Allylation substrate-directed

Hie use of chiral catalysts as an approach to enantiomer icaliy enriched products by means of coppet-mediated substitution reactions is covered in this chapter. Reactions in which a chiral auxiliary resides in the leaving group of the substrate w ill also he dealt with, since these reactions provide direct and efBcient routes to single enantiomers of the desired products. Most studies so far have been concerned with allylic substrates, with a new chiral center being produced in the course of a selec-... 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

Ishikawa s endgame toward of 54 is shown in Scheme 3.12. First, the allylic alcohol function was oxidized by a substrate-directed dihydroxylation reaction, as developed by Donohoue and coworkers (66 % yield) [36]. This reaction is conducted using 1 equiv each of osmium tetroxide and tetramethylethylene diamine (TMEDA) and provides a method to obtain the syn-A i hydroxylation product in the... 

As practiced in the preceding syntheses by Evans and Nishiyama and Yamamura, the A-ring fragment 43 is formed through substrate-directed vinylogous aldol reaction of the Brassard-type diene 19 and the chiral aldehyde 42, which is prepared using Brown s protocols for enantioselective allylation [53], followed by hydroxy-directed nnn-diastereoselective reduction of the C3 ketone (Me4NB(OAc)3H) [41],... 

SCHEME 24. Possible transition state structures for ene reaction of 02 with allylic substrates, with directing effect of the functional groups (right side, TS C) and without this directing effect (left side and middle, TS A and B)... 

In the epoxidation of acyclic allylic alcohols (Scheme 6), the diastereoselectivity depends significantly on the substitution pattern of the substrate. The control of the threo selectivity is subject to the hydroxyl-group directivity, in which conformational preference on account of the steric interactions and the hydrogen bonding between the dioxirane oxygen atoms and the hydroxy functionality of the allylic substrate steer the favored 7r-facial... 

See also the direct reaction of aldehydes and ketones with allylic halides and other allylic substrates plus metals earlier in this section, as well as page 236, Sections 7 and 8, far ene-type reactions. 

Substitution reactions of allylic substrates with nucleophiles have been shown to be catalyzed by certain palladium complexes [2, 42], The catalytic cycle of the reactions involves Jt-allylpalladium as a key intermediate (Scheme 2-22). Oxidative addition of the allylic substrate to a palladium(o) species forms a rr-allylpal-ladium(n) complex, which undergoes attack of a nucleophile on the rr-allyl moiety to give an allylic substitution product. The substitution reactions proceed in an Sn or Sn- manner depending on catalysts, nucleophiles, and substituents on the substrates. Studies on the stereochemistry of the allylic substitution have revealed that soft carbon nucleophiles represented by sodium dimethyl malonate attack the TT-allyl carbon directly from the side opposite to the palladium (Scheme 2-23). 

A direct N-substitution of an allylic substrate with an oxygen leaving group (equation 19) lacks generality and the problem of regio- and stereo-selectivity also arises in Pd-catalyzed reactions. Such a substitution via rr-allyl-palladium intermediates may 1m useful in cases where the steiic situation allows only one mode of attack, as exemplified in the key step of an ibegamine synthesis by Trost, where the intramolecular reaction leads to clean allylic syn substitution (equation 20). ... 

The stereochemistry of the direct substitution reaction has been the subject of some debate. Most recently, it has been reported that reactions of alkylheterocuprates proceed with high syn selectivity, while inversion of allenyl configuration, or anti selectivity, is observ in reactions of phenylcopper reagents. The degree of selectivity is variable and may be a reflection of product isomerization under the reaction conditions. Predominant anti stereoselectivity (anti syn ratios range from 91 9 to >99 1) is observed also in Sn2 reactions of allenyl halides (see Scheme 3), a finding that is consistent with the known preference for anti substitution of allylic substrates (see Section I.5.2.4.5). This method for al-kyne preparation has found application in the leukotriene area, and also for the synthesis of alkoxy al-kynes. ... 

Allylic substitutions. Both carbon and nitrogen nucleophiles are suitable for displacement of allylic substrates. Thus, A -allylation of TV-protected amino acid esters and peptides is readily performed at room temperature under neutral conditions with allyl ethyl carbonate. Regiocontrol of alkylation by addition of Lil is noted. Heteroatom-directed regioselective substitution is observed. ... 

Kishi and co-workers elegantly demonstrated the power of substrate-directed cro-tylation reactions in their synthesis of the C(15)-C(29) segment 83 of rifamycin S (Fig. 11-10) [61]. This synthesis utilizes two crotylation reactions with the Noza-ki-Hiyama crotylchromium reagent 8 [18, 19] and one allylation reaction using allyldichloroiodostannane [79]. 

The excellent diastereoselection of all three of these substrate-directed allylation reactions is consistent with reaction occurring through Felkin transition states analogous to 39 (Fig. 11-6). These examples illustrate the excellent stereochemical control opportunities that exist in ( )-crotylation reactions of a-methyl chiral aldehydes, especially when the -position is branched (as in the (7s)-crotylation of 25 and 32, see above). 

In their synthesis of olivin, the aglycon segment of olivomycin A, Roush and coworkers used a highly diastereoselective substrate-directed y-alkoxy allylation reaction to set the C(l ) stereocenter [80]. Thus, reaction of the aldehyde 90, derived from L-threonine, with the [(Z)-y-methoxyallyl]boronate 91 resulted in the highly diastereoselective formation of adduct 92. The stereochemistry of 92 is consistent... 

Keck and co-workers used substrate-directed Type II allylations on three different occasions for their synthesis of the C(I0)-C(20) segment 145 of rhizoxin (Fig. 11-12) [85]. 

As is the case for the [2,3] Wittig rearrangement, the stereochemical consequences of the [2,3] ylide rearrangement are sensitive to perturbation by external steric and stereoelectronic factors, presenting a useful opportunity for both substrate- and reagent-based asymmetric induction. Rearrangements of carbene-derived ylides of allylic sulfide 1 provide a simple example of substrate-directed diastereosclcction, in which diastereoface selectivity results from attack on the exocyclic olefin via the less-hindered equatorial approach vector112. 

Generation of ylides by reaction of allylic substrates with diazo compounds, catalysed by Rh(OAc)4 and Rh6(CO)i6, has been reported. In this case, a heterocyclic intermediate is not observed and the reaction could proceed directly. 

---