Asymmetric induction 1,2-addition

The following discussion is organized by the location of the introduced chirality X (intraligand asymmetric induction) or MLn (interligand asymmetric induction). Additionally, there is the possibility of a chirality center in the aldehyde, which will normally have an observable influence only in cases where the stereocenter is close to the carbonyl (i.e., Cram s rule situations - see Chapter 4). Most of the examples that have been published to date include chirality centers in either X or MLn, but not both. 

Non-enzymatic cyclizations of educts containing chiral centres can lead to products with additional "asymmetric centres. The underlying effect is called "asymmetric induction . Its systematic exploration in steroid syntheses started when G. Saucy discovered in 1971 that a chiral carbon atom in a cyclic educt induces a stereoselective Torgov condensation several carbon atoms away (M. Rosenberger, 1971, 1972). 

The addition of methylmagnesium iodide to 2-phenylpropanal is stereoselective in producing twice as much syn-3-phenyl-2-butanol as the anti isomer (entry 5). The stereoselective formation of a particular configuration at a new stereogenic center in a reaction of a chiral reactant is called asymmetric induction. This particular case is one in which the stereochemistry can be predicted on the basis of an empirical correlation called Cram s rule. The structural and mechanistic basis of Cramls rule will be discussed in Chapter 3. 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

Comparison witli tlie Hajos-Parrisb asymmetric version of tlie Robinson annulation [81] iSdieme 7.25iaj) shows tlie following distinct differences between tlie two metliods. Firstly, tlie cydoalkenone in tlie CuiOTf)2/ligand 18-catalyzed procedure is tlie Midiael acceptor, whereas tlie cydoalkanone is tlie Midiad donor in tlie proline-mediated annulation. Secondly, tlie asymmetric induction occurs in tlie 1,4-addition step in tlie new metliod, in contrast to tlie asymmetric aldol-cydization in tlie Hajos-Parrisb procedure. 

Formation of C-C Bonds by Addition to Chiral Acyclic Carbonyl Compounds 1.3.1.3.1. Addition to Acyclic a-Alkyl-Substituted Carbonyl Compounds Cram-Selective 1,2-Asymmetric Induction... 

Addition to a-Hydroxy or a-Alkoxy Carbonyl Compounds Chelation-Controlled 1,2-Asymmetric Induction... 

It is interesting to speculate that asymmetric induction may be the consequence of the exo anomeric effect, a stereoelectronic effect that favors the conformation 5 that places the aglycone O-C bond antiperiplanar to the pyran C(1) —C(2) bond7fi. Related asymmetric induction has also been observed in aldehyde addition reactions of the related, but racemic, pinacol (Z)-y-(tetrahydropyranyloxy)allylboronate49. As indicated in the examples above, however, the level of diastereoselectivity is modest and the only application in asymmetric synthesis is Wuts exo-brevicomin synthesis75. 

Commercial A -acetylneuraminic acid aldolase from Clostridium perfringens (NeuAcA EC 4.1.3.3) catalyzes the addition of pyruvate to A-acetyl-D-mannosamine. A number of sialic acid related carbohydrates are obtained with the natural substrate22"24 or via replacement by aldose derivatives containing modifications at positions C-2, -4, or -6 (Table 4)22,23,25 26. Generally, a high level of asymmetric induction is retained, with the exception of D-arabinose (epimeric at C-3) where stereorandom product formation occurs 25 2t The unfavorable equilibrium constant requires that the reaction must be driven forward by using an excess of one of the components in order to achieve satisfactory conversion (preferably 7-10 equivalents of pyruvate, for economic reasons). 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

These results show that chemical yields are generally higher than for most aldol-type additions of ester cnolates. mainly because of the chemical activation of the methylene group by the sulfoxide, which makes this reaction suitable for any aldehyde or ketone. High asymmetric induction is also generally observed. The aldol adducts obtained by addition to aldehydes have been transformed into optically active four- and five-membered lactones38. 

The big difference between the extent of asymmetric induction on the addition to a prostereogenic carbonyl group of simple carbanions a to a chiral sulfoxide on the one hand and enolates of sulfinyl esters on the other, can be attributed to the capacity of the ester function to chelate magnesium in the transition states and intermediates. The results already described for the addition of chiral thioacetal monosulfoxide to aldehydes (see Section 1.3.6.5.) underscore the importance of other functions, e.g., sulfide, for the extent of asymmetric induction. 

The diastereomeric aldehyde adducts are not readily separated by chromatography. Upon direct reduction to the secondary alcohols, the optical purities (25-46%) reflect the poor degree of asymmetric induction in the addition step. 

Table 8. 1,2-Asymmetric Induction in the Addition of Organometallics to N-Alkylimines 4, Cram Selectivity 6...

In addition to the previously described models many of the 1,3-asymmetric inductions can be explained by the extended Cram model 4, especially the allyl-metalation reactions6. 

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