Stereochemistry allylic substitution

Scheme 6.43. Control of allylic substitution stereochemistry with the aid of a chiral carbamate leaving group.

Recently, the scope of the allylic substitution has been extended to sulfinate salts 84 to obtain allylic sulfones 85. Due to solubility problems of both nucleophile 84 and carbonate leaving group, a polar solvent mixture of DMF and 2-methoxyethanol had to be employed, which limits the reaction to the use of a phosphine ligand. Thus, various aryl sulfinates 84 and functionalized carbonates 81 could be converted to the corresponding allylic sulfones 85 with good to excellent yields and regioselectivites and complete retention of stereochemistry (eq. 2 in Scheme 20) [65]. 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

To explain the stereochemistry of the allylic substitution reaction, a simple stereoelectronic model based on frontier molecular orbital considerations has been proposed (155, Fig. 6.2). Organocopper reagents, unlike C-nucleophiles, possess filled d-orbitals (d configuration), which can interact both with the 7t -(C=C) orbital at the y-carbon and to a minor extent with the o- -(C-X) orbital, as depicted... 

Fig. 6.2. Frontier orbital-based model to explain the stereochemistry of allylic substitution.

Lithiated allyl carbamates stereochemistry of electrophilic substitution... 

The transition metal-catalyzed allylic substitution using hard or unstabilized nucleophiles has not been extensively studied, particularly with unsymmetrical allylic alcohol derivatives. This may be attributed to the highly reactive and basic nature of these nucleophiles and the inability to circumvent regiochemical infidehty in unsymmetrical systems. Hard nucleophiles may be characterized as those that undergo substitution with net inversion of stereochemistry [29], due to their propensity to add directly to the... 

Propargylic mesylates such as fluorine-substituted derivative 265 react with PhZnCl in the presence of Pd(PPh3)4 (5 mol%) in THF at 0°C within 2 h to provide the anti-Si 2 product in excellent yield and complete transfer of the stereochemistry leading to the allene 266 (Scheme 78). Copper(I) catalyzed allylic substitutions with functionalized diorganozincs proceed with high 8 2 selectivity. Thus, the reaction of the chiral allylic phosphate 267 with 3-carbethoxypropylzinc iodide in the presence of CuCN 2LiCl (2 equivalents) furnishes the awf/-Sjv2 substitution product 268 in 68% yield. By the addition of w-BuLi (1.2 equivalents) and TMSCl (1.5 equivalents), the bicyclic enone 269 is obtained in 75% yield and 93% ee (Scheme 79) . 

Allylation of organic halides. T wo laboratories2 have reported briefly that in the presence of a radical initiator organic halides undergo allylic substitution reactions with allyltrialkyltin compounds in moderate yield. This reaction was used in a recent Synthesis of the neurotoxin (+ )-perhydrohistrionicotoxin (7) to introduce the n-butyl tide chain.3 AI BN-catalyzed reaction of the bromide 2 with 1 proceeds in unexpectedly igh yield and with complete stereocontrol to give a single product 3. It is the tndesired isomer, but the desired stereochemistry is obtained by epimerization of the Intermediate ketone 5. The hydroxy lactam (6) had previously been used for the Synthesis of 7. 

Substitution reactions allow for the introduction or change of functional groups but rely on the prior formation of the stereogenic center. The approach can allow for the correction of stereochemistry. Reactions of epoxides, and analogous systems such as cyclic sulfates, allow for 1,2-functionality to be set up in a stereospecific manner. Reactions of this type have been key to the applications of asymmetric oxidations. The use of chiral ligands for allylic substitutions does allow for the introduction of a new stereogenic center. With efficient catalysts now identified, it is surely just a matter of time before this methodology is used at scale. 

Indium-mediated allylation of 4-acetoxy-2-azetidinones affords 4-allyl-substituted azetidinones with retention of the stereochemistry (Equation (82)).320 An aminoalkoxy titanium complex is readily allylated with allylindium reagents to give homoallylic amines (Scheme 86).321... 

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). 

Scheme 26 The observed stereochemistry in allylic substitution reaction...

Enantioselective metal-catalysed allylic substitution reactions have attracted considerable attention, especially over recent years. The metal that has been most widely investigated for allylic substitution reactions is palladium. The mechanism of palladium-catalysed allylic substitution typically involves a double inversion, resulting in overall retention of relative stereochemistry. So, if the stereochemistry of the product is simply based on the stereochemistry of the starting material, how can an asymmetric synthesis be possible The answer lies in the choice of substrate for the enantioselective version of the palladium-catalysed allylic substitution reaction. For example, the substrate (10.40) proceeds via a meso intermediate complex (10.41). Which end of the allyl group the nucleophile adds to dictates which enantiomer of product will be formed, (10.42) or e r-(10.42). 

The majority of recent efforts to develop catalytic allylic substitution reactions have focused on enantioselective transformations. Most enantioselective reactions form a stereocenter at one of the allylic carbons, and this new stereocenter is formed within the coordination sphere of the metal. Less common are enantioselective substitutions that form products containing a new stereocenter at the nucleophile. These reactions have been considered challenging because the stereochemistry is set at an atom that is outside of the direct coordination sphere of the metal. 

Careful application of the three simple postulates listed above can yield insight into the mechanism and stereochemistry of biradical reactions as complex as the thermal dimerization of cis, irons-1,5-cyclooctadiene [26] or the isomerization of allyl-substituted cyclopropanes via internal [2 + 2]-cycloaddition [27]. An attempt to do so here would take us too far afield, in view of the ease with which biradical intermediates interconvert. Instead let us move on to the considerably more stereoselective cycloaddition of reactant pairs with complementary polarity, that proceeds stepwise along a zwitterionic pathway. [23]... 

Further examples of stabilized carbon-centered nucleophiles used in Pd-catalyzed allylic substitution are given in Scheme ii.wo]-[47] noteworthy that the dichloroben-zoate group of substrate 55 leaves selectively over the acetate, and that the (Z)-stereo-chemistry of the substrate becomes ( )-stereochemistry in the product 68. Nitromethane 66 is sufficiently acidic that there are no problems in the substitution reaction with acetate 59. Relative stereochemistry is preserved in the product 73. 

There have also been examples of retention of stereochemistry in acyclic substrates (Scheme 15). The enantiomerically pure acetates 97 and 98 undergo Pd-catalyzed allylic substitution with retention of stereochemistry.The regioisomeric ratio of products 99 and 100 is almost identical, indicating that the reaction proceeds via the common intermediate 101. 

Stereochemistry of the Palladium-Catalyzed Allylic Substitution— The Syn-Anti Dichotomy in the Eormation of (-Tr-Allyljpalladium Complexes and Their Equilibration. 

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