Facial bias

J0rgensen and co-workers (229,230) examined the use of a-ketoesters and 1,2-diones as heterodienophiles in reactions with Danishefsky s diene. Catalyst 269c was found to exert the highest facial bias in these reactions, and is generally tolerant of substitution on the dione. These reactions may be conducted with as little as 0.05 mol% catalyst loadings. 

Treatment of the silyl enol ethers of IV-acyloxazolidinones with selected electrophiles that do not require Lewis acid activation similarly results in high induction of the same enolate face (eq 13). The facial bias of this conformationally mobile system improves with the steric bulk of the sUyl group. 

Table 10 summarizes the data for the addition of various achiral tetraalkylaluminates (23) to chiral keto esters as oudined in equation (9). Presumably, the observed diastereoselectivities will reflect the inherent facial bias of the controlling chiral element, namely menthol (R in Table 10). In this case the diastereoselectivities are moderate (67 to 75%), but, since Corey, Oppolzer and WhiteselP have observed superior inherent facial selectivity for the 8-substituted menthol chiral auxiliary, it would be interesting to attempt the alkyl aluminate additions on substrates incorporating this auxiliary.

As mentioned previously, it can be more difficult to predict syn anti diastereoselectivity in Mukaiyama aldol reactions of substituted ketones. However, the reward of high stereocontrol in these reactions is attainable as shown in Scheme 9-12. While the second example shows disappointing aldehyde face selectivity, there is strong enolate facial bias 5-anti in both 32 and 33). Therefore,... 

With protected ketone 85 in hand, the next aldol coupling required its syn-selective reaction with aldehyde 74 to install the C15-C16 stereocenters in 86 (Scheme 9-28). A boron triflate reagent would be expected to generate the desired (Z)-enolate. However, studies earned out on the separate components indicated that this was a mismatched reaction, and it did not prove possible to overturn the aldehyde facial bias by use of a chiral reagent. 

For example, addition of ketone 202 to complex aldehyde 214 led to adduct 215 with high stereocontrol (90% ds). The a-chiral aldehyde 214 could be expected to show a small preference for the und-Felkin adduct 215, and presumably there is a strong facial bias from chiral ketone 202, despite the relatively remote C3-stereo-center. When the silyl-protected ketone 216 was used for this reaction, adduct 217 was also obtained with good stereocontrol [78]. 

Our synthesis of (9S)-dihydroerythronolide A, which constitutes a formal synthesis of erythronolideA (226), depends on a key aldol reaction between the racemic aldehyde 244 and imide auxiliary 245 (Scheme 9-66) [84]. In this reaction, the auxiliary overrides any aldehyde facial bias, thus leading to an equimolar mixture of separable syn adducts 246 and 247. These two compounds were then processed separately and together provide five of the ten necessary stereocenters of erythronolideA (C9 will be oxidized). This synthesis also features the thioalkyla-tion of silyl enol ether 248 giving ketone 249, a process which can be compared with the Mukaiyama addition to aldehydes. Presumably, Felkin selectivity controls the Cii stereocenter while the mixture of C12 epimers was not detrimental as epi-merization could be effected in the subsequent elimination step. 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

Reaction of the /y-benzyloxy-o-methyl chiral aldehyde 97a with (/ )-crolylsi-lanes 217 (R = H, Et) under catalysis by TiC affords the ann,antt-dipropionate adduct 362 (Eq. (11.29)). The diastereoselectivity in this reaction is best explained by anti S e addition of the chiral crotylsilane to the least hindered face of the fi-alkoxy aldehyde chelate, as shown in the synclinal transition state 363. Finally, the anri.syn-dipropionate 364 may be obtained as the major adduct when aldehyde 97a is treated under the same conditions with the enantiomeric crotylsilane reagents (5)-217 (Eq. (11.30), R=Me, Et). This adduct should arise from the antiperiplanar transition state 365, where the anti S e facial selectivity of the crotylsilane reagent and the facial bias of the chiral aldehyde are maintained. In these cases, the factors that dictate the utilization of the synclinal vs the antiperiplanar transition states are (1) the requirement that a small substituent (H) occupy the position over the chelate ring, (2) that C-C bond formation occurs anti to the sterically demanding a-methyl group of the aldehyde and (3) the requirement for an anti Se mechanism, which dictates the stereochemistry of C(5) of the adducts 362 and 364. 

Other applications of this strategy include addition and trapping sequences with exo double bonds to install the a centers. This methodology has been applied to the formation of anri-aldol adducts as well as substituted a-amino acids. Stereocenters located in adjacent positions on the ring provide facial bias for selective hydrogen atom transfer. Equation (13.23) illustrates how this was applied towards the formation of a-amino acids [33]. 

By contrast, the dienoates 13 provide reasonable stereocontrol although the second oxidation uses the facial bias of an osmium oxidation of an allyl alcohol (see Sections 3.1 and 3.2.5.4) as diastereocontrol problems occurred when a chiral ligand was present (Scheme 3.11) [307]. 

Use of the dihydroxylation procedure with the P-lactam-substituted alkenes 16 showed a matched-mismatched phenomenon (Scheme 3.15). Use of an achiral reagent showed little facial bias. With an alkyl or ester group rather than aryl as the other alkene substituent (R1), the selectivity diminished [311]. 

The cleavage of the ether bonds in the oxabicydic framework has been developed into a useful strategy to generate highly-substituted cyclohexyl derivatives from oxabicyclo [2.2.1] systems. This is an attractive approach because the facial bias inherent to the oxabicydic substrate can be exploited to control the stereochemistry before ring opening is induced. 

A further example of a highly diastereoselective hydrogenation involves the acetonide derivative 9 which provides a rigid framework with a strong facial bias for / -attack on the exocyclic double bond. Hydrogenation over platinum oxide leads to the a-methyl isomer 10 as the sole product19. 

Two examples of such processes are shown in Scheme 1.6. One is the titanium TADDOLate-catalyzed addition of diethylzinc to myrtenal (see Section 4.3, [52] the other is the Sharpless asymmetric epoxidation (see Section 8.2.2, [58,63]). In both cases, the diastereoselectivity for the reaction of the substrate with an achiral reagent is low (65-70% ds), while the catalysts have enantioselectivities of >95% with achiral substrates. In these cases of double asymmetric induction, the catalyst completely overwhelms the facial bias of the chiral substrate. 

In his synthesis of the Prelog-Djerassi lactone, Evans tested two auxiliaries cf. footnote 9) that give products with opposite absolute configurations at the two new stereocenters [125]. Here again, the facial bias inherent in the aldehyde is low. Since the two chiral enolates are not enantiomers, we cannot say which is the matched and which is the mismatched case, but it hardly matters the selectivity is >99.8% for both (Scheme 5.24). 

These reactions are, therefore, examples of double asymmetric induction whereby the selectivity of one chiral reactant is overwhelmed by the facial bias of another cf. Section 1.5). 

These selected examples show the importance of Lewis acid in diastereoselective radical reactions. Complexation with Lewis acid, in an endocyclic manner or by using extremely bulky metal complexes such as MABR or MAD, reduces the conformational flexibility of intermediate radicals resulting in an improved facial bias. Lewis acid has been shown to effectively enhance facial selectivity by making a temporary ring a to the radical, thus mimicking the exocyclic effect. Radical reactions involving chiral auxiliaries have also benefited from the use of Lewis acid. 

Occasionally, enantioselective reactions are possible where a prochiral substrate is allowed to react with a chiral reagent such that the diastereomeric transition state provides facial bias for the pending transformation. As previously stated, this is most beneficial when the chiral reagent can be recycled back into a useful form after the reaction has taken place. 

Asymmetric induction increases with increasing steric demands of the alkene, and cis alkenes show the worst selectivity. This can be explained by three-dimensional drawing 149, which shows approach of re,si face of ct[r-2-butene with the less sterically hindered case of the methyl groups down (when the methyl groups are up there is a severe interaction). If cis-2-butene is rotated by 180° along the axis which bisects the C=C bond (C=/=C), the other face (the si,re face) of the alkene is exposed to reaction. There is no facial bias for approach of the cis alkene and, therefore, little or no enantioselectivity in the hydroboration reaction. Examination of 150 for approach of trans-2-hutene from the left face of the pinanyl horane reagent shows... 

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