Diastereomers, alkyl halides

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

An efficient resolntion of the racemic lithinm tert-bntylphosphine-borane complex 203 dnring deprotonation by n-BnLi/(—)-sparteine (11) and alkylation was reported by Liv-inghonse and Wolfe (eqnation 47) . One of the epimers 204/cp/-204 on warming to 0 °C crystallizes during a dynamic thermodynamic resolntion, and reaction with alkyl halides fnmishes the alkylation prodncts 205 with high ee values. Applying dihalides, essentially enantiomerically pure diphosphines snch as 206, besides few of the mcio-diastereomer, were obtained. Borane is removed by treatment with diethylamine to yield the free tertiary phosphines 207. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

Dehydrohalogenation of alkyl halides is stereospecific, requiring an anti arrangement between the hydrogen being lost and the leaving group in the transition state. (Z)-l,2-Diphenylpropene must therefore be formed from the diastereomer shown. 

The asymmetric induction in the alkylation 7- 8 may be explained by the following transition state model. The anion of 7 is planar its two diastereotopic faces are shielded differently (hydrogen versus methyl). The alkyl halide enters predominantely by SN 2 from the top side where the relatively small hydrogen is located. 12 depicts the favored transition state, the one leading to the (3R)-diastereomer. Furthermore, the transition state is supposed to have the folded conformation as far as R is concerned. In this conformation R comes close to the... 

The cyclic a-lithio-l,3-dithiane S-oxide 406 was generated from compound 392 with n-BuLi at —10 °C and reacted with deuterium oxide, alkyl halides, carbonyl compounds and esters to afford the corresponding products 407 as mixture of diastereomers (Scheme 106)605 - 607. (V-Acyl imidazoles were better acylating agents than esters608. However, compound 406 has not been employed properly as acyl anion. Intermediate... 

The results are summarized in Table 2. With the exception of methyl iodide, alkyl halides did not react, but alkyl trifluoromethanesulfonates could be employed instead. After hydrolysis and work-up, the corresponding diastereomeric adducts 7 and 8 were isolated by column chromatography. In several cases, the diastereomers were separated. The diastereomeric excesses were determined using H NMR, or by H.P.L.C., or by weighing the isomers after separation. 

A useful mnemonic for deriving the preferred diastereomer formed in the alkylation reaction of pseudoephedrine amide eno-lates with alkyl halides is as follows the alkyl halide enters from the same face as the methyl group of the pseudoephedrine auxiliary when the (putative) ( -enolate is drawn in a planar, extended conformation (eq 1). ... 

The anions generated from alkylamino carbene complexes can be alkylated in high yields with simple alkyl halides without any detectable amount of dialkylation. This is illustrated for the methyl pyiro-lidine complex (109), which can be alkylated cleanly with ethyl bromide to give the monoalkylated product (110) in 87% yield. The methyl pyrrolidine complex (109) can be prepared in nearly quantitative yield quite simply by treating an ether solution of the methyl methoxy complex (88a) with pyrrolidine at room temperature for a few minutes. A few examples of diastereoselective alkylations are known. The 0-alkylimidate carbene complex (112) can be alkylated with methyl triflate to give a 93 7 mixture of (113) and (114), which are diastereomers as a result of the chiral axis about the aza-allenyl linkage. Other examples of diastereoselective alkylations will be presented in Section 9.2.2.7. 

Problem 8.18 Given that an E2 reaction proceeds with anti periplanar stereochemistry, draw the products of each elimination. The alkyl halides in (a) and (b) are diastereomers of each other. How are the products of these two reactions related ... 

Alkyl sulfonates offer a very real advantage over alkyl halides in reactions where stereochemistry is important this advantage lies, not in the reactions of alkyl sulfonates, but in their preparation. Whether we use an alkyl halide or sulfonate, and whether we let it undergo substitution or elimination, our starting point for the study is almost certainly the alcohol. The sulfonate must be prepared from 4he alcohol the halide nearly always will be. It is at the alcohol stage that any resolution will be carried out, or any diastereomers separated the alcohol is then converted into the halide or sulfonate, the reaction we are studying is carried out, and the products are examined. 

Other activated systems, specifically activated alkynes and hydrazones, have been employed as radical acceptors for alkyl radicals generated from alkyl halides and Sml2 [11]. Radical addition reactions to activated alkynes appear to be more capricious than the reactions with activated alkenes, and thus are perhaps more limited in scope. Additionally, mixtures of diastereomers inevitably result from such systems (Eq. 11) [12]. Diphenylhydrazones were shown to react approximately 200 times faster than the analogous alkenes in 5-exo additions as determined in a series of studies by Fallis and Sturino [13]. Reasonable diastereoselectivities were exhibited in these processes (Eq. 12). 

In the literature, both the (R,S) and the (S,S) diastereomers of lithium alkyl 2 have been proposed as the major diastereomer [4a, 5a]. Based on these predictions, both retention and inversion of the configuration at C(3) have been postulated for the reactions of (/ ,S)-2 with alkyl halides. Our X-ray structural analysis of (R,S)-2 shows that the reaction of the (/ ,iS)-configured stereoisomer and inversion of configuration [for the reaction of R,S)-2 with iodomethane in toluene] do in fact take place. 

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