Heck reaction quaternary carbon centers

Pd-catalyzed Heck reactions are among the most effective methods for the formation of quaternary carbon centers. Considering the significance and the strategic difficulties associated with the synthesis of quaternaiy carbons, particularly in the optically enriched or pure form, it is not a surprise that the development of catalytic asymmetric Heck reactions has held center stage for the past few years. One of the leading labs in this area is that of Shibasaki, who in 1993 reported a concise total synthesis of eptazodne 23 (Scheme 4).141 Thus, treatment of silyl ether 18 with 10 mol% Pd(OAc>2 and 25 mol% (S)-19 leads to the formation of 20 in 90 % yield and 90% ee As illustrated in Scheme 4, once the quaternary carbon center is synthesized efficiently and selectively, the target molecule is accessed in a few steps. 

The seven membered core of iboga alkaloids has also been constructed in an intramolecular Heck reaction. Insertion of a pendant olefin into the indolylpalladium complex, formed from iodoindole, followed by / -hydride elimination gave the complex framework of the natural product (5.5.), Although the insertion step could have led to the formation of a six membered ring, the formed palladium complex would have contained a quaternary carbon center in the -position, blocking the closure of the catalytic cycle under the applied conditions.5... 

Although the coupling of aiyl halides with alkenes (commonly referred to as the Heck reaction) was first reported more than 25 years ago [ 1 ], only in the past decade has its enormous synthetic potential been realized [2], Within that time, the reaction has been extended to many substrates, including vinyl iodides and bromides and enol triflates. Moreover, the intramolecular variant has become one of the more important reactions for the formation of carbon-carbon bonds and has emerged as a premier method for the construction of quaternary carbon centers. The ability of intramolecular Heck reactions to reliably fashion carbon-carbon bonds in polyfunctional molecules has led to wide application of this reaction at the strategy level for the synthesis of complex natural products [2g],... 

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 is a powerful method for the synthesis of constrained tertiary and quaternary carbon centers and has been applied as a key step in the synthesis of a number of pyridine alkaloids. Mann et al. have accessed the bicyclononane core structure of huperzine A 150 in moderate yield by intramolecular Heck reaction of bromopyridine 151 (Equation 117). Another notable application of this methodology is the intramolecular a-arylation of the amide enolate generated from 152 to give the carbon skeleton of cytosine <20040BC1825> (Equation 118). 

L. E. Overman, Application of Intramolecular Heck Reactions for Forming Congested Quaternary Carbon Centers in Complex Molecule Total Synthesis, PureAppl. Chem. 1994, 66, 1423-1430. 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

In this asymmetric Heck reaction, a quaternary carbon center is formed providing a tricyclic dienyl carbamate after reductive elimination of palladium. 

Overman and co-workers have demonstrated the feasibility of using a chiral ligand to cause asymmetric induction in an elegant enantioselective synthesis of (- -)- and (—)-physostigmine (237) (Scheme 3-53) [23a]. An intramolecular Heck reaction of the aryl iodide 234 proceeds smoothly, even though a trisubstituted double bond is being linked to the aryl moiety. This strategy allows the assembly of quaternary carbon centers in a stereoselective manner [214]. 

Although Heck reactions with tetrasubstituted alkenes are known, their examples are rare (Scheme 3-3) [50-52]. One trendsetting observation was that tetrasubstituted alkenes with a conjugated carbonyl group have a sufficiently increased reactivity. The application of such coupling reactions gave a rapid entry to systems with quaternary carbon centers. 

Another illustration of the ability of intramolecular Heck reactions to form quaternary carbon centers is found in Fukumoto and co-workers formal total synthesis of ( )-aphidicolin (28) (Scheme 6-5) [6]. In an early step of this synthesis, bicyclo[3.2.1]octane 27 was fonned in 90% yield by Heck cyclization of 26. 

Ley, S. V., Marsden, S. P. Diastereoselective and enantioseiective formation of quaternary carbon centers via the intramolecular Heck reaction the influence of the coordination state of the palladium catalyst. Chemtracts Org. Chem. 1993, 6, 23-26. 

Iserloh, U., Curran, D. P. Catalytic asymmetric synthesis of quaternary carbon centers investigation of intramolecular Heck reactions and... 

The first examples of asymmetric Heck cyclizations that form quaternary carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physosligmine (184) and congeners (Scheme 6-31) [68], In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(S)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much low er enantioselectivity [68]. 

D.i.b. Insertion of Another Alkenyl Unit In certain cases, however, the 3-exo-trig process may be retarded and an additional alkene moiety participates in the cascade carbopalladation. A pioneering example of this kind has been demonstrated by Overman and co-workers in their total synthesis of scopadulcic acid A, starting from an iodoaUcenyl-substituted methylenecycloheptene derivative (Scheme 24). The first intramolecular carbopalladation occurs across the disubstituted double bond of the exomethylene group, and the trisubstituted endocyclic double bond acts as the terminator to give a tricyclic system, which was further elaborated to the natural product (Scheme 24). It is remarkable that all three quaternary carbon centers can be created by intramolecular Heck reactions. 

With this step accomplished as desired, probes of the key step of the sequence, the tandem asymmetric Heck reaction, could now commence in earnest. Based on several years of intensive research in developing appropriate systems to accomplish asymmetric Heck reactions with the ability to form all-carbon quaternary carbon centers, the Overman group expected that the exposure of 10 to a 1 2 mixture of Pd(OAc)2 and (/ )-BINAP would lead to the desired... 

Ashimori, A., Bachand, B., Caller, M.A. et al. (1998) Catalytic asymmetric synthesis of quaternary carbon centers. Exploratory studies of intramolecular Heckreactions of (Z)-a,/S-unsaturated anilides and mechanistic investigations of asymmetric Heck reactions proceeding via neutral intermediates. J. Am. Chem. Soc., 120, 6488-99. 

Honzawa, S., Mizutani, T. and Shibasaki, M. (1999) Synthetic studies on (-l-)-wortmannm. An as5mmetric constraction of an aUyUc quaternary carbon center by a Heck reaction. Tetrahedron Lett., 40, 311. ... 

Overman, L.E. (1994) Application of intramolecular Heck reactions for forming congested quaternary carbon centers in complex molecule total s5uithesis. Pure Appl. Chem., 66, 1423-30. 

A series of recent reports from three research groups have described the synthesis of spirocychc N-heterocycles utilizing domino Heck reaction/C-H activation sequences (Scheme 3.1). Spirocycles are key stmctural units in many biologically active natural products. These methods ofiered new strategies for constmcting the quaternary carbon center and the spirocyclic scaffold. 

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