Racemization, palladium-catalyzed

Trost, B.M., Godleski, S.A., Genet, J.P. (1978) A Total Synthesis of Racemic and Optically Active Ibogamine. Utilization and Mechanism of a New Silver Ion Assisted Palladium Catalyzed Cyclization. Journal of the American Chemical Society, 100, 3930-3931. 

The palladium-catalyzed substitution of the less reactive racemic ethyl 3-cyclohexe-nyl carbonate could, in a similar fashion, be completed with dimethyl malonate, p-methoxyphenol, or phthalimide as nucleophiles, with satisfactory ee (Eq. 11.38) [55]. These reactions, when irradiated for 1 min with temperatures up to 100 °C, delivered yields (91-96%) and ee values (94—95%) identical with those performed in... 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

The allenyl carboxylate 35 was obtained in an enantiomerically enriched form by the palladium-catalyzed reduction of the racemic phosphate 34 using a chiral proton source [53]. The two enantiomers of the (allenyl)samarium(III) intermediate are in rapid equilibrium and thus dynamic kinetic resolution was achieved for the asymmetric preparation of (i )-35 (Scheme 3.18). 

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

A-Alkylhydroxylamines react with substituted allyl acetates (e.g. 15, equation 11) in palladium catalyzed addition-elimination reactions giving the corresponding A-alkyl, A-allylhydroxylamines 16. The reaction proceeds with high regioselectivity but complete racemization. A similar reaction with 0-acyl hydroxamic acids has been carried out using allylic a-alkoxycarbonyloxyphosphonates. ... 

This conversion of readily available 2-furyl alcohols into unsaturated pyranosuloses proved a very effective route to racemic monosaccharides, through stepwise, selective functionalization of the enone grouping in 325. The shortest synthesis of a natural compound by following this scheme involves palladium-catalyzed hydrogenation of the aldosulose (325, R = Me) obtained from l-(2-furyl)ethanol, resulting209 in cinerulose A, the sugar component of the antibiotic cine-rubin. 

The intramolecular palladium catalyzed ring closure of the tetrahydro-isoquinoline derivative depicted in 8.41. led to the formation of the aporphine derivative in good yield, which was then converted into racemic aporphine in three steps. In the ring closing step 20 mol% palladium acetate and 40 mol% tricyclohexylphosphine were used as catalyst. The removal of the hydroxyl group was also achieved by palladium catalysis through its conversion to triflate and the subsequent reduction with ammonium formate in the presence of palladium acetate and dppf.53... 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

A 1,3-substituted allene, which has axial chirality instead of carbon central chirality, has been prepared by a palladium-catalyzed cross-coupling of 4,4-dimethylpenta-l,2-dienylzinc chloride (83) with phenyl iodide (5c) or by that of l-bromo-4,4-dimethylpenta- 1,2-diene (84) with phenylzinc chloride [60] (Scheme 8F.20). The highest enantiomeric purity (25% ee) of the allene (S)-85 was obtained in the former combination with (f ,/ )-diop (1) as chiral ligand. It is interesting that the enantiomeric purity was independent of the ratio of the reagents though the reaction seems to involve a kinetic resolution of the racemic 83. 

Palladium-catalyzed nucleophilic substitutions of activated allylic alcohols have been investigated using a bicyclic phosphine as the chiral element. Reactions have been reported with racemic acyclic allylic acetates <1999TL7791> and cycloalkenyl carbonates <2001TL1297> using the phosphine 203, with good to excellent enantiomeric excesses. 

The silver-catalyzed cycloisomerization of allenic carboxylic acids to butenolides was also reported by Marshall and co-workers.329 Starting from the enantiomerically enriched propargyl mesylate 390, palladium-catalyzed hydroxycarbonylation led to the chiral allenecarboxylates 391 which afforded the butenolides 392 upon treatment with silver nitrate (Scheme 114). Unfortunately, partial racemization could not be avoided in this two-step sequence. In a related study, Ma and Shi330 have shown that the combination of Pd(PPh3)4 and Ag2C03 promotes the cyclization of allenecarboxylates to the corresponding butenolides, accompanied by the introduction of aryl or alkenyl groups at C3. 

Williams et al. have now demonstrated the compatibility of enzyme and transition metal complexes in one reaction vessel. Two examples illustrate the concept first a palladium-catalyzed racemization f9J of an allylic acetate in the presence of a hydrolase (Scheme 1), and second the racemization of a secondary alcohol [10] through Oppenauer oxidation / Meerwein-Ponn-dorf-Verley reduction with concomitant acylation of one enantiomer with a lipase from Pseudomonas fluorescens (Scheme 2). 

After the intense use of concerted reactions for natural product synthesis, the related metal-catalyzed cyclizations gained ground in the 1980s and 1990s. Several authors demonstrated the effectiveness of these reaction types for the synthesis of dendrobine (82). Takano et al. and Zard et al. used the Pauson-Khand reaction as a key step for their EPC-synthesis efforts (144,165,166). Mori et al. relied on the more stable zirkonacycle in a related key step (167-169), while Trost et al. employed a palladium-catalyzed alkylation as well as a palladium-catalyzed ene reaction as key steps (170). Takano s efforts ended with the tricyclic skeleton of dendrobine, whereas Mori and Trost finished their formal EPC-syntheses with intermediates of Kende s and Roush s racemic S3mtheses, respectively. Both completed dendrobine synthesis would have necessitated more than 20 steps. 

Xia and Kozikowski developed a palladium-catalyzed bicycloannulation route (Scheme 4-4) to racemic HA from 2a in 40% overall yield. The three-carbon bridge was more efficiently introduced by Pd-catalyzed alkylation of 2a with 2-methylenepropane-l,3-diyl diacetate on both sides of the ketone carbonyl. Compared with (—)-HA (IC50 for AChE inhibition 0.047 pM), the racemate exhibited an IC50 of 0.073 pM, which is, within error, as expected if the unnatural enantiomer is inactive. 

In the synthesis of racemic 3-phosphoshikimic acid derivatives a palladium-catalyzed rearrangement of a cyclohexenyl phosphate was used for the stereochemical control of the C-3 oxygen function29. This rearrangement is considerably slower than the analogous reactions of allylic acetates and requires a stoichiometric amount of bis(acetonitrile)palladium(II) chloride. 

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