Acetals asymmetric allylation

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

Pd-catalyzed asymmetric allylic alkylation is a typical catalytic carbon-carbon bond forming reaction [ 126 -128]. The Pd-complex of the ligand (R)-3b bearing methyl, 2-biphenyl and cyclohexyl groups as the three substituents attached to the P-chirogenic phosphorus atom was found to be in situ an efficient catalyst in the asymmetric allylic alkylation of l-acetoxy-l,3-diphenylprop-2-en (4) with malonate derivatives in the presence of AT,0-bis(trimethylsilyl)acetamide (BSA) and potassium acetate, affording enantioselectivity up to 96% and quantitative... 

Moreover, a few chiral ferrocenylsulfur-imine ligands were investigated in the palladium-catalysed asymmetric allylic alkylation of 1,3-diphenylpropenyl acetate and cyclohexenyl acetate with dimethyl maionate (Scheme... 

Bayardon and Sinou have reported the synthesis of chiral bisoxazolines, which also proved to be active ligands in the asymmetric allylic alkylation of l,3-diphenylprop-2-enyl acetate, as well as cyclopropanation, allylic oxidations and Diels-Alder reactions. [62] The ligands do not have a fluorine content greater than 60 wt% and so are not entirely preferentially soluble in fluorous solvents, which may lead to a significant ligand loss in the reaction system and in fact, all recycling attempts were unsuccessful. However, the catalytic results achieved were comparable with those obtained with their non-fluorous analogues. 

Campos et al. reported asymmetric synthesis of the DP receptor antagonist 42 starting from (f )-2-cyclopentene-1-acetic acid obtained via asymmetric allylic... 

Pfaltz s group also investigated ligand 139 in the reaction involving the asymmetric allylic acetate 141. A substitution ratio (142a/142b) of 93 7 was observed in this case and both products were obtained as pure enantiomers (Fig. 9.43h). 

Palladium(0)-catalyzed a-allylation of silyl ethers is a reaction which can be carried out with ketones as well as with aldehydes91. It is highly regiospecific when applied to ketones. a-Allylations can also be performed with enol acetates using allyl carbonates in the presence of catalytic amounts of palladium(O) complexes and (tributyl)methoxytin92,93. The steric course of the reaction has not been studied systematically but a high level of diastereoselectivity is expected and possibilities for asymmetric induction by the use of chiral auxiliaries are envisaged. 

As described in the previous section, when acyclic and symmetric allylic esters such as l,3-diphenyl-2-propenyl acetate and l,3-dialkyl-2-propenyl esters are used as substrates, high to excellent enantioselective allylic alkylation is performed by using a variety of chiral ligands. In contrast, the number of successful examples of the asymmetric allylic alkylation of acyclic and unsymmetric allylic esters is relatively limited. 

Figure 8.9 Results of palladium-catalyzed asymmetric allylic alkylation of 1,3-di phenyl al lyl acetate and dimethyl malonate upon applying a ligand library of self-assembled bidentate ligands. The ligands a-i on the x-axis are defined in Figure 8.8. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

While alkyl halides are typically employed as an electrophile for this transformation, Takemoto developed palladium-catalyzed asymmetric allylic alkylation of 1 using allylic acetates and chiral phase-transfer catalyst 4k, as depicted in Scheme 2.5 [ 2 3 ]. The choice of triphenyl phosphite [(PhO)3P] as an achiral palladium ligand was crucial to achieve high enantioselectivity. 

Takemoto and coworkers extended their palladium-catalyzed asymmetric allylic alkylation strategy using allyl acetate and chiral phase-transfer catalyst to the quaternization of 13 [23b]. A correct choice of the achiral palladium ligand, (PhO P, was again crucial to achieve high enantioselectivity and hence, without chiral phosphine ligand on palladium, the desired allylation product 15 was obtained with 83% ee after hydrolysis of the imine moiety with aqueous citric acid and subsequent benzoylation (Scheme 2.12). 

The asymmetric allylic acetoxylation of cycloalkenes has also been reported. In this case, the catalyst is a bimetallic palladium(II) complex bearing a chiral bisox-azoline or a chiral diphosphine (DIOP). The reaction is performed in acetic acid/ sodium acetate under oxygen atmosphere at room temperature. Under these conditions, acetoxylation products of cyclohexene and cydopentene are obtained with 55 % and 78 % ee, respectively, albeit in low yields [39a]. 

Scheme 3 Asymmetric allylic amination of l,3-diphenyl-l-propene-3-acetate catalyzed by Pyrphos-palladium complexes...

The obtained amino functionalised imidazolium salts could be used to generate the corresponding palladium(ll) carbene complexes using the silver(l) complexes as carbene transfer agents. Application of these palladium(ll) complexes (predominantly in situ) in asymmetric allylic alkylation reactions between ( )-l,3-diphenylprop-3-enyl acetate and dimethyl malonate (a standard reaction for this catalytic process [145]) gave up to 80% ee,... 

A study of the synthesis of chromans from allylic carbonates involving Pd-catalysed asymmetric allylic alkylation has established that the addition of acetic acid results in a pronounced increase in enantioselectivity. Furthermore, (E) allylic carbonates afford (R) chromans and the (Z) substrates the (S) heterocycle (Scheme 13) <03JA9276>. This approach to chromans has been combined with a radical epoxide cyclisation in a total synthesis of (-)-siccanin <03AG(E)3943>. 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

Racemic conduritol B acetates and carbonates provide very versatile substrates for asymmetric allylic substitution reactions. Re-... 

Reactions with Sulfur Nucleophiles. The use of sulfur nucleophiles in palladium-catalyzed allylic substitution reactions is less well documented than that of carbon, nitrogen and oxygen nucleophiles. The asymmetric synthesis of allylic sulfones utilizing a catalytic phase transfer system has been used to produce (35)-(phenylsulfonyl)cyclohex-l-ene on a 45 g scale (eq 10). In many cases, it has been reported that allylic carbonates are more reactive than allylic acetates in asymmetric allylic substitution... 

The final approach was elegantly presented by Panek [44]. Several optically active ( )-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by la to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of la is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (-F)-macbecin I involving triple use of the strategy imderscores the utility of the la-catalyzed asymmetric allylation [44c]. 

Solid-supported synthesis has rapidly emerged as an important strategy in synthetic organic chemistry. Solid-phase methodology is aimed at the direct synthesis of libraries of molecularly diverse compounds for biological evaluation in lead discovery. The asymmetric addition of polymer-supported chiral crotylsilanes to acetals and allylation of polymer-bound acetals linked through an ester with the chiral crotylsilanes has been investigated [44d] la can be employed in these crotylation reactions and results in the formation of polymer-supported homoallylic esters with diastereoselec-tivity similar to that of solution-phase reactions. 

The ferrocenylphosphine (R)-(S)-8a is also effective for the asymmetric allylation of several other active methine compounds, including 2-acetyl-1-tetralone, 6,6-dimethyl-2-acetylcyclohexanone, 2-acetylcyclooctanone, 1 -phenyl-2-methylbutane-1,3-dione, 2-phenylpropanal, and methyl a-isocyano(phenyl)acetate [43, 44], The allylation products and the values of enantiomeric excess are shown in Scheme 2-26. 

---