Axial/equatorial stereoselectivity

Asymmetric induction (See also Enantioselective) chiral ketones, 62, 106-107 chiral sulfoxides, 8-9 steroid synthesis, 27, 278-281 Asymmetric syntheses. See Enantioselective. .. Asymmetry of vesicle membranes, 351 dATP. See 2 -Deoxynucleoside 5 -triphosphates Atropisomers binap chelands, 102-103 Kemp s acid arylimides, 347 porphyrin oligomers, 348—349 5,10,15,20-tetraarylporphyrins, 253 Axial/equatorial stereoselectivity ... 

The stereoselectivity of bromination of 4-f-butylcyclohexanone enamines has been studied and the ratio of axial. equatorial bromine incorporation shown to vary with the amine moiety (pyrrolidine 51 49 piperidine 66 34 morpholine 74 26 Af-methylaniline 52 48, di-isobutylamine 52 48)237. This variation in the axial equatorial selectivity has been rationalized in terms of the nature of the transition state. C-Bromination of the pyrrolidine, Af-methylaniline and di-isobutylamine enamines must occur via an early reactant-like transition state thus resulting in low stereoselectivity (Scheme 99). The... 

The Pd-catalyzed hydrogenation of alkyl-substituted 1-alkoxycyclohexenes is stereoselective. The axial/equatorial stereoisomer predominates no matter where the alkyl substituent is located on the ring. Nishimura suggested that the result indicates that the product-controlling step involves the reductive elimination of the most stable alkyl intermediate which is attached to the metal at the carbon atom that bears the alkoxy group (equation 21). 

If one wants to estimate the ee via/lF g 9 (cf Regioselectivity), it is necessary to consider all possible ligand coordination modes (for example, all possible coordination modes (axial-equatorial ae/equatorial-equatorial ee) are shown in transition states 8,9 for a C2-symmetric bidentate phosphine ligand (e.g., LIO). In the case of Cl symmetry, each coordination mode is duplicated). Each coordination mode contributes with its asymmetric induction to the total stereoselectivity. To achieve high ee values, at least one of the following requirements should be met [7, 37]. 

Addition of MeLi to (1) at -78 C in diethyl ether requires 60 min to reach completion and affords a 6S 3S mixture of axial equatorial alcohols (Figure 1). - In the presence of LiC104, however, the same addition is complete within 5 s and proceeds with higher stereoselectivity to give predominantly the axial alcohol in a 92 8 ratio. Precomplexation of the ketone with the bulky Lewis acid, methylaluminum(2,6-di-r-butyl-4-methylphenoxide) (MAD), on the other hand, affords the equatorial alcohol almost exclusively. ... 

The oxidation of methyl glycopyranosides with periodic acid in DMSO is unusual in that only 1 mole of oxidant is consumed. Most of the stereoselective oxidation observed can be explained on the assumption that nic-cis-diols (axial-equatorial) are more reactive than ei c-tra/w-diols (diequatorial ordiaxial).10h... 

Stereoselectivity. See Asymmetric induction Axial/equatorial-, Cis/trans-, Enantio-, Endo/exo- or Erythro/threo-Selectivity Inversion Retention definition (e.e.), 107 footnote Steric hindrance, overcoming of in acylations, 145 in aldol type reactions, 55-56 in corrin synthesis, 261-262 in Diels-Alder cyclizations, 86 in Michael type additions, 90 in oiefinations Barton olefination, 34-35 McMurry olefination, 41 Peterson olefination, 33 in syntheses of ce-hydrdoxy ketones, 52 Steric strain, due to bridges (Bredt s rule) effect on enolization, 276, 277, 296, 299 effect on f3-lactam stability, 311-315 —, due to crowding, release of in chlorophyll synthesis, 258-259 in metc-cyclophane rearrangement, 38, 338 in dodecahedrane synthesis, 336-337 in prismane synthesis, 330 in tetrahedrane synthesis, 330 —, due to small angles, release of, 79-80, 330-333, 337... 

These conformational preferences can be used for the control of reaction stereoselectivity. For example, whereas the reduction of 4-Me-cyclohexanone mostly gives the trans product, reduction of the 4-Cl-cyclohex-anone leads to the preferential formation of the cis product. Assuming the common axial preference for the nucleophilic attack at the carbonyl, the differences in reaction selectivity should reflect the different axial/ equatorial populations of the two carbonyl reactants. Similar conformational preferences were suggested for the nucleophilic attack at oxonium ions (Figure 6.89). ... 

An interesting aspect of this reaction is the contrasting stereoselective behaviour of the dimethyisulfonium and dimethyloxosuifonium methylides in reactions with cyclic ketones (E.J. Corey, 1963 B, 1965 A C.E. Cook, 1968). The small, reactive dimethyisulfonium ylide prefers axial attack, but with the larger, less reactive oxosulfonium ylide only the thermodynamically favored equatorial addition is observed. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The stereochemistry of this reaction is consistent with transition state 2 in which the ethoxycar-bonyl unit adopts an equatorial position. The same result could occur, however, via boat-like transition state 3 with an axial ethoxycarbonyl group47. The reactions of 2-oxopropanoate esters and 9-(2-butenyl)-9-borabicyclo[3.3.1]nonane occur at — 78°C, reflecting the greater reactivity, but stereoselectivity is generally poor except in cases where a very hindered ester is employed3811. 

The Pummerer reaction346 of conformationally rigid 4-aryl-substituted thiane oxides with acetic anhydride was either stereoselective or stereospecific, and the rearrangement is mainly intermolecular, while the rate-determining step appears to be the E2 1,2-elimination of acetic acid from the acetoxysulfonium intermediates formed in the initial acetylation of the sulfoxide. The thermodynamically controlled product is the axial acetoxy isomer, while the kinetically controlled product is the equatorial isomer that is preferentially formed due to the facile access of the acetate to the equatorial position347. The overall mechanism is illustrated in equation 129. 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

The reaction must occur by axial addition (39) to give (40) which may be protonated on either side of the double bond, but gives the all equatorial product (37) stereoselectively,... 

Another difference between dimethylsulfonium methylide and dimethylsulfoxonium methylide concerns the stereoselectivity in formation of epoxides from cyclohexanones. Dimethylsulfonium methylide usually adds from the axial direction whereas dimethylsulfoxonium methylide favors the equatorial direction. This result may also be due to reversibility of addition in the case of the sulfoxonium methylide.92 The product from the sulfonium ylide is the result the kinetic preference for axial addition by small nucleophiles (see Part A, Section 2.4.1.2). In the case of reversible addition of the sulfoxonium ylide, product structure is determined by the rate of displacement and this may be faster for the more stable epoxide. 

With less hindered hydride donors, particularly NaBH4 and LiAlH4, confor-mationally biased cyclohexanones give predominantly the equatorial alcohol, which is normally the more stable of the two isomers. However, hydride reductions are exothermic reactions with low activation energies. The TS should resemble starting ketone, so product stability should not control the stereoselectivity. A major factor in the preference for the equatorial isomer is the torsional strain that develops in the formation of the axial alcohol.117... 

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