Diastereofacial preference

On the other hand, high levels of diastereoselectivity are relatively easy to achieve in matched double asymmetric reactions since the intrinsic diastereofacial preference of the chiral aldehyde reinforces that of the reagent, and in many cases it has been possible to achieve synthetically useful levels of matched diastereoselection by using only moderately enantioselective chiral allylboron reagents. Finally, it is worth reminding the reader that both components of double asymmetric reactions need to be both chiral and nonracemic for maximum diastereoselectivity to be realized. 

The greater diastereofacial selectivity of 4 is also evident in the attempted mismatched double asymmetric reactions of 3 and 4 with aldehydes 11 and 15. which have greater intrinsic diastereofacial preferences than (S)-2-methylbutanal. 

The reactions with (25,35,45,55)-5-(tm-butyldimethylsilyloxy)-3-(4-methoxyphenylmethoxy)-2,4-dimethylheptanal (15) are particularly informative reagent (5)-3 is incapable of overriding the intrinsic diastereofacial preference of 15, and the normal Felkin product 17 is obtained with >95% selectivity. In contrast, reagent-controlled mismatched double diastereoselectivity is evident in the reaction with (5)-4 that provides 16 as the major component of a 73 22 5 mixture. The minor product 18 apparently derives from a reaction with the contaminating (/ )-4, since (5)-4 that was used is not enantiomerically pure. 

On the other hand, a 10 1 diastereofacial preference in favor of 3b was realized by way of a chelated intermediate starting from (Z)-5-benzyloxy-3-hexen-2-one. 

Relative insensitivity to preexisting chiral centers In allylic alcohols with preexisting chiral centers, the diastereofacial preference of the chiral titanium-tartrate catalyst is often strong enough to override diastereofacial preferences inherent in the chiral olefinic substrate. 

Results of an investigation of the structure of lithiated a-aminonitriles have been used to aid interpretation of the diastereofacial preference found for reaction of their chiral counterparts with Michael acceptors. ... 

The poor diastereoselectivity of the reactions of chiral aldehydes and achiral allylboronates appeared to be a problem that could be solved by recourse to the strategy of double asymmetric synthesis.f Our studies thus moved into this new arena of asymmetric synthesis, our objective being the development of a chiral allylboron reagent capable of controlling the stereochemical outcome of reactions with chiral aldehydes independent of any diastereofacial preference on the part of the carbonyl reaction partner. 

Thus, as this example clearly shows, reagent 36 (and 37 as well)3c.h Is sufficiently enantioselective to control the stereochemical outcome of reactions with aldehydes that possess only modest intrinsic diastereofacial preferences. The consequences of this increased selectivity for organic synthesis are obvious. In the present case, compounds 29 and 30, which are synthetic precursors to 2-deoxyribose and 2-deoxylyxose,i7b are each now easily prepared with excellent selectivity from readily available precursors. 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

The conclusion that emerges from these experiments is that for the development of an effective reagent-control strategy, it is important to use an asymmetric reagent with a much larger diastereofacial preference than the chiral substrate so that the former prevails over the latter. 

In double stereodifferentiation, the inherent diastereofacial preferences of the chiral reactants may reinforce or oppose one another. Heating (/ )-(+)-limonene with bicyclic oxaziridine (+)-(2/ ,3S)-(105) for 2 days at 60 °C resulted in a 90% yield of a 55 45 cis/trans mixture of limonene oxides (106) (Equation (24)) <91JOC809>. The cis/trans selectivity improved to 93 7 when (S)-(—)-limonene was used. 

N, P ] and [P, P ] Aldehydes with an a-stereocenter exhibit unusually high diastereofacial preferences for the addition of silyl enol ethers and ketene acetals with Lewis acid assistance (81). Heathcock and Uehling found good levels of facial discrimination in the addition of silyl enol ethers to chiral enones (Scheme 38, Table 11) (82). With the more substituted silyl enol ether, only one diastereomeric addition product is obtained (Eq. [1], Scheme 38). Use of a prostereogenic silyl enol ether allows control over the relative... 

There is a dichotomy in the sense of syn- vs antz-diastereofacial preference, dictated by the bulkiness of the migrating group [80]. The sterically demanding silyl group shows syn-diastereofacial preference but the less demanding proton leads to anti-preference (Scheme 33). The anfi-diastereoselectivity in carbonyl-... 

Of all the chiral allyl metal reagents repotted to date, the one that is most effective in demanding cases of mismatched double diastereoselection is the a-methoxycrotylboronate (268) developed by Hoffmann. Two illustrative cases are presented in Scheme 52. First, the reaction of (280) and (/ )-(268) provides the 3,4-anti-4,5-anti diastereomer (281) with roughly 84% stereoselectivity. This is remarkable in view of the very high intrinsic diastereofacial selectivity (98 2) for the 3,4-anti-4,5-syn diastereomer exhibited by the structurally related aldehyde (147 Table 4). The second involves ([283), which with (5)-(268) provides 3,4-anti-4,5-anti (284) with 73% stereoselection. By way of comparison, the a-chlorocrotylboronate (5)-(237) is incapable of overriding the intrinsic diastereofacial preference of (283), giving 3,4-anti-4,5-syn diastereomer (E)-(285) with 92% selectivity (compare also 277, Scheme 51). 

The two faces of a chiral aldehyde are diastereotopic, and reaction with an achiral enolate can therefore give two diastereomeric products. Qualitatively, the major and minor products of such a reaction are determined by the intrinsic diastereofacial preference of the chiral aldehyde, which may be evaluated by the use of Cram s rule or one of its more modem derivatives. Quantitatively, the diastereomeric ratio in such a reaction is a function of the enolate. An example is seen in Scheme 8. 2-Phenylpropanal reacts with the lithium enolates of acetone, pinacolone, methyl acetate and N,N-dimethylacetamide to give 3,4-syn and 3,4-ant diastereomers in ratios of 3 1 to 4 1. With ethyl ketones and propionate esters, the diastereofacial ratio is approximately 6 1 and with methyl isobutyrate only a single isomeric product is produced. This tendency of more bulky nucleophiles to give higher diastereofacial ratios in reactions... 

Data for the addition of the lithium enolate of pinacolone to a variety of a-chiral aldehydes are presented in equation (105) and Table 17. The results in the table show that the diastereofacial preference of a chiral aldehyde is a function of the steric bulk and the electronic nature of the groups attached to the stereocenter. In a purely empirical manner, the major isomer may be correctly predicted by the... 

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