Epoxide-Mediated Cyclization

Because of these interesting biological activities and the scarcity of materials from their natural sources through isolation, great emphasis has been placed on synthetic approaches toward the efficient construction of tetrahydropyrans. These approaches include the Prins and related cyclization reactions, the hetero-Diels-Alder cyclizations, radical cyclizations, transition metal mediated cyclizations, as well as more traditional methods such as epoxide-mediated cyclizations and oxa-conjugate addition reactions. 

A silastannation product bearing an epoxide moiety undergoes titanium(m)-mediated cyclization with the vinyl-stannane moiety (Equation (109)).268... 

Oxindole 89 was cleanly demethylated upon treatment with boron tribromide. The resulting oxindole 90 was subjected to the prenylation conditions, and the desired alkylated product 91 was obtained in 52% yield. The epoxidation/Lewis acid-mediated cyclization proved to be successful on this substrate. The epoxide product was directly treated with SnCl4 in THF to provided the desired 92. When oxindole 92 was treated with NaBHt (1.6 equivjand BF3 OEt2 (3.5 equiv) in THF, the desired 93 was obtained. The indole 93 was treated with TBDMSC1 and imidazole in DMF, to provide the required O-silylated indole, which was easily converted to the gramine 94 through the well known Mannich procedure. 

Indeed, these epoxide-facilitated ring closure reactions show advantages over other methods. For example, Clive and Magnuson were able to access a desired tricyclopentanoid intermediate 79 for the synthesis of ( )-ceratopicanol by the Cp2TiCl-mediated cyclization of the bicyclic epoxide 78. Attempts to construct this system through conventional enyne radical cyclizations yielded only the bridged product (i.e., 81) [95TL15]. 

Previous work in Baldwin s group based around cobalt(I)-mediated cyclization had led to syntheses of (-)-a-kainic acid 2, (+)-allokainic acid 3,34 and acromelic acid A 5.35 A cobaloxime-mediated cyclization of 27 gave the separable pyrrolidines 28 and 29, suitable for conversion to (-)-a-kainic acid 2 and (+)-allokainic acid 3, respectively.34 In this instance, the required stereoisomer 28 for the preparation of (-)-a-kainic acid 2 predominated in a ratio of 28 29,1.7 1 (Scheme 6). Both 28 and 29 were carried through to the respective kainoids 2 and 3. In this case, asymmetry was introduced at a very early stage in the synthesis via a Sharpless asymmetric epoxidation. 

GansSuer et al. studied the tandem titanocene-mediated cyclization/inter-molecular addition to Michael acceptors [132]. After treatment with t-butyl acrylate in the presence of Zn, collidine hydrochloride and catalytic amounts of titanocene [133], epoxide 143 yielded the desired bicycUc product 144 in reasonable yield and high diastereoselectivity (Scheme 46). Remarkably, alkyne 145 led to the first example of an intermolecular addition involving a vinylic radical. The success of this reaction was attributed by the authors... 

In the laboratory of P.G. Steel, a five-step synthesis of ( )-epiasarinin from piperonal was developed. The key steps in the sequence involved the Darzens condensation, aikenyi epoxide-dihydrofuran rearrangement and a Lewis acid mediated cyclization. The desired vinyl epoxide intermediate was prepared by treating the solution of ( )-methyl-4-bromocrotonate and piperonal with LDA, then quenching the reaction mixture with mild acid (NH4CI). 

Selective reduction to 128 was achieved in much improved yield (56%). The A ring modification to 129 was then accomplished by Eschenmoser cleavage of the derived epoxide, addition of methyllithium, and trifluoracetic acid mediated cyclization to 130. 

For cyclizations via epoxide opening leading to C-glycosides and related compounds, see [2,204-206]. For the synthesis of C-glycosides and related compounds by episelenonium-mediated cyclizations, see [2, 207]. For episulfonium ion promoted cyclizations of hydroxy alkenes, see [2]. For the preparation of C-glycosides... 

Isamu Shiina of the Tokyo University of Science established (Organic Lett. 2008, 10, 3153) that the acid-mediated cyclization of the Sharpless-derived epoxide 10 proceeded with clean inversion, to give 11. The highly-substituted tetrahydropyran core 11 was then elaborated to the antifungal Botcinin F 12. 

In his synthesis of the Dentrobatid alkaloid pumiliotoxin 25 ID 9, Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451) as his starting material another amino acid, prohne. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racem-ization is a substantial contribution that wiU have many other applications. 

Scheme 28 Lewis acid-mediated epoxide-opening cyclization to D ring of phorboxazole A [57]...

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

The above-mentioned important and impressive applications of titanocene mediated and catalyzed epoxide opening have been achieved by using the already classical 5-exo, 6-exo and 6-endo cyclizations with alkenes or alkynes as radical acceptors. Besides these achievements, the high chemoselectiv-ity of radical generation and slow reduction of the intermediate radicals by Cp2TiCl has resulted in some remarkable novel methodology. 

Fernandez-Matess recently demonstrated that nitriles constitute excellent radical traps in titanocene-mediated epoxide openings, even though these cyclizations are considered as being quite slow. As shown in Scheme 31 cy-clobutanones, cyclopentanones, and cyclohexanones can be prepared in high yields [122]. 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

The oxidative cyclization of vinylallenes need not be directed by a pendant hydroxyl group in order to succeed. The higher reactivity of the allene compared with the exocyclic methylene group in 73 (Eq. 13.23) with monoperphthalic acid leads primarily to the allene oxide which rearranges to cydopentenone 74 [27]. Inevitably some epoxidation of the alkene also takes place during the reaction. When m-CPBA is used as the oxidant, another side reaction is associated with m-chlorobenzoic add-mediated decomposition of the intermediate epoxide. It is possible to overcome this problem by performing the epoxidation in dichloromethane in a two-phase system with aqueous bicarbonate so as to buffer the add [28]. 

The molybdenum-mediated arylamine cyclization was also applied to the total synthesis of pyrano[3,2-a]carbazole alkaloids (Scheme 26). Reaction of the 5-aminochromene 71 with the complex salt 62 affords the complex 72, which on oxidative cyclization provides girinimbine 73, a key compound for the transformation into further pyrano[3,2-a] carbazole alkaloids. Oxidation of 73 with DDQ leads to murrayacine 74, while epoxidation of 73 using meta-chloro-perbenzoic acid (MCPBA) followed by hydrolysis provides dihydroxygirinim-bine75 [113]. 

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 preparation of 1 started with the addition of lithiated 4 to the enantiomcrically-pure epoxide 5, which was prepared from the racemate using the Jacobsen protocol. Reduction followed by selective protection of the primary alcohol gave the monosilyl ether, which was further protected with MOM chloride to give 7. Pd-mediated oxidation to the methyl ketone followed by condensation with the Horner-Emmons reagent gave the unsaturated ester 8 as an inconsequential mixture of geometric isomers. Oxidation then set the stage for the crucial cyclization. 

Chemistry of low-valent titanium and zirconium has produced a number of powerful methods for the transformation of carbohydrates to carbocyclic compounds. The Ti(III)-mediated generation of a radical from epoxides and its subsequent cyclization [32] was discussed earlier under free radical methods (see Scheme 9). As shown in Scheme 12,... 

The mechanism of titanocene (TiCp2Cl2)-mediated 3-exo cyclization of vinyl epoxides containing carbonyl, phenyl, and vinyl groups has been determined by DFT calculations and experimental studies (Scheme 52).86 The reaction is exothermic and reversible, in contradiction to an earlier mechanistic proposal. The energies of activation for ring closure are among the lowest known for radical reactions. The crucial step for a successful completion of the reaction is rapid trapping of the cyclopropylcarbinyl... 

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