Halohydrin regioselectivity

The reversibility of halohydrin dehalogenase-catalyzed reactions has been used for the regioselective epoxide-opening with nonnatural nucleophiles (an example is given in Scheme 10.34) [133]. The stereoselectivity of the enzyme results in the resolution of the racemic substrate. At the same time, the regioselectivity imposed by the active site geometry yields the anti-Markovnikov product. [128]... 

Regioselective anbd Chemoselective Synthesis of Halohydrins by Cleavage of Oxiranes with Metal Halides," Bonini. C. Righi, G. Synthesis, 1994, 225... 

Treating ally lie and homoallylic epoxy alcohols with an equivalent amount of halogen (Br2, I2) in the presence of a stoichiometric amount of Ti(OPr )4 provides halohydrins under mild conditions with a high degree of generality and with good regioselectivity (Scheme 4-12).26... 

Numerous biocatalytic routes to this challenging intermediate have been reported. " For example. Fox et al. have recently developed an efficient regioselective cyanation starting from low-cost epichlorohydrin (Scheme 1.26). Initial experiments found that halohydrin dehydrogenase from Agrobacterium radiobacter expressed in E. coli produced the desired product, but inefficiently. To meet the projected cost requirements for economic viability, the product needed to be produced at 100 g L with complete conversion and a 4000-fold increase in volumetric productivity. The biocatalyst needed to function under neutral conditions to avoid by-product formation, which causes downstream processing issues. 

Alkyl and acyl hypohalites, when adding to carbon-carbon double bond, afford halohydrin ethers and esters, respectively.151 Regioselective and syn stereoselective addition of CF3OF, CF3CF2OF, and CF3COOF to stilbenes was reported.152-154 The stereochemistry was explained to originate from the formation and immediate... 

Ketones from halohydrins. Palladium acetate complexed with a triarylphos-phine, particularly tri-o-tolylphosphine, converts halohydrins into ketones in the presence of K2C03. Yields are about 70-85% for substrates in which the halogen is secondary or tertiary, but less than 50% when the halogen is primary because of epoxide formation. The reaction is useful for conversion of alkenes to ketones in those instances in which halohydrins are formed regioselectively. 

The diastereoselective halohydrin formation, resulting from the reaction of chiral /V -enoyI -2-oxazoI idinones with Br2/l2 and water, promoted in the presence of silver , in aqueous organic solvents, has been found to occur with high regioselectivity and moderate to good diastereoselectivities. The alkenoyl, cinnamoyl, and electron-deficient cinnamoyl substrates readily produced the bromohydrin in aqueous acetone, but no iodohydrin formation was observed under these conditions. On the other hand, ( ) electron-rich cinnamoyl substrates preferred to afford iodohydrins in aqueous acetone with moderate diastereoselectivity enhanced diastereoselectivity was observed for aqueous THF.31... 

Halohydrins. In the presence of 1 equiv. of Ti(0-i-Pr)4, bromine or iodine converts epoxides of rra/ts-allylic or homoallylic alcohols to halohydrins at 0-25° in high yield with marked regioselectivity. The presence of the free hydroxyl group is essential for regioselectivity. 

As discussed in the epoxide formation section, the system CPO/F O chloride (or bromide) reacts with double bonds forming halohydrins [23, 98-100], The selectivity in the reaction has driven the reactivity of the hypohalide ion thus while a good regioselectivity is observed, the diastereoselectivity is almost negligible [23] (Fig. 6.8b). 

The reaction of Grignard reagents with epoxides, at first glance, appears to be an effective method for a two-carbon homoligation. However, there are several competing reactions that limit the use of this method. These deleterious reactions are formation of halohydrins, rearrangements, polymerization of the epoxide, and in asymmetric epoxides, regioselectivity issues. 

The Durst group has taken advantage of these competing reactions (halohydrin intermediate, Lewis acid-catalyzed rearrangement, and regioselectivity issues) to form... 

Bajwa, J.S., and Anderson, R.C., A highly regioselective conversion of epoxides to halohydrins by hthium halides, Tetrahedron Lett.. 32, 3021, 1991. 

The high regioselectivity observed in the transformation of some chiral diols into halohydrins allows various selective reactions to be performed on these intermediates. For example, the reduction of the hahde substituent affords an easy entry into optically active carbinols (Scheme 54). This methodology was used by Keinan [134] in his approach towards aspicilhn 213. Thus, the enantiomerically pure diol 210 was transformed into the bromohydrin 211 which was reduced to... 

Cleavage of terminal epoxides halohydrins. The cleavage of a terminal epoxide (1) can result in two halohydrins. By proper choice of a metal halide either one of the halohydrins can be obtained with about 95% regioselectivity. 

The final enzyme discussed in the chapter, haloalcohol dehalogenase, catalyzes the formation of epoxides from halohydrins. However, the reverse reaction, the ring opening of epoxides with nonhalide nucleophiles such as cyanide, azide, and nitrite, has been exploited commercially to generate /3-substituted alcohols that are potential synthons. For this reason, the regioselectivity of the enzymatic ring opening reaction is of... 

Regioselectivity of Hydrogen Halide Addition 6.17 Conversion of Alkenes to Vicinal Halohydrins 253... 

The argument is closely analogous to that used to explain the regioselectivity of formation of bromoacetoxy compounds (Table 9.2) formed in the addition of bromine to alkenes in acetic acid. Similarly, addition of bromine to alkenes in water produces bromohydrins. Although they are more difficult to synthesize, iodohydrins and fluorohydrins are also known. For a review of the synthesis and reactions of halohydrins, see Rosowsky, A. in Weissberger, A., Ed. Heterocyclic Compounds with Three- and Four-Membered Rings, Part One Wiley-Intersdence New York, 1964 p.l. 

To account for the regioselectivity and anti stereoselectivity of halohydrin reactions, chemists propose a three-step mechanism. 

We Studied the reaction of alkenes with chlorine or bromine in water to form halohydrins in Section 6.3E and saw that it is both regioselective and stereoselective (for an alkene that shows cis-trans isomerism, it is also stereospecific). Conversion of a halohydrin to an epoxide with base is stereoselective as well and can be viewed as an internal Sj. 2 reaction. Hydroxide ion or another base abstracts a proton from the halohydrin hydroxyl group to form an alkoxide ion, a good nucleophile, which then displaces halogen on the adjacent carbon. As with all S 2 reactions, attack of the nucleophile is from the backside of the C—X bond and causes inversion of configuration at the site of substitution. 

In most cases, halohydrin formation is observed to be a regioselective process. Specifically, the OH is generally positioned at the more substituted position ... 

The proposed mechanism for halohydrin formation can justify the observed regioselectivity. Recall that in the second step of the mechanism the bromonium ion is captured by a water molecule ... 

In other words, the transition state for this step will bear partial carbocationic character. This explains why the water molecule is observed to attack the more substituted carbon. The more substituted carbon is more capable of stabilizing the partial positive charge in the transition state. As a result, the transition state will be lower in energy when the attack takes place at the more substituted carbon atom. The proposed mechanism is therefore consistent with the observed regioselectivity of halohydrin formation. 

PROBLEM 10.68 The Halohydrin formation animation was calculated using a symmetrical alkene. The symmetry of the alkene means that nucleophilic addition to the bromonium intermediate will not be regioselective. Select play for this reaction. Stop at the first intermediate and observe the calculated LUMO. Based on this data, where is the positive charge located Show four products that would be formed through nucleo-phihc attack at each of the places of LUMO density. 

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