Thioethers cycloadditions

The type of atoms in the tether have little effect on the cycloaddition process. Both alkyl (98,125-127) and ether tethers (128-131) have been extensively investigated and provide similar levels of reactivity. In addition, thioethers (132), amines (133), silanes (134), and silyl ketals (135) are all compatible with the dipolar cycloaddition. 

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

Triazines are generally more reactive in [2 + 4] cycloaddition in comparison with 1,2,3-tria-zines. The wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene jV,O-acetals, /V-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cychc ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes like ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene and bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene,... 

From the synthetic viewpoint, a particularly interesting trifluoroacetylation reaction of simple vinyl ethers was reported first by Hojo et al in 1976 [73] The scope and limitation of this particular reaction were elaborated intensively, the reaction proved to be of general applicability with practically no restrictions on substituents of the vinyl ether moiety 9] (equation 34) This general validity is particularly beneficial because a trifluoroacetylated vinyl ether is the synthetic equivalent of a specifically protected tnfluoromethyl-substituted 1,3-dicarbonyl compound 19], thus the reaction provides access to a broad spectrum of variously substituted synthetic building blocks with selective reactivities on each carbon acceptor (a) and donor (d) center (equation 35) Obviously, such building blocks can react as heterodiene systems m cycloaddition reactions [< 74] or can be treated with a wide variety ot 1,2 or 1 3-dinucleophihc species to give any desired tnfluoromethyl-substituted carbocychc or heterocyclic system [8 75] Treatment of simple vinyl ethers with an excess of trifluoroacetic anhydride at elevated temperature leads to doubly acylated products [76] Comparable acylation reactions occur with vinyl thioethers [73], and the mesoiomc l,3-oxathiol-4-ones show, at least in a formal sense, similar behavior [77] (equation 36)... 

A wide range of variously substituted thiochromans has been obtained from the readily accessible ot-(benzotriazo-lyl)methyl thioethers by their Lewis acid-catalyzed reaction with styrenes. Initial loss of the benzotriazole unit generates a thionium cation which undergoes an efficient cationic cycloaddition to the alkene. The reaction, which generally proceeds with high diastereoselectivity, is considered to occur in a stepwise manner rather than as a concerted [4++2] process (Scheme 174) <2001JOC5595>. 

The role of the zwitterion intermediate 164 and its rearrangement in the photocyclization of aromatic thioethers 163 to arene dihydro thiophene derivatives 165 is supported [81] by its independent trapping (via 1,3-dipolar cycloaddition) with biphenyl maleimide to obtain 166 in high yields (Scheme 8.47). 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

Troyansky etal. reported that homolytic cycloaddition of dithiols derived from trans- and r-l,2-cyclohexanediols to alkynes, induced by Pr3B-02, offered an extremely simple approach to trans- and m-cyclohexano-fused 12-membered crown thioethers <1995TL11431>. The reaction of 22 (A,A) proceeded with a pronounced remote 1,6-asymmetric induction to give predominantly 23 (1A, 6R, 12A), while 25 (A, R) reacted nonstereoselectively (Scheme 2). 

Irradiation of alkoxycarbene complexes in the presence of aUcenes and carbon monoxide produces cyclobutanones. A variety of inter- and intramolecular [2 + 2]cycloadditions have been reported. The regioselectivity is comparable with those obtained in reactions of ketenes generated from carboxylic acid derivatives. Cyclobutanones can be obtained with a high degree of diastereoselectivity upon reaction of alkoxy carbenes with chiral A-vinyloxazolidinones. For example, photolysis of (19) in the presence of (20) gives cyclobutanone (21) (Scheme 31). In addition to aUcoxycarbenes, carbenes having a thioether or pyrrole substituent can also be employed. Related intramolecular cycloadditions of y,5-unsaturated chromimn carbenes afford bicyclo[2.1. IJhexanones (Scheme 32). 

More recently, an approach to replace the thioether in FTP with a triazole was attempted utilizing a dipolar cycloaddition to join the prenyl and carboxylate groups [57]. These analogs are not substrates for Icmt, but all possess some activity as inhibitors. Despite the dramatic shift from the thioether to the triazole, the most potent compound retains significant binding affinity and is able to reduce Icmt activity by approximately 50%... 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

An interesting rearrangement, which appears to be anion-accelerated, takes place in the enol thioether, anion-terminated vinylcyclopropanes of type 14. ° The rearrangement proceeds at — 78 C and is reasonably stereoselective with regard to the final cyclopentene products (syn selectivity 16 1). Regioisomers are encountered in the formation of the dihydrothiopyran cycloaddition adducts 13 in several instances. The mechanism of this rearrangement appears to involve the enol thioether anion in accord with the well-documented donor acceptor principles " and may be related to similar rearrangements observed with trimethylsilyl enol ether terminated vinylcyclopropanes under fluoride ion or Lewis acid catalysis." " ... 

Bicyclic ether 124, obtained from the intramolecular cycloaddition of 123, was subjected to ozonolysis with a reductive work-up, Eq. 90. Silyl protection gave alcohol 125 and reduction transformed the thioether linkage into the vicinal cis dimethyl groups found in ( )-nemorensic acid [137]. 

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