Natural product synthesis asymmetric Heck reaction

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treaunent) from a total synthesis of ( )-physostigmine 203 (Scheme The reaction occurs in 84% yield with 95% ee,... 

Metal-Catalyzed Cross-Coupling Reactions, Vol. 1,2nd edn (eds A. de Meijere and F. Diederich), Wiley-VCH Verlag GmbH, Weinheim, Germany, pp. 217-315 (c) Dounay, A.B. and Overman, L.E. (2003) The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev., 103, 2945-63 (d) Link, J.T. (2002) The intramolecular Heck reaction. Org. React., 60, 157-534 (e) Shibasaki, M. and Miyazaki, F. (2002) Asymmetric Heck reactions, in... 

Dounay, A.B. and Overman, L.E. (2003) The asymmetric Heck reaction in natural products total synthesis. Chem. Rev., 103, 2945-63. 

Shibasaki (Equation 19.36) and Overman first reported the enantioselective Heck reaction. A few substrate combinations react intermolecularly with high enantiose-lectivity (Equation 19.37),but most enantioselective Heck reactions used in S)mthetic applications have been conducted intramolecularly. The asymmetric Heck reaction in Equation 19.37 has begun to be a test-bed for new chiral ligands. Although most Heck reactions that occur with high enantioselectivity have been conducted with BINAP as ligand, a phosphinooxazoline ligand has been used successfully (vide infra). Overman has applied an intramolecular version of the Heck reaction to form oxindoles (Equation 19.38) in the synthesis of a variety of natural products. ... 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

The intramolecular asymmetric Heck reaction has been extensively exploited in the total synthesis of a wide range of natural products forming the cyclic products attaining high yields and enantioselectivities (Scheme 1.23) [85]. The enantiose-lective Heck reactions are usually conducted using a combination of chiral bidentate ligands and aryl triflates, as a vacant site has to be available on the... 

B. Dounay, L. E. Overman, The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis, Chem. Rev. 2003, 103, 2945-2963. 

Seminal contributions to the development of asymmetric cyclic Heck reaction were made in 1989 by Overman [72] and Shibasaki [73]. These and other groups have since developed the reaction as a useful tool for asymmetric synthesis of complex natural products as indicated by representative examples shown in Schemes 20 [74-76] and 21 [77-79]. For further details, the readers are referred to recent reviews [43,57]. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

A wide variety of synthetic processes have been rendered asymmetric through the use of a chiral catalyst. In addition to the types of reaction described above, chiral transition metal catalysts have been used to influence the stereochemical course of isomerization, cyclization, and coupling reactions. As an example, an approach towards the natural product (-)-epibatidine (158) was recently reported by Namyslo and Kaufmann (166). Epibatidine is a potent analgesic and a nicotinic receptor agonist. The synthesis involves an asymmetric Heck-type hydroarylation between the bicyclic alkene (155) and pyridyl iodide (156). A number of bidentate chiral li-... 

The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis ... 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

In another beautiful application, Overman et al. developed the total synthesis of the natural product (+)-minfiensine (130), having a l,2,3,4,-tetrahydro-9a,4a-(iminoethano)9H-carbazol core (Scheme 7.29) [80]. The key step in their synthesis is a tandem process consisting of a catalytic asymmetric Mizoroki-Heck ring closure and an N-acyliminium ion cyclization of dienyl carbamate triflate 127 (127—>128). The reaction proceeded smoothly using the Pfaltz ligand (S)- Bu-PHOX (85), providing (dihydroiminoethano)carbazole 129 after the addition of excess trifluoroacetic acid, with 75% overall yield and 99% enantiomeric purity (127 129). 

Dounay AB, Overman LE. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 2003 103(8) 2945-2963. 

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