Titanium-mediated cyclization

Improved methods for preparing isoquinolines through ring closure at the C4-aryl bond were reported (Scheme 9). The Pummerer reaction induces cyclization of the iV-formylbenzylamine sulfoxide 40 by treatment with TFAA or BFj OEt/TFAA <99H(51)119>. The unactivated titanium-mediated cyclization of the Schiff base 41 to 6-methoxyisoquinoline is effected through intermediacy of the Ai"-ethylcarbamate-aminophosphate derivative 42 <99SC1617>. 

Titanium Mediated Cyclization of a Diyne 1,2-E, E-bis(Ethylidene)cyclohexane... 

An alternate synthetic approach to tetrathia[24]porphyrin-(2.2.2.2) 4.167 was reported by Cava and coworkers in 1994. It involved the low-valent titanium-mediated cyclization of 2,5-thiophenedicarboxaldehyde 4.164 and afforded 4.167 in... 

An alternative route to 1,2-diselenines involved titanium-mediated cyclizations of terminal alkynes or allenes, followed by trapping with selenocyanogen and then treatment with tetrabutylammonium fluoride or samarium(ll) iodide (Schemes 16 and 17) <2000JA5052>. Mixed alkyne-allene reactions are also successful using this procedure (Scheme 18). Titanacycles 85-87 are key synthetic intermediates in these reactions. 

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

A novel route to 2,3-dihydrothiophenes involved a titanocene-promoted carbene formation and subsequenct intramolecular cyclization onto a thiol ester <99SL1029>. Treatment of thioacetal 9 with the low-valent titanium complex 10 gave 2,3-dihydrothiophene 12 by intramolecular olefination of the thiol ester of titanium-carbene intermediate 11. Another metal-mediated cyclization onto the thiophene ring system involved the palladium-catalyzed cyclization of 1,6-diynes <99T485>. For example, treatment of thioether 1,6-diyne 13 with Pdlj in the presence of CO and Oj in methanol followed by treatment with base gave 14. 

The protected aniline 179 undergoes titanium tetrachloride-mediated cyclization to give the protected indole (Equation 115) <1998EJM839>. 

By choosing an appropriate titanium complex, a /ra r-isomer of 1,2-cyclohexanols can be prepared selectively. Because intramolecular pinacol coupling of hexanedials with Sml2 usually produces t-isomers of cyclohexane-1,2-diols, the titanium-mediated reaction complements the samarium-mediated cyclization (Equation (17)). In addition, when a /-butyl group fixes the conformation of the substrate, one of the diastereomers is produced selectively (Equation (18)). ... 

In place of a Grignard reagent, several homoenolate equivalents have also been employed. Kempt 1 7 reported the titanium-mediated addition of /V-alkylmethylacrylamide dianions to N-protected a-amino aldehydes (Scheme 8). Pyrolytic cyclization affords a 3-methylenetetrahydrofuran-2-one and the side chain of C3 is appended via conjugate addition. The resulting lactone can be converted into the 1-hydroxyethylene dipeptide by hydrolysis. The stereochemistry of the C6 atom is the same as that of the a-amino aldehyde. However, the stereoselectivities of the reactions regarding the C3 and C5 atoms are unsatisfactory. 

Furstner et al. synthesized lamellarin O dimethyl ether following their previous research on carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling reactions <94JOC5215, 95JA4468>. A new titanium-mediated approach to pyrrole synthesis, based on the cyclization of a 3-acylamino-enone, was reported <95JOC6637>. 

Periplanone C. McMurry has reported an enantioselective synthesis of (-)-periplanone C, a sesquiteipene that serves as a sex pheromone for cockroaches, through a route involving a pinacol cyclization of a 1,10-keto aldehyde (Eq. 3.7) [24]. MM2 calculations based on a model for predicting the stereoselection of titanium-mediated pinacol coupling reactions were in qualitative, but not quantitative, agreement with the experimental results. 

Palominol. Corey has reported the application of an intramolecular titanium-mediated pinacol coupling reaction to the synthesis of a 15-membered ring, en route to palominol, a marine diterpenoid that displays cytotoxicity toward the human colon cell line (Eq. 3.10) [28]. Slow addition of the keto aldehyde (32 h) to the titanium reagent furnished the cyclized product in 53% yield as a mixture of diastereomers (2.1 1). 

Mukaiyama has described a total synthesis of taxol wherein pinacol cyclization of a diketone was employed to construct the A ring in good yield (Eq. 3.13) [31J. In this work, partially reduced alcohols and rearranged compounds were the major side products of the titanium-mediated coupling process. 

Similar acid mediated cyclizations have been reported on a variety of substrates. For example, as shown in Scheme 7.3.2, Casiraghi, etal.,14 treated 2,3,4,6-tetra-O-benzyl-D-glucopyranose with a pyrrole-derived Grignard reagent and a titanium based Lewis acid. As shown, the addition proceeded in 64% yield with the formation of a single diasteriomer. Subsequent exposure to an acidic DOWEX resin provided a 50% yield of the p-C-glycoside and an additional 21% isolated as the corresponding a anomer. 

Similar cyclizations using piperidines with leaving groups at C-2 are probably mediated by iminium ions. For example, a total synthesis of epilupinine <83H(20)40i > relies on the anodic oxidation of the lactam (223) to the methoxy derivative (224), which was subsequently converted into the quinolizidine (225) through a titanium tetrachloride-mediated cyclization, a reaction that has been... 

Lewis acid mediated intramolecular C-C bond formations represent another major class of reactions adaptable to seven-membered ring synthesis. A superb example of this class is found in the work of Majetich, which features a titanium-induced cyclization reaction employed in the synthesis of several natural products, including bar-batusol (Eq. 4)7 Although technically this closure has a nucleophilic... 

The preparation of fnnctionalized pyrroles has been accomplished through titanium-mediated reactions (Scheme 3.74) [79]. The first step in the process involves the generation of a metaUocycle from the reaction of a diyne with the titanium reagent that was generated in solntion. Once formed, treatment of the titanacycle with an activated imine followed by hydrolysis generated the pyrrole. The overall reaction can be described as an imino aza-Nazarov cyclization, and the process generated good to excellent yields of the 3-aminopyrroles. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

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 synthesis of p-lactams enantiomerically pure, via a multistep Gilman-Speeter type reaction [139] has been reported to be carried out with chiral oxazo-lidinones [140]. Titanium tetrachloride mediated condensation with imine gave an intermediate p-amino acyloxazolidinone, the major diastereomer of which could readily be purified by Si02 chromatography. Silylation and fluoride catalyzed cyclization gave the final p-lactam (Scheme 53). 

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

The reaction between ClTi(Of-Pr)3 and 7-PrMgBr generates a low-valent titanium reagent, diisopropoxy(q2-prope-ne)titanium, which mediates the cyclization of the alkynic carbonates 1158 to isochroman-3-ones 1160 via the intermediate 1159 (Scheme 287) <1995TL6075, 1996JA2208>. 

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