Diastereomers nucleophilic substitution reactions

T. K. M. Shing and L. H. Wan, Facile synthesis of valiolamine and its diastereomers from (-)-quinic acid. Nucleophilic substitution reactions of 5-hydroxymethyl-cyclohexane-l,2,3,4,5-pentol, J. Org. Chem., 61 (1996) 8468-8479. 

The octahedral hexacoordinate anion (28) is readily hydrolyzed by either acids or alcohols to the spirocycle (110) (Equation (23)). Chiral systems, which are prepared by fractional crystallization of the methyl Brucinium diastereomers, give optically inactive systems on ring cleavage <67LA(705)66>. Octahedral anionic species similar to (46) have been proposed as intermediates in nucleophilic substitution reactions at arsenic <72PS(2)129> (see Section 2.16.9.1). 

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 acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic /3 lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (-)-lasubine (I). Tin tetrachloride mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be aUylated with high diastereoselectivity to give optically active homoaUyhc amines (Scheme 87). 

Chiral ferrocenyl derivatives with a trimethylammonium group in the a-position are known to undergo nucleophilic substitution with complete retention of configuration [2]. Quaternization of 3 with methyl iodide followed by reaction with iV-methylethanolamine, (S)-prolinol, or (lS,2R)-ephedrine gave the corresponding (R,S)-2-iodoferrocenes 4a, 4b, and 4c in 80 — 90% yield with complete retention of configuration (Scheme 3-4). Diastereomers 4d and 4e were similarly prepared starting with (S,R)-3. 

In contrast to that, nucleophilic substitution in a-position to nitrogen by cyanide or methoxide predominates, if the electrolysis is carried out in acetonitrile or methanol in presence of cyanide [49], respectively, in basic methanol [50,51]. This reaction, which is supposed to occur via the iminium ion, is interesting for application in organic synthesis. The formation of synthetically valuable o -aminonitriles from 7V,7V-dialkylani-lines has been reported by Andreades and Zahnow [49]. More recently, a series of papers was published by Hurvois, Moinet, Tallec, et al. on the anodic a-cyanation of A-sub-stituted 1-benzazepines, tetrahydroquinolines, and piperidines [Eq. (9)] [52]. The reactions were performed in a special flow-through cell. In the case of the 3-methyl-substituted benzazepines the reaction is stereospecific, leading only to the trans-a-cyano diastereomer. 

The reaction of (1S,4S)- and racemic camphor thiosemicarbazone [(1S,4S)- and rac-CTSC] leads to the formation of trans- and c/.v-isomers of (1S,4S)- or racemic camphor 5,-fluoro-4 -hydroxy-4, 5 -di(perfluoroalkyl)-l,3,-thiazolinyl-2/-hydrazones 211a-c and 213b,c (Scheme 189). The molecular structure of the two diastereomers (1S,4S,4 R,5 R)- and (1S,4S,4 S,5 S)- of 211a has been established by X-ray crystallography (03JFC(120)41). This result can be explained by a considerable contribution of the SN2 type of nucleophilic substitution both to the epoxide ring... 

The conclusion from spectroscopic evidence that dioxocarbenium ion with an alkoxymethyl group at C5 adopts a pseudoequatorial conformation is consistent with reactivity of the related oxocarbenium ion. Lewis acid-catalyzed nucleophilic substitution of acetate 45 afforded the 1,5-trans product 46 with high diastereos-electivity (Fig. 4.18). This result is inconsistent with the product ratio (70 30) previously reported for this reaction [84] (Fig. 4.18). In that paper, a minor product observed in the unpurified reaction mixture was assumed to be a diastereomer of 46. It was later found that the minor product formed in the reaction mixture is not the cis isomer. This result can be explained by stereoelectronically controlled addition to the half-chair conformer analogous to 38 (or even 40) in which the alkoxymethyl... 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

Similar schemes can be developed easily for analogous reactions of acceptor-substituted polyenes. For example, a triene with an acceptor group in 1-position can form six regioi-someric products of Michael addition and electrophilic capture, and each of these exists as E/Z stereoisomers, diastereomers and/or enantiomers. Thus, reactions of this type are only useful if both the regio- and stereoselectivity can be controlled fortunately, only one isomeric Michael adduct is formed in many cases. This is true in particular for polyunsaturated Michael acceptors which bear at least one triple bond besides one or more double bonds. An additional feature of the latter substrate type is that nucleophilic additions can... 

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

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