmacological activity.
One of the first approaches to the synthesis of 2,5-dihydrofurans was the hydroxylation of furans. Unfortunately, the occurrence of an undesired hydrolization immediately led to malealdehyde hydrates, not allowing the isolation of 2,5-dihydrofuran. In order to avoid the hydrolization step, Thoren et al. performed an anodic oxidation of furan derivative 3.1 in acetonitrile, with aqueous NaHCO3 and LiBF4 as supporting electrolytes.45 The reaction product
was the mixture of cis- and trans-2,5-dihydroxy-2,5-dihydrofurans 3.2. This product can be conveniently converted to diethylmaleic anhydride 3.3 through Jones oxidation (Scheme 3.3).
46
Njardarson et al. performed the synthesis of 2,5-dihydrofurans through vinyl oxirane 3.4 as starting material, using a commercially available and air stable catalyst like Cu(II).46 The study dealt with the ring expansion reaction occurring on vinyl oxiranic systems, in the presence of an electrophilic Cu(II) catalyst substituted with non-nucleophilic ligands. In this way, Cu(II) coordinates the oxirane and the olefin, facilitating the rearrangement to dihydrofuran derivative 3.5a contemporarily decreasing the formation rate of aldehyde 3.5b (Scheme 3.4).
Scheme 3.4 Copper catalyzed vinyl oxirane 3.4 rearrangement
Hocek et al.47 exploited the ring closing metathesis on bis-allylethers, using first and second generation Grubbs catalysts. Starting from study about aryl C-glycosides, a strategic disconnection approach was considered, in order to develop a retrosynthetic analysis which provided 2,5-dihydrofurans as immediate precursor of the RCM reaction (Scheme 3.5 and 3.6).
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Scheme 3.6 Retrosynthetic analysis
Considering this kind of approach, protected butendiols were synthetized starting from 3-butene-1,2-diol 3.6, commercially available both as racemic and pure form (Scheme 3.7). The best protective group among the considered ones, in terms of yields and enantiomeric excess, was R = TBDPS, so to obtain 3.7. Protection of the remaining alcoholic portion as Boc gave derivative 3.8.
Scheme 3.7 Protection as Boc-silylated derivative of the starting diol 3.6
The second step in this direction consisted of the synthesis of aryl-allylic suitable substrates. Considering that t-butyl carbonates are superior to esters as substrates for Ir-catalyzed allylic substitution, cinnamyl derivative 3.9 and isocinnamyl derivative 3.11 (prepared through Boc protection of 3.10) were used. Important to note that the conversion of 3.10 in Boc-derivative 3.11 was conducted in controlled conditions, in order to lower side reactions, in particular allylic rearrangement (Scheme 3.8).
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Scheme 3.8 Unsatured Boc derivatives 3.9 and 3.11 used for the synthesis of aryl-allylic substrates
Allylic substitution was performed between copper (I) alkoxyde of monoprotected diol 3.7 and cinnamyl carbonate 3.9 or isocinnamyl carbonate 3.11 (Scheme 3.9), in order to obtain the corresponding bisallylether 3.12. Reaction was catalyzed by rhodium or iridium, in the presence of Feringa-Alexakis phosphoramidites 3.13a and 3.13b (Scheme 3.10), capable of inducing high enantioselectivity. Actually, reaction between 3.7 readily reacted with 3.11 afforded the bisallylether 3.12 in 72-85% yield, with enantiomeric excesses > 99%.
Scheme 3.9 Formation of bisallylether 3.12, through Ir-mediated catalysis of reaction between allyl ethers 3.7 and 3.11
Scheme 3.10 Feringa-Alexakis phosphoramidites
Then, bisallylether 3.12 was subjected to ring closing metathesis reaction, using a first generation Grubbs catalyst. The optimized reaction conditions turned out to be heating to reflux
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in CH2Cl2 for 3h. With low concentration of catalytic complex (1 mol%), dihydrofuran
derivative 3.14 was isolated in good yields as pure diastereoisomer (Scheme 3.11).
Scheme 3.11 RCM reaction on bisallylether 3.12, to give the desired 2,5-dihydrofuran 3.14
Bicyclic spiro derivatives of 2,5-dihydrofuran (3.17-3.18) are interesting for their antibacterial activity. Avetisyan et al.48 were able to obtain this core through the reaction of 1-acetylcyclohexanol 3.15 with N-aryl substituted amide 3.16 of cyanoacetic acid by activation of acid H via MeONa/MeOH (Scheme 3.12).
Scheme 3.12 Schematic synthesis of spiro derivative of 2,5-dihydrofurans 3.18
Substituted α-hydroxyallene 3.19 was easily converted in the corresponding 2,5-dihydrofuran 3.20. The reaction was promoted by HCl gas in chloroform and the product was isolated in excellent yields and with perfect transfer of chirality (Scheme 3.13).49
50
An alternative method 50 consisted in conversion of 3.19 to 3.20, using the acidic Amberlyst 15 resin in refluxing dichloromethane. Also in this case there was complete transfer of chirality, as well as obtainment of quantitative yields. Due to the potential failure of this approach for acid-labile substrates, a different promoter was considered. Catalytic amount of AuCl3 turned out to promote the cyclization of hydroxyallene 3.21 to dihydrofuran 3.22, as
hypothesized from the observation that the same catalyst induces the cyclization of allenyl ketones to furans (Scheme 3.14).
Scheme 3.14 Electrophilic cyclization of α-hydroxyallene 3.21 to 2,5-dihydrofuran 3.22
Cycloisomerization of α-hydroxyalkyl-allenephosphonate 3.23 was carried out with AgNO3 as catalyst, in order to obtain a 2,4-disubstituted 2,5-dihydrofuran 3.24. Optimization of
reaction conditions resulted in a preference for dichloromethane as solvent and room temperature (Scheme 3.15).
Scheme 3.15 AgNO3-catalyzed cycloisomerization of allene 3.23 in 3.24 2,5-dihydrofuran derivative
Higher yields were obtained after screening of the catalysts, whose AuCl and AuCl3 5
mol% showed the best results, in a very short reaction time. Considering the cost of Au-based catalysts, the last step was to find a suitable cheaper alternative in terms of yields. AgClO4
turned out to be a good candidate, showing good yields in reasonable reaction time for the synthesis of several substituted 2,5-dihydrofurans 3.23-3.24 (Scheme 3.16).
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Scheme 3.16 Metal-catalyzed cycloisomerization of 3.23a and 3.23b to 3.24a and 3.24b
Use of phenylselenyl chloride on omoallylic alcohol 3.25 resulted in a rearrangement to tetra substituted tetrahydrofuran 3.26, that could be easily converted in dihydrofuran derivative 3.27,51 through cleavage of the selenyl substituent by ammonium persulfate (Scheme 3.17).
Scheme 3.17 Formation of 2,5-dihydrofuran 3.27 by the use of selenyl chloride on omoallylic alcohol 3.25
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Synthesis of polysubstituted dihydrofuran 3.33 has been approached performing a Wittig reaction52 of 2-hydroxy ketone 3.30 with dialkyl-acetylenedicarboxylate 3.28 in the presence of triphenylphosphine, in order to obtain vinyltriphenylphosphonium salt 3.29 (Scheme 3.18)
Scheme 3.18 Wittig reaction for the synthesis of 2,5-dihydrofuran derivative 3.33
Gleason and his group53 studied cobalt-mediated cycloisomerization of 1,6-enyne 3.34 to vinylcyclopentenes 3.36a, in high yields with excellent diastereoselectivity. The reaction proceeded through the oxidative addition of cobalt-complex to the allylic CH bond to form 3.35. Reductive elimination allowed the formation of the cyclopentene derivative 3.36a, accompanied by the corresponding allylic rearrangement side product 3.36b (Scheme 3.19).
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Exploiting the results of this observation, the same group successfully extended the protocol for the synthesis of 2,5-dihydrofurans.53 In this case the starting material was allyl propargyl ether 3.37 and the reaction was performed in different solvents at different temperatures, in presence of 1.1 eq of Co2(CO)8 for 24h, to afford the 2,5-dihydrofuran 3.38
(Scheme 3.20).
Scheme 3.20 Synthesis of 2,5-dihydrofuran 3.38 by cycloisomerization of allyl-propargyl ether 3.37
Stereoselective total synthesis of (+)-varitriol A was performed by Rao and his research group.54 Interest toward this compound derived from its potential therapeutic effects and low availability from natural source. Important intermediate of the protocol is dihydrofuran 3.44a that, in this case, was dihydroxylated and modified in order to obtain the desired enantiopure product 3.45.
Starting material of the synthetic process was lactaldehyde 3.38, which was subjected to reaction of olefination through Stille-Gennari reaction to obtain β-unsatured ester 3.39 (prominent Z-stereoselectivity). Reduction to alcohol 3.40 gave the substrate for Swern oxidation and the resulted aldehyde was subjected to Wittig olefination, in order to obtain 3.41, with predominant trans-selectivity. Reduction of the ester afforded alcohol 3.42, epoxidized to 3.43. Desilylation with TBAF gave a mixture of diastereoisomeric dihydrofurans 3.44a and 3.44b. Complete cyclization was ensured by CSA and the major product was isolated in 68% yield (Scheme 3.21).
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