Nucleophilic substrate-controlled

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

There are many reports on the asymmetric addition of nucleophiles to carbon-nitrogen double bonds [6]. However, the majority of these reports are based on substrate control and rely on chiral auxiliaries in imines. Moreover, almost all of these reports are just for aldo-imine cases [7]. 

The simplest case of substrate-controlled diastereoselection is the incorporation of the controlling stereocenter and the prostereogenic center into a cyclohexane or cyclopentane ring. In the classical example of nucleophilic attack on a conformationally anchored cyclohexanone, axial and equatorial attack are possible, leading to diastereomers 1 and 2, respectively. 

For the syn substrate 8, the approach of the organometallic nucleophile is controlled by the steric bias imposed by the bulky DiTOX ring (Fig. 2). The nucleophile approaches the prochiral carbonyl group from the direction of the... 

The majority of the reported examples are diastereoselective conjugate additions (Section 7.3.1.). This section has been organized into reactions where the chiral information is located on the nucleophile (Section 7.3.1.1.), on the electrophile (Section 7.3.1.2.), or on both the nucleophile and the electrophile (Section 7.3.1.3.). Further division has then been made, i.e., substrate-controlled vs. auxiliary-controlled diastereoselective reactions, and subdivision according to whether the reactions are inter- or intramolecular in nature. 

A systematic and in-depth study involving bio-imprinted subtilisin using nucleophilic substrates as the templates has been reported by Rich and Dordrick [19]. They allowed subtilisin Carlsberg to interact with thymidine (the template) in an aqueous buffer solution and the resulting complex was lyophilised. After removing the template, catalytic activity of the imprinted enzyme was studied by the acylation reaction of thymidine. Compared to the control (enzyme lyophilised from the aqueous solution in the absenee of the nucleotide template), the imprinted enzyme... 

The epoxidation proceeds via substrate control to yield the a-epoxide 41 selectively. The C-nucleophile 42 that results from deprotonation of 27 opens the epoxide from above through an attack at C-8, and the resulting alcoholate 43 cyclizes upon reacting with the electrophilic carbon to form the five-membered ring, which becomes the hemiacetal 28 after hydrolysis. 

RichJO and DordickJS. Controlling Subtilisin Activity and Selectivity in Organic Media by Imprinting with Nucleophilic Substrates. /Am Chem Soc 1997 119 3245-3252. 

Table 7 summarizes several important aspects of substrate control of diastereoselectivity. Variation of either the relative configuration of the lactone or of the olefin geometry allows access to the opposite diastereochemical series (Table 7, entries 2-5)80. Since only the ( )-olefins are formed, a successful chirality transfer either requires ionization of the lactone from a single conformation B with nucleophilic attack being faster than stereorandomization or an involvement of solely the, mi,.n -7t-allyl complex generated via n-a-n rearrangement prior to C —C bond formation. The soft carbanion attacks the allyl complex charge directed distal to the carboxylate anion. 

The individual modules of polyketide synthases (PKSs) and of NRPSs represent another example of modularity. An electrophile and a nucleophile are covalently attached to two different subunits of a multidomain enzyme. The selectivity for the electrophile resides in the domain catalyzing bond formation between two substrates and the selectivity for the nucleophile is controlled by a transfer domain which attaches the nucleophile onto a carrier domain. ... 

The Pd(Quinox)Cl2, (Quinox = 2-(2-quinolyl)-4,5-dihydrooxazole) catalysed Wacker-type oxidation of olefins bearing homoallylic alcohols by TBHP led to the corresponding /3-hydroxy ketones in good yields. Since the oxidation was catalyst controlled, it was significantly faster than the substrate-controlled Tsuji-Wacker oxidation. The bis- and fra-homoallylic alcohols were oxidized to cyclic peroxyketals, presumably via nucleophilic attack of the methyl ketone. Kinetics of the Wacker-type oxidation of olefins by TBHP in the presence of Quinox (ligand), and (54) as the catalyst reveal first-order dependence on ligand and olefin, and rate saturation in TBHP, as expected of the proposed mechanism (Scheme 9)... 

In the cases discussed in subsections 8.2.1, 8.2.2, 8.2.3, and 8.2.5, the chiral auxiliary is removed during or after the reaction is completed to provide the desired chiral substitution product the reaction is said to be auxiliary controlled. When the formation of a new axial, central, or planar stereo-genic unit is induced by a preexisting stereogenic element in the substrate or in the entering nucleophile, which is not removed at the end of the process (such as in Section 8.2.4), the reaction is said to be chiral substrate controlled. 

In auxiliary- and substrate-controlled Sj Ar reactions, stoichiometric amounts of enantiomeri-cally pure compounds are required. In recent years, major progress has come from the development of chiral catalyzed reactions (Section 8.3). In the approach conceptualized by Tomioka (Section 8.3.1), the formation of a new stereogenic unit is induced by substoichiometric or catalytic amounts of a chiral neutral ligand able to chelate the nucleophile. Jprgensen and Maruoka have shown that chiral quaternary ammonium and phosphonium cations Q can induce asymmetry during the Sj Ar process by acting as chiral phase-transfer catalysts (Section 8.3.2). Finally, recent advances in absolute asymmetric Sj Ar rely on new developments in homochiral crystallization (Section 8.4). 

AUXILIARY- AND SUBSTRATE-CONTROLLED ASYMMETRIC NUCLEOPHILIC AROMATIC SUBSTITUTION... 

Substrate-controlled routes to optically enriched materials via diastereoselective oxidative dearomatizations constitute a second strategy for harnessing this process in asymmetric synthesis. Best results are obtained in intramolecular dearomatizations in which a preexisting stereogenic center is present on the side-chain nucleophile of a prochiral arene substrate [50]. For example, intramolecular oxidative dearomatization of 54 proceeds diastereoselectively as a consequence of conformational effects operative in the course of acetal formation (Scheme 15.20) [51]. 

Only a few examples of substrate-controlled diastereoselective intramolecular oxidative dearomatization have appeared. These transformations are analogous to the reaction shown in Scheme 15.20 in that stereogenic centers present on the linker connecting the carbon nucleophile to the arene substrate are responsible for diastereoselectivity [69, 70]. A rare example of a true metal-catalyzed oxidative dearomatization of substituted 2-naphthols is shown in Scheme 15.25. Treatment of naphthol 67 with Fe(salen) catalyst 68 in the presence of nitromethane (as a carbon nucleophile) and air (O as stoichiometric oxidant) gave naphthone 69 possessing a quaternary carbon center in 90% ee [71]. 

Metal-activated alkene additions can be classified as stoichiometric or catalytic processes. Stoichiometric processes for THP synthesis typically involve the use of mercury(II) salts and to a lesser extent iodo and seleno reagents. The progress of intramolecular oxymercuration is determined by the stabiUty of the cationic intermediates. Product stereochemistry is under substrate control and usually leads to the thermodynamically more stable THP product. Catalytic variations generally involve palladium complexes [44], but other transition metals are becoming more common (e.g., Pt [45], Ag [46], Sn [47], Ce [48]). The oxidation state of Pd determines the catalyst reactivity. Palladium(O) complexes are nucleophilic and participate in tetrahydropyran synthesis through jt-allyl cation intermediates, whereas Pd(II) complexes possess electrophilic character and progress through a reversible t-complex. 

Many other examples illustrate substrate control in asymmetric synthesis, wherein an existing stereogenic center in the ketone or aldehyde biases the attack of a nucleophile preferentially to one of the two diastereotopic faces. From the reduction of very simple chiral ketones such as 3 (Equation 2) [36] to the synthesis of highly complex molecules exemplified by Kishi s breathtaking synthesis of palytoxin (8, Scheme 2.1) [26, 38], the ability to conduct diastereoselective additions to carbonyl groups provides synthetic chemists with a powerful means to prepare chiral alcohols. 

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