Enantioselective Cross Coupling

In a third form, the cross-coupling process forms a biaryl compoimd that possesses axial chirality as a result of slow atropisomerism (Equations 19.22 and 19.23). In most cases, this reaction has been studied for the formation of 1,1 -binaphthyls (Equation 19.22), which are found in BINAP, BINOL, and related ligands. In a fourth form, ttie Heck reaction has been conducted in a manner that forms a product containing a new stereocenter (Equations 19.24-19.26). This type of enantioselective coupling has been the most widely used of the four in the synthesis of natural products.  

CHAPTER 19 TRANSITION METAL-CATALYZED COUPLING REACTIONS 

Ligands used with nickel and palladium catalyst precursors for the coupling of phenethyl Grignard reagents with vinyl halides in 80% ee. 

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.  

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The use of chiral bidentate phosphines (such as BINAP) in enantioselective cross-coupling reactions has been described, though only modest stereoselectivity has been achieved.431... 

The sequential approach is also common in proposals written by synthetic chemists (a multistep synthesis is inherently step by step). Vyvyan (excerpt 13N), for example, proposes a strategy to synthesize a select group of heliannuols (alleo-pathic natural products isolated from the sunflower) in an optically pure form. One approach that he will explore involves enantioselective cross-coupling reactions between an alkyl zinc reagent and an aryl bromide. He begins with experiments that will utilize recently developed catalysts and produce products with known optical rotation data. Subsequent reactions are described that will lead potentially to the desired stereospecific heliannuols A and D. 

Scheme 52. Enantioselective cross-coupling of naphthols in the presence of the chiral amine sparteine and copper(ll).

Scheme 56. Enantioselective cross-coupling of 2-naphthol catalyzed by copper(ll)/sparteine.

Scheme 14.5 Ni-catalysed enantioselective cross-couplings of benzylic bromides and secondary alkylzinc reagents.

A one-pot oxidative and enantioselective cross-coupling reaction of aldehyde and nitromethane employs diphenylproUnol TMS-silyl ether as organocatalyst the catalyst helps generate both an enamine and an a,j8-unsaturated iminium ion. ... 

Scheme 3-183. Enantioselective cross-coupling of phenylsilanes with or-bromo...

Nickel-catalyzed enantioselective cross-couplings of racemic secondary benzylic halides with organozinc reagents have been further extended to the synthesis of chiral indanes. Indanes are useful building blocks for the synthesis of a variety of bioactive substances. For example, (/ )-3-ethylindanone 129 has been used for the preparation of the nonsteroidal androgen receptor agonist LG 121071. Fu and co-workers have reported on the rapid preparation... 

SCHEME 13.35. Nickel-catalyzed enantioselective cross-coupling in the preparation of the nonsteroidal androgen receptor agonist LG 121071. 

SCHEME 13.36. Enantioselective cross-coupling in the synthesis of dihydrofolate reductase inhibitor 136. 

The chemo- and enantioselective cross-coupling of two different aldehydes via a benzoin reaction remains a significant challenge. Four different benzoin products can be formed (two homo- and two cross-benzoin products), each as two possible enantiomers. The challenge is compounded by the commonly observed reversibility of the reaction. 

Wang and co-workers have developed enantioselective cross-coupling reactions of Waryl tetrahydroisoquinolines (538) with diethyl ethoxy-carbonylmethylphosphonate (539), catalysed by a chiral BOX(541)/Cu" complex, for the synthesis of Cl-modified tetrahydroisoquinolines (540)... 

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