Stereoselectivity asymmetric variants

One of the first attempts to extend polymer-assisted epoxidations to asymmetric variants were disclosed by Sherrington et al. The group employed chiral poly(tartrate ester) hgands in Sharpless epoxidations utilizing Ti(OiPr)4 and tBuOOH. However, yields and degree of stereoselection were only moderate [76]. In contrast to most concepts, Pu and coworkers applied chiral polymers, namely polymeric binaphthyl zinc to effect the asymmetric epoxidation of a,/9-unsaturated ketones in the presence of terPbutyl hydroperoxide (Scheme 4.11). 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

Acetate-derived silyl ketene acetals (11, 13 and 14) react with aldehydes with good stereoselectivity (equation 10) significant results are reported in Table 5. Removal of the auxiliary, with methanolic KOH, gave the corresponding (3-hydroxy acids in good enantiomeric excess (ee). The asymmetric variants of the Mukaiyama reaction also helped to solve the long-standing problem of an efficient anti selec-... 

Consequently, chemists must have at their disposal simple, effective, efficient, and stereoselective synthetic methods to construct the necessary frameworks. Development of catalytic asymmetric variants of the phospho-aldol reaction provides, arguably, the most versatile such process for the simultaneous construction of the [P-C] bond and associated a-carbon functionality with control over the stereochemistry at the newly generated alpha-carbon site. 

The introduction of the activated allylic bromides and Morita-Baylis-HiUman acetates and carbonates pioneered the development of a number of phosphine-catalyzed reactions in subsequent years [45]. Interestingly, the asymmetric variant of this type of transformation only appeared in the literature seven years later. In 2010, Tang, Zhou, and coworkers disclosed a highly enantioselective intramolecular ylide [3-1-2] annulation using spirobiindane-based phosphine catalyst 31 (Scheme 20.27). BINAP was found inactive in this reaction even at an elevated temperature (70°C). Notably, both optically active benzobicyclo[4.3.0] compounds 32 and 32 with three continuous stereogenic centers could be obtained as major products in high yields and stereoselectivities just by a choice of an additive [Ti(OPr )4], which can block the isomerization of the double bond [46]. 

In the 15 years since Fiirstner et al. developed the first NHK reaction using catalytic quantities of chromium, the subsequent stereoselective, catalytic variant has become a valuable tool in catalytic asymmetric synthesis. Many studies on the NHK reaction have focused on the application of ligands that have proven successful in a range of other catalytic asymmetric processes. For example, the salen- and oxazoline-derived ligands that have been applied have advanced the scope of the NHK reaction in terms of reactivity and asymmetric induction in a wide array of carbon-carbon forming processes. These processes now include allylation, crotylation, vinylation, methallylation, aUenylation, homoallenylation, and propargylation. Xia and Yamamoto s TBOxCr(III)Cl complex has afforded some of the highest levels of enantioselectivity in a series of allylation, crotylation, aUenylation, and more recent dienylation and alkynylation studies. 

While the transition metal-catalyzed Alder-ene reaction has been developed to offer excellent regio- and chemos-electivity, stereoselective variants have only recently begun to appear in the literature.58 The scope and limitations of many of these protocols have yet to be established. Nonetheless, several groups have published exciting examples of asymmetric Alder-ene cyclizations. 

Mannich reactions give rise to (i-amino carbonyl compounds which are amenable to further synthetic manipulations. Numerous stereoselective variants have been achieved by means of different types of catalysts including both metal complexes and organic molecules. In 2004, the groups of Akiyama and Terada independently selected this transformation as a model reaction for the introduction of a novel chiral motif to asymmetric catalysis [14, 15]. 

Two general reactions of this type are shown. There appears to be no report on stereoselective cyclizations of type a . Although transformation b has often been employed, e.g., for the construction of the chromanone skeleton 1, no stereoselective variants (simple diastereoselec-tion or enantioselection) appear to have been reported either. Since base catalysis has usually been applied, asymmetric induction by use of a chiral base catalyst appears feasible. However, this assumption still awaits experimental proof. 

Ortho ester rearrangements also lack control over vinyl double-bond geometry. As a consequence, the reactions proceed without internal asymmetric induction yielding mixtures of diastereomers. Therefore, stereoselective syntheses by the ortho ester variant are often useful only in those cases in which the stereocenter that cannot" be controlled is destroyed in a following step. 

Abstract This chapter provides an overview of emerging strategies for the selective introduction of functionality at oxindole C3. Specific emphasis has been devoted toward asymmetric methods for the introduction of C3 quaternary centers and spirocyclic ring systems. The chapter has been divided into two sections oti general methodology for the stereoselective synthesis of oxindoles and spirooxin-doles, respectively. A third section is devoted toward efforts in natural product total synthesis involving oxindole or spirocyclic variants as targets or key intermediates. 

The asymmetric a-sulfenylation of ketones is a particularly challenging reaction, as demonstrated by the poor success reported in the stereoselective variants via classical enolate/azaenolate reaction with an electrophilic sulfur reagent [71]. An umpolung approach has been devised by Coltart and co-workers [72] to effect the first asymmetric a-sulfenylation of ketones with arene thiols. Nitroso alkene derivatives, in i/tM-generated under basic conditions from a-chloro oximes, reacted with arene thiols in the presence of cinchona thiourea 27, which promoted the conjugate addition of thiophenol (Scheme 14.25). The chiral nonracemic a-sulfenylated oximes were directly hydrolyzed by IBX to ketones in high yield and good enantioselectivity. 

A fascinating variant of the enzymatic cyanohydrin formation consists in the use of nitroalkanes (as nonnatural nucleophiles) instead of cyanide (Scheme 2.209) [1568,1569]. Overall, this constitutes a biocatalytic equivalent to the Henry-reaction producing vicinal nitro-alcohols, which are valuable precursors for amino alcohols. Using (5)-HNL, the asymmetric addition of nitromethane to benzaldehyde gave the nitroalcohol in 92% e.e., while for p-nitrobenzaldehyde the stereoselectivity dropped sharply. With nitroethane, two stereocenters are created Whereas the stereoselectivity for the alcoholic center was high (e.e. 95%), the recognition for the adjacent center bearing the nitro moiety was modest and other (dia)stereomers were formed in up to 8%. 

In a related fashion, asymmetric amination of ( )-cinnamic acid yields L-phenylalanine using L-phenylalanine ammonia lyase [EC 4,3,1,5] at a capacity of 10,000 t/year [1274, 1601], A fascinating variant of this biotransformation consists in the use of phenylalanine aminomutase from Taxus chinensis (yew tree), which interconverts ot- to p-phenylalanine in the biochemical route leading to the side chain of taxol [1602], In contrast to the majority of the cofactor-independent C-0 and C-N lyases discussed above, its activity depends on the protein-derived internal cofactor 5-methylene-3,5-dihydroimidazol-4-one (MIO) [1603], Since the reversible a,p-isomerization proceeds via ( )-cinnamic acid as achiral intermediate, the latter can be used as substrate for the amination reaction. Most remarkably, the ratio of a- vs, 3-amino acid produced (which is 1 1 for the natural substrate, R = H) strongly depends on the type and the position of substituents on the aryl moiety While o-substituents favor the formation of a-phenylalanine derivatives, / -substituted substrates predominantly lead to p-amino analogs, A gradual switch between both pathways occurred with m-substituted compounds. With few exceptions, the stereoselectivity remained exceUent (Scheme 2,215) [1604, 1605],... 

Burke et al. employed a cyclic variant of the glycolate Ireland-Claisen rearrangement in the asymmetric synthesis of (-I-)-breynolide (Scheme 4.128) [122]. The rearrangement of the Z-silyl ketene acetal via a boat transition state generated the C3,C4 stereochemistry of the natural product in high yield and stereoselectivity. 

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