Radical Racemization

The data provide other evidence against competing radical racemization and reductive trapping. If trapping hy MNaph were competing with the racemi/alion of any species, including R-. then the optical purity of the product would decrease with decreasing [MNaph]. For (Br.I)/(Na.K)/THF. this prediction fails—optical purities are independent of [MNaph] [96,11()[. Also, retention in KNaph/(CI,Br,l)/THF reactions are independent of the order of addition of reactant solutions [96,1 lOj. 

The association of this thiol radical racemization reaction with a lipase-catalyzed enzymatic resolution enables the dynamic kinetic resolution of nonbenzylic amines with the CAL-B lipase. It leads to (i )-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. For optimum results, a slight modification of the thiol is required (eq 9). ... 

DKR of primary amines with CAL-B and a radical racemizing agent. 

S5mthesis of (R)-amides using CAL-B as biocatalyst, octanethiol as radical racemization agent, and methyl-p-methoxypropionate as acyl donor at38-40 °C in MTBE [250]. 

Addition to double bonds is not the only kind of reaction that converts an achiral molecule to a chiral one Other possibilities include substitution reactions such as the formation of 2 chlorobutane by free radical chlorination of butane Here again the prod uct IS chiral but racemic... 

For those dmgs that are administered as the racemate, each enantiomer needs to be monitored separately yet simultaneously, since metaboHsm, excretion or clearance maybe radically different for the two enantiomers. Further complicating dmg profiles for chiral dmgs is that often the pharmacodynamics and pharmacokinetics of the racemic dmg is not just the sum of the profiles of the individual enantiomers. 

There have been many studies aimed at deducing the geometiy of radical sites by examining the stereochemistry of radical reactions. The most direct kind of study involves the generation of a radical at a carbon which is a stereogenic center. A planar or rapidly inverting radical would lead to racemization, whereas a rigid pyramidal structure should... 

Further evidence for a bromine-bridged radical comes from radical substitution of optically active 2-bromobutane. Most of the 2,3-dibromobutane which is formed is racemic, indicating that the stereogenic center is involved in the reaction. A bridged intermediate that can react at either carbon can explain the racemization. When the 3-deuterated reagent is used, it can be shown that the hydrogen (or deuterium) that is abstracted is replaced by bromine with retention of stereochemistry These results are also consistent with a bridged bromine radical. 

Total syntheses of racemic Melinonine E (316) and Strychnoxanthine (317) were performed using a radical cyclization process as the key step (98JOC968). Melinonine E was first isolated from the bark of Strychnos melinoniana in 1957 (57HCA1167), but structure elucidation was not carried... 

Carboxylates, which are chiral in the a-position totally lose their optical activity in mixed Kolbe electrolyses [93, 94]. This racemization supports either a free radical or its fast dynamic desorption-adsorption at the electrode. A clearer distinction can be made by looking at the diastereoselectivity of the coupling reaction. Adsorbed radicals should be stabilized and thus react via a more product like transition state... 

Sheldon et al. have combined a KR catalyzed by CALB with a racemization catalyzed by a Ru(II) complex in combination with TEMPO (2,2,6,6-tetramethylpi-peridine 1-oxyl free radical) [28]. They proposed that racemization involved initial ruthenium-catalyzed oxidation of the alcohol to the corresponding ketone, with TEMPO acting as a stoichiometric oxidant. The ketone was then reduced to racemic alcohol by ruthenium hydrides, which were proposed to be formed under the reaction conditions. Under these conditions, they obtained 76% yield of enantiopure 1-phenylethanol acetate at 70° after 48 hours. 

One type of evidence for an SET mechanism is the finding of some racemization. A totally free radical would of course result in a completely racemized product RY, but it has been suggested that inversion can also take place in some SET processes. The suggestion is that in step 1 the Y still approaches from the backside, even though an ordinary Sn2 mechanism will not follow, and that the radical R-, once formed, remains in a solvent cage with Y- still opposite X , so that steps 1, 2, and 3 can lead to inversion. 

The radicals do not drift apart because they are held together by the solvent cage. According to this mechanism, the radicals must recombine rapidly in order to account for the fact that does not racemize. Other evidence in favor of mechanism a is that in some cases small amounts of coupling products (R R have been isolated,which would be expected if some R leaked from the solvent cage. However, not all the evidence is easily compatible with mechanism a. It is possible that another mechanism (b) similar to mechanism a, but involving ion... 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

---