Selectivity Stereoselective reactions

Many stereoselective reactions have been most thoroughly studied with steroid examples because the rigidity of the steroid nucleus prevents conformational changes and because enormous experience with analytical procedures has been gathered with this particular class of natural products (J. Fried, 1972). The name steroids (stereos (gr.) = solid, rigid) has indeed been selected very well, if one considers stereochemical problems. We shall now briefly point to some other interesting, more steroid-specific reactions. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

The multi-component systems developed quite recently have allowed the efficient metal-catalyzed stereoselective reactions with synthetic potential [75-77]. Multi-components including a catalyst, a co-reductant, and additives cooperate with each other to construct the catalytic systems for efficient reduction. It is essential that the active catalyst is effectively regenerated by redox interaction with the co-reductant. The selection of the co-reductant is important. The oxidized form of the co-reductant should not interfere with, but assist the reduction reaction or at least, be tolerant under the conditions. Additives, which are considered to contribute to the redox cycle directly, possibly facilitate the electron transfer and liberate the catalyst from the reaction adduct. Co-reductants like Al, Zn, and Mg are used in the catalytic reactions, but from the viewpoint of green chemistry, an electron source should be environmentally harmonious, such as H2. 

The general relation which must be satisfied in order to bring about an appreciable stabilization energy in the chemical interaction has been given by Eq. (3.20) and Eq. (3.25 b). Such relations frequently provide a selection rule for the occurrence of stereoselective reactions. 

Recently, silicon-tethered diastereoselective ISOC reactions have been reported, in which effective control of remote acyclic asymmetry can be achieved (Eq. 8.91).144 Whereas ISOC occur stereoselectively, INOC proceeds with significantly lower levels of diastereoselection. The reaction pathways presented in Scheme 8.28 suggest a plausible hypo thesis for the observed difference of stereocontrol. The enhanced selectivity in reactions of silyl nitronates may he due to 1,3-allylie strain. The near-linear geometry of nitrile oxides precludes such differentiating elements (Scheme 8.28). 

In stereoselective reactions, Zn11 Lewis acids work well to achieve high selectivities (Scheme 54). Chiral complexes of Zn11 with chiral bis(oxazoline) ligands act as effective catalysts in Diels-Alder reactions of reactive dienes with dienophiles having bidentate chelating moieties such as... 

For both catalytic and stoichiometric reactions, each step of the process taking place on the metal can be influenced by the nature of ligands, cations, anions, or solvent. The effects of these factors on reaction rate, selectivity, stereoselectivity, etc. cannot be easily predicted, because each step can be influenced in different ways. The reader is referred to the literature cited below. 

A typical procedure calls for reaction of the hemiacetal donor with dicydohexyl carbodiimide and copper(I) chloride (0.1 equiv) at 80 °C, followed by an addition of the acceptor and continued heating. As an early demonstration of this protocol, oc-riboside 86 was prepared in moderate yield but with exclusive stereoselectivity [141]. Further measures were required for the glycosylation of monosaccharide acceptors, such as addition of p-toluenesulfonic add (0.1 equiv) to promote the formation of disaccharide 87 [144]. The method was more suitably applied to the synthesis of O-acyl glycopeptides, as evidenced by the formation of 88 in 60% yield [143,144]. Various peptides with non-nudeophilic side chains were found to be amenable to this stereoselective reaction. The [3-selectivity was suggested to arise from a preponderance of the a-isourea intermediate 85 in the activation step. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Hoch U, ScheUer G, Schmitt M, Schreier P, Adam W, Saha-MoUer CR (1995) Enzymes in synthetic organic chemistry selective oxidoreductions catalyzed by the metaUoenzymes lipoxygenase and peroxidase. In Werner H, Simdermeyer J (eds) Stereoselective reactions of metal-activated molecules, 2nd Symposium. Vieweg, Braimschweig, p 33 Adam W, Korb MN (1997) Tetrahedron Asymmetry 8 1131... 

Besides stereoselective synthesis of various monosaccharides, stereoselective reaction for the preparation of glycosides is an important problem in the synthetic field of carbohydrate chemistry. However, the classical methods, which require the assistance of heavy metal salts or drastic reaction conditions, are still employed by and large in the synthesis of such compounds. Taking these disadvantages into consideration, new glycosylation reactions, which proceed under mild reaction conditions with high selectivity, have been developed and exploited. 

This chapter will address the development of selected stereoselective rhodium-catalyzed carbonylation reactions and their application to problems in organic synthesis. It is in no way intended to serve as a comprehensive review of rhodium-catalyzed carbonylation chemistry. The focus, rather, is on the development of stereoselective rhodium-catalyzed carbonylation reactions for use in the synthesis of stereochemically complex natural products, particularly polyketides. 

This unnatural acid is used as a chiral intermediate for the synthesis of a number of products. Chemical asymmetric synthesis was very difficult and so the stereoselective synthetic properties of enzymes were exploited to carry out a selective reduction reaction. The stereoselective hydrolysis of protein amino acid esters had already been commercialised by Tanabe in Japan using immobilised aminoacylase, and selective reduction reactions using whole yeast cells are already used in a number of processes, such as the selective reduction of the anti-cancer drag Coriolin. 

The design and development of a Z-selective CM reaction faces two major challenges first, the thermodynamic preference for the formation of -olefms renders their Z-counterparts difficult to prepare second, any inherent kinetic Z-preference demonstrated by a catalyst can erode via secondary metathesis if the -pathway is not blocked. Consequently, most efforts to effect stereoselective olefin formation have focused on the preparation of -olefins. 

In 1985, Warwel and Winkelmiiller reported a series of catalyst systems for the CM of either styrene or 4-vinylcyclohexane with unfunctionalized olefins (Scheme 9). Using heterogeneous catalyst systems of RceOy/ AI2O3, among others, the authors demonstrated that both a substrate s electronic and steric properties govern CM product selectivity. Unfortunately, as the stereoselectivities of these reactions were not reported, the effect of a secondary allylic carbon on olefin stereoselectivity was not determined. Nevertheless, the non-statistical product distribution obtained in these reactions constitutes the first example of a product selective CM reaction. 

Clifford, Rayner and co-workers at the University of Leeds [66,67] have used the density of SCCO2 to control the stereoselectivity of reactions in a novel way. Previous workers have observed an influence of density on selectivity in reactions very close to the critical point. The novelty of the Leeds work is that the effects are observed at densities considerably above pc and temperatures higher than Tc. This selectivity has no obvious counterpart in reaction chemistry in conventional solvents. Effects have been observed in a whole range of reactions, and this approach may well have widespread applicability. 

A stereoselective reaction on the other hand is one in which the stereo-electronic requirement of the reaction mechanism is such that two equally valid alternative pathways are available for the same mechanistic interaction between reactant and reagent. However, either the free energies of activation of the alternative reactions or the thermodynamic stabilities of the products differ, so that one isomer is formed in preference to the other selection has occurred. An example is provided by the reduction of cholestan-3-one (32). Equatorial attack (i) or axial attack (ii) of the hydride ion is mechanistically equally feasible and stereoelectronically defined. However, steric interactions between the hydride ion source and the conformationally fixed steroid molecule, together with considerations as to whether the reaction was under kinetic or thermodynamic control, would determine that the reaction is proceeding in a stereoselective manner. 

Many complex reactions consisting of several elementary steps feature a strongly temperature-sensitive overall selectivity as well as an inversion point with a maximum or minimum selectivity parameter. However, the empirical rule that stereoselective reactions should be performed at the lowest possible temperatures to achieve the highest selectivities is not always followed. Instead, the competition of enthalpy and entropy determines the overall selectivity, depending on the temperature range. 

Stereoselective reactions are those that result in the selective production of one of the stereoisomers of the product. The extent of the selectivity may be recorded as the enantiomeric excess (e.e.) when the reaction produces a mixture of enantiomers and the diastereoisomeric excess (d.e.) when it produces a mixture of diastereoisomers. These quantities are defined by the expression ... 

The condition 1) states that unequal amounts of stereoisomers are produced or destroyed by the reaction together conditions 2) and 3) assure that the increase in chiral genus is due to a stereoselectivity which is caused by chiral influences alone. Condition 1) is an essential part of the definition it is interrelated with condition 3), and together they restrict the type of chirality increasing stereoselective reactions that will be called an asymmetric synthesis34. In fact, a stereoselective reaction is never infinitely selective , because this would require an infinite free enthalpy difference of stereoisomers, stereoisomeric transition states respectively (with thermodynamic control, or with productive selectivity) in the case of an idealized destructive selectivity infinite selectivity would be reached at infinite reaction time, when none of the considered stereoisomers would be left over3S ... 

The selectivity of a productive reaction refers to the relative amounts of P, P at the time of observation. The ratio of the amounts of P and P which are formed is the ratio of the corresponding rate constants, if the stereoselective is a pair of corresponding reactions53. If, however, the productive stereoselective reaction is a more complex kinetic scheme, then the ratio of the amounts of any two stereoisomeric products, P and P , which depends on time and pairs of the appropriate kinetic constants, has a positive lower bound and a finite upper bound. Both of these bounds are the ratios of two rate constants54. However, since the free enthalpy difference of stereoisomeric transition states is due to different non-bonded interaction and does not, as a rule, exceed 3 kcal/mole, and since the rate constant ratio depends on the free enthalpy difference, this ratio has a rather low upper bound. Accordingly, the stereoselectivity of productive reactions is generally low (50—90% relative yield of the preferred product in most cases). 

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