Enantioselective version

The multistrategic retrosynthetic analysis of ginkgolide B, which led to the synthesis outlined below, is presented in Section 6.7 of Part One. The synthetic route, an enantioselective version of which was demonstrated, also led to ginkgolide A. 

We are now standing in the middle of the next step of the development of cycloaddition reactions - catalytic and catalytic enantioselective versions. The last two decades have been important in catalysis - how can we increase the reaction rate, and the chemo-, regio, diastereo-, and enantioselectivity of cycloaddition reactions. Metal catalysis can meet all these requirements ... 

The Claisen rearrangement has attracted much attention as an attractive tool for the construction of new carbon-carbon bonds. Various catalytic systems have been developed to afford enantioselective versions of this process. On the other hand, relatively few chiral sulfur-containing ligands have been investigated for this type of reaction. As an example, Taguchi et al. have... 

Enantioselective Cyclopropanation. Enantioselective versions of both copper and rhodium cyclopropanation catalysts are available. The copper-imine class of catalysts is enantioselective when chiral imines are used. Some of the chiral ligands that have been utilized in conjunction with copper salts are shown in Scheme 10.10. 

Cationic palladium complex 121 reductively coupled enynes (Eq. 20) using trichlorosilane as the stoichiometric reductant [71]. This combination of catalyst and silane afforded silylated methylenecyclopentanes such as 122 in good yield from enynes such as 123. Attempts to develop an enantioselective version of this reaction were not successful [71]. When enediyne 124 was cyclized in the presence of trichlorosilane, the reaction favored enyne cycli-zation 126 by a 3 1 ratio over diyne cyclization to 125 (Eq. 21). In contrast, when the more electron-rich dichloromethylsilane was used as the reductant, diyne cyclization product 125 was preferred in a ratio of 4 1 [71]. Selectivities of up to 10 1 for enyne cyclization were observed, depending on the substrate employed [72],... 

In 1975, Sharpless et al. reported that imino-osmium trioxides underwent aminohydroxylation (Scheme 54).208,209 t0 perform aminohydroxylation with high efficiency, regio-, chemo-, and enantioselectivity must be addressed. This had made the practical realization of aminohydroxylation difficult. However, the development of asymmetric dihydroxylation, as described in the preceding section, propelled the study of asymmetric aminohydroxylatyion forward and, in 1996, Sharpless et al. reported a highly enantioselective version of catalytic aminohydroxylation... 

G-H functionalization at acetal C-H bonds generates protected forms of /3-ketoesters (Figure 4). /3-Ketoesters are often formed by Claisen condensation, but the asymmetric version is not a viable process, because the products would very likely racemize under the reaction conditions. Therefore, the C-H insertion equivalent to the Claisen condensation is very attractive, because the resulting /3-ketoester is protected, which allows for the enantioselective version to be feasible (Figure 4). 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

These different reaction modes are now presented. As most of this chemistry has been extensively reviewed from a synthetic" and a mechanistic point of view,185 186 focus here is particularly on enantioselective versions of these reactions and the processes transiting through the path d mechanism since this is a rather new and rapidly growing field of research. 

Although palladium catalysts have played the most prominent role in this area, other metals have also been found to catalyze allylic etherification reactions, often providing complementary stereochemical outcomes. A few ruthenium catalyst systems have been used for the O-allylation of phenols,143,144 including an enantioselective version utilizing [Cp Ru(MeCN)3]PF6 that provides promising ee s, albeit with diminished control of regioselectivity (Equation (25)).145... 

Palladium complexes are general and versatile catalysts for allylic amination.1,la lh The palladium-catalyzed allylic aminations of 1,3-symmetrically disubstituted substrates, including enantioselective versions, have been widely studied.1, a h It has been important to control the regioselectivity in allylic amination of unsymmetrical substrates 1 or 2 (Equation (1)). In general, palladium-catalyzed allylic amination gives the ( )-linear product 3Tla lh regiocontrol in amination has recently attracted much attention in approaches toward the branched product 4. 

In hydrogenation, early transition-metal catalysts are mainly based on metallocene complexes, and particularly the Group IV metallocenes. Nonetheless, Group III, lanthanide and even actinide complexes as well as later metals (Groups V-VII) have also been used. The active species can be stabilized by other bulky ligands such as those derived from 2,6-disubstituted phenols (aryl-oxy) or silica (siloxy) (vide infra). Moreover, the catalytic activity of these systems is not limited to the hydrogenation of alkenes, but can be used for the hydrogenation of aromatics, alkynes and imines. These systems have also been developed very successfully into their enantioselective versions. 

One year after reporting the experiments outlined in Section 7.3.1, Kishi s group carried out an enantioselective version of the synthesis based on the experience obtained in the above synthesis of the racemate ( )-66.7 This version adopted the concept of double asymmetric induction demonstrated in the synthesis of 6-deoxythronolide B (see Section 7.2). 

An interesting recent report by Shibasaki deals with a Zr-catalyzed process whereby various cyclic and acyclic alkenes are directly converted to their corresponding p-cyanohy-drins, presumably via an intermediate epoxide [114]. One catalytic enantioselective version has been reported, as shown in Eq. 6.23. This promising initial result augurs well for future developments of this synthetically useful transformation. 

Hydrosilylation can be applied to alkenes, alkynes, and aldehydes or ketones. A wide range of metal compounds can be used as a catalyst. The most common and active ones for alkenes and alkynes are undoubtedly based on platinum. Hydrosilylation of C-0 double bonds gives silyl ethers, which are subsequently hydrolysed to their alcohols. The reaction is of interest in its enantioselective version in organic synthesis for making chiral alcohols, as the achiral hydrogenation of aldehydes or ketones does not justify the use of expensive silanes as a reagent. 

The chiral ligand (5,5)-Jl, derived from chiral 13., is a controller group that has shown to provide a highly enantioselective version of several powerful synthetic methods, as Diels-Alder, aldol and carbonyl allylation processes. 

Abstract 1,3-Dipolar cycloaddition reactions (DCR) are atom-economic processes that permit the construction of heterocycles. Their enantioselective versions allow for the creation of up to four adjacent chiral centers in a concerted fashion. In particular, well-defined half-sandwich iridium (111) catalysts have been applied to the DCR between enals or methacrylonitrile with nitrones. Excellent yield and stereoselectivities have been achieved. Support for mechanistic proposals stems from the isolation and characterization of the tme catalysts. 

Based on the CCM system described above, an enantioselective version thereof was presented by Togni and coworkers a decade later [9]. The use of a new class of catalyst precursors led to substantially improved reactivity, and the system now was truly catalytic, with turnover frequency (TOP) values reaching up to 3.37 h at 348 K (Equation 6.5 Table 6.1). The absolute configuration of the resultant amine was determined by internal comparison of the X-ray crystal structure of the... 

Recently, the power of designer acid catalysts has generally increased as a result of the development of the catalytic enantioselective versions described here. In particular, combined acid catalysis is still very much in a state of infancy, and there is still much more to learn with regard to new reactivity. The ultimate goal is a more reactive, more selective, and more versatile catalyst. We beheve that the realization of such an objective would be a tremendous benefit for the further development of organic synthesis, including green chemistry. 

The first enantioselective version was also accomplished with this class of substrates. For example, the rearrangement of ether rac-103 with f-BuLi/bis(oxazoline) 27 afforded ketones 104a and 104b in 48%-50% ee (equation 58) . 

The enantioselective version of a retro-[ 1,4]-Brook rearrangement was accomphshed as the subsequent reaction of enantioselective cyclocarbolithiation by Hoppe and colleagues (equation 111) . The cyclization precursor 179 was treated with s-BuLi/(—)-sparteine (24) in ether, providing the cyclized and silyl-rearranged product (/f,/f,/f)-180 in 58% yield as a single stereoisomer. 

Phosphate-derived a-oxycarbanions can rearrange into a-hydroxy phosphonates. This class of rearrangement is known to proceed with retention of configuration at the carban-ion terminus. The enantioselective version of this rearrangement has been developed using a chiral lithium amide as a base (equation 115) . The reaction of benzyl dimethyl phosphate 182 with amide R,R)-63 in THF gave the hydroxy phosphonate (5 )-183 in 30% in enantioenriched form (52% ee). 

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