Heck reaction natural products synthesis

For overviews of applications of the Heck reaction in natural products synthesis, see (a) Link, J. T. Overman, L. E. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F., Stang, P. J., Eds. Wiley-VCH New York, 1998 Chapter 6. (b) Brase, S. de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions Diederich, F., Stang, P. J., Eds. Wiley New York, 1998 Chapter 3.6. (c) Nicolaou, K. C. Sorensen, E. J. Classics in Total Synthesis VCH New York, 1996 Chapter 31. These authors refer to the Heck reaction as "one of the true "power tools" of contemporary organic synthesis" (p. 566). 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

The Heck reaction of 1,3 -diene systems via 7r-allylpalladium is also useful. This cyclization, which forms very congested quaternary carbon centers involving the intramolecular insertion of di-, tri- and tetrasubstituted alkenes, is particularly useful for natural products synthesis. In the synthesis of morphine, bis-cyclization of the octahydroisoquninoline precursor 112 by the intramolecular Heck reaction proceeded using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the 7i-allylpalladium intermediate 113, which attacks the phenol intramolecularly to form the benzofuran ring 114. Based on this method, the elegant total syntheses of (—)- and (+)-dihydrocodeinone, and (—)- and (+)-morphine (115) have been achieved [50],... 

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

Several 1-exo intramolecular Heck reactions have been employed in natural product synthesis (Scheme 6-14). Trust s pioneering synthesis of ibogamine (81) is an early... 

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,... 

Corey and coworkers [45] later described the application of this reaction in the total synthesis of okaramine N (Scheme 9.16). Bisindole 110 was oxidatively cyclized using stoichiometric Pd(OAc)2 to form compound 111 in 38% yield. Although the yield was modest, the dihydroindoloazocine product could be elaborated in just two steps to afford okaramine N. This remarkably rapid synthesis highlights the efficacy of the palladium(II)-mediated oxidative Heck reaction to construct complex ring systems that can immediately expedite natural product synthesis. 

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... 

These substrate-directed Heck reactions allowed the synthesis of pharmacologically active compounds in a very straightforward way. For example, compotmd 26 was oxidized with DDQ to provide the natural product yango-nine 27. Additionally, methysticin 28 was obtained in 59% yield (95% based on recovered starting material) directly from the Heck-Matsuda reaction. The chemoselective reduction of the least hindered double bond of 28, using Pd/C as catalyst, provided dehydromethysticine 29 in 95% yield (Scheme 11). 

One of the most enabling features of the Heck reaction is the ability to facilitate polyene cyclizations in the synthesis of complex multiple ring systems. In the context of natural product synthesis, Overman pioneered this approach towards the synthesis of the scopadulcic acid family of... 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

A combination of a Tsuji-Trost and a Heck reaction was also used by Poli and Gi-ambastiani [122] for the synthesis of the aza analogues 6/1-252 of the natural products podophyllotoxin 6/l-247a and etoposide 6/l-247b, which show pronounced... 

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