Tertiary stereocentres

Other examples of efficient enzymatic resolutions by reaction at a remote position from stereocentres have been reported, such as the lipase-catalysed resolution of a synthetic intermediate of escitalopram." This property of enzymes has also been effectively used to resolve sterically hindered compounds by the introduction of a tether so that the enzyme-catalysed reaction can be performed at an artificially created, but less hindered, remote location. An example is the resolution of tertiary alcohols by the introduction of a glyoxylate ester. 

Nitrogen heterocycles with contiguous quaternary and tertiary stereocentres (118) have been prepared in high enantiomeric purity (<95% ee) by intramolecular conju- gate addition of enolates generated from a-amino acid derivatives (117) via memory of chirality.160... 

Syntheses of natural aceric acid have been achieved from L-xylose by dihydroxylation (10 steps, 14% yield) and trimethylsilylthiazole addition (8 steps 13% yield) routes. In addition, C-2 ep/-aceric acid was prepared from L-arabinose (13 steps, 6% yield). The configuration of newly formed tertiary stereocentres was determined by X-ray crystallography and H NMR spectroscopy. With a series of variously substituted derivatives in hand, studies to investigate aceric acid glycosylation chemistry are ongoing. 

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

The absolute configuration (S) of the stereocentre was assigned based on comparison of the optical rotation values of analogous tertiary a-aryl cyclopentanones and cyclohexanones reported in the literature. This was further confirmed by obtaining an X-ray crystal structure of cyclopentanone 7a and cyclohexanone 24b (Fig. 6.1). 

For the enantioselective formation of tertiary stereocentres, endocyclic alkenes or acyclic alkenes with -hydride-elimination-directing groups, such as allylsilanes, are often employed. In the case of endocyclic alkenes, the migratory insertion intermediate lacks a syn j8-hydrogen at the newly formed stereocentre and, therefore, cannot undergo termination. For instance, conjugated diene substrates such as 97 lead to a 7r-allylpalladium... 

The lack of efficient methods for enantiocontrolled construction of tertiary and quaternary carbon stereocentres largely inspired the discovery and development of the asymmetric Mizoroki-Heck reaction [3], Shibasaki and coworkers [4] and Overman and coworkers [5] described the first catalytic asymmetric intramolecular Mizoroki-Heck reactions in 1989. Following these initial reports, research efforts worldwide led to enormous improvements... 

Natural Product Total Synthesis Formation of Tertiary Stereocentres 16.3.1 Terpenoids... 

Overman and Rosen [76] reported a total synthesis of spirotryprostatin B (137), a structurally novel diketopiperazine alkaloid, that featured a cascade Mizoroki-Heck cyclization/jj -allylpalladium capture process and the exploration of a related catalytic asymmetric sequence (Scheme 16.36). The plan was to relay the relative configurations of the quaternary stereocentre and the adjacent tertiary stereocentre in the natural product from the geometry of the trisubstimted alkene in the Mizoroki-Heck cyclization substrate. It was anticipated that the favoured 5-exo intramolecular Mizoroki-Heck cyclization of enantiopure triene precursor 135 would generate an -allylpalladium intermediate, with a chiral palladium catalyst controlling the absolute configuration of the initially formed quaternary carbon stereocentre. 

Shortly after, the same laboratory developed a highly enantioselective and diastereoselective catalytic conjugate addition of an exceptionally wide range of trisubstituted carbon nucleophiles (cyclic and acyclic p-ketoesters, 2-substituted 1,3-diketones, a-nitroesters and ot-cyanoesters) to nitroalkenes mediated by related CPN and CPD derivatives (Scheme 14.2). This simple methodology allowed the efficient synthesis of important building blocks containing adjacent quaternary and tertiary stereocentres. 

While the formation of a variety of carbon stereocentres has been effectively achieved, stereoselective approaches for the preparation of P-stereogenic phosphines have, until recently, been non-existent. In this context, Bergman s group has developed several chiral ruthenium catalysts to be investigated for the enantioselective ruthenium-catalysed alkylation of secondary phosphines into the corresponding chiral air- and moisture-tolerant tertiary phosphine-borane products after a subsequent treatment with BHs.THF. " These reactions proceeded through the intermediacy of nucleophilic phosphido species, which had low barriers to pyramidal inversion, allowing a DKR process. 

Asymmetric Michael addition of a-cyanoacetates to enones, constructing densely adjacent quaternary and tertiary stereocentres, has been attained by combination of a catalytic action of soft Pd complexes as soft Lewis acids and Brpnsted acids, for example, AcOH. Investigation of the kinetics revealed that the C-C-bond-forming step takes place almost instantaneously with the bis-palladium complex right after the substrate coordination. ... 

Perhaps one of the most challenging aspects of complex molecule synthesis is control of the absolute sense of stereochemistry for the preparation of optically-active compounds. In 1989, Shibasaki and Overman independently reported the first examples of asymmetric Heck reactions. These efforts focused on intramolecular cyclization reactions, which display extra elements of regiocontrol. To date, the asymmetric intramolecular Heck has been exploited in the synthesis of terpenoids, akaloids and polyketides, forging key tertiary and quaternary stereocentres. ... 

The configurational stability of several a-amino tertiary benzylic organolithiums has been demonstrated at low temperatures on two different heterocycles in the absence of any chiral ligand or auxiliary." A variety of 2,2-disubstituted piperidines and pyrrolidines have been synthesized bearing a-amino quaternary stereocentres. The racemiza-tion has been found to be faster in THF than in Et20 and mostly entropy controlled. 

An efficient regioselective and enantioselective bifunctional chiral thiourea-tertiary amine (25) catalysed hydroxyamination of C(3)-substituted oxindoles has been presented. 3-Amino-2-oxindoles with chiral quaternary stereocentres have been... 

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