Selected oxazaborolidines

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

The proposed catalytic cycle for reduction of acetophenone is illustrated in Figure 1.28. The (5)-oxazaborolidine catalyst (5)-28A has both Lewis acidic and basic sites, and its borane adduct 28B acts as a chiral Lewis acid. The B center in the borolidine ring selectively interacts with a stericaUy more accessible electron... 

One popular method that has been apphed to industrial processes for the enantio-selective reduction of prochiral ketones, leading to the corresponding optically active secondary alcohols, is based on the use of chiral 1,3,2-oxazaborolidines. The original catalyst and reagent system [diphenyl prolinol/methane boronic acid (R)] is known as the Corey-Bakshi-Shibata reagent. Numerous examples... 

In particular, reduction of unsymmetric ketones to alcohols has become one of the more useful reactions. To achieve the selective preparation of one enantiomer of the alcohol, chemists first modified the classical reagents with optically active ligands this led to modified hydrides. The second method consisted of reaction of the ketone with a classical reducing agent in the presence of a chiral catalyst. The aim of this chapter is to highlight one of the best practical methods that could be used on an industrial scale the oxazaborolidine catalyzed reduction.1 1 This chapter gives an introductory overview of oxazaborolidine reductions and covers those of proline derivatives in-depth. For the oxazaborolidine derivatives of l-amino-2-indanol for ketone reductions see Chapter 17. 

Since the discoveries of Itsuno32 and Corey,33 remarkable advances have been made in the enantio-selective reduction of prochiral ketones using amino alcohol-derived oxazaborolidines (see Chapter 16).34 35 In most cases, these amino alcohols were obtained from chiral pool sources. Consequently, extensive synthetic manipulations were often necessary to access their unnatural antipode. Didier and co-workers were first to examine the potential of m-aminoindanol as a ligand for the asymmetric oxazaborolidine reduction of ketones.36 Several acyclic and cyclic amino alcohols were screened for the reduction of acetophenone (Scheme 17.2), and m-aminoindanol led to the highest enantioselectivity (87% ee). 

Researchers at Sepracor later disclosed the use of a new class of chiral oxazaborolidines derived from r/. v-aminoindanol in the enantioselective borane reduction of a-haloketones.6,7 The 5-hydrogen oxazaborolidine ligand 10 was prepared in situ from d,v-aminoindanol 1 and BH3 THF.8 Stock solutions of 5-methyl oxazaborolidine 11-16 were obtained by reaction of the corresponding N-alkyl aminoindanol with trimethyl boroxine.6,7 5-Methyl catalyst 11 was found to be more selective (94% ee at 0°C) than the 5-hydrogen catalyst 10 (89% ee at 0°C), and enantioselectivities with 11 increased at lower temperatures (96% ee at -20°C). The catalyst structure was modified by introduction of A-a I kyI substituents. As a general trend, reactivities and selectivities decreased as the steric bulk or the chelating ability of the A -alkyl substituent increased (Scheme 17.4). 

R) -1 on a preparative scale. Variation of several reaction parameters such as catalyst loading, solvent, temperature, and addition order, have led to the development of an optimized procedure for this reduction. To achieve a selectivity of >90% ee, the reaction requires the use of 10 mol% of the oxazaborolidine catalyst, which is easily prepared in two steps from natural proline4 or in one step from commercially available... 

For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. [35] also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic a,//-enones and -ynones only on the carbonyl group. In the re-... 

The Lewis acid catalysed Diels-Alder cycloaddition of the ketone (4i) with cyclopentadiene allows a complete endo selectivity to be reached. Accordingly, the reaction of (4i) with 1.5 equivalents of cyclopentadiene in the presence of one equivalent of Cl2Ti(OiPr)2 in toluene at 0°C fori2 hrs led exclusively to (5i) which has been isolated in 70 % yield. In the presence of 1.5 equivalents of the oxazaborolidine derived from L-N-... 

Fig. 4.9. Enantio-selective reduction of prochiral ketones using oxazaborolidines as catalysts. The transition state of the reaction and a stable transition state analogue are represented.

However, also in this case enantio-selectivities never exceeded the values obtained with the oxazaborolidine in solution, probably because of diffusional limitations within the polymer support, which enhanced the contribution of the non-selective, direct borane reduction of the ketone. In spite of the rather low imprinting effects obtained in these initial attempts, we feel that this approach still represents a most interesting application of molecularly imprinted polymers in catalysis and deserves further attention in the near future. 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Other approaches to the bryostatins have also used enantio- or diastereoselective aldol reactions. An interesting iterative strategy for the synthesis of the Cj-Cg polyacetate region 134 has been disclosed where each aldol addition proceeds with excellent stereocontrol (99 1) under the catalytic influence of oxazaborolidine 135 (Scheme 9-42) [60J. Finally, a moderately selective, auxiliary controlled, acetate aldol reaction has been used for the introduction of the C3 stereocenter of the bryostatins giving adduct 136 (84% d.s) [61]. 

Both enantiomeric (R)- and (S)-oxazaborolidines are available so it is possible to obtain at will either enantiomeric alcohol. The selectivity depends upon the geometry of the complex formed by coordination of the carbonyl oxygen to the Lewis acidic heterocyclic boron atom, complex 3.72 being favored. The catalytic cycle is shown in Figure 3.25. 

The influence of temperature on the selectivity of the reduction of acetophenone and cyclohexylmethylketone by various oxazaborolidines 3.71 (Ar = Ph, R = Me, Bu, Ph) has been examined [S5]. The use of polymer-bound 3.71 has also been proposed [FS3]. Some mechanistic [DTIJ and theoretical investigations of the reductions have also been carried out [DLl, LS6, N4, NU2, QBl]. 

In many stereoselective reactions, the effect of temperature on the selectivity is as expected, with better results being obtained at lower temperature. A lower tempertaure is often required to increase the selectivitty. From the practical point of view, one of the most attractive feature of this enantioselective reduction is that excellent enantioselectivity is obtained at a relatively high temperature such as room temperature. In some cases, the selectivity of the oxazaborolidine catalyzed borane reduction increases with increasing temperature until an optimal range is reached (30-50 °C) where the selectivity then begins to decrease [76]. Interpretation of this phenomena is not so easy. The amount of catalyst dimer that exists in a temperature-dependent equiUbrium with the monomeric form, might have an effect on the selectivity. 

Hydroboration of the C-C unsaturated bond may be a possible side reaction in the reduction of a,P-unsatuxated ketones. However, in many cases, some ox-azaborolidines successfully catalyze the selective reduction of ketone carbonyls (Scheme 6). The borane reduction of 2-methylnon-l-en-3-one with oxazaborolidine 45 showed a clean conversion to the allylic alcohol (98%, 92% ee S) [82]. The same catalyst [83] and 4b [84] were effective for the reduction of a,P-ynones [83]. 

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