Homoallylic position

The zirconocene catalysts described above are very oxophilic, which provides several synthetically useful transformations. Oxygen substitution at the al-lylic or homoallylic position of an olefin substrate allows for excellent regio-and diastereocontrol in the ethyl magnesiation reactions of a-olefins and dienes [21]. When 29 is substituted with a hydroxyl group (29a), syn 30a is favored over anti in a 95 5 ratio, while substitution with OCH3 (29b) reversed the diastereoselectivity to 11 89 (Eq. 6). Use of THF in place of diethyl ether as the reaction solvent for the reaction of 29a lowered the overall diastereo-... 

Pioneering studies of Trost and his co-workers have explored all the parameters of this reaction. An interesting piece of work has, for instance, shown that the presence of an ether or a silyl ether in a substrate also exerts a profound effect on the regioselectivity of the cyclization. Thus, a silyl ether group at the allylic position (202) furnishes the corresponding 1,3-diene 203, whereas an ether group at the homoallylic position gives exclusively the 1,4-diene 205 (Scheme 50).210... 

In the case of cyclopentenyl carbamate in which a directive group is present at the homoallyl position, the cationic rhodium [Rh(diphos-4)]+ or iridium [Ir(PCy3)(py)(nbd)]+ catalyst cannot interact with the carbamate carbonyl, and thus approaches the double bond from the less-hindered side. This affords a cis-product preferentially, whereas with the chiral rhodium-duphos catalyst, directivity of the carbamate unit is observed (Table 21.7, entry 7). The presence of a hydroxyl group at the allyl position induced hydroxy-directive hydrogenation, and higher diastereoselectivity was obtained (entry 8) [44]. 

Finally, a homoallylic THP ether may be involved in directing the cyclopropanation reaction of a trimethylsilyl enol ether (equation 54) . The lower diastereoselectivity may be a consequence of the remote position of the directing group (homoallylic position). 

For alkenylmetals bearing two stereocenters at both the allylic and homoallylic positions, two situations have to be distinguished depending on their relative influence (matched or mismatched) with respect to the stereochemical outcome of the allylzincation. Not surprisingly, in the matched case, as illustrated for substrate 232, the diastereoselectivity was excellent and 233 was obtained as a single diastereomer. The allyl moiety was delivered anti to both the allylic and homoallylic substituents in the chelated allyl alkenylzinc species (equation 113). 

Fluorocholcst-5-cnc, whose C-F bond is in the homoallylic position of the A5-doublc bond, is successfully hydrogenolyzed to cholest-5-ene with potassium dissolved in crown ether/toluene mixture in 88% yield.25... 

Double bonds further removed from the incipient carbocation than the homoallylic position can also assist, in jonizatien-if the..geometry of the system. allows Tt. For example -nitrobenzoate (59) solvolyzes 1500 times faster than the corresponding saturated compound in aqueous acetone. The product is trans,trans-1 -decalol (60). If after 12 half-lives the product is iso-... 

The hydroxyl group at the allylic position has a significant effect on the syn/anti methyl stereoselectivity [67,68] and the diastereoselectivity [63,64] of the photo-oxygenation ene reaction (see Sec. II.B). To assess the effect of the hydroxyl at the more remote homoallylic position, the reaction of O with the geminal dimethyl trisubstituted homoallylic alcohols (85, 86, 89) and the cis dis-ubstituted 90 was examined in nonpolar solvents [116], The regioselectivity trend was compared with that of the structurally similar trisubstituted alkenes (87, 88, 91) [105], The results are summarized in Table 12. 

These sulfoxides, 99(/ ) and 99(5), which mimic the homoallylic position of sulfur at S13 oleic acid, were used as models to determine the best chiral shift agent for analyzing the stereochemistry of dialkyl sulfoxides with complex spin systems43 generated in the oxidation of thio-oleic acid formed in in vivo experiments. 

C). Also, the presence of a lithium alkoxide group allows the cyclization of primary as well as tertiary alkyllithiums at temperatures as low as — 78 °C. Thus, cyclopentanol derivatives 160 are easily obtained from alcohols 159 in very high yields and as single diastereoisomers (Scheme 45). As shown with thioether 161, when the alkoxide group is placed in a homoallylic position, the reaction is even more effective and cyclized product... 

The reaction shows moderate to high regioseleciivity as well as fair to good diastereo-selectivity when the substrate is substituted in the allylic or homoallylic position. 

Chlorohydroxylation of alkenes.1 Anhydrous f-butyl hydroperoxide or di-f-butyl peroxide (1, 211-212) in the presence of TiCl4 effects chlorohydroxylation of alkenes. The reaction shows moderate to high regioselectivity as well as fair to good diastereo-selectivity when the substrate is substituted in the allylic or homoallylic position. Examples ... 

Diastereoselective hydroxylation has also been observed at an alkenic center in an acyclic system that is guided by a sulfoxide group that is more remote than the homoallylic position. Alkenes (18 equation... 

Interestingly, the titanium(IV) isopropoxide catalyzed process can still be highly diastereoselec-tivc28. In certain cases with more Lewis acidic catalysts (Cl, TiO-/-Pr or EtAlCl2) even acetalic oxygen in a homoallylic position can induce stereospecificity22. 

The process was simple and accommodated a wide range of substrates. Indeed, the initial paper32 reported successful application to allylic alcohols containing five of the six possible mono- and disubstitution patterns. Removal of the hydroxy group to a homoallylic position reduced the enantioselectivity below useful levels (<50%). 

Cyclic Alkenes. The directing effect of alcohol substituents is perhaps most dramatically demonstrated with cyclic alkenes in which products are formed via hydrogenation from the more hindered face (Table 1). Entries 1-3 serve to illustrate that the directing alcohol may reside in either the allylic, homoallylic, or bis(homoallylic) position relative to the alkene undergoing hydrogenation, while synthetically useful levels of selectivity are retained. Entry 4 is included to illustrate the dramatic steric congestion which can be overcome in directed hydrogenation... 

The presence of a heteroatom in the olefin at an allylic or homoallylic position considerably stablizes the zinc organometallic compound obtained after the hydrozincation of the olefin. Thus allylic alcohols and amines are especially well suited as substrates for this hydrozincation procedure. 

The effect of a stereogenic center in the homoallylic position on the diastereoselectivity of cyclization is illustrated in entries 6 and 79. Only moderate 4,6-cis stereoselectivity is observed for alkyl substituents (cf. Table 14). The alkyl group is situated preferentially in the pseudoe-quatorial position of a chair-like transition state, thereby minimizing steric interactions with the enolate moiety. Since the diastereomeric ratio is independent of the reaction time, an irreversible reaction is indicated. Interestingly, Michael addition of a nucleophile to the corresponding 3,/ -unsaturated lactone leads predominantly to the 4,6-//-[Pg.215]

The influence of adjacent stereogenic centers on the diastereoselectivity of the cyclization is addressed in entries 4 13. Alkyl or aryl substituents in the homoallylic position lead only to a moderate preference for the 4,6-m-product (Table 14, entries 4 7)9. Surprisingly, the triflu-oromethyl group exerts complete stereocontrol, which is attributed to its steric and additional electronic repulsion of the enolate moiety in the cyclization transition state (for a detailed discussion see the preceding section). The intramolecular reactions of the bissulfone derivatives (Table 14, entries 11 -14)19 feature a contrathermodynamic production of mainly civ-substituted vinylcyclopentanes. Epimerization of the zr-allyl complex is faster than cyclization, so that an equilibrium between the different isomeric zwitterions is established. Due to unfavorable steric interactions with the substituent R, palladium is preferentially located irunx to R in the cyclization transition state favoring the m-product. The use of toluene, tetrahydrofuran, and acetonitrile as solvents results in poorer diastereoselectivities. Some restrictions apply to the kind of nucleophile employed, thus 2-oxo esters may only give the 0-alkylated product (cf. Table 12)2 19-20. 

Using Simmons-Smith type reagents, hydroxy and alkoxy groups in the allylic or homoallylic position exhibit a very strong syn-directing effect on methylene transfer, which usually overrides the steric influence of further substituents in an alkene2,5 (see Table 2 for the transformation of simple cyclic alkenes)29 32. 

The reactions of cycloalkenes bearing a methoxy group in the allylic or homoallylic position with the chlorocarbenoid generated from butyllithium and dichloromethane are highly syn selective19. For 3-methoxy-substituted olefins the diastereofacial selectivity can be as high as 97 3, while 4-methoxycycloalkenes react with remarkably less selectivity. A precomplexation of the carbenoid to the methoxy group is plausibly assumed to be responsible for the predominant delivery from the sterically more hindered side. 

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