Regiocontrolled -cycloadditions

Substituted TMM complexes also cycloadd to aldehydes in the presence of a tin cocatalyst such as MesSnOAc and MesSnOTs [31]. Reaction of 2-heptenal with methyl precursor (6) gave a mixture of methylenetetrahydrofurans (68) and (69). This regioselectivity is reversed with 10-undecenal and methyl precursor (5), where adduct (70) now predominates over (71). As in the carbocyclic system, the phenylthio group also functions as a regiocontrol element in reaction with cyclohexyl aldehyde. The initially formed adduct (72) eliminates the element of thio-phenol on attempted allyl rearrangement, and the overall process becomes a cycloaddition approach to furans (Scheme 2.21) [20]. 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

Wang, J. Pettus, L. H. Pettus, T. R. R. Cycloadditions of o-quinone dimethides with p-quinol derivatives regiocontrolled formation of anthracyclic ring systems. Tetrahedron Lett. 2004, 45, 1793-1796. 

Albeit nitrile oxides are more regioselective than nitrones towards MCP, in cycloadditions with alkylidenecyclopropanes they show a lower regiocontrol than nitrones. The same trend, however, on passing from electron-donating to electron-withdrawing substituents is observed. Benzylidenecyclopropane (156) gives (entry 1, Table 28) only a 1 4 mixture (compared with 1 19 with nitrone... 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

However, replacement of LiBr with AgOAc inverted the ratio of exo to endo products. For Ar = 334, the major adduct was isolated in 42% yield with an endo/ exo ratio of 1 1.7, while Ar = 335 gave 333 in 36% yield with an endo/exo ratio of 1 2.3. Note that attempts at the thermal reaction met with low yields of complex reaction mixmres containing all possible regio- and stereoisomers. This smdy exemplifies the value of metal mediation in the stereo- and regiocontrol of azomethine ylide cycloadditions. 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

Since a magnesium alkoxide undergoes rapid ligand exchange with free alcohols even in dichloromethane at ambient temperature, the regiocontrol of nitrile oxide cycloadditions of multisubstituted allylic alcohols can be effectively attained... 

N/L recorded was 16,000 for the reactions using the magnesium aUcoxide of 3-methyl-2-buten-l-ol as a multisubstituted internal allylic alcohol substrate, which is why regiocontrol is still effective in the reactions in a highly coordinating solvent such as THE. Rate enhancement is much lower in the nitrile oxide cycloaddition reactions using homoallylic alcohol substrates. 

Regiocontrol of nitrile oxide cycloadditions through inclusion complexes has been reported by Easton and co-workers (143). The 1,3-dipolar cycloaddition of... 

High stereo- and regiocontrol in nitrile oxide cycloadditions to allylic alcohols in the presence of magnesium ions (see Section 11.2.2) makes extension of this... 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

Since the work of Kelly, there have been very few reports that focus upon applications of synthetic linear templates to chemical synthesis. Most recent studies have focused on systems that self-replicate [13]. A synthetic system based on a barbituric acid has been shown to organize two cinnamates in apolar media, by way of N-H N and N-H O forces, for a regiocontrolled [2 + 2] ultraviolet-(UV) induced cycloaddition reaction (Figure 3b) [16]. Similar to the system of Kelly, a mixture of products was attributed to free rotation about C-C bonds of the reactants. 

The ability of a linear template to orient two identical pyridyl units in a face-to-face stacked arrangement suggested that a linear template might be used to assemble two unsymmetrical reactants for a head-to-head photodimerization. Since different combinations of hydrogen-bond acceptor sites may be employed for the reaction (i.e. I runs-1 -( -pyndyl)-2-(n/-pyridyl)e(hylene (where n,m =2, 3, or 4 n f m)), a general means to establish regiocontrol of the cycloaddition could be achieved. 

Consistent with most tethered photocycloadditions, the photoproducts obtained from silicon tethered irradiations are formed with complete regiocontrol [19]. Several examples of silyl tethered groups have been reported. Scheme 16 lists the variants that have been successful. As mentioned previously, the mechanistic pathway that is most consistent with the results involves interaction between the alkenes prior to cycloaddition. The experimental observation is that cycloadducts are formed only when the alkenes have extended n systems attached. 

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