Tandem asymmetric allylation

Catechol undergoes a Pd-catalysed tandem asymmetric allylic substitution on reaction with 1,4-diacyloxybut-2-enes to give 2-vinylbenzo-l,4-dioxanes with good enantioselectivity in the presence of a chiral P-ligand 64 <04TL7277>. 

Scheme 7.37 Tandem asymmetric allylation/diastereoselective epoxidation.

Scheme 17 Tandem asymmetric allylic alkylation and intramolecular Heck coupling...

Scheme 18 Tandem asymmetric allylic alkylation/ring closing metathesis for the synthesis of N-and 0-heterocycles...

Starting from earher data showing the positive role of Lewis acid for asymmetric tandem addition/allylation of unsaturated compounds derived from... 

Tandem Asymmetric Heck and Pd-Allyl Cation Reactions... 

With environmental consideration in mind, the group has developed a version in concentrated media, i.e. without dichloromethane and only three equivalents of isopropanol. ° For instance, the ketone 64 was converted into the alcohol 65 in 93% yield and 95% enantiomeric excess using only 10 mol% of titanium-BINOL catalyst (Conditions B, Scheme 7.36). A slight decrease of efficiency was observed using 5 mol% of catalyst (Conditions C). The efficiency of the method was illustrated by a tandem asymmetric ally-lation/diastereoselective epoxidation reaction of cyclic enones that is based on the use of the allylation catalyst for a subsequent epoxidation with TBHP, as illustrated in Scheme 7.37. ° ... 

MBH diene adduct 197, derived from methyl acrylate and crotonaldehyde, has been employed successfully in a palladium-catalyzed asymmetric allylic alkylation (AAA) reaction with Meldrum s acid to provide product 198 that can undergo further manipulations, as well as act as an intermediate in a one-pot tandem palladium AAA reaction. The versatility of these products for various synthetic manipulations was further illustrated by alkene metathesis to form the optically active cyclopentene 201 (Scheme 3.81). ... 

Allyl aryl ethers undergo accelerated Claisen and [1,3] rearrangements in the presence of a mixture of trialkylalanes and water or aluminoxanes. The addition of stoichiometric quantities of water accelerates both the trimethylaluminum-mediated aromatic Claisen reaction and the chiral zirconocene-catalyzed asymmetric carboalumination of terminal alkenes. These two reactions occur in tandem and, after oxidative quenching of the intermediate trialkylalane, result in the selective formation of two new C-C bonds and one C-0 bond (Eq. 12.70).153 Antibodies have also been developed to catalyze Claisen154 and oxy-Cope155 rearrangements. 

The reaction of vinylcarbenoids with allylic C-H bonds leads to a remarkable transformation, a combined C-H insertion/Cope rearrangement, which is reminiscent of the tandem cyclopropanation/Cope rearrangement of vinylcarbenoids. An interesting application of this chemistry is the asymmetric synthesis of the antidepressant (-i-)-ser-traline 191 (Scheme 14.26) [134]. The Rh2(S-DOSP)4-catalyzed reaction of the vinyldia-zoacetate 189 with 1,3-cyclohexadiene generates the 1,4-cyclohexadiene 190 in 99% enantiomeric excess. The further conversion of 190 to (-t)-sertraline 191 is then achieved using conventional synthetic transformations. 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

Analogous reactions have been achieved recently with molecular oxygen as the sole stoichiometric oxidant by employing (-)-sparteine (sp) as the chiral ligand [153,163]. Stoltz and coworkers demonstrated asymmetric oxidative cychzation of a 2-allylphenol substrate (Eq. 34). A stoichiometric quantity of the sp hgand was necessary, perhaps because it also serves as a base in the reaction. Enantioselective oxidative tandem cychzation of 2-allyl anilides was achieved by Yang and coworkers (Eq. 35). The reactions proceed exclusively to the five-membered exocyclization products. 

A tandem palladium-catalyzed reaction can effect a similar transformation to produce 2-vinyl-substituted heterocyclic systems as in Eq. 8E.11. By varying the amino acid moiety of the ligand, 83% ee could be obtained from the use of the glycine-derived ligand 129 [161]. A maximum enantioselectivity of 65% ee has been recorded for this type of reaction in an earlier study with BINAP as ligand [ 162]. Because both ( )- and (Z)-isomers gave the same enantioselectivity, attack on the rapidly interconverting 7t-allyl intermediates seems to determine the selectivity. Modest enantioselectivities have been reported for the related asymmetric preparation of 2-vinylpiperazine and 1,4-benzodioxane derivatives [163,164],... 

Recent applications of the Nazarov reaction, the cyclization of a 3-hydroxyphenyl-penta-l,4-dienyl cation, were reviewed.142 Tandem processes and asymmetric cycliza-tions were a particular focus of attention. Irradiation of (40) in aqueous base results in regioselective and stereoselective formation of (42).143 The allylic cation (41) is proposed as the key intermediate. A computational investigation was performed into the cofacial intermolecular n-n orbital interaction between n-conjugated main chains (C H +2) and allylic cations C3H54".144... 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

The chiral anisole derivative 37 has been used in the synthesis of several asymmetric functionalized cyclohexenes (Table 9) [22]. In a reaction sequence similar to that employed with racemic anisole complexes, 37 adds an electrophile and a nucleophile across C4 and C3, respectively, to form the cyclohexadiene complex 38. The vinyl ether group of 38 can then be reduced by the tandem addition of a proton and hydride to C2 and Cl, respectively, affording the alkene complex 39. Direct oxidation of 39 liberates cydohexenes 40 and 41, in which the initial asymmetric auxiliary is still intact. Alternatively, the auxiliary may be cleaved under acidic conditions to afford /y3 -allyl complexes, which can be regioselectively attacked by another nucleophile at Cl. Oxidative decomplexation liberates the cyclohexenes 42-44. HPLC analysis revealed high ee values for the organic products isolated both with and without the initial asymmetric group. 

The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(ll)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1. If). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-configuration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained... 

Scheme 30 Tandem action of chiral Pd(II) and Co/C catalyst for the asymmetric synthesis of cydopentenones from propargyl malonate and allylic acetates...

The molybdenum complex Mo(NAr)(CHCMe2Ph)[(3)-Me2SiBiphen] 43 was used for catalytic asymmetric olefin metathesis reactions such as desymmetrization of trienes, kinetic resolution of allylic ethers, tandem catalytic asymmetric ring-opening metathesis/cross-metathesis. Interestingly, tandem catalytic asymmetric ring-opening... 

Kinetic resolntion of cyclic allylic ethers can be performed by asymmetric Zr-catalyzed carbomagnesation. Six-, seven-or eight-membered ethers can readily be resolved by the Zr-catalyzed protocol (with ee between 81 to 99%). As an example, the tandem Zr-catalyzed kinetic resolution followed by a Ru-catalyzed ring-opening/ring-closing metathesis affords chiral chromenes with high optical purity (ee > 99%). ... 

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