Carbonyl compounds chiral

In his original paper,2 Cram disclosed an alternative model that rationalizes the preferred stereochemical course of nucleophilic additions to chiral carbonyl compounds containing an a heteroatom that is capable of forming a complex with the organometallic reagent. This model, known as the Cram cyclic or Cram chelate model, has been extensively studied by Cram9 and by others,410... 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

In most cases of diastereoselective nucleophilic addition reactions where achiral organometallic reagents are added to chiral carbonyl compounds, the chirulity inducing asymmetric center is in close vicinity to the newly created center and cannot be removed without the loss of chirality of either the inducing center or the newly formed center. This type of reaction is very useful in propagating chirality in a molecule from one center to an adjacent one, or in immolative processes. 

In addition reactions to chiral carbonyl compounds, the stereochemical course taken by resonance-stabilized alkali metals or magnesium benzyl anions resembles that taken by localized carbanions of similar bulk. Thus, conditions can be delineated which lead to either the steric approach or chelation control the following serve as examples. 

Volume F. 21 D. 1.3.4.3. Addition of Achiral Enolates to Chiral Carbonyl Compounds... 

Addition of Achiral Enolates to Chiral Carbonyl Compounds... 

Further examples of additions of chiral enolates to chiral carbonyl compounds are listed in Table 2. 

Volume E 21 D.l.3.4.4. Addition of Chiral Enolates to Chiral Carbonyl Compounds 1729... 

The stereochemistry of addition of organometallic reagents to chiral carbonyl compounds parallels the behavior of the hydride reducing agents, as discussed in Section 5.3.2. Organometallic compounds were included in the early studies that established the preference for addition according to Cram s rule.118... 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

Nitrophenyl)ethylene glycol was used to protect simple aldehydes and ketones, as well as some steroids. Acetals were prepared under acid catalysis, leading, in the case of chiral carbonyl compounds to diaste-reoisomers. The photochemical removal of the protecting group was in several instances complicated by the instability of some carbonyl derivatives to irradiation at 350 nm otherwise, yields were in the range of 83-90% (see Scheme 19). 

In addition to 9—12, several useful chiral carbonyl compounds have been obtained from the diols obtained by yeast treatment of the corresponding a-hydroxyketones. As a part of a study (2) on the substrate specificity of the multienzymic conversion shown in Eq. 2, a serie of racemic a-hydroxyketones has been prepared and submitted to the yeast treatment. The reduction process is stereospecific, but depending upon... 

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. 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

For many years acyclic stereoselection has been one of the main interests in organic chemistry35. The most studied case is 1,2-induction, usually with a-chiral carbonyl compounds or olefins. 

Another chiral aldehyde suitable for such transformations is the recently prepared pyridoxal derivative (121).323 Even more recent examples of chiral carbonyl compounds (122) have been used for the partial resolution of amino acids. The enantiomers of compounds (122) undergo reaction with racemic a-amino acids and copper(II) ions to give preferential formation of enantiomeric copper complexes. The ( -enantiomers of (122) preferentially form complexes containing the... 

As stated previously, the addition of nucleophiles to chiral carbonyl compounds is a very common type of reaction which produces diastereomeric mixtures. The diastereoselectivity varies with the reagents and conditions. Some examples are... 

The cyclocondensation of the diene (1) with (R)-glyceraldehyde acetonide (9) results in high asymmetric induction at C5 of the dihydropyrone (10). The configuration (S) was established by degradation to 2-deoxyribonolactone (11). The result is in accord with the Cram rule for addition to chiral carbonyl compounds. The paper also describes conversion of the pyrone (10) to chiral 2,4-dideoxy-D-glucose. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

G. Fronza, C. Fuganti, P. Grasselli, G. Pedrocchi-Fantoni, and C. Zirotti, On the steric course of the addition of diallylzinc onto a,P-dialkoxy chiral carbonyl compounds Stereospecific synthesis of 2,6-dideoxysugars of the L-series, Tetrahedron Lett., 23 (1982) 4143 1146. 

Molecular dynamics simulations have been used to predict solvent and temperature effects in the nucleophilic addition of a-chiral carbonyl compounds.253 Prediction of diastereoselectivity break temperatures (i.e. inversion points) has been achieved with fair accuracy by comparison with experimental data on n-BuLi addition. Dramatic differences are seen for additions to 2-phenylpropanol in pentane solvent, compared with octane. 

In this section as well as in Section 10.5.3, carbonyl compounds that contain a stereocenter in the position a to the C=0 group are referred to succinctly with the term oc-chiral carbonyl compound. Because of the presence of the stereocenter, the half-spaces on both sides of the plane of the C=0 double bond of these compounds are diastereotopic. In this section, we will study in detail stereogenic addition reactions of hydride donors to the C=0 double bond of oc-chiral carbonyl compounds. Additions of this type can take place faster from one half-space than from the other—that is, they can be diastereoselective. 

Additions of hydride donors to oc-chiral carbonyl compounds that bear only hydrocarbon groups or hydrogen at C-oc typically take place with the diastereoselectivities of Figure 10.14. One of the resulting diastereomers and the relative configuration of its stereocenters are referred to as the Cram product. The other diastereomer that results and its stereochemistry are referred to with the term anti-Cram product. 

Fig. 10.14. Examples and structural requirements for the occurrence of Cram-selective additions of hydride donors to tt-chiral carbonyl compounds. In the three compounds at the bottom RUrge refers to the large...

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