Transition diastereomeric

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Preparation of enantiomerically enriched materials by use of chiral catalysts is also based on differences in transition-state energies. While the reactant is part of a complex or intermediate containing a chiral catalyst, it is in a chiral environment. The intermediates and complexes containing each enantiomeric reactant and a homochiral catalyst are diastereomeric and differ in energy. This energy difference can then control selection between the stereoisomeric products of the reaction. If the reaction creates a new stereogenic center in the reactant molecule, there can be a preference for formation of one enantiomer over the other. 

Enby 6 is an example of a stereospecific elimination reaction of an alkyl halide in which the transition state requires die proton and bromide ion that are lost to be in an anti orientation with respect to each odier. The diastereomeric threo- and e/ytAra-l-bromo-1,2-diphenyl-propanes undergo )3-elimination to produce stereoisomeric products. Enby 7 is an example of a pyrolytic elimination requiring a syn orientation of die proton that is removed and the nitrogen atom of the amine oxide group. The elimination proceeds through a cyclic transition state in which the proton is transferred to die oxygen of die amine oxide group. 

These reactions will be discussed in more detail under the topic of 3,3-sigmatropic rearrangements in Chapter 11. For the present we simply want to focus on the fact that the reaction is stereospecific-, the -isomer gives one diastereomeric product whereas the related Z-isomer gives a different one. The stereochemical relationship between reactants and products can be explained if the reaction occurs through a chairlike transition state in... 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

The lower diastereoselectivity found with aldehyde 15 (R = CH3) can be explained by the steric influence of the two methyl substituents in close vicinity to the stereogenic center, which probably diminishes the ability of the ether oxygen to coordinate. In contrast, a significant difference in the diastereoselectivity was found in the additions of phenyllithium and phenylmagnesium bromide to isopropylidene glyceraldehyde (17)58 (see also Section 1.3.1.3.6.). Presumably the diastereo-sclcctivity of the phenyllithium addition is determined by the ratio of chelation-controlled to nonchelation-controlled attack of the nucleophile, whereas in the case of phenylmagnesium bromide additional chelation with the / -ether oxygen may occur. Formation of the -chelate 19 stabilizes the Felkin-Anh transition state and therefore increases the proportion of the anZz -diastereomeric addition product. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

When an (/. )-cnolate is the starting material, the corresponding argument indicates that the transition state with R1 in an equatorial position 6a is favored compared to the diastereomeric alternative 6b, Thus, the anti-product is assumed to form predominantly. 

The tris(diethylainino)sulfoiiium difluorotrimethylsiliconate induced aldol addition of enolsi-lancs, which delivers predominantly syw-aldols independent of the cnolate geometry (sec p 1608), calls for another mechanistic model. A.n open transition state model has been proposed which assumes that the naked" ionic oxygens are as far apart as possible28. For (Z)-enolates, one transition state is favored over the diastereomeric orientation due to the avoidance of a repulsive R /CHj interaction. 

The preferential conversion of the aluminum enolatc 2 c to diastereomer 3 is consistent with the boat-like transition state A where the enolate has adopted the usual antiperiplanar E geome-try42-50. The aldehyde substituent occupies the lower energy equatorial position of a boat-like transition state which places the bulky dialkylaluminum moiety away from the iron ligands. Possible transition states for the other observed diastereomeric products are also illustrated. 

Structures F and G are two model transition states for the reaction of an ( )-enolate with an ( )-enone. Although the same syn and anti diastereomeric pairs are formed as in the case of the closed transition states, the ratios will in general be different. 

A diastereomeric ratio (synjanti) of 90 10 is found, whereas within the syn-adduct the ratio between the ( ,5)/(S, )-isomers is 95 5. With methyl (Z)-2-butenoate the diastereomeric ratio (synjanti) is 25 75, and in the anti-adduct the (R,S) (S,S) ratio is 88 12186. These results are consistent with a chelated transition state as shown in Section 1.5.2.4.1. This enantioselcctivc Michael addition was used in the synthesis of 7,20-diisocyanoadocianc18 7. 

Addition of the lithium dienolate of 3-(tm-butyldimethylsilyloxy)-2,6-diinethyl-2-cyclohexenonc to ( + )-(.S )-4-( 3-methyl-3-butenyl)-3-(4-mcthylphenylsulfinyl)-2(5//)-furanonc in THF at — 95 °C for 2 hours gave an 88 12 mixture of diastereomeric adducts. A transition state has been proposed that involves chelation between both reacting partners20. 

Abbott and coworkers229 found that nucleophilic addition of amines to a, p-unsaturated sulfoxide gave asymmetrically induced adducts. For example, treatment of (R)-(—)-cis-propenyl p-tolyl sulfoxide 184 with piperidine in methanol gave a quantitative mixture of the diastereomeric adduct 185. Reduction of this mixture gave (Rs)-(Sc)-2-piperidinopropyl p-tolyl sulfide 186 in 74% optical yield, suggesting that the amines attack from the opposite side of the bulky aryl group at the transition state, as shown above (Figure 6). 

This type of procedure is referred to as a kinetic resolution since the enantiomers of the racemic substrate exhibit different rates of reaction with the optically active compound, i.e. the diastereomeric transition states that arise from differences in e.g. non-bonded interactions have different free energies. Horeau and Nouaille (1966) estimate that a rate difference corresponding to A AG of the order of 0 2 cal mol at 25°C could in principle be revealed by this method. 

Efficiency and selectivity are the two keywords that better outline the outstanding performances of enzymes. However, in some cases unsatisfactory stereoselectivity of enzymes can be found and, in these cases, the enantiomeric excesses of products are too low for synthetic purposes. In order to overcome this limitation, a number of techniques have been proposed to enhance the selectivity of a given biocatalyst. The net effect pursued by all these protocols is the increase of the difference in activation energy (AAG ) of the two competing diastereomeric enzyme-substrate transition state complexes (Figure 1.1). 

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