Racemization catalysts primary alcohols

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. 

DKR requires two catalysts one for resolution and one for racemization. We and others have developed a novel strategy using enzyme as the resolution catalyst and metal as the racemization catalyst as shown in Scheme 1. The R-selecfive DKR can be achieved by combining a R-selective enzyme with a proper metal catalyst and its counterpart by the combination of the metal catalyst with a -selective enzyme. This strategy has been demonstrated to be applicable to the DKR of secondary alcohols, allylic esters, and primary amines. Among them, the DKR of secondary alcohols has been the most successful. 

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

Other ruthenium-based catalysts for the aerobic oxidation of alcohols have been described where it is not clear if they involve oxidative dehydrogenation by low-valent ruthenium, to give hydridoruthenium intermediates, or by high-valent oxoruthenium. Masutani et al. [107] described (nitrosyl)Ru(salen) complexes, which can be activated by illumination to release the NO ligand. These complexes demonstrated selectivity for oxidation of the alcoholic group versus epoxidation, which was regarded as evidence for the intermediacy of Ru-oxo moieties. Their excellent alcohol coordination properties led to a good enantiomer differentation in the aerobic oxidation of racemic secondary alcohols (Fig. 19) and to a selective oxidation of primary alcohols in the presence of secondary alcohols [108]. 

This procedure enabled versatile hydrolysis of pyrrohdinones followed by decarboxylation (Scheme 12.191) [347]. It has been disclosed that a neutral organotin dimer [tBu2SnOH(Cl)]2 is an efficient catalyst for deacetylation (Scheme 12.192) [348]. When an MeOH solution of an acetate was heated at 30 °C in fhe presence of a catalytic amount of the organotin dimer deacetylation proceeded quite smoothly to furnish the parent alcohol, in which a variety of acid-labile functional groups remained intact. Acetates of primary alcohols and phenols underwent rapid deacetylation whereas acetates of secondary alcohols reacted only sluggishly. When fhis deacetylation procedure was apphed to acetates derived from tertiary alcohols fhey remained intact, and decomposed under harsher conditions. When nonracemic acetates derived from chiral alcohols and aminoalcohols were treated wifh [tBu2SnOH(Cl)]2 in MeOH, the desired deacetylation proceeded, and no racemization was observed. Exclusive deacetylation of primary alcohols in fhe reaction of peracetates of carbohy-... 

This idea (Fig. 6) was based on an alternative process developed for the racemic product with heterogeneous catalysts in the gas phase [7] and some results of the N-alkylation of aliphatic amines with primary alcohols using homogeneous Ru phosphine catalysts [8],... 

Alcohol 143 (Scheme 6.26), prepared from (R)-glyceraldehyde derivative, was subjected to deoxygenation and epoxidation to give the racemic epoxide 144. Kinetic resolution with (S,S)-Jacobsen catalyst gave diol 145, which on further transformations was converted into the alcohol 146. Swern oxidation of 146 followed by Wittig olefination, acetonide deprotection under acidic conditions furnished the diol 147. Primary alcohol on deoxygenation through LAH reduction of tosylate afforded the alcohol 148. 

A review describes the asymmetric epoxidation of allylic alcohols,369 another the role of metal oporphyrins in oxidation reactions.370 jhe TiiOPrMi, catalysed self-epoxidation of allylic peroxides proceeds via an intermolecular mechanism.371 Racemic allyl alcohols can be resolved by asymmetric epoxidation (eq.35).372 a Pd(II)/Mn02/benzoquinone system catalyses the oxidative ring-closure of 1,5-hexadienes (eq.36).373 propenyl phenols are oxidatively degraded to aryl aldehydes and MeCHO in the presence of Co Schiff-base catalysts.374 An Oppenauer-type oxidation with Cp2ZrH2/cyclohexanone converts primary alcohols selectively into aldehydes.375 co macrocycles catalyse the oxidation of aryl liydrazones to diazo compounds in high yields.376 similar Co complexes under CO oxidise primary amines to azo compounds.377 Arene Os complexes in the presence of base convert aldehydes and water slowly into carboxylic acids and H2.378... 

Aside from the titanium-mediated process described above, the asymmetric addition of aUcyl groups to aldehydes can also be performed by nickel catalysts. This traces back to seminal work of Fujisawa et al. who had found that the addition of AlMc3 to aldehydes can be catalyzed by Ni(acac)2 and is strongly accelerated by phosphines and phosphites [50]. Racemic additions to aromatic and aliphatic aldehydes thus occurred in good yields with as little as 0.1 mol% of nickel. Interestingly, the reaction with AlEt3 and Al(/Bu)3 predominantly led to the respective addition products with only small amounts of the reduced primary alcohols. This is in contrast to the nickel-catalyzed 1,4-addition of higher aluminum trialkyls to enones, in which the rate of p-hydride elimination surpasses that of 1,4-addition [51]. 

Racemic diols, in particular those bearing a primary alcohol adjacent to a secondary or a tertiary carbinol, which are traditionally more difficult to resolve, were also shown to be viable substrates for catalyst 98 [108]. Indeed, high levels of selectivity ranging from s = 8 to >50 were obtained independently of the substitution pattern (Schemes 41.39 and 41.40). Hoveyda and Snapper et al. [109] eventually developed conditions for the KR of diols bearing sterically and electronically similar substituents. Hence, by running the reactions in the presence of 30mol% of catalyst 98 and 1.5 equiv. of either ... 

It should be highlighted that this catalyst has not only been employed in the racemization of sec-alcohols but also primary alcohols with an unfunctionalized stereo-genic center in the p-position [25]. In this case the metal complex causes a previous... 

The first example of racemization catalyst applied to the DKR of amines was described by Reetz and Schimossek, contemporary to the report of first cases of scc-alcohol DKRs [96]. Nevertheless, reported racemization catalysts for amines are not so numerous, due to the severe conditions required for ttie racemization, which frequently are not compatible with the activity of the enzyme. That pioneering work reported the use of 5% Pd/C as heterogeneous racemization catalyst and combined its action with CALB activity in the DKR of 1-phenylethylamine (rac-91). Although just moderate yields could be achieved after Sdays, palladium was, since then, considered a very attractive catalyst in the racemization of primary amines. 

As in the case of sec-alcohols, ruthenium complex has also been investigated as a catalyst in the racemization of primary amines. In fact, Shvo s complex 2 (Figure 14.3) was employed by the Backvall s group as the catalyst of the racemization of amines under transfer hydrogenation conditions [105]. However, temperatures up to 110 °C were required for amine racemization, incompatible with the lipase resolution, and furthermore, side products were formed in the medimn and a hydrogen source was needed. To avoid these drawbacks, the racemization at high temperature was carried out after a first lipase-catalyzed KR, followed by a second KR process, and a hydrogen source such as 2,4-dimethylpentan-3-ol was employed. 

Almost at the same time, Backvall et al. demonstrated that PSL and metal-catalyzed DKR can also be applied to other primary alcohols bearing an unfunctionalized stereo-genic center in the (3-position. The chosen substrates were racemic 2-arylpropan-l-ols (rac-10 is included, as an example, in Scheme 57.4), which are precursors of the nonsteroidal anti-inflammatory 2-arylpropionic acids (profens). DKR processes were performed in toluene at 80 C, with catalyst la, Amano PS-D 1 lipase, and 4-nitrophenyl 3-[4-(trifluoromethyl)phenyl]propanoate as the acyl donor. In this case, the metal catalyst is also indirectly involved in the racemization of the primary alcohol. Initially, metal-catalyzed dehydrogenation of the alcohol takes place, with the resulting aldehyde undergoing enoUzation, which can be facilitated by the elevated temperature. 

In Pd-catalyzed selective oxidations of primary alcohols, identify the oxidative addition, reductive elimination, and /J-hydride elimination steps. In the kinetic resolution of a racemic secondary alcohol using 8.21 as the catalyst, assuming that the mechanism is similar to that of Figure 8.2, what would be the enantioselection step ... 

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