Asymmetric allyl amides

Nitrene transfer to selenide is also possible. Catalytic asymmetric induction in this process has been studied with Cu(OTf)/bis(oxazoline) catalyst (Scheme 22). When prochiral selenide 206 and TsN=IPh are allowed to react in the presence of Cu(OTf)/chiral bis(oxazoline) 122b, selenimide 207 is obtained with enantioselectivity of 20-36% ee. When arylcinnamyl selenide 208 is applied to this reaction, corresponding selenimide 209 is produced which undergoes [2,3]-sigmatropic rearrangement to afford chiral allylic amides 211 in up to 30% ee. 

Planar chiral phosphaferrocene-oxazolines (379) constitute another family of complexes that are usefiil as ligands in asymmetric catalysis. Preparation of these takes advantage of a modified Friedel-Crafts acylation of (373) and an unusual conversion of the resulting trifluoromethyl ketone into an amide that is then cyclized to an oxazoline. The diastereomeric complexes thus formed are chromatographically separable and are used in a palladium-catalyzed asymmetric allylic substitution. Modification of this complex by using the anion derived from 3,4-dimethyl-2-phenylphosphole gives more... 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

A plausible mechanism for this asymmetric allylation has been formulated (Fig. 7). The first step involves the transmetallation of allyltributylstannane to palladium. The resulting bis-7t-allylpalladium complex 69 would react with im-ine 67 to give the 7t-allylpalladium complex 70 this coordination stage is the key step for the asymmetric induction observed in this reaction. The addition step would produce the 7t-allylpalladium amide 71, and another transmetallation of allyltributylstannane to palladium would lead to the formation of the desired product and the regeneration of complex 69. 

The degree of asymmetric induction for a substrate bearing a remote chiral auxiliary is discussed in the next example. Palladium(0)-catalyzed asymmetric allylation of (S)-proline allyl ester amides gives the (S.-SJ-diastereomer with d.r. 93 7s7. If the electrophile is not attached to the proline moiety but added as allyl acetate, the diastereoselectivity is only moderate (d.r. 65.5 34.5-74 26 for the methyl or ethyl proline esters). At 0 =C, the reaction does not yield the expected products and at higher temperatures (40 C), only d.r. 82.5 17.5 is obtained. The alkylation with j cr-butyllithium and allyl iodide at — 78 =C gives the epimeric (7 )-enantiomer with d.r. 88.5 11.5. 

Overman and co-workers carried out extensive studies on Pd(II)-catalyzed asymmetric allylic rearrangement of allylic imidates to form enantioenriched allylic amides. They achieved 97 % ee as the best result by the reaction of the allylic imidate 612 using the cyclopalladated ferrocenyl oxazoline 613 having elements of planar chirality as a catalyst precursor, and discussed the mechanism of the reaction [220]. 

As an extension, A-acylated A-chlorohydantoins have been shown to be competent sources of C1+ in the asymmetric chlorolactonization of y,5-unsaturated acids catalysed by (DHQD)2PHAL (dihydroquinidine 1,4-phthalazinediyl diether). The same i system can also catalyse asymmetric chlorocyclization of allylic amides to produce the corresponding chlorinated oxazolidines. ... 

The first report of asymmetric catalysis with a chiral ADC ligand utilized cationic derivatives of isocyanide-derived Pd-bis(ADC) complexes 10 (Scheme 16.3) and 39 (Figure 16.6) [23b]. The catalyst derived from 10 promoted the aza-Claisen rearrangement of allylic benzimidate 42 to chiral allylic amide 43 in 30% ee, although the yield was moderate due to the presence of side products (Scheme 16.13). Replacement of the chiral diaminocyclohexane backbone of 10 with a 1,2-diphenylethane backbone in 39 led to an improvement in the ee to 59%, likely due to the steric influence of the phenyl substituents, although the yield decreased. This study established the value of the isocyanide-based approach for rational modification of chiral ADC ligands by simple variation of the amine synthon. 

Figure 4.10 Dependence of regio- and enantioselectivity in the asymmetric hydroformylation of allyl amides with a Rh(S,ff)-Yanphos catalyst (10 bar, toluene, 20 h) on the N-protective group.

Scheme 4.79 Asymmetric hydroformylation of A/-Boc allyl amide and subsequent steps to chiral building blocks.

Hydroformylation of 1,1-disubstituted allyl amides gives access to p -amino acids such as (S )-(-i-)-3-isobutyl-GABA (pregabalin). In 2005, the compound was launched in the United States by Pfizer (Lyrica ) for the treatment of central nervous system disorders and is one of the most prescribed drugs worldwide ( 1.8 billion in 2007). Today, several routes exist including kinetic resolution processes and enzymatic pathways [54]. The key step of an asymmetric catalytic approach recommended by Zhangs group [55] is the hydroformylation of an allyl phthahmide (Scheme 4.80). Under the conditions depicted in the scheme. 

Scheme 4.80 Asymmetric and chemoselective hydroformylation of 1,1-disubstituted allyl amides for the construction of biologically active compounds.

Atom-transfer radical cyclization (ATRC) is an atom-economical method for the formation of cyclic compounds, which proceeds under mild conditions and exhibits broad functional group tolerance. Okamura and Onitsuka described a planar-chiral Cp-Ru complex 124-catalyzed asymmetric auto-tandem allylic amidation/ATRC reaction in 2013. This protocol proceeds highly regio, diastereo, and enantioselec-tively to construct optically active y-lactams from readily available substrates in a one-pot manner (Scheme 2.32). In this process, a characteristic redox property of ruthenium complexes would work expediently in different types of catalyzes involving mechanistically distinct allylic substitutions (Ru /Ru ) and atom-transfer radical cyclizations (Ru /Ru ), thus leading to the present asymmetric auto-tandem reaction [48]. 

The first asymmetric allylic alkylation on the At-methoxy amide proceeds nicely under argon atmosphere in 3.5 h using (15 mol%) and [Pd2(dba)3]-CHCl3... 

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