Hydride shifts stereochemistry

Nucleophilic substitution in cyclohexyl systems is quite slow and is often accompanied by extensive elimination. The stereochemistry of substitution has been determined with the use of a deuterium-labeled substrate (entry 6). In the example shown, the substitution process occurs with complete inversion of configuration. By NMR amdysis, it can be determined that there is about 15% of rearrangement by hydride shift accon any-ing solvolysis in acetic acid. This increases to 35% in formic acid and 75% in trifiuoroacetic acid. The extent of rearrangement increases with decreasing solvent... 

In the steroid field, Henbest and Wrigley18 - have examined a number of epoxides with reference to boron trifluoride, which is a much stronger Lewis add than magnesium bromide and hence requires much milder operating temperatures. In all instances studied, hydride shifts look place in preference to ring contraction. The product stereochemistry indicated unequivocally a Walden inversion at the site of... 

As shown in the biosynthesis of granaticin, a hydride shift occurs intramolecularly. This process is mediated by an enzyme-bond pyridine nucleotide. A concerted abstraction of H-4 as a hydride in la and a C-5 deprotonation in 2a leads to the 4,5-enol ether 3a. The reduced form of the pyridine nucleotide transfers the hydride to C-6, simultaneously releasing a hydroxide to give 4a. Final tautomerization yields the dTDP-4-keto-6-deoxy-sugar in v-xylo configuration 4a. In other enzymes of the oxidoreductase type, the active site may show a different configuration. Thus, the intermediate 3a can be protonated from above at C-5 to yield the l-arabino isomer of 4a [2]. The stereochemistry of this mechanism was demonstrated by double labelling (cf. l-4b series), and as a net result proved a suprafacial 4—>6 hydride shift. 

CHAPTER 7 Inversion of Configuration in the Sn2 Reaction 244 Racemization in the Sn1 Reaction 252 Hydride Shift in an Sn1 Reaction 253 Methyl Shift in an Sn1 Reaction 254 Rearrangement in an E1 Reaction 261 Dehydrohalogenation by the E2 Mechanism 304 Stereochemistry of the E2 Reaction 306 E2 Debromination of a Vicinal Dibromide 310... 

In summary, these important investigations have rationalized the stereochemistry of the 1,3-hydride shift (which transfers a positive centre from C-10 or C-11 at the distal end of FPP to C-1 and so allows initiation of further isomerization or a second cyclization of the Cio or Ci i ring) on the basis of the ring size of the products. This presumably results from fixation of specific conformations of the intermediates on a hypothetical enzyme surface. The larger diversity of structure for sesquiterpenoids than for di- or tri-terpenoids could then reflect the larger conformational flexibility of a Cio or Cii ring (which are often involved in the formation of the former) than of the Ce rings that are usually implicated in the latter. 

A significantly more complicated situation exists in the case of the side-chain methylation leading to ergosterol, where the initial transfer of the methyl group is followed by a hydride shift from the acceptor carbon and proton loss from the methyl group to give a methylene intermediate (I), which is then reduced stereo-specifically. The stereochemistry of each of these reaction steps has been determined by Arigoni and co-workers (61, 97), with the outcome summarized in Scheme 26 (p. 285). 

We assume that a mechanism via diazonium ions is not ruled out. See also Section 7.3 for the striking difference in the stereochemistry of deaminations starting with (Z)- and ( )-diazenolates. X = HO , ArNH-, RCOO HY=R COOH (solvent). For another position of [X---H ]-after a 2,1-hydride shift in such an ion pair, see Maskill and Whiting (1976, Scheme 2). 

The stereochemistry of a sigmatropic hydride shift depends on the highest occupied molecular orbital (HOMO) of the T framework. In the transition state, a three-centered bond is required, which involves overlap between the s orbital of the hydrogen and lobes of p orbitals of the two terminal carbons. From the HOMO configuration of a seven-carbon allylic radical in the ground state, we see that the symmetry-allowed shift is in an ahtarafacial manner (see Figure 1). 

Comforth and his colleagues have investigated the stereochemistry of isomerization of isopentenyl to dimethylallyl pyrophosphate in isoprenoid biosynthesis. They find that the prototropic change involved is stereochemically different from the superficially analogous association of C5 units. Bisabolene appears to be excluded as an intermediate in the biosynthesis of helicobasidin and trichothecin by recent labelling studies (see also Vol. 1, p. 232, ref. 81) and a 1,4-hydride shift in the initially formed intermediate is indicated. The loss of the C-14 methyl group in cholesterol biosynthesis differs from loss of the C-4 methyl groups. The 32-carbon atom is released at the aldehyde oxidation level as formic acid. 

The 6,2-hydride shift in the primarily developing nonclassical carbocations can be assumed to occur with the formation of either a nortricyclonium ion 34 or an edge-protonated nortricyclene 35. A choice between these two possibilities has been made from the reaction stereochemistry of unsaturated acids 84 and 85 with 50 % sulphuric acid. The product in either case turned out to be lactone 86. The formation of this product clearly indicates the 6,2-hydride shifts in this system to occur by endo,endo-migrations. If the intermediate here were a nortricyclonium ion, then besides lactone 86 the formation of two other isomers of the deuterium position would be equally probable. Suche isomers, however, have not been found This makes it... 

Berson, j. a., j. H. Hammons, A. W. McRowe, R. G. Bergman, A. Remanick, and D. Houston The Chemistry of Mcthylnorbomyl Cations. VI. The Stereochemistry of Vicinal Hydride Shift. Evidence for the Nonclassical Structure of 3-Methyl-2-norbornyl Cations. J. Amer. Chem. Soc. 89, 2590 (1967). 

An oxidation-reduction sequence was used to invert stereochemistry at C-3 in a preparation of some 2 -deoxy-p-D-threo-pentofuranosyl pyrrolo-P3nimidines (42, R=OH). i A hydride shift process (Scheme 5) was used to make 3 -deoxy-p-D-threo-pentofuranosyl nucleosides of type (43), 2 whilst a similar process is Involved in the formation of (43, B=Ad) by treatment of 2, 3 -di-0-tosyladenoslne with liEtaBH the same product (43, B=Ad) was also obtained, in higher yields, by the same reduction of the analogous D-arabino-and D-lyxo-systems. ... 

The Homer-Emmons addition of dialkyl carboalkoxymethylenephosphonates to aldehydes [22] has been widely used to generate a,p-unsaturated esters which, in turn, can be reduced to allylic alcohols. Under the original conditions of the Homer-Emmons reaction, the stereochemistry of the oc,(3-unsaturated ester is predominantly trans and therefore the trans allylic alcohol is obtained upon reduction. Still and Gennari have introduced an important modification of the Homer-Emmons reaction, which shifts the stereochemistry of the a,[i-unsaturated ester to predominantly cis [23], Diisobutylaluminum hydride (DIBAL) has frequently been used for reduction of the alkoxycarbonyl to the primary alcohol functionality. The aldehyde needed for reaction with the Homer-Emmons reagent may be derived via Swern oxidation [24] of a primary alcohol. The net result is that one frequently sees the reaction sequence shown in Eq. 6A. 1 used for the net preparation of 3E and 3Z allylic alcohols. 

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