Carbonyl groups, 40. facial selectivity

Control of the stereoselectivity in nucleophilic additions to the carbonyl group. Facial selectivity. Felkin Anh s and Cram s models. Reactivity of TMS enol ethers towards electrophiles. 

Deformation of symmetrical orbital extension of carbonyl or olefin compounds was proposed to be the origin of the facial selectivities. We illustrate the unsymmetrical orbital phase environment of % orbitals of carbonyl and olefin groups and facial selectivities in Fig. 1 [3, 4]. There are in-phase and out-of-phase combinations of... 

The carbonyl n orbital is also assumed to be unsymmetrized arising from the out-of-phase interaction of the orbital attached to the more electron-donating aryl group (9 and 10). These unsymmetrizations of the carbonyl k orbital correspond well to syn addition (9) and anti addition (10), respectively. Thus, the electron-donation of the p-a orbitals controls the facial selectivities. The cyclopentane system was more sensitive to stereoelectronic effects, showing larger induced biases, than the adamantanone system [63]. 

The exo reactivity of 2-norbomanone 25 in nucleophilic addition (such as reduction with hydride) is a classical example of the facial selectivity of carbonyl groups in bicyclic systems [80]. 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Entry 4 has siloxy substituents in both the (titanium) enolate and the aldehyde. The TBDPSO group in the aldehyde is in the large Felkin position, that is, perpendicular to the carbonyl group.121 The TBDMS group in the enolate is nonchelated but exerts a steric effect that governs facial selectivity.122 In this particular case, the two effects are matched and a single stereoisomer is observed. 

Mandelate and lactate esters have been found to generate diastereoselectivity in reactions of hydroxy-substituted quinodimethanes generated by thermolysis of benzo-cyclobutenols.88 The reactions are thought to proceed by an exo TS with a crucial hydrogen bond between the hydroxy group and a dienophile carbonyl. The phenyl (or methyl in the case of lactate) group promotes facial selectivity. 

The development of facial selective addition reactions of cyclohexa-1,4-dienes 7 and 14 has greatly extended the value of the asymmetric Birch reduction-alkylation. For example, amide directed hydrogenation of 15 with the Crabtree catalyst system occurs with outstanding facial selectivity iyw to the amide carbonyl group to give 16 (Scheme 5)."... 

In contrast to the sulfinyl acrylates, the behavior of the enantiomerically pure sulfinyl enones as dienophiles has been very little studied. The first report in this field was due to Maignan et al. [53], who described the synthesis of several sulfinyl enones and the reaction of 3-p-tolylsulfinyl butenone 47 with cyclopenta-diene. The reaction required 12 h at room temperature to reach completion, and a 60 40 mixture of the two exo adducts was obtained (Scheme 24). This result suggested that the endo-orientating character of the carbonyl group is much higher than that of the sulfinyl one, thus resulting in only exo-adducts (endo with respect to the carbonyl group). By contrast, the 7r-facial selectivity is very low. 

The stereochemical outcome can be rationalized by considering the approach of the aldehyde to the preferred conformation of the allylindium. The approach of the aldehyde is postulated to be in antiperiplanar to the OPG group as for the Felkin-Anh model. The allylindium prefers to adopt the conformation 12 rather than 13, where the 1,3-allylic strain with R is minimized and the steric interaction with the aldehyde is also reduced (Scheme 18). The facial selection with respect to the aldehyde is determined by the aldehyde residue (R ) to occupy in the least sterically demanding position, away from the substituted allylic carbon. The carbonyl allylation then proceeds via a six-membered chairlike transition state, in which the aldehyde substitutent attains an equatorial position, to afford the 1,4-syn product. 

The observed change in stereoselectivity can be rationalized by consideration of the conformation of the 2-(arylsulfinyl)-2-cyclopentenone (24) (Fig. 3). The sul-finyl and carbonyl moieties are normally arranged in an anti periplanar orientation (27). The bulky aromatic substituent on the chiral sulfinyl group shields one face of the alkene and thereby controls the facial selectivity of the reaction. In the presence of the Lewis acid the sulfinyl and carbonyl moieties are locked in a syn orientation (28) as a result of chelation between the two moieties and the metal. Thus, the opposite face of the alkene is shielded and (3-addition results in the other diastereoisomer being formed. 

In this fourth part we outline some aspects of the reaction of lithium enolates with electrophilic reagents and their nucleophilic addition onto saturated carbonyl groups. Two significant problems associated with these reactions are (i) the site (C/O) selectivity due to the ambident character of enolates, and (ii) the facial discrimination which controls the stereochemistry of the overall process. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

For spiro 1,3-oxothiolane species such as 167-169, a study of the influence of the S and O atoms on the facial selectivity of nucleophilic addition to the carbonyl group has been undertaken. Under normal conditions, the addition to C=0 takes place anti to S and syn to O. However, the use of a chelating reagent such as NaBH4 or t -Pr2AlH for a hydride reduction reversed this facial preference <1998TL2527, 1998TL2531>. 

On p. 1023, it was mentioned that electronic effects can play a part in determining which face of a carbon-carbon double bond is attacked. The same applies to additions to carbonyl groups. For example, in 5-substituted adamantanones (2) electron-withdrawing (-/) groups W cause the attack to come from the syn face, while electron-donating groups cause it to come from the anti face. In 5,6-disubstituted norborn-2-en-7-one systems, the carbonyl appears to tilt away from the 7i-bond, with reduction occurring from the more hindered face. An ab initio study of nucleophilic addition to 4-ferf-butylcyclohexanones attempted to predict 7i-facial selectivity in that system. ... 

The C-linked (1 6)-disaccharides 176, 178 and 180 are all obtained in good yields (83 to 89%). The addition of the organosamarium reagents to the carbonyl group of aldehyde 175 also occurred with a high facial selectivity (diastereomeric ratio of about 95 5), exclusively controlled by the asymmetry of the C-glycosyl donor. 

Treatment of N-acyloxazolidinones with di-n-butylboron triflate in the presence of Et3N furnishes the (Z)-(O) boron enolates. These on treatment with aldehydes give the corresponding 2,3-syn aldol products (the ratio of syn- to anti- isomers is typically 99 1 ). On hydrolysis they produce chiral a-methyl-(3-hydroxy carboxylic acids, as exemplified below. The facial selectivity of the chiral boron enolate is attributed to the favored rotomeric orientation of the oxazolidinone carbonyl group, where its dipole is opposed to the enolate oxygen dipole. At the Zimmerman-Traxler transition state, the aldehyde approaches the oxazolidinone appendage from the face of the hydrogen rather than from the benzyl substituent. 

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

The next milestone appeared in the 1950s in the context of the development of asymmetric reactions. Various stereochemical reactions induced by facial discrimination of the carbonyl group have always been pivotal in this field. Cram s rule inspired an explosion of studies on diastereoselective reactions followed by enan-tioselective versions. The recent outstanding progress in the non-linear effect of chirality or asymmetric autocatalysis heavily relies on the carbonyl addition reactions. Thanks to these achievements, natural products chemistry has enjoyed extensive advancement in the synthesis of complex molecules. It is no exaggeration to say that we are now in a position to be able to make any molecules in as highly selective a manner as we want. 

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