Chiral center, creation

Thermal cyclization of 2-vinyl-N,N-dialkylanilines 138 afforded 139 with creation of a new chiral center in 98% purity (89JOC199). In case of pyrrolidine with methyl or methoxymethyl substituent, cyclization with ZnCl2 occurs via an irreversible 1,5-hydrogen shift in boiling acetonitrile (87JA3136) or BuOH (91RTC115) to afford the diastereoisomers 140 (33%), 141 (35%) and 142 (6%) (87JA3136) (Scheme 27). 

Figure 10.34 Aldolase-based creation of two independent chiral centers in the total synthesis of the complex microbial plant defence elicitor (—)-syringolide.

To understand the interdependence of the creation of the two chiral centers relative to each other and to the sulfoxide, monosubstituted vinyl sulfoxides (S)-53 and (S)-54 were prepared and reduced with BH3-THF under the same conditions (Scheme 5.19). Both the 2- and 3-phenyl substituted substrates gave the chiral products 54 and 55 with complete stereo specificities dictated by the configuration of the starting sulfoxides. These results again were unexpected and indicated that both hydrogens were delivered solely directed by the chiral sulfoxide. This was not consistent with the mechanism in which the chirality of the initially formed chiral center at the 3-postion dictates the chirality of the subsequently formed chiral center at the 2-position. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

Chiral methylzinc aminoalkoxides 146a-c were obtained from the reaction of ZnMe2 with aminoalcohols, having chiral centers in their carbon backbones (Scheme 92).211 The methylzinc aminoalkoxides crystallize dimeric and trimeric with the formation of intermolecular zinc-oxygen bonds and creation of additional chiral centers. 

In a similar way, a mixture consisting of 2% boron trifluoride etherate in trifluoroacetic acid and triethylsilane brings about the regioselective reduction of the acyclic carbonyl group of the diketovinyl chloride shown in Eq. 215 in high yield (>94%), but with formation of approximately equal amounts of the two possible diastereomers formed from the creation of a new chiral center.396... 

The Diels-Alder reaction is a powerful synthetic process for constructing complex molecules. The reaction has been extensively studied and refined since its discovery in 1928.1 The most attractive feature of the Diels-Alder reaction is its simultaneous, regioselective construction of two bonds, resulting in the creation of up to four chiral centers with largely predictable relative stereochemistry at the bond formation sites. Theoretically, there are a total of 24 = 16 stereoisomers when atoms marked with an asterisk are all chiral centers (Scheme 5-1) therefore, the complete control of the reaction process to obtain enantiomeri-cally pure products has been the object of active research in many laboratories. 

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. 

The creation of a descriptor that takes into consideration the number of chiral centers, their location in the molecule, and how their handedness affects the bioactivities is needed. Through the use of a descriptor of this nature, when a QSAR program is presented with the correct information (bioactivities for individual enantiomers and correctly constructed molecules), it will be able to construct QSAR models that incorporate chirality. 

Asymmetric synthesis, either enantioselective or diastereoselective, has seldom been performed by photochemical reactions. One of the first examples that may be classified as a photochemical asymmetric synthesis is the photoalkylation of the most simple amino acid, glycine. Elad and Sperling 220) demonstrated that, if glycine is part of a polypeptide chain, there is good control (up to 40 % e.e.) in the creation of the new chiral center. A radical mechanism operates after the first step of photoinitiation of the process. 

The creation of all-carbon quaternary chiral centers by asymmetric conjugate addition is a challenging task. A chiral heterocyclic carbene 199 has been used as a ligand for this reaction. Chiral 3,3-disubstituted cyclohexanones 200 were obtained by this method with up to 85% ee (equation 126) . ... 

In another development, the statin side chain en route to Atorvastatin (Lipitor , Pfizer) is synthesized via the key intermediate alkyl 3-hydroxy-4-cyanobutyrate (Figure 13.17). Instead of the currently practiced six-step route, a much more concise three-step route starts from epichlorohydrin via Cl chain length enhancement by both nucleophilic substitution of chloride and nucleophilic ring opening of the epoxide with cyanide to yield symmetric dicyanoisopropanol. Nitrilase action desymmetrizes the dinitrile intermediate with the creation of a chiral center in C3 to yield (R)-3-hydroxy-4-cyanobutyrate, which is esterified to the key intermediate ethyl (R)-3-hydroxy-4-cyanobutyrate. 

The synthesis of enantiomerically pure compounds is the challenging problem for organic chemists. The synthesis becomes obsolete if the intermediates produce racemic mixtures. The problem is particularly acute when the asymmetric centers do not reside in a rigid cyclic or polycyclic framework. To be able to carry out efficient syntheses of complex molecules, chemists have to control the sense of chirality at each chiral center as it is introduced in the course of synthesis. Monoalkyl- or dialkyl-boranes exhibit a remarkable chemo-, stereo-, and regioselectivity for the hydroboration of unsaturated compounds. This property, coupled with the capability for asymmetric creation of chiral centers with chiral hydroboration agents, makes the reaction most valuable for asymmetric organic synthesis. In some of the cases, however, this has been achieved by diborane itself as shown in the synthesis of monensin by Kishi et al. A stereospecific synthesis of its seven carbon. component has been accomplished by two hydroboration reactions (Eq. 129) 209. ... 

When one of the initial reagents is optically active and the other is used in excess, then the diastereomeric preference results in kinetic resolution. An example is the reaction of racemic (149 sixfold excess) with (-)-isopiperitenone (158), which gives (-h)-(159) and (-)-(160) in a ratio of 4.8 1. After s aration each of these undergoes anionic oxy-Cope rearrangement to the optically active cyclodecadi-enones (161) and (162). These incisive studies demonstrate that the oxy-Cope rearrangement can be used to nqridly assemble complex polycyclic skeletons with remarkable control over the creation of multiple chiral centers. 

Another major contribution of polydentate ligands is the creation of a chiral pocket around the catalytic center providing, an appropriate chiral environment. The chiral pocket concept has been introduced by Trost for catalytic enantioselective allylic alkylation with the tetradentate aminophosphine ligand 33 [133]. The nucleophile fits into the chiral environment created by the chiral ligand and the allyl Pd intermediate. As a result, the enantiocontrol of the newly formed chiral center is very effective. In addition, the chiral control is likely to be efficient even at positions remote from the chiral ligand. That auxiliary has been widely... 

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