Stereochemistry of alkylation

Amine (1) was needed to study the stereochemistry of alkylation reactions. The primary alkyl group had best come from an amide or an Imine while the secondary alkyl group must come from an imine. The disconnections may be carried out in any order. 

In acyclic systems, the stereochemistry of alkylation depends on steric factors. Stereoselectivity is low for small substituents.71... 

The same authors studied the stereochemistry of alkylation of 4-t-butyl-cyclohexanone. Alkylation of enolate ion 467 with triethyloxonium fluorobor-ate yielded a mixture of 0-alkyl product and approximately equal amounts of... 

Chiral amino acids The stereochemistry of alkylation (quasi-equatorial) at C3 of the anion of 1 results from the conformation of the seven-membered ring in a boat form. The products can be hydrolyzed to (S)-amino acids (3). 

Static and Dynamic Stereochemistry of Alkyl and Analogous Groups... 

Goering, H. L. Tseng, C. C. Alkylation of allylic derivatives. 7. Stereochemistry of alkylation of the isomeric trans-a,y-methyl(phenyl)-allyl acetates with lithium dialkylcuprates and alkylcyanocuprates. J. Org. Chem. 1983, 48, 3986-3990. 

The stereochemistry of alkylation in 2-cyano-6-alkylpiperidines is controlled by the substituent on nitrogen. When the N-substituent is a group such as phenyl or benzyl, such as in Wbenzylpiperidine 273, alkylation gives predominantly the 2,6-cA-dialkyl product 274, with retention of stereochemistry with regard to the cyano group (Equation 27). However, when the N-substituent is a carbamate, such as in t/-butoxycarbonylpiperidine 275, alkylation results in the formation of the 2,6-/ra r-dialkyl product 276 (Equation 28) <2005T3371>. 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

More recently some further interesting features of 4,4-dialkylation have been uncovered. As mentioned in the earlier discussion of enolisation, the reaction proceeds through the kinetically-preferred A. -fiienolate anion which is permitted to equilibrate in favour of the stable A qsomer by the low reactivity of the alkyl halide. The intervention of the A -diene was demonstrated by the total loss of deuterium when a 2jS-deutero-A 3 ketone was 4,4-dimethylated [no]. Studies on the stereochemistry of alkylation have revealed a strong preference for introduction of the second alkyl group at the 4 -position (7) [163], as would be predicted in view of the... 

J.l Regiochemistry and Stereochemistry of Alkylations of Nitrogen Derivatives of Carbonyl Compounds... 

Angular alkylations of lithium enolates of hydrindanones with carbonyl groups in the five- or six-membered rin yield cw-fused products with almost complete stereoselectivity. The lithium enolate of bicyclo [2.2.1]heptan-2-one undergoes exo alkylation with very high stereoselectivity. The presence of a syn methyl group at C-7 reduces the preference for exo alkylation, but it is still preferred over endo alkylation by about 3 1 unless a 5,6-double bond is also present then, endo attack is preferred. The expected steric effects control the stereochemistry of alkylation of other bridged bicyclic systems. - ... 

The stereochemistry of alkylations of extended dienolates of enones such as (70) has been extensively investigated (Scheme 33).In general, the results are similar to those found for the related decalone enolates (43a) and (44), i.e. steric factors within the anion play a dominant role. Thus, axial attack is preferred with (70 R = H), but equatorial attack is strongly favored when an angular methyl group is present (70 R = Me). There is a modest preference for axial alkylation when an angular ethoxycarbonyl... 

As will be described below, self-reproduction of chirality can be accomplished through alkylations of endocyclic as well as exocyclic enolates. It generally entails (i) production of a ring containing a temporary, auxiliary chiral center by derivatization of an optically active a-hydroxy or a-amino ester (ii) formation of an enolate by deprotonation at the original asymmetric a-carbon atom (iii) use of intramolecular chirality transfer to control the stereochemistry of alkylation of the enolate and (iv) generation of the chiral a-alkylated ester by hydrolysis. 

Optically active comoounds have been employed to investigate the nature of intermediates in model cationic reactions involving alkylaluminum compounds. Alberola (IS) in 1969 investigated the stereochemistry of alkylation using (—)a-phenylethyl chloride with Et3Al in p-xylene. The formation of predominantly racemic product was taken as evidence for carbenium ion-counter anion intermediates. Kennedy, Desai and Sivaram (7) modified this scheme to avoid undesirable side reactions by using a nonreactive solvent such as ethyl chloride at — 65° C. Analysis of the products again confirmed the fact that the stereochemical consequence of alkylation is predominant racemization which is consistent with the hypothesis that the intermediate involved in alkylation is a loose carbenium ion-counteranion pair. 

The stereochemistry of alkylation was next investigated. 2-Methylcyclohexanone (43) was treated with MeLi to afford predominantly the trans methylated product 45. However, when the aluminium compounds MAD or MAT were present, they coordinate to the carbonyl group and cause the configuration to be reversed (14). Very complex cases using other sophisticated alkylating reagents are not reported. When 2-methyl-l-propenyl magnesium bromide was reacted with the ketone 27, the isomer of natural product 46 was the... 

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