Inversion of stereochemistry

Formation of a Tr-allylpalladium complex 29 takes place by the oxidative addition of allylic compounds, typically allylic esters, to Pd(0). The rr-allylpal-ladium complex is a resonance form of ir-allylpalladium and a coordinated tt-bond. TT-Allylpalladium complex formation involves inversion of stereochemistry, and the attack of the soft carbon nucleophile on the 7r-allylpalladium complex is also inversion, resulting in overall retention of the stereochemistry. On the other hand, the attack of hard carbon nucleophiles is retention, and hence Overall inversion takes place by the reaction of the hard carbon nucleophiles. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

Substituted 2-haloaziridines are also known to undergo a number of reactions without ring opening. For example, displacement of chlorine in (264) with various nucleophilic reagents has been found to occur with overall inversion of stereochemistry about the aziridine ring (65JA4538). The displacements followed first order kinetics and faster rates were noted for (264 R = Me) than for (264 R = H). The observed inversion was ascribed to either ion pairing and/or stereoselectivity. 

Secondary bromides and tosylates react with inversion of stereochemistry, as in the classical SN2 substitution reaction.24 Alkyl iodides, however, lead to racemized product. Aryl and alkenyl halides are reactive, even though the direct displacement mechanism is not feasible. For these halides, the overall mechanism probably consists of two steps an oxidative addition to the metal, after which the oxidation state of the copper is +3, followed by combination of two of the groups from the copper. This process, which is very common for transition metal intermediates, is called reductive elimination. The [R 2Cu] species is linear and the oxidative addition takes place perpendicular to this moiety, generating a T-shaped structure. The reductive elimination occurs between adjacent R and R groups, accounting for the absence of R — R coupling product. 

Inversion of configuration can be also observed when the Sn2 reaction takes place at a stereocenter (with complete inversion of stereochemistry at the chiral carbon center) ... 

A related N-methylated zinc methoxide (323) also polymerizes cis- and trans- BO with inversion of stereochemistry. In this case, coordination of the monomer trans to the axial alkoxide is hindered by the N-Me group, so a modified mechanism has been proposed based on cis-coordination of the monomer, but which still involves the simultaneous participation of two metal centers. 

Typically, the organic substrate in these reactions is a haloalkane. Primary haloalkanes will generally give 100% substitution products, but tertiary and cyclohexyl halides usually undergo 100 % elimination, with secondary haloalkanes producing a mixture of the two. Studies of the chloride and bromide displacements of (R)-2-octyl methanesulfonate have shown that phase transfer displacements proceed with almost complete inversion of stereochemistry at the carbon centre, indicating an Sjv2-like mechanistic pathway [41],... 

First we consider the acyl sector of the epothilones, which proved to be intolerant of modification. For example, inversion of stereochemistry at C3 (S toR), or reduction at C5 results in serious arrest of activity. Analogs with functionality at C3, C5, C6, C7 and C8 removed demonstrate both diminished tubulin-binding activity and cytotoxidty (structures not shown). Ddetion of the single methyl group at C8 has a highly pronounced deleterious effect on activity. Removal of the C9 methylene group resulting in a 15-membered macrolide, 87, results in a major loss of activity in tubulin polymerization/depolymerization assays. 

Bacillus subtilis, engineered to overproduce epoxide hydrolase, was used as a whole-cell biocatalyst to resolve racemic 1-benzyloxymethyl-1-methyloxirane with high (5)-selectivity. The remaining (/ )-epoxide was subsequently ring opened in situ, with inversion of stereochemistry, to obtain highly enantiomerically enriched (/ )-3-benzyloxy-2-methylpropane-l,2-diol in greater than 50 % theoretical yield (Figure 5.2). 

A series of imidate esters derived from secondary alcohols has been found to react with potassium benzoate or potassium phthalimide to give products of 5 n2 substitution in excellent yields and with clean inversion of stereochemistry. ... 

Further, it is noted that most of them involve inversion of stereochemistry at the particular centre, a feature of the concerted nature of these rearrangements, so that as one group leaves another approaches from the rear. Thus, we have the features of Sn2 reactions in a carbocation mechanism. 

A variety of rhodium complexes, including [Rh(CO)2Cl]2 and [Rh(COD)Cl]2 when used in combination with a variety of bisphosphine ligands, will catalyze the ring opening of vinyl epoxides in the presence of aniline nucleophiles [19, 20]. These reactions occur under very mild and neutral conditions (at room temperature or with mild heating) and are highly regio- and stereoselective. In all cases, nucleophilic attack occurs at the allylic epoxide carbon atom and proceeds with inversion of stereochemistry (Scheme 9.11). 

The transition metal-catalyzed allylic substitution using hard or unstabilized nucleophiles has not been extensively studied, particularly with unsymmetrical allylic alcohol derivatives. This may be attributed to the highly reactive and basic nature of these nucleophiles and the inability to circumvent regiochemical infidehty in unsymmetrical systems. Hard nucleophiles may be characterized as those that undergo substitution with net inversion of stereochemistry [29], due to their propensity to add directly to the... 

S[ 2 reactions lead to an inversion of stereochemistry. Nucleophilicity is decreased by protic solvents in Sp 2 reactions. The presence of a polcir aprotic solvent is a clue that the mechanism is Sf 2. 

A very mild procedure for converting alcohols to iodides uses triphenylphosphine, diethyl azodicarboxylate (DEAD) and methyl iodide.24 This reaction occurs with clean inversion of stereochemistry.25 26 The key intermediate is again an alkoxyphosphonium ion. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

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