Quaternary carbon centers asymmetric Heck reaction

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 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]. 

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]. 

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. 

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