Diastereoselection with Chiral Carbonyl Substrates

Double Diastereoselection with Chiral Carbonyl Substrates... 

The stereochemistry of the reactions of chiral carbonyl compounds with nucleophiles has been a topic of considerable theoretical and synthetic interest since the pioneering study by Cram appeared in 1952. The available predictive models focus entirely on the conformational and stereoelectronic demands of the chiral carbonyl substrate, the implicit assumption being that the relative stabilities of the competing transition states are determined only by stereoelectronics and the minimization of nonbonded interactions between the substituents on the chiral center and the nucleophile. These models totally ignore the possibility, however, that the geometric requirements of the nucleophile may also have an effect on reaction diastereoselectivity. Considerable evidence is now available, particularly in the reactions of Type I (Z)-crotylboronates and Z(0)-metal enolates, that the stereochemistry of the nucleophile is indeed an important issue that must be considered when assessing reaction diastereoselectivity. 

With chiral auxiliaries1,41 a remote chiral moiety is temporarily introduced into the substrate in order to direct the nucleophilic addition diastereoselectively. The chiral auxiliary can be removed from the initial addition product with complete conservation of the chirality of the desired product and also of the chiral auxiliary. The recovered chiral auxiliary can then be reused in further reactions. Therefore, chiral auxiliaries are used to chiralize an a priori achiral carbonyl substrate by the introduction of a covalently bound, but nevertheless easily removable, chiral source. 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The addition of a hydride donor to a /i-hydroxyketo ne can also be conducted in such a way that the opposite diastereoselectivity is observed. However, the possibility previously discussed for additions to a-chiral carbonyl compounds is not applicable here. One must therefore use a different strategy as is shown in Figure 10.22, in which the OH group at the stereocenter C-/i of the substrate is used to bind the hydride donor before it reacts with the C=0 double bond. Thus, the hydridoborate A reacts intramolecularly. This species transfers a hydride ion to the carbonyl carbon after the latter has been protonated and thereby made more electrophilic. The hydride transfer takes place via a six-membered chair-like transition state,... 

Radical anions of carbonyl groups and imines also seem to be produced in the presence of titanium (IV) chloride in methanol as solvent. Consecutive oxidation and deprotonation of methanol leads to hydroxymethyl radicals which combine with the carbonyl radical anions to give 1,2-diols and 1,2-aminoalcohols, respectively. The synthesis of the pheromone frontalin has been achieved in a one-pot reaction by hydroxy-methylation of a diketone [127-129]. Likewise triplet sensitizers [130] can be used for direct excitation of the substrate in methanol [131]. Chiral aldimines can be conveniently hydroxymethylated with moderate diastereoselectivity by irradiation of methanolic solutions in the presence of an excess TiCU (Scheme 34) [132]. 

Compared with chiral nonracemic a-amino carbonyl compounds - which are not suitable substrates for MBH reaction, mainly due to their racemization under normal conditions after prolonged exposure times to catalyst or due to poor diastereoselectivity " a-keto lactams, enantiopure 3-oxo-azetidin-2-ones 168, readily react with various activated vinyl systems promoted by DABCO to afford the corresponding optically pure MBH adducts 169 without detectable epimerization (Scheme 1.69). " However, the Lewis acid-mediated reaction of electron-deficient alkynes with azetidine-2,3-diones 168 as an entry to p-halo MBH adduets was not very sueeessful the coupling product 170 was achieved with concomitant acetonide cleavage as a single ( )-isomer in low yield, in the presence of trimethylsilyl iodide under BF3 OEt2-induced catalysis (Scheme 1.69). 

Many other examples illustrate substrate control in asymmetric synthesis, wherein an existing stereogenic center in the ketone or aldehyde biases the attack of a nucleophile preferentially to one of the two diastereotopic faces. From the reduction of very simple chiral ketones such as 3 (Equation 2) [36] to the synthesis of highly complex molecules exemplified by Kishi s breathtaking synthesis of palytoxin (8, Scheme 2.1) [26, 38], the ability to conduct diastereoselective additions to carbonyl groups provides synthetic chemists with a powerful means to prepare chiral alcohols. 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

II]. This latter feature facilitates racemate resolutions and allows the concurrent determination of three contiguous chiral centers in final products, which are obtained enantiopure and with high d.e. (>95) even when starting from more readily accessible racemic material. For certain substrates, however, diastereoselectivity of Class II aldolases can be compromised in the control of the stereocenter at C4, which points to occasional inverse binding of the respective aldehyde carbonyl [1,... 

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