Chiral transformation products

Chiral transformation products can be formed from chiral or achiral parent compoimds in the environment. Enantiomers are generally considered... 

The axially chiral natural product mastigophorene A (70) was synthesized via a copper-catalyzed asymmetric homocoupling of bromooxazoline 68. Treatment of 68 with activated copper in DMF afforded 69 in 85% yield as a 3 1 mixture of atropisomers. The major atropisomer was converted into mastigophorene A (70) the minor regioisomer was transformed into the atropisomeric natural product mastigophorene... 

The advent of fs pulse lasers recently opened new perspectives for asymmetric photochemistry. The elaboration of this field still is in the theoretical realm. Pulse sequence [125,126] and coherence [127] scenarios are set up for chiral molecular products from achiral precursors. If, for example, phosphinothiotic acid H2PO(SH) molecules are preoriented, which can be effected by laser action, and a special sequence of cpl pulses is used, then the theoretical prediction is that the l enantiomer is transformed to the r enantiomer, but the reverse process is suppressed and vice versa for a different pulse sequence [125]. Chapter 2 of this book is dedicated to these coherent phenomena controlling asymmetric photoreactions. 

Enantioselective reactions are defined as transformations in which a prochiral substrate is converted into a chiral product such that one of the two enantiomers is formed in significant excess. The degree of enantioselectivity is measured by the enantiomeric excess (ee), as defined in Scheme 1. In this schematic example the prochiral substrate S represented by a triangle, is converted into the two enantiomeric, chiral tetrahedral products P1 and ent-P1 (enantioface-differentiat-ing reaction). Alternatively, but less commonly used, enantioselectivity can be induced by the differentiation of enantiotopic substituents, as depicted for S2 and Y 2lent-P2. 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

On this basis the choice of a specific catalytic step is usually determined by an economic analysis of the catalytic route vi. alternative routes (such as the separation of enantiomers by resolution, organic synthesis starting from chiral natural products used as building blocks (the chiral pool concept), or the use of enzymatic and microbial transformations) and time to market considerations (see also Chapter 1). 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

Reactions that involve asymmetric synthesis are traditionally classified separately from other dia-stereoselective transformations of chiral substrates, even though there is little fundamental differoice between them. The degree of success realized in both categories depends on the ability of the chemist to distinguish between competing, diastereomeric transition states the critical objective is to maximize AAG - This classification system undoubtedly evolved since the chiral auxiliary used in asymmetric reactions, whether it is introduced as part of a catalyst or is covalently bound to the substrate, is not destined to be an integral structural component of subsequent transformation products, while the reverse situation obviously pertains in the more frequently encountered diastereoselective transformations of chiral substrates. Work that has been reported for asymmetric IMDA reactions is summarized in this section." ... 

Composition The ISO standard for aniseed [15] specifies the E-anethole content as 87-94%. Z-anethole (the more toxic isomer and transformation product of E-anethole when exposed to UV light [16]) is limited to 0.4%. The typical constituent of aniseed oil, pseudoisoeugenyl 2-methylbutyrate ]17] can occur up to 2%. Eor further confirmation of its natural origin by chirality GC, see ] 18]. Further constituents are methyl chavicol (up to 3%), gamma-himachalene (up to 5%), anisic aldehyde (up to 1.4%) and e.g. small amounts of monoterpenes. 

This chemistry was extended to a number of bicyclic alkenes and dienes utilizing various chelating axially chiral bisphosphine iridium catalysts (Scheme 11.5) [29]. Further synthetic transformations of the chiral hydroamination product 13 provide access to functionally substituted chiral cyclopentylamines with multiple stereocenters, such as 14 and IS. It should be noted that alkylamines, such as octylamine or N methyl aniline, and sterically encumbered aniline derivatives, such as 0 toluidine or o anisidine did not undergo hydroamination reactions under these conditions. 

When the allylboranes react with a chiral aldehyde, products with three stereocenters are formed, and two examples of such transformations are given in Figure 6.52 [1211],... 

In nature, aldolase enzymes use this transformation to produce enantiomerically pure compounds [3]. Other biochemical methods such as the use of antibodies [4] have provided a practical methodology for the synthesis of chiral aldol products. However, both methodologies have a shortage of substrate scope. 

Aldehydes cannot undergo direct enantioselective reduction due to the formation of an achiral product, but List s group discovered an interesting variation on this theme with the direct reductive amination of a-branched aldehydes via an efficient dynamic kinetic resolution (DKR) [56]. Under the reductive amination conditions, an a-branched aldehyde undergoes a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then have to be faster than that of the other, resulting in an enantiomerically enriched product via a dynamic kinetic resolution (Figure 15.6). TRIP once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine product in 50%... 

Similarly, the product from a DHAP-depending aldolase-catalyzed reaction is a chemically labile 2-oxo-l,3,4-triol, which is phosphorylated at position 1. Dephosphorylation under mild conditions, without isolation of the intermediate phosphate species, by using acid phosphatase is a method frequently used to obtain the chiral polyol products [512-515]. As shown in Scheme 2.76, enzymatic dephosphorylation of the aldol product obtained from 5-substituted hexanal derivatives under mild conditions gave the sensitive chiral keto-triol in good yield. In this case the product could be transformed into (-i-)-exo-brevicomin, the sex pheromone of the pine bark beetle. 

The observations of the conformation dependence of chiral amide ligand and autoinduction phenomenon in the catalytic process mentioned above allow Walsh to use achiral or meso ligand for conducting asymmetric diethylzinc addition to aldehydes in the presence of chiral titanium alkoxides. As shown in Scheme 14.4, either meso bis-(sulfonamide) ligand based on cis-l,2-diaminocyclohexane or achiral bis(phenol) ligand in combination of chiral titanium alkoxide [Ti(OR )4] can induce the chiral transformation in the newly formed product with 83% and 84% ee, respectively [17]. 

Copper(II)-catalyzed Boryl Addition to Allylic Carbonates. The conversion of allylic carbonates to chiral a-substituted allylboronates was also investigated by Hoveyda, who was able to accon ilish this transformation with a Cu(II)-NHC complex. This reaction proceeds in a vinylogous fashion to Sawamura s, but under these conditions, (E)- and (Z)-allylic carbonates undergo substitution to produce opposite enantiomers of product with similar yields and selectivity. This methodology is also tolerant of substitution at the a- or -position and is effective for di-or trisubstituted alkyl (linear or branched) or aryl alkenes delivering a quaternary a-chiral allylboronate product with up to 98% enantioselectivity (eq 49). 

The functionalization of C—H bonds through a transition metal carbenoid insertion has been known for over a century and has become a powerful method to achieve new C—C bonds. In most cases, these transformations have been completed with dirhodium (II) carboxylate catalysts. The development of chiral dirhodium (II) complexes has allowed the enantioselective version of these reactions and has led to a straightforward method for the preparation of chiral natural products and dmgs. 

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