Cyclization mediated reactions

Cyclization-Mediated Reactions Synthesis of Deoxy Sugars.186... 

FIGURE 14.23 RNA splicing in TetraAjimejta rRNA matnradon (a) the gnanosine-mediated reaction involved in the antocatalytic excision of the Tetrahymena rRNA intron, and (b) the overall splicing process. The cyclized intron is formed via nncleophilic attack of the 3 -OH on the phosphodiester bond that is 15 nncleotides from the 5 -GA end of the spliced-ont intron. Cyclization frees a linear 15-mer with a 5 -GA end. 

The chemistry and utility of zinc-based Lewis acids are similar to those of their magnesium analogs. Their mild Lewis acidity promotes several synthetic reactions, such as Diels-Alder reactions, hetero Diels-Alder reactions,229 radical-mediated reactions,230 ene-type cyclization, and Simmons-Smith reactions. 

The mechanism presumably involves initial oxidative addition of the alkenyl halide to the Cu(I) species and ensuing cyclization analogy for this type of process is provided by the Cu(I)-mediated reaction of phthalimide anions with alkenyl and aryl halides.40 The -isomer of 15 reacts in a different fashion to give an isothiazolidinone derivative, albeit in low yield. 

To probe the reaction mechanism of the silane-mediated reaction, EtjSiD was substituted for PMHS in the cyclization of 1,6-enyne 34a.5 The mono-deuterated reductive cyclization product 34b was obtained as a single diastereomer. This result is consistent with entry of palladium into the catalytic cycle as the hydride derived from its reaction with acetic acid. Alkyne hydrometallation provides intermediate A-7, which upon cw-carbopalladation gives rise to cyclic intermediate B-6. Delivery of deuterium to the palladium center provides C-2, which upon reductive elimination provides the mono-deuterated product 34b, along with palladium(O) to close the catalytic cycle. The relative stereochemistry of 34b was not determined but was inferred on the basis of the aforementioned mechanism (Scheme 24). 

The formation of C—C bonds is generally considered to be more important than the formation of C—H bonds. It is therefore not surprising that these reactions have attracted more attention. Of special importance in organic synthesis are 5 -exo cyclizations [17], and the titanocene-mediated reactions are a valuable tool for carrying out these transformations. Three examples are shown in Scheme 12.9. 

Although cyclizations from the direct anodic oxidation of acyclic 1,3-dicarbonyl compounds have not been reported, the analogous mediated reactions have been studied [24]. Snider and McCarthy compared oxidative cyclization reactions using a stoichiometric amount of Mn(OAc)3 with oxidations using a catalytic amount of Mn(OAc)3 that was recycled at an anode surface (Scheme 11). In the best case, the anodic oxidation procedure led to a 59% yield of the desired bridged bicyclic product with the use of only 0.2 equivalents (10% of the theoretical amount needed) of Mn(OAc)3- Evidence that the reaction was initiated by the presence of the mediator was obtained by examining the electrolysis reaction without the added Mn(OAc)3. In this case, none of the cyclized product was obtained. For comparison, the oxidation using... 

Reaction (7.13) shows the simplest and most popular type of hex-5-en-l-yl radical cyclization mediated by (TMS)3SiH. Thus, a 50 mmol solution of 5-hexenyl bromide and silane in the reported conditions leads to a 24 1 ratio of cyclized vs uncyclized products [6]. Similar results were obtained by replacing the bromide with isocyanide [7]. 

The construction of an indolizidine skeleton has been successfully obtained by radical cyclizations mediated by (TMS)3SiH. Reaction (7.44) represented a key step in the total synthesis of (—)-slaframine. The two pairs of diastereomers were first separated and then hydrolysed to the corresponding alcohols in a 76% overall yield [55]. On the other hand the cyclization of the A-iodopropyl pyridinones in Reaction (7.45) occurs smoothly at room temperature using Et3B/02 as initiator, to give the desired products with a trifluoromethyl group at the bridgehead position in a syn/anti ratio of 7 3 [56]. 

Cyclizing ca-chloro Reissert compound 136 gives rise to tricyclic lactam 137 (72JHC541). In a study of the cobalt-mediated reaction of pyridones with alkynes, in the case of the N-hexynyl compound, C-H activation with... 

Reactions of 5-siloxy-5-en-l-ynes are summarized in Table 5.2. In every case the reaction proceeds at rt in the presence of H2O to give cyclized p,y-unsaturated ketones in good yield without isomerization of the double bond, even using only 10 mol% W(CO)5(thf). The most characteristic feature of this reaction is that the endo mode of cyclization occurs more readily than in other related cyclization reactions such as HgCl2-mediated reactions. 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

The nitrone 127 (96% ee) containing an additional carbon atom was synthesized in a similar manner as 124. However, for nitrone 127, no spontaneous cyclization took place (Scheme 12.43). Upon heating of 127 in toluene, an inseparable mixmre of product isomers was formed. It was also found that in the presence of a stoichiometric amount of ZnCl2, the reaction proceeded to give the bicyclo[4.2.1] product 128 as the only observed product with close to complete retention of enantiopurity (ee=94%). The authors propose a more polarized transition state of the Zn-mediated reaction with a well-developed positive charge on one of the carbon atoms of the alkene moiety to account for the inverted direction of the regioselectivity of the reaction (230). A subsequent reduction gave the functionalized cycloheptane 129. 

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 1998, Oshima and coworkers ° reported few examples of radical cyclization mediated by Grignard reagents in the presence of iron(II) chloride (Scheme 57). However, this reaction often gives moderate yields. 

Radical carbonylation can also be conducted in a zinc-induced reduction system. A similar three-component transformation reaction to that illustrated in the second equation of Scheme 6.14 can be attained using zinc and protic solvents (Scheme 6.38) [59]. The observed stereochemical outcome is identical to that for the tin hydride-mediated reaction, providing a additional evidence for free-radical generation, radical carbonylation, and acyl radical cyclization taking place simultaneously, even in the zinc-induced system. In this system, however, the final step is reduction to form a carbanion and protonation. 

Neutral aminyl radicals generated from tin hydride-mediated reactions of sulfenamides (Section II,F) have been shown to undergo cyclizations when energetically favored by addition to a strained alkene or by formation of a stabilized intermediate benzylic radical. In both cases, the reverse reaction, cleavage of the /3-amino radical, apparently did not occur (92TL4993). 

---