Diastereoselective Palladium-Catalyzed Allylation Reactions

H In 1789, Lavoisier defined the element as du dernier terme auquel parvient I analyse (the last point that analysis can reach).  

Simplified stereochemical outcome for palladium-catalyzed allylic substitutions [8, 13] 

Classics in Stereoselective Synthesis. Erick M. Carreira and Lisbet Kvaerno Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32452-1 (Hardcover) 

Trost has reported an elegant case of stereochemical relay in a conforma-tionally flexible system. In the presence of palladium catalysts, lactone 11 was shown to react with malonate in high yield (Equation 1) [45]. It is noteworthy that the putative. r-allylpalladium intermediate 12 is configurationally stable and affords product 13 with high diastereo- and regioselectivity ( 95 5 dr, 90% yield). 

In a useful extension of such strategies, weso-diacetate 22 could be converted into the corresponding dibromide and subjected to enzymatic hydrolysis. After reduction, 26 was isolated in 98 % ee [50]. The conversion of the allylic alcohol in 26 into the corresponding carbonate allowed subsequent substitution by malonate to provide access to optically pure 25 [51]. Alternatively, ent-25 could be accessed through a palladium-catalyzed displacement of the acetate leaving group in 26 and subsequent acetylation of the free hydroxyl substituent. These experiments exploit the well known reactivity 

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Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substimtions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. 

Najera and coworkers introduced a new class of cyclic alanine templates (227, equation 59), the structure of which was anchored on Schollkopf s bislactim ether . Palladium-catalyzed allylations of the chiral pyrazinone derivative 227 with allylic carbonates (228) as substrates led to the formation of y,i5-unsaturated amino acids (229a-c) under very mild and neutral reaction conditions, whereas the required base for enolate preparation has been generated in situ from the allylic carbonate during jr-allyl complex formation. With this protocol in hand, the alkylated pyrazinones 229 were obtained with excellent regio- and diastereoselectivities (>98% ds). Finally, hydrolysis with 6 N aqueous HCl under relatively drastic conditions (150 °C) led to the free amino acids. 

These peptide enolates could also be used as excellent nucleophiles in palladium-catalyzed allylic alkylations. Reactions of numerous dipeptides (e.g. 263) with different allylic substrates (e.g. 264) and [AllPdClja as catalyst delivered (S,/f)-configured peptides with y,5-unsaturated side chains (265), usually in high yields and diastereoselectivities (equation 69). 

Zinc enolates like 41 served as nucleophiles in a study aimed at a rhodium-catalyzed reaction with enantiomerically enriched allylic phosphates. Nonracemic products were obtained under efficient chirality transfer from the substrate and with remarkable diastereoselectivity [23]. Kazmaier enolates were used to manipulate the backbone of small peptides [27] by palladium-catalyzed allylations of a terminal glycine ester [28]. In the course of these studies, central glycine was also allylated in a diastereoselective manner through assumed chelated zinc enolates of glycine in a peptidic bond to proline or JV-alkyl amino acids [29]. Although this is, of course, not an asymmetric synthesis, the protocol is remarkable inasmuch as, in contrast to the palladium-mediated conversion, the noncatalyzed reaction of the enolate with the corresponding allylic bromide occurs in a more or less stereorandom manner. 

Enantio- and diastereoselective syntheses of a variety of heterocycles were accomplished by combining the ruthenium-catalyzed Alder-ene reaction with a palladium-catalyzed asymmetric allylic alkylation (AAA) (Scheme 7). For the AAA, y>-nitrophenol was found to function as a suitable leaving group and yet was stable to the Alder-ene conditions. Extensive solvent studies were performed to determine the best conditions for the one-pot procedure. 

Benzamido allylic acetates 242 and 243 undergo palladium-catalyzed cychza-tion to oxazolines. Excellent yields and very high diastereoselectivity is observed for the conversion of several acyclic primary and secondary benzamido aUyhc acetates to tran -5-vinyl substituted oxazolines 244. The diastereoselectivity of the reaction is determined by the the steric interactions between the R group and the hydrogen of the 7i-allylpalladium complex in the transition state, trans-Oxazolines are obtained since transition state A is favored over transition state B (Scheme 8.66). 

Fused tetrahydrofurans are obtained with total diastereoselection by palladium-catalyzed oxidation of diene alcohols. The reaction is run in a mixture of acetone/acetic acid and the oxidant employed is 4-benzoquinone. The nucleophilic attack by an acemte ion on the 7t-allyl... 

Only a few reports on the simple diastereoselectivity within palladium(0)-catalyzed allylic alkylation exist. Either the diastereomeric ratio is not reported7-8 or determined because stereoisomeric products have been simplified by further manipulation, or the reaction gives only moderate to no selectivity. This section is divided into two subsections discussing inter-and intramolecular palladium(0)-catalyzed substitutions, respectively. The different classes of substrates are treated separately. 

Carbonylation and Related Reactions. The first stereoselective, palladium-catalyzed and reductive cyclocarbonylation of 8,/-substituted allylic alcohols has heen reported. Thus, -allylic alcohols are converted, with high diastereoselectivity, into trans-2,3-disubstituted /-lactones (eq 97). ... 

Thereafter, a serial of palladium-catalyzed intramolecular C-ff activation of allylic C-H bonds (Scheme 2.4) was reported by White [9], who first developed a novel route for accessing chiral syn-l,2-amino alcohols enabled through the discovery of a Pd/sulfoxide-catalyzed diastereoselective allylic C-H activation reaction of chiral homoallylic Af-tosyl carbamates. The author discovered that the addition of bis-sulfoxide ligands (L-1) to Pd(OAc)2 promoted allylic C-H cleavage of a-olefins versus oxypalladation in the presence of weak oxygen nucleophiles (i.e., carboxylic acids). Evidences presented that the mechanism proceeds via Pd(ll)/sulfoxide-promoted allylic C-H cleavage to furnish a n-allylic palladium intermediate followed by counterion-promoted functionalization with the tethered Af-tosyl carbamate nucleophile. 

Palladium remains the most widely recognized transition metal to effect stereoselective allylic alkylation reactions. Consequently, diastereoselective and enantioselective Pd-catalyzed processes are extensively discussed in Sections 14.2 and 14.3. More recent advances in the field of metal-catalyzed al-lylation reactions include the use of chiral iridium complexes, dealt with in Section 14.4 [33, 34]. Section 14.5 describes selected stereoselective copper-catalyzed SN2 -allylation reactions [33, 35-37], while a brief presentation of allylation reactions with other transition metals including Mo and Rh is given in Section 14.6 [8, 13, 33, 38, 39]. The closing Section 14.7 deals with selected methods for asymmetric ring-opening reactions of unsaturated heterocycles [38, 40, 41]. 

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. 

Lewis acids and Bu4NI catalyzed allylboration with potassium allyl- and crotyltrifluoroborates (Equation (154)).30,40 620,621 The reaction of pinacol ester derivatives was very slow even at room temperature, but Sc(OTf)3 smoothly catalyzed the addition at — 78 °C with high diastereoselectivity (Equation (155)622 and (156)623,624). A palladium pincer complex catalyzed the addition of trifluoroborate to tosylimines (Equation (157)).625... 

Sulfoximines are versatile reagents for diastereoselective and asymmetric synthesis. They continue to find many synthetic applications as both nucleophilic and electrophilic reagents. While the nucleophilic character of sulfoximine reagents has been well exploited,1 the use of the sulfoximine group as a nucleofuge is more recent and adds to the synthetic use of these compounds. The palladium(0)-catalyzed chemistry of allylic sulfoximines and the use of chiral sulfoximines as ligands in catalytic asymmetric synthesis are areas of recent development that have potentially useful applications. Further work is required to understand the factors that determine the diastereoselection and the stereochemical outcomes of these reactions. These studies will result in enhanced product diastereo- and enantioselectivities and make these reagents even more attractive to the wider synthetic chemistry community. 

Trost has reported enhanced enantioselectivity in the desymmetrization of mero-biscarbamates in the presence of triethylamine. Under these conditions, high yields (>80%) and enantiomeric excesses (93-99% ee) are obtained. This methodology has been applied to the synthesis of (—)-swainsonine. a-Amino esters have been used as nucleophiles in the reaction with acyclic allylic esters and isoprene monoepoxide, providing access to diastereoselective N-alkylated a-amino esters. By employing the feature ligand, asymmetric palladium(0)-catalyzed cychzation of 2-(tosylamino)phenol with ( -l,4-bis[(methoxycarbonyl)oxy]but-2-ene provides 2-vinylbenzomorpholine in 79% ee. A number of alternative diphosphine ligands were studied and found to be inferior. 

Oxazolidines are obtained in good to excellent yields by the palladium(II)-catalyzed cyclization of A-Boc protected iV-allyl-A -hydroxymethylamines (191) <94CC357>. The palladium species is regenerated by molecular oxygen in DMSO (Scheme 94). Allyl carbamoylmethyl ethers cyclize to oxazolidines by reaction with mercuric acetate <89H(28)663>. Silver triflate catalyzes the cyclization of (9-propargyl isoureas to 4-alkylidene-oxazolidines with high diastereoselectivity <88CC1175>. 

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